Turnover promoter and use thereof

Abstract

Provided is a turnover promoter capable of promoting the turnover of epidermis. In the present invention, a turnover promoter for epidermis is prepared, the turnover promoter containing at least one 3-hydroxybutyric acid component selected from 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and a 3-hydroxybutyric acid alkyl ester represented by formula (1) (wherein R represents an alkyl group). The turnover promoter may further contain a skin whitening agent. The skin whitening agent may contain a tyrosinase inhibitor and / or a melanin transport inhibitor.

Description

Turnover promoter and its use

[0001] The present disclosure relates to an epidermal turnover (metabolism) promoter containing at least one selected from 3-hydroxybutyric acid, a salt thereof, and an alkyl ester thereof, and uses thereof.

[0002] Human skin has a three-layer structure consisting of the epidermis, dermis, and subcutaneous tissue, stacked in this order from the surface side. Furthermore, the stratum corneum (horny layer) forms on the surface side of the epidermis as the outermost layer of the skin. This stratum corneum is composed of multiple keratinocytes (corneocytes) stacked like tiles or bricks and intercellular lipids such as sphingolipids (ceramides) present between these keratinocytes. These keratinocytes are repeatedly generated and regenerated through the following mechanism: basal cells (keratinocytes) formed in the basal layer at the deepest part of the epidermis are pushed up by newly generated basal cells, transform into spinous cells and granular cells, and then migrate to the skin surface, where they transform into corneocytes, ultimately sloughing off as scum on the skin surface. This cycle of transformation from basal cells to keratinocytes and sloughing off as scum is called "turnover," and it is generally estimated to take approximately 4 to 6 weeks. However, when the turnover cycle becomes longer due to aging or irregular lifestyle habits, rough skin (dullness, roughness, hangnails, wrinkles, etc.) worsens, it becomes difficult to maintain moisturized skin, and pigmentation spots such as senile lentigo (age spots), freckles, melasma, post-inflammatory pigmentation, and birthmarks are more likely to occur, and acne scars are more likely to remain. Therefore, when such symptoms appear, it is necessary to promote epidermal turnover in order to maintain or improve skin health. Whether or not epidermal turnover is functioning normally can be evaluated using proteins such as keratin 10 (K10), involucrin (IVL), and filaggrin (FLG) as epidermal differentiation markers.

[0003] Japanese Patent No. 2564690 (Patent Document 1) discloses an external preparation for inhibiting melanin production, characterized in that the active ingredient is a compound selected from the group consisting of 2-hydroxybutyric acid, 3-hydroxybutyric acid, 4-hydroxybutyric acid, and sodium salts thereof.

[0004] Japanese Patent Application Laid-Open No. 2024-46365 (Patent Document 2) discloses a transglutaminase promoter containing 3-hydroxybutyric acid and / or a salt thereof.

[0005] Japanese Patent No. 2564690 Japanese Patent Application Laid-Open No. 2024-46365

[0006] Patent Documents 1 and 2 describe the use of 3-hydroxybutyric acid in cosmetics, but do not describe its use as a turnover promoter.

[0007] Therefore, an object of the present disclosure is to provide a turnover promoter capable of promoting epidermal turnover and uses thereof.

[0008] As a result of intensive research to achieve the above object, the present inventors have found that at least one 3-hydroxybutyric acid component selected from 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and an alkyl ester of 3-hydroxybutyric acid can promote epidermal turnover, and have completed the present invention (or the present disclosure).

[0009] That is, the present disclosure includes the following aspects.

[0010] Aspect [1]: A promoter for promoting epidermal turnover, comprising 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and a compound represented by the following formula (1):

[0011]

[0012] A turnover promoter comprising at least one 3-hydroxybutyric acid component selected from 3-hydroxybutyric acid alkyl esters represented by the formula: (wherein R represents an alkyl group).

[0013] Aspect [2]: The turnover promoter according to aspect [1], further comprising a skin whitening agent.

[0014] Aspect [3]: The turnover promoter according to aspect [2], wherein the whitening agent comprises a tyrosinase inhibitor and / or a melanin transport inhibitor.

[0015] Aspect [4]: ​​The turnover promoter according to any one of Aspects [1] to [3], wherein the 3-hydroxybutyric acid component contains an R-isomer.

[0016] The present disclosure also includes at least one production promoter selected from a keratin 10 production promoter, an involucrin production promoter, and a filaggrin production promoter, which contains the 3-hydroxybutyric acid component described in aspect [1] above, as well as a production promoter which further contains a whitening agent.

[0017] That is, the present disclosure includes the following aspects.

[0018] Aspect [5]: A keratin 10 (or mRNA thereof) production promoter comprising the 3-hydroxybutyric acid component according to aspect [1].

[0019] Aspect [6]: The keratin 10 production promoter according to aspect [5], further comprising a whitening agent.

[0020] Aspect [7]: An involucrin (or mRNA thereof) production promoter comprising the 3-hydroxybutyric acid component according to Aspect [1].

[0021] Aspect [8]: The involucrin production promoter according to aspect [7], further comprising a whitening agent.

[0022] Aspect [9]: A filaggrin (or mRNA thereof) production promoter comprising the 3-hydroxybutyric acid component according to Aspect [1].

[0023] Aspect

[10] : The filaggrin production promoter according to aspect [9], further comprising a whitening agent.

[0024] Aspect

[11] : A composition comprising the turnover promoter according to any one of Aspects [1] to [4], the keratin 10 production promoter according to Aspect [5] or [6], the involucrin production promoter according to Aspect [7] or [8], or the filaggrin production promoter according to Aspect [9] or

[10] .

[0025] Aspect

[12] : The composition according to aspect

[11] , which is a transdermal composition.

[0026] Aspect

[13] : The composition according to aspect

[11] or

[12] , which is a liquid or semi-solid composition.

[0027] Aspect

[14] : The composition according to any one of aspects

[11] to

[13] , which is a cosmetic.

[0028] Aspect

[15] : A method for promoting epidermal turnover by penetrating the turnover promoter according to any one of aspects [1] to [4] into the skin.

[0029] Aspect

[16] : A method (or topical skin preparation) for promoting the production of at least one selected from the group consisting of keratin 10, involucrin, and filaggrin, by penetrating the 3-hydroxybutyric acid component according to Aspect [1] into the skin.

[0030] In addition, the present disclosure may achieve the following secondary objectives (solve the problems).

[0031] Another object of the present disclosure is to provide a promoter capable of promoting the production of at least one selected from the group consisting of keratin 10, involucrin, and filaggrin.

[0032] In the present specification and claims, the number of carbon atoms in a substituent or the like is represented by C １ , C ６ , C １０ For example, "C １ "Alkyl group" means an alkyl group having one carbon atom, １－６ The term "alkyl group" means an alkyl group having 1 to 6 carbon atoms.

[0033] Furthermore, in this specification and claims, when a numerical range is indicated using "X to Y," the numerical range may include both the extreme values ​​X and Y.

[0034] According to the present disclosure, a turnover promoter capable of promoting epidermal turnover can be provided.

[0035] Figure 1 is a graph comparing the amount of 3HB-Na and sodium vitamin C added with the change in keratin 10 mRNA expression level. Figure 2 is a graph comparing the amount of 3HB-Na and sodium vitamin C added with the change in involucrin mRNA expression level. Figure 3 is a graph comparing the amount of 3HB-Na and sodium vitamin C added with the change in filaggrin mRNA expression level. Figure 4 is a graph comparing the amount of 3HB-Na and sodium vitamin B ３ 5 is a graph comparing the amount of 3HB-Na and vitamin B ３ 6 is a graph comparing the amount of 3HB-Na and vitamin B ３ 1 is a graph comparing the amount of added filaggrin and the change in the expression level of filaggrin mRNA.

[0036] [Turnover Promoter] The epidermal turnover promoter (epidermal metabolism promoter) of the present disclosure contains at least one member (3-hydroxybutyric acid component, 3HB component) selected from 3-hydroxybutyric acid, salts of 3-hydroxybutyric acid, and 3-hydroxybutyric acid alkyl esters represented by the formula (1). The turnover promoter of the present disclosure can promote epidermal turnover, which can be evaluated by measuring the production levels of keratin 10 (K10), involucrin (IVL), and filaggrin (FLG) as epidermal differentiation markers or the expression levels of genes involved in the production of these proteins.

[0037] (3-Hydroxybutyric Acid Component) Commercially available 3-hydroxybutyric acid (3HB or BHB) may be used. Examples of commercially available products include chemically synthesized 3HB and 3HB produced by fermentation using microorganisms. Among these, fermentation-produced 3HB (fermentation-derived 3HB) is preferred because of its high purity of the R-isomer, and 3HB produced by fermentation using microorganisms from biomass raw materials (biologically derived resources) is particularly preferred.

[0038] The pH of 3HB (free 3HB) in a 40% by mass aqueous solution (temperature: 20° C.) may be, for example, about 1.5 to 2.5, and preferably 1.6 to 2.3.

[0039] The salt of 3HB may be a salt with a physiologically or pharmacologically acceptable basic compound, and may be a salt obtained by completely neutralizing the acid form of 3HB, or may be a salt obtained by partially neutralizing the acid form of 3HB (partially neutralized salt).

[0040] The pH of a 3HB salt (including a partially neutralized salt) in a 5% by mass aqueous solution (at 20°C) may be 2 or higher, for example, about 2 to 8.5, preferably about 3 to 8.3, even more preferably about 4 to 8.2, even more preferably about 5 to 8.1, and most preferably about 6 to 8.

[0041] Examples of salts include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; amine salts such as trimethylamine salt, triethylamine salt, ethanolamine salt, and diethanolamine salt; and salts with basic amino acids such as lysine salt and arginine salt. These 3HB salts (3HB salts) can be used alone or in combination of two or more. Among these, alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as magnesium salt and calcium salt are preferred because of their relatively low deliquescence and excellent handling properties.

