HK40000200A - External preparation for skin for wrinkle improvement - Google Patents

Description

External preparation for skin for improving wrinkles

Technical Field

The present invention relates to a skin preparation for external use suitable as a cosmetic (including quasi-drug), and more particularly, to an oil gel type skin preparation for external use characterized by containing 1) a compound represented by the following general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof, and 2) a partially crosslinked methylpolysiloxane.

[ chemical formula 1]

[ in the formula, R₁Represents 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 a C1-4 alkyl chain, R₂And R₃Each independently represents a C1-4 linear or branched alkyl group]。

Background

As a representative symptom of the skin aging phenomenon due to an increase in youth, wrinkle formation is cited. Wrinkles can be roughly classified into shallow wrinkles formed on the skin surface, which can be improved by moisturizing, and deep wrinkles generated by exposure to ultraviolet rays, accumulating physical stimulus, and the prevention or improvement of the formation of the latter deep wrinkles is very difficult. In addition, various wrinkle-improving agents have been developed (for example, see non-patent document 1). As such wrinkle-improving agents, retinoic acid is known as an active ingredient. Although retinoic acid has been approved as a pharmaceutical for the treatment of wrinkles and acne in the united states, it has not been approved in japan because of its safety problems such as skin irritation. Further, as other wrinkle-improving agents, collagen production-promoting agents (for example, see patent document 1), hyaluronic acid production-promoting agents (for example, see patent document 2), and the like have been reported. However, the wrinkle-improving agents described above cannot be said to achieve sufficient effects, and effective means have not been established. One of the causes of this is the presence of a wrinkle-improving agent which is problematic in terms of stability of the wrinkle-improving agent and the external preparation for skin, skin permeability, storage properties, and the like.

The wrinkle-improving agent having a different mechanism of action from the above wrinkle-improving agents contains an elastase inhibitor. Elastin, one of the structural proteins present in skin tissue, maintains the elasticity of the tissue by building a cross-linked structure. It is known that exposure to skin irritation such as ultraviolet rays modifies and destroys elastin by excessively expressing and activating elastase, an elastin degrading enzyme, thereby causing reduction in firmness and elasticity of skin and further promoting wrinkle formation. The elastase inhibitor exerts a preventive or ameliorating effect on wrinkle formation by inhibiting the aforementioned elastin degrading enzymes. On the other hand, although studies on structural analysis and structural activity of elastin degradation enzymes and substrates have been made, it is difficult to achieve high enzyme inhibitory activity and selectivity by organic low molecules, and many peptides and derivatives thereof exist as components having high enzyme inhibitory activity (for example, see patent document 3). As an elastase inhibitor of such a peptide derivative, a peptide derivative such as WS7622A monosulfate or disulfate is known (for example, see patent document 4), and the application to ischemic diseases is achieved by the pharmacological action involved. Further, it is known that the compound represented by the above general formula (1) has a leukocyte elastase inhibitory effect as in WS7622A, and a skin aging preventive or therapeutic effect has been reported (for example, see patent document 5). However, the peptides and derivatives thereof are also relatively large in molecular size, and have chemical structural characteristics that are not preferable for having a plurality of amide bonds or the like that reach the dermis, and therefore it is concerned that an effective amount does not reach the wrinkle formation site. Actually, when a peptide or a derivative thereof is transdermally administered, there are many problems in terms of stability of an active ingredient and an external preparation for skin, skin permeability, storage property, and the like, and it is not uncommon that a desired effect cannot be obtained.

In general, when an external preparation for skin such as a cosmetic contains a wrinkle-improving agent, an aqueous preparation such as an emulsion, a serum, or a cream can be selected as a selected preparation. Since the above-described elastase inhibitors, particularly peptides and derivatives thereof expected to have a high elastase inhibitory activity, have a relatively large molecular weight and a chemical structure in which a lipophilic portion contains a small hydrophilic portion, when an aqueous formulation is selected and a wrinkle-improving agent is contained, the wrinkle-improving agent does not easily infiltrate into the dermis from the skin surface, but tends to fall off from the skin in a short time by means of sweat or the like. Therefore, in most cases, the bioavailability becomes extremely low, and the expected preventive or ameliorating effect on wrinkle formation is not exerted. On the other hand, a conventional oil-and-gel preparation obtained by solidifying a liquid oil or fat with wax or the like has an advantage that the above-mentioned peeling of a wrinkle-improving agent due to sweat or the like can be suppressed, or the deterioration of a wrinkle-improving agent unstable to water can be suppressed, but on the contrary, it is very good that the skin is not infiltrated or penetrated in many cases. In addition, the oil-gel preparation has a problem of stickiness and the like in use. Therefore, in order to improve the usability of cosmetics as an oil gel preparation, an oil gel type external preparation containing a silicone oil has been reported (for example, see patent documents 6 and 7). Furthermore, it is known that a cosmetic composition in which a silicone oil is mixed in an oil gel type is less likely to change the property of fragrance with time (see, for example, patent document 8).

Further, there is known a technique for improving the appearance of the whole skin such as fine lines by forming a smooth film to smooth the fine lines and wrinkles when a cosmetic composition is made to contain a crosslinked silicone elastomer (partially crosslinked methylpolysiloxane) and the composition is applied to the skin, or by adding spherical particles to impart a function as an optical diffuser for optically scattering the fine lines and wrinkles to change the surface inspection of the skin (for example, see patent document 9).

