TW201832761A - Transdermal absorption formulation - Google Patents

Abstract

The subject of the present invention is to provide a transdermal absorption formulation with sufficient skin adhesiveness, low skin irritation, and excellent skin penetration of rivastigmine for exhibiting sufficient transdermal absorption capability. To solve the problem, the present invention provides a transdermal absorption formulation, which includes a support body, and an adhesive layer formed on the support body. The adhesive layer contains rivastigmine or its pharmaceutically tolerable salt, a thermoplastic elastomer, and nonvolatile hydrocarbon oil in an amount exceeding 50 parts by weight and not more than 800 parts by weight per 100 parts by weight of the thermoplastic elastomer. The thermoplastic elastomer is a mixture of styrene-isoprene-styrene tri-block copolymer and styrene-isoprene di-block copolymer. In the mixture, the content of the styrene-isoprene di-block copolymer is 20 weight% or more, the solution viscosity in 25 weight% toluene solution of the thermoplastic elastomer at 25 DEG C is 0.9 Pa.s or more, and the kinematic viscosity of the nonvolatile hydrocarbon oil at 40 DEG C is 80mm 2/s or more.

Description

 Percutaneous absorption preparation  

The present invention relates to a percutaneous absorption preparation, and more particularly to a percutaneous absorption preparation having high skin permeability, good percutaneous absorption, and low skin irritation with respect to rivastigmine.

Alzheimer's type dementia, characterized by the deposition of extracellular β-type starch in the cerebral cortex, resulting in necrosis of nerve cells and changes in neurofibrils and formation of age spots, resulting in atrophy of the cerebral cortex, brain Decreased glucose utilization, decreased perfusion of the parietal lobe, temporal cortex, and prefrontal cortex, resulting in progressive cognitive decline. Although the patients with dementia are over 65 years old and about 5% of the population, 40% of them are called Alzheimer's disease type. Among the diseases that cause the disappearance and degeneration of nerve cells, the most patients can be said to be It will become a serious disease in an aging society in the future.

Therefore, patients with Alzheimer's type dementia are difficult to live alone, and the quality of life (QOL) of the patients themselves and the caregivers are reduced, and they are forced to exert a large social burden on the mental and economic aspects.

Livsamine, also known as 3-[(1S)-1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate, is deficient in Alzheimer's disease The effect of mental illness is generally believed to be caused by the inhibition of acetylcholinesterase and acetylcholinesterase, which increases the concentration of acetylcholine in the brain and activates the choline mobilizing nervous system in the brain.

Recently, "EXELON PATCH", a patch for rivastigmine (ie, a percutaneous absorption preparation), was marketed. Since the lysine does not directly enter the stomach like an orally administered drug, it has an advantage of suppressing the side effects such as vomiting and suppressing the rapid increase in blood concentration.

However, for EXELON PATCH, in 858 cases of safety analysis in domestic clinical trials, 663 cases (77.3%) of skin reactions and irritations at the applicable site were observed. Irritability becomes a problem (Non-Patent Document 1). In particular, among the patients with Alzheimer's type dementia, the elderly are mostly elderly. In the skin of elderly people, the amount of sebum is reduced, the moisturizing function is lowered, and the barrier function of the skin is also lowered. The tendency is high, so it is easier to express skin symptoms. If elderly patients attach a patch with strong skin irritation, the possibility of causing some harmful effects on the skin is very high.

In the case of a lysine-containing patch, it is disclosed that a matrix composed of polyacrylate or polymethacrylate contains a rivastigmine and an antioxidant, and a percutaneous absorption preparation (Patent Document) 1), or contain: backing layer (support), and polyacrylate, polymethacrylate, polyisobutylene, polybutene, styrene-isoprene-styrene block copolymer a lyophilized storage layer of rivastigmine and a percutaneous absorption type preparation containing an anthraquinone polymer and an adhesive layer of an adhesion-imparting agent (Patent Document 2), but the above-mentioned affixing agent containing rivastigmine The problem of skin irritation cannot be said to have been fully solved.

On the other hand, percutaneous absorption type preparations of other medicines, for example, for the attachment of tolterodine as an antimuscarinic drug, reveal the use of an acrylate-based or anthrone-based adhesive layer. Adhesive (Patent Document 3).

Further, from the viewpoint of the stability of the drug, a patch using a rubber-based adhesive having little interaction with a drug has been proposed (Patent Documents 4 to 6).

 [Previous Technical Literature]    [Patent Document]  

[Patent Document 1] International Publication No. 99/034782

[Patent Document 2] International Publication No. 2007/064407

[Patent Document 3] International Publication No. 2000/12070 Manual

[Patent Document 4] Japanese Patent Laid-Open Publication No. 2001-302502

[Patent Document 5] Japanese Patent Laid-Open Publication No. 9-291028

[Patent Document 6] Japanese Patent Laid-Open No. Hei 10-316559

 [Non-patent literature]  

[Non-Patent Document 1] Pharmaceutical Interview Form "EXELON PATCH" (Rivastigmine percutaneous absorption type preparation); July 2011 revised version

The present inventors attempted to develop a patch containing rivastigmine as a drug, using, for example, the adhesive layer components described in Patent Documents 3 to 6. However, it has been found that in the patch having a conventional adhesive layer containing a rubber-based adhesive or the like, it is not possible to ensure sufficient release of rivastigmine. Further, in the above-mentioned patch, it is also considered that in order to impart sufficient skin adhesion, it is usually necessary to add an adhesion-imparting agent, but skin irritation is caused by the adhesion-imparting agent.

In view of the above problems and the like, an object of the present invention is to provide a transdermal absorption preparation which has sufficient skin adhesion and low skin irritation, and which has good skin permeability of rivastigmine and exhibits sufficient transdermal absorbability.

The present inventors have confirmed that by using a thermoplastic elastomer and a nonvolatile hydrocarbon oil having a specific weight ratio with respect to the elastomer as a component for forming an adhesive layer, and reducing the content of the adhesion-imparting agent, one side can be confirmed. It is effective in reducing skin irritation while ensuring sufficient skin adhesion. In addition, the drug of rivastigmine has good skin permeability and exhibits sufficient transdermal absorbability. Next, it was found that in the thermoplastic elastomer, a mixture of a triblock copolymer and a diblock copolymer was used, and the content of the diblock copolymer in the mixture was 20% by weight or more of the thermoplastic elastomer, and the relative use was used. The elastomer has a specific amount of non-volatile hydrocarbon oil having a specific dynamic viscosity, thereby obtaining a sufficient periplasmic property with sufficient adhesive properties and low skin irritation even without an adhesion-imparting agent, and having a sufficient periplasm of pervas The absorbent percutaneous absorption preparation thus completes the present invention.

That is, the present invention relates to the following [1] to [5].

[1] A percutaneous absorption preparation comprising a percutaneous absorption preparation comprising an adhesive layer containing Rivastigmine or a pharmaceutically acceptable salt thereof on a support, the adhesive layer containing rivar a pharmaceutically acceptable salt, a thermoplastic elastomer, and a non-volatile hydrocarbon oil in an amount of more than 50 parts by weight and less than 800 parts by weight relative to 100 parts by weight of the thermoplastic elastomer, the thermoplastic elastomer Is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, and the content of the styrene-isoprene block copolymer in the mixture is 20 The viscosity of the solution of the 25% by weight toluene solution of the thermoplastic elastomer at 25 ° C is 0.9 Pa ‧ or more, and the dynamic viscosity of the nonvolatile hydrocarbon oil at 40 ° C is 80 mm ² /s or more.

[2] The percutaneous absorption preparation according to the above [1], wherein the content of the styrene-isoprene block copolymer in the mixture is 30% by weight or more.

