JP2000143486A - Skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin preparation for external use capable of extremely improving not only a were rough skin, but also rough skin symptoms associated with atopic dermatitis, drying skin diseases represented by eczema of a housewife or the like, and inflammatory skin diseases, and effective for treating or preventing these rough skin symptoms. SOLUTION: This skin preparation for external use contains a heparinoid and a betaine, and further an antiinflammatory agent. The heparinoid used in the skin preparation for external use of the present invention is a polysulfate of a mucopolysaccharide, and the polysulfate of a mucopolysaccharide described in the non-official drug standard can be used suitably. The betaine used in the skin preparation for external use of the present invention is an N-trialkyl substitution product of an amino acid, and concrete examples include glycine- betaine, γ-butyrobetaine, β-alanine-betaine and glutamic acid betaine, and especially glycine-betaine or the like out of these compounds is more suitably used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for skin having an excellent therapeutic effect on dry skin diseases such as atopic dermatitis and housewife eczema, and rough skin caused by inflammatory skin diseases.

[0002]

2. Description of the Related Art With the westernization of eating habits, changes in the living environment, aging and increased stress, various skin diseases, especially atopic dermatitis and housewife eczema, are to be solved. The number of people suffering from dry skin diseases, inflammatory skin diseases, etc. is increasing. For these diseases, symptomatic treatment is mainly given, and treatment with steroids and non-steroids is performed for pharmaceuticals, and glycerin, urea, collagen and hyaluronic acid are mainly used for quasi drugs and cosmetics. Care is being provided by a formulation containing a humectant such as sodium.

[0003] However, these symptomatic treatments and cares have not been able to improve skin roughness associated with dry skin diseases and inflammatory skin diseases such as atopic dermatitis and housewife eczema. That is, it has been reported that administration of conventional steroids or non-steroids suppresses inflammatory symptoms, but it is difficult to improve rough skin conditions, and conversely causes side effects such as redness and tightness. In addition, quasi-drugs and cosmetics mainly containing moisturizers are effective to some extent on rough skin caused by a low amount of sebum and moisture, but are effective against rough skin accompanied by inflammation such as atopic dermatitis. Has almost no effect and has a problem that it cannot be expected to have a sufficient effect on improvement of a wide range of types of rough skin.

[0004] The present invention has been made in view of the above circumstances, and is not limited to mere skin roughness, but also to dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema. It is an object of the present invention to provide a skin external preparation having excellent improvement and prevention effects.

[0005]

Means for Solving the Problems and Embodiments of the Invention The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have focused on a heparin-like substance as a symptom ameliorating agent for rough skin symptoms. Finally, by using betaines in combination with the heparin-like substance, the keratin water retention enhancing action, anti-inflammatory action, and blood circulation promoting action of the heparin-like substance and the moisturizing action of the betaines work synergistically to perform the following steps. As shown in Examples and Comparative Examples, compared to the case of using these alone, for the symptoms of dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema, etc. It has been found that they exhibit a remarkable improvement and preventive effect, and as a result of further intensive studies, they have been found to be effective in improving glycyrrhetic acid compounds By combining the inflammatory agent, and found that exhibit superior improvement and prevention effect, leading to completion of the present invention.

That is, the present invention provides a skin external preparation characterized by containing a heparin-like substance and betaines. Here, it is more preferable that the skin external preparation further contains an anti-inflammatory agent.

Hereinafter, the present invention will be described in more detail.
The topical skin preparation of the present invention is a combination of a heparin-like substance and betaines, and the heparin-like substance used in the topical skin preparation of the present invention is a polysulfate ester of mucopolysaccharide, Those listed in the foreign pharmaceutical standards are preferably used.

[0008] The amount of the above-mentioned heparin-like substance in the external preparation for skin of the present invention can be appropriately selected depending on the kind of betaines used in combination, and the amount is not particularly limited. 0.0 for the whole
It is desirable that the content be 1 to 5% (% by weight, hereinafter the same), particularly 0.05 to 2%. 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 betaines.

