HK40000200B - External preparation for skin for wrinkle improvement - Google Patents

Description

Skin topical preparations for wrinkle improvement

Technical Field

The present invention relates to a skin external preparation suitable as a cosmetic (including a quasi-drug), and more specifically, to an oleogel-type skin external preparation characterized by containing 1) a compound represented by the following general formula (1), its isomers and/or pharmacologically acceptable salts thereof, and 2) a partially cross-linked methyl polysiloxane.

【Chemical Formula 1】

[wherein, _R1 represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, or a C1-4 linear or branched alkyl group substituted with a carboxylate group having an alkyl chain having C1-4; _R2 and _R3 each independently represent a C1-4 linear or branched alkyl group].

Background Art

As a representative symptom of the skin aging phenomenon caused by increasing youthfulness, wrinkle formation can be cited. Wrinkles can be roughly classified into shallow wrinkles formed on the skin surface that can be improved by moisturizing, and deep wrinkles caused by exposure to ultraviolet rays and accumulation of physical stimulation. The prevention or improvement of the formation of the latter deep wrinkles is very difficult. In addition, various wrinkle-improving agents have been developed to date (for example, refer to Non-Patent Document 1). As such wrinkle-improving agents, it is well known that retinoic acid is used as an active ingredient. Although retinoic acid has been approved as a pharmaceutical for treating wrinkles and acne in the United States, it has not been approved in Japan due to safety issues such as skin irritation. In addition, as other wrinkle-improving agents, collagen production promoters (for example, refer to Patent Document 1), hyaluronic acid production promoters (for example, refer to Patent Document 2), etc. have been reported. However, it cannot be said that all of the above wrinkle-improving agents can achieve sufficient effects, and no effective means have been established. One of the reasons for this is the presence of wrinkle-improving agents that have problems with the stability of wrinkle-improving agents and external skin preparations, as well as with skin permeability and storage properties.

Wrinkle-modifying agents with a mechanism of action different from the aforementioned wrinkle-modifying agents contain elastase inhibitors. Elastin, one of the structural proteins present in skin tissue, maintains tissue elasticity by forming a cross-linked structure. Exposure to skin irritants such as ultraviolet rays is known to modify and destroy elastin by overexpressing and activating the elastin-degrading enzyme elastase, thereby causing a decrease in skin firmness and elasticity, and thus promoting wrinkle formation. Elastase inhibitors exert a preventive or ameliorative effect on wrinkle formation by inhibiting the aforementioned elastin-degrading enzyme. On the other hand, although structural analysis and structure-activity correlation studies of elastin-degrading enzymes and substrates have been conducted, it is difficult to achieve high enzyme inhibitory activity and selectivity using low-molecular-weight organic compounds. Many peptides and their derivatives exist as components with high enzyme inhibitory effects (e.g., see Patent Document 3). Peptide derivatives such as WS7622A monosulfate or disulfate are known as such elastase inhibitors (e.g., see Patent Document 4), and their pharmacological effects enable their application in ischemic diseases. In addition, it is known that the compound represented by the general formula (1) has the same leukocyte elastase inhibitory effect as WS7622A, and has been reported to have a preventive or therapeutic effect on skin aging (for example, see Patent Document 5). However, the molecular size of the above-mentioned peptides and their derivatives is also relatively large, and there are chemical structural characteristics that are not preferred for reaching the dermis, such as having multiple amide bonds, so there is a concern that the effective amount will not reach the wrinkle formation site. In fact, when peptides and their derivatives are administered transdermally, there are many problems with the stability of the active ingredients and the external preparations for skin use, as well as skin permeability or storage properties, and it is not uncommon that the expected effect cannot be achieved.

Typically, when cosmetics and other topical skin preparations contain wrinkle-modifying agents, aqueous formulations such as lotions, serums, and creams are chosen as the dosage form. The aforementioned elastase inhibitors, especially peptides and their derivatives expected to have high elastase inhibitory activity, have relatively large molecular weights and chemical structures with a lipophilic portion and a small hydrophilic portion. Therefore, when aqueous formulations are selected to contain wrinkle-modifying agents, the wrinkle-modifying agents do not readily penetrate the dermis from the skin surface and tend to be lost from the skin quickly through perspiration and other means. Consequently, in most cases, bioavailability is extremely low, and the desired wrinkle-preventing or wrinkle-modifying effects are not achieved. On the other hand, conventional oil-gel formulations, which solidify liquid oils with waxes or other methods, have the advantage of suppressing the loss of the aforementioned wrinkle-modifying agents due to perspiration and the deterioration of water-labile wrinkle-modifying agents. However, in most cases, they cannot be said to penetrate the dermis very well. Furthermore, oil-gel formulations also present usability issues such as stickiness. Therefore, in order to improve the usability of cosmetics in the form of oleogel formulations, oleogel-type external skin preparations incorporating silicone oil have been reported (e.g., see Patent Documents 6 and 7). Furthermore, it is known that the fragrance properties of cosmetics in the form of oleogel formulations incorporating silicone oil do not readily change over time (e.g., see Patent Document 8).

Furthermore, there is known a technology for improving the overall appearance of the skin, such as fine lines, by including a cross-linked silicone elastomer (partially cross-linked methylpolysiloxane) in a cosmetic composition. When the composition is applied to the skin, a smooth film is formed to smooth fine lines and wrinkles, or spherical particles are included to impart a function as an optical diffuser that scatters light on fine lines and wrinkles, thereby changing the surface texture of the skin (for example, see Patent Document 9).

