阅读说明：本技术 含有阿塞那平的贴剂 (Patch containing asenapine ) 是由 行弘政树 高木祐香 道中康也 于 2019-09-25 设计创作，主要内容包括：本发明提供了具有优异缓释性能的含阿塞那平的贴剂,所述贴剂使用有硅酮类粘合基剂并因此具有增加的皮肤渗透性。本发明涉及具备支撑体及粘合剂层的贴剂,粘合剂层包含有阿塞那平和/或其药学上可接受的盐、硅酮类粘合基剂以及控释剂,其中,从达到最大皮肤渗透速度的时间至24小时,阿塞那平的最大皮肤渗透速度与最小皮肤渗透速度之比小于1.62。(The present invention provides an asenapine-containing patch having excellent sustained-release properties, which uses a silicone-based adhesive base and thus has increased skin permeability. The present invention relates to a patch preparation comprising a support and an adhesive layer containing asenapine and/or a pharmaceutically acceptable salt thereof, a silicone-based adhesive base and a controlled-release agent, wherein the ratio of the maximum skin permeation rate to the minimum skin permeation rate of asenapine is less than 1.62 from the time of reaching the maximum skin permeation rate to 24 hours.)

1. A patch preparation comprising a support and an adhesive layer,

the adhesive layer comprises asenapine and/or pharmaceutically acceptable salt thereof, a silicone adhesive base agent and a controlled release agent,

the ratio of the maximum skin permeation rate of asenapine to the minimum skin permeation rate from the time to reach the maximum skin permeation rate to 24 hours is less than 1.62.

2. The patch according to claim 1, wherein the silicone-based adhesive base is an amine-compatible silicone-based adhesive base.

3. The patch according to claim 1 or 2, wherein the silicone adhesive base comprises one or more selected from the group consisting of a high-tack amine-compatible silicone adhesive base, a medium-tack amine-compatible silicone adhesive base, and a low-tack amine-compatible silicone adhesive base.

4. The patch of claim 3, wherein the silicone-based adhesive base comprises a high-tack amine-compatible silicone-based adhesive base and a medium-tack amine-compatible silicone-based adhesive base.

5. The patch according to any one of claims 1 to 4, wherein the content of the silicone-based adhesive base in the adhesive layer is 72 to 96 mass%.

6. The patch according to any one of claims 1 to 5, wherein the controlled-release agent is at least one selected from the group consisting of oleic acid, magnesium aluminum silicate, a copolymer of methacrylic acid and methacrylic acid ester, N-methyl-2-pyrrolidone, and a (meth) acrylate (co) polymer.

7. The patch according to claim 6, wherein the controlled-release agent is at least one selected from the group consisting of oleic acid and magnesium aluminum silicate, and the content in the adhesive layer is 2.5 to 7.5 mass%.

8. The patch according to claim 6, wherein the controlled-release agent is at least one selected from the group consisting of a copolymer of methacrylic acid and methacrylic acid ester and N-methyl-2-pyrrolidone, and the content of the adhesive layer is 1.0 to 5.0 mass%.

9. The patch according to claim 6, wherein the controlled-release agent is at least one selected from the group consisting of (meth) acrylate (co) polymers, and the content in the adhesive layer is 12 to 25.0 mass%.

Technical Field

The present invention relates to a patch containing asenapine in an adhesive layer and a method for producing the same.

Background

Asenapine is known as a therapeutic agent for central nervous system diseases such as schizophrenia, and sublingual tablets (sylvest (registered trademark) sublingual tablet and Saphris (registered trademark) sublingual tablet) are commercially available. Currently, dosage forms other than sublingual tablets are not sold.

The adhesive patch containing asenapine is described in, for example, patent documents 1 to 5, and intensive studies have been made on an adhesive patch using a rubber-based adhesive base or an acrylic-based adhesive base.

An asenapine-containing adhesive patch in which a polysiloxane adhesive and a polyacrylate adhesive are combined is described in, for example, patent document 6, particularly in example 14.

