JP6729584B2 - Transdermal patch - Google Patents

Description

The present invention relates to a transdermal patch, which contains a pharmaceutically acceptable salt of solifenacin as an active ingredient.

Conventionally, oral administration methods using tablets, capsules, syrups, etc. have been known as administration methods for drugs, but in recent years, attempts have been made to administer these drugs through the skin using a transdermal patch. Has been done. The transdermal patch has the advantages of reducing the number of administrations, improving compliance, and facilitating administration and discontinuation in addition to solving the problems in the oral administration method. It is expected as a useful drug administration method in the treatment of

Solifenacin ((R)-quinuclidin-3-yl(S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate) has a high affinity for muscarinic M3 receptors. It is a receptor antagonist (Patent Document 1) and is currently used in the clinical field as a therapeutic agent for overactive bladder. The currently practically used preparations are solifenacin succinate tablets and orally disintegrating tablets, which are prescribed as oral preparations for overactive bladder patients under the trade name of "Vesicare (registered trademark)".

Overactive bladder patients are known to refrain from drinking water on a daily basis, and solifenacin is a drug that is often taken by elderly people with impaired swallowing function. Rather, transdermal patches are suitable.

In addition, as a drug for overactive bladder, oxybutynin hydrochloride is currently used clinically as a transdermal patch under the trade name of "Neoxy (registered trademark) tape", but side effects include dermatitis and dermatitis. Erythema is frequently observed (Non-patent Document 1), and from the viewpoint of patient safety, development of a formulation with less odor and skin irritation is desired.

The “Guidelines for Impurities in Pharmaceutical Preparations of Pharmaceuticals Containing New Active Ingredients” announced by the Japan-US EU International Conference on Harmonization of Pharmaceutical Regulations (ICH) describes the concept of degradation products (impurities) in pharmaceutical products that are recognized in stability tests. It is written. According to this, when the amount of the drug substance administered per day is 10 mg or more and less than 100 mg, the threshold value required to confirm the safety of the degradation product in the drug product is the degradation product contained in the drug substance. The percentage of substances is 0.5% or the daily intake of decomposition products is 200 μg, whichever is lower. Therefore, as a standard value of the amount of degradation products that can be generally set without confirming the safety of the degradation products, the percentage of the degradation products is 0.5% or less in the case of 10 mg formulation. It is preferable.

Solifenacin is known to be decomposed with time in the general formulation method, solifenacin, which is the main drug in the formulation, and various stabilization methods are used to suppress the formation of degradation products in the formulation. It has been proposed (Patent Documents 2, 3, 4 and 5). However, these references do not describe the stability of solifenacin in a transdermal patch.

As a transdermal patch containing solifenacin, Patent Document 6 proposes a transdermal patch (tape) containing a solifenacin-free body and fatty acid esters as a transdermal absorption promoter, There is no description on the stability of this patch over time.

Further, Patent Document 7 contains a thermoplastic elastomer, a liquid component exceeding 300 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and a therapeutic agent for overactive bladder having an anticholinergic effect (solifenacin, darifenacin, etc.). Skin-absorptive patches have been proposed. However, Patent Document 7 does not describe the stability over time of this patch.

Japanese Patent No. 3014457 Patent No. 4636445 Patent No. 4816828 Patent No. 5168711 Patent No. 5177156 WO2005/077364 WO2013/081014

Neoxy (registered trademark) tape 73.5 mg, drug interview form

The present inventor evaluated the storage stability of the solifenacin-free product by a severe test, and confirmed that the decomposition products increased with time (see Test Example 1). From this, it was found that the solifenacin free form was decomposed with time by the ordinary storage method. Therefore, when a transdermal patch is prepared using a solifenacin-free drug substance as a drug substance, the degradation product contained in the drug substance itself is mixed during the preparation of the patch, and the resulting degradation product of the patch is contained. The amount may exceed 0.5%.

On the other hand, it has been confirmed that a pharmaceutically acceptable salt form such as solifenacin succinate has improved stability over time and almost no decomposition by a normal storage method (see Test Example 1). Therefore, when preparing a transdermal patch, it is preferable to use a pharmaceutically acceptable salt of solifenacin as a drug substance.

However, as a result of evaluating the storage stability of a general transdermal patch containing a pharmaceutically acceptable salt of solifenacin (see Test Example 3, Comparative Examples 2 and 3), solifenacin was decomposed with time. However, it was confirmed that the percentage of the decomposition product may exceed 0.5%. Therefore, a patch having excellent storage stability that can suppress the degradation of solifenacin over time has been desired.

As a percutaneous absorption type patch, of course, it is also necessary to have desirable skin permeability of solifenacin and to be mild to the skin.

That is, the present invention, in at least one active ingredient, in a transdermal patch containing a pharmaceutically acceptable salt of solifenacin, retains good skin permeability of solifenacin, degradation of solifenacin over time. It is an object of the present invention to provide a preparation that suppresses skin irritation and has low skin irritation.

The present inventors, as a result of repeated studies to achieve the above problems, a transdermal patch containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in the drug-containing layer, transdermal absorption and It has been found that the storage stability is excellent and the skin irritation is small. Based on such findings, the present invention has been completed through further studies.

That is, the present invention is as follows.
[1] A percutaneous absorption type patch having 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 transdermal skin according to [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 resin and an acrylic resin as a main component. Absorption type patch.
[3] The transdermal patch according to [2], wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer.
[4] The transdermal patch according to [2] or [3], wherein the drug-containing layer further contains a tackifier.
[5] The transdermal patch according to [4], wherein the tackifier is an alicyclic saturated hydrocarbon resin.
[6] The transdermal 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.
[7] The drug-containing layer further contains an absorption enhancer, and the absorption enhancer is at least one selected from the group consisting of alcohols and esters. [1] to [6] Percutaneous absorption type patch.
[8] The transdermal patch according to any one of [1] to [7], wherein the pharmaceutically acceptable salt of solifenacin is solifenacin succinate.
[9] The transdermal patch according to any one of [1] to [8], which further has a release liner, and a support, a drug-containing layer, and a release liner are laminated in this order.
[10] The method for producing the transdermal patch according to [1], wherein a mixture containing a pharmaceutically acceptable salt of solifenacin and an inorganic base is applied (spread) onto a release liner. A drug-containing layer is formed by applying the support to the drug-containing layer.
[11] The transdermal patch according to any one of [1] to [9], which is used as a therapeutic agent for overactive bladder.
[12] Use of the transdermal patch according to any one of [1] to [9] above for producing a transdermal preparation for treating overactive bladder.
[13] A method for treating overactive bladder, which comprises applying (pasting) the transdermal patch of any one of [1] to [9] to the skin of a patient in need of the treatment. A method characterized by.

