KR20040043775A - Composition comprising the extract of angelica purpuraefolia chung having potent anticancer activity - Google Patents
Composition comprising the extract of angelica purpuraefolia chung having potent anticancer activity Download PDFInfo
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- KR20040043775A KR20040043775A KR1020020072168A KR20020072168A KR20040043775A KR 20040043775 A KR20040043775 A KR 20040043775A KR 1020020072168 A KR1020020072168 A KR 1020020072168A KR 20020072168 A KR20020072168 A KR 20020072168A KR 20040043775 A KR20040043775 A KR 20040043775A
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- cancer
- extract
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- polar
- soluble
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/38—Other non-alcoholic beverages
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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
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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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
- A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
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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
- A23V2250/00—Food ingredients
- A23V2250/20—Natural extracts
- A23V2250/21—Plant extracts
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- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Botany (AREA)
- Mycology (AREA)
- Medicines Containing Plant Substances (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
Description
본 발명은 항암 활성을 갖는 지리강활(Angelica purpuraefoliaChung)의 조추출물, 극성 또는 비극성용매 가용추출물 및 이를 함유하는 조성물에 관한 것이다.The present invention relates to crude extracts of Angelica purpuraefolia Chung, anti-polar solvent soluble extracts having anticancer activity and compositions containing them.
암은 인류가 해결해야될 난치병 중의 하나로, 전세계적으로 이를 치유하기 위한 개발에 막대한 자본이 투자되고 있는 실정이며, 우리 나라 질병 사망원인 중 제 1위의 질병으로서 연간 약 10 만명 이상이 진단되고, 약 6 만명이 사망하고 있다. 이러한 암의 유발 인자인 발암물질로는 흡연, 자외선, 화학물질, 음식물, 기타 환경인자들이 있으나, 그 유발 원인이 다양하여 치료제의 개발이 어려울 뿐만 아니라 발생하는 부위에 따라 치료제의 효과 또한 각기 다르며, 현재 치료제로 사용되는 물질들은 상당한 독성을 지니고 있고, 암 세포만을 선택적으로 제거하지 못하기 때문에 암의 발생 후 이를 치료하는 대응 방법보다는 암의 발생을 미리 방지하는 암 예방(chemoprevention)이 암을 정복한다는 전제하에서 훨씬 효율적인 방법이 될 것이다.Cancer is one of the incurable diseases to be solved by humans, and huge capital is being invested in the development to cure it all over the world, and it is the number one cause of disease death in our country. About 60,000 people are dead. Carcinogens that cause cancer include smoking, ultraviolet rays, chemicals, foods, and other environmental factors, but the causes of various cancers are difficult to develop, as well as the effects of treatments vary depending on the site of occurrence. The substances currently used as therapeutic agents are highly toxic and cannot selectively remove only cancer cells, suggesting that cancer prevention (chemoprevention) conquers cancer rather than countermeasures after cancer. It would be a much more efficient way under the premise.
암을 치료하기 위한 항암제의 연구 방법에는 암세포에 대한 직접적인 세포독성 물질을 탐색하는 법, 생체의 면역능을 조절하는 물질을 탐색하는 법, 암세포의 전이를 억제하는 물질을 탐색하는 법 및 최근에 주목되고 있는 혈관신생을 억제하는 물질을 탐색하는 법 등 다양한 방법들이 진행되고 있으며, 암의 예방을 위해서는 암 발생의 여러 기전을 효율적으로 차단함으로써 정상세포가 암세포로 전이되는 과정을 미연에 방지하거나 또는 발암기전의 진행을 지연시키거나 회복시킬 수 있는 물질을 사용할 수 있는데, 이러한 물질은 단기 또는 장기 독성이 없어야하며, 복용이 용이하고 가격이 저렴해야만 한다. 암의 발생은 매우 복잡하며 여러 단계에 의하여 진행된다고 알려져 있으며 발암의 작용기전을 이해하는 것이 암의 예방 및 치료에 쓰이는 약제의 개발이 가능하다.Research methods of anticancer agents for treating cancer have recently been investigated, such as searching for a direct cytotoxic substance to cancer cells, searching for a substance that modulates the immune ability of the living body, searching for a substance that inhibits the metastasis of cancer cells, and recently Various methods are in progress, such as the search for a substance that inhibits angiogenesis, and in order to prevent cancer, various mechanisms of cancer development are effectively blocked, thereby preventing normal cells from transferring to cancer cells or carcinogenic mechanisms. Substances that can delay or recover the process of the drug may be used, which should be free of short or long term toxicity, be easy to take and inexpensive. The incidence of cancer is known to be very complex and progresses through several stages. Understanding the mechanism of action of carcinogenesis enables the development of drugs for the prevention and treatment of cancer.
현재, 새로운 개념의 암 정복 전략인 암 예방 물질의 개발이 절실히 요구되고 있으며, 이러한 암 예방물질의 개발은 암 뿐만 아니라, 모든 질병을 억제하거나 치료하는데 매우 유용하게 이용될 수 있다. 이와 같은 이유로 인해, 암 예방 물질의 개발이 암 연구의 새로운 방향으로 인식되고 관심이 집중됨에 따라, 암 예방물질 소재의 개발이 실제 의약분야 뿐만 아니라 식품 화학 분야에서도 활발하여 천연물 소재에 대한 연구가 적극적으로 이루어지고 있는 실정이며, 또한 식품 분야에도 실제 도입되고 있다.At present, there is an urgent need for the development of a new concept of cancer prevention strategy, a cancer prevention substance, and the development of such a cancer prevention substance can be very useful for inhibiting or treating all diseases as well as cancer. For this reason, as the development of cancer prevention substances is recognized as a new direction of cancer research and attention is focused, the development of cancer prevention substance materials is active not only in the real medicine field but also in the food chemistry field. The situation is made of, and is actually introduced in the food field.
