A decade ago, AMD patients were elated to have any chance at an intervention that might improve their visual acuity. Intravitreal injection of anti-VEGF was considered a godsend. Nowadays, tedium, expense and risk have dimmed the procedure’s halo, but a new study may reveal a promising alternative. 

Might doctors one day be able to treat AMD and other posterior segment conditions with an eye drop? Such an advance would provide quantum leaps forward in convenience, safety and perhaps cost, all ideally without sacrificing efficacy.

Can’t Get There From Here
Historically, topical drug delivery has been used to treat anterior segment disease, as most of the instilled drop is lost due to blinking, tear dilution, nasolacrimal drainage and tear turnover.1 Also, the corneal epithelium, a lipophilic tissue with tight junctions, acts a barrier to reduce ocular penetration by hydrophilic drugs. Rapid systemic absorption also contributes to reduction of ocular absorption; thus, less than 5% of the initial dose is able to reach the aqueous humor, and even less can penetrate through to the posterior chamber.3,4 Although the conjunctival epithelium is more permeable to larger and more hydrophilic molecules, most clinical drugs are small and lipophilic, thus favoring the corneal pathway and the lipophilic corneal epithelium.4 The instilled drop slowly diffuses across the corneal epithelium, through the stroma and into the anterior chamber in about 20 to 30 minutes, but with a concentration much lower than upon instillation. 

Upon joining the aqueous humor, the drug continues to the iris and ciliary body, and then onto the lens. The crystalline lens is a tightly packed protein matrix that is more resistant than the uvea to drug penetration. While some quantity of a topical drug may flow through the bulbar conjunctiva to the sclera and back to the posterior segment, the amount is clinically insignificant and thus would be ineffective in treating posterior segment diseases.5 

Various additives can help. Viscosity enhancers improve precorneal residence time and bioavailability, or the amount of an administered dose that reaches the systemic circulation unchanged, upon topical drop administration. As a point of reference, a drug administered intravenously has a bioavailability of 100%.13 Permeation enhancers, on the other hand, increase corneal uptake by modifying the corneal integrity to enhance drug bioavailability; however, these additives have been thought to cause local corneal toxicity. Cyclodextrins, meanwhile, act as carriers for hydrophobic drug molecules in aqueous solution. They remain in aqueous solution while a hydrophobic drug is absorbed by the biological membrane.6

Additionally, emulsions, suspensions and ointments allow for improved solubility, or the dissolution of one solid, liquid or gas into another to form a homogenous system; precorneal contact time; and ocular bioavailability.6 However, these formulations are associated with side effects such as irritation, redness, inflammation, vision interference and stability issues.14

Posterior segment disease requires site-specific drug delivery systems that target the vitreous cavity, RPE and choroid.7 Other modes of administration for posterior segment delivery include systemic, intravitreal and periocular routes, as well as laser and/or surgical procedures.4 

While injections can be effective, they must occur frequently to maintain therapeutic effect because of the drug’s rapid elimination from the vitreous; this adds to the already considerable cost, inconvenience and host of potential complications (e.g., risk of hemorrhage, infection, retinal detachment, endophthalmitis and cataract).8 Systemic administration also works, but the high doses necessary for therapeutic effect are often associated with significant side effects. Periocular delivery using subconjunctival or retrobulbar injection is safer and less invasive than intravitreal injection.4 

Deep Impact
Recently, Ohr Pharmaceutical announced preliminary results from a Phase II trial of topical squalamine to treat wet AMD (the IMPACT study). Squalamine is a small-molecule, anti-angiogenic aminosterol isolated in 1993 from the dogfish shark that works by inhibiting multiple growth factors and pathways responsible for angiogenesis (VEGF, PDGF and bFGF). 

The nine-month, double-masked, placebo-controlled study reported data on 62 patients; 29 were treated with an initial ranibizumab injection, then as-needed in combination with squalamine eye drops BID, while 33 were treated with an initial ranibizumab injection, then as-needed and in combination with placebo eye drops BID. 

The results suggested a significant treatment breakthrough: 48.3% of patients using the squalamine drops in conjunction with intravitreal ranibizumab gained 15 or more letters, compared to 21.2% using placebo drops. Subjects were also twice as likely to gain over four lines of visual acuity. And, while the results were comparable to previously reported results with anti-VEGF and anti-PDGF intravitreal combinations, the visual benefit reported in the IMPACT study was achieved with far fewer injections (3.8 vs. 12 over 24 weeks). Additionally, the drops were well tolerated, with no adverse events, intraocular pressure rise or cataractous formation.2 

After administration, this small-molecule drop enters the conjunctiva and anterior sclera, and begins penetrating the corneal epithelium. An mucoadhesive agent is believed to increase corneal residence time so that the drug diffuses slowly over time to the posterior sclera, resulting in delivery of sustained concentrations of squalamine via retardation of loss of the drug through nasolacrimal duct drainage. This also possesses viscosity enhancing properties that may result in a desirable soothing or lubricating effect. 

