KR101880776B1 - Hair Growth Agent Composition - Google Patents

Abstract

And provides a hair restorer with a more hair wool effect. A hair restorer composition containing 3'-phosphoadenosine 5'-phosphosulfuric acid or a salt thereof represented by the following formula (1).

Description

Hair Growth Agent Composition}

The present invention relates to hair restorative compositions.

Hair is produced in an organ called hair follicle. Human hair follicles autonomously repeat the process of tissue regeneration and degeneration (called the hair cycle) during a lifetime. In normal people, 90% of the total hair is the growing head of growing period. However, as the proportion of the growing head decreases due to any cause and the proportion of the hair of the retrogressive head and the resting head increases, hair thinning or hair loss becomes prominent and alopecia occurs. The most common type of alopecia is male pattern hair loss. In this case, as the growing period is shortened, the hair becomes thin and short. Alopecia is thought to be caused by intricate entanglement of factors such as male hormones, genetic factors, stress, nutrition, and aging. In today's aging society, men and women are increasingly worried about alopecia due to changes in diet and social stress. In modern society, hair is part of fashion, and the social demand for hair-raising hair is increasing. In response to such societal demands, various hair hair wipes are being developed. As a preferable example thereof, there can be mentioned minoxidil (chemical name: 6- (1-piperidinyl) -2,4-pyrimidinediamine-3-oxide) or adenosine-related compounds.

Minoxidil has peripheral vasodilating action and is used as an oral tonic for the treatment of hypertension. On the other hand, attention has been paid to hairy hair as a side effect, and an application as a hair-growing hair preparation has been proposed (for example, Patent Documents 1 and 2). After that, the hair wool function of minoxidil was confirmed in the clinic and it is now marketed as hair tonic.

On the other hand, adenosine and adenosine-related compounds are also known to have effects of preventing hair loss and promoting hair growth. Heretofore, there have been known herbicides containing adenosine 5'-2 phosphate (Patent Document 3), adenosine having adenosine receptor stimulating action and adenosine-related compounds as active ingredients (Patent Document 4), adenosine as an active ingredient (Patent Document 5) and the like have been reported.

Patent Document 1: U.S. Patent No. 4,139,619 Patent Document 2: U.S. Patent No. 4596812 Patent Document 3: JP-A-2-311411 Patent Document 4: Japanese Patent Application Laid-Open No. 2000-297015 Patent Document 5: Japanese Patent Application Laid-Open No. 2004-143184

Non-Patent Document 1: Progress in Medicine, 1992, Vol. 12, No. 7, p. 1553-1565

As described above, minoxidil and adenosine-related compounds are conventionally known as hair tonic hairs. However, it is also true that his effect is limited. For example, minoxidil has no effect on hair loss of the forehead and hairline, typical of male alopecia, as described in the instruction manual of Rogaine (R). In addition, the use of minoxidil 2% lotion agent makes it possible to reproduce the hair to such an extent that there is no problem in appearance, which is only about 10% in male (Non-Patent Document 1).

SUMMARY OF THE INVENTION Accordingly, it is an object of the present invention to provide a hair restorer composition having a high hair wool effect.

Accordingly, the present inventors have made intensive studies in order to solve such problems, and as a result, they have found that 3'-phosphoadenosine 5'-phosphosulfuric acid (hereinafter abbreviated as PAPS) promotes hair- And that it has a remarkable effect of maintaining and extending the growth phase of the plant. That is, PAPS has found to have a highly effective hair wool effect.

PAPS plays an important role as a sulfate group donor in the in vivo sulfation reaction. PAPS is a substance essential for biosynthesis of chondrosaminoglycans such as chondroitin sulfate, desmatan sulfate, heparan sulfate, and keratan sulfate, and various sulfated glycolipids and sulfated proteins. However, since PAPS is highly water-soluble and has a high negative charge, it is difficult to think of permeating the cell membrane. On the other hand, since it was thought that the sulfuric acid transfer reaction using PAPS as a donor occurs in the Golgi body in the cells, it could not be considered that the extracellularly added PAPS exhibits a physiological action on various cells. Therefore, the physiological activity of extracellularly added PAPS has not been known to date.

