JPS59164715A - Manufacture of member for external use - Google Patents

Abstract

PURPOSE:To obtain a member for external use having improved uniformity and releasability of a chemical without depositing a water-soluble chemical, by coating the surface of a support material with a mixture containing an aqueous or alcoholic solution of the water-soluble chemical dissolved in a solution of a specific adhesive high polymer. CONSTITUTION:An aqueous and/or alcoholic solution of a water-soluble chemical, e.g. ''Clonidine hydrochloride'' or quinidine hydrochloride, is incorporated with and dissolved uniformly in a solution of an adhesive high polymer consisting essentially of an alkyl acrylate or methacrylate, preferably having <=10wt/ wt%/24hr water absorption at 25 deg.C, and the resultant mixture is then applied onto the surface of a support material, e.g. a plastic film, nonwoven fabric or cloth. 0.5-20wt%, expressed in terms of solid, chemical is suitably added to the high polymer solution. A functional monomer, e.g. acrylic or methacylic acid, is copolymerized with the above-mentioned adhesive high polymer to impart more cohesiveness, and a hydrophilic alkoxyalkyl acrylate is copolymerized therewith to improve the compatibility with the chemical.

Description

DETAILED DESCRIPTION OF THE INVENTION O is manufactured by adding a drug into a polymeric material layer or applying a drug solution dissolved in an appropriate solvent to the surface of a preformed polymeric material layer. When manufacturing external medical parts by adding drugs directly into polymeric materials, most of the water-soluble drugs exist in an undissolved state in the polymeric material layer, resulting in lack of uniformity in content and release properties. It is something. In addition, when adopting the method of dissolving a drug in an appropriate solvent and applying it to the surface of a polymeric substance, it is important that the solvent has a suitable affinity (compatibility) with the polymeric substance. Although this is necessary to prevent the drug solution from being deposited on the surface of the polymeric material layer, it has the disadvantage that when a water-soluble drug solution is applied to the surface of the polymeric material that is used as a part, it will not be adsorbed and will be deposited on the surface.

As a result of extensive research from this point of view, the present inventors have found that after dissolving hydrochloride salts such as clonidine hydrochloride, sulfates such as atrobin sulfate, and other water-soluble drugs below their saturation solubility in water, By adding and mixing into a solution of a polymeric substance that is sticky at room temperature and dissolving it uniformly, forming a layer of the polymeric substance on a carrier, the non-uniformity of the content can be eliminated, and it can also be used for external use. It has been found that a member for external use with excellent release properties can be obtained without precipitation of water-soluble drugs in the member.

That is, the present invention provides an external member prepared by coating the surface of a carrier with a mixture obtained by dissolving a water-soluble drug and/or an alcohol solution in a solution of an adhesive polymer substance containing an alkyl (meth)acrylic acid ester as a main component. The manufacturing method is provided.

According to the manufacturing method of the present invention, an opening member in which a water-soluble drug is uniformly present in an adhesive polymeric material layer can be obtained through a simple process,
Moreover, an external member having uniform release properties can be obtained.

As the carrier used in the present invention, various plastic films, non-woven fabrics, woven fabrics, navy blue, metal foils, NN films of these and plastic films, etc. are used.

Adhesive polymers/substances used in the present invention include (
It is a polymer mainly composed of meth)acrylic acid alkyl ester, and more specifically includes (meth)acrylic acid ethyl ester, (meth)acrylic acid butyl ester, (meth)acrylic acid propyl ester, and (meth)acrylic acid pentyl ester. , (meth)acrylic acid hexyl ester, (
meth)acrylic acid octyl ester, (meth)acrylic acid 2-ethylhexyl ester, (meth)acrylic acid nonyl ester, (meth)acrylic acid decyl ester, (
It is formed by polymerizing one or two or more alkyl (meth)acrylate monomers such as dodecyl meth)acrylate and stemaryl (meth)acrylate ester.

In addition, in order to add more cohesiveness to the polymer substance,
(meth)acrylic acid, itaconic acid, maleic acid, 4nF
Hydromaleic acid, acrylic acid hydroxyethyl ester,
Functional monomers such as hydroxyl esters of acrylic acid, (meth)acrylamide, dimethyl acrylamide, vinyl esters such as acrylonitrile, vinyl acetate, vinyl propionate, etc. In addition, for the purpose of improving the solubility of drugs, parent monomers such as acrylic acid methoxyethyl ester, acrylic acid ethoxyethyl ester, acrylic acid butoxyethyl ester, and aqueous alkoxyalkyl acrylate monomers can be copolymerized with ester monomers. It is also possible to use polymers as copolymerization components.

Polymer substances that are homopolymerized or copolymerized with the above monomers and have tackiness at room temperature, or mixtures of two or more polymers that have tackiness at room temperature include skin adhesion, cohesion, In order to maintain a balance in terms of properties, etc., it is desirable to use a material with a water absorption rate of 10vy&%/24h or less at 25°C.

