Respiratory Technology, Woolcock Institute of Medical Research, Glebe, Australia; Discipline of Pharmacology, Sydney Medical School, University of Sydney, Australia.
Institute of Pharmaceutical Science, King's College London, London, UK.
Eur J Pharm Biopharm. 2014 Jan;86(1):83-9. doi: 10.1016/j.ejpb.2013.06.024. Epub 2013 Jul 10.
Liposomal ciprofloxacin formulations have been developed with the aim of enhancing lung residence time, thereby reducing the burden of inhaled antimicrobial therapy which requires multiple daily administration due to rapid absorptive clearance of antibiotics from the lungs. However, there is a lack of a predictive methodology available to assess controlled release inhalation delivery systems and their effect on drug disposition. In this study, three ciprofloxacin formulations were evaluated: a liposomal formulation, a solution formulation and a 1:1 combination of the two (mixture formulation). Different methodologies were utilised to study the release profiles of ciprofloxacin from these formulations: (i) membrane diffusion, (ii) air interface Calu-3 cells and (iii) isolated perfused rat lungs. The data from these models were compared to the performance of the formulations in vivo. The solution formulation provided the highest rate of absorptive transport followed by the mixture formulation, with the liposomal formulation providing substantially slower drug release. The rank order of drug release/transport from the different formulations was consistent across the in vitro and ex vivo methods, and this was predictive of the profiles in vivo. The use of complimentary in vitro and ex vivo methodologies provided a robust analysis of formulation behaviour, including mechanistic insights, and predicted in vivo pharmacokinetics.
脂质体环丙沙星制剂的开发旨在延长肺部驻留时间，从而减少因抗生素在肺部的快速吸收清除而需要每日多次给药的吸入抗菌治疗的负担。然而，目前缺乏一种可用于评估控制释放吸入给药系统及其对药物处置影响的预测方法。在这项研究中，评估了三种环丙沙星制剂：脂质体制剂、溶液制剂和两者的 1:1 混合物（混合制剂）。利用多种方法研究了这些制剂中环丙沙星的释放特性：（i）膜扩散，（ii）气-液界面 Calu-3 细胞和（iii）离体灌注大鼠肺。将这些模型中的数据与制剂在体内的性能进行了比较。溶液制剂提供了最高的吸收转运速率，其次是混合物制剂，而脂质体制剂提供了明显较慢的药物释放。不同制剂从不同制剂中释放/转运药物的顺序在体外和离体方法中是一致的，这可以预测体内的情况。互补的体外和离体方法的使用为制剂行为提供了稳健的分析，包括对机制的深入了解，并预测了体内药代动力学。
