JPS61151122A - Plaster for external use - Google Patents

Abstract

PURPOSE:To provide a plaster for external use, containing especially an anti- inflammatory corticosteroid as a drug component, having excellent transcutaneous absorbability and high bioavailability, and free from skin stimulation. CONSTITUTION:A drug-containing pressure-sensitive adhesive layer is applied to one surface of a substrate. The adhesive is a copolymer containing 25-85mol% alkyl acrylate having 4-12C alkyl group (e.g. butyl acrylate), 15-75mol% vinyl acetate, and 1X10<-3>-1mol% (based on the above monomers) monomer having >=2 polymerizable unsaturated groups [e.g. ethylene glycol di(meth)acrylate]. An anti-inflammatory corticosteroid (e.g. prednisolone) is added as a drug component to the adhesive composition in an amount of 0.04-2wt%. The plaster for external use has excellent internal cohesivity and can be applied without leaving the adhesive on the skin or causing the treading phenomenon.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a topical patch, particularly a topical patch containing an anti-inflammatory corticosteroid as a drug.

(Prior art) A large number of patches with an adhesive layer containing corticosteroids as anti-inflammatory agents have already been produced for the purpose of obtaining local or systemic effects through transdermal absorption of corticosteroids. has been done.

Acrylic adhesives are usually used as adhesives for such patches. For example, JP-A-52-18813, JP-A-56-20514, JP-A-58-83.
No. 961 and Japanese Patent Application Laid-Open No. 126809/1987 disclose adhesive patches containing a corticosteroid and a copolymer containing an acrylic acid alkyl ester and a monomer having a polar group as copolymer components. Agents are disclosed. A monomer having a polar group.

For example, monomers with carboxyl groups such as (meth)acrylic acid and itaconic acid; 2-hydroxyethyl (meth)acrylate, 2-hydroxypropyl (meth)
Monomers having a hydroxyl group such as acrylate; monomers having an ether group such as methoxyethyl acrylate and butoxyethyl acrylate; and monomers having an amide group such as niacrylamide. This is because polar groups derived from such monomers are introduced into the above copolymer.

Shows good compatibility with the drug corticosteroid,
The drug has excellent release properties, and the drug does not precipitate from the adhesive layer during storage of the patch. However, if these patches are stored for a long time.

The corticosteroid contained in the copolymer may undergo modification due to the influence of the polar group contained in the copolymer. For example, it undergoes chemical changes depending on the active hydrogen contained in the polar group and the degree of acid/base. Furthermore, if a monomer having a polar group remains unreacted in the copolymer, even a small amount may cause skin irritation. This effect is particularly large when the monomer has a carboxyl group, such as (meth)acrylic acid.

Incidentally, it is generally desirable that a patch has appropriate adhesiveness when applied to the skin, and that so-called adhesive residue or stringy phenomena do not occur. Therefore, methods include adding monomers containing epoxy groups, isocyanate groups, etc. to acrylic polymers; methods of radically crosslinking peroxides to acrylic polymers; methods of ionic crosslinking by causing metal ions to act on acrylic polymers The cohesive force of the adhesive is increased by forming a crosslinked structure using methods such as; All of these are called post-crosslinking. However, in these methods, if even a small amount of the post-crosslinking agent, such as peroxide, remains unreacted, it will cause a chemical reaction with the drug contained.
Medicinal efficacy may be reduced. There is also a risk of skin irritation due to unreacted post-crosslinking agent.

(Problems to be Solved by the Invention) The present invention solves the above-mentioned conventional drawbacks.

Its purpose is to contain anti-inflammatory corticosteroids as drugs in the adhesive layer, and to have excellent transdermal absorption, in other words, high bioavailability.

Another object of the present invention is to provide an external patch that does not cause skin irritation. Another object of the present invention is to provide an acrylic adhesive layer that does not contain polar groups that may cause skin irritation or alter the quality of the drug, and that has appropriate compatibility with corticosteroids. An object of the present invention is to provide a corticosteroid-containing topical patch. Still another object of the present invention is to provide a corticosteroid-containing patch with an adhesive layer that has appropriate adhesive strength and internal cohesive force and that does not cause adhesive residue or stringiness when the patch is peeled off. The purpose of the present invention is to provide a patch for external use.

(Means for Solving the Problems) The external patch of the present invention is provided with a drug-containing adhesive layer on one side of a support, and the adhesive has 4 to 4 carbon atoms as a copolymer component.
Acrylic acid alkyl ester having 12 alkyl groups in a proportion of 25 to 85 mol%, vinyl acetate in a proportion of 15 to 75 mol%, and a monomer having two or more polymerizable unsaturated groups to all the above monomers. The drug is an anti-inflammatory corticosteroid.

This achieves the above objective.

The alkyl group of the acrylic acid alkyl ester, which is a copolymerization component of the copolymer used in the adhesive of the external patch of the present invention, has 4 to 12 carbon atoms. Even if the number of carbon atoms in the alkyl group is too small or too large.

Both have the disadvantage that it is difficult to have adhesive properties. Examples of the acrylic acid alkyl esters used in the present invention include butyl acrylate, isoamyl acrylate, 2-ethylhexyl acrylate, octyl acrylate, decyl acrylate, and dodecyl acrylate. Acrylic acid alkyl ester is 2 in the copolymer.
Vinyl acetate, another copolymerization component, is contained in the copolymer in a proportion of 5 to 85 mol%, and in a proportion of 15 to 75 mol%. If the acrylic acid alkyl ester is too small and the vinyl acetate is too large, the copolymer will have insufficient tackiness. Conversely, if the acrylic acid alkyl ester is too much and the vinyl acetate is too little, the solubility of the corticosteroid in the resulting copolymer will be insufficient. The copolymerization components of the copolymer constituting the adhesive layer of the present invention include only the above-mentioned acrylic acid alkyl ester and vinyl acetate, excluding the monomer having two or more polymerizable unsaturated groups described below. is used. The monomer having two or more polymerizable unsaturated groups is a monomer having two or more polymerizable unsaturated groups such as a (meth)acryloyl group, a vinyl group, an allyl group, or a (meth)acrylamide group.

For example, ethylene glycol di(meth)acrylate, polyethylene glycol di(meth)acrylate, propylene glycol di(meth)acrylate, polypropylene glycol di(meth)acrylate, 1.
4-Ptylene gelicol di(meth)acrylate 1.
6-Hexane gelicol di(meth)acrylate, neopentyl glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate Tetramethylolmethanetetra(meth)acrylate Divinylbenzene, divinyltoluene, diallyl phthalate, diallyl maleate Diallyl adipate , triallyl isocyanurate, diethylene glycol bisallyl carbonate, and methylene bisacrylamide. One or more of these monomers are added during the preparation of the copolymer.

Copolymerized with acrylic acid alkyl esters and vinyl acetate. By copolymerizing monomers having two or more polymerizable unsaturated groups, slight crosslinking occurs between one polymer,
This increases the internal cohesive force of the adhesive. Therefore,
When a patch applied to the skin is removed, the adhesive does not remain on the skin, and the so-called stringing phenomenon of the adhesive does not occur. Moreover, it has no effect on the solubility or percutaneous absorption of corticosteroids. The monomer having two or more polymerizable unsaturated groups is added at a ratio of 3 to 1 mol% of the total monomer components used in the polymerization of the adhesive. - If it is less than 1 mol%, the effect of improving internal cohesive force due to crosslinking will be small, and if it is in excess, gelation will occur during the polymerization reaction, making it difficult to produce a copolymer (adhesive).

It becomes difficult.

To prepare the adhesive, the above-mentioned acrylic acid alkyl ester, vinyl acetate, and a monomer having two or more polymerizable unsaturated groups are subjected to a polymerization reaction by a conventional method. The form of polymerization reaction is solution polymerization.