That is, the present invention provides a hair restorer composition containing PAPS or a salt thereof represented by the following formula (1).

The present invention also provides PAPS or a salt thereof represented by the above formula (1) for hair growth.

The present invention also provides the use of PAPS or a salt thereof represented by the above formula (1) for the production of a hair restorer.

The present invention also provides a hair growth method characterized by administering an effective amount of PAPS or a salt thereof represented by the above formula (1).

PAPS not only promotes the hair growth, but also has the effect of maintaining and extending the growth period in the hair cycle, and the hair loss inhibiting effect is also remarkably high. Accordingly, the hair care composition of the present invention exhibits a strong hair wool effect as compared with the conventional hair rest composition. In addition, PAPS is an in vivo component, so its safety is high.

Fig. 1 is a view showing the ratio of the state of the hair follicle organ of each group after 6 days from the start of the test of the test (1). Fig.
[Fig. 2] Fig. 2 is a view showing the ratio of the state of the follicular organ of each group after 6 days from the start of the test of the test (2).
[Fig. 3] Fig. 3 is a view showing the ratio of the state of the follicular organ of each group after 6 days from the start of the test of the test (3).
[Fig. 4] Fig. 4 is a view showing the ratio of the state of all hair follicular organ in each group after 6 days from the start of the tests (1) to (3).
5 is a view showing the ratio of the state of the follicular organ of each group after 6 days from the start of the test of the test (4).
FIG. 6 is a graph showing a change over time in the ratio of the number of hair follicles of "head elongation" / "hair regrowth" of the first group (distilled water group).
7 is a graph showing a change over time in the ratio of the number of hair follicles of "head elongation" / "hair regrowth" of the second group (0.05% minoxidil group).
8 is a graph showing a change with time in the ratio of the number of hair follicles of "head elongation" / "head degeneration" of the third group (0.05% PAPS group).
FIG. 9 is a diagram showing the number of days of hair growth lasting in each group. FIG.
Fig. 10 is a diagram showing the head elongation of each group. Fig.
[Fig. 11] Fig. 11 is a graph showing a change with time in the hair follicle status ratio of the first group (distilled water group).
12 is a graph showing a change over time in the hair follicle status ratio of the second group (0.05% adenosine group).
[Fig. 13] Fig. 13 is a graph showing a change with time in the hair follicle status ratio of the third group (0.05% PAPS group).

The hair rest composition of the present invention contains PAPS or a salt thereof as an active ingredient. Herein, "containing" means that the hair rest composition of the present invention may be composed of PAPS alone, and that the hair rest composition may contain components other than PAPS. The wool effect refers to an effect of maintaining and extending the growth period of human hair follicles, or an effect of suppressing hair loss. The hair growth effect also means an effect of promoting the elongation of human hair.

PAPS is a known in vivo component and may be produced by any of enzymatic and chemical methods. For example, as a method of synthesizing PAPS, Patent No. 3098591, Patent No. 3078067, Patent No. 3029915, Nucleic Acids Symp. Ser. , 27, 171-172 (1992), WO2006-080313, etc. can be used.

Examples of salts of PAPS include metal salts such as sodium salts, ammonium salts and various amine salts, amino acid salts and imidazole salts. Further, it may be a prodrug of PAPS or a salt thereof, or a pharmaceutically acceptable salt of prodrug.

The content of PAPS in the hair rest composition of the present invention is preferably 0.001 to 10% (w / v), more preferably 0.01 to 1% (w / v) from the viewpoint of its effectiveness and safety.

Various optional ingredients used in external preparations for skin, such as various optional ingredients, quasi-drugs, medicines, etc. generally used in cosmetics can be suitably blended into the hair care composition of the present invention within the range not impairing the effects of the present invention. Examples of such optional components include purified water, ethanol, oily components, moisturizing agents, thickeners, preservatives, emulsifiers, medicinal components, powders, ultraviolet absorbers, coloring matters, fragrances and emulsion stabilizers.

