US20090258865A1 - Administration of benzodiazepine compositions - Google Patents
Administration of benzodiazepine compositions Download PDFInfo
- Publication number
- US20090258865A1 US20090258865A1 US12/413,439 US41343909A US2009258865A1 US 20090258865 A1 US20090258865 A1 US 20090258865A1 US 41343909 A US41343909 A US 41343909A US 2009258865 A1 US2009258865 A1 US 2009258865A1
- Authority
- US
- United States
- Prior art keywords
- combinations
- benzodiazepine
- pharmaceutical composition
- seizure
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 *C1([4*])C([5*])N([6*])[C@](*)([3*])C2=C(C=CC=C2)N1[1*].[2*]C Chemical compound *C1([4*])C([5*])N([6*])[C@](*)([3*])C2=C(C=CC=C2)N1[1*].[2*]C 0.000 description 2
- ANUCDXCTICZJRH-UHFFFAOYSA-N CC1COC2(C3=CC=CC=C3Cl)C3=C(C=CC(Cl)=C3)NC(=O)CN12 Chemical compound CC1COC2(C3=CC=CC=C3Cl)C3=C(C=CC(Cl)=C3)NC(=O)CN12 ANUCDXCTICZJRH-UHFFFAOYSA-N 0.000 description 2
- SAADBVWGJQAEFS-UHFFFAOYSA-N CCN(CC)CCN1C(=O)CN=C(C2=CC=CC=C2F)C2=C1C=CC(Cl)=C2 Chemical compound CCN(CC)CCN1C(=O)CN=C(C2=CC=CC=C2F)C2=C1C=CC(Cl)=C2 SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 description 2
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N CC(C)O.CCCO Chemical compound CC(C)O.CCCO ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N CC1=C(O)C(C)=C2CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)OC2=C1C Chemical compound CC1=C(O)C(C)=C2CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)OC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- DDLIGBOFAVUZHB-UHFFFAOYSA-N CC1=NC=C2CN=C(C3=CC=CC=C3F)C3=C(C=CC(Cl)=C3)N21 Chemical compound CC1=NC=C2CN=C(C3=CC=CC=C3F)C3=C(C=CC(Cl)=C3)N21 DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N CC1=NN=C2CN=C(C3=CC=CC=C3)C3=C(C=CC(Cl)=C3)N12 Chemical compound CC1=NN=C2CN=C(C3=CC=CC=C3)C3=C(C=CC(Cl)=C3)N12 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- SEQDDYPDSLOBDC-UHFFFAOYSA-N CN1C(=O)C(O)N=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 Chemical compound CN1C(=O)C(O)N=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 Chemical compound CN1C(=O)CN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N CN1CCN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 Chemical compound CN1CCN=C(C2=CC=CC=C2)C2=C1C=CC(Cl)=C2 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 description 1
- DIWRORZWFLOCLC-UHFFFAOYSA-N O=C1NC2=C(C=C(Cl)C=C2)C(C2=CC=CC=C2Cl)=NC1O Chemical compound O=C1NC2=C(C=C(Cl)C=C2)C(C2=CC=CC=C2Cl)=NC1O DIWRORZWFLOCLC-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
Definitions
- This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.
- the benzodiazepine family consists of drugs such as diazepam, lorazepam, and medazepam.
- the drugs in this family have been observed as possessing sedative, tranquilizing and muscle relaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants. They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia, agitation, seizures (such as those caused by epilepsy), muscle spasms and rigidity (which can be caused by tetanus), the symptoms of drug withdrawal associated with the continuous abuse of central nervous system depressants, and exposure to nerve agents.
- Benzodiazepines are thought to act by binding to the GABA A receptor of a neuron, possibly causing the receptor to change shape and making it more accessible to gama-aminobutyric acid (GABA).
- GABA gama-aminobutyric acid
- GABA is an inhibitory neurotransmitter that, when bound to the GABA A receptor, facilitates Cl ⁇ ions flooding into the neuron to which the receptor is bound.
- the increase in Cl ⁇ ions hyperpolarizes the membrane of the neuron. This completely or substantially reduces the ability of the neuron to carry an action potential.
- Targeting this receptor is particularly useful in treating many disorders, such as tetanus and epilepsy, which may result from too many action potentials proceeding through the nervous system.
- the oral route of administration may be considered sub-optimal due to several disadvantages.
- the amount of time required for an orally administered benzodiazepine drug to reach therapeutically relevant concentrations in blood plasma may be rather long, such as an hour or more.
- benzodiazepine drugs pass through the liver a significant amount may be metabolized. Thus, it may require large doses to achieve therapeutic plasma levels.
- due to the nature of seizures and muscle spasms it can be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drug orally.
- Intravenous administration perhaps provides a faster route of administration.
- intravenous administration is generally limited to trained health care professionals in tightly controlled clinical settings. Additionally, sterility must be maintained. Furthermore, administering any drug intravenously can be painful and is likely impractical for patients suffering from a phobia of needles.
- Suppository compositions of benzodiazepine drugs can have a rapid onset of action.
- the inconvenience of suppositories is an obvious impediment to their being administered by anyone outside a very small group of the patient's intimate acquaintances and the patient's professional medical caretakers.
- the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient.
- the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w).
- the benzodiazepine drug is dissolved in a carrier system.
- at least part of the benzodiazepine drug is in a form comprising benzodiazepine microparticles, nanoparticles or combinations thereof.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof.
- the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the benzodiazepine drug is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
- a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate).
- synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
- a glycol polymer such as polyethylene glycol
- the compositions described herein exclude Vitamin E TPGS.
- one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof.
- the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
- the glycols exclude glycol polymers.
- the glycols exclude glycol polymers having an average molecular weight of greater than 200.
- the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200.
- the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20 mg/mL to about 50 mg/mL.
- the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w).
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w).
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w).
- the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- the composition comprises one or more additional excipients, such as one or more parabens, one or more povidones, and/or one or more alkyl glycosides.
- the invention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug.
- the patient is a human.
- the method comprises: administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%, preferably about 10% to about 70% (w/w).
- the benzodiazepine is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%, preferably about 10% to about 70% (w/w).
- the benzodiazepine drug is dissolved in a carrier system.
- the benzodiazepine drug includes benzodiazepine microparticles, nanoparticles, or combinations thereof.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof.
- the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug is fully dissolved in a single phase comprising one or more one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols or glycols. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some such embodiments, the composition further comprises water. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
- the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof.
- the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
- the alcohol or glycol is free of water (dehydrated, USP).
- the alcohol is ethanol (dehydrated, USP).
- the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 20 mg/mL to about 50 mg/mL.
- the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w).
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 30% (w/w).
- the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- the composition is in a pharmaceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient.
- the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine.
- the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 ⁇ L to 200 ⁇ L.
- the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
- compositions of one or more benzodiazepine drugs are provided herein. Such pharmaceutical compositions are administered nasally.
- the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient.
- the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w).
- the benzodiazepine drug is dissolved in a carrier system.
- at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient.
- the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w).
- the benzodiazepine drug is dissolved in a carrier system.
- at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof.
- the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof.
- the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof.
- the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
- the carrier system includes one or more synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in U.S. Pat. No. 6,193,985, which is incorporated herein by reference in its entirety.
- Vitamin E TPGS can be a desirable excipient for stabilizing the particulate (microparticle, nanoparticle or combination) suspension.
- the carrier system specifically excludes synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in U.S. Pat. No. 6,193,985, which is incorporated herein by reference in its entirety.
- one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof.
- the alcohol is ethanol (dehydrated, USP).
- the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
- the glycol is propylene glycol USP.
- a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate).
- synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
- a glycol polymer such as polyethylene glycol
- the compositions described herein exclude Vitamin E TPGS.
- the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20 mg/mL to about 50 mg/mL.
- the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w). In some embodiments, a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate).
- synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol).
- a glycol polymer such as polyethylene glycol
- the compositions described herein exclude Vitamin E TPGS.
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55% (w/w).
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w). In some embodiments, the alcohol is ethanol or contains ethanol. In some preferred embodiments, the glycols exclude glycol polymers. In some preferred embodiments, the glycols exclude glycol polymers having an average molecular weight of greater than 200. In some embodiments, the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200.
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w).
- the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- compositions comprise at least one alkyl glycoside.
- the at least one alkyl glycoside is one described in U.S. Pat. No. 5,661,130, which is incorporated by reference herein.
- the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. In some embodiments, the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol and an alcohol or glycol, wherein the solution is at least substantially free of water.
- the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides.
- the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides wherein the solution is at least substantially free of water.
- the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides.
- the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of water.
- a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of water.
- substantially free of water indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.
- the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol and an alcohol or glycol, wherein the solution is at least substantially free of water.
- the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides.
- the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides wherein the solution is at least substantially free of water.
- the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.)
- the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol and one or more alcohols or glycols. In some embodiments, substantially all the benzodiazepine drug is in a particulate form. In some embodiments, at least part of the benzodiazepine drug is in a microparticulate or nanoparticulate form.
- the carrier system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system.
- a carrier system in such a composition includes water. In some embodiments, such a liquid carrier system contains water and one or more excipients.
- one or more excipients are dissolved or suspended in the carrier system. In some embodiments, at least one such excipient stabilizes the suspension of benzodiazepine particulates in the carrier system.
- the carrier system may contain varying concentrations of parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrolidinone).
- benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene glycol.
- benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols having a molecular weight greater than about 200 g/mol.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
- the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol, one or more alcohols or glycols, and an alkyl glycoside.
- substantially all the benzodiazepine drug is in a particulate form.
- at least part of the benzodiazepine drug is in a microparticulate or nanoparticulate form.
- the carrier system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system.
- a carrier system in such a composition includes water.
- such a liquid carrier system contains water and one or more excipients.
- one or more excipients are dissolved or suspended in the carrier system.
- at least one such excipient stabilizes the suspension of benzodiazepine particulates in the carrier system.
- the carrier system may contain varying concentrations of parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrolidinone).
- benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene glycol.
- benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols having a molecular weight greater than about 200 g/mol.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyglycoside and water.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside and water.
- the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyl glycoside, optionally a surfactant, and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside, optionally a povidone and water.
- the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside, optionally a povidone, and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyl glycoside, optionally one or more surfactants, and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside, optionally a povidone and water.
- the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside, optionally a povidone and water.
- the invention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug.
- the patient is a human.
- the method comprises: administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w).
- the benzodiazepine is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w).
- the benzodiazepine drug is dissolved in a carrier system.
- at least part of the benzodiazepine drug is in a form including microparticles, nanoparticles, or combinations thereof.
- the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof.
- the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm.
- the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
- a synthetic tocopherol may include a tocopherol that has been modified to include a hydrophilic group, such as a polyethylene glycol group, which may be directly covalently bonded to the tocopherol or may be linked to the tocopherol through a covalent linking group, such as a diacid.
- a hydrophilic group such as a polyethylene glycol group
- An exemplary synthetic tocopherol of this type is Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), although the person skilled in the art will be able to envision other synthetic tocopherols that have similar diacid and/or hydrophilic groups.
- the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof.
- the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof.
- one or more glycols specifically excludes polymeric glycols, such as polyethylene glycol.
- one or more glycols specifically excludes a polymeric glycol having a molecular weight of greater than about 200 g/mol.
- the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 20 mg/mL to about 50 mg/mL.
- the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w).
- the compositions may include a tocopherol, especially a synthetic tocopherol having a hydrophilic group covalently linked to a tocopherol.
- the tocopherol is substantially or completely free of Vitamin E TPGS.
- the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 30% (w/w).
- the amount of one or more alcohols or glycols in the carrier system is about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55% (w/w).
- the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- a composition comprises at least one penetration enhancer in addition to a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol.
- the penetration enhancer is an alkyl glycoside.
- the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which is incorporated herein by reference in its entirety.
- the hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about 10 to about 14 carbons in length.
- the hydrophobic alkyl can be branched and/or partially or wholly unsaturated.
- the alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed.
- a suitable alkyl glycoside will have the characteristics of being nontoxic, nonionic, and capable of increasing the absorption of a benzodiazepine drug when it is administered intranasally as described herein.
- Exemplary saccharides that may be covalently joined to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose and trehalose.
- alkyl glycosides that may be employed include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl ⁇ - or ⁇ -D-maltoside, -glucoside or sucroside.
- the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms. Where present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of a benzodiazepine drug administered by the intranasal route.
- the amount of alkyl glycoside in the composition is selected so as to enhance absorption of the benzodiazepine drug, while at the same time not significantly irritating the nasal mucosa. In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.05% (w/v) to about 0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).
- the composition is in a pharmaceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient.
- the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine.
- the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 ⁇ L to 200 ⁇ L.
- the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
- therapeutically effective amount includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a patient in need of particular treatment.
- therapeutically effective amount of drug will depend upon the patient, the indication and the particular drug administered.
- the modifier “about” is intended to have its regularly recognized meaning of approximately. In some embodiments, the term may be more precisely interpreted as meaning within a particular percentage of the modified value, e.g. “about” may in some embodiments mean ⁇ 20%, ⁇ 10%, ⁇ 5%, ⁇ 2%, or ⁇ 1% or less.
- analogs or derivatives includes molecules that differ from one another molecule due to one or more atoms or functional groups having been replaced with a different atom or functional group. This may result in molecules with similar chemical formulas but different chemical and/or biological properties.
- propanol has the chemical formula C 3 H 7 OH. It may be found as propan-1-ol, wherein the —OH is found attached to an end carbon. Alternatively, it may be found as propan-2-ol, wherein the —OH is found attached to the second carbon.
- seizure includes commonly recognized types of seizures, including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura that will be familiar to the patient or those familiar with the patient. Each patient will generally experience a different type of aura, which is unique to the patient; however auras may be classified as audible, visual, olfactory or tactile sensations that usually, or at least often, precedes a patient's experiencing a seizure. (Not all patients who suffer seizures experience aura; however aura are not uncommon amongst those who suffer the worst type of seizures, especially tonic-clonic seizures.)
- prevention refers to a forestalling, including temporary forestalling, of the onset of a disorder. In the case of seizures, this can occur either with or without the benefit of a warning aura.
- treatment refers to a reduction in the intensity and/or duration of a disorder, or similar effects. The term also encompasses the side-effects of such a “treatment.”
- the phrase “consisting essentially of” is a transitional phrase used in a claim to indicate that the a following list of ingredients, parts or process steps must be present in the claimed composition, machine or process, but that the claim is open to unlisted ingredients, parts or process steps that do not materially affect the basic and novel properties of the invention.
- benzodiazepine drug includes any therapeutically effective benzodiazepine compound, or pharmaceutically acceptable salt, or combinations thereof.
- benzodiazepine comprises a member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.
- benzodiazepine compounds that have heretofore been considered to have marginal or little therapeutic benefit, either because of low bioavailability, poor pharmacokinetic properties or poor pharmacodynamic properties, may find use through the present invention, which can provide for improved bioavailability of benzodiazepine drugs, delivery of higher concentrations of benzodiazepine drugs via the nasal route, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the liver portal vein and concomitant avoidance of first pass effects and/or faster presentation of benzodiazepine drug to the brain.
- the present invention allows benzodiazepine drugs to be administered to one or more mucosal membranes, including to nasal mucosal membranes. This can allow one to administer the drug without hospitalization or unnecessary discomfort. Additionally, in some embodiments of the present invention, such as nasal administration, the digestive system largely may be bypassed. This latter improvement can yield improved bioavailability, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the liver portal vein, and/or concomitant avoidance of first pass effects.
- Nasal administration of the composition can result in faster presentation of the one or more benzodiazepine drugs to the brain due to the close proximity of the membranes and the brain.
- a seizing patient for example, suffers from rigid muscles and uncontrollable movement. This can make oral and/or intravenous administration difficult or inconvenient.
- the nasal passageways remain open and easily accessible, and therefore is a useful route of administration for of the present invention.
- the pharmaceutical composition is used to treat a patient suffering from a disorder that is amenable to treatment or prevention with an effective amount of the one or more benzodiazepine drugs.
- disorders can include: insomnia, anxiety, seizures, muscle spasms and rigidity, and the symptoms of drug withdrawal.
- the one or more benzodiazepine drugs are used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Alprazolam (8-chloro-6-phenyl-1-methyl-4H-1,2,4-triazolo[4,3-a][1,4]benzodiazepine).
- Alprazolam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic. Alprazolam has also been shown to be useful in the treatment of panic disorder. The dosage of alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- alprazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- alprazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Alprazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of alprazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of alprazolam may prevent occurrence of seizure.
- alprazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with alprazolam to provide an anticonvulsant or synergistic anticonvulsant effect.
- Alprazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the alprazolam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the alprazolam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Diazepam (7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one)
- Diazepam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic and skeletal muscle relaxant. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnesic properties.
- the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085; 3,109,843; 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- diazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- diazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Diazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of diazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of diazepam may prevent occurrence of seizure.
- diazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with diazepam to provide a synergistic anticonvulsant effect.
- Diazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the diazepam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the diazepam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Flurazepam is a benzodiazepine drug having sedative (especially soporific and hypnotic), anxiolytic, anticonvulsant and muscle relaxing properties. It is classified as an sedative, hypnotic. Flurazepam has been shown to be useful in the treatment of insomnia.
- the dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- flurazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- flurazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Flurazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of flurazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of flurazepam may prevent occurrence of seizure.
- flurazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with flurazepam to provide a synergistic anticonvulsant effect.
- Flurazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- Flurazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the flurazepam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the flurazepam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Lorazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Lorazepam has also been shown to be useful in the treatment of nausea. The dosage of lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- lorazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- lorazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Lorazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of lorazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of lorazepam may prevent occurrence of seizure.
- lorazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with lorazepam to provide a synergistic anticonvulsant effect.
- Lorazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the lorazepam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the lorazepam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Medazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Medazepam has also been shown to be useful in the treatment of nausea. The dosage of medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- medazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- medazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Medazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of medazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of medazepam may prevent occurrence of seizure.
- medazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with medazepam to provide a synergistic anticonvulsant effect.
- Medazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the medazepam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the medazepam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Mexazolam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Mexazolam has also been shown to be useful in the treatment of nausea. The dosage of mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- mexazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- mexazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Mexazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of mexazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of mexazolam may prevent occurrence of seizure.
- mexazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with mexazolam to provide a synergistic anticonvulsant effect.
- Mexazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- Mexazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- the mexazolam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the mexazolam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Midazolam is a tricyclic benzodiazepine having anxiolytic, amnesic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties.
- Midazolam is considered soluble in water at a pH lower than about 4, but is relatively insoluble in most aqueous solutions at neutral pH (e.g. about 6 to 8).
- neutral pH e.g. about 6 to 8.
- aqueous nasal preparations of midazolam to have a pH above about 5.5, preferably above about 6.0, or above about 6.5.
- the pH is between about 6 and 9, between about 6 and 8.
- midazolam preparations of midazolam are particularly suitable for nasal administration as the lipid-soluble (at approximately neutral pH) midazolam is rapidly absorbed across nasal mucosa, leading to efficient uptake of midazolam. It is further considered that midazolam may be formulated in a non-aqueous delivery vehicle, such as is known in the aerosol administration art, such as hydrofluorocarbon propellants, hydrocarbon propellants, etc.
- midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- midazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- midazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Midazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of midazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of midazolam may prevent occurrence of seizure.
- midazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- benzodiazepines such as diazepam
- other anti-convulsant drugs may be combined with midazolam to provide a synergistic anticonvulsant effect.
- Midazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the midazolam formulations of the invention, and in particular nasal formulations provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the midazolam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Temazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Temazepam has also been shown to be useful in the treatment of nausea. The dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- temazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- temazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Temazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of temazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of temazepam may prevent occurrence of seizure.
- zazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure.
- other anti-convulsant drugs may be combined with temazepam to provide a synergistic anticonvulsant effect.
- Temazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- Temazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure.
- another person e.g. an acquaintance or associate, a family member or a health care professional
- one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally.
- beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing are: reduction in the severity of the seizure (e.g.
- the temazepam formulations of the invention provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes.
- the temazepam formulations of the invention, and in particular nasal formulations also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura.
- such intra-aural administration of benzodiazepine drug for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure.
- prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Benzodiazepines have the generally basic structure of formula I:
- R 1 -R 5 are substituents.
- R 1 is an optionally substituted alkyl or forms a ring with R 4
- R 2 is a halogen (e.g. Cl, Br)
- R 3 is optionally substituted aryl (e.g.
- R 5 is H or OH
- R 4 and R 4 ′ together form a carbonyl (C ⁇ O) with the carbon to which they are attached or R 4 and R 1 form an optionally substituted heterocyclic ring with the diazepam ring atoms to which they are respectively attached;
- R 3 ′ and R 6 together form a double bond or may be combined to form an optionally substituted heterocyclic ring along with the diazepam ring atoms to which they are respectively attached.
- Such basic compounds may form acid addition salts with pharmaceutically acceptable acids, such as pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids.
- Pharmaceutically acceptable mineral acids include HCl, H 2 SO 4 , H 2 SO 3 , H 3 PO 4 , H 3 PO 3 , and others that will be recognized by those of skill in the art.
- Pharmaceutically acceptable organic acids include acetic acid, benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid, malonic acid, etc.
- the pharmaceutically acceptable acid may be selected from the group consisting of: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acidascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acidfumaric acid, galactaric acid, gentisic acid,
- compositions may be pharmaceutically acceptable acidic (anionic) polymers or pharmaceutically acceptable amphoteric polymers.
- anionic acidic
- amphoteric polymers pharmaceutically acceptable amphoteric polymers.
- other basic active pharmaceutical ingredients may be combined with the foregoing acids to produce acid addition salts.
- the person skilled in the art will recognize that in some embodiments it may be advantageous that some or all of the added acid be an active pharmaceutical ingredient in its own right.
- the invention provides nasal compositions comprising one or more acidic pharmaceutically active ingredients. It is considered well within the ordinary skill in the art to determine which of the compounds set for the above are acidic. Such compounds may be prepared as base addition salts, e.g. by the addition of one or more mineral bases (e.g. NaOH, KOH, NaHCO 3 , Na 2 CO 3 , NH 3 ) or organic bases. It is considered within the skill in the art to choose a pharmaceutically acceptable base.
- mineral bases e.g. NaOH, KOH, NaHCO 3 , Na 2 CO 3 , NH 3
- Known benzodiazepine compounds have anxiolytic, anticonvulsant, sedative and/or skeletal muscle relaxant effect.
