KR20200126505A - A composition for preventing or treating hair loss comprising marliolide derivatives - Google Patents

Abstract

The present invention relates to a composition for preventing or treating hair loss, comprising a marliolide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The composition of the present invention grows hair by promoting the proliferation of dermal papilla cells.

Description

A composition for preventing or treating hair loss comprising a maliolide derivative {A COMPOSITION FOR PREVENTING OR TREATING HAIR LOSS COMPRISING MARLIOLIDE DERIVATIVES}

The present invention relates to a composition for preventing or treating hair loss comprising a maliolide derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The composition of the present invention grows hair by promoting proliferation of dermal papilla cells.

Around 35 million men and 25 million women worldwide suffer from hair loss, and the number of hair loss patients is increasing every year. Hair has various functions such as appearance, heat insulation, scalp protection, and friction dampening. Among them, since hair is directly related to self-esteem and sociality in particular, concerns such as hair loss and scalp disease are expanding to the interests of everyone, and the importance and interest in this are gradually increasing.

Human hair is an aggregate of about 100,000 individual hairs, each of which is produced by a hair follicle. The hair follicle serves as a reservoir for stem cells that can generate all the cell lines needed to rebuild the follicle itself, the epithelium, and the sebaceous gland. Hair follicles are composed of dermal papilla cells, hair germinal matrix cells, outer walls of hair follicle cells, inner walls, and bulges.

Hair repeats the growth cycle of anagen, catagen and telogen. The growth phase usually lasts for 3 to 5 years, and is a stage in which hair grows by proliferating and keratinizing keratinocytes of the hair cells as the dermal papilla cells and hair cells develop. The degeneration period lasts for 10 to 14 days, and it is a stage in which the hair follicles shrink as overall apoptosis occurs. The resting period is maintained for about 3 to 4 months, and hair generation is stopped, and new cells are supplied to the entire hair follicle to prepare for the next growth period.

In this way, human hair always maintains a constant number of hairs because it has a constant hair growth cycle. However, as hair loss progresses, the nipples present in the hair root become smaller, and when the hair nipples become smaller, the thickness of the hair hair becomes thinner, and the hair cycle becomes shorter at the same time, and the newly grown hair becomes thinner. Therefore, when hair loss progresses, the hair of the hair turns into fluffy and the hair cycle becomes shorter and grows a little and then falls out.

Hair loss can be largely divided into male-pattern hair loss, female-pattern hair loss, alopecia areata, and telogen effluvium.

The cause of male pattern hair loss is largely a genetic cause, and is related to 5α-reductase. 5α-reductase is an enzyme that converts the male hormone testosterone into 5α-dihydrotestosterone (DHT), a more powerful androgen by reduction of delta 4 and 5, and DHT causes hair loss by shrinking hair follicles. In addition, overproduction of 5α-dihydrotestosterone (DHT) causes various androgenic diseases such as androgenic alopecia, benign prostate cancer, and acne.

Androgenic alopecia (AGA) is the most important type of scalp alopecia, affecting about two-thirds of the world's population, and affects 50% of men by age 50 and 70% of men after age 50. Reported.

The main cause of female pattern hair loss is an unbalanced secretion of hormones due to childbirth or menopause. Other mental stress in social life, exposure to air pollution, consumption of processed foods, severe illness due to high fever, nutritional imbalance, use of anticancer and antithyroid drugs, administration of oral contraceptives, shampoo, strong ultraviolet rays or sweat during exercise, eating habits, Various habits and environments such as psychological pressure are also known as the main culprit of hair loss.

Currently, finasteride (trade name Propecia ^® ), dutasteride (trade name Avodart ^® ), and minoxidil (trade name Myoxydil ^® or Rogaine ^® ) are the most frequently used hair loss treatments in Korea. Finasteride and dutasteride are 5α-reductase inhibitors that inhibit the conversion of testosterone to 5α-dihydrotestosterone (DHT). However, this product has side effects such as decreased libido, impotence, and loss of driving and performance capabilities. On the other hand, in the case of minoxidil, its mechanism has not yet been fully elucidated, but it is a potassium chaennel opener that hyperpolarizes cell membranes. Through vasodilation and opening of potassium channels, oxygen, blood, nutrients, etc. It is believed to increase the supply and thus make the hair follicles healthy. However, this product also has side effects such as itchiness, erythema, skin irritation, and eye irritation at the application site, and unwanted hair growth is also observed on body parts other than the head. Since the side effects of these existing products amplify patients' anxiety and lead to refusal of administration in severe cases, efforts are being made to develop drugs with less side effects.

Meanwhile, maliolide is a natural product first isolated from the hexane extract of the leaves of Mollinedia marliae. Korean Patent No. 1890058 discloses a composition for preventing, suppressing or treating chronic inflammatory diseases including maliolide derivatives. However, the document does not mention whether maliolide is effective in promoting hair growth and preventing or treating hair loss.

Korean Patent No. 1890058

The present inventors have completed the present invention by confirming that maliolide or maliolide derivatives have excellent effects thereon as a result of researching to develop a therapeutic agent for preventing hair loss or promoting hair growth.

