Design, development and characterization of carrier mediated drug delivery system for effective management of Osteoarticular Tuberculosis
Authors: Prabhu Pratiksha , Fernandes Trinette , Chaubey Pramila , Sawarkar Sujata Pralhad 
Published: April 2021

Abstract
Tuberculosis (TB) is a potentially fatal contagious disease and is a second leading infectious cause of death in world. Bone and joint TB (BJTB)/ Osteoarticular TB is a secondary form of TB occurring most commonly due to hematogenous seeding of mycobacterium (MTB) from the primary site of infection. The prevalence of the disease is around 30 million globally and approximately 30% or 10 million cases exist in India. Osteoarticular tuberculosis, is found in about 10–20% of all diagnosed tuberculosis, is the most common extrapulmonary tuberculosis. Osteoarticular TB is treated using standard regimen of 1 st and 2 nd line Anti- Tubercular drugs (ATDs) for extensive period of 8 - 20 months. These drugs are commonly administered in high doses by oral route or by intravenous route, because of their compromised bioavailability. The common drawbacks associated with conventional therapy are poor patient compliance due to long treatment period, frequent and high dosing and toxicity. Additionally failure by the patients to follow therapeutic regimen properly has given rise to development of resistance against these ATDs. This aspect marks for the need of formulations to eliminate these drawbacks. MTB is an intracellular pathogen of mononuclear phagocyte. This attribute makes nanotherapeutics an ideal approach for MTB treatment as macrophages capture nano forms. Polymeric nanoparticles are removed from the body by opsonization and phagocytosis, this forms an ideal strategy to target macrophage containing mycobacteria. To further improve targetability, the nanoparticles are conjugated with ligand, which serves as an easy substrate for the receptors present on the macrophage surface. The purpose of present work was to develop intra articular injectable in-situ gelling system containing polymeric nanoparticles, which would have promising advantages over conventional method of treatment. The rationale behind formulating nanoparticle incorporated in situ gel based system was to ensure localization of the formulation in intra articular cavity along with sustained release and conjugation of nanoparticles with mannose as ligand to improve uptake by macrophages. Rifampicin standard ATD was formulated into Chitosan nanoparticles. Chitosan with 85% degree of deacetylation (DDA) and Sodium tripolyphosphate (TPP) as the crosslinking agent was used for preparing nanoparticles. The percent entrapment was found to be about 71%. The prepared nanoparticles were conjugated with mannose. Conjugation of ligand was ascertained by performing Fourier transformed Infrared spectroscopy. The particle size was found to be in the range of 130 -140 nm and zeta potential of 38.5 mV. Additionally we performed scanning electron microscopy to characterize the surface morphology of ligand-conjugated nanoparticles. The conjugated Chitosan nanoparticles were incorporated into in situ gelling system comprising of Poloxamer 407 and HPMC K4M. The gelling system was evaluated for viscosity, gelling characteristics and syringeability. The drug release from conjugated nanoparticles incorporated in in situ gel was found to be about 70.3% at the end of 40 hours in simulated synovial fluid following zero order release kinetics. Based on the initial encouraging results obtained, the nanoparticles are being envisaged for ex-vivo cellular uptake study using TB infected macrophages