KR20130058299A - A composition for improving, preventing or treating skin hyper-pigmented diseases and for whitening skin containing 1,3-diolein or 1,3-dilinoleoyl-rac-glycerol - Google Patents

Abstract

PURPOSE: A pharmaceutical composition and a health functional food composition for preventing or treating hyperpigmentary disorders, and a composition for skin whitening, containing 1,3-diolein or 1,3-dilinoleoyl-rac-glycerol are provided to suppress alpha-glucosidase and melanogenesis, and to prevent, treat, or alleviate hyperpigmentary disorders due to excessive melanin generation and to ensure effective skin whitening activities. CONSTITUTION: A pharmaceutical composition for preventing or treating hyperpigmentary disorders due to excessive melanin generation contains 1,3-diolein of chemical formula 1 or 1,3-dilinoleoyl-rac-glycerol of chemical formula 2, or a pharmaceutically acceptable salt thereof as an active ingredient. A food composition for preventing or treating hyperpigmentary disorders contains the compound of chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof as an active ingredient. A cosmetic composition for skin whitening contains the compound of chemical formula 1 or 2, or a pharmaceutically acceptable salt thereof as an active ingredient.

Description

A composition for improving, preventing or treating skin hyper-pigmented containing 1,3-diolein or 1,3-dilinoreyl-lac-glycerol diseases and for whitening skin containing 1,3-Diolein or 1,3-Dilinoleoyl-rac-glycerol}

The present invention relates to a composition for improving, preventing or treating skin hyperpigmented diseases containing 1,3-diolein or 1,3-dilinoleyl-lac-glycerol, and more specifically, It contains two major constituent compounds, 1,3-Diolein and 1,3-Dyinoleoyl-lac-glycerol, as active ingredients. The present invention relates to a pharmaceutical composition for preventing or treating skin pigmentary diseases due to excessive melanin formation, a health functional food composition for improving disease, and a composition for skin whitening.

Melanin, which determines human skin color, is made from skin cells called melanocytes and migrates to epidermal cells called keratinocytes. Here, melanin plays an important role in forming a cap-like structure around the nucleus to protect genes from ultraviolet rays and to remove free radicals to protect intracellular proteins.

Melanogenesis refers to the biosynthesis of melanin pigments in melanocytes, which are regulated by intracellular and extracellular environments. This melanogenesis is triggered by tyrosinase, which oxidizes tyrosine to dopaquinone, which continues to convert to a pale yellow / red compound, pheomelanin, and light brown to black eumelanin. do. In the skin, melanin affects pigmentation and protects the skin from ultraviolet and other causes of skin disease, while abnormal accumulation of melanin may also cause spots and freckles.

Skin pigmented diseases caused by melanin hyperplasia include genetic skin diseases such as alum, Badenburgh syndrome, acquired skin diseases such as episodic white nasal mucus, unexplained droplets melaninosis, blemishes, medication Skin diseases caused by, for example, minocycline, bleomycin, busulfan, zidovudine, and skin diseases that have spread through infection, such as stumps.

There are no enzymes that break down melanin in the body, but when keratinocytes break away from the epidermis, they are removed by falling off the skin with melanin. However, if more melanin is produced than necessary, it causes hyperpigmentation such as blemishes, freckles, and spots, resulting in cosmetically bad results. In addition, as the leisure population increases, more people enjoy working outside, and the demand to prevent melanin pigmentation due to ultraviolet rays is increasing. Therefore, it was necessary to develop a whitening agent that prevents excessive melanin production and many efforts have been made.

Until now, the development of whitening agents has been mainly focused on finding a substance that reduces melanin by inhibiting the activity of tyrosinase, a basic and most important enzyme in melanin biosynthesis. Recent studies on synthetic whitening agents have explored the use of alkoxy benzoates and alkoxy cinnamate derivatives, and hydroxamic acid. Other studies have shown derivatives of known tyrosinase inhibitors, for example 5-[(3-aninopropyl) phosphinooxy] -2- (hydroxymethyl) -4 H- pyran-4-one (5- [ (3-aminopropyl) phosphinooxy] -2- (hydroxymethyl) -4 H- pyran-4-one), and N-hydroxy-cinnamoyl pen alkyl- the focal point in the synthesis of amides (N -hydroxycinnamoylphenalkyl-amide) derivative tailored there was.

