Drug loaded surfactant nanoparticles for aerosol therapy in pulmonary tuberculosis

       Pulmonary tuberculosis is a chronic disease affecting the respiratory system. It has high morbidity in the form of lung fibrosis and alveolar collapse. In this disease, pulmonary function decreases and work of breathing increases. The alveolar collapse in pulmonary tuberculosis is due to a dysfunction of pulmonary surfactant in this condition.
       Normally, our lungs are lined by a surface active material called the pulmonary surfactant which prevents alveolar collapse and maintains alveolar stability. In tuberculosis, the bacilli and the surfactant system are in close proximity. We have established that certain components of the mycobacterial cell wall interfere with the pulmonary surfactant system by destabilizing the surfactant film. This leads to a higher surface tension in the alveoli and causes alveolar collapse. Thus, there is a need to develop surfactants that overcome the inhibitory surface properties of the mycobacterial cell wall constituents for therapeutic benefit in tuberculosis.
       Further, conventional drug therapy in tuberculosis is associated with problems of drug intolerance and toxicity leading to permanent damage in certain organs. The long duration of therapy and the drug related toxicity are common causes for non-compliance resulting in multi-drug resistant tuberculosis. When administered orally, the anti-tubercular agents cause adverse reactions like ototoxicity and nephrotoxicity. Further, only a small fraction of the anti-tubercular drugs reach the alveoli which is the desired site of drug action. There is a need to develop drug delivery forms that can be directly administered to the lungs as nanoparticulate aerosols to reduce the systemic side effects associated with the present anti-tubercular drugs. A nanoparticulate aerosol delivery system will also increase the amounts of drug reaching the target alveoli. Nanoparticles of pulmonary surfactant can be employed as delivery agents for the anti-tubercular drugs to the infected lung tissue.
       This proposal aims at developing such anti-tubercular drug loaded surfactants in the form of nanoparticles for inhalation therapy in tuberculosis. Such nanoparticles will stabilize the alveoli and prevent alveolar collapse. The surfactants will open up the collapsed alveoli and thus allow the drug to reach the diseased alveoli uniformly. Such nanoparticulate aerosols would be a significant improvement over existing therapies in pulmonary tuberculosis.
       Projected Research plan:
       In the proposed study, we will develop triple anti-tubercular drug loaded surfactant nanoparticles for aerosol therapy in pulmonary tuberculosis. The nanoparticles will allow the drugs to be delivered in a non-invasive manner and the aerosols will be optimized for superior reach in the alveoli. The surface activity of the drug loaded surfactants will be optimized to ensure that they act as anti-atelectatic agents, opening up the collapsed alveoli and helping in the homogenous distribution of the drugs within the lungs.
       The drug loaded surfactant nanoparticles will be developed and optimized for biophysical properties of relevance to pulmonary surfactant function as well as for drug release. The surface properties that will be optimized include the minimum surface tension on dynamic compression, the adsorption time for film formation, film compressibility and stability. A minimum surface tension of near zero mN/m and adsorption within milliseconds to form a film with an equilibrium surface tension of approximately 25-30 mN/m will be considered as optimal properties of the proposed nanoparticulate surfactant. These properties will ensure that the nanoparticulate drug loaded surfactant will be able to form a film quickly in the alveoli on inhalation and will prevent alveolar collapse during expiration. Further, the surface properties will be evaluated in the presence of the mycobacterial inhibitors and the ability of the surfactants to withstand mycobacterial inhibition will be evaluated and optimized. Drug loaded surfactant nanoparticles that are able to fulfill the required surface properties even in the presence of inhibitory mycobacterial components will be chosen for further evaluation.
       For further development of the formulation, the effects of the surfactants on the activity of the anti-tubercular drugs will be evaluated. The nanoparticle aerosols will be characterized in terms of particle size, zeta potential, shelf life, aerodynamic diameter, efficiency of deposition in the alveoli, drug release kinetics and biological efficacy. The drug loaded surfactant nanoparticles that attain favorable surface properties while maintaining a high anti-tubercular efficacy will be chosen for formulation development.