WO2007061169A1

WO2007061169A1 - Composition for hair growth promotion containing vitamin b and pyrimidine oxide derivatives

Info

Publication number: WO2007061169A1
Application number: PCT/KR2006/002413
Authority: WO
Inventors: Nok Hyun Park; Won Seok Park; Ji Sook Han; Jae Sung Hwang; Ih Seop Jang
Original assignee: Amorepacific Corporation
Priority date: 2005-11-25
Filing date: 2006-06-22
Publication date: 2007-05-31
Also published as: KR101127331B1; KR20070065950A

Abstract

Disclosed is a hair growth-promoting composition containing water- soluble B-group vitamins and pyrimidine oxide derivatives. More particularly, the hair growth-promoting composition contains, as active ingredients, B-group vitamins and pyrimidine oxide derivatives, and thus directly induces hair growth by promoting the transition from the telogen phase to the anagen phase through the vasodilation of blood vessels around hair follicles.

Description

[DESCRIPTION]

[Invention Title]

COMPOSITION FOR HAIR GROWTH PROMOTION CONTAINING VITAMIN B AND PYRIMIDINE OXIDE DERIVATIVES [Technical Field]

The present invention relates to a hair growth-promoting composition containing water-soluble B-group vitamins and pyrimidine oxide derivatives. More particularly, the hair growth-promoting composition according to the present invention contains, as active ingredients, B-group vitamins and pyrimidine oxide derivatives, and thus directly induces hair growth by promoting the transition from the telogen phase to the anagen phase through the vasodilation of blood vessels around hair follicles. [Background Art]

Various studies to treat hair loss and promote hair growth in men and women who suffer serious mental anguish due to genetic or environmental hair loss in the modern society attaching importance to beauty are being actively conducted worldwide.

Human hairs are about 100,000-150,000 in number, and each individual hair grows and falls out through three main phases of the hair growth cycle: anagen, catagen and telogen. For normal persons, this cycle is repeated at an interval of generally 3-6 years, and, as a result, 60-100 hairs in average per day fall out. On the other hand, in the case of alopecia patients, the ratio of hairs in the anagen phase of the hair growth cycle decreases, and the ratio of hairs in the catagen and telogen phases increases, so that the falling of hairs abnormally increases. This alopecia can cause serious stress in a person suffering therefrom and cause the person to lose self-confidence in person relations. For this reason, it is preferable to treat alopecia at the initial stage of the onset thereof. However, most of hair loss-preventing agents or hair nutrients, which are known to date, have an insignificant effect or are not medically proven, and thus have a risk of causing serious side effects on the body.

Among existing therapeutic agents for hair loss prevention, minoxidil for external application approved by the USA FDA was reported to have, in addition to vasodilation function as the characteristic potassium channel opener thereof, activities to induce the anagen phase from the telogen phase of the hair cycle and to continuously maintain the induced anagen phase (British Journal of Dermatology. 2004; 150: 186-194). However, minoxidil is inconvenient in that it will show a slight effect, only when it should continually applied two times daily and remain on the scalp for 3-4 hours. Also, it has an insignificant effect and shows side effects, including itching and irritation.

Also, oral administration drugs, including Finasteride (MSD) and Propecia (MSD), which inhibit the action of 5-alpha-reductase to inhibit the production of dihydrotestosterone (DHT) as active male hormone, have been marketed as hair growth stimulants with the approval of the US FDA. However, the use of these drugs has been limited, because they are expensive and has been reported to have side effects, including impotence and sexual desire disorder, and the birth of deformed babies for women. Thus, there has been a continued demand for a drug, which shows hair growth promotion effects and has no side effects, compared to the two major drugs developed in the prior art. Meanwhile, vitamin B 12, which is also called "cyanocobalamin", one of vitamin B complexes, is known to be used to treat pernicious anemia and peripheral neuropathy and as a diet supplement. Patents relating to cyanocobalamin include Korean Patent Application No. 10-2003-0022249, entitled "Nutrient composition for brain activation", and Korean Patent Application No. 10-2003-0087897, entitled "Composition for treatment of degenerative arthritis".

However, there is no report on the use of cyanocobalamin (B 12) in combination with pyrimidine oxide derivatives for vasodilation and hair growth.

[Disclosure] [Technical Problem]

The present inventors have found that the vitamin B group, preferably cyanocobalamin (B 12), shows a potassium channel opening effect through antagonistic action against a potassium channel opening-inhibitory drug, has the effect of stimulating the transition from the telogen phase to the anagen phase of the hair cycle in mice in the telogen phase, and shows the effect of promoting hair growth, when it is used in combination with pyrimidine oxide derivatives having a hair growth effect and hair growth activity, thereby completing the present invention.

