JPS5846959A - Production of adhesive drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a patch that is directly attached to the body for the purpose of treating diseased areas or administering drug components to the circulatory system.

Hitherto, various types of patches have been known that have an adhesive plaster layer or a water-containing plaster layer in which a drug is dissolved on a support such as a synthetic resin film. In some cases, the medicinal effect may be insufficient because the hydrated plaster layer generally has no adhesive strength, and the medicinal components may decompose or change during storage, resulting in adhesive extrusion or adhesive residue during use. There are problems with adhesive strength, medicinal efficacy, preservability,
There were few products that exhibited comprehensively balanced performance in various properties such as shape retention.

As a result of extensive research in order to solve the above-mentioned conventional problems and obtain a patch with overall excellent performance, the inventors discovered that a cross-linked anhydrous water-soluble polymer was coated on a substrate using a specific method. By forming a single layer and absorbing drug ingredients to form a plaster layer, it was discovered that very good results could be obtained for the above purpose, which led to the completion of this invention. be.

In other words, the present invention uses a water-soluble polymer having a functional group reactive with incyanate groups and a water-soluble liquid substance to produce a patch comprising a drug-containing plaster layer provided on a support. An aqueous solution containing an adhesive component mainly consisting of an adhesive component and a crosslinking agent component consisting of a blocked isocyanate compound whose regeneration temperature of incyanate groups is 100°C or higher is applied onto the substrate, and dried by heating at 100°C or higher. This invention relates to a method for producing a patch, which is characterized in that a crosslinking reaction is carried out at the same time, and after the reaction is completed, a non-aqueous solution of a drug is absorbed into the obtained anhydrous water-soluble polymer layer to form a plaster layer.

The patch obtained by this method has adhesive strength that allows it to be directly attached to the body surface, and since the plaster layer is made of a water-soluble polymer, the drug component has excellent diffusibility and solubility. It has a good distribution rate and excellent medicinal efficacy, and since it is anhydrous, it prevents the drug components from decomposing, oxidizing, rearranging, etc. under water-containing conditions and has excellent storage stability.Furthermore, because it is a crosslinked type, it can be used as a plaster. It has various advantages such as excellent cohesive strength of the layer, good shape retention, and preservation prevention.

The components and materials used to produce the patch according to the method of this invention will be described below.

The water-soluble polymer constituting the adhesive (including pressure-sensitive adhesive) component is one in which a functional group that reacts with an isocyanate group, such as a carboxyl group or a hydroxyl group, is introduced into the polymer by means such as modification, copolymerization, or graft polymerization. Examples include polymers or copolymers, and two or more types may be used in combination.

Specific examples of the water-soluble polymer include carboxylated polyvinyl alcohol and poly(meth)acrylamide. Specific examples of water-soluble copolymers include methyl vinyl ether-maleic anhydride copolymer and its derivatives, (meth)acrylamide-(meth)acrylic acid copolymer and its derivatives, and polyisobutyne-maleic anhydride copolymer and its derivatives. copolymers and their derivatives, (meth)acrylic acid-(meth)acrylic acid ester copolymers and their derivatives, styrene-maleic acid copolymers and their derivatives, (meth)acrylamide-acrylonitrile-(
(meth)acrylic acid copolymer and its derivatives, (meth)
Examples include water-soluble compounds selected from the group of acrylamide-acrylonitrile-(meth)acrylic acid ester copolymers and derivatives thereof.

The water-soluble liquid substances that make up the adhesive component together with the water-soluble polymer include water-soluble plasticizers that have good compatibility with the water-soluble polymer and have low volatility, such as polyether polyols or polyhydric alcohols. water-soluble ethylenically unsaturated monomers such as (meth)acrylic acid in the presence of polyether polyols or polyhydric alcohols,
Graft polymers obtained by polymerizing crotonic acid, maleic acid, etc. can also be used, and two or more of these may be used in combination. The amount of such water-soluble liquid substance blended is preferably in the range of 50 to 500 parts by weight based on 100 parts by weight of the water-soluble polymer.

It is recommended that the adhesive component consisting of the water-soluble polymer and the water-soluble liquid substance be made into an aqueous solution having a concentration of 40 to 50% by weight, with the addition of a drug release auxiliary substance to be described later, if desired.

