WO2020149636A1 - Pharmaceutical composition containing aucubin for preventing or treating dry-eye syndrome - Google Patents

Pharmaceutical composition containing aucubin for preventing or treating dry-eye syndrome Download PDF

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Publication number
WO2020149636A1
WO2020149636A1 PCT/KR2020/000725 KR2020000725W WO2020149636A1 WO 2020149636 A1 WO2020149636 A1 WO 2020149636A1 KR 2020000725 W KR2020000725 W KR 2020000725W WO 2020149636 A1 WO2020149636 A1 WO 2020149636A1
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dry eye
syndrome
dry
eye syndrome
prevention
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PCT/KR2020/000725
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French (fr)
Korean (ko)
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김정현
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전북대학교산학협력단
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to a pharmaceutical composition for the prophylaxis or treatment of dry eye syndrome comprising aucvin.
  • Dry eye syndrome causes damage to the eye surface by causing eye discomfort, deterioration of eyesight, and instability of the tear layer due to tear and inflammation of the eye surface (cornea and conjunctiva).
  • corneal ulcers There is a high risk of developing pain, irregular corneal surfaces, blurred and fluctuating vision, and corneal ulcers.
  • inflammation plays an important role, including infiltration of inflammatory cells, increased immune activation molecule and adhesion molecule expression, Th1 and Th17 responses, and abnormal changes in apoptosis markers and chemokines. have.
  • foods rich in potassium and anthocyanins are recommended for the treatment of dry eye syndrome.
  • Korean Patent Publication No. 10-2018-0065933 discloses a composition for preventing or treating inflammatory eye diseases comprising a maple leaf extract or a fraction thereof
  • Korean Patent No. 10-1910908 discloses Gly-T ⁇ 4
  • a pharmaceutical composition for treating dry eye syndrome containing (Gly-thymosin ⁇ 4) is disclosed.
  • Aucubin is a major component (Aucuba japonica) of the main tree (Aucuba japonica), the present inventors have confirmed the efficacy of the dry eye of the extract of the tree, while the active ingredient was confirmed while the increase in the secretion of tears and corneal drying damage , It was confirmed that it is possible to treat dry eye syndrome by suppressing corneal inflammation, thereby completing the present invention.
  • the present invention has been devised to solve the above problems, and while the present inventors are studying the composition for the prevention and treatment of dry eye syndrome, Aucubin increases the amount of tear secretion and prevents dryness of the cornea, and prevents dry eye through suppressing corneal inflammation. It was confirmed that can be treated, and the present invention was completed.
  • An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome, which comprises the acubin represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a health functional food composition for the prevention or improvement of dry eye syndrome, which includes acubin represented by the following Chemical Formula 1.
  • Another object of the present invention is to provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin in a pharmaceutically effective amount to an individual in need thereof.
  • Another object of the present invention is to provide a use for use in the composition for preventing or treating dry eye syndrome.
  • the present invention can provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising an acubin represented by Formula 1 below or a pharmaceutically acceptable salt thereof:
  • composition can be administered orally.
  • the acubin may be included at a concentration of 1 mg/kg to 150 mg/kg.
  • composition is any one selected from the group consisting of solutions, suspensions, syrups, emulsions, liposomes, powders, powders, granules, tablets, sustained release preparations, eye drops, capsules, contact lens cleaners and contact lens lubricants It may be a formulation of.
  • the dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
  • the present invention can also provide a health functional food composition for the prevention or improvement of dry eye syndrome comprising acubin represented by the following Chemical Formula 1:
  • the acubin may be included at a concentration of 1 mg/kg to 150 mg/kg.
  • the dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
  • the present invention can provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin to a subject in need thereof in a pharmaceutically effective amount.
  • the present invention can provide a use for the use of aucvin in a composition for preventing or treating dry eye syndrome.
  • Aucubin of the present invention has no cytotoxicity at a concentration of 30 ⁇ g/mL in human corneal epithelial cells, reduces cell death under dry stress, and reduces the expression of genes of inflammation that promote dry eye syndrome.
  • it in the animal model inducing dry eye, it has an effect of increasing the secretion of tears, restoring damage due to drying of the cornea, and reducing cell death due to drying. Through this, there is an effect of treating, preventing, or improving acuvin's dry eye syndrome.
  • 1 is a result of confirming the cell viability after inducing dry stress by inducing dry stress by exposing air to the air after 24 hours pre-treatment and after confirming the cytotoxicity after 24 hours after concentration-dependent treatment of aqubin.
  • Figure 3 is a result of confirming the effect of aucoubin on inflammatory cytokines in human corneal epithelial cells by mRNA level
  • (A) is IL-1 ⁇
  • (B) is IL-8
  • (C) is TNF- ⁇ This is the result of confirming the mRNA level by PCR.
  • Figure 4 is a result of confirming the effect of acubin on the amount of tears and corneal damage in the dry eye animal model, (A) is a result of measuring the amount of tears, (B) is a result showing the state of the corneal surface, ( C) is the result of quantifying the result of (B).
  • Figure 5 is a result of confirming the effect of aqubin in apoptosis cells on the surface of the eye in the dry eye animal model, (A) is the result of TUNEL stained image, (B) is the result of quantifying the result of (A) .
  • Dry eye syndrome causes damage to the eye surface by causing eye discomfort, deterioration of eyesight, and instability of the tear layer due to tear and inflammation of the eye surface (cornea and conjunctiva). There is a high risk of developing pain, irregular corneal surfaces, blurred and fluctuating vision, and corneal ulcers.
  • inflammation plays an important role, including infiltration of inflammatory cells, increased immune activation molecule and adhesion molecule expression, Th1 and Th17 responses, and abnormal changes in apoptosis markers and chemokines. have.
  • treatments are used to control the amount of tears discharged by blocking artificial tears and tears.
  • dry eye syndrome is a common disease that occurs in about 20% of adults in Korea. Especially, the number of patients with dry eye syndrome continues to increase due to the rising temperature and environmental pollution due to global climate change, especially the El Ni ⁇ o phenomenon. There is no food.
  • the present inventors have studied the pharmaceutical composition for the prevention and treatment of dry eye syndrome, and confirmed that Aucubin has the effect of preventing and treating dry eye syndrome and completed the present invention.
  • Aucubin was not toxic to human corneal epithelial cells up to 30 ⁇ g/mL, and had an effect of increasing cell viability in an experiment inducing dry stress by exposure to air for 25 minutes (FIG. 1 ).
  • FIG. 1 As a result of confirming the death of cells under the dry stress through TUNEL staining, it was confirmed that the cells dying in the drying process were significantly reduced by pre-treatment with Aucubin (FIG. 2).
  • the present invention is to provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising an acubin (aucubin) represented by Formula 1 or a pharmaceutically acceptable salt thereof:
  • Alcubin (aucubin) is one of the physiologically active substances contained in the tree, it promotes uric acid excretion and is effective in gout, and is also effective in antioxidant by scavenging free radicals.
  • composition can be administered topically, transdermally, orally or parenterally, most preferably orally.
  • the acubin may be included at a concentration of 1 mg/kg to 150 mg/kg, preferably at a concentration of 1 mg/kg to 100 mg/kg, and most preferably 75 mg/kg.
