WO1999030702A1 - Percutaneously absorbable levodopa-containing preparation - Google Patents
Percutaneously absorbable levodopa-containing preparation Download PDFInfo
- Publication number
- WO1999030702A1 WO1999030702A1 PCT/JP1998/005670 JP9805670W WO9930702A1 WO 1999030702 A1 WO1999030702 A1 WO 1999030702A1 JP 9805670 W JP9805670 W JP 9805670W WO 9930702 A1 WO9930702 A1 WO 9930702A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- levodopa
- acid
- sensitive adhesive
- preparation
- transdermal absorption
- Prior art date
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- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
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- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 230000003020 moisturizing effect Effects 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 1
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
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- 229920001194 natural rubber Polymers 0.000 description 1
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- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940073665 octyldodecyl myristate Drugs 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
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- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 239000007870 radical polymerization initiator Substances 0.000 description 1
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- 238000010992 reflux Methods 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229940116353 sebacic acid Drugs 0.000 description 1
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- 239000001540 sodium lactate Substances 0.000 description 1
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- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 229920006132 styrene block copolymer Polymers 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 239000003760 tallow Substances 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
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- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Definitions
- the present invention relates to a transdermal preparation containing levodopa.
- Lepodopa a dopamine precursor
- Levodopa a dopamine precursor
- Levodopa in the treatment of Parkinson's disease, in which dyskinesia occurs due to decreased production of dopamine in the brain, levodopa circulates through the body and enters the brain, where it is converted to dopamine by the action of nerve cells to reduce symptoms. Because of its improvement, levodopa is widely used as an effective therapeutic agent (Pharmaceutical Journal; Vo 1.31, No. 12, 1995 / ⁇ . 2998).
- levodopa administration has the following problems, which can have a significant effect on daily life.
- Lepodopa is easily metabolized in various tissues, including the gastrointestinal tract, and has a very low rate of translocation into the brain, requiring large doses.
- intravenous drip infusion requires complicated treatment for long-term treatment, which causes pain to the patient.
- the present invention has been made in view of the above problems, and an object of the present invention is to provide a levodopa-containing transdermal absorption preparation which can be used easily and has excellent drug efficacy.
- the percutaneous absorption preparation according to the present invention contains, as a drug, at least one selected from levodopa and a pharmaceutically acceptable ester thereof in a base, and the site where the above-mentioned drug exhibits a drug effect is other than the site of administration. It is unique.
- the transdermal absorption preparation according to the present invention preferably contains a metabolic inhibitor of levodopa in the base.
- the content of the drug in the preparation is preferably from 0.1 to 30% by weight.
- the above-mentioned percutaneous absorption preparation contains, as an additive, at least one selected from the group consisting of an organic acid, a hygroscopic substance, and a surfactant in a base. .
- the hygroscopic substance at least one selected from the group consisting of a water-absorbing polymer and a polyhydric alcohol is preferably used.
- the polyhydric alcohol preferably comprises glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight of from 200 to 600 as determined by a terminal group assay. At least one selected from the group is used.
- the base is a polymer, a gay acid, a gold silicate earth metal-based mineral, a hydrocarbon, an oil or fat, a polyhydric alcohol, a higher alcohol, a lower alcohol, a higher fatty acid, a fatty acid ester, and water. It consists of at least one selected from the group consisting of:
- the transdermal absorption preparation is in at least one form selected from the group consisting of a cream, a gel, a paste, a lotion, and a poultice.
- a pressure-sensitive adhesive layer containing a drug is provided on one surface of a support.
- the pressure-sensitive adhesive layer at least one selected from the group consisting of an acryl-based pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicon-based pressure-sensitive adhesive and a urethane-based pressure-sensitive adhesive is preferably used.
- the acrylic pressure-sensitive adhesive preferably contains 40 to 90 mol% of (meth) acrylic acid alkyl ester and 10 to 60 mol% of vinylpyrrolidone and has a water absorption of 1.5% or more.
- a polymer is used.
- the drug used in the present invention is at least one selected from levodopa and its pharmaceutically acceptable ester, and if its content is too small, sufficient drug efficacy may not be obtained. 0.1 to 30% by weight in the base is preferable because it may adversely affect the physical properties and make it impossible to endure practical use.
- metabolic inhibitors can also be used.
- the above metabolic inhibitors include benzylazide hydrochloride and carbidopa, and the content thereof is preferably 0.1 to 30% by weight in the base.
- the transdermal absorbability of levodopa and / or its ester is enhanced.
- an organic acid, a hygroscopic substance or a surfactant may be added as an additive to the base.
- organic acids enhance the solubility of the drug in the base and the skin
- hygroscopic substances enhance the release of the drug from the base and transfer to the skin
- surfactants enhance the keratin of the skin It acts on the layer and reduces its lubricity to drugs and other additives.
- organic acids examples include lauric acid, palmitic acid, stearic acid, oleic acid, adipic acid, pendecilenic acid, lactic acid, citric acid, butyric acid, maleic acid, fumaric acid, lingoic acid, and gallic acid.
- lactic acid which has a large absorption promoting effect, is preferred.
- the content of the organic acid is less than 0.1% by weight in the base, the effect of improving the transdermal absorbability of the drug is low, and if it exceeds 20% by weight, skin irritation may occur.
- the content is preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight in the base.
- Examples of the hygroscopic substance include a water-absorbing polymer and a polyhydric alcohol, and a water-absorbing polymer and a polyhydric alcohol can be particularly preferably used.
- water-absorbing polymer examples include polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, sodium polyacrylate, gelatin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl.
- Cell mouth sodium carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl butyral, polyvinyl ether, starch, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene block copolymer, ethylene glycol-propylene glycol block Copolymers, dextran and the like.
- polyhydric alcohol examples include those other than those falling under the category of the water-absorbing polymer, and include, for example, glycerin, butanediol, hexanetriol, propylene glycol, sorbitol, glucose, 1,3-butylene glycol and diethylene glycol. No.
- hygroscopic substance it is also possible to use polysaccharides such as sorbitol and dextrin; sodium lactate, 2-pyrrolidone-5-sodium carboxylate, and the like.
- hygroscopic substances may be used alone or in combination of two or more.
- the polyhydric alcohol it is more preferable to use at least one selected from the group consisting of glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight in the range of 200 to 600.
- glycerin glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight in the range of 200 to 600.
- These are liquids at 40 ° C or lower, are highly hygroscopic, have a moisturizing effect on the skin, and are extremely low-irritant when applied to the skin. They increase skin permeability by increasing the hydration properties of the skin and transporting organic acids that effectively dissolve levodopa into the skin.
- the content of the hygroscopic substance is less than 10% by weight, the effect of reducing skin irritation may not be sufficient, and if it exceeds 40% by weight, in the case of a patch, the inside of the adhesive layer Since the cohesive force is excessively reduced and adhesive residue may be generated at the time of release, the content is preferably 10 to 40% by weight, more preferably 15 to 35% by weight in the base.
- surfactant examples include peraroyl sarcosine, diethanolamide laurate, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, sorbitan fatty acid ester, and polyglycerin fatty acid ester.
- the content of the above surfactant is less than 0.01% by weight, the effect of improving the skin absorbability of the drug may be too low. Since skin irritation may occur, the content is preferably from 0.1 to 10% by weight, more preferably from 0.1 to 5% by weight in the base.
- the base used in the present invention is any as long as it can stably retain levodopa and its pharmaceutically acceptable ester and can absorb levodopa and its pharmaceutically acceptable ester into the body when administered to the skin.
- bases such as ointments, creams, gels, pastes, lotions, and patches can be used.
- One or a composition containing it is preferred as a base.
- polymer examples include polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyacrylic acid salt (for example, sodium salt), methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyacrylic acid.
- examples include amide, sodium alginate, gelatin, corn starch, tragacanth, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, dextrin, carboxymethyl starch and the like.
- geic acid and silicate metal earth minerals examples include colloidal hydrated magnesium silicates such as colloidal silicon dioxide, heavy kaolin and bentonite, and colloidal hydrated magnesium silicate such as bi-gum. Pum ⁇ Aluminum-based minerals.
- hydrocarbons examples include white iselin, paraffin, liquid paraffin, and hydrogel bongel ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.).
- examples of the fats and oils include beeswax, olive oil, cocoa oil, sesame oil, soybean oil, laccase oil, beef tallow, lard, lanolin, castor oil and the like.
- polyhydric alcohol examples include glycerin, butanediol, hexanetriol, propylene glycol, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene block copolymer, and the like.
- Examples of the higher alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.
- Examples of the lower alcohol include ethyl alcohol and isopropyl alcohol.
- fatty acids examples include, for example, acetic acid, acrylic acid, pallic acid, lauric acid, tridecylic acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidonic acid, linoleic acid, and linolenic acid. Saturated or unsaturated fatty acids are mentioned.
- fatty acid ester examples include an ester of a fatty acid having 8 to 20 carbon atoms and an aliphatic alcohol having 1 to 32 carbon atoms.
- fatty acids examples include, for example, hydrauric acid, hydrauric acid, lauric acid, tridecylic acid, myristic acid, palmitic acid, stearic acid, pendecilenic acid, oleic acid, arachidonic acid, linoleic acid, linolenic acid, sebacic acid And the like.
- fatty acid esters include, for example, isopiryl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, white wax and the like.
- the transdermal preparation of the present invention may contain a solubilizer, Accelerators, stabilizers, fillers, antioxidants, tackifiers and the like may be added.
- the above-mentioned dissolving agents are used to adjust the properties (viscosity, homogeneity, etc.) of the preparation, and include, for example, hydrocarbons such as liquid paraffin; isopropyl myristate, glyceryl monolaurate, and ethyl ethyl sebacate. Esters of fatty acids with monohydric or polyhydric alcohols; and oils and fats derived from natural products such as lanolin and olive oil.
- the above-mentioned percutaneous absorption enhancer is used to increase the skin permeability of levodopa and its pharmaceutically acceptable ester by acting on the skin. For example, it enhances the hydration of the skin, or enhances levodopa. Good dissolution and transport into the skin enhances skin permeability.
- percutaneous absorption enhancers include polysorbate, diethanolamide diphosphate, lauroyl sarcosine, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, sorbitan fatty acid ester, and glycerin fatty acid ester. And the like.
- the stabilizing agent is used to suppress oxidation, decomposition, etc. of levodopa and its pharmaceutically acceptable ester and other components, and to prevent the preparation from changing over time.
- oxidation, decomposition, etc. of levodopa and its pharmaceutically acceptable ester and other components for example, butylhydroxytoluene, sorbic acid, etc.
- Antioxidants; cyclodextrin, ethylenediaminetetraacetic acid, etc .; and the above fillers are used for the purpose of adjusting the viscosity and hardness of the preparation, uniform dispersion and retention of levodopa, and the like.
- examples include calcium carbonate, titanium oxide, lactose, and crystalline cellulose.
- the transdermal preparation of the present invention can be produced by a conventional method.
- the necessary base materials are kneaded, emulsified, suspended or dissolved according to the dosage form, and then the drug is manufactured.
- the drug is manufactured.
- a solubilizer e.g., a solubilizer, a percutaneous absorption enhancer, a stabilizing agent, a filler, etc., and mixing with a commonly used kneader.
- the levodopa-containing transdermal absorption preparation of the present invention can also be used as a transdermal patch with a drug-containing pressure-sensitive adhesive layer provided on one surface of a support.
- the support is not particularly limited as long as the support has a function of protecting the surface opposite to the application surface, and is usually a plastic film or sheet, a tape, a nonwoven fabric, or the like.
- a single or laminated material such as a woven fabric, a foam sheet, or a metal foil (for example, an aluminum foil) is used.
- the support those having flexibility capable of following the movement of the skin surface and barrier properties for preventing the escape of drugs and other additives are preferably used.
- polyester copolymers such as polyethylene terephthalate and polyvinyl terephthalate; polyethylene, polypropylene, polybutadiene, polybutene, and ethylene-vinyl acetate copolymers.
- Polyolefin (co) polymers such as polymer, ethylene-propylene copolymer, ethylene-alkyl (meth) acrylate copolymer, ethylene-methyl acrylate copolymer; styrene-isoprene-styrene copolymer Styrene-based copolymers such as styrene-butadiene-styrene copolymers and hydrogenated products thereof; vinylidene chloride-based (co) polymers such as polyvinylidene chloride and vinylidene chloride-styrene copolymer; Vinyl, vinyl chloride-ethylene copolymer, chloride Vinyl chloride-based (co) polymers such as vinyl-acrylic acid alkyl ester copolymers; silicone resins; polyfluoroethylene; polyurethane; and polyimides.
- polymers such as polymer, ethylene-propylene copolymer, ethylene-alkyl (meth) acrylate copo
- Examples of the material of the nonwoven fabric and the woven fabric include fibrous materials made of acryl-based resins such as polyester, polyolefin, and atarilonitrile, polyamide, rayon, and cotton.
- Examples of the material of the foam include polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, polyolefin-based resin such as polyethylene oxide; and styrene-butadiene copolymer. No.
- the thickness of the support is too thin, the strength of the preparation is insufficient, and the skin tends to become stiff at the time of application.When it is thick, the discomfort when applied to the skin increases, and the thickness of the support becomes poor due to the sticking of the application end. It is preferably 20 to 300, because it may be easily damaged.
- the thickness of the support varies depending on the material used, but in the case of a film, the thickness is preferably 500 / im or less, more preferably 40 to 200 ⁇ m.
- the base used in the pressure-sensitive adhesive layer is a base that stably holds levodopa and a pharmaceutically acceptable ester thereof and that can absorb levodopa and its pharmaceutically acceptable ester into the body when administered to the skin.
- a base that stably holds levodopa and a pharmaceutically acceptable ester thereof and that can absorb levodopa and its pharmaceutically acceptable ester into the body when administered to the skin.
- those conventionally used as bases for non-hydrous or hydrous plasters, tapes, patches, cataplasms and the like can be used.
- the above-mentioned base include, for example, polymers such as acryl, rubber, silicone, and urethane, as required, a crosslinking agent, a plasticizer, a stabilizer, water, a pH adjuster, and a filler. And the like.
- a pressure-sensitive adhesive mainly composed of an alkyl (meth) acrylate is preferred, and a functional monomer and Z or a polyfunctional monomer copolymerizable with the alkyl (meth) acrylate are preferred. And a copolymer thereof.
- alkyl (meth) acrylate examples include: (meth) methyl acrylate, (meth) ethyl acrylate, (meth) propyl acrylate, (meth) isopropyl acrylate, and (meth) acrylic acid n-butyl.
- Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a hydroxyl group, a monomer having an amide group, a monomer having an amino group, a monomer having a nitrogen-containing heterocyclic ring, and the like. Specific examples include (meth) acrylic acid-2-hydroxyhydroxyl, (meth) acrylic acid-12-hydroxypropyl, (meth) acrylic acid, maleic acid, acrylamide, ethoxymethylacrylic acid. Media, diacetone acrylamide, dimethylaminoethyl acrylate, vinyl pyrrolidone, vinyl imidazole and the like.