보고된 암의 예방과 관련된 활성물질의 예로는 β-카로텐(β-carotene) (Suda,Carcinogenesis,7, pp711-715, 1986), 세셀린형 쿠마린(coumarin) (Nishino,Carcinogenesis,11, pp1557-1561, 1990), 강황(Curcuma longa)으로부터 분리된 쿠르쿠민(curcumin)(Rao, Carcinogenesis,14, pp2219-2225, 1993), 파슬리 (parsley)에서 분리된 미리스티신 (myristicin)(Zheng,Carcinogenesis,13, pp1921-1923, 1992) 그리고 녹차의 에피갈로카테킨-3-갈릭산 (epigallocatechin-3-gallic acid)(Katiyar,Nutrition and Cancer,18, pp73-73, 1992) 등이 있다.Examples of active substances associated with the prevention of reported cancers are β-carotene (Suda, Carcinogenesis , 7 , pp711-715, 1986), and ceselin type coumarin (Nishino, Carcinogenesis , 11 , pp1557- 1561, 1990), curcumin isolated from Curcuma longa (Rao, Carcinogenesis, 14 , pp2219-2225, 1993), myristicin isolated from parsley (Zheng, Carcinogenesis , 13). , pp1921-1923, 1992) and epigallocatechin-3-gallic acid of green tea (Katiyar, Nutrition and Cancer , 18 , pp73-73, 1992).
또한, 문헌(Annual Reports of Medicinal Chemistry)에 의하면, 1983년부터 1994년까지 새롭게 승인된 항암제 31종 중에 19종인 약 61%의 약물이 천연물로부터 분리되어 개발되었거나 반합성 유도체 또는 천연 모델에서 기인된 합성품이었으며, 1994년까지 개발되어 사용되고 있는 항암제 93종 중에는 인터페론(interferon), 인터루킨-2(interleukin-2)와 같은 생물원로부터의 약물이 6종, 파클리탁솔 (paclitaxol), 빈크리스틴(vincristine), 빈블라스틴(vinblastin), 독소루비신(doxorubicin)과 같은 천연물 자원으로부터의 약물이 15종, 에토포시드 (etoposide), 이리노테칸 히드로클로라이드(irinotecan hydrochloride)와 같은 천연물 자원의 반합성 유도체가 25종, 시스플라틴(cisplatin), 암사크린(amsacrine)과 같은 순수 합성품이 33종, 사이토신 아라비노시드(cytosine arabinoside), 플루오로우라실(fluorouracil)과 같은 합성품이지만 천연 모델에서 기인된 약물이 14종이었다.In addition, according to the International Reports of Medicinal Chemistry, 19 out of 31 newly approved anticancer drugs from 1983 to 1994, about 61% of drugs were developed separately from natural products or were derived from semisynthetic derivatives or natural models. Among the 93 anticancer drugs that have been developed and used until 1994, six drugs from biological sources such as interferon and interleukin-2 are known as paclitaxol, vincristine and vin. 15 drugs from natural sources such as vinblastin, doxorubicin, 25 semisynthetic derivatives of natural products such as etoposide, irinotecan hydrochloride, cisplatin , 33 pure compounds like amsacrine, cytosine arabinoside, fluorouracil There were 14 drugs that were synthetic but originated from natural models.
상기한 바와 같이, 이미 여러 종의 식물추출물로부터 암 예방 또는 치료활성을 지닌 물질이 보고되어 식물 추출물로부터 암 예방제로서의 활성을 보이는 물질이 탐색될 확률이 높은 편이고, 식물 추출물은 장기복용에 따른 독성 발생의 위험부담이 적고, 원료의 생산이 용이하며, 보존 상태가 외부환경에 대해 비교적 안정적이라는 점에서 암 예방 및 치료제 개발에 있어서 식물의 추출에 대한 항암 활성 검색과 그에 따른 순수물질의 분리 및 활성검색 등의 방법으로 접근하는 것은 높은 효율적인 많은 잇점을 가지고 있다.As described above, substances with cancer prevention or therapeutic activity have already been reported from various plant extracts, and thus, a substance with a cancer prevention agent is highly likely to be searched for from plant extracts, and plant extracts are toxic by long-term use. In the anti-cancer activity detection of plant extraction in the development of cancer prevention and treatment, and the isolation and activity screening of pure substances according to the low risk, the easy production of raw materials, and the preservation state are relatively stable to the external environment. This approach has many advantages, such as high efficiency.
본 발명에서 사용된 지리강활(Angelica purpuraefoliaChung)은 미나리과(Umbelliferae)의 다년생 식물로서 남강활, 개당귀, 남당귀라 불리우며, 지리산 해발 1500m 고도에서 많이 서식하고, 유독(有毒)식물로서 약용으로 사용하지 않으나, 일부에서는 피부염, 염증의 치료목적으로 사용하기도 한다.As used in the present invention, Angelica purpuraefolia Chung is a perennial plant of the genus Minamidae (Umbelliferae), called Namgang bow, canopy ear, and Namdang ear , and inhabits a lot at altitude of 1500m above sea level of Jiri, and is used as a medicinal plant as a poisonous plant. In some cases, it is used to treat dermatitis and inflammation.
그러나, 암 예방 효능을 나타내는 천연 물질에 대한 많은 연구와 관심에도 불구하고, 본 발명의 지리강활 추출물이 암 질환에 대한 연구, 치료 및 예방 효과의 효능이 전혀 알려진 바 없으며, 여러 종류의 천연물을 대상으로 하여 암예방 및치료에 유용한 활성이 기대되는 식물을 탐색하는 과정에서 지리강활이 암세포주에 대하여 유의한 억제효과를 나타내어 이에 대한 항암활성 연구를 진행하였다However, despite much research and interest in natural substances exhibiting cancer prevention efficacy, the geological activity extract of the present invention has no known efficacy of research, treatment and prophylaxis for cancer diseases, and targets various kinds of natural products. In the process of searching for plants that are expected to be useful for cancer prevention and treatment, geological activity showed a significant inhibitory effect on cancer cell lines.
이에 본 발명자들은 식물의 구성 성분을 분리 및 정제하여 연구를 계속해오던 중, 지리강활 추출물이 암세포의 성장을 저해하여 탁월한 암 예방 및 치료 효과를 가짐을 확인함으로써 본 발명을 완성시켰다.Accordingly, the present inventors have completed the present invention by confirming that geological activity extract has excellent cancer prevention and treatment effect by inhibiting the growth of cancer cells while continuing to study the separation and purification of plant components.
