Composition for the prevention, improvement, or treatment of hair loss or graying by regulating type 2 aldehyde dehydrogenase.

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

[0002] The present invention claims priority based on Korean Patent Application Nos. 10-2022-0011538 filed on January 26, 2022, 10-2022-0079800 filed on June 29, 2022, and 10-2022-0152981 filed on November 15, 2022, and all the contents disclosed in the specifications and drawings of the applications are incorporated herein by reference.

Background Art

[0003] Hair follicles, which are organs that generate hair, repeat the hair growth cycle, which is divided into the anagen phase in which hair is generated and the generated hair grows actively, the catagen phase in which hair degenerates, the telogen phase in which hair is maintained until it falls out, and the exogen phase in which hair loss occurs, and are involved in hair growth, maintenance, and loss. During the anagen phase of hair follicles, in adults, it is known that hair grows about 0.3 mm per day on average, grows about 1 cm in a month, and lasts for about 5 to 8 years. Generally, after about 3 weeks of the catagen phase and an average of 3 months of the telogen phase after the anagen phase, hair falls out. The reason why the length of human hair is different depending on the part can be said to be because the duration of the anagen phase, which is a unique feature of hair follicles, is different for each part.

[0004] Hair is formed from hair follicles. Hair follicles are very complex organs, composed of the inner root sheath, outer root sheath, hair shaft, and hair matrix cells. In particular, hair dermal papilla cells play a core role in hair follicle formation and are therefore directly linked to the ability to form hair follicles. If hair papilla cells are absent or non-functional, proper interaction between hair papilla cells and epidermal cells cannot occur, making it impossible to form hair follicles.

[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 interplay of factors, including not only genetic causes and the effects of male hormones, but also endocrine disorders, nutritional deficiencies, drug use, childbirth, fever, surgery, and other severe physical and mental stress. In recent years, not only has male pattern baldness increased, but the number of women experiencing hair loss has also been increasing due to changes in diet and increased stress from the social environment. As a result, the number of people suffering from abnormal symptoms of the scalp and hair is increasing, and the age at which they experience these problems is also decreasing.

[0006] Research into hair loss prevention and hair growth agents is accelerating both domestically and internationally, and a variety of products are being developed. However, the development of hair loss prevention agents that are both highly effective and safe for the human body is still insufficient. Currently, the only topical product developed is minoxidil from the United States. In Japan, herbal extracts are being developed as hair growth or hair restoration agents, but in terms of efficacy, it is still too early to expect them to effectively prevent hair loss and promote hair growth. In particular, high doses of minoxidil have been reported to cause side effects such as weight gain, edema, increased heart rate, angina, dermatitis, and itching. Therefore, there is a need to discover more effective hair loss treatments that can replace minoxidil, or combination therapies that can enhance the hair growth effects of minoxidil while reducing its side effects.

[0007] Currently, the only effective treatments for male pattern baldness are the 5α-reductase inhibitors finasteride and dutasteride. However, there is significant individual variation in treatment effectiveness, and hair loss may recur or serious side effects such as sexual dysfunction may occur when the product is discontinued. In particular, most conventional hair loss treatments approved by the US FDA have been developed primarily for male pattern baldness, and therefore have limitations in addressing female pattern baldness, and may even cause side effects in women. Consequently, 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 part of the aging process and occurs in a variety of ways from person to person. While it is understood that gray hair is caused by the loss or decreased activity of melanocytes in the hair bulb and outer root sheath, the cellular and molecular mechanisms are not clearly understood. Melanin-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 or abnormalities in the processes regulating melanocyte migration and differentiation. In human hair follicles, melanocytes located in the hair bulb begin to organize around the dermal papilla after division during the hair growth phase. Tyrosinase and TRP-1 enzymes expressed in melanocytes are observed only during the growth phase and are not produced during the regression phase. Therefore, pigment can be regenerated in the hair at the top of the outer root sheath through melanocytes that are periodically activated during the growth phase.

[0009] When reactive oxygen species generated during melanin production accumulate, they damage the antioxidant system and induce oxidative stress. Excessive oxidative stress is known to make melanocytes vulnerable to production. In particular, accumulated oxidative stress can disrupt the homeostasis of melanocytes, potentially leading to cell death or deformation. Therefore, suppressing oxidative stress on melanocytes is crucial not only for preventing hair loss but also for preventing or improving gray hair.

[0010] Because gray hair strongly conveys an impression of old age, many dyes have been researched to conceal gray hair by dyeing it black. However, dyeing is only a temporary solution and, being chemical-based, can damage the scalp and worsen the health of hair follicles. Therefore, there is a need to discover new methods that can fundamentally prevent and improve gray hair.

[0011] On the other hand, aldehyde dehydrogenase 2 (ALDH2) is an enzyme found in the mitochondria of the body, and is known to primarily convert acetaldehyde to acetic acid, thus aiding in the breakdown of alcohol absorbed into the body. However, the effects of activating this enzyme on preventing hair loss or promoting hair growth have not yet been reported. [Overview of the Initiative] [Problems that the invention aims to solve]

[0012] This invention was devised to solve the aforementioned problems and was completed after confirming that a type II aldehyde dehydrogenase activator has excellent effects in preventing hair loss, promoting hair growth, and preventing or improving gray hair by promoting hair follicle formation and hair growth. Furthermore, it has been confirmed that when a type II aldehyde dehydrogenase activator is used in combination with minoxidil, it can exert a synergistic effect in treating hair loss.

[0013] Therefore, the object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of alopecia or gray hair, comprising 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 graying, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient.

[0015] Another object of the present invention is to provide a quasi-drug composition for preventing or improving hair loss or graying, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient.

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

[0017] Furthermore, an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of hair loss, comprising a type 2 aldehyde dehydrogenase activator as an active ingredient, characterized in that it is administered in combination with minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0018] Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof as an active ingredient.

[0019] A further object of the present invention is 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 an active ingredient.

[0020] A further object of the present invention is to provide a quasi-drug composition for the prevention or improvement of hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof as an active ingredient.

[0021] A further object of the present invention is to provide a food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a food-safe salt thereof, or an analog thereof as an active ingredient.

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

[0023] However, the technical problems to be solved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those having ordinary knowledge in the technical field to which the present invention pertains from the following description.

Means for Solving the Problems

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

[0025] In addition, the present invention provides a method for preventing or treating hair loss or white hair, which includes the step of administering an ALDH2 activator to an individual who needs it.

[0026] In addition, the present invention provides the use of an ALDH2 activator for preventing or treating hair loss or white hair.

[0027] In addition, the present invention provides the use of an ALDH2 activator for manufacturing a medicament for treating hair loss or white hair.

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

[0029] In another embodiment of the present invention, the hair loss may be any one or more selected from the group consisting of alopecia areata, hereditary androgenetic alopecia, telogen effluvium, traumatic alopecia, trichotillomania, traction alopecia, anagen effluvium, pityriasis amiantacea, 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 pharmaceutically acceptable salt thereof.

[0031] In yet another embodiment of the present invention, the Alda-1 or a pharmaceutically 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 feature selected from the group consisting of: (a) promoting the proliferation of dermal papilla cells or outer root sheath cells; (b) promoting hair follicle growth; (c) inducing the hair growth phase; 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 bFGF, FGF-7, IGF-1, and PDGF.

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

[0035] Furthermore, the present invention provides a cosmetic composition for preventing or improving hair loss or graying, comprising an ALDH2 activator as an active ingredient.

[0036] In one embodiment of the present invention, the composition may be in the form of a topical skin preparation such as a scalp treatment, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid preparation, solution, emulsion, dispersant, micelle, liposome, ointment, lotion, essence, patch, or spray.

[0037] Furthermore, the present invention provides a quasi-drug composition for preventing or improving hair loss or graying, comprising an ALDH2 activator as an active ingredient.

[0038] Furthermore, the present invention provides a food composition for preventing or improving hair loss or graying, comprising an ALDH2 activator as an active ingredient.

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

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

[0041] Furthermore, the present invention provides an application of an ALDH2 activator for the prevention or improvement of gray hair.

[0042] Furthermore, the present invention provides an application for an ALDH2 activator for the manufacture of a drug for preventing or improving gray hair.

