CN1689628A - Medicinal uses of Andrographis paniculata extract - Google Patents
Medicinal uses of Andrographis paniculata extract Download PDFInfo
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Abstract
本发明涉及一种穿心莲提取物的医药用途，具体涉及一种穿心莲提取物在制备TNF－α和/或IL－1β抑制剂中的用途，特别是涉及一种穿心莲提取物在制备治疗溃疡性结肠炎或克隆病的药物中的用途。The present invention relates to the medical use of Andrographis paniculata extract, in particular to the use of Andrographis paniculata extract in preparing TNF-α and/or IL-1β inhibitors, in particular to the application of Andrographis paniculata extract in preparing and treating ulcerative colon Use in medicine for inflammation or Crohn's disease.
Description
技术领域technical field
本发明涉及一种穿心莲提取物的医药用途，具体涉及一种穿心莲提取物在制备TNF-α和/或IL-1β抑制剂中的用途，特别是涉及一种穿心莲提取物在制备治疗溃疡性结肠炎或克隆病的药物中的用途。The present invention relates to the medical use of Andrographis paniculata extract, in particular to the use of Andrographis paniculata extract in the preparation of TNF-α and/or IL-1β inhibitors, in particular to the use of Andrographis paniculata extract in the preparation and treatment of ulcerative colon Use in medicine for inflammation or Crohn's disease.
背景技术Background technique
炎症是机体对各种致炎症因子引起的损伤所发生的以防御为主的反应，炎症的局部表现为红，肿，热，痛及功能障碍。这些表现在急性体表炎症时较为明显，而内脏的炎症和慢性炎症则多不明显。炎症不仅表现在局部，而且也常引起全身反应。常见的全身反应有发热，血液中的白细胞数目增多以及心，肝，肾等实质性器官可出现不同程度的变性，坏死等病变。Inflammation is the body's defense-based response to the damage caused by various inflammatory factors. The local manifestations of inflammation are redness, swelling, heat, pain and dysfunction. These manifestations are more obvious in acute body surface inflammation, but less obvious in visceral inflammation and chronic inflammation. Inflammation is not only local, but also often causes systemic reactions. Common systemic reactions include fever, increased leukocyte count in the blood, and varying degrees of degeneration and necrosis of heart, liver, kidney and other solid organs.
按病理分类，炎症可分为变质性炎、浆液性炎、纤维素性炎、化脓性炎、出血性炎、卡他性炎、增生性炎和慢性肉芽肿性炎。According to pathological classification, inflammation can be divided into degenerative inflammation, serous inflammation, fibrinous inflammation, suppurative inflammation, hemorrhagic inflammation, catarrhal inflammation, proliferative inflammation and chronic granulomatous inflammation.
TNFα是一种前体炎症细胞因子，主要由单核细胞和巨噬细胞产生，参与许多炎症反应的过程。内毒素(LPS)是TNFα的诱导剂。研究发现，TNFα具有多种生物学活性：1)杀伤或抑制肿瘤细胞；2)提高中性粒细胞的吞噬能力，增加过氧化物阴离子产生，参与炎症反应；3)抗感染等。据文献报道，TNFα抑制剂可用于类风湿性关节炎、幼年型类风湿关节炎、骨性关节炎、脊柱关节病、炎性肠病(包括克隆病和溃疡性结肠炎)、心力衰竭、糖尿病、系统性红斑狼疮、硬皮病、结节病、皮肌炎、银屑病、多发性骨髓瘤、骨髓增生异常综合征、急性髓型白血病、帕金森氏症、艾滋病痴呆综合征、早老性痴呆、抑郁症、脓毒症、坏疽性脓皮病、败血症、感染性休克、白塞氏病、移植物抗宿主病、葡萄膜炎、Wegener′s肉芽肿、休格连氏干燥症、慢性阻塞性肺病、哮喘、急性胰腺炎、牙周病、恶病质、癌症、中枢神经系统损伤、呼吸道病毒感染、肥胖等多种病症的治疗(1-25)(1.Ogata H，Hibi T.et al Curr Pharm Des.2003；9(14)：1107-13.2.Moller DR.et al J Intern Med.2003 Jan；253(1)：31-40.3.Taylor PC.Etal Curr Pharm Des.2003；9(14)：1095-106.4.Wilkinson N et al Arch Dis Child.2003 Mar；88(3)：186-91.5.Nishimura F et al J Periodontol.2003 Jan；74(1)：97-102.6.Weinberg JM et al Cutis.2003 Jan；71(1)：41-5.7.Burnham E et al CritCare Med.2001 Mar；29(3)：690-1.8.Sack M.et al Pharmacol Ther.2002 Apr-May；94(1-2)：123-35.9.Barnes PJ.Et al Annu Rev Pharmacol Toxicol.2002；42：81-98.10.Mageed RA et al Lupus.2002；11(12)：850-5.11.Tsimberidou AM et al ExpertRev Anticancer Ther. 2002 Jun；2(3)：277-86.12.Muller T.et al Curr Opin InvestigDrugs.2002 Dec；3(12)：1763-7.13.Calandra T et al Curr Clin Top Infect Dis.2002；221-23.14.Girolomoni G et al Curr Opin Investig Drugs.2002 Nov；3(11)：1590-5.15.Tutuncu Z et al Clin Exp Rheumatol.2002 Nov-Dec；20(6 Suppl 28)：S146-51.16.Braun J et al Best Pract Res Clin Rheumatol.2002 Sep；16(4)：631-51.17.Barnes PJ.Et al Novartis Found Symp.2001；234：255-67；discussion 267-72.18.Brady M，et al Baillieres Best Pract Res Clin Gastroenterol.1999 Jul；13(2)：265-89.19.Goldring MB.et al Expert Opin Biol Ther.2001 Sep；1(5)：817-29.20.MarietteX.Rev Prat.2003 Mar 1；53(5)：507-11.21.Sharma R et al Int J Cardiol.2002 Sep；85(1)：161-71.22.Wang CX et al Prog Neurobiol.2002 Jun；67(2)：161-72.23.VanReeth K et al Vet Immunol Immunopathol.2002 Sep 10；87(3-4)：161-8.24.LeonardBE et al Int J Dev Neurosci.2001 Jun；19(3)：305-12.25.Hays SJ et al Curr PharmDes.1998 Aug；4(4)：335-48.)。TNFα is a precursor inflammatory cytokine, mainly produced by monocytes and macrophages, involved in many inflammatory processes. Endotoxin (LPS) is an inducer of TNFα. Studies have found that TNFα has a variety of biological activities: 1) killing or inhibiting tumor cells; 2) improving the phagocytosis of neutrophils, increasing the production of superoxide anions, and participating in inflammatory reactions; 3) anti-infection, etc. According to literature reports, TNFα inhibitors can be used for rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondyloarthropathy, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), heart failure, diabetes , systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, Parkinson's disease, AIDS dementia syndrome, premature aging Dementia, depression, sepsis, pyoderma gangrenosum, sepsis, septic shock, Behcet's disease, graft-versus-host disease, uveitis, Wegener's granulomatosis, Sugarlen's xerosis, chronic Treatment of various diseases such as obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection, obesity (1-25) (1.Ogata H, Hibi T.et al Curr Pharm Des.2003;9(14):1107-13.2.Moller DR.et al J Intern Med.2003 Jan;253(1):31-40.3.Taylor PC.Etal Curr Pharm Des.2003;9(14) : 1095-106.4. Wilkinson N et al Arch Dis Child. 2003 Mar; 88(3): 186-91.5. Nishimura F et al J Periodontol. 2003 Jan; 74(1): 97-102.6. Weinberg JM et al Cutis. 2003 Jan;71(1):41-5.7.Burnham E et al CritCare Med.2001 Mar;29(3):690-1.8.Sack M.et al Pharmacol Ther.2002 Apr-May;94(1-2) :123-35.9.Barnes PJ.Et al Annu Rev Pharmacol Toxicol.2002; 42:81-98.10.Mageed RA et al Lupus.2002;11(12):850-5.11.Tsimberidou AM et al ExpertRev Anticancer Ther. 2002 Jun ;2(3):277-86.12.Muller T.et al Curr Opin InvestigDrugs.2002 Dec;3(12):1763-7.13.Calandra T et al Curr Clin Top Infect Dis.2002;221-23.14.Girolomoni G et al Curr Opin Investig Drugs.2002 Nov;3(11):1590-5.15.Tutuncu Z et al Clin Exp Rheumatol.2002 Nov-Dec;20(6 Suppl 28):S146-51.16.Braun J et al Best Pract Res Clin Rheumatol.2002 Sep;16(4):631-51.17.Barnes PJ.Et al Novartis Found Symp.2001;234:255-67;discussion 267-72.18.Brady M, et al Baillieres Best Pract Res Clin Gastroenterol.1999 Jul. ;13(2):265-89.19.Goldring MB.et al Expert Opin Biol Ther.2001 Sep;1(5):817-29.20.MarietteX.Rev Prat.2003 Mar 1;53(5):507-11.21. Sharma R et al Int J Cardiol.2002 Sep;85(1):161-71.22.Wang CX et al Prog Neurobiol.2002 Jun;67(2):161-72.23.VanReeth K et al Vet Immunol Immunopathol.2002 Sep 10 ;87(3-4):161-8.24.LeonardBE et al Int J Dev Neurosci.2001 Jun;19(3):305-12.25.Hays SJ et al Curr PharmDes.1998 Aug;4(4):335-48 .).
IL-1β是由单核巨噬细胞、树突状细胞、纤维母细胞等产生的一种细胞因子。它能刺激T细胞和B细胞的增殖和分化、刺激造血以及参与炎症反应。据文献报道，IL-1β抑制剂可用于类风湿性关节炎、败血症、牙周病、心力衰竭、皮肌炎、急性胰腺炎、慢性阻塞性肺病、早老性痴呆、骨性关节炎、细菌感染、多发性骨髓瘤、骨髓增生异常综合征、葡萄膜炎、中枢神经系统损伤、呼吸道病毒感染、哮喘、抑郁症、硬皮病等多种病症的治疗(26～45)(26.Taylor PC.et al CurrPharm Des.2003；9(14)：1095-106.27.Dellinger RP et al Clin Infect Dis.2003 May15；36(10)：1259-65.28.Takashiba S et al J Periodontol.2003 Jan；74(1)：103-10.29.Diwan A，et al Curr Mol Med.2003 Mar；3(2)：161-82.30.Lundberg IE，et alRheum Dis Clin North Am.2002 Nov；28(4)：799-822.31.Makhija R，et al JHepatobiliary Pancreat Surg.2002；9(4)：401-10.32.Chung KF.Et al Eur Respir JSuppl.2001 Dec；34：50s-59s.33.Hallegua DS，et al Ann Rheum Dis.2002 Nov；61(11)：960-7.34.Goldring MB.Et al Expert Opin Biol Ther.2001 Sep；1(5)：817-29.35.Mrak R E，Griffin WS.Et al Neurobiol A ging.2001 Nov-Dec；22(6)：903-8.36.Brady M，et al Baillieres Best Pract Res Clin Gastroenterol.1999 Jul；13(2)：265-89.37.Van der Meer JW，et al Ann N Y Acad Sci.1998 Sep 29；856：243-51. 38.Rameshwar P et al Acta Haematol.2003；109(1)：1-10.39.deKozak Y et al Int Rev Immunol.2002 Mar-Jun；21(2-3)：231-53.40.Wang CX et alProg Neurobiol.2002 Jun；67(2)：161-72.41.Van Reeth K et al Vet ImmunolImmunopathol.2002 Sep 10；87(3-4)：161-8.42.Stirling RG et al Br Med Bull.2000；56(4)：1037-53.43.Leonard BE et al Int J Dev Neurosci.2001 Jun；19(3)：305-12.44.Allan SM et al Ann N Y Acad Sci.2000；917：84-93.45.Cafagna D et al MinervaMed.1998 May；89(5)：153-61)。IL-1β is a cytokine produced by mononuclear macrophages, dendritic cells, fibroblasts, etc. It can stimulate the proliferation and differentiation of T cells and B cells, stimulate hematopoiesis, and participate in inflammatory responses. According to literature reports, IL-1β inhibitors can be used for rheumatoid arthritis, sepsis, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, Alzheimer's disease, osteoarthritis, bacterial infection , multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, respiratory virus infection, asthma, depression, scleroderma and other diseases (26～45) (26.Taylor PC. et al CurrPharm Des.2003;9(14):1095-106.27.Dellinger RP et al Clin Infect Dis.2003 May15;36(10):1259-65.28.Takashiba S et al J Periodontol.2003 Jan;74(1) : 103-10.29. Diwan A, et al Curr Mol Med. 2003 Mar; 3(2): 161-82.30. Lundberg IE, et al Rheum Dis Clin North Am. 2002 Nov; 28(4): 799-822.31. Makhija R , et al JHepatobiliary Pancreat Surg.2002; 9(4):401-10.32.Chung KF.Et al Eur Respir JSuppl.2001 Dec;34:50s-59s.33.Hallegua DS, et al Ann Rheum Dis.2002 Nov; 61(11): 960-7.34. Goldring MB. Et al Expert Opin Biol Ther. 2001 Sep; 1(5): 817-29.35. Mrak R E, Griffin WS. Et al Neurobiol Aging. 2001 Nov-Dec; 22( 6): 903-8.36. Brady M, et al Baillieres Best Pract Res Clin Gastroenterol. 1999 Jul; 13(2): 265-89.37. Van der Meer JW, et al Ann N Y Acad Sci. 1998 Sep 29; 856: 243 -51. 38.Rameshwar P et al Acta Haematol.2003;109(1):1-10.39.deKozak Y et al Int Rev Immunol.2002 Mar-Jun;21(2-3):231-53.40.Wang CX et alProg Neurobiol.2002 Jun;67(2):161-72.41.Van Reeth K et al Vet ImmunolImmunopathol.2002 Sep 10;87(3-4):161-8.42.Stirling RG et al Br Med Bull.2000;56( 4): 1037-53.43. Leonard BE et al Int J Dev Neurosci. 2001 Jun; 19(3): 305-12.44. Allan SM et al Ann N Y Acad Sci. 2000; 917: 84-93.45. Cafagna D et al MinervaMed .1998 May;89(5):153-61).
穿心莲为爵床科植物穿心莲Andrographis Paniculata(Brun.f.)Nees的干燥地上部分，其性寒味苦，具有清热解毒、凉血消肿的功效。穿心莲在中国和印度都有广泛应用，常用于治疗感冒发热，咽喉肿痛，口舌生疮，顿咳劳嗽，泄泻痢疾，毒蛇咬伤等症(国家药典委员会，中华人民共和国药典2000版一部，200页，2000)。据报道穿心莲中的主要活性成分为二萜内酯类化合物穿心莲内酯(Andrographolide)，其它的活性成分还有脱氧穿心莲内酯，新穿心莲内酯等(Chem WM.，et al.，Planta Medica；15：245-246.1982；Siripong，P.，B.et al.，J.Sci.Soc.Thailand 18(4)：187-94.1992)。Andrographis paniculata is the dry aerial part of Andrographis Paniculata (Brun.f.) Nees, a plant of the Acanthaceae family. It is cold in nature and bitter in taste, and has the effects of clearing heat and detoxifying, cooling blood and reducing swelling. Andrographis paniculata is widely used in China and India. It is often used to treat colds, fever, sore throat, sores, coughing, diarrhea, dysentery, snake bites and other diseases (National Pharmacopoeia Committee, Pharmacopoeia of the People's Republic of China 2000 Edition 1 Department, 200 pp., 2000). It is reported that the main active ingredient in Andrographis paniculata is diterpene lactone compound andrographolide (Andrographolide), and other active ingredients also have deoxyandrographolide, neoandrographolide etc. (Chem WM., et al., Planta Medica; 15:245-246.1982; Siripong, P., B. et al., J.Sci.Soc.Thailand 18(4):187-94.1992).
现代医学研究证明，穿心莲具有免疫增强(Puri A.，et al.，J Nat Prod，56(7)，995-9，1993)、抗肿瘤(李玉祥等，中国药科大学学报，30(1)，37-41，1999)、保肝(Trivedi NP.，et al.，Indian J Exp Biol.39(1)：41-6，2001)、抗生育(Akbarsha MA.，et al.，Indian J Exp Biol.May；28(5)：421-6，1990)、抗病毒和抗炎等作用(陈国祥等，现代中西医结合杂志，10(11)，1004-5，2001)。另外，据报道穿心莲提取物具有治疗糖尿病的作用(Zhang XF.，et al.，Acta Pharmacol Sin.21(12)：1157-64，2000)。最近，美国Bastyr大学的研究证明穿心莲能够抗HIV病毒，可能用于治疗艾滋病(Calabrese C.et al.，Phytother Res.14(5)：333-8，2000)。Modern medical research has proved that Andrographis paniculata has immune enhancement (Puri A., et al., J Nat Prod, 56 (7), 995-9, 1993), anti-tumor (Li Yuxiang, etc., Journal of China Pharmaceutical University, 30 (1) , 37-41, 1999), hepatoprotective (Trivedi NP., et al., Indian J Exp Biol.39(1):41-6, 2001), antifertility (Akbarsha MA., et al., Indian J Exp Biol.May; 28(5):421-6, 1990), antiviral and anti-inflammatory effects (Chen Guoxiang et al., Modern Journal of Integrated Traditional Chinese and Western Medicine, 10(11), 1004-5, 2001). In addition, it is reported that the extract of Andrographis paniculata has the effect of treating diabetes (Zhang XF., et al., Acta Pharmacol Sin. 21(12): 1157-64, 2000). Recently, the study of Bastyr University in the United States proved that Andrographis paniculata can resist HIV virus and may be used for the treatment of AIDS (Calabrese C. et al., Phytother Res. 14 (5): 333-8, 2000).
现有文献未见有关穿心莲提取物、穿心莲内酯及其衍生物、类似物具有抑制TNFα和IL-1β表达活性的报道。There is no report in the existing literature about the inhibitory activity of Andrographis paniculata extract, andrographolide and its derivatives and analogues on the expression of TNFα and IL-1β.
发明内容Contents of the invention
本发明的目的旨在提供穿心莲提取物的一种新的制药用途。The purpose of the present invention is to provide a new pharmaceutical application of Andrographis paniculata extract.
本发明的一个方面是涉及穿心莲提取物在制备TNFα和/或IL-1β抑制剂中的用途。One aspect of the present invention relates to the use of Andrographis paniculata extract in the preparation of TNFα and/or IL-1β inhibitors.
尤其是，本发明涉及穿心莲提取物在制备治疗溃疡性结肠炎或克隆病的药物中的用途。In particular, the present invention relates to the use of Andrographis paniculata extract in the preparation of medicines for treating ulcerative colitis or Crohn's disease.
所述“TNFα抑制剂”可用于治疗下列病症，包括但不限于：脊柱关节病、炎性肠病(包括克隆病和溃疡性结肠炎)、心力衰竭、糖尿病、系统性红斑狼疮、硬皮病、结节病、皮肌炎、银屑病、多发性骨髓瘤、骨髓增生异常综合征、急性髓型白血病、帕金森氏症、早老性痴呆、抑郁症、艾滋病痴呆综合征、白塞氏病、移植物抗宿主病、葡萄膜炎、Wegener′s肉芽肿、休格连氏干燥症、慢性阻塞性肺病、哮喘、急性胰腺炎、牙周病、恶病质、癌症、中枢神经系统损伤、呼吸道病毒感染或肥胖。The "TNFα inhibitor" can be used to treat the following diseases, including but not limited to: spondyloarthropathy, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), heart failure, diabetes, systemic lupus erythematosus, scleroderma , sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, Parkinson's disease, Alzheimer's disease, depression, AIDS dementia syndrome, Behcet's disease , graft-versus-host disease, uveitis, Wegener's granulomatosis, Sugarlin's xerosis, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory virus infection or obesity.
所述“IL-1β抑制剂”可用于治疗下列病症，包括但不限于：败血症、牙周病、心力衰竭、皮肌炎、急性胰腺炎、慢性阻塞性肺病、早老性痴呆、骨性关节炎、细菌感染、多发性骨髓瘤、骨髓增生异常综合征、葡萄膜炎、中枢神经系统损伤、呼吸道病毒感染、哮喘、抑郁症或硬皮病。The "IL-1β inhibitor" can be used to treat the following diseases, including but not limited to: sepsis, periodontal disease, heart failure, dermatomyositis, acute pancreatitis, chronic obstructive pulmonary disease, Alzheimer's disease, osteoarthritis , bacterial infection, multiple myeloma, myelodysplastic syndrome, uveitis, central nervous system injury, respiratory viral infection, asthma, depression, or scleroderma.
本发明的另一个方面是涉及穿心莲提取物在制备治疗炎性病症药物中的用途，所述药物可用于治疗选自下组病症的一种或多种，这些病症包括但不限于：炎性肠病(包括克隆病和溃疡性结肠炎)、心力衰竭、糖尿病、系统性红斑狼疮、硬皮病、结节病、皮肌炎、银屑病、多发性骨髓瘤、骨髓增生异常综合征、急性髓型白血病、帕金森氏症、早老性痴呆、抑郁症、艾滋病痴呆综合征、白塞氏病、移植物抗宿主病、葡萄膜炎、Wegener′s肉芽肿、休格连氏干燥症、慢性阻塞性肺病、哮喘、急性胰腺炎、牙周病、恶病质、癌症、中枢神经系统损伤、呼吸道病毒感染或肥胖。Another aspect of the present invention relates to the use of Andrographis paniculata extract in the preparation of a medicament for the treatment of inflammatory conditions, which can be used to treat one or more of the conditions selected from the group consisting of but not limited to: inflammatory bowel disease disease (including Crohn's disease and ulcerative colitis), heart failure, diabetes mellitus, systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute Myeloid leukemia, Parkinson's disease, Alzheimer's disease, depression, AIDS dementia syndrome, Behcet's disease, graft-versus-host disease, uveitis, Wegener's granulomatosis, Sugarlin's xerosis, chronic Obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory viral infection, or obesity.
本发明各个方面的细节将在随后的章节中得以详尽描述。通过下文以及权利要求的描述，本发明的其它特点、目的和优势将会更为明显。Details of various aspects of the invention are set forth in the ensuing sections. Other features, objects and advantages of the present invention will be apparent from the description below and from the claims.
本发明的问世部分是基于这样一个意外的发现：穿心莲提取物在体外可显著抑制前体炎症因子TNFα和IL-1β的表达。因此，穿心莲提取物可用于制备TNFα和/或IL-1β抑制剂。The advent of the present invention is partly based on the unexpected discovery that the extract of Andrographis paniculata can significantly inhibit the expression of pro-inflammatory factors TNFα and IL-1β in vitro. Therefore, the extract of Andrographis paniculata can be used to prepare TNFα and/or IL-1β inhibitors.
特别是，本发明的穿心莲提取物可显著缓解溃疡性结肠炎或克隆病小鼠模型的病情，因而可用于制备治疗溃疡性结肠炎或克隆病的药物。In particular, the Andrographis paniculata extract of the present invention can significantly alleviate the condition of ulcerative colitis or Crohn's disease mouse model, and thus can be used to prepare medicines for treating ulcerative colitis or Crohn's disease.
本发明的穿心莲提取物可用本领域的常规方法制得，例如可将穿心莲粗粉用乙醇热提，合并提取液，冷却、过滤，滤液浓缩至干燥制得。本发明的穿心莲提取物中优选含有穿心莲内酯2％～20％、14-去氧穿心莲内酯1％～6％、14-去氧-11，12去氢-穿心莲内酯1％～12％、新穿心莲内酯1％～5％(重量比)，更优选含有穿心莲内酯3～5％、14-去氧穿心莲内酯3～8％、14-去氧-11，12去氢-穿心莲内酯7～9％、新穿心莲内酯2～4％(重量比)，最优选含有穿心莲内酯4.2％、14-去氧穿心莲内酯4.4％、14-去氧-11，12去氢-穿心莲内酯8％、新穿心莲内酯2.1％(重量比)。The Andrographis paniculata extract of the present invention can be prepared by conventional methods in the art, for example, the Andrographis paniculata powder can be thermally extracted with ethanol, the extracts are combined, cooled, filtered, and the filtrate is concentrated to dryness. The Andrographis paniculata extract of the present invention preferably contains 2% to 20% of andrographolide, 1% to 6% of 14-deoxyandrographolide, 1% to 12% of 14-deoxy-11,12 dehydro-andrographolide , neoandrographolide 1%～5% (weight ratio), more preferably contain andrographolide 3～5%, 14-deoxyandrographolide 3～8%, 14-deoxy-11,12 dehydro-andrographolide 7-9% of lactone, 2-4% of neoandrographolide (weight ratio), most preferably containing 4.2% of andrographolide, 4.4% of 14-deoxyandrographolide, 14-deoxy-11,12 dehydro- Andrographolide 8%, neoandrographolide 2.1% (weight ratio).
所述“TNF-α抑制剂”可用于治疗下列病症，包括但不限于：脊柱关节病(spondyloarthropathies)、炎性肠病(inflammatory bowel disease)、心力衰竭(heart failure)、糖尿病(diabetes mellitus)、系统性红斑狼疮(systemic lupuserythematosus)、硬皮病(scleroderma)、结节病(sarcoidosis)、皮肌炎(polymyositis/dermatomyositis)、银屑病(psoriasis)、多发性骨髓瘤(multiplemyeloma)、骨髓增生异常综合征(myelodysplastic syndrome)、急性髓型白血病(acute myelogenous leukemia)、帕金森氏症(Parkinson′s disease)、艾滋病痴呆综合征(AIDS dementia complex)、早老性痴呆(Alzheimer′s disease)、抑郁症(depression)、白塞氏病(Behcet′s syndrome)、移植物抗宿主病(graft-versus-hostdisease)、葡萄膜炎(uveitis)、Wegener′s肉芽肿(Wegener′s granulomatosis)、休格连氏干燥症(Sjogren′s syndrome)、慢性阻塞性肺病(chronic obstructivepulmonary disease)、哮喘(asthma)、急性胰腺炎(acute pancreatitis)、牙周病(Periodontal disease)、恶病质(cachexia)、癌症(cancer)、中枢神经系统损伤(central nervous system injury)、呼吸道病毒感染(viral respiratory disease)、肥胖(obesity)等。The "TNF-α inhibitor" can be used to treat the following diseases, including but not limited to: spondyloarthropathies, inflammatory bowel disease, heart failure, diabetes mellitus, Systemic lupus erythematosus, scleroderma, sarcoidosis, polymyositis/dermatomyositis, psoriasis, multiple myeloma, myelodysplasia myelodysplastic syndrome, acute myelogenous leukemia, Parkinson's disease, AIDS dementia complex, Alzheimer's disease, depression (depression), Behcet's syndrome, graft-versus-host disease, uveitis, Wegener's granulomatosis, Sugarlian Sjogren's syndrome, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer , central nervous system injury (central nervous system injury), respiratory virus infection (viral respiratory disease), obesity (obesity), etc.
所述“IL-1β抑制剂”可用于治疗下列病症，包括但不限于：败血症(hematosepsis)、牙周病(Periodontal disease)、心力衰竭(heart failure)、皮肌炎(polymyositis/dermatomyositis)、急性胰腺炎(acute pancreatitis)、慢性阻塞性肺病(chronic obstructive pulmonary disease)、早老性痴呆(Alzheimer′sdisease)、骨性关节炎(osteoarthritis)、多发性骨髓瘤(multiple myeloma)、骨髓增生异常综合征(myelodysplastic syndrome)葡萄膜炎(uveitis)、中枢神经系统损伤(central nervous system injury)、呼吸道病毒感染(viral respiratorydisease)、哮喘(asthma)、抑郁症(depression)、硬皮病scleroderma)等。The "IL-1β inhibitor" can be used to treat the following diseases, including but not limited to: sepsis (hematosepsis), periodontal disease (Periodontal disease), heart failure (heart failure), dermatomyositis (polymyositis/dermatomyositis), acute Acute pancreatitis, chronic obstructive pulmonary disease, Alzheimer's disease, osteoarthritis, multiple myeloma, myelodysplastic syndrome ( Myelodysplastic syndrome, uveitis, central nervous system injury, viral respiratory disease, asthma, depression, scleroderma, etc.
其中“脊柱性关节病”(spondyloarthropathies)是指一组具有内在联系的多系统炎症性疾病。因此类疾病患者其血中的类风湿因子(rheumatoid factor)为阴性，所以又称为“血清阴性脊柱关节病(seronegative spondyloarthropathies)。本病可累及脊柱、外周关节、关节周围结构或三者均累及，并伴有各种特征性的关节外表现，如急慢性胃肠或泌尿生殖系统炎症(有时可为感染)、眼前部炎症、银屑病性皮肤、指甲损害等。本组疾病主要包括：强直性脊柱炎(Ankylosingspondylitis)、瑞特氏综合症(Reiter′s syndrome)、银屑病性关节炎(Psoriaticarthropathy)、炎性肠病性关节炎(Inflammatory bowel disease arthritis)、未分化型脊柱关节病(Undifferentiated spondyloarthropathy)等。Among them, "spondyloarthropathies" (spondyloarthropathies) refers to a group of multi-system inflammatory diseases with intrinsic links. Therefore, the rheumatoid factor (rheumatoid factor) in the blood of patients with such diseases is negative, so it is also called "seronegative spondyloarthropathies". The disease can involve the spine, peripheral joints, structures around the joints, or all three , accompanied by various characteristic extra-articular manifestations, such as acute and chronic gastrointestinal or genitourinary system inflammation (sometimes infection), frontal inflammation, psoriatic skin, nail damage, etc. This group of diseases mainly includes: Ankylosing spondylitis, Reiter's syndrome, Psoriatic arthritis, Inflammatory bowel disease arthritis, Undifferentiated spondyloarthropathy (Undifferentiated spondyloarthropathy) and so on.
其中“炎性肠病”(inflammatory bowel disease)是克隆病(Crohn’s disease)、和溃疡性结肠炎(ulcerative colitis)两种非特异性肠炎的统称。Among them, "inflammatory bowel disease" (inflammatory bowel disease) is a general term for two non-specific enteritis, Crohn's disease and ulcerative colitis.
其中“慢性阻塞性肺病”(chronic obstructive pulmonary disease，COPD)是指具有气流阻塞特征的慢性支气管炎和/或肺气肿(美国胸科学会(ATS)和中华医学会呼吸系统学会定义)。某些支气管哮喘，在疾病进程中发展为不可逆性气流阻塞，当支气管哮喘与慢性支气管炎和(或)肺气肿重叠存在或难以鉴别时，也可列入COPD范围。COPD的主要特征是慢性进行性气流阻塞。Among them, "chronic obstructive pulmonary disease" (chronic obstructive pulmonary disease, COPD) refers to chronic bronchitis and/or emphysema with characteristics of airflow obstruction (defined by the American Thoracic Society (ATS) and the Respiratory Society of the Chinese Medical Association). Certain bronchial asthma develops into irreversible airflow obstruction during the disease process. When bronchial asthma overlaps with chronic bronchitis and/or emphysema or is difficult to distinguish, it can also be included in the scope of COPD. The cardinal feature of COPD is chronic progressive airflow obstruction.
可以理解，本发明的穿心莲提取物可用于制备治疗上述炎性病症的药物。术语“炎性病症”是指一组存在炎症反应病理变化的病症，包括但不限于：类风湿性关节炎、幼年型类风湿关节炎、骨性关节炎、脊柱关节病、炎性肠病、心力衰竭、糖尿病、系统性红斑狼疮、硬皮病、结节病、皮肌炎、银屑病、多发性骨髓瘤、骨髓增生异常综合征、急性髓型白血病、帕金森氏症、早老性痴呆、抑郁症、艾滋病痴呆综合征、脓毒症、坏疽性脓皮病、败血症、感染性休克、白塞氏病、移植物抗宿主病、葡萄膜炎、Wegener′s肉芽肿、休格连氏干燥症、慢性阻塞性肺病、哮喘、急性胰腺炎、牙周病、恶病质、癌症、中枢神经系统损伤、呼吸道病毒感染、细菌感染或肥胖。It can be understood that the Andrographis paniculata extract of the present invention can be used to prepare medicines for treating the above-mentioned inflammatory diseases. The term "inflammatory disease" refers to a group of diseases with pathological changes of inflammatory response, including but not limited to: rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, spondyloarthropathy, inflammatory bowel disease, Heart failure, diabetes, systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis, psoriasis, multiple myeloma, myelodysplastic syndrome, acute myeloid leukemia, Parkinson's disease, Alzheimer's disease , depression, AIDS dementia syndrome, sepsis, pyoderma gangrenosum, septicemia, septic shock, Behcet's disease, graft-versus-host disease, uveitis, Wegener's granuloma, Sugarlin's Sjogren's disease, chronic obstructive pulmonary disease, asthma, acute pancreatitis, periodontal disease, cachexia, cancer, central nervous system injury, respiratory viral infection, bacterial infection, or obesity.
应该理解，所述“炎性病症”可能会在日后被证明具有其它的、未必与TNFα和IL-1β的表达密切相关的发病机理。但这并不影响本发明的穿心莲提取物在制备治疗上述病症的药物的应用。It should be understood that said "inflammatory disorder" may later be shown to have other pathogenesis, not necessarily closely related to the expression of TNFα and IL-1β. But this does not affect the application of the Andrographis paniculata extract of the present invention in the preparation of medicines for treating the above diseases.
本发明的穿心莲提取物可以单独使用或以药物组合物的形式使用。药物组合物包括作为活性成份的本发明的穿心莲提取物及可药用载体。较佳的，本发明的药物组合物含有0.1-99.9％重量百分比的作为活性成份的本发明的穿心莲提取物。“可药用载体”不会破坏本发明的穿心莲提取物的药学活性，同时其有效用量，即能够发挥药物载体作用时的用量对人体无毒。The Andrographis paniculata extract of the present invention can be used alone or in the form of a pharmaceutical composition. The pharmaceutical composition comprises the Andrographis paniculata extract of the present invention as an active ingredient and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition of the present invention contains 0.1-99.9% by weight of the Andrographis paniculata extract of the present invention as an active ingredient. The "pharmaceutically acceptable carrier" will not destroy the pharmaceutical activity of the Andrographis paniculata extract of the present invention, and its effective dosage, that is, the dosage when it can play the role of a drug carrier, is non-toxic to the human body.
“可药用载体”包括但不限于：离子交换材料、氧化铝、硬脂酸铝、卵磷脂、自乳化药物传递系统(SEDDS)如d-α-维生素E聚乙二醇1000琥珀酸酯、吐温(Tweens)或其它类似聚合介质等药物制剂用的表面活化剂、血清蛋白如人血清白蛋白、缓冲物质如磷酸盐、氨基乙酸、山梨酸、山梨酸钾、饱和植物脂肪酸部分甘油酯混合物、水、盐、电解质如硫酸盐精蛋白、磷酸氢二纳、磷酸氢钾、氯化钠、锌盐、硅胶、硅酸镁等。聚乙烯吡咯酮、纤维素物质、聚乙烯醇、羧甲基纤维素钠、聚丙稀酸酯、乙烯-聚氧乙烯-嵌段聚合物和羊毛酯、环糊精如α-、β-及γ-环糊精或其经化学修饰的衍生物如2-和3-羟丙基-β-环糊精等羟烷基环糊精或其它可溶性衍生物等均可用于促进本发明的穿心莲提取物的药物传递。"Pharmaceutically acceptable carriers" include, but are not limited to: ion exchange materials, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-alpha-tocopherol polyethylene glycol 1000 succinate, Surfactants for pharmaceutical preparations such as Tweens or other similar polymerization media, serum proteins such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid partial glycerides , water, salt, electrolytes such as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, silica gel, magnesium silicate, etc. Polyvinylpyrrolidone, cellulosic substances, polyvinyl alcohol, sodium carboxymethylcellulose, polyacrylates, ethylene-polyoxyethylene-block polymers and lanolins, cyclodextrins such as alpha-, beta- and gamma -Cyclodextrin or its chemically modified derivatives such as 2- and 3-hydroxypropyl-β-cyclodextrin and other hydroxyalkyl cyclodextrins or other soluble derivatives, etc. can be used to promote the Andrographis paniculata extract of the present invention drug delivery.
其它可药用辅料如填充剂(如无水乳糖、淀粉、乳糖珠粒和葡萄糖)、粘合剂(如微晶纤维素)、崩解剂(如交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素和交联PVP)、润滑剂(如硬酯酸镁)、吸收促进剂、香味剂、甜味剂、稀释剂、赋形剂、润湿剂、溶剂、增溶剂和着色剂等也可加入本发明的药物组合物中。Other pharmaceutically acceptable excipients such as fillers (such as anhydrous lactose, starch, lactose beads and glucose), binders (such as microcrystalline cellulose), disintegrants (such as cross-linked sodium carboxymethyl starch, cross-linked carboxymethyl starch Sodium methylcellulose, low-substituted hydroxypropylcellulose and cross-linked PVP), lubricants (such as magnesium stearate), absorption enhancers, flavoring agents, sweeteners, diluents, excipients, wetting agents , solvents, solubilizers and colorants, etc. can also be added to the pharmaceutical composition of the present invention.
上述本发明的穿心莲提取物以及药物组合物可通过肠道或者非肠道途径给药。非肠道给药制剂包括注射液、霜剂、软膏剂、贴剂、喷雾剂等。给药途径包括皮下、皮内、动脉内、静脉内、肌内、关节内、滑液内、胸骨内、鞘内、病灶内、颅内注射或输注。其给药途径包括口服、局部、直肠、经鼻、经颊、阴道、舌下、皮内、粘膜、气管、尿道。本发明的穿心莲提取物以及药物组合物还可以通过吸入气雾或植入蓄积或者针刺方式给药。The above-mentioned Andrographis paniculata extract and the pharmaceutical composition of the present invention can be administered through enteral or parenteral route. Preparations for parenteral administration include injections, creams, ointments, patches, sprays, and the like. Routes of administration include subcutaneous, intradermal, intraarterial, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, intracranial injection or infusion. The routes of administration include oral, topical, rectal, nasal, buccal, vaginal, sublingual, intradermal, mucosal, tracheal, and urethral. The Andrographis paniculata extract and the pharmaceutical composition of the present invention can also be administered through aerosol inhalation, implant accumulation or acupuncture.
本发明的穿心莲提取物以及药物组合物的口服制剂包括但不限于胶囊、片剂、乳剂、水悬浮剂、溶液、微胶囊、丸剂、锭剂、颗粒剂或粉剂。常用于片剂的可药用载体包括乳糖和玉米淀粉。通常还可加入硬脂酸镁等润滑剂。常用于胶囊剂的可药用载体包括乳糖和干玉米淀粉。当制成口服水悬浮剂和/或乳剂时，所述穿心莲提取物可悬浮或溶解于油相里并与乳化剂或悬浮剂相结合。也可以按需加入一些甜味剂和/或香味剂和/或增色剂。Oral preparations of the Andrographis paniculata extract and pharmaceutical composition of the present invention include but not limited to capsules, tablets, emulsions, aqueous suspensions, solutions, microcapsules, pills, lozenges, granules or powders. Pharmaceutically acceptable carriers commonly used in tablets include lactose and corn starch. Lubricants such as magnesium stearate are also usually added. Pharmaceutically acceptable carriers commonly used in capsules include lactose and dried cornstarch. When formulated into an oral aqueous suspension and/or emulsion, the Andrographis paniculata extract can be suspended or dissolved in an oil phase and combined with an emulsifying or suspending agent. Some sweetening and/or flavoring and/or coloring agents may also be added as desired.
本发明的穿心莲提取物以及药物组合物可被制成无菌注射剂，如无菌水相或油相的悬浮液。该悬浮液可按本领域的常规方法即使用适宜的分散剂或湿润剂(如Tween 80)及悬浮剂等制得。所述无菌注射剂还可以是在可肠道外给药的无毒稀释剂或溶剂中的溶液或悬浮液，如在1，3-丁二醇中的溶液。其可用载体或溶剂包括甘露醇、水、林格氏液、等渗氯化钠等。另外，无菌的固定油常被作为溶剂或悬浮剂的媒介，因而各种温和的固定油(bland fixed oil)如合成的甘油单酯或甘油二酯等均适用。脂肪酸，如十八烯酸及其甘油酯衍生物可用于制备所述注射剂，如橄榄油或蓖麻油及其聚氧乙烯基衍生物等。所述油溶液或悬浮液还可包含一种长链的乙醇稀释剂或分散剂或羧甲基纤维素或类似的分散剂，此类物质常用于制备可药用乳剂和/或悬浮剂。其它一些药物制剂常用的表面活性剂如Tweens或Spans和/或其它类似的乳化剂或生物利用度促进剂等均可用于制备本制剂。The Andrographis paniculata extract and the pharmaceutical composition of the present invention can be made into sterile injections, such as sterile aqueous or oily suspensions. The suspension can be prepared by using a suitable dispersant or wetting agent (such as Tween 80) and a suspending agent according to a conventional method in the art. The sterile injectable preparation may also be a solution or suspension in a non-toxic parenterally administrable diluent or solvent, such as a solution in 1,3-butanediol. Usable carriers or solvents include mannitol, water, Ringer's solution, isotonic sodium chloride, and the like. In addition, sterile fixed oils are often used as solvents or suspending agents, so various bland fixed oils such as synthetic monoglycerides or diglycerides are suitable. Fatty acids, such as octadecenoic acid and its glyceride derivatives can be used to prepare the injections, such as olive oil or castor oil and their polyoxyethylene derivatives. The oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant or carboxymethyl cellulose or similar dispersing agents which are commonly used in the preparation of pharmaceutically acceptable emulsions and/or suspensions. Other surfactants commonly used in pharmaceutical preparations such as Tweens or Spans and/or other similar emulsifiers or bioavailability accelerators can be used to prepare the preparation.
本发明的穿心莲提取物以及药物组合物可制成栓剂以直肠给药，方法是将所述穿心莲提取物与适宜的非刺激性赋形剂混合，后者在室温下为固体而在直肠温度下为液体，因而该栓剂可融解于直肠中并释放出活性成份。此类赋形剂包括但不限于：可可油、蜂蜡、聚乙二醇。本发明的穿心莲提取物以及药物组合物的局部给药制剂(如油膏)可直接应用于患处。该局部制剂含有活性成份及可药用载体，所述可药用载体包括但不限于矿物油、液体石油、白石油、丙二醇、聚氧乙烯或聚氧丙稀化合物、乳化腊和水。另外，本发明的穿心莲提取物以及药物组合物还可制成洗剂或油剂。其适用的载体包括但不限于：矿物油、山梨醇单硬脂酸酯、聚山梨醇酯60、鲸腊酯、十六烷醇、2-十八烷醇、苯甲基乙醇和水。本发明的穿心莲提取物以及药物组合物还可制成灌肠剂等进行直肠局部给药。局部透皮贴剂亦在本发明的保护范围之内。本发明的穿心莲提取物以及药物组合物亦可经鼻喷雾或者吸入给药，即按本领域的常规方法使用苯甲基乙醇或其它防腐剂、吸收促进剂、碳氟化合物和/或其它增溶剂或分散剂制得盐溶液。Andrographis paniculata extract and pharmaceutical composition of the present invention can be made into suppositories for rectal administration by mixing said Andrographis paniculata extract with suitable non-irritating excipients, which are solid at room temperature and solid at rectal temperature. Being liquid, the suppository dissolves in the rectum and releases the active ingredient. Such excipients include, but are not limited to: cocoa butter, beeswax, polyethylene glycols. The local administration preparation (such as ointment) of the Andrographis paniculata extract and the pharmaceutical composition of the present invention can be directly applied to the affected part. The topical formulation contains the active ingredient and a pharmaceutically acceptable carrier including, but not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene or polyoxypropylene compound, emulsifying wax, and water. In addition, the Andrographis paniculata extract and the pharmaceutical composition of the present invention can also be made into lotion or oil. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters, cetyl alcohol, 2-stearyl alcohol, benzyl alcohol and water. The Andrographis paniculata extract and the pharmaceutical composition of the present invention can also be made into an enema or the like for rectal local administration. Topically transdermal patches are also within the scope of the invention. Andrographis paniculata extract and pharmaceutical composition of the present invention can also be administered through nasal spray or inhalation, that is, use benzyl alcohol or other preservatives, absorption accelerators, fluorocarbons and/or other solubilizers according to conventional methods in the art Or a dispersant to prepare a salt solution.
本发明的穿心莲提取物以及药物组合物还可通过植入给药。采用植入给药方式可达到在给药对象体内持续、定时释放本发明的穿心莲提取物以及药物组合物的效果。另外，植入给药还能在局部组织和器官定位给药(Negrin et al.，Biomaterials 22(6)：563，2001)定时释放技术亦可用于本发明的穿心莲提取物以及药物组合物的给药，如基于聚合体技术的定时释药胶囊、缓释技术和制剂包裹技术(如聚合体和脂质体)等。The Andrographis paniculata extract and the pharmaceutical composition of the present invention can also be administered through implantation. The effect of sustained and timed release of the Andrographis paniculata extract and the pharmaceutical composition of the present invention can be achieved by adopting the implantation administration method. In addition, implant administration can also localize administration in local tissues and organs (Negrin et al., Biomaterials 22 (6): 563, 2001). Timed release technology can also be used for the administration of Andrographis paniculata extract and pharmaceutical composition of the present invention. Drugs, such as time-release drug capsules based on polymer technology, sustained-release technology and formulation encapsulation technology (such as polymers and liposomes), etc.
贴剂同样包括在本发明的范围之内。其包括基层(如聚合体、布、纱和绷带)和本发明的药物组合物。基层的一边可设有一保护层以防止活性成份的流出。所述贴剂还可含有一用于固定的粘合剂，后者可以是一种自然的或者合成的物质，当其与给药对象的皮肤接触时可暂时粘附于皮肤上。粘合剂可以是防水的。Patches are also included within the scope of the present invention. It includes substrates such as polymers, cloths, gauze and bandages and the pharmaceutical composition of the invention. One side of the base layer can be provided with a protective layer to prevent the outflow of active ingredients. The patch may also contain an adhesive for fixation, which may be a natural or synthetic substance that temporarily adheres to the skin of the subject when it comes into contact with it. The adhesive can be waterproof.
治疗有效量的本发明的穿心莲提取物及药物组合物介于0.001～100mg/kg/d之间。任何介于上述范围之内的用量皆为本发明的有效量，其中较低剂量介于0.001mg/kg/d和99.999mg/kg/d之间，较高剂量介于0.002mg/kg/d和100mg/kg/d之间。所述“治疗有效量”可用于相关疾病的单一用药或联合用药治疗。本领域的专业人员能够理解，在实际给药时的用量可高于或低于上述剂量范围。针对某一对象(如哺乳动物-人)的“治疗有效量”和具体治疗方案可受诸多因素的影响，包括所用化合物或其前药的药效活性、给药对象的年龄、体重、一般情况、性别、饮食、给药时间、疾病易感性、疾病进程以及收治医师的判断等。The therapeutically effective dose of the Andrographis paniculata extract and the pharmaceutical composition of the present invention is between 0.001-100 mg/kg/d. Any dosage within the above range is the effective amount of the present invention, wherein the lower dosage is between 0.001mg/kg/d and 99.999mg/kg/d, and the higher dosage is between 0.002mg/kg/d And between 100mg/kg/d. The "therapeutically effective amount" can be used for single drug or combined drug treatment of related diseases. Those skilled in the art can understand that the actual dosage can be higher or lower than the above dosage range. The "therapeutically effective amount" and the specific treatment regimen for a subject (e.g., mammal-human) may be affected by many factors, including the pharmacodynamic activity of the compound used or its prodrug, age, body weight, general condition of the subject to be administered , gender, diet, administration time, disease susceptibility, disease process, and the judgment of the treating physician, etc.
为了便于理解本发明，特列举以下实施例。其作用应被理解为是对本发明的诠释而非对本发明的任何方式的限制。上文所列的各相关文献均以全篇引入本文作为参考。In order to facilitate the understanding of the present invention, the following examples are enumerated. Its role should be understood as an explanation of the present invention rather than a limitation of the present invention in any way. All relevant documents listed above are incorporated herein by reference in their entirety.
附图说明Description of drawings
图1在正常人外周血单核细胞中穿心莲提取物剂量依赖性抑制内毒素诱导的前体炎症因子TNFα的表达；Figure 1 In normal human peripheral blood mononuclear cells, Andrographis paniculata extract dose-dependently inhibits the expression of endotoxin-induced precursor inflammatory factor TNFα;
图2在正常人外周血单核细胞中穿心莲提取物剂量依赖性抑制内毒素诱导的前体炎症因子IL1-β的表达；Figure 2 In normal human peripheral blood mononuclear cells, Andrographis paniculata extract dose-dependently inhibits the expression of endotoxin-induced precursor inflammatory factor IL1-β;
图3各给药组对TNBS诱导炎性肠病小鼠体重的影响(与模型组比较：*P＜0.05，**P＜0.01)；The effect of each administration group on the body weight of TNBS-induced inflammatory bowel disease mice in Fig. 3 (compared with the model group: * P<0.05, ** P<0.01);
图4各给药组对TNBS诱导炎性肠病小鼠结肠比重及病变的影响(与模型组比较：*P＜0.05，**P＜0.01)。Fig. 4 Effects of each administration group on colon specific gravity and lesions of TNBS-induced inflammatory bowel disease mice (compared with model group: * P<0.05, ** P<0.01).
具体实施方式Detailed ways
实施例1制备穿心莲提取物Embodiment 1 prepares andrographis paniculata extract
1000g穿心莲粗粉用85％的乙醇热提两次，每次2小时，合并提取液，冷却，过滤，滤液浓缩至干燥，得105g穿心莲提取物。经高压液相色谱法(HPLC)测定，其中含有穿心莲内酯4.2％、14-去氧穿心莲内酯4.4％、14-去氧-11，12去氢-穿心莲内酯8％、新穿心莲内酯2.1％(重量比)。1000g of Andrographis paniculata powder was extracted twice with 85% ethanol, each time for 2 hours, the extracts were combined, cooled, filtered, and the filtrate was concentrated to dryness to obtain 105g of Andrographis paniculata extract. As determined by high pressure liquid chromatography (HPLC), it contains andrographolide 4.2%, 14-deoxyandrographolide 4.4%, 14-deoxy-11,12 dehydro-andrographolide 8%, neoandrographolide 2.1% (by weight).
实施例2穿心莲提取物抑制前体炎症因子实验研究Example 2 Experimental Study on the Inhibition of Proinflammatory Factors by Andrographis paniculata Extract
实验材料：Experimental Materials:
1、细胞：正常人外周血单核细胞(PBMC)1. Cells: normal human peripheral blood mononuclear cells (PBMC)
2、受试药物：穿心莲提取物(按实施例1方法制备)2. Test drug: Andrographis paniculata extract (prepared by the method of Example 1)
3、阳性对照：地塞米松(美国Sigma公司产品)3. Positive control: dexamethasone (product of Sigma, USA)
4、试剂：Ficoll-Paque Plus(Amersham Bioscience)；内毒素(LPS，lipopolysaccharide)和地塞米松(CalBiochem.)；TNFa ELISA Kit及IL-1βELISAKit(晶美生物工程公司)；二甲基亚砜(DMSO)为美国Sigma公司产品；细胞培养基及胎牛血清Gibco公司为产品4. Reagents: Ficoll-Paque Plus (Amersham Bioscience); endotoxin (LPS, lipopolysaccharide) and dexamethasone (CalBiochem.); TNFa ELISA Kit and IL-1βELISA Kit (Jingmei Bioengineering Company); dimethyl sulfoxide (DMSO ) is the product of Sigma Company in the United States; cell culture medium and fetal bovine serum are products of Gibco Company
方法与结果：Method and Results:
新鲜血液以EDTA为抗凝剂，Ficoll分离血细胞，重悬细胞于含有10％胎牛血清的RIMP 1640培养基中。在96孔板中加入100μl密度为1×105细胞/ml新分离的细胞，每孔细胞总数为104个，每个样品作3个孔。Fresh blood was treated with EDTA as an anticoagulant, and blood cells were separated by Ficoll, and the cells were resuspended in RIMP 1640 medium containing 10% fetal bovine serum. Add 100 μl of freshly isolated cells at a density of 1×10 5 cells/ml to a 96-well plate, the total number of cells per well is 10 4 , and each sample is made into 3 wells.
1)在细胞中加入指定浓度的(终浓度分别为1、3、10、30、100ug/ml，加样量为10ul)供试药物和阳性对照(地塞米松，10uM)。置于37℃含5％CO2的培养箱中保温15分钟；1) Add specified concentrations (final concentrations are 1, 3, 10, 30, 100ug/ml, respectively, and the sample volume is 10ul) of the test drug and positive control (dexamethasone, 10uM) to the cells. Place in an incubator containing 5% CO2 at 37°C for 15 minutes;
2)加入10ul浓度为100ug/ml的LPS，置于37℃含5％CO2的培养箱中保温16小时；2) Add 10ul of LPS with a concentration of 100ug/ml, and place in an incubator containing 5% CO2 at 37°C for 16 hours;
3)与1000rpm离心15分钟，将上清转移入新的培养板中，测定TNFa及IL-1β浓度；或冻藏于-20℃，避免反复冻融。3) Centrifuge at 1000rpm for 15 minutes, transfer the supernatant to a new culture plate, and measure the concentration of TNFα and IL-1β; or freeze and store at -20°C to avoid repeated freezing and thawing.
实验结果：Experimental results:
表1.穿心莲提取物物抑制TNFα及IL1表达
表2.穿心莲提取物抑制TNFα表达呈剂量依赖关系
表3.穿心莲提取物抑制IL1表达呈剂量依赖关系
以上实验表明，在正常人外周血单核细胞中穿心莲提取物明显抑制内毒素诱导的前体炎症因子TNF-α和IL-1β的表达，穿心莲提取物对TNF-α和IL-1β的抑制呈剂量依赖关系。The above experiments show that Andrographis paniculata extract significantly inhibits the expression of endotoxin-induced pro-inflammatory factors TNF-α and IL-1β in normal human peripheral blood mononuclear cells, and the inhibition of Andrographis paniculata extract on TNF-α and IL-1β Dose dependence.
实施例3穿心莲提取物对小鼠炎性肠病模型的作用Example 3 The effect of Andrographis paniculata extract on mouse inflammatory bowel disease model
实验材料Experimental Materials
1、药物1. Drugs
(1)受试样品名称：(1) Test sample name:
穿心莲提取物(按实施例1方法制备)Andrographis paniculata extract (prepared by the method of Example 1)
莲必治注射液(LBZ)：山禾药业(SHANHE PHARMACERTICAL)；批号：030302；主要成分：亚硫酸氢钠穿心莲内酯；规格：2ml，0.1g。Lianbizhi injection (LBZ): Shanhe Pharmaceutical (SHANHE PHARMACERTICAL); batch number: 030302; main ingredient: sodium bisulfite andrographolide; specification: 2ml, 0.1g.
穿心莲内酯(AR)：常州市神马麦迪蒲植物提取有限公司(C.Z.MediproBotanical Laboratories Pty)批号：Cz3-0806CXL；规格：98％(标准品)；数量：5g。Andrographolide (AR): Changzhou Shenma Medipro Botanical Laboratories Pty Batch number: Cz3-0806CXL; specification: 98% (standard); quantity: 5g.
(2)阳性对照药：柳氮磺胺吡啶片(Sulfasalazine)，上海三维制药有限公司，200206C11，250mg/片；规格：12片×5。(2) Positive control drug: Sulfasalazine tablets (Sulfasalazine), Shanghai Sanwei Pharmaceutical Co., Ltd., 200206C11, 250 mg/tablet; specification: 12 tablets×5.
2、动物：Balb/c小鼠，雄性，18-24g，2003/09/16中科院上海动物实验中心。2. Animals: Balb/c mice, male, 18-24g, 2003/09/16 Shanghai Animal Experimental Center, Chinese Academy of Sciences.
合格证：SCXK(沪)2002-0010，每组7-8只。Certificate of Conformity: SCXK (Shanghai) 2002-0010, 7-8 per group.
3、试剂3. Reagents
TNBS(2，4，6-Trinitrobenzenesulfonic acid，Picrylsulfonic acid)：Sigma公司；批号：033K5020；规格：5％(w/v)，10ml/瓶。TNBS (2,4,6-Trinitrobenzenesulfonic acid, Picrylsulfonic acid): Sigma company; batch number: 033K5020; specification: 5% (w/v), 10ml/bottle.
4、仪器 天平(Metler，AB104-N，0.01g，0-2100g)4. Instrument balance (Metler, AB104-N, 0.01g, 0-2100g)
实验方法experimental method
1.模型制作[1]：1. Model making [1]:
5％TNBS用双蒸水稀释与50％乙醇等体积混合成1.5％TNBS。小鼠用1％戊巴比妥0.05mg/10g麻醉，麻醉后，用灌胃器由肛门轻缓插入深约3cm，生理盐水组以0.1ml/只的50％生理盐水溶液，模型组以1.5％含(150mg/kg)TNBS的50％乙醇溶液0.1ml/只缓缓推入结肠，诱导炎性肠病形成，正常对照组仅单独接受50％乙醇，每只0.1ml。5% TNBS was diluted with double distilled water and mixed with equal volume of 50% ethanol to form 1.5% TNBS. Mice were anesthetized with 0.05mg/10g of 1% pentobarbital. After anesthesia, a gastric infusion device was gently inserted from the anus to a depth of about 3cm. The normal saline group was treated with 0.1ml/mouse of 50% normal saline solution, and the model group was treated with 1.5 0.1ml of 50% ethanol solution containing (150mg/kg) TNBS was slowly pushed into the colon to induce the formation of inflammatory bowel disease. The normal control group only received 50% ethanol alone, each 0.1ml.
