KR20080082087A - Compositon for treating or preventing amyloid-related diseases comprising magnolia officinalis rehd. et wils. extract - Google Patents
Compositon for treating or preventing amyloid-related diseases comprising magnolia officinalis rehd. et wils. extract Download PDFInfo
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- KR20080082087A KR20080082087A KR1020070022430A KR20070022430A KR20080082087A KR 20080082087 A KR20080082087 A KR 20080082087A KR 1020070022430 A KR1020070022430 A KR 1020070022430A KR 20070022430 A KR20070022430 A KR 20070022430A KR 20080082087 A KR20080082087 A KR 20080082087A
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Classifications
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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)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/57—Magnoliaceae (Magnolia family)
- A61K36/575—Magnolia
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/322—Foods, ingredients or supplements having a functional effect on health having an effect on the health of the nervous system or on mental function
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
Abstract
Description
도 1은 본 발명의 후박 추출물의 고성능 액체크로마토그래피 스펙트럼을 나타낸 것이다.Figure 1 shows the high performance liquid chromatography spectrum of the thick extract of the present invention.
도 2는 본 발명에 따라 분리 및 정제한 오보바톨의 고성능 액체크로마토그래피 스펙트럼을 나타낸 것이다.Figure 2 shows the high performance liquid chromatography spectrum of obovatol separated and purified according to the present invention.
도 3은 본 발명의 후박 추출물에 의한 실험쥐의 공간학습능력 개선률(%)을 나타낸 그래프이다.Figure 3 is a graph showing the improvement rate (%) of the spatial learning capacity of the rat by the hakbak extract of the present invention.
도 4는 본 발명의 후박 추출물에 의한 실험쥐의 명시적 기억능력 개선률(%)을 나타낸 그래프이다.Figure 4 is a graph showing the explicit memory improvement rate (%) of the rats by the hupak extract of the present invention.
도 5는 본 발명의 후박 추출물에 의한 아세틸콜린 에스테라제(Acetylcholinesterase) 활성억제 개선률(%)을 나타낸 그래프이다.Figure 5 is a graph showing the improvement rate (%) of acetylcholine esterase (Acetylcholinesterase) activity inhibition by the thick extract of the present invention.
도 6은 본 발명의 후박 추출물에 의한 베타-세크리테이즈(β-secretase) 활성억제 개선률(%)을 나타낸 그래프이다.Figure 6 is a graph showing the improvement rate (%) of the beta-secretase (β-secretase) activity inhibited by the extract of the present invention.
도 7은 본 발명의 후박 추출물에 의한 감마-세크리테이즈(γ-secretase) 활성억제 개선률(%)을 나타낸 그래프이다.7 is a graph showing the improvement rate (%) of gamma-secretase (γ-secretase) activity inhibitory by the thick extract of the present invention.
본 발명은 후박추출물을 함유하는 아밀로이드 관련 질환의 치료 또는 예방용 조성물에 관한 것으로, 더욱 구체적으로는 후박추출물을 유효성분으로 함유하는 알츠하이머 병, 다운증후군, 인지장애(cognitive disorder), 기억력 감퇴, 아밀로이드증(amyloidosis) 등 아밀로이드 관련 질환의 치료 또는 예방에 유용한 기능성 식품 또는 약학적 조성물에 관한 것이다.The present invention relates to a composition for the treatment or prevention of amyloid-related diseases containing thick extract, more specifically Alzheimer's disease, Down syndrome, cognitive disorders (cognitive disorder), memory loss, amyloidosis containing the thick extract as an active ingredient A functional food or pharmaceutical composition useful for the treatment or prevention of amyloid-related diseases such as amyloidosis.
최근 노인 인구의 급격한 증가로 인하여 노화와 관련된 알츠하이머의 발생이 심각한 사회 문제화 되고 있다. 알츠하이머 질환은 환자 자신의 인간적인 삶을 황폐화 시킬 뿐 아니라 가족들의 삶까지도 망가뜨리는 질환으로 심각한 사회적, 경제적 문제를 야기하고 있다. 미국치매협회의 자료에 의하면 65세 이상 노인의 10.3%가 치매를 앓고 있으며, 치매를 치료하는데 연간 950억 달러의 비용이 소모되는 것으로 보고되고 있다. 우리나라의 경우도 한국보건산업진흥원의 보고에 의하면 2000년 치매 유병률이 65세 이상의 노인 중 8.3%인 34만 여명인 것으로 추정하고 있는 상황이다(서울신문 2005년 5월 10일자).Recently, due to the rapid increase in the elderly population, the development of Alzheimer's disease associated with aging has become a serious social problem. Alzheimer's disease not only destroys the patient's own human life but also destroys the family's life, causing serious social and economic problems. Data from the American Dementia Association report that 10.3 percent of seniors aged 65 or older suffer from dementia and cost $ 95 billion annually to treat dementia. In Korea, according to the report of the Korea Health Industry Development Institute, the prevalence of dementia in 2000 is estimated to be 340,000, or 8.3% of the elderly aged 65 or older (Seoul Newspaper, May 10, 2005).
치매(Dementia)는 일상생활에 손상을 주는 기억과 인지능력의 악화로 정의되며, 크게 혈관성 치매와 노인성 치매로 나눌 수 있다. 혈관성 치매는 주로 혈관 내에 형성된 혈전에 의해 뇌출혈과 뇌졸증 등이 발생하는 경우에 해당되는 것으로, 출혈이 발생된 부위의 뇌세포가 상해를 입어 기억력 상실 등이 증상이 유발되는 것 으로 알려져 있다. 반면, 혈관성 치매보다 훨씬 높은 발생빈도를 보이는 노인성 치매는 알츠하이머성 치매(Alzheimer disease)로 베타-아밀로이드의 뇌내 축적과, 그로 인한 독성으로 신경세포가 지속적으로 파괴되어 발생되는 것으로 알려져 있다(Gandy et al., J Clin Invest, 2005). 또 이 과정에서 활성산소종이 중요한 작용을 하는 것으로 보고되고 있다(Zhu et al., Brain Research, 2004). 염증반응 역시 비스테로이드 항염제를 투여할 경우 알츠하이머 병의 감소가 보고되는(Gasparini et al., Brain Research Reviews, 2005) 등 알츠하이머 병의 발병과 관련이 있는 것으로 보고되고 있다.Dementia is defined as the deterioration of memory and cognitive abilities that damage daily life and can be classified into vascular dementia and senile dementia. Vascular dementia is mainly related to the occurrence of cerebral hemorrhage and stroke due to blood clots formed in blood vessels, and it is known that brain cells in the bleeding region are injured and memory loss is caused. On the other hand, senile dementia, which is much higher than vascular dementia, is known as Alzheimer's disease, which is caused by the continuous destruction of nerve cells due to the accumulation of beta-amyloid in the brain and its toxicity (Gandy et al. , J Clin Invest , 2005). In addition, reactive oxygen species have been reported to play an important role in this process (Zhu et al., Brain Research , 2004). Inflammatory responses have also been reported to be associated with the development of Alzheimer's disease, such as a decrease in Alzheimer's disease when nonsteroidal anti-inflammatory drugs are administered (Gasparini et al., Brain Research Reviews , 2005).
다운증후군(Down's syndrome)은 염색체 가운데서 21번째 염색체의 수가 1개 더 많아서 나타나는 유전성 질환이다. 다운증후군을 앓고 있는 환자의 뇌 내에서 아밀로이드 단백질의 축적이 다운증후군을 앓고 있지 않는 일반인에 비해 많다고 보고되어 있어 아밀로이드가 다운증후군의 발병과 관련이 있는 것으로 알려져 있다(Crystal et al., Neurobiology of Aging, 1997, Yasuhiro et al., Brain & Development, 1997).Down's syndrome is a hereditary disorder caused by one more chromosome in the 21st chromosome. The accumulation of amyloid protein in the brain of patients with Down syndrome has been reported to be higher than that of the general population without Down syndrome, suggesting that amyloid is associated with the development of Down syndrome (Crystal et al., Neurobiology of Aging). , 1997, Yasuhiro et al., Brain & Development , 1997).
