CN105902507A - 一种乙磺酸尼达尼布制剂及其应用 - Google Patents
一种乙磺酸尼达尼布制剂及其应用 Download PDFInfo
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- CN105902507A CN105902507A CN201610406068.9A CN201610406068A CN105902507A CN 105902507 A CN105902507 A CN 105902507A CN 201610406068 A CN201610406068 A CN 201610406068A CN 105902507 A CN105902507 A CN 105902507A
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- sulfonic acid
- nintedanib
- ethyl sulfonic
- acid nintedanib
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Abstract
本发明公开了一种乙磺酸尼达尼布制剂及其应用,它是由乙磺酸尼达尼布、乳糖、微晶纤维素以及药学上可以接受的载体制备而成。可以获得流动性、稳定性、溶出度较好的乙磺酸尼达尼布制剂,从而适合工业化大生产。本发明的治疗特发性肺纤维化(IPF)的药物组合,配比合理,可以快速释放药物,对所述病症能产生很好的疗效。
Description
技术领域
本发明涉及乙磺酸尼达尼布用于制备药物的用途,尤其是用于制备适于口服的片剂和胶囊剂。
乙磺酸尼达尼布(Nintedanib esylate),分子式: C31H33N5O4·C2H6O3S,分子量: 649.76
是用于治疗特发性肺纤维化(IPF)的三类新药,目前正在进行临床前研究。
背景技术
尼达尼布(Nintedanib)是勃林格殷格翰公司开发的一种口服三联血管激酶抑制剂,2014年10月经FDA批准 OFEV® (尼达尼布) 用于治疗特发性肺纤维化 (IPF),成为首个获准用于治疗IPF的 酪氨酸激酶抑制剂 (TKI) 。尼达尼布(Nintedanib)针对已被证实在肺纤维化病理机制中具有潜在影响的生长因子受体发挥作用,其中最为重要的就是血小板源性生长因子受体(PDGFR)、成纤维细胞生长因子受体(FGFR)和血管内皮生长因子受体(VEGFR)。通过阻断这些参与纤维化进程的信号转导通路,尼达尼布(Nintedanib)能够通过减少肺功能下降速度、从而减缓IPF疾病进展。特发性肺纤维化是一种病因不明,以肺部的进行性纤维化损害为特征的慢性进展性疾病,是最为常见的特发性间质性肺炎 。目前尚无预防方法或除肺移植外国际公认的有确切疗效的治疗方法。该在全球范围的患病率达到14-43例/每100000人。据此估算我国现有的特发性肺纤维化患者在60万人左右。2014年6月EMA宣布尼达尼布(Nintedanib)治疗特发性肺纤维化(IPF)的上市许可申请获得确认、并被EMA纳入加速审批名单。9月欧盟宣布尼达尼布(Nintedanib)联合多西他赛在一线化疗之后应用于组织学诊断为腺癌的、局部晚期或转移性或局部复发性非小细胞肺癌(NSCLC)成年患者的支持性意见。公司目前还在针对尼达尼布(Nintedanib)作为癌症治疗选择开展临床研发工作,包括非小细胞肺癌、卵巢癌、结直肠癌和肝细胞肝癌。
发明内容
本发明涉及含有乙磺酸尼达尼布的药物组合物及这类组合物用于安全有效治疗特发性肺纤维化(IPF)的应用。
本发明还涉及含有乙磺酸尼达尼布与其他药物活性物质的口服给药的药物组合物。该组合物是通过使药物活性物质的颗粒粘着在载体基质的表面获得的。使药物活性物质沉着在载体基质上的方法是为了使活性物质/载体基质颗粒的聚集降低到最少。
本发明涉及含有约50mg--300 mg乙磺酸尼达尼布的药物组合物,该组合物每日给药三次用于治疗特发性肺纤维化(IPF)优选的药物组合物含有约50mg--250 mg的乙磺酸尼达尼布,最优选的药物组合物含有约100mg--200 mg的乙磺酸尼达尼布。并且,这类优选的和最优选的药物组合物每日给药三次用于治疗特发性肺纤维化(IPF)。
用于每日给药的上述乙磺酸尼达尼布药物组合物还可不太经常性的对某些患者给药。例如,对通过每日服用乙磺酸尼达尼布药物组合物进行治疗而使他们的上呼吸道感染,急性支气管炎,肺炎及肺结核,肺癌,慢性支气管炎的镇咳得到控制的患者可施行维持治疗方案以使其免受进一步的感染。这种维持治疗方案包括每日不足一次的服用乙磺酸尼达尼布药物组合物。例如,每三或四天给药一次就足矣。
本发明的乙磺酸尼达尼布药物组合物可配制成经任何适当途径给药的形式,例如优选的口服给药组合可以是片剂、胶囊、颗粒或粉末形式。按照本领域熟知的方法,乙磺酸尼达尼布药物组合物还可以配制成非胃肠、直肠或经鼻腔给药的形式。这类制剂可包括可药用赋形剂,所述赋形剂包括这类组合物中常用的填充剂、助流剂、润滑剂、崩解剂、粘合剂等。本发明还包括缓释制剂。
含有约50mg—250mg乙磺酸尼达尼布的片剂和胶囊制剂可按照下述方法进行制备,以确保产品的高效力和良好的均匀性。首先将乙磺酸尼达尼布沉着到载体基质的表面上来制备组合物。该步骤通过下列操作完成:形成乙磺酸尼达尼布和粘合性物质的溶液,然后在载体基质颗粒保持运动的同时以喷雾的方式应用该溶液。控制条件以使颗粒的聚集降到最低。
干燥后将颗粒与组合物中包含的任何其他成分,例如崩解剂/助流剂/润滑剂混合。然后将得到的粉末压成片或填充到胶囊。
上述方法中的优选溶剂是水或不同浓度的乙醇。
粘合性物质优选是具有高稠度的聚合物。适合的物质包括聚维酮、甲基纤维素、羟甲基纤维素、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素,聚维酮、羟甲基纤维素是优选的。终组合物中粘合性物质的含量优选为组合物总重的约1%--约10%(重量)。
终组合物中包括的崩解剂含量优选为组合物总重的约1%--7%。适合的崩解剂包括交联聚维酮、交联羧甲基纤维素、低取代羟丙甲纤维素、淀粉乙醇酸钠、预胶化淀粉和玉米淀粉,交联聚维酮是优选的。
终组合物中包括的润滑剂含量优选为组合物总重的约1%--5%。适合的润滑剂包括微粉硅胶、硬脂酸镁、硬脂酸、硬脂基富马酸钠和月桂基硫酸钠,微粉硅胶、硬脂酸镁是优选的。
具体实施方式
下列实施例说明本发明的乙磺酸尼达尼布组合物
实施例1
采用上述方法制备50毫克乙磺酸尼达尼布胶囊
成分 | 量%(重量/重量) | 量/粒 |
乙磺酸尼达尼布 | 20.00 | 50mg |
微晶纤维素 | 37.60 | 94 mg |
乳糖 | 28.00 | 70 mg |
聚维酮 | 4.00 | 10 mg |
低取代羟丙甲纤维素 | 8.00 | 20.0mg |
硬脂酸镁 | 0.80 | 2.0mg |
二氧化硅 | 1.6 | 4.0 mg |
纯化水 | 适量 | 适量 |
总计 | 100.00 | 250.00 mg |
实施例2
采用上述方法制备100毫克乙磺酸尼达尼布胶囊
成分 | 量%(重量/重量) | 量/粒 |
乙磺酸尼达尼布 | 27.60 | 100 mg |
微晶纤维素 | 27.60 | 100 mg |
乳糖 | 41.44 | 150 mg |
聚维酮 | 8.29 | 30mg |
交联聚维酮 | 8.29 | 30mg |
二氧化硅 | 0.55 | 2.00mg |
纯化水 | 适量 | 适量 |
总计 | 100.00 | 362.00 mg |
实施例3
采用上述方法制备150毫克乙磺酸尼达尼布胶囊
成分 | 量%(重量/重量) | 量/枚 |
乙磺酸尼达尼布 | 25.50 | 150 mg |
微晶纤维素 | 25.50 | 50 mg |
乳糖 | 38.30 | 150 mg |
聚维酮 | 2.50 | 10 mg |
交联聚维酮 | 5.00 | 20 mg |
低取代羟丙甲纤维素 | 2.50 | 10 mg |
硬脂酸镁 | 0.4 | 1.5 mg |
纯化水 | 适量 | 适量 |