[3] The percutaneous absorption preparation according to the above [1], wherein the content of the nonvolatile hydrocarbon oil in the adhesive layer is 23.5% by weight or more and 88% by weight or less.

[4] The percutaneous absorption preparation according to the above [1], wherein the adhesive layer may further contain an adhesive-imparting agent, and the content of the adhesive-providing agent in the adhesive layer is 10% by weight or less.

[5] The percutaneous absorption preparation according to the above [1] or [2] wherein the adhesive layer does not contain an adhesion-imparting agent.

The percutaneous absorption preparation of the present invention contains rivastigmine as a medicine, and rivastigmine has good skin permeability and exhibits excellent transdermal absorbability. In addition, it has sufficient skin adhesion when attached to the skin, and has low skin irritation.

The percutaneous absorption preparation of the present invention contains rivastigmine or a salt thereof as an active ingredient for transdermal absorption in the adhesive layer.

That is, the percutaneous absorption preparation of the present invention forms an adhesive layer on the support, and the adhesive layer contains a thermoplastic elastomer, and is more than 50 parts by weight and less than 800 parts by weight relative to 100 parts by weight of the elastomer. Non-volatile hydrocarbon oil, and rivastigmine or its salt.

Further, the adhesive layer may contain an adhesion-imparting agent, and in the case where the adhesion-imparting agent is contained, the content in the adhesive layer is 10% by weight or less.

A salt of rivastigmine (a pharmaceutically acceptable salt), specifically, a carboxylic acid, a propionic acid, a butyric acid or the like; oxalic acid, malonic acid, and a rich acid; a dicarboxylic acid such as horse acid, succinic acid or maleic acid; a hydroxycarboxylic acid such as glycolic acid, lactic acid, malic acid, citric acid or tartaric acid; carbonic acid; an alkanesulfonic acid such as methanesulfonic acid or ethanesulfonic acid; An acid addition salt of an acid such as an acid or an acid addition salt of an organic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like with an inorganic acid. Among them, from the viewpoint of easy availability and dispersibility in the adhesive layer, etc., it is preferably rivastigmine tartrate.

In the present invention, one or two or more selected from the group consisting of the above-mentioned rivastigmine and its salt can be used. Further, from the viewpoint of dispersibility and transdermal absorbability in the adhesive layer, it is preferred to use a free (alkali) type of rivastigmine.

The content of rivastigmine in the patch is not particularly limited, but it is preferably 1% by weight to 30% by weight in the adhesive layer in consideration of dispersibility and transdermal absorbability in the adhesive layer. More preferably, it is 2.5% by weight to 25% by weight, and most preferably 4% by weight to 20% by weight. Moreover, in the case of considering the peeling resistance of the patch at the time of bathing, etc., it is preferable that it is 15 weight% or less.

The "thermoplastic elastomer" used in the present invention refers to an elastomer which softens to exhibit fluidity upon heating and exhibits thermoplasticity which returns to the rubber-like elastomer upon cooling, and is sufficient for the purpose of the present invention. From the viewpoint of skin adhesion and low skin irritation, a styrene-based thermoplastic elastomer, particularly a styrene block copolymer, is used for the thermoplastic elastomer. In addition, various thermoplastic elastomers such as urethane-based thermoplastics, acrylics, and olefins other than the styrene-based thermoplastic elastomer may be used as long as the object of the present invention is not inhibited.

Further, from the viewpoint of improving the balance of the adhesive properties of the percutaneous absorption preparation, the thermoplastic elastomer of the present invention preferably has a solution viscosity of 0.5 Pa in 25 ° C of a 25% by weight toluene solution. Above s, more preferably 0.7 Pa‧s or more, and particularly preferably 0.9 Pa‧s or more. The upper limit of the viscosity of the solution is not particularly limited, but is preferably 2.0 Pa ‧ or less, more preferably 1.8 Pa ‧ or less.

In addition, the "solution viscosity at 25 ° C of a 25 wt% toluene solution" refers to styrene ‧ isoprene according to page 375 of "Pharmaceutical Addendum Specification 2003" (issued by Pharmaceutical Daily) ‧ The value measured by the viscosity measurement method of the styrene block copolymer.

The styrene-based block copolymer, specifically, a styrene-butadiene block copolymer, a styrene-butadiene-styrene block copolymer, a styrene-isoprene block Copolymer, styrene-isoprene-styrene block copolymer, styrene-ethylene/butylene block copolymer, styrene-ethylene/butylene-styrene block copolymer, styrene-ethylene/ A propylene block copolymer, a styrene-ethylene/propylene-styrene block copolymer, a styrene-isobutylene block copolymer, a styrene-isobutylene-styrene block copolymer, and the like. In the above, "ethylene/butene" means a copolymer block of ethylene and butene, and "ethylene/propylene" means a copolymer block of ethylene and propylene.

In addition to having sufficient skin adhesion and low skin irritation, the styrene-based block copolymer is preferably ethylene-isoprene from the viewpoint of availability and handleability of the product for a patch. a mixture of a styrene block copolymer and a styrene-isoprene block copolymer, and a styrene-isoprene block copolymer as a diterpene copolymer in the mixture is used in an amount of 20 parts by weight More than %, preferably 30% by weight or more. When the mixing ratio of the styrene-isoprene block copolymer as the diblock copolymer is too low, the skin adhesiveness tends to be lowered, and if it is too high, the shape retainability of the adhesive layer tends to be lowered. There is a possibility that a defect such as an adhesive residue on the skin after peeling occurs when attached to the skin. Therefore, the mixing ratio of the styrene-isoprene block copolymer in the mixture is the weight ratio of the styrene-isoprene-styrene block copolymer as the triblock copolymer (benzene) The ethylene-foreignadiene block copolymer/styrene-isoprene-styrene block copolymer is preferably 20/80 to 75/25, more preferably 30/70 to 70/30.

For the purpose of the present invention, the styrene-isoprene-styrene block copolymer preferably has a styrene content of from 5% by weight to 60% by weight, more preferably 10% by weight to the copolymer. 50% by weight. Further, it is preferably those having a weight average molecular weight of from 20,000 to 500,000, more preferably from 30,000 to 300,000, as measured by gel filtration chromatography. Further, the styrene-isoprene block copolymer preferably has a styrene content of from 5% by weight to 50% by weight, more preferably from 10% by weight to 40% by weight, based on the copolymer. Further, it is preferably those having a weight average molecular weight measured by gel filtration chromatography of from 10,000 to 500,000, more preferably from 20,000 to 300,000. Further, the mixture of the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer preferably has a weight average molecular weight measured by gel filtration chromatography. 20,000 to 500,000, more preferably 30,000 to 300,000.

The styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer may each be a copolymer produced by a method known per se. Further, as the styrene-isoprene-styrene block copolymer and the styrene-isoprene block copolymer, commercially available products satisfying the above characteristics can be used, respectively. Further, a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer can also be sold, so that it is possible to suitably mix at the above mixing ratio by satisfying the above characteristics. A commercial product of a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer.

For example, KRATON D1161, KRATON D1163, KRATON D1113, KRATON D1119, JSR SIS5229, JSR SIS5403, JSR SIS5505, manufactured by KRATON POLYMERS, Inc. "Wait.

When the content of the thermoplastic elastomer in the adhesive layer is too small, the shape retainability of the adhesive layer tends to be lowered, and if it is too large, the skin adhesiveness tends to be insufficient. Therefore, the content of the thermoplastic elastomer in the adhesive layer of the percutaneous absorption preparation of the present invention is preferably 8% by weight or more, more preferably 10% by weight or more, still more preferably 12% by weight or more, and still more It is preferably 15% by weight or more, more preferably 18% by weight or more, particularly preferably 20% by weight or more, still more preferably 24% by weight or more, and most preferably 28% by weight or more. Further, it is preferably 66% by weight or less, more preferably 65% by weight or less, still more preferably 64% by weight or less, still more preferably 49% by weight or less, and still more preferably 39% by weight or less.

