JPH01297068A - Tacky adhesive agent for treatment and tacky tacky adhesive agent formulation for treatment - Google Patents

Abstract

PURPOSE:To adequately obtain the balance between lipophilicity and hydrophilicity and to obtain the tacky adhesive agent for treatment having excellent skin affinity and skin adhesive strength by polymerizing an unsatd. monomer having a residual phenoxypolyalkylene glycol group or residual alkylphenoxypolyalkylene glycol group in the side chain as a polymer component at a specific ratio. CONSTITUTION:The unsatd. monomer to be used as the polymer component is expressed by the general formula. In the X-Y-Z formula, X is a residual group having unsatd. double bonds such as vinyl group or (meth)acryloyl group and is more preferably a (meth)acryloyl group. Y is a residual polyalkylene glycol group and is a residual group which imparts the adequate hydrophilicity to the resulted polymer. Z denotes a phenyl group or alkyl phenyl group and is the residual group which imparts the lipophilicity to the resulted polymer. This unsatd. monomer is incorporated into the resulted polymer in an at least 10wt.%, more preferably 15-50wt.% range; in addition, a drug is incorporated as the tacky adhesive formulation for treatment therein.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a medical adhesive and a therapeutic adhesive preparation comprising a drug contained in the adhesive.

<Conventional technology> Medical adhesives have traditionally been used in a variety of tapes and sheets, including adhesive tapes for protecting wound surfaces, adhesive tapes for fixing instruments such as injection needles, emergency bandages, and adhesive tapes for transdermal administration of drugs. has been done.

Such medical adhesives must not only have appropriate cohesive strength and skin adhesion, but also be resistant to oil present on the skin surface and moisture from sweat, etc., so that their adhesive properties are not impaired. It is necessary to have a good balance of lipophilicity and hydrophilicity.

A medical adhesive that satisfies these required properties is one that adheres to the skin surface for a long time without slipping or peeling, even if it is provided on a support and applied in the form of a tape to the skin surface.
In addition to the above characteristics, it does not cause rash on the skin surface, does not damage the skin surface and does not cause pain when peeled off, does not leave any adhesive on the skin surface after peeling off, and is used for transdermal administration of drugs. For this purpose, it is necessary to satisfy various conditions such as having poor reactivity with drugs and not decomposing the contained drugs, and effectively releasing the contained drugs to the skin surface.

Drug-containing adhesives that satisfy these characteristics to some extent are disclosed in JP-A-57-85318 and JP-A-61-85318.
It is disclosed in Japanese Patent No. 33114.

The former uses a monomer having an ether group in its molecule as a copolymerization component, and copolymerizes it with a (meth)acrylic acid ester and a polar monomer. Since this copolymer is endowed with appropriate hydrophilicity, it has good drug solubility and release properties, and also exhibits the effect that adhesion is not inhibited even during sweating.

On the other hand, the latter uses a monomer in which at least one of the hydroxyl groups of polyoxyalkylene glycol is esterified with (meth)acrylic acid as a copolymerization component, and a methacrylic acid alkyl ester monomer and an acrylic acid alkyl ester monomer are used. It is made by copolymerizing with. Since this copolymer also has appropriate hydrophilicity, it exhibits the same effects as the former.

<Problem to be solved by the invention> However, as mentioned above, medical adhesives to be applied to the skin have to have sufficient skin adhesion to not damage the skin surface when peeled off, and to prevent slipping or peeling during use. It is required to have a skin adhesion strength that does not cause skin adhesion.

Moreover, since the skin surface has both lipophilic and hydrophilic properties, medical adhesives themselves need to have both lipophilic and hydrophilic properties in order to achieve skin adhesion. There is a desire to develop and diversify adhesives that satisfy the following requirements.

Means for Solving the Problems〉 The present inventors have conducted intensive studies to develop a medical adhesive that satisfies the above properties, and have found that an unsaturated adhesive containing a specific high molecular weight residue in the side chain The adhesive, which is made of a polymer containing a monomer as a polymerization component, has excellent skin adhesion and does not slip or peel during application, and has an appropriate skin adhesion that does not damage the skin surface when peeled off. The present inventors have now completed the present invention by discovering that when the above-mentioned adhesive is incorporated with a drug to form an adhesive preparation for transdermal administration, the drug does not decompose and an effective amount of the drug is released.

