CN112438954B - 一种奥拉帕利释放相关的药物组合物 - Google Patents
一种奥拉帕利释放相关的药物组合物 Download PDFInfo
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- CN112438954B CN112438954B CN202011365949.3A CN202011365949A CN112438954B CN 112438954 B CN112438954 B CN 112438954B CN 202011365949 A CN202011365949 A CN 202011365949A CN 112438954 B CN112438954 B CN 112438954B
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Abstract
本发明涉及药物组合物,涉及与奥拉帕利释放相关的组合物,本发明公开了含有较低水平杂质和较高释放度的奥拉帕利的组合物,和维持此类药物组合物稳定性的方法。
Description
技术领域
本发明属于药物领域,特别涉及一种奥拉帕利释放相关的药物组合物。
背景技术
奥拉帕利是一种首创、口服多聚ADP核糖聚合酶(PARP)抑制剂,可利用肿瘤DNA损伤修复(DDR)通路的缺陷优先杀死癌细胞,这种作用模式赋予了奥拉帕利治疗存在DNA损伤修复缺陷的广泛类型肿瘤的潜力,其结构式如下:
奥拉帕利是全球上市的首个PARP抑制剂,于2014年12月首次获美国FDA批准。阿斯利康与默沙东于2017年7月达成肿瘤学全球战略合作,共同开发和商业化奥拉帕利及另一种MEK抑制剂selumetinib治疗多种类型肿瘤。在PARP抑制剂范畴,奥拉帕利拥有最广泛和最先进的临床试验开发项目。在中国市场,奥拉帕利(利普卓)于2018年8月获批,用于铂敏感复发性卵巢癌的维持治疗。奥拉帕利是中国市场首个获批治疗卵巢癌的靶向药物,标志着中国卵巢癌治疗进入PARP抑制剂时代。
目前申请上市的奥拉帕利制剂为普通片剂。但奥拉帕利属于大剂量、极难溶性药物,采用传统的片剂生产工艺制备出的奥拉帕利片的溶出度达不到较为理想的数值,且奥拉帕利已报道的杂质很多,大多通过酰胺键断裂和苄位氧化降解,一些杂质来自于用于制造奥拉帕利的过程,而另一些则是由于活性成分的逐步降解。为提高药物的溶出度,研究者已经采取了很多方法,制备工艺为将纯的奥拉帕利晶体与聚维酮多聚物混合,然后经过240度的高温处理,奥拉帕利会气化并与多聚物形成气固分散体系,均匀分布于分散介质(聚维酮多聚物)中。通过这种方式,使奥拉帕利的溶解度增加了10倍,高温处理后的熔出物中均匀地含有奥拉帕利,将熔出物冷却研磨成粉、压片及包衣。但目前奥拉帕利片剂服用量仍然较大,推荐剂量为300mg(2片150mg片剂),每日2次,相当于每日总剂量为600mg,且片剂片重较大,患者顺应性较差。
本发明的目的是为解决现有技术中奥拉帕利普通片剂易出现溶出慢、杂质水平高的问题,本发明提出了一种奥拉帕利片剂及其制备方法。
发明内容
本发明公开了一种奥拉帕利释放相关的药物组合物:
第一方面其包含作为活性成分的奥拉帕利或其任何药用盐,奥拉帕利为1份计,增溶剂为0.1-10份,填充剂0.1-3份、崩解剂0.05-0.8份、抗黏剂0.01-0.1份、助流剂0.01-1份。
第二方面当所述组合物保存在有效温度下时,所述组合物的有关物质的水平等于或低于0.1%。
本发明公开了一种药物组合物的制备方法:取1重量份数的奥拉帕利,后加入0.1-10重量份数的增溶剂,搅拌使之混合均匀,熔融加热得到混悬液,将混悬液减压干燥或喷雾干燥制备成干燥的奥拉帕利固体分散体,将该奥拉帕利固体分散体与崩解剂、填充剂、抗黏剂、助流剂混合压片得到奥拉帕利片剂。
本发明涉及一种奥拉帕利的组合物,其组成为:奥拉帕利、聚乙二醇(6000)、十二烷基硫酸钠、甘露醇、滑石粉、交联聚维酮、微粉硅胶。
本发明涉及一种奥拉帕利的组合物,其组成为:奥拉帕利、β环糊精、十二烷基硫酸钠、甘露醇、滑石粉、交联聚维酮、微粉硅胶。
