WO2023048528A1 - Pharmaceutical composition comprising inflammasome inhibitor as active ingredient for prevention, alleviation, or treatment of atopic dermatitis - Google Patents

Abstract

The present invention relates to a composition comprising a novel inflammasome inhibitor as an active ingredient for prevention, alleviation, or treatment of atopic dermatitis.

Description

A pharmaceutical composition for preventing, improving or treating atopic dermatitis comprising an inflammatory complex inhibitor as an active ingredient

The present invention relates to a pharmaceutical composition for preventing, improving or treating atopic dermatitis, containing a novel inflammatory complex inhibitor as an active ingredient.

In 1925, Coca first described the tendency to develop dermatitis, asthma, and hay fever with respect to substances exposed to food and respiratory organs as atopy. Atopic diseases include asthma, allergic rhinitis, and allergic conjunctivitis in addition to atopic dermatitis. The incidence of atopic dermatitis is rapidly increasing worldwide due to the increase in environmental pollutants, and the prevalence of atopic dermatitis reaches 20% of the total population. Patients with atopic dermatitis have a reduced quality of life due to restrictions in their daily life, and socially, the economic burden of treatment is increasing. Therefore, there is an urgent need for atopic treatment management measures. Atopic dermatitis (Atopic Dermatitis) is a recurrent chronic skin disease accompanied by severe itching that usually starts in infancy or childhood and is a very common skin disease accompanied by a family history. Symptoms begin in infancy and infancy, especially around the age of 2 months, of which about 50% occur before the age of 2 years, most of which appear before the age of 5 years, whereas first symptoms appear in adults are very rare. . In some patients, symptoms are alleviated or cured spontaneously with growth, and more than half of patients with infancy symptoms improve before the age of 2 years. The shape and distribution of skin lesions are characteristic, accompanied by pruritus (pruritus), dry skin, and characteristic eczema. In infancy, it begins as eczema on the spread side of the face and limbs, but as it grows, it develops in the form of eczema, characteristically on the bends of the arms and behind the knees. In adults, lichenification, in which the skin folds, becomes thicker, occurs, and eczema occurs on the face, chest, and nape other than extremities compared to children and infants.

Atopy usually involves an allergic reaction. In particular, atopic dermatitis is not only a skin disease, but also a signal of an allergic march such as allergic asthma and rhinitis. However, since the exact cause and mechanism of atopic dermatitis have not yet been identified, a suitable treatment drug that can cure it completely has not been developed. Currently, steroids, PDE4 inhibitors, JAK inhibitors, and antibody treatments are used as treatments for atopic dermatitis. Anti-inflammatory analgesics and steroid-based immunosuppressants are mainly used to alleviate inflammation and immune response. They have the advantage of showing rapid improvement, but if they are reduced or stopped, symptoms may rapidly worsen, and when taken for a long time, secondary adrenocortical insufficiency, diabetes, peptic ulcer , systemic side effects such as hirsutism, alopecia, and pigmentation may appear, and in particular, cataracts may occur in children. In the case of steroid ointments, they cause serious side effects such as thinning or atrophy of the skin, redness due to the expansion of blood vessels, and folliculitis. Elidel (pimecrolimus) cream and Protopic (tacrolimus, FK506) ointment, which are non-steroidal immunomodulatory agents, were developed as agents that can replace steroid ointments, and when applied for a long time, there are no side effects seen with existing steroid ointments, It is often used for sensitive skin such as the neck and has grown rapidly to 30% of the entire atopic dermatitis market. However, recently, the risk of cancer induction of calcineurin inhibitors has been raised, and sales are declining as only low concentration use is recognized for patients under the age of 16, and low concentration use is not recognized for children under 2 years of age. . In the case of Eucrisa's PDE4 inhibitor, which was approved by the FDA for patients with mild to moderate symptoms in 2016, it showed an improvement of 32% compared to 18 to 25% of clinical improvement for placebo in clinical trials, resulting in ongoing controversy about its effectiveness. there is. In addition, it has been reported that many patients avoid prescription due to the patient's burning sensation problem. In the case of JAK inhibitors, which are the most actively studied for the treatment of atopic dermatitis, four types, abrocitinib, baricitinib, upadacitinib, and ruxolitinib, are currently in the process of FDA approval. Safety issues such as blood clots have been identified, and as a result, FDA review is pending as of 2021. And because of these safety issues with JAK inhibitors, the FDA has safety concerns about the entire class of JAK inhibitors and, accordingly, recommends their use only to limited patients. Specifically, in September 2021, it was decided to include information on serious side effects and deaths in the label for JAK inhibitors from Pfizer, Lilly, and Abbvie. Because of this, many experts recommend limiting the use of JAK inhibitors in atopic dermatitis, which is not a life-threatening disease. Meanwhile, in the case of monoclonal antibody treatment, in 2017, the most recent, Dupicent received FDA approval for the first time in patients with moderate to severe atopic dermatitis. Dupicent controls the symptoms of severe allergic diseases such as atopy and asthma. However, more than 10% of Dupicent users reported a gradual decrease in efficacy and redness at the injection site due to an increase in the blood concentration of antibodies to the drug. In addition, insomnia, oral viral infection, gastritis, toothache, eosinophilia, Hermes infection, conjunctivitis, sore throat, and arthralgia were observed in 1-10% of users of Dupicent, and in less than 1%, hypersensitivity reaction, dry eye, and eosinophilic Side effects of granulosa, eosinophilic pneumonia, and erythema nodosum were identified. Due to the above safety and efficacy issues, use in children and adolescents is not recommended. In addition, along with the high drug price, Dupicent is only covered by insurance for the treatment of patients who do not respond to steroids, calcineurin inhibitors, Eucrisa, and systemic treatments. As a result, patients' access to Dupicent treatment is very limited. In other atopic treatments, antihistamines and, in severe cases, taking short-term adrenocortical hormones and applying external agents, and skin UV treatment or interferon treatment are being implemented. However, in most cases, only temporary improvement is induced, and atopic dermatitis recurs when the medication is stopped. Therefore, most patients with atopic dermatitis still desperately need the development of therapeutic and preventive drugs with fewer side effects than conventional treatments and high efficacy.