That is, the first aspect of the present invention consists of a polymer obtained by polymerizing at least 10% by weight of an unsaturated monomer having a phenoxypolyalkylene glycol residue or an alkylphenoxypolyalkylene/glycol residue side chain as a polymerization component. A second object is to provide a medical adhesive, and a second object is to provide a therapeutic adhesive preparation comprising the above-mentioned medical adhesive containing a drug.

The unsaturated monomer used as a polymerization component in the present invention is
This is shown by the following formula.

-Y-Z Is X in the above general formula a vinyl group? It is a residue having an unsaturated double bond such as a (meth)acryloyl group, and preferably a (meth)acryloyl group.

Y is a polyalkylene glycol residue, which imparts appropriate hydrophilicity to the resulting polymer.

Therefore, in order to impart appropriate hydrophilicity, the number of repeating alkylene glycol units is preferably 4 or more, and from the viewpoint of polymerization reactivity as a monomer, it is preferably in the range of 4 to 9.

Further, 2 in the above general formula represents a phenyl group or an alkylphenyl group, and is a residue that imparts lipophilicity to the resulting polymer. The number of carbon atoms in the alkyl group in the alkylphenyl group is preferably 12 or less from the viewpoint of polymerization reactivity as a monomer, and if it exceeds 12, the bulk as a side chain portion becomes large and causes steric hindrance, resulting in polymerization. Reactivity decreases.

The monomers preferably used as the monomers represented by the above general formula are as follows: [However, R is a hydrogen atom or a methyl group, m is 2 or 3
, n is 4 to 9, R' is a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, and the CmHzm portion includes a straight chain or a branched state. ], specifically (meth)acrylic acid phenoxytetraethylene glycol ester, (meth)acrylic acid phenoxypolyethylene glycol ester, (meth)acrylic acid phenoxypolypropylene glycol, (
Examples include meth)acrylic acid nonylphenoxy diethylene glycol ester, (meth)acrylic acid nonylphenoxy polyethylene glycol ester, and (meth)acrylic acid nonylphenoxy polypropylene glycol ester.

The above-mentioned unsaturated monomer is present in at least 10
If the content is less than 10% by weight, the medical adhesive of the present invention will not have a suitable balance between skin adhesion and IP lipophilicity/hydrophilicity. When applied to the skin in the form of a tape, the adhesion may be insufficient or the skin may be damaged when peeled off.

In addition, when a drug is contained in a therapeutic adhesive preparation, the -Y-Z group in the molecule of the unsaturated monomer exhibits the same effect as a type of nonionic surfactant, and the drug contained therein is efficiently absorbed. It shows the effect of diffusing and transferring to the skin surface and releasing it. In order to exhibit such surfactant ability more markedly, it is preferable to design the weight average molecular weight of the unsaturated monomer to be 300 or more, preferably in the range of 300 to 1000.

The polymer used in the medical adhesive of the present invention is obtained by polymerizing the above-mentioned unsaturated monomers, but in order to exhibit good adhesion to the skin surface, the number of carbon atoms in the alkyl group must be adjusted. It is preferable to polymerize 4 to 12 (meth)acrylic acid alkyl esters as copolymerization components. Note that the alkyl group may be linear or branched.

It is preferable to copolymerize at least 50% by weight of such (meth)acrylic acid alkyl ester, and the shear retention strength of the resulting polymer at 40°C is 90 minutes or less, preferably in the range of 1 to 70 minutes. It is preferable to adjust to If the shear retention force is 90 minutes or more, the adhesion of the adhesive to the skin surface will be insufficient, making it impossible to ensure good skin adhesion, and therefore, it will be able to sufficiently follow the movements of the skin surface that occur during use when applied to the skin surface. This makes peeling and falling off more likely. The shear holding force was measured by the method described in Examples below.

In addition, in order to impart appropriate cohesive force to the obtained polymer and adjust it to exhibit appropriate skin adhesion, copolymerizable monomers other than those mentioned above are copolymerized in an amount of 40% by weight or less. You can also do that.

