Composition for preventing, improving, or treating hair loss or graying by regulating aldehyde dehydrogenase type 2

Abstract

The present invention relates to a composition for preventing, ameliorating, and / or treating hair loss or canities (or canities), and was completed after confirming that an aldehyde dehydrogenase type 2 (ALDH2) activator promotes hair follicle formation and hair growth and has excellent effects in suppressing oxidative stress in hair follicles. Therefore, the ALDH2 activator of the present invention can be used as a preparation for preventing, ameliorating, and / or treating hair loss and canities. Furthermore, it has been shown that combined use of an ALDH2 activator and minoxidil exhibits even more effective hair loss prevention and treatment effects. Therefore, the ALDH2 of the present invention not only effectively promotes hair growth by itself, but is also expected to be useful in the medical, cosmetic, and food fields for the prevention, amelioration, and treatment of hair loss when used in combination with minoxidil.

Description

[Technical field]

[0001] The present invention relates to the prevention, amelioration, or treatment of hair loss or gray hair by regulating aldehyde dehydrogenase type 2. The present invention also relates to a combination therapy for the prevention, amelioration, or treatment of hair loss by regulating aldehyde dehydrogenase type 2.

[0002] The present invention claims priority to Korean Patent Application No. 10-2022-0011538 filed on January 26, 2022, Korean Patent Application No. 10-2022-0079800 filed on June 29, 2022, and Korean Patent Application No. 10-2022-0152981 filed on November 15, 2022, and all contents disclosed in the specification and drawings of such applications are incorporated by reference into this application. [Background technology]

[0003] Hair follicles, which are organs that produce hair, repeat a hair growth cycle that is divided into the anagen phase, in which hair is generated and the generated hair actively grows, the catagen phase, in which the hair degenerates, the telogen phase, in which the hair is maintained until it falls out, and the exogen phase, in which hair falls out, and are involved in the growth, maintenance, and shedding of hair. During the growth phase of hair follicles, in adults, hair grows at an average rate of about 0.3 mm per day, grows about 1 cm per month, and lasts for about 5 to 8 years. In general, hair falls out after a catagen phase of about 3 weeks after the growth phase and a telogen phase of an average of 3 months. The reason why the length of human hair varies depending on the area is that the duration of the growth phase, which is a unique characteristic of hair follicles, differs from area to area.

[0004] Hair is formed from hair follicles. Hair follicles are very complex organs, consisting of the inner root sheath, outer root sheath, hair shaft, and hair matrix cells. In particular, hair dermal papilla cells play a key role in the formation of hair follicles, and are directly linked to the formation of hair follicles. If hair papilla cells are not present or do not function, proper interaction between the hair papilla cells and epidermal cells is not established, and hair follicles cannot be formed.

[0005] Alopecia refers to a condition in which there is little or no hair in areas where hair should normally be present. It is known that hair loss is caused by a complex combination of factors, including genetic causes, the effects of male hormones, endocrine disorders, nutritional deficiencies, drug use, childbirth, fever, and intense physical and mental stress such as surgery. In recent years, the number of women suffering from hair loss has been increasing due to not only male pattern hair loss but also changes in diet and increased stress from the social environment, and the number of people suffering from abnormal symptoms of the scalp and hair is increasing, and the age of those suffering from such symptoms is also decreasing.

[0006] Research into hair loss prevention and hair growth agents is accelerating both at home and abroad, and various products have been developed, but the reality is that there is still a lack of development of hair loss prevention agents that are effective and safe for the human body. Currently developed topical products include Minoxidil from the United States, and herbal extracts have been developed as hair growth or hair growth agents mainly in Japan, but in terms of efficacy, it is still too early to expect hair loss prevention and hair growth, respectively. In particular, it has been reported that when used in high doses, Minoxidil can cause side effects such as weight gain, edema, increased heart rate, angina, dermatitis, and itching. Therefore, it is necessary to find a more effective hair loss treatment agent that can replace Minoxidil, or a combination therapy that can enhance the hair growth effect of Minoxidil and reduce side effects.

[0007] Currently, the only effective treatments for male pattern hair loss are the 5α-reductase inhibitors finasteride and dutasteride, but the effectiveness of the treatment varies greatly from person to person, and when the product is discontinued, hair loss may recur or serious side effects such as sexual dysfunction may occur. In particular, most of the existing hair loss treatments approved by the US FDA were developed with a focus on male pattern hair loss, so they have limitations in solving female pattern hair loss and may even cause side effects in women. Therefore, there is a great need for research into new hair loss prevention and hair growth agents that can be proven safe and effective for both men and women.

[0008] Gray hair is a process of aging and occurs in various ways depending on the individual. It is understood that the cause of gray hair is the loss and decreased activity of melanocytes in the hair bulb and outer root sheath, but the cellular and molecular mechanisms are not clearly known. Amelanin-deficient melanocytes remain in the outer root sheath of gray hair but are not found in the hair bulb, suggesting a decrease in melanocyte stem cells and abnormalities in the process regulating melanocyte migration and differentiation. In human hair follicles, melanocytes located in the hair bulb begin to organize around the dermal papilla during the hair growth phase after division. Tyrosinase and TRP-1 enzymes expressed in melanocytes are only observed during the growth phase and are not produced during the catagen phase. Therefore, pigment can be regenerated in hair at the top of the outer root sheath through melanocytes that are periodically activated during the growth phase.

[0009] Accumulation of reactive oxygen species generated during the melanin production process causes damage to the antioxidant system and induces oxidative stress. Excessive oxidative stress is known to be vulnerable to melanocyte production. In particular, accumulated oxidative stress may disturb the homeostasis of melanocytes and cause cell death or deformation. Therefore, in order to prevent or improve not only hair loss but also gray hair, it is very important to suppress oxidative stress in melanocytes.

[0010] Since gray hair gives a strong impression of aging, many studies have been conducted on dyes that dye gray hair black to hide the gray hair that has developed. However, dyeing is only a temporary method and is based on chemicals, which can damage the scalp and deteriorate the health of hair follicles. Therefore, it is necessary to discover new methods that can fundamentally prevent and improve gray hair.

[0011] On the other hand, aldehyde dehydrogenase type 2 (ALDH2) is an enzyme present in mitochondria in the body, which mainly plays a role in converting acetaldehyde to acetic acid and is known to be useful for breaking down alcohol absorbed into the body. However, the effect of activation of the enzyme on preventing hair loss or promoting hair growth has not yet been reported. Summary of the Invention [Problem to be solved by the invention]

[0012] The present invention has been devised to solve the above problems, and has been completed by confirming that the type 2 aldehyde dehydrogenase activator promotes the formation of hair follicles and hair growth, and has excellent effects in preventing hair loss, promoting hair growth, and preventing or improving gray hair. Furthermore, it has been confirmed that the type 2 aldehyde dehydrogenase activator can exert a synergistic hair loss treatment effect when used in combination with minoxidil.

[0013] Therefore, an object of the present invention is to provide a pharmaceutical composition for preventing or treating alopecia or gray hair, which comprises a type 2 aldehyde dehydrogenase activator as an active ingredient.

[0014] Another object of the present invention is to provide a cosmetic composition for preventing or improving hair loss or gray hair, which comprises a type 2 aldehyde dehydrogenase activator as an active ingredient.

[0015] It is still another object of the present invention to provide a quasi-drug composition for preventing or improving hair loss or gray hair, which comprises a type 2 aldehyde dehydrogenase activator as an active ingredient.

[0016] It is still another object of the present invention to provide a food composition for preventing or improving hair loss or gray hair, comprising an aldehyde dehydrogenase type 2 activator as an active ingredient. The food composition includes a functional health food composition.

[0017] A further object of the present invention is to provide a pharmaceutical composition for preventing or treating hair loss, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient, which is characterized in that it is administered in combination with minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof.

[0018] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof, as active ingredients.

[0019] It is still another object of the present invention to provide a cosmetic composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a cosmetically acceptable salt thereof, or an analog thereof, as active ingredients.

[0020] It is still another object of the present invention to provide a quasi-drug composition for preventing or ameliorating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, as active ingredients.

[0021] It is still another object of the present invention to provide a food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a nutrient-based acceptable salt thereof, or an analog thereof as active ingredients.

[0022] It is still another object of the present invention to provide a health functional food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a nutrient-based acceptable salt thereof, or an analog thereof as active ingredients.

[0023] However, the technical problems that the present invention aims to achieve are not limited to those mentioned above, and other problems not mentioned will be clearly understood by a person having ordinary skill in the art to which the present invention pertains from the following description. [Means for solving the problem]

[0024] The present invention provides a pharmaceutical composition for preventing or treating hair loss or gray hair, which comprises an aldehyde dehydrogenase 2 (ALDH2) activator as an active ingredient.

[0025] The present invention also provides a method for preventing or treating hair loss or gray hair, comprising administering an ALDH2 activator to an individual in need thereof.

[0026] The present invention also provides use of an ALDH2 activator for preventing or treating hair loss or gray hair.

[0027] The present invention also provides use of an ALDH2 activator for the manufacture of a medicament for treating hair loss or gray hair.

[0028] In one embodiment of the present invention, the composition may be for promoting hair growth or hair regrowth, but is not limited thereto.

[0029] In another embodiment of the present invention, the hair loss may be one or more selected from the group consisting of alopecia areata, hereditary androgenetic alopecia, telogen effluvium, traumatic alopecia, trichotillomania, pressure induced alopecia, anagen effluvium, pityriasis nivea, syphilitic alopecia, seborrheic alopecia, symptomatic alopecia, cicatricial alopecia, and congenital alopecia, but is not limited thereto.

[0030] In yet another embodiment of the present invention, the type 2 aldehyde dehydrogenase activator may be, but is not limited to, Alda-1 or a pharma- ceutically acceptable salt thereof.

[0031] In yet another embodiment of the present invention, the Alda-1 or a pharma- ceutical acceptable salt thereof may be contained in the composition at a concentration of 0.0001 to 50 mM, but is not limited thereto.

[0032] In yet another embodiment of the present invention, the composition may satisfy at least one characteristic selected from the group consisting of, but not limited to, (a) promoting proliferation of dermal papilla cells or outer root sheath cells, (b) promoting hair follicle growth, (c) inducing the anagen phase of hair, and (d) increasing mitochondrial activity.

[0033] In yet another embodiment of the present invention, the composition can increase the level or activity of at least one protein selected from the group consisting of, but not limited to, bFGF, FGF-7, IGF-1, and PDGF.

[0034] In yet another embodiment of the present invention, the composition may reduce oxidative stress in dermal papilla cells or outer root sheath cells, but is not limited thereto.

[0035] The present invention also provides a cosmetic composition for preventing or improving hair loss or gray hair, which comprises an ALDH2 activator as an active ingredient.

[0036] In one embodiment of the present invention, the composition may be in the form of an external skin preparation, such as, but not limited to, a scalp treatment agent, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid, solution, emulsion, dispersion, micelle, liposome, ointment, lotion, essence, patch, or spray.

[0037] The present invention also provides a quasi-drug composition for preventing or ameliorating hair loss or gray hair, which comprises an ALDH2 activator as an active ingredient.

