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Inhaled Delivery of Clofazimine (CFZ) – An Important Anti-tuberculosis Drug


Fast Track proposals will be accepted Number of anticipated awards: 2-3 Budget (total costs):
Phase I: $300,000/year for up to2 years
Phase II: $1,000,000/year for up to 3 years
Development of improved drug regimens to shorten treatment for MDR and DS TB and improve tolerance and safety is an extremely high research priority. Clofazimine is a drug approved decades ago for treatment of leprosy. Animal studies of the drug for TB treatment indicate that it may significantly reduce treatment duration, particularly in combinations including
PZA. The effectiveness of the “Bangladesh” regimen provides support that inclusion of CFZ in MDR regimens may shorten
treatment from 18 to 9-10 months, at least in populations with a low rate of resistance to other MDR drugs.
However, tolerance to orally administered clofazimine is often limited by skin discoloration and GI adverse events. In addition, CFZ substantially increased the QT interval. Inhaled delivery offers the potential to bypass these barriers while still maintaining effectiveness in the lungs by achieving high drug concentrations in the infected pulmonary tissue with lower systemic exposure, thus allowing increased immediate potency. A published study of inhaled delivery of a microparticle formulation of CFZ in a mouse TB model demonstrated that inhaled CFZ reduced lung CFUs much more substantially at 4 weeks than similar doses given by gavage. Given these potential benefits, an easy-to-use inhalation delivery system for CFZ would represent a significant advance in the treatment of tuberculosis. Though anti-tubercular drugs have been formulated into aerosolized particles by multiple research groups and numerous papers are available in the literature on formulating inhaled therapies for TB, no formulation has yet to be commercialized.
Project Goal
The goal of this solicitation is to develop an inexpensive, easy-to-use, inhaled delivery system for clofazimine to be used with combinations of systemic anti-tubercular drugs to improve the treatment of MDR and DS TB.
Phase I activities
Development of an inhaled formulation of clofazimine.
Development of an inexpensive, hand-held, self-contained platform for delivery of this formulation.
Initial testing to quantitatively assess for drug efficacy, toxicity, and pharmacokinetics including required in-vitro studies.
Phase II activities
Preclinical studies including required in-vivo testing in a standardized, reproducible, validated small animal model.
Development of a well-defined formulation and delivery platform under good manufacturing practices (GMP).
Quality control for ensuring and certifying uniformity from lot to lot.
Scale-up and production for future Phase I clinical study.

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