JP2002114626A - Bleaching agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an agent capable of promoting bleaching by applying onto the skin suffered from pigmentation by UV rays. SOLUTION: This bleaching agent contains a compound expressed by formula 1 (wherein R1 and R2 are the same or different and express H or methyl) or its pharmaceutically acceptable salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a whitening agent used for the purpose of a lightening effect on pigmented skin due to sunburn, and more particularly to a formula (I)

Embedded image (Wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom or a methyl group) or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Sunburn includes sunburn, which is a kind of burn that causes inflammation and erythema on the skin, and suntan, which increases and deposits melanin pigment on the skin. These are known as two distinct reactions that UV light causes to the skin. Of these, suntan occurs in very shallow parts of the skin, which darkens the skin in appearance. When light, the suntan usually fades in a few months and the skin returns to its original color, but the pigments deposited do not disappear easily and the skin often does not fade easily. In addition, although recovery from the suntan is generally fast in young people, it tends to be slow with age and the stains and the like tend to remain, so it is particularly important to deal with the suntan from the viewpoint of beauty.

[0003] The most effective way to prevent suntan is to reduce exposure to ultraviolet rays by using a sunshade, dark clothing, etc., and to prevent sunburn with the ability to block ultraviolet rays or to prevent the formation of melanin pigments. It is also possible to some extent by applying a sufficient amount of cream or the like to the exposed part of the skin. However, in many cases, sunshades cannot completely shield from scattered light, and even when wearing clothes, the exposed skin portion is exposed to ultraviolet rays. Also, UV protection creams cannot block 100% of UV rays. For this reason, it is practically difficult to completely prevent suntan by these daily means.

[0004] In particular, from the viewpoint of beauty, not only prevention of suntan but also means for lightening the skin once the suntan has occurred is required. A variety of products that claim skin lightening are commercially available as cosmetics, except for those that form a layer of a composition containing white or light-colored pigments on the skin surface and make the skin look white, melanin. There is no known product that has been widely recognized as a product having a satisfactory effect that is intended to help restore the original skin color by lightening the skin itself by decolorization of the pigment itself.
Other than cosmetics, there is no known product that can promote the lightening of the skin caused by suntan.

[0005]

In such a background, the present invention provides a method for reducing the color of a skin by administering it by internal administration, injection or application when the skin is exposed to ultraviolet rays and causes pigmentation. It is intended to provide a drug that can be promoted.

[0006]

As a system for evaluating the effect of a drug on skin pigmentation due to ultraviolet rays, pigmentation caused by irradiating guinea pigs with ultraviolet rays is used as an index, and a drug is applied to the index to increase or decrease the pigmentation. A model for evaluating is known. The present inventors evaluated various compounds using this model. As a result, the formula (I)

Embedded image (Wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom or a methyl group) or a pharmaceutically acceptable salt thereof promotes the lightening of pigmented skin. The present invention has been completed by adding headings and further studies.

That is, the present invention provides a compound of the formula (I)

Embedded image Wherein R ₁ and R ₂ are the same or different and represent a hydrogen atom or a methyl group. Or a pharmaceutically acceptable salt thereof. I do.

The compound represented by the above formula (I) is as follows: (a) L-ascorbic acid, DL-α-tocopherol phosphate diester (that is, in the formula (I), R ₁ = R ₂ =
Methyl group), (b) L-ascorbic acid, DL-β-tocopherol phosphate diester (that is, R ₁ = methyl group, R ₂ = hydrogen atom in formula (I)), (c) L-ascorbic acid, DL -Γ-tocopherol phosphate diester (that is, R ₁ = hydrogen atom, R ₂ = methyl group in formula (I)), (d) L-ascorbic acid, DL-δ-tocopherol phosphate diester (ie, formula (I) ) In R ₁
= R ₂ = hydrogen atom), and all of these compounds have the same activity and can be used for the purpose of the present invention. Among these, L-ascorbic acid and DL-α-tocopherol phosphate diester are particularly advantageous in terms of handling since they have already been used in other applications. Among the pharmaceutically acceptable salts of the compound represented by the formula (I), particularly preferable examples include a sodium salt, a potassium salt, a magnesium salt and a calcium salt.

