Application of tetrahydrocortisol in preparation of product for preventing and treating symptoms related to white hair

Abstract

The invention relates to application of tetrahydrocortisol in preparation of a product for preventing and treating symptoms related to white hair. According to the application, corticosterone downstream metabolites are systematically evaluated through an in-vitro mouse whisker hair follicle model, and tetrahydrocortisol is found to play an important role in hair follicle microenvironment homeostasis, can remarkably improve hair pigment deficiency of stress-induced white hair mice, and is a new hormone with an extremely remarkable white hair improving effect.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and in particular to the use of tetrahydrocortisol in preparing products for preventing and treating diseases or symptoms associated with gray hair. Background Art

[0002] Natural hair color is often a symbol of health, youth, and vitality, while gray hair can easily trigger emotional distress and affect social activities. A vicious cycle can form between emotional disorders and gray hair. Therefore, the prevention and treatment of gray hair has become a public health issue and a social pain point that urgently needs to be addressed. Gray hair is a physiological and pathological condition caused by the loss or dysfunction of melanin in the hair shaft, which may affect part or all of the hair. Physiological gray hair is generally considered a significant sign of the natural aging process and is also known as senile gray hair. In addition to natural aging factors, genetic factors and stimulation from various stressors can also cause gray hair to appear before natural aging. This type of gray hair is defined as pathological gray hair. According to studies, the incidence of pathological gray hair in my country is approximately 15-32%. Therefore, the treatment and improvement of pathological gray hair has always been a focus of medical and social attention and a research challenge.

[0003] At present, physical methods such as shampoo and hair dye are mainly used to improve gray hair. Although they can improve gray hair quickly and briefly, these two mainstream intervention measures only treat the symptoms and not the root cause, and are accompanied by some potential risks, such as dermatitis, hair loss, itching and even cancer caused by repeated and frequent use. There are certain limitations.

[0004] Therefore, there is an urgent need to develop safe and effective intervention strategies to improve the symptoms of gray hair. Summary of the Invention

[0005] The following is an overview of the subject matter described in detail herein. This overview is not intended to limit the scope of protection of this application.

[0006] Tetrahydrocortisol (THC), a tetrahydro derivative of corticosterone (CORT), is a type of inactive glucocorticoid metabolite. Research has shown that while THC lacks glucocorticoid activity, it may possess other strong biological activities, such as promoting angiogenesis. This application systematically evaluated CORT downstream metabolites using an in vitro mouse vibrissa follicle model and found that THC plays an important role in the homeostasis of the hair follicle microenvironment. Furthermore, it can significantly improve hair pigmentation loss in mice with stress-induced hair greying (Str-HG), making it a new hormone with extremely significant effects in improving grey hair.

[0007] The first aspect of the present application provides a use of tetrahydrocortisol in preparing a product for preventing and treating diseases or symptoms associated with gray hair; Optionally, use of tetrahydrocortisol in preparing a product for preventing and treating diseases or symptoms related to hair graying caused by stress.

[0008] In an exemplary embodiment, the tetrahydrocortisol has one or more of the following properties: promoting hair pigmentation; regulating the hair follicle microenvironment.

[0009] In an exemplary embodiment, the diseases or symptoms associated with gray hair include any one or more of the following: premature graying of hair, graying, localized graying of hair, and leucorrhea.

[0010] In an exemplary embodiment, the product is any one of medicine, health care product, and daily chemical product.

[0011] In an exemplary embodiment, the product can be administered by any of the following ways: topical application on the skin, oral administration, or injection.

[0012] In an exemplary embodiment, when applied topically to the skin, the content of tetrahydrocortisol in the product is 0.01 mg / ml-0.3 mg / ml, for example, 0.01 mg / ml, 0.05 mg / ml, 0.1 mg / ml, 0.15 mg / ml, 0.2 mg / ml, 0.25 mg / ml, 0.3 mg / ml or any two values ​​thereof as the range between the endpoint values, but are not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; Preferably, it is 0.1 mg / ml-0.3 mg / ml.

[0013] In an exemplary embodiment, when administered by injection, the dosage of the tetrahydrocortisol in the product is 0.01 mg / kg-0.3 mg / kg, for example, 0.01 mg / kg, 0.05 mg / kg, 0.1 mg / kg, 0.15 mg / kg, 0.2 mg / kg, 0.25 mg / kg, 0.3 mg / kg, or any two values ​​thereof as the range between the endpoint values, but are not limited to the listed values, and other values ​​not listed within the numerical range are also applicable; Preferably, it is 0.1 mg / kg-0.3 mg / kg.

[0014] In an exemplary embodiment, the tetrahydrocortisol can be the sole active ingredient in the product, or can be co-administered with other pharmaceutical ingredients.