본 발명은 항암 활성을 갖는 지리강활 조추출물, 극성 또는 비극성용매 가용추출물을 함유하는 암 질환의 치료 및 예방용 약학조성물 및 건강보조식품을 제공하는 것이다.The present invention is to provide a pharmaceutical composition and health supplement for the treatment and prevention of cancer diseases containing geographic activity crude extract, a polar or non-polar solvent soluble extract having anticancer activity.
도 1은 본 발명의 지리강활 클로로포름 가용추출물의 성분 분석 HPLC 크로마토그램도이며,1 is a chromatogram of HPLC analysis of constituent extracts of geographic activity chloroform soluble extract of the present invention,
도 2는 동물모델에서 무처리군, 항암제인 아드리아마이신을 처리한 양성대조군, 지리강활 추출물 투여군(125, 250㎎/㎏)의 고형암 세포주 억제 효과를 나타낸 도이다.2 is a diagram showing the solid cancer cell line inhibitory effect of the untreated group, the positive control group treated with the anti-cancer drug adriamycin, geography active extract administration group (125, 250mg / ㎏) in the animal model.
상기 목적에 따라, 본 발명은 암 질환의 예방 및 치료에 효과적인 지리강활(Angelica purpuraefoliaChung)의 조추출물, 극성 또는 비극성용매 가용추출물을 제공한다.In accordance with the above object, the present invention provides a crude extract of Angelica purpuraefolia Chung, a polar or nonpolar solvent soluble extract effective for the prevention and treatment of cancer diseases.
상기 조추출물은 물, 메탄올, 부탄올 또는 이들의 혼합용매로부터 선택되어진 극성용매에 가용한 추출물을 의미한다.The crude extract means an extract available in a polar solvent selected from water, methanol, butanol or a mixed solvent thereof.
상기 극성용매 가용추출물은 물, 메탄올, 부탄올 또는 이들의 혼합용매로부터 선택되어진 극성용매에 가용된 추출물이고, 비극성용매 가용추출물은 에틸아세테이트, 클로로포름 또는 헥산과 같은 비극성 용매에 가용된 추출물을 의미한다.The polar solvent soluble extract means an extract soluble in a polar solvent selected from water, methanol, butanol or a mixed solvent thereof, and the non-polar solvent soluble extract means an extract soluble in a nonpolar solvent such as ethyl acetate, chloroform or hexane.
본 발명의 지리강활로부터 조추출물, 극성 또는 비극성용매 가용추출물을 분리하는 방법은 하기와 같다.The method of separating the crude extract, polar or nonpolar solvent soluble extract from the geographic activity of the present invention is as follows.
이하 본 발명을 상세히 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명의 지리강활 추출물은 음건하에 세절한 지리강활의 지하부 무게(㎏)의 약 5배 내지 25배, 바람직하게는 약 10배 내지 15배의 물, 메탄올 또는 에탄올 등의 저급 알콜 또는 약 1:0.1 내지 1:10, 바람직하게는 1:0.2 내지 1:5의 혼합비(㎏/ℓ)를 갖는 이들의 혼합용매, 더욱 더 바람직하게는 90 내지 100% 메탄올로 5 내지 80℃, 바람직하게는 30 내지 55℃ 추출온도에서 약 15분 내지 2일, 바람직하게는 30분 내지 12시간동안 용매 추출, 단수 열수추출 또는 초음파 추출 등의 추출방법에 의하여 물, 저급 알코올 또는 이들의 혼합 용매에 따른 가용추출물인 조추출물을 추출, 감압농축 및 동결건조하여 수득할 수 있다.Geographically active extract of the present invention is about 5 to 25 times, preferably about 10 to 15 times the water, methanol or ethanol lower alcohol or about 1: 1 of the underground weight (kg) of gelatinous ribs cut in the shade. Mixed solvents thereof having a mixing ratio (kg / L) of 0.1 to 1:10, preferably 1: 0.2 to 1: 5, still more preferably 5 to 80 ° C, preferably 30 to 90 to 100% methanol Soluble extract according to water, lower alcohol or a mixed solvent thereof by an extraction method such as solvent extraction, singular hydrothermal extraction or ultrasonic extraction for about 15 minutes to 2 days, preferably 30 minutes to 12 hours at an extraction temperature of 55 ° C. Phosphorous crude extract can be obtained by extraction, concentration under reduced pressure and lyophilization.
본 발명은 상기 추출공정에서 얻어지는 조추출물들을 포함하는 암 질환의 예방 및 치료용 조성물을 제공한다.The present invention provides a composition for the prevention and treatment of cancer diseases, including crude extracts obtained in the extraction process.
또한 본 발명의 유효성분이 정제된 극성 또는 비극성용매 가용추출물은 상기 조추출물을 물에 현탁한 후, 이를 현탁액의 약 1 내지 100배, 바람직하게는 약 1 내지 5배 부피의n-헥산, 클로로포름 또는 에틸아세테이트와 같은 비극성 용매를 가하여 수층과 비극성용매 가용층을 1회 내지 10회, 바람직하게는 2회 내지 5회 분획하여 수득할 수 있으며, 또한 추가로 통상의 분획 공정을 수행할 수도 있다(Harborne J.B. Phytochemical methods:A guide to modern techniques of plant analysis. 3rd Ed. pp6-7, 1998).In addition, the polar or non-polar solvent soluble extract purified from the active ingredient of the present invention, after suspending the crude extract in water, it is about 1 to 100 times, preferably about 1 to 5 times the volume of n -hexane, chloroform or By adding a nonpolar solvent such as ethyl acetate, the aqueous layer and the nonpolar solvent soluble layer can be obtained by fractionation of 1 to 10 times, preferably 2 to 5 times, and may also be carried out in a conventional fractionation process (Harborne). JB Phytochemical methods: A guide to modern techniques of plant analysis . 3rd Ed. Pp 6-7, 1998).