According to the present invention, by containing a pharmaceutically acceptable salt of solifenacin and an inorganic base in the drug-containing layer, it is possible to obtain high skin permeability, so that the decomposition of solifenacin over time does not occur, so storage It is possible to provide a percutaneous absorption type patch having excellent stability and less skin irritation.

By using a pharmaceutically acceptable salt of solifenacin as a transdermal patch, the convenience of administration is improved for patients with dysphagia and overactive bladder patients who refrain from drinking water. Further, since transdermal absorption patch of a pharmaceutically acceptable salt of solifenacin enables visual confirmation of medication, it is expected to improve medication adherence.

The transdermal patch of the present invention can achieve a blood concentration of solifenacin that is effective for treating overactive bladder. In addition, the sustained transdermal absorption of solifenacin makes it possible to maintain a desired plasma concentration for a long period of time.

An example of the production flow of the transdermal patch of the present invention is shown. The result of the in-vivo skin permeability test in Test Example 5 is shown.

In the present invention, the transdermal patch is a parenteral preparation, which is used by being applied to the skin, and the active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermal patch of the present invention is a patch having a support and a drug-containing layer, and examples thereof include tapes, poultices, plasters and the like.

The transdermal patch of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and on the skin patch side of the drug-containing layer, a controlled-release film for controlling transdermal absorption of the drug and It may be a reservoir-type patch preparation further having an adhesive layer for sticking to the skin. With such a structure, it becomes possible to efficiently absorb solifenacin transdermally.

From the viewpoint of ease of formulation design and production, a matrix-type patch is preferable. Hereinafter, the matrix type patch will be described as an example, but the present invention is not limited thereto.

As used herein, the terms “comprising” or “including” also include the meanings “consisting essentially of” or “consisting solely of”.
<Drug-containing layer>
1. Active ingredient In the transdermal patch of the present invention, the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin as an active ingredient. Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates; and organic acid salts such as formates, acetates, Trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate , Lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate , Succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate) and the like, but are not limited thereto.

The pharmaceutically acceptable salt of solifenacin may be used alone or in an appropriate combination of two or more kinds. In the present invention, it is preferable to use solifenacin succinate, whose utility in oral administration has already been established, as a muscarinic receptor antagonist.

The content of the pharmaceutically acceptable salt of solifenacin in the transdermal patch of the present invention is an effective amount for treating overactive bladder. Here, the effective amount is an amount that can achieve a blood concentration of solifenacin effective for treating overactive bladder when the transdermal patch of the present invention is applied to the skin of a living body. Such a content can be appropriately adjusted based on the information on the pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptom and the like. For example, with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same applies hereinafter), 0.2 to 50 mass% is preferable, 0.5 to 35 mass% is more preferable, and 0.5 to 25 mass%. Mass% is more preferable.

The blood concentration of solifenacin effective for the treatment of overactive bladder can be similar to that of an oral pharmaceutically acceptable salt of solifenacin.

In the transdermal patch of the present invention, by adjusting the skin permeation rate of solifenacin, a blood concentration effective for treating overactive bladder can be achieved. The skin permeation rate can be adjusted by any means such as adjusting the content and administration area of a pharmaceutically acceptable salt of solifenacin in the drug-containing layer. In the present invention, the skin permeation rate of a pharmaceutically acceptable salt of solifenacin means a value measured by an in vitro skin permeation test described in Examples below.

Skin permeation rate of solifenacin is preferably 5~40μg / cm ² / time at a value in terms of warpage phenacyl down free form, 5~35μg / cm ² / time is more preferable. When the skin permeation rate is 5 μg/cm ² /hour or more, a sufficient blood concentration can be obtained. When the skin permeation rate is 40 μg/cm ² /hour or less, skin irritation such as erythema of the applied skin is unlikely to occur, which is preferable from the viewpoint of safety.

2. Inorganic base An inorganic base is contained in the drug-containing layer in order to improve the skin permeability of solifenacin and suppress the decomposition of solifenacin in the preparation. Specifically, alkali metal hydroxides (potassium hydroxide, sodium hydroxide, etc.), alkali metal carbonates (potassium carbonate, sodium carbonate, etc.), alkali metal hydrogen carbonates (potassium hydrogen carbonate, sodium hydrogen carbonate, etc.), etc. Are listed. Particularly, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate and the like are preferable, and sodium hydroxide and potassium hydroxide are more preferable.

Such inorganic bases can be used alone or in combination of two or more. The content of the inorganic base is preferably 0.5 to 3 equivalents, and more preferably 0.5 to 2 equivalents, relative to the equivalent of the pharmaceutically acceptable salt of solifenacin (particularly, acid addition salt). More preferable. Further, the content of the inorganic base is preferably 0.1 to 35% by mass, more preferably 1 to 30% by mass, and further preferably 1 to 20% by mass with respect to the drug-containing layer. preferable. By containing such an inorganic base, the inorganic base acts on a pharmaceutically acceptable salt of solifenacin (particularly an acid addition salt), and the skin permeability of solifenacin is improved. In particular, by setting the content of the inorganic base within the above range, the effect of improving skin permeability becomes more remarkable as compared with the case where the content is outside the above range. Moreover, by using an inorganic base, the decomposition of solifenacin in the drug-containing layer can be suppressed. This effect is remarkably superior to the case where an organic base is used.

3. The adhesive drug-containing layer may further contain an adhesive. Examples of the adhesive contained in the drug-containing layer include those containing a rubber resin, an acrylic resin, a silicone resin, and the like.

