JPH0545569B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention relates to a preventive and therapeutic agent for gray hair, particularly to an improvement in a preventive and therapeutic agent for gray hair having a melanocyte activation function. [Prior Art] In recent years, gray hair not only due to aging but also due to various types of stress has become a problem, and there is a strong demand for preventive and therapeutic agents. There are various possible causes of hair graying, but one of the major causes is the inactivation of melanocytes, which are melanin-producing cells present in the hair bulb of the scalp hair roots. Therefore, activating melanocytes can be expected to have a preventive and therapeutic effect on gray hair. By the way, C-AMP was discovered by Sutherland (1956) as a mediator substance when blood sugar increasing hormones such as adrenaline and glucagon act on the activation of glycogen phosphorylase in the liver. As a messenger that transmits various extracellular information into cells, C-AMP is thought to be involved in the activation of various enzymes, the increase in cell membrane permeability of water and sugar, and the regulation of cell differentiation. . However, it has recently been discovered that C-AMP or C-AMP derivatives also have the function of activating melanocytes (Developmental
Genetics 2:349-356 (1981), Journal of
Endocrinology (1981), 90, 89-96). [Problems to be Solved by the Invention] However, simply applying the C-AMP or its derivative externally to the scalp may not be able to sufficiently prevent or treat gray hair. As a result of further investigation on this point, the present inventors found that there is a large amount of phosphodiesterase in the scalp, and the action of this phosphodiesterase decomposes C-AMP, making it impossible for C-AMP to function adequately. I've come to a conclusion. The present invention has been made in view of the problems of the prior art, and its purpose is to provide a method for preventing gray hair containing C-AMP or its derivatives, which can sufficiently prevent and treat gray hair even when applied externally to the scalp. ,
The aim is to provide therapeutic agents. [Means for Solving the Problem] As a result of intensive studies by the present inventors to achieve the above object, the decomposition of C-AMP in the scalp can be suppressed by coexisting theophylline, papaverine, or isobutylmethylxanthine. This discovery led to the completion of the present invention. That is, the agent for preventing and treating gray hair according to the present invention comprises C
- It is characterized by blending 0.001 to 5% by weight of at least one selected from the group consisting of AMP and its derivatives, and at least one selected from the group consisting of theophylline, papaverine, and isobutylmethylxanthine. Hereinafter, the configuration of the present invention will be explained in detail. The C-MAP used in the present invention is adenosine-3',5'-cyclic phosphate and its salt, and the C-AMP derivative is 2'-0-dibutyladenosine-3',5'-cyclic phosphate. and its salts. All of these C-AMPs and their derivatives are white crystals or crystalline powders. Easily soluble in water, methanol, and ethanol, and slightly soluble in fatty oils. One or more of C-AMP and its derivatives may be arbitrarily selected and used in the agent for preventing and treating gray hair of the present invention. The blending amount is preferably 0.01 to 5% by weight in the hair graying prevention and treatment agent of the present invention. 0.001
If the amount is less than 5% by weight, the effect of preventing or treating gray hair will not be sufficient, and if the amount exceeds 5% by weight, no enhancement of the effect can be expected. Further, in the present invention, one or more selected from the group consisting of theophylline, papaverine and isobutylmethylxanthine are used in combination,
It is possible to enhance the effects of preventing and treating gray hair, which are not sufficient with C-AMP or its derivatives alone. This is thought to be because theophylline, papaverine, and isobutylmethylxanthine inhibit the activity of C-AMP degrading enzyme. C-AMP is degraded by the action of phosphorylase, but theophylline, papaverine and isobutylmethylxanthine have the effect of inhibiting the action of phosphorylase. The blending amount of at least one of theophylline, papaverine and isobutylmethylxanthine is 0.001 to 5% by weight, C-
A molar ratio of 1:1 to 1:2 is desirable for one or more of AMP and its derivatives. If the molar ratio is less than 1:1, the decomposition of C-AMP on the scalp cannot be sufficiently suppressed;
Even if two or more are blended, the effect of suppressing the decomposition of C-AMP cannot be further improved. The dosage form of the gray hair prevention and treatment agent of the present invention is a cream,
Any formulation that can be used externally such as lotion, milky lotion, or ointment may be used. For example, the preparation of the agent for preventing and treating gray hair of the present invention can be carried out by adding C-AMP or C-AMP, which is an active ingredient, directly into the base.