[0038] The present invention also provides a food composition for preventing or improving hair loss or gray hair, which contains an ALDH2 activator as an active ingredient.

[0039] The present invention also provides a functional health food composition for preventing or improving hair loss or gray hair, comprising the food composition as an active ingredient.

[0040] The present invention also provides a method for preventing or improving gray hair, comprising administering an ALDH2 activator to an individual in need thereof. The method may be a cosmetic method.

[0041] The present invention also provides use of an ALDH2 activator for preventing or improving gray hair.

[0042] The present invention also provides use of an ALDH2 activator for the manufacture of a medicament for preventing or improving gray hair.

[0043] The present invention also provides a pharmaceutical composition for preventing or treating hair loss, comprising an aldehyde dehydrogenase 2 activator as an active ingredient, which is administered in combination with minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof.

[0044] The present invention also provides for the use of a type 2 aldehyde dehydrogenase activator administered in combination with minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof.

[0045] The present invention also provides a method for preventing or treating hair loss, comprising administering (a) an aldehyde dehydrogenase type 2 activator, and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof to an individual in need thereof.

[0046] The present invention also provides use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for preventing or treating hair loss.

[0047] The present invention also provides use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for the manufacture of a medicament for preventing or treating hair loss.

[0048] In one embodiment of the present invention, the pharmaceutical composition may be administered simultaneously or sequentially with the minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, but is not limited thereto.

[0049] In another embodiment of the present invention, the composition may be for promoting hair growth or hair regrowth, but is not limited thereto.

[0050] In yet another embodiment of the present invention, the type 2 aldehyde dehydrogenase activator can enhance the hair loss treatment effect of the minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, but is not limited thereto.

[0051] In yet another embodiment of the present invention, the type 2 aldehyde dehydrogenase activator may be, but is not limited to, Alda-1 or a pharma- ceutically acceptable salt thereof.

[0052] In yet another embodiment of the present invention, the Alda-1 or a pharma- ceutically acceptable salt thereof may be included in a concentration of 0.0001 to 50 mM based on the total composition, but is not limited thereto.

[0053] In yet another embodiment of the present invention, the composition may satisfy at least one characteristic selected from the group consisting of, but not limited to, (a) promoting proliferation of dermal papilla cells or outer root sheath cells, (b) promoting hair follicle growth, (c) inducing the anagen phase of hair, and (d) increasing mitochondrial activity.

[0054] In yet another embodiment of the present invention, the composition can increase the level or activity of at least one protein selected from the group consisting of, but not limited to, bFGF, FGF-7, IGF-1, and PDGF.

[0055] In yet another embodiment of the present invention, the composition may reduce oxidative stress in dermal papilla cells or outer root sheath cells, but is not limited thereto.

[0056] The present invention also provides a pharmaceutical composition for preventing or treating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof, as active ingredients.

[0057] In one embodiment of the present invention, the type 2 aldehyde dehydrogenase activator may be, but is not limited to, Alda-1 or a pharma- ceutically acceptable salt thereof.

[0058] In another embodiment of the present invention, the composition may be in the form of a mixture in which the (a) type 2 aldehyde dehydrogenase activator and the (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof are mixed, but is not limited thereto.

[0059] In yet another embodiment of the present invention, the composition may be in a form in which the (a) type 2 aldehyde dehydrogenase activator and the (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof are each formulated and administered simultaneously, separately, or sequentially, but is not limited thereto.

[0060] The present invention also provides a cosmetic composition for preventing or ameliorating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutical (or cosmetically) acceptable salt thereof, or an analog thereof, as active ingredients.

[0061] In one embodiment of the present invention, the composition may be in the form of an external skin preparation, such as, but not limited to, a scalp treatment agent, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid, solution, emulsion, dispersion, micelle, liposome, ointment, lotion, essence, patch, or spray.

[0062] The present invention also provides a quasi-drug composition for preventing or ameliorating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, as active ingredients.

[0063] The present invention also provides a food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically (or food-wise) acceptable salt thereof, or an analog thereof as active ingredients.

[0064] The present invention also provides a health functional food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically (or food-wise) acceptable salt thereof, or an analog thereof as active ingredients.

[0065] The present invention also provides a method for preventing or ameliorating hair loss, comprising administering to an individual in need thereof a composition comprising (a) an aldehyde dehydrogenase type 2 activator, and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof. The method may be a cosmetic method.

[0066] The present invention also provides use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for preventing or improving hair loss.

[0067] The present invention also provides use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for the manufacture of a medicament for preventing or improving hair loss.

[0068] The present invention further provides a pharmaceutical composition for use in combination with an agent for treating hair loss, which comprises a type 2 aldehyde dehydrogenase activator as an active ingredient.

[0069] The present invention also provides use of a type 2 aldehyde dehydrogenase activator for the manufacture of a preparation for use in combination with an agent for treating hair loss. Effect of the Invention

[0070] The present invention relates to a composition for preventing, improving, and / or treating hair loss or gray hair, and has been completed by confirming that an aldehyde dehydrogenase type 2 (ALDH2) activator promotes the formation and growth of hair follicles and has excellent effects in suppressing oxidative stress in hair follicles. Specifically, the present inventors confirmed that an ALDH2 activator promotes the proliferation of hair papilla cells and outer root sheath cells, which are core cells for the formation and growth of hair follicles, and promotes cell division in hair follicles, and confirmed that the anagen phase of hair growth is induced when a mouse model is treated with an ALDH2 activator. In addition, it was confirmed that treatment with an ALDH2 activator increases the level of hair growth promoting factors in hair papilla cells and the like, and suppresses oxidative stress, which is the cause of hair loss and gray hair. Thus, the ALDH2 activator according to the present invention can effectively promote the formation and growth of hair follicles, and can be used as a preparation for preventing, improving, and / or treating hair loss and gray hair. In particular, the ALDH2 activator according to the present invention exerts the same or better effect as minoxidil, a conventional hair loss treatment, even at a much smaller dose when administered to a mouse model, and is therefore expected to not only reduce costs in the development of treatments, but also be safer in clinical applications.

[0071] Furthermore, it was shown that the combined treatment of ALDH2 activator and minoxidil exhibits better hair loss prevention and treatment effects. Therefore, the ALDH2 according to the present invention not only effectively promotes hair growth by itself, but also achieves synergistic hair loss treatment effects when combined with minoxidil, so it is expected to be usefully utilized in the medical, cosmetic, and food fields for the prevention, improvement, and treatment of hair loss. [Brief description of the drawings]

[0072] [Figure 1a] FIG. 1a shows the results of treating human hair follicle-derived dermal papilla cells with an ALDH2 activator (Alda-1, hereinafter the same) according to one embodiment of the present invention and conducting a CCK8 analysis to confirm the effect of the ALDH2 activator on the proliferation of dermal papilla cells. [Figure 1b]FIG. 1b shows the results of treating outer root sheath cells derived from human hair follicles with an ALDH2 activator and performing CCK8 analysis to confirm the effect of ALDH2 activation on the proliferation of outer root sheath cells. [Diagram 2] 2a and 2b are diagrams showing the results of a human hair follicle organ culture test to confirm the hair growth effect of hair follicles due to ALDH2 activation. Fig. 2a shows the hair elongation effect in hair follicles treated with an ALDH2 activator, and Fig. 2b shows the results of immunofluorescence staining with Ki-67 antibody to confirm cell proliferation in hair follicles cultured after treatment with an ALDH2 activator. [Diagram 3] FIG. 3 shows the results of comparing the extent to which anagen hair growth was achieved by group after treating a mouse model with an ALDH2 activator to confirm the anagen-inducing effect of ALDH2 activity. [Figure 4] FIG. 4 shows the results of histological analysis of the extent of hair follicle formation during the anagen phase of a mouse model induced by ALDH2 activation through hematoxylin and eosin staining. [Figure 5a] FIG. 5a shows the results of confirming the growth phase induction score by an ALDH2 activator in a mouse model. [Figure 5b] FIG. 5b shows the results of confirming changes in skin thickness caused by an ALDH2 activator in a mouse model. [Figure 6] FIG. 6 shows the results of examining the protein levels of hair growth-promoting factors by ELISA analysis after treating dermal papilla cells and outer root sheath cells derived from human hair follicles with an ALDH2 activator in order to confirm the hair growth-promoting mechanism of the ALDH2 activator. [Figure 7] FIG. 7 shows the results of detecting fluorescently labeled DCFDA after treating hair papilla cells with an ALDH2 activator in order to confirm the oxidative stress suppressing effect of the ALDH2 activator. [Figure 8] Figures 8a and 8b show the results of measuring the DCFDA level (Figure 8a) and the ROS scavenging ratio (Figure 8b) after treating outer root sheath cells with an ALDH2 activator to confirm the oxidative stress suppression effect of the ALDH2 activator. [Figure 9a] FIG. 9a is an image taken after fluorescent staining of mitochondrial outer membrane protein (VDAC, green) and ALDH2 protein (red) in tissue from a patient with hair loss (blue: DPAI). [Figure 9b] FIG. 9b shows the results of comparing the expression levels of ALDH2 in telogen and anagen hair follicles. [Figure 10a] FIG. 10a shows the results of examining the oxygen consumption rate of outer root sheath cells derived from human hair follicles after treating them with an ALDH2 activator in order to confirm changes in mitochondrial activity due to ALDH2 activity in human hair follicles. [Fig. 10b-10d] Figures 10b to 10d show the results of measuring the basal respiration rate (Figure 10b), maximum respiration rate (Figure 10c), and mitochondrial ATP production (Figure 10d) of outer root sheath cells derived from human hair follicles after treating them with an ALDH2 activator. [Figure 11] FIG. 11 shows the results of observing the degree of hair growth after applying an ALDH2 activator and / or minoxidil to the backs of mice from which hair had been removed in order to confirm the effectiveness of the combined use of an ALDH2 activator and minoxidil in treating hair loss (upper row) and the results of detecting versican, a marker for hair papilla cells, by immunofluorescence staining (lower row). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0073] The present invention relates to a composition for preventing, improving, and / or treating hair loss or gray hair (or gray hair syndrome), and was completed based on the finding that an activator of aldehyde dehydrogenase 2 (ALDH2) promotes the formation of hair follicles and hair growth, and has excellent effects in suppressing oxidative stress in hair follicles.

[0074] The present invention also relates to a combination therapy for preventing, improving, and / or treating hair loss, and has been completed based on the finding that an aldehyde dehydrogenase 2 (ALDH2) activator promotes the formation and growth of hair follicles and suppresses oxidative stress in hair follicles, and not only exhibits excellent hair loss treatment effects by itself, but also exhibits even more remarkable hair loss treatment effects when used in combination with minoxidil.

[0075] Specifically, in one embodiment of the present invention, it was confirmed that the proliferation of dermal papilla cells and outer root sheath cells derived from human hair follicles was promoted when treated with Alda-1, an ALDH2 activator (Example 1).

[0076] In another embodiment of the present invention, a human hair follicle organ culture test was conducted in which hair follicles were treated with Alda-1 and cultured, and it was confirmed that hair elongation and cell proliferation were increased in the hair follicles (Example 2).

