JPH0332526B2 - - 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. 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 is an object of the present invention to provide a sustained release preparation that has excellent sustained release properties that are maintained substantially constant, and furthermore allows the release rate of a drug to be controlled over a wide range. The sustained release preparation of the present invention comprises a lining member, a porous layer laminated on the lining member, a drug-containing powder obtained by impregnating and absorbing a drug into a carrier powder and dispersing it in the porous layer. The porous layer is characterized by comprising a drug-soluble solvent filled into the pores of the porous layer. The present invention will be described below based on drawings showing examples. 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-vinyl 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 porous layer 2 is laminated on one surface of this backing member 1,
A drug-containing powder 3 obtained by impregnating and absorbing a drug into a powder carrier is uniformly dispersed in this porous layer. The drug used in the present invention is not particularly limited as long as it is absorbed into the body through the skin and mucous membranes and exerts the desired drug effect. Cardiac drugs, anticonvulsants such as atropine and scopolamine, antibiotics such as penicillin, tetracycline, chlorotetracycline, oxytetracycline, and sulfonamides, barbital, phenobarbital, pentobarbital, α-bromoisovaleryl urea, codeine, etc. sedative hypnotic,
Anti-inflammatory agents such as indomethacin, mefuenamic 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. In the present invention, a drug is impregnated and absorbed into a powder carrier, and is uniformly dispersed in a drug-permeable porous layer. As the carrier powder, resin powder having a diameter of several tens of micrometers is usually preferably used. The drug is
It can be impregnated and absorbed into a carrier as it is, or by mixing it with a carrier powder as an appropriate solution or dispersion if necessary. The porous layer is preferably made of a drug-permeable resin, such as a silicone resin such as polydimethylsiloxane, a poly(meth)acrylic resin such as polyhydroxyethyl (meth)acrylate, polymethyl acrylate, polybutyl acrylate, etc. Acid esters, polyacrylic acid, its salts, polyvinyl alcohol, polyvinyl acetate, polyethylene wax, polyethylene oxide, polyvinylpyrrolidone, hydroxyethyl cellulose,
Carboxymethyl cellulose, plasticized polyvinyl chloride, plasticized polyamide, polyurethane, polyisobutylene, styrene-butadiene rubber, ethylene-carbon oxide copolymer, collagen, gelatin,
Synthetic or natural trees and rubbers such as gum acacia and gum tragacanth are preferably used. In the sustained release preparation of the present invention, the pores 4 of the porous layer are filled with a drug-soluble solvent 5. This solvent is appropriately selected from solvents that do not dissolve the porous layer and those that dissolve the drug, but generally, in addition to mineral oil and silicone oil, glycols such as diethylene glycol, propylene glycol, and polyethylene glycol,
Oils and fats such as olive oil, squalene, and lanolin,
Polar organic solvents such as dimethyldecyl phosphooxide, methyl octyl sulfoxide, dimethyl laurylamide, dodecyl pyrrolidone, isosorbitol, dimethyl acetamide, dimethyl sulfoxide, dimethyl formamide, water, or a mixed solvent of two or more of these are used. . By selecting this solvent, it is possible not only to make the release rate of the drug in the sustained release preparation substantially constant, but also to control it to a desired rate depending on the drug. The sustained release preparation of the present invention is usually provided with a pressure-sensitive adhesive layer 6 on the surface of the porous layer for adhesive application to the skin or mucous membrane. This adhesive may be any adhesive as long as it is dermatologically and mucosologically acceptable and is permeable to the drug used, but specific examples include acrylic resin adhesives, silicone resin adhesives, and other adhesives. , rubber adhesives such as natural rubber, polyurethane, polyisoprene, polyisobutylene, and polybutadiene, vinyl adhesives such as polyvinylpyrrolidone and polyvinyl acetate, and cellulose adhesives such as ethylcellulose and methylcellulose. If necessary, a release sheet 7 made of a resin film coated with silicone resin, paper, or the like is adhered to the surface of the adhesive layer. An example of the method for producing the sustained release preparation of the present invention will be given below. For example, a resin powder with a diameter of several tens of micrometers is adsorbed and impregnated with a drug, and this is uniformly mixed with a drug-permeable resin and a foaming agent such as azodicarbonamide, azobisisobutyronitrile, or sulfonyl hydrazide, and then a