JPH046169B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to sustained release drug formulations that release pharmacologically active drugs at a controlled rate over an extended period of time. In order to achieve the desired therapeutic effect by administering a drug, it is desirable to maintain the drug at an effective concentration or higher in the diseased area or the circulatory system over a long period of time. Various sustained-release drugs have been proposed. Typically, as described in Japanese Patent Publication No. 54-16566,
It is a laminate consisting of a lining member forming the outer surface, a pressure-sensitive adhesive layer forming the adhesive surface to the skin or mucous membrane, and a drug storage layer containing a drug between the lining member and the adhesive layer. The storage layer consists of a resin layer that is permeable to the drug and controls its release rate, and a drug that is dispersed, for example, simply or as microcapsules, in such a resin layer, and the drug is released from the storage layer. It diffuses through the adhesive layer, is released slowly from the surface at a controlled rate, and is absorbed into the body through the skin or mucous membrane at the adhesive surface. In some cases, a control layer in which the diffusion rate of the drug is lower than that of the storage layer may be interposed between the storage layer and the adhesive layer. However, even in such sustained release formulations,
However, sustained release, in which the drug is released at a substantially constant rate over a long period of time, is not fully satisfactory, and furthermore, it is difficult to control the release rate by varying it depending on the type of drug. and release rates are often limited. Furthermore, when such sustained-release preparations are applied to the skin for a long period of time, the adhesive surface may develop a rash due to sweating or the like. The present invention has been made to solve the above-mentioned problems, and it releases a drug at a substantially constant rate over a long period of time, thereby reducing the blood concentration of the drug absorbed into the body from the application surface. It has excellent sustained release properties that keep it virtually constant, and the release rate of the drug can be controlled over a wide range.The surface that is attached to the skin is breathable, so it has sustained release properties that do not cause irritation. The purpose is to provide formulations. The sustained release preparation of the present invention comprises (a) a lining member, (b) a drug storage layer containing a drug and laminated on the lining member, and (c) a drug storage layer laminated on the drug storage layer. (d) a drug-permeable tube wall;
It is characterized by comprising a hollow fiber whose open end penetrates the drug impermeable layer and opens into the drug storage layer. The present invention will be described below with reference to the drawings showing embodiments. The backing member 1 may be either non-flexible or flexible, but is preferably flexible and drug-impermeable since many sustained-release preparations are applied adhesively onto the skin or mucous membranes. Preferred specific examples include resin sheets or films of cellulose acetate, ethyl cellulose, cellophane, polyethylene terephthalate, plasticized vinyl acetate-banal chloride copolymer, polyamide, polyethylene, polyvinylidene chloride, aluminum foil, etc. metal foils, and laminates of two or more of these metal foils. In the sustained-release preparation of the present invention, a drug storage layer 2 is laminated on one surface of this lining member 1 . This storage layer consists of a drug-permeable resin or a drug-soluble solvent and a drug contained therein. The manner in which the drug is contained in the drug-permeable resin is not particularly limited. For example, a resin and a drug may be melt-mixed and molded into a sheet, or a powder or liquid drug may be uniformly dispersed in a resin layer. Furthermore, the drug may be dispersed in the resin layer as microcapsules. When a drug is contained in a drug-soluble solvent, the drug usually forms a drug storage layer as a solution dissolved in the solvent. The drug used in the present invention is not particularly limited as long as it is absorbed into the body through the skin or mucous membrane and exerts the desired pharmacological effect. Cardiac drugs, anticonvulsants such as atropine and scopolamine, antibiotics such as penicillin, tetracycline, chlorotetracycline, oxytetracycline, and sulfonamides, barbital, phenobarbital, pentobarbital, α-bromoisovaleryl urea, and codeine. Analgesic hypnotics, anti-inflammatory analgesics such as indomethacin, mefenamic acid, diclofenac, alclofenac, phenylbutazone, chloropromazine, thioridazine,
Tranquilizers such as diacepam, reserpine, haloperidol, psychoactive agents such as 3-(2-aminobutyl)indole acetate, prednisolone,
Hydrocortisone, fluocinolone acetonide, triamcinolone acetonide, methyltestosterone, megesterol acetate, fluoximesterone, esterone, estradiol,
Contains steroid hormones such as ethinyl estradiol, 17α-hydroxyprogesterone acetate, 19-norprogesterone, and medroxyprogesterone acetate, and antipyretics such as acetylsalicylic acid, salicylamide, and sodium salicylate. In addition, when these drugs are difficult to absorb through the skin or mucous membranes, they may be made into a pharmaceutically acceptable solution or, if necessary, may be made into a pharmaceutically acceptable derivative. The resin for forming the drug storage layer is not particularly limited as long as it has drug permeability, but examples include silicone resins such as polydimethylsiloxane,
polyhydroxylethyl (meth)acrylate,
Poly(meth)acrylic esters, such as polymethyl acrylate, polybutyl acrylate, etc.
Polyacrylic acid, its salts, polyvinyl alcohol, polyvinyl acetate, polyethylene wax, polyethylene oxide, polyvinylpyrrolidone,