In addition, in a more specific preferred aspect, the thermoplastic elastomer content in the adhesive layer may be 8% by weight to 66% by weight, more preferably 10% by weight to 64% by weight, and particularly preferably 12% by weight. %~49% by weight, most preferably 15% by weight to 38% by weight.

In the percutaneous absorption preparation of the present invention, the adhesive layer contains a non-volatile hydrocarbon oil.

The nonvolatile hydrocarbon oil is preferably a chain saturated hydrocarbon having a carbon number of about 20 to 40 or a chain unsaturated hydrocarbon having a carbon number of about 20 to 40, and examples thereof include mobile paraffin, squalene, and squalane. , pristane, etc. Among them, from the viewpoint of ease of availability, liquid paraffin is preferred. The liquid paraffin is a colorless and odorless liquid alkane mixture having a carbon number of 20 or more. However, in the present invention, those suitable for specifications such as the Japanese Pharmacopoeia and the United States Pharmacopoeia can be preferably used. The non-volatile hydrocarbon oil is preferably one having a high viscosity, and in particular, from the viewpoint of adhesion, it is preferred to use a liquid paraffin having a high viscosity.

Specifically, the non-volatile hydrocarbon oil is preferably a dynamic viscosity of 40 mm ² /s or more at 40 ° C, more preferably 70 mm ² /s or more, still more preferably 80 mm ² /s or more, particularly preferably It is 100mm ² /s or more. In addition, the upper limit of the dynamic viscosity is not particularly limited, and is preferably 500 mm ² /s or less, and more preferably 250 mm ² /s or less, from the viewpoints of easiness of handling or ease of preparation.

The term "dynamic viscosity" as used herein refers to the "second method rotational viscosity meter method (2.12 single cylindrical rotational viscosity) in the "2.53 viscosity measurement method" which is based on the general test method of the "Sixteenth Correction Japanese Pharmacopoeia". The viscosity (mPa‧s) measured by the (Brook non-viscosity meter)) (page 59) is converted to the value obtained by the dynamic viscosity.

The percutaneous absorption preparation of the present invention contains the above-mentioned nonvolatile hydrocarbon oil in a weight ratio of more than 50 parts by weight to 800 parts by weight or less based on 100 parts by weight of the thermoplastic elastomer. If the content of the nonvolatile hydrocarbon oil relative to 100 parts by weight of the thermoplastic elastomer is more than 800 parts by weight, it is difficult to maintain the shape of the adhesive layer. On the other hand, when the content of the non-volatile hydrocarbon oil is 50 parts by weight or less, the adhesive tends to be too hard, and sufficient skin adhesion tends not to be obtained, and in particular, the movement of the skin at the time of attachment is followed. Sex will deteriorate, and there will be cases where the attachment is detached. From such a viewpoint, the content of the non-volatile hydrocarbon oil in the adhesive layer is 100 parts by weight, preferably 51 parts by weight to 800 parts by weight, more preferably 60 parts by weight to 600 parts by weight, based on the total amount of the thermoplastic elastomer. It is particularly preferably from 70 parts by weight to 500 parts by weight.

In addition, even if the content of the non-volatile hydrocarbon oil is too large, the peeling stress tends to be low in the adhesive performance, and the adhesive is observed to ooze during storage or attachment. The tendency to adhere to defects in the packaging material or clothing is liable to occur. On the other hand, if the content of the non-volatile hydrocarbon oil is small, in particular, the skin adhesiveness at the time of sweating or bathing may be lowered, and there is a possibility that the percutaneous absorption preparation may fall off. From such a viewpoint, the content of the non-volatile hydrocarbon oil in the adhesive layer is 100 parts by weight, preferably 80 parts by weight to 400 parts by weight, more preferably 90 parts by weight to 350 parts by weight, based on the total amount of the thermoplastic elastomer. It is particularly preferably from 100 parts by weight to 300 parts by weight.

In addition, if the viscosity of the solution in the 25 ° C toluene solution at 25 ° C is less than 0.5 Pa ‧ for the thermoplastic elastomer, the non-volatile hydrocarbon oil with low dynamic viscosity is used, for example, the dynamic viscosity at 40 ° C is less than 80 mm ² In the case of /s, when the content of the nonvolatile hydrocarbon oil is large, the bleeding of the adhesive at the time of storage or attachment is observed, and there is a tendency that adhesion to the packaging material or the clothing is likely to occur.

Further, the content of the nonvolatile hydrocarbon oil in the adhesive layer is preferably 23.5% by weight or more, more preferably 25% by weight or more, still more preferably 26.5% by weight or more, still more preferably 35% by weight or more. More preferably, it is 45% by weight or more, and particularly preferably 50% by weight or more. Further, it is preferably 88% by weight or less, more preferably 85% by weight or less, still more preferably 83% by weight or less, still more preferably 70% by weight or less, and still more preferably 68% by weight or less.

In addition, in a more specific preferred aspect, the content of the non-volatile hydrocarbon oil in the adhesive layer may be, for example, from 26.5% by weight to 83% by weight, more preferably from 35% by weight to 80% by weight, particularly preferably 50% by weight to 70% by weight.

In the present invention, from the viewpoint of reducing skin irritation, it is preferred that the adhesive layer does not contain an antioxidant. Here, the antioxidant is added for the purpose of preventing oxidative degradation of the drug, and examples thereof include dibutylhydroxytoluene, ascorbyl stearate, tocopherol, and tocopheryl acetate. And other tocopherol derivatives, butyl hydroxy methoxybenzene, 2-mercaptobenzimidazole, anthocyanin, catechin and the like.

In the percutaneous absorption preparation of the present invention, the adhesive layer may further contain an alcohol solvent, a guanamine, from the viewpoint of improving the dispersibility or transdermal absorbability of rivastigmine in the adhesive layer. One or two or more selected from the group consisting of a solvent, an ester solvent, a liquid organic acid, a carboxylate, a lactone, and a surfactant.

Examples of the alcohol-based solvent include high-grade saturated aliphatic alcohols having a carbon number of about 12 to 20, such as lauryl alcohol, isostearyl alcohol, and 2-octyldodecanol, which are liquid at normal temperature, and carbon such as oleyl alcohol. a high-grade unsaturated aliphatic alcohol which is liquid at room temperature of about 12 to 20; ethylene glycol, propylene glycol, glycerol, 1,3-butanediol, polyethylene glycol having a molecular weight of about 100 to 600, etc. at room temperature The following are liquid polyols and the like. In addition, the term "normal temperature" as used in the specification refers to the range of 15 to 25 ° C in the general principles of the Japanese Pharmacopoeia.

Among them, from the viewpoint of improving the solubility of rivastigmine, it is preferably a mixture of ethylene glycol, propylene glycol, glycerin, 1,3-butylene glycol, polyethylene glycol, etc. which is liquid at normal temperature. The alcohol is more preferably a glycol which is liquid at room temperature, such as ethylene glycol, propylene glycol, 1,3-butanediol, or polyethylene glycol having a molecular weight of about 100 to 600.

Examples of the amide-based solvent include pyrrolidinone such as N-methyl-2-pyrrolidone and 2-pyrrolidone; and imidazolidinone such as 1,3-dimethyl-2-imidazolidinone. N-substituted toluidine such as crotamiton; formamide, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, N, An alkane guanamine such as N-dimethylacetamide or N-methylpropionamide.

