KR20140037316A - Pharmaceutical composition comprising extract of lonicera japonica for prevention and treatment of crohn's disease - Google Patents
Pharmaceutical composition comprising extract of lonicera japonica for prevention and treatment of crohn's disease Download PDFInfo
- Publication number
- KR20140037316A KR20140037316A KR1020120101754A KR20120101754A KR20140037316A KR 20140037316 A KR20140037316 A KR 20140037316A KR 1020120101754 A KR1020120101754 A KR 1020120101754A KR 20120101754 A KR20120101754 A KR 20120101754A KR 20140037316 A KR20140037316 A KR 20140037316A
- Authority
- KR
- South Korea
- Prior art keywords
- disease
- crohn
- extract
- ulcerative colitis
- treatment
- Prior art date
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- A—HUMAN NECESSITIES
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- 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
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/32—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the digestive tract
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- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
Abstract
Description
본 발명은 크론병 또는 궤양성대장염 손상에 대한 치료효과를 가진 금은화 분획물 또는 이로부터 분리한 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방용 조성물에 관한 것으로, 보다 상세하게는 우수한 항산화 활성 및 크론병 또는 궤양성대장염에 우수한 치료효과를 가지면서 세포독성을 나타내지 않는 금은화 분획물 또는 3,5-디-O-카페오일 퀴닌산(3,5-di-O-caffeoylquinic acid), 4,5-디-O-카페오일 퀴닌산(4,5-di-O-caffeoylquinic acid)로 구성되는 군으로부터 선택되는 하나 이상의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방 효과를 갖는 약학적 조성물, 건강기능식품 조성물에 관한 것이다.
The present invention relates to a composition for treating or preventing Crohn's disease or ulcerative colitis, which contains, as an active ingredient, a gingival fraction having a therapeutic effect on Crohn's disease or ulcerative colitis damage or a compound isolated therefrom, (3,5-di-O-caffeoylquinic acid), 4 (4-di-O-caffeoylquinic acid) which has excellent therapeutic effect on Crohn's disease or ulcerative colitis and does not show cytotoxicity, , 5-di-O-caffeoylquinic acid as an active ingredient in the treatment or prevention of Crohn's disease or ulcerative colitis. And a health functional food composition.
궤양성대장염(ulcerative colitis) 및 크론병(Crohn's disease)은 아직 원인이 명확히 밝혀져 있지 않은 장질환(bowel disease)이다. 궤양성 대장염은 대장의 점막에 진무름(미란)이나 궤양이 연속적으로 형성되는 질환으로, 혈변, 점혈변, 설사, 복통이 일어나고, 중증인 경우에는 발열, 체중감소, 빈혈 등의 전신성의 증상이 나타난다. Ulcerative colitis and Crohn's disease are bowel diseases that have not yet been clearly identified. Ulcerative colitis is a disease in which erosions (erosions) and ulcers are continuously formed in the mucous membranes of the large intestine. Bleeding, dyspepsia, diarrhea and abdominal pain occur in the colon. In severe cases, systemic symptoms such as fever, weight loss and anemia appear .
또한, 크론병은 입에서 항문에 이르는 소화관의 임의의 부위에 궤양 등의 병변이 비연속적으로 발생하는 질환으로서, 복통, 설사, 혈변과 더불어, 중증의 경우에는 발열, 하혈, 체중감소, 전신권태감, 빈혈 등의 증상이 나타난다. 궤양성대장염 및 크론병 모두 일시적으로 증상이 좋아지다가, 재발이 반복하는 만성 난치성 질환으로, 통칭하여 염증성 장질환(inflammatory bowel disease)으로 칭해지기도 한다. 이들 질환의 병인으로서는 유전적 요인이나 면역 이상, 식사 등의 환경인자가 관여한다는 지적이 있지만, 원인은 아직 불분명하다.In addition, Crohn's disease is a disease in which lesions such as ulcers are generated discontinuously in any part of the digestive tract from the mouth to the anus. In addition to abdominal pain, diarrhea and stool, severe cases include fever, hemorrhage, weight loss, , And anemia. Both ulcerative colitis and Crohn's disease are chronic refractory diseases in which the symptoms recur temporarily and recurrence recurs, collectively referred to as inflammatory bowel disease. Although there is an indication that environmental factors such as genetic factors, immune disorders, and diet are involved in the pathogenesis of these diseases, the cause is still unclear.
종래, 궤양성대장염 및 크론병의 발생율은 서양인에게 높다고 알려져 있었지만, 최근, 식습관 등의 생활습관의 변화로 인해 우리나라 등 동양에서도 환자수가 급증하고 있다. 그렇지만, 원인이 불분명한 이유도 있어 근본적 치료법은 확립되어 있지 않다. 이 때문에 완전한 치료를 목표로 하는 것이 아니라, 증상을 완해(관해(寬解); 일시적으로 증상이 좋아진 상태)시키고, 이러한 상태를 가능한 한 장기간 유지하는 약제가 사용되고 있는 실정이다. 이러한 대증요법을 위한 약제로서, 주로 아미노살리실산제제, 부신피질 스테로이드제, 면역억제제 등이 사용되지만, 다양한 부작용이 보고되고 있다. 예를 들어, 아미노살리실산제제로서 자주 사용되는 살라조설파피리딘은 구역질, 구토, 식욕부진, 발진, 두통, 간장해, 백혈구 감소, 이상 적혈구, 단백뇨, 설사 등의 부작용이 보고되고 있다. 또한 부신피질스테로이드제는 일반적으로는 프레드니솔론의 경구투여, 관장, 좌약, 정맥 주사 등으로 사용되지만, 위궤양이나 장기사용에 의한 대퇴골두 괴사 등 부작용이 강하다. 그러나 투약의 중단은 증상을 재발시키기 때문에, 이들 약제는 계속적으로 사용하지 않을 수 없다. In the past, the incidence of ulcerative colitis and Crohn's disease was known to be high in westerners, but recently, the number of patients has increased rapidly in Korea and other countries due to changes in lifestyle such as eating habits. However, there is a reason why the cause is unclear, and fundamental treatment is not established. For this reason, it is not the goal of complete treatment, but rather the use of medicines that alleviate symptoms (remission, temporary symptom improvement) and maintain these conditions for as long as possible. Aminosalicylic acid preparations, adrenocorticosteroids, immunosuppressants and the like are mainly used as medicines for such symptomatic therapy, but various side effects have been reported. For example, salazosulfapyridine, which is frequently used as an aminosalicylic acid preparation, has been reported to have side effects such as nausea, vomiting, anorexia, rash, headache, liver damage, leukocytosis, abnormal red blood cells, proteinuria and diarrhea. Adrenocortical steroids are generally used for oral administration of prednisolone, enema, suppository, intravenous injection, etc. However, side effects such as gastric ulcer necrosis caused by gastric ulcer or long-term use are strong. However, since discontinuation of the medication recurs, the medicines must be continuously used.
따라서, 효과가 우수하면서도, 안전하고 부작용을 일으키지 않는 궤양성대장염, 크론병 등의 장질환 치료제의 개발이 요구되고 있다.Therefore, there is a demand for the development of therapeutic agents for intestinal diseases such as ulcerative colitis and Crohn's disease which are excellent in efficacy, safe, and do not cause side effects.
