External preparation for skin for wrinkle improvement

Abstract

An oil-gel-form external preparation for skin contains a compound represented by the following General Formula (1), an isomer thereof, and/or a pharmaceutically acceptable salt thereof. A partially cross-linked methyl polysiloxane; allows easy penetration of the compound from the preparation into the skin while enhancing the percutaneous absorbability and improving the intradermal retentivity. ##STR00001##
In the formula, R.sub.1 represents a C.sub.1-C.sub.4 linear or branched alkyl group substituted by a carboxyl group(s), or a C.sub.1-C.sub.4 linear or branched alkyl group substituted by a carboxylic acid ester group(s) having a C.sub.1-C.sub.4 alkyl chain, and R.sub.2 and R.sub.3 each independently represent a C.sub.1-C.sub.4 linear or branched alkyl group.

Claims

1. An oil-gel-form external preparation for skin, comprising: 1) a compound represented by the following General Formula (1): ##STR00006## wherein in the formula, R.sub.1 represents a C.sub.1-C.sub.4 linear or branched alkyl group substituted by a carboxyl group(s), or a C.sub.1-C.sub.4 linear or branched alkyl group substituted by a carboxylic acid ester group(s) having a C.sub.1-C.sub.4 alkyl chain; and R.sub.2 and R.sub.3 each independently represent a C.sub.1-C.sub.4 linear or branched alkyl group, an isomer thereof, and/or a pharmaceutically acceptable salt thereof; and 2) a partially cross-linked methyl polysiloxane.

2. The oil-gel-form external preparation for skin according to claim 1, wherein the compound represented by the General Formula (1) is a compound represented by the following General Formula (2): ##STR00007## wherein in the formula, R.sub.4 represents a C.sub.1-C.sub.4 linear or branched alkyl group substituted by a carboxyl group(s); and R.sub.5 and R.sub.6 each independently represent a C.sub.1-C.sub.4 linear or branched alkyl group, an isomer thereof, and/or a pharmaceutically acceptable salt thereof.

3. The oil-gel-form external preparation for skin according to claim 2, wherein the compound represented by the General Formula (2) is 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane represented by the following Formula (3): ##STR00008## an isomer thereof, and/or a pharmaceutically acceptable salt thereof.

4. The oil-gel-form external preparation for skin according to claim 1, further comprising a spherical powder.

5. The oil-gel-form external preparation for skin according to claim 4, wherein the spherical powder is an organic spherical powder.

6. The oil-gel-form external preparation for skin according to claim 4, wherein the spherical powder is polymethyl methacrylate.

7. The oil-gel-form external preparation for skin according to claim 4, wherein the spherical powder is contained at 12 to 50% by mass with respect to the total amount of the external preparation for skin.

Description

EXAMPLES

(1) The present invention is described below in more detail by way of Examples. Needless to say, however, the present invention is not limited to these Examples.

Production Example 1: Method for Producing External Preparation for Skin for Comparison (Emulsion Formulation) in Present Invention

(2) According to the formulation shown in Table 1, an emulsion-form external preparation for skin was prepared. More specifically, Components (A) and (B) were separately heated to 70° C., and then (A) was slowly added to (B) with stirring. After cooling the resulting mixture to 40° C. with stirring, Component (C) was slowly added to the mixture, and the resulting mixture was uniformly stirred. At 30° C., the cooling and the stirring were stopped to obtain an emulsion-form external preparation for skin (Emulsion Formulation 1).

(3) TABLE-US-00001 TABLE 1 Weight Component (g) (A) Triglyceryl isostearate (Nikkol DIS) 10.0 (manufactured by Nippon Surfactant Industries Co., Ltd.) Cetyl alcohol (Cetanol HP) 0.5 (manufactured by Kokyu Alcohol Kogyo Co., Ltd.) Behenyl alcohol (Toho BH65) 0.2 (manufactured by TOHO Chemical Industry Co., Ltd.) Ethylparaben (manufactured by 0.2 Ueno Fine Chemicals Industry, Ltd.) Propylparaben (manufactured by 0.2 Ueno Fine Chemicals Industry, Ltd.) Glyceryl monostearate (Nikkol MGS-BV) 0.5 (manufactured by Nippon Surfactant Industries Co., Ltd.) Polyoxyethylene polyoxypropylene 1.5 stearyl ether (Unisafe 34S23) (manufactured by NOF Corporation) Polyoxyethylene (100) 0.6 hydrogenated castor oil (Nikkol DC100) (manufactured by Nippon Surfactant Industries Co., Ltd.) Dipropylene glycol (DPG-M) 4.0 (manufactured by Asahi Glass Company, Limited) (B) 1,3-Butanediol (1,3 BG) 1.0 (manufactured by Daicel Chemical Industries, Ltd.) Xanthan gum (Ketorol) 0.3 (manufactured by Dainippon Pharmaceutical Co., Ltd.) Water 60.0 (C) Compound represented by 1.0 the General Formula (1) (KSK32) Water 20.0