[0009] The whitening agent of the present invention includes tablets, granules, powders,
It may be in the form of a capsule or other preparation for internal use or injection, or may be in the form of an external preparation. The external preparation mentioned here includes pharmaceuticals and cosmetics. Preferred examples of such external preparations are aqueous solutions such as lotions, emulsions, creams or ointments.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, the term "whitening agent" refers to a composition having a function of promoting lightening of skin darkened by melanin pigmentation. “External use” broadly refers to a form that is applied directly to the skin surface.

[0011] In the present specification, "aqueous liquid preparation"
A liquid preparation prepared by using water as a main medium is broadly used, and includes a liquid form such as a lotion and the like which is taken by hand and applied to the skin, and a liquid form which is sprayed on the skin. As long as the main part of the medium is water, the medium may contain other solvents miscible with water, for example, ethanol, glycerol and the like.

Various actions and uses of the compound of the formula (I) or a pharmaceutically acceptable salt thereof have been known. That is, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is an anti-cataract [JP-B 2-44478].
No.], prevention and treatment, as well as skin softening effect of menopause [Kokoku No. 2-44478], an anti-inflammatory [Kokoku No. 5-23274], phospholipase A ₂ inhibitory (anti-inflammatory) [JP 62-145019], Anti-dandruff and split ends prevention (Japanese Patent Publication No. 6-78214), antioxidant
-81138], skin aging prevention (Japanese Patent No. 2851701) and skin drying prevention (Japanese Patent Application Laid-Open No. H4-270212) can be used by internal use, injection or external use. However, the effect of promoting the lightening of the skin on which the melanin pigment has been once deposited has not been known so far, and this effect was first discovered by the present inventors.

Particularly preferred among the compounds of the above formula (I) are those having a structure in which DL-α-tocopherol and L-ascorbic acid are linked via a phosphodiester. The compound of the formula (I) or a pharmaceutically acceptable salt thereof is a known compound, and details of its production method are described in, for example, JP-B-2-44478 and JP-B-5-23274. The outline is L-ascorbic acid, D
The L-α-tocopherol phosphoric acid diester will be described below (see Japanese Patent Publication No. 2-44478): Decomposition of pyridine and the like in a non-reactive solvent such as benzene with respect to α-tocopherol. A halophosphate esterifying agent such as phosphorus oxytrichloride or phosphorus oxybromide is allowed to act in the presence of an acid agent. The compound obtained by subjecting the phenolic hydroxyl group of α-tocopherol to halophosphoric acid esterification in the presence of a deoxidizing agent such as pyridine in a solvent such as tetrahydrofuran is converted to a compound such as isopropylidene at the 5- and 6-positions. React with ascorbic acid protected by various protecting groups. The elimination of the protecting group from the reaction product can be performed by hydrolysis under mild conditions, for example, using 1N hydrochloric acid. Also, L-ascorbic acid, DL-β-tocopherol phosphate diester, L-ascorbic acid, DL-γ-tocopherol phosphate diester, and L-ascorbic acid, DL-δ-
The tocopherol phosphate diester is also the same as the above method except that β-, γ- or δ-tocopherol is used instead of α-tocopherol as a raw material, respectively (see Japanese Patent Publication No. 5-23274).

The compound of formula (I) thus obtained can be converted into a preferred salt form by carrying out a neutralization reaction with a base giving a pharmaceutically acceptable salt. Typical examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts and the like, which are respectively the corresponding alkali metal or alkaline earth metal hydroxides and compounds of formula (I) Can be easily obtained by mixing with Sodium and potassium salts are well soluble in water, and calcium salts are insoluble in water.

The compound of the formula (I) can be used as it is in a free form or in a salt form. The salt may be an inorganic amine salt as described above or an organic amine salt. Examples of organic amine salts include monoethanolamine salt, diethanolamine salt, triethanolamine salt, isopropanolamine salt, aminomethylpropanol salt, aminohydroxymethylpropanediol salt, aminomethylpropanediol salt, morpholine salt, glucosamine salt, Isopropanolamine salts and the like.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof is stable with various base components usually used for the production of solid preparations for internal use such as tablets, powders, granules, capsules and the like. Can be mixed. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be added to water or oil and mixed as it is or by dissolving it in water or an aqueous alcohol solution.