- anticonvulsant includes treatment of seizures, protection against seizure, reduction or amelioration of the intensity of seizure, reduction or amelioration of the frequency of seizure, and/or prevention of the occurrence or re-occurrence of seizure.
- treatment of seizure includes cessation of an ongoing seizure, reduction in the severity of an ongoing seizure, reduction in the duration of an ongoing seizure.
- Protection against seizure includes forestalling an oncoming seizure.
- Vitamin E is a class of fat soluble methylated phenols. There are at least eight naturally-occurring compounds that comprise this class: ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocotrienol, ⁇ -tocotrienol, ⁇ -tocotrienol, and ⁇ -tocotrienol, all of which may be used in the compositions and methods of the present invention. There are multiple isomers of each of these compounds, all of which may be used in the compositions and methods of the present invention. There are also multiple esters of each of these compounds, including tocophersolan, all of which may be used in the compositions and methods of the present invention. As used herein, Vitamin E refers to any of the natural or synthetic tocopherols, tocotrienols, any isomers thereof, any esters thereof, any analogs or derivatives thereof, or any combinations thereof.
- Vitamin E are antioxidants. There is also evidence that they can prevent, delay the onset of, or ameliorate the symptoms of heart disease, cancer, cataracts, macular degeneration, glaucoma, Alzheimer's, and Parkinson's disease.
- Vitamin E can provide an effective carrier for benzodiazepine drugs.
- benzodiazepines are soluble, or partially soluble, in Vitamin E.
- Vitamin E may be present as microparticles, nanoparticles, or any combination thereof.
- use of Vitamin E can have the added benefit of either avoiding irritation of sensitive mucosal membranes and/or soothing irritated mucosal membranes.
- Vitamin E is generally classified as hydrophobic, and when used as a carrier may be limited to formulations as an emulsion.
- emulsions can have several drawbacks. For instance, they may be difficult to create and can be highly unstable. Additionally, they can leave an oily film on the surface of the skin.
- some embodiments of the present invention comprise solutions of one or more benzodiazepine drugs in Vitamin E and one or more lower alkyl alcohols or one or more lower alkyl glycols, or any combinations thereof.
- Lower alkyl alcohols are those with six or fewer carbon atoms. Thus, any of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof can be used.
- Lower alkyl glycols are those with six or fewer carbon atoms. Thus, any of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, or any combinations thereof can be used.
- a composition comprises at least one penetration enhancer in addition to a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol.
- the penetration enhancer is at least one alkyl glycoside.
- the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which is incorporated herein by reference in its entirety.
- the hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about 10 to about 14 carbons in length.
- the hydrophobic alkyl can be branched and/or partially or wholly unsaturated.
- the alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed.
- a suitable alkyl glycoside will have the characteristics of being nontoxic, nonionic, and capable of increasing the absorption of a benzodiazepine drug when it is administered intranasally as described herein.
- Exemplary saccharides that may be covalently joined to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose and trehalose.
- alkyl glycosides that may be employed include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl ⁇ - or ⁇ -D-maltoside, -glucoside or sucroside.
- the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms.
- alkylsaccharide is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or combinations of two or more thereof.
- Alkyl glycosides that are particularly considered useful in embodiments of the invention include those marketed under the name Intravail® by Aegis Therapeutics, LLC, San Diego, Calif.
- Other alkyl glycosides may be selected from those having a hydrophile-lipophile balance (HLB) number of from about 10-20, especially about 1′-15. The HLB number may be determined as set forth in the publication US2009/0047347, published on 19 Feb.
- the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of a benzodiazepine drug administered by the intranasal route.
- the amount of alkyl glycoside in the composition is selected so as to enhance absorption of the benzodiazepine drug, while at the same time not significantly irritating the nasal mucosa.
- the amount of alkyl glycoside in the composition is in a range of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.05% (w/v) to about 0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).
- penetration enhancer means any material which acts to increase absorption across the mucosa and/or increases bioavailability.
- such materials include mucolytic agents, degradative enzyme inhibitors and compounds which increase permeability of the mucosal cell membranes.
- Whether a given compound is an “enhancer” can be determined by comparing two formulations comprising a non-associated, small polar molecule as the drug, with or without the enhancer, in an in vivo or good model test and determining whether the uptake of the drug is enhanced to a clinically significant degree.
- the enhancer should not produce any problems in terms of chronic toxicity because in vivo the enhancer should be non-irritant and/or rapidly metabolized to a normal cell constituent that does not have any significant irritant effect.
- preferred enhancing materials lysophospholipids, for example lysophosphatidylcholine obtainable from egg or soy lecithin.
- lysophosphatidylcholines that have different acyl groups as well as lyso compounds produced from phosphatidylethanolamines and phosphatidic acid which have similar membrane modifying properties may be used.
- Acyl carnitines e.g. palmitoyl-dl-camitine-chloride
- a suitable concentration is from 0.02 to 20% w/v.
- enhancing agents that are appropriate include chelating agents (EGTA, EDTA, alginates), surface active agents (especially non-ionic materials), acyl glycerols, fatty acids and salts, tyloxapol and biological detergents listed in the SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by reference).
- agents that modify the membrane fluidity and permeability are appropriate such as enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates (e.g. diethyleneoxymethylene malonate), salicylates, bile salts and analogues and fusidates. Suitable concentrations are up to 20% w/v.
- the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient.
- the alkyl glycoside is an Intravail® brand alkyl glycoside.
- the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof.
- the alkyl glycoside is dodecyl maltoside.
- the alkyl glycoside is tetradecyl maltoside.
- the alkyl glycoside is sucrose dodecanoate.
- the alkyl glycoside is sucrose monostearate.
- the alkyl glycoside is sucrose distearate.
- the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
- the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, which benzodiazepine drug comprises microparticles, nanoparticles or both, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient.
- the alkyl glycoside is an Intravail® brand alkyl glycoside.
- the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof.
- the alkyl glycoside is dodecyl maltoside.
- the alkyl glycoside is tetradecyl maltoside.
- the alkyl glycoside is sucrose dodecanoate.
- the alkyl glycoside is sucrose monostearate.
- the alkyl glycoside is sucrose distearate.
- the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
- Mucosal membrane preparations are generally administered in metered sprays having volumes of less than 250 ⁇ L, preferably less than 150 ⁇ L, and ideally from 25 to 100 ⁇ L. Although not prohibited in this invention, administration of volumes larger than about 300 ⁇ L per dose usually exceeds the absorption capacity of the membranes. This results in a large portion of the pharmaceutically-active ingredient being lost.
- the dosage volume of preparations, in particular nasal preparations preferably ranges from 25 to 100 ⁇ L. Volumes in excess of the aforementioned ranges may bypass the sinuses and flow down the back of the throat where the excess is swallowed.
- alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- alprazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays
- the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- diazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, diazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- the dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- flurazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, flurazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- Lorazepam The dosage of Lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- lorazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, lorazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- medazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, medazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- mexazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, mexazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- midazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, midazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- the dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- temazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, temazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays.
- Some embodiments comprise administering to one or more mucosal membranes of a patient a therapeutically effective amount of one or more benzodiazepine drugs, or pharmaceutically-acceptable salts thereof.
- Some embodiments of the composition disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration up to about 600 mg/mL.
- Other compositions disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 10 mg/mL up to about 250 mg/mL.
- some embodiments disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 20 mg/mL up to about 50 mg/mL.
- Some embodiments disclose a carrier system that is about 50% to about 90% (w/w) Vitamin E and about 10% to about 50% (w/w) lower alcohol or lower alkyl glycol, or any combinations thereof. Some embodiments disclose a carrier system that is about 65% to about 75% (w/w) Vitamin E and about 25% to about 35% (w/w) lower alkyl alcohol or lower alkyl glycol, or any combinations thereof. Further, some embodiments disclose a carrier system that is about 70% (w/w) Vitamin E and about 30% (w/w) lower alkyl alcohol or lower alkyl glycol, or any combinations thereof.
- Some embodiments of the invention provide a method of administering the benzodiazepine drug composition to a patient.
- the preferred embodiment comprises use of diazepam.
- Some embodiments of the method disclose a dosage level of diazepam of about 1.0 mg to about 20.0 mg until achievement of the desired result.
- Other dosage levels disclose a dosage level of about 2.0 mg to about 15.0 mg until the desired result is achieved.
- Some embodiments disclose a dosage level of about 5.0 mg to about 10.0 mg until the desired result is achieved.
- the dosage volume ranges from about 10 ⁇ L to about 200 ⁇ L. In some embodiments, the dosage volume ranges from about 20 ⁇ L to about 180 ⁇ L. Further, some embodiments disclose a dosage volume of about 50 ⁇ L to about 140 ⁇ L.
- the composition for nasal administration is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- the composition is made by slowly warming or heating the Vitamin E until it is liquefied.
- the one or more benzodiazepine drugs are added.
- the mixture is stirred and heated until the one or more benzodiazepine drugs dissolve or are substantially dissolved.
- the one or more alcohols or glycols, or any combinations thereof are added to the composition. This composition is stirred until a less viscous composition is achieved.
- the aforementioned formulations are preferably sterile with a bacteria count of 10 below the allowable level on a per mL basis. Additionally, pathogens are preferably absent.
- the benzodiazepine drug is formulated as a microparticulate and/or nanoparticulate suspension of the benzodiazepine.
- Preparation of microparticulate and nanoparticulate benzodiazepine may be accomplished by methods such as milling, etc. Such methods are known to those skilled in the art.
- the benzodiazepine drug is formulated as a solution. It is considered an aspect of the invention that employment of microparticulate and/or nanoparticulate benzodiazepine drug during the process of preparing the formulation, can improve the overall solubility of the benzodiazepine drug in the solvent system.
- compositions and methods of using the compositions comprise an additional ingredient in the composition selected from active ingredients.
- active ingredients include insulin, calcitonins (for example porcine, human, salmon, chicken, or eel) and synthetic modifications thereof, enkephalins, LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone (solatotropir polypeptides or their derivatives (preferably with a molecular weight from 1000 to
- compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants.
- active ingredients include: paraldehyde; aromatic allylic alcohols (such as stiripentol); barbiturates (e.g.
- phenobarbitol phenobarbitol, primidone, methylphenobarbital, metharbital and barbexaclone
- bromides such as potassium bromide
- carbamates such as felbamate
- carboxamides such as carbamazepine and oxcarbazepine
- fatty acids such as valproic acid, sodium valproate, and divalproex sodium, vigabatrin, progabide, tiagabine
- fructose topiramate
- Gaba analogs e.g. gabapentin and pregabalin
- hydantoins e.g.
- oxazolidinediones such as paramethadione, trimethadione, ethadione
- propionates e.g. beclamide
- pyrimidinediones e.g. primidone
- pyrrolidines e.g. brivaracetam, levetiracetam and seletracetam
- succinimides e.g. ethosuximide, phensuximide and mesuximide
- sulfonamides e.g.
- acetazolamide, sulthiame, methazolamide and zonisamide triazines (such as lamotrigine); ureas (such as pheneturide, phenacemide); valproylamides (such as valpromide and valnoctamide); as well as other anticonvulsants or pharmaceutically acceptable salts or combinations thereof.
- compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants.
- active ingredients include: antibiotics and antimicrobial agents such as tetracyline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone; local anaesthetics such as benzocaine; vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride; cardiotonics such as digitalis and digoxin; vasodilators such as nitroglycerine and papaverine hydrochloride; antiseptics such as chlorhexidine hydrochloride, hexylresorcinol, dequaliniumchloride and ethacridine; enzyme
- compositions and methods of using the compositions comprise an additional inactive ingredient in the composition.
- minor amounts of ingredients such as stabilizers, coloring agents, pH adjusters, buffering agents, preservatives such as agents which may prevent degradation, wetting agents, and flavoring agents may also be present.
- coloring agents include ⁇ -carotene, Red No. 2 and Blue No. 1.
- preservatives include stearic acid, ascorbyl stearate and ascorbic acid.
- corrigents include menthol and citrus perfume.
- the drug delivery system of the invention may advantageously comprise an absorption enhancer.
- such materials include mucolytic agents, degradative enzyme inhibitors and compounds which increase permeability of the mucosal cell membranes. Whether a given compound is an “enhancer” can be determined by comparing two formulations comprising a non-associated, small polar molecule as the drug, with or without the enhancer, in an in vivo or good model test and determining whether the uptake of the drug is enhanced to a clinically significant degree.
- the enhancer should not produce any problems in terms of chronic toxicity because in vivo the enhancer should be non-irritant and/or rapidly metabolized to a normal cell constituent that does not have any significant irritant effect.
- preferred enhancing materials lysophospholipids, for example lysophosphatidylcholine obtainable from egg or soy lecithin.
- lysophosphatidylcholines that have different acyl groups as well as lyso compounds produced from phosphatidylethanolamines and phosphatidic acid which have similar membrane modifying properties may be used.
- Acyl carnitines e.g. palmitoyl-dl-carnitine-chloride
- a suitable concentration is from 0.02 to 20% w/v.
- enhancing agents that are appropriate include chelating agents (EGTA, EDTA, alginates), surface active agents (especially non-ionic materials), acyl glycerols, fatty acids and salts, tyloxapol and biological detergents listed in the SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by reference).
- agents that modify the membrane fluidity and permeability are appropriate such as enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates (e.g. diethyleneoxymethylene malonate), salicylates, bile salts and analogues and fusidates. Suitable concentrations are up to 20% w/v.
- the invention takes advantage of delivery of a drug incorporated into or onto a bioadhesive microsphere with an added pharmaceutical adjuvant applies to systems that contain active drug and mucolytic agent, peptidase inhibitors or non-drug polypeptide substrate singly or in combination.
- mucolytic agents are thiol-containing compounds such as N-acetylcysteine and derivatives thereof.
- Peptide inhibitors include actinonin, amastatin, bestatin, chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, diprotin A and B, ebelactone A and B, E-64, leupeptin, pepstatin A, phisphoramidon, H-Thr-(tBu)-Phe-Pro-OH, aprotinin, kallikrein, chymostatin, benzamidine, chymotrypsin and trypsin. Suitable concentrations are from 0.01 to 10% w/v. The person skilled in the art will readily be able to determine whether an enhancer should be included.
- the administration of the composition comprises administering at least a portion of the therapeutically effective amount of the composition onto at least one mucosal membrane. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- alprazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- the dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- diazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, diazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- the dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- flurazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, flurazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- Lorazepam The dosage of Lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- lorazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, lorazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- medazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, medazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- mexazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, mexazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- midazolam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, midazolam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- the dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day.
- Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- temazepam may be administered in 25 to 250 ⁇ L metered sprays. In some preferred embodiments, temazepam is administered in 50 to 150 ⁇ L, especially about 100 ⁇ L, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient.
- benzodiazepine drugs for treating the aforementioned disorders will vary with age, size, weight, and general physical condition of the patient as well as the severity of the disease. Frequency of administration will likewise vary with the formulation of the composition and it can be adjusted so that any suitable number of doses per day may be used.
- a pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device.
- the composition is used to treat or prevent seizures associated with epilepsy in adults. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 5.0 mg/puff (5.0 mg/0.1 mL and 0.1 mL/puff)) every 5 minutes until cessation of the seizure. However, it can be given as 1 puff per nostril in each nostril (2 puffs at 2.5 mg/puff (5.0 mg/0.1 mL and 0.05 mL/puff)) every 5 minutes until cessation of the seizure.
- the composition according to this example is set forth in the following table.
- a pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device.
- the composition is used to treat or prevent seizures associated with epilepsy in children. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 2.0 mg/puff (2.0 mg/0.1 mL and 0.1 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes. However, it can be given as 1 puff per nostril in each nostril (2 puffs at 1.0 mg/puff (2.0 mg/0.1 mL and 0.05 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes.
- the composition according to this example is set forth in the following table.
- benzodiazepine solutions may be formulated by combining one or more natural or synthetic tocopherols or tocotrienols and one or more lower alcohols or glycols and mixing until a homogeneous mixture is formed, adding the benzodiazepine drug to the homogeneous mixture, heating and mixing the ingredients until the benzodiazepine is fully dissolved in the homogeneous mixture, cooling the mixture, and bringing the mixture to its final mass or volume with lower alcohol or glycol.
- Vitamin E USP and dehydrated ethanol USP were combined in the amounts set forth in the following table and mixed to form a homogeneous mixture.
- Diazepam in the amounts set forth in the following table was then added to the homogeneous mixture.
- the ingredients were heated to 40-45° C. with mixing until the diazepam was fully dissolved, thereby forming a solution.
- the solution was cooled to 20-25° C., whereupon the solution was brought to its final target weight with dehydrated ethanol USP and the solution was mixed thoroughly to assure homogeneity.
- the solution was then sampled for in-process testing and packaged in 3 mL amber glass vials.
- diazepam at varying concentrations are made in a similar manner, by varying the amount of diazepam and the relative amounts of Vitamin E and ethanol.
- Other benzodiazepine solutions are made by substituting one or more benzodiazepines for diazepam.
- Other ingredients, such as alkyl glycoside, can be added at a suitable step in the process (e.g. before or concurrently with the addition of benzodiazepine).
- benzodiazepine suspensions are formulated by micronizing benzodiazepine and combining the benzodiazepine with a carrier.
- the carrier is prepared by combining one or more lower alcohols or glycols with water, adding a natural or synthetic tocopherol or tocotrienol, heating the mixture until the tocopherol or tocotrienol is dissolved, adding one or more parabens and mixing until the parabens are dissolved and cooling the carrier.
- additional excipients such as surfactants, can optionally be added and dissolved in the carrier.
- the suspension is then brought up to its final mass or volume with water.
- Two different diazepam suspensions were formulated by the foregoing general process. Two different diazepam particle sizes were prepared—A: a small particle size by prepared by high pressure micronization, and B: a large particle size prepared by low pressure micronization.
- the carrier was prepared by combining propylene glycol USP and purified water USP, then adding Vitamin E Polyethylene Glycols Succinate NF, then mixing and heating the combined ingredients to about 45° C. Mixing was continued until the Vitamin E Polyethylene Glycol Succinate was fully dissolved. The carrier was then cooled to 20-25° C. The micronized diazepam (A and B) was then added to the carrier with vigorous mixing until the diazepam was fully dispersed in the carrier.
- Polyvinylpyrrolidone Povidone USP/NF was then added to the mixture and mixed until fully dissolved.
- the suspension was then brought up to weight with purified water USP.
- the suspension was then mixed until homogeneous, sampled for in-process testing, and packaged in 3 mL amber glass bottles.
- Diazepam Suspension Formulations Suspension 03 Suspension 01 (200 mg/mL Diazepam) (100 mg/mL Diazepam) Component Concentration (mg/mL) Concentration (mg/mL) Diazepam USP 200.00 100.00 Vitamin E 100.0 100.0 Polyethylene Glycol Succinate NF Methylparaben NF 2.0 2.0 Propylparaben NF 0.5 0.5 Propylene Glycol 100.0 100.0 USP Povidone USP/NF 25.0 25.0 Purified Water q.s. to 1 mL q.s. to 1 mL USP/EP
- Additional suspensions of diazepam at varying concentrations are made in a similar manner, by varying the amount of diazepam and optionally other excipients.
- Other benzodiazepine suspensions are made by substituting one or more benzodiazepines for diazepam.
- Other ingredients such as alkyl glycoside, can be added at a suitable step in the process.
- an alkylglycoside may be added to the carrier during compounding of the carrier, or may be added to the suspension mixture concurrently with or after addition of the povidone.
- Solutions 00 and 02 (Example 3) and Suspensions 01 and 03 (Example 4) were setup on stability at 25° C./60% RH, 30° C./65% RH and 40° C./75% RH.
- One batch each of four different formulations, packaged in 3-ml vials with screw-top closures, along with corresponding actuators, were set up at three storage conditions. They are listed in Table 1 with their corresponding Particle Sciences initial sample control numbers.
- Samples were tested for spray content uniformity, spray volume, diazepam content, diazepam related substances, and methylparaben and propylparaben assay (suspension samples only). Unit weights were determined as per USP ⁇ 755>.
- Solution 00 results Solution 00, 1 1 1 3 3 3 6 6 6 70 mg/mI, month month month month month month month month month 65% 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Vitamin E Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH Description Yellow to Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber orange solution solution solution solution solution solution solution solution
- the solutions and suspensions of Examples 3, 4 and 6 are evaluated for pharmacokinetics in a suitable animal model, such as in mice, rats, rabbits or dogs.
- a suitable animal model such as in mice, rats, rabbits or dogs.
- each animal e.g. rabbit
- the amount of intravenously dosed benzodiazepine drug is selected to be less, e.g. roughly half, of what is considered an effective dose administered nasally.
- the intravenous dose of diazepam administered to rabbits is about 0.05 to about 0.2 mg/kg, e.g. about 0.1 mg/kg.
- Blood is collected immediately before administration and at specific time points post-administration. Plasma blood levels of the drug are assayed for each of the blood samples.
- each animal is administered, intranasally, an amount of a solution or suspension as described in Examples 3, 4 and 6.
- Blood is collected immediately before administration and at substantially the same specific time points as the IV dose post-administration.
- Pharmacokinetic curves blood plasma concentration of drug versus time are constructed for the intravenous route of administration and for each of the solutions and suspensions administered by the intranasal administration route.
- Toxicity is assessed by known means.
- histological samples are collected from the nasal mucosal tissues of the test animals.
- Other toxological methods are optionally employed as well.
- the solutions and suspensions of Examples 3, 4 and 6 are evaluated for their ability to deliver drug across the blood brain barrier in a suitable animal model, such as in mice, rats, rabbits or dogs.
- a suitable animal model such as in mice, rats, rabbits or dogs.
- Each animal is administered, intranasally, an amount of a solution or suspension as described in Examples 3, 4 and 6, with the solution or suspension optionally containing an imaging agent, such as a dye, that may be used as a proxy for determining the ability of the drug to cross the blood brain barrier.
- an imaging agent such as a dye
- the above-described solutions and/or suspensions can be evaluated for pharmacokinetics in humans.
- Normal, healthy human test subjects are administered an amount of the drug intravenously.
- the amount chosen for intravenous administration may be any amount, but is conveniently a dose that is considered effective in treating seizure in humans.
- an IV dose of diazepam administered to humans may be in the range of 1 to 15 mg, e.g. about 7.5 mg.
