JPS632413B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a pharmaceutical preparation that has appropriate air permeability and excellent skin adhesion, and a method for producing the preparation. Pharmaceutical preparations comprising a backing member and a drug-containing pressure-sensitive adhesive layer formed on the surface of the backing member are known. One of the drawbacks of this formulation is that it is not breathable and therefore cannot prevent irritation due to skin whitening that occurs after applying the formulation to the skin. Another drawback is that red rashes may occur on the skin around the preparation because the properties of the preparation and the skin are different. To solve the former drawback, for example, adding a foaming agent to the drug-containing pressure-sensitive adhesive before application, stirring at high speed to entrap air bubbles, or adding a substance that can be extracted after application. There is a method of obtaining a breathable pharmaceutical preparation by coating or extracting the same on the surface of a breathable material, but pressure-sensitive adhesives may The bubbles formed in the adhesive layer due to flow deformation are crushed and disappear, making it impossible to obtain sufficient air permeability during use. In addition, as a method to solve the latter drawback, there is a method to improve the flexibility of the adhesive layer and increase its thickness, but it is said that the adhesive erodes over time and that adhesive remains on the skin application surface. There's a problem. The present invention provides a novel pharmaceutical formulation that solves these problems of air permeability and skin irritation. The pressure adhesive layer is composed of an elastic porous body and a drug-containing crosslinked pressure-sensitive adhesive film covering the matrix surface forming the pores of the porous body. According to the present invention, the drug-containing pressure-sensitive adhesive film is held in the pore matrix and is cross-linked, so that the countless minute pores surrounded by the adhesive film will collapse even over time. Therefore, it is possible to obtain a pharmaceutical preparation that has air permeability for a long period of time. Examples of the breathable member, elastic porous material, pressure-sensitive adhesive, and drug used in carrying out the present invention include the following. a: Breathable member, such as a porous plastic film or sheet, nonwoven fabric, paper, cloth, foam film or sheet, etc. b: Elastic porous material, such as an open cell foam sheet with a thickness of 0.1 to 3 mm, thick nonwoven fabric, etc. , c: Pressure-sensitive adhesives, such as polyacrylic esters, polyvinyl alkyl ethers, polyurethanes, polyesters, polyamides, synthetic resins such as ethylene-vinyl acetate copolymers, and/or styrene-isoprene-styrene block copolymer rubber, Mainly made of rubbers such as styrene-butadiene rubber, polybutene rubber, polyisobutylene rubber, butyl rubber, silicone rubber, and natural rubber, and are crosslinked with crosslinking agents such as polyisocyanate compounds, epoxy compounds, melamine compounds, and peroxides. Adhesive substances with pressure-sensitive adhesives. d: Drugs such as the following a. Corticosteroids: such as hydrocortisone, prednisolone, paramethasone,
Beclomethasone propionate, flumethasone, betamethasone, beclomethasone propionate, dexamethasone, triamcinolone, triamcinolone acetonide, fluocinolone, fluocinolone acetonide, fluocinolone acetonide acetate, clobetasol propionate, etc. (b) Analgesic anti-inflammatory agents: e.g. acetaminophen ,
mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, oxyphenbutazone, phenylbutazone, ibuprofen, flurbuprofen,
Salicylic acid, l-menthol, camphor and their combinations, etc. (c) Hypnosedatives: e.g. phenobarbital,
Barbitals such as amobarbital and cyclobarbital, (d) Tranquilizers: e.g. fluphenazine, thioridazine, benzodiazepines (e.g. diazepam, lorazepam, flunitrazepam), chlorpromazine, etc. (e) Antihypertensive agents: e.g. clonidine, kallikrein, etc. (f) Antihypertensive diuretics: For example, hydrothiazide, bendroflumethiazide, etc. G. Antibiotics: For example, β-lactam antibiotics (penicillins, cephalosporins), oxytetracycline, fradiomycin sulfate, erythromycin, chloramphenicol, etc. Anesthetics: For example, lidocaine. , benzocaine, ethyl aminobenzoate, etc. Antibacterial substances: such as nitrofurazone, nystatin, acetosulfamine, clotrimazole, etc. Antifungal substances: such as pentamycin, amphotericin B, pyrrolnitrine, clotrimazole, etc. Vitamins: e.g. vitamin A, ergocalciferol, cholecalciferol, octothiamine, riboflavin butyrate, etc. E Antiepileptic drugs: e.g. nitrazepam, meprobamate, etc. W Coronary vasodilators: e.g. nitroglycerin,