Prior art documents

Patent document

Patent document 1: japanese laid-open patent publication No. 2002 + 255847

Patent document 2: japanese laid-open patent publication 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 laid-open publication No. 2003-300851

Patent document 9: japanese laid-open patent application No. 2001-294510

Non-patent document

Non-patent document 1: development technology of anti-aging, whitening and moisturizing cosmetics, CMC publishing, Suzuki Zhengren Shenshui, Chapter 2 anti-aging and anti-wrinkle) functional cosmetics

Disclosure of Invention

Problems to be solved by the invention

As described above, it is known to use an oil gel type as a cosmetic preparation, but it is not clear how the active ingredient affects the percutaneous absorbability of the skin in an oil gel type external preparation containing the active ingredient for the purpose of application to the skin. Therefore, there has been no attempt to make such an oil gel preparation contain the compound represented by the general formula (1).

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

Means for solving the problems

In view of the above circumstances, the present inventors have found that by incorporating the compound represented by the above general formula (1), its isomer and/or its pharmacologically acceptable salt into an external preparation for skin of an oil gel type containing a cross-linked methylpolysiloxane as a structural matrix, the compound represented by the above general formula (1), its isomer and/or its pharmacologically acceptable salt, the balance between the ease of existence of the compound in the external preparation for skin and the penetration into the skin is improved, and the storage property for skin is further improved.

Further, it has been found that an external preparation for skin of an oil gel type containing a spherical powder reduces the viscosity and increases the fluidity of the external preparation for skin, thereby improving the feeling of use and facilitating the spreading of the external preparation for skin to the skin, and further, the percutaneous absorbability is improved. Based on this finding, the present inventors have found that an oil-gel type external preparation for skin improves the skin storage property of the compound represented by the general formula (1) and the like in the external preparation for skin, and have completed the present invention. That is, the present invention is as follows.

< 1 > an oil gel type external preparation for skin, which is characterized by comprising: 1) a compound represented by the following general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof, and 2) a partially crosslinked 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 a C1-4 alkyl chain, and R2 and R3 each independently represent a C1-4 linear or branched alkyl group ]

< 2 > < 1 > the oil-gel-type external preparation for skin, wherein 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, R₄Represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, R₅And R₆Each independently represents a C1-4 linear or branched alkyl group.]

[ 3] the oil-gel-type external preparation for skin described in the above (3) or (2), wherein the compound represented by the above 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), an isomer thereof, and/or a pharmacologically acceptable salt thereof.

[ chemical formula 4]

The oil-gel-type external preparation for skin of any one of < 4 >, < 1 > - < 3 >, which further comprises a spherical powder.

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

The oil gel type skin external preparation is less than 6, less than 4 or less than 5, and is characterized in that the spherical powder is polymethyl methacrylate.

The oil-gel-type external preparation for skin of 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 preparation for skin.

Effects of the invention

When the oil gel type external preparation for skin of the present invention is used, the compound represented by the general formula (1), its isomer and/or a pharmacologically acceptable salt thereof reaches the dermis to improve the skin storage property of the compound, thereby solving cosmetic problems such as prevention or improvement of wrinkle formation.

Detailed Description

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

The oil gel type external preparation for skin 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 crosslinked methylpolysiloxane. The oil-gel-type external preparation for skin of the present invention can improve the skin storage properties of the compound represented by the general formula (1), its isomer, and/or a pharmacologically acceptable salt thereof, and thus can exhibit an excellent effect of preventing or improving wrinkle formation. The compound represented by the general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof of the present invention can be produced, for example, by the method described in Japanese patent application laid-open No. H04-297446. The compound represented by the general formula (1) of the present invention has an inhibitory activity against human leukocyte elastase, and thus can be expected to have a therapeutic effect on ischemic brain diseases such as cerebral infarction. Further, for example, as described in WO1999/43352, the composition has a preventive or therapeutic effect on skin aging. The compound represented by the general formula (1) of the present invention has an action such as neogenesis of elastic fibers in the dermal papilla, neogenesis of fine collagen fibrils in the dermal region directly below the epidermis, and increase in the thickness of the epidermis, and exhibits an effect of preventing or improving wrinkle formation by the action. In addition, since the compound represented by the general formula (1) of the present invention has an optically active compound having a plurality of asymmetric carbon atoms in its molecular structure, enantiomers and diastereomers exist as isomers thereof. Further, as the compound represented by the general formula (1) of the present invention, there are a racemate, an enantiomer, and a diastereomer, and there are also compounds in which the isomers are mixed at an arbitrary ratio.

With respect to the compound of the present invention represented by the general formula (1), wherein R₁Represents 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 a C1-4 alkyl chain, R₂And R₃Each independently represents a C1-4 linear or branched alkyl group.

If the R is specifically illustrated₁Preferred groups, which may preferably be exemplified by a carboxyl groupAn oxymethyl group, a carboxyethyl group, a carboxypropyl group, a carboxybutyl group, a methoxycarbonylmethyl group, a methoxycarbonylethyl group, a methoxycarbonylpropyl group, a methoxycarbonylbutyl group, an ethoxycarbonylmethyl group, an ethoxycarbonylethyl group, an ethoxycarbonylpropyl group, an ethoxycarbonylbutyl group, a propoxycarbonylmethyl group, a propoxycarbonylethyl group, a propoxycarbonylpropyl group, a propoxycarbonylbutyl group, a butoxycarbonylmethyl group, a butoxycarbonylethyl group, a butoxycarbonylpropyl group, a butoxycarbonylbutyl group, etc., and a carboxymethyl group is more preferably exemplified.

If the R is specifically illustrated₂And R₃Examples of the preferable groups each independently include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like, and isopropyl is more preferable.

