WO1996014069A1

WO1996014069A1 - Percutaneously absorbable patch

Info

Publication number: WO1996014069A1
Application number: PCT/JP1995/001011
Authority: WO
Inventors: Tetsuya Ota; Michiari Hashimoto; Mikiya Kitamura; Kunio Yoneto
Original assignee: Sekisui Kagaku Kogyo Kabushiki Kaisha
Priority date: 1994-11-04
Filing date: 1995-05-26
Publication date: 1996-05-17
Also published as: JPH08133974A

Abstract

A percutaneously absorbable patch which can release ibudilast, an ameliorant for bronchial asthma and cerebrovascular disorder, stably for long. The patch comprises a support and, provided thereon, a pressure-sensitive adhesive layer comprising 100 parts by weight of a pressure-sensitive adhesive, 1-30 parts by weight of a percutaneous absorption accelerator and 1-30 parts by weight of ibudilast, and the accelerator comprises a C8-C18 long-chain fatty acid or an ester thereof with a C1-C5 aliphatic alcohol.

Description

95/01 11

Rui Meisho Transdermal Patch Technical Field

The present invention relates to a percutaneous absorption patch which stably releases ibudilast, which is an agent for improving bronchial asthma and cerebrovascular disorders, over a long period of time. Background art

Ibudilast (3-isobutylyl-2-isopropylvirazolo [1,5-a] pyridin) is a useful drug as an agent for improving bronchial asthma and cerebrovascular disorders. However, when ibudilast is orally administered to humans as it is, the blood concentration rapidly increases due to rapid absorption from the gastrointestinal tract, which causes side effects such as nausea and vomiting.

In Japanese Patent Publication No. 60-1939313, a capsule, tablet, etc., which has been released and released as an oral preparation, has been proposed. However, bronchial asthma is a disease that is common in children, Since vascular disorders are diseases that are common among the elderly, it has been strongly desired to develop a dosage form of ibudilast that is easier to administer.

Japanese Patent Application Laid-Open No. H11-1536333 discloses a transdermal absorption preparation containing ibudilast as an active ingredient, but the blood concentration of ibudilast which is transdermally absorbed is low and the effect of administration is low. However, in order to compensate for this, it was necessary to increase the area of application.

Japanese Patent Publication No. 5-333929 discloses a technique for promoting absorption by an acrylic or rubber transdermal transmucosal preparation containing a fatty acid dialkylolamide as an absorption promoter. However, ibudilast was not indicated as a drug and it was not known whether it would be effective if applied to ibudilast: On the other hand, a tape formulation in which a skin absorption enhancer is added to ibudilast has been proposed, but when a large amount of the skin absorption enhancer is added, the cohesive strength of the adhesive is reduced and the adhesive property is deteriorated. There was also communication.

An object of the present invention is to provide a percutaneous absorption patch which stably releases ibudilast, which is an agent for improving tracheal asthma and cerebrovascular disorders, over a long period of time, as described above. Guidance of invention

The gist of the first invention is a transdermal absorption patch comprising a support and an adhesive layer laminated thereon, wherein the adhesive layer comprises 100 parts by weight of an adhesive, and a transdermal absorption enhancer. 1 to 30 parts by weight and ibudilast 1 to 30 parts by weight, wherein the percutaneous absorption enhancer is composed of a long-chain fatty acid having 10 to 18 carbon atoms and an aliphatic alcohol having 1 to 5 carbon atoms. It is a long-chain fatty acid ester that is a reaction product or a long-chain fatty acid having 8 to 18 carbon atoms.

First, the first present invention will be described.

The support used in the present invention is not particularly limited as long as it is flexible and does not allow vegetation to pass therethrough. For example, cellulose acetate, ethyl cellulose, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer , Nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyethylene, polyurethane, polyvinylidene chloride, aluminum and the like. These may be used as a single eyebrow sheet (film) or as a laminate (laminate) of two or more sheets.

As the pressure-sensitive adhesive used in the present invention, those having pressure sensitivity to the skin at room temperature are used.For example, an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, or the like is preferable.c Even if these are solvent-based, Emulsion-based or hot-melt-based. The acryl-based pressure-sensitive adhesive is a pressure-sensitive adhesive mainly composed of alkyl (meth) acrylate, and is a functional monomer or multifunctional copolymer that can be copolymerized with alkyl (meth) acrylate. It may be a copolymer with a functional monomer.

Alkyl (meth) acrylates include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, and 2-ethylhexyl (meth) acrylate. Relate, n-octyl (meta) acrylate, dodecyl (meta) acrylate, and the like. When the number of carbon atoms in the alkyl group of the acrylate becomes smaller, Since the cohesive strength is improved but the cohesive strength is reduced, and if the cohesive strength is increased, the cohesive strength is reduced but the cohesive strength is reduced.

