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Current Drug Therapy


ISSN (Print): 1574-8855
ISSN (Online): 2212-3903

Research Article

Quality-by-design Enabled Chitosan Nanoparticles for Antitubercular Therapy: Formulation, Statistical Optimization, and In Vitro Characterization

Author(s): Manasi M. Chogale, Sujay S. Gaikwad, Savita P. Kulkarni and Vandana B. Patravale*

Volume 16, Issue 1, 2021

Published on: 22 July, 2020

Page: [64 - 82] Pages: 19

DOI: 10.2174/1574885515666200722150305

Price: $65


Background: Tuberculosis (TB) continues to be among the leading causes of high mortality among developing countries. Though a seemingly effective treatment regimen against TB is in place, there has been no significant improvement in the therapeutic rates. This is primarily owing to the high drug doses, their associated side-effects, and prolonged treatment regimen. Discontinuation of therapy due to the severe side effects of the drugs results in the progression of the infection to the more severe drug-resistant TB.

Objectives: Reformulation of the current existing anti TB drugs into more efficient dosage forms could be an ideal way out. Nanoformulations have been known to mitigate the side effects of toxic, high-dose drugs. Hence, the current research work involves the formulation of Isoniazid (INH; a first-line anti TB molecule) loaded chitosan nanoparticles for pulmonary administration.

Methods: INH loaded chitosan nanoparticles were prepared by ionic gelation method using an anionic crosslinker. Drug-excipient compatibility was evaluated using DSC and FT-IR. The formulation was optimized on the principles of Quality-by-Design using a full factorial design.

Results: The obtained nanoparticles were spherical in shape having an average size of 620±10.97 nm and zeta potential +16.87±0.79 mV. Solid-state characterization revealed partial encapsulation and amorphization of INH into the nanoparticulate system. In vitro release study confirmed an extended release of INH from the system. In vitro cell line-based safety and efficacy studies revealed satisfactory results.

Conclusion: The developed nanosystem is thus an efficient approach for antitubercular therapy.

Keywords: Tuberculosis, isoniazid, chitosan, nanoparticles, factorial design, quality-by-design.