[0077] In yet another example of the present invention, Alda-1 was applied to a hair-removed mouse model, and then a histological analysis was performed to compare the degree of hair growth. As a result, it was confirmed that ALDH2 activation induces the hair growth phase, thereby increasing hair growth and skin thickness (Example 3).

[0078] In yet another example of the present invention, hair papilla cells were treated with Alda-1 to examine the expression levels of hair growth-promoting factors, and it was found that ALDH2 activation increased the protein levels of bFGF, FGF-7, IGF-1, and PDGF (Example 4).

[0079] In yet another example of the present invention, it was confirmed that oxidative stress in dermal papilla cells and outer root sheath cells was reduced when treated with Alda-1 (Example 5).

[0080] In yet another example of the present invention, it was confirmed that hair follicles in the anagen phase have higher levels of ALDH2 and mitochondria, and that ALDH2 and mitochondria are present in the same location, demonstrating that the interaction between ALDH2 and mitochondria is important for hair growth (Example 6).

[0081] In yet another example of the present invention, changes in mitochondrial activity in outer root sheath cells due to treatment with Alda-1 were examined, and it was found that activation of ALDH2 enhances mitochondrial function and contributes to the induction of the hair follicle anagen phase (Example 7).

[0082] In yet another example of the present invention, the combined effect of Alda-1 and minoxidil was examined, and it was found that combined administration of the two drugs can promote hair growth and hair follicle formation more effectively than treatment with either drug alone (Example 8).

[0083] Therefore, the activation of ALDH2 not only contributes to hair growth by increasing the level of hair growth promoting factors, reducing oxidative stress, and inducing the proliferation of hair follicle cells, but also achieves an excellent anti-gray hair effect, and can therefore be a therapy for preventing, improving, and / or treating hair loss and gray hair. Furthermore, the activation of ALDH2 can exert a more synergistic hair loss treatment effect when used in combination with minoxidil, and therefore can be usefully used as a combination therapy for preventing, improving, and / or treating hair loss together with minoxidil.

[0084] The present invention will be specifically described below.

[0085] The present invention provides a pharmaceutical composition for preventing or treating hair loss or gray hair, comprising an aldehyde dehydrogenase type 2 activator as an active ingredient. In one embodiment of the present invention, the pharmaceutical composition (i.e., the aldehyde dehydrogenase type 2 activator) may be administered in combination with a hair loss treatment agent, but is not limited thereto.

[0086] In the present invention, "alopecia" refers to a state in which hair is not present in a region where hair should normally be present, and generally refers to the loss of adult hair (thick, black hair) on the scalp. Adult hair is different from colorless, thin, vellus hair, and when it falls out, it may cause cosmetic problems. Alopecia is clinically divided into two types: one that forms a scar and one that does not. In the case of alopecia that forms a scar, the hair follicle is destroyed and hair does not regenerate, while in the case of alopecia that does not form a scar, the hair follicle is maintained and hair regenerates after the symptom site disappears. Examples of non-scarring alopecia that does not form a scar include hereditary androgenetic alopecia (baldness), alopecia areata, tinea capitis due to fungal infection, telogen effluvium, trichotillomania, and hair production disorder diseases, and examples of scarring alopecia that forms a scar include hair loss due to lupus, alopecia barbae folliculitis, lichen planus pilaris, and hair loss due to burns and trauma. The most common types of hair loss are hereditary androgenetic alopecia and alopecia areata, neither of which produces scars.The most common types of hair loss include baldness (androgenetic alopecia), female pattern alopecia, alopecia areata, and telogen effluvium.The hair loss according to the present invention includes both male pattern alopecia and female pattern alopecia.

[0087] Preferably, the alopecia according to the present invention may be selected from the group consisting of alopecia areata, hereditary androgenetic alopecia, telogen effluvium, traumatic alopecia, trichotillomania, compression alopecia, anagen alopecia, pityriasis nivea, syphilitic alopecia, seborrheic alopecia, symptomatic alopecia, cicatricial alopecia and congenital alopecia. In addition to the above diseases, the alopecia according to the present invention may include all problems caused by the phenomenon of a large amount of hair falling out, such as cosmetic problems. Preferably, in the present invention, the alopecia is hair loss from the scalp.

[0088] The present invention may further be used for the prevention and treatment of white hair.

[0089] In the present invention, "gray hair" (or "white hair") refers to hair (particularly scalp hair) that has lost its original color and turned gray or white due to aging or stress. The concept of "gray hair" includes not only naturally occurring gray hair during the aging process, but also premature gray hair that occurs on the heads of young people who have not yet aged. The concept of "gray hair" includes not only the state in which the entire scalp hair turns white, but also the state in which a part of the scalp hair turns white, and includes not only the state in which the entire hair turns white, but also the state in which a part of a hair turns white (i.e., a white stripe appears on the hair). The molecular mechanism that causes gray hair is not clearly known, but it is known that the function and numerical reduction of melanocytes contribute to gray hair. In particular, since oxidative stress generated during the melanin production process in melanocytes damages melanocytes, reducing oxidative stress in hair follicles is particularly important for preventing gray hair.

[0090] The white hair includes poliosis. In the present invention, poliosis means a disease in which melanin in hair is reduced or lost, resulting in bleaching of hair color. Poliosis can occur in both adults and children, and can occur due to genetic diseases, autoimmune diseases, or damage to hair follicles. Poliosis can occur not only in scalp hair, but also in other body hairs such as eyelashes and eyebrows. Preferably, in the present invention, poliosis is poliosis occurring in scalp hair.

[0091] In the present invention, "aldehyde dehydrogenase (ALDH)" refers to a group of enzymes that catalyze the oxidation of aldehydes. ALDHs are involved in various biological processes including the detoxification of exogenous and endogenous aldehydes, and 19 types of aldehyde dehydrogenase genes have been identified in the human genome to date.

[0092] In the present invention, "aldehyde dehydrogenase 2 (ALDH2)" is an enzyme of the second subtype of aldehyde dehydrogenase, and is encoded by the ALDH2 gene present on chromosome 12. ALDH2 exists in mitochondria and functions to convert acetaldehyde to acetic acid, contributing to the decomposition of alcohol absorbed into the body. However, the effect of activation of ALDH2 on hair loss and hair growth has not yet been reported. ALDH2 protein and the gene encoding it are well known in the art, and can be typically identified from the protein database Uniprot (accession number: P05091).

[0093] The composition according to the present invention may be for promoting hair growth and / or hair regrowth. In the present invention, the term "hair growth" means new hair growth, and "hair regrowth" means an increase in the length of existing hair (i.e., hair growth), and hair regrowth is used synonymously with "hair care."

[0094] Throughout this specification, "hair" includes both scalp hair (hair strands) and body hair. Scalp hair means hair that grows from the human scalp, and body hair includes hair that grows from body parts other than the scalp. Scalp hair and body hair show differences in thickness and pore size, and as a representative example, in the case of scalp hair, usually 1 to 5 hair strands grow from one pore, whereas in the case of body hair, one hair strand grows from one pore in most cases. In addition, although the number of scalp hairs varies depending on race, there are about 80,000 to 120,000 hair strands per person. The thickness of scalp hair is also various, about 17 μm to 180 μm, and generally thicker than body hair, but the average thickness of scalp hair is known to be 80 μm to 150 μm, 90 μm to 150 μm, 100 μm to 150 μm, 110 μm to 150 μm, 120 μm to 150 μm, 130 μm to 150 μm, 80 μm to 140 μm, or 90 μm to 130 μm. The growth rate of hair varies depending on the growing area, for example, eyebrows and pubic hair grow about 0.05 to 0.2 mm per day, whereas scalp hair grows about 0.3 to 0.5 mm per day, and grows about 1 cm or more per month. That is, scalp hair is characterized by a faster growth rate than other body hairs. Preferably, the composition according to the present invention is for promoting hair growth and / or hair regrowth of scalp hair.

[0095] In the present invention, the term "ALDH2 activator" refers to a substance that can promote hair follicle growth, hair growth, and / or hair regrowth by enhancing the expression or activity of ALDH2 protein. The ALDH2 activator also includes a substance that can prevent or improve gray hair by enhancing the expression or activity of ALDH2 protein. Although not limited to a specific type, examples of the ALDH2 activator include an expression vector containing an ALDH2 coding gene, an ALDH2 agonist, an ALDH2 function activator, etc.

[0096] In the present invention, "expression of ALDH2 protein" means the final production of ALDH2 protein, and "enhancement of ALDH2 protein expression" means both increasing the expression of mRNA at the transcription stage of ALDH2 coding gene or increasing the translation of the mRNA. In the present invention, the increase in mRNA expression may be activation of a mechanism of action that can increase the transcription of ALDH2 gene in a higher action mechanism of ALDH2 coding gene, or conversely, inhibition of a higher action mechanism that can suppress the transcription of ALDH2 gene, and all concepts that can directly or indirectly promote ALDH2 expression, such as demethylation of the ALDH2 gene promoter site or histone modification related to ALDH2 gene expression, are included in the present invention. In the present invention, the increase in translation of ALDH2 mRNA may include all mechanisms that can enhance the translation of the produced ALDH2 mRNA, for example, suppression of the expression or activity of miRNA that prevents the translation of ALDH2 mRNA, or enhancement of the activity of an enzyme related to the translation of ALDH2 mRNA, but is not limited thereto.

[0097] In addition, in the present invention, "ALDH2 protein activity" refers to the activity of ALDH2 protein produced through the translation process or the activity of ALDH2 protein already produced and present in cells, and "enhancement of ALDH2 protein activity" includes any increase in ALDH2 protein activity through processes such as post-translational modification or due to the activity / inactivity of proteins that interact with it.

[0098] In the present invention, the type 2 aldehyde dehydrogenase activator may include, without limitation, a substance capable of enhancing the expression or activity of type 2 aldehyde dehydrogenase protein, and may preferably be selected from the group consisting of Alda-1, AD-9308, compound I-6, and pharma- ceutical acceptable salts thereof.

[0099] In the present invention, the aldehyde dehydrogenase type 2 activator may preferably be Alda-1. Alda-1 is a compound that is an agonist of ALDH2 and can activate ALDH2 protein by penetrating the cell membrane. It is known that Alda-1 can reduce oxidative stress in liver cells, but the effect of Alda-1 on hair follicles or hair growth has not been reported. The present inventors have newly discovered through specific experiments using Alda-1 that Alda-1 can promote hair growth through ALDH2 activation and can be used for hair loss treatment. Minoxidil, a potassium channel activator, promotes hair growth by hyperpolarizing the cell membrane and expanding the blood vessels of the hair follicle to increase blood flow, but due to the strong vasodilatory effect of minoxidil, overuse of minoxidil may rather cause fluid retention and edema formation. Meanwhile, it has been confirmed that Alda-1 according to the present invention can improve cell stress by removing cytotoxic aldehydes through activation of ALDH2, and in particular, can suppress oxidative stress in hair follicle cells, which is one of the main causes of hair loss. In particular, the present inventors confirmed in an experiment using a hair loss mouse model that Alda-1 can be treated at a lower dose than minoxidil to achieve equal or better hair loss treatment effects, and that the combination of the two drugs can induce hair growth more effectively than the use of the two drugs alone. That is, since Alda-1 can achieve excellent hair growth promotion effects even at a low dose, it can not only significantly reduce the risk of side effects caused by excessive use of minoxidil, but also can exert a synergistic hair loss treatment effect through combination with minoxidil. Furthermore, it has been confirmed that Alda-1 promotes mitochondrial function in hair follicles and significantly reduces oxidative stress in hair follicles, and can be used for the purpose of preventing, improving, and treating gray hair or gray hair syndrome caused by oxidative stress.

