JP5777156B2 - Topical treatment for chronic urticaria - Google Patents

Description

  The present invention relates to a skin external preparation effective for treating chronic urticaria.

  There are various types of itch-related diseases, and the causes, mechanisms of occurrence, and symptoms differ depending on the disease. Therefore, an optimal therapeutic drug and method for each disease type are being sought.

Among itch-related diseases, urticaria is characterized by papules or urticaria-like nodules with intense itching, and chronic progression over several months is called chronic urticaria. Among chronic urticaria, nodular urticaria is the most widely known intractable rash. Nodular rash is a rash with a severe itch that has a hard core and is crushed like a wart. Insect bites, allergies, atopic dermatitis, etc. are the triggers, exacerbated by scratching, etc., forming nodules and becoming intractable diseases.
Atopic dermatitis is known as one of the causes of nodular urticaria, but nodular urticaria is positioned as a disease different from atopic dermatitis.

In order to treat nodular rash, ultraviolet therapy using medium-long wave UVB, cryotherapy with liquid nitrogen, local injection of steroids, oral administration of steroids and immunosuppressants, and the like have been performed.
However, treatment with ultraviolet therapy, cryotherapy, and local injection needs to go to a medical institution, so there is a problem that the burden on the patient is large and the treatment takes time.
In addition, oral administration of steroids and immunosuppressants has a problem that systemic side effects occur.

Therefore, treatment with an external preparation that can be easily used and has fewer side effects than oral administration is desired.
As an external preparation for treating nodular rash, steroids are mainly used. However, steroids have problems such as skin atrophy, local infectivity, and suppression of self-steroid formation. Since nodular rash is chronic, the use of drugs with few side effects is desired.

Examples of external preparations that can be used for skin diseases involving itching and do not contain steroids include external preparations disclosed in Patent Documents 1 to 3.
Patent Document 1 discloses a skin external preparation composed of chondroitin polysulfate and zinc oxide as an external preparation used as an atopic dermatitis recurrence preventing agent.
As described in the examples, this external preparation for skin is first treated with a steroid-containing anti-inflammatory agent to treat patients with atopic dermatitis, the symptoms of skin rash and itching are improved, and the dose of steroid is reduced. It is applied at the time. That is, it is not effective for atopic dermatitis alone, but only prevents the symptoms once alleviated again. Patent Document 1 does not disclose a chronic urticaria.

Patent Document 2 discloses an antipruritic agent containing a specific galactosaminoglycan or a pharmacologically acceptable salt thereof as an active ingredient.
In paragraphs [0009] and [0010] of Patent Document 2, galactosaminoglycan, which is an active ingredient of Patent Document 2, is a polysulfate ester of chondroitin sulfate (polysulfated chondroitin sulfate; It is disclosed that chondroitin polysulfate is not the same substance.
Patent Document 2 demonstrates that the specific galactosaminoglycan significantly suppressed the number of curettage behaviors in mice in atopic dermatitis model mice. There are no examples of treatment for urticaria.

  Patent document 3 is the applicant's own application and discloses a therapeutic agent for psoriasis containing polysulfated chondroitin sulfate as an active ingredient. Psoriasis is an erythematous disease with thick scales and crusts, which is different from chronic urticaria.

Japanese Patent Laid-Open No. 11-060494 JP 2001-151680 A JP 09-286731 A

As described above, Patent Documents 1 to 3 do not disclose any external preparations for skin against chronic prurigo.
Especially in chronic urticaria, nodular urticaria forms a crushed hard core like a wart due to the progress of symptoms, and because of its hard skin, treatment methods using conventional external preparations for skin, including steroids, etc. Then, the penetration of the drug is insufficient, leading to a pathological condition where the therapeutic effect cannot be exhibited, and it becomes intractable. Therefore, an external preparation for skin that can effectively treat refractory chronic urticaria such as nodular urticaria and has few side effects has been desired.

  In light of the above situation, the present inventors have continued research on an external preparation for skin effective for the treatment of chronic prurigo, and as a result, a composition containing polysulfated chondroitin sulfate significantly improves the symptoms of nodular prurigo patients. Successfully completed the present invention.