The blocked incyanate compound, which is a crosslinking agent component, has an isocyanate group regeneration temperature of 100'C or higher, and by using this, it is possible to react in an aqueous solution containing a water-soluble polymer at room temperature before coating on the support. After coating, it is possible to evaporate water by heating and drying at 100° C. or more, preferably 120° C. or more, and simultaneously regenerate the active incyanate groups and carry out the crosslinking reaction. In contrast, ordinary polyisocyanates cannot be used because they react with water.

Specific examples of commercially available products of such blocked incyanate compounds include Millionate MS-59 and Coronate 2501 manufactured by Nippon Polyurethane Industries Co., Ltd. for Ml)I (meta-phenylene diisocyanate) type, and TDI () lylene diisocyanate) type. Coronate APStable M manufactured by Nippon Polyurethane Kogyo Co., Ltd. is available, but it goes without saying that other blocked isocyanate compounds can also be used, and two or more types may be used in combination.

The amount of the blocked isocyanate compound is 0.05 to 5% by weight based on the adhesive component containing the water-soluble polymer.
It is preferably used in the form of a solution in dimethylformamide or the like which is compatible with water.

As the support for the patch, a single material that makes it difficult for the drug to be absorbed into the plaster layer to migrate, or a composite material coated on at least one side with these materials is used.For example, the former is made of cellophane. , acetic acid se/? There are films or foils made of loin, polyester, polypropylene, polyamide, polyvinylidene chloride, polyvinyl alcohol, metal, etc. The latter include films made of polyethylene, polyurethane, polyacrylic, etc., and nonwoven fabrics, woven fabrics made of various plastics, etc. Examples include composite materials in which the non-migration material is laminated on the surface of a sheet-like base material such as a foam.

Drugs that can be used in this invention include corticosteroids, anesthetics, antihistamines, antibacterial substances, antifungals, analgesic and antiinflammatory agents, keratin emollients, vitamins, anticonvulsants, and systemic drugs. These include antihypertensive agents, antibiotics, central nervous system agents, vasodilators, antispasmodics, sedatives, sex hormones, and antidiabetic agents. An appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug.

Specifically, the corticosteroids include prezonisolone acetate, prezonisolone, hydrocortide acetate, hydrocortide, dexamethacin, fluocinolone acetonide, betamethasone, heclomethasone propionate, fludroxycortide, fluocinonide, and the like.

Anesthetics include pensicaine, lidocaine, and ethyl aminobenzoate; antihistamines include diphenhydramine hydrochloride, isocybenzyl hydrochloride, and diphenylimidazole; antibacterial agents include benzalkonium chloride and nitrofurazone; antifungal agents include Examples of analgesic and anti-inflammatory agents include indomethacin, methyl salicylate, glycol salicylate, salicylic acid amide, and sodium salicylate.

Further, salicylic acid, vitamin A, atropine, methscobolamine promide, etc. can be mentioned as keratin softeners, vitamin A, and antispasmodic agents. Furthermore, antihypertensive drugs such as reserpine and clonidine as systemic drugs,
Antibiotics such as erythromycin, chloramphenicol, cephalexin, tetracycline, neomycin sulfate, oxytetracycline, penicillin, central nervous system acting agents such as parvicylate, diazepam, nitrazepam, chlorpromazine, vasodilators such as nitroglycerin, insorbitocinitrate Examples include agents.

In this invention, drug release aids may be used in conjunction with the above-mentioned drugs. This release supporting substance can be simply defined as something that promotes the release of drugs to the body surface, but it also includes substances that have the function of improving the solubility and diffusion of drugs within a thin film, and Products that have functions that improve transdermal absorption, such as the water retention capacity of the stratum corneum, keratin softening properties, stratum corneum permeability (loosening), functions as a penetration aid and name tag pore opening agent, and the function of changing the skin interface condition. , and further includes a wide range of drugs that have both of the above-mentioned functions or, in addition to these functions, also have a drug efficacy promotion function that increases the drug efficacy.

