KR101928988B1 - Composition for skin whitening comprising functional peptide and fermented product - Google Patents

Abstract

The present invention relates to a skin whitening composition comprising a functional peptide and a fermented product. More particularly, the present invention relates to a skin whitening composition containing a functional peptide and a fermented product. More specifically, the present invention relates to a skin whitening composition comprising a tranexamoyl- The present invention relates to a composition for skin whitening comprising peptides (Nicotynoly-peptide), tranexamic acid, lemon peel fermentation extract and orange peel fermentation extract as active ingredients.
The composition for skin whitening according to the present invention inhibits melanin production and inhibits tyrosinase activity to exert excellent effects on skin whitening, and is excellent in heat stability and light stability, and is useful for skin whitening cosmetics, medicines and health functional foods It can be very useful for development.

Description

Technical Field [0001] The present invention relates to a skin whitening composition comprising a functional peptide and a fermented product,

The present invention relates to a skin whitening composition comprising a functional peptide and a fermented product. More particularly, the present invention relates to a skin whitening composition containing a functional peptide and a fermented product. More specifically, the present invention relates to a skin whitening composition comprising a tranexamoyl- The present invention relates to a composition for skin whitening comprising peptides (Nicotynoly-peptide), tranexamic acid, Bifida fermented lysate and citrus peel fermented extract as active ingredients.

Skin is the largest tissue in the body and functions to protect the inside of the body from sunlight, physical and chemical stimuli, which is absolutely necessary for the maintenance of human life and is constantly regenerated to maintain homeostasis. The skin is composed of the epidermis, the dermis and the subcutaneous fat in order from the outside. The skin which is the thinnest tissue plays an important function for moisturizing and protecting the skin, and it plays a role to prevent water loss, damage and invasion of bacteria. Skin is a tissue that covers the whole body and has various functions. It has a barrier function between the inside and the outside of the body, so it has an immune system by Langerhans, and it has moisture control function by epidermis. It also synthesizes vitamin D in the proper sunlight and also excretes lipids into the reservoir and sweat glands. The stratum corneum, which is produced by the normal differentiation process in healthy skin, has the function of maintaining the moisturization of the skin and protecting it from the stimulation of the external environment. This function is called skin barrier function and it is the most important role of the epidermis.

The research methods and trends of the development of the new whitening material are melanin biosynthesis which determines skin color, tyrosinase, TRP-1 (tyrosinase related protein 1) in melanocyte present in the basal layer together with external stimuli such as ultraviolet ray, , And TRP-2 (tyrosinase related protein 2), and the interaction of various cell signaling substances such as α-MSH hormone, IL-1, α-TNF and GMCSF, (Hearing & Jimenez, 1987; Funasaka et al., 1999; Kameyama et al., 1993). Tyrosinase is an enzyme involved in the initial reaction, which is the rate determining step of melanin biosynthesis. The tyrosine hydroxylase activity, which converts tyrosine to 3,4-dihydroxylphenyl alanine (DOPA) and DOPAquinone And DOPA oxidase activity. TRP-1 oxidizes DHICA (5,6-dihydroxyindole-2carboxylic acid) to indole-5,6-quinone-2-carboxyl acid and TRP-2 is an enzyme that isomerizes DOPA chrome to DHICA (Kameyama et al. , 1993). The resulting melanin is transmitted to the surrounding keratinocytes in the form of a melanin-like envelope by the dendritic processes of melanocytes (Hearing & Jimenez, 1987; Prota, 1980; Pavelm & Muskiet, 1983). Therefore, the whitening ingredients can inhibit or block the melanin biosynthesis process and the post-synthesis transfer process at the same time or at the same time, and ultimately, whitening effect can be expected. The melanin synthesis process and the post- Can be a target of whitening effect (Ministry of Commerce, Industry & Energy, 2002). Melanin synthesis biosynthetic metabolism has recently become an intensive study subject because of its relevance to skin cancer

Most of the whitening functional materials currently on the market are focused on relieving the symptomatic part by removing the melanin pigment accumulation site and the existing dermatologic procedure is also intended to artificially remove the accumulation site through the laser have.

However, elimination of these symptomatic parts may have a short-term effect, but it is accompanied by the side effect of accumulating melanin again in a short period of time because it is not accompanied by the improvement of the turnover of the root cause. Therefore, it can solve the root cause of melanin pigment accumulation rather than solving symptom relief that simply removes the melanin pigment accumulation area if the skin turnover cycle is normally returned and the hyperkeratosis of the skin can be prevented or eliminated by moisturizing action. It is expected that it will be possible to change into healthy skin as well.

Accordingly, the present inventors have made a careful effort to develop a new functional cosmetic composition that induces a whitening effect through skin turnover improvement and a return to healthy skin. As a result, it has been found that the use of tranexamoyl-peptide, nicotinoyl A composition comprising as an active ingredient a peptide (Nicotynoly-peptide), Tranexamic acid, Bifida fermented lysate and citrus peel fermented extract is obtained through different mechanisms of each component And can exhibit a very excellent whitening activity, thus completing the present invention.

Accordingly, it is an object of the present invention to provide a method of treating a disease or condition selected from the group consisting of Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida fermented lysate and citrus, And a skin whitening cosmetic composition comprising a perianthic acid fermented extract as an active ingredient.

A further object of the present invention is to provide a method for the production of a medicament for the treatment and / or prophylaxis of diseases or disorders associated with the use of a medicament for the treatment or prophylaxis of a disease or condition selected from the group consisting of Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida ferment lysate, The present invention provides a pharmaceutical composition for preventing or treating a melanin pigment hyperpigmentation disease, which comprises a fermented extract as an active ingredient.

A further object of the present invention is to provide a method for the production of a medicament for the treatment and / or prophylaxis of diseases or disorders associated with the use of a medicament for the treatment or prophylaxis of a disease or condition selected from the group consisting of Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida ferment lysate, And to provide a health functional food composition for preventing or ameliorating hyperpigmentation of melanin pigment comprising fermented extract as an active ingredient.