The betaines used in the external preparation for skin of the present invention are N-trialkyl-substituted amino acids, and specifically include, for example, glycine betaine, γ-butyrobetaine, β-alanine betaine, betaine glutamate, and phenylalanine betaine. , Alanine betaine, valine betaine, lysine betaine, ornithine betaine, taurobetaine, tomalin, trigonine, carnitine, atrinin, homoserine betaine, antopreurin, stachidrine, etc., and in the case of the present invention, among these, glycine betaine Etc. are more preferably used. These betaines can be used alone or in an appropriate combination of two or more.

The amount of the betaines in the external preparation for skin of the present invention can be appropriately selected depending on the kind and the like, and the amount is not particularly limited.
Usually 0.01 to 10%, especially 0.05, based on the whole preparation
It is desirable to set it to 5%. If the amount is too large, stickiness of the preparation may become a problem, and if the amount is too small, a sufficient synergistic effect may not be obtained.

The betaines described above are used in combination with the above-mentioned heparin-like substances to synergistically improve and prevent the effects of dry skin diseases and rough skin symptoms associated with inflammatory skin diseases. There is no particular limitation on the mixing ratio (total amount when two or more types are used in combination) with respect to the heparin-like substance,
Normal heparin analog: betaines (weight ratio) = 1: 5
It is desirable that the ratio be from 00 to 10: 1, especially from 1: 100 to 5: 1. Outside the above range, the effects of the present invention due to the combined use thereof may not be sufficiently obtained.

The external preparation for skin of the present invention is more effective when an anti-inflammatory agent is further added thereto. Examples of the anti-inflammatory agent used in the present invention include glycyrrhetinic acid compounds, glycyrrhizic acid compounds, and steroidal compounds. And non-steroidal anti-inflammatory agents, anti-inflammatory enzyme agents and the like. In the case of the present invention, among these, glycyrrhetic acid compounds, glycyrrhizic acid compounds and the like are particularly preferably used.

More specifically, glycyrrhetinic acid compounds such as glycyrrhetinic acid, stearyl glycyrrhetinate, glycyrrhetinic acid glycerin, and pyridoxine glycyrrhetinic acid; glycyrrhizic acid compounds such as glycyrrhizic acid, trisodium glycyrrhizinate, and dipotassium glycyrrhizinate And monoammonium glycyrrhizinate, methyl glycyrrhizinate, and the like. These can be used alone or in an appropriate combination of two or more.

The compounding amount of the above-mentioned anti-inflammatory agent in the external preparation for skin of the present invention can be appropriately selected depending on the kind of the compounding anti-inflammatory agent and the like, and the compounding amount is not particularly limited. 0.01 to 10% of the whole,
In particular, it is desirable to set it to 0.05 to 5%. If the amount is too large, not only does it have no significance in terms of efficacy, but also there may be inconveniences such as deterioration in the feeling of use of the preparation. If the amount is too small, the effect of the compounding may not be sufficiently obtained.

The blending ratio of the heparin-like substance (total amount when two or more kinds are used in combination) is not particularly limited, but usually, heparin-like substance: anti-inflammatory agent (weight ratio) = 1: 100- The ratio is desirably 5: 1, particularly 1:20 to 2: 1. Outside the above range, the effects of the present invention due to the combined use thereof may not be sufficiently obtained.

The external preparation for skin of the present invention may contain, if necessary, an antihistamine, a local anesthetic, in addition to the above components, in order to further enhance the effects on various skin diseases and symptoms as long as the effects of the present invention are not impaired. , A variety of agents such as bactericides, vitamins, and cooling agents.

Specific examples of these drugs include antihistamines such as diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, and isotipedil hydrochloride. These may be used alone or in combination of two or more. The compounding amount is preferably 0.1 to 2% based on the whole preparation. Examples of the local anesthetic include lidocaine, dibucaine or a hydrochloride thereof, and ethyl aminobenzoate. These can be used alone or in appropriate combination of two or more kinds. Is preferably 0.1 to 2% based on the whole preparation.