Therefore, it is an object of the present invention to provide a hair growth-promoting composition, which contains, as active ingredients, B- group vitamins and pyrimidine oxide derivatives, and thus inhibits general male-pattern or female-pattern hair loss and promotes hair growth. [Technical Solution]

To achieve the above object, the present invention provides a hair growth-promoting composition, which contains, as active ingredients, B- group vitamins and pyrimidine oxide derivatives, and thus has a function of opening potassium channels in a condition of antagonist tolbutamide to vasodilate blood vessels, and increases the flow of blood to hair follicles so as to supply an increased amount of nutrients to the follicles, thus preventing hair loss and promoting hair growth.

Hereinafter, the present invention will be descried in further detail. As the active ingredient of the hair growth-promoting composition according to the present invention, the vitamin B group consists of six members, including vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B12 (cyanocobalamin), vitamin B9 (folic acid), and biotin. In the present invention, one or a mixture of two or more selected from the vitamin B group is preferably used.

Vitamin Bl (thiamine) is present as thiamine pyrophosphate (TPP) in the body and plays a very important role as a coenzyme in a carbohydrate metabolism process.

It is known that vitamin B2 (riboflavin) is the constituent of FMN (flavin mononucleotide) and FAD (flavin adenine dinucleotide) as dehydrogenase coenzymes, and is essential for the metabolism of energy sources, including carbohydrates, fats and proteins, and when it is deficient, the metabolism of the energy sources will be reduced, thus causing various physical disorders.

Vitamin B6 (pyridoxine) facilitates the synthesis and activity of insulin. The deficiency of vitamin B6 in the metabolism of tryptophane abundant in animal proteins results in the production of xanthurenic acid, which reduces the activity of insulin. Vitamin B9 (folic acid) facilitates the metabolism of proteins, is involved in the synthetic of nucleic acids, and stimulates the production of red blood cells so as to prevent pernicious anemia.

Biotin is a member of the vitamin B complex and also called vitamin H. It stimulates the production of fatty acids and the oxidation of fatty acids and carbohydrates, enhances the availability of proteins, folic acid, pantothenic acid and vitamin B 12.

Among the B-group vitamins, cyanocobalamin (B 12) is more preferably used as the active ingredient of the inventive composition for hair loss prevention or hair growth promotion.

Vitamin B 12, also called cyanocobalamin, is known to have various effects as follows: 1) producing and regenerating red blood cells; 2) preventing and treating anemia; 3) promoting the growth and metabolism of infants; 4) acting as a substance for activating the nervous system and brain to enhance concentration and memory; 5) stabilizing nerves; 6) possibly preventing cancer; 7) enhancing immune functions; 8) reducing arteriosclerosis risk; and 9) reducing overall cholesterol levels together with other components, including folic acid and vitamin B6. It is known that the deficiency of the vitamins used in the present invention results in pernicious anemia, anorexia and incomplete development in infants, and chronic fatigue, malaise, shoulder pain and reduced concentration and memory abilities in adults. Moreover, it has been used as a raw material for cosmetics and healthy foods, while the hair growth effect thereof is not yet known.

Also, cyanocobalamin (0₆₃H₈₈CoNi₄Oi₄P^"-) is also known as Alphamine, B 12, Crystamine, Cyanocobalamin, Cyanoject, Cyomin, Cytamen, Hydrobexan, Rubesol, Rubramin, Rubramin PC, or Vitamin B 12, and has the most complex structure among vitamins, and the molecular structure thereof is represented by Formula 1 below: [Formula 1 ]

The present inventors have found that cyanocobalamin used in the hair growth-promoting composition has the effect of opening potassium channels at the cell level, and increases the flow of blood around follicles in mice to directly promote hair growth, and shows a synergistic effect in combination with pyrimidine oxide derivatives, which are generally known to have hair growth activity.

