WO2009113504A1

WO2009113504A1 - Patch

Info

Publication number: WO2009113504A1
Application number: PCT/JP2009/054466
Authority: WO
Inventors: 弘子宇田川; 俊一薦田; 紗貴子柴田; 勝浜辺
Original assignee: 積水メディカル株式会社
Priority date: 2008-03-10
Filing date: 2009-03-09
Publication date: 2009-09-17
Also published as: JPWO2009113504A1

Abstract

Provided is a patch which has a high storage stability and transdermal absorbability of midodrine or a pharmacologically acceptable salt thereof and exhibits an excellent stickiness. A patch which contains in the ointment layer midodrine or a pharmacologically acceptable salt thereof and a specific acrylic pressure-sensitive adhesive together with one or both of a saturated aliphatic monohydric alcohol (A) and a saturated fatty acid ester each in a definite amount. Owing to this constitution, the solubility and diffusibility of the midodrine or a salt thereof in the ointment layer are improved and thus the transdermal absorbability is elevated without damaging the storage stability of the midodrine or a salt thereof. Thus, a sufficient amount of the midodrine or a salt thereof is contained in the diffused state in the ointment layer, which enables continuous administration of midodrine.

Description

Patch

The present invention relates to a patch for transdermal administration of midodrine or a pharmacologically acceptable salt thereof.

Middolin is an active metabolite, 2-amino-1- (2 ′, 5′-dimethoxyphenyl) ethanol (hereinafter referred to as “DMAE”), which selectively stimulates α ₁ -receptor to contract peripheral blood vessels. Is known to increase blood pressure and is used to treat essential hypotension and orthostatic hypotension. Further, in recent years, in the clinical field, paying attention to the smooth muscle contraction effect of DMAE stimulated by α ₁ -receptor, it is also expected that midodrine and DMAE are applied to the treatment of stress urinary incontinence.

Currently, in Japan, an oral preparation based on midodrine hydrochloride, which is the middolin hydrochloride, is commercially available as a drug containing the above-mentioned middolin as a component. Take twice a day. However, after taking the above oral preparation, the blood concentration of DMAD, which is a metabolite of midodrine hydrochloride, suddenly increased, and supine hypertension, a side effect, sometimes developed.

Therefore, as a method for solving the above problem, a method of transdermally administering middolin by applying a patch containing middolin to the skin has been proposed (Patent Document 1). Advantages of administering midodrine by means of the patch as described above are as follows: (1) Since midodrine can be absorbed at a gentle rate over a long period of time from the skin, it is difficult for a rapid increase in DMAE blood concentration to occur. (2) The primary metabolism of middolin in the liver is avoided and bioavailability (bioavailability) is improved. (3) Even if a side effect occurs, middolin can be administered by removing the patch. It can be stopped immediately.

In particular, when middolin is used for the treatment of stress urinary incontinence, the patient does not originally need blood pressure control, and in the case of a patch, it may cause side effects of hypertension on such patients. It is preferable because it is easy to continuously administer an amount of a small amount.

Further, Patent Document 1 proposes to use a transdermal application agent containing middolin as a patch, and further, as an additive for enhancing the transdermal absorbability of middolin, a polar solvent, an absorption accelerator, a base An agent for transdermal application containing an active substance has been proposed. In addition, as a dosage form of a transdermal application agent, a patch, a soft writing agent, a cream agent or a lotion agent has been proposed.

However, as a result of investigations by the inventors, it has been clarified that the additive used in the above-mentioned transdermal application agent may cause decomposition of middolin in some cases. Furthermore, in the patch, the combination of the adhesive used and the decomposition of middolin occurs, the content is reduced, or the percutaneous absorbability of middolin is not expressed well.

JP 2001-131062 A

The present invention provides a patch having excellent storage stability and transdermal absorbability of middolin or a pharmacologically acceptable salt thereof and good patchability.

The patch of the present invention is a patch comprising a support and a paste layer laminated and integrated on one surface of the support, wherein the paste layer is middolin or its pharmacologically acceptable. And a monomer containing 30 to 99% by weight of alkyl methacrylate having 4 to 22 carbon atoms in the alkyl group and 1 to 70% by weight of alkyl alkyl ester having 2 to 20 carbon atoms in the alkyl group. Copolymerized acrylic pressure-sensitive adhesive 40 to 98% by weight, saturated aliphatic monohydric alcohol (A) having an alkyl group having 10 to 30 carbon atoms, or saturated having an alkyl group having 10 to 20 carbon atoms 1 to 40% by weight of the total amount of either or both of fatty acid esters obtained by dehydration condensation of a fatty acid and a saturated aliphatic monohydric alcohol (B) having 2 to 20 carbon atoms in the alkyl group. Features.

The plaster layer of the above patch contains midodrine or a pharmacologically acceptable salt thereof. The pharmacologically acceptable salt of midodrine includes, for example, a salt of midodrine and an inorganic acid or an organic acid. Examples of such inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of organic acids include formic acid, acetic acid, trifluoroacid, propionic acid, lactic acid, Examples include tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, malonic acid, and methanesulfonic acid.

The content of midodrine or a pharmacologically acceptable salt thereof (hereinafter collectively referred to as “midodrines”) in the plaster layer is preferably 1 to 30% by weight, more preferably 2 to 25% by weight. 5 to 25% by weight is particularly preferred, and 5 to 20% by weight is most preferred. If the content of midodrines in the plaster layer is small, the amount of percutaneous absorption of midodrines decreases, and the blood concentration of DMAE may not be increased to the desired range unless the area of the patch is increased. On the other hand, if the amount is too large, crystals of midodrine precipitate excessively in the plaster layer, and the adhesive strength of the patch and the diffusibility of midodrine may be reduced.

In the patch of the present invention, it is necessary that midodrines absorbed as a therapeutic agent are converted into DMAE in the body and the blood concentration thereof is increased to a desired range. In the plaster layer, a sufficient amount of midodrines is stably contained, and in the dissolved state of the middolin, it diffuses into the plaster layer, and the middolins continue to adhere to the skin. Supply is required. In order to constitute a plaster layer excellent in storage stability and transdermal absorbability of such midodrines, the patch of the present invention uses a midodrine as a monomer as an adhesive constituting the plaster layer. Alkyl methacrylate that is excellent in storage stability and diffusibility of midodrines with excellent storage stability, and excellent in solubility and diffusibility of middolins in inferior storage stability of midodrine in monomers An acrylic pressure-sensitive adhesive obtained by copolymerizing monomers each containing a predetermined amount of alkyl acrylate is used. By using this pressure-sensitive adhesive, the solubility and diffusibility of midodrines, which are insufficient with only alkyl methacrylate, are complemented by the excellent solubility and diffusibility that are the advantages of alkyl acrylate. The problem of storage stability with respect to midodrines, which are disadvantages of acid alkyl esters, is solved by the excellent storage stability of midodrines, which is an advantage of alkyl methacrylates.