The functional monomers include (meth) acrylic acid, 2-hydroxyhydroxy (meth) acrylate, 2-hydroxypropyl (meth) acrylate, glycidyl methacrylate, N —Methylol (meth) acrylamide, N-butoxymethylacrylamide, etc.

If these functional monomers are copolymerized, they can be cross-linked by gold salts such as sodium hydroxide and calcium hydroxide, isocyanate, epoxy resin, melamine resin, urea resin, ammonium, etc. The cohesive force of the adhesive can be improved.

The polyfunctional monomer is co-polymerized to improve the cohesive strength of the pressure-sensitive adhesive. For example, 1,6-hexane glycol dimethacrylate, tetraethylene glycol diacrylate , Trimethylol pulp pan triacrylate, divinyl benzene, divinyl toluene, diaryl phthalate, diaryl maleate, diaryl adipate, diaryl glycolate, triallyl isocyanurate, diethylene glycol bisaryl carbonate, etc. Can be

The acrylic thread adhesive is an alkyl (meta) acrylate as a single S unit. And a copolymer containing a vinyl compound copolymerizable therewith. Examples of the vinyl compound include vinyl acetate, acrylonitrile, styrene, and N-vinyl-2-pyrrolid. Don and others are given.

In particular, from a copolymer of 55-95% by weight of 2-dimethylhexyl acrylate, 5-45% by weight of N-vinyl 2-pyrrolidone and 0-0.5% by weight of a multifunctional monomer. Acryl-based pressure-sensitive adhesives are preferred.

Further, as the acrylic pressure-sensitive adhesive, one comprising a copolymer containing a plurality of (meth) acrylic acid alkyl esters as monomer units is also used.

In particular, 2-ethylhexyl methacrylate 65 to 90% by weight, 2-ethylhexyl acrylate 5 to 30% by weight, dodecylmethacrylate 5 to 30% by weight, and a polyfunctional monomer — Preferred is an acrylic pressure-sensitive adhesive consisting of a copolymer of 0 to 0.5% by weight.

The acryl-based pressure-sensitive adhesive has an alkyl (meth) acrylate as a main component, and other components may be appropriately determined depending on required performance. Generally, a functional monomer is contained in the pressure-sensitive adhesive. 0% by weight or less, preferably 1 to 10% by weight is copolymerized. The S of the polyfunctional monomer is generally from 0 to 0.5% by weight in the adhesive. The Viel compound is generally copolymerized in the pressure-sensitive adhesive in an amount of 50% by weight or less, preferably 40% by weight or less.

Needless to say, a tackifier, a filler, and the like may be added to the acrylic pressure-sensitive adhesive within a pharmaceutically acceptable range.

The polymerization method of the acrylic pressure-sensitive adhesive is not particularly limited, and examples thereof include known methods such as solution polymerization and bulk polymerization.

The rubber-based pressure-sensitive adhesive used as one of the pressure-sensitive adhesives is preferably composed of a rubbery substance, a tackifier resin, a modifier such as an emulsifier, and an antioxidant.

Examples of the rubbery substance include cis-1,4-isoprene and the like. Natural rubber; synthetic rubber such as trans-1,4-isobrene: styrene-isoprene-styrene block copolymer, polyisobutylene, polyvinyl ether, polyurethane, polybutadiene, polystyrene Examples include styrene-butadiene copolymer, styrene-isoprene copolymer, styrene-isoprene-butylene block copolymer, and silicone rubber.

Examples of the tackifying resin include rosin, hydrogenated rosin, disproportionated rosin, polymerized rosin, rosin rosin-based resin such as rosin, α-binene, β-binene, and other terpene resins: Petroleum resins such as aliphatic, aromatic, alicyclic, and cross-linked resins; and coumarone-indene resins, alkyl phenol resins, and xylene resins.

Examples of the above iS softener include polybutene, process oil, liquid isobutylene, liquid boria acrylate, castor oil, cottonseed oil, palm oil, palm oil, beeswax, carnauba wax, lanolin and the like.

As the antioxidant, those commonly used are used.

The cinnamon absorption enhancer used in the present invention is a long-chain fatty acid ester, which is a reaction product of a long-chain fatty acid having a prime number of 10 to 1 and an aliphatic alcohol having 1 to 5 carbon atoms, or 8 carbon atoms. ~ 18 long-chain fatty acids. The long-chain fatty acid ester which is a reaction product of the above-mentioned long-chain fatty acid having 10 to 18 carbon atoms with an aliphatic alcohol having 1 to 5 carbon atoms is not particularly limited, and is, for example, ethyl laurate. Propyl laurate, isopropyl laurate, butyl laurate, ethyl myristate, propyl myristate, isopropyl myristate, butyl myristate, isobutyl myristate, isopentyl myristate And propyl noremitate, isopropylamine panolemitate, butyl palmitate, propyl stearate, isopropyl stearate, butyl stearate and the like. Preferably, 'isobrovir myristate. The long-chain fatty acid having 8 to 18 carbon atoms is not particularly limited, and includes, for example, capric acid, lauric acid, myristic acid, myristic acid, linoleic acid, linoleic acid, linolenic acid, Examples include palmitic acid, oleic acid, and stearic acid, and preferably decilenic acid.

