KR20160142488A - A composition comprising sesamin, and fenofibrate or rosuvastatin for preventing or treating angioplasty restenosis - Google Patents
A composition comprising sesamin, and fenofibrate or rosuvastatin for preventing or treating angioplasty restenosis Download PDFInfo
- Publication number
- KR20160142488A KR20160142488A KR1020150078281A KR20150078281A KR20160142488A KR 20160142488 A KR20160142488 A KR 20160142488A KR 1020150078281 A KR1020150078281 A KR 1020150078281A KR 20150078281 A KR20150078281 A KR 20150078281A KR 20160142488 A KR20160142488 A KR 20160142488A
- Authority
- KR
- South Korea
- Prior art keywords
- sesamin
- composition
- rosuvastatin
- smooth muscle
- pharmaceutically acceptable
- Prior art date
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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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
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- A—HUMAN NECESSITIES
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
본 발명은 세사민과, 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물을 유효성분으로 포함하는 혈관재협착증의 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating vascular restenosis comprising at least one compound selected from the group consisting of sesamin, phenobibrate and rosuvastatin.
혈관재협착증(angioplasty restenosis)은 혈관조영술에 의한 진단으로, 혈관성형술 후 추적 조영술 상의 혈관내경 협착이 50% 이상인 경우를 말한다. 최근에는 스텐트를 이용하는 시술이 증가하면서 혈관재협착증의 발생율이 감소하기는 하였으나, 여전히 혈관성형술(풍선확장술 및 스텐트 삽입)을 시술받은 환자의 30% 정도는 혈관재협착증이 발생하고 있다.Angioplasty restenosis (angioplasty restenosis) is an angiographic diagnosis. It refers to a case of angiographic stenosis of 50% or more on follow - up angiography after angioplasty. Recently, the incidence of vascular restenosis has decreased with the increase in the use of stents. However, about 30% of patients who underwent angioplasty (balloon dilatation and stenting) still have vascular restenosis.
정상적인 경우의 내피세포는 혈관 평활근 세포의 증식을 억제하는 물질을 분비하여 세포 증식이 일어나지 않지만, 스텐트 시술 등을 통하여 내피세포가 손상되는 경우에는 활성화된 혈소판에서 분비되는 혈소판 유래 성장인자(PDGF, platelet-derived growth factor)와 혈장 중에 포함되어 있는 다양한 사이토카인이 분비되어, 혈관 평활근 세포의 증식, 이동, 단백질 합성능력 등의 급격한 변화를 유도한다(Ross, R., 1999; Sachinidis, A. et al., 1990). 그 결과 동맥내강이 좁아져서 혈관재협착증에 이르게 되는 것으로 알려져 있으며, 선행문헌에는 혈관 평활근 세포의 증식이 혈관성형술의 효율을 제한하는 주요한 임상상의 문제로 제기되어 혈관 평활근 세포의 증식을 억제하는 약물이나 물질을 방출하는 스텐트를 개발하여 임상에 사용하였음을 보고하였다(Ross, R., 1990; Ross, 1995; Schwartz, S. M., 1997). 그러나 이러한 목적으로 사용되고 있는 약물들은 혈관 평활근 세포를 사멸시키는 기전을 통해 내막의 과형성을 방지하지만, 약물이 지닌 독성에 의해 평활근 세포뿐만 아니라 내피세포의 사멸까지 유도하므로 임상 사용에 있어 한계를 드러내고 있다. 따라서 혈관 평활근 세포의 성장은 선택적으로 억제하면서 독성이 나타나지 않는 약물의 개발이 시급한 실정이다.Normally, endothelial cells secrete a substance that inhibits vascular smooth muscle cell proliferation. However, when endothelial cells are damaged through stenting or the like, platelet-derived growth factor (PDGF, platelet (1999), Sachinidis, A., et al., 1999). In addition, a variety of cytokines are secreted in the blood, , 1990). As a result, it has been known that the lumen of the artery narrows and leads to vascular restenosis. In the prior art, proliferation of vascular smooth muscle cells has been suggested as a major clinical problem that limits the efficiency of angioplasty, (Ross, R., 1990; Schwartz, SM, 1997). In the present study, However, the drugs used for this purpose prevent the intimal hyperplasia through the mechanism of vascular smooth muscle cell death, but they also limit the clinical use because they lead to the death of endothelial cells as well as smooth muscle cells due to the toxicity of the drug. Therefore, it is urgent to develop a drug that inhibits the growth of vascular smooth muscle cells and does not show toxicity.
한편, 혈관 평활근 세포의 증식을 억제하기 위해서는 세포 주기(cell cycle)의 조절도 중요한 요인으로 작용할 수 있으며, 일반적으로 동물 세포의 증식은 복합적이면서도 순차적인 G0/G1, S, G2/M의 세포 주기 통제를 받는다(Sherr, C. J., 1996). 정상적인 조건의 경우, 혈관에 있는 대부분의 혈관 평활근 세포는 G0 상태이지만 기구(balloon)에 의해 손상(injury)되거나 PDGF 자극 등이 있는 경우에는 세포 주기의 변화가 유도된다(Xiong, Y. et al., 1993).In addition, the regulation of the cell cycle may also be an important factor to inhibit the proliferation of vascular smooth muscle cells. In general, the proliferation of animal cells is complex and sequential G 0 / G 1 , S, G 2 / M (Sherr, CJ, 1996). Under normal conditions, most vascular smooth muscle cells in the blood vessels are in the G 0 state, but when they are injured by balloon or PDGF stimulation, changes in the cell cycle are induced (Xiong, Y. et al , 1993).
또한, 세포 주기를 조절하는데 있어 CDK(cyclin-dependent kinases)는 중요한 인자이다. CDK의 활성은 사이클린 조절 서브유닛(cyclin regulatory subunits)에 의해 조절되고, 효소활성을 가진 CDK 서브유닛으로 구성된 복합체를 형성하며, 대부분의 세포에서는 G1구간에서 S구간으로 진입 시에 사이클린 D/CDK4(cyclin D/CDK4)나 사이클린 E/CDK2(cyclin E/CDK2)와 같은 사이클린/CDK 복합체(cyclin/CDK complexes)의 결합 및 활성이 요구된다. 이러한 복합체의 활성화는 Rb(retinoblastoma) 단백질의 인산화반응을 촉진하고 PCNA(proliferating cell nuclear antigen)의 발현을 향상시킴으로써 세포의 증식에 영향을 미친다.In addition, CDK (cyclin-dependent kinases) is an important factor in regulating cell cycle. Of CDK activity of cyclin control subunit (cyclin regulatory subunits) and controlled by, and form a complex consisting of a CDK subunit has enzymatic activity, most of the cells in the cyclin D / CDK4 upon entering the S period from the G 1 period the binding and activity of cyclin / CDK complexes such as cyclin D / CDK4 and cyclin E / CDK2 are required. Activation of these complexes promotes the phosphorylation of Rb (retinoblastoma) proteins and enhances proliferating cell nuclear antigen (PCNA) expression, thereby affecting cell proliferation.
반면, 사이클린/CDK 복합체의 키나아제(kinase) 활성은 CKI(cyclin-dependent kinase inhibitors)에 의해 억제된다. 상기 CKI 중에서 INK4 패밀리(INK4 family, p16INK4a 및 p15INK4b)는 CDK4와 CDK6만을 저해하지만, Cip 패밀리(Cip family, p21CIP1 및 p27KIP1)는 모든 CDK를 억제하여, 세포 증식의 억제에 영향을 미치므로 세포 주기를 조절하는 경우에 고려할 만한 인자이다(Hunter, T. et al., 1994; Coqueret, O., 2003).On the other hand, the kinase activity of the cyclin / CDK complex is inhibited by CKI (cyclin-dependent kinase inhibitors). Among the CKIs, the INK4 family (INK4 family, p16INK4a and p15INK4b) inhibits only CDK4 and CDK6, while the Cip family (p21 CIP1 and p27 KIP1 ) inhibits all CDKs and affects the inhibition of cell proliferation. (Hunter, T. et al., 1994; Coqueret, O., 2003).