Examples of such monomers include (meth)acrylic acid methyl ester, (meth)acrylic acid lower alkyl ester such as (meth)acrylic acid ethyl ester, (meth)acrylic acid hydroxyethyl ester, (meth)acrylic acid ethyl ester, and (meth)acrylic acid hydroxyethyl ester. Containing hydroxyl groups such as hydroxyglobil ester (
(meth)acrylic acid lower alkyl esters, (meth)acrylamide, dimethyl (meth)acrylamide, etc.
Vinyl monomers such as meth)acrylamides, acrylonitrile, vinyl acetate, vinyl globionate, vinylpyrrolidone, vinyl caprolactam, polyfunctionals such as di(meth)acrylic acid diethylene glycol ester, di(meth)acrylic acid tetraethylene glycol ester Polymer monomers can be used. In addition, in order to improve the solubility of the drug contained in a therapeutic adhesive preparation, (meth)acrylic acid methoxyethyl ester, (meth)acrylic acid ethoxyethyl ester should be added in the same amount as the above copolymerizable monomer. , (meth)acrylic acid alkoxy lower alkyl ester such as (meth)acrylic acid ethoxyethyl ester is preferably copolymerized.

The medical adhesive of the present invention is composed of a polymer obtained by copolymerizing each of the above monomers alone or by copolymerizing the above monomers, and may optionally contain various fillers, plasticizers, liquid substances such as silicone oil, and polyethylene glycol. Components and various crosslinking agents may be blended.

From the viewpoint of ease of handling, the medical adhesive of the present invention includes polyethylene, polyester, poly(ethylene/vinyl acetate),
Generally, 10 to 10% of the support material is coated on one side of a support material containing appropriate flexibility such as various plastic films such as polyurethane, non-woven fabrics, woven fabrics, paper, metal foils, or laminated films thereof.
It is applied and laminated to a thickness of 1000 μm, preferably 20 to 500 μm, and used in the form of a tape or sheet.

Although the medical adhesive of the present invention has the above-described structure, a therapeutic adhesive preparation can be obtained by incorporating a drug into the adhesive. By containing a drug, the drug can be easily administered into the body through the skin, that is, transdermally, and the preparation can exert a sustained pharmacological effect over a long period of time.

Examples of such drugs include the following: (a) Corticosteroids: For example, hydrocortiscin, glednisolone, beclomethasone globionate, flumethacin, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide,
Fluocinolone acetonide acetate, clopetazole propionate, etc. r+) Anti-inflammatory analgesics: e.g. acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyphengetacin, phenylbutacin, ibuprofen , flurbiprofen, ketoprofen, salicylic acid, methyl salicylate, l-menthol, camphor, sulindac, tolmetin sodium, nagloxen, fuenbufuen, etc. c) Hypnosedatives: for example, phenoparbital, amobarbital, cyfrobarbital, lorazepam, Haloperidol, etc. 2) Tranquilizers: e.g. fluphenazine, thioridazine, diazepam, flunitrazepam, chlorpromazine, etc. e) Antihypertensive agents: e.g. clonidine, clonidine hydrochloride, etc.
Bintrol, propranolol, propranolol hydrochloride, gufranolol, indenolol, bucumolol,
nifedipine, diltiazem hydrochloride, etc. f) Antihypertensive diuretics: e.g. hydrothiazide, bendroflumethiazide, cyclobenthiazide, g) Antibiotics: e.g. penicillin, tetracycline,
Oxytetracycline, fradiomycin, fludiomycin sulfate, erythromycin, chloramphenicol natate, 1) Anesthetic agents such as docaine, benzicaine, ethyl aminobenzoate, etc. 4) Antibacterial substances: such as benzalkonium chloride, nitrofurazone, Nicecutin, acetosulfamine, clotrimazole, etc. Antifungal substances: e.g. pentamycin, amphotericin B1 virolnitrone, clotrimazole, etc. l) Vitamin preparations: e.g. vitamin A1 ergocalciferol, cholecasyphenol, octothiazine, riboflavin, etc. Acid esters, etc., 2) Antiepileptic agents, such as nitrazebam, meprobamate, clonazebam, etc.; 4) Circulatory vasodilators, such as nitroglycerin, nitroglycenol, insorbidoniitrate, erythritol tetranitrate, pentaerythritol tetranitrate, Antihistamines: e.g. diphenhydramine hydrochloride,
chlorpheniramine, diphenylimidazole, etc. ii) Antitussives: e.g. dextromethorphan, tilgetalin, ephedrine, ephedrine hydrochloride, etc. li) Sex hormones: e.g. progesterone, estradiol, etc. c) Antidepressants: e.g. doxepin hydrochloride, etc. Others: For example, isoproterenol hydrochloride, 5-fluorouracil, dihydroergotamine, phenicol, desmobrecin, digoxin, metoclopramide, donbelide/,
Scopolamine, scopolamine hydrobromide, etc.