Documents of the prior art

Patent document

Patent document 1: international publication No. 2014/017593

Patent document 2: international publication No. 2014/017594

Patent document 3: international publication No. 2014/017595

Patent document 4: international publication No. 2017/018321

Patent document 5: international publication No. 2017/018322

Patent document 6: international publication No. 2010/127674

Disclosure of Invention

The present inventors have found that, in the course of studying an asenapine-containing adhesive patch, an adhesive patch using asenapine and a silicone-based adhesive base has higher skin permeability than an adhesive patch using a rubber-based adhesive base, and on the other hand, the quick-acting property tends to be high, and therefore an adhesive patch having excellent sustained-release properties is required.

Accordingly, an object of the present invention is to provide an asenapine-containing adhesive patch having high skin permeability and excellent sustained release properties by using a silicone-based adhesive base.

As a result of intensive studies to solve the problems, the present inventors have found that an asenapine-containing adhesive patch which is excellent in sustained release property while improving skin permeability of an adhesive patch containing asenapine and a silicone-based adhesive base can be provided by adjusting the ratio of the maximum skin permeation rate of asenapine to the minimum skin permeation rate from the time of reaching the maximum skin permeation rate to 24 hours within a predetermined range, and have completed the present invention as a result of further studies. That is, the present invention relates to the following.

[1] A patch preparation comprising a support and an adhesive layer,

the adhesive layer comprises asenapine and/or pharmaceutically acceptable salt thereof, a silicone adhesive base agent and a controlled release agent,

the ratio of the maximum skin permeation rate of asenapine to the minimum skin permeation rate from the time to reach the maximum skin permeation rate to 24 hours is less than 1.62.

[2] The patch according to [1], characterized in that the silicone-based adhesive base is an amine-compatible silicone-based adhesive base.

[3] The patch according to [1] or [2], wherein the silicone adhesive base comprises one or more selected from the group consisting of a high-viscosity amine-compatible silicone adhesive base, a medium-viscosity amine-compatible silicone adhesive base, and a low-viscosity amine-compatible silicone adhesive base.

[4] The patch according to [3], characterized in that the silicone-based adhesive base comprises a high-viscosity amine-compatible silicone-based adhesive base and a medium-viscosity amine-compatible silicone-based adhesive base.

[5] The adhesive patch according to any one of [1] to [4], wherein the content of the silicone-based adhesive base in the adhesive layer is 72 mass% to 96 mass%.

[6] The patch according to any one of [1] to [5], wherein the controlled-release agent is at least one selected from the group consisting of oleic acid, magnesium aluminum silicate, a copolymer of methacrylic acid and methacrylic acid ester, N-methyl-2-pyrrolidone, and a (meth) acrylate (co) polymer.

[7] The patch according to [6], wherein the controlled-release agent is at least one selected from the group consisting of oleic acid and magnesium aluminum silicate, and the content in the adhesive layer is 2.5 to 7.5 mass%.

[8] The patch according to [6], wherein the controlled-release agent is at least one selected from the group consisting of a copolymer of methacrylic acid and methacrylic acid ester and N-methyl-2-pyrrolidone, and the content of the adhesive layer is 1.0 to 5.0 mass%.

[9] The patch according to [6], wherein the controlled-release agent is at least one selected from the group consisting of (meth) acrylate (co) polymers, and the content in the adhesive layer is 12 to 25.0 mass%.

According to the present invention, in a patch preparation comprising a silicone-based adhesive layer containing asenapine and/or a pharmaceutically acceptable salt thereof, high skin permeability and excellent sustained release can be achieved. Therefore, a patch that can be involved in having a longer application time can be provided.

Detailed Description

The adhesive patch of the present invention includes, for example, a support and an adhesive layer laminated on the support.

The support may be any support as long as it can hold the shape of the adhesive patch, particularly the adhesive layer. The material of the support includes synthetic resins such as polyamide, polyester, cellulose derivative, polyurethane, and the like, such as polyethylene, polypropylene, polybutadiene, ethylene-vinyl chloride copolymer, polyvinyl chloride, nylon (trade name), and the like. The support is in the form of a fabric such as a film, a sheet-like porous body, a sheet-like foam, a woven fabric, a knitted fabric, a nonwoven fabric, or the like, a laminate thereof, or the like. The thickness of the support is not particularly limited, but is preferably about 2 to 3000 μm.

