JP6725207B2 - Skin pigmentation inhibitor - Google Patents

Description

The present invention relates to a skin pigmentation inhibitor capable of suppressing pigmentation of skin spots, freckles, dullness, dark spots, liver spots, senile pigment spots and the like.

Pigmentation such as skin spots, freckles, dullness, darkening, melasma, and senile pigment spots is caused by excessive melanin formation due to UV exposure, hormonal abnormalities and physical irritation. It is known to be caused by deposits on the. Such skin pigmentation is a great cosmetic problem especially for women.

BACKGROUND ART Conventionally, the search for components that suppress skin pigmentation and produce beautiful skin has been vigorously carried out, and it is possible to suppress skin pigmentation for components such as vitamin C, vitamin C derivatives, arbutin, and chamomile extract. It has been reported. However, conventionally, components that have been reported to suppress skin pigmentation have drawbacks such as a slow and insufficient effect, insufficient stability and formulation difficulty, etc. I am not completely satisfied. Against the background of such conventional techniques, there is a strong demand for the search for new skin pigmentation inhibitors.

On the other hand, the heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, is a known drug having a moisturizing action, and is known to be compoundable in an external composition for the purpose of moisturizing (for example, Patent Document 1 reference). However, conventionally, no correlation between a moisturizing action and a skin pigmentation suppressing action has been reported, and it is not known at all that a heparin-like substance has a skin pigmentation suppressing action.

JP 2009-234957 JP

An object of the present invention is to search for a new skin pigmentation inhibitor which has not been reported so far, and to provide an external composition having an excellent skin pigmentation inhibitory action.

The present inventor has conducted earnest studies to solve the above problems, and surprisingly found that heparin-like substances have an excellent skin pigmentation-inhibiting action. Furthermore, the present inventor has also found that the combined use of a heparin-like substance and crotamiton dramatically improves the skin pigmentation-inhibiting action of the heparin-like substance. The present invention has been completed by further studies based on these findings.

That is, the present invention provides the inventions of the following modes.
Item 1. A skin pigmentation inhibitor comprising a heparin-like substance as an active ingredient.
Item 2. The skin pigmentation inhibitor according to Item 1, further comprising crotamiton as an active ingredient.
Item 3. Item 3. The skin pigmentation inhibitor according to Item 2, which contains 3 to 3500 parts by weight of crotamiton per 100 parts by weight of the heparin-like substance.
Item 4. An external composition for suppressing skin pigmentation, which comprises the skin pigmentation inhibitor according to any one of Items 1 to 3.
Item 5. Item 5. The topical composition for suppressing skin pigmentation according to Item 4, wherein the content of the heparin-like substance is 0.001 to 10% by weight.
Item 6. Item 6. The external composition for suppressing skin pigmentation according to Item 4 or 5, which is an emulsified preparation.

According to the present invention, by using a heparin-like substance as an active ingredient, it is possible to effectively suppress pigmentation such as skin spots, freckles, dullness, darkening, melasma, and senile pigment spots. Furthermore, according to the present invention, by using a heparin-like substance and crotamiton in combination, it is possible to exert a remarkably excellent effect of suppressing skin pigmentation. Therefore, it becomes possible to effectively suppress the skin pigmentation by using a novel skin pigmentation inhibitor which has never been obtained, and to bring beautiful skin.

FIG. 5 is a diagram showing the results of evaluation of the tyrosinase inhibitory action of heparin-like substances in Test Example 1. FIG. 7 is a diagram showing the results of evaluation of the pigmentation suppression effect when a cream containing a heparin-like substance is applied in Test Example 2.

The skin pigmentation inhibitor of the present invention is characterized by containing a heparin-like substance as an active ingredient. Hereinafter, the skin pigmentation inhibitor of the present invention will be described in detail.

(Active ingredient)
The skin pigmentation inhibitor of the present invention uses a heparin-like substance as an active ingredient. The heparin-like substance is a polysulfated mucopolysaccharide such as chondroitin polysulfate, which is a known drug known to have a moisturizing action and a blood flow increasing action.

The origin of the heparin-like substance used in the present invention is not particularly limited, but examples thereof include those obtained by polysulfating mucopolysaccharides, edible animal tissues (for example, lung containing bovine tracheal cartilage). ) And the like. In the skin pigmentation inhibitor of the present invention, as a heparin-like substance, a heparin-like substance included in the Japanese Pharmacopoeia Standards is preferably used.