Among the compounds represented by the above general formula (1), isomers thereof and/or pharmacologically acceptable salts thereof, preferable examples thereof include the compound represented by the above general formula (2), isomers thereof and/or pharmacologically acceptable salts thereof, more preferable examples thereof include 3- [ [4- (carboxymethylaminocarbonyl) phenylcarbonyl ] -valyl-prolyl ] amino-1, 1, 1-trifluoro-4-methyl-2-oxopentane, isomers thereof and/or pharmacologically acceptable salts thereof, still more preferable examples thereof include 3(RS) - [ [4- (carboxymethylaminocarbonyl) phenylcarbonyl ] -L-valyl-L-prolyl ] amino-1, 1, 1-trifluoro-4-methyl-2-oxopentane or sodium salt thereof (hereinafter, this sodium salt may be abbreviated as KSK 32).

The compound represented by the general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof of the present invention is contained in an oil-gel type external skin preparation together with a partially crosslinked methylpolysiloxane, whereby the skin storage property is improved, and the effect of preventing or improving the formation of wrinkles is improved.

With respect to the compound of the present invention represented by the general formula (2), wherein R₄Represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, R₅And R₆Each independently represents a C1-4 linear or branched alkyl group. The R is₄Represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, and specifically exemplifies the R₄Preferred examples of the group include a carboxymethyl group, a 1-carboxyethyl group, a 2-carboxyethyl group, a 1-carboxypropyl group, a 2-carboxypropyl group, a 3-carboxypropyl group, a 1-carboxybutyl group, a 2-carboxybutyl group, a 3-carboxybutyl group, and a 4-carboxybutyl group.

The R is₅And R₆Each independently represents a C1-4 linear or branched alkyl group, and specifically, R is₅And R₆Preferable examples of the group include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, and more preferable examples of the group include isopropyl. Further, preferable examples of the compound represented by the general formula (2) include N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxyethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxyethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) amino acid2-oxopropyl radical]-L-prolinamide, N- [4- [ [ (carboxyethyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-alanyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxyethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxyethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-ethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide (3(RS) -N- [4- [ [ (carboxymethyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide), N- [4- [ [ (carboxyethyl) amino]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxypropyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, N- [4- [ [ (carboxybutyl) amino group]Carbonyl radical]Benzoyl radical]-L-valyl-N- [3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxoPropyl radical]The more preferable compound is N- [4- [ [ (carboxymethyl) amino group) represented by the general formula (3)]Carbonyl radical]Benzoyl radical]-L-valyl-N- [ (RS) -3, 3, 3-trifluoro-1- (1-methylethyl) -2-oxopropyl]-L-prolinamide, isomers thereof and/or pharmacologically acceptable salts thereof. Further, the compound represented by the general formula (3) can also be expressed as 3(RS) - [ [4- (carboxymethylaminocarbonyl) phenylcarbonyl group, as described above]-L-valyl-L-prolyl]Amino-1, 1, 1-trifluoro-4-methyl-2-oxopentane.

Hereinafter, 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 KSK 32. The KSK32 mentioned above refers to the same compound only named differently.

By containing the compound represented by the general formula (1), its isomer and/or its pharmacologically acceptable salt of the present invention together with a partially crosslinked methylpolysiloxane in an oil-gel type external preparation for skin, the storage stability of the skin is improved, the formation of wrinkles is suppressed, the balance between the new formation and the disappearance of wrinkles tends to disappear, and the effect of preventing or improving the formation of wrinkles is improved.

Further, although the compound represented by the general formula (1) of the present invention may be contained in an external preparation for skin in the form of an oil gel as it is, it may be treated with a pharmacologically acceptable acid or base and converted into a salt form to be used as a salt. Examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate and carbonate; organic acid salts such as maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, p-toluenesulfonate, benzenesulfonate and the like; alkaline earth metal salts such as alkali metal salts, calcium salts and magnesium salts of sodium salts and potassium salts; organic amine salts such as triethylamine salt, triethanolamine salt, ammonium salt, monoethanolamine salt, and piperidine salt, and basic amino acid salts such as lysine salt and alginate salt; and so on. The external preparation for skin of the oil gel type of the present invention may contain 1 or 2 or more compounds selected from the compounds represented by the general formula (1), isomers thereof and/or pharmacologically acceptable salts thereof.

In order to allow the compound represented by the general formula (1), its isomer and/or a pharmacologically acceptable salt thereof of the present invention to exhibit the above-mentioned effects when contained in an oil-based external preparation for skin, the content is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass, based on the total amount of the external preparation for skin. This is because, when the amount of the compound represented by the general formula (1), its isomer and/or its pharmacologically acceptable salt contained in the external preparation for skin of an oil gel type is too small, the effect tends to be decreased, and even if it is too large, the effect tends to peak.

< partially crosslinked methylpolysiloxane of the present invention >

The external preparation for skin of the present invention is characterized by containing 1) the compound represented by the general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof, and 2) a partially crosslinked methylpolysiloxane. The partially crosslinked methylpolysiloxane classified as a partially crosslinked organopolysiloxane polymer is a silicone oil having a structure in which linear polymer portions formed by siloxane bonds are crosslinked. The "partially crosslinked type" as used in the present invention means a product produced by crosslinking so that the crosslinking rate, which indicates the degree of crosslinking, is about 20 to 30%.

From the viewpoint of stability and feeling upon use, it is preferable to use a partially crosslinked methylpolysiloxane having a consistency of 100 to 500 at 25 ℃.

