JPH0648935A - Melamine production-inhibiting external agent - Google Patents

Abstract

PURPOSE:To provide the skin external agent exhibiting a good percutaneous absorbing property, effectively inhibiting the coloration.decomposition of skin with light or heat, having an excellent melanogenesis-inhibiting action, and useful for preventing and also treating stains and ephelis. CONSTITUTION:The melanogenesis-inhibiting external agent contains at least one selected from a group of iminodibenzyl compounds, dibenzocycloheptadiene compounds and ketotifen fumarate as an active ingredient in an amount of 0.00015-10wt.%, preferably 0.01-5wt.%. The addition of a whitening agent selected from a group of kojic acid, ascorbic acid, hydroquinone, liquiritin or their derivatives and a placenta extract gives a synergistic effect. The addition of an UV light absorbent (e.g. a dibenzoylmethane UV light absorbent or a plant extract having an absorption spectrum in a region ranging from the UV-B region to the UV-A region) and/or an antioxidant (e.g. a tocopherol compound) permits to effectively inhibit the coloration.decomposition of skin with light and heat.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for suppressing melanin production, and more specifically, it has excellent transdermal absorbability and effectively suppresses coloring / decomposition due to light or heat and is excellent. The present invention relates to a skin external preparation having a melanin production suppressing action.

[0002]

2. Description of the Related Art It is known that spots such as spots and freckles appearing on human skin are mainly caused by deposition of Eumelanin. Various types of whitening cosmetics have been researched for a long time in order to suppress the production of melanin, which causes stains and freckles, and to whiten the entire skin. For example, hydrogen peroxide and peroxides such as zinc perborate have been tried to be added to cosmetics, and vitamin C, cysteine, colloidal sulfur and the like have been added to cosmetics. However, none of them are satisfactory in terms of preservability and whitening effect.

The inventors of the present invention have been studying external preparations for inhibiting melanin production, such as fair skin cosmetics, for the purpose of removing spots such as spots and freckles that appear on human skin for many years and enhancing the whitening effect of the entire skin. Has been researching
Among them, as factors involved in normal human skin color, we obtained the finding that melanin, carotene amount, blood flow (oxidized and reduced hemoglobin), skin thickness and transparency are involved. It is reflected, absorbed, and scattered depending on a factor, and it becomes the color of the skin. Among these, it was clarified that melanin, especially brown or black eumelanin, was the largest cause of pigmentation, and this melanin We have been searching for a substance that suppresses the generation of.

In the study, it was found that kojic acid (5-hydroxy-2-hydroxymethyl-γ-pyrone) and its derivatives have an extremely excellent melanin production inhibitory action. For example, Japanese Patent Publication No. 56-18569. Bulletin,
JP-A-54-92632, JP-A-56-7961
6, JP-A-56-77272, JP-A-56
As disclosed in JP-A-7776, JP-A-56-7710, JP-A-56-20330, and JP-B-63-24968, many fair-white cosmetics and external preparations containing these as active ingredients. The invention has been proposed.

These light-whitening cosmetics and external preparations are used in commercial forms such as creams, lotions, emulsions, packs, lotions, ointments and poultices, all of which suppress excellent melanin production, It is used as a cosmetic or external preparation that has a whitening effect.

However, these cosmetics may be required to be absorbed through the skin after use, that is, to have excellent transdermal absorbability. In particular, cosmetics containing kojic acid or a kojic acid derivative as an active ingredient do not cause any problem in normal use, but absorbability immediately after use, that is, initial transdermal absorbability is rather slow. There is a tendency to improve such a tendency, it is preferable that it be absorbed into the skin immediately after use, such as ointments, pasta agents, poultices, creams, emulsions, lotions, and essences. In order to further improve the transdermal absorbability, it has been practiced to incorporate a transdermal absorbent into the external preparation.

Examples of the absorption aid include C ₁₀ to C ₁₄
Fatty acid esters, fatty acids, PEG (M <1000)
However, many of these absorption auxiliaries have skin irritation, and the amount of drug used in the formulation is limited, so that the desired drug effect cannot be achieved. Met.

[0008]

Therefore, an object of the present invention is to provide a skin external preparation which has good transdermal absorbability, effectively suppresses coloring / degradation due to light or heat, and has an excellent melanin production inhibitory effect. To provide.