- polyfunctional monomers examples include, for example, alkylene glycol which is a reaction product of (meth) acrylic acid and alkylene glycols; ethylene glycol, butylene glycol, hexamethylene glycol, and the like. Di (meth) acrylate, (meth) acrylic acid and polyalkylene glycols; polyalkylene glycol di (meth) acrylate, which is a reaction product of polyethylene glycol, polypropylene dalicol, and the like.
- the rubber-based adhesive examples include natural rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and styrene-olefin-styrene block copolymer.
- Polymers. These are generally used by adding a tackifier such as rosin, hydrogenated rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin.
- silicon-based pressure-sensitive adhesive examples include polydimethylsiloxane and polydimethylsiloxane.
- any urethane-based pressure-sensitive adhesive that has been conventionally used as a pressure-sensitive adhesive for transdermal patches can be used, and is not particularly limited.
- crosslinking agent examples include aluminum hydroxide, calcium hydroxide, magnesium stearate, isocyanates, epoxy resins, melamine resins, urea resins, and ammoniums.
- plasticizer those similar to those used as the solubilizer can be used.
- hydrocarbons such as liquid paraffin; isopropyl myristate, glyceryl monolaurate, and getyl sebacate Esters of fatty acids with monohydric or polyhydric alcohols; higher fatty acids such as oleic acid and lauric acid; higher alcohols such as octyldodecanol and myristyl alcohol; natural such as lanolin, olive oil, and coconut oil Fats and oils derived from products.
- the content of the above plasticizer is appropriately determined depending on the amount of levodopa and its pharmaceutically acceptable ester and the type of the above-mentioned pressure-sensitive adhesive, but when the content is small, the plasticizing effect is reduced, and when the content is large, the sticking property is reduced. Therefore, the content is preferably 1 to 50% by weight in the pressure-sensitive adhesive layer.
- the same stabilizers and fillers as those described above can be used.
- a pressure-sensitive adhesive mainly containing a copolymer composed of 40 to 90 mol% of (meth) acrylic acid alkyl ester and 10 to 60 mol% of vinylpyrrolidone can be suitably used.
- the copolymer comprising the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% may be selected from the alkyl (meth) acrylates according to the required adhesive properties.
- a monomer copolymerizable with the ester may be added.
- Examples of the monomer copolymerizable with the alkyl (meth) acrylate include, for example, vinyl acetate, diacetone acrylamide, atarilonitrile, dimethyl acrylamide, and ethylene glycol mono (meth) acrylic acid. Examples include esters and styrene.
- the constituent components of the copolymer consisting of the above-mentioned alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% a monomer copolymerizable with the above-mentioned alkyl (meth) acrylate can be used.
- the proportion of the monomer is preferably not more than 40 mol%, which does not adversely affect the adhesiveness and cohesiveness of the adhesive.
- the component of the copolymer consisting of 10 to 60 mol% of rupyrrolidone may contain a polyfunctional monomer having two or more polymerizable double bonds in one molecule.
- the polyfunctional monomer include divinylbenzene, methylene bisacrylamide, ethylene glycol di (meth) acrylate, propylene glycol (meth) acrylate, and polyethylene glycol
- Examples thereof include (meth) acrylate, hexylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, and trimethylolpropanetri (meth) acrylate.
- the copolymer is partially crosslinked, that is, in a so-called slightly crosslinked state, and a copolymer having a higher degree of polymerization can be obtained.
- the fine cross-linking imparts appropriate cohesiveness to the pressure-sensitive adhesive, increases the adhesiveness, prevents adhesive residue upon separation, and improves the stability of the pressure-sensitive adhesive solution.
- the amount of the polyfunctional monomer used is too small, the aggregation effect cannot be obtained, and if the amount is too large, the reaction solution is likely to gel or is unstable, so the above (meth) acrylic acid alkyl ester 40 to 9
- 0.001 to 0.1 mol% is preferred, more preferably 0.003 to 0.1 mol%. 07 mol%.
- the copolymer consisting of 40 to 90 mol% of the alkyl (meth) acrylate and 10 to 60 mol% of vinylpyrrolidone has a water absorption rate so that a large amount of a hygroscopic substance can be retained. Should be 1.5% or more.
- the water absorption is the ratio of the increased weight to the initial weight after storage for 10 days in an atmosphere adjusted to 25 ° C; 90% relative humidity.
- the water absorption of the copolymer consisting of the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% is caused by vinylpyrrolidone in the copolysynthesis, especially vinylpyrrolidone. Is significantly increased by the presence of a block in the copolymer. Therefore, in order to increase the water absorption, it is preferable to use a vinylpyrrolidone block copolymer or a graft copolymer.
- Examples of the method for producing the block copolymer or the graft copolymer include a macromonomer, a reactive monomer, and living polymerization.
- the copolymer consisting of the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% does not require the vinylpiperidone to be completely present in a block form. It is sufficient that vinyl viridone is present in the copolymer in a rich composition.
- the above copolymer of alkyl (meth) acrylate of 40 to 90 mol% and vinyl pyrrolidone of 10 to 60 mol% having a water absorption of 1.5% or more is, for example, vinylpyrrolidone at the start of polymerization. 90% or more of the total amount of the dong and 0.1 to 5% of the total amount of the alkyl (meth) acrylate coexist, and at least the initial stage of the polymerization (the polymerization rate is 10% or less).
- the alkyl (meth) acrylates are successively added. Can be obtained by a solution polymerization method in which the remainder is added.
- solvent used for the solution polymerization examples include ester solvents such as ethyl acetate, propyl acetate, and butyl peroxide; ketone solvents such as methyl ethyl ketone and cyclohexanone; and aromatic solvents such as benzene and toluene. ; Cellosolve-based solvents such as Solvent in Tiltose and Solvent in Etilse are listed. These may be used alone or in combination of two or more.
- a generally used thermal radical polymerization initiator can be used, and specific examples thereof include hydroxycarbonate, ketone peroxide, and peroxide.
- Organic peroxides such as ketals, hydropoxides, dialkylpoxides (eg, lauroylpoxides, benzoylpoxides, etc.), diasilboxides, and peroxyesters; 2,2'-azobisisobutyrate Lonitrile, 2, 2'-azobis (2-methylbutyronitrile), 2,2, -azobis (2,4-dimethylvaleronitrile), 2,
- Azo compounds such as dimethyl 2'-azobisisobutyrate. These may be used alone or in combination of two or more.
- the amount of the polymerization initiator to be used is preferably 0.001 to 5 parts by weight based on 100 parts by weight of the monomers constituting the copolymer.
- a predetermined amount may be initially supplied collectively, or may be supplied separately.
- the method for producing the transdermal patch of the present invention varies depending on the kind of the adhesive, but the adhesive layer can be produced by a conventional method such as a hot melt method, a solution method, and a solvent coating method.
- a drug and, if necessary, other components are added to the pressure-sensitive adhesive solution obtained by polymerization, followed by stirring and mixing. This solution is After applying on a release paper and drying, the support is heat-laminated to prepare a transdermal patch.
- the pressure-sensitive adhesive composition may be once coated on a release paper and dried to form a pressure-sensitive adhesive layer, and then the pressure-sensitive adhesive layer may be transferred to a support and laminated.
- the thickness of the pressure-sensitive adhesive layer is not particularly limited. However, if the thickness of the pressure-sensitive adhesive layer is less than 20 m, it becomes difficult to contain a necessary amount of the drug. Usually, 20 to 100 / m is preferable because the efficiency is reduced.
- a pretreatment such as an undercoating treatment, a corona discharge treatment, a chemical oxidation treatment, and an ozone treatment may be performed in order to enhance the adhesiveness.
- the release paper is used for the purpose of protecting the pressure-sensitive adhesive layer, and is usually formed by releasing the surface of a single layer or a laminate of a plastic film, paper, or the like with silicone or the like. used.
- the thickness of the release paper is usually preferably 300 ⁇ m or less, more preferably 10 ⁇ 200 ⁇ .
- plastic film of the release paper examples include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, and polyvinylidene chloride.
- Examples of the paper include a paper impregnated with polyvinyl alcohol or the like.
- Levodopa (1.23 g) was suspended in glycerin (1.987 g), and 3.51 g of clospovidone (a crosslinked polymer of 1-vinyl-2-pyrrolidone) was added to the suspension.
- clospovidone a crosslinked polymer of 1-vinyl-2-pyrrolidone
- levodopa (1.44 g) suspended in glycerin (2.49) and clospovidone (1-vinyl) in 6.2.75 g of a solution of the polymer in ethyl acetate (solid content: 3.5.76%) — Crosslinked polymer of 2-pyrrolidone) 2.
- 49 g was added and uniformly mixed to obtain a coating liquid.
- the obtained coating liquid was applied onto a siliconized polyethylene terephthalate (PET) film having a thickness of 35 tzm so that the levodopa content was 0.75 mgZcm 2, and the coating was performed at 60 with 30. After drying for a minute, an adhesive layer was obtained.
- a transdermal patch was prepared by laminating the EVA side of a support composed of a laminate of PET film and ethylene-vinyl monoxide copolymer (EVA) on the obtained pressure-sensitive adhesive layer.
- EVA ethylene-vinyl monoxide copolymer
- CMC-Na sodium carboxycellulose
- Example 1 The whole back of New Zealand White (male, 1 year old) was shaved and the transdermal preparation obtained in Examples 1 and 2 was applied as a repo-dopa to an area of 200 cm2 above the skin as a reportopa.
- Each animal was applied to two egrets (Example 1: 3 g applied, Example 2: applied in a size of 200 cm 2 ).
- the preparation obtained in Comparative Example 1 was orally administered to other egrets at a concentration of 1 lmg / kg of levodopa (about 5 OmgZ individuals as levodopa). After each administration, blood was collected over time up to 24 hours, and the concentration of levodopa in the plasma was measured by high performance liquid mouth chromatography. The results are shown in Table 1.
- ND means not detected.
- Ethyl acetate was added to 1.0 g of lauroyl peroxyside to prepare a solution having a total volume of 30 ml. This solution was copolymerized while being dropped at a rate of 1 m 1 Zh to the monomer composition solution.
- the copolymerization was stopped, and ethyl acetate was added so that the solid content was 30% by weight.
- the mixture was mixed to obtain a solution of the adhesive A in ethyl acetate.
- the water absorption of the adhesive A was measured and found to be 12.4%.
- composition shown in Table 2 a drug, an adhesive solution, a hygroscopic substance, an organic acid, a surfactant, an additive, and a metabolic inhibitor were mixed so as to be uniform throughout to obtain a coating liquid.
- This coating solution was spread on a polyethylene terephthalate film so as to have a thickness after drying of 150 / zm, dried at 60 ° C for 30 minutes, and adhered. An agent layer was formed. A laminating film of polyester 12 // m ethylene-vinyl acetate copolymer resin 2 O ⁇ m was adhered to the pressure-sensitive adhesive layer to obtain a patch. Table 2
- Hygroscopic substance * 1 Gly: glycerin, PG: propylene glycol surfactant BL9: polyoxyethylene (9) lauryl ether,
- Lepodopa blood concentration was measured over time using a rat, and the area under the blood concentration curve (AUC) at 24 hours was calculated.
- the AUC of each of the examples was at least 300 ng ⁇ hr / L, and the AUC of the comparative example was at most 600 ng ⁇ hr / L. It can be seen that the percutaneous absorbability is significantly improved. Also, AUC at oral administration is 2 6 5 0 ng * h rZL , in the embodiment, c (stability test were all found to be continuously absorbed levodopa one day )
- the efficacy of the transdermal preparation containing levodopa was evaluated using the rat (the inhibitory effect on haloperidol-induced talepsi).
- the back of a wister rat male, 7 weeks old was shaved, and the samples of Examples and Comparative Examples were respectively applied to the skin in an area of 12 cm 2 .
- the haloperidol solution was orally administered so that the dose of fodoperidol was 1.0 mg Z kg.
- the efficacy of levodopa was evaluated by the following measurement method. For the evaluation of drug efficacy, rats were used in groups of 10 rats, and the number of rats that showed a suppuration effect was evaluated.
- the evaluation method was to install a stainless steel pipe with a diameter of 2 mm horizontally at a height of 7 cm.
- the mouse is forcibly hooked with both forelimbs on this pipe, and the posture holding until both forelimbs are separated from the pipe is determined to be force talepsi.
- the percutaneous absorption preparation of the present invention is a levodopa-containing percutaneous absorption preparation containing, as a drug, at least one selected from levodopa and a pharmaceutically acceptable ester thereof in a base, so that administration is simple. Yes, excellent persistence of effective blood concentration. For this reason, it is possible to prepare a preparation with less side effects and less fluctuation in drug efficacy.
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Abstract
A percutaneously absorbable levodopa-containing preparation which can be readily used and is excellent in the persistence of drug efficacy. The preparation contains at least one member selected from among levodopa and pharmaceutically acceptable esters thereof as the drug in the base and the drug exhibits its effect at a site other than the site of administration.
Description
明 細 書 レポドパ含有経皮吸収製剤 技術分野 Description Lepodopa-containing transdermal preparation Technical field
本発明は、 レポドパ含有経皮吸収製剤に関する。 背景技術 TECHNICAL FIELD The present invention relates to a transdermal preparation containing levodopa. Background art
ドーパミン前駆体であるレポドパは、 体内でドーパミンに変換される ことにより様々な生理活性を発現する薬物である。 特に、 ド一パミ ンの 脳内産生低下によって運動障害が起こるパーキンソン病の治療において は、 レポドパが体内循環して脳内に移行した後、 神経細胞の働きでド一 パミンに変換されて症状を改善することから、 レポドパは有効な治療薬 として広く用いられている (医薬ジャーナル; V o 1 . 3 1 , N o . 1 2 , 1 9 9 5 / ρ . 2 9 9 8 ) 。 Lepodopa, a dopamine precursor, is a drug that expresses various physiological activities by being converted to dopamine in the body. In particular, in the treatment of Parkinson's disease, in which dyskinesia occurs due to decreased production of dopamine in the brain, levodopa circulates through the body and enters the brain, where it is converted to dopamine by the action of nerve cells to reduce symptoms. Because of its improvement, levodopa is widely used as an effective therapeutic agent (Pharmaceutical Journal; Vo 1.31, No. 12, 1995 / ρ. 2998).
しかしながら、 レポドパ投与には下記に掲げる問題点があり、 日常生 活に多大な影響を与えることがある。 However, levodopa administration has the following problems, which can have a significant effect on daily life.
(1) レポドパは、 消化管をはじめ各組織で容易に代謝され、 脳内に移 行する割合が非常に小さいため、 大量投与が必要となる。 (1) Lepodopa is easily metabolized in various tissues, including the gastrointestinal tract, and has a very low rate of translocation into the brain, requiring large doses.
