CN1334742A - 促生长素抑制素类似物兰瑞肽的应用方法 - Google Patents
促生长素抑制素类似物兰瑞肽的应用方法 Download PDFInfo
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- CN1334742A CN1334742A CN99808953A CN99808953A CN1334742A CN 1334742 A CN1334742 A CN 1334742A CN 99808953 A CN99808953 A CN 99808953A CN 99808953 A CN99808953 A CN 99808953A CN 1334742 A CN1334742 A CN 1334742A
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Abstract
本发明涉及治疗一种或多种下述疾病和/或病症的方法,其包括给需要治疗的病人施用化合物H－g(b)－D－Nal－Cys－Tyr－D－Trp－Lys－Val－Cys－Thr－NH2、或其药物上可接受的盐,更优选是该化合物的醋酸盐,式中半胱氨酸由二硫键连接。所述的某些疾病和/或病症如肠胃疾病和/或病症、内分泌疾病和/或病症、与癌症如癌性恶病质有关的各种类型的癌症和病症;及低血压和焦虑发作。
Description
发明背景
本发明涉及治疗一种或多种下述疾病和/或病症的方法，其包括给需要治疗的病人施用结构式为H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2[也被称做兰瑞肽(lanretide)]的化合物、或其药物上可接受的盐，更优选是该化合物的醋酸盐，其中两个半胱氨酸由二硫键连接。所述的某些疾病和/或病症为例如肠胃疾病和/或症状如节段性回肠炎、系统硬化症、胰腺外和胰腺内的假性囊肿和腹水、血管活性肠多肽肿瘤(VIPoma)、胰岛细胞增殖症(nesidoblastosis)、胰岛素分泌过多、胃泌素瘤、佐林格—埃利森综合症、腹泻、爱滋病相关性腹泻、化疗相关性腹泻、硬皮病、过敏性肠综合症、胰腺炎、上胃肠出血、特别是肝硬化病人的餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、肠胃食管回流、十二指肠胃回流；和治疗的内分泌疾病和/或病症，例如库兴氏综合症、促性腺激素瘤、甲状旁腺机能亢进、格雷夫斯病、糖尿病性神经病、黄斑变性、恶性血钙过多症、佩吉特病和多囊性卵巢疾病；和各种类型的癌症、例如甲状腺癌、白血病、脑膜瘤和与癌症有关的如癌性恶病质的病症；低血压如直立性低血压和餐后低血压；以及焦虑发作。
兰瑞肽是一种促生长素抑制素类似物，并且众所周知其能抑制生长激素的释放，并且能抑制胰岛素、胰高血糖素和胰腺外分泌物的分泌。
美国专利号4,853,371公开了兰瑞肽、制备兰瑞肽的方法和使用其来抑制生长激素的分泌、抑制胰岛素、胰高血糖素和胰腺外分泌物的分泌的方法。
美国专利号5,147,856公开了兰瑞肽治疗再狭窄的用途。
美国专利号5,411,943公开了兰瑞肽治疗肝细胞瘤的用途。
美国专利号5,073,541公开了兰瑞肽治疗肺癌的用途。
1993年7月9日申请的美国申请号08/089,410公开了兰瑞肽治疗黑素瘤的用途。
美国专利号5,504,069公开了兰瑞肽抑制固体瘤快速生长的用途。
1997年5月13日申请的美国申请号08/854,941公开了兰瑞肽减轻体重的用途。
1997年5月13日申请的美国申请号08/854,943公开了兰瑞肽治疗胰岛素抗性和X综合症的用途。
美国专利号5,688,418公开了兰瑞肽延长胰腺细胞存活的用途。
PCT申请号PCT/US97/14154公开了兰瑞肽治疗纤维症的用途。
1997年5月13日申请的美国申请号08/855,311公开了兰瑞肽治疗血脂过高的用途。
1995年5月12日申请的美国申请号08/440,061公开了兰瑞肽治疗淀粉粒纤维素膜过高症的用途。
1997年5月7日申请的美国申请号08/852,221公开了兰瑞肽治疗催乳激素过高症和催乳激素瘤的用途。
上述专利和申请的内容在此被引作参考。
发明概述
本发明涉及治疗下述疾病或病症的方法，其包括给需要治疗的病人施用有效量的化合物H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2、或其药物上可接受的盐，式中两个半胱氨酸由二硫键连接。其中所述的疾病或病症选自系统硬化症、胰腺假性囊肿、胰腺腹水、血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、佐林格—埃利森综合症、分泌过多性腹泻、硬皮病、过敏性肠综合症、上胃肠出血、餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、十二指肠胃回流、库兴氏综合症、促性腺激素瘤、甲状旁腺机能亢进、糖尿病性神经病、黄斑变性、恶性血钙过多症、佩吉特病、脑膜瘤、癌性恶病质、银屑病、低血压以及焦虑发作。
紧接上述方法的优选方法是，其中所述的疾病或病症选自血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、分泌过多性腹泻、过敏性肠综合症、上胃肠出血、特别是肝硬化病人的餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、糖尿病性神经病、脑膜瘤和癌性恶病质。