한편 알츠하이머 증상 중 하나인 기억력 감퇴 현상은 콜린계 신경계와 밀접한 관련이 있는 것으로 보고되고 있다. 베타-아밀로이드 단백질이 뇌세포에서 아세틸콜린(acetylcholine)의 합성을 저해시키고, 아세틸콜린 분해효소(acetylcholinesterase)의 활성을 증가시켜 뇌신경세포에 독성을 나타낸다고 보고된 바 있다(Small et al., Curr Alzheimer Res, 2004). Memory loss, one of Alzheimer's symptoms, has been reported to be closely related to the cholinergic nervous system. It has been reported that beta-amyloid protein inhibits the synthesis of acetylcholine in brain cells and increases the activity of acetylcholinesterase, which is toxic to brain neurons (Small et al., Curr Alzheimer Res). , 2004).
최소인지장애는 기억장애를 연구하는 신경 과학자들에 의해서 만들어진 용어 로, 정상적인 나이가 듦에 따라 발생하는 생리적 건망증과 알쯔하이머병에 의한 기억장애 사이의 중간 상태를 이야기하는 새로운 용어이다. 과학자들은 나이에 비해 건망증이 심하나, 알쯔하이머병의 치매증상은 가지고 있지 않은 환자들을 따로 분류하였고, 여기에 해당하는 환자들이 보여주는 기억장애에 대한 용어가 최소인지장애이다. 이러한 최소인지장애가 나이에 따른 생리적인 기억장애와 치매에 의해서 나타나는 기억장애의 중간상태라는 것은 아직까지는 매우 주관적이고 결론적이지 못하다. 이 사람들에 대한 연구결과에 의하면 이러한 최소 인지장애를 보이는 환자들은 전문가를 통해서 보다 정확한 진단과 치료에 대해 조언을 받아야 하는데, 이들 중에는 알쯔하이머병으로 발전할 가능성이 높은 환자들이 포함되어 있기 때문이다. 최근에는 이러한 최소인지장애를 보이는 환자를 대상으로 비타민E와 아세틸콜린에스테라제 억제제에 대한 효과를 알아보기 위한 연구가 진행중이다. 이 연구는 최소인지장애에 해당하는 환자들이 비타민E나 아세틸콜린에스테라제 억제제를 복용했을 경우 알쯔하이머병으로 발전하는 비율을 줄일 수 있는가하는 것을 보기 위한 것이다. Minimal cognitive impairment is a term coined by neuroscientists who study memory impairment and is a new term that describes the intermediate state between physiological forgetfulness that occurs with normal age and memory impairment caused by Alzheimer's disease. Scientists have classified patients with forgetfulness for their age but who do not have Alzheimer's dementia, and the term impaired by those patients is minimal cognitive impairment. It is still very subjective and inconclusive that this minimal cognitive impairment is an intermediate state between physiological memory impairment and dementia caused by dementia. The study of these people suggests that patients with these minimal cognitive impairments should be advised by a specialist for more accurate diagnosis and treatment, including those who are more likely to develop Alzheimer's disease. Recently, studies to investigate the effects of vitamin E and acetylcholinesterase inhibitors in patients with this minimal cognitive impairment. The study aimed to see if patients with minimal cognitive impairment could reduce the rate of development of Alzheimer's disease when taking vitamin E or acetylcholinesterase inhibitors.
아밀로이드증(amyloid degeneration)은 아밀로이드변성이라고도 한다. 유녹말은 녹말과 같은 반응을 나타내므로 이렇게 부른다. 이것은 왁스 모양으로 반투명한데, 자색소(紫色素)로 염색하여도 붉게 물들어 이색반응(異色反應)을 나타낸다. 이 물질은 혈관벽 또는 주위의 섬유 사이에 나타나거나, 지라 ·간의 세포 사이나 심근(心筋) ·설근(舌筋)의 간질조직 사이에 잘 출현한다. 소량의 경우는 유녹말변성이라고 하지만, 넓은 부위에 출현할 경우는 유녹말증 또는 아밀로이드시스(아밀 로이드증)라 한다. Amyloid degeneration is also known as amyloid degeneration. This is called because starch reacts like starch. It is translucent in wax shape, and even when dyed with purple pigment, it turns red and shows a dichroic reaction. This substance appears between the walls of blood vessels and the surrounding fibers, or between interstitial tissues of the spleen and liver or between the interstitial tissues of the myocardium and heart muscle. Small amounts are called starch degeneration, but appearing in large areas are called starchosis or amyloidosis (amyloidosis).
이와 같은 병인을 기초로 지금까지 개발된 알츠하이머 병의 치료 및 개선을 위한 약물로는 시냅스에서 콜린 분해를 감소시킴으로써 뇌내 작용하는 콜린의 양을 증가시키는 작용을 하는 타크린(Tacrine), 아리셉트(Aricept) 및 엑셀론(Exelon)과 같은 아세틸콜린 분해효소 억제제(cholinesterase inhibitior) 등이 사용되고 있으나, 단지 알츠하이머의 증상만을 완화시키는 효과를 가지며 효과가 크지 않고 일시적이며, 간독성 등의 부작용이 심해 폭넓은 사용이 어려운 현실이다(Forchetti et al., Prim Care Companion J Clin Psychiatry, 2005).Drugs for the treatment and improvement of Alzheimer's disease, which have been developed based on such etiology, have been shown to reduce the amount of choline in the synapse, thereby increasing the amount of choline acting in the brain. And acetylcholinease inhibitors such as Exelon, etc. are used, but they have the effect of alleviating the symptoms of Alzheimer's only, are not effective and temporary, and have severe side effects such as hepatotoxicity. (Forchetti et al., Prim Care Companion J Clin Psychiatry , 2005).
따라서 국내외의 많은 연구 기관에서는 근원적인 알츠하이머 등의 아밀로이드 관련 질환 치료제의 개발을 위해 베타-아밀로이드 형성 억제 효능을 갖는 물질을 찾거나, 신경세포의 아팝토시스(apoptosis)를 억제시키는 약물의 탐색에 많은 노력을 기울여 왔다. Therefore, many research institutes at home and abroad are searching for a substance having inhibitory effects on beta-amyloid formation or developing a drug that inhibits apoptosis of neurons in order to develop a drug for treating amyloid-related diseases such as Alzheimer's. Efforts have been made.
한편 후박(厚朴, Magnolia officinalis Rehd. et Wils.)은 한국과 일본, 그리고 중국에서 오랜 기간 건위제로 사용되어 왔으며, 잎은 한국과 일본에서 식용으로도 사용되었다(정보섭, 신민교, 향약대사전, 영림사, 469-471, 1998). 후박나무에는 알파, 베타-유데스몰(α,β-eudesmol), 마그놀올(magnolol), 호노키올(honokiol), 오보바톨(obovatol) 등의 포함되어 있는 것으로 알려져 있다(생약학연구회, 현대생약학, 학창사, 567-571, 2003). 최근 국내에서 후박을 이용한 연구가 진행되어 마그놀올 성분의 효능을 활용한 당뇨억제제 특허(김진숙 외, 대한민국특허 출원번호 제2003-0039241호)가 출원된 바 있으며, 오보바톨 성분을 활용한 항 불안 억제제 특허(홍진태 외, 대한민국특허 출원번호 제2005-0037854호)가 출원된바 있으나 알츠하이머 등의 아밀로이드 관련 질환의 치료 혹은 예방에 대한 연구는 없다. 또한, 신경보호작용을 갖는 후박 추출물 및 이를 함유하는약학적 제제 특허(대한민국특허 출원번호 제2001-0026691호)가 출원된 바 있으나, 이는 뇌허혈로 인한 산소 및 영양공급의 차단에 의해 유발되는 신경세포 고사, 즉 뇌졸증의 예방 및 치료의 용도만을 개시하고 있을 뿐, 뇌허혈과 전혀 다른 기전으로 세포사를 일으키는 아밀로이드 관련 질환의 치료 혹은 예방에 대하여는 개시하고 있지 못하다.Meanwhile, Huno ( Magnolia officinalis Rehd . Et Wils.) Has long been used as a health agent in Korea, Japan, and China, and leaves have been used for food in Korea and Japan. 469-471, 1998). It is known that the hummus tree contains alpha, beta-eudesmol, α-β-eudesmol, magnool, honokiol, obovatol, etc. Hakchangsa, 567-571, 2003). Recently, a research using groceries was conducted in Korea, and a patent for diabetic inhibitor (Jin-Sook Kim et al., Korea Patent Application No. 2003-0039241) utilizing the efficacy of the magolol component has been filed. Patent (Hong Jin-tae et al., Korean Patent Application No. 2005-0037854) has been filed, but there is no research on the treatment or prevention of amyloid-related diseases such as Alzheimer's. In addition, although a patent for a thick extract and a pharmaceutical preparation containing the same (Korean Patent Application No. 2001-0026691) has a neuroprotective action has been filed, it is a nerve cell caused by the blocking of oxygen and nutrient supply due to cerebral ischemia It only discloses the use of the prevention and treatment of apoptosis, that is, stroke, but does not disclose the treatment or prevention of amyloid-related diseases that cause cell death by a mechanism completely different from cerebral ischemia.