The pressure-sensitive adhesive preferably contains at least one selected from the group consisting of acrylic resins, rubber-based resins and silicone-based resins as a main component, and at least selected from the group consisting of acrylic-based resins and rubber-based resins. Those containing one kind as a main component are more preferable. Here, the "main component" means usually 70 mass% or more, further 80 mass% or more, further 90 mass% or more, and particularly 100 mass% with respect to the total mass of the pressure-sensitive adhesive.

Examples of the rubber resin include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, polyisobutylene (PIB). ), polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, but SIS is preferable. Further, commercially available rubber-based resins such as Clayton D polymer series (made by Clayton Polymer Japan), JSR SIS/TR series (made by JSR Life Science), and Quintac series (made by Zeon Corporation) may be used.

As the acrylic resin, for example, as a monomer unit, (meth)acrylic acid ester represented by 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. A polymer or copolymer containing at least one kind may be mentioned. Specifically, for example, acrylic acid/acrylic acid octyl ester copolymer, acrylic acid 2-ethylhexyl/vinylpyrrolidone copolymer solution, acrylic acid 2-ethylexyl/N-vinyl-2-pyrrolidone/dimethacrylic acid-1 , 6-hexane glycol copolymer, acrylic ester/vinyl acetate copolymer, 2-ethylhexyl acrylate/2-hydroxyethyl acrylate/vinyl acetate copolymer, 2-ethylhexyl acrylate/2-ethylhexyl methacrylate/methacrylic acid Dodecyl copolymer solution, methyl acrylate/2-ethylhexyl acrylate copolymer resin emulsion, acrylic resin alkanolamine solution and the like can be mentioned. In addition, 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: Henkel A commercially available acrylic resin such as MAS-683, MAS-683, MAS-811, MASCOS10, MAS11D1 (manufactured by Cosmedy Pharmaceutical Co., Ltd.) may be used.

Examples of the silicone resin include polymers having an organopolysiloxane skeleton and derivatives thereof, and specific examples thereof include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, diphenylsiloxane and the like. Moreover, you may use commercially available silicone resin, such as BIO-PSA series (made by Dow Corning).

As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermal patch of the present invention, one of the above-mentioned rubber-based resin, acrylic resin, and silicone-based resin may be used alone or in combination of two or more. Can be used. More preferably, an acrylic or rubber-based resin is used, and even more preferably, a rubber-based resin is used.

The amount of the adhesive contained in the drug-containing layer of the transdermal patch of the present invention is determined in consideration of the formation of the drug-containing layer, sufficient skin permeability of the pharmaceutically acceptable salt of solifenacin, etc. Adjusted. 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 in the drug-containing layer of the transdermal patch of the present invention, the content of the rubber-based resin is a total with respect to the drug-containing layer in consideration of sufficient cohesive force as a patch. Is preferably 10 to 70% by mass, more preferably 10 to 60% by mass, still more preferably 10 to 50% by mass.

When using an acrylic resin in the drug-containing layer of the transdermal patch of the present invention, the content of the acrylic resin, considering the sufficient cohesive force and adhesive strength as a patch, relative to the drug-containing layer The total amount is preferably 20 to 90% by weight, more preferably 20 to 80% by weight.

When a silicone resin is used in the drug-containing layer of the transdermal patch of the present invention, the content of the silicone resin is determined with respect to the drug-containing layer in consideration of sufficient cohesive force and adhesive strength as the patch. The total amount is preferably 20 to 90% by weight, more preferably 20 to 80% by weight.

4. Tackifier The drug-containing layer may further contain a tackifier to improve the adhesive strength. As the tackifier, for example, rosin, glycerin ester of rosin, hydrogenated rosin, rosin derivatives such as glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic Saturated hydrocarbon resin, aliphatic hydrocarbon resin, resin maleate, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose , Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like. As the tackifier, commercially available products such as Alcon series (made by Arakawa Chemical Co., Ltd.), Pine Crystal series (made by Arakawa Chemical Co., Ltd.), Clearon series (made by Yasuhara Chemical Co., Ltd.) and YS resin series (made by Yasuhara Chemical Co., Ltd.) You may use it suitably. In particular, when the rubber-based resin is used as the tackifier, it is preferable to use glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, terpene resin, and aliphatic saturated hydrocarbon resin as the tackifier. The tackifiers may be used alone or in combination of two or more.

When the rubber-based resin is used as the pressure-sensitive adhesive, the content of the tackifier is preferably 5 to 70% by mass in total with respect to the drug-containing layer, and 10 to 10 when the rubber-based resin is used as the pressure-sensitive adhesive. 60 mass% is more preferable, and 20-50 mass% is still more preferable. 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 even more preferably 5 to 20% by mass, based on the drug-containing layer. When a silicone resin is used as the adhesive, the content of the drug-containing layer is preferably 1 to 40% by mass, more preferably 5 to 30% by mass, and even more preferably 5 to 20% by mass.

5. Plasticizer The drug-containing layer may further contain a plasticizer. Examples of the plasticizer include petroleum oils (for example, paraffinic process oils, naphthenic process oils, aromatic process oils, liquid paraffin, etc.), squalane, squalene, and vegetable oils (for example, olive oil, camellia oil, castor oil, tall oil). Oil, peanut oil etc.), silicone oil, dibasic acid ester (eg dibutyl phthalate, dioctyl phthalate etc.), liquid rubber (eg polybutene, liquid isoprene rubber etc.), diethylene glycol, polyethylene glycol, glycol salicylate, triacetin, citric acid Examples include triethyl and crotamiton. Further, as the plasticizer, commercially available products such as High Coal series (manufactured by Kaneda) may be appropriately used. Especially when the rubber-based resin is used as the adhesive, liquid paraffin is preferably used as the plasticizer. The plasticizers may be used alone or in combination of two or more.

