JPH11349477A - Percutaneous absorptive patch - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a percutaneous absorptive patch which is excellent in the sustainability of therapeutic activity, gives no itch during pasting and is useful in the treatment for stenocardia or the like by including a vasodilator and a substance having antipruritic effect in specific proportions in a base. SOLUTION: This percutaneous absorptive patch is obtained by including (B) a vasodilator, e.g. isosorbide nitrate or the like, in a proportion of 0.1-30 wt.% and (C) a substance having antipruritic effect, e.g. crotamiton or the like, in a proportion of 0.1-15 wt.%, preferably 3-12 wt.% in (A) a base. As the component A, an acrylic polymer or the like obtained by, for example, copolymerizing 2-ethylhexyl acrylate, vinyl pyrrolidone and hexamethylene glycol methacrylate is used. This preparation is obtained by, for example, adding the components B and C and a solvent, e.g. ethyl acetate or the like, to the component A followed by mixing under stirring, applying the resultant solution to a mold release-treated polyester film or the like and laminating a supporter, e.g. a polyethylene terephthalate or the like, after evaporating the solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a transdermal patch containing a vasodilator.

[0002]

2. Description of the Related Art Vasodilator drugs are effective drugs for angina pectoris, and isosorbide dinitrate, nitroglycerin and the like are known. When administered by intravenous injection, these drugs temporarily and rapidly increase blood levels, but their effects last only for a very short time and cause side effects such as headache, dizziness and orthostatic hypotension . Therefore, a transdermal patch that maintains the blood concentration at a predetermined value for a relatively long time has been desired. As such a transdermal patch, a patch of isosorbide dinitrate (Japanese Patent Publication No. 1-3737)
5), nitroglycerin patch (Japanese Patent Publication No. 7-11603)
2) and the like, these patches are excellent for continuous administration of the drug, but the peripheral blood vessels at the patch site are dilated, so that extravasation of the itch-inducing substance occurs,
There was a problem that itching occurred.

[0003]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the above problems, and an object of the present invention is to provide a transdermal drug containing a vasodilator drug which is excellent in persistence of drug efficacy and does not cause itching during application. It is to provide an absorption patch.

[0004]

The transdermal patch according to claim 1 is characterized in that a vasodilator drug is contained in an amount of 0.1 to 30% by weight in a base.
And a transdermal patch comprising 0.1 to 15% by weight of a substance having an antipruritic effect.

[0005] In the transdermal patch according to claim 2, the base is at least one selected from the group consisting of acrylic polymers, rubber polymers, silicone polymers, urethane polymers and hydrophilic polymers. The transdermal patch according to claim 2, wherein the patch comprises:

[0006] The vasodilator used in the present invention includes, for example, isosorbide dinitrate, nitroglycerin, diltiazem, verapamil, pentaeristol tetranitrate, dipyridamole, nifedipine and the like.

[0007] If the amount of the vasodilator compound is too small, sufficient medicinal effects cannot be obtained, and if it is too large, the amount of the vasodilator drug is excessive with respect to the amount absorbed into the body, and not only is the drug wasted,
Since it may adversely affect the physical properties of the drug, it is usually preferably in the range of 0.1 to 30% by weight, though it depends on the base component. The drug may be dissolved in the base or may be incorporated in a partially dispersed state.

The substance having an antipruritic effect used in the present invention includes, for example, crotamiton, ethyl aminobenzoate and the like. Crotamiton, which has been used as an additive, is preferred.

If the amount of the substance having an antipruritic effect is too small, a sufficient itch suppressing effect cannot be obtained, and if it is too large, the physical properties of the base are adversely affected. The range is preferably 1 to 15% by weight, more preferably 3 to 12% by weight.

The base used in the present invention is one which can stably hold the vasodilator and absorb the vasodilator into the body when administered to the skin. There is no particular limitation. For example, those conventionally used as a base such as non-hydrous or hydrous plasters, tapes, patches, cataplasms and the like can be used. Specific examples include acrylic polymers, rubber polymers,
Examples thereof include those in which a crosslinking agent, a plasticizer, a stabilizer, water, a pH adjuster, a filler, and the like are added to a main component selected from a silicon-based polymer, a urethane-based polymer, and a hydrophilic polymer as needed.

The acrylic polymer is preferably a pressure-sensitive adhesive mainly composed of (meth) acrylic ester, and is a copolymer of a functional monomer and / or a polyfunctional monomer copolymerizable with (meth) acrylic ester. It may be united.

Examples of the above (meth) acrylate include methyl (meth) acrylate, ethyl (meth) acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate,
Heptyl (meth) acrylate, 2- (meth) acrylate
Ethylhexyl, n-octyl (meth) acrylate,
Dodecyl (meth) acrylate, stearyl (meth) acrylate, trimethylhexyl (meth) acrylate, isodecyl (meth) acrylate, and the like.

Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, a monomer having an amino group, and a monomer having a nitrogen-containing heterocyclic ring. Specifically, 2-hydroxyethyl (meth) acrylate, hydroxypropyl (meth) acrylate, (meth) acrylic acid, maleic acid, acrylamide, ethoxymethylacrylamide diacetone acrylamide, dimethylaminoethyl acrylate, vinylpyrrolidone, And vinylimidazole.

Examples of the polyfunctional monomer include, for example,
Di (meth) acrylate, tri (meth) acrylate, tetra (meth) acrylate obtained by reacting (meth) acrylic acid with polymethylene glycols such as hexamethylene glycol, polyalkylene glycols such as polyethylene glycol, glycerin, pentaerythritol, etc. (Meth) acrylate and the like.

Examples of the rubber-based polymer include natural rubber, styrene-butadiene rubber, polyisobutylene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, and styrene-olefin-styrene block copolymer. Polymers. Generally, tackifier resins such as rosin, hydrogenated rosin, rosin ester, terpene resin, terpene phenol resin, petroleum resin, cumarone resin, and cumarone-indene resin are added to these.

Examples of the silicon-based polymer include polydimethylsiloxane and polydiethylsiloxane.

As the urethane-based polymer, any urethane-based pressure-sensitive adhesive conventionally used for a pressure-sensitive adhesive for transdermal patches can be used, and is not particularly limited.

Examples of the hydrophilic polymer include polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyacrylic acid, polymethacrylic acid, sodium polyacrylate, gelatin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and carboxymethylcellulose. Examples include sodium, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl ether, starch, polyethylene glycol, polypropylene glycol, polyoxyethylene polyoxypropylene glycol, dextran and the like.

Examples of the crosslinking agent include aluminum hydroxide, calcium hydroxide, magnesium stearate, isocyanates, epoxy resins, melamine resins,
Examples include urea resins and ammoniums.

Examples of the plasticizer include hydrocarbons such as liquid paraffin, fatty acid esters such as isopropyl myristate, glyceryl monolaurate and diethyl sebacate, esters of monohydric or polyhydric alcohols, oleic acid, and the like.
Examples include higher fatty acids such as lauric acid, higher alcohols such as octyldodecanol and myristyl alcohol, and oils and fats derived from natural products such as lanolin, olive oil, and coconut oil. When the content of the plasticizer is too small, the medicinal effect does not appear, and when the content is too large, the sticking property may be deteriorated. Therefore, the content of the plasticizer differs depending on the combination with the base or drug.
A range of 0% by weight is preferred.

The above-mentioned stabilizer is used to oxidize drugs and other components.
It is used to suppress decomposition and prevent the patch from changing over time, and examples thereof include antioxidants such as butylhydroxytoluene and sorbic acid, as well as cyclodextrin and ethylenediaminetetraacetic acid.

The above-mentioned filler is used for controlling the sticking property of the base and for uniformly dispersing and holding the drug in the base. Examples of the filler include calcium carbonate, titanium oxide, lactose, crystalline cellulose, and silicic anhydride. Is mentioned.

As the transdermal patch of the present invention, for example, a drug-containing adhesive base layer comprising a base, a vasodilator drug and a substance having an antipruritic effect is provided on one side of a support, and a release paper is provided thereon. And the like protected by the above method. Further, instead of the drug-containing pressure-sensitive adhesive base layer, a drug-containing reservoir layer may be used, and a pressure-sensitive adhesive layer may be provided on the surface of the reservoir layer opposite to the support. Examples of the pressure-sensitive adhesive layer include those made of the acrylic polymer, rubber-based polymer, silicon-based polymer, urethane-based polymer, and the like.

The above-mentioned reservoir layer does not need to be sticky to the skin, and may be any as long as it can hold the vasodilator drug stably and release the vasodilator drug at a required rate.

For the above-mentioned reservoir layer, polymers such as (meth) acrylic acid, (meth) acrylic acid ester, polyvinyl alcohol and polyvinylpyrrolidone, lactose, celluloses, fats and oils, alcohols and the like are appropriately used. Emulsifiers, solubilizers, plasticizers, stabilizers, water, pH adjusters, fillers and the like are added. Further, there may be a release controlling film between the reservoir layer and the pressure-sensitive adhesive layer, through which the drug can pass.

The support of the present invention protects the opposite side of the surface to be stuck, and is not particularly limited. Usually, a single layer or a laminate of a film, a nonwoven fabric, a woven fabric, a foam, an aluminum foil or the like is used. Can be

Examples of the film include polyethylene terephthalate, polyethylene, polypropylene,
Ethylene-vinyl acetate copolymer, ethylene-methyl acrylate copolymer, polyurethane, nylon, styrene
And an isoprene-styrene copolymer.

