WO2006121209A1

WO2006121209A1 - Therapeutic agent for eczema and dermatitis

Info

Publication number: WO2006121209A1
Application number: PCT/JP2006/309974
Authority: WO
Inventors: Isao Serizawa; Hideki Goto; Hiroyuki Miyazaki
Original assignee: Takata Seiyaku Co., Ltd.
Priority date: 2005-05-13
Filing date: 2006-05-11
Publication date: 2006-11-16
Also published as: JPWO2006121209A1

Abstract

It is intended to provide a therapeutic agent for eczema and dermatitis comprising a complex (associate) of hyaluronic acid and zinc as an active ingredient. This complex has a synergistic effect compared with the case of hyaluronic acid or zinc alone which is a constituent of the complex.

Description

Description Eczema · Dermatitis Group Treatment Technology

The present invention relates to a therapeutic agent for eczema / dermatitis group such as atopic dermatitis. Background art

Eczema · Dermatitis group

The eczema / dermatitis group, including contact dermatitis and atopic dermatitis, is a common and extremely common disease that accounts for approximately 30% of patients with skin diseases. From the viewpoint of pathological conditions, exogenous eczema involving external factors (eg, primary irritation contact dermatitis) and endogenous eczema involving internal factors of each individual (eg, allergic contact dermatitis) In general, it is often treated as a group of eczema / dermatitis in general. Specific examples of diseases included in the group of eczema / dermatitis include contact dermatitis, a Topy dermatitis, seborrheic dermatitis, progressive sebaceous keratoderma, coin-like eczema, stasis dermatitis, chronic simple lichen, self-sensitizing dermatitis, sebum-deficient eczema, etc. . .

In the eczema / dermatitis group, atopic dermatitis, especially in infants, causes erythema and serous papules on the vagina, spreading over the entire face, moistening and ligating, and the affected area gradually becomes bent from infants to adults. It moves to the side and the skin becomes dry and thickened and not moistened. In either case, it is often accompanied by severe hemorrhoids, and scars and blood clots are often observed. Most cases occur during infancy, but it takes years or decades to treat. Nearly 10% of them remain as adult-type refractory atopic dermatitis that does not improve after 21 years of age.

Therapeutic agents such as steroids, antihistamines, and antiallergic agents are also used in atopic dermatitis, but it is difficult to cure this dermatitis by any treatment method or therapeutic agent. And, especially in the case of infants, administration of internal medicine such as tablets is not preferable in terms of dosage adjustment and side effects. Under such circumstances, it has been desired to develop a preparation for external use having an excellent healing promoting effect on the eczema / dermatitis group including the atopic dermatitis.

Existing treatments, drugs

For the treatment of eczema / dermatitis group including contact dermatitis, atopic dermatitis, etc., use of external preparations such as topical steroids and non-sterolide anti-inflammatory agents, antiallergic agents, antihistamines, linolenic acid, Including herbal medicine, steroids, cyclosborin, etc., specific desensitization therapy, non-specific desensitization therapy, bacterial vaccine therapy, drug bath therapy, PUVA therapy (a type of photochemical therapy), skin care, isolation Various attempts have been made to improve the living environment, clean room therapy, house dust mite countermeasures, and allergen-removing diet therapy.

Steroid topical agents, which are the main agents for the treatment of eczema and dermatitis groups, are divided into five stages according to the strength of action: we ak, me di uin, str ong, ve ry str ong, str on ge st, It is properly used depending on the severity. In addition, if the itch is strong, oral antihistamines and antiallergic agents are used in combination, and in mild cases, moisturizers and non-sterile external preparations are used instead of sterol external preparations. In some cases, oral steroids are used. Recently, evening chlorimus ointment, an immunosuppressive agent, has been used against atopic dermatitis. Disclosure of the invention

However, at present, it is difficult to completely cure these dermatitis by any treatment method or treatment agent.

Of the drugs used for the treatment of eczema and dermatitis including contact dermatitis and atopic dermatitis, oral medications such as tablets require time to onset of action and the dosage is adjusted depending on the degree of symptoms In addition, it has been difficult to use for a long time because of the side effects such as general malaise and drowsiness. Furthermore, topical antihistamines are often ineffective for itching such as atopic dermatitis and sebum-deficient eczema.

