WO2007054378A1 - Anti-misuse microparticulate oral pharmaceutical form - Google Patents
Anti-misuse microparticulate oral pharmaceutical form Download PDFInfo
- Publication number
- WO2007054378A1 WO2007054378A1 PCT/EP2006/062627 EP2006062627W WO2007054378A1 WO 2007054378 A1 WO2007054378 A1 WO 2007054378A1 EP 2006062627 W EP2006062627 W EP 2006062627W WO 2007054378 A1 WO2007054378 A1 WO 2007054378A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- microparticles
- pharmaceutical form
- form according
- coated
- sequestering agent
- Prior art date
Links
Classifications
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- 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
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/785—Polymers containing nitrogen
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
- A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- 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
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P25/06—Antimigraine agents
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- 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
- A61P25/20—Hypnotics; Sedatives
-
- 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
-
- 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
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
Definitions
- the field of the present invention is that of solid microparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid the misuse of the pharmaceutical or veterinary active ingredient (PA) they contain.
- the active ingredients considered (PA) are pharmaceutical or veterinary PAs, for example those classified in the category of narcotics, analgesics or narcotics. Abuse of these active pharmaceutical ingredients can lead to addictive behaviors.
- PA refers to both a single active ingredient, a mixture of several active ingredients.
- microparticulate pharmaceutical form in the sense of the present invention any form in which the PA is contained in microparticles smaller than 1000 microns.
- These PA-containing particles may be modified release PA coated microparticles.
- the coated microparticles are, for example, coated with a polymer film which controls the rate of release of PA after oral administration.
- the purpose of the present invention is to prevent the diversion of oral solid drugs, for any use other than the use or therapeutic uses officially approved by the competent public health authorities. In other words, it is to avoid the intentional or involuntary misuse of solid oral drugs.
- Obtaining a liquid form from a solid oral drug passes through an aqueous or organic extraction step of the targeted PA.
- This extraction is usually preceded by grinding.
- the modes of administration by inhalation or injection are particularly suitable for drug addicts because they are modes that can accentuate the effects of AP and promote its absorption into the body over short times.
- the powder obtained by grinding is sucked by the nose or dissolved in water and injected, the desired effects, doping or euphoric, of PA, manifest very rapidly and exacerbated.
- PAs analgesic PAs
- morphine and opiate derivatives are especially morphine and opiate derivatives.
- Teenagers prepare for their holidays a cocktail of vodka with oxycodone, which they easily extract with water and alcohol. This process involves grinding the tablet and pouring the powder into a glass of vodka or water and then waiting long enough to fully extract the morphine derivatives, which can then be absorbed.
- US-B-6 696 088 discloses a multiparticulate oral pharmaceutical form, indicated as being resistant to misuse.
- This comprises opioid agonist PA particles in a modified release form and particles comprising an opioid antagonist.
- the form containing the antagonist is described as releasing less than 36% and even more preferably less than 6.2% of the antagonist AP over a period of 36 hours. Both types of particles are interdispersed.
- this invention is based on the use of an active substance other than PA and does not propose among other solution to reduce the impact of grinding or reduce the extraction of PA.
- US-A-2003/0068371 discloses an oral pharmaceutical formulation comprising an opiate PA (oxycodone), an AP antagonist (naloxone) and a gelling agent (e.g., xanthan gum).
- opiate PA oxycodone
- AP antagonist naloxone
- a gelling agent e.g., xanthan gum
- matrix granules of PA comprising lactose, xanthan gum, povidone and an overcoating based on EUDRAGIT RS 30D® / triacetin / antagonist.
- the gelling agent is presented as conferring on the formulation a viscosity such that it can not be administered nasally and parenterally. According to our understanding, this parry is not sufficient since, according to this invention, the use of an antagonist is inter alia mandatory.
- this formulation does not include anti-grinding means, can be put into powder form and, therefore, be misused nasally or orally.
- Patent Application WO-A-2004/054542 discloses a semi-liquid oral pharmaceutical form. It is in the form of a capsule (for example of gelatin) comprising PA in a matrix phase composed of a liquid of high viscosity (sucrose acetate isobutyrate) insoluble in water and a polymer (cellulose acetate butyrate). ) to form a network in the liquid phase.
- the formulation may optionally include a rheology-modifying compound of the pharmaceutical form and a solvent.
- US-A-2003/0224051 discloses an osmotic form with modified release of oxycodone.
- This form consists of a tablet comprising an oxycodone core or one of its salts, a semipermeable membrane at least partially enveloping the heart, an exit orifice provided in the membrane and allowing the release of oxycodone .
- This type of tablet allows easy extraction of the opioid by immersion in water for e.g., at least 12 hours. According to our understanding, this tablet is not a suitable solution to the problem of misuse.
- the patent application EP-AI 293 209 discloses a solid oral anti-misuse oral dosage form, sustained release of an opioid derivative (PA) contained in an ion exchange resin.
- PA opioid derivative
- the PA / resin complex thus obtained makes it possible to limit the plasma concentration obtained after misuse by chewing, inhalation or injection, at a therapeutic concentration which is much lower than that sought by the author of the misuse.
- the PA / resin complex is in matrix form. According to our understanding, no anti-grinding means is provided in the pharmaceutical form according to this prior document. Moreover, this pharmaceutical form does not comprise anti-solvent extraction means of PA. It can not therefore prevent a solvent extraction of the PA, provided that the extraction time is longer than the normal time of PA release. If this oral pharmaceutical form is left in a glass of water for 24 hours, almost all of the AP is extracted.
- an ion exchange resin particles less than 50 ⁇ m in size at a rate of 5 to 15% by weight
- Interlay document WO-A-2005/079760 discloses a pharmaceutical formulation consisting of extruded rubber chewable microparticles provided with sustained release of AP and having anti-misuse properties. These extruded microparticles comprise a matrix formed by a neutral poly (ethyl acrylate, methyl methacrylate: EUDRAGIT® NE 30D or NE 4 OD copolymer which contains PA (oxycodone), another Eudragit® RS PO, a plasticizer and a lubricant.
- a neutral poly ethyl acrylate, methyl methacrylate: EUDRAGIT® NE 30D or NE 4 OD copolymer which contains PA (oxycodone), another Eudragit® RS PO, a plasticizer and a lubricant.
- Another object of the invention is to provide new solid oral drugs, the misuse of which will be made difficult or impossible, especially for the cases (a.) (B.) (C.) Mentioned above, and preferably without the use of substances other than AP, which may be pharmaceutically active and therefore dangerous for the users, or even inhibitory to PA, such as, for example, PA antagonists.
- Another object of the invention is to provide new solid oral drugs, the misuse of which will be made difficult or impossible, especially for the cases (a.) (B.) (C.) Mentioned above, even after a "long" liquid extraction of PA (eg analgesic). As used herein, "long" liquid extraction is extraction for more than 10 minutes.
- Another object of the invention is to provide novel solid oral drugs preventing misuse by short liquid extraction and / or grinding.
- Another object of the invention is to provide novel oral solid drugs, having the following characteristics:
- these oral solid drugs have a therapeutic effect, for example for 12 or 24 hours;
- Another object of the invention is to provide new oral solid drugs:
- Another object of the invention is to provide new oral solid drugs whose in vitro dissolution profile is independent of the dose of PA.
- Another object of the invention is to provide new oral solid drugs, to avoid the fraudulent diversion of the properties of the PA they contain, preventing any transformation of the drug giving access to oral, nasal and / or injectable (intravenous, subcutaneous, intramuscular ...) out of the therapeutic. In doing so the risks associated with these drifts would be prevented or at least greatly reduced.
- Another object of the invention is to provide new solid oral drugs, to prevent misuse, while ensuring for the patient normally followed, a quality of treatment, especially a dose, consistent with his needs.
- Another object of the invention is to provide new solid oral drugs, to prevent misuse, without affecting the pharmacological properties of the drug, and without putting additional risks to the patient normally using the drug and finally without harming the comfort of the latter during the administration.
- Another object of the invention is to provide new solid oral drugs, administered once or several times a day and limiting the risk of tissue degradation due to local over-concentration of AP.
