JPS6250447B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is in the form of a tape (sheet) that can be cut to a predetermined size and is used for continuous and quantitative administration of systemic and/or local active drugs by adhering to the outer skin or mucous membrane of the body. Alternatively, it relates to a flake-shaped preparation designed in advance to a predetermined size. As one method for administering drugs to the human body, a so-called transdermal absorption method is known, in which drugs are absorbed through the body's outer skin or mucous membranes. In this method, for example, a drug, a penetration aid, and a polymeric substance such as a pressure-sensitive adhesive are mixed and molded, brought into contact with the skin or mucous membrane, and absorbed by a concentration gradient. There are problems in that the drug is decomposed or denatured during storage and the polymeric substance is plasticized due to contact with the drug. In order to solve this problem, it has been proposed to form a drug-containing plaster layer on the central surface of a flaky support and form a pressure-sensitive adhesive layer on the outside with a drug-impermeable layer interposed therebetween. However, there are disadvantages such as insufficient contact between the plaster layer and the skin. Therefore, the first object of the present invention is to provide a tape or strip preparation in which the drug is not degraded or altered, and the pressure-sensitive adhesive layer is not plasticized. Another object of the present invention is to provide a tape or strip preparation in which a drug is constantly in contact with the outer skin or mucous membrane of the body, and which provides rapid, uniform, and long-term drug efficacy. These objects are tape or strip preparations for continuously and quantitatively administering systemically and/or locally active drugs from the outer skin or mucous membranes of the body, in which the preparations consist of (a) a backing member, and (b) one of the members. An adhesive layer formed on the application surface for adhesion to the application surface, c. The adhesive layer surface and/or the member and the layer to the extent that the adhesive layer can reliably adhere to the application surface. A hollow fiber disposed between the outer surface and the hollow fiber whose hollow portion is filled with at least a drug or a penetration aid alone or in a mixed system, and whose peripheral wall is microporous. achieved by. The drawings show typical examples of formulations of the invention. In Figure 1, reference numeral 1 indicates a flexible film, sheet, or foil designed to have a moisture permeability level that does not substantially allow the penetration aid described below to pass through or cause side effects such as irritation or whitening on the skin. , a backing member made of one or more types of nonwoven fabric, 2 is the member 1
A pressure-sensitive adhesive layer formed on one surface of the adhesive layer 2 for adhesion to an application surface such as the outer skin or mucous membrane of the body; 3 is a hollow fiber formed by being mostly embedded in the surface portion of the adhesive layer 2; (Outer diameter approximately 0.01~3000μ,
The hollow fibers have an inner diameter of approximately 0.0001 to 100 μ), and the distance between the hollow fibers (approximately 0.5 to 30 mm) is designed such that the formulation of the present invention can be adhesively fixed to the application surface by the exposed surface 2a of the adhesive layer 2. . Therefore, those skilled in the art will understand that even if most of the hollow fibers 3 are exposed, they can be adhesively fixed to the application surface by keeping a sufficient distance from each other. The hollow portion 3a of the hollow fiber 3 in FIG. 1 is filled with at least a selected active drug and a penetration aid. Although not shown, both ends of the hollow fiber 3 or any part of the intermediate portion are sealed to form one or more compartments, and a mixture of drug and penetration aid is encapsulated therein. It controls the protrusion of 4. The tape or strip preparation of the present invention, which is adhesively fixed to the outer skin or mucous membrane by the exposed surface 2a, provides the mixture 4 that has passed through and/or diffused through the peripheral wall of the hollow fiber 3 to the outer skin or mucous membrane surface. In FIG. 2, the contents encapsulated in the hollow fiber 3 are different from those in FIG. They are alternately