Therefore, for the treatment of eczema and dermatitis, including contact dermatitis, atopic dermatitis, etc., external preparations are preferred. Steroid external preparations can dilate capillaries by long-term administration. Side effects such as associated erythema, skin atrophy, infectious disease induction and exacerbation were problems.

There has been a demand for external preparations that have fewer side effects and have different mechanisms of action than steroids and external preparations that reduce itchiness.

As a result of various studies to solve the above-mentioned problems, the present inventors have found that a complex of hyaluronic acid and zinc (referred to herein as “zinc hyaluronate complex (aggregate)”) is contact dermatitis, It has been found that it exhibits an excellent therapeutic effect on the eczema / dermatitis group including atopic dermatitis.

Accordingly, the present invention provides a therapeutic agent for eczema / dermatitis group comprising a zinc hyaluronate complex (aggregate).

The present invention also relates to the use of a zinc hyaluronate complex (aggregate) for the manufacture of a therapeutic agent for eczema and dermatitis.

The present invention further relates to a method for treating an eczema / dermatitis group therapeutic agent, comprising administering a zinc hyaluronate complex (aggregate) to a patient having eczema and dermatitis. Effects of the present invention

Traditionally, topical steroids have been used to treat the eczema / dermatitis group, including contact dermatitis and atopic dermatitis, etc., but erythema with dilation of capillaries, skin atrophy, induction of infection, Has local side effects such as exacerbations. In addition, oral antihistamines and allergic agents frequently used in combination with topical steroids have side effects such as general malaise and sleepiness. It provides treatment for the eczema / dermatitis group without these side effects.

The zinc hyaluronate complex (associate) of the present invention exhibits a higher effect than hyaluronic acid (sodium salt), zinc (chloride) and a simple mixture thereof, and exhibits a synergistic effect due to being a complex. Brief Description of Drawings

FIG. 1 is a graph showing the results of Example 1 showing the effects (skin symptom scores) of gel agents of various concentrations of the zinc hyaluronate complex (associate) of the present invention on an atopic dermatitis model. is there.

Figure 2 shows the results of Example 1 showing the effect (number of scratches) of gel agents of various concentrations of the zinc hyaluronate complex (associate) of the present invention on the atopic dermatitis model. It is a graph to represent. .

Figure 3 shows the results of comparing the effects (skin symptom scores) of the zinc hyaluronate complex of the present invention (aggregate) and the existing betamethanoic acid valerate preparation on an atopic dermatitis model. A draft representing the results obtained in Example 2.

Figure 4 shows the effect of the zinc hyaluronate complex (associate) of the present invention and the existing 0.12% betamethanoic acid benzoate preparation (number of scratches) on the atopic dermatitis model. 6 is a graph showing the results obtained in Example 2, showing the comparison results. Figure 5 compares the effects of the gel-free control, gel-based control, and various concentrations of the zinc hyaluronate complex (associate) of the present invention on allergic contact dermatitis. 6 is a graph showing the results obtained in Example 3.

Figure 6 compares the effects of the no-application control, the gel base control, the zinc hyaluronate complex (associate) gel agent, sodium hyaluronate, and zinc chloride on allergic contact dermatitis. FIG. 5 is a graph showing the results obtained in Example 4. FIG. This result shows that the zinc hyaluronate complex (aggregate) of the present invention has a synergistic effect on the single use of sodium hyaluronate and zinc.

Figure 7 shows the effects of the no-application control, gel base control, various concentrations of the zinc hyaluronate complex (associate) of the present invention, white petrolatum, and simple zinc ointment on allergic contact dermatitis. FIG. 6 is a graph showing the results obtained in Example 5. FIG.

Figure 8 compares the effects of gel-free controls, gel-based controls, and various concentrations of the zinc hyaluronate complex (associate) of the present invention on irritant contact dermatitis. 10 is a graph showing the results of time-lapse observation obtained in Example 6.

Figure 9 is a graph showing the cumulative total for 7 days in Figure 8.

FIG. 10 shows a synergistic effect of the zinc hyaluronate complex (aggregate) of the present invention on irritant contact dermatitis, and is a draaf showing the results of time-lapse observation in Example 7.

