JPH042562B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an ointment or cream that suppresses the increase in melanin formation that causes melasma and sparrow spots, prevents the suntan effect of ultraviolet rays, and bleaches the formed melanin pigment to create fair and beautiful skin. . Although melanogenesis has not been completely elucidated, researchers generally agree on the existence of the following three processes. (1) The process leading to the formation of tyrosine → dopa… → dopachrome (catalyzed by tyrosinase) (2) The polymerization process that leads to dopachrome…→ melanin, which does not involve enzymes and includes an oxidation reaction, (3) In addition, It is said that the melanin production process includes a process activated by active enzymes (superoxides). Therefore, to suppress melanin production, (a) inhibition of tyrosinase, (b) inhibition of generation of active enzymes, removal of active enzymes, (c) blocking of ultraviolet rays, (d) inhibition of oxidation reaction, and (v) inhibition of polymerization process. , (f) decomposition of generated melanin, and (g) adsorption of melanin. As is well known, in the skin, melanin pigment is formed by melanocytes present in the basal layer of the epithelium, migrates to keratinocytes, and is eventually lost to the outside of the body as the keratinized cells exfoliate. Therefore, the amount of melanin pigment in the skin is determined by the production-disappearance equilibrium. The present inventor paid attention to this point and invented a strong adsorbent for melanin pigment. Another feature, which can be called a fundamental feature, of the present invention is that melanin production is divided into many processes, each of which has many points of attack. Therefore, a feature of the present invention is to use a variety of drugs and to expect their synergistic effects. Even now,
Anti-melasma and whitening effects by suppressing melanin production were not necessarily impossible, but by simplifying and unifying the point of attack, the use of powerful or highly concentrated drugs could be fatal. This was because I had to avoid side effects. According to the present invention, β-thujaplicin, as a tyrosinase inhibitor,
Hydroquinone, one or more pyrone compounds, and as a melanin pigment adsorbent Molecular formula: xAl ₂ O ₃・SiO ₂・yH ₂ O (where x = 2 ~
By blending hydrated aluminum silicate represented by 5, y = 18 to 20 with an adsorbent carrying one or more reducing substances, anti-melasma and skin whitening that overcome the above defects can be achieved. A targeted ointment or cream is provided. The fundamental features of the present invention can be summarized as follows. (1) There are various points of attack for suppressing the melanin production process, and by using various attack methods, a synergistic effect can be produced and the side effects caused by exclusive use of each attack can be attenuated. (2) The equilibrium between production and disappearance of melanin pigment is shifted toward disappearance by using an adsorbent. The above principle will be specifically explained below. Tyrosinase Inhibitors There are many substances known to have tyrosinase inhibitory effects, among which hydroquinone and its derivatives are well known as those that have been used clinically. Among these, hydroquinone itself has obtained numerous clinical results to date. In conclusion, long-term use of hydroquinone at high concentrations (4-6%) clearly has a skin-lightening effect, but it is unusable due to side effects such as vitiligo. Although there are no side effects when using up to 2% hydroquinone, the effects are not clear either. The tyrosinase inhibitory action of β-thujaplicin, which is different from the reducing agent hydroquinone, and the inhibitory action of pyrone compounds are completely different from the reducing action. The present inventor discovered that the combined use of hydroquinone and β-thujaplicin and the combined use of hydroquinone and a pyrone compound exhibit a synergistic effect in inhibiting tyrosinase. Therefore, hydroquinone,
It has been learned that when a pyrone compound and β-thujaplicin are used in combination, a strong effect can be obtained at a dose that is not effective or shows only a mild effect when used alone, but it can be expected that no side effects will occur. Note that there is no synergistic effect between β-thujaplicin and the pyrone compound, but only an additive effect. Example 1 (Tyrosinase inhibitory effect of each and the combination of β-thujaplicin and hydroquinone) Tyrosinase from Pinus rum (manufactured by Sigma)
The method of Pomerantz (1963) was used to measure dopachrome produced using tyrosine as a substrate. Pyrocomenic acid as a pyrone compound
was used. Pyrone compounds such as maltol, ethyl maltol, hydroxymaltol, and kojic acid all had some degree of tyrosinase inhibitory activity, and a similar synergistic effect was observed. The experimental results are summarized in Table . -(A) Inhibitor of photochemical reaction generating active oxygen Various inhibitors are known, but superoxide dismutase (SOD) catalyzes the reaction of 2O ₂ ^- +2H ⁺ →H ₂ O ₂ + O ₂ Glucosamine salts inhibit O ₂ ^- generation through photochemical reactions. The combination of these substances with different mechanisms of action is meaningful. Glucosamine is unstable and cannot be used;
Since glucosamine hydrochloride cannot be expected to have long-term stability, it is better to use an acyl form of glucosamine (acetyl-, palmitoyl-, steatyl-glucosamine, etc.). Glucosamine is also known to inhibit melanosome formation. −(B) Active oxygen scavenger The active oxygen scavenging effect was evaluated using the pyrogallol autoxidation method (S. Marklund and G. Marklund, Eur.J.