- Another object of the invention is to provide new oral solid drugs, which may be in various dosage forms, such as tablets, powder sachets, capsules and the like.
- Another object of the invention is to provide new oral solid drugs, anti-misuse and whose preparation is easy and economical.
- the inventors had the merit of reformulating the general problem of the misuse of pharmaceutical forms.
- the invention relates primarily to an oral and solid pharmaceutical form, characterized in that it comprises anti-misuse means, in that at least part of the PA that it comprises is contained in coated microparticles, with modified PA release, and in that the coated PA microparticles comprise a coating layer (Ra), which provides the modified release of PA and which simultaneously confers resistance to grinding with PA microparticles coated, to avoid misuse.
- a coating layer
- the pharmaceutical form according to the invention in particular solves the main problem and satisfies at least part of the objectives set, efficiently, simply and economically, using physicochemical means. These are completely harmless to the normal user. These are pharmacologically neutral (inert) compounds approved by the pharmacopoeia and the public health authorities responsible for issuing authorizations for the marketing of medicinal products.
- the oral and solid pharmaceutical form according to the invention comprises, in addition to the anti-grinding coating layer (Ra), at least one agent viscosifier (Vb) making it very difficult or even prevent the extraction of the AP contained in the coated PA microparticles, to avoid the misuse of the PA after a liquid extraction.
- Vb agent viscosifier
- viscosifier refers to both a single viscosifier, a mixture of several viscosifiers.
- At least a part of the AP is in a modified-release form, namely in the form of modified-release coated microparticles of said PA.
- the active ingredients (PA) considered in the present invention are pharmaceutical or veterinary PAs, for example those classified in the category of analgesics or narcotics. Misuse of these APs can lead to addictive behaviors.
- PA designates an active ingredient or a mixture of several active ingredients.
- microparticulate form is meant in the sense of the present invention any pharmaceutical form in which the PA is contained in microparticles smaller than 1000 microns.
- These PA-containing particles may be individually film-coated microparticles leading to the modified release of PA.
- the coated microparticles are, for example, coated with a polymer-based film controlling the release rate of the AP.
- modified release form is meant herein a form in which at least a fraction of the AP is released at a rate below the rate of an immediate release form. This fraction may be, for example between 1 and 100%, preferably between 10 and 100%, and more preferably between 30 and 100%.
- a modified release may be in particular prolonged and / or delayed and / or in the form of one or more release peaks (pulses).
- Modified release formulations are well known in the art; see for example Remington: The Science andpractice ofpharmacy, 1 Coedition, Mack Publishing Co. Pennsylvania, USA.
- immediate release form a form that releases most of the amount of PA it contains in a relatively short time: at least 70% of the AP are released in 1 hour, preferably in thirty minutes, at any pH between 1.4 and 6.8 in an in vitro dissolution test. All in vitro dissolution profiles discussed in this paper are carried out according to the indications of the European Pharmacopoeia 4 th edition entitled: “Dissolution test of solid oral forms”: dissolutest of type II performed under SINK conditions at 37 ° C and stirred at 75 rpm.
- the pharmaceutical formulation according to the invention is therefore a modified-release formulation of PA.
- pharmaceutical formulation must be understood in the broad sense, that is to say that this term also includes veterinary and dietary formulations.
- This pharmaceutical formulation may further comprise one or more immediate release forms of the AP.
- the pharmaceutical formulation according to the invention which is new in its structure, in its presentation and in its composition, can exist for example in the form of a tablet, a powder bag, a powder bag for a multidose suspension to be reconstituted, or capsule.
- the modified-release PA coated microparticles are, advantageously, microparticles each coated with at least one coating (comprising for example at least one polymer) deposited according to the techniques known to those skilled in the art. For example, see the publication New Pharmaceutical Forms: Technological, Biopharmaceutical and Medical Aspects of Buri, Incieux, Doelker and Benoit, published by Lavoisier 1985, pages 175 to 227.
- these coated microparticles are preferably each constituted of a core comprising PA and a coating comprising at least one coating layer that envelops (preferably entirely) the core and regulates the modified release (from continuous preference) of PA.
- This release occurs when PA-coated microparticles are brought into contact with the gastrointestinal tract fluid.
- Uncoated PA microparticles. before coating may be for example: neutral hearts covered with at least one layer containing PA; - or microparticles of pure PA;
- the neutral core or support may be composed of sucrose and / or sucrose and / or dextrose and / or lactose, and / or sucrose / starch mixture.
- the neutral core or support may also be a cellulose microsphere or other pharmaceutically acceptable excipient particle.
- a neutral support mention may be made of particles of xanthan gum, guar gum, calcium phosphate and calcium carbonate. Their average diameter may be between 10 and 200 microns, or between 20 and 150 microns or between 50 and 100 microns.
- coated microparticles of the "reservoir” type can be likened to vehicles allowing the transport and the release of at least one AP, in the small intestine or even in the large intestine.
- coated microparticles with modified PA release include those described in the following patent documents: EP-B-0 709 087 and WO-A-03/030878.
- the microparticles coated with AP comprise at least one coating layer (Ra), better still, a single coating layer (Ra), which provides the modified release of the AP and which simultaneously confers resistance grinding with microparticles coated PA, to avoid misuse.
- the coating layer (Ra) is designed such that it allows, in case of grinding, the maintenance of a non-immediate release ⁇ Le. a modified PA release) for at least a portion of the modified release PA coated microparticles.
- the milling contemplated herein may be, for example, any grinding carried out according to the techniques usually employed by the misusers, namely in particular: mortar / pestle, coffee grinder, between two spoons, crunching / chewing, etc.
- the coating layer (Ra) is designed so that, in case of grinding, it allows the maintenance of a modified release for at least 40%, preferably at least 60%, and more preferably still at least 80% of the coated microparticles with modified release of AP.
- the anti-grinding coating layer (Ra) comprises:
- A4 optionally at least one surfactant and / or lubricant and / or a mineral and / or organic filler (A4).
- (Al) is selected from the group consisting of:
- non-water-soluble derivatives of cellulose preferably ethylcellulose and / or cellulose acetate,
- acrylic polymers for example copolymers of (meth) acrylic acid and of alkyl ester (eg methyl), copolymers of acrylic and methacrylic acid ester carrying at least one quaternary ammonium group (preferably at least one a copolymer of alkyl (meth) acrylate and trimethylammonioethyl methacrylate chloride) and more specifically the products marketed under the trade names EUDRAGIT ® RS and / or RL
- (A2) is selected from the group consisting of:
- the nitrogenous (co) polymers preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams,
- alkylene polyoxides preferably ethylene polyoxides (POE)
- POE ethylene polyoxides
- PEG polyethylene glycols
- (A3) is selected from the group consisting of:
- glycerol and its esters preferably in the following subgroup: acetylated glycerides, glycerolmonostearate, glyceryl triacetate, glycerol tributrate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, citrates, preferably in the following subgroup: acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate,
- the sebacates preferably in the following subgroup: diethylsébaçate, dibutylsébaçate, adipates,
- the iumarates preferably diethylfumarate
- the malates preferably the diethylmalate
- oxalates preferably diethyloxalate
- succinates preferably dibutylsuccinate
- malonates preferably diethyl malonate
- (A4) is selected from the group consisting of:
- anionic surfactants preferably in the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred,
- nonionic surfactants preferably in the following subgroup: polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil,
- polyoxyethylenated castor oil derivatives stearates, preferably calcium, magnesium, aluminum or zinc,
- stearyl fumarates preferably sodium
- colloidal silica titanium oxide, magnesium oxide,
- microcrystalline cellulose - kaolin
- the coating layer (Ra) comprises, in% by weight relative to the total mass of the coating:
- ⁇ A1 ⁇ 90 preferably 15 ⁇ A1 ⁇ 80, and still more preferably 60 ⁇ A1 ⁇ 80;
- ⁇ A2 ⁇ 50 preferably 10 ⁇ A2 ⁇ 40, and more preferably 10 ⁇ A2 ⁇ 25;
- the release speed is regulated for example as follows:
- the coating of the coated microparticles with modified release of AP may comprise, in addition to the essential constituents A1, A2, A3 and possibly A4, other conventional ingredients and known to those skilled in the art, such as, in particular, dyes, pigments, preservatives, flavors ... and their mixtures.
