WO2018062922A1 - Composition containing water-solubilized ursodeoxycholic acid for preventing or treating inflammatory skin disease or serious pruritus - Google Patents

Abstract

The present invention relates to a composition for preventing or treating inflammatory skin diseases or severe pruritus, the composition containing water-solubilized ursodeoxycholic acid (UDCA). According to the present invention, inflammatory skin diseases, such as atopic skin disease, acne, psoriasis, urticaria, inflammatory dermatitis, seborrheic dermatitis, and contact dermatitis, and severe pruritus can be effectively alleviated or treated. Therefore, the composition comprising water-solubilized ursodeoxycholic acid disclosed in the present specification can be favorably used as a pharmaceutical, food, or cosmetic composition, and the composition can be used as, especially, an externally-applied dermal preparation, and thus can exhibit effects thereof.

Description

Composition for preventing or treating inflammatory skin disease or severe pruritus containing solubilized ursodeoxycholic acid

The present invention relates to a composition for preventing or treating inflammatory skin diseases or severe pruritus containing solubilized ursodeoxycholic acid (UDCA). More specifically, the present invention provides a pharmaceutical composition excellent for preventing or treating a typical inflammatory skin disease or severe pruritus, such as atopic dermatitis, acne, psoriasis, urticaria, inflammatory dermatitis, seborrheic dermatitis and contact dermatitis, and symptoms caused by inflammatory skin disease. It relates to an external preparation for skin that alleviates.

Atopic dermatitis, acne, psoriasis, urticaria, allergic contact dermatitis or irritant contact dermatitis and seborrheic dermatitis are very typical inflammatory skin disorders, accompanied by local inflammation, edema, keratin hyperplasia and intolerable pruritus.

Recently, the incidence of irritable or inflammatory skin diseases has increased greatly due to changes in the living environment such as industrialization and western eating habits, and those suffering from inflammatory skin diseases have to pay a long treatment period and high costs as well. The disease may result in a passive change in external activity, or, in extreme cases, obesity or depression. The most widely known inflammatory skin diseases include atopic skin diseases, acne and psoriasis.

Atopic dermatitis is a long-lasting chronic dermatitis that usually occurs from 2 to 3 months of age and develops itchy eczema lesions on the skin, and when symptoms appear, the area is scratched or rubbed, resulting in worse skin symptoms. Patients with atopic dermatitis are on the rise worldwide. By the 1970s, about 3% of children under 6 were reported to have atopic dermatitis, but recently, about 1% to 3% of children are diagnosed. It is estimated. In addition, atopic dermatitis causes itching, which is difficult to tolerate, which may cause insomnia, emotional disorders, learning disabilities, decreased ability to adapt to the environment, and reduced social activity. It may also be accompanied by severe itching and eczema, which can be misinterpreted as having poor skin care or a contagious skin disease, which can affect interpersonal relationships, especially in adolescents. . The cause of atopic dermatitis is not yet known, and topical steroids are used as basic treatments, but if applied for a long time, they may cause side effects such as fat, hairy skin, atrophy, capillary expansion, and steroid acne. There are disadvantages (Source: National Health Information Portal http://health.mw.go.kr/).

Acne, on the other hand, is an inflammatory skin disease that develops clogged pores (open and closed cotton), rashes, and deep boils (cysts or nodules) in the face, neck, chest, back, and shoulders. It is common for men between 15 and 19 years old and between 14 and 16 years old. In about 80% of patients, acne lesions gradually disappear until mid-20 years, but sometimes persist after 30-40 years, which is called adult acne. Inflammatory and non-inflammatory lesions appear on the face, body, especially the breast. It is reported that 8% of the population aged 15-34 have acne disease (Source: National Health Information Portal http://health.mw.go.kr/). Acne is not a life-threatening illness, but it puts psychological burden on the patient, and severe acne has been a cosmetic problem because it can leave permanent scars if not treated seriously and appropriately. The exact cause of acne is not clear, and several causes are known to work in combination (Source: National Health Information Portal http://health.mw.go.kr/). Acne treatment generally varies depending on the severity of symptoms and can be divided into drug, edible and surgical treatment (Source: National Health Information Portal http://health.mw.go.kr/). Topical medications include antibiotics such as clindamycin and erythromycin, vitamin A derivatives such as tretnoin and adapalene which have antibacterial action, exfoliation and sebum release. In addition to the strong antibacterial effect, there is a slight anti-inflammatory and cotton soluble benzoyl peroxide (benzoyl peroxide). In recent years, many complexing agents in which two or more of these components are mixed are used. However, there are few side effects to acne to date, and the development of effective treatments is insignificant.

In addition, psoriasis is characterized by erythematous skin lesions covered with a clear, white-white squama, which occurs mainly in the most irritated areas such as elbows, knees, hips, and scalp. From small papules to plaque, pustules, deprived psoriasis and psoriatic arthritis, various clinical features are shown. Exacerbation and improvement are occasional chronic inflammatory skin diseases. The cause of psoriasis is not yet known for certain. There are many different methods for the treatment of psoriasis, including topical treatment with drugs, phototherapy with light, systemic therapy with medicine, and recently developed biologic therapy (Source: The Korean Society for Psoriasis, http://kspder.or.kr). However, psoriasis is still known to be difficult to cure.

Currently, the market for inflammatory skin disease is estimated to be about $ 3 billion, but various folk remedies and biological agents are used without obvious treatments. Medically, corticosteroids are widely used for oral, topical ointments, and nasal sprays. However, due to their serious side effects, there are many restrictions. Various biological agents are also expensive and have limited limitations in general use with limited methods of administration.

Registered patent (Registration No .: 10-1645355) related to external skin preparations for improving inflammatory skin diseases uses three extracts to measure the effects of inhibiting inflammatory cytokine expression, antibacterial effect, antioxidant effect, moisturizing effect, and skin barrier effect. A topical skin improvement agent for improving atopic skin is described.

Ursodeoxycholic acid (UDCA), which is intended to be used as an agent for alleviating and treating inflammatory skin diseases herein, has anti-inflammatory, antioxidant, cellular and cell membrane protective, anti-inflammatory, immunomodulatory, mitochondrial protective and cellular properties in vitro tests. It is known to have a suicide inhibitory effect, and thus will show an excellent effect in the treatment of inflammatory skin diseases.

However, in order to be used as a skin external preparation for improving and treating inflammatory skin diseases and severe pruritus, it is necessary to overcome the problem of being classified as a skin irritant, which is a major disadvantage of only ursodeoxycholic acid, and skin impermeability.

In order to overcome the above disadvantages and to produce a therapeutic effect, the present inventors had to first dissolve ursodeoxycholic acid in high concentration in water, which is an aqueous layer material of the skin coating. This is because the main factors that need to be supplemented and modified in order to enhance the drug metabolism and pharmacokinetics in drug development are problems of low solubility of the drug candidate in water and its low permeability.

Ursodeoxycholic acid should be present in a form that is sufficiently dissolved in water at a high concentration. Due to its molecular nature, ursodeoxycholic acid is a planar amphoteric molecule having both a hydrophobic surface without a substituent and a hydrophilic surface including a hydroxyl group, and bile acid (bile). Since it exists in protonated form like dihydroxy-bile acids, which are two kinds of acid, which is a kind of acid, it is practically insoluble in water. The solubility of ursodeoxycholic acid in water is low as high as 53 μM (20 mg / L). This low reason is because the crystal structure of the ursodeoxycholic acid molecule is very stable. These bile acid anions self-associate at very narrow concentrations in water to form micelles. Micelles consisting solely of bile acid anions and accompanying counter ions) are called simple micelles, and the main characteristic of these simple bile acid micelles is their ability to convert into mixed micelle lipid bilayers. Therefore, bile acid or ursodeoxycholic acid are difficult to pharmacologically act as a single molecule in the skin due to the formation of a large molecule size of micelles, and also cannot be permeable to human skin due to the molecular size of micelles. Therefore, there is a big disadvantage in expressing various effects of UDCA. As such, ursodeoxycholic acid could not penetrate through the skin in an amount effective enough to alleviate or treat skin diseases because of its crystal structure.

In addition, pKa, the acid dissociation constants of crystalline UDCA, is acidic in water at around 5.0, which may cause skin irritant when applied to the skin or may be harmful when contacted with the skin. There are serious drawbacks in the development of skin coatings. In other words, the crystalline ursodeoxycholic acid has a very sharp needle-like structure, and when applied to the skin, it does not dissolve well in acid because the pH of the skin is in an acidic condition between the skin and into the pores and wounded skin. Instead of being washed off and staying in place, the skin continues to irritate and cause skin redness.

In addition, since crystalline ursodeoxycholic acid dissolves well in ethanol or anhydrous ethanol, it can be devised to develop a topical preparation of skin effective in dissolving ursodeoxycholic acid in a solvent, but the ursodeoxycholic acid molecule is hydrophilic. Depending on the unique chemical properties of both (hydrophilic) and lipophilic (hydrophobic), even if it is temporarily dissolved in oily parts (lipophilic) raw materials such as ethanol, hydrophilic raw materials are added for emulsification when preparing skin coatings. The molecules clump together to form micelles or precipitates. That is, although the crystalline ursodeoxycholic acid preparation is dissolved in ethanol and temporarily mixed well with the oily raw material of the skin coating agent, it is not evenly mixed and emulsified as a whole as time passes after the oily raw material is added. That is, even if the crystalline ursodeoxycholic acid is sometimes mixed and emulsified, it self-associates again to form ursodeoxycholic acid micelles or precipitates, which is not suitable for use as a raw material for skin coating preparation. As described above, ursodeoxycholic acid (UDCA) is insoluble in water due to its molecular nature (53 μM), and is acidic, and when applied to the skin, it causes skin irritant and does not penetrate the skin. There are disadvantages.

Many researchers around the world have long tried to use as a raw material for external skin to lower inflammation with ursodeoxycholic acid, but it was difficult to dissolve ursodeoxycholic acid in water at high concentrations, and the form of crystalline ursodeoxycholic acid which is poorly soluble in water itself It was classified as a skin irritant and could not be used as a skin coating material.

To date, there is no known external skin composition for improving and treating inflammatory skin diseases and severe pruritus, including ursodeoxycholic acid dissolved in water at a high concentration of 0.15 M.