紧接上述方法的优选方法是，其中所述的疾病或病症选自血管活性肠多肽肿瘤、胰岛细胞增殖症、分泌过多性腹泻、过敏性肠综合症、小肠梗阻和糖尿病性神经病。
另一方面，本发明涉及一种药物组合物，其包括药物上可接受的载体和用于治疗下述疾病或病症的有效量的H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2的醋酸盐，其中所述的疾病或病症选自系统硬化症、胰腺假性囊肿、胰腺腹水、血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、佐林格—埃利森综合症、分泌过多性腹泻、硬皮病、过敏性肠综合症、上胃肠出血、特别是肝硬化病人的餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、十二指肠胃回流、库兴氏综合症、促性腺激素瘤、甲状旁腺机能亢进、糖尿病性神经病、黄斑变性、恶性血钙过多、佩吉特病、脑膜瘤、癌性恶病质、银屑病、低血压以及焦虑发作。
详细描述
兰瑞肽根据被引作参考的美国专利号4,853,371公开的方法或美国专利号5,411,843公开的方法很容易制备，兰瑞肽目前以30mg长效形式的醋酸盐商品化，并可从法国巴黎的Ipsen Biotech得到。
正如本领域技术人员众所周知的，促生长素抑制素公知和潜在的用途是变化和多样的。公知促生长素抑制素被用于治疗下述的疾病和/或病症。促生长素抑制素的不同用途可综合如下：库兴氏综合症(参见Clark，R.V.等，Clin.Res.38，p.943A，1990)；促性腺激素瘤[参见Ambrosi B.等，Acta Endocr.(Copenh.)122，569-576，1990]；甲状旁腺机能亢进(参见Miller，D.等，Canad.Med.Ass.J.，Vol.145，pp.227-228，1991)；佩吉特病(参见Palmieri，G.M.A.等，J.of Bone and MineralResearch，7，(Suppl.1)，p.S240(Abs.591)，1992)；血管活性肠多肽肿瘤(参见Koberstein，B.等，Z.Gastroenterology，28，295-301，1990和Christensen，C.，Acta Chir.Scand.155，541-543，1989)；胰岛细胞增殖症和胰岛素分泌过多(参见Laron，Z.，lsrael J.Med.Sci.，26，No.1，1-2，1990，Wilson，D.C.，Irish J.Med.Sci.，158，No.1，31-32，1989和Micic，D.等，Digestion，16，Suppl.1.70.Abs.193，1990)；胃泌素瘤(参见Bauer，F.E.等，Europ.J.Pharmacol.，183，551990)；佐林格—埃利森综合症(参见Mozell，E.等，Surg.Gynec.Obstet.，170，476-484，1990)；与爱滋病和其他病症有关的分泌过多性腹泻(与爱滋病引起的，参见Cello，J.P.等，Gastroenterology，98，No.5，Part 2，Suppl.，A163 1990；与升高的胃泌素释放肽引起的，参见Alhindawi，R.等，Can.J.Surg.，33，139-142，1990；由寄生疾病的肠移植继发的，参见Bianco J.A.等，Transplanation，49，1194-1195，1990；与化疗相关的腹泻，参见Petrelli，N.等，Proc.Amer.Soc.Clin.Oncol.，Vol.10，P 138，Abstr.No.417 1991)；过敏性肠综合症(参见O’Donnell，L.J.D.等，Aliment，Pharmacol.Therap.，Vol.4.，177-181，1990)；胰腺炎(参见Tulassay，Z.等，Gastroenterology，98，No.5，Part 2，Suppl.，A238，1990)；节段性回肠炎(参见Fedorak，R.N.等，Can.J.Gastroenterology，3，No 2，53-57，1989)；系统硬化病(参见Soudah，H.等，Gastroenterology，98，No.5，Part 2，Suppl.，A129，1990)；甲状腺癌(参见Modigliani，E.等，Ann.，Endocr.(巴黎)，50，483-488，1989)；银屑病(参见Camisa，C.等，Cleveland Clinic J.Med.，57，No.1，71-76，1990)；低血压(参见Hoeldtke，R.D.等，Arch.Phys.Med.Rehabil.，69，895-898，1988和Kooner，J.S.等，Brit.J.Clin.Pharmacol.，28，735P-736P，1989)；焦虑发作(参见Abelson J.L.等，Clin.Psychopharmacol.，10，128-132，1990)；硬皮病(参见Soudah，H.等，Clin Res.，Vol.39，p.303A，1991)；小肠梗阻(参见Nott，D.M.等，Brit.J.Srug.，Vol.77，p.A691，1990)；胃食管回流(参见Branch，M.S.等，Gastroenterology，Vol.100，No.5，Part 2 Suppl.，A425，1991)；十二指肠胃回流(参见Hasler，W.等，Gastroenterology，Vol.100，No.5，Part 2，Suppl.，p.A448，1991)；格雷夫斯病(参见Chang，T.C.等，Brit.Med.J.，304，P.158，1992)；多囊性卵巢疾病(参见Prelevic，G.M.等，Metabolism Clinical and Experimental，41，Suppl.2，pp 76-79，1992)；上胃肠出血(参见Jenkins，S.A.等，Gut.，33，pp.404-407，1992和Arrigoni，A.等，American Journal ofGastroenterology，87，p.1311，(abs.275)，1992)；胰腺假性囊肿和腹水(参见Hartley，J.E.等，J.Roy.Soc，Med.，85，pp.107-108，1992)；白血病(参见Santini等，78，(Suppl.1)，p.429A(Abs.1708).1991)；脑膜病(参见Koper，J.W.等，J.Clin.Endocr.Metab.，74，pp.543-547，1992)；和癌性恶病质(参见Bartlett，D.L.等，Surg.Forum.，42，pp.14-16，1991)。以上的内容在此被引作参考。
令人吃惊的是，申请人目前已发现特别是兰瑞肽自身可用于治疗上述的病症、紊乱和疾病。
可通过与上胃肠出血治疗有关的试验结果来对公开的兰瑞肽的各种不同的新医疗用途进行更好地理解。
兰瑞肽或其药物上可接受的盐可通过口服、肠胃外(例如肌肉、腹腔、静脉或皮下注射或植入)、鼻腔、阴道、直肠、舌下或局部给药的途径给药，兰瑞肽或其药物上可接受的盐也可与药物上可接受的载体制成适合每一给药途径的剂型。
用于口服给药的固体剂型包括胶囊、片剂、药丸、粉剂和颗粒。在这些类体剂型中，活性物质是与至少一种药物上可接受的载体例如蔗糖、乳糖或淀粉混合。通常，这些剂型还包含除非惰性稀释剂外的其他物质，如硬脂酸镁的润滑剂。在胶囊、片剂和药丸的情况下，所述剂型还可包含缓冲剂。此外，在制备片剂和药丸时可用肠衣包覆。
用于口服给药的液体剂型包括药物上可接受的乳液、溶液、悬浮液、糖浆、驰剂，其含有本领域通常使用的惰性稀释剂例如水。除这些惰性稀释剂外，组合物还可包含辅剂，例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
根据本发明制备的肠胃外给药的制剂包括消毒的水溶液或非水溶液、悬浮液或乳液。非水溶剂或介质的例子是丙二醇、聚乙二醇，植物油、例如橄榄油和玉米油、明胶和诸如油酸乙酯的可注射的有机酯。这些剂型也可包含诸如防腐剂、润湿剂、乳化剂和分散剂的辅剂。它们可通过例如细菌保持过滤的过滤法来消毒、通过在组合物中加入消毒剂、通过照射组合物、或通过加热组合物的方法来消毒。它们还可被制备成消毒固体组合物的形式，在使用前可将这些消毒固体组合物迅速溶解在消毒水或某些其它消毒注射介质中。
用于直肠或阴道给药的组合物优选为栓剂，除活性物质外，其可包括诸如可可脂或栓剂蜡的赋形剂。
用于鼻腔或舌下给药的组合物也可与本领域熟知的标准赋形剂一起来制备。
在本发明的组合物中的活性成分的剂量是可变的，然而，活性成分的量必须使得其能得到合适的剂型。剂型的选择是根据所希望的治疗效果、给药途径、和治疗持续时间来决定的。通常，给药剂量为25mg/kg体重/天-100mg/kg体重/天，其可一次或分多次给人或其他动物例如哺乳动物施用以达到所希望的治疗效果。
通常的优选给药剂量为25mg/kg体重/天-5.0mg/kg体重/天，其可一次或分多次施用。
此外，可如以下述专利所述以持续释放组合物的形式施用兰瑞肽。在这些配方中以14天或28天缓慢释放的配方为优选。美国专利号5,672,659指出了包括兰瑞肽和聚酯的持续释放组合物，美国专利号5,595,760指出了包含以凝胶形式的兰瑞肽的持续释放组合物，1997年9月9日申请的美国申请号08/929,363指出了包含兰瑞肽和几丁质的聚合型的持续释放组合物，1996年11月1日申请的美国申请号08/740,778指出了包含兰瑞肽和环糊精的持续释放组合物，1998年1月29日申请的美国申请号09/015,394指出了兰瑞肽的可吸收持续释放组合物。上述专利和申请的内容在此被引作参考。
是使用立刻释放还是持续释放组合物是根据准备治疗的目标适应症的类型而定，如果适应症为急性或过急性疾病，优选在使用延长释放组合物的同时使用立刻释放类型组合物。相反，对预防性或长期治疗来说，通常优选使用延长释放组合物。
典型地是，对急性或过急性的上胃肠出血适应症在大约5天期间的治疗剂量为80-120mg/天。经过内窥镜检查治疗后，可将持续释放形式的兰瑞肽用于防止复发的预防性治疗，其是作为平常治疗的辅助治疗。对这种形式的治疗，可使用总剂量大约为30mg兰瑞肽的14天持续释放型组合物，或可使用28天兰瑞肽型组合物。
对于与上胃肠出血比较的其他适应症而言，这些适应症适合于可长时间的治疗，即适于使用总剂量大约为30mg兰瑞肽的14天持续释放型组合物或28天兰瑞肽型组合物。
Claims (5)
1、一种治疗下述疾病或病症的方法，其包括给需要治疗的病人施用有效量的化合物H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2、或其药物上可接受的盐，式中两个半胱氨酸由二硫键连接，其中所述疾病或病症选自系统硬化症、胰腺假性囊肿、胰腺腹水、血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、佐林格—埃利森综合症、分泌过多性腹泻、硬皮病、过敏性肠综合症、上胃肠出血、餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、十二指肠胃回流、库兴氏综合症、促性腺激素瘤、甲状旁腺机能亢进、糖尿病性神经病、黄斑变性、恶性血钙过多、佩吉特病、脑膜瘤、癌性恶病质、银屑病、低血压和焦虑发作。
