Porphyrin production inhibitors and cosmetics and topical skin preparations containing them.

Abstract

To improve acne and reduce pores or hidden freckles by providing an excellent porphyrin production inhibitor.SOLUTION: This invention has been completed with the findings that combinational use of ascorbic acid and a derivative thereof with ergothioneine causes dramatic reduction in the amount of porphyrin, which is a metabolite of Propionibacterium acnes in the skin.SELECTED DRAWING: None

Description

[[Technical Field]]

[0001] The present invention relates to a porphyrin production inhibitor and an external preparation containing ascorbic acid, a derivative thereof, and ergothioneine as active ingredients. [[Background Art]]

[0002] Porphyrin is a general term for macrocyclic compounds in which four 5-membered ring compounds each containing one nitrogen atom (pyrrole) are alternately bonded with four carbon atoms. It is known that conjugation spreads across the entire molecular plane of porphyrin, which is characterized by strongly absorbing light in the visible region (Non-Patent Document 1). When porphyrin coordinates Fe, it forms heme; when it coordinates Mg, it forms chlorophyll; when it coordinates Cu, it forms hemocyanin. Heme binds to various proteins, and besides hemoglobin which transports oxygen, it plays an important role in the enzymatic activities of cytochrome c, cytochrome P450, catalase, and the like, and is a metabolite involved in the biosynthesis of molecules essential for life (Non-Patent Document 2).

[0003] In the skin, porphyrin is produced by *Cutibacterium acnes*, a commensal bacterium of human skin, and migrates to the skin surface along with sebum secretion. It is known that when porphyrin is exposed to ultraviolet light there, singlet oxygen is generated via a photosensitization reaction, and this singlet oxygen reacts with squalene, which is the most reactive component of skin surface lipids, to generate peroxides. Porphyrin is also involved in inflammation around hair follicles by exerting cytotoxicity and stimulating the expression of IL-8 derived from epidermal cells. It has been reported that these various reactions induce skin aging and cause deterioration of skin conditions (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5).

[0004] Propionibacterium acnes produces extracellular inflammation-inducing substances such as bacterial lipase, protease, and neutrophil chemotactic factors, adding inflammation to acne. Bacterial lipase hydrolyzes triglycerides in lipids into free fatty acids, which are involved in keratinization and inflammation excitation in the hair follicle infundibulum (Non-Patent Literature 6). Furthermore, it has been reported that abnormal keratinization of the epidermis due to unsaturated fatty acids can cause pore enlargement (Non-Patent Literature 7, Non-Patent Literature 8). In addition, inflammation caused by Propionibacterium acnes can result in post-inflammatory erythema and post-inflammatory hyperpigmentation (Non-Patent Literature 9).

[0005] Acne (acne vulgaris) is an inflammatory skin disease that develops when sebum clogs hair follicles, causing inflammation. It mainly develops during puberty, and skin lesions are found on the face, chest, and back, corresponding to the hair follicles. The mechanisms of acne development are said to be the following three: 1) increased sebum secretion, 2) obstruction due to abnormal keratinization of the hair follicle infundibulum, and 3) proliferation of acne bacteria and the resulting inflammation (Non-patent Literature 10).

[0006] On the other hand, acne patients have been shown to have higher levels of porphyrin, particularly around lesion sites, compared to healthy individuals, and it has been reported that porphyrin production is an important pathogenic mechanism that induces the inflammatory response in acne (Non-Patent Literature 11).

[0007] Traditionally, acne prevention and treatment have involved improving facial cleansing, as well as using topical antibiotics, sulfur-containing preparations, and vitamin A derivatives (retinoic acid). Most acne-fighting cosmetics to date are designed for oily skin, focusing on controlling excessive sebum secretion. However, many adults with acne also have dry skin, creating a need for moisturizing cosmetics and topical skin preparations. Unfortunately, products that adequately address these symptoms are currently unavailable.