It is an object of the present invention to increase the skin permeability of crystalline UDCA which is difficult to permeate skin and causes skin redness and harmful to the human body upon skin contact, and also can be used as an external preparation for skin that does not cause skin redness. Ursodeoxycholic acid solubilized in the form of a clean aqueous solution to the) to provide a composition for improving and treating inflammatory skin diseases.

An object of the present invention is to remove the intermolecular cohesion caused by the chemical properties of ursodeoxycholic acid having a unique chemical property having both hydrophilic and hydrophobic at the same time to the aqueous phase of the skin external composition ( Lipophilic) and oil phase parts (hydrophilic) raw materials, and even after a period of time solubilized in water in the form of a clean solution in water so that emulsification (emulsification) without precipitation or coagulation phenomena to provide a ursodeoxycholic acid composition will be.

An object of the present invention is that the ursodeoxycholic acid does not aggregate or precipitate again even when emulsified with the composition raw material for preparing the external preparation for skin, and exists as a single molecule, and thus can fully exhibit pharmacological action through high efficiency through human skin cells. It is to provide an aqueous solubilized ursodeoxycholic acid composition.

An object of the present invention is a solubilized urethane solution in the form of a clean aqueous solution capable of applying urethane deoxycholic acid to the skin at a high concentration while reducing skin discomfort and high discomfort. It is to provide a composition for the prevention or treatment of inflammatory skin diseases comprising oxycholic acid and maltodextrin as an active ingredient.

Another object of the present invention is to provide a skin external preparation for improving and treating inflammatory skin diseases including the composition as an active ingredient, which reduces discomfort such as foreign body tingling and tingling after skin application.

Still another object of the present invention is to provide an external preparation for skin containing the composition as an active ingredient, which has an effect of alleviating the symptoms of inflammatory skin disease.

Other objects and advantages of the present invention will become apparent from the following detailed description, claims and drawings.

According to one aspect of the invention, (a) ursodeoxycholic acid (ursodeoxycholic acid, UDCA); (b) water soluble starch preparations; And (c) water as an active ingredient, but a composition for preventing or treating inflammatory skin diseases or severe pruritus in a clear aqueous solution for all pH values is provided.

According to an embodiment of the present invention, the UDCA is solubilized with UDCA selected from a water-soluble UDCA, a water-soluble UDCA derivative, a UDCA salt, and a UDCA conjugated with an amine, an inflammatory skin disease or severe pruritus. Provided are compositions for the prophylaxis or treatment.

According to one embodiment of the invention, the UDCA is solubilized with at least one UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA). Provided is a composition for preventing or treating inflammatory skin disease or severe pruritus.

According to one embodiment of the invention, the UDCA is characterized in that it comprises 0.01 to 6 parts by weight based on the total weight of the composition, there is provided a composition for the prevention or treatment of inflammatory skin disease or severe pruritus.

According to one embodiment of the present invention, the water-soluble starch preparation is maltodextrin, the maltodextrin is characterized in that it comprises 1.0 to 70 parts by weight based on the total weight of the composition, prevention of inflammatory skin disease or severe pruritus Or a therapeutic composition is provided.

According to one embodiment of the invention, the pH value is 3 to 9, the water-soluble starch invert is maltodextrin, characterized in that the minimum weight ratio of maltodextrin to UDCA is 1:16-1:30. Provided is a composition for preventing or treating inflammatory skin disease or severe pruritus.

According to one embodiment of the invention, the pH value is 6 to 9, the water-soluble starch invert is maltodextrin, characterized in that the minimum weight ratio of maltodextrin to UDCA is 1:13-1:30. Provided is a composition for preventing or treating inflammatory skin disease or severe pruritus.

According to one embodiment of the invention, the water-soluble starch invert is characterized in that at least one of maltodextrin, dextrin, liquid glucose, corn syrup solids, soluble starch, dextran, guar gum, pectin and soluble non-starch polysaccharides, A composition for preventing or treating inflammatory skin disease or severe pruritus is provided.

 According to one embodiment of the present invention, the inflammatory skin disease is atopic dermatosis, acne, psoriasis, inflammatory skin disease, seborrheic dermatitis and contact dermatitis. Provided is a composition for the prophylaxis or treatment of inflammatory skin disease or severe pruritus, selected from (contact dermatitis).

According to an embodiment of the present invention, the severe pruritus is provided with a composition for preventing or treating inflammatory skin disease or severe pruritus, including when the skin itch interferes with sleep and daily life, thereby preventing normal activities.

According to one embodiment of the invention, the UDCA is contained in an effective amount, there is provided a composition for the prevention or treatment of inflammatory skin disease or severe pruritus.

According to one embodiment of the present invention, an effective amount is provided in a composition for preventing or treating inflammatory skin disease or severe pruritus, which is an amount capable of preventing or treating inflammatory diseases or severe pruritus of the skin or alleviating or treating a disease already produced.

According to another aspect of the present invention, there is provided a composition for preventing or treating inflammatory skin disease or severe pruritus, wherein the composition of the substrate is dried and formulated in powder form.

According to an embodiment of the present invention, a composition for preventing or treating inflammatory skin disease or severe pruritus, which is formulated by mixing the powder with water at pH 7 or less, is provided.

According to another aspect of the present invention, there is provided an external preparation for skin for the prevention or treatment of inflammatory skin disease or severe pruritus comprising the composition of the substrate as an active ingredient.

According to one embodiment of the present invention, the external preparation for skin is provided with an external preparation for the prophylaxis or treatment of inflammatory skin disease or severe pruritus having a formulation of an ointment, gel, cream, patch and spray.

According to one embodiment of the present invention, a skin external preparation for preventing or improving inflammatory skin disease or severe pruritus, which is used for at least one week and at least once a day, is provided.

According to an embodiment of the present invention, a skin external preparation is provided, comprising the composition of the substrate as an active ingredient, alleviating the symptoms caused by burns or inflammatory skin diseases.

According to an embodiment of the present invention, the external preparation for skin is provided with an external preparation for skin, characterized in that it alleviates one or more symptoms of itching, keratinogenesis, and skin redness caused by an inflammatory skin disease.

According to an embodiment of the present invention, the external preparation for skin is provided with an external preparation for skin.

According to an embodiment of the present invention, the cosmetic is a flexible cosmetics, astringent cosmetics, nourishing cosmetics, eye cream, nutrition cream, massage cream, cleansing cream, cleansing foam, cleansing water, body lotion, body cream, body essence, shampoo, External skin preparations are provided that are rinse, body cleansers, essences or packs.

According to one embodiment of the invention, the skin external preparation is characterized in that the pH of 3 to 9, the external preparation for the skin is provided.

The composition for the prevention or treatment of inflammatory skin disease or severe pruritus according to an embodiment of the present invention is a form of ursodeoxycholic acid, which is solubilized in water at high concentration, so that the skin problem is a fundamental problem of conventional crystalline ursodeoxycholic acid ( There is a merit that can solve skin irritation.

The composition for the prevention or treatment of inflammatory skin disease or septic pulmonary disease according to an embodiment of the present invention has a high skin permeability, and a large amount of ursodeoxycholic acid is delivered to the skin cells, which was limited due to the limitation of the conventional crystalline ursodeoxycholic acid formulation. And by enabling the absorption there is an advantage that can achieve an excellent prophylactic or therapeutic effect against inflammatory skin diseases or severe pruritus.

The composition for the prevention or treatment of inflammatory skin disease or septic pruritus according to an embodiment of the present invention has the advantage of achieving the effect of preventing or treating inflammatory skin disease even with a small amount of high skin permeability.

When the external preparation for skin according to an embodiment of the present invention is used, there is almost no discomfort such as foreign body tingling and tingling of ursodeoxycholic acid, and a skin external preparation for preventing or treating inflammatory skin disease with enhanced stability of the ursodeoxycholic acid preparation is provided. can do.

There is an advantage that can effectively treat acne by using an external preparation for skin according to an embodiment of the present invention.

Using an external preparation for skin according to an embodiment of the present invention has an advantage of suppressing excessive sebum secretion, which is one of the causes of acne.

There is an advantage that can effectively treat atopy using the external preparation for skin according to an embodiment of the present invention.

There is an advantage that can effectively treat psoriasis by using an external preparation for skin according to an embodiment of the present invention.

Using an external preparation for skin according to an embodiment of the present invention has an advantage of effectively inhibiting and treating an inflammatory response, which is a main symptom in various inflammatory skin diseases.

Using the external preparation for skin according to an embodiment of the present invention has the advantage of further increasing the moisturizing effect of the conventional skin coating.

Using the external preparation for skin according to an embodiment of the present invention, it is possible to provide an external preparation for skin that can alleviate the symptoms caused by burns or inflammatory skin diseases.

Therefore, according to the present invention, edema and keratin hyperplasia due to skin dryness, itching and local inflammation, which are the main clinical features of typical inflammatory skin diseases such as atopic dermatitis, acne, psoriasis, urticaria, inflammatory dermatitis, seborrheic dermatitis and contact dermatitis It is excellent in preventing, reducing symptoms, alleviating and treating each step of microbial infection.

1 shows whether a clean aqueous solution is generated according to a pH value of a solution of ursodeoxycholic acid prepared according to Example 3 of the present invention.

Figure 2 shows whether or not to generate a clean aqueous solution according to the pH value of the solution of ursodeoxycholic acid prepared by Example 4 of the present invention.

3 shows whether a clean aqueous solution is generated according to the pH value of the solution of ursodeoxycholic acid prepared according to Example 5 of the present invention.

4 shows whether a clean aqueous solution is produced according to the pH value of the solution of ursodeoxycholic acid prepared according to Example 6 of the present invention.

5 shows whether a clean aqueous solution is produced according to the pH value of the solution of ursodeoxycholic acid prepared according to Example 7 of the present invention.

Figure 6 shows a comparison of the skin permeability of the cream formulation and the patch formulation of the composition according to an embodiment of the present invention.

7A and 7B are numerical changes of acne grade (a) and numerical improvement rate of acne grade (%) before, after 2 weeks, after 4 weeks, and after 8 weeks of use of the composition according to one embodiment of the present invention. b) is shown.

