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.