The water absorption rate here means 5crnX5 at a water temperature of 25℃.
A polymer material test piece cut to a size of - is immersed in water, and it is defined as the ratio of the weight increase after 24 hours to the weight before immersion.

The drug used in the present invention is a water-soluble drug, and is added and mixed into the above-mentioned polymeric substance solution in the form of a bath solution containing water and/or alcohol as a solvent. The term "water-soluble" used here for water-soluble drugs refers to "extremely soluble,""easilysoluble," and "slightly soluble-I property," which is defined as a term indicating solubility V in the Japanese Pharmacopoeia's general rules. Specifically, the powdered drug is placed in water and heated to 20±5°C.
When the drug is shaken vigorously for 30 seconds every 5 minutes, 12 or 1 me drug will dissolve in water less than 30 me within 30 minutes.

Specific water-soluble drugs include hydrochloride salts such as ephedrine hydrochloride, chlorpromazine hydrochloride, clonidine hydrochloride, diphenhydramine hydrochloride, dibucaine hydrochloride, pleomycin hydrochloride, and atropine sulfate.

Sulfates such as quinidine sulfate, fradiomycin sulfate, scopolamine hydrobromide, butyl scopolamine bromide, distigmine bromide, and provantyline bromide.

Bromides such as phenoparbital sodium.

Diclofenac - alkali metal salts such as sodium,
Other examples include chlorpheniramine maleate, codine phosphate, dihydrocodine phosphate, and thiotepa.
Particularly good results are obtained when clonidine hydrochloride is used.

The external member obtained by the manufacturing method of the present invention is formed on a carrier by adding and mixing a water-soluble drug solution with a solid content of 0.5 to 20% by weight to a solution of a polymeric substance that is sticky at room temperature. Specifically, the water-soluble drug is dissolved in a solvent below its saturation solubility, and then added and mixed into a solution of a polymeric substance that is sticky at room temperature to be uniformly dissolved, and then formed on a carrier. It is something that

The solvent for water-soluble drugs is preferably water and/or alcohol, and in the case of a mixed solution, the more alcohol there is, the better the dissolution and solubility of the water-soluble drug will be, in terms of compatibility with polymeric substances.
The content of pharmacological substance in the drug-containing polymeric material layer can be increased.

The solvent for the polymeric substance solution may be replaced with or added to other solvents from the viewpoint of dissolution for preparing (polymerizing) the polymeric substance and compatibility when blending with a water-soluble drug solution. , preferably ethyl acetate, toluene, acetone, alcohols, and chain ethers.

One or two or more of the cyclic ethers can be used in combination.

According to the manufacturing method of the present invention, the drug-containing polymer material layer prepared as described above is manufactured by making the drug into a solution state in a good solvent and blending it into the polymer material solution. The drug can be contained in a state exceeding the solubility in the drug, that is, in a supersaturated state, and an external medical member containing a high concentration of the drug can be obtained.

Therefore, it is possible to eliminate the inconvenience of not being able to raise the blood concentration necessary for the treatment of disease due to drug KK, and to provide a blood concentration sufficient for the treatment of the disease.

Since the drug in the polymer substance N is uniformly dissolved in a solvent-retaining state, it is prevented from undissolving and crystallizing, and the content is uniformly -f'
A medical external member with good release properties of l and drug can be obtained.

In order to release a large amount of drug from the external use member obtained by the production method of the present invention, alcohols such as propylene glycol, diethylene glycol, and ethanol, salicylic acid, urea, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, diethyl sebacate, and surfactants are used. It is possible to add one or more auxiliary agents such as additives, but when considering skin adhesion and 80% properties, these additives have a concentration of 0.5 to 20% by weight based on the polymeric material. It is desirable to add within this range.

After being applied to the applied skin surface, the externally used member obtained by the manufacturing method of the present invention effectively releases the water-soluble drug contained therein, exhibits sufficient pharmacological effects, and has good drug stability and solubility. It is something. Furthermore, when the measuring member is removed from the skin surface to which it is applied, the polymeric substance remains on the skin surface to which it is applied, and the properties such as skin adhesion may be poor.

The present invention will be explained in more detail below with reference to Examples.
The present invention is not limited to the specific embodiments, and can be applied to other ways without departing from the technical scope of the present invention.

Example 1 For a single moth M base consisting of 90 parts by weight of 2-ethylhexyl acrylate and 10 parts by weight of acrylic acid, ATBN (azohisisobutyronitrile) was added as a polymerization initiator.
Using 0.2 parts by weight, polymerize in ethyl acetate at a temperature of 60°C, react for 8 hours, further raise the temperature to 75-80°C, and age for 2 hours to obtain a polymer that is sticky at room temperature. A solution of the substance in ethyl acetate was obtained.

