Progress of Controlled Drug Delivery Systems in Topical Ophthalmology: Focus on Nano and Micro Drug Carriers

  • Ameeduzzafar Zafar
  • Javed Ahmad
  • Richard T. Addo
  • Sohail AkhterEmail author


Corneal and conjunctival epithelia, along with the tear film, serve as biological barriers to protect the eye from the entrance of potentially harmful substances. These barriers create constraint effective drug medication of ocular diseases with topical ocular formulations. Designing an effective therapy for ocular diseases, especially for the anterior segment, has been considered a challenging task. Nano-drug carriers giving us an array of hope for ocular drug therapy, owing to its potential to improve the ocular retention, controlled release, trans-corneal permeation and thus intra-ocular drug availability. Nanotechnology-based formulation design is important in ocular pharmaceuticals yet knowledge of anatomy and physiology of eyes are critical along with the understanding of nanoparticles design. Here, we discussed the ocular transport of topically applied drug, different barriers in its path and how the nanoparticles as drug carriers can improve the drug delivery to the eyes.


Ocular drug delivery Topical administration Drug transport barriers Controlled drug release Nanotechnology Targeting 


  1. Abdelkader H, Ismail S, Kamal A, Alany RG (2011) Design and evaluation of controlled release niosomes and discomes for naltrexone hydrochloride ocular delivery. J Pharm Sci 100:1833–1846PubMedGoogle Scholar
  2. Abrishami M, Zarei-Ganavati S, Soroush D, Rouhbakhsh M, Jaafari MR, Malaekeh Nikouei B (2009) Preparation, characterization, and in vivo evaluation of nanoliposomes-encapsulated bevacizumab (avastin) for intravitreal adminis-tration. Retina 29:699–703PubMedGoogle Scholar
  3. Abuzaid SS, El-Ghamry HA, Hammad M (2003) Liposomes as ocular drug delivery system for atenolol. Egypt J Pharm Sci 44:227–245Google Scholar
  4. Addo RT, Siddig A, Patel NJ, Siwale R, Akande J, Uddin AU, D’Souza MJ (2010) Formulation, characterization, and testing of tetracaine hydrochloride-loaded albumin-chitosan microparticles for ocular drug delivery. J Microencapsul 27(2):95–104PubMedGoogle Scholar
  5. Addo RT, Yeboah KG, Siwale RC, Siddig A, Jones A, Ubale RV, Akande J, Nettey H, Patel NJ, Addo E, D’Souza MJ (2015) Formulation and characterization of atropine sulfate in albumin-chitosan microparticles for in vivo ocular drug delivery. J Pharm Sci 104(5):1677–1690PubMedGoogle Scholar
  6. Aggarwal D, Kaur IP (2005) Improved pharmacodynamics of timolol maleate from mucoadhesive niosomal ophthalmic drug delivery system. Int J Pharm 16:155–159Google Scholar
  7. Aggarwal D, Pal D, Mitra AK, Kaur IP (2007) Study of the extent of ocular absorption of acetazolamide from a developed niosomal formulation, by micro dialysis sampling of aqueous humor. Int J Pharm 29:21–26Google Scholar
  8. Agnihotri SM, Vavia PR (2009) Diclofenac-loaded biopolymeric nanosuspensions for ophthalmic application. Nanomed Nanotech Boil Med 5:90–95Google Scholar
  9. Ahmed I, Patton TF (1985) Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci 26(4):584–587Google Scholar
  10. Ahmed I, Patton TF (1987) Disposition of timolol and inulin in the rabbit eye following corneal versus non-corneal absorption. Int J Pharm 38:9–21 Google Scholar
  11. Ahmed S Guinedi, Nahed DM, Samar M, Rania MH (2005) Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide. Int J Pharm 306:71–82Google Scholar
  12. Akhter S, Talegaonkar S, Khan ZI, Jain GK, Khar RK, Ahmad FJ (2011) Assessment of ocular pharmacokinetics and safety of ganciclovir loaded nanoformulation. Biomed Nanotechnol 7:144–145Google Scholar
  13. Aksungur P, Demirbilek M, Denkbas EB, Vandervoort J, Ludwig A, Unlu N (2011) Development & characterization of cyclosporine A loaded nanoparticles for ocular drug delivery: cellular toxicity, uptake and kinetic studies. J Control Rel 151:286–294Google Scholar
  14. Ameeduzzafar Ali J, Bhatnagar A, Kumar N, Ali A (2014) Chitosan nanoparticles amplify the ocular hypotensive effect of cateolol in rabbits. Int J Biol Macromol 65:479–491PubMedGoogle Scholar
  15. Ammar HO, Salama HA, Ghorab M, Mahmoud AA (2009) Nanoemulsion as a potential ophthalmic delivery system for dorzolamide hydrochloride. AAPS PharmSciTech 10(3):808PubMedPubMedCentralGoogle Scholar
  16. Araujo J, Gonzalez E, Egea MA, Garcia ML, Souto EB (2009) Nanomedicines for ocular NSAIDs: safety on drug delivery. Nanomedicine 5:394–401PubMedGoogle Scholar
  17. Arunothayanun P, Bernard MS, Craig DQ, Uchegbu IF, Florence AT (2000) The effect of processing variables on the physical characteristics of non-ionic surfactant vesicles (niosomes) formed from hexadecyl diglycerol ether. Int J Pharm 201:7–14PubMedGoogle Scholar
  18. Badawi AA, El-Laithy HM, El Qidra RK, El Mofty H, El dally M (2008) Chitosan based nanocarriers for indomethacin ocular delivery. Arch Pharm Res 31(8):1040-1049PubMedGoogle Scholar
  19. Bai S, Thomas C, Rawat A, Ahsan F (2006) Recent progress in dendrimer-based nanocarriers. Crit Rev Ther Drug Carrier Syst 23:437–495PubMedGoogle Scholar
  20. Balakrishnan P, Shanmugam S, Lee WS, Lee WM (2009) Formulation and in vitro assessment of minoxidil niosomes for enhanced skin delivery. Int J Pharm 377:1–8PubMedGoogle Scholar
  21. Bangham D, Standish MM, Watkins JC (1965) Diffusion of univalent ions across the lamellae of swollen phospholipids. J Mol Biol 13:238–252PubMedGoogle Scholar
  22. Barbault-Foucher S, Gref R, Russo P, Guechot J, Bochot A (2002) Design of poly--caprolactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery. J Control Release 83(3):365–375PubMedGoogle Scholar
  23. Başaran, E, Demirel, M, Sırmagül, B, Yazan, Y (2011) Polymeric cyclosporine-A nanoparticles for ocular application. J Biomed Nanotechnol 7(5):714–723PubMedGoogle Scholar
  24. Başaran E, Yenilmez E, Berkman MS, Büyükköroğlu G, Yazan Y (2014) Chitosan nanoparticles for ocular delivery of cyclosporine A. J Microencapsul 31(1):49–57PubMedGoogle Scholar
  25. Basha M, Hosam , El-Alim A, Shamma RN, Awad GEA (2013) Design and optimization of surfactant based nanovesicles for ocular delivery of clotrimazoleGoogle Scholar
  26. Baspinar Y, Bertelmann E, Pleyer U, Buech G, Siebenbrodt I, Borchert HH (2008) Corneal permeation studies of everolimus microemulsion. J Ocul Pharmacol Ther 24(4):399–402PubMedGoogle Scholar
  27. Biswal S, Murthy PN, Sahu J, Sahoo P, Amir F (2008) Vesicles of non-ionic surfactants (niosomes) and drug delivery potential. Int J Pharm Sci Nanotechnol 1:1–8Google Scholar
  28. Bochot A, Fattal E, Grossiord JL, Puisieux F, Couvreur P (1998a) Characterization of a new drug delivery system based on dispersion of liposomes in a thermosensitive gel. Int J Pharm 162:119–127Google Scholar
  29. Bochot A, Gulik FA, Couarraze G, Couvreur P (1998b) Liposomes dispersed within a thermosensitive gel: a new dosage form for ocular delivery of oligonucleotides. Pharm Res 15:1364–1369PubMedGoogle Scholar
  30. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R (1998) Ophthalmic drug delivery systems: recent advances. Prog Retin Eye Res 17:33–58PubMedGoogle Scholar
  31. Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ (1997) Novel hydrophilic chitosan-polyethylene oxide nanoparticles as protein carriers. J Appl Polym Sci 63:125–132Google Scholar
  32. Carafa M, Santucci E, Lucania G (2002) Lidocaine loaded non ionic surfactant vesicles: characterization and in vitro permeation studies. Int J Pharm 231:21–32PubMedGoogle Scholar
  33. Carol L, Keita AV (2010) Translocation of Crohn’s disease Escherichia coli across M cells: contrasting effects of soluble plant fibers and emulsifiers. Gut 59:1331–1339Google Scholar
  34. Chen Y, Lu Y, Zhong Y, Wang Q, Wu W, Gao S (2012) Ocular delivery of cyclosporine A based on glyceryl monooleate/poloxamer 407 liquid crystallinenanoparticles: preparation, characterization, in vitro corneal penetration and ocular irritation. J Drug Target 20(10):856–863PubMedGoogle Scholar
  35. Chetoni P, Rossi S, Burgalassi S, Monti D, Mariotti S, Saettone MF (2004) Comparison of liposome-encapsulated acyclovir with acyclovir ointment: ocular pharmacokinetics in rabbits. J Ocul Pharmacol Ther 20:169–177PubMedGoogle Scholar
  36. Cruysberg LP, Nuijts RM, Geroski DH, Koole LH, Hendrikse F, Edelhauser HF (2002) In vitro human scleral permeability of fluorescein, dexamethasone-fluorescein, methotrexate-fluorescein and rhodamine 6G and the use of a coated coil as a new drug delivery system. J Ocul Pharmacol Ther 18:559–569PubMedGoogle Scholar
  37. Dai Y, Zhou R, Liu L, Lu Y, Qi J, Wu W (2013) Liposomes containing bile salts as novel ocular delivery systems for tacrolimus (FK506): in vitro characterization and improved corneal permeation. Int J Nanomed 8:1921–1933Google Scholar
  38. Danion A, Arsenault I, Vermette P (2007) Antibacterial activity of contact lenses bearing surface-immobilized layers of intact liposomes loaded with levofloxacine. J Pharm Sci 96:2350–2363PubMedGoogle Scholar
  39. De Campos AM, Sanchez A, Gref R, Calvo P, Alonso MJ (2003) The effect of a PEG versus a chitosan coating on the interaction of drug colloidal carriers with the ocular mucosa. Eur J Pharm Sci 20:73–81PubMedGoogle Scholar
  40. De Campos AM, Diebold Y, Carvaiho ELS, Sanchez A, Alonso MJ (2004) Chitosan nanoparticles as new ocular drug delivery system: in vitro stability, in vivo fate, and cellular toxicity. Pharm Res 21:803–810PubMedGoogle Scholar
  41. Dhubhghaill SN, Humphries MM, Kenna PF (2012) Further development of barrier modulation as a technique for systemic ocular drug delivery. Adv Exp Med Biol 723:155–159PubMedGoogle Scholar
  42. Ding S (1998) Recent developments in ophthalmic drug delivery. Pharm Sci Technol Today 1:328–335Google Scholar
  43. Ding X, Alani WG, Robinson JR (2005) Extended-release and targeted drug delivery systems. In: Troy DB (ed) Remington: the science and practice of pharmacy. Lippincott Williams and Wilkins, Philadelphia, PA, USAGoogle Scholar
  44. Djekic L, Ibric S, Primorac M (2008) The application of artificial neural networks in the prediction of microemulsion phase boundaries in PEG-8 caprylic/capric glycerides based systems. Int J Pharm 361:41–46PubMedGoogle Scholar
  45. Du Toit LC, Govender T, Carmichael T, Kumar P, Choonara YE, Pillay V (2013) Design of an anti-inflammatory composite nanosystem and evaluation of its potential for ocular drug delivery. J Pharm Sci 102(8):2780–2805PubMedGoogle Scholar
  46. Duchfine D, Touchard F, Peppas NA (1988) Pharmaceutical and medical aspects of bioadhesive systems of drug administration. Drug Dev Ind Pharm 14:283–318Google Scholar
  47. Elbayoumi TA, Torchilin VP (2010) Current trends in liposome research. Methods Mol Biol 605:1–27PubMedGoogle Scholar
  48. Felt O, Furrer P, Mayer JM, Plazonnet B, Buri P, Gurny R (1999) Topical use of chitosan in ophthalmology: tolerance assessment and evaluation of pre-corneal retention. Int J Pharm 180:185–193PubMedGoogle Scholar
  49. Fessi H, Puisieux F, Devissaguet JP, Ammoury N, Benitas S (1989) Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm 55:R1–R4Google Scholar
  50. Fialho SL (2004) New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Exp Ophthalmol 32:626–632PubMedGoogle Scholar
  51. Fischbarg J (2006) The corneal endothelium. In: Fischbarg J (ed) The Biology of Eye. Academic Press, New York, NY, USA, pp 113–125Google Scholar
  52. Fitzgerald P, Wilson C (1994) Polymeric systems for ophthalmic drug delivery. In: Severian D (ed) Polymeric systems for ophthalmic drug delivery. Marcel Dekker, New York. 373–398Google Scholar
  53. Gajbhiye V, Palanirajan VK, Tekade RK, Jain NK (2009) Dendrimers as therapeutic agents: a systematic review. J Pharm Pharmacol 61:989–1003PubMedGoogle Scholar
  54. Garty N, Lusky M (1994) Pilocarpine in submicron emulsion formulation for treatment of ocular hypertension: a phase II clinical trial. Invest Ophthalmol Vis Sci 35:2175–2185Google Scholar
  55. Gasco MR, Gallarate M, Trotta M, Bauchiero L, Gremmo E and Chiappero O (1989) Microemulsions as topical delivery vehicles: Ocular administration of timolol. J Pharm Biomed Analysis 7(4):433–439PubMedGoogle Scholar
  56. Gausas RE, Gonnering RS, Lemke BN, Dortzbach RK, Sherman DD (1999) Identification of human orbital lymphatics. Ophthal Plast Reconstr Surg 15:252–259PubMedGoogle Scholar
  57. Gipson IK, Argueso P (2003) Role of mucin in the function of the corneal and conjunctival epithelia. Int Rev Cytol 231:1–49PubMedGoogle Scholar
  58. Govender S, Pillay V, Chetty DJ, Essack SY, Dangor CM, Govender T (2005) Optimization and characterization of bioadhesive controlled release tetracycline microspheres. Int J Pharm 306:24–40PubMedGoogle Scholar
  59. Greaves JL, Wilson CG, Birmingham AT (1993) Assessment of the precorneal residence of an ophthalmic ointment in healthy subjects. Br J Clin Pharmacol 35:188–192PubMedPubMedCentralGoogle Scholar
  60. Guinedi AS, Mortada ND, Mansour S, Hathout RM (2005) Preparation and evaluation of reverse-phase evaporation and multilamellar niosomes as ophthalmic carriers of acetazolamide. Int J Pharm 306:71–82PubMedGoogle Scholar
  61. Gupta S, Moulik SP (2008) Biocompatible Microemulsions and their prospective uses in drug delivery. J Pharm Sci 97:22–45PubMedGoogle Scholar
  62. Gupta H, Aqil M, Khar RK, Ali A, Bhatnagar A, Mittal G (2010) Sparfloxacin-loaded PLGA nanoparticles for sustained ocular drug delivery. Nanomed Nanotech Biol Med 6:324–333Google Scholar
  63. Gupta H, Aqil M, Khar RK, Ali A, Bhatnagar A, Mittal G (2011) Biodegradable levofloxacine nanoparticles for sustained ocular drug delivery. J Drug Target 19(6):409–417PubMedGoogle Scholar
  64. Hanrahan F, Campbell M, Nguyen AT, Suzuki M, Kiang AS, Tam LC, Gobbo OL, Dhubhghaill SN, Humphries MM, Kenna PF (2012) Further development of barrier modulation as a technique for systemic ocular drug delivery. Adv Exp Med Biol 723:155–159PubMedGoogle Scholar
  65. Hait SK and Moulik SP (2002) Gemini surfactants: A distinct class of self-assembling molecules. Curr Sci 82:1101–1111Google Scholar
  66. Hamdy A, Sayed I, Amal K, Raid GA (2011) Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. J Pharm Sci 100(5):1833–1846Google Scholar
  67. Hathout RM, Mansour S, Mortada ND (2007) Liposomes as an ocular delivery system for acetazolamide: in vitro and in vivo studies. AAPS Pharm Sci Tech 8:1–12Google Scholar
  68. Henriksen I, Green KL, Smart JD, Smistad G, Karlsen J (1996) Bioadhesion of hydrated chitosans: an in vitro and in vivo study. Int J Pharm 145:231–240Google Scholar
  69. Her Y, Lim JW, Han SH (2013) Dry eye and tear film functions in patients with psoriasis. Jpn J Ophthalmol 57(4):341–346PubMedGoogle Scholar
  70. Higashiyama M, Tajika T, Inada K, Ohtori A (2006) Improvement of the ocular bioavailability of carteolol by ion pair. J Ocular Pharmacol Ther 22:333–339Google Scholar
  71. Hill JM, O’Callaghan RJ, Hobden JA, Kaufman E (1993) Corneal collagen shields for ocular drug delivery. Ophthalmic drug delivery systems. Marcel Dekker, New York, pp 261–275Google Scholar
  72. Hirano S, Seino H, Akiyama I, Nonaka I (1990) Chitosan: a biocompatible material for oral and intravenous administration. In: Gebelein CG, Dunn RL (eds) Progress in biomedical polymers. Plenum Press, New York, pp 283–289Google Scholar
  73. Hitzenberger CK, Baumgartner A, Drexler W et al (1994) Interferometric measurement of corneal thickness with micrometer precision. Am J Ophthalmol 118:468–476PubMedGoogle Scholar
  74. Honda M, Asai T, Oku N, Araki Y, Tanaka M, Ebihara N (2013) Liposomes and nanotechnology in drug development: focus on ocular targets. Int J Nanomed 8:495–503Google Scholar
  75. Hosoya K, Vincent HL, Kim LKJ (2005) Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport mechanisms and their regulation. Eur J Biopharm 60:227–240Google Scholar
  76. Ikeda I (2003) Synthesis of gemini and elated substances. In: Zana R, Xia J (eds) Gemini surfactants synthesis, interfacial and solution phase-behavior, and applications, vol 1. Marcel Dekker, New York, pp 26–30Google Scholar
  77. Irache JM, Merodio M, Arnedo A, Camapanero MA, Mirshahi M, Espuelas S (2005) Albumin nanoparticles for the intravitreal delivery of anticytomegaloviral drugs. Mini Rev Med Chem 5:293–305PubMedGoogle Scholar
  78. Jain NK, Gupta U (2008) Application of dendrimer-drug complexation in the enhancement of drug solubility and bioavailability. Expert Opin Drug Discov 4:1035–1051Google Scholar
  79. Jain K, Kumar RS, Sood S, Dhyanandhan G (2013) Betaxolol hydrochloride loaded chitosan nanoparticles for ocular delivery and their anti-glaucoma efficacy. Curr Drug Deliv 10:493–499PubMedGoogle Scholar
  80. Jain S, Thompson JR, Foot B, Tatham A, Eke T (2014) Severe intraocular pressure rise following intravitreal triamcinolone: a national survey to estimate incidence and describe case profiles. Eye (Lond) 28(4):399–401. doi: 10.1038/eye.2013.306CrossRefGoogle Scholar
  81. Javadzadeh Y, Ahadi F, Davaran S, Mohammadi G, Sabzevari A, Adibkia K (2010) Preparation and physicochemical characterization of naproxen-PLGA nanoparticles. Colloids Surf B Biointerfaces 81:498–502PubMedGoogle Scholar
  82. Jesorka A, Orwar O (2008) Liposomes: technologies and analytical applications. Ann Rev Anal Chem 1:801–832Google Scholar
  83. Jóhannesson G, Moya-Ortega MD, Asgrímsdottir GM, Agnarsson BA, Lund SH, Loftsson T, Stefansson E (2014) Dorzolamide cyclodextrin nanoparticle suspension eye drops and Trusopt in rabbit. J Ocul Pharmacol Ther 30(6):464–467PubMedGoogle Scholar
  84. Jtirvinen K, Tomi J, Arto Urttia S (1995) Ocular absorption following topical delivery. Adv Drug Deliv Rev 16:3–19Google Scholar
  85. Jwala J, Boddu SHS, Shah S, Sirimulla S, Pal D, Mitra AK (2011) Ocular sustained release nanoparticles containing stereoisomeric dipeptide prodrugs of acyclovir. J Ocul Pharmacol Ther 27(2):163–172PubMedPubMedCentralGoogle Scholar
  86. Kalam MA (2016) The potential application of hyaluronic acid coated chitosan nanoparticles in ocular delivery of dexamethasone. Int J Biol Macromol 6(89):559–568Google Scholar
  87. Kambhampati SP, Kannan RM (2013) Dendrimer nanoparticles for ocular drug delivery. J Ocul Pharmacol Ther 29(2):151–165PubMedGoogle Scholar
  88. Kapadia R, Khambete H, Katara R (2009) Novel approach for ocular delivery of acyclovir via niosomes entrapped in situ hydrogel system. J Pharm Res 2:745–751Google Scholar
  89. Karim KM, Mandal AS, Biswas N, Guha A, Chatterjee S, Behera M, Kuotsu K (2012) Niosome: a future of targeted drug delivery systems. J Adv Pharm Tech Res 1:374–380Google Scholar
  90. Katiyar S, Pandit J, Mondal RS, Mishra AK, Chuttani K, Aqil M, Ali A, Sultana Y (2014) In situ gelling dorzolamide loaded chitosan nanoparticles for the treatment of glaucoma. Carbohydr Polym 15(102):117–124Google Scholar
  91. Kaur IP, Kanwar M (2002) Ocular preparations: the formulation approach. Drug Dev Ind Pharm 28:473–493PubMedGoogle Scholar
  92. Kaur IP, Garg A, Singla AK, Aggarwal D (2004) Vesicular systems in ocular drug delivery: an overview. Int J Pharm 269:1–14PubMedGoogle Scholar
  93. Kaur IP, Aggarwal D, Singh H, Kakkar S (2010) Improved ocular absorption kinetics of timolol maleate loaded into a bioadhesive niosomal delivery system. Graefes Arch Clin Exp Ophthalmol 248:1467–1472PubMedGoogle Scholar
  94. Kaur H, Ahuja M, Kumar S, Dilbaghi N (2012) Carboxymethyl tamarind kernel polysaccharide nanoparticles for ophthalmic drug delivery. Int J Biol Macromol 50:833–839PubMedGoogle Scholar
  95. Kesavan K, Kant S, Singh PN, Pandit JK (2013) Mucoadhesive chitosan-coated cationic microemulsion of dexamethasone for ocular delivery: in vitro and in vivo evaluation. Curr Eye Res 38:342–352PubMedGoogle Scholar
  96. Khan A, Sharma PK, Visht S, Malviya R (2011) Niosomes as colloidal drug delivery system: a review. J Chronotherapy Drug Deliv 2:15–21Google Scholar
  97. Khazaeli P, Pardakhty A, Shoorabi H (2007) Caffeine-loaded niosomes: characterization and in vitro release studies. Drug Deliv 14:447–452PubMedGoogle Scholar
  98. King-Smith PE, Fink BA, Fogt N et al (2000) The thickness of the human precorneal tear film: evidence from reflection spectra. Invest Ophthalmol Visual Sci 41:3348–3359Google Scholar
  99. Klibanov AL, Maruyama K, Torchilin VP, Huang L (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235–237PubMedGoogle Scholar
  100. Kumari A, Yadav SK, Yadav SC (2010) Biodegradable polymeric nanoparticles based drug delivery systems. Colloids Surf A 72(1):1–18Google Scholar
  101. Kumbhar D, Wavikar P, Vavia P (2013) Niosomal gel of lornoxicam for topical delivery: in vitro assessment and pharmacodynamic activity. AAPS Pharm Sci Tech 14(3):1072–1082Google Scholar
  102. Lang JC (1995) Ocular drug delivery conventional ocular formulations. Advanced Drug Delivery Reviews 16:39–43Google Scholar
  103. Lawrence MJ, Chauhan S, Lawrence SM, Barlow DJ (1996) The formation, characterization and stability of non-ionic surfactant vesicles. STP Pharm Sci 1:49–60Google Scholar
  104. Lee SJ, He W, Robinson SB, Robinson MR, Csaky KG, Kim H (2010) Evaluation of clearance mechanisms with trans-scleral drug delivery. Invest Ophthalmol Vis Sci 51:5205–5212PubMedGoogle Scholar
  105. Li J, Wu L, Wu W, Wang B, Wang Z, Xin H, Xu Q (2013) A potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate. Int J Pharm 15 455(1–2):75–84Google Scholar
  106. Lin J, Wu H, Wang Y, Lin J, Chen Q, Zhu X (2016) Preparation and ocular pharmacokinetics of hyaluronan acid-modified mucoadhesive liposomes. Drug Deliv 23(4):1144–1151PubMedGoogle Scholar
  107. Liu R, Wang S, Fang S, Wang J, Chen J, Huang X, He X, Liu C (2016) Liquid crystalline nanoparticles as an ophthalmic delivery system for tetrandrine: development, characterization, and in vitro and in vivo. Nanoscale Res Lett 11(1):254. doi: 10.1186/s11671-016-1471-0 Cited 2016 May 17CrossRefPubMedPubMedCentralGoogle Scholar
  108. Ludwig A (2005) The use of mucoadhesive polymers in ocular drug delivery. Adv Drug Delivery Rev 57:1595–1639Google Scholar
  109. Ludwig A, Ooteghem VM (1992) Influence of, viscoslysers on the residence of ophthalmic solutions evaluated by slip lamp fluorophotometry. STP Pharm Sci 2(1):81–87Google Scholar
  110. Lv FF, Zheng LQ, Tung CH (2005) Phase behavior of the microemulsions and the stability of the chloramphenicol in the microemulsion-based ocular drug delivery system. Int J Pharm 301(1–2):237–246PubMedGoogle Scholar
  111. Ma SW, Gan Y, Gan L, Zhu CL, Zhu JB (2008) Preparation and in vitro corneal retention behaviour of novel cationic microemulsion/in situ gel system. Yao Xue Xue Bao 43:749–755Google Scholar
  112. Mahale NB, Thakkar PD, Mali RG, Walunj DR, Chaudhari SR (2012) Niosomes: novel sustained release nonionic stable vesicular systems—an overview. Adv Colloid Interface Sci 15:46–54Google Scholar
  113. Mainardes RM, Urban MCC, Cinto PO (2005) Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets 6:363–371PubMedGoogle Scholar
  114. Manosroi A, Wongtrakul P, Manosroi J, Sakai H, Sugawara F, Yuasa N (2003) Characterization of vesicles prepared with various nonionic surfactants mixed with cholesterol. Colloids Surf B Biointerfaces 30:129–138Google Scholar
  115. Marfurt CF, Kingsley RE, Echtenkamp SE (1989) Sensory and sympathetic innervation of the mammalian cornea. A retrograde tracing study. Invest Ophthalmol Vis Sci 30:461–472PubMedGoogle Scholar
  116. Maurice DM, Mishima S (1984) Pharmacology of the eye. Handb Exp Pharmacol 69:109–116Google Scholar
  117. McDonald TO, Shadduck JA (1977) Eye irritation. Adv Mod Toxicol 4:139–191Google Scholar
  118. Meisner D, Mezei M (1995) Liposome ocular delivery systems. Adv Drug Deliv Rev 16:75–93Google Scholar
  119. Meng J, Sturgis TF, Youan BC (2011) Engineering tenofovir loaded chitosan nanoparticles to maximize microbicide mucoadhesion. Eur J Pharm Sci 44:57–67PubMedPubMedCentralGoogle Scholar
  120. Merodio M, Irache JM, Valamanesh F, Mirshahi M (2002) Ocular disposition and tolerance of ganciclovir-loaded albumin nanoparticles after intravitreal injection in rats. Biomaterials 23:1587–1594PubMedGoogle Scholar
  121. Meseguer G, Buri P, Plazonnet B, Rozier A, Gurny R (1996) Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers. J Ocul Pharmacol Ther 12:481–488PubMedGoogle Scholar
  122. Miao H, Wu B, Tao Y, Li X. (2013). Diffusion of macromolecules through sclera. Acta Ophthamologica 91(1):e1–e6PubMedGoogle Scholar
  123. Mintzer MA, Grinstaff MW (2011) Biomedical applications of dendrimers: a tutorial. Chem Soc Rev 40(1):173–190PubMedGoogle Scholar
  124. Mishra GP, Bagui M, Tamboli V, Mitra AK (2011) Recent applications of liposomes in ophthalmic drug delivery. J Drug Deliv 14:205–2018Google Scholar
  125. Mohammed N, Rejinold NS, Mangalathillam S, Biswas R, Nair SV, Jayakumar R (2013) Fluconazole loaded chitin nanogels as a topical ocular drug delivery agent for corneal fungal infections. J Biomed Nanotechnol 9(9):1521–1531PubMedGoogle Scholar
  126. Monem AS, Ali FM, Ismail MW (2000) Prolonged effect of liposomes encapsulating pilocarpine HCl in normal and glaucomatous rabbits. Int J Pharmaceutics 198:29–38PubMedGoogle Scholar
  127. Montes-Mico R, Cervino A, Ferrer-Blasco T, Garcia-Lazaro S, Madrid-Costa D (2010) The tear film and the optical quality of the eye. Ocul-Surf 8:185–192PubMedGoogle Scholar
  128. Motwani SK, Chopra S, Talegaonkar S, Kohli K, Ahmad FJ, Khar RK (2008) Chitosan–sodium alginate nanoparticles as submicroscopic reservoirs for ocular Delivery: formulation, optimization and in-vitro characterization. Eur J Pharm Biopharm 68:513–525PubMedGoogle Scholar
  129. Mujoriya RZ, Bodla RB (2011) Niosomes—challenge in preparation for pharmaceutical scientist. Int J App Pharm 3:11–15Google Scholar
  130. Muller LJ, Marfurt CF, Kruse F, Tervo TM (2003) Corneal nerves: structure, contents and function. Exp Eye Res 76:521–542PubMedPubMedCentralGoogle Scholar
  131. Myles ME, Neumann DM, Hill JM (2005) Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis. Adv Drug Del Rev 57:2063–2079Google Scholar
  132. Nagarwal RC, Kumar R, Pandit JK (2012) Chitosan coated sodium alginate-chitosan nanoparticles loaded with 5-FU for ocular delivery: in vitro characterization and in vivo study in rabbit eye. Eur J Pharm Sci 47(4):678–685PubMedGoogle Scholar
  133. Nagyova B, Tiffany JM (1999) Components responsible for the surface tension of human tears. Curr Eye Res 19:4–11PubMedGoogle Scholar
  134. Newell FW (1993) Ophthalmology: principles and concepts. 7th edn. Mosby Year Book, St. LouisGoogle Scholar
  135. Newkome GR, Shreiner CD (2008) Amidoamine, polypropylenimine, and related dendrimers and dendrons possessing different 1 → 2 branching motifs: An overview of the divergent procedures. Polymer 49:1–173Google Scholar
  136. Norley SG, Huang L, Rouse BT (1986) Targeting of drug loaded immunoliposomes to herpes simplex virus infected corneal cells: an effective means of inhibiting virus replication in vitro. J Immunol 136(2):681–685Google Scholar
  137. Omidi, Y., Barar, J., Hamzeiy, H., 2012. Nanomedicines Impacts in Ocular Delivery and Targeting. Nanotechnol Health Care, 43–106Google Scholar
  138. Pandit JC, Nagyova B, Bron AJ, Tiffany JM (1999) Physical properties of stimulated and unstimulated tears. Exp Eye Res 68:247–253PubMedGoogle Scholar
  139. Pardakhti A, Moshefi MH, Moteshafi H (2007) Preparation of niosomes containing chloramphenicol sodium succinate and evaluation of their physicochemical and antimicrobial properties. Pharm Sci Spr 1:11–21Google Scholar
  140. Parra A, Mallandrich M, Clares B, Egea MA, Espina M, García ML, Calpena AC (2015) Design and elaboration of freeze-dried PLGA nanoparticles for the transcorneal permeation of carprofen:Ocular anti-inflammatory applications. Colloids Surf B Biointerfaces 136:935–943PubMedGoogle Scholar
  141. Pathak MK, Chhabra G, Pathak K (2013) Design and development of a novel pH triggered nanoemulsified in-situ ophthalmic gel of fluconazole: ex-vivo transcorneal permeation, corneal toxicity and irritation testing. Drug Dev Ind Pharm 39:780–790PubMedGoogle Scholar
  142. Pescina S, Santi P, Ferrari G, Nicoli S (2011) Trans-scleral delivery of macromolecules. Ther Deliv 2:1331–1349PubMedGoogle Scholar
  143. Pignatello R, Bucolo C, Spedalieri G, Maltese A, Puglisi G (2002) Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials 23:3247–3255PubMedGoogle Scholar
  144. Ponchel G, Touchard F, Duchfine D, Peppas NA (1987) Bioadhesive analysis of controlled-release systems. I. Fracture and interpenetration analysis in poly (acrylic acid)-containing systems. J Control Release 5:129–141Google Scholar
  145. Qi HP, Gao XC, Zhang LQ, Wei SQ, Bi S, Yang ZC, Cui H (2013) In vitro evaluation of enhancing effect of borneol on transcorneal permeation of compounds with different hydrophilicities and molecular sizes. Eur J Pharmacol 705:20–25PubMedGoogle Scholar
  146. Rathore KS, Nema PK (2009) An insight into ophthalmic drug delivery system. Int J Pharm Sci Drug Res 1:1–5Google Scholar
  147. Raviola G (1983) Conjunctival and episcleral blood vessels are permeable to blood-borne horseradish peroxidase. Invest Ophthalmol Vis Sci 24:725–736PubMedGoogle Scholar
  148. Raymzond CR, Paul JS, Sian CO (2006) Polyoxyethylenealkyl ethers. Handbook of pharmaceutical excipients, 5th edn. Pharmaceutical Press, London, pp 564–571Google Scholar
  149. Robinson JC (1993) Ocular anatomy and physiology relevant to ocular drug delivery. In: Mitra AK (ed) Ophthalmic drug delivery systems. Marcel Dekker, New York, pp 29–57Google Scholar
  150. Rojanasakul Y, Wang LY, Bhat M (1992) The transport barrier of epithelia: a comparative study on membrane permeability and charge selectivity in the rabbit. Pharm Res 9:1029–1934PubMedGoogle Scholar
  151. Rooijen VN, Nieuwmegen VR (1980) Liposomes in immunology: multilamellar phosphatidylcholine liposomes as a simple, biodegradable and harmless adjuvant without any immunogenic activity of its own. Immunol Commun 9:243–256PubMedGoogle Scholar
  152. Round A, Berry M, McMaster T, Stoll S, Gowers D, Corfield A, Miles M (2002) Heterogeneity and persistence length in human ocular mucins. Biophys J 83:1661–1670PubMedPubMedCentralGoogle Scholar
  153. Sabzevari A, Adibkia K, Hashemi H, De-Geest BG, Mohsenzadeh N, Atyabi F, Ghahremani MH, Khoshayand MR, Dinarvand R (2013) Improved anti-inflammatory effects in rabbit eye model using biodegradable poly beta-amino ester nanoparticles of triamcinolone acetonide. Invest Ophthalmol Vis Sci 54:5520–5526PubMedGoogle Scholar
  154. Sahoo SK, Labhasetwar V (2003) Nanotech approaches to drug delivery and imaging. Drug Discov Today 8:1112–1120PubMedGoogle Scholar
  155. Sahoo SK, Dilnawaz F, Krishnakumar S (2008) Nanotechnology in ocular drug delivery. Drug Discov Today 13:144–151PubMedGoogle Scholar
  156. Salama AH, Mahmoud AA, Kamel R (2015) A novel method for preparing surface-modified fluocinolone acetonide loaded PLGA nanoparticles for ocular use: in vitro and in vivo evaluations. AAPS Pharm Sci Tech, 1–14Google Scholar
  157. Samad A, Alam MI, Saxena K (2009) Dendrimers: a class of polymers in the nanotechnology for the delivery of active pharmaceuticals. Curr Pharm 15(25):2958–2969Google Scholar
  158. Sasaki H, Karasawa K, Hironaka K, Tahara K, Tozuka Y, Takeuchi H (2013) Retinal drug delivery using eyedrop preparations of poly-L-lysine-modifiedliposomes. Eur J Biopharm 83:364–369Google Scholar
  159. Schipper NG, Olsson S, Hoogstraate JA, deBoer AG, Varum KM, Artursson P (1997) Chitosans as absorption enhancers for poorly absorbable drugs 2: mechanism of absorption enhancement. Pharm Res 14:923–929PubMedGoogle Scholar
  160. Schoenwald RD (1990) Ocular drug delivery: pharmacokinetic considerations. Clin Pharmacokinet 18:255–269PubMedGoogle Scholar
  161. Schoenwald RD, Ward RL, Desantis LM, Roehrs RE (1978) Influence of high viscosity vehicles on miotic effect of pilocarpine. J Pharm Sci 67:1280–1283PubMedGoogle Scholar
  162. Schoenwald RD, Vidvauns S, Wurster DE, Barfknecht CF (1998) The role of tear proteins in tear film stability in the dry eye patient and in the rabbit. In: Sullivan DA, Dartt DA and Menerary MA (eds) Lacrimal gland, Tear Film and Dry Eye Sydromes. 2. Plenum Press: New York, pp 391–400Google Scholar
  163. Sechoy O, Tissiiee G, Sebastian C, Maurin F, Driot JY, Trinquand C (2000) A new long acting ophthalmic formulation of Carteolol containing alginic acid. Int J Pharm 207:109–116PubMedGoogle Scholar
  164. Shahiwala A, Misra A (2002) Studies in topical application of niosomally entrapped nimesulide. J Pharm Sci 5:220–225Google Scholar
  165. Shan W, Liu H, Shi J, Yang L, Hu N (2008) Self-assembly of electroactive layer-by-layer films of heme proteins with anionic surfactant dihexadecyl phosphate. Biophys Chem 134:101–109PubMedGoogle Scholar
  166. Shen Y, Tu J (2007) Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS Pharm Sci Tech 9:371–377Google Scholar
  167. Singh D (2003) Conjunctival lymphatic system. J Cataract Refract Surg 29:632–633PubMedGoogle Scholar
  168. Singh V, Ahmad R, Heming T (2011) The challenges of ophthalmic drug delivery: a review. Int J Drug Discov 3:56–62Google Scholar
  169. Slovin EM, Robinson JR (1993) Bioadhesive in ocular drug delivery. In: Edman P (ed) Biopharmaceutics of ocular drug delivery. CRC Press, Boca Raton, Florida, pp 145–157Google Scholar
  170. Soukharev AR, Wojciechowska J (2005) Microemulsions as potential ocular drug delivery systems: phase diagrams and physical depending on ingredients. Acta Pol Pharm Drug Res 62:465–471Google Scholar
  171. Stahl U, Willcox M, Stapleton F (2012) Osmolality and tear film dynamics. Clin Exp Optom 95(1):3–11PubMedGoogle Scholar
  172. Sugar HS, Riazi A, Schaffner R (1957) The bulbar conjunctival lymphatics and their clinical significance. Trans Am Acad Ophthalmol Otolaryngol 61:212–223PubMedGoogle Scholar
  173. Sun KX, Wang AP, Huang LJ, Liang RC, Liu K (2006) [Preparation of diclofenac sodium liposomes and its ocular pharmacokinetics]. Yao Xue Xue Bao. 41(11):1094–1098PubMedGoogle Scholar
  174. Szczesna DH, Jaronski J, Kasprzak HT, Stenevi U (2006) Interferometric measurements of dynamic changes of tear film. J Biomed Opt 11(3):340–352Google Scholar
  175. Szczesna DH, Kasprzak HT, Jaronski J, Rydz A, Stenevi U (2007) An interferometric method for the dynamic evaluation of the tear film. Acta Ophthalmol Scand 85:202–208PubMedGoogle Scholar
  176. Szczesna-Iskander DH, Iskander DR (2012) Future directions in non-invasive measurements of tear film surface kinetics. Optom Vis Sci 89(5):749–759PubMedGoogle Scholar
  177. Szulc J, Woyczikowski B, De Laval W (1988) Effect of pilocarpine hydrochloride liposomes on the intraocular pressure of the rabbit eye pupil. Farm Pol 44:462–465Google Scholar
  178. Takeuchi H, Yamamoto H, Niwa T, Hino T, Kawashima Y (1996) Enteral absorption of insulin in rats from mucoadhesive chitosan coated liposomes. Pharm Res 13:896–901PubMedGoogle Scholar
  179. Tayel SA, El-Nabarawi MA, Tadros MI, Abd-Elsalam WH (2013) Positively charged polymeric nanoparticle reservoirs of terbinafine hydrochloride: preclinical implications for controlled drug delivery in the aqueous humor of rabbits. AAPS Pharm Sci Tech 14:782–793Google Scholar
  180. Tiffany JM (2003) Tears in health and disease. Eye 17:1–4Google Scholar
  181. Tissie G, Sebastian C, Elena PP, Driot JY, Trinquand C (2002) Alginic acid effect on carteolol ocular pharmacokinetic in the pigmented rabbit. J Ocul Pharmacol Ther 18:65–73PubMedGoogle Scholar
  182. Van Ooteghem M (1995) Preparations ophtalmiques. In: Galenica (ed) Technique and documentation. Lavoisier, ParisGoogle Scholar
  183. Vandamme TF, Brobeck L (2005) Poly (amidoamine) dendrimers as ophthalmic vehicles for ocular delivery of pilocarpine nitrate and tropicamide. J Control Release 102(1):23–38PubMedGoogle Scholar
  184. Vandervoort J, Ludwig A (2004) Preparation and evaluation of drug-loaded gelatin nanoparticles for topical ophthalmic use. Eur J Biopharm 57:251–261Google Scholar
  185. Vyas, S.P., Khar, R.K., 2008. Ocular drug delivery, in controlled drug delivery. 384–385Google Scholar
  186. Wadhwa S, Paliwal R, Paliwal SR, Vyas SP (2009) Nanocarriers in ocular drug delivery: an update review. Curr Pharm Des 15:2724–2750PubMedGoogle Scholar
  187. Wadhwa S, Paliwal R, Paliwal SR, Vyas SP (2010) Hyaluronic acid modified chitosan nanoparticles for effective management of glaucoma: development, characterization, and evaluation. J Drug Target 18(4):292–302PubMedGoogle Scholar
  188. Warsi MH, Anwar M, Garg V, Jain GK, Talegaonkar S, Ahmad FJ, Khar RK (2014) Dorzolamide-loaded PLGA/vitamin E TPGS nanoparticles for glaucoma therapy: pharmacoscintigraphy study and evaluation of extended ocular hypotensive effect in rabbits. Colloids Surf B Biointerfaces 122:423–431PubMedGoogle Scholar
  189. Wen H, Hao J, Li SK (2013) Characterization of human sclera barrier properties for transscleral delivery of bevacizumab and ranibizumab. J Pharm Sci 102:892–903PubMedGoogle Scholar
  190. Wenger Y, Schneider RJ, Reddy GR, Kopelman R, Jolliet O, Philbert MA (2011) Tissue distribution and pharmacokinetics of stable polyacrylamide nanoparticles following intravenous injection in the rat. Toxicol Appl Pharmacol 251:181–190PubMedGoogle Scholar
  191. Wilson CG (2004) Topical drug delivery in the eye. Exp Eye Res 78(3):737–743PubMedGoogle Scholar
  192. Wolff E (1946) The muco-cutaneous junction of the lid margin and the distribution of the tear fluid. Trans Ophthamol Soc UK 66:291–308Google Scholar
  193. Wolff E (1954) The Anatomy of the Eye and Orbit, fourth ed. H.K Lewis and Co, London. 49Google Scholar
  194. Worakul N, Robinson JR (1997) Ocular pharmacokinetics-pharmacodynamics. Eur J Pharm Biopharm 44(1627):71–83Google Scholar
  195. Yan Y, Ting L, Huang J (2009) Recent advances in bolaamphiphiles and oppositely charged conventional surfactants. J Colloid Interface Sci 337:1–10PubMedGoogle Scholar
  196. Yang H, Kao WJ (2006) Dendrimers for pharmaceutical and biomedical applications. J Biomater Sci Polym Ed 17:13–19Google Scholar
  197. Zeng W, Li Q, Wan T, Liu C, Pan W, Wu Z, Zhang G, Pan J, Qin M, Lin Y, Wu C, Xu Y (2016) Hyaluronic acid-coated niosomes facilitate tacrolimus ocular delivery: mucoadhesion, precorneal retention, aqueous humor pharmacokinetics, and transcorneal permeability. Colloids Surf B Biointerfaces 1(141):28–35Google Scholar
  198. Zhou W, Wang Y, Jian J, Song S (2013) Self-aggregated nanoparticles based on amphiphilic poly (lactic acid)-grafted-chitosan copolymer for ocular delivery of amphotericin B. Int J Nanomed 8:3715–3728Google Scholar
  199. Zhu X, Su M, Tang S, Wang L, Liang X, Meng F, Hong Y, Xu Z (2012) Synthesis of thiolated chitosan and preparation nanoparticles with sodium alginate for ocular drug delivery. Mol Vis 18:1973–1982PubMedPubMedCentralGoogle Scholar
  200. Zimmer AK, Kreuter J, Robinson JR (1991) Studies on the transport pathway of PBCA nanoparticles in ocular tissues. J Microencapsul. 8(4):497–504PubMedGoogle Scholar
  201. Zimmer AK, Zerbe H, Kreuter J (1994) Evaluation of pilocarpine-loaded albumin particles as drug delivery systems for controlled delivery in the eye. In vitro and in vivo characterisation. J Control Release 32:57–70Google Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Ameeduzzafar Zafar
    • 1
  • Javed Ahmad
    • 2
  • Richard T. Addo
    • 3
  • Sohail Akhter
    • 4
    • 5
    Email author
  1. 1.Department of Pharmaceutics, Faculty of PharmacyJamia Hamdard UniversityNew DelhiIndia
  2. 2.Department of PharmaceuticsNational Institute of Pharmaceutical Education and Research (NIPER)RaebareliIndia
  3. 3.Department of Pharmaceutical Sciences, School of PharmacyUnion UniversityJacksonUSA
  4. 4.LE STUDIUM® Loire Valley Institute for Advanced Studies, Centre-Val de Loire regionOrléansFrance
  5. 5.Nucleic Acids Transfer by Non-Viral MethodsCentre de Biophysique MoléculaireOrléansFrance

Personalised recommendations