Therefore, the acrylic pressure-sensitive adhesive is very excellent in the storage stability of midodrines, and can dissolve and diffuse a sufficient amount of middolins to exhibit medicinal effects. It is also excellent in compatibility with the saturated aliphatic monohydric alcohol (A) and fatty acid ester to be blended in order to further improve the skin absorbability. In addition, since the acrylic pressure-sensitive adhesive has different contributions to the physical properties of the pressure-sensitive adhesives of the methacrylic acid alkyl ester component and the acrylic acid alkyl ester component constituting the pressure-sensitive adhesive, the plaster can be obtained by adjusting these compositions. The adhesive strength of the layer can be easily adjusted.

The number of carbon atoms in the alkyl group of the methacrylic acid alkyl ester is limited to 4 to 22, and preferably 4 to 16. When the carbon number of the alkyl group of the methacrylic acid alkyl ester is 3 or less, the plasticizing effect by the alkyl group is lowered, and the elasticity and viscosity as the pressure-sensitive adhesive are insufficient. On the other hand, when the carbon number of the alkyl group is 23 or more, the entanglement of the alkyl groups of the methacrylic acid alkyl ester component in the acrylic pressure-sensitive adhesive becomes strong, and the elasticity and viscosity of the pressure-sensitive adhesive become too high. Therefore, even if the number of carbon atoms of the alkyl group of the methacrylic acid alkyl ester is large or small, the adhesive force of the acrylic pressure-sensitive adhesive to the skin is lowered. Furthermore, if the number of carbon atoms in the alkyl group of the methacrylic acid alkyl ester is too large, the solubility and diffusibility of midodrines may decrease.

The methacrylic acid alkyl ester having 4 to 22 carbon atoms in the alkyl group is not particularly limited, and examples thereof include butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, n-octyl methacrylate, decyl methacrylate, dodecyl methacrylate, Examples include decyl methacrylate, tetradecyl methacrylate, hexadecyl methacrylate, octadecyl methacrylate, and behenyl methacrylate, and butyl methacrylate, hexyl methacrylate, 2-ethylhexyl methacrylate, and dodecyl methacrylate are preferable. In addition, a methacrylic acid alkylester may be used independently, or 2 or more types may be used together.

And, if the content of the alkyl methacrylate ester in the monomer that is the raw material of the acrylic pressure-sensitive adhesive is small, the reactivity of the acrylic pressure-sensitive adhesive to the middolin is increased, and the storage stability of the middolin is increased. It decreases, or the elasticity of the acrylic adhesive is reduced, and adhesive residue on the skin is likely to occur. On the other hand, if it is large, the solubility and diffusibility of midodrines in the plaster layer are reduced. Since the layer becomes hard and the initial adhesive strength to the skin decreases, it is limited to 30 to 99% by weight, preferably 50 to 99% by weight, more preferably 70 to 99% by weight.

The carbon number of the alkyl group of the acrylic acid alkyl ester is limited to 2 to 20, and preferably 4 to 16. When the alkyl group of the acrylic acid alkyl ester is methyl, the stability of midodrines is remarkably lowered, and the elasticity and viscosity of the pressure-sensitive adhesive are lowered. On the other hand, when the carbon number of the alkyl group is 21 or more, the solubility and diffusibility of midodrines decrease and the elasticity and viscosity of the pressure-sensitive adhesive become too high. Therefore, even if the number of carbon atoms of the alkyl group of the acrylic acid alkyl ester is large or small, the adhesive force to the skin is lowered.

The alkyl alkyl ester having 2 to 20 carbon atoms in the alkyl group is not particularly limited. For example, ethyl acrylate, propyl acrylate, butyl acrylate, isobutyl acrylate, hexyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, decyl Examples include acrylate, dodecyl acrylate, tridecyl acrylate, hexadecyl acrylate, octadecyl acrylate, and the like, and 2-ethylhexyl acrylate is preferable. In addition, an alkyl acrylate ester may be used independently or 2 or more types may be used together.

In addition, if the content of the acrylic acid alkyl ester in the monomer that is the raw material of the acrylic adhesive is small, the solubility and diffusibility of the middolins in the plaster layer may be reduced, or the initial adhesion to the skin may be reduced. On the other hand, when the strength decreases, the storage stability of the middolins in the paste layer decreases, or the internal cohesive force of the paste layer decreases, and the saturated aliphatic monohydric alcohol (A) described later applies the paste. Since the body layer is excessively plasticized and adhesive residue tends to be generated on the skin, it is limited to 1 to 70% by weight, preferably 1 to 50% by weight, and more preferably 1 to 30% by weight.

The acrylic pressure-sensitive adhesive is preferably an acrylic pressure-sensitive adhesive obtained by copolymerizing a monomer containing 70 to 95% by weight of 2-ethylhexyl methacrylate and 1 to 30% by weight of 2-ethylhexyl acrylate. An acrylic pressure-sensitive adhesive prepared by copolymerizing a monomer containing 70 to 95% by weight of ethylhexyl methacrylate, 1 to 20% by weight of 2-ethylhexyl acrylate and 4 to 29% by weight of dodecyl methacrylate is more preferable. In particular, when used in combination with a saturated aliphatic monohydric alcohol (A) or a fatty acid ester, which will be described later, the acrylic pressure-sensitive adhesive has superior storage stability and transdermal absorbability of midodrines, and excellent This is because the adhesiveness to the skin is expressed.

In addition, if the content of the acrylic adhesive in the plaster layer is small, the adhesive strength to the skin is reduced or adhesive residue is liable to occur. On the other hand, if the content is large, the desired DMAE blood concentration is decreased. The amount of midodrine and saturated aliphatic monohydric alcohol (A) or fatty acid ester necessary to obtain it cannot be blended, so it is limited to 40 to 98% by weight, preferably 45 to 90% by weight, preferably 50 to 85% by weight is more preferable, and 55 to 85% by weight is particularly preferable.

Further, the acrylic pressure-sensitive adhesive is an alkyl methacrylate having 4 to 22 carbon atoms in the alkyl group as long as it does not impair the storage stability and transdermal absorbability of middolins and the adhesiveness to the skin. A monomer obtained by copolymerizing a monomer containing a monomer other than an alkyl acrylate ester having an ester group and an alkyl group having 2 to 20 carbon atoms may be used.