The inventors of the present invention found that a composition containing a deoxycholic acid derivative compound of Formula 1 has a significant effect on treating atopic dermatitis and proposes it as a pharmaceutical component for preventing, treating, and improving atopic dermatitis.

[Formula 1]

Until now, no example of attempting to improve or treat atopic dermatitis with a composition containing the deoxycholic acid derivative compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof has been known, and the therapeutic effect of atopic dermatitis has not been known. There are no reports of any

An object of the present invention is to provide a composition for preventing, improving or treating atopic dermatitis, comprising a deoxycholic acid derivative compound of Formula 1 as an active ingredient, or a pharmaceutically acceptable salt or solvate thereof.

In addition, another object of the present invention is to provide a method for preventing, improving or treating atopic dermatitis comprising administering the pharmaceutical composition to a subject.

In addition, another object of the present invention is to provide the use of the pharmaceutical composition for use in preventing, improving or treating atopic dermatitis.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing, improving or treating atopic dermatitis, containing a deoxycholic acid derivative compound of Formula 1 below, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[Formula 1]

In one aspect of the present invention, the compound of Formula 1 may have an isomeric form as shown in Formula 2 below.

[Formula 2]

In one aspect of the present invention, the compound of Formula 1 may be in the form of a salt selected from the group consisting of alkali metal salts, inorganic acid salts, organic acid salts, alkaline earth metal salts, and ammonium salts, but is not limited thereto.

In one aspect of the present invention, the compound of Formula 1 may be a sodium salt, and may be a compound of Formula 3 below.

[Formula 3]

In one aspect of the present invention, the compound of Formula 3 may have an isomeric form as shown in Formula 4 below.

[Formula 4]

In one aspect of the present invention, the pharmaceutical composition may be formulated in the form of oral preparations, injection preparations or external preparations, but is not limited thereto. In addition, pharmaceutically acceptable additives may be further included therein.

In one aspect of the present invention, the oral preparation may be formulated into a dosage form selected from the group consisting of tablets, granules, pills, powders, capsules and solutions, but is not limited thereto.

In one aspect of the present invention, the composition for external application may be formulated into a formulation selected from the group consisting of creams, gels, ointments, emulsions, suspensions, sprays, and transdermal delivery patches, but is not limited thereto.

In one aspect of the present invention, the external preparation may be applied in an amount of 0.01 to 50 mg per day.

In another aspect of the present invention, a cosmetic composition for preventing or improving atopic dermatitis containing a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient is provided.

[Formula 1]

In one aspect of the present invention, the cosmetic composition is a soap for atopy, cleansing foam, cleansing cream, cleansing water, bath agent, skin lotion, skin softener, skin toner, lotion, cream, essence, astringent, emulsion, gel, lipstick, spray , Shampoo, rinse, treatment, body cleanser, pack, massage agent, face powder, compact, foundation, two-way cake and may be prepared in one or more formulations selected from the group consisting of a makeup base, but is not limited thereto.

In another aspect of the present invention, a composition for preventing, improving or treating atopic dermatitis in animals other than humans containing a compound having the structure of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient Provided.