In order to accomplish the above object of the present invention, the present invention provides a pharmaceutical composition comprising a Tranexamoyl-peptide, a Nicotynoly-peptide, a Tranexamic acid, a Bifida fermented lysate ) And citrus peel fermented extract as an active ingredient.

In order to accomplish the other object of the present invention, the present invention provides a method for producing a peptide comprising Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida fermented lysate, And a pharmaceutical composition for preventing or treating a melanin pigment hyperproliferative disorder comprising an extract of citrus peel as an active ingredient.

In order to accomplish the other object of the present invention, the present invention provides a method for producing a peptide comprising Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida fermented lysate, And a citrus peel fermentation extract as an active ingredient. The present invention also provides a health functional food composition for preventing or ameliorating hyperpigmentation of melanin pigment.

Hereinafter, the present invention will be described in detail.

The present invention relates to a pharmaceutical composition comprising Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida ferment lysate and citrus peel-derived fermentation extract A cosmetic composition for skin whitening comprising as an active ingredient.

The inventors of the present invention found that some peptides combined with tranexamoic acid, which is known to have an effect on whitening by acting on blood vessels and angiogenic factors on the inflamed blood vessels through the previous invention, suppress melanin production, And has applied for a patent (Korean Patent Application No. 10-2016-0081998). Also known as a whitening functional ingredient, it is chemically synthesized peptides effective for niacinamide, which acts on the pathway of melanin and has an effect on whitening, and has filed a patent for a nicotinyl-peptide fused compound with increased stability and efficacy compared to pure niacinamide (Korean Patent No. 10-1167285). The contents described in the above-mentioned prior art can be referred to in the present invention.

On the other hand, the inventors of the present invention have found that the effect of traxexamoyl-peptide, nicotinoyl-peptide, and tranexamic acid, which have been known to be effective in skin whitening, The peeled fermentation extract of Citrus fruit was also included in the composition of the present invention.

Since the functional raw materials constituting the skin whitening composition of the present invention act as a raw material for acting on the skin and whitening the skin through different mechanisms, the respective raw materials are used singly, The effect can be further enhanced.

The term " whitening effect " means the effect of improving or preventing dark skin, spots, freckles and dark circles caused by various factors such as exposure to ultraviolet rays, changes in hormone balance, genetic programs, The effect of maintaining beautiful skin with transparency, and the effect of reducing the dullness of the skin to increase the gloss and tautness. In general, it is known that the skin, spots, freckles, and dark circles of the skin, stamens, freckles and dark circles are stimulated by melanocytes due to stimulation by ultraviolet rays or changes in hormone balance, and melanin pigment is deposited on the skin. Therefore, if the production of melanin can be inhibited, it is possible to prevent or improve gross skin, spots, freckles and dark circles.

In the present invention, the term " traxamoyl-peptide " includes at least one selected from the group consisting of traxemoyl-AS, traxemoyl-AT, traxemoyl-AP, traxexamoyl-GP, traxemoyl- TR, tranexamnoyl-WA, traxexamoyl-HA, traxexamoyl-AG, traxexamoyl-WA, traxexamoyl- TR, trinexamonyl-EGF, trnexamycin-EGF, trnexamonyl-EGF, Tranexamycin-VV, Tranexamoxyl-VP, Tranexamoxyl-AA, Tranexamoxyl-PS, Tranexamoxyl-HA, Tranexamoxyl-GK, Tranexoxamoyl-KV, TR, trnexamoyl-PQ, traxemoyl-QG, traxemoyl-PP, traxemoylVR, traxemoyl-SV, traxemoyl-ET, NT It may be selected from the group. Preferably, the traxamoyl-peptide may be traxemoyl-AP, traxemoyl-HK, traxemoyl-VS or traxemoyl-PS, and most preferably may be traxemoyl-VS But is not limited to.

As used herein, the term " peptide " refers to a linear molecule formed by peptide bonds with amino acid residues joined together, and the truncexamoyl-peptide is obtained by chemically bonding the carboxyl group of the tranexamic acid and the N- Refers to the form of the fused body.

The inventors of the present invention have made efforts to search for peptides showing the effect of improving the skin whitening effect of existing tranexamic acid in a library by constructing a library by fusing the above various peptides to the tranexamic acid through chemical linkage, It has been found that some peptides improve the skin whitening effect of tranexamic acid. The present inventors prepared a variety of libraries by fusing tranexamic acid and peptides, prepared candidate groups, and then screened for tranexamoxyl-peptides having excellent melanin production inhibitory activity among the candidate groups. The inventors of the present invention found that the trinxamoyl- It can be used as a material.

In the present invention, the term "nicotinoyl peptide" includes nicotinoyl-EQ, nicotinoyl-E, nicotinoyl-FP, nicotinoyl-NI, nicotinoyl-NL, nicotinoyl- Nicotinoyl-VG, nicotinoyl-VG, nicotinoyl-VG, nicotinoyl-VG, nicotinoyl-VG, nicotinoyl-VG, , Nicotinoyl-YR, nicotinoyl-YT, nicotinoyl-AHK, nicotinoyl-FWY, nicotinoyl-GHR, nicotinoyl-GPHyp, nicotinoyl-TYR, nicotinoyl-YGY, Nicotinoyl-GKPR, nicotinoyl-GRK, nicotinoyl-KAKA, nicotinoyl-GKPR, , Nicotinoyl-SSNA, nicotinoyl-VPAA, nicotinoyl-YPFF, nicotinoyl-YPFF-NH2, nicotinoyl-GPRPA, nicotinoyl-GPRPA-NH2, nicotinoyl-ISELGW, nicotinoyl -KLAKK, nicotinoyl-KRGDR, nicotinoyl-KRGKP, nicotinoyl-KTTKS, nicotinoyl-KVARP, Nicotinoyl-VGVAPG, nicotinoyl-EEMQRR, nicotinoyl-EEMQRR-NH2, nicotinoyl-VGVAPG, nicotinoyl-VGVAPG, nicotinoyl-EEMQRR, nicotinoyl-EEMQRR-NH2, nicotinoyl-YGGFM, nicotinoyl- -GPQGPQ and nicotinoyl-YGYTGA, most preferably nicotinoyl-VS, but not limited thereto. Specific details of the nicotinoyl peptide can be found in Korean Patent No. 10-1167285.

