JPS6124366B2 - - Google Patents

Description

[Detailed description of the invention]

This invention is primarily intended to treat inflammation such as plaque psoriasis, chronic eczema, atopic dermatitis, palmoplantar pustulosis, and hives. The present invention relates to a member for external use, and more specifically, to provide a member for external use that has a high drug utilization rate and adheres well to the skin surface. BACKGROUND ART Externally used members are known in which a drug having percutaneous absorption is blended with a polymer having pressure-sensitive adhesive properties at room temperature, and the polymer is formed on a carrier. However, the amount of drug compounded in the member is
In general, drugs are absorbed transdermally, in excess of the amount that exerts their pharmacological effects. This is because some of the drug is incorporated into the polymer. Therefore, the drugs used are limited to those that can produce pharmacological effects with a small amount (effective blood concentration of 10 ng/ml). This invention provides an external member containing a drug that can obtain pharmacological effects with such a small amount of drug,
This was done for the purpose of providing a member with a high effective utilization rate of drugs. The purpose is to form a flexible carrier layer, a flexible intermediate layer made of a substance with low drug dissolution ability, an acrylic polymer material that has pressure-sensitive adhesive properties at room temperature and high drug dissolution ability, and a drug dissolution layer. This was achieved by laminating in this order a drug-containing pressure-sensitive adhesive layer whose essential components are a substance with low potency and a drug with an effective blood concentration of 10 ng/ml or less. According to the external member of the present invention, although the concentration of drug contained per unit volume is low, it supplies a sufficient amount of drug to exert a pharmacological effect, so it has the advantage of high drug utilization efficiency and the intermediate layer This has the advantage that the adhesion area between the application surface and the polymer layer is increased by the intervention of the polymer layer. The material forming the flexible carrier layer used in the present invention forms one surface of the external member according to the present invention, that is, the surface opposite to the application surface, and also supports the member. . Therefore, the material used as the carrier can be a flexible and extensible plastic film or sheet such as polyolefin, polyurethane, polyamide, etc., and can also be a porous body or foamed film made of these plastics. can.
Other materials such as paper, cloth, and nonwoven fabrics can also be used. It is preferable to form cuts, holes, etc. in a material having a structure lacking air permeability, such as the plastic film or sheet, to impart air permeability. The use of a material that is inherently breathable or has been made breathable effectively prevents skin irritation, itching, etc. that may occur when the external member of the present invention is applied for a long period of time. do. The intermediate layer interposed between the carrier layer and the polymer layer (pressure-sensitive adhesive layer) has the function of increasing the adhesion area between the application surface and the polymer layer, and the function of increasing the adhesion area between the application surface and the polymer layer, and the ability of the drug blended in the polymer layer to It has the function of preventing migration into the body layers. The intermediate layer that exhibits this function is composed of a flexible substance with low drug-dissolving ability (solubility index value of 10 or less). The selection of the substance is made in relation to the drug used in the external member of the present invention, and preferably the substance has a solubility index difference of 0.5 or more with the drug. Materials that can be used include polyvinyl alkyl ether, styrene-isoprene (or butadiene)-styrene copolymer, natural rubber, polyvinyl acetate, ethylene copolymer such as ethylene-vinyl acetate copolymer, or polysiloxane. If necessary, a resin having a low molecular weight or a low glass transition temperature, a softening substance, etc. may be added to these materials. The drug-containing pressure-sensitive adhesive layer has pressure-sensitive adhesive properties at room temperature and is composed of an acrylic polymer substance with a high drug-dissolving ability, a substance with a low drug-dissolving ability, and a drug as essential components. Here, the substance with low drug-dissolving ability contributes to reducing the amount of drug in the pressure-sensitive adhesive layer. That is, the drug is blended within the saturation solubility range of the aforementioned acrylic polymeric substance, but at this time, a substance with low drug solubility is blended into the drug-containing pressure-sensitive adhesive layer that is mainly composed of the polymeric substance. Particularly, since the drug is not dissolved in this substance, the drug content per unit volume of the drug-containing pressure-sensitive adhesive layer is lower than when it is formed from the polymeric substance alone. In other words, when a substance with low drug solubility is mixed with a substance with high drug solubility, the system is brought to a saturated dissolution state with a small amount of drug compared to when the high drug solubility is used alone. By using a pressure-sensitive adhesive layer with such a structure, the amount of drug released is the same as when the drug is blended to a saturation solubility in a substance with high drug solubility (acrylic polymer material), resulting in a unit volume of Although the drug content per drug is small, a sufficient amount of drug can be obtained to obtain a pharmacological effect. Although it is not clear why the same amount of drug release can be obtained by blending a substance with low drug solubility with an acrylic polymer substance with high drug solubility, the addition of the substance with low drug solubility can improve the matrix of acrylic polymer substances. It is thought that this is because the drug becomes looser, improving the diffusion and mobility of the drug, or because the state of distribution between the water-containing layer on the skin surface and the pressure-sensitive adhesive layer becomes easier to reach equilibrium. Examples of substances with low drug solubility that exhibit such functions include polyvinyl alkyl ether, but styrene-isoprene (or butadiene)-styrene copolymer rubber can also be used. These substances with low drug solubility are preferably contained in a drug-containing pressure-sensitive adhesive layer made of an acrylic polymer material in an amount of 10 to 60% by weight, practically 20 to 50% by weight.
It can be blended within the following range. Examples of acrylic polymer substances that have pressure-sensitive adhesive properties at room temperature and high drug solubility that are used in carrying out this invention include methyl (meth)acrylate;
Ethyl (meth)acrylate, butyl (meth)acrylate, 2-ethylhexyl (meth)acrylate,