[Formula 1]

In one aspect of the present invention, the deoxycholic acid derivative compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof, is administered in an amount of 0.001 mg to 1000 mg/day to an individual in need of prevention, improvement, or treatment of atopic dermatitis. , or an amount of 0.001 mg to 100 mg/day, or an amount of 0.01 mg to 10 mg/day may be administered to a warm-blooded animal weighing 75 kg to prevent, ameliorate, or treat atopic dermatitis.

The dosage of the deoxycholic acid derivative compound of Formula 1 or its pharmaceutically acceptable salt or solvate for use in the present invention depends on various factors, such as the effectiveness and duration of action of the active ingredient, the mode of administration, the sex of the warm-blooded animal, It may vary depending on individual conditions such as age, weight, and the severity of other diseases. A specific administration route and dosage may be selected by a doctor/veterinarian in charge according to conditions such as the characteristics of the subject to be administered, that is, age, weight, disease state, and physical condition.

The administration route of the composition may be administered through any general route as long as it can reach the target tissue. Depending on the purpose, the composition of the present invention may be administered orally, intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, intranasally, pulmonaryly, or intrarectally, but is not limited thereto. don't In addition, the composition may be administered by any device capable of transporting an active substance to a target cell.

In one embodiment of the present invention, pharmaceutical preparations for oral administration may be presented in dosage unit form such as, for example, dragees, tablets, pills, powders, granules or capsules, and in ampoules. They are prepared by methods known per se, for example by conventional mixing, granulation, confectioning, dissolving or lyophilization methods. For example, pharmaceutical preparations for oral administration are prepared by mixing the active ingredient with a solid carrier, granulating the mixture, and formulating the mixture or granules into tablets or dragees, after adding suitable excipients, if desired. It can be.

Suitable carriers include in particular fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulosic agents and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as for example corn, Starch paste using wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone and, if necessary, disintegrants such as the aforementioned starches, carboxymethyl starch, crosslinked polyvinylpyrrolidone money, agar or alginic acid or a salt thereof such as sodium alginate.

Additives are in particular flow-regulating agents and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Concentrated sugar solutions, which provide dragee cores with suitable coatings which can be resistant to gastric juices, and which optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycols and/or titanium dioxide in suitable organic solvents or solvent mixtures; Alternatively, a lacquer solution may be used, or, to form a coating resistant to gastric fluid, a solution of a suitable cellulosic agent such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate may be used.

Other orally administrable pharmaceutical preparations include capsules, dry-filled capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Dry-filled capsules contain the active ingredients in the form of particles, for example in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, if appropriate, stabilizers. You may. In soft capsules, the active ingredient is dissolved or suspended in a suitable liquid, such as fatty oil, paraffin oil or liquid polyethylene glycol, to which stabilizers may be added.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Parenteral preparations can be injectable solutions effective in several ways, such as intravenous, intraarterial, intramuscular, intraperitoneal, intranasal, intradermal, subcutaneous, preferably intravenous. Such liquids are preferably isotonic aqueous solutions or suspensions which may be prepared prior to use from lyophilized preparations containing the active ingredient alone or together with a pharmaceutically acceptable carrier.

The pharmaceutical preparations may be sterile and/or may contain additives such as preservatives, stabilizers, wetting and/or emulsifying agents, solubilizing agents, salts to adjust osmotic pressure and/or buffers.

Specifically, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.

In one embodiment of the present invention, the deoxycholic acid derivative compound of Formula 1 according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, is administered in combination/combination with other drugs for the prevention, improvement, or treatment of atopic dermatitis. It can be. Therefore, the present invention also includes a method for treating atopic patients, including combination therapy with the deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt or solvate thereof, and different agents for preventing/treating atopic dermatitis.

In another aspect according to the present invention, an external preparation for preventing, improving or treating atopic dermatitis containing the deoxycholic acid derivative compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient is provided.

In one aspect according to the present invention, the composition for external application may be selected from the group consisting of creams, gels, ointments, emulsions, suspensions, sprays, and transdermal delivery patches, but is not limited thereto.

In one aspect according to the present invention, the external preparation may be applied in an amount of 0.01 to 50 mg per day, specifically 0.1 to 20 mg per day, 1 to several times a day, specifically 1 It can be applied 1 to 3 times a day. It can be applied until the symptoms of atopic dermatitis get better.

In another aspect according to the present invention, a cosmetic composition for preventing or improving atopic dermatitis containing a deoxycholic acid derivative compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient is provided.

In one aspect according to the present invention, the cosmetic composition is a soap for atopy, cleansing foam, cleansing cream, cleansing water, bath agent, skin lotion, skin softener, skin toner, lotion, cream, essence, astringent, emulsion, gel, lipstick, Sprays, shampoos, rinses, treatments, body cleansers, packs, massages, face powders, compacts, foundations, two-way cakes, and makeup bases may be prepared in any one or more formulations selected from, but are not limited thereto.