arranged in parallel at intervals that allow sufficient adhesive fixation. FIG. 3 shows a modification of the example shown in FIG. 2, in which the hollow fibers 3 containing the penetration aid 5 are arranged in the adhesive layer 2, and the drug 6 is placed on the surface of the layer 2. Enclosed hollow fibers 3 are buried. FIG. 4 shows an example in which hollow fibers 3 in which a penetration aid 5 and a drug 6 are individually encapsulated are plain-woven and arranged on the surface of the adhesive layer 2. Those skilled in the art will appreciate the shape not shown in the drawings, for example, a configuration in which hollow fibers 3 in which a penetration aid 5 and a drug 6 are individually encapsulated are arranged in pairs or in a twisted manner on the surface portion of the adhesive layer 2; The shape of the hollow fibers 3 in which the drug agent is dispersed and/or dissolved in the drug-containing adhesive layer and the penetration aid encapsulated therein, the inner thickness of the hollow fibers, the substrate, the micropore diameter, etc. A configuration that combines different factors, such as the concentration of the filler in the hollow part, may be considered. The penetration aid encapsulated in the hollow fibers 3 passes or diffuses through the peripheral wall of the hollow fibers 3 and is provided to the skin surface, promoting absorption of the drug through the skin. Furthermore, the drug stored in the hollow fiber 3 or the adhesive layer 2 passes through or diffuses through the peripheral wall of the hollow fiber 3 and is absorbed into the skin, or moves through the adhesive layer and is absorbed into the skin from the exposed surface 2a. be absorbed into. These embodiments of the tape or strip preparation of the present invention are adhered to or brought into contact with the outer skin or mucous membrane surface of the body. Active drugs absorbed through the skin enter the circulatory system and become effective in treating diseases. Penetration aids used in the practice of this invention refer to all substances that contribute to promoting the absorption of active drugs by the body surface applied to the formulation, and include Examples of promoting functions include a water retention function of the stratum corneum (skin), a function of promoting swelling or softening of the stratum corneum, a function of improving wettability of the stratum corneum, and a function of opening pores. These multiple functions can often be obtained from a single substance. Substances used as penetration aids include dimethyl sulfoxide, dodecyl sulfoxide,
Methyl octyl sulfoxide, dimethyldecyl phosphooxide, mono- or diethylacetamide,
N-hydroxyethyl lactamide, dimethylacetamide, N/N-dimethyldodecamide, dimethylformamide, toluic acid diethylamide, tetrahydrofurfuryl alcohol, tetrahydrofuran, sorbitol, dodecylpyrrolidone, methylpyrrolidone, urea, glycerin, diethyl adipate, squalene, Squalane, acetylated lanolin, cetyl lactate, olive free, castor oil, dioctyl sebacate, ethoxylated stearyl alcohol, lanolin acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, liquid paraffin, petrolatum, amino acids, protease,
Benzyl nicotinate, l-menthol, camphor, methyl salicylate, Salocol, sodium lauryl sulfate, sodium laurate, stearylglycerin stearate, higher fatty acid triglyceride, polyoxyalkylene glycol, fatty acid mono(or di)ethanolamide, ethylene glycol monoethyl Examples include, but are not limited to, ether, polyoxypropylene alkyl ether, and higher alkyl sulfone. Preferred active drugs for use in this invention are:
It has transdermal absorption ability and is not substantially dissolved in water supplied from the outer skin or mucous membrane, and examples thereof include the following. B Corticosteroids: For example, hydrocortisone, prednisolone, paramethasone, beclomethasone propionate, flumethasone, betamethasone, beclomethasone propionate,
Dexitazone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic and anti-inflammatory agents: such as acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, Alclof Enatsuk,
Oxyphenbutazone, phenylbutazone, ibuprofen, flurbuprofen, salicylic acid, methyl salicylate, l-menthol, camphor and combinations thereof, etc. (c) Hypnosedatives: such as phenobarbital, amobarbital, cyclobarbital, etc. Stabilizers: For example, fluphenazine, thioridazine, diazepam, chlorpromazine, etc. Antihypertensive agents: For example, clonidine, etc. Antihypertensive diuretics: For example, hydrothiazide,
