JPH0427210B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to a sustained release patch for transdermal administration. More specifically, the present invention mainly consists of an adhesive layer containing hollow fibers containing a specific drug in the hollow portions of the specific hollow fibers, and a support that supports the layer. The present invention relates to a sustained release patch for transdermal administration that has excellent sustained drug release effects and can suppress side effects such as stuffiness and rash by providing voids. <Conventional technology> In the development of pharmaceuticals, it is necessary to develop new compounds that are excellent drugs, 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 the drug in the body, the drug may be administered at a concentration above the minimum effective concentration and below the maximum safe concentration, that is, within the effective blood concentration range. Development of so-called sustained-release patches in which medicinal 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, problems such as irritation to the skin, residue on the skin, and 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, the area of skin that is irritated increases, which is undesirable, or the areas to which it can be applied are limited. <Problems to be Solved by the Invention> As a solution to this problem, a method has been proposed in which a drug and/or an absorption aid is present in hollow porous fibers and brought into contact with the skin surface (for example, Japanese Patent Application Laid-Open No. 57-1999) -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 making it more likely to cause problems such as rash. The present inventors have found that local irritation can be avoided by placing the hollow fibers in an adhesive layer. However, even in this case, in the case of evaporative drugs, the drug transfers quickly to the adhesive layer, so as a result, the drug is released quickly and lasts for a long time, just like in a preparation made by mixing the drug into the adhesive layer. It was necessary to make further improvements in order to put it into practical use as a sustained-release preparation. <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 research aimed at creating a sustained-release patch that can suppress side effects such as rash, we have developed a method that uses specific hollow fibers containing a drug that evaporates when applied to the human body as an adhesive in the hollow part. The inventors have discovered that the above-mentioned drawbacks can be eliminated by allowing the hollow fibers to exist in the agent layer and providing voids around the hollow fibers, and have arrived at the present invention. That is, the present invention provides hollow fibers made of polyester having holes penetrating in the outer circumferential direction, and comprising an adhesive layer containing hollow fibers in which the hollow fibers contain an evaporative drug; This sustained-release patch for transdermal administration consists of a supporting body and a void around the hollow fibers. 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 over the entire 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 part may both be approximately circular, one of the outer shape and the hollow part may be approximately circular and the other irregularly shaped, or both the outer shape and the hollow part 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 holes penetrating in the outer circumferential direction to the cross-sectional area of the fibers is
It is preferably 0.001 to 70%, particularly preferably 0.01 to 50%, and more preferably 1 to 50% of the fiber cross-sectional area excluding hollow portions. 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. The hollow fibers of the present invention have a shape that is almost infinitely long with respect to the outer diameter of the fibers, and when used in textured forms such as plain woven fabrics, knitted fabrics, and nonwoven fabrics, good handling properties and
It has a good feel on the skin and a moderately sustained release of the drug, maximizing its characteristics. The material for the hollow fibers used in the present invention is, for example, polyester such as polyethylene terephthalate. Particularly preferred is polyethylene terephthalate. 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 containing a drug in the hollow portions of the hollow fibers having holes penetrating in the outer circumferential direction 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. The drug is applied to the hollow part of the hollow fiber by mixing it with a drug, a solubilizing agent, a diffusion aid, and a skin absorption enhancer, making it into a solution, ointment, etc., and then immersing or contacting the hollow fiber in the solution or ointment. Alternatively, means such as heating, pressurization, vacuum pressurization, ultrasonic vibration, etc. can also be used to aid infiltration of the drug mixture. In the present invention, a drug that is vaporizable when applied to the human body means a drug that is originally solid but evaporates by sublimation, or a drug that is originally a liquid and evaporates from that state. It may be something you do. Typical examples of such drugs include nitrate esters such as isosorbide nitrate and nitroglycerin, but also include guaiazulene, halomethane, chloral hydrate, menthol,
Examples include salicylic acid esters such as camphor and methyl salicylate. 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 other factors. 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 composition mainly composed of silicone rubber, polyisoprene rubber, styrene-butadiene copolymer rubber, acrylic rubber, natural rubber, etc. Vinyl viscous compositions such as polyvinyl alcohol and ethylene-vinyl acetate copolymer; Viscous compositions whose main components are silicone adhesives, polyurethane elastomers, polyester elastomers, polybutadiene elastomers, etc.; Acrylic resins, etc. You can choose from. Among these, acrylic resins are preferred, especially since they are less irritating to the skin.