한편, 혈관재협착증의 치료를 위해 택솔(Herdeg, C. et al., 1999), 헤파린, EPA, 에스트로겐 등을 연구 개발 중에 있으나, 이 역시 뚜렷한 실효를 거두지 못하는 실정이다. 한국등록특허 제478671호에는 클로트리마졸을 유효성분으로 포함하는 혈관 재협착 예방 및 치료용 약학 조성물이 개시되어 있으며, 한국등록특허 제516026호에는 3'-디옥시아데노신(3'-deoxyadenosine)을 유효성분으로 하는 혈관 재협착 예방 및 치료용 조성물이 개시되어 있다. 또한, 한국등록특허 제817932호에는 베르바민을 유효성분으로 포함하는 스텐트 시술 후에 발생하는 혈관재협착의 예방제에 관한 조성물이 개시되어 있지만, 이러한 혈관재협착 억제제는 혈관재협착을 방지하는 것 이외의, 상처재생억제, 혈관손상, 간독성, 신장손상, 혈소판응집억제에 의한 출혈량 증가 등의 다양한 부작용을 나타내기 때문에, 안전성이 입증된 다양한 천연물로부터 유래된 혈관재협착을 억제할 수 있는 물질을 개발하려는 연구가 활발히 진행되고 있으나, 별다른 연구 성과가 보고되지 않는 실정이다. 따라서 안전하면서도 효과적으로 혈관재협착을 억제할 수 있는 물질을 개발하여야 할 필요성이 끊임없이 대두되고 있다.In the meantime, taxol (Herdeg, C. et al., 1999), heparin, EPA and estrogen are under research and development for the treatment of vascular restenosis, but this is also not clear. Korean Patent No. 478671 discloses a pharmaceutical composition for the prevention and treatment of vascular restenosis comprising clotrimazole as an active ingredient, Korean Patent No. 516026 discloses a pharmaceutical composition comprising 3'-deoxyadenosine A composition for preventing and treating vascular restenosis comprising an effective ingredient is disclosed. Korean Patent No. 817932 discloses a composition relating to a preventive agent for vascular restenosis which occurs after stenting comprising verbamine as an active ingredient. However, such a vascular restenosis inhibitor is not limited to prevent vascular restenosis , And to develop a substance capable of inhibiting vascular restenosis derived from various natural substances that have been proven to be safe because it exhibits various side effects such as inhibition of wound regeneration, vascular injury, hepatotoxicity, renal injury, and increase in blood loss due to inhibition of platelet aggregation Research has been actively conducted, but no research results have been reported. Therefore, there is a constant need to develop a substance that can safely and effectively inhibit vascular restenosis.
세사민(sesamin)은 참깨 종자유(sesame seed oil) 내에 가장 많이 함유된 리그난(lignan)의 일종으로 민족두리풀(Asiasarum heterotropoides), 흰털오갈피 및 가시오가피(Acanthopanax senticosus) 등의 여러 약용식물에서도 발견된다(Ryu, J. et al., 2004). 또한, 세사민은 항콜레스테롤(Rogi, T. et al., 2011), 항고혈압(Lee, C. C. et al., 2004), 항산화(Nakano, D. et al., 2008), 항균성(Bankole, M. A. et al., 2007), 간의 보호 작용(Periasamy, S. et al., 2014) 및 항암 활성(Hibasami, H. et al., 2000; Ju, Y. et al., 2001; Miyahara, Y. et al., 2000) 효과 등의 다양한 약리학적 활성을 나타내는 것으로도 알려져 있다.Sesamin is one of the most abundant lignans in sesame seed oil and is also found in several medicinal plants such as Asiasarum heterotropoides , Acanthopanax senticosus and the like (Ryu, J. et al., 2004). In addition, sesamin has been shown to have anticholesterol (Rogi, T. et al., 2011), antihypertensive (Lee, CC et al., 2004), antioxidant (Nakano, Y. et al., 2001; Miyahara, Y. et al., 2007), liver protective action (Periasamy, S. et al., 2014) and anticancer activity (Hibasami, H. et al., 2000; ., 2000), which are known to exhibit various pharmacological activities.
페노피브레이트(fenofibrate)는 일반적으로 물에 잘 녹지 않으며 메탄올과 에탄올에는 부분적으로 녹으며 아세톤, 에테르, 벤젠에는 잘 녹는 성질을 가지고 있다. 또한, 피브레이트 계열의 의약품으로 콜레스테롤을 낮추기 위한 용도로 주로 사용되며, 성인의 내인성 고지질혈증(hyperlipidemias), 과콜레스테롤혈증(hypercholesterolemias), 고중성지방혈증(hypertriglyceridemias)의 치료에 이용된다. 페노피브레이트와 관련하여, 한국등록특허 제1286743호에는 패혈증에 대한 치료 효과가 있음을 나타내었으며, PPARα의 활성을 촉진시켜서 중성지방은 감소시키고 고밀도지단백 콜레스테롤은 증가시키는 효과가 있음을 나타낸 문헌도 있다(Costet, P. et al., 1998).Fenofibrate is generally insoluble in water, partially soluble in methanol and ethanol, and soluble in acetone, ether, and benzene. It is also used for lowering cholesterol in fibrates and is used for the treatment of endogenous hyperlipidemias, hypercholesterolemias and hypertriglyceridemias in adults. Regarding phenobibrate, Korean Patent No. 1286743 shows that there is a therapeutic effect on sepsis, and there is also a document that promotes the activity of PPAR alpha to reduce triglyceride and increase high density lipoprotein cholesterol (Costet , P. et al., 1998).
로수바스타틴(rosuvastatin)은 고콜레스테롤혈증(hypercholesterolemia), 고지질단백질혈증(hyperlipidproteinemia) 및 죽상동맥경화증(atherosclerosis)의 치료에 사용된다. 또한, 로수바스타틴의 경우 20%의 높은 생체이용률을 보이며, 반감기는 약 19시간으로 길다. 90% 정도가 대변으로 배설되며, 다른 스타틴 제제와 달리 cytochrome P(CYP) 450 3A4와 상호작용을 나타내지 않으므로 근육병증(myopathy)의 위험이 높지 않다. 또한, Shionogi사에 의하여 헤미칼슘염으로 판매(CRESTOR)되고 있고, 로수바스타틴 헤미칼슘염은 현존하는 스타틴 제제 중 가장 우수한 LDL 콜레스테롤 수치 감소 효과를 가지고 있으며, 약물학적으로 수용성이고 간에 대한 선택성이 뛰어나 우수한 약리효과 및 안정성을 가지고 있다.Rosuvastatin is used in the treatment of hypercholesterolemia, hyperlipid proteinemia and atherosclerosis. In addition, rosuvastatin has a high bioavailability of 20% and a half-life of about 19 hours. 90% are excreted in the feces, and unlike other statins, they do not interact with cytochrome P (CYP) 450 3A4, so the risk of myopathy is not high. In addition, Shionogi has been selling it as a hemicalcium salt (CRESTOR), and rosuvastatin hemicalcium salt has the best LDL cholesterol level reduction effect of existing statins, and is pharmacologically soluble and excellent in liver selectivity It has excellent pharmacological effect and stability.
이에 본 발명자들은 세사민을 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물과 병용하는 것에 의해 혈관재협착증의 발생을 효과적으로 억제할 수 있음을 확인함으로써 본 발명을 완성할 수 있었다.Thus, the present inventors have completed the present invention by confirming that the use of sesamin in combination with at least one of phenobibrate and rosuvastatin can effectively inhibit the occurrence of vascular restenosis.
본 발명의 목적은 세사민과, 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물을 유효성분으로 포함하는 혈관재협착증의 예방 또는 치료용 조성물을 제공하는데 있다. 보다 더 자세하게는 상기 조성물이 혈관 평활근 세포의 증식을 억제하는 효과가 우수한 것을 특징으로 하는 혈관재협착증의 예방 또는 치료용 조성물을 제공하는데 있다.It is an object of the present invention to provide a composition for preventing or treating vascular restenosis comprising at least one compound selected from the group consisting of sesamin, phenobibrate and rosuvastatin as an active ingredient. More specifically, the present invention provides a composition for preventing or treating vascular restenosis, wherein the composition is excellent in inhibiting vascular smooth muscle cell proliferation.
본 발명은, 유효성분으로서, (a) 세사민(sesamin) 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트(fenofibrate) 및 로수바스타틴(rosuvastatin) 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 혈관재협착증의 예방 또는 치료용 조성물에 관한 것이다.The present invention provides, as an active ingredient, (a) sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, to a composition for preventing or treating vascular restenosis.
상기 (a) 세사민 또는 이의 약학적으로 허용가능한 염, 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염은, 1:0.5~4의 중량비로 혼합된 것을 특징으로 한다.Characterized in that the above-mentioned sesamin or its pharmaceutically acceptable salt and / or (b) at least one compound selected from the group consisting of phenobibrate and rosuvastatin or a pharmaceutically acceptable salt thereof are mixed at a weight ratio of 1: 0.5 to 4 .
상기 조성물은 혈관 평활근 세포의 증식을 억제하는 것을 특징으로 한다.The composition is characterized by inhibiting proliferation of vascular smooth muscle cells.