Bendrofluna thiadide, etc. Antibiotics: For example, penicillin, oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. Anesthetics: For example, lidocaine, benzocaine,
Antibacterial substances such as ethyl aminobenzoate, e.g. benzalkonium chloride,
Nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc. Antifungal substances: e.g. pentamycin, amphotericin B, pyrrolnitrine, clotrimazole, etc. Vitamins: e.g. vitamin A, ergocalciferol, cholecalcin ferols, octothiacin, riboflavin butyrate, etc. E. Antiepileptic drugs: e.g. nitrazepam, mepropamate, etc. W. Coronary vasodilators: e.g. nitroglycerin, nitroglycol, isosorbite dinitrate, erythritose stetranitrate, bentaerytose stetrani. Antihistamines: For example, diphenhydramine hydrochloride, chlorpheniramine, siphenylimidazole, etc. Two or more of these drugs can be used in combination as necessary. Further, these drugs can be used alone or in a mixed system with a solubilizing agent that can dissolve the drug. Solvents used include benzyl alcohol, butyl benzoate, isopropyl myristate, octanol, 1,3-butanediol, propylene glycol, crotamiton, polypropylene glycol, ethylene glycol, and the like. The hollow fibers in which these penetration aids and/or drugs are encapsulated will be explained. The hollow fibers have the function of holding the above-mentioned penetration aid and/or drug, and also have the function of passing and/or diffusing the penetration aid and/or drug enclosed in the hollow portion and supplying it to the skin surface. It has the following. Therefore, the material constituting the hollow fiber, the outer diameter or inner diameter of the hollow fiber, the wall thickness, and the structure of the peripheral wall, such as the state of micropores, porosity, etc., are variously selected depending on the auxiliary agent and/or drug. The hollow fibers used in carrying out this invention are:
For example, it can be obtained by the following manufacturing method. That is, acetylcellulose, ethylene-vinyl alcohol copolymer, polyurethane, polyvinyl chloride, polyethylene, polypropylene, polyacrylonitrile, hydrophilic acrylic polymer, polyvinyl alcohol, polyvinyl acetate, polyamide, polyimide, polytetrafluoroethylene, polysulfonated styrene, silicone rubber,
A base material such as wax or gelatin is dissolved in an organic solvent with good compatibility with water, such as acetone, dimethylformamide, dimethylacetamide, or dimethyl sulfoxide, and then this solution is used to dissolve the base material using a conventional method. This is a method in which hollow fibers are prepared, immersed in a water bath to remove solvent and coagulate to form micropore walls, which are washed with water and then dried to obtain hollow fibers. Other methods include extruding a blend of a base material and a water-insoluble fine powder into a hollow fiber shape and extracting the powder in a water bath; extruding a blend of a base material and a water-insoluble fine powder into a hollow fiber shape; There are methods such as stretching. Therefore, in addition to forming micropores in the peripheral wall of the hollow fiber as described above, the hollow fiber is made using a polymer capable of diffusing and transferring a penetration aid and/or an active drug as a constituent material of the hollow fiber. A device configured such that the auxiliary agent and/or drug can pass through a peripheral wall portion made of a polymer can also be used. Therefore, the term "the peripheral wall is microporous" used in the "claims" and the previous explanation means that the auxiliary agent and/or drug enclosed in the hollow part is It refers to a structure that has a wall structure that allows it to diffuse through the air and reach the surface of the hollow part. Encapsulation of the auxiliary agent and/or drug into the hollow fiber can be carried out by a conventional method such as suction under reduced pressure, injection, or suction using capillary pressure. The hollow fibers encapsulating the penetration aid and/or the active drug in this way can be used on the adhesive layer surface of the adhesive base material consisting of the backing member and the adhesive layer, and/or on the outside of the adhesive layer and the backing member. An adhesive layer is disposed between the adhesive layer and the surface to the extent that it can reliably adhere to the application surface, resulting in the tape or strip preparation of the present invention. Specific examples of the backing material include cellophane, cellulose acetate, polyester, soft polyvinyl chloride,