[0015] In an exemplary embodiment, the drug may further include pharmaceutically acceptable excipients.

[0016] In an exemplary embodiment, the dosage form of the drug includes any one of the following: cream, patch, ointment, cream preparation, gel, spray, tablet, granule, capsule, oral liquid preparation, pill, suspension, pellet, injection, etc.

[0017] In an exemplary embodiment, the daily chemical products are cosmetics, care products or beauty products.

[0018] The second aspect of the present application provides a product for preventing and treating diseases or symptoms associated with gray hair, wherein the product comprises tetrahydrocortisol.

[0019] In an exemplary embodiment, the product is applied topically to the skin, and the content of tetrahydrocortisol in the product is 0.01 mg / ml-0.3 mg / ml, preferably 0.1 mg / ml-0.3 mg / ml.

[0020] The third aspect of the present application provides a product for preventing and treating diseases or symptoms associated with gray hair, wherein the product comprises tetrahydrocortisol.

[0021] In an exemplary embodiment, the product is administered by injection, and the dosage of the tetrahydrocortisol in the product is 0.01 mg / kg-0.3 mg / kg; preferably, 0.1 mg / kg-0.3 mg / kg.

[0022] The fourth aspect of the present application provides a method for improving or treating diseases or symptoms related to gray hair, comprising administering a therapeutically effective amount of tetrahydrocortisol to a subject.

[0023] Compared with the existing technology, this application has the following technical effects: This application systematically evaluated CORT downstream metabolites using an in vitro mouse vibrissa follicle model and found that THC plays a crucial role in hair follicle microenvironment homeostasis. Furthermore, it significantly improved hair pigmentation in mice with stress-induced hair graying (Str-HG), demonstrating its potential as a novel hormone with remarkable efficacy in improving gray hair. THC, whether administered internally or topically, promoted hair pigmentation in animal models. Topical THC demonstrated good efficacy at concentrations of 0.1 part per ten thousand (e.g., 0.01 mg / mL-0.3 mg / mL), with no significant toxic or side effects observed. Given THC's significant effect in promoting hair pigmentation, the novelty of THC-related scientific research, and the scarcity of high-value, original products, the development of a Class 1 new chemical drug, THC, for the prevention and treatment of gray hair has significant market value and strategic significance.

[0024] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained by the solutions described in the description and the drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings are used to provide an understanding of the technical solution of the present application and constitute a part of the specification. Together with the embodiments of the present application, they are used to explain the technical solution of the present application and do not constitute a limitation on the technical solution of the present application.

[0026] Figure 1 This is a comparison of the effects of THC on the stress-induced gray hair mouse model in Example 1; Figure 2 This is a comparison of the back skin condition of the stress-induced gray hair mouse model treated with THC in Example 1; Figures 3(A) and 3(A') are typical images and statistical analysis of melanin staining of hair follicles on the back of mice (using Masson-Fontana melanin staining), respectively. Compared with the control group, the melanin content of the hair follicles on the back of mice subjected to stress-induced hair graying during the second growth phase was significantly reduced, and this phenomenon was alleviated by local administration of THC. Figure 3 (B) shows a typical image of Ki67 staining of hair follicles on the back of mouse skin. Ki67 is a cell proliferation marker that can be used to understand the hair follicle cycle. Ki67 staining shows that local THC intervention does not affect the hair follicle cycle of mice with stress-induced graying hair. Figure 3 (C) is a typical image of melanocyte staining in the dorsal skin of mice, where MITF (microphthalmia-associated transcription factor) is a melanocyte marker; Figure 3 (D) shows a typical staining image of melanocyte stem cells in the dorsal skin of mice. TRP2 (tyrosinase-related protein 2) is a melanocyte stem cell marker. By observing TRP2-stained cells, we can understand the distribution and number of melanocyte stem cells in the mouse skin. Compared with the control group, during the second growth period of mice, the number of melanocyte stem cells in the dorsal skin hair follicles of stress-induced gray hair model mice was significantly reduced, and even their basic ecological niche was lost. This phenomenon was reversed after topical THC administration. Figure 3 (E) shows a statistical analysis of the number of Ki67-stained positive cells in the hair follicles of the mouse back skin. The number of Ki67-stained positive cells showed no significant difference in the number of Ki67-positive cells between the groups compared with the stress-induced hair graying model group. This suggests that THC does not affect the hair follicle cycle in stress-induced hair graying mice. Figure 3 (F) shows a statistical analysis of the percentage of melanocytes in each hair follicle on the back skin of mice. This figure shows that, compared with the control group, the number of melanocytes in the hair follicles on the back skin of mice with stress-induced graying hair was significantly reduced during the second growth phase, while the number of melanocytes in the THC topical administration group increased significantly after the intervention. Figure 3 (G) is a statistical analysis of the number of melanocytes in each hair follicle on the back skin of mice. According to the figure, compared with the control group, the number of melanocyte stem cells in the hair follicles of the back skin of mice with stress-induced gray hair model was significantly reduced during the second growth period of mice, while the number of melanocytes in the THC local administration group increased significantly after drug intervention. DETAILED DESCRIPTION

[0027] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0028] The raw materials used in this application are all conventional products on the market.