Specific examples of these release aids include glycols (mainly drug-soluble) such as diethylene glycol, propylene glycol, and polyethylene glycol, oils and fats (mainly drug-diffusible) such as olive oil, squalene, and lanolin, urea, and allantoin. Polar solvents such as urea derivatives (mainly for the water retention capacity of stratum corneum), dimethyldecyl phosphooxide, methylocdyl sulfoxide, dimethyl laurylamide, dodecylpyrrolidone, insorbitol, dimethylacetamide, dimethylsulfoxide, and dimethylformamide. (mainly keratin permeability), salicylic acid (mainly keratin softening), amino acids (mainly penetration aid), benzyl nicotinate (mainly pore opening emulsion), sodium lauryl sulfate (mainly functions to change the skin interface condition) ), Salokor (
(combined with drugs that have good transdermal absorption). Other examples include plasticizers such as diisopropyl adipate, phthalate esters, and diethyl sebacate, hydrocarbons such as fluidized rough-in, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of chrycerin, isopropyl myristate, and ethyl laurate. can be used.

The amount of such a drug release aid to be blended is preferably in the range of 50 to 500 parts by weight per 100 parts by weight of the water-soluble polymer, and may be added in advance to the aqueous solution for forming a single layer of the polymer for the mounting body. After forming one layer of polymer for plaster, it may be used together with this drug and absorbed.

In the method of this invention, the substrate used to apply the aqueous solution containing the adhesive component and the crosslinking agent component may be the material itself that will eventually become the support for the patch, or it may be released on one side by silicone treatment or the like. A moldable release paper or the like may also be used. In the latter case, the above-mentioned support may be attached to the adhesive surface of the upper layer, and the drug may be absorbed by peeling off the release paper.

The aqueous solution applied to the substrate is dried by heating at 100″C or higher,
It is preferably carried out at 120 to 140°C. After this drying, knee zinc is preferably performed to complete the crosslinking reaction, and the aging temperature is approximately 20°C to 80°C.
The time is preferably 3 to 72 hours. Furthermore, during aging, both sides of the polymer layer may be covered with a support and a release paper.

The absorption of the drug is carried out by applying a non-aqueous solution such as alcohol to the surface of the polymer layer from which the release paper has been removed, once the cross-linking reaction has been completed and there are no incyanate groups in the cross-linked anhydrous water-soluble polymer solution. , spray, etc. so that it is evenly contained inside. After this absorption,
A release paper is attached without drying, and the final patch is cut to a predetermined size.

In addition, when the above-mentioned drugs are pre-blended in an aqueous solution to form a single layer of a crosslinked anhydrous water-soluble polymer, their medicinal efficacy may be significantly affected, such as decomposition or alteration during the crosslinking reaction by heating, in addition to deterioration in the aqueous solution. This will result in serious damage.

The patch obtained by the above method exhibits comprehensively well-balanced and excellent performance in terms of medicinal efficacy, stability, toxicity, adhesiveness and cohesive force of the plaster, etc.

Examples of this invention will be shown below. All parts in the examples mean parts by weight.

Example 1 100 parts of ethyl acrylate and 30 parts of acrylic acid were polymerized in 195 parts of ethyl alcohol at 60°C in an inert gas atmosphere using 0.3 parts of potassium persulfate as a polymerization catalyst, and the polymerization reaction was completed. Thereafter, the mixture was neutralized with an aqueous sodium hydroxide solution to obtain a water-soluble polymer consisting of a sodium salt of an ethyl acrylate-acrylic acid copolymer. Next, add water to this polymer solution.

was added to form a 30% solution, and 100 parts of polyoxypropylated sorbitol as a water-soluble plasticizer and 4 parts of Coronate 2501 (described above) were blended with 100 parts of this solid content.

This aqueous solution was applied to a 1,0011 m thick rayon nonwoven fabric-P.
It was applied to the surface of the E-laminate product to a dry thickness of 300 μm, dried at 140°C for 5 minutes, then attached with release paper and aged in a heating chamber at 50°C for 2 days to complete the crosslinking reaction. Ta. Next, remove the release paper and apply a 5:1:1 mixture of ethanol, indomethacin, and propylene glycol to the adhesive surface with an indomethacin content of 20%.
0119/ctj, and after absorbing it uniformly into one layer of polymer, a release paper was pasted to form a 10 x 10
It was cut into am pieces and used as a patch.

Example 2 Maleic anhydride-PO1J isobutylene copolymer (maleic anhydride content 50% by weight, molecular weight 190,000 to 200,000) 15
Thoroughly mix 11 parts of chrycerin and 50 parts of water, and add a dimethylformamide solution of Coronate AP 5table M (mentioned above) to the mixture so that the amount of crosslinking agent is 0.3 weight based on the solid content of the above mixture. %.