[0100] Alda-1 according to the present invention is also called N-(1,3-Benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide. Preferably, Alda-1 according to the present invention may have the following structure:

[0101] [ka]

[0102] In the present invention, AD-9308 is a water-soluble ALDH2 activator that is more potent than the prototype Alda-1. Recently, it has been reported that AD-9308 is effective in improving myocardial fibrosis and inflammation and treating cardiac dysfunction, but the effect of AD-9308 in treating hair loss is unknown. Specific information such as the chemical structure and properties of AD-9308 can be found in the references [Antioxidants (Basel). 2021 Mar 13; 10 (3): 450.] and U.S. Patent No. 9,879,036 B2.

[0103] In the present invention, compound I-6 refers to compound I-6 disclosed in the reference [Journal of Saudi Chemical Society Volume 23, Issue 3, March 2019, Pages 255-262]. Compound I-6 is a compound prepared by modifying Alda-1, and is an ALDH2 activator with higher water-solubility and ALDH2 activation effect. Specific information such as the chemical formula structure and properties of compound I-6 can be found in the reference.

[0104] In the present invention, the term "hair loss treating agent" refers to a substance that can directly or indirectly exert a preventive or therapeutic effect against hair loss through promoting the formation and growth of hair follicles, inducing the hair growth phase, relieving stress on hair follicles, etc. The hair loss treating agent is not limited to a specific type as long as it exerts a preventive or therapeutic effect against hair loss by promoting hair growth or hair development, and may be preferably selected from minoxidil, finasteride, dutasteride, and pharma- ceutical acceptable salts thereof, or analogs thereof. In a preferred embodiment, the hair loss treating agent is minoxidil or a pharma-ceutical acceptable salt thereof.

[0105] Minoxidil is a vasodilator used to treat hair loss, also known as "Rogaine" and its IUPAC ID is 6-piperidin-1-ylpyrimidine-2,4-diamine 3-oxide. Topical application of minoxidil increases the supply of blood and nutrients to hair follicles, strengthening existing hair and promoting its growth. Although the molecular mechanism by which minoxidil promotes hair growth has not been specifically elucidated, it is known that minoxidil induces hair growth by reversing hair follicle miniaturization, increasing blood flow around hair follicles, stimulating hair follicles to enter the anagen phase, and extending the anagen phase of hair follicles. However, it is known that high doses of minoxidil can cause side effects such as rash, inflammation, itching, weight gain, edema, and angina. Therefore, the present invention aims to provide a better hair loss treatment effect by using ALDH2 activator in combination with minoxidil to reduce the risk of side effects of minoxidil.Specifically, the present invention uses a relatively low concentration of minoxidil in combination with minoxidil, but can generally show the same or higher level of hair loss prevention, hair growth, and hair growth promotion effect compared to the case of using a fixed amount of minoxidil to show hair loss prevention or treatment effect.In the entire specification, "minoxidil" is a concept that includes not only minoxidil itself, but also its salts and its analogs.

[0106] In the present invention, minoxidil may be 0.1-10(w / v)%, 0.1-8(w / v)%, 0.1-6(w / v)%, 0.1-5(w / v)%, 0.1-3(w / v)%, 1-10(w / v)%, 1-8(w / v)%, 1-6(w / v)%, 1-5(w / v)%, 1-3(w / v)%, or 2-5(w / v)% minoxidil. Also, the minoxidil of the present invention may be 2(w / v)%, 3(w / v)%, or 5(w / v)% minoxidil. In general, it is known that minoxidil of 5% or more is particularly suitable for use by men, and it is known that low-concentration minoxidil of 1-3% can be used by both women and men. The minoxidil may be dissolved in water, distilled water, deionized water, ultrapure water, or DMSO.

[0107] In the present invention, the ALDH2 activator includes not only the ALDH2 activator itself, but also all of its pharma- ceutically acceptable salts, analogs, and derivatives. For example, "Alda-1" includes not only Alda-1 itself, but also its pharma- ceutically acceptable salts, analogs, and derivatives. The "hair loss treatment agent" of the present invention also includes not only the hair loss treatment agent itself, but also its pharma- ceutically acceptable salts, analogs, and derivatives. For example, "minoxidil" is a concept that includes not only minoxidil itself, but also its pharma- ceutically acceptable salts, analogs, and derivatives.

[0108] In the present invention, the term "pharmaceutical acceptable salts" includes salts derived from pharmaceutical acceptable inorganic acids, organic acids, or bases. In addition, the derivatives include pharmaceutical acceptable salts, pharmaceutical acceptable solvates, pharmaceutical acceptable hydrates, pharmaceutical acceptable anhydrides, pharmaceutical acceptable enantiomers, pharmaceutical acceptable esters, pharmaceutical acceptable polymorphs, pharmaceutical acceptable prodrugs, pharmaceutical acceptable complexes, etc.

[0109] Additionally, as used herein, the term "pharmacologically acceptable" means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., a human) without undue toxicity, irritation, allergic response or other problem or complication, at a reasonable benefit / risk ratio, and within the bounds of sound medical judgment.

[0110] Examples of suitable acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, gluconic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, etc. The acid addition salts may be prepared by conventional methods, for example by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. They may also be prepared by heating equal molar amounts of the compound and the acid or alcohol in water, and then evaporating the mixture to dryness or filtering the precipitated salt with suction.

[0111] Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. For example, alkali metal or alkaline earth metal salts can be obtained by dissolving the compound in an excess of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is particularly suitable for pharmaceutical purposes to prepare sodium, potassium, or calcium salts as metal salts, and the corresponding silver salts can be obtained by reacting the alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

[0112] The scope of the compounds of the present invention includes not only pharma- ceutically acceptable salts, but also all isomers, hydrates and solvates that can be prepared by conventional methods.

[0113] The ALDH2 activator according to the present invention may be administered in combination with a hair loss treatment agent. The term "co-administration" as used herein means that each component of the treatment can be administered simultaneously, sequentially, or separately. The combined treatment effect can be obtained by administering two or more drugs simultaneously, sequentially, or alternately at regular or irregular intervals, and the combined treatment is defined as providing a synergistic effect while providing therapeutically superior efficacy measured, for example, through the degree of response, the rate of response, the time to disease progression, or the survival time, compared to the efficacy obtained by administering one or the rest of the components of the combined treatment at a normal dose. For example, the ALDH2 activator of the present invention can be administered in combination with minoxidil to enhance the hair loss treatment effect of minoxidil or reduce the side effects caused by minoxidil. The administration (treatment) is a concept that includes all of injection, oral intake, inhalation, spraying, and application.

[0114] In the present invention, the ALDH2 activator may be administered simultaneously, separately, or sequentially with a hair loss treatment agent (e.g., minoxidil). When the ALDH2 activator is administered sequentially with the hair loss treatment agent, the order of administration is not limited, and the administration regimen may be appropriately adjusted depending on the type of hair loss treatment agent, the condition of the patient, the sex, age, etc. of the patient.

[0115] The present invention further provides a pharmaceutical composition for preventing or treating hair loss, which comprises a type 2 aldehyde dehydrogenase activator and minoxidil as active ingredients.

[0116] The composition may be in the form of a mixture of the ALDH2 activator and minoxidil, and may be in the form for simultaneous administration of the ALDH2 activator and minoxidil. For example, the ALDH2 activator and minoxidil may be in a single dosage form prepared by mixing with a pharma- ceutically acceptable adjuvant, diluent, or carrier. In this case, the ALDH2 activator and minoxidil may each contain various ingredients within the category of the drug. The single dosage form may also be administered together with a separate formulation containing another therapeutic agent as a dosage form separate from the above dosage form.

[0117] Alternatively, the composition may be in a form in which the ALDH2 activator and minoxidil are each formulated and administered simultaneously, separately, or sequentially. In this case, the composition may be a pharmaceutical composition for combined administration for simultaneous or sequential administration, comprising a first pharmaceutical composition containing a pharmacologic effective amount of the ALDH2 activator as an active ingredient, and a second pharmaceutical composition containing a pharmacologic effective amount of the minoxidil as an active ingredient. In other words, the ALDH2 activator and minoxidil may be provided as pharmaceutical dosage forms separated from each other, and each formulation may be administered simultaneously or at different times. The ALDH2 activator and minoxidil may be in the same dosage form or different dosage forms, and may be administered independently according to the dosage form. In this case, in the case of sequential administration, the administration order is not limited, and the administration therapy may be appropriately adjusted according to the patient's condition, etc.

[0118] For example, when the pharmaceutical composition is a combination pharmaceutical composition for sequential administration, the composition may be one in which the ALDH2 activator ("first component") is administered first, followed by the minoxidil ("second component"), or the reverse order is also possible.

[0119] The content of the ALDH2 activator (e.g., Alda-1), hair loss treatment agent (e.g., minoxidil), and / or pharma- ceutically acceptable salts thereof in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the degree of progression of the symptoms, the condition of the patient, etc., and may be, for example, 0.0001 to 99.9 wt. % or 0.001 to 50 wt. % based on the total composition weight, but is not limited thereto. The content ratio is a value based on the dry weight after removing the solvent.

[0120] In one embodiment of the present invention, the ALDH2 activator (e.g., Alda-1) or a pharma- ceutically acceptable salt thereof may be contained at a concentration of 0.0001 to 50 mM relative to the total composition, but is not limited thereto. More specifically, the Alda-1 or a pharma- ceutically acceptable salt thereof according to the present invention may be contained at a concentration of 0.0001 to 50 mM, 0.0001 to 40 mM, 0.0001 to 30 mM, 0.0001 to 20 mM, 0.0001 to 10 mM, 0.0001 to 9 mM, 0.0001 to 8 mM, 0.0001 to 7 mM, 0.0001 to 6 mM, 0.0001 to 5 mM, 0.0001 to 4 mM, 0.0001 to 3 mM, 0.001 to The concentration of the compound contained in the composition may be, but is not limited to, 2 mM, 0.0001 to 1 mM, 0.0005 to 10 mM, 0.001 to 10 mM, 0.005 to 10 mM, 0.01 to 10 mM, 0.05 to 10 mM, 0.1 to 10 mM, 0.5 to 10 mM, 1 to 30 mM, 1 to 20 mM, 1 to 15 mM, 1 to 10 mM, 1 to 9 mM, 1 to 8 mM, 1 to 7 mM, 1 to 6 mM, or 1 to 5 mM.

