Zhou Qi Tony, Gengenbach Thomas, Denman John A, Yu Heidi H, Li Jian, Chan Hak Kim
Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
AAPS J. 2014 Jan;16(1):37-47. doi: 10.1208/s12248-013-9537-8. Epub 2013 Oct 16.
For many respiratory infections caused by multidrug-resistant Gram-negative bacteria, colistin is the only effective antibiotic despite its nephrotoxicity. A novel inhaled combination formulation of colistin with a synergistic antimicrobial component of rifampicin was prepared via co-spray drying, aiming to deliver the drug directly to the respiratory tract and minimize drug resistance and adverse effects. Synergistic antibacterial activity against Acinetobacter baumannii was demonstrated for the combination formulation with high emitted doses (96%) and fine particle fraction total (FPFtotal; 92%). Storage of the spray-dried colistin alone formulation in the elevated relative humidity (RH) of 75% resulted in a substantial deterioration in the aerosolization performance because the amorphous colistin powders absorbed significant amount of water up to 30% by weight. In contrast, the FPFtotal values of the combination formulation stored at various RH were unchanged, which was similar to the aerosolization behavior of the spray-dried rifampicin-alone formulation. Advanced surface chemistry measurements by XPS and ToF-SIMS demonstrated a dominance of rifampicin on the combination particle surfaces, which contributed to the moisture protection at the elevated RH. This study shows a novel inhalable powder formulation of antibiotic combination with the combined beneficial properties of synergistic antibacterial activity, high aerosolization efficiency, and moisture protection.
对于许多由耐多药革兰氏阴性菌引起的呼吸道感染，尽管粘菌素具有肾毒性，但它仍是唯一有效的抗生素。通过共喷雾干燥制备了一种新型的吸入用粘菌素与利福平协同抗菌成分的组合制剂，旨在将药物直接递送至呼吸道，并最大限度地减少耐药性和不良反应。对于高发射剂量（96%）和细颗粒分数总量（FPFtotal；92%）的组合制剂，证明了其对鲍曼不动杆菌具有协同抗菌活性。单独的喷雾干燥粘菌素制剂在75%的较高相对湿度（RH）下储存会导致雾化性能大幅下降，因为无定形粘菌素粉末吸收了高达30%重量的大量水分。相比之下，在不同RH条件下储存的组合制剂的FPFtotal值没有变化，这与喷雾干燥的单独利福平制剂的雾化行为相似。通过XPS和ToF-SIMS进行的先进表面化学测量表明，利福平在组合颗粒表面占主导地位，这有助于在较高RH下提供防潮保护。这项研究展示了一种新型的可吸入抗生素组合粉末制剂，具有协同抗菌活性、高雾化效率和防潮保护等综合有益特性。