Examples include bulk polymerization, emulsion polymerization, and suspension polymerization. As a catalyst used in the polymerization reaction, a radical reaction initiator such as an azobis compound or a peroxide compound is used.

An anti-inflammatory corticosteroid is added as a drug to the adhesive thus obtained. Anti-inflammatory corticosteroids include corticosteroids used externally. For example, prednisolone, prednisolone acetate, methylprednisolone, methylprednisolone acetate.

Hydrocortisone acetate, hydrocortisone butyrate.

Hydrocortisone, dexamethacin, dexamethacin acetate, dexamethacin sodium phosphate, doriamcinolone acetonide, betamethasone, betamethasone valerate, betamethasone dipropionate.

Fluocinolone acetonide, fluocinonide, fluoromesolone, fludroxycortide, beclomethasone propionate, flumethacin pivalate.

There is clobetasol propionate. The amount of corticosteroid to be added to the adhesive is determined depending on the desired drug content, and is not particularly limited.

It usually accounts for 0.04 to 2% by weight of the adhesive. The amount to be added varies depending on the thickness of the patch, but is usually 1.

It contains 2 μs/aj to 100 μg/aJ of drug.

For the support that supports the adhesive layer, materials commonly used as supports for adhesive patches may be used. When a flexible support is used, it causes less skin irritation when applied to the body (and exhibits good adhesion.9 Examples of these materials include polyolefin, ethylene-vinyl acetate copolymer, polyurethane, polyester, nylon, There are rayon, acrylic, cellulose, etc.These are processed and used as films, ￥a cloth, non-woven fabrics, etc.If the support has low rigidity and tends to stretch, use an adhesive with low adhesive strength. Then, a patch having appropriate adhesive strength and removability is prepared.The desired adhesive strength can be obtained depending on the composition of the adhesive.

The above-mentioned adhesive and drug are mixed and finished into an adhesive layer by a method such as coating on a support.

To mix these adhesive layer components 9 For example, add a drug to an organic solvent solution of the adhesive and mix; add the drug to the adhesive and heat it to melt the adhesive and mix. method (hot melt method) is used. To form the adhesive layer, the above mixture is applied directly onto the support; after the mixture is applied onto a release paper such as silicone,
A method of transferring the image onto a support is used. The thickness of the adhesive layer formed is not particularly limited, but is usually 30 to 3
00 μm. Since the thinner the adhesive layer is, the higher the rate of drug transfer to the skin, the thickness is preferably 30 to 100 μm.

(Function) The polar groups contained in the adhesive of the patch thus obtained are only ester groups derived from acrylic acid alkyl esters, and are carboxyl groups.

It does not contain polar groups such as hydroxyl groups, ether groups, or amino groups. Therefore, there is almost no skin irritation caused by polar groups, especially carboxyl groups (and there is no denaturation of drugs. Such adhesives have moderate compatibility with corticosteroid drugs, so they can be absorbed through the skin. The adhesive has excellent adhesive properties and does not precipitate during storage. Because it is a combination.

Excellent internal cohesion. Therefore, no adhesive residue or stringy phenomenon occurs. Since post-crosslinking is not used, there is no change in the drug over time or skin irritation caused by residual post-crosslinking agents.

(Example) The invention will be explained below with reference to examples.

Example 1 (A) Preparation of patch: 52 mol of 2-ethylhexyl acrylate, 48 mol of vinyl acetate and 0.007 mol of 1,6-hexanethiol dimethacrylate were added to ethyl acetate, and lauric peroxide was used as a catalyst. The copolymer was polymerized to obtain a copolymer having a weight average molecular weight of 620,000. This copolymer 10
0 parts by weight and 0.6 hydrocortisone acetate as drug
A patch was obtained by applying an ethyl acetate solution containing 50% of ethyl acetate onto a polyethylene film so that the thickness after drying was 50 μm.