Examples of the bactericide include chlorhexidine hydrochloride, benzalkonium chloride, benzethonium chloride, depotassium chloride, biosol, and phenol. These can be used alone or in combination of two or more. The compounding amount is preferably 0.05 to 1% based on the whole preparation. 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 combination of two or more. , The amount of the compound is 0.05 to
3% is preferred. Examples of the cooling agent include menthol, camphor and the like.
More than one species can be used in appropriate combination, and the compounding amount is preferably 0.1 to 5% based on the whole preparation.

Further, the skin external preparation of the present invention may further contain, in addition to the above-mentioned components, surfactants, oils, alcohols, humectants, thickeners, etc., unless otherwise impaired. An agent, a preservative, an antioxidant, a chelating agent, a pH adjuster, a fragrance, a dye, and the like can be appropriately compounded as needed.

The external preparation for skin 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. The preparation method is not particularly limited, and for example, a suitable component such as a known excipient necessary for preparing various formulations may be blended together with the above essential components and optional components to prepare each formulation. Can be prepared by a conventional method.

The amount and usage of the external preparation for skin of the present invention are not particularly limited, and can be appropriately selected depending on the above-mentioned dosage forms and the like. The usual amount of various skin external preparations such as conventional medicines, quasi-drugs, cosmetics, etc. used for treatment or care several times a day in the affected area where dry skin disease or inflammatory skin disease occurs and in the vicinity thereof By applying it to the skin with the above-mentioned disease or the skin with the possibility that the skin may be roughened by applying it uniformly, the heparin-like substance enhances keratin water retention, anti-inflammatory action and promotes blood circulation. In combination with the moisturizing action of betaines, it quickly improves rough conditions due to skin dryness, resulting in dry skin diseases and inflammations such as atopic dermatitis and housewife eczema Rough skin symptoms associated with sexual skin diseases can be effectively improved or prevent further, when formulated with anti-inflammatory agents, since the anti-inflammatory effect of anti-inflammatory agents act synergistically, which is more effective.

As described above, according to the external preparation for skin of the present invention, it is possible to obtain a remarkable improvement effect and a preventive effect on the rough skin symptoms associated with dry skin diseases and inflammatory skin diseases.

[0023]

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 to 3 and Comparative Examples 1 and 2] For the compositions shown in Table 1, components A (oil phase) and component B (aqueous phase) were each dissolved by heating at 60 ° C. After the component B was gradually added and emulsified and cooled, the emulsion was neutralized with potassium hydroxide to prepare emulsions (external preparations for skin) of Examples 1 to 3 and Comparative Examples 1 and 2, and the following tests were performed. Table 2 shows the results.

<Evaluation of Improvement of Roughness Due to Dry / Inflammatory Skin Disease> Ten Hartley female guinea pigs, 6 weeks old, were shaved at their backs, and acetone / ether (50/50) was used.
(Volume part) After immersion in the mixed solution for 10 minutes, washing with warm water was performed to prepare a rough skin model associated with dryness / inflammatory skin disease. For each of these guinea pigs, the six sites on the back were used as sample application sites, and non-application was performed at each site, and the samples were randomly allocated as the sample application of any of the emulsions of Examples 1 to 3 and Comparative Examples 1 and 2, The test was performed as follows.

