KR20120045591A - Composition comprising an combined herb extract including rhei radix et rhizoma for treating or preventing cognitive dysfunction - Google Patents
Composition comprising an combined herb extract including rhei radix et rhizoma for treating or preventing cognitive dysfunction Download PDFInfo
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- KR20120045591A KR20120045591A KR1020100107222A KR20100107222A KR20120045591A KR 20120045591 A KR20120045591 A KR 20120045591A KR 1020100107222 A KR1020100107222 A KR 1020100107222A KR 20100107222 A KR20100107222 A KR 20100107222A KR 20120045591 A KR20120045591 A KR 20120045591A
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- South Korea
- Prior art keywords
- extract
- rhubarb
- disease
- gall bladder
- cognitive dysfunction
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Abstract
Description
본 발명은 대황, 소목, 및 오배자 생약조합을 이용한 인지기능 장애의 예방 및 치료용 조성물에 관한 것이다. The present invention relates to a composition for the prevention and treatment of cognitive impairment using rhubarb, joiner, and gall bladder herbal combination.
[문헌 1] 미국제약협회 2009년 통계, (www.pharmafoundation.org)[Reference 1] American Pharmaceutical Association 2009 Statistics, (www.pharmafoundation.org)
[문헌 2] Greig et al., J. Med. Chem. 44, pp.4062-4071, 2001; Medical News Today 2004년 9월 4일 기사, www.medicalnewstoday.com; 미국 알츠하이머 협회 홈페이지, www.alzforum.org/drg/drc[2] Greig et al., J. Med. Chem. 44 , pp. 4042-4071, 2001; Medical News Today September 4, 2004 article, www.medicalnewstoday.com; American Alzheimer's Association website, www.alzforum.org/drg/drc
[문헌 3] Nature Review Drug Discovery (2007) 6, 341Nature Review Drug Discovery (2007) 6, 341
[문헌 4] 中華本草編纂委:中華本草,上海科學技術出版社, 제2권. p710,715~716,1996[Ref. 4] Naka-Kawamoto-cho, Nagasaki-cho, Nagasaki-chogawa, Vol. 2, Vol. p710,715 ~ 716,1996
[문헌 5] 김창민 외, 중약대사전, 도서출판 정담, pp.3130, 1998[Document 5] Kim, Min-Min et al., Chinese Medicine Dictionary, Book Publishing Jungdam, pp.3130, 1998
[문헌 6] 정보섭 외, 향약대사전,99.pp.380~384, 영림사, 1998[Ref. 6] Jung-Seop et al, 99.pp.380 ~ 384, Yeonglimsa, 1998
[문헌 7] KIM Hee et al, Effects of Naturally Occurring Compounds on Fibril Formation and Oxidative Stress of beta-Amyloid, Journal of Agricultural and Food Chemistry (2005) 53, pp.8537-8541KIM Hee et al, Effects of Naturally Occurring Compounds on Fibril Formation and Oxidative Stress of beta-Amyloid, Journal of Agricultural and Food Chemistry (2005) 53 , pp.8537-8541
[문헌 8] Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005 ; 280 (7 ): 5892-901.[Reference 8] Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem. 2005; 280 (7): 5892-901.
[문헌 9] Behl C, Widmann M, Trapp T, HolsboerF. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 1995 ;216(2):473-82.9 Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem Biophys Res Commun. 1995; 216 (2): 473-82.
[문헌 10] Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V.Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrolJ Biol Chem. 2001(25):22586-94.Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V. Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol J Biol Chem. 2001 (25): 22586-94.
[문헌 11] Tsai KJ, Tsai YC, Shen CK.G-CSF rescues the memory impairment of animal models of Alzheimer's disease.J Exp Med. 2007;204(6):1273-80.[11] Tsai KJ, Tsai YC, Shen CK.G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J Exp Med. 2007; 204 (6): 1273-80.
[문헌 12] Laursen, S.E., Belknap, J.K., 1986. Intracerebroventricular injections in mice. Some methodological refinements. J. Pharmacol. Methods 16, 355- 35712 Laursen, S.E., Belknap, J.K., 1986. Intracerebroventricular injections in mice. Some methodological refinements.
[문헌 13] Yamaguchi Y et el ., Effects of a novel cognitive enhancer,spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on learning impairments induced by amyloid-beta 1-40 in the rat. J Pharmacol ., 317(3), pp.1079-87, 2006[Reference 13] Yamaguchi Yet el ., Effects of a novel cognitive enhancer, spiro [imidazo- [1,2-a] pyridine-3,2-indan] -2 (3H) -one (ZSET1446), on learning impairments induced by amyloid-beta 1-40 in the rat.J Pharmacol ., 317 (3), pp. 1079-87, 2006
[문헌 14] MA Chacon, MI Barria, C Soto and NC Inestrosa. 2004. b-sheet breaker peptide prevents Ab-induced spatial memory impairments with partial reduction of amyloid deposits. Molecular Psychiatry 9, 953-961[14] MA Chacon, MI Barria, C Soto and NC Inestrosa. 2004. b-sheet breaker peptide prevents Ab-induced spatial memory impairments with partial reduction of amyloid deposits. Molecular Psychiatry 9, 953-961
[문헌 15] 한국 특허공개 제10-2008-0032494호[Document 15] Korean Patent Publication No. 10-2008-0032494
[문헌 16] 한국 특허등록 제0725839호[Document 16] Korean Patent Registration No. 0725839
[문헌 17] 한국 특허등록 제0846522호[Document 17] Korean Patent Registration No. 0846522
[문헌 18] 한국 특허등록 제0726266호[Document 18] Korean Patent Registration No. 0726266
[문헌 19] 한국 특허등록 제0699945호[Document 19] Korean Patent Registration No. 0699945
뇌(brain)와 척수(spinal cord)로 구성된 중추신경계는 생명현상을 운영하는 중심센터로서 감각과 (불)수의적인 운동에서부터 사고, 기억, 감정, 언어 등에 이르기까지 인체의 모든 기능을 총괄하는 아주 필수적인 기관이다. 따라서 뇌졸중, 외상 등으로 야기된 급행적인 신경세포의 사멸이나, 알츠하이머병으로 대표되는 노인성 치매, 파킨슨 질환 등과 같은 중추신경계 퇴행성 질환을 유발시키는 서행적인 신경세포의 사멸등과 같은 모든 경우에서는 곧 바로 신경회로망의 비가역적인 기능장애를 초래하게 되며 결국에는 해당 인체 기능의 영구적인 손실을 초래하게 된다. 알츠하이머병으로 대표되는 노인성 치매는 인간 평균수명의 연장과 의료복지시설의 현대화와 맞물려 비례적으로 증가하는 특성을 가지고 있다. 보건사회연구원 통계조사에 따르면 우리나라의 노인인구가 2000년에 7%를 넘어 고령사회에 진입한 이래 2003년 397만 명으로 노인인구의 비율이 8.3%에 이르렀고 2019년에는 14.4%에 이르러 완전고령사회에 진입할 것으로 예견된다. 65세 이상 노인인구 중 한 가지 이상 만성질환을 가지고 있는 노인은 90%에 이르며 특히 65세 이상 노인의 치매 유병율도 8.2%로 추정된다. 서구사회에서는 65세 이상인구의 약 10%, 80세 이상 인구의 약 40 ~ 50%에서 알츠하이머병이 발생하고 있으며, 이미 미국에서는 이 질환 환자가 500만 명 이상으로 이로 인한 의료비 지출이 연간 1000억 달러로 추정되고 있다. 또한 우리나라에서는 약 20만 명 이상이 치매 환자인 것으로 나타났다. 미국의 경우 2030년까지 현재의 2배 규모로 증가하고, 2050년까지는 350% 이상 늘어난 1,400만 명에 달할 것으로 추정되어지고 있다. (미국제약협회 2009년 통계, (www.pharmafoundation.org))The central nervous system, composed of the brain and spinal cord, is the central center for life phenomena and is responsible for all functions of the human body, from sensory and (involuntary) movements to thoughts, memories, emotions, and language. It is an essential organ. Therefore, in all cases such as the rapid death of nerve cells caused by stroke, trauma, or the death of slow neurons that cause central nervous system degenerative diseases such as Alzheimer's disease, senile dementia and Parkinson's disease, etc. This results in irreversible dysfunction of the network and eventually a permanent loss of the human body's function. Geriatric dementia, represented by Alzheimer's disease, has a characteristic of increasing proportionately with the extension of the average human life expectancy and the modernization of medical welfare facilities. According to the statistics of the Korea Institute of Health and Social Affairs, Korea's elderly population exceeded 7% in 2000 and entered the aged society in 2003, reaching 3.97 million in 2003, accounting for 8.3% of the elderly population in 2019 and 14.4% in 2019. It is expected to enter. 90% of the elderly aged 65 or older have chronic disease, and the prevalence of dementia of older than 65 years is 8.2%. In Western society, Alzheimer's disease occurs in about 10% of the population aged 65 and over, and about 40-50% of the population aged 80 and over. Already in the United States, there are more than 5 million people with this disease. It is estimated in dollars. In Korea, more than 200,000 people have dementia. In the United States, it is estimated to reach 14 million people by 2030, more than double the present, and more than 350% by 2050. (American Pharmaceutical Association 2009 Statistics, (www.pharmafoundation.org))
인지 기능 장애로 시작되어지는 알츠하이머병은 인간 본성이 파괴되며 장기간에 걸쳐 진행되는 퇴행성 질환이기 때문에 환자를 수용하는 수동적인 방법으로는 도저히 사회 경제적 부담을 감당할 수가 없으므로 예방제 및 원인 치료제를 개발하는 적극적인 시도를 해야 한다. 그러나 현재까지는 알츠하이머 질환의 근본적인 발병원인을 치료할 수 있는 치료제는 개발되어 있지 않으며, 일반적인 치료제로서 사용 가능한 것으로는 아세틸콜린 에스테라제 저해제인 화이자사의 아리셉트(Aricept), 노바티스사의 엑셀론(Exelon), 그리고 얀센사의 레미닐(Reminyl)과 최근에 미국 FDA로부터 허가를 받은 NMDA수용체의 길항제 기전의 룬드벡사의 에빅사(Ebixa; Memantine)가 있다. 그러나 아세틸콜린 에스테라제 저해제의 경우는 감퇴된 인지 능력을 개선해 줄 뿐 알츠하이머 질환의 근본적인 발병 원인을 치료하지는 못한다. 또한, 단지 일부 환자의 경우 (약 40-50%)에서 일시적인 증세 완화 효과를 보이며, 그 약효가 오래 지속되지 못하므로 근본적인 치료제라 하기 어렵다. 또한 질환의 특성상 장기 복용을 요하게 되는데, 상기 의약품들의 경우 간 독성, 구토, 식욕감퇴를 비롯한 여러 가지 부작용을 수반하는 등의 문제점을 안고 있다. 따라서 질환의 진행 과정을 막아 줄 수 있는 치료제의 개발이 시급한 과제가 되고 있다. 이를 위해서 많은 다국적 제약회사들이 이 분야에 대한 연구 개발에 막대한 투자를 하고 있으며 특히 알츠하이머 질환의 근본적인 발병 원인으로 추정되고 있는 40여개의 아미노산으로 구성된 베타아밀로이드의 생성량을 감소시키는 베타 또는 감마 시크리테아제 저해제의 개발이 그 주종을 이루고 있다. 국내의 경우 알츠하이머 질환에 대한 기초 연구는 어느 정도 이루어지고 있으나 치매 치료제 개발 그 자체의 경우는 거의 전무한 실정이라고 사료된다. 감마 시크리테아제(secretase) 저해제의 경우 동물 실험 모델에서 뿐만 아니라 최근의 임상 실험 결과에서도 상당한 독성을 수반함으로써 그 전망이 불투명하다. 비교적 연구 개발 기간은 상대적으로 짧으나 베타 시크리테아제의 경우에 유전자 결핍 형질 전환 동물모델의 결과에서도 나타난 것처럼 좀 더 안전하고도 효율적인 치매 치료제 개발을 위한 타겟으로써 유망하다고 할 수 있다. 또한 베타아밀로이드의 응집에 관여하는 인자를 타겟으로 하는 것도 비교적 안전하게 효과를 보는 것으로 생각되고 있다. 최근 베타아밀로이드를 타겟으로 하는 신약 개발에서 미국의 앤소닉스사에서 펜세린(Phenserine)이라는 약물에 대해 임상 3상이 진행되었으나 약효가 대조군에 비해 월등하지 않아 진행이 더 이상 되지 않았으나 이 약물은 이중 기능을 가지고 있어 콜린에스테라제(cholineesterase) 저해 효과도 함께 가지고 있는 것으로 보고된 바 있다(Greig et al., J. Med. Chem. 44, pp.4062-4071, 2001; Medical News Today 2004년 9월 4일 기사, www.medicalnewstoday.com; 미국 알츠하이머 협회 홈페이지, www.alzforum.org/drg/drc).Alzheimer's disease, which begins as a cognitive dysfunction, is a degenerative disease that destroys human nature and is a long-term degenerative disease. Therefore, passive methods of accommodating patients cannot afford socioeconomic burdens. Should. However, to date, no therapeutic agents have been developed to treat the underlying cause of Alzheimer's disease.Available as general therapeutic agents are Aricept, Pfizer's Aricept, Novartis's Exelon, and Janssen. Lundbeck's Ebixa (Memantine), a mechanism of antagonists of Reminyl and the recently approved NMDA receptor by the US FDA. However, acetylcholine esterase inhibitors only improve the cognitive ability that has been impaired and do not cure the underlying cause of Alzheimer's disease. In addition, only some patients (approximately 40-50%) show temporary relief of symptoms, and the drug does not last long, and thus is not a fundamental treatment. In addition, the nature of the disease is required to take long-term, the drug has problems such as accompanied by various side effects, including liver toxicity, vomiting, loss of appetite. Therefore, the development of a therapeutic agent that can prevent the progress of the disease is an urgent task. Many multinational pharmaceutical companies are investing heavily in research and development in this area, especially beta or gamma secretase inhibitors, which reduce the production of beta amyloid, which consists of about 40 amino acids that are believed to be the underlying cause of Alzheimer's disease. Development is the dominant. In Korea, basic research on Alzheimer's disease has been conducted to some extent, but there is almost no case in developing dementia treatment itself. Gamma secretase inhibitors are opaque because they involve significant toxicity not only in animal experimental models but also in recent clinical trials. Although the research and development period is relatively short, it is promising as a target for the development of safer and more effective dementia treatment, as shown in the results of the gene deficient transgenic animal model. In addition, targeting a factor involved in the aggregation of beta amyloid is thought to be relatively safe. Recently, in the development of a new drug targeting beta amyloid,
가능성이 있는 다른 방법으로는 베타아밀로이드를 이용한 백신(Vaccine)의 개발이다. 엘란(Elan)회사를 중심으로 진행된 일련의 연구 및 임상의 결과로 베타아밀로이드 펩타이드를 백신으로 이용 가능하다는 결과가 보고되었으나 임상 2상에서 소수의 환자에서 뇌염증 반응이 일어나 중단된 상태이다. 현재 다양한 베타아밀로이드 구조를 이용한 백신 개발이 진행되고 있다. 동물실험의 결과로 베타아밀로이드 백신은 뇌 속에 형성된 노인반의 수를 줄이고 모델동물의 인지능을 향상시키는 것으로 알려졌다. 또한 뇌세포의 활성을 증진하고 손상을 입은 뇌신경세포의 활성을 증진시켜 인지 기능을 향상시킴으로 알츠하이머를 완화할 수도 있다.