Further, the consistency of the partially crosslinked methylpolysiloxane at 25 ℃ can be measured in accordance with JIS K2220.

Among the partially crosslinked methylpolysiloxanes described above, there are commercially available products as general-purpose raw materials for cosmetics. The partially crosslinked methylpolysiloxane of the present invention can be used as it is commercially available.

As a commercially available product, a product containing other silicone oil such as decamethylcyclopentasiloxane, methylpolysiloxane, octamethylcyclotetrasiloxane, methylphenylpolysiloxane, etc., in addition to the partially crosslinked methylpolysiloxane, or a product containing only partially crosslinked methylpolysiloxane may be used.

Among commercially available partially crosslinked methylpolysiloxanes, examples of preferable products include KSG-15 (a mixture of about 5 parts by mass of a partially crosslinked methylpolysiloxane and about 95 parts by mass of decamethylcyclopentasiloxane), KSG-16 (a mixture of about 20 to 30 parts by mass of a partially crosslinked methylpolysiloxane and about 70 to 80 parts by mass of a methylpolysiloxane), KSG-17 (a mixture of about 5 parts by mass of a partially crosslinked methylpolysiloxane and about 95 parts by mass of octamethylcyclotetrasiloxane), KSG-18 (a mixture of about 10 to 20 parts by mass of a partially crosslinked methylpolysiloxane and about 80 to 90 parts by mass of a methylphenylpolysiloxane), and KSG-16 is particularly preferable.

The external preparation for skin of the oil gel type of the present invention may contain 1 or 2 or more kinds selected from the above-mentioned commercially available products of partially crosslinked methylpolysiloxane, or may contain another silicone oil in a commercially available product containing only partially crosslinked methylpolysiloxane. The partially crosslinked methylpolysiloxane of the present invention functions as a gel-forming agent in the external preparation for skin, and provides an effect of maintaining the oil gel structure of the external preparation for skin. In order to exert such an effect, the content of the partially crosslinked methylpolysiloxane is preferably 5 to 25% by mass, more preferably 10 to 20% by mass, based on the total amount of the external preparation for skin of an oil gel type. This is because, when the amount is too small, the structure tends to be difficult to maintain, and when the amount is too large, the degree of freedom of preparation tends to be impaired.

< external preparation for skin of the present invention >

The oil gel type external preparation for skin 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 crosslinked methylpolysiloxane. The oily gel type external preparation for skin of the present invention has an effect of effectively improving the anti-aging, wrinkle formation preventing or improving action by increasing the concentration of an active ingredient in the dermis by promoting the release from the preparation of the compound represented by the general formula (1), improving the skin storage property, or the like.

Although the external preparation for skin of the oil gel type of the present invention is formed into an oil gel type by using the aforementioned partially crosslinked methylpolysiloxane, it may contain components other than the aforementioned silicone oil in addition to the crosslinked methylpolysiloxane. The silicone oil contained in the aforementioned commercially available product functions as a gelled oily component in the oil-and-gel formulation, and a volatile silicone oil having a boiling point of 200 ℃ or lower under 1 atm is particularly preferable as such an oily component. Examples of such volatile silicone oils include methylpolysiloxane at 25 ℃ of 1 mPas or less, the aforementioned decamethylcyclopentasiloxane, methylpolysiloxane, octamethylcyclotetrasiloxane and the like.

The volatile silicone oil is preferably contained in an amount of 30 to 60% by mass based on the total amount of the oil gel type external preparation for skin. The external skin preparation of the oil gel type of the present invention can improve the skin storage property of the compound represented by the general formula (1) by gelling the oil component by the partially crosslinked methylpolysiloxane and forming the oil gel into a dosage form. Further, the prevention or improvement effect on wrinkle formation is enhanced by the enhancement of skin storage of the compound represented by the general formula (1).

The external preparation for skin of the oil gel type of the present invention is preferably a spherical powder containing a fat-soluble enhancer that favorably spreads the external preparation for skin. The term "spherical" in the present invention includes not only a regular spherical shape but also a substantially spherical shape having a surface with a concave-convex portion.

The average particle diameter of the spherical powder is preferably 5 to 20 μm. This is because, when the thickness is less than 5 μm, the feeling of astringency is strongly felt at the time of coating, and when the thickness exceeds 20 μm, the feeling of unevenness due to spherical disputes is strongly felt at the time of coating.

In the present specification, the particle diameter of the spherical dispute can be measured by the macbeck (Microtrac) method (laser diffraction and scattering method), for example, the Microtrac MT3000II series manufactured by japan ltd.

The spherical powder contained in the oil-gel type external preparation for skin of the present invention includes, for example, spherical inorganic powder such as spherical silica, spherical calcium carbonate, spherical magnesium carbonate, spherical calcium silicate, spherical silicate such as spherical magnesium silicate, and organic spherical powder such as polyamide powder, polymethyl methacrylate, and polyester powder, and among these, organic spherical powder is more preferably used, and polymethyl methacrylate is particularly preferably used.

This is because the organic spherical powder has an effect of remarkably enhancing the skin storage property of the compound represented by the general formula (1), an isomer thereof, and/or a pharmacologically acceptable salt thereof, in addition to the above-described effect of improving the usability.

As the polymethyl methacrylate of the organic spherical powder of the present invention, commercially available products can be used, and as a commercially available product, microspheres M330 sold by masson oil pharmaceutical co. In order to achieve the above-described effects, the spherical powder is preferably contained in an amount of 12 to 50% by mass, more preferably 15 to 45% by mass, and particularly preferably 20 to 30% by mass, based on the total amount of the external preparation for skin of an oil gel type. This is because the effect tends to be reduced when the amount is too small, and the degree of freedom of prescription may be impaired when the amount is too large. The external preparation for skin of the oil gel type of the present invention may contain 1 or 2 or more kinds selected from the spherical powder.