The pyrimidine oxide derivatives, with which cyanocobalamin shows a synergistic effect, may be selected from the group consisting of pyrimidine oxide derivatives having a structure of Formula 2 below, and salts thereof: [Formula 2]

wherein Ri is a group represented by Formula 3 below; and R₂ is selected from the group consisting of lower alkoxy, lower alkyl, alkenyl, alkoxyalkyl, cycloalkyl, aryl, alkylaryl, arylalkyl, alkylarylalkyl, alkoxyarylalkyl, and haloarylalkyl: [Formula 3]

wherein R₃ and R₄ are each independently selected from the group consisting of hydrogen, lower alkyl, alkenyl, alkylaryl, and cycloalkyl, or R₃ and R₄, together with a nitrogen atom attached thereto, form a heterocyclic ring selected from the group consisting aziridinyl, azetidinyl, pyrolidinyl, piperidino, hexahydrolazepinyl, heptamethylenimino, octa-methylenimino, morpholine and 4-(lower alkyl)piperazinyl, wherein the heterocyclic ring is unsubstituted or is substituted on the carbon atoms with one to three lower alkyl, hydroxy, or alkoxy groups.

The composition containing, as active ingredients, B-group vitamins and pyrimidine oxide derivatives, can be formulated into hair tonic, scalp treatment, hair shampoo, hair cream, general ointment, skin lotion, milk lotion, eye cream, nourishing cream, massage cream, cleansing cream, cleansing foam or powder, but the scope of the present invention is not limited thereto. When the B-group vitamins in the present invention are used for the promotion of hair growth, they can be used in an amount of 0.00001-5 wt% based on the total weight of the composition depending on the intended use and formulation thereof. The group-B vitamins are preferably used in an amount of 0.0001-1 wt% in view of the solubility and formulation stability thereof. Generally, if the B-group vitamins are not solubilized in a specific formulation or have a stability problem, they can aggregate into crystals or can be modified, thus causing discoloration or degradation.

Meanwhile, the cosmetic composition according to the present invention contains pyrimidine oxide derivatives. The pyrimidine oxide derivatives are preferably contained in an amount of 0.0001-1 wt% based on the total weight of the composition. This is because of the solubility and color of the B-group vitamins.

For hair growth promotion resulting from vasodilation as described above, the B-group vitamins and pyrimidine oxide derivatives can be suitably selected and used by a person skilled in the art without any particular difficulty. [Description of Drawings]

FIG. 1 is a graphic diagram showing the effect of cyanocobalamin on potassium channel opening. FIG. 2 is a graphic diagram showing the effect of cyanocobalamin on the promotion of hair growth in mice.

FIG. 3 is a graphic diagram showing the synergistic effects of cyanocobalamin with pyrimidine oxide derivatives (minoxidil).

FIG. 4 is a graphic diagram showing the effects of B-group vitamins on the promotion of proliferation of dermal papilla cells. FIG. 3 is a graphic diagram showing the synergistic effects of cyanocobalamin with pyrimidine oxide derivatives (minoxidil). [Mode for Invention]

Hereinafter, the present invention will be described in further detail with reference to Test Examples.

Test Example 1 : Test on potassium channel opening effect of cyanocobalamin

5% bovine fetal serum and 100 IU penicillin G were added to a

DMEM medium containing phenol red, and a mouse-derived fibroblast NIH3T3 cell line was dispensed onto a 24-well microtiter plate at a density of

10,000 cells/well. Potassium channel antagonist tolbutamide was added to the medium at a final concentration of 2.5 mM, and cyanocobalamin according to the present invention was 1000-fold diluted in the medium to concentrations of 0.1 μM, 1 μM and 10 μM and added to the microtiter plate. Then, the medium in each well was incubated at 37 °C for 3 days. After the incubation, a solution of 0.2% MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide) was added to the mitrotiter plate in an amount

of 200 μ# per well, and the medium was further incubated at 37 ^°C for 3 days.

Then, the produced formazane was dissolved in DMSO (dimethylsulfoxide). The absorbance of the dissolved formazane was measured at 570 nm using a microplate reader. The cyanocobalamin offset the potassium channel- antagonistic action of the tolbutamide at each concentration to promote the proliferation of NIH3T3. The promotion results of the cyanocobalamin are shown in FIG. 1 in comparison with a control group. As can be seen in FIG. 1 , the cyanocobalamin showed the effect of opening potassium channels in the presence of tolbutamide as a potassium channel antagonist.

Test Example 2: Test on hair growth effect of cyanocobalamin in mice In order to observe the hair growth effect of cyanocobalamin according to the present invention, the following groups were used to test the hair growth effect of cyanocobalamin: a negative control group: a solution of water/ethanol/l,3-butyleneglycol (5/3/2); a positive control group: a solution of pyrimidine oxide derivatives (minoxidil) in the solution of the negative control group; test group 1: a solution of 0.5 wt% cyanocobalamin in the solution of the negative control group; and test group 2: a solution of 0.5 wt% cyanocobalamin and minoxidil in the solution of the negative control group.

