WO2022102819A1 - Pharmaceutical composition for preventing or treating systemic sclerosis - Google Patents

Pharmaceutical composition for preventing or treating systemic sclerosis Download PDF

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WO2022102819A1
WO2022102819A1 PCT/KR2020/016068 KR2020016068W WO2022102819A1 WO 2022102819 A1 WO2022102819 A1 WO 2022102819A1 KR 2020016068 W KR2020016068 W KR 2020016068W WO 2022102819 A1 WO2022102819 A1 WO 2022102819A1
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systemic sclerosis
butyrate
pharmaceutical composition
preventing
skin
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PCT/KR2020/016068
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French (fr)
Korean (ko)
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이상일
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경상대학교병원
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Publication of WO2022102819A1 publication Critical patent/WO2022102819A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating systemic sclerosis.
  • Systemic sclerosis is an intractable autoimmune disease characterized by vasculopathy, inflammation, and fibrosis. A clear etiology and therapeutic agent are not known. Recently, a close association between the occurrence of autoimmune diseases and imbalance of the intestinal microflora has been reported, and attempts to treat and improve autoimmune diseases by regulating the intestinal microflora are increasing. The association with microbiota (microbiota) has also been reported in patients with systemic sclerosis, so targeting substances that improve the intestinal environment as candidates for systemic sclerosis prevention and treatment will be a promising strategy for the development of new therapeutic agents for systemic sclerosis. will be able
  • Short chain fatty acid a metabolite produced by intestinal microbial fermentation, plays an important role in maintaining intestinal homeostasis, and one of short chain fatty acids, butyrate, is a major energy source for colonic cells It is known to help maintain the health of the colonic mucosa and intestinal epithelial barrier.
  • the present inventors investigated whether butyrate, a metabolite of the intestinal microbial metabolite, has an effect on the prevention and treatment of systemic sclerosis, and used an animal model of systemic sclerosis to evaluate whether the related mechanism is related to intestinal immunity. Immune cell changes were analyzed.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating systemic sclerosis.
  • a pharmaceutical composition for preventing or treating systemic sclerosis comprising butyrate or a pharmaceutically acceptable salt thereof.
  • Health functional food for preventing or improving systemic sclerosis including butyrate or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention has an excellent preventive or therapeutic effect on systemic sclerosis.
  • FIG. 1 shows the skin and lung fibrosis inhibitory effect according to sodium butyrate administration
  • FIGS. 1A and 1B show sodium butyrate oral administration ( FIG. 1A ) and subcutaneous administration ( FIG. 1A ) in a BLM (Bleomycin)-induced skin fibrosis model
  • 1b) shows the fibrosis inhibitory effect
  • FIG. 1c shows the fibrosis inhibitory effect upon oral administration of sodium butyrate in an LPS-induced skin fibrosis model.
  • Figure 2 shows the inhibitory effect of sodium butyrate on myofibroblast expression in the skin of a BLM-induced skin fibrosis model. -SMA protein expression measurement results are shown.
  • Figure 3 shows the anti-inflammatory function improvement effect of MLN (mesenteric lymph node) immune cells according to sodium butyrate administration in a BLM-induced skin fibrosis model
  • Figure 3a is representative flow cytometry data for the monocyte / macrophage composition in MLN
  • MLN 3b is a result of inflammatory monocyte (P1, P2)/macrophage (P3) analysis in MLN
  • FIG. 3c is a result of measuring the concentration of IL-10 secreted in the culture medium after stimulation of MLN cells with CD3/CD28 or LPS by ELISA.
  • Figure 4 shows the inhibitory effect on the differentiation of human dermal fibroblasts (HDF) into myofibroblasts according to sodium butyrate treatment.
  • Figure 4b shows the results of analysis of ⁇ -SMA gene expression according to TGF- ⁇ 1 and SB treatment in dermal fibroblasts of normal and systemic sclerosis patients.
  • the present invention relates to a pharmaceutical composition for preventing or treating systemic sclerosis, comprising butyrate or a pharmaceutically acceptable salt thereof.
  • Butyrate is a conjugate base of butyric acid, and butyric acid is one of short chain fatty acids (SCFA), a metabolite produced by intestinal microbial fermentation, and the intestinal mucosa and intestinal epithelial barrier. It is known to help maintain the health of Specifically, the butyrate may be sodium butyrate, potassium butyrate, calcium butyrate, or magnesium butyrate, and more specifically, sodium butyrate, but is not limited thereto.
  • SCFA short chain fatty acids
  • Systemic sclerosis is a disease that causes the skin to thicken or the function of each organ is impaired due to excessive production and accumulation of collagen among connective tissue components.
  • systemic sclerosis of the lung, skin, liver, kidney or cardiovascular system can
  • the systemic sclerosis may be diffuse cutaneous systemic sclerosis or limited cutaneous systemic sclerosis. Diffuse cutaneous systemic sclerosis develops rapidly and causes hardening of the skin of the extremities, face, and trunk, and has a high possibility of causing abnormalities in the kidneys and internal organs. These include CREST syndrome with deposition or Raynaud's phenomenon, hypomotility of the esophagus, sclerosis of the feet and fingers, and telangiectasia.
  • systemic sclerosis may be scleroderma, progressive systemic sclerosis, Crest's syndrome, drug and chemical-induced systemic sclerosis, systemic sclerosis with pulmonary involvement, or systemic sclerosis with myopathies, more specifically pulmonary involvement It may be accompanied by systemic sclerosis or skin sclerosis, but is not limited thereto.
  • pharmaceutically acceptable means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
  • pharmaceutically acceptable salt refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and the pharmaceutically acceptable salt is, for example, an acid addition salt or a metal salt.
  • Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids.
  • These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda.
  • the metal salt may be a sodium, potassium or calcium salt.
  • Metal salts can be prepared using a base, for example an alkali metal or alkaline earth metal salt by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating the filtrate and/or Or it can be obtained by drying
  • prevention refers to any action that suppresses the onset or delays the onset by administration of the composition.
  • treatment refers to treatment that results in a beneficial effect in a subject or patient suffering from the condition being treated, including not only cure, but also any degree of remission, including mild remission, substantial remission, major remission, the degree of remission being At least it's mild relief.
  • the pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can, but is not limited thereto.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • it is prepared using usually used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
  • Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc., but these solid preparations include at least one or more excipients in the compound, for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc. are mixed and prepared.
  • excipients for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • various excipients for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of disease in the patient; Sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field.
  • the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art.
  • the effective amount in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 6000 mg per kg of body weight, preferably 60 to 600 mg per kg of body weight, may be administered once or divided into three doses. there is. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
  • the present invention provides a health functional food for preventing or improving systemic sclerosis, including butyrate or a pharmaceutically acceptable salt thereof.