[0043] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of hair loss, comprising an aldehyde dehydrogenase 2 type 2 activator as an active ingredient, characterized in that it is administered in combination with minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0044] Furthermore, the present invention provides a use for co-administration with minoxidil, a type 2 aldehyde dehydrogenase activator, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0045] Furthermore, the present invention provides a method for preventing or treating hair loss, comprising the steps of (a) administering a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof to an individual in need.

[0046] Furthermore, the present invention provides for the prevention or treatment of hair loss a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0047] Furthermore, the present invention provides applications for the manufacture of agents for the prevention or treatment of hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

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

[0049] In other embodiments of the present invention, the composition may, but is not limited to, promote hair growth or regeneration.

[0050] In yet another embodiment of the present invention, the type 2 aldehyde dehydrogenase activator may enhance the hair loss treatment effect of minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[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 pharmaceutically acceptable salt thereof.

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

[0053] In yet another embodiment of the present invention, the composition may satisfy at least one feature selected from the group consisting of: (a) promoting the proliferation of dermal papilla cells or outer root sheath cells; (b) promoting hair follicle growth; (c) inducing the hair growth phase; 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 bFGF, FGF-7, IGF-1, and PDGF.

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

[0056] Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically 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 pharmaceutically acceptable salt thereof.

[0058] In other embodiments of the present invention, the composition may be in the form of a mixture comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0059] In yet another embodiment of the present invention, the composition may be formulated in a manner in which (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analogue thereof are administered simultaneously, individually, or sequentially.

[0060] Furthermore, the present invention provides a cosmetic composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically (or cosmetically) acceptable salt thereof, or an analog thereof as an active ingredient.

[0061] In one embodiment of the present invention, the composition may be in the form of a topical skin preparation such as a scalp treatment, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid preparation, solution, emulsion, dispersant, micelle, liposome, ointment, lotion, essence, patch, or spray.

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

[0063] Furthermore, the present invention provides a food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically (or food-safe) salt thereof, or an analog thereof as an active ingredient.

[0064] Furthermore, the present invention provides a health functional food composition for preventing or improving hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically (or food-grade) acceptable salt thereof, or an analog thereof as an active ingredient.

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

[0066] Furthermore, the present invention provides for the prevention or improvement of hair loss using a composition comprising (a) a type 2 aldehyde dehydrogenase activator and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

[0067] Furthermore, the present invention provides applications for the manufacture of agents for the prevention or improvement of hair loss, comprising (a) a type 2 aldehyde dehydrogenase activator and (b) a composition comprising minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

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

[0069] Furthermore, the present invention provides a use for a type 2 aldehyde dehydrogenase activator for the production of a combination formulation with a hair loss treatment agent. [Effects of the Invention]

[0070] This invention relates to compositions for the prevention, improvement, and / or treatment of hair loss or graying, and was completed after confirming that a type 2 aldehyde dehydrogenase (ALDH2) activator promotes hair follicle formation and hair growth, and has an excellent effect in suppressing oxidative stress in hair follicles. Specifically, the inventors confirmed that the ALDH2 activator promotes the proliferation of dermal papilla cells and outer root sheath cells, which are core cells in hair follicle formation and hair growth, and promotes cell division of hair follicles, and confirmed that the growth phase of hair growth is induced when the ALDH2 activator is treated in a mouse model. Furthermore, it was confirmed that treatment with the ALDH2 activator increases the level of hair growth promoting factors in dermal papilla cells and the like, and suppresses oxidative stress, which is the cause of hair loss and graying. Thus, the ALDH2 activator according to the present invention can effectively promote hair follicle formation and growth, and can therefore be used as a formulation for the prevention, improvement, and / or treatment of hair loss and graying. In particular, the ALDH2 activator according to the present invention exhibits equivalent or even greater effects at much lower doses than the conventional hair loss treatment minoxidil when applied to a mouse model. Therefore, it is expected that this will not only result in cost savings in the development of therapeutic agents, but also lead to safer clinical applications.

[0071] Furthermore, it has been shown that combined treatment with an ALDH2 activator and minoxidil exhibits superior hair loss prevention and treatment effects. Therefore, the ALDH2 according to the present invention not only effectively promotes hair growth on its own, but also achieves a synergistic hair loss treatment effect when used in combination with minoxidil. As such, it is expected to be usefully utilized in the medical, cosmetic, and food fields for the prevention, improvement, and treatment of hair loss. [Brief explanation of the drawing]

[0072] [Figure 1a] Figure 1a shows the results of treating dermal papilla cells derived from human hair follicles with an ALDH2 activator (Alda-1, hereinafter the same) according to one embodiment of the present invention, and performing CCK8 analysis to confirm the effect of the ALDH2 activator on the proliferation of dermal papilla cells. [Figure 1b]Figure 1b shows the results of treating human hair follicle-derived outer root sheath cells with an ALDH2 activator and performing CCK8 analysis to confirm the effect of ALDH2 activation on the proliferation of outer root sheath cells. [Figure 2] Figures 2a and 2b show the results of a human hair follicle organ culture test conducted to confirm the hair growth effect of ALDH2 activation on hair follicles. Figure 2a shows the hair elongation effect in hair follicles treated with an ALDH2 activator, and Figure 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. [Figure 3] Figure 3 shows the results of comparing the degree of hair growth in each group after treating a mouse model with an ALDH2 activator to confirm the effect of ALDH2 activity on inducing the growth phase. [Figure 4] Figure 4 shows the results of histological analysis of the degree of hair follicle formation during the growth phase of a mouse model induced by ALDH2 activation, using hematoxylin and eosin staining. [Figure 5a] Figure 5a shows the results of confirming the growth induction score by ALDH2 activators in a mouse model. [Figure 5b] Figure 5b shows the results of examining the change in skin thickness caused by an ALDH2 activator in a mouse model. [Figure 6] Figure 6 shows the results of ELISA analysis to confirm the protein levels of hair growth factors after treating dermal papilla cells and outer root sheath cells derived from human hair follicles with an ALDH2 activator, in order to confirm the mechanism by which the ALDH2 activator promotes hair growth. [Figure 7] Figure 7 shows the results of detecting fluorescently labeled DCFDA after treating dermal papilla cells with an ALDH2 activator to confirm the oxidative stress-suppressing effect of the ALDH2 activator. [Figure 8] Figures 8a and 8b show the results of measuring DCFDA levels (Figure 8a) and checking the ROS scavenging ratio (Figure 8b) after treating outer root sheath cells with an ALDH2 activator to confirm the oxidative stress-suppressing effect of the ALDH2 activator. [Figure 9a] Figure 9a shows images taken from tissue of a patient with alopecia after fluorescent staining of mitochondrial outer membrane proteins (VDAC, green) and ALDH2 protein (red) (blue: DPAI). [Figure 9b] Figure 9b shows the results of comparing ALDH2 expression levels in hair follicles during the resting phase and hair follicles during the growing phase. [Figure 10a] Figure 10a shows the results of examining the oxygen consumption rate of cells after treating human hair follicle-derived outer root sheath cells with an ALDH2 activator to confirm changes in mitochondrial activity due to ALDH2 activity in human hair follicles. [Figures 10b-10d] Figures 10b-10d show the results of measuring the basal respiration rate (Figure 10b), maximal respiration rate (Figure 10c), and mitochondrial ATP production rate (Figure 10d) of human hair follicle-derived outer root sheath cells after treatment with an ALDH2 activator. [Figure 11] Figure 11 shows the results of observing hair growth after applying an ALDH2 activator and / or minoxidil to the backs of hairless mice to confirm the effectiveness of combined use of an ALDH2 activator and minoxidil in treating hair loss (top panel), and the results of detecting the dermal papilla cell marker Versican by immunofluorescence staining (bottom panel). [Modes for carrying out the invention]

[0073] The present invention relates to compositions for the prevention, improvement, and / or treatment of hair loss or graying hair (or alopecia), and was completed after confirming that an activator of type 2 aldehyde dehydrogenase (ALDH2) promotes hair follicle formation and hair growth, and has an excellent effect in suppressing oxidative stress in hair follicles.

[0074] Furthermore, the present invention relates to a combination therapy for the prevention, improvement, and / or treatment of hair loss, and was completed after confirming that an aldehyde dehydrogenase 2 (ALDH2) activator promotes the formation and growth of hair follicles, suppresses oxidative stress in hair follicles, and exhibits not only an excellent hair loss treatment effect on its own, but also exhibits an even more remarkable hair loss treatment effect 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 showed that treating hair follicles with Alda-1 and culturing them resulted in increased hair elongation and cell proliferation in the hair follicles (Example 2).