  • composition is a formulation selected from the group consisting of solutions, suspensions, syrups, emulsions, liposomes, powders, powders, granules, tablets, sustained release preparations, eye drops, capsules, contact lens cleaners and contact lens lubricants Can.
  • the dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
  • the composition when it is a pharmaceutical composition, it may include a pharmaceutically acceptable diluent or carrier.
  • the diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, or mannitol, as a lubricant, magnesium stearate, talc, or a combination thereof.
  • the carrier may be an excipient, a disintegrant, a binder, a lubricant, or a combination thereof.
  • the excipient may be microcrystalline cellulose, lactose, low-substituted hydroxycellulose, or a combination thereof.
  • the disintegrant may be carboxymethyl cellulose calcium, sodium starch glycolate, calcium monohydrogen phosphate anhydride, or a combination thereof.
  • the binder may be polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a combination thereof.
  • the lubricant may be magnesium stearate, silicon dioxide, talc, or a combination thereof.
  • the pharmaceutical composition may contain the extract in an effective amount or as an active ingredient. The effective amount can be appropriately selected depending on the individual. The severity of the disease, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration, the route of administration and rate of excretion, the duration of treatment, factors including drugs used in combination with or concurrently with the composition and other medical fields. It can be determined according to well-known factors.
  • the composition may contain the extract in an effective amount or as an active ingredient depending on its use.
  • the effective amount can be appropriately selected depending on the individual.
  • the severity of the disease or condition, the age, weight, health, sex of the individual, sensitivity to the extract of the individual, time of administration, route of administration and rate of excretion, duration of administration, factors including other compositions combined with or concurrently used with the composition, and others It may be determined according to factors well known in the physiological or medical field.
  • the present invention can also provide a health functional food composition for the prevention or improvement of dry eye syndrome, which includes an acubin represented by Formula 1 below:
  • composition for a dietary supplement When the composition is a composition for a dietary supplement, it may be formulated into a formulation of a conventional dietary supplement known in the art.
  • the composition for health functional food may be prepared in general formulations such as powders, granules, tablets, pills, capsules, suspensions, emulsions, syrups, needles, liquids, ex-agents, meat, sausage, bread, chocolate, etc.
  • Candy, snacks, confectionery, pizza, ramen, other noodles, gums, jelly, dairy products including ice cream, various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes may be prepared in any form of health food. .
  • a food-acceptable carrier or additive may be used, and any carrier or additive known to be available in the art may be used for preparing a formulation to be prepared.
  • any carrier or additive known to be available in the art may be used for preparing a formulation to be prepared.
  • it may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks.
  • These additive components may be used independently or in combination, and the proportion of the additive may be 0.001 to 5% by weight, or 0.01 to 3% by weight based on the total weight of the composition.
  • the content of the acubin in the composition for health functional food may be appropriately determined according to the purpose of use (prevention or improvement). In general, it may contain from 0.01 to 15% by weight of the total food weight, and when prepared as a beverage, may contain 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 mL.
  • the beverage may further include other components other than the extract, and may further contain various flavoring agents or natural carbohydrates commonly used in beverages.
  • the natural carbohydrates include conventional sugars such as monosaccharides (eg glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), polysaccharides (eg, dextrin, cyclodextrin, etc.) and xylitol, sorbitol, erythritol, etc. Sugar alcohol may be contained.
  • a flavoring agent it may contain natural flavoring agents (eg, taumatin, stevia extract, etc.) and synthetic flavoring agents (eg, saccharin, aspartame, etc.).
  • the proportion of the natural carbohydrate may be contained in about 1 to 20 g, preferably about 5 to 12 g per 100 mL of beverage.
  • the acubin may be included at a concentration of 1 mg/kg to 150 mg/kg, preferably at a concentration of 1 mg/kg to 100 mg/kg, and most preferably 75 mg/kg.
  • the dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
  • the present invention can provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin to a subject in need thereof in a pharmaceutically effective amount.
  • “individual” means a subject in need of treatment of a disease, and more specifically, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, including humans, Means all animals, including rabbits or guinea pigs, and the above-mentioned diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual.
  • the pharmaceutical composition of the present invention may be administered in parallel with existing therapeutic agents.
  • the present invention can provide a use for the use of aucvin in a composition for preventing or treating dry eye syndrome.
  • Corneal epithelial cells (PCS-700-010, American Type Culture Collection, Manassas, VA, USA) were prepared in corneal epithelial cell base medium containing growth supplements according to the manufacturer's instructions (American Type Culture Collection, Manassas, VA, USA). Cultured. Cell toxicity test was performed using the MTS assay kit (Promega Corporation). Cells (1 ⁇ 10 4 ) were grown in 96-well plates and then treated with aucubin at 0.1-30 ⁇ g/mL. Cytotoxicity was measured 24 hours after culture. As a result of the MTS analysis, absorbance was measured at 490 nm using a microplate reader (Tecan Group Ltd., Mannedorf, Switzerland). As a result, it was confirmed that acuvin had no cytotoxicity up to 30 ⁇ g/mL (FIG. 1 ).
  • the viability of dried cells was measured using an MTS assay kit. Aucubin was pretreated for 24 hours. The medium was then removed and exposed to air for 25 minutes to induce dry stress. Thereafter, as a result of experimenting cell survival with the method of Example 1, aucvin increased cell viability under dry stress in a dose-dependent manner (FIG. 1B ). To detect cell death cells after drying, the cells were grown on autoclaved cover slips. After pre-incubation of aucubin for 24 hours, the cells were exposed to dryness for 25 minutes and cell death was detected by TUNEL staining. The number of dying cells increased during the drying process, and the killing cells were significantly decreased in the 15 ⁇ g/mL acubin treatment group (FIGS. 2A and B ).
  • RNA expression of IL-1 ⁇ , IL-8 and TNF- ⁇ was significantly increased in the dry state and decreased by aucvin treatment (FIGS. 3A to 3C ).
  • the amount of tear secretion was measured by contacting the phenol-red thread tear level test paper (FCI Opthalmics Zone Quick, Japan) to the ocular surface at the outer end of the eyelid, and measuring the amount of tear secretion by measuring the length of the color change of the test paper by tears after 30 seconds. .
  • the dry eye model showed a lower amount of tears than the normal group, but recovered normally with aucvin treatment (Fig. 4).
  • the dryness damage of the cornea was analyzed by evaluating the degree of distortion caused by the dryness damage of the cornea of the circular illumination after photographing the reflection type by shining a circular illuminator (ring type light illuminator) on the cornea.
  • the dry eye model showed irregular circular light, but improved in the group treated with Aucubin (Fig. 4B).
  • the score of corneal staining showed a high score in the dry eye group, but the acubin treatment group confirmed that the score was low (FIG. 4C ).
  • Tissue apoptotic cells were measured using terminal deoxyribonucleotide transfer enzyme (TdT)-mediated dUTP nick end labeling (TUNEL) staining according to the manufacturer's instructions.
  • TdT terminal deoxyribonucleotide transfer enzyme
  • TUNEL dUTP nick end labeling

Abstract

The present invention relates to a pharmaceutical composition containing aucubin for preventing or treating dry-eye syndrome.

Description

아우쿠빈을 포함하는 안구 건조증의 예방 또는 치료용 약학적 조성물 Pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising aucvin
본 출원은 2019년 01월 15일 출원된 대한민국 특허출원 제10-2019-0005417호를 우선권으로 주장하고, 상기 명세서 전체는 본 출원의 참고문헌이다.This application claims priority to Korean Patent Application No. 10-2019-0005417 filed on January 15, 2019, and the entire specification is a reference of the present application.