The backs of 47-53-day-old mice (C57BL/6) were shaved, and among the mice, mice having a clean back portion were selected. The selected mice were divided into 4 groups each consisting of 8 animals. The above four solutions were applied to the four mouse groups, respectively, in an amount of

150 μ# per animal daily for 21 days. After 21 days, the mice were

photographed to observe the growth of hair in the mice, and the weight of newly grown in the test groups was measured, and compared with those in the negative and positive control groups. The measurement results are shown in FIG. 2.

As can be seen in FIG. 2, the cyanocobalamin according to the present invention acted directly on the mice in the telogen phase to promote the transition from the telogen phase to the anagen phase, thus showing the effect of promoting hair growth. Also, it increased the effect of pyrimidine oxide derivatives (minoxidil). Test Example 3: Test on synergistic effect of cyanocobalamin with pyrimidine oxide derivatives (minoxidil)

5% bovine fetal serum and 100 IU penicillin G were added to a

DMEM medium, and a rat-derived dermal papilla cell line was dispensed onto a 24-well microtiter plate at a density of 10,000 cells/well. Cyanocobalamin, minoxidil and a mixture of cyanocobalamin and minoxidil were 1000-fold diluted in the medium to concentrations of 1 μM (cyanocobalamin), 100 μM

(minoxidil), and 1 μM (cyanocobalamin) and 100 μM (minoxidil) for the mixture, and added to each well. Then, the medium in each well was incubated at 37 "C for 3 days. After the incubation, a solution of 0.2% MTT

(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was added to

the mitrotiter plate in an amount of 200 μ# per well, and the medium was

further incubated at 37 ^°C for 3 hours. Then, the produced formazane was dissolved in DMSO (dimethylsulfoxide). The absorbance of the dissolved formazane was measured at 570 nm using a microplate reader. The synergistic effect of cyanocobalamin with pyrimidine oxide derivatives is shown in FIG. 3 in comparison with a control group.

As can be seen in FIG. 3, the cyanocobalamin increased the effect of the pyrimidine oxide derivatives. Test Example 4: Test on hair growth promotion effect of B-group vitamins

5% bovine fetal serum and 100 IU penicillin G were added to a

DMEM medium, and a rat-derived dermal papilla cell line was dispensed onto a 24-well microtiter plate at a density of 10,000 cells/well. Each of vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B 12

(cyanocobalamin), vitamin B9 (folic acid) and biotin was diluted in the medium to a concentration of 1 ppm and added to each well. Then, the medium in each well was incubated at 37 ^°C for 3 days. After the incubation, a solution of 0.2% MTT (3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide) was added to the mitrotiter plate in an amount

of 200 [i£ per well, and the medium was further incubated at 37 ^°C for 3 hours.

Then, the produced formazane was dissolved in DMSO (dimethylsulfoxide). The absorbance of the dissolved formazane was measured at 570 nm using a microplate reader. The effects of the vitamins on the proliferation of dermal papilla cells are shown in FIG. 4 in comparison with a control group. As can be seen in FIG. 4, it was considered that the B-group vitamins according to the present invention, including cyanocobalamin, would all effectively induce the proliferation of dermal papilla cells in hair follicles to induce hair growth.

Test Example 5: Test on hair growth promotion effects of B-group vitamins and pyrimidine oxide derivatives

5% bovine fetal serum and 100 IU penicillin G were added to a DMEM medium, and a rat-derived dermal papilla cell line was dispensed onto a 24-well microtiter plate at a density of 10,000 cells/well. Each of vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B 12 (cyanocobalamin), vitamin B9 (folic acid) and biotin was diluted in the medium in a concentration of 1 ppm and added to each well. A mixture of each of these b-group vitamins with 100 μM minoxidil was 1000-fold diluted in the medium and added to each well. Then, the medium in each well was incubated at 37 °C for 3 days. After the incubation, a solution of 0.2% MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was added to

the mitrotiter plate in an amount of 200 \\.i per well, and the medium was further incubated at 37°C for 3 hours. Then, the produced formazane was dissolved in DMSO (dimethylsulfoxide). The absorbance of the dissolved formazane was measured at 570 nm using a microplate reader. The synergistic effects of the B-group vitamins with the pyrimidine oxide derivatives (minoxidil) are shown in FIG. 5 in comparison with a control group.

As can be seen in FIG. 5, the B-group vitamins increased the effect of the pyrimidine oxide derivatives.

Hereinafter, various cosmetic formulation examples will be given based on the results of the above Test Examples. It will however be obvious to those skilled in the art that these formulation examples are presented to explain the present invention, and the scope of the present invention is not limited thereto.