The skin pigmentation inhibitor of the present invention may be used as an active ingredient in combination with clotamiton together with the heparin-like substance. Thus, by using the heparin-like substance and crotamiton in combination, it becomes possible to more effectively exert the skin pigmentation suppressing action.

Crotamiton is also called N-ethyl-N-(2-methylphenyl)-2-butenamide, N-ethyl-No-tolyl-2-butenamide, etc., and is used as an antipruritic agent and a therapeutic agent for scabies. It is a known drug.

In the skin pigmentation inhibitor of the present invention, when a heparin-like substance and crotamiton are used in combination as an active ingredient, the ratio thereof is not particularly limited, but, for example, crotamiton is 3 to 3500 per 100 parts by weight of the heparin-like substance. Parts by weight, preferably 30 to 3500 parts by weight, more preferably 30 to 2000 parts by weight.

(Usage mode)
The skin pigmentation inhibitor of the present invention is used by adding it to an external composition such as an external drug for skin, cosmetics, and a skin cleanser for the purpose of imparting a skin pigmentation inhibitory action.

The content of the skin pigmentation inhibitor of the present invention in the composition for external use is not particularly limited, but for example, the content of the heparin-like substance is 0.01 to 1% by weight, preferably 0.01 to 0.5% by weight. %, and more preferably 0.05 to 0.5% by weight. When the skin pigmentation inhibitor of the present invention contains crotamiton, the content of crotamiton in the composition for external use is, for example, 0.01 to 10% by weight, preferably 0.1 to 10% by weight, and further preferably Is 1 to 5% by weight.

(Components that can be blended in the composition for external use)
The topical composition for external use containing the skin pigmentation inhibitor of the present invention may contain other pharmacological components, if necessary, in addition to the skin pigmentation inhibitor. Such pharmacological components include, for example, antihistamines (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), local anesthetics (lidocaine, dibucaine, methyl aminobenzoate, procaine, tetracaine, bupipacaine, mepipacaine, chloroprocaine. , Proparacaine, meprilukaine or salts thereof, orthocaine, oxesazein, oxypolyentoxydecane, funnel extract, percaminpase, tesitdecitin, etc., anti-inflammatory agents (allantoin, glycyrrhizic acid methyl, glycyrrhizinate stearyl, dipotassium glycyrrhizinate, diglycyrrhizinate, glycyrrhizinate) Monoammonium, glycyrrhetinic acid, pyridoxine glycyrrhetinic acid, stearyl glycyrrhetinic acid, glyceryl glycyrrhetinic acid, monoglucuronide glycyrrhetinic acid, salicylic acid, methyl salicylate, glycol salicylate, indomethacin, felbinac, diclofenac sodium, loxoprofen sodium, ufenaphenol, daufenfen, ibuprofen Zac, suprofen, bufexamac, etc., fungicides (benzalkonium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, aqueous ammonia, sulfadiazine, lactic acid, phenol) Etc.), skin protectants (colodion, castor oil, etc.), blood circulation promoters (nonyl acid vanillyl amide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), cooling agents (menthol, camphor, etc.), vitamins (vitamin A, B, C, D, etc.), mucopolysaccharides (sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.) and the like.

