WO1996014069A1 - Pastilles absorbables par voie percutanee - Google Patents

Pastilles absorbables par voie percutanee Download PDF

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Publication number
WO1996014069A1
WO1996014069A1 PCT/JP1995/001011 JP9501011W WO9614069A1 WO 1996014069 A1 WO1996014069 A1 WO 1996014069A1 JP 9501011 W JP9501011 W JP 9501011W WO 9614069 A1 WO9614069 A1 WO 9614069A1
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WIPO (PCT)
Prior art keywords
weight
parts
ibudilast
sensitive adhesive
adhesive
Prior art date
Application number
PCT/JP1995/001011
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English (en)
Japanese (ja)
Inventor
Tetsuya Ota
Michiari Hashimoto
Mikiya Kitamura
Kunio Yoneto
Original Assignee
Sekisui Kagaku Kogyo Kabushiki Kaisha
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Application filed by Sekisui Kagaku Kogyo Kabushiki Kaisha filed Critical Sekisui Kagaku Kogyo Kabushiki Kaisha
Publication of WO1996014069A1 publication Critical patent/WO1996014069A1/fr

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    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • the present invention relates to a percutaneous absorption patch which stably releases ibudilast, which is an agent for improving bronchial asthma and cerebrovascular disorders, over a long period of time.
  • Ibudilast 3-isobutylyl-2-isopropylvirazolo [1,5-a] pyridin
  • Ibudilast is a useful drug as an agent for improving bronchial asthma and cerebrovascular disorders.
  • the blood concentration rapidly increases due to rapid absorption from the gastrointestinal tract, which causes side effects such as nausea and vomiting.
  • bronchial asthma is a disease that is common in children, Since vascular disorders are diseases that are common among the elderly, it has been strongly desired to develop a dosage form of ibudilast that is easier to administer.
  • Japanese Patent Application Laid-Open No. H11-1536333 discloses a transdermal absorption preparation containing ibudilast as an active ingredient, but the blood concentration of ibudilast which is transdermally absorbed is low and the effect of administration is low. However, in order to compensate for this, it was necessary to increase the area of application.
  • Japanese Patent Publication No. 5-333929 discloses a technique for promoting absorption by an acrylic or rubber transdermal transmucosal preparation containing a fatty acid dialkylolamide as an absorption promoter.
  • ibudilast was not indicated as a drug and it was not known whether it would be effective if applied to ibudilast:
  • a tape formulation in which a skin absorption enhancer is added to ibudilast has been proposed, but when a large amount of the skin absorption enhancer is added, the cohesive strength of the adhesive is reduced and the adhesive property is deteriorated. There was also communication.
  • An object of the present invention is to provide a percutaneous absorption patch which stably releases ibudilast, which is an agent for improving tracheal asthma and cerebrovascular disorders, over a long period of time, as described above.
  • Guidance of invention is to provide a percutaneous absorption patch which stably releases ibudilast, which is an agent for improving tracheal asthma and cerebrovascular disorders, over a long period of time, as described above.
  • the gist of the first invention is a transdermal absorption patch comprising a support and an adhesive layer laminated thereon, wherein the adhesive layer comprises 100 parts by weight of an adhesive, and a transdermal absorption enhancer. 1 to 30 parts by weight and ibudilast 1 to 30 parts by weight, wherein the percutaneous absorption enhancer is composed of a long-chain fatty acid having 10 to 18 carbon atoms and an aliphatic alcohol having 1 to 5 carbon atoms. It is a long-chain fatty acid ester that is a reaction product or a long-chain fatty acid having 8 to 18 carbon atoms.
  • the support used in the present invention is not particularly limited as long as it is flexible and does not allow vegetation to pass therethrough.
  • These may be used as a single eyebrow sheet (film) or as a laminate (laminate) of two or more sheets.
