CN114832112A - 含有alk激酶抑制剂的药物制剂组合物及其制备方法 - Google Patents
含有alk激酶抑制剂的药物制剂组合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及含有ALK激酶抑制剂的药物制剂组合物及其制备方法,所述ALK激酶抑制剂如式(I)所示。具体涉及药物和亲水性聚合物材料的新型组合物以及制备方法。
Description
技术领域
本发明属于药物制剂领域,涉及一种含有ALK激酶抑制剂为活性成分的药物组合物及其制备方法。
背景技术
间变性淋巴瘤激酶(Anaplastic Lymphoma Kinase,ALK)是一种受体酪氨酸激酶,与血液、间质和实体三大类型肿瘤相关。ALK的异常激活的机理包括点突变导致的功能增强(gain offunction)、ALK基因重排、ALK融合基因的形成和癌性融合蛋白的生成。约3-7%非小细胞肺癌(NSCLC)患者体内肿瘤染色体EML4基因外显子与ALK基因外显子融合,形成EML4-ALK融合酪氨酸激酶,EML4-ALK融合变异体具有高度的致癌性,且ALK在多种肿瘤细胞中高表达。因此,ALK成为一个极具吸引力的癌症治疗靶点。
式(I)化合物N2-(4-(4-(二甲胺基)哌啶-1-基)-2-甲氧基苯基)-N4-(2-(异丙基磺酰基)苯基)-6,7-二氢-5H-吡咯并[2,3-d]嘧啶-2,4-二胺是新一代ALK蛋白激酶小分子抑制剂,该化合物最早公开于中国专利201710009761.7中。中国专利201710009761.7中还明确式(I)化合物或其药学上可接受的盐可用于ALK介导的疾病包括ALK阳性的非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、全身组织细胞增生症和神经母细胞瘤。
式(I)化合物疏水性强、水溶性差且热不稳定,高温会产生降解杂质。因此,克服式(I)化合物疏水性强、水溶性差且热不稳定的缺点,将其制备成质量稳定、患者顺应性好、能在临床上广泛使用的制剂是亟待解决的问题。
本发明旨在提供临床上安全、有效、质量可控的ALK激酶抑制剂式(I)化合物的组合物及其制备方法。将热降解杂质控制在可接受范围内,同时提高体外溶出以达到提高其生物利用度的目的。具体涉及药物和亲水性聚合物材料的新型组合物以及制备方法.该组合物是针对式(I)化合物的性质特点而设计,溶出度好,质量稳定,并能同时满足临床用药、患者顺应性等各项要求。
发明内容
本发明提供一种含ALK激酶抑制剂式(I)化合物的组合物及其制备方法。所述组合物含有式(I)化合物或其药学上可接受的盐和药学上可接受的赋形剂。
式(I)化合物疏水性强、水溶性差且热不稳定的缺点,是制剂开发及制备主要面临的问题。以亲水性聚合物材料做干粘合剂干法制粒可避免活性成分长时间处于湿热环境中从而减少热降解杂质的产生,同时能有效改善药物的疏水性从而提高生物利用度.以亲水性聚合物材料作为载体制备固体分散体也是提高药物溶解度从而提高体内生物利用度有效手段之一,喷雾干燥制备固体分散体,并进一步干法制粒制备成片剂、胶囊剂或颗粒剂,即可避免式(I)化合物的热降解,又可显著提高药物的溶解性从而提高生物利用度。
本发明提供一种式(I)化合物组合物及其制备方法,以亲水性聚合物材料做干粘合剂干法制粒制备片剂、胶囊剂和颗粒剂。干法制粒避免活性成分长时间处于湿热环境中从而减少热降解杂质的产生,亲水性聚合物材料有助于增加物料的可压性和成型性,同时改善式(I)化合物强疏水性,进而提高生物利用度。
本发明还提供一种式(I)化合物组合物及其制备方法,以亲水性聚合物材料做载体喷雾干燥制备固体分散体,将式(I)化合物和亲水性聚合物材料溶于合适的有机溶剂,进行喷雾干燥,将喷干粉末、填充剂、崩解剂和润滑剂进一步干法制粒制备成片剂、胶囊剂或颗粒剂。
所述亲水性聚合物材料包括:聚维酮(PVP)、共聚维酮(PVP/VA)、羟丙纤维素(HPC)及羟丙甲纤维素(HPMC)中的一种或多种.其中聚维酮(PVP)的规格包括但不限于PVP K29/32、PVP K25、PVP K 90、PVP C 15和PVP C 30中的一种或多种;共聚维酮(PVP/VA)的规格包括但不限于PVP VA64及PVP S-630;羟丙纤维素(HPC)的规格包括但不限于HPC EXF、HPCLF、HPC JF和HPC GF中的一种或多种;羟丙甲纤维素(HPMC)的规格包括但不限于HPMC HME15cP、HPMC HME 100cP及HPMC HME 4M中的一种或多种。
所述填充剂包括:微晶纤维素、硅化微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇、磷酸二氢钙等中的一种或几种混合物,优选微晶纤维素及硅化微晶纤维素。
