achieve efficacious treatments is facilitated when the drug can be formulated as a high concentration topical solution.

In several of the case studies cited in this article, there is good evidence of local (rather than systemic) delivery contributing to the drug’s action in the back of the eye. Demonstration that treated eye effects are greater than that of untreated eye and observation of low systemic drug levels (relative to ocular tissue) are the strongest hallmarks of a local effect. Often less clear is the detailed route of local transit in the eye. One can usually distinguish between trans-vitreous vs. uvea-scleral/periocular routes based on concentration gradients between ocular compartments, but discriminating between the latter two routes is often difficult. It would appear that these two mechanisms account for most of the examples cited in the case studies. The mechanism of transit may actually involve more than one mechanism or additional hybrid mechanisms. For example, periocular drug delivery may involve access of drug to the uvea-scleral space in the anterior portion of these tissues, followed by lateral diffusion to the posterior regions.

To date, there is not a clear understanding of what properties of a molecule impart the ability for local transit to the back of the eye. As with any drug delivery paradigm, high potency will facilitate success. From the examples listed, it is clear that both large and small molecules possess the potential to reach posterior tissues. However, analyses of physiochemical parameters of molecules have yet to yield an understanding of the properties more likely to yield posterior delivery. One interesting observation is that several of the examples cited in this article (Brimonidine, Nipradilol, Memantine) have been reported to bind to melanin (Acheampong et al. 2002; Mizuno et al. 2002; Hughes et al. 2005). A couple of these reports have suggested that it is possible that melanin binding of Memantine and Brimonidine may act as a drug depot and facilitate sustained delivery of these particular drugs. Finally, our understanding around transporters and their role in ocular PK is developing, and lead to increased hope that one will better be able to design drugs which enhance their influx properties within the eye (Hosoya and Tachikawa 2009; Mannermaa et al. 2006).

As our understanding develops around the detailed routes of drug transit for topical medications and molecular properties associated with such drugs, one thing is clear – there is a burgeoning number of examples of topical ophthalmic medications targeting the back of the eye progressing through clinical development, and the potential of one of them becoming the first eye drop medication for a posterior disease is within reach. Compared to presently validated methods for local delivery of drugs for posterior indications (implants, intravitreal injections, periocular injections), eye drops offer a minimally invasive and more patient-friendly option for local therapy.

References

Acheampong AA, Shackleton M, John B et al (2002) Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes. Drug Metab Dispos 30:421–429

Ahmed I, Patton TF (1985) Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci 26:584–587

Ahmed I, Gokhale RD, Shah MV et al (1987) Physicochemical determinants of drug diffusion across the conjunctiva, sclera, and cornea. J Pharm Sci 76:583–586

Alm A, Nilsson SF (2009) Uveoscleral outflow – a review. Exp Eye Res 88:760–768

Ambati J, Canakis CS, Miller JW et al (2000) Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci 41:1181–1185

Bill A, Phillips CI (1971) Uveoscleral drainage of aqueous humour in human eyes. Exp Eye Res 12:275–281

Campochiaro PA, Shah SM, Hafiz G et al (2010) Topical mecamylamine for diabetic macular edema. Am J Ophthalmol 49:839–851

Chung YB, Han K, Nishiura A et al (1998) Ocular absorption of Pz-peptide and its effect on the ocular and systemic pharmacokinetics of topically applied drugs in the rabbit. Pharm Res 15:1882–1887

Doukas J, Mahesh S, Umeda N et al (2008) Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol 216:29–37

Durairaj C, Shah JC, Senapati S et al (2009) Prediction of vitreal half-life based on drug physicochemical properties: quantitative structure-pharmacokinetic relationships (QSPKR). Pharm Res 26:1236–1260

Furrer E, Berdugo M, Stella C (2009) Pharmacokinetics and posterior segment biodistribution of ESBA105, an anti-TNFa single-chain antibody, upon topical administration to the rabbit eye. Invest Ophthalmol Vis Sci 50:771–778

Geroski DH, Edelhauser HF (2000) Drug delivery for posterior segment eye disease. Invest Ophthalmol Vis Sci 41:961–964

Geroski DH, Edelhauser HF (2001) Transscleral drug delivery for posterior segment disease. Adv Drug Deliv Rev 52:37–48

Ghate D, Brooks W, McCarey BE, Edelhauser HF (2007) Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry. Invest Ophthalmol Vis Sci 48:2230–2237

Goodman A, Gilman L (2005) The pharmacological basis of therapeutics. In: Brunton L, Lazo J, Parker K (eds), 10th edn. McGraw-Hill, NY. Chapter 63 Natural Products in Cancer Chemo­ therapy: Hormones and Related Agents http://accessmedicine.com/resourceTOC.aspx?resource ID=651

Hosoya K, Tachikawa M (2009) Inner blood-retinal barrier transporters: role of retinal drug delivery. Pharm Res 26:2055–2065

Huang HS, Schoenwald RD, Lach JL (1983) Corneal penetration behavior of beta-blocking agents II: assessment of barrier contributions. J Pharm Sci 72:1272–1279

Hughes PM, Olejnik O, Chang-Lin JE et al (2005) Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev 57:2010–2032

Kent AR, Nussdorf JD, David R et al (2001) Vitreous concentration of topically applied brimonidine tartrate 0.2%. Ophthalmology 108:784–787

Kiuchi K, Matsuoka M, Wu JC et al (2008) Mecamylamine suppresses Basal and nicotine-stimulated choroidal neovascularization. Invest Ophthalmol Vis Sci 49:1705–1711

Koeberle MJ, Hughes PM, Skellern GG et al (2006) Pharmacokinetics and disposition of memantine in the arterially perfused bovine eye. Pharm Res 23:2781–2798

Lichtlen PD, Lam T, Nork M et al (2010) Relative contribution of VEGF and TNFα in the cynomolgus laser-induced CNV model: comparing efficacy of bevacizumab, adalimumab and ESBA105. Invest Ophthalmol Vis Sci 51:4738–4745

Lipinski CA, Lombardo F, Dominy BW et al (2001) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 46:3–26

Mannermaa E, Vellonen KS, Urtti A (2006) Drug transport in corneal epithelium and blood-retina barrier: emerging role of transporters in ocular pharmacokinetics. Adv Drug Deliv Rev 58:1136–1163

Mizuno K, Koide T, Saito N et al (2002) Topical nipradilol: effects on optic nerve head circulation in humans and periocular distribution in monkeys. Invest Ophthalmol Vis Sci 43:3243–3250

Mizuno K, Koide T, Shimada S et al (2009) Route of penetration of topically instilled nipradilol into the ipsilateral posterior retina. Invest Ophthalmol Vis Sci 50:2839–2847

Ottiger M, Thiel MA, Feige U et al (2009) Efficient intraocular penetration of topical anti-TNFa single-chain antibody (ESBA105) to anterior and posterior segment without penetration enhancer. Invest Ophthalmol Vis Sci 50:779–786

Pade V, Stavchansky S (1997) Estimation of the relative contribution of the transcellular and paracellular pathway to the transport of passively absorbed drugs in the Caco-2 cell culture model. Pharmacol Res 14:1210–1215

Palanki MS, Akiyama H, Campochiaro P et al (2008) Development of prodrug 4-chloro-3-(5- methyl-3-{[4-(2-pyrrolidin-1-ylethoxy)phenyl]amino}-1,2,4-benzotria zin-7-yl)phenyl benzoate (TG100801): a topically administered therapeutic candidate in clinical trials for the treatment of age-related macular degeneration. J Med Chem 51:1546–1559

Rao VR, Prescott E, Shelke NB et al (2010) Delivery of SAR 1118 to retina via ophthalmic drops and its effectiveness in reduction of retinal leukostasis and vascular leakiness in rat streptozotocin (STZ) model of diabetic retinopathy (DR). Invest Ophthalmol Vis Sci 51:5198–5204