In the present invention, " tranexamic acid " is a kind of amino acid, and has anti-inflammatory and hemostatic functions. Since 1963, it has been used as a hemostatic agent. Since 1979, whitening function has been known. Especially, It was actively used for treatment. It is known that tranexamic acid regulates the production of melanin by controlling the melanocyte stimulating substance.

In the present invention, the " Bifida ferment lysate " can be used in combination with Bifida fermentation broth, Bifida fermentation extract, Bifidus fermentation broth, etc., and can be used as an anaerobic lactic acid bacterium, Bifidobacteria, It is a raw material obtained by fermentation and crushing by engineering technique. Bifidobacterium fermented fructooligosaccharide is known to be effective in preventing skin damage caused by ultraviolet rays and effective in preventing cell senescence because it contains active ingredients such as polysaccharide complexes as well as metabolites of Bifidobacterium, cytoplasma fractions, cell wall components and the like.

In the present invention, the citrus peel-derived fermentation extract means a substance obtained by extracting the perilla of a fruit belonging to the genus Citrus and then fermenting the microorganism. Preferably, the citrus rind can be a rind of a fruit selected from the group consisting of lemon, orange, citrus, hirabond, mandarin, lime and citron, more preferably lemon and / or orange, It is not.

In the present invention, the above-mentioned " orange juice fermentation extract " can be produced by the following method:

(a) extracting at least two peels selected from the group consisting of lemon, orange, citrus, hyaline, mandarin, lime and citron with water, ethanol, butanol or a mixed solvent thereof; And

(b) adding to the pea extracts Lactobacillus acidophilus , Lactobacillus rhamnosus , Lactobacillus plantarum , Lactobacillus paracasei , Lactobacillus paracasei , J. (Lactobacillus casei) and Lactobacillus brevis (Lactobacillus brevis) step for fermentation was inoculated with Lactobacillus spp two kinds selected from the group consisting of.

The ratio of mixing two or more peels in the step (a) is not particularly limited, and may be an extract of a perianthous mixture preferably mixed at the same ratio. In addition, the most preferable solvent for extracting citrus peel may be 70% ethanol, but is not limited thereto.

The step (b) is a step of fermenting by selecting two kinds of lactobacillus strains and inoculating them to the pea extracts prepared in step (a), more specifically, culturing the cultures of the two strains selected from 10 ⁷ to 10 ^{10 to 10} cfu / ml, 0.5 to 10 parts by weight of the extract is inoculated with respect to 100 parts by weight of the pea extract, and fermented at 25 to 45 ° C for 2 to 10 days. In the present invention, the strain of the genus Lactobacillus is preferably a lactobacillus paracasei and / or a lactobacillus lambosus, but is not limited thereto.

According to a preferred embodiment of the present invention, the composition of the present invention does not show toxicity to human-derived cells, and thus it has been confirmed that the composition is highly utilized as a skin whitening composition. According to the present invention, when HaCat cells and NIH3T3 cells were treated with the composition at a concentration of 100 ng / ml-1000 μg / ml, no remarkable cytotoxicity was measured, and even when the morphology of cells was visually observed, Not observed.

According to the present invention, the whitening composition exhibits excellent thermal stability even at a temperature of 50 캜 and is stable under the sunlight. That is, it means that the composition of the present invention can be advantageously applied to products requiring long-term storage such as medicines, quasi-drugs and cosmetics.

According to a preferred embodiment of the present invention, the composition of the present invention has been found to have a very excellent inhibitory effect on melanogenesis. According to the present invention, when melanin cells were treated with α-MSH to induce melanogenesis, the composition of the present invention was treated and cultured and melanin production was compared. As a result, it was found that when melanin production was treated, The efficacy was inhibited up to about 30%.

According to another embodiment of the present invention, after the reaction of L-tyrosine, niacinamide or whitening composition with tyrosinase, absorbance was measured at 475 nm and the inhibition rate against tyrosinase was examined. As a result, A significant inhibitory effect on tyrosinase activity appeared in the experimental group treated with the composition.

In addition, the inventor of the present invention commissioned an authorized clinical institution to check the whitening effect of the whitening composition according to the present invention, and found that the whitening effect of the cream of the present invention and the non- Was found to be superior to the non-prescribed cream in terms of whitening improvement in clinical conditions.

Thus, in the case of a composition comprising the composition of the present invention, various formulations can be used to very effectively use for skin whitening.

Preferably, the cosmetic composition of the present invention contains 0.001 to 1% (w / v) of the tranexamoyl-peptide, 0.001 to 1% (w / v) of the nicotinoyl peptide, , And 0.1 to 5.0% (v / v) of the bifidobacterium fermented mash extract and 0.1 to 5.0% (v / v) of the mugwort extract are included .

More specifically, the trinxamoyl-peptide, nicotinoyl-peptide, and tranexamic acid may be contained in an amount of 0.01 to 0.5% (w / v), and most preferably 0.05 to 0.1% w / v). < / RTI > Preferably, the Bifidobacterium fermented mash and the fermented mugwort extract are contained in an amount of 0.3 to 5.0% (v / v), and most preferably 0.5 to 2.5% (v / v) But is not limited thereto.

In the composition of the present invention, the trancexamoyl-peptide and the nicotinoyl-peptide-bound peptide used as an active ingredient are composed of 2 to 6 amino acid residues and have a very small molecular weight and thus have excellent skin permeability. Therefore, when the composition of the present invention is locally applied to the skin, an excellent skin whitening effect can be achieved due to a high skin penetration rate. The composition of the present invention suppresses the production of melanin, so it brightens skin color, keeps skin tone constant, and is effective for removal of skin pigment and removal of black pigment. In addition, the composition of the present invention inhibits the production of melanin pigment in keratinocytes by various processes and prevents or reduces the emission of melanin generated in keratinocytes, thereby exerting an effect of brightening the color of keratinocyte layer.

