WO1994022423A1 - Drug administration system - Google Patents
Drug administration system Download PDFInfo
- Publication number
- WO1994022423A1 WO1994022423A1 PCT/DK1994/000145 DK9400145W WO9422423A1 WO 1994022423 A1 WO1994022423 A1 WO 1994022423A1 DK 9400145 W DK9400145 W DK 9400145W WO 9422423 A1 WO9422423 A1 WO 9422423A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- drug
- supporting means
- drug substance
- mucosa
- skin
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
Definitions
- the present invention relates to a method for parenteral administration of a drug substance comprising penetration of the skin or the mucosa of a human or an animal by a body of an appropriately formed solid pharmaceutical composition.
- the present invention also relates to a body of a solid pharma ⁇ ceutical composition which has a shape and/or strength which enables it to penetrate unbroken skin or mucosa of a human or an animal in order to deliver an active substance to the animal and to a process for the preparation of this composi ⁇ tion.
- the present invention relates to a novel drug delivery system comprising a solid body of a pharma ⁇ ceutical composition and to a process for the preparation of such a drug delivery system.
- the oral route is the preferred administration route in that numerous drug substances are readily absorbed from the gastrointestinal tract.
- This form of administration is easy and well accepted by the patient, and generally results in good patient compliance.
- advanced techniques within the field of drug formulation such as time controlled-release systems, have made it pos ⁇ sible to administer a wide range of different types of phar ⁇ maceuticals in an acceptable manner
- the bioavailability of the drug substance i.e. the rate of drug absorption and the extent to which the drug substance is absorbed, still depends to a considerable extent on the nature of the active drug substance itself, i.e. on its physical and chemical proper ⁇ ties. Accordingly, many drug substances, e.g. numerous pepti- des, still cannot be administered satisfactorily by the oral route.
- Parenteral administration is the route of choice for drugs which are degraded or are erratically or unreliably absorbed when administered orally.
- the parenteral route pro ⁇ vides a reliable dose-response relationship.
- Parenteral admi ⁇ nistration routes can be divided up into invasive and non- invasive routes, i.e. routes in which delivery of the active drug substance takes place with or without physical disrup ⁇ tion of the skin or mucosa, respectively.
- non-invasive routes are transcutaneous delivery of a drug sub ⁇ stance applied in form of plasters (and in rare cases oint- ments) , and transmucosal delivery, such as nasal administra ⁇ tion or sublingual administration whereby the drug substance is protected from first-pass metabolism by the liver.
- Both the invasive and the non-invasive parenteral administration routes are associated with several disadvantages. For instance, the use of the non-invasive parenteral route is limited to the relatively small number of drug substances which are able to penetrate the skin or mucosa at a suffi ⁇ cient rate.
- injection relates to the administration of liquid formulations to the body by means of needles or cathe- ters
- implants are generally employed for administra ⁇ tion of formulations in solid form which can be incorporated into the body by various mechanical methods involving the use of some kind of invasive equipment or which can be inserted into a lesion, e.g. in connection with surgery.
- implants are normally employed when sustained release of a drug is desired. Due to the need for rather specialized equipment and skill of the person performing the implanta ⁇ tion, this administration route is normally restricted to situations wherein a special sustained administration is desired or to administration to locations where the blood supply for some reason is limited.
- European Patent No. 139 286 Bl discloses an injectable sus ⁇ tained-release preparation which comprises an active ingredi ⁇ ent and a pharmaceutically acceptable proteinaceous biodegra ⁇ dable carrier.
- the preparation is described as having a needle-like or bar-like shape.
- the preparation is employed as an implant which is inserted into the body e.g. by injection, for example by inserting a fine tube (such as a catheter) into the body, and inserting the needle-like shaped prepara ⁇ tion via the fine tube, or by inserting the preparation directly into the body by means of forceps needles which are capable of penetrating the skin.
- a specific embodiment of a device for administering the preparation is also disclosed which comprises a fine tube and an inner needle.
- the inner needle is stabbed into a portion of the body, whereafter the fine tube is inserted into the body by sliding its inner wall along the outer wall of the inner needle.
- the needle-like preparation is inserted into the body by passing it through the fine tube.
- Usually the insertion of the preparation into the fine tube is carried out by withdrawing the inner needle and then pushing the preparation into the body via the fine tube with a pushing pole.
- a solid needle-like or bar-like sustained-release preparation suitable for injection is disclosed in US Patents Nos. 5,021,241 and 4,774,091.
- the preparations comprise a physio ⁇ logically active ingredient that is unstable to heat and a pharmaceutically acceptable biodegradable protein carrier.
- the needle-like or bar-like preparations according to the examples disclosed in these patents are formed by compression of the preparation obtained by mixing the active ingredient and the carrier under aqueous condition. It is mentioned that the preparation can be inserted into a body by operation or with a forceps needle for a fibrescope, or via an indwelling needle.
- US Patent Nos. 5,081,156 and 4,855,134 disclose sustained- release preparations comprising interferon or indomethacin or a salt thereof as an active ingredient and collagen or gela ⁇ tin or albumin as a biodegradable carrier, the preparation being in form of powder particles suspended in a viscous solvent suitable for injection, or being in the form of a shaped preparation suitable for use as an injection in a solid state or for implanting into a body.
- the preparations according to the cited patents are prepared by a process which comprises mixing the active ingredient with the carrier to form a liquid mixture, and drying the resultant mixture.
- a needle-like or bar-like preparation is formed under compres- sion, and it is mentioned that such preparations can be inserted into a body by operation or with a forceps needle for a fibrescope or via an indwelling needle. It is also mentioned that the preparation may be formed into other conventional sustained-release oral preparations, a medicine for external application, suppositories or the like by con ⁇ ventional techniques.
- US Patent No. 4,849,141 discloses a method for preparing a sustained-release formulation. It is mentioned that the formulation may have a variety of sizes and shapes, such as a spherical, hemispherical, column, tubular, or sheet-like shape as well as needle- or bar-like shape. In addition, it is mentioned in this patent that the formulation may be admi ⁇ nistered to a living body, for example, by subcutaneous in ⁇ sertion or implantation into a body cavity, depending on the lesional region to be treated.
- the method for preparing the formulation comprises blending of a physiologically active ingredient together with collagen and/or gelatin using a solvent such as pure water or water in admixture with a hydrophilic organic solvent. It is also mentioned that the formation of fibres in the composition should be avoided.
- Lin et al. (Biomat., Art. Cells, Art. Org., (1988), 16(4) , 801-814 and Biomat., Art. Cells, Art. Org., (1989), 17(2) . 189-203) describe controlled release polymeric needle devices containing adriamycin HC1 for local treatment of solid tumours.
- the polymeric needles are made of polylactic acid or ethylene-vinyl acetate and hydroxypropylmethylcellulose is said to be used as a release regulator.
- formulations adapted for invasive parenteral administration are administered through catheters or needles which are used to provide a passageway for the drug sub ⁇ stance.
- the drug substance is normally forced through the needle or catheter by use of a syringe, stiletto, or pushing pole, or simply by gravity.
- parenteral administration is associated with an appre ⁇ ciable risk of life-threatening septicemia. It is clear that every penetration of the skin or the mucosal barrier is associated with a considerable risk of infection, and accor ⁇ dingly every effort should be made to minimize the necessary number of insertions or penetrations.
- a body of a solid pharmaceutical composition with a shape and consistency enabling it to penetrate the skin would solve most of the above-discussed problems related to invasive parenteral administration. If such a body of a solid phar a- ceutical composition consists essentially of the active drug substance itself, its size can be reduced, thus minimizing pain and leaving no superfluous equipment and therefore no risk of infection to others, and, if properly designed, it would be easy to use by the end user. Such a body could be designed for immediate release or for delayed release of the drug.
- the object of the present invention is the provision of such bodies and drug delivery systems.
- the present invention relates to a body of a solid pharmaceutical composition comprising at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in order to deliver said drug substance to an underlying tissue or into the blood stream of said human or animal.
- the invention in another aspect, relates to a method for parenteral administration of a drug substance to a human or an animal, the method comprising: i) contacting the skin or the mucosa of said human or animal with a body of a solid pharmaceutical composition which comprises the drug substance and which has a shape and/or a strength which enables it to penetrate unbroken skin or mucosa in order to deliver said drug substance to an underlying tissue or into the blood stream of the human or of the animal; and ii) penetrating said skin or mucosa with said body so as to position at least a part of said body in said underlying tissue or in said blood stream.
- the present invention further relates to a drug delivery system comprising i) at least one body of a solid pharmaceutical composition comprising at least one drug substance and having a shape and/or a strength enabling penetration of unbroken skin or mucosa by said body in order to deliver said drug substance to an underlying tissue or into the blood stream of a human or of an animal, and ii) supporting means adapted to facilitate said penetration.
- a further aspect of the present invention relates to a process for the preparation of a body of a pharmaceutical composition
- a process for the preparation of a body of a pharmaceutical composition comprising: i) mixing a material, preferably a polymer material and optionally a filler with an active drug substance, ii) extruding the mixture containing the active drug through a die to form an elongated body or, alterna ⁇ tively, shaping the mixture to the body by means of injection moulding, iii) drying the body and cutting the body to form a pointed end.
- the invention relates to a process for the preparation of a drug delivery device comprising embedding at least one body of a solid pharmaceutical compo- sition which comprises at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in a supporting means which is adapted to facilitate said penetration.
- a pharmaceutical composition according to the invention should be shaped so as to ensure that penetration of the skin or mucosa results in as little tissue damage (and pain) as possible, while also ensuring that administration is safe and reproducible.
- the body of a pharmaceutical composition according to the present invention normally has an elongated shape with at least one pointed end.
- Other shapes may also be used, for example a tetrahedral shape, in which the pointed end will always be opposite a plane surface, thereby facili- tating correct administration.
- Such tetrahedral shaped compo ⁇ sitions can easily be administered by pressing the pointed end of the composition against the skin or mucosal surface to be penetrated, pressure being applied to the opposite plane surface e.g. using the tip of a finger.
- the body of a pharmaceutical composition according to the invention can have any shape which, taking into consideration the strength of the body in question, enables the body to penetrate the mucosa or skin in order to deliver an active drug substance to the underlying tissue or a blood vessel.
- an elongated or otherwise pointed shape normally will be most suitable, the size of the body also influences its penetration properties. Accordingly, it is contemplated that bodies having other shapes, e.g. spheri- cal, may be able to penetrate the mucosa or skin when the bodies are very small.
- the cross sectional shape of the elongated bodies will often be circular, but other cross sectional shapes will also be suitable, such as an oval, a triangle, a quadrangle a penta- gon, etc.
- An elongated body whose cross section has defined edges, e.g. a triangle or square, will also facilitate easy penetration of the skin or mucosa. In some case an elongated form with a hook shaped penetrating end may be preferred so that the body cannot be retrieved after penetration.
- the body of the solid pharmaceutical composition has the needle-shaped described above, which allows easy penetration of the skin without any use of some kind of penetrating equipment apart from the composition itself.
- the skin is clearly easily accessible, and because of its large surface area, areas where pain or discomfort is minimal can be identified. lso, finding new sites where no drug has previously or recently been administered is easy. The skin normally repairs itself easily as evidenced by the relative rapid healing following injections.
- Blood vessels represent a particular case of administration through the skin in which the target is a vein or artery. Special steps must be taken to ensure access to the blood vessels (see the description below and Fig. 4) .
- Other target organs and sites for administration according to the inven ⁇ tion are intrapenile, intralesional (tumours, papules, psoriatic plaques, acne cysts, warts, intradermal parasites, vesicles, scar tissue, keloids, cellulitis, furuncles, nails, bullae, hyper- or hypopigmented areas, angiomas, etc.) or into any organ accessible through the skin (testicles, corpus cavernosum, thyroid glands, etc.). Also administration to body cavities such as intra-articular, intraperitoneal, etc. will in some situations be of interest.
- Mucosa have a very rich blood supply, and the oral mucosa is a particularly suitable administration site according to the invention, especially when it is desirable that the active drug substance enters the oral venous drainage system to the right heart and bypasses the stomach and liver, thus avoiding first-pass destruction of the drug.
- the capillaries are very close to the surface, such as in the mucosa, whereby the length of penetration of the body of a solid composition according to the invention need not be longer than about 2 mm.
- the alveolar connective tissue below the skin has to be reached, and accordingly, the body of the solid composition according to the invention should preferably be about 3 mm long.
- Preferred routes of administration according to the invention are subcutaneous injection (i.e. under the skin), submucosal injection (i.e. under the mucosa), intradermal injection (i.e. within the vascular inner layer of the skin, this route usually being employed for a local action within the skin such as in skin tests), intramucosal injection (i.e. within the mucosa), intramuscular injection (i.e. within a muscle), intravenous injection (i.e. within a vein), and intra-arte- rial injection (i.e. within a artery) .
- the body con ⁇ tains the active substance or drug alone, which allows a larger amount of the active ingredient to be administered using a given size body.
- the active substance will generally not be able to be moulded into a needle strong enough and with the right volume to penetrate the skin or mucosa alone. Therefore, the most common implementation comprises of a material to give strength (such as, e.g., a polymer mate ⁇ rial) , optionally together with a filler to compensate for different dosages in addition to the drug.
- a material to give strength such as, e.g., a polymer mate ⁇ rial
- a filler to compensate for different dosages in addition to the drug.
- the filler is e.g. a sugar which also imparts improved physical properties to the gelatin.
- the invention is particularly suitable for the administration of active substances which are digested in the gastro ⁇ intestinal tract or which are labile in an aqueous medium or an aqueous environment.