본 발명자들은 본 발명의 후박추출물이 베타-아밀로이드 형성에 관여하는 베타와 감마-세크리테이즈(β, γ-secretase) 활성을 억제한다는 사실을 처음으로 밝혀내어 아밀로이드 관련 질환의 치료 또는 예방에 사용될 수 있음을 확인하였으며, 실험쥐를 이용한 수중미로(워터-메이지, water maze) 시험, 수동적 회피(패시브-어보이던스, passive avoidance) 시험 등의 동물실험을 실시하여 오보바톨을 포함하는 후박추출물이 아밀로이드 관련 질환인 알츠하이머 병, 기억력 감퇴, 인지장애 등에 효능이 있음을 확인하였고, 쥐의 해마조직을 이용한 아세틸콜린 분해효소 활성억제 시험을 통하여 아밀로이드 관련 질환 중에서도 알츠하이머 병의 치료 또는 예방에 더욱 효과적임을 추가적으로 확인함으로써 본 발명을 완성하였다.The inventors have found for the first time that the thick extract of the present invention inhibits the beta and gamma-secretase activity involved in beta-amyloid formation and can be used for the treatment or prevention of amyloid-related diseases. After experiment, animal experiments such as underwater maze (water maze) test and passive avoidance (passive-avoidance, passive avoidance) test using mice were carried out. It has been shown to be effective in Alzheimer's disease, memory loss, cognitive impairment, etc., and it is further confirmed that it is more effective in the treatment or prevention of Alzheimer's disease among amyloid-related diseases by testing acetylcholine degrading enzyme activity test using hippocampal tissues of rats. By this, the present invention was completed.
본 발명의 목적은 인체에 부작용이 거의 없어 안전하면서도 알츠하이머 병, 다운증후군, 인지장애, 기억력 감퇴, 아밀로이드증 등과 같은 아밀로이드 관련 질환의 치료 또는 예방에 효과적인 후박추출물의 새로운 용도를 제공하는 데 있다.It is an object of the present invention to provide a new use of a thick extract effective in treating or preventing amyloid-related diseases such as Alzheimer's disease, Down's syndrome, cognitive impairment, memory loss, amyloidosis, etc., while being safe with little side effects in the human body.
본 발명의 또 다른 목적은 상기와 같은 용도를 갖는 후박 추출물을 유효성분으로 함유하는 기능성 식품 또는 약학적 조성물을 제공하는 데 있다.Still another object of the present invention is to provide a functional food or pharmaceutical composition containing the thick extract having the use as an active ingredient.
상기 기술적 과제를 달성하기 위하여, 본 발명은 후박 추출물을 유효성분으로 함유하는 아밀로이드 관련 질환의 치료 또는 예방용 조성물을 제공한다.In order to achieve the above technical problem, the present invention provides a composition for the treatment or prevention of amyloid-related diseases containing a thick extract as an active ingredient.
본 발명의 조성물에 있어서, 상기 아밀로이드 관련 질환은 아밀로이드의 축적, 변성 또는 그로 인한 독성에 의해 유발되는 모든 질환을 포함하나, 바람직하게는 알츠하이머 병, 다운증후군, 인지장애(cognitive disorder), 기억력 감퇴 및 아밀로이드증(amyloidosis)으로 이루어진 군으로부터 선택된 어느 하나인 것을 특징으로 하며, 보다 바람직하게, 알츠하이머 병(Alzheimer disease)인 것을 특징으로 한다 (상기 선행기술 참조).In the composition of the present invention, the amyloid related diseases include all diseases caused by amyloid accumulation, degeneration or toxicity thereof, but preferably Alzheimer's disease, Down's syndrome, cognitive disorder, memory loss and It is characterized in that it is any one selected from the group consisting of amyloidosis, more preferably, Alzheimer's disease (Alzheimer's disease) (see above prior art).
본 발명에서는, 상기 후박추출물이 베타-아밀로이드 형성에 관여하는 베타와 감마-세크리테이즈(β, γ-secretase) 활성을 억제한다는 사실을 처음으로 밝혀내어 아밀로이드 관련 질환의 치료 또는 예방에 사용될 수 있음을 확인하였으며, 실험쥐를 이용한 수중미로(워터-메이지, water maze) 시험, 수동적 회피(패시브-어보이던스, passive avoidance) 시험 등의 동물실험을 실시하여 후박추출물이 아밀로이드 관련 질환인 알츠하이머 병, 기억력 감퇴, 인지장애 등에 효능이 있음을 확인하였고, 쥐의 해마조직을 이용한 아세틸콜린 분해효소 활성억제 시험을 통하여 아밀로이드 관련 질환 중에서도 알츠하이머 병의 치료 또는 예방에 더욱 효과적임을 추가적으로 확인하였다.In the present invention, it can be used for the treatment or prevention of amyloid-related diseases by revealing for the first time that the thin extract extract inhibits the beta and gamma-secretase (β, γ-secretase) activity involved in the beta-amyloid formation Animal experiments such as underwater maze (water maze) test and passive avoidance test using passive mice (passive-aboyance, passive avoidance) test were carried out to determine that the late extract is Alzheimer's disease, which is an amyloid-related disease, It was confirmed that it is effective in memory loss and cognitive impairment, and further confirmed that it is more effective in the treatment or prevention of Alzheimer's disease among amyloid-related diseases through the test of inhibition of acetylcholine degrading enzyme activity using the hippocampus tissue of rats.
본 발명의 조성물에 있어서, 상기 후박 추출물은 본 발명의 활성을 가지는 한 열수 추출, 유기 용매 추출, 초임계 추출 등 종래 알려진 어떤 추출방법에 의해 추출된 것도 포함하나, 바람직하게는 물, 알코올 또는 이들의 혼합 용매와 같은 극성용매의 추출물인 것을 특징으로 한다.In the composition of the present invention, the thick extract is one that has been extracted by any conventionally known extraction method such as hydrothermal extraction, organic solvent extraction, supercritical extraction, so long as it has the activity of the present invention, preferably water, alcohol or these It is characterized in that the extract of the same polar solvent as the mixed solvent.
본 발명의 조성물에 있어서, 상기 후박 추출물은 극성이 다른 유기용매를 이용하여 더욱 분획할 수 있으며, 각종 크로마토그래피를 이용하여 더욱 정제할 수도 있으나, 바람직하게는 상기 극성용매 추출을 거친 후 실리카겔 크로마토그래피 및 고성능액체크로마토그래피를 이용하여 분리 정제된 활성분획인 것을 특징으로 한다.In the composition of the present invention, the thick extract may be further fractionated using an organic solvent having a different polarity, and may be further purified using various chromatography. Preferably, the silica gel chromatography is subjected to the polar solvent extraction. And it is characterized in that the active fraction separated and purified using high performance liquid chromatography.
본 발명의 조성물에 있어서, 상기 활성 분획은 하기 화학식 1로 표시되는 오보바톨(obovatol)을 함유하는 것을 특징으로 한다.In the composition of the present invention, the active fraction is characterized in that it contains obovatol represented by the following formula (1).
