The AAPS Journal

, Volume 12, Issue 3, pp 348–360 | Cite as

Ocular Drug Delivery

  • Ripal Gaudana
  • Hari Krishna Ananthula
  • Ashwin Parenky
  • Ashim K. Mitra
Review Article Theme: Established Drug Delivery Technologies: Successes and Challenges

Abstract

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood–retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

Key words

nanoparticles retina transporter 

References

  1. 1.
    Ananthula HK, Vaishya RD, Barot M, Mitra AK. Duane's Ophthalmology. In: Tasman W, Jaeger EA, editors. Bioavailability. Philadelphia: Lippincott Williams & Wilkins; 2009.Google Scholar
  2. 2.
    Gipson IK, Argueso P. Role of mucins in the function of the corneal and conjunctival epithelia. Int Rev Cytol. 2003;231:1–49.PubMedCrossRefGoogle Scholar
  3. 3.
    Ahmed I. The noncorneal route in ocular drug delivery. In: Mitra AK, editor. Ophthalmic drug delivery systems. New York: Marcel Dekker; 2003. pp. 335–63.CrossRefGoogle Scholar
  4. 4.
    Klyce SD, Crosson CE. Transport processes across the rabbit corneal epithelium: a review. Curr Eye Res. 1985;4(4):323–31.PubMedCrossRefGoogle Scholar
  5. 5.
    McLaughlin BJ, Caldwell RB, Sasaki Y, Wood TO. Freeze-fracture quantitative comparison of rabbit corneal epithelial and endothelial membranes. Curr Eye Res. 1985;4(9):951–61.PubMedCrossRefGoogle Scholar
  6. 6.
    Barar J, Javadzadeh AR, Omidi Y. Ocular novel drug delivery: impacts of membranes and barriers. Expert Opin Drug Deliv. 2008;5(5):567–81.PubMedCrossRefGoogle Scholar
  7. 7.
    Sunkara GKU. Membrane transport processes in the eye. In: Mitra AK, editor. Ophthalmic drug delivery systems. New York: Marcel Dekker, Inc; 2003. pp. 13–58.CrossRefGoogle Scholar
  8. 8.
    Saha P, Kim KJ, Lee VH. A primary culture model of rabbit conjunctival epithelial cells exhibiting tight barrier properties. Curr Eye Res. 1996;15(12):1163–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Geroski DH, Edelhauser HF. Transscleral drug delivery for posterior segment disease. Adv Drug Deliv Rev. 2001;52(1):37–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Kim SH, Lutz RJ, Wang NS, Robinson MR. Transport barriers in transscleral drug delivery for retinal diseases. Ophthalmic Res. 2007;39(5):244–54.PubMedCrossRefGoogle Scholar
  11. 11.
    Pitkanen L, Ranta VP, Moilanen H, Urtti A. Permeability of retinal pigment epithelium: effects of permeant molecular weight and lipophilicity. Invest Ophthalmol Vis Sci. 2005;46(2):641–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131–5.PubMedCrossRefGoogle Scholar
  13. 13.
    Kim JH, Kim KW, Kim MH, Yu YS. Intravenously administered gold nanoparticles pass through the blood-retinal barrier depending on the particle size, and induce no retinal toxicity. Nanotechnology. 2009;20(50):505101.PubMedCrossRefGoogle Scholar
  14. 14.
    Zhu C, Zhang Y, Pardridge WM. Widespread expression of an exogenous gene in the eye after intravenous administration. Invest Ophthalmol Vis Sci. 2002;43(9):3075–80.PubMedGoogle Scholar
  15. 15.
    Singh SR, Grossniklaus HE, Kang SJ, Edelhauser HF, Ambati BK, Kompella UB. Intravenous transferrin, RGD peptide and dual-targeted nanoparticles enhance anti-VEGF intraceptor gene delivery to laser-induced CNV. Gene Ther. 2009;16(5):645–59.PubMedCrossRefGoogle Scholar
  16. 16.
    Suzuki T, Uno T, Chen G, Ohashi Y. Ocular distribution of intravenously administered micafungin in rabbits. J Infect Chemother. 2008;14(3):204–7.PubMedCrossRefGoogle Scholar
  17. 17.
    Regnier A, Schneider M, Concordet D, Toutain PL. Intraocular pharmacokinetics of intravenously administered marbofloxacin in rabbits with experimentally induced acute endophthalmitis. Am J Vet Res. 2008;69(3):410–5.PubMedCrossRefGoogle Scholar
  18. 18.