Films made of polyethylene, polypropylene, polyamide, polyvinylidene chloride, polyurethane, polyacrylic, etc. (including those with metal vapor deposited on the film surface), nonwoven fabrics, woven fabrics, foams, etc., or laminated films or sheets of these. In some cases, a material whose moisture permeability is designed so as not to allow the penetration aid to pass through or to cause irritation or whitening of the skin is used. formed on one surface of this member. A pressure-sensitive adhesive layer that has good adhesion to the surface to which it is applied, is non-irritating to the skin, and has excellent hollow fiber retention properties may be selected from the following compositions, for example: Ru. One preferred pressure-sensitive adhesive composition includes n-butyne (meth)acrylate, hexyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, isooctyl (meth)acrylate, and di(meth)acrylate. -Ethylhexyl, decyl (meth)acrylate, dodecyl (meth)acrylate (meth)
(Meth)acrylic acid esters such as tridecyl acrylate, and (meth)acrylic acid, itaconic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, and dimethyl copolymerizable with the esters. Functional monomers such as acrylamide, methylaminoethyl methacrylate, methoxyethyl (meth)acrylate and/or acrylonitrile,
An example is an acrylic composition which is a copolymer with a vinyl monomer such as vinyl acetate or vinyl propionate. Other examples include rubbers such as silicone rubber, polyisoprene rubber, polyisobutylene rubber, styrene-butadiene (or isoprene)
-Rubber-based viscous compositions mainly composed of styrene block copolymer rubber, acrylic rubber, natural rubber, etc., vinyl-based polymers such as polyvinyl ether, polyvinyl alcohol, polyvinyl acetate, polyvinyl pyrrolidone, etc. Examples include viscous compositions or viscous compositions containing cellulose derivatives, polyurethane elastomers, polybutadiene elastomers, polyester elastomers, etc. as main components. These compositions can be made into tapes or strips by using cross-linking agents or cross-linking means to balance cohesive and adhesive properties, and by carefully selecting the combination of penetration aids and/or active drugs used. maintains the adhesion of the preparation to the outer skin or mucous membrane of the body,
Provides sufficient medicinal efficacy. The unique effects of the tape or strip preparation according to the structure of this invention will be demonstrated in the examples described below, and in particular, the rapid effect, uniformity, and persistence of the drug targeted by this invention are satisfied. Moreover, it is believed that it has excellent adhesive properties and cohesive properties. Examples are shown below. Example 1 Acetyl cellulose with a degree of acetylation of 54% is dissolved using a mixed solvent of acetone/methanol = 9/1 (weight ratio) to obtain a 18% base solution. This melt is put into a hopper of a hollow fiber spinning device, and a melt hollow fiber having an outer diameter of 200 μm and an inner diameter of 25 μm is extruded, and the fiber is immersed in a water bath while the solvent is evaporated to extract the solvent. Next, this is washed with water and dried to obtain hollow fibers. Next, 40 μg of dodecylpyrrolidone and 40 μg of propylene glycol were added to the hollow part of the hollow fiber per 1 cm of the fiber.
40 μg of ethanol and 70 μg of diclofenac sodium. On the other hand, on one surface of a 12μ thick polyester film, 2-ethylhexyl acrylate: hydroxyethyl acrylate = 90:10 (weight ratio) was copolymerized in ethyl acetate using azobisisobutyronitrile. A copolymer solution (25% base) made of 30% polyester is applied and dried to a dry thickness of 50μ to obtain an adhesive base material. Next, the aforementioned drug-containing hollow fibers were arranged in parallel at 1 cm intervals on the adhesive layer surface of the base material, and heated and pressurized.
Approximately half of the hollow fibers are embedded in an adhesive layer and cut by heating at a predetermined position in the length direction to obtain a tape-like preparation of the present invention in which the ends of the hollow fibers are sealed. Table 1 shows the test results for this tape-like preparation. The sample size is 5 cm x 5 cm square, and the total length of the hollow fibers is 20 cm.

[Table] Comparative Example 1 in Table 1 is obtained by mixing the copolymer solution used in Example 1 with the penetration aid, solubilizer, and drug used in Example 1. Test method in Table 1 Holding force: Sample a width of 1 cm and a length of 10 cm.