본 발명은 아우쿠빈을 포함하는 안구 건조증의 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for the prophylaxis or treatment of dry eye syndrome comprising aucvin.
안구 건조증(건성안: dry eye syndrome)은 단순히 눈물부족이 아닌, 눈물과 안구표면(각막 및 결막)의 염증에 의한 안구의 불편감, 시력저하, 눈물층의 불안정성을 유발하여 안구표면에 손상을 주어, 통증, 불규칙한 각막표면, 흐리고 변동폭이 커진 시력 및 각막궤양 등의 발병 위험성이 크다. 그러나 이러한 발병기전은 아직 완전히 규명되지 않았으나, 염증세포의 침윤, 면역활성화 분자 및 접착분자발현 증가, Th1 및 Th17 반응, 세포사멸마커 및 케모카인의 비정상적인 변화 등 염증이 중요한 역할을 한다는 연구결과가 보고되고 있다. 일반적으로 안구 건조증 치료를 위해서 칼륨과 안토시아닌이 풍부한 음식섭취를 권장하고 있고, 이외에도 케일, 키위, 사과 등의 과일섭취도 적극 권장하고 있다, 또한 인공눈물 점안, 눈물점을 막아 배출되는 눈물의 양을 조절하는 치료법을 사용하기도 한다. 그러나 안구 건조증은 우리나라 성인의 20% 내외로 발생하는 흔한 질병으로, 특히 전 세계적인 기후 변화 특히 엘리뇨 현상으로 온도가 올라가고 있는 상황과 환경오염으로 인해 안구 건조증 환자가 지속적으로 증가하고 있으나, 특별한 치료제 또는 기능성 식품이 없는 상황이다. 이에 연구자들이 안구 건조증을 치료하기 위한 연구가 진행 중이다. 예를 들어, 한국공개특허번호 제 10-2018-0065933호에는 단풍잎 추출물 또는 이의 분획물을 포함하는 염증성 안구질환 예방 또는 치료용 조성물이 개시되어 있고, 한국등록특허번호 제 10-1910908호에는 Gly-Tβ4 (Gly-티모신β4)을 함유하는 안구 건조증 치료용 약학적 조성물이 개시되어 있다. Dry eye syndrome (dry eye syndrome) causes damage to the eye surface by causing eye discomfort, deterioration of eyesight, and instability of the tear layer due to tear and inflammation of the eye surface (cornea and conjunctiva). There is a high risk of developing pain, irregular corneal surfaces, blurred and fluctuating vision, and corneal ulcers. However, the mechanism of this onset has not been fully elucidated, but studies have reported that inflammation plays an important role, including infiltration of inflammatory cells, increased immune activation molecule and adhesion molecule expression, Th1 and Th17 responses, and abnormal changes in apoptosis markers and chemokines. have. In general, foods rich in potassium and anthocyanins are recommended for the treatment of dry eye syndrome. In addition, fruit intakes such as kale, kiwi, and apple are also highly recommended. Also, the amount of tears discharged by blocking artificial tears and tears is prevented. Some modulating therapies are also used. However, dry eye syndrome is a common disease that occurs in about 20% of adults in Korea. Especially, the number of patients with dry eye syndrome continues to increase due to the rising temperature and environmental pollution due to global climate change, especially the El Niño phenomenon. There is no food. Therefore, research is ongoing for researchers to treat dry eye syndrome. For example, Korean Patent Publication No. 10-2018-0065933 discloses a composition for preventing or treating inflammatory eye diseases comprising a maple leaf extract or a fraction thereof, and Korean Patent No. 10-1910908 discloses Gly-Tβ4 A pharmaceutical composition for treating dry eye syndrome containing (Gly-thymosin β4) is disclosed.
아우쿠빈 (aucubin)은 식나무 (Aucuba japonica)의 주요성분 (major compound)으로 본 발명자들은 식나무 추출물의 안구 건조증 효능을 확인하였으며, 유효성분을 확인하던 중 아우쿠빈이 눈물 분비량의 증가 및 각막 건조손상 예방, 각막 염증억제를 통해 안구 건조증을 치료할 수 있음을 확인하여, 본 발명을 완성하였다.Aucubin (aucubin) is a major component (Aucuba japonica) of the main tree (Aucuba japonica), the present inventors have confirmed the efficacy of the dry eye of the extract of the tree, while the active ingredient was confirmed while the increase in the secretion of tears and corneal drying damage , It was confirmed that it is possible to treat dry eye syndrome by suppressing corneal inflammation, thereby completing the present invention.
본 발명은 상기의 문제를 해결하기 위해 안출된 것으로, 본 발명자들은 안구 건조증의 예방 및 치료용 조성물을 연구하던 중, 아우쿠빈이 눈물 분비량의 증가 및 각막 건조손상 예방, 각막 염증억제를 통해 안구 건조증을 치료할 수 있음을 확인하여, 본 발명을 완성하였다.The present invention has been devised to solve the above problems, and while the present inventors are studying the composition for the prevention and treatment of dry eye syndrome, Aucubin increases the amount of tear secretion and prevents dryness of the cornea, and prevents dry eye through suppressing corneal inflammation. It was confirmed that can be treated, and the present invention was completed.
본 발명의 목적은 하기 화학식 1로 표시되는 아우쿠빈 또는 이의 약학적으로 허용되는 염을 포함하는, 안구 건조증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome, which comprises the acubin represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 하기 화학식 1로 표시되는 아우쿠빈을 포함하는 안구 건조증의 예방 또는 개선용 건강기능식품조성물을 제공하는 것이다. Another object of the present invention is to provide a health functional food composition for the prevention or improvement of dry eye syndrome, which includes acubin represented by the following Chemical Formula 1.
본 발명의 다른 목적은 아우쿠빈을 이를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는 안구 건조증 예방 또는 치료방법을 제공하는 것이다. Another object of the present invention is to provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin in a pharmaceutically effective amount to an individual in need thereof.
본 발명의 다른 목적은 아우쿠빈을 안구 건조증 예방 또는 치료용 조성물에 사용하기 위한 용도을 제공하는 것이다. Another object of the present invention is to provide a use for use in the composition for preventing or treating dry eye syndrome.
본 발명은 하기 화학식 1로 표시되는 아우쿠빈（aucubin) 또는 이의 약학적으로 허용되는 염을 포함하는 안구 건조증의 예방 또는 치료용 약학적 조성물을 제공할 수 있다:The present invention can provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising an acubin represented by Formula 1 below or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
Figure PCTKR2020000725-appb-I000001
.
Figure PCTKR2020000725-appb-I000001
.
상기 조성물은 경구 투여 될 수 있다. The composition can be administered orally.
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있다. The acubin may be included at a concentration of 1 mg/kg to 150 mg/kg.
상기 조성물은 용액, 현탁액, 시럽제, 에멀젼, 리포좀, 산제, 분말제, 과립제, 정제, 서방형 제제, 점안제(eye drop), 캡슐제, 콘택트렌즈 세정제 및 콘택트렌즈 윤활제로 구성된 군에서 선택되는 어느 하나의 제형일 수 있다. The composition is any one selected from the group consisting of solutions, suspensions, syrups, emulsions, liposomes, powders, powders, granules, tablets, sustained release preparations, eye drops, capsules, contact lens cleaners and contact lens lubricants It may be a formulation of.