- the active substance is embedded or encapsulated in a body which is substantially dry and in such a medium degradation of the active substance with respect to e.g. hydrolysis cannot take place.
- active substance as used herein broadly in ⁇ cludes any compound, or mixture thereof, that can be deli ⁇ vered from the composition to produce a beneficial result.
- the active and beneficial agents include pharmaceutically or physiologically active substances (drugs) , food supplements, nutrients, cosmetics, vitamins, and other agents that benefit the environment in which they are used.
- drug and drug substance include any physiologically or pharmacologically active sub ⁇ stance that produces a localized or systemic effect in ani ⁇ mals, in particular mammals, including humans and primates.
- Other animals include domestic household, sport or farm ani ⁇ mals such as sheep, goats, cattle, horses and pigs, labora- tory animals such as mice, rats and guinea pigs, fishes, to avians, reptiles and zoo animals.
- Hormones and their derivatives such as: - hypothalamus hormones pituitary gland hormones such as growth hormone, oxytocin, and LH-RH adrenal hormones, corticosteroids and derivatives thereof - thyroid gland hormones such as calcitonin
- pancreatic hormones and derivatives thereof pancreatic hormones and derivatives thereof such as insulin and glucagon cardiovascular regulatory hormones such as natriure- tic hormone sex hormones
- Proteins including adhesive matrix proteins such as, e.g., fibronectin, vitronectin, laminin, collagens, thrombospondin; growth factors such as, e.g., acidic and basic fibroblast growth factor (acidic FGF and basic FGF, respectively), interleukin-2 (int-2) , hst/ks, FGF-5, FGF- 6, keratinocyte growth factor (KGF) , heparin-binding epidermal growth factor (HB-EGF) , vascular endothelial growth factor (VEGF) , tumour growth factors (TGF) , plate- let derived growth factor (PDGF) and interferon 7; pro ⁇ teins involved in lipid metabolism such as, e.g., lipo- protein lipase, hepatic triglyceride lipase, apolipopro- tein B, apolipoprotein E; serine protease inhibitors such as, e.g.,
- CNS-stimulants anxiolytics, sympatomimetics, parasympa- tomimetics, parasy patolytics, vasoconstrictors and vaso ⁇ dilators, antineoplastic, antiviral drugs and antitu our drugs, anoretics, antimimitics, anastethics, analgetica, antibiotics, anti-allergic drugs, anticholinergics, anti- depressants, antiepileptica, antiinflammatory drugs, vasoactive drugs, cardial active drugs, blood factors, antihypertensiva, prostaglandins, growth factors, cyto- kines such as interferons, enzymes, including enzymes associated with lysomal defects, vaccines, including antibodies, diagnostic drugs such as substances used for skin tests, vitamins such as vitamin D, and nutrients.
- the drug substance which is incorporated in a pharmaceutical composition according to the invention can be in various forms, such as uncharged molecules, molecular complexes, a pharmacologically acceptable salt such as a hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate.
- a pharmacologically acceptable salt such as a hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate.
- salts of metals, amines, amino acids or organic cations, quaternary ammonium can be used.
- Derivatives of drugs such as esters, ethers and amides can be used alone or mixed with other drugs and after their release from the composition they may be converted by enzymes, hydrolyzed by body pH or other metabolic processes to the original form, or to a biologically active form.
- One class of active drugs which are particularly suitable for administration according to the invention are interferons such as (X J - - ⁇ X ⁇ - 1 ⁇ and 7-interferons.
- the dose of the active drug to be used in each particular case will of course depend upon the effect to be achieved and the intended use.
- a body of a pharmaceutical compo ⁇ sition according to the invention or at least a part of it must have a sufficient strength to enable penetration of skin or mucosa.
- suitable examples of materials which can form the basis of the body of a pharmaceutical composition according to the invention and/or which may be added to another basic material for such a body and/or which may increase the strength of such a body are inorganic salts such as, e.g., calcium, magnesium, bismuth or zinc salts; lipids; carbohy ⁇ drates; proteins such as, e.g., gelatins, collagens, modified collagens, albumins, caseins and derivatives thereof; natural polymers; synthetic polymers such as, e.g., poly-epsilon- aminocaproic acid, poly-isobutyric acid and derivatives thereof, polylactic acid and derivatives thereof, polyglyco- lic acid and derivatives thereof, poly(lactide-glycolide)- copolymers and derivative
- An interesting embodiment according to the invention is a body comprising the carbohydrate in crystalline or caramelized form.
- Suitable carbohydrates are celluloses, cellulose deri ⁇ vatives, modified celluloses, modified cellulose derivatives and mixtures thereof.
- a higher concentration of a strength-improving material can be incorporated, either as a core in the body or applied as a cap at the penetration end portion or covering the hole body.
- the strength-improving material can also be distributed uniformly throughout the body or in defined layers or zones within the body.
- the compressive strength of bodies according to the present invention is usually at least about 15 x 10 3 pounds/sq in. With increasing compressive strength of the materials used, the size of the composition can be decreased.
- the specific compressive strength of each individual composi ⁇ tion will depend on the active drug itself as well as the other components and the manner in which the composition is prepared.
- the compressive strength is preferably at least about 30 x 10 3 pounds/sq in. For some embodiments according to the invention the compressive strength will be at least about 50 x 10 3 pounds/sq in.
- compositions comprising carbohydrates in caramelized form the compressive strength of the compositions is very often more than 100 x 10 3 pounds/sq in.
- the material for preparation of the pharmaceutical composition is preferably biodegradable or substantially biodegradable and/or soluble or substantially soluble in an aqueous medium.
- the choice of material for preparation of a pharmaceutical composition according to the invention depends primarily on the nature of the active drug substance, i.e. its physical and chemical structure. As a consequence of the variation in the physical and chemical properties of the materials en- tioned above, a given material may have different effects in different compositions, and different materials can therefore act e.g. as fillers or carriers.
- compositions according to the invention may further comprise various pharmaceutically acceptable excipients.
- One or more excipients may be added to modify the dissolution rate after administration, for example by increasing the content of water in the area of delivery by osmotic force.
- dissolution rate modifiers are monosacchari- des, disaccharides, oligosaccharides, gellans, cyclodextrins, and mixtures thereof which can enhance the dissolution of drug substances such as, e.g., insulin.
- penetration enhancers can be added to the composition.
- the penetration enhancer may e.g. be an enzyme, for example a catabolic enzyme which acts by cleaving components of the supporting matrix of the tissue, thereby increasing the flow rate of body fluids through the tissue.
- enzymes are proteases, lipases and deoxyribonucleases.
- Speci- fie enzymes which may be employed are for example amylase, dextranase, hyaluronidase, brinolase, bromelains, pancreatin, chymopapain, chymotrypsins, papain, pepsin, plasmin, rennet, trypsin, urokinase, deanase, streptodornase, streptokinase, pancrealipase, muramidase, and mixtures thereof.
- An interesting embodiment of the invention is a pharmaceuti ⁇ cal composition from which the drug substance is freely released, in contrast to sustained released compositions.
- the term "free release” refers to situations in which no excipient has been added to the composition for the purpose of influencing the delivery rate of the active substance from the composition itself. In other words, the release profile of the drug is substantially unaltered by the composition containing it.
- modified release When an excipient that influences the release is added, this is referred to as "modified release”. This includes excipients which either increase or decrease the rate of release. Examples of types of modified release are sustained release, where the drug is released over a prolonged period, and pulsed release, where the release is not continuous, but rather occurs in pulses or bursts.
- a body of a pharmaceutical composition according to the invention may be prepared by means of extrusion or injection moulding, i.e. the material forming the basis of the body is preferably able to undergo an extrusion process or an injec ⁇ tion moulding process.
- the invention relates to a drug delivery system or device comprising
- At least one body of a solid pharmaceutical composi- tion comprising at least one drug substance and having a shape and/or a strength enabling penetration of unbroken skin or mucosa by said body in order to deliver said drug substance to an underlying tissue or into the blood stream of a human or of an animal, and ii) supporting means adapted to facilitate said penetra ⁇ tion.
- a device constituting the drug delivery system of the present invention will thus comprise a supporting means.
- supporting means may be employed according to the invention including supporting means where the body of the pharmaceutical composition according to the invention, preferably in the form of a needle, is driven through a cylindrical device such as a piston-like device.
- the support ⁇ ing means may typically of a compressible or contractible material, often a sponge or sponge-like material, in which one or more often needle-shaped bodies containing the drug are embedded.
- Administration of the drug takes place by first placing one side of the device in contact with the skin or mucosa through which the drug is to be administered.
- the actual administra ⁇ tion of the drug is accomplished by applying pressure, e.g. using a finger or a hand, thereby compressing the supporting material. This in turn leads to penetration of the skin by the needles or other bodies containing the drug and thus to release of the drug in the underlying tissue or blood stream.
- the pressure applied to administer the drug is typically applied to the side of the device opposite the skin or mucosa.
- another possibility is to apply pressure indirectly. This possibility can for example be used when the drug is to be administered via the oral mucosa.
- the device may be placed in the mouth of the patient in such a manner that one side of the device (i.e. the side through which the drug is to be delivered) is in contact with the inner side of the cheek, while the opposite side of the device is in contact with the teeth and/or gum. Compression of the supporting material and administration of the drug can in this case be obtained by applying pressure on the outside of the cheek.
- the foam or sponge of the supporting means is optionally covered on the surface which is to be in contact with the skin or mucosa with an adhesive and/or disinfecting material.
- the opposite surface is preferably covered by a backing designed to effectively transfer pressure to the needles, e.g. of a rigid, non-flexible material.
- the material in which the needle or other body is embedded com ⁇ prises components which are substantially biodegradable and/or which can be swallowed by the patient with no signifi ⁇ cant discomfort.
- the needles or bodies are embedded in a sup ⁇ porting means such as a foam or sponge designed to insulate them from the environment, in particular from humidity and from contamination.
- the supporting means may also be in the form of a plate, a pad, a patch, a disc, a strip, or a plas ⁇ ter.
- the structure of the supporting device should allow displacement of the needle in the needle's axial direction but not to the sides, thus guiding the needle into the skin and preventing it from breaking due to pressure applied during administration of the drug.
- the supporting means is preferably made of a compressible or collapsible material and preferably has at least one surface covered by a backing which preferably cannot be penetrated by the needle or other body containing the drug.
- the backing may be flexible or non- flexible.
- the supporting means may contain or may have a surface covered with a disinfecting material.
- the surface which is to be in contact with the skin or mucosa may further be covered with an adhesive material to facilitate placement.
- the side of the supporting means facing the skin or mucosa may have a concave shape to ensure that the blood vessel into which the drug is to be administered remains fixed and does not slip or move in the subcutaneous tissue, thus allowing the needle containing the drug to penetrate the thickest part holding the vein or artery (confer Fig. 4) .
- the supporting means may be made of any suitable material such as, e.g., gums such as guar gum, locust bean gum, gum arabic, agar, carrageenan, liquorice, open cell polyure hane foam, synthetic and/or natural rubber and their foams, cellu ⁇ loses and derivatives thereof such as, e.g., methylcellulose, plastic materials and the like.
- gums such as guar gum, locust bean gum, gum arabic, agar, carrageenan, liquorice, open cell polyure hane foam, synthetic and/or natural rubber and their foams, cellu ⁇ loses and derivatives thereof such as, e.g., methylcellulose, plastic materials and the like.
- Crystallized and caramelized sugars may also be used for the backing of the supporting means.
- Caramelized sugars are obtained heating sugars in the absence of water heated in a concentrated solution.
- a drug delivery system according to the invention may be prepared by injection moulding which makes it possible to prepare the body of the pharmaceutical composition according to the invention as well as the sup ⁇ porting means by an economical and relatively simple process.
- flavours and/or sweeteners can be added to the body or the device according to the invention.
- the invention relates to a method for parenteral administration of a drug substance to a human or an animal, the method comprising:
- a body of a solid pharmaceutical composition which comprises the drug substance and which has a shape and/or a strength which enables it to penetrate unbroken skin or mucosa in order to deliver said drug substance to an underlying tissue or into the blood stream of the human or of the animal; and ii) penetrating said skin or mucosa with said body so as to position at least a part of said body in said underlying tissue or in said blood stream.
- the invention relates to a method for preparing a body of a pharmaceutical composition according to the invention, the method comprises
- the invention also relates to a method for preparing a drug delivery system according to the invention, the method co - prises embedding at least one body of a solid pharmaceutical composition which comprises at least one drug substance and having a shape and/or a strength which enables it to pene ⁇ trate unbroken skin or mucosa of a human or animal in a supporting means which is adapted to facilitate said penetra- tion.
- Fig. IA shows a drug delivery system according to the inven- tion wherein a body of a solid pharmaceutical composition according to the invention 1 is embedded in a compressible or collapsible supporting material 2 having a contact surface 4 adapted to be brought into contact with skin or mucosa 5.
- the supporting material 2 is covered with a backing 3 made of a flexible material which enables transfer of pressure applied to the backing material 3 to the body 1.
- Fig. IB shows the drug delivery system shown in Fig. IA after pressure has been applied (as indicated by the arrow in the figure) to the flexible backing material 3 so as to compress the supporting material 2, causing the body 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
- Fig. 2A shows an alternative embodiment of a drug delivery system according to the invention and having a compressible or collapsible supporting material 2 as described in connec ⁇ tion with Fig. IA, but in which the backing material 3 is a substantially rigid, i.e. non-flexible, material.