The hair restoration composition of the present invention is preferably a skin external preparation having the form of liquid, lotion, ointment, cream, gel, aerosol and the like. In addition, the hair-restoring composition of the present invention can be used in various fields such as medicines, quasi-drugs or cosmetics. The hair care composition of the present invention can be used for the treatment or prevention of hair loss. For example, it can be widely used for treating or preventing male pattern hair loss, for treating or preventing diffuse hair loss, for treating female alopecia, and the like. Also, the name of the alopecia indicated here is an example, and the usable disease of the hair restoration of the present invention is not limited to such alopecia. The hair care composition of the present invention can be used not only for hair hair growth but also for hair growth of eyebrows and inner eyebrows.

The hair care composition of the present invention is characterized not only in promoting hair growth, but also in maintaining and extending the growth period in the hair cycle and inhibiting hair loss.

Among the various methods for evaluating the hair wool effect of drugs, one of the most reliable evaluation methods is a human hair follicle culture method in which a hair follicle is separated from a human scalp and cultured, and the effect of the drug on the hair follicle culture is evaluated. The hair follicle is an independent unit of hair growth control, as is evident from the fact that implant surgery (micrograft) into the follicular unit is practiced in the plastic surgery field. This human hair follicle organ culture method is regarded as a highly reliable evaluation method because the cell-cell interactions or the cell-extracellular matrix interactions are maintained in vivo. However, in order to maintain the hair growth of the hair follicle in the human hair follicle organ culture method, that is, to maintain the growth period in the hair cycle, addition of IGF-I or insulin to the medium is indispensable. When IGF-I or insulin is cultured without supplementation to the medium, the hair follicle changes into a regressive form in just a few days, the hair growth is stopped, and the hair is removed from the hair follicle (J. Invest. Dermatol., 1994, 102, 6, p.857-861). Thus, the hair cycle can be induced from the growing phase to the regressor by organ culturing human hair follicles without adding IGF-I or insulin to the medium. At this time, by adding a drug to be evaluated, it is possible to evaluate the effect of maintaining and extending the growth period of the drug against the human hair follicle, or the effect of suppressing hair loss. That is, the wool effect can be evaluated. In addition, the hair growth promoting effect of the medicament can be evaluated by comparing the elongation of the hair before and after the test. In other words, the hair growth effect can be evaluated

 have.

The present inventors evaluated the effect of PAPS by this human hair follicle organ culture method and found that the hair growth promoting effect which was not expected from conventional common sense and the remarkable effect of maintaining and extending the growth period in the hair cycle and suppressing hair loss I have discovered that PAPS has it. In other words, we found that PAPS has a highly effective hair wool effect.

The hair-restoring composition of the present invention may be applied to the skin 1 to 3 times a day, and the amount thereof is preferably 0.1 to 10 mg per one time as PAPS or a salt thereof.

Example

Hereinafter, the present invention will be described in more detail with reference to examples, but the technical scope of the present invention is not limitedly interpreted by these examples. % Means all weight percent (w / v).

(Example 1) Evaluation of wool effect of PAPS (1)

The following tests were carried out three times using the hair follicles collected from each of three males (37 years old male, 63 years old male and 62 year old male) (each of the tests (1), (2) ). Human scalp tissues (occipital area) of about 10 mm 2 were collected and rapidly immersed in ice-cold phosphate buffered physiological saline. Then, it was immersed and disinfected with iodine solution for 10 seconds, then immersed and washed twice with 70% ethanol for 20 seconds, and further immersed and washed twice with phosphate buffered saline solution. Then, the tissue was immersed in Dulbecco's modified MEM medium (DMEM medium) supplemented with 10% fetal bovine serum, and the hair follicular organ was separated one by one under a stereomicroscope using a micrometer. The hair follicles were divided into four groups (8 to 10 hair follicle organ numbers [n] in each group per test) so that the size and shape of hair follicles were uniformly distributed. 0.5 ml of follicular culture medium (2mML-Glutamine, 100 μg / ml of streptomycin and 100 units / ml of penicillin added to William's Medium E medium) was placed in each well of a 12-well plate in advance, The separated hair follicles were placed one by one in each well. After preincubation for 24 hours in a carbonic acid gas incubator (carbonic acid gas concentration 5%) adjusted to 37 ° C, the following four kinds of test substances were added to each group to start the test, The medium was replaced every 48 hours and the addition of the test substance was repeated. In the first group, distilled water was added as a control. In the second group, PAPS and 4Na were added to give a final concentration of 0.25%. In the third group, PAPS and 4Na were added to a final concentration of 0.05%. In the fourth group, a medium supplement containing insulin (all at a final concentration of 10 μg / mL insulin, 10 ng / mL hydrocortisone, 10 μg / mL transferrin, 10 ng / mL sodium selenite) (hereinafter referred to as insulin syringe) did. The state of each hair follicle was periodically evaluated after the start of the test and classified into the following three groups according to the state of the hair follicles. The hair follicles continued to grow at the time of evaluation, the hair follicles were termed "head regression" with the "head height", degenerative changes of the hair bulb, As "unchanged".

