JP3534843B2 - Transdermal patch - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermal patch. [0002] Percutaneous absorption patches absorb the drug into the body by distributing, diffusing, and transferring the drug from the base of the patch and the drug reservoir layer to the skin and transferring it to the blood. . However, even for drugs that need to be administered continuously, for example, drugs or hormonal agents that suppress the attack of angina, etc. Must be sampled, and the burden on the patient being administered is large. [0003] Therefore, there is an idea that a stable administration can be performed by controlling the application time.
For birth control pills and the like, a method of changing the color for each day of the week or attaching a calendar to the box is used. However, these are merely control of the application time, and the dose may increase or decrease depending on the person, and there is a problem that the dose cannot be controlled. [0004] In addition, some stomach drugs and the like vary the dose depending on the material whose release is changed by the pH in the stomach. However, there is a problem that oral drugs are limited to pH-dependent oral drugs. Was. SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned drawbacks, and an object of the present invention is to provide a transdermal system capable of visually monitoring the remaining amount of a drug during application. It is to provide an absorption patch. In the transdermal patch of the present invention, a pressure-sensitive adhesive layer containing an acidic or basic drug and a remaining amount of a labeling substance on the support is formed on a support. Have been. The support is not particularly limited as long as the drug is impermeable or hardly permeable. Examples of such a support material include cellulose acetate, ethyl cellulose, polyethylene terephthalate, polypropylene, and plastic. Resin films such as vinylated vinyl acetate-vinyl chloride copolymer, nylon, ethylene-vinyl acetate copolymer, plasticized polyvinyl chloride, polyurethane, polyvinylidene chloride, etc .: aluminum sheets, etc., which are used as single-layer sheets Or may be used as a laminate of two or more types. In addition, materials other than the aluminum sheet may be used as a woven fabric or a nonwoven fabric. The pressure-sensitive adhesive used in the pressure-sensitive adhesive layer is preferably water-insoluble, and examples thereof include an acrylic pressure-sensitive adhesive, a rubber-based pressure-sensitive adhesive, a silicon-based pressure-sensitive adhesive, and a urethane-based pressure-sensitive adhesive. In particular, an acrylic pressure-sensitive adhesive mainly containing 2-ethylhexyl (meth) acrylate described below is preferable. As the acrylic pressure-sensitive adhesive, for example,
(Co) polymers containing alkyl (meth) acrylate as a main component are preferably used, and even copolymers of a functional monomer copolymerizable with an alkyl (meth) acrylate, a vinyl compound, etc. Good. As the alkyl (meth) acrylate, when the number of carbon atoms in the alkyl group is small, the cohesive strength is improved but the cohesive strength is reduced. When the number is large, the cohesive strength is improved but the cohesive strength is reduced. Those of the formulas 1 to 18 are preferred, for example, methyl (meth) acrylate, (meth)
Ethyl acrylate, butyl (meth) acrylate, isobutyl (meth) acrylate, hexyl (meth) acrylate, 2-ethylhexyl (meth) acrylate, (meth)
Octyl acrylate, isooctyl (meth) acrylate, decyl (meth) acrylate, isodecyl (meth) acrylate, dodecyl (meth) acrylate, lauryl (meth) acrylate, stearyl (meth) acrylate, and the like. Two or more of these may be used in combination. Examples of the functional monomer include a monomer having a hydroxyl group, a monomer having a carboxyl group, a monomer having an amide group, and a monomer having an amino group. Examples of the monomer having a hydroxyl group include 2-hydroxyethyl (meth) acrylate,
Hydroxyalkyl (meth) acrylate such as hydroxypropyl (meth) acrylate is preferably used. Examples of the monomer having a carboxyl group include α, β such as (meth) acrylic acid.
-Unsaturated carboxylic acids; monoalkyl esters of maleic acid such as butyl maleate; (anhydride) maleic acid, fumaric acid, crotonic acid and the like are preferably used. Examples of the monomer having an amide group include alkyl (meth) acrylamide such as acrylamide, dimethylacrylamide and diethylacrylamide; alkyl ether methylol (meth) acrylamide such as butoxymethylacrylamide and ethoxymethylacrylamide; and diacetone acrylamide. It is preferably used. As the monomer having an amino group, for example, dimethylaminoethyl acrylate is preferably used. As the vinyl compound, vinyl acetate,
Examples thereof include styrene, α-methylstyrene, N-vinyl-2-pyrrolidone, vinyl chloride, acrylonitrile, ethylene, propylene, and butadiene, which may be copolymerized. If necessary, a tackifier, a plasticizer, etc. may be added to the acrylic pressure-sensitive adhesive. The (co) polymer mainly composed of the (meth) acrylic acid alkyl ester is usually prepared by blending the above monomers in the presence of a polymerization initiator and performing solution polymerization. When performing solution polymerization, ethyl acetate or other polymerization solvents are added to a predetermined amount of various monomers, and an azobis-based
7 in a nitrogen atmosphere in the presence of a polymerization initiator such as a peroxide
What is necessary is just to raise temperature to 0-90 degreeC, and to make it react for 8 to 40 hours.
Further, the monomer may be charged in a lump or divided. The azobis-based polymerization initiator includes 2,2
2-azobis-iso-butyronitrile, 1,1′-azobis (cyclohexane-1-carbonitrile), 2,2′-
Examples include azobis (2,4-dimethylvalerinitrile), and examples of the peroxide-based polymerization initiator include lauroyl peroxide, benzoyl peroxide, and di (tert-butyl) peroxide. The rubber-based pressure-sensitive adhesive is preferably mainly composed of a rubber elastic body.