- the coating layer (Ra) represents a mass fraction Tp, expressed in% by dry weight relative to the total mass of the coated microparticles, such that: Tp > 15; preferably between 30 and 60, and even more preferably between 40 and 60, and more preferably between 45 and 55 or about 50.
- this relatively large coating rate allows the coating layer (Ra) to ensure the modified release of the PA and, simultaneously, to confer grinding resistance to the coated PA microparticles, to avoid misuse.
- the microparticles of coated PA which have an average diameter less than or equal to 1000 ⁇ m, preferably between 50 and 800 ⁇ m and, more preferably, between 100 and 600, are preferred in accordance with the invention. ⁇ m, and better still, between 100 and 300 ⁇ m.
- the microparticle diameters referred to herein are, unless otherwise indicated, mean diameters by volume.
- the techniques advantageously used for the deposition of the coating allowing the modified release of the PA or the deposition of the active layer based on the PA are techniques known to the man of the art, such as for example the spray coating technique fluidized air bed, wet granulation, compaction, extrusion-spheronization.
- the modified-release PA coated microparticles comprise an overcoating designed in such a way that the overcoating contributes, during the manufacture of tablets, to the maintenance of a modified release for at least a portion of said coated PA microparticles with modified PA release.
- the overcoating is composed of at least one deformable organic component having a melting temperature of between 40 ° C. and 120 ° C., preferably between 45 ° C. and 100 ° C.
- the overcoating comprises at least 10% by weight of deformable organic constituent.
- the deformable organic constituent included in the overcoating is selected from polyalkylene glycols, polyethylene glycols having a molecular weight of 6000 to 20000 D, being particularly preferred.
- the deformable organic constituent of the overcoating is a fatty substance or mixture of fatty substances, for example selected from the group of fatty substances comprising: hydrogenated vegetable oils, fatty acids, fatty alcohols, acid esters fatty and / or fatty alcohol, polyolefins and mineral, vegetable, animal or synthetic waxes, esters of fatty acids such as di and triglycerides and mixtures thereof, glycerol behenate and hydrogenated oils of castor oil, soy, cotton and palm being particularly preferred.
- the overcoating comprises:
- a mineral filler such as silica or titanium dioxide, for example, or an organic filler such as microcrystalline cellulose, for example, and / or at least one lubricant such as magnesium stearate or sodium benzoate, for example,
- hydrophilic polymer such as the water-soluble derivatives of cellulose, the synthetic polymers preferably polyvinylpyrrolidone, the acrylic and methacrylic polymers, or the polyvinyl alcohols (PVAs),
- the over-coating represents from 5 to 50%, preferably from 10 to 30%, and even more preferably from approximately 20% by dry weight of the total mass of the super-coated PA microparticles.
- Supercoated microparticles means a microparticle of coated PA, also comprising a supercoat as defined above, that is to say an overcoating which contributes, during the production of tablets, to the maintenance of a modified release for at least a portion of said coated PA microparticles with modified PA release.
- Viscosifying agent (Vb) Viscosifying agent (Vb)
- the viscosifying agent (Vb) is chosen from viscosifiers which are soluble in at least one of the following solvents: water, alcohols, ketones and mixtures thereof, this agent (s) being suitable for increase the viscosity of the extraction liquid so as to counter misuse, particularly by injection.
- water any aqueous solvent, such as water stricto sensu or any aqueous solution, for example organic acid (e.g. acetic acid), saline solutions, sodas or beverages.
- organic acid e.g. acetic acid
- saline solutions e.g. saline solutions
- sodas or beverages e.g. saline solutions
- alcohols e.g. acetic acid
- ketones e.g. ketones
- the viscosifier (Vb) is selected from the following groups of polymers:
- polyacrylic acids and their derivatives and / or polyalkylene glycols (e.g. polyethylene glycol), and / or
- alkylene polyoxides e.g. ethylene
- alkylene polyoxides e.g. ethylene
- polysaccharides preferably in the subgroup comprising: sodium alginate, pectins, guars, xanthans, carrageenans, gellanes and cellulose derivatives (eg hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose ) - and their mixtures.
- the viscosifying agent Vb is a polyoxyethylene having a high molecular weight, for example having a molecular weight of 1 million g / mol to 8 million g / mol, for example 2 million or 5 million, or 7 million g / mole.
- the viscosifying agent Vb for example high molecular weight polyoxethylene, is included in microparticles, distinct from the microparticles of PA.
- the microparticles of PA and the microparticles of viscosifying agent Vb have a near size distribution, a close density and are not separable by sieving.
- the viscosifying agent (Vb) is capable of increasing the viscosity of the liquid used for the possible extraction, so as to trap the extracted PA in the viscous medium.
- This viscosifying agent (Vb) makes it possible to increase the viscosity of the extraction liquid, for example above 100 mPa.s, preferably 200 mPa.s, and more preferably still above 500 mPa.s, and better still another 1000 mPa.s.
- viscosifiers (Vb) that are effective both in the case of an extraction in an aqueous phase or in an organic solvent.
- these viscosifiers (Vb) are mixtures of hydrophilic compounds and hydrophobic compounds, so as to ensure a high viscosity (greater than 100 mPa.s for example) of the extraction liquid, whether aqueous or organic.
- Vb As regards the amount of viscosifying agent (Vb), it is readily determinable by those skilled in the art. This amount corresponds to the minimum amount necessary to make the viscosity of 2.5 mL of extraction liquid to a value greater than or equal to 100 mPa.s.
- At least one viscosifying agent (Vb) is present:
- the viscosifying agent is at least partly in the form of non-separable microparticles of coated or uncoated PA microparticles.
- the pharmaceutical form may optionally comprise one or more pharmaceutically acceptable excipients, in the free state, that is to say not contained in, or supported by microparticles of PA, said excipient contributing to the resistance of the microparticles of PA coated on grinding.
- these excipients contributing to the resistance to grinding of the coated PA microparticles are chosen from the group comprising: calcium stearate;
- polyalkylene e.g. ethylene glycols
- colloidal silica zinc stearate, magnesium
- the viscosifying agent is at least partly in the free state, that is to say not contained in, or supported by coated or uncoated microparticles of PA ( alternative 1),
- microparticles distinct from the coated or uncoated microparticles of PA (alternative 2).
- the viscosifying agent microparticles are not separable from the coated or uncoated microparticles of PA.
- non-separable means, for example, not separable by conventional means, such as sieving or centrifugation.
- the viscosifying agent is, for example:
- the microparticles comprising the viscosifying agent are physically indistinguishable from the microparticles of PA, and this to prevent their sorting by any appropriate physical means.
- the microparticles comprising the viscosifying agent are indistinguishable from the microparticles of PA, in particular because they are of the same size and / or of the same density and / or even shape and / or of the same color.
- the viscosifying agent is, for example:
- the pharmaceutical form according to the invention is multimicroparticulate. It is preferable that when this pharmaceutical form comprises PA microparticles (eg PAa) and viscosifying agent microparticles (Vb), said microparticles have a near size distribution, a close density and are not separable by sieving. Thus, the microparticles of viscosifying agent are not separable from coated or uncoated microparticles of PA.
- PAa PA microparticles
- Vb viscosifying agent microparticles
- the pharmaceutical form according to the invention is multimicroparticulate. It is preferable that when this pharmaceutical form comprises PA microparticles (eg PAa) and viscosifying agent microparticles (Vb), said microparticles have the same size distribution, the same density and are not separable by sieving. Thus, the microparticles of viscosifying agent are not separable from coated or uncoated microparticles of PA.
- PAa PA microparticles
- Vb viscosifying agent microparticles
- the multimicroparticulate pharmaceutical form comprises at least one salt of at least one analgesic active ingredient
- one skilled in the art may add to said pharmaceutical form, at least one sequestering agent forming, in solution in an aqueous beverage or hydroalcoholic, a weakly soluble complex with PA.
