KR102234320B1 - Composition for preventing, improving or treating hair loss comprising apolipoprotein e - Google Patents

Abstract

The present invention relates to a composition for preventing or treating hair loss containing apolipoprotein E (ApoE) or an inducer thereof as an active ingredient, and more particularly, the apolipoprotein E or an inducer thereof is menopausal, ovariectomy or Since it has a significant effect on the improvement of hair loss symptoms due to decreased ovarian function, by using the apolipoprotein E or its inducer as a pharmaceutical composition, a health functional food composition, and a cosmetic composition, the hair loss symptoms more effectively without toxicity or side effects. It can be prevented, improved and cured.

Description

A composition for preventing, improving or treating hair loss containing apolipoprotein E {COMPOSITION FOR PREVENTING, IMPROVING OR TREATING HAIR LOSS COMPRISING APOLIPOPROTEIN E}

The present invention relates to a pharmaceutical composition for preventing, improving or treating hair loss, including apolipoprotein E, a health functional food composition, and a cosmetic composition.

Human hair is considered one of the most important aspects of human appearance. Human hair is very important because it not only plays a primary role in protecting the skin and scalp, but also plays a unique role in social and sexual communication. Hair loss refers to a condition in which there is no hair in the area where the hair should normally exist, or refers to a phenomenon in which the hair that has stopped growing naturally falls out, and generally refers to the loss of hair on the scalp (thick black hair). Hair loss is usually 50 to 100 or more per day, and the more hair falls out, the more it is defined as alopecia. Hair loss is a disease that causes emotional pain to humans, and alopecia or alopecia in women faces considerable emotional pain and anxiety.

There are various causes of such hair loss, and genetic causes and hormones are considered important factors, among which estrogen is attracting the most attention as a hormone that increases the risk of female hair loss. Estrogen, a female hormone, plays an important role in activating hair growth factors and inhibiting hair loss factors to make strong hair, but the balance of hormones is disrupted by excessive secretion or deficiency of estrogen, causing hair loss. In particular, when a woman's climacterium or menopause begins, the female hormone secreted from the ovaries decreases due to ovarian function decline and ataxia, which induces various metabolic diseases, including hair loss, and relatively hair loss. The secretion of androgen, a male hormone that causes, increases, further increasing the risk of hair loss.

There are many studies on hair loss in Korea, and in recent years, studies on many regulatory factors involved in hair growth and hair loss mechanisms have been actively conducted. Currently, there are various and many products related to hair growth on the market, but most of the hair loss prevention and hair growth effects are inadequate or temporary, thus failing to meet the needs of users. In addition, the evidence for the efficacy or safety of the product is insufficient, and when the use of the product is discontinued, serious side effects such as recurrence of alopecia or sexual dysfunction are reported, making it difficult to use.

Therefore, there is an urgent need to develop a hair loss treatment that has little toxicity or side effects and has excellent effects.

Korean Patent Publication No. 10-2016-0121122 (published on October 19, 2016)

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating hair loss comprising apolipoprotein E (ApoE) or an inducer thereof.

The present invention provides a health functional food composition for preventing or improving hair loss comprising apolipoprotein E or an inducer thereof.

The present invention provides a cosmetic composition for preventing or improving hair loss comprising apolipoprotein E or an inducer thereof.

In addition, the present invention provides a method for screening a hair loss improving agent using apolipoprotein E.

The pharmaceutical composition for preventing or treating hair loss according to the present invention may contain apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

The health functional food composition for preventing or improving hair loss according to the present invention may contain apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

The cosmetic composition for preventing or improving hair loss according to the present invention may contain apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

A method for screening a hair loss improving agent according to the present invention comprises the steps of treating a test substance in a biological sample isolated from a human body; Measuring the expression level of apolipoprotein E (ApoE) in the sample treated with the test substance; And comparing the expression level with the expression level of apolipoprotein E in a control group not treated with the test substance, and selecting a test substance having an increased expression level of the apolipoprotein E.

Apolipoprotein E (ApoE) or an inducer thereof according to the present invention has a significant effect on relieving symptoms of hair loss due to menopause, ovariectomy or ovarian decline.