The adhesive waste used in the present invention is composed of 100 parts by weight of the adhesive, 1 to 30 parts by weight of the transdermal absorption enhancer, and 1 to 30 parts by weight of ibudilast.

If the content of the percutaneous absorption enhancer is less than 1 part by weight, the required area of the above ibudilast must be secured by increasing the application area, so that the application property is poor and it is difficult to apply for a long time. When the content exceeds 30 parts by weight, the cohesive force of the pressure-sensitive adhesive is reduced and it becomes difficult to apply the pressure-sensitive adhesive.

If the ibudilast content is less than 1 part by weight, the necessary application amount of the above ibudilast must be secured by increasing the application area, so that the application property is high and it is difficult to apply for a long time. If the amount is more than 10 parts by weight, the cohesive force of the pressure-sensitive adhesive is reduced and it becomes difficult to apply the pressure-sensitive adhesive. The method for producing the transdermal patch of the present invention is not particularly limited, and examples thereof include known methods for producing a pressure-sensitive adhesive tape such as a solvent coating method, a hot melt coating method, and an emulsion coating method.

When the solvent coating method is performed, for example, the above-mentioned pressure-sensitive adhesive, the above-mentioned ibudilast, and the above-mentioned transdermal absorption enhancer are dissolved or dispersed in a solvent such as ethyl acetate, and the obtained solution is coated on a support and dried. Preferred is a method of coating on paper and drying, followed by transfer onto a support. The release paper may be used to protect the adhesive eyebrows until the time when the transdermal patch of the present invention is used.

The thickness of the pressure-sensitive adhesive layer is not particularly limited, and is preferably 30. ~ 200 jtz m. If it is less than 300 m, the required amount of the above ibudilast cannot be contained, and if it exceeds 200 m, the above ibudilast contained in the vicinity of the support of the adhesive brow is effectively used. Can not do it.

The transdermal patch of the present invention is preferably cut into a predetermined shape, collected and stored in a packaging material. The packaging material is not particularly limited as long as it does not transmit oxygen or does not easily transmit oxygen. For example, aluminum foil whose surface is coated with polyethylene terephthalate or polyethylene, polyvinylidene chloride And a polyvinyl chloride film. A second gist of the present invention is a transdermal absorption patch comprising a support having an adhesive eyebrow ridge layer, wherein the adhesive eyebrow comprises 100 parts by weight of an adhesive, and a transdermal absorption enhancer. 0.1 to 15 parts by weight & ibudilast 5 to 50 parts by weight, wherein the percutaneous absorption enhancer is composed of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms and monoethanolamine or diethanolamine. It is a fatty acid amide which is a reaction product of the above.

Hereinafter, the second present invention will be described.

The support used in the second present invention includes the support used in the first present invention. The pressure-sensitive adhesive used in the second present invention includes the pressure-sensitive adhesive used in the first present invention. Examples of the rubber-based pressure-sensitive adhesive that can be used as the pressure-sensitive adhesive include 100 parts by weight of a rubber elastic body, 2 to 3 oag parts of a tackifier resin, an appropriate amount of a modifier such as a drinking agent, and aging prevention Those consisting of agents are preferred. Examples of the rubber elastic body, the tackifying resin, the softening agent, and the antioxidant include those used in the first present invention. The skin absorption enhancer used in the second invention is a fatty acid amide, which is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with monoethanolamine or diethanolamine. It consists of

Examples of the fatty acid amide which is a reaction product of an aliphatic monocarboxylic acid having a carbon number of 10 to 14 and monoethanolamine or diethanolamine include, for example, monoethanolamide cabrate, laurine Acid monoethanolamide, capric acid diethanolamide, lauric acid diethanolamide and the like. Of these, monoethanolamide laurate and diethanolamide laurate are preferred.

The pressure-sensitive adhesive eyebrows used in the second transdermal patch of the present invention include 100 parts by weight of the adhesive, 0.1 to 15 parts by weight of the fatty acid amide, and 5 to 50 parts by weight of ibudilast. Part.

If the fatty acid amide content is less than 0.1 part by weight, the required application amount of ibudilast must be secured by increasing the application area, so that the application property is high and it is difficult to apply for a long time. When the amount exceeds 15 parts by weight, the adhesive strength of the above-mentioned pressure-sensitive adhesive decreases and it becomes difficult to apply the adhesive.Moreover, the adhesive migrates excessively to the skin and develops skin irritation and toxicity. Limited.

