KR20240019477A - Composition for preventing or treating inflammatory skin disease comprising bazedoxifen as an active ingredient - Google Patents

Abstract

The present invention relates to a composition for preventing or treating inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
Bazedoxifene of the present invention has the effect of alleviating the external symptoms of dermatitis, epidermal thickening, and itching by suppressing the expression of inflammatory interleukin, and can be used as a material for medicines, foods, cosmetic compositions, feed compositions, etc.

Description

Composition for preventing or treating inflammatory skin disease comprising bazedoxifen as an active ingredient}

The present invention relates to a composition for preventing or treating dermatitis diseases comprising bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.

Inflammation occurring on the skin is a skin disease that damages the skin's appearance and requires prompt and effective treatment, and can be classified into various types depending on the cause of the disease. Dermatitis commonly presents with lesions such as skin redness, swelling, and itching, and depending on the type, various symptoms such as rashes and scars.

Atopic dermatitis is a type of intractable eczema with increasing prevalence worldwide. It is characterized by inflammatory, chronic recurrent, non-infectious, and pruritic skin disease, including erythema, infiltrates, papule formation, exudate with crusts, and excoriations. It is known to exhibit symptoms such as lichenification and lichenification. Atopic dermatitis often becomes severe or, if it becomes extremely severe, can become an incurable condition. In addition, it can cause high socioeconomic costs, psychological problems, severe sleep deprivation, and reduced quality of life. Atopic dermatitis is one of the most common inflammatory skin diseases in children, and is reported to generally appear in early infancy and childhood, and may persist into adulthood. Atopic dermatitis is often considered to be the first stage of the atopic march (progression from one atopic disease to another); approximately 60% of patients with atopic dermatitis have symptoms of asthma, allergic rhinitis, or food-related symptoms. Reported to be suffering from allergies.

Despite this severity, all currently available atopic dermatitis alleviation technologies have limitations such as low efficacy and dangerous side effects, resulting in an unmet need with virtually no effective treatment technology for the treatment of atopic dermatitis. Topical corticosteroid (TCS) drugs are mainly prescribed for patients with atopic dermatitis, but long-term application of TCS is known to cause skin atrophy, abnormal pigmentation, acne-like rash, hypothalamic-pituitary contractile effect, or Cushing's disease. there is. Topical calcineurin inhibitors (TCI) are generally effective as short-term treatments, but long-term application has side effects such as concerns about skin malignancy and increased risk of lymphoma. Additionally, any of these topical therapies may result in poor patient compliance when used for long periods of time or when repeatedly applied to large surface areas. In addition, first-generation antihistamines are widely prescribed to relieve acute itching caused by dermatitis, but their effectiveness is limited and they can only soothe itching, but do not show a fundamental therapeutic effect. As such, all currently released atopic dermatitis alleviation technologies have serious side effects or limitations, so there is a need to develop new treatment technologies.

The incidence of allergic contact dermatitis tends to increase every year, and the causes are diverse, including natural substances, industrial products, therapeutic agents, and chemicals increased by environmental pollution. Allergic contact dermatitis is known to occur when antigens penetrate the skin and cause inflammatory reactions accompanied by eczema and erythema and tissue damage in the contacted area. In some cases, it is accompanied by acne lesions, urticaria lesions, erythema multiforme, and pigmentation, and if exposed over a long period of time to antigenic substances, it progresses into chronic contact dermatitis that lasts for several years.

Currently, there is no fundamental treatment method for allergic contact dermatitis, and most treatments are aimed at relieving symptoms. The most effective treatment method is to identify and avoid the causative agent, but because the time between antigen contact and symptom onset is long, it is difficult to identify the causative agent, and even if the causative agent is found, symptoms have already progressed significantly. Most cases of allergic contact dermatitis are treated based on eczema treatment, and depending on the severity of symptoms, steroids or antihistamines are used to calm the inflammatory response. However, this treatment only relieves the symptoms of allergic contact dermatitis, but when used long-term, it causes various side effects as described above. In fact, there is no effective treatment technology for allergic contact dermatitis.