[0077] In yet another embodiment of the present invention, after applying Alda-1 to a mouse model from which hair had been removed, the degree of hair growth was compared and histological analysis was performed. The results showed that ALDH2 activation induced the hair growth phase, increasing hair growth and also increasing skin thickness (Example 3).

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

[0079] In yet another embodiment of the present invention, it was confirmed that oxidative stress on dermal papilla cells and outer root sheath cells was reduced during Alda-1 treatment (Example 5).

[0080] In yet another embodiment of the present invention, it was confirmed that hair follicles in the growth phase have even higher levels of ALDH2 and mitochondria, and that ALDH2 and mitochondria are located in the same position, thus confirming that the interaction between ALDH2 and mitochondria is important for hair growth (Example 6).

[0081] In yet another embodiment of the present invention, we confirmed that changes in mitochondrial activity in outer root sheath cells induced by Alda-1 treatment can enhance mitochondrial function and contribute to the induction of hair follicle growth (Example 7).

[0082] In yet another embodiment of the present invention, the combined effect of Alda-1 and minoxidil was confirmed, and it was found that the combined administration of the two drugs was more effective in promoting hair growth and hair follicle formation compared to the treatment of the two drugs alone (Example 8).

[0083] Therefore, activating ALDH2 not only contributes to hair growth by increasing the levels of hair growth factors, reducing oxidative stress, and inducing the proliferation of hair follicle cells, but also achieves an excellent gray hair prevention effect, making it a potential therapy for preventing, improving, and / or treating hair loss and gray hair. Furthermore, ALDH2 activation, when used in combination with minoxidil, exhibits a more synergistic effect in treating hair loss, and can therefore be usefully utilized as a combination therapy with minoxidil for preventing, improving, and / or treating hair loss.

[0084] The present invention will be described in detail below.

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

[0086] In this invention, "alopecia" refers to a condition in which there is no hair in areas where hair should normally be present, and generally means the shedding of mature hair (thick, black hair) on the scalp. Unlike vellus hair, which is colorless and thin, mature hair can cause cosmetic problems if it falls out. Alopecia can be clinically divided into two types: those that form scars and those that do not. In alopecia that forms scars, the hair follicle is destroyed and hair does not regenerate, while in alopecia that does not form scars, the hair follicle is maintained and hair regenerates after the affected area disappears. Non-scarring alopecia that does not form scars include hereditary androgen alopecia (baldness), alopecia areata, tinea capitis due to fungal infection, telogen effluvium, trichotillomania, and hair growth disorders. Scarring alopecia that forms scars include alopecia due to lupus, bald folliculitis, lichen planus pilaris, burns, and trauma. The most common types of hair loss are hereditary androgen alopecia and alopecia areata, neither of which causes scarring. Common hair loss disorders include male pattern baldness, female pattern baldness, alopecia areata, and telogen effluvium. The hair loss described in the present invention includes both male pattern baldness and female pattern baldness.

[0087] Preferably, the alopecia according to the present invention may be selected from the group consisting of alopecia areata, hereditary androgen alopecia, telogenous alopecia, traumatic alopecia, trichotillomania, pressure alopecia, anagenous alopecia, seborrheic alopecia, syphilitic alopecia, seborrheic alopecia, symptomatic alopecia, scarring alopecia, and congenital alopecia. In addition to the aforementioned diseases, the hair loss according to the present invention may include all problems caused by the phenomenon of losing a large amount of hair, such as cosmetic problems. Preferably, in the present invention, hair loss is hair loss from the scalp.

[0088] The present invention may also be used for the purpose of preventing and treating gray hair.

[0089] In this invention, "gray hair" or "white hair" refers to hair (especially scalp hair) that has lost its original color due to aging or stress, and has changed to gray or white. The term "gray hair" includes not only gray hair that occurs naturally during the aging process, but also premature graying that occurs on the heads of young people who have not yet aged. Furthermore, the term "gray hair" includes not only cases where the entire scalp hair turns white, but also cases where only a part of the scalp hair turns white, and not only cases where the entire strand of hair turns white, but also cases where only a part of a strand of hair turns white (i.e., white stripes appear on the hair). The molecular mechanisms causing gray hair are not clearly understood, but it is known that a decrease in the function and number of melanocytes contributes to gray hair. In particular, oxidative stress generated during the melanin production process of melanocytes damages melanocytes, so reducing oxidative stress in hair follicles is especially important for preventing gray hair.

[0090] The aforementioned white hair includes poliosis. In this invention, "poliosis" means a disorder in which melanin in the hair decreases or disappears, causing the hair to lose its color. Polioosis can occur in both adults and children and may be caused by genetic disorders, autoimmune diseases, or damage to hair follicles. Polioosis can occur not only in scalp hair but also in other body hair such as eyelashes and eyebrows. Preferably, in this invention, poliosis refers to poliosis occurring in scalp hair.

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

[0092] In this invention, "Aldehyde dehydrogenase 2 (ALDH2)" is the second subtype of aldehyde dehydrogenase, coded by the ALDH2 gene located on chromosome 12. ALDH2 resides in mitochondria and functions to convert acetaldehyde to acetic acid, contributing to the breakdown of alcohol absorbed into the body. However, the effects of ALDH2 activation on hair loss and hair growth have not yet been reported. The ALDH2 protein and the gene that codes for it are well known in the industry and can typically be found in the protein database Uniprot (registration number: P05091).

[0093] The compositions according to the present invention may also be for promoting hair growth and / or hair regeneration. In the present invention, the term "hair regeneration" means the growth of new hair, and "hair growth" means the lengthening of existing hair (i.e., hair growth), and "hair growth" is used interchangeably with "hair nourishment."

[0094] Throughout this specification, "hair" includes both scalp hair and body hair. Scalp hair refers to hair growing from the scalp, while body hair includes hair growing from other parts of the body. Scalp hair and body hair differ in thickness and follicle size, but as a typical example, typically 1 to 5 scalp hairs grow from one follicle, while body hair usually grows from one follicle. Also, the number of scalp hairs varies by race, but there are approximately 80,000 to 120,000 per person. The thickness of scalp hair varies widely, from approximately 17 μm to 180 μm, and is generally thicker than body hair. However, 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. Hair growth rates also differ depending on the growth site. For example, eyebrows and pubic hair grow at a rate of approximately 0.05 to 0.2 mm per day, while scalp hair grows at a rate of approximately 0.3 to 0.5 mm per day, resulting in a growth rate of approximately 1 cm or more per month. In other words, scalp hair has the characteristic of growing faster than other body hair. Preferably, the composition according to the present invention is for promoting hair growth and / or hair regeneration of the scalp.

[0095] In the present invention, "ALDH2 activator" means a substance that can promote hair follicle growth, hair growth, and / or hair regeneration by increasing the expression or activity of the ALDH2 protein. The ALDH2 activator also includes substances that can prevent or improve gray hair by increasing the expression or activity of the ALDH2 protein. While not limited to specific types, examples of the ALDH2 activator include expression vectors containing the ALDH2 coding gene, ALDH2 agonists, and ALDH2 function activators.

[0096] In the present invention, "ALDH2 protein expression" ultimately means the production of ALDH2 protein, and "enhancement of ALDH2 protein expression" includes increasing mRNA expression or increasing the translation of said mRNA at the transcription stage of the ALDH2 coding gene. In the present invention, increased mRNA expression may be achieved by activating a mechanism of action that can increase the transcription of the ALDH2 gene at a higher level of action of the ALDH2 coding gene, or conversely, by suppressing a higher level of action that can suppress the transcription of the ALDH2 gene. Furthermore, all concepts that can directly or indirectly promote ALDH2 expression, such as demethylation of the ALDH2 gene promoter site or modification of histone proteins related to ALDH2 gene expression, are included in the present invention. In the present invention, increased translation of ALDH2 mRNA may include, but is not limited to, any mechanism that can enhance the translation of the produced ALDH2 mRNA, such as suppressing the expression or activity of miRNAs that prevent the translation of ALDH2 mRNA, or enhancing the activity of ALDH2 mRNA translation-related enzymes.

[0097] Furthermore, in this invention, "ALDH2 protein activity" refers to the activity of ALDH2 protein produced through the translation process or ALDH2 protein already produced and present in the cell, and "enhancement of ALDH2 protein activity" includes all cases in which the activity of ALDH2 protein increases 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 contain any substance that can enhance the expression or activity of the type 2 aldehyde dehydrogenase protein, but is preferably selected from the group consisting of Alda-1, AD-9308, compound I-6, and pharmaceutically acceptable salts thereof.