Examples of the nonwoven fabric and woven fabric include those formed using fibers made of polyester, polyolefin, rayon, cotton, acryl, nylon, and the like.

Examples of the foam include polyethylene, ethylene-vinyl acetate copolymer, polypropylene,
Examples include polyolefins such as polyethylene oxide and rubbers such as styrene-butadiene copolymer.

If the thickness of the support alone or the laminate is too thin, the strength of the patch is insufficient and the patch becomes difficult to stick and wrinkles are easily formed. Usually, the thickness is preferably in the range of 20 to 3000 μm, since the film is easily peeled off by being caught on the surface.

The support may be partially or wholly processed as necessary, such as by making holes or providing irregularities such as embossing and point seals. by this,
The effect of increasing the air permeability, improving the ability to follow the skin, and increasing the strength is obtained.

The release paper of the present invention is not particularly limited as long as it protects the drug-containing pressure-sensitive adhesive base layer or the pressure-sensitive adhesive layer. Usually, the surface of a single layer or a laminate such as a film or paper is subjected to a release treatment. Is used. Examples of the film include polyethylene terephthalate, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene chloride, and the like. As the paper, those impregnated with a resin such as poval can also be used.

The preparation method of the patch of the present invention varies depending on the base and the constitution. For example, a drug-containing adhesive base layer, a support,
In the case of a configuration made of release paper, a conventional method such as a hot melt method or a solution method can be used. For example, a drug and necessary additives and an appropriate solvent such as ethyl acetate and ethanol are added to the acrylic polymer, and the mixture is stirred and mixed until uniform. This solution is applied to a release-treated polyethylene terephthalate film or the like so as to have a uniform thickness, and after drying the solvent, a support is laminated. This sheet
It can be cut to the required size to make a patch.

[0034]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 (Preparation of acrylic pressure-sensitive adhesive) 65 mol% (302.0 g) of 2-ethylhexyl acrylate, 35 mol% (98.0 g) of vinylpyrrolidone, 0.02 wt% of hexamethylene glycol methacrylate (40.0 mg) was placed in a separable flask, and 70.6 g of ethyl acetate was added to bring the initial monomer concentration to 85% by weight. The solution was heated to 65 ° C. under a nitrogen atmosphere, and a solution of lauroyl peroxide, a polymerization initiator, in cyclohexane / ethyl acetate was sequentially added in portions, and polymerization was carried out for 32 hours. After completion of the polymerization, ethyl acetate was further added and mixed uniformly, and then taken out to obtain an ethyl acetate solution of acrylic adhesive (nonvolatile content: 35.76%).

(Preparation of Dosing Sample) A coating liquid was prepared by adding 15 g of isosorbide dinitrate and 10 g of crotamiton to 209.7 g of an ethyl acetate solution of an acrylic pressure-sensitive adhesive and mixing until uniform. This coating liquid is uniformly coated on a polyester film that has been subjected to a release treatment so that the isosorbide dinitrate content becomes 1.5 mg / cm ² per unit area,
Dry at 60 ° C. for 30 minutes. As a support, a laminated film of polyethylene terephthalate and an ethylene-vinyl acetate copolymer was adhered to obtain a tape.

Comparative Example 1 15 g of isosorbide dinitrate was added to 237.7 g of an ethyl acetate solution of the acrylic pressure-sensitive adhesive of Example 1, and mixed until uniform to prepare a coating solution. This coating liquid was uniformly applied onto a polyester film which had been subjected to a release treatment so that the content of isosorbide dinitrate became 1.5 mg / cm ² per unit area, and dried at 60 ° C. for 30 minutes. As a support, a laminated film of polyethylene terephthalate and an ethylene-vinyl acetate copolymer was adhered to obtain a tape.

Evaluation of Performance (Evaluation of Itching) The patch of Example 1 or Comparative Example 1 was applied to the arm of a healthy person, and itching was evaluated 30 minutes later. The results are shown in Table 1.

[0039]

[Table 1]

[0040]

As described in detail above, the transdermal patch of the present invention is a transdermal patch containing a vasodilator and a substance having an antipruritic effect in the base. It is excellent in persistence and does not cause itching during application.

Claims (2)

[Claims] 1. A transdermal patch containing 0.1 to 30% by weight of a vasodilator and 0.1 to 15% by weight of a substance having an antipruritic effect in a base. 2. The method according to claim 1, wherein the base is at least one selected from the group consisting of acrylic polymers, rubber polymers, silicone polymers, urethane polymers and hydrophilic polymers. The transdermal patch according to the above.