JPH0574569B2 - - Google Patents

Description

[Detailed Description of the Invention] <Industrial Application Field> 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. <Conventional technology> 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 and produced. When administered into the body, 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, it has been proposed to include a drug encapsulated in microcapsules in the preparation, or to provide a drug diffusion control layer. <Problems to be solved by the invention> However, although transdermal absorption enhancers exhibit excellent effects on rapid pharmacological effects, when incorporated into adhesives constituting skin patch preparations, There are many problems in developing formulations, such as decreased cohesive strength of the agent, adhesive residue on the applied skin surface, and decreased content due to volatilization.Furthermore, the pharmacological effect only lasts about 12 hours at most, making it a long-term drug. It could not be used as a long-lasting preparation. In addition, although sustained-release drug preparations 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, and are still not available. A formulation that is both fast-acting and long-lasting has not 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 surprisingly excellent pharmacological effects can be exhibited by laminating a porous membrane-like holding material on a portion 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 in that it is provided with a porous membrane-like holding 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 they may be added in an amount of 0.01 to 20% by weight in the adhesive.
The porous membrane contains the same kind of drug in a range of 1 to 1000 μg/cm ² . The adhesive containing the above-mentioned drug is not limited as long as it can be attached to the skin 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 skin adhesion are not limited. Acrylic pressure-sensitive adhesives are preferred from the viewpoint of properties and the like. Specifically, those listed in Japanese Patent Application Laid-Open No. 57-116011 can be used.
The thickness of the adhesive layer is appropriately selected in the range of 5 to 200 μm, taking into account 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 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 films with metal vapor deposited on the film surface), nonwoven fabrics, and woven A cloth, a foam film, or a laminated film or sheet of these materials 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 effects of the drug it contains, and is used to contain 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. It is desirable that the drug can have a permeation route and have high diffusion mobility. The material of the membrane-like retaining material is not particularly limited as long as it contains a transdermal absorption enhancer and a drug, and the porous membrane may be a sheet or film with a porous structure, such as synthetic fibers and/or natural fibers. Nonwoven fabric or paper (basis weight 10 to 300 g/m ² ), woven fabric, knitted fabric, felt, mat (pad), or open-cell foamed film or sheet are used.
These porous membranes contain drugs and transdermal absorption enhancers, which will be described later, either as they are, or after being dissolved in a suitable solvent, by rubbing them or impregnating them by immersion. Porous membrane materials include, for example, acetyl cellulose, ethylene-vinyl alcohol copolymer,
polyurethane, polyvinyl chloride, polyethylene,
Examples include polypropylene, polyacrylonitrile, hydrophilic acrylic polymer, polyvinyl alcohol, polyvinyl acetate, polyamide, polyimide, polytetrafluoroethylene, polysulfonated styrene, silicone rubber, and gelatin. Methods for manufacturing porous membranes using these materials include acetone, dimethylformamide,
It is dissolved in an organic solvent with good compatibility with water, such as dimethylacetamide or dimethyl sulfoxide, and then this solution is immersed in a non-solvent to remove the solvent.The obtained membrane is heat treated, and then There are methods such as drying at a temperature below the heat treatment temperature. Such a porous membrane of the present invention has through holes,
It preferably has a pore diameter of 10 μm or less, practically 0.01 to 5 μm, and a porosity of at least 30 μm.
% (volume ratio), a porous membrane of 70% or more is practically preferable, and a membrane holding material having a thickness of 5 to 2000 μm is preferable. The transdermal absorption enhancer that increases the transdermal absorption amount of the drug contained in the membranous retention material is a component that imparts quick-acting properties to the composite preparation of the present invention. It has a function of promoting swelling or softening, a function of improving wettability of the stratum corneum, a function of opening pores, etc., and these multiple functions can often be obtained from one substance. Examples of percutaneous absorption enhancers include dimethyl sulfoxide, dodecyl sulfoxide, methyl octyl sulfoxide, dimethyl decyl phosphooxide, mono- or diethylacetamide, N-hydroxyethyl lactamide, dimethylacetamide, N. N-dimethyldodecamide, dimethylformamide, toluic acid diethylamide, 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, lanolin acid, lanolin alcohol, higher fatty acid alcohol, salicylic acid, liquid paraffin, petrolatum, amino acids, protease,