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나 일 수 있다. The dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
본 발명은 또한 하기 화학식 1로 표시되는 아우쿠빈을 포함하는 안구 건조증의 예방 또는 개선용 건강기능식품조성을 제공할 수 있다:The present invention can also provide a health functional food composition for the prevention or improvement of dry eye syndrome comprising acubin represented by the following Chemical Formula 1:
[화학식 1][Formula 1]
Figure PCTKR2020000725-appb-I000002
.
Figure PCTKR2020000725-appb-I000002
.
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있다.The acubin may be included at a concentration of 1 mg/kg to 150 mg/kg.
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나 일 수 있다. The dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
본 발명은 아우쿠빈을 이를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는 안구 건조증 예방 또는 치료방법을 제공할 수 있다.The present invention can provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin to a subject in need thereof in a pharmaceutically effective amount.
본 발명은 아우쿠빈을 안구 건조증 예방 또는 치료용 조성물에 사용하기 위한 용도를 제공할 수 있다.The present invention can provide a use for the use of aucvin in a composition for preventing or treating dry eye syndrome.
본 발명의 아우쿠빈은 인간 각막 상피 세포에서 30 ㎍/mL 농도에서 세포 독성이 없으며, 건조 스트레스에서 세포의 사멸을 감소시키고, 안구 건조증을 촉진하는 염증의 유전자의 발현을 감소시키는 효과가 있다. 또한 안구 건조증을 유발한 동물모델에서 눈물의 분비량을 증가시키고, 각막의 건조로 인한 손상을 회복시키며, 건조로 인한 세포의 사멸을 감소시키는 효과가 있다. 이를 통해 아우쿠빈의 안구 건조증의 치료, 예방 또는 개선의 효과가 있다. Aucubin of the present invention has no cytotoxicity at a concentration of 30 µg/mL in human corneal epithelial cells, reduces cell death under dry stress, and reduces the expression of genes of inflammation that promote dry eye syndrome. In addition, in the animal model inducing dry eye, it has an effect of increasing the secretion of tears, restoring damage due to drying of the cornea, and reducing cell death due to drying. Through this, there is an effect of treating, preventing, or improving acuvin's dry eye syndrome.
도 1은 아우쿠빈을 농도 의존적으로 처리한 후 24시간 후 세포 독성을 확인 및 아우쿠빈을 24시간 사전 처리 후 공기에 노출 시켜 건조 스트레스를 유도한 후 이의 세포 생존력을 확인한 결과이다. 1 is a result of confirming the cell viability after inducing dry stress by inducing dry stress by exposing air to the air after 24 hours pre-treatment and after confirming the cytotoxicity after 24 hours after concentration-dependent treatment of aqubin.
도 2는 아우쿠빈이 세포 사멸 속도에 미치는 영향을 본 결과로서, (A)는 24시간동안 아우쿠빈을 처리한 후 공기에 노출 시켜 건조 스트레스를 유도한 뒤, 세포를 고정 시킨 후 TUNEL 염색을 수행하여 총 세포 수에 대한 TUNEL 양성 세포의 비율을 비교하여 세포 자멸사 비율을 계산한 결과이고, (B)는 TUNEL 염색후 현미경으로 본 이미지 결과이다. 2 is a result of seeing the effect of the acubin on the cell death rate, (A) after the treatment with aucubin for 24 hours to induce dry stress by exposure to air, after fixing the cells to perform TUNEL staining By comparing the ratio of TUNEL-positive cells to the total number of cells, the apoptosis ratio was calculated, and (B) is the result of the image seen under a microscope after TUNEL staining.
도 3은 아우쿠빈이 인간 각막 상피 세포에서의 염증성 사이토카인에 미치는 영향을 mRNA 수준으로 확인한 결과로서, (A)는 IL-1β, (B)는 IL-8, (C)는 TNF-α의 mRNA 수준을 PCR로 확인한 결과이다. Figure 3 is a result of confirming the effect of aucoubin on inflammatory cytokines in human corneal epithelial cells by mRNA level, (A) is IL-1β, (B) is IL-8, (C) is TNF-α This is the result of confirming the mRNA level by PCR.
도 4는 안구 건조증 동물 모델에서 아우쿠빈이 눈물량 및 각막 손상에 미치는 영향을 확인한 결과로서, (A)는 눈물량을 측정한 결과이고, (B)는 각막 표면의 상태를 나타내는 결과이고, (C)는 (B)의 결과를 정량화한 결과이다. Figure 4 is a result of confirming the effect of acubin on the amount of tears and corneal damage in the dry eye animal model, (A) is a result of measuring the amount of tears, (B) is a result showing the state of the corneal surface, ( C) is the result of quantifying the result of (B).
도 5는 안구 건조증 동물 모델에서 안구 표면에서 세포 자멸사한 세포에서 아우쿠빈의 효과를 확인한 결과로서, (A)는 TUNEL 염색한 이미지 결과이고, (B)는 (A)의 결과를 정량화한 결과이다. Figure 5 is a result of confirming the effect of aqubin in apoptosis cells on the surface of the eye in the dry eye animal model, (A) is the result of TUNEL stained image, (B) is the result of quantifying the result of (A) .
이하에서 본 발명을 자세하게 설명한다. The present invention will be described in detail below.
안구 건조증(건성안: dry eye syndrome)은 단순히 눈물부족이 아닌, 눈물과 안구표면(각막 및 결막)의 염증에 의한 안구의 불편감, 시력저하, 눈물층의 불안정성을 유발하여 안구표면에 손상을 주어, 통증, 불규칙한 각막표면, 흐리고 변동폭이 커진 시력 및 각막궤양 등의 발병 위험성이 크다. 그러나 이러한 발병기전은 아직 완전히 규명되지 않았으나, 염증세포의 침윤, 면역활성화 분자 및 접착분자발현 증가, Th1 및 Th17 반응, 세포사멸마커 및 케모카인의 비정상적인 변화 등 염증이 중요한 역할을 한다는 연구결과가 보고되고 있다. 또한 인공눈물 점안, 눈물점을 막아 배출되는 눈물의 양을 조절하는 치료법을 사용하기도 한다. 그러나 안구 건조증은 우리나라 성인의 20% 내외로 발생하는 흔한 질병으로, 특히 전 세계적인 기후 변화 특히 엘리뇨 현상으로 온도가 올라가고 있는 상황과 환경오염으로 인해 안구 건조증 환자가 지속적으로 증가하고 있으나, 특별한 치료제 또는 기능성 식품이 없는 상황이다. Dry eye syndrome (dry eye syndrome) causes damage to the eye surface by causing eye discomfort, deterioration of eyesight, and instability of the tear layer due to tear and inflammation of the eye surface (cornea and conjunctiva). There is a high risk of developing pain, irregular corneal surfaces, blurred and fluctuating vision, and corneal ulcers. However, the mechanism of this onset has not been fully elucidated, but studies have reported that inflammation plays an important role, including infiltration of inflammatory cells, increased immune activation molecule and adhesion molecule expression, Th1 and Th17 responses, and abnormal changes in apoptosis markers and chemokines. have. In addition, treatments are used to control the amount of tears discharged by blocking artificial tears and tears. However, dry eye syndrome is a common disease that occurs in about 20% of adults in Korea. Especially, the number of patients with dry eye syndrome continues to increase due to the rising temperature and environmental pollution due to global climate change, especially the El Niño phenomenon. There is no food.