- Fig. 2B shows the drug delivery system as shown in Fig. 2A after pressure has been applied (as indicated by the arrows in the figure) to the substantially rigid backing material 3 so as to compress the supporting material 2, causing the body 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
- Fig. 3A shows an alternative embodiment of a drug delivery system according to the invention and having a compressible or collapsible supporting material 2 as described in connec- tion with Fig. 2A but in which three bodies 1 are embedded in the supporting material.
- Fig. 3B shows the drug delivery as shown in Fig. 3A after pressure has been applied (as indicated by the arrows in the figure) to the substantially rigid backing material 3 so as to compress the supporting material 2, causing the bodies 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
- Fig. 4A and 4B illustrate a modification of the embodiment of a drug delivery system according to the invention as shown in Fig. 2A and 2B and its use in administering a body 1 accord ⁇ ing to the invention to a blood vessel 6 underlying a surface 5 of skin or mucosa.
- the surface 4 of the supporting material 2 which is to be brought into contact with the skin or mucosa has a concave form adapted to be brought into position above, and substantially match the contour of, that part of the skin or mucosa which overlies the blood vessel which has a lumen 5 and a wall 6 positioned just beneath the skin or the mucosa, the body 1 being located substantially at the bottom of the depression resulting from the concavity of the surface .
- the concave form of the surface 4 thus facilitates positioning of the body 1 relative to the blood vessel 6 and 7 so as to ensure correct penetra ⁇ tion of the body 1 through the wall 7 of the blood vessel and into the lumen of the blood vessel 6 upon applying pressure to the backing material 3 in the manner shown in Fig. 3B.
- Fig. 5 illustrates the results of an in vivo test in Mini- Pigs.
- the test is a comparison test between a conventional insulin composition Actrapid® and an insulin-containing com- position according to the invention.
- the results shown in Fig. 5 clearly indicate that a composition according to the invention may replace a conventional product like Actrapid®.
- a saturated solution of gelatin in water is mixed with beta- cyclodextrin to form a paste, an active drug is added and the mixture is extruded through a 0.2 mm die.
- the resulting, cy- linder is left to dry until a firm and crystallized consist ⁇ ency is achieved.
- the dried cylinder is cut diagonally to form a pointed cutting edge.
- Example 1 10% gelatin and 1% agarose are mixed with an active drug and the mixture is milled to a particle size of less than 100 ⁇ m. The milled mixture is extruded through a needle and then dried and cut as explained in Example 1.
- compositions according to the invention are prepared by dissolving 10% w/w of gelatin and 2% w/w of gellen in water and left to gellify. The resulting gel is then milled to a particle size of less than 50 ⁇ m. The resul- ting "powder” is mixed with insulin (or any other drug sub ⁇ stance) and extruded using a hypodermic syringe. The result ⁇ ing "spaghetti"-like material is suspended and left to dry in the air, optionally in a desiccator. After 6 hours in the open air, the spaghetti-like material has acquired the desired crystalline structure.
- compositions containing insulin were prepared as described in Example 3 herein and with a content of 5% w/w of methylene blue (i.e. 5% w/w of methylene blue was added to the powder described above) .
Abstract
A method for parenteral administration of a drug substance comprising penetration of the skin or the mucosa of a human or an animal by a body of an appropriately formed solid pharmaceutical composition is disclosed. The body of the pharmaceutical composition may be needle-shaped so that it is possible to avoid any external penetration equipment when the composition is administered. The composition is preferably made by materials which are biodegradable such as, e.g., materials selected from the group consisting of inorganic salts such as, e.g., calcium, magnesium, bismuth and zinc salts; lipids; carbohydrates, such as, e.g., polysaccharides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixtures thereof; proteins such as, e.g., gelatins, collagens, modified collagens, albumins, caseins and derivatives thereof, and mixtures thereof; natural polymers, synthetic polymers such as, e.g., poly-epsilon-aminocaproic acid, poly-isobutyric acid and derivatives thereof, polylactic acid and derivatives thereof, polyglycolic acid and derivatives thereof, poly(lactide-glycolide)-copolymers and derivatives thereof, polyesters, polyethylene glycols, polypropylene glycols, Pluronics®; and mixtures thereof. Especially gelatin has proved suitable as basic material. A drug delivery system comprising a body of a pharmaceutical composition and supporting means for facilitating the administration is also disclosed.
Description
DRUG ADMINISTRATION SYSTEM
FIELD OF THE INVENTION
The present invention relates to a method for parenteral administration of a drug substance comprising penetration of the skin or the mucosa of a human or an animal by a body of an appropriately formed solid pharmaceutical composition. The present invention also relates to a body of a solid pharma¬ ceutical composition which has a shape and/or strength which enables it to penetrate unbroken skin or mucosa of a human or an animal in order to deliver an active substance to the animal and to a process for the preparation of this composi¬ tion. Furthermore, the present invention relates to a novel drug delivery system comprising a solid body of a pharma¬ ceutical composition and to a process for the preparation of such a drug delivery system.
BACKGROUND OF THE INVENTION
Many different methods and systems for delivery of drug substances are available today.
In general, the oral route is the preferred administration route in that numerous drug substances are readily absorbed from the gastrointestinal tract. This form of administration is easy and well accepted by the patient, and generally results in good patient compliance. However, even though advanced techniques within the field of drug formulation, such as time controlled-release systems, have made it pos¬ sible to administer a wide range of different types of phar¬ maceuticals in an acceptable manner, the bioavailability of the drug substance, i.e. the rate of drug absorption and the extent to which the drug substance is absorbed, still depends to a considerable extent on the nature of the active drug substance itself, i.e. on its physical and chemical proper¬ ties. Accordingly, many drug substances, e.g. numerous pepti-
des, still cannot be administered satisfactorily by the oral route.
An administration route which circumvents the gastrointesti¬ nal tract is normally referred to as a parenteral administra- tion route. Parenteral administration is the route of choice for drugs which are degraded or are erratically or unreliably absorbed when administered orally. The parenteral route pro¬ vides a reliable dose-response relationship. Parenteral admi¬ nistration routes can be divided up into invasive and non- invasive routes, i.e. routes in which delivery of the active drug substance takes place with or without physical disrup¬ tion of the skin or mucosa, respectively. Examples of non- invasive routes are transcutaneous delivery of a drug sub¬ stance applied in form of plasters (and in rare cases oint- ments) , and transmucosal delivery, such as nasal administra¬ tion or sublingual administration whereby the drug substance is protected from first-pass metabolism by the liver. Both the invasive and the non-invasive parenteral administration routes are associated with several disadvantages. For instance, the use of the non-invasive parenteral route is limited to the relatively small number of drug substances which are able to penetrate the skin or mucosa at a suffi¬ cient rate. Some of the risks associated with invasive admi¬ nistration are discussed in greater detail below.
The administration of drugs which are intended to reach the vascular or circulatory system of a human or of an animal within a rather short time normally involves an invasive administration route wherein the intact external barrier of the body (the skin or the mucosa) is disrupted or penetrated. Such methods all have specific advantages and disadvantages.
With respect to the invasive route of parenteral administra¬ tion, it is difficult to make a clear distinction between injections and implants. Nevertheless, it is normally accepted that injection relates to the administration of liquid formulations to the body by means of needles or cathe-
ters, whereas implants are generally employed for administra¬ tion of formulations in solid form which can be incorporated into the body by various mechanical methods involving the use of some kind of invasive equipment or which can be inserted into a lesion, e.g. in connection with surgery. In addition, implants are normally employed when sustained release of a drug is desired. Due to the need for rather specialized equipment and skill of the person performing the implanta¬ tion, this administration route is normally restricted to situations wherein a special sustained administration is desired or to administration to locations where the blood supply for some reason is limited.
In the patents and literature cited below solid preparations and methods for parenteral administration of such solid preparations are disclosed.
European Patent No. 139 286 Bl discloses an injectable sus¬ tained-release preparation which comprises an active ingredi¬ ent and a pharmaceutically acceptable proteinaceous biodegra¬ dable carrier. The preparation is described as having a needle-like or bar-like shape. The preparation is employed as an implant which is inserted into the body e.g. by injection, for example by inserting a fine tube (such as a catheter) into the body, and inserting the needle-like shaped prepara¬ tion via the fine tube, or by inserting the preparation directly into the body by means of forceps needles which are capable of penetrating the skin. A specific embodiment of a device for administering the preparation is also disclosed which comprises a fine tube and an inner needle. The inner needle is stabbed into a portion of the body, whereafter the fine tube is inserted into the body by sliding its inner wall along the outer wall of the inner needle. The needle-like preparation is inserted into the body by passing it through the fine tube. Usually the insertion of the preparation into the fine tube is carried out by withdrawing the inner needle and then pushing the preparation into the body via the fine tube with a pushing pole.
A solid needle-like or bar-like sustained-release preparation suitable for injection is disclosed in US Patents Nos. 5,021,241 and 4,774,091. The preparations comprise a physio¬ logically active ingredient that is unstable to heat and a pharmaceutically acceptable biodegradable protein carrier. The needle-like or bar-like preparations according to the examples disclosed in these patents are formed by compression of the preparation obtained by mixing the active ingredient and the carrier under aqueous condition. It is mentioned that the preparation can be inserted into a body by operation or with a forceps needle for a fibrescope, or via an indwelling needle.
US Patent Nos. 5,081,156 and 4,855,134 disclose sustained- release preparations comprising interferon or indomethacin or a salt thereof as an active ingredient and collagen or gela¬ tin or albumin as a biodegradable carrier, the preparation being in form of powder particles suspended in a viscous solvent suitable for injection, or being in the form of a shaped preparation suitable for use as an injection in a solid state or for implanting into a body. The preparations according to the cited patents are prepared by a process which comprises mixing the active ingredient with the carrier to form a liquid mixture, and drying the resultant mixture. A needle-like or bar-like preparation is formed under compres- sion, and it is mentioned that such preparations can be inserted into a body by operation or with a forceps needle for a fibrescope or via an indwelling needle. It is also mentioned that the preparation may be formed into other conventional sustained-release oral preparations, a medicine for external application, suppositories or the like by con¬ ventional techniques.
US Patent No. 4,849,141 discloses a method for preparing a sustained-release formulation. It is mentioned that the formulation may have a variety of sizes and shapes, such as a spherical, hemispherical, column, tubular, or sheet-like shape as well as needle- or bar-like shape. In addition, it
is mentioned in this patent that the formulation may be admi¬ nistered to a living body, for example, by subcutaneous in¬ sertion or implantation into a body cavity, depending on the lesional region to be treated. The method for preparing the formulation comprises blending of a physiologically active ingredient together with collagen and/or gelatin using a solvent such as pure water or water in admixture with a hydrophilic organic solvent. It is also mentioned that the formation of fibres in the composition should be avoided.
Lin et al. (Biomat., Art. Cells, Art. Org., (1988), 16(4) , 801-814 and Biomat., Art. Cells, Art. Org., (1989), 17(2) . 189-203) describe controlled release polymeric needle devices containing adriamycin HC1 for local treatment of solid tumours. The polymeric needles are made of polylactic acid or ethylene-vinyl acetate and hydroxypropylmethylcellulose is said to be used as a release regulator.
It appears from the patents and literature cited above that all the solid formulations disclosed therein for parenteral administration should be administered using some sort of penetrating equipment or means which is separate from and does not form a part of the preparation or formulation itself.
In general, formulations adapted for invasive parenteral administration are administered through catheters or needles which are used to provide a passageway for the drug sub¬ stance. The drug substance is normally forced through the needle or catheter by use of a syringe, stiletto, or pushing pole, or simply by gravity.
Among the disadvantages of conventional invasive parenteral administration routes, such as injection through a needle or via other penetration means, are the direct local pain caused at the site of penetration and the psychological unpleasant¬ ness which is generally associated with needles and injec¬ tions; the latter disadvantages reduce the applicability of
such conventional routes in self-administration. In addition, the necessity for using correct techniques in handling the injection means and carrying out the injection requires spe¬ cial skills on the part of the person performing the admini- stration, especially in the case of intravenous and intramus¬ cular injections.
It is well-known that failure to follow aseptic procedures is a common problem even among trained hospital employees when preparing and administering parenteral medicaments; accord- ingly, parenteral administration is associated with an appre¬ ciable risk of life-threatening septicemia. It is clear that every penetration of the skin or the mucosal barrier is associated with a considerable risk of infection, and accor¬ dingly every effort should be made to minimize the necessary number of insertions or penetrations.
Other serious disadvantages in addition to infection are complications due to the unintended introduction of particulate matter, air embolism, and breakage of catheters, needles, or other penetration means used. For example, there is the possibility of injection into the patient of glass particles formed during opening or breakage of ampoules, or of rubber particles cut off by the needle when penetrating the closure (e.g. a septum) . Furthermore, there is a risk of infection from contaminated equipment such as used needles.
SUMMARY OF THE INVENTION
A body of a solid pharmaceutical composition with a shape and consistency enabling it to penetrate the skin would solve most of the above-discussed problems related to invasive parenteral administration. If such a body of a solid phar a- ceutical composition consists essentially of the active drug substance itself, its size can be reduced, thus minimizing pain and leaving no superfluous equipment and therefore no risk of infection to others, and, if properly designed, it would be easy to use by the end user. Such a body could be
designed for immediate release or for delayed release of the drug.
The object of the present invention is the provision of such bodies and drug delivery systems.
In one aspect, the present invention relates to a body of a solid pharmaceutical composition comprising at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in order to deliver said drug substance to an underlying tissue or into the blood stream of said human or animal.