Figures 8a and 8b shows the change in sebum (a) and the rate of improvement (%, b) of sebum before use, after 2 weeks, after 4 weeks and after 8 weeks of use of the composition according to an embodiment of the present invention will be.

Figures 9a and 9b shows the result of photographing the composition according to Example 2 with an omnocular imaging system after applying for 8 weeks to the acne skin to determine the improvement suitability of acne skin.

Figure 10 shows the evaluation results for the total atopic dermatitis patients evaluated using the composition (formulation example 1) in the form of a cream (1) according to the present invention.

FIG. 11 shows the evaluation results of 11 patients with severe atopic symptoms among all atopic dermatitis patients evaluated using the composition of the cream (1) form according to the present invention.

12 is a schematic diagram showing the overall experimental method of the efficacy test in the psoriasis animal model for determining the suitability of the use of psoriasis skin according to the present invention, G1 is a control group applied petrolatum lotion from day 1 to 11 and G2 is 5 % Imiquimod (IMQ) cream applied to psoriasis by applying from 1 to 8 days and G3 is applied 5% imiquimod (IMQ) cream from 1 to 8 days at the same time, 5 to 11 days A group of test creams were applied at the same time to test for psoriasis symptoms.

Figure 13a to 13c shows the results of the efficacy test in the psoriasis animal model according to the present invention, Figure 13a is a photograph of the extent of keratinization on the skin of each group on day 10 and Figure 13b is a disease of these psoriasis symptoms Figure 13c is a graph showing the numerical value by measuring the activity activity (Disease activity index, DAI) as an indicator, and the level of the hyperkeratosis in the skin of psoriasis-induced animals.

FIG. 14 shows the results of potency 12-myristate 13-acetate test showing the effect of solubilized ursodeoxycholic acid on the inhibition of the inflammatory response, which is the main symptom of various inflammatory skin diseases in the acute dermatitis animal model according to the present invention. TPA) is a graph showing the change in the thickness of the ear caused by inflammation.

Certain terms are defined herein for convenience of understanding the invention. Unless defined otherwise herein, scientific and technical terms used herein have the meanings that are commonly understood by one of ordinary skill in the art. Also, unless specifically indicated in the context, the singular forms "a", "an", and "the" are intended to include their plural forms as well.

As used herein, the term "treatment" refers to any action in which the symptoms of an inflammatory skin disease improve or benefit from administration of a composition of the present invention.

As used herein, the term "comprising as an active ingredient" means the extent to be effective as a composition for preventing or treating inflammatory skin diseases, a composition for external application for skin and an external preparation for skin, for example, a prophylactic effect, a therapeutic effect, It means that it contains enough to relieve itching, atopic dermatitis, moisturizing effect, alleviating effect.

As used herein, the term "relaxation", "mitigation", or "calm" means any action that at least reduces the parameters associated with the condition being treated, such as the extent of symptoms.

As used herein, the term "corn syrub" may include both corn syrup and liquid glucose.

As used herein, the term "clean aqueous solution" or "clear aqueous solution" means an aqueous solution in a clear state in a solution state substantially free of visual deposits.

According to one aspect of the invention, (a) ursodeoxycholic acid (ursodeoxycholic acid, UDCA); (b) water soluble starch preparations; And (c) water as an active ingredient, but a composition for preventing or treating inflammatory skin diseases or severe pruritus in a clear aqueous solution for all pH values is provided.

The ursodeoxycholic acid may be stabilized together with maltodextrin, resulting in an increase in solubility of the pure ursodeoxycholic acid molecule in water by at least 3,000 times. The solubilized ursodeoxycholic acid (UDCA) dissolved in water as described above is dissolved in an aqueous solution in a nonionic molecular state having amphiphilic properties due to its molecular characteristics, so The absorption rate of ursodeoxycholic acid can be dramatically increased since it is absorbed in vivo by the intercellular, intracellular diffusion as well as the passive mechanism. In conclusion, solubilized ursodeoxycholic acid (UDCA), which contains ursodeoxycholic acid dissolved in water at a high concentration up to 60 g / L, is the most ideal multifunctional anti-inflammatory drug. When applied as a skin coating, various inflammatory skin diseases, pruritus and allergic skin diseases can be prevented, alleviated or treated.

UDCA is a nontoxic hydrophilic bile acid and is orally administrable. Total bile acid in humans is at a low concentration of about 3%, but is also present in human bile and is a drug approved by the US FDA. The pharmacological action of UDCA can act as an anti-inflammatory agent that not only regulates the mRNA expression levels of phospholipase A2 and TNF-α, which produce inflammatory factors, but also inhibits cellular damage caused by inflammation. have. In addition, UDCA has a cytoprotective action, stabilization / protection of cell membranes in a dose-dependent manner, an anti-cell killing effect in a dose-dependent manner, an immunomodulatory effect by activation of intracellular glucocorticoid receptors in a dose-dependent manner, Anti-inflammatory effects by inhibition of alpha (TNF-α) expression and inhibition of nitric oxide synthase (Hepology Research 2008; 38: 123-131).

The composition of the present invention is not limited thereto, but the solubility of the UDCA in the composition may be about 3,000 times or more (0.15 M vs. 0.05 mM) compared to existing commercially available UDCA formulations, and compared to the taurine conjugated metabolite TUDCA of UDCA. , About 300 times or more. The solubility of the protonated form of UDCA is about 0.05 mM, the solubility of TUDCA is 0.45 mM, and TUDCA has a relatively low solubility when quantized, but is about 10 times higher than the solubility of commercialized UDCA (pH 1-8). Accordingly, the present invention includes UDCA, TUDCA and the like.

When orally administered UDCA, about 30 to 60% is absorbed along the intestines and dolma by nonionic passive diffusion, and the crystalline structure of UDCA (crystalline UDCA) in small amounts due to insolubility Only 20% of the ingested dose) is absorbed by the dorsum by the active transport mechanism. When UDCA is absorbed by hepatocytes, it can be conjugated with taurine and glycine, and the TUDCA and GUDCA thus formed are excreted by hepatic first-pass clearance to bile acids secreted by humans. Therefore, after oral administration, the concentration of UDCA in the blood is very low, which is insufficient as an effective amount for treating skin diseases. Therefore, in order to provide a composition for preventing or treating inflammatory diseases, a large amount of dosage is required.

However, the composition of the present invention has a high skin permeability of UDCA in aqueous solution compared to conventional oral dosage forms and formulations in powder form (forms achievable by conventional formulations in which bile is incompletely solubilized), and the UDCA in the formulation of the present invention. Since all are dissolved, it is possible to achieve a prophylactic or therapeutic effect of high inflammatory skin disease even at a lower dose.

Using the preparations according to the invention, various concentrations of bile acids (salts) and their corresponding minimum amounts of DE (dextrose equivalent) are 15 to 25 high molecular weight water soluble starch inverts [eg Maltrin M150 (DE = 15). ), Maltrin M180 (DE = 18), Maltrin M200 (DE = 20), Matrin M250 (corn syrup component: DE = 25, liquid glucose)] or soluble non-starch polysaccharides (eg guar gum, pectin, arivia) Aqueous solution formulations) can be prepared.

According to one embodiment of the present invention, the ursodeoxycholic acid is selected from a water-soluble ursodeoxycholic acid, a water-soluble ursodeoxycholic acid derivative, a ursodeoxycholic acid salt, and a ursodeoxycholic acid conjugated with an amine. It can be solubilized as sodeoxycholic acid. Water-soluble metal salts of ursodeoxycholic acid, clathrate compounds between ursodeoxycholic acid and cyclodextrins and derivatives thereof and water-soluble O-sulfonated bile acids may also be included as water-soluble ursodeoxycholic acid salts.

According to one embodiment of the invention, the ursodeoxycholic acid is one or more UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) Characterized by being solubilized.

According to an embodiment of the present invention, ursodeoxycholic acid is provided for the prevention or treatment of inflammatory skin disease or severe pruritus, characterized in that it comprises 0.01 to 6 parts by weight based on the total weight of the composition.

Although not limited thereto, ursodeoxycholic acid may be less than 0.01 part by weight based on the total weight of the composition, and may be ineffective in preventing or treating inflammatory skin diseases or severe pruritus. Can be. Although not limited thereto, it may be difficult to use as a skin coating agent when the precipitation is cloudy without being a clean aqueous solution. When precipitation occurs, ursodeoxycholic acid may be present as crystalline UDCA without dissolving in water. When it is prepared with a skin coating agent, skin redness is likely due to crystalline UDCA. The preparation of a clean aqueous solution is to remove all crystalline UDCA causing skin flare problem in the preparation of the skin coating agent.

According to one embodiment of the present invention, the water-soluble starch preparation is maltodextrin, the maltodextrin is characterized in that it comprises 1.0 to 70 parts by weight based on the total weight of the composition, prevention of inflammatory skin disease or severe pruritus Or a therapeutic composition is provided.

Although not limited thereto, maltodextrin may not be dissolved in water in an effective amount of less than 1.0 part by weight of maltodextrin, which may have a negligible effect of preventing or treating inflammatory skin disease or severe pruritus. This can cause UDCA or maltodextrin to precipitate out of aqueous solution, resulting in skin redness.

According to one embodiment of the invention, the water-soluble starch compound is maltodextrin, the minimum weight ratio of maltodextrin to ursodeoxycholic acid may be 1:30, but is not limited thereto, 1:25, 1: 20, 1:15, 1:12, 1: 6. The amount of high molecular weight, water soluble starch integrant used in the composition can be defined as the amount that is soluble in the selected concentration of ursodeoxycholic acid and in the pH ranges described herein. The minimum amount of maltodextrin can be equally applied to taurusodeoxycholic acid and glycoursodeoxycholic acid.

According to one embodiment of the invention, the pH value is 3 to 9, the water-soluble starch invert is maltodextrin, characterized in that the minimum weight ratio of maltodextrin to UDCA is 1:16-1:30. Provided is a composition for preventing or treating inflammatory skin disease or severe pruritus. Although not limited thereto, the minimum weight ratio of maltodextrin to UDCA is 1: 16-1: 20, 1: 16-1: 25, 1: 16-1: 30, 1: 20-1: 25, 1: 20-1: 30, 1: 25-1: 30.