Prior art literature

Patent Literature

Patent Document 1: Japanese Patent Application Laid-Open No. 2002-255847

Patent Document 2: Japanese Patent Application Laid-Open No. 2004-123637

Patent Document 3: International Publication No. 2001/40263

Patent Document 4: International Publication No. 1998/27998

Patent Document 5: International Publication No. 1999/43352

Patent Document 6: Japanese Patent No. 3242874

Patent Document 7: Japanese Patent No. 3492483

Patent Document 8: Japanese Patent Application Laid-Open No. 2003-300851

Patent Document 9: Japanese Patent Application Laid-Open No. 2001-294510

Non-patent literature

Non-Patent Literature 1: Development Technology for Anti-Aging, Whitening, and Moisturizing Cosmetics, CMC Publishing, supervised by Masato Suzuki, Chapter 2: Anti-Aging and Anti-Wrinkle Functional Cosmetics

Summary of the Invention

Problems to be solved by the invention

As mentioned above, the use of an oleogel formulation as a cosmetic formulation is a known technology. However, in an oleogel formulation for external use on the skin containing an active ingredient for application to the skin, it is not clear how the active ingredient affects transdermal absorption. Therefore, no attempt has been made to incorporate the compound represented by the general formula (1) into such an oleogel formulation.

The present invention has been made under such circumstances, and an object of the present invention is to provide a method for improving the skin storage properties of the compound represented by the general formula (1), its isomers and/or its pharmacologically acceptable salts.

Means for solving problems

In view of this situation, the present inventors sought a method for improving the skin storage properties of the compound represented by the general formula (1), its isomers and/or its pharmacologically acceptable salts. As a result of repeated studies, the present inventors found that by incorporating the compound represented by the general formula (1), its isomers and/or its pharmacologically acceptable salts into an oil-gel-type skin external preparation containing cross-linked methyl polysiloxane as a structural matrix, the ease of presence of the compound in the skin external preparation and the balance of penetration into the skin are improved, thereby improving the skin storage properties.

Furthermore, the inventors discovered that the addition of spherical powders to an oil-gel formulation for external use on skin reduces viscosity and increases fluidity, thereby improving feel during use and facilitating the spreading of the skin formulation on the skin, which in turn leads to improved transdermal absorbability. Based on this finding, the inventors discovered that an oil-gel formulation for external use on skin improves the skin storage properties of the compound represented by the general formula (1) and the like in the skin formulation, thereby completing the present invention. Specifically, the present invention is as follows.

<1> An oil-gel-type external preparation for skin, characterized by comprising: 1) a compound represented by the following general formula (1), its isomers and/or pharmacologically acceptable salts thereof, and 2) a partially cross-linked methylpolysiloxane.

【Chemical Formula 2】

[wherein, R1 represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, or a C1-4 linear or branched alkyl group substituted with a carboxylate group having an alkyl chain having C1-4; R2 and R3 each independently represent a C1-4 linear or branched alkyl group]

<2> The oil-gel-type external skin preparation according to <1> is characterized in that the compound represented by the general formula (1) is a compound represented by the following general formula (2), an isomer thereof, and/or a pharmacologically acceptable salt thereof.

【Chemical Formula 3】

[In the formula, _R4 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and _R5 and _R6 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.]

The oil-gel-type external skin preparation described in <3> and <2> is characterized in that 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), its isomers and/or pharmacologically acceptable salts thereof.

【Chemical Formula 4】

<4>, The oil-gel-type external skin preparation according to any one of <1> to <3>, further comprising spherical powder.

The oil-gel-type external skin preparation described in <5> and <4> is characterized in that the spherical powder is an organic spherical powder.

The oil-gel-type external skin preparation according to <6>, <4> or <5>, wherein the spherical powder is polymethyl methacrylate.

The oil-gel-type external skin preparation according to any one of <7> and <4> to <6>, wherein the spherical powder is contained in an amount of 12 to 50% by mass based on the total amount of the external skin preparation.

Effects of the Invention

When the oil-gel-type external skin preparation of the present invention is used, the compound represented by the general formula (1), its isomers and/or pharmacologically acceptable salts thereof reach the dermis, thereby improving the skin storage properties of the compound, thereby solving cosmetic problems such as the prevention or improvement of wrinkle formation.

DETAILED DESCRIPTION

<The compound represented by the general formula (1) of the present invention, its isomers and/or its pharmacologically acceptable salts>

The oil-gel-type skin external preparation of the present invention is characterized by containing 1) a compound represented by the general formula (1), its isomers and/or pharmacologically acceptable salts thereof, and 2) a partially cross-linked methyl polysiloxane. In addition, the oil-gel-type skin external preparation of the present invention improves the skin storage properties of the compound represented by the general formula (1), its isomers and/or pharmacologically acceptable salts thereof, thereby exerting an excellent preventive or ameliorative effect on wrinkle formation. The compound represented by the general formula (1) of the present invention, its isomers and/or pharmacologically acceptable salts thereof can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. 04-297446. The compound represented by the general formula (1) of the present invention has human leukocyte elastase inhibitory activity, and thus can be expected to have a therapeutic effect on cerebral ischemic diseases such as cerebral infarction. In addition, as described in WO1999/43352, it has a preventive or therapeutic effect on skin aging. The compound represented by the general formula (1) of the present invention has the effects of promoting the regeneration of elastic fibers in the dermal papilla, the regeneration of fine collagen fibrils in the dermis immediately below the epidermis, and increasing epidermal thickness, and exerts a preventive or ameliorative effect on wrinkle formation through these effects. Furthermore, since the compound represented by the general formula (1) of the present invention is an optically active compound having multiple asymmetric carbon atoms in its molecular structure, enantiomers and diastereomers exist as its isomers. Furthermore, the compound represented by the general formula (1) of the present invention exists as a racemate, enantiomers, and diastereomers, and there are also compounds in which the isomers are mixed at any ratio.

