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Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis

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Abstract

Tuberculosis (TB) is a potentially fatal contagious disease and is a second leading infectious cause of death in the world. Osteoarticular TB is treated using standard regimen of 1st and 2nd 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. 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, which 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 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 h 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

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Availability of data and materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

TB:

Tuberculosis

BJTB:

Bone and joint tuberculosis

MTB:

Mycobacterium

ATDs:

Anti-tubercular drugs

TPP:

Sodium tripolyphosphate

STAB:

Sodium triacetoxy borohydride

HPMC:

Hydroxy propyl methyl cellulose

DDA:

Degree of deacetylation

%EE:

Percent entrapment efficiency

FTIR:

Fourier transformed infrared spectroscopy

DSC:

Differential scanning calorimetry

MCNPs:

Mannose-conjugated chitosan nanoparticles

PDI:

Polydispersity index

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Acknowledgements

The authors wish to thank Sophisticated Analytical Instrument Facility, IIT-Bombay, Powai for their providing SEM analysis samples which are used in this manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutics, SVKM’s Dr Bhanuben Nanavati College of Pharmacy, University of Mumbai, Mumbai, India

    Pratiksha Prabhu, Trinette Fernandes & Sujata P. Sawarkar

  2. Department of Pharmaceutics, College of Pharmacy, Shaqra University, Al-Dawadmi, Saudi Arabia

    Pramila Chaubey

  3. Foundation for Neglected Disease Research, Veerapura Village, Doddaballapur, Bangalore, 561203, India

    Parvinder Kaur, Shridhar Narayanan & Ramya VK

Authors
  1. Pratiksha Prabhu
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  2. Trinette Fernandes
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  3. Pramila Chaubey
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  4. Parvinder Kaur
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  5. Shridhar Narayanan
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  6. Ramya VK
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  7. Sujata P. Sawarkar
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Contributions

All authors contributed to the study and manuscript conception and design. Material preparation, data collection, and analysis and experiments were performed by Ms Pratiksha Prabhu and Ms. Trinette Fernandes. The research activity planning, execution, and supervision were carried out under the guidance of Dr Sujata Sawarkar and Dr Pramila Chaubey. Dr. Shridhar Dr Ramya VK and Dr. Parminder Kaur conducted the MIC studies of formulation against M. tb. All authors commented on previous versions of the manuscript, read, and approved the final manuscript.

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Correspondence to Sujata P. Sawarkar.

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Prabhu, P., Fernandes, T., Chaubey, P. et al. Mannose-conjugated chitosan nanoparticles for delivery of Rifampicin to Osteoarticular tuberculosis. Drug Deliv. and Transl. Res. 11, 1509–1519 (2021). https://doi.org/10.1007/s13346-021-01003-7

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