[0121] In other words, the composition of the present invention may contain the ALDH2 activator or a pharma- ceutically acceptable salt thereof in an amount such that the ALDH2 activator or a pharma- ceutically acceptable salt thereof is administered (applied) at a concentration of 0.0001 to 50 mM relative to the total composition (or solvent) when administered or applied once to an individual in need thereof. That is, in the present invention, the ALDH2 activator or a pharma- ceutically acceptable salt thereof may be administered (to an individual in need thereof) at a concentration of 0.0001 to 50 mM relative to the total composition (or solvent).

[0122] The composition according to the present invention may be in the form of a liquid preparation. When the composition according to the present invention is a liquid preparation, the ALDH2 activator or a pharma- ceutically acceptable salt thereof may be contained in a concentration of 0.0001 to 50 mM relative to the total liquid preparation. In addition, the liquid preparation may be administered in a volume of 10 μL to 20 mL, 10 μL to 10 mL, 10 μL to 5 mL, 10 μL to 1 mL, 10 μL to 900 μL, 10 μL to 800 μL, 10 μL to 700 μL, 10 μL to 500 μL, 10 μL to 400 μL, 10 μL to 300 μL, 10 μL to 200 μL, or 10 μL to 100 μL at one administration (application), but is not limited thereto.

[0123] In one embodiment of the present invention, the hair loss treating agent (e.g., minoxidil) or a pharma- ceutically acceptable salt thereof may be contained at a concentration of 0.0001-10 (w / v)% based on the total composition, but is not limited thereto. More specifically, the hair loss treating agent or a pharma- ceutically acceptable salt thereof according to the present invention may be contained at a concentration of 0.0001-10 (w / v), 0.0001-5 (w / v), 0.0001-3 (w / v), 0.0001-2 (w / v), 0.0001-1 (w / v), 0.0005-5 (w / v), 0.0005-3 (w / v), 0.0005-2 (w / v), 0.0005-1 (w / v), 0.001-5 (w / v), 0.00 The composition may be contained at a concentration of, but is not limited to, 1 to 3 (w / v)%, 0.001 to 2 (w / v)%, 0.001 to 1 (w / v)%, 0.005 to 5 (w / v)%, 0.005 to 3 (w / v)%, 0.005 to 2 (w / v)%, 0.01 to 5 (w / v)%, 0.01 to 3 (w / v)%, 0.01 to 2 (w / v)%, 0.05 to 2 (w / v)%, 0.1 to 2 (w / v)%, or 0.1 to 1 (w / v)%.

[0124] Furthermore, the composition of the present invention may contain the hair loss treating agent or a pharma- ceutically acceptable salt thereof in an amount such that the hair loss treating agent or a pharma- ceutically acceptable salt thereof is administered (applied) at a concentration of 0.0001 to 10 (w / v)% relative to the total composition (or solvent) when administered or applied once to an individual in need thereof. That is, in the present invention, the hair loss treating agent or a pharma- ceutically acceptable salt thereof may be administered (to an individual in need thereof) at a concentration of 0.0001 to 10 (w / v)% relative to the total composition (or solvent).

[0125] As described above, the composition according to the present invention may be in the form of a liquid formulation, and when the composition according to the present invention is a liquid formulation, the hair loss treatment agent (e.g., minoxidil) or a pharma- ceutically acceptable salt thereof may be contained in a concentration of 0.0001-10 (w / v)% relative to the total liquid formulation, but is not limited thereto. In addition, the liquid formulation may be administered in a volume of 10 μL-20 mL, 10 μL-10 mL, 10 μL-5 mL, 10 μL-1 mL, 10 μL-900 μL, 10 μL-800 μL, 10 μL-700 μL, 10 μL-500 μL, 10 μL-400 μL, 10 μL-300 μL, 10 μL-200 μL, or 10 μL-100 μL at one administration (application), but is not limited thereto.

[0126] The ALDH2 activator of the present invention and the hair loss treatment agent (e.g., minoxidil, its analogs, or pharma- ceutically acceptable salts thereof) may be used in combination at a weight ratio of 1:0.01 to 100, but is not limited thereto. Specifically, the ALDH2 activator and minoxidil may be used in a ratio of 1:0.01 to 100, 1:0.01 to 80, 1:0.01 to 60, 1:0.01 to 50, 1:0.01 to 40, 1:0.01 to 30, 1:0.01 to 20, 1:0.01 to 10, 1:1 to 100, 1:1 to 80, 1:1 to 50, 1:1 to 20, 1:1 to 10, They may be used in combination at a weight ratio of, but is not limited to, 1:10-100, 1:10-50, 1:10-40, 1:10-30, 1:20-100, 1:20-80, 1:20-50, 1:20-40, 1:30-100, 1:30-80, 1:30-50, 1:30-40, 1:35-40, or 1:37.

[0127] In addition, when the ALDH2 activator and the hair loss treatment agent of the present invention are used together in the form of a liquid preparation, the liquid preparations may be mixed together to be used together in the form of a mixed preparation. The mixed preparation may be produced, for example, by mixing a liquid preparation containing an ALDH2 activator at a concentration of 0.0001-50 mM with a liquid preparation containing a hair loss treatment agent at a concentration of 0.0001-10 (w / v)%. Here, the liquid preparation containing the ALDH2 activator: the liquid preparation containing the hair loss treatment agent may be mixed in a volume ratio of 1:0.1-10, 1:0.1-5, 1:0.1-2, 1:0.1-1.5, 1:0.1-1, 1:0.5-5, 1:0.5-2, 1:0.5-1.5, or 1:1, but is not limited thereto. Furthermore, the mixed preparation may be administered in a volume of 10 μL to 20 mL, 10 μL to 10 mL, 10 μL to 5 mL, 10 μL to 1 mL, 10 μL to 900 μL, 10 μL to 800 μL, 10 μL to 700 μL, 10 μL to 500 μL, 10 μL to 400 μL, 10 μL to 300 μL, 10 μL to 200 μL, or 10 μL to 100 μL at one time (application or treatment), but is not limited thereto.

[0128] The treatment concentration, treatment volume, etc. of the ALDH2 activator and hair loss treatment agent described above are particularly suitable when the pharmaceutical composition according to the present invention is applied to the skin of an individual. However, the administration form of the pharmaceutical composition according to the present invention is not limited to a specific type, and a person skilled in the art may select an appropriate dose, concentration, mixing ratio, etc. based on the technical common knowledge in the art, taking into consideration the drug administration route, administration method, type of drug used in combination, and condition of the subject.

[0129] Preferably, the composition according to the present invention can satisfy at least one characteristic selected from the group consisting of, but not limited to, (a) promoting proliferation (or cell division) of dermal papilla cells and / or outer root sheath, (b) promoting hair follicle growth (i.e., promoting cell growth or cell division within the hair follicle), (c) inducing hair anagen, and (d) increasing mitochondrial activity.

[0130] Preferably, the composition according to the present invention is capable of increasing the level or activity of at least one protein selected from the group consisting of bFGF (basic fibroblast growth factor), FGF-7 (keratinocyte growth factor), IGF-1 (insulin-like growth factor 1), and PDGF (platelet-derived growth factor), but is not limited thereto.

[0131] Preferably, the composition according to the present invention can reduce oxidative stress in hair papilla cells or outer root sheath cells, but is not limited thereto.

[0132] The pharmaceutical composition according to the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions, such as at least one selected from the group consisting of diluents, binders, disintegrants, lubricants, adsorbents, moisturizers, film-coating materials and controlled release additives.

[0133] The pharmaceutical composition according to the present invention may be formulated by a conventional method into the form of a powder, granule, sustained-release granule, enteric-coated granule, liquid, eye drop, elucic, emulsion, suspension, spirit, troche, aromatic perfume, lemonade, tablet, sustained-release tablet, enteric-coated tablet, sublingual tablet, hard capsule, soft capsule, sustained-release capsule, enteric-coated capsule, pill, tincture, soft extract, dry extract, fluid extract, injection, capsule, perfusion solution, plaster, lotion, paste, spray, inhalant, patch, sterile injection, or external preparation such as aerosol, and the external preparation may have the form of a cream, gel, patch, spray, ointment, plaster, lotion, liniment, paste, or cataplasm.

[0134] Carriers, excipients and diluents that may be included in pharmaceutical compositions according to the invention include lactose, dextrose, sucrose, oligosaccharides, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

[0135] When the formulation is made, it is usually prepared by using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc.

[0136] Additives for the tablets, powders, granules, capsules, pills and lozenges according to the present invention include excipients such as corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, calcium hydrogen phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropylmethylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate and Primozel, gelatin, gum arabic, ethanol, agar powder, cellulose acetate phthalate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, casein sodium, Binders such as cellulose, glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, purified shellac, starch paste, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, etc. may be used, and binders such as hydroxypropyl methylcellulose, corn starch, agar powder, methylcellulose, bentonite, hydroxypropyl starch, sodium carboxymethylcellulose, sodium alginate, calcium carboxymethylcellulose, calcium citrate, sodium lauryl sulfate, anhydrous silicic acid, 1-hydroxypropyl cellulose, dextran, ion exchange resins, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, guar gum (Guargum), baking soda, polyvinylpyrrolidone, calcium phosphate, gelling starch, gum arabic, amylopectin, pectin, sodium polyphosphate, ethylcellulose, white sugar, magnesium aluminum silicate, D-sorbitol liquid, disintegrants such as hard anhydrous silicic acid, calcium stearate, magnesium stearate, stearic acid, hydrogenated vegetable oil, talc, lycopodium, kaolin, petrolatum, sodium stearate, cocoa butter, sodium salicylate, magnesium salicylate, polyethylene glycol (PEG) 4000, PEG 6000, liquid paraffin, hydrogenated soybean oil (Lubri Lubricants such as wax, aluminum stearate, zinc stearate, sodium lauryl sulfate, magnesium oxide, Macrogol, synthetic aluminum silicate, anhydrous silicic acid, higher fatty acids, higher alcohols, silicone oil, paraffin oil, polyethylene glycol fatty acid ether, starch, sodium chloride, sodium acetate, sodium oleate, dl-leucine, and hard anhydrous silicic acid may be used.

[0137] Examples of additives that may be used in the liquid preparation according to the present invention include water, dilute hydrochloric acid, dilute sulfuric acid, sodium citrate, sucrose monostearate, polyoxyethylene sorbitol fatty acid esters (twin esters), polyoxyethylene monoalkyl ethers, lanolin ethers, lanolin esters, acetic acid, hydrochloric acid, aqueous ammonia, ammonium carbonate, potassium hydroxide, sodium hydroxide, prolamine, polyvinylpyrrolidone, ethyl cellulose, and sodium carboxymethylcellulose.

[0138] The syrup according to the present invention may contain a solution of white sugar, other sugars or sweeteners, and may contain flavorings, coloring agents, preservatives, stabilizers, suspending agents, emulsifiers, thickening agents, etc., as necessary.

[0139] The emulsion of the present invention may contain purified water, and may contain emulsifiers, preservatives, stabilizers, fragrances, etc., as required.

[0140] The suspension according to the present invention may contain a suspending agent such as acacia, tragacanth, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropylmethylcellulose (HPMC), HPMC1828, HPMC2906, or HPMC2910, and may also contain a surfactant, a preservative, a stabilizer, a coloring agent, or a fragrance, as necessary.

