JPS5984815A - Pharmaceutical for prolonged release of chemical - Google Patents

Abstract

PURPOSE:The titled pharmaceutical, having a chemical storage layer laminated on a backing member and a chemical-impermeable layer laminated on the above-mentioned chemical storage layer in order and further hollow fibers having opened parts, passing through the above-mentioned chemical-impermeable layer, and opened to the chemical storage layer, and capable of releasing the chemical at a controlled rate for a long term. CONSTITUTION:A pharmaceutical for prolonged release of a chemical prepared by laminating a chemical storage layer 2 consisting of a chemical-permeable resin, e.g. a silicone resin or polyvinyl alcohol (PVA), on a backing member 1 consisting of preferably a flexible chemical-impermeable sheet material, laminating a chemical-impermeable layer 3 on the above-mentioned chemical storage layer 2 in order, and placing hollow fibers 4, having chemical-permeable tube walls so that opened ends 5 thereof may be passed through the chemical-impermeable layer 3 and opened to the interior of the chemical storage layer 2 and the body parts 6 may be exposed from the opposite side of the chemical storage layer 2 to the outside with respect to the chemical-impermeable layer 3. Hollow fibers having 50-1,000mum tube diameter and individual chemical- impermeable tube walls or micropores having preferably <=10mum pore diameter in the impermeable tube walls are used as the above-mentioned hollow fibers 4.

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. 54-46566, 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. The rate of release is often limited because it is difficult to vary and control the rate. Furthermore,
When such sustained-release preparations are applied to the skin for a long period of time, the surface to which they are applied may develop a rash due to memos, etc.

The present invention has been devised to solve the problem mentioned above, and is to release a drug at a substantially constant rate over a long period of time so that it is absorbed into the body from the surface to which it is applied. It has a sustained release property that keeps the blood concentration of the drug at a substantially constant level, and also allows the release rate of the drug to be controlled over a wide range, and the surface to which it is attached to skin debris is breathable. Therefore, the purpose of the present invention is to provide a sustained release preparation that does not cause rash.

The sustained release preparation of the present invention has (δ) lining 7i1 (shrine) and (
b) A drug storage layer containing a drug and layered on top of the above-mentioned lining 591-7j; The device is characterized in that it has a front wall, and an opening f+1M thereof is made of a hollow fiber that penetrates the drug impermeable layer and opens into the drug storage layer.

The present invention will be described below based on drawings showing examples.

The eave part 41 may be non-flexible or flexible, but since many sustained release preparations are applied by adhering to the skin or mucous membranes, it is preferable to A flexible, drug-impermeable sheet!
As an example, l! '(Il: iu i silulose, niebour cell + -se, sei 1 han, borie chisi, ntelephthalate 1-3 plasticizing spring Y acid fur salt 1 hibinyl combination polyamide, polyethylene, polyvinyl chloride
Examples include resin sheets such as LEAN) or FILNO 1, metal foils such as aluminum foil, and laminates of two or more of these.

In the sustained release preparation of the present invention, 4J, this backing part]
A table of ``111 on drug 11'i'ir1 tile Jet 2
There are 171 layers.

This storage layer consists of a drug-permeable resin or a tit 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. Alternatively, it may be in liquid form and uniformly dispersed in the resin layer. Additionally, the drug may be dispersed in the resin layer as Microphone 1:i capsules. If the drug is contained in a drug-soluble solvent,
Typically, the drug is dissolved in a solvent to form the drug reservoir.

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.・1
Anti-anginal agents such as coglycerin and isosorbic acid nitrate, anti-KJ1 agents such as atrophin and scopolamine, penicillin,
Antibiotics such as detradi-iclin, chlorotetracycline, oxytetracycline, sulvonamide, etc.
Analgesic f1 old II (agents such as parvicur, phenoharbital, pentohalchtal, α-dibu 1:1 moisovaleryl urea:l din, indomezacin, mefenamic acid,
Anti-inflammatory analgesics such as diclozenac, alclofenac, fuconinil), tranquilizers such as Ipromacin, thioridazine, diasebam, reserpine, heroperidol, 3-(2-aminobutyl)
Mental energizers such as indole acetate, hydrocortisone, fluocinolone acetate, triamcinolone, methyltestosterone 1:1, megesuwo L:l-acetate, Flureo Go 1-Jimste LJ, Esteninone, Nis 1 Sidiol, Ethinyl Estradiol, J7α-Hi 11,1
Xyprogesteone acetate 1, L9-norprogesterone, Nodoshi Jxyp11-1 gesteone 1: Stereoco-() hormones such as acetate, acetyl lythyl acid, lythyl amide, xyridyl scattering. Contains anti-PJH agents such as 1lium.If these drugs are difficult to absorb through skin or mucus, they may be made into a pharmaceutically acceptable solution, and if necessary, pharmaceutically acceptable solutions may be used. may be a legally acceptable derivative.

The resin for forming the drug storage layer is not particularly limited as long as it has drug permeability;
Poly(vine) acrylic esters, polyacrylic acid, etc. Salt, 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 Synthetic or natural resins and rubbers such as , collagen, gelatin, gum acacia, and gum tragacanth are 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. still,
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. This drug-impermeable layer includes, in addition to the above-mentioned "resin" that constitutes the backing member, for example,
Polypropylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, vinyl chloride-ethylene copolymer, polysulfone, polyphenylene oxide, polycarbonate,
Sheets or films made of aromatic polyamide, polyacetal, polyfluoroethylene, etc. are preferred, but if necessary, epoxy resins, melamine resins, etc. may also be used.

In the sustained release preparation of the present invention, hollow fibers 4 having drug-permeable tube walls penetrate the drug-impermeable layer, and the open ends 5
is opened into the drug storage layer, and the main body portion 6, which occupies most of the hollow fibers, is exposed to the outside from the side opposite to 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 a hollow fiber woven fabric into a predetermined shape, and then cutting the periphery with the open ends into a drug-impermeable resin solution. Alternatively, the woven fabric may be immersed in the molten liquid while keeping the temperature higher than the liquid level, and then the solution or molten liquid may be heated to evaporate the solvent, or may be cooled and solidified. However, it is not limited to these methods; for example, casting may also be used.

In the present invention, the hollow fiber may have a tube wall itself that allows the drug to diffuse through it, or a drug-impermeable tube wall that has micropores that allow the drug to pass through. Hollow fiber material, wall thickness,
The diameter etc. 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 100 mm.
0 μm, and if the tube wall has micropores, the appropriate pore diameter is 10 tt m or less.

Furthermore, if necessary, the speed at which the drug diffuses within the hollow fibers can be adjusted by filling the hollow fiber tubes described in section 2 with a solvent used to form the drug storage layer.

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 and enters the hollow fibers from the open end opening into the storage layer. diffuses outward across the drug-impermeable layer and from the tube wall of the hollow fiber directly to the surface in contact with the skin or mucous membrane, thereby being 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. It is possible to maintain the blood concentration of drugs absorbed into the body at a nearly constant level, and in addition, because the breathable structure such as woven fabric made of hollow fibers comes into contact with the skin, mucous membranes, etc., conventional Unlike sustained-release preparations, the contact surface is breathable, so skin irritation due to the contact surface does not occur.

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 100μ)
A woven fabric having a thickness of 0.2 mm and an apparent porosity of 40% was cut into a circular shape with a diameter of IQc+n. 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 into a film. In this way, a structure consisting of a resin film and a hollow fiber having an open end on one side of a 0.2 inch thick film was formed.

Next, add this to polyethylene glycol (molecular weight 400)
The hollow fibers were immersed in an ethanol solution and dried to impregnate polyethylene glycol into the hollow fibers.

Separately, 10 parts by weight of 30% isosorbide nitrate lactose mixture, 1 part by weight of polyethylene glycol (molecular weight 400), and 89 parts by weight of hydroxyethyl acrylate-ethyl acrylate (weight ratio 3/1) copolymer were dissolved in a methanol-acetone mixed solvent. This was applied to an aluminum foil to form a homogeneous solution, and the solvent was evaporated and dried at a temperature of 50° C. to form a drug storage layer with a thickness of 0.2 mm.

A structure made of the hollow fibers and polyvinyl chloride film described above is laminated and bonded on top of the drug storage layer so that the open ends of the hollow fibers are buried in the drug storage layer. A formulation was obtained.

Take this formulation to your body! The blood concentration of isosorbide nitrate was measured by applying it to the depilated back of a 3.7 kg rabbit.

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 μρ of ethyl acetate, and measured by ECD-gas chromatography.

Furthermore, even after long-term use of this preparation, no rash caused by sweat was observed on the contact surface.

Example 2 Polysulfone hollow fiber (inner diameter 300μ, □tube wall thickness 10
0 μ, tube wall micropore diameter (average 100), thickness 0.3 x m
A woven fabric with an apparent porosity of 40% was cut into a circle with a diameter of 10. The open ends of the hollow fibers at the periphery of this woven fabric are held so as to be positioned above the polyethylene molten bath and immersed in the bath, and then the polyethylene is cooled and solidified to a thickness of Q.
The hollow fibers formed a structure with open ends on one side of a 2 mm polyethylene film.

Next, this was immersed in a 10% ethanol solution of polyethylene glycol and then dried to impregnate polyethylene glycol into the hollow fibers.

Separately, 2 parts by weight of indomethacin was added to 1 part of 2-ethylhexyl acrylate/acrylic acid (96/4 weight ratio) copolymer.
A solution prepared by dissolving 00 parts by weight in ethyl acetate is applied onto an aluminum foil, the solvent is evaporated and dried to form a drug storage layer, and the above-described hollow fiber structure is placed on top of the drug storage layer so that the open end thereof forms a storage layer. The sustained-release preparation of the present invention was obtained by stacking the tablets so that they were buried in each other.

[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 impermeable layer, 4... Hollow fiber, 5... Hollow fiber open end. Patent applicant: Mototoshi Fujinuma, representative of Kayakami Chemical Industry Co., Ltd.

Claims (1)

[Claims] (11(a) a lining member; (b) a drug storage layer containing a drug and laminated on the lining member; (C1) 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.