da Silva Camila Morais Gonçalves, Franz-Montan Michelle, Limia Cíntia Elisabeth Gomez, Ribeiro Lígia Nunes de Morais, Braga Mário Antônio, Guilherme Viviane Aparecida, da Silva Camila Batista, Casadei Bruna Renata, Cereda Cíntia Maria Saia, de Paula Eneida
Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas-UNICAMP, Campinas, SP, Brazil.
Department of Physiological Sciences, Piracicaba Dental School, University of Campinas, UNICAMP, Piracicaba, SP, Brazil.
PLoS One. 2017 Oct 5;12(10):e0185828. doi: 10.1371/journal.pone.0185828. eCollection 2017.
Ropivacaine is a local anesthetic with similar potency but lower systemic toxicity than bupivacaine, the most commonly used spinal anesthetic. The present study concerns the development of a combined drug delivery system for ropivacaine, comprised of two types of liposomes: donor multivesicular vesicles containing 250 mM (NH4)2SO4 plus the anesthetic, and acceptor large unilamellar vesicles with internal pH of 5.5. Both kinds of liposomes were composed of hydrogenated soy-phosphatidylcholine:cholesterol (2:1 mol%) and were prepared at pH 7.4. Dynamic light scattering, transmission electron microscopy and electron paramagnetic resonance techniques were used to characterize the average particle size, polydispersity, zeta potential, morphology and fluidity of the liposomes. In vitro dialysis experiments showed that the combined liposomal system provided significantly longer (72 h) release of ropivacaine, compared to conventional liposomes (45 h), or plain ropivacaine (4 h) (p <0.05). The pre-formulations tested were significantly less toxic to 3T3 cells, with toxicity increasing in the order: combined system < ropivacaine in donor or acceptor liposomes < ropivacaine in conventional liposomes < plain ropivacaine. The combined formulation, containing 2% ropivacaine, increased the anesthesia duration up to 9 h after subcutaneous infiltration in mice. In conclusion, a promising drug delivery system for ropivacaine was described, which can be loaded with large amounts of the anesthetic (2%), with reduced in vitro cytotoxicity and extended anesthesia time.
罗哌卡因是一种局部麻醉剂，其效力与布比卡因相似，但全身毒性低于布比卡因，布比卡因是最常用的脊髓麻醉剂。本研究关注罗哌卡因复合给药系统的开发，该系统由两种脂质体组成：含有250 mM硫酸铵和麻醉剂的供体多囊泡囊泡，以及内部pH值为5.5的受体大单层囊泡。两种脂质体均由氢化大豆磷脂酰胆碱：胆固醇（2:1摩尔%）组成，并在pH 7.4条件下制备。采用动态光散射、透射电子显微镜和电子顺磁共振技术对脂质体的平均粒径、多分散性、zeta电位、形态和流动性进行表征。体外透析实验表明，与传统脂质体（约45小时）或普通罗哌卡因（约4小时）相比，复合脂质体系统使罗哌卡因的释放时间显著延长（72小时）（p<0.05）。所测试的预制剂对3T3细胞的毒性显著降低，毒性顺序为：复合系统<供体或受体脂质体中的罗哌卡因<传统脂质体中的罗哌卡因<普通罗哌卡因。含有2%罗哌卡因的复合制剂在小鼠皮下浸润后可将麻醉持续时间延长至9小时。总之，本文描述了一种有前景的罗哌卡因给药系统，该系统可负载大量麻醉剂（2%），具有降低的体外细胞毒性和延长的麻醉时间。
