JP7001356B2 - Skin pigmentation inhibitor - Google Patents

Description

The present invention relates to a skin pigmentation inhibitor capable of suppressing pigmentation such as skin spots, freckles, dullness, darkening, chloasma, and senile pigmented spots.

Pigmentation of skin spots, freckles, dullness, darkening, chloasma, senile pigmented spots, etc. causes excessive formation of melanin in the skin due to UV exposure, hormonal abnormalities, physical irritation, etc. It is known to be caused by deposition in. Such skin pigmentation is a major cosmetic concern, especially for women.

Conventionally, the search for components that suppress skin pigmentation and bring about beautiful skin has been vigorously conducted, and components such as vitamin C, vitamin C derivatives, arbutin, and chamomile extract can suppress skin pigmentation. It has been reported. However, the components that have been reported to have an inhibitory effect on skin pigmentation have drawbacks such as slow effect and insufficient effect, insufficient stability and difficulty in formulation, which do not necessarily meet consumer needs. Not quite satisfactory. Against the background of such conventional techniques, the search for new skin pigmentation inhibitors is eagerly desired.

On the other hand, lidocaine and its salts are the most used local anesthetics in the world, and are known drugs used in various sites because of their rapid onset of action. It is known that it can be added to an external cream or tape for the purpose of local anesthesia (see, for example, Patent Documents 1 and 2). However, conventionally, no correlation between the local anesthetic effect and the skin pigmentation inhibitory effect has been reported, and it is not known at all that lidocaine and its salt have a skin pigmentation inhibitory effect.

In addition, prednisolone and its derivatives are known as external corticosteroids. In particular, it is known that prednisolone valeric acid ester acetate shows an excellent effect on the affected part of the skin surface, and when it is absorbed into the body, it decomposes into a substance having a weak action and can reduce side effects. Therefore, conventionally, prednisolone and its derivatives have been used in combination with an external cream for the purpose of preventing itching and treating eczema (see, for example, Patent Document 3). On the other hand, it has been reported that prednisolone valeric acid ester acetate has an effect of increasing melanin production and does not have an effect of suppressing increased pigmentation (see Patent Document 4).

Japanese Unexamined Patent Publication No. 7-291856 Japanese Unexamined Patent Publication No. 2005-23907. Japanese Unexamined Patent Publication No. 2007-277194 Japanese Unexamined Patent Publication No. 2011-178777

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

As a result of diligent studies to solve the above problems, the present inventor has surprisingly found that lidocaine and / or a salt thereof has an excellent skin pigmentation inhibitory effect. Furthermore, the present inventor has also found that the combined use of lidocaine and / or a salt thereof with prednisolone and / or a derivative thereof dramatically improves the skin pigmentation inhibitory effect of lidocaine and / or a salt thereof. rice field. The present invention has been completed by further studies based on these findings.

That is, the present invention provides the inventions of the following aspects.
Item 1. A skin pigmentation inhibitor comprising lidocaine and at least one lidocaine selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof.
Item 2. Item 2. The skin pigmentation inhibitor according to Item 1, further comprising at least one prednisolone selected from the group consisting of prednisolone and a pharmaceutically acceptable derivative thereof.
Item 3. Item 2. The skin pigmentation inhibitor according to Item 2, wherein the prednisolones are prednisolone valeric acid ester acetate.
Item 4. Item 2. The skin pigmentation inhibitor according to Item 2 or 3, which contains 0.1 to 100,000 parts by weight of prednisolone per 100 parts by weight of the lidocaines.
Item 5. An external composition for suppressing skin pigmentation, which comprises the skin pigmentation inhibitor according to any one of Items 1 to 4.
Item 6. Item 5. The external composition for suppressing skin pigmentation according to Item 5, which is an emulsified preparation.

According to the present invention, the use of lidocaine and / or a salt thereof can effectively suppress pigmentation of skin spots, freckles, dullness, darkening, chloasma, senile pigment spots and the like. Furthermore, according to the present invention, by using prednisolone and / or a derivative thereof in combination with lidocaine and / or a salt thereof, a remarkably excellent skin pigmentation inhibitory effect can be exhibited. Therefore, a new skin pigmentation inhibitor, which has never existed before, can effectively suppress skin pigmentation and bring about beautiful skin.