An object of the present invention is to provide a composition for preventing, improving, or treating hair loss comprising maliolide or a maliolide derivative, or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention provides a composition for preventing, improving, or treating hair loss, comprising malioride or a maliolide derivative, or a pharmaceutically acceptable salt thereof as an active ingredient. Maliolide or maliolide derivative is a compound represented by the following formulas 1 to 5. The composition may be a pharmaceutical composition, a cosmetic composition, or a health food composition.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

Maliolide or a maliolide derivative may promote the proliferation of dermal papilla cells, thereby exerting an effect in preventing or treating hair loss.

In one embodiment, the hair loss may be male-type hair loss, female-type hair loss, circular hair loss, telogen hair loss, stress-related hair loss, or hair loss caused by chemotherapeutic agents.

The composition of the present invention can promote the proliferation of dermal papilla cells to promote hair growth or prevent or treat hair loss.

1 shows the growth of dermal papilla cells according to the treatment concentration of maliolide and maliolide derivative.
2 and 3 show the effect of promoting hair growth according to the growth cycle of maliolide in mice.

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

In the entire specification of the present application, when a certain part "includes" a certain constituent element, it means that other constituent elements may be further included rather than excluding other constituent elements unless otherwise stated.

The present invention is characterized in that it was first discovered that maliolide or maliolide derivatives prevent or treat hair loss or promote hair growth. In one embodiment, the maliolide or maliolide derivative of the present invention is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Formula I]

In the above formula, R ₁ is hydrogen, a hydroxyl group, or a 3-methylbutanoate group; R ₂ is C4-18 alkyl, and forms a single bond or a double bond with carbon of an adjacent furan ring.

The compound represented by Formula I is a malioide or malioide in a form in which substituents R ₁ and R ₂ are bonded to (S)-dihydro-5-methylfuran-2(3H)-one represented by the following Formula Ia. It is a lide derivative.

[Formula Ia]

Specifically, the compound represented by Formula I may be one of the compounds represented by the following formula.

In a preferred embodiment, the maliolide or maliolide derivative of the present invention is a compound represented by the following Chemical Formulas 1 to 5. Accordingly, the present invention is a pharmaceutical composition for preventing or treating hair loss comprising a maliolide represented by the following Formula 1 or a maliolide derivative represented by any one of the following Formulas 2 to 5, or a pharmaceutically acceptable salt thereof as an active ingredient Provides.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

In one embodiment, the maliolide or malioride derivative may promote proliferation of dermal papilla cells.

In the present specification, "pharmaceutically acceptable salt" refers to a salt according to an aspect of the present invention that is pharmaceutically acceptable and has a desirable pharmacological activity of a parent compound. The salt is not particularly limited as long as it is pharmaceutically acceptable, and examples include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, maleic acid, succinic acid, methanesulfonic acid. , Benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, and the like can be used.

"Hair loss" of the present invention refers to a state where there is no hair in the area where hair should normally exist, regardless of the cause, and, for example, male-type hair loss, female-type hair loss, circular hair loss, telogen hair loss, stress hair loss , Or hair loss caused by chemotherapy.

The "treatment" of the present invention is to improve hair loss symptoms by delaying or stopping the progression of hair loss by administration of the composition of the present invention, or to beneficially change hair loss symptoms such as promoting hair growth and hair growth, such as lengthening or increasing the number of hair. It means all actions.

The pharmaceutical composition of the present invention can be administered parenterally or orally according to a desired method, and the dosage may be according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and disease severity. Its range is diverse. In addition, the therapeutically effective amount of the composition may vary depending on the method of administration, the target site, and the condition of the patient, and when used in the human body, the dosage should be determined as an appropriate amount in consideration of safety and efficiency.

In one embodiment, the pharmaceutical composition of the present invention, according to a conventional method, respectively, oral formulations such as powders, granules, tablets, soft or hard capsules, suspensions, emulsions, syrups, aerosols, and skin external preparations such as ointments and creams , Suppositories, injections and sterile injectable solutions, etc., can be formulated and used in any form suitable for pharmaceutical preparations.

Excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and diluents commonly used for the formulation may be further included. For example, excipients that may be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate. , Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methylhydroxy benzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like may be used, but are not limited thereto. Further, in addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, and injectable ester such as ethyl oleate may be used. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like can be used.

The composition according to the present invention may be a cosmetic composition. Specifically, the cosmetic composition may be, for example, a cosmetic for hair, and the formulation is not particularly limited, and may be appropriately selected depending on the intended purpose.

For example, the cosmetic composition is formulated as a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, and spray. May be, but is not limited thereto. In more detail, it may be a cosmetic composition for hair such as cleaning agents such as shampoo, conditioner, and body cleanser, hairdressing agents such as hair tonic, gel or mousse, and hair dye or hair dye.

In one embodiment of the present invention, the cosmetic composition may contain a variety of suitable bases and additives as needed, and the types and amounts of these ingredients can be easily selected by the inventor. It may contain acceptable additives as needed, and for example, it may further include components such as preservatives, colors, additives, etc. that are common in the art.

