JP2006131544A - External preparation for treating skin disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation which can cover a lesion to make it less conspicuous or to positively remove unwanted skin produced by the hyperproliferation of skin cells and hardly causes wetting of a lesion by perspiration and side effect by excessive medicament absorption. <P>SOLUTION: The external preparation for treating skin disorders comprises an emulsion adhesive component, water, and a medicament for treating skin disorders. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to an external preparation for treating skin diseases such as psoriasis.

  Skin diseases such as psoriasis and dermatitis are not fatal unless they are malignant tumors themselves. However, there are many unpleasant things such as itching, and it may be impossible to sleep well or the skin that peels off may be scattered around. Above all, there is a problem that it looks bad. For this reason, the quality of life of patients with skin disorders, such as having to stop and change daily general activities, have to wear clothes to hide skin disorders, and sometimes even consider suicide, Both mentally and mentally.

  Nevertheless, the causes of many skin diseases are still unclear. Although some are referred to as genetic diseases and autoimmune diseases, no specific therapeutic method has yet been found. In addition, the improvement and worsening of symptoms are repeated alternately, and the treatment often takes a long time. On the other hand, the fact is that they continue to receive drugs that may cause side effects, and patients always have anxiety and irritation about treatment.

  For these skin diseases, ointments and creams containing steroids and the like are generally applied. However, simply applying an external preparation has a problem that it adheres to clothes and the like, and the drug effect is not sufficiently exhibited. Therefore, when a sufficient effect is not seen by simple application of external preparation, Occclusive Dressing Therapy (ODT for short) is covered with a plastic film slightly larger than the affected area. Was sometimes performed).

  However, seal closure therapy has the problem of increasing the side effects of the drug. The skin's stratum corneum has about 10% moisture under normal conditions, but its main component, keratin, has the property of absorbing water. %, The water content increases by 10-30%. And since the chemical | medical agent in the apply | coated formulation spread | diffuses into a stratum corneum according to the density | concentration difference, transdermal absorbability will increase with the increase in the amount of stratum corneum. In addition, since the drug can easily move in the stratum corneum, the amount transferred to the dermis also increases. As a result, side effects such as skin atrophy and dilatation of capillaries became serious, especially when steroids were used in sealing closure therapy.

  In addition, not only can closed sealing therapy be used for moist lesions such as ulcers, but side effects are particularly problematic in infants who are prone to systemic effects and elderly people who have a large amount of drug absorption from the skin.

  In addition, hermetically closed therapy may cause bacterial infections such as keratitis and bruises, and sweats caused by sweat accumulation. Also, especially in the summer, the affected area may become stuffy and give off a foul odor.

  Although this is a closed closure therapy with various problems, it became popular as a treatment method for skin diseases in the 1960s, and improved methods have been studied since then.

  For example, Patent Document 1 discloses a nail polish treatment for nail psoriasis containing a glucocorticoid (a kind of steroid), a solvent, and a water-insoluble film forming agent. However, the preparation is only a nail polish solution for nail psoriasis, and is intended for quick drying. Therefore, some of the solvents used in each example contain 96% ethanol, but are a mixed solvent of ethyl acetate and butyl acetate. That is, since the nail polish is an organic solvent solution of an organic polymer, the film formed after drying is very dense and does not have the ability to dissipate water. As a result, when applied to affected areas of skin diseases, problems similar to those of sealed closure therapy such as side effects and stuffiness of steroids occur.

  Patent Document 2 describes a method of forming a film by applying a cyanoacrylate ester composition to an affected area of a skin disease and polymerizing it in situ. However, since the composition is similar to a so-called instant adhesive and does not dissipate water, problems similar to those of the sealed closure therapy still occur. Actually, in the [Technical field to which the invention belongs] section of Patent Document 2, it is clearly indicated that the coating formed by the composition functions as a blocking layer.

Patent Document 3 describes a substance containing an anionic polymer or the like and a cationic polymer, which forms a film or gel in the presence of water. Here, although it is described in the document that “film or gel” is formed, each polymer is cross-linked (gelled) by electrostatic action of anion and cation in the presence of water. Even though it is film-like, it is a gel in the academic definition. In such a case, water molecules bonded to the periphery of the polar group cannot evaporate, and moisture is always included. As a result, water is given to the affected area, and naturally the water in the affected area is not released. Therefore, if the preparation is administered to the affected area of the skin disease, the same problem as that of the sealed closure therapy occurs.
Japanese Patent Laid-Open No. 11-130679 (Claim 1, Paragraph [0015], Example) Japanese Patent Laid-Open No. 13-521914 (Claim 1, Paragraph [0002]) Japanese Patent Laid-Open No. 13-513549 (Claims)

  As described above, external preparations containing steroids are mainly used for skin diseases, and sealing closure therapy may be used in combination. However, there are side effects due to excessive absorption of the drug and adverse effects due to stuffiness, etc., which are not necessarily effective for skin diseases.

