WO1998008547A1

WO1998008547A1 - Stanozolol-containing percutaneously absorbable preparation

Info

Publication number: WO1998008547A1
Application number: PCT/JP1997/003014
Authority: WO
Inventors: Takeshi Wakiya; Tsutomu Nekama; Hiroshi Kuroda
Original assignee: Sekisui Kagaku Kogyo Kabushiki Kaisha
Priority date: 1996-08-29
Filing date: 1997-08-29
Publication date: 1998-03-05
Also published as: AU4031897A

Abstract

A stanazolol-containing percutaneously absorbable preparation excellent in the releasability of the drug from the base, percutaneous absorbability and persistence of effective blood level. The base contains at least one drug selected from the group consisting of stanozolol and pharmaceutically acceptable esters thereof.

Description

Akira Stanozolol-containing transdermal preparation Technical field

TECHNICAL FIELD The present invention relates to a stanozolol-containing transdermal preparation,

Stanozolol; (5α, 17S)-17-Me thy l-2'H-andr

ost-2-eno [3, 2-c] pyrazo]-17 -ol: is a steroid that has anabolic action and is osteoporotic, hyperlipidemic, or chronic renal disease. It is used as a remedy for severe wasting due to post-traumatic burns. Administration of such hormones having a steroid skeleton has been used as an effective treatment for various diseases including osteoporosis. However, in general, steroid hormones are heavily involved in liver metabolism, so that the burden on the liver is large. In addition, due to the low bioavailability of the drug, it is necessary to administer a large amount at a time in oral administration. Long-term prolonged use may cause carcinogenesis or liver damage, which is not preferable. Stanozolol has a similar tendency. At higher doses, it also has side effects such as virilization, feminization due to promotion of conversion to estradiol, liver damage, and cardiovascular disease.

When steroid hormones are used in the form of transdermal preparations instead of conventional oral and injectable preparations, the steroid hormone concentration can be increased over a long period of time without temporarily increasing the blood concentration. Controllable, especially avoiding hepatic metabolism. In addition, the effective blood concentration is maintained, so that not only the number of administrations of the drug is reduced, but also the administration is simple and it can withstand long-term administration, so that patient compliance and quality · Life can be easily improved. For example, regarding estradiol, which is a female hormone, Japanese Patent Publication No. 7-911193 discloses an estradiol transdermal patch. However, up to now, transdermal preparations of stanozolol have not yet been known. Summary of the Invention

An object of the present invention is to provide a stanozolol-containing transdermal absorption preparation having excellent release from a base, absorption to the skin, and long-lasting effective blood concentration. The stanozolol-containing transdermal absorption preparation of the present invention is a transdermal absorption preparation containing a drug in a base, wherein the drug is at least one selected from stanozolol and a pharmaceutically acceptable ester thereof. It is.

In the stanozolol-containing transdermal absorption preparation of the present invention, the content of the drug in the base is preferably from 0.01 to 20% by weight.

The stanozolol-containing percutaneous absorption preparation of the present invention comprises, as a base, a polymer, colloid-containing hydrous metal earth metal mineral, oil and fat, hydrocarbon, polyhydric alcohol, higher fatty acid, higher alcohol, lower alcohol and water. It is preferable that the composition is at least one selected from the group consisting of or a composition containing the same.

The stanozolol-containing transdermal absorption preparation of the present invention can contain, in the base, at least one or more transdermal absorption enhancers selected from the group consisting of alcohols, organic acids, fatty acid esters and surfactants. .

The stanozolol-containing percutaneous absorption preparation of the present invention can be used as a percutaneous absorption preparation comprising at least one base selected from the group consisting of descendants, creams, juries, pastes and lotions.

Further, the stanozolol-containing transdermal absorption preparation of the present invention is a transdermal absorption patch in which a pressure-sensitive adhesive layer is provided on one side of a support, wherein the pressure-sensitive adhesive layer comprises a drug-containing base. Can be used as a transdermal absorption preparation. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a perspective view showing a diffusion cell for a drug skin permeability test. Detailed Disclosure of the Invention

Hereinafter, the present invention will be described in detail.

