KR20060080131A - Composition comprising an extract of cassia mimosoides var. nomame makino for the prevention and treatment of ischemic diseases - Google Patents
Composition comprising an extract of cassia mimosoides var. nomame makino for the prevention and treatment of ischemic diseases Download PDFInfo
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- KR20060080131A KR20060080131A KR1020060000805A KR20060000805A KR20060080131A KR 20060080131 A KR20060080131 A KR 20060080131A KR 1020060000805 A KR1020060000805 A KR 1020060000805A KR 20060000805 A KR20060000805 A KR 20060000805A KR 20060080131 A KR20060080131 A KR 20060080131A
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- ischemic
- extract
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Abstract
본 발명은 저산소 조건에서 세포생존 개선능력을 갖는 차풀 (Cassia mimosoides var. nomame MAKINO) 추출물을 함유하는 조성물에 관한 것으로, 본 발명의 차풀 추출물은 허혈성 질환 동물모델에서 세포자살 (apoptosis)에 대한 강력한 억제활성을 나타내므로, 상기 조성물은 허혈성 질환의 예방 및 치료용 약학조성물 및 건강기능식품으로 유용하게 이용될 수 있다. The present invention is a tea pool having improved cell viability under hypoxic conditions (Cassia mimosoidesvar. nomame The present invention relates to a composition containing MAKINO) extract, and the chapul extract of the present invention exhibits potent inhibitory activity against apoptosis in an ischemic disease animal model, and the composition is a pharmaceutical composition for preventing and treating ischemic disease and health. It can be usefully used as a functional food.
차풀, 세포자살, 허혈성 질환, 약학조성물, 건강기능식품 Tea grass, apoptosis, ischemic disease, pharmaceutical composition, health functional food
Description
도 1a는 저산소 조건에서 배양배지에 농도를 달리한 차풀 조추출물의 첨가에 따른 HepG2 세포의 생존율 개선을 나타내는 그래프이고,Figure 1a is a graph showing the improvement of survival rate of HepG2 cells according to the addition of the extract of the green tea extract at different concentrations in the culture medium in hypoxic conditions,
도 1b는 정상산소 조건에서 배양배지에 농도를 달리한 차풀 조추출물의 첨가에 따른 HepG2 세포의 생존율 개선을 나타내는 그래프이고,Figure 1b is a graph showing the improvement of the survival rate of HepG2 cells according to the addition of the tea extract crude extract with different concentration in the culture medium under normal oxygen conditions,
도 2a는 저산소 조건에서 배양배지에 차풀 조추출물의 첨가에 따른 HepG2 세포의 생존율 개선을 나타내는 그래프이고, Figure 2a is a graph showing the survival rate of HepG2 cells according to the addition of the crude extract extract to the culture medium in hypoxic conditions,
도 2b는 저산소 조건에서 HepG2 세포의 DNA 분절을 나타낸 도이고, Figure 2b is a diagram showing the DNA segment of HepG2 cells in hypoxic conditions,
도 2c는 저산소 조건에서 배양배지에 차풀 조추출물의 첨가에 따른 HepG2 세포의 DNA 분절 억제 효과를 나타낸 도이고, Figure 2c is a diagram showing the effect of inhibiting the DNA segmentation of HepG2 cells according to the addition of the crude extract extract in culture medium under hypoxic conditions,
도 3은 저산소 조건에서 배양배지에 농도를 달리한 차풀 헥산, 에틸아세테이트, 부탄올가용성 분획물 및 수가용성 분획물의 첨가에 따른 HepG2 세포의 생존 정도를 나타낸 MTT 어세이 결과이고,Figure 3 is a MTT assay result showing the survival of HepG2 cells according to the addition of the chapul hexane, ethyl acetate, butanol soluble fraction and water soluble fraction in different concentrations in the culture medium in low oxygen conditions,
도 4a는 뇌경색 동물모델에 복강주사시 차풀 조추출물의 경색 억제 효과를 나타낸 그래프이며,Figure 4a is a graph showing the infarct inhibitory effect of tea extract crude intraperitoneal injection in cerebral infarction animal model,
도 4b는 뇌경색 동물모델의 뇌를 TTC (2,3,5-triphenyltetrazolium chloride) 염색한 결과이며,Figure 4b is a result of staining TTC (2,3,5-triphenyltetrazolium chloride) in the brain of the cerebral infarction animal model,
도 4c는 차풀 조추출물을 복강주사한 뇌경색 동물모델의 뇌를 TTC 염색한 결과이며,Figure 4c is the result of TTC staining of the brain of the cerebral infarct animal model intraperitoneally injected with chapul crude extract,
도 4d는 뇌경색 동물모델에 복강주사시 차풀 에틸아세테이트 가용성 분획물의 농도별 경색 억제 효과를 나타낸 그래프이며,Figure 4d is a graph showing the infarction inhibitory effect of the concentration of Chapul ethyl acetate soluble fraction intraperitoneal injection in animal models of cerebral infarction,
도 5는 혈중 크레아티닌 농도 검사에서 허혈성 급성신부전증 동물모델에 복강주사시 차풀 조추출물의 신장 손상 억제 효과를 나타낸 도이다.5 is a diagram showing the effect of inhibiting the kidney damage of the extract of tea extract during intraperitoneal injection in ischemic acute renal failure animal model in blood creatinine concentration test.
본 발명은 차풀 추출물을 함유하는 허혈성 질환의 예방 및 치료용 조성물에 관한 것이다. The present invention relates to a composition for the prevention and treatment of ischemic diseases containing tea extract.
대표적인 허혈성 질환인 뇌경색과 심근경색은 고혈압, 고지혈증, 당뇨, 흡연 등에 의해 혈관이 좁아지는 동맥경화증에 빠진 상태에서 혈전 등에 의해 뇌에 혈액을 공급하는 뇌동맥 또는 심장에 혈액을 공급하는 관상동맥이 막혀 주위조직이 괴사됨으로써 발생한다.Cerebral infarction and myocardial infarction, which are typical ischemic diseases, are blocked due to hypertension, hyperlipidemia, diabetes, smoking, and atherosclerosis, in which blood vessels are narrowed. It is caused by necrosis of tissue.
심혈관질환은 세계적으로 전체 사망 원인의 30 %를 차지하고 있어 사망원인 1위를 차지하고 있으며, 이 중의 75 %는 심근경색과 뇌경색과 같은 허혈성 질환이다. 심근경색과 뇌경색 각각은 암과 더불어 사망률 최고를 차지하고 있다. 이러한 심근경색과 뇌경색에 의한 사망률을 줄이는 방법에는 고혈압과 고지혈증을 치료하여 혈관의 폐색을 방지하는 방법과 혈관 폐색 시 주위조직의 괴사를 감소시키는 방법이 있다.Cardiovascular disease accounts for 30% of all deaths worldwide and is the number one cause of death, 75% of which are ischemic diseases such as myocardial infarction and cerebral infarction. Myocardial infarction and cerebral infarction each account for the highest mortality rates with cancer. The methods of reducing the mortality caused by myocardial infarction and cerebral infarction include the treatment of hypertension and hyperlipidemia to prevent the blockage of blood vessels and the reduction of necrosis of surrounding tissues when the vessel is blocked.
이 중, 괴사 부위를 감소시키는 최선의 방법은 빠른 시간 내에 막힌 혈관을 혈전용해제 등으로 뚫어 혈관을 재관류 시키는 것이나, 호흡에 의해 에너지를 얻는 심장과 뇌는 혈관이 막히는 폐색 3~ 6 시간 이내에 조직들이 괴사되어 이후에는 재관류를 시키더라도 그 치료효과를 기대할 수 없다. 그러나, 치료효과를 높이는데 필요한 시간인 폐색 3~ 6 시간 이내에 병원에 도착하여 치료를 받아 재관류 시키는 것이 어려운 현실이며, 또한 심장과 뇌는 일단 손상을 입으면 재생이 잘 되지 않는다. 따라서 병원에서 재관류 시킬 때까지 허혈상태에서의 세포생존력을 개선할 수 있다면 치료효과를 높일 수 있다. 이때, 조직괴사 원인 중 하나는 세포자살이며 (Crow MT et al., Circ . Res., 95(10), pp957-970, 2004; Friedlander RM, N. Engl. J. Med ., 348(14), pp1365-1375, 2003), 이를 억제함으로써 세포생존력을 개선할 수 있다.Among these, the best way to reduce the necrotic site is to perforate the blood vessels by thrombolytics to block them, but the heart and the brain, which are energized by breathing, are exposed to tissues within 3-6 hours of blockage. Necrosis and subsequent reperfusion can not expect the therapeutic effect. However, it is difficult to get to the hospital within three to six hours of occlusion, which is the time required to increase the treatment effect, and to reperfusion after treatment, and the heart and brain are not regenerated once damaged. Therefore, if the cell viability in the ischemic state can be improved until reperfusion in the hospital, the therapeutic effect can be increased. At this time, one of the causes of tissue necrosis is apoptosis (Crow MT et al., Circ . Res., 95 (10), pp957-970, 2004; Friedlander RM, N. Engl. J. Med . , 348 (14) , pp1365-1375, 2003), by inhibiting this can improve cell viability.