Figure 11 is a graph showing the cumulative total for 7 days in Figure 10. BEST MODE FOR CARRYING OUT THE INVENTION

Eczema · Dermatitis group • The eczema / dermatitis group, which is the subject of the present invention, is an eczema lesion, that is, a skin disease whose main field is the epidermis. ), But there are exceptions. In addition, punctate states such as papules and small blisters, erythema, papules, and various rash elements such as scabs, and wrinkles are considered as three signs. When it becomes chronic, skin symptoms become monotonous, and lichenification and infiltration become prominent. The onset mechanism can be broadly divided into primary irritant and allergic mechanisms, but it is difficult to differentiate between clinical and histopathology.

Histologically, the spongy state of the epidermis is the most important. Besides, keratinization, thickening of the epidermis, infiltration of cells such as dermal lymphocytes are observed in various degrees, and thickening is characteristic in chronic lesions. It becomes. Eczema · Dermatitis group is contact dermatitis, atopic dermatitis, seborrheic dermatitis, monetary eczema, autosensitizing dermatitis, stasis dermatitis, sebum-deficient eczema, sweat blister, V idal moss It is classified as scabies. The treatment method, except for the cause, is to apply an external preparation, mainly a topical external preparation, but it must be carefully selected. In the case of significant contact, it is necessary to use an antihistamine or an antiallergic agent (a chemical mediator release inhibitor).

Skin diseases to be treated

, Specifically, atopic dermatitis, neural dermatitis, contact dermatitis, seborrheic dermatitis, self-sensitizing dermatitis, caterpillar dermatitis, sebum-deficient eczema, senile dermatitis, insect bite Photosensitivity, numbness, prurigo, blister, impetigo rash, eczema, ringworm, lichen, psoriasis, scabies, acne vulgaris, allergic dermatitis, infectious dermatitis, contact dermatitis, parasitic skin Targets include diseases, insect bites, eczema, rashes, mosquitoes, scratches, insect bites, rashes and athlete's foot caused by sweat and skin waste.

About zinc hyaluronate complex (aggregate) The active ingredient of the present invention is a zinc hyaluronate complex (associate)

. Hyaluronic acid usually exists as a sodium salt and is a macromolecule described by Meyer et al., J. Biol. Chem. Vol. 107, p. 629 (1934). Hyaluronic acid is a highly viscous darcosaminoglycan having alternating iS 1,3-glucuronic acid components and / 3 1,4-darcosamine components, and has a molecular weight of 50 kD to several million D. Hyaluronic acid is found in connective tissue in all mammals and is present at high levels in the skin, vitreous body of the eye, synovial fluid, umbilical cord and cartilage tissue. Since hyaluronic acid is a fundamental component of connective tissue, it is biocompatible, biosorbable, and not immunogenic. For this reason, hyaluronic acid performs many biological functions such as lubrication and protection of articular cartilage.

In the zinc hyaluronate complex (associate) of the present invention, the ratio of hyaluronic acid to zinc is a range in which these components exert a synergistic action as a therapeutic agent for the eczema / dermatitis group, and the weight ratio As the hyaluronic acid: zinc is in the range of about 5: 1 to 20: 1, preferably about 10: 1. The average molecular weight of the zinc hyaluronate complex (aggregate) used in the present invention is preferably about 100 kD to 2, OOOkD, more preferably about 400 to 1,200 kD, for example, an average of about lOOOkD Molecular weight is preferred. The zinc hyaluronate complex (aggregate) of the present invention can be produced, for example, by mixing an aqueous solution of sodium hyaluronate and a zinc salt such as an aqueous solution of zinc chloride (European Patent Specification). No. EP 0413016).

Toxicity of zinc hyaluronate complex (aggregate)

Zinc hyaluronate complex (aggregate) was not systemically toxic even when administered subcutaneously to rats and mice at a physical maximum dose of 200 mg Zkg.

About dosage forms The dosage form is, for example, a cream, paste, gel, emulsion, liquid, etc. by dissolving or mixing the zinc hyaluronate complex (compound) of the present invention or additives in the base. Products formed into shapes, liniments, ointments, lotions, etc., in which the zinc hyaluronate complex (associate) or additive of the present invention is dissolved or mixed and dispersed in the base are spread on the support. Elongated (powder etc.), Zinc hyaluronate complex (associate) or additive etc. of the present invention dissolved or mixed and dispersed in the adhesive (Plaster, Tapes, etc.), sprayed (sprayed) and the like.

Administration method

The zinc hyaluronate complex (aggregate) is preferably administered parenterally, particularly applied directly to the skin.