The whitening agents developed in this way include kojic acid, arbutin, glutathione, vitamin A, and vitamin C. However, the whitening agent does not have a satisfactory whitening effect. Therefore, it is an urgent time to develop a whitening agent that is more effective and safer than ever.

Tyrosinase, an enzyme that synthesizes melanin, is a glycoprotein and is produced through glycosylation, a glycoprotein synthesis in vivo. If there is a problem in the glycosylation process, and the abnormal part of the tyrosinase sugars, the tyrosinase cannot move to the melanosome, a place of intracellular melanin biosynthesis, and thus the melanin production cannot be achieved.

Many enzymes are involved in the glycosylation process, an important enzyme of which is glucosidase. If the enzyme can inhibit the enzymatic activity, it can inhibit the melanin biosynthesis and thus bring about a whitening effect.

In this regard, Korean Patent Application No. 10-2004-0025053 'Skin Whitening Composition Containing Actinomycetes Culture Extract' includes actinomycetes strain or Actinomycetes culture extract, which is an enzyme involved in melanin biosynthesis. Glycosylation of tyrosinase by inhibiting the enzymatic activity of beta-glucosidase, an important enzyme involved in the process of glycosylation to synthesize tyrosinase It is disclosed that the whitening effect is obtained by inhibiting melanin production by inhibiting.

Peach Kernel (Persicae Semen) is a seed of Prunus persica Batsch or Prunus davidiana Maximowicz (Rosaceae). Seeds are used as herbal medicine and are called Persicae Semen.

Doin is a blood clot (혈), blood, anti-inflammatory, analgesic, menstrual irregularity, constipation is effective in improving blood circulation. Generally, the fruits of the radish tree belonging to the Rosaceae are collected after maturation to remove the pulp and core grains, and only the seedlings are dried and dried to make powder.The ingredients are 40 ~ 50% fatty oil, 3.49% cyanide glycoside, 3.8% prunasin, 0.38% emusin , And anticoagulant active substance, and has anticoagulant action and weak hemolysis action to release blood stiffness.瘀血 腫痛) to loosen (Chinese medicine dictionary, p1788) has the effect of turning the blood well. In addition, bleeding, expectoration and lubrication, such as pharmacological action.

The effects of doin from recent scientific research have shown that it protects against cytotoxicity of normal human keratinocytes and fibroblasts due to UV (Archives of Phamacial Research, 2000, 23 (4), 396-400), containing inhibitors for mutagens have been reported (Yakugaku Zasshi-J, Pharmaceutical Society of Japan, 1992, 112 (12), 934-9), hypocholesterolemic It has been reported to lower the cholesterol level of mice (Kor. J. Pharmacogn., 1990, 21 (2), 153-157) and oxygen radical scavenging activity (Yakugaku Zasshi-J. Pharmaceutical Society of Japan , 1985, 105 (9), 895-901).

Doin extract is a whitening agent in a mixed form of various herbal medicines, for example, Korean Patent Application No. 10-2007-0082003 'Cosmetic Composition Containing Extracts and Fractions of Stein' and Korean Patent Application No. 10-2004-0103894 Preparation of Doin Extract Containing Camperol-3-Galactopyranoside, Camperol-3-0-Alpha-L-Rhamnopyranoside, Camperol-3-0-Beta-L-Glucopyranoside and Its There is an example developed as a 'whitening cosmetics used.'

As such, the present inventors have searched for the ability to inhibit the activity of glycosidase enzyme in various plant extracts in order to develop a new whitening substance that is more effective and safer than ever before, and the phosphorus extract has a very high inhibitory activity of glucosidase enzyme activity. This was found to be due to 1,3-diolein and 1,3-dilinoreyl-lac-glycerol to complete the present invention.