상기 오보바톨은 후박나무(Magnolia officinalis Rehd. et Wils.)의 잎 혹은 줄기껍질의 한 성분이다. 오보바톨을 함유한 후박은 민간에서 조습소담(操濕消痰), 하기제만(下氣除滿) 등에 효과가 있는 것으로 알려져 있다 (생약규격집, 한국의약품수출입협회, 2000).The obovatol is a component of the leaf or stem bark of Magnolia officinalis Rehd. Et Wils. Huvax containing obovatol is known to be effective in hygroscopic fever and Hagijeman in the private sector (National Herbal Medicine Specification Collection, Korea Drug Export and Import Association, 2000).
본 발명의 조성물에 있어서, 조성물 총 중량에 대하여 상기 후박 추출물을 0.0001 내지 90 중량%로 포함하는 것을 특징으로 한다.In the composition of the present invention, it is characterized in that it comprises 0.0001 to 90% by weight based on the total weight of the composition.
본 발명의 조성물에 있어서, 상기 조성물은 아밀로이드 관련 질환의 치료 또는 예방용 기능성 식품으로 사용되는 것을 특징으로 한다. 상기 기능성 식품은 식품학적으로 허용 가능한 식품보조 첨가제를 더 포함할 수도 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료 형태로 제제화될 수 있다.In the composition of the present invention, the composition is characterized in that it is used as a functional food for the treatment or prevention of amyloid-related diseases. The functional food may further comprise a food acceptable food supplement additive, it may be formulated in the form of pills, powders, granules, acupuncture, tablets, capsules or beverages.
본 발명의 조성물에 있어서, 상기 조성물은 아밀로이드 관련 질환의 치료 또는 예방용 약학적 조성물로 사용되는 것을 특징으로 한다. 상기 약학적 조성물은 약학적으로 허용가능한 부형제 또는 희석제 등을 더 포함할 수 있으며, 분말, 과립, 정제, 캡슐 등과 같은 경구용 제제 또는 주사제와 같은 비경구용 제제로 제제화될 수 있다.In the composition of the present invention, the composition is characterized in that it is used as a pharmaceutical composition for the treatment or prevention of amyloid-related diseases. The pharmaceutical composition may further include a pharmaceutically acceptable excipient or diluent, and may be formulated into an oral preparation such as powder, granules, tablets, capsules, or the like, or a parenteral preparation such as an injection.
본 발명을 위해 후박추출물은 후박나무로부터 추출할 수 있다. 구체적으로 후박나무 잎과 줄기껍질을 음건, 세절하여 무게(㎏)의 약 2배 내지 20배, 바람직하게는 약 2배 내지 5배의 물, 메탄올 또는 에탄올 등의 저급(C1-C4) 알코올의 극성용매 또는 이들의 혼합용매, 바람직하게는 에탄올로 0℃ 내지 100℃, 바람직하게는 10℃ 내지 30℃ 추출온도에서 약 1일 내지 15일, 바람직하게는 약 2일 내지 7일 동안 냉침 추출, 환류 냉각 추출, 열수 추출, 초음파 추출등의 추출방법을 이용하여 수득한 추출액을 여과, 감압농축하여 극성용매에 가용한 조추출물을 수득 가능하 다.Thick extract for the present invention can be extracted from the pear tree. Specifically, the leaves and stem bark of the walnut tree are shaded and shredded, and the lower (C1-C4) alcohol, such as water, methanol or ethanol, is about 2 to 20 times, preferably about 2 to 5 times the weight (kg). Cold extraction with a polar solvent or a mixed solvent thereof, preferably ethanol at 0 ° C. to 100 ° C., preferably at 10 ° C. to 30 ° C. for about 1 to 15 days, preferably about 2 to 7 days, The extract obtained by using extraction methods such as reflux cooling extraction, hot water extraction and ultrasonic extraction can be filtered and concentrated under reduced pressure to obtain crude extracts soluble in polar solvents.
추출에 있어 사용되는 추출 용매로서 헥산, 클로로포름, 에틸아세테이트, 아세톤 등의 비극성용매의 사용이 가능하다. 구체적으로 후박나무 잎과 줄기껍질을 음건, 세절하여 무게(kg)의 약 2 내지 20배, 바람직하게는 약 2배 내지 5배의 헥산, 클로로포름, 에틸아세테이트, 아세톤 등의 비극성용매 또는 이들의 약 1:1 내지 1:10의 혼합비를 갖는 혼합용매로, 바람직하게는 클로로포름을 가하여 25℃에서 약 24시간 냉침 추출, 환류 냉각 추출, 열수 추출, 초음파 추출 등의 추출방법을 이용하여 수득한 추출액을 여과, 감압농축하여 비극성용매에 가용한 조추출물을 수득 가능하다. As the extraction solvent used in the extraction, non-polar solvents such as hexane, chloroform, ethyl acetate, acetone can be used. Specifically, the leaves and stem bark of the walnut tree are shaded and shredded to about 2 to 20 times of the weight (kg), preferably about 2 to 5 times of a nonpolar solvent such as hexane, chloroform, ethyl acetate, acetone or the like. A mixed solvent having a mixing ratio of 1: 1 to 1:10, preferably, extracted with chloroform by using extraction methods such as cold extraction, reflux cooling extraction, hot water extraction, and ultrasonic extraction at 25 ° C. for about 24 hours. Filtration and concentration under reduced pressure afford crude extracts soluble in nonpolar solvents.
또한, 상기 극성 또는 비극성 용매 가용 추출물을 증류수 등으로 수회 분획 및 세척하여 정제한 후에 추가로 통상의 분획 공정을 수행할 수도 있다(Harborne J .B. et al., Phytochemical methods: A guide to modern techniques of plant analysis., 3rd Ed., pp 6-7, 1998). 예를 들어, 상기 정제된 극성 또는 비극성용매 가용추출물을 감압농축하고, 이 감압농축액을 에틸아세테이트와 물을 넣어 분획하고 유기용매 부분을 모아 감압 농축하였다. 얻어진 용매 분획을 용출용매, 바람직하게는 메탄올과 물(4:1) 혼합용매를 용출용매로 하여 C18 컬럼 크로마토그래피를 실시하여 용출물을 얻고, 또한, 실리카겔 컬럼 크로마토그래피를 용출용매, 바람직하게는 헥산:초산에틸 혼합용매로 수행하여 정제한 후 헥산:초산에탈(9:1-6:4)을 변환시키면서 용출하였다.In addition, the polar or non-polar solvent soluble extract may be purified by fractionation and washing several times with distilled water or the like, followed by a conventional fractionation process (Harborne J.B. et al., Phytochemical methods: A guide to modern techniques of plant analysis. , 3rd Ed., pp 6-7, 1998). For example, the purified polar or non-polar solvent soluble extract was concentrated under reduced pressure, and the concentrated concentrate was extracted with ethyl acetate and water, and the organic solvent was collected and concentrated under reduced pressure. The obtained solvent fraction was subjected to C18 column chromatography using an eluting solvent, preferably a mixed solvent of methanol and water (4: 1) as an eluting solvent, to obtain an eluate. Further, silica gel column chromatography was used as an eluting solvent, preferably Purification was carried out with a hexane: ethyl acetate mixed solvent, followed by elution with conversion of hexane: ethyl acetate (9: 1-6: 4).
고성능액체크로마토그래피(LC-6AD, SHIMATZU사; Shim-Pak prep-ODS column, SHIMATZU사; 자외선분광검출기, λ=254 nm)를 사용하여 활성 성분들은 메탄올:물(4:1)을 용매로 사용하여 오보바톨 화합물을 수득할 수 있다. 그러나 본 발명에 따른 오보바톨을 분리하는 방법은 이에 한정되지 않으며, 후박나무로부터 오보바톨을 분리할 수 있는 방법이라면 모두 사용할 수 있다.Using high performance liquid chromatography (LC-6AD, SHIMATZU; Shim-Pak prep-ODS column, SHIMATZU; UV spectrometer, λ = 254 nm), the active ingredients were methanol: water (4: 1) as solvent. To obtain an obovatol compound. However, the method of separating ovobatol according to the present invention is not limited thereto, and any method capable of separating ovobatol from hawthorn may be used.
