KR20230107141A - A composition for treating hair loss comprising gpr40 agonist - Google Patents

Abstract

The present invention relates to a composition for the treatment of hair loss containing a GPR40 agonist, wherein the GPR40 agonist increases the activity of GPR40 to promote the growth of hair follicles or hair, and is thus usefully used for preventing or treating hair loss It can be.

Description

Composition for treating hair loss containing a GPR40 agonist {A COMPOSITION FOR TREATING HAIR LOSS COMPRISING GPR40 AGONIST}

The present invention relates to a composition for treating hair loss comprising a GPR40 agonist. Specifically, the composition of the present invention has an effect of promoting hair growth by increasing the activity of GPR40 by including a GPR40 agonist.

Hair grows, maintains, and falls out through three cycles of anagen, catagen, and telogen. In the anagen period, which is the period during which hair grows, it is known that in the case of adults, hair grows at an average of about 0.3 mm per day, grows at about 1 cm per month, and usually lasts for 3 to 7 years. In general, apoptosis of hair follicle cells occurs for 10 to 14 days after the anagen phase, and the catagen phase, in which hair follicles shrink, and the telogen phase, which is a phase of preparing for the next anagen phase, lasts an average of 3 months. The reason why the length of the hair is different depending on the part is that the duration of the anagen phase, which is a unique feature of the hair follicle, is different for each part.

In this way, since human hair has a certain hair growth cycle, a certain number of hairs is always maintained. However, as hair loss progresses, the dermal papilla present in the hair root becomes smaller, and when the dermal papilla becomes smaller, the thickness of the hair becomes thinner, and at the same time, the hair growth cycle is shortened. Therefore, as hair loss progresses, the hair becomes very thin and the hair growth cycle becomes shorter, so it grows a little and then falls out.

In addition, human hair is an aggregate of about 100,000 individual hairs, and hair is produced by hair follicles. The hair follicle serves as a reservoir of stem cells capable of generating all the cell lines needed to reconstitute the hair follicle itself, the epithelium and the sebaceous gland. Hair follicles are composed of dermal papilla cells (DPC), hair germinal matrix cells, outer root sheath cells (ORS), inner root sheath cells (IRS), and the like.

The outer root sheath cells are cells that help hair growth and development and protect hair, and are in contact with the basal layer, the innermost layer of the epidermal layer. Together with the inner root sheath, it protects the hair generated in the hair bulb, the lower part of the hair follicle, until keratinization is complete, and plays a role in transporting it to the epidermis. The outer root sheath cells are produced by cell division in the vicinity of the hair follicle, and after fulfilling their role by transporting hair to the epidermis, they are separated from the scalp.

Meanwhile, GPR40 (G-protein coupled receptor 40), a G-protein coupled receptor, is a type of receptor that is expressed in pancreatic β cells and activated by fatty acids. Recent research on GPR40 has revealed the mechanism of promoting insulin secretion by free fatty acids. Since activation of GPR40 promotes insulin secretion, it has attracted attention as a target for treatment of type 2 diabetes. However, despite many studies, the roles and functions of GPR40 related to hair growth are not well known.

Accordingly, the present inventors, as a result of efforts to develop a novel hair loss treatment, confirmed that hair growth was promoted when treated with a GPR40 agonist, a G-protein coupled receptor, and completed the present invention.

An object of the present invention is to provide a composition for preventing or treating hair loss comprising a GPR40 agonist.

In addition, an object of the present invention is to provide a composition for preventing or treating hair loss comprising a hair loss treatment agent and a GPR40 agonist. The hair loss treatment agent may be minoxidil or finasteride.

The present invention provides a pharmaceutical composition for preventing or treating hair loss comprising a GPR40 agonist.

The GPR40 agonist may be AMG-837, TAK-875, or TUG-770.

The GPR40 agonist can promote hair growth.

The hair loss is circular hair loss, hereditary androgenetic hair loss, telogen hair loss, traumatic hair loss, hair growth, pressure hair loss, anagen hair loss, pityriatal hair loss, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, congenital hair loss, or drug side effects. It may be due to hair loss.

The composition of the present invention may be administered in combination with a hair loss treatment agent, and may exhibit a more excellent hair growth effect when administered in combination.

