Development and in vivo Analysis of Inhaled Clofazimine for the Treatment of Pulmonary Tuberculosis

Tuberculosis (TB) is a leading cause of death globally, despite current treatment options. The old and rarely used oral antibiotic, clofazimine (CFZ), is a potentially viable treatment option against TB infections due to its activity against TB, multidrug-resistant TB (MDR), and extensively drug-resistant TB (XDR-TB). CFZ is a highly hydrophobic with poor pharmacokinetic and adverse drug reaction profiles following oral administration. Development of an inhaled CFZ formulation could achieve high drug concentrations in infected lung tissue, reduce systemic drug exposure, and lessen the adverse effects associated with oral delivery. This project explores the formulation and processing parameters for inhaled CFZ formulations and the inhaled CFZ dose amount in vivo. Dry powder inhalations of CFZ or CFZ – salt (CFZ – mesylate, CFZ – tosylate, CFZ – lactate) with dipalmitoylphosphatidylcholine (DPPC) were prepared in 80 : 20 ratios of CFZ or CFZ-salt to DPPC using aqueous spray drying of suspensions. The resulting powder formulations were characterized for, batch yield, drug content, hydrodynamic and aerodynamic particle size distribution, antibacterial efficacy, cytotoxicity, and solubility. Moreover, formulations were also characterized for their solid state and particle morphology. Lead formulation was dosed in BALB/c mice to analyze the amounts of inhaled CFZ. CFZ DPPC formulation, among all others, had the highest batch yield, narrowest range of hydrodynamic particle size distribution, and a roughly spherical morphology. CFZ DPPC also demonstrated the best aerodynamic performance with the fine particle fraction of 56% and mass median aerodynamic diameter of 3.2 µm and thus, was superior to CFZ – salt DPPC formulations. Additionally, CFZ DPPC had improved anti - bacterial efficacy compared to unprocessed CFZ and a selectivity index of greater than 2000, indicative of its safety. In vivo analysis of CFZ DPPC in BALB/c mice using a validated dosing chamber revealed an inhaled CFZ concentration of about 16.79 µg/g of wet lung suggesting that CFZ DPPC particles were inhalable in potentially effective amounts. CFZ DPPC formulation was found to have the best outcomes as compared to other CFZ-salt DPPC formulations with no compromise in anti-TB activity and acceptable inhaled amounts, in vivo, thus, being preferable for inhaled lung delivery.

Grantor dc:publisher

Creighton University

Year dc:date.issued

2020

Author dc:creator

• Arte, Kinnari S.

Advisor dc:contributor.advisor

• Tolman, Justin A.

Statement dc:rights

• Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.

Language dc:language.iso

en_US

Handle dc:identifier.uri

http://hdl.handle.net/10504/127626

OAI identifier oai:identifier

oai:cdr.creighton.edu:10504/127626