[0042] The 3-hydroxybutyric acid alkyl ester is represented by the above formula (1). The 3-hydroxybutyric acid alkyl ester is converted into 3HB and / or a salt thereof by hydrolysis in vivo, and therefore can exhibit functions similar to those of 3HB and / or a salt thereof.

[0043] In the formula (1), examples of the alkyl group (linear or branched alkyl group) represented by R include C groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, a pentyl group, an isopentyl group, a hexyl group, an isohexyl group, an octyl group, a decyl group, a dodecyl group (lauryl group), an isododecyl group (isolauryl group), a tetradecyl group (myristyl group), an isotetradecyl group (isomyristyl group), a hexadecyl group (cetyl group or palmityl group), an isohexadecyl group (isocetyl group), an octadecyl group (stearyl group), an isooctadecyl group (isostearyl group), and an eicosyl group. １－２８ Among these, C １－１０ Alkyl groups are preferred, and C １－６ Alkyl groups are more preferred, and C １－４ An alkyl group is more preferred. The alkyl group represented by R may be appropriately selected depending on the usage form of the turnover accelerator of the present disclosure. These 3-hydroxybutyric acid alkyl esters can be used alone or in combination of two or more.

[0044] Specific examples of 3-hydroxybutyric acid alkyl esters include linear or branched C alkyl esters of 3HB such as 3HB methyl ester and 3HB ethyl ester. １－４ Alkyl esters and the like.

[0045] The 3-hydroxybutyric acid alkyl ester may be produced by esterifying 3-hydroxybutyric acid with an alcohol [an alcohol (R—OH) corresponding to the group R in the formula (1)] in accordance with a commonly used method, for example, the method described in Japanese Patent No. 6,979,918.

[0046] The 3-hydroxybutyric acid component (3HB component) may be an optical isomer (R- or S-form) or a racemate, but from the viewpoints of biocompatibility, safety, etc., it is preferable to contain at least the R-form of the 3HB component [R-3-hydroxybutyric acid component, (R)3HB component].

[0047] The proportion of the R-isomer in the 3HB component, particularly the optical purity (enantiomer or optical isomer excess), may be, for example, 50% e.e. or more, preferably in the following stepwise manner: 80 to 100% e.e., 90 to 100% e.e., 95 to 100% e.e., 98 to 100% e.e., 99 to 100% e.e., and particularly preferably substantially 100% e.e. When the optical purity is above the lower limit, biocompatibility is easily improved.

[0048] In addition, the R-isomer [(R) 3HB component] and the S-isomer [(S) 3HB component] and / or racemic mixture may be used in combination, but the proportion of the S-isomer is preferably low, and it is particularly preferable that the S-isomer is inevitably contained. The mass proportion of the R-isomer in the 3HB component is preferably 10% by mass or more, more preferably 50% by mass or more, more preferably 90% by mass or more, and most preferably 100% by mass. A high proportion of the R-isomer has high biocompatibility, so the function of the 3HB component can be efficiently expressed in vivo.

[0049] The 3HB component may be any of 3HB alone in the form of an acid; a 3HB salt alone in the form of a salt; a 3HB alkyl ester alone; or a combination (mixture) of at least two or more selected from 3HB, a 3HB salt, and a 3HB alkyl ester.

[0050] The 3HB component can be selected appropriately depending on the form of use, etc. For example, when used under hydrophilic conditions, it may contain at least one selected from 3HB and a 3HB salt, and when used under lipophilic conditions, it may contain at least a 3HB alkyl ester.

[0051] Of the 3HB components, it is preferable to contain at least a salt of 3HB, as this exhibits weak acidity close to the pH of the skin and can reduce irritation to the skin.

[0052] When the 3HB component contains at least a 3HB salt, the mass ratio of the 3HB salt to other 3HB components (3HB and / or 3-hydroxybutyric acid alkyl ester, particularly 3-hydroxybutyric acid alkyl ester, etc.) may be about 100 / 0 to 5 / 95 (former / latter), preferably in the following stepwise manner: 100 / 0 to 20 / 80, 100 / 0 to 50 / 50, 100 / 0 to 75 / 25, 100 / 0 to 90 / 10, and particularly preferably 100 / 0 to 95 / 5.

[0053] In particular, the 3HB component is preferably a 3HB salt alone, and typical 3HB components (particularly 3HB salts) include, for example, 3HB alkali metal salts such as sodium salt and potassium salt of 3HB, and 3HB alkaline earth metal salts such as magnesium salt and calcium salt of 3HB, with 3HB alkali metal salts such as sodium salt of 3HB being preferred.

[0054] The proportion of the 3HB component (particularly, a 3HB salt) in the turnover accelerator may be 10% by mass or more (e.g., 10 to 100% by mass), preferably 50% by mass or more, even more preferably 80% by mass or more, even more preferably 90% by mass or more, and most preferably 95% by mass or more (e.g., 95 to 99.9% by mass).

[0055] (Whitening Agent) The turnover promoter of the present disclosure preferably further contains a whitening agent in addition to the 3HB component in order to synergistically promote epidermal turnover.

[0056] Examples of whitening agents include tyrosinase inhibitors [hydroquinone or derivatives thereof (hydroquinone, α-arbutin, β-arbutin, etc.), ascorbic acid (vitamin C) or derivatives thereof, salicylic acid or derivatives thereof (4-methoxysalicylic acid potassium salt, etc.), phytic acid or derivatives thereof, tranexamic acid or derivatives thereof (tranexamic acid, etc.), ellagic acid or derivatives thereof, kojic acid or derivatives thereof, rucinol, rhododenol, etc.], endothelin-1 receptor inhibitors (chamomile extracts such as chamomilla ET, etc.), tyrosinase protein degradation promoters [linoleic acid (free linoleic acid), etc.], melanin excretion promoters (adenosine monophosphate disodium salt, etc.), melanin transport inhibitors (vitamin B ３ Examples of suitable whitening agents include nicotinic acid or its derivatives (e.g., nicotinic acid or its derivatives), cysteine, placenta extract, plant extracts, and essential oils. These whitening agents can be used alone or in combination. Even if the primary function of a whitening agent is different from whitening, it may be conveniently classified as a component (or agent) having a whitening effect, as described above. For example, ascorbyl tetraisopalmitate (VCIP), described below, is primarily known as a component having anti-inflammatory activity, but also has tyrosinase inhibitory activity, and is therefore classified as a tyrosinase inhibitor in this specification and claims.

[0057] Of these skin whitening agents, those that contain a tyrosinase inhibitor and / or a melanin transport inhibitor are preferred because they facilitate the promotion of epidermal turnover, and those that contain at least one selected from hydroquinone or a derivative thereof (hydroquinone, α-arbutin, β-arbutin, etc.), ascorbic acid (vitamin C) or a derivative thereof, ellagic acid or a derivative thereof, kojic acid or a derivative thereof, and rucinol, and / or nicotinic acid or a derivative thereof are even more preferred, with ascorbic acid or a derivative thereof and / or nicotinic acid or a derivative thereof being even more preferred.

[0058] In addition, tyrosinase inhibitors inhibit tyrosinase, an enzyme that acts when melanin is synthesized in melanocytes, thereby suppressing melanin production.Melanin transport inhibitors inhibit the transport of produced melanin to the epidermis.Although it is not clear how melanin acts and affects epidermal turnover, by combining a tyrosinase inhibitor and / or a melanin transport inhibitor, which are involved in the production and transport of melanin and have a common action, with the 3HB component that promotes epidermal turnover, unexpectedly, epidermal turnover can be further promoted.

[0059] Examples of ascorbic acid (vitamin C) or derivatives thereof include water-soluble vitamin C or derivatives thereof such as ascorbic acid, metal ascorbic acid salts (alkali metal ascorbic acid salts such as sodium ascorbate and potassium ascorbate, alkaline earth metal ascorbate salts such as calcium ascorbate), 2-O-ethyl ascorbic acid, 3-O-ethyl ascorbic acid, ascorbic acid glucoside, sodium ascorbyl phosphate (sodium ascorbyl phosphate or sodium ascorbyl phosphate), and magnesium ascorbyl phosphate; oil-soluble vitamin C derivatives such as ascorbyl tetraisopalmitate [tetra-2-hexyldecanoate (VCIP)] and alcorbyl dipalmitate; and water-oil-soluble vitamin C derivatives such as sodium ascorbyl palmitate phosphate. These ascorbic acid or derivatives thereof can be used alone or in combination. Of these, ascorbic acid or metal salts thereof are preferred, and alkali metal ascorbate salts such as sodium ascorbate are more preferred.

[0060] Examples of nicotinic acid or its derivatives include nicotinic acid (niacin), nicotinamide (niacinamide), nicotinic acid riboside, nicotinamide riboside, nicotinamide adenine dinucleotide (NAD), and nicotinamide adenine dinucleotide phosphate (NADP). These nicotinic acids or their derivatives can be used alone or in combination. Among these, nicotinic acid, nicotinamide (niacinamide), nicotinic acid riboside, and nicotinamide riboside are preferred, and vitamin B 1000 containing these is also preferred. ３ is more preferable.

[0061] The proportion of the whitening agent can be selected, for example, from a range of about 0.01 to 10,000 parts by mass relative to 100 parts by mass of the 3HB component, and is preferably selected in the following stepwise manner: 0.01 to 1,000 parts by mass, 0.01 to 500 parts by mass, 0.01 to 100 parts by mass, 0.01 to 50 parts by mass, 0.05 to 40 parts by mass, 0.1 to 30 parts by mass, 0.2 to 20 parts by mass, and 0.3 to 10 parts by mass. In view of the ease with which a synergistic effect is achieved in combination with the 3HB component, the proportion is more preferably 0.5 to 7 parts by mass, and most preferably 0.7 to 5 parts by mass.