The adhesive layer comprises asenapine and/or a pharmaceutically acceptable salt thereof, a silicone-based adhesive base, and a controlled release agent. The patch preparation of the present invention may further contain, in addition to asenapine and/or a pharmaceutically acceptable salt thereof, a silicone-based adhesive base and a controlled-release agent, other additives such as an antioxidant, a tackifier resin, a plasticizer, an absorption enhancer, a dissolving agent, a crosslinking agent, a preservative, a filler, a storage agent and a perfume, as required.

Asenapine according to the present invention is a compound known as trans-5-chloro-2-methyl-2, 3, 3a, 12 b-tetrahydro-1H-dibenzo [2, 3: 6, 7 oxetane [4, 5-c ] pyrrole compounds. Asenapine has a plurality of optical isomers, and any optical isomer may be used, and a mixture of optical isomers such as a racemate may be used. The acid to be added to asenapine is not particularly limited as long as it is a pharmaceutically acceptable acid. The acid addition salts of asenapine may be anhydrous or hydrated.

Acids in the acid addition salts of asenapine include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, succinic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid, benzoic acid, and the like. For example, asenapine maleate is marketed as sublingual tablets (Sycrest (registered trademark) sublingual tablets and Saphris (registered trademark) sublingual tablets).

The desalting agent may be any agent which can convert an acid addition salt of asenapine into asenapine free base by a salt exchange reaction with the acid addition salt of asenapine. That is, the desalting agent refers to a component that converts an acid addition salt of asenapine into asenapine free base. Examples of the desalting agent include alkali metal hydroxides, alkali metal salts, alkaline earth metal hydroxides, alkaline earth metal salts, and low-molecular amines. Examples of the alkali metal hydroxide include lithium hydroxide, sodium hydroxide, and potassium hydroxide, and one of them may be used alone, or two or more of them may be used in combination. The alkali metal salts include sodium carbonate, potassium carbonate, sodium bicarbonate, trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, tripotassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium lactate, sodium citrate, disodium tartrate, sodium hydrogen tartrate, sodium oleate, etc. The low-molecular amine is an amine having a molecular weight of 30 to 300, and examples thereof include monoethanolamine, diethanolamine, triethanolamine, isopropanolamine and diisopropanolamine. The desalting agent may be selected by taking into account the pKa of the acid added to the asenapine. When the desalting agent is sodium hydroxide or sodium acetate, the drug is less decomposed during the preparation of the patch.

The content of asenapine and/or a pharmaceutically acceptable salt thereof may be appropriately set by those skilled in the art, but is preferably 0.5 to 30 mass%, more preferably 1 to 20 mass%, even more preferably 1.5 to 12 mass%, and particularly preferably 2 to 10 mass%, in terms of asenapine free body, relative to the total amount of the adhesive layer.

In the patch of the present invention, the ratio of the maximum skin permeation rate of asenapine to the minimum skin permeation rate from the time of reaching the maximum skin permeation rate to 24 hours is preferably less than 1.62, more preferably 1 to 1.47, and particularly preferably 1 to 1.43. Sufficient sustained-release property can be ensured by making the ratio of the maximum skin permeation rate of asenapine to the minimum skin permeation rate from the time of reaching the maximum skin permeation rate to 24 hours less than 1.62.

The term "maximum skin permeation rate" refers to the maximum value among the numerical values of the permeation amount of asenapine per unit area of the skin-applied surface of the adhesive layer, which are converted per unit time, that is, the maximum value of the skin permeation rate of the drug per measurement time. The "minimum skin permeation rate from the time to reach the maximum skin permeation rate to 24 hours" means the minimum value among the numerical values of the permeation amount of asenapine per unit area of the skin application surface of the adhesive layer from the time to reach the maximum skin permeation rate to 24 hours in terms of unit time.

The silicone-based adhesive base is a compound having an organopolysiloxane skeleton.

Examples of the silicone-based adhesive base include a mixture of silicone rubber and silicone resin, and a product obtained by dehydrating and polycondensing the mixture in the presence of an alkali catalyst, etc., but a condensate of silicone rubber and silicone resin is preferable.