In another aspect, the invention relates to a method for parenteral administration of a drug substance to a human or an animal, the method comprising: i) contacting the skin or the mucosa of said human or animal with a body of a solid pharmaceutical composition which comprises the drug substance and which has a shape and/or a strength which enables it to penetrate unbroken skin or mucosa in order to deliver said drug substance to an underlying tissue or into the blood stream of the human or of the animal; and ii) penetrating said skin or mucosa with said body so as to position at least a part of said body in said underlying tissue or in said blood stream.
The present invention further relates to a drug delivery system comprising i) at least one body of a solid pharmaceutical composition comprising at least one drug substance and having a shape and/or a strength enabling penetration of unbroken skin or mucosa by said body in order to deliver said drug substance to an underlying tissue or into the blood stream of a human or of an animal, and ii) supporting means adapted to facilitate said penetration.
A further aspect of the present invention relates to a process for the preparation of a body of a pharmaceutical composition comprising: i) mixing a material, preferably a polymer material and optionally a filler with an active drug substance, ii) extruding the mixture containing the active drug through a die to form an elongated body or, alterna¬ tively, shaping the mixture to the body by means of injection moulding, iii) drying the body and cutting the body to form a pointed end.
In a still further aspect the invention relates to a process for the preparation of a drug delivery device comprising embedding at least one body of a solid pharmaceutical compo- sition which comprises at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in a supporting means which is adapted to facilitate said penetration.
DETAILED DESCRIPTION OF THE INVENTION
As appears from the above, a pharmaceutical composition according to the invention should be shaped so as to ensure that penetration of the skin or mucosa results in as little tissue damage (and pain) as possible, while also ensuring that administration is safe and reproducible.
As mentioned above, the body of a pharmaceutical composition according to the present invention normally has an elongated shape with at least one pointed end. Other shapes may also be used, for example a tetrahedral shape, in which the pointed end will always be opposite a plane surface, thereby facili- tating correct administration. Such tetrahedral shaped compo¬ sitions can easily be administered by pressing the pointed end of the composition against the skin or mucosal surface to be penetrated, pressure being applied to the opposite plane surface e.g. using the tip of a finger.
Quite generally, the body of a pharmaceutical composition according to the invention can have any shape which, taking into consideration the strength of the body in question, enables the body to penetrate the mucosa or skin in order to deliver an active drug substance to the underlying tissue or a blood vessel. Though an elongated or otherwise pointed shape normally will be most suitable, the size of the body also influences its penetration properties. Accordingly, it is contemplated that bodies having other shapes, e.g. spheri- cal, may be able to penetrate the mucosa or skin when the bodies are very small.
The cross sectional shape of the elongated bodies will often be circular, but other cross sectional shapes will also be suitable, such as an oval, a triangle, a quadrangle a penta- gon, etc. An elongated body whose cross section has defined edges, e.g. a triangle or square, will also facilitate easy penetration of the skin or mucosa. In some case an elongated form with a hook shaped penetrating end may be preferred so that the body cannot be retrieved after penetration.
In a preferred embodiment of the invention, the body of the solid pharmaceutical composition has the needle-shaped described above, which allows easy penetration of the skin without any use of some kind of penetrating equipment apart from the composition itself.
Other possibilities are for example a thicker "nail-like" shape or needles mounted in a strip adapted to facilitate administration with automatic equipment. Such bodies would be suited to be applied with the help of an instrument for serial administration (i.e. for vaccination, veterinary uses, etc.) .
Three different areas for administration are contemplated: The skin, the mucosa (especially the oral mucosa) , and the blood vessels.
The skin is clearly easily accessible, and because of its large surface area, areas where pain or discomfort is minimal can be identified. lso, finding new sites where no drug has previously or recently been administered is easy. The skin normally repairs itself easily as evidenced by the relative rapid healing following injections.
Blood vessels represent a particular case of administration through the skin in which the target is a vein or artery. Special steps must be taken to ensure access to the blood vessels (see the description below and Fig. 4) . Other target organs and sites for administration according to the inven¬ tion are intrapenile, intralesional (tumours, papules, psoriatic plaques, acne cysts, warts, intradermal parasites, vesicles, scar tissue, keloids, cellulitis, furuncles, nails, bullae, hyper- or hypopigmented areas, angiomas, etc.) or into any organ accessible through the skin (testicles, corpus cavernosum, thyroid glands, etc.). Also administration to body cavities such as intra-articular, intraperitoneal, etc. will in some situations be of interest.
Mucosa have a very rich blood supply, and the oral mucosa is a particularly suitable administration site according to the invention, especially when it is desirable that the active drug substance enters the oral venous drainage system to the right heart and bypasses the stomach and liver, thus avoiding first-pass destruction of the drug. For purposes of the present invention it is desirable that the capillaries are very close to the surface, such as in the mucosa, whereby the length of penetration of the body of a solid composition according to the invention need not be longer than about 2 mm. For administration to the skin, the alveolar connective tissue below the skin has to be reached, and accordingly, the body of the solid composition according to the invention should preferably be about 3 mm long.
Preferred routes of administration according to the invention are subcutaneous injection (i.e. under the skin), submucosal
injection (i.e. under the mucosa), intradermal injection (i.e. within the vascular inner layer of the skin, this route usually being employed for a local action within the skin such as in skin tests), intramucosal injection (i.e. within the mucosa), intramuscular injection (i.e. within a muscle), intravenous injection (i.e. within a vein), and intra-arte- rial injection (i.e. within a artery) .
In an interesting embodiment of the invention the body con¬ tains the active substance or drug alone, which allows a larger amount of the active ingredient to be administered using a given size body. The active substance will generally not be able to be moulded into a needle strong enough and with the right volume to penetrate the skin or mucosa alone. Therefore, the most common implementation comprises of a material to give strength (such as, e.g., a polymer mate¬ rial) , optionally together with a filler to compensate for different dosages in addition to the drug. This enables the formulation of a needle to easily be adapted to new drugs. One such preferred polymer is gelatin, since it is regarded as being innocuous and because it fulfils the requirements of strength and solubility in body fluids. The filler is e.g. a sugar which also imparts improved physical properties to the gelatin.
The invention is particularly suitable for the administration of active substances which are digested in the gastro¬ intestinal tract or which are labile in an aqueous medium or an aqueous environment. In a composition according to the invention, the active substance is embedded or encapsulated in a body which is substantially dry and in such a medium degradation of the active substance with respect to e.g. hydrolysis cannot take place.
The expression "active substance" as used herein broadly in¬ cludes any compound, or mixture thereof, that can be deli¬ vered from the composition to produce a beneficial result. The active and beneficial agents include pharmaceutically or
physiologically active substances (drugs) , food supplements, nutrients, cosmetics, vitamins, and other agents that benefit the environment in which they are used.
In the present context, the term "drug" and "drug substance" include any physiologically or pharmacologically active sub¬ stance that produces a localized or systemic effect in ani¬ mals, in particular mammals, including humans and primates. Other animals include domestic household, sport or farm ani¬ mals such as sheep, goats, cattle, horses and pigs, labora- tory animals such as mice, rats and guinea pigs, fishes, to avians, reptiles and zoo animals.
A number of active drug substances which may be delivered according to the invention are listed below:
Hormones and their derivatives such as: - hypothalamus hormones pituitary gland hormones such as growth hormone, oxytocin, and LH-RH adrenal hormones, corticosteroids and derivatives thereof - thyroid gland hormones such as calcitonin
- gastrointestinal hormones and derivatives thereof pancreatic hormones and derivatives thereof such as insulin and glucagon cardiovascular regulatory hormones such as natriure- tic hormone sex hormones
Proteins including adhesive matrix proteins such as, e.g., fibronectin, vitronectin, laminin, collagens, thrombospondin; growth factors such as, e.g., acidic and basic fibroblast growth factor (acidic FGF and basic FGF, respectively), interleukin-2 (int-2) , hst/ks, FGF-5, FGF- 6, keratinocyte growth factor (KGF) , heparin-binding epidermal growth factor (HB-EGF) , vascular endothelial growth factor (VEGF) , tumour growth factors (TGF) , plate-
let derived growth factor (PDGF) and interferon 7; pro¬ teins involved in lipid metabolism such as, e.g., lipo- protein lipase, hepatic triglyceride lipase, apolipopro- tein B, apolipoprotein E; serine protease inhibitors such as, e.g., antithrombin III, heparin co-factor II, pro¬ tease nexins; and other proteins such as, e.g., super¬ oxide dismutase, elastase, platelet factor 4, N-CAM, viral coat protein, transcription fractions, coagulase enzymes;
CNS-stimulants, anxiolytics, sympatomimetics, parasympa- tomimetics, parasy patolytics, vasoconstrictors and vaso¬ dilators, antineoplastic, antiviral drugs and antitu our drugs, anoretics, antimimitics, anastethics, analgetica, antibiotics, anti-allergic drugs, anticholinergics, anti- depressants, antiepileptica, antiinflammatory drugs, vasoactive drugs, cardial active drugs, blood factors, antihypertensiva, prostaglandins, growth factors, cyto- kines such as interferons, enzymes, including enzymes associated with lysomal defects, vaccines, including antibodies, diagnostic drugs such as substances used for skin tests, vitamins such as vitamin D, and nutrients.
Examples of specific active substances are:
Codeine, ethylmorphine, dextromethorphan, noscapine, pentoxi- verine, acetylcysteine, bromhexine, epinephrine, isoprenali- ne, orciprenaline, ephedrine, fenoterol, rimiterol, ipratro- pium, cholinetheophyllinate, proxiphylline, bechlomethasone, budesonide, deslanoside, digoxine, digitoxin, disopyramide, proscillaridin, chinidine, procainamide, mexiletin, flecaini- de, alprenolol, proproanolol, nadolol, pindolol, oxprenolol, labetalol, timolol, atenolol, pentaeritrityltetranitrate, isosorbiddinitrate, isosorbidmononitrate, niphedipin, phenyl- amine, verapamil, diltiazem, cyclandelar, nicotinylalcohol, inositolnicotinate, alprostatdil, etilephrine, prenalterol, dobutamine, dopa ine, dihydroergota ine, guanetidine, betani- dine, methyldopa, reserpine, guanfacine, trimethaphan, hydra-
lazine, dihydralazine, prazosine, diazoxid, captopril, nife- dipine, enalapril, nitroprusside, bendroflumethiazide, hydro- chlorthiazide, metychlothiazide, polythiazide, chlorthalidon, cinetazon, clopa ide, mefruside, metholazone, bumetanide, ethacrynacide, spironolactone, a iloride, chlofibrate, nico- tinic acid, nicheritrol, brompheniramine, cinnarizine, dex- chlorpheniramine, clemastine, antazoline, cyproheptadine, promethazine, cimetidine, ranitidine, sucralfat, papaverine, moxaverine, atropine, butylscopolamin, emepron, glucopyrron, hyoscyamine, mepensolar, methylscopolamine, oxiphencyclimine, probanteline, terodilin, sennaglycosides, sagradaextract, dantron, bisachodyl, sodiumpicosulfat, etulos, diphenolxy- late, loperamide, salazosulfapyridine, pyrvin, mebendazol, dimeticon, ferrofu arate, ferrosuccinate, ferritetrasemi- sodium, cyanochobalamine, folic acid heparin, heparin co- factor, diculmarole, warfarin, streptokinase, urokinase, factor VIII, factor IX, vitamin K, thiotepa, busulfan, chlorambucil, cyclophosphamid, melfalan, carmustin, ercapto- purin, thioguanin, azathioprin, cytarabin, vinblastin, vin- christin, vindesin, procarbazine, dacarbazine, lomustin, estramustin, teniposide, etoposide, cisplatin, amsachrin, aminogluthetimid, phosphestrol, medroxiprogresterone, hydro- xiprogresterone, megesterol, noretisteron, tamoxiphen, ciclo- sporin, sulfisomidine, bensylpenicillin, phenoxymethylpenici- llin, dicloxacillin, cloxacillin, flucloxacillin, ampicillin, amoxicillin, pivampicillin, bacampicillin, piperacillin, mezlocillin, mecillinam, pivmecillinam, cephalotin, cepha- lexin, cephradin, cephadroxil, cephaclor, cefuroxim, cefot- axim, ceftazidim, cefoxitin, aztreonam, imipenem, cilastatin, tetracycline, lymecycline, demeclocycline, metacycline, oxi- tetracycline, doxycycline, chloramphenicol, spiramycin, fusi- dic acid, lincomycin, clindamycin, spectinomycin, rifampicin, amphotericin B, griseofulvin, nystatin, vancomycin, etro- nidazole, tinidazole, trimethoprim, norfloxacin, salazosulfa- pyridin, aminosalyl, isoniazid, etambutol, nitrofurantoin, nalidixic acid, metenamine, chloroquin, hydroxichloroquin, tinidazol, ketokonazol, acyclovir, interferon idoxuridin, retinol, tiamin, dexpantenol, pyridoxin, folic acid, ascorbic
acid, tokoferol, phytominadion, phenfluramin, corticotropin, tetracosactid, tyrotropin, somatotropin, somatrem, vaso- pressin, lypressin, des opressin, oxytocin, chloriongonado- tropin, cortison, hydrocortison, fludrocortison, prednison, prednisolon, fluoximesteron, mesterolon, nandrolon, stanozo- lol, oximetolon, cyproteron, levotyroxin, liotyronin, propyl- thiouracil, carbimazol, tiamazol, dihydrotachysterol, alfa- calcidol, calcitirol, insulin, tolbutamid, chlorpropamid, tolazamid, glipizid, glibenclamid, phenobarbital, methypry- Ion, pyrityldion, meprobamat, chlordiazepoxid, diazepam, nitrazepam, oxazepam, dikaliumchlorazepat, lorazepam, flu- nitrazepa , alprazolam, midazolam, hydroxizin, chlomethiazol, propionmazine, alimemazine, chlorpromazine, levomepromazine, acetophenazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, dixyrazine, thioridazine, periciazin, chlo- prothixene, zuclopentizol, flupentizol, thithixen, haloperi- dol, trimipramin, opipramol, chlomipramin, desipramin, lofe- pramin, amitriptylin, nortriptylin, protriptylin, maptroti- lin, coffein, cinnarizine, cyclizine, dimenhydinate, meclozi- ne, prometazine, thiethylperazine, metoclopramide, scopol- a ine, phenobarbital, phenytoine, ethosuximide, primidone, carbamazepine, chlonazepam, orphenadrine, atropine, bensatro- pine, biperiden, metixene, procylidine, levodopa, bromocrip- tin, amantadine, ambenon, pyridostigmine, synstigmine, di- sulfiram, morphine, codeine, pentazocine, buprenorphine, pethidine, phenoperidine, phentanyl, methadone, piritramide, dextropropoxyphene, ketobemidone, acetylsalicylic acid, phe- nazone, phenylbutazone, azapropazone, piroxicam, ergotamine, dihydroergotamine, cyproheptadine, pizitifen, flumedroxon, allopurinol, probenecid, sodiummaurothiomalate auronofin, penicillamine, estradiol, estradiolvalerianate, estriol, ethinylestradiol, dihydrogesteron, lynestrenol, medroxipro- gresterone, noretisterone, cyclophenile, clomiphene, levonor- gestrel, mestranol, ornidazol, tinidazol, ekonazol, chlotri- mazol, natamycine, miconazole, sulbentin, methylergotamine, dinoprost, dinoproston, gemeprost, bromocriptine, phenylpro- panolamine, sodiumchromoglicate, azetazolamide, dichlophen- a ide, betacarotene, naloxone, calciumfolinate, in particular
clonidine, theophylline, dipyradamol, hydrochlorthiazide, scopolamine, indo ethacine, furosemide, potassium chloride, morphine, ibuprofen, salbuta ol, terbutalin.