[0029] Unless otherwise specified, the materials, reagents, etc. used in the examples of the present invention can be obtained from commercial sources.

[0030] The experimental methods without specific conditions specified in the examples are generally carried out under conventional conditions or conditions recommended by the manufacturers.

[0031] Example 1. Treatment of stress-induced gray hair mouse model The experiment used 3-week-old SPF-grade C57BL / 6J healthy female mice. After 3 days of adaptive feeding, they were randomly divided into lysozyme control group (Vehicle), stress-induced hair graying group (RTX), intraperitoneal injection low-dose group (0.01 mg / kg), intraperitoneal injection medium-dose group (0.1 mg / kg), intraperitoneal injection low- and high-dose groups (0.3 mg / kg), local application low-dose group (i.e., external application group, 0.01 mg / ml), local application medium-dose group (i.e., external application group, 0.1 mg / ml) and local application high-dose group (0.3 mg / ml), with 3 mice in each group. Except for the control group, mice in the other groups were subcutaneously injected with a capsaicin analog (resiniferatoxin, RTX) to induce high-intensity stress during the late growth phase of the hair follicle cycle (approximately day 31-36 after birth). The capsaicin analog was prepared in a solution of 2% DMSO and 0.15% Tween 80 in phosphate-buffered saline (PBS) and injected continuously for three consecutive days at increasing doses of 30 μg / kg, 70 μg / kg, and 100 μg / kg. The control group was also injected with the solution. By the second growth phase (approximately day 72 after birth), significant whitening of the hair was observed, indicating successful modeling.

[0032] After the model was successfully established, the control group and the stress-induced gray hair group were subcutaneously injected with a THC-free solvent, and the other groups were administered with THC. Among them, the mice in the intraperitoneal injection group were given intraperitoneal injection of THC once a day at a dose of 0.01-0.3 mg / kg; the mice in the topical application group were given THC applied to the backs of the mice, with a frequency of once a day and a dosage of 50 μl / day for 14 consecutive days. The hair color changes of the mice were closely observed during the experiment.

[0033] At the end of the experiment, the mice were observed for hair whitening. At the same time, each mouse was depilated, with the removal of 4 square centimeters (2 cm × 2 cm) of hair as the standard. The back skin condition of all experimental mice was observed.

[0034] Conclusion: According to Figure 1 The stress-induced gray hair mouse model shown in the figure showed that, except for the control group, all other groups experienced the process of hair graying, and the groups administered with THC reversed this trend of hair graying. At the same time, no allergic reactions such as itching, redness, and swelling were observed on the skin of the mice in each group, indicating that the drug was extremely safe ( Figure 2 ).

[0035] Example 2. Study on the hair follicle microenvironment of a stress-induced gray hair mouse model According to Example 1, both intraperitoneal injection and topical application of THC can significantly improve stress-induced gray hair in mice. Since topical administration can directly deliver the drug to the skin, it has a rapid and targeted effect and does not require first-pass metabolism through systemic blood circulation and the liver to reduce the impact on other organs. Therefore, at the end of the experiment, the back skin tissue of the mice in the topical administration group was collected, embedded, sectioned, and stained with Ki67 to observe the melanin content in the mouse hair follicles, hair cycle, and the number and location of melanocytes and melanocyte stem cells.

[0036] Among them, Figure 3 (A) and Figure 3 (A') are typical images of mouse skin hair follicle melanin staining (using Masson-Fontana melanin staining, which uses the principle of argyrophilic reaction that melanin has the property of reducing silver ammonia solution to metallic silver to display melanin, and the melanin appears black after staining) and statistical analysis graphs, respectively; According to Figure 3 (A) and Figure 3 (A'), compared with the control group, the melanin content in the back skin hair follicles of stress-induced gray hair model mice was significantly reduced, and this phenomenon could be alleviated after local administration of THC.

[0037] Figure 3 (B) is a typical image of Ki67 staining of mouse skin hair follicles; Ki67 staining shows that local THC intervention does not affect the hair follicle cycle of stress-induced gray hair mice.