In the combined administration of the GPR40 agonist and the hair loss treatment, the GPR40 agonist and the hair loss treatment may be administered simultaneously or sequentially, or may be administered as one formulation or as separate formulations.

The hair loss treatment agent may be minoxidil or finasteride, preferably minoxidil.

The present invention provides a composition comprising a GPR40 agonist for use in preventing or treating hair loss.

The present invention provides the use of a composition comprising a GPR40 agonist for preventing or treating hair loss.

The present invention provides a method for preventing or treating hair loss by administering a GPR40 agonist or a composition comprising the same to a subject having hair loss.

The present invention relates to a composition for the treatment of hair loss containing a GPR40 agonist, wherein the GPR40 agonist increases the activity of GPR40 to promote the growth of hair follicles or hair, and is thus usefully used for preventing or treating hair loss It can be.

1 and 2 show the results of hair growth according to the treatment of three kinds of GPR40 agonists on mouse bristles.
3 and 4 show the results of hair growth according to the treatment of three kinds of GPR40 agonists for mice.
Figure 5 shows the results of hair growth according to the treatment of GPR40 siRNA for mice.
6 and 7 show the results of hair growth according to the combined treatment of a GPR40 agonist and minoxidil for mice.

Hereinafter, with reference to the accompanying drawings, embodiments and examples of the present disclosure will be described in detail so that those skilled in the art can easily practice the present invention. However, the present application may be implemented in various forms and is not limited to the embodiments and examples described herein.

Throughout the present specification, when a part "includes" a certain component, it means that it may further include other components without excluding other components unless otherwise stated.

The present invention relates to a composition for treating hair loss containing a GPR40 agonist, and provides a pharmaceutical composition for preventing or treating hair loss containing a GPR40 agonist.

The GPR40 agonist may be AMG-837, TAK-875, or TUG-770, but is not limited thereto.

The composition of the present invention may be administered in combination with a hair loss treatment agent, and may exhibit a more excellent hair growth effect when administered in combination. In addition, the hair loss treatment and the GPR40 agonist may be simultaneously administered in one formulation or administered simultaneously or sequentially in separate formulations.

The hair loss treatment agent may be minoxidil or finasteride, but is not limited thereto.

Minoxidil induces hair growth promotion by dilating blood vessels and reducing the dormant period of hair roots, and is a hair loss treatment approved by the US Food and Drug Administration (FDA).

Finasteride induces hair loss inhibition by inhibiting the production of dihydrotestosterone (DHT), a hormone involved in hair loss, and is a hair loss treatment approved by the US Food and Drug Administration (FDA).

The hair loss is circular hair loss, hereditary androgenetic hair loss, telogen hair loss, traumatic hair loss, hair growth, pressure hair loss, anagen hair loss, pityriatal hair loss, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, congenital hair loss, or drug side effects. It may be hair loss due to, but is not limited thereto.

The "G-protein coupled receptor 40 (GPR40)" of the present invention is a type of receptor that is expressed in pancreatic beta cells (β-cell) and activated by fatty acids.

In the present invention, "agonist" refers to a substance that acts to increase the expression of a target gene or protein or the activity of a target protein, that is, a gene, protein, compound, etc. is also called

The GPR40 agonist of the present invention may be AMG-837, TAK-875 (Fasiglifam), or TUG-770, but is not limited thereto.

The AMG-837 is (S)-3-(4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methoxy)phenyl)hex-4-ino Iksan, and the structural formula is as follows.

The TAK-875 (Fasiglifam) is (S)-2-(6-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl ]-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid, and the structural formula is as follows.

The TUG-770 is 3-(4-((2-(cyanomethyl)phenyl)ethynyl)-2-fluorophenyl)propanoic acid, and the structural formula is as follows.

In the present invention, "siRNA (small interfering RNA)" means a short double-stranded RNA capable of inducing RNA interference through cleavage of a specific mRNA, and the sugar structure of one or more ribonucleic acids, or base structure, or between the ribonucleic acids. The binding site may be chemically modified.