  • Butyrate and systemic sclerosis may be within the ranges described above.
  • food acceptable means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
  • food acceptable salt refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and may be within the range described above for "salt”.
  • the health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of improving systemic sclerosis.
  • the health functional food of the present invention refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
  • the health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
  • Examples of the items listed in the Food Additives Code include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations such as sodium L-glutamate preparation, noodles added alkali agent, preservative agent, tar color agent, etc. are not limited thereto.
  • a health functional food in the form of a tablet is granulated in a conventional manner by mixing the composition with an excipient, a binder, a disintegrant and other additives, followed by compression molding by adding a lubricant, or the mixture directly. Compression molding is possible.
  • the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
  • hard capsules can be prepared by filling a mixture of the composition and additives such as excipients in conventional hard capsules, and soft capsules are gelatin obtained by mixing the composition with additives such as excipients. It can be prepared by filling in a capsule base such as The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
  • a health functional food in the form of a ring can be prepared by molding a mixture of the composition and an excipient, a binder, a disintegrant, etc. by a known method, and if necessary, it can be coated with sucrose or other skinning agent, or starch , it is also possible to coat the surface with a material such as talc.
  • a health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing the composition with an excipient, a binder, a disintegrant, etc., and may contain a flavoring agent, a corrosive agent, etc. as necessary.
  • Health functional foods include beverages, meat, chocolate, foods, and sweets. It may be pizza, ramen, other noodles, gums, candies, ice cream, alcoholic beverages, vitamin complexes, health supplements, and the like.
  • Health functional foods may be orally applied for the purpose of nutritional supplements, and the application form is not particularly limited.
  • the daily intake is preferably 5000 mg or less, more preferably 2000 mg or less, and most preferably 500 to 1500 mg or 650 mg daily.
  • 1 tablet may be administered with water once a day.
  • mice C57BL/6 male mice aged 8 to 10 weeks were used. After removing the dorsal hair at the injection site, bleomycin (BLM, 1 mg/ml) or LPS (lipopolysaccharide, 50 ⁇ g/ml, Sigma) dissolved in PBS (phosphate buffer saline) was subcutaneously administered to the dorsal side of the rat for 2 weeks. were injected 5 times a week.
  • BLM bleomycin
  • LPS lipopolysaccharide
  • Sodium butyrate was orally administered 5 times a week for a total of 4 weeks from 2 weeks before induction of systemic sclerosis animal models with BLM or LPS until the end of the experiment.
  • Sodium butyrate (Sigma, 303410) was dissolved in distilled water (DW, distilled water) to a concentration of 50 mg/ml, placed in an Oral zoned, 20 G, 7 cm, and 200 ⁇ l each was orally administered to mice.
  • HDF Primary human dermal fibroblast
  • rat skin and lung tissue were extracted to prepare formalin-fixed and paraffin blocks. Fibrosis was evaluated by Masson-Trichrome tissue staining and ⁇ -smooth muscle actin antibody (-SMA, Abcam) immunofluorescence staining.
  • -SMA ⁇ -smooth muscle actin antibody
  • the thickness of the dermis stained with Masson-Trichrome was measured, and cells stained with ⁇ -SMA were identified to evaluate fibrosis.
  • the extent and degree of staining in the alveolar wall and interstitial region was quantified on a scale of 0 to 8 (Ashcroft score) to evaluate the degree of fibrosis.
  • Proteins were extracted from skin tissues and cells with radioimmunoprecipitation assay (RIPA) lysis buffer (Thermo). After electrophoresis of 20 - 30 ⁇ g protein with SDS-polyacrylamide gel, it was transferred to polyvinylidene difluoride membranes (Millipore) and ⁇ -SMA primary antibody (Abcam) was attached to evaluate ⁇ -SMA protein expression with Chemidoc image system (Bio-rad). . In addition, after RNA extraction using Trizol (Thermo) from cells, cDNA was synthesized using the iScript cDNA synthesis kit (Biorad).
  • RIPA radioimmunoprecipitation assay
  • cDNA was mixed with Taqman gene expression master mix (Thermo), ⁇ -SMA Taqman probe and primer (Thermo), and then ⁇ -SMA gene expression was measured with ViiA 7 Real-time PCR Detection System (Applied biosystems).
  • Rat mesenteric lymph node was removed and physically ground on a mesh of 100 ⁇ m pore size to separate MLN immune cells.
  • the isolated MLN cells (1 ⁇ 106 cells) were analyzed by flow cytometry (BD, LSRFortessatm X-20) by attaching a rat-anti-mouse fluorescent surface marker.
  • the fluorescent surface markers used are as follows. MHCII-BV421 (Biolegend), FVD506 (Ebioscience), Ly-6C-BV605 (BD), CD64-BV780 (BD), CD11b-BB515 (BD), CD103-PE (BD), CD11c-BB700 (BD), CX3CR1 -APC (Biolegend), CD45-APC-Cy7 (BD).
  • Rat mesenteric lymph node was removed and physically ground on a mesh of 100 ⁇ m pore size to separate MLN immune cells.
  • MLN Rat mesenteric lymph node
  • RPMI media Gibco
  • Fetal bovine serum Gibco
  • Penicillin/streptomycin Gibco
  • 0.1% b-mercaptoethanol Gibco
  • glutamax Gibco
  • 96 wells Put 200 ⁇ l into each plate (5 ⁇ 105/well), and incubate for 48 hours with or without stimulation with CD3/CD28 (1 ⁇ g/ml each, BD) and LPS (1 ⁇ g/ml, Sigma) added.
  • CD3/CD28 (1 ⁇ g/ml each, BD
  • LPS 1 ⁇ g/ml, Sigma
  • FIGS. 1A to 1C the skin fibrosis inhibition efficacy of subcutaneous administration of SB topically to the BLM-induced skin fibrosis site was evaluated.
  • Administration of SB in the BLM or LPS-induced skin fibrosis model decreased skin dermal thickness and lung fibrosis score (Ashcroft score) ( FIGS. 1A to 1C ).
  • the degree of fibrosis was evaluated through dermal thickness and the expression level of ⁇ -SMA, known as a myofibroblast marker.
  • the BLM-induced skin fibrosis model after oral administration of SB, the reduction of ⁇ -SMA+ cells and the expression of ⁇ -SMA protein were decreased in the skin tissue ( FIGS. 2A and 2B ).
  • MSN mesenteric lymph node
  • Gut-associated lymph node By analyzing mesenteric lymph node (MLN) immune cells known as Gut-associated lymph node, it was evaluated whether SB had an effect on intestinal immune regulation.