    Goldblum D, Rohrer K, Frueh BE, Theurillat R, Thormann W, Zimmerli S. Ocular distribution of intravenously administered lipid formulations of amphotericin B in a rabbit model. Antimicrob Agents Chemother. 2002;46(12):3719–23.PubMedCrossRefGoogle Scholar
  19. 19.
    Santulli RJ, Kinney WA, Ghosh S et al. Studies with an orally bioavailable alpha V integrin antagonist in animal models of ocular vasculopathy: retinal neovascularization in mice and retinal vascular permeability in diabetic rats. J Pharmacol Exp Ther. 2008;324(3):894–901.PubMedCrossRefGoogle Scholar
  20. 20.
    Shirasaki Y, Miyashita H, Yamaguchi M. Exploration of orally available calpain inhibitors. Part 3: Dipeptidyl alpha-ketoamide derivatives containing pyridine moiety. Bioorg Med Chem. 2006;14(16):5691–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Kampougeris G, Antoniadou A, Kavouklis E, Chryssouli Z, Giamarellou H. Penetration of moxifloxacin into the human aqueous humour after oral administration. Br J Ophthalmol. 2005;89(5):628–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Sakamoto H, Sakamoto M, Hata Y, Kubota T, Ishibashi T. Aqueous and vitreous penetration of levofloxacin after topical and/or oral administration. Eur J Ophthalmol. 2007;17(3):372–6.PubMedGoogle Scholar
  23. 23.
    Shirasaki Y. Molecular design for enhancement of ocular penetration. J Pharm Sci. 2008;97(7):2462–96.PubMedCrossRefGoogle Scholar
  24. 24.
    Kaur IP, Smitha R, Aggarwal D, Kapil M. Acetazolamide: future perspective in topical glaucoma therapeutics. Int J Pharm. 2002;248(1–2):1–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Coppens M, Versichelen L, Mortier E. Treatment of postoperative pain after ophthalmic surgery. Bull Soc Belge Ophtalmol. 2002;(285):27–32.PubMedGoogle Scholar
  26. 26.
    Samtani S, Amaral J, Campos MM, Fariss RN, Becerra SP. Doxycycline-mediated inhibition of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2009;50(11):5098–106.PubMedCrossRefGoogle Scholar
  27. 27.
    Rajpal, Srinivas A, Azad RV et al. Evaluation of vitreous levels of gatifloxacin after systemic administration in inflamed and non-inflamed eyes. Acta Ophthalmol. 2009;87(6):648–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Smith VA, Khan-Lim D, Anderson L, Cook SD, Dick AD. Does orally administered doxycycline reach the tear film? Br J Ophthalmol. 2008;92(6):856–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Chong DY, Johnson MW, Huynh TH, Hall EF, Comer GM, Fish DN. Vitreous penetration of orally administered famciclovir. Am J Ophthalmol. 2009;148(1):38–42 e1.PubMedCrossRefGoogle Scholar
  30. 30.
    Takahashi K, Saishin Y, King AG, Levin R, Campochiaro PA. Suppression and regression of choroidal neovascularization by the multitargeted kinase inhibitor pazopanib. Arch Ophthalmol. 2009;127(4):494–9.PubMedCrossRefGoogle Scholar
  31. 31.
    Kokke KH, Morris JA, Lawrenson JG. Oral omega-6 essential fatty acid treatment in contact lens associated dry eye. Cont Lens Anterior Eye. 2008;31(3):141–6. quiz 70.PubMedCrossRefGoogle Scholar
  32. 32.
    Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3(2):275–87.PubMedCrossRefGoogle Scholar
  33. 33.
    Hosseini K, Matsushima D, Johnson J et al. Pharmacokinetic study of dexamethasone disodium phosphate using intravitreal, subconjunctival, and intravenous delivery routes in rabbits. J Ocul Pharmacol Ther. 2008;24(3):301–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Weijtens O, Feron EJ, Schoemaker RC et al. High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am J Ophthalmol. 1999;128(2):192–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim SH, Csaky KG, Wang NS, Lutz RJ. Drug elimination kinetics following subconjunctival injection using dynamic contrast-enhanced magnetic resonance imaging. Pharm Res. 2008;25(3):512–20.PubMedCrossRefGoogle Scholar
  36. 36.
    Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479–88.PubMedCrossRefGoogle Scholar
  37. 37.
    Mitra AK, Anand BS, Duvvuri S. Drug delivery to the eye. In: Fischbarg J, editor. The biology of eye. New York: Academic Press; 2006. pp. 307–51.Google Scholar
  38. 38.
    Pitkanen L, Ruponen M, Nieminen J, Urtti A. Vitreous is a barrier in nonviral gene transfer by cationic lipids and polymers. Pharm Res. 2003;20(4):576–83.PubMedCrossRefGoogle Scholar
  39. 39.