[0099] In the present invention, the type 2 aldehyde dehydrogenase activator may preferably be Alda-1. Alda-1 is a compound that is an agonist of ALDH2 and can penetrate the cell membrane and activate the ALDH2 protein. Although Alda-1 is known to reduce oxidative stress in liver cells and other cells, there have been no reports on the effects of Alda-1 on hair follicles or hair growth. Through specific experiments using Alda-1, the inventors have newly discovered that Alda-1 can be used in the treatment of hair loss by promoting hair growth through ALDH2 activation. Minoxidil, a potassium channel activator, promotes hair growth by causing hyperpolarization of the cell membrane and dilating blood vessels in hair follicles to increase blood flow. However, due to the strong vasodilatory effect of minoxidil, overuse of minoxidil may instead cause fluid retention and edema. On the other hand, Alda-1 according to the present invention can improve cellular stress by removing cytotoxic aldehydes through the activation of ALDH2, and it has been confirmed that it can suppress oxidative stress in hair follicle cells, which is one of the main causes of hair loss. In particular, the inventors confirmed in experiments using a mouse model of hair loss that Alda-1 could exert an equivalent or greater hair loss treatment effect even when administered at a lower dose than minoxidil, and that the combination of the two drugs could induce hair growth more effectively than using either drug alone. That is, since Alda-1 can achieve an excellent hair growth promoting effect even at low doses, it can not only significantly reduce the risk of side effects due to the overuse of minoxidil, but can also exert a synergistic hair loss treatment effect when used in combination with minoxidil. Furthermore, since it has been confirmed that Alda-1 enhances mitochondrial function in hair follicles and significantly reduces oxidative stress in hair follicles, it may be used for the purpose of preventing, improving, and treating gray hair or alopecia 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 structure shown in Chemical Formula 1 below, but is not limited thereto.

[0101] [ka]

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

[0103] In this 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 produced by modifying Alda-1 and is an ALDH2 activator with higher water solubility and ALDH2 activating effect. Specific information such as the chemical formula structure and properties of compound I-6 can be found in the aforementioned reference.

[0104] In the present invention, "hair loss treatment agent" means a substance that can exert a preventive or therapeutic effect against hair loss directly or indirectly through the formation and growth promotion of hair follicles, induction of the hair growth period, and stress relief of hair follicles. The hair loss treatment agent is sufficient as long as it promotes hair growth or hair development and exerts a preventive or therapeutic effect against hair loss, and is not limited to specific types, but may preferably be selected from minoxidil, finasteride, dutasteride, and pharmaceutically acceptable salts thereof, or analogs thereof. In a preferred embodiment, the hair loss treatment agent is minoxidil or a pharmaceutically acceptable salt thereof.

[0105] Minoxidil, also known by the brand name "Rogaine," is a vasodilator used to treat hair loss. 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, thereby strengthening existing hair and promoting growth. While the specific molecular mechanism by which minoxidil promotes hair growth has not been fully elucidated, it is known that minoxidil induces hair growth by reversing the miniaturization of hair follicles, increasing blood flow around the follicles, stimulating them to enter the growth phase, and extending the growth phase of hair follicles. However, high doses of minoxidil are known to cause side effects such as rash, inflammation, itching, weight gain, edema, and angina. Therefore, the present invention aims to reduce the risk of side effects of minoxidil and provide a superior hair loss treatment effect by using an ALDH2 activator in combination with minoxidil. Specifically, by using an ALDH2 activator in combination with minoxidil, the present invention can exhibit hair loss prevention, hair growth, and hair regeneration promotion effects at a level equivalent to or better than when using a quantitative amount of minoxidil to generally show hair loss prevention or treatment effects, even when using a relatively low concentration of minoxidil. Throughout this specification, "minoxidil" is a concept that includes not only minoxidil itself, but also its salts and 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. Furthermore, the minoxidil of the present invention may be 2(w / v)%, 3(w / v)%, or 5(w / v)% minoxidil. Generally, minoxidil at concentrations of 5% or higher is known to be particularly suitable for use in men, while low-concentration minoxidil of 1-3% is known to be usable in both women and men. The minoxidil may be dissolved in water, distilled water, deionized water, ultrapure water, or DMSO.

[0107] In this invention, the ALDH2 activator includes not only the ALDH2 activator itself, but also all pharmaceutically acceptable salts thereof, analogs thereof, derivatives thereof, etc. For example, "Alda-1" includes Alda-1 itself, as well as pharmaceutically acceptable salts thereof, analogs thereof, or derivatives thereof. The "hair loss treatment agent" of this invention also includes the hair loss treatment agent itself, as well as pharmaceutically acceptable salts thereof, analogs thereof, or derivatives thereof. For example, "minoxidil" is a concept that includes minoxidil itself, as well as pharmaceutically acceptable salts thereof, analogs thereof, or derivatives thereof.

[0108] In this invention, the term "pharmaceutically acceptable salt" includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. Furthermore, such derivatives include pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable anhydrides, pharmaceutically acceptable enantiomers, pharmaceutically acceptable esters, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable complexes.

[0109] Furthermore, as used herein, “pharmaceutically acceptable” means a compound or composition that is suitable for use in contact with the tissues of a subject (e.g., human) without excessive toxicity, irritation, allergic reactions or other problems or complications, and is within the bounds of sound medical judgment.

[0110] Examples of suitable acids include hydrochloric acid, bromate, 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, and benzenesulfonic acid. Acid addition salts may be produced by conventional methods, for example, by dissolving the compound in an excess of an aqueous acid solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone, or acetonitrile. Alternatively, the same molar amount of the compound and an acid or alcohol in water may be heated, and then the mixture may be evaporated and dried, or the precipitated salt may be filtered by suction.

[0111] Salts derived from a suitable base may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. Alkali metal or alkaline earth metal salts can be obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering out the insoluble compound salt, and then evaporating and drying the filtrate. In this case, sodium, potassium, or calcium salts are particularly suitable as metal salts from a pharmaceutical perspective, and corresponding silver salts can be obtained by reacting an 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 may include not only pharmaceutically acceptable salts, but also all isomers, hydrates, and solvates that can be produced by conventional methods.

[0113] The ALDH2 activator according to the present invention may be administered in combination with a hair loss treatment agent. As used herein, "combined administration" means that the individual components of the treatment are administered simultaneously, sequentially, or individually. A combined treatment is defined as a method by which a combined therapeutic effect is obtained by administering two or more drugs simultaneously, sequentially, or alternately at fixed or indefinite intervals, thereby providing a synergistic effect while being therapeutically superior to the effect obtained by administering one or the remaining components of the combined treatment at normal doses, for example, in terms of the degree of response, response rate, time to disease progression, or survival time. For example, the ALDH2 activator of the present invention, when administered in combination with minoxidil, can enhance the hair loss treatment effect of minoxidil or reduce the side effects of minoxidil. The administration (treatment) is a concept that includes injection, oral administration, inhalation, spraying, and topical application.

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

[0115] The present invention provides a pharmaceutical composition for the prevention or treatment of hair loss, further comprising a type II 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, or it may be in a form for simultaneous administration of the ALDH2 activator and minoxidil. For example, the ALDH2 activator and minoxidil may be a single dosage form produced by mixing them with a pharmaceutically acceptable adjuvant, diluent, or carrier. In this case, the ALDH2 activator and minoxidil may each contain various components within their respective drug categories. Furthermore, the single dosage form may be administered separately from such a dosage form together with other preparations containing other therapeutic agents.

[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 combination-administered pharmaceutical composition for simultaneous or sequential administration, comprising a first pharmaceutical composition containing a pharmaceutically effective amount of the ALDH2 activator as an active ingredient, and a second pharmaceutical composition containing a pharmaceutically effective amount of the minoxidil as an active ingredient. In other words, the ALDH2 activator and minoxidil may be provided as separate pharmaceutical dosage forms, 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 depending on the dosage form. In the case of sequential administration, the order of administration is not restricted, and the administration therapy may be appropriately adjusted according to the patient's condition, etc.