本发明涉及一种奥拉帕利的组合物,其组成为:奥拉帕利、β环糊精、辅酶Q10、十二烷基硫酸钠、甘露醇、滑石粉、交联聚维酮、微粉硅胶。
所述有关物质的量为等于或低于0.08%。
所述有关物质OP-B、有关物质OP-K、有关物质OP-01的量为等于或低于0.05%。
其中任一项的组合物用于制造肿瘤DNA损伤修复药物的用途。
其中任一项的组合物中杂质的控制方法,其包括:将增溶剂加热到70℃至82℃之间;将奥拉帕利加入到加热的增溶剂中并将混合物加热到78℃;均质化混悬液;有关物质的量等于或低于0.1%:
其中所述的增溶剂为高分子聚合物、阴离子表面活性剂。
其中所述高分子聚合物选自聚乙二醇、聚乙烯醇、聚乙烯醇衍生物、聚乙烯与聚乙烯衍生物中的一种或多种,所述阴离子表面活性剂选自烷基硫酸盐和/或烷基磺酸盐。
所述崩解剂为羧甲淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠和交联聚维酮中的任意一种或多种;
所述填充剂为微晶纤维素、甘露醇、乳糖、糊精、滑石粉、二氧化硅、硫酸钙和磷酸氢钙中的任意一种或多种;
所述助流剂为滑石粉、硬脂酸镁、微粉硅胶中的任意一种或多种;
所述抗黏剂为滑石粉、硬脂酸镁、微粉硅胶中的任意一种或多种。
本发明描述了许多杂质,由氯维地平通过水解、脱羧作用和缩合反应产生。
奥拉帕利的有关物质
取奥拉帕利组合物产品12.5mg,置50ml量瓶中,加乙腈10ml超声使溶解,用水稀释至刻度,摇匀,精密量取2ml,置10ml量瓶中,用乙腈稀释至刻度,摇匀,取溶液10ml,滤过,弃去初滤液5ml,取续滤液作为供试品溶液;
奥拉帕利组合物产品涉及实施例1-5的产品。
取奥拉帕利对照品12.5mg,置50ml量瓶中,加乙腈10ml超声使溶解,用水稀释至刻度,摇匀,精密量取2ml,置10ml量瓶中,用乙腈稀释至刻度,摇匀,作为对照品溶液;
高效液相色谱法测定,用十八烷基硅烷键合硅胶为填充剂;以0.01mol/L磷酸二氢铵水溶液(用磷酸调节pH值至3.0)-乙腈(70:30)为流动相,等度洗脱;流速为每分钟1.0ml;检测波长为235nm;柱温为30℃;精密量取上述供试品溶液和对照品溶液各20μl,分别注入液相色谱仪,记录色谱图。
实施例1的奥拉帕利组合物杂质检测峰汇总结果(检测器A 220nm)
溶出方法检测实施例
溶出曲线测定法,以水1000ml为溶出介质,转速为每分钟50转,依法操作,经10分钟、20分钟、30分钟、45分钟和60分钟时,取溶液10ml,滤过,弃去初滤液5ml,取续滤液作为供试品溶液;另取奥拉帕利对照品约12.5mg,精密称定,置50ml量瓶中,加乙腈10ml超声使溶解,用溶出介质稀释至刻度,摇匀,精密量取2ml,置10ml量瓶中,用溶出介质稀释至刻度,摇匀,作为对照品溶液。
照高效液相色谱法(附录ⅤD)测定,用十八烷基硅烷键合硅胶为填充剂(推荐色谱柱:Ultimate XB-C18 150×4.6mm,3μm);以0.01mol/L磷酸二氢铵水溶液(用磷酸调节pH值至3.0)-乙腈(70:30)为流动相,等度洗脱;流速为每分钟1.0ml;检测波长为235nm;柱温为30℃。精密量取上述供试品溶液和对照品溶液各20μl,分别注入液相色谱仪,记录色谱图。
有关物质检测实施例
有关物质测定法,供试品溶液的配制:取本品,精密称取适量(约相当于奥拉帕利12.5mg),置25ml量瓶中,加溶剂[乙腈-水(80:20)]适量,超声10分钟使奥拉帕利溶解,用溶剂稀释至刻度,摇匀,滤过,取续滤液作为供试品溶液;取供试品溶液0.5ml,置100ml量瓶中,加溶剂稀释至刻度,摇匀,作为对照溶液。
另分别取OP-A、OP-B、OP-C、OP-D、OP-E对照品各适量,精密称定,加溶剂溶解并稀释制成每1ml中约含杂质0.5mg的各杂质贮备液,再精密量取各杂质贮备液适量,加溶剂稀释制成每1ml中约含各杂质50μg的杂质混合贮备液;取奥拉帕利对照品12.5mg,精密称定,置25ml量瓶中,加入杂质混合贮备液2.5ml,加溶剂溶解并稀释至刻度,摇匀,作为系统适用性溶液。