  • Ly6C + one monocyte (P1, P2) decreased and Ly6C-MHCII + one macrophage (P3) increased in MLN (Fig. 3b).
  • Ly6C+ monocytes are known to increase in the intestine and MLN when there is an intestinal abnormality such as inflammation, and secrete a pro-inflammatory cytokine.
  • MLN cells of SB-administered mice showed increased IL-10 secretion when stimulated with LPS, so administration of SB in BLM-induced skin fibrosis is expected to improve the anti-inflammatory function of MLN cells, which It is expected to contribute to suppression of skin and lung fibrosis through immune regulation in immune organs.
  • Human dermal fibroblasts were stimulated with TGF- ⁇ 1 to promote differentiation into myofibroblasts, and it was evaluated whether differentiation into myofibroblasts was inhibited by butyrate treatment (FIGS. 4a and 4b, Normal #1: Primary HDF from ATCC, Normal #2). : Primary fibroblast obtained from skin of normal patient, SSc #1&2: Primary fibroblast obtained from skin of SSc patients).
  • Human dermal fibroblasts were stimulated with TGF- ⁇ 1 to promote differentiation into myofibroblasts, that is, ⁇ -SMA was increased, and TGF- ⁇ 1-induced differentiation into myofibroblasts was inhibited ( ⁇ -SMA decreased) after butyrate treatment. Butyrate inhibited TGF- ⁇ 1-induced myofibroblast differentiation not only in normal dermal fibroblasts but also in dermal fibroblasts derived from SSc patients (Figs. 4a and 4b).

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Abstract

The pharmaceutical composition of the present invention is superbly effective in preventing or treating systemic sclerosis, the pharmaceutical composition being effective in inhibiting skin and lung fibrosis, enhancing intestinal immunological functions, and inhibiting differentiation of skin fibroblasts into myofibroblasts.

Description

전신경화증 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating systemic sclerosis
본 발명은 전신경화증의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating systemic sclerosis.
전신경화증(Systemic sclerosis: SSc)은 혈관병증, 염증, 섬유화를 특징으로 하는 난치성 자가 면역 질환으로 명확한 병인 기전과 치료제는 알려져 있지 않다. 최근 자가 면역 질환 발생과 장내 미생물총 불균형과의 밀접한 연관성이 보고되고 있으며, 장내 미생물총을 조절함으로써 자가 면역 질환을 치료하고 개선하고자 하는 시도들이 증가하고 있다. 전신경화증 환자에서도 미생물총(마이크로바이오타)과의 관련성이 보고되어 있어, 전신경화증 예방 및 치료 후보 물질로서 장내 환경을 개선하는 물질을 타깃으로 하는 것은 전신경화증의 새로운 치료제 개발을 위한 유망한 전략이 될 수 있을 것이다.Systemic sclerosis (SSc) is an intractable autoimmune disease characterized by vasculopathy, inflammation, and fibrosis. A clear etiology and therapeutic agent are not known. Recently, a close association between the occurrence of autoimmune diseases and imbalance of the intestinal microflora has been reported, and attempts to treat and improve autoimmune diseases by regulating the intestinal microflora are increasing. The association with microbiota (microbiota) has also been reported in patients with systemic sclerosis, so targeting substances that improve the intestinal environment as candidates for systemic sclerosis prevention and treatment will be a promising strategy for the development of new therapeutic agents for systemic sclerosis. will be able
장내미생물 발효에 의해 생성되는 대사 산물인 단쇄 지방산(short chain fatty acid; SCFA)은 장내 항상성 유지에 중요한 역할을 하며, 단쇄 지방산 중 하나인 부티레이트(butyrate)는 대장 상피 세포(colonocyte)의 주요 에너지원으로 대장 점막 및 장 상피 장벽의 건강을 유지하는데 도움을 주는 것으로 알려져 있다.Short chain fatty acid (SCFA), a metabolite produced by intestinal microbial fermentation, plays an important role in maintaining intestinal homeostasis, and one of short chain fatty acids, butyrate, is a major energy source for colonic cells It is known to help maintain the health of the colonic mucosa and intestinal epithelial barrier.
본 발명자들은 장내 미생물 대사 산물인 부티레이트가 전신경화증 예방 및 치료에 효과를 나타내는지를 알아보고, 그 관련 기전으로 장내 면역과의 관련성이 있는지를 평가하고자 전신경화증 동물 모델을 활용하여 부티레이트의 섬유화 억제 효과 및 장내 면역 세포 변화를 분석하였다.The present inventors investigated whether butyrate, a metabolite of the intestinal microbial metabolite, has an effect on the prevention and treatment of systemic sclerosis, and used an animal model of systemic sclerosis to evaluate whether the related mechanism is related to intestinal immunity. Immune cell changes were analyzed.
본 발명은 전신경화증 예방 또는 치료용 약학적 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating systemic sclerosis.
1. 부티레이트(butyrate) 또는 이의 약학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 치료용 약학적 조성물.1. A pharmaceutical composition for preventing or treating systemic sclerosis, comprising butyrate or a pharmaceutically acceptable salt thereof.
2. 위 1에 있어서, 상기 부티레이트는 소듐 부티레이트(sodium butyrate)인, 전신경화증 예방 또는 치료용 약학적 조성물.2. The pharmaceutical composition for preventing or treating systemic sclerosis according to the above 1, wherein the butyrate is sodium butyrate.
3. 위 1에 있어서, 상기 전신경화증은 폐 침범을 동반한 전신경화증 또는 피부경화증인, 전신경화증 예방 또는 치료용 약학적 조성물.3. The pharmaceutical composition for preventing or treating systemic sclerosis according to the above 1, wherein the systemic sclerosis is systemic sclerosis or skin sclerosis accompanied by lung involvement.
4. 부티레이트(butyrate) 또는 이의 식품학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 개선용 건강기능식품.4. Health functional food for preventing or improving systemic sclerosis, including butyrate or a pharmaceutically acceptable salt thereof.
본 발명의 약학적 조성물은 전신경화증에 대한 우수한 예방 또는 치료 효과를 갖는다.The pharmaceutical composition of the present invention has an excellent preventive or therapeutic effect on systemic sclerosis.
