KR102089476B1 - A composition for preventing or treating of skin inflammation disease - Google Patents

Abstract

The present invention relates to a composition for preventing, improving or treating skin inflammatory diseases, comprising a ceranib-2 compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
The composition of the present invention can be applied to a variety of pharmaceutical, cosmetic, and food uses by controlling the inflammatory reactions in skin inflammatory diseases, thereby having a remarkable prevention, improvement or treatment effect on skin inflammation, especially psoriasis.

Description

Composition for preventing or treating skin inflammatory diseases {A COMPOSITION FOR PREVENTING OR TREATING OF SKIN INFLAMMATION DISEASE}

The present invention relates to a composition for preventing, improving or treating skin inflammatory diseases comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

Psoriasis (psoriasis) is a common chronic immune disease, usually expressed in the skin and joints, occurs in about 2% of the population. It is characterized by skin lesions with a thick, definite red plaque accompanied by scale, and the pathogenesis is not clear, but it is thought that the genetic, immunological, and environmental factors work in combination. Among the immunological causes, it is known that T cells and their cytokines (IFN-γ, IL-2, TNF-α, etc.) are involved. Recently, Th17 cells and regulatory T cells (Treg) contribute to the pathogenesis of psoriasis. Is being reported. Mainly, the appearance changes ugly, keratin occurs, and erythematous plaques can cause pain or often cause severe itching and serious quality of life problems. Psoriasis is a chronic disease that may worsen or alleviate during a patient's lifetime. It is a disease that is alleviated by the initiation and discontinuation of treatment and has little natural disappearance. Examples of psoriasis include psoriatic arthritis, psoriasis psoriasis, pustules psoriasis, red skin psoriasis, scalp psoriasis, nail psoriasis, and osteophysitis.

Psoriasis is a complex genetic disease with immune dysregulation, but the mechanism of inheritance is not fully understood. In addition, many environmental factors, including Koebner's phenomenon, infection, and stress, play an important role in the development of psoriasis.

In the treatment of psoriasis, treatments such as cyclosporine or acitretin, short-wave UV B therapy, and methotrextate as topical agents are appropriately selected and treated according to the patient's condition, but they do not exert sufficient therapeutic effects. According to one study, 1,197 patients with psoriasis were evaluated for satisfaction with typical psoriasis treatments (MTX, PUVA, cyclosporine, acitretin), and their satisfaction was found to be less than 50%. Moreover, there are no practical and effective treatments, and various clinical studies are in progress, but a therapeutic agent that still exhibits sufficient effects has not been developed.

Therefore, there is a need to develop treatment methods for the treatment of these skin inflammatory diseases, especially psoriasis.

Republic of Korea Patent Publication No. 10-2014-0135263 Republic of Korea Patent Publication No. 10-2010-0033471

The present invention provides a pharmaceutical composition for preventing or treating skin inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

.

.

The present invention also provides a food composition for preventing or improving skin inflammatory diseases, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a skin external agent for preventing or treating skin inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention also provides a cosmetic composition for alleviating or inhibiting itching, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present inventors tried to find a therapeutic agent capable of preventing or treating skin inflammatory diseases, particularly psoriasis-related diseases, and as a result, the compound represented by Formula 1, ceranib-2, reduces skin redness, exfoliation of the skin, exfoliation of the skin, and epidermis. By reducing the tissue thickness and suppressing the overall immune response, it was confirmed that it shows an excellent effect on the prevention, improvement or treatment of skin diseases, and the present invention has been completed.

The present invention provides a pharmaceutical composition for preventing or treating skin inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[Formula 1]

.

.

The compound represented by Chemical Formula 1 is 3- [3- (4-methoxyphenyl) -1-oxo-2-propen-1-yl] -4-phenyl-2 (1H) -quinolinone 3- [ 3- (4-methoxyphenyl) -1-oxo-2-propen-1-yl] -4-phenyl-2 (1H) -quinolinone, also called ceranib-2 It is a compound. Commercially available ones can be purchased and used Therapeutic Discovery, Mol Cancer Ther; It can also be synthesized according to the method described in 10 (11) 2052-2061.

In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid , Inorganic acid salts made of perchloric acid and sulfuric acid, acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galactu Organic acid salts, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Sulfonic acid salts made from phosphonic acid and naphthalenesulfonic acid, etc., amino acid salts made from glycine, arginine, lysine, and trimethylamine, triethylamine, ammonia, Naphthyridine, but include a salt made of a-picoline or the like, is not a salt type, which means in the present invention by the enumeration of these salts is not limited.

The compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof may be useful for the prevention or treatment of skin inflammatory diseases. In particular, it exhibits a ceramidase inhibitory effect, regulates an immune response, and inhibits the differentiation of virgin CD4 T lymphocytes into Th17.