Although not limited thereto, when the pH value is 3 or more and less than 6, when the minimum weight ratio of maltodextrin to UDCA is 1: 1 to 1:15, precipitation may occur and thus may not be a clean aqueous solution.

According to one embodiment of the invention, the pH value is 6 to 9, the water-soluble starch invert is maltodextrin, characterized in that the minimum weight ratio of maltodextrin to UDCA is 1:13-1:30. Provided is a composition for preventing or treating inflammatory skin disease or severe pruritus.

The water-soluble starch inverts of the present invention comprise carbohydrates obtained directly from a portion or incomplete hydrolysis of starch under various pH conditions. Non-limiting examples can be maltodextrin, dextrin, liquid glucose, corn syrup solids (dry powder of liquid glucose). The solid corn syrup is Maltrin M200, maltodextrin may be Maltrin M700, but not limited to, but may be prepared by the brand name GPC of Grain Processing Corporation of Muscutin, Iowa, USA.

When the starch invert is made of a polymer, the polymer may have at least one reducing end and at least one non-reducing end, and may be straight or branched chain. In addition, the molecular weight may be at least about 100 mass units, or at least 106 mass units. Although not limited thereto, high molecular weight water-soluble starch inverts may have a molecular weight of at least 105 mass units.

According to one embodiment of the invention, it may further comprise a soluble non-starch polysaccharide. The water-soluble non-starch polysaccharides can be obtained under various pH conditions by various hydrolysis or synthesis mechanisms. Non-limiting examples include dextran, guar gum, pectin, indigestible soluble fibers and the like. When made of a polymer, the polymer has at least one reducing end and at least one non-reducing end. The polymer may be straight or branched chain. The molecular weight of the polysaccharide of the present invention may be at least about 100 mass units, or at least 106 mass units. Although not limited to this, the molecular weight is preferably at least 105 mass units. The composition may be provided with a composition that is an aqueous solution comprising a combination of water soluble starch inverts and / or soluble non-starch polysaccharides.

According to one embodiment of the invention, the minimum weight ratio of liquid glucose (eg, corn syrup) to ursodeoxycholic acid required to prevent precipitation of the composition is about 1:25 (ie, ursodeoxy in 100 ml of water). About 12.5 g per 500 mg of cholic acid, and about 25 g per 1 g of ursodeoxycholic acid in 200 ml of water), but is not limited thereto.

In addition, from the dosage form of the composition of the present invention, the minimum amount of dry powder of liquid glucose (corn syrup solids, such as Maltrin M200) required to prevent precipitation may be about 30 g per 1 g of ursodeoxycholic acid in 100 ml of water. And about 60 g per 2 g of ursodeoxycholic acid in 200 ml of water, but is not limited thereto.

From the dosage form of the composition according to an embodiment of the present invention, the minimum amount of soluble non-starch polysaccharides necessary to prevent precipitation may be about 50 g of guar rubber per 500 mg of ursodeoxycholic acid in 100 ml of water and urine in 100 ml of water. 80 g of pectin per 500 mg of sodeoxycholic acid. Provided that the minimum required amount of high molecular weight water soluble starch inverts or soluble non-starch polysaccharides can be determined primarily by the absolute amount of ursodeoxycholic acid in the solution formulation, rather than by concentration.

The composition of the present invention may further comprise a dietary fiber. Non-limiting examples of dietary fiber include, but are not limited to, guar rubber, pectin, psyllium, oat rubber, soy fiber, oat bran, corn cob, cellulose and wheat bran.

The composition of the present invention may further comprise an emulsifier and suspending agent. Non-limiting examples of emulsifiers include guar gum, pectin, acacia, carrageenan, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinyl alcohol, povidone, tragacanth rubber, xanthan gum and sorbitan Ester is mentioned.

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

In addition, the composition of the present invention may be administered in a topical skin preparation formulation during actual clinical administration, and when formulated, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, etc. that are commonly used. Can be.

According to an embodiment of the present invention, the pH of the solubilized ursodeoxycholic acid composition is 3 to 9, the composition for preventing or treating inflammatory skin diseases in which the composition is a stable aqueous solution without visual precipitation at the pH value. This may be provided. The composition may be solubilized in water and may be in an aqueous solution without precipitation at the pH. The selected pH range that does not precipitate ursodeoxycholic acid and water-soluble starch integrant in the composition may be between about pH 1 and about pH 10, with about pH 3 to about pH 9 being suitable, but not limited to, 6 to 9 are more suitable, and 6.5 to 7.5 are more suitable. It may also contain acids, bases and buffers if necessary to maintain the pH. The pH adjusting material is not limited thereto, but is not limited to HCl, H ₃ PO ₄ , H ₂ SO ₄ , HNO ₃ , CH ₃ COOH, citric acid, malic acid, tartaric acid, lactic acid, phosphate, edetic acid and alkali. Can be. The nature and manner of use of such pH adjusting materials are well known in the art. The pH range is any subset of pH levels that can be obtained in an aqueous system sufficient for various formulations to remain in solution from the formulation and to be applied to and absorbed by the skin, depending on the method of administration. Thus, the composition can be used as a formulation in solution without the composition according to the present invention being precipitated at the pH level of the skin. Ursodeoxycholic acid according to some embodiments of the present invention remains free under acidic conditions as a free state despite being generally insoluble under acidic conditions. When the composition is added to the skin coating formulation may further comprise a composition in a form that is maintained solubility. In addition, the composition may provide a transparent and stable solution to provide a composition for the prevention or treatment of inflammatory skin disease or severe pruritus.

According to an embodiment of the present invention, the inflammatory skin disease is provided with a composition for the prevention or treatment of inflammatory skin diseases or severe pruritus selected from atopic skin diseases, acne, psoriasis, urticaria, inflammatory dermatitis, seborrheic dermatitis and contact dermatitis. Can be.

Urticaria refers to a common skin disease in which plasma components accumulate in tissues temporarily due to increased permeability of blood vessels in the skin or mucous membranes, causing skin redness or swelling and accompanied by severe itching. By swelling the skin, often accompanied by severe itching or tingling. The swelling of the skin, like when bitten by insects, is called swelling. The rash is characterized by varying sizes and red swelling. Angioedema is similar to urticaria, but swelling from the depths of the skin is called angioedema. Urticaria or angioedema is a common disease that is experienced once in a lifetime. Urticaria is also divided into acute and chronic urticaria and angioedema over time. Most acute urticaria is usually caused by food or drugs, and usually improves within a few days up to six weeks. define. Hives are often not found to be the cause. It is reported that 50% of acute urticaria and 70% of chronic urticaria cannot find the cause of urticaria, and only a part of all urticaria patients can identify the cause (Seoul National University Hospital Medical Information).

Inflammatory dermatitis is not limited to this, but the symptoms caused by inflammation during skin disease are mainly considered to mean that parasites, microorganisms, allergies, etc. can not be considered as a cause (Agricultural Dictionary: Rural Development Administration).

Seborrheic dermatitis is a type of eczema that lasts for a long time. Chronic inflammatory skin disease that occurs mainly in the scalp and face where sebum secretion is increased due to increased sebaceous gland activity, especially eyebrows, nose, around the lips, ears, armpits, chest, and inguinal area. Such as the theory that sebum is directly or indirectly involved in the development of the disease, the theory that it is caused by bacteria and yeast, the theory that it may be related to abnormalities of neurotransmitters, and the theory that it may be caused by seasonal changes or abnormal epidermal growth. Theories have been reported, but the cause of seborrheic dermatitis is not yet clear. Seborrheic dermatitis occurs more frequently within three months of age and between 40 and 70 years of age, and there is no gender difference in infants, but it is more common in men and is related to oily skin in adults. It is characterized by dry or greasy yellow scales (salts) that develop on the erythema and can be accompanied by itching. It may appear systemic with repeated improvement and deterioration, but it may also appear as a localized rash. The scalp can cause the appearance of rice bran epidermis, which is called dandruff. Seborrheic dermatitis on the face can appear as papular (less than 1 cm) rashes on the cheeks, nose and forehead. Peeling scales and erythema are found on the eyebrows and the skin under the scales is reddish. The eyelids are yellowish red and covered with fine scales. Seborrheic dermatitis in the ear develops scales with severe itching and can also occur on the back of the ear and under the earlobe. In the armpit area, the rash starts bilaterally and spreads to the surrounding skin, which is similar to allergic contact dermatitis caused by deodorants. Wrinkles between furrows and buttocks also have fine scales, less clear boundaries, and tend to be bilateral and symmetrical. Cracks may occur in areas where skin overlaps (Medical Information, Seoul National University Hospital).

Contact dermatitis refers to all dermatitis caused by contact with foreign substances. It is divided into primary contact dermatitis caused by stimulation of contact substance itself and allergic contact dermatitis which occurs only in people who have allergic reaction to contact substance. Contact dermatitis is divided into primary contact dermatitis and allergic contact dermatitis, but the symptoms are similar. It mainly causes eczema-type lesions with erythema (round red dots) and edema. In some cases, acne lesions, urticaria lesions, polymorphic erythema, pigmentation, and granulomatous lesions may also occur (Seoul National University Hospital Medical Information).

In the case of psoriasis or atopic skin disease, the roughness of the skin appears as an abnormal increase in keratinocytes or keratinocytes constituting the stratum corneum, and the composition of the present invention regulates the proliferation rate of these keratinocytes and hyperproliferative skin diseases. It can be used to alleviate and treat hyperproliferative skin disorders.

According to an embodiment of the present invention, the severe pruritus is provided with a composition for preventing or treating inflammatory skin disease or severe pruritus, including when the skin itch interferes with sleep and daily life, thereby preventing normal activities.

According to one embodiment of the present invention, a composition for preventing or treating inflammatory skin disease or severe pruritus, which includes an effective amount of the solubilized ursodeoxycholic acid, may be provided.