상기 방법에 의해 수득된 후박 추출물은 오보바톨을 포함하며, 오보바톨의 함량은 추출물 총 중량에 대하여 약 5내지 20중량%이다. 바람직하게는 약 15중량%이다.The thick gourd extract obtained by the above method comprises obovatol, and the content of obovatol is about 5 to 20% by weight based on the total weight of the extract. Preferably about 15% by weight.
또한, 후박나무는 오랫동안 생약 및 식용으로 사용되어 오던 약재로서 이들로부터 추출된 본 발명의 추출물 또는 이로부터 분리된 화합물 역시 독성 등의 부작용이 없을 것으로 생각된다. In addition, as a medicinal herb has been used for a long time as a herbal medicine and edible extracts of the present invention extracted from them or compounds isolated there are also considered to have no side effects such as toxicity.
본 발명은 또한 상기 오보바톨을 포함하는 후박추출물 및 식품학적으로 허용가능한 식품보조첨가제를 포함하는 알츠하이머와 같은 아밀로이드 관련 질환의 예방을 위한 건강 보조 식품을 제공한다. 본 발명의 오보바톨을 포함하는 후박추출물을 첨가할 수 있는 식품으로는, 각종 식품류, 예를 들어, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있으며, 환제, 분말, 과립, 침제, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The present invention also provides a dietary supplement for the prevention of amyloid-related diseases such as Alzheimer's, including the thick thin extract comprising the obovatol and a food supplement acceptable food supplement. Foods to which the thick thin extract containing the obovatol of the present invention can be added include various foods, for example, beverages, gums, teas, vitamin complexes, health supplements, and the like. It can be used in the form of a tablet, capsule or beverage.
이때, 식품 또는 음료 중의 상기 오보바톨을 포함하는 후박추출물과 화합물의 양은, 일반적으로 본 발명의 건강식품 조성물의 경우 전체 식품 중량의 0.0001 내지 20 중량%로 가할 수 있으며, 건강 음료 조성물의 경우 100㎖를 기준으로 0.0001 내지 20 중량% 가할 수 있다.At this time, the amount of the thick extract and the compound containing the obovatol in the food or beverage can be generally added to 0.0001 to 20% by weight of the total food weight in the case of the health food composition of the present invention, 100ml for the health beverage composition It can be added 0.0001 to 20% by weight based on.
본 발명에서 정의되는 식품보조첨가제는 당업계에 통상적인 식품첨가제, 예를 들어 향미제, 풍미제, 착색제, 충진제, 안정화제 등을 포함하며 하기에 예시한다.Food additives defined in the present invention include food additives conventional in the art, for example, flavors, flavors, colorants, fillers, stabilizers and the like and are exemplified below.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 액체 성분에는 특별한 제한 점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 동을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예로는 예를 들어, 포도당, 과당 등의 모노사카라이드 예를 들어, 말토스, 슈크로스 등의 디사카라이드 예를 들어, 덱스트린, 시클로덱스트린 등의 폴리사카라이드 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진 등)) 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 on the liquid component except for containing the extract as an essential ingredient in the indicated proportions, and may contain various flavoring agents or natural carbohydrate copper as additional ingredients, such as ordinary beverages. Examples of the above-mentioned natural carbohydrates include, for example, monosaccharides such as glucose and fructose, for example, disaccharides such as maltose and sucrose, for example, conventional polysaccharides such as dextrin, cyclodextrin, and the like. Sugars and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (tauumatin, stevia extracts (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) are advantageously used. Can be. The proportion of said natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 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, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 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 composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring and neutralizing agents (such as cheese and chocolate), pectic acid and salts thereof, alginic acid and its Salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated beverages, and the like. The compositions of the present invention may also contain pulp 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 from the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 후박 추출물을 유효성분으로 함유하는 약학적 조성물은 경구 또는 비경구의 여러 가지 제형으로 투여될 수 있는데, 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 후박 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. 비경구투여를 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.The pharmaceutical composition containing the thick extract of the present invention as an active ingredient may be administered in various oral or parenteral formulations, and when formulated, the commonly used fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like, may be used. Prepared using diluents or excipients. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose ( Sucrose) or lactose (Lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, 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.
본 발명에 따른 후박 추출물의 투여량은 환자의 성별, 나이, 체중, 및 질환의 정도 등에 따라 차이가 있을 수 있으나, 일반적으로 성인 하루당 10∼3000mg이 되도록 투여하는 것이 적당하다.The dosage of the extract according to the present invention may vary depending on the sex, age, weight, and degree of disease of the patient, but it is generally appropriate to administer 10-3000 mg per adult.
이하, 본 발명을 하기의 실시예 및 실험예에 의해 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 하기 실시예 및 실험예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited by the following Examples and Experimental Examples.
실시예 1. 후박나무 추출물의 제조Example 1 Preparation of Twig Extract
건조 및 세절하여 얻은 후박나무 줄기껍질 3kg을 95% 에탄올 9L을 가하여 실온에서 3회 반복 추출한 후 여과하여 얻은 여과액을 감압농축기(EYELA사, N-1000, 일본)로 농축하여 건조된 조추출물 470g을 얻었다. After drying and cutting the 3 kg of dried bark trunk bark with 95% ethanol 9L, the mixture was extracted three times at room temperature, and the filtrate was filtered and concentrated by a vacuum condenser (EYELA, N-1000, Japan). Got.
실시예 2. 오보바톨 화합물의 분리 및 정제Example 2. Isolation and Purification of Obovatol Compounds
상기 실시예 1에서 수득한 후박나무 극성용매 가용추출물 200g을 2L 증류수로 현탁시킨 다음, 500ml의 초산에틸을 가하여 용해한 다음, 이를 분별 추출하였다. 이 과정을 2회 반복 수행하고 유기용매에 녹는 부분을 모았다. 유기용매층을 감압농축하여 농축액 180g을 수득하였다. 이 농축액 180g을 500ml의 메탄올에 녹이고 500g의 C18에 흡착시킨 후 메탄올 : 물 = 4 : 1 혼합용액 1L를 사용하여 활성물질 분획을 얻었다. 용리액을 감압 하에서 농축하여 얻은 황갈색의 농축액 100g을 메틸렌클로라이드에 용해시켰다. 실리카겔(머크사, 상품명: 9385) 1kg을 헥산 : 에틸아세테이트 = 9 : 1 혼합 용액을 사용하여 칼럼(4.5x40cm)에 충진 한 후, 활성성분 분획을 실리카겔에 흡착시키고 헥산과 초산에틸의 비율을 9 : 1부터 6 : 4로 변환시키면서 2회의 실리카겔 칼럼 크로마토그래피를 수행하여 활성분획을 분리하였다. 최종적으로 고성능액체크로마토그래피(Prep-HPLC; LC-6AD, SHIMATZU사; Capcell-Pak prep-ODS column, Shiseido사; 자외선분광검출기, λ=254 nm; 80% 메탄올, 18 ml/min)를 이용하여 오보바톨 화합물 1g을 정제하였다. 실시예 2에서 수득한 후박추출물 및 오보바톨의 고성능액체크로마토그래피(HPLC; LC-6AD, SHIMATZU 사; Capcell Pak C18 4.6 X 250mm Shiseido사; 자외선분광검출기, λ=254 nm; 80% 메탄올, 1 ml/min) 스펙트럼은 도 1 내지 도 2에 나타내었는데, 오보바톨은 상기조건에서 머무른시간(retention time)이 약 6.8-7.1분으로 분석되었다.200 g of the Pak polar polar solvent soluble extract obtained in Example 1 was suspended with 2 L distilled water, and then dissolved in 500 ml of ethyl acetate, which was then fractionally extracted. This process was repeated twice and the parts dissolved in the organic solvent were collected. The organic solvent layer was concentrated under reduced pressure to obtain 180 g of concentrate. 180 g of this concentrate was dissolved in 500 ml of methanol and adsorbed onto 500 g of C18, and then the active substance fraction was obtained using 1 L of methanol: water = 4: 1 mixed solution. 100 g of a yellowish brown concentrate obtained by concentrating the eluent under reduced pressure was dissolved in methylene chloride. After filling 1 kg of silica gel (Merck, trade name: 9385) in a column (4.5x40 cm) using a mixed solution of hexane: ethyl acetate = 9: 1, the active ingredient fraction was adsorbed onto silica gel and the ratio of hexane and ethyl acetate was 9 The active fractions were separated by two silica gel column chromatography conversion from 1 to 6: 4. Finally using high performance liquid chromatography (Prep-HPLC; LC-6AD, SHIMATZU; Capcell-Pak prep-ODS column, Shiseido; UV spectrometer, λ = 254 nm; 80% methanol, 18 ml / min) 1 g of obovatol compound was purified. High performance liquid chromatography of thick extract and obovatol obtained in Example 2 (HPLC; LC-6AD, SHIMATZU; Capcell Pak C 18 4.6 X 250mm Shiseido; UV spectrometer, λ = 254 nm; 80% methanol, 1 ml / min) spectra are shown in FIGS. 1-2, where obovatol was analyzed to have a retention time of about 6.8-7.1 minutes at these conditions.