Antihistamines: such as diphenhydramine hydrochloride, chlorpheniramine, diphenylimidazole, etc. These drugs may be administered as needed. Two or more types can be used together. The pharmaceutical formulation of the present invention can be produced, for example, by the method described below. One method is to impregnate an elastic porous material with a mixture of a pressure-sensitive adhesive composition containing a crosslinking agent and a drug, prepared by a conventional method, and press it to form pores on the inner wall surface of the matrix. In this method, a drug-containing pressure-sensitive adhesive film is formed on the surface, and then a breathable member is attached to one surface. Another method is to apply a pressure-sensitive adhesive composition containing a cross-linking agent prepared by a conventional method into an elastic porous body using appropriate means such as impregnating, spraying, or laminating the composition in a controlled amount. A pressure-sensitive adhesive film is formed on the inner wall surface of the matrix that holds objects and dries to form pores, and then a drug-containing solution is supplied by means such as impregnation, spraying, or bonding to adhere the drug. This is a method in which the agent is adsorbed onto the matrix constituting the agent film and the elastic porous body, and then a breathable member is attached to one surface. According to the latter method, the crosslinking agent added at the stage of obtaining the pressure-sensitive adhesive composition is used up in the crosslinking reaction during the drying stage, so even drugs that are easily degraded or altered by the crosslinking agent will not have any adverse effects. This method has the advantage that it can be formulated without any damage, and even drugs that are easily degraded or altered by heat can be formulated. The pressure-sensitive adhesive composition held in the elastic porous body is one that is substantially fixed to the inner wall surface of the matrix forming the pores without completely filling the pores of the porous body. Therefore, it will be understood that the pore size and density of the elastic porous body and the viscosity of the pressure-sensitive adhesive composition are appropriately selected. In the pharmaceutical formulation configured in this way, a drug-containing crosslinked pressure-sensitive adhesive film is formed on the inner wall surface of the matrix that forms the pores of the elastic porous body, and
A countless number of fine pores are formed in the peripheral wall of the membrane, and the membrane has air permeability. In the pharmaceutical preparation of the present invention, a drug-containing crosslinked pressure-sensitive adhesive film is firmly formed on the matrix surface forming the pores made of an elastic porous body to form ventilation holes, so that the flow deformation of the pressure-sensitive adhesive is prevented. As a result, the pores are not crushed, and breathability is maintained for a long period of time. In addition, the drug-containing pressure-sensitive adhesive layer is held by an elastic porous material and is cross-linked, so even if the thickness is increased to retain a large amount of drug, the adhesive may ooze out or remain on the skin surface. Furthermore, since the porous material has elasticity, it has excellent conformability to the skin and has the advantage of causing less irritation to the skin. Examples of the present invention will be shown below. The text middle part means the weight part. Example 1 On one side of a polyester urethane open-cell foam sheet (expansion ratio 30 times) with a thickness of 1 mm,
A 30 μm polyethylene film was thermocompressed and laminated, and this was inserted through a heat protrusion roll to perforate the polyethylene film. On the other hand, 0.5 parts (based on 100 parts of solid content) of triglycidyl isocyanurate as a crosslinking agent is added to an acrylic pressure-sensitive adhesive liquid obtained by emulsion polymerization of 96 parts of 2-ethylhexyl acrylate and 4 parts of acrylic acid. The surface of the foam was impregnated with a solid content of 210 g/m ² and heated at 120°C.
It was dried for 10 minutes and further stored at 50°C for 24 hours to age (crosslink) the pressure sensitive adhesive. Next, an alcoholic solution of indomethacin is coated on the surface of the foam using a coater so that the solid content is 400 μg/cm ² , and indomethacin is adsorbed onto the adhesive film and the foam structure (matrix). Obtain a pharmaceutical formulation. Example 2 On one side of a 1.5 mm thick soft polyvinyl chloride open cell foam sheet (expansion ratio 15 times),
A 150 μm nylon nonwoven fabric was attached. Separately, a mixture consisting of 60 parts of 2-ethylhexyl acrylate, 40 parts of vinyl acetate, and 1 part of hydroxyethyl acrylate was polymerized in ethyl acetate by a conventional method, and 1 part of a polyisocyanate compound was added thereto to give a solid content of 20 parts. % acrylic pressure sensitive adhesive solution is obtained. Pour this solution onto the mold release liner to a solids content of 100%.