The silicone rubber constituting the silicone-based adhesive base is, for example, a long-chain polymer having hydroxyl groups at both ends of polyorganosiloxane. The organosiloxane unit of the silicone rubber is preferably a silicone rubber containing dimethylsiloxane as a main component.

The silicone resin constituting the silicone-based adhesive base is not particularly limited, but a three-dimensional silicate resin is preferable.

Examples of the silicone-based adhesive base include dimethylpolysiloxane, polymethylvinylsiloxane, and polymethylphenylsiloxane. Specific examples of the silicone-based adhesive base include MD series (Dow Corning) such as MD7-4502 silicone adhesive (silicone adhesive) and MD7-4602 silicone adhesive; such as BIO-PSA (registered trademark) 7-4301 silicone adhesive, BIO-PSA (registered trademark) 7-4302 silicone adhesive, BIO-PSA (registered trademark) 7-4201 silicone adhesive, BIO-PSA (registered trademark) 7-4202 silicone adhesive, BIO-PSA (registered trademark) 7-4101 silicone adhesive, BIO-PSA (registered trademark) 7-4102 silicone adhesive, BIO-PSA (registered trademark) 7-4601 silicone adhesive, BIO-PSA (registered trademark) 7-4602 silicone adhesive, BIO-PSA (registered trademark) 7-4501 silicone adhesive, BIO-PSA (registered trademark) 7-4502 silicone adhesive, BIO-PSA (registered trademark) 7-4401 silicone adhesive, BIO-PSA (registered trademark) 7-4402 silicone adhesive, BIO-PSA (registered trademark) 7-4100 silicone adhesive, BIO-PSA (registered trademark) 7-4200 silicone adhesive, BIO-PSA (registered trademark) 7-4300 silicone adhesive, BIO-PSA (registered trademark) 7-4400 silicone adhesive, BIO-PSA (registered trademark) 7-4500 silicone adhesive, BIO-PSA series (manufactured by Dow Corning Co., Ltd.) such as BIO-PSA (registered trademark) 7-4600 silicone adhesive, Dow Corning (registered trademark) 7-9800A, Dow Corning (registered trademark) 7-9800B, Dow Corning (registered trademark) 7-9700A, and Dow Corning (registered trademark) 7-9700B.

The silicone-based adhesive base of the present invention is preferably an amine-compatible silicone-based adhesive base. As the amine-compatible silicone-based adhesive base, for example, a silicone-based adhesive base in which, after condensation of polydimethylsiloxane and silicone resin, the remaining silanol groups are blocked by trimethylsilyl groups or the like upon condensation by trimethylsilyl groups or the like, and the concentration of the remaining silanol groups is suppressed is used.

Further, the silicone-based adhesive base can be roughly classified into three types of high tackiness, medium tackiness and low tackiness by tackiness, but in the present invention, these can be used in combination as appropriate.

Tack refers to the property of an adhesive that is understood to form a bond after being brought into contact with the surface of an adherend with very light force, according to jis k6800-1985 or ISO 6354.

The high-viscosity amine-compatible silicone-based adhesive base of the present invention is a silicone resin to silicone rubber weight ratio of about 52.5: 47.5(w/w) -57.5: 42.5(w/w), preferably 55: 45(w/w) of an amine-compatible silicone adhesive base. Examples of the highly adhesive amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4302 silicone adhesive and BIO-PSA (registered trademark) 7-4301 silicone adhesive.

The medium viscosity amine compatible silicone based adhesive base of the present invention is a silicone resin to silicone rubber weight ratio of about 57.5: 42.5(w/w) to 62.5: 37.5(w/w), preferably 60: 40(w/w) of an amine-compatible silicone adhesive base. Examples of the medium-tack amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4202 silicone adhesive and BIO-PSA (registered trademark) 7-4201 silicone adhesive.

The low viscosity amine compatible silicone-based adhesive base of the present invention is a silicone resin to silicone rubber weight ratio of about 62.5: 37.5(w/w) to 67.5: 32.5(w/w), preferably 65: 35(w/w) of an amine-compatible silicone adhesive base. Examples of the low-tack amine-compatible silicone adhesive base include BIO-PSA (registered trademark) 7-4102 silicone adhesive and BIO-PSA (registered trademark) 7-4101 silicone adhesive.