Regarding the compound represented by the general formula (1) of the present invention, wherein _R1 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted by a carboxyl group or a linear or branched alkyl group having 1 to 4 carbon atoms substituted by a carboxylate group having an alkyl chain having 1 to 4 carbon atoms, and _R2 and _R3 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms.

When specifically exemplifying the preferred groups for R ₁ , carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, methoxycarbonylmethyl, methoxycarbonylethyl, methoxycarbonylpropyl, methoxycarbonylbutyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, ethoxycarbonylpropyl, ethoxycarbonylbutyl, propoxycarbonylmethyl, propoxycarbonylethyl, propoxycarbonylpropyl, propoxycarbonylbutyl, butoxycarbonylmethyl, butoxycarbonylethyl, butoxycarbonylpropyl, butoxycarbonylbutyl and the like are preferably exemplified, and carboxymethyl is more preferably exemplified.

Specifically, when R ₂ and R ₃ are independently preferred, preferably, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and the like are exemplified, and more preferably, isopropyl is exemplified.

As preferred examples of the compound represented by the general formula (1), its isomers and/or pharmacologically acceptable salts thereof, the compound represented by the general formula (2), its isomers and/or pharmacologically acceptable salts thereof can be preferably exemplified. As a more preferred compound, 3-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-valyl-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, its isomers and/or pharmacologically acceptable salts thereof can be preferably exemplified. As a further preferred compound, 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane or its sodium salt (hereinafter, this sodium salt may be abbreviated as KSK32) can be preferably exemplified.

By incorporating the compound represented by the general formula (1) of the present invention, its isomers and/or pharmacologically acceptable salts thereof together with a partially cross-linked methylpolysiloxane into an oil-gel type external skin preparation, the skin storage property is improved, thereby enhancing the effect of preventing or improving wrinkle formation.

Regarding the compound represented by the general formula (2) of the present invention, in the formula, _R4 represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted by a carboxyl group, and _R5 and _R6 each independently represent a linear or branched alkyl group having 1 to ₄ carbon atoms. Specifically, preferred groups for _R4 include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, 2-carboxypropyl, 3-carboxypropyl, 1-carboxybutyl, 2-carboxybutyl, 3-carboxybutyl, and 4-carboxybutyl. Further preferred groups include carboxymethyl.

_R5 and _R6 each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. Specific examples of preferred groups for _R5 and _R6 include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. An isopropyl group is a further preferred group. Furthermore, when specifically exemplifying preferred compounds of the compound represented by the general formula (2), preferred examples include N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, alanylamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl -N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide -L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-alanyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl] yl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide ,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-ethyl)-2-oxopropyl]-L-prolinamide, 3-Hydroxybenzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide (3(RS)-N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide), N-[4-[[(carboxyethyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxypropyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide -1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, N-[4-[[(carboxybutyl)amino]carbonyl]benzoyl]-L-valyl-N-[3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide, isomers and/or pharmacologically acceptable salts thereof. As further preferred compounds, N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[(RS)-3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide represented by general formula (3), isomers and/or pharmacologically acceptable salts thereof can be preferably exemplified. In addition, as described above, the compound represented by the general formula (3) can also be expressed as 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane.

In the following, the sodium salt of N-[4-[[(carboxymethyl)amino]carbonyl]benzoyl]-L-valyl-N-[(RS)-3,3,3-trifluoro-1-(1-methylethyl)-2-oxopropyl]-L-prolinamide may be abbreviated as KSK32. KSK32 refers to the same compound with only a different name.

By incorporating the compound represented by the general formula (1) of the present invention, its isomers and/or pharmacologically acceptable salts thereof together with a partially cross-linked methylpolysiloxane into an oil-gel type external skin preparation, the skin storage property is improved, wrinkle formation is suppressed, and the balance between new wrinkle formation and disappearance is tilted toward disappearance, thereby enhancing the effect of preventing or improving wrinkle formation.

In addition, although the compound represented by the general formula (1) of the present invention can be contained in an oil-gel-type external skin preparation as it is, it can also be treated with a pharmacologically acceptable acid or base and converted into a salt form and used as a salt. For example, inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, and carbonates; organic acid salts such as maleates, fumarates, oxalates, citrates, lactates, tartrates, methanesulfonates, p-toluenesulfonates, and benzenesulfonates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; organic amine salts such as triethylamine salts, triethanolamine salts, ammonium salts, monoethanolamine salts, and piperidine salts; basic amino acid salts such as lysine salts and arginine salts; and the like can be mentioned. The oil-gel-type external skin preparation of the present invention can contain one or more selected from the compound represented by the general formula (1), its isomers, and/or pharmacologically acceptable salts thereof.

In order for the compound represented by the general formula (1), its isomers, and/or pharmacologically acceptable salts thereof of the present invention to exhibit the aforementioned effects when contained in an oil-jelly external skin preparation, the amount thereof is preferably 0.01% to 10% by mass, more preferably 0.1% to 5% by mass, relative to the total amount of the external skin preparation. This is because if the amount of the compound represented by the general formula (1), its isomers, and/or pharmacologically acceptable salts thereof contained in an oil-jelly external skin preparation is too small, the aforementioned effects tend to be reduced, while if the amount is too large, the aforementioned effects tend to peak.