In the case of an external preparation, the action is direct and a rapid effect can be expected. This means that by suppressing sputum in the case of dermatitis, especially atopic dermatitis, it is possible to avoid a vicious circle in which the symptoms worsen due to the breakage. Therefore, it has the advantage of leading to a reduction in the time to complete atopic dermatitis.

The effective dose of the zinc hyaluronate complex (aggregate) of the present invention is 0.01 to 1 mg, preferably 0.03 to 0.5 mg per person, depending on the symptoms. It can be administered one to several times a day.

About external preparation base

Bases for producing zinc hyaluronate composites (associates) as external preparations should be applicable to ordinary liquids, plasters, ointments, creams, lotions, sprays, etc. That's fine. For example, purified water, alcohol, propylene glycol, polyethylene glycol, polyoxyethylene, medium chain fatty acid glyceride, beeswax, olive oil, cocoa butter, lausin butter, beef tallow, hard fat, beeswax , Petrolatum, glycerin, liquid paraffin, squalane, squalene, higher fatty acids and esters such as palmitic acid, myristic acid, isopropyl myristate, stearic acid, cetanol, stearyl alcohol, lauryl alcohol, lano Higher alcohols such as linalcohol, carnauba wax, sodium alginate, gelatin, corn starch, tragacanth gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, dextrin, strong hydroxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methoxy Examples thereof include ethylene monomaleic anhydride copolymer, polyvinyl ether, polyvinyl pyrrolidone, and other surfactants. These bases may be used alone or in combination of two or more.

An ointment can be produced by using a method for producing an ordinary ointment. For example, the active ingredient and the base can be heated and stirred, dispersed by heating, and then cooled to room temperature with stirring.

Creams can usually be produced by using a method for producing creams. For example, first, the base can be produced under heating and stirring, and the active ingredient itself or a solution containing it can be added under heating and stirring, and the resulting emulsion can be cooled to room temperature.

Lotions can usually be produced by using a method for producing a lotion, such as an oily base or a mixture of a heated and melted oily base and an aqueous base, the active ingredient itself or A solution containing this can be added under heating and stirring, then an aqueous base is added, and the resulting liquid can be cooled to room temperature.

Patches can usually be manufactured by using the method of manufacturing patches. For example, an additive is added to a mixed base of a heated and melted oily base and an aqueous base while stirring. Active ingredient itself or containing it The active ingredient itself by adding the solution to be heated under stirring and spreading the resulting plaster into a non-woven fabric and cutting it into an appropriate size, or by mixing it with a heated and melted oily base. Alternatively, a solution containing this is added under heating and stirring, and then this is added to the heated and melted mixture of synthetic resin with stirring, and the resulting plaster is spread on a nonwoven fabric or woven fabric, It can be manufactured by cutting to an appropriate size.

Gels can usually be produced by using a method for producing a gel. For example, after a gel base is uniformly dissolved, an active ingredient is added, heated, dissolved, dispersed, etc. Any of the dosage forms can be produced by a normal manufacturing method.

When the support is used, it is appropriately selected depending on the dosage form, but it is preferable that the effective component is impermeable or hardly permeable and flexible, for example, cellulose acetate, ethyl cellulose, polyethylene, polypropylene, Polyvinyl chloride, vinyl acetate-vinyl chloride copolymer, ethylene monovinyl acetate copolymer, ethylene vinyl acetate-carbon monoxide copolymer, ethylene monobutyl acrylate-carbon monoxide copolymer, polyvinylidene chloride, polyurethan, Nylon, polyethylene terephthalate, polybutylene terephthalate, etc. resin film, aluminum sheet, woven fabric, non-woven fabric, etc., and laminated sheets of these, etc. Any known one can be used, for example, Lil pressure-sensitive adhesives, rubber adhesives, silicone-based adhesive, a urethane adhesive or the like can be mentioned, et al is an acrylic pressure-sensitive adhesives, rubber-based adhesive is preferably used. Further, when spreading on the above-mentioned support, any property such as solvent-based, emulsion-based, or hot-melt-based adhesive can be used. Furthermore, if necessary, inorganic fillers such as kaolin, bentonite and titanium oxide, viscosity modifiers, anti-aging agents, PH modifiers, humectants such as glycerin and propylene glycol, buffering agents, preservatives, fragrances, etc. May be added.

The therapeutic agent for eczema and dermatitis according to the present invention comprises 0.001% to 5%, preferably 0.01% to 2%, of the zinc hyaluronate complex (associate) of the present invention together with a conventional pharmaceutical carrier. Can be contained.

Moreover, other drugs can be blended and used in the composition according to the present invention. The type of the drug is not particularly limited, and for example, a local anesthetic, a vasoconstrictor, an antihistamine, an astringent, a bactericidal agent, an anti-inflammatory enzyme, vitamins, a crude drug component, and the like can be blended. Example

Next, the present invention will be described more specifically with reference to examples.

Example 1. Action against atopic dermatitis.

For the purpose of investigating the inhibitory effect and dose response of the gel of the hyaluronan complex (aggregate) on the progression of dermatitis, male NC / Nga mice (hereinafter referred to as “NC mice”), which are models of fatpy dermatitis The test was conducted using a complex of hyaluronic acid and zinc as a test substance. The group treated with zinc hyaluronate complex (aggregate) was administered 0.1, 0.2, 0.5 and 1.0% gel preparations 3 times a day, 15 OmgZ times on the shaved neck of the animal. Repeated application for 10 days. Similarly, a placebo group (base) was applied in the same manner (15 animals in each group). The efficacy of the zinc hyaluronate complex (aggregate) was evaluated by scoring the cervical dorsal symptom on a five-point basis, counting the number of scratches on the test substance application site, and histopathological examination. Evaluation was performed.

The results are shown in Figs. From this result, zinc hyaluronate complex In the combined (aggregate) gel, dose responsiveness peaking at a concentration of 0.5% was observed in NC mice when the skin symptom score decreased and the number of scratching wounds decreased. At all doses, a trend toward a decrease with a statistically significant concentration was observed. In mast cells in the dermis, a tendency to decrease up to a concentration of 1.0% depending on the dose was confirmed. Based on this, the gel of zinc hyaluronate complex (aggregate) has the effect of inhibiting the progression of dermatitis according to the dose and the effect of improving the symptoms in NC mice with symptoms similar to atopic dermatitis. It was considered a thing.

Example 2. Action against atopic dermatitis

Using a male NC / Nga mouse, a topical corticosteroid (0.5% zinc hyaluronate complex (aggregate)) for the prevention of the progression of dermatitis, For the purpose of comparison with 0.12% valerate (valerate), a test was conducted using a zinc hyaluronate complex (aggregate) as a test substance. The 0.5% zinc hyaluronate complex (associate) gel group received 0.5% zinc hyaluronate complex (aggregate) gel daily on the shaved neck of the animal. It was applied 3 times and 1 50 mgZ times for 10 days. The valerate solid zonate group was applied to the shaved cervical dorsal area of the animal 0.12% of valerate solid zonate once a day on the 1st, 3rd, 5th, 7th, and 9th days. l O Omg / application. The base group and the non-treated group were applied in the same manner as the zinc hyaluronate complex (aggregate) (15 per group).

The efficacy of the zinc hyaluronate complex (aggregate) was evaluated by scoring the cervical dorsal symptom on a 6-point basis, measuring the percentage by leukocyte type, measuring IgE, and histopathological examination. .

The results are shown in FIGS. From this result, under the present test conditions, the gel of zinc hyaluronate complex (aggregate) has the effect of suppressing the progression of dermatitis and the effect of improving symptoms in NC mice. The improvement effect was superior to the existing betamethasone valerate formulation.

Example 3. Symptom improvement effect of allergic contact dermatitis

In order to investigate the effect of the zinc hyaluronate complex (associate) of the present invention on dinitrochlorobenzene (hereinafter referred to as “DNCB”) sensitized and induced delayed earlobe swelling model, Tests were conducted using male BALB / C mice with various concentrations of zinc hyaluronate complexes (associates) as test substances.

(1) Preparation of ear wing swelling model

Remove the mouse's abdomen, apply 1% DNCB solution (solvent acetone / olive oil 4: 1) and sensitize (day 0), then put 0.1% DNCB into the right ear wing on day 5. Apply and induce to create an ear wing swelling model.

