TW201713316A - Transdermal-absorption-type patch - Google Patents

Abstract

The present invention provides a transdermal-absorption-type patch containing a pharmacologically acceptable salt of solifenacin and having exceptional transdermal absorption properties, storage stability, and safety. The present invention pertains to a transdermal-absorption-type patch having a support and a drug-containing layer, wherein the drug-containing layer of the transdermal-absorption-type patch contains a pharmacologically acceptable salt of solifenacin and an inorganic base.

Description

Percutaneous absorption type patch

The present invention relates to a transdermal absorption type patch containing an pharmaceutically acceptable salt of solifenacin as an active ingredient.

Conventionally, the pharmaceutical administration method is a method of oral administration using a tablet, a capsule, a syrup, etc., but in recent years, it has been attempted to administer such drugs from the skin using a percutaneous absorption type patch. In addition to solving the problem of oral administration, the percutaneous absorption type patching agent has the advantages of reducing the number of administrations, improving compliance, ease of administration, and suspending, and thus is particularly expected to be used as a treatment for elderly and child patients. Effective drug administration.

Solinasin ((R)- Pyridin-3-yl(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate) is a muscarine with high affinity for the muscarinic M3 receptor. A receptor antagonist (Patent Document 1) is currently used as a therapeutic drug for hyperactive bladder. The currently used preparation is a lozenge of solifenacin succinate and an orally disintegrating tablet, and an oral preparation according to the trade name "VesiCare (registered trademark)" is a prescription for an overactive bladder patient.

It is known that patients with overactive bladder control drinking water from a daily basis, and because solifenacin is a drug that has a higher chance of taking an elderly person with reduced swallowing function, In contrast, transdermal absorption type patches are more suitable than oral administration.

Further, as a therapeutic medicine for overactive bladder, a percutaneous absorption type patch which is sold under the trade name "NEOXY (registered trademark) patch" by oxybutynin hydrochloride is currently used clinically, but it is high. It is expected that a side effect of dermatitis and erythema at the site of use (Non-Patent Document 1) can be found, and it is expected that a formulation having less odor and less skin irritation can be developed from the viewpoint of patient safety.

In the "Guidelines for Related Preparation Impurities in New Active Ingredient Pharmaceuticals" published by the Japan-US Joint Meeting of the United States and the United States, the United States Pharmaceuticals Association (ICH) describes the decomposition products in the preparations that appear in the stability test ( Thinking about impurities). Accordingly, when the amount of the pharmaceutical ingredient administered in a single day is 10 mg or more and less than 100 mg, it is necessary to confirm the safety of the decomposition product in the preparation, which is a decomposition product contained in the raw material medicine. The percentage is 0.5% or the decomposition product has a single daily intake of 200 μg. Therefore, in general, in the case of a 10 mg preparation, the percentage of the decomposition product to be produced is preferably 0.5% or less in the case where the safety of the decomposition product is not confirmed.

In the general formulation method of solifenacin, the solifenacin which is a main drug in the preparation is decomposed over time, and various methods for stabilization are proposed in order to suppress the formation of decomposition products in the preparation (Patent Document 2) 3, 4 and 5). However, these documents do not have a relevant record of the solifenacin stability of the percutaneous absorption type patch.

As a percutaneous absorption type patching agent containing solifenacin, Patent Document 6 proposes a percutaneous absorption type patching agent containing a solifenacin free body and a fatty acid ester as a transdermal absorption enhancer. Cloth), but the time stability of the patch is not described.

Further, the percutaneous absorption type patching agent proposed in Patent Document 7 contains a thermoplastic elastomer, a liquid component of more than 300 parts by weight based on 100 parts by weight of the thermoplastic elastomer, and an anti-biliary agent. The action of the overactive bladder treatment (Soliatin, darifenacin, etc.). However, Patent Document 7 does not describe the temporal stability of the patch.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] Japanese Patent No. 3014457

[Patent Document 2] Japanese Patent No. 4636445

[Patent Document 3] Japanese Patent No. 4816828

[Patent Document 4] Japanese Patent No. 5168711

[Patent Document 5] Japanese Patent No. 5177156

[Patent Document 6] WO2005/077364

[Patent Document 7] WO2013/081014

[Non-patent literature]

[Non-Patent Document 1] NEOXY (registered trademark) patch 73.5mg, pharmaceutical product interview version (interview form)

The present inventors evaluated the preservation stability by using a severe test for the solifenacin free body, and as a result, it was confirmed that the decomposition product increased with time (see Test Example 1). In this way, it is known that the ordinary storage method of the Solinasin free body will be decomposed over time. Therefore, when the solifenacin free body is used as a raw material medicine and a percutaneous absorption type patching agent is produced, the decomposition product contained in the raw material medicine is mixed in the preparation of the patching agent, and the decomposition product of the patching agent is obtained. The possibility that the product content exceeds 0.5%.

On the other hand, a pharmaceutically acceptable salt form such as solifenacin succinate is confirmed to have improved stability over time and hardly decomposes in an ordinary storage method (see Test Example 1). Therefore, in the preparation of a transdermal absorption type patch, it is preferred to use the pharmaceutically acceptable salt of solifenacin as a drug substance.

However, the results of the evaluation of the storage stability (see Test Example 3, Comparative Examples 2 and 3) for the general percutaneous absorption type patch containing the pharmaceutically acceptable salt of solifenacin confirmed that the Solinasin was passed. Temporary decomposition, the case where the percentage of decomposition products exceeds 0.5%. Therefore, an excellent storage stability patch which can suppress the time-dependent decomposition of solifenacin is expected.

Of course, the percutaneous absorption type patch preferably has the skin penetration of solifenacin and must also be low irritation to the skin.

That is, an object of the present invention is to provide a pharmaceutically acceptable salt containing solifenacin as A percutaneous absorption type patch of at least one active ingredient which is a preparation which maintains good skin penetration of solifenacin, inhibits the decomposition of solifenacin over time, and has low skin irritation.

The present inventors have intensively studied to solve the above problems, and as a result, found that a percutaneous absorption type patch containing a pharmaceutically acceptable salt and an inorganic base containing solifenacin in a drug-containing layer is percutaneous absorption and preservation stability. Excellent and less skin irritation. Based on this finding, a further review is made to complete the present invention.

That is, the present invention is as follows.

[1] A percutaneous absorption type patch comprising a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin and an inorganic base.

[2] The percutaneous absorption type patch according to the above aspect, wherein the drug-containing layer further contains an adhesive, and the adhesive contains a group selected from the group consisting of a rubber resin and an acrylic resin. At least one of them is used as a main component.

[3] The percutaneous absorption type patch according to [2], wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer.

[4] The percutaneous absorption type patch according to [2], wherein the drug-containing layer further contains an adhesive.