[0008] To date, the use of ascorbic acid derivatives has been reported for preventing the worsening of acne (Non-Patent Document 12). Ascorbic acid and ascorbic acid derivatives are known to have functions such as antioxidant, whitening, and collagen-promoting effects, and many reports have been made on their usefulness, but there have been no reports on porphyrins, which has not been entirely satisfactory (Patent Documents 1 and 2).

[0009] On the other hand, ergothioneine is a component synthesized by fungi such as mushrooms and some bacteria, and is known as a type of sulfur-containing amino acid. It has excellent antioxidant properties, and when used as an active ingredient, it has been reported to be utilized as an antioxidant, tyrosinase inhibitor, lipase inhibitor, 5α-reductase inhibitor, anti-aging agent, and anti-metabolic syndrome agent (Patent Document 3). However, there are no reports on the inhibition of porphyrin production by ergothioneine, nor have there been any studies on the synergistic effect of the above-mentioned components in inhibiting porphyrin production. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] Chemistry and Education, 2015;63(12) [Non-Patent Document 2] Keiichiro Suzuki et al., Medical View Co., Ltd., Intensive Lecture: Biochemistry [Non-Patent Document 3] Journal of the Japan Society for Cosmetic Science, 1995;19-1;1-6 [Non-Patent Document 4] Br J Dermatol. 2005 Jul;153(1):66-71. [Non-Patent Document 5] Oil Chemistry, 1995;44(4) [Non-Patent Document 6] Journal of the University of Occupational and Environmental Health, Japan 2007;29(1);63-71 [Non-Patent Document 7] J Invest Dermatol 2005;124(5);1008-1013 [Non-Patent Document 8] Fragrance Journal 2004;3;41-47 [Non-Patent Document 9] Journal of the Japanese Society of Cosmetic Science 2016;40(1);12-19 [Non-Patent Document 10] Yoshiki Miyaji, Masako Naganuma, Bunko-do, Dermatology for Cosmetics and Topical Drug Researchers [Non-Patent Document 11] AMS Journals. 2020 Jan;5(1) [Non-Patent Document 12] Nikko Chemicals Co., Ltd., NIKKOL VC-IP Catalog, https: / / www.chemical-navi.com / product-search / view2069.html [Patent Documents]

[0011] [Patent Document 1] Japanese Patent Publication No. 2019-081718 [Patent Document 2] Japanese Patent Publication No. 2020-075911 [Patent Document 3] Japanese Patent Publication No. 2009-126863 [Overview of the project] [Problems that the invention aims to solve]

[0012] The present invention aims to provide an excellent porphyrin production inhibitor and cosmetics and topical skin preparations containing it, thereby suppressing porphyrin production and improving acne, as well as reducing pores or hidden blemishes. [Means for solving the problem]

[0013] The present inventors have found that the combined use of ascorbic acid or a derivative thereof and ergothioneine dramatically reduces the amount of porphyrin, which is a metabolite of Cutibacterium acnes present in the skin, and thus completed the present invention. [Effects of the Invention]

[0014] According to the present invention, it has been found that the combined use of ascorbic acid or a derivative thereof and ergothioneine as active ingredients significantly reduces the amount of porphyrin, which is a metabolite of Cutibacterium acnes present in the skin. Furthermore, by incorporating these substances as active ingredients, it is possible to provide a cosmetic or external preparation for skin that exhibits effects of improving acne, and reducing the number of pores and the number of hidden spots by inhibiting porphyrin production. [Mode for Carrying Out the Invention]

