JPS5984814A - Pharmaceutical for prolonged release of chemical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, prepared by laminating a chemical stroage layer on a backing member, and further laminating a porous chemical-permeable resin layer containing pores filled with a solvent incapable of dissolving the chemical on the above-mentioned chemical storage layer in order, and capable of releasing the chemical at a controlled rate for a long term. CONSTITUTION:A pharmaceutical for prolonged release of a chemical consisting of a backing member 1 preferably consisting of a flexible chemical-impermeable sheet material, a chemical storage layer 2, laminated on the above-mentioned backing member 1, and consisting of the chemical contained in a chemical- permeable resin, e.g. a silicone resin or polymethacrylic acid ester, and a diffusion controlling layer 3, laminated on the above-mentioned chemical storage layer 2, and consisting of a porous chemical-permeable resin 4 containing pores 5 filled with a solvent, e.g. mineral oil or glycol, incapable of dissolving the chemical. The permeation of the chemical is prevented by the solvent dispersed in the chemical-permeable resin layer, and complicated continuous chemical passages are formed in the diffusion controlling layer 3.

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.

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 for a long period of time, and for this reason it is conventional to release the drug at a controlled rate. Various sustained release drugs have been proposed. Typically, as described in Japanese Patent Publication No. 54-16566, a backing member forming the outer surface, a pressure-sensitive adhesive layer forming the adhesive surface to the skin or mucous membrane, and these backing members and adhesive. It is a laminate consisting of a drug storage layer containing a drug between the layers. 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. diffuses through the adhesive layer and is released slowly from the surface at a controlled rate.
It 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 preparations, the sustained-release property of releasing the drug at a substantially constant rate over a long period of time is not fully satisfactory, and furthermore, the release rate varies depending on the type of drug. It is difficult to vary and control the release rate, and the release rate is often limited.

The present invention has been made to solve the above-mentioned problems, and the present invention is to release a drug at a substantially constant rate over a long period of time, thereby substantially 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 maintain a constant drug release rate, and that also allows the release rate of a drug to be controlled over a wide range.

The sustained-release preparation of the present invention comprises: (al) a lining member, (bl) a drug storage layer made of a drug-permeable resin containing a drug and laminated on the lining member; It is characterized by comprising a porous resin made of a drug-permeable resin filled with an insoluble solvent, and a drug diffusion control layer laminated on the drug storage 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 because many sustained-release preparations are applied on the skin or mucous membranes by adhesion. 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, etc., and aluminum. Examples include metal foils such as foils, and laminates of two or more thereof.

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 is made of a drug-permeable resin and a drug contained therein, and the manner in which the drug is contained 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 the resin layer. Furthermore, the drug may be dispersed in the resin layer as microcapsules.

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 membranes and exerts the desired pharmacological effect. Anginal drugs, anticonvulsants such as atropine and scopolamine, antibiotics such as penicillin, tetracycline, chlorotetracytaline, oxytetracycline, and sulfonamides, barbital, phenobarbital, bendoparbital, and α-bromoisovaleryl urea. , analgesic hypnotics such as Codin, anti-inflammatory analgesics such as indomethacin, mefenamic acid, diclofenac, alclofenac, phenylbutacin, tranquilizers such as chloropromacine, thioridazine, diacepam, reserpine, haloperidol, 3-(2- aminobutyl)
Psychoactive agents such as indole acetate, prednisolone, hydrocortisone, fluocinolone acetonide, triamcinolone acetonide, methyltestosterone, megesterol acetate, fluoximusterone, esterone, estradiol, ethinyl estradiol, 17α-hydroxyprogesterone acetate, 19
-Steroid hormones such as norprogesterone, methoxyprogesterone acetate, acetylsalicylic acid,
Contains antipyretics such as 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.

Further, the resin for constituting the drug storage layer is not particularly limited as long as it has drug permeability, but examples include silicone 41711 such as polydimethylsiloxane, polyhydroxylethyl (meth)acrylate, polymethyl Acrylates, poly(meth)acrylic esters such as polybutyl acrylate, polyacrylic acid, its salts, polyvinyl alcohol, polyvinyl acetate, polyethylene wax, polyethylene oxide, polyvinylpyrrolidone, hydroxyethylcellulose, carboxymethylcellulose, plasticized polychloride Synthetic or natural resins and rubbers such as vinyl, plasticized polyamide, polyurethane, polyisobutylene, styrene-butadiene rubber, ethylene-carbon oxide copolymer, collagen, gelatin, gum acacia, and gum tragacanth are preferably used.

Next, in the sustained release preparation of the present invention, a drug diffusion control layer 3 for controlling the release rate of the drug is laminated on the drug storage layer. This control layer consists of a drug-permeable porous resin layer 4 and a drug-insoluble solvent 6 contained in the pores 5 of the porous resin layer 4 .

