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Transscleral Drug Delivery to Retina and Posterior Segment Disease

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Book cover Drug Delivery for the Retina and Posterior Segment Disease

Abstract

The complexities of the anatomical and physiological barriers pose a challenge for the treatment of posterior segment eye disease. Ineffective delivery of the drug to the posterior site is regarded a major contributing factor for treatment failure. Transscleral drug delivery aims the large surface area of the sclera for increased drug absorption when compared to the intravitreal injections. This chapter addresses posterior segment diseases, treatment approaches and routes of drug administration, with emphasis on transscleral drug delivery. Application of novel strategies such as iontophoresis have been useful for improved permeability and drug delivery of ionized drugs. Further, newer techniques such as, polymeric colloids, implants, and thermoresponsive gels are currently investigated for efficiency.

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References

  1. Shah JN, Shah HJ, Groshev A, Hirani AA, Pathak YV, Sutariya VB. Nanoparticulate transscleral ocular drug delivery. J Biomol Res Ther. 2014;3(3):1–14.

    Google Scholar 

  2. Gaudana R, Jwala J, Boddu SH, Mitra AK. Recent perspectives in ocular drug delivery. Pharm Res. 2009;26(5):1197–216.

    Article  CAS  Google Scholar 

  3. Idrees F, Vaideanu D, Fraser SG, Sowden JC, Khaw PT. A review of anterior segment dysgeneses. Surv Ophthalmol. 2006;51:213–31.

    Article  Google Scholar 

  4. Addo E, Bamiro OA, Siwale R. Anatomy of the eye and common diseases affecting the eye. In: Addo RT, editor. Ocular drug delivery: advances, challenges and applications. Cham: Springer; 2016. p. 11–25.

    Chapter  Google Scholar 

  5. Cunha-Vaz JG, Marques FB, Fernandes R, Alves C, Velpandian T. Drug transport across blood-ocular barriers and pharmacokinetics. In: Velpandian T, editor. Pharmacology of ocular therapeutics. Cham: Springer; 2016. p. 37–63.

    Chapter  Google Scholar 

  6. Willoughby CE, Ponzin D, Ferrari S, Lobo A, Landau K, Omidi Y. Anatomy and physiology of the eye: effect of mucopolysaccharidoses disease on structure and function – a review. Clin Exp Ophthalmol. 2010;38:2–11.

    Article  Google Scholar 

  7. Cunha-Vaz JG. The blood-retinal barriers. Doc Ophthalmol. 1976;41(2):287–327.

    Article  CAS  Google Scholar 

  8. Bourne R, Flaxman S, Braithwaite T, Cicinelli M, Das A, Jonas J, Keeffe J, Kempen J, Leasher J, Limburg H, Naidoo K, Pesudovs K, Resnikoff S, Silvester A, Stevens G, Tahhan N, Wong T, Taylor H, Vision Loss Expert Group. Magnitude, temporal trends, and projections of the global prevalence of blindness and distance and near vision impairment: a systematic review and meta-analysis. Lancet Glob Health. 2017;5(9):e888–97.

    Article  Google Scholar 

  9. World Health Organization. Media center. Facts sheet: visual impairment and blindness. Website: http://www.who.int/mediacentre/factsheets/fs282/en/. Updated Oct 2017; Accessed 25 Oct 2017.

  10. del Amo EM, Urtti A. Current and future ophthalmic drug delivery systems – a shift to the posterior segment. Drug Discov Today. 2008;13(3/4):135–43.

    PubMed  Google Scholar 

  11. Edelhauser H, Rowe-Rendleman C, Robinson M, Dawson D, Chader G, Grossniklaus H, Rittenhouse K, Wilson C, Weber D, Kupperman B, Csaky K, Olson T, Kompella U, Holers M, Hageman G, Gilger B, Campochiaro P, Whitcup S, Wong W. Ophthalmic drug delivery systems for the treatment of retinal diseases: basic research to clinical applications. Investig Ophthalmol Vis Sci. 2010;51(11):5403–20.

    Article  Google Scholar 

  12. Geroski D, Edelhauser H. Drug delivery for posterior segment eye disease. Invest Ophthalmol Vis Sci. 2000;41(5):961–4.