이에 본 발명자들은 안구 건조증의 예방 및 치료용 약학적 조성물을 연구하던 중, 아우쿠빈이 안구 건조증의 예방 및 치료효과가 있는 것을 확인하고 본 발명을 완성하였다. 아우쿠빈은 인간 각막 상피 세포에서 30 ㎍/mL까지 독성이 없으며, 공기 중에 25분간 노출하여 건조 스트레스를 유발한 실험에서 세포 생존력을 증가시키는 효과가 있었다 (도 1). 상기 건조 스트레스에서 세포의 사멸을 TUNEL 염색을 통해서 확인한 결과, 아우쿠빈을 사전 처리하면 건조과정에서 죽어가는 세포를 유의적으로 감소시키는 것을 확인하였다 (도 2). 안구 건조증을 악화시키는 염증인자들의 발현을 확인한 결과, 아우쿠빈을 처리한 결과 염증과 관련된 인자인 IL-1β, IL-8 및 TNF-α의 mRNA 발현이 감소하는 것을 확인하였다 (도 3). 안구 건조증 동물 모델에서 눈물량을 증가시키고 (도 4), 건조로 인한 각막의 손상을 감소시켜주며 (도 4), 건조 인한 세포의 사멸을 감소시키는 효과(도 5)가 있었다. Accordingly, the present inventors have studied the pharmaceutical composition for the prevention and treatment of dry eye syndrome, and confirmed that Aucubin has the effect of preventing and treating dry eye syndrome and completed the present invention. Aucubin was not toxic to human corneal epithelial cells up to 30 μg/mL, and had an effect of increasing cell viability in an experiment inducing dry stress by exposure to air for 25 minutes (FIG. 1 ). As a result of confirming the death of cells under the dry stress through TUNEL staining, it was confirmed that the cells dying in the drying process were significantly reduced by pre-treatment with Aucubin (FIG. 2). As a result of confirming the expression of inflammatory factors that exacerbates dry eye syndrome, it was confirmed that the expression of IL-1β, IL-8 and TNF-α, which are factors related to inflammation, was decreased as a result of treatment with Aucubin (FIG. 3 ). In the dry eye animal model, there was an effect of increasing the amount of tears (FIG. 4), reducing damage to the cornea due to drying (FIG. 4), and reducing cell death due to drying (FIG. 5).
본 발명은 하기 화학식 1로 표시되는 아우쿠빈 (aucubin) 또는 이의 약학적으로 허용되는 염을 포함하는 안구 건조증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다:The present invention is to provide a pharmaceutical composition for the prevention or treatment of dry eye syndrome comprising an acubin (aucubin) represented by Formula 1 or a pharmaceutically acceptable salt thereof:
[화학식 1] [Formula 1]
Figure PCTKR2020000725-appb-I000003
.
Figure PCTKR2020000725-appb-I000003
.
"아우쿠빈 (aucubin)"은 식나무에 포함되어 있는 생리활성 물질 중에 하나로, 요산배설을 촉진하여 통풍에 효과가 있고, 유리 라디칼을 소거하여 항산화에도 효과가 있다. "Aucubin (aucubin)" is one of the physiologically active substances contained in the tree, it promotes uric acid excretion and is effective in gout, and is also effective in antioxidant by scavenging free radicals.
상기 조성물은 국소, 경피, 경구 또는 비경구로 투여 될 수 있으며, 가장 바람직하게는 경구로 투여 될 수 있다. The composition can be administered topically, transdermally, orally or parenterally, most preferably orally.
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있으며 바람직하게는 1 mg/kg 내지 100 mg/kg의 농도로 포함될 수 있으며, 가장 바람직하게는 75 mg/kg일 수 있다. The acubin may be included at a concentration of 1 mg/kg to 150 mg/kg, preferably at a concentration of 1 mg/kg to 100 mg/kg, and most preferably 75 mg/kg.
상기 조성물은 용액, 현탁액, 시럽제, 에멀젼, 리포좀, 산제, 분말제, 과립제, 정제, 서방형 제제, 점안제(eye drop), 캡슐제, 콘택트렌즈 세정제 및 콘택트렌즈 윤활제로 구성된 군에서 선택되는 제형일 수 있다. The composition is a formulation selected from the group consisting of solutions, suspensions, syrups, emulsions, liposomes, powders, powders, granules, tablets, sustained release preparations, eye drops, capsules, contact lens cleaners and contact lens lubricants Can.
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다. The dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
상기 조성물이 약학적 조성물인 경우, 약제학적으로 허용 가능한 희석제 또는 담체를 포함할 수 있다. 상기 희석제는 유당, 옥수수 전분, 대두유, 미정질 셀룰로오스, 또는 만니톨, 활택제로는 스테아린산 마그네슘, 탈크, 또는 그 조합일 수 있다. 상기 담체는 부형제, 붕해제, 결합제, 활택제, 또는 그 조합일 수 있다. 상기 부형제는 미정질 셀룰로오스, 유당, 저치환도 히드록시셀룰로오스, 또는 그 조합일 수 있다. 상기 붕해제는 카르복시메틸 셀룰로오스 칼슘, 전분 글리콜산 나트륨, 무수인산일수소 칼슘, 또는 그 조합일 수 있다. 상기 결합제는 폴리비닐피롤리돈, 저치환도 히드록시프로필셀룰로오스, 히드록시프로필셀룰로오스, 또는 그 조합일 수 있다. 상기 활택제는 스테아린산 마그네슘, 이산화규소, 탈크, 또는 그 조합일 수 있다. 상기 약학적 조성물은 상기 추출물을 유효한 양, 또는 유효 성분으로서 포함할 수 있다. 상기 유효한 양은 개체에 따라 적절하게 선택할 수 있다. 질환의 중증도, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 상기 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. When the composition is a pharmaceutical composition, it may include a pharmaceutically acceptable diluent or carrier. The diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, or mannitol, as a lubricant, magnesium stearate, talc, or a combination thereof. The carrier may be an excipient, a disintegrant, a binder, a lubricant, or a combination thereof. The excipient may be microcrystalline cellulose, lactose, low-substituted hydroxycellulose, or a combination thereof. The disintegrant may be carboxymethyl cellulose calcium, sodium starch glycolate, calcium monohydrogen phosphate anhydride, or a combination thereof. The binder may be polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a combination thereof. The lubricant may be magnesium stearate, silicon dioxide, talc, or a combination thereof. The pharmaceutical composition may contain the extract in an effective amount or as an active ingredient. The effective amount can be appropriately selected depending on the individual. The severity of the disease, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration, the route of administration and rate of excretion, the duration of treatment, factors including drugs used in combination with or concurrently with the composition and other medical fields. It can be determined according to well-known factors.
