Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal.
Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Int J Pharm. 2015 May 15;485(1-2):171-82. doi: 10.1016/j.ijpharm.2015.03.016. Epub 2015 Mar 12.
The aim of the present study was to develop novel daptomycin-loaded acrylic microparticles with improved release profiles and antibacterial activity against two clinically relevant methicillin-susceptible and methicillin-resistant Staphylococcus aureus strains (MSSA and MRSA, respectively). Daptomycin was encapsulated into poly(methyl methacrylate) (PMMA) and PMMA-Eudragit RL 100 (EUD) microparticles by a double emulsion-solvent evaporation method. For comparison purposes similar formulations were prepared with vancomycin. Particle morphology, size distribution, encapsulation efficiency, surface charge, physicochemical properties, in vitro release and biocompatibility were assessed. Particles exhibited a micrometer size and a spherical morphology. The addition of EUD to the formulation caused a shift in the surface charge of the particles from negative zeta potential values (100% PMMA formulations) to strongly positive. It also improved daptomycin encapsulation efficiency and release, whereas vancomycin encapsulation and release were strongly hindered. Plain and antibiotic-loaded particles presented comparable biocompatibility profiles. The antibacterial activity of the particles was assessed by isothermal microcalorimetry against both MSSA and MRSA. Daptomycin-loaded PMMA-EUD particles presented the highest antibacterial activity against both strains. The addition of 30% EUD to the daptomycin-loaded PMMA particles caused a 40- and 20-fold decrease in the minimum inhibitory (MIC) and bactericidal concentration (MBC) values, respectively, when compared to the 100% PMMA formulations. On the other hand, vancomycin-loaded microparticles presented the highest antibacterial activity in PMMA particles. Unlike conventional methods, isothermal microcalorimetry proved to be a real-time, sensitive and accurate method for assessment of antibacterial activity of antibiotic-loaded polymeric microparticles. Finally, the addition of EUD to formulations proved to be a powerful strategy to improve daptomycin encapsulation efficiency and release, and consequently improving the microparticles activity against two relevant S. aureus strains.
本研究的目的是开发新型达托霉素负载的丙烯酸微球，以改善其释放特性和对两种临床相关的耐甲氧西林敏感金黄色葡萄球菌（MSSA）和耐甲氧西林金黄色葡萄球菌（MRSA）的抗菌活性。达托霉素通过双乳液-溶剂蒸发法包封在聚甲基丙烯酸甲酯（PMMA）和 PMMA-Eudragit RL 100（EUD）微球中。为了进行比较，还制备了类似的载万古霉素的制剂。评估了颗粒的形态、粒径分布、包封效率、表面电荷、物理化学性质、体外释放和生物相容性。颗粒呈微米级大小和球形形态。制剂中加入 EUD 会使颗粒表面电荷从负 zeta 电位值（100% PMMA 制剂）变为强正电荷。它还提高了达托霉素的包封效率和释放，而万古霉素的包封和释放则受到强烈阻碍。普通和载抗生素的颗粒具有相似的生物相容性特征。通过等温微量量热法评估了颗粒对 MSSA 和 MRSA 的抗菌活性。载达托霉素的 PMMA-EUD 颗粒对两种菌株均表现出最高的抗菌活性。与 100% PMMA 制剂相比，将 30%的 EUD 加入载达托霉素的 PMMA 颗粒中，可使最小抑菌（MIC）和杀菌浓度（MBC）值分别降低 40 倍和 20 倍。另一方面，载万古霉素的微球在 PMMA 颗粒中表现出最高的抗菌活性。与传统方法不同，等温微量量热法被证明是一种实时、敏感和准确的方法，可用于评估载抗生素的聚合物微球的抗菌活性。最后，制剂中加入 EUD 被证明是一种提高达托霉素包封效率和释放的有效策略，从而提高了微球对两种相关金黄色葡萄球菌的活性。
Zotero 插件