Formulation Approaches for Ocular Drug Delivery

  • Vivek S. DaveEmail author


This chapter aims to provide the readers a comprehensive review of the current trends and approaches used in the development of ocular drug delivery systems. After the introduction to the topic, the chapter begins with a brief description of the common anatomical and physiological factors that are barriers to ocular drug transport and presents a persistent challenge to the development of formulations targeted to ophthalmic tissues. Further, traditional as well as relatively newer approaches used in the development of ocular formulations are discussed. Approaches such as viscosity modifiers, penetration enhancers, liposomal delivery, niosomes, microemulsions, prodrugs, and nanotechnology-derived approaches are extensively reviewed. These approaches are described with respect to the materials, formulation development, formulation performance, relative advantages and drawbacks, and recent advances in the technology. Additionally, the design approaches for the modified ocular drug delivery such as ocular implants, inserts, lenses, and ocular shields are described with respect to the formulation development. Finally, ocular drug delivery systems that are relatively newer or employed less frequently such as intravitreal injections, ocular iontophoresis, etc. are discussed. All approaches described are supported with relevant examples and up-to-date literature reports.


Ocular drug delivery Formulation approaches Nanotechnology Implants Inserts 


  1. 1.
    Patel PB et al (2010) Ophthalmic drug delivery system: challenges and approaches. Syst Rev Pharm 1(2):113–120CrossRefGoogle Scholar
  2. 2.
    Peyman GA, Ganiban GJ (1995) Delivery systems for intraocular routes. Adv Drug Deliv Rev 16(1):107–123CrossRefGoogle Scholar
  3. 3.
    Janoria KG et al (2007) Novel approaches to retinal drug delivery. Expert Opin Drug Deliv 4(4):371–388PubMedCrossRefGoogle Scholar
  4. 4.
    Pal Kaur I, Kanwar M (2002) Ocular preparations: the formulation approach. Drug Dev Ind Pharm 28(5):473–493CrossRefGoogle Scholar
  5. 5.
    Prausnitz MR, Noonan JS (1998) Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci 87(12):1479–1488PubMedCrossRefGoogle Scholar
  6. 6.
    Keister JC et al (1991) Limits on optimizing ocular drug delivery. J Pharm Sci 80(1):50–53PubMedCrossRefGoogle Scholar
  7. 7.
    Kaur IP, Kanwar M (2002) Ocular preparations: the formulation approach. Drug Dev Ind Pharm 28(5):473–493PubMedCrossRefGoogle Scholar
  8. 8.
    Meseguer G et al (1996) Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers. J Ocul Pharmacol Ther 12(4):481–488PubMedCrossRefGoogle Scholar
  9. 9.
    Zaki I et al (1986) A comparison of the effect of viscosity on the precorneal residence of solutions in rabbit and man. J Pharm Pharmacol 38(6):463–466PubMedCrossRefGoogle Scholar
  10. 10.
    Deshpande AA, Heller J, Gurny R (1998) Bioerodible polymers for ocular drug delivery. Crit Rev Ther Drug Carrier Syst 15(4):40CrossRefGoogle Scholar
  11. 11.
    Bottari F et al (1974) Influence of drug concentration on in vitro release of salicylic acid from ointment bases. J Pharm Sci 63(11):1779–1783PubMedCrossRefGoogle Scholar
  12. 12.
    Rozier A et al (1989) Gelrite®: a novel, ion-activated, in-situ gelling polymer for ophthalmic vehicles. Effect on bioavailability of timolol. Int J Pharm 57(2):163–168CrossRefGoogle Scholar
  13. 13.
    Hui H-W, Robinson JR (1985) Ocular delivery of progesterone using a bioadhesive polymer. Int J Pharm 26(3):203–213CrossRefGoogle Scholar
  14. 14.
    Stevens LE, Missel PJ, Lang JC (1992) Drug release profiles of ophthalmic formulations. 1. Instrumentation. Anal Chem 64(7):715–723PubMedCrossRefGoogle Scholar
  15. 15.
    Cohen S et al (1997) A novel in situ-forming ophthalmic drug delivery system from alginates undergoing gelation in the eye. J Control Release 44(2–3):201–208CrossRefGoogle Scholar
  16. 16.
    Lee VHL (1993) Ophthalmic drug delivery systems. Precorneal Corneal and Postcorneal factors. In: Mitra AK (ed) Marcel Dekker, New York, pp 59–82Google Scholar
  17. 17.
    Lee VHL (1993) Biopharmaceutics of ocular drug delivery. Formulation Approaches to Improve Ocular Bioavailability. In: Edman P (ed) CRC Press, Boca Raton, pp 121–143Google Scholar
  18. 18.
    Liaw J, Robinson JR (1992) The effect of polyethylene glycol molecular weight on corneal transport and the related influence of penetration enhancers. Int J Pharm 88(1–3):125–140CrossRefGoogle Scholar
  19. 19.
    Sasaki H et al (1995) Different effects of absorption promoters on corneal and conjunctival penetration of ophthalmic beta-blockers. Pharm Res 12(8):1146–1150PubMedCrossRefGoogle Scholar
  20. 20.
    Sasaki H et al (1995) Penetration of β-blockers through ocular membranes in a1bino rabbits. J Pharm Pharmacol 47(1):17–21CrossRefGoogle Scholar
  21. 21.