The compound of the formula (I) or a pharmaceutically acceptable salt thereof can be used as a whitening agent in the form of an oral preparation or parenteral preparation (injection), or as an external preparation applied to the skin. Can also be used.

The form of the oral preparation containing the compound of the formula (I) or a pharmaceutically acceptable salt thereof is not particularly limited. For example, in the case of a solid preparation, tablets, granules, powders, hard capsules, etc. It may be in any suitable form. Alternatively, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be dissolved or dispersed in an appropriate medium to form a soft capsule enclosing a liquid. In addition, it may be a syrup. When a liquid preparation such as an injection is used, any form generally used for a liquid preparation can be used. In particular, in the case of an injection, a ready-to-use solution comprising a sterile dry powder containing a compound of the formula (I) or a pharmaceutically acceptable salt thereof, prepared by freeze-drying or the like, and a sterile solution is used. Is also good. Any of these preparations can be manufactured by a conventional method. These preparations include commonly used excipients, binders, thickeners, dispersants, absorption enhancers, buffers, surfactants, dissolution aids, preservatives, emulsifiers, isotonic agents, Various additives commonly used in each formulation such as an agent and a pH adjuster may be appropriately used.

When the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered, for example, in the form of an injection, the concentration of the compound in the preparation is, for example, about 0.01 to 1 w / v%.
, But is not necessarily limited to this.

In the case of an external preparation, the concentration of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof in the whitening agent of the present invention is 0.0005-6.
0 W / V%, more preferably 0.05 to
3.0 W / V%, more preferably 0.05 to 0.2 W /
V%.

The compounds of formula (I) and their pharmaceutically acceptable salts have very low toxicity and excellent safety. For example, the LD ₅₀ of potassium salt of L-ascorbic acid, DL-α-tocopherol phosphate diester, which is an example of the compound of the formula (I), is 5 g / kg or more (rat, oral),
And 100 mg / kg or more (rat, intravenous injection). Such very low toxicity is particularly advantageous for the use of the compounds of formula (I) or pharmaceutically acceptable salts thereof for the purposes of the present invention. When the whitening agent of the present invention is administered, for example, in the form of an injection, the dose of the compound of the formula (I) or a pharmaceutically acceptable salt thereof is usually about 1 hour per day for an adult.
When administered in the form of an oral preparation, the dose of the compound is usually several times a day for an adult once a day.
The dose may be 10 to about 1000 mg. However, the dose is not necessarily limited to these ranges, and the dose may be appropriately increased or decreased in consideration of the patient's body weight, age, degree of pigmentation, and the like.

