Department of Chemical Engineering, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
J Pharm Sci. 2012 Oct;101(10):3877-85. doi: 10.1002/jps.23269. Epub 2012 Jul 20.
SR13668 [2,10-Dicarbethoxy-6-methoxy-5,7-dihydro-indolo-(2,3-b)carbazole] has been proven effective in cancer prevention, but the limited bioavailability has hindered its clinical translation. In this study, we have developed a continuous, scalable process to form stable poly(lactic-co-glycolic acid) nanoparticles encapsulating SR13668, based on understanding of the competitive kinetics of nanoprecipitation and spray drying. The optimized formulation achieved high drug loading (33.3 wt %) and small particles (150 nm) with narrow size distribution. The prepared nanoparticle suspensions through flash nanoprecipitation were spray dried to achieve long-term stability and to conveniently adjust the nanoparticle concentration before use. In vitro release of SR13668 from the nanosuspensions was measured in a solution with separated organic and aqueous phases to overcome the limit of SR13668 low water solubility. Higher oral bioavailability of SR13668 by employing polymeric nanoparticles compared with the Labrasol® formulation was demonstrated in a mouse model.
SR13668 [2,10-二乙氧基-6-甲氧基-5,7-二氢吲哚并-(2,3-b)咔唑]已被证明在癌症预防方面有效，但有限的生物利用度阻碍了其临床转化。在这项研究中，我们基于对纳米沉淀和喷雾干燥竞争动力学的理解，开发了一种连续、可扩展的工艺，用于形成稳定的包载 SR13668 的聚（乳酸-共-乙醇酸）纳米粒。优化的配方实现了高载药量（33.3wt%）和小粒径（150nm），且粒径分布较窄。通过闪式纳米沉淀制备的纳米粒混悬液喷雾干燥后可实现长期稳定性，并可在使用前方便地调节纳米粒浓度。通过在具有分离的有机相和水相的溶液中测量 SR13668 从纳米混悬剂中的体外释放，克服了 SR13668 低水溶性的限制。与 Labrasol®制剂相比，采用聚合物纳米粒可显著提高 SR13668 的口服生物利用度，这在小鼠模型中得到了验证。
