Chen Xiaojin, Wang Ting, Lu Mengmeng, Zhu Luyan, Wang Yan, Zhou WenZhong
Department of Preventitive Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing, People's Republic of China.
Int J Nanomedicine. 2014 May 27;9:2655-64. doi: 10.2147/IJN.S58898. eCollection 2014.
Three tilmicosin-loaded hydrogenated castor oil nanoparticle (TMS-HCO-NP) suspensions of different particle sizes were prepared with different polyvinyl alcohol surfactant concentrations using a hot homogenization and ultrasonic technique. The in vitro release, in vitro antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability study were conducted to evaluate the characteristics of the suspensions. The in vitro tilmicosin release rate, antibacterial activity, mammalian cytotoxicity, acute toxicity in mice, and stability of the suspensions were evaluated. When prepared with polyvinyl alcohol concentrations of 0.2%, 1%, and 5%, the mean diameters of the nanoparticles in the three suspensions were 920±35 nm, 452±10 nm, and 151±4 nm, respectively. The three suspensions displayed biphasic release profiles similar to that of freeze-dried TMS-HCO-NP powders, with the exception of having a faster initial release. Moreover, suspensions of smaller-sized particles showed faster initial release, and lower minimum inhibitory concentrations and minimum bactericidal concentrations. Time-kill curves showed that within 12 hours, the suspension with the 151 nm particles had the most potent bactericidal activity, but later, the suspensions with larger-sized particles showed increased antibacterial activity. None of the three suspensions were cytotoxic at clinical dosage levels. At higher drug concentrations, all three suspensions showed similar concentration-dependent cytotoxicity. The suspension with the smallest-sized particle showed significantly more acute toxicity in mice, perhaps due to faster drug release. All three suspensions exhibited good stability at 4°C and at room temperature for at least 6 months. These results demonstrate that TMS-HCO-NP suspensions can be a promising formulation for tilmicosin, and that nanoparticle size can be an important consideration for formulation development.
采用热均质化和超声技术，使用不同浓度的聚乙烯醇表面活性剂制备了三种不同粒径的替米考星负载氢化蓖麻油纳米颗粒（TMS-HCO-NP）混悬液。进行了体外释放、体外抗菌活性、哺乳动物细胞毒性、小鼠急性毒性及稳定性研究，以评估混悬液的特性。对混悬液的替米考星体外释放速率、抗菌活性、哺乳动物细胞毒性、小鼠急性毒性及稳定性进行了评估。当聚乙烯醇浓度分别为0.2%、1%和5%时，三种混悬液中纳米颗粒的平均直径分别为920±35 nm、452±10 nm和151±4 nm。除初始释放较快外，三种混悬液呈现出与冻干TMS-HCO-NP粉末相似的双相释放曲线。此外，较小粒径颗粒的混悬液初始释放更快，最低抑菌浓度和最低杀菌浓度更低。时间-杀菌曲线显示，在12小时内，粒径为151 nm颗粒的混悬液杀菌活性最强，但之后，较大粒径颗粒的混悬液抗菌活性增强。三种混悬液在临床剂量水平均无细胞毒性。在较高药物浓度下，三种混悬液均表现出相似的浓度依赖性细胞毒性。粒径最小的颗粒混悬液在小鼠中表现出明显更高的急性毒性，可能是由于药物释放更快。三种混悬液在4℃和室温下至少6个月均表现出良好的稳定性。这些结果表明，TMS-HCO-NP混悬液可能是替米考星一种有前景的剂型，并且纳米颗粒大小可能是剂型开发的一个重要考虑因素。