The whitening agent of the present invention is applied externally (for example, cosmetics)
In the case of the form of, unless contrary to the object of the present invention,
Various components used in external preparations such as ordinary cosmetics, quasi-drugs, and pharmaceuticals may be added. These various components are, for example, but not limited to: nicotinic acids such as nicotinic acid, nicotinamide, benzyl nicotinate, retinol, retinol acetate, vitamin A
Vitamin A such as oil, vitamin B ₂ such as riboflavin, riboflavin acetate, flavin adenine dinucleotide
S, pyridoxine hydrochloride, vitamin B ₆ such as pyridoxine dioctanoate, L- ascorbic acid, L- ascorbic acid-2-sodium sulfate, vitamin C such as L- ascorbic acid dipalmitate esters, calcium pantothenate, Pantothenic acids such as pantothenyl ethyl ether, D-pantothenyl alcohol, and acetyl pantothenyl ethyl ether; vitamin D such as cholecalciferol and ergocalciferol; α-tocopherol, tocopherol acetate, DL-α-tocopherol nicotinate, and succinic acid Vitamin E such as acid DL-α-tocopherol and other vitamins; glycine, alanine,
Phenylalanine, valine, leucine, isoleucine,
Serine, threonine, asparagine, aspartic acid,
Amino acids such as aspartate, glutamine, glutamic acid, glutamate, lysine, methionine, cysteine, cystine, arginine, histidine, tryptophan, proline, hydroxyproline, N-coconut fatty acid-sodium L-glutamate, N-palmitoyl-
N-acyl acidic amino acid salts such as diethyl L-aspartate, sodium lauroylmethyl-β-alanine, acyl neutral amino acid salts such as coconut oil fatty acid sarcosine triethanolamine, pyrrolidone carboxylic acid and salts thereof,
Polyoxyethylene hydrogenated castor oil monopyroglutamic acid monoisostearate diester, coconut oil fatty acid-L-
Amino acid derivatives such as arginine ethyl ester-DL-pyrrolidone carboxylate, rice bran oil, peanut oil, palm oil, tallow, avocado oil, jojoba oil, lanolin, liquid paraffin, squalane, carnauba wax, isostearyl alcohol, isostearyl palmitate, Tri-2-
Oils such as glycerol ethylhexanoate, glycerin,
Polyhydric alcohols such as sorbitol, mannitol and 1,3-butylene glycol, polyhydric alcohol ethers such as polyethylene glycol, collagen, viscous polysaccharides such as sodium hyaluronate, chondroitin sulfate and sodium dextran sulfate, parahydroxyanisole, erythorbic acid Antioxidants such as sodium, carboxyvinyl polymer, cellulose derivatives such as carboxymethylcellulose, hydroxypropylmethylcellulose, sodium stearyl sulfate, diethanolamine cetyl sulfate, cetyltrimethylammonium saccharin, polyethylene glycol isostearate, diglyceryl diisostearate, phospholipids, etc. Surfactants, preservatives such as ethylparaben, propylparaben, butylparaben, hinoki Ol, salicylic acid derivatives, glycyrrhizinic acid derivatives, glycyrrhetinic acid derivatives, allantoin, anti-inflammatory agents such as zinc oxide, other pH adjusting agents, buffering agents, perfumes, and coloring agents.

[0023]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to typical test examples and examples, but it is not intended that the present invention be limited to these examples.

<Test Example 1> Lightening effect of compound of formula (I) on skin pigmentation due to sunburn.
-Ascorbic acid, DL-α-tocopherol phosphoric acid diester (potassium salt) was examined for the effect of lightening by applying as follows.

(Materials and Methods) A shaved back skin of an A-1 colored guinea pig was irradiated with ultraviolet light once a day (0.838 mV / cm ² × 50 minutes) using a xenon lamp as a light source.
A pigmentation model was created by irradiating a total of four times every four days (n = 6 for each group). L-ascorbic acid prepared using a 50% ethanol solution as a solvent,
3% and 6% of DL-α-tocopherol phosphate diester (potassium salt) (hereinafter referred to as “test compound”)
The solution was applied twice daily for 3 consecutive weeks each (10 μl / site). A 50% ethanol solution alone was similarly applied to the control group. During the application period, the lightness (L value: Lightness) of the application site was measured by a color difference meter once a week.

The apparatus used for measuring the L value and its specifications are as follows. Equipment: Dental color meter of OFC-300A (Nippon Denshoku Industries Co., Ltd.) Specifications: (1) Color system: XYZ, Lab, ΔLΔaΔbΔE, L ^* a ^* b ^* (2) Optical condition: 30 ° -coaxial (3 ) Measurement area: 2mmφ (4mmφ) (4) Light source: 12V 500W halogen lamp (5) Light receiving element: Silicon photocell (6) Filter rotation method

(Results) The results are shown in FIGS. FIG.
Shows the transition of the L value of each group at each time after the start of application of the test compound solution or the base as an absolute value, and FIG. 2 shows the transition of the L value of each group at each time after the start of application. Is shown as a difference (ΔL value) from the L value at the start of application for the group of.