<Partially Cross-linked Methyl Polysiloxane of the Present Invention>

The skin external preparation of the present invention is an oil-jelly-type skin external preparation characterized by containing 1) a compound represented by the general formula (1), its isomers, and/or pharmacologically acceptable salts thereof, and 2) a partially cross-linked methylpolysiloxane. Partially cross-linked methylpolysiloxane, classified as a partially cross-linked organopolysiloxane polymer, is a silicone oil having a structure in which linear polymers formed by siloxane bonds are partially cross-linked. Furthermore, the term "partially cross-linked" as used herein refers to a substance produced by cross-linking to a cross-linking ratio (cross-linking ratio) of approximately 20 to 30%.

Furthermore, from the viewpoint of stability and feel during use, it is preferred to use the partially cross-linked methylpolysiloxane used in the present invention having a viscosity of 100 to 500 at 25°C.

The viscosity of partially cross-linked methyl polysiloxane at 25° C. can be measured in accordance with JIS K2220.

Some of the partially cross-linked methylpolysiloxanes described above are commercially available as general-purpose raw materials for cosmetics. The partially cross-linked methylpolysiloxane of the present invention can be purchased from such commercial products and used.

As commercially available products, those containing other silicone oils such as decamethylcyclopentasiloxane, methylpolysiloxane, octamethylcyclotetrasiloxane, and methylphenylpolysiloxane in addition to partially cross-linked methylpolysiloxane may be used, or those containing only partially cross-linked methylpolysiloxane may be used.

Preferred commercially available partially cross-linked methylpolysiloxanes include KSG-15 (a mixture of approximately 5 parts by mass of partially cross-linked methylpolysiloxane and approximately 95 parts by mass of decamethylcyclopentasiloxane), KSG-16 (a mixture of approximately 20 to 30 parts by mass of partially cross-linked methylpolysiloxane and approximately 70 to 80 parts by mass of methylpolysiloxane), KSG-17 (a mixture of approximately 5 parts by mass of partially cross-linked methylpolysiloxane and approximately 95 parts by mass of octamethylcyclotetrasiloxane), and KSG-18 (a mixture of approximately 10 to 20 parts by mass of partially cross-linked methylpolysiloxane and approximately 80 to 90 parts by mass of methylphenylpolysiloxane), all manufactured by Shin-Etsu Chemical Co., Ltd. KSG-16 is particularly preferred.

The oleogel-type skin preparation of the present invention may contain one or more of the commercially available partially cross-linked methylpolysiloxanes, or a commercially available product containing only partially cross-linked methylpolysiloxane may contain other silicone oils. The partially cross-linked methylpolysiloxane acts as a gel-forming agent in the skin preparation of the present invention, maintaining the oleogel structure of the skin preparation. To achieve this effect, the content of the partially cross-linked methylpolysiloxane is preferably 5-25% by weight, more preferably 10-20% by weight, relative to the total amount of the oleogel-type skin preparation. This is because too little of a content tends to make it difficult to maintain the structure, while too much of a content tends to compromise the flexibility of formulation.

<External skin preparation of the present invention>

The oil-gel-type external skin preparation of the present invention is characterized by containing 1) a compound represented by the general formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof, and 2) a partially cross-linked methylpolysiloxane. The oil-gel-type external skin preparation of the present invention increases the concentration of the active ingredient in the dermis by promoting the release of the compound represented by the general formula (1) from the preparation and improving the skin storage property, thereby effectively enhancing the anti-aging effect and the preventive or ameliorative effect on wrinkle formation.

While the oil-jelly formulation of the present invention utilizes the aforementioned partially cross-linked methylpolysiloxane to form an oil-jelly formulation, it may contain ingredients other than the aforementioned silicone oil in addition to the cross-linked methylpolysiloxane. The silicone oil contained in the aforementioned commercially available product functions as a gelled oily component in the oil-jelly formulation. Preferred examples of such oily components include volatile silicone oils having a boiling point of 200°C or less at 1 atmosphere. Preferred examples of such volatile silicone oils include methylpolysiloxane having a boiling point of 1 mPa·s or less at 25°C, the aforementioned decamethylcyclopentasiloxane, methylpolysiloxane, and octamethylcyclotetrasiloxane.

The volatile silicone oil is preferably present in an amount of 30 to 60% by mass relative to the total amount of the oil-gel formulation for external use on skin. The oil-gel formulation for external use on skin of the present invention is gelled using a partially cross-linked methylpolysiloxane to form an oil-gel formulation, thereby improving the skin storage properties of the compound represented by the general formula (1). Furthermore, the improved skin storage properties of the compound represented by the general formula (1) enhance the preventive or ameliorative effect on wrinkle formation.

The oil-gel-type external skin preparation of the present invention preferably contains, for example, spherical powders with enhanced fat solubility to achieve good spreading of the external skin preparation. Furthermore, "spherical" in the present invention includes not only true spherical shapes but also substantially spherical shapes having concavo-convex portions on the surface.

The average particle size of such spherical powders is preferably 5 to 20 μm. This is because if the particle size is less than 5 μm, a strong astringent feeling may be felt during application, while if the particle size exceeds 20 μm, the unevenness caused by the spherical powder may be strongly felt during application.

