Transdermal absorption preparation

Abstract

The present invention provides a transdermally absorbable preparation in which an adhesive layer containing a drug is formed on a support, the adhesive layer containing at least a thermoplastic elastomer and a higher fatty acid ester, and the content of a tackifier is not more than 10% by weight, the preparation being excellent in terms of drug solubility and release properties, as well as adhesiveness to the skin and low irritation to the skin.

Description

[0001] This application is a divisional application of PCT application No. 201680081472.1 (International filing date: December 9, 2016) entitled "Transdermal absorption preparation" entered the national phase. TECHNICAL FIELD

[0002] The present application relates to a transdermal absorption preparation having sufficient drug solubility, transdermal permeability, and sufficient adhesion to the skin, and showing low skin irritation. BACKGROUND

[0003] When a drug is to be transdermally absorbed, the drug is added to an adhesive base or the like and formed into a transdermal absorption preparation. In recent years, in transdermal absorption preparations, a tape preparation, which is more excellent in adhesion than a poultice preparation containing a large amount of water as a constituent component, is often used. As an adhesive base for the tape preparation, an oleophilic adhesive base, such as a rubber, an acrylic, a silicone type, or the like, is used. Among them, a rubber adhesive base is widely used because it can easily blend an additive compared to other adhesive bases (Patent Documents 1 to 3).

[0004] However, even for a transdermal absorption preparation using a rubber adhesive base, problems such as insufficient drug release, generation of skin irritation due to a tackifier generally added to the transdermal absorption preparation, and the like, have been pointed out.

[0005] In such a case, the present inventors have found that, even without using a tackifier, by using a thermoplastic elastomer and a large amount of liquid paraffin with respect to the elastomer, an adhesive sheet for attaching to the skin having sufficient adhesion and showing low skin irritation can be obtained, and by adding a drug or a pharmaceutically acceptable salt thereof to the adhesive sheet, a transdermal absorption preparation having sufficient transdermal absorption can be obtained (Patent Document 4).

[0006] However, depending on the contained medicament, and in some cases, the solubility of the medicament in the base is insufficient, crystals are precipitated, or sufficient transdermal permeability cannot be achieved.

[0007] On the other hand, donepezil (i.e., l-benzyl-4-(5,6-dimethoxyindanone-2-yl)methylpiperidine) is widely used in the form of a hydrochloride (i.e., donepezil hydrochloride) for the treatment of mild to moderate Alzheimer-type dementia. Alzheimer-type dementia is a disease in which the normal function of the brain is gradually lost due to a faster decrease (degeneration) of nerve cells constituting the brain than usual aging. About 5% of the population of 65 years of age or older are said to be patients of dementia; 40% of them are of Alzheimer-type, and the number of patients is the largest among neurodegenerative diseases. The number of patients is expected to increase in the future aging society, and its treatment will become increasingly important. The effect of donepezil on Alzheimer-type dementia is considered to be based on an increase in acetylcholine in the brain, which is achieved mainly by inhibiting acetylcholinesterase and activating the cholinergic nervous system in the brain.

[0008] Conventionally, donepezil is mainly administered orally, and is marketed in the form of tablets, gels, and the like. However, patients having deteriorated symptoms of dementia have difficulty in taking the drug orally. Therefore, it is desired to administer donepezil by a route other than orally, particularly transdermally using a transdermal absorption preparation.

[0009] Patent Document 5 describes the use of an ester of a fatty acid with a lower alcohol, for example, diisopropyl adipate, and the like, to promote the transdermal absorption of donepezil and the like in a transdermal absorption preparation. Further, Patent Document 6 describes the use of an acetate to improve the transdermal absorption of donepezil hydrochloride in a transdermal absorption preparation. However, the methods disclosed in these documents fail to provide good transdermal absorption. On the other hand, Patent Document 7 describes the use of a higher fatty acid salt to improve the transdermal absorption of donepezil hydrochloride in a transdermal absorption preparation, and a relatively good transdermal absorption is achieved. However, in some cases, crystals are precipitated from the preparation during storage, resulting in a decrease in adhesion properties, an increase in skin irritation, and a decrease in transdermal absorption.

[0010] Prior Art Documents Patent Documents Patent Document 1: JP-A-2001-302502 Patent Document 2: JP-A-9-291028 Patent Document 3: JP-A-10-316559 Patent Document 4: WO 2012 / 029325 Patent Document 5: JP-A-11-315016 Patent Document 6: WO 2003 / 032960 Patent Document 7: WO 2013 / 035850. SUMMARY

[0011] Problems to be Solved by the Invention An object of the present application is to provide a transdermal absorption preparation which has sufficient drug solubility, transdermal permeability, and sufficient adhesion to skin, and which shows low skin irritation. In particular, an object of the present application is to provide a transdermal absorption preparation which shows good transdermal absorption of donepezil.

[0012] Means for Solving the Problems The present inventors have conducted intensive studies to solve the aforementioned problems, and have found that, by using a thermoplastic elastomer and a fatty acid ester as an adhesive base without using an adhesion enhancer, a transdermal absorption preparation having sufficient adhesion to skin, sufficient drug solubility, and sufficient transdermal absorption can be obtained, which led to completion of the present application.

[0013] Further, it has been found that, when the drug is donepezil, by adding a long-chain fatty acid (higher fatty acid) to the above-mentioned adhesive base together with donepezil, the transdermal absorption of donepezil can be further improved.

[0014] The present application based on these findings is described below.

[0015] [1] A transdermal absorption preparation comprising: a support; and a drug-containing adhesive layer formed on the support, wherein the drug-containing adhesive layer contains a thermoplastic elastomer and a higher fatty acid ester, the content of the higher fatty acid ester in the drug-containing adhesive layer is greater than 50 parts by weight and not more than 500 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and the content of the adhesion enhancer in the drug-containing adhesive layer is not more than 10% by weight (including 0% by weight) with respect to the total amount of the drug-containing adhesive layer.

[0016] [2] The transdermal absorption preparation according to the above-mentioned [1], wherein the higher fatty acid of the higher fatty acid ester has a carbon number of not less than 12 and not more than 30.

[0017] [3] The transdermal absorption preparation according to the above-mentioned [1] or [2], wherein the thermoplastic elastomer contains a styrene-based block copolymer.

[0018] [4] The transdermal absorption preparation according to the above-mentioned [3], wherein the styrene-based block copolymer contains a styrene-isoprene-styrene block copolymer.

[0019] [5] The transdermal absorption preparation according to any one of the above-mentioned [1] to [4], wherein the drug-containing adhesive layer does not contain an adhesion enhancer.