In another aspect, the present invention comprises a high tack amine compatible silicone based adhesive base and a medium tack amine compatible silicone based adhesive base. The mass ratio of the high-viscosity amine-compatible silicone-based adhesive base to the medium-viscosity amine-compatible silicone-based adhesive base can be appropriately determined, but is preferably 90: 10-10: 90, more preferably 87.5: 12.5-12.5: 87.5, even more preferably 75: 25-25: 75.

in another aspect, the invention comprises a high tack amine compatible silicone based adhesive base and a low tack amine compatible silicone based adhesive base. The mass ratio of the high-viscosity amine-compatible silicone-based adhesive base to the low-viscosity amine-compatible silicone-based adhesive base can be appropriately determined, but is preferably 90: 10-30: 70, more preferably 90: 10-50: 50, even preferably 87.5: 12.5-50: 50, even more preferably 75: 25-50: 50.

in the adhesive patch of the present invention, the content of the silicone-based adhesive base in the adhesive layer is preferably 60 to 98 mass%, more preferably 66 to 97 mass%, and particularly preferably 72 to 96 mass%.

The patch of the present invention contains a controlled-release agent in the adhesive layer.

The release-controlling agent is not particularly limited as long as it can control the release of asenapine and/or a pharmaceutically acceptable salt thereof in the silicone-based adhesive base, and preferable examples thereof include oleic acid, magnesium aluminum silicate, a copolymer of methacrylic acid and methacrylic acid ester, N-methyl-2-pyrrolidone, and a (meth) acrylic acid ester (co) polymer. Therefore, the controlled-release agent of the present invention is at least one selected from the group consisting of oleic acid, magnesium aluminum silicate, a copolymer of methacrylic acid and methacrylic acid ester, N-methyl-2-pyrrolidone, and a (meth) acrylate (co) polymer, and particularly preferably at least one selected from the group consisting of oleic acid, magnesium aluminum silicate, a copolymer of methacrylic acid and methacrylic acid ester, and a (meth) acrylate (co) polymer.

In the controlled-release agent, the content in the adhesive layer may be appropriately selected according to the kind thereof, but is preferably about 1.0 to 25.0 mass%.

When the controlled-release agent is at least one selected from the group consisting of oleic acid and aluminum magnesium silicate, the content in the binder layer is preferably 1.0 to 10.0 mass%, and particularly preferably 2.5 to 7.5 mass%.

When the controlled-release agent is at least one selected from the group consisting of a copolymer of methacrylic acid and methacrylic acid ester and N-methyl-2-pyrrolidone, the content in the adhesive layer is preferably 1.0 to 10.0 mass%, more preferably 1.0 to 5.0 mass%, and particularly preferably 1.0 to 3.0 mass%.

In the case where the release-controlling agent is at least one selected from the group consisting of (meth) acrylate (co) polymers, the content in the adhesive layer is preferably 1.0 to 25.0 mass%, and particularly preferably 12 to 25.0 mass%.

Examples of the copolymer of methacrylic acid and methacrylic acid ester include poly (methacrylic acid-co-methacrylic acid) and poly (methacrylic acid-co-ethacrylic acid). Specifically, Eudragit (registered trademark) L100 (manufactured by Evonik corporation) and the like can be cited.

The (meth) acrylate (co) polymer is, for example, a (co) polymer of one or two or more alkyl (meth) acrylates. Examples of the alkyl (meth) acrylate include butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, octyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, and decyl (meth) acrylate. And, (meth) acrylic acid means acrylic acid or methacrylic acid.

The (meth) acrylate (co) polymer may also be a (co) polymer formed from an alkyl (meth) acrylate (main monomer) and a comonomer. The comonomer may be a component copolymerizable with the alkyl (meth) acrylate. Examples of the comonomer include hydroxyalkyl (meth) acrylate, ethylene, propylene, styrene, vinyl acetate, N-vinylpyrrolidone, and (meth) acrylic acid amide. The comonomer may be used singly or in combination of two or more.