  Therefore, the problem to be solved by the present invention is an external preparation that can coat an affected part in order to make the affected part inconspicuous or to positively remove debris caused by excessive proliferation of skin cells. Since it is not a thing, it is providing the thing by which the side effect by the overheating | steaming and chemical | medical agent absorption is suppressed.

  In order to solve the above-mentioned problems, the inventors of the present invention have made extensive studies on components for forming a film particularly in the affected area. As a result, if the affected area is covered with a so-called emulsion-type adhesive component suspended in water, moisture in the affected area can be dissipated as the moisture evaporates, and the humidity of the affected area can be kept moderate even after drying. Thus, the present invention has been completed by finding that it is possible to suppress stuffiness of the affected area and excessive absorption of the drug.

  That is, the external preparation for skin disease treatment of the present invention is characterized by containing an emulsion-type adhesive component, water, and a skin disease treatment drug.

  The water content is preferably 20% by mass or more. If it is less than 20% by mass, it may not only be difficult to uniformly disperse the emulsion-type adhesive component, but if the initial water content is not sufficient, the formed film may not be able to fully exhibit the water permeability. Because there is.

  As the emulsion type adhesive component, one or a mixture of two or more selected from the group consisting of polyvinyl acetate, polyacrylate ester, polyurethane and rubber latex is preferred, and polyvinyl acetate is most suitable. is there. This is because not only the adverse effects on the human body and the like are small as an external preparation component, but also the humidity of the affected area can be appropriately maintained after solidification.

  As the drug for treating skin diseases, one or a mixture of two or more selected from the group consisting of steroids, coal tars, vitamin D3 derivatives, vitamin A derivatives, salicylic acid and immunosuppressants is preferable. Particularly preferred. This is because these have proven results as drugs for treating skin diseases.

  The external preparation for treatment of skin diseases of the present invention can actively dissipate the water in the affected area as the contained water evaporates, and can keep the water in the affected area moderate even after solidification. As a result, it is possible to effectively reduce the drawbacks of the conventional hermetically closed therapy, such as excessive skin absorption of the drug and stuffiness of the affected area. In addition, after solidification, the affected part can be adhered and covered, so that the affected part can be protected and not noticeable. In particular, in diseases where excessive skin growth such as psoriasis is observed, the residue of the skin can be adsorbed and removed together with the solidified preparation. Therefore, the external preparation for treatment of skin diseases of the present invention is extremely excellent in industry as it can provide an unprecedented means for treating skin diseases.

  The skin disease targeted by the external preparation for treatment of skin diseases of the present invention is not particularly limited as long as it is other than those that may be exacerbated by the immunosuppressive action of the drug such as infection or the covering of the affected part. For example, psoriasis, eczema , Dermatitis, nodular eruption, palmoplantar pustulosis, squamous red lichen, amyloid lichen, ring granulomas, luster lichen, chronic discoid lupus erythematosus, fox fordice disease, hypertrophic scar, keloid, vulgaris vulgaris , Schaumburg disease, lymphoma.

  The topical preparation for skin disease treatment of the present invention has a gist in that at least an emulsion-type adhesive component, water, and a drug for skin disease treatment are essential constituents and applied to the affected area while containing water. Since moisture from the affected area is also released as the moisture evaporates from the preparation, and the moisture can be kept moderately while protecting the affected area even after solidification, it is possible to inhibit the affected area from stuffy and excessive skin absorption of drugs. It is.

  A preparation called a conventional plaster is generally produced by drying an organic solvent solution of a fat-soluble polymer, but is produced by drying a suspension of the fat-soluble polymer in water. (Emulsion method). However, according to the findings found by the present inventors, the water permeability of the plaster agent is not sufficient. This is because even a plaster produced by the emulsion method is dried until it is substantially free of water, the resulting fat-soluble polymer base has a complete affinity for water from the affected area. It is thought that it is due to being lost.