  • the pressure-sensitive adhesive used in the present invention those having pressure sensitivity to the skin at room temperature are used.
  • an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, or the like is preferable.c Even if these are solvent-based, Emulsion-based or hot-melt-based.
  • the acryl-based pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of alkyl (meth) acrylate, and is a functional monomer or multifunctional copolymer that can be copolymerized with alkyl (meth) acrylate. It may be a copolymer with a functional monomer.
  • Alkyl (meth) acrylates include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. Relate, n-octyl (meta) acrylate, dodecyl (meta) acrylate, and the like. When the number of carbon atoms in the alkyl group of the acrylate becomes smaller, Since the cohesive strength is improved but the cohesive strength is reduced, and if the cohesive strength is increased, the cohesive strength is reduced but the cohesive strength is reduced.
  • the functional monomers include (meth) acrylic acid, 2-hydroxyhydroxy (meth) acrylate, 2-hydroxypropyl (meth) acrylate, glycidyl methacrylate, N —Methylol (meth) acrylamide, N-butoxymethylacrylamide, etc.
  • these functional monomers are copolymerized, they can be cross-linked by gold salts such as sodium hydroxide and calcium hydroxide, isocyanate, epoxy resin, melamine resin, urea resin, ammonium, etc.
  • gold salts such as sodium hydroxide and calcium hydroxide, isocyanate, epoxy resin, melamine resin, urea resin, ammonium, etc.
  • the cohesive force of the adhesive can be improved.
  • the polyfunctional monomer is co-polymerized to improve the cohesive strength of the pressure-sensitive adhesive.
  • the acrylic thread adhesive is an alkyl (meta) acrylate as a single S unit. And a copolymer containing a vinyl compound copolymerizable therewith.
  • the vinyl compound include vinyl acetate, acrylonitrile, styrene, and N-vinyl-2-pyrrolid. Don and others are given.
  • acrylic pressure-sensitive adhesive one comprising a copolymer containing a plurality of (meth) acrylic acid alkyl esters as monomer units is also used.
  • 2-ethylhexyl methacrylate 65 to 90% by weight, 2-ethylhexyl acrylate 5 to 30% by weight, dodecylmethacrylate 5 to 30% by weight, and a polyfunctional monomer —
  • Preferred is an acrylic pressure-sensitive adhesive consisting of a copolymer of 0 to 0.5% by weight.
  • the acryl-based pressure-sensitive adhesive has an alkyl (meth) acrylate as a main component, and other components may be appropriately determined depending on required performance.
  • a functional monomer is contained in the pressure-sensitive adhesive. 0% by weight or less, preferably 1 to 10% by weight is copolymerized.
  • the S of the polyfunctional monomer is generally from 0 to 0.5% by weight in the adhesive.
  • the Dahl compound is generally copolymerized in the pressure-sensitive adhesive in an amount of 50% by weight or less, preferably 40% by weight or less.
  • a tackifier, a filler, and the like may be added to the acrylic pressure-sensitive adhesive within a pharmaceutically acceptable range.
  • the polymerization method of the acrylic pressure-sensitive adhesive is not particularly limited, and examples thereof include known methods such as solution polymerization and bulk polymerization.
  • the rubber-based pressure-sensitive adhesive used as one of the pressure-sensitive adhesives is preferably composed of a rubbery substance, a tackifier resin, a modifier such as an emulsifier, and an antioxidant.
  • Examples of the rubbery substance include cis-1,4-isoprene and the like. Natural rubber; synthetic rubber such as trans-1,4-isobrene: styrene-isoprene-styrene block copolymer, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, polystyrene Examples include styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-butylene block copolymer, and silicone rubber.
  • Natural rubber synthetic rubber such as trans-1,4-isobrene: styrene-isoprene-styrene block copolymer, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, polystyrene Examples include styrene-butadiene copolymer, styren