Apply this aqueous solution to the silicone-treated surface of release paper until the dry thickness is 50 mm.
After coating to a thickness of .mu.m and drying at 130.degree. C. for 5 minutes, it was laminated onto a 50 .mu.m thick polyvinyl alcohol film and aged in a drying room at 70.degree. C. for 1 day to complete the crosslinking reaction.

Next, peel off the release paper and apply a 10:1 mixture of ethanol and prezonisolone to the adhesive surface with a prezonisolone content of 3.
After coating with a spray to give a concentration of 0 μy/arl and allowing it to be absorbed uniformly into the polymer layer, a release paper was attached and 101
It was cut into 0x10 pieces to make a patch.

Example 3 90 parts of acrylic acid, 10 parts of butyl acrylate, 50 parts of polyoxypropylated sorbitol, and 2 parts of ammonium persulfate were dissolved in 350 parts of water and heated at 60°C in an inert gas stream.
Polymerization was carried out for 8 hours. The viscous solution obtained by this person 1
00 parts polyethylene glycol (molecular weight 400) 50
3 parts of the crosslinking agent based on the solid content of this liquid.
Millionate MS-50 (mentioned above) was blended as a dimethylamide solution so as to give a concentration of %.

This aqueous solution was applied to a urethane foam sheet (foaming ratio: 20 times) with a thickness of 1 dragon so that the dry coating thickness was 200 μm, and after drying at 140°C for 3 minutes, a release paper was attached and
The crosslinking reaction was completed by aging in a drying room at 1 day. Next, remove the release paper and apply a 5% ethanol solution of nitroglycerin to the adhesive surface so that the nitroglycerin content is 400μy/cd, and after uniformly absorbing it into the polymer layer, apply the release paper. then 10×1
It was cut into pieces of 0 m to make a patch.

Example 4 To 100 parts of a 20% aqueous solution of methyl vinyl ether-maleic anhydride copolymer (maleic anhydride content: 50% by weight), 15 parts of diethylene glycol and 1 part of triethanolamine were added and mixed, and the solid Coronate 2501 (supra) was blended as a dimethylformamide solution in an amount of 0.3% by weight per minute.

Apply this aqueous solution to the silicone-treated surface of release paper until the dry thickness is 15 mm.
After coating it to a thickness of 0 μm and drying it at 130°C for 5 minutes, it was laminated on a 25 μm thick cellophane film.
The crosslinking reaction was completed by aging for 2 days in a drying room at 0°C. Next, peel off the release paper and apply a 2% clonidine ethanol solution to the adhesive surface so that the clonidine content is 2%.
After applying the mixture at a concentration of 0.00 parts g/7 and allowing it to be uniformly absorbed into one layer of the polymer, a patch was prepared by adhering release paper and cutting it into 1010×10 pieces.

The patches obtained in the above Examples, and corresponding to each Example, A.. one without the blocked incyanate compound, and... a drug containing a crosslinking agent and 15% water. Various performance tests were conducted on comparative examples, including one in which the polymer was blended at the same time, and one in which a C/non-crosslinked natural rubber-based polymer was used.

The results are shown in the table below. The drug efficacy is determined by pasting a test piece (1'OX 10 cm) on the back of a rabbit at the hair removal site, collecting blood after each time period, and quantifying the drug amount in the blood using gas chromatography. Also, the evaluation symbol is ◎
・-Very good, O...Good, △...Slightly poor, X
Marked as defective.

Claims (1)

[Claims] fi+ In producing a patch comprising a plaster layer containing a medicinal benefit on a support, a water-soluble polymer having a functional group reactive with i/cyanate groups and a water-soluble forming substance are used. If the adhesive component is based on , an aqueous solution containing a crosslinking agent component consisting of a blocked isocyanate compound whose isocyanate group regeneration temperature is 100°C or higher is applied onto the substrate, and heated at 100°C or higher with L. A method for producing a patch, which comprises drying and carrying out a crosslinking reaction, and after the completion of the reaction, a single layer of the obtained crosslinked anhydrous water-soluble polymer absorbs a non-aqueous solution of a drug to form a plaster layer.