WO2018062922A1 - Composition contenant de l'acide ursodésoxycholique solubilisé dans l'eau afin de prévenir ou de traiter une maladie cutanée inflammatoire ou un prurit grave - Google Patents

Composition contenant de l'acide ursodésoxycholique solubilisé dans l'eau afin de prévenir ou de traiter une maladie cutanée inflammatoire ou un prurit grave Download PDF

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WO2018062922A1
WO2018062922A1 PCT/KR2017/010893 KR2017010893W WO2018062922A1 WO 2018062922 A1 WO2018062922 A1 WO 2018062922A1 KR 2017010893 W KR2017010893 W KR 2017010893W WO 2018062922 A1 WO2018062922 A1 WO 2018062922A1
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Prior art keywords
skin
composition
udca
ursodeoxycholic acid
inflammatory skin
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PCT/KR2017/010893
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English (en)
Korean (ko)
Inventor
송영호
고휘진
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주식회사 유스바이오팜
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Priority claimed from KR1020170125571A external-priority patent/KR20180036580A/ko
Application filed by 주식회사 유스바이오팜 filed Critical 주식회사 유스바이오팜
Priority to EP17856808.5A priority Critical patent/EP3520796A4/fr
Priority to CA3032072A priority patent/CA3032072C/fr
Priority to JP2019520351A priority patent/JP2019524876A/ja
Priority to CN201780045135.1A priority patent/CN109475564A/zh
Publication of WO2018062922A1 publication Critical patent/WO2018062922A1/fr
Priority to US16/221,303 priority patent/US11331326B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/63—Steroids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • Acne 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.
  • 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.
  • 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 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.
  • 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 ⁇ M (20 mg / L). This low reason is because the crystal structure of the ursodeoxycholic acid molecule is very stable.
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrophilic raw materials are added for emulsification when preparing skin coatings. The molecules clump together to form micelles or precipitates.
  • ursodeoxycholic acid is insoluble in water due to its molecular nature (53 ⁇ M), and is acidic, and when applied to the skin, it causes skin irritant and does not penetrate the skin. There are disadvantages.
  • 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.
  • ursodeoxycholic acid ursodeoxycholic acid, UDCA
  • water soluble starch preparations 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 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.
  • UDCA water-soluble UDCA
  • a water-soluble UDCA derivative e.g., a water-soluble UDCA derivative
  • a UDCA salt e.g., a UDCA conjugated with an amine, an inflammatory skin disease or severe pruritus.
  • the UDCA is solubilized with at least one UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA).
  • UDCA ursodeoxycholic acid
  • TDCA taurusodeoxycholic acid
  • GUIA glycoursodeoxycholic acid
  • 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.
  • 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.
  • 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.
  • a composition for preventing or treating inflammatory skin disease or severe pruritus is provided.
  • 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.
  • a composition for preventing or treating inflammatory skin disease or severe pruritus is provided.
  • 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.
  • the inflammatory skin disease is atopic dermatosis, acne, psoriasis, inflammatory skin disease, seborrheic dermatitis and contact dermatitis.
  • a composition for the prophylaxis or treatment of inflammatory skin disease or severe pruritus selected from (contact dermatitis).
  • 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.
  • 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.
  • 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.
  • compositions for preventing or treating inflammatory skin disease or severe pruritus wherein the composition of the substrate is dried and formulated in powder form.
  • 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.
  • 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.
  • 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.
  • 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.
  • a skin external preparation comprising the composition of the substrate as an active ingredient, alleviating the symptoms caused by burns or inflammatory skin diseases.
  • 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.
  • the external preparation for skin is provided with an external preparation for skin.
  • 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.
  • the skin external preparation is characterized in that the pH of 3 to 9, the external preparation for the skin is provided.
  • composition for the prevention or treatment of inflammatory skin disease or severe pruritus 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.
  • composition for the prevention or treatment of inflammatory skin disease or septic pulmonary disease 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.
  • composition for the prevention or treatment of inflammatory skin disease or septic pruritus has the advantage of achieving the effect of preventing or treating inflammatory skin disease even with a small amount of high skin permeability.
  • 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.
  • an external preparation for skin 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.
  • 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.
  • 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.
  • Example 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.
  • Example 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.
  • Example 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.
  • 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
  • IMQ Imiquimod
  • 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
  • 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.
  • DAI Disease activity index
  • 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.
  • 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.
  • 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.
  • 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.
  • corn syrub may include both corn syrup and liquid glucose.
  • clean aqueous solution or "clear aqueous solution” means an aqueous solution in a clear state in a solution state substantially free of visual deposits.
  • ursodeoxycholic acid ursodeoxycholic acid, UDCA
  • water soluble starch preparations 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.
  • solubilized ursodeoxycholic acid which contains ursodeoxycholic acid dissolved in water at a high concentration up to 60 g / L, is the most ideal multifunctional anti-inflammatory drug.
  • UDCA solubilized ursodeoxycholic acid
  • 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- ⁇ , which produce inflammatory factors, but also inhibits cellular damage caused by inflammation. have.
  • 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- ⁇ ) 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
  • TUDCA has a relatively low solubility when quantized, but is about 10 times higher than the solubility of commercialized UDCA (pH 1-8).
  • the present invention includes UDCA, TUDCA and the like.
  • UDCA 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.
  • UDCA 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.
  • 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.
  • 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.
  • the ursodeoxycholic acid is one or more UDCA selected from ursodeoxycholic acid (UDCA), taurusodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) Characterized by being solubilized.
  • UDCA ursodeoxycholic acid
  • TDCA taurusodeoxycholic acid
  • GUIA glycoursodeoxycholic acid
  • ursodeoxycholic acid 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a composition for preventing or treating inflammatory skin disease or severe pruritus 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.