[0020] [6] The transdermal absorption preparation according to any one of the above-mentioned [1] to [5], wherein the drug-containing adhesive layer contains a polyisobutylene.

[0021] [7] The transdermal absorption formulation described in any one of [1]-[6] above, wherein the drug-containing adhesive layer comprises donepezil or a salt thereof as the drug.

[0022] [8] The transdermal absorption formulation described in [7] above, wherein the drug-containing adhesive layer comprises donepezil or a salt thereof, and higher fatty acids.

[0023] [9] The transdermal absorption formulation described in [8] above, wherein the higher fatty acids have a carbon number of not less than 12 and not more than 30.

[0024]

[10] The transdermal absorption formulation described above [8], wherein the higher fatty acid comprises oleic acid.

[0025] The effects of the invention The transdermal absorption formulation of the present invention is excellent in terms of drug solubility and release, as well as adhesion to the skin and low irritation to the skin.

[0026] Furthermore, the donepezil-containing transdermal absorption formulation of the present invention exhibits excellent donepezil transdermal absorption. Attached Figure Description

[0027] Figure 1 This is a graph showing the transdermal permeation of scopolamine after 24 hours in an in vitro transdermal permeation test of Examples 1-3, Comparative Example 1, and a commercially available transdermal permeation formulation containing scopolamine.

[0028] Figure 2 This is a graph showing the relationship between the transdermal penetration rate of scopolamine in rats and the application time in an in vitro transdermal permeation test of Example 3 and a commercially available transdermal absorption formulation containing scopolamine.

[0029] Figure 3 This is a graph showing the transdermal permeation of donepezil 24 hours after in vitro transdermal permeation tests of Examples 4-5 and Comparative Examples 2-4.

[0030] Figure 4 This is a graph showing the relationship between the percutaneous penetration rate of donepezil in rats and the adhesion time in the in vitro percutaneous penetration test of Examples 4-5.

[0031] Figure 5 This is a graph showing the transdermal permeation volume of flurbiprofen or diclofenac after 24 hours in the in vitro transdermal permeation tests of Examples 6-8 and Comparative Examples 5-6. Detailed Implementation

[0032] The transdermal absorption preparation of the present application is a transdermal absorption preparation comprising a support, and a drug-containing adhesive layer (hereinafter also simply referred to as "adhesive layer") formed on the support, wherein the adhesive layer contains a thermoplastic elastomer and a higher fatty acid ester, the content of the higher fatty acid ester in the drug-containing adhesive layer is greater than 50 parts by weight and not more than 500 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and the content of the tackifier in the drug-containing adhesive layer is not more than 10% by weight (including 0% by weight) with respect to the total amount of the drug-containing adhesive layer.

[0033] Further, the transdermal absorption preparation of the present application is characterized by the following embodiment, wherein the drug-containing adhesive layer contains donepezil or a salt thereof, and a higher fatty acid.

[0034] The transdermal absorption preparation of the present application contains a thermoplastic elastomer and a higher fatty acid ester, wherein The content of the higher fatty acid ester in the drug-containing adhesive layer is preferably greater than 50 parts by weight and not more than 500 parts by weight with respect to 100 parts by weight of the thermoplastic elastomer, and the content of the tackifier in the drug-containing adhesive layer is preferably not more than 10% by weight (including 0% by weight). With such a large amount of the higher fatty acid ester, good adhesiveness can be achieved even when the content of the tackifier in the drug-containing adhesive layer is limited to 10% by weight or less. By limiting the content of the tackifier, a transdermal absorption preparation showing lower skin irritation can be obtained. Further, the presence of a large amount of the higher fatty acid ester also improves the transdermal absorption of the drug, further improves the drug solubility, and can inhibit, for example, crystallization thereof.

[0035] The "thermoplastic elastomer" for the drug-containing adhesive layer of the present application is an elastomer having thermoplasticity, wherein it softens when heated to thereby show flowability, and returns to a rubber-like elastomer by cooling, and various thermoplastic elastomers of urethane, acrylic, styrene, olefin series, and the like can be mentioned. Further, in the present application, as the thermoplastic elastomer, a mixture of a triblock copolymer and a diblock copolymer is preferably used, wherein the content of the diblock copolymer in the mixture is not less than 20% by weight, thereby imparting sufficient skin adhesiveness to the adhesive sheet and the transdermal absorption preparation. When the mixing ratio of the diblock copolymer is too low, the skin adhesiveness tends to decrease. When it is too high, the shape retention property of the drug-containing adhesive layer tends to decrease, which in turn can cause inconvenience such as adhesive residue on the skin after peeling, and the like when attached to the skin. Therefore, the mixing ratio of the triblock copolymer to the diblock copolymer [(triblock copolymer) / (diblock copolymer)] is preferably 20 / 80 to 75 / 25, further more preferably 30 / 70 to 70 / 30, in terms of weight ratio.

[0036] In particular, the solution viscosity of a 25% by weight toluene solution of the thermoplastic elastomer at 25°C is preferably not less than 0.5 Pa・s, further preferably not less than 0.7 Pa・s, particularly preferably not less than 0.9 Pa・s, thereby providing a good balance (balance between adhesiveness and easy peelability) of the adhesion properties of the resulting skin-adhering adhesive sheet and transdermal absorption preparation, and the like. Although the upper limit of the solution viscosity is not particularly limited, it is preferably not more than 2.0 Pa・s, more preferably not more than 1.8 Pa・s.

[0037] As used herein, the "solution viscosity of a 25% by weight toluene solution at 25°C" refers to a value measured based on the "Viscosity Measurement Method for Styrene-Isoprene-Styrene Block Copolymer" described in page 375 of "Japanese Pharmaceutical Additives Standards 2003" (issued by YAKUJI NIPPO LIMITED).

[0038] It is preferable to use a styrene-based thermoplastic elastomer, particularly a styrene-based block copolymer, as the thermoplastic elastomer, thereby simultaneously achieving sufficient skin adhesiveness and low skin irritability as the object of the present application. Examples of the styrene-based block copolymer include styrene-diene block copolymers, styrene-diene-styrene block copolymers, styrene-isoprene block copolymers, styrene-isoprene-styrene block copolymers, styrene-ethylene / butylene block copolymers, styrene-ethylene / butylene-styrene block copolymers, styrene-ethylene / propylene block copolymers, styrene-ethylene / propylene-styrene block copolymers, styrene-isobutylene block copolymers, styrene-isobutylene-styrene block copolymers, and the like. In the foregoing, "ethylene / butylene" indicates a copolymer block of ethylene and butylene, and "ethylene / propylene" indicates a copolymer block of ethylene and propylene. Of these styrene-based block copolymers, a triblock copolymer and a diblock copolymer can be preferably used in combination at a mixing ratio described above, and 3 or more kinds can be used in combination. That is, 1 or more kinds of triblock copolymers and diblock copolymers can be used, respectively.