(2) レポドパの体内半減期が短いため、 効果の持続性がなく、 日内で の症状の変動が激しい。 (2) Because of the short half-life of levodopa in the body, its effects are not sustained and the symptoms fluctuate greatly within the day.
(3) 投与量が多すぎるとジスキネジァ等の副作用が起こる。 (3) If the dose is too large, side effects such as dyskinesia occur.
—方、 上記問題点は、 内服薬として腸溶錠とすること、 点滴静注等に よる用量調節や持続投与等で、 ある程度改善されている。 また、 レボド パとレボドパの代謝阻害剤とを含む配合剤とすることで、 脳内に移行す るまでのレポドパ代謝を抑制し、 脳内におけるレポドパの利用率を向上
させた製剤も開発されている。 —On the other hand, the above problems have been improved to some extent by using enteric-coated tablets as oral medication, dose adjustment by intravenous drip infusion, and continuous administration. In addition, a combination drug containing levodopa and a levodopa metabolism inhibitor suppresses levodopa metabolism until it is transferred to the brain, improving the utilization of levodopa in the brain Formulated formulations have also been developed.
但し、 内服では血中濃度の急激な立ち上がりを抑えることは難しく、 かつまた消化管でも代謝されるため、 効果の持続性向上には限界があつ た。 また、 点滴静注では長期にわたって治療を行うには処置が煩雑であ り、 患者に苦痛を与える。 However, it is difficult to suppress the rapid rise in blood concentration with oral administration, and it is also metabolized in the gastrointestinal tract. In addition, intravenous drip infusion requires complicated treatment for long-term treatment, which causes pain to the patient.
発明の開示 Disclosure of the invention
本発明は上記問題点に鑑みてなされたものであり、 その目的は、 簡便 に使用でき、 且つ薬効の持続性に優れた、 レポドパ含有経皮吸収製剤を 提供することである。 The present invention has been made in view of the above problems, and an object of the present invention is to provide a levodopa-containing transdermal absorption preparation which can be used easily and has excellent drug efficacy.
本発明に係る経皮吸収製剤は、 基剤中に、 薬物としてレポドパ及びそ の薬学上許容されるエステルから選ばれた少なくとも一種を含有し、 前 記薬物の薬効の発現部位が投与部位以外であることを特徵とする。 本発明に係る経皮吸収製剤は、 好ましくは、 基剤中に、 レポドパの代 謝阻害剤を含有する。 The percutaneous absorption preparation according to the present invention contains, as a drug, at least one selected from levodopa and a pharmaceutically acceptable ester thereof in a base, and the site where the above-mentioned drug exhibits a drug effect is other than the site of administration. It is unique. The transdermal absorption preparation according to the present invention preferably contains a metabolic inhibitor of levodopa in the base.
本発明において、 薬物の製剤中の含有率は、 好ましくは、 0 . 1 〜 3 0重量%とされる。 In the present invention, the content of the drug in the preparation is preferably from 0.1 to 30% by weight.
本発明の特定の局面では、 上記経皮吸収製剤は、 基剤中に、 添加剤と して、 有機酸、 吸湿性物質及び界面活性剤よりなる群から選ばれた少な くとも一種を含有する。 In a specific aspect of the present invention, the above-mentioned percutaneous absorption preparation contains, as an additive, at least one selected from the group consisting of an organic acid, a hygroscopic substance, and a surfactant in a base. .
上記吸湿性物質としては、 好ましくは、 吸水性ポリマー及び多価アル コールからなる群より選ばれた少なくとも一種が用いられる。 As the hygroscopic substance, at least one selected from the group consisting of a water-absorbing polymer and a polyhydric alcohol is preferably used.
また、 上記多価アルコールとしては、 好ましくは、 グリセリン、 プロ ピレングリコール、 1 , 3—ブチレングリコ一ル及び末端基定量法によ る分子量 2 0 0 〜 6 0 0の範罔のポリエチレングリコールよりなる群か ら選ばれた少なくとも一種が用いられる。
本発明の特定の局面では、 上記基剤は、 ポリマー、 ゲイ酸、 ゲイ酸金 属土類系鉱物、 炭化水素、 油脂類、 多価アルコール、 高級アルコール、 低級アルコール、 高級脂肪酸、 脂肪酸エステル及び水よりなる群から選 ばれた少なくとも一種により構成される。 The polyhydric alcohol preferably comprises glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight of from 200 to 600 as determined by a terminal group assay. At least one selected from the group is used. In a specific aspect of the present invention, the base is a polymer, a gay acid, a gold silicate earth metal-based mineral, a hydrocarbon, an oil or fat, a polyhydric alcohol, a higher alcohol, a lower alcohol, a higher fatty acid, a fatty acid ester, and water. It consists of at least one selected from the group consisting of:
本発明の特定の局面では、 上記経皮吸収製剤は、 クリーム剤、 ゲル剤、 ペースト剤、 口一ション剤及びパップ剤からなる群より選ばれた少なく とも一種の形態とされる。 In a specific aspect of the present invention, the transdermal absorption preparation is in at least one form selected from the group consisting of a cream, a gel, a paste, a lotion, and a poultice.
本発明のさらに他の特定の局面では、 経皮吸収製剤において、 支持体 の片面に、 薬物を含有する粘着剤層が設けられている。 In still another specific aspect of the present invention, in a transdermal absorption preparation, a pressure-sensitive adhesive layer containing a drug is provided on one surface of a support.
上記粘着剤層としては、 好ましくは、 ァクリル系粘着剤、 ゴム系粘着 剤、 シリコン系粘着剤及びウレタン系粘着剤よりなる群から選ばれた少 なくとも一種が用いられる。 As the pressure-sensitive adhesive layer, at least one selected from the group consisting of an acryl-based pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicon-based pressure-sensitive adhesive and a urethane-based pressure-sensitive adhesive is preferably used.
また、 上記アクリル系粘着剤としては、 好ましくは、 (メタ) アタリ ル酸アルキルエステル 4 0〜9 0モル%及びビニルピロリ ドン 1 0〜6 0モル%からなる吸水率が 1 . 5 %以上の共重合体が用いられる。 In addition, the acrylic pressure-sensitive adhesive preferably contains 40 to 90 mol% of (meth) acrylic acid alkyl ester and 10 to 60 mol% of vinylpyrrolidone and has a water absorption of 1.5% or more. A polymer is used.
本発明で用いられる薬物は、 レポドパ及びその薬学上許容されるエス テルから選ばれた少なくとも一種であり、 その含有量は、 少なくなると 十分な薬効が得られないことがあり、 多くなると基剤の物性に悪影響を 与え、 実使用に耐えれなくなることがあるので、 基剤中 0 . 1〜3 0重 量%が好ましい。 The drug used in the present invention is at least one selected from levodopa and its pharmaceutically acceptable ester, and if its content is too small, sufficient drug efficacy may not be obtained. 0.1 to 30% by weight in the base is preferable because it may adversely affect the physical properties and make it impossible to endure practical use.
本発明では、 皮膚からの吸収や体循環の過程でのレボドパの代謝を抑 制することにより、 脳内への移行性を高め、 より高い薬効を得ると同時 に低血圧等の副作用を防止するため、 代謝阻害剤を用いることもできる。 上記代謝阻害剤としては、 例えば、 塩酸べンゼラジド、 カルビドパなど が挙げられ、 その含有量は、 基剤中 0 . 1〜3 0重量%が好ましい。 本発明では、 レポドパ及び または、 そのエステルの経皮吸収性を高
めるため、 基剤中に添加剤として、 有機酸、 吸湿性物質あるいは界面活 性剤を添加してもよい。 このうち、 有機酸は、 基剤及び皮膚中での薬物 の溶解性を高め、 吸湿性物質は基剤からの薬物の放出性、 皮膚への移行 性を高め、 界面活性剤は、 皮膚の角質層に働き、 薬物や他の添加物に対 するノくリァ性を低下させるものと考えられる。 In the present invention, the metabolism of levodopa in the process of absorption from the skin and systemic circulation is suppressed, thereby enhancing the translocation into the brain, and obtaining higher drug efficacy and simultaneously preventing side effects such as hypotension. Therefore, metabolic inhibitors can also be used. Examples of the above metabolic inhibitors include benzylazide hydrochloride and carbidopa, and the content thereof is preferably 0.1 to 30% by weight in the base. In the present invention, the transdermal absorbability of levodopa and / or its ester is enhanced. For this purpose, an organic acid, a hygroscopic substance or a surfactant may be added as an additive to the base. Of these, organic acids enhance the solubility of the drug in the base and the skin, hygroscopic substances enhance the release of the drug from the base and transfer to the skin, and surfactants enhance the keratin of the skin It acts on the layer and reduces its lubricity to drugs and other additives.
上記有機酸としては、 例えば、 ラウリン酸、 パルミチン酸、 ステアリ ン酸、 ォレイン酸、 アジピン酸、 ゥンデシレン酸、 乳酸、 クェン酸、 酪 酸、 マレイン酸、 フマル酸、 リ ンゴ酸、 没食子酸等が挙げられるが、 吸 収促進効果が大きい、 乳酸が好ましい。 Examples of the organic acids include lauric acid, palmitic acid, stearic acid, oleic acid, adipic acid, pendecilenic acid, lactic acid, citric acid, butyric acid, maleic acid, fumaric acid, lingoic acid, and gallic acid. However, lactic acid, which has a large absorption promoting effect, is preferred.
上記有機酸の含有量が、 基剤中 0 . 1重量%未満であると、 薬物の経 皮吸収性の向上効果が低く、 2 0重量%を超えると、 皮膚刺激を生じる ことがあるので、 基剤中 0 . 1〜2 0重量%が好ましく、 より好ましく は、 0 . 5〜 1 0重量%である。 If the content of the organic acid is less than 0.1% by weight in the base, the effect of improving the transdermal absorbability of the drug is low, and if it exceeds 20% by weight, skin irritation may occur. The content is preferably 0.1 to 20% by weight, more preferably 0.5 to 10% by weight in the base.
上記吸湿性物質としては、 例えば、 吸水性ポリマ一や多価アルコール 等が挙げられ、 特に吸水性ポリマ—及び多価アルコールを好適に用いる ことができる。 Examples of the hygroscopic substance include a water-absorbing polymer and a polyhydric alcohol, and a water-absorbing polymer and a polyhydric alcohol can be particularly preferably used.
上記吸水性ポリマ一としては、 例えば、 ポリビニルピロリ ドン、 架橋 型ポリ ビニルピロリ ドン、 ポリアクリル酸、 ポリメタクリル酸、 ポリァ クリル酸ナトリウム、 ゼラチン、 メチルセルロース、 ヒドロキシェチル セルロース、 ヒ ドロキシプロピルセルロース、 カルボキシメチルセル口 ース、 カルボキシメチルセルロースナトリウム、 カルボキシビニルポリ マー、 ポリビニルアルコール、 ポリビニルプチラール、 ポリビニルェ一 テル、 デンプン、 ポリエチレングリコール、 ポリプロピレングリコール、 ポリオキシエチレンポリオキシプロピレンプロック共重合体、 エチレン グリコール—プロピレングリコールブロック共重合体、 デキストランな どが挙げられる。
上記多価アルコールとしては、 上記吸水性ポリマーの範疇に入るもの 以外として、 例えば、 グリセリ ン、 ブタンジオール、 へキサントリオ一 ル、 プロピレングリコール、 ソルビトール、 グルコース、 1, 3 —プチ レングリコール、 ジエチレングリコールなどが挙げられる。 Examples of the water-absorbing polymer include polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, sodium polyacrylate, gelatin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl. Cell mouth, sodium carboxymethylcellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl butyral, polyvinyl ether, starch, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene block copolymer, ethylene glycol-propylene glycol block Copolymers, dextran and the like. Examples of the polyhydric alcohol include those other than those falling under the category of the water-absorbing polymer, and include, for example, glycerin, butanediol, hexanetriol, propylene glycol, sorbitol, glucose, 1,3-butylene glycol and diethylene glycol. No.
上記吸湿性物質として、 ソルビトール、 デキストリン等の多糖類;乳 酸ソーダ、 2 —ピロリ ドン— 5 —カルボン酸ソ一ダ等を用いることもで さる。 As the hygroscopic substance, it is also possible to use polysaccharides such as sorbitol and dextrin; sodium lactate, 2-pyrrolidone-5-sodium carboxylate, and the like.
これらの吸湿性物質は、 単独で用いても、 2種以上を併用してもよい。 上記多価アルコールとして、 グリセリン、 プロピレングリコール、 1, 3 —ブチレングリコール、 分子量 2 0 0〜 6 0 0の範囲のポリェチレン グリコールからなる群から選択された少なくとも一種を用いるのがより 好ましい。 これらは、 いずれも 4 0 °C以下で液体であり、 吸湿性が高く、 皮膚への湿潤作用があり、 かつ、 皮膚への適用で刺激性が極めて低い安 全な物質である。 これらは、 皮膚の水和性を高めたり、 レポドパを有効 に溶解する有機酸類を皮膚内に運んだりすることで皮膚浸透性を高める。 上記吸湿性物質の含有量は、 1 0重量%未満であると、 皮膚刺激低減 化の効果が十分でないことがあり、 4 0重量%を超えると、 貼付剤の場 合、 粘着剤層の内部凝集力が過度に低下し、 剝離時に糊残りが生じるこ とがあるので、 基剤中 1 0〜4 0重量%が好ましく、 1 5〜3 5重量% がより好ましい。 These hygroscopic substances may be used alone or in combination of two or more. As the polyhydric alcohol, it is more preferable to use at least one selected from the group consisting of glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight in the range of 200 to 600. These are liquids at 40 ° C or lower, are highly hygroscopic, have a moisturizing effect on the skin, and are extremely low-irritant when applied to the skin. They increase skin permeability by increasing the hydration properties of the skin and transporting organic acids that effectively dissolve levodopa into the skin. If the content of the hygroscopic substance is less than 10% by weight, the effect of reducing skin irritation may not be sufficient, and if it exceeds 40% by weight, in the case of a patch, the inside of the adhesive layer Since the cohesive force is excessively reduced and adhesive residue may be generated at the time of release, the content is preferably 10 to 40% by weight, more preferably 15 to 35% by weight in the base.
上記界面活性剤としては、 例えば、 ゥラロイルザルコシン、 ラウリン 酸ジエタノールアミ ド、 ポリオキシエチレンアルキルエーテル、 ポリオ キシエチレンアルキルァミ ン、 ソルビタン脂肪酸エステル、 ポリグリセ リン脂肪酸エステル等が挙げられる。 Examples of the surfactant include peraroyl sarcosine, diethanolamide laurate, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, sorbitan fatty acid ester, and polyglycerin fatty acid ester.