It is a figure which shows the result of having evaluated the tyrosinase inhibitory action by lidocaine alone, and the combined use of lidocaine and prednisolone valeric acid ester acetate in Test Example 1. It is a figure which shows the result of having evaluated the pigmentation suppressing effect of each cream agent in Test Example 2.

The skin pigmentation inhibitor of the present invention is characterized by containing at least one lidocaine selected from the group consisting of lidocaine and a pharmaceutically acceptable salt thereof. Hereinafter, the skin pigmentation inhibitor of the present invention will be described in detail.

(Ingredients to be used)
The skin pigmentation inhibitor of the present invention contains lidocaine and / or a salt thereof.

Lidocaine is a known drug known to have a local anesthetic effect and is also referred to as xylocaine. The salt of lidocaine is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include inorganic acid salts such as hydrochloride.

In the skin pigmentation inhibitor of the present invention, one of lidocaine and a salt thereof may be selected and used alone, or two or more thereof may be used in combination. Among lidocaine and salts thereof, lidocaine and lidocaine hydrochloride are preferably mentioned.

In addition, the skin pigmentation inhibitor of the present invention may be used in combination with the lidocaines at least one prednisolone selected from the group consisting of prednisolone and pharmaceutically acceptable derivatives thereof. As described above, by using lidocaines and prednisolone in combination, it becomes possible to exert a skin pigmentation inhibitory effect even more effectively.

Prednisolone is a known drug as an external corticosteroid. Further, the derivative of prednisolone is not particularly limited as long as it is pharmaceutically acceptable, but for example, prednisolone such as prednisolone valerate acetate, prednisolone acetate, prednisolone succinate and mono or dicarboxylic acid ( Examples thereof include an ester form having 2 to 7 carbon atoms; methylprednisolone; an ester form of methylprednisolone such as methylprednisolone acetate and methylprednisolone succinate and a mono or dicarboxylic acid (2 to 7 carbon atoms).

Among the prednisolones, preferably prednisolone, an ester of prednisolone and mono or dicarboxylic acid (2 to 7 carbon atoms), more preferably an ester of prednisolone and mono or dicarboxylic acid (2 to 7 carbon atoms), particularly preferable. Examples include prednisolone valerate acid ester acetate.

In the skin pigmentation inhibitor of the present invention, one compound may be selected from prednisolone and / or a derivative thereof and used alone, or two or more compounds may be used in combination. ..

When lidocaine and prednisolone are used in combination in the skin pigmentation inhibitor of the present invention, the ratio thereof is not particularly limited, but for example, per 100 parts by weight of lidocaine, the total amount of prednisolone is 0. Examples thereof include 1 to 100,000 parts by weight, preferably 0.625 to 10000 parts by weight, and more preferably 1 to 500 parts by weight.

(Usage mode)
The skin pigmentation inhibitor of the present invention is used by adding it to an external composition such as a skin external medicine, a cosmetic, a skin cleaning agent, etc. for the purpose of imparting a skin pigmentation inhibitory action.

The content of the skin pigmentation inhibitor of the present invention in the external composition is not particularly limited, but for example, the content of lidocaines is 0.01 to 10% by weight, preferably 0.1 to 8% by weight, and further. Preferably, it is 1 to 5% by weight. When the skin pigmentation inhibitor of the present invention contains prednisolone, the content of the prednisolone in the external composition is, for example, 0.01 to 10% by weight, preferably 0.05 to 10% by weight. More preferably, 0.05 to 5% by weight is mentioned.