2.给药方式：造模前24、2小时及造模后每天给药一次，连续7天服用，末次给药一小时取材。2. Administration method: 24, 2 hours before modeling and once a day after modeling, take it for 7 consecutive days, and collect materials one hour after the last administration.
3.评价指标3. Evaluation indicators
(1)体重(1) weight
造模后，每一天测体重1次，并记录；After modeling, measure body weight once a day and record it;
(2)炎症评价(2) Inflammation evaluation
A称重：末次给药后24小时，打开腹腔，观察结肠与其它器官的粘连程度，取出每段结肠，对每段结肠称重，计算结肠与体重比率：A Weighing: 24 hours after the last administration, open the abdominal cavity, observe the degree of adhesion between the colon and other organs, take out each colon, weigh each colon, and calculate the ratio of colon to body weight:
减少百分率＝(对照组比率/正常组比率-给药组比率/正常组比率)/(对照组比率/正常组比率)×100。Percent reduction = (ratio of control group/ratio of normal group-ratio of administration group/ratio of normal group)/(ratio of control group/ratio of normal group)×100.
B组织切片B tissue section
对结肠取一部分结肠做病理切片，病理评分标准：0分 无炎症症状；1分 低水平炎症，无结构改变；2分 低水平白细胞浸润；3分 高水平白细胞浸润，高血管密度，腺窝延伸，结肠壁增厚，浅表溃疡；4分 高水平白细胞浸润超过粘膜层，腺窝延伸，杯状细胞减少，高血管密度，肠壁增厚，广泛溃疡。A part of the colon was taken for pathological sectioning, and the pathological scoring criteria were: 0 points, no inflammatory symptoms; 1 point, low-level inflammation, no structural changes; 2 points, low-level leukocyte infiltration; 3 points, high-level leukocyte infiltration, high blood vessel density, and crypt extension , colon wall thickening, superficial ulceration; 4 points High level of leukocyte infiltration beyond the mucosal layer, crypt extension, goblet cell reduction, high vascular density, intestinal wall thickening, extensive ulceration.
实验结果Experimental results
1、对小鼠体重的影响1. Effect on body weight of mice
从附图4可以看出，穿心莲提取物对炎性肠病导致的小鼠体重减轻有明显的改善作用，与模型组比较有显著性差异。It can be seen from Figure 4 that the extract of Andrographis paniculata has a significant effect on improving the weight loss of mice caused by inflammatory bowel disease, and there is a significant difference compared with the model group.
2、对小鼠结肠重量、死亡率及结肠组织病变的影响2. Effects on mouse colon weight, mortality rate and colon tissue lesions
表1：各给药组对TNBS诱导炎性肠病小鼠结肠比重及死亡率的影响
与模型组比较：*P＜0.05，**P＜0.01Compared with the model group: * P<0.05, ** P<0.01
小鼠诱导结肠炎后，模型组存活鼠结肠占体重比重明显增加，死亡率达到了50％(表1和附图5)，直肠端结肠均有明显溃疡，与周围组织重度粘连。病理组织检查表现高水平白细胞浸润超过粘膜层，腺窝延伸，杯状细胞减少，高血管密度，肠壁增厚，广泛溃疡，而穿心莲提取物500mg/kg口服可明显减轻小鼠结肠比重，减轻率达到了88％，死亡率也明显降低，肠组织无粘连现象，粘膜壁大部分光滑，未见明显病变。阳性药也可明显减轻结肠比重，减轻率达到了66％，但对死亡率无影响，有部分小鼠出现肠粘连及粘膜病变现象。After the colitis was induced in the mice, the proportion of the colon in the body weight of the surviving mice in the model group increased significantly, and the mortality rate reached 50% (Table 1 and Figure 5). The colons at the end of the rectum had obvious ulcers and were heavily adhered to the surrounding tissues. Histopathological examination showed high levels of leukocyte infiltration beyond the mucosal layer, extension of crypts, reduction of goblet cells, high blood vessel density, thickening of the intestinal wall, and extensive ulcers. Oral administration of 500 mg/kg of Andrographis paniculata extract can significantly reduce the proportion of colon in mice, relieve The rate reached 88%, and the mortality rate was also significantly reduced. There was no adhesion phenomenon in the intestinal tissue, most of the mucosal walls were smooth, and no obvious lesions were seen. The positive drug can also significantly reduce the specific gravity of the colon, with a reduction rate of 66%, but has no effect on the mortality rate, and some mice have intestinal adhesions and mucosal lesions.
本发明所涉及的多个方面已做如上阐述。然而，应理解的是，在不偏离本发明之精神与范围的前提下，对上述描述的任何修饰都是允许的。同样，类似的情况也包括在权利要求中。Various aspects involved in the present invention have been described above. It should be understood, however, that any modification of the foregoing description is permissible without departing from the spirit and scope of the invention. Likewise, similar cases are also included in the claims.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008084283A3 (en) * | 2006-07-07 | 2008-11-27 | Avestha Gengraine Tech Pvt Ltd | Andrographis paniculata plant extracts for treating osteoporosis and the extraction process thereof |
| CN1864704B (en) * | 2005-05-20 | 2010-04-21 | 英属维京群岛商贺亚药业股份有限公司 | Herbal composition for treating arthritic conditions, skin inflammatory conditions and pain |
| CN101422494B (en) * | 2007-11-02 | 2012-08-01 | 和记黄埔医药（上海）有限公司 | Creat extract and medical use thereof |
| CN103766901A (en) * | 2014-01-08 | 2014-05-07 | 浙江大学 | Application of andrographolide C to preparation of weight-losing food or medicine |
| CN104337773A (en) * | 2013-08-06 | 2015-02-11 | 天士力制药集团股份有限公司 | Application of andrographolide in the preparation of drugs for inflammatory bowel disease, andrographolide enteric-coated targeted pellets and preparation method thereof |
| CN111920802A (en) * | 2020-09-11 | 2020-11-13 | 华侨大学 | Application of andrographolide in the preparation of drugs for the prevention and treatment of adult T-cell leukemia |
| US11191798B2 (en) | 2016-11-02 | 2021-12-07 | Nutrition Science Partners Limited | Extracts of Andrographis paniculata, methods for preparation and use thereof |
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2004
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864704B (en) * | 2005-05-20 | 2010-04-21 | 英属维京群岛商贺亚药业股份有限公司 | Herbal composition for treating arthritic conditions, skin inflammatory conditions and pain |
| WO2008084283A3 (en) * | 2006-07-07 | 2008-11-27 | Avestha Gengraine Tech Pvt Ltd | Andrographis paniculata plant extracts for treating osteoporosis and the extraction process thereof |
| CN101422494B (en) * | 2007-11-02 | 2012-08-01 | 和记黄埔医药（上海）有限公司 | Creat extract and medical use thereof |
| CN104337773A (en) * | 2013-08-06 | 2015-02-11 | 天士力制药集团股份有限公司 | Application of andrographolide in the preparation of drugs for inflammatory bowel disease, andrographolide enteric-coated targeted pellets and preparation method thereof |
| CN103766901A (en) * | 2014-01-08 | 2014-05-07 | 浙江大学 | Application of andrographolide C to preparation of weight-losing food or medicine |
| US11191798B2 (en) | 2016-11-02 | 2021-12-07 | Nutrition Science Partners Limited | Extracts of Andrographis paniculata, methods for preparation and use thereof |
| CN111920802A (en) * | 2020-09-11 | 2020-11-13 | 华侨大学 | Application of andrographolide in the preparation of drugs for the prevention and treatment of adult T-cell leukemia |
| CN111920802B (en) * | 2020-09-11 | 2024-01-23 | 华侨大学 | Application of andrographolide in preparing medicament for preventing and treating adult T cell leukemia |
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