Examples thereof include 1,4-isoprene (natural rubber), styrene-isoprene-styrene block copolymer, polyisoprene, polybutene, polyisobutylene, and ethylene-vinyl acetate copolymer. If necessary, a tackifier such as a terpene resin or a rosin resin, a softener, a filler, an antioxidant, and the like may be added to the rubber-based pressure-sensitive adhesive. As the silicone-based pressure-sensitive adhesive, one containing polydimethylsiloxane or the like as a main component is preferable. The drug used in the present invention is a drug having a physiological activity which is usually used as a drug, and preferably has a pKa of 5 or less, or 9 or more. Examples thereof include acetylsalicylic acid and indomethacin. Antipyretic analgesic / anti-inflammatory drugs; local anesthetics such as lidocaine. [0025] As the labeling substance of the drug residual amount A down <br/> Toshianin compound. Examples of the anthocyanin compound include pelargonidin, delphinidin, cyanidin and the like. The above-mentioned anthocyanin compound usually shows a neutral and purple color, but shows a blue color when it is basic,
It is red in acidity. Therefore, while a basic (or acidic) drug is contained in the pressure-sensitive adhesive layer, the color of the pressure-sensitive adhesive layer is blue (or red), but the color changes with a decrease in the drug. When the drug is gone, it turns purple. If the amount of the labeling substance used is small, the change in color cannot be recognized, and if the amount is large, there is a possibility that the medicine effect or the human body may be adversely affected. Department. If necessary, a transdermal absorption enhancer may be added to the pressure-sensitive adhesive layer for the purpose of improving the amount of drug absorbed. The transdermal patch of the present invention comprises a pressure-sensitive adhesive composition containing the above-mentioned pressure-sensitive adhesive and, if necessary, a drug and other additives, coated on a support and dried. It is obtained by forming a layer. As a method for forming the pressure-sensitive adhesive layer on the support, a conventionally known method for producing a pressure-sensitive adhesive tape such as a solvent coating method, a hot melt coating method, an electron beam curing method, and an emulsion coating method can be used. Particularly, a solvent coating method is preferable. To form the pressure-sensitive adhesive layer by the solvent coating method, for example, the pressure-sensitive adhesive is diluted with an appropriate solvent, and a drug, and if necessary, a transdermal absorption enhancer and other additives are added. After mixing uniformly, the resulting solution is applied to a support and dried. Alternatively, the pressure-sensitive adhesive composition may be applied to release paper coated with a silicone resin or the like, dried to form a pressure-sensitive adhesive layer, and then transferred and adhered to a support. In this case, the release paper may be transferred together with the pressure-sensitive adhesive and used to protect the pressure-sensitive adhesive layer of the patch until use. The thickness of the pressure-sensitive adhesive layer varies depending on the purpose of use. However, when the pressure-sensitive adhesive layer is thin, the adhesive force is reduced and the amount of the drug is insufficient. When the thickness is large, the diffusion of the drug becomes insufficient and the drug is not effectively used. 30 to 200 μm is preferred. Next, an embodiment of the present invention will be described. Synthesis of Acrylic Adhesive 100 parts by weight of a mixed solution containing 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone at a molar ratio of 65:35 and 400 parts by weight of ethyl acetate were separable flasks equipped with a stirrer and a cooling device. After heating to 60 ° C. while stirring and purging with nitrogen, a solution obtained by dissolving 2 parts by weight of lauroyl peroxide in 100 parts by weight of cyclohexane was divided into 10 parts in a reaction system, and 1 was added to a separable flask. The polymerization was started. The remaining 9 was added at one-hour intervals from the fifth hour after the start of the reaction, and after the addition was completed, the reaction was further performed for 19 hours to synthesize an adhesive. In order to adjust the viscosity, 50 parts by weight of ethyl acetate was added 5 times every 5 hours after the start of the reaction. After completion of the reaction, the mixture was cooled, and ethyl acetate was added so as to have a solid content of 35% by weight to prepare an acrylic pressure-sensitive adhesive solution. (Examples 1 to 3 , Comparative Examples 1 to 3) A predetermined amount of an adhesive, a drug and a labeling substance shown in Table 1 were mixed, and ethyl acetate was further added so that the solid content concentration became 30% by weight. In addition, a pressure-sensitive adhesive composition was obtained. The obtained pressure-sensitive adhesive composition was applied on a polyethylene terephthalate film (thickness: 40 μm) that had been subjected to a silicone release treatment, and then dried to form a pressure-sensitive adhesive layer having a thickness of 60 μm. Next, a laminate (thickness: 50 μm) of a polyethylene terephthalate film and an ethylene / vinyl acetate copolymer film was used as a support,
The pressure-sensitive adhesive layer was transferred and adhered to the ethylene / vinyl acetate copolymer film side to obtain a transdermal patch. The transdermal patches obtained in the above Examples and Comparative Examples were punched out into a size of 10 cm × 10 cm, and applied to the chests of 10 healthy males, and the blood concentration of the drug was measured over time. Table 1 shows the AUC (area under blood concentration).
It was shown to. In addition, the percutaneous absorption patch of the example was replaced when it was judged that the color changed, and the percutaneous absorption patch of the comparative example was continuously administered for 3 days while being replaced every 24 hours. did. [Table 1] The constitution of the transdermal patch of the present invention is as described above, and the remaining amount of the drug is visually monitored by the labeling substance of the remaining amount of the drug incorporated in the adhesive layer. Since it is possible, when the amount of the drug is reduced, it can be replaced with a good timing, and a stable drug effect can always be maintained.

Claims (1)

(57) on to the Claims 1] support, acidic or basic drug and drug residual amount of labeling substance to percutaneous absorption adhesive layer containing formed a A anthocyanin compound a patch transdermal patch, characterized in that a anthocyanin compound is 0.1 to 10% by weight compounded with respect to adhesive layer 100 weight parts.