또한, 신장이식 (Daemen MA et al., Transplantation, 73(11), pp1693-1700, 2002)이나 성형외과적인 수술 (Gastman BR et al., Plast. Reconstr . Surg ., 111, pp1481-1496, 2003) 등에서 이식된 조직의 손상도 허혈에 이은 재관류에 따른 세포자살에 의해 발생한다. In addition, kidney transplantation (Daemen MA et al., Transplantation , 73 (11), pp 1693-1700, 2002) or plastic surgery (Gastman BR et al., Plast. Reconstr . Surg . , 111, pp1481-1496, 2003). Caused by apoptosis.
또한, 심장을 정지시키고 시행하는 수술의 경우, 심폐기에 의해 공급되는 산소량보다 요구되는 산소량이 많게 되면 심근손상 또는 저혈압에 의한 뇌손상이 발생할 수 있다. 예를 들어, 관상동맥 폐색 시에 실시하는 우회로이식 (bypass graft) 수술, 뇌동맥이나 대동맥에 발생한 동맥류 (aneurysm) 수술 등, 혈액을 일부 차단하는 수술 시에 허혈로 인한 심근손상 및 뇌손상으로 심부전 및 반신불수 등의 부작용이 발생할 수 있다. 실제로 대동맥류의 수술적 또는 중재적 치료 시, 3-16 %의 환자에게서 심근허혈, 신부전, 하지마비 등의 부작용이 나타난다. 따라서 허혈조건에서 세포자살을 억제하는 약물을 전처치에 이용한다면, 상기 부작용을 감소시킬 수 있다.In addition, in the case of surgery to stop the heart, if the amount of oxygen required more than the amount of oxygen supplied by the cardiopulmonary system, myocardial damage or brain damage due to hypotension may occur. Heart failure due to ischemia and myocardial damage and brain damage, for example, in cases where some blood is blocked, such as bypass graft surgery during coronary artery occlusion, aneurysm surgery in the cerebral artery or aorta. Side effects such as involuntary return may occur. Indeed, surgical or interventional treatment of aortic aneurysms results in adverse events such as myocardial ischemia, renal failure and paraplegia in 3-16% of patients. Therefore, if a drug that inhibits apoptosis in ischemic conditions is used for pretreatment, the side effects can be reduced.
신경세포자살의 원인은 아직 명확하게 밝혀지지 않았지만 대뇌에 일시적인 뇌허혈이 유발되는 경우, 산소와 포도당의 공급이 차단되어 신경세포에서는 아데노신 삼인산 (ATP)이 감소하고 부종 (edema)이 발생되면서 신경세포자살이 유발되는 것으로 알려져있다. 뇌허혈에 의한 신경세포자살 기전으로는 허혈에 의해서 세포 밖에 과도한 글루탐산 (glutamate)이 축적되게 되고 이 글루탐산이 세포 내로 유입되어 결국 과도한 세포 내 칼슘의 축적으로 신경세포자살이 유발된다는 흥분성 신경세포자살 기전 (Kang TC et al., J. Neurocytol ., 30(12), pp945-955, 2001)과 허혈-재관류 시에 갑작스러운 산소 공급으로 인한 생체 내 라디칼의 증가가 DNA 및 세포질에 손상을 입혀 신경세포사가 유발된다는 산화성 신경세포자살 기전 (Won MH et al., Brain Res., 836(1-2), pp70-78, 1999)이 있다. 이러한 기전적인 연구를 바탕으로 뇌허혈로 인한 신경세포자살을 효과적으로 억제하는 물질을 탐색하거나 물질에 대한 기전을 밝히는 연구가 많이 수행되고 있지만 아직까지 신경세포자살을 효과적으로 억제하는 물질은 거의 발견되지 않았다.The cause of neuronal suicide is not yet clear, but in the case of transient cerebral ischemia in the cerebrum, the supply of oxygen and glucose is blocked, resulting in the reduction of adenosine triphosphate (ATP) and edema in neurons. It is known to be induced. Neuronal suicide mechanism by cerebral ischemia is an excitatory neuronal suicide mechanism in which excess glutamate accumulates outside the cell by ischemia, and this glutamic acid is introduced into the cell, resulting in neuronal cell death due to excessive accumulation of intracellular calcium. Kang TC et al., J. Neurocytol . , 30 (12), pp945-955, 2001) and the increase of radicals in vivo due to sudden oxygen supply during ischemia-reperfusion damages DNA and cytoplasm, resulting in neuronal death. There is an oxidative neuronal cell death mechanism (Won MH et al., Brain Res. , 836 (1-2), pp70-78, 1999). Based on these mechanisms, many researches have been conducted to search for substances that effectively inhibit neuronal cell death caused by cerebral ischemia or to reveal the mechanism of the substance. However, few substances have been found to effectively inhibit neuronal cell suicide.
다만, 허혈조건에서 세포자살을 억제하는 테트라사이클린 계열의 항생제인 미노사이클린의 경우, 뇌경색 (Yrjanheikki J et al., Proc . Natl . Acad . Sci . USA, 96(23), pp13496-13500, 1999), 심근경색 (Scarabelli TM et al., J. Am. Coll. Cardiol ., 43(5), pp865-874, 2004) 및 허혈성 급성신부전증 (Wang J et al., J. Biol . Chem ., 279(19), pp19948-19954, 2004) 등의 허혈성 질환의 치료에도 효과가 있다는 것이 알려져 있다. 또한, 본 발명자들은 이러한 테트라사이클린 계열의 항생제가 본 연구와 유사한 허혈조건에서 세포의 생존을 개선 시키는 것을 확인하였다 (대한민국특허등록번호 0404134호; 미국특허등록번호 6716822, 6818625호). 더군다나 미노사이클린 뿐만 아니라 아미노글리코사이드 계열, 퀴놀론 계열의 항생제들도 미노사이클린과 마찬가지로 허혈조건에서 세포의 생존을 개선시켰으며, 이 중에서 특히 아미노글리코사이드 계열의 G418 (제네티신)은 심근경색 치료 효과가 관찰되었다 (미국특허등록번호 6716822). 이 후의 실험에서 G418은 허혈조건에서 세포자살을 억제하며 심근경색뿐만 아니라 뇌경색에도 치료효과를 나타내는 것을 확인하였다. 상기의 결과로, 허혈조건에서 G418과 동일한 세포 생존 개선 효과를 나타내는 시료들이 궁극적으로 심근경색 등의 허혈성 질환의 치료에 효과를 나타낼 것으로 예상되어 왔으나, 차풀 추출물 및 그 분획이 허혈성 질환에 탁월한 효과를 가지는 것에 대하여 개시된 바는 없다.However, in the case of minocycline, a tetracycline antibiotic that inhibits apoptosis under ischemic conditions, cerebral infarction (Yrjanheikki J et al., Proc . Natl . Acad . Sci . USA , 96 (23), pp13496-13500, 1999), Myocardial infarction (Scarabelli TM et al., J. Am. Coll. Cardiol . , 43 (5), pp865-874, 2004) and ischemic acute renal failure (Wang J et al., J. Biol . Chem . , 279 (19) , pp19948-19954, 2004), is also known to be effective in the treatment of ischemic diseases. In addition, the present inventors have confirmed that such tetracycline-based antibiotics improve the survival of cells in ischemic conditions similar to this study (Korean Patent No. 0404134; US Patent No. 6716822, 6818625). Furthermore, aminoglycoside-based and quinolone-based antibiotics, as well as minocycline, improved cell survival under ischemic conditions. Among them, the aminoglycoside-based G418 (Genetisin) has been shown to treat myocardial infarction. (US Patent No. 6716822). In subsequent experiments, G418 suppressed apoptosis in ischemic conditions and showed a therapeutic effect on myocardial infarction as well as cerebral infarction. As a result, it has been expected that the samples showing the same cell survival improvement effect as G418 under ischemic condition will ultimately be effective in the treatment of ischemic diseases such as myocardial infarction. There is no disclosure about having.
