Particulate carriers as drug delivery systems for anti-tubercular and anti-cancer agents

Abstract

Part I: Design and Evaluation of Polyethylene Sebacate-Anti-tubercular drug Nanoparticles: Conventional therapy for tuberculosis (TB) exhibits serious limitation of toxicity, insufficient bioavailability at the target sites (macrophages) and emergence of multidrug resistance. Nanoparticles enable enhanced drug bioavailability, controlled release, and the possibility of targeting to the site of action (i.e. infected macrophages). Infected macrophages express a number of receptors, amongst these one of the widely investigated receptor is folate receptor. Ligand anchoring with folic acid (FA) could further enhance macrophage uptake. Oral drug administration with high bioavailability, sustained release and enhanced pulmonary uptake represents an ideal drug delivery strategy for the treatment of tuberculosis. The present studies discuss the design and evaluation of PES-Rifampicin (RIF), PES-RIF-Ethambutol (EMB) and PES-RIFMSDNC- 22 nanoparticles with and without folic acid. Poly (ethylene sebacate) (PES) a new biodegradable, non-mutagenic and non-genotoxic polymer was selected for the present study. UV and HPLC methods have been developed and validated for all drugs and drug combinations to enable assay, in vitro release, stability and quantification in presence of biological samples. PES nanoparticles of RIF and RIF-MSDNC-22 were developed and optimized by nanoprecipitation method. RIF-ETH nanoparticles were prepared by multiple emulsion method to enable high entrapment of hydrophilic ETH. FA was anchored by simple physical adsorption. Nanoparticles were freeze dried using a combination of trehalose and lutrol-f-68 as cryoprotectant. Nanoparticles with adequate drug loading and particle size 350-450nm were developed and found to be stable as per ICH guidelines. Nanoparticles were characterized for zeta potential, hydrophobicity, SEM, FTIR, DSC, pXRD, in vitro drug release etc. Nanoparticles revealed high uptake in human macrophage cells U-937 which further increased with folate anchoring.