Two or more of the above drugs can be used in combination if necessary, and are contained in the above medical adhesive in an amount of 0.1 to 50% by weight, preferably 1 to 40% by weight.

If the content is too low, a sufficient pharmacological effect will not be expressed, and if the content is too high, skin adhesion will be affected and the amount-increasing effect will not be exhibited, which is undesirable.

<Effects of the Invention> As described above, the medical adhesive of the present invention is a polymer obtained by polymerizing a specific amount of unsaturated monomers in the side chains of phenoxypolyalkylene glycol residues or alkylphenoxypolyalkylene glycol residues. is used, so when it is laminated on a carrier and applied to the skin in the form of a tape or sheet, the polyalkylene glycol fi group of the side chain of the unsaturated monomer, ! : Phenylmata has an appropriate balance between lipophilicity and hydrophilicity due to the alkylphenyl group, and has excellent skin affinity and skin adhesion. Also,
Since it has appropriate hydrophilicity, it does not cause pain when peeled from the skin surface, and is useful for protecting wound surfaces and fixing instruments such as injection needles.

Furthermore, when the above-mentioned medical adhesive contains a drug to form a therapeutic adhesive preparation for transdermal drug administration, the side chain of the unsaturated monomer exhibits a type of nonionic surfactant action. , which improves the release properties of the contained drugs and exhibits excellent effects in disease treatment.

<Example> Examples of the present invention will be shown below and specifically explained. Note that the following parts mean parts by weight.

Example 1 60 parts of acrylic acid 2-ethylhexyl ester, 10 parts of methacrylic acid methyl ester, acrylic acid phenoxypolyethylene glycol ester (weight average molecular weight 770
) was thoroughly purged with nitrogen while stirring in a reaction vessel, and 0.2 part of azobisin butyronitrile was added to carry out a polymerization reaction. During the reaction, the reaction temperature was controlled in the temperature range of about 60 to 65 °C by adjusting the stirring speed, external temperature cooling, and dropping ethyl acetate as a diluting solvent, and the polymerization reaction was carried out for 8 hours. The temperature was raised to C and aged for 10 hours to obtain a medical adhesive solution. The shear retention strength of this adhesive was 12.5 minutes.

Example 2 Ketoprofen (50% by weight methanol solution) was added to the medical adhesive solution obtained in Example 1 so that the content was 15% by weight in terms of solid content, to obtain a therapeutic adhesive solution.

Example 3 70 parts of isononyl acrylate and 0.2 part of diethylene glycol diacrylate were added to Example 1.
In the same polymerization reaction as above, 30 parts of acrylic acid nonylphenoxy polyethylene glycol ester (weight average molecular weight 950) was added dropwise over 5 hours to react,
After reacting for 8 hours, the temperature was raised to about 75-80°C and aged for 10 hours to obtain a medical adhesive solution. The shear retention force of this adhesive was 1.2 minutes.

Example 4 Ingroterenolol hydrochloride (40% by weight methanol solution) was added to the medical adhesive solution obtained in Example 3 so that it contained 20% by weight in terms of solid content, and the resulting mixture was combined with the therapeutic adhesive solution. Ta.

Example 5 65 parts of acrylic acid n-glyster, 15 parts of acrylic acid
and 20 parts of methacrylic acid phenoxypolyethylene glycol ester (weight average molecular weight [1050)] were polymerized in the same manner as in Example 1 to obtain a medical adhesive solution. The shear retention force of this adhesive was 20.2 minutes.

Example 6 85 parts of acrylic acid n-glutyl ester and 15 parts of acrylic acid were subjected to a polymerization reaction in the same manner as in Example 1 to obtain an adhesive solution.

The obtained adhesive solution and the medical adhesive solution obtained in Example 1 were mixed in a solid content ratio of 40/60 to obtain a medical adhesive solution. The shear retention force of this adhesive was 20.1 minutes.

Comparative Example 1 An adhesive solution having a shear retention strength of 15.5 minutes was obtained in the same manner as in Example 1 except that the phenoxypolyethylene glycol acrylate was omitted.