Among the above amide-based solvents, N-methyl-2-pyrrolidone, croprofenone, and N are preferred from the viewpoint of improving the solubility, dispersibility, and transdermal absorbability of rivastigmine. N-dimethylformamide, N,N-dimethylacetamide, more preferably N-methyl-2-pyrrolidone or crotheter.

Examples of the ester solvent include an ester of a long-chain fatty acid and a monovalent aliphatic alcohol, a medium chain fatty acid triglyceride, an ester of a polybasic acid and a monovalent aliphatic alcohol, and a carbonate.

The ester of a long-chain fatty acid and a monovalent aliphatic alcohol is preferably an ester of a long-chain saturated fatty acid having 12 to 20 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms at a normal temperature, and for example, : myristic acid ethyl ester, isopropyl myristate, octyldodecanol myristate, etc., which are liquid at room temperature, myristic acid ester, ethyl palmitate, isopropyl palmitate, palmitic acid A fatty acid ester such as a palmitate or a isopropyl stearate which is liquid at normal temperature and the like is a liquid stearate at a normal temperature. Further, an ester of a long-chain unsaturated fatty acid having 12 to 20 carbon atoms and a monovalent aliphatic alcohol having 1 to 20 carbon atoms may be preferably used, and examples thereof include ethyl oleate, decyl oleate, and oleic acid oil. A linoleic acid ester or the like which is liquid at room temperature, such as oleate, linoleic acid ethyl ester or linolenic acid isopropyl ester, which is liquid at normal temperature.

The medium chain fatty acid triglyceride is a fatty acid having a carbon number of about 6 to 12 such as caproic acid, caprylic acid, citric acid or lauric acid, and a triglyceride formed with glycerin. In the present invention, it can be used at room temperature. The following are liquid octanoic acid triglyceride, octanoic acid and citric acid triglyceride mixture, octanoic acid, citric acid and lauric acid triglyceride mixture and the like. Further, a large amount of fats and oils containing such a liquid at normal temperature can be used. Examples of the fats and oils include peanut oil, olive oil, and castor oil.

Further, in the present invention, a liquid fatty acid triglyceride at a normal temperature or a medium-chain fatty acid triglyceride which is liquid at a normal temperature may be used as a pharmaceutical product. Products sold.

Examples of the ester of a polyvalent carboxylic acid and a monovalent aliphatic alcohol include adipic acid diester and sebacic acid which are liquid at normal temperature, such as diethyl adipate or diisopropyl adipate. Ethyl ester, diisopropyl sebacate, dioctyldodecanol sebacate, etc., liquid selenic acid diester, etc. at room temperature, carbon number 2 to 12 dicarboxylic acid, and carbon number 1 ~20 A monovalent aliphatic alcohol which is a liquid diester at normal temperature.

The carbonate, which is a cyclic carbonate of carbonic acid and a diol having 2 to 10 carbon atoms, may, for example, be ethylene carbonate, propylene carbonate or vinyl carbonate, and is preferably propylene carbonate.

Among the above ester solvents, preferred are myristate, medium chain fatty acid triglyceride mixture, sebacic acid diester, carbonate, more preferably isopropyl myristate, caprylic acid and capric acid triacid. A mixture of glycerides, diethyl sebacate, propylene carbonate.

In the present invention, the alcohol-based solvent, the guanamine-based solvent, and the ester-based solvent may be used singly or in combination of two or more kinds as needed. The content of these solvents is preferably from 0.1% by weight to 20% by weight, more preferably from 0.5% by weight to 15% by weight, based on the total amount of the adhesive layer.

Examples of the liquid organic acid include acetic acid, propionic acid, butyric acid, valeric acid, isovaleric acid, caproic acid, heptanoic acid, heptanoic acid, caprylic acid, and nonanoic acid. An aliphatic monocarboxylic acid; an aliphatic unsaturated monocarboxylic acid such as oleic acid, linoleic acid, arachidonic acid or docosahexaenoic acid; lactic acid (DL-lactic acid, or L-lactic acid and/or D-) a hydroxycarboxylic acid such as a mixture of lactic acid and lactic acid anhydride; an alkoxy-substituted liquid carboxylic acid such as methoxyacetic acid; a sulfonic acid such as methanesulfonic acid or the like.

These liquid organic acids have a function of assisting the dissolution of rivastigmine, and as a result, the adhesive layer contains a high concentration and low solubility of rivastigmine, and can also improve dispersibility, thereby further Improves the effect of transdermal absorption. From such a viewpoint, among these liquid organic acids, the Japanese Pharmacopoeia lactic acid and oleic acid are preferably used, and it is particularly preferable to use the Japanese Pharmacopoeia lactic acid.

In the present invention, one or two or more kinds of the above-mentioned liquid organic acids may be selected as needed. The content of the liquid organic acid is preferably from 0.1% by weight to 20% by weight, more preferably from 0.5% by weight to 15% by weight, based on the total amount of the adhesive layer.

The carboxylate may, for example, be a salt of an aliphatic monocarboxylic acid, an alicyclic monocarboxylic acid or an aliphatic dicarboxylic acid.

Examples of the aliphatic monocarboxylic acid include short-chain fatty acids having a carbon number of 2 to 7 such as acetic acid, butyric acid, and caproic acid, and, for example, a octanoic acid or a citric acid having a carbon number of 8 to 11 medium chain fatty acids, for example, : long-chain fatty acids having 12 or more carbon atoms such as myristic acid, stearic acid, isostearic acid, oleic acid, etc., for example, hydroxy monocarboxylic acids such as glycolic acid, lactic acid, 3-hydroxybutyric acid, and mandelic acid For example, an alkoxy-substituted monocarboxylic acid such as methoxyacetic acid, for example, a ketomonocarboxylic acid such as γ-ketulinic acid or the like.

Examples of the alicyclic monocarboxylic acid include an alicyclic monocarboxylic acid having 6 to 8 carbon atoms such as cyclohexanecarboxylic acid.

Examples of the aliphatic dicarboxylic acid include azelaic acid, adipic acid, malic acid, maleic acid, and fumaric acid.

The preferred carboxylic acid is a long-chain fatty acid having 12 or more carbon atoms and a hydroxymonocarboxylic acid, and examples thereof include myristic acid, stearic acid, isostearic acid, oleic acid, and lactic acid. More preferably, it is oleic acid or lactic acid.

The salt of the above-mentioned carboxylic acid may, for example, be an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or an amine salt, but is easy to obtain, stable, and transdermally absorbable. From the viewpoint of enhancing the effect, it is preferred to use a sodium salt.

Further, examples of the lactone include a 5-membered ring lactone such as ascorbic acid and erythorbic acid.

In the percutaneous absorption preparation of the present invention, in view of the effect of improving the stability of the drug or the effect of improving the transdermal absorbability, it is preferred to use sodium oleate, sodium lactate, ascorbic acid or erythorbic acid as the carboxylate or lactone.

The content of the carboxylate or lactone in the adhesive layer in the adhesive layer of the present invention is not particularly limited, but is preferably 0.1 mol or more relative to rivastigmine. 5 moles or less, more preferably 0.2 moles or more and 3 moles or less. When the amount of the melamine in the relative rival is less than 0.1 mol, the effect of improving the transdermal absorbability may not be obtained, and the amount of the melamine in the relative rival is higher than that of the limus. When it is 5 moles, there is a case where the physical properties of the preparation such as adhesive properties are deteriorated.