sheet is formed. The resin powder containing the drug is uniformly dispersed within the porous layer by molding and foaming. Next, this porous layer is impregnated with a solvent to fill the pores with the solvent, and then a backing member is laminated on one side of the porous layer, and a pressure-sensitive adhesive layer is laminated on the other side. Note that the porous layer in which the resin powder containing the drug is dispersed is not limited to the method using the above-mentioned foaming agent, but can be made by conventionally known methods of making the resin layer porous, such as so-called solvent substitution, stretching, and extraction. Any method can be adopted as appropriate. As described above, according to the sustained release preparation of the present invention,
The drug impregnated and absorbed into the resin powder diffuses to the surface in contact with the skin or mucous membrane through a drug-permeable porous layer and a passageway formed continuously or discontinuously within this layer. is released at a substantially constant and controlled rate so that its blood concentration remains approximately constant. In addition, when the porous layer has pores that are continuous in the thickness direction, depending on the type and thickness of the resin layer forming the porous layer, its porosity, and the type of solvent filled in the pores, The rate of drug release can be selected and controlled within a wide range. Example 1 100 g of 2-hydroxyethyl methacrylate and 0.2 g of ethylene glycol dimethacrylate were mixed in 100 g of water at 70°C under a nitrogen stream using 0.2 g of t-butyl peroxide as a polymerization initiator.
After polymerization for a period of time, the resulting polymer was separated, dried, and ground into a powder of approximately 25 μm. 10 g of this resin powder was mixed with an acetone solution containing 1 g of isosorbide nitrate and impregnated until the resin had absorbed the above drug to saturation, then 50 g of dimethyl silicone rubber and 5 g of azodicarbonamide blowing agent were added.
g was added thereto, mixed uniformly, formed into a sheet, and then heated and foamed to obtain a porous layer. After this porous layer was impregnated with diethylene glycol, it was laminated on the surface of aluminum foil to a thickness of 200 μm, and on top of this porous layer, 50 parts by weight of 2-ethylhexyl methacrylate, 50 parts by weight of butyl acrylate, and 1,6- 20% by weight copolymer consisting of 0.02 parts by weight of hexanediol dimethacrylate
Apply a solution of ethyl acetate and dry to a thickness of approx.
A 50 μm adhesive layer was formed. Cut this preparation into a circle with a diameter of 3 cm and weigh 3.7 cm.
The blood concentration of isosorbide nitrate was measured by pasting it on the depilated back of a rabbit weighing 1 kg. The results are shown in the table. The unit of blood concentration is ng/ml. 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,
It was dissolved in 100 μl of ethyl acetate and measured using ECD-gas chromatography. Example 2 10 g of resin layer powder impregnated with isosorbide nitrate in the same manner as in Example 1 was uniformly mixed with 100 g of a 10% by weight aqueous polyvinyl alcohol solution and 10 g of calcium carbonate, coated on an appropriate base material, dried, and After forming into a film, this film was biaxially stretched at a temperature of 100° C. to obtain a porous layer having pores with an average pore diameter of 62 μm, a porosity of 50%, and a thickness of 200 μm. This porous layer was impregnated with polyethylene glycol in the same manner as in Example 1, and a room-temperature curable silicone resin adhesive was applied to both surfaces, and then aluminum foil was adhered to one side, and the sustained-release preparation of the present invention was applied. Obtained. This preparation was also cut into circles with a diameter of 5 cm, and in the same manner as in Example 1, its sustained release properties were measured from the rabbit blood concentration. The results are shown in the table.

[Table] From the above, it is understood that the sustained release preparation of the present invention has excellent sustained drug release properties and maintains the blood concentration of the drug constant over a long period of time.

[Brief explanation of drawings]

The drawing shows a sectional view of essential parts of the sustained release preparation of the present invention. DESCRIPTION OF SYMBOLS 1... Backing member, 2... Porous layer, 3... Drug-containing powder, 4... Holes, 5... Solvent, 6... Adhesive layer, 7...
Peeling sheet.

Claims (1)

[Claims] 1. A backing member, a porous layer laminated on the backing member, and a drug-containing powder obtained by impregnating and absorbing a drug into a carrier powder and dispersing it in the porous layer;
A sustained drug release preparation comprising a drug-soluble solvent filled into the pores of the porous layer.