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Recent Patents on Drug Delivery & Formulation


ISSN (Print): 1872-2113
ISSN (Online): 2212-4039

Review Article

Advanced Hydrogels Based Drug Delivery Systems for Ophthalmic Delivery

Author(s): Srividya Gorantla, Tejashree Waghule, Vamshi Krishna Rapalli, Prem Prakash Singh, Sunil Kumar Dubey, Ranendra Narayan Saha and Gautam Singhvi *

Volume 13 , Issue 4 , 2019

Page: [291 - 300] Pages: 10

DOI: 10.2174/1872211314666200108094851

Price: $65


Hydrogels are aqueous gels composed of cross-linked networks of hydrophilic polymers. Stimuli-responsive based hydrogels have gained focus over the past 20 years for treating ophthalmic diseases. Different stimuli-responsive mechanisms are involved in forming polymer hydrogel networks, including change in temperature, pH, ions, and others including light, thrombin, pressure, antigen, and glucose-responsive. Incorporation of nanocarriers with these smart stimuli-responsive drug delivery systems that can extend the duration of action by increasing ocular bioavailability and reducing the dosing frequency. This review will focus on the hydrogel drug delivery systems highlighting the gelling mechanisms and emerging stimuli-responsive hydrogels from preformed gels, nanogels, and the role of advanced 3D printed hydrogels in vision-threatening diseases like age-related macular degeneration and retinitis pigmentosa. It also provides insight into the limitations of hydrogels along with the safety and biocompatibility of the hydrogel drug delivery systems.

Keywords: Ophthalmic drug delivery, hydrogel, stimuli-responsive, nanogel, vision-threatening diseases, macular degeneration.