The oily skin preparation of the present invention may contain, in addition to the above-mentioned components, any of the components usually used for skin preparations for external use. 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; hydrocarbons such as liquid paraffin, squalane, pristane, ozokerite (ozokerite), paraffin, siloxine (ceresin), petrolatum, and microcrystalline wax; higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid phosphoric acid, behenic acid, and undecylenic acid; higher alcohols such as cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, and palmityl alcohol; cetyl isooctanoate, isopropyl myristate, hexyldecanol isostearate, diisopropyl adipate, dioctyl sebacate, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate (ethylene glycol di-2-ethylhexanoate), neopentyl glycol dicaprate, glycerol di-2-heptylundecanoate (glycerol di-2-hexyluncanoate), glycerol tri-2-ethylhexanoate (glycerol tri-2-ethylhexanoate), trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate; synthetic ester oils such as pentaerythritol tetra-2-ethylhexanoate; oil agents such as silicone oils not classified into the above silicones, e.g., modified polysiloxanes such as amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and fluorine-modified polysiloxanes; fatty acid soaps such as sodium laurate and sodium palmitate, and anionic surfactants such as potassium lauryl sulfate and triethanolamine alkyl sulfate; cationic surfactants such as stearyl trimethyl ammonium chloride, benzalkonium chloride, and lauryl amine oxide; 2-Cocoyl-2-imidazoline hydroxide-1-carboxyethoxy disodium salt (2-coyl-2-imidazolium hydroxide-1-car)Imidazoline-based amphoteric surfactants such as boxyethyyloxide salts), betaine-based surfactants such as alkylbetaines, amidobetaines and sulfobetaines, and amphoteric surfactants such as acylmethyltaurates (acylmethyltaurines); sorbitol fatty acid esters such as sorbitol monostearate and sorbitan sesquioleate, glycerin fatty acids such as glyceryl monostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, hardened castor oil derivatives, glycerin alkyl ethers, POE sorbitol oleate (POE sorbitol monooleate), POE sorbitol fatty acid esters such as polyoxyethylene sorbitol monostearate, POE sorbitol fatty acid esters such as POE-sorbitol monolaurate, POE glycerin fatty acid esters such as POE-glycerin monoisostearate, POE fatty acid esters such as polyethylene glycol monooleate and POE distearate, POE alkyl ethers such as POE 2-octyldodecyl ether, POE alkylphenyl ethers such as POE nonylphenyl ether, POE alkyl phenyl ethers such as Pluronic (Pluronic) type, POE POP alkyl ethers such as POE 2-decyltetradecyl ether, Tetronic type, POE castor oil, POE hardened castor oil derivatives such as POE hardened castor oil, Nonionic surfactants such as sucrose fatty acid esters and alkyl glycosides; polyhydric alcohols such as polyethylene glycol, glycerin, 1, 3-butanediol, erythritol, sorbitol, xylitol, maltitol, propylene glycol, dipropylene glycol, diglycerin, isoprene glycol, 1, 2-pentanediol, 2, 4-hexanediol, 1, 2-hexanediol, and 1, 2-octanediol; moisture-retaining ingredients such as sodium pyrrolidone carboxylate, lactic acid, and sodium lactate; powder such as sericite, mica, talc, kaolin, synthetic mica, barium sulfate, etc. which can be surface-treated; inorganic pigments such as red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine blue, iron blue (iron blue), titanium oxide, and zinc oxide, which can be surface-treated; pearling agents such as mica titanium, fish scale foil (pearl science), bismuth oxychloride and the like which can be subjected to surface treatment; organic pigments 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, which can be laked; polyethylene powder and polymethacryleneMethyl ester acid, nylon powder; a p-aminobenzoic acid-based ultraviolet absorber; anthranilic acid-based ultraviolet absorbers; salicylic acid-based ultraviolet absorbers; cinnamic acid-based ultraviolet absorbers; benzophenone-based ultraviolet absorbers; sugar-based ultraviolet absorbers; ultraviolet absorbers such as 2- (2 ' -hydroxy-5 ' -t-octylphenyl) benzotriazole and 4-methoxy-4 ' -t-butyldibenzoylmethane; lower alcohols such as ethanol and isopropanol; vitamin A or its derivative, vitamin B₆Hydrochloride, vitamin B₆Tripalmitate, vitamin B₆Dicaprylate and vitamin B₂Or its derivative, vitamin B₁₂Vitamin B₁₅Vitamin B compounds such as α -tocopherol, β -tocopherol, gamma-tocopherol, vitamin E acetate and other vitamin E compounds, vitamin D compounds, vitamin H, pantothenic acid, pantethine, pyrroloquinoline quinone and other vitamins, and phenoxyethanol and other antibacterial agents.

The external preparation for skin of the oil gel type of the present invention can be produced by treating the essential components, preferred components, optional components, and the like according to a conventional method, and for example, it is preferable to produce them in the order described below. The oil-gel-type external preparation for skin of the present invention thus produced can be applied to cosmetics including quasi-drugs, pharmaceutical compositions for external application for skin, miscellaneous goods for external application for skin, and the like, but is particularly preferably applied to cosmetics.

