WO2004085486A1

WO2004085486A1 - Composition for external use on skin

Info

Publication number: WO2004085486A1
Application number: PCT/JP2004/004168
Authority: WO
Inventors: Tatsuo Shimizu; Kiyoshi Kuriyama
Original assignee: Sekisui Chemical Co., Ltd.
Priority date: 2003-03-25
Filing date: 2004-03-25
Publication date: 2004-10-07
Also published as: JPWO2004085486A1

Abstract

A composition for external use on the skin which is exceedingly highly effective in mitigating troubles concerning dry skin. The composition contains a chitosan represented by the following general formula (1) and/or a chitin which is a product of acetylation of the chitosan, in a total amount of 0.5 to 20 wt.%.

Description

Specification

Skin external composition Technical field

The present invention relates to a composition for external use on the skin, which has an excellent effect of improving skin dryness troubles such as a skin paria function improving effect, an anti-inflammatory effect and an antipruritic effect, and a good feeling of use. Background art

Conventionally, various pharmaceuticals such as urea, heparin-like substances or petrolatum have been used as external preparations for preventing skin drying problems. However, they are not effective enough and have an unpleasant feeling such as stickiness, discomfort or irritation. ·

On the other hand, chitosan and its derivatives have been used as cosmetic raw materials, but no report has been reported on the effect of improving skin drying problems relating to these (see, for example, Japanese Patent Application Laid-Open No. 10-182332 and Japanese Unexamined Patent Publication No. 2000-212123). On the other hand, as an attempt to improve the feeling of use, emulsified formulations such as emulsions and creams are being developed. However, many of these emulsified formulations use surfactants and emulsifiers, which are known to show cytotoxicity due to cell membrane destruction and protein denaturation. However, there is a problem that the drying of the skin may be worsened. Summary of the Invention

The present invention has been made in view of the above circumstances, and has as its object to provide a skin external composition having an extremely excellent effect of improving skin drying trouble.

As a result of intensive studies, the present inventors have found that chitosan represented by the following general formula (1) or that chitosan forms a salt together with an acid at an amino group, but is otherwise modified And / or chitin, which is an acetylated product of the chitosan, using a new evaluation system to show that it has excellent skin barrier function improving effect and anti-inflammatory effect. It was also found that it had an extremely excellent antipruritic effect. Furthermore, in the conventional formulation, a surfactant, an amphoteric base and a sulfur atom-containing compound having an inhibitory effect on the Maillard reaction, which have been indispensable for improving the product properties such as coating comfort, are required. In addition, they found that the effect of chitosan and Z or chitin on percutaneous water evaporation was significantly impaired, and that the effect of chitosan and / or chitin was significantly improved by not incorporating them in the preparation.

The present invention contains chitosan represented by the general formula (1) and / or chitin, which is an acetylated compound of the chitosan (hereinafter, simply referred to as chitosan and Z or chitin in the present specification), Preferably, the composition for external use on the skin is characterized by not containing a surfactant, both solvent bases and a sulfur atom-containing compound having a Maillard reaction suppressing effect. Detailed Disclosure of the Invention

Hereinafter, the present invention will be described in detail.

The chitosan used in the present invention is a compound represented by the above general formula (1), and is capable of deacetylating 4 O mo 1 / mo 1% or more by heating chitin with a concentrated alkaline solution or the like. This is poly-N-acetyl-D-darcosamine obtained by the above method. The chitosan used in the present invention includes those in which the chitosan represented by the general formula (1) forms a salt with an organic acid or an inorganic acid at an amino group. However, the chitosan used in the present invention does not include a modified chitosan derivative other than salt formation. The type of chitin, which is a raw material for producing chitosan used in the present invention, and the method for producing chitosan are not particularly limited. The composition for external use on skin of the present invention contains chitosan and / or chitin in an amount of 0.5 to 20% by weight / ₀ . If the amount is less than 0.5% by weight, a sufficient effect may not be obtained. If the amount exceeds 20% by weight, the effect is not further increased, but rather the viscosity is increased and it becomes difficult to dissolve. Therefore, formulation becomes difficult. The preferred content is 0.5 to 10% by weight, more preferably 0.5 to 8% by weight / _0, still more preferably 1 to 6% by weight, and most preferably 1 to 4% by weight. It is.

The chitosan and / or chitin preferably has an average degree of polymerization of 5 or more and less than 100. If it is less than 5, the effect of improving skin drying trouble may not be sufficiently obtained, and if it is more than 1000, the physical properties may be changed, and the effect of improving skin drying trouble may not be obtained sufficiently. It is more preferably at least 10 and less than 800, and even more preferably at least 50 and less than 500.