이하 구체적으로 지리강활의 극성용매 및 비극성용매 가용추출물의 분리공정을 설명하면,Hereinafter, the separation process of the polar solvent and the non-polar solvent soluble extract of geographic activity,
예를 들어 지리강활을 물, 메탄올 또는 부탄올과 같은 극성용매로 냉침추출한 후에 여과하고, 감압농축 및 동결건조하여 극성용매에 가용한 조추출물을 얻는 제 1 단계;For example, a first step of cold extraction of a geographic activity with a polar solvent such as water, methanol or butanol, followed by filtration and concentration under reduced pressure and lyophilization to obtain a crude extract soluble in a polar solvent;
상기의 조추출물을 물에 현탁하여 순차적으로 헥산, 클로로포름, 에틸아세테이트와 같은 비극성용매로 녹여 현탁시킨 후, 분액깔대기로 분획 및 여과하여 용매 극성에 따라 순차적 분획화에 의한 비극성용매 가용추출물을 얻는 제 2 단계;The crude extract is suspended in water, dissolved in a non-polar solvent such as hexane, chloroform, ethyl acetate, and then suspended. The crude extract is fractionated and filtered with a separatory funnel to obtain a non-polar solvent soluble extract by sequential fractionation according to the polarity of the solvent. Two steps;
이어서 순차적으로 수층을 부탄올 또는 물과 같은 극성 용매를 사용하여 분획 및 여과하여, 부탄올 가용추출물 및 물 가용추출물을 얻는 제 3단계;A third step of sequentially fractionating and filtering the aqueous layer using a polar solvent such as butanol or water to obtain a butanol soluble extract and a water soluble extract;
상기의 클로로포름 가용추출물, 에틸아세테이트 가용추출물, 부탄올 가용추출물 및 물 가용추출물을 감압농축하여 건조하는 제 4 단계로 구성된 분리공정을 포함한다.And a fourth step of concentrating and drying the chloroform soluble extract, ethyl acetate soluble extract, butanol soluble extract, and water soluble extract under reduced pressure.
상기 제법으로 얻어진 조추출물, 클로로포름 가용추출물, 에틸아세테이트 가용추출물, 부탄올 가용추출물 및 물 가용추출물을 시험관 상태에서 암세포 성장억제활성 및 고형암세포 억제유도효과를 실험한 결과, 유의성 있는 저해활성을 나타내었으므로, 이들은 상기 암세포억제 활성과 관련된 각종 암 질환, 특히 피부암, 췌장암, 혈액암 등의 예방 및 치료에 유용하게 사용할 수 있다.Crude extracts, chloroform soluble extracts, ethyl acetate soluble extracts, butanol soluble extracts and water soluble extracts obtained by the above method were tested for cancer cell growth inhibitory activity and solid cancer cell inhibition-inducing effect in vitro, and thus showed significant inhibitory activity. These can be usefully used for the prevention and treatment of various cancer diseases, particularly skin cancer, pancreatic cancer, blood cancer, etc. related to the cancer cell inhibitory activity.
본 발명은 상기 제법으로 얻어지고 암 질환의 예방 및 치료에 효과적인 조추출물, 극성 및 비극성용매 가용추출물을 제공한다.The present invention provides crude extracts, polar and non-polar solvent soluble extracts obtained by the above-mentioned preparation and effective for the prevention and treatment of cancer diseases.
또한 본 발명은 상기의 지리강활 조추출물, 극성 또는 비극성용매 가용추출물을 유효성분으로 함유하고, 약학적으로 허용되는 담체를 포함하는 암 질환의 예방 및 치료에 효과적인 약학 조성물을 제공한다.In another aspect, the present invention provides a pharmaceutical composition containing the above geological activation crude extract, a polar or non-polar solvent soluble extract as an active ingredient, and effective in the prevention and treatment of cancer diseases, including a pharmaceutically acceptable carrier.
본 발명의 암 질환 예방 및 치료용 조성물은, 조성물 총 중량에 대하여 상기 조추출물, 극성용매 또는 비극성용매 가용추출물을 0.1 ~ 20 중량%로 포함하며, 상기 조성물의 1일 투여량이 체중 1kg당 125 내지 250mg인 약학조성물을 제공한다.The composition for preventing and treating cancer diseases of the present invention comprises 0.1 to 20% by weight of the crude extract, the polar solvent or the nonpolar solvent soluble extract based on the total weight of the composition, the daily dosage of the composition is 125 to 1 kg body weight Provide 250 mg of pharmaceutical composition.
상기의 암은 폐암, 골암, 췌장암, 피부암, 혈액암, 두부 또는 경부 암, 피부 암, 자궁암, 난소암, 직장암, 위암, 결장암, 유방암, 음문암종, 식도암, 소장암 또는 이들 암의 하나 이상의 조합을 포함하는 것을 의미한다.The cancer may include lung cancer, bone cancer, pancreatic cancer, skin cancer, blood cancer, head or neck cancer, skin cancer, uterine cancer, ovarian cancer, rectal cancer, gastric cancer, colon cancer, breast cancer, vulvar carcinoma, esophageal cancer, small intestine cancer or one or more combinations of these cancers. It means to include.
또한, 본 발명은 지리강활 조추출물, 극성 또는 비극성용매 가용추출물을 유효성분으로 포함하는 암세포 발생억제 유도활성을 갖는 암치료 보조제를 제공한다.The present invention also provides an adjuvant for cancer treatment, which has a geological activation crude extract, a polar or non-polar solvent soluble extract as an active ingredient, and inhibits cancer cell development.
본 발명의 지리강활 추출물을 포함하는 조성물은 약학적 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.Compositions containing geological activity 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 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 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 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 지리강활 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 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. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 (tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.Compositions comprising extracts according to the invention are formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterile injectable solutions, respectively, according to conventional methods. Carriers, excipients and diluents which may be used in combination with the extract, and which 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 include at least one excipient such as starch, calcium carbonate, and sucrose in the gelatin extract. (sucrose), lactose (lactose), gelatin, etc. are mixed and prepared. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. . 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 추출물의 사용량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으나, 일반적으로 1 내지 500mg/㎏의 양, 바람직하게는 100 내지 300mg/㎏의 양을 일일 1회 내지 3회로 나누어 투여할 수 있다. 또한 그 추출물의 투여량은 투여경로, 질병의 정도, 성별, 체중, 나이, 건강상태, 식이, 투여시간, 배설율, 질환의 중증도 등에 따라서 증감될 수 있으나, 상기 투여량은 어떠한 면으로든 본 발명의범위를 한정하는 것은 아니다.The amount of the extract of the present invention may vary depending on the age, sex, and weight of the patient, but in general, an amount of 1 to 500 mg / kg, preferably 100 to 300 mg / kg, may be divided once or three times daily. Can be. In addition, the dosage of the extract may be increased or decreased depending on the route of administration, the degree of disease, sex, weight, age, health status, diet, administration time, excretion rate, severity of the disease, etc. It does not limit the scope of.