In addition to the oily components such as silicone oil, the compound represented by the general formula (1), its isomer and/or its pharmacologically acceptable salt may be uniformly dispersed by wet pulverization using wet pulverization means such as a ball mill or a mortar machine. An oily skin preparation for external use can be prepared by kneading the dispersion with a partially crosslinked methylpolysiloxane ("KSG-16" (manufactured by shin-Etsu chemical Co., Ltd)).

Further, by adding a compatible cyclomethicone (for example, "DC 345" (manufactured by Dow Corning Tokeny Co., Ltd.) or the like thereto, the dilution can be made uniform and the hardness can be adjusted, and when the cyclomethicone is contained, it is preferably contained in an amount of 20 to 60% by mass based on the total amount of the skin external preparation.

In this case, since the structure is too relaxed when the content of the partially crosslinked methylpolysiloxane is too small, it is preferable to adjust the content of the partially crosslinked methylpolysiloxane to 5 to 25% by mass relative to 0.01 to 10% by mass of the content of the oil-gel type external preparation for skin represented by the above general formula (1) in order to maintain the stability of the formulation.

Examples

The present invention will be described in more detail below with reference to examples, but it is needless to say that the present invention is not limited to the examples.

Production example 1: method for producing comparative skin preparation for external use (emulsion type) of the present invention

An emulsion type skin external preparation was manufactured according to the recipe shown in table 1 below. That is, the components (A) and (B) were heated to 70 ℃ respectively, and gradually added while stirring (A) in (B). After cooling while stirring to 40 ℃, the component (C) was gradually added and stirred uniformly. The cooling and stirring were stopped at 30 ℃ to obtain an emulsion-type external preparation for skin (emulsion formulation 1).

[ TABLE 1]

TABLE 1

[ example 1]

Production example 2: method for producing an oil gel type external preparation for skin of the present invention 1 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.)" 60.0(g) "and" Triisooctanoic acid glyceride (Nomcort TIO) (Nisshin Oillio Co., Ltd.) "5.0 (g)" were weighed and kneaded. To "KSK 32" 1.0(g), "Triisooctanoic acid glyceride" 9.0(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To these, 20.0(g) of "polymethyl methacrylate spherical powder (microsphere M330) (Songbu oil & fat pharmaceuticals Co., Ltd)" and 5.0(g) of "sericite (sericite FSE, Sanxin mineral Co., Ltd)" were added and kneaded to prepare an oil-gel formulation. Thus, an external preparation for skin (cosmetic 1) of a formula of an oil gel type was obtained.

Comparative production example: a process for producing an external preparation for skin (gloss preparation) of the present invention

Rheopearl KL2 (Kyowa Kagaku Co., Ltd.) 10(g), triisooctanoic acid glyceride (Nisshin Oillio Co., Ltd.) 40(g), and Lusplan (Japanese Kogyo Co., Ltd.) 45(g) were weighed and dissolved at 85 ℃. To "KSK 32" (0.5 g), "triisooctanoic acid glyceride (riqing oiritomo group co.)" 4.5(g) was added, and the KSK32 dispersion pulverized by a pulverizer was added, and the mixture was stirred and mixed while being returned to normal temperature, thereby obtaining a glossy skin external preparation (comparative example 1).

< test example 1: evaluation of skin storage Properties of external preparation for skin in the form of oil gel of the present invention 1 >

The skin storage properties of KSK32 were evaluated for the comparative external skin preparation (emulsion formulation 1), the oil gel type external skin preparation (cosmetic 1), and the comparative example 1 (gloss preparation) manufactured by the above-described methods. Extirpated human skin (caucasian, 50 year old male, dorsal skin) was placed in Franz (Franz) type diffusion cells and the receiving side was filled with PBS. The prescription prepared as described above was added to the supply side, left at 37 ℃ for 24 hours, and then wiped off the residual prescription attached to the skin surface, followed by washing with methanol. After removing the upper horny layer of the washed skin using a tape, KSK32 was extracted from the skin (epidermis and dermis parts except horny layer) treated with methanol, and the storage amount in the skin was calculated by HPLC (column: reverse phase column (3.0X 100mm), column temperature: room temperature, mobile phase: aqueous anionic sulfonic acid type surfactant/THF 25%, pH; 3, flow rate; 0.4mL/min., detection; 240 nm). The results are shown in Table 2. In the case of emulsion formula 1, no KSK32 was detected. In addition, in the gloss preparation of comparative example 1, a slight storage of KSK32 was confirmed. On the other hand, the in-skin storage of KSK32 in the oil gel type skin external preparation (cosmetic 1) was confirmed, and it was thus understood that the skin storage property was improved by formulating the oil gel type.

[ TABLE 2]

TABLE 2

[ example 2]

Production example 3: method for producing an oil gel type external preparation for skin of the present invention 2 >

"Silicone KSG-16 (manufactured by shin-Etsu chemical Co., Ltd.)" 65.0(g) and "Nomcort TIO (Rinay Oliway Co., Ltd.)" 15.0(g) were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 15.0(g) of "Microbeads M330 (manufactured by Songbo oil & fat pharmaceuticals Co., Ltd.) were added and kneaded to prepare an oil-gel type skin preparation for external use (cosmetic 2).

[ example 3]

Production example 4: method for producing an oil gel type external preparation for skin of the present invention 3 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.)" 65.0(g) "and" Nomcort TIO (Ri Qing Oliway Co., Ltd.) "15.0 (g)" and "Silicone KF96-6 (shin-Etsu Silicone Co., Ltd.)" 5.0(g) "were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 10.0(g) of "Microbeads M330 (manufactured by Songbo oil & fat pharmaceuticals Co., Ltd.) were added and kneaded to prepare an oil-gel type skin preparation for external use (cosmetic 3).