The chitosan and / or chitin have an average degree of polymerization of 5 or more and less than 100 (low chitosan and / or chitin) and an average degree of polymerization of 100 or more and less than 500 (high). (A degree of polymerization of chitosan and / or chitin). With chitosan and Z or chitin having a high degree of skin dry trap improvement and an average degree of polymerization of 5 or more and less than 1000, it is possible to obtain a smooth and light feeling of use (freshness) and permeability (ease of adaptation). By mixing and using chitosan and / or chitin having an average degree of polymerization of 100 or more and less than 500, a composition for external use having both characteristics can be obtained.

The mixing ratio of the low polymerization degree chitosan and / or chitin and the high polymerization degree chitosan and / or chitin is such that the high polymerization degree chitosan and / or chitin is based on 100 parts by weight of the low polymerization degree chitosan and Z or chitin. 30 to 300 parts by weight is preferred. If the ratio is out of this range, the two may be easily separated from each other, making formulation difficult. More preferably, it is 50 to 150 parts by weight.

Note that the average polymerization degree of the chitosan and / or chitin, chitosan 〇 _{6 Η η} N 0 ₄ as a unit (n = l), is that the numerical values determined from the intrinsic viscosity. Furthermore, when the molecular weight distribution of the composition for external use on the skin of the present invention was measured by gel filtration and high speed liquid chromatography (GPC), the ratio of the above-mentioned chitosan and / or chitin to the number average molecular weight (weight) (Average molecular weight / number average molecular weight) is 10 or more It is preferable that When the chitosan and Z or chitin used in the present invention is a mixture of low-polymerization chitosan and chitin or chitin and high polymerization degree chitosan and / or chitin, the ratio of the weight average molecular weight to the number average molecular weight becomes 10 or more. easy. When the ratio of the weight average molecular weight to the number average molecular weight is less than 10, sufficient effects may not be obtained or formulation may be difficult.

The composition for external use on the skin of the present invention may contain an acid in order to form a salt in the chitosan and to make it soluble in water.

As the acid, either an inorganic acid or an organic acid can be used. Examples of the inorganic acid include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and the like. Examples of the organic acid include acetic acid, succinic acid, malic acid, lactic acid, butyric acid, fumaric acid, malonic acid, itaconic acid, dalconic acid, glyconoleic acid, tartaric acid, and citric acid. Particularly, a hydroxy acid which is a fatty acid having a chemical structure having a hydroxyl group in a carboxylic acid is preferable. These acids may be used alone or in combination of two or more.

The content of the acid is preferably 0.1 to 20% by weight. If it is less than 0.1% by weight, it may not be sufficiently water-soluble, and if it exceeds 20% by weight, skin irritation may occur depending on the application site. More preferably, 0.5 to 10% by weight? is there.

The composition for external use on the skin of the present invention preferably further contains a liquid oil. Liquid oils are commonly used in cosmetics and the like. Examples of the liquid oils include hydrocarbons such as squalane, and glyceride oils such as triglyceride. Of these, squalane is particularly preferred.

The content of the above liquid oils is 2 to 20 weight. / Is preferably _0, more rather preferably is 5-1 5 weight ^_0/0.

It is preferable that the skin external composition of the present invention further contains urea. In the aqueous solution, the chitosan and / or Z or chitin may cause a Maillard reaction and cause a browning easily.However, the present inventors added that urea added the chitosan and / or chitin. It has been found that it can be stabilized to prevent browning. The urea content is preferably 0.1 to 3% by weight. 0.1 weight ° / ₀ If it is less than 3, sufficient effect may not be obtained, and the weight is 3 weight. If the ratio exceeds / ₀ , not only the effect will not increase any more, but also chitosan will precipitate, which may make formulation difficult. More preferably, it is 0.1 to 1.5% by weight.

The composition for external use on the skin of the present invention preferably does not contain a sulfur atom-containing compound having a Maillard reaction-preventing effect, such as a sulfite, since the effect of the present invention may be lost.

It is preferable that the external composition for skin of the present invention further does not contain a surfactant and an amphoteric base. For example, an ionic surfactant such as sodium dodecyl sulfate, or an amphoteric base such as glycerin may cause the effects of the present invention to be lost or make formulation difficult. In the present invention, not containing a surfactant, an amphoteric base and a sulfur atom-containing compound having an inhibitory effect on a mask reaction not only means that these substances are not contained at all but also contains This includes cases where these substances are mixed within a range that does not normally cause emulsification or Maillard reaction suppression reaction. For example, when the skin external composition of the present invention contains less than 0.1% of sodium dodecyl sulfate as a surfactant, or less than 1% of glycerin as an amphoteric base. It is assumed that the composition for external use on skin of the present invention does not contain these compounds.