The AMP derivative and theophylline, papaverine or isobutylmethylxanthine are combined to form a suitable dosage form. In addition, forskolin, cholera toxin, and prostacyclin, which increase the intracellular C-AMP concentration, can also be added. Furthermore, in the present invention, in addition to the above-mentioned active ingredients, other pharmaceutical ingredients such as vitamins such as vitamin A, vitamin B ₆ , vitamin E, and pantothenic acid, amino acids such as methionine, cysteine, cystine, and tyrosine, salicylic acid, Bactericidal agents such as hinokitiol, resorcinol, trichlorocarbanilide, etc., hormones such as ethinyl estradiol, progesterone, etc. can be added. Furthermore, components such as carpronium chloride, swelltinogen, and glycyrrhizinic acid may be added as desired within a range that does not impair the effects of the present invention. [Effects of the Invention] The preventive and therapeutic agent for gray hair according to the present invention contains, in addition to C-AMP or its derivative, at least one member selected from the group consisting of theophylline, papaverine, and isobutylmethylxanthine against C-AMP or its derivative. Since it is blended in a ratio of 1:1 to 1:2, it is possible to efficiently activate melanocytes even in the scalp where phosphodiesterase is present, and to fully exhibit gray hair prevention and treatment effects. [Example] Next, the present invention will be explained in more detail with reference to Examples. Note that the present invention is not limited to this. Further, the blending amount is shown in weight%. Confirmation of gray hair prevention and treatment effects First, a gray hair prevention and treatment agent was manufactured using the following formulation, and its effects were examined. Furthermore, X and Y
are being changed sequentially. 95% ethanol 80.0 Vitamin E acetate 0.3 Hinokitiol 0.01 Adenosine-3',5'-cyclic phosphate
X Papaverine Y Polyoxyethylene hydrogenated castor oil (EO40mol)
0.5 Purified water Residual fragrance, coloring trace amount (manufacturing method) Adenosine-3',5'-cyclic phosphate, papaverine, vitamin E acetate, hinokitiol, polyoxyethylene hydrogenated castor oil, fragrance, and coloring are added to 95% ethanol. The mixture was stirred and dissolved, and then purified water was added to obtain a transparent liquid preventive and therapeutic agent for gray hair. In addition, C _- AMP is _C10H12O7N5P (molecular weight ₃₄₅ ), _and papaverine _{is C20H21O4N} (molecular weight ₃₃₉ ). Therefore, the weight ratio is approximately the molar ratio. In addition, the effectiveness of preventing and treating gray hair was confirmed as follows. The test subjects were 15 men and women aged 35 to 60 for each sample.
Apply 1.5g of this product to the scalp twice a day,
Used continuously for a month. The condition of the applied area was photographed and compared before and after using the sample, and the gray hair prevention and treatment effects were evaluated. The evaluation criteria were as follows in each case. Significant effect ++ Considerable effect + Somewhat effect ± No effect −

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[Table] As is clear from Table 1 (A) and (B) above, C
-When AMP is less than 0.001% by weight, no significant gray hair prevention or treatment effects are observed. On the other hand, as shown in Tables 1(C) to (G), C-
Adding 0.001% by weight or more of AMP can prevent gray hair,
Therapeutic effects are observed. Here, in the groups where the amount of papaverine in each table is 0% by weight and 0.005% by weight, some gray hair prevention and treatment effects are observed, but it is not sufficient, especially in Table 1.