The cosmetic composition according to the present invention can be applied to a gel type, a skin type, a cream type, an ointment type, and the like, but is not limited thereto. The above composition can be suitably prepared by known methods, adding appropriate conventional softening agents, emulsifying agents, thickening agents or other materials known in the art depending on the type thereof.

The gel-type composition may be prepared by adding a softening agent such as trimethylolpropane, polyethylene glycol or glycerin, a solvent such as propylene glycol, ethanol, isocetyl alcohol, or the like.

The skin-type composition may contain at least one of fatty alcohols such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol and isocetyl alcohol, butylene glycol, 2-sodium, xanthan gum, dimethicone, polyethylene glycol-60 hydrogeneate castor oil, polysorbate 60 and purified water.

The cream-type composition may be formulated by dissolving or dispersing the above-mentioned cream type composition in an aqueous medium such as alcohols such as stearyl alcohol, myristyl alcohol, behenyl alcohol, arachidyl alcohol, isostearyl alcohol, isocetyl alcohol and the like, lecithin, phosphatidylcholine, phosphatidylethanolamine, Emulsifiers such as glyceryl stearate, sorbitan palmitate, and sorbitan stearate; natural fats or oils such as avocado oil, apricot oil, barba water oil, glass fat oil and camellia oil; Propylene glycol and the like, purified water, and the like.

The ointment type composition may be prepared by adding a softening agent, an emulsifying agent, and a wax such as microcrystalline wax, paraffin, ceresin, wax, spermaceti, vaseline or the like.

The cosmetic composition of the present invention may further contain at least one skin whitening active ingredient showing the same or similar functions in addition to the active ingredient. Skin whitening active ingredients include kojic acid and its derivatives, arbutin, ascorbic acid and its derivatives, hydroquinone and its derivatives, resorcinol, cycloalkanone, methylenedioxyphenylalkanol, 2,7-dinitroindazole or Plant extracts such as mandarin orange extract, rice extract, licorice extract, and the like, but are not limited thereto. The cosmetic composition of the present invention may further contain an excipient including a fluorescent substance, a fungicide, a hygroscopic substance, a moisturizing agent, a fragrance, a fragrance carrier, a protein, a solubilizer, a sugar derivative, a sunscreen, a vitamin, .

The present invention also relates to the use of a composition comprising Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida ferment lysate and citrus peel fermentation extract As an active ingredient, a pharmaceutical composition for preventing or treating a melanin pigment hyperpigmentation disease.

The constituent components of the active ingredient of the pharmaceutical composition are as described above.

The term " melanin pigment hyperpigmentation " as used herein means darker or darker than other areas due to excessive increase of melanin in specific areas of skin or hands and toenails. The melanin pigment hyperpigmentation disorder may be selected from the group consisting of freckles, senile spots, liver, spots, brown or black spots, daylight pigmentation, cyanicmelasma, hyperpigmentation after drug use, gravidic chloasma, Hyperpigmentation after inflammation due to wound or dermatitis, including but not limited to

The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier in addition to the active ingredient. Such carriers are conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, Calcium carbonate, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and minerals Oils, and the like, but are not limited thereto. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc., in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences, 19th ed., 1995.

The appropriate dosage of the pharmaceutical composition according to the present invention may vary depending on such factors as the formulation method, the administration method, the patient's age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . On the other hand, the dosage of the pharmaceutical composition of the present invention is preferably 0.0001 to 100 mg / kg (body weight) per day. The pharmaceutical composition of the present invention may be administered orally or parenterally. In the case of parenteral administration, the composition may be administered topically to the skin, intravenously, subcutaneously, intramuscularly, intraperitoneally, or transdermally. In view of the fact that the pharmaceutical composition of the present invention is applied for the treatment or prevention of a melanin pigment hyperpigmentation disease, it is preferable that the composition is topically applied to the skin.

The concentration of the active ingredient contained in the composition of the present invention can be determined in consideration of the purpose of treatment, the condition of the patient, the period of time required, and the like, and is not limited to a specific range of concentration.

The pharmaceutical composition of the present invention may be prepared in the form of a unit dose by formulating it using a pharmaceutically acceptable carrier or excipient according to a method which can be easily carried out by those having ordinary skill in the art to which the present invention belongs Into a multi-dose container. The formulations may be formulated into any one of the formulations selected from injectables, creams, patches, sprays, ointments, alerts, lotions, liniments, pastes and cataplasms, and may additionally contain dispersing or stabilizing agents have.

The present invention also relates to the use of a composition comprising Tranexamoyl-peptide, Nicotynoly-peptide, Tranexamic acid, Bifida ferment lysate and citrus peel fermentation extract As an active ingredient, a health functional food composition for preventing or ameliorating hyperpigmentation of melanin pigment.

When the health functional food composition of the present invention is used as a food additive, the health functional food composition may be added as it is, or may be used together with other food or food ingredients, and suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably used depending on the purpose of use (prevention or improvement). Generally, the health functional food composition of the present invention is added in an amount of not more than 15 parts by weight, preferably not more than 10 parts by weight based on the raw material, when the food or beverage is produced. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.

There is no particular limitation on the kind of the health functional food. Examples of the foods to which the health functional food composition can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, soups, Drinks, alcoholic beverages, and vitamin complexes, all of which include health foods in a conventional sense.

In addition, the health functional food composition of the present invention can be produced as a food, particularly a functional food. The functional food of the present invention includes components that are ordinarily added in food production, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, in the case of a drink, a natural carbohydrate or a flavoring agent may be included as an additional ingredient in addition to the active ingredient. The natural carbohydrate may be selected from the group consisting of monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g., dextrin, cyclodextrin, For example, xylitol, sorbitol, erythritol, etc.). The flavoring agent may be a natural flavoring agent (e.g., tau Martin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.).

In addition to the above health functional food composition, it is also possible to use various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, A carbonating agent used in beverages, and the like. Although the ratio of the above-mentioned ingredients is not critical, it is generally selected in the range of 0.01 to 0.1 part by weight based on 100 parts by weight of the health functional food composition of the present invention.