上記界面活性剤の含有量は、 0 . 0 1重量%未満であると、 薬剤の皮 膚吸収性の向上効果が低すぎることがあり、 1 0重量%を超えると、 皮
膚剌激を生じることがあるので、 基剤中 0 . 0 1〜1 0重量%が好まし く、 より好ましくは、 0 . 1〜5重量%である。 If the content of the above surfactant is less than 0.01% by weight, the effect of improving the skin absorbability of the drug may be too low. Since skin irritation may occur, the content is preferably from 0.1 to 10% by weight, more preferably from 0.1 to 5% by weight in the base.
本発明で用いられる基剤は、 レポドパ及びその薬学上許容されるエス テルを安定に保持し、 皮膚投与した際に、 レポドパ及びその薬学上許容 されるエステルを体内に吸収させ得るものであればよく、 例えば、 従来 より、 軟膏剤、 クリーム剤、 ゲル剤、 ペースト剤、 ローション剤、 パッ プ剤などの基剤として用いられているものが使用できる。 特に、 ポリマ 一、 ゲイ酸、 ゲイ酸金属土類系鉱物、 炭化水素、 油脂類、 多価アルコ— ル、 高級アルコール、 低級アルコール、 高級脂肪酸、 脂肪酸エステル及 び水よりなる群から選ばれた少なくとも一種、 又は、 それを含む組成物 が基剤として好ましい。 The base used in the present invention is any as long as it can stably retain levodopa and its pharmaceutically acceptable ester and can absorb levodopa and its pharmaceutically acceptable ester into the body when administered to the skin. For example, those conventionally used as bases such as ointments, creams, gels, pastes, lotions, and patches can be used. In particular, at least one selected from the group consisting of polymers, gay acid, metal earth metal oxides of gay acid, hydrocarbons, oils and fats, polyhydric alcohols, higher alcohols, lower alcohols, higher fatty acids, fatty acid esters and water One or a composition containing it is preferred as a base.
上記ポリマーとしては、 例えば、 ポリビニルピロリ ドン、 架橋型ポリ ビニルピロリ ドン、 ポリビニルアルコール、 ポリアクリル酸、 ポリアク リル酸塩 (例えばナトリウム塩) 、 メ トキシエチレン—無水マレイン酸 共重合体、 ポリビニルエーテル、 ポリアクリルアミ ド、 アルギン酸ナト リウム、 ゼラチン、 コーンスターチ、 トラガントガム、 メチルセルロー ス、 ヒドロキシェチルセルロース、 ヒドロキシプロピルセルロース、 力 ルボキシメチルセルロース、 カルボキシメチルセルロースナトリウム、 デキストリン、 カルボキシメチルデンプンなどが挙げられる。 Examples of the polymer include polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyacrylic acid salt (for example, sodium salt), methoxyethylene-maleic anhydride copolymer, polyvinyl ether, and polyacrylic acid. Examples include amide, sodium alginate, gelatin, corn starch, tragacanth, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, dextrin, carboxymethyl starch and the like.
上記ゲイ酸及びゲイ酸金属土類系鉱物としては、 例えば、 コロイド状 二酸化ケイ素、 重質カオリン、 ベントナイ トなどのコロイド性含水ゲイ 酸アルミニウム系鉱物、 ビ一ガムなどのコロイ ド性含水ゲイ酸マグネシ ゥム · アルミニウム系鉱物が挙げられる。 Examples of the above-mentioned geic acid and silicate metal earth minerals include colloidal hydrated magnesium silicates such as colloidal silicon dioxide, heavy kaolin and bentonite, and colloidal hydrated magnesium silicate such as bi-gum. Pum · Aluminum-based minerals.
上記炭化水素としては、 例えば、 白色ヮセリン、 パラフィン、 流動パ ラフィ ン、 ハイ ドロ力一ボンゲル軟膏 (例えば、 商品名プラスチベース、 大正製薬社製) などが挙げられる。
上記油脂類としては、 例えば、 ミツロウ、 オリ一ブ油、 カカオ油、 胡 麻油、 大豆油、 ラッカセィ油、 牛脂、 豚脂、 ラノリン、 ヒマシ油などが 挙げられる。 Examples of the above-mentioned hydrocarbons include white iselin, paraffin, liquid paraffin, and hydrogel bongel ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.). Examples of the fats and oils include beeswax, olive oil, cocoa oil, sesame oil, soybean oil, laccase oil, beef tallow, lard, lanolin, castor oil and the like.
上記多価アルコールとしては、 例えば、 グリセリン、 ブタンジオール、 へキサントリオール、 プロピレングリコール、 ポリエチレングリコール、 ポリプロピレングリコール、 ポリオキシエチレンポリオキシプロピレン プロック共重合体などが挙げられる。 Examples of the polyhydric alcohol include glycerin, butanediol, hexanetriol, propylene glycol, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene block copolymer, and the like.
上記高級アルコールとしては、 例えば、 ラウリルアルコール、 ミ リス チルアルコール、 セチルアルコール、 ステアリルアルコール、 セトステ ァリルアルコール、 ォレイルアルコールなどが挙げられる。 Examples of the higher alcohol include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol.
上記低級アルコールとしては、 例えば、 エチルアルコール、 イソプロ ピルアルコールなどが挙げられる。 Examples of the lower alcohol include ethyl alcohol and isopropyl alcohol.
上記高級脂肪酸としては、 例えば、 力プリン酸、 力プリル酸、 ゥンデ シル酸、 ラウリン酸、 トリデシル酸、 ミ リスチン酸、 パルミチン酸、 ス テアリン酸、 ォレイン酸、 ァラキドン酸、 リノール酸、 リノレン酸など の飽和または不飽和脂肪酸が挙げられる。 Examples of the above higher fatty acids include, for example, acetic acid, acrylic acid, pallic acid, lauric acid, tridecylic acid, myristic acid, palmitic acid, stearic acid, oleic acid, arachidonic acid, linoleic acid, and linolenic acid. Saturated or unsaturated fatty acids are mentioned.
上記脂肪酸エステルとしては、 例えば、 炭素数 8〜 2 0の脂肪酸と炭 素数 1〜3 2の脂肪族アルコールとのエステルが挙げられる。 Examples of the fatty acid ester include an ester of a fatty acid having 8 to 20 carbon atoms and an aliphatic alcohol having 1 to 32 carbon atoms.
上記脂肪酸としては、 例えば、 力プリン酸、 力プリル酸、 ラウリン酸、 トリデシル酸、 ミ リスチン酸、 パルミチン酸、 ステアリン酸、 ゥンデシ レン酸、 ォレイン酸、 ァラキドン酸、 リノール酸、 リノレン酸、 セバシ ン酸などが挙げられる。 Examples of the above-mentioned fatty acids include, for example, hydrauric acid, hydrauric acid, lauric acid, tridecylic acid, myristic acid, palmitic acid, stearic acid, pendecilenic acid, oleic acid, arachidonic acid, linoleic acid, linolenic acid, sebacic acid And the like.
上記脂肪酸エステルの具体例としては、 例えば、 ミ リスチン酸イソプ 口ピル、 ミ リスチン酸ォクチルドデシル、 パルミチン酸イソプロピル、 パルミチン酸セチル、 白ロウなどが挙げられる。 Specific examples of the above fatty acid esters include, for example, isopiryl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, white wax and the like.
また、 本発明の経皮吸収製剤には、 必要に応じて、 溶解剤、 経皮吸収
促進剤、 安定化剤、 充塡剤、 酸化防止剤、 粘着付与剤等が添加されても よい。 In addition, the transdermal preparation of the present invention may contain a solubilizer, Accelerators, stabilizers, fillers, antioxidants, tackifiers and the like may be added.
上記溶解剤は、 製剤の性状 (粘度、 均質性等) を調節するために用い られるものであり、 例えば、 流動パラフィ ン等の炭化水素; ミ リスチン 酸ィソプロピル、 モノラウリン酸グリセリン、 セバシン酸ェチル等の脂 肪酸と 1価又は多価のアルコールとのエステル;ラノリン、 ォリーブ油 等の天然物由来の油脂などが挙げられる。 The above-mentioned dissolving agents are used to adjust the properties (viscosity, homogeneity, etc.) of the preparation, and include, for example, hydrocarbons such as liquid paraffin; isopropyl myristate, glyceryl monolaurate, and ethyl ethyl sebacate. Esters of fatty acids with monohydric or polyhydric alcohols; and oils and fats derived from natural products such as lanolin and olive oil.
上記溶解剤の含有量は、 少なくなるとその改善効果が上がらなくなり、 多くなると製剤の物理性状が劣化することがあるので、 基剤中 1〜 1 5 %が好ましい。 When the content of the above-mentioned solubilizer is reduced, the improvement effect is not improved, and when the content is increased, the physical properties of the preparation may be deteriorated.
上記経皮吸収促進剤は、 皮膚に作用してレポドパ及びその薬学上許容 されるエステルの皮膚透過性を高めるために用いられるものであり、 例 えば、 皮膚の水和性を高めるたり、 レポドパを良好に溶解して皮膚内に 運んだりすることで皮膚透過性が高められる。 The above-mentioned percutaneous absorption enhancer is used to increase the skin permeability of levodopa and its pharmaceutically acceptable ester by acting on the skin. For example, it enhances the hydration of the skin, or enhances levodopa. Good dissolution and transport into the skin enhances skin permeability.
上記経皮吸収促進剤の具体例としては、 例えば、 ポリソルべ一ト、 ラ ゥリン酸ジエタノールアミ ド、 ラウロイルサルコシン、 ポリオキシェチ レンアルキルエーテル、 ポリオキシエチレンアルキルァミ ン、 ソルビタ ン脂肪酸エステル、 グリセリ ン脂肪酸エステルなどが挙げられる。 Specific examples of the above-mentioned percutaneous absorption enhancers include polysorbate, diethanolamide diphosphate, lauroyl sarcosine, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, sorbitan fatty acid ester, and glycerin fatty acid ester. And the like.
上記安定化剤は、 レポドパ及びその薬学上許容されるエステルやその 他成分の酸化、 分解等を抑え、 製剤の経時変化を防ぐために用いられる ものであり、 例えば、 プチルヒ ドロキシトルエン、 ソルビン酸等の酸化 防止剤; シクロデキストリ ン、 エチレンジアミ ン四酢酸などが挙げられ 上記充塡剤は、 製剤の粘度や硬度の調節、 レポドパの均一分散や保持 などを目的として用いられるものであり、 例えば、 炭酸カルシウム、 酸 化チタン、 乳糖、 結晶セルロースなどが挙げられる。
本発明の経皮吸収製剤は、 常法により製造することができる。 例えば、 軟膏、 クリーム、 ゲル、 ペースト、 ローション又はパップ基剤の場合、 それぞれの剤型に応じて、 必要な基剤原料を混練、 乳化、 懸濁または溶 解させ基剤を製造した後、 薬物 (レポドパ及びその薬学上許容されるェ ステル) 及び必要に応じて溶解剤、 経皮吸収促進剤、 安定化剤、 充塡剤 などを添加し、 通常使用される混練機で混合することによつて製造され る The stabilizing agent is used to suppress oxidation, decomposition, etc. of levodopa and its pharmaceutically acceptable ester and other components, and to prevent the preparation from changing over time. For example, butylhydroxytoluene, sorbic acid, etc. Antioxidants; cyclodextrin, ethylenediaminetetraacetic acid, etc .; and the above fillers are used for the purpose of adjusting the viscosity and hardness of the preparation, uniform dispersion and retention of levodopa, and the like. Examples include calcium carbonate, titanium oxide, lactose, and crystalline cellulose. The transdermal preparation of the present invention can be produced by a conventional method. For example, in the case of ointments, creams, gels, pastes, lotions or pulp bases, the necessary base materials are kneaded, emulsified, suspended or dissolved according to the dosage form, and then the drug is manufactured. (Repodopa and its pharmaceutically acceptable ester) and, if necessary, a solubilizer, a percutaneous absorption enhancer, a stabilizing agent, a filler, etc., and mixing with a commonly used kneader. Manufactured
本発明のレポドパ含有経皮吸収製剤は、 支持体の片面に、 薬物を含有 する粘着剤層が設けられた経皮吸収貼付剤としても使用できる。 The levodopa-containing transdermal absorption preparation of the present invention can also be used as a transdermal patch with a drug-containing pressure-sensitive adhesive layer provided on one surface of a support.
上記支持体は、 上記支持体は、 貼付面の反対面を保護する働きを有す るものであれば特に限定されるものではなく、 通常は、 プラスチックフ イルムもしくはシ一卜、 テープ、 不織布、 織布、 発泡体シ—ト、 金属箔 (例えば、 アルミニウム箔) などの単体もしくは積層体が用いられる。 上記支持体としては、 皮膚表面の動きに追従できる柔軟性と、 薬物及 びその他の添加物の散逸を防ぐバリァー性を有するものが好適に用いら れる。 The support is not particularly limited as long as the support has a function of protecting the surface opposite to the application surface, and is usually a plastic film or sheet, a tape, a nonwoven fabric, or the like. A single or laminated material such as a woven fabric, a foam sheet, or a metal foil (for example, an aluminum foil) is used. As the support, those having flexibility capable of following the movement of the skin surface and barrier properties for preventing the escape of drugs and other additives are preferably used.
上記プラスチックフィルムもしくはシ一卜の材質としては、 例えば、 ポリエチレンテレフタレ一ト、 ポリブヂレンテレフタレ一ト等のポリェ ステル系共重合体;ポリェチレン、 ポリプロピレン、 ポリブタジェン、 ポリブテン、 エチレン—酢酸ビニル共重合体、 エチレン一プロピレン共 重合体、 エチレン一アルキル (メタ) ァクリレ一卜共重合体、 エチレン ーァクリル酸メチル共重合体等のポリオレフィ ン系 (共) 重合体;スチ レン一イソプレンースチレン共重合体、 スチレン一ブタジエン—スチレ ン共重合体及びこれらの水添物などのスチレン系共重合体;ポリ塩化ビ 二リデン、 塩化ビニリデンースチレン共重合体などの塩化ビニリデン系 (共) 重合体; ポリ塩化ビニル、 塩化ビニル -エチレン共重合体、 塩化
ビニルーァクリル酸アルキルエステル共重合体などの塩化ビニル系 ( 共) 重合体; シリコン樹脂;ポリフッ化工チレン;ポリウレタン;ポリ ァミ ドなどが挙げられる。 Examples of the material of the plastic film or sheet include polyester copolymers such as polyethylene terephthalate and polyvinyl terephthalate; polyethylene, polypropylene, polybutadiene, polybutene, and ethylene-vinyl acetate copolymers. Polyolefin (co) polymers such as polymer, ethylene-propylene copolymer, ethylene-alkyl (meth) acrylate copolymer, ethylene-methyl acrylate copolymer; styrene-isoprene-styrene copolymer Styrene-based copolymers such as styrene-butadiene-styrene copolymers and hydrogenated products thereof; vinylidene chloride-based (co) polymers such as polyvinylidene chloride and vinylidene chloride-styrene copolymer; Vinyl, vinyl chloride-ethylene copolymer, chloride Vinyl chloride-based (co) polymers such as vinyl-acrylic acid alkyl ester copolymers; silicone resins; polyfluoroethylene; polyurethane; and polyimides.