Comparative Example 2 A therapeutic adhesive solution was obtained in the same manner as in Example 2, except that the adhesive solution obtained in Comparative Example 1 was used.

Comparative Example 3 50 parts of acrylic acid methoxyethyl ester, 25 parts of acrylic acid inoctyl ester, and 25 parts of vinyl acetate were added to about 7 parts.
A polymerization reaction was carried out in the same manner as in Example 1, except that the aging at 5 to 80°C was carried out for 2 hours, to obtain an adhesive solution having a shear retention strength of 50.2 minutes.

Comparative Example 4 A therapeutic adhesive solution was prepared in the same manner as in Example 4, except that the adhesive solution obtained in Comparative Example 3 was used. Obtained.

Comparative Example 5 65 parts of acrylic acid n-butyl ester, 15 parts of acrylic acid
20 parts of polyethylene glycol methacrylate (weight average molecular weight: 780) were subjected to a polymerization reaction in the same manner as in Example 1 to obtain a medical adhesive solution having a shear retention strength of 10.3 minutes.

The shear holding strength in each of the above Examples and Comparative Examples was measured by the following method.

Shear retention force> Tape pieces made from each adhesive solution on a Bakelite plate polished with No. 280 water-resistant abrasive paper (supporting body: 25 μm thick polyester, adhesive layer thickness: 40 μWI, size:
10111@X 20xx length) and 40°C
A load of 30 of was suspended under constant temperature, and the time until natural fall due to cohesive failure was measured.

The adhesive solution obtained in each example and comparative example was
A medical adhesive tape or therapeutic adhesive tape having an adhesive layer having a thickness of 40 μm after drying was prepared by casting on a thick polyester film and drying, and the following tests were conducted. The test results are shown in Table 1.

Adhesive Feeling Tape pieces cut into 51 square pieces were applied to the backs of six healthy volunteers for 24 hours, and the following evaluations were made.

◎~ There is no sense of discomfort when using Kinutsuke.

○~ There is a slight discomfort when pasting.

Δ〜〃〃〃It feels very strange.

×～I I feel extremely strange.

Adhesion Rate> The adhesion state after the 24-hour application was measured with respect to the area immediately after application, and judged as follows.

Adhesion rate 90% or more after 0 to 24 hours.

○〜　　　　　　　　　　 //fJQ% or more and less than 9ochi.

Δ~ 6o% or more and less than 8ochi.

X ~ Less than 60 articles.

Pain when peeling off> After applying the patch for 24 hours, the pain when peeling off was judged as follows: 〇◎~ means almost no pain.

○～Slight pain.

Δ~ It hurts.

X~Extremely painful.

Skin irritation> The condition of the skin surface after the above peeling was observed and judged as follows.

◎～No irritation.

O ~ Slight erythema.

Δ ~ Obviously erythema.

X ~ Erythema and edema present.

Skin adhesion> 1.2C11 width x 7. A piece of tape cut to a length of 0 cm was pasted on the inside of the forearm of 6 healthy volunteers, and 2
The skin adhesion strength was measured after 4 hours.

The measurement was carried out using a Tensilon measuring machine and by 90 degree beer peeling.

Drug transfer rate> Tape pieces cut into 3 asφ pieces were applied to the inner side of the upper arms of six healthy volunteers for 24 hours, and the skin transfer rate of the drug contained in the adhesive layer was measured. Quantification of the drug was performed by methanol extraction and high performance liquid chromatography.

Stability over time> A tape piece cut into 51 square pieces was stored under a 40'CX75mm R0 degree for 6 months, and the residual rate of the drug contained therein was measured.

The drug was quantified in the same manner as above.

Claims (3)

[Claims] (1) At least one unsaturated monomer having a phenoxypolyalkylene glycol residue or an alkylphenoxypolyalkylene glycol residue in its side chain as a polymerization component
A medical adhesive consisting of a polymer obtained by polymerizing 0% by weight. (2) The polymer has an alkyl group having 4 to 12 carbon atoms (
The medical adhesive according to claim 1, which is obtained by copolymerizing at least 50% by weight of an alkyl meth)acrylate. (3) A therapeutic adhesive preparation comprising the medical adhesive according to claim (1) or (2) containing a drug.