The stanozolol-containing transdermal absorption preparation of the present invention contains a drug in a base. The drug used in the present invention is stanozolol and its pharmaceutically acceptable ester. At least one species selected from the

The base may be any as long as it can dissolve stanozolol and its pharmaceutically acceptable ester and is pharmaceutically acceptable. When the stanozolol-containing transdermal absorption preparation of the present invention is used as a delicate, cream, jewelry, paste, lotion, etc., for example, ointments, creams, jeries, pastes, lotions, etc. What is used as a base can be used. In particular, at least one selected from the group consisting of polymers, colloid-containing hydrous metal earth metal minerals, fats and oils, hydrocarbons, polyhydric alcohols, higher fatty acids, higher alcohols, lower alcohols and water, or at least one of them Compositions comprising are preferred.

Examples of the above polymer include sodium alginate, gelatin, corn starch, tragacanth gum, methylcellulose, hydroxyquinethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose sodium, dextrin, carboxymethyl. Examples include denbum, polyvinyl alcohol, polyacrylic acid, polyacrylic acid salt (eg, sodium salt), methoxyethylene maleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, and polyacrylamide.

Examples of the above-mentioned colloidal hydrated metal earth metal minerals include colloidal hydrated aluminum maleate minerals such as kaolin and bentonite, and colloidal hydrated magnesium and aluminum minerals such as veegum. Can be

Examples of the fats and oils include beeswax, olive oil, cocoa oil, sesame oil, soybean oil, camellia oil, laccase oil, beef oil, pork oil, lanolin and the like.

Examples of the hydrocarbon include white petrolatum, paraffin, liquid paraffin, and hydrocarbon gel II (for example, trade name: Blastibase, manufactured by Taisho Pharmaceutical Co., Ltd.).

Examples of the polyhydric alcohol include ethylene glycol, polyethylene glycol, propylene glycol, and polypropylene glycol. Examples of the higher fatty acids include acetic acid, nonanoic acid, acetic acid, prillic acid, pendecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, and palmiic acid. Saturation of formic acid, heptadecylic acid, stearic acid, oleic acid, nonadecanoic acid, arachidonic acid, linoleic acid, behenic acid, lignoceric acid, serotinic acid, hebutacosanoic acid, palmitoleic acid, vaccenic acid, linolenic acid, etc. Or unsaturated fatty acids.

Examples of the above higher alcohols include lauryl alcohol, dodecyl alcohol, myristyl alcohol, pentadecyl alcohol, cetyl alcohol, sodium desinoleno alcohol, hebutadecino alcohol, stearino alcohol, o Examples include rail alcohol, nonadecyl alcohol, eicosyl alcohol, seryl alcohol, mesyl alcohol, and cetyl alcohol.

Examples of the lower alcohol include isopropyl alcohol and ethanol.

The stanozolol-containing transdermal preparation of the present invention can also be used as a transdermal patch in which a pressure-sensitive adhesive layer comprising a drug-containing base is provided on one surface of a support.

The support is preferably a material in which the drug used in the present invention is impermeable or poorly permeable and is flexible. For example, ethylene-vinyl acetate copolymer, ethylene-methyl acrylate copolymer, Polyesters such as polybutyrene terephthalate and polyethylene terephthalate; Polyamides such as nylon-16; Polyurethane, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, polyvinyl chloride, and vinyl acetate-vinyl chloride copolymer And resin films such as ethylene-vinyl acetate-carbon oxide copolymer, ethylene-butyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, etc .: aluminum sheets, and the like. Or a laminate of these and a woven or non-woven fabric. No. The pressure-sensitive adhesive layer is not particularly limited as long as it is pharmaceutically acceptable, and any conventionally known pressure-sensitive adhesive can be used. Preferably, an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicone-based pressure-sensitive adhesive, At least one selected from the group consisting of urethane-based adhesives. As the properties of the pressure-sensitive adhesive, any properties such as a dissolution type, an emulsion type and a hot melt type can be used.

The acrylic pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of alkyl (meth) acrylate. And may be a copolymer of a functional monomer and / or a polyfunctional monomer copolymerizable with an alkyl (meth) acrylate.