(Ingredients that can be added to external compositions)
The external composition containing the skin pigmentation inhibitor of the present invention may contain other pharmacological components in addition to the skin pigmentation inhibitor, if necessary. Examples of such pharmacological components include antipruritic agents (diphenhydramine, diphenhydramine hydrochloride, chlorpheniramine maleate, crotamiton, etc.) and local anesthetics (dibucaine, methyl aminobenzoate, prokine, tetrakine, bupipacain, mepipacane, chloro). Prokine, proparakine, meprilkine or salts thereof, orthokine, oxesazein, oxypolyentoxydecane, funnel extract, percuminpase, tesitdecitin, etc.), anti-inflammatory agents (alantin, glycyrrhizinic acid, methyl glycyrrhizinate, stearyl glycyrrhizinate, dipotassium glycyrrhizinate, stearyl glycyrrhizinate, etc. Monoammonium acid, glycyrrhetinic acid, pyridoxin glycyrrhetinate, stearyl glycyrrhetinate, glyceryl glycyrrhetinate, monoglucuronide glycyrrhetinate, salicylic acid, methyl salicylate, glycol salicylate, indomethacin, fervinac, diclofenac sodium, loxoprofen sodium, ufenamate Vendazac, sprofene, bufexamac, etc.), bactericides (benzalconium chloride, decalinium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine chloride, chlorhexidine gluconate, isopropylmethylphenol, aqueous ammonia, sulfaziazine, lactic acid, Phenol, etc.), skin protectant (corodion, castor oil, etc.), blood circulation promoter (nonyl acid vanillylamide, nicotinic acid benzyl ester, capsaicin, capsicum extract, etc.), refreshing agent (menthol, camphor, etc.), vitamins (vitamin A) , B, C, D, etc.), mucopolysaccharides (hepalin-like substances, sodium chondroitin sulfate, glucosamine, hyaluronic acid, etc.) and the like.

In addition, 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 pharmaceutical form. Such bases and additives are not particularly limited as long as they are pharmaceutically acceptable, but for example, water, lower alcohols (ethanol, isopropanol, etc.), polyhydric alcohols (glycerin, propylene glycol, dipropylene, etc.) Aqueous bases such as glycols, 1,3-butylene glycols, etc .; oils (olive oil, saflower 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, vaseline, etc.), waxes / waxes (mitsurou, carnauba wax, candelilla wax, selecin, rice wax, microcrystallin wax, etc.), ester oil (isopropyl myristate, etc.) , Isopropyl adipate, diethyl sebacate, isopropyl sebacate, isopropyl palmitate, cetyl palmitate, ethyl oleate, glyceryl tri2-ethylhexanoate, etc.), fatty acid alkyl esters, fatty acids (stearic acid, oleic acid, palmitic acid, etc.) 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, linoleil alcohol, octyldodecanol, hexyldecanol, isostearyl alcohol, etc.), cetyl 2-ethylhexanoate, silicone oil (dimethylpolysiloxane, cyclic) Oil-based bases such as (silicone, etc.); 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) Decyltetradecyl ether, POE (10-50 mol) oleyl ether, POE (2-50 mol) cetyl ether, POE (5-50 mol) behenyl ether, POE (5-30 mol) polyoxypropylene (5-30 mol) ) 2-Deciltetradecyl ether, POE (10-50 mol) Polyoxypropylene (2-30 mol) Polyoxyethylene alcohols such as cetyl ether Lucil ether, these phosphates and phosphates (POE cetyl ether sodium phosphate, etc.), POE (20-60 mol) sorbitan monoolate, POE (10-60 mol) sorbitan monoisostearate, POE (10-80 mol) Mol) Glyceryl monoisostearate, POE (10-30 mol) Glyceryl monostearate, POE (20-100 mol) / polyoxypropylene-modified silicone, POE / alkyl-modified silicone, monolaurate polyethylene glycol, monopalmitate polyethylene glycol , Monostearate Polyethylene Glycol, Dilaurate Polyethylene Glycol, Dipalmitate Polyethylene Glycol, Distearate Polyethylene Glycol, Dioleate Polyethylene Glycol, Diricinoleate Polyethylene Glycol, Polyoxyethylene Hardened Himasi Oil (5-100), Polysorbate (20- 85), Surfactants such as glycerin fatty acid esters (glycerin monostearate, etc.), hydrogenated soybean phospholipids, hydrogenated lanolin alcohol, etc .; (Methylparaben, propylparaben, benzoic acid, sodium benzoate, sorbic acid, etc.), flavoring agents (citral, 1,8-sionel, citronyl, farnesol, etc.), coloring agents (tar pigments (brown 201, blue 201, etc.) Yellow No. 4, Yellow No. 403, etc.), cocoa pigment, chlorophyll, aluminum oxide, etc.), viscous agent (carboxyvinyl polymer, hypromellose, polyvinylpyrrolidone, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, xanthan gum, carrageenan, etc.), pH adjustment Agents (phosphate, hydrochloric acid, citrate, sodium citrate, succinic acid, tartrate acid, sodium hydroxide, potassium hydroxide, triethanolamine, triisopropanolamine, etc.), wetting agents (dl-sodium pyrrolidone carboxylate, D- Sorbitol solution, 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 absorption Examples thereof include additives such as a collector, a chelating agent, a pressure-sensitive adhesive, a buffering agent, a solubilizing agent, a solubilizing agent, and a preservative.