In this specification, the particle diameter of the spherical powder can be measured using the Microtrac method (laser diffraction and scattering method), for example, using the Microtrac MT3000II series manufactured by Nikkiso Co., Ltd.

Preferred examples of the spherical powder contained in the oil-gel type external skin preparation of the present invention include spherical inorganic powders such as spherical silica, spherical calcium carbonate, spherical magnesium carbonate, spherical calcium silicate, spherical magnesium silicate, and other spherical silicates; and organic spherical powders such as polyamide powder, polymethyl methacrylate, and polyester powder. Among them, the use of organic spherical powders is more preferred, and the use of polymethyl methacrylate is particularly preferred.

This is because the organic spherical powder has, in addition to the aforementioned effect of improving usability, an effect of significantly enhancing the skin storage properties of the compound represented by the general formula (1), its isomers and/or its pharmacologically acceptable salts.

The polymethyl methacrylate of the organic spherical powder of the present invention can be a commercially available product. A preferred example of a commercially available product is Microsphere M330 sold by Matsumoto Oil & Pharmaceutical Co., Ltd. Furthermore, to achieve the aforementioned effects, the spherical powder is preferably present in an amount of 12 to 50% by mass, more preferably 15 to 45% by mass, and particularly preferably 20 to 30% by mass, relative to the total amount of the oil-gel formulation for external use on skin. This is because too little of the spherical powder tends to reduce the aforementioned effects, while too much of the spherical powder may impair the degree of freedom in formulation. Furthermore, the oil-gel formulation for external use on skin of the present invention may contain one or more of the spherical powders described above.

The oleogel-type external preparation for skin of the present invention may contain, in addition to the aforementioned ingredients, any ingredients commonly used in external preparations for skin. Preferred examples of such optional ingredients include oils and waxes such as macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, hardened coconut oil, hardened oil, wood wax, hardened castor oil, beeswax, candelilla wax, carnauba wax, insect wax, lanolin, hydrogenated lanolin, hard lanolin, and jojoba wax; and liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, and the like. in), petrolatum, microcrystalline wax and other hydrocarbons; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearyl phosphate, behenic acid, and undecylenic acid; higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, and palmitic alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, diisopropyl adipate, dioctyl sebacate, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate Synthetic ester oils such as tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, and pentaerythritol tetra-2-ethylhexanoate; modified polysiloxanes such as amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and fluorine-modified polysiloxanes, and other silicone oils not classified as the above-mentioned silicones; anionic surfactants such as fatty acid soaps such as sodium laurate and sodium palmitate, potassium lauryl sulfate, and triethanolamine alkyl sulfate ether; cationic surfactants such as stearyltrimethylammonium chloride, benzalkonium chloride, and dodecylamine oxide; 2-cocoyl-2-imidazoliniumhydroxide-1-carboxyethyloxy disodium salt salt) and other imidazoline-based amphoteric surfactants, alkyl betaine, amido betaine, sulfobetaine and other betaine-based surfactants, acylmethyltaurine and other amphoteric surfactants; sorbitol fatty acid esters such as sorbitan monostearate and sorbitan sesquioleate, glycerol fatty acids such as glyceryl monostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, hardened castor oil derivatives, glyceryl alkyl ethers, POE sorbitan oleate (POE sorbitan sesquioleate), etc. monooleate), polyoxyethylene sorbitan monostearate and other POE sorbitan fatty acid esters, POE sorbitan monolaurate and other POE glycerol fatty acid esters, POE monoisostearate and other POE glycerol fatty acid esters, polyethylene glycol monooleate, POE distearate and other POE fatty acid esters, POE alkyl ethers such as POE2-octyldodecyl ether, POE alkylphenyl ethers such as POE nonylphenyl ether, Pluronic type, POE·POP2-decyltetradecyl ether and other POE·POP alkyl ethers, Tetronic type, POE castor oil, POE hardener Castor oil and other POE castor oil, hardened castor oil derivatives, sucrose fatty acid esters, alkyl glucoside and other nonionic surfactants; polyethylene glycol, glycerin, 1,3-butylene glycol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerol, isopentyl glycol, 1,2-pentanediol, 2,4-hexanediol, 1,2-hexanediol, 1,2-octanediol and other polyols; moisturizing ingredients such as sodium pyrrolidonecarboxylate, lactic acid, sodium lactate; surface-treated sericite, mica, talc, kaolin, synthetic mica, barium sulfate and other powders; surface-treated iron oxide red, iron oxide yellow, iron oxide black, cobalt oxide, ultramarine blue, iron blue, titanium oxide, zinc oxide and other inorganic pigments; surface-treated mica titanium, pearl foil and other essence), bismuth oxychloride, and other pearlescent agents; organic pigments that can be laked, such as Red 202, Red 228, Red 226, Yellow 4, Cyan 404, Yellow 5, Red 505, Red 230, Red 223, Orange 201, Red 213, Yellow 204, Yellow 203, Cyan 1, Green 201, Violet 201, and Red 204; polyethylene powder, polymethyl methacrylate, and nylon powder; para-aminobenzoic acid-based UV absorbers; anthranilic acid-based UV absorbers; salicylic acid-based UV absorbers; cinnamic acid-based UV absorbers; benzophenone-based UV absorbers; sugar-based UV absorbers; UV absorbers such as 2-(2'-hydroxy-5'-t-octylphenyl)benzotriazole and 4-methoxy-4'-tert-butyldibenzoylmethane; lower alcohols such as ethanol and isopropyl alcohol; vitamin A or its derivatives, and vitamin B Vitamin B compounds such as _riboflavin hydrochloride, vitamin _B6 tripalmitate, vitamin _B6 dioctanoate, vitamin _B2 or its derivatives, vitamin _B12 , vitamin _B15 or its derivatives; vitamin E compounds such as α-tocopherol, β-tocopherol, γ-tocopherol, vitamin E acetate, vitamin D compounds, vitamin H, pantothenic acid, pantethine, pyrroloquinoline quinone, etc.; antibacterial agents such as phenoxyethanol, etc.

