CN1774240A - 含有左旋多巴和卡比多巴的药物组合物 - Google Patents
含有左旋多巴和卡比多巴的药物组合物 Download PDFInfo
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Abstract
本发明涉及口服固体药物组合物，用于左旋多巴/卡比多巴组合的恒定和延长释放，所述组合物用于治疗帕金森病。
Description
本发明涉及含有左旋多巴/卡比多巴组合的延长释放口服固体药物组合物，以及其在治疗帕金森病或相关病理中的用途。
技术背景
帕金森病是涉及脑的不同区域、特别是“黑质”的神经变性疾病，利用多巴胺作为神经递质，导致运动的缓慢、渐进性失调。主要症状是运动徐缓、肌肉僵硬、静止性震颤和体位不稳定。通常通过对药理学治疗的有利应答证实诊断。
药理学治疗基于使用司来吉兰、抗胆碱能药、金刚胺、多巴胺能激动剂、麦角生物碱、左旋多巴、CMOT抑制剂。
左旋多巴当经口施用时，穿过血脑屏障并经酶促在脑水平转化成多巴胺。
抗帕金森药物的选择是信尼麦(Sinemet)，其含有左旋多巴和卡比多巴的组合；后者不穿过血脑屏障，因此减少了左旋多巴通过外周酶向多巴胺的转化，从而增加了中枢神经系统中可利用的活性成分的量。
治疗性治疗通常以每天1/2片信尼麦25mg/100mg(卡比多巴/左旋多巴)开始，数周后增加剂量直到达到临床有效剂量，其通常为每天3到4次，每次1片。作为替代选择，用信尼麦CR(Sinemet控释剂)50mg/200mg治疗，每天1/2片开始，缓慢增加直到每天两次，每次1片。信尼麦CR的生物利用度较信尼麦低约30％。
左旋多巴在1-2小时内达到最大血浆浓度，其半衰期为1-3小时。因此，该药物必须每天反复施用，结果血浆浓度的峰值(Cmax)在患者中导致不希望的副作用。商业途径可得到的卡比多巴/左旋多巴CR(控释)片剂在8小时期间是治疗有效的，但是具有多种缺点和不希望的副作用，包括恶心和呕吐、直立性低血压、运动摆荡、运动障碍和精神病。
发明内容
本发明提供了含有卡比多巴和左旋多巴组合的固体口服药物组合物，其确保活性成分在24小时内稳定释放，从而避免血浆峰值或者波动。
根据本发明的组合物含有经乙基纤维素膜包衣的单独的左旋多巴和卡比多巴颗粒，卡比多巴/左旋多巴重量比为1∶4。颗粒状混合物以适宜的药物形式分布，优选为预定剂量的小药囊或者硬明胶胶囊。
每单一剂量的活性成分的剂量可以为10至200mg卡比多巴和40-800mg左旋多巴，保持1∶4的重量比。日剂量可以根据疾病的严重性、患者的一般状况和其他参数而异。优选每天施用一次250mg剂量，相当于每单一剂量50mg卡比多巴+200mg左旋多巴。
根据优选实施方案，从混合物制备包衣的颗粒，所述混合物含有：
活性成分(左旋多巴或卡比多巴) 90％
聚乙二醇(碳蜡) 3％
乙基纤维素 1.70％
滑石粉 0.80％
聚乙烯吡咯烷酮 4.50％
偏亚硫酸氢钾 适量(＜0.01％)
制粒方法包括将活性成分与粘合剂在溶剂中混合，随后将混合物制粒，例如借助具有适宜网孔的筛子得到所需颗粒大小分布，并用乙基纤维素将颗粒包衣。
根据优选实施方案，通过分别将活性成分与聚乙二醇和聚乙烯吡咯烷酮混合，并通过筛子将所得混合物制粒，任选通过更细的筛子重复该过程。随后，将由丙酮和变性酒精中的乙基纤维素和偏亚硫酸氢钾组成的包衣溶液喷雾到颗粒上，加入滑石粉促进颗粒的流动；最后将包衣颗粒干燥以除去任何痕量溶剂。完成制粒和包衣后，将包衣颗粒后处理成最终药物形式，例如分布在胶囊或者小药囊中。
根据本发明的药物组合物的每天一次施用尤其有利，因为
1)防止血浆浓度峰，
2)促进缓慢肠吸收，
3)确保在24小时内，根据预定量和比例稳定提供活性成分。
因此治疗功效和患者的依从性得到改善，同时使不希望的作用降至最小。
由于其药物动力学特征，本发明的药物组合物方便地用于防止或者治疗性治疗帕金森病和相关疾病。
以下实施例更详细地阐明本发明。
实施例1大批量左旋多巴/卡比多巴的制备
400Kg制剂
左旋多巴 359.960Kg
碳蜡 400012.000Kg
乙基纤维素 6.800Kg
滑石粉 3.200Kg
聚乙烯吡咯烷酮 22.000Kg
偏亚硫酸氢钾 0.040Kg
丙酮*
变性酒精*
软化水*
100Kg制剂
卡比多巴 89.990Kg
碳蜡4000 3.000Kg
乙基纤维素 1.700Kg
滑石粉 0.800Kg
聚乙烯吡咯烷酮 4.500Kg
偏亚硫酸氢钾 0.010Kg
丙酮*
变性酒精*
软化水*
*溶于该方法中的溶剂在该方法结束时蒸除。
粘合剂溶液的制备
将碳蜡4000置于安装气动搅拌器的不锈钢容器中，然后以小量倾入聚乙烯吡咯烷酮，搅拌直到溶解。
制粒
将左旋多巴和卡比多巴准确称重并用以上粘合剂溶液作为聚集剂使左旋多巴和卡比多巴通过制粒机。