The drug substance which is incorporated in a pharmaceutical composition according to the invention can be in various forms, such as uncharged molecules, molecular complexes, a pharmacologically acceptable salt such as a hydrochloride, hydrobromide, sulfate, laurylate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, and salicylate. For acid drugs, salts of metals, amines, amino acids or organic cations, quaternary ammonium, can be used. Derivatives of drugs such as esters, ethers and amides can be used alone or mixed with other drugs and after their release from the composition they may be converted by enzymes, hydrolyzed by body pH or other metabolic processes to the original form, or to a biologically active form.
One class of active drugs which are particularly suitable for administration according to the invention are interferons such as (XJ- - <Xχχ- 1 β~ and 7-interferons.
The dose of the active drug to be used in each particular case will of course depend upon the effect to be achieved and the intended use.
As appears from the above, a body of a pharmaceutical compo¬ sition according to the invention or at least a part of it must have a sufficient strength to enable penetration of skin or mucosa. Suitable examples of materials which can form the basis of the body of a pharmaceutical composition according to the invention and/or which may be added to another basic material for such a body and/or which may increase the strength of such a body are inorganic salts such as, e.g., calcium, magnesium, bismuth or zinc salts; lipids; carbohy¬ drates; proteins such as, e.g., gelatins, collagens, modified collagens, albumins, caseins and derivatives thereof; natural polymers; synthetic polymers such as, e.g., poly-epsilon-
aminocaproic acid, poly-isobutyric acid and derivatives thereof, polylactic acid and derivatives thereof, polyglyco- lic acid and derivatives thereof, poly(lactide-glycolide)- copolymers and derivatives thereof, polyesters, polyethylene glycols, polypropylene glycols, Pluronics®; and mixtures thereof. Suitable carbohydrates include polysaccharides, sucrose, glucose, agarose, dextrin and cyclodextrin.
An interesting embodiment according to the invention is a body comprising the carbohydrate in crystalline or caramelized form.
Other suitable carbohydrates are celluloses, cellulose deri¬ vatives, modified celluloses, modified cellulose derivatives and mixtures thereof.
To further improve the strength of the penetrating end or other parts of the body, a higher concentration of a strength-improving material can be incorporated, either as a core in the body or applied as a cap at the penetration end portion or covering the hole body. The strength-improving material can also be distributed uniformly throughout the body or in defined layers or zones within the body.
One way of measuring the strength of the body is to measure the compressive strength of the body, i.e. the pressure per unit area which can be applied to a sample of the body before it breaks. The compressive strength of bodies according to the present invention is usually at least about 15 x 103 pounds/sq in. With increasing compressive strength of the materials used, the size of the composition can be decreased. The specific compressive strength of each individual composi¬ tion will depend on the active drug itself as well as the other components and the manner in which the composition is prepared. The compressive strength is preferably at least about 30 x 103 pounds/sq in. For some embodiments according to the invention the compressive strength will be at least about 50 x 103 pounds/sq in. or even at least about 80 x 103
pounds/sq in. or as much as at least 100 x 103 pounds/sq in. For compositions comprising carbohydrates in caramelized form the compressive strength of the compositions is very often more than 100 x 103 pounds/sq in.
Due to the fact that a pharmaceutical composition according to the invention is to penetrate the skin or mucosa, the material for preparation of the pharmaceutical composition is preferably biodegradable or substantially biodegradable and/or soluble or substantially soluble in an aqueous medium.
The choice of material for preparation of a pharmaceutical composition according to the invention depends primarily on the nature of the active drug substance, i.e. its physical and chemical structure. As a consequence of the variation in the physical and chemical properties of the materials en- tioned above, a given material may have different effects in different compositions, and different materials can therefore act e.g. as fillers or carriers.
The compositions according to the invention may further comprise various pharmaceutically acceptable excipients.
One or more excipients may be added to modify the dissolution rate after administration, for example by increasing the content of water in the area of delivery by osmotic force. Examples of such dissolution rate modifiers are monosacchari- des, disaccharides, oligosaccharides, gellans, cyclodextrins, and mixtures thereof which can enhance the dissolution of drug substances such as, e.g., insulin.
To increase the absorption rate from the site of delivery, penetration enhancers can be added to the composition. The penetration enhancer may e.g. be an enzyme, for example a catabolic enzyme which acts by cleaving components of the supporting matrix of the tissue, thereby increasing the flow rate of body fluids through the tissue. Examples of such enzymes are proteases, lipases and deoxyribonucleases. Speci-
fie enzymes which may be employed are for example amylase, dextranase, hyaluronidase, brinolase, bromelains, pancreatin, chymopapain, chymotrypsins, papain, pepsin, plasmin, rennet, trypsin, urokinase, deanase, streptodornase, streptokinase, pancrealipase, muramidase, and mixtures thereof.
An interesting embodiment of the invention is a pharmaceuti¬ cal composition from which the drug substance is freely released, in contrast to sustained released compositions. In the context of the present invention the term "free release" refers to situations in which no excipient has been added to the composition for the purpose of influencing the delivery rate of the active substance from the composition itself. In other words, the release profile of the drug is substantially unaltered by the composition containing it. When an excipient that influences the release is added, this is referred to as "modified release". This includes excipients which either increase or decrease the rate of release. Examples of types of modified release are sustained release, where the drug is released over a prolonged period, and pulsed release, where the release is not continuous, but rather occurs in pulses or bursts.
A body of a pharmaceutical composition according to the invention may be prepared by means of extrusion or injection moulding, i.e. the material forming the basis of the body is preferably able to undergo an extrusion process or an injec¬ tion moulding process.
In another aspect, the invention relates to a drug delivery system or device comprising
i) at least one body of a solid pharmaceutical composi- tion comprising at least one drug substance and having a shape and/or a strength enabling penetration of unbroken skin or mucosa by said body in order to deliver said drug substance to an underlying tissue
or into the blood stream of a human or of an animal, and ii) supporting means adapted to facilitate said penetra¬ tion.
A device constituting the drug delivery system of the present invention will thus comprise a supporting means. In principle all types of supporting means may be employed according to the invention including supporting means where the body of the pharmaceutical composition according to the invention, preferably in the form of a needle, is driven through a cylindrical device such as a piston-like device. The support¬ ing means may typically of a compressible or contractible material, often a sponge or sponge-like material, in which one or more often needle-shaped bodies containing the drug are embedded.
Administration of the drug takes place by first placing one side of the device in contact with the skin or mucosa through which the drug is to be administered. The actual administra¬ tion of the drug is accomplished by applying pressure, e.g. using a finger or a hand, thereby compressing the supporting material. This in turn leads to penetration of the skin by the needles or other bodies containing the drug and thus to release of the drug in the underlying tissue or blood stream. The pressure applied to administer the drug is typically applied to the side of the device opposite the skin or mucosa. However, another possibility is to apply pressure indirectly. This possibility can for example be used when the drug is to be administered via the oral mucosa. In this case, the device may be placed in the mouth of the patient in such a manner that one side of the device (i.e. the side through which the drug is to be delivered) is in contact with the inner side of the cheek, while the opposite side of the device is in contact with the teeth and/or gum. Compression of the supporting material and administration of the drug can in this case be obtained by applying pressure on the outside of the cheek.
The foam or sponge of the supporting means is optionally covered on the surface which is to be in contact with the skin or mucosa with an adhesive and/or disinfecting material. The opposite surface is preferably covered by a backing designed to effectively transfer pressure to the needles, e.g. of a rigid, non-flexible material. In one embodiment of a drug delivery system according to the invention, the material in which the needle or other body is embedded com¬ prises components which are substantially biodegradable and/or which can be swallowed by the patient with no signifi¬ cant discomfort.
In a drug delivery system containing one or more needles or other bodies, the needles or bodies are embedded in a sup¬ porting means such as a foam or sponge designed to insulate them from the environment, in particular from humidity and from contamination. The supporting means may also be in the form of a plate, a pad, a patch, a disc, a strip, or a plas¬ ter. The structure of the supporting device should allow displacement of the needle in the needle's axial direction but not to the sides, thus guiding the needle into the skin and preventing it from breaking due to pressure applied during administration of the drug. The supporting means is preferably made of a compressible or collapsible material and preferably has at least one surface covered by a backing which preferably cannot be penetrated by the needle or other body containing the drug. The backing may be flexible or non- flexible. The supporting means may contain or may have a surface covered with a disinfecting material. The surface which is to be in contact with the skin or mucosa may further be covered with an adhesive material to facilitate placement.
In the case of intravenous administration, the side of the supporting means facing the skin or mucosa may have a concave shape to ensure that the blood vessel into which the drug is to be administered remains fixed and does not slip or move in the subcutaneous tissue, thus allowing the needle containing
the drug to penetrate the thickest part holding the vein or artery (confer Fig. 4) .
The supporting means may be made of any suitable material such as, e.g., gums such as guar gum, locust bean gum, gum arabic, agar, carrageenan, liquorice, open cell polyure hane foam, synthetic and/or natural rubber and their foams, cellu¬ loses and derivatives thereof such as, e.g., methylcellulose, plastic materials and the like.
Crystallized and caramelized sugars may also be used for the backing of the supporting means. Caramelized sugars are obtained heating sugars in the absence of water heated in a concentrated solution.
It is contemplated that a drug delivery system according to the invention may be prepared by injection moulding which makes it possible to prepare the body of the pharmaceutical composition according to the invention as well as the sup¬ porting means by an economical and relatively simple process.
When appropriate, e.g. for oral mucosal use, flavours and/or sweeteners can be added to the body or the device according to the invention.
In a further aspect, the invention relates to a method for parenteral administration of a drug substance to a human or an animal, the method comprising:
i) contacting the skin or the mucosa of said human or animal with a body of a solid pharmaceutical composition which comprises the drug substance and which has a shape and/or a strength which enables it to penetrate unbroken skin or mucosa in order to deliver said drug substance to an underlying tissue or into the blood stream of the human or of the animal; and
ii) penetrating said skin or mucosa with said body so as to position at least a part of said body in said underlying tissue or in said blood stream.
Furthermore, the invention relates to a method for preparing a body of a pharmaceutical composition according to the invention, the method comprises
i) mixing a polymer and optionally a filler with an active drug substance, ii) extruding the mixture containing the active drug through a die to form an elongated body, iii) drying the body and cutting the body to form a pointed end.
The invention also relates to a method for preparing a drug delivery system according to the invention, the method co - prises embedding at least one body of a solid pharmaceutical composition which comprises at least one drug substance and having a shape and/or a strength which enables it to pene¬ trate unbroken skin or mucosa of a human or animal in a supporting means which is adapted to facilitate said penetra- tion.
As will be understood, details and particulars concerning the above-mentioned aspects of the invention will be the same as or analogous to the details and particulars concerning the aspects discussed above (i.e. the aspects concerning a body of a pharmaceutical composition and concerning a drug deli¬ very system) , and this means that wherever appropriate, the statements above concerning the pharmaceutical composition or the drug delivery system, their preparation, improved proper¬ ties and uses apply mutatis mutandis to the other aspects of the invention.
DESCRIPTION OF THE DRAWING
The invention is further described below with reference to the drawings in which:
Fig. IA shows a drug delivery system according to the inven- tion wherein a body of a solid pharmaceutical composition according to the invention 1 is embedded in a compressible or collapsible supporting material 2 having a contact surface 4 adapted to be brought into contact with skin or mucosa 5. The supporting material 2 is covered with a backing 3 made of a flexible material which enables transfer of pressure applied to the backing material 3 to the body 1.