Examples of the alkyl (meth) acrylate include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and n. —Examples include octyl (meth) acrylate and dodecinole (meth) acrylate. When the number of carbon atoms in the alkyl group of the acrylate decreases, the cohesive strength increases, but the adhesive strength decreases. When the content is increased, the adhesive strength is improved, but the cohesive strength is reduced.

Examples of the functional monomer include (meth) acrylic acid, 2-hydroxyethyl (meth) acrylate, 2-hydroxyquinpropyl (meth) acrylate, glycidyl dimethacrylate, and N-methylol (meth) acrylamide. And N-butoxymethylacrylamide.

If these functional monomers are copolymerized, metal salts such as sodium hydroxide and calcium hydroxide, isocyanates, epoxy resins, melamine resins, urea resins, ammonia, etc. will be used to coagulate the adhesive. Strength can be improved. The above-mentioned polyfunctional monomers are copolymerized to improve the cohesive strength of the pressure-sensitive adhesive. For example, 1,6-hexaneglycol dimethacrylate, tetraethylene glycol diacrylate, trimethylolpropane Triacrylate, divinylbenzene, divinyltoluene, diarylphthalate, diarylmaleate, diaryldiabate, diarylglycolate, triarylisocyanurate, diethyleneglycolbisarylcarbonate And the like.

As the acryl-based pressure-sensitive adhesive, a copolymer containing an alkyl (meth) acrylate and a vinyl compound as a functional monomer copolymerizable therewith is also preferable. Examples of the vinyl compound include vinyl acetate, acrylonitrile, styrene, N-vinyl-2-pyrrolidone and the like, and N-vinyl-2-pyrrolidone is particularly preferable.

Particularly, a copolymer of 55 to 95% by weight of 2-ethylhexyl acrylate, 5 to 45% by weight of 1 ^ -vinyl-2-pyrrolidone, and 0 to 0.5% by weight of a polyfunctional monomer is preferable. As the acrylic pressure-sensitive adhesive, one composed of a copolymer containing a plurality of alkyl (meth) acrylates is also preferable. Particularly, 2-ethylhexyl methacrylate 65 to 90% by weight, 2-ethylhexyl acrylate 5 to 30% by weight, dodecyl methacrylate 5 to 30% by weight, and polyfunctional monomer 0 to 0%. It is preferable to use a copolymer composed of 5% by weight.

In general, the acryl-based pressure-sensitive adhesive has an alkyl (meth) acrylate as a main component as described above, and other components may be appropriately determined according to required performance. Is preferably copolymerized at 20% by weight or less, preferably 1 to 10% by weight in the pressure-sensitive adhesive, and the amount of the polyfunctional monomer is generally preferably 0.5 to 0.5% by weight in the pressure-sensitive adhesive. When the above-mentioned vinyl compound is used, it is generally preferable to copolymerize the pressure-sensitive adhesive in an amount of 50% by weight or less, preferably 40% by weight or less.

The acrylic pressure-sensitive adhesive may contain an inorganic filler such as silicic acid, zinc oxide, or titanium oxide, a plasticizer such as a higher fatty acid ester, or a tackifier such as ester gum, if necessary. It may be added within the permissible IS range.

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. A pressure-sensitive adhesive containing a rubber such as a polymer. Generally, rosin, hydrogenated rosin, rosin ester, terpene resin, terpene fuanol resin, petroleum resin, bear mouth resin, cumarone-indene resin, etc. A tackifier is added. In addition, oils such as black oil, olive oil, camellia oil, persic oil, peanut oil, sesame oil, soybean oil, mink oil, cottonseed oil, corn oil, safflower oil, coconut oil, castor oil, etc.

Higher fatty acids such as oleic acid and lauric acid, and liquid paraffin may be added.

As the silicone-based pressure-sensitive adhesive, any of the silicone-based pressure-sensitive adhesives that have been conventionally used for pressure-sensitive adhesives for transdermal patches can be used, and is not particularly limited. 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. In the transdermal absorption preparation of the present invention, a transdermal absorption enhancer may be contained in the base, if necessary. As the above-mentioned percutaneous absorption enhancer, those usually used in percutaneous absorption preparations can be used, and preferably at least one selected from the group consisting of alcohols, organic acids, fatty acid esters and surfactants is used. More than a species.