Example 1

Production Example 2: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 1

(4) After weighing 60.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 5.0 (g) of “Glyceryl Triisooctanate (Nomcort TIO) (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 1.0 (g) of “KSK32”, 9.0 (g) of “Glyceryl Triisooctanate” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the dispersion liquid, 20.0 (g) of “Polymethyl Methacrylate Spherical Powder (Microsphere M 330) (Matsumoto Yushi-Seiyaku Co., Ltd.)” and 5.0 (g) of “Sericite (Sericite FSE, Sanshin Mining Ind. Co., Ltd.)” were added, and the resulting mixture was kneaded together to produce an oil gel formulation. Thus, an external preparation for skin as an oil gel formulation (Cosmetic 1) was obtained.

Comparative Production Example: Method for Producing External Preparation for Skin (Gloss Preparation) of Present Invention

(5) After weighing 10 (g) of Rheopearl KL2 (Chiba Flour Milling Co., Ltd.), 40 (g) of glyceryl triisooctanate (Nisshin Oillio Group, Ltd.), and 45 (g) of Lusplan (Nippon Fine Chemical Co., Ltd.), these were melt together by heating at 85° C. A KSK32 dispersion liquid prepared by adding 4.5 (g) of “Glyceryl Triisooctanate (Nisshin Oillio Group, Ltd.)” to 0.5 (g) of “KSK32” followed by pulverization using a pulverizer was added to the above mixture, and the temperature of the resulting mixture was allowed to cool to normal temperature with stirring and mixing, to obtain a gloss-form external preparation for skin (Comparative Example 1).

Test Example 1: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 1

(6) The external preparation for skin for comparison (Emulsion Formulation 1), the oil-gel-form external preparation for skin (Cosmetic 1), and Comparative Example 1 (gloss preparation) produced according to the above methods were evaluated for the KSK32 dermal retentivity. In a Franz-type diffusion cell, isolated human skin (Caucasian, 50-year-old male, skin of the back) was placed, and the receptor side was filled with PBS. Each formulation prepared as described above was placed in the donor side, and then left to stand at 37° C. for 24 hours, followed by removing the residual formulation attached to the skin surface and rinsing with methanol. After removing the horny layer from the rinsed skin using a tape, KSK32 was extracted from the treated skin (the epidermal and dermal portions excluding the horny layer) using methanol, and its amount retained in the skin was calculated by HPLC (column, reverse-phase column (3.0×100 mm); column temperature, room temperature; mobile phase, aqueous anionic sulfonic acid type surfactant solution/THF 25%, pH 3; flow rate, 0.4 mL/min.; detection, 240 nm). The results are shown in Table 2. In the case where Emulsion Formulation 1 was used, KSK32 was not detected. In the gloss preparation of Comparative Example 1, a small amount of KSK32 was found to be retained. On the other hand, the oil-gel-form external preparation for skin (Cosmetic 1) showed retention of KSK32 in the skin, indicating that the dermal retentivity was improved by the oil gel formulation.

(7) TABLE-US-00002 TABLE 2 Intradermal retention at Hour 24 Sample (μg/cm.sup.2) Emulsion Formulation 1 N.D. Cosmetic 1 1.2 Comparative Example 1 (Gloss Preparation) 0.5

Example 2

Production Example 3: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 2

(8) After weighing 65.0 (g) of “Silicone KSG-16 (manufactured by Shin-Etsu Chemical Co., Ltd.)” and 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 15.0 (g) of “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 2).

Example 3

Production Example 4: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 3

(9) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)”, 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, and 5.0 (g) of “Silicone KF96-6 (Shin-Etsu Silicone Co., Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 10.0 (g) of “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 3).