As the drug-permeable resin forming the drug passage, the above-mentioned
Resins and intermediates constituting the drug storage layer are preferably used. In the sustained release preparation of the present invention, a drug-insoluble solvent is dispersed within such a drug-permeable resin layer to prevent drug permeation, and therefore the drug-permeable resin has a complex continuous drug path in the diffusion control layer. form.

The method for forming the porous resin layer is not particularly limited, but examples include adding a foaming agent such as azodicarbonamide to a drug-permeable resin and foaming it, as well as solvent substitution, stretching, Any conventionally known method such as extraction can be used. In order to fill the pores of such a porous resin layer with a solvent, for example, the porous resin may be impregnated with a solvent.

The solvent is appropriately selected depending on the type of drug, but examples include mineral oil, silicone oil, glycols such as diethylene glycol, propylene glycol, and polyethylene glycol, oils and fats such as olive oil, squalene, and lanolin, and dimethyldecyl Phosphoxide, methyl octyl sulfoxide, dimethyl laurylamide,
Polar organic solvents such as dodecylpyrrolidone, isosorbitol, dimethylacetamide, dimethylsulfoxide, dimethylbormamide, water, or a mixed solvent of two or more of these solvents are used.

In the sustained-release preparation of the present invention, a pressure-sensitive adhesive layer 7 is usually provided on the other surface of the above-mentioned backing member in order to apply the preparation to the skin or mucous membrane.

The adhesive is dermatologically and mucosologically acceptable and
Any adhesive can be used as long as it is permeable to the agent used, but specific examples include acrylic resin-based adhesives, silicone resin-based adhesives, and rubber-based adhesives such as natural rubber, polyurethane, polyisoprene, polyisobutylene, and polybutadiene. Adhesives, vinyl adhesives such as polyvinylpyrrolidone and polyvinyl acetate, and cellulose adhesives such as ethyl cellulose and methyl cellulose are used.

If necessary, a suitable release sheet 8 such as a resin film coated with silicone resin is pasted on the adhesive layer.

As described above, according to the sustained release preparation of the present invention, the drug contained in the drug-permeable resin layer diffuses from the storage layer and reaches the control layer, where the drug-permeable resin is formed. As the drug diffuses to the skin or mucous membrane-contacting surface through drug channels, it is released and absorbed into the body at a substantially constant and controlled rate, so that its blood concentration remains approximately constant. Here, the drug path is intricately convoluted in the control layer, and therefore the drug path has the same effect as increasing the thickness of the control layer.

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 High molecular weight polyisobutylene (viscosity average molecular weight 1.2 million)
32.3 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 35,000), 4'6.2 parts by weight, and 10 parts by weight of isosorbide nitrate were dissolved in chloroform to make a homogeneous solution, and this was placed on aluminum foil. Apply, dry, thickness approx.
A drug storage layer of 0 μm was formed.

Separately, 100 parts by weight of a 10% polyvinyl alcohol aqueous solution and 10 parts by weight of calcium carbonate were mixed, coated on an appropriate base material, dried to form a film, and heated at 100°C.
Biaxial stretching was carried out at a temperature of C to obtain a porous film with a porosity of 50% and a thickness of 100 .mu.m having pores with an average pore diameter of 62 .mu.m.

This porous film is impregnated with water, a room temperature curing polydimethylsiloxane elastomer is applied thinly to both sides, the above storage layer is attached to the lower side, an acrylic ester adhesive is applied to the other side, and then dried. Then, an adhesive layer having a thickness of about 50 μm was formed to obtain a sustained release preparation of the present invention.

This preparation was cut into a circle with a diameter of 5 and applied to the depilated back of a rabbit weighing 3.7 kg to measure the blood concentration of isosorbide nitrate. 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 100 μC ethyl acetate, and measured by ECD-gas chromatography.

Example 2 A sustained release preparation of the present invention was obtained in exactly the same manner as in Example 1, except that prednisolone was used as the drug.

It can be used as a sustained release formulation for the treatment of skin diseases.

[Brief explanation of the drawing]

The drawing shows a sectional view of essential parts of the sustained release preparation of the present invention. DESCRIPTION OF SYMBOLS 1... Lining member, 2... Drug storage layer, 3... Drug diffusion control layer, 4... Porous resin layer, 5... Holes,
6... Solvent, 7... Adhesive layer, 8... Release sheet. Patent applicant Mototoshi Fujinuma, representative of Sekisui Chemical Co., Ltd.

Claims (1)

[Claims] (1) (a) A lining member, a drug storage layer made of a drug-permeable resin containing a BL drug, and laminated on the lining member, and a drug-insoluble solvent in the C1 pores. 1. A drug sustained release preparation comprising a porous resin filled with drug-permeable resin, and a drug diffusion control layer laminated on the drug storage layer.