title: In Vitro Evaluation of Inhalable Verapamil-Rifapentine Particles for Tuberculosis Therapy.
abstract: 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 (FPFtotal, 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.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Parumasivam
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales 2006, Australia.|JHL Biotech, Incorporated , Hsinchu 300, Taiwan.
authors.forename: J G Y
authors.initials: JG
authors.lastname: Chan
authors.affiliation: Tuberculosis Research Program, Centenary Institute, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Pang
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Quan
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Triccas
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney , Sydney, New South Wales 2006, Australia.|Tuberculosis Research Program, Centenary Institute, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: W J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney , Sydney, New South Wales 2006, Australia.
authors.forename: H K
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000280:Administration, Inhalation; D000336:Aerosols; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008826:Microbial Sensitivity Tests; D009000:Monocytes / Q000187:drug effects / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010316:Particle Size; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D014700:Verapamil / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000336:Aerosols; D000889:Anti-Arrhythmia Agents; D000904:Antibiotics, Antitubercular; D014700:Verapamil; D012293:Rifampin; C018421:rifapentine
keywords: aerosols; efflux pump inhibitor; rifapentine; tuberculosis; verapamil