  That is, the present invention is an external preparation for treating chronic urticaria containing polysulfated chondroitin sulfate as an active ingredient.

The external preparation according to the present invention contains polysulfated chondroitin sulfate as an active ingredient. Polysulfated chondroitin sulfate becomes hard due to the progression of refractory nodular urticaria, and shows good penetrability due to high moisturizing property even to skin where steroids etc. cannot penetrate sufficiently, and urticaria It is considered to exert an anti-inflammatory effect on the skin, and thereby symptoms can be remarkably improved.
In addition, polysulfated chondroitin sulfate is a component that has already been found to have almost no side effects in the field of topical skin preparations, and is very safe.

  The preparation of the present invention exerts an excellent therapeutic effect on intractable chronic urticaria such as nodular urticaria, exhibits an effect even in cases ineffective with steroids, and exhibits a recurrence suppressing effect. Furthermore, since the safety of the active ingredient is very high, an external preparation with few side effects can be provided.

FIG. 1 is a photograph of the skin at the start of treatment for a patient with nodular rash. FIG. 2 is a photograph of the skin after treating the patient shown in the photograph of FIG. 1 for 2 months with a composition containing polysulfated chondroitin sulfate. FIG. 3 is a photograph of the skin after treating the patient shown in the photograph of FIG. 1 for 7 months with a composition containing polysulfated chondroitin sulfate. FIG. 4 is a photograph of the skin after the patient shown in the photograph of FIG. 1 was treated with a composition containing polysulfated chondroitin sulfate for 6 months and then treated with a steroid for 1 month.

The external preparation according to the present invention contains polysulfated chondroitin sulfate as an active ingredient.
Polysulfated chondroitin sulfate is a polymer containing about 2 to 4 sulfate ester residues, preferably about 2 to 3 per disaccharide unit composed of D-galactosamine and D-glucuronic acid.

  Polysulfated chondroitin sulfate can be easily obtained by a known method of reacting chondroitin components such as chondroitin and chondroitin sulfate (A, C, D, E) with a sulfating agent such as chlorosulfuric acid, concentrated sulfuric acid, sulfur trioxide-pyridine complex, etc. Can be manufactured.

Preferred examples of the polysulfated chondroitin sulfate include heparin-like substances listed in the Japanese Pharmacopoeia Pharmaceutical Component Standards.
The following values are shown as physicochemical properties.
a) Sulfate group content: 25.8 to 37.3%
b) Intrinsic viscosity: 0.09 to 0.18

  Polysulfated chondroitin sulfate may be used in the form of a free acid derived from a sulfate residue, but usually a base salt is used.

  Examples of the base salt include alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as magnesium.

The external preparation according to the present invention contains the above-described polysulfated chondroitin sulfate as an active ingredient, and is effective in treating chronic urticaria (nodular rash, polymorphic chronic rash, chronic simple rash, etc.).
The reason why the external preparation of the present invention exerts an excellent therapeutic effect on nodular rash, which is difficult to exert even with steroids, is not clear, but the following reasons are conceivable. Nodular eruption forms hard skin and does not sufficiently penetrate the therapeutic agent, and as a result, it is considered difficult to treat, but the polysulfated chondroitin sulfate is an effective component of the external preparation according to the present invention. Since it has a moisturizing action, when applied to the skin, the moisturizing action softens the skin, penetrates the polysulfated chondroitin sulfate into the skin, and improves the rash by the polysulfated chondroitin sulfate itself Because of its anti-inflammatory action, it exhibits excellent therapeutic effects.
Thus, the external preparation according to the present invention exhibits an excellent effect even for nodular prurigo, which is known to be intractable, among chronic prurigo.

  The concentration of the polysulfated chondroitin sulfate in the external preparation according to the present invention is preferably about 0.1 to 1.0% by weight, and more preferably about 0.2 to 0.5% by weight. Since polysulfated chondroitin sulfate is highly safe, side effects hardly occur at the above concentrations.

  The external preparation for chronic rash treatment of the present invention can be used as a pharmaceutical composition in a dosage form such as an ointment, a plaster, a patch, a cream, a lotion, and a gel, and preferably with a pharmaceutically acceptable additive.