도 1은 소듐 부티레이트(sodium butyrate) 투여에 따른 피부 및 폐 섬유화 억제 효과를 나타낸 것으로, 도 1a 및 도 1b는 BLM(Bleomycin) 유발 피부 섬유증 모델에서 소듐 부티레이트 경구 투여(도 1a) 및 피하 투여(도 1b) 시 섬유화 억제 효과를 나타낸 것이고, 도 1c는 LPS 유발 피부 섬유증 모델에서 소듐 부티레이트 경구 투여 시 섬유화 억제 효과를 나타낸다.1 shows the skin and lung fibrosis inhibitory effect according to sodium butyrate administration, and FIGS. 1A and 1B show sodium butyrate oral administration ( FIG. 1A ) and subcutaneous administration ( FIG. 1A ) in a BLM (Bleomycin)-induced skin fibrosis model. 1b) shows the fibrosis inhibitory effect, and FIG. 1c shows the fibrosis inhibitory effect upon oral administration of sodium butyrate in an LPS-induced skin fibrosis model.
도 2는 BLM 유발 피부 섬유증 모델의 피부에서 소듐 부티레이트의 근섬유 아세포(myofibroblast) 발현 억제 효과를 나타낸 것으로, 도 2a는 피부 조직에서 α-SMA에 대한 면역 형광 염색 결과를, 도 2b는 피부 조직에서 α-SMA 단백질 발현 측정 결과를 나타낸 것이다.Figure 2 shows the inhibitory effect of sodium butyrate on myofibroblast expression in the skin of a BLM-induced skin fibrosis model. -SMA protein expression measurement results are shown.
도 3은 BLM 유발 피부 섬유증 모델에서 소듐 부티레이트 투여에 따른 MLN(mesenteric lymph node) 면역 세포의 항염증 기능 향상 효과를 나타낸 것으로, 도 3a는 MLN에서 monocyte/macrophage 구성에 대한 대표적 flow cytometry 데이터이고, 도 3b는 MLN에서 inflammatory monocyte(P1, P2)/macrophage(P3) 분석 결과이고, 도 3c는 MLN cells을 CD3/CD28 또는 LPS로 자극 후 배양액 내 분비된 IL-10 농도를 ELISA로 측정한 결과이다.Figure 3 shows the anti-inflammatory function improvement effect of MLN (mesenteric lymph node) immune cells according to sodium butyrate administration in a BLM-induced skin fibrosis model, Figure 3a is representative flow cytometry data for the monocyte / macrophage composition in MLN 3b is a result of inflammatory monocyte (P1, P2)/macrophage (P3) analysis in MLN, and FIG. 3c is a result of measuring the concentration of IL-10 secreted in the culture medium after stimulation of MLN cells with CD3/CD28 or LPS by ELISA.
도 4는 소듐 부티레이트 처리에 따른 human dermal fibroblast(HDF)에서 근섬유 아세포로의 분화 억제 효과를 나타낸 것으로, 도 4a는 normal human dermal fibroblast에서 TGF- β1 및 소듐 부티레이트 처리에 따른 α-SMA 단백질 발현 분석 결과를, 도 4b는 정상 및 전신경화증 환자 dermal fibroblast에서 TGF-β1 및 SB 처리에 따른 α-SMA 유전자 발현 분석 결과를 나타낸다.Figure 4 shows the inhibitory effect on the differentiation of human dermal fibroblasts (HDF) into myofibroblasts according to sodium butyrate treatment. Figure 4b shows the results of analysis of α-SMA gene expression according to TGF-β1 and SB treatment in dermal fibroblasts of normal and systemic sclerosis patients.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 부티레이트(butyrate) 또는 이의 약학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating systemic sclerosis, comprising butyrate or a pharmaceutically acceptable salt thereof.
부티레이트(butyrate)는 부티르산(butyric acid)의 짝염기(conjugate base)로, 부티르산은 장내 미생물 발효에 의해 생성되는 대사 산물인 단쇄 지방산(short chain fatty acid; SCFA) 중 하나이며, 대장 점막 및 장 상피 장벽의 건강을 유지하는데 도움을 주는 것으로 알려져 있다. 구체적으로, 부티레이트는 소듐 부티레이트, 포타슘 부티레이트, 칼슘 부티레이트, 또는 마그네슘 부티레이트일 수 있고, 보다 구체적으로 소듐 부티레이트일 수 있으나, 이에 제한되는 것은 아니다.Butyrate is a conjugate base of butyric acid, and butyric acid is one of short chain fatty acids (SCFA), a metabolite produced by intestinal microbial fermentation, and the intestinal mucosa and intestinal epithelial barrier. It is known to help maintain the health of Specifically, the butyrate may be sodium butyrate, potassium butyrate, calcium butyrate, or magnesium butyrate, and more specifically, sodium butyrate, but is not limited thereto.
전신경화증(systemic sclerosis)은 결합 조직 성분 중 콜라겐이 과다하게 생성되고 축적되어서 피부가 두꺼워지거나 각 장기의 기능에 장애를 일으키는 병으로, 구체적으로 폐, 피부, 간, 신장 또는 심혈관계의 전신경화증일 수 있다.Systemic sclerosis is a disease that causes the skin to thicken or the function of each organ is impaired due to excessive production and accumulation of collagen among connective tissue components. Specifically, systemic sclerosis of the lung, skin, liver, kidney or cardiovascular system can
전신경화증은 미만성 피부 전신경화증(diffuse cutaneous systemic sclerosis) 또는 제한성 피부 전신경화증(limited cutaneous systemic sclerosis)일 수 있다. 미만성 피부 전신경화증은 급속히 발생하며 사지, 얼굴, 몸통 등의 피부 경화를 초래하며 콩팥 및 내장 기관의 이상을 초래할 수 있는 가능성이 높고, 제한성 피부 전신경화증은 말단 사지 및 얼굴에 주로 나타나며 피부에 칼슘이 침착 되거나 레이노 현상, 식도 운동 저하, 발과 손가락의 경화증, 모세 혈관 확장증이 동반되는 CREST 증후군이 이에 속한다. 구체적으로, 전신경화증은 피부경화증, 진행성 전신경화증, 크레스트 증후군, 약물 및 화학물질로 유발된 전신경화증, 폐 침범을 동반한 전신경화증 또는 근병증을 동반한 전신경화증일 수 있고, 보다 구체적으로 폐 침범을 동반한 전신경화증 또는 피부경화증일 수 있으나, 이에 제한되는 것은 아니다.The systemic sclerosis may be diffuse cutaneous systemic sclerosis or limited cutaneous systemic sclerosis. Diffuse cutaneous systemic sclerosis develops rapidly and causes hardening of the skin of the extremities, face, and trunk, and has a high possibility of causing abnormalities in the kidneys and internal organs. These include CREST syndrome with deposition or Raynaud's phenomenon, hypomotility of the esophagus, sclerosis of the feet and fingers, and telangiectasia. Specifically, the systemic sclerosis may be scleroderma, progressive systemic sclerosis, Crest's syndrome, drug and chemical-induced systemic sclerosis, systemic sclerosis with pulmonary involvement, or systemic sclerosis with myopathies, more specifically pulmonary involvement It may be accompanied by systemic sclerosis or skin sclerosis, but is not limited thereto.