본 발명의 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 (intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, humans by various routes. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
본 발명은 암질환의 예방효과를 나타내는 지리강활의 조추출물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강보조식품을 제공한다.The present invention provides a dietary supplement comprising a crude extract of geological activity and a food-acceptable food supplement additive exhibiting a preventive effect of cancer diseases.
또한, 암질환의 예방효과를 나타내는 지리강활의 극성용매 또는 비극성용매 가용추출물 및 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 건강보조식품을 제공한다.In addition, the present invention provides a dietary supplement comprising a polar solvent or a non-polar solvent soluble extract of geological activity that exhibits a prophylactic effect of cancer disease, and a food acceptable additive.
상기의 지리강활 조추출물, 극성 또는 비극성용매 가용추출물에 강활(Angelica koreanaMAX) 추출물을 유효적으로 포함하는 건강보조음료를 제공한다.It provides a health supplement beverage comprising an active extract of Angelica koreana MAX in the geologically active crude extract, polar or non-polar solvent soluble extract.
본 발명의 추출물들을 포함하는 조성물은 암질환의 예방을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 지리강활의 조추출물, 극성용매 및 비극성용매 가용추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 육류, 초코렛, 과자류, 피자, 라면, 기타 면류, 아이스크림류, 알콜 음료류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Compositions comprising the extracts of the present invention can be used in a variety of drugs, food and beverages for the prevention of cancer diseases. Examples of the food to which the crude extract, polar solvent and non-polar solvent soluble extract of the present geographic activity can be added include, for example, various foods, meat, chocolate, confectionery, pizza, ramen, other noodles, ice cream, alcoholic beverages, beverages. , Gums, teas, vitamin complexes, dietary supplements, and the like, and may be used in the form of powders, granules, tablets, capsules, or beverages.
본 발명의 지리강활 조추출물, 극성용매 및 비극성용매 가용추출물 자체의독성 및 부작용은 동물실험시 일정한 농도 이상에서, 예를 들면 조추출물은 350 내지 400mg/kg 이상에서 나타나므로 암의 예방 목적으로 복용시 적절한 농도에서 사용할 수 있는 약제이다.Toxicity and side effects of geological active crude extract, polar solvent and non-polar solvent soluble extract itself of the present invention at a certain concentration or higher in animal experiments, for example, crude extracts appear at 350 to 400 mg / kg or more, so they are used for the prevention of cancer. It can be used at the right concentration.
본 발명의 상기 추출물은 암질환의 예방을 목적으로 식품 또는 음료에 첨가될 수 있다. 이 때, 식품 또는 음료 중의 상기 추출물의 양은 일반적으로 본 발명의 건강 식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ㎖를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.The extract of the present invention may be added to food or beverages for the purpose of preventing cancer diseases. At this time, the amount of the extract in the food or beverage is generally added to the health food composition of the present invention 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 10 g, preferably based on 100 ml Can be added in a ratio of 0.3 to 1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물을 함유하는 외에는 액체성분에는 특별한 제한점은 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등의 디사카라이드, 예를 들어 말토스, 슈크로스 등의 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, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 ㎖당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g이다.The health beverage composition of the present invention has no particular limitation on the liquid component 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 are conventional monosaccharides such as disaccharides such as glucose and fructose, such as maltose, sucrose and the like, and 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 extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of natural carbohydrates is generally about 1-20 g, preferably about 5-12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러가지 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 salts thereof. , 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 발명은 다음의 실시예에 의거하여 더욱 상세히 설명되나, 본 발명이 이에 의해 제한되지는 않는다.The present invention is described in more detail based on the following examples, although the present invention is not limited thereto.
실시예 1. 지리강활 조추출물의 제조방법Example 1 Method of Producing Geographically Active Crude Extracts
본 발명에서 사용한 국내 여러 산야에 자생하는 지리강활을 채취 후 이물을 제거하고, 지리강활 83g을 세절하여 100% 메탄올 1ℓ를 가하여 상온에서 냉침추출한 후, 상층액을 여과하여 지리강활의 찌꺼기를 제거하였다. 추출액을 여과지에 거른 후 감압농축기(EYLA, 일본)로 감압농축하여 5.4g을 얻어 시료로 사용하였다.After removing the foreign geological ligaments indigenous to the various fields in Korea used in the present invention, foreign substances were removed, and 83 g of geographic limbs were cut into pieces, and 1 liter of 100% methanol was added and cold-extracted at room temperature. The supernatant was filtered to remove the residues . The extract was filtered on filter paper and concentrated under reduced pressure with a vacuum condenser (EYLA, Japan) to obtain 5.4 g and use it as a sample.
실시예 2. 지리강활 극성용매 및 비극성용매 가용추출물의 제조방법Example 2 Method for Producing Geographically Active Polar Solvents and Nonpolar Solvent Soluble Extracts
상기 실시예 1에서 제조된 지리강활 조추출물 5.4g을 300㎖의 물에 현탁한 후, 클로로포름 600㎖를 가하여, 분액깔대기에 넣고 클로로포름 불용성층(상층)과 클로로포름 가용성층(하층)으로 분획하여 클로로포름 가용부를 수집하였다. 상층(물층)과 동일한 부피의 클로로포름용매를 상기한 방법과 동일한 방법으로 5회 반복하여 용액의 색이 옅어질 때까지 최대한 클로로포름층에 용해가 가능한 물질을 얻어낸 후, 지리강활의 클로로포름 추출물 3.04g을 수득하여 시료로 사용하였으며, 에틸아세테이트를 상기의 클로로포름과 같은 방법으로 분획하여, 에틸아세테이트 가용추출물 0.96g을 얻어 시료로 사용하였다. 상기의 수층에 다시 순차적으로 부탄올과 물을 가하여 분획하여, 부탄올 추출물 0.43g, 물 추출물 0.47g을 수득하였으며, 지리강활의 극성용매 가용추출물 시료로 사용하였다.After 5.4 g of the gelatinous active crude extract prepared in Example 1 was suspended in 300 ml of water, 600 ml of chloroform was added to the separatory funnel, and fractionated into a chloroform insoluble layer (upper layer) and a chloroform soluble layer (lower layer) to form chloroform. Soluble parts were collected. The same volume of chloroform solvent as in the upper layer (water layer) was repeated five times in the same manner as described above to obtain a substance that can be dissolved in the chloroform layer as much as possible until the color of the solution became light. Then, 3.04 g of chloroform extract of geological activity was added. Obtained and used as a sample, ethyl acetate was fractionated in the same manner as in the above chloroform to obtain 0.96 g of ethyl acetate soluble extract was used as a sample. Butanol and water were sequentially added to the aqueous layer and fractionated to obtain 0.43 g of butanol extract and 0.47 g of water extract, which was used as a polar solvent soluble extract sample of geographic activity.
