JPS6038368B2 - Manufacturing method of patch - Google Patents

Description

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

Conventionally, various types of adhesive patches of this type have been known, in which an adhesive tube layer in which a drug is dissolved or a water-containing tube layer is provided on a support such as a synthetic resin film. There have been disadvantages such as insufficient medicinal efficacy because the drug is incorporated into the drug, and the water-containing tube layer generally does not have adhesive strength, and drug components decompose or change in quality during storage, making it impossible to exert sufficient medicinal efficacy. .

In addition, most of the products have poor shape retention, resulting in problems such as adhesive extrusion and adhesive residue after use during storage or use. There were few that demonstrated well-balanced performance. 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 adhesive patch was formed on the substrate using a specific method. By forming a polymer layer and allowing the drug component to be absorbed into it to form a tubular body layer, it was discovered that very good results were obtained for the above purpose, which led to the completion of this invention. It is.

That is, in producing a patch comprising a sound layer containing a drug on a support, the present invention uses a water-soluble polymer having a functional group reactive with isocyanate groups, this polymer and An adhesive component mainly consisting of a water-soluble liquid substance consisting of an alcohol-based water-soluble plasticizer with a phase-off and low brightness, and a crosslinking agent component consisting of a blocked isocyanate compound whose isocyanate group regeneration temperature is 100 qo or higher. The blended aqueous solution is applied onto the substrate and dried by heating at a temperature of 10,000 or higher to perform a crosslinking reaction. After the reaction is complete, the resulting anhydrous water-soluble polymer layer absorbs a non-aqueous solution of the drug to form a tube layer. The present invention relates to a method for producing a patch characterized by:

The patch obtained by this method has adhesive strength that allows it to be adhered to the body surface, and since the tube layer is a bathable polymer, it has good diffusibility, solubility, and 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. It has various advantages such as excellent cohesive strength of the body layer, good moldability, and prevention of glue extrusion and glue residue during storage, use, and use.

The components and materials used to manufacture 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 carpoxyl 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 polymers 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 polysobrene monomer water. Maleic acid copolymer and its derivatives, (meth)acrylic acid-(meth)acrylic acid ester copolymer and its derivatives, styrene-maleic acid copolymer and its derivatives, (meth)acrylamide-acrylonitrile-(meth)acrylic acid copolymer and its derivatives, ) acrylic acid copolymers and their derivatives, (meth)acrylamide-acrylic nitrile-(meth)acrylic acid ester copolymers and their derivatives, and the like. The water-soluble liquid substance that constitutes the adhesive component together with the water-soluble polymer is an alcohol-based water-soluble monoplasticizer that has good compatibility with the water-soluble polymer and has low volatility, such as polyether polyol or polyhydric alcohol. In addition, graft polymers obtained by polymerizing water-soluble ethylenically unsaturated monomers such as (meth)acrylic acid, crotonic acid, and maleic acid in the presence of polyether polyols or polyhydric alcohols are also used. However, two or more of these may be used in combination.

The blending amount of such water-soluble liquid substance is preferably in the range of 50 to 50 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-droppable polymer and the water-soluble liquid substance be made into an aqueous solution having a concentration of 40 to 5% by weight by adding, if desired, a drug release auxiliary substance to be described later.

The blocked isocyanate compound, which is a crosslinking agent component, has an isocyanate group regeneration temperature of 1000C or higher, and by using this, it can be coated on a support without reacting in an aqueous solution containing a water-soluble polymer at room temperature before coating. latter one
By heating and drying at a temperature of 0,000° C. or higher, preferably 120° C. or higher, it is possible to evaporate water and at the same time regenerate the active isocyanate groups to carry out the crosslinking reaction.

In contrast, ordinary polyisocyanates cannot be used because they react with water. A specific example of a commercially available blocked isocyanate compound is MD1 (
For metaphenylene diisocyanate) systems, Millionate MS-50 manufactured by Nippon Polyurethane Kogyo Co., Ltd.

Among the TD1 (tolylene diisocyanate) compounds, such as Nate 2501, there are Coronate APS NebleM manufactured by Nippon Polyurethane Industries, Ltd., but it goes without saying that other blocked isocyanate compounds can also be used, and two or more types can be used in combination. You may. The amount of the flocculated isocyanate compound to be blended is preferably in the range of 0.05 to 5% by weight based on the adhesive component containing the water-soluble polymer, and its usage form is such that it is used as a solution in dimethylformamide, etc., which is compatible with water. Good.

The support for the patch is either a single material that makes it difficult for drugs to be absorbed into the bone layer, or a composite material coated on at least one side with these materials; for example, the former includes cellophane. There are films and foils made of cellulose acetate, polyester, polypropylene, polyamide, polyvinylidene chloride, polyvinyl alcohol, metal, etc. The latter include films made of polyethylene, polyurethane, polyacrylic, etc., and nonwoven fabrics and woven fabrics made of various plastics. Examples include composite materials in which the non-migratory material is laminated on the surface of a sheet-like base material such as cloth or foam.