[0062] When the whitening agent contains a tyrosinase inhibitor (particularly, ascorbic acid or a derivative thereof), the proportion of the tyrosinase inhibitor relative to 100 parts by mass of the 3HB component can be selected, for example, from a range of about 0.01 to 10,000 parts by mass, and preferably in the following stepwise manner: 0.01 to 1,000 parts by mass, 0.01 to 500 parts by mass, 0.01 to 100 parts by mass, 0.01 to 50 parts by mass, 0.05 to 30 parts by mass, 0.1 to 10 parts by mass, 0.2 to 5 parts by mass, and 0.3 to 3 parts by mass. In view of the ease with which a synergistic effect is achieved in combination with the 3HB component, the proportion of the tyrosinase inhibitor is more preferably 0.5 to 2.5 parts by mass, and most preferably 0.7 to 1.5 parts by mass.

[0063] When the whitening agent contains a melanin transport inhibitor (particularly, nicotinic acid or a derivative thereof), the proportion of the melanin transport inhibitor relative to 100 parts by mass of the 3HB component can be selected, for example, from a range of about 0.01 to 10,000 parts by mass, preferably in the following stepwise manner: 0.01 to 1,000 parts by mass, 0.01 to 500 parts by mass, 0.01 to 100 parts by mass, 0.01 to 50 parts by mass, 0.05 to 30 parts by mass, 0.1 to 10 parts by mass, 0.3 to 5 parts by mass, 0.5 to 4 parts by mass. In view of the ease with which a synergistic effect is exhibited in combination with the 3HB component, the proportion of the melanin transport inhibitor is more preferably 1 to 3 parts by mass, and most preferably 1.5 to 2.5 parts by mass.

[0064] (3HB Oligomer) The turnover accelerator of the present disclosure may further contain a 3HB oligomer. The average degree of polymerization of the 3HB oligomer may be 2 or more, for example, 2 to 10, preferably 2 to 5, even more preferably 2 to 4, more preferably 2 to 3, and most preferably 2. The 3HB oligomer may be an oligomer that is inevitably mixed in during the 3HB production process, etc.

[0065] The proportion of the 3HB oligomer may be 10 parts by mass or less, preferably 5 parts by mass or less, more preferably 3 parts by mass or less, and most preferably 1 part by mass or less, per 100 parts by mass of the 3HB component (active ingredient). The turnover accelerator of the present disclosure may be substantially free of 3HB oligomer, and is particularly preferably free of 3HB oligomer.

[0066] The total proportion of the 3HB component and the whitening agent in the turnover accelerator may be 10% by mass or more, preferably 30% by mass or more, 40% by mass or more, 50% by mass or more, 80% by mass or more, 90% by mass or more, 95% by mass or more, 99% by mass or more, and more preferably 100% by mass. The turnover accelerator of the present disclosure may be an accelerator consisting only of the 3HB component, or may be an accelerator consisting only of the 3HB component and the whitening agent.

[0067] (Characteristics of the Turnover Accelerator) The turnover accelerator of the present disclosure can be used to promote epidermal turnover in vivo in mammals such as humans, and is preferably used to promote turnover in the epidermis of humans and non-human animals, for example, medium-sized or large mammals (particularly humans).

[0068] The turnover promoter of the present disclosure may be applied orally (administered or given) or parenterally. Of these, parenteral application is preferred. Examples of parenteral application methods include inhalation application, injection application, transdermal application, and nasal application. Of these, transdermal application is preferred because it can effectively promote epidermal turnover.

[0069] The method of percutaneous application is not particularly limited, as long as the turnover accelerator applied to the skin surface can penetrate into the epidermis.Specific methods include, for example, the method of directly applying the turnover accelerator to the skin by dripping or spraying, and the method of contacting the skin with a carrier (mask, cotton, sponge, film, etc. made of nonwoven fabric, etc.) impregnated with the turnover accelerator.The application site on human skin is not particularly limited, and can be applied to the skin of the whole body, including, for example, the head (including face), neck, upper limbs, chest, back, lower back, buttocks, lower limbs, etc.

[0070] The application amount (or dosage) of the turnover accelerator of the present disclosure can be selected appropriately depending on the subject, age and weight of the subject, application time, form of the turnover accelerator, application route, application method, etc. For example, when applied transdermally, the turnover accelerator of the present disclosure may be applied to the required site (such as skin) about 1 to 10 times per day, preferably 1 to 5 times, more preferably 1 to 4 times, even more preferably 1 to 3 times, and most preferably 1 to 2 times.

[0071] Applying the turnover promoter of the present disclosure to the skin can promote epidermal turnover. The turnover cycle is generally estimated to be about 4 to 6 weeks. Therefore, the turnover promoter of the present disclosure is preferably applied intermittently (or periodically) repeatedly over a predetermined number of days to affect turnover. For example, it may be applied intermittently repeatedly over 24 hours or more, preferably for 1 week or more (e.g., 1 to 20 weeks), even more preferably for 4 weeks or more, more preferably for 6 weeks or more, and most preferably for 8 weeks or more. For example, applying it 1 to 2 times per day for 4 weeks or more can effectively promote epidermal turnover.

[0072] The application concentration (final concentration per application) of the 3HB component of the turnover accelerator of the present disclosure may be an effective amount, for example, can be selected from a range of approximately 0.0001 mM to 1 M in terms of 3HB, preferably in the following stepwise order: 0.001 to 500 mM, 0.01 to 400 mM, 0.1 to 300 mM, 1 to 200 mM, 5 to 150 mM, 10 to 100 mM. In view of the ease of obtaining a high synergistic effect when combined with a whitening agent, a concentration of 20 to 80 mM is more preferable, and a concentration of 30 to 70 mM is most preferable. When the concentration of the 3HB component is above the lower limit, epidermal turnover tends to be promoted, while when it is below the upper limit, economic efficiency tends to be improved.

[0073] In a cell-level experiment using normal human epidermal keratinocytes, the number of cells to be seeded (cells before culture) was, for example, 1.0 × 10 ３ ~1.0 x 10 ５ cells, preferably 5.0 x 10 ３ ~7.5 x 10 ４ cells, more preferably 7.5 x 10 ３ ~5.0 x 10 ４ cells.

[0074] When the turnover promoter of the present disclosure is applied to the skin, the amount of the 3HB component to be applied is equivalent to 1 cm of skin in terms of the solid content of 3HB. ２For example, the amount is 0.001 to 10 mg, preferably 0.005 to 5 mg, further preferably 0.01 to 1 mg, even more preferably 0.05 to 0.5 mg, and most preferably 0.075 to 0.3 mg.

[0075] The turnover accelerator of the present disclosure contains a 3HB component and can promote or improve epidermal turnover, thereby normalizing epidermal metabolism even when the turnover rate slows due to aging, lifestyle disorders, etc., and the turnover cycle is delayed. For example, even cells (epidermal keratinocytes) that have aged due to aging, UV exposure, dietary habits, etc. can be promoted or improved to transform into keratinocytes, making it effective in preventing or treating (improving or alleviating) rough skin (dullness, roughness, hangnails, wrinkles, etc.), dry skin, pigmentation (age spots, freckles, melasma, post-inflammatory hyperpigmentation, birthmarks, etc.), acne scars, etc.

[0076] Furthermore, the turnover accelerator of the present disclosure contains a 3HB component or a 3HB component that is converted to 3HB, and since the 3HB component is a component produced in the body, it is highly biocompatible. Therefore, even if the turnover accelerator of the present disclosure is applied to the skin in the form of a composition as needed, it is low in irritation to the skin and is highly safe even for sensitive skin or aged skin that has experienced rough skin due to a decrease in epidermal turnover function.

[0077] Furthermore, since the turnover promoter of the present disclosure can promote the production of keratin 10, involucrin, and filaggrin in the process of promoting epidermal turnover, it can also be used as a production promoter that further contains at least one production promoter selected from a keratin 10 production promoter, an involucrin production promoter, and a filaggrin production promoter, and further contains a whitening agent. Therefore, the turnover promoter may be a keratin 10 production promoter, an involucrin production promoter, and / or a filaggrin production promoter in the epidermis.

[0078] (Keratin 10 Production Accelerator) When the turnover accelerator of the present disclosure is used as a keratin 10 production accelerator, the keratin 10 production accelerator only needs to contain a 3HB component, and preferably further contains a whitening agent. When the keratin 10 production accelerator contains a whitening agent, the whitening agent preferably contains a tyrosinase inhibitor and / or a melanin transport inhibitor, more preferably contains nicotinic acid or a derivative thereof, and more preferably contains vitamin B ３ By including a keratin 10 production promoter in combination with a 3HB component and a tyrosinase inhibitor and / or a melanin transport inhibitor, a synergistic effect of the two is exerted, and the production of keratin 10 can be further promoted.

[0079] (Involucrin Production Promoter) When the turnover promoter of the present disclosure is used as an involucrin production promoter, the involucrin production promoter contains a 3HB component and a whitening agent, which facilitates the promotion of involucrin production. The whitening agent preferably contains a tyrosinase inhibitor and / or a melanin transport inhibitor, more preferably ascorbic acid or a derivative thereof, and even more preferably a metal ascorbate such as sodium ascorbate. By including a combination of a 3HB component and a tyrosinase inhibitor and / or a melanin transport inhibitor in the involucrin production promoter, a synergistic effect between the two is exerted, further promoting the production of involucrin.

[0080] (Filaggrin production promoter) When the turnover promoter of the present disclosure is used as a filaggrin production promoter, the filaggrin production promoter comprises a 3HB component and a whitening agent, since it is easy to promote the production of filaggrin.The whitening agent preferably comprises a tyrosinase inhibitor and / or a melanin transport inhibitor, more preferably ascorbic acid or its derivative, and more preferably a metal ascorbate such as sodium ascorbate.By comprising a combination of a 3HB component and a tyrosinase inhibitor and / or a melanin transport inhibitor in the filaggrin production promoter, the synergistic effect of both is exhibited, and the production of filaggrin can be further promoted.

[0081] [Composition for Promoting Epidermal Turnover] The composition of the present disclosure is a composition for promoting epidermal turnover (or promoting the production of keratin 10, involucrin, and filaggrin), and contains at least the turnover promoter (or keratin 10 production promoter, involucrin production promoter, and / or filaggrin production promoter).