또 다른 일면에 있어서, 본 발명은, (a) 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 혈관재협착증의 예방 또는 개선용 건강기능식품에 관한 것이다.In another aspect, the present invention provides a pharmaceutical composition comprising: (a) sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a health functional food for preventing or ameliorating vascular restenosis.
이하 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 (a) 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 혈관재협착증의 예방 또는 치료용 조성물에 관한 것이다. (A) sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of vascular restenosis.
상기 조성물에 있어서, 유효성분인 (a)와 (b)는, 1:0.5~4의 중량비로 혼합될 수 있고, 보다 바람직하게는 1:0.5~2의 중량비로 혼합될 수 있으며, 가장 바람직하게는 1:1~2의 중량비로 혼합될 수 있다.In the above composition, the active ingredients (a) and (b) may be mixed in a weight ratio of 1: 0.5 to 4, more preferably 1: 0.5 to 2, and most preferably May be mixed in a weight ratio of 1: 1 to 2.
또한, 유효성분 (b)로서, 페노피브레이트 및 로수바스타틴을 동시에 포함하는 경우라면, 이들 페노피브레이트 및 로수바스타틴은 1:0.5~2의 중량비로 혼합되는 것이 바람직하다.In the case of simultaneously containing phenobibrate and rosuvastatin as the active ingredient (b), these phenobibrate and rosuvastatin are preferably mixed in a weight ratio of 1: 0.5 to 2.
상기 세사민은 흰털오갈피나무(Acanthopanax divaricatus var. albeofructus)를 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매 흰털오갈피나무 추출물을 크로마토그래피로 분획하여 얻을 수 있고, 상기 C1 내지 C4의 저급 알코올로는 메탄올, 에탄올, 프로판올, 이소프로판올, 부탄올 등을 이용할 수 있다. 보다 바람직하게는, 흰털오갈피나무의 건조된 줄기를 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로 흰털오갈피나무 추출물을 얻어, n-헥산 및 에틸아세테이트를 이용하여 순차적으로 분획하며, 상기 각 분획물을 크로마토그래피로 분리하여 세사민을 얻을 수 있다.The sesamin may be obtained by fractionating Acanthopanax divaricatus var. Albeofructus with water, C1 to C4 lower alcohols, or a mixture of them with the extract of Alnus japonica . The C1 to C4 lower alcohols Methanol, ethanol, propanol, isopropanol, butanol and the like can be used. More preferably, the dried stalks of P. falciparum are extracted with water, C1 to C4 lower alcohols or a mixed solvent thereof, followed by sequential fractionation with n-hexane and ethyl acetate, The fractions can be separated by chromatography to give sesamin.
상기 크로마토그래피는 실리카겔 컬럼 크로마토그래피(silica gel column chromatography), RP 컬럼 크로마토그래피(reverse-phase column chromatography), 박층 크로마토그래피(thin layer chromatography, TLC), 이온교환수지 크로마토그래피(ion exchange resin chromatography), 중압 액체 크로마토그래피(medium pressure liquid chromatography), 실리카겔 진공 액체 크로마토그래피(silica gel vacuum liquid chromatography) 및 고성능 액체 크로마토그래피(high performance liquid chromatography, HPLC) 중에서 선택될 수 있다.The chromatography can be carried out by silica gel column chromatography, reverse-phase column chromatography, thin layer chromatography (TLC), ion exchange resin chromatography, For example, medium pressure liquid chromatography, silica gel vacuum liquid chromatography and high performance liquid chromatography (HPLC).
또한, 세사민은 당해 기술 분야에서 통상적인 방법에 따라 합성될 수 있으며, 약학적으로 허용 가능한 염 형태로 제조될 수 있다. 세사민의 약학적으로 허용가능한 염으로는, 바람직하게는 염산, 브롬산, 황산 및 인산 등의 무기산에 의해 형성된 부가염이나, 초산, 말레인산, 푸마르산, 포름산, 구연산, 젖산, 주석산, 글리콜산, 숙신산 등의 유기산에 의해 형성된 부가염을 들 수 있으나, 이에 제한되는 것은 아니다.In addition, the sesamin can be synthesized according to a conventional method in the art, and can be prepared in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salt of sesamin is preferably an addition salt formed by an inorganic acid such as hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid, or an acid addition salt formed with inorganic acid such as acetic acid, maleic acid, fumaric acid, formic acid, citric acid, lactic acid, , And the like, but the present invention is not limited thereto.
본 발명의 유효성분 (b)에 있어서, 페노피브레이트는 약학적으로 허용가능한 염으로서 금속, 유기아민, 4급 암모늄, 염기성 아미노산, 또는 암모니아와 염을 형성한 형태로 이용할 수 있다. 약제학적으로 허용가능한 금속의 예로는 리튬, 나트륨, 칼륨, 칼슘, 마그네슘, 스트론튬, 아연, 철 등을 들 수 있고, 유기아민의 예로는 메틸아민, 디메틸아민, 트리메틸아민, 에틸아민, 디에틸아민, 에틸렌디아민, 에탄올아민, 1-아미노-2-프로판올, 3-아미노-1-프로판올 등을 들 수 있으며, 4급 암모늄의 예로는 테트라메틸암모늄, 콜린 등을 들 수 있고, 염기성 아미노산의 예로는 아르기닌, 리신 등을 들 수 있으나, 이에 한정되지 않는다.In the active ingredient (b) of the present invention, the phenobibrate can be used in the form of a salt with a metal, organic amine, quaternary ammonium, basic amino acid, or ammonia as a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable metal include lithium, sodium, potassium, calcium, magnesium, strontium, zinc and iron. Examples of the organic amine include methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine Aminoethyl-2-propanol, and 3-amino-1-propanol. Examples of the quaternary ammonium include tetramethylammonium and choline, examples of the basic amino acid include Arginine, lysine, and the like, but are not limited thereto.
또한, 본 발명의 유효성분 (b)에 있어서, 로수바스타틴은 약제학적으로 허용가능한 염 형태로 이용될 수 있으며, 바람직하게는, 로수바스타틴 칼슘염, 로수바스타틴 염산염, 로수바스타틴 푸마르산염, 로수바스타틴 숙신산염, 로수바스타틴 말레인산염 등을 이용할 수 있으나, 이에 한정되는 것은 아니다.In the active ingredient (b) of the present invention, rosuvastatin may be used in the form of a pharmaceutically acceptable salt, and preferably rosuvastatin calcium salt, rosuvastatin hydrochloride, rosuvastatin fumarate , Rosuvastatin succinate, rosuvastatin maleate, and the like, but the present invention is not limited thereto.
또한, 본 발명은 (a) 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 혈관재협착증의 예방 또는 치료용 조성물을 제공한다. 상기 약학 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 있다. 또한, 상기 약학 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 본 발명의 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스 또는 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 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.The present invention also relates to a pharmaceutical composition comprising (a) sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of vascular restenosis. The pharmaceutical compositions may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, oral preparations, suppositories and sterilized injection solutions according to conventional methods. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate , Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient, such as starch, calcium carbonate, sucrose or lactose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
본 발명의 혈관재협착증의 예방 또는 치료용 약학 조성물의 투여량은 치료받을 대상의 연령, 성별, 체중, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여경로 및 처방자의 판단에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01㎎/㎏/일 내지 대략 2000㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1㎎/㎏/일 내지 500㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수도 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition for preventing or treating vascular restenosis of the present invention varies depending on the age, sex, body weight, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the administration route and the judgment of the prescriber will be. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
본 발명의 혈관재협착증의 예방 또는 치료용 약학 조성물은 쥐, 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 주사에 의해 투여될 수 있다. 본 발명의 조성물은 독성 및 부작용이 거의 없으므로 예방 목적으로 장기간 복용시에도 안심하고 사용할 수 있는 약제이다.The pharmaceutical composition for preventing or treating vascular restenosis of the present invention can be administered to mammals such as rats, livestock, and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. Since the composition of the present invention has little toxicity and side effects, it can be safely used for long-term administration for preventive purposes.
또한, 본 발명은 (a) 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 포함하는 조성물에, 추가적으로 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 혈관재협착증의 예방 또는 개선용 건강기능식품을 제공한다. 상기 조성물은 본 발명의 건강기능식품에 0.001~100 중량%로 하여 첨가될 수 있다. 본 발명의 건강기능식품은 정제, 캡슐제, 환제 또는 액제 등의 형태를 포함하며, 본 발명의 조성물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제 등이 있다.The present invention also relates to a pharmaceutical composition comprising (a) sesamin or a pharmaceutically acceptable salt thereof; And (b) a composition comprising at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, as well as a health function for the prevention or amelioration of vascular restenosis, Provide food. The composition may be added to the health functional food of the present invention in an amount of 0.001 to 100% by weight. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquids, and examples of foods to which the composition of the present invention can be added include various foods, beverages, gums, tea, vitamins .