[0015] Hereinafter, the configuration of the present invention will be described in further detail. The porphyrin production inhibitor of the present invention contains ascorbic acid or a derivative thereof and ergothioneine as active ingredients. The ascorbic acid and derivatives thereof used in the present invention are not particularly limited, and examples include ascorbic acid; ascorbic acid alkyl esters such as ascorbyl dipalmitate and ascorbyl tetrahexyldecanoate; ascorbic acid phosphate ester; ascorbic acid sulfate ester; and ascorbic acid alkyl ethers such as 3-O-cetyl ascorbic acid. Ascorbic acid and derivatives thereof according to the present invention can be obtained not only through various synthesis methods but also as reagents. Furthermore, commercially available products can also be used, such as ascorbyl dipalmitate, NIKKOL VC-IP (ascorbyl tetrahexyldecanoate), NIKKOL VC-PMG (magnesium ascorbyl phosphate), NIKKOL VC cetyl ether (ascorbyl cetyl ether), and NIKKOL VC-SS (disodium ascorbyl sulfate) manufactured by Nikko Chemicals. One of the above ascorbic acid and derivatives thereof may be used alone, or two or more thereof may be used in combination.

[0016] The amount of ascorbic acid and its derivatives incorporated into the topical preparation varies depending on the application, dosage form, and purpose of incorporation, and is not particularly limited. However, generally, the amount of ascorbic acid and its derivatives in the topical preparation is preferably 0.01 to 50.0% by mass, and more preferably 0.1 to 40.0% by mass.

[0017] The ergothioneine used in this invention is not particularly limited in terms of its manufacturing method or origin, but commercially available thiotaine (manufactured by AGI Dermatics, containing 0.045% ergothioneine) or phytothioneine(r) (manufactured by Koei Kogyo Co., Ltd., containing 0.15 w / v% ergothioneine) can be used. The amount of ergothioneine to be incorporated into the topical preparation varies depending on the use, dosage form, and purpose of incorporation, and is not particularly limited. However, generally, 0.00001 to 0.1% by mass of ergothioneine in the topical preparation is preferred, and more preferably 0.00002 to 0.01% by mass.

[0018] Examples of topical skin preparations of the present invention include, but are not limited to, lotions, milk lotions, gels, creams, and oily ointments. Furthermore, the topical skin preparation of the present invention may contain known components that are commonly used in topical skin preparations, as long as they do not impair the effects of the present invention. Specifically, these include, but are not limited to, oils and fats such as hydrocarbons and vegetable oils, waxes, humectants, thickeners, UV absorbers, powders, pigments, colorants, anionic surfactants, cationic surfactants, nonionic surfactants, amphoteric surfactants, sugars, polymer compounds, physiologically active ingredients, transdermal absorption enhancers, solvents, fragrances, preservatives, and stabilizers. Furthermore, the topical skin preparation of the present invention is preferably used at a pH of 4 to 10 in order to maintain the stability of the active ingredient.

[0019] In this invention, porphyrin refers to, for example, an index of the total number of porphyrins in the skin calculated by image analysis using UV light irradiation during skin imaging; pores refer to, for example, pores calculated by image analysis using skin imaging; and hidden blemishes refer to, for example, accumulated melanin present in the epidermis calculated by image analysis using UV light irradiation during skin imaging. However, the above skin parameters are not limited to these measurements. [Examples]

[0020] The present invention will be described in more detail below with reference to examples, but the present invention is not to be limited by these examples.

[0021] Example 1. Improvement effect on skin parameters (porphyrins) 1. Overview of the exam The improvement effect of a formulation containing tetrahexyldecyl ascorbate (NIKKOL VC-IP) and ergothioneine (thiotaine) on skin parameters (porphyrins) was evaluated.