The alcohol is preferably a monohydric alcohol or polyhydric alcohol having 8 to 14 carbon atoms. In the case of monohydric alcohol, when the carbon number is 7 or less, the volatility increases, and when it is 15 or more, the absorption promoting effect decreases. Preferred alcohols include lauryl alcohol, oleyl alcohol, and cetyl alcohol. Propylene glycol, 1,3-butanediol, and glycerin are preferably used as the polyhydric alcohol.

The organic acid is preferably a monovalent or polyvalent organic acid, for example, a monocarboxylic acid having 8 to 20 carbon atoms, a dicarboxylic acid having 2 to 8 carbon atoms or a salt thereof, and a hydrone having 3 to 8 carbon atoms. Xydicarboxylic acid or its salt is mentioned. In the case of monocarboxylic acid, when the number of carbon atoms is 7 or less, the acidity is so strong that it cannot be applied to the human body, and when it is 21 or more, the absorption promoting effect tends to decrease. As the monocarboxylic acid, for example, aliphatic monocarboxylic acids such as capric acid, nonanoic acid, caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, and oleic acid are preferably used. The dicarbonic acid preferably has 2 to 8 carbon atoms since the absorption effect tends to decrease when the number of carbon atoms is 9 or more. For example, oxalic acid, malonic acid, succinic acid, glutaric acid, pimelic acid, suberin Saturated aliphatic direct sales such as acids Dicarboxylic acids, aromatic dicarboxylic acids such as phthalic acid, isophthalic acid and terephthalic acid, and salts of these dicarboxylic acids such as sodium salt, potassium salt, magnesium salt, calcium salt and aluminum salt are preferably used. Is done.

The hydroxycarboxylic acid preferably has 3 to 8 carbon atoms since the absorption promoting effect tends to decrease when the number of carbon atoms is 9 or more. For example, malic acid, tartaric acid, and sodium salts and potassium salts of these dicarboxylic acids are preferred. , Magnesium salt, calcium salt, aluminum salt and the like are preferably used.

As the fatty acid ester, an ester of a fatty acid having 10 to 18 carbon atoms and an aliphatic monohydric alcohol having 1 to 18 carbon atoms is preferable. Fatty acid esters have i If it is 0 or less, it is easy to volatilize, and if it is 37 or more, the absorption promoting effect tends to decrease, so that 11 to 36 is preferable. Examples of the above fatty acids include saturated aliphatic monocarboxylic acids such as lauric acid, palmitic acid, myristic acid, capric acid, stearic acid, etc .: panolemitoleic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid And unsaturated aliphatic dicarboxylic acids such as sebacic acid. Examples of the above-mentioned alcohols include aliphatic saturated alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, pentinoleanolecohol, hekinoleno alcohol, heptyl alcohol, octinoreal alcohol, decyl alcohol, and cetyl alcohol. Is preferred. As the fatty acid ester, isopropyl myristate and isopropyl palmitate are particularly preferred.

As the surfactant, any of a nonionic surfactant, an anionic surfactant, a surfactant, and an amphoteric surfactant can be used. Nonionic surfactants include, for example, sorbitan monolaurate, sorbitan alkyl ethers such as sorbitan monopallate, polyquineethylene (9) lauryl ether, boroxyethylene (2) lauryl ether, etc. Fatty acid alkanol amides such as polyoxyethylene alkyl ethers and diethanol laurate, polyoxyethylene fatty acid amides, and alkyl amine oxides. Examples of the anionic surfactant include an anionic surfactant having at least one carboxy group, sulfo group, sulfate group, or phosphate group in the molecule. Examples of those having a carboxy group include fatty acid stones, ether carboxylic acids and salts thereof, and carboxylate salts such as condensates of amino acids and fatty acids. Examples of those having a sulfo group include alkyl sulfonic acid salts. , Sulfosuccinic acid, ester sulfonate, alkylaryl or alkylnaphthalenesulfonate, N-acylsulfonate, etc. having a sulfate group include, for example, sulfated oil, ester sulfate, ether sulfate, alkyla Examples of those having a phosphoric ester group such as alkyl ether sulfate, amide sulfate and the like include alkyl phosphate, amidolinate, ether phosphate, alkylaryl phosphate and the like. No.