The oleogel-type external skin preparation of the present invention can be produced by treating the essential ingredients, preferred ingredients, and optional ingredients described above according to conventional methods. For example, it is preferably produced according to the following sequence. The oleogel-type external skin preparation of the present invention thus produced can be used in cosmetics including quasi-drugs, pharmaceutical compositions for external skin use, and sundry products for external skin use, but is particularly preferably used in cosmetics.

In addition to oily components such as silicone oil, the compound represented by the general formula (1), its isomers, and/or pharmacologically acceptable salts thereof can be uniformly dispersed by wet pulverization using a ball mill, a mortar mill, or the like. This dispersion can be kneaded with partially cross-linked methylpolysiloxane ("KSG-16" (manufactured by Shin-Etsu Chemical Co., Ltd.) to prepare an oil-gel-type external skin preparation.

Furthermore, by adding a compatible cyclomethicone (e.g., "DC345" (manufactured by Dow Corning Toray Industries, Ltd.) or the like, uniform dilution can be achieved and the hardness can be adjusted. When cyclomethicone is included, it is preferably contained in an amount of 20 to 60% by mass relative to the total amount of the external skin preparation.

In this case, if the content of the partially cross-linked methylpolysiloxane is too low, the structure becomes too loose. Therefore, in order to maintain the stability of the formulation, it is preferred to adjust the content of the partially cross-linked methylpolysiloxane to 5 to 25% by mass relative to the content of the oil-gel type external skin preparation of 0.01 to 10% by mass of the compound represented by the general formula (1).

Example

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to the examples.

<Manufacturing Example 1: Method for manufacturing the comparative skin external preparation (emulsified formulation) of the present invention>

An emulsified external skin preparation was prepared according to the formulation shown in Table 1 below. Specifically, components (A) and (B) were heated to 70°C, and (A) was gradually added to (B) while stirring. The mixture was cooled while stirring to 40°C, and then component (C) was gradually added and stirred until uniformly mixed. Cooling and stirring were stopped at 30°C, yielding an emulsified external skin preparation (emulsified formulation 1).

【Table 1】

Table 1

[Example 1]

<Production Example 2: Method 1 for producing the oil-gel-type external skin preparation of the present invention>

60.0 g of silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.) and 5.0 g of triisooctanate (Nomcort TIO) (Nisshin Oilliyo Co., Ltd.) were weighed and kneaded. 9.0 g of triisooctanate was added to 1.0 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. 20.0 g of polymethyl methacrylate spherical powder (Microspheres M330) (Matsumoto Yushi Pharmaceutical Co., Ltd.) and 5.0 g of sericite (Sericite FSE, Sanshin Mining Co., Ltd.) were added and kneaded to produce an oil-gel formulation. This yielded an oil-gel formulation for external use on the skin (cosmetics 1).

<Comparative Production Example: Method for Producing the Skin External Preparation (Glossing Preparation) of the Present Invention>

10 g of Rheopearl KL2 (Chiba Flour Mills Co., Ltd.), 40 g of triethylhexanoin (Nisshin Oillio Group Ltd.), and 45 g of Lusplan (Nippon Seika Co., Ltd.) were weighed and dissolved by heating at 85°C. 4.5 g of triethylhexanoin (Nisshin Oillio Group Ltd.) was added to 0.5 g of KSK32, and a KSK32 dispersion pulverized in a mill was added. The mixture was stirred and mixed, and then returned to room temperature to obtain a brightening external skin preparation (Comparative Example 1).

<Test Example 1: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 1>

The skin storage properties of KSK32 were evaluated using a comparative skin external preparation (emulsified formulation 1), an oil-gel formulation (cosmetics 1), and Comparative Example 1 (glossy formulation) prepared according to the method. Excised human skin (50-year-old Caucasian male, back skin) was placed in a Franz-type diffusion cell, and the receiving side was filled with PBS. The formulation prepared as described above was added to the donor side and left at 37°C for 24 hours. Any residual formulation adhering to the skin surface was wiped off and then washed with methanol. The stratum corneum of the washed skin was removed with tape. KSK32 was then extracted from the methanol-treated skin (epidermis and dermis excluding the stratum corneum). The skin storage level was calculated using HPLC (column: reversed-phase column (3.0 x 100 mm), column temperature: room temperature, mobile phase: aqueous anionic sulfonic acid surfactant/25% THF, pH 3, flow rate: 0.4 mL/min, detection: 240 nm). The results are shown in Table 2. KSK32 was not detected when using emulsified formulation 1. In addition, a small amount of KSK32 was observed in the glossing preparation of Comparative Example 1. Meanwhile, KSK32 was observed to be accumulated in the skin in the oil-gel formulation for external use on skin (Cosmetic 1), demonstrating that the oil-gel formulation improves skin storability.

【Table 2】

Table 2

[Example 2]

<Production Example 3: Production Method 2 of the Oil-Gel Formulation Skin External Preparation of the Present Invention>

65.0 g of KSG-16 (Shin-Etsu Chemical Co., Ltd.) and 15.0 g of Nomcort TIO (Nissin Oilliyo Co., Ltd.) were weighed and kneaded. 4.5 g of DC345 (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 15.0 g of Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.) were added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (cosmetics 2).