  • tackifying resin examples include rosin, hydrogenated rosin, disproportionated rosin, polymerized rosin, rosin rosin-based resin such as rosin, ⁇ -binene, ⁇ -binene, and other terpene resins: Petroleum resins such as aliphatic, aromatic, alicyclic, and cross-linked resins; and coumarone-indene resins, alkyl phenol resins, and xylene resins.
  • Examples of the above iS softener include polybutene, process oil, liquid isobutylene, liquid boria acrylate, castor oil, cottonseed oil, palm oil, palm oil, beeswax, carnauba wax, lanolin and the like.
  • antioxidant those commonly used are used.
  • the cinnamon absorption enhancer used in the present invention is a long-chain fatty acid ester, which is a reaction product of a long-chain fatty acid having a prime number of 10 to 1 and an aliphatic alcohol having 1 to 5 carbon atoms, or 8 carbon atoms. ⁇ 18 long-chain fatty acids.
  • the long-chain fatty acid ester which is a reaction product of the above-mentioned long-chain fatty acid having 10 to 18 carbon atoms with an aliphatic alcohol having 1 to 5 carbon atoms is not particularly limited, and is, for example, ethyl laurate.
  • 'isobrovir myristate isopropyl laurate, butyl laurate, ethyl myristate, propyl myristate, isopropyl myristate, butyl myristate, isobutyl myristate, isopentyl myristate
  • propyl noremitate isopropylamine panolemitate, butyl palmitate, propyl stearate, isoprop
  • the long-chain fatty acid having 8 to 18 carbon atoms is not particularly limited, and includes, for example, capric acid, lauric acid, myristic acid, myristic acid, linoleic acid, linoleic acid, linolenic acid, Examples include palmitic acid, oleic acid, and stearic acid, and preferably decilenic acid.
  • the adhesive waste used in the present invention is composed of 100 parts by weight of the adhesive, 1 to 30 parts by weight of the transdermal absorption enhancer, and 1 to 30 parts by weight of ibudilast.
  • the content of the percutaneous absorption enhancer is less than 1 part by weight, the required area of the above ibudilast must be secured by increasing the application area, so that the application property is poor and it is difficult to apply for a long time.
  • the content exceeds 30 parts by weight, the cohesive force of the pressure-sensitive adhesive is reduced and it becomes difficult to apply the pressure-sensitive adhesive.
  • the method for producing the transdermal patch of the present invention is not particularly limited, and examples thereof include known methods for producing a pressure-sensitive adhesive tape such as a solvent coating method, a hot melt coating method, and an emulsion coating method.
  • the solvent coating method for example, the above-mentioned pressure-sensitive adhesive, the above-mentioned ibudilast, and the above-mentioned transdermal absorption enhancer are dissolved or dispersed in a solvent such as ethyl acetate, and the obtained solution is coated on a support and dried.
  • a solvent such as ethyl acetate
  • Preferred is a method of coating on paper and drying, followed by transfer onto a support.
  • the release paper may be used to protect the adhesive eyebrows until the time when the transdermal patch of the present invention is used.
  • the thickness of the pressure-sensitive adhesive layer is not particularly limited, and is preferably 30. ⁇ 200 jtz m. If it is less than 300 m, the required amount of the above ibudilast cannot be contained, and if it exceeds 200 m, the above ibudilast contained in the vicinity of the support of the adhesive brow is effectively used. Can not do it.
  • the transdermal patch of the present invention is preferably cut into a predetermined shape, collected and stored in a packaging material.
  • the packaging material is not particularly limited as long as it does not transmit oxygen or does not easily transmit oxygen.
  • aluminum foil whose surface is coated with polyethylene terephthalate or polyethylene, polyvinylidene chloride And a polyvinyl chloride film.
  • a second gist of the present invention is a transdermal absorption patch comprising a support having an adhesive eyebrow ridge layer, wherein the adhesive eyebrow comprises 100 parts by weight of an adhesive, and a transdermal absorption enhancer.
