JP2000038352A - External composition - Google Patents

Abstract

(57) Abstract: An external composition comprising a non-steroidal anti-inflammatory agent and a heparin-like substance. EFFECTS OF THE INVENTION According to the present invention, there is provided an externally applied composition which remarkably improves the symptoms of dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema, and is excellent in safety. be able to.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an external composition having an excellent therapeutic effect on dry skin diseases and inflammatory skin diseases represented by atopic dermatitis and housewife eczema.

[0002]

2. Description of the Related Art Conventionally, treatment of various skin diseases, especially dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema has been known. Topical, steroidal and non-steroidal external preparations are widely used.

[0003] However, steroidal external preparations may cause side effects such as increased susceptibility to infection, thinning of the skin, and weakening of the blood vessel wall at the site of application, and in addition, the dermally-administered drug may be absorbed by the skin. Can cause systemic side effects, and its use requires extreme caution.

[0004] On the other hand, non-steroidal external preparations are less effective than steroidal external preparations and are only used as supplements to steroidal external preparations.

[0005] Japanese Patent Application Laid-Open No. 7-316075 discloses that the inflammation of atopic dermatitis can be effectively suppressed by using a large amount of a moisturizing component of 20 to 40% by weight together with a steroidal and / or nonsteroidal anti-inflammatory analgesic external preparation. It is shown that it is possible. However, blending a large amount of humectant of 20% by weight or more in preparing an external preparation is not preferable in terms of increasing the stickiness and ensuring the storage stability of the formulation, and exhibits an effect with as little blending amount as possible. Moisturizing ingredients are desirable.

Furthermore, when a large amount of a water-absorbing water-soluble substance such as polyhydric alcohols such as glycerin and propylene glycol and mucopolysaccharides such as hyaluronic acid and chondroitin sulfate is blended as a moisturizing component, the composition is affected by environmental conditions. Conversely, especially under low humidity, water on the skin is sucked up, which may worsen the condition of the skin, and it is not expected to enhance the anti-inflammatory effect by the combined use with an anti-inflammatory analgesic.

The present invention has been made in view of the above circumstances, and it is an object of the present invention to provide a composition for external use which has an excellent therapeutic effect on dry skin diseases and inflammatory skin diseases and has few side effects. .

[0008]

Means for Solving the Problems and Embodiments of the Invention The present inventors have conducted intensive studies in order to achieve the above-mentioned object, and as a result, they have come to focus on heparin-like substances among skin moisturizers. By using a heparin-like substance in combination with a nonsteroidal anti-inflammatory agent, the heparin-like substance quickly improves rough conditions due to dry skin, and suppresses inflammation in combination with the nonsteroidal anti-inflammatory agent, as described below. As shown in Examples and Comparative Examples, the therapeutic effect on skin dryness and inflammatory symptoms is synergistically improved as compared with the case of using each of them alone, even if a large amount of a heparin-like substance is not blended. It has been found that the drug efficacy as a non-steroidal external preparation is remarkably improved, and the present invention has been accomplished.

That is, the present invention provides an external composition comprising a non-steroidal anti-inflammatory agent and a heparin-like substance.

Hereinafter, the present invention will be described in more detail.

The composition for external use of the present invention is a combination of a non-steroidal anti-inflammatory agent and a heparin-like substance, wherein the non-steroidal anti-inflammatory agent of the present invention includes eczema, dermatitis and the like. Although it is not particularly limited as long as it is used for the treatment, specifically, for example, bufexamac, ibuprofen piconol, ufenamate, suprofen, loxoprofen, bendazac, indomethacin, diclofenac, flurbiprofen, ibuprofen, ketoprofen, piroxicam , Felbinac, glycyrrhetinic acid, glycyrrhizic acid and salts thereof and the like.
Glycyrrhetinic acid and salts thereof are effective.
These drugs can be used alone or in an appropriate combination of two or more.