[0009]

[Means for Solving the Problems] The inventors of the present invention have conducted earnest research based on the recognition of such prior art.
As a result, iminodibenzyls, dibenzocycloheptadienes, and ketotifen fumarate have good transdermal absorbability and excellent melanin production inhibitory effect, and a specific ultraviolet absorber and / or antioxidant is added thereto. This has led to the finding that coloring and decomposition due to light and heat can be effectively suppressed, and the present invention has been completed based on this finding.

That is, according to the present invention, there is provided an external preparation for inhibiting melanin production, which comprises at least one active ingredient selected from the group consisting of iminodibenzyls, dibenzocycloheptadienes and ketotifen fumarate.

Further, according to the present invention, there is provided an external preparation for inhibiting melanin production, which comprises at least one skin-whitening agent selected from the group consisting of kojic acid, ascorbic acid, hydroquinone, liquiritin or derivatives thereof, and placenta extract. Provided.

Further, according to the present invention, a group consisting of a dibenzoylmethane compound, an oxybenzone compound, a cinnamic acid compound, and a plant extract having an absorption spectrum from the UV-B region to the UV-A region is further selected. There is provided an external preparation for suppressing melanin production, which comprises at least one selected ultraviolet absorber.

Further, according to the present invention, tocopherols, gallic acids, catechin and its derivatives, flavonoids, tannins, cyclodextrins, EDT.
There is provided an external preparation for suppressing melanin production, which comprises at least one antioxidant selected from the group consisting of A, erythorbic acid, caffeic acid, and a compound having a radical scavenging action.

Further, according to the present invention, a lower alcohol,
An external preparation for suppressing melanin production is provided which contains at least one selected from the group consisting of sugar alcohols and polyhydric alcohols.

[0015]

DETAILED DESCRIPTION OF THE INVENTION Iminodibenzyls and dibenzocycloheptadienes are represented by the following general formulas, and both are known as a group of drugs that act on the central nervous system. Imipramine, which is a typical iminodibenzyl compound, was discovered by Kuhn in 1957 to have a significant effect on depression, and has now become the mainstay of drug therapy for depression. In addition, amitriptyline and nortriptyline, which are typical dibenzocycloheptadienes, have anticholinergic and antihistamine effects, and even in depression, when imipramine is ineffective, especially for depressed patients with anxiety and excitement. However, its use as an external preparation for suppressing melanin production has not yet been known.

The iminodibenzyls and dibenzocycloheptadienes are represented by the following formulas (1) and (2). Formula (1) Formula (2)

Examples of iminodibenzyls used as an active ingredient of the external preparation of the present invention include 2,2'-iminodibenzyl, imipramine, imipramine hydrochloride, desipramine, desipramine hydrochloride, chlorimipramine, trimipramine and the like. Examples of the dibenzocycloheptadienes include amitriptyline, amitriptyline hydrochloride, nortriptyline, noxiptyline and the like.

The ketotifen fumarate used as an active ingredient of the external preparation of the present invention is represented by the following general formula (3) and is useful for dermatitis, bronchial asthma, allergic rhinitis, urticaria and the like. Although it has been used as a tablet or a syrup, its use as an external preparation for suppressing melanin production is not yet known. Formula (3)

The external preparation for inhibiting melanin production of the present invention is prepared by mixing the above-mentioned active ingredient into a known dosage form such as pharmaceuticals, quasi drugs, cosmetics, etc.
0.00015 to 10% by weight based on the whole external preparation,
Preferably, it may be added in an amount of about 0.01 to 5% by weight.

It is preferable to use a whitening agent in combination with the external preparation for suppressing melanin production of the present invention. The whitening agent that can be used in combination with the active ingredient of the present invention is not particularly limited, but preferred among those that can obtain a synergistic effect are, for example, kojic acid, ascorbic acid, hydroquinone, liquiritin or derivatives thereof, and placenta. Examples thereof include those selected from the group consisting of extracts, and these may be used in combination of two or more kinds. The whitening agent is 0.01 to 10.0% by weight, preferably 0.1
To 5.0% by weight.

As kojic acid, the following formula (4) and formula (4) 5-hydroxy-2-hydroxymethyl-γ represented by
A pure product of pyrone, a fermentation solution containing kojic acid as a main component obtained by culturing a strain having a kojic acid-producing ability, a concentrated solution of the fermentation solution, and crystallized by extracting kojic acid from the fermentation solution. Things are used.