  • the percutaneous absorption enhancer is composed of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms and monoethanolamine or diethanolamine. It is a fatty acid amide which is a reaction product of the above.
  • the support used in the second present invention includes the support used in the first present invention.
  • the pressure-sensitive adhesive used in the second present invention includes the pressure-sensitive adhesive used in the first present invention.
  • the rubber-based pressure-sensitive adhesive that can be used as the pressure-sensitive adhesive include 100 parts by weight of a rubber elastic body, 2 to 3 oag parts of a tackifier resin, an appropriate amount of a modifier such as a drinking agent, and aging prevention Those consisting of agents are preferred.
  • Examples of the rubber elastic body, the tackifying resin, the softening agent, and the antioxidant include those used in the first present invention.
  • the skin absorption enhancer used in the second invention is a fatty acid amide, which is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with monoethanolamine or diethanolamine. It consists of
  • Examples of the fatty acid amide which is a reaction product of an aliphatic monocarboxylic acid having a carbon number of 10 to 14 and monoethanolamine or diethanolamine include, for example, monoethanolamide cabrate, laurine Acid monoethanolamide, capric acid diethanolamide, lauric acid diethanolamide and the like. Of these, monoethanolamide laurate and diethanolamide laurate are preferred.
  • the pressure-sensitive adhesive eyebrows used in the second transdermal patch of the present invention include 100 parts by weight of the adhesive, 0.1 to 15 parts by weight of the fatty acid amide, and 5 to 50 parts by weight of ibudilast. Part.
  • the fatty acid amide content is less than 0.1 part by weight, the required application amount of ibudilast must be secured by increasing the application area, so that the application property is high and it is difficult to apply for a long time.
  • the amount exceeds 15 parts by weight the adhesive strength of the above-mentioned pressure-sensitive adhesive decreases and it becomes difficult to apply the adhesive.
  • the adhesive migrates excessively to the skin and develops skin irritation and toxicity. Limited.
  • the ibudilast content is less than 5 parts by weight, the required amount of ibudilast must be ensured by increasing the stoma of the pasted area, so that the pasting property is poor and it is difficult to adhere for a long time. If the amount is more than 10 parts by weight, the cohesive strength of the adhesive is reduced, making it difficult to apply the adhesive for a long period of time.
  • the method for producing the transdermal patch of the second invention the method for producing the transdermal patch of the first invention can be applied.
  • the second method of storing and storing the transdermal patch of the present invention includes the first method of storing and storing the transdermal patch of the present invention.
  • the fatty acid amide which is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with monoethanolamine or diethanolamine, is obtained from ibudilast.
  • an effective formulation can be obtained with a small-area preparation, the blood concentration gradually increases, it works for a long time, and side effects such as nausea and vomiting are suppressed. Pain can be reduced.
  • a third aspect of the present invention is a transdermal absorption patch comprising a support and a pressure-sensitive adhesive layer laminated thereon, wherein the pressure-sensitive adhesive eyebrow comprises 100 parts by weight of an adhesive, and 100 parts by weight of silicic anhydride.
  • Percutaneous absorption enhancer 25 to 100 parts by weight and ibudilast 1 to 40 parts by weight, wherein the percutaneous absorption enhancer has a carbon number of 10 to 18 Is a fatty acid ester, which is a reaction product of a fatty acid with 1-5 aliphatic alcohols.
  • the support used in the third present invention includes the support used in the first present invention.
  • the pressure-sensitive adhesive used in the third invention includes the pressure-sensitive adhesive used in the first invention.