[0039] From the viewpoint of simultaneously achieving sufficient skin adhesiveness and low skin irritability, as well as the availability and handling properties of the product for adhering a skin preparation, of the above-described styrene-based block copolymers, it is preferable to use a mixture containing a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer. In particular, from the viewpoint of adhesiveness, it is preferable to use a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

[0040] From the viewpoint of the object of the present application, the styrene-isoprene-styrene block copolymer preferably has a styrene content of 5% by weight to 60% by weight, more preferably 10% by weight to 50% by weight, in the copolymer. Further, it preferably has a weight average molecular weight having a weight average molecular weight as measured by gel permeation chromatography of not less than 20,000 and not more than 500,000, more preferably not less than 30,000 and not more than 300,000. Further, the styrene-isoprene block copolymer preferably has a styrene content of not less than 5% by weight and not more than 50% by weight, more preferably not less than 10% by weight and not more than 40% by weight, in the copolymer. Further, it preferably has a weight average molecular weight having a weight average molecular weight as measured by gel permeation chromatography of not less than 10,000 and not more than 500,000, more preferably not less than 20,000 and not more than 300,000. The mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer preferably has a weight average molecular weight having a weight average molecular weight as measured by gel permeation chromatography of not less than 20,000 and not more than 500,000, more preferably not less than 30,000 and not more than 300,000.

[0041] As the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, copolymers produced by methods known per se can be used respectively. As the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, commercially available products satisfying the above-described characteristics can be used respectively. Further, mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer are also commercially available, and commercially available products of mixtures of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer satisfying the above-described characteristics can be preferably used in the above-described mixing ratio.

[0042] Examples of commercially available products include, for example, "KRATON D1111", "KRATON D1163", "KRATON D1113", and "KRATON D1119" manufactured by KRATON POLYMERS, "JSR SIS5002", "JSR SIS5229", "JSR SIS5403", and "JSR SIS5505" manufactured by JSR, "Quintac 3421", "Quintac 3433N", "Quintac 3520", "Quintac 3450", and "Quintac 3270" manufactured by Nippon Zeon Co., Ltd., and the like. Among these, from the viewpoint of the mixing ratio of the above-mentioned triblock copolymer and diblock copolymer, and the solution viscosity, it is preferable to use "KRATON D1163", "KRATON D1113", "JSR SIS5403", "JSR SIS5505", "Quintac 3433N", "Quintac 3520", and particularly preferably "JSR SIS5505", "Quintac 3520".

[0043] When the content of the thermoplastic elastomer in the drug-containing adhesive layer is too small, it is difficult to maintain the shape of the drug-containing adhesive layer, and when it is too large, the skin adhesiveness tends to be insufficient. Therefore, the content of the thermoplastic elastomer in the drug-containing adhesive layer of the transdermal absorption preparation of the present application is preferably not less than 8% by weight, more preferably not less than 10% by weight, further preferably not less than 12% by weight, particularly preferably not less than 15% by weight. Furthermore, it is preferably not more than 44% by weight, more preferably not more than 42% by weight, further preferably not more than 40% by weight, particularly preferably not more than 35% by weight.

[0044] In a more specifically preferable embodiment, the content of the thermoplastic elastomer in the drug-containing adhesive layer is, for example, 8% by weight to 44% by weight, more preferably 8% by weight to 42% by weight, particularly preferably 10% by weight to 40% by weight.

[0045] In the present application, the higher fatty acid ester is a compound in which the carboxyl group of a higher fatty acid forms an ester bond with a fatty alcohol. The higher fatty acid ester moderately plasticizes the thermoplastic elastomer, contributes to imparting adhesiveness, and has moderate affinity with a drug, thereby improving drug solubility, preventing crystal precipitation, and improving transdermal absorption.

[0046] In the present application, "fatty acid" means a chain monocarboxylic acid as described in the 5th edition of the Dictionary of Chemistry (IWANAMI SHOTEN), "higher fatty acid" means a fatty acid having a carbon number of not less than 10, and "lower fatty acid" means a fatty acid having a carbon number of not more than 9.

[0047] The higher fatty acid constituting the higher fatty acid ester can be linear or branched. Although the higher fatty acid can be saturated or unsaturated, it is preferable to be a saturated fatty acid from the viewpoints of the plasticizing effect and thermal stability of the thermoplastic elastomer. The carbon number of the higher fatty acid is preferably not less than 12, more preferably not less than 14, further preferably not less than 16, and is preferably not more than 30, more preferably not more than 24, further preferably not more than 20.

[0048] Examples of the saturated higher fatty acid include capric acid (carbon number: 10), lauric acid (carbon number: 12), myristic acid (carbon number: 14), palmitic acid (carbon number: 16), stearic acid (carbon number: 18), isostearic acid (carbon number: 18), arachidic acid (carbon number: 20), behenic acid (carbon number: 22), lignoceric acid (carbon number: 24), cerotic acid (carbon number: 26), montanic acid (carbon number: 28), melissic acid (carbon number: 30), and the like. Among these, myristic acid, palmitic acid, or stearic acid is preferable.

[0049] Examples of the unsaturated higher fatty acid include palmitoleic acid (carbon number: 16), oleic acid (carbon number: 18), linoleic acid (carbon number: 18), (9, 12, 15)-linolenic acid (carbon number: 18), (6, 9, 12)-linolenic acid (carbon number: 18), eleostearic acid (carbon number: 18), and the like. Among these, oleic acid and linoleic acid are preferable, and oleic acid is more preferable.

[0050] As the aliphatic alcohol constituting the higher fatty acid ester, a saturated or unsaturated aliphatic alcohol having a carbon number of 1 to 20 is preferable. For example, methanol, ethanol, propanol, isopropanol, butanol, hexanol, pentanol, heptanol, octanol, decanol, sperm whale alcohol, palmityl alcohol, hexyl decanol, oleyl alcohol, octyldodecyl alcohol, and the like can be mentioned.