Paste it on a Bakelite board with a length of 2 cm,
A load of 300 g was applied in the shear direction, and the time until cohesive failure and falling was measured in a 40°C thermostat. Adhesive residue after application: The sample was applied to the side of the upper arm, and 24 hours later, it was determined whether or not adhesive remained on the skin surface when removed. Carrageenin foot edema suppression rate: Imen (body weight 1.8-2.0
The hair on the back of a male Wister rat (150-180 g) was shaved, a sample of the drug administration member was pasted there using a bandage, and it was removed after a predetermined period of time. paste. After 2 hours, the sample was removed, and 0.3 μl of carrageenan 0.5% saline solution was injected subcutaneously into the sole of the foot, and the edema volume was measured 3 hours after injection. As a control, carrageenan alone was injected into untreated rats. This was compared to the resulting edema volume. In addition, the suppression rate is calculated as follows. Suppression rate = V _s2 −V _s1 /V _c2 −V _c1 ×100 However, V _s2 is the foot volume with edema in the sample treatment group, V _s1 is the foot volume before sample treatment, and V _c2 is the foot volume in the non-treatment group. The paw volume with edema, _Vc2 , is the paw volume of the untreated group before treatment. Remaining amount of drug: A 2 cm x 2 cm square sample was pasted on the hair removal site on the back of a rabbit, peeled off at each time, and the amount of drug remaining in the tape was quantified by gas chromatography. The percentage of the initial blending amount was measured. Example 2 Using a 20% dimethyl sulfoxide solution of ethylene-vinyl alcohol copolymer (ethylene content: 35% by weight, softening point: 180°C), hollow fibers were prepared in the same manner as in Example 1. (outer diameter 300μ, inner diameter 200μ). Next, 10 mg of methyl octyl sulfoxide, 10 mg of isopropyl myristate, 10 mg of ethanol, and clonidine were added to the hollow part of the hollow fiber per 1 cm of the fiber.
Inject 20 μg. On the other hand, an adhesive layer having the following composition (thickness: 80 μm) was formed on the surface of a polyethylene film on which aluminum was vapor-deposited on one side to obtain an adhesive base material. Compound Tengo 100 parts by weight Polyterpene resin (softening point 110°C) 100 parts by weight Polybutene (HV-300) 20 parts by weight Sulfur 2 parts by weight
cm), which is then bonded to the adhesive layer surface of the above-mentioned adhesive base material, heated and pressurized, and then heated and cut to obtain terminal-sealed flaky preparations of the present invention. Table 2 shows the test results for this flaky preparation.

[Table] Comparative Example 2 in Table 2 is obtained by mixing the adhesive formulation used in Example 2 with the penetration aid, solubilizer, and drug used in Example 2. Test method in Table 2 Pharmacological effect on rats: The hair on the back of rats was removed, and samples (2 cm x 3 cm square, total length of hollow fibers 12 cm) were attached for 3 hours, 12 hours, 24 hours, and 48 hours. Systolic blood pressure (mm-Hg) is measured after an hour by indirect blood pressure measurement (tail pulse wave method). On the other hand, oral clonidine was administered to rats (approximately 1/18 of the dose administered to humans).
0...Body weight ratio) to measure the change in blood pressure decrease over time. Judgment is made on the basis of whether there is a decrease in systolic blood pressure that is equal to or greater than oral drug administration, and whether there is no decrease in systolic blood pressure. Drug blood concentration: Remove the hair from the back of the dog, attach a sample (4 cm x 4 cm square, total length of hollow fiber 24 cm), collect 2 ml of plasma after 3, 24 and 48 hours, and check the pH. After adjustment, shake and extract with an organic solvent for 10 minutes, separate the solvent by centrifugation, dry, dissolve in methanol, and quantify by gas chromatography. Effective blood concentration is 1.0 mg/ml. Example 3 A hollow fiber (outer diameter 300μ,
Obtain an inner diameter of 260μ). Next, drug-containing hollow fiber A containing 30 mg of squalane, 30 mg of propylene glycol, and 50 mg of isosorbitol dinitrate and 50 mg of cyclohexyl methanol are placed in the hollow part of the hollow fiber.
and a penetration aid-containing hollow fiber B in which 50 mg of dimethyl sulfoxide was encapsulated. On the other hand, a soft polyvinyl chloride film (thickness: 70 μm) was prepared as a backing member, and an adhesive base material was obtained using the following formulation as an adhesive composition. Compounded styrene-isoprene-styrene block copolymer rubber 100 parts by weight Hydrogenated rosin (softening point 100°C) 90 parts by weight Polybutene (HV-300) 20 parts by weight Liquid paraffin 30 parts by weight Antioxidant 2 parts by weight Next, adhesive base The above hollow fiber A is placed on the adhesive layer surface of the material.
and B are arranged side by side alternately at 1 cm intervals and heated and pressurized to obtain the tape-shaped preparation of the present invention. Table 3 shows the test results for this tape-like preparation.