본 발명은 (a) 세사민과, (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물을 유효성분으로 포함하는 혈관재협착증의 예방 또는 치료용 조성물에 관한 것이며, 상기 조성물은 혈관 평활근 세포의 증식을 억제하는 효과가 우수하여 혈관재협착증의 예방 또는 치료용 조성물로 유용하게 사용될 수 있다.The present invention relates to a composition for the prevention or treatment of vascular restenosis comprising (a) sesamin and (b) at least one compound selected from the group consisting of phenobibrate and rosuvastatin as an active ingredient, wherein said composition inhibits proliferation of vascular smooth muscle cells And thus can be effectively used as a composition for preventing or treating vascular restenosis.
도 1은 본 발명의 실시예 4-2 내지 4-4, 4-7 내지 4-9 및 4-11 내지 4-22에 대한 세포생존율을 확인하는 WST-1 어세이 결과이다.
도 2는 본 발명의 세사민이 혈관 평활근 세포의 증식을 억제하는 효과가 있음을 나타내는 WST-1 어세이의 분석 결과이다.
도 3은 본 발명의 세사민이 혈관 평활근 세포의 증식을 억제하는 효과가 있음을 나타내는 혈관 평활근 세포 수의 측정 결과이다.
도 4는 본 발명의 실시예 4-1 내지 4-22가 혈관 평활근 세포의 증식을 억제하는 효과가 있음을 나타내는 DNA 합성 어세이의 분석 결과이다.
도 5는 본 발명의 세사민이 혈관 평활근 세포의 세포 주기 조절 활성을 갖는 PCNA(도 5A), p27KIP1(도 5B) 및 p21CIP1(도 5C)의 단백질 발현을 확인하는 공초점 레이저 현미경 측정 결과이다.
도 6은 본 발명의 세사민이 혈관 평활근 세포의 세포 주기 조절 활성을 갖는 PCNA(도 6A), p27KIP1, p21CIP1 및 p53(도 6B)의 단백질 발현을 확인하는 웨스턴 블롯 분석 결과이다.Brief Description of the Drawings Figure 1 is a WST-1 assay result confirming the cell survival rate for Examples 4-2 to 4-4, 4-7 to 4-9 and 4-11 to 4-22 of the present invention.
Fig. 2 shows the results of analysis of the WST-1 assay showing that the sesamin of the present invention has an effect of inhibiting vascular smooth muscle cell proliferation.
FIG. 3 shows the results of measurement of the number of vascular smooth muscle cells showing that the sesamin of the present invention has an effect of inhibiting vascular smooth muscle cell proliferation.
4 shows the results of analysis of DNA synthesis assays showing that Examples 4-1 to 4-22 of the present invention have an effect of inhibiting the proliferation of vascular smooth muscle cells.
FIG. 5 is a result of confocal laser microscopy measurement of the protein expression of PCNA (FIG. 5A), p27 KIP1 (FIG. 5B) and p21 CIP1 (FIG. 5C) having the cell cycle regulating activity of the vascular smooth muscle cells of the present invention .
FIG. 6 is a Western blot analysis result of confirming the expression of PCNA (FIG. 6A), p27 KIP1 , p21 CIP1 and p53 (FIG. 6B) in which the sesamin of the present invention has cell cycle control activity of vascular smooth muscle cells.
이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.
<실시예 1. 세사민의 분리>≪ Example 1: Separation of sesamin &
본 발명에서 사용된 흰털오갈피나무는 충남 천안시 수신면의 오가피 농장에서 직접 채취하였다. 상기 흰털오갈피나무의 건조된 줄기 6.0㎏에 메탄올(30ℓ×3회)을 넣고 환류추출하여 300g의 메탄올 추출물을 얻었다. 상기 메탄올 추출물을 1.6ℓ의 물에 현탁하고, n-헥산(1.6ℓ×3회) 및 에틸아세테이트(1.6ℓ×3회)를 순차적으로 가해 n-헥산 분획물(120g) 및 에틸아세테이트 분획물(40g)과 마지막으로 물층 잔사를 포함하는 분획물(130g)을 얻었으며, 에틸아세테이트 분획물에서 본 발명의 세사민을 분리하였다.The Acanthopanax species used in the present invention were directly collected from the Ogapi farm in Cheonan, Chungnam, Korea. Methanol (30 L 3 times) was put into 6.0 kg of the dried stalks of P. falciparum, and 300 g of methanol extract was obtained by reflux extraction. The methanol extract was suspended in 1.6 L of water, and then n-hexane fraction (120 g) and ethyl acetate fraction (40 g) were added sequentially by adding n-hexane (1.6 L x 3) and ethyl acetate (1.6 L x 3) And finally a water layer residue (130 g) was obtained. The sesamin of the present invention was isolated from the ethyl acetate fraction.
상기 에틸아세테이트 분획물을 클로로포름:아세톤:메탄올(1:0:0 →1:1:0.2[v:v:v])의 농도구배 용출 조건으로 실리카겔 컬럼 크로마토그래피(Φ 5×30㎝, 70-230 mesh MERCK ASTM)로 분획하여 7개의 소분획물 A1-A7을 얻었다. 상기 소분획물 중 A2를 n-헥산:에틸아세테이트:메탄올(20:1:0.1 → 2:1:0.1[v:v:v])의 농도구배 용출 조건으로 실리카겔 컬럼 크로마토그래피(Φ 2×40㎝, 230-400 mesh MERCK ASTM)로 분획하여 6개의 소분획물 A2.1-A2.6을 얻었다.The ethyl acetate fraction was purified by silica gel column chromatography (Φ 5 × 30 cm, 70-230 cm) using a gradient elution gradient of chloroform: acetone: methanol (1: 0: 0 → 1: 1: 0.2 [v: v: mesh MERCK ASTM) to obtain 7 small fractions A1-A7. Among the above fractions, A2 was subjected to silica gel column chromatography (Φ 2 × 40 cm (10 cm)) under the conditions of a concentration gradient of n-hexane: ethyl acetate: methanol (20: 1: 0.1 → 2: , 230-400 mesh MERCK ASTM) to obtain 6 small fractions A2.1-A2.6.
상기 소분획물 중 A2.3을 메탄올:물(1:2[v:v])의 조건으로 RP-컬럼 크로마토그래피(Φ 1.5×50㎝, Cosmosil 75C18-PREP, Nacalai tesque, Japan)를 이용하여 (+)-세사민 10㎎을 분리하였다.A2.3 was fractionated by RP-column chromatography (Φ 1.5 × 50 cm, Cosmosil 75C18-PREP, Nacalai Tesque, Japan) under the conditions of methanol: water (1: 2 [v: v] +) - sesamin (10 mg).
또한, 상기 세사민은 DMSO(dimethyl sulfoxide)에 용해하였으며, 이때 세포배지에서의 DMSO 최종 농도가 0.1%[v/v]를 넘지 않도록 사용하였다. In addition, the sesamin was dissolved in dimethyl sulfoxide (DMSO), and the final concentration of DMSO in the cell medium was used so as not to exceed 0.1% [v / v].
<실시예 2. 세사민의 물리화학적 구조 확인>Example 2. Identification of physicochemical structure of sesamin < RTI ID = 0.0 >
(+)-Sesamin;(+) - sesamin;
white amorphous powder; white amorphous powder;
mp: 122-123℃; mp: 122-123 [deg.] C;
EI-MS, m/z 354 [M]+, C20H18O6; EI-MS, m / z 354 [M] +, C 20 H 18 O 6;
1H-NMR (pyridine-d5, 400 ㎒): δ 7.13 (2H, s, H-2', 2"), 6.97 (2H, d, J = 8.3 ㎐, H-6', 6"), 6.95 (2H, d, J = 8.3 ㎐, H-5', 5"), 6.01 (4H, s, H-OCH2O), 4.95 (2H, s, H-2, 6), 4.28 (2H, m, H-4, 8), 3.98 (2H, m, H-4, 8), 3.09 (2H, m, H-1, 5); 1 H-NMR (pyridine- d 5 , 400 ㎒): δ 7.13 (2H, s, H-2 ', 2 "), 6.97 (2H, d, J = 8.3 ㎐, H-6', 6"), 6.95 (2H, d, J = 8.3 ㎐, H-5 ', 5 "), 6.01 (4H, s, H-OCH 2 O), 4.95 (2H, s, H-2, 6), 4.28 (2H, m, H-4,8), 3.98 (2H, m, H-4,8), 3.09 (2H, m, H-1,5);
13C-NMR (pyridine-d5, 100 ㎒): δ 148.6 (C-4', 4"), 147.6 (C-3', 3"), 136.5 (C-1', 1"), 119.9 (C-6', 6"), 108.6 (C-5', 5"), 107.3 (C-2', 2"), 101 (C-OCH2O), 86.1 (C-2, 6), 71.9 (C-4, 8), 54.8 (C-1, 5). 13 C-NMR (pyridine- d 5 , 100 ㎒): δ 148.6 (C-4 ', 4 "), 147.6 (C-3', 3"), 136.5 (C-1 ', 1 "), 119.9 ( C-6 ', 6 ") , 108.6 (C-5', 5"), 107.3 (C-2 ', 2 "), 101 (C-OCH 2 O), 86.1 (C-2, 6), 71.9 (C-4, 8), 54.8 (C-1, 5).