(1974) 47 , 469) and the 5-hydroxydopamine autoxidation method (REHeikkila and F.
Cabbat.Analyt.Biochem. (1976) 75 , 356), ascorbic acid and cysteine (C ₃ H ₇ NO ₂ S) derivatives were the strongest. Example 2 (Active oxygen removal effect) Pyrogallol autoxidation method and 5-hydroxyde
Cysteine derivatives, using pamine autoxidation method,
The completed oxygen scavenging action of ascorbic acid, etc. was measured. The experimental results are summarized in the table. Dopa oxidation and polymerization inhibitor Many reducing substances can inhibit the melanin formation reaction using dopa as a starting material, but L-cysteine derivatives and ascorbic acid have the strongest effects. Example 3 (Suppression effect of reducing agent) Dopa 0.5% phosphate buffer solution (PH7.0)
Blow air into the sample for 3 days and measure the melanin produced (measure absorbance at 470 mμ). Inhibition by inhibitors was determined in % with non-inhibiting substances as 100% (see table) Example 4 of inhibitors of dopa oxidation-polymerization promoting effect of long ultraviolet rays (Inhibitory effect of long ultraviolet rays) Experiment conducted in Example 3 When carried out under long ultraviolet irradiation,
Formation of melanin is observed after 3 hours. Using a high-pressure mercury lamp whose emission spectrum has a strong line spectrum between 365 and 597.1 nm,
Melanin formation in 0.5% DOPA/phosphate buffer solution was measured at absorbance at 470 mμ (see table).
The inhibitory effect of cysteine derivatives was outstanding, but
Pyrone compounds and ascorbic acid also showed clear inhibitory effects. Melanin decomposing agent example 5 (Melanin decomposing ability) It was discovered that substances that decompose melanin include oxidizing agents such as hydrogen peroxide and soda percarbonate, and reducing agents such as cysteine and glutathione. however,
Oxidizing agents are not preferred because they have the effect of accelerating the polymerization process. Cysteines have the strongest melanin-degrading action as reducing agents (see table). A cysteine derivative was added to a 0.01% melanin solution (PH6.2), and the decomposition of melanin was investigated at an absorbance of 470 mμ. The experimental results are summarized in the table. Melanin Adsorbent Research conducted by the present inventor proved that various natural silica-alumina compounds have melanin adsorbing properties, and subsequently, various silica-alumina-based melanin adsorbents were synthesized by the present inventor. . Among them, the adsorption capacity of hydrated silica/alumina supporting reducing substances was the highest. These adsorbents are insoluble in water and consist of particles of several microns, so they cannot be expected to penetrate deeply into the skin. Keratolytic agents such as urea and salicylic acid were used to aid in the penetration of this adsorbent and to speed up the disappearance of melanin pigment. The reducing substance-supported hydrated silica/alumina (hydrated aluminum silicate) adsorbent used as a melanin pigment adsorbent in the present invention is patented under Patent No. 1403942.
No. 62-11610 specification (see Publication No. 62-11610). The method for synthesizing hydrated aluminum silicate itself is described in detail in JP-A-55-136118. In summary, silica was added to a strongly acidic solution of an aluminum compound, such as aluminum sulfate, and then gradually neutralized with an alkali to a weakly acidic to neutral state. This hydrated aluminum silicate has the molecular formula xAl ₂ O ₃ .