1. Republic of Korea Patent Application No. 10-2007-0082003 2. Korean Patent Application No. 10-2004-0103894

Archives of Phamacial Research, 2000, 23 (4), 396-400 Yakugaku Zasshi-J, Pharmaceutical Society of Japan, 1992, 112 (12), 934-9 3. Kor. J. Pharmacogn., 1990, 21 (2), 153-157 4. Yakugaku Zasshi-J. Pharmaceutical Society of Japan, 1985, 105 (9), 895-901

Accordingly, an object of the present invention is a pharmaceutical for preventing or treating skin pigmentation diseases caused by melanin excess production containing 1,3-diolein derived from doin and 1,3-dilinoreyl-lac-glycerol as an active ingredient. It is to provide a composition.

Another object of the present invention is a health functional food for preventing or improving skin pigment disease caused by the excessive production of melanin containing 1,3-diolein derived from doin and 1,3-dilinoleyl-lac-glycerol as an active ingredient. It is to provide a composition.

It is another object of the present invention to provide a cosmetic composition for skin whitening containing 1,3-diolein derived from phosphorus and 1,3-dilinoreyl-lac-glycerol as an active ingredient.

The object of the present invention as described above is to prepare an extract from the indoin, and to prepare a fraction from the extract again, to derive a fraction excellent in alpha glucosidase inhibitory effect of these fractions, and then to identify the chemical structure of the fraction Was achieved.

The present invention is directed to melanin excess production containing 1,3-diolein of formula 1 and 1,3-dirirenoyl-lac-glycerol of formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient. It provides a pharmaceutical composition for preventing or treating dermal pigmentary diseases caused.

The present invention also provides a melanin-excessive production containing 1,3-diolein of Formula 1 and 1,3-dilinoreyl-lac-glycerol of Formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient It provides a health functional food composition for preventing or improving the skin pigment disease caused.

The present invention is also for skin whitening containing 1,3-diolein of the formula (1) and 1,3- dirinoleoyl-lac-glycerol of the formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient It provides a cosmetic composition.

In the present invention, the term "active ingredient" refers to a substance or a group of substances (a medicinal agent whose pharmacologically active ingredient is not known, etc.) which is expected to express the efficacy or effect of the drug directly or indirectly by inherent pharmacological action. It means containing a main component).

In the present invention, "health functional food" means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to the Health Functional Food Act No. 6767, and "functional" means a human body It means the ingestion for the purpose of obtaining a useful effect in health use such as nutrient control or physiological action on the structure and function of.

Compounds of formulas (1) and (2) according to the present invention effectively inhibit the enzymatic activity of glucosidase involved in the glycosylation process, a synthesis process of tyrosinase, an enzyme that biosynthesizes melanin in skin cells. By inhibiting the biosynthesis of melanin to vaporize the skin whitening activity, it is possible to prevent, ameliorate or treat the resulting skin pigmentation disease by inhibiting the excessive formation of melanin.

In the present invention, the skin pigmentation diseases caused by the melanin over-forming, such as genetic skin diseases, such as alum, Badenburgh syndrome, acquired skin diseases, such as infectious white nasal mucus, unknown cause of water droplet melanin Hypolipidemia, blemishes, skin diseases due to pharmacotherapy, such as minocycline, bleomycin, busulfan, zidovudine, and skin diseases metastasized through infection, such as clumps and the like.

Pharmaceutical compositions comprising the compounds of Formula 1 and Formula 2 of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.

Pharmaceutical compositions comprising the compounds of formulas (1) and (2) of the present invention may be oral formulations, external preparations, suppositories, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc. It can be formulated and used in the form of sterile injectable solutions.

Carriers, excipients and diluents which may be included in pharmaceutical compositions comprising the compounds of Formulas 1 and 2 of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia Rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Can be. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose in the extract. Or lactose, gelatin, or the like is mixed. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

Preferred dosages of the compounds of formulas (1) and (2) according to the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the compound of formula 1 of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 100 mg / kg per day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.

The compounds of Formula 1 and Formula 2 according to the present invention can be administered to mammals such as mice, mice, livestock, humans, etc. by various routes. All modes of administration can be expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injections and directly to the skin.