용어 "약학적으로 허용 가능한"은 화합물 또는 조성물이 투여되는 개체, 세포, 조직 등에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 특성을 나타내는 것을 의미한다.The term "pharmaceutically acceptable" means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
용어 "약학적으로 허용 가능한 염"은, 본 발명에 따른 특정 화합물과 비교적 무독성인 산 또는 염기를 이용해서 조제되는 염을 의미하며, 약학적으로 허용 가능한 염은 예를 들어 산 부가염 또는 금속염일 수 있다.The term "pharmaceutically acceptable salt" refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and the pharmaceutically acceptable salt is, for example, an acid addition salt or a metal salt. can
산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 형성될 수 있다. 이러한 약학적으로 무독한 염은 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트, 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피을레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴- 1,4-디오에이트, 핵산-1，6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 를투엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β_하이드톡시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함할 수 있다.Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It can be formed from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. These pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, ioda. Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propylate, oxalate, malonate, succinate, suberate, Sebacate, fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxy Benzoate, phthalate, terephthalate, benzenesulfonate, etuenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β_hydroxybutyrate, glycol lactate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.
금속염은 나트륨, 칼륨 또는 칼슘염일 수 있다. 금속염은 염기를 사용하여 제조할 수 있으며, 예를 들어, 알칼리 금속 또는 알칼리 토금속 염은 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고 여액을 증발 및/또는 건조시켜 수득할 수 있다The metal salt may be a sodium, potassium or calcium salt. Metal salts can be prepared using a base, for example an alkali metal or alkaline earth metal salt by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt and evaporating the filtrate and/or Or it can be obtained by drying
용어 "예방"은 조성물의 투여로 발병을 억제하거나 발병을 지연시키는 모든 행위를 의미한다.The term "prevention" refers to any action that suppresses the onset or delays the onset by administration of the composition.
용어 "치료"는 치유뿐만 아니라 경미한 완화, 실질적인 완화, 주요 완화를 포함하는 임의의 정도의 완화를 포함하여 치료될 병태를 앓고 있는 대상체 또는 환자에게 유리한 효과를 초래하는 처치를 지칭하고, 완화 정도는 적어도 경미한 완화이다.The term “treatment” refers to treatment that results in a beneficial effect in a subject or patient suffering from the condition being treated, including not only cure, but also any degree of remission, including mild remission, substantial remission, major remission, the degree of remission being At least it's mild relief.
본 발명의 약학적 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으나, 이에 제한되지 않는다.The pharmaceutical composition of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. can, but is not limited thereto.
조성물에 함유될 수 있는 담체, 부형제 및 희석제로는 락토오즈, 덱스트로즈, 수크로스, 덱스트린, 말토덱스트린, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있으나, 이에 제한되지 않는다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면 활성제 등의 희석제 또는 부형제를 사용하여 조제되나, 이에 제한되지 않는다.Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared using usually used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants, but is not limited thereto.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며 이에 제한되지는 않으나, 이러한 고형제제는 상기 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다.Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, etc., but these solid preparations include at least one or more excipients in the compound, for example, starch, calcium carbonate , sucrose or lactose, gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients, for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. . Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 통상의 기술자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is determined by the type, severity, activity of the drug, and the type of disease in the patient; Sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, factors including concomitant drugs and other factors well known in the medical field. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiple times. In consideration of all of the above factors, it is important to administer an amount capable of obtaining the maximum effect with a minimum amount without side effects, which can be easily determined by a person skilled in the art.
본 발명의 약학적 조성물에서 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 1 내지 6000 ㎎, 바람직하게는 60 내지 600 ㎎을 1회 또는 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The effective amount in the pharmaceutical composition of the present invention may vary depending on the age, sex, and weight of the patient, and generally 1 to 6000 mg per kg of body weight, preferably 60 to 600 mg per kg of body weight, may be administered once or divided into three doses. there is. However, since it may increase or decrease depending on the route of administration, disease severity, sex, weight, age, etc., the dosage is not intended to limit the scope of the present invention in any way.
본 발명은 부티레이트(butyrate) 또는 이의 식품학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 개선용 건강기능식품을 제공한다.The present invention provides a health functional food for preventing or improving systemic sclerosis, including butyrate or a pharmaceutically acceptable salt thereof.
부티레이트 및 전신경화증은 전술한 범위 내의 것일 수 있다.Butyrate and systemic sclerosis may be within the ranges described above.
용어 "식품학적으로 허용 가능한"은 화합물 또는 조성물이 투여되는 개체, 세포, 조직 등에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 특성을 나타내는 것을 의미한다.The term “food acceptable” means exhibiting properties that do not cause serious irritation to the subject, cell, tissue, etc. to which the compound or composition is administered and do not impair the biological activity and physical properties of the compound.
용어 "식품학적으로 허용 가능한 염"은, 본 발명에 따른 특정 화합물과 비교적 무독성인 산 또는 염기를 이용해서 조제되는 염을 의미하며, "염"에 관한 전술한 범위 내일 수 있다.The term "food acceptable salt" refers to a salt prepared using a specific compound according to the present invention and a relatively non-toxic acid or base, and may be within the range described above for "salt".
본 발명의 건강기능식품은 전신경화증 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. for the purpose of improving systemic sclerosis.
본 발명의 건강기능식품이라 함은, 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The health functional food of the present invention refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards.
식품 첨가물 공전에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류 첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 포함하나, 이에 제한되지 않는다.Examples of the items listed in the Food Additives Code include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations such as sodium L-glutamate preparation, noodles added alkali agent, preservative agent, tar color agent, etc. are not limited thereto.
예를 들어, 정제 형태의 건강기능식품은 상기 조성물을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다.For example, a health functional food in the form of a tablet is granulated in a conventional manner by mixing the composition with an excipient, a binder, a disintegrant and other additives, followed by compression molding by adding a lubricant, or the mixture directly. Compression molding is possible. In addition, the health functional food in the form of tablets may contain a corrosive agent and the like, if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 상기 조성물을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 상기 조성물을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.Among health functional foods in capsule form, hard capsules can be prepared by filling a mixture of the composition and additives such as excipients in conventional hard capsules, and soft capsules are gelatin obtained by mixing the composition with additives such as excipients. It can be prepared by filling in a capsule base such as The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary.
환 형태의 건강기능식품은 상기 조성물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.A health functional food in the form of a ring can be prepared by molding a mixture of the composition and an excipient, a binder, a disintegrant, etc. by a known method, and if necessary, it can be coated with sucrose or other skinning agent, or starch , it is also possible to coat the surface with a material such as talc.