- the sequestering agent is, for example, a salt whose ion of opposite polarity to that of PA, is preferably an organic ion.
- this sequestering agent is, for example, an organic salt such as sodium docusate, or an anionic polymer.
- the sequestering agent may also for example be a salt of an ion exchange resin.
- a sequestering agent Q is an agent present in the pharmaceutical form in a free form, that is to say uncomplexed.
- “Non-complexed” means that there is no complex or chemical interaction between the sequestering agent Q and the active ingredient salt PA in the solid pharmaceutical form.
- the sequestering agent Q is capable of inducing a complexation or a chemical interaction with salt PA in said solvent.
- the sequestering agent Q is considered as "capable of inducing a complexation" with the PA salt when the sequestering agent Q is capable of inducing the complexation of the PA salt in at least one usual solvent selected among water and aqueous solutions, such as water-ethanol mixtures, alcohol, alcoholic beverages, sodas, vinegar, hydrogen peroxide, and mixtures thereof.
- the sequestering agent Q is capable of inducing a complexation of the PA salt in more than one of these usual solvents.
- the sequestering agents Q used to trap PA are harmless even for regular use. These are pharmaceutically inert products approved by the different pharmacopoeias and drug registration authorities.
- At least one sequestering agent Q is present:
- microparticles free of PA and / or on microparticles, and / or
- the sequestering agent Q is present in a first phase separated by at least a second phase, said second phase containing at least one PA salt.
- the dosage form comprises PA salt microparticles and separate Q sequestering agent microparticles.
- said microparticles have a near size distribution, a close density and are not separable from each other by sieving.
- the sequestering agent Q comprises a salt, which contains ions able to form a complex with the PA in solution.
- these ions are preferably organic ions of opposite polarity to that of PA in solution: if in solution the PA is in anionic form, the sequestering agent Q comprises an organic cation, a metal cation, or a mixture thereof.
- the sequestering agent Q when the PA in solution is in cationic form, the sequestering agent Q comprises an organic anion.
- anionic organic salts such as sodium dodecyl sulfate or sodium docusate
- anionic polymers such as (meth) acrylic copolymers (for example Eudragit® S and Eudragit® L), crosslinked acrylic polyacids (for example Carbopol), carboxymethylcellulose and its derivatives, cross-linked carboxymethylcellulose and its derivatives and other polysaccharides (for example: for example, alginate, xanthan gum or arabic), alginate- (sulfonate) propylene glycol; - mono- or polyvalent salts, such as glucuronates, citrates, acetates, carbonates, gluconates, succinates, phosphates, glycerophosphates, lactates, trisilicates, fumarates, adipates, benzoates, salicylates, tartrates, sulfonamides, acesulfames;
- acrylic copolymers for example Eudragit® S and Eudragit® L
- crosslinked acrylic polyacids for example Carbopol
- saponified fatty acids such as the salts of acetic acid, succinic acid, citric acid, stearic acid, palmitic acid, and self-emulsifying glyceryl mono-oleates;
- polyamino acids such as albumins, caseins, globulins and enzymes;
- the ion of opposite polarity to that of the PA in solution is a metal, organic cation, or a mixture thereof.
- a metal, organic cation, or a mixture thereof for example, the following salts which contain an organic or metallic cation:
- cationic salts for example metals Ca, Fe, Mg, Zn, in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicates, phosphates, salicylates, succinates, sulfonamides, tartrates;
- metals Ca, Fe, Mg, Zn in the form of acesulfames, acetates, adipates, benzoates, carbonates, chlorides, citrates, fluorides, fumarates, gluconates, glucuronates, glycerophosphates, hydroxides, iodates, iodides, lactates, oxides, phosphates, trisilicate
- organic cationic salts such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;
- cationic polymers such as chitosan and (meth) acrylic copolymers (for example, Eudragit® RS, Eudragit® RL or Eudragit® E);
- polyamino acids proteins or peptides
- the sequestering agent Q may be an ion exchange resin, preferably a strongly acidic cation exchange resin when the PA is cationic or a strongly basic anion exchange resin, when the AP is anionic.
- an ion exchange resin is contained in a first phase distinct from a second phase which contains the PA.
- the ion exchange resin is for example a derivative of a copolymer of styrene and divinylbenzene.
- the highly acidic cation exchange resin will be, for example a derivative of a copolymer of styrene and divinylbenzene sulfonic such as Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and the like.
- the strongly basic anion exchange resin will for example be chosen from derivatives of styrene and divinylbenzene copolymers bearing quaternary ammonium functional groups, such as Duolite® AP 143. (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow).
- the sequestering agent Q in the form of a resin may also be chosen from cross-linked copolymers of methacrylic acid and divinylbenzene or one of their salts, such as Amberlite® IRP88 and Amberlite® IRP64 (Rohm and Haas) DOWEX MAC-3 (Dow).
- the sequestering agent Q in the form of an ion exchange resin may also be chosen from phenolic polyamines such as Amberlite® IRP58 (Rohm and Haas); and their mixtures.
- the sequestering agent Q in the form of an ion exchange resin is in a first phase separated from at least a second phase, said second phase comprising the PA salt.
- the sequestering agent Q in the form of an ion exchange resin is contained in microparticles distinct from the microparticles comprising the PA salt.
- the PA microparticles and the Q-sequestering agent microparticles in the form of an ion exchange resin may be in such a form that they have a near size distribution, a close density and are not separable by sieving.
- the sequestering agent Q is chosen from:
- anionic organic salts such as sodium dodecyl sulfate or sodium docusate
- cationic organic salts such as quaternary ammonium salts, in particular trimethyl tetradecyl ammonium bromide or benzethonium chloride;
- the sequestering agent Q is chosen from:
- - strongly acidic cation exchange resins Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas); Amberlite 200, Amberlite 200C (Rohm and Haas), or Dowex 88 (Dow) and mixtures thereof, when the AP is canonical; - strongly basic anion exchange resins: Duolite® AP143 (Rohm and Haas) Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22 (Dow), and mixtures thereof, when the PA is anionic.
- the amount of agent Q is adapted by those skilled in the art by a calculation of the amount of ionic charge necessary to trap all or part of the dose of AP contained in the unit form.
- the amount of sequestering agent Q must be such as to complex enough PA so that the remaining amount of free PA in solution is insufficient to achieve the desired effect, if used illegally.
- the amount of sequestering agent Q is sufficient to complex the whole AP of the unit dose.
- the dosage form may also be a monolithic form (tablet e.g.).
- the pharmaceutical form according to the invention comprises microparticles of viscosifying agent V and / or microparticles of sequestering agent Q, preferably microparticles of viscosifying agent V and microparticles of sequestering agent Q.
- the viscosifier microparticles V and the sequestering agent microparticles Q are distinct from the microparticles of AP.
- the pharmaceutical form comprises PA microparticles, as well as V-viscosifying agent microparticles and / or Q-sequestering agent microparticles.
- the pharmaceutical form comprises these three types. microparticles, that is to say, microparticles of PA, microparticles of V viscosifier and microparticles of sequestering agent Q, in the same unit form.
- these microparticles have a near size distribution, a close density and are not separable from each other by sieving.
- the pharmaceutical form according to the invention is not convertible into a dry form which can be administered by nasal aspiration and immediate release of AP.
- the pharmaceutical form according to the invention is not convertible into an injectable form and to immediate release of AP.
- the pharmaceutical form according to the invention comprises modified-release PA and optionally immediate-release PA. This variant can be combined with the first and second variants mentioned above. This means that in a dosage form that includes modified release PA and immediate release AP, the modified release AP is not convertible into a dry form that can be administered by nasal aspiration or injectable form, and immediate release.
- the pharmaceutical form according to the invention is characterized in that the extraction of PA by chewing and / or grinding is not effective.
- the pharmaceutical form according to the invention is characterized in that it is free of agent (s) antagonist (s) of the PA.
- the pharmaceutical form according to the invention is characterized in that it comprises at least one agent (s) antagonist (s) of PA.
- the skilled person can easily determine the appropriate antagonist (s).
