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Effect of Ultra-Small Chitosan Nanoparticles Doped with Brimonidine on the Ultra-Structure of the Trabecular Meshwork of Glaucoma Patients

  • Indu Barwal (a1), Rahul Kumar (a1), Tanuj Dada (a2) and Subhash Chandra Yadav (a1)


Brimonidine, an anti-glaucoma medicine, acts as an adrenergic agonist which decreases the synthesis of aqueous humour and increases the amount of drainage through Schlemm's canal and trabecular meshwork, but shows dose-dependent (0.2% solution thrice daily) toxicity. To reduce the side effects and improve the efficacy, brimonidine was nanoencapsulated on ultra-small-sized chitosan nanoparticles (nanobrimonidine) (28 ± 4 nm) with 39% encapsulation efficiency, monodispersity, freeze–thawing capability, storage stability, and 2% drug loading capacity. This nanocomplex showed burst, half, and complete release at 0.5, 45, and 100 h, respectively. Nanobrimonidine did not show any in vitro toxicity and was taken up by caveolae-mediated endocytosis. The nanobrimonidine-treated trabeculectomy tissue of glaucoma patients showed better dilation of the trabecular meshwork under the electron microscope. This is direct evidence for better bioavailability of nanobrimonidine after topical administration. Thus, the developed nanobrimonidine has the potential to improve the efficacy, reduce dosage and frequency, and improve delivery to the anterior chamber of the eye.


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*Author for correspondence: Subhash Chandra Yadav, E-mail:


