Challenges in Ocular Pharmacokinetics and Drug Delivery

  • Joyce S. Macwan
  • Anjali Hirani
  • Yashwant PathakEmail author


The ideal ophthalmic drug delivery system must be able to deliver the effective therapeutic concentrations in the target tissues for the intended duration with minimal adverse effects. Successful tissue-targeted delivery of ocular drugs is a challenging task for pharmaceutical scientists. The principal reasons are inherent and unique anatomical and physiological differences among ocular tissues. Ocular drug delivery is restricted by the barriers protecting the eye. The chief ocular membrane barriers are located in the cornea and conjunctiva of the eye which can significantly affect drug entry into the eye.

Conventional routes for ophthalmic drug delivery include topical, systemic, intravitreal, and periocular. The topical route is the most common, mainly for the treatment of anterior segment diseases. However, the tear film drainage and permeation through the cornea and conjunctiva are the key barriers encountered by topically administered drugs resulting in poor ocular bioavailability. Following systemic administration of ocular drugs, the blood-aqueous barrier and blood-retinal barrier prevent entry of substances from the systemic circulation into the intraocular compartments of the anterior and posterior segments of the eye, respectively. Intravitreal injections are good treatment option for posterior segment diseases; however; it is an invasive approach and associated with severe complications. The periocular/transscleral route is a safer substitute to the intravitreal route, and therefore, it has gained significant interest in recent years.

This chapter provides an overview of the main aspects of the primary ocular barriers and challenges associated with various routes of ophthalmic drug administration. Advances in understanding the significance of challenges and barriers will facilitate the development of safe and effective novel ocular drug delivery systems.


Ocular pharmacokinetics Drug delivery Barriers Ophthalmic Eye Challenges Routes of ocular drug administration Ocular membranes 


  1. 1.
    Kang-Mieler JJ, Osswald CR, Mieler WF (2014) Advances in ocular drug delivery: emphasis on the posterior segment. Expert Opin Drug Deliv 30:1–14Google Scholar
  2. 2.
    Hughes PM, Olejnik O, Chang-Lin JE, Wilson CG (2005) Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev 57(14):2010–2032CrossRefPubMedGoogle Scholar
  3. 3.
    Lee VH, Robinson JR (1986) Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol 2(1):67–108CrossRefPubMedGoogle Scholar
  4. 4.
    Duvvuri S, Majumdar S, Mitra AK (2003) Drug delivery to the retina: challenges and opportunities. Expert Opin Biol Ther 3(1):45–56CrossRefPubMedGoogle Scholar
  5. 5.
    Ranta VP, Mannermaa E, Lummepuro K, Subrizi A, Laukkanen A, Antopolsky M et al (2010) Barrier analysis of periocular drug delivery to the posterior segment. J Control Release 148(1):42–48CrossRefPubMedGoogle Scholar
  6. 6.
    Cholkar K, Patel SP, Vadlapudi AD, Mitra AK (2013) Novel strategies for anterior segment ocular drug delivery. J Ocul Pharmacol Ther 29(2):106–123CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gaudana R, Ananthula HK, Parenky A, Mitra AK (2010) Ocular drug delivery. AAPS J 12(3):348–360CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gaudana R, Jwala J, Boddu SH, Mitra AK (2009) Recent perspectives in ocular drug delivery. Pharm Res 26(5):1197–1216CrossRefPubMedGoogle Scholar
  9. 9.
    Tanaka M, Ohnishi Y, Kuwabara T (1983) Membrane structure of corneal epithelium: freeze-fracture observation. Jpn J Ophthalmol 27(3):434–443PubMedGoogle Scholar
  10. 10.
    Chien DS, Sasaki H, Bundgaard H, Buur A, Lee VH (1991) Role of enzymatic lability in the corneal and conjunctival penetration of timolol ester prodrugs in the pigmented rabbit. Pharm Res 8(6):728–733CrossRefPubMedGoogle Scholar
  11. 11.
    Kishida K, Otori T (1980) A quantitative study on the relationship between transcorneal permeability of drugs and their hydrophobicity. Jpn J Ophthalmol 24:251–259Google Scholar
  12. 12.
    Mosher GL, Mikkelson TJ (1979) Permeability of the n-alkyl p-aminobenzoate esters across the isolated corneal membrane of the rabbit. Int J Pharm 2(3–4):239–243CrossRefGoogle Scholar
  13. 13.
    Schoenwald RD, Huang HS (1983) Corneal penetration behavior of beta-blocking agents I: physiochemical factors. J Pharm Sci 72(11):1266–1272CrossRefPubMedGoogle Scholar
  14. 14.