차풀(Cassia mimosoides var. nomame MAKINO)은 콩과의 1년 초로 차대용으로 쓴다고 하여 차풀로 불리게 되었으며, 어린 순은 나물로 먹기도 한다. 전초는 산편두 (Nomame Herba)라 하여 생약으로 쓰이기도 하는데, 습열에 의한 황달, 여름철 식중독에 의한 토사곽란, 야맹증, 종창의 치료에 쓰이고 주성분은 에모딘 (emodin), 피숀 (physcion), 미리스틱산 (myristic acid), 베타-시토스테롤 (β-sistosterol) 등이 있다 (안덕균, 원색한국본초도감, 5, p174, 2002). Cassia mimosoides var. nomame MAKINO) is called Chapul because it is used for teasing at the beginning of the year of legumes, and young sprouts are also eaten as herbs. Outpost is mountain migraine ( Nomame Herba ) is also used as a herbal medicine. It is used for the treatment of jaundice caused by moist heat, soil erosion caused by food poisoning in summer, night blindness, and swelling. The main ingredients are emodin, physcion, myristic acid, Beta-sistosterol and the like (Andok-kyun, primary Korean book of primary color, 5, p174, 2002).
차풀을 이용한 특허로는 혈중지질을 낮추는 음식품으로 개발한 특허 (대한민국 특허등록번호 10-331064호), 다른 약재와의 혼합물을 혈액순환 개선제로 이용한 특허(중국 특허등록번호 1065793호 및 1176814호) 등이 있고 문헌으로는 차풀의 혈중지질 감소효과에 대해 기재된 논문 (Patil UK et al., J. Ethnopharmacol., 90(2-3), pp249-252, 2004) 등이 있으나, 차풀 추출물의 허혈 성질환과 관련된 용도에 관해서는 상기 문헌 어디에도 교시되거나 기재된 바가 없다. As a patent using cha grass, a patent was developed for foods that lower blood lipids (Korean Patent Registration No. 10-331064), and a patent using a mixture with other medicines as a blood circulation improving agent (China Patent Registration Nos. 1065793 and 1176814). And the literature on the effect of Chapulse on reducing blood lipids (Patil UK et al., J. Ethnopharmacol., 90 (2-3), pp249-252, 2004). There is no teaching or description anywhere in the literature regarding uses associated with diseases.
이에 본 발명자들은 허혈성 질환의 치료에 있어서 종래 기술상의 문제점을 인식하고, 저산소 조건에서 세포생존능을 개선시키는 세포자살 억제제로서 차풀 추출물의 허혈성 질환 동물모델에서의 개선 및 치료 효과를 확인함으로써 본 발명을 완성하였다.Accordingly, the present inventors have completed the present invention by recognizing the problems of the prior art in the treatment of ischemic diseases and confirming the improvement and therapeutic effect of chapul extract in ischemic disease animal model as an apoptosis inhibitor that improves cell viability in hypoxic conditions. It was.
본 발명의 목적은 허혈조건에서 세포자살을 효과적으로 억제하는 차풀 추출물 및 이를 함유하는 허혈성 질환의 예방 및 치료를 위한 조성물을 제공하는 것이 다.It is an object of the present invention to provide a composition for preventing and treating ischemic diseases containing chapul extract and an extract that effectively inhibits apoptosis in ischemic conditions.
상기 목적을 수행하기 위하여, 본 발명은 차풀 (Cassia mimosoides var. nomame MAKINO) 조추출물 또는 정제 분획물을 유효성분으로 함유하고 약학적으로 허용되는 담체 또는 부형제를 함유하는 허혈성 질환의 예방 및 치료용 약학조성물을 제공한다.In order to accomplish the above object, the present invention provides a chapul ( Cassia mimosoides var. nomame MAKINO) Provides a pharmaceutical composition for the prevention and treatment of ischemic diseases containing crude extracts or purified fractions as an active ingredient and a pharmaceutically acceptable carrier or excipient.
상기 허혈성 질환은 심근경색, 뇌경색, 허혈성 급성신부전증, 허혈성 급성간부전증, 당뇨성 족부궤양, 당뇨성 신증, 외과수술 부작용에 기인한 허혈성 질환 또는 기관 조직 손상을 포함한다.The ischemic disease includes myocardial infarction, cerebral infarction, ischemic acute renal failure, ischemic acute liver failure, diabetic foot ulcer, diabetic nephropathy, or ischemic disease or organ tissue damage due to surgical side effects.
상기 외과수술 부작용에 기인한 허혈성 질환은 허혈성 심부전, 허혈성 신부전, 허혈성 간부전 또는 허혈성 뇌졸중을 포함한다.Ischemic diseases due to surgical side effects include ischemic heart failure, ischemic renal failure, ischemic liver failure or ischemic stroke.
상기 기관 조직 손상은 허혈 후 재관류를 동반하는 장기 수술 또는 이식, 외상성 절단사지 재접합으로 인한 것임을 특징으로 한다.The organ tissue damage is characterized in that it is due to long-term surgery or transplantation, recurrent traumatic limb rejoint with reperfusion after ischemia.
상기 장기는 신장, 간장, 췌장, 폐 또는 심장 등의 내부장기를 포함한다.The organs include internal organs such as kidneys, liver, pancreas, lungs or heart.
본 발명의 추출물은 차풀 조추출물 및 정제분획물을 포함한다.The extract of the present invention includes a crude extract and chaff extract.
본 발명의 조추출물은 물, 에탄올, 메탄올과 같은 C1 내지 C4의 저급 알콜 또는 이들의 혼합용매, 바람직하게는 메탄올에 가용한 추출물을 포함한다.The crude extract of the present invention comprises water, ethanol, C 1 to C 4 lower alcohols such as methanol or mixed solvents thereof, preferably extracts soluble in methanol.
또한 본 발명의 정제분획물은 차풀 조추출물을 물에 녹인 후 헥산, 에틸아세 테이트 또는 부탄올로부터 선택된 용매로, 바람직하게는 에틸아세테이트에 가용한 분획물을 포함한다. In addition, the purified fraction of the present invention is a solvent selected from hexane, ethyl acetate or butanol after dissolving the crude extract of water in the water, preferably comprises a fraction available in ethyl acetate.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 차풀 조추출물 및 정제분획물은 하기와 같이 수득될 수 있다. Crude crude extract and purified fraction of the present invention can be obtained as follows.
본 발명의 차풀 조추출물은 건조 후, 세절한 차풀에 그 중량의 약 1 내지 15배의 부피, 바람직하게는 약 5 내지 10배 분량의 물, 에탄올, 메탄올 등과 같은 C1 내지 C4의 저급알콜 또는 약 1: 0.1 내지 1:10의 혼합비를 갖는 혼합용매, 바람직하게는 메탄올을 가하고 0 내지 100℃, 바람직하게는 20 내지 100 ℃의 추출온도에서 약 0.5시간 내지 2일, 바람직하게는 1시간 내지 1일 동안 냉침추출, 열수추출, 초음파 추출, 환류냉각 추출, 약탕기 추출 등이 추출방법으로, 바람직하게는 초음파 추출법으로 1회 내지 12회, 바람직하게는 2회 내지 4회 반복하여 추출한 후 여과하고, 여과한 추출물을 감압농축기로 20 내지 100 ℃, 바람직하게는 30 내지 70 ℃에서 감압농축한 후 추출된 잔사를 진공동결건조기로 건조하여 물, 저급 알코올 또는 이들의 혼합 용매에 가용하여 수득할 수 있다.The tea extract crude extract of the present invention is dried, and then, in a fine tea paste, a C 1 to C 4 lower alcohol such as about 1 to 15 times the volume, preferably about 5 to 10 times the amount of water, ethanol, methanol, etc. Or a mixed solvent having a mixing ratio of about 1: 0.1 to 1:10, preferably methanol, and at an extraction temperature of 0 to 100 ° C, preferably 20 to 100 ° C, for about 0.5 to 2 days, preferably 1 hour Cold extraction, hot water extraction, ultrasonic extraction, reflux cooling extraction, medicinal extractor, etc. for 1 to 1 days are extracted by extraction, preferably 1 to 12 times, preferably 2 to 4 times by filtration by ultrasonic extraction and then filtered The filtered extract was concentrated under reduced pressure at 20 to 100 ° C., preferably at 30 to 70 ° C., under reduced pressure, and the residue was dried with a vacuum freeze dryer to be soluble in water, lower alcohols, or a mixed solvent thereof. Can.