From the viewpoint of appropriate tackiness, adhesion, high internal cohesion, and excellent solvent resistance, (1) at least 90 to 98 mol% of (meth)acrylic acid alkyl ester of an alkyl group having 4 or more carbon atoms; (2) Acrylic resins copolymerized with 2 to 6 mol% of acrylic acid and/or methacrylic acid are particularly preferred. Examples of (meth)acrylic 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, Examples include nonyl (meth)acrylate, decyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, and the like. These adhesives are one or two types.
More than one species may be used in combination. In the present invention, in addition to containing a drug in the hollow portion of the hollow fiber, the adhesive may also contain a drug. In the case of a preparation that also contains a drug in the adhesive, when the preparation is administered, the drug first diffuses into the adhesive and is absorbed into the skin. As a result, the drug concentration in the adhesive decreases, but the decreased concentration is filled into the hollow portions of the hollow fibers and replenished by a high concentration of drug. Such a mechanism results in a formulation in which the drug dosage can be controlled within a certain range over a longer period of time. The thickness of the adhesive layer is usually 5 to 1000 microns, preferably 10 to 500 microns. The adhesive layer containing hollow fibers can be manufactured as follows. That is, for example, a method in which a hollow fiber is placed on a support described below and a pressure-sensitive adhesive is applied to the surface of the hollow fiber; after the hollow fiber is placed on a support and an adhesive monomer is applied, heating or UV irradiation, A method of reacting with ionizing radiation; Alternatively, a layer of adhesive is formed on the support in advance, and then hollow fibers filled with the drug in the hollow portion are pressed against this layer of adhesive to form the hollow fibers as needed. Examples include methods of burying the body to a certain extent. 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 the escape of the drug, 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. In the present invention, by providing voids around the hollow fibers as described above, it is possible to supply the drug in a sustained manner without delay in a small area, which was unsolved in conventional formulations, and to prevent stuffiness and rash. Can be suppressed. In order to efficiently create the voids in the present invention, it is advantageous to make the hollow fibers into a fabric, knitted fabric, non-woven fabric, or the like to facilitate the creation of voids. It is surprising that the presence of these voids allows the drug to be supplied more smoothly at an almost constant rate than when they do not exist. It can be considered that absorption and diffusion into the adhesive layer, which has a large surface area, is more gradual and at a constant rate than when it is diffused from the hollow fibers to the adhesive layer without being substantially vaporized. Furthermore, although the voids are not substantially open to the skin surface,
As mentioned above, the reason why stuffiness and rash can be suppressed is not known, but the flexibility of the formulation is significantly improved by creating voids around the hollow fibers, which reduces physical irritation when applied to the skin. It is thought that this drastic reduction contributes to the reduction in skin irritation. In addition, the moisture that comes from the skin to the area around the hollow fibers through the adhesive layer is released from the ends through the voids, so it causes bloat, rash, etc. compared to when it is released only through the support film. It is also thought that it is unlikely to occur. Although water is expelled through this route, it was surprising that the drug, which has evaporative properties, reaches the skin and exerts its medicinal effect rather than escaping. As is obvious to those skilled in the art, if the void is made too large due to the emphasis on the effect of suppressing stuffiness, interlayer peeling of the formulation is likely to occur from that area, so it is necessary to take measures to prevent interlayer peeling. Care must be taken. For this purpose, it is important to sufficiently bond the adhesive layers present on both sides of the fibrous structure to each other and/or through the fibrous structure. In the present invention, even after the adhesive layers are attached to both sides of the fiber structure, 10% or more, preferably 50% or more of the total surface area of each single fiber of the hollow fibers is not adhered to the adhesive layer. First, a void exists around the hollow fiber whose both sides are covered with the adhesive layer. If it is less than 10% of the total surface area, it will be difficult to ensure sufficient voids and therefore difficult to control drug release. 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, etc. as necessary. Examples of absorption aids or diffusion aids used in the present invention include sodium laurate, 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, pyroglutamate 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, and the like 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 the adhesive and voids around the fibers, and has a sustained drug release effect.
This is a significantly superior formulation. <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. Repeat the washing a specified number of times, then dry the sample and place it horizontally, and pour one drop of water from a height of 1 cm above the sample.
Add a drop (0.04 cc) and measure the time until the water is completely absorbed by the sample and no reflected light is observed. (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,
Extracted with 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. Added 0.090 parts of a 56% aqueous solution of orthophosphoric acid and 0.135 parts of antimony trioxide as a polycondensation catalyst, and reacted at a temperature of 275°C for 20 minutes under normal pressure and 15 minutes under reduced pressure of 30 mmHg, and then under high vacuum for 100 minutes. . The final internal pressure is
The resulting copolymer had an intrinsic viscosity of 0.402 and a softening point of about 200°C.