[5] The percutaneous absorption type patch according to [4], wherein the tackifier is an alicyclic saturated hydrocarbon resin.

[6] The percutaneous absorption type patch according to any one of [1] to [5], wherein the inorganic base is at least one selected from the group consisting of potassium hydroxide and sodium hydroxide.

The percutaneous absorption type patch according to any one of the above aspects, wherein the drug-containing layer further contains an absorption enhancer, and the absorption enhancer is derived from an alcohol and an ester. At least one of the selected groups is selected.

[8] The percutaneous absorption type patch according to any one of [1] to [7] wherein the pharmaceutically acceptable salt of solifenacin is a solifenacin succinate.

[9] The percutaneous absorption type patch according to any one of [1] to [8], further comprising a release liner, laminated in the order of the support, the drug-containing layer, and the release liner. .

[10] A method for producing a percutaneous absorption type patch according to the above [1], which is characterized in that a mixture containing a pharmaceutically acceptable salt of solifenacin and an inorganic base is applied ( The film is formed on the release liner to form a drug-containing layer, and the support is attached to the drug-containing layer.

[11] The percutaneous absorption type patch according to any one of the above [1] to [9], wherein a therapeutic agent that is an overactive bladder is used.

[12] The use of the percutaneous absorption type patch according to any one of the above [1] to [9], which is used for the preparation of a transdermal drug preparation for the treatment of hyperactive bladder.

[13] A method of treating a hyperactive bladder, the percutaneous absorption type patch according to any one of the above [1] to [9], used (posted) on the skin of a patient in need of the treatment .

According to the present invention, by containing the pharmaceutically acceptable salt and the inorganic base of solifenacin in the drug-containing layer, high skin penetration can be obtained, and the decomposition of the solitary solifenacin does not occur, thereby providing preservation and stability. Percutaneous absorption type with excellent sex and less skin irritation Agent.

By forming a percutaneous absorption patching agent for the pharmaceutically acceptable salt of solifenacin, it is possible to improve the administration convenience for patients with dysphagia and overactive bladder patients who control drinking water. Further, by the percutaneous absorption type of the pharmaceutically acceptable salt of solifenacin, it is possible to visually confirm the administration, and it is also expected to improve the medication adherence.

The percutaneous absorption type patch of the present invention can achieve a blood concentration of solifenacin which is effective for treating an overactive bladder. Further, by continuously percutaneous absorption of solifenacin, the desired plasma concentration can be maintained for a long period of time.

Fig. 1 shows an example of a production flow of the percutaneous absorption type patch of the present invention.

Fig. 2 shows the results of the in vivo skin penetration test of Test Example 5.

In the present invention, the "transdermal absorption type patch" means a parenteral preparation which is applied to the skin, and the active ingredient is absorbed through the skin to be delivered to the bloodstream. The percutaneous absorption type patch of the present invention contains a support and a drug-containing layer-containing patch, and examples thereof include a patch, a warm-wet cloth, and a patch.

The percutaneous absorption type patching agent of the present invention may be a homogeneous dispersion type patch containing an adhesive in a drug-containing layer, or may be a skin-applied side on a drug-containing layer, and further has a regulating effect. A release control film for transdermal absorption of a medicament, and a storage-type patch preparation for adhering to an adhesive layer of the skin. With this configuration, solifenacin can be efficiently percutaneously absorbed.

From the viewpoint of ease of formulation design and manufacture, a homogeneous dispersion type patch is preferred. Hereinafter, the homogeneous dispersion type patching agent will be described as an example, but the present invention is not limited thereto.

In this manual, "including..." or "including..." means the meaning of "consisting essentially of" or "consisting only of".

<Drug-containing layer> Active ingredient

In the percutaneous absorption type patch of the present invention, the active ingredient of the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin. The pharmaceutically acceptable salt may, for example, be a mineral acid salt (for example, hydrochloride, hydrobromide, nitrate, sulfate, phosphate, etc.); and an organic acid salt (for example, formic acid salt, acetate, trifluoromethane) Acetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, citrate, adipic acid Salt, sorbate, lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate, citrate, water Salicylate, stearate, isostearate, succinate, propionate, butyrate, pamoic acid, tosylate, besulfate ), etc., but not limited to these.

The pharmaceutically acceptable salts of solifenacin may be used singly or in combination of two or more kinds as appropriate. In the present invention, as the muscarinic receptor antagonist, solifesin succinate which has established the usefulness of oral administration is preferably used.

The pharmaceutically acceptable salt content of solifenacin of the percutaneous absorption type patch of the present invention is an effective amount for the treatment of hyperactive bladder. Here, the "effective amount" means that when the percutaneous absorption type patch of the present invention is applied to the skin of a living body, the amount of the concentration of solifenacin in the treatment of the hyperactive bladder can be achieved. Such a content may be appropriately adjusted according to the information on the dynamics of the drug administered orally, and may vary depending on the subject, disease, symptom, and the like. For example, it is preferably 0.2 to 50% by mass, more preferably 0.5 to 35% by mass, and particularly preferably 0.5 to 25% by mass based on the drug-containing layer (i.e., based on the total mass of the drug-containing layer; the same applies hereinafter).

The concentration of solifenacin in the effective treatment of the overactive bladder can be set to the same extent as the oral administration of the pharmaceutically acceptable salt of solifenacin.

In the percutaneous absorption type patch of the present invention, by adjusting the skin penetration speed of solifenacin, the blood concentration of the effective bladder can be effectively treated. The adjustment of the skin penetration rate can be carried out by any means such as adjusting the pharmaceutically acceptable salt content and the administration area of solifenacin in the drug-containing layer. In the present invention, the "skin penetration rate of the pharmaceutically acceptable salt of solifenacin" means a value measured by the in vitro skin penetration test described in the examples below.

The skin penetration rate of solifenacin is preferably from 5 to 40 μg/cm ² /hr, more preferably from 5 to 35 μg/cm ² /hr, based on the value of the solifenacin free body. If the skin penetration speed is 5 μg/cm ² /hr or more, a sufficient blood concentration can be obtained. When the skin penetration speed is 40 μg/cm ² /hour or less, skin irritation such as skin erythema is less likely to occur, which is preferable from the viewpoint of safety.

2. Inorganic base

In order to enhance the skin penetration of solifenacin and inhibit the decomposition of solifenacin in the preparation, an inorganic base is contained in the drug-containing layer. Specific examples thereof include alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), alkali metal carbonates (potassium carbonate, sodium carbonate, etc.), alkali metal hydrogencarbonates (potassium hydrogencarbonate, sodium hydrogencarbonate, etc.), and the like. . Particularly preferred are potassium hydroxide, sodium hydroxide, sodium hydrogencarbonate, etc., more preferably sodium hydroxide or potassium hydroxide.