Examples of such strains having the ability to produce kojic acid include, for example, Aspergillus albus, Aspergillus candidas, Aspergillus oryzae, Aspergillus nidulans, Aspergillus parasiteticus, Aspergillus awamori, Aspergillus tamari, Aspergillus nyubus. , Aspergillus flavus, Aspergillus wenchi, Aspergillus glaucus, Aspergillus clavatus, Aspergillus fumigatus, Aspergillus digantus, etc., Aspergillus spp., Penicillium spp. , Acetobacter aceti, Acetobacter gluconicus, Acetobacter xylinum, etc. Strains Gluconobacter-Roshiusu, strain, etc. of Gluconobacter, such as Gluconobacter, Gurunikasu is preferably used.

The medium composition of these strains is as follows:
Usually, sucrose, sucrose, fructose, glucose, starch, maltose, glycerin, mannitol, rhamnose,
Carbon sources such as xylose, gluconic acid, arabinose, dihydroxyacetone, inosit, lactose, and ethanol are about 2 to 15% (wt%, the same applies hereinafter), ammonium sulfate, polypeptone, sodium nitrate, baker's yeast extract, brewer's yeast extract, etc. Nitrogen source is about 0.1 to 1
%, 0.01 to 0.05% of magnesium source such as magnesium sulfate, 0.01 to 0.1% of phosphorus and potassium source such as potassium monohydrogen phosphate and potassium dihydrogen phosphate, and other ferric sulfate and chloride. An inorganic salt such as ferric iron, sodium chloride or calcium chloride having a concentration of about 0.001 to 0.005% may be used.

Examples of the kojic acid derivative used in the present invention include 2-methoxymethyl-hydroxy-4H-pyran-4-one, 2-ethoxymethyl-5-hydroxy-4H-pyran-4-one and 2-pen. Zolyloxymethyl-5-hydroxy-4H-pyran-4-one, 2-
Cinnamoyloxymethyl-5-hydroxy-4H-pyran-4-one, 2-phenoxymethyl-5-hydroxy-4H-pyran-4-one, kojic acid glycoside, or
Formula (5) Formula (5) below An esterified product of kojic acid represented by the formula (wherein R is a saturated or unsaturated aliphatic hydrocarbon group) is exemplified.
In the formula, the saturated or unsaturated aliphatic hydrocarbon group represented by R is, for example, a saturated or unsaturated aliphatic carboxylic acid.

Examples of the saturated aliphatic carboxylic acid include acetic acid, propionic acid, n-valeric acid, iso-valeric acid, methylethylacetic acid, 2,2-dimethylpropionic acid, caproic acid, enanthic acid, caprylic acid and pelargonic acid. , Capric acid, undecylenic acid, lauric acid, tridecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, nonadecanoic acid, arachidic acid or lignoceric acid are used, but the skin irritation of acid is reduced. For this reason, it is preferable to use a saturated aliphatic carboxylic acid having 8 or more carbon atoms, particularly a saturated aliphatic carboxylic acid having 14 to 20 carbon atoms. The use of the aliphatic carboxylic acid having more than 20 carbon atoms is not particularly limited, but it is extremely difficult to obtain the aliphatic carboxylic acid, which is not preferable in terms of production cost.

Besides these saturated aliphatic carboxylic acids, for example, unsaturated aliphatic carboxylic acids such as linoleic acid, linolenic acid, maleic acid, fumaric acid, oleic acid and arachidonic acid are all particularly limited. Used without.

The kojic acid glycoside is obtained by stabilizing a kojic acid molecule by binding a saccharide to the -CH ₂ OH group at the 2-position of kojic acid, which is represented by the following formula (6). It has the structural formula shown. Formula (6)

In the formula (6), R is a 6-carbon saccharide, a 5-carbon saccharide, an amino acid, a disaccharide or a trisaccharide. Examples of the 6-carbon saccharide include glucose, galactose, mannose,
Fructose, sorbose and the like, the five-carbon sugars include ribose, arabinose, xylose, liquirice, xylulose, and the like, the amino sugars such as glucosamine, mannosamine, and galactosamine, and the disaccharides such as Maltose, lactose, cellobiose, sucrose and the like, and the trisaccharides include, for example, maltotriose,
Examples include cellotriose.