  Examples of the additive blended in the ointment include a base, a humectant, a thickener, and an emulsifier. As the base, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Examples include acids and oleic acid. Examples of higher alcohols include lanolin alcohol and cetostearyl alcohol. Examples of esters include isopropyl myristate and stearyl myristate.

  Examples of the humectant include glycerin and 1,3-butylene glycol. Examples of the thickener include carboxyvinyl polymer and carboxymethyl cellulose. Examples of the emulsifier include a cationic surfactant and an anionic interface. An activator, an amphoteric surfactant, a nonionic surfactant, etc. are mentioned.

  Examples of the additive added to the plaster or the patch include a thickener, a humectant, a filler, a crosslinking agent, a solubilizer, and an emulsifier. Specifically, examples of the thickener include sodium alginate, gelatin, methylcellulose, carboxyvinyl polymer, sodium polyacrylate and the like, examples of the humectant include glycerin and the like, and examples of the filler include kaolin, titanium dioxide, and zinc. The cross-linking agent includes acetaldehyde, dimethyl ketone, aluminum sulfate and the like, the solubilizer includes alcohols such as ethanol and isopropanol, and the emulsifier includes an anionic surfactant. And nonionic surfactants and the like are exemplified.

  Examples of the additive added to the cream include oil-soluble substances, water-soluble substances, and emulsifiers. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Acid, oleic acid, etc., higher alcohols include lanolin alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, cholesterol, etc., and esters include isopropyl myristate, stearyl myristate, etc. Can be mentioned.

  As the water-soluble substance, water, a thickener, a humectant, or the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethylcellulose, and examples of the humectant include glycerin, propylene glycol, and 1,3-butylene glycol.

  Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.

  Additives blended into the lotion agent include oil-soluble substances, water-soluble substances, emulsifiers and the like. As the oil-soluble substance, higher hydrocarbons, fats and oils, waxes, fatty acids, higher alcohols, esters and the like can be used. Examples of higher hydrocarbons include squalane, synthetic paraffin, liquid paraffin, white petrolatum, microcrystalline wax, etc., waxes include beeswax, white beeswax, lanolin, ceresin wax and the like, and fatty acids include stearin. Examples include acids and oleic acid, examples of higher alcohols include lanolin alcohol, cetyl alcohol, and cetostearyl alcohol, and examples of esters include isopropyl myristate and stearyl myristate.

  As the water-soluble substance, water, a thickener, a humectant, or the like can be used. Examples of the thickener include carboxyvinyl polymer and carboxymethylcellulose, and examples of the humectant include glycerin and 1,3-butylene glycol.

  Examples of the emulsifier include a cationic surfactant, an anionic surfactant, an amphoteric surfactant, and a nonionic surfactant.

  Examples of the additive blended in the gel include bases, and isopropanol, propylene glycol and the like are used as the base.

  Specific examples of the cationic surfactant that can be used in each of the above preparations in the present invention include cetyltrimethylammonium chloride, lauryldimethylbenzylammonium chloride, tetrabutylammonium chloride, dioctadecyldimethylammonium chloride, and the like.

  Examples of the anionic surfactant include sodium alkylbenzene sulfonate, sodium dodecyl sulfate, sodium coco alcohol ethoxy sulfate, sodium α-olefin sulfonate, emulsified cetostearyl alcohol and the like.

  Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, glycerin fatty acid ester, diglycerin fatty acid ester and the like.

  Examples of the amphoteric surfactant include N-alkyl-N, N-dimethylammonium betaine and imidazoline type amphoteric surfactant.

  The above surfactants can be used alone or in combination.

  In the above-mentioned dosage forms such as ointments, plasters, patches, creams, lotions, gels, etc., pH adjusters, preservatives, macrogols and the like are used as necessary.

  Examples of the pH adjuster include diisopropanolamine, triisopropanolamine, triethanolamine, potassium hydroxide, sodium hydroxide, sodium citrate, phosphoric acid, tartaric acid, dl-malic acid, glacial acetic acid and the like. Examples of the agent include thymol, dibutylhydroxytoluene, sodium edetate hydrate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate and the like.

The external preparation for treating chronic urticaria according to the present invention varies depending on the age, weight, sex, degree of chronic urticaria (severe, mild), etc., and is not particularly limited, and the amount applied varies depending on the size of the affected area.
Apply once to several times per day to the affected area.