These inorganic bases may be used singly or in combination of two or more. The inorganic base content is preferably 0.5 to 3 equivalents, more preferably 0.5 to 2 equivalents, per equivalent of the pharmaceutically acceptable salt (particularly an acid addition salt) of solifenacin. Further, the content of the inorganic base is preferably 0.1 to 35% by mass, more preferably 1 to 30% by mass, particularly preferably 1 to 20% by mass based on the drug-containing layer. By containing such an inorganic base, the inorganic base acts on the pharmaceutically acceptable salt of solifenacin (especially an acid addition salt) to enhance the skin penetration of solifenacin. In particular, by setting the content of the inorganic base within the above range, the effect of improving skin penetration is more remarkable than when the above range is exceeded. Further, by using an inorganic base, decomposition of solifenacin in the drug-containing layer can be suppressed. This effect is particularly remarkable compared to the case of using an organic base.

3. Adhesive

The drug-containing layer may further contain an adhesive. The adhesive contained in the drug-containing layer may, for example, be a rubber-based resin, an acrylic resin, or a polyoxymethylene resin.

The adhesive preferably contains at least one selected from the group consisting of an acrylic resin, a rubber-based resin, and a polyoxymethylene resin as a main component, and more preferably a group composed of an acrylic resin and a rubber-based resin. At least one of the selected ones is the main component. The term "main component" as used herein means 70% by mass or more, preferably 80% by mass or more, more preferably 90% by mass or more, and particularly preferably 100% by mass based on the total mass of the adhesive.

Examples of the rubber-based resin include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), and styrene-butadiene rubber. (SBR), styrene isoprene rubber, polyisobutylene (PIB), polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic, isoprene rubber, etc., preferably SIS . Further, for example, a commercially available rubber-based resin such as a Kraton D polymer series (manufactured by Kraton Polymers Japan Co., Ltd.), a JSR SIS/TR series (manufactured by JSR Life Sciences Co., Ltd.), or a QUINTAC series (manufactured by Nippon Zeon Co., Ltd.) can be used.

The acrylic resin may, for example, be represented by at least one of 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, and 2-ethylhexyl methacrylate. (Meth) acrylate as a polymer or copolymer of monomer units. Specifically, for example, acrylic acid octyl acrylate copolymer, 2-ethylhexyl acrylate, vinyl pyrrolidone copolymer solution, 2-ethylhexyl acrylate, N-vinyl-2-pyrrolidone ‧1,6-hexanediol dimethacrylate copolymer, acrylate, vinyl acetate copolymer, 2-ethylhexyl acrylate, 2-hydroxyethyl acrylate, vinyl acetate copolymer, acrylic acid 2-ethylhexyl ester ‧ 2-ethylhexyl methacrylate ‧ dodecyl methacrylate copolymer solution, methyl acrylate ‧ 2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin Alkanolamine solution, etc. Also, you can use DURO-TAK (registered trademark) acrylic adhesive series (DURO-TAK 87-900A, DURO-TAK 87-9301, DURO-TAK 87-4098, DURO-TAK 387-2510, DURO-TAK 87-2510, DURO-TAK 387-2287, DURO-TAK 87-2287, DURO-TAK 87-4287, DURO-TAK 387-2516, DURO-TAK 87-2516, DURO-TAK 87-2074, DURO-TAK 387-235A, DURO-TAK 387 -2353, DURO-TAK 87-2353, DURO-TAK 87-2852, DURO-TAK 387-2051, DURO-TAK 87-2051, DURO-TAK 387-2052, DURO-TAK 87-2052, DURO-TAK 387- 2054, DURO-TAK 87-2054, DURO-TAK 87-2194, DURO-TAK 87-2196: manufactured by Henkel, GELVA series (GELVA GMS 3083, GELVA GMS 3253, GELVA GMS 788, GELVA GMS 9073: manufactured by Henkel) ), commercially available acrylic resins such as MAS-683, MAS-811, MASCOS10, and MAS11D1 (manufactured by CosMED Pharmaceutical Co., Ltd.).

The polyoxygenated resin may, for example, be a polymer having a polysiloxane skeleton and a derivative thereof, and specific examples thereof include dimethyl polyoxyalkylene, polymethylvinyloxirane, and polymethyl. Phenyloxyalkane, diphenyloxane, and the like. Further, a commercially available polyoxynenoid resin such as BIO-PSA series (manufactured by Dow Corning Co., Ltd.) can also be used.

The rubber-based resin, the acrylic resin, and the polyfluorene-based resin may be used singly or in combination of two or more kinds of the above-mentioned rubber-based resin in the drug-containing layer of the permeation-receiving type of the present invention. . More preferably, an acrylic or rubber-based resin is used, and a rubber-based resin is particularly preferably used.

The adhesive contained in the drug-containing layer of the percutaneous absorption type patch of the present invention The amount is adjusted in consideration of the formation of a drug layer, the sufficient skin penetration of the pharmaceutically acceptable salt of solifenacin, and the like. The content of the adhesive is usually 10 to 90% by mass, preferably 10 to 80% by mass based on the drug-containing layer.

When a rubber-based resin is used as the drug-containing layer of the percutaneous absorption type patch of the present invention, the content of the rubber-based resin is considered to be sufficient cohesive force when used as a patch, and is preferably 10 to 70 in total with respect to the drug-containing layer. % by mass, more preferably 10 to 60% by mass, and particularly preferably 10 to 50% by mass.

When the drug-containing layer of the percutaneous absorption type patch of the present invention is an acrylic resin, the content of the acrylic resin is considered to be sufficient cohesive force and adhesive force when used as a patch, and is preferably 20% in total with respect to the drug-containing layer. 90% by weight, more preferably 20 to 80% by weight.

When the drug-containing layer of the percutaneous absorption type patch of the present invention is a polyoxyxylene resin, the content of the polyoxyxylene resin is considered to be sufficient cohesive force and adhesion when used as a patch, and is total with respect to the drug-containing layer. It is preferably 20 to 90% by weight, more preferably 20 to 80% by weight.

4. Adhesive

The drug-containing layer may further contain a tackifier in order to improve the adhesion. Examples of the tackifier include rosin derivatives such as rosin, rosin glyceride, hydrogenated rosin, and glycerol ester of hydrogenated rosin; alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, and aliphatic saturated hydrocarbon Resin, aliphatic hydrocarbon resin, maleic acid resin, carnauba wax, sodium carboxymethyl cellulose, tristerin, chitosan, glycerin, magnesium aluminum silicate, light Anhydrous citric acid, benzyl acetate, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyacrylic acid, sodium polyacrylate, polyacrylic acid partial neutralized material, polyvinyl alcohol and the like. In addition, for example, the ARKON series (made by Arakawa Chemical Co., Ltd.), the PINECRYSTAL® series (made by Arakawa Chemical Co., Ltd.), the CLEARON series (made by YASUHARA CHEMICAL Co., Ltd.), and the YS resin series (made by YASUHARA CHEMICAL Co., Ltd.) can be used. Sale. In particular, when the above rubber-based resin is used as the adhesive, it is preferred to use a glycerin ester of a hydrogenated rosin, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a binder. The adhesive may be used singly or in combination of two or more.