    CAS  Google Scholar 

  13. Kaur I, Kakkar S. Nanotherapy for posterior eye disease. J Control Release. 2014;193:100–12.

    Article  CAS  Google Scholar 

  14. Janoria K, Gunda S, Boddu S, Mitra A. Novel approaches to retinal drug delivery. Expert Opin Drug Deliv. 2007;4:371–88.

    Article  CAS  Google Scholar 

  15. Gehrs K, Anderson D, Johnson L, Hageman G. Age- related macular degeneration - emerging pathogenetic and therapeutic concepts. Ann Med. 2006;38:450–71.

    Article  Google Scholar 

  16. National Eye Institute. Facts about age-related macular degeneration. Website: https://nei.nih.gov/health/maculardegen/armd_facts. Last reviewed: Sept 2015. Date accessed 30 Oct 2017.

  17. Friedman D, O’Colmain B, Munoz B, Tomany S, McCarty C, de Jong P, Nemesure B, Mitchell P, Kempen J. Eye diseases prevalence research group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122:564–72.

    Article  Google Scholar 

  18. Ambati J, Fowler B. Mechanism of age-related macular degeneration. Neuron. 2012;75:26–39.

    Article  CAS  Google Scholar 

  19. Wong T, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, Fahrbach K, Probst C, Sledge I. The natural history and prognosis of Neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology. 2008;115:116–26.

    Article  Google Scholar 

  20. Beatty S, Koh H, Phil M, Henson D, Boulton M. The role of oxidative stress on in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2000;45:115–34.

    Article  CAS  Google Scholar 

  21. Klein R, Klein B, Tamany S, Meuer S, Huang G. Ten-year incidence and progression of age-related maculopathy: the beaver dam eye study. Ophthalmology. 2002;109:1767–79.

    Article  Google Scholar 

  22. Ding X, Patel M, Chan C-C. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2009;28(1):1–18.

    Article  CAS  Google Scholar 

  23. Jager R, Mieler W, Miller J. Age-related macular degeneration. N Engl J Med. 2008;358:2606–17.

    Article  CAS  Google Scholar 

  24. Stewart MW. Optimal management of cytomegalovirus retinitis in patients with AIDS. Clin Ophthalmol. 2010;4:285–99.

    Article  Google Scholar 

  25. Gallant J, Moore R, Richman D, Keruly J, Chaisson R. Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis. 1992;166(6):1223–7.

    Article  CAS  Google Scholar 

  26. Bloom J, Palestine A. The diagnosis of cytomegalovirus retinitis. Ann Intern Med. 1988;109(12):963–9.

    Article  CAS  Google Scholar 

  27. Studies of Ocular Complications of AIDS Research Group in collaboration with the AIDS Clinical Trials Group. Foscarnet-ganciclovir cytomegalovirus retinitis trial: 5. Clinical features of cytomegalovirus retinitis at diagnosis. Am J Ophthalmol. 1997;124:141–57.

    Article  Google Scholar 

  28. Pertel P, Hirschtick R, Phair J, Chmiel J, Poggensee L, Murphy R. Risk of developing cytomegalovirus retinitis in persons infected with the human immunodeficiency virus. J Acquir Immune Defic Syndr. 1992;5(11):1069–74.

    CAS  PubMed  Google Scholar 

  29. National Eye Institute. Facts about diabetic eye diseases: diabetic retinopathy. Website: https://nei.nih.gov/health/diabetic/retinopathy. Last Reviewed: Sept 2015. Accessed 10 Oct 2017.

  30. Tarr J, Kaul K, Chopra M, Kohner E, Chibber R. Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. 2013;2013:1–13.

    Article  Google Scholar 

  31. Wani J, Nasti A, Ashai M, Keng M, Qureshi T, Rashid S. Incidence of maculopathy in non-proliferative and proliferative diabetic retinopathy. JK-Practitioner. 2003;10(4):275–8.

    Google Scholar 

  32. Burditt A, Caird F, Draper G. The natural history of diabetic retinopathy. Q J Med. 1968;37(146):303–17.

    CAS  PubMed  Google Scholar 

  33. Li Z-Y, Possin D, Milam A. Histology of bone spicule pigmentation in retinitis Pigmentosa. Ophthalmology. 1995;102(5):805–16.

