Optimization of anti-infective multiparticulate systems for pulmonary delivery

Abstract

Pulmonary fungal infections have dramatically increased in the past few years due to the increase in the number of immunocompromised patients associated with the increase in the number of organ transplantations, HIV and patients receiving chemotherapy for malignancies. These patients lack the basic cellular defense mechanisms which make them more susceptible to less virulent organisms to which normal people are resistant such as Candida and Asperigillus spp. Although being one of the earliest discovered antifungals, miconazole nitrate (MN) is still commonly used. Variations in its antifungal mechanisms of action make it a good candidate against different fungal infections. Being one of the azoles, it inhibits cytochrome P450, an essential enzyme for the biosynthesis of ergosterol, an essential component in the fungal cell wall. It also alters the phospholipids and triglycerides synthesis and inhibits the fungal oxidative enzymes leading to accumulation of the toxic H2O2 inside the fungal cell which eventually leads to its death. In this thesis, our aim is to treat fungal infections in lungs by local pulmonary delivery using dry powder inhalers. These will ensure a high local drug concentration, decrease frequency of administration with an expected reduction of the required dose and hence side effects. The site of deposition of dry powder in the respiratory tract is controlled by the mass mean aerodynamic diameter (MMAD), where particles < 1μm move by Brownian motion and are usually exhaled, particles > 5 μm deposit in the oral cavity and upper respiratory tract, while particles of MMAD between 1-5 μm deposit in the deep alveoli by sedimentation.