[0051] Specific preferable examples of the higher fatty acid ester include isopropyl myristate, ethyl myristate, octyldodecyl myristate, and the like myristate ester, isopropyl palmitate, ethyl palmitate, and the like palmitate ester, isopropyl stearate, and the like stearate ester, decyl oleate, octyldodecyl oleate, oleyloleyl oleate, and the like oleate ester, ethyl linoleate, and the like linoleate ester, and the like.

[0052] The content of the higher fatty acid ester in the drug-containing adhesive layer is preferably more than 50 parts by weight and not more than 500 parts by weight, more preferably not less than 100 parts by weight and not more than 300 parts by weight, with respect to 100 parts by weight of the thermoplastic elastomer. When the higher fatty acid ester is too little, good adhesiveness or drug solubility cannot be achieved, and, on the contrary, when the higher fatty acid ester is too much, it is difficult to maintain the shape of the adhesive layer.

[0053] In order to reduce skin irritation and the like, the content of the tackifier in the drug-containing adhesive layer is preferably not more than 10% by weight, more preferably not more than 8% by weight, further preferably not more than 6% by weight, particularly preferably not more than 3% by weight. Most preferably, the drug-containing adhesive layer does not contain a tackifier (i.e., the content of the tackifier is 0% by weight).

[0054] Tackifiers are well known in the field of transdermal absorption preparations, and generally refer to resins used to impart or improve the tackiness of an adhesive base forming an adhesive layer. Examples of tackifiers include rosin-based resins, polyterpene resins, coumarone-indene resins, petroleum-based resins, terpene resins, terpene-phenol resins, alicyclic saturated hydrocarbon resins, and the like.

[0055] In the present application, polyisobutylene is preferably added to adjust the adhesive properties. The "polyisobutylene" used in the drug-containing adhesive layer of the present application is a polymer of isobutylene, which is an elastic rubbery semi-solid or viscous substance, and is added in the present application to impart sufficient skin adhesion to the transdermal absorption preparation.

[0056] From the object of the present application, low molecular weight polyisobutylene having a viscosity average molecular weight of 30,000 to 100,000, medium molecular weight polyisobutylene having a viscosity average molecular weight of 100,000 to 500,000, and high molecular weight polyisobutylene having a viscosity average molecular weight of 500,000 to 5,000,000 can be used individually or in a mixture. In particular, a mixture of low molecular weight polyisobutylene and high molecular weight polyisobutylene is preferably used, or medium molecular weight polyisobutylene is used alone, to provide a good balance of low skin irritation and high skin adhesion.

[0057] As the polyisobutylene, isobutylene polymers manufactured by methods known per se can be used. In particular, in the adhesive layer of the present application for attachment to the skin, those conforming to the standards defined in the Japanese Standards of Pharmaceutical Additives, the United States Pharmacopoeia, and the like can be preferably used. As the polyisobutylene, commercially available products satisfying the above-mentioned viscosity average molecular weights, respectively, can be used.

[0058] As commercially available products, examples of low molecular weight polyisobutylene include "Oppanol B10 SFN", "Oppanol B10N", "Oppanol B12 SFN", "Oppanol B15 SFN", "Oppanol B15N", and the like manufactured by BASF, examples of medium molecular weight polyisobutylene include "Oppanol B30 SF", "Oppanol B50 SF", "Oppanol B50", and the like manufactured by BASF, and examples of high molecular weight polyisobutylene include "Oppanol B80", "Oppanol B100", "Oppanol B150", "Oppanol B200", and the like manufactured by BASF. Among these, from the viewpoint of the balance of solubility at the time of forming a coating solution, and the adhesive physical properties of the obtained adhesive sheet and transdermal absorption preparation, it is particularly preferable to use "Oppanol B15 SFN" and "Oppanol B15N" having a viscosity average molecular weight of 50,000 to 100,000 as the low molecular weight polyisobutylene, to use "Oppanol B50 SF" and "Oppanol B50" as the medium molecular weight polyisobutylene, and to use "Oppanol B80" as the high molecular weight polyisobutylene.

[0059] When the content of polyisobutylene in the adhesive layer is too small, the enhancement of skin adhesiveness becomes insufficient. When the content is too high, the worsening of skin irritability due to excessive enhancement of skin adhesiveness, adhesive residue at the time of peeling, poor drug solubility, and the like sometimes become problems. Therefore, the content of polyisobutylene in the drug-containing adhesive layer of the transdermal absorption preparation of the present application is not less than 0.1 parts by weight, preferably not less than 0.3 parts by weight, more preferably not less than 0.5 parts by weight, further preferably not less than 1 part by weight, relative to 100 parts by weight of the thermoplastic elastomer. It is also not more than 300 parts by weight, preferably not more than 100 parts by weight, more preferably not more than 50 parts by weight, further preferably not more than 30 parts by weight, relative to 100 parts by weight of the thermoplastic elastomer.

[0060] In a more specific and preferable embodiment, the content of polyisobutylene in the drug-containing adhesive layer is 0.1% by weight to 50% by weight, more preferably 0.2% by weight to 40% by weight, further preferably 0.3% by weight to 30% by weight, particularly preferably 0.5% by weight to 25% by weight.