In one aspect according to the present invention, the cosmetic composition may be commercialized as a formulation selected from the group consisting of soap for atopy, cleansing foam, cleansing cream, cleansing water and bathing agent.

When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide are used as carrier components. It can be.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component, and in particular, in the case of a spray, additional chlorofluorohydrocarbon, propane / May contain a 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, fatty acid esters of glycerol, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Star cellulose, aluminum metahydroxide, bentonite, agar or tragacanth and the like may be used.

When the formulation of the present invention is surfactant-containing cleansing, as carrier components, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives, or ethoxylated glycerol fatty acid esters may be used.

In the specification, “solvate” is a form formed by adding a solvent to a compound, and includes monohydrate, dihydrate, and the like.

In the present invention, "contained as an active ingredient" means that it is contained in a dosage range that improves, prevents, or treats atopic dermatitis, and the dosage range may vary depending on the severity and formulation, and the number of applications is also applied. It can change according to the age, weight and constitution of the subject. In the present invention, "atopic dermatitis" is used in the meaning of including all diseases classified as atopic dermatitis in the art regardless of the direct or indirect cause of its occurrence. Atopic dermatitis usually refers to the time of onset or the subject of the invention. It is classified into infantile atopic dermatitis, juvenile atopic dermatitis, adult-type atopic dermatitis, and maternal atopic dermatitis, and in the present invention, atopic dermatitis is defined to include all types of atopic dermatitis.

In the present invention, if there is "atopic dermatitis", it means a state in which the infected part of the skin is changed by atopic dermatitis, and this state includes both a state considered as a skin disease and a state not considered as a skin disease.

In the present invention, "treatment" includes complete cure of atopic dermatitis symptoms as well as partial cure, improvement, and relief of atopic dermatitis symptoms as a result of applying the pharmaceutical composition of the present invention to the atopic dermatitis site.

In the present invention, “prevention” means preventing the symptoms of atopic dermatitis from occurring in advance by applying the pharmaceutical composition of the present invention to the skin, particularly atopic dermatitis, to suppress or block the symptoms of atopic dermatitis on the skin.

Also, in the present invention, "improvement" is meant to include alleviation, prevention or treatment of symptoms.

In addition, in the present invention, "active ingredient" means a component that exhibits activity alone or exhibits activity together with a carrier (carrier) that itself has no activity.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment or improvement, and the effective dose level is subject type and severity, age, sex, drug activity, drug sensitivity, administration time, route of administration and excretion rate, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field.

As used herein, the term "individual" refers to all animals, including humans, who have already developed or can develop atopic disease, and the deoxycholic acid derivative compound of Formula 1 according to the present invention, a pharmaceutically acceptable salt or solvent thereof By administering a composition containing the cargo to a subject, the disease can be effectively prevented, improved or treated.

Compounds described herein refer to commonly recognized compounds unless otherwise defined.

In addition, the present invention provides a method for preventing, improving or treating atopic dermatitis comprising administering the pharmaceutical composition to a subject.

In addition, the present invention provides the use of the pharmaceutical composition for use in preventing, improving or treating atopic dermatitis.

The composition containing the deoxycholic acid derivative compound of Formula 1 according to the present invention and a pharmaceutically acceptable salt or solvate thereof exhibits excellent effects in treating and improving atopic dermatitis.

1 is a schematic diagram of an experimental schedule for evaluating the effectiveness of a compound (HY303) according to an embodiment of the present invention in a mouse model of atopic dermatitis induced by MC903.

Figure 2 is a diagram showing an image of a mouse ear lesion site when a compound (HY303) according to an embodiment of the present invention is topically or orally administered in an atopic dermatitis mouse model induced by MC903.

Figure 3 is a diagram showing the results of measuring the thickness of the ear when the compound (HY303) according to an embodiment of the present invention was administered topically or orally to each atopic dermatitis-induced mouse model.

4 is a diagram showing clinical score results when a compound (HY303) according to an embodiment of the present invention is administered topically or orally to an atopic dermatitis-induced animal model.

Figure 5 is a diagram and graph showing the results of measuring the thickness of the epidermis and dermis of the mouse ear when the compound (HY303) according to an embodiment of the present invention was administered topically or orally in an atopic dermatitis mouse model induced by MC903.

The present invention relates to a pharmaceutical composition for preventing, improving or treating atopic dermatitis, including a composition containing a deoxycholic acid derivative compound of Formula 1, or a pharmaceutically acceptable salt or solvate thereof.

The present invention will be described in more detail through the following examples. However, the following examples are intended to aid understanding of the present invention and are not intended to limit the scope of the present invention thereto.