상기 농축 단계 직전의 차풀 조추출물을 물에 다시 녹인 수용액을 동량의 헥산, 에틸아세테이트 및 부탄올로 순차적으로 강하게 진탕하여 얻은 비극성용매층을 각각 감압농축 및 동결건조하여 본 발명의 정제분획물인 헥산, 에틸아세테이트 및 부탄올가용 분획물을 수득할 수 있으며, 남은 수층을 감압농축 및 동결건조하여 수 가용 분획물을 수득할 수 있다. The non-polar solvent layer obtained by sequentially shaking the aqueous solution obtained by re-dissolving the crude extract of chapar immediately in the water with the same amount of hexane, ethyl acetate and butanol was concentrated under reduced pressure and lyophilized, respectively, to obtain the purified fractions of the present invention, hexane and ethyl. Acetate and butanol soluble fractions can be obtained, and the remaining aqueous layer can be concentrated under reduced pressure and lyophilized to yield a soluble fraction.
본 발명은 상기 제조방법으로 수득된 본 발명의 차풀 추출물을 유효성분으로 함유하는 허혈성질환의 예방 및 치료에 효과적인 약학조성물을 제공한다.The present invention provides a pharmaceutical composition effective for the prevention and treatment of ischemic diseases containing the chapul extract of the present invention obtained as the active ingredient as an active ingredient.
본 발명에 따른 차풀 조추출물을 처리한 인간간암세포주를 이용한 트립판 블루 색소 배제법 시험 결과 세포생존을 개선하는 효과가 탁월하였으며, 차풀 조추출물을 처리한 인간간암세포주를 이용한 DNA 분절 분석 시험 결과 세포자살을 억제하는 활성이 탁월하였고, 차풀 에틸아세테이트가용 분획물을 처리한 인간간암세포주를 이용한 MTT 어세이 결과 세포생존 개선효과가 탁월하였다.Trypan blue pigment exclusion test using the human liver cancer cell line treated with crude extract of chapul according to the present invention was excellent in improving cell survival, DNA segment analysis test results using human liver cancer cell line treated with crude extract The suicide inhibiting activity was excellent, and MTT assay using human hepatocellular carcinoma cell line treated with Chapul ethyl acetate soluble fraction was effective in improving cell survival.
또한, 차풀 조추출물 및 에틸아세테이트가용 분획물을 허혈성 질환을 유발한 동물 모델에 투여한 결과 조직의 손상을 탁월하게 감소시켰다.In addition, administration of the crude extract and ethyl acetate soluble fraction in the animal model that caused the ischemic disease significantly reduced tissue damage.
본 발명의 차풀 추출물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용 시에도 안심하고 사용할 수 있다.Tea grass extract of the present invention has little toxicity and side effects, so can be used with confidence even during prolonged use for prophylactic purposes.
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 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 있다. 추출물을 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 셀룰로 즈, 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 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 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, 동결건조 제제, 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 (macrogol), 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. Can be formulated and used. Carriers, excipients and diluents that may be included in the composition comprising the extract 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 such solid preparations may include at least one excipient such as starch, calcium carbonate, sucrose in the extract. Or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use may include various excipients, such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are commonly used to include suspensions, solutions, emulsions, and syrups. have. 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. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 조성물은 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있다. The compositions of the present invention can be administered via several routes including oral, transdermal, subcutaneous, intravenous or intramuscular.
본 발명의 차풀 추출물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 달라질 수 있으나, 0.1 내지 1000 mg/㎏의 양을 1일 1회 내지 수회 투여할 수 있다. 따라서, 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. Preferred dosages of the tea extract of the present invention may 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, but the amount of 0.1 to 1000 mg / kg may be administered once to several times a day. Can be. Therefore, the above dosage does not limit the scope of the present invention in any aspect. Administration may be administered once a day or may be divided several times.
또한, 본 발명은 허혈성 질환의 예방 및 개선 활성을 갖는 차풀 조추출물 또는 정제분획물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강기능식품을 제공한다. In addition, the present invention provides a health functional food comprising a tea extract crude extract or purified fraction and food acceptable food additives having an activity of preventing and improving ischemic disease.
본원에서 정의되는 "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.As defined herein, "health functional food" means a food manufactured and processed using raw materials or ingredients having functional properties useful for the human body according to Act No. 6767 of the Health Functional Food Act, and "functional" means It means ingestion for the purpose of obtaining useful effects on health use such as nutrient control or physiological action on structure and function.
본 발명의 허혈성 질환의 예방 및 개선을 위한 건강기능식품은, 조성물 총 중량에 대하여 상기 차풀 추출물을 0.01 내지 95 %, 바람직하게는 1 내지 80 % 중량백분율로 포함한다.The dietary supplement for the prevention and improvement of the ischemic disease of the present invention, the chaff extract based on the total weight of the composition comprises 0.01 to 95%, preferably 1 to 80% by weight.
또한, 허혈성 질환의 예방 및 개선을 위한 목적으로 산제, 과립제, 정제, 캡슐제, 환제, 현탁액, 에멀젼, 시럽 등의 약학투여형태 또는 건강음료 등의 형태인 건강기능식품으로 제조 및 가공이 가능하다.In addition, for the purpose of preventing and improving ischemic diseases, it is possible to manufacture and process as a health functional food in the form of pharmaceutical dosage forms such as powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups, or health drinks. .
본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같 이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 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, 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 ~ 20g, 바람직하게는 약 5 ~ 12g이다.The health functional beverage composition of the present invention is not particularly limited to other ingredients except for containing the 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 glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (tauumatin, stevia extract (e.g., Rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The ratio of the natural carbohydrate 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.
또한, 본 발명의 추출물은 허혈성질환의 예방 효과를 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 5 g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.In addition, the extract of the present invention may be added to food or beverage for the purpose of preventing the ischemic disease. At this time, the amount of the extract in the food or beverage may be added in 0.01 to 15% by weight of the total food weight, the health beverage composition may be added in a ratio of 0.02 to 5 g, preferably 0.3 to 1g based on 100 ml. have.
이하, 본 발명을 하기의 실시예 및 실험예에 의해 상세히 설명한다.Below, The invention is illustrated in detail by the following examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 의해 한정되는 것은 아니다.However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.
실시예Example 1. One. 차풀Chapool 조추출물의Crude extract 제조 Produce
국내에 자생하는 차풀을 수집하여 깨끗이 수세하고 건조한 후, 차풀 시료 500 g에 5 ℓ의 메탄올을 넣고 초음파추출기 (sonicator, 8210R-DTH, Branson, 미국)에서 24시간 동안 2회 반복하여 추출하여 여과하고, 감압농축기 (NP-1, EYELA, Japan)로 감압농축하여 차풀 메탄올추출물 62 g을 수득하였다 (이하 HY2207로 명명함).After collecting domestically grown tea grass, wash it cleanly and dry it, and put 500 liters of tea grass sample into 5 liters of methanol, and extract it twice by using an ultrasonic extractor (sonicator, 8210R-DTH, Branson, USA) for 24 hours and filter it. , Concentrated under reduced pressure with a vacuum concentrator (NP-1, EYELA, Japan) to obtain 62 g of chapul methanol extract (hereinafter referred to as HY2207).
실시예Example 2. 2. 차풀Chapool 정제분획물의Purified fraction 제조 Produce
국내에 자생하는 차풀을 수집하여 깨끗이 수세하고 건조한 후, 그 100 g을 10배수의 메탄올을 사용하여 상기 실시예 1의 방법으로 추출한 후 여과지 (filter paper; Whatman No.3)로 여과한 용액을 38 ℃에서 감압농축하여 메탄올 조추출물을 16 g 수득하였다. 상기 메탄올 조추출물 16 g을 물 200 ㎖에 현탁시켜 1 ℓ 분획여두에 넣고 헥산 200 ㎖를 첨가하여 24시간 경과 후 헥산층을 회수하여 80 ℃에서 농축하였고, 동일한 방법으로 2회 반복하여 헥산 분획물 (이하 CM-HX로 명명함) 2.9 g을 얻었다. 남은 물 현탁액에 에틸아세테이트 용매 200 ㎖를 분획여두에 넣은 후 24시간 경과 후 에틸아세테이트층을 회수하여 38 ℃에서 감압 농축하였고, 위와 같은 방법으로 2회 반복하여 에틸아세테이트 분획물 (이하 CM-EA로 명명함) 3.5 g을 얻었으며 남은 물 현탁액에 다시 부탄올 용매 200 ㎖를 분획여두에 넣어 24시간 경과 후 부탄올층을 회수하여 60 ℃에서 감압농축하였고 위와 같은 방법으로 2회 반복하여 부탄올분획물 (이하 CM-BU로 명명함) 2.6 g을 얻었으며, 남은 물 현탁액은 50 ℃에서 감압농축하여 물분획물 (이하 CM-WA로 명명함) 6.8 g을 얻었다.After collecting domestically grown grass, washed with water and dried, 100 g of the extracted by the method of Example 1 using 10 times the number of methanol and filtered with a filter paper (Whatman No. 3) 38 Concentration under reduced pressure at ° C yielded 16 g of crude methanol extract. 16 g of the crude crude methanol suspension was suspended in 200 ml of water, placed in a 1 L fraction filter, and 200 ml of hexane was added thereto. After 24 hours, the hexane layer was recovered, concentrated at 80 ° C., and repeated twice in the same manner. 2.9 g). After 200 hours of ethyl acetate solvent was added to the remaining water suspension in the remaining water suspension, the ethyl acetate layer was recovered and concentrated under reduced pressure at 38 ° C. The ethyl acetate fractions were repeated twice as described above (hereinafter referred to as CM-EA). Business card) 3.5 g was added to the remaining water suspension, and 200 ml of butanol solvent was added to the fractional filter, and after 24 hours, the butanol layer was recovered and concentrated under reduced pressure at 60 ° C .. The same procedure was repeated twice to obtain butanol fraction (hereinafter, CM- 2.6 g, and the remaining water suspension was concentrated under reduced pressure at 50 ° C. to obtain 6.8 g of a water fraction (hereinafter referred to as CM-WA).