    Peeters L, Sanders NN, Braeckmans K et al. Vitreous: a barrier to nonviral ocular gene therapy. Invest Ophthalmol Vis Sci. 2005;46(10):3553–61.PubMedCrossRefGoogle Scholar
  40. 40.
    Kim H, Robinson SB, Csaky KG. Investigating the movement of intravitreal human serum albumin nanoparticles in the vitreous and retina. Pharm Res. 2009;26(2):329–37.PubMedCrossRefGoogle Scholar
  41. 41.
    Dalkara D, Kolstad KD, Caporale N et al. Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther. 2009;17(12):2096–102.PubMedCrossRefGoogle Scholar
  42. 42.
    Schoenwald RD, Tandon V, Wurster DE, Barfknecht CF. Significance of melanin binding and metabolism in the activity of 5-acetoxyacetylimino-4-methyl-delta2–1, 3, 4,-thiadiazolin e-2-sulfonamide. Eur J Pharm Biopharm. 1998;46(1):39–50.PubMedCrossRefGoogle Scholar
  43. 43.
    Larsson BS. Interaction between chemicals and melanin. Pigment Cell Res. 1993;6(3):127–33.PubMedCrossRefGoogle Scholar
  44. 44.
    Leblanc B, Jezequel S, Davies T, Hanton G, Taradach C. Binding of drugs to eye melanin is not predictive of ocular toxicity. Regul Toxicol Pharmacol. 1998;28(2):124–32.PubMedCrossRefGoogle Scholar
  45. 45.
    Pitkanen L, Ranta VP, Moilanen H, Urtti A. Binding of betaxolol, metoprolol and oligonucleotides to synthetic and bovine ocular melanin, and prediction of drug binding to melanin in human choroid-retinal pigment epithelium. Pharm Res. 2007;24(11):2063–70.PubMedCrossRefGoogle Scholar
  46. 46.
    Salminen L, Imre G, Huupponen R. The effect of ocular pigmentation on intraocular pressure response to timolol. Acta Ophthalmol Suppl. 1985;173:15–8.PubMedCrossRefGoogle Scholar
  47. 47.
    Cheruvu NP, Kompella UB. Bovine and porcine transscleral solute transport: influence of lipophilicity and the Choroid-Bruch's layer. Invest Ophthalmol Vis Sci. 2006;47(10):4513–22.PubMedCrossRefGoogle Scholar
  48. 48.
    Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26(5):1197–216.PubMedCrossRefGoogle Scholar
  49. 49.
    Mannermaa E, Vellonen KS, Urtti A. Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev. 2006;58(11):1136–63.PubMedCrossRefGoogle Scholar
  50. 50.
    Dey S, Anand BS, Patel J, Mitra AK. Transporters/receptors in the anterior chamber: pathways to explore ocular drug delivery strategies. Expert Opin Biol Ther. 2003;3(1):23–44.PubMedCrossRefGoogle Scholar
  51. 51.
    Kawazu K, Yamada K, Nakamura M, Ota A. Characterization of cyclosporin A transport in cultured rabbit corneal epithelial cells: P-glycoprotein transport activity and binding to cyclophilin. Invest Ophthalmol Vis Sci. 1999;40(8):1738–44.PubMedGoogle Scholar
  52. 52.
    Dey S, Patel J, Anand BS et al. Molecular evidence and functional expression of P-glycoprotein (MDR1) in human and rabbit cornea and corneal epithelial cell lines. Invest Ophthalmol Vis Sci. 2003;44(7):2909–18.PubMedCrossRefGoogle Scholar
  53. 53.
    Dey S, Gunda S, Mitra AK. Pharmacokinetics of erythromycin in rabbit corneas after single-dose infusion: role of P-glycoprotein as a barrier to in vivo ocular drug absorption. J Pharmacol Exp Ther. 2004;311(1):246–55.PubMedCrossRefGoogle Scholar
  54. 54.
    Saha P, Yang JJ, Lee VH. Existence of a p-glycoprotein drug efflux pump in cultured rabbit conjunctival epithelial cells. Invest Ophthalmol Vis Sci. 1998;39(7):1221–6.PubMedGoogle Scholar
  55. 55.
    Yang JJ, Kim KJ, Lee VH. Role of P-glycoprotein in restricting propranolol transport in cultured rabbit conjunctival epithelial cell layers. Pharm Res. 2000;17(5):533–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Kennedy BG, Mangini NJ. P-glycoprotein expression in human retinal pigment epithelium. Mol Vis. 2002;8:422–30.PubMedGoogle Scholar
  57. 57.