금은화(Lonicerae Flos)는 인동과(Caprifoliaceae)에 속하는 인동 덩굴(Lonicera japonica Thunb.)의 꽃으로, 한방이나 민간에서는 이뇨, 건위, 관절염, 화농성 피부염, 기관지염에 사용되고 있다. 금은화의 성분으로는 탄닌(tannin), 이노시톨(inositol), 스테롤(sterol), 클롤제닉산(chlorogenic acid), 이소클로제닉산(isochlogenic acid) 등이 보고되어 있으며, 플라보노이드(flavonoid) 성분으로서는 루테올린(luteolin), 에피게닌(apigenin), 루테올린-7-람노글루코시드(luteolin-7-O-rhamnoglucoside), 쿼세틴(quercetin) 등이 알려져 있다. 이러한 금은화의 플라보노이드(flavonoid) 성분은 항염증작용(Lee, S. J.; Arch. Pharm. Res. 16, 25, 1993) 및 항돌연변이 작용 등이 보고되었다. Lonicerae Flos is a flower of Lonicera japonica Thunb. Belonging to the genus Caprifoliaceae. It is used for diuretic, arthritis, purulent dermatitis and bronchitis in a herbal medicine or a civilian. Tannin, inositol, sterol, chlorogenic acid, isochlogenic acid, and the like have been reported as the components of gold silver. Examples of flavonoid components include luteolin luteolin, apigenin, luteolin-7-O-rhamnoglucoside, quercetin and the like are known. The flavonoid component of this gilt-silver was reported to be anti-inflammatory (Lee, SJ; Arch. Pharm. Res. 16, 25, 1993) and antimutagenic action.
금은화에 대한 연구로, 강옥희(금은화의 약리작용에 관한 연구)는 금은화의 메탄올 추출액이 수종의 그람 양성 및 그람 음성균에 항균작용이 있음을 보고하였고, Lee 등은 금은화의 부탄올 분획이 마우스 귀 부종 및 카라기닌(carrageenin) 유발 발바닥 부종실험에서 프레드니솔론(prednisolone)보다는 약하지만, 용량 의존적으로 발바닥 부종을 개선시킴을 보고하였다. 또한, Tae 등은 금은화 꽃의 물 추출물이 LPS (Lipopolysaccharide)로 유도된 랫트 간 패혈증(rat liver sepsis)에서 NFκB p65의 활성 억제와 IκBα의 분해(degradation)억제를 통하여 항염증효과를 나타냄을 보고하였다.(Tae, J.; Clin Chim Acta. 330(1-2), 165-171, 2003) In a study on gingkohwang, Kang Ok-hee (study on the pharmacological action of gingkohwa) reported that the methanol extract of gingkohwa had antibacterial activity against several gram-positive and gram-negative bacteria. Lee et al. Reported that the butanol fraction of gingko- In carrageenin-induced plantar edema experiments, we reported a less potent, but dose-dependent, improvement in plantar edema than prednisolone. In addition, Tae et al. Reported that the water extract of Ganoderma lucidum exhibited anti-inflammatory effects by inhibiting NFκB p65 activity and degradation of IκBα in rat liver sepsis induced by Lipopolysaccharide (LPS) (Tae, J .; Clin Chim Acta . 330 (1-2), 165-171, 2003)
본 발명자들은 대한민국 특허등록 제10-0878436호에서 "금은화 추출물을 포함하는 소화성 궤양 치료 또는 예방용 약학조성물" 이라는 내용으로 금은화 추출물이 위염??위궤양을 포함한 소화성 궤양 치료에 효과가 있음을 확인하였고, 또 대한민국 특허등록 제10-1074839호에서 "금은화 추출물을 포함하는 역류성 식도염 치료 또는 예방용 약학조성물"이라는 내용으로 금은화 추출물이 역류성식도염(GERD)에 치료 효과가 있음을 확인하였다. The inventors of the present invention confirmed in Korean Patent Registration No. 10-0878436 that "Ganoderma lucidum extract" is effective for the treatment of peptic ulcer including gastritis and ulcer, as "a pharmaceutical composition for treating or preventing peptic ulcer including Ginkgo biloba extract" In Korean Patent Registration No. 10-1074839, it was confirmed that the gingkowort extract had a therapeutic effect on GERD with the statement that "a pharmaceutical composition for treating or preventing reflux esophagitis including Ginkgo biloba extract ".
본 발명자들은 금은화 추출물에 대한 위염. 위궤양 및 역류성식도염(GERD) 치료제를 개발 하던 중 금은화의 특정 분획물이 크론병 또는 궤양성대장염 질환에 효과가 우수함을 확인하였으며, 본 발명자들이 발명한 금은화 특정 분획물이 크론병 또는 궤양성대장염의 치료 효과가 우수함을 확인하게 되었다. 이에 본 발명자들은 금은화 분획물 또는 이로부터 분리된 화합물이 크론병 또는 궤양성대장염 치료에 아주 효과가 뛰어날 뿐만 아니라, 나아가 크론병 또는 궤양성대장염에 대한 예방 효과를 나타내어, 이를 유효성분으로 함유하는 조성물을 크론병 또는 궤양성대장염 치료 또는 예방을 위한 의약품 및 건강기능식품으로 사용될 수 있음을 밝힘으로써 본 발명을 완성하였다.
The present inventors have found that gastritis against Gingko nuts extract. While developing a therapeutic agent for gastric ulcer and reflux esophagitis (GERD), it was confirmed that specific fractions of Gil Eul Hwa were excellent in Crohn's disease or ulcerative colitis disease. The inventors of the present invention found that the specific fractions of Gil- . Accordingly, the present inventors have found that the gold-eutectic fraction or the compound isolated therefrom is not only highly effective in treating Crohn's disease or ulcerative colitis, but also exhibits a preventive effect against Crohn's disease or ulcerative colitis, Crohn's disease or Crohn's disease or ulcerative colitis. The present invention has been accomplished on the basis of these findings.
본 발명의 목적은 금은화 분획물 또는 하기 화학식 1 내지 2의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 및 예방용 약학적 조성물을 제공하는 데 있다.It is an object of the present invention to provide a pharmaceutical composition for the treatment and prevention of Crohn's disease or ulcerative colitis, which comprises a gold-eurafil fraction or a compound of the following general formulas 1 to 2 as an active ingredient.
본 발명의 다른 목적은 금은화 분획물 또는 상기 화학식 1 내지 2의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 예방 또는 개선용 건강기능식품 조성물을 제공하는 데 있다.
Another object of the present invention is to provide a health functional food composition for preventing or ameliorating Crohn's disease or ulcerative colitis, which comprises a gingival fraction or the compound of Chemical Formulas 1 to 2 as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 항산화 활성을 가지며 크론병 또는 궤양성대장염을 치료하는 금은화 분획물 또는 상기 화학식 1의 3,5-디-O-카페오일 퀴닌산(3,5-di-O-caffeoylquinic acid, 이하, 3,5-di-CQA라 칭함), 상기 화학식 2의 4,5-디-O-카페오일 퀴닌산(4,5-di-O-caffeoylquinic acid, 이하 4,5-di-CQA라 칭함)로 구성되는 군으로부터 선택되는 하나 이상의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 및 예방용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention relates to a gold-silverated fraction having antioxidant activity and treating Crohn's disease or ulcerative colitis, or a 3,5-di-O-caffeoylquinic acid (3,5-di-O -caffeoylquinic acid, hereinafter referred to as 3,5-di-CQA), 4,5-di-O-caffeoylquinic acid (4,5- di-CQA) as an active ingredient. The present invention also provides a pharmaceutical composition for treating or preventing Crohn's disease or ulcerative colitis, which comprises at least one compound selected from the group consisting of di-CQA
본 발명은 항산화 활성을 가지며 크론병 또는 궤양성대장염을 치료하는 금은화 분획물 또는 상기 화학식 1의 3,5-di-CQA, 상기 화학식 2의 4,5-di-CQA로 구성되는 군으로부터 선택되는 하나 이상의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 개선 및 예방용 건강기능식품 조성물을 제공한다.The present invention relates to a gold-silverated fraction having an antioxidative activity and treating Crohn's disease or ulcerative colitis, or a combination of 3,5-di-CQA of Formula 1 and 4,5-di-CQA of Formula 2 The present invention provides a health functional food composition for improving or preventing Crohn's disease or ulcerative colitis, which comprises the above compound as an active ingredient.
또한, 본 발명의 금은화 추출물은 현재 임상에서 크론병 또는 궤양성대장염 치료제로 사용되고 있는 약물들(예로서, 설파살라진, 부데소니드, 메살라민, 주캅사이신, 사그라모스팀, 니타족사니드, 프레드니솔론, 나탈리주마브, 아달리무마브 등) 중에서 선택된 1종 이상 약물과 병용 또는 조합으로 하여 크론병 또는 궤양성대장염 치료 및 예방용 약학적 조성물을 제공한다.The gold-eutectin extract of the present invention can be used as a medicament for the treatment of Crohn's disease or ulcerative colitis in clinical trials (for example, sulfasalazine, budesonide, mesalamine, capsaicin, Saglamostim, Nitta ysannanide, prednisolone, , Adalimumab, etc.), in combination or in combination, to provide a pharmaceutical composition for the treatment and prevention of Crohn's disease or ulcerative colitis.
이하, 본 발명을 자세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명에 따른 금은화 추출물은 금은화 또는 이의 건조물로부터 추출하여 얻을 수 있으며, 상기 금은화는 야생 및 사람이 재배한 것 등 제한 없이 사용할 수 있다. 본 발명에 따른 금은화 추출물은 초임계 추출, 상온 추출, 고온추출, 고압 추출 또는 초음파 추출법 등의 추출장치를 이용한 방법 또는 XAD 및 HP-20을 포함한 흡착수지를 이용하는 방법 등 당업계의 통상적인 추출방법을 사용할 수 있으며, 바람직하게는 가용하며 환류 추출 또는 상온에서 추출하여 제조할 수 있으나, 이에 한정되는 것은 아니다. 추출 회수는 1 내지 5회인 것이 바람직하며, 3회 반복 추출하는 것이 더욱 바람직하나, 이에 한정되는 것은 아니다.The ginseng extract according to the present invention can be obtained by extracting from gold silver or its dried material, and the ginseng silver can be used without limitation such as wild and human cultivated. The gold-eutectic extract according to the present invention can be obtained by a conventional extraction method such as supercritical extraction, room temperature extraction, high-temperature extraction, high-pressure extraction, ultrasonic extraction or the like, or adsorption resin including XAD and HP- Can be used, and it is preferably soluble and can be prepared by reflux extraction or extraction at room temperature, but is not limited thereto. The number of times of extraction is preferably 1 to 5 times, more preferably 3 times, but is not limited thereto.
상기 추출물은 물, 유기용매 또는 이들의 혼합용매를 이용하여 추출될 수 있다. 상기 유기용매는 C1 내지 C4의 알코올, 에틸아세테이트, 염화메틸렌 및 클로로포름으로 이루어지는 군으로부터 선택되는 어느 하나 또는 이들의 혼합 용매인 것이 바람직하고, C1 내지 C4의 알코올인 것이 더욱 바람직하고, 메탄올, 에탄올 또는 이들의 50~100% 알코올 수용액으로 추출하는 것이 가장 바람직하다.The extract may be extracted using water, an organic solvent or a mixed solvent thereof. The organic solvent is preferably one selected from the group consisting of C1 to C4 alcohols, ethyl acetate, methylene chloride and chloroform, or a mixed solvent thereof, more preferably C1 to C4 alcohols, more preferably methanol, It is most preferable to extract them with an aqueous solution of 50 to 100% alcohol.
일례로, 본 발명에 따른 금은화 추출물은 금은화 건조물을 적당한 크기로 분쇄하여 추출 용기에 넣고 추출 용매를 넣어 용매를 끓이며 환류 추출한 후, 일정시간 방치한 후 여과지 등으로 여과하여 알코올 추출물을 얻을 수 있다. 추출 시간은 2 내지 12시간인 것이 바람직하며, 3 내지 6시간인 것이 더욱 바람직하다. 이후에 농축 또는 동결건조 등의 방법을 추가할 수 있다.For example, the gingkohye extract according to the present invention can be obtained by pulverizing the dried gingivalae to an appropriate size, placing it in an extraction container, boiling the solvent by adding an extraction solvent, refluxing the extract, allowing it to stand for a predetermined time and filtering it with a filter paper or the like. The extraction time is preferably 2 to 12 hours, more preferably 3 to 6 hours. Thereafter, a method such as concentration or freeze-drying can be added.
본 발명에 따른 금은화 분획물은 상기 금은화 추출물을 헥산, 에틸아세테이트 및 부탄올을 사용하여 순차적으로 계통 분획을 수행하여 얻을 수 있다. 나아가, 본 발명은 상기 화학식 1로 표시되는 3,5-di-CQA, 화학식 2로 표시되는 4,5-di-CQA로 구성되는 군으로부터 선택되는 하나 이상의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방용 약학적 조성물을 제공한다.The ginseng fraction according to the present invention can be obtained by sequential fractionation of the ginseng extract using hexane, ethyl acetate and butanol. Further, the present invention relates to a pharmaceutical composition for treating Crohn's disease or Crohn's disease comprising as an active ingredient at least one compound selected from the group consisting of 3,5-di-CQA represented by Formula 1 and 4,5-di-CQA represented by Formula 2 There is provided a pharmaceutical composition for treating or preventing ulcerative colitis.
상기 화학식 1 내지 2의 화합물은 금은화에 물 또는 유기용매 또는 이들의 혼합물을 가하여 금은화 추출물을 수득하는 단계(단계 1): The compounds of Formulas 1 and 2 may be prepared by adding water, an organic solvent or a mixture thereof to silver chelate to obtain a silver sulfite extract (Step 1):
상기 단계 1에서 수득한 금은화 추출물을 물에 현탁시킨 다음 에틸아세테이트 또는 부탄올로 분획하여 분획물을 얻는 단계(단계 2):The step of suspending the Ganoderma lucidum extract obtained in the above step 1 in water and then fractionating it with ethyl acetate or butanol to obtain fractions (step 2):
상기 단계 2에서 수득한 분획물에 대해 실리카겔 크로마토그래피를 수행하여 화학식 1 내지 2의 화합물을 분리하고 정제하는 단계(단계 3);Separating and purifying the compounds of Formulas 1 and 2 (Step 3) by performing silica gel chromatography on the fractions obtained in Step 2 above;
를 포함하여 이루어지는 제조방법에 의해 제조될 수 있다.And the like.
이하 본 발명에 따른 상기 제조방법을 단계별로 더욱 구체적으로 설명한다. 먼저, 본 발명에 따른 상기 단계 1은 추출용매로 금은화 추출물을 수득하는 단계이다. 건조된 금은화를 적당한 크기로 분쇄하여 추출용기에 넣는다. 추출용매는 C1 내지 C4의 알코올, 50~100% C1 내지 C4의 알코올 수용액, 에틸아세테이트, 염화메틸렌, 클로로포름 또는 이들의 혼합용매를 사용할 수 있고, 이들 중에서 메탄올, 에탄올, 또는 이들의 50~100% 알코올 수용액을 사용하는 것이 바람직하다. 이를 60℃에서 초음파로 6 시간동안 추출한 후 여과지 등으로 여과하여 본 발명에 따른 금은화 추출물을 수득할 수 있다.Hereinafter, the manufacturing method according to the present invention will be described in more detail. First, step 1 according to the present invention is a step of obtaining a Ganoderma lucidum extract as an extraction solvent. The dried gold silver is pulverized to an appropriate size and placed in an extraction vessel. The extraction solvent may be an alcohol of C1 to C4, an alcohol aqueous solution of 50 to 100% of C1 to C4, ethyl acetate, methylene chloride, chloroform or a mixed solvent thereof. Of these, methanol, ethanol, or 50 to 100% It is preferable to use an aqueous alcohol solution. It is extracted with ultrasound at 60 ° C for 6 hours, and then filtered with a filter paper or the like to obtain a gingival extract according to the present invention.
다음으로, 상기 단계 2는 상기 단계 1에서 얻은 금은화 추출물을 극성을 달리하는 용매로 분획하여 분획물을 얻는 단계이다. 상기 용매로는 에틸아세테이트 또는 부탄올을 사용할 수 있다.Next, the step 2 is a step of obtaining the fractions by fractionating the gold and silver europium extract obtained in the step 1 with a solvent having a different polarity. As the solvent, ethylacetate or butanol can be used.
다음으로, 상기 단계 3은 상기 단계 2에서 얻은 분획물에 대해 실리카겔 크로마토그래피를 수행하여 화학식 1 내지 화학식 2의 화합물을 분리하고 정제하는 단계이다. 상기 실리카겔 크로마토그래피는 크기배제 크로마토그래피용 컬럼을 사용하여 수행할 수 있으며, 바람직하게는 HP-20을 충진한 컬럼을 사용할 수 있다. 상기 단계 2에서 수득한 분획물에 대하여 에탄올을 이동상으로 하여 HP-20 컬럼을 이용한 실리카겔 크로마토그래피를 수행한다. 이때 수득한 분획물에 대하여 고속액체크로마토그래피를 수행하여 화학식 1 내지 화학식 2의 화합물을 분리할 수 있다. 상기 고속액체크로마토그래피는 0부피%에서 5부피%, 5부피%에서 10부피% 아세토니트릴로 농도 구배된 물과 아세토니트릴의 혼합용매를 전개용매로 사용하여 수행할 수 있다. 이때, 상기 이동상의 유속은 2-15 mL/분이다.Next, the step 3 is a step of separating and purifying the compounds of the formulas (1) to (2) by performing silica gel chromatography on the fractions obtained in the step (2). The silica gel chromatography can be carried out using a column for size exclusion chromatography, and preferably a column packed with HP-20 can be used. The fraction obtained in the above step 2 is subjected to silica gel chromatography using an HP-20 column using ethanol as a mobile phase. At this time, the obtained fractions can be subjected to high performance liquid chromatography to separate the compounds of the formulas (1) to (2). The high performance liquid chromatography can be carried out using a mixed solvent of water and acetonitrile gradient from 0 vol% to 5 vol% and from 5 vol% to 10 vol% acetonitrile as a developing solvent. At this time, the flow rate of the mobile phase is 2-15 mL / min.
본 발명에 따른 상기 금은화 분획물 또는 상기 화학식 1 내지 2의 화합물은 크론병 또는 궤양성대장염의 치료 또는 예방용으로 사용될 수 있다. The gingival fraction or the compounds of Formulas 1 and 2 according to the present invention may be used for the treatment or prevention of Crohn's disease or ulcerative colitis.
또한 본 발명에 따른 금은화 추출물 또는 화학식 1 내지 2의 화합물을 단독으로 사용되거나, 현재 임상에서 크론병 또는 궤양성대장염 치료제로 사용되고 있는 약물들(예로서, 설파살라진, 부데소니드, 메살라민, 주캅사이신, 사그라모스팀, 니타족사니드, 프레드니솔론, 나탈리주마브, 아달리무마브 등)과 병용 또는 적당한 조합으로 크론병 또는 궤양성대장염의 치료 또는 예방용으로 사용될 수 있다.The compounds of the present invention may be used alone or in combination with other drugs currently used in the treatment of Crohn's disease or ulcerative colitis (for example, sulfasalazine, budesonide, mesalamine, capsaicin, For example, in combination with, or in combination with, an anti-inflammatory agent, for example, Moss Steam, Nitasusanide, Prednisolone, Natalie Juimab, Adalimumab, and the like.
본 발명에 따른 금은화 분획물 또는 화학식 1 내지 2의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방용 약학적 조성물은 하기의 다양한 경구 또는 비경구 투여 형태로 제형화할 수 있으나, 이에 한정하는 것은 아니다.The pharmaceutical composition for treating or preventing ulcerative colitis or ulcerative colitis according to the present invention may be formulated into various oral or parenteral dosage forms as described below, It does not.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캡슐제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 상기 유효성분 이외에 통상적으로 사용되는 충진제, 증량제, 습윤제, 붕해제, 활택제, 결합제, 계면 활성제 등의 희석제 또는 부형제를 1종 이상 사용할 수 있다. 붕해제로는 한천, 전분, 알긴산 또는 이의 나트륨염, 무수인산일수소 칼슘염 등이 사용될 수 있고, 활택제로는 실리카, 탈크, 스테아르산 또는 이의 마그네슘염 또는 칼슘염, 폴리에틸렌 글리콜 등이 사용될 수 있으며, 결합제로는 마그네슘, 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로오스, 나트륨카복시메틸셀룰로오스, 폴리비닐피롤리딘, 저치환도 하이드록시프로필셀룰로오스, 글리신 등을 희석제로 사용할 수 있으며, 경우에 따라서는 일반적으로 알려진 비등 혼합물, 흡수제, 착색제, 향미제, 감미제 등을 함께 사용할 수 있다.Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and the like. These formulations may contain fillers, extenders, wetting agents, One or more diluents or excipients such as disintegrants, lubricants, binders and surfactants may be used. As the disintegrant, agar, starch, alginic acid or its sodium salt, anhydrous calcium monohydrogenphosphate, etc. may be used. As the lubricant, silica, talc, stearic acid or its magnesium salt or calcium salt, polyethylene glycol and the like may be used And as the binder, magnesium, aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low-substituted hydroxypropylcellulose, glycine and the like can be used as a diluent. A boiling mixture, an absorbent, a coloring agent, a flavoring agent, a sweetening agent, and the like, may be used together.
또한 금은화 추출물, 분획물 또는 화학식 1 내지 2의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방용 약학적 조성물은 비경구 투여 할 수 있으며, 비경구 투여는 피하주사제, 정맥주사제, 근육 내 주사제 또는 흉부 내 주사제를 주입하는 방법에 의한다. 이때 비경구 투여용 제형으로 제제화하기 위하여 금은화 추출물, 분획물 또는 화학식 1 내지 2의 화합물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알의 단위 투여형으로 제조할 수 있다.In addition, the pharmaceutical composition for treating or preventing Crohn's disease or ulcerative colitis, which comprises the extract of Gingko nuts, fractions or the compounds of formulas (1) and (2) as an active ingredient, can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, The method of injecting the injector or the injector in the chest is by the method. In order to formulate the composition for parenteral administration, the gingkoffle extract, the fractions or the compounds of Formulas 1 and 2 may be mixed with a stabilizer or a buffer in water to prepare a solution or suspension, which may be prepared into a unit dosage form of ampoule or vial have.
상기 조성물은 멸균되거나 또는 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염, 완충제 등의 보조제 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화 할 수 있다.The composition may be sterilized or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure, buffering agents and other therapeutically useful substances and may be prepared by conventional methods such as mixing, granulating or coating . ≪ / RTI >
본 발명의 금은화 분획물 또는 화학식 1 내지 2의 화합물을 유효성분으로 함유하는 크론병 또는 궤양성대장염 치료 또는 예방용 약학적 조성물을 단위 용량 형태로 제형화하는 경우, 유효성분으로서 이들 금은화 분획물 또는 화학식 1 내지 2의 화합물을 약 0.1~1500 ㎎의 단위용량으로 함유되는 것이 바람직하다. 투여량은 환자의 체중, 나이 및 질병의 특수한 성질과 심각성과 같은 요인에 따라 의사의 처방에 따른다. 그러나, 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 약 1~500 ㎎ 범위가 보통이다. 성인에게 근육 내 또는 정맥 내 투여 시 일회 투여량으로 분리하여 하루에 보통 5~300 ㎎의 전체 투여량이면 충분할 것이나, 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다.When the pharmaceutical composition for treating or preventing Crohn's disease or ulcerative colitis containing the gold-silver fraction of the present invention or the compounds of the formulas (1) and (2) as an active ingredient is formulated in unit dose form, these gold-containing fractions or To 2 in a unit dose of about 0.1 to 1500 mg. The dosage depends on the physician's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult therapy is usually in the range of about 1 to 500 mg per day, depending on the frequency and intensity of administration. A total dosage of 5 to 300 mg per day, usually divided into a single dose when administered intramuscularly or intravenously to an adult, may suffice, but in some patients a higher daily dose may be desirable.
본 발명에 따른 금은화 분획물 또는 화학식 1 내지 2의 화합물을 크론병 또는 궤양성대장염 치료 또는 예방용 목적으로 식품, 음료 등의 건강보조 또는 건강기능성 식품에 첨가할 수 있다. 이 경우, 금은화 분획물 또는 화학식 1 내지 2의 화합물을 식품 첨가물로 사용 시에 원료에 대하여 0.01~30중량%, 바람직하게는 0.1~10중량%의 양으로 첨가할 수 있다. 유효성분의 혼합양은 사용목적에 따라 적합하게 결정 될 수 있다. 그러나 건강 및 위생을 목적으로 하거나 건강 조절을 목적으로 하는 장기간의 섭취의 경우에 상기 양은 상기 범위 이하 일 수 있으며, 안정성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용 될 수 있다. 상기 분획물 또는 화학식 1 내지 2의 화합물을 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다.The gold-silver fraction according to the present invention or the compounds of the formulas (1) and (2) may be added to a health supplement or health functional food such as foods, beverages for the purpose of treating or preventing Crohn's disease or ulcerative colitis. In this case, when using the gingival fraction or the compounds of the formulas (1) and (2) as a food additive, it may be added in an amount of 0.01 to 30% by weight, preferably 0.1 to 10% by weight based on the raw material. The amount of the active ingredient to be mixed can be appropriately determined depending on the purpose of use. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, the amount may be less than the above range, and since there is no problem in terms of stability, the active ingredient may be used in an amount exceeding the above range . The fractions or the compounds of the formulas (1) and (2) can be used together with other food or food ingredients and can be suitably used according to conventional methods.
상기 식품의 종류에는 특별한 제한이 없다. 상기 분획물 또는 화학식 1 내지 2의 화합물을 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 초컬릿, 캔디류, 스넥류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함하는 낙농제품, 각종 스프, 음료수, 드링크제, 알코올 음료 및 비타민 혼합제 등이 있으며, 통상적인 의미에서의 건강식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the foods to which the fractions or the compounds of Formulas 1 and 2 can be added include dairy products including meat, sausage, bread, chocolates, candy, snack, pizza, ramen, other noodles, gums, ice cream, Beverages, drinks, alcoholic beverages, and vitamin mixtures, all of which include health foods in the conventional sense.
본 발명의 식품 보존 첨가제는 여러 가지 향미제 또는 천연 탄수화물 등을 사용할 수 있다. 상기 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드, 말토오스, 수크로오스 등과 같은 디사카라이드 및 덱스트린, 시클로덱스트린과 같은 폴리사카라이드, 자일리톨, 솔비톨, 에르트리톨 등의 당알코올이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명에 따른 조성물 100중량부당 일반적으로 약 0.01~0.04중량부, 바람직하게는 0.02~0.03중량부이다. As the food preservative additive of the present invention, various flavors or natural carbohydrates can be used. The natural carbohydrates are sugar saccharides such as monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau Martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01 to 0.04 part by weight, preferably 0.02 to 0.03 part by weight per 100 parts by weight of the composition according to the present invention.
상기 외에 본 발명에 따른 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 중점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 첨가제의 비율은 크게 중요하지 않지만 본 발명에 따른 조성물 100중량부당 0.001~1중량부의 범위에서 선택되는 것이 일반적이다.
In addition to the above, the composition according to the present invention may further comprise various nutrients, vitamins, electrolytes, flavors, colorants, pect and its salts, alginic acid and its salts, organic acids, protective colloid concentrating agents, pH adjusting agents, stabilizers, preservatives, , A carbonating agent used in carbonated drinks, and the like. These components can be used independently or in combination, and the proportion of the additive is not critical, but is generally selected in the range of 0.001 to 1 part by weight per 100 parts by weight of the composition according to the present invention.
본 발명에 따른 금은화 분획물 또는 상기 화학식 1의 3,5-di-CQA, 상기 화학식 2의 4,5-di-CQA로 구성되는 군으로부터 선택되는 하나 이상의 화합물을 유효성분으로 함유하는 조성물은 크론병 또는 궤양성대장염 질환에 대하여 기존의 치료제보다 부작용 없이 동등 이상의 효과를 나타내며, 크론병 또는 궤양성대장염 질환에 대한 우수한 치료 효과를 나타낸다. The composition comprising the gold-silver fraction according to the present invention or at least one compound selected from the group consisting of 3,5-di-CQA of Formula 1 and 4,5-di- Or ulcerative colitis disease without any adverse effects compared with the existing therapeutic agents and exhibits an excellent therapeutic effect on Crohn's disease or ulcerative colitis disease.
본 발명에 따른 추출물 또는 화학식 1 내지 2의 화합물은 크론병 또는 궤양성대장염 치료 및 예방에 유용하게 사용될 수 있다.
The extract according to the present invention or the compounds of the formulas (1) and (2) can be usefully used for the treatment and prevention of Crohn's disease or ulcerative colitis.
도 1은 TNBS로 유도된 염증성 장질환 동물에 금은화 추출물을 처리한 후 얻어진, 대장의 염증 면적 측정 결과이다.
도 2는 금은화 추출물이 TNBS로 유도된 염증성 장질환 동물모델에서의 IL-1β 활성에 미치는 영향을 측정한 결과이다.
도 3은 TNBS로 유도된 염증성 장질환 동물에 금은화 추출물을 처리한 후 얻어진, 대장 길이와 적출 사진이다.FIG. 1 shows the result of measuring the inflammation area of the large intestine obtained after treating the TNBS-induced inflammatory bowel disease animal with Gingko nail extract.
Fig. 2 shows the results of measuring the effect of Ganoderma lucidum extract on IL-1? Activity in an TNBS-induced inflammatory bowel disease animal model.
Fig. 3 is a photograph of the colon length and the extract obtained after treating the TNBS-induced inflammatory bowel disease animal with Ganoderma lucidum extract.
이하, 본 발명을 실시 예를 통하여 상세히 설명한다. 단, 하기의 실시 예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기의 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.
<< 실시예Example 1> 금은화 에탄올 추출물의 제조 1> Preparation of Ganoderma lucidum ethanol extract
본 발명에 사용된 금은화는 꽃이 피기전 꽃봉오리 건조물로서, 분쇄하여 얻은 분말을 적당한 크기로 세절하여 추출용기에 1 ㎏을 넣고 70% 에탄올 용매 10 L를 가하여 60 ℃에서 6시간 동안 교반하면서 추출하였고, 여과지로 여과하여 추출물을 얻었다. 추출과정을 3회 반복하였고, 이후 용매를 감압 농축 및 건조하여 300 g의 에탄올 추출물을 얻었다.The powder of the granule used in the present invention was dried before blossoming. The powder obtained by pulverization was pulverized to an appropriate size, and 1 kg of the powder was added to the extraction vessel. 10 L of 70% ethanol solvent was added thereto, and the mixture was stirred at 60 캜 for 6 hours And filtered through a filter paper to obtain an extract. The extraction procedure was repeated three times, and then the solvent was concentrated under reduced pressure and dried to obtain 300 g of ethanol extract.
<< 실시예Example 2> 금은화 추출물의 에틸아세테이트 2 > Ethyl acetate 분획물Fraction 제조 Produce
상기 실시예 1의 에탄올 추출물에 물 3L를 가하여 현탁시킨 다음 에틸아세테이트 3 L를 가하여 3회 반복 추출한 후 여과지를 사용하여 감압여과 한 후 얻은 에틸아세테이트 추출물의 용매를 제거 한 후 잔사로서 에틸아세테이트 분획물 30 g을 얻었다.The ethanol extract of Example 1 was suspended in 3 L of water and then extracted 3 times with 3 L of ethyl acetate. The extract was filtered under reduced pressure using a filter paper. The solvent of the obtained ethyl acetate extract was removed, and ethyl acetate fraction 30 g.
<< 실시예Example 3> 금은화 추출물의 3> 부탄올Butanol 분획물Fraction 제조 Produce
상기 실시예 1의 에탄올 추출물에 물 3 L를 가하여 현탁시킨 다음 부탄올 3 L를 가하여 3회 반복 추출한 후 여과지를 사용하여 감압여과 한 후 얻은 부탄올 추출물의 용매를 제거 한 후 잔사로서 부탄올 분획물 75 g을 얻었다.The ethanol extract of Example 1 was suspended in 3 L of water and then 3 L of butanol was added 3 times. The mixture was repeatedly extracted three times. The mixture was filtered under reduced pressure using a filter paper. The solvent of the butanol extract was removed, and 75 g of butanol fraction .
<실시예 4> 금은화 분획물로부터 페놀성 화합물의 제조Example 4: Preparation of phenolic compounds from gold-silver fraction
(실시예 4-1) 3,5-di-CQA의 제조(Example 4-1) Preparation of 3,5-di-CQA
상기 실시예 2에서 수득한 에틸아세테이트 분획물에 100% 에탄올을 이동상으로 하여 HP-20 컬럼을 이용한 크로마토그래피를 수행하여 분획물(subfraction) 1 내지 4를 수득하였다. 상기 분획물 중 분획물 3을 에탄올에 녹인 후, 고속액체크로마토그래피를 수행하여 3,5-di-CQA를 얻었다. 이때 이동상으로 물과 아세토니트릴을 혼합용매를 사용하였고, 50분 동안 0부피%에서 20부피% 아세토니트릴로 순차적으로 극성을 주어 농도구배 하였고, 유속은 10 mL/분, Capcell pak UG120 (6.0ㅧ150㎜, 5㎛) 컬럼을 사용하였다.The ethyl acetate fraction obtained in Example 2 was subjected to chromatography using an HP-20 column with 100% ethanol as a mobile phase to obtain fractions 1 to 4. After fraction 3 of the fraction was dissolved in ethanol, high performance liquid chromatography was performed to obtain 3,5-di-CQA. At this time, a mixed solvent of water and acetonitrile was used as a mobile phase, and the concentration was gradually adjusted with polarity from 0 vol% to 20 vol% acetonitrile for 50 minutes. The flow rate was 10 mL / min, Capcell pak UG120 Mm, 5 탆) column was used.
3,5-di-CQA 화합물: 1H-NMR (CD3OD) δ 2.11-2.34(4H, m, H-2,6), 3.95 (1H, dd, J=3.0, 7.8Hz, H-4), 5.37-5.44 (2H, m, H-3,5), 6.26, 6.36 (1H each, J=15.9Hz, H-8', 8"), 6.77 (2H, d, J=7.8Hz, H-5',5"), 6.96 (2H, dd, J=2.1, 8.1Hz, H-6', 6"), 7.05, 7.06 (1H each, d, J=2.1Hz, H-2', 2"), 7.57, 7.61 (1H each, d, J=15.9Hz, H-7', 7")3,5-di-CQA Compound: 1 H-NMR (CD 3 OD)? 2.11-2.34 (4H, m, H-2,6), 3.95 (1H, dd, J = 3.0, 7.8 Hz, ), 5.37-5.44 (2H, m, H-3,5), 6.26, 6.36 (1H each, J = 15.9Hz, H-8 ', 8 "), 6.77 (2H, d, J = 7.8Hz, H -5 ', 5 "), 6.96 (2H, dd, J = 2.1, 8.1Hz, H-6', 6"), 7.05, 7.06 (1H each, d, J = 2.1Hz, H-2 ', 2 ), 7.57, 7.61 (1H each, d, J = 15.9 Hz, H-7 ', 7 "
13C-NMR (125MHz, CD3OD) δ 36.3 (C-2), 38.2 (C-6), 71.1 (C-4), 72.0 (C-5), 72.9 (C-3), 75.2 (C-1), 115.1, 115. 2 (C2', 2"), 115.3, 115.5 (C-8', 8"), 116.5 (C-5', 5"), 123.0, 123.1 (C-6', 6"), 127.7, 127.8 (C-1', 1"), 146.6 (C-3', 3"), 147.0, 147.2 (C-7', 7"), 149.3, 149.4 (C-4', 4"), 168.5, 168.9 (C-9', 9"), 178.1 (COOH) 13 C-NMR (125MHz, CD 3 OD) δ 36.3 (C-2), 38.2 (C-6), 71.1 (C-4), 72.0 (C-5), 72.9 (C-3), 75.2 (C (C-8 '), 116.5 (C-5', 5 "), 123.0, 123.1 (C-6 ' (C-1 ', 1''), 146.7 (C-3', 3 "), 147.0, 147.2 4 "), 168.5, 168.9 (C-9 ', 9"), 178.1 (COOH)
(실시예 4-2) 4,5-di-CQA의 제조(Example 4-2) Preparation of 4,5-di-CQA
상기 실시예 2에서 수득한 에틸아세테이트 분획물에 100% 에탄올을 이동상으로 하여 HP-20 컬럼을 이용한 크로마토그래피를 수행하여 분획물(subfraction) 1 내지 4를 수득하였다. 상기 분획물 중 분획물 3을 에탄올에 녹인 후, 고속액체크로마토그래피를 수행하여 4,5-di-CQA를 얻었다. 이때 이동상으로 물과 아세토니트릴을 혼합용매를 사용하였고, 50분 동안 0 부피%에서 20 부피% 아세토니트릴로 순차적으로 극성을 주어 농도구배 하였고, 유속은 10mL/분, Capcell pak UG120 (6.0ㅧ150㎜, 5㎛) 컬럼을 사용하였다.The ethyl acetate fraction obtained in Example 2 was subjected to chromatography using an HP-20 column with 100% ethanol as a mobile phase to obtain fractions 1 to 4. After fraction 3 of the fraction was dissolved in ethanol, high performance liquid chromatography was performed to obtain 4,5-di-CQA. At this time, a mixed solvent of water and acetonitrile was used as a mobile phase, and concentration gradient was performed with polarity gradually from 0 vol% to 20 vol% acetonitrile for 50 minutes. The flow rate was 10 mL / min, Capcell pak UG120 , 5 탆) column was used.
4,5-di-CQA 화합물: 1H-NMR (500MHz, CD3OD) δ 1.98-2.30 (4H, m, H-2, 6), 4.33 (1H, br s, H-3), 5.10 (1H, dd, J=2.6, 9.5Hz, H-4), 5.65 (1H, m, H-5), 6.19, 6.27 (1H each, d, J=15.9Hz, H-8', 8"), 6.72, 6.73 (1H each, d, J=8.1Hz, H-5', 5"), 6.88, 6.90 (1H each, dd, J=1.8, 8.1Hz, H-6', 6"), 6.99, 7.01 (1H each, d, J=1.8Hz, H-2', 2"), 7.50, 7.58 (1H each, d, J=15.9Hz, H-7', 7")4,5-di-CQA Compound: 1 H-NMR (500 MHz, CD 3 OD)? 1.98-2.30 (4H, m, H-2, 6), 4.33 (1H, br s, 1H, dd, J = 2.6, 9.5Hz, H-4), 5.65 (1H, m, H-5), 6.19, 6.27 (1H each, d, J = 15.9Hz, H-8 ', 8 "), 6.72, 6.73 (1H each, d, J = 8.1 Hz, H-5 ', 5''), 6.88, 6.90 (1H each, dd, J = 1.8, 8.1 Hz, H- D, J = 15.9 Hz, H-7 ', 7 "), 7.01 (1H each, d, J = 1.8 Hz, H-
13C-NMR (125MHz, CD3OD) δ 76.1 (C-1), 38.3 (C-2), 69.8 (C-3), 75.8 (C-4), 69.0 (C-5), 39.8 (C-6), 127.3, 127.4 (C-1', 1"), 146.5 (C-3', 3"), 149. 4 (C-4'. 4"), 116.1 (C-5', 5"), 122.9 (C-6', 6"), 147.2, 147.3 (C-7', 7"), 114.4 (C-8', 8"), 168.1, 168.3 (C-9', 9") 13 C-NMR (125MHz, CD 3 OD) δ 76.1 (C-1), 38.3 (C-2), 69.8 (C-3), 75.8 (C-4), 69.0 (C-5), 39.8 (C C-4 '), 116.1 (C-5', 5 ''), 146.4 (C- ), 122.9 (C-6 ', 6 "), 147.2, 147.3 (C-7', 7"
<실험예 1> 금은화 추출물의 크론병 또는 궤양성대장염에 대한 약효실험<Experimental Example 1> Experimental study on Crohn's disease or Ulcerative Colitis of Gold Euphoria Extract
7주령 된 Sprague Dawley(SD) 랫트 오리엔트 바이오 코리아(Orient bio korea)로부터 구입하여 일반 고형사료로 안정화시킨 후, 염증성 장 질환 약효 시험에 이용하였다. 실험 기간 중 사료와 물을 자유로이 공급하였고, 사육실의 온도는 20ㅁ2 ℃, 상대습도 50ㅁ20%로 유지하였다. 실험군은 각 군당 8마리로 하여 평균체중이 220ㅁ20g이 되도록 난괴법(randomized block design)에 의하여 4군으로 나누었다. Seven-week-old Sprague Dawley (SD) rats were purchased from Orient bio Korea and stabilized with common solid feeds and used in inflammatory bowel disease drug efficacy studies. During the experimental period, feed and water were freely supplied, and the temperature of the breeding room was kept at 20 ° C and 2 ° C and relative humidity of 50 ° C and 20%. The experimental group was divided into 4 groups according to the randomized block design so that the average body weight was 220 and 20 g per 8 groups.
24시간 절식한 SD 랫트를 디에틸에테르로 마취한 후, 폴리에틸렌 카테터를 1㎖ 시린지를 이용하여, 결장(colon)의 강(lumen)에 50% (v/v) 에탄올로 희석한 2.5% 트리니트로벤젠 술폰산(trinitrobenzene sulfonic acid, TNBS) 0.5 ㎖을 천천히 주입한 후, 항문으로 2.5% TNBS가 새어나오는 것을 방지하기 위하여 랫트를 거꾸로 세워 마취가 깰 때까지 정치시켰다. TNBS 투여 후 4일 동안 실시예 2의 금은화 추출물을 50 ㎎/㎏, 3,5-di-CQA 10 ㎎/㎏, 4,5-di-CQA 10 ㎎/㎏으로 각각 경구 투여하였다. 또한 염증성 장 질환 치료제로 알려진 설파살라진(sulfasalazine)의 활성 대사체인 5-ASA(5-아미노살리실산)를 양성대조군으로 100 ㎎/㎏ 경구투여하였다. SD rats fasted for 24 hours were anesthetized with diethyl ether. Then, the polyethylene catheter was placed in a lumen of a colon using a 1 ml syringe, using 2.5% trinitrobenzene diluted with 50% (v / v) ethanol After 0.5 ml of sulfonic acid (trinitrobenzene sulfonic acid, TNBS) was slowly injected, the rat was inverted to prevent 2.5% TNBS from leaking into the anus and allowed to stand until the anesthesia was awakened. Kg of 3,5-di-CQA and 10 mg / kg of 4,5-di-CQA, respectively, for 4 days after the administration of TNBS. 5-ASA (5-aminosalicylic acid), an active metabolite of sulfasalazine known as an agent for the treatment of inflammatory bowel disease, was orally administered at a dose of 100 mg / kg as a positive control.
<실험예 2> 랫트의 TNBS 모델 내 염증면적 측정실험<Experimental Example 2> Measurement of inflammation area in a rat TNBS model
트리니트로벤젠 술폰산(trinitrobenzene sulfonic acid, TNBS) 투여 4일 후에 해부하여 항문에서 맹장까지 절개하여 대장점막 손상을 관찰한 결과는 도 1과 같다. 대장을 펼친 후에 실체현미경 (×10)으로 대장병변의 면적(㎟)을 측정하고 하기의 수학식을 이용하여 대장병변 치료율을 계산하였다.After 4 days of administration of trinitrobenzene sulfonic acid (TNBS), dissection was performed and an incision was made from the anus to the cecum to observe damage to the colon mucosa. After expanding the large intestine, the area (mm 2) of the colon lesion was measured with a stereomicroscope (× 10) and the colonic lesion cure rate was calculated using the following equation.
도 1에서 알 수 있는 바와 같이, 실시예 2의 금은화 추출물 50 ㎎/㎏ 투여 용량에서 TNBS에 의한 대장의 손상을 약 43% 억제하였으며 5-ASA를 경구투여 한 것 보다 우수한 경향을 확인하였다. 또한 3,5-di-CQA 10 ㎎/㎏, 4,5-di-CQA 10 ㎎/㎏ 투여 용량에서 TNBS에 의한 대장의 손상을 우수하게 억제하는 것을 관찰하였다.As can be seen from FIG. 1, the inhibition of TNBS-induced intestinal damage by about 43% was observed at a dose of 50 mg / kg of the Euglena extract of Example 2, which was superior to that of 5-ASA administered orally. It was also observed that TNBS-induced colonic injury was excellently suppressed at a dose of 10 mg / kg of 3,5-di-CQA and 10 mg / kg of 4,5-di-CQA.
<실험예 3> IL-1β의 활성 측정<Experimental Example 3> Measurement of activity of IL-1?
실험동물 부검 후 식도조직을 취한 뒤 10배수의 homogenizing buffer를 넣어 준 후 호모게나이저(homogenizer)로 파쇄시킨다. 10,000rpm에서 10분간 원심분리하여 균질화 조직액(상층액)을 분리한 후, 조직 내 IL-1β의 활성을 측정하였다. IL-1β의 활성의 측정은 고마바이오에서 구입한 Elisa kit를 통하여 분석 하였으며, ELISA Reader(Bio-Rad)를 통하여 detection하였다.After the autopsy, the esophageal tissue is taken, and 10 times more homogenizing buffer is added, followed by disruption with a homogenizer. After centrifugation at 10,000 rpm for 10 minutes, the homogenized tissue solution (supernatant) was separated and the activity of IL-1 beta in the tissue was measured. The activity of IL-1β was assayed by ELISA kit purchased from Gomavio and detected by ELISA Reader (Bio-Rad).
※ Homogenizing buffer(pH7.4) : 1.15% KCl, 50 mM Tris-HCl, 1mM EDTA* Homogenizing buffer (pH 7.4): 1.15% KCl, 50 mM Tris-HCl, 1 mM EDTA
도 2에서 알 수 있는 바와 같이 TNBS에 의해 증가된 조직 내 IL-1β의 activity를 실시예 2의 금은화 추출물 50 ㎎/㎏ 투여 용량에서 약 37% 유의적으로 억제하였다. 또한 3,5-di-CQA 10 ㎎/㎏, 4,5-di-CQA 10 ㎎/㎏ 투여 용량에서 TNBS에 의해 증가된 IL-1β의 activity 활성을 억제하는 것을 관찰하였다.As can be seen in FIG. 2, the activity of IL-1β increased by TNBS significantly inhibited the activity of IL-1β by about 37% at the dose of 50 mg / kg of the Euglena extract of Example 2. In addition, we observed that the inhibitory activity of IL-1β increased by TNBS at a dose of 10 mg / kg of 3,5-di-CQA and 10 mg / kg of 4,5-di-CQA.
<실험예 4> 대장 길이의 측정<Experimental Example 4> Measurement of colon length
트리니트로벤젠 술폰산(trinitrobenzene sulfonic acid, TNBS) 투여 4일 후에 해부하여 항문에서 맹장까지 절개하여 사진 촬영을 한 결과는 도 3 같고, 항문에서부터 맹장(cecum) 까지의 장 길이(colon length)를 측정한 결과는 도 3과 같다. 5% TNBS로 대장염을 유발시킨 랫트의 대장은 정상대조군에 비하여 현저히 짧아지고 충혈도 관찰되었으나, 실시예 2의 금은화 추출물 50 ㎎/㎏ 투여 용량에서 대장의 길이는 약 20% 유의적으로 증가시킴을 알 수 있다. 또한 3,5-di-CQA 10 ㎎/㎏, 4,5-di-CQA 10 ㎎/㎏ 투여 용량에서 대장의 길이를 증가시키는 효과를 관찰하였다.After 4 days of administration of trinitrobenzene sulfonic acid (TNBS), dissection was performed and the photograph was taken from the anus to the appendix. The result was as shown in Fig. 3, and the length of the colon from the anus to the cecum was measured Is shown in FIG. The colony of 5% TNBS-induced colitis in rats was markedly shortened and hyperemic compared to the normal control group, but the length of the colon was significantly increased at a dose of 50 mg / kg of the Euglena extract of Example 2 by about 20% Able to know. In addition, the effects of increasing the length of the colon in the dose of 10 mg / kg of 3,5-di-CQA and 10 mg / kg of 4,5-di-CQA were observed.
<약학적 제제예>≪ Example of pharmaceutical preparation >
(제제예 1) 금은화 에틸아세테이트 분획물의 산제 제조 (Formulation Example 1) Powdered ethyl acetate fraction
실시예 2의 금은화 에틸아세테이트 분획물 20 ㎎, 20 mg of the germanium ethyl acetate fraction of Example 2,
유당 100 ㎎,
탈크 10 ㎎10 mg of talc
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above components are mixed and filled in airtight bags to prepare powders.
(제제예 2) 정제의 제조(Formulation Example 2) Preparation of tablets
실시예 2의 금은화 에틸아세테이트 분획물 10 ㎎10 mg of the germanium ethyl acetate fraction of Example 2
옥수수전분 100 ㎎
유당 100 ㎎
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
(제제예 3) 캅셀제의 제조(Formulation Example 3) Preparation of capsule
실시예 2의 금은화 에틸아세테이트 분획물 10 ㎎10 mg of the germanium ethyl acetate fraction of Example 2
결정성 셀룰로오스 30 ㎎
락토오스 14.8 ㎎Lactose 14.8 mg
마그네슘 스테아레이트 0.2 ㎎0.2 mg of magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
(제제예 4) 주사제의 제조(Formulation Example 4) Preparation of injections
실시예 2의 금은화 에틸아세테이트 분획물 10 ㎎10 mg of the germanium ethyl acetate fraction of Example 2
만니톨 180 ㎎180 mg mannitol
주사용 멸균 증류수 2974 ㎎2974 mg of sterile distilled water for injection
Na2HPO4,12H2O 26 ㎎Na 2 HPO 4 , 12 H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.(2 ml) per ampoule in accordance with the usual injection method.
(제제예 5) 액제의 제조예(Formulation Example 5) Production example of liquid agent
실시예 2의 금은화 에틸아세테이트 분획물 20 ㎎20 mg of the germanium ethyl acetate fraction of Example 2
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량 Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음, 상기의 성분을 혼합한 후 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed and purified water was added thereto to adjust the total volume to 100 ml. The mixture was filled in a brown bottle and sterilized, .
<식품 제조예> <Example of food production>
(식품제조예 1) 음료의 제조(Food Preparation Example 1) Production of beverage
꿀 522 ㎎Honey 522 mg
치옥토산아미 5 ㎎5 mg of chitosanic acid ami
니코틴아미드 10 ㎎
염산리보플라빈나트륨 3 ㎎3 mg of sodium riboflavin hydrochloride
염산피리독신 3 ㎎Pyridoxine hydrochloride 3 mg
이노시톨 30 ㎎
오르트산 50 ㎎Orthoic acid 50 mg
금은화 에틸아세테이트 분획물 100 ㎎100 mg of gum ethoxide ethyl acetate fraction
정제수 200 mLPurified water 200 mL
상기 조성 및 함량으로 하여 통상적인 방법을 사용하여 음료를 제조하였다.A beverage was prepared using the above-mentioned composition and content by a conventional method.
(식품제조예 2) 비타민 혼합제(Food Preparation Example 2) Vitamin blend
금은화 초산 에틸 분획물 100 ㎎100 mg of the germanium ethyl acetate fraction
페놀산 화합물 100 ㎎Phenolic acid compound 100 mg
비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎0.13 mg vitamin B1
비타민 B2 0.15 ㎎0.15 mg of vitamin B2
비타민 B6 0.2 ㎍0.2 [mu] g vitamin B6
비타민 C 10 ㎎10 mg vitamin C
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 50 ㎍50 ㎍ of folic acid
판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg
황산 제1철 1.75 ㎎1.75 mg of ferrous sulfate
산화아연 0.82 ㎎0.82 mg of zinc oxide
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎15 mg of potassium phosphate monobasic
제2인산칼륨 55 ㎎55 mg of potassium secondary phosphate
구연산칼륨 90 ㎎Potassium citrate 90 mg
탄산칼슘 100 ㎎100 mg of calcium carbonate
염화마그네슘 24.8 ㎎24.8 mg of magnesium chloride
상기의 비타민 및 미네랄 혼합물은 비교적 건강식품에 적합한 성분으로 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하며, 통상의 건강식품 제조 방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.The above-mentioned vitamin and mineral mixture is a component suitable for relatively healthy food, and is mixed with a preferred embodiment. However, the compounding ratio is arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing health food, , And can be used in the manufacture of a health food composition according to a conventional method.
Claims (3)
As an extract of C1-C4 alcohol or 50-100% C1-C4 alcohol in Lonicerae Flos, 3,5-di-O-caffeoylquinic acid of the following formula 1 or 4,5-di-O - A pharmaceutical composition for the treatment or prevention of Crohn's disease or ulcerative colitis, which comprises caffeic oil quinic acid as an active ingredient.
상기 약학 조성물은 크론병 또는 궤양성대장염 치료제인 설파살라진, 부데소니드, 메살라민, 주캅사이신, 사그라모스팀, 니타족사니드, 프레드니솔론, 나탈리주마브, 아달리무마브 중에서 선택된 1종 이상 약물을 추가로 함유된 것을 특징으로 하는 크론병 또는 궤양성대장염 치료 또는 예방용 약학 조성물.
The method according to claim 1,
The pharmaceutical composition may further comprise at least one drug selected from the group consisting of sulfasalazine, budesonide, mesalamine, capsaicin, saglamostim, nitazonide, prednisolone, natalizumab and adalimumab, which are therapeutic agents for Crohn's disease or ulcerative colitis. ≪ / RTI > or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of Crohn's disease or ulcerative colitis.
As an extract of C1-C4 alcohol or 50-100% C1-C4 alcohol in Lonicerae Flos, 3,5-di-O-caffeoylquinic acid of the following formula 1 or 4,5-di-O - a health functional food composition for improving or preventing Crohn's disease or ulcerative colitis, which comprises caffeic oil quinic acid as an active ingredient.
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Cited By (4)
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KR20180119508A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
KR20180119507A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
KR20180119506A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
WO2021034139A3 (en) * | 2019-08-22 | 2021-04-15 | (주)녹십자웰빙 | Functional food composition for alleviation of irritable bowel syndrome |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20180119508A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
KR20180119507A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
KR20180119506A (en) * | 2017-04-25 | 2018-11-02 | 대구한의대학교산학협력단 | A composition comprising mixture of the herb extract and sulfasalazine for preventing or treating colitis |
WO2021034139A3 (en) * | 2019-08-22 | 2021-04-15 | (주)녹십자웰빙 | Functional food composition for alleviation of irritable bowel syndrome |
CN114786503A (en) * | 2019-08-22 | 2022-07-22 | 绿十字生命健康有限公司 | Functional food composition for relieving irritable bowel syndrome |
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