Another possibility is the development of a vaccine using beta amyloid. As a result of a series of studies and clinical trials conducted by Elan, it has been reported that beta amyloid peptide can be used as a vaccine, but the encephalitis reaction was stopped in a few patients in phase II. Currently, vaccine development using various beta amyloid structures is in progress. As a result of animal testing, beta amyloid vaccine has been shown to reduce the number of senile plaques formed in the brain and improve the cognition of model animals. It can also alleviate Alzheimer's by enhancing the activity of brain cells and enhancing the activity of damaged brain neurons to improve cognitive function.
따라서, 새로운 기능의 알츠하이머병의 치료제 개발을 위해서는 아세틸콜린 에스테라제 저해 효능 약물에 베타아밀로이드 응집, 독성 저해 효과 및 항산화 효과 등에서의 활성이 확인된다면 매우 우수한 치료약물이 될 수 있을 것으로 판단된다. 이러한 전략은 Datamonitor 등이 제안한 질병의 치료목적과 효능의 극대화를 이룰 수 있을 것으로 생각된다. 치료제 개발은 원인을 제거하는 방법과 기존의 약물과 같은 증상완화제를 동시에 개발하는 것을 알 수 있다(Nature Review Drug Discovery (2007) 6, p.341).Therefore, for the development of a novel therapeutic agent for Alzheimer's disease, if the activity of beta amyloid aggregation, toxic inhibitory effect, and antioxidant effect is identified in the acetylcholine esterase inhibitory drug, it may be a very good therapeutic drug. Such a strategy is expected to maximize the purpose and efficacy of the disease proposed by Datamonitor. The development of therapeutics can be found to simultaneously remove the cause and develop symptomatic relief, such as conventional drugs (Nature Review Drug Discovery (2007) 6 , p.341).
한편, 대황(Rhei Rhizoma)은 마디풀과에 속한 다년생 초본류인 장군풀 및 동속 근연식물의 근 및 근경으로서 약 15종의 식물이 존재하는데, 이중에서도 한국에서는 장군풀(Rheum coreanum Nakail), 종대황(Pheum undulatum Linne) 등의 건조한 근 및 근경을 기원식물로 하고 있으며, 중국에서는 장엽대황(Rheum palmatum Linne), 당고특대황(Pheum tanguticum Maxim) 및 약용대황(Rheum offcinale Baill) 등의 건조한 근 및 근경을 그 기원으로 삼고 있다. 대황의 성분에 대한 연구는 최근까지 계속되고 있으며, 센노사이드 A(sennoside A)에 의한 사하작용, 소화기점막손상방지, 알로에-에모딘(aloe-emodin) 및 레인(rhein)의 항균작용 등이 보고되어 있다(中華本草編纂委:中華本草,上海科學技術出版社, 제2권. p710,715~716,1996). 또한 대황은 임상적으로 소화불량, 변비, 급성염증, 전염병, 기생충병, 출혈, 혈소판 감소증, 화상 및 피부병의 치료에 응용된다.On the other hand, Rhei Rhizoma is a root and rhizome of perennial herbaceous genus Genus herbaceous and related plant of the genus Periaceae, and there are about 15 kinds of plants. Among them, Rheum coreanum Nakail and Pheum undulatum The roots of the roots are the roots of rhizomes and rhizomes, such as Linne.In China, the roots and roots of the root roots of Rheum palmatum Linne, Pheum tanguticum Maxim and Rheum offcinale Baill I'm taking it. Studies on the components of rhubarb continue until recently, and reports on the lowering action of sennoside A, prevention of gastrointestinal mucosa damage, and antibacterial action of aloe-emodin and rhine (中華 本草 編纂 委: 中華 本草, 上海 科學 技術 出版社, Vol. 2, p710, 715-716, 1996). Rhubarb is also clinically used for the treatment of indigestion, constipation, acute inflammation, infectious diseases, parasites, bleeding, thrombocytopenia, burns and skin diseases.
소목(蘇木,Caesalpinia sappan Linne)은 콩과(Leguminosae)에 속하는 식물로 소방목(蘇方木), 소방(蘇方), 적목(赤木), 홍자(紅紫) 등으로 불리고, 한국에는 자생하고 있지 않으며, 중국의 푸젠성(副建省), 광동성(廣東省), 광시성(廣西省), 하이남(海南), 타이완 등에 분포하고 있다. 소목나무의 줄기가 굵은 가지의 속부분(心材)을 소목(蘇木)이라고 하며, 심장과 혈관에 대한 작용, 항균작용 및 중추억제 작용이 있다고 알려져 있다. 소목의 주요성분으로는 브라질린이 알려져 있으며, 브라질린(brazilin)은 공기중에서 산화되어 브라질레인(brazilein)이 되며, 기타 성분으로 알라닌(Alanine), 발린(Valine), 그리신(Glycine), 로이신(Leusine), 이소로이신(Isoleusine), 시스틴(Systine), 라이신(Lysine), 트리프토판(Tryptophan), 프로린(Proline), 드레오닌(Threonine)등의 아미노산(Amino acid)와 갈산(Gallic acid)등의 유기산 및 사파닌(Sappannin)등 다양한 성분이 함유되어 있다.(김창민 외, 중약대사전, 도서출판 정담, pp.3130, 1998)
Caesarpinia sappan Linne is a plant belonging to the legume (Leguminosae), and is called firewood, firefighting, red-eye, red, etc., and is native to Korea. It is distributed in Fujian, Guangdong, Guangxi, Hainan and Taiwan of China. The inner part of the trunk of the coarse tree branch (心 材) is called joiner (蘇木), it is known that the action on the heart and blood vessels, antibacterial action and central inhibition. The main component of joiner is known as brazilin, and brazilin is oxidized in air to become brazilein, and other ingredients are alanine, valine, glycine, leucine ( Amino acid and gallic acid, such as Leusine, Isoleusine, Cystine, Lysine, Tryptophan, Proline, Threonine, etc. It contains various organic acids such as organic acid and sappannin (Kim Changmin et al., Chinese medicinal dictionary, book publishing Jungdam, pp.3130, 1998).
오배자는 옻나무과(Anacardiaceae)에 속하는 붉나무(Rhus javanica L.)의 잎에 오배자진딧물(Aphis chinensis J.Bell)이 자상(刺傷)을 주면서 생긴 벌레집을 말하는데 우리나라의 각지에 분포한다. 형태는 길이 3~7㎝, 폭 2~5㎝, 두께 2㎜로 단단하면서도 쉽게 부숴지고, 외면에 회갈색으로 연한 털이 있다. 속은 대개 비어 있거나 회백색의 죽은 벌레와 분비물이 남아 있을 때도 있고, 역겨운 냄새가 나기도 한다. 오배자의 주성분으로는 피로갈롤 탄닌(pyrogalloltannin)이며 몰식자산, 갈산(Gallic acid)등이 있다.(정보섭 외, 향약대사전,99.pp.380~384, 영림사, 1998)The gall bladder refers to the insect worm house formed by the aphid chinensis J.Bell on the leaves of Rhus javanica L. belonging to the family Anacardiaceae. It is distributed all over Korea. Its shape is 3-7cm long, 2-5cm wide, and 2mm thick, hard and easily crushed, and has light gray hair on the outer surface. The inside is usually empty or grayish white with dead bugs and secretions, sometimes with a disgusting smell. The main components of the gall bladder are pyrogalloltannin, and there are glutaric acid and gallic acid. (Information et al., Hyangjedae, 99.pp.380 ~ 384, Younglimsa, 1998)
본 발명에서는 이미 확립된 스크리닝 방법으로 천연식물로부터 인지 기능 장애의 치료 및 예방 효과를 갖는 물질을 분리하는 목적으로 하여 다양한 천연식물을 스크리닝 하였다. 그 중에서 대황의 다양한 생리활성에 대하여 많은 연구가 이루어져 왔으나 본 발명에서 분리한 피시온류의 화합물의 인지 기능 장애에 대한 생리활성은 본 연구를 통해 규명되어, 관련 특허 출원들을 즉, 한국특허 공개 제10-2008-0032494호 (대황 추출물 또는 이로부터 분리된 피시온 화합물을 유효성분으로 함유하는 인지기능 장애의 예방 또는 치료용 조성물, 출원인; 일성신약(주), 디지털바이오텍); 한국 특허 등록 제0725839호 ( 단삼으로부터 분리된 탄시논류의 화합물을 함유한 인지기능 장애의 예방 및 치료용 조성물, 특허등록자: 일성신약주식회사, (주)디지탈바이오텍, 2007년 5월31일); 한국 특허 등록 제0846522호 (대황으로부터 분리된 피시온 화합물을 유효성분으로 함유하는 인지 기능 장애의 예방 또는 치료용 조성물; 특허등록자: 일성신약주식회사, (주)디지탈바이오텍, 2007년 7월 9일); 한국 특허 등록 제 0726266호 (플라보노이드계 화합물을 함유하는 인지기능 장애의 예방 및 치료용 조성물; 특허등록자: (주)디지탈바이오텍, 2007년 6월 1일); 한국 특허 등록 제0699945호 (나프토퀴논계 화합물을 함유하는 인지기능 장애의 예방 및 치료용 조성물, 특허등록자: (주)디지탈바이오텍, 2007년 3월 20일) 및 문헌 (KIM Hee et al, Effects of Naturally Occurring Compounds on Fibril Formation and Oxidative Stress of beta-Amyloid, Journal of Agricultural and Food Chemistry (2005) 53, pp.8537-8541)을 보고한 바가 있다.In the present invention, various natural plants were screened for the purpose of separating substances having a therapeutic and prophylactic effect of cognitive dysfunction from natural plants by the already established screening method. Among them, many researches have been made on various physiological activities of rhubarb, but the physiological activity of cognitive dysfunction of the compounds of fish species isolated in the present invention has been identified through the present study, and related patent applications, that is, Korean Patent Publication No. 10 -2008-0032494 (compositions for the prevention or treatment of cognitive impairment containing rhubarb extract or psion compound isolated therefrom as an active ingredient, Applicant; Ilsung New Drug Co., Digital Biotech); Korean Patent Registration No. 0725839 (Composition for the Prevention and Treatment of Cognitive Impairment Containing Tanshinone Compounds Isolated from Salvia Militiorrhiza, Patent Registered by Ilsung New Pharmaceutical Co., Ltd., Digital Biotech Co., May 31, 2007); Korean Patent Registration No. 0846522 (A composition for the prevention or treatment of cognitive dysfunction, which contains a pion compound isolated from rhubarb as an active ingredient; Patent registered: Ilsung New Pharmaceutical Co., Ltd., Digital Biotech, July 9, 2007) ; Korean Patent Registration No. 0726266 (composition for the prevention and treatment of cognitive impairment containing flavonoid compound; Patent registered: Digital Biotech Co., Ltd., June 1, 2007); Korean Patent Registration No. 0699945 (composition for the prevention and treatment of cognitive impairment containing naphthoquinone compounds, patentee: Digital Biotech Co., March 20, 2007) and literature (KIM Hee et al, Effects of Naturally Occurring Compounds on Fibril Formation and Oxidative Stress of beta-Amyloid, Journal of Agricultural and Food Chemistry (2005) 53 , pp.8537-8541).