[0061] The "drug or pharmaceutically acceptable salt thereof" in the present application means a drug or pharmaceutically acceptable salt thereof for transdermal absorption, and is not particularly limited. Examples of the drug include: anti-inflammatory agents such as acetaminophen, phenacetin, mefenamic acid, diclofenac sodium, flufenamic acid, aspirin, sodium salicylate, methyl salicylate, glycol salicylate, aminopyrine, alclofenac, ibuprofen, naproxen, flurbiprofen, ketoprofen, sodium amfenac, piroxicam, indomethacin, piroxicam, diflunisal, and the like; steroidal anti-inflammatory agents such as hydrocortisone, triamcinolone acetonide, dexamethasone, prednisolone, and the like; vasodilators such as diltiazem hydrochloride, pentaerythritol tetranitrate, isosorbide dinitrate, trimetazidine, nicorandil, nitroglycerin, molsidomine, nitrosopentamethyleneamine, benzazoline hydrochloride, nifedipine, and the like; antiarrhythmic agents such as procainamide hydrochloride, lidocaine hydrochloride, propranolol hydrochloride, alprenolol hydrochloride, atenolol, nadolol, metoprolol tartrate, amarin, disopyramide, mexiletine hydrochloride, and the like; antihypertensive agents such as ecarazine hydrochloride, indapamide, clonidine hydrochloride, bunolol hydrochloride, labetalol hydrochloride, captopril, clonidine hydrochloride, mebutamate, dimetiyg guanidine sulfate, and the like; antitussive and expectorant agents such as benzoic acid pentoxyverine citrate, clobutinastine, oxilapine tannate, chlorbutanol hydrochloride, chlophendianol hydrochloride, noscapine hydrochloride, ephedrine hydrochloride, isopropyl adrenaline hydrochloride, clorprenaline hydrochloride, methoxyphenamine hydrochloride, procaterol hydrochloride, tulobuterol hydrochloride, clenbuterol fumarate, and the like; antitumor agents such as cyclophosphamide, fluorouracil, tegafur, mitomycin C, procarbazine hydrochloride, deoxyfluorouridine, ranimustine, and the like; local anesthetics such as amino benzoic acid ethyl ester, tetracaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, benoxinate hydrochloride, prilocaine hydrochloride, and the like; hormone preparations such as propylthiouracil, methimazole, metyronol acetate, estradiol, estriol, progesterone, and the like; antihistamines such as diphenhydramine hydrochloride, chlorpheniramine maleate, promethazine, cyproheptadine hydrochloride, diphenylpyraline hydrochloride, and the like; anticoagulants such as warfarin potassium, ticlopidine hydrochloride, and the like; anticonvulsants such as bromomethylatropine, scopolamine, and the like; general anesthetics such as thiopental sodium, pentobarbital sodium, and the like; hypnotic and analgesic agents such as bromisovalum, amobarbital, phenobarbital, and the like; antiepileptic agents such as phenytoin sodium, and the like; stimulants or stimulators such as methylphenidate hydrochloride, and the like; antivertigo agents such as difenhydramine hydrochloride, betahistine mesylate, and the like; psychoneurotic agents such as chloφromazine hydrochloride, thioridazine, meprobamate, imipramine hydrochloride, chlordiazepoxide, diazepam, risperidone, paliperidone, olanzapine, aripiprazole, paroxetine, duloxetine, and the like; muscle relaxants such as succinylcholine chloride, eperisone hydrochloride, and the like; autonomic nervous agents such as neostigmine bromide, bethanechol chloride, and the like; anti-Parkinson's disease agents such as amantadine hydrochloride, rotigotine, ropinirole, and the like;antialzheimer's disease agents such as donepezil, galantamine, memantine, rivastigmine, etc.; diuretics such as hydroflumethiazide, isosorbide dinitrate, furosemide, etc.; vasoconstrictors such as phenylephrine hydrochloride, etc.; respiratory stimulants such as lobeline bromide, dimorpholamine, naloxone hydrochloride, etc.; peptic ulcer treating agents such as glycopyrronium bromide, propicilline, cimetidine hydrochloride, cimetidine, spiroxazoline, etc.; choleretics such as ursodesoxycholic acid, salicylaminophen, etc.; urogenital and anal agents such as methenamine, sparteine, dinoprost, ritodrine hydrochloride, oxybutynin, tolterodine, solifenacin, darifenacin, etc.; agents for parasitic skin diseases such as salicylic acid, ciclopirox, chlorconazole hydrochloride, etc.; skin softening agents such as urea, etc.; vitamins such as calcitriol, thiamine hydrochloride, riboflavin sodium phosphate, pyridoxine hydrochloride, nicotinamide, panthenol, ascorbic acid, etc.; inorganic agents such as calcium chloride, potassium iodide, sodium iodide, etc.; hemostatic agents such as etamsylate, etc.; agents for liver diseases such as tiopronin, etc.; agents for habitual intoxication such as cyanamide, etc.; gout treating agents such as colchicine, probenecid, sulfinpyrazone, etc.; diabetes agents such as tolbutamide, chlorpropamide, glibenclamide sodium, gliclazide, buformin hydrochloride, insulin, etc.; antibiotics such as benzylpenicillin potassium, phenoxypenecillin potassium, oxacillin sodium, ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium, cephaloridine, cefoxitin sodium, erythromycin, chloramphenicol, kanamycin sulfate, cycloserine, etc.; chemotherapeutic agents such as isonitrile, pyrazinamide, ethionamide, etc.; narcotics such as morphine hydrochloride, codeine phosphate, cocaine hydrochloride, pethidine hydrochloride, fentanyl citrate, etc. As the pharmaceutically acceptable salts of these drugs, not only the above salts but also various salts can be used, and the drugs in free form can also be used.

[0062] As one of the typical examples of the drugs of the transdermal absorption preparation of the present application, donepezil or a salt thereof (pharmacologically acceptable salt) can be mentioned. Donepezil refers to 1-benzyl-4-(5,6-dimethoxyindanone-2-yl)methylpiperidine. The drug-containing adhesive layer can contain both donepezil and a salt thereof. Furthermore, one kind of donepezil salt can be used, or two or more kinds thereof can be used in combination. From the viewpoints of easy availability and the like, donepezil or a salt thereof is preferably donepezil (free form of donepezil).

[0063] The content of donepezil or a salt thereof (total amount when they are used in combination) in the drug-containing adhesive layer is preferably 0.5 to 20% by weight, more preferably 1 to 15% by weight, further preferably 2 to 10% by weight, particularly preferably 2.5 to 7.5% by weight, so as to ensure the dispersibility and good transdermal absorption in the drug-containing adhesive layer, but the present application is not limited thereto.

[0064] One of the features of the present application is to use a higher fatty acid so as to improve the percutaneous absorption of donepezil. The "higher fatty acid" referred to herein is used as a component different from the above-mentioned "higher fatty acid ester".

[0065] The higher fatty acid can be linear or branched. It can be saturated or unsaturated. The number of carbons of the higher fatty acid is preferably not less than 12, more preferably not less than 14, further preferably not less than 16, and is preferably not more than 30, more preferably not more than 24, further preferably not more than 20.

[0066] Examples of the saturated higher fatty acid include capric acid (carbon number: 10), lauric acid (carbon number: 12), myristic acid (carbon number: 14), palmitic acid (carbon number: 16), stearic acid (carbon number: 18), isostearic acid (carbon number: 18), arachidic acid (carbon number: 20), behenic acid (carbon number: 22), lignoceric acid (carbon number: 24), cerotic acid (carbon number: 26), montanic acid (carbon number: 28), melissic acid (carbon number: 30), and the like.

[0067] Examples of the unsaturated higher fatty acid include palmitoleic acid (carbon number: 16), oleic acid (carbon number: 18), linoleic acid (carbon number: 18), (9, 12, 15)-linolenic acid (carbon number: 18), (6, 9, 12)-linolenic acid (carbon number: 18), eleostearic acid (carbon number: 18), and the like.