Drugs that can be used in this invention include corticosteroids, anesthetics, antihistamines, antibacterial agents, antifungal agents, anti-inflammatory agents, softening agents, vitamins, anticonvulsants, and antihypertensive agents as systemic agents. drugs, antibiotics, central nervous system agents, vasodilators, locksmiths, sedatives, sex hormones, and antidiabetic agents.

The appropriate amount of these drugs is selected to obtain the desired treatment or administration effect depending on the type of drug. in particular,
Corticosteroids include prezonisolone acetate, prezonisolone, hydrocortide acetate, hydrocortide,
Dexamethasone, fluocinolone acetonide, betamethazoso, fu.

Examples include beclomethasone lopionate, fludroxycortide, and fluocinonide. Anesthetics include penzocaine, lidocaine, and ethyl aminobenzoate; antihistamines include diphenhydramine hydrochloride, isocybesodil hydrochloride, and diphenyl imidazole; antibacterial agents include penzalkonium chloride and nitrofurazone; and antifungal agents include penzalkonium chloride and nitrofurazone. Nystatin, undecylenic acid, etc., and anti-inflammatory agents include indomethacin, methyl salicylate, glycol salicylate, salicylic acid amide, sodium salicylate, etc. Examples of keratin softeners, vitamin A, and antispasmodic agents include salicylic acid, vitamin A, atropine, and methscopolamine furomide.

In addition, systemic drugs such as antihypertensive agents such as reserpine and clonidine, antibiotics such as erythromycin, chloramphenicol, cephalexin, butracyclone, neomycin sulfate, oxytetracycline, and penicillin, barbicylates, diaze/gym, and nitrase/gum , Klorp. Examples include central nervous system acting agents such as Mazine, and vasodilators such as nitroglycerin and isosorbite dinitrate. In this invention, drug release aids may be used in conjunction with the above-mentioned drugs.

This release aid substance can be simply defined as one that promotes the release of the drug to the body surface, but it also includes substances that have the function of improving the solubility and diffusion of the drug within a thin film, and those that have the function of improving drug solubility and diffusion within a thin film. Those that have functions that improve transdermal absorption, such as water retention capacity, keratin softening properties, keratin permeability (loosening), functions as penetration aids and pore barrier agents, and functions to change the skin interface condition. Furthermore, it includes a wide range of drugs that combine both of the above functions or have, in addition to these functions, a function of promoting drug efficacy to further enhance the drug's 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 phunolin, urea, Polar substances such as urea derivatives such as allanthin (mainly for the water retention capacity of stratum corneum), dimethyldecyl phosphooxide, methyl octyl sulfoxide, dimethyl laurylamide, dodecyl pyrrolidone, isosorbitol, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, etc. Solvent (mainly keratin permeability), salicylic acid (mainly keratin softening), amino acid (mainly penetration aid), penzyl nicotinate (mainly pore opening agent), sodium lauryl sulfate (
(mainly functions to change the interfacial condition of the skin scales), Sarokol (used in combination with drugs with good transdermal absorption), etc.

Others diisopropylazibate, phthalate,
Plasticizers such as diethyl sebacate, hydrocarbons such as liquid paraffin, various emulsifiers, ethoxylated stearyl alcohol, higher ester ethers of glycerin, myristic acid isop. pills, ethyl laurate, etc. The blending amount of such a drug release auxiliary substance is preferably in the range of 50 to 50 parts by weight based on the weight of the water-soluble polymer 10, and may be added in advance to the aqueous solution for forming the polymer layer for the tube body. However, it may be used together with a drug and absorbed after forming the polymer layer for the tube body.

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 support is attached to the adhesive surface of the anhydrous water-soluble polymer layer formed after coating and drying the aqueous solution,
The drug can be absorbed by peeling off the release paper. The aqueous solution applied to the substrate is heated and dried at a temperature of 100 oo or more, preferably 1
20 to 14,000.

In addition, it is preferable to perform aging to complete the cross-sealing reaction after drying, and the aging temperature is 20qo.
Preferably, the temperature is about 80°C and the time is 3 to 7 hours. Furthermore, during aging, it is preferable that both sides of the polymer layer be covered with a support and a release paper. The drug is absorbed by applying a non-aqueous solution such as alcohol to the surface of the polymer layer from which the release paper has been removed, when the crosslinking reaction is completed and there are no isocyanate groups in the crosslinked water-soluble polymer layer. Apply it by coating, spraying, etc. so that it is evenly contained inside.

After this absorption, a release paper is attached without drying, and the final patch is cut into a predetermined size. In addition, when the above-mentioned drugs are mixed in advance into an aqueous solution in which a crosslinked anhydrous water-soluble polymer layer is to be formed, in addition to deterioration in the aqueous solution,
When the crosslinking reaction is carried out by heating, decomposition and alteration occur, resulting in a significant loss of medicinal efficacy.

The patch obtained by the above method exhibits comprehensively balanced and excellent performance in terms of medicinal efficacy, stability, toxicity, tube adhesion and cohesive strength, etc.

Examples of this invention will be shown below.