  The emulsion-type adhesive component used in the present invention is an adhesive component that can disperse the fine particles in water as a dispersion medium and maintain the state, and has low irritation to humans and animals as patients. There are no particular restrictions on the type of the product. However, preferred are polyvinyl acetate, vinyl acetate-acrylic acid ester copolymer, vinyl acetate-vinyl ester copolymer such as vinyl acetate-versaic acid copolymer, vinyl acetate-ethylene copolymer, acetic acid. Polyvinyl acetates such as vinyl-acrylic acid copolymer, vinyl acetate-acrylic acid amide copolymer; polyacrylic acid ester, acrylic acid ester-acrylic acid copolymer, acrylic acid ester-styrene copolymer, etc. Examples thereof include acrylic acid ester systems; urethane systems; natural rubber, polyisoprene, polybutadiene, rubber latex systems such as styrene-butadiene, and the like. One of these may be selected, or a mixture of two or more of these may be used. it can. Here, the “copolymerized product of the ~ system and other monomers” refers to a copolymer having ~ as a main monomer (50% or more). For example, in the case of a polyvinyl acetate-based vinyl acetate-acrylic acid ester copolymer, there are more vinyl acetates as monomers than acrylic acid esters. The reason why the copolymer is used is mainly to improve water resistance and emulsion stability.

  As a compounding quantity of an emulsion type adhesive agent component, 10 mass% or more and 75 mass% or less are preferable. This is because if it is less than 10% by mass, it is difficult to solidify, whereas if it exceeds 75% by mass, it is difficult to disperse in water.

  The emulsion-type adhesive component of the present invention contains water as an essential component. When the affected part is covered with an adhesive component, it is also conceivable to use an organic solvent solution of the adhesive component and form a film along with the evaporation of the organic solvent at the affected part. However, organic solvents are not suitable as an external preparation component because they are low in safety and high in irritation. On the other hand, water is safe and low in irritation, and is highly convenient as an external preparation component. In addition, when an emulsion in which the adhesive component is dispersed in water is administered to the affected area, the moisture in the affected area can be removed to some extent as the water in the preparation evaporates, and the moisture in the affected area can be continuously dissipated even after solidification. Therefore, it is possible to suppress stuffiness in the affected area and excessive skin permeation of the drug.

  20 mass% or more and 85 mass% or less are suitable for the compounding quantity of the water to the external preparation which concerns on this invention. If it is less than 20% by mass, it may not only be difficult to uniformly disperse the emulsion-type adhesive component, but if the initial water content is not sufficient, the formed film may not be able to fully exhibit the water permeability. Because there is. On the other hand, if it exceeds 85% by mass, it may take too long to solidify.

  What is necessary is just to select suitably the medicine for skin disease treatment added to the external preparation of this invention suitably for the treatment of the skin disease which is a treatment object. Examples of the type include steroid agents, coal tar agents, vitamin D3 derivatives, vitamin A derivatives, salicylic acid, and immunosuppressants, and one or more of these can be selected and used. In addition, according to the preparation for external use of the present invention, side effects can be reduced by suppressing excessive skin permeation of the drug, so that it is possible to suitably use a steroid agent which is excellent in effect but is anxious about side effects.

  In order to adjust the solidification time, that is, the film formation time, the external preparation of the present invention may be mixed with a moisture transpiration accelerator as necessary. Examples of such moisture transpiration promoters include ethanol and isopropanol. Naturally, it is necessary to limit the amount added in consideration of safety and irritation.

  Further, if necessary, a surfactant may be blended in order to improve the dispersion stability of the adhesive component. Examples of such surfactants include polyvinyl alcohol, polysorbates, sucrose fatty acid esters, polyglycerin fatty acid esters and the like.

  Furthermore, you may mix | blend a plasticizer as needed. The plasticizer can adjust the physical performance of the formulation after film formation. Examples of such plasticizers include esters such as isopropyl myristate and diisopropyl sebacate; macrogol; fatty acids; glycerin esters of fatty acids; alcohols and the like.

  In addition, unless departing from the object of the present invention, excipients, coloring agents, fragrances, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solubilizers, buffers, pH adjustments You may mix | blend an agent etc.

  The dosage form of the external preparation for skin disease treatment according to the present invention is not particularly limited as long as it is relatively plastic from the gist of the present invention, and examples thereof include aerosols, ointments, creams, lotions and the like. be able to. Even in the case of a dosage form such as an ointment, it is possible to reduce adhesion to clothes and the like after the adhesive component is solidified.