<Example>

1. Animal models

7-week-old male Balb/C mice (Samtako, Korea) were purchased and for topical treatment Group1 (Vehicle(EtOH) + Vehicle(HA)) 3 mice, Group2 (MC903 + Vehicle(HA)) 5 mice, Group3 (MC903 + 0.5% HY303) 5 dogs and oral treatment Group4 (Vehicle(EtOH) + Vehicle(CMC)) 3 animals, Group5 (MC903 + Vehicle (CMC)) 5 animals, Group6 (MC903 + 10mg/kg HY303) 5 animals each set and used it.

2. Reagents

- 0.5% HY303 in 1% hyaluronic acid (HA) gel was prepared according to the composition shown in Table 1 and used for topical treatment.

division	To make 1ml Gel	To make 10ml Gel
Usage (Material)	working size
HY303	5mg	50 mg
Polysorbate 80 (Polysorbates) 80	0.5mg	5mg
hyaluronic acid (Hyaluronic acid)	10 mg	100 mg
chlorobutanol (Chlorobutanol)	3 mg	30mg
Purified water (3' Distilled water)	top up to 1ml	top to 10ml

Here, HY303 represents the sodium salt of a deoxycholic acid derivative compound according to Formula 1, and the compound of Formula 3 (2-([3α,12α-dihydroxy-24-oxo-5β-cholan-24-yl] It is the sodium salt of amino)benzensulfonic acid (2-([3α,12α-Dihydroxy-24-oxo-5β-cholan-24-yl]amino)benzensulfonic acid sodium salt).

[Formula 3]

.

- 10mg/kg HY303 in 0.5% CMC was prepared by dissolving 500mg carboxymethylcellulose (CMC) in 100mL of distilled water to prepare 0.5% CMC, and then adding 100mg HY303 to 80mL of 0.5% CMC to prepare 1.25mg/ml HY303. According to the schedule shown in Figure 1, 200 μl of 1.25 mg/ml HY303 (calculated as 25 g of mouse weight) was used for oral treatment in mice of the 10 mg/kg HY303 group.

- MC903 (Sigma, C4369-10MG) for inducing atopic dermatitis on the skin of mice was dissolved in 100% ethanol (Merck, CAS-No. 64-17-5) to prepare 1 nM MC903 1mL, 10 μL was applied to both ears.

3. Test method and test result

- Experiment method

Atopic dermatitis was induced by applying the same amount of MC903 to cover both ears of Balb/C mice. HY303 was topically and orally administered to an atopic dermatitis-induced mouse model. Each processing schedule and method are as shown in FIG. After installing the cage the day before the experiment, mice were placed in the cage and experimental groups were set as follows.

On day 1, mice were labeled with a marker pen either at the ear-punch or at the tail. 10 μL of MC903 was applied to both sides (inner and outer) of the ears of Balb/C mice using a pipette according to the schedule shown in FIG. 1 . At this time, the same amount of MC903 was applied to the entire ear in all mice. Also, the MC903 solution was not applied twice to one area, and the mouse ears were observed until the MC903 was completely dry.

30 minutes after MC903 application, 10 μL of 0.5% HY303 was applied topically to both ears (internal and external) of each designated group and 200 μL of 10 mg/kg HY303 was orally treated.

A. From day 1 to day 9, MC903 was treated q.d (2:00 pm), and oral administration and topical treatment of HY303 were performed b.i.d. at 10:00 am and 5:00 pm.

B. The experiment period may take more than 10 days depending on the degree of recovery of the thickness of the ear. Ear thickness and weight were measured on the 1st, 3rd, 5th, 7th, and 11th days, and images of the lesion area were collected.

C. After collecting skin tissues from each group of mice, the collected tissue samples were cut and fixed in 10% formalin solution for 24 hours, washed with distilled water, and the fixed skin tissues were made into paraffin blocks with a thickness of 7 μm. was cut into slices. Observation and image were collected using an optical microscope after H&E staining using Hematoxylin (Muto Pure Chemical Co. Ltd., Japan) and Eosin (FUJIFILM Wako Pure Chemical Co., Japan) After measuring epidermal and dermal thickness using image analysis software, they were analyzed using analysis software.

- Experiment result

In the group to which MC903 was applied, the skin became red, and an atopic model with a different form from that of the normal group was established. In contrast, in the 0.5% HY303 topical administration group and the 10 mpk HY303 oral administration group, atopic symptoms were visually confirmed to be reduced (FIG. 2). As a result of measuring the ear thickness of mice from day 1 to day 11, it was confirmed that the ear thickness of the HY303-administered group, in which HY303 was topically and orally administered, decreased compared to the MC903 group. As a result of measuring the ear thickness on the 11th day of the last day of administration, when topical administration, the MC903 group was 265.00±6.52 μm, 43.33 μm thicker than the control group, 221.67±1.67 μm, and the 0.5% HY303 group was 227.00±4.90 μm, compared to the MC903 group. It was confirmed that it decreased by 38.00 μm. Upon oral administration, the MC903 group was 290.00 ± 13.04 μm, 68.33 μm thicker than the control group 221.67 ± 1.67 μm, and the 10 mpk HY303 group was 258.00 ± 7.18 μm, a decrease of 32.00 μm compared to the MC903 group (FIG. 3).