[0141] The injections according to the present invention may contain distilled water for injection, 0.9% sodium chloride injection, Ringer's injection, dextrose injection, dextrose + sodium chloride injection, PEG, lactated Ringer's injection, ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, solvents such as ethyl oleate, isopropyl myristate, and benzene benzoate, solubilizers such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidine, propylene glycol, twines, nidiotinamide, hexamine, and dimethylacetamide, weak acids and their salts (acetic acid and sodium acetate), and weak bases and their salts (ammonia and ammonium acetate). It may also contain buffers such as organic compounds, proteins, albumin, peptones, and gums, isotonicity agents such as sodium chloride, stabilizers such as sodium hydrogen sulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid, sulfating agents such as sodium bisulfide 0.1%, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and acetone sodium bisulfite, soothing agents such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate, and suspending agents such as sodium CMC, sodium alginate, Tween 80, and aluminum monostearate.

[0142] The solid preparation for oral administration includes tablets, pills, powders, granules, capsules, etc., and such solid preparations are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium styrenate talc are also used.

[0143] Liquid preparations for oral administration include suspensions, liquid preparations, emulsions, syrups, etc., and may contain various excipients such as wetting agents, sweeteners, flavorings, preservatives, etc. in addition to water and liquid paraffin, which are commonly used simple diluents. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc.

[0144] The pharmaceutical composition according to the present invention is administered in a pharma- ceutical effective amount. In the present invention, the term "pharma-ceutical effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level may be determined by factors including the type and severity of the patient's disease, the activity of the drug, sensitivity to the drug, administration time, administration route and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, the composition according to the present invention may be administered (applied) to an individual in need thereof 1-5 times, 1-3 times, 1-2 times, or once a day. In this case, the dose per dose may be adjusted according to the degree of the hair loss-related lesion.

[0145] The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. Taking into consideration all of the above factors, it is important to administer an amount that provides maximum effect at a minimum amount without side effects, which may be easily determined by a person skilled in the art to which the present invention pertains.

[0146] Furthermore, the pharmaceutical composition according to the present invention may be administered to an individual in need thereof 1 to 10 times, 1 to 5 times, 1 to 3 times, or 1 to 2 times per day, and may be administered every 1 to 10 days, 1 to 5 days, 1 to 3 days, or every day, but is not limited thereto.

[0147] The pharmaceutical compositions of the present invention may be administered to an individual by a variety of routes, including, for example, oral ingestion, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, paraspinal space (intradural) injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ocular administration, aural administration, nasal administration, inhalation, spraying through the mouth or nose, dermal administration, transdermal administration, and the like, although all modes of administration are contemplated.

[0148] The pharmaceutical composition of the present invention will be determined by the type of drug as the active ingredient, as well as various related factors such as the disease to be treated, the administration route, the patient's age, sex, weight, and the severity of the disease.

[0149] In the present invention, the term "individual" refers to a subject in need of treatment for a disease, and more specifically, refers to mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cows.

[0150] In the present invention, "administration" means providing a given composition of the present invention to an individual by any suitable method.

[0151] In the present invention, "prevention" means any action that suppresses or delays the onset of the desired disease, "treatment" means any action that ameliorates or beneficially alters the symptoms of the desired disease and associated metabolic disorders by administration of the pharmaceutical composition according to the present invention, and "amelioration" means any action that reduces parameters related to the desired disease, such as the severity of symptoms, by administration of the composition according to the present invention.

[0152] The present invention also provides a cosmetic composition for preventing or improving hair loss or gray hair, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient. The cosmetic composition may be administered in combination with a hair loss treatment agent. The present invention also provides a cosmetic composition for preventing or improving hair loss, comprising a type 2 aldehyde dehydrogenase activator and a hair loss treatment agent as active ingredients.

[0153] Preferably, the ALDH2 activator is Alda-1, an analog thereof, or a cosmetically acceptable salt thereof, and the hair loss treatment agent may be minoxidil, an analog thereof, or a cosmetically acceptable salt thereof.

[0154] Here, prevention or improvement of gray hair means suppressing bleaching of hair and maintaining its original color, and such an effect can be achieved particularly through maintaining the function and number of melanocytes.

[0155] The cosmetic composition according to the present invention may be in the form of a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisture lotion, nourishing lotion, massage cream, nourishing cream, mist, moisture cream, hand cream, hand lotion, foundation, essence, nourishing essence, pack, soap, cleansing foam, cleansing lotion, cleansing cream, cleansing oil, cleansing balm, body lotion or body cleanser.

[0156] Preferably, the composition may be in the form of an external skin preparation, such as a scalp treatment agent, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid, solution, emulsion, dispersion, micelle, liposome, ointment, lotion, essence, patch, or spray.

[0157] The cosmetic composition of the present invention may further comprise a composition selected from the group consisting of water-soluble vitamins, oil-soluble vitamins, polymeric peptides, polymeric polysaccharides, and sphingolipids.

[0158] In addition to the above-mentioned essential components, the cosmetic composition of the present invention may contain other components that are usually blended in cosmetics, if necessary.

[0159] Other ingredients that may be added include oils and fats, moisturizers, emollients, surfactants, organic and inorganic pigments, organic powders, UV absorbers, preservatives, bactericides, antioxidants, plant extracts, pH adjusters, alcohol, colorants, fragrances, blood circulation promoters, cooling agents, antiperspirants, purified water, etc.

[0160] Furthermore, other ingredients that may be added are not limited to those mentioned above, and any of the above ingredients may be added within a range that does not impair the objects and effects of the present invention, and may be added at a weight percentage of 0.01-5% or 0.01-3% based on the total weight.

[0161] When the dosage form of the present invention is a lotion, paste, cream or gel, animal fibers, plant fibers, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component.

[0162] When the dosage form of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and, particularly when it is a spray, may further contain a propellant such as chlorofluorohydrocarbon, propane / butane or dimethyl ether.

[0163] When the dosage form of the present invention is a solution or emulsion, a solvent, solvator or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, aliphatic esters of glycerol, polyethylene glycol or fatty acid esters of sorbitan.

[0164] When the dosage form of the present invention is a suspension, the carrier component may be a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant.

[0165] When the dosage form of the present invention is a surfactant-containing cleanser, fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, isethionic acid, imidazolinium derivatives, methyl taurate, sarcosinate, fatty acid amide ether sulfates, alkylamido betaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters may be used as carrier components.

[0166] The composition according to the present invention may be provided in the form of a quasi-drug composition. In the present invention, the term "quasi-drug" refers to a product used for the purpose of treating, alleviating, treating, or preventing a disease in humans or animals, which has a minor effect on the human body or does not directly act on the human body.

[0167] In addition to the above-mentioned components, the quasi-drug composition of the present invention may further contain a pharma- ceutically acceptable carrier, excipient, or diluent as necessary. The pharma- ceutically acceptable carrier, excipient, or diluent is not limited as long as it does not affect the effects of the present invention, and may include, for example, a filler, a bulking agent, a binder, a wetting agent, a disintegrant, a surfactant, a lubricant, a sweetener, a flavoring agent, a preservative, etc.

[0168] Representative examples of carriers, excipients, or diluents acceptable for the quasi-drug composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, gelatin, glycerin, gum acacia, alginate, calcium phosphate, calcium carbonate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, propylene glycol, polyethylene glycol, vegetable oil, injectable esters, witepsol, macrogol, Tween 61, cocoa butter, lauric butter, and the like.

[0169] When the composition of the present invention is provided as an external preparation, it may be in the form of, but is not limited to, a liquid, ointment, patch, gel, cream, or spray. According to an embodiment of the present invention, the quasi-drug of the present invention may include oral care products including dentifrices, mouthwashes, and mouth sprays, ointments, masks, poultices, patches, and transdermal absorbents. The formulation method, dosage, method of use, and components of the quasi-drug may be appropriately selected from conventional techniques known in the art.

[0170] The present invention also provides a food composition for preventing or improving hair loss or gray hair, comprising an aldehyde dehydrogenase type 2 activator as an active ingredient. The composition may be used in combination with a hair loss treatment agent. The present invention also provides a food composition for preventing or improving hair loss, comprising an ALDH2 activator and a hair loss treatment agent as active ingredients. Preferably, the hair loss treatment agent is minoxidil, an analogue thereof, or a food-based acceptable salt thereof.

[0171] The aldehyde dehydrogenase type 2 activator may preferably be Alda-1 or a food-based acceptable salt thereof. In the present invention, the "food-based acceptable salt" includes salts derived from food-based acceptable organic acids, inorganic acids, or bases.

[0172] When the ALDH2 activator of the present invention is used as a food additive, the ALDH2 activator may be added as it is, or may be used together with other foods or food ingredients, and may be used appropriately by a conventional method. The amount of the active ingredient mixed may be appropriately determined depending on the purpose of use (prevention, health, or therapeutic treatment). In general, when producing a food or beverage, the ALDH2 activator of the present invention may be added in an amount of 15% by weight or less, or 10% by weight or less, based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or health regulation, 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 greater than the above range.

[0173] The type of the food is not particularly limited. Examples of the food to which the substance can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, drinking water, tea, energy drinks, alcoholic beverages, and vitamin complexes, and include all health functional foods in the usual sense.

[0174] The health drink composition according to the present invention may contain various flavorings or natural carbohydrates as additional ingredients, like ordinary drinks. The above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As sweeteners, natural sweeteners such as thaumatin and stevia extract, and synthetic sweeteners such as saccharin and aspartame may be used. The proportion of the natural carbohydrates is generally about 0.01 to 0.20 g, or about 0.04 to 0.10 g per 100 mL of the composition of the present invention.

[0175] In addition to the above, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated drinks, etc. In addition, the composition of the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These ingredients may be used independently or in combination. The proportion of such additives is not very important, but is generally selected from the range of 0.01 to 0.20 parts by weight per 100 parts by weight of the composition of the present invention.

[0176] In this specification, the term "health functional food" is the same as food for special health use (FoSHU), and refers to food with high medical and therapeutic effects that is processed to efficiently exhibit bioregulatory functions in addition to providing nutrition, and the food may be manufactured in various forms such as tablets, capsules, powders, granules, liquids, pills, etc. to obtain useful effects in preventing or improving hair loss.

[0177] The health functional food of the present invention can be manufactured by a method commonly used in the art, and may be manufactured by adding raw materials and ingredients commonly added in the art. Also, unlike general medicines, it has the advantage of being free of side effects that may occur when taking medicines for a long period of time, as it is made from food as a raw material, and is highly portable.

[0178] In the following, preferred examples are presented to aid in understanding the present invention. However, the following examples are provided to facilitate understanding of the present invention, and are not intended to limit the scope of the present invention. EXAMPLES

[0179] Example 1. Induction of cell division and activation of dermal papilla cells and outer root sheath cells derived from human hair follicles by ALDH2 activation To evaluate the effect of ALDH2 activators on hair follicle cell proliferation, human hair follicle-derived hair dermal papilla cells (HDPCs) and outer root sheath cells (ORSs) were treated with the ALDH2 activator Alda-1 or the known hair loss treatment Minoxidil at a concentration of 1 μM, and CCK8 analysis was performed. Primary cultured hair papilla cells were treated with Alda-1 at concentrations of 0, 25, 50, or 100 μM and cultured for 24 or 48 hours, after which each cell was treated with CCK8 reagent and reacted at 37°C for 15 minutes. The absorbance was then measured at 450 nm using a luminometer, and the degree of cell proliferation was confirmed by comparing with the negative control group and the positive control group, Minoxidil.