Results of judging the hair follicle condition 6 days after the start of the test are shown in Figs. 1-3. The proportion of "hair-growing" hair follicles in the test (1) (donor: 37 years old male) was only 13% in the distilled water group (n = 8), while the 0.25% PAPS group (n = 8) (62% and 74%, respectively) in the PAPS group (n = 8), which was higher than that of the insulin group (n = 8) in the positive control group by 50%. The proportion of hair follicles in the "head kidney" condition in test (2) (male: 63 years old) was 45% in the distilled water group (n = 9), 0.25% PAPS group (n = 9) (N = 10) were 56% and 60%, respectively. The equivalent of insulin group (n = 9) was 67%. The proportion of hair follicles in the "head kidney" state in test (3) (donor: 62 years old male) was 0% in the distilled water group (n = 10), 0.25% PAPS group (n = 10) In the PAPS group (n = 10), all of them were as high as 20%. The equivalent of insulin group (n = 9) was 33%. From these results, it was found that PAPS has the effect of increasing the ratio of hair follicles in the "hair growth" state regardless of the donor difference, ie maintaining and extending the growth period in the hair cycle. As shown in FIG. 4, the ratio of hair follicles in the "hair growth" state was 19% in the distilled water group (n = 27), but the proportion of the hair follicles in the 0.25% PAPS group (n = 27) and 0.05% in the PAPS group (n = 28), respectively, more than two times higher than those in the control group (n = 26) Results.

(Example 2) Evaluation of the wool effect of PAPS (2)

New male alopecia were newly tested (referred to as test (4)) using the hair follicles taken from two males (56-year-old male, 63-year-old male). A hair follicular organ was obtained in the same manner as in Example 1. The follicular organs were divided into three groups so that the size and shape of the hair follicles were evenly distributed. To each well of a 12-well plate was added 0.5 mL of follicular culture medium (2 mM L-Glutamine and ampicillin (50 μg / mL) added to William's Medium E medium), and the isolated hair follicles were added to each well for 1 It was politics. After culturing for 24 hours in a carbonic acid gas incubator (carbonic acid gas concentration 5%) adjusted to 37 DEG C, the following three kinds of test substances were added to each group to start the test, and then 48 The medium was changed every hour and the addition of the test substance was repeated. In the first group, distilled water was added as a control group. In the second group, minoxidil was added as a positive control to a final concentration of 0.05%. In the third group, PAPS and 4Na were added to a final concentration of 0.05%. After the start of the test, the state of each hair follicle was checked periodically as in Example 1 and classified into three groups of "hair growth", "head regression" and "no change".

The results of judging the hair follicle condition 6 days after the start of the test are shown in Fig. The proportion of hair follicles in the "head kidney" state was 15% in the distilled water group (n = 20) and only 10% in the 0.05% minoxidil group (n = 20) %. ≪ / RTI > The percentage of "hair regressed" hair follicles was 55% in the distilled water group and 65% in the 0.05% minoxidil group, while it was remarkably low in the 0.05% PAPS group.

(Example 3) Evaluation of the wool effect of PAPS (3)

The state of each hair follicle of Example 2 was judged every two days and classified into three groups of "hair growth", "hair regression" and "unchanged" as in Example 1, . The ratio of the remaining two groups of hair follicles of "head height" and "hair regression" was obtained at each evaluation point, and the change with time was followed.