上記不織布及び織布の材質としては、 例えば、 ポリエステル、 ポリオ レフイ ン、 アタリロニトリル等のァクリル系樹脂、 ポリアミ ド、 レーョ ン、 綿などからなる繊維状物が挙げられる。 Examples of the material of the nonwoven fabric and the woven fabric include fibrous materials made of acryl-based resins such as polyester, polyolefin, and atarilonitrile, polyamide, rayon, and cotton.
上記発泡体の材質としては、 例えば、 ポリエチレン、 ポリプロピレン、 エチレン一プロピレン共重合体、 エチレン一酔酸ビニル共重合体、 ポリ エチレンォキサイ ド等のポリオレフィン系榭脂;スチレン—ブタジエン 共重合体などが挙げられる。 Examples of the material of the foam include polyethylene, polypropylene, ethylene-propylene copolymer, ethylene-vinyl acetate copolymer, polyolefin-based resin such as polyethylene oxide; and styrene-butadiene copolymer. No.
上記支持体の厚さは、 薄くなると製剤の強度が不足するとともに、 貼 付時にシヮになりやすくなり、 厚くなると皮膚に貼付したときの違和感 が大きくなったり、 貼付端部の引っ掛かりによって剝がれ易くなつたり することがあるので、 2 0〜3 0 0 0 が好ましい。 When the thickness of the support is too thin, the strength of the preparation is insufficient, and the skin tends to become stiff at the time of application.When it is thick, the discomfort when applied to the skin increases, and the thickness of the support becomes poor due to the sticking of the application end. It is preferably 20 to 300, because it may be easily damaged.
また、 上記支持体の厚さは、 使用する材料によって異なるが、 フィル ム状の場合は、 5 0 0 /i m以下が好ましく、 より好ましくは、 4 0〜2 0 0 μ mである。 The thickness of the support varies depending on the material used, but in the case of a film, the thickness is preferably 500 / im or less, more preferably 40 to 200 μm.
上記粘着剤層に用いられる基剤は、 レポドパ及びその薬学上許容され るエステルを安定に保持し、 皮膚投与した際に、 レポドパ及びその薬学 上許容されるエステルを体内に吸収させ得るものであり、 良好な皮膚貼 付性を有するものであれば特に制限はない。 例えば、 従来より非含水系 又は含水系のプラスター剤、 テープ剤、 パッチ剤、 パップ剤などの基剤 として用いられているものが使用できる。 The base used in the pressure-sensitive adhesive layer is a base that stably holds levodopa and a pharmaceutically acceptable ester thereof and that can absorb levodopa and its pharmaceutically acceptable ester into the body when administered to the skin. There is no particular limitation as long as it has good skin sticking properties. For example, those conventionally used as bases for non-hydrous or hydrous plasters, tapes, patches, cataplasms and the like can be used.
上記基剤の具体例としては、 例えば、 ァクリル系、 ゴム系、 シリコン 系、 ウレタン系などのポリマーに、 必要に応じて架橋剤、 可塑剤、 安定 剤、 水、 p H調節剤、 充塡剤などが添加されたものが挙げられる。
上記アクリル系粘着剤としては、 (メタ) アクリル酸アルキルエステ ルを主体とする粘着剤が好ましく、 (メタ) アクリル酸アルキルエステ ルと共重合可能な官能性モノマ一及び Z又は多官能性モノマ—との共重 合体であってもよい。 Specific examples of the above-mentioned base include, for example, polymers such as acryl, rubber, silicone, and urethane, as required, a crosslinking agent, a plasticizer, a stabilizer, water, a pH adjuster, and a filler. And the like. As the acrylic pressure-sensitive adhesive, a pressure-sensitive adhesive mainly composed of an alkyl (meth) acrylate is preferred, and a functional monomer and Z or a polyfunctional monomer copolymerizable with the alkyl (meth) acrylate are preferred. And a copolymer thereof.
上記 (メタ) アクリル酸アルキルエステルとしては、 例えば、 (メ タ) アクリル酸メチル、 (メタ) アクリル酸ェチル、 (メタ) アクリル 酸プロピル、 (メタ) アクリル酸イソプロピル、 (メタ) アクリル酸 n 一プチル、 (メタ) アクリル酸イソプチル、 (メタ) アクリル酸 n—へ キシル、 (メタ) アクリル酸イソへキシル、 (メタ) アクリル酸へプチ ル、 (メタ) アクリル酸一 2—ェチルへキシル、 (メタ) アクリル酸 n 一才クチル、 (メタ) アクリル酸イソォクチル、 (メタ) アクリル酸ノ ニル、 (メタ) アクリル酸デシル、 (メタ) アクリル酸ドデシル、 (メ 夕) アクリル酸ステアリル、 (メタ) アクリル酸トリメチルへキシル、 (メタ) アクリル酸イソデシルなどが挙げられる。 これらは、 単独で用 いても、 2種以上を併用してもよい。 Examples of the alkyl (meth) acrylate include: (meth) methyl acrylate, (meth) ethyl acrylate, (meth) propyl acrylate, (meth) isopropyl acrylate, and (meth) acrylic acid n-butyl. Isoptyl (meth) acrylate, n-hexyl (meth) acrylate, isohexyl (meth) acrylate, heptyl (meth) acrylate, 1-ethylhexyl (meth) acrylate, (meth) ) N-year-old acrylate, isooctyl (meth) acrylate, nonyl (meth) acrylate, decyl (meth) acrylate, dodecyl (meth) acrylate, (meth) stearyl acrylate, (meth) acrylic acid Trimethylhexyl, isodecyl (meth) acrylate and the like. These may be used alone or in combination of two or more.
上記官能性モノマ一としては、 例えば、 水酸基を有するモノマー、 力 ルポキシル基を有するモノマ一、 アミ ド基を有するモノマ一、 アミノ基 を有するモノマー、 窒素含有複素環を有するモノマーなどが挙げられ、 その具体例としては、 例えば、 (メタ) アクリル酸— 2—ヒ ドロキシェ チル、 (メタ) アクリル酸一 2 —ヒ ドロキシプロピル、 (メタ) アタリ ル酸、 マレイン酸、 ァクリルァミ ド、 エトキシメチルァクリルァミ ド、 ジアセトンアクリルアミ ド、 アクリル酸ジメチルアミノエチル、 ビニル ピロリ ドン、 ビニルイミダゾ一ルなどが挙げられる。 Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a hydroxyl group, a monomer having an amide group, a monomer having an amino group, a monomer having a nitrogen-containing heterocyclic ring, and the like. Specific examples include (meth) acrylic acid-2-hydroxyhydroxyl, (meth) acrylic acid-12-hydroxypropyl, (meth) acrylic acid, maleic acid, acrylamide, ethoxymethylacrylic acid. Media, diacetone acrylamide, dimethylaminoethyl acrylate, vinyl pyrrolidone, vinyl imidazole and the like.
上記多官能性モノマ一としては、 例えば、 (メタ) アクリル酸とアル キレングリコール類;ェチレングリコール、 プチレングリコール、 へキ サメチレングリコールなどとの反応生成物であるアルキレングリコール
ジ (メタ) ァクリレー卜、 (メタ) アクリル酸とポリアルキレングリコ ール類;ポリエチレングリコール、 ポリプロピレンダリコールなどとの 反応生成物であるポリアルキレングリコールジ (メタ) アタリレートな どが挙げられる。 Examples of the polyfunctional monomers include, for example, alkylene glycol which is a reaction product of (meth) acrylic acid and alkylene glycols; ethylene glycol, butylene glycol, hexamethylene glycol, and the like. Di (meth) acrylate, (meth) acrylic acid and polyalkylene glycols; polyalkylene glycol di (meth) acrylate, which is a reaction product of polyethylene glycol, polypropylene dalicol, and the like.
上記ゴム系粘着剤としては、 例えば、 天然ゴム、 スチレンーブタジェ ンゴム、 ポリイソプチレン、 スチレン一イソプレン一スチレンブロック 共重合体、 スチレン—ブタジエン—スチレンブロック共重合体、 スチレ ン一ォレフィ ン—スチレンプロック共重合体などが挙げられる。 これら は一般に、 ロジン、 水添ロジン、 ロジンエステル、 テルペン樹脂、 テル ペンフヱノール樹脂、 石油系樹脂、 クマロン樹脂、 クマロン—インデン 樹脂などの粘着付与剤が添加されて用いられる。 Examples of the rubber-based adhesive include natural rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and styrene-olefin-styrene block copolymer. Polymers. These are generally used by adding a tackifier such as rosin, hydrogenated rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin.
上記シリコン系粘着剤としては、 例えば、 ポリジメチルシロキサン、 ポリジェチルシロキサンなどが挙げられる。 Examples of the silicon-based pressure-sensitive adhesive include polydimethylsiloxane and polydimethylsiloxane.
上記ウレタン系粘着剤としては、 従来から経皮吸収貼付剤用の粘着剤 に用いられてきたウレタン系粘着剤のいずれをも使用可能であり、 特に 限定されない。 As the urethane-based pressure-sensitive adhesive, any urethane-based pressure-sensitive adhesive that has been conventionally used as a pressure-sensitive adhesive for transdermal patches can be used, and is not particularly limited.
上記架橋剤としては、 例えば、 水酸化アルミニウム、 水酸化カルシゥ ム、 ステアリン酸マグネシウム、 イソシァネート類、 エポキシ樹脂、 メ ラミン樹脂、 尿素樹脂、 アンモニゥム類などが挙げられる。 Examples of the crosslinking agent include aluminum hydroxide, calcium hydroxide, magnesium stearate, isocyanates, epoxy resins, melamine resins, urea resins, and ammoniums.
上記可塑化剤は、 前記溶解剤として用いられたものと同様のものを使 用することができ、 例えば、 流動パラフィ ン等の炭化水素類; ミ リスチ ン酸ィソプロピル、 モノラウリン酸グリセリン、 セバシン酸ジェチル等 の脂肪酸と 1価又は多価アルコールとのエステル;ォレイン酸、 ラウリ ン酸等の高級脂肪酸;ォクチルドデカノ一ル、 ミ リスチルアルコール等 の高級アルコール;ラノリン、 オリ一ブ油、 ヤシ油等の天然物由来の油 脂などが挙げられる。
上記可塑化剤の含有量は、 レポドパ及びその薬学上許容されるエステ ルの量や上記粘着剤の種類によって適宜決定されるが、 少なくなると可 塑化効果が低下し、 多くなると貼付性が低下するので、 粘着剤層中 1〜 5 0重量%が好ましい。 As the plasticizer, those similar to those used as the solubilizer can be used. For example, hydrocarbons such as liquid paraffin; isopropyl myristate, glyceryl monolaurate, and getyl sebacate Esters of fatty acids with monohydric or polyhydric alcohols; higher fatty acids such as oleic acid and lauric acid; higher alcohols such as octyldodecanol and myristyl alcohol; natural such as lanolin, olive oil, and coconut oil Fats and oils derived from products. The content of the above plasticizer is appropriately determined depending on the amount of levodopa and its pharmaceutically acceptable ester and the type of the above-mentioned pressure-sensitive adhesive, but when the content is small, the plasticizing effect is reduced, and when the content is large, the sticking property is reduced. Therefore, the content is preferably 1 to 50% by weight in the pressure-sensitive adhesive layer.
上記安定化剤及び充塡剤は、 前記安定化剤及び充塡剤と同様のものが 使用できる。 As the stabilizer and the filler, the same stabilizers and fillers as those described above can be used.
上記アクリル系粘着剤として、 (メタ) アクリル酸アルキルエステル 4 0— 9 0モル%及びビニルピロリ ドン 1 0〜 6 0モル%からなる共重 合体を主成分とするものを好適に用いることができる。 (メタ) アタリ ル酸アルキルエステルの割合は、 低くなると粘着性が低下し、 高くなる と薬物の初期除放性が低下することがあるので、 4 0〜9 0モル%が好 ましく、 5 0〜 8 0モル%がより好ましい。 As the acrylic pressure-sensitive adhesive, a pressure-sensitive adhesive mainly containing a copolymer composed of 40 to 90 mol% of (meth) acrylic acid alkyl ester and 10 to 60 mol% of vinylpyrrolidone can be suitably used. The lower the ratio of the alkyl (meth) acrylate, the lower the tackiness, and the higher the ratio, the lower the initial release of the drug may be. 0 to 80 mol% is more preferable.
上記 (メタ) アクリル酸アルキルエステル 4 0 - 9 0モル%及びビニ ルピロリ ドン 1 0〜6 0モル%からなる共重合体には、 必要とする粘着 物性に応じて、 上記 (メタ) アクリル酸アルキルエステルと共重合可能 な単量体が添加されてもよい。 The copolymer comprising the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% may be selected from the alkyl (meth) acrylates according to the required adhesive properties. A monomer copolymerizable with the ester may be added.
上記 (メタ) アクリル酸アルキルエステルと共重合可能な単量体とし ては、 例えば、 酢酸ビニル、 ジァセトンアクリルアミ ド、 アタリロニト リル、 ジメチルアクリルアミ ド、 エチレングリコールモノ (メタ) ァク リル酸エステル、 スチレン等が挙げられる。 Examples of the monomer copolymerizable with the alkyl (meth) acrylate include, for example, vinyl acetate, diacetone acrylamide, atarilonitrile, dimethyl acrylamide, and ethylene glycol mono (meth) acrylic acid. Examples include esters and styrene.
上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ ルピロリ ドン 1 0〜6 0モル%からなる共重合体の構成成分中、 上記 (メタ) ァクリル酸アルキルエステルと共重合可能な単量体の比率は、 粘着剤の粘着性、 凝集性に悪影響を及ぼさない範囲である 4 0モル%以 下が好ましい。 Among the constituent components of the copolymer consisting of the above-mentioned alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol%, a monomer copolymerizable with the above-mentioned alkyl (meth) acrylate can be used. The proportion of the monomer is preferably not more than 40 mol%, which does not adversely affect the adhesiveness and cohesiveness of the adhesive.