상기 조성물은 그 용도에 따라 상기 추출물을 유효한 양, 또는 유효 성분으로서 포함할 수 있다. 상기 유효한 양은 개체에 따라 적절하게 선택할 수 있다. 질환 내지 상태의 중증도, 개체의 연령, 체중, 건강, 성별, 개체의 추출물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 투여 기간, 상기 조성물과 배합 또는 동시 사용되는 다른 조성물을 포함한 요소 및 기타 생리 내지 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다.The composition may contain the extract in an effective amount or as an active ingredient depending on its use. The effective amount can be appropriately selected depending on the individual. The severity of the disease or condition, the age, weight, health, sex of the individual, sensitivity to the extract of the individual, time of administration, route of administration and rate of excretion, duration of administration, factors including other compositions combined with or concurrently used with the composition, and others It may be determined according to factors well known in the physiological or medical field.
본 발명은 또한 하기 화학식 1로 표시되는 아우쿠빈（aucubin)를 포함하는 안구 건조증의 예방 또는 개선용 건강기능식품조성물을 제공할 수 있다:The present invention can also provide a health functional food composition for the prevention or improvement of dry eye syndrome, which includes an acubin represented by Formula 1 below:
[화학식 1][Formula 1]
Figure PCTKR2020000725-appb-I000004
.
Figure PCTKR2020000725-appb-I000004
.
상기 조성물이 건강기능식품용 조성물인 경우, 당해 기술 분야에 공지되어 있는 통상적인 건강기능식품의 제형으로 제제화 될 수 있다. 상기 건강기능식품용 조성물은 예를 들어 산제, 과립제, 정제, 환제, 캅셀제, 현탁액, 유제, 시럽제, 침제, 액제, 엑스제 등의 일반적인 제형으로 제조될 수도 있고, 육류, 소세지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 젤리, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등의 임의의 건강식품 형태로 제조될 수도 있다. 상기 건강식품의 제제화를 위해 식품학적으로 허용 가능한 담체 또는 첨가제를 사용할 수 있으며, 제조하고자 하는 제형의 제조에 당해 기술 분야에서 사용 가능한 것으로 공지되어 있는 임의의 담체 또는 첨가제가 이용될 수 있다. 상기 첨가제로서 각종 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 이외에도 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 첨가제 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 첨가제의 비율은 조성물 전체 중량을 기준으로 0.001 내지 5 중량%, 또는 0.01 내지 3 중량%일 수 있다.When the composition is a composition for a dietary supplement, it may be formulated into a formulation of a conventional dietary supplement known in the art. The composition for health functional food may be prepared in general formulations such as powders, granules, tablets, pills, capsules, suspensions, emulsions, syrups, needles, liquids, ex-agents, meat, sausage, bread, chocolate, etc. Candy, snacks, confectionery, pizza, ramen, other noodles, gums, jelly, dairy products including ice cream, various soups, beverages, teas, drinks, alcoholic beverages and vitamin complexes may be prepared in any form of health food. . For the formulation of the health food, a food-acceptable carrier or additive may be used, and any carrier or additive known to be available in the art may be used for preparing a formulation to be prepared. Used as various additives, various nutrients, vitamins, electrolytes, flavoring agents, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohol, carbonated beverages Carbonic acid, and the like. In addition, it may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These additive components may be used independently or in combination, and the proportion of the additive may be 0.001 to 5% by weight, or 0.01 to 3% by weight based on the total weight of the composition.
상기 건강기능식품용 조성물 중의 상기 아우쿠빈의 함량은 사용 목적(예방 또는 개선)에 따라 적합하게 결정될 수 있다. 일반적으로, 전체 식품 중량의 0.01 내지 15 중량%로 포함할 수 있으며, 음료로서 제조될 경우 100 mL를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 함유할 수 있다. 상기 음료는 상기 추출물 이외의 다른 성분을 더 포함할 수 있으며, 통상적으로 음료에 사용되는 다양한 향미제 또는 천연 탄수화물 등을 더 함유할 수 있다. 상기 천연 탄수화물로는 단당류(예: 포도당, 과당 등), 이당류(예: 말토즈, 수크로즈 등), 다당류(예: 덱스트린, 시클로덱스트린 등)와 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이 함유될 수 있다. 또한, 향미제로서 천연 향미제(예: 타우마틴, 스테비아 추출물 등) 및 합성 향미제(예:사카린, 아스파탐 등)를 함유할 수 있다. 상기 천연 탄수화물의 비율은 음료 100 mL 당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g으로 함유될 수 있다.The content of the acubin in the composition for health functional food may be appropriately determined according to the purpose of use (prevention or improvement). In general, it may contain from 0.01 to 15% by weight of the total food weight, and when prepared as a beverage, may contain 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 mL. The beverage may further include other components other than the extract, and may further contain various flavoring agents or natural carbohydrates commonly used in beverages. The natural carbohydrates include conventional sugars such as monosaccharides (eg glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), polysaccharides (eg, dextrin, cyclodextrin, etc.) and xylitol, sorbitol, erythritol, etc. Sugar alcohol may be contained. In addition, as a flavoring agent, it may contain natural flavoring agents (eg, taumatin, stevia extract, etc.) and synthetic flavoring agents (eg, saccharin, aspartame, etc.). The proportion of the natural carbohydrate may be contained in about 1 to 20 g, preferably about 5 to 12 g per 100 mL of beverage.
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있으며 바람직하게는 1 mg/kg 내지 100 mg/kg의 농도로 포함될 수 있으며, 가장 바람직하게는 75 mg/kg일 수 있다. The acubin may be included at a concentration of 1 mg/kg to 150 mg/kg, preferably at a concentration of 1 mg/kg to 100 mg/kg, and most preferably 75 mg/kg.
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다.The dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (Visual Display Terminal) It can be any one selected from the group consisting of dry eye-like conditions, including tear reduction in workers and without any systemic symptoms caused by dry rooms due to air conditioning.
본 발명은 아우쿠빈을 이를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는 안구 건조증 예방 또는 치료방법을 제공할 수 있다.The present invention can provide a method for preventing or treating dry eye syndrome, comprising the step of administering aucoubin to a subject in need thereof in a pharmaceutically effective amount.
본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환들을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, including humans, Means all animals, including rabbits or guinea pigs, and the above-mentioned diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention may be administered in parallel with existing therapeutic agents.
본 발명은 아우쿠빈을 안구 건조증 예방 또는 치료용 조성물에 사용하기 위한 용도를 제공할 수 있다.The present invention can provide a use for the use of aucvin in a composition for preventing or treating dry eye syndrome.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only intended to illustrate the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예 1. 세포 독성 실험 Example 1. Cytotoxicity experiment
각막 상피 세포 (PCS-700-010, American Type Culture Collection, Manassas, VA, USA)를 제조사 (American Type Culture Collection, Manassas, VA, USA)의 지시에 따라 성장 보충제를 포함하는 각막 상피 세포 기본 배지에서 배양하였다. 세포의 독성 실험은 MTS 분석 키트(Promega Corporation)를 이용하였다. 세포 (1 x 104)을 96 웰 플레이트에 키운 후 아우쿠빈을 0.1 내지 30 ㎍/mL으로 처리하였다. 배양한지 24 시간 후에 세포 독성을 측정 하였다. MTS 분석의 결과는 490 nm에서 마이크로 플레이트 리더 (Tecan Group Ltd., Mannedorf, Switzerland)를 사용하여 흡광도를 측정하였다. 그 결과 아우쿠빈을 30 ㎍/mL까지 세포 독성이 없다는 것을 확인하였다 (도 1). Corneal epithelial cells (PCS-700-010, American Type Culture Collection, Manassas, VA, USA) were prepared in corneal epithelial cell base medium containing growth supplements according to the manufacturer's instructions (American Type Culture Collection, Manassas, VA, USA). Cultured. Cell toxicity test was performed using the MTS assay kit (Promega Corporation). Cells (1×10 4 ) were grown in 96-well plates and then treated with aucubin at 0.1-30 μg/mL. Cytotoxicity was measured 24 hours after culture. As a result of the MTS analysis, absorbance was measured at 490 nm using a microplate reader (Tecan Group Ltd., Mannedorf, Switzerland). As a result, it was confirmed that acuvin had no cytotoxicity up to 30 μg/mL (FIG. 1 ).
