JPH0427211B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to sustained-release pharmaceutical preparations for transdermal administration. More specifically, the present invention relates to a patch mainly consisting of an adhesive layer containing hollow fibers containing a specific drug in the hollow portion of the specific hollow fibers, and a support supporting the layer, and the production thereof. Regarding the law. <Conventional technology> In the development of pharmaceuticals, it is necessary to develop new compounds with excellent medicinal efficacy, and at the same time, to develop agents to further enhance the effects of these new chemical substances and chemical substances already used as pharmaceuticals. Various attempts are being made to change the type and optimize the dosage form. For example, in order to prolong the duration of a drug with a short half-life, which is a parameter for the effective duration of a drug in the body, it is possible to increase the drug's efficacy at a concentration above the minimum effective concentration and above the maximum safe concentration, that is, within the effective blood concentration range. The development of so-called sustained-release preparations in which the ingredients are absorbed into the human body over a long period of time is actively underway. Examples of sustained release preparations include transdermal absorption preparations such as ointments and spray applications. Since these preparations are applied to the skin in eye-doses, there are problems in that the dosage is not constant and that ointments and the like adhere to clothes and stain them. Furthermore, drugs in ointments are absorbed into human skin depending on the initial concentration, applied thickness, drug diffusion rate in the ointment base material, skin absorption rate, etc., but there are uncertain conditions at the time of use. The problem is that it is difficult to apply to pharmaceuticals where there are many factors and effective concentration and side effects are problematic. As a remedy for this drawback, there are tapes and patches that contain a certain amount of medicinal ingredients in an adhesive and are molded into a certain size (for example, Japanese Patent Application Laid-Open No. 57-116011).
(Refer to Japanese Patent Application Laid-Open No. 1983-134020). The method using tapes and patches can solve many of the problems that occur with methods such as ointment and spray application. In addition, the problems of skin irritation, skin residue, and irritation during peeling that may occur when using such tapes and patches can be improved by appropriately combining types and compositions of adhesives. (For example, see Japanese Unexamined Patent Publication No. 18924/1983). Conventional tapes and patches contain pharmaceuticals at a concentration above the minimum effective concentration and below the maximum safe concentration.
If you want to administer it for as long as possible, e.g.
If the drug concentration in the adhesive is simply increased, the initial concentration absorbed into the human body will be higher and skin damage may occur. Furthermore, if the composition of the adhesive is changed to slow down the diffusion rate of the drug in order to reduce the absorption rate of the drug, there is a problem in that the initial absorption concentration of the drug decreases. Another method of increasing the sustained release effect is to increase the thickness of the adhesive layer, but this generally increases skin irritation or leaves some of the adhesive on the skin as a residue. Problems are likely to occur. Another method is to lower the drug concentration in the adhesive,
Efforts have also been made to increase the area of application to the skin. However, if the area to be applied is increased, the patch becomes difficult to handle, increases the area of the skin that is irritated, which is undesirable, or the areas to which it can be applied are limited. <Problems to be Solved by the Invention> As one solution to this problem, a method has been proposed in which a drug and/or an absorption aid remains in hollow porous fibers and is brought into contact with the skin surface (for example, Japanese Patent Laid-Open No. 57 −31611). However, even with this method, the concentration of the drug in the very small part of the skin that comes into contact with the drug becomes abnormally high, causing undesirable irritation to the skin and causing problems such as rash. As a result of various studies, the inventors of the present invention have found that the above problem can be avoided to some extent by completely burying the fibers in the adhesive layer. When formulations with such improvements were actually applied to human skin, the problem of rash still could not be completely solved. <Means for Solving the Problems> In view of the above drawbacks, the present inventors have devised a method that ensures that the medicinal ingredient can be applied to a small patch area, that allows the desired amount of drug to be gradually administered over a long period of time, and that does not cause stuffiness. As a result of intensive studies aimed at creating a sustained-release patch that can suppress side effects such as rash, it was discovered that a small portion of the solvent used in the formulation remained in the patch, which caused the rash to move. I discovered that Moreover, it has been found that it is necessary to keep the residual amount of the solvent at 50 ppm or less. Heating is generally used to remove residual solvent. However, in the case of a drug that has evaporative properties, simply using heating means causes the solvent to be removed and the drug to escape, resulting in a patch that does not cause irritation and has no medicinal effect. In order to overcome these difficulties, the present inventor conducted further studies and finally completed the present invention. That is, the present invention provides hollow fibers made of polyester having holes penetrating in the outer circumferential direction, an adhesive layer containing hollow fibers in which the hollow fibers contain an evaporable drug, and supporting the layer. A patch comprising a support for the drug and/or