    Article  CAS  Google Scholar 

  34. Dhoot D, Huo S, Yuan A, Xu D, Srivistava S, Ehlers J, Traboulsi E, Kaiser P. Evaluation of choroidal thickness in retinitis pigmentosa using enhanced depth imaging optical coherence tomography. Br J Ophthalmol. 2013;97:66–9.

    Article  Google Scholar 

  35. Kiernan D, Lim J. Topical drug delivery for posterior segment disease. Retina Today. 2010;5:48–51.

    Google Scholar 

  36. Lee V, Robinson J. Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol. 1986;2(1):67–108.

    Article  CAS  Google Scholar 

  37. Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol. 2016;10:2433–41.

    Article  CAS  Google Scholar 

  38. Scruggs J, Wallace T, Hanna C. Route of absorption of drugs and ointment after application to the eye. Ann Ophthalmol. 1978;10(3):267–71.

    CAS  PubMed  Google Scholar 

  39. Prausnitz M, Noonan J. Permeability of cornea, sclera and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87(12):1479–88.

    Article  CAS  Google Scholar 

  40. Boyer D. Drug delivery to the posterior segment: an update. Retina Today. 2013;8:52–6. http://retinatoday.com/2013/08/drugdelivery-to-the-posterior-segment-an-update/

  41. Hughes P, Olejnik O, Chang-Lin J, Wilson C. Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev. 2005;57:2010–32.

    Article  CAS  Google Scholar 

  42. Inoue J, Oka M, Aoyama Y, Kobayashi S, Ueno S, Hada N, Takeda T, Takehana M. Effects of dorzolamide hydrochloride on ocular tissues. J Ocul Pharmacol Ther. 2004;20(1):1–13.

    Article  CAS  Google Scholar 

  43. Loftson 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.

    Article  Google Scholar 

  44. Acheampong A, 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.

    Article  CAS  Google Scholar 

  45. Sigurdsson H, 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.

    Article  CAS  Google Scholar 

  46. Cunha-Vaz J. The blood-retinal barrier system: basic concepts and clinical evaluation. Exp Eye Res. 2004;78:715–21.

    Article  CAS  Google Scholar 

  47. Pitkänen K, 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.

    Article  Google Scholar 

  48. Guadana R, Ananthula H, Parenky A, Mitra A. Ocular drug delivery. AAPS J. 2010;12(3):348–60.

    Article  Google Scholar 

  49. Inoue M, Takeda K, Morita K, Yamada M, Tanigawara Y, Oguchi Y. Vitreous concentrations of triamcinolone acetonide in human eyes after intravitreal or Subtenon injection. Am J Ophthalmol. 2004;138:1046–8.

    Article  CAS  Google Scholar 

  50. Gragoudas E, Adamis A, Cunningham E Jr, Feinsod M, Guyer D. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351(27):2805–16.

    Article  CAS  Google Scholar 

  51. Ferrara N, Damico L, Shams N, Lowman H, Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina. 2006;26(8):859–70.

    Article  Google Scholar 

  52. Heier J, Brown D, Chong V, Korobelnik J, Kaiser P, Nguyen Q, Kirchhof B, Ho A, Ogura Y, Yancopoulos G, Stahl N, Vitti R, Berliner A, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U. Intravitreal Aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–48.

    Article  Google Scholar 

  53. Ventrice P, Leporini C, Aloe JF, Greco E, Leuzzi G, Marrazzo G, Scorcia GB, Bruzzichesi D, Nicola V, Scorcia V. Anti-vascular endothelial growth factor drugs safety and efficacy in ophthalmic diseases. J Pharmacol Pharmacother. 2013;4(Suppl1):S38–42.

    PubMed  PubMed Central  Google Scholar 

  54. Mitra A, Anand B, Duvvuri S. Drug delivery to the eye. In: Fischbarg J, editor. The biology of the eye. New York: Academic Press; 2006. p. 307–51.