In addition, the compounds of the formulas (1) and (2) according to the present invention may be added to food or beverages for the purpose of preventing or ameliorating the skin pigment disease caused by melanin overproduction. Examples of foods to which the compounds of formulas (1) and (2) can be added include various foods, beverages, gums, teas, vitamin complexes, health functional foods, powders, granules, tablets, capsules or beverages. At this time, the amount of the compound of formula 1 in the food or beverage may be added to 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 5 g, preferably 0.3 to 1 g based on 100 ml Can be added in proportion.

The food composition of the present invention is not particularly limited to other ingredients except for containing the compounds of the formulas (1) and (2) as essential ingredients in the proportions indicated, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary beverages. Can be. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of said natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.

In addition to the above, the compounds of the formulas (1) and (2) of the present invention include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents such as natural flavoring agents, colorants and neutralizing agents (cheese, chocolate, etc.), pectic acid and Salts, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like. In addition, the compounds of the formulas (1) and (2) of the present invention may contain flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical but it is generally the intent of the present invention to be selected in the range of 0 to about 20 parts by weight per 100 parts by weight.

In the cosmetic composition of the present invention, the composition is characterized in that the formulation of the lotion (skin lotion), lotion, cream, massage cream, essence, pack. The formulations may be prepared using methods known in the art. In addition, the content of the compounds of Formula 1 and Formula 2 in the formulation may also be included within the content range (about 1-10% by weight) conventionally known in the art.

Components included in the cosmetic composition of the present invention as an active ingredient may include components commonly used in cosmetic compositions in addition to the compounds of Formula 1 and Formula 2, for example, stabilizers, solubilizers, vitamins, pigments and Conventional adjuvants such as perfumes and carriers.

In the present invention, Persicae semen ) was crushed into 30-40 mesh, roasted at high temperature, and pressed using a milking machine to obtain compressed oil, which was used as a raw material after the filter.

Using the above-mentioned pressurized oil, alpha-glucosidase recognizes the glucoside portion of p -nitrophenyl ( p NP) alpha-D-glucoside as a substrate, and breaks p NP and alpha-D-glucoside by enzymatic reaction. , The amount of p NP released here was measured by absorbance at 405 nm, thereby indirectly measuring alpha-glucosidase activity. As a result, the pressed oil was found to have an enzyme activity inhibitory effect (see Fig. 1).

By identifying the structure of the compressed oil, it was confirmed that the main substances of the compressed oil were 1,3-diolein and 1,3-dilinoreyl-lac-glycerol, and the glucosidase inhibitory effect on the substance was measured. It was confirmed excellent (see Fig. 2).

As described above, 1,3-diolein, 1,3-dilinoreyl-lac-glycerol, which is a phosphorus-derived compound according to the present invention, has an excellent effect on inhibiting alpha glucosidase and inhibiting melanogenesis, resulting in melanin overproduction. While it can prevent, treat or ameliorate the skin pigmentation resulting from the skin, it can be very effective for the skin whitening activity, which is a very useful invention for the pharmaceutical industry and the cosmetic industry.

1 is a graph showing the results of the evaluation of inhibition of alpha-glucosidase activity of cabbage oil.
Figure 2 is a graph showing the effect of inhibiting alpha glucosidase of 1,3-diolein, 1,3-dilinoleyl-lac-glycerol, which is a major component of the pressed oil.
Figure 3 is a graph of the major components of the quenching criterion by GC-MASS.
Figure 4 is a photograph showing the pigmentation inhibitory effect on the skin tissue of the pressed oil.
Figure 5 is a graph showing the change in brightness by measuring the L value of skin tissue treated with cabbage oil.
Figure 6 is a photograph showing that the melanin granules formation was inhibited by staining the skin tissue treated with cavern oil.

Hereinafter, preferred embodiments of the present invention will be described in more detail with reference to Examples. However, the scope of the present invention is not limited to these examples.

Example  1: Manufacture of Doin Extract

Persicae semen ) After grinding to 30-40 mesh, roasted at a high temperature, compressed by using a milking machine to obtain a pressurized oil was used as a raw material after the filter.

