An Inhaled Clofazimine Formulation for the Treatment of Tuberculosis

PROJECT SUMMARY According to the World Health Organizationabout one third of the world s population is infected with Mycobacterium tuberculosisMtband as many asof infected individuals will develop active tuberculosisTBat some point after infectionTB is a curable diseaseyet it still has a high mortality rateinmillion people died from the diseaseThe global control of TB is complicated due to the high incidence of TB in developing countriesand the emergence of drug resistant TBCfz is a drug that has been recently added to WHO recommended list of drugs to treat drug resistant TB strainseffectively able to shorten treatment timesHoweveroral administration of Cfz poses problems such as delayed onset and deleterious side effectsgastrointestinaldermalcardiacAn existing goal to improve TB treatment consists of developing effective aerosolized delivery of drugssuch as Cfzto directly target the lungsThe development of improved drug therapeutics for treatment of diseases has been listed as a priority in the strategic plan of the National Institute of Allergy and Infectious DiseasesNIAIDMicroparticle encapsulation has been studied for aerosol delivery of TB drugsCritical parameters in the development of an efficient particle delivery system aredeep lung deliveryparticle uptake by alveolar macrophagesthe primary site of invasion and replication of Mtbdrug releasedrug dosageandsafetyBalancing the mass of drug delivered against release as well as ensuring efficient dispersal and safety is critical to an effective formulationMicroparticles with precise control over particle size for deep lung delivery and size mediated phagocytosis can be prepared using spray dryingTo address the limitations in drug release and dosageLynntech proposes to develop polymeric acetalated dextranAc Dexencapsulating CfzDifferential drug release can be achieved through the use of pHresponsive Ac Dex particlesable to release Cfz within the acidic environment in phagolysosomesquickly increasing where the bulk of Mtb infection occursThis release mechanism can quickly enable MIC of Cfz to be reached within macrophagessimultaneously increasing effectiveness while reducing the required dosage of Cfzthus reducing side effectsAdditionallythe by products of Ac Dex degradationethanolacetonedextranare relatively benignOur specific aims are devised to provide proof of concept on using and tuning these AcDex particles for active Cfz release within Mtb infected cellsThese aims includedeveloping novel Ac Dex particles encapsulating Cfzdemonstrate that particle uptake and release enhances in vitro Cfz delivery and bactericidal effectandevaluate uptake and release in pharmacokineticPKand efficacy in vivo studiesThe successful completion Phase I will demonstrate feasibility of developing Ac Dex particles for inhaled delivery of CfzWe will then incorporate optimal samples into dry powder formulations for aerosol delivery in a future Phase II effortThis research ultimately forms a platform for delivery of a variety of TB drugs and combinations thereof for TB treatment PROJECT NARRATIVE This project will provide proof of concept for the feasibility of developing clofazimine loaded inhalable drug formulationsSuccessful development of these inhalable formulations will be useful in tuberculosisTBtreatment regimensparticularly for multidrug resistant TBThe expected benefit of the proposed work is to provide an efficient administration of clofazimine to increase drug efficacyreduce risk of systemic toxicityand potential reduce the length of TB treatment