Reed KK (2008) Diseases of the lacrimal system. In: Bartlett JD, Jaanus SD (eds) Clinical ocular pharmacology, 5th edn. Butterworth, St. Louis, pp 415–435

Rojanasakul Y, Robinson JR (1991) The cytoskeleton of the cornea and its role in tight junction permeability. Int J Pharm 68:135–149

Scheppke L, Aguilar E, Gariano RF et al (2008) Retinal vascular permeability suppression by topical application of a novel VEGFR2/Src kinase inhibitor in mice and rabbits. J Clin Invest 118: 2337–2346

Stjernschantz J, Selén G, Astin M et al (1999) Effect of latanoprost on regional blood flow and capillary permeability in the monkey eye. Arch Ophthalmol 117:1363–1367

Struble C, Choinski R, Martin M (2007) Ocular and systemic distribution, and excretion of radioactivity following topical ocular administration of 14C-TG100801 to pigmented rabbits. Acta Ophthalmol Scand 85(s240):0–0

Thiel MA, Coster DJ, Standfield SD et al (2002) Penetration of engineered antibody fragments into the eye. Clin Exp Immunol 128:67–74

Tojo K (1988) Pharmacokinetic model of transcorneal drug delivery. Math Biosci 89:53–77 Wang BG, König K, Halbhuber KJ (2010) Two-photon microscopy of deep intravital tissues and

its merits in clinical research. J Microsc 238:1–20

Williams KA, Brereton HM, Farrall A et al (2005) Topically applied antibody fragments penetrate into the back of the rabbit eye. Eye (Lond) 19:910–913

Wong WT, Kam W, Cunningham D et al (2010) Treatment of geographic atrophy by the topical administration of OT-551: results of a phase II clinical trial. Invest Ophthalmol Vis Sci 51:6131–6139

Zhang X, Kengatharan M, Cooke JP et al (2007) Topical mecamylamine formulations for ocular administration and uses thereof. Int Patent App WO/2007/075720

Zhang T, Xiang CD, Gale D et al (2008) Drug transporter and cytochrome P450 mRNA expression in human ocular barriers: implications for ocular drug disposition. Drug Metab Dispos 36:1300–1307

Chapter 6

Principles of Retinal Drug Delivery from Within the Vitreous

Clive G. Wilson, Lay Ean Tan, and Jenifer Mains

Abstract  In recent years, vitreous humour, a connective tissue at the centre of the eye, emerged as a preferred reservoir for back of the eye drug delivery. Although vitreous humour is largely composed of water (>99%), its physical form can range from a firm gel in the youth to a collapsed gel in the elderly. These changes in the physical form of the vitreous, in conjunction with changes in its composition and turnover, can potentially influence drug delivery to target tissues from the vitreous. In order to enable the reader with the development of personalised medicines for the back of the eye, this chapter discusses vitreal anatomy, convective flow patterns, barriers to drug delivery, drug clearance mechanisms, and the influence of vitrectomy and vitreous substitutes on drug delivery. Further, it presents case studies on interactions of drug delivery systems with vitreous gel as well as the influence of eye movements on drug delivery from the vitreous. Wherever feasible, the above parameters were compared between normal and ageing eyes.

6.1  Introduction

The vitreous humour, the gel body separating lens and retina, is at first consideration not a tissue capable of generating a lot of interest for the physiologist. On maturity, it is one of the simplest of connective tissues, devoid of vasculature, whose functional importance in the maintenance of retinal health would not be obvious. If it is removed from the globe, the structure collapses with free water and remnants of gel remaining. In youth, it is a firm gel structure and in old age, a collapsed system consisting of more liquid than gel phase.

C.G. Wilson (*)

Strathclyde Institute of Pharmaceutical and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow, G4 0NR, Scotland, UK

e-mail: c.g.wilson@strath.ac.uk

U.B. Kompella and H.F. Edelhauser (eds.), Drug Product Development for the Back of the Eye, 125 AAPS Advances in the Pharmaceutical Sciences Series 2, DOI 10.1007/978-1-4419-9920-7_6,

© American Association of Pharmaceutical Scientists, 2011