The dosage form of the composition for external use on the skin of the present invention is not particularly limited, and examples thereof include an ointment, a cream, a liquid, and the like. Examples of the liquid include a gel, a sol, an aqueous solution, an alcohol, and an oil. And suspension-type lotions, emulsion-type lotions, varnishes, poultices, sprays and the like.

The method for producing the skin external composition of the present invention is not particularly limited, and can be produced by a conventionally known method.

The application amount of the composition for external use on the skin of the present invention is appropriately determined depending on the type and concentration of the active ingredient and the condition of the site to be applied, and is not particularly limited. It is preferable to apply about 0 g Zl times. The method for applying the composition for external use on the skin of the present invention is not particularly limited. In addition to the usual method for applying the composition for external use on the skin using an instrument such as a finger or a spatula, a pump type, a spray type, or a tube type A method of applying directly from a container and the like can be mentioned. The composition for external use on the skin of the present invention appropriately contains powder, oil, a thickener, an organic solvent, a plasticizer, a pigment, a pigment, a fragrance, a preservative, an antioxidant and the like as long as the object of the present invention is not impaired. May be. The invention's effect

The composition for external use on the skin of the present invention has an excellent effect of suppressing water evaporation from the skin, has an anti-inflammatory effect and an antipruritic effect, and has an excellent effect of improving skin drying trouble due to a good feeling of use. . That is, it can be used as an agent for improving skin drying troubles due to various causes of skin drying troubles, for example, decrease in environmental humidity, malnutrition, aging, skin diseases and the like.

In addition, the composition for external use on the skin of the present invention includes skin dryness due to atopic dermatitis, skin dryness due to contact dermatitis, senile xeroderma, skin dryness after renal dialysis, cracks, dermis, and fingertip angle. It is also effective for skin drying troubles such as dermatosis. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to only these Examples.

(Examples 1 to 14, 26 to 28)

Chitosan (manufactured by Wako Pure Chemical Industries, Ltd.) having an average degree of polymerization of 300 or 300 and whose amino group is not modified, and lactic acid, tartaric acid or acetic acid, or an average degree of polymerization of 30 or 300 The prepared water-soluble chitin was added to distilled water so as to have a blending amount (% by weight) shown in Table 1 and dissolved by stirring using a magnetic stirrer. Examples 1 to 14, 26 to The composition of 28 was obtained.

(Comparative Example 1)

Lactic acid was added to distilled water so as to be 2% by weight, and dissolved by stirring using a magnetic stirrer to obtain a composition of Comparative Example 1. (Comparative Examples 2, 3)

In Comparative Example 2, white petrolatum (Japanese Pharmacopoeia, manufactured by Maruishi Pharmaceutical Co., Ltd.) was used. In Comparative Example 3, urea (manufactured by Wako Pure Chemical Industries, Ltd.), which is often used as a moisturizing agent, was used as a base for McGall's ointment. (Japanese Pharmacopoeia product, manufactured by Maruishi Pharmaceutical Co., Ltd.) to prepare a 20% urea-containing Macguchil ointment containing 20% urea.

(Comparative Examples 4 to 6)

As the chitosan derivatives, succinyl chitosan (manufactured by Katakura Tikkalin Co.), succinyl carboxymethyl chitosan (manufactured by Kawaken Fine Chemical Co., Ltd.) or chitosan monopyrrolidone carboxylate (manufactured by Katakura Tikkalin Co., Ltd.), and lactic acid are shown in Table 1. The compositions of Comparative Examples 4 to 6 were obtained by the same operation as in Examples 1 to 14 by using them in such amounts as to be blended amounts.

(Evaluation)

The compositions obtained in Examples 1 to 14, 26 to 28 and Comparative Examples 1 to 6 were evaluated by the following methods. The results are shown in Table 1.

(1) Improving the barrier function of guinea pig exfoliated skin on dry skin model Shaving the back of a 5-week-old Hartley male guinea pig, then applying a 2.5-cm ni-width adhesive tape (Sekisui Chemical Co., Ltd. A 2.5 cm square part on the back of the guinea pig was repeatedly adhered and peeled four times using cellophane tape to remove a certain amount of stratum corneum, and used as a dry skin model. 0.1 mL of each composition was applied to the exfoliation site of the stratum corneum. One hour and 24 hours after the application, the transepidermal water loss (hereinafter referred to as TEWL) was measured using an evaporator EP-1 (manufactured by SERVOMED). The test used three guinea pigs for each composition, and TEWL indicated the average of the results for three animals. The lower the value of TEWL, the higher the barrier function improvement effect.