과립 형태의 건강기능식품은 상기 조성물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.A health functional food in the form of granules can be prepared in granular form by a conventionally known method by mixing the composition with an excipient, a binder, a disintegrant, etc., and may contain a flavoring agent, a corrosive agent, etc. as necessary.
건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류. 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.Health functional foods include beverages, meat, chocolate, foods, and sweets. It may be pizza, ramen, other noodles, gums, candies, ice cream, alcoholic beverages, vitamin complexes, health supplements, and the like.
건강기능식품은 영양제의 용도로 경구 적용될 수 있으며, 적용 형태는 특별히 제한되지 않는다. 예를 들면 경구 투여되는 경우, 하루 섭취량은 5000mg 이하인 것이 바람직하고, 하루 섭취량이 2000mg 이하인 것이 보다 바람직하며, 하루 섭취량이 500 내지 1500mg, 또는 650mg인 것이 가장 바람직하다. 캡슐제 또는 정제로 제제화하는 경우, 1일 1회 1정을 물과 함께 투여할 수 있다.Health functional foods may be orally applied for the purpose of nutritional supplements, and the application form is not particularly limited. For example, in the case of oral administration, the daily intake is preferably 5000 mg or less, more preferably 2000 mg or less, and most preferably 500 to 1500 mg or 650 mg daily. When formulated as a capsule or tablet, 1 tablet may be administered with water once a day.
이하, 본 발명을 구체적으로 설명하기 위해 실시예를 들어 상세하게 설명하기로 한다.Hereinafter, examples will be given to describe the present invention in detail.
실시예Example
실험 재료 및 방법Experimental materials and methods
1. 전신경화증 동물 모델 유발1. Induced Systemic Sclerosis Animal Model
8 내지 10주령의 C57BL/6 수컷 쥐를 사용하였다. 주사할 부위의 등쪽 털을 제모한 뒤, PBS(phosphate buffer saline)에 녹인 bleomycin(BLM, 1 ㎎/㎖) 또는 LPS(lipopolysaccharide, 50 ㎍/㎖, Sigma)를 쥐 등쪽 피하로 100 ㎕씩 2주 동안 주 5회 주사하였다.C57BL/6 male mice aged 8 to 10 weeks were used. After removing the dorsal hair at the injection site, bleomycin (BLM, 1 mg/ml) or LPS (lipopolysaccharide, 50 μg/ml, Sigma) dissolved in PBS (phosphate buffer saline) was subcutaneously administered to the dorsal side of the rat for 2 weeks. were injected 5 times a week.
2. 전신경화증 동물 모델에서 부티레이트(butyrate) 투여2. Butyrate administration in an animal model of systemic sclerosis
소듐 부티레이트(sodium butyrate)를 BLM 또는 LPS로 전신경화증 동물 모델을 유발하기 2주 전부터 실험 종료 시까지 총 4주 동안 주 5회 경구 투여하였다. 소듐 부티레이트(Sigma, 303410)는 증류수(DW, distilled water)에 50 ㎎/㎖의 농도로 녹인 후 쥐용 존대(Oral zoned, 20 G, 7 ㎝)에 넣어 200 ㎕씩 쥐에 경구 투여하였다.Sodium butyrate was orally administered 5 times a week for a total of 4 weeks from 2 weeks before induction of systemic sclerosis animal models with BLM or LPS until the end of the experiment. Sodium butyrate (Sigma, 303410) was dissolved in distilled water (DW, distilled water) to a concentration of 50 mg/ml, placed in an Oral zoned, 20 G, 7 cm, and 200 μl each was orally administered to mice.
3. Dermal fibroblast 배양 및 처리3. Dermal fibroblast culture and processing
Primary human dermal fibroblast(HDF) cell은 ATCC에서 구입하였다. 또한 정상 및 전신경화증 환자 샘플의 피부에서 분리한 dermal fibroblast를 실험에 사용하였다. Fibroblast는 10 ng/㎖ TGF-β1(R&D system)로 48시간 처리하여 myofibroblast로의 분화를 유도하였다. TGF-β1로 처리하거나 처리하지 않은 fibroblast에 sodium butyrate를 0, 0.1, 0.5, 1 mM의 농도로 동시에 처리하였다. 이 후 세포는 단백질 및 RNA 추출을 위해 사용할 때까지 -70℃ 에 보관하였다.Primary human dermal fibroblast (HDF) cells were purchased from ATCC. In addition, dermal fibroblasts isolated from the skin of normal and systemic sclerosis patient samples were used in the experiment. Fibroblasts were treated with 10 ng/ml TGF-β1 (R&D system) for 48 hours to induce differentiation into myofibroblasts. Sodium butyrate was simultaneously treated at concentrations of 0, 0.1, 0.5, and 1 mM to fibroblasts treated with or without TGF-β1. The cells were then stored at -70°C until used for protein and RNA extraction.
4. 피부 및 폐 조직 섬유화 평가4. Assessment of Skin and Lung Tissue Fibrosis
실험 종료 후 쥐 피부 및 폐 조직을 적출하여 포르말린 고정 및 파라핀 블락을 제작하였다. Masson-Trichrome 조직 염색과 α- smooth muscle actin antibody(-SMA, Abcam) 면역 형광 염색을 통해 섬유화를 평가하였다. 피부의 경우, Masson-Trichrome으로 염색된 진피의 두께(Dermal thickness)를 측정하였으며, α-SMA로 염색된 세포를 확인하여 섬유화를 평가하였다. 폐의 경우, 폐포벽 및 간질 부위에 염색된 범위 및 정도를 0~8점으로 수치화(Ashcroft score)하여 섬유화 정도를 평가하였다.After the end of the experiment, rat skin and lung tissue were extracted to prepare formalin-fixed and paraffin blocks. Fibrosis was evaluated by Masson-Trichrome tissue staining and α-smooth muscle actin antibody (-SMA, Abcam) immunofluorescence staining. In the case of skin, the thickness of the dermis stained with Masson-Trichrome was measured, and cells stained with α-SMA were identified to evaluate fibrosis. In the case of the lung, the extent and degree of staining in the alveolar wall and interstitial region was quantified on a scale of 0 to 8 (Ashcroft score) to evaluate the degree of fibrosis.