    Marshall W, Klyce D (1983) Cellular and paracellular pathway resistances in the ‘tight’ Cl-secreting epithelium of rabbit cornea. J Membr Biol 73(3):275–282PubMedCrossRefGoogle Scholar
  22. 22.
    Lee VHL (1990) Mechanisms and facilitation of corneal drug penetration. J Control Release 11(1–3):79–90CrossRefGoogle Scholar
  23. 23.
    Chiou GCY, Chuang CY (1989) Improvement of systemic absorption of insulin through eyes with absorption enhancers. J Pharm Sci 78(10):815–818PubMedCrossRefGoogle Scholar
  24. 24.
    Godbey REW, Green K, Hull DS (1979) Influence of cetylpyridinium chloride on corneal permeability to penicillin. J Pharm Sci 68(9):1176–1178PubMedCrossRefGoogle Scholar
  25. 25.
    Higaki K, Takeuchi M, Nakano M (1996) Estimation and enhancement of in vitro corneal transport of S-1033, a novel antiglaucoma medication. Int J Pharm 132(1–2):165–173CrossRefGoogle Scholar
  26. 26.
    Marsh RJ, Maurice DM (1971) The influence of non-ionic detergents and other surfactants on human corneal permeability. Exp Eye Res 11(1):43–48PubMedCrossRefGoogle Scholar
  27. 27.
    Mikkelson TJ, Chrai SS, Robinson JR (1973) Competitive inhibition of drug-protein interaction in eye fluids and tissues. J Pharm Sci 62(12):1942–1945PubMedCrossRefGoogle Scholar
  28. 28.
    Morimoto K, Nakai T, Morisaka K (1987) Evaluation of permeability enhancement of hydrophilic compounds and macromolecular compounds by bile salts through rabbit corneas in-vitro. J Pharm Pharmacol 39(2):124–126PubMedCrossRefGoogle Scholar
  29. 29.
    Sasaki H et al (1995) Ophthalmic preservatives as absorption promoters for ocular drug delivery. J Pharm Pharmacol 47(9):703–707PubMedCrossRefGoogle Scholar
  30. 30.
    Sasaki H et al (1994) Effect of preservatives on systemic delivery of insulin by ocular instillation in rabbits. J Pharm Pharmacol 46(11):871–875PubMedCrossRefGoogle Scholar
  31. 31.
    Tang-Liu DDS et al (1994) Effects of four penetration enhancers on corneal permeability of drugs in vitro. J Pharm Sci 83(1):85–90PubMedCrossRefGoogle Scholar
  32. 32.
    Van Santvliet L, Ludwig A (1998) The influence of penetration enhancers on the volume instilled of eye drops. Eur J Pharm Biopharm 45(2):189–198PubMedCrossRefGoogle Scholar
  33. 33.
    Lee VH, Robinson JR (1986) Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol 2(1):67–108PubMedCrossRefGoogle Scholar
  34. 34.
    Green K (1993) Biopharmaceutics in ocular drug delivery. The effects of preservatives on corneal permeability of drugs. In: Edman P (ed) CRC PRess, Boca Raton, pp 43–49Google Scholar
  35. 35.
    Pfister RR, Burstein N (1976) The effects of ophthalmic drugs, vehicles, and preservatives on corneal epithelium: a scanning electron microscope study. Invest Ophthalmol 15(4):246–259PubMedGoogle Scholar
  36. 36.
    Hochman J, Artursson P (1994) Mechanisms of absorption enhancement and tight junction regulation. J Control Release 29(3):253–267CrossRefGoogle Scholar
  37. 37.
    Saettone MF et al (1996) Evaluation of ocular permeation enhancers: in vitro effects on corneal transport of four Î2-blockers, and in vitro/in vivo toxic activity. Int J Pharm 142(1):103–113CrossRefGoogle Scholar
  38. 38.
    Grass GM, Robinson JR (1988) Mechanisms of corneal drug penetration I: in vivo and in vitro kinetics. J Pharm Sci 77(1):3–14PubMedCrossRefGoogle Scholar
  39. 39.
    Newton C, Gebhardt BM, Kaufman HE (1988) Topically applied cyclosporine in azone prolongs corneal allograft survival. Invest Ophthalmol Vis Sci 29(2):208–215PubMedGoogle Scholar
  40. 40.
    Green K et al (1987) Detergent penetration into young and adult rabbit eyes: comparative pharmacokinetics. Cutan Ocul Toxicol 6(2):89–107CrossRefGoogle Scholar
  41. 41.
    Grass GM, Robinson JR (1984) Relationship of chemical structure to corneal penetration and influence of low-viscosity solution on ocular bioavailability. J Pharm Sci 73(8):1021–1027PubMedCrossRefGoogle Scholar
  42. 42.
    Ismail IM et al (1992) Comparison of azone and hexamethylene lauramide in toxicologic effects and penetration enhancement of cimetidine in rabbit eyes. Pharm Res 9(6):817–821PubMedCrossRefGoogle Scholar
  43. 43.
    Merkus FWHM et al (1993) Absorption enhancers in nasal drug delivery: efficacy and safety. J Control Release 24(1–3):201–208CrossRefGoogle Scholar
  44. 44.