Hereinafter, the present invention will be described in further detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The composition prepared in the examples of the present invention can be applied to pharmaceutical compositions and cosmetic compositions such as gel type, skin type, cream type, ointment type and the like, but is not limited thereto.

The composition for skin whitening according to the present invention inhibits melanin production and inhibits tyrosinase activity to exert excellent effects on skin whitening, and is excellent in heat stability and light stability, and is useful for skin whitening cosmetics, medicines and health functional foods It can be very useful for development.

FIG. 1 shows the results of evaluating the inhibitory activity (%) of melanin formation of each treatment material (TXA-dipeptide-3, -7, -23, -27: traxemoyl- peptide, Dipeptide-3, -27: dipeptide without tranexamic acid binding, TXA: tranexamic acid).
Figure 2 shows the results of evaluating the tyrosinase inhibitory activity of the composition according to the present invention.
FIGS. 3 and 4 are graphs showing the results of measurement of thermal stability or light stability of the composition according to the present invention. FIG.
FIG. 5 and FIG. 6 show the cytotoxicity of the composition according to the present invention in HACAT cells or NIH3T3 cells by MTT assay.
FIG. 6 is comparative photograph data showing the effect of improving whitening wrinkles confirmed through clinical tests.

Hereinafter, the present invention will be described in detail with reference to preferred embodiments. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately The present invention should be construed in accordance with the meaning and concept consistent with the technical idea of the present invention. Accordingly, it is to be understood that the constituent features of the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the inventive concepts of the present invention, so that various equivalents, And the like.

< Example  1>

Peptides  Synthesis of libraries

Nsc-Ala, nsc-Asp (OtBu), nsc-Asn (trt), nsc-Gly, nsc-Glu (OtBu), and nsc- Thr (tBu), nsc-Trp (Boc), nsc-Leu, nsc-Ile, nsc- Chloro trityl chloride resin (Novabiochem Cat No. 01-64-0021), to which nsc-Val, nsc-Phe, nsc-Met and nsc-Lys (Boc) To the well teflon reactor, 50 mg of each of 19 lines was added to each series, 1 ml of methylene chloride (MC) was added, and the mixture was stirred for 3 minutes. The solution was removed and 1 ml of dimethylformamide (DMF) was added. After stirring for 3 minutes, the solvent was removed again. The prepared tranexamic acid-peptidyl resin was washed three times with DMF, MC and methanol, dried slowly by flowing nitrogen air, and then completely dried under reduced pressure in a vacuum under P ₂ O ₅ . The prepared resin was immersed in a solution of maltitol solution (Trifluroacetic acid (TFA) 81.5%, distilled water 5%, thioanisole 5%, phenol 5%, EDT (1,2-Ethanedithiol) 2.5% (Containing 1% of triisopropylsilane)] was added, and the mixture was shaken occasionally at room temperature, and the reaction was maintained for 1 hour in an ice water bath. The resin was filtered, washed with a small amount of TFA solution, and then combined with the mother liquor. Thereafter, the tranexamic acid-peptide was obtained.

As a result of synthesis and purification, 40 kinds of tranexamic acid-peptide having different sequences of peptides were obtained (Table 1). The yield of the synthesized tranexamic acid-peptide varies depending on the difference in physical properties depending on the sequence of the peptide, but shows an average yield of about 10%. The elution time for the column separation was also different but the peak was confirmed at the 8th minute.

< Example  2>

Tranexamic acid - Of peptide  Melanin production Inhibition  Screening

Mouse melanocytes B16F1 cells were cultured in DMEM (Dulbecco's modified Eagle's media, Sigma) supplemented with 10% fetal bovine serum (Sigma) at 37 ° C and 5% CO ₂ . Cells were cultured in a 24-well plate at a concentration of 1 × 10 ⁵ cells / well. After confirming cell adhesion, the cells were treated without any treatment and only a solvent was added. The positive control group was a 20 μg / ml a-MSH The remaining dishes were treated with 20 μg / ml of α-MSH and 40 kinds of tranexamic acid-peptides in a concentration of 1 μg / ml, 10 μg / ml, 100 μg / ml and 250 μg / ml Respectively. In the case of four kinds of tranexamic acid-peptides (Tranexamil-AP, -HK, -VS, and -PS), peptides without binding to tranexamic acid (i.e., AP, HK, VS , And PS), respectively. The test material was added to each dish and cultured for 3 days. After 3 days, the culture solution was removed by centrifugation. To measure the intracellular melanin production, the cells were lysed to collect intracellular melanin and observed at 490 nm.

The results are shown in Table 1 and FIG.

As can be seen in Table 1 and FIG. 1, the amount of melanin was significantly higher in the group treated with the tranexamic acid-bound peptide than in the group without the tranexamic acid (TXA) and the tranexamic acid-bound peptide I can confirm that it is shrinking. In addition, four synthetic Tranexamic acid peptides (Tranexamil-AP, -HK, -VS, and -PS) superior in α-MSH inhibition (%) were found to be superior to the existing whitening functional materials Arbutin and AA2G (Fig. 1). These results suggest that when the factor inducing the production of melanin in the skin is applied, the synthesized tranexamic acid - dipeptide may inhibit its activity and brighten the skin tone.

The candidate peptides showing good activity by screening were divided into separate groups and experiments were conducted after mass synthesis. Table 1 shows screening results of tranexamic acid-peptide.

(In the above table, each test substance represents a tranexamic acid-peptide in which the N-terminal of the dipeptide shown on the right side of the peptide name is bound to tranexamic acid.) TXA:

< Example  3>

Whitening function  Selection of combination of raw materials

Through the above Examples 1 and 2, it was tried to prepare a composition showing excellent whitening effect through combination of a tranexamic acid-peptide having an inhibitory effect on melanin production and other substances known to be effective for skin whitening.

3-1. Experimental material

(1) Tranexamic acid-peptide (Tranexamoyl-peptide)

In Example 2, Tranexamic acid-VS (Tranexamoyl-AS) exhibiting excellent melanin production inhibitory ability was selected and the following experiment was conducted.

(2) Tranexamic acid

In the present invention, tranexamic acid was purchased from Sigma-Aldrich.