2、根据权利要求1的方法，其中施用H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2的醋酸盐。
3、根据权利要求2的方法，其中所述疾病或病症选自血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、分泌过多性腹泻、过敏性肠综合症、上胃肠出血、特别是肝硬化病人的餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、糖尿病性神经病、脑膜瘤和癌性恶病质。
4、根据权利要求3的方法，其中所述疾病或病症选自血管活性肠多肽肿瘤、胰岛细胞增殖症、分泌过多性腹泻、过敏性肠综合症、小肠梗阻和糖尿病性神经病。
5、一种用于治疗下述疾病或病症的药物组合物，其包括药物上可接受的载体和有效量1的H-β-D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2的醋酸盐，其中所述疾病或病症选自系统硬化症、胰腺假性囊肿、胰腺腹水、血管活性肠多肽肿瘤、胰岛细胞增殖症、胰岛素分泌过多、胃泌素瘤、佐林格—埃利森综合症、分泌过多性腹泻、硬皮病、过敏性肠综合症、上胃肠出血、特别是肝硬化病人的餐后门静脉高血压、门静脉高血压并发症、小肠梗阻、十二指肠胃回流、库兴氏综合症、促性腺激素瘤、甲状旁腺机能亢进、糖尿病性神经病、黄斑变性、恶性血钙过多、佩吉特病、脑膜瘤、癌性恶病质、银屑病、低血压和焦虑发作。
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101935252A (zh) * | 2010-07-29 | 2011-01-05 | 广东省农业科学院科技情报研究所 | 一种园林植物生长延缓剂及其制备方法 |
| CN104321074A (zh) * | 2012-04-12 | 2015-01-28 | 诺华股份有限公司 | 生长抑素类似物与11β-羟化酶抑制剂的组合 |
| CN105168115A (zh) * | 2015-09-02 | 2015-12-23 | 中国药科大学 | 生长抑素类似物多肽药物的口服给药途径 |
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| EP1040837A3 (en) * | 1999-02-26 | 2002-01-02 | Erasmus Universiteit Rotterdam | Medicaments for the treatment of a choroidal neovascularization (CNV) related disorder |
| AU2001283957A1 (en) * | 2000-07-27 | 2002-02-13 | Novartis Ag | Treatment of ocular disorders with somatostatin analogues |
| US6316414B1 (en) | 2000-07-31 | 2001-11-13 | Dabur Research Foundation | Somatostatin analogs for the treatment of cancer |
| ATE430162T1 (de) | 2001-03-06 | 2009-05-15 | Il Consorzio Ferrara Richerche | Verfahren zur modulation der proliferation von schilddrüsenkrebszellen |
| GB0109461D0 (en) * | 2001-04-18 | 2001-06-06 | Univ London | New Gene |
| AU2003216084A1 (en) | 2002-01-22 | 2003-09-02 | New York University | Methods for therapeutic treatment of benign prostatic hypertrophy (bph) |
| US20110171191A1 (en) | 2008-06-12 | 2011-07-14 | Syntaxin Limited | Suppression of neuroendocrine diseases |
| US10240138B2 (en) | 2008-06-12 | 2019-03-26 | Ipsen Bioinnovation Limited | Polypeptides that bind to and inhibit secretion from growth hormone secreting cells |
| GB0820970D0 (en) | 2008-11-17 | 2008-12-24 | Syntaxin Ltd | Suppression of cancer |