Examples of the monomer other than the alkyl methacrylate having 4 to 22 carbon atoms in the alkyl group and the acrylic acid alkyl ester having 2 to 20 carbon atoms in the alkyl group include, for example, methyl methacrylate, ethyl methacrylate, propyl methacrylate and the like. A polyfunctional monomer having two or more polymerizable functional groups in one molecule such as alkyl methacrylate, divinylbenzene, methylenebisacryloside, ethylene glycol dimethacrylate, ethylene glycol diacrylate or the like, wherein the alkyl group has 3 or less carbon atoms Body, acrylic acid, methacrylic acid, vinyl pyrrolidone, vinyl acetate, (meth) acrylic acid hydroxyalkyl ester and the like. By containing such a monomer, the solubility and diffusibility of midodrine in the plaster layer and the adhesive strength of the patch can be adjusted.

Furthermore, the monomer used as the raw material of the acrylic pressure-sensitive adhesive may be an epoxy compound, a polyisocyanate compound, a metal other than the polyfunctional monomer as long as it does not impair the storage stability of midodrines. Crosslinking agents such as chelate compounds and metal alkoxide compounds may be added. By adding a crosslinking agent to the monomer used as the raw material for the acrylic adhesive, the internal cohesive strength of the acrylic adhesive is increased, so that adhesive residue is left on the skin when the patch is peeled from the skin. Can be difficult.

The acrylic pressure-sensitive adhesive may be polymerized by a conventionally known method. For example, in the presence of a polymerization initiator, the above-mentioned monomer is blended and solution polymerization is performed. To polymerize. Specifically, a predetermined amount of alkyl methacrylate having 4 to 22 carbon atoms in the alkyl group, alkyl alkyl ester having 2 to 20 carbon atoms in the alkyl group, a polymerization initiator, and a crosslinking agent to be added as necessary Together with the polymerization solvent is supplied to a reactor equipped with a stirrer and a cooling / refluxing device for the vaporized solvent and heated at a temperature of 60 to 80 ° C. for 4 to 48 hours to cause radical polymerization reaction of the monomer. .

Examples of the polymerization initiator include 2,2′-azobisisobutyronitrile (AIBN), 1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-azobis- (2 Azobis-based polymerization initiators such as benzoyl peroxide (BPO), lauroyl peroxide (LPO), and di-tert-butyl peroxide, and the like. Examples of the polymerization solvent include ethyl acetate and toluene. Furthermore, the polymerization reaction is preferably performed in a nitrogen gas atmosphere.

The patch of the present invention absorbs the middolins contained in the plaster layer from the skin by sticking the plaster layer to the skin, and is required to have high transdermal absorbability. In order to improve this transdermal absorbability, it is preferable to increase the solubility and diffusibility of midodrines in the plaster layer. However, if the solubility of middolins is too high, the storage stability of middolins is improved. It may be damaged. In addition, midodrines may not be distributed or diffused from the plaster layer to the skin, and the percutaneous absorbability of midodrines may be reduced. Therefore, in the present invention, the saturated aliphatic monohydric alcohol (A) in which the alkyl group has 10 to 30 carbon atoms or the saturated fatty acid in which the alkyl group has 10 to 20 carbon atoms and the alkyl group are included in the plaster layer. By containing either or both of fatty acid esters obtained by dehydration condensation with saturated aliphatic monohydric alcohol (B) having 2 to 20 carbon atoms, the solubility and diffusibility of midodrines in the plaster layer can be improved. It enhances the transdermal absorbability of midodrines.

The saturated aliphatic monohydric alcohol (A) and the fatty acid ester can stably hold, disperse and dissolve a sufficient amount of midodrine in the plaster to obtain a desired DMAE blood concentration, Since the compatibility with the above-mentioned acrylic adhesive is good, the acrylic adhesive can be plasticized to increase the diffusibility of midodrines in the plaster layer. Furthermore, it has the effect of increasing the flexibility of the stratum corneum of the skin, increasing hydration, and acting as a carrier for carrying middolins into the skin. Therefore, by using the saturated aliphatic monohydric alcohol (A) and the fatty acid ester, the transdermal absorbability of midodrines can be greatly improved. In particular, a saturated aliphatic monohydric alcohol (A) in which the alkyl group has 12 to 22 carbon atoms, a saturated fatty acid in which the alkyl group has 12 to 18 carbon atoms, and a saturated fat in which the alkyl group has 2 to 6 carbon atoms. Fatty acid ester formed by dehydration condensation with the group monohydric alcohol (B) has low reactivity with the above middolins, is excellent in storage stability of the middolins, plasticizes the plaster layer, and is excellent Since there exists an effect which brings sticking property, it can be used conveniently. In particular, as saturated aliphatic monohydric alcohol (A) and fatty acid ester, those having a branched structure in the hydrocarbon chain portion show good compatibility with acrylic adhesives, and the adhesive has excellent adhesiveness. Since it expresses, it is more preferable.

Here, when the plaster layer contains a dihydric or higher alcohol instead of the saturated aliphatic monohydric alcohol (A), the solubility of the middolin is improved, but the compatibility with the acrylic adhesive is improved. Reduced, the plasticization of the acrylic adhesive becomes insufficient, the diffusibility of midodrines in the plaster layer decreases, and the percutaneous absorbability of midodrines decreases. Storage stability will fall and the content of midodrine in the plaster layer will decrease. In addition, when the above-mentioned plaster layer contains an unsaturated aliphatic alcohol instead of the saturated aliphatic monohydric alcohol (A), the unsaturated aliphatic alcohol reacts with midodrines and the storage stability of the middolins decreases. Thus, the content of midodrine in the plaster layer is reduced. Therefore, the alcohol contained in the plaster layer of the patch of the present invention is limited to the saturated aliphatic monohydric alcohol (A).

The saturated aliphatic monohydric alcohol (A) is a monohydric alcohol represented by the formula R—OH (R is an alkyl group). The carbon number of the alkyl group of the saturated aliphatic monohydric alcohol (A) is limited to 10 to 30, preferably 12 to 22, and more preferably 14 to 20. When the carbon number of the alkyl group of the saturated aliphatic monohydric alcohol is 9 or less, the compatibility with the acrylic pressure-sensitive adhesive is lowered and the adhesiveness is deteriorated. Further, the saturated aliphatic monohydric alcohol (A) itself has high volatility, and is not sufficiently retained in the patch. In addition, the solubility of midodrines may become too high and the storage stability of midodrines may decrease. On the other hand, when the carbon number of the alkyl group is 31 or more, the solubility and diffusibility of midodrines decrease, the transdermal absorbability of middolins decreases, and compatibility with an acrylic adhesive and plasticizing action In some cases, a large amount of saturated aliphatic monohydric alcohol crystals are precipitated in the plaster layer, so that the adhesive strength of the patch tends to decrease.

The saturated aliphatic monohydric alcohol (A) in which the alkyl group has 10 to 30 carbon atoms is not particularly limited, and examples thereof include lauryl alcohol, myristyl alcohol, cetanol, stearyl alcohol, isostearyl alcohol, hexyl decanol, and octyldodecane. Examples include nol, behenyl alcohol, tetracosanol, and octacosanol, and myristyl alcohol, hexyl decanol, octyldodecanol, and isostearyl alcohol are preferable. These saturated aliphatic monohydric alcohols (A) may be used alone or in combination of two or more. Moreover, you may combine with the below-mentioned fatty acid ester.

