In Vitro Evaluation of Inhalable Verapamil-Rifapentine Particles for Tuberculosis Therapy

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• 作者：T. Parumasivam ; J. G. Y. Chan ; A. Pang ; D. H. Quan ; J. A. Triccas ; W. J. Britton ; H. K. Chan
• 刊名：Molecular Pharmaceutics
• 出版年：2016
• 出版时间：March 7, 2016
• 年：2016
• 卷：13
• 期：3
• 页码：979-989
• 全文大小：594K
• ISSN：1543-8392

文摘

Recent studies have demonstrated that efflux pumps of Mycobacterium tuberculosis (M. tb) provide a crucial mechanism in the development of drug resistant to antimycobacterial drugs. Drugs that inhibit these efflux pumps, such as verapamil, have shown the potential in enhancing the treatment success. We therefore hypothesized that the combined inhaled administration of verapamil and a first-line rifamycin antibiotic will further improve the treatment efficacy. An inhalable dry powder consisting of amorphous verapamil and crystalline rifapentine with l-leucine as an excipient was produced by spray drying. The in vitro aerosol characteristic of the powder, its microbiological activity and stability were assessed. When the powder was dispersed by an Osmohaler, the total fine particle fraction (FPF_total, wt % of particles in aerosol <5 μm) of verapamil and rifapentine was 77.4 ± 1.1% and 71.5 ± 2.0%, respectively. The combination drug formulation showed a minimum inhibitory concentration (MIC₉₀) similar to that of rifapentine alone when tested against both M. tb H37Ra and M. tb H37Rv strains. Importantly, the combination resulted in increased killing of M. tb H37Ra within the infected macrophage cells compared to either verapamil or rifapentine alone. In assessing cellular toxicity, the combination exhibited an acceptable half maximal inhibitory concentration (IC₅₀) values (62.5 μg/mL) on both human monocytic (THP-1) and lung alveolar basal epithelial (A549) cell lines. Finally, the powder was stable after 3 months storage in 0% relative humidity at 20 ± 3 °C.