    Rojanasakul Y, Liaw J, Robinson JR (1990) Mechanisms of action of some penetration enhancers in the cornea: laser scanning confocal microscopic and electrophysiology studies. Int J Pharm 66(1–3):131–142CrossRefGoogle Scholar
  45. 45.
    Komatsu A et al (1988) Application of lipid microsphere drug delivery system to steroidal ophthalmic preparation. Jpn J Ophthalmol 32(1):41–43PubMedGoogle Scholar
  46. 46.
    Oppenheim RC (1980) Drug delivery systems characteristics and biomedical applications. Nanoparticle. In: Juliano RJ (ed) Oxford University Press, New York, pp 177–188Google Scholar
  47. 47.
    Meisner D, Mezei M (1995) Liposome ocular delivery systems. Adv Drug Deliv Rev 16(1):75–93CrossRefGoogle Scholar
  48. 48.
    Dharma SK, Fishman PH, Peyman GA (1986) A preliminary study of corneal penetration of 125l-labelled idoxuridine liposome. Acta Ophthalmol (Copenh) 64(3):298–301CrossRefGoogle Scholar
  49. 49.
    Smolin G et al (1981) Idoxuridine-liposome therapy for herpes simplex keratitis. Am J Ophthalmol 91(2):220–225PubMedCrossRefGoogle Scholar
  50. 50.
    Schaeffer HE, Krohn DL (1982) Liposomes in topical drug delivery. Invest Ophthalmol Vis Sci 22(2):220–227PubMedGoogle Scholar
  51. 51.
    Shek PN, Barber RF (1987) Liposomes are effective carriers for the ocular delivery of prophylactics. Biochim Biophys Acta Biomembr 902(2):229–236CrossRefGoogle Scholar
  52. 52.
    Al-Muhammed J et al (1996) In-vivo studies on dexamethasone sodium phosphate liposomes. J Microencapsul 13(3):293–305PubMedCrossRefGoogle Scholar
  53. 53.
    El-Gazayerly ON, Hikal AH (1997) Preparation and evaluation of acetazolamide liposomes as an ocular delivery system. Int J Pharm 158(2):121–127CrossRefGoogle Scholar
  54. 54.
    Milani JK et al (1993) Prolongation of corneal allograft survival with liposome-encapsulated cyclosporine in the rat eye. Ophthalmology 100(6):890–896PubMedCrossRefGoogle Scholar
  55. 55.
    Lee VHL et al (1985) Ocular drug bioavailability from topically applied liposomes. Surv Ophthalmol 29(5):335–348PubMedCrossRefGoogle Scholar
  56. 56.
    Liddell MR et al (2007) Evaluation of glass dissolution vessel dimensions and irregularities. Dissolution Technol 14(1):28–33CrossRefGoogle Scholar
  57. 57.
    Durrani AM et al (1992) Pilocarpine bioavailability from a mucoadhesive liposomal ophthalmic drug delivery system. Int J Pharm 88(1–3):409–415CrossRefGoogle Scholar
  58. 58.
    Pleyer U et al (1994) Ocular absorption of cyclosporine A from liposomes incorporated into collagen shields. Curr Eye Res 13(3):177–181PubMedCrossRefGoogle Scholar
  59. 59.
    Kaur IP et al (2004) Vesicular systems in ocular drug delivery: an overview. Int J Pharm 269(1):1–14PubMedCrossRefGoogle Scholar
  60. 60.
    Uchegbu IF, Vyas SP (1998) Non-ionic surfactant based vesicles (niosomes) in drug delivery. Int J Pharm 172(1–2):33–70CrossRefGoogle Scholar
  61. 61.
    Carafa M et al (1998) Preparation and properties of new unilamellar non-ionic/ionic surfactant vesicles. Int J Pharm 160(1):51–59CrossRefGoogle Scholar
  62. 62.
    Carafa M, Santucci E, Lucania G (2002) Lidocaine-loaded non-ionic surfactant vesicles: characterization and in vitro permeation studies. Int J Pharm 231(1):21–32PubMedCrossRefGoogle Scholar
  63. 63.
    Abdelbary G, El-gendy N (2008) Niosome-encapsulated gentamicin for ophthalmic controlled delivery. AAPS PharmSciTech 9(3):740–747PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Vyas SP et al (1998) Discoidal niosome based controlled ocular delivery of timolol maleate. Pharmazie 53(7):466–469PubMedGoogle Scholar
  65. 65.
    Pandita A, Sharma P (2013) Pharmacosomes: an emerging novel vesicular drug delivery system for poorly soluble synthetic and herbal drugs. ISRN Pharm 2013:1–10Google Scholar
  66. 66.
    Fialho SL, da Silva-Cunha A (2004) New vehicle based on a microemulsion for topical ocular administration of dexamethasone. Clin Experiment Ophthalmol 32(6):626–632PubMedCrossRefGoogle Scholar
  67. 67.
    Vandamme TF (2002) Microemulsions as ocular drug delivery systems: recent developments and future challenges. Prog Retin Eye Res 21(1):15–34PubMedCrossRefGoogle Scholar
  68. 68.
    Hasse A, Keipert S (1997) Development and characterization of microemulsions for ocular application. Eur J Pharm Biopharm 43(2):179–183CrossRefGoogle Scholar
  69. 69.