The saturated fatty acid is a monovalent carboxylic acid represented by the formula R-COOH (R is an alkyl group). The carbon number of the alkyl group R of the saturated fatty acid is limited to 10-20, and preferably 12-18. If the carbon number of the alkyl group R of the saturated fatty acid is small, the compatibility between the resulting fatty acid ester and the acrylic pressure-sensitive adhesive is lowered, the plasticization of the acrylic pressure-sensitive adhesive becomes insufficient, and the adhesiveness is deteriorated. In addition, when the volatility of the fatty acid ester itself is high and not sufficiently retained in the patch, the diffusibility of midodrines in the plaster layer may be reduced, and the transdermal absorbability may be reduced. On the other hand, when the carbon number of the alkyl group R of the saturated fatty acid is large, the solubility and diffusibility of the middolins are reduced, and the transdermal absorbability of the middolins is reduced, and the compatibility with the acrylic adhesive and plasticization The action is reduced, and in some cases, a large amount of saturated aliphatic monohydric alcohol crystals are precipitated in the plaster layer, and the adhesive strength is likely to be reduced.

The saturated aliphatic monohydric alcohol (B) is a monohydric alcohol represented by the formula R′—OH (R ′ is an alkyl group). The number of carbon atoms of the alkyl group R ′ of the saturated aliphatic monohydric alcohol (B) is limited to 2 to 20, and preferably 2 to 6. When the carbon number of the alkyl group R ′ of the saturated aliphatic monohydric alcohol (B) is small, the compatibility between the resulting fatty acid ester and the acrylic pressure-sensitive adhesive is lowered, and the plasticization of the acrylic pressure-sensitive adhesive is insufficient. As a result, the adhesiveness deteriorates. In addition, if the volatility of the fatty acid ester itself is high and not sufficiently retained in the patch, the diffusibility of midodrines in the plaster layer may be reduced, and the transdermal absorbability of midodrines may be reduced. is there. On the other hand, if the alkyl group R ′ of the saturated aliphatic monohydric alcohol (B) has a large number of carbon atoms, the solubility and diffusibility of the middolins are lowered, and the transdermal absorbability of the middolins is lowered. The compatibility with the agent and the plasticizing effect are lowered, and in some cases, a large amount of fatty acid ester crystals are deposited on the surface of the plaster layer, and the adhesive force is likely to be lowered.

Examples of such fatty acid esters include, but are not limited to, hexyl laurate, isopropyl myristate, myristyl myristate, octyldodecyl myristate, isocetyl myristate, isopropyl palmitate, and the like. Isopropyl palmitate is preferred. In addition, these fatty acid ester may be used independently, or 2 or more types may be used together. Moreover, you may combine with the above-mentioned saturated aliphatic monohydric alcohol.

If the total content of saturated aliphatic monohydric alcohol (A) and fatty acid ester in the plaster layer is small, the solubility and diffusibility of midodrines in the plaster layer are reduced, and the transdermal absorbability of midodrines On the other hand, if the amount is too large, the acrylic adhesive in the plaster layer is excessively plasticized, and adhesive residue is left on the skin when the patch is peeled from the skin. The content is preferably 5 to 30% by weight, more preferably 10 to 25% by weight, and particularly preferably 10 to 20% by weight.

In addition, a plasticizer, a solubilizer, an absorption accelerator, a stabilizer, a filler and the like may be added to the plaster layer within a range not impairing the effects of the present invention.

The plasticizer is added for the purpose of improving the adhesive strength of the patch and the diffusibility of midodrines in the plaster layer. Examples of such plasticizers include hydrocarbons such as squalane and liquid paraffin; esters of aliphatic carboxylic acids and mono- or polyhydric alcohols such as glyceryl monolaurate and diethyl sebacate; lanolin and olive oil. Examples include oils and fats derived from natural products. The plasticizer may be added in an amount of 1 to 10% by weight in the plaster layer.

Moreover, the above-mentioned solubilizer is added for the purpose of increasing the solubility of midodrines in the plaster layer. Examples of such a solubilizer include polyhydric alcohols such as polyethylene glycol, propylene glycol, and glycerin, and esters such as triacetin, which may be added in an amount of 1 to 10% by weight in the plaster layer.

The absorption enhancer is used to act on the skin and increase the skin permeability of midodrines, and those that soften the stratum corneum and those that increase the hydration property of the stratum corneum are used. Examples of such absorption promoters include surfactants such as polysorbate, lauric acid diethanolamide, lauroyl sarcosine, polyoxyethylene alkyl ether, and polyoxyethylene alkylamine. The absorption promoter may be added in an amount of 0.05 to 10% by weight in the plaster layer.

The stabilizer is added for the purpose of suppressing oxidation and decomposition of midodrines. Examples of such a stabilizer include antioxidants such as butylhydroxytoluene and sorbic acid, cyclodextrin, ethylenediaminetetraacetic acid and the like, and 0.05 to 10% by weight is added to the plaster layer. Good.

Further, the filler is added to adjust the adhesive strength of the patch and the transdermal absorbability of midodrines. Examples of such fillers include inorganic fillers such as organic metal salts such as calcium carbonate and magnesium stearate, silicic anhydride, and titanium oxide; celluloses such as lactose, crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose. Derivatives; vinyl pyrrolidone, and polymers using (meth) acrylic acid and (meth) acrylic acid derivatives as monomers are listed. The filler may be added in an amount of 1 to 15% by weight in the plaster layer.

The thickness of the plaster layer is preferably 10 to 250 μm, more preferably 20 to 200 μm. This is because when the thickness of the plaster layer is less than 10 μm, the plaster layer cannot contain the amount of midodrine necessary to obtain the desired blood concentration of DMAE, or the adhesion to the skin surface is reduced. May be peeled off during application. On the other hand, if the thickness of the plaster layer is more than 250 μm, the plaster layer is likely to protrude from the patch at the time of storing or sticking the patch, or the feeling of sticking at the time of sticking deteriorates. .

The support that is laminated and integrated with the plaster layer to constitute the patch of the present invention prevents the loss of midodrines in the plaster layer and protects the plaster layer. It is required to have the flexibility to give a good patch feeling of the patch while having the strength to give the self-supporting property.

Such a support is not particularly limited, and examples thereof include resin films, foamed resin sheets, non-woven fabrics, woven fabrics, knitted fabrics, aluminum films, and the like. It may be made.