- the PA used belongs to at least one of the following families of active substances: amphetamines, analgesics, anorectics, analgesics, antidepressants, anti-epileptics, anti-migraine, antiparkinsonian, antitussives, anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics opiates, psychostimulants, psychotropic drugs, sedatives, stimulants.
- PAa an analgesic PA
- PAa an opioid
- the AP used is chosen from the following compounds: anileridine, acetorphin, acetylalphamethylfentanyl, acetyldihydrocodeine, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphameprodine, alphaprodine, alphamethadol, alphamethylfentanyl, alpha-methylthio-fentanyl, alphaprodine, anileridine, atropine, butorphanol, benzethidine, benzylmorphine, beta- hydroxyfentanyl, beta-hydroxy-methyl-3-fentanyl, betacetylmethadol, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, dioxaphetyl butyrate, clonitazene, cyclazocine, cannabis, cetobemidone, clonita
- the pharmaceutical form according to the invention may comprise at least one analgesic active ingredient (PAa) and at least one additional PA different from PAa.
- This non-analgesic PA is preferably chosen from the group comprising: anti-depressants, amphetamines, anorexics, non-analgesic painkillers, anti-epileptics, anti-migraine, anti-parkinsonian, anti-tussive agents , anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives, neuroleptics, psychostimulants, psychotropics, sedatives, stimulants, anti-inflammatory agents, and their salts, esters, hydrates, polymorphs and their pharmacologically acceptable isomers, and mixtures thereof.
- anti-inflammatory active principles that may be envisaged, mention may be made of: ibuprofen, acetaminophen, diclofenac, naproxen, benoxaprofen, flurbiproiene, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, trioxaproiene, suprofen, amineoprofen, acid tiaprofenic, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetine, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, ox
- the analgesic PA implemented is selected from the group consisting of oxycodone hydrochloride, morphine sulfate, oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodone hydrochloride, and tramadol hydrochloride. .
- the expression "pharmaceutical formulation” is understood in a broad sense, that is to say that includes veterinary or dietetic formulations in particular.
- the invention is directed to a formulation characterized in that it comprises a plurality of microparticles (PA, coated or uncoated, optionally viscosifying agent) as defined above, for example at less
- 500 preferably from 1,000 to 1,000,000, and still more preferably from 5,000 to
- the invention is directed to a pharmaceutical formulation, comprising a plurality of populations of coated PA microparticles, said populations being distinguished from each other by their release kinetics and / or by the PA they contain.
- a pharmaceutical formulation according to the invention is particularly advantageous in that it may be in the form of a single daily oral dose comprising from 500 to 500,000 microparticles, including the coated PA microparticles. .
- the pharmaceutical formulation comprising coated microparticles according to the invention is in a dosage form chosen from the group comprising: (advantageously orodispersible or gastrodispersible) tablets, powders, suspensions, syrups, powders for suspension to be reconstituted or capsules.
- the invention also relates to the use of the coated microparticles described above for the manufacture of new pharmaceutical formulations, in particular, but not exclusively, in the context of the therapeutic treatment against pain.
- the invention also relates to a method of therapeutic treatment characterized in that it consists in administering to the patient the pharmaceutical formulation as defined above.
- the invention also relates to a method of therapeutic treatment characterized in that it consists of ingestion according to a specific dosage, of the pharmaceutical formulation as defined above.
- the invention also relates to a method of therapeutic treatment against pain characterized in that it consists in administering to the patient the pharmaceutical formulation as defined above.
- the invention also relates to a therapeutic treatment method for pain characterized in that it consists of an ingestion according to a specific dosage, of the pharmaceutical formulation as defined above, the PA used comprising at least one pain-relieving agent, for example an analgesic.
- the invention also relates to a method for controlling the misuse of PA, characterized in that it consists essentially in implementing a pharmaceutical form as defined above.
- the invention also relates to a method for controlling the misuse of PA, characterized in that it consists essentially in implementing in a pharmaceutical form, coated PA microparticles, with modified PA release and comprising a coating layer ( Ra), which provides the modified release of PA and which simultaneously confers grinding resistance to the coated PA microparticles to avoid misuse; and optionally at least one viscosifying agent (Vb) capable of preventing the extraction of the AP contained in the coated PA microparticles, to avoid misuse.
- a coating layer Ra
- Vb viscosifying agent
- the coating layer (Ra) and the viscosifying agent (Vb), if any, are as defined above.
- FIG. 1 represents the dissolution profile in a reference test (% of dissolution D as a function of time T) in vitro of the microparticles of example 1: - m -.
- FIG. 2 represents the dissolution profile in a reference test (% of dissolution D as a function of time T) in vitro of the microparticles of example 1: - m - and of example 2: (a) - D- , (b) - ⁇ o-, (c) - • -, (d) - A-.
- Figure 3 shows (A) a photograph of an observation with the naked eye and (B) under an optical microscope the contents of a capsule according to Example 3.
- Figure 4 shows the release profile (% by weight of PAa versus time in hours) of microcapsules in 0.1N HCl (Example 8).
- Figure 5 shows (A) a photograph of an observation with the naked eye and (B) under an optical microscope of the contents of a capsule according to Example 9.
- Figure 6 shows the release profile of crushed microparticles (empty bead) or intact (solid square) of Example 9.
- the reference dissolution test in the examples which follow is an in vitro dissolution test carried out according to the indications of the European Pharmacopoeia 5 ⁇ 6 edition entitled: "Dissolution test of solid oral forms”: dissolutest of type II performed in SINK conditions maintained at 37 ° C and stirred at 75 rpm in 900 ml of 0.1N HCl.
- Example 1 Microparticles of Oxycodone HCl According to the Invention A mixture of 1600 g of oxycodone HCl, 100 g of Klucel® EF (Hydroxypropyl cellulose / Aqualon) and 12052 g of water is filmed on 300 g of inert cellulose beads (Asahi-Kasei ) in a fluidized air bed GPCGl (Glatt®).
- 450 g of granules thus obtained are then coated with a mixture composed of 315 g of ethylcellulose (Ethocel Premium / DOW), 81 g of povidone (Plasdone PVP K29 / 32 / ISP), 36 g of castor oil, 18 g of Cremophor RH 40 (Macrogolglyceroli hydroxystearas / B ASF) and 12020g of ethanol.
- the coating represents 50% of the mass of the microparticle and ensures a release of the active ingredient over approximately 4 hours, as shown in FIG. 1.
- the release profile is produced under the conditions of the reference dissolution test.
- Example 2 200 mg of microparticles prepared in Example 1 (ie a dose of 80 mg of Oxycodone HCl) are milled according to various methods, which represent various possibilities of misuse: (a) with the pestle and mortar (25OmL) ground strongly for 2 minutes ( -120 rotations)
- the release profiles of the crushed microparticles are reported in FIG. 2.
- the release profile is carried out under the conditions of the reference dissolution test.
- Example 1 intact microparticles
- Example 2 ground microparticles
- f2 similarity factor test
- EXAMPLE 3 Aspect of the Content of a Capsule According to the Invention 200 mg of microparticles prepared in Example 1 (ie a dose of 80 mg of Oxycodone HCl) are mixed with the following viscosifiers: 90 mg of Klucel HF (hydroxypropylcellulose / Aqualon), 20mg of PoIyOx WSR 303 Sentry (polyethylene oxide / Dow) and 20mg of Xantural 180 (xanthan / cpKelco) previously sieved between 100 and 600 ⁇ m. The whole is incorporated in a gelatin capsule of size 0.
- FIG. 3 shows the photographs of an observation with the naked eye (A) and under an optical microscope (B) of the contents of the capsule.
- the microparticles of active principle and the microparticles of viscosifying agents are: - not distinguishable, - not separable by sieving.
- Example 4 Syringe extraction test of a form according to the invention
- Example 2 200 mg of microparticles prepared in Example 1 (ie a dose of 80 mg of Oxycodone HCl) are mixed with 90 mg of Klucel HF (hydroxypropylcellulose)
- Xantural 180 (xanthan / cpKelco) previously sieved between 100 and 600 ⁇ m. The whole is incorporated in a size 0 gelatin capsule.
