【作者】 吴俊珠；

【导师】 金拓；

【作者基本信息】 上海交通大学 ， 药剂学， 2007， 硕士

【摘要】 目前,心血管疾病的治疗和二级预防常常需要多种药物联合使用。鱼油在心血管疾病治疗中具有明显的辅助疗效。临床用药实践表明,鱼油与赖诺普利、洛伐他汀、阿替洛尔、阿司匹林、叶酸等药物合用在防治多种心血管疾病中取得了积极的效果。联合用药虽有必要,但一次服用多种药丸,用药不方便,患者的顺应性成为一个问题,开发使用方便的复方剂型是一个解决方案。在研究中,我们将用于治疗心血管疾病的复方制剂命名为Lifepill。Lifepill中含赖诺普利、洛伐他汀、阿替洛尔、阿司匹林、叶酸和鱼油6种具有治疗活性的成分,其中鱼油为液体,剂量大,且容易氧化变质,如何将众多固体活性成分与鱼油制备成一个稳定、使用方便的复方剂型是本研究希望突破的技术难点。作为固-液复方制剂的可行性研究,本实验中我们在5种固体活性成分中,选择一种成分--赖诺普利(LIS)作为研究对象,构建含有LIS与鱼油复方制剂的剂型方案,并考察方案对提高LIS与鱼油在复方制剂中稳定性的作用。为了避免或减少复方制剂中药物之间的相互作用,特别是液体成分和固体成分的接触,我们采用了两种LIS和鱼油的隔离方案:A)以明胶、阿拉伯胶为囊材,复凝聚法将鱼油制成微囊,将鱼油固态化,再与赖诺普利、适宜的辅料制备片剂;B)以聚乙烯醇为载体材料制备赖诺普利聚乙烯醇微球(LIS-PVA-MS),使之能够稳定地分散在鱼油中,制备软胶囊。前者因鱼油微囊体积过大,明显不适合;试验中着重对后者进行了考查。方案B中的LIS-PVA-MS通过乳化-物理交联和喷雾干燥两种方法进行了制备和比较,发现后者可行性更好,所以采取正交试验对PVA分子量、PVA浓度、LIS-PVA投料比、雾化器转速4个因素进行了进一步优化。按优化方案制备3批LIS-PVA-MS,验证试验结果表明以该优化方案制得的微球平均粒径为17.29 um,跨度为0.88,载药量为31.4%,包封率为94.20 %,微球表面有孔。对微球进行体外溶出实验,微球中LIS在30min溶出90 %以上。初步的常温留样及40℃、60℃加速试验稳定性试验表明:以样品外观变化、样品中LIS百分含量为考查指标,以PVA为载体材料采用喷雾干燥法将LIS制成的多孔LIS-PVA-MS和充氮气两项措施在一定程度上可以提高含LIS与鱼油复合制剂(Lifepill)的稳定性。结论:采用喷雾干燥法制备的LIS-PVA-MS可明显改善LIS在鱼油中的稳定性,且微球中LIS溶出迅速;采用RP-HPLC所建立的含量测定方法简单、方便、准确、可靠;复方制剂中充氮气和多孔PVA-MS两项措施在一定程度对含LIS和鱼油的复方制剂具有保护作用。更多还原

【Abstract】 Drug therapy with multiple ingredients is widely accepted nowadays for treatment of cardiovascular diseases. However, for treatment of chronic conditions, taking multiple pills each time could be a daunting task especially for senior citizens. An integrated dosage form containing all the functioning ingredients may be a good solution. The well used cardiovascular drugs and supplements include lisinopril, lovastatin, atenolol, aspirin, folic acid and fish oil. While fish oil is an important supplement for maintaining cardiovascular conditions, incorporating liquid fish oil of large volume into a single formulation together with solid ingredients is a technical challenge (because physical contact between solid and liquid is much more intimate than that between solid and solid).The present study is aimed to develop an integrated pill in which solid ingredients can be mixed with fish oil without drug-drug interaction, especially between solid ingredients and liquid oil. To establish the proof-of-concept, lisinopril was selected as a model drug to be mixed with fish oil and examined. In order to avoid lisinopril-fish oil contact, the solid drug was microencapsulated in polyvinyl alcohol microspheres (abbreviated as LIS-PVA-MS) prior to suspending into fish oil, followed by fabricating soft gel capsules. (the approach to microencapsulate fish oil into solid particles for tableting was ruled out for its large dose volume).LIS-PVA-MS were prepared via two procedures, water-in-oil emulsification, followed by a freeze-thaw process and spray-drying. The former produces particles with dense matrix, but the process is lengthy with low drug loading efficiency. The later is more doable while particles possess some pore structures. Due to the good doability, we focused on the spray-drying method and optimized formulation parameters as PVA molecular weight, PVA concentration, LIS/PVA ratio, and rotation speed of the spray atomizer.According to the optimized parameters, LIS-PVA-MS with mean diameter of 17.29 um, span of 0.88, drug loading of 31.4% and encapsulation efficiency of 94.20 % were prepared. When the these microspheres were subjected to in vitro dissolution tests, 90% of the LIS-loads were released within 30min.A preliminary stability study of Lifepill containing LIS-PVA-MS and fish oil at room temperature, 40℃and 60℃, evaluated by appearance and remained LIS, indicates that the PVA protection improved LIS stability when the LIS-PVA-MS were suspended in fish oil under a nitrogen atmosphere as compared with bare LIS particles suspended in fish oil.Conclusion: Lisinopril protected in LIS-PVA-MS prepared by spray-drying exhibited significantly improved stability in fish oil and immediate dissolution profile. The HPLC method to determine lisinopril content in microspheres is simple, fast and reliable. Nitrogen atmosphere used to feel porous LIS-PVA-MS into capsules also improved drug stability.更多还原