Examples of the cationic surfactant include fatty acid amines, alkyl quaternary ammonium salts, aromatic quaternary ammonium salts, pyridium salts, and imidazolym salts.

Examples of the amphoteric surfactant include carboquine betaine such as betaine lauryl dimethylaminoacetate, sulfobetaine, aminocarboxylate, and imidazoline derivative.

Among these surfactants, particularly preferred are polyoxyethylene (2) lauryl ether, polyoxyethylene (9) lauryl ether, and diethanol laurate.

The percutaneous absorption preparation of the present invention may further comprise, if necessary, an inorganic filler such as silica, zinc oxide, or titanium oxide; a humectant; a viscosity modifier; an antioxidant; Flavoring agent: A stabilizer and the like can also be added.

In the percutaneous absorption preparation of the present invention, the optimal content of the drug in the base varies depending on the base component and the percutaneous absorption enhancer added as needed, but if it is small, it is sufficient. The skin / * permeability of the drug cannot be obtained, the therapeutic effect cannot be expected, and if it is large, crystals will precipitate over time, and if the amount of precipitation is large, the feeling of use will be significantly impaired. 1 to 20% by weight is preferred, and 0.1 to 15% by weight is more preferred.

In the percutaneous absorption preparation of the present invention, the content of the percutaneous absorption enhancer in the base, which is added as necessary, varies depending on the components of the base. Since it is not obtained and the compatibility with the base decreases as the content increases, the content is preferably 0.1 to 20% by weight, more preferably 1 to 15% by weight. The transdermal absorption enhancer may be contained as a base component, and in this case, the amount added is not limited to the above range.

When the transdermal absorption preparation of the present invention is used as a descendant or a jewel, the most preferred form is 0.5 or less of stanozolol, one or more accelerators required for an ointment or a gizzle base. ~ 15% by weight.

When the transdermal preparation of the present invention is used as a patch, the most preferred form is The acryl-based pressure-sensitive adhesive contains a required amount of stanozolol and one or more accelerators in an amount of 0.5 to 15% by weight.

The transdermal preparation of the present invention can be produced by a conventional method. For example, in the case of ointments, creams, pastes, lotions, and diluent bases, the necessary base materials are kneaded, emulsified, suspended or dissolved to produce the base, and then the drug and It is manufactured by adding a percutaneous absorption enhancer, adjuvant, etc., if necessary, and mixing with a commonly used kneader.

When the percutaneous absorption preparation of the present invention is a patch, the production method varies depending on the type of the adhesive, but the adhesive waste must be produced by a conventional method such as a hot melt method or a solution method. Can be. For example, in the case of an acrylic pressure-sensitive adhesive, a solution of the drug and, if necessary, a transdermal absorption enhancer in ethanol or ethyl acetate is added to the pressure-sensitive adhesive obtained by polymerization, and the solid component (after the organic solvent is dried) (The sum of the weight of the polymer, drug and transdermal absorption enhancer) is 25% by weight, and mixed with stirring. This solution was applied on a silicon-treated polyethylene terephthalate film with a thickness of 35 Atm to a thickness of 60 m after drying, and then dried. A transdermal patch is prepared by laminating terephthalate.

The thickness of the pressure-sensitive adhesive layer is not particularly limited, but when the pressure-sensitive adhesive layer is thin, it is necessary to add a large amount of the drug, and the sticking property is deteriorated. Generally, the cost is preferably increased, so that 20 to 200 m is preferable, and 30 to 100 m is more preferable. 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)

89 g of Plastibase (Taisho Pharmaceutical Co., Ltd.), 10 g of isopropyl myristate and 1 g of stanozolol (manufactured by Steroid Srl) are homogenized using a homomixer (manufactured by Tokushu Kika Kogyo). Ointment was prepared by spinning for 150 minutes.