The content of the plasticizer is adjusted in consideration of sufficient permeability of solifenacin and maintenance of sufficient cohesive force as a patch. 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 even more preferably 1 to 50% by mass based on the drug-containing layer. When an acrylic resin is used as the adhesive, it is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and further preferably 1 to 30% by mass, based on the drug-containing layer. When a silicone-based resin is used as the pressure-sensitive adhesive, the total amount is preferably 1 to 50% by mass, more preferably 1 to 40% by mass, and even more preferably 1 to 30% by mass based on the drug-containing layer.

6. The absorption enhancer drug-containing layer may further contain an absorption enhancer in order to improve the skin permeability of solifenacin. The absorption enhancer may be any compound that has been observed to have a skin permeation promoting action in transdermal administration, and examples thereof include capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oleic acid, and linole. Fatty acids or their esters such as acids, linolenic acid, isopropyl myristate, oleyl oleate, glycerin tri(caprylic/capric acid), isopropyl palmitate, octyldodecyl myristate, glyceryl oleate monoester, hexadecyl isostearate; lactic acid, Acetic acid, malic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, succinic acid, glutaric acid, glycolic acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, salicylic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, Organic acids such as toluenesulfonic acid and saccharin or salts thereof; polyvalent carboxylic acid esters such as diisopropyl adipate, diethyl sebacate and diisopropyl sebacate; inorganic acids such as phosphoric acid or salts thereof; lauryl alcohol, myristyl alcohol , Oleyl alcohol, isostearyl alcohol, cetyl alcohol, benzyl alcohol, oleyl alcohol, propylene glycol monocaprylate, propylene glycol dicaprylate, polyethylene glycol monooleate, etc., their esters or their ethers; 8 polyhydric alcohols (for example, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); sorbitan esters such as sorbitan monolaurate and sorbitan monooleate, or Ethers: polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monopalmitate; phenol ethers such as polyoxyethylene nonyl phenyl ether, polyoxyethylene octyl phenyl ether Castor oil or hydrogenated castor oil; ionic surfactants such as oleoyl sarcosine, betaine lauryl dimethylaminoacetate, sodium lauryl sulfate; polyoxyethylene alkyl ethers having 10 to 22 carbon atoms (for example, polyoxyethylene lauryl ether, poly Oxyethylene oleyl ether, polyoxyethylene stearyl ether Ter, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether, etc.); nonionic surfactants such as dimethyllaurylamine oxide; alkylmethyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide; 2-pyrrolidone , N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone and other pyrrolidones; 1-dodecylazacycloheptan-2-one, 1-geranylazacycloheptan-2-one and other azacycloalkanes; menthol , Terpenes such as camphor and limonene.

Of these, alcohols and esters are preferable. Examples of alcohols include polyhydric alcohols having 3 to 8 carbon atoms such as propylene glycol, dipropylene glycol and 1,3-butanediol; aliphatic alcohols such as oleyl alcohol and isostearyl alcohol. As the esters, for example, polyvalent carboxylic acid ester, fatty acid ester and the like are preferable. Examples of the polyvalent carboxylic acid ester include divalent aliphatic carboxylic acid esters such as diisopropyl adipate, diethyl sebacate, and diisopropyl sebacate. Examples of the fatty acid ester include isopropyl myristate, isopropyl palmitate, oleyl oleate, hexyl laurate, propylene glycol monocaprylate, propylene glycol dicaprylate, and glycerin tri(caprylic/caprate). More preferred are propylene glycol, dipropylene glycol, isopropyl myristate, isopropyl palmitate, hexyl laurate, and propylene glycol dicaprylate. The absorption enhancer may be used alone or in combination of two or more.

The content of the absorption enhancer can be appropriately adjusted according to the type of pharmaceutically acceptable salt of solifenacin, but is usually 30% by mass or less, and 25% by mass or less based on the drug-containing layer. preferable. When an absorption promoter is included, it is preferably 0.1 to 30% by mass, more preferably 0.5 to 25% by mass, and even more preferably 1 to 25% by mass.

7. Other optional components The drug-containing layer further contains known additives such as a pH adjusting agent, a cross-linking agent, an antioxidant, a colorant, an ultraviolet absorber, a filler, or a preservative, if necessary. You may.

The pH adjusting agent is a pharmaceutically acceptable salt of solifenacin, or a solvate thereof, for improving the solubility, stability, and skin permeability of the drug-containing layer for the purpose of improving the skin safety and the like. It can be used to adjust pH. The pH adjustor may be any compound as long as it is an acid or a base or a salt thereof which is usually used for pH adjustment in the field of pharmaceuticals, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, gluconic acid and succinic acid. Acid, acetic acid, lactic acid, methanesulfonic acid, edetic acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, trometamol, glycine, potassium hydroxide, calcium hydroxide, hydroxylation Examples thereof include sodium, magnesium hydroxide, sodium citrate, sodium acetate, sodium hydrogen carbonate, potassium hydrogen carbonate, and sodium carbonate.

Examples of the crosslinking agent include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, inorganic crosslinking agents such as metals or metal compounds. Are listed. Of these, isocyanate compounds or blocked isocyanate compounds are preferred.

Examples of the antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearic acid ester, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.

As the colorant, for example, indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitizer No. 201, Kumazasa extract, black iron oxide, quette, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water. Examples thereof include sodium oxide, talc, copper chlorophyllin sodium, green leaf extract of Hadakamugi, d-borneol, octyldodecyl myristate, methylene blue, manganese ammonium phosphate, and rose oil.

Examples of the ultraviolet absorber include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives and dioxane derivatives. Can be mentioned.

Examples of the filler include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium hydrogen carbonate, silicates (for example, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate). Sodium etc.), magnesium hydroxide, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.

Examples of preservatives include ethyl paraoxybenzoate, propyl paraoxybenzoate and butyl paraoxybenzoate.

The total content of other optional components is usually 10% by mass or less, preferably 5% by mass or less, based on the drug-containing layer. When other optional components are included, 0.05 to 10% by mass is preferable, and 0.1 to 5% by mass is more preferable.