- Blood is collected immediately before administration and at selected time points after administration. Plasma blood levels of the drug are assayed for each of the blood samples. After at least a one day washout period, each subject is administered, intranasally, an amount of a solution or suspension as described herein. Blood is collected immediately before administration and at substantially the same time points after administration as the intravenous time points. Pharmacokinetic curves (blood plasma concentration of drug versus time) are constructed for the intravenous and intranasal administration routes.
- solutions and/or suspensions can be evaluated for efficacy in a suitable animal model. Briefly, for each dose of suspension or solution to be tested, a test animal is stimulated with a seizure inducing stimulus. The stimulus may be light, sound, chemical or other stimulus effective to induce seizure in the model animal. Once the animal has begun to seize, a solution or suspension as described herein is administered intranasally to the animal. The efficacy of the dose of the solution and/or suspension is evaluated based upon the animal's response to the test dose. This procedure is repeated through sufficient iterations, and at sufficient numbers of doses, to identify a dose that is considered effective to treat seizure by intranasal administration of the drug.
Abstract
Description
- This application claims priority under 35 U.S.C. § 119(e) from U.S. provisional patent application No. 61/040,558, which was filed on Mar. 28, 2008, and which is incorporated herein in its entirety.
- This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.
- By way of non-limiting example, the benzodiazepine family consists of drugs such as diazepam, lorazepam, and medazepam. The drugs in this family have been observed as possessing sedative, tranquilizing and muscle relaxing properties. They are frequently classified as an anxiolytic and skeletal muscle relaxants. They are thought to be useful in preventing, treating, or ameliorating the symptoms of anxiety, insomnia, agitation, seizures (such as those caused by epilepsy), muscle spasms and rigidity (which can be caused by tetanus), the symptoms of drug withdrawal associated with the continuous abuse of central nervous system depressants, and exposure to nerve agents.
- Benzodiazepines are thought to act by binding to the GABAA receptor of a neuron, possibly causing the receptor to change shape and making it more accessible to gama-aminobutyric acid (GABA).
- GABA is an inhibitory neurotransmitter that, when bound to the GABAA receptor, facilitates Cl− ions flooding into the neuron to which the receptor is bound. The increase in Cl− ions hyperpolarizes the membrane of the neuron. This completely or substantially reduces the ability of the neuron to carry an action potential. Targeting this receptor is particularly useful in treating many disorders, such as tetanus and epilepsy, which may result from too many action potentials proceeding through the nervous system.
- Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally. The ability to utilize these and other types of formulations has been significantly limited due, in many cases, to solubility challenges.
- The oral route of administration may be considered sub-optimal due to several disadvantages. For example, the amount of time required for an orally administered benzodiazepine drug to reach therapeutically relevant concentrations in blood plasma may be rather long, such as an hour or more. Moreover, as benzodiazepine drugs pass through the liver a significant amount may be metabolized. Thus, it may require large doses to achieve therapeutic plasma levels. Furthermore, due to the nature of seizures and muscle spasms, it can be extremely difficult for either a patient or a care-giver to administer the benzodiazepine drug orally.
- Intravenous administration perhaps provides a faster route of administration. However intravenous administration is generally limited to trained health care professionals in tightly controlled clinical settings. Additionally, sterility must be maintained. Furthermore, administering any drug intravenously can be painful and is likely impractical for patients suffering from a phobia of needles.
- Suppository compositions of benzodiazepine drugs can have a rapid onset of action. However, the inconvenience of suppositories is an obvious impediment to their being administered by anyone outside a very small group of the patient's intimate acquaintances and the patient's professional medical caretakers.
- In some embodiments, the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient. In some embodiments the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form comprising benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the benzodiazepine drug is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. In some embodiments, a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate). In some embodiments, on the other hand, synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol). Thus, in some embodiments, the compositions described herein exclude Vitamin E TPGS.
- In some embodiments, one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof. In some embodiments, the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In some preferred embodiments, the glycols exclude glycol polymers. In some preferred embodiments, the glycols exclude glycol polymers having an average molecular weight of greater than 200. In some embodiments, the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200.
- In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20 mg/mL to about 50 mg/mL.
- In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w).
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w).
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w).
- In some embodiments, the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- In some embodiments, the composition comprises one or more additional excipients, such as one or more parabens, one or more povidones, and/or one or more alkyl glycosides.
- The invention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug. In some embodiments, the patient is a human. In some embodiments, the method comprises: administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%, preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70%, preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, the benzodiazepine drug includes benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug is fully dissolved in a single phase comprising one or more one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols or glycols. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some such embodiments, the composition further comprises water. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof.
- In some embodiments, the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof. In some embodiments, the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In some embodiments, the alcohol or glycol is free of water (dehydrated, USP). In some embodiments, the alcohol is ethanol (dehydrated, USP).
- In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 20 mg/mL to about 50 mg/mL.
- In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w).
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 30% (w/w).
- In some embodiments, the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- In some embodiments, the composition is in a pharmaceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient. In some embodiments, the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine. In some embodiments, the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 μL to 200 μL.
- In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- In some embodiments, the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
- Additional embodiments, uses, and advantages of the invention will become apparent to the person skilled in the art upon consideration of the disclosure set forth herein.
- All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
- Provided herein are pharmaceutical compositions of one or more benzodiazepine drugs and methods of using such pharmaceutical compositions. Such pharmaceutical compositions are administered nasally.
- In some embodiments, the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient. In some embodiments the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the pharmaceutical composition for nasal administration comprises: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w) in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of the patient. In some embodiments the benzodiazepine drug is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least part of the benzodiazepine drug is in a form of microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically-acceptable salts thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. In some embodiments, the carrier system includes one or more synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in U.S. Pat. No. 6,193,985, which is incorporated herein by reference in its entirety.
- In particular, it has been found that in some particulate suspensions of benzodiazepines, wherein the benzodiazepine is not dissolved in a tocopherol phase, Vitamin E TPGS can be a desirable excipient for stabilizing the particulate (microparticle, nanoparticle or combination) suspension. In some embodiments, on the other hand, the carrier system specifically excludes synthetic tocopherols having a polymer glycol covalently bonded or linked to a tocopherol core, such as Vitamin E TPGS, which is described in U.S. Pat. No. 6,193,985, which is incorporated herein by reference in its entirety.
- In some embodiments, one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof. In some embodiments, the alcohol is ethanol (dehydrated, USP). In some embodiments, the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In some embodiments, the glycol is propylene glycol USP. In some embodiments, a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate). In some embodiments, on the other hand, synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol). Thus, in some embodiments, the compositions described herein exclude Vitamin E TPGS.
- In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in a carrier system in a concentration from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine is present in a carrier system in a concentration from about 20 mg/mL to about 50 mg/mL.
- In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w). In some embodiments, a synthetic tocopherol can include Vitamin E TPGS (Vitamin E polyethylene glycol succinate). In some embodiments, on the other hand, synthetic tocopherols exclude tocopherols covalently bonded or linked (e.g. through a diacid linking group) to a glycol polymer, such as polyethylene glycol). Thus, in some embodiments, the compositions described herein exclude Vitamin E TPGS.
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w). In some embodiments, the alcohol is ethanol or contains ethanol. In some preferred embodiments, the glycols exclude glycol polymers. In some preferred embodiments, the glycols exclude glycol polymers having an average molecular weight of greater than 200. In some embodiments, the glycols exclude polyethylene glycol having an average molecular weight of greater than about 200.
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 15% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount of about 30% (w/w).
- In some embodiments, the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- In some embodiments, the compositions comprise at least one alkyl glycoside. In some embodiments, the at least one alkyl glycoside is one described in U.S. Pat. No. 5,661,130, which is incorporated by reference herein.
- In some embodiments, the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. In some embodiments, the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol and an alcohol or glycol, wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.)
- In some embodiments, the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. Thus, in some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition comprises a benzodiazepine drug that is fully dissolved in a solvent comprising a natural or synthetic tocopherol or tocotrienol and an alcohol or glycol, wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition consists essentially of a benzodiazepine drug that is fully dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.) In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is at least substantially free of water. (In some embodiments, “substantially free of water” indicates that the solution contains less than about 1%, less than about 0.5%, less than about 0.25% or less than about 0.1% water.)
- In some embodiments, the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol and one or more alcohols or glycols. In some embodiments, substantially all the benzodiazepine drug is in a particulate form. In some embodiments, at least part of the benzodiazepine drug is in a microparticulate or nanoparticulate form. The carrier system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system. In some embodiments, a carrier system in such a composition includes water. In some embodiments, such a liquid carrier system contains water and one or more excipients. In some embodiments, one or more excipients are dissolved or suspended in the carrier system. In some embodiments, at least one such excipient stabilizes the suspension of benzodiazepine particulates in the carrier system. In some embodiments, the carrier system may contain varying concentrations of parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrolidinone). In some embodiments, benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene glycol. In some embodiments, benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols having a molecular weight greater than about 200 g/mol. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, one or more surfactants and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone and water.
- In some embodiments, the composition contains a benzodiazepine drug that at least partially in a particulate form suspended in a carrier system containing a natural or synthetic tocopherol or tocotrienol, one or more alcohols or glycols, and an alkyl glycoside. In some embodiments, substantially all the benzodiazepine drug is in a particulate form. In some embodiments, at least part of the benzodiazepine drug is in a microparticulate or nanoparticulate form. The carrier system is one in which the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system. In some embodiments, a carrier system in such a composition includes water. In some embodiments, such a liquid carrier system contains water and one or more excipients. In some embodiments, one or more excipients are dissolved or suspended in the carrier system. In some embodiments, at least one such excipient stabilizes the suspension of benzodiazepine particulates in the carrier system. In some embodiments, the carrier system may contain varying concentrations of parabens (e.g. methylparaben, propylparaben, etc.), and/or varying amounts of one or more surfactants, such as povidone (polyvinyl pyrrolidinone). In some embodiments, benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols, such as polyethylene glycol. In some embodiments, benzodiazepine particulate suspensions specifically exclude one or more polymeric glycols having a molecular weight greater than about 200 g/mol. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyglycoside and water. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside and water. In some embodiments, the composition comprises a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system comprising Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyl glycoside, optionally a surfactant, and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside, optionally a povidone and water. In some embodiments, the composition consists essentially of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting essentially of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside, optionally a povidone, and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of a synthetic tocopherol, one or more parabens, one or more alcohols or glycols, an alkyl glycoside, optionally one or more surfactants, and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, an alkyl glycoside, optionally a povidone and water. In some embodiments, the composition consists of a benzodiazepine drug in a form including benzodiazepine microparticles and/or nanoparticles suspended in a carrier system consisting of Vitamin E TPGS, methylparaben, propylparaben, propylene glycol, an alkyl glycoside, optionally a povidone and water.
- The invention also discloses a method of treating a patient with a disorder that may be treatable with a benzodiazepine drug. In some embodiments, the patient is a human. In some embodiments, the method comprises: administering to one or more nasal mucosal membranes of a patient a pharmaceutical composition for nasal administration comprising a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine is dissolved in the one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); and the one or more alcohols or glycols, or any combinations thereof, in an amount from about 5% to about 70% (w/w), preferably about 10% to about 70% (w/w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In other embodiments, at least part of the benzodiazepine drug is in a form including microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof.
- In some embodiments, the benzodiazepine drug is selected from the group consisting of: alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepam, demoxazepam, diazepam, flumazenil, flurazepam, halazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, medazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically-acceptable salts thereof, and any combinations thereof. In some embodiments, the benzodiazepine drug is diazepam, or a pharmaceutically-acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm.
- In some embodiments, the one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolan, any isomers thereof, any esters thereof, any analogs or derivatives thereof, and any combinations thereof. A synthetic tocopherol may include a tocopherol that has been modified to include a hydrophilic group, such as a polyethylene glycol group, which may be directly covalently bonded to the tocopherol or may be linked to the tocopherol through a covalent linking group, such as a diacid. An exemplary synthetic tocopherol of this type is Vitamin E Polyethylene Glycol Succinate (Vitamin E TPGS), although the person skilled in the art will be able to envision other synthetic tocopherols that have similar diacid and/or hydrophilic groups.
- In some embodiments, the one or more alcohols are selected from the group consisting of: ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combinations thereof. In some embodiments, the one or more glycols are selected from the group consisting of: ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combinations thereof. In some embodiments, one or more glycols specifically excludes polymeric glycols, such as polyethylene glycol. In some embodiments, one or more glycols specifically excludes a polymeric glycol having a molecular weight of greater than about 200 g/mol.
- In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration from about 1 mg/mL to about 600 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 10 mg/mL to about 250 mg/mL. In some embodiments, the benzodiazepine drug is present in the carrier system in a concentration of from about 20 mg/mL to about 50 mg/mL.
- In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 45% to about 85% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 60% to about 75% (w/w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount of about 70% (w/w). In some embodiments, especially where particulate suspensions of a benzodiazepine drug are contemplated, the compositions may include a tocopherol, especially a synthetic tocopherol having a hydrophilic group covalently linked to a tocopherol. In other embodiments, especially where a solution of benzodiazepine drug is contemplated, the tocopherol is substantially or completely free of Vitamin E TPGS.
- In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 55% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 25% to about 40% (w/w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combinations thereof, in an amount from about 30% (w/w). In some embodiments the amount of one or more alcohols or glycols in the carrier system is about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5% or about 55% (w/w).
- In some embodiments, the composition comprises at least one additional ingredient selected from the group consisting of: active pharmaceutical ingredients; enhancers; excipients; and agents used to adjust the pH, buffer the composition, prevent degradation, and improve appearance, odor, or taste.
- In some embodiments, a composition comprises at least one penetration enhancer in addition to a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. In some embodiments, the penetration enhancer is an alkyl glycoside. In some embodiments, the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which is incorporated herein by reference in its entirety. The hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about 10 to about 14 carbons in length. The hydrophobic alkyl can be branched and/or partially or wholly unsaturated. The alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed. A suitable alkyl glycoside will have the characteristics of being nontoxic, nonionic, and capable of increasing the absorption of a benzodiazepine drug when it is administered intranasally as described herein. Exemplary saccharides that may be covalently joined to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose and trehalose. Exemplary alkyl glycosides that may be employed include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D-maltoside, -glucoside or sucroside. In some embodiments, the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms. Where present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of a benzodiazepine drug administered by the intranasal route. In some embodiments, the amount of alkyl glycoside in the composition is selected so as to enhance absorption of the benzodiazepine drug, while at the same time not significantly irritating the nasal mucosa. In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.05% (w/v) to about 0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).
- In some embodiments, the composition is in a pharmaceutically-acceptable spray formulation, and further comprising administering the composition to one or more nasal mucosal membranes of the patient. In some embodiments, the therapeutically effective amount is from about 1 mg to about 20 mg of the benzodiazepine. In some embodiments, the pharmaceutical composition is in a pharmaceutically-acceptable spray formulation having volume from about 10 μL to 200 μL.
- In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- In some embodiments, the administration of the composition begins at any time before or after onset of symptoms of a disorder which may be treatable with the composition.
- As used herein the phrase “therapeutically effective amount” (or more simply “effective amount”) includes an amount sufficient to provide a specific therapeutic response for which the drug is administered to a patient in need of particular treatment. The skilled clinician will recognize that the therapeutically effective amount of drug will depend upon the patient, the indication and the particular drug administered.
- As used herein, the modifier “about” is intended to have its regularly recognized meaning of approximately. In some embodiments, the term may be more precisely interpreted as meaning within a particular percentage of the modified value, e.g. “about” may in some embodiments mean±20%, ±10%, ±5%, ±2%, or ±1% or less.
- As used herein, the phrase “analogs or derivatives” includes molecules that differ from one another molecule due to one or more atoms or functional groups having been replaced with a different atom or functional group. This may result in molecules with similar chemical formulas but different chemical and/or biological properties.
- As used herein, the term, “isomer” includes molecules with identical chemical formulas, but between which the arrangement of the molecules may vary. These varying arrangements may result in molecules with identical chemical formulas but different chemical properties. By way of non-limiting example, propanol has the chemical formula C3H7OH. It may be found as propan-1-ol, wherein the —OH is found attached to an end carbon. Alternatively, it may be found as propan-2-ol, wherein the —OH is found attached to the second carbon.
- As used herein, the term “seizure” includes commonly recognized types of seizures, including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura that will be familiar to the patient or those familiar with the patient. Each patient will generally experience a different type of aura, which is unique to the patient; however auras may be classified as audible, visual, olfactory or tactile sensations that usually, or at least often, precedes a patient's experiencing a seizure. (Not all patients who suffer seizures experience aura; however aura are not uncommon amongst those who suffer the worst type of seizures, especially tonic-clonic seizures.)
- As used herein, the term “prevention” refers to a forestalling, including temporary forestalling, of the onset of a disorder. In the case of seizures, this can occur either with or without the benefit of a warning aura.
- As used herein, the term “treatment” refers to a reduction in the intensity and/or duration of a disorder, or similar effects. The term also encompasses the side-effects of such a “treatment.”
- As used herein, unless otherwise qualified, “a” and “an” can mean one or more.
- As used herein, the term “comprising” in all its variants, is a transitional phrase used in a claim to indicate that the invention includes or contains, but is not limited to, the specifically recited claim elements.
- As used herein, the phrase “consisting essentially of” is a transitional phrase used in a claim to indicate that the a following list of ingredients, parts or process steps must be present in the claimed composition, machine or process, but that the claim is open to unlisted ingredients, parts or process steps that do not materially affect the basic and novel properties of the invention.
- As used herein, the term “consisting of” is a transitional phrase used in a claim to indicate that the claimed invention includes only those elements set forth in the claim.
- In the context of the present invention, the term “benzodiazepine drug” includes any therapeutically effective benzodiazepine compound, or pharmaceutically acceptable salt, or combinations thereof. In some embodiments, benzodiazepine comprises a member of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts and combinations thereof.
- It should be recognized by those of skill in the art that additional benzodiazepine compounds that have heretofore been considered to have marginal or little therapeutic benefit, either because of low bioavailability, poor pharmacokinetic properties or poor pharmacodynamic properties, may find use through the present invention, which can provide for improved bioavailability of benzodiazepine drugs, delivery of higher concentrations of benzodiazepine drugs via the nasal route, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the liver portal vein and concomitant avoidance of first pass effects and/or faster presentation of benzodiazepine drug to the brain.
- For example, most benzodiazepines are so slightly soluble in water that a therapeutically effective amount cannot be dissolved in a volume of aqueous solvent that is amenable to application to a mucosal membrane. By use of the present carrier system, which in some embodiments, provides an improved ability to dissolve benzodiazepine drugs, the present invention allows benzodiazepine drugs to be administered to one or more mucosal membranes, including to nasal mucosal membranes. This can allow one to administer the drug without hospitalization or unnecessary discomfort. Additionally, in some embodiments of the present invention, such as nasal administration, the digestive system largely may be bypassed. This latter improvement can yield improved bioavailability, faster attainment of therapeutic levels of benzodiazepine in the blood plasma, avoidance of the liver portal vein, and/or concomitant avoidance of first pass effects.
- Nasal administration of the composition can result in faster presentation of the one or more benzodiazepine drugs to the brain due to the close proximity of the membranes and the brain. A seizing patient, for example, suffers from rigid muscles and uncontrollable movement. This can make oral and/or intravenous administration difficult or inconvenient. However, the nasal passageways remain open and easily accessible, and therefore is a useful route of administration for of the present invention.
- In some embodiments, the pharmaceutical composition is used to treat a patient suffering from a disorder that is amenable to treatment or prevention with an effective amount of the one or more benzodiazepine drugs. By way of non-limiting example such disorders can include: insomnia, anxiety, seizures, muscle spasms and rigidity, and the symptoms of drug withdrawal.
- In some embodiments, the one or more benzodiazepine drugs, are used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure.
- Alprazolam (8-chloro-6-phenyl-1-methyl-4H-1,2,4-triazolo[4,3-a][1,4]benzodiazepine).
- Alprazolam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic. Alprazolam has also been shown to be useful in the treatment of panic disorder. The dosage of alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- In some embodiments, alprazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, alprazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Alprazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of alprazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of alprazolam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of alprazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with alprazolam to provide an anticonvulsant or synergistic anticonvulsant effect.
- Alprazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the alprazolam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The alprazolam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Diazepam (7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one)
- Diazepam is a benzodiazepine drug having sedative, tranquilizing and muscle relaxing properties. It is classified as an anxiolytic and skeletal muscle relaxant. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnesic properties. The dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085; 3,109,843; 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- In some embodiments, diazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, diazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Diazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of diazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of diazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of diazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with diazepam to provide a synergistic anticonvulsant effect.
- Diazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the diazepam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The diazepam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Flurazepam (7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1-(2-(diethylamino)ethyl)-1H-1,4-benzodiazepin-2-one)
- Flurazepam is a benzodiazepine drug having sedative (especially soporific and hypnotic), anxiolytic, anticonvulsant and muscle relaxing properties. It is classified as an sedative, hypnotic. Flurazepam has been shown to be useful in the treatment of insomnia. The dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- In some embodiments, flurazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, flurazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Flurazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of flurazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of flurazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of flurazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with flurazepam to provide a synergistic anticonvulsant effect.
- Flurazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the flurazepam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The flurazepam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Lorazepam (7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one)
- Lorazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Lorazepam has also been shown to be useful in the treatment of nausea. The dosage of lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- In some embodiments, lorazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, lorazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Lorazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of lorazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of lorazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of lorazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with lorazepam to provide a synergistic anticonvulsant effect.
- Lorazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the lorazepam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The lorazepam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Medazepam ((7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine)
- Medazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Medazepam has also been shown to be useful in the treatment of nausea. The dosage of medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- In some embodiments, medazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, medazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Medazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of medazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of medazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of medazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with medazepam to provide a synergistic anticonvulsant effect.
- Medazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the medazepam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The medazepam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Mexazolam (10-Chloro-11b-(2-chlorophenyl)-1,3,7,11b-tetrahydro-3-methyloxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one)
- Mexazolam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Mexazolam has also been shown to be useful in the treatment of nausea. The dosage of mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- In some embodiments, mexazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, mexazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Mexazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of mexazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of mexazolam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of mexazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with mexazolam to provide a synergistic anticonvulsant effect.
- Mexazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the mexazolam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The mexazolam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a]benzodiazepine).