참고예Reference Example 1. 실험동물의 준비 1. Preparation of experimental animals
실험동물은 체중 250-300 g의 스프라그-다우리 (Sprague-Dawley)계 수컷 랫트 (효창사이언스 사)를 사용하였고, 대구카톨릭의대 동물사육실에서 일정한 조건 (온도: 21± 2 ℃, 명암: 12시간 명암주기)에서, 사료와 음수의 자유로운 섭취가 가능하도록 하였으며, 실험시작 전까지 물과 먹이를 충분히 제공하며 실험시작 전에 실험동물을 10분 동안 사전취급 (handling) 하였다.Experimental animals used Sprague-Dawley male rats (Hyochang Science Co., Ltd.) weighing 250-300 g in weight, and constant conditions (temperature: 21 ± 2 ℃, contrast: 12) in Daegu Catholic University medical school. In the time-contrast cycle, free intake of food and water was allowed, and sufficient water and food were provided before the start of the experiment, and the animals were pretreated for 10 minutes before the start of the experiment.
실험예Experimental Example 1. One. 차풀Chapool 조추출물의Crude extract 세포생존능Cell viability 개선 활성 측정 ( Improve activity measurement ( in vitroin vitro ))
차풀 조추출물이 저산소 및 정상산소 조건에서 세포의 생존에 미치는 영향을 조사하기 위하여 세포에 상기 실시예 1에서 준비한 HY2207을 농도별로 적용한 배지를 첨가한 후, 저산소 조건 및 정상산소 조건에서 하기와 같이 실험을 수행함으로써 세포생존을 개선시키는 정도를 문헌 (Sambrook J and Russel DW, Molecular Cloning 3rd ed., Vol.3, A8.6-8.8, Cold Spring Harbor Laboratory Press, New York, 2001)에 기재된 트립판 블루 염색 배제법 (trypan blue dye exclusion)을 변형하여 측정하였다. In order to investigate the effect of the extract of chapul crude extract on the survival of cells in hypoxic and normal oxygen conditions, after adding the medium to which the concentration of HY2207 prepared in Example 1 was added to the cells, the experiment as follows in hypoxic and normal oxygen conditions The degree to which cell survival is improved by performing the following methods is described in Trypan Blue, described in Sambrook J and Russel DW, Molecular Cloning 3rd ed., Vol. 3, A8.6-8.8, Cold Spring Harbor Laboratory Press, New York, 2001. It was measured by modifying trypan blue dye exclusion.
인간 간암세포주 (human hepatoma cell line)인 HepG2 (ATCC HB 8065, 미국)를 항생제로는 페니실린 지 (penicillin G sodium, 100 Units/ℓ, Invitrogen, USA) 및 스트렙토마이신 (streptomycin sulfate, 100 mg/L, Invitrogen, USA)과 혈청으로는 10 % 우태아혈청 (fetal bovine serum, Invitrogen. USA)이 첨가된 이글 최소 배지 (EMEM, Eagle's minimum essential midium; Invitrogen, 미국)를 사용하여 12웰 플레이트 (12well-plate)에서 2×105 세포수/800 ㎕배지로 배양하였다. 세포들을 37 ℃ 및 5 % CO2-95% 대기상태에서 48시간 동안 배양하고 동일한 새 배양배지로 교체한 후, 상기 실시예 1의 HY2207을 50 % 에탄올에 용해시켜 100 ㎍/㎖, 1000 ㎍/㎖의 농도로 배양배지에 첨가한 실험군 및 아무것도 첨가하지 않은 음성대조군 (negative control)을 저산소 (산소농도 3 %) 및 정상산소 조건에서 각각 2일 동안 배양하면서 하기의 트립판 블루 염색 배제법을 이용하여 세포수를 측정하였다. 배지를 제거하고 인산염완충액 (phosphate buffered-saline, PBS)으로 한번 씻어준 다음 트립신 (trypsin) 처리를 하였다. 그리고 원심분리를 해서 세포를 모으고 새로운 배지를 첨가해 세포 현탁액을 만든 다음 0.4 % 트립판 블루 용액 (trypan blue solution, Invitrogen, 미국)과 세포 현탁액을 1: 1로 섞어서 5분이 지난 뒤에 푸른 빛으로 염색된 세포를 죽은 세포로 염색되지 않은 세포는 살아있는 세포로 간주하고 세포계산기 (hemocytometer)를 이용하여 세포수를 측정하였다. HepG2 (ATCC HB 8065, USA), a human hepatoma cell line, contains penicillin G sodium (100 Units / L, Invitrogen, USA) and streptomycin sulfate (100 mg / L). 12 well-plate using Invitrogen, USA) and Eagle's minimum essential midium (EMEM, Invitrogen, USA) added with 10% fetal bovine serum (Invitrogen. USA) as serum. ) Was incubated in 2 × 10 5 cell number / 800 μl medium. After incubating the cells for 48 hours at 37 ° C. and 5% CO 2 -95% atmosphere and replacing with the same fresh culture medium, HY2207 of Example 1 was dissolved in 50% ethanol to 100 μg / ml, 1000 μg / The experimental group added to the culture medium at the concentration of ㎖ and the negative control group (negative control) without any addition were incubated for 2 days at low oxygen (
도 1a에 나타난 바와 같이, 저산소 조건에서는 배양 1일 후 음성대조군 (Control)인 경우 세포들이 거의 모두 죽는데 반해 (Ratio = 0), 본 발명의 HY2207은 100-1000 ㎍/㎖ 농도 범위에서 세포의 생존을 개선시켰으며 (Ratio > 0), 도 1b에 나타난 바와 같이, 정상산소 조건에서는 HY2207이 100-1000 ㎍/㎖ 사이의 농도범위에서 세포의 생존을 약간 저해하는 것을 확인하였다. 이에 따라 본 발명의 HY2207이 저산소 조건에서 효과적으로 세포의 생존을 개선한다는 것을 확인하였으며, 정상산소 조건에서 세포성장을 저해하지 않음과 동시에 저산소 조건에서 효과를 나타내기 위해서는 100-1000 ㎍/㎖ 사이의 농도로 투여되어야 함을 확인하였다.As shown in FIG. 1A, in the hypoxic condition, almost all cells die in the negative control group (Control) after one day of culture (Ratio = 0), whereas the HY2207 of the present invention survives cells in a concentration range of 100-1000 µg / ml. (Ratio> 0), as shown in Figure 1b, it was confirmed that under normal oxygen conditions HY2207 slightly inhibited the survival of cells in the concentration range of 100-1000 ㎍ / ㎖. Accordingly, it was confirmed that the HY2207 of the present invention effectively improves cell survival under hypoxic conditions, and does not inhibit cell growth under normal oxygen conditions and at the same time concentrations between 100 and 1000 ㎍ / ml It was confirmed that it should be administered.