Examples of the surfactant include polyoxyethylene fatty acid esters such as polyoxyethylene monolaurate, polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitol tetraoleate, and polyoxyethylene sorbitan. Polyoxyethylene sorbitan fatty acid esters such as monooleate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, sorbitan monolaurate, sorbitan A sorbitan fatty acid ester such as oleate, sorbitan sesquioleate or sorbitan trioleate, glycerol monooleate, polyoxyethylene castor oil derivative, polyoxyethylene hardened castor oil, etc. Polyoxyethylene higher aliphatic alcohol ether such as glycerin fatty acid ester, polyoxyethylene lauryl ether or polyoxyethylene oleyl ether, polyoxyethylene alkyl phenyl ether such as polyoxyethylene nonylphenyl ether, Pluronic Anionic surfactant such as a nonionic surfactant such as a polyoxyethylene polyoxypropylene copolymer such as L-31 or Pluronic L-44, or an alkyl sulfate such as sodium lauryl sulfate, or an alkyltrimethyl group. Cationic surfactants such as ammonium salts and alkyl dimethyl ammonium salts, and alkane Dimethyl amine oxide, alkyl carboxy betaine amphoteric surfactant, and the like can be selected whereby one or two or more kinds.

Among the above surfactants, in terms of improving transdermal absorbability, a nonionic surfactant which is liquid at normal temperature is preferred, and a sorbitan fatty acid ester which is liquid at normal temperature is more preferred. It is sorbitan monolaurate.

In the transdermal absorption preparation of the present invention, the content of the surfactant in the adhesive layer is preferably from 0.01% by weight to 10% by weight, more preferably from 0.1% by weight to 5% by weight.

In the percutaneous absorption preparation of the present invention, by using a thermoplastic elastomer and a nonvolatile hydrocarbon oil as the adhesive layer in the content and content ratio as described above, good skin adhesion can be exhibited, but adhesion is achieved. In the agent layer, an adhesion-imparting agent may be contained as needed.

The adhesive-imparting agent is a resin widely used for imparting skin adhesion in the field of a usual patch, and examples thereof include a rosin-based resin, a polyterpene resin, a benzofuran-indene resin, and a petroleum system. The resin, the terpene-phenol resin, the alicyclic saturated hydrocarbon resin, and the like can be used in one or two or more types.

However, when the adhesive layer contains the adhesion-imparting agent, the content of the adhesion-imparting agent in the adhesive layer is 10% by weight or less from the viewpoint of reducing skin irritation and the like. The content is preferably 5% by weight or less, more preferably 2% by weight or less, still more preferably 1% by weight or less, and most preferably no adhesion-imparting agent. That is, based on the association between the transdermal absorption preparation and the skin adhesion, the content of the adhesion-imparting agent is modulated according to the type, content, and content ratio of the thermoplastic elastomer and the non-volatile hydrocarbon oil, and is not provided with adhesion. When the agent can obtain sufficient skin adhesion, it is not necessary to adhere the agent.

In the adhesive layer forming the percutaneous absorption preparation of the present invention, an excipient, a dispersing agent, a stabilizer, a thickener, and a softening agent may be contained as an optional component within a range not detracting from the characteristics of the present invention. , a general additive such as a fragrance, a coloring agent, and the like.

The excipient used in the present invention may, for example, be an anthracene compound such as phthalic anhydride, light phthalic anhydride or aqueous citric acid; ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl group A cellulose derivative such as methyl cellulose; a synthetic water-soluble polymer such as polyvinyl alcohol; an aluminum compound such as dried aluminum hydroxide gel or aqueous aluminum citrate; a pigment such as kaolin or titanium oxide.

In the present invention, one or two or more of them may be used as needed.

Examples of the dispersing agent used in the present invention include gum arabic, propylene glycol alginate, dioctyl sulfosuccinate, and lecithin.

In the present invention, one or two or more of them may be used as needed.

The stabilizer for use in the present invention may, for example, be zinc stearate, gelatin, polydextrose or pravone.

In the present invention, one or two or more of them may be used as needed.

The viscous agent used in the present invention may, for example, be a carboxyvinyl polymer, xanthan gum, gum tragacanth, locust bean gum or the like.

In the present invention, one or two or more of them may be used as needed.

The softener used in the present invention may, for example, be almond oil, rapeseed oil or cottonseed oil. Oils such as soybean oil mixture, processing oil, tallow, etc.; waxes such as purified lanolin; esters such as cetyl lactate which are solid at normal temperature; polyisoprene rubber, polybutene, raw rubber, etc. Rubber; polymer such as crystalline cellulose; allantoin.

In the present invention, one or two or more of them may be used as needed.

Examples of the flavoring agent used in the present invention include d-camphor, d1-camphor, d-borneol, d1-borneol, cinnamaldehyde, peppermint oil, d1-menthol, 1-menthol, and the like.

In the present invention, one or two or more of them may be used as needed.

The coloring agent used in the present invention may, for example, be iron oxide, yellow iron oxide, yellow iron oxide, carbon black or the like.

In the present invention, one or two or more of them may be used as needed.

The percutaneous absorption preparation of the present invention can be prepared by stretching an adhesive layer composed of the above structure onto a support.

In the present invention, the "support" is not particularly limited, and a wide range of users can be used as a patch. Examples thereof include stretchable or non-stretchable woven fabrics such as polyethylene and polypropylene, non-woven fabrics, polyesters such as polyethylene, polypropylene, and polyethylene terephthalate, ethylene vinyl acetate copolymers, and chlorine. A film such as ethylene or a foamable support such as a urethane or a polyurethane. These may be used alone or in combination with a plurality of layers. Further, in order to prevent static electricity from accumulating on the support, the woven fabric, the nonwoven fabric, the film, and the like constituting the support may contain an antistatic agent. Further, in order to obtain good anchoring property with the adhesive layer, a non-woven fabric or a woven fabric, or a laminate of these and a film may be used as a support. The thickness of the support is usually 10 μm to 100 μm, preferably 15 μm to 50 μm, and the porous sheet for a woven fabric, a nonwoven fabric, a foamable support or the like is usually 50 μm to 2,000 μm, preferably 100 μm to 1,000 μm. .

Further, the percutaneous absorption preparation of the present invention may be provided with a general release liner in the field of a patch. For the release liner, a polyester film such as cellophane, polyethylene, polypropylene, polyethylene terephthalate or the like, a resin film of polystyrene or the like, an aluminum foil film, a foamed polyethylene film or a foamed polypropylene film can be used. For example, one or more of the above-mentioned laminates may be used, or those which have been subjected to fluorenone processing, fluororesin processing, imprint processing, hydrophilic processing, hydrophobic processing, etc. . The thickness of the release liner is usually from 10 μm to 200 μm, preferably from 15 μm to 150 μm.

The percutaneous absorption preparation of the present invention can be prepared, for example, by dissolving a thermoplastic elastomer and rivastigmine or a salt thereof in a nonvolatile hydrocarbon oil, and dissolving or dispersing it in a solution of toluene or the like. The coating liquid for forming an adhesive layer is applied to a support by applying the obtained coating liquid, followed by drying. In the case of using a release liner, the release liner may be pressed against the adhesive layer to perform lamination. Alternatively, the coating liquid may be applied onto a release liner, dried to form an adhesive layer on the surface of the release liner, and then the support is pressed against the adhesive layer to be bonded.

For coating of the coating liquid for forming an adhesive layer, for example, a roll coater, a die coater, a gravure roll coater, a reverse roll coater, a conformal roll coater, or the like can be used. It is carried out by a conventional coater such as a dip roll coater, a bar coater, a knife coater, or a spray coater. Further, the drying of the coating liquid is preferably carried out under heating at a temperature of, for example, about 40 ° C to 150 ° C. The adhesive layer containing the dried rivastigmine is preferably 10 g/m ² to 1,000 g/m ² , more preferably 20 g/m ² to 800 g/m ² .