    Klang S, Abdulrazik M, Benita S (2000) Influence of emulsion droplet surface charge on indomethacin ocular tissue distribution. Pharm Dev Technol 5(4):521–532PubMedCrossRefGoogle Scholar
  70. 70.
    Chan J et al (2007) Phase transition water-in-oil microemulsions as ocular drug delivery systems: in vitro and in vivo evaluation. Int J Pharm 328(1):65–71PubMedCrossRefGoogle Scholar
  71. 71.
    Kapoor Y, Chauhan A (2008) Ophthalmic delivery of cyclosporine A from Brij-97 microemulsion and surfactant-laden p-HEMA hydrogels. Int J Pharm 361(1–2):222–229PubMedCrossRefGoogle Scholar
  72. 72.
    G.Wilson C, Y.P.Zhu, P.Kurmala, L.S.Rao, B.Dhillon. Ophthalmic Drug Delivery. In: M.Hillery A, W.Lloyd A, Swarbrick J, editors. Drug Delivery and Targeting for Pharmacists and Pharmaceutical Scientists. London: Taylor & Francis; 2005. p. 298–319Google Scholar
  73. 73.
    Pignatello R et al (2002) Flurbiprofen-loaded acrylate polymer nanosuspensions for ophthalmic application. Biomaterials 23(15):3247–3255PubMedCrossRefGoogle Scholar
  74. 74.
    Adibkia K et al (2007) Inhibition of endotoxin-induced uveitis by methylprednisolone acetate nanosuspension in rabbits. J Ocul Pharmacol Ther 23(5):421–432PubMedCrossRefGoogle Scholar
  75. 75.
    Adibkia K et al (2007) Piroxicam nanoparticles for ocular delivery: physicochemical characterization and implementation in endotoxin-induced uveitis. J Drug Target 15(6):407–416PubMedCrossRefGoogle Scholar
  76. 76.
    Kassem MA et al (2007) Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int J Pharm 340(1–2):126–133PubMedCrossRefGoogle Scholar
  77. 77.
    Pignatello R et al (2006) Preparation and characterization of eudragit retard nanosuspensions for the ocular delivery of cloricromene. AAPS PharmSciTech 7(1):E192–E198PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Sahoo SK, Dilnawaz F, Krishnakumar S (2008) Nanotechnology in ocular drug delivery. Drug Discov Today 13(3–4):144–151PubMedCrossRefGoogle Scholar
  79. 79.
    Sakurai E et al (2001) Effect of particle size of polymeric nanospheres on intravitreal kinetics. Ophthalmic Res 33(1):31–36PubMedCrossRefGoogle Scholar
  80. 80.
    Gan L et al (2013) Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug Discov Today 18(5–6):290–297PubMedCrossRefGoogle Scholar
  81. 81.
    Bourges JL et al (2003) Ocular drug delivery targeting the retina and retinal pigment epithelium using polylactide nanoparticles. Invest Ophthalmol Vis Sci 44(8):3562–3569PubMedCrossRefGoogle Scholar
  82. 82.
    Li VH et al (1986) Ocular drug delivery of progesterone using nanoparticles. J Microencapsul 3(3):213–218PubMedCrossRefGoogle Scholar
  83. 83.
    Cavalli R et al (2002) Solid lipid nanoparticles (SLN) as ocular delivery system for tobramycin. Int J Pharm 238(1–2):241–245PubMedCrossRefGoogle Scholar
  84. 84.
    Amrite AC et al (2008) Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration. Mol Vis 14:150–160PubMedPubMedCentralGoogle Scholar
  85. 85.
    Irache JM et al (2005) Albumin nanoparticles for the intravitreal delivery of anticytomegaloviral drugs. Mini Rev Med Chem 5(3):293–305PubMedCrossRefGoogle Scholar
  86. 86.
    Calvo P, Vila-Jato JL, Alonso MJ (1996) Comparative in vitro evaluation of several colloidal systems, nanoparticles, nanocapsules, and nanoemulsions, as ocular drug carriers. J Pharm Sci 85(5):530–536PubMedCrossRefGoogle Scholar
  87. 87.
    De Campos AM et al (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(1):73–81PubMedCrossRefGoogle Scholar
  88. 88.
    Xu J et al (2007) Inhibitory efficacy of intravitreal dexamethasone acetate-loaded PLGA nanoparticles on choroidal neovascularization in a laser-induced rat model. J Ocul Pharmacol Ther 23(6):527–540PubMedCrossRefGoogle Scholar
  89. 89.
    Motwani SK et al (2008) Chitosan-sodium alginate nanoparticles as submicroscopic reservoirs for ocular delivery: formulation, optimisation and in vitro characterisation. Eur J Pharm Biopharm 68(3):513–525PubMedGoogle Scholar
  90. 90.
    Arnedo A et al (2004) Albumin nanoparticles improved the stability, nuclear accumulation and anticytomegaloviral activity of a phosphodiester oligonucleotide. J Control Release 94(1):217–227PubMedCrossRefGoogle Scholar
  91. 91.
    Gaudana R et al (2009) Recent perspectives in ocular drug delivery. Pharm Res 26(5):1197–1216PubMedCrossRefGoogle Scholar
  92. 92.
    Gunda S, Hariharan S, Mitra AK (2006) Corneal absorption and anterior chamber pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV): in vivo comparative evaluation of these prodrugs with Val-GCV and GCV in rabbits. J Ocul Pharmacol Ther 22(6):465–476PubMedCrossRefGoogle Scholar
  93. 93.
    Majumdar S et al (2005) Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. J Ocul Pharmacol Ther 21(6):463–474PubMedCrossRefGoogle Scholar
  94. 94.
    Kansara V, Hao Y, Mitra AK (2007) Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina. J Ocul Pharmacol Ther 23(4):321–334PubMedCrossRefGoogle Scholar
  95. 95.
    Janoria KG, Mitra AK (2007) Effect of lactide/glycolide ratio on the in vitro release of ganciclovir and its lipophilic prodrug (GCV-monobutyrate) from PLGA microspheres. Int J Pharm 338(1–2):133–141PubMedCrossRefGoogle Scholar
  96. 96.
    Dias C et al (2002) Ocular penetration of acyclovir and its peptide prodrugs valacyclovir and val-valacyclovir following systemic administration in rabbits: an evaluation using ocular microdialysis and LC-MS. Curr Eye Res 25(4):243–252PubMedCrossRefGoogle Scholar
  97. 97.
    Anand BS et al (2003) In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model. Invest Ophthalmol Vis Sci 44(6):2529–2534PubMedCrossRefGoogle Scholar
  98. 98.
    Katragadda S, Talluri RS, Mitra AK (2006) Modulation of P-glycoprotein-mediated efflux by prodrug derivatization: an approach involving peptide transporter-mediated influx across rabbit cornea. J Ocul Pharmacol Ther 22(2):110–120PubMedCrossRefGoogle Scholar
  99. 99.
    Doukas J et al (2008) Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol 216(1):29–37PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Al-Ghananeem AM, Crooks PA (2007) Phase I and phase II ocular metabolic activities and the role of metabolism in ophthalmic prodrug and codrug design and delivery. Molecules 12(3):373–388PubMedCrossRefGoogle Scholar
  101. 101.
    Lallemand F et al (2007) Biological conversion of a water-soluble prodrug of cyclosporine A. Eur J Pharm Biopharm 67(2):555–561PubMedCrossRefGoogle Scholar
  102. 102.
    Juntunen J, Jarvinen T, Niemi R (2005) In-vitro corneal permeation of cannabinoids and their water-soluble phosphate ester prodrugs. J Pharm Pharmacol 57(9):1153–1157PubMedCrossRefGoogle Scholar
  103. 103.
    Nambu H et al (2003) Combretastatin A-4 phosphate suppresses development and induces regression of choroidal neovascularization. Invest Ophthalmol Vis Sci 44(8):3650–3655PubMedCrossRefGoogle Scholar
  104. 104.
    Takahashi K et al (2003) Topical nepafenac inhibits ocular neovascularization. Invest Ophthalmol Vis Sci 44(1):409–415PubMedCrossRefGoogle Scholar
  105. 105.
    Punch PI et al (1987) The release of insoluble antibiotics from collagen ocular inserts in vitro and their insertion into the conjunctival sac of cattle. J Vet Pharmacol Ther 10(1):37–42PubMedCrossRefGoogle Scholar
  106. 106.
    Rawas-Qalaji M, Williams CA (2012) Advances in ocular drug delivery. Curr Eye Res 37(5):345–356PubMedCrossRefGoogle Scholar
  107. 107.
    Jalil R-U (1990) Biodegradable poly(lactic acid) and poly (lactide-co-glycolide) polymers in sustained drug delivery. Drug Dev Ind Pharm 16(16):2353–2367CrossRefGoogle Scholar
  108. 108.
    Hashizoe M et al (1994) SCleral plug of biodegradable polymers for controlled drug release in the vitreous. Arch Ophthalmol 112(10):1380–1384PubMedCrossRefGoogle Scholar
  109. 109.
    Kimura H et al (1994) A new vitreal drug delivery system using an implantable biodegradable polymeric device. Invest Ophthalmol Vis Sci 35(6):2815–2819PubMedGoogle Scholar
  110. 110.
    Kunou N et al (1995) Controlled intraocular delivery of ganciclovir with use of biodegradable scleral implant in rabbits. J Control Release 37(1–2):143–150CrossRefGoogle Scholar
  111. 111.
    Sanborn GE et al (1992) Sustained-release ganciclovir therapy for treatment of cytomegalovirus retinitis: use of an intravitreal device. Arch Ophthalmol 110(2):188–195PubMedCrossRefGoogle Scholar
  112. 112.
    Gurtler F, Gurny R (1995) Patent literature review of ophthalmic inserts. Drug Dev Ind Pharm 21(1):1–18CrossRefGoogle Scholar
  113. 113.
    Chien YW (1992) Ocular drug delivery and delivery systems. In: Chien YW (ed) Novel drug delivery systems, 2nd edn. Taylor and Francis, New YorkGoogle Scholar
  114. 114.
    Karthikeyan D et al (2008) The concept of ocular inserts as drug delivery systems: an overview. Asian J Pharm 2(4):192–200CrossRefGoogle Scholar
  115. 115.
    Khar RK, Vyas SP (2002) Targeted and controlled drug delivery novel carrier systems. In: Khar RK, Vyas SP (eds), 1st edn. CBS Publishers and Distributors, New DelhiGoogle Scholar
  116. 116.