참조예 1. 기기 분석Reference Example 1. Instrument Analysis
암세포 생장억제 성분의 분석을 위하여, 역상 고성능 액체크로마토그래피 (Reversed-phase HPLC, SCL10A, Shimadzu사, 일본)를 사용하였다.For analysis of cancer cell growth inhibitory components, reversed phase high performance liquid chromatography (Reversed-phase HPLC, SCL10A, Shimadzu Co., Japan) was used.
HPLC의 이동상 조건으로 메탄올과 물을 같은 비율로 섞은 용매로 시작점으로 하였으며, 메탄올과 물의 비율이 9:1이 될 때까지 20분의 시간을 두었고, 메탄올이 100퍼센트가 되기까지 30분의 시간을 두었다. 이때 역상컬럼을 통과하는 이동상의 유속은 실온에서 유속 2㎖/분으로 설정하였으며, 함께 박층 크로마토그래피(TLC)를 수행하여 재확인하였다.As a starting point, the solvent was a mixture of methanol and water in the same ratio as the mobile phase condition of HPLC, and the time was 20 minutes until the ratio of methanol and water became 9: 1, and the time of 30 minutes until methanol became 100%. Put it. At this time, the flow rate of the mobile phase passing through the reverse phase column was set to a flow rate of 2ml / min at room temperature, and reconfirmed by performing thin layer chromatography (TLC) together.
상기 실시예 2에서 제조된 지리강활 클로로포름 가용추출물을 상기와 같은 방법으로 수행하여 성분을 분석하였다(도 1 참조).Geologically active chloroform soluble extract prepared in Example 2 was carried out in the same manner as above to analyze the components (see FIG. 1).
실험예 1. 시험관상에서 암세포 성장 억제 효과 시험Experimental Example 1. Test of cancer cell growth inhibition effect in vitro
실시예 1 및 2에서 제조된 지리강활의 조추출물, 극성 또는 비극성용매 가용추출물의 암세포 성장억제 효과를 알아보기 위하여 하기와 같은 실험을 수행하였다.In order to determine the cancer cell growth inhibitory effect of the crude extract, polar or non-polar solvent soluble extract of geographic activity prepared in Examples 1 and 2 was carried out as follows.
쥐의 췌장세포주인 MS 1 세포주(ATCC, 미국)와 사람의 혈액암세포인 HL60 세포주(ATCC사, 미국)를 배양한 후, 음성 대조군으로는 0.5% 디메틸술폭시드(DMSO)를, 양성 대조군으로는 캠토테친(Camptothecin)(최종 농도 0.5㎍/㎖)을 처리하였고, 대상 시험물질들을 농도별로 처리하였다. 48시간 동안 배양한 후 용해 완충액(lysis buffer)으로 용해시키고, 여기에 MTT가 들어있는 반응 혼합물을 넣어 37℃에서 50분간 배양기에서 반응시킨 후, 마이크로플레이트 판독기를 사용하여 610nm에서 흡광도를 측정하였다(Scott. G,J. Clin. Microbial.,36, pp362-366, 1998).After culturing the mouse pancreatic cell line MS 1 (ATCC, USA) and human blood cancer cells HL60 cell line (ATCC, USA), 0.5% dimethylsulfoxide (DMSO) as a negative control, and a positive control Camptothecin (final concentration 0.5 μg / ml) was treated and subject test substances were treated by concentration. After 48 hours of incubation, the solution was dissolved in lysis buffer, and the reaction mixture containing MTT was added thereto and reacted in an incubator at 37 ° C. for 50 minutes, and then the absorbance was measured at 610 nm using a microplate reader ( Scott, G, J. Clin.Microbial . , 36 , pp 362-366, 1998).
실험 결과, 지리강활 조추출물은 62㎍/㎖에서 쥐의 췌장세포주인 MS 1에 대하여 50% 세포성장 억제율을 보였으며, 10㎍/㎖에서 사람의 혈액암세포인 HL60 세포주에 대하여 50% 세포성장 억제율을 나타냈으며, 클로로포름 가용추출물은 사람의 혈액암세포인 HL60 세포주에 대하여 8㎍/㎖ 농도에서 50% 세포성장 억제율을 보여 탁월한 암세포 성장억제 저해 효과를 나타내었다(표 1 참조).As a result, geological activation crude extract showed 50% cell growth inhibition of MS 1, which is a mouse pancreatic cell line, at 62µg / ml, and 50% cell growth inhibition rate of HL60 cell line of human blood cancer cells at 10µg / ml. Chloroform soluble extract showed a 50% cell growth inhibition rate at 8 μg / ml concentration against HL60 cell line of human blood cancer cells, showing an excellent cancer cell growth inhibitory effect (see Table 1).
실험예 2. 마우스에 대한 항암활성 농도시험Experimental Example 2. Anticancer Activity Concentration Test in Mice
건강한 마우스의 암컷과 수컷에 상기 실시예 1의 지리강활 조추출물을 적정농도를 투여하여 24시간내에 일어나는 쥐의 외관상의 변화 또는 조직병리학적 장기의 변화를 관찰하였다(한국화학연구소 독성연구실, 한국화학연구소 독성시험법, pp125-128, 1996).The geological activation crude extract of Example 1 was administered to females and males of healthy mice to observe changes in appearance or histopathological organs occurring within 24 hours (Toxicology Laboratory, Korea Chemical Research Institute, Korea Chemical Research Institute). Laboratory Toxicity Assay, pp 125-128, 1996).