    Wang W, Sasaki H, Chien DS, Lee VH (1991) Lipophilicity influence on conjunctival drug penetration in the pigmented rabbit: a comparison with corneal penetration. Curr Eye Res 10(6):571–579CrossRefPubMedGoogle Scholar
  15. 15.
    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):1479–1488CrossRefPubMedGoogle Scholar
  16. 16.
    Hamalainen KM, Kontturi K, Auriola S, Murtomäki L, Urtti A (1997) Estimation of pore size and pore density of biomembranes from permeability measurements of polyethylene glycols using an effusion-like approach. J Control Release 49(2–2):97–104CrossRefGoogle Scholar
  17. 17.
    Hamalainen KM, Kananen K, Auriola S, Kontturi K, Urtti A (1997) Characterization of paracellular and aqueous penetration routes in cornea, conjunctiva, and sclera. Invest Ophthalmol Vis Sci 38(3):627–634PubMedGoogle Scholar
  18. 18.
    Palmgren JJ, Toropainen E, Auriola S, Urtti A (2002) Liquid chromatographic-electrospray ionization mass spectrometric analysis of neutral and charged polyethylene glycols. J Chromatogr A 976(1–2):165–170CrossRefPubMedGoogle Scholar
  19. 19.
    Tangri P, Khurana S (2011) Basics of ocular drug delivery systems. Int J Res Pharm Biomed Sci 2(4):1541–1552Google Scholar
  20. 20.
    Achouri D, Alhanout K, Piccerelle P, Andrieu V (2013) Recent advances in ocular drug delivery. Drug Dev Ind Pharm 39(11):1599–1617CrossRefPubMedGoogle Scholar
  21. 21.
    Edward A, Prausnitz MR (2001) Predicted permeability of the cornea to topical drugs. Pharm Res 18(11):1497–1508CrossRefPubMedGoogle Scholar
  22. 22.
    Molokhia SA, Thomas SC, Garff KJ, Mandell KJ, Wirostko BM (2013) Anterior eye segment drug delivery systems: current treatments and future challenges. J Ocul Pharmacol Ther 29(2):92–105CrossRefPubMedGoogle Scholar
  23. 23.
    Hosoya K, Lee VH, Kim KJ (2005) Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport mechanisms and their regulation. Eur J Pharm Biopharm 60(2):227–240CrossRefPubMedGoogle Scholar
  24. 24.
    Stjernschantz J, Astin M (1993) Anatomy and physiology of the eye. Physiological aspects of ocular drug therapy. In: Edman P (ed) Biopharmaceutics of ocular drug delivery. CRC Press, Boca RatonGoogle Scholar
  25. 25.
    Huang AJ, Tseng SC, Kenyon KR (1989) Paracellular permeability of corneal and conjunctival epithelia. Invest Ophthalmol Vis Sci 30(4):684–689PubMedGoogle Scholar
  26. 26.
    Urtti A (2006) Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev 58(11):1131–1135CrossRefPubMedGoogle Scholar
  27. 27.
    Gukasyan HJ, Yerxa BR, Pendergast W, Lee VH (2002) Metabolism and transport of purinergic receptor agonists in rabbit conjunctival epithelial cells. Adv Exp Med Biol 506(Pt A):255–259PubMedGoogle Scholar
  28. 28.
    Yang JJ, Kim KJ, Lee VH (2000) Role of P-glycoprotein in restricting propranolol transport in cultured rabbit conjunctival epithelial cell layers. Pharm Res 17(5):533–538CrossRefPubMedGoogle Scholar
  29. 29.
    Ganapathy ME, Ganapathy V (2005) Amino acid transporter ATB0,+ as a delivery system for drugs and prodrugs. Curr Drug Targets Immune Endocr Metabol Disord 5(4):357–364CrossRefPubMedGoogle Scholar
  30. 30.
    Hosoya K, Horibe Y, Kim KJ, Lee VH (1998) Nucleoside transport mechanisms in the pigmented rabbit conjunctiva. Invest Ophthalmol Vis Sci 39(2):372–377PubMedGoogle Scholar
  31. 31.
    Foster CS, Sainz de la Maza M (1994) The sclera. Springer, New YorkCrossRefGoogle Scholar
  32. 32.
    Olsen TW, Aaberg SY, Geroski DH, Edelhauser HF (1998) Human sclera: thickness and surface area. Am J Ophthalmol 125(2):237–241CrossRefPubMedGoogle Scholar
  33. 33.
    Olsen TW, Edelhauser HF, Lim JI, Geroski DH (1995) Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci 36(9):1893–1903PubMedGoogle Scholar
  34. 34.