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Aburahma, MH & Mahmoud, AA (2011). Biodegradable ocular inserts for sustained delivery of brimonidine tartarate: Preparation and in vitro/in vivo evaluation. AAPS PharmSciTech 12(4), 13351347.
Acheampong, AA, Small, D, Baumgarten, V, Welty, D & Tang-Liu, D (2002). Formulation effects on ocular absorption of brimonidine in rabbit eyes. J Ocul Pharmacol Ther 18(4), 325337.
Agnihotri, SA, Mallikarjuna, NN & Aminabhavi, TM (2004). Recent advances on chitosan-based micro- and nanoparticles in drug delivery. J Control Release 100(1), 528.
Aksungur, P, Demirbilek, M, Denkbas, EB, Vandervoort, J, Ludwig, A & Unlu, N (2011). Development and characterization of cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. J Control Release 151(3), 286294.
Almeida, H, Amaral, MH, Lobao, P & Sousa Lobo, JM (2013). Applications of poloxamers in ophthalmic pharmaceutical formulations: An overview. Expert Opin Drug Deliv 10(9), 12231237.
Almeida, H, Amaral, MH, Lobao, P & Lobo, JM (2014). In situ gelling systems: A strategy to improve the bioavailability of ophthalmic pharmaceutical formulations. Drug Discov Today 19(4), 400412.
Alonso, MJ & Sanchez, A (2003). The potential of chitosan in ocular drug delivery. J Pharm Pharmacol 55(11), 14511463.
Anderberg, EK, Bisrat, M & Nyström, C (1988). Physiochemical aspects of drug release. VII. The effect of surfactant concentration and drug particle size on solubility and dissolution rate of felodipine, a sparingly soluble drug. Int J Pharm 47(1–3), 6777.
Banerjee, T, Mitra, S, Kumar Singh, A, Kumar Sharma, R & Maitra, A (2002). Preparation, characterization and biodistribution of ultrafine chitosan nanoparticles. Int J Pharm 243(1–2), 93105.
Binks, BP & Lumsdon, SO (2001). Pickering emulsions stabilized by monodispersed latex particles: Effects of particle size. Langmuir 17(15), 45404547.
Bonferoni, MC, Sandri, G, Rossi, S, Ferrari, F & Caramella, C (2009). Chitosan and its salts for mucosal and transmucosal delivery. Expert Opin Drug Deliv 6(9), 923939.
Bowman, RJ, Cope, J & Nischal, KK (2004). Ocular and systemic side effects of brimonidine 0.2% eye drops (Alphagan) in children. Eye (Lond) 18(1), 2426.
Calvo, P, Remu án-López, C, Vila-Jato, JL & Alonso, MJ (1997). Novel hydrophilic chitosan–polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 63, 125132.
Cantor, LB (2006). Brimonidine in the treatment of glaucoma and ocular hypertension. Ther Clin Risk Manag 2(4), 337346.
Chen, F, Zhang, ZR & Huang, Y (2007). Evaluation and modification of N-trimethyl chitosan chloride nanoparticles as protein carriers. Int J Pharm 336(1), 166173.
Cho, IS, Park, CG, Huh, BK, Cho, MO, Khatun, Z, Li, Z, Kang, SW, Choy, YB & Huh, KM (2016). Thermosensitive hexanoyl glycol chitosan-based ocular delivery system for glaucoma therapy. Acta Biomater 39, 124132.
De, TK, Rodman, DJ, Holm, BA, Prasad, PN & Bergey, EJ (2003). Brimonidine formulation in polyacrylic acid nanoparticles for ophthalmic delivery. J Microencapsul 20(3), 361374.
De Campos, AM, Sanchez, A & Alonso, MJ (2001). Chitosan nanoparticles: A new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A. Int J Pharm 224(1–2), 159168.
de Campos, AM, Diebold, Y, Carvalho, EL, Sanchez, A & Alonso, MJ (2004). Chitosan nanoparticles as new ocular drug delivery systems: In vitro stability, in vivo fate, and cellular toxicity. Pharm Res 21(5), 803810.
de la Fuente, M, Seijo, B & Alonso, MJ (2008). Novel hyaluronic acid-chitosan nanoparticles for ocular gene therapy. Invest Ophthalmol Vis Sci 49(5), 20162024.
Elzatahry, AA & Eldin, MSM (2008). Preparation and characterization of metronidazole-loaded chitosan nanoparticles for drug delivery application. Polym Adv Technol 19(12), 17871791.
Fan, W, Yan, W, Xu, Z & Ni, H (2012). Formation mechanism of monodisperse, low molecular weight chitosan nanoparticles by ionic gelation technique. Colloids Surf B Biointerfaces 90, 2127.
Hagens, WI, Oomen, AG, de Jong, WH, Cassee, FR & Sips, AJ (2007). What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul Toxicol Pharmacol 49(3), 217229.
Ibrahim, MM, Abd-Elgawad, AH, Soliman, OA & Jablonski, MM (2015). Natural bioadhesive biodegradable nanoparticle-based topical ophthalmic formulations for management of glaucoma. Transl Vis Sci Technol 4(3), 12.
Jarvinen, K, Jarvinen, T & Urtti, A (1995). Ocular absorption following topical delivery. Adv Drug Deliv Rev 16, 319.
Kim, SN, Ko, SA, Park, CG, Lee, SH, Huh, BK, Park, YH, Kim, YK, Ha, A, Park, KH & Choy, YB (2018). Amino-functionalized mesoporous silica particles for ocular delivery of brimonidine. Mol Pharm 15(8), 31433152.
Lehr, CM, Bowstra, JA, Schacht, EH & Juginger, HE (1992). In vitro evaluation of mucoadhesive properties of chitosan and some others natural polymers. Int J Pharm 78, 4348.
Luo, Q, Zhao, J, Zhang, X & Pan, W (2011). Nanostructured lipid carrier (NLC) coated with chitosan oligosaccharides and its potential use in ocular drug delivery system. Int J Pharm 403(1–2), 185191.
Maiti, S, Paul, S, Mondol, R, Ray, S & Sa, B (2011). Nanovesicular formulation of brimonidine tartrate for the management of glaucoma: In vitro and in vivo evaluation. AAPS PharmSciTech 12(2), 755763.
Malhotra, M, Kulamarva, A, Sebak, S, Paul, A, Bhathena, J, Mirzaei, M & Prakash, S (2009). Ultrafine chitosan nanoparticles as an efficient nucleic acid delivery system targeting neuronal cells. Drug Dev Ind Pharm 35(6), 719726.
Motwani, SK, Chopra, S, Talegaonkar, S, Kohli, K, Ahmad, FJ & Khar, RK (2008). Chitosan-sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: Formulation, optimisation and in vitro characterisation. Eur J Pharm Biopharm 68(3), 513525.
Mundada, AS & Avari, JG (2009). In situ gelling polymers in ocular drug delivery systems: A review. Crit Rev Ther Drug Carrier Syst 26(1), 85118.
Natarajan, JV, Darwitan, A, Barathi, VA, Ang, M, Htoon, HM, Boey, F, Tam, KC, Wong, TT & Venkatraman, SS (2014). Sustained drug release in nanomedicine: A long-acting nanocarrier-based formulation for glaucoma. ACS Nano 8(1), 419429.
Newton, MJ & Rimple, (2018) Impact of ocular compatible Lipoids and Castor oil in fabrication of brimonidine tartrate nanoemulsions by 33 full factorial design. Recent Pat Inflamm Allergy Drug Discov.
Paolicelli, P, de la Fuente, M, Sanchez, A, Seijo, B & Alonso, MJ (2009). Chitosan nanoparticles for drug delivery to the eye. Expert Opin Drug Deliv 6(3), 239253.
Prabhu, P, Nitish, KR, Koland, M, Harish, N, Vijayanarayan, K, Dhondge, G & Charyulu, R (2010). Preparation and evaluation of nano-vesicles of brimonidine tartrate as an ocular drug delivery system. J Young Pharm 2(4), 356361.
Qun, G & Ajun, W (2006). Effects of molecular weight, degree of acetylation and ionic strength on surface tension of chitosan in dilute solution. Carbohydr Polym 64, 2936.
Santra, S (2010). Chitosan-based nanoparticles and methods for making and using the same. In 20110158901, US, O. F. (Ed.), USA.
Santra, S & Tallury, P (2011). Ultra-small chitosan nanoparticles useful as bioimaging agents and methods of making same. FSU (Ed.), USA: US20110021745A1.
Shahrouz, T, Seyedali, M, Mehdi, M & Hossein, D (2014). Development of ultrasmall chitosan/succinyl β-cyclodextrin nanoparticles as a sustained protein-delivery system. J Appl Polym Sci 131(1), 3964839648.
Shang, L, Nienhaus, K & Nienhaus, GU (2014). Engineered nanoparticles interacting with cells: Size matters. J Nanobiotechnology 12, 5.
Shi, S, Fliss, BC, Gu, Z, Zhu, Y, Hong, H, Valdovinos, HF, Hernandez, R, Goel, S, Luo, H, Chen, F, Barnhart, TE, Nickles, RJ, Xu, ZP & Cai, W (2015). Chelator-free labeling of layered double hydroxide nanoparticles for in vivo PET imaging. Sci Rep 5, 16930.
Singh, KH & Shinde, UA (2011). Chitosan nanoparticles for controlled delivery of brimonidine tartrate to the ocular membrane. Pharmazie 66(8), 594599.
Sunkireddy, P, Kanwar, RK, Ram, J & Kanwar, JR (2016). Ultra-small algal chitosan ocular nanoparticles with iron-binding milk protein prevents the toxic effects of carbendazim pesticide. Nanomedicine (Lond) 11(5), 495511.
Tallury, P, Kar, S, Bamrungsap, S, Huang, YF, Tan, W & Santra, S (2009). Ultra-small water-dispersible fluorescent chitosan nanoparticles: Synthesis, characterization and specific targeting. Chem Commun 0(17), 23472349.
Tang, S, Huang, Z, Zhang, H, Wang, Y, Hu, Q & Jiang, H (2014). Design and formulation of trimethylated chitosan-graft-poly(epsilon-caprolactone) nanoparticles used for gene delivery. Carbohydr Polym 101, 104112.
Wang, X, Chi, N & Tang, X (2008). Preparation of estradiol chitosan nanoparticles for improving nasal absorption and brain targeting. Eur J Pharm Biopharm 70(3), 735740.
Wu, Y, Yang, W, Wang, C, Hu, J & Fu, S (2005). Chitosan nanoparticles as a novel delivery system for ammonium glycyrrhizinate. Int J Pharm 295(1–2), 235245.
Yadav, SC, Sunkireddy, P, Tripathi, C & Adholeya, A (2013). Novel chitosan based nanoparticles/ultra nanoparticles and method for the preparation of same. In IN 3060/DEL/2013, India (Ed.), India.
Yang, H, Tyagi, P, Kadam, RS, Holden, CA & Kompella, UB (2012). Hybrid dendrimer hydrogel/PLGA nanoparticle platform sustains drug delivery for one week and antiglaucoma effects for four days following one-time topical administration. ACS Nano 6(9), 75957606.


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Effect of Ultra-Small Chitosan Nanoparticles Doped with Brimonidine on the Ultra-Structure of the Trabecular Meshwork of Glaucoma Patients

  • Indu Barwal (a1), Rahul Kumar (a1), Tanuj Dada (a2) and Subhash Chandra Yadav (a1)


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