[Table] In Comparative Example 3 in Table 3, the penetration aid, solubilizer, and drug used in Example 3 were added to the adhesive formulation used in Example 3. Test method in Table 3 Drug blood concentration: Hair was removed from the back of a family member, a sample (4 cm x 4 cm square, total length of hollow fibers A and B 8 cm each) was pasted, and blood was collected at a specified time. Nitroglycerin and n-heptane are added as internal standards to 2 ml of plasma obtained by centrifugation and shaken. After shaking, transfer the n-heptane to a Spitz tube.
Evaporate the solvent with scrubbed inert gas. After adding n-hexane to the residue and shaking, the sample is detected using a gas chromatograph equipped with an electron capture detector. Setting conditions for gas chromatograph with electron capture detector Radiation source: 10 mCi of ⁶³ Ni Chiariel gas: Nitrogen gas 20 ml/mm (flow rate) Column temperature: 130°C Injection temperature: 165°C Tedector temperature: 180°C Column: Internal diameter 2.4 mm, 1.2 m long glass column (silane treated) Packing material: 3% silicon OV-101 (80-100 mesh) Example 4 The following was carried out using a 15% N・N'-dimethylformamide solution of polyvinyl chloride. A hollow fiber (outer diameter 600μ, inner diameter 300μ) is obtained by the same operation as in Example 1. 600 μg of a mixed penetration aid of N-hydroxyethyl lactamide:diethylacetamide=1:1 (weight ratio) is sealed per 1 cm into the hollow portion of the hollow fiber. On the other hand, isooctyl acrylate-acrylonitrile-acrylic acid = 70:28:2 ( A copolymer solution obtained by copolymerizing (weight ratio) in acetone using azobisisobutyronitrile and diazepam content are
A mixed solution with diazepam formulated at a concentration of 100μg/cm ² (thickness: 40μ) was
Apply to a thickness of 40μ and dry. Next, the above-mentioned hollow fibers containing the penetration aid are arranged side by side at 1 cm intervals on the surface of this adhesive layer, heated and pressurized, and cut into a predetermined size by heating, and the ends of the hollow fibers are sealed to obtain the tape-shaped preparation of the present invention. get. Table 4 shows the test results for this tape-like preparation.

[Table] In Comparative Example 4 in Table 4, the mixed penetration aid used in Example 4 was added to the mixed solution used in Example 4. Test method in Table 4 Animal pharmacology experiment: The effect when oral diazepam was administered (0.012 mg) to mice (20 g) was used as the standard. A tape-like preparation adjusted in size to give the same amount of drug was pasted on the back of a mouse, and a grip strength test (the muscle relaxing effect of diazepam was measured in an animal pharmacology test to reduce grip strength in mice) was carried out at predetermined intervals. Measure. The evaluation was 0 if the grip strength decreased more than the oral agent, and × if the decrease was less than that.

[Brief explanation of the drawing]

FIG. 1 is a partially enlarged sectional view showing an example of the present invention, and FIGS. 2 to 4 are partially enlarged sectional views showing other examples. 1...Backing member, 2...Adhesive layer, 3...Hollow fiber.

Claims (1)

[Scope of Claims] 1. A tape or strip preparation used to continuously and quantitatively administer a systemically and/or locally active drug from the outer skin or mucous membrane of the body, which preparation comprises: (a) a lining; (b) An adhesive layer formed on one surface of the member to adhere to the application surface; (c) The adhesive layer surface and/or or a hollow fiber disposed between the member and the outer surface of the layer, the hollow portion of which is filled with at least a drug or a penetration aid alone or with a mixed system, and whose peripheral wall is microporous; A tape or strip preparation comprising: