KR101978624B1 - Composition for treatment and prevention of dry eye syndrome comprising aucubin - Google Patents
Composition for treatment and prevention of dry eye syndrome comprising aucubin Download PDFInfo
- Publication number
- KR101978624B1 KR101978624B1 KR1020190005417A KR20190005417A KR101978624B1 KR 101978624 B1 KR101978624 B1 KR 101978624B1 KR 1020190005417 A KR1020190005417 A KR 1020190005417A KR 20190005417 A KR20190005417 A KR 20190005417A KR 101978624 B1 KR101978624 B1 KR 101978624B1
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- South Korea
- Prior art keywords
- dry eye
- eye syndrome
- dry
- syndrome
- composition
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- 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
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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
- 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
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- 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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
Description
본 발명은 아우쿠빈을 포함하는 안구건조증의 예방 또는 치료용 약학적 조성물에 관한 것이다. The present invention relates to a pharmaceutical composition for the prevention or treatment of dry eye syndrome including auchin.
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 안구건조증은 우리나라 성인의 20% 내외로 발생하는 흔한 질병으로, 특히 전 세계적인 기후 변화 특히 엘리뇨 현상으로 온도가 올라가고 있는 상황과 환경오염으로 인해 안구건조증 환자가 지속적으로 증가하고 있으나, 특별한 치료제 또는 기능성 식품이 없는 상황이다. 이에 연구자들이 안구건조증을 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 안구건조증 치료용 약학적 조성물이 개시되어 있다. Dry eye syndrome is not simply a tear defect, but it causes eyeball discomfort due to inflammation of the tear and ocular surface (cornea and conjunctiva), decreased visual acuity, instability of the tear layer, Pain, irregular corneal surface, blurred vision, and corneal ulceration. However, the mechanisms of this pathogenesis have not yet been fully elucidated, but studies have shown that inflammation plays an important role in infiltration of inflammatory cells, increased expression of immune activation molecules and adhesion molecules, Th1 and Th17 responses, abnormalities of apoptotic markers and chemokines have. In general, it is recommended to consume foods rich in potassium and anthocyanins for the treatment of dry eye syndrome. In addition, fruits such as kale, kiwi and apple are also highly recommended, and the amount of tears released by artificial tear drops and tear points They also use controlled treatments. However, dry eye syndrome is a common disease that occurs in about 20% of adults in Korea. In particular, global warming due to global climate change, especially El Niño phenomenon, and environmental pollution, There is no food. Researchers are working on the treatment of dry eye syndrome. For example, Korean Patent Laid-Open No. 10-2018-0065933 discloses a composition for preventing or treating an inflammatory eye disease, comprising a maple leaf extract or a fraction thereof, and Korean Patent No. 10-1910908 discloses a composition for preventing or treating inflammatory eye diseases, (Gly-thymosin < RTI ID = 0.0 > 4) < / RTI >
아우쿠빈 (aucubin)은 식나무 (Acuba japonica)의 주요성분 (major compound)으로 본 발명자들은 식나무 추출물의 안구건조증 효능을 확인하였으며, 유효성분을 확인하던 중 아우쿠빈이 눈물 분비량의 증가 및 각막 건조손상 예방, 각막 염증억제를 통해 안구건조증을 치료할 수 있음을 확인하여, 본 발명을 완성하였다.Aucubin is a major compound of Acuba japonica. The present inventors have confirmed the effect of dryness of the extract of the Japanese cinnamon tree on ocular damage. During the ascertainment of effective ingredients, aucubin increased the amount of tear secreted and prevented the dry damage of the cornea , And it is possible to treat dry eye syndrome through inhibition of corneal inflammation, thus completing the present invention.
본 발명은 상기의 문제를 해결하기 위해 안출된 것으로, 본 발명자들은 안구건조증의 예방 및 치료용 조성물을 연구하던 중, 아우쿠빈이 눈물 분비량의 증가 및 각막 건조손상 예방, 각막 염증억제를 통해 안구건조증을 치료할 수 있음을 확인하여, 본 발명을 완성하였다.DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention has been made in order to solve the above problems, and the present inventors have studied a composition for the prevention and treatment of dry eye syndrome. The present inventors have found that augubin inhibits dry eye injury, The present invention has been completed.
본 발명의 목적은 하기 화학식 1로 표시되는 아우쿠빈 또는 이의 약학적으로 허용되는 염을 포함하는, 안구건조증의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition for preventing or treating dry eye syndrome, which comprises an aUCBIN represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 하기 화학식 1로 표시되는 아우쿠빈을 포함하는 안구건조증의 예방 또는 개선용 건강기능식품조성물을 제공하는 것이다. Still another object of the present invention is to provide a health functional food composition for preventing or ameliorating dry eye syndrome comprising augubin represented by Formula 1 below.
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 preventing or treating dry eye syndrome comprising aucubin represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
상기 조성물은 경구 투여 될 수 있다. The composition may be administered orally.
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있다. The aubun may be contained 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 may be in the form of a solution, suspension, syrup, emulsion, liposome, powder, granule, tablet, sustained release, eye drop, capsule, Lt; / RTI >
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구건조증, 알레르기성 결막염 수반 안구건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나 일 수 있다. The above-mentioned dry eye syndrome includes dry eye syndrome, dry eye syndrome, dry eye corneal conjunctivitis, Stevens-Johnson syndrome, eye-like blisters, dry eye syndrome after ophthalmic surgery, dry eye syndrome associated with allergic conjunctivitis, VDT (Visual Display Terminal) An ocular dryness-like condition that includes tear reduction without worker's tear reduction and any systemic symptoms caused by a dry room due to an air conditioning device.
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 preventing or ameliorating dry eye syndrome comprising augubin represented by the following formula 1:
[화학식 1][Chemical Formula 1]
상기 아우쿠빈은 1 mg/kg 내지 150 mg/kg의 농도로 포함될 수 있다.The aubun may be contained 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 안구건조증, 알레르기성 결막염 수반 안구건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나 일 수 있다.The above-mentioned dry eye syndrome includes dry eye syndrome, dry eye syndrome, dry eye corneal conjunctivitis, Stevens-Johnson syndrome, eye-like blisters, dry eye syndrome after ophthalmic surgery, dry eye syndrome associated with allergic conjunctivitis, VDT (Visual Display Terminal) An ocular dryness-like condition that includes tear reduction without worker's tear reduction and any systemic symptoms caused by a dry room due to an air conditioning device.
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 안구건조증의 치료, 예방 또는 개선의 효과가 있다. The augubun of the present invention has no cytotoxicity at a concentration of 30 μg / mL in human corneal epithelial cells, reduces cell death in dry stress, and reduces the expression of inflammatory genes promoting dry eye syndrome. In addition, it has the effect of increasing the amount of tear secretion, restoring the damage caused by drying of the cornea, and decreasing the death of cells due to drying, in an animal model that causes dry eye syndrome. This has the effect of treating, preventing or improving ocular dryness of aubiquin.
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.
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.
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.
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.
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. FIG. 1 shows the results of confirming cytotoxicity after 24 hours after treatment of aubucine in a concentration-dependent manner, and confirming cell viability after inducing dry stress by exposure to air after pretreatment of aucubin for 24 hours.
FIG. 2 is a graph showing the effect of aucubin on cell death rate. FIG. 2 (A) shows the results of treatment of aucubin for 24 hours and exposure to air to induce dry stress, followed by TUNEL staining The ratio of TUNEL positive cells to total cells was compared to calculate the apoptosis rate. (B) is the result of microscopy after TUNEL staining.
FIG. 3 shows the results of confirming the effect of aukubin on inflammatory cytokines in human corneal epithelial cells at the level of mRNA. (A) shows IL-1β, (B) shows IL-8, mRNA levels were confirmed by PCR.
FIG. 4 shows the result of examining the effect of auchubin on eye volume and corneal damage in an animal model of dry eye syndrome, wherein (A) is a result of measuring eye mass, (B) is a result of representing the state of the corneal surface, C) is the result of quantifying the result of (B).
FIG. 5 shows the results of confirming the effect of auccubin on apoptotic cells in the ocular surface in an animal model of dry eye syndrome. (A) is a result of TUNEL staining, and (B) is a result of quantifying the result of (A) .
이하에서 본 발명을 자세하게 설명한다. Hereinafter, the present invention will be described in detail.
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 안구건조증은 우리나라 성인의 20% 내외로 발생하는 흔한 질병으로, 특히 전 세계적인 기후 변화 특히 엘리뇨 현상으로 온도가 올라가고 있는 상황과 환경오염으로 인해 안구건조증 환자가 지속적으로 증가하고 있으나, 특별한 치료제 또는 기능성 식품이 없는 상황이다. Dry eye syndrome is not simply a tear defect, but it causes eyeball discomfort due to inflammation of the tear and ocular surface (cornea and conjunctiva), decreased visual acuity, instability of the tear layer, Pain, irregular corneal surface, blurred vision, and corneal ulceration. However, the mechanisms of this pathogenesis have not yet been fully elucidated, but studies have shown that inflammation plays an important role in infiltration of inflammatory cells, increased expression of immune activation molecules and adhesion molecules, Th1 and Th17 responses, abnormalities of apoptotic markers and chemokines have. It also uses treatments to control the amount of tear that is released by artificial tear drops and tear points. However, dry eye syndrome is a common disease that occurs in about 20% of adults in Korea. In particular, global warming due to global climate change, especially El Niño phenomenon, and environmental pollution, 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 inventors of the present invention confirmed that augubin has a preventive and therapeutic effect on dry eye syndrome while studying a pharmaceutical composition for the prevention and treatment of dry eye syndrome, and completed the present invention. AUCUBIN was not toxic to human corneal epithelial cells up to 30 mu g / mL and was effective in increasing cell viability in an experiment in which dry stress was induced by exposure to air for 25 minutes (Fig. 1). As a result of the TUNEL staining of the cell death in the above drying stress, it was confirmed that pretreatment of augubin significantly reduced the number of cells dying in the drying process (FIG. 2). As a result of confirming the expression of inflammatory factors which exacerbate dry eye syndrome, it was confirmed that the expression of IL-1β, IL-8 and TNF-α mRNAs, which are factors related to inflammation, was reduced by treating augubin (FIG. (Fig. 4), decreased corneal damage due to drying (Fig. 4), and an effect of decreasing dry cell death (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 provides a pharmaceutical composition for preventing or treating dry eye syndrome comprising aucubin represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
[화학식 1] [Chemical Formula 1]
"아우쿠빈 (aucubin)"은 식나무에 포함되어 있는 생리활성 물질 중에 하나로, 요산배설을 촉진하여 통풍에 효과가 있고, 유리 라디칼을 소거하여 항산화에도 효과가 있다. "Aucubin" is one of the physiologically active substances contained in the Japanese persimmon tree. It promotes excretion of uric acid and thus has an effect on gout. It also has an effect on antioxidation by eliminating free radicals.
상기 조성물은 국소, 경피, 경구 또는 비경구로 투여 될 수 있으며, 가장 바람직하게는 경구로 투여 될 수 있다. The composition may be administered topically, transdermally, orally or parenterally, and 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 aubun may be contained at a concentration of 1 mg / kg to 150 mg / kg, preferably 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 may be in the form of a solution, suspension, syrup, emulsion, liposome, powder, granule, tablet, sustained release, eye drop, capsule, contact lens cleaner and contact lens lubricant .
상기 안구 건조증은 무루증, 각막건조증, 쇼그렌 증후군, 건조 각막결막염, 스티븐-존슨 증후군, 눈 유사물집증, 안과 수술 후 안구건조증, 알레르기성 결막염 수반 안구건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다. The above-mentioned dry eye syndrome includes dry eye syndrome, dry eye syndrome, dry eye corneal conjunctivitis, Stevens-Johnson syndrome, eye-like blisters, dry eye syndrome after ophthalmic surgery, dry eye syndrome associated with allergic conjunctivitis, VDT (Visual Display Terminal) An ocular dryness-like condition that includes tear reduction without worker's tear reduction and any systemic symptoms caused by a dry room due to an air conditioning device.