Example 4

Production Example 5: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 4

(10) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)”, 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, and 7.5 (g) of “Silicone KF96-6 (manufactured by Shin-Etsu Chemical Co., Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 7.5 (g) of “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 4).

Example 5

Test Example 2: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 2

(11) The microsphere formulations at different concentrations produced according to the methods described in Examples 3 to 5 (Cosmetic 2 to Cosmetic 4) were evaluated for the intradermal retentivity according to the method described in Test Example 1. The results are shown in Table 3.

(12) TABLE-US-00003 TABLE 3 Sample (amount of Microsphere M330 Intradermal retention included at Hour 24 (% by weight)) (μg/cm.sup.2) Cosmetic 2 (15.0) 0.6 Cosmetic 3 (10.0) 0.3 Cosmetic 4 (7.5) 0.2

(13) It was suggested that, by increasing the content of microsphere M330 in the oil-gel-form external preparations for skin (Cosmetics 2 to 4), the dermal retentivity of KSK32 can be increased.

Example 6

Production Example 6: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 5

(14) After weighing 75.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 5.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 15.0 (g) of “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 5).

Example 7

Production Example 7: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 6

(15) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 5.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 25.0 (g) of “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 6).

Example 8

Test Example 3: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 3

(16) The microsphere formulations at different concentrations produced according to the methods described in Examples 6 and 7 (Cosmetic 5 and Cosmetic 6) were evaluated for the intradermal retentivity according to the method described in Test Example 1. The results are shown in Table 4.

(17) TABLE-US-00004 TABLE 4 Sample (amount of Microsphere M330 Intradermal retention included at Hour 24 (% by weight)) (μg/cm.sup.2) Cosmetic 5 (15.0) 0.5 Cosmetic 6 (25.0) 0.6

(18) According to the results in Table 3 and Table 4, it was found that there is a threshold at about 15% by mass regarding the content of the spherical powder. It was found that the content of the spherical powder is preferably not less than 12% by mass, more preferably not less than 15% by mass, still more preferably not less than 20% by mass, and that the content is preferably not more than 50% by mass, more preferably not more than 45% by mass, still more preferably not more than 30% by mass.

Production Example 8: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 7

(19) By kneading 71.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)”, 2.4 (g) of “Polyether-modified Silicone (Silicone KF-6017 (Shin-Etsu Chemical Co., Ltd.))”, 18.3 (g) of “DC345 (Dow Corning Toray Co., Ltd.)”, 0.4 (g) of “Phenoxyethanol (Yokkaichi Chemical Company, Limited)”, 5.9 (g) of “Ethanol (Wako Pure Chemical Industries, Ltd.)”, and 2 (g) of “KSK32” together, an oil-gel-form external preparation for skin containing no powder (external preparation for skin containing no powder) was produced.

Example 9

Production Example 9: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 8

(20) “Silicone KSG-16 (manufactured by Shin-Etsu Silicone Co., Ltd.)” in an amount of 60.0 (g) and “Microsphere M 330 (Matsumoto Yushi-Seiyaku Co., Ltd.)” in an amount of 15.0 (g) were kneaded together. By kneading with 2.0 (g) of “Polyether-modified Silicone (Silicone KF-6017 (Shin-Etsu Chemical Co., Ltd.)”, 15.7 (g) of “DC345 (Dow Corning Toray Co., Ltd.)”, 0.3 (g) of “Phenoxyethanol (Yokkaichi Chemical Company, Limited)”, 5.0 (g) of “Ethanol (Wako Pure Chemical Industries, Ltd.)”, and 2.0 (g) of “KSK32”, an oil-gel-form external preparation for skin containing “Polymethyl Methacrylate Spherical Powder (Microsphere M 330, Matsumoto Yushi-Seiyaku Co., Ltd.)” (Cosmetic 7) was produced.

Example 10

Production Example 10: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 9

(21) “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” in an amount of 60.0 (g) and “Spherical Polyamide Resin (Nylon SP 500, manufactured by Toray Industries, Inc.)” in an amount of 15.0 (g) were kneaded together. By kneading with 2.0 (g) of “Silicone KF-6017 (Shin-Etsu Chemical Co., Ltd.)”, 15.7 (g) of “DC345 (Dow Corning Toray Co., Ltd.)”, 0.3 (g) of “Phenoxyethanol (Yokkaichi Chemical Company, Limited)”, 5.0 (g) of “Ethanol (Wako Pure Chemical Industries, Ltd.)”, and 2.0 (g) of “KSK32”, an oil-gel-form external preparation for skin containing a spherical polyamide resin powder (Cosmetic 8) was produced.