所述崩解剂包括:交联聚维酮、羧甲淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠等中一种或几种的混合物,优选交联羧甲基纤维素钠。
所述润滑剂包括:硬脂酸镁、硬脂酸、硬脂酸钙、滑石粉、十二烷基硫酸钠、氢化植物油、聚乙二醇、硬脂富马酸钠、山嵛酸甘油酯、胶态二氧化硅等中一种或几种的混合物,优选硬脂酸镁及滑石粉。
本发明的目的是为克服式(I)化合物疏水性强、水溶性差且热不稳定的缺点,开发溶出度好,生物利用度高,质量稳定,并能同时满足临床用药、患者顺应性等各项要求组合物及制备方法。
附图说明
图1显示实施例1、2、3、4及5的样品在pH6.8磷酸盐缓冲液中的溶出曲线。
图2显示实施例1、2、3、4及5的样品在pH4.5磷酸盐缓冲液中的溶出曲线。
图3显示实施例2的样品加速条件放置0、1、2及3个月样品在pH4.5磷酸盐缓冲液中的溶出曲线。
图4显示实施例4的样品加速条件放置0、1、2及3个月样品在pH4.5磷酸盐缓冲液中的溶出曲线。
具体实施方式
以下通过实施例进一步说明本发明,但不作为对本发明的限制。
实施例1
本发明的药物组合物,优选的配方组成如下(%,w/w):
式(I)化合物的粒度为D50约10.258μm,D90约25.342μm。
制备工艺如下:
1)将式(I)化合物、微晶纤维素PH102、交联羧甲基纤维素钠及硬脂酸镁(内加)混合均匀;
2)取混合好的物料加入干法制粒机料斗进行制粒,送料频率25Hz,压片频率10Hz,制粒频率10Hz,油压40~50kg/cm2,二级筛网孔径1.2mm;
3)将制好颗粒与外加物料混合均匀,胶囊填充机进行胶囊填充。
实施例2
本发明的药物组合物,优选的配方组成如下(%,w/w):
原辅料 | 比例 |
式(I)化合物 | 40.00 |
微晶纤维素PH102 | 41.00 |
HPC EXF | 10.00 |
交联羧甲基纤维素钠 | 3.00 |
硬脂酸镁(内加) | 0.50 |
硬脂酸镁(外加) | 0.50 |
滑石粉(外加) | 5.00 |
总和 | 100.00 |
式(I)化合物的粒度为D50约12.312μm,D90约27.356μm。
制备工艺如下:
1)将式(I)化合物、微晶纤维素PH102、交联羧甲基纤维素钠、HPC EXF及硬脂酸镁(内加)混合均匀;
2)取混合好的物料加入干法制粒机料斗进行制粒,送料频率25Hz,压片频率10Hz,制粒频率10Hz,油压40~50kg/cm2,二级筛网孔径1.2mm;
3)将制好颗粒与外加物料混合均匀,胶囊填充机进行胶囊填充。
实施例3
本发明的药物组合物,优选的配方组成如下(%,w/w):
式(I)化合物的粒度为D50约20.056μm,D90约37.258μm.
制备工艺如下:
1)将式(I)化合物、微晶纤维素PH101、乳糖、PVP S-630、羧甲淀粉钠(内加)及硬脂酸镁(内加)混合均匀;
2)取混合好的物料加入干法制粒机料斗进行制粒,送料频率20Hz,压片频率12Hz,制粒频率12Hz,油压20~30kg/cm2,二级筛网孔径0.8mm;
3)将制好颗粒与外加物料混合均匀,旋转压片机压片,并进行薄膜包衣。
实施例4
本发明的药物组合物,优选的配方组成如下(%,w/w):
原辅料 | 比例 |
式(I)化合物 | 20.00 |
Povidone K-30 | 40.00 |
胶态二氧化硅 | 0.50 |
微晶纤维素PH102 | 35.5 |
交联羧甲基纤维素钠 | 3.00 |
硬脂酸镁(内加) | 0.50 |
硬脂酸镁(外加) | 0.50 |
总和 | 100.00 |
制备工艺如下:
1)将式(I)化合物和Povidone K-30完全溶于二氯甲烷中,得到固含量20%(质量比)的溶液;
2)加入胶态二氧化硅,搅拌均匀,得到混悬液;
3)采用B-290型实验室用小型喷雾干燥机将混悬液进行喷雾干燥,送液速度15ml/min,进口温度为75℃,得到式(I)化合物和Povidone K-30的固体分散体;
4)将固体分散体与所有内加辅料混合均匀进行干法制粒,送料频率15Hz,压片频率10Hz,制粒频率10Hz,油压15~25kg/cm2,二级筛网孔径1.0mm;
5)将制好颗粒与外加物料混合均匀,胶囊填充机进行胶囊填充。
实施例5
本发明的药物组合物,优选的配方组成如下(%,w/w):
原辅料 | 比例 |
式(I)化合物 | 10.00 |
Plasdone S-630 | 50.00 |
胶态二氧化硅 | 0.50 |
微晶纤维素PH101 | 33.50 |
羧甲淀粉钠(内加) | 3.00 |
硬脂酸镁(内加) | 0.50 |
羧甲淀粉钠(外加) | 2.00 |
硬脂酸镁(外加) | 0.50 |
总和 | 100.00 |
制备工艺如下:
1)将式(I)化合物和Plasdone S-630完全溶于混合溶剂(二氯甲烷∶甲醇=2∶1)中,得到固含量20%(质量比)的溶液;