The content of the relevant adhesive is considered to be a sufficient adhesion when used as a patch, and when a rubber-based resin is used as the adhesive, the total amount of the adhesive is preferably 5 to 70% by mass, more preferably 10 ~60% by mass, and particularly good 20 to 50% by mass. When an acrylic resin is used as the adhesive, the total amount is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, and particularly preferably 5 to 20% by mass based on the drug-containing layer. When a polyoxyxylene resin is used as the adhesive, it is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, and particularly preferably 5 to 20% by mass based on the drug-containing layer.

5. Plasticizer

The drug-containing layer may further contain a plasticizer. Examples of the plasticizer include petroleum oil (for example, paraffin-based processing oil, naphthalene-based processing oil, aromatic processing oil, and liquid paraffin), squalane, squalene, and vegetable oil. (for example: olive oil, bitter tea oil, castor oil, turpentine oil, peanut oil, etc.), polyoxyl oil, dibasic acid ester (for example: dibutyl phthalate, dioctyl phthalate, etc.), Liquid rubber (example Such as: polybutene, liquid isoprene rubber, etc.), diethylene glycol, polyethylene glycol, ethylene glycol salicylate, triacetin, triethyl citrate, clopidogrel Ketone (Crotamiton) and the like. Further, as the plasticizer, a commercially available product such as a HIGHCALL series (manufactured by KANEDA Co., Ltd.) can be suitably used. Particularly in the case where the above rubber-based resin is used as the adhesive, the plasticizer is preferably a liquid paraffin. The plasticizer may be used alone or in combination of two or more.

The content of the plasticizer is adjusted in consideration of maintaining sufficient penetration of solifenacin and sufficient cohesive force as a sticking agent. When a rubber-based resin is used as the adhesive, the total amount is preferably 1 to 70% by mass, more preferably 1 to 60% by mass, and particularly preferably 1 to 50% by mass based on the drug-containing layer. When an acrylic resin is used as the adhesive, the total amount of the drug-containing layer is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and particularly preferably 1 to 30% by mass. When a polyfluorene-based resin is used as the adhesive, the total amount of the drug-containing layer is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and particularly preferably 1 to 30% by mass.

6. Absorption enhancer

The drug-containing layer may further contain an absorption enhancer in order to enhance the skin penetration of solifenacin. The absorption enhancer may be any compound which exhibits skin penetration promoting action upon transdermal administration, and examples thereof include citric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oleic acid, and linseed oil. Acid, linoleic acid, isopropyl myristate, oleyl oleate, tris(octanoic acid) glyceride, isopropyl palmitate, octyl dodecyl myristate, oil Fatty acids such as acid monoglyceride or cetyl isostearate or esters thereof; lactic acid, acetic acid, malic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, glycol Organic acids such as acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, salicylic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, saccharin or the like; or adipic acid a polycarboxylic acid ester such as diisopropyl ester, diethyl sebacate or diisopropyl sebacate; an inorganic acid such as phosphoric acid or the like; lauryl alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol Alcohols such as cetyl alcohol, benzyl alcohol, oleyl alcohol, propylene glycol monocaprylate, propylene glycol dioctanoate, and polyethylene glycol monooleate or esters thereof a class, or an ether thereof; a polyol having 3 to 8 carbon atoms (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); monolauric acid Sorbitol esters or ethers such as sorbitan ester and sorbitan monooleate; polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene monopalmitate Polyoxyethylene sorbitan fatty acid esters such as sorbitan ester; phenol ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether; castor oil or hardened castor oil; (oleoyl sarcosine), lauryl dimethylamine acetate beet , sodium lauryl sulfate plasma surfactant; polyoxyethylene alkyl ether having a carbon number of 10 to 22 (for example: polyoxyethylene lauryl ether, polyoxyethylene ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl wax) Ether, polyoxyethylene oxime dialkyl ether, etc.; nonionic surfactant such as dimethyl laurylamine oxide; alkylmethyl group such as dimethyl hydrazine or fluorenylmethyl hydrazine Azulene; 2-pyrrolidone, N-methyl-2-pyrrolidone, pyrrolidone such as N-ethyl-2-pyrrolidone; 1-dodecyldiazocycloheptane-2- Diazocycloalkanes such as ketone, 1-geranyl-diazocycloheptan-2-one; terpenes such as menthol, camphor, and limonene.

Among them, alcohols and esters are preferred. Examples of the alcohols include polyhydric alcohols having 3 to 8 carbon atoms such as propylene glycol, dipropylene glycol, and 1,3-butylene glycol; and aliphatic alcohols such as oleyl alcohol and isostearyl alcohol. The ester is preferably a polycarboxylic acid ester, a fatty acid ester or the like. Polycarboxylic acid esters can be exemplified Such as: diisopropyl adipate, diethyl sebacate, diisopropyl sebacate and other dicarboxylic acid esters. Examples of the fatty acid esters include isopropyl myristate, isopropyl palmitate, oleic acid oleate, hexyl laurate, propylene glycol monocaprylate, propylene glycol dicaprylate, and tris(octanoic acid) glycerol. Ester and the like. More preferred are propylene glycol, dipropylene glycol, isopropyl myristate, isopropyl palmitate, hexyl laurate, and propylene glycol dioctoate. The absorption enhancer may be used alone or in combination of two or more.

The content of the absorption enhancer can be appropriately adjusted in accordance with the type of the pharmaceutically acceptable salt of solifenacin, and is usually 30% by mass or less, preferably 25% by mass or less based on the drug-containing layer. When the absorption enhancer is contained, it is preferably 0.1 to 30% by mass, more preferably 0.5 to 25% by mass, and particularly preferably 1 to 25% by mass.

7. Other optional ingredients

The drug-containing layer may further contain, for example, a known additive such as a pH adjuster, a crosslinking agent, an antioxidant, a colorant, a UV absorber, a filler, or a preservative.

The pH adjusting agent is used for regulating the drug-containing layer for the purpose of enhancing the solubility, stability, skin penetration, and skin safety of the salt or the solvate of the solifenacin. The pH is used instead. If the pH adjuster is an acid or a base or a salt thereof which is usually used for pH adjustment in the pharmaceutical field, any compound such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, gluconic acid, succinic acid, acetic acid, or the like may be used. Lactic acid, methanesulfonic acid, ethylenediaminetetraacetic acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, tromethamine (trometamol), glycine acid, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium citrate, sodium acetate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium carbonate, and the like.