[0082] The composition of the present disclosure may be in any form, such as a liquid, semi-solid, or solid, in which case the turnover accelerator is incorporated into a liquid composition, a semi-solid composition, or a solid composition.

[0083] Examples of liquid compositions include liquid preparations, drinks (beverages), suspensions, emulsions, syrups, and injections.

[0084] Examples of semi-solid compositions (semi-solid preparations) include gels, poultices, creams, slurries, and pastes.

[0085] Examples of solid compositions (solid preparations) include powders, fine granules, granules, pills, tablets, flakes, cakes, gummies, nougat, films, and capsules.

[0086] Of these, topical compositions (or topical preparations), such as liquid compositions and semi-solid compositions, are preferred, with liquid compositions being particularly preferred, because the compositions of the present disclosure are particularly effective on the skin and can be easily applied or administered transdermally.

[0087] The proportion of the turnover accelerator (active ingredient) in the composition can be selected from a range of approximately 0.01 to 99% by mass, preferably 0.1 to 95% by mass, and more preferably 0.5 to 90% by mass. The proportion of the turnover accelerator may be selected depending on the form of the composition. In the composition of the present disclosure, the 3HB component contained in the turnover accelerator is highly biocompatible, so even a small amount of the turnover accelerator can significantly accelerate epidermal turnover.

[0088] The method of application of the composition of the present disclosure, including preferred embodiments, is the same as the method of application described for the cell turnover promoter. Therefore, the composition of the present disclosure is preferably a transdermal composition (a transdermal application agent or a transdermal composition).

[0089] The transdermal composition of the present disclosure may be a liquid transdermal composition or a semi-solid transdermal composition.

[0090] (Transdermal Liquid Composition) The proportion of the turnover promoter (3HB component) in the transdermal liquid composition (or topical liquid composition) is, for example, 0.01% by mass or more, preferably 0.1% by mass or more, more preferably 0.2% by mass or more, more preferably 0.3% by mass or more, particularly preferably 0.5% by mass or more, and most preferably 0.8% by mass or more. When the proportion of the turnover promoter is above the lower limit, epidermal turnover tends to be easily promoted. Furthermore, the proportion of the turnover promoter in the transdermal liquid composition is, for example, 30% by mass or less, preferably 10% by mass or less, more preferably 5% by mass or less, even more preferably 3% by mass or less, particularly preferably 2% by mass or less, and most preferably 1.5% by mass or less. The proportion of the turnover promoter in the transdermal liquid composition may be 0.1 to 5% by mass, particularly 0.3 to 3% by mass. Furthermore, when the proportion of the 3HB component is below the upper limit, handling ease and economy tend to be improved.

[0091] The transdermal liquid composition of the present disclosure may further contain a liquid base, which includes a solvent, a liquid oil, and the like.

[0092] The solvent may be a lipophilic solvent, but a hydrophilic solvent is preferred from the viewpoint of safety, etc. Examples of hydrophilic solvents include water, lower aliphatic alcohols (e.g., C １－４ Alkyl alcohols, particularly C such as ethanol and isopropanol ２－３Alkyl alcohols, etc. These solvents can be used alone or in combination of two or more. Examples of liquid oils include animal and vegetable oils (e.g., jojoba oil, olive oil, coconut oil, camellia oil, macadamia nut oil, avocado oil, corn oil, sesame oil, wheat germ oil, linseed oil, castor oil, etc.), mineral oils (e.g., liquid paraffin, polybutene, silicone oil, etc.), and synthetic oils (e.g., synthetic ester oil, synthetic polyether oil, etc.). These liquid oils can be used alone or in combination of two or more.

[0093] As the liquid base, a hydrophilic solvent such as water or ethanol may be used in combination with a liquid oil as an additive (oil component). Among these liquid bases, water, lower alcohols or mixtures thereof are preferred, with water and / or ethanol (especially water) being particularly preferred. １－４ Alkyl alcohols (especially C such as ethanol and isopropanol) ２－３ Lower aliphatic alcohols, such as alkyl alcohols, may act as solvents.

[0094] The proportion of the liquid base in the transdermal liquid composition is 50 to 99.9% by mass, preferably 55 to 99.5% by mass (e.g., 60 to 99% by mass), further preferably 60 to 98% by mass (e.g., 70 to 95% by mass), even more preferably 65 to 97% by mass (e.g., 80 to 93% by mass), and most preferably 70 to 95% by mass (e.g., 85 to 90% by mass).

[0095] The transdermal liquid composition of the present disclosure may further contain a humectant. The humectant may be used as a wetting agent. Examples of humectants include alkylene glycols (e.g., polyalkylene glycols such as ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, pentanediol (pentylene glycol), polyethylene glycol, polyoxyethylene-polyoxypropylene block copolymers, diethylene glycol monoethyl ether, and polyoxyethylene polyoxypropylene dimethyl ether, or monoalkyl esters thereof), higher alcohols (e.g., hexyldecanol, isostearyl alcohol, octyldodecanol, and decyltetradecanol), water-soluble vinyl polymers (e.g., polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymers, polyacrylic acid, and polyacrylamide), and polyhydric alcohols (e.g., concentrated glycerin). glycerin, pentaerythritol, diglycerin, diglycerin propylene oxide adduct, etc.), organic acids (for example, lactic acid, sodium lactate, sodium pyrrolidonecarboxylate, etc.), amino acids (for example, serine, glycine, threonine, alanine, etc.), sugars (for example, sugar alcohols such as xylitol, sorbitol, maltitol, etc.; polysaccharides such as hyaluronic acid, sodium hyaluronate, sodium chondroitin sulfate, chondroitin heparin, etc.), water-soluble cellulose ethers (methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, etc.), proteins (for example, vitronectin, fibronectin, keratin, elastin, royal jelly, sericin, etc.), and the like.

[0096] These moisturizing agents can be used alone or in combination of two or more. Among these moisturizing agents, alkylene glycols such as dipropylene glycol, 1,3-butylene glycol, pentanediol, and polyethylene glycol, higher alcohols such as octyldodecanol, polyhydric alcohols such as glycerin, and sugars such as sodium hyaluronate are preferred.

[0097] The proportion of the humectant is, for example, 1 to 100 parts by mass, preferably 3 to 80 parts by mass, more preferably 5 to 50 parts by mass, more preferably 8 to 30 parts by mass, and most preferably 10 to 20 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the humectant in the transdermal liquid composition is 1 to 45% by mass, preferably 2 to 40% by mass, more preferably 3 to 30% by mass, more preferably 4 to 25% by mass, most preferably 5 to 20% by mass, and particularly preferably 7 to 15% by mass.

[0098] The transdermal liquid composition of the present disclosure may further contain an emollient (or oil). Examples of the emollient include higher fatty acids, higher alcohols, or oils (e.g., oleic acid, stearic acid, lauric acid, isostearic acid, oxystearic acid, cetyl alcohol, oleyl alcohol, stearyl alcohol, isopropyl stearate, octyl oxystearate, glycerin oxystearate, decyl oleate, octyldodecyl 12-stearoyl stearate, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene hydrogenated castor oil, triethylhexanoin or glyceryl tri-2-ethylhexanoate, dimethicone, esters of macadamia seed oil-derived fatty acids and phytosterols such as macadamia nut fatty acid phytosteryl, etc.), sugars (e.g., polyoxyethylene methylglycoside, Examples of the surfactant include methylglycoside sesquistearate, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene sorbitan oleate, polyoxyethylene sucrose oleate, polyoxyethylene methylglycoside dioleate, polyoxyethylene methylglycoside sesquistearate, etc.), ceramides, hydrocarbons (for example, waxes such as lanolin, lanolin alcohol, lanolin oil, polyoxyethylene lanolin, polyoxyethylene propylene lanolin, beeswax, polyoxyethylene beeswax, petrolatum, liquid paraffin, squalane, squalene, etc.), honey, emulsions of oily components (for example, emulsions obtained by emulsifying oily components such as triglyceride oils and ester oils with nonionic emulsifiers such as monoglycerides, etc.), and the like.

[0099] These emollients can be used alone or in combination of two or more. Among these emollients, preferred are higher fatty acids such as stearic acid, higher alcohols such as cetyl alcohol, oleyl alcohol, stearyl alcohol, and cetearyl alcohol, oils and fats such as glycerin oxystearate, polyoxyethylene hydrogenated castor oil, triethylhexanoin, dimethicone, and macadamia nut fatty acid phytosteryl, polyoxyethylene group-containing sugars such as polyoxyethylene methylglycoside, and hydrocarbons (for example, waxes such as beeswax and lanolin, petrolatum, liquid paraffin, and squalane).

[0100] The proportion of the emollient may be, for example, 50 parts by mass or less, and is preferably 0.01 to 30 parts by mass, more preferably 0.05 to 25 parts by mass (e.g., 0.1 to 20 parts by mass), more preferably 0.07 to 20 parts by mass (e.g., 0.5 to 20 parts by mass), and most preferably 0.1 to 15 parts by mass (e.g., 1 to 10 parts by mass), relative to 100 parts by mass of the liquid base. The proportion of the emollient in the transdermal liquid composition is 0.01 to 30% by mass, preferably 0.02 to 25% by mass, more preferably 0.03 to 20% by mass, more preferably 0.05 to 20% by mass, and most preferably 0.07 to 15% by mass.

[0101] The transdermal liquid composition of the present disclosure may further contain a surfactant. The surfactant may be used as a solubilizer or emulsifier. The surfactant may be any of anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants.

[0102] In this specification and claims, "POE" means polyoxyethylene (polyethylene oxide), "POP" means polyoxypropylene (polypropylene oxide), and "POE·POP" means an addition polymer of ethylene oxide and propylene oxide.