[ example 4]

Production example 5: method for producing an oil gel type external preparation for skin of the present invention 4 >

"Silicone KSG-16 (manufactured by shin-Etsu chemical Co., Ltd.)" 65.0(g) "and" Nomcort TIO (manufactured by Nisshin Ohio Co., Ltd.) "15.0 (g)" and "Silicone KF96-6 (manufactured by shin-Etsu chemical Co., Ltd.)" 7.5(g) were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 7.5(g) of "Microbeads M330 (manufactured by Songbo oil & fat pharmaceuticals Co., Ltd.) were added and kneaded to prepare an oil-gel type skin preparation for external use (cosmetic 4).

[ example 5]

< test example 2: evaluation of skin storage Property of external preparation for skin in the form of oil gel of the present invention 2 >

The skin storability of the formulation of the microspheres mixed in at different concentrations (cosmetics 2 to 4) prepared by the methods described in examples 3 to 5 was evaluated by the method described in test example 1. The results are shown in Table 3.

[ TABLE 3]

TABLE 3

It is suggested that increasing the content of microspheres M330 in the formula of oil gel type skin external preparations (cosmetics 2-4) will improve the skin storage property of KSK 32.

[ example 6]

Production example 6: method for producing an oil gel type external preparation for skin of the present invention 5 >

"Silicone KSG-16 (shin Etsu chemical Co., Ltd.)" 75.0(g) "and" Nomcort TIO (Nisshin-oillo Co., Ltd.) "5.0 (g)" were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 15.0(g) of "Microbeads M330 (manufactured by Songbo oil & fat pharmaceuticals Co., Ltd.) were added and kneaded to prepare an oil-gel type skin preparation for external use (cosmetic 5).

[ example 7]

Production example 7: the method for producing an oil gel type external preparation for skin of the present invention 6 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.)" 65.0(g) and "Nomcort TIO (Rinay Oliway Co., Ltd.)" 5.0(g) were weighed and kneaded. To 0.5(g) "KSK 32", 4.5(g) "DC 345" (Dow Corning Tokenli Co., Ltd.) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To the composition of "KSK 32 and Nomcort TIO", KSK32 dispersion and "Microbeads M330 (manufactured by Songbo oil pharmaceuticals Co., Ltd.)" 25.0(g) were added and kneaded to prepare an oil-gel type skin preparation for external use (cosmetic 6).

[ example 8]

< test example 3: evaluation of skin storage Property of external preparation for skin in the form of oil gel of the present invention 3 >

The skin storability of the formulation of the microsphere blend (cosmetics 5 and 6) prepared by the methods described in examples 6 and 7 and having different blend concentrations was evaluated by the method described in test example 1. The results are shown in Table 4.

[ TABLE 4]

TABLE 4

As is clear from the results in tables 3 and 4, the content of the spherical powder has a threshold value in the vicinity of 15 mass%, and the content of the spherical powder is preferably 12 mass% or more, more preferably 15 mass% or more, and still more preferably 20 mass% or more, and on the other hand, preferably 50 mass% or less, more preferably 45 mass% or less, and still more preferably 30 mass% or less.

Production example 8: the invention relates to a method for preparing an oil gel type external preparation for skin

An external preparation for skin (external preparation for skin without powder) of the powdery oil-and-gel type was prepared by kneading 71.0(g) of "silicone KSG-16 (shin-Etsu chemical Co., Ltd.)," 2.4(g) "of" polyether-modified silicone KF-6017, shin-Etsu chemical Co., Ltd., "18.3 (g)" of "DC 345 (Dow Corning Tokenli Co., Ltd.)," 0.4(g) "of" phenoxyethanol (synthetic Co., Ltd., Siri) "," 5.9(g) "of" ethanol (Wako pure chemical industries, Ltd., "KSK 32" 2 (g)).

[ example 9]

Production example 9: the invention relates to a method for preparing an oil gel type external preparation for skin

"Silicone KSG-16 (manufactured by shin Silicone K.K.)" 60.0(g) and "microsphere M330 (manufactured by Songban grease pharmacy K.K.)" 15.0(g) were kneaded. An oil-and-gel-type external preparation for skin (cosmetic 7) containing "polymethyl methacrylate spherical powder (microspheres M330, sukorson fat pharmaceutical co., ltd.)" 2.0(g), "DC 345 (dow corning dongli corporation)" 15.7(g), "phenoxyethanol (seiko corporation)" 0.3(g), "ethanol (wako pure chemical industries, ltd.)" 5.0(g), "KSK 32" 2.0(g) was prepared by kneading.

[ example 10]

Production example 10: the invention relates to a method for preparing an oil gel type skin external preparation

60.0(g) "of silicone KSG-16 (shin-Etsu chemical Co., Ltd)" and 15.0(g) "of spherical polyamide resin (Nylon SP500, Toho Co., Ltd.)" were kneaded together. An oil-and-gel-type external preparation for skin (cosmetic 8) containing spherical polyamide resin powder was produced by kneading "silicone KF-6017 (shin-shikoku co., ltd.)" 2.0(g), "DC 345 (daokning dongli co., ltd.)" 15.7(g), "phenoxyethanol (seikagaku corporation)" 0.3(g), "ethanol (wako pure chemical industries, ltd.)" 5.0(g), "KSK 32" 2.0 (g).