Examples of the resin constituting the resin film include cellulose acetate, ethyl cellulose, rayon, polyethylene terephthalate, plasticized vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride. , Polyurethane, polyethylene, polypropylene, polyvinylidene chloride and the like, and polyethylene terephthalate is preferable.

The above support is preferably one in which a polyethylene terephthalate film and a non-woven fabric or a flexible resin film are laminated and integrated from the viewpoint of the flexibility and the effect of preventing the loss of midodrines. Examples of the material constituting the nonwoven fabric and flexible sheet include polyethylene, polypropylene, ethylene-vinyl acetate copolymer, ethylene- (meth) methyl acrylate copolymer, nylon, polyester, vinylon, SIS copolymer, SEBS copolymer, rayon, cotton and the like can be mentioned. In addition, these materials may be used independently or 2 or more types may be used together.

In addition, when the support is formed by laminating and integrating a polyethylene terephthalate film and a nonwoven fabric, the thickness of the polyethylene terephthalate film cannot be uniformly adhered when laminated and integrated with the nonwoven fabric. In addition, the strength of the obtained support is insufficient, or pinholes are generated and peeling may easily occur at the interface between the polyethylene terephthalate film and the nonwoven fabric. Since the followability to the skin at the time of application of the patch is lowered and the feeling of application of the patch may be deteriorated, 2 to 50 μm is preferably used, and 2 to 25 μm is particularly preferable.

Further, when the support is formed by laminating and integrating a polyethylene terephthalate film and a nonwoven fabric, if the thickness of the nonwoven fabric is thin, the adhesiveness with the polyethylene terephthalate film is deteriorated or the strength of the support is insufficient. On the other hand, if it is thick, the flexibility of the support may be lowered, so 10 to 300 g / m ² is preferable.

The method for producing the support by laminating and integrating the polyethylene terephthalate film and the nonwoven fabric is not particularly limited, and examples thereof include a method of laminating and integrating with a binder and a method of heat-sealing. In addition, at the time of manufacture of a support body, the intensity | strength and feel of a support body can be adjusted by adding a binder or carrying out partial heat-fusion of the polyethylene terephthalate film and a nonwoven fabric.

In order to prevent the loss of midodrines in the plaster layer of the patch of the present invention and to protect the plaster layer, it is preferable that the release paper is laminated and integrated on the surface of the plaster layer of the patch in a peelable manner. .

Examples of the release paper include resin films and paper made of polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, and the like, and a release treatment is performed on the surface facing the plaster layer. It is preferable. The release paper may be a single layer or a plurality of layers.

In addition, for the purpose of improving the barrier property of the release paper, the release paper may be provided with an aluminum foil or an aluminum vapor deposition layer. Furthermore, when the release paper is made of paper, the release paper may be impregnated with a resin such as polyvinyl alcohol for the purpose of improving the barrier property of the release paper.

Next, a method for producing the patch of the present invention will be described. The method for producing the patch is not particularly limited. For example, in the case of a solvent coating method, either or both of saturated aliphatic monohydric alcohol (A) and fatty acid ester in addition to midodrines and acrylic adhesives. Then, an additive added as necessary is added to a solvent such as ethyl acetate, and a plaster layer solution obtained by stirring until uniform is obtained. After coating this uniformly on one side of the support with a coater, the plaster layer is laminated and integrated on one side of the support by drying, and the release paper is released from the release paper if necessary. Applying the paste layer solution on the surface where the release paper release process has been performed by the method of laminating and integrating so that the coated surface is in a state facing the paste layer, or the coating method similar to the above, Examples include a method of forming a paste layer on a release paper by drying, and laminating and integrating a support on the paste layer.

The patch of the present invention contains any of middolin or a pharmacologically acceptable salt thereof, a specific acrylic adhesive, a saturated aliphatic monohydric alcohol (A) or a saturated fatty acid ester in the plaster layer. Because the total amount of either or both is contained, the solubility and diffusibility of midodrines are improved and the transdermal absorbability is improved without impairing the storage stability of midodrines in the plaster layer. In addition, since a sufficient amount of midodrine is contained in a diffused state in the plaster layer, continuous transdermal administration of middolin is possible.

Furthermore, the patch of the present invention is suitable for use as a patch that not only does not unexpectedly peel off from the skin at the time of application, but also hardly causes adhesive residue on the skin at the time of peeling. Have power.

The patch is a plaster layer containing a specific acrylic adhesive and one or both of saturated aliphatic monohydric alcohol (A) and saturated fatty acid ester, and has its own skin irritation. Furthermore, since the storage stability of midodrines is good, the occurrence of skin irritation caused by the degradation products of middolins is hardly caused.

That is, the patch of the present invention is excellent in percutaneous absorbability of midodrines and has good patchability, low irritation to skin, and excellent storage stability as a preparation. Midodrines, which are therapeutic agents for hypotension and orthostatic hypotension, can be suitably used as a preparation for continuous administration while avoiding side effects. In particular, it can be suitably used as a patch for administering midodrines that are expected to be applied to the treatment of stress urinary incontinence in the future.

First, in the methacrylic acid alkyl ester, acrylic acid alkyl ester and other monomers, midodrine, tulobuterol (TB), indomethacin (IMT) and isosorbide nitrate (ISDN) (hereinafter, these four compounds are also referred to as “ The solubility and the active substance residual ratio (% by weight) of the “active substance” were evaluated in the following manner, and the results are shown in Table 1.

(Active substance solubility)
An active substance liquid is prepared by sufficiently mixing 100 parts by weight of the monomer shown in Table 1 and 3 parts by weight of any one compound of middolin, TB, IMT and ISDN, and the activity in this active substance liquid The dissolution state of the substance was visually observed. Then, this active substance solution was stored at a temperature of 25 ° C. for 7 days, and then the state of dissolution of the active substance in the active substance solution was visually observed again, and the active substance solubility was evaluated according to the following criteria.
High: No precipitation of active substance was observed in any active substance liquid immediately after preparation and after storage for 7 days.
Middle: Active substance deposition was observed in the active substance liquid immediately after preparation, but no active substance deposition was observed in the active substance liquid after storage for 7 days.
Low: Precipitation of the active substance was observed in any active substance liquid immediately after preparation and after storage for 7 days.