  • the silicic anhydride used in the third aspect of the present invention is not particularly limited, and is, for example, one composed of silicon oxide, the surface of which is composed of hydrophilic silicic anhydride or silicon oxide covered with a hydroxyl group. Hydrophobic silicic anhydride whose surface is greatly degraded by dimethylsilanol. These may be used alone or in combination of two or more.
  • the diameter of the silicic anhydride is preferably from 0.01 to 10 m.
  • the skin-absorbing patch used in the third invention has 10 to 18 carbon atoms. It is composed of a long-chain fatty acid ester which is a reaction product of a chain fatty acid and an aliphatic alcohol having 1 to 5 carbon atoms.
  • Examples of the long fatty ester include a fatty acid having a Ginseng number of 10 to 18 used in the present invention and a fatty acid having a carbon number of 1 to 18.
  • the pressure-sensitive adhesive layer used in the third transdermal patch of the present invention comprises: 100 parts by weight of the pressure-sensitive adhesive, 100 to 40 parts by weight of silicic anhydride, 25 to 50 parts by weight of the percutaneous absorption enhancer. It is composed of 100 parts by weight and 1 to 40 parts by weight of ibudilast.
  • the above silicic anhydride content is less than 10 parts by weight, it is not possible to impart sufficient cohesive force to the pressure-sensitive adhesive layer, which causes stringing and adhesive residue, and if it exceeds 40 parts by weight, Since the adhesiveness is reduced and the sticking property is deteriorated, the content is limited to the above range.
  • the application area must be increased to secure the required dose of K ibudilast, so that the application property is poor and it is difficult to apply for a long time.
  • the amount exceeds 25 parts by weight, the cohesive force of the adhesive decreases and the application becomes difficult.Therefore, the content is limited to the above range.
  • the required dosage of the above ivudilast must be ensured, so that the sticking property is poor and it is difficult to stick for a long time, and if it exceeds 100 parts by weight, the cohesive force of the pressure-sensitive adhesive is reduced. It is limited to the above range because it will lower and make it difficult to attach.
  • the method for producing the transdermal patch of the first present invention can be applied.
  • the third method of storing and storing the transdermal patch of the present invention includes the method of storing and storing the transdermal patch of the first present invention.
  • FIG. 1 is a perspective view of the diffusion cell used in the skin transitivity test of Examples 11 to 11 and Comparative Examples 11 to 11.
  • 1 represents a diffusion cell.
  • 2 represents a receptor tank.
  • 3 represents a donor tank.
  • 4 indicates an opening.
  • 5 represents a flange.
  • 6 indicates a flange.
  • 7 represents a sample ring.
  • 8 represents peel / f piece.
  • 9 represents a magnetic stirrer.
  • E HA ethylhexyl
  • the acid 2 ethylhexyl 3 13.3 g (80 mol%) and the dimethacrylic acid 1,6—hexamethylene glycol 52 mg (0.0 double ⁇ %)
  • the solution was charged into a separable flask equipped with a cooling device, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight
  • the solution was heated to 60.C under a nitrogen atmosphere, and lauroyl peroxide 2 was added.
  • Acrylic pressure-sensitive adhesive A 100 weight parts (solid content), ibudilast 14 weight parts, isobropir myristate 13 weight parts, solid content concentration 25 weight% Then, ethyl acetate was added thereto, and the mixture was uniformly mixed with a dissolver to obtain a pressure-sensitive adhesive composition solution. The resulting solution was applied on a silicon-treated polyethylene terephthalate film (48 m thick) and dried in a microwave oven at 60 for 30 minutes to form an 80 ⁇ m thick adhesive layer.
  • PET-EVA polyethylene terephthalate polyethylene mono-vinyl acetate copolymer
  • a transdermal patch was obtained in the same manner as in Example 1-1 except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate so that
  • a transdermal patch was obtained in the same manner as in Example 11 except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate.