[0068] Among these, the higher fatty acid that is liquid at ambient temperature is preferred, and at least one selected from the group consisting of oleic acid, isostearic acid, and linoleic acid is more preferred, at least one selected from the group consisting of oleic acid and isostearic acid is further preferred, and oleic acid is particularly preferred.

[0069] The content of the higher fatty acid in the drug-containing adhesive layer is preferably not less than 0.1 mol, more preferably not less than 0.2 mol, further preferably not less than 0.3 mol, particularly preferably not less than 0.5 mol, relative to 1 mol of donepezil, and is preferably not more than 5 mol, more preferably not more than 3 mol, further preferably not more than 2 mol, but the present application is not limited thereto. When the amount of the higher fatty acid is too small, sufficient improvement effect on the percutaneous absorption cannot be obtained. On the contrary, when the amount of the higher fatty acid is too large, the formulation properties, such as the adhesive properties, and the like can be reduced.

[0070] In order to further improve the percutaneous absorption of the drug, the drug-containing adhesive layer preferably contains an ester solvent.

[0071] Examples of the ester solvent include triacetin, a medium-chain fatty acid ester, an ester of a polycarboxylic acid and a monohydric aliphatic alcohol, an ester of a polyhydric alcohol and a monohydric fatty acid, a carbonate, and the like.

[0072] Examples of the medium-chain fatty acid ester include mono-alcohol esters of medium-chain fatty acids such as ethyl 2-ethylhexanoate, cetyl 2-ethylhexanoate, and the like, medium-chain fatty acid triglycerides, and the like. Examples of the medium-chain fatty acid triglycerides include caprylic acid triglyceride, caproic acid triglyceride, and the like. Examples of the large number of fats and oils containing medium-chain fatty acid triglycerides include peanut oil, olive oil, castor oil, and the like. Examples of the ester of a polybasic carboxylic acid with a monovalent aliphatic alcohol include decanoic acid diethyl ester, decanoic acid diisopropyl ester, and the like decanoic acid esters, adipic acid diethyl ester, adipic acid diisopropyl ester, and the like adipic acid esters. Examples of the ester of a polyhydric alcohol with a monovalent fatty acid include fatty acid esters of ethylene glycol and propylene glycol, and examples of the carbonate include propylene carbonate and the like. Among these, cetyl 2-ethylhexanoate, medium-chain fatty acid triglycerides, decanoic acid esters, adipic acid esters, carbonates are preferable, and adipic acid diisopropyl ester, cetyl 2-ethylhexanoate are more preferable.

[0073] Further, in the present application, liquid paraffin is preferably added to adjust the adhesiveness or to improve the coating properties. In the present application, the liquid paraffin refers to a paraffin having a kinematic viscosity at 40°C of 0.1 to 10,000 cSt as measured in accordance with ASTM D-445. The liquid paraffin is generally a mixture of alkanes that are liquid at ambient temperature and have a carbon number of not less than 20. As the liquid paraffin, commercially available products, particularly those that meet the standards related to pharmaceutical products defined in the Japanese Pharmacopoeia, the United States Pharmacopoeia, and the like can be preferably used. For example, liquid paraffin is commercially available under the trade name of "KAYDOL" from Sonneborn.

[0074] The transdermal absorption preparation of the present application has a support having an adhesive layer containing a drug. The support in the present application is not particularly limited, and a support widely used in the art can be used. Examples of the support include stretchable or non-stretchable woven cloth such as polyethylene, polypropylene, and the like; non-woven fabric; film such as polyethylene, polypropylene, ethylene-vinyl acetate copolymer, vinyl chloride, polyester (e.g., polyethylene terephthalate (PET)), and the like; foamed support such as urethane, polyurethane, and the like. The support can be a single layer structure or a layered structure. Further, in order to prevent static electricity accumulation, an antistatic agent can be applied to the support. In order to achieve good anchorage with the adhesive layer, non-woven fabric or woven cloth is preferably used as the support. The thickness of the support is preferably not less than 10 μm, more preferably not less than 15 μm, preferably not more than 100 μm, more preferably not more than 50 μm for film, and preferably not less than 50 μm, more preferably not less than 100 μm, preferably not more than 2000 μm, more preferably not more than 1000 μm for porous sheet such as woven cloth, non-woven fabric, foamed support, and the like.

[0075] The transdermal absorption preparation of the present application can contain a surfactant, an excipient, an antioxidant, an emollient, a perfume, a coloring material, and the like as optional components. One of these optional components can be used alone, or two or more of them can be used in combination.

[0076] The surfactant can be any one of an anionic surfactant, a nonionic surfactant, a cationic surfactant, or an amphoteric surfactant. Examples of the surfactant include natural emulsifiers, soaps, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylene higher alcohol ethers, polyoxyethylene alkyl phenol, and the like.

[0077] Examples of the natural emulsifiers include gum arabic, gelatin, gum tragacanth, lecithin, cholesterol, and the like. Examples of the polyoxyethylene sorbitan fatty acid esters include monooleyl polyoxyethylene sorbitan, and the like. Examples of the glycerin fatty acid esters include polyoxyethylene castor oil derivatives, polyoxyethylene hydrogenated castor oil, glycerin monostearate, and the like. Examples of the sorbitan fatty acid esters include sorbitan monostearate, sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, and the like. As the polyoxyethylene higher alcohol ethers, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, and the like can be mentioned. Examples of other surfactants include sodium alkyl sulfates (e.g., sodium lauryl sulfate, and the like), polyoxyethylene polyoxypropylene copolymers (e.g., Pluronic, and the like), cetyl trimethylammonium chloride, and the like.

[0078] Examples of the excipients include silicon compounds such as silicic anhydride, light silicic anhydride, hydrous silicic acid, and the like; cellulose derivatives such as ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and the like; water-soluble polymers such as polyvinyl alcohol, and the like; aluminum compounds such as dry aluminum hydroxide gel, hydrous aluminum silicate, and the like; kaolin, titanium oxide, and the like.

[0079] Examples of the antioxidants include, for example, dibutylhydroxytoluene, ascorbic acid, tocopherol, tocopherol ester derivatives, butylhydroxyanisole, 2-mercaptobenzimidazole, and the like.