The kojic acid glycoside of the present invention can be produced by any of the synthetic method, the enzymatic method and the culturing method, and any of them can be used, but in consideration of productivity and economic efficiency. For example, kojic acid glycosides produced by the enzymatic method or the culture method are preferable. Generally, it is synthesized by utilizing a transglycosylation reaction of an enzyme such as amylase, phosphorylase or lysozyme, or is produced by chemically binding unreacted -OH group at 1-position of sugar and kojic acid. You can

As ascorbic acid derivatives, known derivatives, for example, glycosides such as ascorbic acid glucoside, L-ascorbyl palmitate, L-ascorbyl isopalmitate, L-ascorbyl dipalmitate, L-isocormitic acid L are used. -Ascorbyl, L-ascorbyl stearate, L-Ascorbyl isostearate, L-Ascorbyl distearate, L-Ascorbyl diisostearate, L-Ascorbyl myristate, L-Ascorbyl isomyristate, L-Ascorbyl dimyristate, Diisomyristin Acid L-ascorbyl, 2-ethylhexanoic acid L-ascorbyl, di-2-
L-ascorbyl ethylhexanoate, L-ascorbyl oleate, L-ascorbyl dioleate, etc.
Ascorbic acid alkyl ester; L-ascorbic acid phosphoric acid ester such as L-ascorbic acid-2-phosphoric acid ester and L-ascorbic acid-3-phosphoric acid ester;
L-ascorbic acid 2-sulfate, L-ascorbic acid 3-sulfate and other L-ascorbic acid sulfates; their alkali metal salts such as sodium and potassium; their alkaline earth metals such as calcium and magnesium Salt and the like.

Examples of the hydroquinone derivative include arbutin and the like.

Examples of the liquiritin derivative include, for example, liquiritin-α-in which glucose is α-bonded to liquiritin.
Examples thereof include glucoside and liquiritin-α-maltoside.

The active ingredient of the external preparation for suppressing melanin production of the present invention tends to be decomposed with time by light or heat to cause a color change. Particularly, in ketotifen fumarate, the stability becomes higher in the alkaline region. Is reduced,
This tendency is promoted by heat and light. However, according to the present invention, by adding a specific ultraviolet absorber to this, it is possible to eliminate the possibility of causing such an adverse effect.

That is, according to the research by the present inventor, 4- (1,1 dimethylethyl) -4 'was used as an ultraviolet absorber.
-Methoxydibenzoylmethane {trade name: Parsol (registered trademark) 1789, manufactured by Divodan Rule Co., Ltd.} and 2-hydroxy-4-methoxybenzophenone {trade name: A. S. L
-24, manufactured by Ogawa Fragrance Co., Ltd., etc., such as oxybenzone compounds having strong absorption in the UV-A region, octyl methoxycinnamate {trade name: Parsol MCX, manufactured by Givaudanru Co.}, etc. UV-B such as cinnamic acid-based compounds represented by :, rutin, quercetin, oil-soluble licorice extract, lavender extract, sardine extract, aloe extract, shea butter, γ-oryzanol, etc.
The compound or plant extract having an absorption spectrum in the UV to UV-A region can remarkably suppress the stability of the active ingredient of the external preparation for suppressing melanin production of the present invention, particularly, the coloring and decomposition in the neutral region.

The blending amount of these ultraviolet absorbers is preferably 0.01 to 10% by weight, more preferably 0.1 to 5% by weight, based on the whole preparation. According to the research conducted by the present inventor, among the ultraviolet absorbers, paraaminobenzoic acid compounds such as glyceryl PABA {trade name: Escalol 106, manufactured by Ina Trading Co., Ltd.} have no effect and are not photodegradable. Promoted. Further, for example, a light scattering agent such as titanium oxide is effective for suppressing the decrease in the content of the active ingredient, but it is not preferable because it tends to promote coloring.

Further, in the present invention, it is effective to add a specific antioxidant in order to prevent not only the coloring and decomposition of the above-mentioned active ingredient but also the reduction of the content thereof. Antioxidants that can be blended in the present invention, tocopherols, gallic acids, epicatechin, epigallocatechin, catechins such as epigallocatechin gallate and its derivatives, flavonoids, tannins and known plant extracts containing them, cyclodextrin. Class, EDT
A, erythorbic acid, caffeic acid, and other compounds having a radical scavenging action are particularly preferable, and the compounding amount thereof is 0.0001 to 5% by weight, especially 0.00
1 to 0.5% by weight is preferred.

By blending these antioxidants, the coloring of the active ingredient in the neutral range is markedly suppressed, and when used in combination with the above-mentioned UV absorber, the effect is synergistically enhanced, and in the content reduction prevention. Is also effective.