- Midazolam is a tricyclic benzodiazepine having anxiolytic, amnesic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties. Midazolam is considered soluble in water at a pH lower than about 4, but is relatively insoluble in most aqueous solutions at neutral pH (e.g. about 6 to 8). Thus it is desirable in some embodiments for aqueous nasal preparations of midazolam to have a pH above about 5.5, preferably above about 6.0, or above about 6.5. In some preferred embodiments, the pH is between about 6 and 9, between about 6 and 8. It is considered that preparations of midazolam are particularly suitable for nasal administration as the lipid-soluble (at approximately neutral pH) midazolam is rapidly absorbed across nasal mucosa, leading to efficient uptake of midazolam. It is further considered that midazolam may be formulated in a non-aqueous delivery vehicle, such as is known in the aerosol administration art, such as hydrofluorocarbon propellants, hydrocarbon propellants, etc.
- The dosage of midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- In some embodiments, midazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, midazolam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Midazolam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of midazolam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of midazolam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of midazolam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with midazolam to provide a synergistic anticonvulsant effect.
- Midazolam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the midazolam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The midazolam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Temazepam (7-chloro-1-methyl-5-phenyl-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-one)
- Temazepam is a benzodiazepine drug having sedative, tranquilizing, anticonvulsant, amnesic and muscle relaxing properties. It is classified as an anxiolytic. Temazepam has also been shown to be useful in the treatment of nausea. The dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- In some embodiments, temazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect or combinations of the foregoing effects.
- In some embodiments, temazepam is used alone or in combination with another anticonvulsant drug to treat seizure, protect against seizure, reduce or ameliorate the intensity of seizure, reduce or ameliorate the frequency of seizure, and/or prevent occurrence or re-occurrence of seizure. Temazepam may be administered by the patient or other person (such as a healthcare professional) while the patient is in a non-seizing state to protect against seizure. Even where protection against seizure is not absolute, administration of temazepam may reduce or ameliorate the intensity of seizure and/or reduce or ameliorate the frequency of seizure. In some embodiments, administration of temazepam may prevent occurrence of seizure. In some embodiments, especially where the patient is prone to experiencing serial seizures or status epilepticus, administration of temazepam may aid in interrupting the seizure cycle and may thus prevent the re-occurrence of seizure. In addition to the benzodiazepines (such as diazepam), other anti-convulsant drugs may be combined with temazepam to provide a synergistic anticonvulsant effect.
- Temazepam may also be administered by another person (e.g. an acquaintance or associate, a family member or a health care professional) to the patient while the patient is in a state of seizure. Thus, one of the advantages of the formulations according to the present invention is the ability to administer them in an acute therapeutic environment to treat the seizure victim, for example, nasally. Among the beneficial therapeutic effects that may be imparted by acute dosing of benzodiazepine anticonvulsants, such as nasal dosing, are: reduction in the severity of the seizure (e.g. general relaxation of the muscles, reduction in seizure-induced anxiety experienced by the patient and a general impartation of a feeling of well-being to the patient), reduction in the duration of the seizure, reduction in the probability that the patient will experience a repeat seizure, an increase in the interval between the current seizure and the next seizure. Thus, the temazepam formulations of the invention, and in particular nasal formulations, provide fast onset of therapeutic benefit—in some instances less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The temazepam formulations of the invention, and in particular nasal formulations, also provide convenient administration of a therapeutically beneficial drug to a patient that does not require intravenous drug administration or rectal drug administration.
- Often seizures, particularly severe tonic or tonic-clonic seizures, will be presaged by one or more aura events that will be familiar to the patient or those familiar with the patient. These auras are practically sui generis for each patient, but may be classified as audible, visual, olfactory or tactile sensations that usually, or typically, precedes a patient's experiencing a seizure. In some embodiments of the invention, the method includes prompt administration of a preparation of a benzodiazepine drug according to the invention during the aura. In some embodiments, such intra-aural administration of benzodiazepine drug, for example by nasal administration, will prevent or at least ameliorate the effects (intensity, duration or both) of the impending seizure. Thus, in the context of this invention, prevention of seizure refers to a temporary forestalling of the onset of seizure, either with or without the benefit of a warning aura.
- Benzodiazepines have the generally basic structure of formula I:
- wherein R1-R5 are substituents. In particular embodiments, R1 is an optionally substituted alkyl or forms a ring with R4, R2 is a halogen (e.g. Cl, Br), R3 is optionally substituted aryl (e.g. 2-Chloro or 2-Fluorophenyl), R5 is H or OH, R4 and R4′ together form a carbonyl (C═O) with the carbon to which they are attached or R4 and R1 form an optionally substituted heterocyclic ring with the diazepam ring atoms to which they are respectively attached; R3′ and R6 together form a double bond or may be combined to form an optionally substituted heterocyclic ring along with the diazepam ring atoms to which they are respectively attached. Such basic compounds may form acid addition salts with pharmaceutically acceptable acids, such as pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids.
- Pharmaceutically acceptable mineral acids include HCl, H2SO4, H2SO3, H3PO4, H3PO3, and others that will be recognized by those of skill in the art. Pharmaceutically acceptable organic acids include acetic acid, benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid, malonic acid, etc. Thus, in some embodiments, the pharmaceutically acceptable acid may be selected from the group consisting of: 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acidascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acidfumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (−L), malonic acid, mandelic acid (DL), methanesulfonic acid, benzenesulfonic acid (besylic acid), naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid (−L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p) and undecylenic acid. Other pharmaceutically acceptable acids may be pharmaceutically acceptable acidic (anionic) polymers or pharmaceutically acceptable amphoteric polymers. One skilled in the art will recognize that other basic active pharmaceutical ingredients may be combined with the foregoing acids to produce acid addition salts. Likewise the person skilled in the art will recognize that in some embodiments it may be advantageous that some or all of the added acid be an active pharmaceutical ingredient in its own right.
- In some embodiments, the invention provides nasal compositions comprising one or more acidic pharmaceutically active ingredients. It is considered well within the ordinary skill in the art to determine which of the compounds set for the above are acidic. Such compounds may be prepared as base addition salts, e.g. by the addition of one or more mineral bases (e.g. NaOH, KOH, NaHCO3, Na2CO3, NH3) or organic bases. It is considered within the skill in the art to choose a pharmaceutically acceptable base.
- Known benzodiazepine compounds have anxiolytic, anticonvulsant, sedative and/or skeletal muscle relaxant effect. The term “anticonvulsant” includes treatment of seizures, protection against seizure, reduction or amelioration of the intensity of seizure, reduction or amelioration of the frequency of seizure, and/or prevention of the occurrence or re-occurrence of seizure. In this regard, treatment of seizure includes cessation of an ongoing seizure, reduction in the severity of an ongoing seizure, reduction in the duration of an ongoing seizure. Protection against seizure includes forestalling an oncoming seizure.
- Vitamin E is a class of fat soluble methylated phenols. There are at least eight naturally-occurring compounds that comprise this class: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, all of which may be used in the compositions and methods of the present invention. There are multiple isomers of each of these compounds, all of which may be used in the compositions and methods of the present invention. There are also multiple esters of each of these compounds, including tocophersolan, all of which may be used in the compositions and methods of the present invention. As used herein, Vitamin E refers to any of the natural or synthetic tocopherols, tocotrienols, any isomers thereof, any esters thereof, any analogs or derivatives thereof, or any combinations thereof.
- The compounds that comprise Vitamin E are antioxidants. There is also evidence that they can prevent, delay the onset of, or ameliorate the symptoms of heart disease, cancer, cataracts, macular degeneration, glaucoma, Alzheimer's, and Parkinson's disease.
- The inventors have found that Vitamin E can provide an effective carrier for benzodiazepine drugs. In some embodiments, benzodiazepines are soluble, or partially soluble, in Vitamin E. In some embodiments, Vitamin E may be present as microparticles, nanoparticles, or any combination thereof. Furthermore, use of Vitamin E can have the added benefit of either avoiding irritation of sensitive mucosal membranes and/or soothing irritated mucosal membranes.
- Vitamin E is generally classified as hydrophobic, and when used as a carrier may be limited to formulations as an emulsion. However, emulsions can have several drawbacks. For instance, they may be difficult to create and can be highly unstable. Additionally, they can leave an oily film on the surface of the skin. Thus, to avoid the drawbacks of emulsions, some embodiments of the present invention comprise solutions of one or more benzodiazepine drugs in Vitamin E and one or more lower alkyl alcohols or one or more lower alkyl glycols, or any combinations thereof.
- Lower alkyl alcohols are those with six or fewer carbon atoms. Thus, any of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, or any combinations thereof can be used.
- Lower alkyl glycols are those with six or fewer carbon atoms. Thus, any of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, or any combinations thereof can be used.
- In some embodiments, a composition comprises at least one penetration enhancer in addition to a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol. In some embodiments, the penetration enhancer is at least one alkyl glycoside. In some embodiments, the alkyl glycoside refers to any sugar joined to any hydrophobic alkyl, as described in U.S. Pat. No. 5,661,130, which is incorporated herein by reference in its entirety. The hydrophobic alkyl can be any suitable length, for example about 9 to about 24 carbons in length, especially about 10 to about 14 carbons in length. The hydrophobic alkyl can be branched and/or partially or wholly unsaturated. The alkyl may be joined to the saccharide core for example through a carbonyl group, whereby an ester group may be formed. A suitable alkyl glycoside will have the characteristics of being nontoxic, nonionic, and capable of increasing the absorption of a benzodiazepine drug when it is administered intranasally as described herein. Exemplary saccharides that may be covalently joined to an alkyl according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose and trehalose. Exemplary alkyl glycosides that may be employed include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D-maltoside, -glucoside or sucroside. In some embodiments, the preferred glycosides include maltose, sucrose or glucose linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18 or 20 carbon atoms. Specific excipients that may be employed in a nasal composition according to the invention include alkylsaccharide is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or combinations of two or more thereof. Alkyl glycosides that are particularly considered useful in embodiments of the invention include those marketed under the name Intravail® by Aegis Therapeutics, LLC, San Diego, Calif. Other alkyl glycosides may be selected from those having a hydrophile-lipophile balance (HLB) number of from about 10-20, especially about 1′-15. The HLB number may be determined as set forth in the publication US2009/0047347, published on 19 Feb. 2009, the entirety of which, and especially paragraphs [0075]-[0079], is incorporated herein by reference. Where present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of a benzodiazepine drug administered by the intranasal route. In some embodiments, the amount of alkyl glycoside in the composition is selected so as to enhance absorption of the benzodiazepine drug, while at the same time not significantly irritating the nasal mucosa. In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.01% (w/v) to about 1% (w/v). In some embodiments, the amount of alkyl glycoside in the composition is in a range of about 0.05% (w/v) to about 0.5% (w/v), or about 0.125% (w/v) to about 0.5% (w/v).
- The term “penetration enhancer”, means any material which acts to increase absorption across the mucosa and/or increases bioavailability. In some embodiments, such materials include mucolytic agents, degradative enzyme inhibitors and compounds which increase permeability of the mucosal cell membranes. Whether a given compound is an “enhancer” can be determined by comparing two formulations comprising a non-associated, small polar molecule as the drug, with or without the enhancer, in an in vivo or good model test and determining whether the uptake of the drug is enhanced to a clinically significant degree. The enhancer should not produce any problems in terms of chronic toxicity because in vivo the enhancer should be non-irritant and/or rapidly metabolized to a normal cell constituent that does not have any significant irritant effect.
- In some embodiments, preferred enhancing materials lysophospholipids, for example lysophosphatidylcholine obtainable from egg or soy lecithin. Other lysophosphatidylcholines that have different acyl groups as well as lyso compounds produced from phosphatidylethanolamines and phosphatidic acid which have similar membrane modifying properties may be used. Acyl carnitines (e.g. palmitoyl-dl-camitine-chloride) is an alternative. In some embodiments, a suitable concentration is from 0.02 to 20% w/v.
- In some embodiments, enhancing agents that are appropriate include chelating agents (EGTA, EDTA, alginates), surface active agents (especially non-ionic materials), acyl glycerols, fatty acids and salts, tyloxapol and biological detergents listed in the SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by reference). Also agents that modify the membrane fluidity and permeability are appropriate such as enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates (e.g. diethyleneoxymethylene malonate), salicylates, bile salts and analogues and fusidates. Suitable concentrations are up to 20% w/v.
- Thus, in some embodiments, the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient. In some embodiments, the alkyl glycoside is an Intravail® brand alkyl glycoside. In some embodiments, the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof. In some embodiments, the alkyl glycoside is dodecyl maltoside. In some embodiments, the alkyl glycoside is tetradecyl maltoside. In some embodiments, the alkyl glycoside is sucrose dodecanoate. In some embodiments, the alkyl glycoside is sucrose monostearate. In some embodiments, the alkyl glycoside is sucrose distearate. In some embodiments, the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
- Thus, in some embodiments, the invention provides a pharmaceutical composition for nasal administration comprising: a benzodiazepine drug, which benzodiazepine drug comprises microparticles, nanoparticles or both, one or more natural or synthetic tocopherols or tocotrienols, or any combinations thereof, in an amount from about 30% to about 95% (w/w); one or more alkyl glycosides; and one or more alcohols or glycols, or any combinations thereof, in an amount from about 10% to about 70% (w/w), in a pharmaceutically-acceptable formulation for administration to one or more nasal mucosal membranes of a patient. In some embodiments, the alkyl glycoside is an Intravail® brand alkyl glycoside. In some embodiments, the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or a combination of two or more thereof. In some embodiments, the alkyl glycoside is dodecyl maltoside. In some embodiments, the alkyl glycoside is tetradecyl maltoside. In some embodiments, the alkyl glycoside is sucrose dodecanoate. In some embodiments, the alkyl glycoside is sucrose monostearate. In some embodiments, the alkyl glycoside is sucrose distearate. In some embodiments, the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.
- Mucosal membrane preparations are generally administered in metered sprays having volumes of less than 250 μL, preferably less than 150 μL, and ideally from 25 to 100 μL. Although not prohibited in this invention, administration of volumes larger than about 300 μL per dose usually exceeds the absorption capacity of the membranes. This results in a large portion of the pharmaceutically-active ingredient being lost. The dosage volume of preparations, in particular nasal preparations, preferably ranges from 25 to 100 μL. Volumes in excess of the aforementioned ranges may bypass the sinuses and flow down the back of the throat where the excess is swallowed.
- The dosage of alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- As a nasal formulation, alprazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays
- The dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, diazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, diazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, flurazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, flurazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of Lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- As a nasal formulation, lorazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, lorazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- As a nasal formulation, medazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, medazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- As a nasal formulation, mexazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, mexazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, midazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, midazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- The dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, temazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, temazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays.
- Some embodiments comprise administering to one or more mucosal membranes of a patient a therapeutically effective amount of one or more benzodiazepine drugs, or pharmaceutically-acceptable salts thereof. Some embodiments of the composition disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration up to about 600 mg/mL. Other compositions disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 10 mg/mL up to about 250 mg/mL. Further, some embodiments disclose a composition comprising one or more benzodiazepine drugs or pharmaceutically-acceptable salts thereof in a concentration of about 20 mg/mL up to about 50 mg/mL.
- Some embodiments disclose a carrier system that is about 50% to about 90% (w/w) Vitamin E and about 10% to about 50% (w/w) lower alcohol or lower alkyl glycol, or any combinations thereof. Some embodiments disclose a carrier system that is about 65% to about 75% (w/w) Vitamin E and about 25% to about 35% (w/w) lower alkyl alcohol or lower alkyl glycol, or any combinations thereof. Further, some embodiments disclose a carrier system that is about 70% (w/w) Vitamin E and about 30% (w/w) lower alkyl alcohol or lower alkyl glycol, or any combinations thereof.
- Some embodiments of the invention provide a method of administering the benzodiazepine drug composition to a patient. The preferred embodiment comprises use of diazepam. Some embodiments of the method disclose a dosage level of diazepam of about 1.0 mg to about 20.0 mg until achievement of the desired result. Other dosage levels disclose a dosage level of about 2.0 mg to about 15.0 mg until the desired result is achieved. Some embodiments disclose a dosage level of about 5.0 mg to about 10.0 mg until the desired result is achieved.
- In some embodiments of the method, the dosage volume ranges from about 10 μL to about 200 μL. In some embodiments, the dosage volume ranges from about 20 μL to about 180 μL. Further, some embodiments disclose a dosage volume of about 50 μL to about 140 μL.
- In some embodiments, the composition for nasal administration is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition is made by slowly warming or heating the Vitamin E until it is liquefied. Next, the one or more benzodiazepine drugs are added. The mixture is stirred and heated until the one or more benzodiazepine drugs dissolve or are substantially dissolved. Next, the one or more alcohols or glycols, or any combinations thereof, are added to the composition. This composition is stirred until a less viscous composition is achieved.
- The aforementioned formulations are preferably sterile with a bacteria count of 10 below the allowable level on a per mL basis. Additionally, pathogens are preferably absent.
- In some embodiments, the benzodiazepine drug is formulated as a microparticulate and/or nanoparticulate suspension of the benzodiazepine. Preparation of microparticulate and nanoparticulate benzodiazepine may be accomplished by methods such as milling, etc. Such methods are known to those skilled in the art.
- In some embodiments, the benzodiazepine drug is formulated as a solution. It is considered an aspect of the invention that employment of microparticulate and/or nanoparticulate benzodiazepine drug during the process of preparing the formulation, can improve the overall solubility of the benzodiazepine drug in the solvent system.
- Additionally, some embodiments of the compositions and methods of using the compositions comprise an additional ingredient in the composition selected from active ingredients. By way of non-limiting example, such active ingredients include insulin, calcitonins (for example porcine, human, salmon, chicken, or eel) and synthetic modifications thereof, enkephalins, LHRH and analogues (Nafarelin, Buserelin, Zolidex), GHRH (growth hormone releasing hormone), nifedipin, THF (thymic humoral factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, Pizotizin, nasal vaccines (particularly HIV vaccines, measles, rhinovirus Type 13 and respiratory syncitial virus), pentamidine, CCK (Cholecystikinine), DDVAP, Interferons, growth hormone (solatotropir polypeptides or their derivatives (preferably with a molecular weight from 1000 to 300000), secretin, bradykinin antagonists, GRF (Growth releasing factor), THF, TRH (Thyrotropin releasing hormone), ACTH analogues, IGF (Insulin like growth factors), CGRP (Calcitorin gene related peptide) Atrial Natriuretic peptide, Vasopressin and analogues (DDAVP, Lypressin), Metoclopramide, Migraine treatment (Dihydroergotamine, Ergometrine, Ergotamine, Pizotizin), Nasal Vaccines (Particularly AIDS vaccines) FACTOR VIII, Colony Stimulating factors, G-CSF (granulocyte-colony stimulating factor), EPO (Erythropoitin) PTH (Parathyroid hormone) or pharmaceutically acceptable salts or combinations thereof.
- Additionally, some embodiments of the compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants. By way of non-limiting example, such active ingredients include: paraldehyde; aromatic allylic alcohols (such as stiripentol); barbiturates (e.g. phenobarbitol, primidone, methylphenobarbital, metharbital and barbexaclone); bromides (such as potassium bromide); carbamates (such as felbamate); carboxamides (such as carbamazepine and oxcarbazepine); fatty acids (such as valproic acid, sodium valproate, and divalproex sodium, vigabatrin, progabide, tiagabine); fructose, topiramate, Gaba analogs (e.g. gabapentin and pregabalin); hydantoins (e.g. ethotoin, phenyloin, mephenyloin and fosphenyloin); oxazolidinediones (such as paramethadione, trimethadione, ethadione); propionates (e.g. beclamide), pyrimidinediones (e.g. primidone); pyrrolidines (e.g. brivaracetam, levetiracetam and seletracetam); succinimides (e.g. ethosuximide, phensuximide and mesuximide); sulfonamides (e.g. acetazolamide, sulthiame, methazolamide and zonisamide); triazines (such as lamotrigine); ureas (such as pheneturide, phenacemide); valproylamides (such as valpromide and valnoctamide); as well as other anticonvulsants or pharmaceutically acceptable salts or combinations thereof.
- Additionally, some embodiments of the compositions and methods of using the compositions comprise an additional ingredient in the composition selected from other anticonvulsants. By way of non-limiting example, such active ingredients include: antibiotics and antimicrobial agents such as tetracyline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulphathiazole and nitrofurazone; local anaesthetics such as benzocaine; vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride and tramazoline hydrochloride; cardiotonics such as digitalis and digoxin; vasodilators such as nitroglycerine and papaverine hydrochloride; antiseptics such as chlorhexidine hydrochloride, hexylresorcinol, dequaliniumchloride and ethacridine; enzymes such as lysozyme chloride, dextranase; bone metabolism controlling agents such as vitamin D, active vitamin D and vitamin C; sex hormones; hypotensives; sedatives; anti-tumor agents; steroidal anti-inflammatory agents such as hydrocortisone, prednisone, fluticasone, prednisolone, triamcinolone, triamcinolone acetonide, dexamethasone, betamethasone, beclomethasone, and beclomethasone dipropionate; non-steroidal anti-inflammatory agents such as acetaminophen, aspirin, aminopyrine, phenylbutazone, medanamic acid, ibuprofen, diclofenac sodium, indomethacine, colchicine, and probenocid; enzymatic anti-inflammatory agents such as chymotrypsin and bromelain seratiopeptidase; anti-histaminic agents such as diphenhydramine hydrochloride, chloropheniramine maleate and clemastine; anti-allergic agents and antitussive-expectorant antasthmatic agents such as sodium chromoglycate, codeine phosphate, and isoproterenol hydrochloride or pharmaceutically acceptable salts or combinations thereof.
- Additionally, some embodiments of the compositions and methods of using the compositions comprise an additional inactive ingredient in the composition. By way of non-limiting example, minor amounts of ingredients such as stabilizers, coloring agents, pH adjusters, buffering agents, preservatives such as agents which may prevent degradation, wetting agents, and flavoring agents may also be present. Examples of coloring agents include β-carotene, Red No. 2 and Blue No. 1. Examples of preservatives include stearic acid, ascorbyl stearate and ascorbic acid. Examples of corrigents include menthol and citrus perfume.
- In some embodiments, the drug delivery system of the invention may advantageously comprise an absorption enhancer. The term “enhancer”, means any material which acts to increase absorption across the mucosa and/or increases bioavailability. In some embodiments, such materials include mucolytic agents, degradative enzyme inhibitors and compounds which increase permeability of the mucosal cell membranes. Whether a given compound is an “enhancer” can be determined by comparing two formulations comprising a non-associated, small polar molecule as the drug, with or without the enhancer, in an in vivo or good model test and determining whether the uptake of the drug is enhanced to a clinically significant degree. The enhancer should not produce any problems in terms of chronic toxicity because in vivo the enhancer should be non-irritant and/or rapidly metabolized to a normal cell constituent that does not have any significant irritant effect.