- Example 2 (a) using a mortar and pestle and then mixed for 10 min, at room temperature or boiling, in
- Example 5 Syringe extraction test of a form according to the invention
- Example 2 200 mg of microparticles prepared in Example 1 (ie a dose of 80 mg of Oxycodone HCl) are mixed with 150 mg of Klucel HXF (hydroxypropylcellulose)
- Example 2 (a) using a mortar and pestle and then mixed for 10 min, at room temperature or boiling, in
- Example 6 Syringe extraction test of a form according to the invention
- Example 2 The capsule is opened and the contents are ground according to Example 2 (a) by means of a mortar and pestle and then mixed for 10 min at room temperature or at boiling point. The solution is then removed by means of a 10L syringe with a 18G needle through a hydrophilic cotton cotton cloth as a filter The extracted oxycodone HCl level is analyzed by HPLC or UV and reported in Table 3.
- Example 2 200 g of microparticles prepared in Example 1 are mixed with 90 g of Klucel HF (hydroxypropylcellulose / Aqualon), 20 g of PolySyOx WSR 303 Sentry (polyethylene oxide / Dow), 20 g Xanthural 180 (xanthan / cpKelco), 100 g of Lactose (Tablettose / Meggle GmbH), 10g magnesium stearate (Brenntag AG) and 30g croscarmellose sodium (Ac-Di-SoI / FMC Bipolymer). 470 mg tablets (a dose of 80 mg oxycodone) are manufactured using a Korsch alternative press.
- Klucel HF hydroxypropylcellulose / Aqualon
- 20 g of PolySyOx WSR 303 Sentry polyethylene oxide / Dow
- 20 g Xanthural 180 xanthan / cpKelco
- 100 g of Lactose Tablettose
- the tablet obtained is ground according to Example 2 (a) using a mortar and pestle and then mixed for 10 min at room temperature or boiling in 2.5 ml of extraction liquid.
- the solution is then removed by means of a 2.5 mL syringe with a 18G needle through a hydrophilic cotton as a filter.
- the extracted oxycodone HCl level is analyzed by HPLC or UV and reported in Table 4.
- K29-32 / ISP 18 g of Macrogolglyceroli hydroxystearas (Cremophor RH40 / BASF) and 36 g of castor oil (Garbit oil mill) are solubilized in a mixture consisting of 3105 g of acetone and 2070 g of isopropanol. This solution is sprayed on 450 g of granulate
- the coating represents 50% of the mass of the microparticle and ensures the release of it as shown in FIG. 4.
- the release profile is produced under the conditions of the reference dissolution test.
- the microparticles of active principle and the microparticles of viscosifying agents are:
- Example 9 The contents of the capsule prepared in Example 9 is ground for 2 minutes using a mortar and pestle.
- the release profiles of the crushed microparticles are reported in FIG. 6.
- the release profile is carried out under the conditions of the reference dissolution test.
- Example 11 Syringe extraction test of the contents of a capsule prepared according to Example 9.
- a capsule prepared according to Example 9 is opened and the content is ground for 2 minutes using a mortar and pestle and then mixed for 10 min at room temperature (A) or boiling (B) in 2.5 ml of extraction liquid. The solution is then removed using a 2.5 mL syringe with either a 18G needle or a 27G needle through a hydrophilic cotton as a filter. The extracted oxycodone HCl level is analyzed by HPLC or UV and reported in Tables 5 and 6.
- Example 12 Extraction Test in Beverages of the Contents of a Capsule According to Example 9
- a capsule prepared according to Example 9 is opened and the contents are crushed for 2 minutes by means of a mortar and pestle and then mixed in 100 ml of non-alcoholic beverage or 50 ml of alcoholic beverage as indicated in the table below. below:
Abstract
Description
Claims
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020087013970A KR101425196B1 (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
AU2006311116A AU2006311116C1 (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
MX2008006042A MX2008006042A (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form. |
KR1020147014471A KR20140090222A (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
CA002627058A CA2627058A1 (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
EP06763289A EP1945230A1 (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
BRPI0618502-9A BRPI0618502A2 (en) | 2005-11-10 | 2006-05-24 | oral dosage form of microparticles against misuse |
JP2008539368A JP5537030B2 (en) | 2005-11-10 | 2006-05-24 | Misuse-preventing fine particle oral pharmaceutical form |
IL190749A IL190749A (en) | 2005-11-10 | 2008-04-09 | Anti-misuse microparticulate oral pharmaceutical form |
IL233925A IL233925A (en) | 2005-11-10 | 2014-08-03 | Anti-misuse microparticulate oral pharmaceutical form |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0553437A FR2892937B1 (en) | 2005-11-10 | 2005-11-10 | MICROPARTICULAR ORAL PHARMACEUTICAL FORM ANTI-MEASURING |
FR0553437 | 2005-11-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2007054378A1 true WO2007054378A1 (en) | 2007-05-18 |
Family
ID=36930690
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2006/062627 WO2007054378A1 (en) | 2005-11-10 | 2006-05-24 | Anti-misuse microparticulate oral pharmaceutical form |
Country Status (12)
Country | Link |
---|---|
EP (1) | EP1945230A1 (en) |
JP (1) | JP5537030B2 (en) |
KR (2) | KR101425196B1 (en) |
CN (1) | CN101304752A (en) |
AU (1) | AU2006311116C1 (en) |
BR (1) | BRPI0618502A2 (en) |
CA (1) | CA2627058A1 (en) |
FR (1) | FR2892937B1 (en) |
IL (2) | IL190749A (en) |
MX (1) | MX2008006042A (en) |
WO (1) | WO2007054378A1 (en) |
ZA (1) | ZA200803140B (en) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011045769A2 (en) | 2009-10-16 | 2011-04-21 | Flamel Technologies | Anti-misuse solid oral dosage form provided having a modified specific release profile |
US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
JP2013501763A (en) * | 2009-08-12 | 2013-01-17 | デブルジャ・ゼ・タソシエ・ファルマ | New pharmaceutical formulations for drug misuse |
WO2014091437A1 (en) | 2012-12-13 | 2014-06-19 | Flamel Technologies | Oral form, comprising immediate-release coated particles of at least one active compound that are grinding-resistant |
US9023400B2 (en) | 2006-05-24 | 2015-05-05 | Flamel Technologies | Prolonged-release multimicroparticulate oral pharmaceutical form |
US9814684B2 (en) | 2002-04-09 | 2017-11-14 | Flamel Ireland Limited | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
EP1986616B1 (en) * | 2006-02-16 | 2018-08-15 | Flamel Ireland Limited | Microparticulate pharmaceutical forms resistant to immediate release of the active principle in the presence of alcohol |
US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
US11576974B2 (en) | 2013-02-05 | 2023-02-14 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7776314B2 (en) | 2002-06-17 | 2010-08-17 | Grunenthal Gmbh | Abuse-proofed dosage system |
DE10336400A1 (en) | 2003-08-06 | 2005-03-24 | Grünenthal GmbH | Anti-abuse dosage form |
DE102005005446A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Break-resistant dosage forms with sustained release |
US20070048228A1 (en) | 2003-08-06 | 2007-03-01 | Elisabeth Arkenau-Maric | Abuse-proofed dosage form |
DE10361596A1 (en) | 2003-12-24 | 2005-09-29 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
DE102004032049A1 (en) | 2004-07-01 | 2006-01-19 | Grünenthal GmbH | Anti-abuse, oral dosage form |
DE102005005449A1 (en) | 2005-02-04 | 2006-08-10 | Grünenthal GmbH | Process for producing an anti-abuse dosage form |