[0118] For example, if the pharmaceutical composition is a pharmaceutical composition for combination administration for sequential administration, the composition may be such that 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), the hair loss treatment agent (e.g., minoxidil), and / or pharmaceutically acceptable salts thereof in the composition of the present invention can be appropriately adjusted according to the symptoms of the disease, the progression of the symptoms, the patient's condition, etc., and may be, for example, 0.0001 to 99.9% by weight, or 0.001 to 50% by weight, based on the total weight of the composition, 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 pharmaceutically acceptable salt thereof may be contained in 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 pharmaceutically acceptable salt thereof according to the present invention may be contained in 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 5 mM relative to the total composition. The above-mentioned composition may contain, but is not limited to, concentrations of 2 mM, 0.0001-1 mM, 0.0005-10 mM, 0.001-10 mM, 0.005-10 mM, 0.01-10 mM, 0.05-10 mM, 0.1-10 mM, 0.5-10 mM, 1-30 mM, 1-20 mM, 1-15 mM, 1-10 mM, 1-9 mM, 1-8 mM, 1-7 mM, 1-6 mM, or 1-5 mM.

[0121] In other words, the composition of the present invention may contain an ALDH2 activator or a pharmaceutically acceptable salt thereof in such a concentration that the ALDH2 activator or a pharmaceutically 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 requiring it. That is, in the present invention, the ALDH2 activator or a pharmaceutically acceptable salt thereof may be administered (to an individual requiring it) 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 also be in the form of a liquid formulation. When the composition of the present invention is a liquid formulation, the ALDH2 activator or a pharmaceutically acceptable salt thereof may be included at a concentration of 0.0001 to 50 mM relative to the total liquid formulation. Furthermore, the liquid formulation may be administered in volumes 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 a time of single administration (application), but is not limited thereto.

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

[0124] Furthermore, the composition of the present invention may contain a hair loss treatment agent or a pharmaceutically acceptable salt thereof in such a content that, when administered or applied once to an individual requiring it, the hair loss treatment agent or a pharmaceutically acceptable salt thereof is administered (applied) at a concentration of 0.0001 to 10 (w / v)% of the total composition (or solvent). That is, in the present invention, the hair loss treatment agent or a pharmaceutically acceptable salt thereof may be administered (to an individual requiring it) at a concentration of 0.0001 to 10 (w / v)% of 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 if the composition according to the present invention is a liquid formulation, the hair loss treatment agent (e.g., minoxidil) or a pharmaceutically acceptable salt thereof may be contained at a concentration of 0.0001 to 10 (w / v)% of the total liquid formulation, but is not limited thereto. Furthermore, the liquid formulation may be administered in a single dose (application) 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, but is not limited thereto.

[0126] The ALDH2 activator: hair loss treatment agent of the present invention (e.g., minoxidil, its analogues, or pharmaceutically acceptable salts thereof) may be used in combination in a weight ratio of 1:0.01 to 100, but is not limited thereto. Specifically, the ALDH2 activator: minoxidil may be used in a weight 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 in weight ratios of 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, but are not limited to these.

[0127] Furthermore, when the ALDH2 activator and the hair loss treatment agent of the present invention are used in combination in the form of liquid formulations, the liquid formulations may be mixed and used in combination in the form of a mixed formulation. The mixed formulation may be manufactured, for example, by mixing a liquid formulation containing the ALDH2 activator at a concentration of 0.0001 to 50 mM with a liquid formulation containing the hair loss treatment agent at a concentration of 0.0001 to 10 (w / v)%. Here, the liquid formulation containing the ALDH2 activator and the liquid formulation containing the hair loss treatment agent may be mixed in a volume ratio of 1:0.1 to 10, 1:0.1 to 5, 1:0.1 to 2, 1:0.1 to 1.5, 1:0.1 to 1, 1:0.5 to 5, 1:0.5 to 2, 1:0.5 to 1.5, or 1:1, but is not limited thereto. Furthermore, the mixed formulation may be administered in the following volumes per single dose (application or treatment): 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, but is not limited to these volumes.

[0128] The aforementioned treatment concentrations and volumes of the ALDH2 activator and hair loss treatment agent 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 specific types, and those skilled in the art may select appropriate doses, concentrations, and mixing ratios based on the common technical knowledge of the industry, taking into consideration the drug treatment route, treatment method, types of drugs used in combination, the condition of the target body, etc.

[0129] Preferably, the composition according to the present invention can satisfy at least one feature selected from the group consisting of the following: (a) promotes proliferation (or cell division) of dermal papilla cells and / or outer root sheath; (b) promotes hair follicle growth (i.e., promotes the growth or cell division of cells within the hair follicle); (c) induces the hair growth phase (anagen); and (d) increases mitochondrial activity.

[0130] Preferably, the compositions according to the present invention can increase 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).

[0131] Preferably, the composition according to the present invention can reduce oxidative stress in dermal 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. The excipient may be at least one selected from the group consisting of, for example, diluents, binders, disintegrants, lubricants, adsorbents, humectants, film-coating materials, and controlled-release additives.

[0133] The pharmaceutical compositions according to the present invention may be used in the form of external preparations such as powders, granules, sustained-release granules, enteric-coated granules, liquids, eye drops, elsilics, emulsions, suspensions, alcoholic preparations, lozenges, aromatic preparations, limonades, tablets, sustained-release tablets, enteric-coated tablets, sublingual tablets, hard capsules, soft capsules, sustained-release capsules, enteric-coated capsules, pills, tinctures, softened extracts, dried extracts, liquid extracts, injections, capsules, perfusion solutions, ointments, lotions, pastes, sprays, inhalants, patches, sterile injections, or aerosols, respectively, by conventional methods. The external preparations may also have dosage forms such as creams, gels, patches, sprays, ointments, ointments, lotions, liniments, pastes, or cataplasms.

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

[0135] When formulating, the product is typically prepared using fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, or other diluents or excipients.

[0136] Excipients for tablets, powders, granules, capsules, pills, and lozenges according to the present invention include corn starch, potato starch, wheat starch, lactose, sucrose, glucose, fructose, D-mannitol, precipitated calcium carbonate, synthetic aluminum silicate, monocalcium phosphate, calcium sulfate, sodium chloride, sodium bicarbonate, purified lanolin, microcrystalline cellulose, dextrin, sodium alginate, methylcellulose, sodium carboxymethylcellulose, kaolin, urea, colloidal silica gel, hydroxypropyl starch, hydroxypropyl methylcellulose (HPMC) 1928, HPMC 2208, HPMC 2906, HPMC 2910, propylene glycol, casein, calcium lactate, primozel, gelatin, gum arabic, ethanol, agar powder, cellulose phthalate acetate, carboxymethylcellulose, calcium carboxymethylcellulose, glucose, purified water, and sodium casein. Binders such as glycerin, stearic acid, sodium carboxymethylcellulose, sodium methylcellulose, methylcellulose, microcrystalline cellulose, dextrin, hydroxycellulose, hydroxypropyl starch, hydroxymethylcellulose, refined shellac, starch paste, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone may be used. 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-hydroxypropylcellulose, dextran, ion exchange resin, polyvinyl acetate, formaldehyde-treated casein and gelatin, alginic acid, amylose, and guar gum may be used.Gum, baking soda, polyvinylpyrrolidone, calcium phosphate, gelled starch, acacia gum, amylopectin, pectin, sodium polyphosphate, ethylcellulose, sucrose, magnesium aluminum silicate, D-sorbitol solution, 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] Additives to the liquid formulation according to the present invention may 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, ethylcellulose, sodium carboxymethylcellulose, and the like.

[0138] The syrup according to the present invention may contain a solution of sucrose, other sugars, or sweeteners, and may also contain, if necessary, fragrances, colorants, preservatives, stabilizers, suspending agents, emulsifiers, viscosity enhancers, etc.

[0139] Purified water may be used in the emulsion of the present invention, and emulsifiers, preservatives, stabilizers, fragrances, etc. may be used as needed.

[0140] The suspending agent according to the present invention may contain suspending agents such as acacia, tragacantha, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, sodium alginate, hydroxypropyl methylcellulose (HPMC), HPMC1828, HPMC2906, HPMC2910, and, if necessary, surfactants, preservatives, stabilizers, colorants, and fragrances may be used.