The clinical score was also confirmed to decrease by 0.13 compared to the MC903 group from 1.00±0.05 in the MC903 group to 0.87±0.03 in the 0.5% HY303 group. When administered orally, it was confirmed that the MC903 group decreased by 0.12 compared to the MC903 group from 1.22±0.04 to 10 mpk HY303 group 1.10±0.04 (FIG. 4).

It is known that the skin epithelium and dermis become thicker in the case of atopic lesions. H&E staining was performed to confirm the thickness change in the skin upon topical administration of HY303. In the MC903-applied group, it was confirmed that the epidermis and dermis were formed thickly, whereas in the 0.5% HY303 group, the skin thickness was visually confirmed to be reduced. In order to confirm this as an accurate numerical value, the thickness of the epidermis and dermis were measured and graphed. The epithelial thickness of the MC903 group was 23.40±1.00 μm, 7.60 μm thicker than the control group’s 15.80±0.66 μm, and the 0.5% HY303 group was 20.10±1.08 μm, a decrease of 3.30 μm compared to the MC903 group. In addition, as a result of measuring the dermal thickness, the MC903 group was 189.00 ± 8.22 μm, 65.17 μm thicker than the control group 123.84 ± 4.58 μm, and the 0.5% HY303 group was 145.88 ± 7.74 μm, a decrease of 43.13 μm compared to the MC903 group (FIG. 5).

Therefore, the efficacy of the drug was confirmed inside and outside the skin through topical and oral administration of HY303 in an atopic mouse model induced by MC903.

Hereinafter, production examples of each formulation according to the present invention are exemplified. The following preparation examples are intended to aid understanding of the practice of the present invention, but do not mean that the preparation method of the formulation according to the present invention is limited to the following preparation examples.

Preparation Example 1. manufacture of powders

Deoxycholic acid derivative compound of Formula 1 10 mg of a pharmaceutically acceptable salt thereof or a solvate thereof

Sucrose 100 mg

Talc 10 mg

After powdering and mixing the above ingredients, the powder is prepared by filling in an airtight bag.

Preparation Example 2. Preparation of tablets

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

Starch 100 mg

Sucrose 100 mg

Magnesium stearate 2 mg

Tablets are prepared by mixing the above ingredients according to a conventional tablet manufacturing method and then tableting them.

Production Example 3. Production of capsule formulation

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

crystalline cellulose 3 mg

Lactose 15 mg

Magnesium stearate 1 mg

After mixing the above ingredients according to a conventional capsule preparation method, the capsule preparation is prepared by filling a gelatin capsule.

Preparation Example 4. Preparation of granules

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

Soybean Extract 50 mg

Glucose 200 mg

Starch 500 mg

After mixing the above components, 100 mL of 30% ethanol is added and dried at 60° C. to form granules, and then filled into bags to prepare granules.

Preparation Example 5. Preparation of pills

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

lactose 1,500 mg

Glycerin 1,500 mg

Starch 980 mg

After mixing the above components, it is prepared to be 4 g per pill according to the conventional method for preparing pills.

Preparation Example 6. Preparation of injection

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

Mannitol 180 mg

Sterile Distilled Water for Injection 2,970 mg

Na ₂ HPO ₄ 12H ₂ O 30 mg

It is prepared by mixing the above ingredients so that 1 ampoule (2 mL) is prepared according to a conventional injection preparation method.

Preparation Example 7. Preparation of liquid formulation

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 10 mg

Isomerized sugar 10,000 mg

Mannitol 5,000 mg

Appropriate amount of purified water

It is prepared by dissolving the above components in purified water according to a conventional liquid preparation method, adding an appropriate fragrance, and then filling a bottle and sterilizing it.

Production Example 8. Production of soap

After completely dissolving by mixing 330 mL of water and 175 g of NaOH, 10 mg of the deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof was added little by little for about 30 minutes while mixing. The mixture was dried in a shady and well-ventilated place until dry.

Production Example 9. Preparation of bath agent

10 mg of the deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof was heated to about 60° C., and then sun salt was added to make a saturated solution, and water was evaporated. After cooling the solution at room temperature, it was rapidly frozen and lyophilized. A bathing agent was prepared by pulverizing the lyophilized solid preparation.