Synthetic or natural resins such as hydroxyethyl cellulose, carboxymethyl cellulose, plasticized polyvinyl chloride, plasticized polyamide, polyurethane, polyisobutylene, styrene-butadiene rubber, ethylene-carbon oxide copolymer, collagen, gelatin, gum acacia, gum tragacanth, etc. Rubber is preferably used. In addition, the solvent for forming the drug storage layer is appropriately selected in consideration of the type of drug and the release rate of the drug to be controlled, but examples include mineral oil, silicone oil, diethylene glycol, propylene glycol, polyethylene glycol, etc. Glycols such as glycol, oils and fats such as olive oil, squalene, and lanolin are preferably used. If necessary, these solvents may be mixed with the resin to contain a drug to form a drug storage layer. In the sustained release preparation of the present invention, a drug impermeable layer 3 is provided on this drug storage layer. In addition to the resin constituting the above-mentioned backing member, this drug-impermeable layer includes, for example, polypropylene, ethylene-
Preferably, sheets or films made of vinyl acetate copolymer, polyvinyl chloride, vinyl chloride-ethylene copolymer, polysulfone, polyphenylene oxide, polycarbonate, aromatic polyamide, polyacetal, polyfluoroethylene, etc.
If necessary, epoxy resin, melamine resin, etc. may also be used. In the sustained release preparation of the present invention, the hollow fibers 4 having a drug-permeable tube wall penetrate the drug-impermeable layer, open their open ends 5 into the drug storage layer, and open most of the hollow fibers. The main body portion 6 is exposed to the outside from the side opposite the drug storage layer with respect to the impermeable layer. Hollow fibers made of various polymers are already known and easily available. In the present invention, the hollow fibers are preferably woven or knitted in advance, structured integrally with the drug-impermeable layer, and then laminated onto the drug storage layer. A structure in which the open ends of the hollow fibers penetrate the drug-impermeable layer can be obtained by, for example, cutting the hollow fiber cloth into a predetermined shape, and then cutting the periphery of the hollow fiber cloth into a predetermined shape and then melting the periphery of the hollow fiber cloth in a solution or melting agent of the drug-impermeable resin. After immersing the woven fabric in the liquid while keeping the temperature higher than the liquid level, the solution or melt may be heated to evaporate the solvent, or cooled and solidified. However, it is not limited to these methods; for example, casting may also be used. In the present invention, the tube wall of the hollow fiber itself may allow the drug to diffuse through, or the drug-impermeable tube wall may have micropores that allow the drug to pass through. The material, wall thickness, diameter, etc. of the hollow fibers are appropriately selected depending on the type of drug used, the required diffusion rate, etc., but for example, the tube diameter is usually 50 to 1000 μm, and the tube wall has micropores. In this case, the appropriate pore diameter is 10 μm or less. Further, if necessary, the speed at which the drug diffuses within the hollow fibers can be adjusted by filling the hollow fiber tube with a solvent used for forming the drug storage layer. To apply the drug sustained release preparation of the present invention to the skin, etc., place the hollow fiber laminated side in contact with the skin, etc., and then fix the preparation to the skin surface using an appropriate fixing means, such as a medical bandage. This is done by As described above, according to the sustained release preparation of the present invention,
The drug contained in the drug-permeable resin layer diffuses through the storage layer, passes through the drug-impermeable layer inside the hollow fibers from the open end of the storage layer, and diffuses outside the hollow fibers. It diffuses from the vessel wall directly to the skin or mucous membrane contacting surface and is thus released at a substantially constant and controlled rate. In particular, according to the sustained-release preparation of the present invention, the release rate of various drugs can be adjusted to a required constant value by adjusting the material of the hollow fiber, the thickness of the tube wall, and the diameter of the micropores. In addition to being able to keep the blood concentration of drugs absorbed into the body almost constant. Unlike conventional sustained-release preparations, the breathable structure, such as a woven fabric made of hollow fibers, comes into contact with the skin, mucous membranes, etc.
Since the contact surface is breathable, skin irritation due to sweat or the like does not occur on the contact surface. The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples in any way. Example 1 Polyamide hollow fiber (inner diameter 300μ, tube wall thickness
100 μm, tube wall micropore diameter (average 30 Å), thickness 0.2 mm,
A woven fabric with an apparent porosity of 40% and a diameter of 10 cm.
Cut into a circular shape. In this woven fabric, the open ends of the hollow fibers at the periphery are held above the level of the solution of polyvinyl chloride in tetrahydrofuran, and the solvent is evaporated to form the polyvinyl chloride into a film. Thus, a structure consisting of a resin film and a hollow fiber having an open end on one side of a 0.2 mm thick film was formed. Next, this is mixed with polyethylene glycol (molecular weight
400) and then dried to impregnate polyethylene glycol into the hollow fibers. Separately, 10 parts by weight of 30% isosorbide nitrate lactose mixture, 1 part of polyethylene glycol (molecular weight 400)
parts by weight and 89 parts by weight of hydroxyethyl acrylate-ethyl acrylate (weight ratio 3/1) copolymer were dissolved in a methanol-acetone mixed solvent,
Make a homogeneous solution, apply this on aluminum foil, evaporate the solvent at a temperature of 50°C, and measure the thickness.
A 0.2 mm drug storage layer was formed. The sustained-release preparation of the present invention is prepared by laminating and adhering the above-mentioned structure made of hollow fibers and polyvinyl chloride film on the drug storage layer so that the open ends of the hollow fibers are buried in the drug storage layer. I got it. This preparation was applied to the depilated back of a rabbit weighing 3.7 kg, and the blood concentration of isosorbide nitrate was measured. The results are shown in the table. The method for measuring blood concentration is as follows. After applying the preparation as described above, 3 ml of blood was collected at predetermined intervals, plasma was separated, and extracted with 4 ml of hexane. Next, this was evaporated to dryness in an inert gas, dissolved in 100μ of ethyl acetate, and measured using ECD-gas chromatography.