따라서 이에 본 발명자들은, 대황으로부터 분리된 피시온류의 화합물을 포함하는 추출물과 기타 항산화 효과와 아세틸콜린 에스테라제 저해 효능을 갖는 기타 생약 추출물을 조합하여 보다 진보된 형태의 알츠하이머병 치료 및 예방제를 개발하고자 항산화 효능과 아세틸콜린 에스테라제 저해 효과가 탁월한 오배자 및 베타아밀로이드 응집 저해, 독성 저해 뿐만 아니라 아세틸 콜린 에스테라제 저해 효능을 갖는 소목을 조합하여 이 조합물들의 상승효과가 이용하여 알츠하이머병의 치료 및 예방제를 개발하고자 다양한 기억 학습 모델을 이용하여 동물에서 인지 기능의 향상과 베타아밀로이드 독성을 저해하는 효능을 확인하여 본 발명을 완성하였다. Therefore, the present inventors have developed a more advanced form of treatment and prevention of Alzheimer's disease by combining an extract containing a compound of psions isolated from rhubarb and other herbal extracts having other antioxidant and acetylcholine esterase inhibitory effects. Treatment of Alzheimer's disease using the synergistic effect of these combinations by combining gall bladder with excellent antioxidant and acetylcholine esterase inhibitory effects and joining with beta amyloid aggregation inhibitory effect and toxicity inhibition as well as acetylcholine esterase inhibitory effect And to develop a preventive agent using a variety of memory learning model to confirm the efficacy of improving cognitive function and inhibiting beta amyloid toxicity in animals to complete the present invention.
본 발명은 대황, 소목, 및 오배자의 생약조합 추출물을 함유한 인지 기능 장애의 예방 및 치료용 조성물을 제공하는 것이다.The present invention is to provide a composition for the prevention and treatment of cognitive impairment containing rhubarb, joiner, and medicinal herb combination extracts.
또한 본 발명은 대황, 소목, 및 오배자의 생약조합 추출물을 함유한 인지 기능 장애의 예방 및 치료제로서의 용도를 제공하는 것이다.The present invention also provides a use as a prophylactic and therapeutic agent for cognitive impairment containing rhubarb, lumberjack, and medicinal herb combination extracts of the quintet.
상기 목적을 달성하기 위하여, 본 발명은 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물을 유효성분으로 함유하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물을 제공한다. In order to achieve the above object, the present invention is a disease of cognitive impairment related disease containing beta amyloid coagulation inhibitory effect and memory learning recovery effect rhubarb and soybean or a combination of one or more herbal medicines selected from galleng as an active ingredient It provides a pharmaceutical composition for the prevention and treatment.
구체적으로, 본 발명은 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황, 소목 및 오배자의 생약조합 추출물을 유효성분으로 함유하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물을 제공한다. Specifically, the present invention provides a pharmaceutical composition for the prevention and treatment of diseases related to cognitive dysfunction, which contains the extract of the combination of rhubarb, lumber and gall bladder having the effect of inhibiting beta amyloid aggregation and memory learning recovery as an active ingredient.
본원에서 정의되는 “생약조합”은 대황, 소목 및 오배자의 건조 중량 배합비가 바람직하게는, 대황 1-20: 소목 1-5: 및 오배자 1-5 (w/w), 보다 바람직하게는 대황 2-10: 소목 1-3: 및 오배자 1-3 (w/w), 보다 더 바람직하게는, 대황 2-6: 소목 1-2: 및 오배자 1-2 (w/w)로 배합된 조합을 포함한다.As defined herein, the “medicinal herb combination” is preferably a dry weight compounding ratio of rhubarb, joiner and gall, preferably rhubarb 1-20: joiner 1-5: and gall bladder 1-5 (w / w), more preferably rhubarb 2 -10: a combination formulated with joiner 1-3: and blastane 1-3 (w / w), even more preferably rhubarb 2-6: joiner 1-2: and blastula 1-2 (w / w) Include.
또한 , 본원에서 정의되는 개개 생약 중, “대황 추출물”은 지표성분으로서 전체 건조 추출물 대비 에모딘(C15H10O5), 피시온(C16H12O5) 및 알로에-에모딘(C15H10O5)을 약 0.3%(w/w)이상, 바람직하게는 약 0.5%(w/w)이상 함유함을 특징으로 하고; “소목 추출물”은 지표성분으로서 전체 건조 추출물 대비, 브라질린 함량이 약 1.0%(w/w)이상, 바람직하게는 약 2.0%(w/w)이상 함유함을 특징으로 하고; “오배자 추출물”은 지표성분으로서 탄닌(C76H52O46)을 약 10.0%(w/w)이상, 바람직하게는 약 12.5%(w/w)이상 함유함을 특징으로 한다.
In addition, among the individual herbal medicines defined herein, “Rhubarb extract” is an indicator component compared to whole dry extracts such as emodine (C 15 H 10 O 5 ), fishion (C 16 H 12 O 5 ) and aloe-emodin (C 15 H 10 O 5 ) at least about 0.3% (w / w), preferably at least about 0.5% (w / w); “Short-necked extract” is characterized in that it contains at least about 1.0% (w / w), preferably at least about 2.0% (w / w) of brazilian content as an indicator component, compared to the total dry extract; “Gallja extract” is characterized by containing at least about 10.0% (w / w), preferably at least about 12.5% (w / w), of tannin (C 76 H 52 O 46 ) as an indicator component.
또한 본 발명은 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물 및 약학적으로 허용 가능한 담체, 희석제 또는 부형제를 포함하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물을 제공한다. In addition, the present invention relates to a cognitive impairment, including a herbal combination extract and a pharmaceutically acceptable carrier, diluent or excipient combined with at least one herbal medicine selected from rhubarb and joiner or gall bladder having beta amyloid aggregation inhibitory effect and memory learning recovery effect It provides a pharmaceutical composition for the prevention and treatment of diseases.
또한 본 발명은 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물의 인지 기능 장애관련 질환의 예방 및 치료제를 제조하기 위한 용도를 제공한다. In another aspect, the present invention provides a use for the preparation of a preventive and therapeutic agent for cognitive dysfunction-related diseases of the herbal combination extract combining at least one herbal medicine selected from rhubarb and joiner or gall bladder having a beta amyloid aggregation inhibitory effect and memory learning recovery effect .
또한 본 발명은 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물을 인간을 포함하는 포유동물에 투여함을 포함하는 인지 기능 장애관련 질환을 치료하기 위한 치료 방법을 제공한다. In another aspect, the present invention is a disease related to cognitive dysfunction comprising administering to the mammals, including humans, a herbal combination extract combining at least one herb selected from rhubarb and joiner or gall bladder having a beta amyloid aggregation inhibitory effect and memory learning recovery effect It provides a treatment method for treating.
본원에서 정의되는 “인지 기능 장애 관련 질환”은 알츠하이머형 치매증, 뇌혈관성 치매증, 픽(pick)병, 크루츠펠트-야곱(Creutzfeldt-jakob)병, 두부손상에 의한 치매 또는 파킨슨(Parkinson)병을 포함하며, 바람직하게는 알츠하이머병을 의미한다.
“Cognitive dysfunction related disease” as defined herein includes Alzheimer's dementia, cerebrovascular dementia, Pick's disease, Creutzfeldt-jakob's disease, dementia due to head injury or Parkinson's disease. And, preferably, Alzheimer's disease.
이하, 본 발명을 더욱 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
예를 들어, 한국 식약청 규정에 적합한 국산, 중국산 및 기타 수입산의 건조된 대황, 소목, 및 오배자를 각각, 일정한 배합비, 바람직하게는, 대황 1-20: 소목 1-5: 및 오배자 1-5 (w/w), 보다 바람직하게는 대황 2-10: 소목 1-3: 및 오배자 1-3 (w/w), 보다 더 바람직하게는, 대황 2-6: 소목 1-2: 및 오배자 1-2 (w/w)로 배합하는 제 1단계; 상기 약재 전체 부피의 약 1-20배, 바람직하게는 약 1-10 부피의 추출용매, 바람직하게는 물, 메탄올, 에탄올, 부탄올 등과 같은 C1 내지 C4의 저급 알콜의 극성 용매 또는 이들의 혼합용매, 보다 바람직하게는 물 및 메탄올 또는 에탄올 혼합용매, 보다 더 바람직하게는 약 1:0.1 내지 1:10의 혼합비를 갖는 물 및 메탄올 혼합용매를 가하여 0.5 내지 10시간, 바람직하게는 2 내지 5시간씩 1 내지 10회, 바람직하게는 2 내지 5회 반복하여 냉침추출, 열수추출, 초음파 추출, 환류냉각 추출법 등의 추출방법으로, 바람직하게는 2 내지 3회 환류냉각 추출법을 수행하여 생약조합 추출물을 수득하는 제 2단계; 상기 단계에서 얻은 추출액을 약 20 내지 60℃, 바람직하게는 35 내지 45℃에서 추출용매를 제거하는 제 3단계 ; 상기 제 3단계에서 얻은 복합 추출물을 물로 현탁하고 결정화 (동결건조)시키는 제 4단계를 포함하는 공정을 통하여 본 발명의 생약 조합추출물을 수득가능하다. For example, dried rhubarb, fructose, and gall of domestic, Chinese and other imported products conforming to the Korean Food and Drug Administration regulations, respectively, have a fixed ratio, preferably, rhubarb 1-20: beetle 1-5: and gall bladder 1-5 ( w / w), more preferably rhubarb 2-10: joiner 1-3: and blastula 1-3 (w / w), even more preferably rhubarb 2-6: joiner 1-2: and blastogen 1- The first step of combining 2 (w / w); About 1-20 times the total volume of the medicinal herb, preferably about 1-10 volumes of an extraction solvent, preferably a polar solvent of C 1 to C 4 lower alcohols such as water, methanol, ethanol, butanol, or the like, or a mixture thereof 0.5 to 10 hours, preferably 2 to 5 hours by adding a solvent, more preferably a water and methanol or ethanol mixed solvent, even more preferably a water and methanol mixed solvent having a mixing ratio of about 1: 0.1 to 1:10. 1 to 10 times, preferably 2 to 5 times repeated cold extraction, hot water extraction, ultrasonic extraction, reflux cooling extraction method, etc., preferably by performing
본 발명자는 놀랍게도 대황의 추출물로부터 베타아밀로이드의 응집 저해 활성과 독성 저해 활성을 관찰하였고, 활성추적에 따른 용매 분획 및 칼럼크로마토그래피를 수행하여 대황으로부터 베타아밀로이드 응집저해 활성 및 베타아밀로이드에 의한 독성을 저해하는 화합물을 단리하였으며, 분리된 화합물은 다양한 분광학적 방법을 이용하여 그 구조를 동정하였으며 화합물이 갖는 생리활성 값을 표시하였다 (도 1 참조). 각 약재의 분획을 이용하여 유효성분 또는 지표성분을 확인하는 경우에는 상기 제조방법으로 추출한 후에 디에틸에테르 등의 비극성 용매를 가하여 혼합한 후 3 내지 6차례 분획하여 수가용성 분획물 및 디에틸에테르 가용성 분획물을 얻은 후 디에틸에테르 가용성 분획물을 건조하여 디에틸에테르 가용 추출물을 수득하는 제 2단계; 상기 제 2단계의 디에틸에테르 가용 추출물을 전개용매로서 헥산: 에틸아세테이트의 20 :1의 혼합용매를 사용하고, 고정상으로는 실리카겔 60(Silica gel 60, 70-230 mesh)을 사용하여 실리카겔 컬럼 크로마토그래피를 수행하여 15개의 하부 분획물로 나눈 후, 각 분획물들의 시험관 내 시험법(in vitro assay)을 실시하여 베타아밀로이드 응집 억제, 독성 저해 효과, 항산화 효과, 아세틸 콜린 에스테라제 저해 효과 등을 확인하고, 베타아밀로이드 응집 억제 효과를 일차적인 실험으로 실시하여 (도 1 및 도 5 참조) 개재 분획들의 각 실험값을 비교한 바, 대황, 소목, 오배자의 메탄올 추출물이 각각의 실험에서 좋은 효과를 보였으며, 원생약 재료를 적절한 비율로 섞어 추출한 경우에 각각의 효과가 잘 보존됨을 확인하였다 (도 6 참조). The inventors surprisingly observed beta amyloid agglutination inhibitory activity and toxic inhibitory activity from the extract of rhubarb, and inhibited beta amyloid agglutination inhibitory activity and beta amyloid toxicity from rhubarb by performing solvent fraction and column chromatography according to activity tracking. Compounds were isolated, and the isolated compounds were identified by various spectroscopic methods, and their bioactive values were displayed (see FIG. 1). When confirming the active ingredient or the indicator component using the fraction of each medicine, after extracting by the above preparation method, mixed by adding a non-polar solvent such as diethyl ether, and then fractionated three to six times, water-soluble fraction and diethyl ether-soluble fraction Obtaining a diethyl ether soluble extract by drying the diethyl ether soluble fraction; Silica gel column chromatography using the diethyl ether soluble extract of the second step as a developing solvent using a mixed solvent of hexane: ethyl acetate 20: 1 and using silica gel 60 (
따라서, 본 발명은 상기의 제조방법으로 얻어진 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물을 유효성분으로 함유하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물을 제공한다. Accordingly, the present invention provides a pharmaceutical composition for the prevention and treatment of cognitive dysfunction-related diseases containing as an active ingredient a herbal extract extract combining at least one herbal medicine selected from rhubarb and soybean or gallnut obtained by the above production method.
구체적으로, 본 발명은 상기의 제조방법으로 얻어진 베타아밀로이드 응집 억제효과 및 기억 학습 회복 효과를 갖는 대황, 소목 및 오배자의 생약조합 추출물을 유효성분으로 함유하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물을 제공한다. Specifically, the present invention for the prevention and treatment of cognitive dysfunction-related diseases containing beta amyloid aggregation inhibitory effect and memory learning recovery effect obtained by the above production method containing rhubarb, joiner, and medicinal herb extract extract as an active ingredient. Provide a pharmaceutical composition.
본 발명의 인지 기능 장애 관련 질환 예방 및 치료용 약학조성물은, 조성물 총 중량에 대하여 상기 복합 추출물을 0.1 내지 50 중량%로 포함한다. The pharmaceutical composition for preventing and treating diseases related to cognitive dysfunction of the present invention comprises 0.1 to 50% by weight of the complex extract based on the total weight of the composition.
본 발명의 추출물을 포함하는 약학조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.Pharmaceutical compositions comprising the extract of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
본 발명의 추출물은 단독으로 또는 타 약학적 활성 화합물 또는 추출물과 결합뿐만 아니라 적당한 조합으로 사용될 수 있다.Extracts of the present invention can be used alone or in combination with other pharmaceutically active compounds or extracts, as well as in suitable combinations.
본 발명에 따른 추출물을 포함하는 약학조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 복합추출물을 포함하는 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜 (propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Pharmaceutical compositions comprising extracts according to the invention, in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterile injectable solutions, respectively, according to conventional methods. Carriers, excipients and diluents which may be formulated and used in compositions comprising complex extracts include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate , Gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. ) Or lactose, gelatin and the like are mixed. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 추출물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 본 발명의 추출물은 1일 0.0001 내지 100㎎/㎏으로, 바람직하게는 0.001 내지 10㎎/㎏으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Preferred dosages of the extracts of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the preferred effect, the extract of the present invention is preferably administered at 0.0001 to 100 mg / kg, preferably 0.001 to 10 mg / kg per day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.
본 발명의 복합추출물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관내(intracerebroventricular) 주사에 의해 투여될 수 있다. The complex extract of the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
또한 본 발명은 인지 기능 장애관련 질환의 예방 효과를 나타내는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물을 유효성분으로 함유하는 건강기능식품을 제공한다. In another aspect, the present invention provides a health functional food containing as an active ingredient a herbal extract extract combining at least one herbal medicine selected from rhubarb and joiner or gall bladder showing a preventive effect of cognitive dysfunction-related diseases.
또한 본 발명은 인지 기능 장애관련 질환의 예방 효과를 나타내는 대황 및 소목 또는 오배자로부터 선택된 하나 이상의 생약을 조합한 생약조합 추출물을 주성분으로 함유하는 식품 및 식품 첨가제를 제공한다. In another aspect, the present invention provides a food and food additive containing as an active ingredient a herbal combination extract combining at least one herbal medicine selected from rhubarb and joiner or gall bladder showing a prophylactic effect of cognitive impairment-related diseases.
본 발명의 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있다.Examples of the food to which the extract of the present invention can be added include various foods, beverages, gums, teas, vitamin complexes, and health functional foods.
또한, 인지 기능 장애관련 질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다.이 때, 식품 또는 음료 중의 상기 추출물의 양은 일반적으로 본 발명의 건강 기능 식품 조성물은 전체 식품 중량의 0.01 내지 50 중량%, 바람직하게는 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.It may also be added to foods or beverages for the purpose of preventing cognitive dysfunctions. The amount of said extract in foods or beverages is generally from 0.01 to 50 of the total food weight. It can be added in a weight percent, preferably 0.01 to 15% by weight, the health beverage composition may be added in a ratio of 0.02 to 5 g, preferably 0.3 to 1 g based on 100 ml.
본 발명의 건강기능식품은 정제, 캡슐제, 환제, 액제 등의 형태를 포함한다. Health functional food of the present invention includes the form of tablets, capsules, pills, liquids and the like.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 복합추출물을 함유하는 외에는 다른 성분에는 특별한 제한점이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health beverage composition of the present invention has no particular limitation except for containing the complex extract as an essential ingredient in the indicated ratio, and may contain various flavors or natural carbohydrates as additional ingredients, such as ordinary drinks. Examples of the above-mentioned natural carbohydrates include monosaccharides such as disaccharides such as glucose and fructose, for example polysaccharides such as maltose and sucrose, and conventional sugars such as dextrin and cyclodextrin. And sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 복합추출물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 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. 그밖에 본 발명의 추출물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the complex extract of the present invention includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and flavoring agents such as natural flavoring agents, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and Salts, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the extracts of the present invention may contain flesh for the production of natural fruit juices and fruit juice beverages and vegetable beverages. These components can be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
상기에 언급한 바와 같이, 본 발명의 대황, 소목, 오배자 복합 추출물은 기존 치료제로의 한계를 극복한 근본적인 치료 및 예방제로서 사용이 가능하도록 질병의 근원을 치료하는 베타아밀로이드 응집 및 독성 저해, 항산화, 아세틸콜린 에스테라제 저해능을 모두 갖춘 복합제로서, 인지기능 장애의 예방 및 치료용 약학 조성물 및 건강기능식품으로 유용하게 이용될 수 있다.As mentioned above, the rhubarb, rhododendron, and gall bladder complex extracts of the present invention can be used as a fundamental therapeutic and prophylactic agent that overcomes the limitations of existing therapeutic agents. As a combination with both acetylcholine esterase inhibitory ability, it can be usefully used as a pharmaceutical composition and health functional food for the prevention and treatment of cognitive impairment.
도 1은 대황의 분획이 베타아밀로이드 응집 억제 효능을 보이는 것을 나타낸 도이며,
도 2은 대황 추출물의 유효성분 및 지표성분 분석의 결과를 나타낸 도이며,
도 3은 소목 추출물의 지표성분 분석의 결과를 나타낸 도이며,
도 4은 오배자 추출물의 지표성분 분석의 결과를 나타낸 도이며
도 5는 대황 및 소목, 오배자 등의 추출물이 베타아밀로이드 응집 저해능, 베타아밀로이드 독성 저해능, 항산화능, 아세틸콜린 에스테라제 저해능을 나타낸 도이며,
도 6는 대황, 소목, 오배자 복합물의 비율에 따른 베타아밀로이드 응집 저해능, 베타아밀로이드 독성 저해능, 항산화능, 아세틸콜린 에스테라제 저해능을 나타낸 도이며,
도 7은 대황, 소목, 오배자 복합물의 인지기능 회복 활성을 Y maze 시험을 통해 나타낸 도이며,
도 8는 대황, 소목, 오배자 복합물의 인지기능 회복 활성을 수동회피(Passive avoidance) 시험을 통해 나타낸 도이다.1 is a diagram showing the fraction of rhubarb showing beta amyloid aggregation inhibitory effect,
2 is a view showing the results of the active ingredient and indicator component analysis of rhubarb extract,
Figure 3 is a diagram showing the results of the indicator component analysis of the seedling extract,
Figure 4 is a diagram showing the results of the indicator component analysis of the five gall extract
5 is a diagram showing the extracts of rhubarb and soybean, gall bladder and the like inhibiting beta amyloid aggregation, beta amyloid toxicity, antioxidant activity, acetylcholine esterase inhibition,
6 is a diagram showing beta amyloid aggregation inhibitory activity, beta amyloid toxicity inhibitory activity, antioxidant activity, acetylcholine esterase inhibitory activity according to the ratio of rhubarb, joiner, gall bladder complex,
Figure 7 is a diagram showing the cognitive function recovery activity of rhubarb, joiner, gall bladder complex through the Y maze test,
Figure 8 is a diagram showing the cognitive function recovery activity of rhubarb, joiner, gall bladder complex through a passive avoidance test.
이하, 본 발명을 하기의 실시예 및 실험예에 의해 상세히 설명한다. Hereinafter, the present invention will be described in detail by the following Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예, 참고예 및 실험예에 의해 한정되는 것은 아니다.
However, the following Examples and Experimental Examples are only illustrative of the present invention, the contents of the present invention is not limited by the following Examples, Reference Examples and Experimental Examples.
실시예Example 1. One. 복합추출물 메탄올 가용 추출물의 제조Preparation of Methanol Soluble Extract of Complex Extract
건조된 대황(동경종합상사, Rhei Radix et Rhizoma ;대한약전) 80g, 소목(동경종합상사, Caesapinia sappan Linne;대한약전) 20g, 오배자(송림무약, Galla Rhois ;대한약전) 20g을 약전 규격에 맞추어 세절한 다음에 다양한 배합비, 즉, (1) 4:1:1, (2) 4:2:2, (3) 4:2:1, (4) 4:1:2로 각각 섞은 조합물 120g에 메탄올(98%) 1440g(720gX2회)를 가하여 64℃에서 4시간씩 2회에 걸쳐 반복하여 추출장치(스테인레스추출기,한립G/L)를 이용하여 환류 추출한다. 상기에서 여과하여 얻은 추출액을 진공펌프(아일라)로 40℃에서 감압농축하여 메탄올을 제거한 다음 정제수 240g을 가하여 현탁시키고 동결건조기(일신랩바이오)로 동결건조하여 다양한 배합비를 갖는 갈색의 결정성 가루형태의 조합 건조 추출물들, 즉, (1) 4:1:1(이하 "RCRM1"이라 함), (2) 4:2:2(이하 "RCRM2"이라 함),(3) 4:2:1(이하 "RCRM3"이라 함), 및 (4) 4:1:2(이하 "RCRM4"이라 함)을 각각 (1)48.0g, (2)48.0g, (3)48.0g 및 (4)48.0g을 수득하였다. (수율 40%)
80g of dried rhubarb (Rhei Radix et Rhizoma; Korea Pharmacopoeia), 20g of small tree (Tokyo Pharmacopoeia, Caesapinia sappan Linne; Korea), 20g of Baeja (Songlim medicinal herb, Galla Rhois; Korea) 120 g of a mixture of finely divided into various compounding ratios (1) 4: 1: 1, (2) 4: 2: 2, (3) 4: 2: 1, (4) 4: 1: 2 Methanol (98%) was added to 1440g (720gX2 times), and the mixture was repeatedly extracted at 64 ° C. twice over 4 hours using an extractor (stainless extractor, granule G / L). The extract obtained by filtration was concentrated under reduced pressure at 40 ° C. with a vacuum pump (ILA) to remove methanol, suspended in 240 g of purified water, and lyophilized with a lyophilizer (Ilshin Lab Bio) to form a brown crystalline powder having various compounding ratios. Combination dry extracts, i.e. (1) 4: 1: 1 (hereinafter referred to as "RCRM1"), (2) 4: 2: 2 (hereinafter referred to as "RCRM2"), (3) 4: 2: 1 (Hereinafter referred to as "RCRM3"), and (4) 4: 1: 2 (hereinafter referred to as "RCRM4") are (1) 48.0g, (2) 48.0g, (3) 48.0g and (4) 48.0, respectively. g was obtained. (Yield 40%)
실시예 2. 개개 생약의 지표성분 함량 실험Example 2 Indicative Component Content Test of Individual Herbs
2-1. 2-1. 대황rhubarb 디에틸에테르Diethyl ether 가용 추출물의 제조 Preparation of Soluble Extracts
대황의 유효성분을 확인하기 위해 대황 6kg을 이용하여 메탄올 추출 후 디에틸에테르로 2회 컬럼크로마토그래피 방법을 이용하여 유효성분을 확인하였다(도 1 참조). To confirm the active ingredient of rhubarb, methanol was extracted using 6 kg of rhubarb and methanol was extracted using diethyl ether twice to confirm the effective ingredient (see FIG. 1).
대황의 유효성분으로 에모딘, 알로에 에모딘, 피시온 등을 확인하고 각각의 베타아밀로이드 응집 억제 효과, 베타아밀로이드 독성 억제 효과 등을 하기 실험예에서 확인하였다.
As an active ingredient of rhubarb, emotein, aloe emodine, fish, and the like were confirmed, and the effects of inhibiting beta amyloid aggregation and beta amyloid toxicity were confirmed in the following experimental examples.
2-2. 2-2. 대황rhubarb 지표성분 분석 Indicator component analysis
지표물질이 에모딘(Emodin), 알로에에모딘(Aloe-emodin), 피시온(Physcion)인 실시예 1의 대황 2.5mg을 정밀하게 달아 메탄올 1mL을 넣어 녹인 것을 검액으로 하였다. 에모딘, 알로에-에모딘을 정밀하게 달아 에탄올을 넣어 80㎍/1mL가 되게 하고 피시온은 에탄올을 넣어 40㎍/1mL가 되게 한다. 이 액을 각각 2mL씩 정밀하게 취하여 에탄올을 넣어 10mL가 되게 하여 표준액으로 사용한다. 검액과 표준액을 0.45㎛ filter 하여 하기 표 1의 HPLC 조건으로 HPLC (1100 series, Agilent) 분석을 수행하였다(표 1 참조).2.5 mg of rhubarb of Example 1, in which the indicator material was Emodin, Aloe-emodin, and Physcion, was precisely weighed, and 1 mL of methanol was added to dissolve the sample solution. Emodine and Aloe-Emodine are precisely weighed and added to ethanol to 80 ㎍ / 1mL, and fish to ethanol to 40 ㎍ / 1mL. Take 2 mL of this solution precisely and add ethanol to make 10 mL, and use it as a standard solution. HPLC (1100 series, Agilent) analysis was performed under the HPLC conditions of Table 1 by filtering the sample solution and the standard solution to 0.45 μm (see Table 1).
본 실험 결과, 에모딘(C15H10O5), 피시온(C16H12O5) 및 알로에-에모딘(C15H10O5)을 0.5% 이상(함량:0.66%) 함유함을 확인하였다(도 2 참조).
As a result of the experiment, it contains more than 0.5% (content: 0.66%) of emodin (C 15 H 10 O 5 ), fish (C 16 H 12 O 5 ) and aloe-emodin (C 15 H 10 O 5 ). It was confirmed (see FIG. 2).
2-2. 소목 지표성분 분석2-2. Joiner index component analysis
지표물질이 브라질린(Brazilin)인 실시예 1의 소목 30mg을 정밀하게 달아 메탄올 10mL을 넣어 녹인 후 물을 넣어 20mL로 하여 검액으로 한다. 브라질린 10mg을 정밀하게 달아 메탄올10mL을 넣어 녹인 후 물을 넣어 20mL로 하여 표준액으로 한다. 검액과 표준액을 0.45㎛ filter 하여 하기 표 2의 HPLC 조건으로 HPLC (1100 series, Agilent) 분석을 수행하였다(표 2 참조).30 mg of seedlings of Example 1, in which the indicator is Brazilin, are precisely weighed, dissolved in 10 mL of methanol, and water is added to make 20 mL. Accurately weigh 10 mg of braziline, add 10 mL of methanol to dissolve it, and add water to make 20 mL. HPLC (1100 series, Agilent) analysis was performed under the HPLC conditions of Table 2 by filtering the sample solution and the standard solution to 0.45 μm (see Table 2).
이동상 A : 20mM KH2PO4(monobasic)을 물에 녹인 후 인산으로 pH 3.0으로 한 용액.
이동상 B : 100% 아세토니트릴
시간(분)(이동상 B(%))= 5(5%), 45(65%), 50(95%), 53(85%), 55(5%)A: B = Gradient
Mobile phase A: A solution of 20 mM KH 2 PO 4 (monobasic) dissolved in water and then adjusted to pH 3.0 with phosphoric acid.
Mobile phase B: 100% acetonitrile
Minutes (Mobile Phase B (%)) = 5 (5%), 45 (65%), 50 (95%), 53 (85%), 55 (5%)
본 실험 결과, 브라질린 함량이 2.0%이상(함량:6.06%) 함유함을 확인하였다(도 3 참조).
As a result of the experiment, it was confirmed that braziline content was 2.0% or more (content: 6.06%) (see FIG. 3).
2-3. 오배자 지표성분 분석2-3. Governor Index Component Analysis
지표물질이 탄닌(Tannin)인 오배자에 대한 함량분석실험을 차광조건에서 하기와 같이 실시하였다.
The content analysis experiment for the gall bladder with the tannin (Tannin) as the indicator material was carried out in the light shielding conditions as follows.
표준원액 제조Standard Stock Preparation
:Gallic acid 표준품 100mg을 정밀하게 취하여 100mL 갈색 용량플라스크에 넣고 물을 이용하여 표선을 맞추었다.
: 100mg of gallic acid standard was precisely taken and placed in a 100mL brown flask.
표준액 제조Standard solution preparation
: Gallic acid 표준원액 50mL를 정밀하게 취하여 100mL 갈색 용량플라스크에 넣고 물을 넣어 표선을 맞추었다. 이 액 5mL을 정밀하게 취하여 50mL 갈색 용량플라스크에 넣고 물을 넣어 표선을 맞추었다.(0.05mg/mL)
: 50 mL of Gallic acid standard stock solution was precisely taken and placed in a 100 mL brown flask. 5 mL of this solution was precisely taken and placed in a 50 mL brown volumetric flask to add water (0.05 mg / mL).
검량선Calibration curve
: 표준액 1.0mL, 2.0mL, 3.0mL, 4.0mL, 5.0mL를 정밀하게 취하여 25mL 갈색 용량플라스크에 넣고 여기에 1mL phosphotungstomolybdic acid 씩 넣었다. 그리고 11mL, 10mL, 9mL, 8mL, 7mL의 물을 넣고 29% 탄산나트륨 용액으로 표선을 맞추고 30분 동안 방치하였다. 측정에 사용된 용액들을 공시험액으로 하여 760nm파장에서흡광도를 측정하였다. 흡광도를 Y축으로 농도를 X축으로 하여 검량선을 그었다.
: 1.0 mL, 2.0 mL, 3.0 mL, 4.0 mL, and 5.0 mL of standard solution were precisely taken into a 25 mL brown volumetric flask and 1 mL of phosphotungstomolybdic acid was added thereto. 11 mL, 10 mL, 9 mL, 8 mL, and 7 mL of water were added thereto, lined with 29% sodium carbonate solution, and left for 30 minutes. The absorbance was measured at 760 nm wavelength using the solution used for the measurement as a blank test solution. A calibration curve was drawn with the absorbance as the Y axis and the concentration as the X axis.
검액Sample 제조 Produce
:검체 400mg을 정밀하게 취하여 250mL 갈색 용량플라스크에 넣고 물 150mL 넣어 overnight하여 방치하였다. 10분 동안 초음파진탕을 실시하고 냉각한 후 물을 넣어 표선을 맞추었다. 이 액을 고형분을 가라앉도록 일정시간 방치한 후 여과를 실시하는데, 초기여과액 50mL을 버린 후 재여과액 20mL를 정밀하게 취하여 100mL 갈색 용량플라스크에 넣고 물을 넣어 표선을 맞추었다.
: 400 mg of the sample was precisely taken into a 250 mL brown volumetric flask, and 150 mL of water was stored overnight. Ultrasonic shaking was performed for 10 minutes, cooled, and water was added to set the mark. The solution was left for a certain period of time to settle the solids, and then filtered. After 50 mL of the initial filtrate was discarded, 20 mL of the re-filtrate was precisely taken into a 100 mL brown volumetric flask and water was added to adjust the mark.
시험방법Test Methods
총 페놀양 : 검액 2mL를 정밀하게 취하여 25mL 갈색용량플라스크에 넣고 여기에 1mL phosphotungstomolybdic acid를 넣은 후 물 10mL를 넣고 29% 탄산나트륨 용액으로 표선을 맞추고 30분 동안 방치한다. 측정에 사용된 용액들을 공시험액으로 하여 760nm파장에서 흡광도를 측정하였다. 흡광도를 검량선에 넣어 Gallic acid의 양(농도)을 계산하였다.Total phenolic amount: 2 ml of the sample solution is precisely placed in a 25 mL brown volumetric flask, and 1 mL phosphotungstomolybdic acid is added thereto, 10 mL of water is added, the mark is adjusted with 29% sodium carbonate solution and left for 30 minutes. The absorbance was measured at 760 nm wavelength using the solution used for the measurement as a blank test solution. Absorbance was added to the calibration curve to calculate the amount of gallic acid (concentration).
미검출된 폴리페놀 : 검액 25mL를 정밀하게 취하여 100mL 삼각플라스크에 넣고 0.6g casein을 넣고 30℃ 수욕에서 1시간 방치하였다. 충분히 흔들어 주고 냉각한 후 여과하고 초기 여과액은 버렸다. 재 여과액 2mL를 정밀하게 취하여 25mL 갈색용량플라스크에 넣고 여기에 1mL phosphotungstomolybdic acid를 넣은 후 물 10mL를 넣고 29% 탄산나트륨 용액으로 표선을 맞추고 30분 동안 방치하였다. 측정에 사용된 용액들을 공시험액으로 하여 760nm파장에서 흡광도를 측정하고 흡광도를 검량선에 넣어 Gallic acid의 양(농도)를 계산하였다.
Undetected polyphenol: 25 mL of the test solution was precisely taken into a 100 mL Erlenmeyer flask, and 0.6 g casein was added thereto and left to stand in a 30 ° C. water bath for 1 hour. Shake well, cool, filter, and discard the initial filtrate. 2 mL of the filtrate was precisely taken and placed in a 25 mL brown volumetric flask. Then, 1 mL phosphotungstomolybdic acid was added thereto, 10 mL of water was added, the mark was adjusted with 29% sodium carbonate solution, and left for 30 minutes. The absorbance was measured at 760 nm wavelength using the solutions used as the test solution, and the absorbance was added to the calibration curve to calculate the amount of gallic acid (concentration).
공시험액Blank
: 물12mL에 1mL phosphotungstomolybdic acid를 첨가 한 후 29% 탄산나트륨을 넣어 표선한 용액
: 1mL phosphotungstomolybdic acid in 12mL of water and 29% sodium carbonate
계산Calculation
: 총 탄닌 양 = 총 페놀양 - 미검출된 폴리페놀 양 : Total amount of tannin = total amount of phenol-amount of undetected polyphenol
기준standard
: 탄닌 함량이 12.5%이상
: Tannin content more than 12.5%
본 실험 결과, 탄닌 함량이 12.5%이상(함량:18.51%) 함유함을 확인하였다(도 4 참조).
As a result of the experiment, it was confirmed that the tannin content is 12.5% or more (content: 18.51%) (see Fig. 4).
참고예Reference Example 1. 약물 및 시약 1. Drugs and reagents
베타아밀로이드 1-42 (H-1368)는 Bachem, USA 에서 구입하여 사용하였으며, 그 외 시약은 시중에서 구입할 수 있는 최상급을 사용하였다.
Beta-amyloid 1-42 (H-1368) was purchased from Bachem, USA, and the other reagents were commercially available.
참고예Reference Example 2. 실험동물의 준비 2. Preparation of experimental animals
4주령의 ICR 마우스 (20-25g)를 (주) 오리엔트 (Seoul, Korea)에서 공급받아 메디프론디비티의 동물실내 동물장에서 약 5일간 적응시켜 사용하였으며, 물과 사료는 자유롭게 섭취하도록 하였고, 온도 (25±2℃), 습도 (50±5%) 및 명암주기 (12 시간)는 자동으로 조절되도록 하였다.
Four-week-old ICR mice (20-25g) were supplied from Orient Co., Ltd. (Seoul, Korea) and used for about five days in an indoor animal farm in Medipron Diti, where water and feed were freely ingested. Temperature (25 ± 2 ° C.), humidity (50 ± 5%) and contrast cycle (12 hours) were allowed to be adjusted automatically.
참고예Reference Example 3. 통계처리 3. Statistical Processing
모든 시험 결과는 ANOVA (one-way analysis of variance)를 이용하여 분석 후 , Fisher's LSD test를 이용하여 대조물질 투여군 대비 시험 물질 투여군에 대하여 통계적 유의성을 검정한다. 유의성 인정은 p<0.05, p<0.01로 한다. 이러한 모든 통계적 분석은 SPSS 소프트웨어를 사용하였다.
All test results are analyzed using ANOVA (one-way analysis of variance) and then statistically significant for the test group compared to the control group using Fisher's LSD test. Significance recognition shall be p <0.05, p <0.01. All these statistical analyzes used SPSS software.
실험예Experimental Example 1. 베타아밀로이드 응집 및 독성 억제 효능 평가 1. Evaluation of beta amyloid aggregation and toxicity inhibition efficacy
상기 실시예에서 수득한 본 발명의 추출물의 베타아밀로이드 응집 및 독성억제효능을 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 수행하였다.(Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM. Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 2005 ; 280 (7): pp5892-901. )
In order to confirm the beta amyloid aggregation and toxicity inhibitory effect of the extract of the present invention obtained in the above example, the experiment was performed by the following method by applying the method disclosed in the literature. (Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen PP, Kayed R, Glabe CG, Frautschy SA, Cole GM.Curcumin inhibits formation of amyloid beta oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J. Biol. Chem. 2005; 280 (7) : pp5892-901.)
1-1. 베타아밀로이드 응집 억제 효능 평가1-1. Evaluation of beta amyloid aggregation inhibitory efficacy
Fluorescence black plate에 PBS 45μl씩 넣은 후 DMSO를 이용해 250uM 농도로 녹인 베타아밀로이드와 vehicle인 DMSO를 5μl씩 넣는다. 여기에 본 발명의 추출물들을 25배의 농도로 DMSO에 희석하여 2μl씩 첨가한다. 대조군으로 Aβ42와 vehicle만을 넣은 시료를 실온에서 1시간 동안 반응시킨다. 1시간 후 50mM glycine buffer에 Thioflavin T 용액을 5mM로 희석시킨 용액을 plate well당 150μl씩 첨가한다. After 45μl of PBS was added to the fluorescence black plate, add 5μl of beta amyloid and DMSO, which were dissolved at 250uM, using DMSO. Here, the extracts of the present invention are diluted in DMSO at a concentration of 25 times and added by 2 μl. As a control, a sample containing only Aβ 42 and a vehicle was reacted at room temperature for 1 hour. After 1 hour, add 150 μl of Thioflavin T solution diluted to 5 mM in 50 mM glycine buffer per plate well.
Fluorescence intensity는 microplate reader(SAFIRE; TECAN)로 excitation 450nm emission 480nm에서 10초 동안 진탕(shaken)후 측정하였다. 통상적으로 시료 10μg/ml 의 농도에서 50% 이상 응집 저해를 보이면 농도 별 실험을 통해 IC50 값을 산출한다.Fluorescence intensity was measured after shaking for 10 seconds at excitation 450 nm emission 480 nm with a microplate reader (SAFIRE; TECAN). In general, when 50% or more of aggregation inhibition is observed at a concentration of 10 μg / ml, an IC 50 value is calculated through concentration-specific experiments.
본 실험 결과, 대황, 소목, 오배자 추출물을 10μg/ml의 농도에서 베타아밀로이드 응집 억제 효능을 확인했고, 도 5에 표로 나타냈다. 특히 대황과 소목에서 각각 대조군 대비 57.3%, 57.9%로 강력한 응집 억제 효능을 나타냈다. 도 6에서 나타낸 바와 같이, 대황을 주성분으로 소목과 오배자를 혼합한 추출물에서도 베타아밀로이드 응집 억제 효능을 나타냈다. 4:1:1로 혼합한 추출물에서 23.6%로 대황, 소목, 오배자 각각의 응집 억제 효능보다 더 우수한 베타아밀로이드 응집 억제능을 나타냈다(도 5 ; 도 6 참조).
As a result of the experiment, rhubarb, seedlings, gall bladder extract was confirmed beta amyloid aggregation inhibitory effect at a concentration of 10μg / ml, it is shown in the table in FIG. In particular, rhubarb and soybean showed potent aggregation inhibitory effects of 57.3% and 57.9%, respectively. As shown in FIG. 6, beta amyloid coagulation inhibitory effect was also exhibited from rhubarb as an active ingredient and extracts mixed with lumber and gallnut. 23.6% of extracts mixed with 4: 1: 1 showed better beta amyloid aggregation inhibitory effect than rhubarb, joiner, and gall bladder inhibition effect (Fig. 5; Fig. 6).
1-2. 베타아밀로이드 독성 억제 효능 평가1-2. Evaluation of beta amyloid toxicity inhibitory efficacy
Beta amyloid 1-42 peptide를 250uM 농도로 100% DMSO에 완전히 녹인 후 PBS로 1:10 으로 희석하여 25μM농도로 만든다. 4일간 실온에서 응집 반응이 일어나게 유도한 후 1.5ml tube에 나누어 냉동 보관하여 사용한다. 100mm dish에 약 80% 정도로 confluent 하게 배양한 HT22 (mouse hippocampal cell line) 세포를 trypsin-EDTA 용액(1X)를 500μl 처리하여 dish에서 떨어뜨린다. 배양배지 5ml을 넣고 부유시킨 후 hemocytometer를 이용하여 세포수를 측정한다. 96 well plate에 세포 부유액을 5x103 /well로 넣고 37℃, 5% CO2 세포 배양기에서 4시간 이상 배양한다. 세포가 plate에 붙은 걸 확인 후 serum이 없는 배지로 100μl/well로 갈아주고 1시간 배양한다. 본 발명의 추출물을 50% DMSO에 20배의 농도로 희석한 후 5μl/well씩 넣고 1시간 배양한다. 응집시킨 베타아밀로이드를 1μM 농도로 세포에 처리한 후 18-20시간 동안 배양한다. 5mg/ml의 MTT 용액을 15μl/well로 세포에 처리하고 3시간 동안 배양 후 DMSO를 150μl/well 로 넣어 세포를 solublization 시킨다. Microplate reader인 SUNRISE (TECAN)기기를 이용하여 흡광도를 측정하였다. (Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochem. Biophys. Res. Commun. 1995 ;216(2):pp.473-82.)Beta amyloid 1-42 peptide was dissolved completely in 100% DMSO at 250uM concentration and diluted 1:10 with PBS to 25μM concentration. Induce flocculation reaction at room temperature for 4 days and use it by dividing into 1.5ml tube and freezing. HT22 (mouse hippocampal cell line) cells cultured confluent about 80% in a 100mm dish were treated with 500 μl of trypsin-EDTA solution (1X) and dropped from the dish. 5 ml of the culture medium is added and suspended, and the cell number is measured by using a hemocytometer. Into a 96-well plate, add the cell suspension to 5x10 3 / well and incubate for 4 hours at 37 ℃, 5% CO 2 cell incubator. After confirming that the cells adhered to the plate, change to 100μl / well with medium without serum and incubate for 1 hour. After diluting the extract of the present invention in a concentration of 20-fold in 50% DMSO, 5 μl / well was added and incubated for 1 hour. The aggregated beta amyloid is treated with cells at a concentration of 1 μM and then incubated for 18-20 hours. 5mg / ml MTT solution was treated to the cells at 15μl / well, and cultured for 3 hours, solublization of the cells by adding 150μl / well of DMSO. Absorbance was measured using a microplate reader, SUNRISE (TECAN). (Behl C, Widmann M, Trapp T, Holsboer F. 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro.Biochem.Biophys.Res.Commun. 1995; 216 (2) : pp.473-82. )
베타아밀로이드 1μM에 의한 세포사가 50-60% 일어난 실험 결과만을 사용한다. Only experimental results with 50-60% cell death by 1 μM of beta amyloid are used.
본 실험 결과, 세포에 베타아밀로이드 독성을 유도한 후 대황, 소목, 오배자 추출물을 10μg/ml의 농도로 처리해 독성 억제 효능을 확인했고, 도 5에 표로 나타냈다. 특히 소목에서 베타아밀로이드 독성 유도한 값을 100으로 계산했을 때 181.5%로 강력한 독성 억제 효능을 나타냈다. 도 6에서 보면 대황을 주성분으로 소목과 오배자를 혼합한 추출물에서도 베타아밀로이드 독성 억제 효능이 나타났다. 4:1:1로 혼합한 추출물에서 113.6% 로 다른 혼합비율보다 높은 베타아밀로이드 독성 억제 효능을 나타냈다.
As a result of the experiment, after inducing beta amyloid toxicity to the cells, rhubarb, seedlings, and gall bladder extracts were treated at a concentration of 10 μg / ml to confirm the inhibitory efficacy, and are shown in Table 5. In particular, when the beta amyloid toxicity-induced value in the joiner was calculated as 100, 181.5% showed a strong toxicity inhibitory effect. In FIG. 6, beta-amyloid toxicity was also inhibited in rhubarb extracts containing rhubarb as a main component. The extract mixed with 4: 1: 1 showed 113.6% higher beta amyloid toxicity inhibitory effect than the other mixing ratios.
실험예Experimental Example 2. 항산화 효능 평가 2. Evaluation of antioxidant efficacy
상기 실시예에서 수득한 본 발명의 추출물의 항산화효과를 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 수행하였다.(Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V.Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol, J. Biol. Chem., 2001(25):pp22586-94.) In order to confirm the antioxidant effect of the extract of the present invention obtained in the above example, the experiment was carried out in the following manner by applying the method disclosed in the literature. (Stivala LA, Savio M, Carafoli F, Perucca P, Bianchi L, Maga G, Forti L, Pagnoni UM, Albini A, Prosperi E, Vannini V. Specific structural determinants are responsible for the antioxidant activity and the cell cycle effects of resveratrol, J. Biol. Chem., 2001 (25): pp22586-94 .)
DPPH 자유 래디칼에 대한 전자 공여능 측정하여 항산화 효과를 확인한다. DPPH 용액을 50% 에탄에 녹여 0.2M이 되게 만든 후 well당 190μl씩 넣고 DMSO로 제조한 시료를 10μl씩 넣어 1시간 동안 상온에서 반응시킨 후 517nm에서 흡광도를 측정한다. 하기 수학식 1에 따라 시료를 첨가하지 않은 대조군과 비교하여 유리 래디칼 소거 활성을 백분율로 나타냈다. The electron donating ability of DPPH free radicals was measured to confirm the antioxidant effect. After dissolving the DPPH solution in 50% ethane to make 0.2M, put 190μl per well, and add 10μl of the sample prepared by DMSO for 1 hour, and measure absorbance at 517nm. Free radical scavenging activity was expressed as a percentage compared to the control without the sample according to
본 실험 결과, 소목, 오배자 추출물에서 높은 항산화 효능을 확인했고, 도 5에 표로 나타냈다. 도 6에서 보면 4:1:2로 혼합추출물과 4:1:1로 혼합추출물에서 47.1%, 52.5%로 강력한 항산화 효능을 나타냈다. As a result of the experiment, it was confirmed the high antioxidant efficacy in the seedlings, gall bladder extract, it is shown in the table in FIG. In Figure 6 shows a 4: 1: 2 mixed extract and 4: 1: 1 in a mixed extract 47.1%, 52.5% showed a strong antioxidant effect.
실험예Experimental Example 3. 아세틸콜린 3. Acetylcholine 에스테라제Esterase 저해능Inhibition 평가 evaluation
상기 실시예에서 수득한 본 발명의 추출물의 아세틸콜린 에스테라제 억제효과를 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 수행하였다(Tsai KJ, Tsai YC, Shen CK.G-CSF rescues the memory impairment of animal models of Alzheimer's disease. J. Exp. Med., 2007;204(6):pp.1273-80.).In order to confirm the acetylcholine esterase inhibitory effect of the extract of the present invention obtained in the above example, the experiment was performed by the following method by applying the method disclosed in the literature (Tsai KJ, Tsai YC, Shen CK.G- CSF rescues the memory impairment of animal models of Alzheimer's disease.J. Exp. Med., 2007; 204 (6) : pp.1273-80.).
(1) 시약(1) reagent
아세틸콜린 에스테라제 저해 효능을 평가하기 위해 invitrogen사에서 Amplex Red Acetylcholine/Acetylcholinesterase Assay Kit (A12217)구입하여 사용하였다.To evaluate the inhibitory effect of acetylcholine esterase, Amplex Red Acetylcholine / Acetylcholinesterase Assay Kit (A12217) was purchased from invitrogen.
가. Amplex red reagent : 실온에서 따뜻하게 데운 후에 1mg에 200μl DMSO을 넣어 약 20mM의 농도로 만들어 사용한다.end. Amplex red reagent: After warming up at room temperature, add 200μl DMSO to 1mg and use it at a concentration of about 20mM.
나. 1X reaction buffer : 5X reaction buffer를 D.W.에 1/5로 희석하여 1X로 만들어 사용한다.I. 1X reaction buffer: Dilute
다. 200U/ml Horseradish peroxidase (HRP) : 1X reaction buffer 1ml을 넣어 작은 볼륨으로 나누어 얼려서 보관하여 사용한다.All. 200U / ml Horseradish peroxidase (HRP): Add 1ml of 1X reaction buffer into small volumes and freeze.
라. 20mM H2O2 : 3% H2O2 23μl에 D.W. 977 μl를 섞어 만들어 사용한다.la. 20mM H 2 O 2 : Mix 23% of 3% H 2 O 2 with DW 977 μl and use.
마. 20U/ml Choline oxidase : 1X reaction buffer 600μl를 넣어 작은 볼륨으로 나우어 얼려서 보관하여 사용한다.hemp. 20U / ml Choline oxidase: Add 600μl of 1X reaction buffer, divide into small volumes, freeze and store.
바. 100mM acetylcholine chloride : acetylcholine chloride 5mg에 D.W. 275μl를 넣어 사용전에 만들어 사용한다.bar. 100 mM acetylcholine chloride: D.W. I put 275μl and make it before use.
사. 100U/ml acetylcholinesterase : 1X reaction buffer 600μl를 넣어 작은 볼륨으로 나누어 얼려서 보관하여 사용한다.
four. 100U / ml acetylcholinesterase: Add 600μl of 1X reaction buffer, divide it into small volumes and freeze.
(2) 실험 방법(2) Experiment method
96 well plate에 1X 반응완충액(reaction buffer)로 시료 추출물들을 희석하여 각 well당 50μl씩 넣는다. (Black plate) Reaction buffer로 acetylcholinesterase를 0.2U/ml로 희석하여 well 당 50μl씩 넣었다. 양성대조군(positive control)인 H2O2 를 10μM 이 되게 1X 반응 완충액(reaction buffer)로 만들어 넣는다. working solution을 하기 표 3와 같이 준비한다(표 3 참조).Dilute the sample extracts with 1X reaction buffer in a 96 well plate and add 50μl to each well. (Black plate) Diluted acetylcholinesterase to 0.2U / ml with Reaction buffer and added 50μl per well. Positive control H 2 O 2 is made into 1 × reaction buffer to 10 μM. Prepare a working solution as shown in Table 3 (see Table 3).
실온에서 반응을 10~30min 또는 상황에 따라 더 긴 시간 동안 수행하고 Excitation 560nm, Emission 600nm에서 형광을 측정하였다.The reaction was performed at room temperature for 10-30 min or longer depending on the situation, and fluorescence was measured at Excitation 560 nm and Emission 600 nm.
아세틸콜린에스테라아제 저해능은 하기 수학식 2에 의해 계산되었다.Acetylcholinesterase inhibitory ability was calculated by the following equation.
(3) 실험 결과(3) experimental results
상기 실시예에서 각각 제조한 추출물에 대해서 아세틸콜린에스테라아제 활성 억제 실험을 실시한 결과, 대조군 대비 대황 (46.2%), 소목(54%), 오배자 (49.7%)로 모든 추출물에서 아세틸콜린에스테라아제 활성 억제 효능을 확인했고, 도 5에 표로 나타냈다. 혼합추출물에서는 4:1:1로 혼합한 비율이 다른 혼합비율보다 상대적으로 높은 아세틸콜린에스테라아제 활성 억제 효능을 나타냈고 도 6에 표로 나타냈다.
As a result of the acetylcholinesterase activity inhibition experiments for the extracts prepared in each of the above examples, rhubarb (46.2%), joiner (54%), and gall bladder (49.7%) were compared to the control group to inhibit the acetylcholinesterase activity. It confirmed and shown in the table | surface in FIG. In the mixed extract, the ratio of 4: 1: 1 mixed showed relatively higher acetylcholinesterase activity inhibitory effect than the other mixed ratios and is shown in Table 6.
실험예Experimental Example 4. 베타아밀로이드 독성 유도 동물에서의 약리 효능 평가 4. Assessment of Pharmacological Efficacy in Animals Inducing Beta Amyloid Toxicity
베타아밀로이드 1-42 10μM 로 유도된 ICR 마우스에서 다음과 같은 기억학습 테스트를 실시하여 약리효능을 평가한다.
Pharmacological efficacy was evaluated by performing the following memory learning test in ICR mice induced with beta amyloid 1-42 10 μM.
4-1. 4-1. AcuteAcute ADAD modelmodel ( ( AbetaAbeta 1-42 1-42 intracerebroventricularintracerebroventricular injectioninjection )생성)produce
상기 실시예에서 수득한 본 발명의 추출물의 급성 AD 모델에서의 효과를 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같은 방법으로 실험을 수행하였다 (Laursen, S.E., Belknap, J.K., 1986. Intracerebroventricular injections in mice. Some methodological refinements. J. Pharmacol. Methods, 16, 355- 357).In order to confirm the effect in the acute AD model of the extract of the present invention obtained in the above example, the experiment was carried out in the following manner by applying the method disclosed in the literature (Laursen, SE, Belknap, JK, 1986. Intracerebroventricular injections in mice.Some methodological refinements.J. Pharmacol.Methods, 16,355-357).
응집성(Aggregated) Aβ1-42 (37℃에서 4일 또는 6 일) 10nM i.c.v. 주사하고, 26-gauge needle을 부착한 50㎕ hamilton microsyringe를 가지고 bregma부분에 2.4mm 깊이로 투여(볼륨5㎕)하였다.
Aggregated Aβ1-42 (4 or 6 days at 37 ° C.) was injected with 10 nM icv, and 50 μl hamilton microsyringe attached with a 26-gauge needle was administered to the bregma portion at a depth of 2.4 mm (5 μl).
4-2. Y-미로실험4-2. Y-Maze Experiment
상기 실시예에서 수득한 본 발명의 추출물의 기억력에 대한 효과를 확인하기 위하여 기존문헌에 기재된 Y미로 방법을 응용하여 하기와 같은 실험을 하였다 (Yamaguchi Y et el ., Effects of a novel cognitive enhancer,spiro[imidazo-[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on learning impairments induced by amyloid-beta 1-40 in the rat. J Pharmacol ., 317(3), pp.1079-87, 2006)In order to confirm the effect on the memory of the extract of the present invention obtained in the above example was subjected to the following experiment by applying the Y maze method described in the existing literature (Yamaguchi Y et el . , Effects of a novel cognitive enhancer, spiro [imidazo- [1,2-a] pyridine-3,2-indan] -2 (3H) -one (ZSET1446), on learning impairments induced by amyloid-beta 1-40 in the rat. J Pharmacol ., 317 (3), pp. 1079-87, 2006)
Y미로 실험 장치는 동일한 3개의 arm(길이 40 cm, 높이 10 cm, 넓이 5 cm)으로 구성되어 있으며 각각은 서로 120°의 일정한 각도로 배치되어 있다. 마우스를 미로의 가장 가운데 위치시킨 다음에 8분 동안 자유롭게 Y미로를 돌아다니도록 하였다. 각 arm에 들어간 횟수 및 순서를 측정하여 spontaneous alteration (%)을 평가하였다. alteration은 3개의 arm을 순차적으로 들어가는 경우, 즉 ABC, BCA, CAB 등으로 정의하였다. 따라서 % alteration은 하기 수학식 3으로 계산하였다.
The labyrinth Y is composed of three identical arms (40 cm long, 10 cm high and 5 cm wide), each of which is placed at a constant angle of 120 ° to each other. The mouse was placed in the center of the maze and allowed to move freely around the Y maze for eight minutes. The spontaneous alteration (%) was evaluated by measuring the number and order of each arm. Alteration is defined as the case of entering three arms sequentially, that is, ABC, BCA, CAB. Therefore,% alteration was calculated by the following equation.
상기 Y미로 실험결과, 도 7에 나타내는 바와 같이 정상군(control)에 비해 베타아밀로이드를 icv 투여한 군 (vehicle)에서 통계적으로 유의한 기억학습 능력의 감퇴가 확인되었고 베타아밀로이드를 icv 투여한 동물에 본 발명의 추출물을 50mg/kg 및 100mg/kg 으로 경구 투여한 군에서 농도 의존적으로 기억학습 능력이 회복됨을 확인할 수 있었다. 복합추출물에 의한 기억학습 능력의 회복은 대조군 (vehicle) 에 비해 통계적으로 유의한 차이를 보였다 (도 7, ##p<0.01 : control group vs. Abeta icv + vehicle group, *p<0.05 : Abeta + vehicle group vs. Abeta + 복합추출물 group).
As a result of the labyrinth Y, as shown in FIG. 7, the statistically significant decrease in memory learning ability was confirmed in the group of beta amyloid-icv-treated group compared to the control group. In the group orally administered with the extract of the present invention 50mg / kg and 100mg / kg it was confirmed that the memory learning ability is recovered in a concentration-dependent manner. Recovery of memory learning ability by the composite extract showed a statistically significant difference compared to the control (vehicle) (Fig. 7, ## p <0.01: control group vs. Abeta icv + vehicle group, * p <0.05: Abeta + vehicle group vs. Abeta + complex extract group).
4-3. 수동회피실험4-3. Manual Evasion Experiment
상기 실시예에서 수득한 추출물들의 수동회피실험에서의 효과를 확인하기 위하여 문헌에 개시된 방법을 응용하여 하기와 같이 실험을 수행하였다 (MA Chacon, MI Barria, C Soto and NC Inestrosa. 2004. b-sheet breaker peptide prevents Ab-induced spatial memory impairments with partial reduction of amyloid deposits. Molecular Psychiatry 9, 953-961).In order to confirm the effect in the passive avoidance experiments of the extracts obtained in the above examples, the experiments were carried out as follows (MA Chacon, MI Barria, C Soto and NC Inestrosa. 2004. b-sheet breaker peptide prevents Ab-induced spatial memory impairments with partial reduction of amyloid deposits.Molecular Psychiatry 9, 953-961).
수동회피상자는 어두운 상자와 밝은 상자로 구성되어 있으며, 각각의 상자 크기는 18cm x 9.5cm x 17cm로 어두운 상자는 검은색 아크릴로, 밝은 상자는 흰색 아크릴로 만들어졌다. 상자의 바닥에는 전기적으로 충격 (shock)을 가할수 있는 격자로 구성되었으며, 밝은 상자는 10w bulb로 상자내 밝은 조건을 만들어주었다.The manual evacuation box consists of a dark box and a light box. Each box is 18cm x 9.5cm x 17cm, and the dark box is made of black acrylic and the light box is made of white acrylic. The bottom of the box consists of a grid of electrical shocks, and the bright box is a 10-watt bulb that creates bright conditions inside the box.
첫째날(acquisition trial), 시험 그룹을 정상군(control), 베타아밀로이드 icv 투여 후 DMSO 를 먹인 그룹(vehicle), 베타아밀로이드 icv 투여 후 50mg/kg 으로 실시예의 복합추출물을 먹인 그룹, 100mg/kg 으로 복합추출물을 먹인 그룹 등 4개의 그룹으로 나누어 각 그룹의 동물을 밝은 상자에 넣고 10초가 경과한 후, 상자의 문이 자동으로 열리게 하였다. 각 그룹의 동물은 어두운 상자로 이동하였고 바닥의 격자를 통해 피할수 없는 전기적인 충격 (0.6mA, 3s, once)을 준 10초 후 자신의 home cage로 옮겨주었다. 이때 쥐들은 전기충격의 기억을 하게 된다.On the first day (acquisition trial), the test group was the control group, the group fed DMSO after the beta amyloid icv administration, the group fed the composite extract of the example at 50 mg / kg after the beta amyloid icv administration, and the combined group at 100 mg / kg. The animals in each group were divided into four groups such as the group fed with the extract and placed in a bright box, and after 10 seconds, the door of the box was automatically opened. Animals in each group moved to dark boxes and moved to their home cages after 10 seconds of inevitable electrical shock (0.6 mA, 3 s, once) through the bottom grid. At this time, the mice will remember the electric shock.
24시간 경과 후 (retention trial), 각 그룹의 동물을 다시 밝은 상자에 넣은 후 어두운 상자로 넘어갈 때 까지의 시간 (step-through latency)을 측정하였고, 차단시간은 (cut-off latency)는 최대 300초로 하였다. 어두운 상자로 넘어가는 시간의 지연이 길수록 기억학습이 좋음을 뜻한다.After 24 hours (retention trial), we measured the step-through latency from each group of animals back to the bright box and then to the dark box, with a cut-off latency of up to 300 Seconds. The longer the delay in the dark box, the better the memory learning.
도 8를 보면 베타아밀로이드를 icv 로 주입한 쥐에서 정상쥐에 비해 기억학습이 현저히 떨어져 있음을 확인할 수 있었고 (control vs. vehicle)상기 실시예에서 준비한 복합추출물을 먹인 그룹에서 농도 의존적으로 기억학습 능력이 회복되는 것을 확인할 수 있었다. 베타아밀로이드를 icv 투여한 그룹의 기억학습 감퇴 효과와 기억학습 감퇴 유도 모델에서 복합추출물을 먹여 기억학습능력이 회복된 그룹간에 통계적으로 유의한 차이를 확인할 수 있었다 (도 8, ##p<0.01 : control group vs. Abeta icv + vehicle group, **p<0.01 : Abeta + vehicle group vs. Abeta + 복합추출물 group).
Referring to FIG. 8, it was confirmed that memory learning was significantly separated from the rat injected with beta amyloid with icv (control vs. vehicle), and the concentration-dependent memory learning ability in the group fed the composite extract prepared in the above example. It was confirmed that this recovery. In the memory learning decay effect of the beta amyloid-administered group and the induction model of memory learning decay, the composite extract was fed and the statistically significant difference was found between the groups that recovered the memory learning ability (FIG. 8, ## p <0.01: control group vs. Abeta icv + vehicle group, ** p <0.01: Abeta + vehicle group vs. Abeta + complex extract group).
본 발명의 화합물을 포함하는 약학조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Examples of the pharmaceutical compositions containing the compounds of the present invention will be described, but the present invention is not intended to be limited thereto, but is intended to be described in detail.
제제예Formulation example 1. One. 산제의Powder 제조 Produce
복합추출물(RCRM1) 20 ㎎Compound Extract (RCRM1) 20 mg
유당 100 ㎎
탈크 10 ㎎
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예Formulation example 2. 정제의 제조 2. Preparation of tablets
복합추출물(RCRM2) 10 ㎎Compound Extract (RCRM2) 10 mg
옥수수전분 100 ㎎
유당 100 ㎎
스테아린산 마그네슘 2 ㎎2 mg 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 a conventional method for preparing tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Manufacture of capsule
복합추출물 (RCRM1) 10 ㎎Compound Extract (RCRM1) 10 mg
결정성 셀룰로오스 3 ㎎3 mg of crystalline cellulose
락토오스 14.8 ㎎Lactose 14.8 mg
마그네슘 스테아레이트 0.2 ㎎Magnesium Stearate 0.2mg
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.
제제예Formulation example 4. 주사제의 제조 4. Preparation of injections
복합추출물 (RCRM1) 10 ㎎Compound Extract (RCRM1) 10 mg
만니톨 180 ㎎Mannitol 180 mg
주사용 멸균 증류수 2974 ㎎Sterile distilled water for injection 2974 mg
Na2HPO4?12H2O 26 ㎎Na 2 HPO 4 -12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.
According to the conventional method for preparing an injection, the amount of the above ingredient is prepared per ampoule (2 ml).
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
복합추출물 (RCRM3) 20 ㎎Complex Extract (RCRM3) 20 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.
Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.
제제예Formulation example 6. 건강 식품의 제조 6. Manufacture of health food
복합추출물 (RCRM4) 1000㎎Complex Extract (RCRM4) 1000mg
비타민 혼합물 적량Vitamin mixture proper amount
비타민 A 아세테이트 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎0.13 mg of vitamin B 1
비타민 B2 0.15 ㎎0.15 mg of vitamin B 2
비타민 B6 0.5 ㎎0.5 mg of vitamin B 6
비타민 B12 0.2 ㎍Vitamin B 12 0.2 g
비타민 C 10 ㎎
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍50 μg folic acid
판토텐산 칼슘 0.5 ㎎Calcium Pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 ㎎Ferrous Sulfate 1.75 mg
산화아연 0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎Potassium monophosphate 15 mg
제2인산칼슘 55 ㎎Dibasic calcium phosphate 55 mg
구연산칼륨 90 ㎎
탄산칼슘 100 ㎎
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 제제예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.
The composition ratio of the above-mentioned vitamin and mineral mixtures is composed of relatively suitable ingredients for health foods as a preferred formulation, but the formulation ratio may be arbitrarily modified, and the above ingredients may be mixed according to a general health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제제예Formulation example 7. 건강 음료의 제조 7. Manufacture of health drinks
복합추출물 (RCRM1) 100㎎Complex Extract (RCRM1) 100mg
비타민 C 15 g15 g of vitamin C
비타민 E(분말) 100 g100 g of vitamin E (powder)
젖산철 19.75 gIron lactate 19.75 g
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinamide 3.5 g
비타민 A 0.2 g0.2 g of vitamin A
비타민 B1 0.25 gVitamin B 1 0.25 g
비타민 B2 0.3gVitamin B 2 0.3 g
물 정량Water quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components in accordance with the conventional healthy beverage production method, and stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained in a sterilized 2 L container, sealed sterilization and refrigerated Used to prepare the healthy beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 제제예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.
Although the composition ratio is a composition suitable for a preferred beverage in a preferred formulation example, the compounding ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
Claims (11)
대황, 소목 및 오배자의 생약조합 추출물을 유효성분으로 함유하는 인지 기능 장애관련 질환의 예방 및 치료를 위한 약학조성물.The method of claim 1,
A pharmaceutical composition for the prevention and treatment of diseases related to cognitive dysfunction, comprising the extract of the combination of rhubarb, lumberjack, and gall bladder as an active ingredient.
상기 대황, 소목 및 오배자의 건조 중량 배합비가 대황 1-20: 소목 1-5: 및 오배자 1-5 (w/w)로 배합된 조합인 약학조성물.The method of claim 2,
The pharmaceutical composition of claim 1, wherein the dry weight compounding ratio of rhubarb, rhubarb and gall is combined with rhubarb 1-20: rhubarb 1-5: and gall bladder 1-5 (w / w).
상기 대황 추출물은 지표성분으로서 전체 건조 추출물 대비 에모딘(C15H10O5), 피시온(C16H12O5) 및 알로에-에모딘(C15H10O5)을 0.3%(w/w)이상 함유함을 특징으로 하는 약학 조성물.The method of claim 1,
The rhubarb extract is 0.3% (w) of the emodine (C 15 H 10 O 5 ), fish (C 16 H 12 O 5 ) and Aloe-Emodine (C 15 H 10 O 5 ) compared to the total dry extract as an indicator component / w) containing more than one pharmaceutical composition.
상기 소목 추출물은 지표성분으로서 전체 건조 추출물 대비, 브라질린 함량이 1.0%(w/w)이상 함유함을 특징으로 하는 약학 조성물.The method of claim 1,
The joiner extract is a pharmaceutical composition, characterized in that it contains more than 1.0% (w / w) brasil content as a indicator component, compared to the total dry extract.
상기 오배자 추출물은 지표성분으로서 탄닌(C76H52O46)을 10.0%(w/w)이상 함유함을 특징으로 하는 약학 조성물.The method of claim 1,
The gall bladder extract is characterized in that it contains more than 10.0% (w / w) tannin (C 76 H 52 O 46 ) as an indicator component.
A food additive containing as an active ingredient a herbal extract extract combining at least one herb selected from rhubarb and soybeans or gall bladder which exhibits a prophylactic effect of a cognitive dysfunction-related disease.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101414988B1 (en) * | 2012-03-26 | 2014-07-04 | 김현기 | Composition for improving recognition and treating or preventing alzheimer's disease comprising Galla rhois extract |
WO2015020241A1 (en) * | 2013-08-06 | 2015-02-12 | Kim Hyun Kee | Composition containing galla rhois extract as active ingredient for improving cognition and preventing or treating alzheimer's disease |
KR20160054097A (en) | 2014-11-05 | 2016-05-16 | 농업회사법인 경북대학교포도마을주식회사 | Composition for memory, cognition, or learning abilities |
KR101887178B1 (en) * | 2017-02-13 | 2018-09-06 | 경희대학교 산학협력단 | A composition comprising extract of rhei undulatai rhizoma for preventing or treating neurodegenerative disease and stress disease |
CN110934858A (en) * | 2018-09-25 | 2020-03-31 | 天津科技大学 | Application of brazilin as α -synuclein aggregation inhibitor in preparation of medicines, health products or foods |
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2010
- 2010-10-29 KR KR1020100107222A patent/KR20120045591A/en not_active Application Discontinuation
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101414988B1 (en) * | 2012-03-26 | 2014-07-04 | 김현기 | Composition for improving recognition and treating or preventing alzheimer's disease comprising Galla rhois extract |
WO2015020241A1 (en) * | 2013-08-06 | 2015-02-12 | Kim Hyun Kee | Composition containing galla rhois extract as active ingredient for improving cognition and preventing or treating alzheimer's disease |
KR20160054097A (en) | 2014-11-05 | 2016-05-16 | 농업회사법인 경북대학교포도마을주식회사 | Composition for memory, cognition, or learning abilities |
KR101887178B1 (en) * | 2017-02-13 | 2018-09-06 | 경희대학교 산학협력단 | A composition comprising extract of rhei undulatai rhizoma for preventing or treating neurodegenerative disease and stress disease |
CN110934858A (en) * | 2018-09-25 | 2020-03-31 | 天津科技大学 | Application of brazilin as α -synuclein aggregation inhibitor in preparation of medicines, health products or foods |
CN110934858B (en) * | 2018-09-25 | 2021-01-08 | 天津科技大学 | Application of brazilin as alpha-synuclein aggregation inhibitor in preparation of medicines, health products or foods |
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