실시예 2. 건조 스트레스에서 세포의 생존력 및 세포 사멸 측정Example 2. Measurement of cell viability and cell death under dry stress
건조된 세포의 생존력은 MTS 분석 키트를 사용하여 측정하였다. 아우쿠빈을 24시간 동안 사전 처리한 하였다. 그 후 배지를 제거하여 25분간 공기에 노출 시켜 건조 스트레스를 유도하였다. 그 후에 상기 실시예 1의 방법으로 세포 생존을 실험한 결과, 아우쿠빈은 용량 의존적으로 건조 스트레스에서 세포 생존력을 증가시켰다 (도 1B). 건조 후 세포 사멸 세포를 검출하기 위해, 세포를 고압 멸균된 커버 슬립상에 키웠다. 아우쿠빈을 24시간동안 사전 배양한 후, 세포를 25분 도안 건조한 상태로 노출 시켰고 TUNEL 염색으로 세포 사멸을 검출하였다. 건조과정에서 죽어가는 세포가 증가하였고, 사멸하는 세포는 15 μg/mL 아우쿠빈 처리군에서 유의적으로 감소하였다 (도 2A, B). The viability of dried cells was measured using an MTS assay kit. Aucubin was pretreated for 24 hours. The medium was then removed and exposed to air for 25 minutes to induce dry stress. Thereafter, as a result of experimenting cell survival with the method of Example 1, aucvin increased cell viability under dry stress in a dose-dependent manner (FIG. 1B ). To detect cell death cells after drying, the cells were grown on autoclaved cover slips. After pre-incubation of aucubin for 24 hours, the cells were exposed to dryness for 25 minutes and cell death was detected by TUNEL staining. The number of dying cells increased during the drying process, and the killing cells were significantly decreased in the 15 μg/mL acubin treatment group (FIGS. 2A and B ).
실시예 3. 실시간 PCRExample 3. Real-time PCR
안구 건조증은 염증에 의해 더욱 촉진된다. 아우쿠빈의 항염증 효과를 확인하기 위해 실시간 PCR을 진행하였다. Trizol 시약 (Invitrogen, Carlsbad, CA, USA)을 사용하여 각막 상피 세포의 총 RNA를 추출하고, M-MLV 역전사 효소 (Bioneer, 대전, 한국)를 사용하여 cDNA를 합성하였다. PCR은 2x SYBR Green PCR Master Mix (SYBR Premix Ex Taq, TaKaRa, Tokyo, Japan)와 함께 iQ5 Continuous Fluorescence Detector System (Bio-Rad, CA, USA)을 사용하여 수행되었다. 모든 절차는 제조업체의 지시에 따라 수행되었다. 프라이머 서열은 하기 표 1과 같다. 그 결과 IL-1β, IL-8 및 TNF-α의 mRNA 발현은 유의하게 건조 상태에서 증가하였고, 아우쿠빈 처리에 의해 감소되었다 (도 3A 내지 3C).Dry eye syndrome is further promoted by inflammation. Real-time PCR was performed to confirm the anti-inflammatory effect of Aucubin. Total RNA of corneal epithelial cells was extracted using Trizol reagent (Invitrogen, Carlsbad, CA, USA), and cDNA was synthesized using M-MLV reverse transcriptase (Bioneer, Daejeon, Korea). PCR was performed using the iQ5 Continuous Fluorescence Detector System (Bio-Rad, CA, USA) with 2x SYBR Green PCR Master Mix (SYBR Premix Ex Taq, TaKaRa, Tokyo, Japan). All procedures were performed according to the manufacturer's instructions. Primer sequences are shown in Table 1 below. As a result, mRNA expression of IL-1β, IL-8 and TNF-α was significantly increased in the dry state and decreased by aucvin treatment (FIGS. 3A to 3C ).
유전자gene 염기서열 Sequence
IL-1bIL-1b ForwardForward 5-AGCTACGAATCTCCGACCAC-35-AGCTACGAATCTCCGACCAC-3
ReverseReverse 5-CGTTATCCCATGTGTCGAAGAA-35-CGTTATCCCATGTGTCGAAGAA-3
IL-8IL-8 ForwardForward 5-ATGCTTTTGATCTGCACAGCTGCAC-35-ATGCTTTTGATCTGCACAGCTGCAC-3
ReverseReverse 5-TGGTCCAGCAGGAATAACCCTCAG-35-TGGTCCAGCAGGAATAACCCTCAG-3
TNF-αTNF-α ForwardForward 5-CAGCCTCTTCTCCTTCCTGA-35-CAGCCTCTTCTCCTTCCTGA-3
ReverseReverse 5-GGAAGACCCCTCCCAGATAGA-35-GGAAGACCCCTCCCAGATAGA-3
GAPDHGAPDH ForwardForward 5-ATGTTCGTCATGGGTGTGAA-35-ATGTTCGTCATGGGTGTGAA-3
ReverseReverse 5-GGTGCTAAGCAGTTGGTGGT-35-GGTGCTAAGCAGTTGGTGGT-3
실시예 4. 안구 건조증 모델동물을 이용한 아우쿠빈의 in vivo 기능성 평가 Example 4. Evaluation of in vivo functionality of Aucubin using dry eye model animals
4.1 실험 동물 및 디자인 4.1 Experimental animals and design
6주령 SD 랫트를 (주)오리엔트로부터 구입후 1주일 동안 순화하였다. 1주일 뒤 깊은 마취하에 눈물샘(exorbital lacrimal gland)을 수술로 제거하여 안구 건조증을 유발하였다. 1주일 뒤, 페놀-레드 스레드(phenol-red thread) 눈물량 검사지(FCI Opthalmics Zone Quick, Japan)를 눈꺼풀 외측 끝 부위 안구표면에 접촉시킨 후 30초 후 눈물에 의해 검사지의 색이 변한 길이를 측정하였다. 이들 중 비수술군에 비해 현저하게 눈물 분비량이 감소된 개체들만 선별하여 약효시험을 진행하였다. 군 분리 후 약물은 1일 1회씩 각군 (아우쿠빈 75mg/kg)에 맞게 조제하여 5일 동안 경구 투여하였다. 실험동물의 사육 및 실험동물을 이용한 모든 실험과정은 전북대학교 동물실험윤리위원회의 승인을 받았고, 규정에 따라 실행하였다.Six-week-old SD rats were purified from Orient Inc. for one week after purchase. One week later, under deep anesthesia, the tear glands (exorbital lacrimal gland) were surgically removed to cause dry eye. A week later, after contacting the phenol-red thread tear volume test paper (FCI Opthalmics Zone Quick, Japan) with the ocular surface at the outer end of the eyelid, the length of the color of the test paper was changed by tearing after 30 seconds. Did. Among these, only the individuals with significantly reduced tear secretion compared to the non-surgical group were screened for drug efficacy testing. After group separation, the drug was prepared once a day for each group (Aucubin 75mg/kg) and administered orally for 5 days. Breeding of laboratory animals and all experimental procedures using laboratory animals were approved by the Animal Experimental Ethics Committee of Chonbuk National University and implemented according to regulations.