The technique described above for the percutaneous absorption preparation containing the rivastigmine of the present invention can also be applied to a percutaneous absorption preparation of a drug capable of transdermal absorption other than rivastigmine.

That is, the present invention also provides that "the adhesive layer is formed on the support, the adhesive layer contains a thermoplastic elastomer and 100 parts by weight relative to the thermoplastic elastomer, and more than 50 parts by weight and less than 800 parts by weight of non-volatile matter a hydrocarbon oil, the adhesive sheet for skin attachment of the non-volatile hydrocarbon oil having an kinetic viscosity at 40 ° C of 80 mm ² /s or more, and the adhesive layer of the adhesive sheet for skin attachment containing rivastigmine A transdermal absorption preparation of a drug other than percutaneous absorption."

In the adhesive sheet for skin attachment, the content of the nonvolatile hydrocarbon oil in the adhesive layer is 23.5% by weight or more and 88% by weight or less. Further, the dynamic viscosity of the nonvolatile hydrocarbon oil at 40 ° C is preferably 100 mm ² /s or more. Further, the thermoplastic elastomer is a mixture of a triblock copolymer and a diblock copolymer, and the content of the diblock copolymer in the mixture is preferably 20% by weight or more, more preferably 30% by weight or more. Further, it is preferred that the thermoplastic elastomer is a styrenic block copolymer, more preferably the styrenic block copolymer is a styrene-isoprene-styrene block copolymer, and styrene-isoprene A mixture of diene block copolymers. Further, the solution viscosity at 25 ° C of the 25% by weight toluene solution of the thermoplastic elastomer is preferably 0.5 Pa ‧ or more, more preferably 0.7 Pa ‧ or more, and particularly preferably 0.9 Pa ‧ or more. Further, the adhesive layer may further contain an adhesion-imparting agent, and in this case, the content in the adhesive layer of the adhesion-imparting agent is 10% by weight or less. By providing the adhesive layer of the adhesive sheet for the skin with a drug which can be absorbed percutaneously other than rivastigmine, it is possible to provide the drug with good skin permeability and excellent transdermal absorbability, and to attach it. A transdermal absorption preparation having sufficient skin adhesion and low skin irritation on the skin.

Further, the adhesive sheet for skin attachment and the "thermoplastic elastomer (styrene block copolymer)", "nonvolatile hydrocarbon oil", "adhesive layer" and "support" in the percutaneous absorption preparation The preferred embodiments of the present invention are the same as those in the above-mentioned percutaneous absorption preparation containing rivastigmine, and the description thereof is omitted here. Further, in the percutaneous absorption preparation, the adhesive layer may further contain an alcohol solvent, a guanamine solvent, or an ester from the viewpoint of improving the dispersibility or transdermal absorbability of the drug in the adhesive layer. One or more selected from the group consisting of a solvent, a liquid organic acid, a carboxylate, a lactone, and a surfactant. For specific examples of such additives, the above-mentioned rivaris may also be used. The content of the smectin percutaneous absorption preparation.

The drug capable of transdermal absorption other than rivastigmine in the percutaneous absorption preparation includes the concept of a drug and a pharmaceutically acceptable salt thereof, and examples thereof include acetaminophen and phenacetin. ), Mefenamic Acid, Diclofenac Sodium, Flufenamic Acid, Aspirin, Sodium Salicylate, Methyl Salicylate, Salicylic Acid Ethylene glycol ester, aminopyrinoline, aclofenac, Ibuprofen, Naproxen, Flupuriprofen, Ketoprofen , anti-inflammatory analgesics such as Amfenac sodium, Mepirizole, Indomethacin, Piroxicam, Felbinac, etc. Hydrocorticosterone, Te An Steroid anti-inflammatory agents such as cortisol, dicortisol, dehydrocortisol, etc.; Diltiazem Hydrochloride, pentaerythritol tetranitrate, isosorbide nitrate, Trapidil, Nikola Nicorandil, nitroglycerin, prenylamine lactate, and dolomite (Mols Iodimine, vasodilators such as aluminum nitrite, Tolazoline hydrochloride, Nifedipine, etc. Procainamide hydrochloride, Lidocaine hydrochloride , Propranolol hydrochloride, Alprenolol hydrochloride, Atenolol, Nadolol, Metoprolol Tartrate, Aztec Ajmaline), dipyridamine, mexiletine hydrochloride, etc.; anti-arrhythmia; Ecarazine hydrochloride, Indapamide, Clonidine hydrochloride, hydrochloric acid Bunitrolol hydrochloride, Labetalol hydrochloride, Captopril, Guanabenza acetate, mebutamate, Bethanidine Sulfate And other hypotensive agents; Carbetapentane Citrate, Cloperastine, oxeladin tannate, clophenanol hydrochloride (Cl) Obutinol hydrochloride, Clofedanol hydrochloride, Noscapine hydrochloride, ephedrine hydrochloride, isoproterenol hydrochloride, clorprenaline hydrochloride, Methoxyphenamine hydrochloride , anti-cough decoction, such as Procaterol hydrochloride, Tulobuterol hydrochloride, Clenbuterol hydrochloride, Ketotifen Fumarate, etc. , anti-neoplastic agents such as fluorouracil, tegafur, mitomycin C, Procarbazine hydrochloride, Doxifluridine, Ranimustine, etc.; Ethyl benzoate, Tetracaine hydrochloride, Procaine hydrochloride, Dibucaine hydrochloride, Oxybuprocaine hydrochloride, and prilocaine hydrochloride Local anesthetic such as (Propitocaine hydrochloride); propofolone, thiamazole, metinol acetate Lone acetate), estradiol, estriol, progesterone and other hormonal agents; Diphenhydramine hydrochloride, Chlorpheniramine Maleate, promethazine An antihistamine agent such as Cyproheptadine hydrochloride or Diphenylpyraline hydrochloride; warfarin potassium, Ticlopidine hydrochloride, etc. Blood coagulation inhibitors; anti-caries agents such as Atropine Methylbromide, Scopolamine, etc.; general anesthetics such as sodium thiopental, pentobarbital sodium, etc.; (bromvalerylurea), amobarbital (Amobarbital), phenobarbital (Phenobarbital) and other hypnosis. Analgesic; antiepileptic agent such as diphenylethyl carbazide sodium; stimulant such as methyl amphetamine hydrochloride. Awakening agent; diphenidol hydrochloride, Betahistine Mesylate, etc.; chlorophene hydrochloride (Chlorpromazine hydrochloride), salithiophene (Thioridazine), Meprobamate, Imipramine hydrochloride, Chlordiazepoxide, diazapine, Risperidone, Paliperidone, Austria An anti-psychotic agent such as olanzapine, aripiprazole, Paroxetine, or duloxetine; succinyl hydrochloride, Eperisone hydrochloride, etc. Skeletal muscle relaxant; neostigmine bromide, chloride Such as autonomic nerve agents; Amantadine hydrochloride, Rotigotine, Ropinirole and other anti-Bakinson's agent; Donepezil, Galantamine ), Memantine and other anti-Alzheimer's dementia drugs; hydroflumethiazole (Hydroflumethiazide), isosorbide, Fussima (Furosemide) and other diuretics; a vasoconstrictor; a respiratory enhancer such as brominated sorbine, dimorpholamine, Naloxone hydrochloride; glycopyrronium bromide, proglumide, a therapeutic agent for peptic ulcer such as Cetraxate hydrochloride, Cimetidine or Spizofurone; a choleretic agent such as deoxycholic acid or osalmid; Hexamine, Sparteine, dinoprost, Ritodrine hydrochloride, Oxybutynin, tolterodine, Soly Urogenital and anal agents such as Solifenacin, Darifenacin; parasitic skin diseases such as salicylic acid, ciclopiroxolamine, chlorconazole hydrochloride; skin of urea Softener; calcified triol, Thiamine hydrochloride, riboflavin sodium phosphate, Pyridoxine hydrochloride, niacinamide, panthenol, ascorbic acid, etc.; calcium chloride, potassium iodide Sodium iodide Inorganic preparation; hemostatic agent of Ethamsylate; liver disease agent such as Tiopronin; habitual poisoning agent such as cyanamide; Colchicine, probenecid Probenecid), gout therapeutic agent such as Sulfinpyrazone; tolbutamide, chlorpheniramine, glycimidine sodium, glybuzole, buformin hydrochloride Diabetic agents such as hydrochloride, insulin, etc.; benzylpenicillin potassium, propicillin potassium, chlorthacillin sodium, ampicillin sodium, bacampicillin hydrochloride, carbenicillin sodium , anti-biomass such as cilostromycin, simvastatin sodium, erythromycin, chloramphenicol, tetracycline, scleromycin, cyclosylamine, etc.; isonitrile, pyridyl A chemotherapeutic agent such as methotrexate or ethionamide; an anesthetic such as morphine hydrochloride, codeine phosphate, cocaine hydrochloride, Pethidine hydrochloride, and Fentanyl Citrate. Further, the salt is not limited to the above, and may be used in various salts or free forms.