Examples of the crosslinking agent include thermosetting resins such as an amine resin, a phenol resin, an epoxy resin, an alkyd resin, and an unsaturated polyester; an isocyanate compound, a blocked isocyanate compound, an organic crosslinking agent, a metal or a metal. An inorganic crosslinking agent such as a compound. Among them, an isocyanate compound or a blocked isocyanate compound is preferred.

Examples of the antioxidant include tocopherol and such ester derivatives, ascorbic acid, ascorbyl stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylated hydroxy anise. Ether, etc.

The coloring agent may, for example, be sulfonated indigo, iron oxide yellow, yellow ferric oxide, carbon black, caramel, photoreceptor No. 201, mountain white bamboo essence, iron oxide black, Indonesian blood (Daemonorops draco), zinc oxide. , titanium oxide, ferric oxide, amaranth, sodium hydroxide, talc, copper chlorophyll potassium, rye green leaf extract powder, d-borneol, octyl dodecyl myristate, methylene blue, ammonium manganese phosphate Rose oil, etc.

Examples of the ultraviolet absorber include an amino acid compound, a diphenyl ketone compound, a cinnamic acid derivative, a cyanoacrylate derivative, a p-aminobenzoic acid derivative, an ortho-aminobenzoic acid derivative, and a water yang. Acid derivative, coumarin derivative, imidazoline derivative, pyrimidine derivative, two Alkane derivatives and the like.

The filler may be, for example, calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, or carbonic acid. Potassium, potassium bicarbonate, bismuth salt (for example: aluminum citrate, magnesium citrate, calcium citrate, magnesium aluminum silicate, magnesium magnesium citrate, etc.), magnesium hydroxide, citric acid, barium sulfate, calcium sulfate, zinc Calcium acid, zinc oxide, titanium oxide, and the like.

The preservative may, for example, be ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate or butyl p-hydroxybenzoate.

The total content of the other optional components is usually 10% by mass or less, preferably 5% by mass or less based on the drug-containing layer. In the case of containing other optional components, it is preferably 0.05 to 10% by mass, more preferably 0.1 to 5% by mass.

The area of the drug-containing layer of the percutaneous absorption type patch of the present invention can be appropriately adjusted in accordance with the content of the pharmaceutically acceptable salt of the solifenacin and/or the skin penetration speed, and the like is typically 2 to 140 cm ² . Good range 2~100cm ² , better range 2~50cm ² range. Further, the shape thereof is not particularly limited, and may be a square, a rectangle, a circle, an ellipse or the like.

The thickness of the drug-containing layer of the percutaneous absorption type patch of the present invention can be appropriately adjusted in accordance with the type of the adhesive, the pharmaceutically acceptable salt content of solifenacin, and/or the skin penetration speed, etc., and is not particularly limited. The limitation is typically 20 to 300 μm, preferably 25 to 150 μm, and more preferably 25 μm to 100 μm.

The drug-containing layer of the percutaneous absorption type patch of the present invention must contain a pharmaceutically acceptable salt of solifenacin and an inorganic base.

The pharmaceutically acceptable salt of solifenacin is preferably an organic acid salt (especially a succinate), The content thereof is preferably 0.5 to 25% by mass based on the drug-containing layer.

The inorganic base is preferably an alkali metal hydroxide (particularly potassium hydroxide or sodium hydroxide), and the content thereof is preferably from 1 to 20% by mass based on the drug-containing layer.

Further, when the drug-containing layer contains an adhesive, the adhesive is preferably a rubber-based resin (particularly SIS) or an acrylic resin. When the adhesive is a rubber-based resin, the content thereof is preferably 10 to 50% by mass based on the drug-containing layer. When the adhesive is an acrylic resin, the content thereof is preferably from 20 to 80% by mass based on the drug-containing layer.

Further, when the drug-containing layer contains an adhesive, the adhesive is preferably an alicyclic saturated hydrocarbon resin. When a rubber-based resin is used as the adhesive, the content of the adhesive is preferably 20 to 50% by mass based on the drug-containing layer, and when an acrylic resin is used as the adhesive, the content of the adhesive is It is preferably 5 to 20% by mass based on the drug-containing layer.

Further, when the drug-containing layer contains an absorption enhancer, the absorption enhancer is preferably isopropyl myristate. The content of the absorption enhancer is preferably from 1 to 25% by mass based on the drug-containing layer.

<support>

The support for the percutaneous absorption type patch of the present invention can be a support which is non-penetrable, stretchable or non-stretchable. Such a support is not particularly limited as long as it is generally used in the pharmaceutical field, and examples thereof include polyethylene, polypropylene, polybutadiene, ethylene-vinyl acetate copolymer, polyvinyl chloride, and polyester (poly). a synthetic resin film such as ethylene terephthalate or the like, a nylon or a polyurethane, or a sheet, or a laminate, a porous body, a foam, a vapor-deposited aluminum film, or a paper, Weaving, not weaving Cloth and so on.

<release liner>

The transdermal absorption type patch of the present invention may further have a release liner. In this case, the release liner is laminated on the opposite side of the drug-containing layer of the layer deposited on the support adjacent to one side of the support, and the drug-containing layer can be protected until the percutaneous absorption type patch is applied to the skin. The release liner is not particularly limited as long as it is non-penetrating to the solifenacin in the drug-containing layer, and may be, for example, polyethylene, polypropylene, polyester, polyterephthalic acid. A film made of a polymer material such as ethylene glycol ester, a person who vapor-deposits aluminum on a film, a polyfluorene oil coated on paper, or the like.

<Manufacture of percutaneous absorption type patching agent>

The percutaneous absorption type patch of the present invention can be produced in accordance with a known method. Preparing a mixture comprising: a pharmaceutically acceptable salt of solifenacin, an inorganic base, and optionally any of the above ingredients, coating (expanding) the release onto the release liner to form a drug-containing layer, and then The support can be manufactured by attaching a support to the drug-containing layer.

Specifically, for example, a pharmaceutically acceptable salt of solifenacin, an inorganic base, and optionally an adhesive, a tackifier, a plasticizer, an absorption enhancer, and/or other additives are used as the above-mentioned content. The coating liquid is prepared by adding to an organic solvent and mixing and stirring. The mixing method may employ, for example, stirring, inline mixing, ultrasonic treatment, or the like. The organic solvent may be, for example, ethyl acetate, hexane, pentane, toluene, cyclohexane, chloroform, dichloromethane, methanol, ethanol, isopropanol, methyl ethyl ketone, cyclohexanone, acetone, or a mixed solvent thereof. Wait. The amount of organic solvent in the coating liquid is not In particular, it is, for example, 30 to 90% by mass, preferably 40 to 80% by mass based on the entire coating liquid system.