실험예Experimental Example 2. 2. 차풀Chapool 조추출물의Crude extract 저산소조건에서의Under hypoxic conditions 세포자살 억제 활성 측정 ( Apoptosis Inhibition Activity Measurement in vitroin vitro ))
저산소 조건에서 HY2207이 세포생존에 도움을 주는 기전을 확인하기 위해서 문헌에 기재된 DNA 분절 분석방법 (DNA fragmentation assay; Yoshida A et al., In Apoptosis : A practical approach (Studzinski GP (Ed.)), pp47-48, Oxford University Press, New York, 1999)을 변형하여 수행하였다.DNA fragmentation assay; Yoshida A et al., In Apoptosis : A practical approach (Studzinski GP (Ed.)), Pp47 to determine the mechanism by which HY2207 helps cell survival in hypoxic conditions. -48, Oxford University Press, New York, 1999).
인간 간암세포주 (human hepatoma cell line)인 HepG2 (ATCC HB 8065, 미국)를 항생제로는 페니실린 지 (penicillin G sodium, 100 Units/ℓ, Invitrogen, USA) 및 스트렙토마이신 (streptomycin sulfate, 100 mg/L, Invitrogen, USA)과 혈청으로는 10 % 우태아혈청 (fetal bovine serum, Invitrogen. USA)이 첨가된 이글 최소 배지 (EMEM, Eagle's minimum essential midium; Invitrogen, 미국)를 사용하 여 60 ㎜ dish에서 1×106 세포수 /4㎖배지로 배양하였다. 세포들을 37 ℃ 및 5 % CO2-95 % 대기상태에서 48시간 동안 배양한 후 새로운 배양배지로 교체한 다음, 상기 실시예 1의 HY2207을 50 % 에탄올에 용해시켜 300 ㎍/㎖의 농도로 배양배지에 첨가한 실험군 및 아무것도 첨가하지 않은 음성대조군 (negative control)을 저산소와 정상산소 조건에서 각각 2일 동안 배양하면서 DNA 분절 분석(DNA fragmentation assay)을 실시하여 DNA 사다리가 나타나는 양상을 조사하였다. 그 결과, HY2207을 300 ㎍/㎖로 첨가한 실험군 (HY2207)이 첨가하지 않은 대조군 (Control)보다 상기 실험예 1에서와 마찬가지로 세포의 생존을 개선시켰으며 (도 2a 참조), 아울러 HY2207을 첨가한 실험군 (도 2c 참조)이 대조군 (도 2b 참조)보다 DNA 사다리 (ladder)의 출현 시간이 지연되었다. 따라서 HY2207이 세포자살을 억제하여 세포의 생존을 개선시키는 효과가 있음을 확인할 수 있었다.HepG2 (ATCC HB 8065, USA), a human hepatoma cell line, contains penicillin G sodium (100 Units / L, Invitrogen, USA) and streptomycin sulfate (100 mg / L). Invitrogen, USA) and 1 × in a 60 mm dish using Eagle's minimum essential midium (EMEM, Invitrogen, USA) added with 10% fetal bovine serum (Invitrogen. USA) as serum. The cells were cultured in 10 6 cell numbers / 4 ml medium. The cells were incubated for 48 hours at 37 ° C. and 5% CO 2 -95% atmosphere, and then replaced with fresh culture medium. The HY2207 of Example 1 was dissolved in 50% ethanol and incubated at a concentration of 300 μg / ml. DNA fragmentation assay was performed by incubating the experimental group added to the medium and the negative control group without adding the medium for 2 days under hypoxic and normal oxygen conditions to investigate the appearance of the DNA ladder. As a result, the experimental group (HY2207) to which the HY2207 was added at 300 µg / ml improved the survival of cells as in Experimental Example 1 as compared to the control group (HY2207) without addition (see FIG. 2A), and also added HY2207. The experimental group (see FIG. 2C) delayed the appearance time of the DNA ladder than the control group (see FIG. 2B). Therefore, it was confirmed that HY2207 has an effect of suppressing apoptosis and improving cell survival.
실험예Experimental Example 3. 3. 차풀Chapool 정제분획물의Purified fraction 세포생존능Cell viability 개선 활성 측정 ( Improve activity measurement ( in vitroin vitro ))
차풀 조추출물로부터 정제분리된 분획의 활성을 확인하기 위해서 문헌에 기재된 MTT 어세이법 (Hoffman RM, In Cell Biology (Celis JE (Ed.)), Vol. 1, pp369-370, Academic Press, New York, 1994)을 변형하여 인간 간암세포주 HepG2 세포주에 각각 농도를 달리한 분획물을 넣은 배지를 첨가한 후, 저산소 조건에서 하기와 같이 실험을 수행함으로써 세포생존능을 개선시키는 정도를 조사하였다. MTT assays described in the literature (Hoffman RM, In Cell Biology (Celis JE (Ed.)), Vol. 1, pp369-370, Academic Press, New York to confirm the activity of fractions purified from crude extracts of Chapul) , 1994) was added to the human liver cancer cell line HepG2 cell line was added to the medium containing fractions of varying concentrations, and the degree of improving cell viability was examined by performing the experiment as described below in hypoxic conditions.
인간 간암세포주 (human hepatoma cell line)인 HepG2 (ATCC HB 8065, 미국) 를 항생제로는 페니실린 지 (penicillin G sodium, 100 Units/ℓ, Invitrogen, USA) 및 스트렙토마이신 (streptomycin sulfate, 100 mg/L, Invitrogen, USA)과 혈청으로는 10 % 우태아혈청 (fetal bovine serum, Invitrogen. USA)이 첨가된 이글 최소 배지 (EMEM, Eagle's minimum essential midium; Invitrogen, 미국)를 사용하여 12웰 플레이트 (12 well-plate)에서 2×105 세포수/800 ㎕배지로 배양하였다. 세포들을 37 ℃ 및 5 % CO2-95 % 대기상태에서 48시간 동안 배양한 후, 상기 실시예 2의 차풀 정제분획물들을 디메틸술폭시화물 (DMSO; 에틸아세테이트 분획물의 경우) 또는 50 % 에탄올 (수가용성 분획물의 경우)에 용해시켜 10, 100 및 1000 ㎍/㎖의 농도로 배양배지에 첨가한 실험군, 아무것도 첨가하지 않은 음성대조군 (negative control)과 이미 세포생존능을 개선시키는 것으로 확인된 G418 10 ㎍/㎖를 첨가한 양성대조군 (positive control)을 저산소 조건하에서 각각 2일 동안 배양하면서, MTT 어세이를 수행하였다. HepG2 (ATCC HB 8065, USA), a human hepatoma cell line, contains penicillin G sodium (100 Units / L, Invitrogen, USA) and streptomycin sulfate (100 mg / L). Invitrogen, USA) and 12-well plate (12 well-) using Eagle's minimum essential midium (EMEM, Invitrogen, USA) added with 10% fetal bovine serum (Invitrogen. USA) as serum. plate) was incubated in 2 × 10 5 cell number / 800 μl medium. After incubating the cells for 48 hours at 37 ° C. and 5% CO 2 -95% atmosphere, the chapul purified fractions of Example 2 were purified using dimethyl sulfoxide (DMSO; for ethyl acetate fraction) or 50% ethanol (water Soluble fractions) were added to the culture medium at concentrations of 10, 100 and 1000 μg / ml, the negative control group to which nothing was added and G418 10 μg /, which was already found to improve cell viability. MTT assay was performed while the positive control (ml) was incubated for 2 days under hypoxic conditions.
상기 실험 수행의 결과, 도 3에서 보는 바와 같이, 저산소조건 (hypoxia)에서 HY2207 (WH) 및 CM-HX (HX)는 1000 ㎍/㎖ 농도에서 세포의 생존을 개선시키는 효과를 나타내고, CM-BU는 1000 ㎍/㎖ 농도에서조차도 세포생존을 개선시키지 못하는 반면에, CM-EA (EA)의 경우에는 1000 ㎍/㎖ 뿐만 아니라 100 ㎍/㎖ 농도에서도 세포생존을 개선시키는 효과가 관찰되었다. 따라서 세포생존 관련 활성성분이 CM-EA에 선택적으로 농축되어 있음을 확인할 수 있었다. As a result of the above experiment, as shown in FIG. 3, under hypoxia (hypoxia), HY2207 (WH) and CM-HX (HX) showed an effect of improving cell survival at a concentration of 1000 μg / ml, and CM-BU Did not improve cell survival even at a concentration of 1000 μg / ml, whereas in CM-EA (EA), the effect of improving cell survival was observed not only at 1000 μg / ml but also at 100 μg / ml. Therefore, it was confirmed that the active ingredient related to cell survival is selectively concentrated in CM-EA.