Psoriasis is a common chronic idiopathic inflammatory disease of the skin, which begins with a small, millet-like rash on the skin and appears as layers of dead skin in the form of white dandruff. It is accompanied by an inflammatory reaction in which capillaries become distorted and dilated, causing the skin to become red. Psoriasis generally appears on the scalp, knees, elbows, and hands and feet, and in severe cases, all skin on the body may be covered with a rash. In the progression of psoriasis, keratinocyte transformation is triggered by increased activity of the cellular immune system, and numerous studies have revealed that various inflammatory cytokines and chemokines secreted by immune cells are involved.

All currently available psoriasis relief technologies have limitations such as low efficacy and dangerous side effects, resulting in an unmet need with virtually no effective technology for the treatment of psoriasis. Currently approved treatments for psoriasis include topical agents (corticosteroids, charcoal preparations, retinoids, phototherapy, etc.), systemic treatments (methotrexate, retinoids, cyclosporine, etc.), and biological agents (etanercept, aralimumab, alepha). Sept, ustekinumab, etc.), but most of them are not effective in treating psoriasis and are known to have serious side effects such as toxicity.

Against this background, the present inventors confirmed that bazedoxifene is effective in preventing, improving, or treating inflammatory skin diseases including atopic dermatitis, allergic contact dermatitis, and psoriasis by suppressing the expression of inflammatory interleukins. The invention was completed.

Chinese Patent Publication No. 113244240

The present invention aims to solve the above-described problems and other problems associated therewith.

An exemplary object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory skin diseases containing bazedoxifene as an active ingredient.

Another exemplary object of the present invention is to provide a quasi-drug composition for preventing, improving, or treating inflammatory skin diseases containing bazedoxifene as an active ingredient.

Another exemplary object of the present invention is to provide a food composition for preventing or improving inflammatory skin diseases containing bazedoxifene as an active ingredient.

Another exemplary object of the present invention is to provide a health functional food for preventing or improving inflammatory skin diseases containing bazedoxifene as an active ingredient.

Another exemplary object of the present invention is to provide a cosmetic composition for preventing or improving inflammatory skin diseases containing bazedoxifene as an active ingredient.

Another exemplary object of the present invention is to provide a feed composition for preventing or improving inflammatory skin diseases containing bazedoxifene as an active ingredient.

The technical problem to be achieved according to the technical idea of the invention disclosed in this specification is not limited to the problem to solve the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below. There will be.

This is explained in detail as follows. Meanwhile, each description and embodiment disclosed in the present application may also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this application fall within the scope of this application. Additionally, the scope of the present application cannot be considered limited by the specific description described below.

In one aspect for achieving the above object, the present invention provides a pharmaceutical composition for preventing or treating inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, 'bazedoxifene' is 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H -Indol-5-ol (1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol) has the following chemical formula: It refers to a compound with a chemical structure of 1.

[Formula 1]

In the present invention, 'inflammatory skin disease' is a skin disease that can be caused by a T cell-dependent inflammatory reaction or an autoimmune reaction, and may include various dermatitis, symptoms of skin allergies, and diseases, such as skin itching. , atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurodermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, nummular eczema, dermatitis herpetiformis or seasonal It may be dermatitis, but is not limited thereto.

In the present invention, bazedoxifene includes a pharmaceutically or foodologically acceptable salt form within the range having the same efficacy. These salts are pharmaceutically or foodologically acceptable salts and may be basic salts or acid salts. The basic salts may be used in the form of either organic base salts or inorganic base salts, such as sodium salts, potassium salts, or calcium salts. , lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt, and pyridinium salt.

A useful type of such salt is an acid salt, an acid addition salt formed by a free acid. Inorganic acids and organic acids can be used as free acids. Hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, double phosphoric acid, and nitric acid can be used as inorganic acids, and citric acid, acetic acid, maleic acid, malic acid, and fumaric acid can be used as organic acids. , glucolic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, Glutamic acid, citric acid, aspartic acid, stearic acid, etc. may be used, but are not limited thereto and may include all salts formed using various inorganic acids and organic acids commonly used in the art.

The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc.