If the ibudilast content is less than 5 parts by weight, the required amount of ibudilast must be ensured by increasing the stoma of the pasted area, so that the pasting property is poor and it is difficult to adhere for a long time. If the amount is more than 10 parts by weight, the cohesive strength of the adhesive is reduced, making it difficult to apply the adhesive for a long period of time.

As the method for producing the transdermal patch of the second invention, the method for producing the transdermal patch of the first invention can be applied.

The second method of storing and storing the transdermal patch of the present invention includes the first method of storing and storing the transdermal patch of the present invention. In the second transdermal patch of the present invention, the fatty acid amide, which is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with monoethanolamine or diethanolamine, is obtained from ibudilast. By acting as an absorption enhancer, the skin of ibudilast when applied to the skin! * Improves permeability. As a result, an effective formulation can be obtained with a small-area preparation, the blood concentration gradually increases, it works for a long time, and side effects such as nausea and vomiting are suppressed. Pain can be reduced. Furthermore, it is easier to administer to children with bronchial asthma and elderly people with cerebrovascular disorder. A third aspect of the present invention is a transdermal absorption patch comprising a support and a pressure-sensitive adhesive layer laminated thereon, wherein the pressure-sensitive adhesive eyebrow comprises 100 parts by weight of an adhesive, and 100 parts by weight of silicic anhydride. Percutaneous absorption enhancer 25 to 100 parts by weight and ibudilast 1 to 40 parts by weight, wherein the percutaneous absorption enhancer has a carbon number of 10 to 18 Is a fatty acid ester, which is a reaction product of a fatty acid with 1-5 aliphatic alcohols.

Hereinafter, the third present invention will be described.

The support used in the third present invention includes the support used in the first present invention. The pressure-sensitive adhesive used in the third invention includes the pressure-sensitive adhesive used in the first invention.

The silicic anhydride used in the third aspect of the present invention is not particularly limited, and is, for example, one composed of silicon oxide, the surface of which is composed of hydrophilic silicic anhydride or silicon oxide covered with a hydroxyl group. Hydrophobic silicic anhydride whose surface is greatly degraded by dimethylsilanol. These may be used alone or in combination of two or more. The diameter of the silicic anhydride is preferably from 0.01 to 10 m.

The skin-absorbing patch used in the third invention has 10 to 18 carbon atoms. It is composed of a long-chain fatty acid ester which is a reaction product of a chain fatty acid and an aliphatic alcohol having 1 to 5 carbon atoms. Examples of the long fatty ester include a fatty acid having a Ginseng number of 10 to 18 used in the present invention and a fatty acid having a carbon number of 1 to 18.

And long fatty acid esters, which are reaction products with aliphatic alcohols of No. 5.

The pressure-sensitive adhesive layer used in the third transdermal patch of the present invention comprises: 100 parts by weight of the pressure-sensitive adhesive, 100 to 40 parts by weight of silicic anhydride, 25 to 50 parts by weight of the percutaneous absorption enhancer. It is composed of 100 parts by weight and 1 to 40 parts by weight of ibudilast.

If the above silicic anhydride content is less than 10 parts by weight, it is not possible to impart sufficient cohesive force to the pressure-sensitive adhesive layer, which causes stringing and adhesive residue, and if it exceeds 40 parts by weight, Since the adhesiveness is reduced and the sticking property is deteriorated, the content is limited to the above range.

If the ibudilast content is less than 1 part by weight, the application area must be increased to secure the required dose of K ibudilast, so that the application property is poor and it is difficult to apply for a long time. When the amount exceeds 25 parts by weight, the cohesive force of the adhesive decreases and the application becomes difficult.Therefore, the content is limited to the above range. In addition, the required dosage of the above ivudilast must be ensured, so that the sticking property is poor and it is difficult to stick for a long time, and if it exceeds 100 parts by weight, the cohesive force of the pressure-sensitive adhesive is reduced. It is limited to the above range because it will lower and make it difficult to attach.

As the third method for producing the transdermal patch of the present invention, the method for producing the transdermal patch of the first present invention can be applied.