In the present invention, an effective amount means an amount capable of preventing inflammatory skin disease or severe pruritus of skin or alleviating or treating a disease already produced, and including a therapeutically active amount. The effective amount depends on the form to be commercialized, the method applied to the skin and the time to stay on the skin.For example, if the composition is commercialized as a skin external preparation for the improvement and treatment of skin diseases or severe pruritus, the daily dosage will be 0.1 to 100 mg / kg based on ursodeoxycholic acid, but not limited to, 30 to 80 mg / kg may be suitable, 50 to 60 mg / kg may be more suitable, 1 to 6 per day Can be applied once.

In addition, the effective amount may be usually 0.001 to 1.5 parts by weight, 0.005 to 1.0 parts by weight, and more preferably 0.01 to 0.5 parts by weight with respect to the entire skin coating composition.

According to one embodiment of the invention, the composition may be formulated into a powder form by drying the composition. The powder form of the composition is easy to store and handle, there is an advantage in the preparation of the composition of the desired form of the formulation.

According to one embodiment of the invention, the powder may be prepared in liquid form by mixing with water at a pH of 7 or less. The powder form of the composition can be mixed even in weak acid and neutral, such as water has the advantage of being easy to prepare a composition of the desired form of the formulation.

According to another aspect of the present invention, a skin external preparation for preventing or treating inflammatory skin disease or severe pruritus comprising the solubilized ursodeoxycholic acid as an active ingredient is provided.

The skin external preparation composition containing the composition is maintained at the above pH in a state of no aggregation of ursodeoxycholic acid molecules (without forming micelles), and the selected pH range in which the compound is not aggregated is about pH 3 to about pH 9 is suitable, but not limited to, 4.5 to 8 is more suitable, and 6 to 7 is more suitable. It may also contain acids, bases and buffers if necessary to maintain the pH.

The external preparation composition for skin is Carbopol # 941 (1%), EDTA-2Na, Nipagin M (M-P), DL-panthenol, 1,3-B.G, Nipasol M (P-P), Vit. E. Acetate, Tween # 60, Arlacel # 60, Arlacel # 165, GMS105, Kalcol6850, Stearic Acid, CEH, Macadamia Nut Oil, Lily 70, TCG-M, KF-96A, (6cs), KF 995, DC200f100cs, TEA , Sepigel305, Bacillus / Soybean / Polyacid Fermented Extract, Cedar Extract, Mugwort Extract, Citrus Seed Extract, Portulaca Extract, Hawthorn Fruit Extract, Cacao Extract, Chamomile Flower Extract, Propolis Extract, White Bark Mushroom Extract, Guava Leaf Extract , Green tea extract, witch hazel extract, rose extract, white willow bark extract, hawthorn fruit extract, honey extract and royal jelly extract, may contain one or more of marine collagen, preservatives, fragrances, pigments, purified water, etc. A small amount may be included as needed.

When the extract is used, the antibacterial, anti-inflammatory action and moisturizing ability is excellent, for example, in the case of the white mushrooms extract, there is an advantage of high moisture retention by forming a moisture barrier. In addition, in the case of mugwort extract, it may also have a skin soothing effect. In addition, synergistic effects can be obtained when the extract is added to the composition in a specific combination.

In the external preparation composition for skin according to the present invention, in addition to a water-soluble aqueous solution of ursodeoxycholic acid, a fatty substance, an organic solvent, a dissolving agent and a gelling agent, an emollient, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance , Surfactants, water, ionic or nonionic emulsifiers, fillers, metal ion sequestrants and chelating agents, preservatives, vitamins, blockers, wetting agents, skin sealants, moisturizers including ceramides, essential oils, dyes, pigments, fragrances, hydrophilic Or adjuvants commonly used in the field of dermatology, such as lipophilic actives, lipid vesicles or any other ingredients conventionally used in dermal coatings. And the above ingredients may be introduced in amounts generally used in the field of dermatology.

According to an embodiment of the present invention, the external preparation for skin may be provided with an external preparation for preventing or treating inflammatory skin disease or severe pruritus selected from a composition having a formulation of an ointment, gel, cream, patch, powder and spray. . The topical skin preparations of the present invention may be prepared in any formulation conventionally prepared in the art and include, for example, solutions, suspensions, emulsions, pastes, soaps, surfactant-containing cleansing, oils, foundations, emulsion foundations It may be formulated as a wax foundation and a spray, but is not limited thereto.

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

When the formulation of the present invention is a solution or emulsion, a solvent, solubilizing agent or emulsifying agent is used as the carrier component, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene Fatty acid esters of glycol, 1,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.

When the formulation of the present invention is a suspension, liquid carrier diluents such as water, ethanol or propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline Cellulose, aluminum metahydroxy, bentonite, agar or tracant may be used.

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

A preferred embodiment of the formulation of the skin applicator composition containing the solubilized aqueous solution of ursodeoxycholic acid is a cream. The creams include W / O types, such as cold creams and emollient creams, and O / W types, such as shaving creams, varnishing creams, hand creams, and lining creams. More preferred creams are typically varnishing creams containing water and stearic acid. Usually patients or doctors prefer creams to ointments because O / W creams are easier to wash off than ointments. In this regard, the preferred formulations of the compositions of the present invention are creams.

One preferred embodiment of the formulation of the external preparation composition for skin comprising the above solubilized aqueous solution of ursodeoxycholic acid is a lotion. The lotions are prepared by methods such as suspending agents, emulsions, solutions and the like, which also belong to those of ordinary skill in the art to those skilled in the pharmaceutical formulation art. More preferred in the present invention is a white lotion and this formulation can also be prepared by techniques conventional to those skilled in the formulation arts.

Another preferred embodiment of the formulation of the external preparation composition for skin including the above-solubilized aqueous solution of ursodeoxycholic acid is a wax. The friction agent may be prepared as either an oily agent or an ethanol agent. Preferred are oily waxes with low irritation to the skin. In the case of oil-based lubricants, nonvolatile oils such as almond oil, peanut oil and cottonseed oil, volatile oils such as wintergreen and turpentine, or nonvolatile oils are blended.

In addition, the range of palliative and therapeutic doses for each inflammatory skin disease and severe pruritus dermatitis may vary with severity and formulation. In addition, the frequency of application may also vary depending on the age, weight and constitution of the patient.

According to an embodiment of the present invention, the external preparation for skin may be provided with an external preparation for preventing or treating inflammatory skin disease or severe pruritus having a cream formulation.

In the case of the cream formulation or paste or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component. The formulations of the present invention can act as a carrier, adjuvant or enhancer for the delivery of a pharmaceutical material dissolved in the composition of the present invention over a desired pH range. In addition, the composition may include, but is not limited to, incompletely soluble non-bile acid agents.

According to one embodiment of the present invention, an external preparation for skin for the prevention or improvement of inflammatory skin disease or severe pruritus, which is used for at least one week and at least once a day, may be provided.

According to the experimental results of the experimental example of the present invention and Figures 7 to 9 as a result of applying the external application of the skin according to the present invention to the test subject having acne skin disease was confirmed that the effect is apparent from two weeks later.

According to another aspect of the invention, the composition may be provided with an external preparation for skin, characterized in that to relieve symptoms caused by burns or inflammatory skin diseases.

The compositions and methods of administration of the present invention may be designed on any scale to prevent or / or treat subjects of different ages, subjects with additional allergic or disease states, and subjects with varying severity of symptoms. Dosage doses may be adapted to variations over time. These equivalents and surrogates with obvious variations and modifications may be included within the scope of the present invention. Thus, it will be apparent to one skilled in the art that a single embodiment, use and / or advantage is not intended to be excluded from other embodiments.

The present disclosure contains extensive information on the current recognition of the genetics, biochemistry and cell biology of inflammatory skin diseases, but future studies may reveal that these aspects of recognition are inaccurate or incomplete. Thus, it will be understood by those skilled in the art that the present invention is not limited to a specific model or mechanism of action, whether part or all of it is taken.

Those skilled in the art will also recognize that other equivalent or alternative compositions and methods may be used. For example, while many compounds have been described as being capable of being administered with ursodeoxycholic acid, other compounds may of course be included.

In addition, the application of other agents may be performed at the same time as the administration of the solubilized ursodeoxycholic acid composition of the invention, or the two may be the same or overlapping time periods (eg, the same time, the same date or During the same week).

According to an embodiment of the present invention, the external preparation for skin may be a cosmetic. The cosmetics include softening cream, astringent makeup, nutrition cream, eye cream, nutrition cream, massage cream, cleansing cream, cleansing foam, cleansing water, body lotion, body cream, body essence, shampoo, rinse, body cleanser, essence and pack have. In addition, skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, moisturizing cream, hand cream, nutrition essence, soap, cleansing cream, milky lotion, eye shadow, etc. It may be, but is not limited thereto.

Cosmetic formulations according to the invention include, in addition to solubilized UDCA, fatty substances, organic solvents, solubilizing and gelling agents, emollients, antioxidants, suspending agents, stabilizers, forming agents, fragrances, surfactants, water, Ionic or nonionic emulsifiers, fillers, metal ion sequestrants and chelating agents, preservatives, vitamins, blockers, wetting agents, skin sealants, moisturizers including ceramides, essential oils, dyes, pigments, flavors, hydrophilic or lipophilic active agents, lipids Auxiliaries commonly used in the cosmetic or dermatology field, such as vesicles or any other ingredients conventionally used in cosmetics. And the above ingredients may be introduced in amounts generally used in the field of dermatology.

According to one embodiment of the invention, the skin external preparation is characterized in that the pH of 3 to 9, the external preparation for the skin is provided.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Example

Example 1 Preparation of a Clean Solution of Water Soluble Ursodeoxycholic Acid

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, 6.7 g of sodium hydroxide pellets were dissolved in 400 ml of purified water. Next, 60 g of ursodeoxycholic acid was dissolved in the sodium hydroxide solution under stirring at room temperature. Subsequently, 360 g of maltodextrin was added little by little to the clear solution and stirred. The preservative was then added to the clear solution obtained with sonication at high throughput (750 W, 20 kHz) in an amount suitable for pharmaceutical formulation and the pH was adjusted by dropwise addition of HCl. Purified water was added to adjust to a total of 1,000 ml. If necessary, the clear solution was filtered by a suitable filter. This filtration is important for removing impurities or sterilization from the raw material, but not for removing particulate matter since the solution is already transparent. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 10.3, 9.2, 6.7 but precipitated at pH 5.4.