Carriers for parenteral administration may also include water, suitable oils, saline solutions, aqueous glucose and glycols, and the like. Additionally, stabilizers and preservatives may be additionally included. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

The pharmaceutical composition of the present invention can be administered to mammals, including humans, by any method. For example, it can be administered orally or parenterally, and parenteral administration methods include intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, It may be administered topically, sublingually, or rectally, and preferably subcutaneously, but is not limited thereto.

The pharmaceutical composition of the present invention can be formulated into a preparation for oral administration or parenteral administration according to the administration route described above. When formulated, one or more buffers (e.g. saline or phosphate buffered saline (PBS)), antioxidants, bacteriostatic agents, chelating agents (e.g. EDTA or glutathione), fillers, extenders, binders, adjuvants (e.g. For example, aluminum hydroxide), suspending agents, thickening agents, wetting agents, disintegrants or surfactants, diluents or excipients.

Solid preparations for oral administration include tablets, pills, powders, granules, solutions, gels, syrups, slurries, suspensions or capsules, etc. These solid preparations include the pharmaceutical composition of the present invention and at least one excipient, e.g. For example, starch (including corn starch, wheat starch, rice starch, potato starch, etc.), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol and maltitol. It can be prepared by mixing cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl-cellulose, or gelatin. For example, tablets or dragees can be obtained by combining the active ingredient with solid excipients, grinding them, adding suitable auxiliaries, and processing them into a granule mixture.

In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Liquid preparations for oral use include suspensions, oral solutions, emulsions, or syrups. In addition to the commonly used simple diluents such as water or liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, or preservatives may be included. there is. In addition, in some cases, cross-linked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may be added as a disintegrant, and anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers, and preservatives may be additionally included. .

When administered parenterally, the pharmaceutical composition of the present invention can be formulated with a suitable parenteral carrier in the form of injections, transdermal administration, and nasal inhalation according to methods known in the art. The above injections must be sterilized and protected from contamination by microorganisms such as bacteria and fungi. For injections, examples of suitable carriers may be, but are limited to, solvents or dispersions including water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), mixtures thereof, and/or vegetable oils. That is not the case. More preferably, suitable carriers include Hanks' solution, Ringer's solution, PBS containing triethanolamine, or sterile water for injection, and isotonic solutions such as 10% ethanol, 40% propylene glycol, and 5% dextrose. . In order to protect the injection from microbial contamination, it may additionally contain various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. Additionally, in most cases, the injection may additionally contain an isotonic agent such as sugar or sodium chloride.

In the case of transdermal administration, forms such as ointments, creams, lotions, gels, external solutions, paste preparations, linear preparations, and aerol preparations are included. Here, 'transdermal administration' means administering a pharmaceutical composition topically to the skin so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.

For inhalation administration, the compositions used according to the invention may be packaged in pressurized packs or using a suitable propellant, such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It can be conveniently delivered in the form of an aerosol spray from a nebulizer. For pressurized aerosols, the dosage unit can be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975 Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, a text generally known in all pharmaceutical chemistry.

In the pharmaceutical composition of the present invention, the amount of the active compound in the unit dose formulation may vary, and specifically, it may be adjusted to about 0.01 mg to about 1 g per time based on an average human weighing 70 kg. However, the administered dose may vary depending on the requirements of humans and mammals, the severity of the disease being treated, and the final composition of the compound used. It falls to those skilled in the art to determine the appropriate dosage for a particular situation.

The pharmaceutical composition of the present invention can be used alone or in combination with surgery, radiation therapy, hormone therapy, chemotherapy, or methods using biological response modifiers.

In the present invention, “prevention” refers to any act of suppressing or delaying the symptoms of an inflammatory skin disease by administering the composition of the present invention, and in the present invention, “improvement” refers to erythema, a symptom of an inflammatory skin disease, by applying the composition of the present invention. , It means that it has the effect of relieving bleeding, scars, dry skin, edema, hematoma, maceration, epidermal thickening, itching, etc. In the present invention, “treatment” refers to any action in which the symptoms of an inflammatory skin disease are improved or beneficially changed by administration of the composition of the present invention.

The composition of the present invention can prevent, improve, or treat inflammatory skin diseases by suppressing or reducing the expression of inflammatory interleukins.