 Skin inflammatory disease in the present invention means a comprehensive inflammation of the skin. Skin inflammatory diseases include atopic dermatitis, contact dermatitis, psoriasis and the like, preferably psoriasis and related diseases thereof.

The psoriasis is an inflammatory disease occurring in the skin or joints caused by an abnormality of the immune system, and the appearance changes unsightly, keratin occurs, erythematous plaques occur, and causes problems such as pain. Stomach psoriasis includes any one or more of the diseases selected from the group consisting of psoriatic arthritis, psoriasis psoriasis, pustular psoriasis, red skin psoriasis, scalp psoriasis, nail psoriasis and osteophysitis.

The compound represented by Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, reduces skin redness, reduces skin keratin, skin keratinization and epidermal tissue thickness, and prevents and improves skin diseases by inhibiting the overall immune response. Or it has an excellent effect on treatment.

The pharmaceutical composition of the present invention may further include at least one active ingredient that exhibits a prophylactic, ameliorating or therapeutic effect on skin inflammatory diseases.

In the present invention, prevention means all actions to suppress or delay the development of skin inflammatory diseases by administration of the composition, and treatment refers to all actions that improve or benefit symptoms of skin inflammatory diseases by administration of the composition.

The composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, hydrogen phosphate calcium, lactose , Mannitol, malt, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, calcium stearate , White sugar, dextrose, sorbitol and talc can be used. The pharmaceutically acceptable additive according to the present invention is preferably included in 0.1 to 90 parts by weight based on the composition, but is not limited thereto.

The composition of the present invention may be administered in various formulations, oral and parenteral, in actual clinical administration. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, etc., which are usually used, are used. Can be prepared. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc. These solid preparations include at least one excipient such as starch, calcium carbonate, sucrose, lactose It can be prepared by mixing (Lactose) or gelatin. In addition, lubricants such as magnesium stearate talc may be used in addition to simple excipients. Liquid preparations for oral use include suspensions, intravenous solutions, emulsions and syrups, and may include various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used simple diluents. . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As a non-aqueous solvent and a suspension solvent, 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 butter, and glycerogelatin may be used.

The composition of the present invention may be administered orally or parenterally according to the desired method, and when administered parenterally, transdermal administration, external skin, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection The injection infusion method can be selected, for example, it can be administered transdermally. The dosage range varies according to the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate and disease severity.

The composition according to the invention is administered in a pharmaceutically effective amount. In the present invention, "a pharmaceutically effective amount" means an amount sufficient to treat the disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, and activity of the drug , Sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including co-drugs and other factors well known in the medical field. The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the compound according to the present invention may vary depending on the patient's age, sex, and body weight. In general, 0.01 mg to 100 mg per kg body weight, preferably 0.1 mg to 50 mg daily, every other day, or It can be administered 1 to 5 times a week or divided into 1 to 5 times a day. However, since the dosage may be increased or decreased depending on the route of administration, severity, sex, weight, age, etc., the above dosage does not limit the scope of the present invention in any way.

Provided is a food composition for preventing or improving skin inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The food composition according to the present invention may further include additives, such as other food compositions, health functional foods or beverages.

For example, the food composition of the present invention includes sweeteners such as white sugar, fructose, glucose, D-sorbitol, mannitol, isomaltoligosaccharide, stevioside, aspartame, acesulfame potassium, sucralose, citric anhydride, DL- Acidifying agents such as malic acid, succinic acid and salts thereof, preservatives such as benzoic acid and derivatives thereof, various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and neutralizing agents (cheese, chocolate And the like), pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonic acid used in carbonated beverages, and the like. In addition, the food compositions of the present invention may contain flesh for the preparation of natural fruit juices and vegetable drinks. The proportion of these additives may be used in the range of about 20 parts by weight or less per 100 parts by weight of the food composition of the present invention.

When the food composition of the present invention is a beverage, it may further include flavoring agents or natural carbohydrates commonly included in beverages. The natural carbohydrate may be monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, or sugar alcohols such as xylitol, sorbitol and erythritol. In addition, the flavoring agent may be a natural flavoring agent of taumatin or stevia extract (rebaudioside A, glycyrrhizine) or a synthetic flavoring agent such as saccharin or aspartame. When the food composition is a beverage, natural carbohydrates may be generally included in an amount of about 1 to 20 g, preferably about 5 to 12 g per 100 mL of the composition.

The food composition of the present invention is prepared in the form of a powder, granule, tablet, capsule or beverage and can be used as foods, beverages, chewing gum, tea, vitamin complexes, and health supplement foods.