The third method of storing and storing the transdermal patch of the present invention includes the method of storing and storing the transdermal patch of the first present invention. Brief description of drawings

FIG. 1 is a perspective view of the diffusion cell used in the skin transitivity test of Examples 11 to 11 and Comparative Examples 11 to 11. 1 represents a diffusion cell. 2 represents a receptor tank. 3 represents a donor tank. 4 indicates an opening. 5 represents a flange. 6 indicates a flange. 7 represents a sample ring. 8 represents peel / f piece. 9 represents a magnetic stirrer. Example

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 11

Acrylate 2—ethylhexyl (hereinafter referred to as “E HA”) 36.4 z (10 m 0 1%), dodecyl methacrylate 50 · 2 g (10 m 0 1, methanol) The acid 2—ethylhexyl 3 13.3 g (80 mol%) and the dimethacrylic acid 1,6—hexamethylene glycol 52 mg (0.0 double 重%) The solution was charged into a separable flask equipped with a cooling device, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight The solution was heated to 60.C under a nitrogen atmosphere, and lauroyl peroxide 2 was added. g was dissolved in 100 g of cyclohexane, the solution was divided into 10 parts, and the i was added to separable flask to initiate the polymerization.After the polymerization was started, the remaining 9 was added at hourly intervals. After the start of the reaction to adjust the viscosity, polymerization was carried out while adding 20 g of ethyl acetate once or twice every two hours, An acrylic adhesive solution having a concentration of 35% by weight (hereinafter referred to as "acrylic adhesive A") was obtained.

Acrylic pressure-sensitive adhesive A 100 weight parts (solid content), ibudilast 14 weight parts, isobropir myristate 13 weight parts, solid content concentration 25 weight% Then, ethyl acetate was added thereto, and the mixture was uniformly mixed with a dissolver to obtain a pressure-sensitive adhesive composition solution. The resulting solution was applied on a silicon-treated polyethylene terephthalate film (48 m thick) and dried in a microwave oven at 60 for 30 minutes to form an 80 βm thick adhesive layer. Then, a 38-meter-thick polyethylene terephthalate polyethylene mono-vinyl acetate copolymer (hereinafter referred to as “PET-EVA”) is transferred to the EVA side of the laminated film, and the first eyebrow is transferred. To obtain the transdermal patch of the invention

0

Example 11

To 100 parts by weight of the acrylic adhesive A (100 parts by weight) (solid content), 30 parts by weight of ibudilast and 5 parts by weight of isoprovir myristate were added and mixed, and the solid content was reduced to 25% by weight. _C ) A transdermal patch was obtained in the same manner as in Example 1-1 except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate so that

7 parts by weight of ibudilast and 25 parts by weight of isoprovir myristate were added to the acrylic adhesive A100 weight S part (solid content) and mixed, and the solid content was further reduced to 25% by weight. except that the addition of acetic acid Echiru adjust the pressure-sensitive adhesive composition solution to a, _c example 1 one 4 to provide a percutaneous patch in the same manner as in example 1 one 1

13 parts by weight of ibudilast and 6 parts by weight of decilenic acid are added to 10 parts by weight of the acrylic adhesive A (D) (solid content) and mixed, and the solid content is further adjusted to 25% by weight. A transdermal patch was obtained in the same manner as in Example 11 except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate.

Example 11

To 100 parts by weight of the acrylic pressure-sensitive adhesive A (solids), 30 parts by weight of ibudilast and 3 parts by weight of pendecylenic acid were added and mixed. A transdermal patch was obtained in the same manner as in Example 11-11, except that the pressure-sensitive adhesive composition solution was adjusted by adding ethyl acetate to a concentration of 0.1% by weight.

Example 11

To 100 parts by weight of the acrylic pressure-sensitive adhesive A (solids), 7 parts by weight of ibcillast and 13 parts by weight of decilenic acid are added and mixed, and the acetic acid is further adjusted to a solids concentration of 25% by weight. A transdermal patch was obtained in the same manner as in Example 11 except that the adhesive composition solution was prepared by adding ethyl.

Example 11

EHA 302 g (65 mo 1%) N-vinylpyrrolidone 98 g (35 m 0 1%) and dimethacrylic acid 1,6-hexamethylene glycol 40 mg (0.02 The weight was charged to a separable flask with a stirrer and a condenser, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight.

This solution was heated to 60 ° C under a nitrogen atmosphere, and a solution of 2 g of lauroyl peroxide dissolved in 100 g of cyclohexane was divided into 10 parts. Started the match. After the start of the polymerization, the remaining 9 was added at hourly intervals, and the reaction was carried out for 2 hours. After the start of the reaction for viscosity adjustment, polymerization was carried out while adding 20 g of ethyl acetate twice every two hours, and an acrylic pressure-sensitive adhesive having a solid content of 35% by weight (hereinafter, referred to as “ Acrylic adhesive B).