(2) Evaluation of guinea pig tri-tubing skin erythema The back of a 4-week-old male Hartley-type guinea pig was shaved, and a predetermined 2.5 cm square back of the back was stripped three times using cellophane tape three times. Was applied so as to spread over the entire stripping site. In addition, stripping was performed on the other side of the median part of the back as a control site. Four hours after application, the erythema intensity at each site where the above-mentioned external composition was applied was measured (a *) with a colorimeter (CR 200, manufactured by Minolta Co., Ltd.), and the effect of the external composition was evaluated according to the following criteria. Valued. Evaluation was performed by using three guinea pigs and determining the average value. The results are shown in Table 1. The effect was higher when the erythema intensity was lower, and the erythema intensity at the control site was 5.6.

Evaluation criteria 〇: Erythema intensity is less than 2.0, X: Erythema intensity is 2.0 or more

(Examples 15 to 25)

Examples of pharmaceutical preparations include chitosans (manufactured by Wako Pure Chemical Industries, Ltd.) having an average degree of polymerization of 300 and 300 and having unmodified amino groups, lactic acid (manufactured by Ebisu Pharmaceutical), squalane ( Example 2 was added to water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.), and the mixture was stirred and suspended so that the compounding amount (weight: / ₀ ) shown in Table 2 was obtained. The compositions of 15 to 25 were obtained.

(Comparative Examples 7, 8)

A commercially available product was used to compare the usability. As Comparative Example 7, petrolatum (made by Maruishi Pharmaceutical Co., Ltd.) was used, and as Comparative Example 8, heparinoid ointment (made by Maruho Pharmaceutical Co., Ltd.) was used.

(Reference Examples 1 to 7)

A surfactant and an amphoteric base, which are usually used for improving usability, were blended in place of chitosan having an average polymerization degree of 300, to prepare a composition of Comparative Example. Except for chitosan having an average polymerization degree of 300, the same raw materials as in Examples 15 to 25 were added to sodium dodecyl sulfate, glycerin, butylene glycol, benzalkonium chloride or polyoxyethylene hydrogenated castor oil (above, (Manufactured by Kojun Pharmaceutical Co., Ltd.) so that the amounts shown in Table 2 were added, and by the same operation as in Examples 15 to 25, the compositions of Reference Examples 1 to 7 were obtained.

(Evaluation)

The compositions of Examples 15 to 25, Comparative Examples 7 and 8, and Reference Examples 1 to 7 were evaluated by the following methods. Table 2 shows the results. (1) Sensory evaluation by healthy people

Sensory evaluation of appearance and usability was performed by 10 healthy persons (5 men and 5 women). For the above items, 5: 'Very good, 4: Good, 3: Neither, 2: Somewhat bad, 1: Bad. I asked. The higher this value, the better the productiveness and usability. (2) Effect of guinea pig exfoliated skin on barrier function for dry skin model

The back of a 5-week-old Hartley male guinea pig is shaved, and then a 2.5 cm-wide cellophane tape is used to apply a 2.5 cm square part on the back of the guinea pig four times. An amount of the stratum corneum was peeled off to obtain a dry skin model. 0.1 mL of each composition was applied to the exfoliation area of the stratum corneum so as to spread over the entire area. One hour and 24 hours after application, the transepidermal water loss (TEWL) was measured using an evaporator EP-1 (manufactured by SE RVOMED). The test was performed on three animals for each case, and TEWL was indicated by the average value. The lower the value of TEWL, the higher the barrier function improvement effect.

IsJ ts>

OO Chitosan (% by weight) Lactic acid Squalane Urea field E activator D EWL (g / m ² h) Average degree of polymerization Average degree of polymerization SB combined amount Mixed amount Mixed amount Mixed amount Sensory evaluation

After 1 hour After 24 hours 300 3000 (% by weight) (% by weight) (% by weight) (% by weight) (% by weight)