<실시예 3. 렛드 대동맥의 혈관 평활근 세포의 분리 및 배양>Example 3 Isolation and Culture of Vascular Smooth Muscle Cells of the Red Aorta [
렛드 대동맥의 혈관 평활근 세포(Rat aortic VSMCs)를 추출하기 위해, 마취된 렛드로부터 적출된 대동맥을 2mm 두께로 잘라 엘라스타아제(elastase, 0.5㎎/㎖, Sigma-aldrich, St. Louis, MO, USA)와 콜라게네이즈(type II collagenase, 1mg/㎖, Invitrogen, Carlsbad, CA, USA)를 1시간 동안 처리하여 내피세포(endothelial cells)를 제거하였고, 이를 세포 배양 배지로 세척하였다. 내피세포가 제거된 대동맥 조직들은 0.1% 젤라틴으로 코팅된 배양접시에서 10일간 세포 배양 배지로 배양하였다. 상기 내피세포를 제거한 후 남은 세포는 베타 평활근 액틴(β-smooth muscle actin)의 면역염색법(immunocytochemical staining)을 이용하여 95% 이상이 렛드 대동맥의 평활근 세포임을 확인하였다.To extract vascular smooth muscle cells (Rat aortic VSMCs) from the aortic aorta, the aorta, which had been extracted from the anesthetized lattice, was cut into 2 mm thick elastase (0.5 mg / ml, Sigma-aldrich, St. Louis, Mo., USA) and collagenase (type II collagenase, 1 mg / ml, Invitrogen, Carlsbad, Calif., USA) for 1 hour to remove endothelial cells and washed with cell culture medium. The aortic tissues from which endothelial cells were removed were cultured in a 0.1% gelatin-coated culture dish for 10 days in a cell culture medium. The cells remaining after removing the endothelial cells were confirmed to be more than 95% of smooth muscle cells of the aortic aorta by immunocytochemical staining of β-smooth muscle actin.
이 후, 4~8번째 계대(passages) 배양된 렛드 대동맥의 혈관 평활근 세포를 10%[v/v] FBS(fetal bovine serum), 100U/㎖ 페니실린, 100μg/㎖ 스트렙토마이신이 포함된 DMEM(Dulbeco's Modified Eagle Medium) 배지를 이용하여 37℃, 5% CO2 조건에서 배양하였다.Vascular smooth muscle cells of the red aortic cultures passaged in the fourth to eighth passages were inoculated into DMEM (Dulbeco's (R)) containing 10% [v / v] FBS (fetal bovine serum), 100 U / ml penicillin, 100 μg / ml streptomycin Modified Eagle Medium) medium at 37 ° C and 5% CO 2 .
<실시예 4. 세사민의 혈관 평활근 세포의 세포생존율><Example 4: Cell viability of vascular smooth muscle cells of sesamin>
본 발명의 상기 실시예 1의 세사민과, 페노피브레이트(Sigma-Aldrich Inc, St. Louis, MO, USA) 및 로수바스타틴(Masung & Co., LTD, Korea)의 세포생존율을 측정하기 위해, WST-1 어세이(2-[4-iodophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H-tetrazolium, monosodium salt assay)를 실시하였다. To measure the cell survival rate of the sesamin and phenobarbital (Sigma-Aldrich Inc, St. Louis, MO, USA) and rosuvastatin (Masung & Co., LTD, Korea) in Example 1 of the present invention, WST- 1 assay (2- [4-iodophenyl] -3- [4-nitrophenyl] -5- [2,4-disulfophenyl] -2H-tetrazolium, monosodium salt assay).
본 발명의 실시예 3에서 추출한 렛드 대동맥의 혈관 평활근 세포를 96-웰 플레이트(96-well plate)에 4×104세포/㎖가 되도록 분주하고 10%[v/v] FBS, 100U/㎖ 페니실린 및 100μg/㎖ 스트렙토마이신이 포함된 DMEM 배지를 첨가하여 37℃, 5% CO2 조건에서 24시간 동안 배양하였다. 이후, 혈청이 없는 DMEM 배지로 교체하여 24시간 동안 배양하고, 하기 표 1의 실시예 4-2 내지 4-4, 4-7 내지 4-9 및 4-11 내지 4-22의 화합물을 각각 처리하여 반응하였다. 반응 46시간째에 WST-1 용액(premix WST-1, Takara, Japan) 10㎕를 더한 뒤, 2시간 동안 동일 조건의 배양기에서 배양하고, 마이크로플레이트 리더(microplate reader, Tecan Group Ltd., Switzerland)로 450㎚에서 흡광도를 측정하여, 이를 도 1에 나타내었다.The vascular smooth muscle cells of the aortic aorta extracted in Example 3 of the present invention were dispensed into a 96-well plate to a concentration of 4 x 10 4 cells / ml, and then 10% [v / v] FBS, 100 U / ml penicillin And 100 μg / ml streptomycin, and the cells were cultured at 37 ° C and 5% CO 2 for 24 hours. Thereafter, the cells were cultured for 24 hours in the absence of serum-free DMEM medium, and the compounds of Examples 4-2 to 4-4, 4-7 to 4-9 and 4-11 to 4-22 in Table 1 were each treated Respectively. 10 μl of WST-1 solution (premix WST-1, Takara, Japan) was added at 46 hours after the incubation, incubated for 2 hours in an incubator under the same conditions and microplate reader (Tecan Group Ltd., Switzerland) Absorbance at 450 nm, which is shown in Fig.
도 1을 참고하면, 본 발명의 실시예 4-9 및 4-18을 제외한 세사민, 페노피브레이트 및 로수바스타틴의 단독 화합물을 처리하는 경우뿐만 아니라, 세사민을 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물과 병용하여 처리 경우에도 대조군(무처리군)과 유사한 세포생존율을 나타내어, 혈관 평활근 세포에 대한 세포독성이 나타나지 않음을 확인할 수 있다.Referring to Figure 1, it can be seen that not only the treatment of the sole compounds of sesamin, phenobibrate and rosuvastatin except Examples 4-9 and 4-18 of the present invention, but also the treatment of sesamin with one or more compounds of phenobibrate and rosuvastatin The cell viability similar to that of the control group (untreated group) was observed, indicating that cytotoxicity to vascular smooth muscle cells was not observed.
<실시예 5. 세사민의 혈관 평활근 세포의 증식 억제 확인>Example 5 Confirmation of the inhibition of vascular smooth muscle cell proliferation of sesamin
혈관 평활근 세포의 증식에 미치는 영향을 확인하기 위해, WST-1 어세이(2-[4-iodophenyl]-3-[4-nitrophenyl]-5-[2,4-disulfophenyl]-2H-tetrazolium, monosodium salt assay), 세포 수 측정 및 DNA 합성 어세이(DNA synthesis assay)를 실시하였다. (4-iodophenyl) -3- [4-nitrophenyl] -5- [2,4-disulfophenyl] -2H-tetrazolium, monosodium salt assay, cell count and DNA synthesis assay.