Ethyl acetate was added to 100 parts by weight (solid content) of the above-mentioned acrylic pressure-sensitive adhesive B so as to give 150 parts by weight of ibudilast, 7 parts by weight of isopropyl myristate, and a solids concentration of 30% by weight. Then, a pressure-sensitive adhesive composition solution was obtained by uniformly mixing with a dissolver. Using the obtained solution, the adhesive layer was formed on the EVA side of the PET-EVA laminated film in the same manner as in Example 11 to obtain the first transdermal patch of the present invention. Was. Example 1-8

To 100 parts by weight of the acrylic pressure-sensitive adhesive B (solids), 16 parts by weight of ibudilast and 4 parts by weight of decilenic acid are added and mixed, and the solid content is further adjusted to 25% by weight. A dermal absorption patch was obtained in the same manner as in Example 11 except that ethyl acetate was added to the mixture to prepare a pressure-sensitive adhesive composition solution.

Example 11

Styrene-Isoprene-Styrene block copolymer (Nur Kagaku Co., Ltd., Califrex TR 1107) 14.6 g, Polybutene (Nisseki Kagaku Co., HV-300) 4.9 _g , 41.2 _{g of} an alicyclic saturated hydrocarbon (Alcon P-70) manufactured by Arakawa Chemical Industries, Ltd. as a tackifier resin and 36.3 g of liquid paraffin are mixed uniformly. A rubber-based adhesive (hereinafter referred to as “rubber-based adhesive A”) was obtained.

To 100 parts by weight (solid content) of the rubber-based pressure-sensitive adhesive A, 18 parts by weight of ibudilast and 6 parts by weight of isopropyl myristate are added and mixed, and the solid content is further reduced to 25 parts by weight. A transdermal patch was obtained in the same manner as in Example 11 except that the solution of the pressure-sensitive adhesive composition was prepared by adding hexane to the mouth as described above.

Comparative Example 11

Example 1 except that no isopropyl myristate was added.

A transdermal patch was obtained in the same manner as in 1.1.

Comparative Example 11

A transdermal patch was obtained in the same manner as in Example 1-2, except that no isoprovir myristate was added at all.

Comparative Example 11

A percutaneous absorption patch was obtained in the same manner as in Example 1-3, except that no isobromopropyl myristate was added. Comparative Example 11

A percutaneous absorption patch was obtained in the same manner as in Example 17 except that no isobromopropyl myristate was added.

Comparative Example 11

A transdermal patch was obtained in the same manner as in Example 19-19, except that no isoprovir myristate was added.

Skin I »Permeability test

The percutaneous absorption patches obtained in Examples 11 to 11 and Comparative Examples 1 to 1 to 15 were measured for the amount of skin permeation (m) using the diffusion cell 1 shown in FIG. . The diffusion cell 1 is formed of a bottomed cylindrical receptor tank 2 and a bottomed cylindrical donor tank 3 disposed on the tank 2. An opening 4 is provided at the center of the bottom wall of the donor tank 3, and the bottom wall extends in the peripheral direction and a flange 5 is provided. A flange 6 is provided at an upper portion of the receiver tank 2, and a laterally protruding sampling blob ⁷ is attached to a side wall. The flange 5 and the flange 6 are overlapped facing each other, and the one-toner tank 3 and the receiver tank 2 are stacked airtightly and concentrically. A magnetic stirrer 9 is placed inside the receiver tank 2.

After a hairless mouse (6 weeks old) was sacrificed by cervical dislocation, the back skin was immediately separated and the subcutaneous fat and muscle layer were removed to obtain a skin piece 8 of about 5 cm × 5 cm. The obtained skin piece 8 was sandwiched between the flanges 5 and 6 of the diffusion cell 1, and the opening 4 of the donor tank 3 was completely closed with the skin piece 8. The obtained sample was cut into a circle (3.1 cm ² ) and attached to the center of the skin piece 8 so that the adhesive layer was in contact with the skin β piece 8.

Receptor tank 2 was filled with the receptor solution, placed in a thermostat kept at a temperature of 37 ° C., and stirred by rotating magnet * stirrer 9 with a magnet stirring device. Examination started 24 o'clock after the cabinet, T / JP95 / 01011

1 6

One mL of the sevtor solution was collected, and the amount of drug in the collected receptor solution was measured by high-speed chromatography, and the results are shown in Table 1. When collecting the receptor liquid, the receptor liquid was replenished after collection. The test was performed with n = 3, and the average was calculated.

Incidentally, the receptor _{solution, N a H z PO, 5} X 1 0 - 'mo 1, at HPQ, 2 1 0 "1 mo N a C 1 1. 5 xl 0 -'mo l and Gentama Lee Shin 1 0 mg was dissolved in distilled water 5 0 0 mL, 0. IN- N a OH after adjusting the p H to 7.2 aqueous solution was added, _c table was 1 0 0 O mL with distilled water 1

HWJ1-1 535

590

J1 -3 440

510

580

430

¾WJl-7 490

500

370

1: Ver. 1-2 440

Jt «Example] — 3 180

H «^ Jl-4 340

iWS example 1—5 340 Example 2-1

100 parts by weight of the acrylic pressure-sensitive adhesive A as a solid content, 11.5 parts by weight of ibudilast, 3.5 parts by weight of diethanolamide laurate, and furthermore, a solid concentration of 2 parts by weight of ethyl ethyl acetate It was added so as to be 5% by weight, and the whole was made uniform to prepare a coating liquid. This noe solution was applied on a release paper treated with siliconized polyethylene terephthalate having a thickness of 48 to a dry thickness of 80 / m, dried for 60 minutes and then dried in a gear oven for 30 minutes. A 38 / m-thick support (a laminate of polyethylene terephthalate and an ethylene-vinyl acetate copolymer (hereinafter referred to as “PET-EVA”)) was laminated to form a skin-absorbing patch.