上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ
ルピロリ ドン 1 0〜6 0モル%からなる共重合体の構成成分には、 1分 子中に重合性二重結合を 2以上有する多官能性単量体が含まれてもよい。 上記多官能性単量体としては、 例えば、 ジビニルベンゼン、 メチレン ビスァクリルァミ ド、 エチレングリコールジ (メタ) ァクリ レート、 プ ロピレングリコ一ルジ (メタ) ァクリ レート、 プチレングリコ一ルジ40 to 90 mol% of the above (meth) acrylic acid alkyl ester and vinyl acetate The component of the copolymer consisting of 10 to 60 mol% of rupyrrolidone may contain a polyfunctional monomer having two or more polymerizable double bonds in one molecule. Examples of the polyfunctional monomer include divinylbenzene, methylene bisacrylamide, ethylene glycol di (meth) acrylate, propylene glycol (meth) acrylate, and polyethylene glycol
(メタ) ァクリ レ一ト、 へキシレングリコールジ (メタ) ァクリ レート、 ポリエチレングリコールジ (メタ) ァクリレー卜、 ポリプロピレングリ コールジ (メタ) ァクリ レート、 トリメチロールプロパントリ (メタ) ァクリレートなどが挙げられる。 Examples thereof include (meth) acrylate, hexylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, and trimethylolpropanetri (meth) acrylate.
上記多官能性単量体の添加によって、 共重合体が部分的に架橋される、 いわゆる微架橋された状態となり、 より重合度の高い共重合体とするこ とができる。 この微架橋により、 粘着剤に適度の凝集性が付与されると ともに、 接着性が高められ、 剝離の際の糊残りを防止することができ、 粘着剤溶液の安定性も向上する。 By the addition of the polyfunctional monomer, the copolymer is partially crosslinked, that is, in a so-called slightly crosslinked state, and a copolymer having a higher degree of polymerization can be obtained. The fine cross-linking imparts appropriate cohesiveness to the pressure-sensitive adhesive, increases the adhesiveness, prevents adhesive residue upon separation, and improves the stability of the pressure-sensitive adhesive solution.
上記多官能性単量体の使用量は、 少なくなると凝集効果が得られず、 多くなると反応液がゲル化しやすくなるか、 不安定であるので、 上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニルピロ リ ドン 1 0〜 6 0モル%からなる共重合体の構成成分中、 0 . 0 0 1〜 0 . 1モル%が好ましく、 より好ましくは、 0 . 0 0 3〜0 . 0 7モル %である。 If the amount of the polyfunctional monomer used is too small, the aggregation effect cannot be obtained, and if the amount is too large, the reaction solution is likely to gel or is unstable, so the above (meth) acrylic acid alkyl ester 40 to 9 Of the constituent components of the copolymer consisting of 0 mol% and 10 to 60 mol% of vinylpyrrolidone, 0.001 to 0.1 mol% is preferred, more preferably 0.003 to 0.1 mol%. 07 mol%.
上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ ルピロリ ドン 1 0〜6 0モル%からなる共重合体は、 吸湿性物質を多く 保持することが可能となるように、 吸水率を、 1 . 5 %以上とするのが よい。 The copolymer consisting of 40 to 90 mol% of the alkyl (meth) acrylate and 10 to 60 mol% of vinylpyrrolidone has a water absorption rate so that a large amount of a hygroscopic substance can be retained. Should be 1.5% or more.
上記吸水率とは、 2 5 °C;、 対湿度 9 0 %に調整された雰囲気下に 1 0日間保存した後の初期重量に対する増加重量の割合である。
上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ ルピロリ ドン 1 0〜6 0モル%からなる共重合体の吸水性は、 共重合成 分のビニルピロリ ドンに起因し、 特にビニルピロリ ドンが共重合体中に ブロック状で存在することにより有意に増大するため、 吸水性を増大さ せるには、 ビニルピロリ ドンのブロック共重合体やグラフ卜共重合体を 用いるのが好ましい。 The water absorption is the ratio of the increased weight to the initial weight after storage for 10 days in an atmosphere adjusted to 25 ° C; 90% relative humidity. The water absorption of the copolymer consisting of the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% is caused by vinylpyrrolidone in the copolysynthesis, especially vinylpyrrolidone. Is significantly increased by the presence of a block in the copolymer. Therefore, in order to increase the water absorption, it is preferable to use a vinylpyrrolidone block copolymer or a graft copolymer.
上記プロック共重合体やグラフト共重合体の製造方法としては、 例え ば、 マクロモノマ一、 反応性モノマ一、 リビング重合などが挙げられる。 上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ ルピロリ ドン 1 0〜 6 0モル%からなる共重合体は、 完全にビニルピ口 リ ドンがブロック状に存在している必要はなく、 共重合体中にビニルビ ロリ ドンがリツチな組成で存在していればよい。 Examples of the method for producing the block copolymer or the graft copolymer include a macromonomer, a reactive monomer, and living polymerization. The copolymer consisting of the alkyl (meth) acrylate 40 to 90 mol% and vinylpyrrolidone 10 to 60 mol% does not require the vinylpiperidone to be completely present in a block form. It is sufficient that vinyl viridone is present in the copolymer in a rich composition.
上記 (メタ) アクリル酸アルキルエステル 4 0〜9 0モル%及びビニ ルピロリ ドン 1 0〜6 0モル%からなる吸水率が 1 . 5 %以上の共重合 体は、 例えば、 重合開始時において、 ビニルピロリ ドンの全使用量の 9 0 %以上と、 (メタ) アクリル酸アルキルエステルの全使用量の 0 . 1 〜 5 %を共存させ、 少なくとも、 重合初期 (重合率が、 1 0 %以下の状 態をいう) に、 単量体組成物中の (メタ) アクリル酸アルキルエステル の割合を 3 5重量%以下、 好ましくは、 3 0重量%以下に保つように、 逐次、 (メタ) アクリル酸アルキルエステルの残部を添加する溶液重合 法により得ることができる。 The above copolymer of alkyl (meth) acrylate of 40 to 90 mol% and vinyl pyrrolidone of 10 to 60 mol% having a water absorption of 1.5% or more is, for example, vinylpyrrolidone at the start of polymerization. 90% or more of the total amount of the dong and 0.1 to 5% of the total amount of the alkyl (meth) acrylate coexist, and at least the initial stage of the polymerization (the polymerization rate is 10% or less). In order to keep the proportion of the alkyl (meth) acrylate in the monomer composition at 35% by weight or less, preferably at 30% by weight or less, the alkyl (meth) acrylates are successively added. Can be obtained by a solution polymerization method in which the remainder is added.
上記溶液重合では、 必要に応じて、 他の単量体や、 通常の重合反応に 用いられる添加剤を用いてもよい。 In the above solution polymerization, other monomers and additives used in ordinary polymerization reactions may be used as necessary.
上記溶液重合に用いる溶剤としては、 例えば、 酢酸ェチル、 酢酸プロ ピル、 酔酸ブチル等のエステル系溶剤;メチルェチルケトン、 シクロへ キサノン等のケトン系溶剤;ベンゼン、 トルエン等の芳香族系溶剤;メ
チルセ口ソルブ、 ェチルセ口ソルブ等のセロソルブ系溶剤等が挙げられ、 これらは単独で用いても、 2種以上を併用して用いてもよい。 Examples of the solvent used for the solution polymerization include ester solvents such as ethyl acetate, propyl acetate, and butyl peroxide; ketone solvents such as methyl ethyl ketone and cyclohexanone; and aromatic solvents such as benzene and toluene. ; Cellosolve-based solvents such as Solvent in Tiltose and Solvent in Etilse are listed. These may be used alone or in combination of two or more.
上記溶液重合に用いる重合開始剤としては、 例えば、 一般に用いられ ている熱ラジカル重合開始剤を用いることができ、 具体的には、 パ一ォ キシカーボネ一ト、 ケトンパーォキサイド、 パーォキシケタール、 ハイ ドロパ一ォキサイ ド、 ジアルキルパ一ォキサイ ド (例えば、 ラウロイル パ一ォキサイ ド、 ベンゾィルパ一ォキサイ ドなど) 、 ジァシルバーォキ サイ ド、 パーォキシエステルなどの有機過酸化物; 2, 2 ' ーァゾビス イソブチロニトリル、 2, 2 ' —ァゾビス ( 2—メチルプチロニトリ ル) 、 2, 2, —ァゾビス (2, 4 —ジメチルバレロニ卜リル) 、 2, As the polymerization initiator used in the above solution polymerization, for example, a generally used thermal radical polymerization initiator can be used, and specific examples thereof include hydroxycarbonate, ketone peroxide, and peroxide. Organic peroxides such as ketals, hydropoxides, dialkylpoxides (eg, lauroylpoxides, benzoylpoxides, etc.), diasilboxides, and peroxyesters; 2,2'-azobisisobutyrate Lonitrile, 2, 2'-azobis (2-methylbutyronitrile), 2,2, -azobis (2,4-dimethylvaleronitrile), 2,
2 ' ーァゾビスイソ酪酸ジメチル等のァゾ化合物が挙げられる。 これら は、 単独で用いても、 2種以上を併用してもよい。 Azo compounds such as dimethyl 2'-azobisisobutyrate. These may be used alone or in combination of two or more.
上記重合開始剤の使用量は、 上記共重合体を構成する単量体 1 0 0重 量部に対し、 0 . 0 0 0 1 ~ 5重量部が好ましい。 The amount of the polymerization initiator to be used is preferably 0.001 to 5 parts by weight based on 100 parts by weight of the monomers constituting the copolymer.
上記重合開始剤の添加に際しては、 所定量を最初に一括して供給して もよく、 また、 分割して供給してもよい。 When the above-mentioned polymerization initiator is added, a predetermined amount may be initially supplied collectively, or may be supplied separately.
上記溶液重合では、 重合反応器に窒素ガスをパージして、 重合反応容 器内に残存する空気を排出し、 窒素置換する。 次いで、 予め、 窒素パブ リングにより溶存酸素を除去した所定量の単量体及び溶剤を供給し、 所 定の重合温度に昇温した後、 重合開始剤を添加することにより共重合を 行う。 In the above solution polymerization, nitrogen gas is purged into the polymerization reactor, and the air remaining in the polymerization reactor is discharged and replaced with nitrogen. Next, a predetermined amount of a monomer and a solvent from which dissolved oxygen has been removed by nitrogen publishing are supplied in advance, and after the temperature is raised to a predetermined polymerization temperature, a polymerization initiator is added to carry out copolymerization.
本発明の経皮吸収貼付剤の製造方法は、 粘着剤種類によって製法は異 なるが、 粘着剤層はホッ トメルト法、 溶液法、 溶剤塗工法などの常法に より製造することができる。 The method for producing the transdermal patch of the present invention varies depending on the kind of the adhesive, but the adhesive layer can be produced by a conventional method such as a hot melt method, a solution method, and a solvent coating method.
例えば、 ァクリル系粘着剤の場合、 重合して得られた粘着剤溶液に、 薬剤及び必要に応じてその他成分を加え、 攪拌混合する。 この溶液を剝
離紙上に塗布し、 乾燥後、 支持体を熱ラミネ一トして経皮吸収貼付剤を 調製する。 For example, in the case of an acryl-based pressure-sensitive adhesive, a drug and, if necessary, other components are added to the pressure-sensitive adhesive solution obtained by polymerization, followed by stirring and mixing. This solution is After applying on a release paper and drying, the support is heat-laminated to prepare a transdermal patch.
また、 粘着剤組成物を剝離紙上に一旦塗工し乾燥させて粘着剤層を形 成したあと、 該粘着剤層を支持体に転写、 積層してもよい。 Alternatively, the pressure-sensitive adhesive composition may be once coated on a release paper and dried to form a pressure-sensitive adhesive layer, and then the pressure-sensitive adhesive layer may be transferred to a support and laminated.
上記粘着剤を支持体に塗工する場合には、 バーコーダ一、 グラビア塗 ェ等、 通常の粘着剤塗工方法が用いられる。 上記粘着剤層の厚みは、 特 に限定されないが、 粘着剤層の厚みが 2 0 m未満では、 必要量の薬剤 を含有させることが困難となり、 1 0 0 0 mを超えると、 薬物の利用 効率が低下するので、 通常は、 2 0〜1 0 0 0 / mが好ましい。 When the above-mentioned pressure-sensitive adhesive is applied to a support, a normal pressure-sensitive adhesive coating method such as bar coder or gravure coating is used. The thickness of the pressure-sensitive adhesive layer is not particularly limited. However, if the thickness of the pressure-sensitive adhesive layer is less than 20 m, it becomes difficult to contain a necessary amount of the drug. Usually, 20 to 100 / m is preferable because the efficiency is reduced.
上記支持体の粘着剤層側には、 必要に応じて、 接着性を高めるために、 あらかじめ下塗り加工、 コロナ放電処理、 薬品酸化処理、 オゾン処理な どの前処理が施されてもよい。 On the pressure-sensitive adhesive layer side of the support, if necessary, a pretreatment such as an undercoating treatment, a corona discharge treatment, a chemical oxidation treatment, and an ozone treatment may be performed in order to enhance the adhesiveness.
上記剝離紙は、 粘着剤層を保護する目的で使用されるものであり、 通 常、 プラスチックフィルム、 紙等の単層もしくは積層体の表面にシリコ ―ン等で離型処理を施したものが使用される。 The release paper is used for the purpose of protecting the pressure-sensitive adhesive layer, and is usually formed by releasing the surface of a single layer or a laminate of a plastic film, paper, or the like with silicone or the like. used.
上記剝離紙の厚みは、 通常 3 0 0 ^ m以下が好ましく、 より好ましく は 1 0〜 2 0 0 μ πιである。 The thickness of the release paper is usually preferably 300 ^ m or less, more preferably 10〜200 μπι.
上記剝離紙のプラスチックフィルムとしては、 例えば、 ポリェチレン テレフタレート、 ポリエチレン、 ポリプロピレン、 ポリ塩化ビニル、 ポ リ塩化ビニリデンなどが挙げられる。 Examples of the plastic film of the release paper include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, and polyvinylidene chloride.
上記紙としては、 例えば、 ポリビニルアルコール等が含浸されたもの が挙げられる。 Examples of the paper include a paper impregnated with polyvinyl alcohol or the like.
発明を実施するための最良の形態 BEST MODE FOR CARRYING OUT THE INVENTION
次に、 実施例を挙げて本発明を詳しく説明するが、 本発明はこれらの 実施例にのみ限定されるものではない。
(実施例 1 ) Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples. (Example 1)
レボドパ 1. 2 3 gをグリセリン 1 9. 8 7 gに懸濁させ、 これにク ロスポビドン ( 1一ビニルー 2—ピロリ ドンの架橋重合物) 3. 5 1 g を加えて均一混合し、 ペースト剤を調製した。 Levodopa (1.23 g) was suspended in glycerin (1.987 g), and 3.51 g of clospovidone (a crosslinked polymer of 1-vinyl-2-pyrrolidone) was added to the suspension. Was prepared.