5. 웨스턴 블롯팅 및 qPCR(quantitative PCR)5. Western blotting and quantitative PCR (qPCR)
피부 조직 및 세포에서 radioimmunoprecipitation assay(RIPA) lysis buffer(Thermo)로 단백질을 추출하였다. 20 - 30 ㎍ 단백질은 SDS-polyacrylamide gel로 전기 영동 후 polyvinylidene difluoride membranes (Millipore)로 옮긴 후 α-SMA primary antibody(Abcam)를 붙여 Chemidoc image system(Bio-rad)으로 α-SMA 단백질 발현을 평가하였다. 또한 세포에서 Trizol(Thermo)을 사용하여 RNA 추출 후 iScript cDNA synthesis kit(Biorad)로 cDNA를 합성하였다. cDNA는 Taqman gene expression master mix(Thermo), α-SMA Taqman probe 및 primer(Thermo)와 섞은 후 ViiA 7 Real-time PCR Detection system(Applied biosystems)으로 α-SMA 유전자 발현을 측정하였다.Proteins were extracted from skin tissues and cells with radioimmunoprecipitation assay (RIPA) lysis buffer (Thermo). After electrophoresis of 20 - 30 ㎍ protein with SDS-polyacrylamide gel, it was transferred to polyvinylidene difluoride membranes (Millipore) and α-SMA primary antibody (Abcam) was attached to evaluate α-SMA protein expression with Chemidoc image system (Bio-rad). . In addition, after RNA extraction using Trizol (Thermo) from cells, cDNA was synthesized using the iScript cDNA synthesis kit (Biorad). cDNA was mixed with Taqman gene expression master mix (Thermo), α-SMA Taqman probe and primer (Thermo), and then α-SMA gene expression was measured with ViiA 7 Real-time PCR Detection System (Applied biosystems).
6. Flow cytometry 분석6. Flow cytometry analysis
쥐 mesenteric lymph node(MLN)를 적출하여 100 ㎛ pore size의 mesh위에서 물리적으로 갈아 MLN 면역세포를 분리하였다. 분리한 MLN 세포 (1×106 세포)는 rat-anti-mouse 형광 surface marker를 붙여 flow cytometry(BD, LSRFortessatm X-20)로 분석하였다. 사용한 형광 surface marker는 다음과 같다. MHCII-BV421(Biolegend), FVD506(Ebioscience), Ly-6C-BV605(BD), CD64-BV780(BD), CD11b-BB515(BD), CD103-PE(BD), CD11c-BB700(BD), CX3CR1-APC(Biolegend), CD45-APC-Cy7(BD).Rat mesenteric lymph node (MLN) was removed and physically ground on a mesh of 100 ㎛ pore size to separate MLN immune cells. The isolated MLN cells (1×106 cells) were analyzed by flow cytometry (BD, LSRFortessatm X-20) by attaching a rat-anti-mouse fluorescent surface marker. The fluorescent surface markers used are as follows. MHCII-BV421 (Biolegend), FVD506 (Ebioscience), Ly-6C-BV605 (BD), CD64-BV780 (BD), CD11b-BB515 (BD), CD103-PE (BD), CD11c-BB700 (BD), CX3CR1 -APC (Biolegend), CD45-APC-Cy7 (BD).
7. Interleukin(IL)-10 농도 분석7. Interleukin(IL)-10 Concentration Analysis
쥐 mesenteric lymph node(MLN)를 적출하여 100 ㎛ pore size의 mesh위에서 물리적으로 갈아 MLN 면역세포를 분리하였다. 10% Fetal bovine serum(Gibco), 1% Penicillin/streptomycin(Gibco), 0.1% b-mercaptoethanol(Gibco), 1% glutamax(Gibco)가 첨가된 RPMI media (Gibco)로 MLN 세포를 부유시킨 후 96 well plate에 200 ㎕씩 넣어 (5×105/well), CD3/CD28(각 1 ㎍/㎖, BD), LPS (1 ㎍/㎖, Sigma)를 첨가하여 자극하거나 첨가하지 않은 상태에서 48 시간 동안 배양하였다. 이 후 배양액을 회수하여 배양액에 분비된 IL-10 농도를 Mouse IL-10 ELISA kit (BD)로 측정하였다.Rat mesenteric lymph node (MLN) was removed and physically ground on a mesh of 100 ㎛ pore size to separate MLN immune cells. After suspending MLN cells in RPMI media (Gibco) supplemented with 10% Fetal bovine serum (Gibco), 1% Penicillin/streptomycin (Gibco), 0.1% b-mercaptoethanol (Gibco), and 1% glutamax (Gibco), 96 wells Put 200 μl into each plate (5×105/well), and incubate for 48 hours with or without stimulation with CD3/CD28 (1 μg/ml each, BD) and LPS (1 μg/ml, Sigma) added. did After that, the culture medium was recovered and the concentration of IL-10 secreted into the culture medium was measured with a Mouse IL-10 ELISA kit (BD).
실험 결과Experiment result
1. 전신경화증 동물 모델에서 부티레이트(butyrate)의 피부 및 폐 섬유화 억제 효과1. Skin and lung fibrosis inhibitory effect of butyrate in an animal model of systemic sclerosis
Bleomycin (BLM) 또는 lipopolysaccharide (LPS)를 2주 동안 피하 주사하여 피부 섬유화를 유도하였다. 소듐 부티레이트(SB, Sodium butyrate)를 BLM 또는 LPS 투여하기 2주전부터 시작하여 실험 종료까지 총 4주동안 경구 투여한 후, butyrate의 피부 섬유화 억제 효능을 평가하였다(도 1a 및 도 1c). BLM을 투여하여 피부 섬유화를 유도한 모델(BLM-induced skin fibrosis model)의 경우 SB의 폐 섬유화 억제 효능도 함께 평가하였다(도 1a). 또한 SB가 직접적으로 피부 섬유화를 억제하는지를 확인하지 위해 BLM으로 유도된 피부 섬유화 부위에 국소적으로 SB를 피하 투여 피부 섬유화 억제 효능을 평가하였다(도 1b). BLM 또는 LPS-induced skin fibrosis 모델에서 SB의 투여는 피부 dermal thickness 및 폐 fibrosis score(Ashcroft score)를 감소시켰다(도 1a 내지 1c). 또한, 섬유 아세포(fibroblast) 활성화, 근섬유 아세포(myofibroblast)로의 분화 및 증식은 섬유화 과정에서 중요한 역할을 하는바, dermal thickness와 함께 myofibroblast marker로 알려진 α-SMA 발현 정도를 통해 섬유화 정도를 평가하였다. BLM-induced skin fibrosis 모델에서 SB 경구 투여 후 피부 조직에서 α-SMA+ cells의 감소 및 α-SMA 단백질 발현이 감소되었다(도 2a 및 2b).Skin fibrosis was induced by subcutaneous injection of Bleomycin (BLM) or lipopolysaccharide (LPS) for 2 weeks. Sodium butyrate (SB, sodium butyrate) was orally administered from 2 weeks before BLM or LPS administration to the end of the experiment for a total of 4 weeks, and then the skin fibrosis inhibitory efficacy of butyrate was evaluated ( FIGS. 1A and 1C ). In the case of the BLM-induced skin fibrosis model by administering BLM, the inhibition effect of SB on lung fibrosis was also evaluated (FIG. 1a). In addition, in order to determine whether SB directly inhibits skin fibrosis, the skin fibrosis inhibition efficacy of subcutaneous administration of SB topically to the BLM-induced skin fibrosis site was evaluated (Fig. 1b). Administration of SB in the BLM or LPS-induced skin fibrosis model decreased skin dermal thickness and lung fibrosis score (Ashcroft score) ( FIGS. 1A to 1C ). In addition, since fibroblast activation, differentiation and proliferation into myofibroblasts play an important role in the fibrosis process, the degree of fibrosis was evaluated through dermal thickness and the expression level of α-SMA, known as a myofibroblast marker. In the BLM-induced skin fibrosis model, after oral administration of SB, the reduction of α-SMA+ cells and the expression of α-SMA protein were decreased in the skin tissue ( FIGS. 2A and 2B ).