As shown in (C), when the amount of C-AMP blended is small, the effect is significantly enhanced by the addition of papaverine. Note that this enhancing effect is significantly observed when the molar ratio of C-AMP:papaverine is 1:1 or more, and below that, the enhancing effect of papaverine is not sufficiently exerted. In addition, as shown in Tables 1(E) and (F), C-
When the molar ratio of AMP:papaverine is 1:2 or more, papaverine hardly has any effect on preventing gray hair or enhancing its therapeutic effect, and adding a large amount not only poses a cost problem, but also reduces the preventive and therapeutic effect on gray hair. Sometimes you end up doing it. Therefore, the molar ratio of C-AMP:papaverine is preferably 1:1 to 1:2. In addition, even when theophylline and isobutylmethylxanthine are added, in order to fully exhibit the gray hair prevention and treatment effects of C-AMP, the molar ratio to C-AMP must be 1:1 to 1, similar to the case of papaverine. A ratio of 1:2 is required. Safety Test An experiment was conducted to examine the safety of the product of the present invention on the skin, and no skin irritation or allergy was observed, indicating that the product was extremely safe on the skin. The results of a human patch test are shown as an example. Test Example 1 manufactured as follows was used as a sample. (Phase A) spermaceti wax 0.5 cetanol 2.0 petrolatum 5.0 squalane 10.0 polyoxyethylene monostearate (EO10 mol) 2.0 sorbitan monooleate 1.0 adenosine-3',5'-cyclic phosphate
0.025 2'-0-Davetyladenosine-3',5'-cyclic phosphate 0.025 Theophylline 0.025 (B phase) Glycerin 10.0 Purified water Residual fragrance, coloring matter, preservative Trace amount (manufacturing method) (A) phase and (B) ) phases are heated to dissolve each
Keep at ℃. Both phases were mixed and emulsified, and cooled to room temperature while stirring to obtain an emulsified type agent for preventing and treating gray hair. A group of 50 adult females were used as subjects for each sample, and a 24-hour human forearm closed patch test was conducted. Judgment criteria were based on the following criteria. Strong erythema ++ Erythema + Slight erythema ± Negative - Table 2 Evaluation Test Example + + 0 + 0 ± 2 - 48 As explained above, gray hair prevention according to the present invention,
The therapeutic agent has extremely high safety for the human body. Example 1 (Phase A) Vaseline 10.0 Liquid paraffin 25.0 Beeswax 5.0 Solid paraffin 3.0 Olive oil 4.0 Stearic acid 1.0 Polyoxyethylene cetyl ether (E.0.20 mol) 2.0 Sorbitan monostearate 1.0 2'-0-dabutyryl adenosine -3',5'-cyclic phosphate 0.1 Isobutylmethylxanthine 0.1 (Phase B) Polyoxyethylene glycol (molecular weight 1500)
2.0 Triethanolamine 1.0 Purified water Trace amounts of residual fragrances, pigments, preservatives (manufacturing method) (A) Dissolve phase by heating and keep at 70℃. Separately, dissolve phase (B) by heating and keep at 70°C. Phase (B) was added to phase (A) and stirred, and the resulting emulsion was cooled to obtain a cream-like agent for preventing and treating gray hair. Example 2 95% Ethanol 60.0 2'-0-Davetyladenosine-3',5'-Cyclic Phosphate 2.0 Papaverine 2.0 Hydrogenated Castor Oil 40 Mol Adduct 2.0 Purified Water Remainder (Production Method) 2 in 95% Ethanol '-0-Davetyladenosine-3',5'-cyclic phosphate, papaverine and polyoxyethylene hydrogenated castor oil were added and dissolved with stirring, and then purified water was added to obtain a transparent liquid gray hair prevention and treatment agent. Ta. Example 3 (Phase A) Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Vaseline 5.5 Glycerin monostearate 3.0 Polyoxyethylene-2-octyldodecyl ether (E.0.20 mol) 3.0 Vitamin E acetate 0.1 Propylparaben 1.3 (Phase B) Adenosine- 3′,5′-cyclic phosphate
5.0 Theophylline 5.0 Glycerin 6.0 Dipropylene glycol 20.0 Polyoxyethylene glycol (molecular weight 4000)
6.0 Sodium hexametaphosphate 0.005 Purified water Residue (manufacturing method) Dissolve phase (A) by heating and keep at 70℃. Separately, dissolve phase (B) by heating and keep at 70°C. Phase (B) was added to phase (A) and stirred, and the resulting emulsion was cooled to obtain an ointment-like agent for preventing and treating gray hair. Example 4 Adenosine-3',5'-cyclic phosphate
0.001 Theophylline 0.002 Isobutylmethylxanthine 0.002 95% ethanol 60.999 Polyoxyethylene hydrogenated castor oil (E.0.40 mol)
2.0 Purified water Residue (manufacturing method) Add adenosine-3',5'-cyclic phosphate, theophylline, isobutylmethylxanthine, and polyoxyethylene hydrogenated castor oil to 95% ethanol, stir and dissolve, then add purified water. A lotion type agent for preventing and treating gray hair was obtained. The anti-grey hair prevention and treatment agent according to each of the Examples described above has an excellent effect of preventing gray hair and turning gray hair to black when used directly on the scalp.

Claims (1)

[Claims] 0.001 to 5% by weight of at least one selected from the group consisting of 1 C-AMP and its derivatives,
A preventive and therapeutic agent for gray hair, comprising at least one member of the group consisting of theophylline, papaverine, and isobutylmethylxanthine.