In the present invention, "hair loss" refers to a state in which there is no hair in an area where hair should normally exist, or a state in which hair is sparse or thinned, regardless of the cause, and includes circular alopecia, hereditary androgenetic alopecia, telogen effluvium, traumatic alopecia, It may be hair growth, pressure alopecia, anagen hair loss, pityriasis hair loss, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss, scarring hair loss, congenital hair loss, or hair loss due to drug side effects, but is not limited thereto.

In the present invention, "hair growth" means that hair grows from a hair follicle, and means that not only the generation of new hair is promoted, but also the existing hair grows healthy, and in the art, the length of the hair is lengthened (i.e., hair growth ) It is used in the same sense as "hair growth" or "wool".

As used herein, the term "prevention" refers to any activity that suppresses or delays the onset of a disease by administration of a composition, and "treatment" means that the symptoms of suspected or affected individuals are improved or advantageously by administration of a composition. It means any action that changes.

The present invention will be described in more detail through the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[Example 1]

Confirmation of hair growth promoting effect according to GPR40 agonist treatment 1

In order to confirm the hair growth promoting effect of the GPR40 agonist, an experiment was performed as follows.

Vibrissae of C57/BL6 female mice were isolated and trimmed to perform organ culture. The trimmed bristles were cultured by inserting one per well in a 96-well plate, divided into a total of 7 groups by dividing the control group and 3 types of GPR40 agonists into 2 concentration treatment groups, respectively, and cultured for 2 days in a 37 ° C incubator. .

As shown in FIGS. 1 and 2, as a result of the bristle culture experiment, it was confirmed that all three types of GPR40 agonists stimulated hair growth.

Therefore, it can be seen that the GPR40 agonist of the present invention has an excellent hair growth effect by promoting hair growth.

[Example 2]

Confirmation of hair growth promoting effect according to GPR40 agonist treatment 2

In order to confirm the hair growth promoting effect on the GPR40 agonist, it was performed as follows.

Twenty-two C3H/HeN mice, 7 weeks old, in a hair telogen state, were shaved as short as possible using a hair removal machine, and the remaining hair was completely removed using a hair remover. After confirming the resting period by checking the condition of the skin of the mouse, etc., the skin was stabilized for one day and used for the experiment.

Experiments were conducted by dividing the positive and negative control groups into 5 animals each, and the experimental group treated with 3 types of GPR40 agonists into 4 animals each. As a positive control group, minoxidil, which is well known for its hair growth effect, was treated at a concentration of 2%. The three types of GPR40 agonists used as the experimental group were treated according to the following concentrations.

- Experiment 1 (AMG-837): 0.03 %

- Experimental group 2 (TAK-875, Fasiglifam): 0.03%

- Experimental group 3 (TUG-770): 0.3%

Each drug was dissolved in a mixed solution composed of propylene glycol, ethanol, and water in consideration of its solubility and absorption into the back skin at the above concentration, and then 100 μL of 100 μL was administered once a day for 14 days. It was evenly applied to the skin of the resting mouse that had been depilated by sheep and followed up. After 14 days, the back of the mouse with newly grown hair was removed with a razor, and the weight of the obtained hair was measured.

As shown in FIGS. 3 and 4, as a result of the mouse hair growth experiment, it was confirmed that all three types of GPR40 agonists stimulated hair growth. In particular, when treated with AMG-837, a better effect was shown compared to the positive control group.

Therefore, it can be seen that the GPR40 agonist of the present invention has an excellent hair growth effect by promoting hair growth.

[Example 3]

Confirmation of the effect of GPR40 on hair growth

In order to confirm the effect of GPR40 on the hair growth effect of Examples 1 and 2, it was performed as follows.

Ten 7-week-old C3H/HeN mice in a hair telogen state were shaved as short as possible using a hair removal machine, and the remaining hair was completely removed using a hair remover. After confirming the resting period by checking the condition of the skin of the mouse, etc., the skin was stabilized for one day and used for the experiment.

The experiment was conducted by distributing 5 animals to each group, and the classification is as follows.

- Group 1 (control group): Scrambeld siRNA treatment group

- Group 2 (experimental group): GPR40 siRNA treatment group

The siRNA used in each experimental group was added to 80 μL of the transfection reagent to be injected at a concentration of 0.6 mg/kg, and then subcutaneously injected into the back skin of mice stabilized after hair removal once every 3 days for a total of 3 times. did Observation of hair growth and growth was carried out for 14 days after the first injection of siRNA, and after 14 days, the back of the mouse with newly grown hair was removed with a razor, and the weight of the hair obtained was measured.

