JPS5984817A - Pharmaceutical for prolonged release of chemical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, having a backing member and at least two chemical storage layers laminated to reduce the chemical content from the layer adjacent to the backing member to the surface thereof, and capable of releasing the chemical at a constant rate for a long term. CONSTITUTION:A pharmaceutical for prolonged release of a chemical having a backing member 1 and at least two chemical storage layers 2 laminated to reduce the chemical content from the layer adjacent to the backing member 1 to surface thereof in order (e.g. the chemical content in a resin layer 21 containing the chemical is maximum, and the chemical content in the layer 23 on the surface side is minimum) on one surface of the above-mentioned backing member 1. A chemical-impermeable sheet, e.g. cellulose acetate, is used as the backing member 1, and a chemical-permeable material, e.g. a silicone resin, is used as the chemical storage layers 2 in the respective constituent parts. The pharmaceutical is capable of releasing the chemical at a constant rate for a long term, and the release rate of the chemical can be optionally controlled by adjusting the gradient of the chemical content.

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 RM 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 absorbed into 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 control the release rate through various changes, 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 maintains a constant drug release rate and has excellent sustained release properties, and further allows the release rate of a drug to be controlled over a wide range.

The sustained release preparation of the present invention includes a backing member and at least two layers laminated on one surface of the backing member such that the drug content decreases in order from the layer adjacent to the backing member toward the surface. It is characterized by comprising a drug storage layer.

FIG. 1 shows an example of the sustained release drug formulation of the present invention.

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, and aluminum foil. Examples include metal foils such as, 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 at least two drug-permeable resin layers containing different drug contents, and N21 adjacent to the lining member has the largest drug content, and the drug content decreases in order toward the surface side. It is layered like this.

For example, in the case of three layers as shown, the drug-permeable resin layer 23 on the front side has the smallest drug content, and the middle layer N22 has a drug content between the above 2N.

There are no particular restrictions on the manner in which the drug is contained in the drug-permeable resin. 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 membrane and exerts the desired pharmacological effect. Cardiac drugs, anticonvulsants such as atropine and scopolamine, antibiotics such as penicillin, tetracycline, chlorotetracycline, oxytetracycline, and sulfonamides, barbiturates, phenobarbital, bendoparbital, α-bromoisovaleryl urea, and codine. analgesic hypnotics 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, doriamcinolone 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.

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, polymethyl acrylate, and polybutyl acrylate. Poly(meth)acrylic esters, polyacrylic acid, its salts, polyvinyl alcohol, polyvinyl acetate, polyethylene wax, polyethylene oxide, polyvinylpyrrolidone, hydroxyethylcellulose, carboxymethylcellulose, etc.
Synthetic or natural resins and rubbers such as plasticized polyvinyl chloride, plasticized polyamide, polyurethane, polyisobutylene, styrene-butadiene rubber, ethylene-carbon oxide copolymer, collagen, gelatin, gum acacia, and 1-ragacanth rubber are preferably used. It will be done.

In order to determine the permeation rate of the drug in the drug storage layer,
The drug storage layer may be formed by containing a drug in a mixture of the above resin and an appropriate solvent.

The solvent is appropriately selected depending on the type of drug used and the release rate of the 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 are preferably used.

FIG. 2 shows another embodiment of the sustained release preparation of the present invention, in which, if necessary, a membrane 3 having a drug permeability different from that of the resin layer is provided between each drug permeable resin 121, 22 and 23. are stacked. This membrane is appropriately selected from the above-mentioned drug-permeable resins in consideration of drug permeability so that the drug diffusion rate between adjacent drug-containing resin layers can be controlled. Microporous membranes made of drug-impermeable resins can also be used for the above purpose. In addition to the resins constituting the lining member described above, examples of the drug-impermeable resin used to construct the microporous membrane include polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, and vinyl chloride-ethylene copolymer. Polymer, polysulfone, polyphenylene oxide, polycarbonate, aromatic polyamide, polyacetal, polyfluoroethylene, etc. are used.

The sustained release preparation of the present invention is usually provided with a pressure-sensitive adhesive layer 4 on the surface of the drug storage layer in order to apply the preparation 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, polyurecne, polyisoprene, polyisoprene, and polybutadiene, vinyl adhesives such as polyvinylpyrrolidone and polyvinyl acetate, and cellulose adhesives such as ethylcellulose and methylcellulose are used.

If necessary, a suitable release sheet 5 such as a resin film coated with a silicone resin is pasted on the adhesive layer.

As described above, according to the sustained release preparation of the present invention, 1. The drug diffuses through the resin layer to the surface in contact with the skin or mucous membrane, but in particular, the drug-containing resin layer is composed of multiple layers, and the lining is The drug content of the drug-containing resin layer has a gradient in the thickness direction so that the layer adjacent to the member has the largest drug content and the layer on the surface side has the smallest drug content, so the drug release rate can be maintained over a long period of time. Not only is it substantially constant, and the blood concentration in the body remains almost constant,
By adjusting the drug content gradient between each layer, the drug release rate can be arbitrarily controlled.

Furthermore, by interposing a drug-permeable membrane between each drug-containing resin layer, the consistency of the drug release rate can be further increased, and the release rate can also be adjusted.

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)
64.5 parts by weight and 92.3 parts by weight of low molecular weight polyisobutylene (viscosity average molecular weight 35,000) were uniformly mixed with 47 parts by weight of isopropyl myristate, and the mixture was divided into 100 parts by weight. Take 20 parts by weight, 30 parts by weight, and 40 parts by weight of a 30% by weight solution of isosorbide nitrate in chloroform, and add and mix these to each of the resin mixtures divided as above to form resin mixtures with different drug contents. Obtained.

Next, on the aluminum-coated polyethylene terephthalate film, first, a resin mixture with the highest drug content was applied and dried to form a drug storage layer with a thickness of about 50 μm,
Next, a resin mixture with an intermediate content and finally a resin mixture with the smallest drug content were sequentially applied and dried to a thickness of about 15 cm.
A 0μ drug reservoir layer was formed. An adhesive was applied thereon and dried to obtain a sustained release preparation of the present invention.

This preparation was cut into a circular shape with a diameter of 4 mm and was applied to the depilated back of a rabbit weighing 3.8 mm 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 μl of ethyl acetate, and measured using ECD-gas chromatography.

Example 2 In Example 1, a porous polypropylene film (manufactured by Polyplastics ■) was laminated between each drug storage layer to obtain a sustained release preparation of the present invention. This can likewise be used as a sustained release formulation for the treatment of skin diseases.

[Brief explanation of the drawing]

FIG. 1 is a sectional view showing an example of a sustained release preparation of the present invention;
FIG. 2 is a sectional view showing another embodiment. 1... Lining member, 2... Drug storage layer, 21.22
．． 23... Drug-containing resin layer, 3... Drug-permeable membrane formation,
4... Adhesive layer, 5... Release sheet. Patent applicant Mototoshi Fujinuma, representative of Sekisui Chemical Co., Ltd.

Claims (1)

[Claims] (1) Consists of a backing member and at least two drug storage layers laminated on one surface of the backing member such that the drug content decreases in order from the layer adjacent to the backing member toward the surface. A sustained release formulation characterized by: