KR20130060585A - Pharmaceutical composition comprising extract of cordyceps militaris showing an inhibitory effect of osteoclast differentiation - Google Patents
Pharmaceutical composition comprising extract of cordyceps militaris showing an inhibitory effect of osteoclast differentiation Download PDFInfo
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- KR20130060585A KR20130060585A KR1020110126720A KR20110126720A KR20130060585A KR 20130060585 A KR20130060585 A KR 20130060585A KR 1020110126720 A KR1020110126720 A KR 1020110126720A KR 20110126720 A KR20110126720 A KR 20110126720A KR 20130060585 A KR20130060585 A KR 20130060585A
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- extract
- pharmaceutical composition
- osteoclast differentiation
- cordyceps militaris
- militaris
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/062—Ascomycota
- A61K36/066—Clavicipitaceae
- A61K36/068—Cordyceps
-
- 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
- A23V2200/306—Foods, ingredients or supplements having a functional effect on health having an effect on bone mass, e.g. osteoporosis prevention
-
- 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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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Mycology (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
본 발명은 밀리타리스동충하초 추출물을 유효성분으로 함유하는 골다공증 억제 효과를 가지는 약학 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition having an inhibitory effect on osteoporosis containing Militaris cordyceps sinensis extract as an active ingredient.
1. Kumamoto H, Ooya K. ExpreASion of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) in ameloblastomas. J Oral Pathol Med. 2004 ; 33(1): 46-52.Kumamoto H, Ooya K. ExpreASion of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF) / receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF) / osteoprotegerin (OPG) in ameloblastomas. J Oral Pathol Med. 2004; 33 (1): 46-52.
2. Reddy SV. Regulatory mechanisms operative in osteoclasts. Crit Rev Eukaryot Gene Expr. 2004; 14(4): 255-70.2. Reddy SV. Regulatory mechanisms operative in osteoclasts. Crit Rev Eukaryot Gene Expr. 2004; 14 (4): 255-70.
3. Pang M, Martinez AF, Fernandez I, Balkan W, Troen BR. AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells. Gene. 2007;403(1-2):151-8.3.Pang M, Martinez AF, Fernandez I, Balkan W, Troen BR. AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells. Gene. 2007; 403 (1-2): 151-8.
4. Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-kappaB and c-Fos in osteoclasts. J Bone Miner Metab. 2005; 23 Suppl: 11-5. Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-kappa B and c-Fos in osteoclasts. J Bone Miner Metab. 2005; 23 Suppl: 11-5.
5. Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001; 142(12):5050-5.Khosla S. Minireview: the OPG / RANKL / RANK system. Endocrinology. 2001; 142 (12): 5050-5.
6. Han SY, Lee NK, Kim KH, Jang IW, Yim M, Kim JH, Lee WJ, Lee SY. Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis. Blood. 2005;106(4):1240-5.6.Han SY, Lee NK, Kim KH, Jang IW, Yim M, Kim JH, Lee WJ, Lee SY. Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis. Blood. 2005; 106 (4): 1240-5.
7. Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, Nakamura E, Takano M, Sada KE, Makino H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010 ;162(1-3):99-1087.Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, Nakamura E, Takano M, Sada KE, Makino H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010; 162 (1-3): 99-108
8. Murakami A, Song M, Ohigashi H. Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis by blocking activation of ERK1/2 and p38 MAPK in RAW264.7 macrophages. Biofactors. 2007;30(1):1-11.Murakami A, Song M, Ohigashi H. Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL) -induced osteoclastogenesis by blocking activation of ERK1 / 2 and p38 MAPK in RAW264.7 macrophages. Biofactors. 2007; 30 (1): 1-11.
9. Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010 ;636(1-3):28-359.H Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010; 636 (1-3): 28-35
10. 성재모, 번데기동충하초(Cordyceps militaris)의 균사 생장. 韓國菌學會誌. 2002; 30(1):1-5 10. Seong Jae-mo, Mycelial Growth of Cordyceps militaris.韓國 菌 學會 誌. 2002; 30 (1): 1-5
11. Park SE, Kim J, Lee YW, Yoo HS, Cho CK. Antitumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude mice. J Acupunct Meridian Stud. 2009;2(4):294-300.Park SE, Kim J, Lee YW, Yoo HS, Cho CK. Antitumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude mice. J Acupunct Meridian Stud. 2009; 2 (4): 294-300.
12. Lee JS, Hong EK. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris. Int Immunopharmacol. 2011;11(9):1226-3312. Lee JS, Hong EK. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris. Int Immunopharmacol. 2011; 11 (9): 1226-33
13. Oh JY, Choi WS, Lee CH, Park HJ. The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice. J Ethnopharmacol. 2011;135(2):422-9.13. Oh JY, Choi WS, Lee CH, Park HJ. The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice. J Ethnopharmacol. 2011; 135 (2): 422-9.
14. Mizuha Y, Yamamoto H, Sato T, Tsuji M, Masuda M, Uchida M, Sakai K, Taketani Y, Yasutomo K, Sasaki H, Takeda E. Water extract of Cordyceps sinensis (WECS) inhibits the RANKL-induced osteoclast differentiation. Biofactors. 2007;30(2):105-16.Mizuha Y, Yamamoto H, Sato T, Tsuji M, Masuda M, Uchida M, Sakai K, Taketani Y, Yasutomo K, Sasaki H, Takeda E. Water extract of Cordyceps sinensis (WECS) inhibits the RANKL-induced osteoclast differentiation . Biofactors. 2007; 30 (2): 105-16.
15. Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010;636(1-3):28-35.
15. Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010; 636 (1-3): 28-35.
골 대사는 골 형성을 담당하는 조골세포와 골 흡수를 담당하는 파골세포의 작용으로 이루어져 있으며, 이들 세포의 기능이 균형을 이루어 항상성을 유지한다. 그러나, 조골세포 활성이 저하되거나 파골세포 활성이 증가되면 골밀도가 감소하여 골다공증이 유발될 수 있다. 골다공증의 유발 요인으로는 여성의 폐경, 갑상선 기능항진, 당뇨병, 스트레스, 흡연 및 운동 부족, 신체적 노화와 glucocorticoid 계열 약물의 복용 등이 알려져 있다(Kumamoto H, Ooya K. ExpreASion of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) in ameloblastomas. J Oral Pathol Med. 2004, 33(1): 46-52; Reddy SV. Regulatory mechanisms operative in osteoclasts. Crit Rev Eukaryot Gene Expr. 2004, 14(4): 255-70; Pang M, Martinez AF, Fernandez I, Balkan W, Troen BR. AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells. Gene., 2007, 403(1-2):151-8).Bone metabolism is composed of osteoblasts responsible for bone formation and osteoclasts responsible for bone resorption, and the function of these cells is balanced to maintain homeostasis. However, when osteoblast activity decreases or osteoclast activity increases, bone density decreases and osteoporosis may be induced. Factors causing osteoporosis include menopause in women, hyperthyroidism, diabetes, stress, smoking and lack of exercise, physical aging and the use of glucocorticoid drugs (Kumamoto H, Ooya K. ExpreASion of parathyroid hormone-related protein ( PTHrP), osteoclast differentiation factor (ODF) / receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF) / osteoprotegerin (OPG) in ameloblastomas.J Oral Pathol Med. 2004, 33 (1): 46- 52; Reddy SV.Regulatory mechanisms operative in osteoclasts.Crit Rev Eukaryot Gene Expr. 2004, 14 (4): 255-70; Pang M, Martinez AF, Fernandez I, Balkan W, Troen BR.AP-1 stimulates the cathepsin K promoter in RAW 264.7 cells.Gen., 2007, 403 (1-2): 151-8).
파골세포는 대식세포 계열의 전구세포에서 다양한 분화유발인자들에 의해 분화된다(Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-kappaB and c-Fos in osteoclasts. J Bone Miner Metab. 2005, 23 Suppl.: 11-5; Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001, 142(12):5050-5). 특히, 조골세포로부터 분비되는 RANKL(receptor activator of nuclear factor kappa B ligand)은 파골전구세포 및 파골세포 표면에 존재하는 RANK(receptor activator of nuclear factor kappa B)와 결합하여 파골전구세포가 파골세포로의 분화와 활성화를 유발한다(Han SY, Lee NK, Kim KH, Jang IW, Yim M, Kim JH, Lee WJ, Lee SY. Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis. Blood. 2005;106(4):1240-5). 분화한 파골세포는 NF-B, c-Fos, c-jun, AP-1, NFATc1의 활성화와 MAPK, ERK, JNK, p38 활성화 과정, Src, Akt 활성화등을 통하여 TRAP (tartarate resistant acid phosphatase) cathepsin K, calcitonin receptor 등 파골세포 특이 단백질 발현을 촉진한다(Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, Nakamura E, Takano M, Sada KE, Makino H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling. Regul Pept. 2010, 162(1-3):99-108; Murakami A, Song M, Ohigashi H. Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL)-induced osteoclastogenesis by blocking activation of ERK1/2 and p38 MAPK in RAW264.7 macrophages. Biofactors. 2007, 30(1):1-11; Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010, 636(1-3):28-35). Osteoclasts are differentiated by various differentiation-causing factors in macrophage progenitor cells (Boyce BF, Yamashita T, Yao Z, Zhang Q, Li F, Xing L. Roles for NF-kappaB and c-Fos in osteoclasts. J Bone Miner Metab. 2005, 23 Suppl .: 11-5; Khosla S. Minireview: the OPG / RANKL / RANK system.Endocrinology. 2001, 142 (12): 5050-5). In particular, RANKL (receptor activator of nuclear factor kappa B ligand) secreted from osteoblasts binds to osteoclast precursor cells and RANK (receptor activator of nuclear factor kappa B) present on the surface of osteoclasts. Induce differentiation and activation (Han SY, Lee NK, Kim KH, Jang IW, Yim M, Kim JH, Lee WJ, Lee SY. Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis.Blood. 2005; 106 (4): 1240-5). Differentiated osteoclasts catarsin TRAP (tartarate resistant acid phosphatase) through activation of NF-B, c-Fos, c-jun, AP-1, NFATc1, MAPK, ERK, JNK, p38 activation process, Src, Akt activation Promote osteoclast specific protein expression such as K, calcitonin receptor (Yamashita M, Otsuka F, Mukai T, Yamanaka R, Otani H, Matsumoto Y, Nakamura E, Takano M, Sada KE, Makino H. Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling.Regul Pept. 2010, 162 (1-3): 99-108; Murakami A, Song M, Ohigashi H. Phenethyl isothiocyanate suppresses receptor activator of NF-kappaB ligand (RANKL) -induced osteoclastogenesis by blocking activation of ERK1 / 2 and p38 MAPK in RAW264.7 macrophages.Biofactors.2007, 30 (1): 1-11; Choi HJ, Park YR, Nepal M, Choi BY, Cho NP , Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kap paB signaling pathways.Eur J Pharmacol. 2010, 636 (1-3): 28-35).