  • 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.
  • a composition for preventing or treating inflammatory skin disease or severe pruritus is provided.
  • 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.
  • the starch invert 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.
  • the molecular weight may be at least about 100 mass units, or at least 106 mass units.
  • high molecular weight water-soluble starch inverts may have a molecular weight of at least 105 mass units.
  • 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.
  • the polymer 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • composition of the present invention may further comprise a dietary fiber.
  • dietary fiber include, but are not limited to, guar rubber, pectin, psyllium, oat rubber, soy fiber, oat bran, corn cob, cellulose and wheat bran.
  • composition of the present invention may further comprise an emulsifier and suspending agent.
  • 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.
  • composition of the present invention may further include a pharmaceutically acceptable additive
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 remains free under acidic conditions as a free state despite being generally insoluble under acidic conditions.
  • the composition may further comprise a composition in a form that is maintained solubility.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • sebum is directly or indirectly involved in the development of the disease
  • bacteria and yeast the theory that it may be related to abnormalities of neurotransmitters
  • the theory that it may be caused by seasonal changes or abnormal epidermal growth 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the white mushrooms extract in the case of mugwort extract, it may also have a skin soothing effect.
  • synergistic effects can be obtained when the extract is added to the composition in a specific combination.
  • the external preparation composition for skin 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • nonvolatile oils such as almond oil, peanut oil and cottonseed oil, volatile oils such as wintergreen and turpentine, or nonvolatile oils are blended.
  • the range of palliative and therapeutic doses for each inflammatory skin disease and severe pruritus dermatitis may vary with severity and formulation.
  • the frequency of application may also vary depending on the age, weight and constitution of the patient.
  • 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.
  • 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.
  • the composition may include, but is not limited to, incompletely soluble non-bile acid agents.
  • 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.
  • the composition may be provided with an external preparation for skin, characterized in that to relieve symptoms caused by burns or inflammatory skin diseases.
  • 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.
  • compositions and methods may be used.
  • compounds have been described as being capable of being administered with ursodeoxycholic acid, other compounds may of course be included.
  • 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).
  • 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.
  • 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.
  • the skin external preparation is characterized in that the pH of 3 to 9, the external preparation for the skin is provided.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • 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.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • Example 2 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.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • Example 2 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.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • Example 2 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.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • Example 2 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.
  • a clear, clear aqueous solution of solubilized ursodeoxycholic acid was prepared comprising native ursodeoxycholic acid (UDCA) and water soluble starch with low glucose equivalents.
  • UDCA native ursodeoxycholic acid
  • Example 2 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.
  • 0.3 g of sodium hydroxide pellets were dissolved in 500 ml of purified water.
  • 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.
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • 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.
  • 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.
  • 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%).
  • 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.
  • Example 6 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.
  • 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
  • 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.
  • 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.
  • Skin stratum cornium (80 mm thick) of human cadaver skin
  • Ursodeoxycholic acid eluted through human cadaver skin
  • 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.
  • 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.
  • 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).
  • 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 ⁇ l of the test substance was dropped into a pin chamber having a diameter of 8 mm and fixed by attaching to the test part.
  • a filter paper disc was placed in a pin chamber having a diameter of 8 mm, and 20 ⁇ l 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).
  • IDRG International Contact Dermatitis Research Group
  • 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.
  • 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.
  • 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).
  • 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.
  • SOP Korean Institute of Dermatology and Clinical Work Standards
  • 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.
  • GGS Global Acne Grading System
  • GGS Global Acne Grading System
  • 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).
  • the appearance of various lesions in one zone is assessed based on the most severe lesions.
  • a semeter (SKIN-O-MAT, Cosmomed GmbH, Germany) was used to evaluate sebum improvement of acne skin.
  • 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 ⁇ g / 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.
  • the experiment manager evaluated the suitability for acne skin before, after 2 weeks, after 4 weeks, and after 8 weeks of using GAGS.
  • 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.
  • 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).
  • 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.
  • test results of the test subjects' feelings on the test substance are as follows (see Table 20).
  • Table 21 shows the results of a questionnaire survey on the skin condition after the test substance was used using the multiple choice.
  • the skin applicator containing the solubilized ursodeoxycholic acid solution showed an acne treatment and sebum improvement effect without causing skin irritation.
  • 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.
  • 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).
  • Test substance 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%).
  • 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).
  • 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.
  • 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.
  • the disease activity index was a statistically significant result (p ⁇ 0.05 ⁇ p ⁇ 0.001).
  • 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.
  • prophylactic substance Tphori (phorbol 12-myristate 13-acetate, TPA) was prepared to have a concentration of 15 ⁇ g / ml, and 20 ⁇ l 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 ⁇ l was applied to the site.
  • 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.
  • a new drug candidate for inflammatory skin disease (YSB301) and a carrier were applied to the ears of rats, and after 30 minutes, 20 ⁇ l of TPA, a trigger, was applied to the skin.
  • 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).
  • 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.