  The general manufacturing method according to the said dosage form can be applied as it is to the manufacturing method of the external preparation for skin disease treatment which concerns on this invention. For example, water or a drug for treating skin diseases and other components may be added to the adhesive component emulsion and stirred well until uniform.

  The external preparation for skin disease treatment of the present invention is applied to the affected area in consideration of the patient's symptoms and age, an appropriate dose of the skin disease treatment drug, and the like. At this time, as long as the preparation contains the amount of moisture specified in the present invention, it may be applied after being dried to some extent in advance.

  Although the external preparation of the present invention is not as quick-drying as the conventional nail polish, the adhesive component solidifies as the moisture evaporates, so that the loss of the drug due to adhesion to clothes can be reduced. Moreover, compared with a normal patch, administration along the unevenness of the skin is also possible at a bent portion or a finger. Furthermore, since it is possible to dissipate moisture from the affected area even after solidification, it is possible to suppress the steaming of the affected area and excessive skin permeation of the drug. Therefore, the external preparation of the present invention is extremely excellent as a means for treating skin diseases. .

  Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto. In addition, the value of the compounding amount in a present Example all shows the mass%.

Production Examples 1 and 2 Production of a film-forming cream formulation First, betamethasone valerate and preservative were dissolved in diethyl sebacate and macrogol, and then 50% polyvinyl acetate emulsion and purified water were added. The resulting mixture was stirred and mixed until it became a film-forming cream formulation according to the formulation in Table 1.

Comparative Production Example 1 Production of Conventional Plaster Agent A plaster agent was produced using the solvent method with the formulation shown in Table 2. That is, butylhydroxytoluene, styrene-isoprene-styrene block copolymer, alicyclic saturated hydrocarbon resin, polybutene, liquid paraffin, diethyl sebacate, and macrogol were added to toluene as a solvent and mixed uniformly. The mixture was applied to a plastic film with a uniform thickness (50 μm) and dried at 80 ° C. for 20 minutes. Next, the plaster surface was laminated with a polyester cloth and cut into a desired size to produce a plaster.

Comparative Production Example 2 Production of Conventional Manicure Agent A nail polish agent was produced with the formulation shown in Table 2 with reference to Example 1 of JP-A-11-130679.

Test Example 1 Moisture Permeability Test The film-forming cream formulation of Production Example 1 was applied to a plastic film with a coating thickness after drying of 50 μm, and dried at 32 ° C. for 30 minutes. Sample 1 was formed by peeling off the formed film from the plastic film, and sample 2 was obtained by removing the formed film by leaving it at room temperature for 7 days after drying. Further, the following test was conducted using Sample 3 as the blaster agent of Comparative Production Example 1 and Sample 4 as a polyvinylidene chloride film (manufactured by Asahi Kasei Co., Ltd., trade name: Saran Wrap).

  After 10 g of purified water was put into a cylindrical bottle having a 3 cm diameter mouth, the bottle mouth was sealed with each sample and allowed to stand at 32 ° C. After 1 hour, 3 hours, 6 hours, 12 hours and 24 hours, the weight was measured and the weight loss of water was measured. The test was performed on 3 samples for each sample, and the average was calculated. The results are shown in FIG.

  As the result, water permeation was hardly observed in the polyvinylidene chloride film and the plaster agent used in the conventional sealed closure therapy. On the other hand, in Samples 1 and 2 which are coatings by the external preparation of the present invention, clear moisture permeability was observed. However, the moisture permeability of sample 2 was lower than that of sample 1. This is because Sample 2 was left for 7 days after the film was formed, so that the adhesive component in the film was aged, and part of the pores for allowing moisture to pass through were blocked. it is conceivable that. Therefore, it is important that the external preparation of the present invention is applied directly to the affected area or applied to the affected area as soon as possible after the film is formed, even when a separately formed film is coated on the affected area.

Test Example 2 Water Permeability Test The nail polish of Comparative Production Example 2 was adjusted to a film thickness after drying of 50 μm, applied to a plastic film, and dried to form a coating. The coating film was peeled off from the plastic film as a sample, and a water permeability test was conducted in the same manner as in Test Example 1 above. The same experiment was conducted on the coating film according to Production Example 1 described above. Table 4 shows the obtained results.

