JPS6216414A - Complex pharmaceutical - Google Patents

Abstract

PURPOSE:A complex pharmaceutical, obtained by laminating a filmy holding material containing a percutaneous absorption promoter and drug on an adhesive surface of an adhesive layer containing a drug on a support leaving a sufficient area to obtain the skin adhesion function of the adhesive surface and having both rapid acting and long acting properties. CONSTITUTION:A complex pharmaceutical obtained by laminating a filmy holding material containing a percutaneous absorption promoter and a drug on an adhesive surface of an adhesive layer containing a drug and laminated on one surface of a support leaving a sufficient area to keep the skin adhesion function of the adhesive surface. After application to the skin, a large amount of the drug is released by the promoter, and the rapid acting property can be expected. Since the adhesive layer containing the drug closely adheres and fixes the complex pharmaceutcal on the skin surface, supplies the drug from the exposed adhesive surface to the skin by the diffusion and migration of the contained drug to the skin and filmy holding material. Thereby, the long acting property can be expected. The filmy holding material is preferably a porous film, and preferably laminated on the central part of the adhesive surface to leave the adhesive surface on the peripheral part thereof.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention relates to a complex preparation for treating or preventing diseases by administering a drug into a living body through the skin surface. This drug has both immediate efficacy due to increased efficiencies and sustained pharmacological effects due to sustained release administration.

<Prior art> In general, the stratum corneum that forms the outer skin of the body has an excellent barrier ability against foreign substances entering the body, and drugs can be absorbed transdermally. When administered in vivo, reduction or loss of such barrier ability is considered to be an important issue.

In order to achieve the above objective, various proposals have been made to combine transdermal absorption enhancers such as dimethyl sulfoxide, methylpyrrolidone, and dimethylalkylamide. It shows.

On the other hand, for sustained release, proposals have been made in which the drug is contained in microcapsules and a drug diffusion control layer is provided.

<Problems to be Solved by the Invention> However, although transdermal absorption enhancers are effective in improving the fast-acting pharmacological effects, when incorporated into adhesives constituting skin patch preparations, There are many problems in developing formulations, such as decreased cohesive force of the agent, adhesive residue on the applied skin, and decreased content due to volatilization.Furthermore, the pharmacological effect only lasts for about 12 hours at most, making it a long-term drug. It was not possible to create a long-lasting drug.

In addition, although sustained-release drug sequences are suitable for the purpose of preventing seizures or for long-term treatment, they cannot be used for applications that expect rapid efficacy due to the initial release of a large amount of drug. A formulation that is both fast-acting and long-lasting has not yet been developed.

<Means for Solving the Problems> In view of the above-mentioned prior art, the present inventors investigated a formulation that can sufficiently exhibit the immediate effect and sustainability of the drug it contains, and found that it contains a transdermal absorption enhancer and a drug. The present inventors have discovered that unexpectedly excellent pharmacological effects can be exhibited by laminating a film-like retaining material prepared on a part of the adhesive surface of a drug-containing adhesive layer, leading to the present invention.

That is, in the present invention, the transdermal absorption enhancer and the drug are applied to the adhesive surface of the drug-containing adhesive layer laminated on one side of the support, leaving enough adhesive surface to maintain the skin adhesion ability of the adhesive surface. An object of the present invention is to provide a composite preparation characterized by being provided with a membrane-like retaining material containing the present invention.

The drug used in the present invention may be any drug that enters the body through transdermal absorption through the skin and exerts a pharmacological effect, and can be appropriately selected depending on the type of disease to be treated. Specifically, the drugs listed in JP-A-58-185515 can be used, and the adhesive contains 0. L11
~20% by weight, and for porous membranes 1~20% by weight.
The same kind of drug is contained in the range of 1000, at/-. ~ The adhesive containing the above-mentioned drug is not limited as long as it can be attached to the skin 1# surface and the drug contained therein can be supplied to the skin surface and into the porous membrane by diffusion transfer, and the stability of the drug and the skin Acrylic pressure-sensitive adhesives are preferred from the viewpoint of adhesive properties. Specifically, those listed in JP-A-57-116011 can be used, and the thickness of the adhesive layer is appropriately selected in the range of 5 to 200 bm, taking into consideration the type and content of the drug contained.

The support supporting the drug-containing adhesive layer is preferably one that can follow the movement of the applied skin surface when the composite preparation of the present invention is adhered and applied to the skin surface, and is capable of peeling off and removing the preparation from the skin surface. A material that does not cause breakage of the support (base material destruction) or peeling of the adhesive layer from the interface (anchor failure) is selected.