The amount of the above non-steroidal anti-inflammatory agent in the composition for external use of the present invention can be appropriately selected depending on the kind of the non-steroidal anti-inflammatory agent to be added, and the amount is not particularly limited. However, it is usually desirable that the content is 0.1 to 10% (% by weight, the same applies hereinafter), particularly 0.3 to 5% based on the whole composition. If the amount is too large, not only does it have no meaning in terms of efficacy, it may be unfavorable in the production process of the product, and if it is too small, sufficient medicinal effects may not be obtained.

The heparin analogue used in the present invention is:
Mucopolysaccharide polysulfate esters listed in the Japanese Pharmacopoeia Non-Pharmacopoeial Standards are preferably used.

The amount of the above-mentioned heparin-like substance in the composition for external use of the present invention can be appropriately selected depending on the kind of the non-steroidal anti-inflammatory agent used in combination, and the amount is not particularly limited. However, it is usually desirable that the content is 0.1 to 1%, particularly 0.2 to 0.5%, based on the whole composition. If the amount is too large, the effect of further compounding cannot be obtained, so that it is not economical. If the amount is too small, a synergistic effect may not be sufficiently obtained even when combined with a nonsteroidal anti-inflammatory agent. Further, the heparin-like substance is used in combination with a non-steroidal anti-inflammatory agent as described above to synergistically improve the efficacy of dry skin disease and inflammatory skin disease. The blending ratio with respect to the inflammatory agent (the total amount when two or more types are used in combination) is not particularly limited, but is usually a nonsteroidal anti-inflammatory agent: heparin-like substance (weight ratio) = 1: 10 to 100: 1, especially 3: 5 to 25: 1. Outside the above range, the effects of the present invention due to the combined use thereof may not be sufficiently obtained.

The composition for external use of the present invention may further contain, if necessary, an antihistamine, a local anesthetic, and the like, in order to further enhance the efficacy against various skin diseases, as long as the effects of the present invention are not impaired. Various agents such as a bactericide, a vitamin agent, a cooling agent and the like can be blended.

[0016] Specific examples of these drugs include antihistamines such as diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, and isotipezil hydrochloride. These may be used alone or in combination of two or more. The compounding amount is preferably from 0.1 to 2% based on the whole composition for external use. Examples of the local anesthetic include lidocaine, dibucaine or a hydrochloride thereof, ethyl aminobenzoate and the like, and these can be used alone or in an appropriate combination of two or more. Is preferably 0.1 to 2% with respect to the whole composition for external use. Examples of fungicides include chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, depotassium chloride, biosol, phenol and the like.
These can be used singly or in an appropriate combination of two or more kinds, and the compounding amount is preferably 0.05 to 1% based on the whole external composition. Further, as vitamins, for example, tocopherol, tocopherol acetate, cholecalciferol, pyridoxine hydrochloride, retinol palmitate, vitamin A oil and the like can be used, and these can be used alone or in appropriate combination of two or more. The amount of the compound is 0.1% based on the whole external composition.
It is preferably from 0.5 to 3%. Examples of the cooling agent include menthol, camphor and the like, and these can be used alone or in an appropriate combination of two or more kinds. ~ 5
% Is preferred.

Furthermore, unless otherwise impairing the effects of the present invention, the composition for external use of the present invention may further contain water-soluble components, preservatives, pH adjusters, thickeners, and the like, which are added to the general composition for external use. , An antioxidant and the like can be appropriately compounded as needed.

The composition for external use of the present invention may be in any form, for example, a solution type, an emulsion type, a cream type, an ointment type, a gel preparation, a solid preparation, a poultice, a pack, a tape and the like. However, the present invention is not limited to these. In addition, the preparation method is not particularly limited, and for example, it is prepared by blending appropriate components such as known excipients necessary for preparing preparations of various dosage forms and by a usual method of each preparation. Can be.

The amount and method of use of the composition for external use of the present invention are not particularly limited, and can be appropriately selected depending on the dosage form and the like. Apply heparin-like substance to a diseased skin by applying it evenly several times a day to the affected area and its surroundings several times a day. It has the effect of remarkably improving the symptoms of dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema, by suppressing inflammation in combination with nonsteroidal anti-inflammatory drugs, An externally applied composition that does not exhibit side effects, such as a steroidal external preparation, can be obtained.