Example 2-2

Example 11 was carried out in the same manner as in Example 21 except that acryl-based pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 25 parts by weight of ibudilast, and 1.2 parts by weight of diethanolamide laurate. This was used as a skin patch.

Example 23

Example 21 was the same as Example 21 except that the acrylic pressure-sensitive adhesive A was mixed in a ratio of 100 parts by weight as solids, 5.8 parts by weight of ibudilast, and 9.2 parts by weight of ethanol laurate. This was performed to obtain a transdermal patch. Example 2-4

100 parts by weight of the acrylic pressure-sensitive adhesive B as a solid content, 11.5 parts by weight of ibudilast, and 3.5 parts by weight of diethanolamide laurate were added, and ethyl acetate was further added to the solid content concentration. Was adjusted to 3% of Offl, and the whole was made uniform to obtain a coating liquid. This coating liquid was applied to a 48-zm-thick PET film that had been treated with silicone, so that the thickness after drying was 80 m, and then 60. C, dried in a gear oven for 30 minutes, P E T— with a thickness of 38 jum

EVA was attached to obtain a transdermal patch. Example 21

100 parts by weight of rubber-based pressure-sensitive adhesive A as solids, 11.5 parts by weight of ibudilast, 3.5 parts by weight of diethanolamide laurate; blended in a ratio of SSI5, and cyclohexane as solids The concentration was 25%], and the whole was made uniform to obtain a coating solution. This S solution was applied on a separator paper treated with a 48 / m-thick PET of silicon so that the thickness after drying was 80 m, then dried for 60 and 30 minutes in a gear oven. Then, PET-EVA having a thickness of 38; zm was bonded to obtain a transdermal patch.

Comparative Example 2 1

A transdermal patch was prepared in the same manner as in Example 2-1 except that diethanolamide laurate, which was an absorption enhancer, was omitted.

Comparative Example 2 — 2

A transdermal patch was prepared in the same manner as in Example 22 except that diethanolamide laurate, which was an absorption enhancer, was omitted.

Comparative Example 2-3

A transdermal patch was prepared in the same manner as in Examples 2-3 except that the absorption enhancer jetanolamide laurate was omitted.

Comparative Example 2 — 4

A transdermal patch was prepared in the same manner as in Example 2-4, except that diethanolamide laurate, which was an absorption enhancer, was omitted.

Comparative Examples 2-5

A transdermal patch was prepared in the same manner as in Examples 2-5, except that diethanolamide perillanate, which was an absorption enhancer, was omitted.

Evaluation

The abdomen of a guinea pig (6 weeks t¾, male) was shaved, and the transdermal patches of Example 2 — 1-2 — 5 and Comparative Example 2 — 1-2 — 5 (3.1 cm ² Punch Was affixed. Twenty-four hours later, the transdermal patch was separated, immersed in tetrahydrofuran, and the drug remaining in the transdermal patch was extracted. The residual S of the drug was measured by a commercial chromatographic method, and its internalization was calculated from the difference from the initial drug dose. 3. Average of 1 4 cm ³ shifts per (n = 3) were shown in Table 2.

Table 2

Example 3-1

Acrylate-based agent A 100 weight: fi part (solid content) is added with silicic anhydride [Kemoto Aerosil Co., Ltd. “Aerosil 200”) 22 weight parts, ibudilast 17 weight parts Then, 50 parts by weight of isopropyl myristate and ethyl acetate were added so that the solid content concentration became 25% by weight, and the mixture was uniformly mixed with a dissolver to obtain a coating liquid. The obtained liquid is used for the silicone-treated po Liethyrene terephthalate film (thickness 48 / m) 塗布 Applied on release paper, dried in a gear oven at 60 to 30 minutes to form an 80 m thick adhesive layer, then thickness 3 8 m polyethylene terephthalate-ethylene-vinyl acetate copolymer (hereinafter referred to as “PET-EVA”) The adhesive layer is placed on the EVA side of the film laminate. An absorption patch was obtained.