Next, the coating liquid is spread on the release liner, and the solvent in the coating liquid is evaporated to form a drug-containing layer, and then the percutaneous absorption type patching agent can be obtained by bonding the support. Alternatively, the coating liquid may be spread on the support, and the solvent in the coating liquid may be evaporated to form a drug-containing layer, and then the percutaneous absorption type patch may be obtained by bonding the release liner. From the viewpoint of easiness of production, a method in which the coating liquid is spread on the release liner and the solvent in the coating liquid is evaporated to form a drug-containing layer, and then the support is bonded. The application of the coating liquid can be carried out using a knife coater, a batch roll coater, a reverse coater, or a die coater. An example of the manufacturing process is shown in Figure 1, but is not limited to this.

Further, the percutaneous absorption type patch of the present invention heat-melts the pharmaceutically acceptable salt of solifenacin, an inorganic base, and optionally other optional components, and then coats (extends) the melt. After the release of the liner and the formation of the drug-containing layer, a percutaneous absorption type patch can also be produced by laminating the support. The percutaneous absorption type patching agent can also be produced by coating (promoting) the melt onto the support to form a drug-containing layer and then attaching the release liner.

<Method of administration>

The hyperactive bladder treatment using the percutaneous absorption type patch of the present invention directly applies the percutaneous absorption type patch of the present invention to the skin of a subject, and can be treated by transdermal administration of solifenacin. The object of the present invention is a mammal such as a human, preferably a human class. In particular, the treatment of an overactive bladder can be carried out by using (posting) the patching agent on the skin of a patient in need of overactive bladder treatment.

In the case of transdermal administration of solifenacin using the percutaneous absorption type patch of the present invention, in order to achieve an effective treatment for the blood concentration of the overactive bladder, the content of solifenacin in the drug-containing layer is appropriately adjusted and/or The transdermal absorption type patch of the present invention is applied to the skin after the skin penetration speed, and the area containing the drug layer and/or the thickness of the drug-containing layer.

The percutaneous absorption type patch of the present invention can be applied to skin of any part of the body if it can be applied, and can be applied to, for example, the upper arm, the abdomen, the chest, the neck, the lower back, the buttocks or the feet.

The transdermal absorption type patch of the present invention can be administered to a subject by transdermal administration, and if necessary, a pharmaceutical composition containing a pharmaceutical ingredient other than the pharmaceutically acceptable salt of solifenacin can be administered. In this case, the administration form may be simultaneous administration, or may be administered with a time difference, and the pharmaceutical composition may be via various routes including intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. Dosing. Further, a pharmaceutical composition containing a pharmaceutical ingredient other than the pharmaceutically acceptable salt of solifenacin is administered to a subject by a administration route generally used for the pharmaceutical ingredient. The pharmaceutical ingredient other than the pharmaceutically acceptable salt of solifenacin may, for example, be an α 1 adrenergic receptor antagonist or a β 3 adrenergic receptor agonist, but is not limited thereto.

[Examples]

Hereinafter, the present invention will be more specifically described based on the embodiments, but the present invention It is not limited to the following embodiments. Further, in each of the examples, "%" means "% by mass" unless otherwise stated.

(Manufacture of percutaneous absorption type patch containing solifenacin succinate) [Example 1]

‧ Preparation of rubber resin composition (1)

A styrene-isoprene-styrene block copolymer (QUINTAC 3570C, manufactured by Japan ZEON Co., Ltd.), an alicyclic saturated hydrocarbon resin (ARKONP-100, manufactured by Arakawa Chemical Industries, Ltd.), and a liquid paraffin (HIGHCALL M-352, KANEDA company), according to the following composition: And the solid content was 50%, and it dissolved in toluene, and the rubber-type resin composition (1) was obtained.

‧Manufacturing of percutaneous absorption type patch

The rubber-based resin composition (1) was added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto to prepare a coating liquid having the composition shown below.

Next, the obtained coating liquid is peeled off from polyethylene terephthalate. (FILMBYNA 75E-0010 BD, manufactured by Fujimori Industrial Co., Ltd.), a thickness of about 50 μm after solvent distillation was applied, and after drying, a 25 μm polyester film of a support was attached (Lumirror T-60, East) A company that produces a percutaneous absorption type patch.

[Embodiment 2]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Example 3]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Comparative Example 1]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Test Example 1 Stability Test of Raw Material Drugs]

The solifesuccinate and solifenin free bodies were separately filled into brown screw cap vials and stored at 60 °C. The solifesin succinate and solifenacin free samples which were sampled over time were separately dissolved in a pH 3.5 phosphate buffer/acetonitrile mixture and analyzed by HPLC. From the peak area of the solifenacin and the decomposition product in the sample, the amount of decomposition product (%) was calculated by the following formula. The results obtained are shown in Table 1.

The amount of decomposition product (%) = (the peak area of the decomposition product) / (the peak area of Solinasin) × 100

<HPLC conditions>

HPLC system: ACQUITY UPLC H-Class system (manufactured by Waters)

Column: Inertsil ODS-3 (2μm, 2.1×100mm, manufactured by GL Sciences)

Column oven: set at a certain temperature around 40 ° C

Mobile phase: pH 3.5 phosphate buffer / acetonitrile mixture

Flow rate: 0.5mL/min

Measurement wavelength: 210 nm

It is known from Table 1 that the solifenacin succinate is decomposed without time, and the free form of solifenacin increases the decomposition product over time.

[Example 4]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Example 5]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition:

The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Embodiment 6]

A rubber-based resin composition (1), propylene glycol (SR Propylene Glychol, manufactured by CRODA Co., Ltd.) was added to the preconcentrated solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Embodiment 7]

‧ Preparation of rubber resin composition (2)

Styrene-isoprene-styrene block copolymer (QUINTAC 3570C, manufactured by ZEON CORPORATION), hydrogenated rosin glyceride (PINECRYSTAL® KE-311, manufactured by Arakawa Chemical Industries, Ltd.), and liquid paraffin (HIGHCALL M-352, KANEDA company), according to the following composition: And the solid content was 50%, and it dissolved in toluene, and obtained the rubber-type resin composition (2).