Graphical Abstract
Mitra, A.K. Ophthalmic drug delivery systems; Marcel Dekker: New York, 2003.
Kwatra, D.; Mitra, A.K. Drug delivery in ocular diseases: Barriers and strategies. World J. Pharmacol., 2013, 2(4), 78-83.
Vadlapatla, R.K.; Vadlapudi, A.D.; Pal, D.; Mitra, A.K. Role of membrane transporters and metabolizing enzymes in ocular drug delivery. Curr. Drug Metab., 2014, 15(7), 680-693.
[] [PMID: 25255873]
Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A.K. Ocular drug delivery systems: An overview. World J. Pharmacol., 2013, 2(2), 47-64.
[] [PMID: 25590022]
Kirchhof, S; Goepferich, AM; Brandl, FP Hydrogels in ophthalmic applications. Eur J Pharm Biopharm 2015; 95(Pt B): 227-38.,
[] [PMID: 26032290]
Destruel, P-L.; Zeng, N.; Maury, M.; Mignet, N.; Boudy, V. In vitro and in vivo evaluation of in situ gelling systems for sustained topical ophthalmic delivery: State of the art and beyond. Drug Discov. Today, 2017, 22(4), 638-651.
[] [PMID: 28017837]
Deshpande, S.G.; Shirolkar, S. Sustained release ophthalmic formulations of pilocarpine. J. Pharm. Pharmacol., 1989, 41(3), 197-200.
[] [PMID: 2568450]
Xinming, L.; Yingde, C.; Lloyd, A.W. Polymeric hydrogels for novel contact lens-based ophthalmic drug delivery systems: A review. Cont. Lens Anterior Eye, 2008, 31(2), 57-64.
[] [PMID: 17962066]
Hehl, E-M.; Beck, R.; Luthard, K.; Guthoff, R.; Drewelow, B. Improved penetration of aminoglycosides and fluorozuinolones into the aqueous humour of patients by means of Acuvue contact lenses. Eur. J. Clin. Pharmacol., 1999, 55(4), 317-323.
[] [PMID: 10424326]
Lee, S.C.; Kwon, I.K.; Park, K. Hydrogels for delivery of bioactive agents: A historical perspective. Adv. Drug Deliv. Rev., 2013, 65(1), 17-20.
[] [PMID: 22906864]
Hu, X.; Hao, L.; Wang, H. Hydrogel contact lens for extended delivery of ophthalmic drugs. Int. J. Polym. Sci., 2011, 1-9.
Khandan A, Jazayeri H, Fahmy MD, Razavi M, Eds. Hydrogels: Types, structure, properties, and applications. Biomat Tiss Eng. 2017; 4(27): 2017; 143-69.
Kim, Y.C.; Chiang, B.; Wu, X.; Prausnitz, M.R. Ocular delivery of macromolecules. J. Control. Release, 2014, 190, 172-181.
Sosnik, A.; Seremeta, K.P.; Sosnik, A.; Seremeta, K.P. Polymeric hydrogels as technology platform for drug delivery applications. Gels, 2017, 3(3), 25.
[] [PMID: 30920522]
Yan, C.; Altunbas, A.; Yucel, T.; Nagarkar, R.P.; Schneider, J.P.; Pochan, D.J. Injectable solid hydrogel: Mechanism of shear-thinning and immediate recovery of injectable β-hairpin peptide hydrogels. Soft Matter, 2010, 6(20), 5143-5156.
[] [PMID: 21566690]
Falavarjani, K.G.; Nguyen, Q.D. Adverse events and complications associated with intravitreal injection of anti-VEGF agents: A review of literature. Eye, 2013, 27(7), 787-794.
Chang, D.; Park, K.; Famili, A. Hydrogels for sustained delivery of biologics to the back of the eye. Drug Discov. Today, 2019, 24(8), 1470-1482.
Yu, Y.; Lau, L.C.M.; Lo, A.C.; Chau, Y. Injectable chemically crosslinked hydrogel for the controlled release of bevacizumab in vitreous: A 6-month in vivo study. Transl. Vis. Sci. Technol., 2015, 4(2), 5.
[] [PMID: 25774331]
Yu, S.; Zhang, X.; Tan, G. A novel pH-induced thermosensitive hydrogel composed of carboxymethyl chitosan and poloxamer cross-linked by glutaraldehyde for ophthalmic drug delivery. Carbohydr. Polym., 2017, 155, 208-217.
[] [PMID: 27702506]
Upadhayay, P.; Kumar, M.; Pathak, K. Norfloxacin Loaded pH triggered nanoparticulate in-situ gel for extraocular bacterial infections: Optimization, ocular irritancy and corneal toxicity. Iran. J. Pharm. Res., 2016, 15(1), 3-22.
[PMID: 27610144]
Yang, X.; Trinh, H.M.; Agrahari, V.; Sheng, Y.; Pal, D.; Mitra, A.K. Nanoparticle-based topical ophthalmic gel formulation for sustained release of hydrocortisone butyrate. AAPS PharmSciTech, 2016, 17(2), 294-306.