(3) nicotinoyl peptide

The nicotinoyl peptide was prepared according to the method described in Korean Patent No. 10-1167285, and nicotinoyl-VS disclosed in the patent document was used in this experiment.

(4) Bifida fermented melted wine

The Bifida fermented fusant used in the present invention was purchased and used from Elsies Biotech.

(5) Citrus fermentation products

The citrus peel fermentation extract used in the present invention was prepared using lemon and orange peel.

Specifically, a 1: 1 mixture of lemon and orange peel was extracted with 70% ethanol (per volume: solvent weight ratio of 1: 9). To the extract, a mixed culture of a mixture of Lactobacillus acidophilus and Lactobacillus paracase was added, and the culture solution of the mixed culture was adjusted to 10 ⁹ cfu / ml and added in an amount of 3 parts by weight based on 100 parts by weight of the extract. Thereafter, the mixture was fermented at 37 DEG C for 3 days to obtain a citrus peel fermentation product.

3-2. Preparation of Composite Composition for Whitening

A total of 20 kinds of combinations were selected by adjusting the concentrations of the raw materials of (1) to (5). The composition ratios of the ingredients in the selected combination are shown in Table 2 below. Tranexamic acid, tranexamnoyl-VS and nicotinoyl-VS were dissolved in water (w / v) at the concentrations shown in the following Table 2, and the Bifida fermented fusant and citrus fermented product were obtained as described in "3-1. (V / v) &lt; / RTI &gt; in water at the concentrations set forth in Table 2 below.

< Example  4>

Identification of intracellular melanin inhibitory activity of skin whitening composition

Mouse melanocytes B16F1 cells were cultured in DMEM (Dulbecco's modified Eagle's media, Sigma) supplemented with 10% fetal bovine serum (Sigma) at 37 ° C and 5% CO ₂ . Cells were cultured in a 24-well plate at a concentration of 1 × 10 ⁵ cells / well. After confirming cell adhesion, the cells were treated without any treatment and only a solvent was added. The positive control group was a 20 μg / ml a-MSH In the remaining dishes, 20 μg / ml of α-MSH and 20 kinds of control groups were treated with 1 μg / ml, 10 μg / ml, 100 μg / ml and 250 μg / ml of niacinamide.

(The treatment concentration of the experimental group was calculated on the basis of the weight of the solid component of each component described in Table 2.)

The test material was added to each dish and cultured for 3 days. After 3 days, the culture solution was removed by centrifugation. To measure the intracellular melanin production, the cells were lysed to collect intracellular melanin and observed at 490 nm.

The results are shown in Table 3 below.

The amount of melanin was found to be decreased in most of the experimental groups compared to the control group of niacinamide, and it was confirmed that there was a difference depending on the combination of the functional ingredient ingredients and the composition in the test group. From these results, it was found that, when the factor inducing the production of melanin in the skin was applied, it was more useful to use various combinations than the case of using a single raw material, thereby suppressing the melanin expression activity and brightening the skin tone .

< Example  5>

Of the skin whitening composition Tyrosinase  Identify inhibitory activity

Tyrosinase, known as an enzyme involved in the melanin biosynthesis process, is oxidized to 3,4-dihydroxy-L-phenylananine (DOPA) in L-tyrosine and to dopaquinone in DOPA among melanin biosynthesis processes starting from L- As a catalyst. Since the subsequent reaction after these two oxidation reactions occurs spontaneously, the reaction involving tyrosinase determines the overall reaction rate. For this reason, tyrosinase inhibitory activity is a very important factor for evaluating whitening activity. In this experiment, in vitro tyrosinase inhibitory activities of the different compositions of five combinations (combination 1, 2, 6, 10, 11) obtained through screening were compared.

Specifically, L-tyrosine, a substrate, was dissolved in phosphate buffer (0.05 M, pH 6.8) to a concentration of 1.5 mM, 0.01 ml of this solution was added to a 0.3 ml spectrophotometer cuvette and cofactor ) L-DOPA was added at a concentration of 0.06 mM and 0.01 ml was added. To this, the composition of the present invention was added and the phosphate buffer was added to make 0.1 ml. The reaction was allowed to proceed by adding 0.1 ml of an enzyme solution in which tyrosinase was dissolved in phosphoric acid buffer at 60 U / mL. The experimental group and the control group were treated with concentration (1 μg / ml, 10 μg / ml, 100 μg / ml, 250 μg / ml)

At this time, as the control (blank), only 0.1 ml of the buffer solution was added instead of tyrosinase. The reaction was carried out at 37 ° C for 10 minutes and the inhibition rate against tyrosinase was determined by measuring the absorbance at 475 nm using a spectrophotometer (Beckman DU-7500) (FIG. 2).

As a result of the experiment, it was confirmed that the optimum combinations were selected among the five experimental groups, and the tyrosinase inhibitory effect was superior to that of the same concentrations of niacinamide and tranexamic acid used as the control group.

< Example  6>

Experiment to confirm stability of skin whitening composition

In order to confirm the heat and light stability of the whitening composition of the present invention, the composition was dissolved in a 50 mM Tris-HCl (pH 8.0) buffer solution so that the whitening composition was 10 mg / , 14, 21, 28, 35, 42 and 60 days, and the loss of peptide components in the composition by heat was measured and the stability of the peptide components in daylight was measured in the same manner (FIGS. As a result of measuring the loss of peptide by heat and measuring stability under daylight conditions, it was confirmed that the peptide showed less than 10% peptide loss until 60 days and had high stability in heat and storage period.

< Example  7>

Cytotoxicity experiment

The cytotoxicity of the composition of the present invention was evaluated by MTT assay. HACAT cells and 3T3 cells were seeded on a 24-well plate at 4 × 10 ⁴ cells / 24 well per well and incubated at 37 ° C and 5% CO ₂ for 24 h. After washing twice with PBS, the cells were treated with synthetic tranexamic acid dipeptide (1 mg to 1 ug / mL) and cultured for 24 h. After incubation, MTT 0.5% in DPBS was mixed with the culture medium at a ratio of 1: 9 (v / v), and the mixture was incubated in a CO ₂ incubator for 2 h. The formazan was dissolved in DMSO and assayed at 570 nm using ELISA Respectively.