Preparation Example 10. Preparation of cleansing lotion (unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Sodium ethylenediamine tetraacetate 0.02

Methyl para-hydroxybenzoate 0.2

glycerin 4

Sodium Hyruronic Acid 2

Propylene glycol 3

Carbomer 5

Cetearyl Alcohol 0.7

Glyceryl Stearate 0.5

shea butter 1

P-hydroxybenzoic acid propyl 0.1

1 macadamia nut oil

Sesquioleic acid 0.5

Glyceryl Stearate 1

Polyoxyethyl sorbitan monooleate 2

polydecene 5

Mineral Oil 20

Dimethicone 5

Stearyl Dimethicone 2

Triethanolamine 0.05

proper amount of spices

right amount of pigment

Remaining amount of purified water

It was prepared according to a conventional method in the cosmetic manufacturing field for manufacturing a cleansing lotion using the above ingredients.

Preparation Example 11. Skin Preparation (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Methyl para-hydroxybenzoate 0.2

Sodium ethylenediamine tetraacetate 0.02

1,3-butylene glycol 0.02

allantoin 3

Sodium Hyaluronic Acid 5

Carbomer 0.1

Cetostearyl Alcohol 0.7

P-hydroxybenzoic acid propyl 0.1

Sorbitan Olivate 1.5

Soy lecithin 0.2

Dimethicone 0.2

Ceciloctanoate 0.2

Shea Butter 0.2

sodium polyacrylate 3

Triethanolamine 0.1

Imidazolidinyl Urea 0.3

proper amount of spices

right amount of pigment

Remaining amount of purified water

It is prepared according to a conventional method in the cosmetic manufacturing field for skin manufacturing using the above ingredients.

Preparation Example 12. Serum Preparation (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Jojoba 5

Black Sesame 2

3 sweet almonds

Emulsing Paying Wax 1

Vitamin E 1

glycerin 2

hyaluronic acid 1

Marine Elastin 1

Remaining amount of purified water

It is prepared according to a conventional method in the cosmetic manufacturing field for serum preparation using the above ingredients.

Preparation Example 13. Preparation of Lotion (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Methyl para-hydroxybenzoate 0.2

Sodium ethylenediamine tetraacetate 0.02

1,3-butylene glycol 0.02

allantoin 3

Sodium Hyaluronic Acid 5

Carbomer 0.1

Cetostearyl Alcohol 0.7

P-hydroxybenzoic acid propyl 0.1

Sorbitan Olivate 1.5

Soy lecithin 0.2

Dimethicone 0.2

Ceciloctanoate 0.2

Shea Butter 0.2

sodium polyacrylate 3

Triethanolamine 0.1

Imidazolidinyl Urea 0.3

proper amount of spices

right amount of pigment

Remaining amount of purified water

It is prepared according to a conventional method in the cosmetic manufacturing field for preparing a lotion using the above ingredients.

Preparation Example 14. Essence Preparation (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Allantoin 0.05

Sodium ethylenediamine tetraacetate 0.02

Triethanolamine 0.2

Sodium Hyaluronic Acid 7

Imidazolidinyl Urea 0.15

Sodium polyacrylate 0.4

Carbomer 0.2

ethanol 3

Polyoxyethylene sorbitan monostearate 0.2

Methyl para-hydroxybenzoate 0.2

proper amount of spices

right amount of pigment

Remaining amount of purified water

It is prepared according to a conventional method in the cosmetics manufacturing field for preparing essence using the above ingredients.

Preparation Example 15. Cream preparation (unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Sodium ethylenediamine tetraacetate 0.02

Allantoin 0.1

glycerin 5

Methyl para-hydroxybenzoate 0.2

Sodium Hyaluronic Acid 6

Carbomer 0.1

Cetostearyl Alcohol 1.7

polydecene 2

Squalane 2

P-hydroxybenzoic acid propyl 0.1

Butylene glycol dicaprylate 3

Cetyloctanoate 5

Microcrystalline Lead 0.1

Triethylpentanediol 0.1

Shea Butter 0.2

Sorbitan Olivate 0.3

Cyclomethicone 0.3

Stearyldimethicone 0.5

Imidazolidinyl Urea 0.15

proper amount of spices

right amount of pigment

Appropriate amount of purified water

It is prepared according to a conventional method in the cosmetic manufacturing field for cream manufacturing using the above ingredients.

Preparation Example 16. Pack Manufacturing (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Sodium ethylenediamine tetraacetate 0.02

betaine 3

Glyceryl Polymethacrylate 2

Allantoin 0.1

Sodium Hyruronic Acid 2

glycerin 3

Dipropylene glycol 5

Methyl para-hydroxybenzoate 0.2

polyvinyl alcohol 10

Polyoxyethylene sorbitan monooleate 0.9

Sesquioleic acid 0.3

jojoba ester 2

Cetearyl Alcohol 1.5

Petrolatium 0.5

proper amount of spices

right amount of pigment

Appropriate amount of purified water

It is prepared according to a conventional method in the cosmetic manufacturing field for pack manufacturing using the above ingredients.