[0103] Examples of anionic surfactants include glycerin fatty acid esters such as glyceryl monostearate (glyceryl stearate, glycerin monostearate); higher fatty acid soaps such as sodium laurate; higher alkyl sulfates such as sodium lauryl sulfate; alkyl ether sulfates such as sodium POE-lauryl sulfate and triethanolamine POE-lauryl sulfate; N-acyl sarcosinate salts such as sodium N-lauroyl sarcosinate; sodium N-stearoyl-N-methyl taurate and sodium N-myristoyl-N-methyl taurate. phosphate ester salts such as sodium POE-oleyl ether phosphate; sulfosuccinates such as sodium di-2-ethylhexyl sulfosuccinate; alkylbenzenesulfonates such as sodium dodecylbenzenesulfonate and triethanolamine dodecylbenzenesulfonate; N-acylglutamates such as sodium N-lauroyl-L-glutamate and disodium N-stearoyl-L-glutamate; and sulfated oils (for example, turmeric oil).

[0104] Examples of nonionic surfactants include sorbitan fatty acid esters such as sorbitan monooleate (sorbitan monooleate), sorbitan monostearate, sorbitan tetraoleate, and sorbitan monolaurate; glycerin fatty acid esters such as glycerin monostearate, glycerin monoisostearate, and glycerin triisostearate; POE-sorbitan monooleate, POE-sorbitan monostearate (polyoxyethylene sorbitan monostearate), POE-sorbitan monostearate (polyoxyethylene sorbitan monostearate), and POE-sorbitan monolaurate. POE-sorbitan fatty acid esters such as POE-sorbitan tetraoleate and POE-sorbitan monolaurate (POE-sorbitan monolaurate); POE-sorbitan fatty acid esters such as POE-sorbitan monolaurate, POE-sorbitan monooleate, POE-sorbitan pentaoleate and POE-sorbitan monostearate; sucrose fatty acid esters such as sucrose laurate; POE-glycerin monostearate, POE-glycerin monoisostearate, POE POE-glycerin fatty acid esters such as POE-glycerin triisostearate; POE-fatty acid esters (e.g., POE-distearate, POE-monodioleate, ethylene glycol distearate, etc.); POE-alkyl ethers (e.g., POE-lauryl ether, POE-oleyl ether, POE-lauryl ether (POE-lauryl alcohol ether), POE-cetyl ether (POE-cetyl alcohol ether), POE-stearyl ether, POE-behenyl ether, POE-2-octyldodecyl ether, POE-cholestanol ether, etc.); Pluronic types (e.g., Pluronic (registered trademark), etc.); POE·POP-alkyl ethers (e.g., POE·POP-cetyl ether, POE·POP-2-decyltetradecyl ether, POE·POP-monobutyl ether, POE·POP-hydrogenated lanolin, POE·POP-glycerin ether, etc.); tetraPOE·tetraPOP-ethylenediamine condensates (e.g., Tetronic, etc.);POE-hydrogenated castor oil derivatives (e.g., POE-hydrogenated castor oils such as POE-castor oil, PEG-60 hydrogenated castor oil, POE-hydrogenated castor oil monoisostearate, POE-hydrogenated castor oil triisostearate, POE-hydrogenated castor oil monopyroglutamic acid monoisostearate diester, POE-hydrogenated castor oil maleic acid, etc.); POE-beeswax / lanolin derivatives (e.g., POE-sorbitol beeswax, etc.); alkanolamides (e.g., coconut oil fatty acid diethanolamide, lauric acid monoethanolamide, fatty acid isopropanolamide, etc.); POE-propylene glycol fatty acid esters; POE-alkylamines; POE-fatty acid amides; alkylethoxydimethylamine oxide; trioleyl phosphate, etc.;

[0105] Examples of cationic surfactants include stearyltrimethylammonium chloride; cetylpyridinium chloride; benzalkonium chloride; and benzethonium chloride.

[0106] Examples of amphoteric surfactants include phospholipid-based amphoteric surfactants such as hydrogenated lecithin; imidazoline-based amphoteric surfactants; and betaine-based surfactants.

[0107] Silicone surfactants can also be used as surfactants, such as polyether-modified silicones (adducts of polydimethylsiloxane with at least ethylene oxide).

[0108] These surfactants can be used alone or in combination of two or more. Among these surfactants, anionic surfactants such as glyceryl stearate, sodium lauryl sulfate, triethanolamine lauryl ether sulfate, and polyoxyethylene disodium lauryl sulfosuccinate, nonionic surfactants such as sorbitan fatty acid esters, glycerin fatty acid esters, POE-sorbitan fatty acid esters, POE-alkyl ethers, and POE-hydrogenated castor oil, and amphoteric surfactants such as hydrogenated lecithin are preferred.

[0109] The proportion of the surfactant may be, for example, 0.01 to 5 parts by mass, preferably 0.02 to 4 parts by mass, more preferably 0.03 to 3 parts by mass, and more preferably 0.05 to 2.5 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the surfactant may be, for example, 0.05 to 1 part by mass, preferably 0.1 to 0.5 parts by mass, and more preferably 0.2 to 0.3 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the surfactant in the transdermal liquid composition is 0.01 to 20% by mass, preferably 0.02 to 15% by mass, more preferably 0.03 to 10% by mass, more preferably 0.05 to 5% by mass, and most preferably 0.1 to 3% by mass.

[0110] The transdermal liquid composition of the present disclosure may further contain a preservative. Preservatives include antiseptics, germicides or antibacterial agents, antioxidants, ultraviolet absorbers or ultraviolet scattering agents, etc.

[0111] Examples of preservatives include phenoxyethanol, chlorphenesin, benzoic acid, salicylic acid, sorbic acid, alkyl parahydroxybenzoates (parabens) such as methyl parahydroxybenzoate, etc. Phenoxyethanol may also act as a solvent for dissolving other ingredients (e.g., fragrances, etc.).

[0112] Bactericides or antibacterial agents include, for example, sodium benzoate.

[0113] Examples of antioxidants include inorganic acids such as phosphoric acid and sodium pyrosulfite; organic acids such as malonic acid, succinic acid, ascorbic acid, maleic acid, fumaric acid, and edetic acid; phosphorus compounds such as cephalin and phytic acid; polyphenols such as anthocyanins; and dibutylhydroxytoluene (BHT).

[0114] Examples of ultraviolet absorbers or ultraviolet scattering agents include tocopherol acetate, ethylhexyl methoxycinnamate, ethylhexyl 4-(N,N-dimethylamino)benzoate, t-butylmethoxydibenzoylmethane, oxybenzone, zinc oxide, and titanium oxide.

[0115] These preservatives can be used alone or in combination of two or more. Among these preservatives, phenoxyethanol, methyl parahydroxybenzoate, etc. are preferred.

[0116] The proportion of the preservative is, for example, 0.01 to 10 parts by mass, preferably 0.05 to 5 parts by mass, more preferably 0.1 to 3 parts by mass, more preferably 0.2 to 1 part by mass, and most preferably 0.3 to 0.5 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the preservative in the transdermal liquid composition is 0.01 to 15% by mass, preferably 0.02 to 10% by mass, more preferably 0.03 to 5% by mass, more preferably 0.05 to 3% by mass, and most preferably 0.1 to 2% by mass.

[0117] The transdermal liquid composition of the present disclosure may further contain a fragrance, which may be a natural fragrance or a synthetic fragrance.

[0118] Examples of natural flavorings include fruit essences or oils (vanillin, lemon oil, etc.) such as strawberry, blueberry, apple, plum, orange, lemon, lime, vanilla, and pepper; peel essences or oils such as orange, white grape, grapefruit, and lemon; bark essences or oils such as cinnamon; bark powders such as cinnamon powder; root vegetable essences or oils such as ginger; root vegetable powders such as ginger powder; seed powders such as vanilla beans and cocoa powder; leafy essences or oils such as peppermint, spearmint, rosemary, shiso, and eucalyptus; leafy powders such as peppermint powder; and flower essences or oils such as jasmine, lavender, rose, rosemary, and hyacinth.

[0119] Examples of synthetic fragrances include benzyl acetate, linalyl acetate, citral, citronellal, citronellol, cis-jasmine, cis-3-hexenol, and menthol.

[0120] These fragrances may be used alone or in combination of two or more.

[0121] The content of the fragrance is, for example, 0.001 to 5 parts by mass, preferably 0.003 to 1 part by mass, more preferably 0.005 to 0.5 parts by mass, more preferably 0.01 to 0.1 parts by mass, and most preferably 0.015 to 0.05 parts by mass, relative to 100 parts by mass of the liquid base. The content of the fragrance in the transdermal liquid composition is 0.001 to 5% by mass, preferably 0.003 to 1% by mass, more preferably 0.005 to 0.5% by mass, more preferably 0.007 to 0.3% by mass, and most preferably 0.01 to 0.1% by mass.

[0122] The transdermal liquid composition of the present disclosure may further contain a pH adjuster. Examples of pH adjusters include bases such as sodium bicarbonate and 2-amino-2-methyl-1-propanol; acids such as citric acid, sodium citrate, and sodium monohydrogen phosphate; and borax. These pH adjusters can be used alone or in combination of two or more. Of these, organic acids such as citric acid and sodium citrate are preferred. The proportion of the pH adjuster can be appropriately selected depending on the desired pH.

[0123] The transdermal liquid composition of the present disclosure may further contain a physiologically or pharmacologically active ingredient other than the turnover promoter.

[0124] Examples of the physiologically active ingredient (or pharmacologically active ingredient) include cell activators (e.g., riboflavin, pyridoxine, pantothenic acid, α-tocopherol or derivatives thereof; plant extracts such as saxifrage extract), skin roughness preventive agents (e.g., vitamin A, vitamin B １ , Vitamin B ２ , Vitamin B ６ , Vitamin B １２, vitamins such as vitamin D, vitamin E, and vitamin K), blemish and freckle inhibitors (for example, melanin reducing agents), acne inhibitors (for example, keratin softeners such as sulfur, anti-inflammatory agents, adrenal cortical hormones, sebum secretion inhibitors), skin emollients (for example, urea), anti-inflammatory agents (for example, allantoin, guaiazulene, glycyrrhizic acid or a salt thereof, glycyrrhetinic acid or a salt thereof, ε-aminocaproic acid, ibuprofen, indomethacin, zinc oxide or a derivative thereof; plant extracts such as arnica extract), skin itch inhibitors, blood circulation promoters, etc. These physiologically active ingredients can be used alone or in combination of two or more.