g/ ^m2 , overlap the foam side of the above bonded product on this coated surface, press lightly to impregnate the adhesive solution into the foam, dry at 100℃ for 10 minutes, and then The pressure sensitive adhesive was stored at 50°C for 24 hours to age (crosslink). Next, an alcohol solution of diclofenac sodium salt was applied to the foam surface at a solid content of 350μg/
A pharmaceutical formulation of the present invention was obtained by spray coating to a thickness of cm ² and adsorption onto an adhesive film and a foam tissue (matrix). Example 3 One side of a 1 mm thick ethylene-vinyl acetate copolymer open-cell foam sheet (expansion ratio: 10 times) was heat-treated to form a breathable skin layer. On the other hand, high molecular weight polyvinylethyl ether; low molecular weight liquid polyvinylethyl ether: glycerol ester of hydrogenated rosin = 4:1:1 (weight ratio)
The mixture was dissolved in toluene to make a polyvinylethyl ether pressure-sensitive adhesive solution containing 20% by weight of toluene, and 1 part of iodine as a crosslinking agent (based on 100 parts of solid content) was added to this to release the mold. Coat on the liner at a solid content of 150 g/m ² . The non-skin layer side of the foam was placed on top of the applied surface and lightly pressed to impregnate the solution into the foam, and heated at 100°C.
Let dry for 10 minutes to crosslink. An alcoholic solution of isosorbite dinitrate is impregnated onto the surface of the foam using a coater to give a solid content of 500 μg/cm ² , and is adsorbed onto the adhesive film and the foam structure (matrix). Obtain the formulation. Example 4 On one side of a polyether urethane open-cell foam sheet (expansion ratio 20 times) with a thickness of 1 mm,
A 20 μm polyvinylidene chloride film was attached, and this was passed through a hot protrusion roll to perforate the film. On the other hand, sodium polyacrylate (average degree of polymerization
10000), 250 parts of glycerin, and 3 parts of glycerin diglycidyl ether (solid content: 40% by weight) was added to the surface of the foam with a solid content of 250 parts.
Spray coating and impregnating it so that it is g/m ² ,
The formulation is gelled (crosslinked) by drying at 120° C. for 5 minutes. Next, an alcoholic solution of flufenamic acid is applied to the surface of the foam using a coater to impregnate it to a solid content of 450 μg/cm ² , and the pharmaceutical preparation of the present invention is adsorbed onto the adhesive film and the foam tissue (matrix). obtain. The test results of Examples 1 to 4 are shown in Table 1.

[Table] Comparative examples in Table 1 are as follows. 1a: Apply the adhesive solution of Example 1 to a polyethylene film with a thickness of 100 μm so that the thickness after drying is 50 μm, dry it, and add an alcohol solution of indomethacin to this so that the solid content is 400 μg/cm ² It is coated and adsorbed onto the adhesive layer, and then passed through a thermal protrusion roll to uniformly perforate the entire surface. 2a: Lay the nylon nonwoven fabric of Example 2 on the adhesive solution surface of the release liner and dry it, and apply an alcoholic solution of diclofenac sodium salt to the adhesive surface so that the solid content is 350 μg/cm ² Spray coated and adsorbed to the adhesive layer. 3a: Lay a 100 μm thick ethylene-vinyl acetate copolymer film on the adhesive solution surface of the release liner, dry it, and apply an alcohol solution of isosorbite dinitrate to the adhesive surface with solid content.
It was applied to a concentration of 500 μg/cm ² and adsorbed to the adhesive layer, and then passed through a hot protrusion roll to uniformly perforate the entire surface. 4a: Spray coat the aqueous solution of Example 4 on a polyvinylidene chloride film with a thickness of 80 μm, dry it, and apply an alcoholic solution of flufenamic acid to the adhesive surface to give a solid content of 450 μg/cm ² for adhesion. The material is adsorbed onto the agent layer and passed through a thermal protrusion roll to uniformly perforate the entire surface. 1b, 2b, 3b, and 4b each correspond to Examples 1 to 4, and no crosslinking agent is added to the pressure-sensitive adhesive composition. The test methods in Table 1 are as follows. Air permeability: The sample was stored at 40°C for 2 months, and the air permeability was measured when the air permeability at the initial stage of production was set as 100. Glue extrusion: Store the sample at 40℃ for 2 months,
This was determined visually. Irritation: The test was applied to 10 panelists for 48 hours, judged using the following criteria, and evaluated by averaging. 5: No texture, no discomfort 4: No texture, a little discomfort 3: No texture, a lot of discomfort 2: Texture on the terminal part 1: Texture on almost the entire surface Adhesiveness: Sample Adhesive strength when pasted on Bakelite plate and peeled off at 180 degrees (pulling speed 300mm/
min, condition 20°C x 60% RH). Adhesion to skin: The sample was pasted on the inside of the upper arm, and it was determined whether it could be maintained for 24 hours.

Claims (1)

[Claims] 1 Consisting of a breathable member and a breathable drug-containing pressure-sensitive adhesive layer formed on the surface of the member, the layer includes a drug-containing material that covers an elastic porous body and a matrix surface that forms the pores of the porous body. A pharmaceutical preparation comprising a crosslinked pressure-sensitive adhesive film.