The L value, which is an index of the lightness of the skin, decreases when pigmentation occurs, and increases when the skin becomes pale due to depigmentation. In this test, the pigmentation of the skin was caused by ultraviolet irradiation as described above, and the effect of the test compound on the recovery, that is, the process of lightening was examined. As a result, as shown in FIG. 1, in the group to which the solution containing the test compound was applied, the L value tended to increase more rapidly than in the control group. This tendency is due to ΔL after application of the test compound.
The values are also clearly shown in FIG. These facts indicate that the application of the test compound tends to promote the recovery of the pigmented skin, that is, the fading of the skin. This shows the usefulness of applying a cosmetic composition containing the compound.

<Example 1> Oral tablet According to the following formulation for one tablet, each component is mixed by a conventional method and tableted to give an oral tablet. The internal tablets may be sugar-coated by a conventional method. (Prescription)

<Example 2> Oral tablets According to the following formulation for one tablet, each component is mixed by a conventional method and tableted to give an oral tablet. The internal tablets may be sugar-coated by a conventional method. (Prescription)

<Example 3> Oral tablet According to the following formulation for one tablet, each component is mixed by a conventional method and tableted to give an oral tablet. The internal tablets may be sugar-coated by a conventional method. (Prescription)

Example 4 Oral tablet According to the following formula for one tablet, each component is mixed by a conventional method and tableted to give an oral tablet. The internal tablets may be sugar-coated by a conventional method. (Prescription)

<Example 5> Injection The following components were mixed and dissolved by a conventional method, and the obtained solution was sterilized by filtration and filled into a 5 ml glass ampule aseptically. (Prescription)

<Example 6> Injection The following components were mixed and dissolved by a conventional method, and the obtained solution was sterilized by filtration, and aseptically filled in a 5 ml glass ampule. (Prescription)

<Example 7> Injection The following components were mixed and dissolved by a conventional method, and the obtained solution was sterilized by filtration and aseptically filled in a 5 ml glass ampule. (Prescription) L-ascorbic acid, DL-α-tocopherol phosphate diester (potassium salt) 200 mg mannitol 5 g 1N sodium hydroxide・ ・ ・ ・ ・ ・ Appropriate amount (pH 6.5) distilled water for injection・ ・ ・ ・ ・・ Appropriate amount 100ml

Example 8 Lotion According to the following formulation, each component is mixed and dissolved by a conventional method to obtain a lotion. (Prescription)

Example 9 Lotion According to the following formulation, each component is mixed and dissolved by a conventional method to obtain a lotion. (Prescription)

Example 10 Lotion According to the following formulation, each component is mixed and dissolved by a conventional method to obtain a lotion. (Prescription)

<Example 11> Lotion According to the following formulation, each component was dissolved in purified water, adjusted to pH 6.0 with 1N sodium hydroxide, filtered to a total volume of 100 ml, and filled in a glass bottle. (Prescription) L-ascorbic acid, DL-β-tocopherol phosphoric acid diester (potassium salt) ··· 1.0 g citric acid ··· 0.1 g glycerin 5.0 g ethyl alcohol 8.0 ml methyl paraben 0.1 g 1N sodium hydroxide・ ・ ・ ・ ・ ・ ・ ・ Appropriate amount (pH 6.0) purified water ・ ・ ・ ・ ・ ・ ・ ・ ・ Appropriate amount 100ml

Example 12 Emulsion According to the following formulation, an aqueous phase and an oil phase were prepared by a conventional method at about 70 ° C. (L-ascorbic acid, DL-α-tocopherol phosphate diester (sodium salt) was dissolved in water. Phase), the oil phase is added to the aqueous phase to carry out preliminary emulsification, and further emulsified with a homomixer, and then cooled to about 30 ° C. with stirring to obtain an emulsion. (Prescription)

Example 13 Emulsion According to the following formulation, an aqueous phase and an oil phase were prepared in a usual manner at about 70 ° C. (L-ascorbic acid, DL-α-tocopherol phosphate diester (magnesium) was converted to an aqueous phase). ), Preliminarily emulsifying by adding an oil phase to a water phase, further emulsifying with a homomixer, and then cooling to about 30 ° C with stirring to obtain an emulsion. (Prescription)

