JP2009096807A - Prophylactic or therapeutic agent for allergic disease - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an excellent prophylactic or therapeutic agent for allergic disease. <P>SOLUTION: Chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, keratan sulfate are cited as a practical polysulfated chondroitin sulfates (heparinoid substances), and are used as the prophylaxis or therapeutic agent for allergic disease. The allergic disease is selected from the group consisting of autoimmune disease, allergic rhinitis, allergic asthma, atopic dermatitis, pollinosis and contact dermatitis. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a therapeutic agent for allergic diseases.

  Polysulfated chondroitin sulfate (a heparin-like substance), a type of polysulfated mucopolysaccharide, has blood coagulation inhibitory action, peripheral blood circulation promoting action, and fibroblast proliferation inhibitory action, and blood circulation such as thrombophlebitis It is useful for treating and preventing inflammatory diseases based on disability, hypertrophic scars and keloids. In addition, polysulfated chondroitin sulfate has a skin moisturizing action and is known to be useful for dry skin diseases such as xeroderma, sebum deficiency, and progressive palm keratoderma.

  The present inventor has paid attention to polysulfated mucopolysaccharides and studied new uses thereof, and as a result, has found that polysulfated mucopolysaccharides such as polysulfated chondroitin sulfate have an excellent allergic disease therapeutic action. .

  The present invention provides the following items 1 and 2.

  Item 1. A preventive or therapeutic agent for allergic diseases comprising polysulfated chondroitin sulfate as an active ingredient.

  Item 2. Item 2. The preventive or therapeutic agent for allergic disease according to Item 1, wherein the allergic disease is selected from the group consisting of allergic rhinitis, allergic asthma, atopic dermatitis, hay fever and contact dermatitis.

  According to the present invention, a safe allergic preventive or therapeutic agent comprising polysulfated mucopolysaccharide as an active ingredient can be provided.

  Examples of type IV allergic diseases include autoimmune diseases, transplantation immunity, and contact dermatitis.

  The preventive or therapeutic agent for allergic diseases of the present invention is effective for type IV allergy and allergic rhinitis, allergic asthma, atopic dermatitis and hay fever.

  The “polysulfated mucopolysaccharide” used in the present invention has a disaccharide repeating unit composed of hexosamine (N-acetylated glucosamine or galactosamine) and uronic acid (D-glucuronic acid or L-iduronic acid). It means one synthesized by chemically introducing a sulfate group into a long-chain polysaccharide. Some naturally occurring mucopolysaccharides have sulfate groups, and those obtained by chemically polysulfating them are also included in the polysulfated mucopolysaccharides of the present invention. In addition, a mucopolysaccharide having no sulfate group chemically introduces a sulfate group. Specific examples of the mucopolysaccharide include chondroitin-4-sulfate, chondroitin-6-sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, hyaluronic acid, and chondroitin. In particular, polysulfated chondroitin sulfate such as a heparin-like substance (hereinafter referred to as MPS) described in the Japanese Pharmacopoeia Standards for Drugs is preferable.

  Examples of the method for introducing a sulfate group into the mucopolysaccharide include a known method, for example, a method of reacting natural mucopolysaccharide with a sulfating agent in a suitable solvent under heating. The sulfating agent is not particularly limited as long as the purpose of polysulfation can be achieved. For example, it is preferable to use a complex of sulfuric anhydride and pyridine or triethylamine. The use ratio of the mucopolysaccharide and the sulfating agent can be arbitrarily selected according to the sulfation rate (or sulfur content) of the target polysulfated mucopolysaccharide and the reaction conditions. In general, it is preferable to use the sulfating agent at a ratio of 2 to 10 parts by weight per 1 part by weight of the mucopolysaccharide.

  Examples of the solvent include prophilic solvents such as dimethylformamide. The reaction temperature and reaction time are not particularly limited as long as the desired sulfation rate can be achieved. For example, the reaction proceeds advantageously by reacting at 40 to 90 ° C. for about 30 minutes to 20 days.

  Purification of polysulfated mucopolysaccharides includes purification operations commonly used for various modified polysaccharides, such as desalting by neutralization dialysis, recovery by adding an organic solvent to precipitate, recovery by lyophilization, etc. A process is mentioned.

  The polysulfated mucopolysaccharide of the present invention can also be used as a physiologically acceptable salt form subjected to a salt-forming reaction using an alkali metal hydroxide or carbonate, amines or the like, if necessary.

  The polysulfated mucopolysaccharide of the present invention or a physiologically acceptable salt thereof is an ointment using pharmaceutically aids such as excipients, additives and the like used in the preparation of ordinary pharmaceutical preparations. , Plasters, tablets, aerosols, liquids, capsules, suspensions, injections, lotions, etc., topical, mucosal, skin, subcutaneous, intravenous, intramuscular, intraarterial, oral or pulmonary, etc. Can be administered.