C number is 4 like isooctyl (meth)acrylate
~10 (meth)acrylic esters, and functional groups copolymerizable with the esters, such as carboxyl groups,
Examples include copolymers with polymerizable monomers having hydroxyl groups, amino groups, amide groups, epoxy groups, etc., and if necessary, 1-vinyl-2-pyrrolidone, 1-vinyl-5-methyl-2 -pyrrolidone,
Vinylpyrrolidones such as 1-vinyl-4-methyl-2-pyrrolidone, or those containing other monomers such as vinyl propionate and vinyl acetate can also be used. The combination of the drug-containing pressure-sensitive adhesive layer and the intermediate layer is
In addition to satisfying the various conditions mentioned above, for example, a substance having the same or similar polarity to the acrylic polymer material constituting the pressure-sensitive adhesive layer and the substance with low drug solubility constituting the intermediate layer may be added to one or both of them. It is also possible to create a combination in which the anchoring properties (adhesion properties) of both layers are improved by containing an appropriate amount. The pressure-sensitive adhesive layer contains the following substances that are transdermally absorbable and have an effective blood concentration of 10 ng/ml or less, but if necessary, the drug in the pressure-sensitive adhesive layer can be transferred to the applied body surface. This may occur due to the application of auxiliary agents or drugs that have the function of assisting in the absorption of drugs through the skin or by, for example, swelling (or softening) the keratinous surface of the skin, which is the application surface, to facilitate transdermal absorption of the drug. An appropriate amount of antibiotics such as fradiomycin sulfate, gentamicin sulfate, oxytetracycline hydrochloride, etc. to prevent infectious diseases such as folliculitis can be added. Examples of drugs that can be used include steroid anti-inflammatory drugs such as petamethasone valerate, dipropion, and beclomethasone, hypertension drugs such as clonidine and reserpine, and heart disease drugs such as isosorbite dinitrate and nitroglycerin. The content of these drugs in the pressure sensitive adhesive layer depends on the percutaneous absorption and effective therapeutic concentration of the drug, but generally ranges from 0.01 to 20% by weight. The auxiliary agents mentioned above include alcohols such as ethyl alcohol, isopropyl alcohol, 1,4-butanediol, 1,3-butanediol, propylene glycol, and glycerin, propyl stearate, ethyl laurate, diisopropyl adibate, and ethyl seba. C ate, butyl sebacate, dibutyl diglycol adivate, etc.
Esters consisting of a class 3 to 22 alkyl carboxylic acid and a C class 1 to 8 alkyl alcohol, cellosolves such as ethyl cellosolve and hexyl cellosolve, polyoxyethylene alkyl ethers such as polyoxyethylene (15) stearyl ether, Examples include polyoxyethylene alkyl esters such as polyoxyethylene lauryl ester, block copolymers of polyoxyethylene and polyoxypropylene, alkylamides, alkyl sulfoxides, alkyl phosphines, and the like. In addition, the pressure-sensitive adhesive layer may also contain a drug stabilizer such as butylated hydroxyanisole, butylated hydroxytoluene, disodium ethylenediaminetetraacetate, thioglycerol, tocopherol, and the like. The pressure-sensitive adhesive layer of the external member, which is composed of the carrier layer, the intermediate layer, and the drug-containing pressure-sensitive adhesive layer, may include a material that substantially inhibits drug migration or a composite material having the material on one surface. A removable member made of a base material and similar articles thereof are temporarily attached. Note that such materials include films such as polyester and polyolefin. The external member of the present invention is used to treat local diseased areas or diseased areas distant from the application site, and although the member contains a small amount of drug, it can deliver sufficient pharmacological effects to the skin. Serve on the surface. Examples of this invention will be shown below. The text middle part means the weight part. Example 1 On the surface of a 50 μm thick polyurethane film,
40 parts of polyvinyl isobutyl ether with a K value (value of 1% tetrahydrofuran solution at 20°C) of 20 to 28 and polyvinyl isobutyl with a K value (value of 0.5% isooctane solution at 20°C) of 123 to 127. Intermediate layer consisting of a mixture with 60 parts of ether (thickness 30μ
form m). The solubility index value of the layer is 7.7. On the other hand, a copolymer (20% solution) is obtained by polymerizing 65 parts of 2-ethylhexyl acrylate and 35 parts of vinyl acetate in ethyl acetate using 0.2 parts of azobisisobutyronitrile as a polymerization initiator. Next, 20 parts of polyvinyl isobutyl ether (K value 123 to 127), 1 part of betamethasone valerate (solubility index value 8.7) and 0.2 part of butylhydroxyanisole were added and mixed to 80 parts (solid content) of the polymer.
It is coated on the intermediate layer surface of the polyurethane film at a solid content of 5 g/m ² and dried to obtain the external member of the present invention. The distribution coefficient between the intermediate layer and the pressure-sensitive adhesive layer is 14, and the drug content per unit area is 5μ.
g/ ^cm2 . Example 2 The polyvinyl isobutyl ether mixture of Example 1 is formed into a layer (30 μm thick) on a polyurethane film (50 μm thick). Separately, 95 parts of 2-ethylhexyl acrylate and 5 parts of acrylic acid were added to 0.2 parts of benzoperoxide as a polymerization initiator to obtain a copolymer (20% solution) in which 95 parts of 2-ethylhexyl acrylate were polymerized in ethyl acetate. Next, 20 parts of polyvinyl isobutyl ether (K value 123 to 127) and 1 part of clonidine (solubility index value 8.4) were added to 80 parts (solid content) of the copolymer and mixed well. 5g/mold
^Coat and dry to obtain a material for external use. The distribution coefficient between the intermediate layer and the pressure-sensitive adhesive layer was 13, and the drug content per unit area was 5 μg/cm ² . Example 3 In Example 2, an external member was obtained by replacing clonidine with diisosorbite dinitrate and adding 5 parts. The drug content at this time was 25 μg/cm ² per unit area. Comparative Example 1 In Example 1, without adding polyvinyl isobutyl ether to the copolymer, one part of betamethasone valerate was added and mixed to prepare an external member.
Drug content is 5 μg/cm ² . Comparative Example 2 One part of betamethasone valerate was added to one side of a polyurethane film having a thickness of 50 μm as in Example 1 without adding polyvinyl isobutyl ether to the copolymer to prepare an external member. Comparative Example 3 In Example 2, one part of clonidine was added and mixed to the copolymer without adding polyvinyl isobutyl ether to prepare an external member. Drug content is 5 μg/cm ² . Comparative Example 4 In Example 2, 5 parts of diisosorbite dinitrate was added in place of clonidine without adding polyvinyl isobutyl ether to the copolymer to prepare an external member. Drug content is 25μg/ ^cm2
It is. Table 1 shows the test results of Example 1 and Comparative Examples 1 and 2.