or a patch characterized in that the total residual amount of the solvent for dissolving the adhesive is 0.5 to 50 ppm of the entire preparation;
and in producing it, the hollow fibers containing the drug are combined with an adhesive layer that does not substantially contain or hardly contains the drug and in which the amount of residual solvent is reduced in advance. The present invention relates to a method for producing a patch, which is characterized in that it is produced with or without heat treatment. It is essential that the hollow fibers used in the present invention have holes penetrating in the outer circumferential direction. Here, the hollow fibers having holes penetrating in the outer circumferential direction are preferably hollow fibers having fine holes scattered throughout the cross section of the hollow fibers, arranged in the fiber axis direction, and at least a part of which communicates with the hollow portion. . Both the outer shape and the shape of the hollow portion in the cross section of the hollow fiber of the present invention may be arbitrary. For example, the outer shape and the hollow portion may both be approximately circular, one of the outer shape and the hollow portion may be approximately circular and the other is irregularly shaped, or both the outer shape and the hollow portion may have similar or dissimilar irregular shapes. . Further, there is no need to particularly limit the size of the external shape. The hollowness ratio of the hollow fibers of the present invention may be arbitrary, but it is particularly preferably 5% or more, and the ratio of the holes penetrating in the outer circumferential direction to the cross-sectional area of the fibers is the cross-sectional area of the fibers excluding the hollow portions. 0.01~70% of
is preferable, particularly 0.01 to 50%, more preferably 1 to 50%. In the present invention, it is preferable to use such hollow fibers by cutting them into an appropriate length of at least 10 times the outer diameter of the fibers. When the drug is cut at a size of 10 times or more, most of the drug filled in the hollow portion is released through the holes penetrating the outer circumferential direction rather than from the cross section, which enhances the sustained release effect, which is preferable. Also
If it is 10 times or more, it is preferable because it causes less stinging irritation when it comes into contact with human skin. In particular, the hollow fibers of the present invention can be shaped almost infinitely with respect to the outer diameter of the fibers, and when used in the form of tissues such as woven fabrics, knitted fabrics, and non-woven fabrics, the hollow fibers have good handling properties, good feel to the skin, and moderate drug absorption. It is a sustained-release drug that maximizes its characteristics. The material for the hollow fibers used in the present invention is, for example, polyester such as polyethylene terephthalate. Among them, polyethylene terephthalate is preferred. The hollow fiber used in the present invention is, for example,
−20612 Publication, JP-A-56-20613, JP-A-Sho
It can be produced by the method described in JP 56-43420 and the like. In the present invention, a plurality of hollow fibers having different materials, shapes, or hollow ratios may be used in combination. In the present invention, the above-described hollow fibers having holes penetrating in the outer circumferential direction and containing a drug are used. The drug may exist alone in the hollow portion, or may exist together with an adhesive described below, or may contain commonly used excipients, dissolution aids, diffusion aids, and accelerators. It may exist together with etc. The drug can be loaded into the hollow portion of the hollow fiber by any method. For example, a method in which hollow fibers are once immersed in a solution in which a drug is dissolved and then taken out and the solvent is removed; a method in which the drug is dissolved in an adhesive solution and then the hollow fibers are immersed; or a method in which the drug is excipiented. A method is used in which the hollow fibers are mixed with agents, solubilizers, diffusion aids, skin absorption enhancers, etc., and then made into a solution, soft tissue, etc., and the hollow fibers are immersed in or brought into contact with the solution. heating to help the drug or drug mixture enter the hollow part of the hollow fiber;