밀리타리스 동충하초(Cordyceps militaris)는 곤충의 시체에 자실체를 내리는 소형 버섯류로 숙주가 되는 곤충에 따라 몇 가지가 알려져 있다. 주로 양기가 부족하여 생기는 허리와 무릎 동통, 하체연약, 유정, 몽정, 조루, 이명, 건망, 정신황홀, 헛기침, 해수, 만성병 후 식은땀 흘릴 때, 찬 것을 꺼리는 증상에 쓰인다(성재모, 번데기동충하초(Cordyceps militaris)의 균사 생장. 韓國菌學會誌. 2002; 30(1):1-5). 밀리타리스 동충하초의 주성분은 cordycepin으로 알려져 있으며, Cordyceps militaris에서는 약 2% 정도를 함유하고 있으며, 항암작용(Park SE, Kim J, Lee YW, Yoo HS, Cho CK. Antitumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude mice. J Acupunct Meridian Stud. 2009;2(4):294-300), 면역 증강작용(Lee JS, Hong EK. Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris. Int Immunopharmacol. 2011;11(9):1226-33), 항알러지 작용(Oh JY, Choi WS, Lee CH, Park HJ. The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice. J Ethnopharmacol. 2011;135(2):422-9) 등이 있는 것으로 보고되고 있다. 동충하초 중 다른 종인 Cordyceps sinensis의 파골세포 분화 효능이 보고되었으나(Mizuha Y, Yamamoto H, Sato T, Tsuji M, Masuda M, Uchida M, Sakai K, Taketani Y, Yasutomo K, Sasaki H, Takeda E. Water extract of Cordyceps sinensis (WECS) inhibits the RANKL-induced osteoclast differentiation. Biofactors. 2007;30(2):105-16), 밀리타리스 동충하초(Cordyceps militaris)에 대한 조골세포 및 파골세포에 대한 작용과 골다공증 효과는 보고되지 않았다.Militaris cordyceps (Cordyceps militaris) is a small mushroom that drops fruiting bodies to insect bodies, some of which are known as host. It is mainly used for symptoms of low back and knee pain, lower body weakness, oil well, dreaming, premature ejaculation, tinnitus, forgetfulness, mental ecstasy, flatulence, seawater, and cold sweating after chronic illnesses. Mycelial growth of Cordyceps militaris, 2002. 30 (1): 1-5). The main component of Militaris cordyceps is known as cordycepin, which contains about 2% in Cordyceps militaris, and anticancer activity (Park SE, Kim J, Lee YW, Yoo HS, Cho CK.Antumor activity of water extracts from Cordyceps militaris in NCI-H460 cell xenografted nude mice.J Acupunct Meridian Stud. 2009; 2 (4): 294-300), Lee JS, Hong EK.Immunostimulating activity of the polysaccharides isolated from Cordyceps militaris.Int Immunopharmacol. 2011 11 (9): 1226-33), Oh JY, Choi WS, Lee CH, Park HJ.The ethyl acetate extract of Cordyceps militaris inhibits IgE-mediated allergic responses in mast cells and passive cutaneous anaphylaxis reaction in mice J Ethnopharmacol. 2011; 135 (2): 422-9). Osteoclast differentiation efficacy of Cordyceps sinensis, another species of Cordyceps sinensis, has been reported (Mizuha Y, Yamamoto H, Sato T, Tsuji M, Masuda M, Uchida M, Sakai K, Taketani Y, Yasutomo K, Sasaki H, Takeda E. Water extract of Cordyceps sinensis (WECS) inhibits the RANKL-induced osteoclast differentiation.Biofactors. 2007; 30 (2): 105-16), the effects on osteoblasts and osteoclasts and osteoporosis effects on Cordyceps militaris Not reported.
이에 본 발명자들은 밀리타리스 동충하초(Cordyceps militaris) 추출물의 파골세포 분화 억제 효과, 파골세포 분화 및 파골세포 활성 관련 인자인 TRAP, JNK, AKT1 등의 유전자 발현 억제 효과를 확인함으로써 본 발명을 완성하게 되었다.
The present inventors have completed the present invention by confirming the effect of inhibiting the osteoclast differentiation, osteoclast differentiation and osteoclast activity-related factors such as TRAP, JNK, AKT1, etc. .
상기 목적을 달성하기 위하여, 본 발명은 파골세포 억제효능을 나타내는 밀리타리스 동충하초 추출물을 유효성분으로 함유하는 골대사성 질환 치료 및 예방용 약학 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for the treatment and prophylaxis of bone metabolic diseases, which contains as an active ingredient millilis cordyceps sinensis extract showing an osteoclast inhibitory effect.
또한 본 발명은 파골세포 억제효능을 나타내는 밀리타리스동충하초 추출물을 유효성분으로 함유하는 골 대사성 질환 예방 및 개선용 건강기능식품을 제공한다. In another aspect, the present invention provides a health functional food for preventing and improving bone metabolic diseases containing the extract Militaris cordyceps sinensis extract showing an osteoclast inhibitory effect as an active ingredient.
본원에서 정의되는 상기 골 대사성 질환은 골다공증(osteoprosis), 파제트병(paget disease), 치주질환(periodontal disease), 골전이암(metastatic cancer) 또는 류마티스 관절염(rheumatoid arthiritis), 바람직하게는 골다공증을 포함하는 것을 특징으로 한다.
The bone metabolic disease as defined herein includes osteoprosis, paget disease, periodontal disease, metastatic cancer or rheumatoid arthiritis, preferably osteoporosis. Characterized in that.
이하 본 발명의 밀리타리스동충하초 추출물은 구입가능하나 하기와 같이 밀리타리스동충하초 자실체로부터 추출가능하다.The militaris Cordyceps sinensis extract of the present invention is commercially available but can be extracted from the millitaris cordyceps sec.
예를 들어, 본 발명의 추출물은 밀리타리스동충하초를 건조시킨 후, 시료 중량의 약 1배 내지 100배, 바람직하게는 약 1배 내지 50배 (w/v) 부피의 물, C1 내지 C4의 저급 알코올 또는 이들의 혼합용매로, 바람직하게는 물 또는 물 및 에탄올의 혼합용매, 10 내지 60% 에탄올 혼합 용매로, 약 10 내지 120, 바람직하게는 30 내지 90의 반응온도에서 약 1시간 내지 1일간, 바람직하게는 2 시간 내지 15시간 동안 가열추출법, 초음파 추출법, 환류 추출법, 초고압추출법 등의 통상적인 추출방법, 바람직하게는 환류 추출법으로 1 내지 10회, 바람직하게는 1 내지 5회 반복 추출하는 제 2단계; 상기 단계에서 수득한 추출액을 여과하여 감압 농축하는 제 3단계; 상기 농축된 추출물을 동결 건조하는 제 4단계의 제조방법을 포함하는 단계를 통하여 본 발명의 밀리타리스동충하초 추출물을 얻을 수 있다.
For example, the extract of the present invention, after drying the millitaris Cordyceps sinensis, about 1 to 100 times the sample weight, preferably about 1 to 50 times (w / v) volume of water, C 1 to C 4 lower alcohol or a mixed solvent thereof, preferably water or a mixed solvent of water and ethanol, and a mixed solvent of 10 to 60% ethanol, about 10 to 120, preferably about 1 hour at a reaction temperature of 30 to 90 1 to 10 days, preferably 2 to 15 hours, such as heating extraction, ultrasonic extraction, reflux extraction, ultra-high pressure extraction, such as conventional extraction methods, preferably reflux extraction 1 to 10 times, preferably 1 to 5 times Extracting a second step; A third step of filtering and extracting the extract obtained in the above step under reduced pressure; Millitaris Cordyceps sinensis extract of the present invention can be obtained through the step comprising the method of the fourth step of freeze-drying the concentrated extract.
또한 본 발명은 상기 제조방법 및 상기 제조방법으로 제조된 밀리타리스동충하초 추출물을 유효성분으로 함유하는 골 대사성 질환의 치료 및 예방을 위한 약학 조성물, 건강기능식품, 또는 식품첨가제를 제공한다. In another aspect, the present invention provides a pharmaceutical composition, health functional food, or food additive for the treatment and prevention of bone metabolic diseases containing the method and the millitaris cordyceps sinensis extract prepared by the production method as an active ingredient.
본 발명에 의한 밀리타리스 동충하초 추출물은 파골세포 분화 억제 효과, 파골세포 분화 및 증식 관련 인자인 TRAP, JNK, AKT1 등의 유전자 발현 억제 효과를 나타내므로, 파골세포 억제용 약학 조성물, 건강기능식품 또는 식품첨가제로서 유용함을 확인하였다.Militaris cordyceps sinensis extract according to the present invention exhibits inhibitory effect on osteoclast differentiation, osteoclast differentiation and proliferation-related factors such as TRAP, JNK, AKT1, etc. It was found to be useful as a food additive.
본 발명의 추출물은, 추출물 총 중량에 대하여 상기 생약 추출물을 0.01 내지 99% 중량으로 포함한다.The extract of the present invention comprises 0.01 to 99% by weight of the herbal extract based on the total weight of the extract.
그러나 상기와 같은 조성은 반드시 이에 한정되는 것은 아니고, 환자의 상태 및 질환의 종류 및 진행 정도에 따라 변할 수 있다.
However, the composition as described above is not necessarily limited thereto, and may vary according to the condition of the patient and the type and extent of the disease.
본 발명의 추출물을 포함하는 조성물은 약학 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The composition comprising the extract of the present invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
본 발명에 따른 추출물을 포함하는 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, 이에 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, 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 화합물에 적어도 하나 이상의 부형제 적어도 면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The composition containing the extract according to the present invention may be formulated in the form of powders, granules, tablets, capsules, oral preparations such as suspensions, emulsions, syrups and aerosols, external preparations, suppositories and sterilized injection solutions, Examples of carriers, excipients and diluents that can be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, 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 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. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
본 발명의 추출물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 그러나 바람직한 효과를 위해서, 추출물은 1일 0.01 mg/kg 내지 10 g/kg으로, 바람직하게는 1 mg/kg 내지 1 g/kg으로 투여하는 것이 좋다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 그러므로 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.Preferred dosages of the extracts of the present invention vary depending on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the extract is preferably administered at a dose of 0.01 mg / kg to 10 g / kg per day, preferably 1 mg / kg to 1 g / kg per day. The administration may be carried out once a day or divided into several doses. Therefore, the dose is not intended to limit the scope of the present invention in any aspect.
본 발명의 추출물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구 및 직장, 또는 정맥등의 방법을 통하여 투여 할 수 있다.
The extract of the present invention can be administered to mammals such as rats, mice, livestock, humans and the like in various routes. All modes of administration can be expected, for example by oral and rectal or intravenous methods.
또한 본 발명은 상기 제조방법 및 상기 제조방법으로 제조된 밀리타리스 동충하초 추출물을 함유하는 골 대사성 질환의 예방 및 개선을 위한 건강기능식품을 제공한다. In another aspect, the present invention provides a health functional food for the prevention and improvement of bone metabolic diseases containing the method and the millitaris Cordyceps sinensis extract prepared by the method.
본 발명의 밀리타리스동충하초 추출물을 유효성분으로 포함하는 건강기능식품은 골 대사성 질환의 예방 및 개선을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 추출물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 침출차, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Health functional foods containing the extract Militaris cordyceps sinensis of the present invention as an active ingredient can be used in a variety of drugs, foods and beverages for the prevention and improvement of bone metabolic diseases. Examples of the foods to which the extract of the present invention can be added include various foods, beverages, gums, tea, vitamin complex, leach tea, health supplement foods and the like, and they are in the form of powder, granule, tablet, capsule or beverage Can be used.
따라서 또한, 본 발명은 골 대사성 질환의 예방 및 개선 효과를 갖는 밀리타리스 동충하초 추출물을 유효성분으로 함유하는 식품 또는 식품첨가제를 제공한다.Therefore, the present invention also provides a food or food additive containing millilis cordyceps sinensis extract as an active ingredient having an effect of preventing and improving bone metabolic diseases.
본 발명의 추출물을 첨가 가능한 식품형태는 캔디류의 각종 식품류, 음료, 껌, 차, 비타민 복합제, 또는 건강보조 식품류인 식품 등을 포함한다.The food forms to which the extract of the present invention can be added include various foods of candy, beverages, gums, tea, vitamin complexes, or foods that are health supplement foods.
본 발명의 추출물은 골 대사성 질환의 예방 및 개선을 목적으로 식품 또는 음료에 첨가될 수 있다. 이때, 식품 또는 음료 중의 상기 추출물의 양은 일반적으로 본 발명의 건강식품 조성물은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 음료 조성물은 100 ml를 기준으로 0.02 내지 10 g, 바람직하게는 0.3 내지 1 g의 비율로 가할 수 있다.Extracts of the present invention may be added to food or beverages for the purpose of preventing and improving bone metabolic diseases. At this time, the amount of the extract in the food or beverage is generally the health food composition of the present invention can be added to 0.01 to 15% by weight of the total food weight, the health beverage composition is 0.02 to 10 g based on 100 ml, preferably It can be added at a ratio of 0.3 to 1 g.
본 발명의 건강 음료 조성물은 지시된 비율로 필수 성분으로서 상기 추출물의 혼합물을 함유하는 것 외에 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 ml당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient, such as ordinary beverages, in addition to containing a mixture of the above extract as an essential ingredient in the indicated ratios, have. Examples of the above-mentioned natural carbohydrates include 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 Sugar, 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 said natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
상기 외에 본 발명의 추출물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 추출물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the extract of the present invention can also be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and aging agents (cheese, chocolate, etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the extracts of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks. These components can be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명에 의한 밀리타리스동충하초 추출물은 파골세포 분화 억제 효과, 파골세포 분화 및 증식 관련 인자인 TRAP, JNK, AKT1 등의 유전자 발현 억제 효과를 나타내므로, 골다공증 억제용 약학 조성물으로 유용하게 이용될 수 있다.Militaris cordyceps sinensis extract according to the present invention exhibits inhibitory effect on osteoclast differentiation, osteoclast differentiation and proliferation related gene expression, such as TRAP, JNK, AKT1, and can be usefully used as a pharmaceutical composition for inhibiting osteoporosis. have.
도 1은 밀리타리스동충하초 추출물 농도에 따른 RANKL 처리 RAW264.7 세포로부터 TRAP(+) 다핵세포 형성에 미치는 영향을 나타낸 도이며
도 2는 밀리타리스동충하초 추출물 농도에 따른 TRAP 발현에 미치는 영향을 나타낸 도이며,
도 3는 밀리타리스동충하초 추출물 농도에 따른 JNK 발현에 미치는 영향을 나타낸 도이며,
도 4는 밀리타리스동충하초 추출물 농도에 따른 AKT1 발현에 미치는 영향을 나타낸 도이며,1 is a diagram showing the effect on the formation of TRAP (+) multinucleated cells from RANKL-treated RAW264.7 cells according to the concentration of Militaris Cordyceps Sinensis
Figure 2 is a diagram showing the effect on TRAP expression according to the concentration of Militaris Cordyceps Sinensis,
Figure 3 is a diagram showing the effect on the expression of JNK according to the concentration of Militaris Cordyceps Sinensis,
Figure 4 is a diagram showing the effect on AKT1 expression according to the concentration of Militaris Cordyceps Sinensis,
이하, 본 발명을 하기 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to the following examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 의해 한정되는 것은 아니다.
However, the following examples and experimental examples are illustrative of the present invention, and the content of the present invention is not limited by the following examples and experimental examples.
실시예 1. 밀리타리스 동충하초 추출물의 제조Example 1 Preparation of Millitaris Cordyceps Sinensis Extract
밀리타리스동충하초를 30% 에탄올을 중량의 10배를 가하한 후 4시간 열탕 추출하였으며, 추출물을 농축한 다음 냉동건조 후 하기 실험예의 시료로 사용하였다.
Militaris Cordyceps sinensis was added to 30
실험예 1. 세포 배양 및 약물처리Experimental Example 1. Cell Culture and Drug Treatment
실험에 사용한 RAW 264.7 세포는 DMEM(Dulbecco's modified eagle medium)/10% FBS(fetal bovine serum)/PC-SM 배지를 이용하여 CO2 세포배양기에서 배양하였으며, 세포수는 5x103 cells/well 로 96 well plate를 이용하여 배양하였다. 24시간 배양 후 배양액을 버린 후, 10 % FBS, 50 ng/ml RANKL, 1 ng/ml TGFb 가 첨가된 a-MEM 으로 교환하여 세포를 배양했다. 배양액에 여러 농도의 AS를 첨가해 주었다. 2일에 한번씩 동일한 배지로 교환해 주면서 6일간 배양하였다. 실험군은 (1) RANKL 처리하지 않은 대조군(N) (2) RANKL 유도 대조군(C), (2) RANKL 유도군 + 1/의 실시예1의 밀리타리스동충하초 추출물을 투여한 군(CM 0.1), (3) RANKL 유도군 + 5/의 실시예1의 밀리타리스동충하초 추출물을 투여한 군(CM1)으로 하였다.
The RAW 264.7 cells used in the experiment were cultured in a CO2 cell incubator using DMEM (Dulbecco's modified eagle medium) / 10% fetal bovine serum (FBS) / PC-SM medium, and the number of cells was 96 well plate at 5x10 3 cells / well. And cultured using. After culturing for 24 hours, the culture medium was discarded, and the cells were cultured by exchanging with a-MEM to which 10% FBS, 50 ng / ml RANKL, and 1 ng / ml TGFb were added. Different concentrations of AS were added to the culture. It was incubated for 6 days while changing to the same medium every two days. The experimental group was administered with (1) RANKL-treated control group (N) (2) RANKL-induced control group (C), (2) RANKL-induced group + 1 / of Millitaris Cordyceps Sinensis extract of Example 1 (CM 0.1) , (3) RANKL induction group + 5 / to the group to which the milliliris cordyceps extract of Example 1 was administered (CM1).
실험예 2. 파골세포 생성능 측정Experimental Example 2. Measurement of osteoclast generation capacity
RANKL(receptor activator for nuclear factor B ligand)로 RAW 264.7 cell를 파골세포로 유도한 후, 성숙한 파골세포의 발현 marker로 알려진 TRAP를 염색하여 TRAP-positive한 다핵세포(TRAP(+) MNCs)를 확인하였다. 분화시킨 세포를 PBS로 세포를 2회 세척하고, 3.7% formaldehyde -citrate-acetone 용액으로 10분 고정시키고 증류수로 2회 세척하였다. 2% TRAP fast garnet GBC base 용액과 NaNO3 용액을 같은 비율로 섞어 만든 용액과 5% naphtha AS-BI phosphoric acid, 4% acetic acid, 2% tartaric acid를 포함한 용액을 고정시킨 세포에 처리하고 상온에 30분 이상 방치하였다. 광학현미경으로 관찰하여 핵이 3개 이상인 TRAP-positive 한 다핵세포 (TRAP(+) MNCs)를 계수하여 파골세포의 생성지표로 하였다(Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways. Eur J Pharmacol. 2010;636(1-3):28-35).
After inducing RAW 264.7 cells to osteoclasts with RANKL (receptor activator for nuclear factor B ligand), TRAP-positive multinucleated cells (TRAP (+) MNCs) were identified by staining TRAP, a marker for expression of mature osteoclasts. . Differentiated cells were washed twice with PBS, fixed with 3.7% formaldehyde-citrate-acetone solution for 10 minutes and washed twice with distilled water. Treat the cells prepared by mixing 2% TRAP fast garnet GBC base solution with NaNO3 solution in the same ratio and a solution containing 5% naphtha AS-BI phosphoric acid, 4% acetic acid and 2% tartaric acid. It was left for more than a minute. Observed by light microscopy, TRAP-positive multinucleated cells (TRAP (+) MNCs) having three or more nuclei were counted as markers for the generation of osteoclasts (Choi HJ, Park YR, Nepal M, Choi BY, Cho NP, Choi). SH, Heo SR, Kim HS, Yang MS, Soh Y. Inhibition of osteoclastogenic differentiation by Ikarisoside A in RAW 264.7 cells via JNK and NF-kappaB signaling pathways.Eur J Pharmacol. 2010; 636 (1-3): 28-35 ).
실험예 3. 유전자 발현에 대한 영향Experimental Example 3. Effect on Gene Expression
상기 실시예 1의 밀리타리스 동충하초 추출물의 파골세포 분화 및 증식 관련 인자인 TRAP, JNK, AKT1 등의 유전자 발현에 대한 영향을 알아보기 위해 하기와 같이 실험을 수행하였다.
Experiments were performed as follows to determine the effect on gene expression of factors related to osteoclast differentiation and proliferation of the Millitaris cordyceps sinensis extract of Example 1, such as TRAP, JNK, AKT1.
3-1. 총 3-1. gun RNARNA 분리 detach
파골세포로 분화한 TRAP(+) 다핵세포에 1 ml 트리졸 용액 (인비트로젠, USA)를 처리하여 총 RNA를 분리하였다. 분리한 RNA에 100 페놀과 100 클로로포름 : 아이소아밀알코올 (24:1)을 넣고 잘 섞은 후 원심분리하는 과정을 2번 반복하여 상층액을 분리한다. 0.5 ml 아이소프로필 알코올을 이용하여 RNA를 침전시킨 후 70% 에탄올로 세척하고 자연 건조시킨다. 알에네이즈 프리워터 (RNAase free water, 프로메가, 미국)에서 RNA를 녹인 후 알에네이즈-프리-디에네이즈 (RNase-free DNase, 프로메가, 미국)를 첨가하고 -70oC에 저장하였다.
Total RNA was isolated from TRAP (+) multinuclear cells differentiated into osteoclasts by treatment with 1 ml Trizol solution (Invitrogen, USA). 100 phenol and 100 chloroform: isoamyl alcohol (24: 1) are added to the isolated RNA, and the mixture is mixed well and centrifuged twice to separate the supernatant. RNA is precipitated using 0.5 ml isopropyl alcohol, washed with 70% ethanol and dried naturally. RNA was thawed in RNAase free water (RNA) free water (Promega, USA), followed by the addition of ALNAISE-free DNase (RNase-free DNase, Promega, USA) and stored at -70 ° C.
3-2. 3-2. cDNAcDNA 제조 Produce
상기 실험예 3-1에서 분리한 대조군 및 실험군 각각의 전체 RNA액 (13 ug RNA 함유)에 올리고 dT 1 을 넣은 후 조심스럽게 혼합한 다음, 70oC에서 5분간 배양하였다. 프라이머가 풀리도록 실온에서 약 10분간 방치한 다음, 사스크립트 버퍼 (cyscript buffer), 0.1 M DTT, dUTP 뉴클레오티드, dUTP 시다이-표지된 뉴클레오티드, 사스크립트 역전사효소 (Cyscript reverse transcriptase)를 첨가한 후, 아주 조심스럽게 혼합하였다. 이 후, 42oC에서 90분간 배양한 후, 얼음 상에 방치하였다. 여기에 2.5 M 수산화나트륨을 가한 후 37oC에서 15분간 배양하였으며, 2 M HEPES 버퍼를 가하여 중화시켜 cDNA를 제조하였다.Oligo dT 1 was added to the total RNA solution (containing 13 ug RNA) of each of the control and experimental groups isolated in Experimental Example 3-1, mixed carefully, and then incubated at 70 ° C. for 5 minutes. Leave primers at room temperature for about 10 minutes to release the primers, then add cyscript buffer, 0.1 M DTT, dUTP nucleotides, dUTP seeded-labeled nucleotides, Cyscript reverse transcriptase, and then add Mix carefully. Thereafter, the cells were incubated at 42 ° C. for 90 minutes and then left on ice. 2.5 M sodium hydroxide was added thereto, followed by incubation at 37 ° C. for 15 minutes, and neutralized by adding 2 M HEPES buffer to prepare cDNA.