Examples of specific (meth) acrylate (co) polymers include DURO-TAK (registered trademark) 87-900A, DURO-TAK (registered trademark) 87-2510, DURO-TAK (registered trademark) 87-235A, DURO-TAK (registered trademark) 87-4287, DURO-TAK (registered trademark) 87-2287, and DURO-TAK (registered trademark) 87-2516 (trade name, manufactured by Henkel corporation, Henkel), and the like.

Examples of the antioxidant include tocopherol and an ester derivative thereof, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid (nordihydroguaiaretic acid), dibutylhydroxytoluene (BHT), Butylhydroxyanisole (BHA), citric acid, 2-mercaptobenzimidazole, and ethylenediaminetetraacetic acid. The antioxidant may be used singly or in combination of two or more.

The plasticizer may be any one that imparts flexibility to the adhesive layer. Examples of the plasticizer include mineral oils (e.g., paraffin oil, naphthene oil, and aromatic oil), animal oils (e.g., squalane and squalene), vegetable oils (e.g., olive oil, camellia oil, castor oil, tall oil, and peanut oil), silicone oils, dibasic acid esters (e.g., dibutyl phthalate and dioctyl phthalate), liquid rubbers (e.g., liquid polybutene and liquid polyisoprene), liquid fatty acid esters (e.g., isopropyl myristate, hexyl laurate, diethyl sebacate, and diisopropyl sebacate), polyhydric alcohols (e.g., diethylene glycol, polyethylene glycol, propylene glycol, and dipropylene glycol, triacetin, triethyl citrate, and crotonamide).

The absorption enhancer is an ingredient that regulates the skin permeability of asenapine and/or a pharmaceutically acceptable salt thereof. The absorption enhancer is not particularly limited as long as it is a compound generally considered to have an absorption enhancing action on the skin, and examples thereof include fatty alcohols such as isostearyl alcohol, fatty acids such as capric acid, fatty acid derivatives such as propylene glycol monolaurate, isopropyl myristate, isopropyl palmitate, and lauric acid diethanolamide, and glycols such as propylene glycol and polyethylene glycol. The absorption enhancer may be used alone or in combination of two or more.

The crosslinking agent is not particularly limited, and preferable examples thereof include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals and metal compounds.

The preservative is not particularly limited, and preferable examples thereof include ethyl paraben, propyl paraben, and butyl paraben. The filler is not particularly limited, and preferable examples thereof include calcium carbonate, magnesium carbonate, silicates (aluminum silicate, calcium silicate, magnesium silicate, and the like), and cellulose derivatives (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and the like).

Examples of the filler include aluminum hydroxide, calcium carbonate, magnesium carbonate, silicates (e.g., aluminum silicate and magnesium silicate), silicic acid, barium sulfate, calcium zincate, zinc oxide, and titanium oxide.

Examples of the storage agent include disodium ethylenediaminetetraacetate, sodium ethylenediaminetetraacetate, ethyl paraben, propyl paraben, and butyl paraben. The storage agent may be used alone or in combination of two or more.

In another aspect of the present invention, the mass of the adhesive layer is preferably 30 to 200g/m²More preferably 30 to 150g/m²Even more preferably 30 to 130g/m². If the mass is too small, problems such as deterioration of adhesiveness and difficulty in manufacturing may occur, and if the mass is too large, problems such as easy generation of cold flow and the like and deterioration of physical properties may occur.

Cold flow is the phenomenon whereby the adhesive flows and deforms at room temperature during storage or application. When cold flow occurs, the adhesive layer protrudes from the side surface of the adhesive patch where the support and the adhesive layer are laminated to the outside along the edge beyond the range covered by the support, and therefore the shape of the adhesive patch cannot be maintained, and problems such as adhesion of the protruding adhesive layer to the inner surface of the packaging material of the adhesive patch, influence on the stability with time of asenapine, decrease in skin permeability with decrease in the content of asenapine, difficulty in taking out the adhesive patch from the packaging material, and the like occur.

The patch may also include a release liner. The release liner is laminated on the side opposite to the support with respect to the adhesive layer. If a release liner is provided, it may be possible to reduce adhesion of dust and the like to the adhesive layer during storage.