As described above, according to the composition for external use of the present invention, the effect of a composition for external use containing a non-steroidal anti-inflammatory agent on dry skin diseases and inflammatory skin diseases can be obtained without impairing the safety. It can be significantly improved.

[0021]

EXAMPLES Hereinafter, the present invention will be described in detail with reference to Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Examples 1 and 2 and Comparative Examples 1 and 2] For the compositions shown in Table 1, components A (oil phase) and component B (aqueous phase) were each heated and dissolved at 60 ° C. After the component B was gradually added, the mixture was emulsified and cooled, and neutralized with potassium hydroxide to prepare the emulsions (external compositions) of Examples 1 and 2 and Comparative Examples 1 and 2. The following tests were performed. Table 2 shows the results. <Evaluation of Rough Skin Improvement and Anti-Inflammation> The backs of five Hartley female guinea pigs, 6 weeks old, were shaved, immersed in a mixed solution of acetone / ether (50/50 parts by volume) for 10 minutes, washed with warm water and dried. A rough skin condition model was prepared. For each of these guinea pigs, 6 sites on the back were used as sample application sites, and at each site, non-application, control (distilled water) and the emulsions of Examples 1 and 2 and Comparative Examples 1 and 2 were randomly assigned as samples. The test was performed as follows.

First, an appropriate amount is applied to each of the allocation sites so that the application amount of each sample becomes the same on the day of the preparation of the rough skin, and the first day of application is performed. Each sample was applied, and sample application was performed on the second and third days. On the 2nd and 3rd days, before the sample application and 24 hours after the 3rd day application (4th day), the symptoms of each site were visually observed.
Scores were evaluated according to the following criteria for rough skin conditions, and the number of guinea pigs corresponding to each score was examined to evaluate the effect of improving rough skin. Then, after observing the skin condition on the fourth day, a tissue section of the skin was prepared according to a conventional method, subjected to hematoxylin and eosin staining, observed, and scored according to the following histopathological evaluation criteria. The number of guinea pigs corresponding to the score was examined to evaluate histopathologically the improvement of rough skin and the anti-inflammatory effect. 0 non-application portion in comparison with the first non-coating portion that is improved compared to 2 non-application portion is remarkably improved as compared with the criterion score determination Priority determination criteria 3 uncoated site of rough skin condition is slightly improved and the difference there is no histopathological evaluation criteria scoring evaluation based on quasi-hyperkeratotic skin thickening the dermis of cell infiltration - that was such and such to ± mild mild mild + moderate moderate moderate ++ high degree high degree of High

[0024]

[Table 1]

[0025]

[Table 2]

According to the results shown in Table 2, according to the composition for external use of the present invention in which bufexamac which is a non-steroidal anti-inflammatory agent and a heparin-like substance were used in combination, Comparative Examples 1 and 2 were used alone. Compared with the composition for external use of No. 2, the dry and rough skin condition was remarkably improved, and the anti-inflammatory effect was further enhanced, and hyperkeratosis, epidermal thickening and cell wetting accompanying inflammation were also remarkably improved. . According to the results of the above rough skin improvement and anti-inflammatory evaluation, the topical composition of the present invention in which a nonsteroidal anti-inflammatory agent and a heparin-like substance were used in combination showed that dry skin diseases represented by atopic dermatitis and housewife eczema And the treatment of the symptoms of inflammatory skin diseases.

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

[Example 3] Emulsion composition (% by weight) A: oil phase part Sprofen 1.0 Sorbitan monostearate 3.0 Polyoxyethylene (20) sorbitan monostearate 4.0 Stearyl alcohol 2.0 Adipic acid diisopropyl 1.0 B: water phase heparinoid 0.3 1,3-butylene glycol 1.0 methylparaben 0.2 carboxyvinyl polymer 0.2 potassium hydroxide Appropriate amount purified water Balance total 100.0

The above component A (oil phase) and component B (water phase)
Was heated and dissolved at 60 ° C. respectively, and then the B component was gradually added to the A component, emulsified and cooled, and then neutralized with potassium hydroxide to obtain an emulsion as an external composition of Example 3.