(Use of external composition / formulation form)
The external composition containing the skin pigmentation inhibitor of the present invention is applied as a skin external agent to a skin site where suppression (prevention, improvement, etc.) of pigmentation is required, and is used for whitening and the like. The type of skin pigmentation to be suppressed by the skin pigmentation inhibitor of the present invention and the external composition is not particularly limited, but for example, skin stains, freckles, dullness, chloasma, senile pigmentation, and physics. Examples include darkening due to stimulus.

The pharmaceutical composition is not particularly limited as long as it is a dosage form that can be applied transdermally, and may be liquid, solid, semi-solid (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 or a water-in-oil emulsified preparation, or may be a non-emulsifying preparation such as an aqueous preparation or an oil-based preparation.

Examples of the dosage form of the external composition include an emulsified preparation, and more preferably a creamy emulsified preparation, from the viewpoint of exerting a pigmentation-suppressing action more effectively.

In addition, the external composition may be in any form of a pharmaceutical product for external use on the skin, a cosmetic, a skin cleansing agent, etc., as long as it is applied to the skin.

Specific examples of the formulation form of the external composition include skin external medicines such as creams, lotions, gels, emulsions, liquids, paps, patches, liniments, aerosols, ointments, and packs. Cosmetics such as ointments, creams, milky lotions, lotions, lotions, packs and gels; skin cleaning agents such as body shampoos, hair shampoos and rinses. Among these pharmaceutical forms, a pharmaceutical product for external use on the skin is preferable, and a cream preparation is more preferable.

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

Test Example 1: Measurement of tyrosinase activity inhibitory effect
<Preparation of enzyme and substrate solution>
Tyrosinase (derived from mushrooms, manufactured by Sigma) was prepared to 55 units / ml using 20% ethanol 1/15 M phosphate buffer (pH 7.2) and used as an enzyme solution. In addition, L-DOPA (3,4-dihydroxy-L-phenylalanine, manufactured by Sigma) was prepared to be 0.61 mM using 20% ethanol 1/15 M phosphate buffer, and used as a substrate solution.

<Preparation of test solution>
Lidokine was dissolved in 100% ethanol, diluted with 1/15 M phosphate buffer immediately prior to reaction with the enzyme solution, and finally in the well 1.32 mg / ml, 5.32 mg / ml, 8.00 mg / ml, 13.32. It was prepared to be mg / ml and used as a test solution. Similarly, prednisolone valerate acetate acetic acid ester, which was dissolved in 100% ethanol, was diluted with 1/15 M phosphate buffer immediately before the reaction with the enzyme solution, and finally 0.40 mg / ml in the well. It was prepared as a test solution. In addition, for the case where lidocaine and prednisolone valerate acetate were mixed, a test solution having twice the concentration was also prepared.

<Measurement of inhibitory activity>
After adding the test solution to a 96-well plate at 50 μl / well, the enzyme solution was added to 50 μl / well, and the mixture was incubated at 37 ° C. for 10 minutes. Then, the substrate solution was added to 100 μl / well, and the mixture was further incubated at 37 ° C. for 10 minutes, and the absorbance at a wavelength of 475 nm was measured. As the test solution Blank, 100 μl of 20% ethanol 1/15 M phosphate buffer was added in place of the substrate solution, and measurement was performed. The evaluation when lidocaine and prednisolone valerate acetate were mixed was measured by adding 25 μl / well of the test solution prepared at double the concentration.

As a control solution, 20% ethanol 1/15 M phosphate buffer was added to a 96-well plate at 50 μl / well instead of the test solution, then the enzyme solution was added to 50 μl / well, and the temperature was 37 ° C. 10 Incubation was performed for 1 minute. Then, the substrate solution was added to 100 μl / well, and the mixture was further incubated at 37 ° C. for 10 minutes, and the absorbance at a wavelength of 475 nm was measured. As a control solution blank, 100 μl of 20% ethanol 1/15 M phosphate buffer was added in place of the substrate solution, and measurement was performed.