[] [PMID: 26085051]
Mazet, R.; Choisnard, L.; Levilly, D. Investigation of combined cyclodextrin and hydrogel formulation for ocular delivery of dexamethasone acetate by means of experimental designs. Pharmaceutics, 2018, 10(4), 249.
[] [PMID: 30513707]
Casolaro, M.; Casolaro, I.; Lamponi, S. Stimuli-responsive hydrogels for controlled pilocarpine ocular delivery. Eur. J. Pharm. Biopharm., 2012, 80(3), 553-561.
[] [PMID: 22138000]
Li, X.; Zhang, Z.; Chen, H. Development and evaluation of fast forming nano-composite hydrogel for ocular delivery of diclofenac. Int. J. Pharm., 2013, 448(1), 96-100.
[] [PMID: 23524120]
Lovett, ML; Wang, X; Yucel, T Silk hydrogels for sustained ocular delivery of anti-Vascular Endothelial Growth Factor (anti-VEGF) therapeutics. Eur J Pharm Biopharm 2015; 95(Pt B): 271-8
[] [PMID: 25592326]
El-Feky, G.S.; Zayed, G.M.; Elshaier, Y.A.M.M.; Alsharif, F.M. Chitosan-gelatin hydrogel crosslinked with oxidized sucrose for the ocular delivery of timolol maleate. J. Pharm. Sci., 2018, 107(12), 3098-3104.
[] [PMID: 30165067]
Patel, N.; Nakrani, H.; Raval, M.; Sheth, N. Development of loteprednol etabonate-loaded cationic nanoemulsified in-situ ophthalmic gel for sustained delivery and enhanced ocular bioavailability. Drug Deliv., 2016, 23(9), 3712-3723.
[] [PMID: 27689408]
Liu, R.; Sun, L.; Fang, S. Thermosensitive in situ nanogel as ophthalmic delivery system of curcumin: Development, characterization, in vitro permeation and in vivo pharmacokinetic studies. Pharm. Dev. Technol., 2015, 1-7.
[PMID: 26024239]
Wang, G.; Nie, Q.; Zang, C. Pharmaceutics, Drug delivery and pharmaceutical technology self-assembled thermoresponsive nanogels prepared by reverse micelle / positive micelle method for ophthalmic delivery of muscone, a poorly water-soluble drug. J. Pharm. Sci., 2016, 105(9), 2752-2759.
Liu, W.; Borrell, M.A.; Venerus, D.C. Characterization of biodegradable microsphere-hydrogel ocular drug delivery system for controlled and extended release of ranibizumab. Transl. Vis. Sci. Technol., 2019, 8(1), 12.
[] [PMID: 30701127]
Fathi, M.; Barar, J.; Aghanejad, A.; Omidi, Y. Hydrogels for ocular drug delivery and tissue engineering. Bioimpacts, 2015, 5(4), 159-164.
[] [PMID: 26929918]
Ramya Devi, D.; Sandhya, P.; Vedha Hari, B. Poloxamer: A novel functional molecule for drug delivery and gene therapy. J Pharm Sci & Res, 2013, 5(8), 159-165.
Fathalla, Z.M.A.; Vangala, A.; Longman, M. Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies. Eur. J. Pharm. Biopharm., 2017, 114, 119-134.
[] [PMID: 28126392]
Escobar-Chávez, J.J.; López-Cervantes, M.; Naïk, A. Applications of thermo- reversible pluronic f-127 gels in pharmaceutical formulations. J. Pharm. Pharm. Sci., 2006, 9(3), 339-358.
Heskins, M.; Guillet, J.E. Solution Properties of poly(N-isopropylacrylamide). J Macromol Sci Part A - Chem, 1968, 2(8), 1441-1455.
Xu, X-D.; Wei, H.; Zhang, X-Z. Fabrication and characterization of a novel composite PNIPAAm hydrogel for controlled drug release. J. Biomed. Mater. Res. A, 2007, 81(2), 418-426.
[] [PMID: 17117471]
Bellotti, E.; Fedorchak, M.V.; Velankar, S.; Little, S.R. Tuning of thermoresponsive pNIPAAm hydrogels for the topical retention of controlled release ocular therapeutics. J. Mater. Chem. B Mater. Biol. Med., 2019, 7(8), 1276-1283.
[] [PMID: 30931126]
Celluvisc Uses. Side Effects & Warnings - Available from
Ultra Tears Ophthalmic (Eye): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD. Available from:
Wu, Y.; Liu, Y.; Li, X. Research progress of in-situ gelling ophthalmic drug delivery system. Asian J Pharma Sci, 2019, 14, 1-15.
Swift, T.; Swanson, L.; Geoghegan, M.; Rimmer, S. The pH-responsive behaviour of poly(acrylic acid) in aqueous solution is dependent on molar mass. Soft Matter, 2016, 12(9), 2542-2549.