실험예Experimental Example 4. 복강주사시, 4. Intraperitoneal injection, 차풀Chapool 조추출물Crude extract 및 And 에틸아세테이트가용Ethyl acetate soluble 분획물의Fraction 뇌경색에 대한 효과 시험 ( Effect test on cerebral infarction ( in in vivovivo ))
HY2207과 CM-EA의 뇌경색에 대한 치료 효과를 검증하기 위하여 문헌 (Han HS et al., J. Neurosci ., 22, pp3921-3928, 2002)에 기재된 실험을 변형하여 상기 참고예 1의 랫트로 뇌경색모델을 만들어 하기와 같이 동물실험을 수행하였다.In order to verify the therapeutic effect of HY2207 and CM-EA on cerebral infarction, the experiment described in (Han HS et al., J. Neurosci ., 22, pp3921-3928, 2002) was modified to rat cerebral infarction of Reference Example 1 above. Animal models were performed as shown below.
4-1. 4-1. 차풀Chapool 조추출물의Crude extract 뇌경색에 대한 효과 시험 Effect Test on Cerebral Infarction
상기 참고예 1의 랫트를 엔플루란 (enflurane, 중외제약, 한국)으로 흡입 마취시킨 후 하지동맥에서 혈압측정 및 혈액 채취 경로를 확보하고 경부를 절개하여 경동맥을 노출시킨 후, 경동맥과 외경동맥을 결찰하고 내경동맥으로 3-0 나이론 봉합사를 넣어 중간대뇌동맥 (middle cerebral artery)을 막아서 뇌경색 모델을 만들었다. Rats of Reference Example 1 were inhaled with enflurane (enflurane, Sino-Pharmaceutical Co., Korea), and then the blood pressure measurement and blood sampling paths were secured in the lower extremity. Ligation and 3-0 nylon sutures were inserted into the internal carotid artery to block the middle cerebral artery to create a cerebral infarction model.
상기 실시예 1의 HY2207을 이 뇌경색모델에 주입하여 괴사부위의 면적을 조사하였다. 이 때 독성을 나타내지 않는 안전량 및 효과를 나타내는 용량인 적정 투여량 결정을 위하여, 상기 실험예 1의 결과를 바탕으로 가능한 최소량을 시작점으로 잡아 단계별로 상승시키는 방법을 이용하였다. 이를 위해 용량 증가는 2배수 증가법을 채택하였으며, 50 mg/kg로 시작할 경우 100, 200 mg/kg 등으로 증가시켰다. HY2207 of Example 1 was injected into this cerebral infarction model to investigate the area of necrotic sites. At this time, in order to determine the appropriate dose which is a safe amount and a dose that does not exhibit toxicity, a method of raising the step amount by taking the minimum amount as a starting point based on the result of Experimental Example 1 was used. To this end, the dose increase was adopted by a fold increase method, starting with 50 mg / kg and increasing to 100 and 200 mg / kg.
중간대뇌동맥을 막아 허혈을 유발하기 20시간과 1시간 전에 각각 HY2207을 200 mg/kg (1 ㎖)씩 복강주사 하였으며, 허혈 유발 후 2 시간동안 허혈상태로 방치한 후 봉합사를 제거하고 동물을 회복시켰다. 22 시간 경과 후 실험동물을 안락사 시 켜 뇌조직을 적출하여 TTC (2,3,5-triphenyltetrazolium chloride, Sigma, 미국) 용액에 넣어 염색한 후, 뇌반구에 대한 손상정도를 영상분석 시스템 (Qunatity One 4.0, Biorad, 미국)으로 측정하여 하기 수학식 1과 같은 방법으로 허혈지수 (ischemic index)를 계산하여 약물의 효과를 비교하였다. HY2207 was intraperitoneally injected 200 mg / kg (1 ml) 20 hours and 1 hour before the middle cerebral artery was blocked to induce ischemia, and after 2 hours of ischemia induction, the suture was removed and the animals were recovered. . After 22 hours, the animals were euthanized, brain tissues were extracted, stained in TTC (2,3,5-triphenyltetrazolium chloride, Sigma, USA) solution, and the degree of damage to the hemispheres was analyzed by image analysis system (Qunatity One). 4.0, Biorad, USA) to calculate the ischemic index (ischemic index) in the same manner as in the following equation 1 to compare the effect of the drug.
A: 뇌 반구(半球) 중 손상 부위의 부피 (㎜3), A: volume of the injury site in the hemisphere of the brain (mm 3 ),
B: 뇌 반구의 전체 부피 (㎜3). B: total volume of brain hemispheres (mm 3 ).
상기 실험을 수행한 결과, HY2207을 투여하지 않은 랫트 (8마리, 대조군, Control)는 허혈지수가 93 %인데 비해, 투여한 랫트 (8마리, 실험군, HY2207)는 62 %로, 괴사부위의 부피가 33 %정도 (p<0.05) 감소한 것으로 나타나 HY2207이 뇌경색모델에서 상당한 효과가 있음을 확인할 수 있었다 (도 4a 참조). 이러한 현상은 TTC 염색 수행 결과, 대조군 (도 4b 참조)에 비해 실험군 (도 4c 참조)에서 조직손상이 현저하게 감소한 것으로도 확인할 수 있었다. As a result of the experiment, rats not administered HY2207 (8 rats, control group) had an ischemic index of 93%, whereas rats (8 rats, experimental group, HY2207) administered 62% had a volume of necrosis area. Was reduced by about 33% (p <0.05), indicating that HY2207 has a significant effect in the cerebral infarction model (see FIG. 4A). This phenomenon was confirmed as a result of the TTC staining, the tissue damage was significantly reduced in the experimental group (see Figure 4c) compared to the control (see Figure 4b).
4-2. 4-2. 차풀Chapool 에틸아세테이트가용Ethyl acetate soluble 분획물의Fraction 뇌경색에 대한 효과 시험 Effect Test on Cerebral Infarction
상기 실시예 3에서 활성물질이 다량 함유된 것으로 확인된 CM-EA를 실험예 4-1과 동일한 방법으로 만든 뇌경색모델에 주입하여 괴사부위의 면적을 측정하였다.The area of the necrotic site was measured by injecting CM-EA, which was found to contain a large amount of the active substance in Example 3, to a cerebral infarction model made by the same method as Experimental Example 4-1.
중간대뇌동맥을 막아 허혈을 유발하기 20시간과 1시간 전에 각각 CM-EA을 각각 5, 10 및 20 mg/kg (1 ㎖)을 복강주사 하였으며, 허혈 유발 후 2 시간동안 허혈상태로 방치한 후 봉합사를 제거하고 동물을 회복시켰다. 22시간 경과 후 실험동물을 안락사시켜 뇌조직을 적출하여 TTC 염색을 시행하고 상기 실험예 4-1과 동일한 방법으로 허혈지수(ischemic index)를 측정하였다.CM-EA was intraperitoneally injected 5, 10 and 20 mg / kg (1 ml), respectively, 20 hours and 1 hour before the middle cerebral artery was blocked, and sutured for 2 hours after ischemia induction. Removed and the animals were recovered. After 22 hours, the animals were euthanized, brain tissues were extracted, TTC staining was performed, and the ischemic index was measured in the same manner as in Experimental Example 4-1.
상기 실험을 수행한 결과, CM-EA를 주사하지 않은 랫트 (8마리, 대조군, 0 mg/kg)는 허혈지수가 93 %인데 비해, CM-EA를 각각 5, 10, 20 mg/kg 투여한 랫트 (4, 8, 8마리; 5 mg/kg, 10 mg/kg, 20 mg/kg)는 허혈지수가 각각 70.8, 61.4, 50.8 %로 괴사부위가 각각 23.9, 34.0, 45.4 % (p<0.05) 감소하였다 (도 4d 참조). 이로부터 HY2207이 200 mg/kg 정도의 농도에서 뇌경색모델에 대해 상당한 효과를 나타내는데 반해, HY2207의 에틸아세테이트가용 분획물인 CM-EA는 10 mg/kg 이상의 농도에서 상당한 효과가 있음을 확인할 수 있었다.As a result of the experiment, rats not injected with CM-EA (8 rats, control group, 0 mg / kg) had an ischemic index of 93%, compared with 5, 10 and 20 mg / kg of CM-EA, respectively. Rats (4, 8, 8; 5 mg / kg, 10 mg / kg, 20 mg / kg) had ischemic indices of 70.8, 61.4, and 50.8%, respectively, and necrotic areas were 23.9, 34.0, and 45.4% (p <0.05, respectively). ) Decreased (see FIG. 4D). From this, HY2207 showed a significant effect on the cerebral infarction model at a concentration of about 200 mg / kg, while CM-EA, an ethyl acetate soluble fraction of HY2207, was found to have a significant effect at a concentration of 10 mg / kg or more.