In the past, it has been pointed out that ketotifen fumarate has instability in the formulation, and in the therapeutic agent for dermatological areas such as dermatitis and eczema, bisulfite,
Although the technology of blending antioxidants such as sulfite, pyrosulfite and dibutylhydroxytoluene (BHT) is known, sodium bisulfite has the effect of preventing discoloration and suppressing the decrease in content, but has a strong pungent odor. , Again, BH
T has a safety problem in terms of skin irritation and cannot be incorporated in the melanin production-inhibiting external preparation of the present invention. Further, sodium polyphosphate has a coloring preventing effect, but suppresses a decrease in content. I couldn't do that.

Further, in the present invention, when the formulation is carried out, it is more preferable that the formulation is carried out using an alcohol solvent than the formulation is carried out using an aqueous solvent. Can be suppressed. As the alcohol-based solvent, ethanol, isopropanol, ethylene glycol, propylene glycol, 1,3-butylene glycol, glycerin, sorbitol, lower alcohols such as mannitol, polyhydric alcohols, sugar alcohols alone or It is preferably used in combination with the above-mentioned ultraviolet absorber and / or antioxidant, and the amount thereof is not particularly limited.

In the case of producing the external preparation of the present invention, various known active ingredients which are usually used, for example, carpronium chloride, cepharanthin, vitamin E, vitamin E nicotinate, nicotinic acid, nicotinic acid amide, benzyl nicotinate, and shaw are shown. Peripheral vasodilators such as tincture, capsicum tincture, cooling agents such as camphor and menthol,
Antibacterial agents such as hinokitiol, benzalkonium chloride and undecylenic acid, anti-inflammatory agents such as lysozyme chloride, glycyrrhizin and allantoin, ascorbic acid, arbutin,
Whitening agents such as kojic acid, assembly extract, garlic extract, carrot extract, sardine extract, rosemary extract, aloe extract, loofah extract, ginkgo extract,
Various extracts derived from animals, plants and microorganisms such as elder extract, placenta extract, liver extract, lactic acid bacterium culture extract and the like can be freely added and used.

Known forms of pharmaceuticals, quasi-drugs and cosmetics mean all forms that can be applied externally, for example, poultices, plasters, pastes, creams, ointments, aerosols, emulsions, lotions, emulsions, Essence, pack, gel, powder, foundation, sun care,
A skin application agent such as bath salt can be exemplified.

In addition to the known active ingredients, base components such as surfactants and oils and fats, known moisturizers, thickeners and antiseptics may be added to the above-mentioned drugs, quasi drugs and cosmetics. Agent,
It goes without saying that various additives such as chelating agents, pH adjusters, fragrances and coloring agents can be used in combination.

As the moisturizer, for example, NM such as amino acid, sodium lactate, sodium pyrrolidonecarboxylate, etc.
F component, hyaluronic acid, collagen, elastin, chondroitin sulfate, dermatan sulfate, fibronectin,
Examples thereof include ceramides, heparin-like substances, and water-soluble polymer substances such as chitosan.

Examples of the thickener include natural high molecular substances such as sodium alginate, xanthan gum, aluminum silicate, quince seed extract, tragacanth gum and starch, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, soluble starch, cationized cellulose and the like. Examples thereof include semi-synthetic polymeric substances, carboxyvinyl polymers, polyvinyl alcohol, and other synthetic polymeric substances.

Examples of preservatives include benzoate, salicylate, dehydroacetate, paraoxybenzoate, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, 3,4,4'-trichlorocarbanide. , Benzalkonium chloride, hinokitiol, resorcin, and the like.

Further, examples of the chelating agent include tartaric acid and gluconic acid, and examples of the pH adjusting agent include sodium hydroxide and potassium hydrogen phosphate.

[0047]

EXAMPLES Next, examples of the present invention and test examples for explaining the effects thereof will be shown, but these do not limit the present invention at all.

<Test Example 1> (Transdermal Absorption Test) 0.1% of imipramine hydrochloride and amitriptyline hydrochloride
% Aqueous solution (containing 5% ethanol) and a 0.02% aqueous solution of ketotifen fumarate were prepared and subjected to the following in vitro permeation test.

(Test Method) A back skin peeled from a 7-week-old (body weight 25 g) male hairless mouse was set in a Franz type (FDC-400 manufactured by Crown Grass).
100 ml of the above sample was mixed with an equal amount of a donor solution, pH 7, 4 phosphate buffer and physiological saline, and 20 ml of kanamycin sulfate as an antiseptic was added as a receptor solution, and 16 ml of the solution was permeated into the receptor solution. The amount of imipramine hydrochloride, amitriptyline hydrochloride, and ketotifen fumarate were quantified by the HPLC method after 24 hours. The test was conducted 3 times for each drug, and the average value was used as data.