[] [PMID: 26822456]
Park, K. Controlled drug delivery systems: past forward and future back. J. Control. Release, 2014, 190, 3-8.
[] [PMID: 24794901]
Faccia, P.A.; Pardini, F.M.; Amalvy, J.I. Uptake and release of Dexamethasone using pH-responsive poly(2-hydroxyethyl methacrylate-co-2-(diisopropylamino)ethyl methacrylate) hydrogels for potential use in ocular drug delivery. J. Drug Deliv. Sci. Technol., 2019, 51, 45-54.
Liu, Y.; Wang, S.; Sun, D. Development of a biomimetic chondroitin sulfate-modified hydrogel to enhance the metastasis of tumor cells. Sci. Rep., 2016, 6(6), 29858.
[] [PMID: 27432752]
Anjali, S.; Rameshwar, D.; Shivani, D.; Ranjit, S. Hydrogels in ophthalmic drug delivery system - A mini review. Asian Pacific J Heal Sci, 2019, 5(2), 96-104.
Li, P.; Wang, S.; Chen, H. A novel ion-activated in situ gelling ophthalmic delivery system based on κ-carrageenan for acyclovir. Drug Dev. Ind. Pharm., 2018, 44(5), 829-836.
[] [PMID: 29212376]
Kushwaha, S.K.; Saxena, P.; Rai, A. Stimuli sensitive hydrogels for ophthalmic drug delivery: A review. Int. J. Pharm. Investig., 2012, 2(2), 54-60.
[] [PMID: 23119233]
Singh, B.; Garg, T.; Goyal, A.K.; Rath, G. Recent advancements in the cardiovascular drug carriers. Artif. Cells Nanomed. Biotechnol., 2016, 44(1), 216-225.
[] [PMID: 25046615]
Kim, J.J.; Park, K. Smart hydrogels for bioseparation. Bioseparation, 1998-1999, 7(4-5), 177-184.
[] [PMID: 10432576]
Osswald, C.R.; Kang-Mieler, J.J. Controlled and extended release of a model protein from a microsphere-hydrogel drug delivery system. Ann. Biomed. Eng., 2015, 43(11), 2609-2617.
[] [PMID: 25835212]
Jiang, S.; Franco, Y.L.; Zhou, Y.; Chen, J. Nanotechnology in retinal drug delivery. Int. J. Ophthalmol., 2018, 11(6), 1038-1044.
[PMID: 29977820]
Zhao, F.; Yao, D.; Guo, R.; Deng, L.; Dong, A.; Zhang, J. Composites of polymer hydrogels and nanoparticulate systems for biomedical and pharmaceutical applications. Nanomaterials (Basel), 2015, 5(4), 2054-2130.
Jain, S.; Cherukupalli, S.K.; Mahmood, A. Emerging nanoparticulate systems: Preparation techniques and stimuli responsive release characteristics. J. Appl. Pharm. Sci., 2019, 9(08), 130-143.
Shah, A.; Singhvi, G. Dendrimer: A Novel System in Pharmaceuticals. PharmaTutor, 2014, 2(1), 83-97.
Buwalda, S.J.; Vermonden, T.; Hennink, W.E. Hydrogels for therapeutic delivery: current developments and future directions. Biomacromolecules, 2017, 18(2), 316-330.
[] [PMID: 28027640]
Singhvi, G.; Banerjee, S.; Khosa, A. Lyotropic liquid crystal nanoparticles: A novel improved lipidic drug delivery system; Org Mater Smart Nanocarriers Drug Deliv, 2018, pp. 471-517.
Girdhar, V.; Patil, S.; Banerjee, S.; Singhvi, G. Nanocarriers for drug delivery: mini review. Curr. Nanomed., 2018, 8(2), 88-99.
Singhvi, G.; Hans, N.; Shiva, N. Xanthan gum in drug delivery Natural Polysaccharides in Drug Delivery and Biomedical Applications; Academic Press, 2019, pp. 121-144.
Singhvi, G.; Patil, S.; Girdhar, V.; Dubey, S.K. Nanocarriers for topical drug delivery: Approaches and advancements. Nanosci. Nanotechnol. Asia, 2019, 9(3), 329-336.
Gómez-Ballesteros, M.; López-Cano, J.J.; Bravo-Osuna, I. Osmoprotectants in Hybrid Liposome/HPMC Systems as Potential Glaucoma Treatment. Polymers (Basel), 2019, 11(6) pii: E929.
Patel, S.P.; Vaishya, R.; Pal, D.; Mitra, A.K. Novel pentablock copolymer-based nanoparticulate systems for sustained protein delivery. AAPS PharmSciTech, 2015, 16(2), 327-343.
[] [PMID: 25319053]
Agrahari, V.; Patel, S.P.; Dhall, N. Nanoparticles in thermosensitive gel based composite nanosystem for ocular diseases. Drug Deliv. Transl. Res., 2018, 8(2), 422-435.
[] [PMID: 29181835]