  • a transdermal patch was obtained in the same manner as in Example 11-11, except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate to a concentration of 0.1% by weight.
  • a transdermal patch was obtained in the same manner as in Example 11 except that the adhesive composition solution was prepared by adding ethyl.
  • Acrylic adhesive B an acrylic pressure-sensitive adhesive having a solid content of 35% by weight
  • Ethyl acetate was added to 100 parts by weight (solid content) of the above-mentioned acrylic pressure-sensitive adhesive B so as to give 150 parts by weight of ibudilast, 7 parts by weight of isopropyl myristate, and a solids concentration of 30% by weight. Then, a pressure-sensitive adhesive composition solution was obtained by uniformly mixing with a dissolver. Using the obtained solution, the adhesive layer was formed on the EVA side of the PET-EVA laminated film in the same manner as in Example 11 to obtain the first transdermal patch of the present invention.
  • Example 1-8 Example 1-8
  • Styrene-Isoprene-Styrene block copolymer (Nur Kagaku Co., Ltd., Califrex TR 1107) 14.6 g, Polybutene (Nisseki Kagaku Co., HV-300) 4.9 g , 41.2 g of an alicyclic saturated hydrocarbon (Alcon P-70) manufactured by Arakawa Chemical Industries, Ltd. as a tackifier resin and 36.3 g of liquid paraffin are mixed uniformly.
  • a rubber-based adhesive (hereinafter referred to as “rubber-based adhesive A”) was obtained.
  • a transdermal patch was obtained in the same manner as in Example 11 except that the solution of the pressure-sensitive adhesive composition was prepared by adding hexane to the mouth as described above.
  • Example 1 except that no isopropyl myristate was added.
  • a transdermal patch was obtained in the same manner as in 1.1.
  • a transdermal patch was obtained in the same manner as in Example 1-2, except that no isoprovir myristate was added at all.
  • a percutaneous absorption patch was obtained in the same manner as in Example 1-3, except that no isobromopropyl myristate was added. Comparative Example 11
  • a percutaneous absorption patch was obtained in the same manner as in Example 17 except that no isobromopropyl myristate was added.
  • a transdermal patch was obtained in the same manner as in Example 19-19, except that no isoprovir myristate was added.
  • the percutaneous absorption patches obtained in Examples 11 to 11 and Comparative Examples 1 to 1 to 15 were measured for the amount of skin permeation (m) using the diffusion cell 1 shown in FIG. .
  • the diffusion cell 1 is formed of a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 disposed on the tank 2.
  • An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the bottom wall extends in the peripheral direction and a flange 5 is provided.
  • a flange 6 is provided at an upper portion of the receiver tank 2, and a laterally protruding sampling blob 7 is attached to a side wall.
  • the flange 5 and the flange 6 are overlapped facing each other, and the one-toner tank 3 and the receiver tank 2 are stacked airtightly and concentrically.
  • a magnetic stirrer 9 is placed inside the receiver tank 2.
  • a hairless mouse (6 weeks old) was sacrificed by cervical dislocation, the back skin was immediately separated and the subcutaneous fat and muscle layer were removed to obtain a skin piece 8 of about 5 cm ⁇ 5 cm.
  • the obtained skin piece 8 was sandwiched between the flanges 5 and 6 of the diffusion cell 1, and the opening 4 of the donor tank 3 was completely closed with the skin piece 8.
  • the obtained sample was cut into a circle (3.1 cm 2 ) and attached to the center of the skin piece 8 so that the adhesive layer was in contact with the skin ⁇ piece 8.
  • Receptor tank 2 was filled with the receptor solution, placed in a thermostat kept at a temperature of 37 ° C., and stirred by rotating magnet * stirrer 9 with a magnet stirring device. Examination started 24 o'clock after the cabinet, T / JP95 / 01011
  • the receptor solution N a H z PO, 5 X 1 0 - 'mo 1, at HPQ, 2 1 0 "1 mo N a C 1 1.
  • 5 xl 0 -'mo l and Gentama Lee Shin 1 0 mg was dissolved in distilled water 5 0 0 mL, 0. IN- N a OH after adjusting the p H to 7.2 aqueous solution was added, c table was 1 0 0 O mL with distilled water 1