The tyrosinase activity inhibition rate (%) was calculated according to the following formula 1 based on the measured value of the absorbance at a wavelength of 475 nm.

<Result>
The obtained results are shown in Table 1 and FIG. From this result, it was confirmed that lidocaine can inhibit tyrosinase activity in a concentration-dependent manner, and it was clarified that lidocaine can be used as a skin pigmentation inhibitor (Examples 1 to 4). It is also known that prednisolone valeric acid ester acetate does not have an inhibitory effect on skin pigmentation, but it has also been clarified that the combined use with lidocaine can dramatically enhance the tyrosinase activity inhibitory effect of lidocaine (). Examples 5-8).

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

For each oil-in-water cream, the effect of suppressing pigmentation induced by tape stripping was evaluated according to the following method. Adhesive tape was applied and peeled off at 5 locations on the lower arm of the subject (approximately 1.5 cm x 1.5 cm square) (test site) 50 times to induce pigmentation on the test site. Then, each oil-in-water cream was applied to each test site in an amount of about 0.1 g at a time, 3 times a day for 8 days. One day, four days, and seven days after application of the cream, the melanin level at each test site was measured with a multi-probe adapter MPA6 (Courage-Khazaka Electronic, manufactured by Koln). In addition, in this test, as a control, the melanin level of the test site where the cream was not applied was also measured in the same manner. The melanin value measured by the multi-probe adapter MPA6 reflects the amount of melanin deposited on the skin, and the larger the value, the larger the amount of melanin deposited on the skin.

Next, the amount of change in the melanin value at each test site when the melanin value before application of the cream was used as a reference was calculated. In this test, as a control, the melanin level of the test site where the cream was not applied was also measured in the same manner.

The obtained results are shown in Table 3 and FIG. From this result, the cream agent containing lidocaine (Examples 9 to 11) had a smaller amount of change in melanin than the cream containing no control or lidocaine (Comparative Example 1), and the deposition of melanin could be suppressed. Was found to have an excellent skin pigmentation inhibitory effect. Further, in the cream agent containing prednisolone valeric acid ester acetic acid ester together with lidocaine (Example 11), the skin pigmentation inhibitory effect is dramatically improved as compared with the case where lidocaine is used alone (Examples 1 and 2). It became clear that they were doing it.

Claims (6)

A skin pigmentation inhibitor containing at least one lidocaine selected from the group consisting of lidocaine and its pharmaceutically acceptable salts (provided;
(A): (a1) The nitroimidazole compound represented by the following formula (I), or a pharmaceutically acceptable salt, ester, ether, carbamoyloxy compound, or amide (R ¹ and R ² are the same or amides thereof). Differently, one or more substitutions selected from the group consisting of halogen atoms, hydroxyl groups, amino groups, aryl groups, heteroaryl groups, cycloalkyl groups and linear or branched alkoxy groups having 1 to 6 carbon atoms. Indicates a linear or branched alkyl group having 1 to 6 carbon atoms, which may be substituted with a group), or
(A2) The nitroimidazole compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (in the formula, R ¹ and R ² are independently hydroxyl groups, benzyl groups, phenyl groups and cycloalkyl groups, respectively ). Indicates a linear or branched alkyl group or alkyl alcohol group which may have an ether group and / or an amino group).

And when;
(B): When containing liranaftate and / or a pharmaceutically acceptable salt thereof;
(C): Except for tinctures containing 10 ml of phenolic acid, 0.8 to 1.2 g of patina, 0.8 to 1.2 g of natural ammonium chloride, and 0.1 to 0.4 g of lidocaine) . The skin pigmentation inhibitor according to claim 1, further comprising at least one prednisolone selected from the group consisting of prednisolone and a pharmaceutically acceptable derivative thereof. The skin pigmentation inhibitor according to claim 2, wherein the prednisolones are prednisolone valeric acid ester acetate. The skin pigmentation inhibitor according to claim 2 or 3, which contains 0.1 to 100,000 parts by weight of prednisolone per 100 parts by weight of the lidocaines. An external composition for suppressing skin pigmentation, which comprises the skin pigmentation inhibitor according to any one of claims 1 to 4. The external composition for suppressing skin pigmentation according to claim 5, which is an emulsified preparation.

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