By using the apolipoprotein E or its inducer having such an effect as a pharmaceutical composition, a health functional food composition, and a cosmetic composition, it is safe to prevent and improve hair loss symptoms caused by menopause, ovariectomy or ovarian decline without toxicity or side effects. And can be treated.

1 shows a change in hair loss in a mouse according to an experimental example of the present invention.

Hereinafter, the present invention will be described in detail.

The present inventor has completed the present invention by confirming that the deficiency of apolipoprotein E accelerates hair loss symptoms due to loss of ovarian function.

In the present specification, "prevention" refers to any action that suppresses the occurrence of at least one or more symptoms of hair loss or hair loss or delays the onset by the use of the pharmaceutical composition, health functional food composition, or cosmetic composition according to the present invention. In addition, it includes treatment of a subject with remission to the disease to prevent or prevent recurrence.

In the present specification, "treatment" refers to any act of improving or beneficially altering the symptoms, such as alleviating, reducing, or eliminating at least one symptom of hair loss or hair loss by administration of the pharmaceutical composition according to the present invention.

In the present specification, the term "improvement" refers to alleviating, reducing, or eliminating at least one symptom of hair loss or hair loss by the use of the health functional food composition or cosmetic composition according to the present invention. It means an act.

As used herein, "pharmaceutical composition" means a composition administered for a specific purpose, and for the purposes of the present invention, it means that it is administered to prevent or treat at least one symptom of hair loss or hair loss.

In the present specification, "health functional food" refers to foods manufactured and processed using raw materials or ingredients having useful functions for the human body, and foods with high medical and medical effects processed so that the biological control function is effectively displayed in addition to supplying nutrition. It means and can be mixed with terms known in the art, such as functional food.

In the present specification, the term "cosmetics" may include functional cosmetics having an effect of improving hair loss, and the functional cosmetics are cosmetics emphasizing specific effects and effects as defined in the Cosmetics Act, which helps to improve the weakening of the function of the hair or It may include alleviating symptoms of hair loss, and the like.

The present invention provides a pharmaceutical composition for preventing or treating hair loss containing apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

In the present invention, "Apolipoprotein E (ApoE)" is a type of protein involved in the metabolism of fat in the body. Like other apolipoproteins, there are 22 amino acid repetitive sequences in the molecule, and thus bipolar helices (amphipathic helices) And can bind to the surface of plasma lipoproteins. Apolipoprotein E contains basic amino acid residues (136-150), so it binds well to the low density lipoprotein receptor (LDL-R), and these structures are important for endocytosis of lipoprotein particles. Plays a role.

In addition, apolipoprotein E can be synthesized not only in hepatocytes but also in macrophages and astrocytes, and triglyceride-rich chylomicron and ultra-low-density lipoproteins ( Because it plays an important role in lipoprotein metabolism by promoting the absorption of the remnant of VLDL) into the cell, knockout mice (ApoE-/-) deficient in apolipoprotein E (ApoE-/-) eat a high-fat diet. , Causes extreme hypercholesterolemia.

In the pharmaceutical composition according to the present invention, the apolipoprotein E may have a significant effect in improving hair loss symptoms. According to an experimental example of the present invention, the mouse deficient in the apolipoprotein E was found to further promote hair loss symptoms due to the decrease in ovarian function.

In the pharmaceutical composition according to the present invention, the inducing agent may be a miRNA or compound capable of inducing the apolipoprotein E and increasing its expression, but is not limited thereto.

The inducing agent may include, for example, a compound such as AZ10606120 or AZD9056. AZ10606120, known as an antagonist with high affinity for P2X7, a purinergic receptor, can increase the expression of apolipoprotein E (Sci Rep 7:725). In addition, AZD9056, a similar P2X7 antagonist, can also increase the expression of apolipoprotein E, and thus can be used as the inducer. AZD9056 is currently being used in phase 2 clinical trials to treat rheumatic arthritis, osteoarthritis, chronic obstructive pulmonary disease, and Crohn's disease (Ann Rheum Dis 71:1630). -1635).