    Saettone MF, Salminen L (1995) Ocular inserts for topical delivery. Adv Drug Deliv Rev 16(1):95–106CrossRefGoogle Scholar
  117. 117.
    Sahane NK et al (2010) Ocular inserts: a review. J Pharm Res 3(1):57–64Google Scholar
  118. 118.
    El-Shanawany S (1992) Ocular delivery of pilocarpine from ocular inserts. Pharma Sci 2(4):337–341Google Scholar
  119. 119.
    Gurtler F et al (1995) Long-acting soluble bioadhesive ophthalmic drug insert (BODI) containing gentamicin for veterinary use: optimization and clinical investigation. J Control Release 33(2):231–236CrossRefGoogle Scholar
  120. 120.
    Pollack IP, Quigley HA, Harbin TS (1976) The Ocusert pilocarpine system: advantages and disadvantages. South Med J 69(10):1296–1298PubMedCrossRefGoogle Scholar
  121. 121.
    Johansen S, Prause JU, Rask-Pedersen E (1996) I: a bioavailability comparison in rabbits after a single topical ocular application of prednisolone acetate formulated as a high-viscosity gel and as an aqueous suspension. Acta Ophthalmol Scand 74(3):253–258PubMedCrossRefGoogle Scholar
  122. 122.
    Urtti A, Salminen L, Miinalainen O (1985) Systemic absorption of ocular pilocarpine is modified by polymer matrices. Int J Pharm 23(2):147–161CrossRefGoogle Scholar
  123. 123.
    Urtti A, Juslin M, Miinalainen O (1985) Pilocarpine release from hydroxypropyl-cellulose-polyvinylpyrrolidone matrices. Int J Pharm 25(2):165–178CrossRefGoogle Scholar
  124. 124.
    Vasantha V, Sehgal PK, Rao KP (1988) Collagen ophthalmic inserts for pilocarpine drug delivery system. Int J Pharm 47(1–3):95–102CrossRefGoogle Scholar
  125. 125.
    Attia MA, Kassem MA, Safwat SM (1988) In vivo performance of [3H]dexamethasone ophthalmic film delivery systems in the rabbit eye. Int J Pharm 47(1–3):21–30CrossRefGoogle Scholar
  126. 126.
    Darougar S (1992) Ocular insert for the fornix. In: U.S.P.A.T. Office (ed) Google. Google Patents, USAGoogle Scholar
  127. 127.
    Urtti A et al (1994) Controlled ocular timolol delivery: systemic absorption and intraocular pressure effects in humans. Pharm Res 11(9):1278–1282PubMedCrossRefGoogle Scholar
  128. 128.
    Dumitriu S et al (1988) Polycomponent ophthalmic inserts with polysaccharide support. J Bioact Compat Polym 3(4):370–389CrossRefGoogle Scholar
  129. 129.
    Kalenak JW, Zakov ZN (1994) Presumed sudden leakage of a pilocarpine ocusert and rhegmatogenous retinal detachment. J Glaucoma 3(2):152–153PubMedCrossRefGoogle Scholar
  130. 130.
    Kushnick H, Liebmann JM, Ritch R (1996) Systemic pilocarpine toxicity from ocusert leakage. Arch Ophthalmol 114(11):1432–1432PubMedCrossRefGoogle Scholar
  131. 131.
    Hitoshi S et al (1993) Drug release from an ophthalmic insert of a beta-blocker as an ocular drug delivery system. J Control Release 27(2):127–137CrossRefGoogle Scholar
  132. 132.
    Fazly Bazzaz BS et al (2014) Preparation, characterization and antimicrobial study of a hydrogel (soft contact lens) material impregnated with silver nanoparticles. Cont Lens Anterior Eye 37(3):149–152PubMedCrossRefGoogle Scholar
  133. 133.
    Maichuk YF, Erichev VP (1981) Soluble ophthalmic drug inserts with pilocarpine: experimental and clinical study. Glaucoma 3:239–242Google Scholar
  134. 134.
    Baeyens V et al (1998) Optimized release of dexamethasone and gentamicin from a soluble ocular insert for the treatment of external ophthalmic infections. J Control Release 52(1–2):215–220PubMedCrossRefGoogle Scholar
  135. 135.
    Aiache JM et al (1997) The formulation of drug for ocular administration. J Biomater Appl 11(3):329–348PubMedCrossRefGoogle Scholar
  136. 136.
    Kamath U, Singh U, Udupa N (1993) Evaluation of ciprofloxacin hydrochloride ocular preparations. Ind J Pharm Sci 55(4):148–150Google Scholar
  137. 137.
    Mundada AS, Shrikhande BK (2006) Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride. Drug Dev Ind Pharm 32(4):443–448PubMedCrossRefGoogle Scholar
  138. 138.
    Mundada AS, Shrikhande BK (2008) Formulation and evaluation of ciprofloxacin hydrochloride soluble ocular drug insert. Curr Eye Res 33(5):469–475PubMedCrossRefGoogle Scholar
  139. 139.
    Gurtler F, Gurny R (1998) Bioadhesive ophthalmic insert. In: U.S.P.A.T. Office, Vetoquinol SA (ed) Google patents, Lure, USAGoogle Scholar
  140. 140.
    Saettone MF et al (1992) Controlled release of pilocarpine from coated polymeric ophthalmic inserts prepared by extrusion. Int J Pharm 86(2–3):159–166CrossRefGoogle Scholar
  141. 141.
    Willoughby CE, Batterbury M, Kaye SB (2002) Collagen corneal shields. Surv Ophthalmol 47(2):174–182PubMedCrossRefGoogle Scholar
  142. 142.
    Poland DE, Kaufman HE (1988) Clinical uses of collagen shields. J Cataract Refract Surg 14(5):489–491PubMedCrossRefGoogle Scholar
  143. 143.
    Kaufman HE (1988) Collagen shield symposium. J Cataract Refract Surg 14(5):487–488PubMedCrossRefGoogle Scholar
  144. 144.
    Kaufman HE et al (1994) Collagen-based drug delivery and artificial tears. J Ocul Pharmacol 10(1):17–27PubMedCrossRefGoogle Scholar
  145. 145.
    Bloomfield SE et al (1978) Soluble gentamicin ophthalmic inserts as a drug delivery system. Arch Ophthalmol 96(5):885–887PubMedCrossRefGoogle Scholar
  146. 146.
    Sawusch MR et al (1988) Use of collagen corneal shields in the treatment of bacterial keratitis. Am J Ophthalmol 106(3):279–281PubMedCrossRefGoogle Scholar
  147. 147.
    Assil KK et al (1992) Efficacy of tobramycin-soaked collagen shields vs tobramycin eyedrop loading dose for sustained treatment of experimental Pseudomonas aeruginosa-induced keratitis in rabbits. Am J Ophthalmol 113(4):418–423PubMedCrossRefGoogle Scholar
  148. 148.
    Clinch TE et al (1992) Collagen shields containing tobramycin for sustained therapy (24 hours) of experimental Pseudomonas keratitis. CLAO J 18(4):245–247PubMedGoogle Scholar
  149. 149.
    O’Brien TP et al (1988) Use of collagen corneal shields versus soft contact lenses to enhance penetration of topical tobramycin. J Cataract Refract Surg 14(5):505–507PubMedCrossRefGoogle Scholar
  150. 150.
    McDonnell PJ (1998) Method for preventing keratocyte loss. In: U.S.P.A.T. Office (ed) Google patents. University of Southern California (Los Angeles), USAGoogle Scholar
  151. 151.
    Sintzel MB et al (1996) Biomaterials in ophthalmic drug delivery. Eur J Pharm Biopharm 42(6):358–374Google Scholar
  152. 152.
    OASIS® Medical, I. SOFT SHIELD collagen corneal shield 2014 [cited 2014 September 22, 2014]; Widest range of dissolution rates available. Thin, purified collagen. 14.5-mm diameter shield. Accurate and consistent dissolution times]. Available from:
  153. 153.
    Lawrenson JG et al (1993) A comparison of the efficacy and duration of action of topically applied proxymetacaine using a novel ophthalmic delivery system versus eye drops in healthy young volunteers. Br J Ophthalmol 77(11):713–715PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Greaves JL, Wilson CG (1993) Treatment of diseases of the eye with mucoadhesive delivery systems. Adv Drug Deliv Rev 11(3):349–383CrossRefGoogle Scholar
  155. 155.
    Greaves JL et al (1992) Scintigraphic studies on the corneal residence of a new ophthalmic delivery system (NODS): rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine. Br J Clin Pharmacol 33(6):603–609PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Bentley PH (1990) A new ophthalmic delivery system (NODS). In: 9th pharmaceutical technology conference. Veldhoven, NetherlandsGoogle Scholar
  157. 157.
    Kelly JA et al (1989) Relative bioavailability of pilocarpine from a novel ophthalmic delivery system and conventional eyedrop formulations. Br J Ophthalmol 73(5):360–362PubMedPubMedCentralCrossRefGoogle Scholar
  158. 158.
    Diestelhorst M, Krieglstein GK (1994) The ocular tolerability of a new ophthalmic drug delivery system (NODS). Int Ophthalmol 18(1):1–4PubMedCrossRefGoogle Scholar
  159. 159.
    Alani S, Hammerstein W (1990) The ophthalmic rod – a new drug-delivery system II. Graefes Arch Clin Exp Ophthalmol 228(4):302–304PubMedCrossRefGoogle Scholar
  160. 160.
    Gwon A et al (1986) Ophthalmic rods. Ophthalmology 93(9):82–85PubMedCrossRefGoogle Scholar
  161. 161.
    Eller MG et al (1985) Topical carbonic anhydrase inhibitors IV: relationship between excised corneal permeability and pharmacokinetic factors. J Pharm Sci 74(5):525–529PubMedCrossRefGoogle Scholar
  162. 162.
    Maren TH et al (1987) Ocular pharmacology of methazolamide analogs: distribution in the eye and effects on pressure after topical application. J Pharmacol Exp Ther 241(1):56–63PubMedGoogle Scholar
  163. 163.
    Putnam ML et al (1987) Ocular disposition of aminozolamide in the rabbit eye. Invest Ophthalmol Vis Sci 28(8):1373–1382PubMedGoogle Scholar
  164. 164.
    Wilson CG, Olejnik O, Hardy JG (1983) Precorneal drainage of polyvinyl alcohol solutions in the rabbit assessed by gamma scintigraphy. J Pharm Pharmacol 35(7):451–454PubMedCrossRefGoogle Scholar
  165. 165.
    Ludwig A, Ooteghem MV (1986) The study of the precorneal dynamics of ophthalmic solutions by fluorophotometry. Pharm Acta Helv 61(8):236–240PubMedGoogle Scholar
  166. 166.
    Ludwig A, Van Ooteghem M (1989) The evaluation of viscous ophthalmic vehicles by slit lamp fluorophotometry in humans. Int J Pharm 54(2):95–102CrossRefGoogle Scholar
  167. 167.
    Shen YC et al (2014) Pharmacokinetics and safety of intravitreal caspofungin. Antimicrob Agents Chemother 2014(22):03324–14Google Scholar
  168. 168.
    Haller JA et al (2014) Efficacy of intravitreal ocriplasmin for treatment of vitreomacular adhesion: subgroup analyses from two randomized trials. Ophthalmology 6420(14):00689–7Google Scholar
  169. 169.
    Inoue M et al (2014) Intravitreal injection of ranibizumab using a pro re nata regimen for age-related macular degeneration and vision-related quality of life. Clin Ophthalmol 8:1711–1716PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Ausayakhun S et al (2005) Treatment of cytomegalovirus retinitis in AIDS patients with intravitreal ganciclovir. J Med Assoc Thai 88(9):S15–S20PubMedGoogle Scholar
  171. 171.
    Ornek N, Ornek K, Erbahceci IE (2014) Corneal and conjunctival sensitivity changes following intravitreal ranibizumab injection in diabetic retinopathy. J Ocul Pharmacol Ther 2014:22Google Scholar
  172. 172.
    Aslan Bayhan S et al (2014) Marginal keratitis after intravitreal injection of ranibizumab. Cornea 2014:12Google Scholar
  173. 173.
    Parkinson TM et al (2003) Tolerance of ocular iontophoresis in healthy volunteers. J Ocul Pharmacol Ther 19(2):145–151PubMedCrossRefGoogle Scholar
  174. 174.
    Vollmer DL et al (2002) In vivo transscleral iontophoresis of amikacin to rabbit eyes. J Ocul Pharmacol Ther 18(6):549–558PubMedCrossRefGoogle Scholar
  175. 175.
    Frucht-Pery J et al (2006) Iontophoretic treatment of experimental pseudomonas keratitis in rabbit eyes using gentamicin-loaded hydrogels. Cornea 25(10):1182–1186PubMedCrossRefGoogle Scholar
  176. 176.
    Hobden JA et al (1989) Tobramycin iontophoresis into corneas infected with drug-resistant Pseudomonas aeruginosa. Curr Eye Res 8(11):1163–1169PubMedCrossRefGoogle Scholar
  177. 177.
    Hobden JA et al (1990) Ciprofloxacin iontophoresis for aminoglycoside-resistant pseudomonal keratitis. Invest Ophthalmol Vis Sci 31(10):1940–1944PubMedGoogle Scholar
  178. 178.
    Eljarrat-Binstock E et al (2005) Transcorneal and transscleral iontophoresis of dexamethasone phosphate using drug loaded hydrogel. J Control Release 106(3):386–390PubMedCrossRefGoogle Scholar
  179. 179.
    Berdugo M et al (2003) Delivery of antisense oligonucleotide to the cornea by iontophoresis. Antisense Nucleic Acid Drug Dev 13(2):107–114PubMedCrossRefGoogle Scholar
  180. 180.
    Barza M, Peckman C, Baum J (1986) Transscleral iontophoresis of cefazolin, ticarcillin, and gentamicin in the rabbit. Ophthalmology 93(1):133–139PubMedCrossRefGoogle Scholar
  181. 181.
    Behar-Cohen FF et al (2002) Transscleral Coulomb-controlled iontophoresis of methylprednisolone into the rabbit eye: influence of duration of treatment, current intensity and drug concentration on ocular tissue and fluid levels. Exp Eye Res 74(1):51–59PubMedCrossRefGoogle Scholar
  182. 182.
    Grossman RE, Chu DF, Lee DA (1990) Regional ocular gentamicin levels after transcorneal and transscleral iontophoresis. Invest Ophthalmol Vis Sci 31(5):909–916PubMedGoogle Scholar
  183. 183.
    Sarraf D et al (1993) Transscleral iontophoresis of foscarnet. Am J Ophthalmol 115(6):748–754PubMedCrossRefGoogle Scholar
  184. 184.
    Lam TT et al (1994) Intravitreal delivery of ganciclovir in rabbits by transscleral iontophoresis. J Ocul Pharmacol 10(3):571–575PubMedCrossRefGoogle Scholar
  185. 185.
    Hayden BC et al (2004) Pharmacokinetics of systemic versus focal Carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of retinoblastoma. Invest Ophthalmol Vis Sci 45(10):3644–3649PubMedCrossRefGoogle Scholar
  186. 186.
    Ghate D et al (2007) Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry. Invest Ophthalmol Vis Sci 48(5):2230–2237PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Pharmaceutical SciencesSt. John Fisher College, Wegmans School of PharmacyRochesterUSA

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