WO1999030702A1

WO1999030702A1 - Percutaneously absorbable levodopa-containing preparation

Info

Publication number: WO1999030702A1
Application number: PCT/JP1998/005670
Authority: WO
Inventors: Hiroko Udagawa; Takayuki Oka; Masaru Hamabe
Original assignee: Sekisui Chemical Co., Ltd.
Priority date: 1997-12-17
Filing date: 1998-12-16
Publication date: 1999-06-24
Also published as: AU1681799A

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

Description Lepodopa-containing transdermal preparation Technical field

TECHNICAL FIELD The present invention relates to a transdermal preparation containing levodopa. Background art

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).

However, levodopa administration has the following problems, which can have a significant effect on daily life.

(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) 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) If the dose is too large, side effects such as dyskinesia occur.

—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.

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.

Disclosure of the invention

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.

In the present invention, the content of the drug in the preparation is preferably from 0.1 to 30% by weight.

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. .

As 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. 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:

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Examples of the surfactant include peraroyl sarcosine, diethanolamide laurate, polyoxyethylene alkyl ether, polyoxyethylene alkylamine, sorbitan fatty acid ester, and polyglycerin fatty acid ester.

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.

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.

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.

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.

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.

Examples of the polyhydric alcohol 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.

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.

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.

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.

Specific examples of the above fatty acid esters include, for example, isopiryl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, white wax and the like.

In addition, 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.

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.

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.

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.

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

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. 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Examples of the silicon-based pressure-sensitive adhesive include polydimethylsiloxane and polydimethylsiloxane.

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.

Examples of the crosslinking agent include aluminum hydroxide, calcium hydroxide, magnesium stearate, isocyanates, epoxy resins, melamine resins, urea resins, and ammoniums.

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.

As the stabilizer and the filler, the same stabilizers and fillers as those described above can be used.

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.

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.

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.

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

Examples thereof include (meth) acrylate, hexylene glycol di (meth) acrylate, polyethylene glycol di (meth) acrylate, polypropylene glycol di (meth) acrylate, and trimethylolpropanetri (meth) acrylate.

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.

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%.

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). 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.

In the above solution polymerization, other monomers and additives used in ordinary polymerization reactions may be used as necessary.

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.

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,

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.

When the above-mentioned polymerization initiator is added, a predetermined amount may be initially supplied collectively, or may be supplied separately.

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.

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.

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.

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.

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.

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.

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 μπι.

Examples of the plastic film of the release paper include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, and polyvinylidene chloride.

Examples of the paper include a paper impregnated with polyvinyl alcohol or the like.

BEST MODE FOR CARRYING OUT THE INVENTION

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)

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.

(Example 2)

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.

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.

(Comparative Example 1)

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

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.

(Levodopa blood concentration measurement test)

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.

In Table 1, ND means not detected.

(Examples 3 to 12, Comparative Example 2 and Reference Examples 1 and 2)

(Preparation of adhesive A)

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.

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.

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%.

(Preparation of adhesive B)

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%.

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.

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,

HE: coconut oil polyoxyethylene (7) glycerin C.P. * 3 Cross-linked polyvinyl pyridone

(Example 10)

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.

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.

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.

(Example 11)

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.

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.

Further, 1 g of gelatin was dissolved in 30 g of purified water heated to 60 ° C. to obtain a mixed solution C.

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.

(Percutaneous absorption evaluation)

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 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.

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 )

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.

(Efficacy evaluation)

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 . 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.

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.

A case of 20 seconds or longer was regarded as positive for positive force. Table 3

A U C Drug evaluation

Stability

(nghr / L) * 1 5 hours% 2 24 hours * 2

4 4 3 1 〇 8 7

3 6 2 3 〇

3 2 9 0 〇

4 1 7 〇

Example 3 5 4 5 〇

5 9 6 8

6 7 3 4 1 0

10 3 1 7 9 〇

11 4 0 2 6 〇

X

Reference example

X

Comparative Example 5 9 3 3 2

* 1 〇: No bleed, X: Bleed * 2 Time after application

The invention's effect

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

The scope of the claims

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. The levodopa-containing transdermal absorption preparation according to claim 1, wherein the base contains a levodopa metabolism inhibitor.

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. 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. 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. 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. 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. 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. 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. 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. 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.