(Test result)

<Test Example 2> (Test for inhibiting melanin production by B16 cells) (Test method) Final concentrations of imipramine hydrochloride, amitriptyline hydrochloride and ketotifen fumarate of the present invention were 5 to 15 μM, 50 to 200 μM, and 25
To the culture medium B16 cells derived from mouse melanoma were seeded in Eagle MEM medium containing 10% fetal bovine serum added to 100 to 100 μM and cultured at 37 ° C. under 5% CO ₂ conditions for 5 days. After scraping and suspending in PBS, centrifugation was performed at 1,000 rpm for 5 minutes, and the color tone of the sediment pellet was visually determined. The number of cells was determined by dispersing the cells with trypsin and measuring with a blood cell counter.

As a control, one to which the above-mentioned chemicals were not added was used. The criteria for judging the results are as follows. -: Shows the same degree of blackening as the non-addition group. +: Shows a slightly lower degree of blackening than the non-addition group. ++: The degree of blackening is clearly smaller than that in the non-addition group. +++: Shows a slightly recognized blackening degree. ++++: White or gray, not black. ++++++: White

(Test Results) As shown in Table 2, imipramine hydrochloride, amitriptyline hydrochloride and ketotifen fumarate of the present invention were found to have excellent melanin production inhibitory effect.

Tables 3 to 5 show the results of the melanin production inhibitory action test by B16 cells when the active ingredient of the present invention and a whitening agent were used in combination.

[0055]

[0056]

[0057]

<Test Example 3> (using human melanoma cells)
Melanin production inhibitory action test) (Test method) imipramine hydrochloride and amitrip of the present invention
The final concentrations of tyrine hydrochloride and ketotifen fumarate are
2.5 to 10 μM, 25 to 100 μM,
10% U added at 12.5 to 50 μM
Human-derived medium was added to Eagle's MEM medium containing fetal calf serum.
Ranoma cells (Ihara strain) were seeded, 37 ° C, 5% CO ₂ 
After culturing for 5 days under the conditions, scrape the cells and add to PBS.
After suspending, centrifuge at 1,000 rpm for 5 minutes and pellet sediment.
The color tone of the let was visually evaluated. The number of cells
The cells were dispersed with pushin and counted with a blood cell counter.

The criteria for judging the results are as follows. -: Shows the same degree of blackening as the non-addition group. +: Shows a slightly lower degree of blackening than the non-addition group. ++: The degree of blackening is clearly smaller than that in the non-addition group. +++: Shows a slightly recognized blackening degree. ++++: White or gray, not black. ++++++: White

(Test result)

Next, Tables 7 to 9 show the results of the melanin production inhibitory action test by human melanoma cells when the active ingredient of the present invention and a skin-whitening agent were used in combination.

[0062]

[0063]

[0064]

<Test Example 4> (Light Stability Test) In order to investigate the light stability of the active ingredient of the present invention and the influence of various additives on it, a test was conducted in the following procedure. 1. Samples (1) Active ingredient Representative of iminobenzyls, representative of imipramine hydrochloride dibenzocycloheptadiene, representative of amitriptyline hydrochloride ketotifen fumarate (2) Additives Various antioxidants of UV absorbers ( 3) Preparation of sample The active ingredient was dissolved in 50 mM phosphate buffer (pH 3.0 to 7.0) or ethanol so as to have a preparation concentration of 0.1%, and this was used as a control solution. Additives were added to this solution so as to have respective concentrations and dissolved to obtain test samples.

2. Test method Wrap 2 ml of each sample in polyvinylidene chloride film,
2. Using a fade meter [tester: regular type light resistance tester, manufactured by Suga Tester Co., Ltd.], ultraviolet rays at 50 ° C.
Irradiation was carried out for 5 hours, and the change with time was measured.

3. Evaluation items For each sample after ultraviolet irradiation, the following items were compared with those at the start of the test. (1) Appearance change (odor, color tone, and degree of coloring) The strength of the odor (presence or absence of unpleasant odor) was sensory evaluated. Color tone and degree of coloring The color tone and coloring (the degree of coloring) of each sample were visually observed. The degree of coloring was evaluated according to the degree, from the lighter to 6 (gradation), ± (1+, 2+, 3+, 4+ (strong)). (2) Ketotifen content The ketotifen content in each sample was measured using HPLC. The results are shown in Tables 10 to 16. As is clear from this result, it becomes clear that the active ingredient of the present invention is excellent in the effect of improving photostability by adding a specific ultraviolet absorber and / or antioxidant.