A penetrating enhancing agent allows for greater penetration into the corneal epithelial layers, while a stabilizing agent acts as an antioxidant and can thwart the chemical degradation of the formulation. Buffering agents allow for the drug to be at a near-neutral pH compatible with ocular administration. The tonicity modifier in the formulation produces the appropriate osmolality of the ophthalmic formulation.15 

Diseases such as AMD can be visually devastating; while today’s treatments are more effective than ever, there are still significant downsides. As such, continued research is necessary. Other topically applied agents being investigated for posterior segment therapy include the NSAID nepafenac to inhibit prostaglandin synthesis in the retina and choroid,16 the kinase inhibitor prodrug TG100801 for neovascularization and retinal edema,17 the nicotinic antagonist mecamylamine for diabetic macula edema,18 the tyrosine kinase inhibitor pazopanib for wet AMD19 and the antisense oligonucleotide aganirsen for retinal neovascularization.20 

Overall, the promising results of the interim data for squalamine is welcome news to both patients and doctors who are looking for less invasive and more convenient ways to treat posterior retinal diseases such as macular degeneration, diabetic macular edema and venous occlusive disease.  

1. Ahmed I, Patton TF. Importance of the noncorneal absorption route in topical ophthalmic drug delivery. Invest Ophthalmol Vis Sci. 1985;26(4):584-547.
2. www.ohrpharmaceutical.com/media-center/press-releases/detail/274/ohr-pharmaceutical-announces-additional-squalamine-eye-drop
3. Hughes PM, Olejnik O, Chang-Lin JE et al. Topical and systemic drug delivery to the posterior segments. Adv Drug Deliv Rev 2005;57:2010-32.
4. Geroski DH, Edelhauser HF. Drug delivery for posterior segment eye disease. Invest Ophthalmol Vis Sci 2000;41:961-964.
5. Prausnitz MR, Noonan JS. Permeability of cornea, sclera and conjunctiva; a literature analysis for drug delivery to the eye. J Pharm Sci 87(1998) 1479-1488.
6. Patel A, Cholkar K, Agrahari V and Mitra AK. Ocular drug delivery systems; An overview. World J Pharmacol 2013;2(2):47-64. 
7. Janoria KG, Gunda S, Boddu SHS, Mitra AK. Novel approaches to retinal drug delivery. Expert Opin Drug Deliv (2007);4(4) :371-388.
8. eyetubeod.com/2013/09/highlights-from-rts-feature-series-the-path-to-the-retina
9. Vulovic N, Primorac M, Stupar M, Brown MW, Ford JL. Some studies on the preservation of indometacin suspensions intended for ophthalmic use. Pharmazie. 1990;45:678-679. 
10. Meseguer G, Buri P, Plazonnet B, Rozier A, Gurny R. Gamma scintigraphic comparison of eyedrops containing pilocarpine in healthy volunteers. J Ocul Pharmacol Ther. 1996;12:481-488. 
11. Gebhardt BM, Varnell ED, Kaufman HE. Cyclosporine in collagen particles: corneal penetration and suppression of allograft rejection. J Ocul Pharmacol Ther. 1995;11:509-517.
12. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: An overview. World J Pharmacol.  2013 June 9; 2(2): 47-64.
13. Sikarra D, Shukla V,  Kharia AA, Chatterjee D. P. Techniques for solubility enhancement of poorly soluble drugs: an overview. Journal of Medical Pharmaceutical and Allied Sciences (2012) 01; 1-22
14. 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;58:1136-1163.
15. www.google.com/patents WO2012024298A1?cl=en
16. Lindstrom R1, Kim T. Ocular permeation and inhibition of retinal inflammation: an examination of data and expert opinion on the clinical utility of nepafenac. Curr Med Res Opin. 2006 Feb;22(2):397-404.
17. Doukas J1, Mahesh S, Umeda N, Kachi S, et al. Topical administration of a multi-targeted kinase inhibitor suppresses choroidal neovascularization and retinal edema. J Cell Physiol. 2008 Jul;216(1):29-37
18. Campochiaro PA, Shah SM, Hafiz G, et al. Topical mecamylamine for diabetic macular edema. Am J Ophthalmol. 2010 May;149(5):839-5
19. Singh R1, Wurzelmann JI, Ye L, Henderson L, et al. Clinical evaluation of pazopanib eye drops in healthy subjects and in subjects with neovascular age-related macular degeneration. Retina. 2014 Sep;34(9):1787-95.
20. Cloutier F, Lawrence M, Goody R, Lamoureux S, et al. Antiangiogenic activity of aganirsen in nonhuman primate and rodent models of retinal neovascular disease after topical administration. Invest Ophthalmol Vis Sci. 2012 Mar 9;53(3):1195-203.