Example  2: manufacture of cabbage extract

Persicae semen ) was pulverized to 30-40 mesh, heat treated with steam in a steamer at a pressure of 2-3 kgf / cm3, the sample was dried at room temperature and extracted by mixing an organic solvent such as ethanol.

Example  3:: dodoin extract manufacture

Persicae semen ) was pulverized into 30 ~ 40 mesh, and then extracted by mixing with a predetermined ratio with an organic solvent (eg ethanol).

Experimental Example  1: alpha Glucosidase  Inhibitory efficacy assessment

For the fraction obtained in Example 1, alpha-glucosidase recognizes the glucoside portion of p -nitrophenyl ( p NP) alpha-D-glucoside as a substrate, and p- NP and alpha-D-glucoside are enzymatically reacted. The amount of p NP released here was measured by absorbance at 405 nm, thereby indirectly measuring alpha-glucosidase activity. Sample material and alpha-glucosidase (0.6 unit / ml) were added to 50 mM phosphate buffer (pH 6.5), and 10 mM p NP alpha-D-glycoside solution was added for enzymatic reaction at 37 ° C. for 50 minutes. After the reaction, 0.1 M Na ₂ CO ₃ was added to stop the reaction. The amount of p NP produced in the enzyme reaction was determined by measuring the absorbance at 405 nm.

As a result, as shown in Figure 1, the pressurized milk fraction was shown to have an enzyme activity inhibitory effect.

Experimental Example  2: 1,3- Diorine , 1,3- Dirinore oil Of rock-glycerol Glucosidase  Inhibitory effect

1,3-diolein, 1,3-dilinoreyl-lac-glycerol fractions, which are the main constituents of the pressurized milk, were obtained with respect to the pressurized pressurized oil which was evaluated to have an excellent effect on inhibiting alpha glucosidase in Experimental Example 1. .

Using this fraction, the effect of inhibiting glucosidase was measured in the same manner as in Experimental Example 1.

As a result, as shown in Figure 2, it was confirmed that the activity of 1,3-diolein (Compound 1), 1,3-dirinoleoyl-lac-glycerol (Compound 2) is excellent, and each compound is represented by Formula 1 , It was confirmed to have a structure of formula (2).

Compound 1 [1,3- Diorine  (1,3- Diolein )]

Formula 1

Compound 2 [1,3- Dirinore oil Rock-glycerol (1,3- Dilinoleoyl - rac - glycerol )]

(2)

Experimental Example  3: inhibitory effect of melanin formation through human skin tissue culture

Human skin tissues were cultured, and the pigmentation progressed on the 3rd, 5th, 7th, and 9th days before the treatment of the cadaveric squeezed milk.

As a result, as shown in FIG. 4, when treated with kojic acid, which is a positive control, as compared to DMSO, which is a negative control, the degree of pigmentation difference was decreased, and the tissues of the tissues over time by the squeezed milk. It was confirmed that the difference in brightness was small.

In addition, as shown in FIG. 5, when the L value of the tissue photograph was measured by Photoshop and the L value before the treatment was plotted for each time zone, the graph of the skin tissue in the squeezed milk over time compared to the negative control DMSO. The brightness was dimmed less, indicating an inhibitory effect on skin pigmentation.

After 9 days of treatment with the skin tissues, melanin and H & E staining were performed to measure melanin pigment formation and distribution. As shown in FIG. 6, melanin granules were treated in the treated group compared to DMSO, a negative control in the treated group. This decrease was confirmed.

Claims (3)

Dermal pigmented disease due to melanin excess production containing 1,3-diolein of formula (1), 1,3-diolinoyl-lac-glycerol of formula (2), or a pharmaceutically acceptable salt thereof as an active ingredient Prophylactic or therapeutic pharmaceutical compositions:
Formula 1

Formula 2

Due to the excessive production of melanin containing 1,3-diolein of formula 1 according to claim 1, 1,3-dirinoleoyl-lac-glycerol of formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient Health functional food composition for preventing or improving skin pigmentation disease.
A cosmetic composition for skin whitening comprising 1,3-diolein of formula 1 according to claim 1, 1,3-dirinoleoyl-lac-glycerol of formula 2 or a pharmaceutically acceptable salt thereof as an active ingredient.

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