The water absorption rate was 1.4% by weight/24h.

Next, an aqueous clonidine hydrochloride solution prepared to have a saturation solubility or less was added to the polymer substance solution obtained in this way (the saturated dissolution amount of clonidine hydrochloride in the substance is about 2 volume %), and the polyester film was The mixture was coated on the surface of the product to a dry thickness of 40 ttm and dried to obtain a water-soluble drug-containing member for external use. The addition tank for clonidine hydrochloride used in this example was set to 120 μud (clonidine hydrochloride content type 3 ant%).

The solubility of clonidine hydrochloride in the obtained external use member was good, and no undissolved matter or crystal precipitation was observed or observed, and the stability of clonidine hydrochloride during oral administration was extremely good. Furthermore, the release of clonidine hydrochloride when adhesively applied was also good, and an effective concentration in the jlJ surface sufficient for treatment was obtained. In addition, after removing the peel, there may be no adhesive residue or rashes on the normal skin.

Example 2 55 parts by weight of acrylic acid nonyl ester, 25 parts by weight of vinyl acetate
parts by weight, and 20 parts by weight of acrylic acid 2-methoxyethyl ester, B as a polymerization initiator.
Using 0.3 parts by weight of PO (benzoyl peroxide), polymerize in toluene at 65°C for 2+ irl, react for 8 hours, further raise the temperature to 75-80°C, age for 2 hours, and leave at room temperature. A toluene solution of a sticky polymer substance was obtained. The water absorption rate was 89 parts%/24h.

Next, a solution of atrobin sulfate in water/methanol (50150 1%) solution was added and mixed, and the thickness after drying was 50% on the surface of the polyethylene film.
The mixture was coated and dried to obtain a water-soluble drug-containing member. The amount of atropine sulfate used in this example was set to 200 μ9/ca (atropine sulfate content: approximately 5% by weight).

The solubility of atropine sulfate in the obtained external use material was good, and no undissolved matter or precipitation of crystals was observed or observed, and the stability of atropine sulfate during oral administration was good. Furthermore, the release of atrobin sulfate when applied as a patch was also good, and an effective plasma concentration value sufficient for treatment was obtained. In addition, there was no adhesive residue after peeling and no rash on the applied skin surface.

Example 3, 50 parts by weight of hexyl acrylate, 40 parts by weight of dodecyl methacrylate, 2-hydroxyethyl acrylate to parts by weight! AI B N O, 5xi as a polymerization initiator for the compound
(11 parts), ethyl acetate/ethanol (69/31
Polymerization was carried out at the boiling point (71.8°C) in
The reaction was carried out for 10 hours to obtain an ethyl acetate/ethanol solution of a polymeric substance that was sticky at room temperature.

The water absorption rate was 3.7%/24h.

Next, the polymer substance solution obtained in this way (reading material y (
The saturated solubility of diclofenac sodium in water is approximately 4.6% by weight), an ethanol solution of diclofenac-sodium prepared below the saturated solubility and 10 parts of dimethyl sulfoxide are added and mixed, and the surface of the nonwoven fabric has a thickness after drying. It was coated to a thickness of 30 μm and dried to obtain a water-soluble drug-containing member for external use. Addition of diclofenac-sodium used in this example: 1 tfl', 1:4
00μy/, i (diclofenac-sodium content: about 13% by weight).

The solubility of diclofenac-sodium in the obtained external use member was good, no undissolved substances or precipitation of crystals were observed, and the stability of diclofenac-sodium over time was very good. The release of diclofenac sodium was also good when it was applied as a patch, and an effective plasma concentration level sufficient for treatment could be maintained.

Further, there was no adhesive residue after peeling and removal, and there was no rash on the legitimate skin.

Comparative Examples 1 to 3 The water-soluble leafy plants added in each example were added and mixed in a solution other than water and/or alcohol, or directly in the form of a powder to obtain a water-soluble drug-containing external member.

In this case, although the stability is good, the solubility of the drug is extremely low, and crystals may precipitate or remain undissolved in the polymeric substance.
1) Due to the presence of 'l' compound, the release property was poor and a therapeutically effective plasma concentration could not be obtained. Furthermore, when applying the adhesive, the skin 1
81 Adhesion was poor, and the terminals peeled off and fell off after application.

patent applicant [1Ken Electric Industry Co., Ltd. Representative: 3rd division

Claims (1)

[Scope of Claims] 1) Applying a mixture obtained by dissolving water-soluble mulberry water and/or alcohol solution in a solution of an adhesive polymer substance containing (meth)acrylic acid alkyl ester as a main component on the surface of the old support. A method for manufacturing external parts, characterized by: 2) Water absorption rate of adhesive polymer material is 10w/w% at 25℃
24h or less, the method for producing an external member according to claim 1.