As shown in FIGS. 5 and 6, no decrease in cell number was observed with HaCat cells, a type of keratinocyte cell line, and NIH3T3 cells, a type of fibroblasts, from a low concentration to a high concentration, No significant changes were observed in the observations

Thus, it can be seen that the whitening improving composition of the present invention has no toxicity to the skin-related cells, and thus it can be predicted that the whitening composition of the present invention will not have a great influence even if it is treated on the skin.

< Example  8>

Clinical trial

In order to confirm the clinical test of the composition for improving whiteness, it was commissioned by an accredited certification body to confirm the improvement effect of whitening on the pigmented part of the cosmetic formulation prescribed.

The composition of Combination 1 of Table 1, which had a high inhibitory effect on melanin synthesis in vitro , was selected and a cream containing the Combination 1 cosmetic composition was prepared in the cream composition shown in Table 8 below. Women. On the other hand, the control group treated only the cream composition according to Table 8, to which the cosmetic composition according to the present invention was not added.

The test product was applied to the facial area according to the method of use, and the effect on the improvement of the pigmentation site whitening was evaluated. The evaluation was carried out in accordance with the SOP of the Center, and the matters not specified in the Food and Drug Safety Guidelines were referred to the references.

For the measurement, the front face photograph was taken using a VISIA-CR (Canfield, USA) equipped with a camera (Canon, EOS5D Mark II, JAPAN) and the standard 2 mode was used. The VISIA-CR (Canfield) was used to fix the forehead and jaws to minimize subject movement, and a gray card was taken to allow the subject to be aware of the change in light when taking pictures. Measurements were made before use (0 weeks), 4 weeks after using the product, and 8 weeks after using the product.

Melanin of the test site was measured using Mexameter (MX-18, Courage and Khazaka Electronic Co., Germany). Mexameter shows the degree of reflection by irradiating light with different wavelength band corresponding to melanin and hemoglobin by optical measurement technique. The measured value represents the Melanin Index and the measurement factor is the Arbitrary unit (AU).

Measurements were made before the product was used (0 weeks), 4 weeks after using the product, and 8 weeks after using the product. The colorimetric measurement was performed using a colorimeter (Spectrophotometer CM-2600D, Minolta, Japan) and a diameter of 8 mm. The pigmentation sites of each subject were measured three times and the average value was used. Measurements were made before the product was used (0 weeks), 4 weeks after using the product, and 8 weeks after using the product. Table 4 and Table 5 show the measurement results of the pigmentation sites using Mexameter and Spectrophotometer.

Melanin index of the test product was 163.17AU before use (0 weeks), 158.63AU after 4 weeks of using the product, and 151.87AU after 8 weeks of using the product. (L-value) was changed from 60.903AU before the product use (0 weeks) to 61.626AU after 4 weeks from using the product and 61.860AU after 8 weeks from using the product.

The melanin index of the control group was 164.22 AU before the product was used (0 week), 161.43 AU after 4 weeks of using the product, and 158.46 AU after 8 weeks of using the product, and the L-value (0 weeks) 61.747AU, 61.968AU after 4 weeks of use and 62.124 AU after 8 weeks of using the product.

In addition, in the test group, it was found that there was a statistically significant improvement in whitening of the pigmentation area in both Melanin Index and L-value after 8 weeks of use (p <0.05) (Table 4 to 7 , Fig. 7).

The results of this clinical study confirm that the whitening composition is effective for skin whitening.

< Manufacturing example >

Cream type composition containing a whitening composition

Each of the ingredients listed in Table 8 below was added to 100 parts by weight of the composition according to the proportions described below, and the &quot; whitening composition &quot; was added to the cream type composition according to the proportions of each component listed in Table 2 above.

While the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, Such modifications and changes are to be considered as falling within the scope of the following claims.

The composition for skin whitening according to the present invention inhibits melanin production and inhibits tyrosinase activity to exert excellent effects on skin whitening, and is excellent in heat stability and light stability, and is useful for skin whitening cosmetics, medicines and health functional foods It can be very useful for development, and is highly industrially applicable.

Claims (9)