In another embodiment, the composition of the present invention may be a food composition, for example a dietary supplement. The "health functional food" refers to a food manufactured and processed using raw materials or ingredients that have useful functions for the human body, and "functional" is used for health purposes such as controlling nutrients or physiological effects on the structure and function of the human body. Means ingested for the purpose of obtaining a useful effect on.

The formulation of the food composition is not particularly limited, but may be formulated into, for example, a tablet, a granule, a powder, a liquid such as a drink, caramel, a gel, or a bar. In the food composition of each formulation, in addition to the active ingredient, ingredients commonly used in the field may be appropriately selected and blended by a person skilled in the art without difficulty depending on the formulation or purpose of use.

The present invention is to 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]

Effects of Maliolide and Maliolide Derivatives Treatment on the Growth of Human Papillary Cells

Human dermal papilla cells (hDPC) purchased from PromoCell were inoculated into hair follicle dermal papilla cell growth medium (Promocell, Heidelberg, Germany) containing 1% Antibiotic and Antimycotic. Then, cells were prepared by incubating for 3 days in a 5% carbon dioxide incubator at 37°C.

The hDPC prepared in a 96-well plate was inoculated into the hair follicle dermal papilla cell growth medium at a concentration of 1×10 ³ cells/well, and after incubation for overnight, maliolide and its derivatives (Formulas 1 to 5) were added to each concentration (31 , 155 and 310 pg/ml) and incubated for 72 hours.

Then, after removing the culture medium in each well, 10 μL of CCK8 reagent and 90 μL of hair follicle dermal papilla cell growth medium were added and incubated at 37°C for 1 hour, and the absorbance was measured at 450 nm using an ELISA reader. Thus, the degree of cell proliferation was confirmed, and the results are shown in FIG. 1.

As shown in Figure 1, it was confirmed that maliolide and its derivatives (Chemical Formulas 2 to 5) promote the proliferation of dermal papilla cells, and the concentration of maliolide and its derivatives (Chemical Formulas 2 to 5) It was confirmed that it has an effect on proliferation.

[Example 2]

Confirmation of the hair growth promoting effect of maliolide in experimental animals

Since it was confirmed in Example 1 that maliolide promotes the proliferation of dermal papilla cells, it was confirmed that when administered in vivo, the hair cycle was induced from the telogen to the anagen, thereby showing the actual hair growth promoting effect.

Specifically, in order to confirm the effect of promoting hair growth when administering maliolide subcutaneously, a 6-week-old male C3H/HeNCr1jOri mouse was purchased and a negative control (PBS+DMSO), a positive control (minoxidil, 0.1 mg/kg) and horses Lyolide (Chemical Formula 1, 0.01 mg/kg, 0.1 mg/kg) was divided into treatment groups and used in the experiment.

When the mouse was 6 weeks old, in order to check the hair growth effect in the mouse, the hair on the back of the mouse was removed using a mouse clipper.

In order to confirm the hair growth promoting effect upon subcutaneous injection of maliolide, PBS containing maliolide (Chemical Formula 1, 0.01 mg/kg, 0.1 mg/kg) daily subcutaneously on the back of the mouse with hair removed for a total of 13 days Injection injection.

After 17 days, the hairs on the back plate were removed with a mouse clipper, and the weight of the collected hairs was measured and compared with the hair weights of the non-administration control group and the minoxidil-administered control group.

As a result, as shown in FIG. 2, when maliolide was injected subcutaneously, the hair cycle was induced by maliolide to the growth phase, and when visually confirmed, the hair grew significantly compared to the non-administration control group, and the weight of the hair was increased. When measured, it was confirmed that the weight of the hair was about 10 times higher than that of the non-administration control group.

In addition, it was confirmed that hairs were grown at an equivalent level at a small concentration compared to the minoxidil administration control group (FIG. 3).

Therefore, it was confirmed that hair growth is promoted by maliolide, and exhibits an equivalent hair growth effect at a small concentration compared to minoxidil, a representative drug that can promote hair growth and hair growth at present.

Claims (5)

A pharmaceutical composition for preventing or treating hair loss comprising a maliolide represented by the following Formula 1 or a maliolide derivative represented by any one of the following Formulas 2 to 5, or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

The pharmaceutical composition according to claim 1, wherein the hair loss is male-type hair loss, female-type hair loss, circular hair loss, telogen hair loss, stress-related hair loss, or hair loss caused by chemotherapeutic agents.
The pharmaceutical composition of claim 1, wherein the maliolide or maliolide derivative promotes proliferation of dermal papilla cells.
A food composition for preventing or improving hair loss comprising a maliolide represented by the following Formula 1 or a maliolide derivative represented by any one of the following Formulas 2 to 5, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

A cosmetic composition for preventing or improving hair loss comprising a maliolide represented by the following Chemical Formula 1 or a maliolide derivative represented by any one of the following Chemical Formulas 2 to 5, or a pharmaceutically acceptable salt thereof as an active ingredient.
[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

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