[0141] The injectable preparation according to the present invention includes distilled water for injection, 0.9% sodium chloride injection solution, Ringer's injection solution, dextrose injection solution, dextrose + sodium chloride injection solution, PEG (PEG), lactating Ringer's injection solution, solvents such as ethanol, propylene glycol, non-volatile oils - sesame oil, cottonseed oil, peanut oil, soybean oil, corn oil, ethyl oleate, isopropyl myristate, and benzene benzoate, solubilizers such as sodium benzoate, sodium salicylate, sodium acetate, urea, urethane, monoethylacetamide, butazolidinedione, propylene glycol, twins, dijontinamide, 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 buffering agents such as organic compounds, proteins, albumin, peptone, and gums; isotonic agents such as sodium chloride; stabilizers such as sodium bisulfite (NaHSO3), carbon dioxide gas, sodium metabisulfite (Na2S2O5), sodium sulfite (Na2SO3), nitrogen gas (N2), and ethylenediaminetetraacetic acid; sulfurizing agents such as 0.1% sodium bisulfide, sodium formaldehyde sulfoxylate, thiourea, disodium ethylenediaminetetraacetate, and sodium acetone bisulfite; analgesics such as benzyl alcohol, chlorobutanol, procaine hydrochloride, glucose, and calcium gluconate; and suspending agents such as sodium CMC, sodium alginate, Twin 80, and aluminum monostearate.

[0142] Orally administered solid dosage forms include tablets, pills, powders, granules, and capsules. Such solid dosage forms are prepared by mixing the extract with at least one excipient, such as starch, calcium carbonate, sucrose, or lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stylate talc are also used.

[0143] Oral liquid formulations include suspensions, liquid preparations, emulsions, and syrups. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as humectants, sweeteners, fragrances, and preservatives may be included. Parenteral formulations include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.

[0144] The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, “pharmaceutically effective amount” means an amount sufficient to treat the 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, the sensitivity to the drug, the time of administration, the route of administration and the elimination ratio, the duration of treatment, drugs used concurrently, and other factors well known in the medical field. For example, the composition according to the present invention may be administered (applied) once to five times, once to three times, once to twice, or once to an individual who needs it. In this case, the single dose may be adjusted according to the degree of hair loss-related lesions.

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

[0146] Furthermore, the pharmaceutical composition according to the present invention may be administered to an individual requiring it once to ten times, once to five times, once to three times, or once to twice a day, and may be administered at intervals of one to ten days, one to five days, one to three days, or one day, but is not limited thereto.

[0147] The pharmaceutical composition of the present invention may be administered to an individual by various routes. All methods of administration are predictable, but may include, for example, oral administration, subcutaneous injection, intraperitoneal administration, intravenous injection, intramuscular injection, perispinal space (intradural) injection, sublingual administration, buccal administration, rectal insertion, vaginal insertion, ocular administration, ear administration, nasal administration, inhalation, spraying through the mouth or nose, skin administration, transdermal administration, etc.

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

[0149] In this invention, "individual" means a subject requiring treatment for a disease, and more specifically, mammals such as humans or non-human primates, mice, rats, dogs, cats, horses, and cattle.

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

[0151] In the present invention, "prevention" means all actions that suppress or delay the onset of a desired disease; "treatment" means all actions that improve or beneficially alter the symptoms of a desired disease and associated metabolic disorders by administering a pharmaceutical composition according to the present invention; and "improvement" means all actions that reduce parameters related to a desired disease, such as the severity of symptoms, by administering a composition according to the present invention.

[0152] Furthermore, the present invention provides a cosmetic composition for preventing or improving hair loss or graying 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, preventing or improving gray hair means suppressing hair discoloration and maintaining its original color, and such effects can be achieved, in particular, through maintaining the function and number of melanocytes.

[0155] The cosmetic composition according to the present invention may take the form of a skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nourishing lotion, massage cream, nourishing cream, mist, moisturizing 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 a topical skin preparation such as a scalp treatment, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid preparation, solution, emulsion, dispersant, micelle, liposome, ointment, lotion, essence, patch, or spray.

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

[0158] In addition to the essential components mentioned above, the cosmetic composition of the present invention may also contain other components commonly used in cosmetics, as needed.

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

[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 purpose and effects of the present invention, but they may be added at a weight of 0.01-5% or 0.01-3% of 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, tracant, 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 a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as the carrier component, and especially when it is a spray, it may further contain propellants such as chlorofluorohydrocarbon, propane / butane, or dimethyl ether.

[0163] When the dosage form of the present invention is a solution or emulsion, a solvent, solvating agent, or emulsifying agent is used as the carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol, or fatty acid ester 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, or polyoxyethylene sorbitan ester; or microcrystalline cellulose, aluminum methhydroxyl, bentonite, aga, or tracant.

[0165] When the dosage form of the present invention is a surfactant-containing cleanser, the carrier component may be an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinate monoester, isethionic acid, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide ether sulfate, alkylamide betaine, aliphatic alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, or ethoxylated glycerol fatty acid ester.

[0166] Furthermore, the composition according to the present invention may be provided in the form of a quasi-drug composition. In the present invention, "quasi-drug" means a product used for the treatment, alleviation, management, or prevention of diseases in humans or animals, which has a minor effect on the human body or does not have a direct effect on the human body.

[0167] In addition to the components described above, the quasi-drug composition of the present invention may further contain, as necessary, pharmaceutically acceptable carriers, excipients, or diluents. The pharmaceutically acceptable carriers, excipients, or diluents are not limited as long as they do not affect the effects of the present invention, and may include, for example, fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants, sweeteners, fragrances, preservatives, and the like.

[0168] Typical 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, acacia gum, alginate, calcium phosphate, calcium carbonate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, propylene glycol, polyethylene glycol, vegetable oil, injectable esters, whetepsol, macrogol, twin 61, cocoa butter, lauric acid butter, and the like.

[0169] When the composition of the present invention is provided as a topical preparation, it may be in the form of a liquid, ointment, patch, gel, cream, or spray, but is not limited thereto. According to one embodiment of the present invention, the quasi-drug of the present invention may include oral care products including toothpaste, mouthwash, and mouth spray, as well as 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 the usual techniques known in the art.

[0170] The present invention also provides a food composition for preventing or improving hair loss or graying hair, comprising a type 2 aldehyde dehydrogenase 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, its analogues, or a food-grade salt thereof.

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

[0172] When the ALDH2 activator of the present invention is used as a food additive, it may be added as is, or used together with other foods or food components, or used appropriately by conventional methods. The amount of active ingredient mixed may be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment). In general, when manufacturing food or beverages, 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, relative to the raw materials. However, in the case of long-term intake for health and hygiene purposes, or for health regulation purposes, the amount may be less than the above range, and there are no safety issues, so the active ingredient may be used in amounts greater than the above range.

[0173] There are no particular restrictions on the types of food products to which the substance may be added. Examples of foods to which the substance may be added include meats, sausages, bread, chocolates, candies, snacks, confectionery, pizzas, ramen noodles, other noodle products, gums, 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 beverage composition according to the present invention may contain various flavorings or natural carbohydrates as additional ingredients, as in ordinary beverages. The aforementioned natural carbohydrates include 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, or 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 foregoing, the composition of the present invention may contain various nutrients, vitamins, electrolytes, flavorings, colorings, pectinic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, and the like. Furthermore, the composition of the present invention may contain fruit pulp for the production of natural fruit juices, fruit juice beverages, and vegetable beverages. These components may be used independently or in combination. The proportion of such additives is not particularly important, but it is generally selected from a 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, "health functional foods" is the same term as "foods for special health use (FoSHU)," and refers to foods with high medical and therapeutic effects that are processed to efficiently exhibit biological regulatory functions in addition to providing nutrients. The said foods may be manufactured in various forms such as tablets, capsules, powders, granules, liquids, or pills in order to obtain effects useful for preventing or improving hair loss.

[0177] The health functional food of the present invention can be manufactured by methods commonly used in the industry, and during such manufacturing, raw materials and ingredients commonly added in the industry may be added. Furthermore, unlike general pharmaceuticals, it has the advantage of being made from food as a raw material and not having the side effects that may occur when pharmaceuticals are taken long-term, and it is highly portable.

[0178] The following are preferred embodiments to aid in understanding the present invention. However, these embodiments are provided to facilitate understanding of the present invention and do not limit the scope of the present invention. [Examples]

[0179] Example 1. Induction of cell division and activation of human hair follicle-derived dermal papilla cells and outer root sheath cells by ALDH2 activation. To evaluate the effects 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 either 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 that, each cell was treated with the CCK8 reagent and reacted at 37°C for 15 minutes. Subsequently, absorbance was measured at 450 nm using a luminometer, and the degree of cell proliferation was confirmed by comparing it with the negative control group and the positive control group (minoxidil).