[0125] The proportion of the physiologically active ingredient is, for example, 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, even more preferably 0.03 to 3 parts by mass, even more preferably 0.05 to 2 parts by mass, and most preferably 0.1 to 1 part by mass, relative to 100 parts by mass of the liquid base.

[0126] The liquid composition of the present disclosure may further contain other ingredients.

[0127] Other ingredients include, for example, astringents or antiperspirants (e.g., hydroxy acids such as lactic acid and tartaric acid or their salts; aluminum compounds such as aluminum chloride; zinc compounds such as zinc sulfate and sulfophenoxozinc; proanthocyanidins; extracts of tannin-containing plants such as witch hazel and birch; star anise extract, rhubarb extract, and horsetail extract), coenzymes (e.g., coenzyme Q10), amino acids (e.g., tryptophan), refreshing agents (e.g., menthol or its derivatives, camphor, thymol), inorganic salts (e.g., sodium sulfate, potassium chloride), fibers (e.g., synthetic fibers such as nylon fibers, natural fibers), binders (e.g., calcium carbonate), Examples of the additives include hydroxymethylcellulose, carboxymethylcellulose sodium, carrageenan, etc.), chelating agents or sequestering agents (for example, gluconic acid, citric acid, succinic acid, ascorbic acid, sodium edetate, 1-hydroxyethane-1,1-diphosphonate sodium, phosphoric acid, sodium hexametaphosphate, etc.), reducing agents (for example, thioglycolic acid or a salt thereof, etc.), enzymes (for example, lipase, protease, etc.), thickeners (for example, gelatin, gluten, fish protein, etc.), basic agents, oxidizing agents, cleansing agents, cooling agents, coloring agents (coloring pigments such as white pigments, yellow pigments, red pigments, black pigments, extender pigments, etc.), opacifying agents, solidifying agents, plasticizers, etc.

[0128] These other components may be used alone or in combination of two or more.

[0129] The proportion (total proportion) of the other components relative to 100 parts by mass of the liquid base is, for example, 0.001 to 30 parts by mass, preferably 0.01 to 20 parts by mass, even more preferably 0.03 to 10 parts by mass, even more preferably 0.05 to 5 parts by mass, and most preferably 0.1 to 3 parts by mass.

[0130] The pH of the transdermal liquid composition of the present disclosure is, for example, 3 to 9, preferably 4 to 8, even more preferably 5 to 7, even more preferably 5.5 to 6.5, and most preferably 5.8 to 6.2.

[0131] When the transdermal liquid composition of the present disclosure contains a liquid base, it can be produced by mixing a turnover accelerator (active ingredient), the liquid base, and, if necessary, ingredients other than the turnover accelerator and the liquid base. A production method in which the turnover accelerator is dissolved or dispersed in the liquid base is preferred.

[0132] (Transdermal Semi-Solid Composition) The proportion of the turnover promoter (3HB component) in the transdermal semi-solid composition (or topical semi-solid composition) is, for example, 0.01% by mass or more, preferably 0.1% by mass or more, more preferably 0.2% by mass or more, more preferably 0.3% by mass or more, particularly preferably 0.5% by mass or more, and most preferably 0.8% by mass or more. When the proportion of the turnover promoter is above the lower limit, epidermal turnover tends to be easily promoted. Furthermore, the proportion of the turnover promoter in the transdermal semi-solid composition is, for example, 30% by mass or less, preferably 10% by mass or less, more preferably 5% by mass or less, more preferably 3% by mass or less, particularly preferably 2% by mass or less, and most preferably 1.5% by mass or less. The proportion of the turnover promoter in the transdermal semi-solid composition may be 0.1 to 5% by mass, particularly 0.3 to 3% by mass. Furthermore, when the proportion of the 3HB component is below the upper limit, handleability tends to be improved.

[0133] The semi-solid transdermal composition of the present disclosure may further contain a liquid base. Examples of the liquid base include the liquid bases exemplified in the section on transdermal liquid compositions. The liquid bases may be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0134] The proportion of the liquid base in the transdermal semi-solid composition is 10 to 95% by mass, preferably 30 to 90% by mass, further preferably 50 to 85% by mass, even more preferably 60 to 80% by mass, and most preferably 65 to 75% by mass.

[0135] The semi-solid transdermal composition of the present disclosure may further contain an emollient. Examples of the emollient include those exemplified in the section on transdermal liquid compositions. The emollients may be used alone or in combination of two or more. Preferred embodiments are also the same as those for the liquid compositions. In particular, the semi-solid transdermal composition may combine multiple emollients, for example, a combination of oils, a higher fatty acid or its derivative, and a hydrocarbon.

[0136] The proportion of the emollient may be, for example, 1 part by mass or more, for example, 1 to 1,000 parts by mass, preferably 5 to 100 parts by mass, more preferably 10 to 80 parts by mass, more preferably 15 to 50 parts by mass, most preferably 15 to 45 parts by mass, and particularly preferably 20 to 40 parts by mass (e.g., 20 to 30 parts by mass), per 100 parts by mass of the liquid base. The proportion of the emollient in the semi-solid transdermal composition is 1 to 95% by mass, preferably 3 to 90% by mass, more preferably 5 to 85% by mass, more preferably 7 to 80% by mass, and most preferably 10 to 75% by mass (e.g., 10 to 30% by mass). If the proportion of the emollient is too low, the semi-solid form may not be maintained, whereas if the proportion is too high, handling may be impaired.

[0137] The semi-solid transdermal composition of the present disclosure may further contain a gelling agent (swelling agent or thickener). Examples of gelling agents include water-soluble or water-swellable polysaccharides such as dextran, pullulan, agar, pectin, alginic acid, sodium alginate, carrageenan, galactomannan, glucomannan, curdlan, gum arabic, tragacanth gum, gellan gum, karaya gum, guar gum, xanthan gum, locust bean gum, tara gum, tamarind seed gum, and psyllium seed gum; proteins such as collagen, casein, albumin, gelatin, and royal jelly; and hydrophilic (or water-swellable) inorganic compounds such as bentonite, organically modified bentonite, magnesium aluminum silicate, and silicic anhydride. These gelling agents can be used alone or in combination of two or more. Of these gelling agents, water-swellable polysaccharides such as xanthan gum and hydrophilic (or water-swellable) inorganic compounds (hydrophilic thickeners or swelling agents) such as bentonite are preferred.

[0138] The proportion of the gelling agent is, for example, 0.01 to 100 parts by mass, preferably 0.03 to 10 parts by mass, more preferably 0.05 to 1 part by mass, more preferably 0.08 to 0.5 parts by mass, and most preferably 0.1 to 0.3 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the gelling agent in the transdermal semi-solid composition is 0.01 to 50% by mass, preferably 0.03 to 30% by mass, more preferably 0.05 to 10% by mass, more preferably 0.07 to 5% by mass, and most preferably 0.1 to 3% by mass.

[0139] The semi-solid transdermal composition of the present disclosure may further contain a moisturizing agent. Examples of the moisturizing agent include those exemplified in the section on the transdermal liquid composition. The moisturizing agents can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0140] The proportion of the humectant is, for example, 1 to 100 parts by mass, preferably 3 to 80 parts by mass, more preferably 5 to 50 parts by mass, more preferably 8 to 30 parts by mass, and most preferably 10 to 20 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the humectant in the transdermal semi-solid composition is 0.1 to 50% by mass, preferably 0.3 to 45% by mass, more preferably 0.5 to 40% by mass, more preferably 1 to 35% by mass, and most preferably 5 to 30% by mass.

[0141] The semi-solid transdermal composition of the present disclosure may further contain a surfactant. Examples of the surfactant include those exemplified in the section on transdermal liquid compositions. The surfactants can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0142] The proportion of the surfactant is, for example, 0.01 to 30 parts by mass, preferably 0.1 to 20 parts by mass, more preferably 0.5 to 15 parts by mass, more preferably 1 to 10 parts by mass, and most preferably 3 to 5 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the surfactant in the transdermal semi-solid composition is 0.01 to 30% by mass, preferably 0.05 to 25% by mass, more preferably 0.1 to 20% by mass, more preferably 0.3 to 15% by mass, and most preferably 0.5 to 10% by mass.

[0143] The semi-solid transdermal composition of the present disclosure may further contain a preservative. Examples of the preservative include those exemplified in the section on the transdermal liquid composition. The preservatives can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0144] The proportion of the preservative is, for example, 0.01 to 10 parts by mass, preferably 0.05 to 5 parts by mass, more preferably 0.1 to 3 parts by mass, more preferably 0.2 to 1 part by mass, and most preferably 0.3 to 0.5 parts by mass, relative to 100 parts by mass of the liquid base. The proportion of the preservative in the transdermal semi-solid composition is 0.01 to 10% by mass, preferably 0.03 to 8% by mass, more preferably 0.05 to 5% by mass, more preferably 0.07 to 3% by mass, and most preferably 0.1 to 1% by mass.

[0145] The semi-solid transdermal composition of the present disclosure may further contain a fragrance. Examples of the fragrance include the fragrances exemplified in the section on the transdermal liquid composition. The fragrances can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0146] The content of the fragrance is, for example, 0.001 to 5 parts by mass, preferably 0.003 to 1 part by mass, more preferably 0.005 to 0.5 parts by mass, more preferably 0.01 to 0.1 parts by mass, and most preferably 0.015 to 0.05 parts by mass, relative to 100 parts by mass of the liquid base. The content of the fragrance is 0.001 to 5% by mass, preferably 0.003 to 1% by mass, more preferably 0.005 to 0.5% by mass, more preferably 0.01 to 0.1% by mass, and most preferably 0.015 to 0.05% by mass in the semi-solid transdermal composition.

[0147] The semi-solid transdermal composition of the present disclosure may further contain a pH adjuster. Examples of the pH adjuster include those exemplified in the section on transdermal liquid compositions. The pH adjusters can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition. The proportion of the pH adjuster can be appropriately selected depending on the target pH.