- In some embodiments, preferred enhancing materials lysophospholipids, for example lysophosphatidylcholine obtainable from egg or soy lecithin. Other lysophosphatidylcholines that have different acyl groups as well as lyso compounds produced from phosphatidylethanolamines and phosphatidic acid which have similar membrane modifying properties may be used. Acyl carnitines (e.g. palmitoyl-dl-carnitine-chloride) is an alternative. In some embodiments, a suitable concentration is from 0.02 to 20% w/v.
- In some embodiments, enhancing agents that are appropriate include chelating agents (EGTA, EDTA, alginates), surface active agents (especially non-ionic materials), acyl glycerols, fatty acids and salts, tyloxapol and biological detergents listed in the SIGMA Catalog, 1988, page 316-321 (which is incorporated herein by reference). Also agents that modify the membrane fluidity and permeability are appropriate such as enamines (e.g. phenylalanine enamine of ethylacetoacetate), malonates (e.g. diethyleneoxymethylene malonate), salicylates, bile salts and analogues and fusidates. Suitable concentrations are up to 20% w/v.
- In some embodiments, the invention takes advantage of delivery of a drug incorporated into or onto a bioadhesive microsphere with an added pharmaceutical adjuvant applies to systems that contain active drug and mucolytic agent, peptidase inhibitors or non-drug polypeptide substrate singly or in combination. Suitably mucolytic agents are thiol-containing compounds such as N-acetylcysteine and derivatives thereof. Peptide inhibitors include actinonin, amastatin, bestatin, chloroacetyl-HOLeu-Ala-Gly-NH.sub.2, diprotin A and B, ebelactone A and B, E-64, leupeptin, pepstatin A, phisphoramidon, H-Thr-(tBu)-Phe-Pro-OH, aprotinin, kallikrein, chymostatin, benzamidine, chymotrypsin and trypsin. Suitable concentrations are from 0.01 to 10% w/v. The person skilled in the art will readily be able to determine whether an enhancer should be included.
- In some embodiments, the administration of the composition comprises administering at least a portion of the therapeutically effective amount of the composition onto at least one mucosal membrane. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into at least one nostril. In some embodiments, the administration of the composition comprises spraying at least a portion of the therapeutically effective amount of the composition into each nostril. In some embodiments, the administration of the composition comprises spraying a first quantity of the composition into the first nostril, spraying a second quantity of the composition into a second nostril, and optionally after a pre-selected time delay, spraying a third quantity of the composition into the first nostril. Some embodiments further comprise, optionally after a pre-selected time delay, administering at least a fourth quantity of the composition to the second nostril.
- The dosage of alprazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Alprazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,987,052, which is incorporated herein by reference in its entirety.
- As a nasal formulation, alprazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, alprazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of diazepam may vary by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 20, preferably about 2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Diazepam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 3,371,085, 3,109,843, 3,136,815 or 3,102,116, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, diazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, diazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of flurazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 5 to 40, preferably about 20 to about 35 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Flurazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,567,710 or 3,299,053, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, flurazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, flurazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of Lorazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,296,249, which is incorporated herein by reference in its entirety.
- As a nasal formulation, lorazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, lorazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of medazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Medazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,243,427, which is incorporated herein by reference in its entirety.
- As a nasal formulation, medazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, medazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of mexazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 10, preferably about 0.2 to about 1 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Mexazolam may be manufactured using the process disclosed in U.S. Pat. No. 3,722,371, which is incorporated herein by reference in its entirety.
- As a nasal formulation, mexazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, mexazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of midazolam varies by indication, however it is expected that a therapeutic dose will be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Midazolam may be manufactured using the process disclosed in one of U.S. Pat. Nos. 4,280,957 or 5,831,089, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, midazolam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, midazolam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- The dosage of temazepam varies by indication, however it is expected that a therapeutic dose will be in the range of about 1 to about 50, preferably about 5 to about 30 mg per dose, from 1 to 8, preferably from 2 to 8, and in some preferred embodiments about 4 to about 6 times per day. Temazepam may be manufactured using the process disclosed in U.S. Pat. No. 3,340,253 or 3,374,225, each of which is incorporated herein by reference in its entirety.
- As a nasal formulation, temazepam may be administered in 25 to 250 μL metered sprays. In some preferred embodiments, temazepam is administered in 50 to 150 μL, especially about 100 μL, metered sprays. In some embodiments, a first metered spray is applied to a first nostril and if necessary a second metered spray is applied to a second nostril. In some optional embodiments, a third metered spray is applied to the first nostril. In some embodiments, a fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied to alternating nostrils until the full target therapeutic dose has been administered to the patient. In some embodiments, there is a time increment of from several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applications of benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the blood stream. Multiple applications of metered sprays to each nostril, optionally separated by a time interval, allows administration of a full therapeutic dose in increments small enough to permit full absorption of the benzodiazepine drug into the blood stream and avoid loss of drug down the back of the throat.
- Those skilled in the art will be aware that a systematic, therapeutically effective amount of benzodiazepine drugs for treating the aforementioned disorders will vary with age, size, weight, and general physical condition of the patient as well as the severity of the disease. Frequency of administration will likewise vary with the formulation of the composition and it can be adjusted so that any suitable number of doses per day may be used.
- The invention will now be illustrated with reference to the following illustrative, non-limiting examples.
- A pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device. The composition is used to treat or prevent seizures associated with epilepsy in adults. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 5.0 mg/puff (5.0 mg/0.1 mL and 0.1 mL/puff)) every 5 minutes until cessation of the seizure. However, it can be given as 1 puff per nostril in each nostril (2 puffs at 2.5 mg/puff (5.0 mg/0.1 mL and 0.05 mL/puff)) every 5 minutes until cessation of the seizure. The composition according to this example is set forth in the following table.
-
TABLE 1-1 5.0 mg/0.1 mL Diazepam 70.0 mg α-tocopherol 0.1 mL ethanol (qs ad to 0.1 mL) - A pharmaceutical composition comprising diazepam is prepared. It is formulated as a solution to be delivered via a nasal delivery device. The composition is used to treat or prevent seizures associated with epilepsy in children. Treatment is administered either before or after a seizure has begun. If the patient is seizing, it is administered as 1 puff from any nasal delivery device (1 puff at 2.0 mg/puff (2.0 mg/0.1 mL and 0.1 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes. However, it can be given as 1 puff per nostril in each nostril (2 puffs at 1.0 mg/puff (2.0 mg/0.1 mL and 0.05 mL/puff)). If the seizure fails to stop another dose may be administered after 5 minutes. The composition according to this example is set forth in the following table.
-
TABLE 2-1 2.0 mg/0.1 mL Diazepam 70.0 mg α-tocopherol 0.1 mL ethanol (qs ad to 0.1 mL) - In general, benzodiazepine solutions may be formulated by combining one or more natural or synthetic tocopherols or tocotrienols and one or more lower alcohols or glycols and mixing until a homogeneous mixture is formed, adding the benzodiazepine drug to the homogeneous mixture, heating and mixing the ingredients until the benzodiazepine is fully dissolved in the homogeneous mixture, cooling the mixture, and bringing the mixture to its final mass or volume with lower alcohol or glycol.
- Two different diazepam solutions were formulated by the foregoing process. Vitamin E USP and dehydrated ethanol USP were combined in the amounts set forth in the following table and mixed to form a homogeneous mixture. Diazepam in the amounts set forth in the following table was then added to the homogeneous mixture. The ingredients were heated to 40-45° C. with mixing until the diazepam was fully dissolved, thereby forming a solution. The solution was cooled to 20-25° C., whereupon the solution was brought to its final target weight with dehydrated ethanol USP and the solution was mixed thoroughly to assure homogeneity. The solution was then sampled for in-process testing and packaged in 3 mL amber glass vials.
-
TABLE 3-1 Diazepam Solutions - 70 mg/mL Solution 00 Solution 02 (65% Vitamin E) (80% Vitamin E) Component Concentration (mg/mL) Concentration (mg/mL) Diazepam USP 70.0 70.0 Vitamin E USP 650.0 800.0 Dehydrated q.s. to 1 mL q.s. to 1 mL Ethanol USP - Additional solutions of diazepam at varying concentrations are made in a similar manner, by varying the amount of diazepam and the relative amounts of Vitamin E and ethanol. Other benzodiazepine solutions are made by substituting one or more benzodiazepines for diazepam. Other ingredients, such as alkyl glycoside, can be added at a suitable step in the process (e.g. before or concurrently with the addition of benzodiazepine).
- In general, benzodiazepine suspensions are formulated by micronizing benzodiazepine and combining the benzodiazepine with a carrier. The carrier is prepared by combining one or more lower alcohols or glycols with water, adding a natural or synthetic tocopherol or tocotrienol, heating the mixture until the tocopherol or tocotrienol is dissolved, adding one or more parabens and mixing until the parabens are dissolved and cooling the carrier. Once the benzodiazepine is added to the carrier, additional excipients, such as surfactants, can optionally be added and dissolved in the carrier. The suspension is then brought up to its final mass or volume with water.
- Two different diazepam suspensions were formulated by the foregoing general process. Two different diazepam particle sizes were prepared—A: a small particle size by prepared by high pressure micronization, and B: a large particle size prepared by low pressure micronization. The carrier was prepared by combining propylene glycol USP and purified water USP, then adding Vitamin E Polyethylene Glycols Succinate NF, then mixing and heating the combined ingredients to about 45° C. Mixing was continued until the Vitamin E Polyethylene Glycol Succinate was fully dissolved. The carrier was then cooled to 20-25° C. The micronized diazepam (A and B) was then added to the carrier with vigorous mixing until the diazepam was fully dispersed in the carrier. Polyvinylpyrrolidone Povidone USP/NF was then added to the mixture and mixed until fully dissolved. The suspension was then brought up to weight with purified water USP. The suspension was then mixed until homogeneous, sampled for in-process testing, and packaged in 3 mL amber glass bottles.
-
TABLE 4-1 Diazepam Suspension Formulations Suspension 03 Suspension 01 (200 mg/mL Diazepam) (100 mg/mL Diazepam) Component Concentration (mg/mL) Concentration (mg/mL) Diazepam USP 200.00 100.00 Vitamin E 100.0 100.0 Polyethylene Glycol Succinate NF Methylparaben NF 2.0 2.0 Propylparaben NF 0.5 0.5 Propylene Glycol 100.0 100.0 USP Povidone USP/NF 25.0 25.0 Purified Water q.s. to 1 mL q.s. to 1 mL USP/EP - Additional suspensions of diazepam at varying concentrations are made in a similar manner, by varying the amount of diazepam and optionally other excipients. Other benzodiazepine suspensions are made by substituting one or more benzodiazepines for diazepam. Other ingredients, such as alkyl glycoside, can be added at a suitable step in the process. For example, an alkylglycoside may be added to the carrier during compounding of the carrier, or may be added to the suspension mixture concurrently with or after addition of the povidone.
- Solutions 00 and 02 (Example 3) and Suspensions 01 and 03 (Example 4) were setup on stability at 25° C./60% RH, 30° C./65% RH and 40° C./75% RH. One batch each of four different formulations, packaged in 3-ml vials with screw-top closures, along with corresponding actuators, were set up at three storage conditions. They are listed in Table 1 with their corresponding Particle Sciences initial sample control numbers.
-
TABLE 5-1 Summary of PSI sample control numbers 25° C./60% 30° C./65% 40° C./75% Formulation # RH RH RH Solution 00 - 70 083101.01 083101.02 083101.02 mg/ml solution, 65% Vitamin E Solution 02 - 70 083102.01 083102.02 083102.03 mg/ml solution, 80% vitamin E Suspension 01 - 100 083103.01 083103.02 083103.03 mg/mi suspension Suspension 03 - 200 083104.01 083104.02 083104.03 mg/ml suspension - Samples were tested for spray content uniformity, spray volume, diazepam content, diazepam related substances, and methylparaben and propylparaben assay (suspension samples only). Unit weights were determined as per USP <755>.
- Summaries of the average assay values and all other results are given in Tables 5-4, 5-5, 5-6 and 5-7. The results for the initial, 1-month and 3-month time points are also shown for comparison. Individual spray content uniformity results are given in Tables 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, and 5-15.
- In general, all of the assays and the other results are similar to the initial data, with the exceptions of diazepam related compounds A and B.
- Related compound A did not meet the specification of not more than (NMT) 0.01% for some samples (see Table 2). Related compound A has increased with time and temperature.
-
TABLE 5-2 Summary of related compound A T6M results Solution/ 25° C./60% 30° C./65% 40° C./75% Suspension # RH RH RH Solution 00 Meets 0.058% 0.051% specification Solution 02 Meets Meets Meets specification specification specification Suspension 01 0.038% 0.046% 0.157% Suspension 03 0.019% 0.029% 0.081% - Related compound B is also increasing with time and temperature, and now fails specification of NMT 0.1% at 40° C. condition for both suspension and one solution formulation. Only formulation 2602 meets all impurity specifications.
-
TABLE 5-3 Summary of related compound B T6M results Solution/ 25° C./60% 30° C./65% 40° C./75% Suspension # RH RH RH Solution 00 Meets Meets 0.398% specification specification Solution 02 Meets Meets Meets specification specification specification Suspension 01 Meets Meets 0.289% specification specification Suspension 03 Meets Meets 0.123% specification specification -
TABLE 5-4 Summary of Solution 00 results Solution 00, 1 1 1 3 3 3 6 6 6 70 mg/mI, month month month month month month month month month 65% 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Vitamin E Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH Description Yellow to Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber orange solution solution solution solution solution solution solution solution solution solution solution Identification - Conforms to pass N/A N/A N/A N/A N/A N/A N/A N/A N/A UV reference std. UV and RT Assay 90.0 to 100.1 100.3 93.9 98.8 96.3 96.9 101.2 97.5 94.6 100.6 Diazepam 110.0% (%) Impurities (%)(1) Nordazepam NMT 0.3% 0.005 0.01 0.014 0.019 0.013 0.013 0.013 0.013 0.013 0.013 Related NMT 0.1% ND 0.002 0.007 0.03 0.008 0.016 0.089 0.024 0.098 0.398 Compound B Related NMT 0.01% 0.002 0.002 0.004 0.011 0.002 0.002 0.01 0.005 0.058 0.051 Compound A Unknown NMT 0.1% 0.011 0.012 0.014 0.02 0.037 0.039 0.047 0.035 0.066 0.055 Total NMT 1.0% 0.0 0.0 0.0 0.1 0.1 0.1 0.2 0.1 0.2 0.5 Microbial Meets USP pass N/A N/A N/A N/A N/A N/A pass not not Limits {61} tested tested Fill weight report results 1.108 1.105 1.111 1.112 1.109 1.109 1.113 1.103 1.111 1.109 (g) Fill volume report results 1.192 1.189 1.195 1.196 1.193 1.193 1.198 1.187 1.195 1.193 (ml) Spray report results 133.9 140.7 146.8 140.5 149.1 143.5 139.6 131.4 not 136.4 delivered tested (μl) Average report results 95.0 101.2 100.4 99.4 99.7 94.6 99.4 95.7 not 108.7 Spray tested Content (%) Viscosity report results 0.14 0.086 0.12 0.12 0.096 0.14 0.12 0.12 0.11 0.11 (Pa * s) (1)LOQ is approximately 0.006%, LOD is approximately 0.002%. Results below LOQ are reported in this table for trending purposes. -
TABLE 5-5 Summary of Solution 02 results Solution 02, 1 1 1 3 3 3 6 6 6 70 mg/mI, month month month month month month month month month 65% 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Vitamin E Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH Description Yellow to Amber Amber Amber Amber Amber Amber Amber Amber Amber Amber orange solution solution solution solution solution solution solution solution solution solution solution Identification - Conforms to pass N/A N/A N/A N/A N/A N/A N/A N/A N/A UV reference std. UV and RT Assay 90.0 to 100.5 94.9 96.2 103.3 98.0 97.2 99.6 97.0 94.3 100.3 Diazepam 110.0% (%) Impurities (%)(1) Nordazepam NMT 0.3% 0.003 0.004 0.005 0.006 0.005 0.005 0.006 0.005 0.004 0.005 Related NMT 0.1% ND 0.002 0.003 0.006 0.003 0.005 0.032 0.007 0.020 0.058 Compound B Related NMT 0.01% 0.003 0.002 0.002 0.003 0.002 0.002 0.004 0.003 0.009 0.007 Compound A Unknown NMT 0.1% 0.01 0.012 0.014 0.018 0.019 0.025 0.032 0.014 0.020 0.018 Total NMT 1.0% 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.1 0.1 Microbial Meets USP pass N/A N/A N/A N/A N/A N/A pass not not Limits {61} tested tested Fill weight report results 1.135 1.117 1.128 1.123 1.116 1.133 1.137 1.124 1.133 1.127 (g) Fill volume report results 1.184 1.165 1.177 1.172 1.164 1.182 1.186 1.172 1.183 1.176 (ml) Spray report results 115.0 137.5 137.6 133.1 143.9 136.3 143.8 129.3 not 124.2 delivered tested (μl) Average report results 98.6 97.6 97.7 100.7 98.7 94.7 100.5 95.8 not 97.1 Spray tested Content (%) Viscosity report results 0.69 0.68 0.64 0.68 0.63 0.65 0.64 0.61 0.55 0.56 (Pa * s) (1)LOQ is approximately 0.006%, LOD is approximately 0.002%. Results below LOQ are reported in this table for trending purposes. -
TABLE 5-6 Summary of Suspension 01 results 1 1 1 3 3 3 6 6 6 Suspension month month month month month month month month month 01, 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 100 mg/mI Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH Description Cloudy to White White White White White White White White pale yellow white solution dis- dispersion dispersion dispersion dispersion dispersion dispersion dispersion yellow dispersion persion dispersion Identification - Conforms to Pass N/A N/A N/A N/A N/A N/A N/A N/A N/A UV reference std. UV and RT Assay 90.0 to 102.8 102.6 100.9 104.3 101.3 101.8 103.6 100.7 104.3 99.4 Diazepam 110.0% (%) Impurities (%)(1) Nordazepam NMT 0.3% ND ND ND ND ND ND ND ND ND ND Related NMT 0.1% ND ND ND 0.004 ND 0.004 0.053 0.005 0.013 0.289 Compound B Related NMT 0.01% ND 0.01 0.02 0.034 0.026 0.036 0.08 0.038 0.046 0.157 Compound A Unknown NMT 0.1% 0.008 0.008 0.008 0.008 0.008 0.007 0.007 0.008 0.007 0.018 Total NMT 1.0% 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.1 0.1 0.5 Methylparaben 80.0%-115.% 97.7 100.2 92.1 100.3 101.4 100.6 101.6 106.0 103.2 103.2 (%) Propylparaben 80.0% 100.2 100.5 92.2 99.2 100.6 99 100 98.5 97.6 96.7 (%) 115.0% Microbial Meets USP Pass N/A N/A N/A N/A N/A N/A pass not not Limits {61} tested tested Fill weight report results 1.254 1.252 1.252 1.244 1.246 1.248 1.247 1.245 1.242 1.235 (g) Fill volume report results 1.198 1.196 1.196 1.188 1.191 1.193 1.191 1.190 1.187 1.180 (ml) Spray report results 132.5 131.2 126 123.9 137.6 137.8 136.3 140.0 not 137.6 delivered tested (μl) Average report results 92.2 94.2 91.1 89.9 101.5 100.4 95.3 101.8 not 95.94 Spray tested Content (%) Viscosity report results 0.0098 0.0098 0.0092 0.0090 0.0092 0.0093 0.0089 0.0082 0.0080 0.0092 (Pa * s) (1)LOQ is approximately 0006%, LOD is approximately o.002%. Results below LOQ are reported in this table for trending purposes. -
TABLE 5-7 Summary of Suspension 03 results 1 1 1 3 3 3 6 6 6 Suspension month month month month month month month month month 03, 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ 200 mg/mL Specifications Initial 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH Description Cloudy to White White White White White White White White pale yellow white dis- dispersion dispersion dispersion dispersion dispersion dispersion dispersion yellow dispersion dispersion persion dispersion Identification - Conforms to Pass N/A N/A N/A N/A N/A N/A N/A N/A N/A UV reference std. UV and RT Assay 90.0 to 100.7 101.2 98.9 101.6 102.6 103.6 103.1 100.5 98.9 100.1 Diazepam 110.0% (%) Impurities (%)(1) Nordazepam NMT 0.3% ND ND ND ND ND ND ND ND ND ND Related NMT 0.1% ND ND ND ND 0.002 ND 0.023 0.002 0.008 0.123 Compound B Related NMT 0.01% ND 0.005 0.01 0.017 0.017 0.012 0.039 0.019 0.029 0.081 Compound A Unknown NMT 0.1% 0.008 0.008 0.008 0.008 0.008 0.008 0.008 0.008 0.007 0.008 Total NMT 1.0% 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.2 Methylparaben 80.0%-115.% 93.4 101.1 93.8 99.7 101.5 101.6 101.2 103.5 97.2 102.1 (%) Propylparaben 80.0% 95.6 100.2 94 98.4 100.1 101.3 99.2 97.1 91.9 95.9 (%) 115.0% Microbial Meets USP Pass N/A N/A N/A N/A N/A N/A pass not not Limits {61} tested tested Fill weight report results 1.276 1.28 1.259 1.272 1.279 1.279 1.276 1.280 1.262 1.260 (g) Fill volume report results 1.186 1.19 1.171 1.183 1.19 1.19 1.187 1.190 1.173 1.172 (ml) Spray report results 112.4 137.4 134.3 119.9 138.9 139.3 134.3 149.4 not 138.0 delivered tested (μl) Average report results 82.8 99.3 97.3 86.7 98.6 102.3 96.2 98.2 not 98.7 Spray tested Content (%) Viscosity report results 0.021 0.017 0.017 0.019 0.016 0.016 0.018 0.014 0.013 0.015 (Pa * s) (1)LOQ is approximately 0.006%, LOD is approximately 0.002%. Results below LOQ are reported in this table for trending purposes. -
TABLE 5-8 Solution 00 25° C./60% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.13061 0.13259 9.59355 97.89 2 0.13217 0.13451 9.78206 99.82 3 0.12365 0.13332 8.85797 90.39 4 0.12761 0.13072 9.39720 95.89 5 0.14702 0.15216 8.91438 90.96 6 0.13414 0.13702 9.22442 94.13 7 0.12959 0.13384 9.84590 100.47 8 0.12367 0.14603 8.88093 90.62 9 0.13367 0.13425 9.92610 101.29 Average 0.13135 0.13716 9.380 95.72 St. Dev. 0.0070 0.0071 0.4309 4.3970 % RSD 5.35 5.20 4.59 4.59 -
TABLE 5-9 Solution 00 40° C./75% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.14139 0.15111 10.57237 107.88 2 0.14731 0.15146 11.62831 118.66 3 0.14489 0.14684 10.94206 111.65 4 0.14237 0.14873 11.94883 121.93 5 0.12188 0.13415 9.78103 99.81 6 0.12756 0.13047 9.78347 99.83 7 0.13549 0.13841 10.45221 106.66 8 0.12323 0.12543 9.41177 96.04 9 0.14299 0.14517 11.35701 115.89 Average 0.13635 0.14131 10.653 108.70 St. Dev. 0.0097 0.0095 0.8884 9.0649 % RSD 7.14 6.76 8.34 8.34 -
TABLE 5-10 Solution 02 25° C./60% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.12280 0.12611 8.88043 90.62 2 0.13318 0.13549 9.55581 97.51 3 0.13260 0.13452 9.71837 99.17 4 0.12064 0.12305 9.48123 96.75 5 0.13215 0.13582 9.34463 95.35 6 0.13559 0.13790 9.48722 96.81 7 0.13158 0.13371 9.43613 96.29 8 0.13357 0.13495 9.79164 99.91 9 0.12165 0.12443 8.84732 90.28 Average 0.12931 0.13178 9.394 95.85 St. Dev. 0.0058 0.0056 0.3303 3.3701 % RSD 4.52 4.25 3.52 3.52 -
TABLE 5-11 Solution 02 40° C./75% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.12336 0.12563 9.02005 92.04 2 0.05723 0.05792 9.43076 96.23 3 0.13554 0.13908 9.93829 101.41 4 0.13619 0.13679 9.87755 100.79 5 0.13227 0.13414 9.64403 98.41 6 0.13331 0.13515 9.80808 100.08 7 0.13455 0.13844 9.31952 95.10 8 0.13314 0.13736 9.28106 94.70 9 0.13249 0.13387 9.32935 95.20 Average 0.12423 0.12649 9.517 97.11 St. Dev. 0.0254 0.0260 0.3148 3.2119 % RSD 20.45 20.57 3.31 3.31 -
TABLE 5-12 Suspension 01 25° C./60% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.12873 0.12999 12.85366 91.81 2 0.14011 0.14247 13.68122 97.72 3 0.14515 0.14757 14.09449 100.67 4 0.13205 0.13347 14.18775 101.34 5 0.14554 0.14743 14.48202 103.44 6 0.14473 0.14682 14.39897 102.85 7 0.13229 0.13411 14.87853 106.28 8 0.14357 0.14581 14.82712 105.91 9 0.14741 0.14940 14.86732 106.20 Average 0.13995 0.14190 14.252 101.80 St. Dev. 0.0070 0.0074 0.6602 4.7154 % RSD 5.03 5.18 4.63 4.63 -
TABLE 5-13 Suspension 01 40° C./75% RH spray content uniformity results Weight Weight Diazepam % Diazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.14411 0.14869 13.04770 93.20 2 0.14066 0.14151 13.23277 94.52 3 0.13012 0.13485 13.78126 98.44 4 0.14667 0.14879 13.36970 95.50 5 0.14294 0.14338 12.54309 89.59 6 0.13797 0.14253 13.25396 94.67 7 0.13374 0.13594 13.41984 95.86 8 0.12388 0.12559 14.34944 102.50 9 0.13790 0.14011 13.88564 99.18 Average 0.13755 0.14015 13.431 95.94 St. Dev. 0.0073 0.0073 0.5223 3.7310 % RSD 5.28 5.19 3.89 3.89 -
TABLE 5-14 Suspension 03 25° C./60% RH spray content uniformity results Weight Weight Diazepam % Disazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.13604 0.13897 25.93418 92.62 2 0.14608 0.14792 26.21721 93.63 3 0.15294 0.15425 30.05570 107.34 4 0.14728 0.14910 25.78804 92.10 5 0.15352 0.15493 26.60721 95.03 6 0.15242 0.15401 29.51030 105.39 7 0.15118 0.15254 28.43104 101.54 8 0.15322 0.15556 28.03664 100.13 9 0.15197 0.15393 26.82906 95.82 Average 0.14941 0.15125 27.490 98.18 St. Dev. 0.0057 0.0053 1.5812 5.6472 % RSD 3.79 3.50 5.75 5.75 -
TABLE 5-15 Suspension 03 40° C./75% RH spray content uniformity results Weight Weight Diazepam % Disazepam Sample Collected, g Actuated, g Recovered, mg Recovered 1 0.13574 0.13797 28.14588 100.52 2 0.13639 0.13803 27.04437 96.59 3 0.14082 0.14195 26.78985 95.68 4 0.12962 0.13249 29.07192 103.83 5 0.12518 0.12683 27.39785 97.85 6 0.14423 0.14541 28.50133 101.79 7 0.13922 0.14096 27.34617 97.66 8 0.14146 0.14313 27.17415 97.05 9 0.14902 0.15344 27.20939 97.18 Average 0.13796 0.14002 27.631 98.68 St. Dev. 0.0073 0.0076 0.7642 2.7294 % RSD 5.28 5.43 2.77 2.77 - All of the solutions and suspensions described in Examples 3 and 4 are formulated as described in Examples 3 and 4, with the addition of a suitable amount of an alkyl glycoside, as described herein, such as dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and/or combinations of two or more thereof, or marketed as Intravail by Aegis Therapeutics, San Diego, Calif. The solutions and suspensions with added alkyl glycoside may then be put up on stability as described in Example 5, mutatis mutandis.