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

[0181] Example 2. Confirmation of the effect of ALDH2 activation on promoting human hair follicle growth through human hair follicle organ culture tests. To evaluate the effect of ALDH2 activation on human hair follicle growth, an ex vivo hair follicle organ culture (EX) study was conducted. For the EX study, scalp tissue obtained from volunteers was isolated at the follicle level. The lower part of the sebaceous gland was removed from the isolated follicles, and the remaining follicles were used. The prepared follicles were cultured in a culture medium containing a negative control reagent and either 1 μM minoxidil or 5, 25, or 50 μM Alda-1 (ALDH2 activator). The length of the hair grown was measured on days 3 and 6, and compared with the negative control group to confirm the hair growth promoting effect of the ALDH2 activator on human hair follicles.

[0182] As a result, as shown in Figure 2a, it was confirmed that ALDH2 was activated in the group treated with Alda-1, thereby promoting hair elongation in human hair follicles. In particular, Alda-1 was shown to enhance hair growth in hair follicles to a higher level compared to minoxidil.

[0183] Furthermore, to confirm cell proliferation in the hair follicles cultured through the above-mentioned tests, immunofluorescence staining was performed using the Ki-67 antibody, a cell division marker. Hair follicles cultured for 2 days after being treated with a negative control group, 1 μM minoxidil, or Alda-1 were prepared as tissue sections, cut into 4 μm thicknesses, and fixed to slides. After treatment with a primary antibody for Ki-67 and a secondary antibody conjugated with a fluorescent protein to detect Ki-67, the cells were observed under a fluorescence microscope, photographs were taken, and the number of Ki-67-positive cells was confirmed. The 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 above, the activation of ADLH2 in hair follicles treated with Alda-1 increased the level of Ki-67-positive cells, i.e., cells in division (proliferation), and it was found that the effect of Alda-1 is even superior to that of minoxidil.

[0185] These results indicate that ALDH2 activation promotes cell proliferation in human hair follicles, thereby stimulating hair growth.

[0186] Example 3. Confirmation of the effect of ALDH2 activation on inducing hair growth during the growth phase. To confirm the effect of ALDH2 activation on hair growth, we investigated the effect of inducing the growth phase of hair growth using the C57BL / 6 mouse model. While the hair cycle differs among individuals in humans, in mice, all hair cycles are the same in the early stages of life. At 7-8 weeks of age, all hair enters the resting phase, and then transitions to the growth phase. To evaluate the effect of ALDH2 activators on inducing the growth phase using these characteristics of mice, we removed the back hair of 8-week-old C57BL / 6 mice in the resting phase, and then applied the ALDH2 activator Alda-1 at doses of 0.5 mM or 3 mM once daily for 3 weeks. We then compared the results with a negative control group and a positive control group (minoxidil 2% by weight; 111 mM) to confirm the presence or absence of hair growth and the degree of induction of the growth phase.

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

[0188] Furthermore, skin tissue with elongated growth hair was fixed with paraffin and stained with hematoxylin and eosin for histological examination. As a result, as shown in Figure 4, it was confirmed that hair follicle formation was promoted in the Alda-1 treated group, similar to the positive control group treated with minoxidil.

[0189] Furthermore, measurements of the degree of growth induction and skin thickness in each mouse revealed, as shown in Figures 5a and 5b, that the growth induction score (Anagen induction score) and skin thickness increased in the ALDH2 activator-treated group compared to the control group.

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

[0191] Example 4. Confirmation of the effect of ALDH2 activation on regulating hair growth-promoting proteins. 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 growth, we examined changes in the protein levels of hair growth factors induced by ALDH2 activation using human dermal papilla cells. For this purpose, we performed enzyme-linked immunosorbent assay (ELISA). Dermal papilla cells cultured in the laboratory were treated with either a negative control group or the ALDH2 activator Alda-1 for 24 hours, after which the cell culture medium was collected and concentrated. The levels of growth factor proteins were then examined in the concentrated culture medium.

[0192] As a result, as shown in Figure 6, it was confirmed that the levels of proteins such as 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 as hair growth promoting factors, increased in samples treated with the activator by ALDH2.

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

[0194] Example 5. Confirmation of reduction in oxidative stress in human hair follicle-derived dermal papilla cells and outer root sheath cells by ALDH2 activation. Oxidative stress in hair follicle cells is known to inhibit hair follicle and hair growth, and adversely affect hair loss. Therefore, to evaluate the effect of ALDH2 activation on oxidative stress in hair follicle cells, human hair follicle-derived dermal papilla cells and outer root sheath cells were treated with Alda-1, an ALDH2 activator, and DCFDA (2',7'-dichlorofluorescin diacetate) analysis was performed to confirm the degree of oxidative stress. The level of oxidative stress was increased by treating each group of cultured cells with H2O2, and DCFDA expression was observed after treating the experimental group with the ALDH2 activator Alda-1 at concentrations of 5, 25, or 50 μM for 3 hours. DCFDA expression was also confirmed by flow cytometry using the same experiment.

[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 oxidative stress was reduced by the ALDH2 activator. In particular, a tendency for oxidative stress to decrease in proportion to the Alda-1 treatment concentration was observed, confirming that the ALDH2 activator has a very excellent effect in reducing oxidative stress in hair follicle cells. Flow cytometry results also showed a significant decrease in oxidative stress in outer root sheath cells in proportion to the Alda-1 treatment concentration (Figures 8a and 8b).

[0196] These results indicate that activating ALDH2 can reduce the risk of hair loss by decreasing oxidative stress on hair follicle cells, which is one of the main causes of hair loss, and can also promote hair growth.

[0197] In particular, these results suggest that activation of type II aldehyde dehydrogenase may contribute not only to hair growth but also to the suppression of gray hair. Specifically, gray hair is mainly caused by a decrease in pigment production due to the 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, damaging the antioxidant system and inducing 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. Through the above examples, the inventors have confirmed that the activation of type 2 aldehyde dehydrogenase is a mechanism that significantly reduces oxidative stress in human hair follicle cells. Therefore, when treated with a type 2 aldehyde dehydrogenase activator, the reactive oxygen species generated during the activation process of melanocytes are reduced, and the occurrence of gray hair due to damage to melanocytes and aging can be effectively suppressed.

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

[0201] The results are shown in Figures 9a-9b (fluorescence images: (VDAC, green fluorescence; ALDH2, red fluorescence; DAPI, blue fluorescence)). While resting hair follicles were observed in the tissues of hair loss patients, growing hair follicles were observed in the tissues of healthy individuals. In human hair follicles, mitochondrial outer membrane markers and type 2 aldehyde dehydrogenase were located at the same position. Furthermore, it was confirmed that type 2 aldehyde dehydrogenase expression was higher in outer root sheath cells than in dermal papilla cells. Similarly, when the proportion of type 2 aldehyde dehydrogenase-expressing cells located in the outer root sheath cells was re-examined, a significant increase was confirmed in growing hair follicles (Figure 9b).

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

[0203] Example 7. Confirmation of changes in mitochondrial activity in human hair follicle-derived outer root sheath cells. To confirm the changes in mitochondrial activity induced by type 2 aldehyde dehydrogenase activity in human hair follicle-derived outer root sheath cells, the oxygen consumption rate was measured. Outer root sheath cells were placed in XF96 plates, 5 × 10³ cells per well. The control group was treated with DMSO, and the experimental group was treated with Alda-1 (25 μM). After 12 hours, the oxygen concentration dissolved in the culture medium during cell culture was measured using a real-time cell metabolism analyzer (Seahorse XFE96 Analyzer). 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 for 60 minutes at 37°C under CO2-free conditions. After sequentially injecting oligomycin (1.5 μM), FCCP (1.5 μM), and rotenone / antimycin A (final concentration of 0.5 μM each) into an XF96Plate port, the oxygen consumption rate of outer root sheath cells was measured.

[0204] As a result, as shown in Figure 10a, the activation of type II aldehyde dehydrogenase after Alda-1 treatment increased the oxygen consumption rate of outer root sheath cells, confirming an increase in mitochondrial activity. Furthermore, outer root sheath cells treated with Alda-1 showed a significant increase in basal respiration (Figure 10b) and a remarkable increase in maximal respiration (Figure 10c). In addition, mitochondrial ATP production increased nearly tenfold after Alda-1 treatment (Figure 10d).