2. 전신경화증 동물 모델에서 부티레이트(butyrate)의 장내 면역 기능 향상 효과2. Intestinal immune function improvement effect of butyrate in an animal model of systemic sclerosis
Gut-associated lymph node로 알려진 mesenteric lymph node(MLN) 면역 세포를 분석하여 SB의 장내 면역 조절 효과가 있는지 평가하였다. BLM-induced skin fibrosis 모델에서 SB 경구 투여 후, MLN에서 Ly6C+한 monocyte(P1, P2)가 감소하였고 Ly6C-MHCⅡ+한 macrophage(P3)가 증가하였다(도 3b). Ly6C+한 monocyte는 염증과 같이 장내 이상이 있는 경우 intestine 및 MLN에서 증가하며 pro-inflammatory cytokine을 분비하는 것으로 알려져 있다. 또한 SB 투여한 쥐의 MLN cell은 LPS로 자극하였을 경우 IL-10 분비가 증가하는 것으로 보아, BLM-induced skin fibrosis에서 SB의 투여는 MLN cell의 항염증 기능을 향상시킬 것으로 보이며, 이는 장내 및 관련 면역 기관에서 면역 조절을 통한 피부 및 폐 섬유화 억제에 기여할 수 있을 것으로 기대된다.By analyzing mesenteric lymph node (MLN) immune cells known as Gut-associated lymph node, it was evaluated whether SB had an effect on intestinal immune regulation. After oral administration of SB in the BLM-induced skin fibrosis model, Ly6C + one monocyte (P1, P2) decreased and Ly6C-MHCII + one macrophage (P3) increased in MLN (Fig. 3b). Ly6C+ monocytes are known to increase in the intestine and MLN when there is an intestinal abnormality such as inflammation, and secrete a pro-inflammatory cytokine. In addition, MLN cells of SB-administered mice showed increased IL-10 secretion when stimulated with LPS, so administration of SB in BLM-induced skin fibrosis is expected to improve the anti-inflammatory function of MLN cells, which It is expected to contribute to suppression of skin and lung fibrosis through immune regulation in immune organs.
3. Human dermal fibroblast cell에서 부티레이트(butyrate)의 근섬유 아세포(myofibroblast)로의 분화 억제 효과3. Inhibitory effect of butyrate on the differentiation of human dermal fibroblast cells into myofibroblasts
Human dermal fibroblast을 TGF-β1으로 자극하여 근섬유 아세포로의 분화를 촉진하였고, 부티레이트 처리하여 근섬유 아세포로의 분화가 억제되는지 평가하였다(도 4a 및 4b, Normal #1: Primary HDF from ATCC, Normal #2: Primary fibroblast obtained from skin of normal patient, SSc #1&2: Primary fibroblast obtained from skin of SSc patients). Human dermal fibroblast을 TGF-β1으로 자극하여 근섬유 아세포로의 분화를 촉진, 즉 α-SMA 증가하였으며, butyrate 처리 후 TGF-β1에 의해 유도된 myofibroblast로의 분화가 억제(α-SMA 감소)되었다. Butyrate는 normal dermal fibroblast 뿐만 아니라 SSc 환자 유래 dermal fibroblast 에서도 TGF-β1에 의해 유도된 myofibroblast 분화를 억제하였다(도 4a 및 4b).Human dermal fibroblasts were stimulated with TGF-β1 to promote differentiation into myofibroblasts, and it was evaluated whether differentiation into myofibroblasts was inhibited by butyrate treatment (FIGS. 4a and 4b, Normal #1: Primary HDF from ATCC, Normal #2). : Primary fibroblast obtained from skin of normal patient, SSc #1&2: Primary fibroblast obtained from skin of SSc patients). Human dermal fibroblasts were stimulated with TGF-β1 to promote differentiation into myofibroblasts, that is, α-SMA was increased, and TGF-β1-induced differentiation into myofibroblasts was inhibited (α-SMA decreased) after butyrate treatment. Butyrate inhibited TGF-β1-induced myofibroblast differentiation not only in normal dermal fibroblasts but also in dermal fibroblasts derived from SSc patients (Figs. 4a and 4b).

Claims (4)

  1. 부티레이트(butyrate) 또는 이의 약학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating systemic sclerosis, comprising butyrate or a pharmaceutically acceptable salt thereof.
  2. 청구항 1에 있어서,The method according to claim 1,
    상기 부티레이트는 소듐 부티레이트(sodium butyrate)인, 전신경화증 예방 또는 치료용 약학적 조성물.The butyrate is sodium butyrate, a pharmaceutical composition for preventing or treating systemic sclerosis.
  3. 청구항 1에 있어서,The method according to claim 1,
    상기 전신경화증은 폐 침범을 동반한 전신경화증 또는 피부경화증인, 전신경화증 예방 또는 치료용 약학적 조성물.The systemic sclerosis is systemic sclerosis or skin sclerosis accompanied by lung involvement, a pharmaceutical composition for preventing or treating systemic sclerosis.
  4. 부티레이트(butyrate) 또는 이의 식품학적으로 허용되는 염을 포함하는 전신경화증(systemic sclerosis) 예방 또는 개선용 건강기능식품.Health functional food for preventing or improving systemic sclerosis, including butyrate or a pharmaceutically acceptable salt thereof.
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KR20190003573A (en) * 2016-04-27 2019-01-09 큠버랜드 파마슈티컬즈 인코포레이티드 This petro van treatment for systemic sclerosis
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