Moreover, the external composition containing the skin pigmentation inhibitor of the present invention may contain a base or an additive, if necessary, in order to obtain a desired formulation form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable. For example, water, lower alcohol (ethanol, isopropanol, etc.), polyhydric alcohol (glycerin, propylene glycol, dipropylene) Aqueous bases such as glycol, 1,3-butylene glycol, etc.; oils (olive oil, safflower oil, soybean oil, camellia oil, corn oil, rapeseed oil, sunflower oil, cottonseed oil, peanut oil, lard, squalane, fish oil, etc. ), mineral oil (liquid paraffin, paraffin, gelled hydrocarbon, petrolatum, etc.), waxes and waxes (beeswax, carnauba wax, candelilla wax, ceresin, rice wax, microcrystalline wax, etc.), ester oil (isopropyl myristate) , Isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, glyceryl tri-2-ethylhexanoate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, Behenic acid, linoleic acid, lanolin, etc.), fatty acid esters (cetyl palmitate, isopropyl palmitate, ethyl linoleate, etc.), medium-chain fatty acid triglycerides, higher alcohols (stearyl alcohol, cetanol, behenyl alcohol, myristyl alcohol, oleyl alcohol, hexadecyl) Alcohol, lanolin alcohol, cholesterol, dihydrocholesterol, phytosterol, lauryl alcohol, cetostearyl alcohol, linoleyl alcohol, octyldodecanol, hexyldecanol, isostearyl alcohol, etc., cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic) Oily base such as silicone; POE (10 to 50 mol) phytosterol ether, POE (10 to 50 mol) dihydrocholesterol ether, POE (10 to 50 mol) 2-octyldodecyl ether, POE (10 to 50 mol) Decyl tetradecyl ether, POE (10 to 50 mol) oleyl ether, POE (2 to 50 mol) cetyl ether, POE (5 to 50 mol) behenyl ether, POE (5 to 30 mol) polyoxypropylene (5 to 30 mol) ) Polydecyl ether such as 2-decyl tetradecyl ether, POE (10 to 50 mol) polyoxypropylene (2 to 30 mol) cetyl ether Alkyl ethers, phosphoric acid/phosphate salts thereof (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monooleate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 Mol) glyceryl monoisostearate, POE (10 to 30 mol) glyceryl monostearate, POE (20 to 100 mol)/polyoxypropylene-modified silicone, POE/alkyl-modified silicone, polyethylene glycol monolaurate, polyethylene glycol monopalmitate , Polyethylene glycol monostearate, polyethylene glycol dilaurate, polyethylene glycol dipalmitate, polyethylene glycol distearate, polyethylene glycol dioleate, polyethylene glycol diricinoleate, polyoxyethylene hydrogenated castor oil (5-100), polysorbate (20- 85), glycerin fatty acid esters (glycerin monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohols, and other surfactants; cooling agents (menthol, camphor, borneol, peppermint water, peppermint oil, etc.), preservatives. (Methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agent (citral, 1,8-cioneal, citronellal, farnesol, etc.), coloring agent (tar dye (brown 201, blue 201, (Yellow No. 4, Yellow No. 403, etc.), cacao dye, chlorophyll, aluminum oxide, etc.), thickener (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjustment Agents (phosphoric acid, hydrochloric acid, citric acid, sodium citrate, succinic acid, tartaric acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl-pyrrolidonecarboxylate sodium liquid, D- Sorbitol liquid, macrogol, etc., stabilizers (dibutylhydroxytoluene, butylhydroxyanisole, sodium edetate, sodium metaphosphate, L-arginine, L-aspartic acid, DL-alanine, glycine, sodium erythorbate, propyl gallate , Sodium sulfite, sulfur dioxide, chlorogenic acid, catechin, rosemary extract, etc.), antioxidant, UV absorber Examples include additives such as scavengers, chelating agents, adhesives, buffers, solubilizers, solubilizers, preservatives and the like.

(Use/formulation of external composition)
The composition for external use containing the skin pigmentation inhibitor of the present invention is used as a skin external preparation for a skin site where suppression of pigmentation (prevention, improvement, etc.) is required, and is used for whitening and the like. The skin pigmentation inhibitor of the present invention and the type of skin pigmentation to be suppressed of the external composition is not particularly limited, for example, skin spots, freckles, dullness, melasma, senile pigment spots, physical. Such as darkening due to physical stimulation.

The composition for external use is not particularly limited as to the formulation form as long as it has a dosage form that can be applied transdermally, and may be liquid, solid, semisolid (cream, gel, ointment, paste) or the like. It may be either. Further, the external composition may be an emulsified preparation such as an oil-in-water emulsified preparation, a water-in-oil emulsified preparation, or a non-emulsified preparation such as an aqueous preparation and an oil-based preparation.

As a dosage form of the external composition, an emulsion preparation is preferable, and a cream-like emulsion preparation is more preferable, from the viewpoint of more effectively exhibiting the pigmentation suppressing effect.

Further, the external composition may be in any form of preparation such as external skin drug, cosmetic, and skin cleanser as long as it is applied to the skin.

As a formulation form of the external composition, specifically, a skin external drug such as a cream, lotion, gel, emulsion, liquid, patch, patch, liniment, aerosol, ointment, pack or the like. Cosmetics such as ointments, creams, emulsions, lotions, lotions, packs and gels; skin cleansing agents such as body shampoos, hair shampoos and rinses. Among these dosage forms, skin external medicines are preferable, and creams are more preferable.

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.