The inflammatory interleukin (interleukin) refers to interleukin related to skin inflammation, for example, interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 6 (IL-6), and interleukin 10 (IL- 10), it may be interleukin 12 (IL-12), interleukin 13 (IL-13), interleukin 18 (IL-18), interleukin 31 (IL-31), or interleukin 32 (IL-32), preferably interleukin It may be, but is not limited to, 4, interleukin 6, interleukin 13, and interleukin 31.

For example, the composition of the present invention improves and alleviates symptoms related to skin inflammation and exhibits efficacy in preventing, improving, or treating inflammatory skin diseases by suppressing the expression of the above-mentioned inflammatory interleukins.

To achieve the above object, a quasi-drug composition for preventing, improving or treating inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient is provided.

The terms 'bazedoxifene', 'inflammatory skin disease', 'prevention', 'improvement', and 'treatment' are the same as described above.

In the present invention, "quasi-drugs" are articles used for the purpose of diagnosing, treating, alleviating, treating or preventing diseases in humans or animals, but are not instruments, machines, or devices, and do not have a pharmacological effect on the structure and function of humans or animals. It refers to products used for the purpose, excluding those that are not instruments, machines, or devices. One specific example may include preparations for internal use, but is not limited thereto, and the formulation method, dosage, usage method, and components of quasi-drugs etc. can be appropriately selected from conventional techniques known in the technical field.

In addition to the above ingredients, the quasi-drug composition of the present invention may further include pharmaceutically acceptable carriers, excipients, or diluents as needed. The pharmaceutically acceptable carrier, excipient, or diluent is not limited as long as it does not impair the effect of the present invention, and includes, for example, fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, sweeteners, fragrances, preservatives, etc. It can be included.

To achieve the above object, a food composition for preventing or improving inflammatory skin disease containing bazedoxifene and a pharmaceutically acceptable salt thereof as an active ingredient is provided.

The terms 'bazedoxifene', 'inflammatory skin disease', 'prevention' and 'improvement' are the same as described above.

The food composition of the present invention includes all forms of functional food, nutritional supplement, health food, food additives, health functional food and feed, etc., for humans or livestock. Animals, including . Food compositions of this type can be prepared in various forms according to conventional methods known in the art.

Food compositions of this type can be prepared in various forms according to conventional methods known in the art. General foods include, but are not limited to, beverages (including alcoholic beverages), fruit and its processed foods (canned fruit, bottled food, jam, marmalade, etc.), fish, meat, and their processed foods (ham, sausage, corned beef, etc.) , bread and noodles (udon, buckwheat noodles, ramen, spagate, macaroni, etc.), fruit juice, various drinks, cookies, taffy, dairy products (butter, cheese, etc.), edible plant oils, margarine, vegetable protein, retort food, frozen food. , can be manufactured by adding the above active ingredients to various seasonings (soybean paste, soy sauce, sauce, etc.).

Additionally, nutritional supplements can be manufactured by adding the above-mentioned active ingredients to capsules, tablets, pills, etc. In addition, health functional foods are not limited to this, but for example, they can be manufactured in the form of tea, juice, and drinks and consumed by liquefying, granulating, encapsulating, and powdering so that they can be consumed as health drinks. Additionally, in order to use the bazedoxifene in the form of a food additive, it can be prepared and used in powder or concentrate form. Additionally, it can be prepared in the form of a composition by mixing it with one or more known active ingredients known to be effective in improving inflammatory skin diseases.

In addition to the above, the health functional food of the present invention includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, and preservatives. , may contain glycerin, alcohol, or carbonating agent.

In one aspect for achieving the above object, the present invention provides a cosmetic composition for preventing or improving inflammatory skin diseases containing bazedoxifene and a pharmaceutically acceptable salt thereof as an active ingredient.

The terms 'bazedoxifene', 'inflammatory skin disease', 'prevention' and 'improvement' are the same as described above.