(Example 2) 40 g of ethanol, 3 Og of propylene glycol and 1 g of ruboxyvinyl polymer were mixed with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) for 150 minutes while stirring, stirring and mixing. Thereafter, 1 g of stanozolol is added to the mixture, and the mixture is further stirred for 60 minutes. Finally, 29 g of distilled water in which 0.2 g of sodium hydroxide had been dissolved was added, and the mixture was subjected to rotary stirring for 150 minutes to prepare a powder. (Example 3)

Rotate 40 g of ethanol, 30 g of propylene glycol, 1 g of carboxyvinyl polymer and 1 g of lauric acid diethanolamide with a homomixer (manufactured by Tokushu Kika Kogyo Co., Ltd.) for 150 minutes to make them uniform. · Search · Mixed. Thereafter, 1 g of stanozolol is added to the mixture, and the mixture is further stirred for 60 minutes. Finally, 28 g of distilled water in which 0.02 g of sodium hydroxide was dissolved was added, and the mixture was stirred for 150 minutes to prepare soft growth. Performance evaluation

The percutaneously absorbable preparations obtained in Examples 1 to 3 were subjected to a drug skin permeability test and a test for measuring a waterfall in a heron blood as follows.

Drug skin permeability test

The diffusion cell 1 shown in FIG. 1 was prepared. The diffusion cell 1 is formed of a bottomed cylindrical receiving tank 1 and a bottomed cylindrical donor tank 3 arranged on the tank 2. An opening 4 is provided at the center of the bottom wall of the donor tank 3, the bottom wall extends in the peripheral direction, and a flange 5 is provided. A flange 6 is provided on the upper part of the receptor tank 2, and a side protruding sambring gro 7 is attached to the side wall. The flange 5 and the flange 6 are overlapped facing each other, and the donor tank 3 and the receiver tank 2 are airtightly and concentrically stacked. In addition, a magnet agitator 9 is placed inside the receptor tank 2.

A hairless mouse (male, 6 weeks of age) was sacrificed by cervical dislocation, and immediately the back skin was removed, and the subcutaneous fat and muscle layer were removed to obtain a skin piece 8 of about 5 cm x 5 cm. The obtained skin piece 8 was attached between the flange 5 and the flange 6 of the diffusion cell 1, and the opening 4 of the donor layer 3 was completely closed with the skin piece 8. Polyethylene of circular shape (area 10 cm ² ) [Nterephthalate film] 0.1 g of the obtained percutaneous absorption preparation is evenly applied to one side of the skin, and affixed to the center of the skin strip 8 so that the percutaneous absorption preparation layer is in contact with the skin strip 8. Receptor tank 2 was filled with the receptor liquid, placed in a thermostat kept at 37 ° C, and stirred by rotating a magnet stirrer with a magnet stirring device. At 5, 18, and 24 hours after the start of the test, 1 ml of the receptor solution was sampled from the sampling □ 7, and 1 ml of a fresh receptor solution was replenished instead. The drug that permeated the skin was dissolved in the collected Received Evening Solution. The drug concentration in one sampled receptor solution was measured by high-performance liquid chromatography, and the drug permeation amount (unit: cm ² ) was calculated. In addition, this test was performed with the number of repetitions of 3, and the average value was shown.

Receptor fluid preparation: distilled water _{_{N aH 2 P0 4 5 xi O-}} 4 M, N a 2 H PO 2 1 0 M, N a C 1 1. 5 x 1 0- l M and sulfuric Gen evening mycin 1 0 The pH was adjusted to 7.2 by adding a 1N—Na0H aqueous solution to the buffer containing g / m1. To 800 ml of this buffer solution, 200 ml of polyethylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) was mixed to obtain 200 ml of receptor solution. table 1

ゥ A heron blood concentration measurement test

The percutaneous absorption preparations obtained in Examples 1 to 3 were subjected to a test for measuring concentration in blood of egret. Egret (New Zealand white, male, 15 weeks old) shaves the entire back, Twenty-four hours after shaving, it was confirmed that there was no damage or inflammation, and a transdermal absorption preparation was applied to an area of 3 O cm ² . As a control, a stanozolol 2 mg tablet (Winstall tablet, manufactured by Yamanouchi Pharmaceutical Co., Ltd.) was orally administered. At 0, 1, 2, 4, 6, 8, and 24 hours after application, blood was collected from the ear vein and the level of stanozolol in the blood was measured by high performance liquid chromatography. The results are shown in Table 2.