    Unlu N, Robinson JR (1998) Scleral permeability to hydrocortisone and mannitol in the albino rabbit eye. J Ocul Pharmacol Ther 14(3):273–281CrossRefPubMedGoogle Scholar
  35. 35.
    Ambati J, Gragoudas ES, Miller JW, You TT, Miyamoto K, Delori FC et al (2000) Transscleral delivery of bioactive protein to the choroid and retina. Invest Ophthalmol Vis Sci 41(5):1186–1191PubMedGoogle Scholar
  36. 36.
    Nicoli S, Ferrari G, Quarta M, Macaluso C, Govoni P, Dallatana D et al (2009) Porcine sclera as a model of human sclera for in vitro transport experiments: histology, SEM, and comparative permeability. Mol Vis 15:259–266PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ambati J, Canakis CS, Miller JW, Gragoudas ES, Edwards A, Weissgold DJ et al (2000) Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci 41(5):1181–1185PubMedGoogle Scholar
  38. 38.
    Bill A (1986) The blood-aqueous barrier. Trans Ophthalmol Soc UK 105(Pt 2):149–155PubMedGoogle Scholar
  39. 39.
    Freddo TF (2001) Shifting the paradigm of the blood-aqueous barrier. Exp Eye Res 73(5):581–592CrossRefPubMedGoogle Scholar
  40. 40.
    Barsotti MF, Bartels SP, Freddo TF, Kamm RD (1992) The source of protein in the aqueous humor of the normal monkey eye. Invest Ophthalmol Vis Sci 33(3):581–595PubMedGoogle Scholar
  41. 41.
    Schlingemann RO, Hofman P, Klooster J, Blaauwgeers HG, Van der Gaag R, Vrensen GF (1998) Ciliary muscle capillaries have blood-tissue barrier characteristics. Exp Eye Res 66(6):747–754CrossRefPubMedGoogle Scholar
  42. 42.
    Urtti A, Salminen L (1993) Animal pharmacokinetic studies. In: Mitra AK (ed) Ophthalmic drug delivery systems. Marcel Dekker, New YorkGoogle Scholar
  43. 43.
    Conrad JM, Robinson JR (1977) Aqueous chamber drug distribution volume measurement in rabbits. J Pharm Sci 66(2):219–224CrossRefPubMedGoogle Scholar
  44. 44.
    Schoenwald RD (2003) Ocular pharmacokinetics and pharmacodynamics. In: Mitra AK (ed) Ophthalmic drug delivery systems. Marcel Dekker, New YorkGoogle Scholar
  45. 45.
    Occhiutto ML, Freitas FR, Maranhao RC, Costa VP (2012) Breakdown of the blood-ocular barrier as a strategy for the systemic use of nanosystems. Pharmaceutics 4(2):252–275CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Yasukawa T, Kimura H, Tabata Y, Ogura Y (2001) Biodegradable scleral plugs for vitreoretinal drug delivery. Adv Drug Deliv Rev 52(1):25–36CrossRefPubMedGoogle Scholar
  47. 47.
    Gardner TW, Antonetti DA, Barber AJ, Lieth E, Tarbell JA (1999) The molecular structure and function of the inner blood-retinal barrier. Penn State Retina Research Group. Doc Ophthalmol 97(3–4):229–237CrossRefPubMedGoogle Scholar
  48. 48.
    Sunkara G, Kompella UB (2003) Membrane transport processes in the eye. In: Mitra AK (ed) Ophthalmic drug delivery systems. Marcel Dekker, Inc, New YorkGoogle Scholar
  49. 49.
    Cunha-Vaz JG (1976) The blood-retinal barriers. Doc Ophthalmol 41(2):287–327CrossRefPubMedGoogle Scholar
  50. 50.
    Aukunuru JV, Sunkara G, Bandi N, Thoreson WB, Kompella UB (2001) 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 18(5):565–572CrossRefPubMedGoogle Scholar
  51. 51.
    Kennedy B, Mangini N (2002) Native and cultured human RPE express P-glycoprotein. Invest Ophthalmol Vis Sci 43:903, E-AbstractGoogle Scholar
  52. 52.
    Urtti A, Pipkin JD, Rork G, Sendo T, Finne U, Repta AJ (1990) Controlled drug delivery devices for experimental ocular studies with timolol 2. Ocular and systemic absorption in rabbits. Int J Pharm Sci 61(3):241–249CrossRefGoogle Scholar
  53. 53.
    Maurice DM (2002) Drug delivery to the posterior segment from drops. Surv Ophthalmol 47(Suppl 1):S41–S52CrossRefPubMedGoogle Scholar
  54. 54.