First, an appropriate amount is applied to each of the sample allocation sites so that the application amount of each sample is the same on the day of preparation of the rough skin state, and the first day of application is performed. On the second day after applying each sample to the assigned site,
The sample was applied on the third day. Before application of the sample on the second and third days, and 24 hours after application on the third day (the fourth day), the symptoms of each site were visually observed, and scored according to the following criteria for rough skin conditions. The average value of the scores of 10 animals was calculated to evaluate the effect of improving skin roughness. 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 No difference from

[0027]

[Table 1] *: Carbopol 934 (brand name) manufactured by Goodrich

[0028]

[Table 2]

According to the results shown in Table 2, the skin external preparations of the present invention (Examples 1 to 3) in which a heparin-like substance and a betaine (glycine betaine) were used in combination were used in Comparative Examples 1 and 2 alone. Compared with the external preparation for skin No. 2, a remarkable improvement effect on rough skin was observed. In particular, the skin external preparations of Examples 2 and 3 to which glycyrrhetinic acid or dipotassium glycyrrhizinate, which is an anti-inflammatory agent, was further added, exhibited a more excellent effect of improving skin roughness.

From the above results, it can be seen that the skin external preparation of the present invention using a heparin-like substance and betaines in combination has a dry skin disease and inflammatory skin disease represented by atopic dermatitis and housewife eczema. It has been found that the compound is useful for improving and preventing the disease, and is more useful when an anti-inflammatory agent is further added.

Hereinafter, the present invention will be described more specifically with reference to examples. Example 4 Transparent lotion composition (% by weight) Heparin-like substance 0.5 γ-butyrobetaine 3.0 Diphenhydramine hydrochloride 1.0 1,3-butylene glycol 3.0 Ethanol 10.0 Hydroxypropyl methylcellulose 0.1 (4 2,000 centistokes) Purified water 82.4 Total 100.0

The above components were sequentially dissolved in purified water to prepare a transparent lotion as a skin external preparation of Example 4. About this transparent lotion, the skin roughness improvement evaluation was performed in the same manner as in Examples 1 to 3 above. As a result, the average score on the fourth day showed a high value of 2.0, indicating a dry skin disease and an inflammatory skin disease. It was confirmed that it was useful for improvement and prevention of accompanying skin roughness.

Example 5 Emulsion Composition (% by Weight) A: Oil Phase Stearyl Glycyrrhetinate 0.5 Sorbitan Monostearate 3.0 Polyoxyethylene (20) Sorbitan Monostearate 4.0 Stearyl Alcohol 5.0 Diisopropyl adipate 1.0 B: Aqueous phase part Heparin analog 0.3 Glycine betaine 3.0 1,3-butylene glycol 1.0 Methyl paraben 0.2 Carboxyvinyl polymer 0.2 [Carbopol 934 manufactured by Goodrich Corporation] (trade name)] 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 a skin external preparation of Example 5. As a result of performing the evaluation of the improvement of skin roughness in the same manner as in Examples 1 to 3 above, the average value of the scores on the fourth day showed a high value of 2.2, which was accompanied by dry skin disease and inflammatory skin disease. It was confirmed that it was useful for improving and preventing rough skin.

[Example 6] Gel ointment composition (% by weight) Monoammonium glycyrrhizinate 2.0 Heparin analog 0.5 Glycine betaine 1.0 Ethanol 10.0 1,3-butylene glycol 10.0 Carboxyvinyl polymer 1 5.5 [Carbopol 934 (trade name) manufactured by Goodrich Co.] Hydroxypropyl methylcellulose 0.1 (4,000 centistokes) Purified water 74.7 Sodium hydroxide 0.2 Total 100.0

The above components were sequentially dissolved in purified water, neutralized with sodium hydroxide, and a gel ointment was prepared as the skin external preparation of Example 6. The gel ointment was evaluated for the improvement of skin roughness in the same manner as in Examples 1 to 3 above. As a result, the average value of the scores on the fourth day showed a high value of 2.4, indicating that the gel ointment was suitable for dry skin diseases and inflammatory skin diseases. It was confirmed that it was useful for improvement and prevention of accompanying skin roughness.