실시예 5-1. 혈관 평활근 세포의 증식 억제 확인 - WST-1 어세이Example 5-1. Confirmation of vascular smooth muscle cell proliferation inhibition - WST-1 assay
WST-1 어세이를 위해, 실시예 3에서 추출한 렛드 대동맥의 혈관 평활근 세포를 96-웰 플레이트(96-well plate)에 4×104세포/㎖가 되도록 분주하고 10%[v/v] FBS, 100U/㎖ 페니실린 및 100㎍/㎖ 스트렙토마이신이 포함된 DMEM 배지를 첨가하여 37℃, 5% CO2 조건에서 24시간 동안 배양하였다. 이후, 혈청이 없는 DMEM 배지로 교체하고 24시간 동안 배양한 뒤, 다시 혈청이 없는 DMEM 배지로 교체하여 본 발명의 세사민(0, 1, 5 및 10μM)을 더하고 24시간 동안 반응하였다. 반응 후, PDGF-BB를 50ng/㎖로 처리하여 24시간 동안 세포 증식을 자극하였으며, 반응 22시간째에 WST-1 용액 10㎕를 더한 뒤 2시간 후인 24시간째에 마이크로플레이트 리더로 450㎚에서 흡광도를 측정하여 도 2에 나타내었다. For the WST-1 assay, the vascular smooth muscle cells of the aortic aorta extracted in Example 3 were dispensed in a 96-well plate at 4 x 10 4 cells / ml and suspended in 10% [v / v] FBS , 100 U / ml penicillin and 100 μg / ml streptomycin, and the cells were cultured at 37 ° C. and 5% CO 2 for 24 hours. Thereafter, the medium was replaced with serum-free DMEM medium, cultured for 24 hours, and then replaced with serum-free DMEM medium to add sesamin (0, 1, 5 and 10 μM) of the present invention and reacted for 24 hours. After the reaction, PDGF-BB was treated with 50 ng / ml to stimulate cell proliferation for 24 hours. Twenty-two hours after the addition of 10 μl of WST-1 solution at 22 hours, The absorbance was measured and shown in Fig.
도 2의 결과를 참고하면, 본 발명의 세사민이 혈관 평활근 세포의 증식을 자극하는 PDGF-BB의 처리 시에 농도 의존적으로 혈관 평활근 세포의 증식을 억제하는 효과를 나타냄을 확인할 수 있다. 2, it can be confirmed that the sesamin of the present invention has an effect of inhibiting proliferation of vascular smooth muscle cells in a concentration-dependent manner upon treatment of PDGF-BB stimulating vascular smooth muscle cell proliferation.
실시예 5-2. 혈관 평활근 세포의 증식 억제 확인 - 세포 수 측정Example 5-2. Confirmation of proliferation inhibition of vascular smooth muscle cells - Measurement of cell number
혈관 평활근 세포의 수를 측정하기 위해, 실시예 3에서 추출한 렛드 대동맥의 혈관 평활근 세포를 12-웰 플레이트에 1×105세포/㎖가 되도록 분주한 뒤, 이후 과정은 상기 실시예 5-1의 WST-1 어세이 방법과 동일하게 실시하되, PDGF-BB 처리 후 WST-1 용액을 더하는 대신, 증식이 자극된 세포를 트립신-EDTA에 현탁하여 헤모사이토미터(hemocytometer)와 현미경을 이용해 세포 수를 측정하고 이를 도 3에 나타내었다.In order to measure the number of vascular smooth muscle cells, vascular smooth muscle cells of the aortic aorta extracted in Example 3 were divided into 12-well plates so as to have a concentration of 1 × 10 5 cells / ml. Instead of adding the WST-1 solution after PDGF-BB treatment, the cells stimulated by proliferation were suspended in trypsin-EDTA and the number of cells was measured using a hemocytometer and a microscope And this is shown in Fig.
도 3을 참고하면, 본 발명의 세사민이 세포 증식을 자극하는 PDGF-BB만을 단독으로 처리하는 군에 비해, 농도 의존적으로 혈관 평활근 세포 수의 증식을 억제하는 것을 확인할 수 있다. Referring to FIG. 3, it can be confirmed that the sesamin of the present invention inhibits the proliferation of vascular smooth muscle cells in a concentration-dependent manner, compared to the group treated with PDGF-BB alone, which stimulates cell proliferation.
실시예Example 5-3. 혈관 평활근 세포의 증식 억제 확인 - DNA 합성 5-3. Confirmation of proliferation inhibition of vascular smooth muscle cells - DNA synthesis 어세이Assay
DNA 합성 어세이를 실시하기 위해, 상기 실시예 5-1의 WST-1 어세이 방법과 동일하게 실시하되, 세사민 대신 상기 표 1을 참고하여 실시예 4-1 내지 4-22의 화합물 및 대조군(무처리군)을 사용하였다(이때, 디기토닌은 제외하였음). 또한, PDGF-BB 처리 후 WST-1 용액을 더하는 대신, 배양 20시간째에 [3H]-티미딘(thymidine)을 2μCi/㎖로 첨가하였다. 4시간 뒤인 배양 24시간째에, 10%[v/v] TCA(trichloroacetic acid)가 포함된 PBS(phosphate buffer saline)와 에탄올/에테르(ethanol/ether, 1/1[v/v])로 세척하였다. 이후, 0.5M의 NaOH를 500㎕씩 각 웰에 분주하고, 3㎖의 신틸레이션 칵테일(scintillation cocktail, Ultimagold, Packard Bioscience, Waltham, MA)과 혼합하여 액체 신틸레이션 카운터(LSC, liquid scintillation counter, LS3801, Beckman, Germany)로 방사능(radioactivity)을 측정하여 도 4에 나타내었다.In order to carry out DNA synthesis assays, the same procedures as in the WST-1 assay of Example 5-1 were carried out except that the compounds of Examples 4-1 to 4-22 and the control group Untreated group) was used (except for digitonin). Further, instead of adding the WST-1 solution after PDGF-BB treatment, [ 3 H] -thymidine was added at 2 μCi / ml at 20 hours after the culture. After 24 hours of incubation, the cells were washed with PBS (phosphate buffer saline) containing 10% [v / v] TCA (trichloroacetic acid) and ethanol / ether (1/1 [v / v] Respectively. Then, 500 쨉 l of 0.5 M NaOH was dispensed into each well and mixed with 3 ml scintillation cocktail (Ultimagold, Packard Bioscience, Waltham, Mass.) To prepare a liquid scintillation counter (LSC, LS3801, Beckman , Germany), and the results are shown in FIG.
도 4를 참고하면, 혈관 평활근 세포의 증식을 자극하는 PDGF-BB의 처리 시에, 본 발명의 실시예 4-1 내지 4-13의 세사민, 페노피브레이트 및 로수바스타틴을 단독으로 처리하는 경우에는, 농도 의존적으로 혈관 평활근 세포의 증식을 억제한다. 또한, 실시예 4-14 내지 4-22의 세사민을 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물과 병용 처리하는 경우에도, PDGF-BB를 처리하지 않은 대조군(무처리군)과 유사한 결과를 나타내어, 혈관 평활근 세포에 대해 PDGF-BB에 의해 유도되는 증식을 억제하는 효과가 우수함을 확인할 수 있다.4, when treating sesamin, phenobibrate and rosuvastatin of Examples 4-1 to 4-13 of the present invention alone in the treatment of PDGF-BB stimulating vascular smooth muscle cell proliferation, Inhibits the proliferation of vascular smooth muscle cells in a concentration-dependent manner. In addition, even when the sesamin of Examples 4-14 to 4-22 was treated together with at least one of phenobibrate and rosuvastatin, the results were similar to those of the control group without PDGF-BB treatment (no treatment group) It is confirmed that the effect of inhibiting PDGF-BB-induced proliferation on vascular smooth muscle cells is excellent.
<실시예 6. 세사민의 혈관 평활근 세포의 세포 주기 조절 확인>Example 6 Confirmation of cell cycle regulation of vascular smooth muscle cells of sesamin
혈관 평활근 세포의 세포 주기 조절 활성을 갖는 인자의 단백질 발현을 확인하고자, 공초점 레이저 현미경(confocal laser microscope) 및 웨스턴 블롯 방법을 사용하였다. Confocal laser microscope and Western blot method were used to confirm protein expression of the factor having cell cycle regulatory activity of vascular smooth muscle cells.