[Table] Furthermore, even after long-term use of this preparation, no rash due to sweating was observed on the contact surface. Example 2 Polysulfone hollow fiber (inner diameter 300μ, tube wall thickness
A woven fabric with a thickness of 0.3 mm and an apparent porosity of 40% was made from a woven fabric having a thickness of 0.3 mm and an apparent porosity of 40%, and was cut into a circle with a diameter of 10 cm. The open ends of the hollow fibers at the periphery of this woven fabric are held so that they are positioned above the polyethylene molten bath, and the polyethylene is then immersed in the bath.Then, the polyethylene is cooled and solidified, and the hollow fibers are placed on one side of a 0.2 mm thick polyethylene film. The fibers formed a structure with open ends. Next, this was immersed in a 10% ethanol solution of polyethylene glycol and then dried to impregnate the hollow fibers with polyethylene glycol. Separately, 2 parts by weight of indomethacin was added to acrylic acid.
2-ethylhexyl/acrylic acid (weight ratio 96/
4) A solution prepared by dissolving 100 parts by weight of the copolymer in ethyl acetate is applied onto an aluminum foil, the solvent is evaporated, a drug storage layer is formed, and the hollow fiber structure described above is placed on top of the open end of the drug storage layer. The sustained-release preparation of the present invention was obtained by stacking the cells so that they were buried in the storage layer.

[Brief explanation of drawings]

The drawing shows a sectional view of essential parts of the sustained release preparation of the present invention. 1... Lining member, 2... Drug storage layer, 3...
Drug-impermeable layer, 4...Hollow fiber, 5...Hollow fiber open end.

Claims (1)

[Claims] 1 (a) a lining member; (b) a drug storage layer containing a drug and laminated on the lining member; (c) a drug-impermeable layer laminated on the drug storage layer; (d)
1. A drug sustained release preparation comprising a hollow fiber having a drug-permeable tube wall, the open end of which penetrates the drug-impermeable layer and opens into the drug storage layer.