[Table] The histamine edema suppression rate in Table 1 is measured by the following method. Prepare a 2 cm square sample A and a sample B that does not contain any drug as a control. Samples A and B were pasted in pairs on the hair-free area of the back of a Wistar rat (male weighing 200 g) across the midline of the spine, and peeled off after 2 hours. Next, 0.2 ml/100 g (body weight) of 1% Pontamine Sky Blue saline was injected through the tail vein, and immediately after that, 2 μg/μ histamine was injected intradermally into the 50 μ peeled scar, and 30 minutes later, intradermal dye was added. Measure the leakage circle area and calculate the suppression rate using the following formula. Suppression rate (%) = So-S/So×100 However, So is the dye leakage area of the control sample S is the dye leakage area of the sample application site. Figures 1 and 2 show Example 2 (and Comparative Example 3) and The test results of Example 3 (and Comparative Example 4) are shown. Note that the dashed line in the figure is the normal value. The graphs shown in Figures 1 and 2 are based on samples (3 cm x 3 cm square) taken from Wistar rats (body weight 200
The abdomen of ~250g) was removed and pasted, and the caudal artery was measured.

[Brief explanation of the drawing]

FIGS. 1 and 2 are graphs showing the test results of the embodiments of the present invention.

Claims (1)

[Claims] 1. A flexible carrier layer, a flexible intermediate layer made of a substance with low drug solubility, an acrylic polymer substance that has pressure-sensitive adhesive properties at room temperature and high drug solubility, and a drug. Substances with low solubility and effective blood concentration of 10ng/ml
An external member comprising the following drugs and a drug-containing pressure-sensitive adhesive layer having the following essential components laminated in this order. 2. The external member according to claim 1, wherein the substance with low drug solubility is polyvinyl alkyl ether.