<Example 14> Ointment A hydrophilic ointment base material was prepared by a conventional method according to the following formulation, and L-ascorbic acid and DL-α-tocopherol phosphoric acid diester (sodium salt) were added to a small amount thereof and mixed. Then, the remaining hydrophilic ointment base is gradually added to obtain a hydrophilic ointment. (Prescription)

Example 15 Ointment According to the following formulation, L-ascorbic acid, DL-α-tocopherol phosphate diester (potassium salt) is dissolved in purified water. The remaining components are combined, heated to about 70 ° C., dissolved and mixed, added to an aqueous solution of L-ascorbic acid, DL-α-tocopherol phosphoric acid diester (potassium salt), uniformly emulsified by a homomixer, and then cooled. To obtain an ointment. (Prescription) L-ascorbic acid, DL-α-tocopherol phosphoric acid diester (potassium salt) 0.1 g stearyl alcohol 22.0 g ... 20.0 g Polyoxyethylene (10) monooleate ... 0.25 g Glyceryl monostearate ... 0.3 g Vaseline ...・ ・ ・ ・ ・ ・ ・ ・ 32.0 g Purified water ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ ・ Suitable amount 100 ml

Example 16 Cream According to the following formulation, an aqueous phase and an oil phase were prepared in a usual manner at about 70 ° C. (L-ascorbic acid, DL-α-tocopherol phosphoric acid diester (sodium salt) was dissolved in water. Phase), an aqueous phase and an oil phase are added to purified water, finely emulsified with a homomixer, and then rapidly cooled with stirring to obtain a cream. (Prescription)

<Example 17> Cream According to the following formulation, propylene glycol and L-ascorbic acid, D-δ-tocopherol phosphate diester (sodium salt) were added to sterile purified water and dissolved to form an aqueous phase. This is heated to 70 ° C. Separately, the other components are mixed, heated and melted to 70 ° C., and the aqueous phase is added thereto under stirring to emulsify uniformly, and cooled to room temperature to make a cosmetic cream, which is filled into a cream container. (Prescription)

[0046]

According to the present invention, it is possible to provide a whitening agent which promotes lightening of skin on which melanin pigment has been once deposited by sunburn.

[Brief description of the drawings]

FIG. 1 is a graph showing a change in L value after the start of application of a test compound.

FIG. 2 is a graph showing a change in ΔL value after the start of application of a test compound.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 9/06 A61K 9/06 9/08 9/08 9/107 9/107 31/661 31/661 A61P 17/00 A61P 17/00 43/00 105 43/00 105 F term (reference) 4C076 AA06 AA12 AA17 BB31 CC18 CC26 DD37A DD38A DD43Z DD51R FF15 FF39 FF61 4C083 AA082 AA122 AB032 AC012 AC022 AC072 AC092 AC102 AC122 AC132 AC182AC AC422 AC482 AC542 AC901 AC902 AD042 AD092 AD212 AD242 AD282 AD512 CC04 CC05 DD15 DD22 DD23 DD31 EE16 4C086 AA01 AA02 BA09 BA18 DA34 MA01 MA04 MA17 MA28 MA63 NA14 ZA89 ZB21

Claims (7)

[Claims] 1. A compound of the formula (I) (Wherein, R ₁ and R ₂ are the same or different and each represent a hydrogen atom or a methyl group) or a pharmaceutically acceptable salt thereof. 2. The whitening agent according to claim 1, wherein the compound represented by the formula (I) is L-ascorbic acid, DL-α-tocopherol phosphate diester. 3. The whitening agent according to claim 2, wherein said pharmaceutically acceptable salt is selected from the group consisting of a sodium salt, a potassium salt, a magnesium salt and a calcium salt. 4. The whitening agent according to claim 1, which is an external preparation. 5. The whitening agent according to claim 4, which is a cosmetic. 6. The compound of the formula (I) or a pharmaceutically acceptable salt thereof in the whitening agent has a concentration of 0.0005 to 0.0005.
The whitening agent according to claim 4 or 5, wherein the whitening agent is 6.0 W / V%. 7. The whitening agent according to claim 4, which is in the form of an aqueous solution, emulsion, cream or ointment.