 [Examples]  

Hereinafter, the present invention will be specifically described by way of examples and comparative examples, but the present invention is not limited thereto.

[Examples 1 to 4, Reference Examples 1 to 7, and Comparative Examples 1 to 4]

According to the position shown in Table 1, the components constituting the adhesive layer were weighed. First, a styrene-isoprene-styrene block copolymer (SIS)/styrene-isoprene block copolymer (SI) mixture (KRAYTON D1111, "KRAYTON D1119", manufactured by Kraton Co., Ltd., "JSR SIS5505" and "JSR SIS5229" manufactured by JSR Co., Ltd. were dissolved in 230 parts by weight of toluene per 100 parts by weight of the mixture. In the above solution, a liquid paraffin ("BENOL", "KAYDOL", "Hydrobrite 550PO", "Hydrobrite HV" manufactured by Sonneborn Co., Ltd.), various additives, and rivastigmine were added and mixed to prepare an adhesive layer. Forming the coating liquid.

Further, the coating liquid is applied to a film of a polybutylene terephthalate (PET) film (release liner) treated with an anthrone, so that the content of rivastigmine in the adhesive layer after drying becomes Modulated in a manner of 1.8 mg/cm ² . After drying in an oven at 80 ° C for 1 hour, a PET film (support) was laminated on the surface of the adhesive layer, and cut into a size of 15 cm × 30 cm to obtain a desired patch (percutaneous absorption preparation). . The SIS/SI ratio in the table is the weight ratio.

Further, in Comparative Examples 1 and 2, the respective components constituting the adhesive layer were weighed according to the prescription shown in Table 1, and the sheet was prepared by the above method. However, in Comparative Example 1, sufficient adhesion could not be obtained, and comparison was made. Example 2 was unable to maintain the adhesive layer and could not be evaluated.

[Comparative Example 5]

In the formulation of Example 1 of Table 1, the styrene-isoprene-styrene block copolymer/styrene-isoprene block copolymer mixture was substituted so that the solid content became the same as in Table 1. A commercially available thermosetting elastic pressure acrylic adhesive ("Duro tak 87-2194", manufactured by Henkel Co., Ltd., solid content = 40% by weight) was weighed in such a manner that the thermoplastic elastomer content was equal, and a liquid paraffin was added to facilitate the profit. The varsamine is dissolved, added, mixed and stirred to prepare a coating liquid for forming an adhesive layer.

The coating liquid was applied to a creped ketone-treated PET film (release liner) so as to have a weight of the adhesive layer after drying to 100 g/m ² , and dried in an oven at 80 ° C for 60 minutes. But it does not harden, and it is impossible to get a patch.

[Test Example 1] Adhesion property test

<peel strength>

The patch cut into 25 mm × 300 mm was attached to a stainless steel (SUS304) plate, and the stress at the time of peeling at a speed of 300 mm/min in the 180° direction was measured.

<ball stickiness>

In the inclined surface with a tilt angle of 30° attached to a 100 mm wide cut patch, the ball of 1/32 吋 to 1 滚动 is rolled over the 100 mm runway, and the stick is allowed to stay on the patch for more than 5 seconds. The largest diameter of the ball.

<retention force>

The patch cut into 25 mm × 300 mm was attached to a stainless steel (SUS304) plate, and a load of 25 g was applied in a direction of 90° for 60 minutes, and the peeled distance was measured.

<exudation>

The end portions of the patch prepared in the examples, the reference examples, and the comparative examples were compressed from the upper side of the support by fingertips, and the degree of exudation was evaluated in accordance with the following criteria.

A: Even if it is compressed, the adhesive layer is completely free of bleeding.

B: Even if it is compressed, the adhesive layer hardly oozes out.

C: During compression, although the adhesive layer is deformed and oozes out from the support, it is restored to its original state when released.

D: When compressing, the adhesive layer is deformed and oozes out from the support, and it is not easy to restore the original state even if the compression is released.

<degree of peeling when entering the bath>

The patch adjusted in the examples, the reference examples, and the comparative examples was punched into a circular shape having a diameter of 36 mm, attached to five healthy volunteer chests, and the degree of peeling at the time of bathing was evaluated based on the following criteria.

A: None of the 5 positions were peeled off.

B: Although the peeling of the end was observed at 1 to 2, it did not fall off.

C: 1~2 sticks are peeled off.

D: 3 or more falls off.

[Test Example 2] Skin irritation test

The back coat of kbs:JW female rabbit (17 weeks old) was removed by electric clipper 3 days before the start date of attachment, and the adhesives of the examples, reference examples and comparative examples were sold and commercially available. The Vasmin's patch was cut into 2.5 cm squares and attached to the skin (n=3). The oil-coated paper is covered with a cover tape to cover the cover from the chest to the abdomen by using an underlying tape (underlap tape; manufactured by NICHIBAN Co., Ltd.), and then a sheath for rabbits (BJ03, BIORESEARCH shares) Limited company). After fixing for 24 hours, the sample was removed, and evaluated at 1 hour, 24 hours, 48 hours, and 72 hours after removal according to the method described in J. Pharmacol. Exp. Ther. 82, 377-390 (1944). The extent of skin irritation.

That is, at the above-mentioned times, the erythema and ecdysis formation and edema formation were evaluated and scored according to the following evaluation criteria. An evaluation value obtained by calculating an average value of each evaluation score was calculated, and an average value of each rabbit was obtained for the average evaluation value of each of the above-mentioned times as a primary irritation index P.I.I. (Primary Irritation Index). The P.I.I. value is at least 0 and the highest is 8, which is classified into the grades of the four skin irritation reactions shown in Table 2.

<Evaluation criteria for skin irritation response>

[Formation of erythema and molt]

Did not see erythema; 0 points

See very mild (and easily recognizable) erythema; 1 point

See a clear erythema; 2 points

See moderate to high erythema; 3 points

From the height of the erythema to the extent of the appearance of the skin that hinders the erythema score; 4 points

[Formation of edema]

Did not see edema; 0 points

See very mild (and easily identifiable) edema; 1 point

See mild edema (identifying the clear edges caused by a clear bulge); 2 points

See a moderate degree of edema (about 1mm bulge); 3 points

See a high degree of edema (1mm or more bulge and width beyond the exposure range); 4 points

[Test Example 3] In vitro skin permeability test

The abdomen-extracted skin of Wister male rats (5 weeks old) was attached to a vertical Franz diffusion cell according to the method described in International Publication No. 2006/093139. The patch of the examples, the reference examples and the comparative examples, and the commercially available patch were respectively punched into a circular shape having an area of 1.0 cm ² as a sample, and attached to the rat skin of the diffusion cell (n=3). . The content of rivastigmine in the receptor solution was quantitatively quantified by high-speed liquid chromatography (HPLC) using 10% by volume of ethanol physiological saline on the receptor side.