Test Example 1: Evaluation of Pigmentation Inhibitory Action 0.5% Triton X-100-containing phosphate buffer (100 mM, pH 6.8) was added so that normal human melanocytes had a concentration of 6.0×10 ⁵ cells/mL. Was added to and dissolved, and this was used as a tyrosinase crude enzyme solution. Further, 0.025% L-3,4-dihydroxyphenylalanine (DOPA) was dissolved in a phosphate buffer to prepare a substrate solution. Furthermore, heparin-like substances were dissolved in phosphate buffer at various concentrations (n=5 or 6) to prepare test sample solutions (n=5 or 6; concentration three times the final treatment concentration). 50 μL of each of the crude tyrosinase enzyme solution, the substrate solution, and the test sample solution was dispensed into a 96-well plate and mixed. The mixed solution of the crude enzyme, the substrate and the test sample was reacted at 37° C. for 2 hours, and the amount of DOPA-melanin produced was quantified by measuring the absorbance at 405 nm. At the same time, the amount of protein in the crude enzyme solution was quantified and the value obtained by dividing the amount of DOPA-melanin by the amount of protein and the reaction time was used as an index of tyrosinase activity. Each tyrosinase activity was tested for significance by Student t test. As a control, the test was conducted under the same conditions as above except that the heparin-like substance was not added to the test sample solution.

The obtained results are shown in FIG. From this result, it was confirmed that the heparin-like substance can inhibit the tyrosinase activity in a concentration-dependent manner, and it became clear that the heparin-like substance has a pigmentation-inhibiting action.

Test Example 2: Evaluation of pigmentation-inhibiting action An oil-in-water cream having the composition shown in Table 1 was prepared according to a conventional method.

The effect of suppressing pigmentation induced by tape stripping was evaluated for each oil-in-water cream according to the following method. The test subject's lower arm (approx. 1.5 cm×1.5 cm square) (test site) was subjected to an operation of sticking and removing the adhesive tape at 5 places 30 times or more to induce pigmentation at the test site. The number of tape stripping operations was adjusted so that the degree of pigmentation induction was the same at the five test sites. Then, each oil-in-water cream was applied to each test site in an amount of about 0.1 g each time at a frequency of 3 times a day for 8 days. One day, four days, and eight days after the application of the cream, the melanin value at each test site was measured with a multiprobe adapter MPA6 (Courage+Khazaka). The melanin value measured by the multi-probe adapter MPA6 reflects the amount of melanin deposited on the skin, and the higher the value, the greater the amount of melanin deposited on the skin. Since the melanin value also varies from day to day at the same site in healthy skin, the melanin value measured to correct the variation was divided by the melanin value at the healthy site on the same day.

Next, the relative value of the melanin value 4 days and 8 days after the application of the cream was calculated with the corrected melanin value 1 day after the application of the cream as 100%. In this test, as a control, the melanin value of the test site where the cream was not applied to the test site was also measured in the same manner.

The obtained results are shown in FIG. From these results, the creams containing heparin-like substances (Examples 1 to 4) were able to suppress the deposition of melanin compared to the control, and the heparin-like substances may have an excellent skin pigmentation suppressing action. It became clear. In addition, it is also clear that the creams containing crotamiton together with the heparin-like substance (Examples 3 and 4) have dramatically improved skin pigmentation-inhibiting effect as compared with the case where the heparin-like substance is used alone. became.

Formulation Example The oil-in-water cream shown in Table 2, the water-in-oil cream shown in Table 3, the hydrophilic ointment shown in Table 4, and the lotion shown in Table 5 were prepared according to a conventional method. When these preparations were evaluated for their skin pigmentation-inhibiting effect in the same manner as in Test Example 2, all of them showed an excellent skin pigmentation-inhibiting effect.

Claims (6)

A skin pigmentation inhibitor for darkening caused by physical stimuli other than trauma, heat, cold, ultraviolet rays, radiation, and electricity, which comprises heparin-like substances and crotamiton as active ingredients. The skin pigmentation inhibitor according to claim 1, which contains 3 to 3500 parts by weight of crotamiton per 100 parts by weight of the heparin-like substance. An external composition for suppressing skin pigmentation, comprising the skin pigmentation inhibitor according to claim 1 or 2 . The external composition for suppressing skin pigmentation according to claim 3 , wherein the content of the heparin-like substance is 0.001 to 10% by weight. The external composition for suppressing skin pigmentation according to claim 3 , wherein the content of the heparin-like substance is 0.1 to 10% by weight. It is emulsified formulation claims 3 to an external composition for skin pigmentation inhibition according to any one of the 5.