실시예 3: 오보바톨 화합물의 동정 Example 3: Identification of Obovatol Compounds
상기 실시예 2에서 수득한 오보바톨의 구조를 1H-NMR(Varian, GEMINI, 400 MHz), 13C-NMR(Varian, GEMINI, 100 MHz)로 분석하였다. 사용된 용매로는 CDCl3(Chloroform-d, 알드리치사)를 사용하였으며, 내부표준 물질로 트리메칠실란을 사용하여 δ값(ppm)으로 나타내었으며 하기와 같은 물성을 지님을 밝혔으며, 이는 이미 발표된 문헌(Kazuo et al., Chem. Pharm. Bull. pp 3347-3353, 1982)과 일치하여 오보바톨임을 확인하였다. The structure of obovatol obtained in Example 2 was analyzed by 1 H-NMR (Varian, GEMINI, 400 MHz) and 13 C-NMR (Varian, GEMINI, 100 MHz). CDCl 3 (Chloroform-d, Aldrich Co., Ltd.) was used as the solvent, and it was expressed as δ value (ppm) using trimethylsilane as an internal standard material. Conformity with Kazuo et al., Chem. Pharm. Bull . Pp 3347-3353, 1982 confirmed that it is obovatol.
1H-NMR (400MHz, CDCl3), δ 6.28(1H, d, J=1.8Hz, H-4), 6.56(1H, d, J=1.8Hz, H-6), 3.18(2H, d, J=6.6Hz, H-7), 5.97(2H, m, H-8 and H-8'), 5.09(4H, m, H-9 and H-9'), 6.93(2H, d, J=4.3Hz, H-2' and H-6'), 7.14(2H, d, J=4.3Hz, H-3' and H-5'), 3.36(2H, d, J=6.6Hz, H-7') 1 H-NMR (400 MHz, CDCl 3 ), δ 6.28 (1H, d, J = 1.8 Hz, H-4), 6.56 (1H, d, J = 1.8 Hz, H-6), 3.18 (2H, d, J = 6.6 Hz, H-7), 5.97 (2H, m, H-8 and H-8 '), 5.09 (4H, m, H-9 and H-9'), 6.93 (2H, d, J = 4.3 Hz, H-2 'and H-6'), 7.14 (2H, d, J = 4.3 Hz, H-3 'and H-5'), 3.36 (2H, d, J = 6.6 Hz, H-7 ')
13C-NMR (100MHz, CDCl3), δ 143(C-1), 132.93(C-2), 144.77(C-3), 110.68(C-4), 132.47(C-5), 111.17(C-6), 39.60(C-7), 137.33(C-8), 115.85(C-9), 154.98(C-1'), 117.84(C-2' and C-6'), 129.82(C-3' and C-5'), 135.18(C-4'), 39.38(C-7'), 137.18(C-8'), 115.75(C-9') 13 C-NMR (100 MHz, CDCl 3 ), δ 143 (C-1), 132.93 (C-2), 144.77 (C-3), 110.68 (C-4), 132.47 (C-5), 111.17 (C -6), 39.60 (C-7), 137.33 (C-8), 115.85 (C-9), 154.98 (C-1 '), 117.84 (C-2' and C-6 '), 129.82 (C- 3 'and C-5'), 135.18 (C-4 '), 39.38 (C-7'), 137.18 (C-8 '), 115.75 (C-9')
실험예 1. 공간학습능력 평가를 위한 수중미로(워터-메이지, water maze) Experimental Example 1. Underwater maze for evaluating spatial learning ability (water maze)
상기 실시예 1에 따라 얻은 오보바톨을 포함하는 후박추출물이 스코폴라민(scopolamine)으로 뇌손상을 유발시킨 실험쥐의 학습능력에 미치는 영향을 평가하기 위해, 기존 문헌에 기재된 수중미로 실험동물 모델을 응용하여 하기와 같은 과정으로 실험을 수행하였다(한국보건공정서연구회, 건강기능식품의 기능성식품 가이드, 663-701, 2004; Widy-Tyszkiewicz et al., Biol Pharm Bull, 2002).In order to evaluate the effect of the pear extract containing obovatol obtained according to Example 1 on the learning ability of a mouse that caused brain damage with scopolamine, the experimental animal model was described in the existing underwater literature. The experiment was carried out by the following procedure (Korean Institute of Health Process, Functional Food Guide of Health Functional Food, 663-701, 2004; Widy-Tyszkiewicz et al., Biol Pharm Bull , 2002).
5-6주령의 ICR계 수컷 마우스(20-28g)(대한바이오링크, 한국)를 적당한 온도(22±2℃)와 일주기(12시간)를 유지하는 동물실에서 키웠고, 10마리를 1군으로 하여 케이지에서 물과 먹이를 자유 공급하였다. 실험 마우스는 실험 전에 1주일간 순화시켜 사용하였다.5-6 week old ICR male mice (20-28 g) (Korea Biolink, Korea) were raised in an animal room maintaining moderate temperature (22 ± 2 ° C) and daily cycle (12 hours). The cage was freely supplied with water and food. Experimental mice were used for 1 week prior to experiment.
직경 180㎝, 높이가 50㎝인 원통형 수조에 수온이 22±3℃로 조절된 물을 30㎝의 높이로 채웠다. 도피대는 직경이 12㎝인 원형 투명아크릴에 받침대를 부착하고 수면보다 1.5㎝ 낮게 위치하였다. 실험쥐는 하루에 180초간 6일간의 적응훈련(acquisition test)을 받았으며, 7일째 자유수영검사(retention test)를 실시하였는데 이때 실험쥐들은 도피대가 제거된 채로 60초간 수영을 하게 하였다. 모든 실험쥐의 행동은 비디오카메라를 이용해 녹화하여, 실험쥐가 도피대에 올라가는 시간과 거리를 측정하였다. 시험물질은 0.1 ml의 에탄올에 녹였고, 실험동물 몸무게 10g당 0.1ml의 양을 투여하기 위하여 0.1%의 트윈-80(Tween-80)으로 희석하였다. 오보바톨을 포함하는 후박추출물(1.5, 3.0 및 5.0mg/kg)은 실험 측정 1시간 전 실험동물에 단회 경구 투여하였다.A cylindrical water bath of 180 cm in diameter and 50 cm in height was filled with water having a water temperature of 22 ± 3 ° C. at a height of 30 cm. The sheath was attached to a round transparent acrylic having a diameter of 12 cm and placed 1.5 cm lower than the water surface. The mice underwent six days of acquisition test for 180 seconds per day, followed by a retention test on the seventh day, where the mice were allowed to swim for 60 seconds with the hides removed. All mouse behaviors were recorded using video cameras to measure the time and distance the mice climbed on the shelters. The test material was dissolved in 0.1 ml of ethanol and diluted with 0.1% Tween-80 to administer an amount of 0.1 ml per 10 g body weight of the experimental animal. Thick extract (1.5, 3.0 and 5.0 mg / kg) containing obovatol was administered orally to the
비교예로는 스코폴라민만을 처리하였다. 각 군을 평가하여 그 평균값 결과 및 개선률(%)을 하기 표 1과 도 3에 나타냈다.As a comparative example, only scopolamine was treated. Each group was evaluated, and the average result and improvement rate (%) are shown in Table 1 and FIG. 3.
상기 표 1에 나타나는 바와 같이 스코폴아민만을 처리한 실험쥐는 escape distance(㎝)가 증가한 반면, 스코폴아민과 시험물질인 후박추출물을 동시 처리한 실험쥐의 경우 농도의존적으로 유의성 있게 escape distance가 감소해, 대조군과 유사한 수준으로 개선됨을 확인하였다. As shown in Table 1, the mice treated with scopolamine only increased the escape distance (cm), while the mice treated with scopolamine and the test substance thick extract decreased concentration-dependently. The solution was confirmed to improve to a level similar to that of the control group.
실험예 2. 명시적 기억능력 시험을 위한 수동적 회피(패시브-어보이던스, passive avoidance)Experimental Example 2. Passive avoidance for explicit memory test
상기 실시예 1에 따라 얻은 오보바톨을 포함하는 후박추출물이 스코폴라민(Scopolamine)으로 뇌손상을 유발시킨 실험쥐의 기억능력에 미치는 영향을 평가하기 위해, 기존 문헌에 기재된 수동적회피(패시브-어보이던스) 실험동물 모델을 응용하여 하기와 같은 과정으로 실험을 수행하였다(한국보건공정서연구회, 건강기능식품의 기능성식품가이드 663-701,2004; Rho et al., Biol Pharm Bull, 2005). In order to evaluate the effect of the pear extract containing obovatol obtained according to Example 1 on the memory capacity of the mice induced brain damage with scopolamine (Scopolamine), passive evacuation (passive-a) VODENCE) The experiment was performed by applying the experimental animal model (Korean Health Procedures Research Institute, Functional Food Guide of Health Functional Food 663-701,2004; Rho et al., Biol Pharm Bull , 2005).
수동적 회피를 위한 시험장치는 전기충격발생기와 회피장치로 구성되어있다. 회피상자는 검은 아크릴로 만들어진 어두운 상자(30x30x30㎝)와 동일한 크기의 조명을 가할 수 있는 밝은 구획, 그리고 두 공간 사이를 연결하는 문으로 구성되어 있으며. 어두운 상자의 바닥에는 알미늄막대가 일정한 간격으로 깔려 있어, 이를 통해 동물의 발바닥에 전기충격을 가할 수 있도록 하였다. 실험쥐를 밝은 구획에 위치시킨 후 상자부위에 위치시킨 후 조명을 키고 문을 열어 실험쥐가 어두운 구획으로 들어갈 수 있게 하였다. 이러한 시행을 3회 반복한 후 3번째 시행에는 어두운 곳으로 들어가는 순간 바닥에 깔려있는 알미늄격자를 통해 전기충격(0.1mA, 5초)을 가하였다. 24시간 경과 후 동일한 절차를 사용해 기억검사를 실시한다. 문이 열린 수 어두운 구획으로 들어가는 시간을 측정해 도달 시간이 길수록 학습과 기억이 좋음을 의미한다. 각 군당 3마리를 평가하여 그 평균값 결과 및 개선률(%)을 하기 표 2와 도 4에 나타내었다.The test apparatus for passive avoidance consists of an electric shock generator and an avoidance device. The evacuation box consists of a dark box made of black acrylic (30x30x30cm), a bright compartment with the same size of illumination, and a door that connects the two spaces. The bottom of the dark box was covered with aluminum bars at regular intervals, which allowed them to apply an electric shock to the animal's paws. The mice were placed in bright compartments, placed in boxes, and illuminated and opened to allow mice to enter dark compartments. After repeating these three times, the third trial was subjected to an electric shock (0.1 mA, 5 seconds) through the aluminum lattice on the floor as soon as it entered the dark place. After 24 hours, the memory test is performed using the same procedure. It measures the time it takes for the door to go into a dark compartment, which means that the longer the arrival time, the better the learning and memory. Three groups of each group were evaluated, and the average value results and improvement rate (%) are shown in Table 2 and FIG. 4.
상기 표 2에 나타나는 바와 같이, 스코폴라민만을 처리할 경우 step through latency(sec)가 감소한 반면, 스코폴아민과 함께 시험물질인 후박추출물을 동시 투여할 경우 농도의존적으로 step through latency(sec)가 증가하여 대조군과 유사하게 개선됨을 확인하였다. As shown in Table 2 above, when only scopolamine is treated, step through latency (sec) decreases, whereas when co-administering a succinate extract as a test substance together with scopolamine, step through latency (sec) is dependent on concentration. The increase was confirmed to improve similar to the control.
실험예 3. 아세틸콜린 에스테라제(Acetylcholinesterase) 활성억제Experimental Example 3. Inhibition of Acetylcholinesterase Activity
행동약리 실험 후 생쥐의 뇌에서 해마(hippocampus)를 분리한 뒤 RO-PREP 단백질 추출 용액(Protein Extraction Solution, iNtRON Bio-tech)으로 균질 분쇄하고 4℃에서 15,000rpm으로 2시간 원심분리하여 상등액만 취하고, 최종 추출물의 단백질양을 Bio-Rad 단백질 분석 키트(Bio-Rad)를 사용하여 측정하였다. 아세틸콜린 에스테라제 활성은 Ellman 방법을 변형하여 실시하였다.After behavioral pharmacological experiments, hippocampus was isolated from the brain of the mouse, homogenized with RO-PREP Protein Extraction Solution (iNtRON Bio-tech) and centrifuged at 15,000 rpm for 2 hours at 4 ° C. The protein amount of the final extract was measured using the Bio-Rad Protein Analysis Kit (Bio-Rad). Acetylcholine esterase activity was performed by modifying the Ellman method.
96 웰 플레이트에 세포 용해물(cell lysate)을 웰당 10㎕씩 넣고 반응 완충액[0.01% DTNB, 0.02% 아세틸티오콜린(Acetylthiocholine) 및 0.1mM isoOMPA를 포함하는 50 mM Tris-HCl(pH 8.0, 0.1M NaCl, 20 mM MgCl2)]를 190㎕ 넣고 37℃에서 5분간 405nm 1차 측정하였다. 반응 10분 후 405nm에서 2차 측정하였다. 아세틸티오콜린 에스테라제 검량은 시료 대신 아세틸콜린 에스테라제를 농도 별로 넣고 표준 완충액[0.01 % DTNB 및 0.02% 0.1mM isoOMPA를 포함하는 50mM Tris-HCl(pH 8.0, 0.1M NaCl, 20 mM MgCl2)]을 처리하여 5분간 37℃에서 405nm 측정하였다. 시료에 1차와 2차 흡광도 차이에 대한 단위시간 당 변화를 검량선에 대입하여 활성도로 나타내었다. 3번 평가하여 평균값 결과 및 개선률(%)는 하기 표 3와 도 5에 나타냈다.10 μl of cell lysate was added per well in a 96 well plate, and 50 mM Tris-HCl (pH 8.0, 0.1 M containing reaction buffer [0.01% DTNB, 0.02% Acetylthiocholine) and 0.1 mM isoOMPA). 190 μl of NaCl, 20 mM MgCl 2 ) was added thereto, and primary measurement was performed at 37 ° C. for 5 minutes. After 10 minutes of reaction, the second measurement was performed at 405 nm. Acetylthiocholine esterase calibration was performed by adding acetylcholine esterase instead of the sample by concentration and 50 mM Tris-HCl (pH 8.0, 0.1 M NaCl, 20 mM MgCl 2 with standard buffer [0.01% DTNB and 0.02% 0.1 mM isoOMPA]). )] And measured 405 nm at 37 ° C. for 5 minutes. The change per unit time for the difference between the primary and secondary absorbance of the sample was expressed as activity by substituting the calibration curve. Evaluating three times, the average value results and improvement rate (%) are shown in Table 3 and FIG. 5.
상기 표 3에 나타나는 바와 같이, 스코폴라민만을 처리할 경우 효소활성도가 증가된 반면 스코폴아민과 함께 시험물질인 후박추출물을 동시 처리할 경우 농도 의존적으로 효소활성도가 감소되어 유의성 있게 대조군과 유사한 수준으로 개선됨을 확인하였다. As shown in Table 3, the enzyme activity was increased when only scopolamine was treated, but the enzyme activity was decreased in a concentration-dependent manner when co-treatment with the scopolamine as a test substance was performed in a concentration-dependent manner. It was confirmed that the improvement.