15 1 1 2 ― ― ― 1 4 7.9 8.4

16 1 1 2 10 0.3 ― ― 5 6.8 7.3

1f 2 1 2 10 0.3 ― ― 5 7.9 7.7

18 1 2 2 10 0.3 1 ― 5 8.3 9.0

19 5 5 2 10 0.3 ― ― 5 7.8 8.1 Example 20 1 1 2 5 11 ― 5 8.0 8.1

21 1 1 2 15 ― ― ― 5 7.0 8.2

22 1 1 2 ― 0.1 ― 4 8.1 9.1

23 1 1 2 ― 1.5 ― ― 4 7.9 9.0

24 1 1 2 ― 0.3 ― 1 4 7.3 7.8

25 10 10 2 10 0.3 ― 1 4 10.0 10.7

7 Vaseline 2 11.2 37.0 Comparative example

8 Heparinoid soft, 1 39.4 41.0

1 1 1 2 10 0.3 Dodecyl sodium sulfate / 0-1 1 1 ― ―

2 1 1 2 10 0.3 1 Geriserin / 1 2 36.8 38.9

3 1-2--1-dote 'Sodium silyl sulfate / 0.1-2 41.2 40.3 Reference example 4 1-2--1-1 2 37.3 36.1

5 1 ― 2 ― ― Polyoxy I-Tylene hydrogenated castor oil / 0.01 ― 2 40.2 39.8

6 1 ― 2 1 ― Salmonium chloride / 0.01 ― 2 42.3 41.1 F 1 ― 2 ― ― 1 F Tirengericol / 1 2 38.4 37.3 Healthy skin ― ― I ― ― ― ― 5.8 6.4 Damaged skin ― ― ― ― ― 1 ― 1 39.4 38.8

(Comparative Examples 9, 10)

In Comparative Example 9, an antihistamine ointment (Koresta Co., Ltd., “Restamine Co.sup.j”) used as an external antipruritic agent was used, and in Comparative Example 10, urea ointment (Kowa Co., Ltd.) was used.

(Evaluation)

The compositions of Examples 1, 2, 3, 6, 13, 13, 15, 16, 19 and 25, and Comparative Examples 2, 9 and 10 were evaluated by the following methods. Table 3 shows the results.

(1) Antipruritic evaluation 1

A 29-year-old woman who had dry itching in the cubital and popliteal fossils after bathing was applied to the affected area, and the itch of the affected area was evaluated from immediately after application to 6 hours after application. "Excellent" was evaluated as ◎, "Effective" as "〇", "Slightly effective" as "mm", and "Invalid" as "X".

(2) Antipruritic evaluation 2

A 57-year-old man who had dry itching on his back at bedtime was used as a test subject, and each composition was applied to the affected area, and the itch of the affected area immediately after application and up to 6 hours after the application was evaluated. "Excellent" was evaluated as ◎, "Effective" as "〇", "Slightly effective" as "mm", and "Invalid" as "X".

(3) Antipruritic evaluation 3

A 43-year-old female with dry itch on the extremities after the bath was used as a test subject, each composition was applied to the affected area, and the itch of the affected area immediately after application and up to 6 hours after the application was evaluated. “Excellent J” was evaluated as ◎, “Effective” as “〇”, “Slightly effective” as “△”, and “Invalid” as X. ' Table 3

Industrial applicability

ADVANTAGE OF THE INVENTION Since this invention is comprised by the above-mentioned structure, it has the skin barrier function improvement effect, the anti-inflammatory effect, and the antipruritic effect, and can provide the skin external composition which shows a good feeling of use.

Claims

The scope of the claims

1. External use for skin, characterized by containing a total of 0.5 to 20% by weight of chitosan represented by the following general formula (1), chitin, or chitin, which is an acetylated compound of chitosan. Composition.

2. The composition for external use on skin according to claim 1, wherein the average degree of polymerization is 5 or more and less than 100.

3. It is characterized by containing chitosan and Z or chitin having an average degree of polymerization of 5 or more and less than 1000, and chitosan and / or chitin having an average degree of polymerization of 100 or more and less than 500. 2. The composition for external use on the skin according to claim 1, wherein

4. The chitosan and Z or chitin according to claim 1, 2, or 3, wherein the ratio of the weight average molecular weight to the number average molecular weight (weight average molecular weight / number average molecular weight) is 10 or more. Skin external use composition. 5. The composition for external use on skin according to claim 1, 2, 3, or 4, further comprising a liquid oil.

6. The skin external composition according to claim 5, wherein the liquid oil is squalane.

7. The composition for external use on the skin according to claim 1, 2, 3, 4, 5, or 6, further comprising urea and not containing a sulfur atom-containing compound having a Maillard reaction inhibitory effect. .

8. The composition for external use on skin according to claim 1, 2, 3, 4, 5, 6, or 7, wherein the composition does not contain a surfactant and an amphoteric solvent.