4.2 눈물량 및 각막 건조손상 분석 4.2 Analysis of tear volume and corneal dryness
눈물 분비량은 페놀-레드 스레드 눈물량 검사지(FCI Opthalmics Zone Quick, Japan)를 눈꺼풀 외측 끝 부위 안구표면에 접촉시킨 후, 30초 후 눈물에 의해 검사지의 색이 변한 길이를 측정하여 눈물 분비량을 측정하였다. 안구 건조 모델은 정상군에 비해 낮은 눈물량을 보였으나 아우쿠빈 처리로 정상적으로 회복되었다 (도 4). 각막의 건조 손상은 원형 일루미네이터(ring type light illuminator)를 각막에 비춰 반사되는 형태를 촬영한 후 원형 조명의 각막 건조 손상에 의해 찌그러지는 정도를 평가하여 분석하였다. 안구 건조 모델은 불규칙한 원 모양의 빛을 보였으나 아우쿠빈을 처리한 군에서는 개선되었다 (도 4B). 또한 각막 얼룩의 점수는 안구 건조증 군이 높은 점수를 보였으나 아우쿠빈 처리군은 점수가 낮은 것을 확인하였다 (도 4C). The amount of tear secretion was measured by contacting the phenol-red thread tear level test paper (FCI Opthalmics Zone Quick, Japan) to the ocular surface at the outer end of the eyelid, and measuring the amount of tear secretion by measuring the length of the color change of the test paper by tears after 30 seconds. . The dry eye model showed a lower amount of tears than the normal group, but recovered normally with aucvin treatment (Fig. 4). The dryness damage of the cornea was analyzed by evaluating the degree of distortion caused by the dryness damage of the cornea of the circular illumination after photographing the reflection type by shining a circular illuminator (ring type light illuminator) on the cornea. The dry eye model showed irregular circular light, but improved in the group treated with Aucubin (Fig. 4B). In addition, the score of corneal staining showed a high score in the dry eye group, but the acubin treatment group confirmed that the score was low (FIG. 4C ).
4.3 TUNEL 염색4.3 TUNEL Dyeing
조직상의 세포 자멸 세포를 제조자의 지시에 따라 말단 디옥시리보 뉴클레오타이드 전달 효소 (TdT)-중재 된 dUTP nick end labelling (TUNEL) 염색을 이용하여 측정하였다. 안구 건조 모델에서는 세포 사멸 세포가 유의하게 증가한 반면에 아우쿠빈 처리군에서는 감소되었다 (도 5A 및 5B).Tissue apoptotic cells were measured using terminal deoxyribonucleotide transfer enzyme (TdT)-mediated dUTP nick end labeling (TUNEL) staining according to the manufacturer's instructions. In the dry eye model, apoptotic cells were significantly increased, while in the acubin treatment group, they were decreased (FIGS. 5A and 5B).

Claims (10)

  1. 하기 화학식 1로 표시되는 아우쿠빈（aucubin) 또는 이의 약학적으로 허용되는 염을 포함하는, 안구 건조증의 예방 또는 치료용 약학적 조성물:A pharmaceutical composition for the prevention or treatment of dry eye syndrome, comprising an acubin represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2020000725-appb-I000005
    .
    Figure PCTKR2020000725-appb-I000005
    .
  2. 제 1항에 있어서, 상기 조성물은 국소, 경피, 경구 또는 비경구투여되는, 안구 건조증의 예방 또는 치료용 약학적 조성물. According to claim 1, The composition is topical, transdermal, oral or parenteral administration, a pharmaceutical composition for the prevention or treatment of dry eye syndrome.
  3. 제 1항에 있어서, 상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함되는, 안구 건조증의 예방 또는 치료용 약학적 조성물.The pharmaceutical composition for preventing or treating dry eye syndrome according to claim 1, wherein the acubin is contained in a concentration of 1 mg/kg to 150 mg/kg.
  4. 제 1항에 있어서, 상기 조성물은 용액, 현탁액, 시럽제, 에멀젼, 리포좀, 산제, 분말제, 과립제, 정제, 서방형 제제, 점안제(eye drop), 캡슐제, 콘택트렌즈 세정제 및 콘택트렌즈 윤활제로 구성된 군에서 선택되는 어느 하나의 제형인, 안구 건조증의 예방 또는 치료용 약학적 조성물. The composition of claim 1, wherein the composition comprises a solution, suspension, syrup, emulsion, liposome, powder, powder, granule, tablet, sustained release preparation, eye drop, capsule, contact lens cleaner and contact lens lubricant. A pharmaceutical composition for the prevention or treatment of dry eye syndrome, which is any one formulation selected from the group.
  5. 제 1항에 있어서, 상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나인, 안구 건조증의 예방 또는 치료용 약학적 조성물. According to claim 1, wherein the dry eye syndrome is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blisters, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (image terminal) (Visual Display Terminal)) of dry eye syndrome, which is one selected from the group consisting of dry eye-like conditions, including tear reduction without any systemic symptoms caused by dry room due to worker tear reduction and air conditioning. Pharmaceutical composition for prevention or treatment.
  6. 하기 화학식 1로 표시되는 아우쿠빈（aucubin)를 포함하는, 안구 건조증의 예방 또는 개선용 건강기능식품조성물:A health functional food composition for the prevention or improvement of dry eye syndrome, which includes an acubin represented by Formula 1 below:
    [화학식 1][Formula 1]
    Figure PCTKR2020000725-appb-I000006
    .
    Figure PCTKR2020000725-appb-I000006
    .
  7. 제 6항에 있어서, 상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함되는, 안구 건조증의 예방 또는 개선용 건강기능식품조성물. According to claim 6, The acubin is contained in a concentration of 1 mg / kg to 150 mg / kg, health functional food composition for the prevention or improvement of dry eye syndrome.
  8. 제 6항에 있어서, 상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구 건조증, 알레르기성 결막염 수반 안구 건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구 건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나인, 안구 건조증의 예방 또는 개선용 건강기능식품조성물. 7. The method of claim 6, wherein the dry eye is anesthesia, corneal dryness, Sjogren's syndrome, dry corneal conjunctivitis, Stephen-Johnson syndrome, eye analog blister, dry eye after ophthalmic surgery, dry eye with allergic conjunctivitis, VDT (image terminal) (Visual Display Terminal)) of dry eye syndrome, which is one selected from the group consisting of dry eye-like conditions, including tear reduction without any systemic symptoms caused by dry room due to worker tear reduction and air conditioning. A health functional food composition for prevention or improvement.
  9. 아우쿠빈을 이를 필요로 하는 개체에 약학적으로 유효한 양으로 투여하는 단계를 포함하는 안구 건조증 예방 또는 치료방법.A method for preventing or treating dry eye syndrome comprising the step of administering aucoubin in a pharmaceutically effective amount to an individual in need thereof.
  10. 아우쿠빈을 안구 건조증 예방 또는 치료용 조성물에 사용하기 위한 용도.Use for use in a composition for the prevention or treatment of dry eye syndrome.
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