2)加入胶态二氧化硅,搅拌均匀,得到混悬液;
3)采用B-290型实验室用小型喷雾干燥机将混悬液进行喷雾干燥,送液速度15ml/min,进口温度为75℃,得到式(I)化合物和Plasdone S-630的固体分散体;
4)将固体分散体与所有内加辅料混合均匀进行干法制粒,送料频率15Hz,压片频率10Hz,制粒频率10Hz,油压15~25kg/cm2,二级筛网孔径1.0mm;
5)将制好颗粒与外加物料混合均匀,旋转压片机压片,并进行薄膜包衣。
实验例1
本发明溶出曲线的测定
取上述实施例样品,采用中国药典2020年版四部通则0931,溶出度及释放度测定第二法,测定溶出曲线。溶出方法为:桨法/桨法(沉降篮),pH6.8磷酸盐缓冲液和pH4.5磷酸盐缓冲液,900ml,75rpm,37±0.5℃,取样时间10,15,30,45及60min。溶出曲线见附图1~2。在pH6.8磷酸盐缓冲液中,实施例1的样品60min溶出仅20%左右,加入亲水性聚合物材料做粘合剂的实施例2和3的样品溶出没有显著变化,但以亲水性聚合物材料为载体制备固体分散体的的实施例4和5的样品的溶出均显著增加;在pH4.5磷酸盐缓冲液中,与实施例1比较加入亲水性聚合物材料的实施例2~5的样品溶出均有增加,但是以亲水性聚合物材料为载体制备固体分散体的的实施例4和5的样品的溶出均显著更为增加。
实验例2
本发明稳定性研究
将实施例2及实施例4的样品,分别置于加速条件(40±2℃,相对湿度75±5%)放置3个月,采用中国药典2020年版四部通则0931,溶出度及释放度测定第二法,考察溶出曲线(具体溶出方法同实验例2),溶出曲线见结果见附图3~4。实验结果显示,样品在加速条件(40±2℃,相对湿度75±5%)放置3个月,溶出曲线没有明显变化。
实验例3
本发明体内生物利用度研究
实验动物分两组,分别给实施例1、实施例2和实施例4中胶囊剂,每组6只比格犬,雌雄各半,口服单次给药,给药剂量100mg/只。实验动物在实验前禁食过夜,禁食时间从给药前12小时至给药后4小时。在给药前和给药后0.25、0.5、1、2、3、4、6、8、12、24、48、72和96小时采血。样品分析使用已确证的液相色谱-串联质谱联用方法(LC-MS/MS)。个体动物的血浆浓度-时间数据用WinNonlin(专业版,版本5.2.1;Pharsight公司)软件进行分析。非房室模型被用于浓度分析。计算得到主要药代动力学参数。可以看出实施例2的样品AUC0~96h是实施例1的2.0倍,而实施例4的样品AUC0~96h是实施例1的5.2倍,显著提高生物利用度。
主要药代动力学参数 | 实施例1 | 实施例2 | 实施例4 |
T<sub>max</sub>(hr) | 8.00 | 8.00 | 15.7 |
C<sub>max</sub>(ng/mL) | 52.8 | 83.1 | 254 |
AUC<sub>0~96h</sub>(hr*ng/mL) | 1305 | 2621 | 6849 |
Claims (9)
2.根据权利要求1所述的药物制剂组合物,其含有活性成分ALK激酶抑制剂式(I)化合物或其药学上可接受的盐,并且还包含亲水性聚合物材料、填充剂、崩解剂和润滑剂中的至少一种,其活性成分质量占比10~70%。
3.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述药物制剂组合物是片剂、胶囊剂或颗粒剂中的一种。
4.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述组合物中亲水性聚合物材料为聚维酮、共聚维酮、羟丙纤维素、或者羟丙甲纤维素、或者其中几种的混合物。
5.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述组合物中亲水性聚合物材料质量占比为5~70%。
6.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述组合物中亲水性聚合物材料质量占比为10~60%。
7.根据权利要求1-2中任一项所述的药物制剂组合物,其所述制剂组合物是一种固体分散体,所述活性成分溶解或分子分散在亲水性聚合物材料中。
8.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述式(I)化合物或其药学上可接受的盐的粒径分布为D50小于30μm,D90小于100μm。
9.根据权利要求1-2中任一项所述的药物制剂组合物,其中所述式(I)化合物或其药学上可接受的盐的粒径分布为D50小于20μm,D90小于50μm。
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