[0080] The transdermal absorption preparation of the present application can be manufactured by a so-called solution method including dissolving or dispersing a drug, a thermoplastic elastomer, a higher fatty acid ester, and the like in a dilution solvent (e.g., toluene, tetrahydrofuran) to prepare a coating solution for forming a drug-containing adhesive layer, applying the resulting coating solution to a support, and then drying it. The application and drying of the coating solution for forming the adhesive layer can be performed by means known in the art of transdermal absorption preparations. Alternatively, it can also be manufactured by a so-called hot melt method including heating and melt-kneading a drug, a thermoplastic elastomer, a higher fatty acid ester, and the like to prepare a coating solution, applying the resulting coating solution to a support, and then cooling it. The drug-containing adhesive layer after drying in the solution method and after cooling in the hot melt method is preferably not less than 10 g / m2, more preferably not less than 20 g / m2, further preferably not less than 30 g / m2, and preferably not more than 2000 g / m2, more preferably not more than 1000 g / m2, further preferably not more than 800 g / m2. 2 2 2 2 2 2 .

[0081] In addition, a release liner can also be formed on the drug-containing adhesive layer of the transdermal absorption preparation of the present application. When a release liner is applied, the transdermal absorption preparation can also be manufactured by a method of applying the above-mentioned coating solution for forming the adhesive layer to a release liner and drying it to form a release liner provided with a drug-containing adhesive layer, and laminating a support on the drug-containing adhesive layer. Examples

[0082] Hereinafter, the present application will be explained in more detail by referring to Examples and Comparative Examples, which are not to be construed as limiting. Hereinafter, "parts" and "%" mean "parts by weight" and "% by weight" unless otherwise specifically stated.

[0083] Examples 1-3, Comparative Example 1 The amounts described in Table 1 below were mixed with heating at 70-100°C and applied to a silicone-treated PET film (release liner). A PET film (support) was laminated on the surface of the resulting adhesive layer to give a laminate. The laminate was cut to a desired size to give the transdermal absorption preparations of Examples 1-3 and Comparative Example 1.

[0084] Experimental Example 1 ​​​​​The following in-vitro percutaneous permeation test was conducted using Examples 1 to 3, Comparative Example 1, and the commercially available scopolamine-containing transdermal absorption preparation Transderm SCOP (Sandoz Corporation). The abdominal skin of male Wister rats (5 weeks old) was mounted on a vertical Franz diffusion cell. Then, the transdermal absorption preparation was punched into a circle having a diameter of 1.0 cm, the release liner was peeled off, and attached to the rat skin on the diffusion cell (n = 3). On the receiver side, the amount of scopolamine permeated through the rat skin after a given time was measured by high performance liquid chromatography (HPLC) under the following measurement conditions using a mixed solution of ethanol and physiological saline (ethanol amount: 10%) as the receiving solution.

[0085] <HPLC Conditions> HPLC system: High performance liquid chromatograph (LC2010C) manufactured by SHIMADZU CORPORATION Column: ODS, 4.6 mmφ x 15 cm, filler particle size 5 μm Column temperature: 40°C Mobile phase: 0.1% phosphoric acid aqueous solution / methanol / acetonitrile / SDS = 4 / 1 / 5 / 0.01 (weight ratio) Detection wavelength: 271 nm Flow rate: 0.7 mL / min.

[0086] The amount of scopolamine permeated at 24 hours after attachment is shown in Table 1. Figure 1 In addition, the relationship between the percutaneous permeation rate of scopolamine and the attachment time in the rats of Example 3 and the commercially available scopolamine-containing transdermal absorption preparation is shown in Figure 2 .

[0087] As is apparent from Tables 1 and 2, Figure 1 and Figure 2 the transdermal absorption preparation of the present application exhibits high percutaneous absorption of scopolamine and maintains high absorption over 24 hours. Specifically, the transdermal absorption preparation of Example 1 having almost the same concentration as the transdermal absorption preparation of Comparative Example 1 exhibits a high percutaneous permeation amount. It has been found that the percutaneous absorption of the transdermal absorption preparation of Comparative Example 1 significantly decreases with time due to storage. As shown in Table 2, the transdermal absorption preparation of Example 3 exhibits a significantly high permeation rate compared to the commercially available product at 3 hours after the start of the test, and maintains a high permeation rate after 6 hours to 24 hours. It also shows a higher value of the cumulative scopolamine percutaneous permeation amount compared to the commercially available product. Figure 2

[0088] Examples 4 to 5 ​The starting materials described in Table 2 below were mixed with heating at 80°C to 105°C in the amounts described in Table 2 below, and the mixture was applied to a silicone-treated PET film (release liner). A PET film (support) was laminated on the surface of the resulting adhesive layer, thereby giving a laminate. The laminate was cut to a desired size, thereby giving the transdermal absorption preparation of Examples 4 to 5.

[0089] Comparative Examples 2 to 4 Styrene-isoprene-styrene block copolymer ("JSR SIS5002" manufactured by JSR) and liquid paraffin ("KAYDOL" manufactured by Sonneborn) were dissolved in tetrahydrofuran (THF) in the amounts described in Table 2 below, thereby giving a solution of styrene-isoprene-styrene block copolymer, etc. Then, fatty acid salt and donepezil hydrochloride were dissolved in ester solvent and alcohol solvent in the amounts described in Table 2 below, thereby giving a solution of fatty acid salt, etc. The resulting solution of styrene-isoprene-styrene block copolymer, etc. and the solution of fatty acid salt, etc. were mixed, thereby giving a coating solution for forming an adhesive layer. The resulting coating solution for forming an adhesive layer was applied to a silicone-treated PET film (release liner) so that the amount of the drug-containing adhesive layer after drying was 300 g / m 2 The release liner coated with the adhesive base was dried in an oven at 80°C for 30 minutes, and a PET film (support) was laminated on the surface of the resulting adhesive layer, thereby giving a laminate. The laminate was cut to a desired size, thereby giving the transdermal absorption preparation of Comparative Examples 2 to 4. The transdermal absorption preparation of Comparative Example 4 using acetate salt showed crystal precipitation, and the drug formulation failed.

[0090] Experimental Example 2 Using the transdermal absorption preparations of Examples 4 to 5 and Comparative Examples 2 to 4, the following in-vitro transdermal permeation test was performed. The abdominal skin of male Wister rats (5 weeks old) was mounted on a vertical-type Franz diffusion cell. Then, the transdermal absorption preparation was punched into a circular shape having a diameter of 1.0 cm, the release liner was peeled off, and attached to the rat skin on the diffusion cell (n = 3). On the receiver side, the amount of donepezil permeated through the rat skin after a given time was measured by high performance liquid chromatography (HPLC) under the following measurement conditions, using a mixed solution of ethanol and physiological saline (ethanol amount: 10%).