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

Formulation examples of the external preparation for suppressing melanin production of the present invention are shown below. In the prescription example, "appropriate amount" is 10 in total.
It means a ratio of 0% by weight.

<Formulation Example 1> Cream (% by weight) A Monostearic acid 2.0 Polyethylene glycol (40.E, O.) Self-emulsifying glyceryl monostearate 5.0 Stearic acid 5.0 Behenyl alcohol 1.0 Flow Paraffin 10.0 Glyceryl trioctanoate 10.0 Imipramine 0.01 Chlorimipramine 0.1 B Glycerin 5.0 Ethylparaben 0.1 Purified water Appropriate amount The components belonging to A are dissolved by heating. Separately, the components belonging to B are melted by heating. After adding B to A, stirring and emulsifying, cooling was performed to produce a cream.

<Formulation Example 2> Cream (% by weight) A Monostearic acid 2.0 Polyethylene glycol (40.E, O.) Self-emulsifying glyceryl monostearate 5.0 Stearic acid 5.0 Behenyl alcohol 1.0 Flow Paraffin 10.0 Glyceryl trioctanoate 10.0 2-Hydroxy-4-methoxybenzophenone 0.1 B Ketotifen fumarate 0.01 Glycerin 5.0 Ethylparaben 0.1 Purified water Appropriate amount The components belonging to A are dissolved by heating. Separately, the components belonging to B are melted by heating. After adding B to A, stirring and emulsifying, cooling was performed to produce a cream.

<Formulation Example 3> Emulsion (% by weight) A Polyoxyethylene sorbitan monostearate (20.E, O.) 1.0 Polyoxyethylene sorbitan monostearate (60.E, O.) 0.5 Lipophilic glyceryl monostearate 1.0 Stearic acid 0.5 Behenyl alcohol 0.5 Avocado oil 4.0 Glyceryl trioctanoate 4.0 Imipramine 4.0 B Ketotifen fumarate 0.5 1,3-Butylene glycol 5.0 Methylparaben 0.2 Purified water Appropriate amount A component belonging to A is dissolved by heating. Separately, the components belonging to B are melted by heating. After adding B to A, stirring and emulsifying, it was cooled to produce an emulsion.

<Formulation Example 4> Emulsion (% by weight) A Polyoxyethylene sorbitan monostearate (20.E, O.) 1.0 Polyoxyethylene sorbitan monostearate (60.E, O.) 0.5 Lipophilic glyceryl monostearate 1.0 Stearic acid 0.5 Behenyl alcohol 0.5 Avocado oil 4.0 Glyceryl trioctanoate 4.0 dl-α-tocopherol 0.05 4- (1,1 Dimethylethyl) -4 ′ -Methoxydibenzoylmethane 0.5 B Ketotifen fumarate 0.5 1,3-butylene glycol 5.0 Methylparaben 0.2 Purified water Appropriate amount A component belonging to A is dissolved by heating. Separately, the components belonging to B are melted by heating. After adding B to A, stirring and emulsifying, it was cooled to produce an emulsion.

<Formulation Example 5> Lotion (% by weight) Polyoxyethylene hydrogenated castor oil (60.E, O.) 1.0 Ethanol 15.0 Amitriptyline hydrochloride 5.0 Ethylparaben 0.1 Citric acid 0. 1 Sodium citrate 0.3 1,3-butylene glycol 4.0 Disodium edetate 0.01 Purified water Appropriate amount The above components were mixed, uniformly stirred and dissolved to produce a lotion.

<Formulation Example 6> Lotion (% by weight) Polyoxyethylene hydrogenated castor oil (60.E, O.) 1.0 Propyl gallate 0.01 Ethanol 15.0 Amitriptyline hydrochloride 5.0 Ethylparaben 0 .1 Octyl paramethoxycinnamate 0.1 Oil-soluble licorice extract 0.3 1,3-Butylene glycol 4.0 Disodium edetate 0.01 Purified water Appropriate amount Mix the above ingredients, stir evenly and dissolve Water was produced.

<Formulation Example 7> Cream pack (% by weight) A Veam 5.0 Squalane 2.0 2,2'-Iminodibenzyl 3.0 Propylene glycol 5.0 Vitamin B ₁₂ 0.05 Purified water Appropriate amount B Zinc oxide 10.0 C Ethanol 5.0 Ingredients belonging to A are mixed and stirred to swell, and B is added little by little. C was gradually added to this and kneaded until a paste was formed to produce a cream pack.