Example 3-2

To 100 parts by weight of the acrylic pressure-sensitive adhesive A (solid content), 20 parts by weight of silicic anhydride, 14.5 parts by weight of ibudilast and 30 parts by weight of isopropyl myristate were added and mixed. A skin-absorbing patch was obtained in the same manner as in Example 3-1 except that ethyl acetate was added to adjust the coating solution so that the solid concentration became 25% by weight.

Example 3-3

Acrylic pressure-sensitive adhesive A 100 parts (solid content), 29 parts by weight of silicic anhydride, 20.4 parts by weight of ibudilast, and isoprovir myristate 81.6 parts Parts by weight, mixed, and further adjusted to a coating solution by adding ethyl acetate to a solid concentration of 25% by weight in the same manner as in Example 3-1. I got

Comparative Example 3-1

A transdermal patch was obtained in the same manner as in Example 3-1 except that silicic anhydride and isopropyl myristate were not added at all.

Comparative Example 3-2

A transdermal patch was obtained in the same manner as in Example 3-2, except that no silicic anhydride was added.

Comparative Example 31

Acrylic adhesive A 100 parts by weight (solid content) and silica anhydride 50 parts by weight / JP95 / 01011

twenty one

Parts, 20 parts by weight of ibudilast and 55 parts by weight of isopropyl myristate were added and mixed, and ethyl acetate was further added so that the solid content concentration became 25% by weight, to thereby prepare a Noe liquid. A dermal absorption patch was obtained in the same manner as in Example 3-1.

The following performance evaluations were performed on the transdermal patches obtained in the above Examples and Comparative Examples, and the results are shown in Table 3.

(1) Skin transfer

The abdomen of a guinea pig (for 6 weeks) was shaved, and a sample obtained by punching the above-mentioned transdermal patch into a circular (area: 3.14 cm ² ) having a diameter of 2 cm was applied.

Twenty-four hours later, the sample was washed and immersed overnight in a tetrahydrofuran solvent to extract the drug remaining in the sample. Next, the amount of the drug in the solvent was measured by a high-speed liquid chromatographic method, and the skin transfer amount was calculated from the difference from the initial drug content of the sample Φ. The test was performed with the number of samples n = 3, and the average value is shown in Table 3;

(2) Stickiness

ゥ Sharp the back of a heron [8 weeks old,], cut the above-mentioned transdermal patch into a 2 cm diameter circle (area 3.14 cm ² ), apply the sample for 24 hours, After observing the presence / absence, the film was separated, and at the time of release, the presence of glue residue and stringing was observed.

If no peeling occurred after pasting for 24 hours and no glue residue or stringing occurred at the time, it was judged to be “good” during removal.

In Comparative Examples 3 to 3, the obtained transdermal patch was not adhesive and could not be applied to the skin surface. Table 3

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ADVANTAGE OF THE INVENTION According to the transdermal patch of the present invention, the percutaneous permeability of ibudilast is enhanced, an effective skin transfer amount can be obtained with a small-sized preparation, and the blood concentration of ibudilast can be reduced. Since it can rise quickly and suppress side effects such as nausea and vomiting, it can be suitably used as a remedy for bronchial asthma, cerebrovascular injuries, etc. for children and seniors.

Claims

The scope of the claims

1. A skin-absorbing patch obtained by applying an adhesive to a support, wherein the adhesive layer comprises 100 parts by weight of an adhesive, and a skin-absorbing accelerator of 1 to 30 parts by weight. It is composed of 1 to 30 parts by weight of bibi blast and the skin absorption enhancer is a reaction product of a long-chain fatty acid having 10 to 18 carbon atoms and an aliphatic alcohol having 1 to 5 carbon atoms. A transdermal patch comprising a long-chain fatty acid ester or a long-chain fatty acid having 8 to 18 carbon atoms.

2. A transdermal absorption patch comprising a support and an adhesive layer laminated thereon, wherein the adhesive layer comprises 100 parts by weight of an adhesive and 0.1 to 15 parts by weight of a transdermal absorption enhancer. And ibudilast in an amount of 5 to 50 weight percent, wherein the percutaneous absorption enhancer is a reaction product of an aliphatic monocarboxylic acid having 10 to 14 carbon atoms with monoethanolamine or ethanolamine. A skin-absorbing patch characterized by being a fatty acid amide.

3. A transdermal absorption patch comprising an adhesive layer on a support, wherein the adhesive layer comprises 100 parts by weight of an adhesive, 100 to 40 parts by weight of silicic anhydride, Percutaneous absorption enhancer 25 to 100 parts by weight and ibudilast 1 to 40 parts by weight, wherein the percutaneous absorption enhancer has a long-chain fatty acid having 10 to 18 carbon atoms and a carbon number of 1 to 5 A transdermal patch, characterized in that it is a long-chain fatty acid ester which is a reaction product with an aliphatic alcohol.