    Koevary SB (2003) Pharmacokinetics of topical ocular drug delivery: potential uses for the treatment of diseases of the posterior segment and beyond. Curr Drug Metab 4(3):213–222CrossRefPubMedGoogle Scholar
  55. 55.
    Ahmed I, Patton TF (1985) Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci 26(4):584–587PubMedGoogle Scholar
  56. 56.
    Ascher KW (1954) Veins of the aqueous humor in glaucoma. Boll Ocul 33(3):129–144PubMedGoogle Scholar
  57. 57.
    Goldmann H (1950) Minute volume of the aqueous in the anterior chamber of the human eye in normal state and in primary glaucoma. Ophthalmologica 120(1–2):19–21CrossRefPubMedGoogle Scholar
  58. 58.
    Bill A, Hellsing K (1965) Production and drainage of aqueous humor in the cynomolgus monkey (Macaca irus). Invest Ophthalmol 4(5):920–926PubMedGoogle Scholar
  59. 59.
    Johnson M, Erickson K (2000) Mechanisms and routes of aqueous humor drainage. In: Albert DM, Jakobiec FA (eds) Principles and practice of ophthalmology. WB Saunders, PhiladelphiaGoogle Scholar
  60. 60.
    Maurice DM, Mishima S (1984) Ocular pharmacokinetics. In: Sears ML (ed) Handbook of experimental pharmacology. Springer, Berlin/HeidelbergGoogle Scholar
  61. 61.
    Maurice DM (1967) The use of fluorescein in ophthalmological research. Invest Ophthalmol 6(5):464–477PubMedGoogle Scholar
  62. 62.
    Hughes PM, Mitra AK (1993) Overview of ocular drug delivery. In: Mitra AK (ed) Drug delivery systems. Marcell Dekker, Inc, New YorkGoogle Scholar
  63. 63.
    Thrimawithana TR, Young S, Bunt CR, Green C, Alany RG (2011) Drug delivery to the posterior segment of the eye. Drug Discov Today 16(5–6):270–277CrossRefPubMedGoogle Scholar
  64. 64.
    Peyman GA, Lad EM, Moshfeghi DM (2009) Intravitreal injection of therapeutic agents. Retina 29(7):875–912CrossRefPubMedGoogle Scholar
  65. 65.
    Mitra AK, Anand BS, Duvvuri S (2006) Drug delivery to the eye. In: Fischbarg J (ed) The biology of eye. Academic, New YorkGoogle Scholar
  66. 66.
    Pitkanen L, Ruponen M, Nieminen J, Urtti A (2003) Vitreous is a barrier in nonviral gene transfer by cationic lipids and polymers. Pharm Res 20(4):576–583CrossRefPubMedGoogle Scholar
  67. 67.
    Macha S, Mitra AK (2001) Ocular pharmacokinetics in rabbits using a novel dual probe microdialysis technique. Exp Eye Res 72(3):289–299CrossRefPubMedGoogle Scholar
  68. 68.
    Lalezari JP, Friedberg DN, Bissett J, Giordano MF, Hardy WD, Drew WL et al (2002) High dose oral ganciclovir treatment for cytomegalovirus retinitis. J Clin Virol 24(1–2):67–77CrossRefPubMedGoogle Scholar
  69. 69.
    Lopez-Cortes LF, Ruiz-Valderas R, Lucero-Munoz MJ, Cordero E, Pastor-Ramos MT, Marquez J (2000) Intravitreal, retinal, and central nervous system foscarnet concentrations after rapid intravenous administration to rabbits. Antimicrob Agents Chemother 44(3):756–759CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Henderly DE, Freeman WR, Causey DM, Rao NA (1987) Cytomegalovirus retinitis and response to therapy with ganciclovir. Ophthalmology 94(4):425–434CrossRefPubMedGoogle Scholar
  71. 71.
    Jabs DA, Newman C, De Bustros S, Polk BF (1987) Treatment of cytomegalovirus retinitis with ganciclovir. Ophthalmology 94(7):824–830CrossRefPubMedGoogle Scholar
  72. 72.
    Dalkara D, Kolstad KD, Caporale N, Visel M, Klimczak RR, Schaffer DV et al (2009) Inner limiting membrane barriers to AAV-mediated retinal transduction from the vitreous. Mol Ther 17(12):2096–2102CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Myles ME, Neumann DM, Hill JM (2005) Recent progress in ocular drug delivery for posterior segment disease: emphasis on transscleral iontophoresis. Adv Drug Deliv Rev 57(14):2063–2079CrossRefPubMedGoogle Scholar
  74. 74.