실시예 6-1. 혈관 평활근 세포의 세포 주기 조절 확인 - 공초점 레이저 현미경Example 6-1. Confirmation of cell cycle regulation of vascular smooth muscle cells - Confocal laser microscope
공초점 레이저 현미경(confocal laser microscope)을 이용한 단백질 발현의 확인을 위해, 실시예 3에서 추출한 혈관 평활근 세포를 24-웰 플레이트의 유리 커버 슬립(glass cover slip)에 접종하였으며, 10%[v/v] FBS, 100U/㎖ 페니실린 및 100㎍/㎖ 스트렙토마이신이 포함된 DMEM 배지를 첨가하여 37℃, 5% CO2 조건에서 24시간 동안 배양하였다. 이후, 혈청이 없는 DMEM 배지로 교체한 후 PDGF-BB를 50ng/㎖로 처리하여 24시간 동안 배양한 뒤, 세포를 차가운 상태의 PBS로 2번 세척하였으며 PBS에 용해한 4%[v/v] 포름알데히드로 15분 동안 고정하였다. 고정 후, PBS에 용해된 100mM 글리신(glycine)을 10분 동안 처리하고, 세포를 다시 PBS로 2번 세척하여 0.1%[v/v] 트리톤(triton) X-100으로 3분간 삼투(permeabilize)한 뒤 PBS에 용해한 5%[v/v] 고트(goat) 혈청으로 1시간 동안 블록킹(blocking)하였다. 각 anti-PCNA 항체 용액(3%[w/v] BSA가 함유되어 있는 PBS 용액에 1/100[v/v]으로 희석한 항체) 또는 anti-p27KIP1 항체 용액(3%[w/v] BSA가 함유되어 있는 PBS 용액에 1/200[v/v]으로 희석한 항체) 및 anti-p21CIP1 항체 용액 (3%[w/v] BSA가 함유되어 있는 PBS 용액에 1/100[v/v]으로 희석한 항체)으로 1시간 30분 동안 반응하고 PBS로 세척한 뒤, 2차 항체(3%[w/v] BSA가 함유되어 있는 PBS 용액에 1/200[v/v]으로 희석한 FITC-IgG)를 넣고 1시간 30분 동안 반응하였다. 반응이 끝난 세포를 PBS로 세척하고 DAPI(Vector Laboratories Inc., Burlingame, CA)가 포함된 봉입제(mounting medium)로 고정하여 공초점 레이저 현미경(LSM5 live configuration Variotwo VRGB; Zeiss, Jena, Germany)으로 분석한 결과를 도 5A 내지 5C에 나타내었다.To confirm protein expression using a confocal laser microscope, the vascular smooth muscle cells extracted from Example 3 were inoculated on a glass cover slip of a 24-well plate, and 10% [v / v ] FBS, 100 U / ml penicillin and 100 μg / ml streptomycin, and cultured at 37 ° C. and 5% CO 2 for 24 hours. Cells were then washed twice with cold PBS and resuspended in 4% [v / v] form dissolved in PBS. Cells were washed twice with DMEM medium supplemented with serum, then treated with 50 ng / And fixed with aldehyde for 15 minutes. After fixation, 100 mM glycine dissolved in PBS was treated for 10 minutes, and the cells were washed again with PBS twice and permeabilized with 0.1% [v / v] triton X-100 for 3 minutes Followed by blocking with 5% [v / v] goat serum in PBS for 1 hour. (3% [w / v] antibody solution diluted to 1/100 [v / v] in PBS solution containing 3% [w / v] BSA) or anti-p27 KIP1 antibody solution (V / v) diluted in PBS containing BSA and anti-p21 CIP1 antibody solution (3% [w / v] BSA in PBS) v) diluted to 1/200 [v / v] in a PBS solution containing a secondary antibody (3% [w / v] BSA) One FITC-IgG) was added and reacted for 1 hour and 30 minutes. The cells were washed with PBS and fixed with a mounting medium containing DAPI (Vector Laboratories Inc., Burlingame, Calif.) To a confocal laser microscope (LSM5 live configuration Variotwo VRGB; Zeiss, Jena, Germany) The results of the analysis are shown in Figs. 5A to 5C.
도 5를 참고하면, 본 발명의 세사민이, 증식하고 있는 S기의 세포핵에서 볼 수 있는 PCNA(도 5A)의 단백질 발현은 감소하는 효과를 나타내며, CDK 억제제의 일종인 p27KIP1(도 5B) 및 p21CIP1(도 5C)의 단백질 발현은 증가하는 효과를 나타내어, 혈관 평활근 세포의 증식을 억제하는 조성물로서의 효과가 우수함을 확인할 수 있다. 5, the expression of the protein of PCNA (FIG. 5A), which is found in the proliferating S-type nucleus of the present invention, is reduced, and p27 KIP1 (FIG. 5B), a kind of CDK inhibitor, protein expression of p21 CIP1 (Fig. 5C) shows an increasing effect, and it is confirmed that the effect as a composition for inhibiting the proliferation of vascular smooth muscle cells is excellent.
실시예 6-2. 혈관 평활근 세포의 세포 주기 조절 확인 - 웨스턴 블롯Example 6-2. Cell cycle control of vascular smooth muscle cells - Western blot
웨스턴 블롯을 이용한 단백질 발현의 측정은 SDS-PAGE(sodium dodecyl sulfate-polyacrylamide gel electrophoresis, 7.5-12.5%[w/v] acrylamide gels) 방법을 사용하였다. 혈관 평활근 세포의 증식을 유도하는 PDGF-BB 50ng/㎖를 처리하여 24시간 동안 배양하고, 상기 배양된 세포를 차가운 PBS로 2번 세척하였다. 이후, SDS 환원 용액(reducing buffer)인 Laemmli sample buffer(62.5mM Tris-HCl pH 6.8, 20%[v/v] glycerol, 2%[w/v] SDS, 5%[v/v] β-Mercaptoethanol)를 더하고 98℃-100℃에서 10분간 끓여주었다. 상기 용해물을 SDS-PAGE에 로딩(loading)하여 전기영동을 실시한 후, PVDF(polyvinylidene fluoride) 멤브레인(membrane, Atto Corp., Tokyo, Japan)에 200㎃의 전류로 2시간 동안 전이시켰다. 상기 단백질이 전이된 멤브레인을 5%[w/v] BSA(bovine serum albumin)가 포함된 TBS-T(tris-buffered saline and tween 20)로 블록킹한 뒤, 상기 실시예 6-1의 1차 항체(1/500 내지 1/1000[v/v]로 희석)를 첨가하여 4℃에서 오버나이트(overnight)동안 반응하고 2차 항체(1/2000[v/v]로 희석)를 더하였다. 단백질은 ECL 키트(Atto Corp., Tokyo, Japan)를 사용하여 확인하였으며, 단백질 밴드(band)의 세기는 Quantity One software(Bio-Rad, Hercules, CA)를 이용하여 도 6A 및 6B에 나타내었다. SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis, 7.5-12.5% [w / v] acrylamide gels) method was used for measurement of protein expression using Western blot. 50ng / ml of PDGF-BB inducing the proliferation of vascular smooth muscle cells was treated and cultured for 24 hours, and the cultured cells were washed twice with cold PBS. Thereafter, a SDS reducing buffer, Laemmli sample buffer (62.5 mM Tris-HCl pH 6.8, 20% [v / v] glycerol, 2% [w / v] SDS, 5% [v / v] ) Were added and boiled at 98 ° C to 100 ° C for 10 minutes. The lysate was loaded on SDS-PAGE, electrophoresed, and transferred to a PVDF (polyvinylidene fluoride) membrane (Atto Corp., Tokyo, Japan) at a current of 200 mA for 2 hours. After the protein-transfected membrane was blocked with TBS-T (tris-buffered saline and tween 20) containing 5% [w / v] bovine serum albumin (BSA), the primary antibody (Diluted 1/1000 to 1/1000 [v / v]) was added and reacted at 4 ° C overnight, and the secondary antibody (diluted to 1/2000 [v / v]) was added. Proteins were identified using an ECL kit (Atto Corp., Tokyo, Japan) and the intensity of the protein band was shown in Figures 6A and 6B using Quantity One software (Bio-Rad, Hercules, Calif.).
도 6을 참고하면, 혈관 평활근 세포의 증식을 자극하는 PDGF-BB의 처리 시, 본 발명의 세사민이 세포 주기를 조절하는 PCNA(도 6A)의 단백질 발현은 감소시키고, p27KIP1, p21CIP1 및 p53(도 6B)의 단백질 발현은 증가시켜, 실시예 6-1과 동일한 결과를 나타내므로, 혈관 평활근 세포의 증식을 억제하는 조성물로서의 효과가 우수함을 확인할 수 있다.6, treatment of PDGF-BB stimulating vascular smooth muscle cell proliferation decreased the protein expression of PCNA (Fig. 6A), in which the sesamin of the present invention regulates cell cycle, and inhibited p27 KIP1 , p21 CIP1 and p53 (Fig. 6B) was increased, showing the same results as in Example 6-1. Thus, it can be confirmed that the effect as a composition for inhibiting the proliferation of vascular smooth muscle cells is excellent.