The amount of the drug that passed through the rat skin was determined 24 hours after the sample was attached.

The results evaluated using the above test methods are shown in Table 3.

According to Table 3, the patch of the present invention exhibits a skin permeation amount of rivastigmine which is equivalent to a commercially available patch containing rivastigmine, and exhibits good skin permeability and excellent adhesion. characteristic. In detail, it can be seen that the patch of the present invention exhibits moderate peel strength and sufficient viscosity. Further, by using a highly viscous flowing paraffin, it is possible to obtain a formulation in which the bleeding of the adhesive layer is small and the peeling at the time of bathing is small. A commercially available patch containing rivastigmine, although having a PII value of 2.92, exhibits moderate irritation, the patch of the present invention has a PII value of 0 and is evaluated as non-irritating, so the skin Low irritation.

[Reference Example 8~15]

Modulation of adhesive patches for skin attachment

According to the conditions shown in Table 4, the components constituting the adhesive layer were weighed. First, a styrene-isoprene-styrene block copolymer (SIS)/styrene-isoprene block copolymer (SI) mixture (KRAYTON D1111, "KRAYTON D1119", manufactured by Kraton Co., Ltd., "JSR SIS5505" and "JSR SIS5229" manufactured by JSR Co., Ltd. were dissolved in 230 parts by weight of toluene per 100 parts by weight of the mixture. To the above solution, a liquid paraffin ("BENOL", "KAYDOL", "Hydrobrite 550PO", "Hydrobrite HV") manufactured by Sonneborn Co., Ltd.) was added and mixed, and a coating liquid for forming an adhesive layer was prepared.

The coating liquid was applied to a film of a polybutylene terephthalate (PET) film (release liner) treated with an anthrone, and the adhesive layer after drying was prepared to have a thickness of about 300 μm. After drying in an oven at 80 ° C for 1 hour, a PET film (support) was laminated on the surface of the adhesive layer, and cut into a size of 15 cm × 30 cm to obtain a desired adhesive sheet. The SIS/SI ratio in the table is the weight ratio.

[Reference Example 16]

Modification of anthrone adhesive sheets

According to the method of the examples of WO2007/064407, the composition after drying is made into an anthrone adhesive (manufactured by Dow Corning, "Bio-PSA Q7-4301"), 98.9 wt%, anthrone oil 1.0 wt%, vitamin E 0.1 wt. The coating liquid was prepared in a % manner so as to be applied to a Teflon-treated polyethylene terephthalate (PET) film (release liner) so that the weight per unit area after drying became 90 g/m 2 . And dry.

A PET film (support) was laminated on the surface of the adhesive layer, and cut into a size of 15 cm × 30 cm to obtain a desired adhesive sheet.

The patch (adhesive sheet) of Reference Examples 8 to 16 and a commercially available patch ("MOHRUS TAPE L 40 mg" manufactured by Jiuguang Pharmaceutical Co., Ltd.) were evaluated in the same manner as the test methods (Test Examples 1 and 2) described above. The results of the first three-part "LOXONIN TAPE 100mg" are shown in Table 5.

As is clear from Table 5, each of the adhesive sheets of Reference Examples 8 to 15 exhibited a lower adhesive property than the commercially available patch, although it was lower in adhesion characteristics than the ketone ketone adhesive sheet of Reference Example 16. On the other hand, the skin irritation was low as compared with the ketone adhesive sheet. In addition, it exhibits high adhesion especially when using mobile paraffin having a high dynamic viscosity.

[Reference Example 17, 18]

Modulation of a patch containing a drug

According to the conditions shown in Table 6, the components constituting the adhesive layer were weighed. First, a styrene-isoprene-styrene block copolymer (SIS)/styrene-isoprene block copolymer (SI) mixture (KRAYTON D1111, "KRAYTON D1119", manufactured by Kraton Co., Ltd., "JSR SIS5505" and "JSR SIS5229" manufactured by JSR Co., Ltd. were dissolved in 230 parts by weight of toluene per 100 parts by weight of the mixture. In the above solution, a liquid paraffin ("BENOL", "KAYDOL", "Hydrobrite 550PO", "Hydrobrite HV") manufactured by Sonneborn Co., Ltd., various additives and a chemical agent are added and mixed, and a coating for forming an adhesive layer is prepared. liquid.

Further, the coating liquid was applied to a film of a polybutylene terephthalate (PET) film (release liner) treated with an anthrone, so that the drug content in the adhesive layer after drying became 1.8 mg/cm. ² way modulation. After drying in an oven at 80 ° C for 1 hour, a PET film (support) was laminated on the surface of the adhesive layer, and cut into a size of 15 cm × 30 cm to obtain a desired patch. The SIS/SI ratio in the table is the weight ratio.

The results of evaluating the patch of Reference Examples 17 and 18 and a commercially available patch in the same manner as the above test methods (Test Examples 1 to 3) are shown in Tables 7 and 8.

As can be seen from Tables 7 and 8, each of the patching agents of Reference Examples 17 and 18 exhibited transdermal absorbability equivalent to or higher than that of a commercially available patch, and was small in skin irritation and exhibited excellent adhesive properties.

 [Industrial Applicability]  

As described in detail above, according to the present invention, it is possible to provide a drug having sufficient skin adhesion and low skin irritation, and a drug such as rivastigmine has good skin permeability and exhibits sufficient transdermal absorbability. Percutaneous absorption preparation.

Claims (7)

A percutaneous absorption preparation for forming a transdermal absorption preparation comprising an adhesive layer containing a transdermally absorbable drug (but not including Rivastigmine or a pharmaceutically acceptable salt thereof) on a support The adhesive layer comprising a transdermally absorbable drug, a thermoplastic elastomer, and 100 parts by weight of the thermoplastic elastomer, more than 50 parts by weight and less than 800 parts by weight of a non-volatile hydrocarbon oil, The thermoplastic elastomer is a mixture of a styrene-isoprene-styrene block copolymer and a styrene-isoprene block copolymer, and the styrene-isoprene block copolymer in the mixture The content of the solution is 20% by weight or more, and the solution viscosity of the 25% by weight toluene solution of the thermoplastic elastomer at 25 ° C is 0.9 Pa ‧ or more, and the dynamic viscosity of the nonvolatile hydrocarbon oil at 40 ° C is 60 mm ² / s above.  The percutaneous absorption preparation according to claim 1, wherein the percutaneously absorbable drug is knitidine or rotiprine.    The percutaneous absorption preparation according to claim 1 or 2, wherein the content of the styrene-isoprene block copolymer in the mixture is 30% by weight or more.    The percutaneous absorption preparation according to claim 1 or 2, wherein the content of the nonvolatile hydrocarbon oil in the adhesive layer is 23.5% by weight or more and 88% by weight or less.   The percutaneous absorption preparation according to claim 1 or 2, wherein the non-volatile hydrocarbon oil has a dynamic viscosity at 40 ° C of 80 mm ² /s or more.  The percutaneous absorption preparation according to claim 1 or 2, wherein the adhesive layer further contains an adhesion-imparting agent, and the content of the adhesive layer in the adhesive-imparting agent is 10% by weight or less.    The percutaneous absorption preparation according to claim 1 or 2, wherein the adhesive layer does not contain an adhesion-imparting agent.