Hu Xi, Chen Xi, Zhang Ling, Lin Xia, Zhang Yu, Tang Xing, Wang Yanjiao
Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.
School of Pharmacy, Shanghai Jiaotong University, Shanghai, PR China.
Int J Pharm. 2014 Sep 10;472(1-2):130-9. doi: 10.1016/j.ijpharm.2014.06.018. Epub 2014 Jun 11.
To prepare a uniform nanosuspension of strongly hydrophobic riboflavin laurate (RFL) allowing sterile filtration, physical modification (bottom-up) was combined with high-pressure homogenization (top-down) method. Unlike other bottom-up approaches, physical modification with surfactants (TPGS and PL-100) by lyophilization controlled crystallization and compensated for the poor wettability of RFL. On one hand, crystal growth and aggregation during freezing was restricted by a stabilizer-layer adsorbed on the drug surface by hydrophobic interaction. On the other hand, subsequent crystallization of drug in the sublimation process was limited to the interstitial spaces between solvent crystals. After lyophilization, modified drug with a smaller particle size and better wettability was obtained. When adding surfactant solution, water molecules passed between the hydrophilic groups of surface active molecules and activated the polymer chains allowing them to stretch into water. The coarse suspension was crushed into a nanosuspension (MP=162 nm) by high-pressure homogenization. For long term stability, lyophilization was applied again to solidify the nanosuspension (sorbitol as cryoprotectant). A slight crystal growth to about 600 nm was obtained to allow slow release for a sustained effect after muscular administration. Moreover, no paw-licking responses and very slight muscular inflammation demonstrated the excellent biocompatibility of this long-acting RFL injection.
为制备可无菌过滤的强疏水性月桂酸核黄素（RFL）均匀纳米混悬液，将物理修饰（自下而上）与高压均质法（自上而下）相结合。与其他自下而上的方法不同，通过冻干用表面活性剂（TPGS和PL - 100）进行物理修饰可控制结晶并弥补RFL润湿性差的问题。一方面，冷冻过程中药物表面吸附的稳定剂层通过疏水相互作用限制了晶体生长和聚集。另一方面，升华过程中药物的后续结晶限于溶剂晶体之间的间隙空间。冻干后，获得了粒径更小、润湿性更好的改性药物。加入表面活性剂溶液时，水分子在表面活性分子的亲水基团之间通过，激活聚合物链使其伸展到水中。通过高压均质将粗混悬液粉碎成纳米混悬液（平均粒径 = 162 nm）。为实现长期稳定性，再次进行冻干以固化纳米混悬液（用山梨醇作为冷冻保护剂）。得到了轻微生长至约600 nm的晶体，以便在肌肉注射后实现缓慢释放以产生持续效果。此外，无舔爪反应且肌肉炎症非常轻微，表明这种长效RFL注射液具有优异的生物相容性。