In the pharmaceutical composition according to the present invention, the apolipoprotein E or an inducer thereof may include functional equivalents and variants of the protein. The functional equivalent of the protein includes proteins and polypeptides that do not change the activity of the protein molecule as a whole, and proteins capable of functionally identical functions may be included. In addition, the variant refers to, for example, deletion, substitution, or addition of one or several amino acids in the amino acid sequence, 95% or more, preferably 98% or more, more preferably 99% or more identity with the amino acid sequence. It refers to having, etc.

In the pharmaceutical composition according to the present invention, the hair loss may be menopausal, ovarian resection, or hair loss due to ovarian deterioration. That is, the hair loss may include hair loss in menopausal women due to menopause, as well as in estrogen deficiency patients due to other causes such as ovariectomy or ovarian function decline.

The pharmaceutical composition according to the present invention can be prepared according to a conventional method in the pharmaceutical field.

The pharmaceutical composition according to the present invention may be blended with an appropriate pharmaceutically acceptable carrier according to the above formulation, and further includes excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc., if necessary. It can be manufactured by doing.

The "pharmaceutically acceptable" means that it is not toxic to cells or humans exposed to the pharmaceutical composition, and the appropriate carrier or the like does not inhibit the activity and properties of apolipoprotein E or its inducer according to the present invention. It may be selected differently depending on the dosage form and formulation.

The pharmaceutical composition according to the present invention may be applied in any dosage form, and more particularly, may be formulated and used in parenteral dosage forms of oral dosage forms, external preparations, suppositories, and sterile injectable solutions according to a conventional method.

Among the oral dosage forms, the solid dosage form is in the form of tablets, pills, powders, granules, capsules, etc., and at least one excipient such as starch, calcium carbonate, sucrose, lactose, sorbitol, mannitol, cellulose, gelatin, etc. It can be prepared by mixing, and in addition to simple excipients, lubricants such as magnesium stearate and talc may also be included. In addition, in the case of the capsul formulation, in addition to the above-mentioned substances, a liquid carrier such as fatty oil may be further included.

Among the oral dosage forms, liquid dosage forms correspond to suspensions, liquid solutions, emulsions, syrups, and the like.In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, preservatives, etc. may be included. have.

The parenteral formulation may include a sterilized aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized formulation, and a suppository. As the non-aqueous solvent and suspension, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like may be used. As a base for suppositories, witepsol, macrogol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used. The present invention is not limited thereto, and any suitable agent known in the art may be used.

In addition, the pharmaceutical composition according to the present invention may further add _{calcium or vitamin D 3 to improve therapeutic efficacy.}

In the pharmaceutical composition according to the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount. The "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects.

The effective dosage level of the pharmaceutical composition is the purpose of use, the age, sex, weight and health condition of the patient, the type of disease, the severity, the activity of the drug, the sensitivity to the drug, the method of administration, the administration time, the administration route and the rate of excretion, the treatment It can be determined differently depending on the duration, factors including the combination or co-used drugs and other factors well known in the medical field. For example, although not constant, generally 0.001 to 100 mg/kg, preferably 0.01 to 10 mg/kg may be administered once to several times a day. The above dosage does not in any way limit the scope of the present invention.

The pharmaceutical composition according to the present invention may be administered to any animal that may cause hair loss, and the animal may include, for example, humans and primates as well as livestock such as cattle, pigs, horses, and dogs.

The pharmaceutical composition according to the present invention may be administered by an appropriate route of administration according to the form of the formulation, and may be administered through various routes, either oral or parenteral, as long as it can reach the target tissue. The method of administration is not particularly limited, and may be administered by conventional methods such as, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrabronchial inhalation, intrauterine dura mater or intracere-broventricular injection. .

The pharmaceutical composition according to the present invention may be used alone to prevent or treat hair loss, or may be used in combination with surgery or other drug treatment.

The present invention provides a health functional food composition for preventing or improving hair loss containing apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

In the health functional food composition according to the present invention, the hair loss may be hair loss due to menopause, ovarian resection, or ovarian deterioration. That is, the hair loss may include hair loss in menopausal women due to menopause, as well as in estrogen deficiency patients due to other causes such as ovariectomy or ovarian function decline.