In the above evaluation, for the monomer determined to be “low” in middolin, in order to evaluate the active substance solubility in more detail, the active substance solution is prepared again by the above-described method and exceeds 10 minutes. The mixture was sonicated and allowed to stand at 25 ° C. for 1 hour. Then, after centrifuging the active substance liquid with a centrifuge at a rotational speed of 3000 rpm, a certain amount of the supernatant is collected, and the collected supernatant is dissolved in the active substance liquid by performing HPLC measurement. The active substance weight W ₁ (g) was quantified, and based on the following formula (2), the solubility (g) of the active substance at 25 ° C. with respect to the monomer as the solvent was calculated.
Active substance solubility (g) = (W ₁ / W ₂ ) × 100 (2)
(W ₂ : weight of monomer as a solvent in the active substance liquid (g))

(Active substance remaining rate)
Prepare the active substance liquid prepared in the above manner and the active substance liquid prepared by storing the active substance liquid prepared in the above manner at a temperature of 25 ° C. for 7 days, and the weight W of the active substance in these active substance liquids ₄ (g) was measured by HPLC, and the residual ratio (% by weight) relative to the active substance addition amount W ₃ (g) was calculated based on the following formula (1).
Active substance residual ratio (% by weight) = (W ₄ / W ₃ ) × 100 Formula (1)

Subsequently, evaluation of the storage stability, midodrine solubility, and midodrine solubility of the saturated aliphatic monohydric alcohol, fatty acid ester and additives used in the patch was performed, and the results are shown in Table 2.

(Medidrin storage stability)
After thoroughly mixing 3 parts by weight of midodrine and 100 parts by weight of the compound shown in Table 2, this mixture was placed in a sealed container and stored at 60 ° C. for 20 days. Then, the color of the mixture after storage was visually observed, and those that showed no discoloration before storage were evaluated as “excellent” and those that discolored were evaluated as “bad”.

Furthermore, the weight W ₆ (g) of midodrine remaining in the mixture after storage without being decomposed was quantified by HPLC, and based on the following formula (3), midodrine remaining relative to the amount of added midodrine W ₅ (g) The rate (% by weight) was calculated.
Middolin residual ratio (% by weight) = (W ₆ / W ₅ ) × 100 (3)

(Midodrine solubility)
A midodrine solution consisting of 50 parts by weight of midodrine and 950 parts by weight of the compound shown in Table 2 as a solvent was prepared. Next, this midodrine solution was kept at 50 ° C. for 15 minutes, and then shaken with an ultrasonic wave in a 25 ° C. water bath for 10 minutes. Then, this middolin solution was transferred to a centrifuge tube and allowed to stand at 25 ° C. for 2 hours, and then the middolin solution was centrifuged at a rotational speed of 3000 rpm using a centrifuge, so that middolin crystals were precipitated at the bottom of the centrifuge tube. The presence or absence was observed. About the thing which the crystal | crystallization of the middolin did not precipitate, the same operation was performed by the ratio which further increased the weight ratio of the middolin: compound to the maximum 200: 800, and prepared the middolin saturated solution, respectively.

Then, a certain amount of the supernatant of the saturated middolin solution after the centrifugation is collected, and the collected supernatant is subjected to HPLC measurement, thereby obtaining the weight W ₈ (g) of the middolin dissolved in the middolin solution. Based on the following formula (4), the solubility (g) of midodrine at 25 ° C. with respect to the compound as a solvent was calculated.
Midodrine solubility (g) = (W ₈ / W ₇ ) × 100 Formula (4)
(W ₇ : weight (g) of a compound serving as a solvent in the middolin solution)

However, for the middolin solution using myristyl alcohol, the middolin solution could not be determined because the middolin solution was solidified at 25 ° C.

Next, the acrylic adhesives A to I and the rubber adhesive used as the adhesives of the patch of the present invention are prepared in the following manner to produce the patches of Examples 1 to 37 and Comparative Examples 1 to 10. did.

(Preparation of acrylic adhesive A)
A reaction solution consisting of 13 parts by weight of dodecyl methacrylate, 78 parts by weight of 2-ethylhexyl methacrylate, 9 parts by weight of 2-ethylhexyl acrylate, and 50 parts by weight of ethyl acetate was put into a 40 liter polymerization machine, and the inside of the polymerization machine was subjected to nitrogen at 80 ° C. The atmosphere. Then, a polymerization initiator solution prepared by dissolving 1 part by weight of benzoyl peroxide in 100 parts by weight of cyclohexane is added to the reaction solution over 24 hours to polymerize, and after polymerization, ethyl acetate is further added to obtain acrylic pressure-sensitive adhesive A. An acrylic pressure-sensitive adhesive A solution having a content of 35% by weight was obtained.

(Preparation of acrylic adhesive B)
A reaction solution consisting of 20 parts by weight of dodecyl methacrylate, 30 parts by weight of hexyl methacrylate, 50 parts by weight of butyl acrylate, and 40 parts by weight of ethyl acetate was put into a separable flask, and then the inside of the separable flask was subjected to a nitrogen atmosphere at 80 ° C. did. Then, a polymerization initiator solution obtained by dissolving 1 part by weight of benzoyl peroxide in 100 parts by weight of cyclohexane is added to this reaction solution over 10 hours to polymerize, and after the polymerization, ethyl acetate is further added, and acrylic adhesive B An acrylic pressure-sensitive adhesive B solution having a content of 35% by weight was obtained.

(Preparation of acrylic adhesive C)
A reaction solution consisting of 15 parts by weight of dodecyl methacrylate, 85 parts by weight of 2-ethylhexyl methacrylate, and 50 parts by weight of ethyl acetate was put into a separable flask, and then the inside of the separable flask was set to a nitrogen atmosphere at 80 ° C. Then, polymerization was performed while adding a polymerization initiator solution obtained by dissolving 0.5 parts by weight of azobisisobutyronitrile in 50 parts by weight of ethyl acetate to this reaction solution over 10 hours. After polymerization, ethyl acetate was further added. An acrylic adhesive C solution having an acrylic adhesive C content of 32% by weight was obtained.

(Preparation of acrylic adhesive D)
A reaction liquid consisting of 75 parts by weight of 2-ethylhexyl methacrylate, 25 parts by weight of 1-vinyl-2-pyrrolidone (50% by weight), and 50 parts by weight of ethyl acetate was put into a separable flask. A nitrogen atmosphere was used. Then, polymerization was performed while adding a polymerization initiator solution obtained by dissolving 0.5 parts by weight of azobisisobutyronitrile in 50 parts by weight of ethyl acetate to this reaction solution over 10 hours. After polymerization, ethyl acetate was further added. An acrylic adhesive D solution having an acrylic adhesive D content of 35% by weight was obtained.

(Preparation of acrylic adhesive E)
A reaction liquid consisting of 95 parts by weight of 2-ethylhexyl acrylate, 5 parts by weight of acrylic acid, and 50 parts by weight of ethyl acetate was put into a separable flask, and then the inside of the separable flask was set to a nitrogen atmosphere at 80 ° C. Then, polymerization was performed while adding a polymerization initiator solution obtained by dissolving 0.5 parts by weight of azobisisobutyronitrile in 50 parts by weight of ethyl acetate to this reaction solution over 10 hours. After polymerization, ethyl acetate was further added. An acrylic adhesive E solution having an acrylic adhesive E content of 35% by weight was obtained.