The material of the release liner is not particularly limited, and a film generally known to those skilled in the art may be used. Examples of the material of the release liner include polyesters such as polyethylene terephthalate and polyethylene naphthalate; polyolefins such as polyethylene and polypropylene; films such as polyvinyl chloride and polyvinylidene chloride; a laminated film of high quality paper and polyolefin; such as a film of nylon (registered trademark), aluminum, or the like. The material of the release liner is preferably polypropylene or polyethylene terephthalate.

Next, an example of the method for producing the adhesive patch of the present invention will be described.

First, a mixture for forming an adhesive layer is prepared. The mixture for forming the adhesive layer is obtained by dissolving or dispersing the above asenapine and/or a pharmaceutically acceptable salt thereof, a silicone-based adhesive base, and other ingredients in a solvent using a mixer.

As the solvent, toluene, hexane, ethyl acetate, cyclohexane, heptane, butyl acetate, ethanol, methanol, xylene, isopropanol, or the like can be used. These are appropriately selected depending on the components to be dissolved or dispersed, and may be used singly or in combination of two or more.

Next, the obtained mixture for forming an adhesive layer may be directly spread on a support and dried to form an adhesive layer, and then, a release liner for protecting the adhesive layer is adhered to the adhesive layer or spread on a release-treated paper or film and dried to form an adhesive layer, the support is placed thereon, the adhesive is laminated and transferred onto the support to obtain a patch.

Examples

Example 1: preparation of Patches

The base agent and the drug shown in the table 1 are prepared1-20 of patch composed of substance concentration and additive. Further, asenapine (free form body) was added to each patch in an amount of 3.2 mass% based on the adhesive layer, and the mass of the adhesive was 100g/m²(set value).

Also, the meanings of abbreviations in table 1 are as follows.

Base agent

PSA 7-4102: BIO-PSA (registered trademark) 7-4102 Silicone adhesive (manufactured by Dow Corning Co., Ltd.)

PSA 7-4202: BIO-PSA (registered trademark) 7-4202 Silicone adhesive (manufactured by Dow Corning Co., Ltd.)

PSA 7-4302: BIO-PSA (registered trademark) 7-4302 Silicone adhesive (manufactured by Dow Corning Co., Ltd.)

Additive agent

L-100: eudragit (registered trademark) L100 (manufactured by winning and creating Co., Ltd.)

NMP: n-methyl-2-pyrrolidone

900A: DURO-TAK (registered trademark) 87-900A (made by Hangao Co., Ltd.)

2510: DURO-TAK (registered trademark) 87-2510 (manufactured by Hangao Co., Ltd.)

Example 2: in vitro skin penetration test

2.5cm in length²The patch of (3) was attached to the stratum corneum side of the skin removed from a hairless mouse, and was attached to a flow-through diffusion cell maintained at 32 ℃ so that the dermis side was on the receptor well side. In the experiment, solutions were collected every 4 hours while changing the phosphate buffered saline in the receptor wells. The concentration of the drug in the resulting liquid was measured by high performance liquid chromatography. Calculating the drug permeation amount of each time segment according to the concentration values, and calculating the maximum skin permeation speed Jmax (mu g/h/cm) based on the calculated skin permeation speed of the drug²)。

And, similarly, the minimum skin permeation rate (Jmin (μ g/h/cm) from the time to reach the maximum skin permeation rate (Tmax) to 24 hours was calculated²))。

The ratio of the maximum skin permeation rate to the minimum skin permeation rate from the time when the maximum skin permeation rate was reached to 24 hours (Jmax/Jmin (after Tmax to 24 hours)) was calculated, and the results are shown in table 1.

TABLE 1

When (patch 1), aluminum magnesium silicate (patches 2 to 4), Eudragit (registered trademark) L100 (patches 5 to 7), N-methyl-2-pyrrolidone (patches 8 to 10), DURO-TAK (registered trademark) 87-900A (patches 11 and 12), and DURO-TAK (registered trademark) 87-2510 (patches 13 and 14) were used as the additive, Jmax/Jmin (24 hours after Tmax) was less than 1.62, and Jmax/Jmin (24 hours after Tmax) was less than 1.43 in the patches 1 to 14 except for N-methyl-2-pyrrolidone (patches 8 to 10).