실험예 4. 베타-세크리테이즈(β-secretase) 활성억제Experimental Example 4. Inhibition of beta-secretase activity
행동약리 실험 후 생쥐의 뇌의 해마(hippocampus)을 분리해 PRO-PREP 단백질 추출 용액(iNtRON Bio technology co., Ltd)으로 균질 분쇄하고 4℃에서 15,000rpm로 2시간 원심분리하여 상등액만 취하고, 최종 추출물의 단백질양을 Bio-rad 단백질 분석 키트(Bio-rad Co.)를 사용하여 측정하였다. BACE1 FRET 분석 키트(PANVERA)를 이용하여 β-세크리테이즈를 정량 하였다. 96 웰 플레이트에 세포 용해물(cell lysate)을 웰당 10㎕씩 넣고 BACE1 기질(substrate)(Rh-EVNLDAEFK-Quencher)를 10㎕를 가하고 실온에서 1 시간 반응시킨 다음, BACE1 종결 완충액(stop buffer, 2.5M 소디움 아세테이트) 10㎕를 넣어 반응을 종료시켰다. 형성된 형광(fluorescence)을 형광 마이크로플레이트 리더(fluorescent microplate reader)를 이용해 여기(excitation) 545nm, 발광(emission) 585nm에서 측정하였다. 3번 수행하여 그 평균값 결과 및 개선률(%)를 하기 표 4와 도 6에 나타냈다.After behavioral pharmacological experiments, hippocampus of the mouse brain was isolated, homogenously pulverized with PRO-PREP protein extraction solution (iNtRON Bio technology co., Ltd), centrifuged at 15,000 rpm for 2 hours at 4 ℃, and only supernatant was taken. Protein amount of the extract was measured using the Bio-rad protein analysis kit (Bio-rad Co.). Β-secretase was quantified using the BACE1 FRET Assay Kit (PANVERA). 10 μl of cell lysate per well was added to a 96 well plate, and 10 μl of BACE1 substrate (Rh-EVNLDAEFK-Quencher) was added thereto, followed by reaction at room temperature for 1 hour, followed by BACE1 termination buffer (stop buffer, 2.5). 10 μl M sodium acetate) was added to terminate the reaction. The fluorescence formed was measured at 545 nm excitation and 585 nm emission using a fluorescent microplate reader. Performed three times, the average value results and the improvement rate (%) are shown in Table 4 and FIG. 6.
상기 표 4에 나타나는 바와 같이, 베타-아밀로이드(β-amyloid)만을 처리할 경우 효소활성도가 증가되었고, 베타-아밀로이드와 함께 시험물질인 후박추출물을 투여할 경우 농도 의존적으로 효소활성도가 감소되어, 유의성있게 개선됨을 확인하였다.As shown in Table 4, the enzyme activity was increased when only beta-amyloid was treated, and the enzyme activity was decreased in a concentration-dependent manner when the beta-amyloid was administered with the test substance, which is a test substance. It was confirmed to improve.
실험예 5. 감마-세크리테이즈(γ-secretase) 활성억제Experimental Example 5. Inhibition of gamma-secretase activity
행동약리 실험 후 생쥐의 뇌의 해마(hippocampus)와 피질(cortex)을 분리해 PRO-PREP 단백질 추출 용액(iNtRON Bio technology Co., Ltd)으로 균질 분쇄하고 4℃에서 15,000rpm로 2시간 원심분리하여 상등액만 취하고, 최종 추출물의 단백질양을 Bio-rad 단백질 분석 키트(Bio-rad Co.)를 사용하여 측정하여 1㎎/㎖으로 조정하였다. γ-세크리테이즈 활성 키트(γ-Secretase Activity Kit, R&D systems)를 이용하여 γ-세크리테이즈를 정량하였다. 96 웰 플레이트에 세포 용해물을 50㎕/웰 넣고 2시간 반응 완충액 50㎕를 첨가하였다. 기질 5㎕를 넣어 조심스럽게 잘 섞어 준 후 빛을 차단한 상태에서 1시간 동안 37℃에서 반응시켰다. 그 후 형광 마이크로플레이트 리더(fluorescent microplate reader)를 이용하여 여기(excitation) 355nm, 발광(emission) 510nm에서 측정하였다. 3번 측정하여 그 평균값 결과 및 개선률(%)를 하기 표 5와 도 7에 나타내었다.After behavioral pharmacological experiments, the hippocampus and cortex of the mouse brain were separated and homogenized with PRO-PREP protein extraction solution (iNtRON Bio technology Co., Ltd) and centrifuged at 15,000 rpm for 2 hours at 4 ℃. Only the supernatant was taken, and the protein amount of the final extract was adjusted to 1 mg / ml by using a Bio-rad protein analysis kit (Bio-rad Co.). γ-secretase was quantified using a γ-Secretase Activity Kit (R & D systems). 50 μl / well of the cell lysate was added to a 96 well plate and 50 μl of the reaction buffer was added thereto for 2 hours. 5 μl of substrate was mixed well and reacted at 37 ° C. for 1 hour while blocking light. Thereafter, a fluorescent microplate reader was used to measure the excitation at 355 nm and the emission at 510 nm. Three times the average value results and the improvement rate (%) is shown in Table 5 and FIG.
상기 표 5에 나타나는 바와 같이, 베타-아밀로이드만을 처리할 경우 효소활성도가 증가되었다가, 베타-아밀로이드와 함께 시험물질인 후박추출물을 투여할 경우 효소활성도가 다시 감소하여 대조군과 유사한 정도로 개선됨을 확인하였다. As shown in Table 5, when only beta-amyloid was treated, the enzyme activity was increased, and when the beta-amyloid was administered with the test substance, the late extract, the enzyme activity was decreased again, and it was confirmed to be improved to a similar level as the control group. .
본 발명의 후박 추출물을 포함하는 기능성 식품 또는 약학적 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다. Examples of the preparation of a functional food or pharmaceutical composition comprising a pakbak extract of the present invention, but the present invention is not intended to limit it, but to explain in detail only.
제제예 1. 건강 식품의 제조Formulation Example 1 Preparation of Healthy Food
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 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. Although the composition ratio of the above-mentioned vitamin and mineral mixtures is mixed with a component suitable for a health food in a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional health food manufacturing method. The granules may be prepared and used for preparing a health food composition according to a conventional method.
제제예 2. 건강 음료의 제조Formulation Example 2 Preparation of Healthy Drinks
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2L용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.After mixing the above components according to the conventional healthy beverage production method, and then stirred and heated at 85 ℃ for about 1 hour, the resulting solution is filtered and obtained by sterilization in a 2L container sterilized sealed sealed and then stored in the present invention For the preparation of healthy beverage compositions.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다. Although the composition ratio is mixed with a component suitable for a favorite beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, and usage.
제제예 3. 정제의 제조Formulation Example 3 Preparation of Tablet
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.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
통상의 주사제의 제조방법에 따라 1 앰플당(2 ml) 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).
이상 설명한 바와 같이, 본 발명의 후박 추출물은 오랜 기간 동안 사용되어 인체에 안전하면서도, 타-아밀로이드 형성에 관여하는 베타와 감마-세크리테이즈 (β, γ-secretase) 활성을 억제함으로써 알츠하이머 병, 다운증후군, 인지장애(cognitive disorder), 기억력 감퇴, 아밀로이드증(amyloidosis) 등과 같은 아밀로이드 관련 질환의 치료 또는 예방을 위한 기능성 식품 또는 약학적 조성물에 효과적으로 사용될 수 있다.As described above, the thick pepper extract of the present invention has been used for a long time and is safe for the human body, while inhibiting the beta and gamma-secretase (β, γ-secretase) activities involved in the formation of ta-amyloid, Alzheimer's disease, It can be effectively used in functional food or pharmaceutical compositions for the treatment or prevention of amyloid-related diseases such as syndrome, cognitive disorders, memory loss, amyloidosis and the like.
Claims (8)
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