Means such as pressurization, vacuum pressurization, and ultrasonic vibration can also be used. Whichever method is used, it is important to reduce the amount of residual solvent as much as possible in order to achieve the object of the present invention. In the present invention, drugs that have evaporative properties when applied to the human body include those that are originally solid but evaporate during sublimation, and those that are originally liquid and evaporate from that state. It's okay to be. Typical examples of such drugs include nitric acid esters such as isosorbide nitrate and nitroglycerin, but also salicylic acid esters such as guaiazulene, menthol, camphor, and methyl salicate. The amount of the drug to be used is appropriately determined depending on the strength of the pharmacological action of the drug used, its absorbability into the skin, and the like. In the formulation of the present invention, the adhesive layer contains hollow fibers as described above. As the adhesive used in the present invention, a normal pressure-sensitive adhesive is used, such as a rubber-based viscous adhesive whose main component is silicone rubber, polyisoprene rubber, styrene-butadiene copolymer rubber, acrylic rubber, natural rubber, etc. Composition: Vinyl viscous composition such as polyvinyl alcohol, ethylene-vinyl acetate copolymer; Viscous composition containing silicone adhesive, polyurethane elastomer, polyester elastomer, polybutadiene elastomer, etc. as main components; Acrylic resin You can choose from among the following. However, acrylic resins are preferred, especially from the viewpoint of less skin irritation, moderate tackiness, adhesion, high internal concentration, and excellent solvent resistance. (1) Alkyl resins having 4 or more carbon atoms Particularly preferred is an acrylic resin copolymerized with at least 90 to 98 mol% of (meth)acrylic acid alkyl ester and 2 to 6 mol% of (2) acrylic acid or/and methacrylic acid. Examples of (meth)acrylic acid esters of alkyl groups having 4 or more carbon atoms include butyl (meth)acrylate,
Amyl (meth)acrylate, hexyl (meth)
Acrylate, heptyl (meth)acrylate,
Octyl (meth)acrylate, nonyl (meth)
Acrylate, decyl (meth)acrylate, 2
-Ethylhexyl (meth)acrylate and the like. In the patch of the present invention, which uses one type or a combination of two or more of these adhesives, it is important to reduce the amount of residual solvent in order to suppress rash. As mentioned,
It is also an object of the present invention to propose a practical method for achieving this. That is, in producing the patch, hollow fibers containing the above-mentioned drug and having a structure such as a woven fabric, a knitted fabric, or a non-woven fabric, which reduces residual solvent as much as possible, and a release paper on a support are used. If necessary, heat and/or pressure treatment is performed to combine the adhesive layer, which has been coated on top of the adhesive layer and removed as much as possible of residual solvents, monomers, and other low-boiling substances by heating, blowing air, etc.
An adhesive layer is provided on both sides of the fiber layer, and if necessary, heat treatment is performed to diffuse the drug into the adhesive layer, thereby efficiently containing the drug and reducing residual solvent to 0.5 to 50 ppm. The patch is manufactured in minute proportions. If this amount exceeds 50 ppm, it may cause side effects such as rash and poisoning, which is not desirable from a safety standpoint.As for the lower limit, the lower the lower limit, the better in principle, but it is extremely low. If not, heating temperature, air flow rate, time, etc. would have to be strict, which would make it impractical, and it is usually impractical to reduce the amount beyond 0.5 ppm. Typical examples of low boiling point substances such as solvents mentioned here are ethyl acetate,
Propyl acetate, butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, methanol, ethanol, isopropanol, butanol, methylene chloride,
Examples include chloroform, carbon tetrachloride, diethyl ether, etc., and one or more of these may be used. When manufacturing the adhesive layer independently, the support may be used only gradually during the process, but the support and release paper used in the final formulation may be used at least as a support. It is convenient and preferable to use it as a part of. Examples of these specific conditions will be described in detail in Examples. Here, the adhesive layer is
0.5 to 500μ, especially 1 to 200μ, especially 3 as necessary.
Produced to a thickness of approximately 100 μm. At this time, the thickness is set in consideration of the need for adhesive strength, drug retention, etc., although a thinner thickness has the advantage of reducing residue. Of course, the present invention also includes making the thickness as thin as possible and then adjusting the thickness to a desired thickness by laminating layers. Further, the drug-containing hollow fibers as described above may have a single layer or may have a multilayer of two or more layers. In this case, the type and amount of drugs and other additives in the hollow fibers can be set for each layer as necessary. Furthermore, the present invention also includes the presence of other supports unrelated to medicinal efficacy in the hollow fiber layer and/or as other layers. Initially, the drug mainly exists in the hollow fibers, and after lamination, by applying heat treatment as necessary, the drug diffuses into the adhesive layer, making the composition distribution stable even over a long period of time as a drug product. will be retained. The heat treatment conditions can be set as appropriate depending on the drug used, the type and amount of hollow fibers, adhesive layers, etc., but are generally 80 to 35℃.