실험예Experimental Example 5. 복강주사시, 5. Intraperitoneal injection, 차풀Chapool 조추출물의Crude extract 허혈성급성신부전증에Ischemic premature failure 대한 효과 시험 ( For effect test ( in in vivovivo ))
차풀 조추출물의 허혈성급성신부전증에 대한 치료 효과를 검증하기 위하여 문헌 (Wang J et al., J. Biol . Chem ., 279(19), pp19948-19954, 2004)에 기재된 실험을 변형하여 상기 참고예 1의 랫트로 허혈성급성신부전증모델을 만들어 하기와 같이 동물실험을 수행하였다. In order to verify the therapeutic effect of Chapul crude crude extract on ischemic acute renal failure, Wang J et al., J. Biol . Chem . , 279 (19), pp19948-19954, 2004. The rat ischemic nephrotic insufficiency model was made of 1 rat and animal experiment was performed as follows.
상기 참고예 1의 랫트를 수술 30분전에 50 mg/kg의 케타민 (ketamine, 유한, 대한민국)과 20 mg/kg의 자이라진 (xylazine, Sigma, 미국)을 투여하여 마취를 시킨 후 복강을 절개하였다. 그리고 왼쪽 신장의 신동맥과 신정맥을 클램프로 집어 혈액의 흐름을 막은 후 오른쪽 신장은 적출하여 허혈성급성신부전증 모델을 만들었다. Rats of Reference Example 1 were anesthetized with 50 mg / kg ketamine (ketamine, Yuhan, Korea) and 20 mg / kg xyazine (xylazine, Sigma, USA) 30 minutes before surgery, followed by an abdominal incision. . The renal artery and renal vein of the left kidney were clamped to block the flow of blood, and then the right kidney was extracted to create a model of ischemic renal failure.
왼쪽 신동맥을 집어 허혈을 유발하기 1시간 전에 0.9 % 생리식염수에 녹인 HY2207 400 mg/kg (1 ㎖)를 복강에 주사하여 투여하고, 허혈 유발 후 45분 동안 허혈상태로 방치한 후 클램프를 풀어 동물을 회복시켰다. 24시간 경과 후 실험동물로부터 혈액을 채취하여 혈액 내의 크레아티닌 (creatinine) 농도 (㎎/㎗)를 측정하였다.Inject the left renal artery into the abdominal cavity with HY2207 400 mg / kg (1 ml) dissolved in 0.9% saline one hour before inducing ischemia, and leave the ischemic state for 45 minutes after ischemic induction. Recovered. After 24 hours, blood was collected from experimental animals, and the concentration of creatinine (mg / dl) in the blood was measured.
상기 실험을 수행한 결과, HY2207을 주사하지 않은 랫트 (4마리, 대조군, Control)의 크레아티닌의 농도가 3.9 ㎎/㎗인데 반해 주사한 랫트 (6마리, 실험군, HY2207)의 농도는 1.5 ㎎/㎗로 크레아티닌 농도가 62 % 정도 (p<0.05) 감소한 것으로 나타나 HY2207이 신장의 손상을 억제함으로써 신장을 통한 크레아틴의 방출을 원활하게 함을 알 수 있었으며, 이러한 결과는 아울러 HY2207이 허혈성급성신부전증모델에서 상당한 효과가 있음을 확인할 수 있었다 (도 5 참조). As a result of the experiment, the concentration of creatinine in rats (4 mice, control group) without injection of HY2207 was 3.9 mg / dl, whereas the concentration of injected rats (6 mice, experimental group, HY2207) was 1.5 mg / dl. The creatinine concentration was reduced by 62% (p <0.05), suggesting that HY2207 inhibits kidney damage, thereby facilitating the release of creatine through the kidneys. It was confirmed that the effect (see Fig. 5).
실험예Experimental Example 6. 독성 실험 6. Toxicity test
상기 실시예 1의 HY2207을 320±20 g의 스프라그 다우리계 (Spague-Dawley) 수컷 랫트 5마리에게 주입하여 변화를 관찰하였다.The change was observed by injecting HY2207 of Example 1 into 5 Sprague-Dawley male rats of 320 ± 20 g.
HY2207 (500 mg/kg)을 복강으로 주사하여 24시간 후 몸무게를 측정하였더니 유의할 정도의 무게변화는 없었다. 또한 별다른 행동양상의 변화도 관찰되지 않았다.24 hours after HY2207 (500 mg / kg) was injected intraperitoneally, weight was not significant. There was also no change in behavior.
본 발명의 차풀 추출물을 함유하는 약학조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.It describes an example of the formulation of the pharmaceutical composition containing the extract tea extract of the present invention, the present invention is not intended to limit this but only to explain in detail.
제제예Formulation example 1. One. 산제의Powder 제조 Produce
상기 실시예 1의 HY2207 300 mg300 mg of HY2207 in Example 1 above
유당 100 mg
탈크 10 mgTalc 10 mg
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
상기 실시예 1의 HY2207 50 mg50 mg of HY2207 of Example 1
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제 조한다.After mixing the above components, the tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Manufacture of capsule
상기 실시예 1의 HY2207 50 mg50 mg of HY2207 of Example 1
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예Formulation example 4. 주사제의 제조 4. Preparation of Injectables
상기 실시예 1의 HY2207 50 mg50 mg of HY2207 of Example 1
주사용 멸균 증류수 적량Appropriate sterile distilled water for injection
pH 조절제 적량pH adjuster
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
상기 실시예 1의 HY2207 100 mg100 mg of HY2207 of Example 1
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.After dissolving each component in purified water according to the usual method of preparing a liquid solution, adding lemon flavor appropriately, mixing the above components, adding purified water, adjusting the whole to 100 ml by adding purified water, and then filling into a brown bottle. The solution is prepared by sterilization.
제제예Formulation example 6. 건강 식품의 제조 6. Manufacture of healthy food
상기 실시예 1의 HY2207 1000 ㎎
비타민 혼합물 적량Vitamin Mixture
비타민 A 아세테이트 70 ㎍70 μg of Vitamin A Acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎Vitamin B1 0.13 mg
비타민 B2 0.15 ㎎Vitamin B2 0.15 mg
비타민 B6 0.5 ㎎Vitamin B6 0.5 mg
비타민 B12 0.2 ㎍0.2 μg of vitamin B12
비타민 C 10 ㎎Vitamin C 10 mg
비오틴 10 ㎍10 μg biotin
니코틴산아미드 1.7 ㎎Nicotinic Acid 1.7 mg
엽산 50 ㎍Folate 50 ㎍
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 ㎎Potassium Citrate 90 mg
탄산칼슘 100 ㎎
염화마그네슘 24.8 ㎎Magnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예 1로 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 mixture is a composition which is relatively suitable for healthy foods in the preferred embodiment 1, the compounding ratio may be arbitrarily modified, and the above-mentioned ingredients may be mixed according to a conventional health food manufacturing method. Next, 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
상기 실시예 1의 HY2207 1000 ㎎
구연산 1000 ㎎
올리고당 100 g100 g oligosaccharides
매실농축액 2 gPlum concentrate 2 g
타우린 1 g1 g of taurine
정제수를 가하여 전체 900 ㎖Add 900 ml of purified water
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. After mixing the above components in accordance with a 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 then refrigerated and 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.
본 발명의 차풀 추출물은, 허혈 동물모델에 투여하였을 때 세포자살을 억제하여 조직의 경색부위를 감소시킬 뿐만 아니라, 장기간 복용해도 부작용이 없으므로 허혈성 질환의 치료를 위한 의약 및 건강기능식품에 사용될 수 있다.The tea extract of the present invention, when administered to an ischemic animal model, not only inhibits apoptosis and reduces infarcts of tissues, but also can be used in medicines and health functional foods for the treatment of ischemic diseases because there are no side effects even when taken for a long time. .
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CN102551065A (en) * | 2012-03-19 | 2012-07-11 | 肖梅芬 | Blood sugar reducing food series |
CN115737698A (en) * | 2022-10-24 | 2023-03-07 | 惠州学院 | Application of sedum aizoon extract in inhibiting glucosidase |
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CN102551065A (en) * | 2012-03-19 | 2012-07-11 | 肖梅芬 | Blood sugar reducing food series |
CN115737698A (en) * | 2022-10-24 | 2023-03-07 | 惠州学院 | Application of sedum aizoon extract in inhibiting glucosidase |
CN115737698B (en) * | 2022-10-24 | 2023-11-17 | 惠州学院 | Application of armored grass extract in inhibiting glucosidase |
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