[0022] 2. Experimental Method In the clinical trial, the study was conducted in accordance with the Declaration of Helsinki, after obtaining written explanations and informed consent from the subjects. Nine subjects applied either Product 1 or Comparative Product 1 to half of their face twice daily, morning and evening, for four weeks. Before use, and after two and four weeks, subjects washed their faces with a designated facial cleanser, wiped them with a wipe-all, and then underwent a 20-minute acclimatization period in an environmental evaluation room (room temperature 22°C, humidity 50%). Subsequently, images of the right and left sides of the face were taken using the VISIA Evolution facial skin imaging counseling system (Canfield Scientific), and the number of porphyrins (metabolites of acne bacteria), a skin parameter, was analyzed. The analysis range was selected according to the system's instructions, and the same range was used for all subsequent analyses. The change in porphyrin count is shown as a relative value, with the initial value before use set to 100%. 3. Formulation for evaluation

[0023] [Table 1]

[0024] (Raw materials used) NIKKOL VC-IP: Ascorbyl tetrahexyldecanoate, manufactured by Nikko Chemicals Co., Ltd. Thiotaine: Contains 0.045% ergothioneine, manufactured by AGI Dermatics. PEMULEN TR-1: Acrylates / C10-30 alkyl acrylate crosspolymer, manufactured by Lubrizol. PEMULEN TR-2: Acrylates / C10-30 alkyl acrylate crosspolymer, manufactured by Lubrizol. NIKKOL Hexaglyn PR-15: Polyglyceryl-6 polyricinoleate, manufactured by Nikko Chemicals Co., Ltd. NIKKOL Syncelane 4SP: Olefin oligomer, manufactured by Nikko Chemicals Co., Ltd. KF-54: Diphenyl dimethicone, manufactured by Shin-Etsu Chemical Co., Ltd. (Preparation method) The aqueous phase and oil phase are uniformly heated and dissolved to emulsify. Cool to room temperature to obtain the formulation. The pH of each was 4.6.

[0025] 4, results The results are shown in Table 2. Continuous use of comparative product 1 showed a decreasing trend in porphyrin levels. On the other hand, continuous use of product 1 of the present invention resulted in a significant decrease in porphyrin levels. Furthermore, product 1 of the present invention significantly reduced porphyrin levels compared to comparative product 1. This suggests that the combined use of ascorbyl tetrahexyldecanoate and ergothioneine exhibits a porphyrin production inhibitory effect.

[0026] [Table 2]

[0027] Example 2. Improvement effect on skin parameters (pores) 1. Overview of the exam The improvement effect of a combination formulation of tetrahexyldecyl ascorbate (NIKKOL VC-IP) and ergothioneine (thiotaine) on skin parameters (pores) was evaluated.

[0028] 2. Experimental Method In the clinical trial, the study was conducted in accordance with the Declaration of Helsinki, after obtaining written explanations and informed consent from the subjects. Nine subjects applied either Product 1 or Comparative Product 1 to half of their face twice daily, morning and evening, for four weeks. Before use, and after two and four weeks, subjects washed their faces with a designated facial cleanser, wiped them with a wipe-all, and then underwent a 20-minute acclimatization period in an environmental evaluation room (room temperature 22°C, humidity 50%). Subsequently, images of the right and left sides of the face were taken using the VISIA Evolution facial skin imaging counseling system (Canfield Scientific), and the number of pores, a skin parameter, was analyzed. The analysis range was selected according to the system's instructions, and the same analysis range was used for all subsequent analyses. The change in the number of pores is shown as a relative value, with the initial value before use set to 100%.

[0029] 3, results The results are shown in Table 3. Continuous use of comparative product 1 showed a decreasing trend in the number of pores. Continuous use of product 1 of the present invention resulted in a significant reduction in the number of pores. This suggests that the combined use of ascorbyl tetrahexyldecanoate and ergothioneine exhibits a pore-improving effect.

[0030] [Table 3]

[0031] Example 3. Improvement effect on skin parameters (hidden blemishes) 1. Overview of the exam The improvement effect of a combination formulation of tetrahexyldecyl ascorbate (NIKKOL VC-IP) and ergothioneine (thiotaine) on skin parameters (hidden blemishes) was evaluated.