Example 2 Preparation of a Clean Solution of Water Soluble Ursodeoxycholic Acid

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, it was prepared according to the same guidelines as in Example 1 except that 720 g of maltodextrin as one high molecular weight water-soluble starch integer per 60 g of ursodeoxycholic acid was used. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 9.6, 7.3, 6.5, 6.0, but precipitated at pH 5.5.

Example 3 Preparation of Aqueous Soluble Ursodeoxycholic Acid Aqueous Solution

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, it was prepared according to the same guidelines as in Example 1 except that 750 g of maltodextrin was used as one high molecular weight water-soluble starch invertant per 50 g of ursodeoxycholic acid. At this time, 5.7 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 9.5, 8.9, 7.9, 7.1, 6.0. However, at pH 5.5, a precipitate formed. 1 is a photograph showing whether the clean solution of the urethane deoxycholic acid solution at each pH value in a test tube.

Example 4 Preparation of Aqueous Soluble Ursodeoxycholic Acid Aqueous Solution

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, it was prepared according to the same guidelines as Example 1 except that 350 g maltodextrin as one high molecular weight water-soluble starch invertant per 17.5 g of ursodeoxycholic acid was used. At this time, 2.0 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 9.4, 7.1, 6.1, 5.5. However, at pH 5.1, a precipitate formed. Figure 2 is a photograph showing whether or not to create a clean aqueous solution by containing a solution of ursodeoxycholic acid at each pH value in a test tube.

Example 5 Preparation of Aqueous Soluble Ursodeoxycholic Acid Aqueous Solution

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, it was prepared according to the same guidelines as in Example 1 except that 350 g of maltodextrin as one high molecular weight water-soluble starch invertant per 14 g of ursodeoxycholic acid was used. At this time, 1.7 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 9.6, 6.1, 5.1. However, at pH 4.0, a precipitate formed. Figure 3 is a photograph showing whether or not to generate a clean aqueous solution of the urethane deoxycholic acid solution at each pH value in a test tube.

Example 6 Preparation of Aqueous Soluble Ursodeoxycholic Acid Aqueous Solution

A clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.

Specifically, it was prepared according to the same guidelines as in Example 1 except that 750 g of maltodextrin as one high molecular weight water-soluble starch invertant per 25 g of ursodeoxycholic acid were used. At this time, 2.8 g of sodium hydroxide pellets were dissolved in 400 ml of purified water and used. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 9.0, 8.0, 7.0, 6.0, 5.1, 4.1, 2.9. 4 is a photograph showing whether or not a clean aqueous solution by containing a solution of ursodeoxycholic acid at each pH value in a test tube.

Example 7 Preparation of Aqueous Soluble Ursodeoxycholic Acid Aqueous Solution

A clear, clear aqueous solution of solubilized ursodeoxycholic acid containing ursodeoxycholic acid and ursodeoxycholic acid derivatives and containing water-soluble starch with low glucose equivalents was prepared.

Specifically, 0.3 g of sodium hydroxide pellets were dissolved in 500 ml of purified water. Next, 1.0 g of ursodeoxycholic acid, 0.5 g of taurusodeoxycholic acid, and 0.5 g of glycourdeoxycholic acid were dissolved in the sodium hydroxide solution under stirring at room temperature. Subsequently, 60 g of maltodextrin was added to the transparent solution little by little and stirred. The preservative was then added to the clear solution obtained with sonication at high throughput (750 W, 20 kHz) in an amount suitable for pharmaceutical formulation and the pH was adjusted by dropwise addition of HCl. Purified water was added to adjust to a total of 1,000 ml. Ursodeoxycholic acid solution prepared as shown in Table 1 to form a clear aqueous solution without visual precipitation at pH 10.2, 9.0, 8.1, 7.1, 6.1, 5.1, 4.1, 2.9. 5 is a photograph showing whether the clean solution of the urethane deoxycholic acid solution at each pH value in a test tube.

Example 8 Preparation of Skin Coatings Containing Solubilized Ursodeoxycholic Acid

A skin coating agent for preventing or treating inflammatory skin disease or severe pruritus was prepared by using the stock solution as a raw material of the aqueous solution of aqueous solubilized ursodeoxycholic acid prepared in Examples 1 to 7. The skin applicators were prepared in the form of creams, lotions, serums, toners, essences and patches, depending on the formulation.

My example

Formulation Example 1 Preparation of Skin Coatings of Cream (1)

Skin permeability experiment and atopic dermatitis improvement human skin test preparation were prepared using the solubilized ursodeoxycholic acid solution (pH 7.0) prepared in Example 6. Table 2 shows the cream (1) composition components (in weight percent). The composition may include 0.1 ~ 5% by weight of extract extracts, 0.1-5% by weight of the extract from Morus bark.

In the prepared cream, the solubilized ursodeoxycholic acid solution was well mixed with the raw material of the skin coating composition, and even after a time, it exhibited a good emulsification without aggregation and phase separation of the oil phase and the aqueous phase.

Formulation Example 2 Preparation of Skin Coatings of Cream (2)

A solubilized ursodeoxycholic acid solution (pH 7.0) prepared in Example 6 was used to prepare a skin coating for sebum secretion and acne treatment. Table 3 shows the cream (2) component (unit: wt%). The composition is 0.005 to 0.05% by weight guchi extract, 0.0001 to 0.001% by weight green tea extract, 0.5 to 2% by weight Centella asiatica extract, 0.01 to 0.1% by weight cacao extract, 0.0001 to 0.001% by weight chamomile flower extract, 0.005 to 0.03% aloe vera leaf It may include weight percent.

In the prepared cream (2), the solubilized urethane deoxycholic acid solution was well mixed with the raw material of the skin coating composition, and even after a time, it exhibited a good emulsification without aggregation and phase separation between the oil phase and the aqueous phase. It was.

Formulation Example 3 Preparation of Skin Coatings of Cream (3)

A test cream, a skin coating for treating psoriasis, was prepared using a solubilized ursodeoxycholic acid solution (pH 7.0) prepared in Example 6. Table 4 shows the cream (3) raw material components (unit: wt%).

In the prepared cream (3), the solubilized urethane deoxycholic acid solution was well mixed with the raw material of the skin coating composition, and even after a time, it exhibited a good emulsification without aggregation and phase separation between the oil phase and the aqueous phase. It was.

Formulation Example 4 Preparation of Hydrogel Patch

In order to determine the skin permeability using the solubilized ursodeoxycholic acid solution (pH 7.0) prepared in Example 6, a skin coating of a hydrogel patch was prepared. Table 5 shows the hydrogel patch raw ingredients in weight percent.

The prepared hydrogel patch is characterized in that the solubilized solution of ursodeoxycholic acid is well mixed with the raw material of the skin coating composition and there is no coagulation even if time passes in the hydrogel, and the emulsion and hydrogel are well formed without phase separation between the oil phase and the aqueous phase. Indicated.

Formulation Examples 5 to 9 Preparation of Skin Coatings by Formulation

A lotion (Formulation Example 5), Serum (Formulation Example 6), Essence (Formulation Example 7), as a skin coating agent, using the solubilized urethane deoxycholic acid solution (pH 7.0) prepared in Example 6, A mask (Formulation Example 8) and a toner (Formulation Example 9) were prepared. Tables 6 to 10 show the raw ingredients for each formulation (content: wt%). The composition of Formulation Example 5 may comprise 1 to 10% by weight of Bacillus / soybean / polyacid fermented extract, 0.5 to 5% by weight of baekryeok extract, 0.1 to 1% by weight of mugwort extract, 0.5 to 1% by weight of citrus seed extract Formulations 6 may include 0.005 to 0.01% by weight of honey extract, 0.0005 to 0.01% of royal jelly extract, 0.005 to 0.1% by weight of hawthorn fruit extract, 0.01 to 0.1% by weight of cacao extract, and 0.0001 to 0.001% by weight of chamomile flower extract. Can be. The composition of Formulation Example 7 may include 0.1 to 1% by weight of wormwood extract, 0.5 to 1% by weight of the bilberry seed extract, 1 to 5% by weight of the fungus extract. Formulation Example 8 may include 0.05 to 1% by weight of the extract of Cuava leaf, 0.05 to 1% by weight of green tea extract, 0.5 to 1% by weight of Machi extract, 0.05 to 1% by weight of witch hazel extract, 0.05 to 0.5% by weight of rose extract And, the composition of Formulation Example 9 may comprise 0.5 to 1% by weight of wormwood extract, 0.5 to 1% by weight of the bilberry seed extract.

In the prepared skin coating formulation, the solubilized urethane deoxycholic acid solution was well mixed with the raw material of the skin coating composition, and after time, there was no aggregation phenomenon and the emulsification was well performed without separating the phase into the oil phase and the aqueous phase.

Experimental Example 1. In vitro  Human skin permeability measurement experiment

To determine if the skin permeability of ursodeoxycholic acid is improved when the formulation form is changed from the crystalline ursodeoxycholic acid formulation to the solubilized ursodeoxycholic acid formulation, Franz diffusion cell according to the OECD guidelines as follows. Skin absorption of ursodeoxycholic acid was measured using human cadaveric skin in vitro .

material

Skin: stratum cornium (80 mm thick) of human cadaver skin

Supplier: Hans Biomed Co., Ltd. (Korea)

Sample area: 0.636 cm ²

Receptor: PBS buffer (pH 7.4)

Analyte

Ursodeoxycholic acid (UDCA) eluted through human cadaver skin

Analytical Devices and Conditions

Agilent 1100 series HPLC according to the method of ursodeoxycholic acid

Analysis

Figure 6 is a solubilized aqueous solution of ursodeoxycholic acid according to the present invention to prepare a skin coating agent (Formulation Example 1) and a hydrogel patch skin coating agent (Example 4) of the cream (1) formulation to obtain the skin permeability for each It is measured. According to the experimental results, the skin permeability of the cream (1) skin coating agent (Example 1) was 70.1% for a specific area (0.636 cm ² ) based on the concentration of the solubilized ursodeoxycholic acid in the skin coating agent. Gel patch skin applicator (Formulation Example 4) showed a skin permeability of 59.2%. This indicates that the solubilized ursodeoxycholic acid penetrates the skin very well in a very high yield compared to the property that the existing crystalline ursodeoxycholic acid rarely passes through the skin.