In the cosmetic composition of the present invention, "inflammatory skin disease" includes various skin conditions and symptoms related to skin inflammation, and as long as it has an effect of improving skin condition such as alleviating such skin symptoms, the bazedoxifen may be included in various amounts. In addition to bazedoxifene, various ingredients commonly used in cosmetic compositions, such as water-soluble ingredients, powder ingredients, oils, surfactants, moisturizers, and viscosity modifiers, as necessary, within the range that does not reduce the effect of the present invention. , preservatives, antioxidants, fragrances, pigments, etc. may be combined.

The cosmetic composition of the present invention includes solutions, external ointments, creams, foams, nourishing lotions, softening lotions, packs, softening waters, emulsions, makeup bases, essences, soaps, liquid cleansers, bath salts, sunscreen creams, sun oils, suspensions, and emulsions. It can be prepared in a formulation selected from the group consisting of liquid, paste, gel, lotion, powder, soap, surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation, patch and spray. no.

The cosmetic composition of the present invention may further include one or more cosmetically acceptable carriers that are blended with general skin cosmetics, and common ingredients include, for example, oil, water, surfactant, moisturizer, lower alcohol, thickener, Chelating agents, pigments, preservatives, fragrances, etc. may be appropriately mixed, but are not limited thereto.

Cosmetically acceptable carriers included in the cosmetic composition of the present invention vary depending on the formulation of the cosmetic composition.

When the formulation of the present invention is an ointment, paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. are used as carrier ingredients. may be used, but is not limited thereto. These may be used alone or in combination of two or more types.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silcate, polyamide powder, etc. may be used as carrier ingredients, and especially in the case of a spray, chlorofluorohydride may be additionally used. It may include, but is not limited to, propellants such as low carbon, propane/butane or dimethyl ether. These may be used alone or in combination of two or more types.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizing agent, or emulsifying agent may be used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3-butyl glycol oil, etc. can be used, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol aliphatic esters, polyethylene glycol or fatty acid esters of sorbitan. may be used, but is not limited thereto. These may be used alone or in combination of two or more types.

When the formulation of the present invention is a suspension, the carrier components include water, liquid diluents such as ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, and miso. Crystalline cellulose, aluminum metahydroxide, bentonite, agar, or tracant may be used, but are not limited thereto. These may be used alone or in combination of two or more types.

When the formulation of the present invention is soap, alkali metal salts of fatty acids, hemiester salts of fatty acids, fatty acid protein hydrolysates, isethionates, lanolin derivatives, fatty alcohols, vegetable oils, glycerol, sugars, etc. are used as carrier components. It may be, but is not limited to this. These may be used alone or in combination of two or more types.

In one aspect for achieving the above object, the present invention provides a feed composition for preventing or improving inflammatory skin diseases containing bazedoxifene and a pharmaceutically acceptable salt thereof as an active ingredient.

The terms 'bazedoxifene', 'inflammatory skin disease', 'prevention' and 'improvement' are the same as described above.

In the present invention, the feed composition may be formulated in the form of a normal feed and may include known feed ingredients. It can also be used as a feed additive, which is added to the feed used in the form of an additive. The feed additive of the present invention corresponds to supplementary feed under the Feed Management Act, and includes mineral preparations such as sodium bicarbonate (sodium bicarbonate), bentonite, magnesium oxide, and complex minerals, and trace minerals such as zinc, copper, cobalt, and selenium. Preparations, vitamin preparations such as kerotene, vitamin E, vitamins A, D, E, nicotinic acid, and vitamin B complex, protective amino acid preparations such as methionine and lysic acid, protective fatty acid preparations such as fatty acid calcium salts, probiotics (lactic acid bacteria), yeast culture Water, live bacteria such as mold fermentation products, yeast, etc. may be additionally included.

The feed or feed additive of the present invention can be applied to a number of animal diets, including mammals, poultry, and fish.