(2) Drug application

Gels of zinc hyaluronate complex (aggregate) at various concentrations (0.125, 0.25, 0.5, 0.75, 1%) with no application and gel base only as controls (each n = 10) 3 hours before induction, apply to both sides of the right ear wing, wipe off the drug just before the induction, remove the drug, 0.1% DNCB solution induction, further 1 hour after induction, 24, 48, 72 Each drug was applied after an hour. The thickness of the ear wings was measured before, 24, 48, 72, and 96 hours after the induction, and the difference in the thickness of the ear wings before the induction was calculated as swelling.

(3) Results

The results are shown in FIG. Based on this result, the gel of zinc hyaluronate complex (compound) was applied in the Effector phase, and the mouse ear wing swelling induced by 1% sensitization of DNCB • 0.1% induction was adjusted to the applicable concentration. Suppressed depending on.

Example 4. Symptom improvement effect of allergic contact dermatitis

Hyaluron as a comparative reference for the effect on ear wing swelling In order to compare the action of sodium and zinc chloride gels with the gel of the zinc hyaluronate complex (associate) of the present invention, a test was conducted using 9-week-old male BALB / C mice. went.

(1) Preparation of ear wing swelling model

In the same manner as in Example 3, a DNCB solution was applied to mice to induce sensitization, and an ear wing swelling model was prepared.

(2) Drug application

As in Example 3, uncoated control, gel base control, 0.5% zinc hyaluronate complex (aggregate) gel, 0.488% sodium hyaluronate gel and 0.083% zinc chloride gel. The drug was applied to the application group (n = 10), and the thickness of the ear wing was measured.

The result is shown in FIG. From this result, the gel of 0.5% zinc hyaluronate complex (aggregate) significantly suppressed the ear wing swelling of mice. 0.48% sodium hyaluronate gel (0.5% zinc hyaluronate complex)

(Including hyaluronic acid corresponding to (associate)), 0.083% zinc chloride gel (containing zinc corresponding to 0.5% zinc hyaluronate complex (associate)), and also showed a tendency to suppress swelling However, its action was weak compared to the gel of zinc hyaluronate complex (aggregate). Therefore, the inhibitory effect of zinc hyaluronate complex (aggregate) on the wing swelling is thought to be due to the synergistic action of hyaluronic acid and zinc.

Example 5. Symptom-improving action of allergic contact dermatitis

9 weeks for the purpose of examining the time course of mouse ear wing swelling induced by sensitization and induction of MCB, and the effects of zinc hyaluronate complex (aggregate) and comparative drug candidates Using male BALB / C mice of the age, the test was carried out using the zinc oxide single ointment as a comparative control substance and the zinc hyaluronate complex (associate) as the test substance. (1) Preparation of ear wing swelling model

In the same manner as in Example 4, DNCB solution was applied to mice to induce sensitization, and an ear wing swelling model was prepared.

(2) Drug application

No application, gel base, 0.125%, 0.25%, 0.5%, 0.75% and 1% zinc hyaluronate complex (associate) gel, white petrolatum, zinc white simple ointment as in Example 4. The drug was applied to the group (n = 6), and the thickness of the ear wing was measured. Figure 7 shows the results. From this result, the gel of zinc hyaluronate complex (aggregate) suppressed mouse ear wing swelling depending on the applied concentration, whereas Zinc Hua simple ointment showed no inhibitory action. Therefore, it was found that the action of the zinc hyaluronate complex (aggregate) is an action that is not found in the zinc ointment, which is a zinc compound already used in clinical practice.

Example 6. Symptom improvement effect of irritant contact dermatitis

The effect of the gel of the zinc hyaluronate complex (associate) of the present invention on a rat dermatitis model by primary stimulation induced by application of sodium lauryl sulfate (SLS) was tested.

The next day after depilation, a model was prepared by applying a patch test adhesive paste with 50 iL of 2% SLS aqueous solution dripped on the left and right backs of Std: HarUy guinea pigs for 12 hours. Each site was made of zinc hyaluronate. The complex (aggregate) gel (0.25%, 0.5%, 0.75% and 1%) or gel base, 0.035 g each, was applied once a day for 6 days. A non-application group was also provided as a control.

Macroscopic findings of skin symptoms were evaluated according to the Draize criteria, and a erythema score was obtained. The results for 7 days are shown in Fig. 8, and the cumulative total for 7 days is shown in the graph in Fig. 9. As can be seen from Fig. 8, in the 1% lead hyaluronate complex (aggregate) gel-coated group, the gel base was applied after the 5th day. A significant decrease in erythema score was observed. In the cumulative period of 7 days, a significantly lower score was obtained in the 1% zinc hyaluronate complex (aggregate) application group compared to the base.