Experimental Example 2. Non-irritant effect test on human skin

To find out if the morphic form of urethane deoxycholic acid can be solved by changing the type of formulation (formulation) to urethane deoxycholic acid, a human application experiment for skin irritation was performed as follows. Was carried out.

The skin irritant effect was tested on 31 subjects of the skin coatings prepared for each formulation (testing institution: Korea Institute of Dermatology and Clinical Research).

Test substance name

Cream (2) (Formulation Example 2)

Lotion (Example 5)

Serum (Example 6)

Essence (Example 7)

Mask (Example 8)

Toner (Example 9)

Experiment method

The test subject conducted a skin patch test using a Finn chamber. Wipe the back part of the test subject with 70% ethanol and dry it. Then, 20 μl of the test substance was dropped into a pin chamber having a diameter of 8 mm and fixed by attaching to the test part. In the case of liquid essence skin coating agent (Example 6), a filter paper disc was placed in a pin chamber having a diameter of 8 mm, and 20 µl of the test substance was added dropwise and fixed to the test site. The patch was attached for 24 hours, and after 30 minutes, 24 hours, and 48 hours after removal of the patch, the degree of stimulation was observed by a dermatologist according to the criteria of the International Contact Dermatitis Research Group (ICDRG).

Experiment result

Formulations 2 and 5 to 9 were applied to the skin for 24 hours, and the skin reactions at the experimental sites 30, 24, and 48 hours after removal of the patch were stimulated according to the criteria of the International Contact Dermatitis Research Council. The grades were classified and the mean skin responsiveness (Mean score) was calculated according to the result determination table. In Formulations 2 and 5 to 9, no stimulation was observed after 30 minutes, 24 hours, and 48 hours after patch removal, respectively. The average skin reactivity was 0.00, which was determined to be non-irritating according to the criteria. Therefore, Formulation Example 2 and Formulation Examples 5 to 9 were found to belong to a non-irritating skin coating agent as a result of human application experiments on the stability evaluation by the skin patch test.

conclusion

Formulation Example 2 and Formulation Examples 5 to 9 according to the present invention was found to belong to the non-irritating skin coating group as a result of human application experiments on the stability evaluation by the skin patch test.

Therefore, according to the present invention, it was possible to overcome the disadvantages of skin redness when changing the form (formulation) of the crystalline ursodeoxycholic acid formulation into a solubilized ursodeoxycholic acid formulation.

Experimental Example 3. Acne Relieving Effect

In order to check whether there is an acne treatment effect, the essence skin coating agent (Example 7) was applied over 8 weeks to 23 adult men and women with acne. The composition was tested by applying the same amount evenly to the face after washing the face twice a day (Test Center: Korean Dermatological Research Institute).

Assessment Methods

The procedure was conducted in accordance with the Korean Institute of Dermatology and Clinical Work Standards (SOP). All procedures were reviewed by a person in charge of reliability assurance. The above test is suitable for use on acne skin: (1) Appropriate for use on acne skin according to Global Acne Grading System (GAGS) Visual evaluation, (2) Sebum improvement evaluation by Semeter, (3) Skin Adverse events were assessed and (4) surveyed.

Appropriate rating for use on acne skin

(1) Visual evaluation suitable for use on acne skin according to Global Acne Grading System (GAGS)

In this experiment, the experiment manager performed visual evaluation according to GAGS to evaluate the suitability of the test material for acne skin (FIGS. 7A and 7B and 9A and 9B). GAGS divides the face, chest, and back into six areas (forehead, sheep cheeks, nose, chin, chest and upper back), each area being 0-4 points (0 = nil, 1 = comedone, 2 = papule, 3 = pustule, 4 = nodule). The appearance of various lesions in one zone is assessed based on the most severe lesions. The acne grade of the test subject (1-18 points = mild, 19-30 points = moderate, 31-38 points = severe, 39) according to the total sum score using the GAGS calculation formula based on the lesion score of each zone. Class = very severe. As the acne grade score decreases compared to before use of the test substance, it means that it is suitable for use on acne skin. Evaluation was made at the time points before and after 2 weeks of use, 4 weeks of use, and 8 weeks of use.

(2) Sebum improvement evaluation by the centimeter

In this experiment, a semeter (SKIN-O-MAT, Cosmomed GmbH, Germany) was used to evaluate sebum improvement of acne skin. As for the measurement of sebum, the same experimental person contacted the probe cassette with oil adsorption tape on the left nostril area of all the subjects at the same pressure for 30 seconds, adsorbed the oil, and then inserted it into the main body. Severmeter analyzes the amount of oil coming out after attaching a special translucent lipid-absorbing tape to the skin by using photometric reflection. The unit of measurement is µg / cm 2 and the maximum value is 350. Sediment secretion was suppressed as the measured value decreased compared with before using the test substance. Instrument measurements were taken before, after 2 weeks, after 4 weeks, and after 8 weeks of use.

Statistical analysis method

Statistical processing of this experiment was analyzed using the SPSS 17.0 for Windows program. Mean, standard deviation, frequency, and percentage were used to analyze the questionnaire of the test subjects, and paired t-test analysis was performed to analyze whether or not there was a significant change in the measurement results for various skin improvement.

Experiment result

① Visual evaluation result suitable for use on acne skin according to Global Acne Grading System (GAGS)

The experiment manager evaluated the suitability for acne skin before, after 2 weeks, after 4 weeks, and after 8 weeks of using GAGS. When the person in charge of the experiment visually evaluated the use of acne on the facial area using GAGS, the acne score was 7.19% after 2 weeks, 8.63% after 4 weeks, and 8 weeks after using the acne. A change of 8.99% was shown. In addition, it was statistically significant after 2 weeks, 4 weeks, and 8 weeks after the use of the test substance (p <.05). 7a and 7b and 9a and 9b).

Table 11 shows the change in acne grade (score), Table 12 shows the improvement rate (%) of acne grades, Table 13 shows the statistical analysis of acne grades, respectively.

② Sebum improvement evaluation result before and after using test substance

The results of evaluating sebum improvement of acne skin before and after the use of the test substance using the severometer, after 2 weeks, after 4 weeks, and after 8 weeks are as follows (see FIGS. 8A and 8B).

As a result of analyzing sebum improvement of the left nostril area using the semeter, the sebum amount decreased by 27.89% after 2 weeks, 46.97% after 4 weeks, and 48.75% after 8 weeks compared to before using the test substance. Indicated. In addition, after 2 weeks, 4 weeks, and 8 weeks after the use of the test substance, it was statistically significant (p <.001), indicating that the test substance has an excellent effect on the inhibition of sebum secretion. 14 to Table 16).

(3) Evaluation of skin adverse reaction

① Evaluation of skin reactions

No adverse reactions to allergic contact dermatitis or irritant contact dermatitis were observed after using the test substance in the subject.

② Results of skin abnormalities by subjects survey

Apart from evaluating adverse reactions by subjects, subjects reported skin abnormalities reported in Table 17. No special skin abnormalities were observed in the surveys of subjects. .

(4) Survey on the test subject before and after use

① Results of general skin condition characteristics of subject

Multiple skin type was used to survey general skin condition characteristics of subjects. Table 18 shows the results.

② Skin condition survey results before and after using test substance

Table 19 shows the results of the questionnaire survey on the skin condition of the test subjects before using the test substance using the multiple-choice or alternative questionnaire.

③ Results of feeling of use after using the test substance of the test subject

Using the satisfactory / dissatisfied alternative type, the test results of the test subjects' feelings on the test substance are as follows (see Table 20).

④ Skin condition investigation result after using test substance of test subject

Table 21 shows the results of a questionnaire survey on the skin condition after the test substance was used using the multiple choice.

As described above, as a result of evaluating the usability of acne skin for the external preparations containing a solubilized aqueous solution of ursodeoxycholic acid, it was statistically significant compared to before use of the test substance (p <.05). Acne grade score improvement rate of 7.19% after 2 weeks, 8.63% after 4 weeks, 8.99% after 8 weeks, and sebum was statistically significant (p <.001) 27.89% after 2 weeks The rate of sebum improvement was 46.97% after 4 weeks and 48.75% after 8 weeks. In addition, no adverse reactions to allergic contact dermatitis or irritant contact dermatitis were observed from the test subjects, and no special skin abnormalities were observed in the survey of the subjects.

Therefore, the skin applicator containing the solubilized ursodeoxycholic acid solution showed an acne treatment and sebum improvement effect without causing skin irritation.

Experimental Example 4. Atopic dermatitis alleviation effect

In order to confirm the atopic dermatitis alleviation effect, 22 patients with atopic dermatitis were applied with a skin coating agent (Formulation Example 1) in the form of cream (1) to the arm area. The skin applicator was tested by applying twice a day to apply to the affected part and confirmed the alleviation effect of atopic dermatitis after one week.

Experiment Outline

Purpose: To verify the efficacy and effectiveness of atopic dermatitis of a skin coating containing solubilized ursodeoxycholic acid (Formulation Example 1)

Method: Apply the site

Period: 7 days of review

Subjects: 22 patients with atopic dermatitis

Table 22 shows the degree of atopic symptoms in patients with atopic dermatitis who participated in the experiment (out of a total of 22, 95% of patients with severe atopic dermatitis).

result

1) For patients with total atopic dermatitis: The higher the score for each item, the better the rating (high score of 5, see Table 23).

2) For 11 subjects with severe atopic symptoms: the higher the score, the better the score (high score of 5, see Table 24).

Result analysis

As a result of the evaluation of all patients with atopic dermatitis, there was no skin irritation with a high score (4.4 points) in skin irritation, which is the most important quality factor of atopy care products, 3.5 points for atopic improvement effect, 3.9 points for itching effect, Overall satisfaction was relatively high at 4.0 points (FIG. 10). In addition, in 11 people with severe atopic symptoms, the itch relieving effect was about 0.3 points higher than in the whole atopic dermatitis patient (FIG. 11).

conclusion

The 22 people reviewed the skin applicator containing the solubilized aqueous solution of ursodeoxycholic acid, showing that it was effective in atopic dermatitis by showing itching and atopic dermatitis, which are the most important factors in atopic care. In addition, in 11 patients with severe atopic dermatitis symptoms, not only the effect of atopic dermatitis was reduced, but also itching, which is an important evaluation factor of atopy, was high, indicating that a skin coating agent containing a solubilized ursodeoxycholic acid was effective for atopic dermatitis ( 10 and 11).