The area of the drug-containing layer in the transdermal patch of the present invention can be appropriately adjusted depending on the content of the pharmaceutically acceptable salt of solifenacin and/or the skin permeation rate, etc. Is in the range of ^{2 to} 140 cm ² , preferably ² to 100 cm ² , and more preferably ² to 50 cm ² . The shape is not particularly limited, and may be square, rectangular, circular, elliptical, or the like.

The thickness of the drug-containing layer in the transdermal patch of the present invention may be appropriately adjusted depending on the type of adhesive, the content of a pharmaceutically acceptable salt of solifenacin, and/or the skin permeation rate. Although it is possible and not particularly limited, it is typically in the range of 20 to 300 μm, preferably 25 to 150 μm, and more preferably 25 μm to 100 μm.

The drug-containing layer in the transdermal patch of the present invention essentially contains a pharmaceutically acceptable salt of solifenacin and an inorganic base.

As the pharmaceutically acceptable salt of solifenacin, an organic acid salt (particularly, succinic acid salt) is preferable, and its content is preferably 0.5 to 25 mass% with respect to the drug-containing layer.

As the inorganic base, alkali metal hydroxides (particularly potassium hydroxide and sodium hydroxide) are preferable, and the content thereof is preferably 1 to 20 mass% with respect to the drug-containing layer.

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

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

Furthermore, when the drug-containing layer contains an absorption enhancer, the absorption enhancer is preferably isopropyl myristate. The content of the absorption enhancer is preferably 1 to 25 mass% with respect to the drug-containing layer.

<Support>
As the support in the transdermal patch of the present invention, a drug-impermeable stretchable or non-stretchable support can be used. Such a support is not particularly limited as long as it is one usually used in the field of pharmaceuticals, and examples thereof include polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets of nylon, polyurethane or the like, or laminates thereof, porous bodies, foams, films obtained by vapor deposition of aluminum, papers, woven fabrics, non-woven fabrics and the like.

<Release liner>
The transdermal patch of the present invention may further have a release liner. In this case, the release liner is laminated on the surface of the drug-containing layer laminated on the support, opposite to the surface in contact with the support, and the drug-containing layer is applied until the transdermal patch is applied to the skin. Can be protected. The release liner is not particularly limited as long as it is impermeable to at least solifenacin in the drug-containing layer.For example, a film made of a polymer material such as polyethylene, polypropylene, polyester, polyethylene terephthalate, or aluminum vapor-deposited on the film. It may be, for example, paper or paper coated with silicone oil.

<Manufacture of transdermal patch>
The transdermal patch of the present invention can be produced according to a known method. A mixture containing a pharmaceutically acceptable salt of solifenacin, an inorganic base, and optionally the above-mentioned optional components is prepared, and the mixture is applied (spread) onto a release liner to form a drug-containing layer. It can be produced by attaching a support to the drug-containing layer.

Specifically, for example, a pharmaceutically acceptable salt of solifenacin, an inorganic base, and, if necessary, an adhesive, a tackifier, a plasticizer, an absorption enhancer, and/or other additives are contained as described above. The amount is added to the organic solvent so as to obtain the amount, and mixed and stirred to prepare a coating liquid. As a mixing method, for example, stirring, in-line mixing, ultrasonic treatment or the like can be used. As the organic solvent, ethyl acetate, hexane, pentane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. The content of the organic solvent in the coating liquid is not particularly limited and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass based on the entire coating liquid.

Next, the coating solution is spread on a release liner, the solvent in the coating solution is evaporated to form a drug-containing layer, and then a support is attached to obtain a transdermal patch. be able to. Alternatively, the transdermal patch can also be obtained by spreading the coating liquid on a support, evaporating the solvent in the coating liquid to form a drug-containing layer, and then laminating a release liner. it can. From the viewpoint of ease of production, a method is preferred in which the coating solution is spread on a release liner, the solvent in the coating solution is evaporated to form a drug-containing layer, and then the support is bonded. The coating liquid can be applied using a knife coater, a comma coater, a reverse coater, or a die coater. Although an example of the manufacturing flow is shown in FIG. 1, the manufacturing flow is not limited to this.

Further, the transdermal patch of the present invention is obtained by heating and melting a pharmaceutically acceptable salt of solifenacin, an inorganic base, and optionally other optional components, and coating the melt on a release liner. It is also possible to produce a percutaneous absorption type patch by spreading the drug-containing layer and then adhering a support. The transdermal patch may be produced by applying (spreading) the melt on a support to form a drug-containing layer, and then laminating a release liner.

<Method of administration>
Treatment of overactive bladder with the transdermal patch of the present invention can be performed by directly applying the transdermal patch of the present invention to the skin of a subject and transdermally administering solifenacin. The subject in the present invention is a mammal such as a human, preferably a human. In particular, the treatment of overactive bladder can be carried out by applying (attaching) the patch to the skin of a patient in need of treatment of overactive bladder.

In the case of transdermal administration of solifenacin by the transdermal patch of the present invention, the content of solifenacin in the drug-containing layer and/or the skin permeation rate so as to achieve a blood concentration effective for the treatment of overactive bladder. , And the area of the drug-containing layer and/or the thickness of the drug-containing layer are appropriately adjusted, and then the transdermal patch of the present invention is applied to the skin.

The transdermal patch of the present invention may be applied to the skin of any part of the body as long as it can be applied, for example, upper arm, abdomen, chest, neck, lower back, buttocks or legs. Can be attached to.

The transdermal administration of the transdermal patch of the present invention to a subject may be combined with the administration of a pharmaceutical composition containing a pharmaceutical component other than a pharmaceutically acceptable salt of solifenacin, if necessary. In this case, the administration form may be simultaneous administration or administration at staggered times, and the pharmaceutical composition may be administered intravenously, intraperitoneally, subcutaneously and intramuscularly, orally, topically or transmucosally. Can be administered by a variety of routes including. A pharmaceutical composition containing a pharmaceutical ingredient other than a pharmaceutically acceptable salt of solifenacin is administered to a subject by an administration route usually used for the pharmaceutical ingredient. Examples of the medicinal component other than the pharmaceutically acceptable salt of solifenacin include, but are not limited to, α1 adrenergic receptor antagonists and β3 adrenergic receptor agonists.