3-3. 3-3. RealReal timetime RTRT -- PCRPCR
우선 시험관에 정량한 RNA 5 ug, 50 ng/의 랜덤 헥사머 (random hexamer) 3 , 10 mM dNTP 1 를 넣고 DEPC-H2O를 가하여 10 의 RNA/프라이머 혼합물을 만들었다. 실험용 sample을 65℃에서 5분간 배양시킨 후 1분 이상 얼음에 방치하였다. 반응 혼합물로 10배의 RT 버퍼 2 , 25 mM 염화마그네슘 4 , 0.1 M DTT 2 , RNAase(프로메가, 미국) 1 을 섞어 준비하였다. 반응 혼합물을 RNA/프라이머 혼합물에 가하여 섞고 실온에 2분간 방치한 후, SuperScript II RT (프로메가, 미국) 1 (50 units)를 가하고 25oC에 10분간 배양 시켰다. 다시 42oC에서 50분간 배양 시킨 다음, 70oC에서 15분간 가열하여 불활성 시키고 얼음 상에서 식혔다. RNase (프로메가, 미국)1 를 가하고 다시 37oC에서 20분간 배양 시킨 다음, 사용 시까지 -20oC에 보관하였다. 각각의 옵티컬 튜브 (optical tube, 깁코, 미국)에 2배의 사이버 그린믹스 (SYBR Green Mix, 다카라, 일본) 12.5 , cDNA 0.2 , 5 pmol/ 프라이머 쌍 혼합 1 , 11.3 H2O를 넣고, 50oC 2 분 1 사이클, 95oC 10분 1 사이클, 95oC 15초, 60oC 30초, 72oC 30초 40 사이클, 72oC 10분 1 사이클로 증폭시켰다. PCR을 마친 후 튜브를 꺼낸 다음, 반응액 5 ul를 사용하여 3% 아가로스 겔에서 PCR 특이성을 측정했다. SDS 7000 소프트웨어를 사용하여 리얼 타임 PCR (real time PCR) 결과를 분석하였다. First, 5 ug of RNA, 50 ng / random hexamer (random hexamer) 3, 10 mM dNTP 1, were added to the test tube, and DEPC-H 2 O was added to make an RNA / primer mixture of 10. The experimental sample was incubated at 65 ° C. for 5 minutes and then left on ice for at least 1 minute. The reaction mixture was prepared by mixing
RAW264.7 세포에 RANKL (receptor activator for nuclear factor B ligand) 처리시 TRAP(+) 다핵세포(MNCs) 발현이 증가하여 파골세포 분화가 촉진되었으며, 상기 실시예에서 밀리타리스동충하초 추출물은 0.1 ug/ml, 1 ug/ml, 농도에서 증 RANKL (receptor activator for nuclear factor B ligand) 유도 파골세포 분화를 억제시키는 것으로 나타났다(도 1) TRAP(tartarate resistance Acid Phosphatase), JNK, AKT1은 RANKL 처리시 발현이 증가하였으며, 상기의 밀리타리스동충하초 추출물은 0.1 ug/ml, 1 ug/ml, 농도에서 증가한 유전자 발현을 현저히 억제함을 확인하였다 (도 2, 도 3 및 도 4 참조). 따라서 밀리타리스동충하초 추출물은 TRAP, JNK, AKT1 유전자 발현을 억제하는데 탁월한 효과가 있음을 알 수 있었다.
Treatment of receptor activator for nuclear factor B ligand (RANKL) in RAW264.7 cells increased the expression of TRAP (+) multinucleated cells (MNCs) to promote osteoclast differentiation, and in this example, the extract of Militaris cordyceps was 0.1 ug /. ml, 1 ug / ml, it was shown to inhibit the receptor activator for nuclear factor B ligand (RANKL) -induced osteoclast differentiation at concentrations (FIG. 1) .TAP (tartarate resistance Acid Phosphatase), JNK, and AKT1 were expressed during RANKL treatment. It was confirmed that the Millitaris cordyceps sinensis extract significantly inhibited the gene expression increased at 0.1 ug / ml, 1 ug / ml (see FIGS. 2, 3 and 4). Therefore, Militaris cordyceps sinensis extract was found to have an excellent effect in inhibiting TRAP, JNK, AKT1 gene expression.
통계처리는 스튜던트의 t-검정을 이용해 개별 비교를 하였으며, p값이 0.05 미만일 때 유의한 차이가 있는 것을 판정하였다.
Statistical treatments were compared individually using Student's t-test and determined that there was a significant difference when the p-value was less than 0.05.
하기에 본 발명의 추출물을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Hereinafter, formulation examples of the composition containing the extract of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.
제제예Formulation example 1. One. 산제의Sanje 제조 Produce
밀리타리스동충하초 추출물 200 mgMilitaris Cordyceps Sinensis Extract 200 mg
유당 100 mgLactose 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.
The above components are mixed and filled in airtight bags to prepare powders.
제제예Formulation example 2. 정제의 제조 2. Preparation of tablets
밀리타리스동충하초 추출물 200 mgMilitaris Cordyceps Sinensis Extract 200 mg
옥수수전분 100 mgCorn starch 100 mg
유당 100 mgLactose 100 mg
스테아린산 마그네슘 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.
After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Preparation of capsules
밀리타리스동충하초 추출물 200 mgMilitaris Cordyceps Sinensis Extract 200 mg
결정성 셀룰로오스 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캅셀제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캅셀제를 제조한다.
The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.
제제예Formulation example 4. 주사제의 제조 4. Preparation of injections
밀리타리스동충하초 추출물 200 mgMilitaris Cordyceps Sinensis Extract 200 mg
만니톨 180 mgMannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4 ,12H2O 26 mgNa 2 HPO 4 , 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2㎖) 상기의 성분 함량으로 제조한다.
(2 ml) per 1 ampoule according to the usual injection preparation method.
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
밀리타리스동충하초 추출물 200 mgMilitaris Cordyceps Sinensis Extract 200 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ml로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.
Each component was added and dissolved in purified water according to the usual liquid preparation method, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and purified water was added thereto. The whole was added with purified water to adjust the total volume to 100 ml, And sterilized to prepare a liquid preparation.
Claims (2)
A pharmaceutical composition for the treatment and prevention of bone metabolic diseases, which contains as an active ingredient militaris cordyceps sinensis extract showing osteoclast inhibition effect.
상기 골 대사성 질환은 골다공증(osteoprosis), 파제트병(paget disease), 치주질환(periodontal disease), 골전이암(metastatic cancer) 또는 류마티스 관절염(rheumatoid arthiritis)인 약학 조성물.
The method of claim 1,
The bone metabolic disease is osteoprosis (osteoprosis), Paget disease (paget disease), periodontal disease (periodontal disease), metastatic cancer (rheumatoid arthiritis) pharmaceutical composition (rheumatoid arthiritis).
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