[0032] 2. Experimental Method In the clinical trial, the study was conducted in accordance with the Declaration of Helsinki, after obtaining written explanations and informed consent from the subjects. Nine subjects applied either Product 1 of the present invention or Comparative Product 1 to half of their face twice daily, morning and evening, for four weeks. Before use, and after two and four weeks of use, subjects washed their faces with a designated facial cleanser, wiped them with a wipe-all, and then underwent a 20-minute acclimatization period in an environmental evaluation room (room temperature 22°C, humidity 50%). Subsequently, images of the right and left sides of the face were taken using the VISIA Evolution facial skin imaging counseling system (Canfield Scientific), and the number of hidden blemishes, a skin parameter, was analyzed. The analysis range was selected according to the system's instructions, and the same analysis range was used for all subsequent analyses. The change in the number of hidden blemishes is shown as a relative value, with the initial value before use set to 100%.

[0033] 3, results The results are shown in Table 4. Continuous use of comparative product 1 showed a decreasing trend in the number of hidden blemishes. Furthermore, continuous use of product 1 of the present invention resulted in a significant decrease in the number of hidden blemishes. This suggests that the combined use of ascorbyl tetrahexyldecanoate and ergothioneine exhibits an inhibitory effect on accumulated melanin present in the epidermis.

[0034] [Table 4]

[0035] Application Example 1: Lotion Phase A: Butylene glycol 5.0 (mass%) Glycerin 3.0 Dipropylene glycol 2.0 PEG-75 0.5 Chelating agent (appropriate amount) pH adjuster (appropriate amount) Preservative (appropriate amount) Water level B phase NIKKOL VC-PMG 0.2 water 3.8 Phase C Thiotaine 0.1 Phase D Ethanol 3.0 Total 100.0 (Raw materials used) NIKKOL VC-PMG: Magnesium ascorbyl phosphate, manufactured by Nikko Chemicals Co., Ltd. Thiotaine: Contains 0.045% ergothioneine, manufactured by AGI Dermatics. (Preparation method) Heat phase A and dissolve it uniformly. Dissolve phase B uniformly. Add phases B, C, and D sequentially to phase A and stir until uniformly mixed. pH 7.6.

[0036] Application example 2: Cream Phase A: Thiotaine 10.00 (mass%) Butylene glycol 6.00 Glycerin 4.00 Carbomer 0.66 PEMULEN TR-2 0.24 Xanthan gum 0.08 Preservative (appropriate amount) Chelating agent (appropriate amount) Water level Phase B Arginine 0.10 Water 0.90 C phase NIKKOL VC-IP 30.00 NIKKOL Hexaglyn PR-15 0.50 KF-995 5.00 Antioxidant 0.10 Total 100.00 (Raw materials used) Thiotaine: Contains 0.045% ergothioneine, manufactured by AGI Dermatics. PEMULEN TR-2: Acrylates / C10-30 alkyl acrylate crosspolymer, manufactured by Lubrizol. NIKKOL VC-IP: Ascorbyl tetrahexyldecanoate, manufactured by Nikko Chemicals Co., Ltd. NIKKOL Hexaglyn PR-15: Polyglyceryl-6 polyricinoleate, manufactured by Nikko Chemicals Co., Ltd. KF-995: Cyclopentasiloxane, manufactured by Shin-Etsu Chemical Co., Ltd. (Preparation Method) Swell the polymer in Phase A thoroughly and mix uniformly. Add Phase B to Phase A and mix uniformly. Then, gradually add Phase C and mix thoroughly and uniformly. pH is 4.3~5.0 (10% aqueous solution) [Industrial applicability]

[0037] By suppressing porphyrin production, it becomes possible to improve acne and reduce the number of pores or hidden blemishes.

Claims

[Claim 1] An acne treatment agent that inhibits porphyrin production, characterized by containing ascorbyl tetrahexyldecanoate and ergothioneine as active ingredients, with ergothioneine present in a concentration of 0.00002 to 0.01% by mass in the topical preparation.

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