Fig. IB shows the drug delivery system shown in Fig. IA after pressure has been applied (as indicated by the arrow in the figure) to the flexible backing material 3 so as to compress the supporting material 2, causing the body 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
Fig. 2A shows an alternative embodiment of a drug delivery system according to the invention and having a compressible or collapsible supporting material 2 as described in connec¬ tion with Fig. IA, but in which the backing material 3 is a substantially rigid, i.e. non-flexible, material.
Fig. 2B shows the drug delivery system as shown in Fig. 2A after pressure has been applied (as indicated by the arrows in the figure) to the substantially rigid backing material 3 so as to compress the supporting material 2, causing the body 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
Fig. 3A shows an alternative embodiment of a drug delivery system according to the invention and having a compressible or collapsible supporting material 2 as described in connec-
tion with Fig. 2A but in which three bodies 1 are embedded in the supporting material.
Fig. 3B shows the drug delivery as shown in Fig. 3A after pressure has been applied (as indicated by the arrows in the figure) to the substantially rigid backing material 3 so as to compress the supporting material 2, causing the bodies 1 to be released from the compressed supporting material 2 and to penetrate the surface 5.
Fig. 4A and 4B illustrate a modification of the embodiment of a drug delivery system according to the invention as shown in Fig. 2A and 2B and its use in administering a body 1 accord¬ ing to the invention to a blood vessel 6 underlying a surface 5 of skin or mucosa. In this modification, the surface 4 of the supporting material 2 which is to be brought into contact with the skin or mucosa has a concave form adapted to be brought into position above, and substantially match the contour of, that part of the skin or mucosa which overlies the blood vessel which has a lumen 5 and a wall 6 positioned just beneath the skin or the mucosa, the body 1 being located substantially at the bottom of the depression resulting from the concavity of the surface . The concave form of the surface 4 thus facilitates positioning of the body 1 relative to the blood vessel 6 and 7 so as to ensure correct penetra¬ tion of the body 1 through the wall 7 of the blood vessel and into the lumen of the blood vessel 6 upon applying pressure to the backing material 3 in the manner shown in Fig. 3B.
Fig. 5 illustrates the results of an in vivo test in Mini- Pigs. The test is a comparison test between a conventional insulin composition Actrapid® and an insulin-containing com- position according to the invention. The results shown in Fig. 5 clearly indicate that a composition according to the invention may replace a conventional product like Actrapid®.
Examples of the formulation of a body according to the inven¬ tion are described in the following.
EXAMPLE 1
A saturated solution of gelatin in water is mixed with beta- cyclodextrin to form a paste, an active drug is added and the mixture is extruded through a 0.2 mm die. The resulting, cy- linder is left to dry until a firm and crystallized consist¬ ency is achieved. The dried cylinder is cut diagonally to form a pointed cutting edge.
EXAMPLE 2
10% gelatin and 1% agarose are mixed with an active drug and the mixture is milled to a particle size of less than 100 μm. The milled mixture is extruded through a needle and then dried and cut as explained in Example 1.
EXAMPLE 3
General method for preparing pharmaceutical compositions according to the invention
Pharmaceutical compositions according to the invention are prepared by dissolving 10% w/w of gelatin and 2% w/w of gellen in water and left to gellify. The resulting gel is then milled to a particle size of less than 50 μm. The resul- ting "powder" is mixed with insulin (or any other drug sub¬ stance) and extruded using a hypodermic syringe. The result¬ ing "spaghetti"-like material is suspended and left to dry in the air, optionally in a desiccator. After 6 hours in the open air, the spaghetti-like material has acquired the desired crystalline structure.
EXAMPLE 4
Pharmaceutical composition containing insulin - animal test¬ ing
Pharmaceutical compositions containing insulin were prepared as described in Example 3 herein and with a content of 5% w/w of methylene blue (i.e. 5% w/w of methylene blue was added to the powder described above) .
Five Mini-Pigs were anaesthetized with Sedaperone® Vet and Dormicum i. . and immobilized. The pharmaceutical composi¬ tions were inserted into the lips in different places (upper lip, lower lip, and commissure) in order to determine the best administration technique. All sites were found to be useful but the lower lip proved easiest to use.
Four Mini-Pigs, fasting since the previous day, were anaesthetized with Sedaperone® Vet and Dormicum i.m. and a blood sample were taken from each. Two of the pigs were dosed with Insulin, Actrapid®, 0.5 IE/kg, subcutaneously in the neck behind the ear; the other two were dosed with a pharma¬ ceutical composition prepared as described above and contain¬ ing about 0.7 IE/kg, into the lower lip (the lip was chosen because it was found that it best resembles human skin) , the lip was wiped dry. Further samples were taken at 10, 15, 20, 30, 60, 90, 120, 240, 300, and 360 minutes after application. The results are shown in Fig. 5 as the concentration of glucose in blood versus time after application. The results show that administration of a pharmaceutical composition according to the present invention gives rise to a peak value of almost the same order of magnitude as the conventional composition Actrapid®.
Claims
1. A body of a solid pharmaceutical composition comprising at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in order to deliver said drug substance to an underlying tissue or into the blood stream of said human or animal.
2. A body according to claim 1 which has an elongated shape.
3. A body according to claim 2 which has a skin- or mucosa- penetrating end portion,
4. A body according to claim 3, wherein said penetrating end portion comprises a material which endows said end portion with sufficient strength to penetrate said skin or mucosa.
5. A body according to claim 1 comprising a material which endows said body with sufficient strength to enable said penetration.
6. A body according to claim 4 or 5, wherein said material is selected from the group consisting of inorganic salts, lipids, carbohydrates, proteins, natural polymers, synthetic polymers and mixtures thereof.
7. A body according to claim 6, wherein said material is a carbohydrate selected from the group consisting of polysac¬ charides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixtures thereof.
8. A body according to claim 7, wherein the carbohydrate is in crystalline or caramelized form.
9. A body according to claim 6 or 7, wherein said material is a carbohydrate selected from the group consisting of cellulo- ses, cellulose derivatives, modified celluloses, modified cellulose derivatives and mixtures thereof.
10. A body according to claim 6, wherein said material is a protein selected from the group consisting of gelatins, collagens, modified collagens, albumins, caseins and deriva¬ tives thereof, and mixtures thereof.
11. A body according to any one of the preceding claims, wherein the composition is substantially biodegradable or substantially soluble in an aqueous medium.
12. A body according to any one of the preceding claims further comprising a pharmaceutically acceptable excipient.
13. A body according to claim 12, wherein said excipient is selected from the group consisting of cyclodextrins, monosac- charides, disaccharides, oligosaccharides, gellans, and mixtures thereof.
14. A body according to claim 12, wherein said excipient is an enzyme selected from the group consisting of proteases, lipases and deoxyribonucleases.
15. A body according to claim 14, wherein said enzyme is selected from the group consisting of amylase, dextranase, hyaluronidase, brinolase, bromelains, pancreatin, chymopapa- in, chymotrypsins, papain, pepsin, plasmin, rennet, trypsin, urokinase, deanase, streptodornase, streptokinase, pancrea- lipase, mura idase and mixtures thereof.
16. A body according to any one of the preceding claims, wherein said drug substance is substantially freely released from the composition, the composition having substantially no effect on the release profile of the drug substance in the tissue or blood stream to which the drug substance is admini- stered.
17. A body according to any one of claims 1-15, wherein the release profile of the drug substance is modified by one or more excipients in the composition.
18. A body according to claim 17, wherein the drug substance is sustain-released or pulse-released from the composition.
19. A body according to any one of the preceding claims which has a hardness of at least about 15 x 103 pound/sq in, such as at least 30 x 103 pound/sq in, such as at least 50 x 103 pound/sq in, such as at least 80 x 103 pound/sq in or at least 100 x 103 pound/sq in.
20. A method for parenteral administration of a drug sub¬ stance to a human or an animal, the method comprising: i) contacting the skin or the mucosa of said human or animal with a body of a solid pharmaceutical composition which comprises the drug substance and which has a shape and/or a strength which enables it to penetrate unbroken skin or mucosa in order to deliver said drug substance to an underlying tissue or into the blood stream of the human or of the animal; and ii) penetrating said skin or mucosa with said body so as to position at least a part of said body in said underlying tissue or in said blood stream.
21. A method according to claim 20 wherein the body has an elongated shape.
22. A method according to claim 21 wherein the body has a skin- or mucosa penetrating end portion,
23. A method according to claim 22, wherein said penetrating end portion comprises a material which endows said end por¬ tion with sufficient strength to penetrate said skin or mucosa.
24. A method according to claim 20 wherein the body comprises a material which endows said body with sufficient strength to enable said penetration.
25. A method according to claim 23 or 24, wherein said mate- rial is selected from the group consisting of inorganic salts, lipids, carbohydrates, proteins, natural polymers, synthetic polymers and mixtures thereof.
26. A method according to claim 25, wherein said material is a carbohydrate selected from the group consisting of polysac- charides, sucrose, glucose, agarose, dextrin, cyclodextrin and mixtures thereof.
27. A method according to claim 25, wherein the carbohydrate is in crystalline or caramelized form.
28. A method according to claim 25 or 26, wherein said material is a carbohydrate selected from the group consisting of celluloses, cellulose derivatives, modified celluloses, modified cellulose derivatives and mixtures thereof.
29. A method according to claim 25, wherein said material is a protein selected from the group consisting of gelatins, collagens, modified collagens, albumins, caseins and deriva¬ tives thereof, and mixtures thereof.
30. A method according to any one of claims 20-29, wherein the composition is substantially biodegradable or substan¬ tially soluble in an aqueous medium.
31. A method according to any one of claims 20-30 wherein the body further comprises a pharmaceutically acceptable excipient.
32. A method according to claim 31, wherein said excipient is selected from the group consisting of cyclodextrins, monosac- charides, disaccharides, oligosaccharides, gellans, and mix¬ tures thereof.
33. A method according to claim 31, wherein said excipient is an a catabolic enzyme selected from the group consisting of proteases, lipases and deoxyribonucleases.
34. A method according to claim 33, wherein said enzyme is selected from the group consisting of amylase, dextranase, hyaluronidase, brinolase, bromelains, pancreatin, chymopapa- in, chymotrypsins, papain, pepsin, plasmin, rennet, trypsin, urokinase, deanase, streptodornase, streptokinase, pancrea- lipase, muramidase and mixtures thereof.
35. A method according to any one of claims 20-34, wherein said drug substance is substantially freely released from the composition, the composition having substantially no effect on the release profile of the drug substance in the tissue or blood stream to which the drug substance is administered.
36. A method according to any one of claims 20-34, wherein the release profile of the drug substance is modified by one or more excipients in the composition.
37. A method according to claim 36, wherein the drug sub¬ stance is sustain-released or pulse-released from the compo¬ sition.
38. A method according to any one, of claims 20-37 wherein the a hardness of said body is between about 15 x 103 pound/sq in and 100 x 103 pound/sq in.
39. A drug delivery system comprising i) at least one body of a solid pharmaceutical composi¬ tion comprising at least one drug substance and having a shape and/or a strength enabling penetration of unbroken skin or mucosa by said body in order to deliver said drug substance to an underlying tissue or into the blood stream of a human or of an animal, and ii) supporting means adapted to facilitate said penetra¬ tion.
40. A drug delivery system according to claim 39, wherein the supporting means is made of a compressible material.
41. A drug delivery system according to claim 39, wherein the supporting means is made of a collapsible material.
42. A drug delivery system according to any one of claims 39-41 wherein the supporting means is in form of a plate, a pad, a patch, a disc, a strip, a sponge, a foam or a plaster.
43. A drug delivery system according to any one of claims 39- 42 wherein the supporting means has a surface covered by a backing of a flexible material.
43. A drug delivery system according to any one of claims 39- 42 wherein the supporting means has a surface covered by a backing of a substantially non-flexible material.
44. A drug delivery system according to any one of claims 39- 43 wherein the supporting means has a concave surface.
45. A drug delivery system according to any one of claims 39- 44 wherein the supporting means has a surface covered with an adhesive material and/or a disinfecting material.
46. A drug delivery system according to any one of claims 39- 45 wherein the supporting means is substantially biodegrad¬ able or substantially soluble in an aqueous medium.
47. A body according to any one of claims 1-19 for use in a drug delivery system according to claim 39.
48. A process for the preparation of a body of a pharmaceuti¬ cal composition comprising: i) mixing a polymer and optionally a filler with an active drug substance, ii) extruding the mixture containing the active drug through a die to form an elongated body, iii) drying the body and cutting the body to form a pointed end.
49. A process for the preparation of a body of a pharmaceuti- cal composition according to claim 48 further comprising adding at least one pharmaceutically acceptable excipient to the mixture, said excipient being selected from the group consisting of dissolution modifying substances, diffusion modifying substances, penetrating enhancers, or strength- improving materials and mixtures thereof.
50. A process for the preparation of a drug delivery device comprising embedding at least one body of a solid pharmaceu¬ tical composition which comprises at least one drug substance and having a shape and/or a strength which enables it to penetrate unbroken skin or mucosa of a human or animal in a supporting means which is adapted to facilitate said penetra¬ tion.
51. A process according to claim 50 wherein the supporting means is made of a compressible material.
52. A process according to claim 50, wherein the supporting means is made of a collapsible material.
53. A process according to any one of claims 50-52 wherein the supporting means is in form of a plate, a pad, a patch, a disc, a strip, a sponge, a foam or a plaster.