总计 | 100.00 | 391.50 mg |
实施例4
采用上述方法制备100毫克乙磺酸尼达尼布片
成分 | 量%(重量/重量) | 量/枚 |
乙磺酸尼达尼布 | 25.00 | 100 mg |
微晶纤维素 | 25.00 | 100 mg |
乳糖 | 37.50 | 150 mg |
聚维酮 | 2.50 | 10 mg |
低取代羟丙甲纤维素 | 5.00 | 20 mg |
硬脂酸镁 | 2.5 | 10 mg |
二氧化硅 | 2.5 | 10 mg |
纯化水 | 适量 | 适量 |
总计 | 100.00 | 401.50 mg |
实施例5
采用上述方法制备150毫克乙磺酸尼达尼布片
成分 | 量%(重量/重量) | 量/枚 |
乙磺酸尼达尼布 | 25.50 | 150 mg |
微晶纤维素 | 25.50 | 50 mg |
乳糖 | 38.30 | 150 mg |
聚维酮 | 2.50 | 10 mg |
交联聚维酮 | 5.00 | 20 mg |
低取代羟丙甲纤维素 | 2.50 | 10 mg |
硬脂酸镁 | 0.4 | 1.5 mg |
纯化水 | 适量 | 适量 |
总计 | 100.00 | 391.50 mg |
Claims (9)
1.乙磺酸尼达尼布用于制备口服给药每日3次用于治疗特发性肺纤维化(IPF),以片剂或胶囊形式的药物组合物的用途,其中所述药物组合物含有50mg—300mg的乙磺酸尼达尼布。
2.权利要求1的用途,其中所述乙磺酸尼达尼布的含量为50mg—250mg。
3.权利要求1的用途,其中所述乙磺酸尼达尼布的含量为50mg—200mg。
4.权利要求3的用途,其中所述乙磺酸尼达尼布的含量为50mg。
5.权利要求3的用途,其中所述乙磺酸尼达尼布的含量为100mg。
6.权利要求3的用途,其中所述乙磺酸尼达尼布的含量为150mg。
7.权利要求3的用途,其中所述乙磺酸尼达尼布的含量为200mg。
8.权利要求1的用途,其中的所述组合物含有一种或多种其他药物活性物质。
9.权利要求书1的用途,其中所述的填充剂选自乳糖、木糖醇、微晶纤维素、糊精、甘露醇、山梨醇、蔗糖、淀粉、预胶化淀粉、葡萄糖、磷酸钙、磷酸氢钙、碳酸钙,及其混合物,并且所述乙磺酸尼达尼布是通过具有足够黏性的聚合黏性物质黏着在所述填充剂上的。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108144069A (zh) * | 2016-12-02 | 2018-06-12 | 广东东阳光药业有限公司 | 一种尼达尼布包合物、制剂及其制备方法 |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104844499A (zh) * | 2015-06-05 | 2015-08-19 | 北京康立生医药技术开发有限公司 | 一锅法制备尼达尼布的合成方法 |
CN105001143A (zh) * | 2015-07-24 | 2015-10-28 | 南京正大天晴制药有限公司 | 一种制备高纯度乙磺酸尼达尼布的方法 |
-
2016
- 2016-06-12 CN CN201610406068.9A patent/CN105902507A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104844499A (zh) * | 2015-06-05 | 2015-08-19 | 北京康立生医药技术开发有限公司 | 一锅法制备尼达尼布的合成方法 |
CN105001143A (zh) * | 2015-07-24 | 2015-10-28 | 南京正大天晴制药有限公司 | 一种制备高纯度乙磺酸尼达尼布的方法 |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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