Nanostructured lipid carrier-mediated lung targeted drug delivery system to enhance the safety and bioavailability of clofazimine

Abstract

Tuberculosis (TB) disease is caused due to the infection of Mycobacterium tuberculosis bacilli which reside in alveolar macrophages (AMs). Clofazimine (CLF) has been reinstated clinically for the treatment of TB. However, major challenge of using CLF is its severe side-effects after oral administration. The present research was aimed to establish the safety and enhance the bioavailability of CLF by loading it into nanostructured lipid carriers (CLF-NLCs) and mannosylated NLCs (M-CLF-NLCs) to selectively target the drug toward AMs. The safety of CLF-NLCs and M-CLF-NLCs was evaluated by in vitro hemocompatibility studies, cell viability studies on macrophage J774 cell lines, and in vivo acute inhalation toxicity studies. The bioavailability was estimated by single-dose pharmacokinetics and biodistribution studies. Hemocompatibility studies showed normal RBCs count and least hemolysis of 0.23 ± 0.081% for M-CLF-NLCs treated group. Cell viability studies revealed greater safety of NLCs than CLF-drug dispersion in the concentration range of 2.5–25 μg/ml. In vivo acute toxicity studies revealed no physiological or behavioral changes and no mortality recorded over 14 days period. In pharmacokinetic studies, a maximum concentration of the drug (C max) of 35.44 ± 0.34 μg/g from M-CLF-NLCs after 48 h and longer residence time in lung tissues observed due to its sustained release and mannose receptor-mediated endocytosis. M-CLF-NLCs showed a maximum AUC0–∞ value of 2691.83 h μg/ml in lungs that indicated twofold greater bioavailability as compared to CLF-drug dispersion. Thus, mannosylated NLCs can be used as promising carriers for the safe and effective delivery of CLF via inhalation route for the management of TB disease.