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

[0206] As mentioned above, it has been confirmed that activating ALDH2 can achieve excellent hair growth and hair regeneration effects, and it is expected that various ALDH2 activators will be used as agents for preventing, improving, and / or treating hair loss. In particular, Alda-1 according to one embodiment of the present invention has been confirmed to be able to effectively induce hair follicle and hair growth even at a much smaller dose compared to minoxidil, a conventional hair loss treatment agent, and is therefore expected to be used as a safer and more economical hair loss treatment agent.

[0207] Furthermore, it was confirmed that ALDH2 activation and mitochondrial interaction in hair follicles can contribute to inducing the growth phase of hair follicles and promoting hair growth. 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 can also effectively suppress the occurrence of gray hair.

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

[0209] Specifically, to confirm the hair growth effect of the ALDH2 activator Alda-1 and minoxidil in combination, we examined whether the hair growth phase was induced after applying the two substances in combination to a C57BL / 6 mouse model. After shaving the back hair of 8-week-old C57BL / 6 mice in the resting phase, Alda-1 and / or minoxidil were applied to the following groups: an untreated group, an Alda-1 (3mM) monotherapy group, a 2% minoxidil monotherapy group, and an Alda-1 3mM and 2% minoxidil combination therapy group. The combination therapy group applied a mixture of 3mM Alda-1 and 2% minoxidil. In the mixture, Alda-1:minoxidil was mixed in a weight ratio of 1:37. In both the monotherapy and combination therapy groups, the drug was applied at a dose of 200 μl per application. Each drug or a mixture of drugs was applied to the back of mice once daily for three weeks, and the presence or absence of hair growth and the degree of induction of hair growth were confirmed by comparing them with a control group.

[0210] As a result, as shown in Figure 11, hair growth was observed in mice treated with each drug alone or in combination compared to the control group. In particular, the group treated with Alda-1 and minoxidil showed significantly wider hair growth during the growth phase compared to the group treated with each drug alone.

[0211] Furthermore, when skin tissue with growing hair was fixed with paraffin and Versican, a marker for dermal papilla cells involved in hair formation and growth, was identified through immunofluorescence staining, a much stronger signal was detected in the group treated with both Alda-1 and minoxidil compared to the group treated with Alda-1 or minoxidil alone, confirming a significant increase in the number of dermal papilla cells.

[0212] These results indicate that Alda-1 itself has excellent hair loss treatment effects, and especially when used in combination with minoxidil, its effects on inducing hair growth and promoting hair follicle formation are further enhanced, resulting in a synergistic hair loss treatment effect.

[0213] As mentioned above, it has been confirmed that activating ALDH2 can achieve excellent hair growth and hair regeneration effects, and it is expected that various ALDH2 activators will be used as agents for preventing, improving, and / or treating hair loss. In particular, Alda-1 according to one embodiment of the present invention has been confirmed to be able to effectively induce hair follicle and hair growth even at a much smaller dose compared to minoxidil, a conventional hair loss treatment agent, and is therefore expected to be used as a safer and more economical hair loss treatment agent.

[0214] Furthermore, it has been confirmed that when ALDH2 is used in combination with minoxidil, hair follicle formation and hair growth are increased even more significantly than when each drug is used alone. Therefore, it is possible to achieve a superior hair loss treatment effect by using ALDH2 in combination with minoxidil. In particular, when using ALDH2 of the present invention, the amount of minoxidil used, which may have side effects, can be reduced, so it is expected that a safer and more effective hair loss treatment will be possible.

[0215] The above-mentioned description of the present invention is illustrative, and a person with ordinary skill in the art to which the invention pertains will understand that it can be readily modified into other specific forms without altering the technical idea or essential features of the invention. Therefore, the above-mentioned embodiments should be understood to be illustrative and not limiting in all respects. [Industrial applicability]

[0216] This invention relates to compositions for the prevention, improvement, and / or treatment of hair loss or graying hair (or alopecia), and was completed after confirming that a type 2 aldehyde dehydrogenase (ALDH2) activator promotes hair follicle formation and hair growth, and has an excellent effect in suppressing oxidative stress in hair follicles. Therefore, the ALDH2 activator according to the present invention can be used as a formulation for the prevention, improvement, and / or treatment of hair loss and graying hair. Furthermore, it has been shown that combined treatment of the ALDH2 activator and minoxidil exhibits even better hair loss prevention and treatment effects. Therefore, the ALDH2 according to the present invention is expected to be useful not only in effectively promoting hair growth on its own, but also in medical, cosmetic, and food fields for the prevention, improvement, and treatment of hair loss as a combined formulation with minoxidil.

Claims

1. A pharmaceutical composition for the prevention or treatment of hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient.

2. The pharmaceutical composition according to claim 1, wherein the composition is for promoting hair growth or hair regeneration.

3. The pharmaceutical composition according to claim 1, wherein the hair loss is one or more selected from the group consisting of alopecia areata, hereditary androgen alopecia, telogenous alopecia, traumatic alopecia, trichotillomania, pressure alopecia, anagenous alopecia, seborrheic alopecia, syphilitic alopecia, symptomatic alopecia, scarring alopecia, and congenital alopecia.

4. The pharmaceutical composition according to claim 1, characterized in that the Alda-1 or a pharmaceutically acceptable salt thereof is contained in the composition at a concentration of 0.0001 to 50 mM.

5. The pharmaceutical composition according to claim 1, characterized in that the composition satisfies at least one feature selected from the group consisting of the following. (a) Promote the proliferation of dermal papilla cells or outer root sheath cells. (b) Promotes hair growth. (c) Induces the hair growth phase. (d) Increase mitochondrial activity.

6. The pharmaceutical composition according to claim 1, characterized in that 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.

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

8. A cosmetic composition for preventing or improving hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. The cosmetic composition according to claim 8, characterized in that the composition is in the form of a scalp treatment, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid preparation, solution, emulsion, dispersant, micelle, liposome, ointment, lotion, essence, patch, or spray preparation as a dosage form for external use on the skin.

10. A quasi-drug composition for the prevention or improvement of hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient.

11. A food composition for preventing or improving hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. A health functional food composition for preventing or improving hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A pharmaceutical composition for the prevention or treatment of hair loss, comprising Alda-1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition is administered in combination with minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

14. The pharmaceutical composition according to claim 13, characterized in that the pharmaceutical composition is administered simultaneously with or sequentially with minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

15. The pharmaceutical composition according to claim 13, characterized in that Alda-1 or a pharmaceutically acceptable salt thereof enhances the hair loss treatment effect of minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

16. A pharmaceutical composition for the prevention or treatment of hair loss, comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof as an active ingredient.

17. The pharmaceutical composition according to claim 16, characterized in that the composition is in the form of a mixture comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof.

18. The pharmaceutical composition according to claim 16, characterized in that the composition is formulated in a form in which (a) Alda-1 or a pharmaceutically acceptable salt thereof and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof are each administered simultaneously, individually, or sequentially.

19. A cosmetic composition for the prevention or improvement of hair loss, comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a cosmetically acceptable salt thereof, or an analog thereof as an active ingredient.

20. The cosmetic composition according to claim 19, characterized in that the composition is in the form of a scalp treatment, soap, hair tonic, shampoo, rinse, hair pack, hair gel, lotion, conditioner, hair oil, mousse, cream, solid preparation, solution, emulsion, dispersant, micelle, liposome, ointment, lotion, essence, patch, or spray preparation as a dosage form for external use on the skin.

21. A quasi-drug composition for the prevention or improvement of hair loss, comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof as an active ingredient.

22. A food composition for preventing or improving hair loss, comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a food-chemically acceptable salt thereof, or an analog thereof as an active ingredient.

23. A health functional food composition for the prevention or improvement of hair loss, comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a food-chemically acceptable salt thereof, or an analog thereof as an active ingredient.

24. Use of Alda-1 or a pharmaceutically acceptable salt thereof for the manufacture of agents for the prevention, improvement, or treatment of hair loss.

25. Use of a composition comprising (a) Alda-1 or a pharmaceutically acceptable salt thereof, and (b) minoxidil, a pharmaceutically acceptable salt thereof, or an analog thereof, for the manufacture of an agent for the prevention, improvement, or treatment of hair loss.

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