(Preparation of acrylic adhesive F)
A reaction solution consisting of 75 parts by weight of 2-ethylhexyl methacrylate, 15 parts by weight of butyl methacrylate, 10 parts by weight of 2-ethylhexyl acrylate, and 50 parts by weight of ethyl acetate was put into a separable flask. A nitrogen atmosphere was used. Then, polymerization was performed while adding a polymerization initiator solution obtained by dissolving 0.5 parts by weight of azobisisobutyronitrile in 50 parts by weight of ethyl acetate to this reaction solution over 10 hours. After polymerization, ethyl acetate was further added. Then, an acrylic adhesive F solution having an acrylic adhesive F content of 33% by weight was obtained.

(Preparation of acrylic adhesive G)
A reaction solution consisting of 98 parts by weight of 2-ethylhexyl methacrylate, 2 parts by weight of acrylic acid and 50 parts by weight of ethyl acetate was put into a separable flask, and then the inside of the separable flask was set to a nitrogen atmosphere at 80 ° C. Then, polymerization is performed while adding a polymerization initiator solution obtained by dissolving 1 part by weight of lauroyl peroxide in 100 parts by weight of ethyl acetate to this reaction solution over 12 hours, and after the polymerization, ethyl acetate is further added to obtain an acrylic pressure-sensitive adhesive. An acrylic pressure-sensitive adhesive G solution having a G content of 40% by weight was obtained.

(Preparation of acrylic adhesive H)
A reaction solution consisting of 14 parts by weight of dodecyl methacrylate, 84 parts by weight of 2-ethylhexyl methacrylate, 1 part by weight of butyl methacrylate, 1 part by weight of butyl acrylate and 40 parts by weight of ethyl acetate was added to the separable flask, A nitrogen atmosphere at 80 ° C. was used. Then, polymerization is performed while adding a polymerization initiator solution obtained by dissolving 1 part by weight of lauroyl peroxide in 100 parts by weight of ethyl acetate to this reaction solution over 12 hours, and after the polymerization, ethyl acetate is further added to obtain an acrylic pressure-sensitive adhesive. An acrylic pressure-sensitive adhesive H solution having an H content of 36% by weight was obtained.

(Preparation of acrylic adhesive I)
A reaction solution consisting of 5 parts by weight of dodecyl methacrylate, 30 parts by weight of 2-ethylhexyl methacrylate, 50 parts by weight of 2-ethylhexyl acrylate, 15 parts by weight of butyl acrylate and 40 parts by weight of ethyl acetate was added to the separable flask, The inside was a nitrogen atmosphere at 80 ° C. Then, polymerization is performed while adding a polymerization initiator solution obtained by dissolving 1 part by weight of lauroyl peroxide in 100 parts by weight of ethyl acetate to this reaction solution over 12 hours, and after the polymerization, ethyl acetate is further added to obtain an acrylic pressure-sensitive adhesive. An acrylic adhesive I solution having an I content of 37% by weight was obtained.

(Preparation of rubber adhesive)
40 parts by weight of polyisobutylene A (trade name “Opanol B80” manufactured by BASF), 30 parts by weight of polyisobutylene B (trade name “Himol 5H” manufactured by Nippon Petrochemical Co., Ltd.), and product of polyisobutylene C (manufactured by Nippon Petrochemical Co., Ltd.) Name “Nisseki Polybutene HV-300F”) 30 parts by weight and 300 parts by weight of toluene were put into a separable flask, and the inside of the separable flask was uniformly mixed in a nitrogen atmosphere. A rubber adhesive solution having a content of 25% by weight was obtained.

In Tables 3-5, “DM” for dodecyl methacrylate, “EHM” for 2-ethylhexyl methacrylate, “EHA” for 2-ethylhexyl acrylate, “HM” for hexyl methacrylate, “BA” for butyl acrylate, 1-vinyl-2 -Pyrrolidone was described as "VP", acrylic acid as "AA", and butyl methacrylate as "BM".

(Examples 1 to 37, Comparative Examples 1 to 10)
The ratio of the weight composition of midodrine, acrylic adhesive, rubber adhesive, saturated aliphatic monohydric alcohol, fatty acid ester, and saturated aliphatic polyhydric alcohol (butylene glycol) in the plaster layer is shown in Tables 3 to 5. So, middolin, acrylic adhesive, rubber adhesive, saturated aliphatic monohydric alcohol, fatty acid ester, saturated aliphatic polyhydric alcohol (butylene glycol) and liquid paraffin are blended, and the solid content concentration is 22 wt. After adding ethyl acetate or toluene so that the amount of the mixture became uniform, the mixture was mixed until uniform to prepare a paste layer solution. In the column of saturated aliphatic monohydric alcohols in Tables 3 to 5, the number of carbon atoms of the alkyl group is described in parentheses on the right side of the compound. Similarly, in the column of fatty acid ester in Tables 3 to 5, the carbon number of the alkyl group of the saturated fatty acid and the carbon number of the alkyl group of the saturated aliphatic monohydric alcohol are shown in order in parentheses on the right side of the compound.

Next, a 38 μm-thick polyethylene terephthalate film that has been subjected to silicon release treatment is prepared, and the plaster layer solution is applied to the silicon release treatment surface of the polyethylene terephthalate film and dried at 60 ° C. for 30 minutes. As a result, a laminate was produced in which the plaster layer having the thickness shown in Tables 3 to 5 was formed on the silicon release treatment surface of the polyethylene terephthalate film.

And the support body formed by laminating and integrating a polyethylene terephthalate film having a thickness of 12 μm and a polyester nonwoven fabric having a basis weight of 40 g / m ² , a polyethylene terephthalate film surface of the support body, and a paste layer of the laminate body, Were laminated so as to face each other, and the plaster layer of the laminate was laminated and integrated with the support to produce a patch.

Next, the patches obtained as described above were evaluated as follows. Specifically, the uniformity of the plaster layer during production was evaluated as appearance. As a stability test, the middolin residual rate and yellowing were evaluated. In order to evaluate drug absorbability to the skin, a rat patch test was performed. In order to evaluate the sticking property, peeling and adhesive residue were evaluated. The evaluation results are shown in Tables 3-5. In Tables 3 to 5, “-” was written in the column of the patch not evaluated, or the evaluation column itself was not provided.

(Midolin residual rate)
Two pieces of 3 cm ² test pieces were cut out from the obtained patch, and 5 ml of an ethyl acetate / ethanol mixed solvent (volume ratio of ethyl acetate and ethanol 80:20) was added to one of the test pieces. The components were extracted, and the obtained ethyl acetate / ethanol extract was subjected to HPLC measurement to quantify the middolin content W ₉ (μg) in the test piece.

Next, the other test piece was sealed in a polyester / aluminum foil laminate packaging material and stored at 60 ° C. for 20 days. Note that, depending on the patch, the plaster layer tends to protrude, and thus it was sandwiched between 38 μm-thick polyethylene terephthalate films subjected to silicon release treatment and sealed in a packaging material.