The present invention also provides a skin external agent for preventing or treating skin inflammatory diseases, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The external preparation may be prepared in any formulation that is conventionally prepared with reference to the known art in the art. For example, it may be prepared as a liquid, ointment, cream, lotion, spray, patch, oil, wax, emulsion, suspension, gel, or the like. The external preparation may include conventional additives, for example, preservatives, solvents to aid in drug penetration, emollients in the case of ointments and creams, and may contain conventional carriers such as ethanol or oleyl alcohol.

The present invention also provides a cosmetic composition for alleviating or suppressing itching, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The itching is also called pruritus and is an unpleasant sensation that causes the desire to scratch or rub the skin, and is a symptom commonly observed in skin diseases. The itching is not particularly limited in the cause or form of the cause, but itching specifically referred to in the present invention may be caused by any one selected from atopic dermatitis, contact dermatitis, or psoriasis.

The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleaning , May be formulated as an oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be prepared in the form of flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, trakant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. may be used as a carrier component. You can.

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder can be used as a carrier component, and in the case of a spray, additionally chlorofluorohydrocarbon, propane / Propellant such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizing agent or emulsifying agent is 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, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

When the formulation of the present invention is a suspension, liquid diluents such as water, ethanol or propylene glycol as carrier components, ethoxylated isostearyl alcohol, suspensions such as polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystals Sex cellulose, aluminum metahydroxide, bentonite, agar or trakant, etc. can be used.

When the formulation of the present invention is a surfactant-containing cleansing, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivatives, methyltaurate, sarcosinate, fatty acid amide as a carrier component Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.

The present invention provides a method for preventing or treating skin inflammatory diseases, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.

The present invention provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for the prevention or treatment of skin inflammatory diseases.

The present invention provides the use of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for producing a medicament for the prevention or treatment of skin inflammatory diseases.

The present invention provides a composition comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of skin inflammatory diseases.

The compound represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof reduces skin redness for skin inflammatory diseases, reduces skin keratin, skin keratinization and epidermal tissue thickness, and suppresses overall immune response to the skin It has a remarkable effect of preventing, improving or treating inflammation, especially psoriasis.

Figure 1 shows the results confirmed through the naked eye, H & E staining and skin epidermal thickness comparison that the disease is alleviated by treatment with the compound represented by Formula 1 according to the present invention in an animal model of skin inflammation disease.
Figure 2 shows the results confirmed through skin redness, keratin, skin keratosis and PASI score that the disease is alleviated by treatment with the compound represented by Formula 1 according to the present invention in an animal model of skin inflammation disease.
Figure 3 shows the results confirmed through the size of the lymph nodes and spleen, the number of cells, the immune response is relieved according to the compound represented by Formula 1 according to the present invention in the animal model of skin inflammation disease.
Figure 4 shows the results confirming that the differentiation of virgin CD4 T lymphocytes (Naive CD4 + T lymphocytes) into Th17 is inhibited by seranib-2.

In order to help the understanding of the present invention, examples and manufacturing examples are presented. The following examples and manufacturing examples are provided only to more easily understand the present invention, and the contents of the present invention are not limited by the examples and the manufacturing examples.

<Example 1> Confirmation of the effect of seranib-2 compound in an animal model of skin inflammatory disease

Experiments were performed using 8-week-old C57BL / 6 mice. 8-week-old male C57BL / 6 was purchased from OrientBio (Emsung, Korea). All animals were maintained freely in a pathogen-free environment with a 12 hour day / night cycle. All procedures were performed with the approval of the Ewha Womans University Animal Experiment Management Committee.

Skin inflammatory disease was induced by removing the hairs of the mice's back and applying Imiquimod cream (5%, Aldara; Dong-Ah Pharmaceutical, Seoul, Korea) to 50 mg, 7 days, etc., and Ceranib-2 (source: Cayman Chemical ) With 25µg, Imiquimod cream for 7 days. Imiquimod and drug application were performed once a day. The control was performed by dividing the control group with only petrolatum, the experimental group with only Imiquimod cream, the experimental group with Imiquimod cream and Ceranib-2 together, and a total of 3 groups.

The experimental efficacy was the skin visual findings and the PASI score scored the same (skin redness, keratin formation, skin keratosis scored on a scale of 4 points each), H & E staining method of the skin, and degree of immune activity through comparison of spleen and lymph node size It was evaluated by analysis and the like.

Example 1-1. Skin visual observation, H & E staining and skin epidermal thickness check

7 days after the experiment was performed, changes in skin tissue were visually confirmed.

In addition, H & E staining was performed after sacrifice of mice. For this purpose, the mouse's back skin specimen was fixed with 4% formaldehyde and embedded in paraffin. 5 μm thick tissue was used for analysis via H & E staining.