- The solutions and suspensions of Examples 3, 4 and 6 are evaluated for pharmacokinetics in a suitable animal model, such as in mice, rats, rabbits or dogs. First each animal (e.g. rabbit) is administered an amount of a benzodiazepine drug intravenously. The amount of intravenously dosed benzodiazepine drug is selected to be less, e.g. roughly half, of what is considered an effective dose administered nasally. For example, the intravenous dose of diazepam administered to rabbits is about 0.05 to about 0.2 mg/kg, e.g. about 0.1 mg/kg. Blood is collected immediately before administration and at specific time points post-administration. Plasma blood levels of the drug are assayed for each of the blood samples. After at least a one day washout period, each animal is administered, intranasally, an amount of a solution or suspension as described in Examples 3, 4 and 6. Blood is collected immediately before administration and at substantially the same specific time points as the IV dose post-administration. Pharmacokinetic curves (blood plasma concentration of drug versus time) are constructed for the intravenous route of administration and for each of the solutions and suspensions administered by the intranasal administration route.
- Toxicity is assessed by known means. In particular, histological samples are collected from the nasal mucosal tissues of the test animals. Other toxological methods are optionally employed as well.
- The solutions and suspensions of Examples 3, 4 and 6 are evaluated for their ability to deliver drug across the blood brain barrier in a suitable animal model, such as in mice, rats, rabbits or dogs. Each animal is administered, intranasally, an amount of a solution or suspension as described in Examples 3, 4 and 6, with the solution or suspension optionally containing an imaging agent, such as a dye, that may be used as a proxy for determining the ability of the drug to cross the blood brain barrier. The drug or imaging agent is detected at selected time points after administration of the suspension or solution to determine how well the drug or imaging agent crosses the blood brain barrier. These results may be compared with analogous result obtained with an intravenous solution containing the drug or imaging agent.
- The above-described solutions and/or suspensions can be evaluated for pharmacokinetics in humans. Normal, healthy human test subjects are administered an amount of the drug intravenously. The amount chosen for intravenous administration may be any amount, but is conveniently a dose that is considered effective in treating seizure in humans. For example, an IV dose of diazepam administered to humans may be in the range of 1 to 15 mg, e.g. about 7.5 mg. Blood is collected immediately before administration and at selected time points after administration. Plasma blood levels of the drug are assayed for each of the blood samples. After at least a one day washout period, each subject is administered, intranasally, an amount of a solution or suspension as described herein. Blood is collected immediately before administration and at substantially the same time points after administration as the intravenous time points. Pharmacokinetic curves (blood plasma concentration of drug versus time) are constructed for the intravenous and intranasal administration routes.
- The above-described solutions and/or suspensions can be evaluated for efficacy in a suitable animal model. Briefly, for each dose of suspension or solution to be tested, a test animal is stimulated with a seizure inducing stimulus. The stimulus may be light, sound, chemical or other stimulus effective to induce seizure in the model animal. Once the animal has begun to seize, a solution or suspension as described herein is administered intranasally to the animal. The efficacy of the dose of the solution and/or suspension is evaluated based upon the animal's response to the test dose. This procedure is repeated through sufficient iterations, and at sufficient numbers of doses, to identify a dose that is considered effective to treat seizure by intranasal administration of the drug.
- While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Claims (47)
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/413,439 US20090258865A1 (en) | 2008-03-28 | 2009-03-27 | Administration of benzodiazepine compositions |
US13/495,942 US8895546B2 (en) | 2009-03-27 | 2012-06-13 | Administration of benzodiazepine compositions |
US14/527,613 US9763876B2 (en) | 2008-03-28 | 2014-10-29 | Administration of benzodiazepine compositions |
US15/470,498 US20170196884A1 (en) | 2008-03-28 | 2017-03-27 | Administration of benzodiazepine compositions |
US15/955,397 US20180235929A1 (en) | 2008-03-28 | 2018-04-17 | Administration of benzodiazepine compositions |
US17/228,514 US11793786B2 (en) | 2008-03-28 | 2021-04-12 | Administration of benzodiazepine compositions |
US17/332,800 US11241414B2 (en) | 2008-03-28 | 2021-05-27 | Administration of benzodiazepine compositions |
US18/062,062 US20230104144A1 (en) | 2008-03-28 | 2022-12-06 | Administration of benzodiazepine compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US4055808P | 2008-03-28 | 2008-03-28 | |
US12/413,439 US20090258865A1 (en) | 2008-03-28 | 2009-03-27 | Administration of benzodiazepine compositions |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/495,942 Continuation-In-Part US8895546B2 (en) | 2008-03-28 | 2012-06-13 | Administration of benzodiazepine compositions |
US15/955,397 Continuation US20180235929A1 (en) | 2008-03-28 | 2018-04-17 | Administration of benzodiazepine compositions |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090258865A1 true US20090258865A1 (en) | 2009-10-15 |
Family
ID=41114811
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/413,439 Abandoned US20090258865A1 (en) | 2008-03-28 | 2009-03-27 | Administration of benzodiazepine compositions |
US15/955,397 Abandoned US20180235929A1 (en) | 2008-03-28 | 2018-04-17 | Administration of benzodiazepine compositions |
US17/228,514 Active 2029-07-06 US11793786B2 (en) | 2008-03-28 | 2021-04-12 | Administration of benzodiazepine compositions |
US17/332,800 Active US11241414B2 (en) | 2008-03-28 | 2021-05-27 | Administration of benzodiazepine compositions |
US18/062,062 Pending US20230104144A1 (en) | 2008-03-28 | 2022-12-06 | Administration of benzodiazepine compositions |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/955,397 Abandoned US20180235929A1 (en) | 2008-03-28 | 2018-04-17 | Administration of benzodiazepine compositions |
US17/228,514 Active 2029-07-06 US11793786B2 (en) | 2008-03-28 | 2021-04-12 | Administration of benzodiazepine compositions |
US17/332,800 Active US11241414B2 (en) | 2008-03-28 | 2021-05-27 | Administration of benzodiazepine compositions |
US18/062,062 Pending US20230104144A1 (en) | 2008-03-28 | 2022-12-06 | Administration of benzodiazepine compositions |
Country Status (8)
Country | Link |
---|---|
US (5) | US20090258865A1 (en) |
EP (1) | EP2271347B1 (en) |
JP (1) | JP5613657B2 (en) |
AU (1) | AU2009228093B2 (en) |
CA (1) | CA2756690C (en) |
DK (1) | DK2271347T3 (en) |
ES (1) | ES2586032T3 (en) |
WO (1) | WO2009121039A2 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20060046969A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Antibacterial compositions for drug administration |
US20080200418A1 (en) * | 2004-08-25 | 2008-08-21 | Aegis Therapeutics, Inc. | Compositions for drug administration |
US20080279784A1 (en) * | 2007-05-07 | 2008-11-13 | Questcor Pharmaceuticals, Inc. | Nasal administration of benzodiazepines |
US20080299079A1 (en) * | 2004-08-25 | 2008-12-04 | Aegis Therapeutics, Llc | Absorption Enhancers for Drug Administration |
US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
US20090130216A1 (en) * | 2007-05-07 | 2009-05-21 | Hale Biopharma Ventures | Multimodal particulate formulations |
US20100160378A1 (en) * | 2008-12-22 | 2010-06-24 | Aegis Therapeutics Llc | Compositions for drug administration |
WO2012054500A3 (en) * | 2010-10-18 | 2012-08-09 | Aegis Therapeutics, Llc | Compositions for drug administration |
WO2013032934A1 (en) * | 2011-08-26 | 2013-03-07 | Aegis Therapeutics, Llc | Compositions and methods thereof for oral administration of drugs |
US8592406B2 (en) | 2008-05-14 | 2013-11-26 | Sk Biopharmaceuticals Co., Ltd. | Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant |
WO2012174158A3 (en) * | 2011-06-14 | 2014-05-01 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine |
US9895444B2 (en) | 2004-08-25 | 2018-02-20 | Aegis Therapeutics, Llc | Compositions for drug administration |
US10046025B2 (en) | 2006-06-23 | 2018-08-14 | Aegis Therapeutics, Llc | Stabilizing alkylglycoside compositions and methods thereof |
US10265402B2 (en) | 2004-08-25 | 2019-04-23 | Aegis Therapeutics, Llc | Absorption enhancers for drug administration |
US10675265B2 (en) | 2012-11-13 | 2020-06-09 | Invictus Biotechnology Pty Ltd | Transmucosal delivery of tocotrienol |
US10682414B2 (en) | 2018-02-06 | 2020-06-16 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
US20210161808A1 (en) * | 2018-07-24 | 2021-06-03 | Zenvision Pharma Llp | Nasal Drug Delivery System of Brivaracetam or Salt Thereof |
US11241414B2 (en) | 2008-03-28 | 2022-02-08 | Neurelis, Inc. | Administration of benzodiazepine compositions |
WO2022261400A1 (en) * | 2021-06-10 | 2022-12-15 | Neurelis, Inc. | Methods and compositions for treating seizure disorders in pediatric patients |
US11554123B2 (en) * | 2017-03-01 | 2023-01-17 | Saint Joseph's University | Compositions and methods for reactivating latent HIV-1 infections |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2481407B (en) * | 2010-06-22 | 2012-05-23 | Special Products Ltd | A rapid onset liquid midazolam composition for buccal administration |
CN110139651A (en) | 2016-11-18 | 2019-08-16 | 欧邦特制药公司 | For treating the excessive composition of opioid and method |
CN111529489A (en) * | 2020-04-17 | 2020-08-14 | 山东省药学科学院 | Nasal spray containing diazepam |
KR20230144019A (en) * | 2021-01-08 | 2023-10-13 | 뉴렐리스 인코포레이티드 | Methods and compositions for rapid delivery of anti-seizure therapeutic agents |
Citations (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3109116A (en) * | 1956-05-16 | 1963-10-29 | Rca Corp | Color-kinescope of the shadow mask variety |
US3136815A (en) * | 1959-12-10 | 1964-06-09 | Hoffmann La Roche | Amino substituted benzophenone oximes and derivatives thereof |
US3243427A (en) * | 1962-06-21 | 1966-03-29 | Hoffmann La Roche | Certain 5-phenyl-1, 2-dihydro (or 1, 2, 4, 5-tetrahydro)-3h-1, 4,-benzodiazepine compounds and their production |
US3296249A (en) * | 1963-06-04 | 1967-01-03 | American Home Prod | 5-monocyclic aryl-1, 3-dihydro-2h-1, 4-benzodiazepin-2-ones |
US3299053A (en) * | 1964-02-11 | 1967-01-17 | Hoffmann La Roche | Novel 1-and/or 4-substituted alkyl 5-aromatic-3h-1, 4-benzodiazepines and benzodiazepine-2-ones |
US3340253A (en) * | 1962-11-28 | 1967-09-05 | Hoffmann La Roche | Preparation of certain benzodiazepine compounds |
US3371085A (en) * | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
US3374225A (en) * | 1963-03-28 | 1968-03-19 | Hoffmann La Roche | Aminobenzodiazepine compounds and methods |
US3567710A (en) * | 1968-06-03 | 1971-03-02 | Hoffmann La Roche | Process for the preparation of 1,3-dihydro-2h-1,4-benzodiazepin-2-ones |
US3609145A (en) * | 1969-01-10 | 1971-09-28 | Upjohn Co | 1h-1,4-benzodiazepine-1-sulfonamides |
US3722371A (en) * | 1970-03-12 | 1973-03-27 | Pneumo Dynamics Corp | High ratio linkage mechanism |
US3987052A (en) * | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
US4280957A (en) * | 1974-09-11 | 1981-07-28 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
US4397951A (en) * | 1981-02-03 | 1983-08-09 | Eisai Co., Ltd. | Elastase-containing composition permitting elastase to be absorbed in increased amount |
US4608278A (en) * | 1983-06-22 | 1986-08-26 | The Ohio State University Research Foundation | Small particule formation and encapsulation |
US4748158A (en) * | 1984-12-10 | 1988-05-31 | Henkel Kommanditgesellschaft Auf Aktien | Alkyl glycosides as potentiating agents in antiseptic, disinfecting and cleaning preparations to increase microbicidal activity |
US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
US4868289A (en) * | 1985-01-14 | 1989-09-19 | Symbicom Aktiebolag | Glycosidic derivatives |
US4921838A (en) * | 1987-06-16 | 1990-05-01 | Trustees Of Boston University | Angiogenic and blood perfusion inducing properties of amphiphilic compounds |
US5091188A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5100591A (en) * | 1989-09-14 | 1992-03-31 | Medgenix Group S.A. | Process for preparing lipid microparticles |
US5118528A (en) * | 1986-12-31 | 1992-06-02 | Centre National De La Recherche Scientifique | Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5182258A (en) * | 1989-03-20 | 1993-01-26 | Orbon Corporation | Systemic delivery of polypeptides through the eye |
US5188837A (en) * | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
US5236707A (en) * | 1991-11-08 | 1993-08-17 | Dallas Biotherapeutics, Inc. | Stabilization of human interferon |
US5308531A (en) * | 1992-08-31 | 1994-05-03 | Henkel Corporation | Pine-oil containing hard surface cleaning composition |
US5317010A (en) * | 1991-10-10 | 1994-05-31 | Peter K. T. Pang | Parathyroid hormone analogues substituted at AA 25, 26, 27, and use in osteoporosis treatment |
US5550220A (en) * | 1987-05-13 | 1996-08-27 | Curtice-Burns, Inc. | Alkyl glycoside fatty acid polyester fat substitute food compositions and process to produce the same |
US5639733A (en) * | 1991-05-16 | 1997-06-17 | Kao Corporation | Alkyl glycoside aqueous solution |
US5661130A (en) * | 1993-06-24 | 1997-08-26 | The Uab Research Foundation | Absorption enhancers for drug administration |
US5662883A (en) * | 1995-01-10 | 1997-09-02 | Nanosystems L.L.C. | Microprecipitation of micro-nanoparticulate pharmaceutical agents |
US5665331A (en) * | 1995-01-10 | 1997-09-09 | Nanosystems L.L.C. | Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers |
US5716642A (en) * | 1995-01-10 | 1998-02-10 | Nano Systems L.L.C. | Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents |
US5738845A (en) * | 1989-03-02 | 1998-04-14 | The Women's Research Institute | Human interferon τ proteins and methods of use |
US5780062A (en) * | 1994-11-09 | 1998-07-14 | The Ohio State University Research Foundation | Small particle formation |
US5789375A (en) * | 1993-10-21 | 1998-08-04 | Hisamitsu Pharmaceutical Co., Inc. | Pernasal composition and pernasal preparation containing the same |
US5795896A (en) * | 1994-12-02 | 1998-08-18 | Astra Aktiebolag | Antithrombotic formulation, process for its manufacturing, and use thereof |
US5814607A (en) * | 1992-09-29 | 1998-09-29 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
US5861510A (en) * | 1995-04-20 | 1999-01-19 | Pfizer Inc | Arylsulfonyl hydroxamic acid derivatives as MMP and TNF inhibitors |
US5863949A (en) * | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
US5955425A (en) * | 1996-08-02 | 1999-09-21 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
US6090925A (en) * | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US6193985B1 (en) * | 1994-05-16 | 2001-02-27 | A/S Dumex (Dumex Ltd) | Tocopherol compositions for delivery of biologically active agents |
US6235224B1 (en) * | 1995-07-21 | 2001-05-22 | Brown University Research Foundation | Process for preparing microparticles through phase inversion phenomena |
US6254854B1 (en) * | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
US6375986B1 (en) * | 2000-09-21 | 2002-04-23 | Elan Pharma International Ltd. | Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate |
US6395300B1 (en) * | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US20020110524A1 (en) * | 2000-12-01 | 2002-08-15 | Cowan Siu Man L. | Method for stabilizing biomolecules in liquid formulations |
US20020127278A1 (en) * | 2000-12-22 | 2002-09-12 | Kipp James E. | Microprecipitation method for preparing submicron suspensions |
US20030017203A1 (en) * | 2001-03-08 | 2003-01-23 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
US20030031719A1 (en) * | 2000-12-22 | 2003-02-13 | Kipp James E. | Method for preparing submicron particle suspensions |
US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US20030040497A1 (en) * | 1997-07-01 | 2003-02-27 | Ching-Leou Teng | Compositions and methods for non-parenteral delivery of oligonucleotides |
US20030087820A1 (en) * | 1999-01-14 | 2003-05-08 | Young Andrew A. | Novel exendin agonist formulations and methods of administration thereof |
US20030100755A1 (en) * | 1995-12-13 | 2003-05-29 | Sham Hing Leung | Retroviral protease inhibiting compounds |
US20030118594A1 (en) * | 1995-06-07 | 2003-06-26 | Bishwajit Nag | Stable formulations of mhc-peptide complexes |
US20030118547A1 (en) * | 2000-01-27 | 2003-06-26 | Vandenberg Grant William | Composition for intestinal delivery |
US20030158206A1 (en) * | 1998-06-22 | 2003-08-21 | Anne Billotte | Intranasal formulations for treating sexual disorders |
US6610271B2 (en) * | 2000-05-10 | 2003-08-26 | University Of Kentucky Research Foundation | System and method for intranasal administration of lorazepam |
US6616914B2 (en) * | 2000-01-10 | 2003-09-09 | Elan Pharmaceuticals, Inc. | Method for pulmonary and oral delivery of pharmaceuticals |
US20030170206A1 (en) * | 1999-08-27 | 2003-09-11 | Maxygen Aps | Interferon beta-like molecules |
US20030181411A1 (en) * | 2002-03-20 | 2003-09-25 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
US6627211B1 (en) * | 1999-07-26 | 2003-09-30 | Sk Corporation | Transnasal anticonvulsive compositions and modulated process |
US20040115135A1 (en) * | 2002-12-17 | 2004-06-17 | Quay Steven C. | Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity |
US20040126358A1 (en) * | 2002-09-16 | 2004-07-01 | Warne Nicholas W. | Delayed release formulations for oral administration of a polypeptide therapeutic agent and methods of using same |
US20040141923A1 (en) * | 1997-10-01 | 2004-07-22 | Dugger Harry A. | Buccal, polar and non-polar spray containing alprazolam |
US20040147473A1 (en) * | 2000-11-10 | 2004-07-29 | Warrell Raymond P. | Methods of treatment of a bcl-2 disorder using bcl-2 antisense oligomers |
US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US20050130260A1 (en) * | 2003-12-15 | 2005-06-16 | Lars Linden | Refolded membrane protein in monodisperse form |
US6908626B2 (en) * | 2001-10-12 | 2005-06-21 | Elan Pharma International Ltd. | Compositions having a combination of immediate release and controlled release characteristics |
US6932962B1 (en) * | 1994-12-22 | 2005-08-23 | Astrazeneca Ab | Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides |
US6991785B2 (en) * | 1999-12-09 | 2006-01-31 | Chiron Corporation | Method for administering a cytokine to the central nervous system and the lymphatic system |
US20060046962A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
US20060046969A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Antibacterial compositions for drug administration |
US20060106227A1 (en) * | 2002-06-13 | 2006-05-18 | Dr Reddy's Laboratories Limited | 3-'2-(Dimethylamino) ethyl!-n-methyl-1h-indole-5-methanesulfonamide and the succinate thereof |
US20060198896A1 (en) * | 2005-02-15 | 2006-09-07 | Elan Pharma International Limited | Aerosol and injectable formulations of nanoparticulate benzodiazepine |
US20070059254A1 (en) * | 2003-08-21 | 2007-03-15 | Transoral Pharmaceuticals, Inc. | Compositions for delivering 5-ht agonists across the oral mucosa and methods of use thereof |
US20070098805A1 (en) * | 1997-03-11 | 2007-05-03 | Elan Pharma International Limited | Methods of making and using novel griseofulvin compositions |
US20080200418A1 (en) * | 2004-08-25 | 2008-08-21 | Aegis Therapeutics, Inc. | Compositions for drug administration |
US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
US20090130216A1 (en) * | 2007-05-07 | 2009-05-21 | Hale Biopharma Ventures | Multimodal particulate formulations |
US20090163447A1 (en) * | 2004-08-25 | 2009-06-25 | Maggio Edward T | Compositions for Drug Administration |
US20100068209A1 (en) * | 2004-08-25 | 2010-03-18 | Aegis Therapeuttics LLC | Antibacterial compositions for drug administration |
US20100203119A1 (en) * | 2003-05-13 | 2010-08-12 | Archimedes Development Limited | Pharmaceutical treatment process using chitosan or derivative thereof |
US20100209485A1 (en) * | 2006-06-23 | 2010-08-19 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
US20110172211A1 (en) * | 2008-05-14 | 2011-07-14 | Myoung-Ki Baek | Transnasal Anticonvulsive Pharmaceutical Composition Comprising Poorly Soluble Anticonvulsant |
US20130065886A1 (en) * | 2009-03-27 | 2013-03-14 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
Family Cites Families (114)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3109843A (en) | 1963-11-05 | Process for preparing | ||
US3102116A (en) | 1963-08-27 | Process for the purification of y-chloeo- | ||
US3547828A (en) | 1968-09-03 | 1970-12-15 | Rohm & Haas | Alkyl oligosaccharides and their mixtures with alkyl glucosides and alkanols |
GB1355998A (en) | 1970-09-30 | 1974-06-12 | Unilever Ltd | Builders for detergent compositions |
US3949072A (en) | 1971-03-11 | 1976-04-06 | Tenta Louis T | Topical composition for treatment of seborrheic keratosis |
US4130709A (en) | 1977-12-08 | 1978-12-19 | Eli Lilly And Company | Pleuromutilin glycoside derivatives |
US4440675A (en) | 1981-08-18 | 1984-04-03 | Meloy Laboratories, Inc. | Human immune interferon |
AU570998B2 (en) | 1983-09-07 | 1988-03-31 | Takeda Chemical Industries Ltd. | Topical steroid compositions for acne |
JPS60208911A (en) | 1984-03-28 | 1985-10-21 | Green Cross Corp:The | Diazepam preparation for rectal infusion |
JPS61267528A (en) | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | Transnasal calcitonin agent containing absorbefacient |
US5192528A (en) | 1985-05-22 | 1993-03-09 | Liposome Technology, Inc. | Corticosteroid inhalation treatment method |
CA1338736C (en) | 1986-12-05 | 1996-11-26 | Roger Baurain | Microcrystals containing an active ingredient with affinity for phospholipids and at least one phospholipid; process for preparing the same |
JPH01151528A (en) | 1987-12-08 | 1989-06-14 | Taiho Yakuhin Kogyo Kk | Transmucous absorbefacient |
WO1990005535A1 (en) | 1988-11-14 | 1990-05-31 | Otsuka Pharmaceutical Co., Ltd. | Interferon preparation for nasal administration |
GB8827305D0 (en) | 1988-11-23 | 1988-12-29 | British Bio Technology | Compounds |
US5122187A (en) | 1989-06-22 | 1992-06-16 | Xerox Corporation | Hot melt ink compositions |
US6482516B1 (en) | 1993-07-20 | 2002-11-19 | Banner Pharmacaps, Inc. | Enrobed tablet |
US5198420A (en) | 1989-10-02 | 1993-03-30 | The General Hospital Corporation | Use of mullerian inhibiting substance and its agonists and antagonists in the treatment of respiratory distress syndrome |
US5369095A (en) | 1990-02-14 | 1994-11-29 | Alcon Laboratories, Inc. | Compositions and method comprising substituted glycosides as mucus membrane permeation enhancers |
DE69129110T2 (en) | 1990-05-10 | 1998-12-10 | Bechgaard Int Res | PHARMACEUTICAL PREPARATION CONTAINING N-GLYCOFUROLE AND N-ETHYLENE GLYCOL |
US5252318A (en) | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
WO1992000310A1 (en) | 1990-06-27 | 1992-01-09 | Dainippon Ink & Chemicals, Inc. | Alkylated oligosaccharide and acetyl derivative thereof |
US5457100A (en) | 1991-12-02 | 1995-10-10 | Daniel; David G. | Method for treatment of recurrent paroxysmal neuropsychiatric |
WO1994005262A1 (en) | 1992-09-10 | 1994-03-17 | F.H. Faulding & Co. Limited | Sustained release matrix composition |
US5455258A (en) | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
US5981719A (en) | 1993-03-09 | 1999-11-09 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
WO1994020116A1 (en) | 1993-03-10 | 1994-09-15 | University Of Alabama Research Foundation | Artificial primers for glycogen synthesis |
US5510264A (en) | 1993-09-28 | 1996-04-23 | Insight Biotech Inc. | Antibodies which bind meningitis related homologous antigenic sequences |
US5556940A (en) | 1994-06-20 | 1996-09-17 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
SE9404468D0 (en) | 1994-12-22 | 1994-12-22 | Astra Ab | Powder formulations |
US5560932A (en) | 1995-01-10 | 1996-10-01 | Nano Systems L.L.C. | Microprecipitation of nanoparticulate pharmaceutical agents |
US6852690B1 (en) | 1995-08-22 | 2005-02-08 | Amylin Pharmaceuticals, Inc. | Method and composition for enhanced parenteral nutrition |
EP0855906B1 (en) | 1995-10-17 | 2008-02-20 | Jagotec AG | Insoluble drug delivery |
PT780386E (en) | 1995-12-20 | 2003-02-28 | Hoffmann La Roche | MATRIX METALOPROTEASE INHIBITORS |
EP0918773A1 (en) | 1996-07-01 | 1999-06-02 | PHARMACIA & UPJOHN COMPANY | Process for the production of 8-chloro-6-(2-fluorophenyl)-1-methyl-4h-imidazo 1,5-a]benzodiazepine |
EP0818442A3 (en) | 1996-07-12 | 1998-12-30 | Pfizer Inc. | Cyclic sulphone derivatives as inhibitors of metalloproteinases and of the production of tumour necrosis factor |
DE69712496T2 (en) | 1996-07-18 | 2002-08-29 | Pfizer | MATRIX METALLOPROTEASE INHIBITORS BASED ON PHOSPHINIC ACIDS |
KR20000068248A (en) | 1996-08-23 | 2000-11-25 | 디. 제이. 우드, 스피겔 알렌 제이 | Arylsulfonylamino Hydroxamic Acid Derivatives |
CA2277100C (en) | 1997-01-06 | 2005-11-22 | Pfizer Inc. | Cyclic sulfone derivatives |
EP0977733B1 (en) | 1997-02-03 | 2003-09-03 | Pfizer Products Inc. | Arylsulfonylamino hydroxamic acid derivatives |
DK1014943T3 (en) | 1997-02-05 | 2002-10-14 | Jago Res Ag | Medical aerosol formulations |
BR9807824A (en) | 1997-02-07 | 2000-03-08 | Pfizer | Derivatives of n-hydroxy-beta-sulfonyl-propionamide and its use as matrix metalloproteinase inhibitors |
ID22809A (en) | 1997-02-11 | 1999-12-09 | Pfizer | ARILSULFONYL HYDROXICAMIC ACID DRIVINGS |
US6245760B1 (en) | 1997-05-28 | 2001-06-12 | Aventis Pharmaceuticals Products, Inc | Quinoline and quinoxaline compounds which inhibit platelet-derived growth factor and/or p56lck tyrosine kinases |
HUP0002960A3 (en) | 1997-08-08 | 2001-12-28 | Pfizer Prod Inc | Aryloxyarylsulfonylamino hydroxamic acid derivatives |
WO1999009997A1 (en) | 1997-08-26 | 1999-03-04 | Board Of Regents, The University Of Texas System | Edta and other chelators with or without antifungal antimicrobial agents for the prevention and treatment of fungal infections |
GB9725782D0 (en) | 1997-12-05 | 1998-02-04 | Pfizer Ltd | Therapeutic agents |
MY120063A (en) | 1997-12-09 | 2005-08-30 | Lilly Co Eli | Stabilized teriparatide solutions |
GB9801690D0 (en) | 1998-01-27 | 1998-03-25 | Pfizer Ltd | Therapeutic agents |
CA2266147A1 (en) | 1998-03-26 | 1999-09-26 | Paul B. Adams | A latent mercaptan as a heat stabilizer |
PA8469401A1 (en) | 1998-04-10 | 2000-05-24 | Pfizer Prod Inc | BICYCLE DERIVATIVES OF HYDROXAMIC ACID |
PA8469501A1 (en) | 1998-04-10 | 2000-09-29 | Pfizer Prod Inc | HYDROXAMIDES OF THE ACID (4-ARILSULFONILAMINO) -TETRAHIDROPIRAN-4-CARBOXILICO |
ITMI981528A1 (en) | 1998-07-03 | 2000-01-03 | Recordati Ind Chimica E Farma | TOPICAL FORMULATIONS OF ACICLOVIR |
WO2000018374A1 (en) | 1998-10-01 | 2000-04-06 | Elan Pharma International, Ltd. | Controlled release nanoparticulate compositions |
US6608073B1 (en) | 1998-10-14 | 2003-08-19 | New Millennium Pharmaceutical Research, Inc. | Intranasal codeine for the rapid suppression of cough and rapid relief of pain |
DK1004578T3 (en) | 1998-11-05 | 2004-06-28 | Pfizer Prod Inc | 5-oxo-pyrrolidine-2-carboxylic acid hydroxamide derivatives |
US6495498B2 (en) | 1999-05-27 | 2002-12-17 | Johnson & Johnson Consumer Companies, Inc. | Detergent compositions with enhanced depositing, conditioning and softness capabilities |
GB9912961D0 (en) | 1999-06-03 | 1999-08-04 | Pfizer Ltd | Metalloprotease inhibitors |
US6316410B1 (en) | 1999-09-22 | 2001-11-13 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
US6458387B1 (en) | 1999-10-18 | 2002-10-01 | Epic Therapeutics, Inc. | Sustained release microspheres |
CN1303674A (en) | 1999-12-02 | 2001-07-18 | 山东省医药工业研究所 | Alprazolam nasal spray |
US7171965B2 (en) | 2000-02-01 | 2007-02-06 | Valois S.A.S. | Breath actuated dry powder inhaler and tape dose strip |
US6316029B1 (en) | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
US6818741B2 (en) | 2000-06-01 | 2004-11-16 | Clf Medical Technology Acceleration Program, Inc. | Alpha-fetoprotein peptides and uses therof |
US6595210B2 (en) | 2000-11-27 | 2003-07-22 | Unisia Jecs Corporation | Inhalator for administering powder composition |
GB0102902D0 (en) | 2001-02-06 | 2001-03-21 | Innovata Biomed Ltd | Medicaments |
US6551578B2 (en) | 2001-02-15 | 2003-04-22 | Aeropharm Technology Incorporated | Modulated release particles for aerosol delivery |
US20040176359A1 (en) | 2001-02-20 | 2004-09-09 | University Of Kentucky Research Foundation | Intranasal Benzodiazepine compositions |
DE60143818D1 (en) | 2001-06-02 | 2011-02-17 | Clf Medical Technology Acceleration Program Inc | ALPHA FETOPROTEIN PEPTIDES AND THEIR USE |
KR100994221B1 (en) | 2001-06-14 | 2010-11-12 | 오츠카 세이야쿠 가부시키가이샤 | Medicinal compositions |
GB0116107D0 (en) | 2001-06-30 | 2001-08-22 | West Pharm Serv Drug Res Ltd | Pharmaceutical composition |
JP4464129B2 (en) | 2001-09-19 | 2010-05-19 | エラン ファーマ インターナショナル,リミティド | Nanoparticulate insulin preparation |
US7220402B1 (en) | 2001-11-20 | 2007-05-22 | Ordway Research Institute, Inc. | Alpha-fetoprotein peptides and uses for imaging |
FR2834212B1 (en) | 2001-12-27 | 2004-07-09 | Besins Int Belgique | USE OF IMMEDIATE RELEASE POWDER IN PHARMACEUTICAL AND NUTRACEUTICAL COMPOSITIONS |
IL165285A0 (en) | 2002-06-07 | 2005-12-18 | Waratah Pharmaceuticals Inc | Compositions and methods for treating diabetes |
US6855332B2 (en) | 2002-07-03 | 2005-02-15 | Lyfjathroun Hf. | Absorption promoting agent |
WO2004093917A2 (en) | 2003-04-22 | 2004-11-04 | Nastech Pharmaceutical Company Inc. | Intranasal administration of triptans |
US20040258663A1 (en) | 2003-05-08 | 2004-12-23 | Nastech Pharmaceutical Company Inc. | Compositions and methods for enhanced mucosal delivery of interferon alpha |
ES2425221T3 (en) | 2003-05-30 | 2013-10-14 | Amylin Pharmaceuticals, Llc | New methods and compositions for enhanced transmucosal delivery of peptides and proteins |
EP1658045A1 (en) | 2003-07-08 | 2006-05-24 | L'oreal | Perfume composition |
EP1686962B9 (en) | 2003-11-05 | 2012-10-03 | Elan Pharma International Limited | Nanoparticulate compositions having a peptide as a surface stabilizer |
US20060074025A1 (en) | 2003-12-26 | 2006-04-06 | Nastech Pharmaceutical Company Inc. | Therapeutic formulations for transmucosal administration that increase glucagon-like peptide-1 bioavailability |
GB0400804D0 (en) | 2004-01-14 | 2004-02-18 | Innoscience Technology Bv | Pharmaceutical compositions |
DE102004017934A1 (en) | 2004-04-14 | 2005-11-03 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New alkyne compounds having MCH antagonist activity and medicaments containing these compounds |
AU2005247369A1 (en) | 2004-05-10 | 2005-12-08 | Mdrna, Inc. | Compositions and methods for enhanced mucosal delivery of parathyroid hormone |
RU2390331C2 (en) * | 2004-06-04 | 2010-05-27 | Камурус Аб | Liquid drug reservoirs |
US20140162965A1 (en) | 2004-08-25 | 2014-06-12 | Aegis Therapeutics, Inc. | Compositions for oral drug administration |
EP1789075A4 (en) | 2004-08-25 | 2009-07-01 | Uab Research Foundation | Absorption enhancers for drug administration |
US20110257096A1 (en) | 2004-08-25 | 2011-10-20 | Aegis Therapeutics, Inc. | Compositions for drug administration |
ES2458991T3 (en) | 2004-11-12 | 2014-05-07 | Novo Nordisk A/S | Stable insulinotropic peptide formulations |
CN101106972A (en) | 2004-11-16 | 2008-01-16 | 伊兰制药国际有限公司 | Injectable nanoparticulate olanzapine formulations |
CA2594710C (en) * | 2005-01-14 | 2011-01-25 | Camurus Ab | Topical bioadhesive formulations |
WO2006091722A2 (en) | 2005-02-23 | 2006-08-31 | Uab Research Foundation | Alkyl-glycoside enhanced vaccination |
TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
WO2007002465A2 (en) | 2005-06-23 | 2007-01-04 | Rapid Pharmaceuticals, Llc | Stabilizing alkylglycoside compositions and methods thereof |
SI1933809T1 (en) * | 2005-10-11 | 2012-08-31 | Yissum Res Dev Co | Compositions for nasal delivery |
US8911751B2 (en) | 2005-10-11 | 2014-12-16 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Compositions for nasal delivery |
EP1951248A4 (en) | 2005-11-14 | 2011-05-25 | Peter D Winch | Novel colored solutions of injectable drugs and their pharmaceutically acceptable salts |
DE102006027795A1 (en) * | 2006-06-16 | 2007-12-20 | Lts Lohmann Therapie-Systeme Ag | Smoking cessation combination wafer |
US7998927B2 (en) | 2006-06-23 | 2011-08-16 | Aegis Therapeutics, Llc | Stabilizing alkylglycoside compositions and methods thereof |
US8084022B2 (en) | 2006-06-23 | 2011-12-27 | Aegis Therapeutics, Llc | Stabilizing alkylglycoside compositions and methods thereof |
US20090326193A1 (en) | 2006-06-23 | 2009-12-31 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
TW200824693A (en) | 2006-08-28 | 2008-06-16 | Jazz Pharmaceuticals Inc | Pharmaceutical compositions of clonazepam and methods of use thereof |
US20080275030A1 (en) | 2007-01-19 | 2008-11-06 | Sveinbjorn Gizurarson | Methods and Compositions for the Delivery of a Therapeutic Agent |
WO2008137960A1 (en) | 2007-05-07 | 2008-11-13 | Questor Pharmaceuticals, Inc. | Nasal administration of benzodiazepines |
US20090004281A1 (en) | 2007-06-26 | 2009-01-01 | Biovail Laboratories International S.R.L. | Multiparticulate osmotic delivery system |
CN101998828A (en) * | 2008-03-28 | 2011-03-30 | 粒子科学有限公司 | Pharmaceutical solutions and method for solubilizing therapeutic agents |
US20090258865A1 (en) | 2008-03-28 | 2009-10-15 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
US8715715B2 (en) | 2008-11-03 | 2014-05-06 | Nal Pharmaceuticals Ltd. | Dosage form for insertion into the mouth |
US8440631B2 (en) | 2008-12-22 | 2013-05-14 | Aegis Therapeutics, Llc | Compositions for drug administration |
US20100203014A1 (en) | 2009-02-04 | 2010-08-12 | Aegis Therapeutics Llc | Zwitterionic buffered acidic peptide and protein formulations |
EP2694076A4 (en) | 2011-04-01 | 2014-08-27 | Cpex Pharmaceuticals Inc | Nasal formulations of benzodiazepine |
EP2747563A4 (en) | 2011-08-26 | 2015-06-24 | Aegis Therapeutics Llc | Compositions and methods thereof for oral administration of drugs |
WO2015095644A1 (en) | 2013-12-20 | 2015-06-25 | AntiOP, Inc. | Intranasal naloxone compositions and methods of making and using same |
-
2009
- 2009-03-27 US US12/413,439 patent/US20090258865A1/en not_active Abandoned
- 2009-03-27 JP JP2011502124A patent/JP5613657B2/en active Active
- 2009-03-27 DK DK09723906.5T patent/DK2271347T3/en active
- 2009-03-27 ES ES09723906.5T patent/ES2586032T3/en active Active
- 2009-03-27 WO PCT/US2009/038696 patent/WO2009121039A2/en active Application Filing
- 2009-03-27 CA CA2756690A patent/CA2756690C/en active Active
- 2009-03-27 EP EP09723906.5A patent/EP2271347B1/en active Active
- 2009-03-27 AU AU2009228093A patent/AU2009228093B2/en active Active
-
2018
- 2018-04-17 US US15/955,397 patent/US20180235929A1/en not_active Abandoned
-
2021
- 2021-04-12 US US17/228,514 patent/US11793786B2/en active Active
- 2021-05-27 US US17/332,800 patent/US11241414B2/en active Active
-
2022
- 2022-12-06 US US18/062,062 patent/US20230104144A1/en active Pending
Patent Citations (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3109116A (en) * | 1956-05-16 | 1963-10-29 | Rca Corp | Color-kinescope of the shadow mask variety |
US3371085A (en) * | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
US3136815A (en) * | 1959-12-10 | 1964-06-09 | Hoffmann La Roche | Amino substituted benzophenone oximes and derivatives thereof |
US3243427A (en) * | 1962-06-21 | 1966-03-29 | Hoffmann La Roche | Certain 5-phenyl-1, 2-dihydro (or 1, 2, 4, 5-tetrahydro)-3h-1, 4,-benzodiazepine compounds and their production |
US3340253A (en) * | 1962-11-28 | 1967-09-05 | Hoffmann La Roche | Preparation of certain benzodiazepine compounds |
US3374225A (en) * | 1963-03-28 | 1968-03-19 | Hoffmann La Roche | Aminobenzodiazepine compounds and methods |
US3296249A (en) * | 1963-06-04 | 1967-01-03 | American Home Prod | 5-monocyclic aryl-1, 3-dihydro-2h-1, 4-benzodiazepin-2-ones |
US3299053A (en) * | 1964-02-11 | 1967-01-17 | Hoffmann La Roche | Novel 1-and/or 4-substituted alkyl 5-aromatic-3h-1, 4-benzodiazepines and benzodiazepine-2-ones |
US3567710A (en) * | 1968-06-03 | 1971-03-02 | Hoffmann La Roche | Process for the preparation of 1,3-dihydro-2h-1,4-benzodiazepin-2-ones |
US3609145A (en) * | 1969-01-10 | 1971-09-28 | Upjohn Co | 1h-1,4-benzodiazepine-1-sulfonamides |
US3987052A (en) * | 1969-03-17 | 1976-10-19 | The Upjohn Company | 6-Phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepines |
US3722371A (en) * | 1970-03-12 | 1973-03-27 | Pneumo Dynamics Corp | High ratio linkage mechanism |
US4280957A (en) * | 1974-09-11 | 1981-07-28 | Hoffmann-La Roche Inc. | Imidazodiazepines and processes therefor |
US4397951A (en) * | 1981-02-03 | 1983-08-09 | Eisai Co., Ltd. | Elastase-containing composition permitting elastase to be absorbed in increased amount |
US4608278A (en) * | 1983-06-22 | 1986-08-26 | The Ohio State University Research Foundation | Small particule formation and encapsulation |