[0091] <HPLC Conditions> HPLC system: High performance liquid chromatograph (LC2010C) manufactured by SHIMADZU CORPORATION Column: ODS, 4.6 mmφ x 15 cm, 5 μm Column temperature: 40°C Mobile phase: 0.1% phosphoric acid aqueous solution / methanol / acetonitrile / SDS = 4 / 1 / 5 / 0.01 (weight ratio) Detection wavelength: 271 nm Flow rate: 0.7 mL / min.

[0092] The amount of donepezil permeated at 24 hours after the attachment is shown in Figure 3 In addition, the relationship between the donepezil permeation rate and the attachment time in the donepezil-containing transdermal absorption preparation of Examples 4 and 5 in rats is shown in Figure 4

[0093] As is apparent from Figure 3 and Figure 4 the transdermal absorption preparation of the present application shows a high donepezil transdermal absorption, and maintains a high absorption for 3 days. Specifically, the transdermal absorption preparations of Examples 4 to 5 using higher fatty acid esters and higher fatty acids show a high donepezil permeation amount, as compared with the transdermal absorption preparations of Comparative Examples 3 and 4 using a large amount of diisopropyl adipate described in Patent Document 5, and acetate described in Patent Document 6.

[0094] In the transdermal absorption preparation of Comparative Example 4 using a lower fatty acid salt (acetate), crystals are precipitated from the drug-containing adhesive layer, and the drug formulation fails. Such crystallization is not observed in the transdermal absorption preparations of Examples 4 to 5 using higher fatty acid esters and higher fatty acids. This also demonstrates that higher fatty acid esters and higher fatty acids are favorably used for the donepezil-containing transdermal absorption preparation.

[0095] Example 6, Comparative Examples 5 to 6 The starting materials described in Table 3 below were mixed with heating at 80°C to 110°C in the amounts described in Table 3, and applied to a silicone-treated PET film (release liner). A PET cloth (support) was laminated on the surface of the resulting adhesive layer, thereby giving a laminate sheet. The laminate sheet was cut to a desired size, thereby giving the transdermal absorption preparations of Example 6 and Comparative Examples 5 to 6.

[0096] Examples 7 to 8 A toluene solution was prepared using the starting materials described in Table 3 below in the amounts described in Table 3, which was coated on a silicone-treated PET film (release liner), and dried with a hot air drier at 80°C for 30 minutes. A PET cloth (support) was laminated on the surface of the resulting adhesive layer, thereby giving a laminate sheet. The laminate sheet was cut to a desired size, thereby giving the transdermal absorption preparations of Examples 7 to 8. ​

[0097] Experimental Example 3 Using the percutaneous absorption preparations of Examples 6 to 8 and Comparative Examples 5 to 6, and Yakuban Tape (Kaken Pharmaceutical Co. Ltd.) as a control of Example 6 and Comparative Example 5, and Naboal Tape (Hisamitsu Pharmaceutical Co. Ltd.) as a control of Examples 7 to 8 and Comparative Example 6, the following in-vitro percutaneous permeation test was carried out. The abdominal skin of male Wister rats (5 weeks old) was mounted on a vertical-type Franz diffusion cell. Then, the percutaneous absorption preparation was punched into a circle having a diameter of 1.0 cm, the release liner was peeled off, and attached to the rat skin on the diffusion cell (n = 3). On the receiver side, the amount of donepezil permeated through the rat skin after a given time was measured by high performance liquid chromatography (HPLC) under the following measurement conditions, using a mixed solution of ethanol and physiological saline (ethanol amount: 10%).

[0098] <HPLC Conditions> HPLC system: High performance liquid chromatograph (LC2010C) manufactured by SHIMADZU CORPORATION Column: ODS, 4.6 mmφ x 15 cm, 5 μm Column temperature: 40°C Mobile phase: 0.1% sodium acetate aqueous solution / acetonitrile / SDS = 7 / 3 (weight ratio) Detection wavelength: 254 nm Flow rate: 0.7 mL / minute.

[0099] The measurement results (the amount of penetration of flurbiprofen or diclofenac at 24 hours after attachment: the ratio with the control being 100) are shown in Figure 5 .

[0100] From Figure 5 it is known that the percutaneous absorption preparations of the present application show higher percutaneous absorption of the drug compared to the commercially available controls. The percutaneous absorption preparation of Example 6 shows a higher percutaneous permeation amount compared to the percutaneous absorption preparation of Comparative Example 5, and the percutaneous absorption preparations of Examples 7 to 8 show a higher percutaneous permeation amount compared to the percutaneous absorption preparation of Comparative Example 6. From this, it is known that, among these percutaneous absorption preparations of the drug, the higher fatty acid ester is more advantageously used compared to liquid paraffin.

[0101] Industrial applicability The percutaneous absorption preparations of the present application show good percutaneous absorption of the drug, and are useful as pharmaceutical products.

[0102] This application is based on Japanese Patent Application No. 2015-257760, the contents of which are incorporated herein in its entirety.

Claims

1. A transdermal absorption formulation comprising a support and a drug-containing adhesive layer formed on the support. in, The drug-containing adhesive layer comprises thermoplastic elastomers and higher fatty acid esters. Thermoplastic elastomers are styrene-based block copolymers comprising styrene-isoprene-styrene block copolymers, wherein the copolymer contains 5%-60% by weight of styrene. The content of thermoplastic elastomer in the drug-containing adhesive layer is 15%-35% by weight. The content of higher fatty acid esters in the drug-containing adhesive layer is greater than 50 parts by weight and not more than 500 parts by weight per 100 parts by weight of thermoplastic elastomer, and The content of the tackifier in the medicated adhesive layer is 0%-10% by weight relative to the total amount of the medicated adhesive layer.

2. The transdermal absorption formulation according to claim 1, wherein, Higher fatty acid esters contain higher fatty acids with a number of not less than 12 and not more than 30 carbons.

3. The transdermal absorption formulation according to claim 1 or 2, wherein, The adhesive layer containing the drug does not contain tackifiers.

4. The transdermal absorption formulation according to claim 1 or 2, wherein, The drug-containing adhesive layer contains polyisobutylene.

5. The transdermal absorption formulation according to claim 1 or 2, wherein, The drug-containing adhesive layer contains donepezil or its salt as a drug.

6. The transdermal absorption formulation according to claim 5, wherein, The adhesive layer containing the drug contains higher fatty acids.

7. The transdermal absorption formulation according to claim 6, wherein, Higher fatty acids have a number of carbons of not less than 12 and not more than 30.

8. The transdermal absorption formulation according to claim 6, wherein, Higher fatty acids include oleic acid.

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