In addition, it was quantified by measuring changes in the thickness of the skin epidermis. Specifically, the epidermal thickness of the H & E stained skin tissue slide was measured using the Image J software program (NIH website, https://imagej.nih.gov/ij/).

 The results are shown in FIG. 1 (3 animals per group, ** p <0.01, *** p <0.001).

1A shows the result of visually confirming the skin tissue. As shown in A of FIG. 1, it was clearly confirmed with the naked eye that skin redness, erythema, blisters, etc. were very severe in the experimental group treated with Imiquimod cream, while the above phenomenon was greatly reduced according to seranib-2 treatment, and erythema It was confirmed that this decreases and the scaling decreases.

B of FIG. 1 shows the result of H & E staining, and C of FIG. 1 shows the result of confirming the change in the thickness of the skin epidermis. As shown in B and C of FIG. 1, it was confirmed that the inflammation of the skin was significantly reduced by the application of seranib-2, resulting in a significant reduction in skin thickness.

Example 1-2. Skin redness scoring

Skin redness, keratin production and skin keratosis were scored on a scale of 4 each day from the day the experiment was started to 7 days, and PASI scoring was performed using the score. The results are shown in FIG. 2 (* p <0.05. Population, 3 animals per group).

As shown in FIG. 2, A in FIG. 2 represents the skin flare score, B in FIG. 2 is the keratin score, C in FIG. 2 is the keratosis score, and D in FIG. 2 is the combined PASI score.

As can be seen from each result of FIG. 2, administration of seranib-2 significantly suppressed redness of the skin, keratinization, and skin keratosis, respectively, thereby suppressing overall skin inflammation and exhibiting excellent effects in the treatment of diseases.

Example 1-3. Confirmation of changes in lymph node and spleen size

The mice were sacrificed on the 7th day of the experiment to measure the size of lymph nodes, the size of the spleen, and the number of cells, and the results are shown in FIG. 3 (* p <0.05, ** p <0.01, *** p <0.001. , 3 per each group).

3A shows a comparison of the size of the lymph nodes, and FIG. 3B shows a result of comparing the sizes of the spleens. It was confirmed with the naked eye.

In addition, C of FIG. 3 quantifies the weight of the spleen, and it was confirmed that the size of the spleen was significantly reduced by the administration of seranib-2.

In addition, the results of confirming the number of cells separated from the spleen are shown in D of FIG. 3, and it was confirmed that the number of cells was also significantly decreased by the administration of seranib-2.

From these results, it was confirmed that seranib-2 administration significantly reduced immune activity in skin inflammatory diseases.

Example 2. Confirmation of differentiation of virgin CD4 T lymphocytes into Th17

 The ability to inhibit the differentiation of virgin CD4 + T cells (naive CD4 + T cells) to Th17 was separated from naive CD4 + T cells using Naive CD4 + T Cell Isolation Kit (Miltenyi Biotec, Auburn, CA, USA) from mice, followed by drug treatment ( Ceranib, 15 μM) was evaluated by inducing differentiation to Th17. Differentiation into Th17 was plate-bound CD3 (5 ug / ml), anti-CD28 (1 μg / ml), IL-6 (25 ng / ml), TGF-β (5 ng / ml), anti-IL-4 ( 10ug / ml) and anti-IFN-γ (10ug / ml) medium.

The results are shown in FIG. 4. When virgin CD4 T lymphocytes are isolated from mice and grown in Th17 differentiation medium, it is common to increase IL-17 secretion, and seranib-2 treatment showed a significant inhibition of this secretion of IL-17, thus leading to differentiation to Th17. It was shown to inhibit.

From the above results, it was confirmed that seranib-2 is effective in the treatment of skin inflammatory diseases by suppressing the differentiation of CD4-T lymphocytes to Th17.

From the above results, it was confirmed that the compound represented by Chemical Formula 1 according to the present invention reduces skin redness against skin inflammatory diseases, reduces skin keratin, skin keratinization and epidermal tissue thickness, and suppresses the overall immune response. Through this, it was confirmed that it has an excellent effect on the prevention, improvement and treatment of skin inflammatory diseases.

Claims (13)

A pharmaceutical composition for preventing or treating contact dermatitis comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
[Formula 1]

. delete delete delete The pharmaceutical composition for preventing or treating contact dermatitis according to claim 1, wherein the compound represented by Formula 1 is a ceramidase inhibitor. The pharmaceutical composition for preventing or treating contact dermatitis according to claim 1, wherein the compound represented by Formula 1 is administered transdermally. A food composition for preventing or improving contact dermatitis comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

. delete delete delete A skin external preparation for preventing or treating contact dermatitis, comprising a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[Formula 1]

.
delete delete

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