[0038] Figure 3 (C) is a typical image of melanocyte staining. MITF (microphthalmia-associated transcription factor) is a melanocyte marker. MITF regulates the expression of multiple genes by binding to specific DNA sequences (such as M-box), thereby participating in melanin synthesis, cell proliferation and survival. According to Figure 3 (C), compared with the stress-induced gray hair model group, after local administration of THC, melanin synthesis increased, thereby alleviating the occurrence of gray hair.

[0039] Figure 3 (D) is a typical melanin stem cell staining image, and TRP2 is a melanin stem cell marker. By observing TRP2-stained cells, we can understand the distribution and number of melanin stem cells in the mouse skin. Compared with the control group, during the second growth period of mice, the number of melanin stem cells in the hair follicles of the back skin of stress-induced gray hair model mice was significantly reduced, and even the basic ecological niche was lost. This phenomenon was reversed after local THC administration intervention.

[0040] Figure 3 (E) is a statistical analysis of the number of Ki67-stained positive cells. The number of Ki67-stained positive cells showed that there was no significant difference in the number of Ki67-positive cells in each group compared with the stress-induced gray hair model group. This indicates that THC does not affect the hair follicle cycle of stress-induced gray hair mice.

[0041] Figure 3 (F) is a statistical analysis of the proportion of melanocytes in each hair follicle. According to the figure, compared with the control group, the number of melanocytes in the hair follicles of the back skin of the stress-induced gray hair model mice was significantly reduced during the second growth period, while the number of melanocytes in the THC topical administration group was significantly increased after the drug intervention.

[0042] Figure 3 (G) is a statistical analysis of the number of melanocytes in each hair follicle, and MITF is a melanocyte marker. According to Figure 3 (G), compared with the control group, the number of melanocytes in the hair follicles of the back skin of the stress-induced gray hair model mice was significantly reduced during the second growth period, while the number of melanocytes in the THC topical administration group was significantly increased after the drug intervention.

[0043] Conclusion: Figures 3(A)-3(G) show that, compared with the control group, during the second growth phase, the melanin content in the dorsal hair follicles of stress-induced graying mice was significantly reduced, as were the number of melanocytes and melanocyte stem cells, and even the loss of their basal niche. Topical administration of THC reversed these phenomena, indicating that THC can promote hair pigmentation in stress-induced graying mice. Furthermore, Ki67 staining results showed no significant changes in the hair follicle cycle across all groups, indicating that THC does not affect the hair follicle cycle in stress-induced graying mice.

[0044] Although the embodiments of the present application have been shown and described above, it can be understood that the above embodiments are exemplary and cannot be understood as limitations on the present application. Ordinary technicians in this field can change, modify, replace and modify the above embodiments within the scope of the present application.

Claims

1. Use of tetrahydrocortisol in the preparation of a product for preventing and treating diseases or symptoms associated with gray hair; Optionally, use of tetrahydrocortisol in preparing a product for preventing and treating diseases or symptoms related to hair graying caused by stress.

2. The use according to claim 1, wherein The tetrahydrocortisol has one or more of the following properties: promoting hair pigmentation; and regulating the hair follicle microenvironment.

3. The use according to claim 1 or 2, wherein The diseases or symptoms associated with gray hair include any one or more of the following: premature graying of hair, graying, localized graying of hair, and leucorrhea.

4. The use according to claim 1 or 2, wherein The product is any one of medicine, health care product, and daily chemical product; Optionally, the product is administered by any of the following means: topical application to the skin, oral administration or injection.

5. The use according to claim 4, wherein When applied topically to the skin, the content of tetrahydrocortisol in the product is 0.01 mg / ml to 0.3 mg / ml; and / or When administered by injection, the tetrahydrocortisol in the product is administered at a dosage of 0.01 mg / kg to 0.3 mg / kg.

6. The use according to claim 1 or 2, wherein The tetrahydrocortisol may be the sole active ingredient in the product, or may be co-administered with other pharmaceutical ingredients.

7. The use according to claim 4, wherein The drug may further include pharmaceutically acceptable excipients.

8. The use according to claim 4, wherein The dosage form of the drug includes any one of the following: cream, patch, ointment, cream preparation, gel, spray, tablet, granule, capsule, oral liquid preparation, pill, suspension, dripping pill, injection; and / or The daily chemical products are cosmetics, care products or beauty products.

9. A product for preventing and treating diseases or symptoms associated with gray hair, comprising tetrahydrocortisol; wherein: The product is applied by topical application on the skin, and the content of tetrahydrocortisol in the product is 0.01 mg / ml-0.3 mg / ml.

10. A product for preventing and treating diseases or symptoms associated with gray hair, comprising tetrahydrocortisol; wherein: The product is administered by injection, and the administration dose of the tetrahydrocortisol in the product is 0.01 mg / kg-0.3 mg / kg.

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