Table 2

(Example 4)

2 Ethylhexyl acrylate (hereinafter referred to as EHA) 65 mol% (302.0 g), vinylpyrrolidone (hereinafter referred to as VP) 35 mol% (98.0 g), and hexamethylene glycol 0.02 parts by weight (80 mg) of dimethacrylate was added to a separable flask with respect to 100 parts by weight of EHA and VA, so that the monomer concentration at the beginning of polymerization was 85% by weight. 70.6 g of ethyl acetate were added. The solution was heated to 65 under a nitrogen atmosphere, and lauroyl peroxide and ethyl acetate as polymerization initiators were sequentially added little by little, followed by polymerization for 32 hours. Polymer (hereinafter referred to as adhesive

A), an alcohol solution of stanozolol (manufactured by Steroid Srl) was added to a solid content (ethyl acetate, polymer after drying alcohol and weight of stanozolol) of 25%. % By weight and the concentration of stanozolol in the solid content was 15% by weight, followed by stirring and mixing. This solution was applied on a silicon-treated 35 / m-thick polyethylene terephthalate (hereinafter referred to as PET) film so that its thickness after drying was about 60 m, and then dried. Thickness A transdermal patch was prepared by laminating a 35 m PET film.

(Example 5)

Dodecyl methacrylate (hereinafter referred to as DMA) 10 mol% (48. 3 g), 21-ethylhexyl acrylate 10 mol% (34. 9 g), 2-ethylhexyl (meta) 80 mole% (301.0 g) of acrylate (hereinafter referred to as EMA) and hexamethylene glycol dimethacrylate were added to DMA and 100 parts by weight of EHA and EMA in total. 0.1 part by weight (38, 4 mg) was charged into a separable flask, and further, 256 g of ethyl acetate was added to adjust the monomer viscosity to 60% by weight. The solution was heated to 70 ° C. under a nitrogen atmosphere, and lauroyl peroxide and ethyl acetate as polymerization initiators were sequentially added little by little, followed by polymerization for 32 hours. After taking out the polymer (hereinafter referred to as adhesive B), a solution of stanozolol and isopir myristate in ethyl acetate was added to the solid content (polymer after drying ethyl acetate, suzonozolol and myristin). And the concentrations of stanozolol and isopropyl myristate in the solid content are 4% by weight and 15% by weight, respectively, followed by stirring and mixing. did. This solution is applied on a silicon-treated PET film with a thickness of 35 // m to a thickness of about 60 / zm after drying, and dried. The films were laminated to prepare a transdermal patch.

(Example 6)

A transdermal patch was prepared in the same manner as in Example 5, except that the concentration of isopropyl myristate in the solid content was changed to 30% by weight.

(Example 7)

In Example 5, except that the concentration of isopropyl myristate in the solid content was changed to 10% by weight, and that diethanolamide laurate was added so that the concentration in the solid content became 5% by weight. Thus, a transdermal patch was prepared in the same manner as in Example 5.

(Example 8)

In Example 7, lauric acid diethanolamide was replaced with lauric acid A transdermal patch was prepared in the same manner as in Example 7 except for the above.

(Example 9)

A transdermal patch was prepared in the same manner as in Example 7, except that lauric acid diethanolamide was replaced with oleic acid.

(Example 10)

A transdermal patch was prepared in the same manner as in Example 7 except that diethanolamide laurate was replaced with lauryl alcohol. (Example 11)

A transdermal patch was prepared in the same manner as in Example 7, except that diethanolamide laurate was replaced with polyquineethylene (9) lauryl ether.

(Example 12)

Dermal skin was obtained in the same manner as in Example 7, except that the concentration of stanozolol in the solid content was changed to 1% by weight and the concentration of diethanolamide laurate in the solid content was changed to 3% by weight. An absorbent patch was prepared.