After the reaction was completed, the copolymer was made into chips according to a conventional method. 15 parts of chips and intrinsic viscosity of this copolymer
0.640 polyethylene terephthalate chips
85 parts were mixed in a Nauta Mixer (manufactured by Hosokawa Iron Works) for 5 minutes, dried at 110°C for 2 hours in a nitrogen stream, and then dried at 150°C for 7 hours, and then dried in 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 a spinneret with circular slits with widths of 0.05 mm and 0.6 mm was used.
Spun according to the conventional method, and the ratio of outer diameter to inner diameter is 2:1
We made hollow fibers (25% hollowness). This raw yarn was 300 denier/24 filaments, and was drawn in a conventional manner at a draw ratio of 4.2 times to obtain a multifilament of 71 denier/24 filaments. This multifilament is knitted into stockinette fabric, and after scouring and drying by the usual method,
Treated with 1% caustic soda aqueous solution at boiling temperature for 2 hours to achieve alkali weight loss rate of 15% and water absorption rate of 3.
In seconds, a fabric with a water absorption rate of 80% 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 a water absorption rate of 38%. This hollow fiber does not have holes penetrating in the outer circumferential direction. (3) Adhesive solution and adhesive layer (1) Cool under reflux 79.4 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. The mixture was placed in a reaction vessel equipped with a stirrer and a stirrer, 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%. The ethyl acetate solution containing the adhesive layer was applied onto a silicone-coated release paper so that the thickness after drying would be 20 μm, and dried at 90° C. for 10 minutes to obtain an adhesive layer (1). Example 1 and Comparative Example 1 100 parts of acetone solution containing 40 parts of isosorbide nitrate
8 parts of the hollow fiber sample (1) was immersed in a container containing 1 minute, and then pulled out after 1 minute and air-dried. Approximately 0.1 part of isosorbide nitrate was present in 1 part of this hollow fiber. A film made of polyethylene terephthalate with a thickness of 5 μm was used as a support, and the above-mentioned adhesive solution was applied onto it so that the thickness after drying was 60 μm.
After drying at 90°C for 10 minutes, the hollow fiber sample containing isosorbide nitrate was placed on the adhesive layer, and the adhesive layer (1) was further placed on top of it so as to cover the hollow fiber sample to obtain a sample. . The content of isosorbide nitrate in this sample was 10 g/ ^m2 , and when the cross section of this sample was observed under magnification, approximately 80% of the total surface area of the single fibers was not in direct contact with the adhesive layer, and the fiber structure The presence of numerous voids around the area was observed. Let this sample be A. On the other hand, the adhesive layer (1) was placed on top of the hollow fiber sample containing isosorbide nitrate, which was placed on the adhesive layer with a thickness of 60μ obtained in the same manner as above, while applying pressure from both ends so as not to entrain air. A sample was obtained by crimping. The total content of isosorbide nitrate was 10 g/m ² . When the cross section of this sample was observed under magnification, no voids were observed around the fiber structure. This sample is called B. Cut this preparation into 2cm x 2cm pieces, weighing approximately 2.7Kg.
It was applied to the depilated back of a rabbit, blood was collected at a predetermined time, and the blood concentration was measured. The results are shown in Table-1.

[Table] Example 2 and Comparative Example 2 In order to evaluate only the feeling of stuffiness, a test was conducted in a drug-free form. That is, in Example 1 and Comparative Example 1, except that the step of incorporating isosorbide nitrate into the hollow fiber sample was omitted, exactly the same operation was performed to prepare a sample corresponding to a so-called placebo. When cross-sectionally observed, sample C with voids and sample D without voids were each cut into 10 cm squares and pasted on the human chest to examine the degree of stuffiness. As a result, it was clear that sample D had a stronger feeling of stuffiness. From the latter half of the day, I started to feel itching on my skin, especially around the edges where sample D was applied.

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; 1. A sustained-release patch for transdermal administration, comprising a support for supporting a layer, and a cavity provided around the hollow fibers. 2. Claim 1 in which at least a part of the hollow fibers is selected from the forms of woven fabric, knitted fabric, and non-woven fabric.
The sustained-release patch described in Section 1. 3. The sustained release patch according to claim 1 or 2, wherein the volatile drug is selected from nitrates, halothane, chloral hydrate, guaiazulene, menthol, camphor, and salicylates. 4. The sustained release patch according to any one of claims 1 to 3, wherein the adhesive layer is made of an acrylic resin.