Formulation Example 1 : Hair tonic containing B-group vitamins and pyrimidine oxide derivatives [Table 1]

Formulation Example 2: Hiar lotion containing B-group vitamins and pyrimidine oxides [Table 2]

Formulation Example 3: Hair nourishing lotion containing group-B vitamins and pyrimidine oxides [Table 3]

Formulation Example 4: Skin lotion containing group-B vitamins and pyrimidine oxide derivatives [Table 4]

Formulation Example 5: Milk lotion containing B-group vitamins and pyrimidine oxide derivatives [Table 5]

Formulation Example 6: Nourishing cream containing B-group vitamins and pyrimidine oxide derivatives [Table 6]

Formulation Example 7: Massage cream containing B-group vitamins and pyrimidine oxide derivatives [Table 7]

Formulation Example 8: Pack containing group-B vitamins and pyrimidine oxide derivatives [Table 8]

Test Example 6: Hair growth effect of hair tonic containing B-group vitamins and pyrimidine oxide derivatives, in mice

Six hair tonic formulations (1-1 to 1-6) prepared in Formulation Example 1 were tested for their hair growth effects in the following manner.

The backs of 47-53-day-old mice were shaved, and among the mice, mice having a clean back portion were selected. The selected mice were divided into 6 groups each consisting of 12 animals. The six hair tonic formulations

were applied to the six mouse groups, respectively, in an amount of 150 [i£

per animal daily for 21 days. After 21 days, the weight of newly grown in the test groups was measured. The measurement results are shown in Table 1 below. As a control group in this test example, a mixture solution of water/ethanol/l,3-butyleneglycol (5/3/2) was used as a standard for hair growth.

As can be seen in Table 1, the hair tonics containing B-group vitamins and pyrimidine oxide derivatives showed an excellent effect on hair growth. [Table 9]

Test Example 7: Hair loss-preventing effect of hair tonic containing B- group vitamins and pyrimidine oxide derivatives On 42 volunteers who show hair loss phenomena above Hamilton

Node 3, six hair tonic formulations (1-1 to 1-6) prepared in Formulation Example 1 were applied to the scalp two times daily, and whether hair loss was reduced was observed. Meanwhile, a formulation, which contains no B- group vitamin and pyrimidine oxide derivatives, was prepared and used as a placebo group.

According to the hair loss state of the volunteers participating in this test example, the hair loss-preventing effect of the hair tonic formulations was evaluated on four scales: -1= worse; 0= fare; l=good; and 2= excellent. The evaluation results are shown in Table 2 below. As can be seen in Table 2, the hair tonics containing B-group vitamins and pyrimidine oxide derivatives showed an excellent effect on hair loss prevention. [Table 10]

[Industrial Applicability]

As described above, the composition according to the present invention contains, as active ingredients, B-group vitamins and pyrimidine oxide derivatives. Accordingly, the composition has a potassium channel opening effect, and thus the effects of preventing hair loss and preventing hair growth.

Claims

[CLAIMS] [Claim 1 ]

A composition for hair loss prevention or hair growth promotion, containing: i) a water-soluble vitamin selected from a water-soluble vitamin B group consisting of vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B6 (pyridoxine), vitamin B 12 (cyanocobalamin), vitamin B9 (folic acid) and biotin; and ii) at least one pyrimidine oxide selected from the group consisting of pyrimidine oxide derivatives having a structure of Formula 2 below, or salts thereof: [Formula 2]

[Claim 2]

The composition of Claim 1, wherein the water-soluble vitamin B group shows a potassium channel opening composition at the intracellular level.

[Claim 3]

The composition of Claim 1, wherein the water-soluble vitamin B group is an active ingredient for promoting follicle cells.

[Claim 4] The composition of Claim 1, wherein the water-soluble vitamin B group is contained in an amount of 0.00001-5 wt% based on the total weight of the composition. [Claim 5]

The composition of Claim 4, wherein the water-soluble vitamin B group is contained in an amount of 0.0001-1 wt% based on the total weight of the composition. [Claim 6]

The composition of Claim 1, wherein the pyrimidine oxide is contained in an amount of 0.0001-1 wt% based on the total weight of the composition. [Claim 7] The composition of Claim 1, which has a formulation selected from the group consisting of hair tonic, scalp treatment, hair shampoo, hair cream, general ointment, skin lotion, milk lotion, eye cream, nourishing cream, massage cream, cleansing cream, cleansing foam and powder.