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 contain a pharmaceutically acceptable diluent or carrier. The diluent may be lactose, corn starch, soybean oil, microcrystalline cellulose, or mannitol, the lubricant may be magnesium stearate, talc, or combinations 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 hydroxy cellulose, or combinations thereof. The disintegrant may be carboxymethylcellulose calcium, starch glycolate sodium, calcium monohydrogen phosphate anhydrate, or a combination thereof. The binder may be polyvinylpyrrolidone, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, or combinations thereof. The lubricant may be magnesium stearate, silicon dioxide, talc, or a combination thereof. The pharmaceutical composition may contain the extract as an effective amount or as an active ingredient. The effective amount may be appropriately selected depending on the individual. The severity of the disease, the age, body weight, health, sex, sensitivity of the patient to the drug, time of administration, route of administration and rate of release, duration of treatment, factors involved in the combination or concurrent use with the composition, 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 an effective amount or an effective ingredient of the extract according to the use thereof. The effective amount may be appropriately selected depending on the individual. The severity of the disease or condition, the age, weight, health, sex, sensitivity of the individual to the extract, time of administration, route and rate of excretion, duration of administration, factors including other compositions combined or co- May be determined according to factors well known in the art, physiology 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 preventing or ameliorating dry eye syndrome comprising aucubin represented by the following formula (1): < EMI ID =
[화학식 1][Chemical Formula 1]
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 health functional food, it can be formulated into a typical health functional food formulation known in the art. The composition for health functional foods may be prepared by conventional formulations such as powders, granules, tablets, pills, capsules, suspensions, emulsions, syrups, And may be manufactured in the form of any health food such as candy, snacks, confectionery, pizza, ramen, other noodles, dairy products including gums, jellies, ice cream, various soups, drinks, tea, drinks, alcoholic beverages and vitamin complexes . A pharmaceutically acceptable carrier or additive may be used for the formulation of the health food, and any carrier or additive known to be usable in the art for the preparation of the formulation to be prepared may be used. As the above-mentioned additives, there can be used various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Carbonating agents, and the like. In addition, it may contain natural fruit juice, fruit juice beverage and flesh for the production of vegetable beverages. These additive components may be used independently or in combination, and the proportion of the additive may be 0.001 to 5 wt%, or 0.01 to 3 wt%, 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 aquin in the composition for health functional food may be suitably determined according to the intended use (prevention or improvement). Generally, it may contain 0.01 to 15% by weight of the total food, and when it is prepared as a beverage, it may contain 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 mL. The beverage may further contain ingredients other than the above extract, and may further contain various flavors or natural carbohydrates commonly used in beverages. Examples of the natural carbohydrate include conventional sugars such as monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrin and cyclodextrin; and sugars such as xylitol, sorbitol, erythritol, Of sugar alcohols may be contained. In addition, as a flavoring agent, a natural flavoring agent (e.g., tau Martin, stevia extract, etc.) and a synthetic flavoring agent (e.g., saccharin, aspartame, etc.) may be contained. The ratio of the natural carbohydrate may be generally 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 aubun may be contained at a concentration of 1 mg / kg to 150 mg / kg, preferably 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 안구건조증, 알레르기성 결막염 수반 안구건조증, VDT (영상 단말기 (Visual Display Terminal)) 노동자의 눈물 감소 및 공기 조절장치로 인한 건조한 방에 의해 야기되는 임의의 전신 증상이 없는 눈물 감소를 포함하는 안구건조증 유사 상태로 이루어지는 군으로부터 선택되는 어느 하나일 수 있다. The above-mentioned dry eye syndrome includes dry eye syndrome, dry eye syndrome, dry eye corneal conjunctivitis, Stevens-Johnson syndrome, eye-like blisters, dry eye syndrome after ophthalmic surgery, dry eye syndrome associated with allergic conjunctivitis, VDT (Visual Display Terminal) An ocular dryness-like condition that includes tear reduction without worker's tear reduction and any systemic symptoms caused by a dry room due to an air conditioning device.