<Formulation Example 8> Essence (% by weight) Trimipramine 10.0 1% carboxyvinyl polymer solution 10.0 Glycerin 20.0 Hyaluronic acid 0.5 Ethanol 1.0 Purified water Appropriate amount The above components are mixed, The essence was manufactured by uniformly stirring and dissolving.

<Formulation Example 9> Essence (% by weight) Ketotifen fumarate 5.0 1% carboxyvinyl polymer solution 10.0 Glycerin 20.0 Hyaluronic acid 0.5 Ethylene glycol salicylate 0.1 Ethanol 5.0 Purified water suitable Amount The above components were mixed, uniformly stirred and dissolved to produce an essence.

<Formulation Example 10> Hydrophilic ointment (% by weight) A Polyoxyethylene cetyl ether 2.0 Glyceryl monostearate 10.0 Liquid paraffin 10.0 Vaseline 4.0 Cetanol 5.0 B Ketotifen fumarate 0. 05 Propylene glycol 10.0 Methylparaben 0.1 Purified water Appropriate amount The components belonging to A are dissolved by heating. Separately, the components belonging to B are dissolved by heating. After adding B to A, stirring and emulsifying, it was cooled to produce a hydrophilic ointment.

<Formulation Example 11> Hydrophilic ointment (% by weight) A Polyoxyethylene cetyl ether 2.0 Glyceryl monostearate 10.0 Liquid paraffin 10.0 Vaseline 4.0 Cetanol 5.0 Tetrahydroxybenzophenone 0.1 B Ketotifen fumarate 0.05 Propylene glycol 10.0 Methylparaben 0.1 Purified water Appropriate amount The components belonging to A are dissolved by heating. Separately, the components belonging to B are dissolved by heating. After adding B to A, stirring and emulsifying, it was cooled to produce a hydrophilic ointment.

<Formulation Example 12> Gel agent (% by weight) A Polyvinyl alcohol (PVA) 2.5 Polyvinylpyrrolidone (PVP) 1.0 Carrageenan 1.0 Polyoxyethylene hydrogenated castor oil (100E.O.) 3.0 Epigallocatechin gallate 0.01 B Ethanol 40.0 C Purified water Appropriate amount D Ketotifen fumarate 1.0 Disodium edetate 0.01 Sodium 2-hydroxy-4-methoxybenzophenone-5-sulfonate 0.7 A Add to B to disperse, add C little by little and stir. Further, D was added little by little and mixed uniformly and stirred to produce a gel agent.

[0088]

According to the present invention, iminodibenzyls,
There is provided a melanin production-inhibiting external preparation containing as an active ingredient at least one member selected from the group consisting of dibenzocycloheptadienes and ketotifen fumarate.
Since it contains an active ingredient with good transdermal absorption, it exhibits an excellent melanin production inhibitory effect and is useful not only for the prevention of spots and freckles, but also for treatment. Furthermore, by adding a whitening agent, a more excellent melanin production inhibitory effect is exhibited, and by adding a specific ultraviolet absorber and / or antioxidant, and further alcohols, coloring by heat or light and Decomposition is effectively suppressed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 7/42 7252-4C

Claims (7)

[Claims] 1. An external preparation for suppressing melanin production, which comprises at least one selected from the group consisting of iminodibenzyls, dibenzocycloheptadienes, and ketotifen fumarate as an active ingredient. 2. The external preparation for suppressing melanin production according to claim 1, which further comprises at least one kind of whitening agent. 3. A whitening agent is kojic acid, ascorbic acid,
Hydroquinone, liquiritin or their derivatives,
And at least one selected from the group consisting of placenta extract
The external preparation for suppressing melanin production according to claim 2, which is a seed. 4. The composition according to claim 1, further comprising an ultraviolet absorber.
An external preparation for suppressing melanin production according to any one of 1 to 3. 5. The ultraviolet absorber is a dibenzoylmethane compound, an oxybenzone compound, a cinnamic acid compound,
And at least one selected from the group consisting of plant extract having an absorption spectrum from the UV-B region to the UV-A region, the external preparation for suppressing melanin production according to claim 4. 6. The external preparation for suppressing melanin production according to claim 1, which further comprises an antioxidant. 7. The method according to claim 1, further comprising an alcohol.
7. The external preparation for suppressing melanin production according to any one of 1 to 6.