[0180] As a result, it was confirmed that the cell viability of dermal papilla cells (Figure 1a) and outer root sheath cells (Figure 1b) was significantly increased by treatment with Alda-1. In particular, it was shown that Alda-1 promoted the proliferation of dermal papilla cells and outer root sheath cells at a level equivalent to or greater than that of minoxidil. These results support the idea that activation of ALDH2 promotes the proliferation of dermal papilla cells and outer root sheath cells, thereby exerting a hair growth promoting effect.

[0181] Example 2. Confirmation of the growth-promoting effect of human hair follicles by ALDH2 activation through human hair follicle organ culture test To evaluate the effect of ALDH2 activation on the growth of human hair follicles, an ex vivo hair follicle organ culture test was performed. To perform the human hair follicle organ culture test, scalp tissue obtained from volunteers was separated into hair follicles, and the lower part of the sebaceous gland of each separated hair follicle was cut off to use the remaining hair follicle. The hair follicles were cultured in a culture medium containing a negative control reagent, 1 μM minoxidil, or 5, 25, or 50 μM Alda-1 (ALDH2 activator), and the length of the hair that grew on the third and sixth days was measured and compared with the negative control group to confirm the effect of ALDH2 activators in promoting hair growth in human hair follicles.

[0182] As a result, as shown in Figure 2a, it was confirmed that the activation of ALDH2 in the group treated with Alda-1 promoted hair elongation in human hair follicles. In particular, Alda-1 was shown to promote hair growth in hair follicles to a higher level than minoxidil.

[0183] In addition, to confirm cell proliferation in the hair follicles cultured through the above test, immunofluorescence staining was performed using Ki-67 antibody, a cell division marker. Hair follicles cultured for 2 days after treatment with negative control group, 1μM concentration of minoxidil, or Alda-1 were cut into tissue sections at a thickness of 4μm and fixed on slides, and then treated with Ki-67 using a primary antibody, treated with a secondary antibody bound to a fluorescent protein to detect Ki-67, and observed and photographed under a fluorescent microscope to confirm the number of Ki-67 positive cells. Nuclei were stained using DAPI reagent.

[0184] The results are shown in Figure 2b (Ki-67, red fluorescence, and DAPI, blue fluorescence). As can be seen from the figure, ADLH2 was activated in hair follicles treated with Alda-1, increasing the level of Ki-67 positive cells, i.e., cells undergoing division (proliferation), in the hair follicles, and the effect of Alda-1 was found to be even more excellent than that of minoxidil.

[0185] These results indicate that activation of ALDH2 can promote cell proliferation in human hair follicles, thereby promoting hair growth.

[0186] Example 3. Confirmation of the hair growth anagen phase induction effect by ALDH2 activation To confirm the effect of ALDH2 activation on hair growth, the anagen induction effect of hair growth was confirmed using a C57BL / 6 mouse model. Human hair has different hair cycles depending on the individual, but in mice, all hair cycles are the same in the early stages of life, and at 7-8 weeks of age, all hairs enter the telogen phase and then switch to the anagen phase. In order to evaluate the anagen induction effect of ALDH2 activators using this characteristic of mice, the hair on the backs of 8-week-old C57BL / 6 mice in the telogen phase was removed, and the ALDH2 activator Alda-1 was applied once a day for three weeks at a dose of 0.5 mM or 3 mM. The presence or absence of hair growth and the degree of anagen induction were confirmed by comparing with the negative control group and the positive control group (minoxidil 2% by weight; 111 mM).

[0187] As a result, as shown in Figure 3, the percentage of areas where hair had grown in the anagen phase was significantly increased in the Alda-1 treatment group, confirming that ALDH2 activation has the effect of promoting the induction of hair growth in the anagen phase. In particular, the Alda-1 treatment group showed a similar or even greater degree of hair growth compared to the minoxidil treatment group, despite being treated with a very low dose of the drug.

[0188] In addition, the skin tissue with growing hair was fixed in paraffin and stained with hematoxylin and eosin for histological examination. As a result, as shown in Figure 4, it was confirmed that the formation of hair follicles was promoted in the Alda-1 treatment group as well as in the positive control group treated with minoxidil.

[0189] In addition, the degree of anagen induction and skin thickness of each mouse were measured. As a result, as shown in Figures 5a and 5b, it was shown that the anagen induction score and skin thickness were increased in the ALDH2 activator-treated group compared to the control group.

[0190] These results indicate that activation of ALDH2 promotes hair growth by inducing the hair anagen phase.

[0191] Example 4. Confirmation of the hair growth promoting protein regulation effect by ALDH2 activation To confirm the molecular biological mechanism by which ALDH2 activation promotes the proliferation of dermal papilla cells and outer root sheath cells and induces hair follicle anagen, changes in the protein levels of hair growth-promoting factors due to ALDH2 activation were confirmed using human dermal papilla cells. For this purpose, an enzyme-linked immunosorbent assay (ELISA) method was performed. Dermal papilla cells cultured in the laboratory were treated with a negative control or the ALDH2 activator Alda-1 for 24 hours, after which the cell culture medium was collected and concentrated. The levels of growth-promoting factor proteins were confirmed in the concentrated culture medium.

[0192] As a result, as shown in Figure 6, it was confirmed that the protein levels of basic fibroblast growth factor (bFGF), keratinocyte growth factor (FGF-7), insulin-like growth factor 1 (IGF-1), and platelet-derived growth factor (PDGF), which are known to be hair growth promoting factors, increased in the samples treated with the ALDH2 activator.

[0193] These results indicate that activation of ALDH2 increases the protein levels of hair growth-promoting factors, promotes the proliferation of cells related to hair growth, and induces the hair follicle anagen phase.

[0194] Example 5. Confirmation of reduction in oxidative stress in dermal papilla cells and outer root sheath cells derived from human hair follicles by ALDH2 activation It is known that oxidative stress in hair follicle cells inhibits hair follicle and hair growth and has a negative effect on hair loss. Therefore, to evaluate the effect of ALHD2 activation on oxidative stress in hair follicle cells, dermal papilla cells and outer root sheath cells derived from human hair follicles were treated with Alda-1, an ALDH2 activator, and DCFDA (2',7'-dichlorofluorescin diacetate) analysis was performed to confirm the level of oxidative stress. Cultured cells in each group were treated with H2O2 to increase the level of oxidative stress, and the experimental groups were treated with the ALDH2 activator Alda-1 at concentrations of 5, 25, or 50 μM for 3 hours to observe DCFDA expression. The same experiment was also performed to confirm the amount of DCFDA expression through flow cytometry.

[0195] As a result, as shown in Figure 7, the fluorescence level indicating DCFDA was significantly reduced in the Alda-1-treated group compared to the untreated control group, confirming that ALDH2 activator reduced oxidative stress. In particular, there was a tendency for oxidative stress to decrease in proportion to the treatment concentration of Alda-1, confirming that the ALDH2 activator is highly effective in reducing oxidative stress in hair follicle cells. The flow cytometry results also showed that oxidative stress in outer root sheath cells was significantly reduced in proportion to the treatment concentration of Alda-1 (Figures 8a and 8b).

[0196] These results indicate that activation of ALDH2 can reduce oxidative stress in hair follicle cells, which is one of the main causes of hair loss, thereby reducing the risk of hair loss and promoting hair growth.

[0197] In particular, these results suggest that activation of aldehyde dehydrogenase type 2 may contribute not only to hair growth but also to the suppression of gray hair. Specifically, gray hair is mainly caused by the decrease in pigment production due to aging of melanocytes and the loss of melanocytes due to the generation of reactive oxygen species. The tyrosinase enzyme in melanocytes mediates the process of oxidizing tyrosine with DOPA during melanin synthesis, and in hair, this process occurs periodically for melanin production.

[0198] However, reactive oxygen species are generated during the melanin production process, and their accumulation accelerates cellular aging, damages the antioxidant system, and induces oxidative stress. Melanocytes are vulnerable to the accumulation of excessive oxidative stress. In particular, accumulated oxidative stress is known to disrupt the homeostasis of melanocytes and may induce cell death or modification.

[0199] Therefore, in order to suppress the occurrence of gray hair, it is particularly important to reduce the exposure of melanocytes to reactive oxygen species, and the present inventors have confirmed through the above examples that activation of aldehyde dehydrogenase type 2 is a mechanism for significantly reducing oxidative stress in human hair follicle cells. Therefore, when treated with an aldehyde dehydrogenase type 2 activator, reactive oxygen species generated during the activation process of melanocytes can be reduced, effectively suppressing the occurrence of gray hair due to damage to melanocytes and aging.

[0200] Example 6. Confirmation of changes in ALDH2 and mitochondrial expression during anagen and telogen in human hair follicles To confirm the change in ALDH2 in hair follicles during the telogen and anagen phases, immunofluorescence staining was performed on tissues from patients with alopecia and normal individuals. To confirm type 2 aldehyde dehydrogenase located in mitochondria, an antibody targeting VDAC (voltage-dependent anion channel), a mitochondrial outer membrane protein marker (anti-VDAC) and type 2 aldehyde dehydrogenase antibody (anti-ALDH2) were used. Each tissue was cut to a thickness of 4 μm, and treated with anti-VDAC and anti-ALDH2 as primary antibodies, and fluorescently labeled secondary antibodies. Nuclei were stained with DAPI reagent, and then observed and photographed under a fluorescent microscope to confirm the number of VDAC and ALDH2 positive cells.

[0201] The results are shown in Figures 9a to 9b (fluorescence images: VDAC, green fluorescence; ALDH2, red fluorescence; DAPI, blue fluorescence). While hair follicles in the telogen phase were observed in the tissue of hair loss patients, hair follicles in the anagen phase were observed in the tissue of healthy individuals. In human hair follicles, the mitochondrial outer membrane marker and aldehyde dehydrogenase type 2 were present in the same position. It was also confirmed that aldehyde dehydrogenase type 2 was expressed more in outer root sheath cells than in dermal papilla cells. When the proportion of aldehyde dehydrogenase type 2-expressing cells located in outer root sheath cells was reconfirmed, it was similarly confirmed that it was significantly increased in hair follicles in the anagen phase (Figure 9b).

[0202] These results suggest that the interaction between aldehyde dehydrogenase type 2 and mitochondria in hair follicle cells is related to the maintenance of the anagen phase of hair follicles and hair growth.