FR2901478B1 (en) * | 2006-05-24 | 2015-06-05 | Flamel Tech Sa | MULTIMICROPARTICULATED ORAL PHARMACEUTICAL FORM WITH PROLONGED RELEASE |
RU2493830C2 (en) | 2008-01-25 | 2013-09-27 | Грюненталь Гмбх | Drug form |
BR112012001547A2 (en) | 2009-07-22 | 2016-03-08 | Gruenenthal Gmbh | hot melt extruded pharmaceutical dosage form |
JP2012533585A (en) | 2009-07-22 | 2012-12-27 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Tamper-resistant dosage forms for oxidation-sensitive opioids |
FR2960775A1 (en) * | 2010-06-07 | 2011-12-09 | Ethypharm Sa | MICROGRANULES RESISTANT TO MISMATCH |
FR2962331B1 (en) * | 2010-07-06 | 2020-04-24 | Ethypharm | PHARMACEUTICAL FORM FOR COMBATING CHEMICAL SUBMISSION, METHOD USING THE SAME |
WO2012028318A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising an anionic polymer |
WO2012028319A1 (en) | 2010-09-02 | 2012-03-08 | Grünenthal GmbH | Tamper resistant dosage form comprising inorganic salt |
US20120070468A1 (en) * | 2010-09-16 | 2012-03-22 | Uop Llc | Removal of toxins from gastrointestinal fluids |
AU2012219322A1 (en) * | 2011-02-17 | 2013-05-09 | QRxPharma Ltd. | Technology for preventing abuse of solid dosage forms |
MX2021000431A (en) * | 2011-03-23 | 2022-10-28 | Ironshore Pharmaceuticals & Dev Inc | Methods and compositions for treatment of attention deficit disorder. |
BR112014002022A2 (en) * | 2011-07-29 | 2017-02-21 | Gruenenthal Gmbh | tamper-resistant tablet providing immediate drug release |
CN103857386A (en) | 2011-07-29 | 2014-06-11 | 格吕伦塔尔有限公司 | Tamper-resistant tablet providing immediate drug release |
FR2983409B1 (en) * | 2011-12-06 | 2013-12-27 | Ethypharm Sa | COMPRESSOR CAPABLE OF COMBATTING INJECTION MISTAKE |
US20130225697A1 (en) | 2012-02-28 | 2013-08-29 | Grunenthal Gmbh | Tamper-resistant dosage form comprising pharmacologically active compound and anionic polymer |
AU2013248351B2 (en) | 2012-04-18 | 2018-04-26 | Grunenthal Gmbh | Tamper resistant and dose-dumping resistant pharmaceutical dosage form |
US10064945B2 (en) | 2012-05-11 | 2018-09-04 | Gruenenthal Gmbh | Thermoformed, tamper-resistant pharmaceutical dosage form containing zinc |
BR112015026549A2 (en) | 2013-05-29 | 2017-07-25 | Gruenenthal Gmbh | tamper-proof dosage form containing one or more particles |
MX2015016254A (en) | 2013-05-29 | 2016-04-20 | Gruenenthal Gmbh | Tamper resistant dosage form with bimodal release profile. |
FR3007651A1 (en) * | 2013-06-27 | 2015-01-02 | Assist Publ Hopitaux De Paris | PHARMACEUTICAL COMPOSITION IN THE FORM OF PELLETS FOR THE TREATMENT OF METABOLIC DISORDERS IN CHILDREN |
AU2014289187B2 (en) | 2013-07-12 | 2019-07-11 | Grunenthal Gmbh | Tamper-resistant dosage form containing ethylene-vinyl acetate polymer |
JP6539274B2 (en) | 2013-08-12 | 2019-07-03 | ファーマシューティカル マニュファクチュアリング リサーチ サービシズ,インコーポレーテッド | Extruded immediate release abuse deterrent pills |
CA2931553C (en) | 2013-11-26 | 2022-01-18 | Grunenthal Gmbh | Preparation of a powdery pharmaceutical composition by means of cryo-milling |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US10172797B2 (en) | 2013-12-17 | 2019-01-08 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
MX2016014738A (en) | 2014-05-12 | 2017-03-06 | Gruenenthal Gmbh | Tamper resistant immediate release capsule formulation comprising tapentadol. |
WO2015181059A1 (en) | 2014-05-26 | 2015-12-03 | Grünenthal GmbH | Multiparticles safeguarded against ethanolic dose-dumping |
ES2809458T3 (en) | 2014-07-17 | 2021-03-04 | Pharmaceutical Manufacturing Res Services Inc | Liquid filled, abuse deterrent and immediate release dosage form |
AU2015336065A1 (en) | 2014-10-20 | 2017-05-04 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
AU2016251854A1 (en) | 2015-04-24 | 2017-10-19 | Grunenthal Gmbh | Tamper-resistant dosage form with immediate release and resistance against solvent extraction |
JP2018526414A (en) | 2015-09-10 | 2018-09-13 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | Protection against oral overdose with abuse-inhibiting immediate release formulations |
CN112402386B (en) * | 2020-12-04 | 2022-06-28 | 江苏恩华药业股份有限公司 | Abuse-preventing opioid oral sustained-release tablet and preparation method thereof |
CN112451493B (en) * | 2020-12-04 | 2022-06-28 | 江苏恩华药业股份有限公司 | Abuse-preventing oxycodone oral sustained-release tablet and preparation method thereof |
Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
WO2001008661A2 (en) * | 1999-07-29 | 2001-02-08 | Roxane Laboratories, Inc. | Opioid sustained-released formulation |
FR2811571A1 (en) * | 2000-07-11 | 2002-01-18 | Flamel Tech Sa | ORAL PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE AND PROLONGED ABSORPTION OF AN ACTIVE INGREDIENT |
WO2003013476A1 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Compositions and methods to prevent abuse of opioids |
US20030118641A1 (en) * | 2000-07-27 | 2003-06-26 | Roxane Laboratories, Inc. | Abuse-resistant sustained-release opioid formulation |
FR2837100A1 (en) * | 2002-03-18 | 2003-09-19 | Flamel Tech Sa | Tablet based on reservoir-type microcapsules, for prolonged release of medicinal or nutritional active agents, including stabilizing external coating of deformable organic material on the microcapsules |
WO2003082204A2 (en) * | 2002-03-26 | 2003-10-09 | Euro-Celtique S.A. | Sustained-release gel coated compositions |
WO2004004693A1 (en) * | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
WO2004026262A2 (en) * | 2002-09-23 | 2004-04-01 | Verion, Inc. | Abuse-resistant pharmaceutical compositions |
WO2004052346A1 (en) * | 2002-12-05 | 2004-06-24 | Eurand, Inc. | Pharmaceutical compositions containing indistinguishable drug components |
US20040126428A1 (en) * | 2001-11-02 | 2004-07-01 | Lyn Hughes | Pharmaceutical formulation including a resinate and an aversive agent |
WO2006056712A1 (en) * | 2004-11-23 | 2006-06-01 | Flamel Technologies | Solid, oral drug form which has been designed to prevent misuse |
WO2006056713A1 (en) * | 2004-11-24 | 2006-06-01 | Flamel Technologies | Solid, oral, microparticulate dosage form which has been designed to prevent misuse |
WO2006089843A2 (en) * | 2005-02-08 | 2006-08-31 | Flamel Technologies | Anti-misuse microparticulate oral drug form |
WO2006125819A2 (en) * | 2005-05-24 | 2006-11-30 | Flamel Technologies | Oral microparticulate, anti-misuse drug formulation |
WO2006134018A2 (en) * | 2005-06-13 | 2006-12-21 | Flamel Technologies | Oral dosage form comprising an antimisuse system |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3693270B2 (en) * | 1995-10-12 | 2005-09-07 | 旭化成ケミカルズ株式会社 | Film-coated granule and method for producing the same |
US20030044458A1 (en) * | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
US20030068276A1 (en) * | 2001-09-17 | 2003-04-10 | Lyn Hughes | Dosage forms |
DE10250084A1 (en) * | 2002-10-25 | 2004-05-06 | Grünenthal GmbH | Dosage form protected against abuse |
-
2005
- 2005-11-10 FR FR0553437A patent/FR2892937B1/en active Active
-
2006
- 2006-05-24 CA CA002627058A patent/CA2627058A1/en not_active Abandoned
- 2006-05-24 KR KR1020087013970A patent/KR101425196B1/en not_active IP Right Cessation
- 2006-05-24 AU AU2006311116A patent/AU2006311116C1/en not_active Ceased
- 2006-05-24 KR KR1020147014471A patent/KR20140090222A/en not_active Application Discontinuation
- 2006-05-24 CN CNA2006800422365A patent/CN101304752A/en active Pending
- 2006-05-24 MX MX2008006042A patent/MX2008006042A/en not_active Application Discontinuation
- 2006-05-24 BR BRPI0618502-9A patent/BRPI0618502A2/en not_active IP Right Cessation