照高效液相色谱法(中国药典2010年版二部附录ⅤD)试验。用十八烷基硅烷键合硅胶为填充剂(Ultimate XB-C18 150×4.6mm,3μm);以0.01mol/L磷酸二氢铵水溶液(用磷酸调节pH值至3.0)为流动相A,乙腈为流动相B,进行梯度洗脱;检测波长为235nm;流速为每分钟1.0ml;柱温为30℃。精密量取系统适用性溶液10μl,注入液相色谱仪,记录色谱图。
奥拉帕利峰与相邻杂质峰之间以及各杂质峰之间的分离度应符合规定,理论塔板数按奥拉帕利峰计应不低于2000。另取对照溶液10μl,注入液相色谱仪,调节仪器灵敏度,使主成分色谱峰的峰高约为满量程的10~20%。再精密量取供试品溶液和对照溶液各10μl,分别注入液相色谱仪,记录色谱图。
对上述有关物质测定方法进行方法学研究
专属性实验:空白辅料经过各强制降解试验,均未产生杂质,对本品有关物质检测无干扰。奥拉帕利市售品及自制品经酸、碱、高温、氧化和光照破坏后,均出现降解,但各破坏条件下主峰与相邻杂质峰分离度均大于1.5,主峰峰纯度均符合规定,破坏前后物料基本平衡
OP-B、OP-K、OP-01线性验证
在0.27-5.46μg/ml浓度范围内,OP-B的线性方程:y=17063x+1636.2,r=0.9996;
在0.20-2.97μg/ml浓度范围内,OP-K的线性方程:y=63649x+861.26,r=0.9999;
在0.20-4.05μg/ml浓度范围内,OP-01的线性方程:y=13989x+418.41,r=0.9995
检测限定量限验证
OP-B、OP-K、OP-01的检测限分别为:1.71ng、0.99ng、1.26ng;占主成分浓度的百分比分别为:0.017、0.010、0.013。
OP-B、OP-K、OP-01的定量限分别为:2.73ng、1.98ng、2.02ng;占主成分浓度的百分比分别为:0.027、0.020、0.020。
准确度验证
各杂质的回收率均在80.0%-120.0%之间,说明采用本方法测定奥拉帕利片的有关物质,回收率高,结果准确。
方法耐用性验证
溶液稳定性:供试品溶液在室温放置24h,有关物质无明显变化,溶液稳定性良好。色谱条件耐用性:通过改变流速(±0.2ml/min)、pH值(±0.2)、初始有机相比例(±2%)以及使用不同品牌的色谱柱,除流速为0.8ml/min时,方法的耐用性均良好,应严格控制流速;采用不同品牌、不同型号色谱柱后,杂质OP-L与奥拉帕尼的分离度均大于1.5,耐用性良好。
有关物质(%)=A×f/AS×100%
总有关物质(%)=有关物质%的总和
式中:A为各有关物质的峰面积;
AS为对照溶液中奥拉帕利的峰面积;
f为各有关物质的校正因子。
上述溶出度及有关物质测定方法均经过验证,且取得较有益的结果,方法支持组合物有关物质的测定。
本发明涉及的处方表(用量为克)
处方表中的聚乙二醇是聚乙二醇6000
有益效果:与现有技术相比,本发明通过利用增溶剂为分散介质,并采用喷雾干燥的方法制备固体分散体,增大了药物的溶解度及溶出速度,促进了药物在体内的吸收,提高了药物的生物利用度。减小了片剂片重,提高了患者服药顺应性,同时有效控制杂质水平,减少患者不良反应。
附图说明
图1:实施例中奥拉帕利体外1小时的累积溶出度曲线
图2:奥拉帕利降解途径
图3:实施例1中奥拉帕利组合物杂质检测结果
以下参照具体的实施例来说明本发明。本领域技术人员能够理解,这些实施例仅用于说明本发明,其不以任何方式限制本发明的范围。
具体实施例
实施例1
按照处方表取原料,制备方法包括如下步骤:
(1)奥拉帕利,加入聚乙二醇6000,加水溶解,加热80℃,均匀化,得到奥拉帕利混悬液,喷雾干燥,制成干燥的奥拉帕利固体分散体;
(2)逐步加入十二烷基硫酸钠、甘露醇、交联聚维酮、滑石粉、微粉硅胶,反复过筛混匀后,直接压片得到奥拉帕利片剂。
试验结果:
可压性:好
脆碎度:符合规定
外观:光洁美观
45min平均溶出度:92.3%
有关物质结果:OP-K、OP-B、OP-01均未检出。
实施例2
按照处方表取原料,制备方法包括如下步骤:
(1)取奥拉帕利、聚乙二醇6000,加水溶解,加热80℃,均匀化,得到奥拉帕利混悬液,喷雾干燥,制成干燥的奥拉帕利固体分散体;
