Alves-Silva Ihatanderson, Marreto Ricardo N, Gelfuso Guilherme M, Sá-Barreto Lívia C L, Lima Eliana M, Cunha-Filho Marcílio S S
a Laboratory of Food, Drugs and Cosmetics (LTMAC) , University of Brasília (UnB) , Brasília , Brazil.
b Brazilian Health Surveillance Agency (ANVISA) , Brasília , Brazil.
Drug Dev Ind Pharm. 2017 May;43(5):762-769. doi: 10.1080/03639045.2016.1220574. Epub 2016 Aug 18.
Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.
恰加斯病治疗的最新进展是采用了对感染具有协同作用的联合药物，主要包括苯硝唑（BNZ）和唑类衍生物。这些药物之间可能存在不相容性、BNZ溶解缓慢以及剂量调整困难等问题，都是多药制剂开发的技术障碍。因此，在本研究中，采用挤出滚圆法制备了BNZ微丸用于药物速释。然后进行了处方前研究，采用热分析和红外光谱法，研究了药物与选定辅料（聚乙二醇6000、淀粉乙醇酸钠、微晶纤维素和交联羧甲基纤维素钠）之间的相容性。即使在经过湿法制粒和热应激的样品中，也未观察到BNZ的化学分解。随后，根据单纯形格子实验设计，以聚乙二醇、淀粉乙醇酸钠和交联羧甲基纤维素钠作为崩解剂进行制剂制备。在这些实验中，BNZ微丸表现出合适的理化特性，包括高载药量和优异的流动性。混合实验设计能够确定崩解剂的合适组成，并实现微丸的快速崩解和溶解。当聚乙二醇和交联羧甲基纤维素钠各为5.0%（w/w）时，可实现最佳性能。目前的BNZ微丸是治疗恰加斯病的通用替代方案，并为多药系统的制备提供了思路。