SiO ₂ yH ₂ O (in the formula, x = 2 ~ 5, y = 18 ~ 20
), and examination of the X-ray diffraction image reveals that it is amorphous. Also, according to differential thermal analysis, an endothermic peak due to favorable water and adsorbed water is observed at 60℃, an endothermic peak due to the OH group of polymerized aluminum hydroxide ions at 215℃ and 320℃, and a small exothermic peak at around 1000℃. . Aluminum silicate having the above characteristics is named hydrated aluminum silicate. When synthesizing this hydrated aluminum silicate, by adding inorganic and organic reducing substances,
A reducing substance-supported hydrated aluminum silicate is produced. Examples of reducing substances to be supported include inorganic substances such as thiosulfate, sulfite, sodium bisulfite (sodium bisulfite), iron salt,
Copper salts, sulfide salts, tripolyphosphates, organic substances such as longalites, hydroquinone, formaldehyde, paraformaldehyde, thiourea, cystene thioglycerin, thiosorbitol, vitamin E, reduced ubiquinone, glutathione, succinic acid, etc. be. By supporting one type or a combination of two or more of these reducing substances, the reducing substance-supported hydrated aluminum silicate used in the present invention can be obtained. Ultraviolet Absorber It is well known that sunlight causes thickening of the skin's keratin and promotes melanin pigment production. Therefore, it is extremely meaningful to take measures to eliminate the effects of sunlight. For this purpose, it is necessary to incorporate a UV absorber. Para-aminobenzoic acid-based, salicylic acid-based, cinnamic acid-based, benzophenone-based, and azo-based compounds are known as ultraviolet absorbers. Any of them may be used, but an example is urocanic acid, which exists in human epidermis. Based on the above experimental results and theory, we attempted to develop an external melanin production suppressing agent and conducted numerous experiments. Due to the use of several reducing agents and inorganic substances, special care is required in the formulation. Commonly used dosage forms include ointments, creams, packs, and patches. Two typical prescription examples are shown below. Example 1 (Formulation example) Ingredients for external ointment to inhibit melanin production Weight% Urea 5-15 Salicylic acid 0-0.5 or sodium salicylate 0-2.0 β-Thuyaprisin 0.03-0.05 Hydroquinone 0-2.0 Pyrone compound 0-2.5 Cysteine hydrochloride 0 ~2.0 Ascorbic acid stearate 0~0.1 Hypo 0~2.0 Sod.metasulphite 0~0.05 Sod.sulphite anhydrous 0~0.02 Acylglucosamine 0~2.0 SOD 0~Adequate amount EDTA 0~0.05 α-Tocopherol 0.05~0.1 Component Weight% Urocanin Acid 0 to 1.0 Water-soluble components are dissolved in water, added to a mixture of Carbowax 400 and 4000 in an appropriate ratio, fat-soluble components are added, and finally 5% melanin adsorbent is added. Add and mix well. All operations are performed under a nitrogen stream, and the sample is packed in a light-tight, airtight container. Example 2 (Prescription example) Ingredients of external cream for inhibiting melanin formation Weight (%) Urea 5-10 Hydroquinone 1.0-2.0 Maltol 1.0 Cysteine hydrochloride 1.0-2.0 Purified water (dissolved air replaced with nitrogen) Appropriate amount of salicylic acid 0.2 β - Thujaplicin 0.03 Hydroquinone 1.0 Ingredients Weight % EDTA 0.03 α-tocopherol 0.1 Ascorbic acid stearate 0.05 Glycerin Appropriate amount Mix with a suitable cream prepared under a nitrogen stream and immediately fill into an airtight, light-shielding container. The table below shows the effects and synergistic effects of the various compounds used individually, in combination, and in the blended amounts of the ointments and creams of the present invention.

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Claims (1)

[Scope of Claims] 1. One or more of β-thujaplicin, hydroquinone, and pyrone compounds as a tyrosinase inhibitor, and a molecular formula xAl ₂ O ₃ · SiO ₂ · yH ₂ O (in the formula, x = 2) as a melanin pigment adsorbent. ~
5, y = 18 to 20) for the purpose of anti-melasma and skin whitening, which is characterized by blending hydrated aluminum silicate with an adsorbent carrying one or more reducing substances. ointments and creams. 2. The ointment and cream according to claim 1, further comprising a non-oxygenated dopa oxidation polymerization inhibitor and one or more of vitamin C, cysteine hydrochloride, cysteine derivatives, and glutathione as an ultraviolet suntan effect inhibitor. 3. The ointment and cream according to claim 1, further comprising one suitable substance among various substances having anti-sunburn and anti-suntan effects. 4. The ointment and cream according to claim 1, which contain an active oxygen generation inhibitor and an active oxygen remover. 5. The ointment and cream according to claim 1, further comprising urea, salicylic acid, or a salt thereof as a keratolytic agent.