[ example 11]

< test example 4: evaluation of skin storage Property of external preparation for skin in oil gel form of the present invention 4 >

The skin storage properties of the external skin preparations (cosmetics 7 and 8) of the oil gel type of the present invention were evaluated by the method described in test example 1. The results are shown in Table 5.

[ TABLE 5]

TABLE 5

Any of the organic spherical powders showed high in-skin storage as compared with the non-mixed spherical powder. In particular, the microspheres M330 show a high skin storage capacity.

Production example 11: the invention relates to a method for preparing an oil gel type external preparation for skin, and more specifically, to a method for preparing an oil gel type external preparation for skin

"organosilicon KSG-16 (shin-Etsu chemical Co., Ltd.) (80.0 (g)) and" Nomcort TIO (Rinay Oliway Co., Ltd.) (15.0 (g)) were weighed and kneaded uniformly. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. An oily gel type external skin preparation (external skin preparation without powder) was prepared by adding the KSK32 dispersion to the KSG-16 and nomcot TIO compositions and kneading them.

[ example 12]

Production example 12: method for producing oil gel type external preparation for skin of the present invention 11 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.) (65.0 (g)) and" Nomcort TIO (Rinay Oliway Co., Ltd.) (15.0 (g)) were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 15.0(g) of "polymethyl methacrylate spherical powder (microsphere M330, Songban oil and fat pharmaceuticals Co., Ltd.) was added and kneaded to prepare an oil-gel type skin external preparation (cosmetic 9).

[ example 13]

Production example 13: method for producing an oil gel type external preparation for skin of the present invention 12 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.) (65.0 (g)) and" Nomcort TIO (Rinay Oliway Co., Ltd.) (15.0 (g)) were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and Nomcort TIO composition, 15.0(g) of "sericite (sericite FSE, Mitsui minerals)" were added and kneaded to prepare an oil-gel type skin external preparation (cosmetic 10).

[ example 14]

< test example 5: evaluation of skin storage Property of external preparation for skin in the form of oil gel of the present invention 5 >

The skin storage properties of the oil gel type external preparations (external preparations for skin containing no powder, cosmetics 9 and 10) of the present invention produced by the methods described in production examples 11, 11 and 12 were evaluated by the method described in test example 1. The results are shown in Table 6.

The skin storability of the unmixed powder formula, the mixed microsphere formula, and the sericite (silicate mineral) mixed formula prepared according to the above contents were tested and compared according to the above method.

[ TABLE 6]

TABLE 6

The spherical powder of the microsphere-containing formulation cosmetic 9 showed a higher skin storage amount than the plate-shaped powder of the cosmetic 10 containing the "sericite" formulation.

[ example 15]

Production example 14: method for producing oil gel type external preparation for skin of the present invention 13 >

"Silicone KSG-16 (shin-Etsu chemical Co., Ltd.) (65.0 (g)) and" Nomcort TIO (Rinay Oliway Co., Ltd.) (15.0 (g)) were weighed and kneaded. To "KSK 32" (0.5 (g) "DC 345 (Dow Corning Tokenli Co., Ltd)" 4.5(g) was added to prepare a KSK32 dispersion which was pulverized by a pulverizer. To KSK32 dispersion and a Nomcort TIO composition, 15.0(g) of spherical anhydrous silicic acid (` carbon dioxide beads P1500 (catalyst chemical industry Co., Ltd.) ` was added and kneaded to prepare an oil gel type skin preparation for external use (cosmetic preparation 11).

[ example 16]

< test example 5: evaluation of skin storage Property of external preparation for skin in the form of oil gel of the present invention 5 >

With respect to cosmetic 9 and the external preparation for skin (cosmetic 11) of the oil gel type of the present invention produced in accordance with example 15, the skin storage property was evaluated in accordance with the method described in test example 1. The results are shown in Table 7.

[ TABLE 7]

TABLE 7

As a typical example of the spherical inorganic powder, when the skin storage property of the skin external preparation (cosmetic 11) of an oil gel type in which carbon dioxide micro beads are mixed is evaluated, the skin storage property is low as compared with the organic spherical powder.

[ industrial applicability ]

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

Claims (7)

1. An oil gel type external preparation for skin, characterized by comprising 1) a compound represented by the following general formula (1), an isomer thereof and/or a pharmacologically acceptable salt thereof, and 2) a partially crosslinked methylpolysiloxane,

[ chemical formula 1]

In the above formula, R₁Is a straight or branched chain of 1 to 4 carbon atoms substituted with a carboxyl groupAn alkyl group, or a C1-4 linear or branched alkyl group substituted with a carboxylate group having an alkyl chain of C1-4, R₂And R₃Each independently represents a C1-4 linear or branched alkyl group.

2. The external preparation for skin of the oil gel type according to claim 1,

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 2]

In the above formula, R₄Represents a C1-4 linear or branched alkyl group substituted with a carboxyl group, R₅And R₆Each independently represents a C1-4 linear or branched alkyl group.

3. The external preparation for skin of the oil gel type according to claim 2,

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), an isomer thereof, and/or a pharmacologically acceptable salt thereof.

[ chemical formula 3]

4. The external skin preparation of the oil gel type according to any one of claims 1 to 3,

also contains spherical powder.

5. The external preparation for skin of the oil gel type according to claim 4,

the spherical powder is organic spherical powder.

6. The external preparation for skin of the oil gel type according to claim 4 or 5,

the spherical powder is polymethyl methacrylate.

7. The external skin preparation of the oil gel type according to any one of claims 4 to 6,

the spherical powder is contained in an amount of 12 to 50% by mass based on the total amount of the external preparation for skin.