Benzyl nicotinate, l-menthol, camphor, methyl salicylate, Salocol, lauryl soda sulfate, stearyl glycerin stearate,
These include, but are not limited to, higher fatty acid triglycerides, polyoxyalkylene glycols, fatty acid mono(or di)ethanolamides, ethylene glycol monoethyl ether, polyoxypropylene alkyl ethers, and higher alkyl sulfones. Two or more types are used in combination. These transdermal absorption enhancers are contained together with the drug in the membrane-like holding material, and the amount used can be arbitrarily determined depending on the type thereof. The composite preparation of the present invention obtained with the above-mentioned configuration can be applied to the membrane-like retaining material while leaving a sufficient adhesive surface on the adhesive surface of the drug-containing adhesive layer to maintain the skin adhesion ability of the adhesive surface. In some cases, a film-like retaining material is provided approximately in the center of the adhesive surface and the adhesive surface is exposed at the periphery, and in others, the film-like retaining material is placed on the adhesive surface in a band-like, lattice-like, etc. Or, in the opposite case, a film-like retaining material is provided so that the adhesive surface is exposed approximately in the center, or a film-like retaining material is provided so that the adhesive surface is exposed in a band-like, lattice-like, etc. shape. You can also The composite preparation of the present invention is attached to the skin surface by the exposed adhesive surface, but it does not bend sharply at the joint site, etc.
Needless to say, medical tape such as surgical tape may be used as an auxiliary means for fixing to the elongated region. <Effects of the Invention> As described above, after the composite preparation of the present invention is applied to the skin using a film-like retaining material containing a drug and a transdermal absorption enhancer, a large amount of the drug contained therein is absorbed by the 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 and movement within the layer, and to the film-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 layer This allows for sustained drug release 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 gravimetric initiator to reduce the solid content. An adhesive solution with a concentration of 25% was obtained. Add and mix 20 parts of isosorbide dinitrate to 100 parts of the solid content of the resulting adhesive solution, apply the mixture to one side of a 12 μm thick polyester film to a dry thickness of 50 μm, and dry to obtain the drug-containing solution. Obtained adhesive tape. On the other hand, 1 part of isosorbide dinitrate, 2 parts of isosorbide dimethyl ether, 0.1 part of dimethyl sulfoxide, and 1 part of polyethylene glycol (molecular weight 400) were added to a polypropylene porous membrane with a thickness of 50 μm (pore diameter 1 to 5 μm, porosity 50% V/V). The drug-containing adhesive tape was impregnated with a mixed solution and laminated on the central part of the drug-containing adhesive tape so as to cover 1/4 of the adhesive surface to obtain a composite preparation of the present invention. The content of isosorbide dinitrate in the porous membrane was adjusted to be four times that of the drug-containing adhesive tape per unit area. Example 2 100 parts of styrene-isoprene-styrene block copolymer, 80 parts of liquid paraffin, 80 parts of hydrogenated rosin
Clonidine was added to a composition consisting of 10 parts of polybutene (molecular weight 1260), mixed, and applied to the aluminum surface of a 25 μm thick aluminum-deposited polyethylene film to a thickness of 100 μm ^. A drug-containing adhesive tape was obtained. On the other hand, 0.5 part of clonidine, 1 part of diisopropyl adipate, 1 part of methylpyrrolidone, 1-dodecyl azacycloheptane 2-one was added to a 30 μm thick cellulose acetate porous membrane (pore diameter 1 μm or less, porosity 50% V/V). The composite preparation of the present invention was obtained by impregnating the drug-containing tape with a mixed solution of 1 part and laminating it in 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 only the drug-containing adhesive tape was used as the formulation. Comparative Example 1b and Comparative Example 2b Comparative Examples 1b and 2b correspond to Examples 1 and 2, in which only a porous membrane impregnated with a drug and a transdermal absorption enhancer was used as a preparation and fixed with surgical adhesive tape. It was used as Each preparation obtained in each example and comparative example was pasted on the chest of three volunteers, and
ml of blood was collected, the amount of drug contained was determined by gas chromatography, and the effective blood concentration (isosorbide dinitrate 2 ng/ml, clonidine 0.4 n) was determined.
g/ml) or higher and the time required to reach an effective blood concentration were measured. The results are shown in Table 1. 【table】

Claims (1)

[Claims] 1. On the adhesive surface of the drug-containing adhesive layer laminated on one side of the support, a porous material containing a transdermal absorption enhancer and a drug is left on the adhesive surface sufficient to maintain the skin adhesion ability of the adhesive surface. A composite preparation characterized by being provided with a membrane-like retaining material.