(実施例 2 ) (Example 2)
アクリル酸一 2—ェチルへキシル (EHA) 6 5モル% ( 3 0 2. 0 g) 、 ビニルピロリ ドン (VP) 3 5モル% (9 8. 0 g) 、 及びへキ サメチレングリコールジメタクリレートを EH Aと VPの合計 1 0 0重 量部に対して 0. 0 2重量部 (8 Omg) をセパラブルフラスコに仕込 み、 重合初期のモノマ一濃度が 8 5重量%となるように酔酸ェチル 7 0. 6 gを加えた。 この溶液を窒素雰囲気下、 6 5°Cに加熱し、 重合開始剤 である過酸化ラウロイル及び酢酸ェチルを逐次、 少量ずつ添加し、 3 2 時間重合した。 65 mol% (302.0 g) of 1,2-ethylhexyl acrylate (EHA), 35 mol% (98.0 g) of vinylpyrrolidone (VP), and hexamethylene glycol dimethacrylate Add 0.02 parts by weight (8 Omg) to the total of 100 parts by weight of EHA and VP in a separable flask, and add sulfuric acid so that the monomer concentration at the beginning of polymerization becomes 85% by weight. 70.6 g of ethyl was added. This solution was heated to 65 ° C. under a nitrogen atmosphere, and lauroyl peroxide and ethyl acetate as polymerization initiators were sequentially added little by little, and polymerization was performed for 32 hours.
次いで、 重合物の酢酸ェチル溶液 (固形分: 3 5. 7 6 %) 6 2. 7 5 gに、 グリセリン 2. 4 9 に懸濁させたレボドパ 1. 4 4 gとクロ スポビドン ( 1—ビニル— 2—ピロリ ドンの架橋重合物) 2. 4 9 gを 加えて均一混合して塗工液を得た。 得られた塗工液を、 シリコン処理し た厚さ 3 5 tzmのポリエチレンテレフタレート (PET) フィルム上に、 レボドパ含有量が 0. 7 5mgZcm2 となるように塗工し、 6 0でで 3 0分乾燥させて粘着剤層を得た。 得られた粘着剤層に、 PETフィル ムとエチレン一齚酸ビニル共重合体 (EVA) との積層体からなる支持 体の EVA側をラミネ一トして経皮吸収貼付剤を調製した。 Then, levodopa (1.44 g) suspended in glycerin (2.49) and clospovidone (1-vinyl) in 6.2.75 g of a solution of the polymer in ethyl acetate (solid content: 3.5.76%) — Crosslinked polymer of 2-pyrrolidone) 2. 49 g was added and uniformly mixed to obtain a coating liquid. The obtained coating liquid was applied onto a siliconized polyethylene terephthalate (PET) film having a thickness of 35 tzm so that the levodopa content was 0.75 mgZcm 2, and the coating was performed at 60 with 30. After drying for a minute, an adhesive layer was obtained. A transdermal patch was prepared by laminating the EVA side of a support composed of a laminate of PET film and ethylene-vinyl monoxide copolymer (EVA) on the obtained pressure-sensitive adhesive layer.
(比較例 1 ) (Comparative Example 1)
カルボキシセルロースナトリウム (CMC— N a) 0. 5 gを水 1 0 0 m 1に攪拌、 溶解させて CMC - N a水溶液を得た。 この水溶液 4 0 m 1にレポドパ 0. 2 2 gを攪拌、 懸濁させて製剤を調整した。
性能評価 0.5 g of sodium carboxycellulose (CMC-Na) was stirred and dissolved in 100 ml of water to obtain a CMC-Na aqueous solution. 0.22 g of levodopa was stirred and suspended in 40 ml of this aqueous solution to prepare a preparation. Performance evaluation
実施例 1、 2及び比較例 1で得られた製剤について、 以下のようにし てゥサギを用いてレポドパ血中濃度測定試験を行った。 For the preparations obtained in Examples 1 and 2 and Comparative Example 1, a test for measuring the concentration of levodopa in blood was performed using a heron as follows.
(レボドパ血中濃度測定試験) (Levodopa blood concentration measurement test)
ニュージーランドホワイ ト (雄、 1歳) の背部全面を剃毛し、 皮膚上 2 0 0 cm2 の面積に、 実施例 1及び 2で得られた経皮吸収製剤をレポ ドパとして約 150 mgZ個体となるよう、 2匹のゥサギに各々適用し た (実施例 1 : 3 g塗布、 実施例 2 : 200 cm2 の大きさで貼付) 。 一方、 他のゥサギに比較例 1で得られた製剤をレポドパ 1 lmg/k gとなるよう経口投与した (レポドパとして約 5 OmgZ個体) 。 各々 投与後、 24時間まで血液を経時的に採取し、 血漿中のレポドパ濃度を 高速液体ク口マトグラフィ一により測定した。 結果を表 1に示した。 The whole back of New Zealand White (male, 1 year old) was shaved and the transdermal preparation obtained in Examples 1 and 2 was applied as a repo-dopa to an area of 200 cm2 above the skin as a reportopa. Each animal was applied to two egrets (Example 1: 3 g applied, Example 2: applied in a size of 200 cm 2 ). On the other hand, the preparation obtained in Comparative Example 1 was orally administered to other egrets at a concentration of 1 lmg / kg of levodopa (about 5 OmgZ individuals as levodopa). After each administration, blood was collected over time up to 24 hours, and the concentration of levodopa in the plasma was measured by high performance liquid mouth chromatography. The results are shown in Table 1.
(実施例 3〜12、 比較例 2及び参考例 1, 2) (Examples 3 to 12, Comparative Example 2 and Reference Examples 1 and 2)
(粘着剤 Aの調製) (Preparation of adhesive A)
ビニルピロリ ドン 25 g、 ァクリル酸— 2—ェチルへキシル 3 g及び 酢酸ェチル 50 gを、 攪拌棒、 温度計、 還流冷却器、 窒素導入管及び滴 下漏斗を取り付けた 5つ口フラスコに投入し、 窒素置換した。 さらに窒
素置換を行いながら 3 0 r p mの回転数で攪拌し、 昇温を開始した。 次 いで、 窒素気流中、 沸点下で、 約 3 0分還流を行って、 余剰の酸素を排 出したあと、 この単量体組成物溶液 (重合初期) を 7 0 °Cに保った。 ラウロイルパーォキサイ ド 1 . 0 gに酢酸ェチルを加え、 全量が 3 0 m lの溶 を調製した。 この溶液を、 1 m 1 Z hの割合で、 上記単量体 組成物溶液に滴下しながら共重合を行った。 25 g of vinylpyrrolidone, 3 g of 2-ethylhexyl acrylate and 50 g of ethyl acetate were put into a five-necked flask equipped with a stir bar, a thermometer, a reflux condenser, a nitrogen inlet tube and a dropping funnel. It was replaced with nitrogen. More The mixture was stirred at a rotation speed of 30 rpm while performing element substitution, and the temperature was raised. Then, the mixture was refluxed for about 30 minutes in a nitrogen stream at a boiling point to discharge excess oxygen, and then the monomer composition solution (initial stage of polymerization) was kept at 70 ° C. Ethyl acetate was added to 1.0 g of lauroyl peroxyside to prepare a solution having a total volume of 30 ml. This solution was copolymerized while being dropped at a rate of 1 m 1 Zh to the monomer composition solution.
重合開始 3時間後に、 窒素バブリングしたァクリル酸— 2 —ェチルへ キシル 3 gと、 酢酸ェチル 5 gを添加して投入し、 共重合を継続した。 さらに、 重合開始 6時間後に窒素バプリングしたァクリル酸— 2—ェチ ルへキシル 3 gと、 酢酸ェチル 5 gを添加して投入し、 共重合を継続し た。 Three hours after the start of the polymerization, 3 g of -2-acrylic acid hexyl acrylate and 5 g of ethyl acetyl acetate were added and charged, and the copolymerization was continued. Further, 6 hours after the start of the polymerization, 3 g of acrylate-2-ethylhexyl which had been subjected to nitrogen bubbling and 5 g of ethyl acetate were added thereto, and the copolymerization was continued.
重合開始から 3 5時間経過した時点で共重合を停止し、 固形分が 3 0 重量%となるように酢酸ェチルを投入♦混合し、 粘着剤 Aの酢酸ェチル 溶液を得た。 粘着剤 Aの吸水率を測定した結果、 1 2 . 4 %であった。 After 35 hours from the start of the polymerization, the copolymerization was stopped, and ethyl acetate was added so that the solid content was 30% by weight. The mixture was mixed to obtain a solution of the adhesive A in ethyl acetate. The water absorption of the adhesive A was measured and found to be 12.4%.
(粘着剤 Bの調製) (Preparation of adhesive B)
重合初期に、 ビニルピロリ ドン 2 5 g、 アクリル酸一 2 —ェチルへキ シル 7 5 g及び酢酸ェチル 1 2 0 gを投入して、 重合を開始し、 開始後 は、 途中で単量体組成物を添加しないこと以外は、 粘着剤 Aと同様にし て重合を行った。 重合終了後、 固形分濃度が 3 0重量%となるように酢 酸ェチルを投入し、 粘着剤 Bの齚酸ェチル溶液を得た。 粘着剤 Bの吸水 率を測定した結果、 1 . 0 %であった。 In the early stage of the polymerization, 25 g of vinylpyrrolidone, 75 g of 12-ethyl acrylate and 120 g of ethyl acetate were added, and the polymerization was started. Polymerization was carried out in the same manner as for pressure-sensitive adhesive A, except that no was added. After completion of the polymerization, ethyl acetate was added so that the solid content concentration became 30% by weight, to obtain a solution of pressure-sensitive adhesive B in ethyl acetate. The water absorption of the adhesive B was measured and found to be 1.0%.
表 2に示す組成で、 薬物、 粘着剤溶液、 吸湿性物質、 有機酸類、 界面 活性剤、 添加剤、 代謝阻害剤を全体が均一となるように混合し、 塗液を 得た。 With the composition shown in Table 2, a drug, an adhesive solution, a hygroscopic substance, an organic acid, a surfactant, an additive, and a metabolic inhibitor were mixed so as to be uniform throughout to obtain a coating liquid.
この塗液を、 乾燥後の厚み 、 1 5 0 /z mとなるように、 ポリエチレ ンテレフタレ一トフイルム上に延展後、 6 0 °Cで 3 0分間乾燥し、 粘着
剤層を形成した。 この粘着剤層に、 ポリエステル 1 2 // m エチレン— 酢酸ビニル共重合体樹脂 2 O ^ mのラミネ一トフイルムを貼りあわせて 貼付剤を得た。 表 2 This coating solution was spread on a polyethylene terephthalate film so as to have a thickness after drying of 150 / zm, dried at 60 ° C for 30 minutes, and adhered. An agent layer was formed. A laminating film of polyester 12 // m ethylene-vinyl acetate copolymer resin 2 O ^ m was adhered to the pressure-sensitive adhesive layer to obtain a patch. Table 2
吸湿性物質 *1 Gly:グリセリン、 PG :プロピレングリコール 界面活性剤 BL9 :ポリオキシエチレン (9 ) ラウリルェ一テル、 Hygroscopic substance * 1 Gly: glycerin, PG: propylene glycol surfactant BL9: polyoxyethylene (9) lauryl ether,
HE :ヤシ油ポリオキシエチレン (7 ) グリセリン C. P. *3 架橋型ポリビニルピ口リドン HE: coconut oil polyoxyethylene (7) glycerin C.P. * 3 Cross-linked polyvinyl pyridone
(実施例 1 0 ) (Example 10)
グリセリ ン 1 0 gに、 ポリオキシエチレンラウリルエーテル 1 g及び レボドパ 5 gを加えて、 均一に混合し混合液 Aを得た。 To 10 g of glycerin, 1 g of polyoxyethylene lauryl ether and 5 g of levodopa were added and mixed uniformly to obtain a mixed solution A.
次に、 グリセリ ン 1 0 gに、 ポリアクリル酸ナトリウム 5 g、 カルボ キシプロピルセルロースナトリウム 5 g及びアルミニウムグリシネ一ト 0 . 1 gを加えて均一に混合し、 混合液 Bを得た。
さらに、 力オリン 5 g、 精製水 5 g及びグリセリン 6 gを加えて均一 に混合し、 混合液 Cを得た。 Next, 5 g of sodium polyacrylate, 5 g of sodium carboxypropylcellulose, and 0.1 g of aluminum glycinate were added to 10 g of glycerin and uniformly mixed to obtain a mixed solution B. Further, 5 g of violin, 5 g of purified water and 6 g of glycerin were added and mixed uniformly to obtain a mixed solution C.
次いで、 精製水 1 0. 9 gに、 酒石酸 1 g及び乳酸 3 gを加えて均一 に混合したあと、 混合液 A、 B及び Cを加えて均一に練合した。 これを ポリエステル不織布上に、 塗布量 0. 1 gZc m2 となるように延展し、 離型処理したポリエステルフィルムをラミネ一トして、 レポドパ含有経 皮吸収製剤を得た。 Next, 1 g of tartaric acid and 3 g of lactic acid were added to 10.9 g of purified water and uniformly mixed, and then mixed liquids A, B and C were added and kneaded uniformly. This on a polyester nonwoven fabric, the coating amount 0. 1 gZc m 2 and so as to extend angel, the releasing treatment polyester films with one bets laminating to give a levodopa-containing transdermal absorption preparation.
(実施例 1 1 ) (Example 11)
グリセリン 1 O gに、 ポリオキシエチレンラウリルエーテル 1 g及び レボドパ 5 gを加えて、 均一に混合し混合液 Aを得た。 To 1 Og of glycerin, 1 g of polyoxyethylene lauryl ether and 5 g of levodopa were added and mixed uniformly to obtain a mixed solution A.
次に、 グリセリン 1 5 gに、 ポリアクリル酸ナトリウム 5 g、 カルボ キシプロピルセルロースナトリウム 2 g及びアルミニウムグリシネー卜 0. 3 gを加えて均一に混合し、 混合液 Bを得た。 Next, 5 g of sodium polyacrylate, 2 g of sodium carboxypropylcellulose, and 0.3 g of aluminum glycinate were added to 15 g of glycerin and mixed uniformly to obtain a mixed solution B.
さらに、 6 0 °Cに加温した精製水 3 0 gにゼラチン 1 gを溶解して、 混合液 Cを得た。 Further, 1 g of gelatin was dissolved in 30 g of purified water heated to 60 ° C. to obtain a mixed solution C.
次いで、 グリセリン 1 0 gに、 酒石酸 2 g、 乳酸 3 g及びァクリ ル酸 0. 5 gを加えて均一に混合したあと、 混合液 A、 B及び Cを加え て均一に練合した。 これをポリエステル不織布上に、 塗布量 0. l gZ c m2 となるように延展し、 離型処理したポリエステルフィルムをラミ ネートして、 レポドパ含有経皮吸収製剤を得た。 Next, 2 g of tartaric acid, 3 g of lactic acid and 0.5 g of acrylic acid were added to 10 g of glycerin and mixed uniformly, and then mixed liquids A, B and C were added and kneaded uniformly. This was spread on a polyester non-woven fabric so as to have a coating amount of 0.1 lgZ cm 2, and a release-treated polyester film was laminated to obtain a levodopa-containing transdermal absorption preparation.