| WO2017212390A1 (en) * | 2016-06-06 | 2017-12-14 | Emcure Pharmaceuticals Ltd, | Process for lanreotide acetate preparation |
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| US4853371A (en) * | 1986-06-17 | 1989-08-01 | The Administrators Of The Tulane Educational Fund | Therapeutic somatostatin analogs |
| US5538739A (en) * | 1989-07-07 | 1996-07-23 | Sandoz Ltd. | Sustained release formulations of water soluble peptides |
| CA2046594A1 (en) * | 1989-12-08 | 1991-06-09 | David H. Coy | Octapeptide analogs of somatostatin having threonine at the sixth position |
| WO1998008528A1 (en) * | 1996-08-30 | 1998-03-05 | Biomeasure Incorporated | Method of inhibiting fibrosis with a somatostatin agonist |
| AU4133997A (en) * | 1996-09-12 | 1998-04-02 | Yarom Cohen | Pharmaceutical composition for the treatment of syndrome x of reaven |
| ES2216290T3 (es) * | 1997-05-13 | 2004-10-16 | Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. | Somatostatina y agonistas de la somatostatina para el tratamiento de insensibilidad a la insulina y de sindrome x. |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101935252A (zh) * | 2010-07-29 | 2011-01-05 | 广东省农业科学院科技情报研究所 | 一种园林植物生长延缓剂及其制备方法 |
| CN101935252B (zh) * | 2010-07-29 | 2013-01-30 | 广东省农业科学院科技情报研究所 | 一种园林植物生长延缓剂及其制备方法 |
| CN104321074A (zh) * | 2012-04-12 | 2015-01-28 | 诺华股份有限公司 | 生长抑素类似物与11β-羟化酶抑制剂的组合 |
| CN104321074B (zh) * | 2012-04-12 | 2017-09-08 | 诺华股份有限公司 | 生长抑素类似物与11β‑羟化酶抑制剂的组合 |
| CN105168115A (zh) * | 2015-09-02 | 2015-12-23 | 中国药科大学 | 生长抑素类似物多肽药物的口服给药途径 |
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| JP2002521456A (ja) | 2002-07-16 |
| HUP0102839A2 (hu) | 2002-01-28 |
| AR023633A1 (es) | 2002-09-04 |
| NO20010481D0 (no) | 2001-01-29 |
| CA2335654A1 (en) | 2000-02-10 |
| AU770193B2 (en) | 2004-02-12 |
| IL181349A0 (en) | 2007-07-04 |
| AU5244799A (en) | 2000-02-21 |
| MXPA01000969A (es) | 2003-04-07 |
| AU2004201783A1 (en) | 2004-05-27 |
| WO2000006185A3 (en) | 2000-08-03 |
| PL346361A1 (en) | 2002-02-11 |
| KR20010071071A (ko) | 2001-07-28 |
| HUP0102839A3 (en) | 2002-02-28 |
| CZ2001157A3 (cs) | 2002-02-13 |
| WO2000006185A2 (en) | 2000-02-10 |
| IL140837A0 (en) | 2002-02-10 |
| NO20010481L (no) | 2001-03-21 |
| BR9912609A (pt) | 2001-05-02 |
| EP1100532A2 (en) | 2001-05-23 |
| NO324123B1 (no) | 2007-08-27 |
| NZ509348A (en) | 2004-02-27 |
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