[Example 4] Oily ointment composition (% by weight) Ufenamate 5.0 Heparin analog 0.2 Stearyl alcohol 5.0 Purified water 2.0 Glycerin monostearate 2.0 Polyoxyethylene (20) monostearin Sorbitan acid 0.3 Plastibase 85.5 Total 100.0

Ufemate, stearyl alcohol, glyceryl monostearate, POE (2
0) After sorbitan monostearate was heated and dissolved at 60 ° C., it was kneaded with a heparin-like substance previously dissolved in purified water and plastibase to prepare an oil-based ointment as an external composition of Example 4.

[Example 5] Gel ointment composition (% by weight) Ibuprofen piconol 3.0 Heparin analog 0.5 Polyoxyethylene (20) cetyl ether 3.0 Ethanol 20.0 1,3-butylene glycol 10. 0 Carboxyvinyl polymer 1.5 Hydroxypropyl cellulose 0.1 Purified water 61.7 Sodium hydroxide 0.2 Total 100.0

After sequentially dissolving the above components, the mixture was neutralized with sodium hydroxide to prepare a gel ointment as the external composition of Example 5.

Example 6 Cream Composition (% by Weight) A: Oil Phase Benzadac 3.0 Stearyl Alcohol 3.0 Squalane 27.0 Sorbitan Monostearate 3.0 Polyoxyethylene (20) Sorbitan Monostearate 4.0 Diisopropyl adipate 1.0 Butylparaben 0.1 B: Aqueous phase part Heparin-like substance 0.3 1,3-butylene glycol 10.0 Methylparaben 0.2 Purified water 48.4 Total 100.0

The above components A (oil phase) and B (water phase)
Was heated and dissolved at 70 ° C. respectively, and then the B component was gradually added to the A component, followed by emulsification and cooling to prepare a cream as an external composition of Example 6.

[Example 7] Transparent lotion composition (% by weight) Glycyrrhetinic acid 0.3 Heparin analog 0.5 Diphenhydramine 1.0 Ethanol 15.0 Polyethylene glycol 400 3.0 Purified water 80.2 Total 100.0

The above components were sequentially dissolved to prepare a transparent lotion as an external composition of Example 7.

When the compositions for external use of Examples 3 to 7 were evaluated for improvement of rough skin and anti-inflammation in the same manner as in Examples 1 and 2, all the preparations showed excellent rough skin improvement and anti-inflammatory effects. Was.

[0039]

As described above, the composition for external use of the present invention, by using a heparin-like substance in combination with a nonsteroidal anti-inflammatory agent, can quickly remove the rough state of the heparin-like substance due to dry skin. It can improve and effectively suppress inflammation in combination with non-steroidal anti-inflammatory drugs. Therefore, according to the composition for external use of the present invention, the composition for external use which significantly improves the symptoms of dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema, and is also excellent in safety Can be provided.

[Procedure amendment]

[Submission date] August 28, 1998 (1998.8.2
8)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0025

[Correction method] Change

[Correction contents]

[0025]

[Table 1]

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0026

[Correction method] Change

[Correction contents]

According to the results shown in Table 2, according to the composition for external use of the present invention in which bufexamac which is a non-steroidal anti-inflammatory agent and a heparin-like substance were used in combination, Comparative Examples 1 and 2 were used alone. Compared to the composition for external use of No. 2, the dry and rough skin condition was remarkably improved, and the anti-inflammatory effect was further enhanced, and hyperkeratosis, epidermal thickening and cell infiltration accompanying inflammation were also remarkably improved. . According to the results of the above rough skin improvement and anti-inflammatory evaluation, the topical composition of the present invention in which a nonsteroidal anti-inflammatory agent and a heparin-like substance were used in combination showed that dry skin diseases represented by atopic dermatitis and housewife eczema And the treatment of the symptoms of inflammatory skin diseases.

Continued on the front page F term (reference) 4C084 AA19 MA63 NA06 ZA542 ZA891 ZB112 4C086 AA01 AA02 BB02 BC15 BC37 BC90 EA27 MA02 MA09 MA10 MA63 NA06 ZA89

Claims (1)

[Claims] 1. A composition for external use comprising a nonsteroidal anti-inflammatory agent and a heparin-like substance.