In the health functional food composition according to the present invention, the health functional food may be prepared as a powder, granule, tablet, capsule, syrup or beverage, and there is no limitation on the form that the health functional food can take. It can include all foods of meaning. For example, beverages and various drinks, fruits and processed foods thereof (canned fruit, jam, etc.), fish, meat and processed foods thereof (ham, bacon, etc.), bread and noodles, cookies and snacks, dairy products (butter, cheese, etc.) ) And the like, and may include all functional foods in the usual sense. In addition, foods used as feed for animals may also be included.

The health functional food composition according to the present invention may be prepared further comprising a food pharmaceutically acceptable food additive and other appropriate auxiliary ingredients commonly used in the art. For example, flavoring agents, natural carbohydrates, sweetening agents, vitamins, electrolytes, colorants, pectic acids, alginic acids, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents, etc. I can. In particular, as the natural carbohydrates, monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, sugar alcohols such as xylitol, sorbitol, and erythritol may be used. , As the sweetener, natural sweeteners such as taumatin and stevia extract, or synthetic sweeteners such as saccharin and aspartame may be used.

The health functional food composition according to the present invention has the advantage of having no side effects that may occur when taking the drug for a long period of time, unlike general drugs, using food as a raw material, and is excellent in portability, and can be ingested as an adjuvant for preventing or improving hair loss. I can.

The present invention provides a cosmetic composition for preventing or improving hair loss containing apolipoprotein E (ApoE) or an inducer thereof as an active ingredient.

In the cosmetic composition according to the present invention, the hair loss may be hair loss due to menopause, ovarian resection, or ovarian deterioration. That is, the hair loss may include hair loss in menopausal women due to menopause, as well as in estrogen deficiency patients due to other causes such as ovariectomy or ovarian function decline.

The cosmetic composition according to the present invention is a skin external preparation formulation, hair tonic, hair conditioner, hair essence, hair lotion, hair nutrition lotion, hair shampoo, hair rinse, hair treatment, hair cream, hair nutrition cream, hair moisture cream, hair Massage cream, hair wax, hair aerosol, hair pack, hair nutrition pack, hair soap, hair cleansing foam, hair dryer, hair preservation agent, hair dye, hair wave agent, hair bleach, hair gel, hair glaze, hairdresser, hair lacquer , Hair moisturizer, hair mousse, and may be any one formulation selected from the group consisting of hair spray, but is not limited thereto.

In addition, the cosmetic composition according to the present invention may include, without limitation, ingredients that are commonly allowed in addition to the active ingredients, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, And it may include a carrier. In addition, the cosmetic composition may further include a skin absorption accelerator to enhance the effect.

In the cosmetic composition according to the present invention, when the formulation of the cosmetic composition is a paste, cream, or gel, as a carrier component, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, Silica, talc, or zinc oxide may be used.

When the formulation of the cosmetic composition is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additional chlorofluorohydrocarbon, Propellants such as propane/butane or dimethyl ether.

When the formulation of the cosmetic composition is a solution or emulsion, a solvent, a solubilizing agent or an emulsifying agent may be used as a 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.

When the formulation of the cosmetic composition is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxide, bentonite, agar or tracant, and the like may be used.

In addition, the cosmetic composition according to the present invention may be prepared as a hair protection composition including a carrier or a carrier mixture suitable for application to hair. The carrier comprises a carrier component other than a solvent or a vehicle component commonly used in hair care compositions, and is from about 0.5% to 99.5%, preferably from about 5.0% to 99.5%, most preferably from about 0.5% to 99.5% of the composition of the total composition. It may be present at about 10.0% to 90.0%.

The solvent as the carrier may be selected by the copolymer used regardless of whether the formulated hair protection composition remains on the hair after use such as hair spray, mousse, tonic, or the like, or is washed such as shampoo, conditioner, or the like. For example, water, lower alcohols (ethanol, isopropanol, etc.), hydroalcohol mixtures, hydrocarbons (isobutane, hexane, decene, etc.), acetone, halogenated hydrocarbons (freon, etc.), hydrocarbon esters (ethyl acetate, dibutylphthalate, etc.) ), volatile silicone derivatives, siloxanes (phenyl pentamethyl disiloxane, methoxypropyl heptamethyl cyclotetrasiloxane, chloropropyl pentamethyl disiloxane, hydroxypropyl pentamethyldisiloxane, octamethyl cyclotetrasiloxane, decamethyl cyclopentasiloxane, etc.) ) And a mixture thereof, but is not limited thereto.