It can be carried out for about 10 minutes to 3 days. These heat treatments may be performed once, or
It may be performed multiple times under the same conditions or under different conditions. Furthermore, it may be possible to include a portion of the drug or other additives in the adhesive layer in advance, but this is not a recommended method because the drug tends to escape under the conditions for removing residual solvent. It's hard to say. When the drug thus diffused into the adhesive layer is applied to a person, it is sequentially absorbed through the skin. Although the drug concentration in the adhesive decreases, the decreased concentration is replenished by the high concentration of drug filled in the hollow fibers. Such a mechanism results in a formulation that allows drug dosage to be controlled within a certain range over a longer period of time. The thickness of the preparation, excluding the release layer, is usually 5 to 1000 microns, preferably 10 to 500 microns. The formulation of the present invention is provided with a support that supports the adhesive layer as described above. The support is preferably one that satisfies the requirements of preventing drug escape, reducing adhesion to the skin, and not causing discomfort when attached to the skin, such as polyolefins such as polyethylene and polypropylene, and polyethylene terephthalate. Polyester, polyamides such as nylon 6 and nylon 66, polyvinyl alcohol, vinylidene chloride, polyurethane, ethylene-
Sheets of vinyl acetate copolymer, metal foil, rubber, etc.
Film, foil, etc. can be used. These supports may be used alone, in combination, or in a layered manner. Furthermore, in the present invention, voids may be provided inside the adhesive layer, such as around intermediate supports such as hollow fibers and/or other fibers used as necessary. These voids tend to cause peeling more easily than in preparations without such voids, but if this is suppressed by maintaining the bonding force of the adhesive layer, the sustained release of the drug can be smoothly delivered. Moreover, it is also effective in suppressing stuffiness, and is one of the preferred embodiments. In order to provide these voids, it is convenient to use a structure such as a fibrous layered fabric, knitted fabric, or nonwoven fabric. Further, in the present invention, a release sheet may be provided on the adhesive layer. The release sheet may be one commonly used, such as paper whose surface is coated with a release layer. The preparation of the present invention may contain an absorption aid, a solubilization aid, a diffusion aid, a filler, etc. as necessary. Examples of absorption aids or diffusion aids used in the present invention include sodium lauryl sulfate, sodium dodecylbenzene sulfonate, sodium alkyl diphenyl ether disulfonate, dioctyl sulfosuccinate, and polyoxyalkyl phenyl ether sulfate. Surfactants such as ammonium salts; alcohols such as ethanol, glycerin, diethylene glycol, propylene glycol, polyethylene glycol, and higher fatty acid alcohols; dimethyl sulfoxide and alkylmethyl derivatives; salicylic acid, urea, dimethylacetamide, dimethylformamide, lanolin,
Allantoin, squalene, carbopol, diisopropyl adipate, pyroglutamic acid lauryl ester, ethyl laurate, methyl nicotinate, sorbitol and dodecylpyrrolidone, pyrrolidone derivatives such as methylpyrrolidone, olive oil, castor oil, liquid paraffin, petrolatum, gelatin, amino acids, Benzyl nicotinate, l-menthol, camphor, dodecyl azacycloheptan-2-one, etc. can be used. Fillers include water, titanium oxide, calcium carbonate, gypsum, calcium silicate, aluminum silicate, diatomaceous earth, carbon black, red iron, various dyes and pigments, liquid paraffin, petrolatum, lactose,
Fragrances, deodorizers, polyethylene, polypropylene,
Examples include powders and molded products of synthetic resins such as polyester and polystyrene. As detailed above, the preparation of the present invention has hollow fibers containing a drug in its adhesive layer to reduce residual low-boiling substances such as solvents, and has a sustained drug release effect. It is an excellent formulation that is extremely superior and does not easily cause rashes. <Example> The present invention will be explained in more detail by giving examples below. Parts in the examples indicate parts by weight, and the characteristics appearing in the examples were measured by the following method. (i) Water absorption rate test method (according to JIS-L1018) The fibers are made into cloth, and the cloth is washed with a 0.3% aqueous solution of anionic detergent Zab (manufactured by Kao Soap Co., Ltd.) at 40℃ for 30 minutes in a household electric washing machine. After washing the sample a specified number of times and then drying it, place the resulting sample horizontally and drop one drop of water (0.04 cc) from a height of 1 cm above the sample until the water is completely absorbed by the sample and reflected light is observed. Measure the time until it runs out. (ii) Water absorption measurement method A sample obtained by drying a fabric is immersed in water for at least 30 minutes, and then dehydrated for 5 minutes in a dehydrator of a household electric washing machine. It was calculated from the weight of the dry sample and the weight of the sample after dehydration using the following formula. Water absorption rate = Sample weight after dehydration - Dry sample weight / Dry sample weight (%) (iii) Blood concentration measurement method of isosorbide nitrate After separating plasma from 3 ml of collected blood,
ml of n-hexane, concentrated, added ethyl acetate to make 100μ, and quantified by GC-ECD. Moreover, the hollow fibers and adhesive solution used in the examples were created by the following method. (1) Hollow fiber sample (1) 297 parts of dimethyl terephthalate, 265 parts of ethylene glycol, 3,5-di(carbomethoxy)
53 parts of sodium benzenesulfonate (11.7 mol% based on dimethyl terephthalate), 0.084 part of manganese acetate tetrahydrate, and sodium acetate trihydrate
1.22 parts was placed in a glass flask equipped with a rectification tower, and transesterification was carried out according to a conventional method. After distillation of the theoretical amount of methanol, the reaction product was placed in a polycondensation flask equipped with a rectification tower, and used as a stabilizer. Add 0.090 parts of a 56% aqueous solution of orthophosphoric acid and 0.135 parts of antimony trioxide as a polycondensation catalyst, and heat to 275°C.