(Example 13)

Example 7 was the same as Example 7 except that the concentration of stanozolol in the solid content was changed to 0.8% by weight and the horn of diethanolamide laurate in the solid content was changed to 2.5% by weight. A transdermal patch was prepared by the same procedure.

(Example 14)

Example 7 The same as Example 7 except that the concentration of stanozolol in the solid content was changed to 0.5% by weight, and the degree of lauric acid diethanolamide in the solid content was changed to 3% by weight. A transdermal patch was prepared by the procedure.

The pressure-sensitive adhesive eyebrows of the transdermal patches of Examples 4 to 14 described above, the type of the pressure-sensitive adhesive, the stannozolol concentration, the concentration of isopropyl myristate as the first transdermal absorption enhancer, and the second Table 3 shows the types and strains of the percutaneous absorption enhancers. Table 3

Performance evaluation

The percutaneous absorption patches obtained in Examples 4 to 14 were subjected to a drug skin penetration test and a heron blood concentration measurement test as follows.

Drug skin permeability test

Examples 1 to 3 except that the transdermal patch 10 was cut into a circle having an area of 3.14 cm ² and applied to the center of the skin piece 8 so that the adhesive layer was in contact with the skin piece 8. The test was conducted in the same manner as in the drug skin permeability test. Table 4 shows the results. Table 4

ゥ A heron blood nakaao degree measurement test

Percutaneous absorption patches obtained in Examples 5, 7, 11, and 14 were subjected to a test for measuring the concentration of rabbits in blood. And have you to Usagi blood concentration measurement test performed in Example 1-3, instead of "applying a percutaneous pharmaceutical preparation in the area 3 0 cm ^2", a percutaneous absorption adhesive preparation was cut into the area 1 2 cm ² Except that 6 sheets (total 72 cm ⁵ ) were attached, the test was carried out in the same manner as in the heron blood concentration measurement test performed for Examples 1 to 3. The results are shown in Table 5. Table 5

Industrial applicability

Since the percutaneous absorption preparation of the present invention has the above-mentioned constitution, it is excellent in the release properties of stanozolol from the base, the absorption to skin, and the retention of effective blood concentration.

Claims

The scope of the claims

1. A transdermal absorption preparation containing a drug in a base,

The transdermal absorption preparation containing stanozolol, wherein the drug is at least one selected from stanozolol and pharmaceutically acceptable esters thereof.

2. The stanozolol-containing transdermal absorption preparation according to claim 1, wherein the content of the drug in the base is 0.01 to 20% by weight.

3. The base is at least one selected from the group consisting of polymers, colloid-containing hydrous metal earth metal minerals, oils and fats, hydrocarbons, polyhydric alcohols, higher fatty acids, higher alcohols, lower alcohols and water. 3. The transdermal absorption preparation containing stanozolol according to claim 1 or 2, which is a seed or a composition containing the same.

4. The claim 1, 2, or 3 wherein the base contains at least one transdermal absorption enhancer selected from the group consisting of alcohols, organic acids, fatty acid esters and surfactants. The stanozolol-containing transdermal absorption preparation according to the above.

5. Claims 1 and 2, wherein the percutaneous absorption preparation comprises at least one base selected from the group consisting of blue, cream, jelly, paste, and lotion. Item 4. The transdermal absorption preparation containing stanozolol according to Item 2, 3 or 4.

6. The transdermal absorption preparation is a transdermal absorption patch in which an adhesive layer is provided on one side of a support,

5. The stanozolol-containing transdermal absorption preparation according to claim 1, wherein the pressure-sensitive adhesive layer comprises a drug-containing base.

7. The pressure-sensitive adhesive layer, 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. 7. The stanozolol-containing transdermal absorption preparation according to item 6 above.

8. The stanozolol-containing skin absorption preparation according to claim 7, wherein the acrylic pressure-sensitive adhesive comprises a copolymer containing an alkyl (meth) acrylate and a vinyl compound copolymerizable therewith.

9. The stanozolol-containing transdermal absorption preparation according to claim 7, wherein the acrylic pressure-sensitive adhesive comprises a copolymer containing a plurality of alkyl (meth) acrylates.