  • a 38 / m-thick support (a laminate of polyethylene terephthalate and an ethylene-vinyl acetate copolymer (hereinafter referred to as “PET-EVA”)) was laminated to form a skin-absorbing patch.
  • PET-EVA ethylene-vinyl acetate copolymer
  • Example 11 was carried out in the same manner as in Example 21 except that acryl-based pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 25 parts by weight of ibudilast, and 1.2 parts by weight of diethanolamide laurate. This was used as a skin patch.
  • Example 21 was the same as Example 21 except that the acrylic pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 5.8 parts by weight of ibudilast, and 9.2 parts by weight of ethanol laurate. This was performed to obtain a transdermal patch.
  • Example 2-4 the acrylic pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 5.8 parts by weight of ibudilast, and 9.2 parts by weight of ethanol laurate. This was performed to obtain a transdermal patch.
  • Example 2-4 the acrylic pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 5.8 parts by weight of ibudilast, and 9.2 parts by weight of ethanol laurate. This was performed to obtain a transdermal patch.
  • Example 2-4 the acrylic pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 5.8 parts by weight of ibudilast, and 9.2 parts by weight of ethanol laurate. This was performed to obtain
  • a transdermal patch was prepared in the same manner as in Example 2-1 except that diethanolamide laurate, which was an absorption enhancer, was omitted.
  • a transdermal patch was prepared in the same manner as in Example 22 except that diethanolamide laurate, which was an absorption enhancer, was omitted.
  • a transdermal patch was prepared in the same manner as in Examples 2-3 except that the absorption enhancer jetanolamide laurate was omitted.
  • a transdermal patch was prepared in the same manner as in Example 2-4, except that diethanolamide laurate, which was an absorption enhancer, was omitted.
  • a transdermal patch was prepared in the same manner as in Examples 2-5, except that diethanolamide perillanate, which was an absorption enhancer, was omitted.
  • the obtained liquid is used for the silicone-treated po Liethyrene terephthalate film (thickness 48 / m) ⁇ Applied on release paper, dried in a gear oven at 60 to 30 minutes to form an 80 m thick adhesive layer, then thickness 3 8 m polyethylene terephthalate-ethylene-vinyl acetate copolymer (hereinafter referred to as “PET-EVA”)
  • PET-EVA polyethylene terephthalate-ethylene-vinyl acetate copolymer
  • Acrylic pressure-sensitive adhesive A 100 parts (solid content), 29 parts by weight of silicic anhydride, 20.4 parts by weight of ibudilast, and isoprovir myristate 81.6 parts Parts by weight, mixed, and further adjusted to a coating solution by adding ethyl acetate to a solid concentration of 25% by weight in the same manner as in Example 3-1. I got
  • a transdermal patch was obtained in the same manner as in Example 3-1 except that silicic anhydride and isopropyl myristate were not added at all.
  • a transdermal patch was obtained in the same manner as in Example 3-2, except that no silicic anhydride was added.
  • Acrylic adhesive A 100 parts by weight (solid content) and silica anhydride 50 parts by weight / JP95 / 01011
  • the abdomen of a guinea pig (for 6 weeks) was shaved, and a sample obtained by punching the above-mentioned transdermal patch into a circular (area: 3.14 cm 2 ) having a diameter of 2 cm was applied.
  • the sample was washed and immersed overnight in a tetrahydrofuran solvent to extract the drug remaining in the sample.
  • the amount of the drug in the solvent was measured by a high-speed liquid chromatographic method, and the skin transfer amount was calculated from the difference from the initial drug content of the sample ⁇ .
  • the percutaneous permeability of ibudilast is enhanced, an effective skin transfer amount can be obtained with a small-sized preparation, and the blood concentration of ibudilast can be reduced. Since it can rise quickly and suppress side effects such as nausea and vomiting, it can be suitably used as a remedy for bronchial asthma, cerebrovascular injuries, etc. for children and seniors.