‧Manufacturing of percutaneous absorption type patch

The rubber-based resin composition (2) was added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. An ethanol solution of potassium hydroxide is added thereto to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Embodiment 8]

Acrylic resin (Duro-Tak 387-2287, manufactured by Henkel Co., Ltd.) and isopropyl myristate were added to the preconcentrated solifenacin succinate, and the mixture was uniformly stirred. A solution of potassium hydroxide in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Comparative Example 2]

The rubber-based resin composition (1) was added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of diisopropanolamine in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Comparative Example 3]

A rubber-based resin composition (1) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. A solution of diisopropanolamine in ethanol was added thereto and stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Comparative Example 4]

A rubber-based resin composition (1) and isopropyl myristate were added to the pre-weighed solifenacin free body, and uniformly stirred to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

[Test Example 2 In vitro skin penetration test]

Using the obtained transdermal absorption type patch, the in vitro skin penetration test was performed in the following order.

The 7-week-old male hairless mice were removed from the stratum corneum side of the skin (Hos: HR-1 line, Hoshino Laboratory Animal Breeding Co., Ltd.), and the percutaneous absorption type patching agents of the respective examples and comparative examples were attached, respectively, in the periphery. In an upright diffusion tank (trade name: PERMCELL upright type TP-6: manufactured by Vidrex Co., Ltd.) which circulates at a temperature of 32 ° C, the skin base film is placed on the receiving side. The receiving tank was filled with phosphate buffered physiological saline (PBS (-), Wako Pure Chemical Industries, Ltd.), and the receiving liquid was sampled over time, and the amount of solifenacin in the receiving liquid was measured by HPLC. From the measurement results, the cumulative penetration of solifenacin 24 hours after the start of the test was calculated, and the penetration speed (the average value of n = 3) was calculated. The results obtained are shown in Table 2 and Table 3.

[Test Example 3 Stability Test]

The percutaneous absorption type patch prepared by each of the examples and the comparative examples was sealed by a heat seal to a composite film (PET 12 μm/PE 15 μm/Al 9 μm/PE 30 μm) in an aluminum foil, and stored in a bag. 60 ° C.

The release liner was peeled off by a percutaneous absorption type patch after storage for 4 weeks at 60 ° C, and extracted by shaking with 2 mL of tetrahydrofuran for 30 minutes. After adding 8 mL of a pH 3.5 phosphate buffer/acetonitrile mixture to the solution, the mixture was filtered through a 0.2 μm membrane filter, and analyzed by HPLC. From the peak area of the solifenacin and the decomposition product in the sample, the amount of decomposition product (%) was calculated from the following formula. The results obtained are shown in Table 2 and Table 3.

Decomposed product amount (%) = (peak area of decomposition product) / (spiral area of Solinasin) × 100

From the results of Test Example 2, Table 2, when using solifenacin succinate as When the active ingredient is added and an inorganic base is added, sufficient skin penetration can be obtained. On the other hand, as seen from Table 3, Comparative Example 1 in which no inorganic base was added exhibited very low penetrability. When the pharmaceutically acceptable salt of solifenacin is used as an active ingredient, the addition of an alkali can increase the effect of improving skin penetration.

When the amount of the decomposition product in the preparation is preferably 0.5% or less, the results of Test Example 3 and Tables 2 and 3 show that the preparations of Examples 1 to 8 using an inorganic base as a base are even at 60. Under the severe conditions of 4 °C for 4 weeks, the amount of decomposition products is still below 0.5%, and it has sufficient stability over time and skin penetration.

On the other hand, as shown in Table 3, in Comparative Examples 2 and 3 using an organic amine as a base, more than 1% of the decomposition product was found after 4 weeks at 60 ° C, compared to Examples 1 to 8 using an inorganic base. Under the stability, the stability is significantly reduced. Further, in Comparative Example 4 in which the solifenacin free body was used as an active ingredient, since the stability of the free body itself was low, the amount of the decomposition product in the preparation exceeded 0.5%.

[Examples 9 to 15]

A transdermal absorption type patch was obtained in the same manner as in Example 2 except that the isopropyl myristate of Example 2 was changed to the ester shown in Table 4.

In Table 4, the skin penetration speed and the amount of decomposition product of each of the percutaneous absorption type patching agents of Examples 9 to 15 were calculated in the same manner as in Test Examples 2 and 3. Moreover, the percutaneous absorption promoting effect of each of the patching agents of Examples 2 and 9 to 15 was calculated by the following formula.

Promotion ratio = (skin penetration rate of each of Examples 2 and 9 to 15) ÷ (skin penetration speed of Example 1)

Each of the patching agents of Examples 2 and 9 to 15 has a decomposition product content of 0.07% or less, and has sufficient stability over time, and exhibits 1.2 to 1.7 times of percutaneous absorption promotion as compared with the patch of Example 1. effect.

[Example 16]

‧ Preparation of rubber resin composition (3)

Styrene-isoprene-styrene block copolymer (QUINTAC 3570C, manufactured by Zeon Corporation, Japan), alicyclic saturated hydrocarbon resin (ARKONP-100, manufactured by Arakawa Chemical Industries, Ltd.), polybutene (polybutene HV) -300, JX Nippon Mining & Energy Co., Ltd.), according to the following composition: Further, the solid content was 50%, and it was dissolved in toluene to obtain a rubber-based resin composition (3).

‧Manufacturing of percutaneous absorption type patch

A rubber-based resin composition (3) and isopropyl myristate were added to the previously weighed solifenacin succinate, and the mixture was uniformly stirred. An ethanol solution of potassium hydroxide is added thereto to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

Using the percutaneous absorption type patch obtained in Example 16, an in vitro skin penetration test was carried out in the same manner as in Test Example 2. The skin penetration rate was 25.9 μg/cm ² /h. Using the percutaneous absorption type patch obtained in Example 16, a stability test was carried out in the same manner as in Test Example 3. The amount of decomposition product was 0.20% (60 ° C for 4 weeks).

[Reference Example 1]

"NEOXY (registered trademark) patch" for the treatment of overactive bladder used in clinical practice.

[Test Example 4 Primary stimuli test of guinea pig skin]

A 6-week-old Hartley male guinea pig was used. On the day before the administration, the left and right side chest circumferences of the guinea pig were depilated and shaved about 4 x 8 cm. The patch of Example 2, Example 3, Example 5, Example 16, Comparative Example 4, and Reference Example 1 (15 mm) on the next day of hair removal ), which is attached to the left and right chests, and is fixed by a sponge sponge M (made by 3M Healthcare Co., Ltd.) with an adhesive, and the body part is wound with a polyethylene film tape (KEEPPORE A, NICHIBAN company), and then Silkytex (ALCARE) is used. , No. 5) fixed. After 24 hours of administration, each patch was removed, and the patch site was wiped with a cotton wool moistened cotton wool. The skin reactions after 24, 48, and 72 hours from the administration of the drug were observed, and the skin irritation index (PII) was calculated with reference to the Draize standard (1959) shown in Table 5, and skin irritation was evaluated. Among them, after 24 hours of administration, observation was performed after about 1 hour of wiping. The scores of the individual bodies after 24, 48, and 72 hours of administration were calculated for each test substance, and the number of observations (3 times) was divided, and PII (Individual PII) of each body was calculated. The Individual PII value was totaled, and the average value thereof was set to PII of the percutaneous absorption type patch.

