Chan John Gar Yan, Chan Hak-Kim, Prestidge Clive A, Denman John A, Young Paul M, Traini Daniela
Faculty of Pharmacy, The University of Sydney, Sydney, NSW 2006, Australia.
Ian Wark Research Institute, The University of South Australia, Mawson Lakes, Australia.
Eur J Pharm Biopharm. 2013 Feb;83(2):285-92. doi: 10.1016/j.ejpb.2012.08.007. Epub 2012 Sep 13.
Treatment for tuberculosis (TB) using the standard oral antibiotic regimen is effective but inefficient, requiring high drug dosing and lengthy treatment times. Three concurrent first-line antibiotics recommended by the World Health Organization (WHO) guidelines are pyrazinamide, rifampicin and isoniazid. Combining these antibiotics in a novel formulation for dry powder inhalation (DPI) may facilitate rapid and efficient resolution of local and systemic infection. However, spray-dried individually, these antibiotics were found to be physically unstable. A solution of the three antibiotics, at the WHO-recommended ratio, was spray-dried. The collected powder was assessed by a series of in vitro methods to investigate aerosol performance, particle physico-chemical characteristics and dissolution profile. Particles obtained were spherical with a surface composed primarily of rifampicin, as identified by TOF-SIMS. A mass median aerodynamic diameter of 3.5 ± 0.1 μm and fine particle fraction (<5 μm) of 45 ± 3% indicated excellent aerosol performance. The combination powder was differentiated by the presence of rifampicin dihydrate and the delta polymorph of pyrazinamide. Quantitative analysis indicated individual particles contained the three antibiotics at the expected proportions (400:150:75 w/w). This excipient-free triple antibiotic DPI formulation could be used as a significant enhanced treatment for TB.
使用标准口服抗生素方案治疗结核病（TB）是有效的，但效率低下，需要高剂量用药和较长的治疗时间。世界卫生组织（WHO）指南推荐的三种一线联合抗生素为吡嗪酰胺、利福平和异烟肼。将这些抗生素组合成一种新型的干粉吸入剂（DPI）剂型可能有助于快速有效地消除局部和全身感染。然而，单独喷雾干燥时，发现这些抗生素在物理上不稳定。将三种抗生素按WHO推荐的比例制成溶液后进行喷雾干燥。通过一系列体外方法对收集的粉末进行评估，以研究气溶胶性能、颗粒物理化学特性和溶解曲线。通过飞行时间二次离子质谱（TOF-SIMS）鉴定，所得颗粒呈球形，表面主要由利福平组成。质量中值空气动力学直径为3.5±0.1μm，细颗粒分数（<5μm）为45±3%，表明气溶胶性能优异。该组合粉末的特征在于含有二水合利福平和吡嗪酰胺的δ多晶型物。定量分析表明，单个颗粒中三种抗生素的比例符合预期（400:150:75 w/w）。这种无赋形剂的三联抗生素DPI剂型可作为一种显著增强的结核病治疗方法。