The composition containing bazedoxifene and a pharmaceutically acceptable salt thereof of the present invention as an active ingredient inhibits the inflammatory response by suppressing the expression of inflammatory interleukins, thereby preventing lesions that specifically appear in inflammatory skin diseases, such as erythema. , relieves bleeding, scars, dry skin, edema, hematoma, maceration, epidermal thickening or itching, and as a result, has the effect of preventing, treating or improving inflammatory skin diseases, and is used in medicines, foods, cosmetics, feed compositions, etc. It can be used as a material for

Figure 1 shows the results of confirming the effect of bazedoxifene on skin lesions appearing in the DNCB (1-chloro-2,4-dinitrobenzene) dermatitis model.
Figure 2 shows the results confirming the effect of bazedoxifene on skin lesions appearing in the imiquimod (IMQ) dermatitis model.
Figure 3 shows the results of confirming the effect of bazedoxifene on changes in epidermal thickening (epidermal thickness) in the DNCB dermatitis model.
Figure 4 shows the results confirming the effect of bazedoxifene on changes in epidermal thickening (epidermal thickness) in the imiquimod (IMQ) dermatitis model.
Figure 5 shows the results of comparing the differences in expression of interleukins (interleukin 4, interleukin 6, interleukin 13, and interleukin 31) in skin tissue according to bazedoxifene administration in the imiquimod dermatitis model.
Figure 6 shows the results showing the itching alleviating effect of bazedoxifene in the DNCB dermatitis model and the imiquimod dermatitis model.
Figure 7 shows the results confirming the anti-inflammatory effect of bazedoxifene on fibroblasts induced in an inflammatory-like environment.

Hereinafter, the present invention will be described in more detail through the following examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example 1. Confirmation of the dermatitis alleviating effect of bazedoxifene

1.1 Bazedoxifene administration to dermatitis animal model

1.1.1. DNCB (1-chloro-2,4-dinitrobenzene) dermatitis model

The dermatitis alleviating effect of bazedoxifene was evaluated using the DNCB (1-chloro-2,4-dinitrobenzene) model, a standardized model representing atopic dermatitis and allergic contact dermatitis. BALB/c mice were divided into three groups (wild type (control group) without drug administration and group administered vehicle and bazedoxifene 10 μg/kg subcutaneously) (n = 5 to 7 per group). ).

The hair on the back of the nape of the mouse was completely removed with a razor 6 days before the experiment, and for the next 3 days, 200 μl of 1% DNCB was dissolved in a mixture of acetone and ethanol (3:1) and applied topically to the skin on the back of the nape of the mouse. For the wild-type group, an equal dose of a mixture of acetone and ethanol (3:1) was topically applied to the skin of the back of the nape of the mouse. After 3 days of DNCB application, followed by a 2-day recovery period, 200 μl of 0.5% DNCB dissolved in a mixture of acetone and olive oil (2:3) was applied to the skin of the back of the nape of the mouse three times a week at daily intervals for 2 weeks. It was applied topically. For the wild type group, the same dose of a mixture of acetone and olive oil (2:3) was topically applied to the skin behind the nape of the mouse. Immediately before application of DNCB, 10 μg/kg of bazedoxifene or 50 μl of excipient was injected subcutaneously into the skin at the back of the neck. The wild type group was not injected.

1.1.2. Imiquimod (IMQ) dermatitis model

The dermatitis alleviating effect of bazedoxifene was evaluated using the imiquimod (5% Imiquimod (IMQ), Aldara cream) model, a standardized model representing psoriatic dermatitis. BALB/c mice were divided into three groups (n = 5–7 per group). The test drug was administered through subcutaneous injection of excipient and bazedoxifene 10 μg/kg subcutaneous injection. The remaining group was given petroleum jelly without any medication. These mice were used to measure the effect of bazedoxifene on inflammatory symptoms.

The hair on the back of the nape of the mouse was completely removed with a razor 1 day before the experiment, and 62.5 mg of 5% imiquimod (Aldara cream) was topically applied to the shaved dorsal skin every day for the next 7 days. For the petroleum jelly group, the same dose of 62.5 mg petroleum jelly was applied topically to the shaved dorsal skin. Immediately before applying imiquimod, 10 μg/kg of bazedoxifene or 50 μl of excipient was injected subcutaneously into the skin at the back of the neck. There was no injection in the vaseline group.