[0148] The semi-solid transdermal composition of the present disclosure may further contain a physiologically active ingredient other than the turnover promoter. Examples of the physiologically active ingredient include the physiologically active ingredients exemplified in the section on the transdermal liquid composition. The physiologically active ingredients can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition.

[0149] The proportion of the physiologically active ingredient is, for example, 0.001 to 10 parts by mass, preferably 0.01 to 5 parts by mass, even more preferably 0.03 to 3 parts by mass, even more preferably 0.05 to 2 parts by mass, and most preferably 0.1 to 1 part by mass, relative to 100 parts by mass of the liquid base.

[0150] The semi-solid transdermal composition of the present disclosure may further contain other components. Examples of the other components include the other components exemplified in the section on transdermal liquid compositions. The components can be used alone or in combination of two or more. Preferred aspects are also the same as those of the transdermal liquid composition. Note that semi-solid transdermal compositions, particularly makeup products (e.g., liquid foundations), may contain colorants such as pigments.

[0151] The proportion (total proportion) of the other components relative to 100 parts by mass of the liquid base is, for example, 0.001 to 30 parts by mass, preferably 0.01 to 20 parts by mass, even more preferably 0.03 to 10 parts by mass, even more preferably 0.05 to 5 parts by mass, and most preferably 0.1 to 3 parts by mass.

[0152] The pH of the semi-solid transdermal composition of the present disclosure is, for example, 3 to 9, preferably 4 to 8, further preferably 5 to 7, more preferably 5.5 to 6.5, and most preferably 5.8 to 6.2.

[0153] When the transdermal semi-solid composition of the present disclosure contains an emollient, it can be produced by mixing a turnover accelerator (active ingredient), an emollient, and, if necessary, ingredients other than the turnover accelerator and the emollient.

[0154] In this specification and claims, it is preferred that the components contained in the transdermal composition are "cosmetic grade" components, "drug or quasi-drug grade" components, and / or pharmaceutically or physiologically acceptable components.

[0155] (Uses of Transdermal Composition) The transdermal composition (topical composition or topical agent) of the present disclosure can be used as various cosmetic preparations, pharmaceuticals, or quasi-drugs. Note that the term "cosmetic preparations" is used in the sense of including cosmetics.

[0156] Examples of cosmetics include moisturizing cosmetics, whitening cosmetics, UV care cosmetics, cleansing agents, and scrubbing agents.

[0157] Cosmetics include skin care products, makeup products, UV protection products, body products, hair care products, and the like.

[0158] Examples of basic cosmetics include lotions, beauty serums, emulsions, creams, facial cleansers, and cleansing cosmetics (oil-type, gel-type, cream-type, lotion-type, milk-type cosmetics, etc.).

[0159] Examples of skin care cosmetics (skin care products or skin cosmetics) include lotions, emulsions, gel creams, skin care creams, and massage lotions.

[0160] Examples of makeup cosmetics include makeup bases, BB creams, foundations (powder foundations, liquid foundations, cream foundations, emulsion foundations, etc.), lipsticks / lip glosses, eye shadows, eyeliners, eyebrow pencils, and mascaras.

[0161] Examples of UV care cosmetics include emulsions, lotions, gels, creams, and sprays of sunscreen cosmetics.

[0162] Examples of body cosmetics include body washes, body lotions, body milks, body creams, body powders, and body massage products.

[0163] Examples of hair care cosmetics include shampoos, conditioners, treatments, after-bath treatments, tonics, hair styling products, hair growth products, and hair creams.

[0164] Examples of pharmaceuticals or quasi-drugs include medicated cosmetics, liquids, aerosols, creams, gels (jelly), ointments, poultices, and liniments.

[0165] Among these uses, cosmetics (including beauty products), pharmaceuticals, and quasi-drugs, which are used in a manner that allows the composition to penetrate into the skin without being washed off immediately after use, are preferred, as the effects of the transdermal composition of the present disclosure are easily exhibited, cosmetics and quasi-drugs are more preferred, and cosmetics are particularly preferred.

[0166] Furthermore, the transdermal composition of the present disclosure is particularly preferably a skin care cosmetic (skin care product or skin cosmetic) for promoting epidermal turnover in skin problems such as rough skin, dry skin, and pigmented spots. The skin care cosmetic may be a transdermal liquid composition such as a lotion, serum, lotion, milk, emulsion, or mist, or a transdermal semi-solid composition such as a cream, gel, paste (balm), or foam (bubble). The transdermal composition of the present disclosure may also be a makeup cosmetic, or a transdermal semi-solid composition such as a makeup base, BB cream, or liquid foundation. The transdermal liquid composition and transdermal semi-solid composition may be a cosmetic composition or a cosmetic composition (cosmetics), or may be an anti-aging care product intended for anti-aging purposes.

[0167] The present disclosure will be described in more detail below based on examples, but the present disclosure is not limited to these examples. The raw materials used in the examples and the evaluation methods of the liquid compositions prepared in the examples are as follows.

[0168] [Raw Materials] 3HB-Na: Crystalline (R) 3HB sodium, "OHALOS (registered trademark)" manufactured by Osaka Gas Chemicals Co., Ltd. VC-Na: Vitamin C sodium (sodium ascorbate), "sodium ascorbate" manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. VB ３ : Vitamin B ３ (Niacinamide), Fujifilm Wako Pure Chemical Industries, Ltd. "Niacinamide"

[0169] [Preparation of normal human epidermal keratinocytes and culture conditions] Normal human epidermal keratinocytes (manufactured by Kurabo Industries, Ltd., hereinafter referred to as "NHEK") were cultured in a 96-well plate at 1.5 x 10 cells using a growth medium (manufactured by Kurabo Industries, Ltd., "HuMedia-KG2", hereinafter referred to as "KG2"). ４ The cells were seeded at a density of 1000 cells / well and cultured at 37°C for 24 hours.

[0170] [Evaluation of mRNA expression of turnover-related genes by turnover promoters using normal human epidermal keratinocytes] The medium in which NHEK cells were cultured was treated with 3HB-Na, VC-Na, and VB at the concentrations shown in Tables 1 and 2.３ The medium was exchanged with KG2 containing HCl and incubated at 37°C for 24 hours.

[0171] After incubation, total RNA was extracted from the cells, and cDNA was synthesized using reverse transcriptase. Using the cDNA as a template, various mRNAs were subjected to relative quantification (ΔΔCt method) by real-time PCR. The mRNAs used were those encoding the production of keratin 10 (K10), involucrin (IVL), or filaggrin (FLG). The expression levels of various mRNAs were also measured using the mRNAs encoding 3HB-Na, VC-Na, and VB. ３ The expression level was expressed as a relative value to the mRNA expression level of a blank containing neither of the above (relative value when the blank was set to 1). It is considered that the higher the mRNA expression level, the more actively the target protein is produced, and therefore the higher the production level.

[0172] Test Example 1 (Examples 1 to 12 and Comparative Examples 1 to 6) 3HB-Na and / or VC-Na were added, and the results of evaluation of the expression levels of K10, IVL, or FLG mRNA are shown in Table 1 and Figures 1 to 3.

[0173] Test Example 2 (Examples 13 to 24 and Comparative Examples 7 to 12) 3HB-Na and / or VB ３ The results of evaluating the expression levels of K10, IVL, or FLG mRNA are shown in Table 2 and FIGS.

[0174] In Table 1, "S.D." means standard deviation, and p means the p value relative to Blank 1 (NHEK containing neither 3HB-Na nor VC-Na) or Blank 2 (NHEK containing only VC-Na). In Table 2, "S.D." means standard deviation, and p means the p value relative to Blank 1 (NHEK containing neither 3HB-Na nor VC-Na). ３ p-value relative to blank 2 (VB ３ (NHK includes only the above).

[0175] In Figures 1 to 3, "*" means that the p-value relative to Blank 1 (NHEK containing neither 3HB-Na nor VC-Na) is less than 0.05 (p<0.05), "**" means that the p-value relative to Blank 1 is less than 0.01 (p<0.01), and "##" means that the p-value relative to Blank 2 (NHEK containing only VC-Na) is less than 0.01 (p<0.01).

[0176] In Figures 4 to 6, "*" indicates blank 1 (3HB-Na and VB ３ "**" means that the p-value is less than 0.01 (p<0.01) relative to blank 1 (VB ３ This means that the p-value for the NHEK (containing only NHEK) is less than 0.01 (p<0.01).

[0177]

[0178]

[0179] (General Considerations) As is clear from the results in Tables 1 and 2 and Figures 1 to 6, it was confirmed that all turnover promoters containing at least 3HB-Na increased the mRNA expression levels of K10, IVL, and FLG, and were able to promote epidermal turnover.

[0180] (Discussion of Test Example 1) As is clear from Table 1 and Figures 1 to 3, in the turnover promoters containing 3HB-Na alone (Examples 1 to 2, 5 to 6, and 9 to 10), increasing the proportion of 3HB-Na also increased the mRNA expression levels of K10, IVL, and FLG.

[0181] Furthermore, in the turnover promoters that combined 3HB-Na and VC-Na (Examples 3-4, 7-8, and 11-12), increasing the proportion of 3HB-Na also increased the mRNA expression levels of K10, IVL, and FLG.

[0182] Furthermore, as is clear from Table 1, a synergistic effect was confirmed in a turnover promoter that combined 3HB-Na and VC-Na, compared with a turnover promoter containing 3HB-Na alone (Examples 1-2, 5-6, and 9-10) and a turnover promoter containing VC-Na alone (Comparative Examples 2, 4, and 6, which are Blank 2). That is, in Table 1, the synergistic effect was evaluated by comparing the increase in mRNA expression level relative to Blank 1 (Comparative Examples 1, 3, or 5), which contained neither 3HB-Na nor VC-Na, and in all cases, the increase due to the combination of 3HB-Na and VC-Na was greater than the total increase due to either 3HB-Na or VC-Na alone. For example, the mRNA expression level of the turnover promoter of Example 3 was 1.41, and the increase relative to Blank 1 of Comparative Example 1 was 0.41. However, this is greater than the total increase relative to Blank 1 of Example 1 and Comparative Example 2, which is 0.31 (0.23 increase in Example 1 + 0.08 increase in Comparative Example 2) (the ratio of increases is 0.41 / 0.31 = 1.32, which exceeds 1), and therefore a synergistic effect is exhibited. In particular, the turnover promoter combining 3HB-Na and VC-Na showed high mRNA expression levels for K10 and IVL, with IVL being the most abundant. Therefore, the combination of 3HB-Na and VC-Na is preferably used as a K10 production promoter or an IVL production promoter, and most preferably as an IVL production promoter.