The temporal changes in the ratio of "hair growth" / "hair regression" hair follicles of each group are shown in FIGS. 6, 7, and 8. In the control group (n = 14), the hair follicle state changed from "head height" to "head regression" with time, and after 4 days, 42% of the hair follicles became "head regression" After 8 days, 92% became "head regression". In the second group (0.05% minoxidil) (n = 15), 40% of hair follicles became "head regression" after 4 days and 100% became "head regression" after 8 days. In contrast, in the 0.05% PAPS group (n = 13) of the third group, hair follicles that became "head degenerated" after 8 days remained at 8%. After 8 days, the "hair regression" hair follicles remained at 62% and 38% of the hair follicles remained "head height".

FIG. 9 shows the result of comparing the number of hair durability days of each hair follicle. The mean number of days of hair growth in group 1 (distilled water group) was 3.1 days, and the equivalent in group 2 (0.05% minoxidil) was 3.3 days. In contrast, the equivalence of the third group (0.05% PAPS group) was 6.0 times, which was about twice as high. In addition, the duration of hair growth in group 3 was statistically significantly higher than that in groups 1 and 2 (p value <0.05 in Mann Whitney U test), PAPS exceeded the same concentration of minoxidil (That is, the effect of maintaining and extending the growth period in the hair cycle).

Fig. 10 shows the results of comparative analysis of hair follicle hair elongation in each group. The group 3 (0.05% PAPS group) had a head growth of 0.67 mm in the first group (distilled water group) at the end of the incubation period and 0.38 mm in the second group (0.05% minoxidil group) The equivalent was 0.82 mm, and it became clear that PAPS had excellent hair growth promoting effect.

(Example 4) Evaluation of the wool effect of PAPS (4)

Male alopecia areis The following test was carried out using a hair follicle taken from one male (male, 66 years old) (referred to as test (5)). A hair follicular tissue was obtained in the same manner as in Example 1. The hair follicles were divided into three groups (n = 12, respectively) to ensure that the size and shape of the hair follicles were uniformly distributed. After 24 hours of pre-culture in the same manner as in Example 2, three kinds of test substances shown below were added to each group one by one. In the first group, distilled water was added as a control. In the second group, adenosine was added as a positive control to a final concentration of 0.05%. In the third group, PAPS and 4Na were added to a final concentration of 0.05%. After the addition of the test substance, the medium was changed every two days and the test substance was added. The test substance was incubated in a carbon dioxide gas incubator (carbon dioxide gas concentration 5%) for 12 days and photographed every two days. In order to further analyze the effect of PAPS on the change of the hair follicle of the organ cultured hair follicle, the state of the hair follicle was evaluated with the same method as in Example 1.

The change with time in the hair follicle status ratio of each group is shown in Figs. 11, 12, and 13. The percentage of hair follicles in the "hairy kidney" state was 67% in the distilled water group and 58% in the 0.05% adenosine group, compared with 92% in the 0.05% PAPS group compared to the other two groups Respectively. The ratio of hair follicles in the "hair growth" state was 17% in the distilled water group and 0% in the 0.05% adenosine group compared to the results after 4 days from the start of the test, In the 0.05% PAPS group, the ratio was as high as 50%. The proportion of "unchanged" hair follicles was 25% in the distilled water group and 42% in the 0.05% adenosine group, compared with 8% in the 0.05% PAPS group. From these results, it was confirmed that PAPS has an effect of raising the ratio of hair follicles in the "hair growth" state, which is not recognized in the same concentration of adenosine, i.e., maintaining and extending the growth period in the hair cycle.

Claims (14)

A hair restorer composition containing 3'-phosphoadenosine 5'-phosphosulfuric acid or a salt thereof represented by the following formula (1).

The hair restorer composition according to claim 1, which contains 0.001 to 10% (w / v) of 3'-phosphoadenosine 5'-phosphosulfuric acid or a salt thereof. The hair restorer composition according to claim 1 or 2, which is an external preparation for skin. delete delete delete delete delete delete delete delete delete delete delete

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