54. A process according to any one of claims 50-53 wherein the supporting means has a surface covered by a backing of a flexible material.
55. A process according to any one of claims 50-53 wherein the supporting means has a surface covered by a backing of a substantially non-flexible material.
56. A process according to any one of claims 50-55 wherein the supporting means has a concave surface.
57. A process according to any one of claims 50-56 wherein the supporting means has a surface covered with a adhesive material and/or a disinfecting material.
58. A process according to any one of claims 50-57 wherein the supporting means is substantially biodegradable or sub¬ stantially soluble in an aqueous medium.
59. Use of a body according to any one of claims 1-19 for the process according to claim 50.
60. A body according to any of claims 1-9 and 47 or to the method according to any of claims 20-38, or to the drug delivery system according to any of claims 39-46, or to the process according to any of claim 48-59 wherein the active drug is an interferon such as c-i-, αIι:_, β- or 7-interferon.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU65348/94A AU6534894A (en) | 1993-04-07 | 1994-04-07 | Drug administration system |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK42093A DK42093D0 (en) | 1993-04-07 | 1993-04-07 | METHOD OF ADMINISTRATION |
DK0420/93 | 1993-04-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994022423A1 true WO1994022423A1 (en) | 1994-10-13 |
Family
ID=8093319
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/DK1994/000145 WO1994022423A1 (en) | 1993-04-07 | 1994-04-07 | Drug administration system |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU6534894A (en) |
DK (1) | DK42093D0 (en) |
WO (1) | WO1994022423A1 (en) |
Cited By (53)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996003978A1 (en) * | 1994-08-04 | 1996-02-15 | Quadrant Holdings Cambridge Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
WO1996007398A2 (en) * | 1994-09-02 | 1996-03-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Sustained release of peptides from pharmaceutical compositions |
WO1996007397A2 (en) * | 1994-09-02 | 1996-03-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Delivery of solid drug compositions |
FR2770134A1 (en) * | 1998-10-28 | 1999-04-30 | Delab | Device for accurate parenteral implantation of solid formulation |
EP0953362A2 (en) * | 1994-09-02 | 1999-11-03 | Delab | Methods and apparatus for the delivery of solid drug compositions |
EP0976382A1 (en) * | 1998-07-30 | 2000-02-02 | L'oreal | Cosmetic or dermopharmaceutical patch |
WO2000062759A1 (en) * | 1999-04-16 | 2000-10-26 | Novo Nordisk A/S | Dry, mouldable drug formulation |
WO2000062734A1 (en) * | 1999-04-16 | 2000-10-26 | Novo Nordisk A/S | Cassette for storing and insertion of solid medicine |
WO2001054647A2 (en) * | 2000-01-28 | 2001-08-02 | Topic Empreendimentos E Participações S/C Ltda. | Pharmaceutical composition comprising carriers for products based on vitamin-e, papain and hyaluronidase |
US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US6419935B1 (en) | 1998-07-30 | 2002-07-16 | L'oreal S.A. | Cosmetic skin treatment method and cleansing treatment patch |
US6485453B1 (en) | 1999-04-16 | 2002-11-26 | Novo Nordisk A/S | Cassette for storing and insertion of solid medicine |
EP1159957A3 (en) * | 1996-12-02 | 2003-06-04 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Device for the local administration of solid or semi-solid formulations, sustained release formulations for parenteral administration and process of preparation |
US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
USRE38185E1 (en) | 1993-06-07 | 2003-07-15 | L'oreal | Process for molding a make-up composition |
WO2004014468A1 (en) | 2002-08-05 | 2004-02-19 | Caretek Medical Limited | Drug delivery system |
EP1435911A1 (en) * | 2001-08-03 | 2004-07-14 | Gel-Del Technologies, Inc. | Devices including protein matrix materials and methods of making and using same |
EP1299114B1 (en) * | 2000-02-21 | 2005-08-10 | Topic Empreendimentos e Participaçoes S/C Ltda. | Diclofenac pharmaceutical composition based on vitamin-e, papain and hyaluronidase |
US6964771B1 (en) | 1995-06-07 | 2005-11-15 | Elan Drug Delivery Limited | Method for stably incorporating substances within dry, foamed glass matrices |
WO2006085908A2 (en) * | 2004-06-01 | 2006-08-17 | Microchips, Inc. | Devices and methods for measuring and enhancing drug or analyte transport to/from medical implant |
GB2446943A (en) * | 2007-02-22 | 2008-08-27 | Glide Pharmaceutical Technolog | Solid pharmaceutical and vaccine dose for parenteral injection |
US7419677B2 (en) | 2001-03-28 | 2008-09-02 | L'oreal S.A. | Treatment device and method of using the same |
EP2065063A1 (en) | 2001-09-11 | 2009-06-03 | Glide Pharmaceutical Technologies Limited | Needleless injection device |
US7615234B2 (en) | 2001-09-11 | 2009-11-10 | Glide Pharmaceutical Technologies Limited | Drug delivery technology |
WO2011042542A1 (en) | 2009-10-08 | 2011-04-14 | Azurebio, S. L. | Formulation of drugs and vaccines in the form of percutaneous injectable needles |
US8454997B2 (en) | 2001-12-18 | 2013-06-04 | Novo Nordisk A/S | Solid dose micro implant |
US8871267B2 (en) | 1998-09-25 | 2014-10-28 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
WO2014174286A1 (en) * | 2013-04-23 | 2014-10-30 | Ndm Technologies Limited | Device for containment and release of a transdermal drug formulation |
US8877162B2 (en) | 2000-05-10 | 2014-11-04 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery |
US9072472B2 (en) | 2005-02-07 | 2015-07-07 | Glide Pharmaceutical Technologies Limited | Disposable assembly containing a skin piercing element |
AU2014253541B2 (en) * | 2007-02-22 | 2016-07-28 | Glide Pharmaceutical Technologies Limited | Solid pharmaceutical and vaccine dose |
US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
JP2016193946A (en) * | 2011-06-29 | 2016-11-17 | ラニ セラピューティクス, エルエルシー | Therapeutic agent preparations for delivery into lumen of intestinal tract using swallowable drug delivery device |
US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
US10004783B2 (en) | 2010-12-23 | 2018-06-26 | Rani Therapeutics, Llc | Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery device |
US10029080B2 (en) | 2010-12-23 | 2018-07-24 | Rani Therapeutics, Llc | Method for delivering exenatide into a lumen of the intestinal tract using a swallowable drug delivery device |
US10039908B2 (en) | 2009-12-24 | 2018-08-07 | Rani Therapeutics, Llc | Swallowable drug delivery device and method of delivery |
JP2019055197A (en) * | 2011-06-29 | 2019-04-11 | ラニ セラピューティクス, エルエルシー | Devices, systems and methods for oral delivery of therapeutic compounds |
US10300010B2 (en) | 2010-12-23 | 2019-05-28 | Rani Therapeutics, Llc | Methods for delivering entanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10307579B2 (en) | 2010-12-23 | 2019-06-04 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10314892B2 (en) | 2010-12-23 | 2019-06-11 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US10322167B2 (en) | 2010-12-23 | 2019-06-18 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US10335463B2 (en) | 2010-12-23 | 2019-07-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10350163B2 (en) | 2010-12-23 | 2019-07-16 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10478396B2 (en) | 2010-12-23 | 2019-11-19 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10487145B2 (en) | 2010-12-23 | 2019-11-26 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10548850B2 (en) | 2010-12-23 | 2020-02-04 | Rani Therapeutics, Llc | Therapeutic composition comprising insulin prepared for delivery into an intestinal tract |
US10632251B2 (en) | 2010-12-23 | 2020-04-28 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US10639272B2 (en) | 2010-12-23 | 2020-05-05 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10752681B2 (en) | 2010-12-23 | 2020-08-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
JP2021112609A (en) * | 2009-12-24 | 2021-08-05 | ラニ セラピューティクス, エルエルシー | Swallowable drug delivery device and drug delivery method |
US11135170B2 (en) | 2015-10-20 | 2021-10-05 | Enesi Pharma Limited | Solid formulation |
US11439817B2 (en) | 2009-08-03 | 2022-09-13 | Incube Labs, Llc | Swallowable capsule and method for stimulating incretin production within the intestinal tract |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
CH678272A5 (en) * | 1988-10-13 | 1991-08-30 | Ars Japan Kk |
-
1993
- 1993-04-07 DK DK42093A patent/DK42093D0/en not_active Application Discontinuation
-
1994
- 1994-04-07 AU AU65348/94A patent/AU6534894A/en not_active Abandoned
- 1994-04-07 WO PCT/DK1994/000145 patent/WO1994022423A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0139286A2 (en) * | 1983-10-14 | 1985-05-02 | Sumitomo Pharmaceuticals Company, Limited | Prolonged sustained-release preparations |
CH678272A5 (en) * | 1988-10-13 | 1991-08-30 | Ars Japan Kk |
Non-Patent Citations (3)
Title |
---|
BIOMAT., ART. CELLS, ART. ORG., Volume 16, No. 4, 1988, SHAN-YANG LIN et al., "Controlled Release of Adriamycin HCl from Polymeric Needle Devices", page 801 - page 814. * |
BIOMAT., ART. CELLS, ART. ORG., Volume 17, No. 2, 1989, S.Y. LIN et al., "Tumoricidal Effect of Controlled-Release Polymeric Needle Devices Containing Adriamycin HCl in Tumor-Bearing Mice", page 189 - page 203. * |
DIALOG INFORMATION SERVICES, File 351, World Patent Index 81-94, Dialog Accession No. 003880810, WPI Accession No. 84-026348/05, MITSUI TOATSU CHEM IND: "Sustained Release Rod-Like Moulded Drug mfr. by Adding Drugs to Melt of Polylactic Acid or Lactic-Acid Glycolic Acid Copolymer and Moulding Mixt"; & JP,A,58 216 117, * |
Cited By (113)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE38185E1 (en) | 1993-06-07 | 2003-07-15 | L'oreal | Process for molding a make-up composition |
US6586006B2 (en) | 1994-08-04 | 2003-07-01 | Elan Drug Delivery Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
WO1996003978A1 (en) * | 1994-08-04 | 1996-02-15 | Quadrant Holdings Cambridge Limited | Solid delivery systems for controlled release of molecules incorporated therein and methods of making same |
EP1595532A3 (en) * | 1994-09-02 | 2007-05-30 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Sustained release of peptides from pharmaceutical compositions |
EP1157703A2 (en) * | 1994-09-02 | 2001-11-28 | Delab | Sustained release of peptides from pharmaceutical compositions |
US5595760A (en) * | 1994-09-02 | 1997-01-21 | Delab | Sustained release of peptides from pharmaceutical compositions |
WO1996007397A3 (en) * | 1994-09-02 | 1996-08-15 | Scras | Delivery of solid drug compositions |
EP0953362A2 (en) * | 1994-09-02 | 1999-11-03 | Delab | Methods and apparatus for the delivery of solid drug compositions |
EP1157703A3 (en) * | 1994-09-02 | 2002-01-30 | Delab | Sustained release of peptides from pharmaceutical compositions |
EP1595532A2 (en) * | 1994-09-02 | 2005-11-16 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Sustained release of peptides from pharmaceutical compositions |
EP0953362A3 (en) * | 1994-09-02 | 2000-03-08 | Delab | Methods and apparatus for the delivery of solid drug compositions |
WO1996007397A2 (en) * | 1994-09-02 | 1996-03-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Delivery of solid drug compositions |
WO1996007398A3 (en) * | 1994-09-02 | 1996-05-17 | Scras | Sustained release of peptides from pharmaceutical compositions |
WO1996007398A2 (en) * | 1994-09-02 | 1996-03-14 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A. | Sustained release of peptides from pharmaceutical compositions |
US6306420B1 (en) | 1994-09-02 | 2001-10-23 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Methods and apparatus for the delivery of solid drug compositions |
US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
US6893657B2 (en) | 1994-12-02 | 2005-05-17 | Quadrant Drug Delivery Ltd. | Solid dose delivery vehicle and methods of making same |
US6964771B1 (en) | 1995-06-07 | 2005-11-15 | Elan Drug Delivery Limited | Method for stably incorporating substances within dry, foamed glass matrices |
EP1159957A3 (en) * | 1996-12-02 | 2003-06-04 | Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) | Device for the local administration of solid or semi-solid formulations, sustained release formulations for parenteral administration and process of preparation |
US9554993B2 (en) | 1997-09-29 | 2017-01-31 | Novartis Ag | Pulmonary delivery particles comprising an active agent |
FR2781667A1 (en) * | 1998-07-30 | 2000-02-04 | Oreal | COSMETIC, PHARMACEUTICAL, OR DERMATOLOGICAL PATCH |
US6419935B1 (en) | 1998-07-30 | 2002-07-16 | L'oreal S.A. | Cosmetic skin treatment method and cleansing treatment patch |
EP0976382A1 (en) * | 1998-07-30 | 2000-02-02 | L'oreal | Cosmetic or dermopharmaceutical patch |
US6623751B2 (en) | 1998-07-30 | 2003-09-23 | L'oreal S.A. | Cosmetic, pharmaceutical, or dermatological patch |
US8871267B2 (en) | 1998-09-25 | 2014-10-28 | Gel-Del Technologies, Inc. | Protein matrix materials, devices and methods of making and using thereof |
FR2770134A1 (en) * | 1998-10-28 | 1999-04-30 | Delab | Device for accurate parenteral implantation of solid formulation |