[Example 3]

<Production Example 4: Method 3 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of KSG-16 (Shin-Etsu Chemical Co., Ltd.), 15.0 g of Nomcort TIO (Nisshin Oilliyo Co., Ltd.), and 5.0 g of KF96-6 (Shin-Etsu Silicone Co., Ltd.) were weighed and kneaded. 4.5 g of DC345 (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 10.0 g of Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.) were added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (Cosmetic Product 3).

[Example 4]

<Production Example 5: Method 4 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of "Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)", 15.0 g of "Nomcort TIO (Nissin Oilliyo Co., Ltd.)", and 7.5 g of "Silicone KF96-6 (Shin-Etsu Chemical Co., Ltd.)" were weighed and kneaded. 4.5 g of "DC345 (Dow Corning Toray Industries, Ltd.)" was added to 0.5 g of "KSK32" to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 7.5 g of "Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.)" were added to the KSG-16 and Nomcort TIO combination and kneaded to produce an oil-gel-type external skin preparation (Cosmetic Product 4).

[Example 5]

<Test Example 2: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 2>

The skin storage properties of the microsphere-incorporated formulations (cosmetics 2 to 4) at different incorporation concentrations, produced by the methods described in Examples 3 to 5, were evaluated according to the method described in Test Example 1. The results are shown in Table 3.

【Table 3】

Table 3

The results suggest that increasing the content of microsphere M330 in the formulation of oil-gel type external skin preparations (cosmetics 2 to 4) will improve the skin storage properties of KSK32.

[Example 6]

<Production Example 6: Method 5 for producing the oil-gel-type external skin preparation of the present invention>

75.0 g of "Organic Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)" and 5.0 g of "Nomcort TIO (Nisshin Oillio Co., Ltd.)" were weighed and kneaded. 4.5 g of "DC345 (Dow Corning Toray Industries, Ltd.)" was added to 0.5 g of "KSK32" to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 15.0 g of "Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.)" were added to the KSG-16 and Nomcort TIO combination and kneaded to produce an oleogel-type external skin preparation (Cosmetic Product 5).

[Example 7]

<Production Example 7: Method 6 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of "Organic Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)" and 5.0 g of "Nomcort TIO (Nissin Oilliyo Co., Ltd.)" were weighed and kneaded. 4.5 g of "DC345" (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of "KSK32" to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 25.0 g of "Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.)" were added to the "KSG-16 and Nomcort TIO" mixture and kneaded to produce an oil-gel-type external skin preparation (Cosmetic Product 6).

[Example 8]

<Test Example 3: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 3>

The skin storage properties of the microsphere-incorporated formulations (cosmetics 5 and 6) at different incorporation concentrations, produced according to the methods described in Test Example 1, were evaluated. The results are shown in Table 4.

【Table 4】

Table 4

According to the results in Tables 3 and 4, there is a threshold value around 15% by mass for the content of spherical powders. The content of spherical powders is preferably 12% by mass or more, more preferably 15% by mass or more, and further preferably 20% by mass or more. On the other hand, it is preferably 50% by mass or less, more preferably 45% by mass or less, and further preferably 30% by mass or less.

<Production Example 8: Method 7 for producing the oil-gel-type external skin preparation of the present invention>

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 Industries, Ltd.)", 0.4 (g) of "Phenoxyethanol (Yokkaichi Gosei Co., Ltd.)", 5.9 (g) of "Ethanol (Wako Pure Chemical Industries, Ltd.)", and 2 (g) of "KSK32" were kneaded to produce a skin external preparation of an oil-gel formulation not mixed with powder (skin external preparation not mixed with powder).

[Example 9]

<Production Example 9: Method 8 for producing the oil-gel-type external skin preparation of the present invention>

60.0 g of "Silicone KSG-16 (Shin-Etsu Silicone Co., Ltd.)" and 15.0 g of "Microspheres M330 (Matsumoto Yushi Pharmaceutical Co., Ltd.)" were kneaded. 2.0 g of "Polyether-modified silicone (Silicone KF-6017, Shin-Etsu Chemical Co., Ltd.)" were also kneaded, along with 15.7 g of "DC345 (Dow Corning Toray Industries, Ltd.)" and 0.3 g of "Phenoxyethanol (Yokkaichi Gosei Co., Ltd.)" and 5.0 g of "Ethanol (Wako Pure Chemical Industries, Ltd.)" and 2.0 g of "KSK32" to produce an oil-gel-type external skin preparation (cosmetics 7) containing "polymethyl methacrylate spherical powder (Microspheres M330, Matsumoto Yushi Pharmaceutical Co., Ltd.)".

[Example 10]

<Production Example 10: Method 9 for producing the oil-gel-type external skin preparation of the present invention>

60.0 g of "Organic Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)" and 15.0 g of "Spherical Polyamide Resin (Nylon SP500, Toho Co., Ltd.)" were kneaded. 2.0 g of "Organic Silicone KF-6017 (Shin-Etsu Chemical Co., Ltd.)", 15.7 g of "DC345 (Dow Corning Toray Industries, Ltd.)", 0.3 g of "Phenoxyethanol (Yokkaichi Gosei Co., Ltd.)", 5.0 g of "Ethanol (Wako Pure Chemical Industries, Ltd.)", and 2.0 g of "KSK32" were kneaded to produce an oil-gel type external skin preparation (cosmetics 8) containing spherical polyamide resin powder.