1.2. Confirmation of the dermatitis alleviating effect of bazedoxifene

1.2.1. Relieves the appearance of dermatitis symptoms

(1) Relief of symptoms of atopic dermatitis and allergic contact dermatitis

To evaluate changes in lesions observed in the DNCB model, skin photos were taken at the time of observation after DNCB treatment, and the four items accompanying symptoms (erythema/bleeding, scarring/dry skin, edema, and hematoma/maceration) were examined. Dermatitis severity was measured by assigning a score of 0 (no symptoms), 1 (mild symptoms), 2 (symptoms significantly advanced), and 3 (severe symptoms). By adding up the scores of each item, it was evaluated by giving a score ranging from a minimum of 0 (no symptoms) to a maximum of 12 (all symptoms were severe).

For reference, all data for the DNCB model and the imiquimod model were tested for statistical significance by applying one-way ANOVA. The skin lesion severity score and itching measurement data of the DNCB model and the imiquimod model (Figures 1 and 7) were tested for statistical significance by applying two-way ANOVA. Statistical significance is indicated in each data plot, and when significance appears, *P<0.05, **P<0.01, ***P<0.005, or P-values are indicated individually.

As a result of the evaluation, it was confirmed that lesion symptoms (erythema, bleeding, keratin, etc.) appearing in the DNCB model were statistically significantly alleviated in the group injected subcutaneously with bazedoxifene compared to the group injected subcutaneously with excipients (Figure 1).

(2) Relief of psoriasis dermatitis symptoms

To evaluate changes in lesions observed in the imiquimod model, skin photographs were taken at the time of observation before imiquimod treatment. To measure the severity of psoriasis, skin lesions are assessed based on the PASI (Psoriasis Area and Severity Index) scoring method, which assigns scores to the three representative symptoms accompanying psoriasis (keratinization, erythema, and skin thickening). The severity and degree of relief of symptoms were measured (van der Fits L et al. J Immunol. 2009 May 1;182(9):5836-45.). By summing the scores of each item, a score was given ranging from a minimum of 0 (no symptoms) to a maximum of 12 (all symptoms were severe).

As a result, lesion symptoms (keratin, epidermal thickness, erythema) in the group injected subcutaneously with bazedoxifene were statistically significantly alleviated from the 3rd day compared to the group injected subcutaneously with excipients (Figure 2).

1.2.2. Relieves epidermal thickening caused by dermatitis

To evaluate changes in epidermal thickness according to skin epidermal lesions, the skin on the back of the nape of each mouse in the dermatitis model was obtained after 14 days (DNCB) and 7 days (imiquimod) and treated with 4% paraformaldehyde. fixed. A paraffin block containing the obtained skin tissue was prepared and sectioned to a thickness of 8 ㎛. Paraffinized skin sections were stained with H&E (Hematoxylin and Eosin) to distinguish skin layers. To evaluate histological changes in the stained area, the thickness of the epidermal layer was checked using an optical microscope (BX51, Olympus).

As a result, in the DNCB model and the imiquimod model, the epidermal layer thickness of the group injected subcutaneously with bazedoxifene showed a decrease compared to the group injected subcutaneously with excipients. (Figures 3 and 4).

1.2.3. Confirmation of changes in dermatitis-related biological indicators

To measure changes in the expression of inflammatory interleukins (4, 6, 13, 31), which are used as inflammation indicators when dermatitis occurs, part of the lesioned skin tissue of mice in which the dermatitis model was completed was collected, and RNA was extracted using Trizol. To confirm changes in the expression of each interleukin, real-time polymerase chain reaction (Real time PCR) was performed using the collected RNA. As a result, in the imiquimod psoriasis dermatitis model, interleukins 4, 6, 13, and 31 were overall decreased in the group injected subcutaneously with bazedoxifene compared to the group injected subcutaneously with the excipient (Figure 5).

1.2.4. Relieves itching symptoms accompanying skin inflammation

(1) Confirmation of itching symptom relief in the DNCB model

In the DNCB model, 50 μl of bazedoxifene 10 μg/kg or excipient was injected subcutaneously into the nape of the neck for two weeks, and DNCB was dissolved in a mixture of acetone and olive oil (2:3) at a concentration of 0.5% and injected into the skin of the back of the nape of the mouse. 200 μl was applied topically. In the DNCB model, scratching behavior was videotaped and recorded for 60 minutes the day after topical application of DNCB and subcutaneous injection of bazedoxifene.