Experimental Example 5. Relief and Treatment of Psoriasis Symptoms

In order to develop a new drug for psoriasis, the effect of psoriasis treatment after the preparation of a skin coating containing solubilized ursodeoxycholic acid was confirmed using an animal model. In order to confirm the effect of psoriasis treatment, a cream-type skin coating agent was applied to the psoriasis-induced dorsal area of the psoriasis-induced psoriasis animal model with 5% imiquimod cream. The following test substance was applied three times a day and confirmed the alleviation effect of psoriasis symptoms from 1 day to 11 days (Laboratory: QB Consulting Co., Ltd.).

Experiment Outline

Purpose: To verify the efficacy and effect of psoriasis on skin coatings containing solubilized ursodeoxycholic acid

Test substance (Test Cream): The external skin test cream (3) for psoriasis treatment drug development was prepared using the aqueous solution of the solubilized ursodeoxycholic acid aqueous solution prepared in Example 6. Table 4 shows the test cream (3) raw material component (unit: weight%).

Method: Applied to the site of psoriasis lesions. 5% imiquimod was applied to the skin of the back of the epidermis 62.5 mg once daily. The composition applicator was applied to the skin about 2 hours before application of the trigger.

Duration: 11 days

Subject: G1 group (5 female rats) applied Vaseline cream for 11 days, G2 group (8 female rats) applied 5% imiquimod cream for 8 days, G3 group (8 female mice) 5% imiquimod The test cream was applied from day 5 to day 11 while the cream was applied for 8 days (FIG. 12).

result

1) The clinical symptoms were visually confirmed by the person in charge of the psoriasis incidence site and expressed as a value from 0 to 4 based on the disease activity index (DAI) of Table 24 (Table 25 and FIG.

2) The disease activity index was 0 in the group applied with Vaseline Cream for 11 days (G1) and the disease activity index was 2.4 in the group (G2) applied with 5% Imiquimod Cream for 8 days, while the average was 5% imiqui. In the group (G3) who applied test cream for 5 to 11 days with mode cream applied for 8 days, the psoriasis was nearly close to the disease activity index value of the control group (G1) with only vacerine cream with an average vaginal activity index of 0.7. Significantly alleviated the symptoms of (FIG. 13B). The disease activity index was a statistically significant result (p <0.05 ~ p <0.001).

3) The degree of epidermal hyperkeratosis of the skin tissues of the rats was observed. About 140% was hyperkeratinized in the group treated with 5% imiquimod cream for 8 days (G2) compared to the group treated with petroleum jelly (G1). In contrast, the test cream-coated group (G3) showed a level similar to that of the control group at 114%, significantly reducing the symptoms of epidermal hyperkeratin induced by imiquimod (see Table 26 and FIG. 13C).

conclusion

Test Cream, a skin coating for drug development for psoriasis treatment containing solubilized ursodeoxycholic acid, showed anti-psoriasis effects when applied to the psoriasis skin of mice 3 times a day for 7 days.

Experimental Example 6. Relief and Treatment Effect of Dermatitis Symptoms

The inhibitory effect of inflammatory response, which is the main symptom in various inflammatory skin diseases, was confirmed.

First, prophylactic substance Tphori (phorbol 12-myristate 13-acetate, TPA) was prepared to have a concentration of 15 µg / ml, and 20 µl was applied to the back of the mouse ear. The test substance was a solubilized ursodeoxycholic acid made from a new drug candidate for inflammatory skin disease (YSB301), which was made to have a content of ursodeoxycholic acid of 0.625%, 1.25%, and 2.5%, 30 minutes before TPA treatment. 20 μl was applied to the site.

Experiment Outline

Purpose: To verify the efficacy and effectiveness of the new drug candidate for inflammatory skin disease (YSB301) containing solubilized ursodeoxycholic acid

Test substance: It is shown in Table 27, and the solubilized solution of aqueous solubilized ursodeoxycholic acid solution of Example 6 (pH 7.0) was designated as 'New drug candidate substance for inflammatory skin disease (YSB301)', diluted with purified water and ursode It was used after the oxycholic acid concentration was 0.625%, 1.25%, 2.5% (% by weight), and in the case of the carrier, it refers to an aqueous solution excluding ursodeoxycholic acid in Example 6.

METHODS: 20 μl of TPA (15 μg / ml), an inflammation-causing substance, was applied to the back of a mouse and the degree of ear thickness increase was measured from 0hr to 4hr. A new drug candidate for inflammatory skin disease (YSB301) and a carrier were applied to the ears of rats, and after 30 minutes, 20 μl of TPA, a trigger, was applied to the skin.

Duration: 4 hours

Subjects: 6 female rats treated with nothing, 6 female rats inflamed with TPA after application of vehicle only, and 18 female rats (3 groups) inflamed with TPA after application of New Drug Candidate (YSB301).

result

As shown in FIG. 14, a vehicle and a new drug candidate for inflammatory skin disease (YSB301) were applied and the ear thickness of the rat induced by inflammation with TPA was measured. %, The inhibitory effect was statistically significantly reduced to 23.4% at 1.25% of ursodeoxycholic acid concentration and 31.2% at 2.5% of ursodeoxycholic acid concentration (p <0.05).

conclusion

A coating agent containing a solubilized ursodeoxycholic acid can be effectively used for the treatment of various inflammatory skin diseases such as atopic dermatitis, psoriasis and eczema by effectively alleviating inflammation, which is the main symptom of various inflammatory skin diseases.

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

Claims (21)

1. (a) ursodeoxycholic acid (UDCA);

   (b) water soluble starch preparations; And

   (c) include water as an active ingredient,

    A composition for the prevention or treatment of inflammatory skin disease or severe pruritus in a clear aqueous solution to all pH values.
2. The method of claim 1,

   The UDCA is water-soluble UDCA, water-soluble UDCA derivatives, UDCA salts, and soluble in the UDCA selected from UDCA conjugated with an amine, characterized in that the composition for the prevention or treatment of inflammatory skin disease or severe pruritus.
3. The method of claim 1,

   The UDCA is an inflammatory skin disease or severely characterized by being solubilized with at least one UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (TUDCA), and glycoursodeoxycholic acid (GUDCA). Composition for the prevention or treatment of pruritus.
4. The method of claim 1,

   The UDCA is characterized in that it comprises 0.01 to 6 parts by weight based on the total weight of the composition, a composition for the prevention or treatment of inflammatory skin disease or severe pruritus.
5. The method of claim 1,

   The water-soluble starch telephone material is maltodextrin,

   The maltodextrin is characterized in that it comprises 1.0 to 70 parts by weight based on the total weight of the composition, a composition for preventing or treating inflammatory skin disease or severe pruritus.
6. The method of claim 1,

   The pH value is 3 to 9,

   The water-soluble starch telephone material is maltodextrin,

   The minimum weight ratio of maltodextrin to UDCA is 1:16-1:30, characterized in that for preventing or treating inflammatory skin disease or severe pruritus.
7. The method of claim 1,

   The pH value is 6 to 9,

   The water-soluble starch telephone material is maltodextrin,

   The minimum weight ratio of maltodextrin to UDCA is 1:13 to 1:30, characterized in that for preventing or treating inflammatory skin disease or severe pruritus.
8. The method of claim 1,

   The water-soluble starch preparation is the prevention of inflammatory skin disease or severe pruritus, characterized in that it is at least one of maltodextrin, dextrin, liquid glucose, corn syrup solids, soluble starch, dextran, guar gum, pectin and soluble non-starch polysaccharides. Therapeutic composition.
9. The method of claim 1,

   The inflammatory skin disease is selected from atopic dermatosis, acne, psoriasis, inflammatory skin disease, seborrheic dermatitis, and contact dermatitis. Composition for the prevention or treatment of skin disease or severe pruritus.
10. The method of claim 1,

    The severe pruritus is a skin itching disturbs sleep and daily life, including when the normal activity is difficult, the composition for the prevention or treatment of inflammatory skin disease or severe pruritus.
11. The method of claim 1,

    The UDCA is contained in an effective amount, wherein the effective amount is an amount capable of preventing or treating inflammatory diseases or severe pruritus of the skin or alleviating or treating a disease already produced, a composition for preventing or treating inflammatory skin disease or severe pruritus.
12. A composition for preventing or treating inflammatory skin diseases or severe pruritus, wherein the composition of claim 1 is dried and formulated in powder form.
13. The method of claim 12,

    Formulated by mixing the powder with water at pH 7 or less, a composition for the prevention or treatment of inflammatory skin disease or severe pruritus.
14. A skin external preparation for preventing or treating inflammatory skin disease or severe pruritus comprising the composition according to any one of claims 1 to 13 as an active ingredient.
15. The method of claim 14,

    The external preparation for skin has a formulation of an ointment, gel, cream, patch and spray, skin external preparation for the prevention or treatment of inflammatory skin disease or severe pruritus.
16. The method of claim 14,

    Skin external preparation for the prevention or improvement of inflammatory skin disease or severe pruritus, characterized in that it is used for at least one week and at least once a day.
17. An external preparation for skin comprising the composition according to any one of claims 1 to 13 as an active ingredient to alleviate symptoms caused by burns or inflammatory skin diseases.
18. The method of claim 17,

    The external preparation for skin is an external preparation for skin, which alleviates one or more symptoms of itching, keratinogenesis, and skin redness caused by an inflammatory skin disease.
19. The method of claim 17,

    The external preparation for skin is a cosmetic external preparation.
20. The method of claim 19,

    The cosmetics include softening cream, astringent makeup, nourishing cream, eye cream, nutrition cream, massage cream, cleansing cream, cleansing foam, cleansing water, body lotion, body cream, body essence, shampoo, rinse, body cleanser, essence or pack, Skin external preparations.
21. The method of claim 19,

    The external preparation of the skin is characterized in that the pH of 3 to 9, the external preparation for the skin.

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