[Example 11]

<Test Example 4: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 4>

The skin storage properties of the oil-gel-type external skin preparations of the present invention (Cosmetic 7 and Cosmetic 8) were evaluated according to the method described in Test Example 1. The results are shown in Table 5.

【Table 5】

Table 5

Comparing any organic spherical powder with a non-spherical powder, the results showed a high skin storage property. In particular, the microsphere M330 showed a high skin storage property.

<Production Example 11: Method 10 for producing the oil-gel-type external skin preparation of the present invention>

80.0 g of KSG-16 (Shin-Etsu Chemical Co., Ltd.) and 15.0 g of Nomcort TIO (Nissin Oillio Co., Ltd.) were weighed and kneaded. 4.5 g of DC345 (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion was added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (no powder was mixed in).

[Example 12]

<Production Example 12: Method 11 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.) and 15.0 g of Nomcort TIO (Nissin Oilliyo Co., Ltd.) were weighed and kneaded. 4.5 g of DC345 (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 15.0 g of polymethyl methacrylate spherical powder (Microspheres M330, Matsumoto Yushi Pharmaceutical Co., Ltd.) were added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (Cosmetic Product 9).

[Example 13]

<Production Example 13: Method 12 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.) and 15.0 g of Nomcort TIO (Nissin Oilliyo Co., Ltd.) were weighed and kneaded. 4.5 g of DC345 (Dow Corning Toray Industries, Ltd.) was added to 0.5 g of KSK32 to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 15.0 g of sericite (Sericite FSE, Sanshin Mining Co., Ltd.) were added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (cosmetics 10).

[Example 14]

<Test Example 5: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 5>

The skin storage properties of the oil-gel-type external skin preparations of the present invention (non-powdered external skin preparations, cosmetics 9 and 10) produced according to the methods described in Production Example 11, Example 11, and Example 12 were evaluated according to the method described in Test Example 1. The results are shown in Table 6.

The skin storage properties of the above-prepared formulations without powder, with microspheres, and with sericite (silicate mineral) were tested and compared using the above-prepared method.

【Table 6】

Table 6

Cosmetic product 9 containing microspheres as spherical powders showed a higher amount of the product stored in the skin than cosmetic product 10 containing sericite as a plate-like powder.

[Example 15]

<Production Example 14: Method 13 for producing the oil-gel-type external skin preparation of the present invention>

65.0 g of "Organic Silicone KSG-16 (Shin-Etsu Chemical Co., Ltd.)" and 15.0 g of "Nomcort TIO (Nissin Oilliyo Co., Ltd.)" were weighed and kneaded. 4.5 g of "DC345 (Dow Corning Toray Industries, Ltd.)" was added to 0.5 g of "KSK32" to prepare a KSK32 dispersion, which was pulverized using a mill. The KSK32 dispersion and 15.0 g of spherical anhydrous silicic acid ("Carbon Dioxide Microspheres P1500 (Catalyst Chemicals Co., Ltd.)) were added to the KSG-16 and Nomcort TIO mixture and kneaded to produce an oil-gel-type external skin preparation (Cosmetic Product 11).

[Example 16]

<Test Example 5: Evaluation of the skin storage properties of the oil-gel-type external skin preparation of the present invention 5>

Cosmetic product 9 and the oil-gel-type external skin preparation of the present invention (Cosmetic product 11) produced in accordance with Example 15 were evaluated for their skin storage properties according to the method described in Test Example 1. The results are shown in Table 7.

【Table 7】

Table 7

As a representative example of spherical inorganic powders, an oil-gel-type external skin preparation (cosmetics 11) in which carbon dioxide microbeads are mixed was evaluated for its skin storage properties. The results showed that the skin storage properties were inferior to those of organic spherical powders.

Industrial Applicability

The present invention can be applied to external skin preparations such as cosmetics.

Claims (7)

1. The use of component 1) a compound represented by the following chemical formula 1, its isomers and/or its pharmacologically permissible salts, and component 2) a partially cross-linked methylpolysiloxane in the manufacture of an oil-based topical skin preparation for improving the skin retention properties of component 1). [Chemical Formula 1] In the above formula, _R1 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxyl group, or a straight-chain or branched alkyl group with 1 to 4 carbon atoms that is substituted with a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms, and _R2 and _R3 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms. 2. The application according to claim 1, characterized in that, The compound represented by the chemical formula 1 is a compound represented by the chemical formula 2 below, its isomers, and/or its pharmacologically permissible salts. [Chemical Formula 2] In the above formula, _R4 represents a straight-chain or branched alkyl group with 1 to 4 carbon atoms that has been substituted with a carboxyl group, and _R5 and _R6 each independently represent a straight-chain or branched alkyl group with 1 to 4 carbon atoms. 3. The application according to claim 2, characterized in that, The compound represented by chemical formula 2 is 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valine-L-proline]amino-1,1,1-trifluoro-4-methyl-2-oxopentane, its isomers, and/or their pharmacologically permissible salts, represented by chemical formula 3 below. 【Chemical Formula 3】 4. The application according to any one of claims 1 to 3, characterized in that, The topical skin agent also contains spherical powder. 5. The application according to claim 4, characterized in that, The spherical powder is an organic spherical powder. 6. The application according to claim 4, characterized in that, The spherical powder is polymethyl methacrylate. 7. The application according to claim 4, characterized in that, The spherical powder contains 12-50% by mass relative to the total amount of the topical skin agent.