As a result, compared to the group injected subcutaneously with excipients, it was confirmed that in the group injected subcutaneously with bazedoxifene, the scratching behavior with the hind paw in response to itching was statistically significantly reduced in the 6th session, that is, the itching was alleviated (Figure 6A).

(2) Confirmation of itching relief in the imiquimod model

In the imiquimod model, 50 μl of bazedoxifene 10 μg/kg or excipient was injected subcutaneously into the nape of the neck for 1 week, and 5% imiquimod was topically applied to the dorsal skin behind the nape of the mouse. In the imiquimod model, scratching behavior was videotaped and recorded for 60 minutes immediately prior to topical application and subcutaneous injection of bazedoxifene.

As a result, in the imiquimod psoriasis model, a statistically significant itching alleviation effect was confirmed on the 6th and 7th days (Figure 6B).

Example 2. Confirmation of the effect of inhibiting inflammatory response by bazedoxifene pretreatment

Among the cells distributed in the skin and directly affected or involved in the development of dermatitis, fibroblasts, which are known to contain a large amount of IL6ST protein, were cultured. Changes in inflammatory indicators that appeared when cultured fibroblasts were pretreated with bazedoxifen and then induced an inflammatory-like environment were observed.

First, shave the skin of the mouse and cut it into 2 mm thick pieces using surgical scissors and a scalpel. The tissue was cultured in a 100 Φ culture dish for 14 days to extract fibroblasts, and then treated with recombinant mouse interleukin 6 at a concentration of 50 ng/ml for 30 minutes to create an inflammation-like environment. Afterwards, changes in the expression of indicator proteins were analyzed by Western blot. did.

The cells were divided into three groups: cells in which only excipients were added, a group in which an inflammatory-like environment was created by treatment with interleukin 6, and a group in which an inflammatory-like environment was created after 2 hours of bazedoxifene treatment. The inflammatory response was measured by quantifying the degree of phosphorylation using an antibody against Stat3 and phosphorylated Stat3 protein. As a result of charting the relief of inflammatory response by bazedoxifene as confirmed by the ratio of phosphorylated Stat3 protein and non-phosphorylated Stat3 protein, the pStat3 in the group pretreated with bazedoxifene was statistically significant compared to the group treated only with interleukin 6. A decrease was confirmed (Figure 7).

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. In this regard, the embodiments described above should be understood in all respects as illustrative and not restrictive. The scope of the present invention should be construed as including the meaning and scope of the patent claims described below rather than the detailed description above, and all changes or modified forms derived from the equivalent concept thereof are included in the scope of the present invention.

Claims (14)

A pharmaceutical composition for preventing or treating inflammatory skin diseases comprising bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
According to paragraph 1,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A pharmaceutical composition comprising at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.
According to paragraph 1,
The pharmaceutical composition is formulated in the form of an oral preparation, an injectable preparation, or an external preparation.
According to paragraph 3,
The external agent is one or more pharmaceutical compositions selected from the group consisting of creams, gels, ointments, emulsions, suspensions, sprays, and transdermal patches.
A quasi-drug composition for preventing, improving, or treating inflammatory skin diseases, comprising bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
According to clause 5,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A quasi-drug composition comprising at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.
A food composition for preventing or improving inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
In clause 7,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A food composition comprising at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.
A health functional food for preventing or improving inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
According to clause 9,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A health functional food that is at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.
A cosmetic composition for preventing or improving inflammatory skin diseases comprising bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
According to clause 11,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A cosmetic composition comprising at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.
A feed composition for preventing or improving inflammatory skin diseases containing bazedoxifene or a pharmaceutically acceptable salt thereof as an active ingredient.
According to clause 13,
The above inflammatory skin diseases include skin itching, atopic dermatitis, chronic recurrent dermatitis, contact dermatitis, seborrheic dermatitis, neurogenic dermatitis, xerosis dermatitis, erythema, pruritus, eczematous skin disease, urticaria, scleroderma, psoriasis, lichen, currency. A feed composition comprising at least one selected from the group consisting of eczema, dermatitis herpetiformis, and seasonal dermatitis.