  The content of the polysulfated mucopolysaccharide in the preparation can be appropriately adjusted depending on the dosage form, and is, for example, about 0.001 to 50 (weight / volume)%, preferably 0.05 to 1 (weight / volume). %.

  Additives blended in the ointment include bases, emulsifiers, preservatives, such as white petrolatum, hydrocarbons such as liquid paraffin, oils and fats such as soybeans, waxes such as beeswax and lanolin, Examples include fatty acids such as stearic acid and oleic acid, higher alcohols such as lanolin alcohol and cetostearyl alcohol, and esters thereof, macrogol, and the like, and emulsifiers include nonionic surfactants and the like as preservatives. Include thymol, methyl paraoxybenzoate, propyl paraoxybenzoate, and the like.

  Additives blended in plasters or patches include thickeners, moisturizers, fillers, cross-linking agents, solubilizers, emulsifiers, and the like. Specific examples of thickeners include sodium alginate and gelatin. , Methylcellulose, carboxyvinyl polymer, sodium polyacrylate, etc .; glycerin, macrogol, etc. as moisturizing agents; kaolin, titanium dioxide, zinc white etc. as fillers; acetaldehyde, dimethyl ketone, aluminum sulfate, etc. as crosslinking agents Examples of the solubilizer include alcohols such as ethanol and 2-propanol, macrogol, and the like; examples of the emulsifier include anionic surfactants and nonionic surfactants.

  When prepared as an injection, examples of additives include pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, and the like. can do. The formulation is administered intravenously, intramuscularly or subcutaneously.

  Examples of additives for preparation as an oral preparation include excipients, disintegrants, lubricants, binders, flavoring agents, and flavoring agents.

  The dose of the polysulfated mucopolysaccharide, which is an active ingredient of the allergy prevention or treatment agent of the present invention, varies depending on the patient's age, weight, sex, symptom level (severe, mild), administration route, etc., and is particularly limited. Not. For example, in the case of an ointment, an appropriate amount of an ointment containing about 0.1 to 10% of a polysulfated mucopolysaccharide is applied several times a day, and about 1 to 1000 mg is applied as an active ingredient daily amount. It is done. Even when an ointment containing about 0.1 to 10% of polysulfated mucopolysaccharide is applied to the skin, side effects such as inflammation are not observed.

  EXAMPLES Hereinafter, although this invention is demonstrated in detail using an Example, this invention is not limited to these.

Example 1 Effect of Compound 48 / 80-stimulated rat peritoneal mast cells on histamine release

Compound 48/80 (250 ng / ml; manufactured by Sigma) was added to mast cells (2 × 10 ⁴ cells) in the presence or absence of MPS or heparin (control group) and incubated for 10 minutes. The amount of histamine in the supernatant and intracellular was measured with a histamine ELISA kit (manufactured by Immunotech), and the histamine release rate was calculated.

  The results are shown in FIG.

* P <0.01 indicates a significant difference from the control group.

  #P <0.01 indicates a significant difference with respect to the heparin addition group.

  From the results of Table 1, it was confirmed that polysulfated chondroitin sulfate suppresses histamine release from mast cells.

Example 2 Mouse Contact Dermatitis Inhibitory Action An ointment containing MPS was used as the polysulfur oxide of chondroitin sulfate.

  After shaving the abdomen of a BALB / c male mouse (7 weeks old), 100 μl of an ethanol solution containing 3% oxazolone (Aldrich) was applied for sensitization. Six days after the sensitization, 10 μl of an acetone solution containing 1% oxazolone was applied to both sides of the right auricle to induce dermatitis. The MPS-containing ointment was applied to both right auricle and 20 mg 6 hours after induction. Twenty-four hours after induction, the left and right auricles were punched out with a disposable punch (diameter 6 mm, manufactured by Maruho Co., Ltd.), and the weight of the slice was measured.

  The auricular edema rate was calculated by the following formula.

[Equation 1]
Auricular edema rate (%) = {(A−B) / B} × 100
A: Weight of right auricle section B: Weight of left auricle section
The results are shown in Table 2 and FIG. In addition, the control group of Table 3 is a result when not applying MPS containing ointment.

*** P <0.001 indicates a significant difference from the control group.

From the results in Table 2, it was confirmed that the MPS-containing ointment suppresses contact dermatitis, which is a type IV allergy.
The present invention can provide a preventive or therapeutic agent for allergic diseases.

The histamine release rate by Compound 48/80 stimulation in the presence of polysulfated chondroitin sulfate and heparin is shown. The effect with respect to contact dermatitis of the ointment containing MPS is shown.

Claims (2)

A preventive or therapeutic agent for allergic diseases comprising polysulfated chondroitin sulfate as an active ingredient. The prophylactic or therapeutic agent for an allergic disease according to claim 1, wherein the allergic disease is selected from the group consisting of allergic rhinitis, allergic asthma, atopic dermatitis, hay fever and contact dermatitis.