The present invention provides a method for screening a hair loss improving agent using Apolipoprotein E (ApoE) expression.

The hair loss improving agent screening method is a method of comparing the increase or decrease of the expression level of the protein in the presence and absence of a hair loss improving agent candidate material, and may be usefully used for screening a hair loss improving agent candidate material that improves hair loss symptoms.

A method for screening a hair loss improving agent according to the present invention comprises the steps of treating a test substance in a biological sample isolated from a human body; Measuring the expression level of apolipoprotein E (ApoE) in the sample treated with the test substance; And comparing the expression level with the expression level of apolipoprotein E in a control group not treated with the test substance, and selecting a test substance having an increased expression level of the apolipoprotein E.

In the hair loss improving agent screening method according to the present invention, the biological sample isolated from the human body may include tissues, cells, whole blood, serum, plasma or saliva, etc., in which the expression level of the protein is different from that of the normal control group, It is not limited.

In the method for screening a hair loss improving agent according to the present invention, the test substance is a material used for screening to examine whether it affects the expression level of the protein, and may be a candidate drug for improving hair loss symptoms, that is, a hair loss improving agent. .

In the method for screening a hair loss improving agent according to the present invention, the hair loss may be hair loss due to menopause, ovarian resection, or ovarian deterioration. That is, the hair loss may include hair loss in menopausal women due to menopause, as well as in estrogen deficiency patients due to other causes such as ovariectomy or ovarian function decline.

In the hair loss improving agent screening method according to the present invention, the protein expression level is Western blot, Enzymelinked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunodiffusion method (Radioimmunodiffusion), Ouchteroni (Ouchterlony) Immune diffusion method, rocket immunoelectrophoresis, tissue immunostaining, immunoprecipitation assay, Complement Fixation Assay, Fluorescence Activated Cell Sorter (FACS) and protein chip chip) may be measured by any one or more methods selected from the group consisting of, but is not limited thereto.

Hereinafter, examples will be described in detail to aid understanding of the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

<Experimental Example 1> Confirmation of the effect of promoting hair loss due to decreased ovarian function due to ApoE deficiency

1. Experimental method

10 weeks old female C57BL/6J mice under anesthesia using 2',2',2'-tribromoethanol (2',2',2'-tribromoethanol, 250 mg/kg, Sigma Chemical) A sham operation or ovariectomy (OVX) was performed.

C57BL/6J genetic background ApoE-/- (ApoE knockout, KO) mice were purchased from Jackson Laboratory. Mice were bred in an animal facility at the University of Ulsan and maintained free of specific pathogens with free access to water and standard dietary diets.

After the operation, for 8 weeks, the mice were subjected to an atherogenic diet. A mouse atheroma control diet containing 1.25% cholesterol, 16% fat and 0.5% cholate was purchased from Research Diets, Inc, New Brunswick, NJ, USA.

Littermates of the same sex and age were used as a control group.

All animal care and procedures were performed according to protocols and guidelines approved by the University of Ulsan Animal Experimental Ethics Committee (UOUACUC) (HSC-14-060).

2. Experiment result

1 shows a change in hair loss in a mouse according to an experimental example of the present invention.

Referring to FIG. 1, extreme hair loss was observed in ApoE-deficient mice (ApoE-KO) subjected to ovariectomy after 8 weeks of surgery, but not in control (WT) mice. Through this, it was confirmed that ApoE deficiency accelerated hair loss due to loss of ovarian function.

As described above, a specific part of the present invention has been described in detail, and for those of ordinary skill in the art, it is obvious that this specific description is only a preferred embodiment, and the scope of the present invention is not limited thereby. Do. That is, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims (9)

A biomarker composition for diagnosis of accelerated hair loss due to decrease or loss of ovarian function containing apolipoprotein E (ApoE) as an active ingredient. delete delete delete delete delete delete delete delete

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