(B) Performance evaluation of patch: The patch obtained in section (A) was subjected to a water elution test, and the results are shown in the table below. Also,
When the patch obtained in section (A) was applied to the inner side of the upper arm of a healthy person and a pallor test was conducted, pallor due to clear vasoconstriction was observed, indicating that the patch has an effective medicinal effect. . No adhesive residue remains when the patch is removed from the skin.

It is clear that it has adequate adhesion. moreover,
A stability test was conducted on the patch obtained in Section (A) after it had been stored for 3 months, but no drug precipitation was observed. When the drug content was measured after the patch was stored at 40° C. for 3 months, it was confirmed that 98% or more of the drug was retained compared to the initial value.

(1) Water elution test, (2) Palarity test, (2) Stability test, and (2) Content test were conducted by the following methods.

■ Water elution test: 20cni of the patch was fixed on a Teflon disk and soaked in 200mj+ deionized water at 20'C for 2 hours.
After immersion for 4 hours, the amount of drug eluted in water was determined. Quantification was performed using high performance liquid chromatography. The dissolution rate was expressed as the percentage of the amount of drug eluted relative to the amount of drug initially contained in the adhesive of the patch.

■ Pallor test: A patch of approximately 4 cnf was applied to the inner side of the upper arm of a healthy person for 6 hours and then removed, and the level of pallor immediately after was observed to judge the medicinal efficacy of the patch.

■ Stability test: After storing the patch at room temperature and 40℃,
The adhesive layer surface of each patch was observed visually and using an optical microscope.

■ Content test: 20ca of patch (30ml of methanol)
The drug in the adhesive was extracted by immersing it in water at room temperature, and the amount of drug in the extract was quantified. Quantification was performed using high performance liquid chromatography.

Taishi Go I (A) Preparation of patch = 40 mol of 2-ethylhexyl acrylate, 60 mol of vinyl acetate, and 0.007 mol of propylene glycol dimethacrylate were added to ethyl acetate, and polymerized using lauric acid peroxide as a catalyst. A copolymer having a weight average molecular weight of t550,000 was obtained.

A methanol solution of 0.6 parts by weight of prednisolone was added to a solution of 100 parts by weight of this copolymer in ethyl acetate.

A solution with a solids content of 20% was obtained. This was coated on a polyethylene film and dried to form a drug-containing adhesive layer with a thickness of 50 μm.

I understand that it is necessary to From Comparative Example 2, it is clear that when a polar group such as a carboxyl group is contained in the adhesive, the stability of the drug is impaired.

Preparation of a low MA1 (A) patch: Same as Example 1 except that 1,6-hexanethiol dimethacrylate was not used.

(B) Performance Evaluation of Patch: Two Comparative Examples When the patch obtained in section (A) was applied to human skin for 24 hours and then peeled off, adhesive residue remained on the entire surface of the patch.

(Effects of the Invention) According to the present invention, as described above, an external patch can be obtained which is provided with a corticosteroid-containing adhesive layer that has excellent transdermal absorbability and is hardly irritating to the skin. Since the corticosteroids contained in the product do not precipitate during storage or undergo changes over time, it can be stored for a long period of time. The adhesive used has excellent adhesive strength and internal cohesiveness, so it does not cause adhesive residue or stringiness.

Claims (1)

[Scope of Claims] 1. A drug-containing adhesive layer is provided on one side of the support, and the adhesive contains 25 to 85 acrylic acid alkyl esters having an alkyl group having 4 to 12 carbon atoms as a copolymer component.
mol%, vinyl acetate in a proportion of 15 to 75 mol%, and a monomer having two or more polymerizable unsaturated groups in a proportion of 1 x 10^-^3 to 1 mol% of the above total monomer amount. A patch for external use, which is a copolymer containing a certain proportion of the drug, and the drug is an anti-inflammatory corticosteroid.