Preparation Example 17. Manufacturing of massage cream (unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Appropriate amount of purified water

Glycerin 4.0

Vaseline 3.5

Triethanolamine 0.5

Liquid Paraffin 24.5

Squalane 2.5

Wax 2.1

Tocopheryl Acetate 0.1

Kavapol 1.0

Sorbitan sesquioleate 3.1

incense traces

trace amounts of preservatives

It is prepared according to a conventional method in the cosmetics manufacturing field for manufacturing massage cream using the above ingredients.

Preparation Example 18. Preparation of makeup base (unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Appropriate amount of purified water

coated silica 1

silica 10

titanium dioxide 5

Zinc Oxide 3

pigment 1

Remaining amount of plate powder

It is prepared according to a conventional method in the cosmetic manufacturing field for manufacturing a makeup base using the above ingredients.

Preparation Example 19. Powder Pact Preparation (Unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Appropriate amount of purified water

Mica 15

titanium dioxide 7

silicone oil 3

Ester oil 3

right amount of pigment

proper amount of spices

remaining amount of talc

A powder pact is prepared using the above ingredients according to a conventional method in the cosmetics manufacturing field for preparing a powder pact.

Preparation Example 20. Preparation of two-way cake (unit: v / v%)

Deoxycholic acid derivative compound of Formula 1, a pharmaceutically acceptable salt thereof or a solvate thereof 0.001

Appropriate amount of purified water

Mica 15

Titanium Dioxide 12

silicone oil 3

Ester oil 5

right amount of pigment

proper amount of spices

remaining amount of talc

It is prepared according to a conventional method in the cosmetics manufacturing field for manufacturing a two-way cake using the above ingredients.

The compound of the present invention can provide a pharmaceutical composition for preventing, improving or treating atopic dermatitis, and thus can be usefully used in the field of medicine.

Claims (12)

1. A pharmaceutical composition for preventing, improving or treating atopic dermatitis containing a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient:

   [Formula 1]

   
2. According to claim 1,

   A pharmaceutical composition for preventing, improving or treating atopic dermatitis, wherein the compound of Formula 1 is in the form of an isomer as shown in Formula 2 below:

   [Formula 2]

   

   .
3. According to claim 1,

   The compound of Formula 1 is a salt selected from the group consisting of alkali metal salts, inorganic acid salts, organic acid salts, alkaline earth metal salts, and ammonium salts, a pharmaceutical composition for preventing, improving or treating atopic dermatitis.
4. According to claim 1,

   The pharmaceutical composition is a composition for preventing, improving or treating atopic dermatitis, characterized in that formulated in the form of oral preparations, injection preparations or external preparations.
5. According to claim 5,

   The oral preparation is a composition for preventing, improving or treating atopic dermatitis, characterized in that the formulation is selected from the group consisting of tablets, granules, pills, powders, capsules and solutions.
6. According to claim 5,

   The composition for external application is a composition for preventing, improving or treating atopic dermatitis, characterized in that selected from the group consisting of creams, gels, ointments, emulsions, suspensions, sprays and transdermal deliverable patches.
7. According to claim 5,

   The external agent is a composition for preventing, improving or treating atopic dermatitis, characterized in that applied in an amount of 0.1 to 50 mg per day.
8. A cosmetic composition for preventing or improving atopic dermatitis containing a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient:

   [Formula 1]

   

   .
9. According to claim 9,

   The cosmetic composition is atopic soap, cleansing foam, cleansing cream, cleansing water, bath agent, skin lotion, skin softener, skin toner, lotion, cream, essence, astringent, emulsion, gel, lipstick, spray, shampoo, rinse, treatment A cosmetic composition for preventing or improving atopic dermatitis, characterized in that it is made of one or more formulations selected from the group consisting of body cleansers, packs, massage agents, face powders, compacts, foundations, two-way cakes and makeup bases.
10. A composition for preventing, improving or treating atopic dermatitis in animals other than humans, containing a compound having the structure of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient:

    [Formula 1]

    
11. A method for preventing, improving or treating atopic dermatitis comprising the step of administering to a subject a pharmaceutical composition comprising a compound having the structure of Formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient:

    [Formula 1]

    
12. Use of a pharmaceutical composition comprising a compound having the structure of Formula 1 below, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient for use as a pharmaceutical composition for preventing, improving or treating atopic dermatitis:

    [Formula 1]

    

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