<< 실시예Example 7. 독성실험> 7. Toxicity test>
실시예Example 7-1. 급성독성 7-1. Acute toxicity
상기 실시예 4-14와 같이 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 단기간에 과량을 섭취하였을 때 급성적(24시간 이내)으로 동물 체내에 미치는 독성을 조사하고, 치사율을 결정하기 위하여 본 실험을 수행하였다. 일반적인 마우스인 ICR 마우스를 20마리를 준비하였고, 각 군별로 10마리씩 배정하였다. 대조군에는 30% PEG-400만을 투여하고, 실험군은 본 발명의 조성물을 1.0g/㎏의 농도로 각각 경구 투여하였다. 투여 24시간 후에 각각의 치사율을 조사한 결과, 대조군과 상기 조성물을 투여한 실험군에서는 모두 생존하였다.The toxicity of the composition prepared by mixing the sesamin and phenobibrate in a molar ratio of 1: 1 (weight ratio 1: 1.02) to the animal body in an excessive amount in a short period of time (within 24 hours) And this experiment was performed to determine the mortality rate. Twenty ICR mice were prepared, and 10 mice were assigned to each group. The control group was administered only 30% PEG-400, and the experimental group was orally administered with the composition of the present invention at a concentration of 1.0 g / kg, respectively. After 24 hours of administration, the respective mortality rates were examined. As a result, both the control group and the test group to which the composition was administered survived.
실시예 7-2. 실험군 및 대조군의 장기 및 조직 독성 실험Example 7-2. Organ organs toxicity test in experimental group and control group
장기 독성 실험은 C57BL/6J 생쥐를 대상으로 동물의 각 장기(조직)에 미치는 영향을 조사하기 위하여, 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 1.0g/㎏의 농도로 투여한 실험군과 용매만을 투여한 대조군의 동물들로부터 8주 후 혈액을 채취하여 GPT(glutamate-pyruvate transferase) 및 BUN(blood urea nitrogen)의 혈액 내 농도를 Select E(vital scientific NV, Netherland) 기기를 이용하여 측정하였다. 그 결과, 간독성과 관계있는 것으로 알려진 GPT와 신장독성과 관계있는 것으로 알려진 BUN의 경우, 대조군과 비교하여 실험군은 별다른 차이를 보이지 않았다. 또한, 각 동물로부터 간과 신장을 절취하여 통상적인 조직절편 제작과정을 거쳐 광학현미경으로 조직학적 관찰을 시행하였으나 특이한 이상은 관찰되지 않았다.To examine the effects of long-term toxicity on C57BL / 6J mice, the composition of sesamin and phenobibrate in a 1: 1 molar ratio (weight ratio 1: 1.02) was administered at 1.0 g / kg And 8 hours after the administration of the vehicle alone, blood was collected from the animals and the concentrations of glutamate-pyruvate transferase (GPT) and blood urea nitrogen (BUN) were measured by Select E (vital scientific NV, Netherland ) Instrument. As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were cut from each animal and histological observation was performed with an optical microscope through a conventional tissue section production process, but no abnormal abnormalities were observed.
<제제예 1. 약학적 제제>≪ Formulation Example 1 >
제제예 1-1. 정제의 제조Formulation Example 1-1. Manufacture of tablets
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물 200g을 락토오스 175.9g, 감자전분 180g 및 콜로이드성 규산 32g과 혼합하였다. 이 혼합물에 10% 젤라틴 용액을 첨가시킨 후, 분쇄해서 14 메쉬체를 통과시켰다. 이것을 건조시키고 여기에 감자전분 160g, 활석 50g 및 스테아린산 마그네슘 5g을 첨가해서 얻은 혼합물을 정제로 만들었다.200 g of a composition obtained by mixing the sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
제제예 1-2. 주사제의 제조Formulation Example 1-2. Injection preparation
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물 1g, 염화나트륨 0.6g 및 아스코르브산 0.1g을 증류수에 용해시켜서 100㎖를 만들었다. 이 용액을 병에 넣고 20℃에서 30분간 가열하여 멸균시켰다.1 g of the composition obtained by mixing the sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02), 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.
<제제예 2. 식품 제조><Formulation Example 2: Food Preparation>
제제예 2-1. 조리용 양념의 제조Formulation Example 2-1. Manufacture of cooking seasonings
본 발명의 본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 조리용 양념에 1 중량%로 첨가하여 건강 증진용 조리용 양념을 제조하였다.A composition prepared by mixing the sesamin and phenobibrate of the present invention at a molar ratio of 1: 1 (weight ratio 1: 1.02) of the present invention was added to the cooking seasoning at 1 wt% to prepare a cooking sauce for health promotion.
제제예 2-2. 밀가루 식품의 제조Formulation Example 2-2. Manufacture of flour food products
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 밀가루에 0.1 중량%로 첨가하고, 이 혼합물을 이용하여 빵, 케이크, 쿠키, 크래커 및 면류를 제조하여 건강 증진용 식품을 제조하였다.Bread, cakes, cookies, crackers and noodles were prepared by adding 0.1% by weight of a composition obtained by mixing sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) Enhancing food was prepared.
제제예 2-3. 스프 및 육즙(gravies)의 제조Preparation Example 2-3. Manufacture of soups and gravies
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 스프 및 육즙에 0.1 중량%로 첨가하여 건강 증진용 수프 및 육즙을 제조하였다.The composition comprising sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) was added to the soup and juice at 0.1 wt% to prepare soup for health promotion and juice.
제제예 2-4. 유제품(dairy products)의 제조Formulation Example 2-4. Manufacture of dairy products
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물을 우유에 0.1 중량%로 첨가하고, 상기 우유를 이용하여 버터 및 아이스크림과 같은 다양한 유제품을 제조하였다.A composition comprising sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) was added to milk in an amount of 0.1 wt%, and various dairy products such as butter and ice cream were prepared using the milk.
제제예 2-5. 야채주스 제조Formulation Example 2-5. Vegetable juice manufacturing
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물 0.5g을 토마토주스 또는 당근주스 1,000㎖에 가하여 건강 증진용 야채주스를 제조하였다.0.5 g of the composition prepared by mixing the sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) was added to 1,000 ml of tomato juice or carrot juice to prepare vegetable juice for health promotion.
제제예Formulation example 2-6. 과일주스 제조 2-6. Manufacture of fruit juice
본 발명의 세사민 및 페노피브레이트를 1:1의 몰비(중량비 1:1.02)로 혼합한 조성물 0.1g을 사과주스 또는 포도주스 1,000㎖에 가하여 건강 증진용 과일주스를 제조하였다.Health enhancing fruit juice was prepared by adding 0.1 g of a composition prepared by mixing the sesamin and phenobibrate of the present invention in a molar ratio of 1: 1 (weight ratio 1: 1.02) to 1,000 ml of apple juice or grape juice.
Claims (6)
(b) 페노피브레이트(fenofibrate) 및 로수바스타틴(rosuvastatin) 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 혈관재협착증의 예방 또는 치료용 조성물. (a) sesamin or a pharmaceutically acceptable salt thereof; And
(b) a composition for preventing or treating vascular restenosis comprising, as an active ingredient, at least one compound selected from the group consisting of fenofibrate and rosuvastatin or a pharmaceutically acceptable salt thereof.
(a) 상기 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염은, 1:0.5~4의 중량비로 혼합된 것을 특징으로 하는 혈관재협착증의 예방 또는 치료용 조성물.The method according to claim 1,
(a) the sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, is mixed at a weight ratio of 1: 0.5 to 4: (1) a composition for preventing or treating vascular restenosis.
상기 조성물은 혈관 평활근 세포의 증식을 억제하는 것을 특징으로 하는 혈관재협착증의 예방 또는 치료용 조성물.The method according to claim 1,
Wherein said composition inhibits the proliferation of vascular smooth muscle cells.
(b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 혈관재협착증의 예방 또는 개선용 건강기능식품.(a) sesamin or a pharmaceutically acceptable salt thereof; And
(b) a health functional food for preventing or ameliorating vascular restenosis comprising at least one compound selected from the group consisting of phenobibrate and rosuvastatin or a pharmaceutically acceptable salt thereof as an active ingredient.
(a) 상기 세사민 또는 이의 약학적으로 허용가능한 염; 및 (b) 페노피브레이트 및 로수바스타틴 중 1종 이상의 화합물 또는 이의 약학적으로 허용가능한 염은, 1:0.5~4의 중량비로 혼합된 것을 특징으로 하는 혈관재협착증의 예방 또는 개선용 건강기능식품.5. The method of claim 4,
(a) the sesamin or a pharmaceutically acceptable salt thereof; And (b) at least one compound selected from the group consisting of fenofibrate and rosuvastatin, or a pharmaceutically acceptable salt thereof, is mixed at a weight ratio of 1: 0.5 to 4, wherein the health functional food is for preventing or improving vascular restenosis.
상기 조성물은 혈관 평활근 세포의 증식을 억제하는 것을 특징으로 하는 혈관재협착증의 예방 또는 개선용 건강기능식품.5. The method of claim 4,
Wherein said composition inhibits vascular smooth muscle cell proliferation.
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