Specifically, films made of cellophane, cellulose acetate, polyester, soft vinyl chloride, polyethylene, polypropylene, polyamide, polyvinylidene chloride, polyurethane, polyacrylic, etc. (including those with metal deposited on the film surface), nonwoven fabrics, Woven fabric, foam film, or a laminated film or sheet-like product of these, 1
．． A material designed to have appropriate moisture permeability to the extent that it does not cause irritation or whitening of the skin is used.

- The membrane-like retention material used in the present invention is used to bring out the immediate effectiveness of the drug it contains, and contains the drug and a transdermal absorption enhancer.

The above-mentioned membrane-like retention material can be swollen by a transdermal absorption enhancer and contained in the retention material itself together with the drug, but it is preferably contained in the pores of a porous membrane having micropores in a filled state. However, it is desirable that a permeation route for the drug can be secured and that the diffusion mobility is also large.

The material of the membrane-like retaining material is not particularly limited as long as it contains a transdermal absorption enhancer and a drug. non-woven fabric or paper (basis weight 10-30
09/d), woven fabric, knitted fabric, felt, mat (pad), or open-cell foamed film or sheet. These porous membranes are impregnated with drugs and transdermal absorption enhancers, which will be described later, either as they are or after being dissolved in a suitable solvent and then impregnated by rubbing or by dipping.

Porous membrane materials include, for example, acetyl cellulose,
Ethylene-vinyl alcohol co-X compound, polyurethane,
Examples include polyvinyl chloride, polyethylene, polypropylene, polyacrylonitrile, hydrophilic acrylic polymer, polyvinyl alcohol, polyvinyl acetate, polyamide, polyimide, polytetrafluoroethylene, polysulfonated styrene, silicone rubber, and gelatin. The method for manufacturing porous membranes using these materials is to dissolve them in organic solvents with good compatibility with water, such as acetone, dimethylformamide, dimethylacetamide, and dimethyl sulfoxide, and then dissolve this solution in a non-solvent. There are methods such as removing the solvent by immersing the film in water, heat treating the obtained film, and drying it at a temperature below the heat treatment temperature.

Such a porous membrane of the present invention has through holes of M, preferably 10 μm or less, practically Q, Q1 to 5 holes, and a porosity of at least 30% (volume ratio). ), a porous membrane of 70% or more is suitable for practical use, and a membrane holding material having a thickness of 5 to 2000 PrrL is preferable.

The transdermal absorption enhancer that increases the transdermal absorption value of the drug contained in the above-mentioned membrane-like retention material is a component that imparts quick-acting properties to the composite preparation of the present invention, and is a component that increases the water retention function of the stratum corneum. It has a function of promoting swelling or softening, a function of improving wettability of the stratum corneum, a function of opening hanging holes, etc., and these multiple functions are often obtained from one substance.

Examples of transdermal absorption enhancers include dimethyl sulfoxide, dodecyl sulfoxide, methyl octyl sulfoxide, dimethyl decyl phosphooxide, mono- or diethylacetamide, N-hydroxyethyl lactamide,
Dimethylacetamide: N,N-dimethyldodecamide,
Dimethylformamide, diethyl toluate, tetrahydrofurfuryl alcohol, tetrahydrofuran, sorbitol, dodecylpyrrolidone, methylpyrrolidone, urea, glycerin, diethyl adipate, squalene, squalane, acetylated lanolin, cetyl lactate, olive oil, castor oil, dioctyl sebacate, Ethoxylated stearyl alcohol, lanolic acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, liquid paraffin, petrolatum, amino acids, protease, benzyl nicotinate,! - menthol, camphor, methyl salicylate, salocol, lauryl soda sulfate, stearylglycerin stearate, higher fatty acid triglycerides, polyoxyalkylene glycol, fatty acid mono(or di)ethanolamide, ethylene glycol monoethyl ether, holoxypropylene alkyl ether,
Examples include high F & alkyl sulfones, but are not limited thereto, and two or more types may be mixed and used as necessary.

These transdermal absorption enhancers are contained together with the drug in the membrane-like holding material, and the amount used can be arbitrarily set depending on the type.

The composite preparation of the present invention obtained by the above configuration is as follows:
The film-like retaining material is provided on the adhesive surface of the drug-containing adhesive layer, leaving a sufficient adhesive surface to maintain the skin adhesion ability of the adhesive surface. one with the adhesive surface exposed at the periphery, one with a film-like retaining material in the shape of a band or grid on the adhesive surface, or the opposite of these, with the adhesive surface exposed on the periphery, or vice versa. It is also possible to provide a film-like holding material so that the adhesive surface is exposed, or to provide a film-like holding material so that the adhesive surface is exposed in a band-like, lattice-like, etc. shape.

In addition, after the film-like retaining material is provided on the adhesive surface of the drug-containing adhesive layer to form the composite preparation of the present invention, the transdermal absorption enhancer contained therein migrates into the adhesive layer during storage before use. If this occurs and the adhesive becomes plasticized, a non-migration barrier film such as a plastic film may be interposed therebetween.

The composite preparation of the present invention is attached to the skin surface using the exposed adhesive surface, but when fixing it to areas that are subject to severe bending or stretching, such as joints, it may be fixed with medical tape such as surgical tape as an auxiliary means. Needless to say, it's good.

<Effects of the Invention> As described above, the composite preparation of the present invention releases a large amount of the drug contained therein by the promoter after being applied to the skin using a film-like retaining material containing a drug and a transdermal absorption enhancer. , it can be expected to have a fast-acting pharmacological effect. In addition, the drug-containing adhesive layer is used to closely fix the composite preparation of the present invention to the skin surface, and to supply the drug contained to the skin surface from the exposed adhesive surface by diffusion movement within the layer and to the membrane-like holding material. It is expected to provide a long-lasting pharmacological effect. The closer the saturated solubility of the drug contained in the membrane retention material and the adhesive layer is, the better its release properties are.When the drug is absorbed into the skin surface and the drug content in the membrane retention material decreases, the adhesive The drug is supplied from the layer, and the drug can be continuously released from the membrane-like holding material.

Furthermore, in the composite preparation of the present invention, if a film-like retaining material is provided approximately in the center of the adhesive surface and the adhesive surface is left in the peripheral area, the content may decrease due to volatilization of the transdermal absorption enhancer, or there may be a large amount of liquid in general. Contamination due to adhesion of the accelerator to clothing does not occur.

<Example> Examples of the present invention will be shown below and specifically explained. In addition, parts and % in the text indicate parts by weight and weight %.

Example 1 A monomer mixture consisting of 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid was solution-polymerized in ethyl acetate by a conventional method using benzoyl peroxide as a polymerization initiator to reduce the solid content concentration. A 25% adhesive solution was obtained.

20 parts of insorbide dinitrate was added and mixed to 100 parts of the solid content of the obtained adhesive solution, and a thickness of 12 μm was obtained.
One side of the polyester film has a dry thickness of 50 mm.
A drug-containing adhesive tape was obtained by coating and drying to obtain a PWL.

On the other hand, a polypropylene polypropylene membrane with a thickness of 50 μm (pore size l
~5PWL, porosity 50% V/V)ic, 1 part of isonrubidodinitrate, 2 parts of isosorbide dimethyl ether, 0.1 part of dimethyl sulfoxide, and 1 part of polyethylene glycol (molecular weight 400) was impregnated, A composite preparation of the present invention was obtained by laminating the drug-containing adhesive tape in the center so as to cover 1/4 of the adhesive surface. The content of insorbide dinitrate in the porous membrane is
It was prepared so that the area per unit area was four times that of the drug-containing adhesive tape.

Example 2 Styrene-isoprene-styrene block copolymer 10
0 parts of liquid paraffin, 80 parts of hydrogenated rosin, and 10 parts of polybutene (molecular weight 1260), clonidine was added and mixed, and 100 parts of the mixture was applied to the aluminum surface of a 25 m thick aluminum-deposited polyethylene film.
) Apply it to a thickness of Lm, and apply it to a thickness of 2.
A drug-containing adhesive tape of 5 meP/cJ was obtained.

On the other hand, 0.5 parts of clonidine, 1 part of diisopropyl adipate, 1 part of methylpyrrolidone, l-dodecyl Azacyclohebutane 2-
The composite preparation of the present invention was obtained by impregnating the tape with a mixture of 1 part of the drug-containing tape and laminating it on the center of the drug-containing tape so as to cover 1/4 of the adhesive surface. The content of clonidine in the porous membrane was adjusted to be four times that of the drug-containing adhesive tape per unit area.

Comparative Example 1a and Comparative Example 2a Comparative Examples 1a and 2a correspond to Examples 1 and 2, and
Comparative Example 1b and Comparative Example 2b Using only drug-containing adhesive tape as a formulation Comparative Examples 1b and 2b correspond to Examples 1 and 2,
A porous membrane impregnated with the drug and transdermal absorption enhancer was used as a preparation, fixed with surgical adhesive tape.

Each preparation obtained in each Example and Comparative Example was pasted on the chests of three volunteers, blood was collected at regular intervals, and the amount of drug contained was determined by gas chromatography, and the effective blood concentration ( Insorbide dinitrate 2 nf
/mI/, clonidine 0.4 nP/rnJ) or more and the time to reach the effective blood concentration were measured. The results are shown in Table 1.

Claims (1)

[Scope of Claims] 1) A transdermal absorption enhancer is added to the adhesive surface of the drug-containing adhesive layer laminated on one side of the support, leaving sufficient adhesive surface to maintain the skin adhesion ability of the adhesive surface. and a membrane-like holding material containing a drug. 2) The composite preparation according to claim 1, wherein the membrane-like holding material is a porous membrane.