As shown in FIG. 5, as a result of the mouse hair growth experiment, it was confirmed that hair growth was inhibited when the GPR40 siRNA was treated, unlike the control group.

Therefore, it can be seen that GPR40 has an effect on hair growth, and it can be seen that the GPR40 agonist of the present invention exhibits a hair growth effect by activating GPR40.

[Example 4]

Confirmation of the hair growth promoting effect according to the combined treatment of the GPR40 agonist with the hair loss treatment composition

Hair loss treatments such as Minoxidil and Finasteride induce hair growth by increasing nutrient supply to hair cells through vasodilation and opening potassium channels, or by inhibiting the production of DHT to induce hair growth. Although it shows efficacy, hair loss progresses again when it is stopped, so the effect of preventing hair loss is greater than the effect of hair growth, and in particular, there is a problem that side effects such as sexual dysfunction and birth defects in pregnant women may occur. Therefore, in order to confirm the effect of the combined treatment of the hair loss treatment and the GPR40 agonist, an experiment was performed as follows.

Seventeen 7-week-old C3H/HeN mice in a hair telogen state were shaved as short as possible using a hair removal machine, and the remaining hair was completely removed using a hair remover. After confirming the resting period by checking the condition of the skin of the mouse, etc., the skin was stabilized for one day and used for the experiment.

To confirm the combined effect of AMG-837, a GPR40 agonist, and minoxidil, the groups were established as follows.

- Group 1 (control group): drug untreated group

- Group 2: Minoxidil 2% treatment group

- Group 3: AMG-837 0.03% treatment group

- Group 4: Minoxidil 2% + AMG-837 0.03% treatment group

As in Example 2, each drug was dissolved in a mixed solution composed of propylene glycol, ethyl alcohol, and water according to the concentration, and then hair was removed in an amount of 100 μL once a day for 14 days. It was evenly applied to the skin of the resting mouse back and followed up. After 14 days, the back of the mouse with newly grown hair was removed with a razor, and the weight of the obtained hair was measured.

As shown in Figures 6 and 7, as a result of hair growth experiments in mice, hair growth is more promoted when minoxidil and GPR40 agonist (AMG-837) are treated in combination than when minoxidil and GPR40 agonist AMG-837 are treated alone. confirmed that

Therefore, it can be seen that the GPR40 agonist of the present invention has a more excellent hair growth effect when treated in combination with a hair loss treatment agent.

Claims (9)

A pharmaceutical composition for preventing or treating hair loss comprising a GPR40 agonist.
The pharmaceutical composition for preventing or treating hair loss according to claim 1, wherein the GPR40 agonist is selected from the group consisting of AMG-837, TAK-875, and TUG-770.
The pharmaceutical composition for preventing or treating hair loss according to claim 1, wherein the GPR40 agonist promotes hair growth.
The pharmaceutical composition for preventing or treating hair loss according to claim 1, characterized in that it is administered in combination with a hair loss treatment agent.
The pharmaceutical composition for preventing or treating hair loss according to claim 4, wherein the hair loss treatment agent and the GPR40 agonist can be administered simultaneously or sequentially.
[Claim 5] The pharmaceutical composition for preventing or treating hair loss according to claim 4, wherein the hair loss treatment agent and the GPR40 agonist are administered as one formulation or as separate formulations.
[Claim 5] The pharmaceutical composition for preventing or treating hair loss according to claim 4, wherein the hair loss treatment is minoxidil or finasteride.
[Claim 5] The pharmaceutical composition for preventing or treating hair loss according to claim 4, wherein the hair loss treatment is minoxidil.
The method of claim 1 to claim 8, wherein the hair loss is circular hair loss, hereditary androgenetic hair loss, telogen hair loss, traumatic hair loss, hair growth, pressure alopecia, anagen hair loss, pityroid hair loss, syphilitic hair loss, seborrheic hair loss, symptomatic hair loss , Scarring alopecia, characterized in that selected from the group consisting of congenital alopecia and hair loss due to drug side effects, a pharmaceutical composition for the prevention or treatment of hair loss.

Images