The present invention relates to a pharmaceutical composition containing, as an active ingredient, tranexamoyl-peptide, nicotynoly-peptide, tranexamic acid, Bifida ferment lysate and citrus peel-derived fermented extract A cosmetic composition for skin whitening comprising
Wherein said traunxamoyl peptide is selected from the group consisting of traxemoyl-AP, traxemoyl-HK, traxemoyl-VS and traxemoyl-PS,
The nicotinoyl peptide includes nicotinoyl-EQ, nicotinoyl-E, nicotinoyl-FP, nicotinoyl-NI, nicotinoyl-NL, nicotinoyl-NP, nicotinoyl- Nicotinoyl-VF, nicotinoyl-VT, nicotinoyl-VT, nicotinoyl-WM, nicotinoyl-VG, nicotinoyl-VF, nicotinoyl- Nicotinoyl-YR, nicotinoyl-YG, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl- Nicotinoyl-GKP, nicotinoyl-GQPR, nicotinoyl-GRKG, nicotinoyl-KAKA, nicotinoyl-GQPR, nicotinoyl-GQPR, nicotinoyl- SSNA, nicotinoyl-VPAA, nicotinoyl-YPFF, nicotinoyl-YPFF-NH2, nicotinoyl-GPRPA, nicotinoyl-GPRPA-NH2, nicotinoyl-ISELGW, nicotinoyl-KLAKK, nicotino -KRGDR, nicotinoyl-KRGKP, nicotinoyl-KTTKS, nicotinoyl-KVARP, nicotinoyl-KRDVY, Nicotinoyl-VGVAPG, nicotinoyl-EEMQRR, nicotinoyl-EEMQRR-NH2, nicotinoyl-GPQGPQ, nicotinoyl-VGPAP, nicotinoyl-EEMQRR, nicotinoyl-GPQGPQ, nicotinoyl- &Lt; / RTI &gt; y-YGYTGA. &Lt; / RTI &gt;
2. The cosmetic composition according to claim 1, wherein the traunxamoyl-peptide is traxemoyl-VS and the nicotinoyl-peptide is nicotinoyl-VS.
The composition according to claim 1, wherein the content of the trinexamoyl-peptide is 0.001 to 1% (w / v), the content of the nicotinoyl-peptide is 0.001 to 1% (w / v) Wherein the bifidobacterium fermented fruit is 0.1 to 5.0% (v / v) and the citrus peel fermentation extract is 0.1 to 5.0% (v / v). Cosmetic composition.
The cosmetic composition according to claim 1, wherein the cosmetic composition inhibits melanin production or inhibits the activity of tyrosinase
[Claim 2] The cosmetic composition according to claim 1, wherein the citrus peel-type fermentation extract is at least two fermented peel extracts selected from the group consisting of lemon, orange, citrus, hara bong, mandarin, lime and citron.
The cosmetic composition according to claim 5, wherein the citrus extract is prepared according to the following method:
(a) extracting at least two peels selected from the group consisting of lemon, orange, citrus, hyaline, mandarin, lime and citron with water, ethanol, butanol or a mixed solvent thereof; And
(b) wherein (a) the extract prepared in step Lactobacillus evil attempts pillar's (Lactobacillus acidophilus), Lactobacillus ramno Saskatchewan (Lactobacillus rhamnosus), Lactobacillus Planta volume (Lactobacillus plantarum), Lactobacillus para casei (Lactobacillus paracasei), Lactobacillus casei (Lactobacillus casei) and Lactobacillus brevis (Lactobacillus brevis) step for fermentation was inoculated with Lactobacillus spp two kinds selected from the group consisting of.
The present invention relates to a pharmaceutical composition containing, as an active ingredient, tranexamoyl-peptide, nicotynoly-peptide, tranexamic acid, Bifida ferment lysate and citrus peel-derived fermented extract A pharmaceutical composition for preventing or treating a melanin pigment hyperproliferative disorder,
Wherein said traunxamoyl peptide is selected from the group consisting of traxemoyl-AP, traxemoyl-HK, traxemoyl-VS and traxemoyl-PS,
The nicotinoyl peptide includes nicotinoyl-EQ, nicotinoyl-E, nicotinoyl-FP, nicotinoyl-NI, nicotinoyl-NL, nicotinoyl-NP, nicotinoyl- Nicotinoyl-VF, nicotinoyl-VT, nicotinoyl-VT, nicotinoyl-WM, nicotinoyl-VG, nicotinoyl-VF, nicotinoyl- Nicotinoyl-YR, nicotinoyl-YG, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl- Nicotinoyl-GKP, nicotinoyl-GQPR, nicotinoyl-GRKG, nicotinoyl-KAKA, nicotinoyl-GQPR, nicotinoyl-GQPR, nicotinoyl- SSNA, nicotinoyl-VPAA, nicotinoyl-YPFF, nicotinoyl-YPFF-NH2, nicotinoyl-GPRPA, nicotinoyl-GPRPA-NH2, nicotinoyl-ISELGW, nicotinoyl-KLAKK, nicotino -KRGDR, nicotinoyl-KRGKP, nicotinoyl-KTTKS, nicotinoyl-KVARP, nicotinoyl-KRDVY, Nicotinoyl-VGVAPG, nicotinoyl-EEMQRR, nicotinoyl-EEMQRR-NH2, nicotinoyl-GPQGPQ, nicotinoyl-VGPAP, nicotinoyl-EEMQRR, nicotinoyl-GPQGPQ, nicotinoyl- Lt; RTI ID = 0.0 &gt; Y-YGYTGA. &Lt; / RTI &gt;
8. The method of claim 7, wherein the melanin pigment hyperpigmentation disorder is selected from the group consisting of freckles, aging spots, liver, spots, brown or black spots, daylight pigmentation, cyanic melasma, hyperpigmentation after drug use, chloasma), hyperpigmentation after scarring including scars and burns, and hyperpigmentation after inflammation due to dermatitis.
The present invention relates to a pharmaceutical composition containing, as an active ingredient, tranexamoyl-peptide, nicotynoly-peptide, tranexamic acid, Bifida ferment lysate and citrus peel-derived fermented extract A health functional food composition for prevention or amelioration of hyperpigmentation of melanin pigment,
Wherein said traunxamoyl peptide is selected from the group consisting of traxemoyl-AP, traxemoyl-HK, traxemoyl-VS and traxemoyl-PS,
The nicotinoyl peptide includes nicotinoyl-EQ, nicotinoyl-E, nicotinoyl-FP, nicotinoyl-NI, nicotinoyl-NL, nicotinoyl-NP, nicotinoyl- Nicotinoyl-VF, nicotinoyl-VT, nicotinoyl-VT, nicotinoyl-WM, nicotinoyl-VG, nicotinoyl-VF, nicotinoyl- Nicotinoyl-YR, nicotinoyl-YG, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl-YG, nicotinoyl-YH, nicotinoyl- Nicotinoyl-GKP, nicotinoyl-GQPR, nicotinoyl-GRKG, nicotinoyl-KAKA, nicotinoyl-GQPR, nicotinoyl-GQPR, nicotinoyl- SSNA, nicotinoyl-VPAA, nicotinoyl-YPFF, nicotinoyl-YPFF-NH2, nicotinoyl-GPRPA, nicotinoyl-GPRPA-NH2, nicotinoyl-ISELGW, nicotinoyl-KLAKK, nicotino -KRGDR, nicotinoyl-KRGKP, nicotinoyl-KTTKS, nicotinoyl-KVARP, nicotinoyl-KRDVY, Nicotinoyl-VGVAPG, nicotinoyl-EEMQRR, nicotinoyl-EEMQRR-NH2, nicotinoyl-GPQGPQ, nicotinoyl-VGPAP, nicotinoyl-EEMQRR, nicotinoyl-GPQGPQ, nicotinoyl- &Lt; / RTI &gt; YGYTGA. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt;

Images