Example 7. Synergistic effect of zinc hyaluronate complex (aggregate) in improving symptoms of irritant contact dermatitis

The same experiment as in Example 6 was repeated. However, in order to confirm the synergistic effect, the concentration of zinc hyaluronate complex (aggregate) in the gel was fixed at 1%, and for comparison, 0.976% sodium hyaluronate gel (on 1% zinc hyaluronate) Corresponding hyaluronic acid), 0.166% zinc chloride gel (containing zinc equivalent to 1% zinc hyaluronate), sodium chloride-containing gel and mixed gel of sodium hyaluronate gel and zinc chloride gel (1 % Containing hyaluronic acid and zinc corresponding to zinc hyaluronate).

The results of observation over time are shown in Figure 10, and the cumulative total for 7 days is shown in Figure II. From the results in Fig. 11, the zinc hyaluronate complex (aggregate) of the present invention has a low erythema score not only when compared with sodium hyaluronate gel and zinc chloride gel but also when compared with mixed gel. Cumulative effect was confirmed by bringing the total to the complex.

Claims

The scope of the claims

I. A therapeutic agent for eczema / dermatitis group comprising a zinc hyaluronate complex (aggregate).

2. The therapeutic agent for eczema / dermatitis group according to claim 1, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about lOOkD to about 2,000 kD.

3. The eczema / dermatitis group therapeutic agent according to claim 2, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 400 to 1,200 kD.

4. The therapeutic agent for eczema / dermatitis group according to claim 3, wherein the zinc hyaluronate complex (aggregate) has an average molecular weight of about 1, OOOkD.

5. The eczema / dermatitis group therapeutic agent according to any one of claims 1 to 4, wherein the weight ratio of hyaluronic acid to zinc is 5: 1 to 20: 1.

6. The therapeutic agent for eczema / dermatitis group according to claim 5, wherein the weight ratio of hyaluronic acid to zinc is about 10: 1.

7. If the eczema / dermatitis is contact dermatitis, atopic dermatitis, seborrheic dermatitis, progressive keratoderma dermatosis, monkey zoster, eczema dermatitis, chronic simple lichen, The therapeutic agent for eczema / dermatitis group according to any one of claims 1 to 5, which is self-sensitizing dermatitis or sebum-deficiency dermatitis.

8. Eczema ♦ Use of zinc hyaluronate complex (aggregate) for the manufacture of dermatitis treatment.

9. Use according to claim 8, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about lOOkD to about 2,000 kD.

10. The use according to claim 9, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 400 to 1,200 kD.

II. Use according to claim 10, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 1, OOOkD.

1 2. Use according to any one of claims 8 to 11, wherein the weight ratio of hyaluronic acid to zinc is 5: 1 to 20: 1.

1 3. Use according to claim 12, wherein the weight ratio of hyaluronic acid to zinc is about 10: 1.

1 4. The eczema and dermatitis are contact dermatitis, atopic dermatitis, seborrheic dermatitis, progressive oil palm keratoderma, monkey zoster, eczema dermatitis, chronic simple lichen The use according to any one of claims 8 to 13, which is self-sensitizing dermatitis or sebum-deficiency dermatitis.

1 5. A method of treating an eczema / dermatitis group therapeutic agent, comprising administering a zinc hyaluronate complex (aggregate) to a patient having eczema and dermatitis.

16. The method according to claim 15, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 100 W) to about 2,0 OOkD.

17. The method according to claim 16, wherein the zinc hyaluronate complex (associate) has an average molecular weight of about 400 to 1,200 kD.

18. The method according to claim 17, wherein the zinc hyaluronate complex (associate) has a molecular weight of about 1, 000 kD.

1 9. The treatment method according to any one of claims 15 to 18, wherein a weight ratio of hyaluronic acid to zinc is 5: 1 to 20: 1.

20. The method of claim 19, wherein the weight ratio of hyaluronic acid to zinc is about 10: 1.

2 1. The eczema and dermatitis are contact dermatitis, atopic dermatitis, seborrheic dermatitis, progressive oil palm keratoderma, monkey zoster, eczema dermatitis, chronic simple lichen The treatment method according to any one of claims 15 to 20, which is self-sensitizing dermatitis or sebum-deficiency dermatitis.