Example 11

Test Example 4: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 4

(22) According to the method described in Test Example 1, the oil-gel-form external preparations for skin of the present invention (Cosmetic 7 and Cosmetic 8) were evaluated for the dermal retentivity. The results are shown in Table 5.

(23) TABLE-US-00005 TABLE 5 Intradermal retention at Hour 24 (relative to the value for the external preparation for skin containing no powder, Sample which is taken as 1.0) External preparation for skin of 1.0 Production Example 8 Cosmetic 7 (formulation containing 1.9 microspheres) Cosmetic 8 (formulation containing 1.7 spherical polyamide resin powder)

(24) Both organic spherical powders showed higher intradermal retention compared to the preparation containing no powder. Microsphere M 330 showed an especially high dermal retentivity.

Production Example 11: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 10

(25) After weighing 80.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid was added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (external preparation for skin containing no powder).

Example 12

Production Example 12: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 11

(26) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 15.0 (g) of “Polymethyl Methacrylate Spherical Powder (Microsphere M 330, Matsumoto Yushi-Seiyaku Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 9).

Example 13

Production Example 13: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 12

(27) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 15.0 (g) of “Sericite (Sericite FSE, Sanshin Mining Ind. Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 10).

Example 14

Test Example 5: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 5

(28) The oil-gel-form external preparations for skin of the present invention produced according to the methods described in Production Example 11, Example 11, and Example 12 (the external preparation for skin containing no powder, and Cosmetics 9 and 10) were evaluated for the dermal retentivity according to the method described in Test Example 1. The results are shown in Table 6.

(29) The intradermal retentivities of the formulation containing no powder, the formulation containing microspheres, and the formulation containing sericite (silicate mineral) were tested according to the method described above, and compared.

(30) TABLE-US-00006 TABLE 6 Intradermal retention at Hour 24 (relative to the value for the preparation containing no Sample powder) Cosmetic 9 (formulation containing 2.2 microspheres) Cosmetic 10 (formulation containing 1.0 Sericite powder)

(31) Cosmetic 9, which is a formulation containing microspheres as a spherical powder, showed a higher level of intradermal retention compared to Cosmetic 10, which is a formulation containing the plate-like powder “Sericite”.

Example 15

Production Example 14: Method for Producing Oil-Gel-Form External Preparation for Skin of Present Invention 13

(32) After weighing 65.0 (g) of “Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)” and 15.0 (g) of “Nomcort TIO (Nisshin Oillio Group, Ltd.)”, these were uniformly kneaded together. To 0.5 (g) of “KSK32”, 4.5 (g) of “DC345 (Dow Corning Toray Co., Ltd.)” was added, and the resulting mixture was pulverized using a pulverizer to prepare a KSK32 dispersion liquid. To the composition of KSG-16 and Nomcort TIO, the KSK32 dispersion liquid and 15.0 (g) of spherical silicic anhydride “Silica Microbead P 1500 (Catalysts & Chemicals Industries Co., Ltd.)” were added, and the resulting mixture was kneaded to produce an oil-gel-form external preparation for skin (Cosmetic 11).

Example 16

Test Example 5: Evaluation of Dermal Retentivity of Oil-Gel-Form External Preparation for Skin of Present Invention 5

(33) Cosmetic 9, and the oil-gel-form external preparation for skin of the present invention produced according to Example 15 (Cosmetic 11) were evaluated for the dermal retentivity according to the method described in Test Example 1. The results are shown in Table 7.

(34) TABLE-US-00007 TABLE 7 Intradermal retention at Hour 24 (relative to the value for the preparation containing no Sample powder) Cosmetic 9 (formulation containing 2.2 microspheres) Cosmetic 11 (formulation containing 0.9 silica microbeads)

(35) The oil-gel-form external preparation for skin containing silica microbeads (Cosmetic 11) as a representative example of spherical inorganic powders was evaluated for the dermal retentivity. As a result, the preparation showed a lower dermal retentivity compared to the organic spherical powder.

INDUSTRIAL APPLICABILITY

(36) The present invention is practically applicable to external preparations for skin such as cosmetics.