US4826689A (en) * | 1984-05-21 | 1989-05-02 | University Of Rochester | Method for making uniformly sized particles from water-insoluble organic compounds |
US4997454A (en) * | 1984-05-21 | 1991-03-05 | The University Of Rochester | Method for making uniformly-sized particles from insoluble compounds |
US4748158A (en) * | 1984-12-10 | 1988-05-31 | Henkel Kommanditgesellschaft Auf Aktien | Alkyl glycosides as potentiating agents in antiseptic, disinfecting and cleaning preparations to increase microbicidal activity |
US4868289A (en) * | 1985-01-14 | 1989-09-19 | Symbicom Aktiebolag | Glycosidic derivatives |
US5118528A (en) * | 1986-12-31 | 1992-06-02 | Centre National De La Recherche Scientifique | Process for the preparation of dispersible colloidal systems of a substance in the form of nanoparticles |
US5550220A (en) * | 1987-05-13 | 1996-08-27 | Curtice-Burns, Inc. | Alkyl glycoside fatty acid polyester fat substitute food compositions and process to produce the same |
US4921838A (en) * | 1987-06-16 | 1990-05-01 | Trustees Of Boston University | Angiogenic and blood perfusion inducing properties of amphiphilic compounds |
US5738845A (en) * | 1989-03-02 | 1998-04-14 | The Women's Research Institute | Human interferon τ proteins and methods of use |
US5182258A (en) * | 1989-03-20 | 1993-01-26 | Orbon Corporation | Systemic delivery of polypeptides through the eye |
US5100591A (en) * | 1989-09-14 | 1992-03-31 | Medgenix Group S.A. | Process for preparing lipid microparticles |
US5188837A (en) * | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
US5091188A (en) * | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5145684A (en) * | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
US5639733A (en) * | 1991-05-16 | 1997-06-17 | Kao Corporation | Alkyl glycoside aqueous solution |
US5317010A (en) * | 1991-10-10 | 1994-05-31 | Peter K. T. Pang | Parathyroid hormone analogues substituted at AA 25, 26, 27, and use in osteoporosis treatment |
US5236707A (en) * | 1991-11-08 | 1993-08-17 | Dallas Biotherapeutics, Inc. | Stabilization of human interferon |
US5308531A (en) * | 1992-08-31 | 1994-05-03 | Henkel Corporation | Pine-oil containing hard surface cleaning composition |
US5814607A (en) * | 1992-09-29 | 1998-09-29 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
US6268053B1 (en) * | 1993-03-09 | 2001-07-31 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US6090925A (en) * | 1993-03-09 | 2000-07-18 | Epic Therapeutics, Inc. | Macromolecular microparticles and methods of production and use |
US5661130A (en) * | 1993-06-24 | 1997-08-26 | The Uab Research Foundation | Absorption enhancers for drug administration |
US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US5789375A (en) * | 1993-10-21 | 1998-08-04 | Hisamitsu Pharmaceutical Co., Inc. | Pernasal composition and pernasal preparation containing the same |
US6193985B1 (en) * | 1994-05-16 | 2001-02-27 | A/S Dumex (Dumex Ltd) | Tocopherol compositions for delivery of biologically active agents |
US5780062A (en) * | 1994-11-09 | 1998-07-14 | The Ohio State University Research Foundation | Small particle formation |
US5795896A (en) * | 1994-12-02 | 1998-08-18 | Astra Aktiebolag | Antithrombotic formulation, process for its manufacturing, and use thereof |
US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
US6932962B1 (en) * | 1994-12-22 | 2005-08-23 | Astrazeneca Ab | Aerosol drug formulations containing hydrofluoroalkanes and alkyl saccharides |
US5716642A (en) * | 1995-01-10 | 1998-02-10 | Nano Systems L.L.C. | Microprecipitation of nanoparticulate pharmaceutical agents using surface active material derived from similar pharmaceutical agents |
US5665331A (en) * | 1995-01-10 | 1997-09-09 | Nanosystems L.L.C. | Co-microprecipitation of nanoparticulate pharmaceutical agents with crystal growth modifiers |
US5662883A (en) * | 1995-01-10 | 1997-09-02 | Nanosystems L.L.C. | Microprecipitation of micro-nanoparticulate pharmaceutical agents |
US5863949A (en) * | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
US5861510A (en) * | 1995-04-20 | 1999-01-19 | Pfizer Inc | Arylsulfonyl hydroxamic acid derivatives as MMP and TNF inhibitors |
US20030118594A1 (en) * | 1995-06-07 | 2003-06-26 | Bishwajit Nag | Stable formulations of mhc-peptide complexes |
US6235224B1 (en) * | 1995-07-21 | 2001-05-22 | Brown University Research Foundation | Process for preparing microparticles through phase inversion phenomena |
US20030100755A1 (en) * | 1995-12-13 | 2003-05-29 | Sham Hing Leung | Retroviral protease inhibiting compounds |
US6254854B1 (en) * | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
US5955425A (en) * | 1996-08-02 | 1999-09-21 | National Research Council Of Canada | Parathyroid hormone analogues for the treatment of osteoporosis |
US20070098805A1 (en) * | 1997-03-11 | 2007-05-03 | Elan Pharma International Limited | Methods of making and using novel griseofulvin compositions |
US20030040497A1 (en) * | 1997-07-01 | 2003-02-27 | Ching-Leou Teng | Compositions and methods for non-parenteral delivery of oligonucleotides |
US20040141923A1 (en) * | 1997-10-01 | 2004-07-22 | Dugger Harry A. | Buccal, polar and non-polar spray containing alprazolam |
US20030158206A1 (en) * | 1998-06-22 | 2003-08-21 | Anne Billotte | Intranasal formulations for treating sexual disorders |
US20030087820A1 (en) * | 1999-01-14 | 2003-05-08 | Young Andrew A. | Novel exendin agonist formulations and methods of administration thereof |
US6395300B1 (en) * | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6627211B1 (en) * | 1999-07-26 | 2003-09-30 | Sk Corporation | Transnasal anticonvulsive compositions and modulated process |
US20030170206A1 (en) * | 1999-08-27 | 2003-09-11 | Maxygen Aps | Interferon beta-like molecules |
US6428814B1 (en) * | 1999-10-08 | 2002-08-06 | Elan Pharma International Ltd. | Bioadhesive nanoparticulate compositions having cationic surface stabilizers |
US6991785B2 (en) * | 1999-12-09 | 2006-01-31 | Chiron Corporation | Method for administering a cytokine to the central nervous system and the lymphatic system |
US6616914B2 (en) * | 2000-01-10 | 2003-09-09 | Elan Pharmaceuticals, Inc. | Method for pulmonary and oral delivery of pharmaceuticals |
US20030118547A1 (en) * | 2000-01-27 | 2003-06-26 | Vandenberg Grant William | Composition for intestinal delivery |
US20060147386A1 (en) * | 2000-05-10 | 2006-07-06 | Wermeling Daniel P | System and method for intranasal administration of lorazepam |
US6610271B2 (en) * | 2000-05-10 | 2003-08-26 | University Of Kentucky Research Foundation | System and method for intranasal administration of lorazepam |
US6375986B1 (en) * | 2000-09-21 | 2002-04-23 | Elan Pharma International Ltd. | Solid dose nanoparticulate compositions comprising a synergistic combination of a polymeric surface stabilizer and dioctyl sodium sulfosuccinate |
US20040147473A1 (en) * | 2000-11-10 | 2004-07-29 | Warrell Raymond P. | Methods of treatment of a bcl-2 disorder using bcl-2 antisense oligomers |
US20020110524A1 (en) * | 2000-12-01 | 2002-08-15 | Cowan Siu Man L. | Method for stabilizing biomolecules in liquid formulations |
US7037528B2 (en) * | 2000-12-22 | 2006-05-02 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
US6607784B2 (en) * | 2000-12-22 | 2003-08-19 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
US6884436B2 (en) * | 2000-12-22 | 2005-04-26 | Baxter International Inc. | Method for preparing submicron particle suspensions |
US6869617B2 (en) * | 2000-12-22 | 2005-03-22 | Baxter International Inc. | Microprecipitation method for preparing submicron suspensions |
US20030031719A1 (en) * | 2000-12-22 | 2003-02-13 | Kipp James E. | Method for preparing submicron particle suspensions |
US20020127278A1 (en) * | 2000-12-22 | 2002-09-12 | Kipp James E. | Microprecipitation method for preparing submicron suspensions |
US20030017203A1 (en) * | 2001-03-08 | 2003-01-23 | Unigene Laboratories, Inc. | Oral peptide pharmaceutical dosage form and method of production |
US6908626B2 (en) * | 2001-10-12 | 2005-06-21 | Elan Pharma International Ltd. | Compositions having a combination of immediate release and controlled release characteristics |
US20030181411A1 (en) * | 2002-03-20 | 2003-09-25 | Elan Pharma International Ltd. | Nanoparticulate compositions of mitogen-activated protein (MAP) kinase inhibitors |
US20060106227A1 (en) * | 2002-06-13 | 2006-05-18 | Dr Reddy's Laboratories Limited | 3-'2-(Dimethylamino) ethyl!-n-methyl-1h-indole-5-methanesulfonamide and the succinate thereof |
US20040126358A1 (en) * | 2002-09-16 | 2004-07-01 | Warne Nicholas W. | Delayed release formulations for oral administration of a polypeptide therapeutic agent and methods of using same |
US20040115135A1 (en) * | 2002-12-17 | 2004-06-17 | Quay Steven C. | Compositions and methods for enhanced mucosal delivery of peptide YY and methods for treating and preventing obesity |
US20100203119A1 (en) * | 2003-05-13 | 2010-08-12 | Archimedes Development Limited | Pharmaceutical treatment process using chitosan or derivative thereof |
US20070059254A1 (en) * | 2003-08-21 | 2007-03-15 | Transoral Pharmaceuticals, Inc. | Compositions for delivering 5-ht agonists across the oral mucosa and methods of use thereof |
US20050130260A1 (en) * | 2003-12-15 | 2005-06-16 | Lars Linden | Refolded membrane protein in monodisperse form |
US20060046962A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
US20060045869A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Absorption enhancers for drug administration |
US20060046969A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Antibacterial compositions for drug administration |
US20080200418A1 (en) * | 2004-08-25 | 2008-08-21 | Aegis Therapeutics, Inc. | Compositions for drug administration |
US20120196941A1 (en) * | 2004-08-25 | 2012-08-02 | Maggio Edward T | Absorption enhancers for drug administration |
US20090163447A1 (en) * | 2004-08-25 | 2009-06-25 | Maggio Edward T | Compositions for Drug Administration |
US20100068209A1 (en) * | 2004-08-25 | 2010-03-18 | Aegis Therapeuttics LLC | Antibacterial compositions for drug administration |
US20060198896A1 (en) * | 2005-02-15 | 2006-09-07 | Elan Pharma International Limited | Aerosol and injectable formulations of nanoparticulate benzodiazepine |
US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
US20100209485A1 (en) * | 2006-06-23 | 2010-08-19 | Aegis Therapeutics Llc | Stabilizing alkylglycoside compositions and methods thereof |
US20090130216A1 (en) * | 2007-05-07 | 2009-05-21 | Hale Biopharma Ventures | Multimodal particulate formulations |
US8530463B2 (en) * | 2007-05-07 | 2013-09-10 | Hale Biopharma Ventures Llc | Multimodal particulate formulations |
US20110172211A1 (en) * | 2008-05-14 | 2011-07-14 | Myoung-Ki Baek | Transnasal Anticonvulsive Pharmaceutical Composition Comprising Poorly Soluble Anticonvulsant |
US20130065886A1 (en) * | 2009-03-27 | 2013-03-14 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
Cited By (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8642564B2 (en) | 2004-08-25 | 2014-02-04 | Aegis Therapeutics, Llc | Compositions for drug administration |
US9642913B2 (en) | 2004-08-25 | 2017-05-09 | Aegis Therapeutics, Llc. | Pharmaceutical composition including alkyl glycoside and an anti-seizure agent |
US10576156B2 (en) | 2004-08-25 | 2020-03-03 | Aegis Therapeutics, Llc | Compositions for drug administration |
US20080299079A1 (en) * | 2004-08-25 | 2008-12-04 | Aegis Therapeutics, Llc | Absorption Enhancers for Drug Administration |
US10265402B2 (en) | 2004-08-25 | 2019-04-23 | Aegis Therapeutics, Llc | Absorption enhancers for drug administration |
US20080200418A1 (en) * | 2004-08-25 | 2008-08-21 | Aegis Therapeutics, Inc. | Compositions for drug administration |
US10512694B2 (en) | 2004-08-25 | 2019-12-24 | Aegis Therapeutics, Llc | Compositions for oral drug administration |
US9895444B2 (en) | 2004-08-25 | 2018-02-20 | Aegis Therapeutics, Llc | Compositions for drug administration |
US8927497B2 (en) | 2004-08-25 | 2015-01-06 | Aegis Therapeutics, Llc. | Absorption enhancers for intranasal administration |
US11173209B2 (en) | 2004-08-25 | 2021-11-16 | Aegis Therapeutics, Llc | Compositions for drug administration |
US8551468B2 (en) | 2004-08-25 | 2013-10-08 | Aegis Therapeutics Llc | Absorption enhancers for intranasal interferon administration |
US20060046969A1 (en) * | 2004-08-25 | 2006-03-02 | Aegis Therapeutics Llc | Antibacterial compositions for drug administration |
US20090047347A1 (en) * | 2005-07-29 | 2009-02-19 | Aegis Therapeutics, Inc. | Compositions for Drug Administration |
US10046025B2 (en) | 2006-06-23 | 2018-08-14 | Aegis Therapeutics, Llc | Stabilizing alkylglycoside compositions and methods thereof |
US20090130216A1 (en) * | 2007-05-07 | 2009-05-21 | Hale Biopharma Ventures | Multimodal particulate formulations |
US8530463B2 (en) | 2007-05-07 | 2013-09-10 | Hale Biopharma Ventures Llc | Multimodal particulate formulations |
US20080279784A1 (en) * | 2007-05-07 | 2008-11-13 | Questcor Pharmaceuticals, Inc. | Nasal administration of benzodiazepines |
US11241414B2 (en) | 2008-03-28 | 2022-02-08 | Neurelis, Inc. | Administration of benzodiazepine compositions |
US9763876B2 (en) | 2008-03-28 | 2017-09-19 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
US11793786B2 (en) | 2008-03-28 | 2023-10-24 | Neurelis, Inc. | Administration of benzodiazepine compositions |
US8592406B2 (en) | 2008-05-14 | 2013-11-26 | Sk Biopharmaceuticals Co., Ltd. | Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant |
US9962392B2 (en) | 2008-05-14 | 2018-05-08 | Sk Biopharmaceuticals Co., Ltd. | Transnasal anticonvulsive pharmaceutical composition comprising poorly soluble anticonvulsant |
US9283280B2 (en) | 2008-12-22 | 2016-03-15 | Aegis Therapeutics, Llc | Compositions for drug administration |
US8440631B2 (en) | 2008-12-22 | 2013-05-14 | Aegis Therapeutics, Llc | Compositions for drug administration |
US20100160378A1 (en) * | 2008-12-22 | 2010-06-24 | Aegis Therapeutics Llc | Compositions for drug administration |
US8895546B2 (en) | 2009-03-27 | 2014-11-25 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine compositions |
CN103189068A (en) * | 2010-10-18 | 2013-07-03 | 爱奇司治疗公司 | Compositions for drug administration |
WO2012054500A3 (en) * | 2010-10-18 | 2012-08-09 | Aegis Therapeutics, Llc | Compositions for drug administration |
WO2012174158A3 (en) * | 2011-06-14 | 2014-05-01 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine |
EP3415139A1 (en) * | 2011-06-14 | 2018-12-19 | Hale Biopharma Ventures, Llc | Administration of benzodiazepine |
CN107737100A (en) * | 2011-06-14 | 2018-02-27 | 哈尔生物药投资有限责任公司 | The administration of Benzodiazepine composition |
EP4085899A1 (en) * | 2011-06-14 | 2022-11-09 | Neurelis, Inc. | Administration of benzodiazepine |
CN103796656A (en) * | 2011-06-14 | 2014-05-14 | 哈尔生物药投资有限责任公司 | Administration of benzodiazepine |
US20130224300A1 (en) * | 2011-08-26 | 2013-08-29 | Edward T. Maggio | Compositions and methods thereof for oral administration of drugs |
WO2013032934A1 (en) * | 2011-08-26 | 2013-03-07 | Aegis Therapeutics, Llc | Compositions and methods thereof for oral administration of drugs |
US11331302B2 (en) | 2012-11-13 | 2022-05-17 | Invictus Biotechnology Pty Ltd. | Transmucosal delivery of tocotrienol |
US10675265B2 (en) | 2012-11-13 | 2020-06-09 | Invictus Biotechnology Pty Ltd | Transmucosal delivery of tocotrienol |
US11554123B2 (en) * | 2017-03-01 | 2023-01-17 | Saint Joseph's University | Compositions and methods for reactivating latent HIV-1 infections |
US10682414B2 (en) | 2018-02-06 | 2020-06-16 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
US20210161808A1 (en) * | 2018-07-24 | 2021-06-03 | Zenvision Pharma Llp | Nasal Drug Delivery System of Brivaracetam or Salt Thereof |
US11191838B2 (en) | 2018-12-21 | 2021-12-07 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
US11717571B2 (en) | 2018-12-21 | 2023-08-08 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
US11744895B2 (en) | 2018-12-21 | 2023-09-05 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
US11918655B2 (en) | 2018-12-21 | 2024-03-05 | Aegis Therapeutics, Llc | Intranasal epinephrine formulations and methods for the treatment of disease |
WO2022261400A1 (en) * | 2021-06-10 | 2022-12-15 | Neurelis, Inc. | Methods and compositions for treating seizure disorders in pediatric patients |
Also Published As
Publication number | Publication date |
---|---|
JP5613657B2 (en) | 2014-10-29 |
EP2271347B1 (en) | 2016-05-11 |
AU2009228093B2 (en) | 2014-08-07 |
ES2586032T3 (en) | 2016-10-11 |
JP2011516425A (en) | 2011-05-26 |
US20230104144A1 (en) | 2023-04-06 |
US20180235929A1 (en) | 2018-08-23 |
US20220062227A1 (en) | 2022-03-03 |
WO2009121039A2 (en) | 2009-10-01 |
US11241414B2 (en) | 2022-02-08 |
EP2271347A2 (en) | 2011-01-12 |
WO2009121039A3 (en) | 2009-11-19 |
DK2271347T3 (en) | 2016-08-15 |
AU2009228093A1 (en) | 2009-10-01 |
EP2271347A4 (en) | 2013-07-03 |
CA2756690A1 (en) | 2009-10-01 |
CA2756690C (en) | 2016-08-16 |
US11793786B2 (en) | 2023-10-24 |
US20210299089A1 (en) | 2021-09-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11241414B2 (en) | Administration of benzodiazepine compositions | |
US20220241187A1 (en) | Administration of benzodiazepine compositions | |
PL219338B1 (en) | Controlled release delivery system for nasal applications | |
CA2723470A1 (en) | Nasal administration of benzodiazepines | |
SA519402324B1 (en) | INTRANASAL Composition Comprising Betahistine | |
US20100256091A1 (en) | Pharmaceutical powder compositions | |
US20130116244A1 (en) | Pharmaceutical powder compositions | |
EP2030610A1 (en) | Non-aqueous pharmaceutical compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: HALE BIOPHARMA VENTURES, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:CARTT, STEVE;MEDEIROS, DAVID;GWOZDZ, GARY THOMAS;AND OTHERS;REEL/FRAME:022897/0583;SIGNING DATES FROM 20090604 TO 20090623 |
|
AS | Assignment |
Owner name: HALE BIOPHARMA VENTURES, LLC, CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MAGGIO, EDWARD T.;REEL/FRAME:027957/0603 Effective date: 20120316 |
|
AS | Assignment |
Owner name: HALE BIOPHARMA VENTURES, LLC, CALIFORNIA Free format text: CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE NAME PREVIOUSLY RECORDED AT REEL: 022897 FRAME: 0583. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT;ASSIGNORS:CARTT, STEVE;MEDEIROS, DAVID;GWOZDZ, GARY THOMAS;AND OTHERS;SIGNING DATES FROM 20090604 TO 20090623;REEL/FRAME:042775/0799 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: NEURELIS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:HALE BIOPHARMA VENTURES LLC;REEL/FRAME:048211/0840 Effective date: 20181219 |