Hereinafter, the present invention will be described more specifically based on Examples, but the present invention is not limited to the following Examples. In addition, in each example, all% are% by mass unless otherwise specified.

(Manufacture of transdermal patch containing solifenacin succinate)
Example 1
-Preparation of rubber-based resin composition (1) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Zeon Corporation), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industry Co., Ltd.) Liquid paraffin (HICOLM M-352, manufactured by Kaneda Co., Ltd.) having the following composition;
Styrene-isoprene-styrene block copolymer 35.0%
Alicyclic saturated hydrocarbon resin 50.0%
Liquid paraffin 15.0%
Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (1).

-Production of transdermal patch The rubber resin composition (1) was added to a pre-weighed solifenacin succinate salt, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 75.5%
4.5% potassium hydroxide
Solifenacin succinate 20.0%
Was prepared.

Next, the obtained coating solution was applied onto a polyethylene terephthalate release film (Film Vina 75E-0010 BD, manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent would be about 50 μm, and dried. After that, a 25 μm polyester film (Lumirror T-60, manufactured by Toray Industries, Inc.) was attached as a support to obtain a transdermal patch.

Example 2
The rubber resin composition (1) and isopropyl myristate were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 65.5%
Isopropyl myristate 10.0%
4.5% potassium hydroxide
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Example 3
The rubber resin composition (1) and isopropyl myristate are added to the pre-weighed solifenacin succinate salt, and the mixture is stirred uniformly. To this, an ethanol solution of sodium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 66.8%
Isopropyl myristate 10.0%
Sodium hydroxide 3.2%
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Comparative Example 1
The rubber-based resin composition (1) and isopropyl myristate were added to a pre-weighed solifenacin succinate salt, and the mixture was uniformly stirred to give the composition shown below;
Rubber-based resin composition (1) 70.0%
Isopropyl myristate 10.0%
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Test Example 1 Stability test of drug substance Solifenacin succinate and solifenacin free form were placed in brown screw vials and stored at 60°C. The solifenacin succinate and the solifenacin free form sampled over time were dissolved in a pH 3.5 phosphate buffer/acetonitrile mixture and analyzed by HPLC. From the peak areas of solifenacin and the decomposition products in the sample, the amount of decomposition products (%) was calculated by the following formula. The results obtained are shown in Table 1.

Degradation product amount (%) =
(Peak area of decomposition product)/(Peak area of solifenacin)×100
<HPLC conditions>
HPLC system: ACQUITY UPLC H-Class system (manufactured by Waters)
Column: Inertsil ODS-3 (2 μm, 2.1×100 mm, manufactured by GL Science)
Column oven: constant temperature around 40°C Mobile phase: pH 3.5 phosphate buffer/acetonitrile mixture Flow rate: 0.5 mL/min
Measurement wavelength: 210nm

As is clear from Table 1, the solifenacin succinate did not decompose with time, whereas the solifenacin free form increased the decomposition products with time.

Example 4
The rubber resin composition (1) and isopropyl myristate were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 77.7%
Isopropyl myristate 10.0%
Potassium hydroxide 2.3%
Solifenacin succinate 10.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Example 5
The rubber resin composition (1) and isopropyl myristate were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of sodium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 78.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Example 6
The rubber-based resin composition (1) and propylene glycol (SR Propylene Glychol, manufactured by Croda) were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 65.5%
Propylene glycol 10.0%
4.5% potassium hydroxide
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Example 7
-Preparation of rubber-based resin composition (2) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Zeon Corporation), hydrogenated rosin glycerin ester (Pine Crystal KE-311, manufactured by Arakawa Chemical Industry Co., Ltd.), Liquid paraffin (Hicol M-352, manufactured by Kaneda) has the following composition;
Styrene-isoprene-styrene block copolymer 35.0%
Hydrogenated rosin glycerin ester 50.0%
Liquid paraffin 15.0%
Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (2).

-Production of transdermal patch The rubber resin composition (2) and isopropyl myristate were added to a pre-weighed solifenacin succinate salt, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (2) 65.5%
Isopropyl myristate 10.0%
4.5% potassium hydroxide
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Example 8
Acrylic resin (Duro-Tak 387-2287, manufactured by Henkel) and isopropyl myristate were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of potassium hydroxide was added and stirred, and the composition shown below;
Acrylic resin (Duro-Tak 387-2287) 65.5%
Isopropyl myristate 10.0%
4.5% potassium hydroxide
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Comparative example 2
The rubber resin composition (1) was added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of diisopropanolamine was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 69.5%
Diisopropanolamine 10.5%
Solifenacin succinate 20.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Comparative Example 3
The rubber resin composition (1) and isopropyl myristate were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of diisopropanolamine was added and stirred, and the composition shown below;
Rubber-based resin composition (1) 59.5%
Isopropyl myristate 10.0%
Diisopropanolamine 10.5%
Solifenacin succinate 20.0%
A coating solution containing the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal patch.

Comparative Example 4
The rubber-based resin composition (1) and isopropyl myristate were added to a solifenacin-free body weighed in advance, and the mixture was stirred uniformly to give the composition shown below;
Rubber-based resin composition (1) 70.0%
Isopropyl myristate 10.0%
Solifenacin free body 20.0%
A coating solution containing the above was prepared and applied in the same manner as in Example 1 to obtain a transdermal patch.

Test Example 2 In Vitro Skin Permeability Test Using the obtained transdermal patch, an in vitro skin permeability test was conducted according to the following procedure.

After applying the transdermal patch of each Example and Comparative Example to the horny layer side of a 7-week-old male hairless mouse excised skin (Hos: HR-1 system, Hoshino Experimental Animal Breeding Co., Ltd.), 32 A vertical diffusion cell (trade name: Palmcell vertical TP-6: manufactured by Beadlex Co.) in which warm water of ℃ was circulated around the outer periphery was attached so that the skin basement membrane was on the receiver side. The receiver cell was filled with phosphate buffered saline (PBS(−), manufactured by Wako Pure Chemical Industries, Ltd.), the receiver solution was sampled with time, and the amount of solifenacin in the receiver solution was measured by the HPLC method. The cumulative amount of solifenacin permeated 24 hours after the start of the test was calculated from the measurement results, and the permeation rate was calculated (n=3 average value). The obtained results are shown in Tables 2 and 3.