    Kawakami S, Yamamura K, Mukai T, Nishida K, Nakamura J, Sakaeda T et al (2001) Sustained ocular delivery of tilisolol to rabbits after topical administration or intravitreal injection of lipophilic prodrug incorporated in liposomes. J Pharm Pharmacol 53(8):1157–1161CrossRefPubMedGoogle Scholar
  75. 75.
    Bourges JL, Bloquel C, Thomas A, Froussart F, Bochot A, Azan F et al (2006) Intraocular implants for extended drug delivery: therapeutic applications. Adv Drug Deliv Rev 58(11):1182–1202CrossRefPubMedGoogle Scholar
  76. 76.
    Choonara YE, Pillay V, Danckwerts MP, Carmichael TR, du Toit LC (2010) A review of implantable intravitreal drug delivery technologies for the treatment of posterior segment eye diseases. J Pharm Sci 99(5):2219–2239CrossRefPubMedGoogle Scholar
  77. 77.
    Hunter RS, Lobo AM (2011) Dexamethasone intravitreal implant for the treatment of noninfectious uveitis. Clin Ophthalmol 5:1613–1621PubMedPubMedCentralGoogle Scholar
  78. 78.
    Raghava S, Hammond M, Kompella UB (2004) Periocular routes for retinal drug delivery. Expert Opin Drug Deliv 1(1):99–114CrossRefPubMedGoogle Scholar
  79. 79.
    Ghate D, Edelhauser HF (2006) Ocular drug delivery. Expert Opin Drug Deliv 3(2):275–287CrossRefPubMedGoogle Scholar
  80. 80.
    Kim SH, Csaky KG, Wang NS, Lutz RJ (2008) Drug elimination kinetics following subconjunctival injection using dynamic contrast-enhanced magnetic resonance imaging. Pharm Res 25(3):512–520CrossRefPubMedGoogle Scholar
  81. 81.
    Weijtens O, Feron EJ, Schoemaker RC, Cohen AF, Lentjes EG, Romijn FP et al (1999) High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am J Ophthalmol 128(2):192–197CrossRefPubMedGoogle Scholar
  82. 82.
    Cheruvu NP, Kompella UB (2006) Bovine and porcine transscleral solute transport: influence of lipophilicity and the Choroid-Bruch’s layer. Invest Ophthalmol Vis Sci 47(10):4513–4522CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Kadam RS, Kompella UB (2010) Influence of lipophilicity on drug partitioning into sclera, choroid-retinal pigment epithelium, retina, trabecular meshwork, and optic nerve. J Pharmacol Exp Ther 332(3):1107–1120CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Castellarin A, Pieramici DJ (2004) Anterior segment complications following periocular and intraocular injections. Ophthalmol Clin North Am 17(4):583–590, viiCrossRefPubMedGoogle Scholar
  85. 85.
    Kalsi GS, Silver HK, Rootman J (1991) Ocular pharmacokinetics of dacarbazine following subconjunctival versus intravenous administration in the rabbit. Can J Ophthalmol 26(5):247–251PubMedGoogle Scholar
  86. 86.
    Lee SJ, He W, Robinson SB, Robinson MR, Csaky KG, Kim H (2010) Evaluation of clearance mechanisms with transscleral drug delivery. Invest Ophthalmol Vis Sci 51(10):5205–5212CrossRefPubMedGoogle Scholar
  87. 87.
    Sasaki H, Ichikawa M, Kawakami S, Yamamura K, Nishida K, Nakamura J (1996) In situ ocular absorption of tilisolol through ocular membranes in albino rabbits. J Pharm Sci 85(9):940–943CrossRefPubMedGoogle Scholar
  88. 88.
    Ali M, Byrne ME (2008) Challenges and solutions in topical ocular drug-delivery systems. Expert Rev Clin Pharmacol 1(1):145–161CrossRefPubMedGoogle Scholar
  89. 89.
    Sanborn GE, Anand R, Torti RE, Nightingale SD, Cal SX, Yates B et al (1992) Sustained-release ganciclovir therapy for treatment of cytomegalovirus retinitis. Use of an intravitreal device. Arch Ophthalmol 110(2):188–195CrossRefPubMedGoogle Scholar

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Joyce S. Macwan
    • 1
  • Anjali Hirani
    • 2
    • 3
  • Yashwant Pathak
    • 3
    Email author
  1. 1.Simulations Plus, Inc.LancasterUSA
  2. 2.Department of Pharmaceutical Sciences, USF College of PharmacyUniversity of SouthFlorida, TampaUSA
  3. 3.School of Biomedical Engineering and SciencesVirginia Tech-Wake Forest UniversityBlacksburgUSA

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