title: In vitro evaluation of novel inhalable dry powders consisting of thioridazine and rifapentine for rapid tuberculosis treatment.
abstract: Thioridazine is an orally administered antipsychotic drug with potential for treatment of drug-resistant tuberculosis (TB). However, drug-induced adverse cardiac effects have been reported when thioridazine was used at an efficacious oral dose of 200mg/day to treat TB. Pulmonary delivery of thioridazine could be a rational approach to reduce dose-related side effects while enabling high drug concentrations at the primary site of infection. The present study compares in vitro aerosol performance, storage stability, and in vitro antimicrobial activity and cytotoxicity of two inhalable powders composed of thioridazine and a first-line anti-TB drug, rifapentine. Formulation 1 is a combination of amorphous thioridazine and crystalline rifapentine, while Formulation 2 consisted of both drugs as amorphous forms. Both thioridazine-rifapentine formulations were found suitable for inhalation with a total fine particle fraction (<5μm) of 68-76%. The two powders had similar MIC90 to rifapentine alone, being 0.000625μg/mL and 0.005μg/ml against Mycobacterium tuberculosis H37Ra and M. tuberculosis H37Rv, respectively. In contrast, thioridazine alone had a MIC90 of 12.5μg/mL and 500μg/mL, against M. tuberculosis H37Ra and M. tuberculosis H37Rv, respectively, demonstrating no synergistic anti-TB activity. However, thioridazine and rifapentine in a ratio of 1:3 enhanced the killing of M. tuberculosis H37Ra within the human monocyte-derived macrophages (THP-1) compared to the single drug treatments. Both powders showed an acceptable half maximal inhibitory concentration (IC50) of 31.25μg/mL on both THP-1 and human lung epithelial (A549) cells. However, Formulation 1 showed greater chemical stability than Formulation 2 after three months of storage under low humidity (vacuum) at 20±3°C. In conclusion, we have demonstrated a novel inhalable powder consisted of amorphous thioridazine and crystalline rifapentine (Formulation 1) with a good aerosol performance, potent anti-TB activity and storage stability, which deserves further in vivo investigations.
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Parumasivam
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia; JHL Biotech, Inc., Hsinchu County, Taiwan.
authors.forename: J G Y
authors.initials: JG
authors.lastname: Chan
authors.affiliation: Tuberculosis Research Program, Centenary Institute, and The University of Sydney, Sydney 2042, NSW, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Pang
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Quan
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Triccas
authors.affiliation: Infectious Diseases and Immunology, Sydney Medical School, The University of Sydney, 2006 NSW, Australia; Tuberculosis Research Program, Centenary Institute, and The University of Sydney, Sydney 2042, NSW, Australia.
authors.forename: W J
authors.initials: WJ
authors.lastname: Britton
authors.affiliation: Advanced Drug Delivery Group, Faculty of Pharmacy, The University of Sydney, 2006 NSW, Australia. Electronic address: kim.chan@sydney.edu.au.
authors.forename: H K
authors.initials: HK
authors.lastname: Chan
mesh_terms: D000280:Administration, Inhalation; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D066298:In Vitro Techniques; D033362:Powder Diffraction; D011208:Powders; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013881:Thioridazine / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011208:Powders; D013881:Thioridazine; D012293:Rifampin; C018421:rifapentine
keywords: Cardiotoxicity; Inhalation; Rifapentine; Thioridazine; Tuberculosis