WO2000062734A1 (en) * | 1999-04-16 | 2000-10-26 | Novo Nordisk A/S | Cassette for storing and insertion of solid medicine |
WO2000062759A1 (en) * | 1999-04-16 | 2000-10-26 | Novo Nordisk A/S | Dry, mouldable drug formulation |
US6485453B1 (en) | 1999-04-16 | 2002-11-26 | Novo Nordisk A/S | Cassette for storing and insertion of solid medicine |
US7666844B2 (en) | 1999-04-16 | 2010-02-23 | Novo Nordisk A/S | Dry mouldable drug formulation |
US8084053B2 (en) | 1999-04-16 | 2011-12-27 | Novo Nordisk A/S | Dry mouldable drug formulation |
US8518430B2 (en) | 1999-04-16 | 2013-08-27 | Novo Nordisk A/S | Dry mouldable drug formulation |
WO2001054647A3 (en) * | 2000-01-28 | 2002-04-11 | Topic Empreendimentos E Partic | Pharmaceutical composition comprising carriers for products based on vitamin-e, papain and hyaluronidase |
WO2001054647A2 (en) * | 2000-01-28 | 2001-08-02 | Topic Empreendimentos E Participações S/C Ltda. | Pharmaceutical composition comprising carriers for products based on vitamin-e, papain and hyaluronidase |
EP1299114B1 (en) * | 2000-02-21 | 2005-08-10 | Topic Empreendimentos e Participaçoes S/C Ltda. | Diclofenac pharmaceutical composition based on vitamin-e, papain and hyaluronidase |
US9439862B2 (en) | 2000-05-10 | 2016-09-13 | Novartis Ag | Phospholipid-based powders for drug delivery |
US8877162B2 (en) | 2000-05-10 | 2014-11-04 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery |
US7419677B2 (en) | 2001-03-28 | 2008-09-02 | L'oreal S.A. | Treatment device and method of using the same |
EP1435911A1 (en) * | 2001-08-03 | 2004-07-14 | Gel-Del Technologies, Inc. | Devices including protein matrix materials and methods of making and using same |
EP1435911A4 (en) * | 2001-08-03 | 2010-03-24 | Gel Del Technologies Inc | Devices including protein matrix materials and methods of making and using same |
US8574188B2 (en) | 2001-09-11 | 2013-11-05 | Glide Pharmaceutical Technologies Limited | Drug delivery technology |
EP2065063A1 (en) | 2001-09-11 | 2009-06-03 | Glide Pharmaceutical Technologies Limited | Needleless injection device |
US7615234B2 (en) | 2001-09-11 | 2009-11-10 | Glide Pharmaceutical Technologies Limited | Drug delivery technology |
US7727223B2 (en) | 2001-09-11 | 2010-06-01 | Glide Pharmaceutical Technologies Limited | Drug delivery technology |
US8088406B2 (en) | 2001-09-11 | 2012-01-03 | Glide Pharmaceutical Technologies Limited | Pioneer projectile drug delivery technology |
US8454997B2 (en) | 2001-12-18 | 2013-06-04 | Novo Nordisk A/S | Solid dose micro implant |
US9421166B2 (en) | 2001-12-19 | 2016-08-23 | Novartis Ag | Pulmonary delivery of aminoglycoside |
US7862543B2 (en) | 2002-08-05 | 2011-01-04 | Glide Pharmaceutical Technologies Limited | Drug delivery system |
WO2004014468A1 (en) | 2002-08-05 | 2004-02-19 | Caretek Medical Limited | Drug delivery system |
WO2006085908A2 (en) * | 2004-06-01 | 2006-08-17 | Microchips, Inc. | Devices and methods for measuring and enhancing drug or analyte transport to/from medical implant |
WO2006085908A3 (en) * | 2004-06-01 | 2007-02-15 | Microchips Inc | Devices and methods for measuring and enhancing drug or analyte transport to/from medical implant |
US9072472B2 (en) | 2005-02-07 | 2015-07-07 | Glide Pharmaceutical Technologies Limited | Disposable assembly containing a skin piercing element |
GB2446943A (en) * | 2007-02-22 | 2008-08-27 | Glide Pharmaceutical Technolog | Solid pharmaceutical and vaccine dose for parenteral injection |
AU2014253541B2 (en) * | 2007-02-22 | 2016-07-28 | Glide Pharmaceutical Technologies Limited | Solid pharmaceutical and vaccine dose |
GB2446780A (en) * | 2007-02-22 | 2008-08-27 | Glide Pharmaceutical Technolog | An elongate parenteral injection body having an injection point of angle 10 to 40 degrees. |
WO2008102136A2 (en) | 2007-02-22 | 2008-08-28 | Glide Pharmaceutical Technologies Limited | Solid pharmaceutical and vaccine dose |
WO2008102136A3 (en) * | 2007-02-22 | 2009-01-15 | Glide Pharmaceutical Technolog | Solid pharmaceutical and vaccine dose |
US9693952B2 (en) | 2007-02-22 | 2017-07-04 | Glide Pharmaceutical Technologies Limited | Solid pharmaceutical and vaccine dose |
US9693951B2 (en) | 2007-02-22 | 2017-07-04 | Glide Pharmaceutical Technologies Limited | Solid pharmaceutical and vaccine dose |
US11872396B2 (en) | 2009-08-03 | 2024-01-16 | Incube Labs, Llc | Swallowable capsule and method for stimulating incretin production within the intestinal tract |
US11439817B2 (en) | 2009-08-03 | 2022-09-13 | Incube Labs, Llc | Swallowable capsule and method for stimulating incretin production within the intestinal tract |
WO2011042542A1 (en) | 2009-10-08 | 2011-04-14 | Azurebio, S. L. | Formulation of drugs and vaccines in the form of percutaneous injectable needles |
US11376405B2 (en) | 2009-12-24 | 2022-07-05 | Rani Therapeutics, Llc | Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10493253B2 (en) | 2009-12-24 | 2019-12-03 | Rani Therapeutics, Llc | Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10039908B2 (en) | 2009-12-24 | 2018-08-07 | Rani Therapeutics, Llc | Swallowable drug delivery device and method of delivery |
US10179228B2 (en) | 2009-12-24 | 2019-01-15 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
US11338118B2 (en) | 2009-12-24 | 2022-05-24 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
US10252039B2 (en) | 2009-12-24 | 2019-04-09 | Rani Therapeutics, Llc | Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US11253686B2 (en) | 2009-12-24 | 2022-02-22 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
JP2021112609A (en) * | 2009-12-24 | 2021-08-05 | ラニ セラピューティクス, エルエルシー | Swallowable drug delivery device and drug delivery method |
US10987499B2 (en) | 2009-12-24 | 2021-04-27 | Rani Therapeutics, Llc | Swallowable drug delivery device and method of delivery |
US10603475B2 (en) | 2009-12-24 | 2020-03-31 | Rani Therapeutics, Llc | Swallowable drug delivery device and methods of drug delivery |
US10596359B2 (en) | 2009-12-24 | 2020-03-24 | Rani Therapeutics, Llc | Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US10004783B2 (en) | 2010-12-23 | 2018-06-26 | Rani Therapeutics, Llc | Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery device |
US10980749B2 (en) | 2010-12-23 | 2021-04-20 | Rani Therapeutics, Llc | Therapeutic preparation comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10350163B2 (en) | 2010-12-23 | 2019-07-16 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10478396B2 (en) | 2010-12-23 | 2019-11-19 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10487145B2 (en) | 2010-12-23 | 2019-11-26 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10322167B2 (en) | 2010-12-23 | 2019-06-18 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US10548850B2 (en) | 2010-12-23 | 2020-02-04 | Rani Therapeutics, Llc | Therapeutic composition comprising insulin prepared for delivery into an intestinal tract |
US10314892B2 (en) | 2010-12-23 | 2019-06-11 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US10314891B2 (en) | 2010-12-23 | 2019-06-11 | Rani Therapeutics, Llc | Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery device |
US10632251B2 (en) | 2010-12-23 | 2020-04-28 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US10639272B2 (en) | 2010-12-23 | 2020-05-05 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US11844867B2 (en) | 2010-12-23 | 2023-12-19 | Rani Therapeutics, Llc | Method of delivering insulin into a lumen of the intestinal tract using a swallowable drug delivery device |
US10752681B2 (en) | 2010-12-23 | 2020-08-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10864254B2 (en) | 2010-12-23 | 2020-12-15 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US10874840B2 (en) | 2010-12-23 | 2020-12-29 | Rani Therapeutics, Llc | Preparation comprising exanatide for delivery into a lumen of the intestinal tract |
US10888517B2 (en) | 2010-12-23 | 2021-01-12 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10926073B2 (en) | 2010-12-23 | 2021-02-23 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10953077B2 (en) | 2010-12-23 | 2021-03-23 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US10967050B2 (en) | 2010-12-23 | 2021-04-06 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10335463B2 (en) | 2010-12-23 | 2019-07-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10307579B2 (en) | 2010-12-23 | 2019-06-04 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US10300010B2 (en) | 2010-12-23 | 2019-05-28 | Rani Therapeutics, Llc | Methods for delivering entanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US11813314B2 (en) | 2010-12-23 | 2023-11-14 | Rani Therapeutics, Llc | Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device |
US11229684B2 (en) | 2010-12-23 | 2022-01-25 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11814427B2 (en) | 2010-12-23 | 2023-11-14 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11304895B2 (en) | 2010-12-23 | 2022-04-19 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11806504B2 (en) | 2010-12-23 | 2023-11-07 | Rani Therapeutics, Llc | Device, system and methods for the oral delivery of therapeutic compounds |
US10029080B2 (en) | 2010-12-23 | 2018-07-24 | Rani Therapeutics, Llc | Method for delivering exenatide into a lumen of the intestinal tract using a swallowable drug delivery device |
US11419812B2 (en) | 2010-12-23 | 2022-08-23 | Rani Therapeutics, Llc | Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device |
US11771879B2 (en) | 2010-12-23 | 2023-10-03 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11555068B2 (en) | 2010-12-23 | 2023-01-17 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11638690B2 (en) | 2010-12-23 | 2023-05-02 | Rani Therapeutics, Llc | Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device |
US11654182B2 (en) | 2010-12-23 | 2023-05-23 | Rani Therapeutics, Llc | Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device |
US11684761B2 (en) | 2010-12-23 | 2023-06-27 | Rani Therapeutics, Llc | Preparation comprising exanatide for delivery into a lumen of the intestinal tract |
JP2016193946A (en) * | 2011-06-29 | 2016-11-17 | ラニ セラピューティクス, エルエルシー | Therapeutic agent preparations for delivery into lumen of intestinal tract using swallowable drug delivery device |
JP2019043967A (en) * | 2011-06-29 | 2019-03-22 | ラニ セラピューティクス, エルエルシー | Therapeutic agent preparations for delivery into lumen of intestinal tract using swallowable drug delivery device |
JP2019055197A (en) * | 2011-06-29 | 2019-04-11 | ラニ セラピューティクス, エルエルシー | Devices, systems and methods for oral delivery of therapeutic compounds |
US10646703B2 (en) | 2013-04-23 | 2020-05-12 | Ndm Technologies Limited | Device for containment and release of a transdermal drug formulation |
WO2014174286A1 (en) * | 2013-04-23 | 2014-10-30 | Ndm Technologies Limited | Device for containment and release of a transdermal drug formulation |
US11135170B2 (en) | 2015-10-20 | 2021-10-05 | Enesi Pharma Limited | Solid formulation |
Also Published As
Publication number | Publication date |
---|---|
DK42093D0 (en) | 1993-04-07 |
AU6534894A (en) | 1994-10-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1994022423A1 (en) | Drug administration system | |
US20230027289A1 (en) | Method and device for transdermal delivery of parathyroid hormone using a microprojection array | |
US20210178138A1 (en) | Implantable sustained-release microneedle patch and preparation method therefor | |
Dabholkar et al. | Biodegradable microneedles fabricated with carbohydrates and proteins: Revolutionary approach for transdermal drug delivery | |
US6740333B2 (en) | Suppository and composition comprising at least one polyethylene glycol | |
KR101400545B1 (en) | Microneedle device and method for producing the same | |
KR100349960B1 (en) | Drug Release Control | |
EP0493513B1 (en) | Controlled release composition | |
JP4459444B2 (en) | Controlled release formulation with multilayer structure | |
CN110870846A (en) | Rapidly implantable sustained-release microneedle patch and preparation method thereof | |
KR102267344B1 (en) | Micro-needle preparation administration member for intradermal placement of target substance and apparatus for rapid administration of micro-needle preparation | |
TW201501732A (en) | Substance delivery device and substance delivery method using the same | |
JP4753471B2 (en) | Long-term drug sustained-release preparation | |
CN101745177A (en) | Disposable drug delivery device with own power | |
US10471021B2 (en) | Transdermal therapeutic system for the administration of peptides | |
CN116712665A (en) | Photothermal-chemotherapy combined therapeutic agent and preparation method and application thereof | |
Lin et al. | Drug delivery: controlled release | |
KR20200000923A (en) | Composition improving pharmacokinetics performance of pharmaceutical material included in microneedle | |
CA3218769A1 (en) | Microneedle patch for immunostimulatory drug delivery | |
JP2004502718A (en) | Suppositories and compositions comprising at least one polyethylene glycol |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BB BG BR BY CA CN CZ CZ DE DK FI FI GE HU JP KG KP KR KZ LK LV MD MG MN MW NO NZ PL RO RU SD SI SK SK TJ TT UA US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |