Chitosan-Based Ocular Drug Delivery Systems



Chitosan is widely used in ocular drug delivery systems due to its biocompatibility, biodegradability, and favorable physicochemical characteristics. Chitosan-based ocular drug delivery systems are widely reported to improve the bioavailability at the anterior/posterior pole of the eye due to its mucoadhesive property that helps to increase efficacy of existing ocular drugs, affords stimuli responsive/targeted-based delivery regimen, enhances the corneal permeability, and improves the accumulation of drugs in the corneal/conjunctival epithelia for an extended period of time. This review summarizes the major ocular diseases affecting the eye, ocular delivery systems, novel ocular drug delivery systems, intraocular drug transport barriers, and ocular transporters. The utilization of chitosan toward the ocular drug delivery systems such as stimuli responsive systems, targeted delivery systems, and gene-based delivery systems is also discussed.


Chitosan Ocular drug delivery Cornea Ocular diseases 



Age-related macular degeneration


Bardet-Biedl syndrome




Chitosan nanoparticle


C-jun NH2 terminal kinase


Core-shell liponanoparticles




Diabetic retinopathy




Diethyl squarate


Enhanced permeability and retention effect


Ethylene glycol diglycidyl ether




Leber congenital amaurosis


Leber congenital amaurosis type 2


Lower critical solution temperature



NF- κB

Nuclear factor-kappa B


Poly(lactic-co-glycolic acid)


Poly(adenosine diphosphate-ribose) polymerase-1


Polyethylene glycol


Protein kinase C




Renin-angiotensin-aldosterone system




Retinitis pigmentosa


Retinal pigment epithelium


Rho-associated protein kinase


Scanning electron microscopy


Selective androgen receptor modulators


Selective estrogen receptor modulators


Self-assembled nanoparticles


Targeted drug delivery system


Vascular endothelial growth factor


  1. Agarwal R, Gupta SK, Agarwal P, Saxena R, Agrawal SS (2009) Current concepts in the pathophysiology of glaucoma. Indian J Ophthalmol 57(4):257–266PubMedPubMedCentralCrossRefGoogle Scholar
  2. Allen TM (2002) Ligand-targeted therapeutics in anticancer therapy. Nat Rev Cancer 2(10):750–763. PubMedCrossRefGoogle Scholar
  3. Bennet BL, Sasaki DT, Murray BW et al (2001) SP600125. An anthrapyrazolone inhibitor of Jun N- terminal kinase. Proc Nat Acad Sci USA 98:13681–13686CrossRefGoogle Scholar
  4. Berger J, Reist M, Mayer JM, Felt O, Peppas NA, Gurny R (2004) Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications. Eur J Pharm Biopharm 57(1):19–34. PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bhattarai N, Gunn J, Zhang M (2010) Chitosan-based hydrogels for controlled, localized drug delivery. Adv Drug Deliv Rev 62(1):83–99. CrossRefPubMedGoogle Scholar
  6. Bowman LM, Si E, Pang J, Archibald R, Friedlaender M (2009) Development of a topical polymeric mucoadhesive ocular delivery system for azithromycin. J Ocul Pharmacol Ther 25(2):133–139PubMedCrossRefGoogle Scholar
  7. Chaira G, Zeina D, Paola S et al (2009) The TGF-β pathway is a common target of drugs that prevent experimental diabetic retinopathy. Diabetes 58:1659–1667CrossRefGoogle Scholar
  8. Chawla SP, Kanatt SR, Sharma AK (2014) Chitosan. In: Ramawat KG, Mérillon J (eds) Polysaccharides bioactivity and biotechnology. Springer, Cham, pp 219–246Google Scholar
  9. Cheng Y, Hung K, Tsai T, Lee C (2014) Sustained delivery of latanoprost by thermosensitive chitosan-gelatin-based hydrogel for controlling ocular hypertension. Acta Biomater. PubMedCrossRefGoogle Scholar
  10. Cheng Y, Tsai T, Jhan Y, Chiu AW, Tsai K, Chien C et al (2016a) Thermosensitive chitosan-based hydrogel as a topical ocular drug delivery system of latanoprost for glaucoma treatment. Carbohydr Polym 144:390–399. PubMedCrossRefGoogle Scholar
  11. Cheng YH, Tsai TH, Jhanb YY, Chiud AW h, Tsai KL, Chien CS, Chioub SH, Liu CJ l (2016b) Thermosensitive chitosan-based hydrogel as a topical ocular drug delivery system of latanoprost for glaucoma treatment. Carbohydr Polym 144PubMedCrossRefGoogle Scholar
  12. Chiou GCY (2001) Review: effects of nitric oxide on eye diseases and their treatment. J Ocul Pharmacol Ther 17(2):189–198. PubMedCrossRefGoogle Scholar
  13. Colligris B, Alkozi HA, Pintor J (2014) Recent developments on dry eye disease treatment compounds. Saudi J Ophthalmol 28(1):19–30. PubMedCrossRefGoogle Scholar
  14. Conley SM, Naash MI (2010) Progress in retinal and eye research nanoparticles for retinal gene therapy. Prog Retin Eye Res 29(5):376–397. PubMedPubMedCentralCrossRefGoogle Scholar
  15. Contreras-Ruiz L, de la Fuente M, García-Vázquez C, Sáez V, Seijo B, Alonso MJ, Calonge M, Diebold Y (2010) Ocular tolerance to a topical formulation of hyaluronic acid and chitosan-based nanoparticles. Cornea 29(5):550–558PubMedCrossRefGoogle Scholar
  16. Dalton JT, Miller DD, Rakov I et al (2008) Selective androgen receptor modulators, analogs and derivatives thereof and uses thereof. Patent application no. PCT/US2007/016311Google Scholar
  17. Davis BM, Pahlitzsch M, Guo L, Balendra S, Shah P, Ravindran N, et al (2018) Topical curcumin nanocarriers are neuroprotective in eye disease. Sci Reps March: 1–13.
  18. De M, Raviña M, Paolicelli P, Sanchez A, Seijo B, Jose M (2010) Chitosan-based nanostructures: a delivery platform for ocular therapeutics. Adv Drug Deliv Rev 62(1):100–117. CrossRefGoogle Scholar
  19. Delgado D, Pozo-rodríguez A, Solinís MA, Bartkowiak A, Rodríguez-gascón A (2013) European Journal of Pharmaceutical Sciences New gene delivery system based on oligochitosan and solid lipid nanoparticles : ‘ In vitro ’ and ‘ in vivo ’ evaluation. Eur J Pharm Sci 50(3–4):484–491. PubMedCrossRefGoogle Scholar
  20. Deng H, Wang Y, Ding Q, Li D, Wei Y (2017) Gene therapy research in Asia 1:572–577. PubMedCrossRefGoogle Scholar
  21. Diebold Y, Calonge M (2010) Progress in retinal and eye research applications of nanoparticles in ophthalmology. Prog Retin Eye Res 29(6):596–609. PubMedCrossRefGoogle Scholar
  22. Dubald M, Bourgeois S, Andrieu V, Fessi H (2018) Ophthalmic drug delivery systems for antibiotherapy-a review. PubMedCentralCrossRefGoogle Scholar
  23. Elsaid N, Jackson TL, Elsaid Z, Alqathama A, Somavarapu S (2016) Article PLGA microparticles entrapping chitosan-based nanoparticles for the ocular delivery of ranibizumab. PubMedCrossRefGoogle Scholar
  24. Gan L, Wang J, Zhao Y, Chen D, Zhu C, Liu J, Gan Y (2013) Biomaterials Hyaluronan-modified core e shell liponanoparticles targeting CD44- positive retinal pigment epithelium cells via intravitreal injection. Biomaterials 34(24):5978–5987. PubMedCrossRefGoogle Scholar
  25. Ginn SL, Amaya AK, Abedi MR, Alexander IE, Edelstein M (2018). Gene therapy clinical trials worldwide to 2017: an update, (February): 1–16. PubMedCrossRefGoogle Scholar
  26. Gratieri T, Martins G, Melani E, Hugo V, De Freitas O, Fonseca R, Lopez V (2010) European Journal of Pharmaceutics and Biopharmaceutics A poloxamer/chitosan in situ forming gel with prolonged retention time for ocular delivery. Eur J Pharm Biopharm 75(2):186–193. PubMedCrossRefGoogle Scholar
  27. Gratieri T, Martins G, Freitas O De, Melani E, Lopez RFV (2011) European Journal of Pharmaceutics and Biopharmaceutics Enhancing and sustaining the topical ocular delivery of fluconazole using chitosan solution and poloxamer / chitosan in situ forming gel 79:320–327. PubMedCrossRefGoogle Scholar
  28. Guo C, Qu X, Rangaswamy N, Leehy B, Xiang C, Rice D et al (2018) A murine glaucoma model induced by rapid in vivo photopolymerization of hyaluronic acid glycidyl methacrylate. PLoS ONE 13(6):e0196529PubMedPubMedCentralCrossRefGoogle Scholar
  29. Gupta H, Aqil M, Khar RK, Ali A, Bhatnagar A (2015) Levofloxacin eye drops for prolong ocular retention 7(1): 9–14. PubMedCrossRefGoogle Scholar
  30. Hanna E, Rémuzat C, Auquier P, Toumi M (2017) Gene therapies development: slow progress and promising prospect. J Mark Access Health Policy 00(00):1–9. CrossRefGoogle Scholar
  31. Harikumar SL, Sonia A (2011) Available online Covered in Official Product of Elsevier, The Netherlands © 2010 IJDDR Nanotechnological approaches in Ophthalmic delivery systems 3(4):9–19
  32. Hennink WE, van Nostrum CF (2002) Novel crosslinking methods to design hydrogels. Adv Drug Deliv Rev 54:13–36PubMedCrossRefGoogle Scholar
  33. Hsiao F, Huang P, Aoyagi T, Chang S (2017) ScienceDirect In vitro and in vivo assessment of delivery of hydrophobic molecules and plasmid DNAs with PEO e PPO e PEO polymeric micelles on cornea. J Food Drug Anal:1–10. PubMedCrossRefGoogle Scholar
  34. Jee D, Kang S, Yuan C, Cho E, Arroyo JG, The Epidemiologic Survey Committee of the Korean Ophthalmologic Society (2016) Serum 25-hydroxyvitamin D levels and dry eye syndrome: differential effects of vitamin D on ocular diseases. PLoS ONE 11(2):e0149294PubMedPubMedCentralCrossRefGoogle Scholar
  35. Jiang S, Franco YL, Zhou Y, Chen J (2018) Nanotechnology in retinal drug delivery. Int J Ophthalmol.
  36. Kalam MA (2016) The potential application of hyaluronic acid coated chitosan nanoparticles in ocular delivery of dexamethasone. Int J Biol Macromol. PubMedCrossRefGoogle Scholar
  37. Kean T, Thanou M (2010) Biodegradation, biodistribution and toxicity of chitosan. Adv Drug Deliv Rev 62(1):3–11. PubMedCrossRefGoogle Scholar
  38. Kirchhof S, Gopeferich AM, Brandl FP (2015) European Journal of Pharmaceutics and Biopharmaceutics Hydrogels in ophthalmic applications. Eur J Pharm Biopharm June. PubMedCrossRefGoogle Scholar
  39. Klausner EA, Zhang Z, Chapman RL, Multack RF, Volin MV (2010) Biomaterials Ultrapure chitosan oligomers as carriers for corneal gene transfer. Biomaterials 31(7):1814–1820. PubMedCrossRefGoogle Scholar
  40. Kompella UB, Amrite AC, Ravi RP, Durazo SA (2013) Progress in retinal and eye research nanomedicines for back of the eye drug delivery , gene delivery , and imaging. Prog Retin Eye Res. April. PubMedPubMedCentralCrossRefGoogle Scholar
  41. Koo H, Moon H, Han H, Hee J, Sook M, Hyung J et al (2012) Biomaterials the movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection. Biomaterials 33(12):3485–3493. PubMedCrossRefGoogle Scholar
  42. Liang H, Brignole-Baudouin F, Rabinovich-Guilatt L, Mao Z, Riancho L, Faure MO, Warnet JM, Lambert G, Baudouin C (2008) Reduction of quaternary ammonium-induced ocular surface toxicity by emulsions: an in vivo study in rabbits. Mol Vis 14:204–216PubMedPubMedCentralGoogle Scholar
  43. Liu Z, Jiao Y, Wang Y, Zhou C, Zhang Z (2008) Polysaccharides-based nanoparticles as drug delivery systems. Adv Drug Deliv Rev 60(15):1650–1662. PubMedCrossRefGoogle Scholar
  44. Ljubimov AV, Saghizadeh M (2015) Progress in Retinal and Eye Research Progress in corneal wound healing. Prog Retin Eye Res 49(June 2018):17–45. PubMedPubMedCentralCrossRefGoogle Scholar
  45. Lopes CM, Barata P, Oliveira R (2018). Chapter 5. Stimuli-responsive nanosystems for drug-targeted delivery. Elsevier. CrossRefGoogle Scholar
  46. Mahlumba P, Choonara YE, Kumar P, Toit LC, Pillay V (2016) Stimuli-responsive polymeric systems for controlled protein and peptide delivery: future implications for ocular delivery. PubMedCentralCrossRefGoogle Scholar
  47. Mohammed MA, Syeda JTM, Wasan KM, Wasan EK (2017) An overview of chitosan nanoparticles and its application in non-parenteral drug delivery. Pharmaceutics 9(4):53. PubMedCentralCrossRefGoogle Scholar
  48. Mohd IN, Marvan A, HHaseeb AK et al (2013) Novel drugs and their targets in the potential treatment of diabetic retinopathy. Med Sci Monit 19:300–308CrossRefGoogle Scholar
  49. Morris GA, Kök SM, Harding SE, Adams GG, Morris GA, Kök SM, et al (2013) Polysaccharide drug delivery systems based on pectin and chitosan Polysaccharide delivery systems systems Polysaccharide drug drug delivery based on pectin and chitosan based on pectin and chitosan. 8725. PubMedCrossRefGoogle Scholar
  50. Natesan S, Pandian S, Ponnusamy C, Palanichamy R, Muthusamy S, Kandasamy R (2017a) Co-encapsulated resveratrol and quercetin in chitosan and pegmodified chitosan nanoparticles: for efficient intra ocular pressure reduction. Int J Biol Macromol 104:1837–1845PubMedCrossRefGoogle Scholar
  51. Natesan S, Krishnaswami V, Radhakrishnan S, Kumar VS, Sonali S, Nirmal J, Gaye S (2017b) New drug targets and drug delivery strategies for various ocular disorders. Bio targets and drug delivery approaches. Taylor & Francis Group, pp 1–32Google Scholar
  52. Otero-Espinar FJ, Fernandez-Ferreiro A, Gonzalez-Barcia M, Blanco-Mendez J, Luzardo A (2018) Drug targeting and stimuli sensitive drug delivery systems. Elsevier. Stimuli Sensitive Ocular Drug Delivery Systems 6. CrossRefGoogle Scholar
  53. Park JH, Saravanakumar G, Kim K, Chan I (2010) Targeted delivery of low molecular drugs using chitosan and its derivatives. Adv Drug Deliv Rev 62(1):28–41. PubMedCrossRefGoogle Scholar
  54. Patel PB, Shastri DH, Shelat PK, Shukla AK (2010) Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm 1(2):113CrossRefGoogle Scholar
  55. Patel A, Cholkar K, Agrahari V, Mitra AK (2013) Ocular drug delivery systems: an overview. World J Pharmacol 2(2):47–64PubMedPubMedCentralCrossRefGoogle Scholar
  56. Pollreisz A, Schmidt Erfurth U (2010) Diabetic cataract pathogenesis, epidemiology and treatment. J Ophthalmol 608751Google Scholar
  57. Puras G, Zarate J, Aceves M, Murua A, Díaz AR, Avilés-triguero M, Fernández E (2013a) European Journal of Pharmaceutics and Biopharmaceutics Low molecular weight oligochitosans for non-viral retinal gene therapy. Eur J Pharm Biopharm 83(2):131–140. PubMedCrossRefGoogle Scholar
  58. Puras G, Zarate J, Díaz-tahoces A, Avilés-trigueros M, Fernández E, Pedraz JL (2013b) European Journal of Pharmaceutical Sciences Oligochitosan polyplexes as carriers for retinal gene delivery. Eur J Pharm Sci 48(1–2):323–331. PubMedCrossRefGoogle Scholar
  59. Ratemi E (2018) pH-responsive polymers for drug delivery applications. Stimuli Responsive Polymeric Nanocarriers for Drug Delivery Applications, Volume 1. Elsevier. CrossRefGoogle Scholar
  60. Richard J, Callaghan O (2018) The pathogenesis of staphylococcus aureus eye infections. Pathogens 7(9):1–22Google Scholar
  61. Sen KK, Maiti S (2017) Basic concept in drug targeting. Bio targets and drug delivery approaches. Taylor & Francis Group, pp 1–32Google Scholar
  62. Shi S, Zhang Z, Luo Z, Yu J, Liang R, Li X, Chen H (2015) Chitosan grafted methoxy poly (ethylene glycol) -poly (ε – caprolactone) nanosuspension for ocular delivery of hydrophobic diclofenac. Nature Publishing Group, (June), pp 1–12.
  63. Singh SR, Grossniklaus HE, Kang SJ, Edelhauser HF, Ambati BK (2010) NIH Public Access 16(5):645–659.
  64. Solinís MÁ, Pozo-rodríguez A, Apaolaza PS (2014) Treatment of ocular disorders by gene therapy. Eur J Pharm Biopharm. PubMedCrossRefGoogle Scholar
  65. Tarr JM, Kaul K, Chopra M, Kohner EM, Chibber R (2013) Pathophysiology of diabetic retinopathy. ISRN Ophthalmol:1–3CrossRefGoogle Scholar
  66. Tsai CY, Woung LC, Yen JC, Tseng PC, Chiou SH, Sung YJ et al (2016) Thermosensitive chitosan-based hydrogels for sustained release of ferulic acid on corneal wound healing. Carbohydr Polym 135:308–315. PubMedCrossRefGoogle Scholar
  67. Vellonen KS, Pelkonen L, Mannermaa E, Ruponen M, Urtti A, Kidron H (2017) Expression, activity and pharmacokinetic impact of ocular transporters. Adv Drug Deliv RevGoogle Scholar
  68. Wadhwa S, Paliwal R, Rai Paliwal S, Vyas SP (2009) Chitosan and its role in ocular therapeutics. Mini Rev Med Chem 9(14):1639–1647. PubMedCrossRefGoogle Scholar
  69. Weng Y, Liu J, Jin S, Guo W (2016) Nanotechnology-based strategies for treatment of ocular disease. Acta Pharm Sin B:1–11. PubMedCrossRefGoogle Scholar
  70. Wu Y, Liu Y, Li X, Kebebe D, Zhang B, Ren J et al (2018) Research progress of in-situ gelling ophthalmic drug delivery system. Asian J Pharm Sci 000:1–15. CrossRefGoogle Scholar
  71. Xu Q et al (2013) Nanotechnology approaches for ocular drug delivery. Middle East African J Ophthalmol 20(1):26–37CrossRefGoogle Scholar
  72. Yoo JW, Irvine DJ, Discher DE, Mitragotri S (2011) Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat Rev Drug Discov 10(7):521–535. PubMedCrossRefGoogle Scholar
  73. Yuan X (2006) Preparation of cholesterol-modified chitosan self-aggregated nanoparticles for delivery of drugs to ocular surface 65:337–345. CrossRefGoogle Scholar
  74. Zhou R, Caspi RR (2010) Ocular immune privilege 3(January): 1–3.
  75. Zulliger R, Conley SM, Naash MI (2015) Non-viral therapeutic approaches to ocular diseases: An overview and future directions. J Control Release. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Technology, Centre for Excellence in Nanobio Translational Research CentreUniversity College of Engineering, Bharathidasan Institute of Technology, Anna UniversityTiruchirappalliIndia
  2. 2.Department of BiotechnologyUniversity College of Engineering, Bharathidasan Institute of Technology, Anna UniversityTiruchirappalliIndia

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