Sivaram, A.J.; Rajitha, P.; Maya, S.; Jayakumar, R.; Sabitha, M. Nanogels for delivery, imaging and therapy. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol., 2015, 7(4), 509-533.
[] [PMID: 25581024]
Yang, X.; Trinh, H.M.; Agrahari, V. Nanoparticle-based topical ophthalmic gel formulation for sustained release of hydrocortisone butyrate. AAPS PharmSciTech, 2016, 17(2), 294-306.
Brannigan, R.P.; Khutoryanskiy, V.V. Synthesis and evaluation of mucoadhesive acryloyl-quaternized PDMAEMA nanogels for ocular drug delivery. Colloids Surf. B Biointerfaces, 2017, 155, 538-543.
[] [PMID: 284944320]
Eljarrat-Binstock, E.; Raiskup, F.; Stepensky, D.; Domb, A.J.; Frucht-Pery, J. Delivery of gentamicin to the rabbit eye by drug-loaded hydrogel iontophoresis. Invest. Ophthalmol. Vis. Sci., 2004, 45(8), 2543-2548.
[] [PMID: 15277475]
Hoare, T.R.; Kohane, D.S. Hydrogels in drug delivery: Progress and challenges. Polymer (Guildf.), 2008, 49(8), 1993-2007.
Shah, S.S.; Denham, L.V.; Elison, J.R. Drug delivery to the posterior segment of the eye for pharmacologic therapy. Expert Rev. Ophthalmol., 2010, 5(1), 75-93.
[] [PMID: 20305803]
Hanif, S.; Lim, A.; Sit, H.; Tan, W.Q.M. Computational Study of Hydrogel Ring Device for Ocular Drug Delivery; Cornell University: NY, 2018.
Rutz, A.L.; Hyland, K.E.; Jakus, A.E.; Burghardt, W.R.; Shah, R.N. A multimaterial bioink method for 3D printing tunable, cell-compatible hydrogels. Adv. Mater., 2015, 27(9), 1607-1614.
[] [PMID: 25641220]
Singhvi, G.; Patil, S.; Girdhar, V.; Chellappan, D.K.; Gupta, G.; Dua, K. 3D-printing: An emerging and a revolutionary technology in pharmaceuticals. Panminerva Med., 2018, 60(4), 170-173.
Li, Z.; Loh, X.J. Four-Dimensional (4D) Printing: Applying soft adaptive materials to additive manufacturing. J Mol Eng Mater, 2017, 5(2)1740003
Malik, H.H.; Darwood, A.R.J.; Shaunak, S. Three-dimensional printing in surgery: A review of current surgical applications. J. Surg. Res., 2015, 199(2), 512-522.
[] [PMID: 26255224]
Müller, M.; Becher, J.; Schnabelrauch, M.; Zenobi-Wong, M. Nanostructured pluronic hydrogels as bioinks for 3D bioprinting. Biofabrication, 2015, 7(3)035006
[] [PMID: 26260872]
Duan, B.; Hockaday, L.A.; Kang, K.H.; Butcher, J.T., III 3D bioprinting of heterogeneous aortic valve conduits with alginate/gelatin hydrogels. J. Biomed. Mater. Res. A, 2013, 101(5), 1255-1264.
[] [PMID: 23015540]
Singhvi, G.; Krishna, R.V.; Krishna, K.V.; Dubey, S.K. Alginate: Drug Delivery and Application. In: Alginates: Versatile Polymers in Biomedical Applications and Therapeutics 2019; Apple Academic Press (ISBN: 9781771887823).
Isaacson, A.; Swioklo, S.; Connon, C.J. 3D bioprinting of a corneal stroma equivalent. Exp. Eye Res., 2018, 173, 188-193.
[] [PMID: 29772228]
Beharry, K.D.; Cai, C.L.; Valencia, G.B. Human retinal endothelial cells and astrocytes cultured on 3-D scaffolds for ocular drug discovery and development. Prostaglandins Other Lipid Mediat., 2018, 134, 93-107.
[] [PMID: 28923362 ]
Ren, T.; Lin, X.; Zhang, Q. Encapsulation of azithromycin ion pair in liposome for enhancing ocular delivery and therapeutic efficacy on dry eye. Mol. Pharm., 2018, 15(11), 4862-4871.
[] [PMID: 30251864]
Kanjickal, D.; Lopina, S.; Evancho-Chapman, M.M.; Schmidt, S.; Donovan, D. Effects of sterilization on poly(ethylene glycol) hydrogels. J. Biomed. Mater. Res. A, 2008, 87(3), 608-617.
[] [PMID: 18186054]
Hammer, N.; Brandl, F.P.; Kirchhof, S.; Messmann, V.; Goepferich, A.M. Protein compatibility of selected cross-linking reactions for hydrogels. Macromol. Biosci., 2015, 15(3), 405-413.
[] [PMID: 25399803]
Lin, C-C.; Anseth, K.S. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm. Res., 2009, 26(3), 631-643.
[] [PMID: 19089601]

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