用力使湿润颗粒穿过840微米筛目的筛子，在强制空气恒温干燥器中40℃干燥15小时，随后过500和840微米筛目的筛子。用与上述相同的步骤将小于500微米的粉末和颗粒重新制粒，使用去离子水作为聚集剂。完成制粒过程后，使颗粒过500和840微米筛。
将所得颗粒(核心)称重并置于包衣锅的不锈钢篮中。包衣锅以适宜速率(12rpm)旋转以确保物质的有效旋转，在包衣锅旋转期间，将粘合剂溶液通过喷雾器喷雾到颗粒上，防止形成小滴，并加入剩余的粉末状活性成分。粘合剂的喷雾和粉末的加入以交替间隔进行，以粘附粉末薄层于颗粒核心上，并使粘合剂溶液中存在的溶剂(水)更好地蒸发，其通过抽吸除去，避免形成泡沫。然后使湿润颗粒过1200微米筛并在强制空气恒温干燥器中40℃干燥15小时。干燥后，将颗粒再次过840和1200微米筛。
包衣膜(溶液)的制备
将丙酮和变性酒精置于不锈钢容器中，然后在连续搅拌下加入乙基纤维素和偏亚硫酸氢钾，直到完成溶解。
颗粒的包衣
将来自以上步骤的颗粒置于流化床中，并通过过滤气流保持悬浮。
将包衣溶液通过喷雾器间歇地喷雾，以防止形成小滴。加入滑石粉以促进颗粒物质的流动。该过程完成后，用力使颗粒通过1200微米筛。将包衣的颗粒在强制空气恒温干燥器中40℃干燥15小时。
大批量制备
将干燥的包衣颗粒过840和1200微米筛，并将产品收集在聚乙烯双层袋中，置于具有密闭封口的金属容器中。
实施例2-大批量药物制剂(胶囊剂)
将如以上实施例1和2中所得的两种颗粒(分别为卡比多巴和左旋多巴)分布在硬明胶胶囊中，保持1∶4重量比(卡比多巴/左旋多巴)。
使用装备有两个装料盘、两个进料器、两个单独的计量给料器(每个进料器一个)并且设定程序为以确定量的颗粒填充半胶囊的机器进行包胶。
为了填充250mg胶囊(50mg卡比多巴+200mg左旋多巴)，将颗粒计量给料器设置为重量分别为约56.6mg卡比多巴和222.3mg左旋多巴。
实施例3-溶出试验
在连续流动溶出室(25ml/分钟，37℃)中用pH 1.1(人工胃液)的溶液试验250mg制剂(50+200)的6份样品。得到了以下的24小时内释放百分数(每个值是6次测量的平均值)：
| 体外释放 | ％释放平均值 | |
| 时间 | 左旋多巴 | 卡比多巴 |
| 第03小时 | 22％ | 26％ |
| 第06小时 | 43％ | 39％ |
| 第09小时 | 59％ | 51％ |
| 第12小时 | 68％ | 63％ |
| 第24小时 | 90％ | 89％ |
表中数据清楚地表明：在整个24小时期间，活性成分的释放保持恒定。实施例4-单次施用时本发明制剂(50mg卡比多巴+200mg左旋多巴-命名为Dopabain)与市售产品信尼麦CR(50mg卡比多巴+200mg左旋多巴)之间的生物等效性研究
为了评估两种制剂在24小时后血浆左旋多巴浓度，在10名健康志愿者中进行了单剂量、随机、两期、两序列的交叉生物利用度研究。
在长达72小时内监视每名受试者的左旋多巴浓度。研究结果在附图中显示。
Claims (7)
1.固体口服药物组合物，其含有1∶4重量比的卡比多巴和左旋多巴，为乙基纤维素包衣的颗粒形式。
2.权利要求1所述的药物组合物，其中所述颗粒包含在明胶胶囊或者小药囊中。
3.权利要求1所述的药物组合物，其含有10至200mg卡比多巴和40至800mg左旋多巴。
4.权利要求3所述的组合物，其含有50mg卡比多巴和200mg左旋多巴。
5.根据任一项前述权利要求的组合物，其含有90％左旋多巴和卡比多巴、3％聚乙二醇、1.70％乙基纤维素、0.8％滑石粉、4.5％聚乙烯吡咯烷酮和适量至100的偏亚硫酸氢钾。
6.权利要求5所述的组合物，其中颗粒的平均直径为500至1200μm。
7.1∶4重量比的卡比多巴和左旋多巴在制备用于治疗帕金森病或者相关病理的乙基纤维素包衣颗粒中的用途。
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| IT000827A ITMI20030827A1 (it) | 2003-04-18 | 2003-04-18 | Composizione farmaceutica contenente l'associazione levodopa/carbidopa. |
| ITMI2003A000827 | 2003-04-18 |
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| US (1) | US20070042037A1 (zh) |
| EP (1) | EP1615627A1 (zh) |
| JP (1) | JP2006523633A (zh) |
| CN (1) | CN1774240A (zh) |
| IT (1) | ITMI20030827A1 (zh) |