The mixture was reacted for 20 minutes under normal pressure, 15 minutes under reduced pressure of 30 mmHg, and then reacted for 100 minutes under high vacuum. The final internal pressure was 0.39 mmHg, the intrinsic viscosity of the obtained copolymer was 0.402, and the softening point was about 200°C. After the reaction was completed, the copolymerized polymer was made into chips according to a conventional method. 15 parts of chips and intrinsic viscosity of this copolymer
0.640 polyethylene terephthalate chips
After mixing 85 parts with Nauta Mixer (manufactured by Hosokawa Iron Works) for 5 minutes, drying in a nitrogen stream at 110°C for 2 hours and then at 150°C for 7 hours, using a twin-screw extruder. The mixture was melted and kneaded at 285°C to form chips. The limiting viscosity of this chip is
0.535, and the softening point was 261°C. The chips were dried in a conventional manner, and then spun in a conventional manner using a spinneret with circular slits with a width of 0.05 mm and a diameter of 0.6 mm, each with an arc-shaped opening closed at two places. An intermediate fiber (hollowness ratio: 25%) with a diameter to inner diameter ratio of 2:1 was produced. This yarn is 300 denier/24 filaments,
This raw yarn was drawn according to a conventional method at a draw ratio of 4.2 times to obtain a multifilament of 71 denier/24 filaments. This multifilament was knitted into a knitted fabric, and after being scoured and dried by the usual method, it was treated with a 1% caustic soda solution at boiling temperature for 2 hours to achieve an alkali weight loss rate of 15%, a water absorption rate of 3 seconds, and a water absorption rate of 80%. fabric was obtained. The obtained hollow fibers were hollow fibers having fine pores scattered throughout the cross section of the hollow fibers and arranged in the fiber direction, and at least a portion of which was in communication with the hollow portion. (2) Hollow fiber sample (2) The stockinette fabric obtained in the preparation of hollow fiber sample (1) is not subjected to alkali treatment,
The fabric has a water absorption rate of 230 seconds and an absorption rate of 38%. This hollow fiber does not have holes penetrating in the outer circumferential direction. (3) Adhesive solution: 97.4 parts of 2-ethylhexyl acrylate, 2.5 parts of methacrylic acid, 0.1 part of polyethylene glycol (degree of polymerization 14) dimethacrylate, 1.0 part of benzoyl peroxide, and 100 parts of ethyl acetate, equipped with a reflux condenser and a stirrer. The mixture was placed in a reaction vessel and polymerization was continued for 9 hours at 60°C under a nitrogen atmosphere with gentle stirring. The polymerization conversion rate was 99.9%. 500 parts of ethyl acetate was added to the obtained polymer solution to adjust the solid content concentration to about 20%. Experimental example 1 Acetone-4 containing 1 part of isosorbide nitrate
The acetone was added to 5 parts of hollow fiber sample (1) and air-dried overnight to remove the acetone. The liquid obtained by immersing the hollow fiber in methanol was inserted into a gas chromatograph to quantify the residual acetone, which was found to be below the detection limit (0.5 ppm).