All parts in the examples mean parts by weight. Example 1 10 parts of ethyl acrylate and 3 parts of acrylic acid were polymerized in 195 parts of ethyl alcohol using 0.3 parts of potassium persulfate as a polymerization catalyst in an inert gas atmosphere at 60o0, 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, water was added to this polymer solution to make a 30% solution,
10 parts of this solid content is mixed with 10 parts of polyoxypropylated sorbitol as a water-soluble plasticizer and a base of 10 parts of polyoxypropylated sorbitol as a water-soluble plasticizer. 4 parts of Nate 2501 (mentioned above) were blended. This aqueous solution was applied to the surface of a rayon nonwoven fabric-PE laminate product with a thickness of 100 fm to a dry thickness of 300 fm, and after drying at 140 m for 5 minutes, a release paper was attached. 50qo
The crosslinking reaction was completed by aging in a heating chamber for 2 days.

Next, peel off the release paper and apply a 5:1:1 mixture of ethanol, indomethacin, and propylene glycol to the adhesive surface so that the indomethacin content is 2001 g/1, and allow it to be evenly absorbed into the polymer layer. After that, release paper was attached and cut into 10-10 pieces to prepare a patch. Example
2. Thoroughly mix 15 parts of maleic anhydride-polyisobutylene copolymer (maleic anhydride content: 5% by weight, molecular weight: 190,000 to 200,000), 11 parts of glycerin, and 5 parts of water;
Add a dimethylformamide solution of Coronate APStable M (previous generation) to a solution with a crosslinking agent of 0 relative to the solid content of the above mixture.
．． The content was 3% by weight.

Apply this aqueous solution to the silicone-treated surface of release paper until the dry thickness is 50 mm.
After drying at 13,000 m for 5 minutes, it was layered on a polyvinyl alcohol film with a thickness of 50 m and aged for 1 day in a drying room at 70 m 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.
The mixture was applied by spraying so as to have a weight of 0 g/g/g and was uniformly absorbed into the polymer layer, and then a release paper was attached and cut into 10×1 pieces to prepare a patch. Example 3 9 parts of acrylic acid, 1 part of butyl acrylate, 5 parts of polyoxypropylated sorbitol, and 2 parts of ammonium persulfate were dissolved in 35 parts of water and polymerized at 6000 for 8 hours in an inert gas stream. did.

5 bases of Japanese polyethylene glycol (molecular weight 400) were added to 10 parts of the viscous steel solution obtained in this way, and Millionate MS-1 was added so that the crosslinking agent was 3% by weight based on the solid content of this liquid. 50 (supra) was formulated as a dimethylamide solution. This aqueous solution was applied to a urethane foam sheet (foaming ratio: 20 times) with a thickness of one square so that the dry coating thickness was 2001 m, and after drying at 140 CC for 3 minutes,
A release paper was attached and the crosslinking reaction was completed by aging in a drying chamber at 70°C for 1 day.

Next, peel off the release paper and apply a 5% ethanol solution of nitroglycerin to the adhesive surface so that the nitroglycerin content is 400.
After applying the mixture in the same manner as the peaks and allowing it to be absorbed uniformly into the polymer layer, a release paper was attached and cut into 10×lo arcs to prepare a patch. Example 4 A 20% aqueous solution of methyl vinyl chloride-maleic anhydride copolymer (maleic anhydride content: 5% by weight) was prepared by adding 15 parts of diethylene glycol and 1 part of triethanolamine and mixing. Coronate 2501 (described above) was blended as a dimethylformamide solution in an amount of 0.3% by weight based on the solid content of the liquid.

Apply this aqueous solution to the silicone-treated surface of release paper until the dry thickness is 15 mm.
After coating at 0 French m, and drying at 130 oo for 5 minutes, it was layered on a 25 French m thick cellophane film and aged for 2 days in a 5,000° drying room to induce a crosslinking reaction. Completed it.

Next, the release paper was peeled off and a 2% ethanol solution of clonidine was applied to the adhesive surface so that the clonidine content was 200 m/g/cm, and the mixture was uniformly absorbed into the polymer layer.
A patch was prepared by adhering release paper and cutting it into 10×10 skin pieces. The patches obtained in the above examples and, corresponding to each example, A...a product without the blocked isocyanate compound, B...a drug containing a crosslinking agent and 15% water. Various performance tests were conducted on comparative examples, including one in which C was simultaneously blended with C, and one in which a non-crosslinked natural rubber-based polymer was used.

Claims (1)

[Claims] 1. When producing a patch consisting of a drug-containing plaster layer on a support, a water-soluble polymer having a functional group reactive with isocyanate groups and a material that is compatible with this polymer and has low volatility are used. The base material is an aqueous solution containing an adhesive component mainly consisting of a water-soluble liquid substance consisting of a water-soluble alcohol-based plasticizer and a crosslinking agent component consisting of a blocked isocyanate compound whose isocyanate group regeneration temperature is 100°C or higher. The above coating is applied and dried by heating at 100°C or higher, and a crosslinking reaction is carried out. After the reaction is completed, the obtained crosslinked anhydrous water-soluble polymer layer is made to absorb a non-aqueous solution of the drug to form a plaster layer. Characteristic method for producing a patch.