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| CN105362252A (zh) * | 2015-10-09 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | 一种含有左旋多巴和卡比多巴的缓释胶囊及其制备方法 |
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| ZA200810834B (en) * | 2006-05-31 | 2010-03-31 | Solvay Pharm Gmbh | Long term 24 hour intestinal administration of levodopa/carbidopa |
| WO2008087882A1 (ja) * | 2007-01-15 | 2008-07-24 | Kissei Pharmaceutical Co., Ltd. | 胃内滞留型レボドパ徐放性製剤 |
| US11426366B2 (en) * | 2015-05-15 | 2022-08-30 | Arizona Board Of Regents On Behalf Of The Universsity Of Arizona | Compositions and methods for treating motor disorders |
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| US4832957A (en) * | 1987-12-11 | 1989-05-23 | Merck & Co., Inc. | Controlled release combination of carbidopa/levodopa |
| SE460947B (sv) * | 1986-08-26 | 1989-12-11 | Lejus Medical Ab | En multiple-unit-dos komposition av l-dopa |
| US5133974A (en) * | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
| US6756056B2 (en) * | 1997-04-08 | 2004-06-29 | Alan A. Rubin | Treatment of Parkinson's disease and related disorders by novel formulations of the combination carbidopa-levodopa |
| ES2211215T3 (es) * | 1998-12-24 | 2004-07-01 | Janssen Pharmaceutica N.V. | Composicion de galantamina de liberacion controlada. |
| CN100579514C (zh) * | 2001-07-06 | 2010-01-13 | 生命周期药物公司 | 通过受控制的凝聚而制备颗粒物的方法以及提高生物利用度的方法 |
| US20030224045A1 (en) * | 2002-05-29 | 2003-12-04 | Chien-Hsuan Han | Combination immediate release sustained release levodopa/carbidopa dosage forms |
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| CN105362252A (zh) * | 2015-10-09 | 2016-03-02 | 北京万全德众医药生物技术有限公司 | 一种含有左旋多巴和卡比多巴的缓释胶囊及其制备方法 |
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| Publication number | Publication date |
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| ITMI20030827A1 (it) | 2004-10-19 |
| JP2006523633A (ja) | 2006-10-19 |
| EP1615627A1 (en) | 2006-01-18 |
| US20070042037A1 (en) | 2007-02-22 |
| WO2004091588A1 (en) | 2004-10-28 |
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