[0183] (Discussion of Test Example 2) As is clear from Table 2 and Figures 4 to 6, 3HB-Na and VB ３ In the turnover promoters (Examples 15-16, 19-20 and 23-24) in which the above was combined, increasing the proportion of 3HB-Na also increased the mRNA expression levels of K10, IVL and FLG.

[0184] Furthermore, as is clear from Table 2, 3HB-Na and VB ３ In the turnover promoter, 3HB-Na and VB ３By combining these, a synergistic effect was confirmed compared to the turnover accelerators containing 3HB-Na alone (Examples 13-14, 17-18, and 21-22) and the turnover accelerators containing VC-Na alone (Comparative Examples 8, 10, and 12, which are Blank 2). ３ The synergistic effect was evaluated by comparing the increase in mRNA expression level with that of Blank 1 (Comparative Examples 7, 9, or 11) which did not contain any of 3HB-Na and VB. ３ The increase in the combination with 3HB-Na or VB ３ The results were greater than the sum of the individual increases (the specific concept of synergistic effect is the same as that discussed in Test Example 1 above). ３ When the turnover promoter was combined with 3HB-Na and VB, the mRNA expression levels of K10 and FLG were high, with FLG being the most abundant. ３ The combination of is preferably used as a K10 production promoter or a FLG production promoter, and most preferably as a FLG production promoter.

[0185] Preparation Example 1 (Lotion 1) Lotion 1 was prepared as follows according to the formulation shown in Table 3. Each component was added so that the concentration relative to the total amount of Lotion 1 (final concentration before filtration) was the concentration shown in the "Amount Added" column in Table 3.

[0186] The components of phase A and phase B were mixed, dissolved, and homogenized to prepare solutions A and B. Solution B was added to solution A and mixed to solubilize. The resulting solubilized solution was filtered, and the filtrate was filled into a container as a lotion (lotion 1).

[0187]

[0188] In Table 3, "POE(n)" means an addition polymer of n ethylene oxide molecules.

[0189] Preparation Example 2 (Lotion 2) Lotion 2 was prepared as follows according to the formulation shown in Table 4. Each component was added so that the concentration relative to the total amount of Lotion 2 (final concentration before filtration) was the concentration shown in the "Amount Added" column in Table 4. Purified water for phases A and E was prepared by heating the purified water in advance at 80°C or higher for 10 minutes and then cooling it to 30°C or lower.

[0190] The ingredients of phase C were heated to 50-60°C, dissolved and homogenized, and the resulting liquid C was cooled to 30°C or below. The flavoring of phase D was added to the cooled liquid C and homogenized by stirring to obtain a [C+D] mixed liquid. The purified water of phase E was added to the resulting [C+D] mixed liquid and homogenized by stirring to obtain a [C+D+E] mixed liquid.

[0191] The components of phase B were added to the components of phase A (components of phase A other than purified water) and thoroughly stirred and mixed. The [C+D+E] mixture was further added to the obtained [A+B] mixture and thoroughly stirred and mixed to obtain an [A+B+C+D+E] mixture. The pH was adjusted to 6.0±0.5 using a 1% by mass aqueous citric acid solution and a 1% by mass aqueous sodium citrate solution of phase F, and then the purified water of phase A was added to a measuring tape until the desired final mass was reached. The obtained mixture was filtered, and the filtrate was filled into a container as a lotion (lotion 2).

[0192]

[0193] Instead of lavender oil in Phase D as a flavoring agent, orange oil, grapefruit peel oil, eucalyptus leaf oil, rosemary leaf oil, etc. may also be used.

[0194] Preparation Example 3 (Emulsion) An emulsion was prepared as follows according to the formulation shown in Table 5. Each component was added so that the concentration of each component relative to the total emulsion (final concentration before filtration) was the concentration shown in the "Amount Added" column in Table 5.

[0195] The components of phase A were heated to 70°C, dissolved, and homogenized to obtain solution A. The components of phase B were heated to 80°C, dissolved, and homogenized to obtain solution B. To solution A, solution B was added while stirring with a homomixer (manufactured by Primix Corporation, "Labo-Lusion (registered trademark) Homomixer MARK II"), and emulsified. The emulsified [A+B] solution was cooled with stirring, and when the temperature reached 40°C or below, the components of phase C were added. The resulting [A+B+C] emulsion was degassed, filtered, and cooled to 30°C or below to prepare an emulsion.

[0196]

[0197] Preparation Example 4 (Cream) A cream was prepared as follows according to the formulation shown in Table 6. Each component was added so that the concentration of each component relative to the total cream (final concentration before filtration) was the concentration shown in the "Amount Added" column in Table 6.

[0198] The ingredients of phase A were heated to 70°C, dissolved, and homogenized to obtain liquid A. The ingredients of phase B were heated to 80°C, dissolved, and homogenized to obtain liquid B. Liquid B was added to liquid A while stirring with a homomixer (manufactured by Primix Corporation, "Labo-Lusion (registered trademark) Homomixer MARK II"), and emulsified. The emulsified [A+B] emulsion was cooled with stirring, and when the temperature reached 40°C or below, the ingredients of phase C were added. The resulting [A+B+C] emulsion was degassed, filtered, and cooled to 30°C or below to prepare a cream.

[0199]

[0200] In Table 6, "POE(n)" means an addition polymer of n ethylene oxide molecules.

[0201] Preparation Example 4 (Liquid Foundation (O / W Emulsion Type)) A liquid foundation was prepared as follows according to the formulation shown in Table 7. Each component was added so that the concentration (final concentration) relative to the total amount of the liquid foundation was the concentration shown in the "Amount Added" column in Table 7.

[0202] The ingredients of phases A to D were prepared in advance as follows. [Phase A] The ingredients of phase A were mixed and crushed to prepare mixed crushed material A. [Phase B] The ingredients of phase B were heated to 70°C and stirred with a homomixer (Primix Corporation, "Labo-Lusion (registered trademark) Homomixer MARK II") to obtain solution B. [Phase C] The ingredients of phase C were mixed, dissolved, and homogenized to obtain solution C. [Phase D] The ingredients of phase D were heated to 70-80°C, dissolved, and homogenized to obtain solution D.

[0203] Solution C was added to solution B and thoroughly stirred to obtain solution [B+C]. Mixed crushed material A was added to the obtained solution [B+C] while stirring, and the mixture was heated to 70°C and stirred with a homomixer (manufactured by Primix Corporation, "Labo-Lusion (registered trademark) Homomixer MARK II") to obtain a mixed solution [A+B+C]. Solution D was gradually added to the obtained [A+B+C] mixed solution, heated to 70°C, and stirred with a homomixer to obtain a mixed solution [A+B+C+D]. The obtained [A+B+C+D] mixed solution was cooled with stirring, and the fragrance of phase E was added at 45°C or below to obtain a mixed solution [A+B+C+D+E]. This was cooled to room temperature, degassed, and then filled into a container as a liquid foundation.

[0204]

[0205] In Table 7, the sodium aluminosilicate used was "OVEIL AR3" manufactured by Osaka Gas Chemicals Co., Ltd., and the bentonite used was "OVEIL BR1" manufactured by Osaka Gas Chemicals Co., Ltd.

[0206] The turnover promoter of the present disclosure can promote epidermal turnover and therefore can be used in a variety of applications, such as beauty products or cosmetics, foods, pharmaceuticals, and quasi-drugs. In particular, since the turnover promoter can promote the regeneration of skin with normal keratin, even in skin that has problems such as rough skin, dry skin, and pigmentation spots due to aging, exposure to ultraviolet rays, or poor eating habits, it can be suitably used in cosmetics, for example, in skin care products such as anti-aging care products.

Claims

1. An agent for promoting epidermal turnover, comprising 3-hydroxybutyric acid, a salt of 3-hydroxybutyric acid, and a compound represented by the following formula (1): A turnover promoter comprising at least one 3-hydroxybutyric acid component selected from 3-hydroxybutyric acid alkyl esters represented by the formula: (wherein R represents an alkyl group).

2. The turnover promoter according to claim 1, further comprising a whitening agent.

3. The turnover promoter according to claim 2, wherein the whitening agent comprises a tyrosinase inhibitor and / or a melanin transport inhibitor.

4. A turnover promoter according to any one of claims 1 to 3, wherein the 3-hydroxybutyric acid component contains the R-isomer.

5. A keratin 10 production promoter containing the 3-hydroxybutyric acid component according to claim 1.

6. The keratin 10 production promoter according to claim 5, further comprising a skin whitening agent.

7. An involucrin production promoter containing the 3-hydroxybutyric acid component according to claim 1.

8. The involucrin production promoter according to claim 7, further comprising a skin whitening agent.

9. A filaggrin production promoter containing the 3-hydroxybutyric acid component according to claim 1.

10. The filaggrin production promoter according to claim 9, further comprising a whitening agent.

11. A composition comprising the turnover promoter according to any one of claims 1 to 3.

12. The composition according to claim 11, which is a transdermal composition.

13. The composition of claim 11 which is a liquid or semi-solid composition.

14. The composition according to claim 11, which is a cosmetic.

15. A method for promoting epidermal turnover by penetrating the turnover promoter according to any one of claims 1 to 3 into the skin.

16. A method for promoting the production of at least one member selected from the group consisting of keratin 10, involucrin, and filaggrin, by penetrating the 3-hydroxybutyric acid component according to claim 1 into the skin.

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