Graphical Abstract
Global tuberculosis report. Global Health TB Report 2018. [Jun 18, 2020];
Global tuberculosis report 2019. Available from: on June 18, 2020).
Pandey R, Ahmad Z. Nanomedicine and experimental tuberculosis: facts, flaws, and future. Nanomedicine (Lond) 2011; 7(3): 259-72.
[] [PMID: 21329765]
Tostmann A, Boeree MJ, Aarnoutse RE, De Lange WCM, Van Der Ven AJAM, Dekhuijzen R. Antituberculosis Drug-induced Hepatotoxicity: Concise up-to-Date Review. J Gastroenterol Hepatol (Australia) 2008; 23(2): 192-202.
Goldman AL, Braman SS. Isoniazid: a review with emphasis on adverse effects. Chest 1972; 62(1): 71-7.
[] [PMID: 4339326]
Singh B, Kapil R, Nandi M, Ahuja N. Developing oral drug delivery systems using formulation by design: vital precepts, retrospect and prospects. Expert Opin Drug Deliv 2011; 8(10): 1341-60.
[] [PMID: 21790511]
Lionberger RA, Lee SL, Lee L, Raw A, Yu LX. Quality by design: concepts for ANDAs. AAPS J 2008; 10(2): 268-76.
[] [PMID: 18465252]
Negi P, Singh B, Sharma G, Beg S, Raza K, Katare OP. Phospholipid microemulsion-based hydrogel for enhanced topical delivery of lidocaine and prilocaine: QbD-based development and evaluation. Drug Deliv 2016; 23(3): 951-67.
[] [PMID: 24892623]
Mandenius CF, Graumann K, Schultz TW, et al. Quality-by-Design for biotechnology-related pharmaceuticals. Biot J 2009.
Mundada PK, Sawant KK, Mundada VP. Formulation and optimization of controlled release powder for reconstitution for metoprolol succinate multi unit particulate formulation using risk based QbD approach. J Drug Deliv Sci Technol 2017; 41: 462-74.
Liu H, Gao C. Preparation and properties of ionically cross-linked chitosan nanoparticles. Polym Adv Technol 2009; 20(7): 613-9.
Deng QY, Zhou CR, Luo BH. Preparation and characterization of chitosan nanoparticles containing lysozyme. Pharm Biol 2006; 44(5): 336-42.
Chandrasekaran CV, Sundarajan K, Edwin JR, Gururaja GM, Mundkinajeddu D, Agarwal A. Immune-stimulatory and anti-inflammatory activities of Curcuma longa extract and its polysaccharide fraction. Pharmacognosy Res 2013; 5(2): 71-9.
[] [PMID: 23798880]
Naik SK, Mohanty S, Padhi A, Pati R, Sonawane A. Evaluation of antibacterial and cytotoxic activity of Artemisia nilagirica and Murraya koenigii leaf extracts against mycobacteria and macrophages. BMC Complement Altern Med 2014; 14: 87.
[] [PMID: 24597853]
Martin A, Morcillo N, Lemus D, et al. Multicenter study of MTT and resazurin assays for testing susceptibility to first-line anti-tuberculosis drugs. Int J Tuberc Lung Dis 2005; 9(8): 901-6.
[PMID: 16104638]
Pai RV, Jain RR, Bannalikar AS, Menon MD. Development and evaluation of chitosan microparticles based dry powder inhalation formulations of rifampicin and rifabutin. J Aerosol Med Pulm Drug Deliv 2016; 29(2): 179-95.
[] [PMID: 26406162]
Beg S, Sandhu PS, Batra RS, Khurana RK, Singh B. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv 2015; 22(6): 765-84.
[] [PMID: 24673611]
Garg NK, Sharma G, Singh B, et al. Quality by Design (QbD)-enabled development of aceclofenac loaded-nano structured lipid carriers (NLCs): An improved dermatokinetic profile for inflammatory disorder(s). Int J Pharm 2017; 517(1-2): 413-31.
[] [PMID: 27956192]
Abraham S, Rajamanick D, Srinivasan B. Preparation, characterization and cross-linking of chitosan by microwave assisted synthesis. Sci Int 2018; 6(1): 18-30.
Verma RK, Garg S. Selection of excipients for extended release formulations of glipizide through drug-excipient compatibility testing. J Pharm Biomed Anal 2005; 38(4): 633-44.
[] [PMID: 15967291]
Pourshahab PS, Gilani K, Moazeni E, Eslahi H, Fazeli MR, Jamalifar H. Preparation and characterization of spray dried inhalable powders containing chitosan nanoparticles for pulmonary delivery of isoniazid. J Microencapsul 2011; 28(7): 605-13.
[] [PMID: 21793647]
Bernkop-Schnürch A, Dünnhaupt S. Chitosan-based drug delivery systems. Eur J Pharm Biopharm 2012; 81(3): 463-9.
[] [PMID: 22561955]
Stat-Ease » v11 » General Sequence of Analysis. Available from: on Jun 11, 2020).
López-León T, Carvalho ELS, Seijo B, Ortega-Vinuesa JL, Bastos-González D. Physicochemical characterization of chitosan nanoparticles: electrokinetic and stability behavior. J Colloid Interface Sci 2005; 283(2): 344-51.
[] [PMID: 15721903]
Silverstein RM, Bassler GC, Morrill T. Chapter three: infrared spectrometryspectrometric identification of organic compounds. 5th ed. John Wiley & Sons, Inc. 1991; pp. 91-164.
Mohammadpourdounighi N, Behfar A, Ezabadi A, Zolfagharian H, Heydari M. Preparation of chitosan nanoparticles containing Naja naja oxiana snake venom. Nanomedicine (Lond) 2010; 6(1): 137-43.
[] [PMID: 19616121]
Zu Y, Sun W, Zhao X, et al. Preparation and characterization of amorphous amphotericin B nanoparticles for oral administration through liquid antisolvent precipitation. Eur J Pharm Sci 2014; 53(1): 109-17.
[] [PMID: 24345795]
Joshi SA, Chavhan SS, Sawant KK. Rivastigmine-loaded PLGA and PBCA nanoparticles: preparation, optimization, characterization, in vitro and pharmacodynamic studies. Eur J Pharm Biopharm 2010; 76(2): 189-99.
[] [PMID: 20637869]
Sadeghi AMM, Dorkoosh FA, Avadi MR, Saadat P, Rafiee-Tehrani M, Junginger HE. Preparation, characterization and antibacterial activities of chitosan, N-trimethyl chitosan (TMC) and N-diethylmethyl chitosan (DEMC) nanoparticles loaded with insulin using both the ionotropic gelation and polyelectrolyte complexation methods. Int J Pharm 2008; 355(1-2): 299-306.
[] [PMID: 18206322]
Sawayanagi Y, Nambu N, Nagai T. Enhancement of dissolution properties of prednisolone from ground mixtures with chitin or chitosan. Chem Pharm Bull 983; 31(7): 2507-9.
Genta I, Pavanetto F, Conti B, Giunchedi P, Conte U. Improvement of Dexamethasone Dissolution Rate from Spray-Dried Chitosan Microspheres. S.T.P. Pharma Prat 1995.
Wardani G. Mahmiah, Sudjarwo SA. In vitro antibacterial activity of chitosan nanoparticles against mycobacterium tuberculosis. Pharmacogn J 2018; 10(1): 162-6.
Qi L, Xu Z, Jiang X, Hu C, Zou X. Preparation and antibacterial activity of chitosan nanoparticles. Carbohydr Res 2004; 339(16): 2693-700.
[] [PMID: 15519328]
Sobhani Z, Mohammadi Samani S, Montaseri H, Khezri E. Nanoparticles of chitosan loaded ciprofloxacin: fabrication and antimicrobial activity. Adv Pharm Bull 2017; 7(3): 427-32.
[] [PMID: 29071225]

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