[0203] Example 7. Confirmation of changes in mitochondrial activity in outer root sheath cells derived from human hair follicles To confirm the change in mitochondrial activity due to the activity of aldehyde dehydrogenase type 2 in outer root sheath cells derived from human hair follicles, the oxygen consumption rate was measured. Outer root sheath cells were plated in an XF96 plate at 5 x 103 cells per well, and the control group was treated with DMSO, while the experimental group was treated with Alda-1 (25 μM). After 12 hours, the concentration of oxygen dissolved in the medium during cell culture was measured using a real-time cell metabolism analyzer (Seahorse XFE96 Analyzer). The cells were washed twice with Substrate Oxidation Assay Media (XF DMEM pH 7.4 and 10 mM XF glucose, 1 mM XF pyruvate, and 2 mM XF glutamine) and cultured at 37°C and CO2-free conditions for 60 minutes. Oligomycin (1.5 μM), FCCP (1.5 μM), and rotenone / antimycin A (final concentration of each = 0.5 μM) were sequentially injected into the XF96Plate port, and then the oxygen consumption rate of the outer root sheath cells was measured.

[0204] As a result, as shown in Figure 10a, the activation of aldehyde dehydrogenase type 2 after Alda-1 treatment increased the oxygen consumption rate of outer root sheath cells, confirming that mitochondrial activity was increased. In addition, the basal respiration rate of outer root sheath cells treated with Alda-1 was significantly increased (Figure 10b), and the maximum respiration rate was also significantly increased (Figure 10c). In addition, the amount of mitochondrial ATP production increased nearly 10-fold after Alda-1 treatment (Figure 10d).

[0205] These results support that activation of aldehyde dehydrogenase type 2 enhances mitochondrial function and induces the anagen phase of hair follicles, thereby promoting hair growth.

[0206] As described above, it has been confirmed that activation of ALDH2 can achieve excellent hair growth and hair regrowth promoting effects, and various ALDH2 activators are expected to be used as hair loss prevention, amelioration, and / or treatment agents. In particular, it has been confirmed that Alda-1 according to an embodiment of the present invention can effectively induce hair follicle and hair growth even at a much smaller dose than the conventional hair loss treatment agent minoxidil, and is expected to be used as a safer and more economical hair loss treatment agent.

[0207] It was also confirmed that ALDH2 activation and mitochondrial interaction in hair follicles can contribute to the induction of the anagen phase of hair follicles and the promotion of hair growth, and in particular, ALDH2 activation was confirmed to be a mechanism that can effectively suppress oxidative stress in hair follicles. Therefore, ALDH2 activation can not only induce hair growth by reducing oxidative stress in hair follicles, but also effectively suppress the occurrence of gray hair.

[0208] Example 8. Confirmation of the combined effect of ALDH2 activator and minoxidil In the previous example, it was confirmed that ALDH2 activators can promote cell division in hair follicles and induce hair growth, and in this example, the hair loss treatment effect of combined use of ALDH2 activators and minoxidil was confirmed.

[0209] Specifically, to confirm the hair growth effect of the combination of ALDH2 activator Alda-1 and minoxidil, the two substances were combined in a C57BL / 6 mouse model to confirm whether the hair growth phase was induced. After shaving the hair on the backs of 8-week-old C57BL / 6 mice in the telogen phase, the mice were divided into groups and Alda-1 and / or minoxidil were applied to the mice as follows: untreated group, Alda-1 (3 mM) single treatment group, 2% minoxidil single treatment group, and Alda-1 3 mM and 2% minoxidil combined treatment group. The combined treatment group was applied with a mixture of 3 mM Alda-1 and 2% minoxidil. In the mixed drug, Alda-1:minoxidil was mixed at a weight ratio of 1:37. The drug was applied at a dose of 200 μl each time to both the single treatment group and the combined treatment group. Each drug or the mixture of drugs was applied to the back of the mice once a day for three weeks, and the presence or absence of hair growth and the degree of induction of the anagen phase were confirmed by comparison with the control group.

[0210] As a result, as shown in FIG. 11, hair growth was observed in both mice treated with each drug alone or in combination compared to the control group, and in particular, the group treated with Alda-1 and minoxidil in combination showed a much wider area of ​​hair growth during the anagen phase compared to the groups treated with each drug alone.

[0211] In addition, skin tissue with growing hair in the anagen phase was fixed in paraffin and examined by immunofluorescence staining for versican, a marker of dermal papilla cells involved in hair formation and growth. Compared to the groups treated with Alda-1 or minoxidil alone, a much stronger signal was detected in the group treated with a combination of Alda-1 and minoxidil, confirming that the number of dermal papilla cells had increased significantly.

[0212] The above results indicate that Alda-1 has excellent hair loss treatment effects by itself, and that when used in combination with minoxidil, the hair growth phase induction and hair follicle formation promotion effects are further increased, resulting in a synergistic hair loss treatment effect.

[0213] As described above, it has been confirmed that activation of ALDH2 can achieve excellent hair growth and hair regrowth promoting effects, and various ALDH2 activators are expected to be used as hair loss prevention, amelioration, and / or treatment agents. In particular, it has been confirmed that Alda-1 according to an embodiment of the present invention can effectively induce hair follicle and hair growth even at a much smaller dose than the conventional hair loss treatment agent minoxidil, and is expected to be used as a safer and more economical hair loss treatment agent.

[0214] Furthermore, it has been confirmed that the combination of ALDH2 and minoxidil increases hair follicle formation and hair growth more significantly than the use of each drug alone, and thus, the combination of ALDH2 and minoxidil can achieve a more excellent hair loss treatment effect. In particular, when using the ALDH2 of the present invention, the amount of minoxidil used, which may cause side effects, can be reduced, so it is expected that a safer and more excellent hair loss treatment can be achieved.

[0215] The above description of the present invention is for illustrative purposes only, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. Therefore, the above-described embodiments should be understood to be illustrative in all respects and not limiting. [Industrial Applicability]

[0216] The present invention relates to a composition for preventing, improving, and / or treating hair loss or gray hair (or gray hair syndrome), and has been completed by confirming that an aldehyde dehydrogenase type 2 (ALDH2) activator promotes the formation of hair follicles and hair growth, and has an excellent effect of suppressing oxidative stress in hair follicles. Therefore, the ALDH2 activator according to the present invention can be used as a preparation for preventing, improving, and / or treating hair loss and gray hair. Furthermore, it has been shown that combined treatment with an ALDH2 activator and minoxidil exhibits a more excellent effect of preventing and treating hair loss. Therefore, the ALDH2 according to the present invention is expected to not only effectively promote hair growth by itself, but also to be usefully used as a combined preparation with minoxidil in the medical, cosmetic, and food fields for the purpose of preventing, improving, and treating hair loss.

Claims

1. A pharmaceutical composition for preventing or treating hair loss or gray hair, comprising an aldehyde dehydrogenase 2 (ALDH2) activator as an active ingredient.

2. The pharmaceutical composition of claim 1 , wherein the composition is for promoting hair growth or regrowth.

3. 2. The pharmaceutical composition according to claim 1, wherein the hair loss is one or more selected from the group consisting of alopecia areata, hereditary androgenetic alopecia, telogen effluvium, traumatic alopecia, trichotillomania, pressure induced alopecia, anagen effluvium, pityriasis nivea, syphilitic alopecia, seborrheic alopecia, symptomatic alopecia, cicatricial alopecia, and congenital alopecia.

4. The pharmaceutical composition according to claim 1, wherein the type 2 aldehyde dehydrogenase activator is Alda-1 or a pharma- ceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, wherein the Alda-1 or a pharma- ceutically acceptable salt thereof is contained in a concentration of 0.0001 to 50 mM in the composition.

6. The pharmaceutical composition of claim 1, characterized in that the composition satisfies at least one characteristic selected from the group consisting of the following: (a) Promoting the proliferation of hair papilla cells or outer root sheath cells. (b) promoting hair follicle growth; (c) Inducing the anagen phase of hair. (d) increasing mitochondrial activity.

7. The pharmaceutical composition according to claim 1, wherein the composition increases the level or activity of at least one protein selected from the group consisting of bFGF, FGF-7, IGF-1, and PDGF.

8. The pharmaceutical composition according to claim 1, characterized in that the composition reduces oxidative stress in hair papilla cells or outer root sheath cells.

9. A cosmetic composition for preventing or improving hair loss or gray hair, comprising a type II aldehyde dehydrogenase activator as an active ingredient.

10. The cosmetic composition according to claim 9, wherein the composition is in the form of an external skin preparation, such as a scalp treatment agent, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid, solution, emulsion, dispersion, micelle, liposome, ointment, lotion, essence, patch, or spray.

11. A quasi-drug composition for preventing or improving hair loss or gray hair, comprising an aldehyde dehydrogenase type II activator as an active ingredient.

12. A food composition for preventing or improving hair loss or gray hair, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient.

13. A functional health food composition for preventing or improving hair loss or gray hair, comprising an aldehyde dehydrogenase type II activator as an active ingredient.

14. A pharmaceutical composition for preventing or treating hair loss, comprising an aldehyde dehydrogenase type 2 activator as an active ingredient, wherein the pharmaceutical composition is administered in combination with minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof.

15. 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is administered simultaneously or sequentially with the minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof.

16. The pharmaceutical composition according to claim 14, wherein the type 2 aldehyde dehydrogenase activator enhances the hair loss treatment effect of the minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof.

17. The pharmaceutical composition according to claim 14, wherein the type 2 aldehyde dehydrogenase activator is Alda-1 or a pharma- ceutically acceptable salt thereof.

18. A pharmaceutical composition for preventing or treating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator, and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, as active ingredients.

19. The pharmaceutical composition according to claim 18, wherein the type 2 aldehyde dehydrogenase activator is Alda-1 or a pharma- ceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 18, characterized in that the composition is in the form of a mixture in which (a) the type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutical acceptable salt thereof, or an analog thereof are mixed.

21. The pharmaceutical composition according to claim 18, characterized in that the (a) type 2 aldehyde dehydrogenase activator and the (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof are each formulated and administered simultaneously, separately, or sequentially.

22. A cosmetic composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator, and (b) minoxidil, a cosmetically acceptable salt thereof, or an analog thereof as active ingredients.

23. The cosmetic composition according to claim 22, wherein the composition is in the form of an external skin preparation, such as a scalp treatment agent, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid, solution, emulsion, dispersion, micelle, liposome, ointment, lotion, essence, patch, or spray.

24. A quasi-drug composition for preventing or ameliorating hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof as active ingredients.

25. A food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a nutrient-acceptable salt thereof, or an analog thereof as active ingredients.

26. A health functional food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a nutrient-based acceptable salt thereof, or an analog thereof as active ingredients.

27. A method for preventing, ameliorating, or treating hair loss or graying, comprising administering an aldehyde dehydrogenase type 2 activator to an individual in need thereof.

28. Use of a type 2 aldehyde dehydrogenase activator for the prevention, improvement, or treatment of hair loss or gray hair.

29. Use of a type 2 aldehyde dehydrogenase activator for the manufacture of a medicament for preventing, improving, or treating hair loss or gray hair.

30. 1. A method for preventing or treating hair loss, comprising administering to an individual in need thereof (a) an aldehyde dehydrogenase type 2 activator, and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof.

31. 1. Use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for the prevention, amelioration, or treatment of hair loss.

32. Use of a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharma- ceutically acceptable salt thereof, or an analog thereof, for the manufacture of a medicament for preventing, ameliorating, or treating hair loss.

Images