Abstract
Tuberculosis (TB), a granulomatous disease primarily affecting the lungs, is caused by the bacterial pathogen Mycobacterium tuberculosis. Despite its treatability, the current regimen faces formidable challenges, principally patient adherence due to the prolonged treatment duration - six months for drug-susceptible TB and two years for multidrug-resistant TB. Additionally, burgeoning resistance to existing TB drugs further exacerbates these challenges. Consequently, two novel urea-based anti-tubercular compounds, Urea-1 and Urea-20, exhibiting potent minimum inhibitory concentration (MICs) of 0.01μg/mL were synthesized. However, their therapeutic utility is hindered by low aqueous solubility.This thesis proposes enhancing the solubility of these compounds by forming a Cyclodextrin Inclusion Complex for targeted delivery to the lungs by formulating a solution for nebulization.
Following synthesis, the compounds were characterized using established characterization methods. An analytical method was developed for quantification of compounds and validated for Liquid Chromatography/Mass Spectrometry (LC/MS). To formulate the inclusion complex, HP-β-CD was selected using molecular docking, with binding energies of -7.4 kcal/mol and -5.6 kcal/mol for Urea-1 and Urea-20 respectively. Complexation efficiency was subsequently evaluated, indicating drug:cyclodextrin molar ratios of 1.78 for Urea-1 and 0.70 for Urea-20. Based on these ratios, the formulation was prepared and further characterized, corroborating the formation of the desired inclusion complexes.
The optimum cyclodextrin concentrations for the nebulization solution, as dictated by aerodynamic characterization, were found to be 5% and 15%. The impact of ethanol on the aerodynamic properties of these concentrations was investigated by formulating a nebulization solution with 3% ethanol. Following assessments of aerodynamic properties, solubility, permeability, and chloride ion concentration, a 5% cyclodextrin solution without ethanol emerged as the optimal formulation for the inclusion complex. Future studies will deliver this formulation to mice via IT instillation followed by PK analysis in blood and lung tissue. This research thus presents a promising pathway to augment the therapeutic efficacy of these novel anti-tubercular compounds.