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  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à une pastille absorbable par voie percutanée, qui peut libérer de façon stable, sur une longue période, de l'ibudilast, qui est un produit que l'on donne aux personnes souffrant d'asthme bronchique ou de troubles cérébrovasculaires pour améliorer leur état. Cette pastille comprend un support sur lequel est placée une couche d'adhésif autocollant comprenant 100 parties en poids d'un adhésif autocollant, 1 à 30 parties en poids d'un accélérateur d'absorption percutanée et 1 à 30 parties en poids d'ibudilast, et l'accélérateur d'absorption comprend un acide gras à chaîne longue C8-C18 ou un esther de cet acide, combiné à un alcool aliphatique C1-C5.
PCT/JP1995/001011 1994-11-04 1995-05-26 Pastilles absorbables par voie percutanee WO1996014069A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6270950A JPH08133974A (ja) 1994-11-04 1994-11-04 経皮吸収貼付剤
JP6/270950 1994-11-04

Publications (1)

Publication Number Publication Date
WO1996014069A1 true WO1996014069A1 (fr) 1996-05-17

Family

ID=17493281

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1995/001011 WO1996014069A1 (fr) 1994-11-04 1995-05-26 Pastilles absorbables par voie percutanee

Country Status (2)

Country Link
JP (1) JPH08133974A (fr)
WO (1) WO1996014069A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007066151A3 (fr) * 2005-12-07 2008-03-27 Pharmakodex Ltd Compositions topiques destinees au traitement de troubles respiratoires

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446818A (en) * 1977-09-21 1979-04-13 Lion Dentifrice Co Ltd Surgical antiiinflammatory and anodyne agent
JPS62215528A (ja) * 1986-03-17 1987-09-22 Taisho Pharmaceut Co Ltd 経皮投与製剤
JPS62228027A (ja) * 1985-08-26 1987-10-06 Sekisui Chem Co Ltd 経皮・経粘膜製剤
JPS6470416A (en) * 1987-09-10 1989-03-15 Taisho Pharmaceutical Co Ltd Pharmaceuticals for percutaneous administration
JPH01153633A (ja) * 1987-12-10 1989-06-15 Kyorin Pharmaceut Co Ltd 経皮吸収製剤
JPH01233212A (ja) * 1988-03-11 1989-09-19 Sekisui Chem Co Ltd 貼付剤
JPH01233213A (ja) * 1988-03-11 1989-09-19 Sekisui Chem Co Ltd 貼付剤
JPH0317018A (ja) * 1989-06-14 1991-01-25 Sekisui Chem Co Ltd 経皮吸収製剤
JPH03291218A (ja) * 1990-04-06 1991-12-20 Sekisui Chem Co Ltd 貼付剤
JPH0499719A (ja) * 1990-08-20 1992-03-31 Riide Chem Kk 外用貼付剤
JPH04312525A (ja) * 1991-04-10 1992-11-04 Sekisui Chem Co Ltd 医療用貼付剤
JPH04368323A (ja) * 1991-06-12 1992-12-21 Sekisui Chem Co Ltd 貼付剤

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5446818A (en) * 1977-09-21 1979-04-13 Lion Dentifrice Co Ltd Surgical antiiinflammatory and anodyne agent
JPS62228027A (ja) * 1985-08-26 1987-10-06 Sekisui Chem Co Ltd 経皮・経粘膜製剤
JPS62215528A (ja) * 1986-03-17 1987-09-22 Taisho Pharmaceut Co Ltd 経皮投与製剤
JPS6470416A (en) * 1987-09-10 1989-03-15 Taisho Pharmaceutical Co Ltd Pharmaceuticals for percutaneous administration
JPH01153633A (ja) * 1987-12-10 1989-06-15 Kyorin Pharmaceut Co Ltd 経皮吸収製剤
JPH01233212A (ja) * 1988-03-11 1989-09-19 Sekisui Chem Co Ltd 貼付剤
JPH01233213A (ja) * 1988-03-11 1989-09-19 Sekisui Chem Co Ltd 貼付剤
JPH0317018A (ja) * 1989-06-14 1991-01-25 Sekisui Chem Co Ltd 経皮吸収製剤
JPH03291218A (ja) * 1990-04-06 1991-12-20 Sekisui Chem Co Ltd 貼付剤
JPH0499719A (ja) * 1990-08-20 1992-03-31 Riide Chem Kk 外用貼付剤
JPH04312525A (ja) * 1991-04-10 1992-11-04 Sekisui Chem Co Ltd 医療用貼付剤
JPH04368323A (ja) * 1991-06-12 1992-12-21 Sekisui Chem Co Ltd 貼付剤

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007066151A3 (fr) * 2005-12-07 2008-03-27 Pharmakodex Ltd Compositions topiques destinees au traitement de troubles respiratoires

Also Published As

Publication number Publication date
JPH08133974A (ja) 1996-05-28

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