Abstract

La présente invention concerne une composition de prévention ou de traitement des maladies cutanées inflammatoires ou le prurit grave, la composition contenant de l'acide ursodésoxycholique solubilisé dans de l'eau (UDCA). Selon la présente invention, les maladies cutanées inflammatoires, telles que la maladie cutanée atopique, l'acné, le psoriasis, l'urticaire, la dermatite inflammatoire, la dermatite séborrhéique, et la dermatite de contact, et le prurit grave peuvent être efficacement atténués ou traités. Par conséquent, la composition comprenant l'acide ursodésoxycholique solubilisé dans l'eau de la présente invention peut être utilisée de manière favorable comme composition pharmaceutique, alimentaire, ou cosmétique, et la composition peut être utilisée, en particulier, comme préparation dermique appliquée au plan externe, et ainsi peut présenter les effets associés.
PCT/KR2017/010893 2016-09-30 2017-09-28 Composition contenant de l'acide ursodésoxycholique solubilisé dans l'eau afin de prévenir ou de traiter une maladie cutanée inflammatoire ou un prurit grave WO2018062922A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP17856808.5A EP3520796A4 (fr) 2016-09-30 2017-09-28 Composition contenant de l'acide ursodésoxycholique solubilisé dans l'eau afin de prévenir ou de traiter une maladie cutanée inflammatoire ou un prurit grave
CA3032072A CA3032072C (fr) 2016-09-30 2017-09-28 Composition de prevention ou traitement de maladies cutanees inflammatoires ou de prurit grave renfermant de l'acide ursodesoxycholique solubilise dans l'eau
JP2019520351A JP2019524876A (ja) 2016-09-30 2017-09-28 水可溶化されたウルソデオキシコール酸を含有する炎症性皮膚疾患または重症掻痒症の予防または治療用組成物
CN201780045135.1A CN109475564A (zh) 2016-09-30 2017-09-28 含有可溶于水的熊去氧胆酸的用于预防或治疗炎症性皮肤病或严重瘙痒症的组合物
US16/221,303 US11331326B2 (en) 2016-09-30 2018-12-14 Composition for prevention or treatment of inflammatory skin diseases or severe pruritus comprising the aqueous solubilized ursodeoxycholic acid

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KR20160126872 2016-09-30
KR10-2016-0126872 2016-09-30
KR1020170125571A KR20180036580A (ko) 2016-09-30 2017-09-27 수가용화(水加溶化)된 우르소데옥시콜산을 함유하는 염증성 피부질환 또는 중증 소양증 예방 또는 치료용 조성물
KR10-2017-0125571 2017-09-27

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US10959933B1 (en) 2020-06-01 2021-03-30 The Procter & Gamble Company Low pH skin care composition and methods of using the same
US11110049B2 (en) 2017-06-23 2021-09-07 The Procter & Gamble Company Composition and method for improving the appearance of skin
US11583488B2 (en) 2020-06-01 2023-02-21 The Procter & Gamble Company Method of improving penetration of a vitamin B3 compound into skin
US11622963B2 (en) 2018-07-03 2023-04-11 The Procter & Gamble Company Method of treating a skin condition

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KR20010074748A (ko) * 1998-07-24 2001-08-09 유서홍 담즙산을 가진 청정 수용액 제형의 제조방법
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Publication number Priority date Publication date Assignee Title
US11110049B2 (en) 2017-06-23 2021-09-07 The Procter & Gamble Company Composition and method for improving the appearance of skin
US11622963B2 (en) 2018-07-03 2023-04-11 The Procter & Gamble Company Method of treating a skin condition
US10959933B1 (en) 2020-06-01 2021-03-30 The Procter & Gamble Company Low pH skin care composition and methods of using the same
US11583488B2 (en) 2020-06-01 2023-02-21 The Procter & Gamble Company Method of improving penetration of a vitamin B3 compound into skin
US11911498B2 (en) 2020-06-01 2024-02-27 The Procter & Gamble Company Low pH skin care composition and methods of using the same

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