(経皮吸収性評価) (Percutaneous absorption evaluation)
ラッ トを用いてレポドパ血中濃度を経時的に測定し、 2 4時間での血 中濃度曲線下面積 (AUC) を算出した。 Lepodopa blood concentration was measured over time using a rat, and the area under the blood concentration curve (AUC) at 24 hours was calculated.
ウィスターラッ ト (雄、 7週齢) の背部を剃毛し、 皮膚上に 1 2 c m 2 の面積に実施例及び比較例の試料をそれぞれ貼付した。 一方、 別のラ ッ トにレボドパ 5 0 mg/k g (ヒトー日投与量) となるよう経口投与
した。 各々投与後、 1 · 2 · 3 · 6 · 1 5 · 2 4時間後の血液を採取し- 血漿中レポドパ濃度を HPL Cにより測定した。 さらに、 2 4時間後の 血中濃度曲線下面積を算出した。 The back of a Wistar rat (male, 7 weeks old) was shaved, and the samples of Examples and Comparative Examples were applied to the skin in an area of 12 cm 2 , respectively. Meanwhile, levodopa was orally administered to another rat at a dose of 50 mg / kg (human-dose). did. Blood was collected at 1, 2, 3, 6, 15, and 24 hours after each administration. The plasma levodopa concentration was measured by HPLC. Furthermore, the area under the blood concentration curve 24 hours later was calculated.
表 3に示すように、 実施例の AUCは、 いずれも 3 0 0 0 n g . h r ノ L以上であり、 比較例では 6 0 0 n g · h r / L以下であることから、 実施例にお L、て経皮吸収性が有意に向上していることが認められる。 ま た、 経口投与時の AUCは、 2 6 5 0 n g * h rZLであり、 実施例で は、 いずれも持続的に一日分のレポドパを吸収していることが分かった c (安定性試験) As shown in Table 3, the AUC of each of the examples was at least 300 ng · hr / L, and the AUC of the comparative example was at most 600 ng · hr / L. It can be seen that the percutaneous absorbability is significantly improved. Also, AUC at oral administration is 2 6 5 0 ng * h rZL , in the embodiment, c (stability test were all found to be continuously absorbed levodopa one day )
上記実施例及び参考例で得られた各貼付剤をアルミ包材で密封し、 2 5°Cの恒温槽で保存した。 保存 1ヶ月後、 各貼付剤の膏体層を観察し、 ブリードの有無を評価した。 実施例では、 いずれも吸湿性液状成分が安 定して多量含有されているのに対して、 吸水率の低い粘着剤 Bで吸湿性 液状成分を多量含有した製剤 (参考例 1, 2) では、 いずれも吸湿性液 状成分がプリードアウトし、 安定でないことが認められた。 Each patch obtained in the above Examples and Reference Examples was sealed with an aluminum packaging material and stored in a thermostat at 25 ° C. One month after storage, the plaster layer of each patch was observed to evaluate the presence or absence of bleed. In all of the examples, while the hygroscopic liquid component was stably contained in large amounts in all cases, the formulation containing a large amount of hygroscopic liquid component in the adhesive B with low water absorption (Reference Examples 1 and 2) In both cases, it was confirmed that the hygroscopic liquid component bleed out and was not stable.
(薬効評価) (Efficacy evaluation)
ラッ 卜を用いてレポドパ含有経皮吸収製剤の薬効評価 (ハロペリ ド— ル誘発力タレプシ一に対する抑制作用) を行った。 The efficacy of the transdermal preparation containing levodopa was evaluated using the rat (the inhibitory effect on haloperidol-induced talepsi).
ウィスターラッ 卜 (雄、 7週齢) の背部を剃毛し、 皮膚上に 1 2 cm 2 の面積に実施例及び比較例の試料をそれぞれ貼付した。 貼付 1時間及 び 2 0時間後に、 ホドぺリ ドール投与量が 1. 0 m g Z k gになるよう に、 ハロペリ ドール溶液を経口投与した。 投与 4時間後 (すなわち貼付 5時間後及び 2 4時間後) に、 以下の測定方法により、 レポドパの薬効 を評価した。 薬効評価に際しては、 ラッ トを一群 1 0匹使用し、 力タレ プシ一抑制効果が認められた匹数で評価した。 The back of a wister rat (male, 7 weeks old) was shaved, and the samples of Examples and Comparative Examples were respectively applied to the skin in an area of 12 cm 2 . One and 20 hours after application, the haloperidol solution was orally administered so that the dose of fodoperidol was 1.0 mg Z kg. Four hours after administration (ie, 5 hours after application and 24 hours after application), the efficacy of levodopa was evaluated by the following measurement method. For the evaluation of drug efficacy, rats were used in groups of 10 rats, and the number of rats that showed a suppuration effect was evaluated.
評価方法は、 直径 2 mmのステンレスパイプを高さ 7 cmに水平に設
置固定し、 このパイプにマウスの両前肢を強制的に掛け、 両前肢がパイ プから離れるまでの姿勢保持を力タレプシ一と判断し、 その保持時間がThe evaluation method was to install a stainless steel pipe with a diameter of 2 mm horizontally at a height of 7 cm. The mouse is forcibly hooked with both forelimbs on this pipe, and the posture holding until both forelimbs are separated from the pipe is determined to be force talepsi.
2 0秒以上の場合を力タレプシ一陽性とした。 表 3 A case of 20 seconds or longer was regarded as positive for positive force. Table 3
A U C 薬 効 評 価 A U C Drug evaluation
安定性 Stability
(ng · hr/L) *1 5時間 %2 24時間 *2 (nghr / L) * 1 5 hours% 2 24 hours * 2
4 4 3 1 〇 8 7 4 4 3 1 〇 8 7
3 6 2 3 〇 3 6 2 3 〇
3 2 9 0 〇 3 2 9 0 〇
4 1 7 〇 4 1 7 〇
実施例 3 5 4 5 〇 Example 3 5 4 5 〇
5 9 6 8 5 9 6 8
6 7 3 4 1 0 6 7 3 4 1 0
10 3 1 7 9 〇 10 3 1 7 9 〇
11 4 0 2 6 〇 11 4 0 2 6 〇
X X
参考例 Reference example
X X
比較例 5 9 3 3 2 Comparative Example 5 9 3 3 2
*1 〇: ブリードなし、 X : ブリードあり *2 貼付後の時間 * 1 〇: No bleed, X: Bleed * 2 Time after application
発明の効果 The invention's effect
本発明の経皮吸収製剤は、 基剤中に、 薬物としてレポドパ及びその薬 学上許容されるエステルから選ばれた少なくとも一種を含有するレポド パ含有経皮吸収製剤であるので、 投与が簡便であり、 有効血中濃度の持 続性に優れる。 このため、 副作用が少なく、 薬効の変動も少ない製剤と することが出来る。
The percutaneous absorption preparation of the present invention is a levodopa-containing percutaneous absorption preparation containing, as a drug, at least one selected from levodopa and a pharmaceutically acceptable ester thereof in a base, so that administration is simple. Yes, excellent persistence of effective blood concentration. For this reason, it is possible to prepare a preparation with less side effects and less fluctuation in drug efficacy.
Claims
1 . 基剤中に、 薬物としてレポドパ及びその薬学上許容されるエステル から選ばれた少なくとも一種を含有し、 前記薬物の薬効の発現部位が投 与部位以外であることを特徴とするレポドパ含有経皮吸収製剤。 1. The base contains at least one selected from the group consisting of levodopa and pharmaceutically acceptable esters thereof as a drug, and the site of exhibiting the medicinal effect of the drug is other than the site of administration; Skin absorption preparation.
2 . 基剤中に、 レポドパの代謝阻害剤を含有する請求項 1記載のレボド パ含有経皮吸収製剤。 2. The levodopa-containing transdermal absorption preparation according to claim 1, wherein the base contains a levodopa metabolism inhibitor.
3 . 薬物の製剤中の含有率が、 0 . 1〜3 0重量%である請求項 1又は 2記載のレポドパ含有経皮吸収製剤。 3. The percutaneously absorbable levodopa-containing preparation according to claim 1 or 2, wherein the content of the drug in the preparation is 0.1 to 30% by weight.
4 . 基剤中に、 添加剤として、 有機酸、 吸湿性物質及び界面活性剤より なる群から選ばれた少なくとも一種を含有する請求項 1〜 3のいずれか 一項記載のレポドパ含有経皮吸収製剤。 4. The transdermal absorption containing levodopa according to any one of claims 1 to 3, wherein the base contains at least one selected from the group consisting of an organic acid, a hygroscopic substance, and a surfactant as an additive. Formulation.
5 . 吸湿性物質が、 吸水性ポリマー及び多価アルコールからなる群より 選ばれた少なくとも一種である請求項 4記載のレポドパ含有経皮吸収製 剤。 5. The levodopa-containing transdermal preparation according to claim 4, wherein the hygroscopic substance is at least one selected from the group consisting of a water-absorbing polymer and a polyhydric alcohol.
6 . 多価アルコールが、 グリセリ ン、 プロピレングリコール、 1, 3— プチレングリコール及び分子量 2 0 0 ~ 6 0 0の範囲のポリェチレング リコールよりなる群から選ばれた少なくとも一種である請求項 5記載の レポドパ含有経皮吸収製剤。 6. The polyhydric alcohol according to claim 5, wherein the polyhydric alcohol is at least one selected from the group consisting of glycerin, propylene glycol, 1,3-butylene glycol, and polyethylene glycol having a molecular weight in the range of 200 to 600. A transdermal preparation containing levodopa.
7 . 基剤が、 ポリマー、 ゲイ酸、 ゲイ酸金属土類系鉱物、 炭化水素、 油 脂類、 多価アルコール、 高級アルコール、 低級アルコール、 高級脂肪酸、 脂肪酸エステル及び水よりなる群から選ばれた少なくとも一種である請 求項 1〜 6のいずれか一項記載のレポドパ含有経皮吸収製剤。 7. The base is selected from the group consisting of polymers, gay acid, metal-earth minerals of gay acid, hydrocarbons, oils and fats, polyhydric alcohols, higher alcohols, lower alcohols, higher fatty acids, fatty acid esters and water. 7. The transdermal absorption preparation containing levodopa according to any one of claims 1 to 6, which is at least one.
8 . 経皮吸収製剤が、 クリーム剤、 ゲル剤、 ペースト剤、 ローション剤 及びパップ剤からなる群より谭ばれた少なくとも一種である請求項 1〜 7のいずれか一項記載のレポドパ含有経皮吸収製剤。
8. The transdermal absorption preparation containing lepodopa according to any one of claims 1 to 7, wherein the transdermal absorption preparation is at least one selected from the group consisting of a cream, a gel, a paste, a lotion, and a poultice. Formulation.
9 . 経皮吸収製剤が、 支持体の片面に、 薬物を含有する粘着剤層が設け られた経皮吸収貼付剤である請求項 1〜 6のいずれか一項記載のレポド パ含有経皮吸収製剤。 9. The transdermal absorption patch according to any one of claims 1 to 6, wherein the transdermal absorption preparation is a transdermal absorption patch in which a drug-containing adhesive layer is provided on one surface of a support. Formulation.
10. 粘着剤層が、 アクリル系粘着剤、 ゴム系粘着剤、 シリコン系粘着剤 及びゥレタン系粘着剤よりなる群から選ばれた少なくとも一種である請 求項 9記載のレポドパ含有経皮吸収製剤。 10. The transdermal absorption preparation containing levodopa according to claim 9, wherein the pressure-sensitive adhesive layer is at least one selected from the group consisting of an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicon-based pressure-sensitive adhesive, and a urethane-based pressure-sensitive adhesive.
11. アクリル系粘着剤が、 (メタ) アクリル酸アルキルエステル 4 0〜 9 0モル%及びビニルピロリ ドン 1 0〜6 0モル%からなる吸水率が 1 . 5 %以上の共重合体からなる請求項 1 0記載のレポドパ含有経皮吸収製 剤。
11. The acrylic pressure-sensitive adhesive is a copolymer comprising 40 to 90 mol% of (meth) acrylic acid alkyl ester and 10 to 60 mol% of vinylpyrrolidone and having a water absorption of 1.5% or more. 10. The transdermal absorption preparation containing levodopa according to 10 above.
Priority Applications (1)
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AU16817/99A AU1681799A (en) | 1997-12-17 | 1998-12-16 | Percutaneously absorbable levodopa-containing preparation |
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JP34799497 | 1997-12-17 | ||
JP9/347994 | 1997-12-17 | ||
JP23418298 | 1998-08-20 | ||
JP10/234182 | 1998-08-20 |
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PCT/JP1998/005670 WO1999030702A1 (en) | 1997-12-17 | 1998-12-16 | Percutaneously absorbable levodopa-containing preparation |
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WO (1) | WO1999030702A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6746688B1 (en) | 1996-10-13 | 2004-06-08 | Neuroderm Ltd. | Apparatus for the transdermal treatment of Parkinson's disease |
JPWO2019171843A1 (en) * | 2018-03-05 | 2021-02-25 | パナソニックIpマネジメント株式会社 | Cosmetics or medical materials |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260066A (en) * | 1992-01-16 | 1993-11-09 | Srchem Incorporated | Cryogel bandage containing therapeutic agent |
WO1998016208A1 (en) * | 1996-10-13 | 1998-04-23 | Analyst Research Lab | Methods and apparatus for treatment of parkinson's disease |
-
1998
- 1998-12-16 AU AU16817/99A patent/AU1681799A/en not_active Abandoned
- 1998-12-16 WO PCT/JP1998/005670 patent/WO1999030702A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5260066A (en) * | 1992-01-16 | 1993-11-09 | Srchem Incorporated | Cryogel bandage containing therapeutic agent |
WO1998016208A1 (en) * | 1996-10-13 | 1998-04-23 | Analyst Research Lab | Methods and apparatus for treatment of parkinson's disease |
Non-Patent Citations (1)
Title |
---|
MUTSUO OKUMURA, KENJI SUGIBAYASHI, YASUNORI MORIMOTO: "EFFECT OF SEVERAL ENHANCERS ON THE SKIN PERMEATION OF WATER-SOLUBLEDRUGS", CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, JP, vol. 37, no. 05, 1 May 1989 (1989-05-01), JP, pages 1375 - 1378, XP002922309, ISSN: 0009-2363 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6746688B1 (en) | 1996-10-13 | 2004-06-08 | Neuroderm Ltd. | Apparatus for the transdermal treatment of Parkinson's disease |
JPWO2019171843A1 (en) * | 2018-03-05 | 2021-02-25 | パナソニックIpマネジメント株式会社 | Cosmetics or medical materials |
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AU1681799A (en) | 1999-07-05 |
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