    Duvvuri S, Gandhi MD, Mitra AK. Effect of P-glycoprotein on the ocular disposition of a model substrate, quinidine. Curr Eye Res. 2003;27(6):345–53.PubMedCrossRefGoogle Scholar
  58. 58.
    Constable PA, Lawrenson JG, Dolman DE, Arden GB, Abbott NJ. P-Glycoprotein expression in human retinal pigment epithelium cell lines. Exp Eye Res. 2006;83(1):24–30.PubMedCrossRefGoogle Scholar
  59. 59.
    Vellonen KS, Mannermaa E, Turner H et al. Effluxing ABC transporters in human corneal epithelium. J Pharm Sci. 2010;99(2):1087–98.PubMedGoogle Scholar
  60. 60.
    Zhang T, Xiang CD, Gale D, Carreiro S, Wu EY, Zhang EY. Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: implications for ocular drug disposition. Drug Metab Dispos. 2008;36(7):1300–7.PubMedCrossRefGoogle Scholar
  61. 61.
    Karla PK, Quinn TL, Herndon BL, Thomas P, Pal D, Mitra A. Expression of multidrug resistance associated protein 5 (MRP5) on cornea and its role in drug efflux. J Ocul Pharmacol Ther. 2009;25(2):121–32.PubMedCrossRefGoogle Scholar
  62. 62.
    Karla PK, Pal D, Quinn T, Mitra AK. Molecular evidence and functional expression of a novel drug efflux pump (ABCC2) in human corneal epithelium and rabbit cornea and its role in ocular drug efflux. Int J Pharm. 2007;336(1):12–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Yang JJ, Ann DK, Kannan R, Lee VH. Multidrug resistance protein 1 (MRP1) in rabbit conjunctival epithelial cells: its effect on drug efflux and its regulation by adenoviral infection. Pharm Res. 2007;24(8):1490–500.PubMedCrossRefGoogle Scholar
  64. 64.
    Aukunuru JV, Sunkara G, Bandi N, Thoreson WB, Kompella UB. Expression of multidrug resistance-associated protein (MRP) in human retinal pigment epithelial cells and its interaction with BAPSG, a novel aldose reductase inhibitor. Pharm Res. 2001;18(5):565–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Karla PK, Earla R, Boddu SH, Johnston TP, Pal D, Mitra A. Molecular expression and functional evidence of a drug efflux pump (BCRP) in human corneal epithelial cells. Curr Eye Res. 2009;34(1):1–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Becker U, Ehrhardt C, Daum N et al. Expression of ABC-transporters in human corneal tissue and the transformed cell line, HCE-T. J Ocul Pharmacol Ther. 2007;23(2):172–81.PubMedCrossRefGoogle Scholar
  67. 67.
    Katragadda S, Talluri RS, Pal D, Mitra AK. Identification and characterization of a Na+-dependent neutral amino acid transporter, ASCT1, in rabbit corneal epithelial cell culture and rabbit cornea. Curr Eye Res. 2005;30(11):989–1002.PubMedCrossRefGoogle Scholar
  68. 68.
    Dun Y, Mysona B, Itagaki S, Martin-Studdard A, Ganapathy V, Smith SB. Functional and molecular analysis of D-serine transport in retinal Muller cells. Exp Eye Res. 2007;84(1):191–9.PubMedCrossRefGoogle Scholar
  69. 69.
    Jain-Vakkalagadda B, Pal D, Gunda S, Nashed Y, Ganapathy V, Mitra AK. Identification of a Na+-dependent cationic and neutral amino acid transporter, B(0,+), in human and rabbit cornea. Mol Pharm. 2004;1(5):338–46.PubMedCrossRefGoogle Scholar
  70. 70.
    Hosoya K, Horibe Y, Kim KJ, Lee VH. Na(+)-dependent L-arginine transport in the pigmented rabbit conjunctiva. Exp Eye Res. 1997;65(4):547–53.PubMedCrossRefGoogle Scholar
  71. 71.
    Jain-Vakkalagadda B, Dey S, Pal D, Mitra AK. Identification and functional characterization of a Na+-independent large neutral amino acid transporter, LAT1, in human and rabbit cornea. Invest Ophthalmol Vis Sci. 2003;44(7):2919–27.PubMedCrossRefGoogle Scholar
  72. 72.
    Nakauchi T, Ando A, Ueda-Yamada M et al. Prevention of ornithine cytotoxicity by nonpolar side chain amino acids in retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2003;44(11):5023–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Gandhi MD, Pal D, Mitra AK. Identification and functional characterization of a Na(+)-independent large neutral amino acid transporter (LAT2) on ARPE-19 cells. Int J Pharm. 2004;275(1–2):189–200.PubMedCrossRefGoogle Scholar
  74. 74.
    Anand BS, Mitra AK. Mechanism of corneal permeation of L-valyl ester of acyclovir: targeting the oligopeptide transporter on the rabbit cornea. Pharm Res. 2002;19(8):1194–202.PubMedCrossRefGoogle Scholar
  75. 75.
    Xiang CD, Batugo M, Gale DC et al. Characterization of human corneal epithelial cell model as a surrogate for corneal permeability assessment: metabolism and transport. Drug Metab Dispos. 2009;37(5):992–8.PubMedCrossRefGoogle Scholar
  76. 76.
    Basu SK, Haworth IS, Bolger MB, Lee VH. Proton-driven dipeptide uptake in primary cultured rabbit conjunctival epithelial cells. Invest Ophthalmol Vis Sci. 1998;39(12):2365–73.PubMedGoogle Scholar
  77. 77.
    Berger UV, Hediger MA. Distribution of peptide transporter PEPT2 mRNA in the rat nervous system. Anat Embryol (Berl). 1999;199(5):439–49.CrossRefGoogle Scholar
  78. 78.
    Macha S, Mitra AK. Ocular pharmacokinetics of cephalosporins using microdialysis. J Ocul Pharmacol Ther. 2001;17(5):485–98.PubMedCrossRefGoogle Scholar
  79. 79.
    Talluri RS, Katragadda S, Pal D, Mitra AK. Mechanism of L-ascorbic acid uptake by rabbit corneal epithelial cells: evidence for the involvement of sodium-dependent vitamin C transporter 2. Curr Eye Res. 2006;31(6):481–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Janoria KG, Hariharan S, Paturi D, Pal D, Mitra AK. Biotin uptake by rabbit corneal epithelial cells: role of sodium-dependent multivitamin transporter (SMVT). Curr Eye Res. 2006;31(10):797–809.PubMedCrossRefGoogle Scholar
  81. 81.
    Hariharan S, Janoria KG, Gunda S, Zhu X, Pal D, Mitra AK. Identification and functional expression of a carrier-mediated riboflavin transport system on rabbit corneal epithelium. Curr Eye Res. 2006;31(10):811–24.PubMedCrossRefGoogle Scholar
  82. 82.
    Hosoya K, Fujita K, Tachikawa M. Involvement of reduced folate carrier 1 in the inner blood-retinal barrier transport of methyltetrahydrofolate. Drug Metab Pharmacokinet. 2008;23(4):285–92.PubMedCrossRefGoogle Scholar
  83. 83.
    Mainardes RM, Urban MC, Cinto PO et al. Colloidal carriers for ophthalmic drug delivery. Curr Drug Targets. 2005;6(3):363–71.PubMedCrossRefGoogle Scholar
  84. 84.
    Rabinovich-Guilatt L, Couvreur P, Lambert G, Dubernet C. Cationic vectors in ocular drug delivery. J Drug Target. 2004;12(9–10):623–33.PubMedCrossRefGoogle Scholar
  85. 85.
    Schaeffer HE, Krohn DL. Liposomes in topical drug delivery. Invest Ophthalmol Vis Sci. 1982;22(2):220–7.PubMedGoogle Scholar
  86. 86.
    Nagarsenker MS, Londhe VY, Nadkarni GD. Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery. Int J Pharm. 1999;190(1):63–71.PubMedCrossRefGoogle Scholar
  87. 87.
    Hathout RM, Mansour S, Mortada ND, Guinedi AS. Liposomes as an ocular delivery system for acetazolamide: in vitro and in vivo studies. AAPS PharmSciTech. 2007;8(1):1.PubMedCrossRefGoogle Scholar
  88. 88.
    Amrite AC, Kompella UB. Size-dependent disposition of nanoparticles and microparticles following subconjunctival administration. J Pharm Pharmacol. 2005;57(12):1555–63.PubMedCrossRefGoogle Scholar
  89. 89.
    Amrite AC, Edelhauser HF, Singh SR, Kompella UB. Effect of circulation on the disposition and ocular tissue distribution of 20 nm nanoparticles after periocular administration. Mol Vis. 2008;14:150–60.PubMedGoogle Scholar
  90. 90.
    Cheruvu NP, Amrite AC, Kompella UB. Effect of eye pigmentation on transscleral drug delivery. Invest Ophthalmol Vis Sci. 2008;49(1):333–41.PubMedCrossRefGoogle Scholar
  91. 91.
    Kompella UB, Sundaram S, Raghava S, Escobar ER. Luteinizing hormone-releasing hormone agonist and transferrin functionalizations enhance nanoparticle delivery in a novel bovine ex vivo eye model. Mol Vis. 2006;12:1185–98.PubMedGoogle Scholar
  92. 92.
    Cheruvu NP, Amrite AC, Kompella UB. Effect of diabetes on transscleral delivery of celecoxib. Pharm Res. 2009;26(2):404–14.PubMedCrossRefGoogle Scholar
  93. 93.
    Peeters L, Lentacker I, Vandenbroucke RE et al. Can ultrasound solve the transport barrier of the neural retina? Pharm Res. 2008;25(11):2657–65.PubMedCrossRefGoogle Scholar
  94. 94.
    Martin NE, Kim JW, Abramson DH. Fibrin sealant for retinoblastoma: where are we? J Ocul Pharmacol Ther. 2008;24(5):433–8.PubMedCrossRefGoogle Scholar
  95. 95.
    Jiang J, Gill HS, Ghate D et al. Coated microneedles for drug delivery to the eye. Invest Ophthalmol Vis Sci. 2007;48(9):4038–43.PubMedCrossRefGoogle Scholar
  96. 96.
    Jiang J, Moore JS, Edelhauser HF, Prausnitz MR. Intrascleral drug delivery to the eye using hollow microneedles. Pharm Res. 2009;26(2):395–403.PubMedCrossRefGoogle Scholar
  97. 97.
    Zderic V, Clark JI, Martin RW, Vaezy S. Ultrasound-enhanced transcorneal drug delivery. Cornea. 2004;23(8):804–11.PubMedCrossRefGoogle Scholar
  98. 98.
    Vaka SR, Sammeta SM, Day LB, Murthy SN. Transcorneal iontophoresis for delivery of ciprofloxacin hydrochloride. Curr Eye Res. 2008;33(8):661–7.PubMedCrossRefGoogle Scholar
  99. 99.
    Frucht-Pery J, Raiskup F, Mechoulam H, Shapiro M, Eljarrat-Binstock E, Domb A. Iontophoretic treatment of experimental pseudomonas keratitis in rabbit eyes using gentamicin-loaded hydrogels. Cornea. 2006;25(10):1182–6.PubMedCrossRefGoogle Scholar
  100. 100.
    Voigt M, de Kozak Y, Halhal M, Courtois Y, Behar-Cohen F. Down-regulation of NOSII gene expression by iontophoresis of anti-sense oligonucleotide in endotoxin-induced uveitis. Biochem Biophys Res Commun. 2002;295(2):336–41.PubMedCrossRefGoogle Scholar
  101. 101.
    Raiskup-Wolf F, Eljarrat-Binstock E, Rehak M, Domb A, Frucht-Pery J. Transcorneal and transscleral iontophoresis of the dexamethasone phosphate into the rabbit eye. Cesk Slov Oftalmol. 2007;63(5):360–8.PubMedGoogle Scholar
  102. 102.
    Eljarrat-Binstock E, Orucov F, Frucht-Pery J, Pe'er J, Domb AJ. Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis. J Ocul Pharmacol Ther. 2008;24(3):344–50.PubMedCrossRefGoogle Scholar
  103. 103.
    Eljarrat-Binstock E, Domb AJ, Orucov F, Dagan A, Frucht-Pery J, Pe'er J. In vitro and in vivo evaluation of carboplatin delivery to the eye using hydrogel-iontophoresis. Curr Eye Res. 2008;33(3):269–75.PubMedCrossRefGoogle Scholar
  104. 104.
    Eljarrat-Binstock E, Domb AJ, Orucov F, Frucht-Pery J, Pe'er J. Methotrexate delivery to the eye using transscleral hydrogel iontophoresis. Curr Eye Res. 2007;32(7–8):639–46.PubMedCrossRefGoogle Scholar
  105. 105.
    Hollo G, Whitson JT, Faulkner R et al. Concentrations of betaxolol in ocular tissues of patients with glaucoma and normal monkeys after 1 month of topical ocular administration. Invest Ophthalmol Vis Sci. 2006;47(1):235–40.PubMedCrossRefGoogle Scholar
  106. 106.
    Acheampong AA, Shackleton M, John B, Burke J, Wheeler L, Tang-Liu D. Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. Drug Metab Dispos. 2002;30(4):421–9.PubMedCrossRefGoogle Scholar
  107. 107.
    Koevary SB. Pharmacokinetics of topical ocular drug delivery: potential uses for the treatment of diseases of the posterior segment and beyond. Curr Drug Metab. 2003;4(3):213–22.PubMedCrossRefGoogle Scholar
  108. 108.
    Koeberle MJ, Hughes PM, Skellern GG, Wilson CG. Pharmacokinetics and disposition of memantine in the arterially perfused bovine eye. Pharm Res. 2006;23(12):2781–98.PubMedCrossRefGoogle Scholar
  109. 109.
    Majumdar S, Hingorani T, Srirangam R, Gadepalli RS, Rimoldi JM, Repka MA. Transcorneal permeation of L- and D-aspartate ester prodrugs of acyclovir: delineation of passive diffusion versus transporter involvement. Pharm Res. 2009;26(5):1261–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Anand BS, Katragadda S, Nashed YE, Mitra AK. Amino acid prodrugs of acyclovir as possible antiviral agents against ocular HSV-1 infections: interactions with the neutral and cationic amino acid transporter on the corneal epithelium. Curr Eye Res. 2004;29(2–3):153–66.PubMedCrossRefGoogle Scholar
  111. 111.
    Gunda S, Hariharan S, Mitra AK. 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. 2006;22(6):465–76.PubMedCrossRefGoogle Scholar
  112. 112.
    Majumdar S, Nashed YE, Patel K et al. Dipeptide monoester ganciclovir prodrugs for treating HSV-1-induced corneal epithelial and stromal keratitis: in vitro and in vivo evaluations. J Ocul Pharmacol Ther. 2005;21(6):463–74.PubMedCrossRefGoogle Scholar
  113. 113.
    Katragadda S, Talluri RS, Mitra AK. Modulation of P-glycoprotein-mediated efflux by prodrug derivatization: an approach involving peptide transporter-mediated influx across rabbit cornea. J Ocul Pharmacol Ther. 2006;22(2):110–20.PubMedCrossRefGoogle Scholar
  114. 114.
    Kansara V, Hao Y, Mitra AK. Dipeptide monoester ganciclovir prodrugs for transscleral drug delivery: targeting the oligopeptide transporter on rabbit retina. J Ocul Pharmacol Ther. 2007;23(4):321–34.PubMedCrossRefGoogle Scholar
  115. 115.
    Janoria KG, Boddu SH, Wang Z et al. Vitreal pharmacokinetics of biotinylated ganciclovir: role of sodium-dependent multivitamin transporter expressed on retina. J Ocul Pharmacol Ther. 2009;25(1):39–49.PubMedCrossRefGoogle Scholar
  116. 116.
    Dalpiaz A, Filosa R, de Caprariis P et al. Molecular mechanism involved in the transport of a prodrug dopamine glycosyl conjugate. Int J Pharm. 2007;336(1):133–9.PubMedCrossRefGoogle Scholar
  117. 117.
    Li N, Zhuang C, Wang M, Sun X, Nie S, Pan W. Liposome coated with low molecular weight chitosan and its potential use in ocular drug delivery. Int J Pharm. 2009;379(1):131–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Hosny KM. Optimization of gatifloxacin liposomal hydrogel for enhanced transcorneal permeation. J Liposome Res. 2010;20(1):31–7.CrossRefGoogle Scholar
  119. 119.
    Liu LP, Li YM, Yang L. Preparation of liposomal sparfloxcain lactate and its corneal penetration and antibacterial activity in vitro. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2008;30(5):589–94.PubMedGoogle Scholar
  120. 120.
    Shen Y, Tu J. Preparation and ocular pharmacokinetics of ganciclovir liposomes. AAPS J. 2007;9(3):E371–7.PubMedCrossRefGoogle Scholar
  121. 121.
    Afouna MI, Khattab IS, Reddy IK. Preparation and characterization of demeclocycline liposomal formulations and assessment of their intraocular pressure-lowering effects. Cutan Ocul Toxicol. 2005;24(2):111–24.PubMedCrossRefGoogle Scholar
  122. 122.
    Valls R, Vega E, Garcia ML, Egea MA, Valls JO. Transcorneal permeation in a corneal device of non-steroidal anti-inflammatory drugs in drug delivery systems. Open Med Chem J. 2008;2:66–71.PubMedCrossRefGoogle Scholar
  123. 123.
    Kim ES, Durairaj C, Kadam RS et al. Human scleral diffusion of anticancer drugs from solution and nanoparticle formulation. Pharm Res. 2009;26(5):1155–61.PubMedCrossRefGoogle Scholar
  124. 124.
    Ayalasomayajula SP, Kompella UB. Subconjunctivally administered celecoxib-PLGA microparticles sustain retinal drug levels and alleviate diabetes-induced oxidative stress in a rat model. Eur J Pharmacol. 2005;511(2–3):191–8.PubMedCrossRefGoogle Scholar
  125. 125.