일반적인 생약시료 검정 농도인 1g, 500mg, 250mg/kg의 농도를 투여하여 24시간내에 일어나는 쥐의 외관상의 변화 또는 조직병리학적 장기의 변화를 관찰한 결과, 250mg 투여 용량에서는 생존에는 전혀 지장을 주지 않고 조직병리학적인 관찰에도 별다른 문제점이 발견되지 않았다. 결과적으로 항암활성시험은 250, 125mg/kg의 농도에서 실시하였다(표 2 참조).As a result of observation of changes in histological or histopathological organs occurring within 24 hours by administering the general herbal test concentrations of 1g, 500mg and 250mg / kg, the 250mg dose did not interfere with survival. Histopathological observations showed no problems. As a result, the anticancer activity test was carried out at concentrations of 250 and 125 mg / kg (see Table 2).
실험예 3. 지리강활 추출물의 마우스 모델에서의 고형암 세포주 억제효과 시험Experimental Example 3. Test of the inhibition effect of solid cancer cell line in mouse model of geological activation extract
지리강활 추출물의 실제 동물 모델에서의 고형암 억제효과를 알아보기 위하여 하기와 같은 실험을 수행하였다.The following experiment was performed to investigate the inhibitory effect of solid cancer in the real animal model of geological activity extract.
동물모델로는 3 내지 4 주령의 C57bl/6 수컷 마우스(13~17g, 한국생명공학연구원)를 사용하여 각 그룹당 5 마리씩 4개 그룹으로 구성하였다. 1주일의 적응기간을 가진 후, 등쪽의 털을 제거하여 2×2cm2의 면적으로 피부를 노출시키고 암 개시제로서 쥐의 루이스 허파 상피암(Lewis lung carcinoma, ATCC, 미국) 세포 계대 배양한 것을 약 10,000개/㎖의 암세포가 되도록 부유시켜 0.1㎖씩 건강한 마우스의 왼쪽 서혜부에 이식하여 고형암을 유발시켰으며, 고형암을 이식함과 동시에 음성대조군은 무처리군으로서 생리식염수 1㎖를, 양성대조군은 항암제인 아드리아마이신 (adriamycin) 3mg/kg, 실험군은 지리강활 조추출물을 각각 125mg/kg, 250mg/kg을 처리하였다.Animal models were composed of 4 groups of 5 to each group using 3 to 4 week old C57bl / 6 male mice (13-17 g, Korea Research Institute of Bioscience and Biotechnology). After one week of adaptation, the back hairs were removed to expose the skin with an area of 2 × 2 cm 2 , and the mouse passage of Lewis lung carcinoma (ATCC, USA) cell passage as a cancer initiator was approximately 10,000. The cancer cells of dogs / ml were suspended and transplanted into the left inguinal part of healthy mice by 0.1ml each to induce solid cancer.The negative control group was untreated group with 1ml of physiological saline and the positive control group was anticancer agent. Adriamycin 3mg / kg, experimental group was treated with geological activation crude extract 125mg / kg, 250mg / kg, respectively.
종양은 유의하게 발생한 날로부터 10일째로부터 3일 간격으로 종양의 장반경과 단반경의 길이를 측정하고 종양의 부피를 계산하여 지리강활 추출물이 종양의 성장을 억제하는 양상을 확인하였으며, 종양을 저지하는 백분율의 결정은 암세포를 이식한지 28일째 되는 날에 마우스를 사망시키고 생성된 고형암을 꺼낸 후 그 중량을 측정하여 평균 종양 중량을 얻어 종량저지 백분율을 계산하였다(Yatsunami, J.,Int. J. Oncol., 17, pp1151-1156, 2000).Tumors were measured by measuring the length of the long and short radius of the tumor and calculating the volume of the tumor at intervals of 3 days from the 10th day from the day of significant occurrence. The decision was made on the 28th day after transplanting the cancer cells, the mice were killed and the resulting solid cancer was taken out and weighed to obtain the average tumor weight to calculate the percentage of the percentage of mass-sustaining inhibition (Yatsunami, J., Int. J. Oncol. , 17, pp 1151-1156, 2000).
쥐의 루이스 허파 상피암 세포로 종양을 유발시킨 마우스 모델을 통한 지리강활 조추출물의 고형암 억제효과를 확인한 결과, 양성 대조군으로 처리한 항암제인 아드리아마이신은 억제효과를 92.1%를 보였으며, 지리강활 조추출물 250mg/kg은 84.9%, 125mg/kg에서 52.1%의 고형암 억제 효과를 보이는 것을 확인하였다(도 2 및 표 3 참조).As a result of confirming the inhibitory effect of GRI-activated crude extracts on solid tumors through the mouse model that induced tumors with Lewis lung lung epithelial cancer cells, Adriamycin, an anticancer drug treated with positive control, showed 92.1% inhibition effect. It was confirmed that 250mg / kg showed a solid cancer suppression effect of 52.1% at 84.9%, 125mg / kg (see Fig. 2 and Table 3).
실험예 4. 지리강활 추출물의 독성실험Experimental Example 4. Toxicity Test of Geological Activity Extract
실시예 1과 실시예 2의 지리강활 조추출물, 극성 및 비극성용매 가용추출물의 독성을 확인하기 위하여 동물실험을 실시하였다.Animal experiments were conducted to confirm the toxicity of the geologically active crude extracts, polar and nonpolar solvent soluble extracts of Examples 1 and 2.
ICR계 BALB 마우스(한국생명공학연구원 유전자원센터) 20내지 25g 정도의 수컷을 각각 10 마리씩 4군으로 나눈 다음 본 발명의 지리강활 조추출물을 각각 125, 250, 500 및 1000 mg/kg의 용량으로 경구투여하였다. 경구 투여 후, 2주간 독성 여부를 관찰한 결과 125, 250mg/kg군에서는 한 마리도 사망하지 않았으며, 500 및 1000 mg/kg군은 모두 사망하였다. 부검결과 조직학적으로는 외견상 대조군과 별다른 증상을 찾아볼 수 없음을 확인하였다.ICR-based BALB mice (Korea Institute of Bioscience and Biotechnology Genetic Genetic Center) 20 to 25 g each of 10 males divided into 4 groups and then the geological activation crude extracts of the present invention were dosed at 125, 250, 500 and 1000 mg / kg, respectively. Oral administration. After oral administration, toxicity was observed for 2 weeks, and none of the 125 and 250 mg / kg groups died. All 500 and 1000 mg / kg groups died. The autopsy revealed that histologically no symptoms were found.
본 발명의 지리강활의 추출물은 아래와 같은 제형으로 투여할 수 있으며, 아래의 제제 실시예는 본 발명을 예시하는 것일 뿐, 이에 의해 본 발명의 내용이 제한되는 것은 아니다.The extract of geographic activity of the present invention can be administered in the following formulations, the formulation examples below are merely to illustrate the invention, whereby the content of the invention is not limited.
1. 산제의 제조1. Preparation of powder
지리강활의 클로로포름 가용추출물100mgChloroform Soluble Extract of Geological Activity 100mg
옥수수전분 100mgCorn Starch 100mg
유 당 100mgLactose 100mg
탈 크 10mgTalc 10mg
상기의 성분들을 혼합하고 기밀 포에 충진하여 산제를 제조한다.The above ingredients are mixed and filled in airtight cloth to prepare a powder.
2. 정제의 제조2. Preparation of Tablets
지리강활의 클로로포름 가용추출물 100mgChloroform Soluble Extract of Geological Activity 100mg
옥수수전분 100mgCorn Starch 100mg
유 당 100mgLactose 100mg
스테아린산 마그네슘 2mg2 mg magnesium stearate
상기의 성분들을 혼합한후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components and tableting according to the manufacturing method of the conventional tablet to prepare a tablet.
3. 캡슐제의 제조3. Preparation of Capsule
지리강활의 클로로포름 가용추출물100mgChloroform Soluble Extract of Geological Activity 100mg
유 당 50mgLactose 50mg
스테아린산 마그네슘 1mg1 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 캡슐제의 제조방법에 따라서 타정하여 젤라틴 캡슐제에 충진하여 제조한다.The above ingredients are mixed and compressed into tablets according to a conventional method for preparing capsules to fill gelatin capsules.
4. 액제의 제조4. Manufacture of liquid
지리강활의 클로로포름 가용추출물 100mgChloroform Soluble Extract of Geological Activity 100mg
이성화당 10g10 g of isomerized sugar
서 당 10g10g per book
레몬향 적량Lemon flavor
정제수 적량Purified water
통상의 액제의 제조방법에 따라서 정제수에 각각의 성분을 가하고 용해시키고 레몬향을 적량 가한 다음 정제수를 가하여 전체를 100㎖로 조절한 후 갈색병에 충진하여 멸균시켜서 액제를 제조한다.According to the conventional method for preparing a liquid solution, each component is added to the purified water, dissolved, and lemon flavor is added, and then purified water is added to adjust the total amount to 100 ml, and then filled into a brown bottle to prepare a liquid solution.
제제예 5. 건강 식품의 제조Formulation Example 5 Preparation of Healthy Food
지리강활의 클로로포름 가용추출물1000 ㎎Chloroform Soluble Extract of Geological Activity1000 mg
비타민 혼합물적량Vitamin mixture
비타민 A 아세테이70 ㎍Vitamin A Acetate70 ㎍
비타민 E1.0 ㎎Vitamin E1.0 mg
비타민 B10.13 ㎎Vitamin B 1 0.13 mg
비타민 B20.15 ㎎Vitamin B 2 0.15 mg
비타민 B60.5 ㎎Vitamin B 6 0.5 mg
비타민 B120.2 ㎍0.2 μg of vitamin B 12
비타민 C10 ㎎Vitamin C10 mg
비오틴10 ㎍Biotin 10 ㎍
니코틴산아미드1.7 ㎎Nicotinic Acid Amide1.7 mg
엽산50 ㎍Folic acid 50 ㎍
판토텐산 칼슘0.5 ㎎Calcium Pantothenate 0.5 mg
무기질 혼합물적량Mineral mixture
황산제1철1.75 ㎎Ferrous Sulfate1.75 mg
산화아연0.82 ㎎Zinc Oxide 0.82 mg
탄산마그네슘25.3 ㎎Magnesium carbonate25.3 mg
제1인산칼륨15 ㎎Potassium phosphate monobasic 15 mg
제2인산칼슘55 ㎎Dibasic calcium phosphate55 mg
구연산칼륨90 ㎎Potassium Citrate 90 mg
탄산칼슘100 ㎎Calcium Carbonate 100 mg
염화마그네슘24.8 ㎎Magnesium chloride24.8 mg
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 6. 건강 음료의 제조Formulation Example 6 Preparation of Healthy Drink
지리강활의 클로로포름 가용추출물1000 ㎎Chloroform Soluble Extract of Geological Activity1000 mg
강활 추출물1000 ㎎Revitalization extract 1000 mg
구연산1000 ㎎Citric Acid1000 mg
올리고당100 gOligosaccharides 100 g
매실농축액2 gPlum concentrate 2 g
타우린1 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, 수요계층, 수요국가, 사용 용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a composition suitable for a preferred beverage in a preferred embodiment, the composition ratio may be arbitrarily modified according to regional and ethnic preferences such as demand hierarchy, demand country, use purpose.
이와 같이 본 발명은 지리강활 추출물을 배합한 각종 식품류 및 음료류를 제조함으로서 암 예방 효과가 기대되는 기능성 식품을 제공할 수 있는 것이다.As described above, the present invention can provide a functional food having anticancer effect by preparing various foods and beverages containing gelatin active extract.
본 발명의 지리강활 조추출물, 극성 및 비극성용매 가용추출물은 시험관상의 암세포의 성장을 저해하고 동물모델에 유발한 고형암을 유의적으로 억제하므로, 각종 암질환의 치료 및 예방에 유용한 의약품으로 사용할 수 있다.Geologically active crude extract, polar and nonpolar solvent soluble extract of the present invention inhibits the growth of cancer cells in vitro and significantly inhibits solid cancer induced in animal models, and thus can be used as a useful medicine for the treatment and prevention of various cancer diseases. .
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