Subsequently, 5 ml of an ethyl acetate / ethanol mixed solvent (volume ratio of ethyl acetate and ethanol 80:20) was added to the test piece after storage at 60 ° C. for 20 days, and the test piece in the test piece after storage for 20 days was added. The components were extracted, and the obtained ethyl acetate / ethanol extract was subjected to HPLC measurement to quantify the middolin content W ₁₀ (μg) in the test piece after storage for 20 days.

Then, the midodrine content W ₉ (μg) in the test piece before storage for 20 days and the middolin content W ₁₀ (μg) in the test piece after storage for 20 days are substituted into the following formula (5). As a result, the residual ratio (% by weight) of midodrine in the test piece after storage for 20 days was calculated.
Middolin residual ratio (% by weight) = (W ₁₀ / W ₉ ) × 100 (5)

(Yellowing)
^Two test pieces having an area of 3 cm ² were cut out from the obtained patch. One specimen was stored at 60 ° C. for 20 days and then placed on white paper. The other test piece was stored at 4 ° C. for 20 days, and then the test piece was placed on white paper. Two test pieces were arranged and visually observed. The case where no difference was observed between both samples was “excellent”, and the sample stored at 60 ° C. was slightly yellowed, “excellent” was stored at 60 ° C. When the test piece clearly showed yellowing, it was determined as “bad”.
(Appearance)
When manufacturing the patch, visually observe the paste layer of the laminate before being superimposed on the support, and the crystals form a substantially uniform paste layer regardless of whether it is in a dissolved state or a precipitated state. `` Excellent '' when recognized, surface condition of the plaster layer is slightly non-uniform, but `` good '' when maintaining smoothness, surface condition of the plaster layer is non-uniform In addition, when it was not smooth, it was judged as “not bad”, and when the plaster layer was extremely uneven and did not form a preparation, it was judged as “bad”.

(Rat sticking test)
A test piece having an area of 3 cm ² was cut out from the obtained patch, and this test piece was applied to the back skin of a rat (wistar male, 7 weeks old) from which the hair on the back had been removed in advance, and 24 hours later. It was made to peel. Then, a mixed solvent of ethyl acetate / ethanol was added to the test piece after the pasting to extract the components of the paste layer, and the residual amount of midodrine in the ethyl acetate / ethanol extract W ₁₁ (μg) was determined by HPLC measurement. It was quantified to calculate the percutaneous absorption (μg / cm ² / 24h) using the following equation (6).
Transdermal absorption (μg / cm ² / 24h) = (W ₉ −W ₁₁ ) / 3 Formula (6)

(Skin irritation)
In the rat sticking test, immediately after the test piece was peeled from the back of the rat, the skin on the back of the rat was visually observed, and skin irritation was evaluated according to the following criteria.
Excellent: No erythema occurred on the skin.
Good: Slight erythema was observed on the skin.
Not bad: Clear erythema was observed on the skin, but recovery was observed after 1 day.
Bad: Significant erythema was observed on the skin, and no apparent recovery was observed after 1 day.

(Peeling)
In the above rat sticking test, the state of sticking before the test piece was peeled off from the back of the rat was observed. If the test piece was not peeled off, it was “excellent”, and the peeled area was 5% or less of the sticking area. If it is recognized as “good”, and if peeling is more than 5% and less than 20% of the applied area, it is “not bad” and exceeds 20% of the applied area. When peeling was recognized, it was evaluated as “bad”.

(Adhesive residue)
Furthermore, in the above rat sticking test, the skin on the back of the rat after the test piece was peeled off from the back of the rat was directly touched with a finger, and when the skin was not sticky, it was `` excellent ''. When the stickiness was recognized only on the outer peripheral edge, “good” was found, and stickiness was found on the entire application site. Stickiness was recognized on the entire surface, and when it was in an unacceptable range for practical use, it was evaluated as “bad”.

The patch of the present invention contains a sufficient amount of midodrines in a stable state in the plaster layer, and is excellent in transdermal absorbability and pasting properties of midodrines. Therefore, the patch is suitably used for therapeutic agents such as essential hypotension, orthostatic hypotension, and stress urinary incontinence.

Claims

A support, laminated and integrated on one surface of the support, and midodrine or a pharmacologically acceptable salt thereof, an alkyl group having 30 to 99% by weight of an alkyl ester having 4 to 22 carbon atoms and an alkyl group 40 to 98% by weight of an acrylic adhesive obtained by copolymerizing a monomer containing 1 to 70% by weight of an acrylic acid alkyl ester having 2 to 20 carbon atoms, and an alkyl group having 10 to 30 carbon atoms. A certain saturated aliphatic monohydric alcohol (A) or a saturated fatty acid having an alkyl group having 10 to 20 carbon atoms and a saturated aliphatic monohydric alcohol (B) having an alkyl group having 2 to 20 carbon atoms is subjected to dehydration condensation. And a paste layer containing 1 to 40% by weight of one or both of the fatty acid esters as a total amount.
The patch according to claim 1, wherein the content of midodrine or a pharmacologically acceptable salt thereof in the plaster layer is 1 to 30% by weight.
A single amount of the acrylic pressure-sensitive adhesive containing 50 to 99% by weight of alkyl methacrylate having 4 to 22 carbon atoms and 1 to 50% by weight of alkyl alkyl having 2 to 20 carbon atoms. The patch according to claim 1, wherein the body is copolymerized.
2. The acrylic pressure-sensitive adhesive is a copolymer obtained by copolymerizing a monomer containing 70 to 95% by weight of 2-ethylhexyl methacrylate and 1 to 30% by weight of 2-ethylhexyl acrylate. The patch described in 1.
The acrylic pressure-sensitive adhesive is a copolymer obtained by copolymerizing a monomer containing 70 to 95% by weight of 2-ethylhexyl methacrylate, 1 to 20% by weight of 2-ethylhexyl acrylate and 4 to 29% by weight of dodecyl methacrylate. The patch according to claim 1, wherein
The patch according to claim 1, wherein the alkyl group of the saturated aliphatic monohydric alcohol (A) has 12 to 22 carbon atoms.
The patch according to claim 1, wherein the saturated aliphatic monohydric alcohol (A) is at least one monohydric alcohol selected from the group consisting of octyldodecanol, hexyldecanol, myristyl alcohol and isostearyl alcohol. Agent.
The patch according to claim 1, wherein the saturated fatty acid has 12 to 18 alkyl group carbon atoms and the saturated aliphatic monohydric alcohol (B) has 2 to 6 carbon atoms.
The patch according to claim 1, wherein the fatty acid ester is at least one fatty acid ester selected from the group consisting of isopropyl myristate and isopropyl palmitate.