- 2006-05-24 JP JP2008539368A patent/JP5537030B2/en not_active Expired - Fee Related
- 2006-05-24 WO PCT/EP2006/062627 patent/WO2007054378A1/en active Application Filing
- 2006-05-24 EP EP06763289A patent/EP1945230A1/en not_active Withdrawn
-
2008
- 2008-04-09 ZA ZA200803140A patent/ZA200803140B/en unknown
- 2008-04-09 IL IL190749A patent/IL190749A/en not_active IP Right Cessation
-
2014
- 2014-08-03 IL IL233925A patent/IL233925A/en not_active IP Right Cessation
Patent Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5780055A (en) * | 1996-09-06 | 1998-07-14 | University Of Maryland, Baltimore | Cushioning beads and tablet comprising the same capable of forming a suspension |
WO2001008661A2 (en) * | 1999-07-29 | 2001-02-08 | Roxane Laboratories, Inc. | Opioid sustained-released formulation |
FR2811571A1 (en) * | 2000-07-11 | 2002-01-18 | Flamel Tech Sa | ORAL PHARMACEUTICAL COMPOSITION FOR CONTROLLED RELEASE AND PROLONGED ABSORPTION OF AN ACTIVE INGREDIENT |
US20030118641A1 (en) * | 2000-07-27 | 2003-06-26 | Roxane Laboratories, Inc. | Abuse-resistant sustained-release opioid formulation |
WO2003013476A1 (en) * | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Compositions and methods to prevent abuse of opioids |
US20040126428A1 (en) * | 2001-11-02 | 2004-07-01 | Lyn Hughes | Pharmaceutical formulation including a resinate and an aversive agent |
FR2837100A1 (en) * | 2002-03-18 | 2003-09-19 | Flamel Tech Sa | Tablet based on reservoir-type microcapsules, for prolonged release of medicinal or nutritional active agents, including stabilizing external coating of deformable organic material on the microcapsules |
WO2003082204A2 (en) * | 2002-03-26 | 2003-10-09 | Euro-Celtique S.A. | Sustained-release gel coated compositions |
WO2004004693A1 (en) * | 2002-07-05 | 2004-01-15 | Collgegium Pharmaceutical | Abuse-deterrent pharmaceutical compositions of opiods and other drugs |
WO2004026262A2 (en) * | 2002-09-23 | 2004-04-01 | Verion, Inc. | Abuse-resistant pharmaceutical compositions |
WO2004052346A1 (en) * | 2002-12-05 | 2004-06-24 | Eurand, Inc. | Pharmaceutical compositions containing indistinguishable drug components |
WO2006056712A1 (en) * | 2004-11-23 | 2006-06-01 | Flamel Technologies | Solid, oral drug form which has been designed to prevent misuse |
WO2006056713A1 (en) * | 2004-11-24 | 2006-06-01 | Flamel Technologies | Solid, oral, microparticulate dosage form which has been designed to prevent misuse |
WO2006089843A2 (en) * | 2005-02-08 | 2006-08-31 | Flamel Technologies | Anti-misuse microparticulate oral drug form |
WO2006125819A2 (en) * | 2005-05-24 | 2006-11-30 | Flamel Technologies | Oral microparticulate, anti-misuse drug formulation |
WO2006134018A2 (en) * | 2005-06-13 | 2006-12-21 | Flamel Technologies | Oral dosage form comprising an antimisuse system |
WO2006133733A1 (en) * | 2005-06-13 | 2006-12-21 | Flamel Technologies | Oral dosage form comprising an antimisuse system |
Non-Patent Citations (1)
Title |
---|
See also references of EP1945230A1 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8101209B2 (en) | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
US10004693B2 (en) | 2002-04-09 | 2018-06-26 | Flamel Ireland Limited | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
US9814684B2 (en) | 2002-04-09 | 2017-11-14 | Flamel Ireland Limited | Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s) |
EP1986616B1 (en) * | 2006-02-16 | 2018-08-15 | Flamel Ireland Limited | Microparticulate pharmaceutical forms resistant to immediate release of the active principle in the presence of alcohol |
US9023400B2 (en) | 2006-05-24 | 2015-05-05 | Flamel Technologies | Prolonged-release multimicroparticulate oral pharmaceutical form |
JP2013501763A (en) * | 2009-08-12 | 2013-01-17 | デブルジャ・ゼ・タソシエ・ファルマ | New pharmaceutical formulations for drug misuse |
WO2011045769A2 (en) | 2009-10-16 | 2011-04-21 | Flamel Technologies | Anti-misuse solid oral dosage form provided having a modified specific release profile |
US20110091537A1 (en) * | 2009-10-16 | 2011-04-21 | Flamel Technologies | Anti-misuse solid oral pharmaceutical form provided with a specific modified release profile |
WO2014091437A1 (en) | 2012-12-13 | 2014-06-19 | Flamel Technologies | Oral form, comprising immediate-release coated particles of at least one active compound that are grinding-resistant |
US11576974B2 (en) | 2013-02-05 | 2023-02-14 | Purdue Pharma L.P. | Tamper resistant pharmaceutical formulations |
US10143706B2 (en) | 2016-06-29 | 2018-12-04 | Cannscience Innovations, Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
US10383892B2 (en) | 2016-06-29 | 2019-08-20 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
US10537592B2 (en) | 2016-06-29 | 2020-01-21 | CannScience Innovations Inc. | Decarboxylated cannabis resins, uses thereof and methods of making same |
Also Published As
Publication number | Publication date |
---|---|
KR20140090222A (en) | 2014-07-16 |
ZA200803140B (en) | 2009-08-26 |
EP1945230A1 (en) | 2008-07-23 |
AU2006311116C1 (en) | 2013-10-24 |
IL233925A (en) | 2017-12-31 |
FR2892937B1 (en) | 2013-04-05 |
KR20080064905A (en) | 2008-07-09 |
IL190749A (en) | 2015-07-30 |
KR101425196B1 (en) | 2014-08-12 |
MX2008006042A (en) | 2008-10-01 |
CA2627058A1 (en) | 2007-05-18 |
CN101304752A (en) | 2008-11-12 |
AU2006311116A1 (en) | 2007-05-18 |
IL190749A0 (en) | 2008-12-29 |
JP5537030B2 (en) | 2014-07-02 |
BRPI0618502A2 (en) | 2011-09-06 |
JP2009537456A (en) | 2009-10-29 |
AU2006311116B2 (en) | 2013-01-31 |
IL233925A0 (en) | 2014-09-30 |
FR2892937A1 (en) | 2007-05-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2007054378A1 (en) | Anti-misuse microparticulate oral pharmaceutical form | |
US8445023B2 (en) | Anti-misuse microparticulate oral pharmaceutical form | |
CA2651451C (en) | Extended release oral multimicroparticle dosage form | |
JP5305902B2 (en) | Oral dosage form including abuse prevention system | |
US9023400B2 (en) | Prolonged-release multimicroparticulate oral pharmaceutical form | |
JP5562428B2 (en) | Exploited solid oral pharmaceutical dosage forms with specific controlled release profiles | |
CA2596965A1 (en) | Anti-misuse microparticulate oral drug form | |
US20070264326A1 (en) | Anti-misuse oral microparticle medicinal formulation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200680042236.5 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2006763289 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 190749 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 754/MUMNP/2008 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2627058 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2006311116 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/a/2008/006042 Country of ref document: MX |
|
ENP | Entry into the national phase |
Ref document number: 2008539368 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2006311116 Country of ref document: AU Date of ref document: 20060524 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2006311116 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1020087013970 Country of ref document: KR |
|
WWP | Wipo information: published in national office |
Ref document number: 2006763289 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: PI0618502 Country of ref document: BR Kind code of ref document: A2 Effective date: 20080509 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 233925 Country of ref document: IL |