Test Example 3 Stability Test The transdermal patch prepared in each of the Examples and Comparative Examples was heat-sealed in a bag of aluminum foil-based composite film (PET 12 μm/PE 15 μm/Al 9 μm/PE 30 μm). It was sealed and stored at 60°C.

The percutaneous absorption-type patch, which had been stored at 60° C. for 4 weeks, was peeled off from the release liner and shake-extracted with 2 mL of tetrahydrofuran for 30 minutes. After adding 8 mL of a pH 3.5 phosphate buffer/acetonitrile mixed solution to this solution, it was filtered through a 0.2 μm membrane filter and analyzed by the HPLC method. From the peak areas of solifenacin and the decomposition products in the sample, the amount of decomposition products (%) was calculated by the following formula. The obtained results are shown in Tables 2 and 3.

Degradation product amount (%) =
(Peak area of decomposition product)/(Peak area of solifenacin)×100

As is clear from Table 2 as a result of Test Example 2, when solifenacin succinate was used as an active ingredient and an inorganic base was added, sufficient skin permeability was obtained. On the other hand, from Table 3, Comparative Example 1 in which the inorganic base was not added exhibited a very low permeability. When a pharmaceutically acceptable salt of solifenacin was used as an active ingredient, the addition of a base was highly effective in improving skin permeability.

The amount of decomposition products in the preparation is preferably 0.5% or less. As a result of Test Example 3, as is clear from Tables 2 and 3, for the preparations of Examples 1 to 8 using an inorganic base as a base. The product had a decomposition product amount of 0.5% or less even under severe conditions of 60° C. for 4 weeks, and had sufficient temporal stability and skin permeability.

On the other hand, from Table 3, in Comparative Examples 2 and 3 using an organic amine as a base, a decomposition product exceeding 1% was observed at 60° C. for 4 weeks, which is remarkably higher than that of Examples 1 to 8 using an inorganic base. Stability is reduced. Further, in Comparative Example 4 in which the solifenacin free form was used as the active ingredient, the amount of decomposition products in the formulation exceeded 0.5% due to the low stability of the free form itself.

Examples 9-15
A transdermal patch was obtained in the same manner as in Example 2, except that isopropyl myristate of Example 2 was replaced with the esters shown in Table 4.

In Table 4, the skin permeation rate and the amount of decomposition products of each transdermal patch of Examples 9 to 15 were calculated in the same manner as in Test Examples 2 and 3. Further, the effect of promoting percutaneous absorption of each patch of Examples 2 and 9 to 15 was calculated by the following formula as an acceleration ratio.

Promotion ratio =
(Skin permeation rate of each of Examples 2 and 9 to 15)/(Skin permeation rate of Example 1)
Each of the patches of Examples 2 and 9 to 15 has a decomposition product amount of 0.07% or less and has sufficient stability over time, and 1.2 to 1. It showed a 7-fold effect of promoting transdermal absorption.

Example 16
-Preparation of rubber-based resin composition (3) Styrene-isoprene-styrene block copolymer (Quintac 3570C, manufactured by Zeon Corporation), alicyclic saturated hydrocarbon resin (Alcon P-100, manufactured by Arakawa Chemical Industry Co., Ltd.) , Polybutene (polybutene HV-300, manufactured by JX Nippon Mining & Energy Corporation) shown below;
Styrene-isoprene-styrene block copolymer 30.0%
Alicyclic saturated hydrocarbon resin 50.0%
Polybutene 20.0%
Was dissolved in toluene so that the solid content concentration was 50% to obtain a rubber-based resin composition (3).

-Production of transdermal patch The rubber resin composition (3) and isopropyl myristate were added to a pre-weighed solifenacin succinate salt, and the mixture was stirred uniformly. To this, an ethanol solution of sodium hydroxide was added and stirred, and the composition shown below;
Rubber-based resin composition (3) 78.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

Using the transdermal patch of Example 16, an in vitro skin permeability test was conducted in the same manner as in Test Example 2. The skin permeation rate was 25.9 μg/cm ² /h. A stability test was conducted in the same manner as in Test Example 3 using the percutaneous absorption type patch obtained in Example 16. The amount of decomposition products was 0.20% (60°C, 4 weeks).

Reference example 1
"Neoxy (registered trademark) tape" for treating overactive bladder, which is currently in clinical use, was used.

Test Example 4 Primary Irritation Test of Guinea Pig Skin A 6-week-old Hartley male guinea pig was used. On the day before administration, the left and right body parts of the guinea pig are shaved and shaved to a size of about 4×8 cm. On the day after cutting, the patch (15 mmφ) of Example 2, Example 3, Example 5, Example 16, Comparative Example 4, and Reference Example 1 was applied to the left and right body parts, and the foam pad M with an adhesive ( After fixing with 3M Healthcare Co., a polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.) is wound around the body, it is fixed with Silky Tech (ALCARE No. 5). 24 hours after administration, each patch was removed, and the patch was wiped with absorbent cotton moistened with acetone. The skin reaction was observed 24, 48, and 72 hours after administration, and the skin irritation index (P.I.I.) was calculated with reference to the Draize standard (1959) shown in Table 5. The skin irritation was evaluated. However, 24 hours after administration, the observation was carried out about 1 hour after wiping. For each test substance, individual individual scores at 24, 48, and 72 hours after administration are calculated, and divided by the number of observations (3 times) to determine the P. I. I. (Individual P.I.I.) was calculated. Individual P.C. I. I. The values are totaled, and the average value is the P.I. of the transdermal patch. I. I. And

The results are shown in Table 6. The evaluation of irritation is given in P. I. When I was 0, it was designated as "non-irritant", when it was greater than 0 and less than 2, it was designated as "mild stimulant", when it was 2 or more and less than 5, it was designated as "moderate stimulant", and when it was 5 or more, it was designated as "strong stimulant". No statistical processing was performed during the evaluation.