    Kompella UB, Bandi N, Ayalasomayajula SP. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci. 2003;44(3):1192–201.PubMedCrossRefGoogle Scholar
  126. 126.
    Gilbert JA, Simpson AE, Rudnick DE, Geroski DH, Aaberg Jr TM, Edelhauser HF. Transscleral permeability and intraocular concentrations of cisplatin from a collagen matrix. J Control Release. 2003;89(3):409–17.PubMedCrossRefGoogle Scholar
  127. 127.
    Eljarrat-Binstock E, Orucov F, Aldouby Y, Frucht-Pery J, Domb AJ. Charged nanoparticles delivery to the eye using hydrogel iontophoresis. J Control Release. 2008;126(2):156–61.PubMedCrossRefGoogle Scholar
  128. 128.
    Frucht-Perry J, Assil KK, Ziegler E et al. Fibrin-enmeshed tobramycin liposomes: single application topical therapy of Pseudomonas keratitis. Cornea. 1992;11(5):393–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Simpson AE, Gilbert JA, Rudnick DE, Geroski DH, Aaberg Jr TM, Edelhauser HF. Transscleral diffusion of carboplatin: an in vitro and in vivo study. Arch Ophthalmol. 2002;120(8):1069–74.PubMedGoogle Scholar
  130. 130.
    Van Quill KR, Dioguardi PK, Tong CT et al. Subconjunctival carboplatin in fibrin sealant in the treatment of transgenic murine retinoblastoma. Ophthalmology. 2005;112(6):1151–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Cruysberg LP, Nuijts RM, Gilbert JA, Geroski DH, Hendrikse F, Edelhauser HF. In vitro sustained human transscleral drug delivery of fluorescein-labeled dexamethasone and methotrexate with fibrin sealant. Curr Eye Res. 2005;30(8):653–60.PubMedCrossRefGoogle Scholar
  132. 132.
    Tsui JY, Dalgard C, Van Quill KR et al. Subconjunctival topotecan in fibrin sealant in the treatment of transgenic murine retinoblastoma. Invest Ophthalmol Vis Sci. 2008;49(2):490–6.PubMedCrossRefGoogle Scholar
  133. 133.
    Misra GP, Singh RS, Aleman TS, Jacobson SG, Gardner TW, Lowe TL. Subconjunctivally implantable hydrogels with degradable and thermoresponsive properties for sustained release of insulin to the retina. Biomaterials. 2009;30(33):6541–7.PubMedCrossRefGoogle Scholar
  134. 134.
    Huang X, Lowe TL. Biodegradable thermoresponsive hydrogels for aqueous encapsulation and controlled release of hydrophilic model drugs. Biomacromolecules. 2005;6(4):2131–9.PubMedCrossRefGoogle Scholar
  135. 135.
    Kang Derwent JJ, Mieler WF. Thermoresponsive hydrogels as a new ocular drug delivery platform to the posterior segment of the eye. Trans Am Ophthalmol Soc. 2008;106:206–13. discussion 13-4.PubMedGoogle Scholar
  136. 136.
    Furrer E, Berdugo M, Stella C et al. Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNF-alpha single-chain antibody, upon topical administration to the rabbit eye. Invest Ophthalmol Vis Sci. 2009;50(2):771–8.PubMedCrossRefGoogle Scholar
  137. 137.
    Sigurdsson HH, Konraethsdottir F, Loftsson T, Stefansson E. Topical and systemic absorption in delivery of dexamethasone to the anterior and posterior segments of the eye. Acta Ophthalmol Scand. 2007;85(6):598–602.PubMedCrossRefGoogle Scholar
  138. 138.
    Loftsson T, Hreinsdottir D, Stefansson E. Cyclodextrin microparticles for drug delivery to the posterior segment of the eye: aqueous dexamethasone eye drops. J Pharm Pharmacol. 2007;59(5):629–35.PubMedCrossRefGoogle Scholar
  139. 139.
    Inoue J, Oka M, Aoyama Y et al. Effects of dorzolamide hydrochloride on ocular tissues. J Ocul Pharmacol Ther. 2004;20(1):1–13.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2010

Authors and Affiliations

  • Ripal Gaudana
    • 1
  • Hari Krishna Ananthula
    • 1
  • Ashwin Parenky
    • 1
  • Ashim K. Mitra
    • 1
  1. 1.Division of Pharmaceutical Sciences, School of PharmacyUniversity of Missouri-Kansas CityKansas CityUSA

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