  As described above, the coating according to Production Example 1 can permeate moisture, but the coating with the nail polish does not show moisture permeability. This is presumably because the nail polish solvent is only a highly volatile organic solvent and does not contain water, so that the formed film becomes very dense. Therefore, it is considered that when the skin disease affected area is covered with such a coating according to the prior art, stuffiness occurs and the risk of infection increases. Also, a solvent such as alcohol itself is not preferable because it has skin irritation.

Test example 3
The film-forming cream preparation of Production Example 1 was applied to the center of the forearm of six subjects to form a film. The relative moisture content of the skin was measured over time using a corneometer (Courage + Khazaka Electronic BmbH, CM825PC). The measurement was performed before coating and at 1, 3, 6 hours after coating. For comparison, the same measurement was performed by the same subject when the treatment was not performed and when the plaster agent or polyvinylidene chloride film (trade name: Saran Wrap) of Comparative Production Example 1 was applied. The results are shown in FIG.

  According to the results, when the skin was covered with a conventional plaster agent and a polyvinylidene chloride film, the moisture content of the skin increased with time, and the skin became moist. With the coating, the skin moisture content hardly changed. Therefore, since the coating film by the external preparation of the present invention has sufficient moisture permeability, it has been proved that the problem of stuffiness of the affected area and excessive absorption of the drug has been solved, unlike the conventional sealing closure therapy.

Test example 4
An appropriate amount of the film-forming cream preparation of Production Example 2 was applied to the affected area of three patients with psoriasis and dried to form a film. The film was peeled off 6 hours after application, and the following items were observed. The results are shown in Table 5.

(1) Appearance of affected area The condition of the affected area after treatment with the external preparation of the present invention was evaluated by the following index.
a: Natural, almost the same as the skin other than the affected area.
b: It was natural although there was some discomfort with the skin other than the affected area.
c: Although a sense of incongruity with the skin other than the affected area is large, it is natural compared to the affected area before application.
d: The appearance is almost the same as the affected area before application.
e: It looked worse than the affected part before application.

(2) Skin dropout amount The skin dropout amount during application of the external preparation of the present invention was evaluated by the following index.
a: There was no skin detachment from the coated surface.
b: There was a slight drop of skin from the affected surface.
c: There was considerable skin detachment from the affected surface.
d: The skin detachment from the application surface was the same as the affected area before application.
e: The amount of skin detachment from the application surface was greater than the affected area before application.

(3) Clearance of the affected area The skin clearance when the coating with the external preparation of the present invention was peeled was evaluated by the following index.
a: During peeling of the film, most of the unnecessary skin pieces were removed by adsorption.
b: At the time of peeling of the film, about half of unnecessary skin pieces were removed by adsorption.
c: At the time of peeling of the film, some unnecessary skin pieces were adsorbed and removed.
d: At the time of peeling of the film, unnecessary skin pieces could hardly be adsorbed and removed.
e: Unnecessary skin pieces in the affected area after peeling of the film increased from before application.

  From these results, it is possible to improve the appearance of the affected part by applying the external preparation of the present invention to the affected part of psoriasis, that the skin does not fall off during the application, and the clearance of the affected part is eliminated by peeling the formed film. Proven to be possible. That is, the external preparation for skin disease treatment of the present invention is remarkably highly effective compared with conventional means for treating skin diseases, such as clearance of affected skin diseases and improvement of the quality of life of patients. .

The result of the moisture permeation test of the sample is shown. The Y axis represents the water loss from the beginning as the water permeation amount of each sample and the X axis represents the elapsed time. The results of the skin relative moisture test are shown, with the X axis representing elapsed time and the Y axis representing relative skin moisture content.

Claims (6)

  An external preparation for treating skin diseases, comprising an emulsion-type adhesive component, water, and a medicament for treating skin diseases.   The external preparation for treating psoriasis according to claim 1, wherein the water content is 20% by mass or more.   The skin disease according to claim 1 or 2, wherein the emulsion type adhesive component is one or a mixture of two or more selected from the group consisting of polyvinyl acetate, polyacrylate, polyurethane and rubber latex. An external preparation for treatment.   The external preparation for treating skin diseases according to claim 1 or 2, wherein the emulsion-type adhesive component is polyvinyl acetate.   The drug for treating skin diseases is one or a mixture of two or more selected from the group consisting of steroids, coal tars, vitamin D3 derivatives, vitamin A derivatives, salicylic acid and immunosuppressants. An external preparation for treating skin diseases according to any one of the above. The external preparation for skin disease treatment according to any one of claims 1 to 4, wherein the skin disease treatment drug is a steroid.

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