The results are shown in Table 6. In addition, the relevant irritant evaluation was rated as "no irritant" when PII was 0, "light irritant" when it was greater than 0 and less than 2, and "moderate" when it was 2 or more and less than 5 "Stimulus", rated as "intensity irritant" when it is 5 or more. Statistical processing was not implemented at the time of evaluation.

As seen in Table 6, the second embodiment, the third embodiment, the fifth embodiment, and the sixteenth embodiment The percutaneous absorption type patch is a mild irritant, and the skin irritation is lower than that of the percutaneous absorption type patch of Comparative Example 4 and Reference Example 1.

[Test Example 5 In vivo skin penetration test (rat)]

The back skin of an 8-week-old male SD rat (manufactured by Charles River, n=5) was cut with an electric clipper. The percutaneous absorption preparation of Example 16 which was cut to a size of 10 cm ² (3.16 cm × 3.16 cm ⁾ (the amount of solifesin succinate per tablet of the preparation: about 5 mg/tablet) was applied to the rat. On the back, a cotton cake (manufactured by White Cross), a Tegaderm Roll (manufactured by 3M Health Care Co., Ltd.), a non-woven adhesive bandage (Silkytex, manufactured by ALCARE Co., Ltd.), were administered for 24 hours. After the application, at 0.5, 1, 3, 6, 12, 20, 24, and 30 hours (6 hours after the preparation was removed), blood was collected from the subclavian vein (about 0.3 mL) under isoflurane inhalation anesthesia. Plasma was obtained by centrifugation (4 ° C, 2000 G, 15 minutes).

Further, for comparison, intravenous administration (n=4) was performed by dissolving solifenacin succinate in physiological saline. The administration amount was adjusted so that the body weight of the rat was 0.3 and 1 mg/kg, and the administration amount was administered in a manner of 1 mL/kg. After administration, blood was collected from the subclavian vein (about 0.3 mL) under isoflurane inhalation anesthesia for 1, 3, 5, 10, 15 and 30 minutes, 1, 2, 3 and 6 hours, and centrifuged (about 0.3 mL). Plasma was obtained at 4 ° C, 2000 G, 15 minutes).

150 μL of acetonitrile was added to 50 μL of the obtained plasma, and the mixture was centrifuged (4° C., 20000 G, 5 minutes) to remove proteins, and a membrane filter (manufactured by Merck Millipore Co., Ltd.) having a pore size of 0.2 μm was used for filtration, and LC/MS/ was used. MS measured at each time Plasma concentration of solifenacin (ng/mL). The results obtained are shown in Figure 2.

<LC/MS/MS measurement conditions>

Device: ACQUITY UPLC H-Class System (made by Waters)

Column: Acquity UPLC BEH C18 1.7μm 2.1×50mm (made by Waters)

Column temperature: 40 ° C

Flow rate: 0.4mL/min

Detector: Xevo G2-S Q-Tof (made by Waters)

Detection conditions: Resolution‧Positive, m/z=363.21

Mobile phase: a mixture of 0.1% aqueous solution of formic acid and 0.1% formic acid-acetonitrile solution

Sample injection amount: 1 μL

As can be seen from Fig. 2, when the solifenacin was administered intravenously, it quickly disappeared from the plasma, and when the percutaneous absorption preparation of Example 16 was attached to the rat, by Solina Peripheral percutaneous absorption confirmed that a certain plasma concentration was maintained within a certain 24-hour period of the patch.

[Example 17]

‧ Preparation of rubber resin composition (4)

A styrene-isoprene-styrene block copolymer (QUINTAC 3570C, manufactured by Japan ZEON Co., Ltd.), an alicyclic saturated hydrocarbon resin (ARKONP-100, manufactured by Arakawa Chemical Industries, Ltd.), and a liquid paraffin (HIGHCALL M-352, KANEDA company), according to the following composition:

The mobile paraffin was dissolved in toluene so as to have a solid content of 20.0%, and the rubber-based resin composition (4) was obtained.

‧Manufacturing of percutaneous absorption type patch

A rubber-based resin composition (4), isopropyl myristate, and dibutylhydroxytoluene (manufactured by Tokyo Chemical Industry Co., Ltd.) were added to the preconcentrated solifenacin succinate, and the mixture was uniformly stirred. An ethanol solution of potassium hydroxide is added thereto to prepare a composition having the following composition: The coating liquid was applied in the same manner as in Example 1 to obtain a transdermal absorption type patch.

Using the percutaneous absorption type patch obtained in Example 17, an in vitro skin penetration test was carried out in the same manner as in Test Example 2. The skin penetration rate was 18.7 μg/cm ² /h. Further, the stability test was carried out in the same manner as in Test Example 3. As a result, the amount of the decomposition product was 0.15% (60 ° C for 4 weeks).

(industrial availability)

According to the present invention, a transdermal absorption type patch containing a pharmaceutically acceptable salt of solifenacin which is excellent in transdermal absorbability, preservation stability, and safety can be provided. The percutaneous absorption type patch of the present invention can more effectively perform treatment of a hyperactive bladder.

Claims (10)

A percutaneous absorption type patch comprising a support and a drug-containing layer, wherein the drug-containing layer comprises a pharmaceutically acceptable salt of solifenacin and an inorganic base. The permeation-receiving type patch according to claim 1, wherein the drug-containing layer further contains an adhesive, and the adhesive contains at least one selected from the group consisting of a rubber-based resin and an acrylic resin. ingredient. The percutaneous absorption type patch according to claim 2, wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer. The percutaneous absorption type patch of claim 2 or 3, wherein the drug-containing layer further contains an adhesive. The percutaneous absorption type patch according to claim 4, wherein the above-mentioned adhesive is an alicyclic saturated hydrocarbon resin. The percutaneous absorption type patch according to any one of claims 1 to 5, wherein the inorganic base is at least one selected from the group consisting of potassium hydroxide and sodium hydroxide. The percutaneous absorption type patch according to any one of claims 1 to 6, wherein the drug-containing layer further contains an absorption enhancer selected from the group consisting of alcohols and esters. At least one. The percutaneous absorption type patch according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of solifenacin is a solifenacin succinate. The percutaneous absorption type patch according to any one of claims 1 to 8, further comprising a release liner, which is laminated in the order of the support, the drug-containing layer and the release liner. A method for producing a transdermal absorption type patch according to claim 1, which comprises a mixture of a pharmaceutically acceptable salt of solifenacin and an inorganic base. It is applied to the release liner to form a drug-containing layer, and the support is attached to the drug-containing layer.