  The external preparation of the present invention may be applied to the skin as an ointment, a plaster, a patch, a cream, a lotion, a gel or the like, or may be occlusion therapy (ODT).

The external preparation according to the present invention preferably contains no steroid. It is because chronic urticaria may worsen by using together with a steroid.
In addition, the external preparation according to the present invention can significantly improve chronic urticaria even if the active ingredient is only polysulfated chondroitin sulfate. Therefore, it is preferable not to include components with many side effects such as steroids and immunosuppressants. Preferably, the external preparation according to the present invention contains only polysulfated chondroitin sulfate as an active ingredient.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[Example 1]
Many patients with refractory nodular prurigo patients (adult women) who are not cured even after 12 months of treatment with topical steroids (active ingredient: clobetasol propionate) and oral steroids (active ingredient: prednisolone) The treatment of applying an oil-in-water emulsion ointment (Hirudoid (registered trademark) cream 0.3%; hereinafter simply referred to as Hirudoid cream) containing sulfated chondroitin sulfate was performed continuously for 2 months.

  The hirudoid cream contains 3.0 mg of polysulfated chondroitin sulfate (heparin analog) as an active ingredient in 1 g of the preparation. Other additives are glycerin, stearic acid, potassium hydroxide, white petrolatum, lanolin alcohol, cetostearyl alcohol, emulsified cetostearyl alcohol, myristyl alcohol, thymol, methyl paraoxybenzoate, propyl paraoxybenzoate, isopropanol.

  A state before treatment is shown in FIG. 1, and a clinical image after 2 months is shown in FIG. As shown in FIGS. 1 and 2, dermatitis mainly composed of papules or nodules was remarkably improved by treatment for 2 months, and only pigmentation was left. After that, when the treatment for applying the hirudoid cream was continued for another 4 months (6 months from the start of treatment), a further marked improvement was observed.

After the treatment for 6 months, only hirudoid cream was applied to the left arm, and hirudoid cream and a steroid preparation (active ingredient: clobetasol propionate) were applied to the right arm, and the treatment was continued for 1 month each. Fig. 3 shows a photograph of the left arm (7 months of treatment with hirudoid cream alone), and Fig. 4 shows a photograph of the right arm (6 months of hirudoid cream treatment). 1 month treatment with the preparation). As can be seen from FIG. 3 and FIG. 4, the left arm treated with only hirudoid cream showed a marked improvement effect, but the right arm combined with steroid showed relapse of dermatitis.
This result was surprising because steroid preparations are standard treatments for nodular urticaria and the combination of steroids and polysulfated chondroitin sulfate was expected to further improve the therapeutic effect.
During this treatment period, no side effects due to the application of hirudoid cream were observed.

[Example 2]
In the same manner as in Example 1, the hirudoid cream was continuously applied for several months to an intractable nodular rash patient (adult male) who was not cured by a topical steroid.

Table 1 summarizes the results of Example 1 and Example 2 with the application of hirudoid cream.

In the “Therapeutic effect” column of Table 1, ◎ indicates that the nodule eruption eruption has been remarkably improved and pigmentation has become predominant, and ◯ indicates that the number and degree of eruption has improved to some extent. In other words, if there is no change in the number or degree of skin eruption, or it has worsened, it is marked as x.
In the “side effect” column of Table 1, a case where no side effect is observed during the treatment period is indicated by “◯”, and a case where any side effect is observed is indicated by “X”.
In the “recurrence” column of Table 1, the case where there is no recurrence is indicated as “◯”, and the case where recurrence is observed is indicated as “X”.

  As shown in Table 1, when an external preparation containing polysulfated chondroitin sulfate was applied, marked improvement of nodular rash was observed, and no recurrence or side effects were observed. Thus, the external preparation of the present invention was also effective against refractory nodular urticaria that was not improved by steroids.

Claims (3)

An external preparation for treating nodular rash , comprising polysulfated chondroitin sulfate as an active ingredient. The external preparation according to claim 1, which does not contain a steroid. The external preparation according to claim 1 or 2, comprising only polysulfated chondroitin sulfate as an active ingredient.