(2)逐步加入十二烷基硫酸钠、甘露醇、交联聚维酮、甘露醇、微粉硅胶,反复过筛混匀后,直接压片得到奥拉帕利片剂。
有关物质和溶出曲线测定方法同实施例1
试验结果:
可压性:好
脆碎度:符合规定
外观:光洁美观
45min平均溶出度:71.5%
有关物质结果:OP-K、OP-B、OP-01均未检出。
实施例3
按照处方表取原料,制备方法包括如下步骤:
(1)取奥拉帕利,加入聚乙二醇6000,搅拌使之混合均匀,加热80℃,均匀化,得到奥拉帕利混悬液,喷雾干燥,制成干燥的奥拉帕利固体分散体;
(2)逐步加入十二烷基硫酸钠、甘露醇、交联聚维酮、甘露醇、微粉硅胶、滑石粉,反复过筛混匀后,直接压片得到奥拉帕利片剂。
有关物质和溶出曲线测定方法同实施例1
试验结果:
可压性:好
脆碎度:符合规定
外观:光洁美观
45min平均溶出度:79.3%
有关物质结果:OP-K、OP-B、OP-01均未检出。
实施例4
按照处方表取原料,制备方法包括如下步骤:
(1)奥拉帕利,加入β环糊精,适量水,搅拌使之混合均匀,加热80℃,均匀化,得到奥拉帕利混悬液,喷雾干燥,制成干燥的奥拉帕利β环糊精包合物;
(2)奥拉帕利β环糊精包合物过80目筛,逐步加入十二烷基硫酸钠、甘露醇、交联聚维酮、微粉硅胶、滑石粉,反复过筛混匀后,直接压片得到奥拉帕利片剂。
有关物质和溶出曲线测定方法同实施例1
试验结果:
可压性:好
脆碎度:符合规定
外观:光洁美观
45min平均溶出度:92.5%
有关物质结果:OP-K、OP-B、OP-01均未检出。
实施例5
按照处方表取原料,制备方法包括如下步骤:
(1)取奥拉帕利,辅酶Q10,加入β-环糊精,适量水,搅拌使之混合均匀,加热80℃,均匀化,得到奥拉帕利辅酶Q10混悬液,喷雾干燥,制成奥拉帕利辅酶Q10环糊精包合物;
⑵奥拉帕利辅酶Q10环糊精包合物过80目筛,逐步加入、十二烷基硫酸钠、甘露醇、交联聚维酮、微粉硅胶、滑石粉,反复过筛混匀后,直接压片得到奥拉帕利辅酶Q10片剂。
有关物质和溶出曲线测定方法同实施例1
试验结果:
可压性:好
脆碎度:符合规定
外观:光洁美观
45min平均溶出度:92.8%
有关物质结果:OP-K、OP-B、OP-01均未检出。
本发明经大量试验摸索,选择聚乙二醇6000和十二烷基硫酸钠,选择环糊精和十二烷基硫酸钠,作为载体制备奥拉帕利固体分散体,采用喷雾干燥的方式制备固体分散体,可以满足大生产的要求,避免有机溶剂及水的存在造成奥拉帕利水解降解产生更多的杂质,将杂质水平有效控制在一定的范围内。
实施例6:本发明的抗肿瘤活性
将以1×107/ml的浓度混悬于PBS的乳腺癌细胞株按照0.1ml的容量移植到(200±20)g的雌性大鼠的右肋腹皮下部。从肿瘤体积达到约100mm3时,连续灌胃药物14天。药物混悬于0.5%羧甲基纤维素钠中,按0.1ml/kg体重剂量给药。末次给药后、给药结束后测定大鼠血压、处死动物后剖瘤称重。
分为7组,每组10只进行。按下列公式计算肿瘤抑制率。
肿瘤抑制率=(对照组平均瘤重-药物组平均瘤重)/对照组平均瘤重×100%。
Claims (2)
2.根据权利要求1的一种奥拉帕利的组合物的分析方法,其特征在于:
取奥拉帕利组合物产品12.5mg,置50ml量瓶中,加乙腈10ml超声使溶解,用水稀释至刻度,摇匀,精密量取2ml,置10ml量瓶中,用乙腈稀释至刻度,摇匀,取溶液10ml,滤过,弃去初滤液5ml,取续滤液作为供试品溶液;
取奥拉帕利对照品12.5mg,置50ml量瓶中,加乙腈10ml超声使溶解,用水稀释至刻度,摇匀,精密量取2ml,置10ml量瓶中,用乙腈稀释至刻度,摇匀,作为对照品溶液;
高效液相色谱法测定,用十八烷基硅烷键合硅胶为填充剂;以0.01mol/L磷酸二氢铵水溶液-乙腈为流动相,等度洗脱,其中,磷酸二氢铵水溶液-乙腈的体积比为70:30;所述磷酸二氢铵水溶液用磷酸调节pH值至3.0;流速为每分钟1.0ml;检测波长为235nm;柱温为30℃;精密量取上述供试品溶液和对照品溶液各20μL,分别注入液相色谱仪,记录色谱图。
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