Example 7 Cream Composition (% by Weight) A: Oil Phase Stearyl Glycyrrhetinate 3.0 Stearyl Alcohol 3.0 Squalane 27.0 Sorbitan Monostearate 3.0 Polyoxyethylene (20) Monostearin Sorbitan acid 4.0 diisopropyl adipate 1.0 butyl paraben 0.1 B: aqueous phase heparin analog 0.3 lysine betaine 1.0 1,3-butylene glycol 5.0 methyl paraben 0.2 purified water 52.4 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 a skin external preparation of Example 7. The cream was evaluated for improvement of skin roughness in the same manner as in Examples 1 to 3 above. As a result, the average value of the scores on the fourth day showed a high value of 2.4, indicating a dry skin disease and an inflammatory skin disease. It was confirmed that it was useful for improvement and prevention of accompanying skin roughness.

[Example 8] Transparent lotion composition (% by weight) Dipotassium glycyrrhizinate 1.0 Heparin analog 1.0 Gamma-butyrobetaine 0.1 Diphenhydramine 1.0 Ethanol 15.0 Polyethylene glycol 400 3.0 Purified water residue The amount total 100.0

The above components were sequentially dissolved in purified water to prepare a transparent lotion as an external preparation for skin of Example 8. This transparent lotion was evaluated for skin roughness improvement in the same manner as in Examples 1 to 3 above, and the average score on the fourth day showed a high value of 2.8, indicating that the dry lotion had a dry skin disease and an inflammatory skin disease. It was confirmed that it was useful for improvement and prevention of accompanying skin roughness.

Example 9 Oily ointment composition (% by weight) Glycyrrhetinic acid 1.0 Heparin analogue 0.2 Alanine betaine 0.1 Stearyl alcohol 5.0 Purified water 2.0 Glycerin monostearate 2.0 Polyoxy Ethylene (20) sorbitan monostearate 0.3 Plastibase 89.4 Total 100.0

Glycyrrhetinic acid, stearyl alcohol, glyceryl monostearate, POE
(20) After sorbitan monostearate was heated and dissolved at 60 ° C., it was kneaded with a heparin analog, alanine betaine, and plastibase previously dissolved in purified water to prepare an oily ointment as a skin external preparation of Example 9. The oily ointment was evaluated for skin roughness improvement in the same manner as in Examples 1 to 3 above. As a result, the average score on the fourth day showed a high value of 2.3, indicating that the ointment was good for dry skin diseases and inflammatory skin diseases. It was confirmed that it was useful for improvement and prevention of accompanying skin roughness.

[0043]

As described above, the skin preparation for external use of the present invention, when used in combination with a heparin-like substance and betaines, enhances the keratin water retention, anti-inflammatory action and blood circulation promoting action of the heparin-like substance. And the moisturizing action of betaines work synergistically to show a remarkable improvement effect on dry skin diseases such as atopic dermatitis and housewife eczema and rough skin symptoms associated with inflammatory skin diseases ,
Furthermore, when an anti-inflammatory agent is blended, the anti-inflammatory effect of the anti-inflammatory agent works synergistically to show a more remarkable improvement effect.

Therefore, the external preparation for skin of the present invention is effective not only for the rough skin symptoms caused by the low amount of sebum and water but also for the rough skin symptoms accompanying the above-mentioned skin diseases. It is useful as an agent for improving / preventing rough skin symptoms.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/205 A61K 31/205 31/727 31/715 610 F term (Reference) 4C083 AB032 AC012 AC022 AC072 AC122 AC372 AC442 AC482 AC552 AC711 AC712 AD042 AD092 AD282 AD311 AD312 AD532 BB51 CC04 CC05 DD22 DD33 DD41 EE12 4C086 AA01 AA02 DA11 EA27 MA03 MA04 MA07 MA10 MA63 NA14 ZB11 ZB13 4C206 AA01 AA02 FA58 MA03 MA04 MA83 NA13 ZB11

Claims (2)

[Claims] An external preparation for skin, comprising a heparin-like substance and betaines. 2. The external preparation for skin according to claim 1, further comprising an anti-inflammatory agent.