    Google Scholar 

  55. Thrimawithana T, Young S, Bunt C, Green C, Alany R. Drug delivery to the posterior segment of the eye. Drug Discov Today. 2011;16(5/6):270–7.

    Article  CAS  Google Scholar 

  56. Ranta VP, Mannermaa E, Lummepuro K, Subrizi A, Laukkaren A, Antopolsky M, Murtomaki L, Hornof M, Urtti A. Barrier analysis of periocular drug delivery to the posterior segment. J Control Release. 2010;148:42–8.

    Article  CAS  Google Scholar 

  57. Ghate D, Edelhauser H. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3(2):275–87.

    Article  CAS  Google Scholar 

  58. Cheruvu N, Amrite A, Kompella U. Effect of eye pigmentation on transscleral drug delivery. Invest Ophthalmol Vis Sci. 2008;49:333–41.

    Article  Google Scholar 

  59. Leder H, Jabs D, Galor A, Dunn J, Thorne J. Periocular triamcinolone acetonide injections for cystoid macular edema complicating noninfectious uveitis. Am J Ophthalmol. 2011;152(3):441–8.

    Article  CAS  Google Scholar 

  60. Ghate D, Brooks W, McCarey B, Edelhauser H. Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry. Invest Ophthalmol Vis Sci. 2007;48(5):2230–7.

    Article  Google Scholar 

  61. Kalsi G, Silver H, Rootman J. Ocular pharmacokinetics of dacarbazine following subconjunctival versus intravenous administration in rabbit. Can J Ophthalmol. 1991;26:247–51.

    CAS  PubMed  Google Scholar 

  62. Review MD. Practical issues in intravitreal drug delivery. J Ocul Pharmacol Ther. 2001;17:393–401.

    Article  Google Scholar 

  63. Geroski D, Edelhauser H. Transscleral drug delivery. In: Kompella U, Edlehauser H, editors. Drug product development for back of the eye. New York: Springer; 2011. p. 159–71.

    Chapter  Google Scholar 

  64. Olsen T, Aaberga S, Geroski D, Edelhauser H. Human sclera: thickness and surface area. Am J Ophthalmol. 1998;125(2):237–41.

    Article  CAS  Google Scholar 

  65. Keeley F, Morin J, Veseely S. Characterization of collagen from normal human sclera. Exp Eye Res. 1984;39:533–42.

    Article  CAS  Google Scholar 

  66. Raghava S, Hammond M, Kompella U. Periocular routes for retinal drug delivery. Expert Opin Drug Deliv. 2004;1(1):99–114.

    Article  Google Scholar 

  67. Almazan A, Lee S, Ross A, Robinson M. Barriers to Transscleral drug delivery to the retina. In: Thassu D, Chader G, editors. Ocular drug delivery systems – barriers and application of nanoparticulate systems. Boca Raton: CRC Press; 2013. p. 134.

    Google Scholar 

  68. Durairaj C. Ocular pharmacokinetics. In: Whitcup S, Azar D, editors. Pharmacologic therapy of ocular disease-Handbook of Experimental Pharmacology: Springer Publishing; 2016. p. 31–55.

    Google Scholar 

  69. Kim S, Lutz R, Wang N, Robinson M. Transport barriers in Transscleral drug delivery for retinal diseases. Ophthalmic Res. 2007;39:244–54.

    Article  CAS  Google Scholar 

  70. Shuler KR, Dioguardi PK, Henjy C, Nickerson J, Cruysberg L, Edelhauser H. Scleral permeability of small, single-stranded oligonucleotide. J Ocul Pharmacol Ther. 2004;20(2):159–68.

    Article  CAS  Google Scholar 

  71. Ambati J, Canakis CS, Miller JW, Gragoudas ES, Edwards A, Weissgold DJ, Kim I, Delori FC, Adamis AP. Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci. 2000;41:1181–5.

    CAS  PubMed  Google Scholar 

  72. Anderson O, Jackson T, Singh J, Hussain A, Marshall J. Human Transscleral albumin permeability and the effect of topographical location and donor age. Invest Ophthalmol Vis Sci. 2008;49(9):4041–5.

    Article  Google Scholar 

  73. Olsen TW, Edelhauser HF, Lim J, Geroski DH. Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci. 1995;36(9):1893–903.

    CAS  PubMed  Google Scholar 

  74. Shah S, Denham L, Elison J, Bhattacharjee P, Clement C, Huq T, Hill J. Drug delivery to the posterior segment of the eye for pharmacological therapy. Expert Rev Ophthalmol. 2010;5(1):75–93.

    Article  CAS  Google Scholar 

  75. Peyman G, Bok D. Peroxidase diffusion in the normal and laser-coagulated primate retina. Investig Ophthalmol. 1972;11:35–45.

    CAS  Google Scholar 

  76. Thakur A, Kadam R, Kompella U. Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids. Drug Metab Dispos. 2011;39(5):771–81.

    Article  CAS  Google Scholar 

  77. 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;28:124–32.

    Article  CAS  Google Scholar 

  78. Kim S, Csaky K, Wang N, Lutz R. Drug elimination kinetics following subconjunctival injection using dynamic contrast-enhanced magnetic resonance imaging. Pharm Res. 2008;25(3):512–20.

    Article  CAS  Google Scholar 

  79. Hosseini K, Matsushima D, Johnson J, Widera G, Nyam K, Kim L, Xu Y, Yao Y, Cormier M. Pharmacokinetic study of dexamethasone disodium phosphate using intravitreal, subconjunctival, and intravenous delivery routes in rabbits. J Ocul Pharmacol Ther. 2008;24(3):301–8.

    Article  CAS  Google Scholar 

  80. Robinson M, Lee S, Kim H, Lutz R, Galban C, Bungay P, Yuan P, Wang N, Kim J, Csaky K. A rabbit model for assessing the ocular barriers to the transscleral delivery of triamcinolone acetonide. Exp Eye Res. 2006;82(3):479–87.

    Article  CAS  Google Scholar 

  81. Karla P, Ako-Adounvo A-M. Advances in ocular iontophoresis research. Recent Pat Nanomed. 2012;2(2):126–32.

    Article  CAS  Google Scholar 

  82. Eljarrat-Binstock E, Domb AJ. Iontophoresis: a non-invasive ocular drug delivery. J Control Release. 2006;110(3):479–89.

    Article  CAS  Google Scholar 

  83. Kompella U, Bandi N, Ayalasomayajula S. Subconjunctival nano- and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Invest Ophthalmol Vis Sci. 2003;44:1192–201.

    Article  Google Scholar 

  84. Madni A, Rahem MA, Tahir N, Sarfraz M, Jabar A, Rehman M, Kashif PM, Badshah SF, Khan KU, Santos HA. Non-invasive strategies for targeting the posterior segment of eye. Int J Pharm. 2017;530(1–2):326–45.

    Article  CAS  Google Scholar 

  85. Yasukawa T, Kimura MD, Tabat Y, Ogura Y. Biodegradable scleral plugs for vitreoretinal drug delivery. Adv Drug Deliv Rev. 2001;52(1):25–36.

    Article  CAS  Google Scholar 

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Acknowledgment

This is supported by Howard University RCMI grant and the research grant from EcoBiotix LLC.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC, USA

    Ann-Marie Ako-Adounvo & Pradeep K. Karla

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  1. Ann-Marie Ako-Adounvo
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  2. Pradeep K. Karla
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Correspondence to Pradeep K. Karla .

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Editors and Affiliations

  1. Faculty of Pharmacy, Sankalchand Patel University, Gujarat, India

    Jayvadan K. Patel

  2. College of Pharmacy, University of South Florida, Tampa, FL, USA

    Vijaykumar Sutariya

  3. School of Medicine, Faculty of Health, Deakin University, Victoria, Australia

    Jagat Rakesh Kanwar

  4. College of Pharmacy, University of South Florida, Tampa, FL, USA

    Yashwant V. Pathak

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Ako-Adounvo, AM., Karla, P.K. (2018). Transscleral Drug Delivery to Retina and Posterior Segment Disease. In: Patel, J., Sutariya, V., Kanwar, J., Pathak, Y. (eds) Drug Delivery for the Retina and Posterior Segment Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-95807-1_12

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