The thus obtained hollow sample containing isosorbide nitrate contained 8 g/m ² of isosorbide nitrate. On the other hand, the adhesive solution was coated onto silicone-coated release paper so that the thickness after drying was 30 μm, and the mixture was heated at 90°C for 3 minutes and then at 110°C for 10 minutes. The resulting adhesive layer was immersed in methanol to extract the residual solvent, and the amount of ethyl acetate was measured by gas chromatography and found to be 12 ppm. The adhesive layer was superimposed on both sides of the hollow sample containing isosorbide nitrate obtained earlier, and a polyethylene terephthalate film with a thickness of 5μ was superimposed on one free surface of the adhesive layer, and the laminated molding was performed by applying pressure. I got something. The obtained laminate was cut into a size of 2 cm x 2 cm to obtain a preparation. The obtained preparation was applied to the dehaired back of a domestic rabbit weighing 2.7 kg, and the blood concentration was measured. Table 2 of the results
Shown below. Comparative Examples 1 to 9 An adhesive solution containing quenching isosorbide was prepared by adding 2 parts of isosorbide nitrate to 20 parts of the solid content in the adhesive solution, and applied so that the adhesive layer thickness after drying was 50μ. Table 1 shows the contents of residual ethyl acetate and isosorbide nitrate in the adhesive layer when dried under various temperature conditions. The contents of ethyl acetate and isosorbide nitrate in the adhesive layer were determined by gas chromatography using an extract obtained by immersing a 2 cm x 2 cm adhesive layer in a methanol solution.

[Table] A film made of polyethylene terephthalate with a thickness of 5μ was crimped on one side of the adhesive layer containing isosorbide nitrate of Comparative Example 2 obtained in this way, and cut into pieces of 2 cm x 2 cm. Table 2 shows the results of measuring the blood concentration of the hair pasted on the back of the hair removed.

[Table] Example 2 and Comparative Examples A so-called placebo preparation was prepared in the same manner as Example 1 and Comparative Examples 1 to 9, except that it did not contain isosorbide nitrate and the drying conditions were changed and the amount of residual solvent was changed. As 2cm x 2cm, age 20
The product was applied to the center of the back of three healthy adults aged ~30 years and weighed 55 to 72 kg for 2 days, and the condition of the skin after the preparation was removed was evaluated. Table 3 shows the results of the judgment based on the total score of the three people, with 0 indicating no reaction, 1 indicating slight redness, 2 indicating obvious redness, and 3 indicating rash such as papules. Indicated.

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Claims (1)

[Scope of Claims] 1. A pressure-sensitive adhesive layer comprising hollow fibers made of polyester having holes penetrating in the direction of the outer periphery, the hollow fibers containing an evaporable drug; In a patch consisting of a layer and a support, the total remaining amount of the solvent for dissolving the drug and/or adhesive is 0.5 to 0.5 of the total amount of the entire preparation.
A patch characterized by a concentration of 50ppm. 2. The adhesive patch according to claim 1, wherein the hollow fibers have a structure selected from woven fabrics, knitted fabrics, and nonwoven fabrics. 3. The patch according to claim 1 or 2, wherein the drug is one or more selected from nitrates, guaiazulene, camphor, menthol, and salicylates. 4 The remaining solvent is ethyl acetate, propyl acetate,
Claims 1 to 1 contain one or more selected from butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, methanol, ethanol, isopropanol, butanol, methylene chloride, chloroform, carbon tetrachloride, and diethyl ether. The patch according to any one of Item 4. 5. An adhesive layer containing hollow fibers made of polyester having holes penetrating in the outer circumferential direction, the hollow fibers containing an evaporable drug in the layer, and a support for supporting the layer. In manufacturing a patch in which the total residual amount of the solvent for dissolving the drug and/or adhesive is 0.5 to 50 ppm of the entire preparation, the hollow fiber containing the drug and substantially the drug. Production of a patch, characterized in that it is produced by combining a pressure-sensitive adhesive layer that does not contain or contains almost no solvent, and in which the amount of residual solvent is reduced in advance, and is produced with or without heat treatment. Method. 6. The method for producing a patch according to claim 5, wherein the hollow fibers have a structure selected from woven fabrics, knitted fabrics, and nonwoven fabrics. 7. The method for producing a patch according to claim 5 or 6, wherein the drug is one or more selected from nitrates, guaiazulene, camphor, menthol, and salicylates. 8 The remaining solvent is ethyl acetate, propyl acetate,
Claims 5 to 5 contain one or more selected from butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, toluene, xylene, methanol, ethanol, isopropanol, butanol, methylene chloride, chloroform, carbon tetrachloride, and diethyl ether. A method for producing a patch according to any one of Item 7.