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 with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with 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 subcultured on a corneal epithelial basal medium containing growth supplements according to the manufacturer's instructions Lt; / RTI > Cells (1 x 10 4 ) were cultured in 96-well plates and treated with 0.1 to 30 μg / mL of augubin. After 24 hours of incubation, cells The results of MTS analysis were used to determine the absorbance at 490 nm using a microplate reader (Tecan Group Ltd., Mannedorf, Switzerland), confirming that the aucubin was not cytotoxic 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 the 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 drying stress. Thereafter, cell viability was examined by the method of Example 1, and as a result, augubin increased cell viability in a dry stress in a dose-dependent manner (Fig. 1B). To detect apoptotic cells after drying, the cells were grown on autoclaved cover slips. AUCUBIN was preincubated for 24 hours, and then cells were exposed to dryness for 25 minutes and cell death was detected by TUNEL staining. Dying cells were increased during the drying process, and apoptotic cells were significantly reduced in the 15 μg / mL of the auxin-treated group (FIG. 2A, 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, Taejon, 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 carried out in accordance with the manufacturer's instructions. The 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 the aubucin treatment (FIGS. 3A to 3C).
실시예 4. 안구건조증 모델동물을 이용한 아우쿠빈의 in vivo 기능성 평가 Example 4. In vivo functional evaluation of aubucin 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 안구건조증을 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 purchased from the Orient and purified for one week. One week later, under deep anesthesia, the exorbital lacrimal gland was surgically removed to induce dry eye syndrome. After one week, the length of the color change of the test paper was measured by the tear after 30 seconds after the phenol-red thread eye volume test (FCI Opthalmics Zone Quick, Japan) was applied to the eye surface at the outer end of the eyelid Respectively. Among them, only the individuals with significantly decreased tear secretion level compared to the non - treated group were selected for the drug efficacy test. After separation of the group, the drug was administered once per day to each group (75 mg / kg augubin) and orally administered for 5 days. All experimental procedures using experimental animals and animal breeding were approved by the Chonbuk National University Animal Experimental Ethics Committee and implemented according to the regulations.
4.2 눈물량 및 각막 건조손상 분석 4.2 Analysis of Eye Volume and Corneal Drying Damage
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 measuring the length of the color change of the test paper by the tear after 30 seconds of contacting the surface of the eyelid with the phenol-red thread eye volume test (FCI Opthalmics Zone Quick, Japan) . The eye dry model showed a lower amount of snow than the normal group, but was normally recovered by treatment with aubucune (FIG. 4). Corneal dry damage was assessed by evaluating the extent to which the cornea was damaged by dry damage to the cornea after a round type illuminator was photographed on the cornea. The ocular dry model showed irregular circular light, but improved in the aubucin treated group (Fig. 4B). In addition, corneal staining scores were higher in the dry eye syndrome group and lower in the aubucune treated group (FIG. 4C).
4.3 TUNEL 염색4.3 TUNEL staining
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 transferase (TdT) -mediated dUTP nick end labeling (TUNEL) staining according to the manufacturer's instructions. In the ocular dry model, apoptotic cells were significantly increased, while in the aubucin treated group, they were decreased (Figs. 5A and 5B).
Claims (8)
[화학식 1]
[Chemical Formula 1]
[화학식 1]
[Chemical Formula 1]
The method of claim 6, wherein the dry eye syndrome is selected from the group consisting of moultosis, keratitis, Sjogren's syndrome, dry corneal conjunctivitis, Stevens-Johnson syndrome, eye-like blisters, ocular dryness, ocular allergic conjunctivitis, Which is selected from the group consisting of ocular dryness-like conditions, including reduction of tearing of workers and reduction of tears without any systemic symptoms caused by dry rooms caused by air conditioning devices, Prevention or amelioration.
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