As is apparent from Table 6, the transdermal patch of Examples 2, 3, 5, and 16 is a mild stimulant, and the transdermal patch of Comparative Example 4 and Reference Example 1 Skin irritation is low compared to.

Test Example 5 In vivo skin permeability test (rat)
The back skin of an 8-week-old male SD rat (Charles River, n=5) was shaved with an electric clipper. The transdermal preparation of Example 16 (content of solifenacin succinate per preparation: about 5 mg/sheet) cut into a size of 10 cm ² (3.16 cm×3.16 cm) was cut on the back of the rat. It was applied, wrapped with Memberon (manufactured by White Cross), Tegaderm Roll (manufactured by 3M Healthcare) and a non-woven adhesive bandage (manufactured by Silky Tech, ALCARE) and administered for 24 hours. At 0.5, 1, 3, 6, 12, 20, 24, and 30 hours (6 hours after formulation removal) after application, blood was collected from the subclavian vein (about 0.3 mL) under isoflurane inhalation anesthesia and centrifuged. Plasma was obtained by separation (4°C, 2000G, 15 minutes).

For comparison, a solution of solifenacin succinate in physiological saline was administered intravenously (n=4). The dose was adjusted so that the dose was 0.3 and 1 mg/kg of the rat body weight, and the dose was 1 mL/kg. At 1, 3, 5, 10, 15 and 30 minutes, 1, 2, 3 and 6 hours after administration, blood was collected from the subclavian vein (about 0.3 mL) under isoflurane inhalation anesthesia and centrifuged (4° C., 2000 G, 15 minutes) to obtain plasma.

Acetonitrile (150 μL) was added to the obtained plasma (50 μL) and mixed, and the mixture was centrifuged (4° C., 20000 G, 5 minutes) for deproteinization, filtered with a membrane filter having a pore size of 0.2 μm (Merck Millipore), and LC /MS/MS was used to measure the plasma concentration of solifenacin (ng/mL) at each time. The obtained results are shown in FIG.
<LC/MS/MS measurement conditions>
Equipment: ACQUITY UPLC H-Class system (Waters)
Column: Acquity UPLC BEH C18 1.7 μm 2.1 x 50 mm (Waters)
Column temperature: 40℃
Flow rate: 0.4 mL/min Detector: Xevo G2-S Q-Tof (Waters)
Detection conditions: Resolution・Positive, m/z=363.21
Mobile phase: 0.1% formic acid aqueous solution and 0.1% formic acid-acetonitrile solution mixed solution Sample injection volume: 1 μL

As is clear from FIG. 2, when solifenacin was intravenously administered, it rapidly disappeared from the plasma, whereas when the transdermal preparation of Example 16 was applied to rats, solifenacin was maintained. It was confirmed that plasma concentration above a certain level was maintained for 24 hours after application by the transdermal absorption.

Example 17
-Preparation of rubber-based resin composition (4) Styrene-isoprene-styrene block copolymer (Quintac 3570C, Nippon Zeon Co., Ltd.), alicyclic saturated hydrocarbon resin (Alcon P-100, Arakawa Chemical Industry Co., Ltd.) Liquid paraffin (HICOLM M-352, manufactured by Kaneda Co., Ltd.) having the following composition;
Styrene-isoprene-styrene block copolymer 30.0%
Alicyclic saturated hydrocarbon resin 50.0%
Liquid paraffin 20.0%
Was dissolved in toluene so that the solid content concentration became 50% to obtain a rubber-based resin composition (4).

-Production of transdermal patch The rubber resin composition (4), isopropyl myristate, and dibutylhydroxytoluene (manufactured by Tokyo Kasei Kogyo Co., Ltd.) were added to the solifenacin succinate salt weighed in advance, and the mixture was stirred uniformly. To this, an ethanol solution of sodium hydroxide was added and stirred, and the composition shown below;
Rubber resin composition (4) 77.4%
Isopropyl myristate 10.0%
Sodium hydroxide 1.6%
Solifenacin succinate 10.0%
Dibutyl hydroxytoluene 1.0%
Was prepared and coated in the same manner as in Example 1 to obtain a transdermal patch.

An in vitro skin permeation test was conducted in the same manner as in Test Example 2 using the transdermal patch of Example 17. The skin permeation rate was 18.7 μg/cm ² /h. A stability test was conducted in the same manner as in Test Example 3, and as a result, the amount of decomposition products was 0.15% (60°C for 4 weeks).

According to the present invention, a transdermal patch containing a pharmaceutically acceptable salt of solifenacin, which is excellent in transdermal absorbability, storage stability and safety, is provided. The transdermal patch of the present invention can more effectively treat overactive bladder.

Claims (10)

A transdermal patch having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of solifenacin and an inorganic base, and the inorganic base is an alkali metal hydroxide. in it, transdermal patch. The transdermal patch according to claim 1, wherein the drug-containing layer further contains a pressure-sensitive adhesive, and the pressure-sensitive adhesive contains at least one selected from the group consisting of a rubber resin and an acrylic resin as a main component. Agent. The transdermal patch according to claim 2, wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer. The transdermal patch according to claim 2 or 3, wherein the drug-containing layer further contains a tackifier. The transdermal patch according to claim 4, wherein the tackifier is an alicyclic saturated hydrocarbon resin. The transdermal 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. 7. The transdermal absorption type according to claim 1, wherein the drug-containing layer further contains an absorption promoter, and the absorption promoter is at least one selected from the group consisting of alcohols and esters. Patch. The percutaneous absorption type patch according to any one of claims 1 to 7, wherein the pharmaceutically acceptable salt of solifenacin is solifenacin succinate. The percutaneous absorption type patch according to any one of claims 1 to 8, which further comprises a release liner and is laminated in the order of a support, a drug-containing layer, and a release liner. The method for producing a percutaneous absorption type patch according to claim 1, wherein a mixture containing a pharmaceutically acceptable salt of solifenacin and an inorganic base is applied onto a release liner to form a drug-containing layer. A method of manufacturing, wherein a support is attached to the drug-containing layer, and the inorganic base is an alkali metal hydroxide .

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