In one of our recent columns, we put forth a primer—or more accurately, a refresher—on the principles of pharmacokinetics as they relate to ocular drug therapies. (See Therapeutic Topics, October 2015) In that article, we described the specifics of drug design and formulation that focus on balancing therapeutic dose and duration with adverse effects and cost optimization. Although the eye has the unique advantage of access, and topicals account for about 90 percent of all aqueous ophthalmic formulations,¹ a significant barrier to ocular drug delivery is posed by the pre-corneal tear film, the corneal epithelium, the stroma and the conjunctiva. The combined action of these tissues and cellular constructs can render topical ocular drug delivery methods inefficient or ineffectual, and often necessitates higher drug concentrations, increased dosing frequency or both.

This central challenge for ophthalmic drug developers is being addressed through a number of chemical and physical sleight-of-hand strategies to improve the absorption, bioavailability or retention of therapeutics. By enhancing the amount of drug that can reach its target, or the duration of the drug at the target site, we use pharmacokinetic principles to achieve greater efficacy without onerous dosing regimens or amplified side effects. This month, we’ll describe several novel strategies for increasing drug concentrations, enhancing drug penetration and extending drug retention.

Increasing Drug Concentrations

It’s well-known that the small, hydrophilic molecules are generally the best therapeutics.² But how do we deal with hydrophobic drug candidates with good in vitro profiles? Enhancing the solubility of any drug allows for greater drug loading, resulting in more drug being delivered. While a potential drug candidate with a hydrophobic character may be better if corneal penetration is part of the goal, limits on aqueous solubility will affect the ability of the drug to achieve sufficient therapeutic concentrations in aqueous.³ An example of this is cyclosporine, a drug used to treat dry eye. One promising approach to this problem is the use of water-soluble compounds called hydrotropes, designed to enhance the aqueous solubility of hydrophobic compounds. Compounds demonstrating hydrotropic properties include caffeine; nicotinamide; urea; cyclodextrins; N,N-diethyl-nicotinamide; and N,N-dimethylbenzamide. The solubility enhancement of these compounds has ranged from relatively modest to upwards of 10,000-fold. These hydrotropes have only been tested on a limited set of hydrophobic drugs, but results are promising.^2,3

Innovative colloidal dosage forms for ocular drug delivery also offer solutions to drug solubility. In particular, polymeric nanoparticles, nanomicelles, liposomes and niosomes are known to increase drug solubility. These nanostructures, which range in particle size from 1 to 1,000 nm, capture the poorly soluble drug, allowing for improved distribution within an aqueous solution. Biodegradable polymeric nanoparticles take either the form of nanospheres, within which the parent drug is dispersed in a polymeric matrix or is otherwise adsorbed to the surface of the nanosphere; or the form of a nanocapsule, within which the parent drug is dissolved and surrounded by the polymeric membrane.⁴ These nanoparticle carriers are then dispersed within a water-based vehicle.⁵ Micelles are nanoscale phospholipid balloons that form when molecules possessing both hydrophilic and hydrophobic groups are exposed to a suitable solvent and the molecules orient with the hydrophilic portions orienting outwards, forming a hydrophobic core, which can also then encapsulate a hydrophobic parent drug.⁶ Liposomes form nanovesicles capable of entrapping both hydrophilic and hydrophobic drugs by virtue of the molecule’s inner hydrophilic core and peripheral hydrophobic compartments^.5 Niosomes are vesicles composed of non-ionic surfactants that are structurally and functionally similar to liposomes.  

Enhancing Access

The two primary strategies for improving ocular drug delivery are developing prodrugs and adding penetration-enhancing agents that modify the ocular surface. Enhancing penetration improves site-specificity, consequently increasing the amount of drug that reaches the target tissue while decreasing toxicity.

By comparing tear-film breakup, caking, blurring and comfort scores, it’s possible to determine an optimal viscosity (usually about 70 to 135 centipoise) for each drop formulation.

Prodrugs are commonly used to enhance drug penetration, and are inactive or less-active derivatives of active drug molecules that are converted to the active form in vivo. The concept of prodrugs isn’t new, although development of prodrugs has surged recently. In the first decade of this century, pro-drugs accounted for nearly 20 percent of approved new chemical entities.⁷ Approved ophthalmic prodrugs are currently in use for managing intraocular pressure and open-angle glaucoma (e.g., latanoprost, bimatoprost, travoprost and unoprostone isopropyl), as well as for managing ocular pain and inflammation following ocular surgery (e.g., nepafenac). These topically administered ophthalmic prodrugs take advantage of lipophilic pro-moieties to enhance penetration of the corneal barrier. While this remains a successful strategy, a new generation of ocular prodrugs that seeks greater tissue specificity by targeting cell-specific or tissue-specific endogenous enzymes or transporters is on the horizon.⁸ Examples of this shift in pro-drug strategy are compounds that target peptide or amino acid transporters to facilitate uptake of prodrug variants of antiviral drugs such as acyclovir and gancyclovir.⁶

Another method for enhancing ocular penetration is to add enhancers that directly modify the physical barriers of the ocular surface; for example, by disrupting tight cell junctions between superficial epithelial cells, or by partially solubilizing and removing cell membrane phospholipids on the ocular surface.^9,10 These enhancers can be effective at promoting paracellular and transcellular transport of drugs, but modifying physical barriers can have consequences. Eye irritation and cellular damage have been associated with early generation penetration-enhancing agents, so the current focus is on penetration enhancers that act with minimal toxicity, maximal comfort and are compatible with formulation ingredients. These agents are also designed to act at low concentrations, with a fast yet reversible onset of action.¹¹ Examples include Gelucire 44/14 (Gattefossé, Lyon, France), an amphiphilic molecule, and cyclodextrin, a compound with multiple pharmacokinetic-enhancement effects.^11,12 It’s thought that the amphiphilic character of Gelucire 44/14 allows it to act as a surfactant, promoting both transcellular and paracellular transport by its actions on cell membranes and tight junctions.¹¹ Cyclodextrin has been shown to interact with the sterols in cell membranes, swapping a cholesterol in exchange for a drug held within its hydrophobic core.¹² These enhancers have garnered the interest of pharma due to their favorable tolerability and ability to solubilize drugs.^1,11,12

Extending Drug Duration

Retention strategies are continually evolving as drug developers seek to improve the bioavailability of ophthalmic drugs by extending the duration of the drug. One approach we’ve tested in pre-clinical studies is adding lysine homo-polymers, compounds that can adhere to the epithelial surface and to the drug molecule, acting as tethers to keep drug molecules resident at the surface. More often, residence time is prolonged through the use of agents such as hydroxy propyl methyl cellulose to increase drop viscosity, and by the use of drug carriers that can act as drug reservoirs.

Raising the viscosity of an ocular drug-delivery formulation helps to slow the rapid dilution and drainage caused by tear-film turnover. This approach must be weighed against a few distinct disadvantages, however: Highly viscous solutions can cause transient blurring of vision upon instillation, and are subject to imprecise dosing. An alternative approach involves gelling systems that undergo a phase transition from a liquid to a gel upon exposure to certain physiological conditions, such as temperature or pH. These systems can be delivered with the precision of a drop, but retain the ability of viscosity-enhanced delivery systems to retard the dilution and drainage of the pre-corneal tear film. At the same time, they also minimize gels’ transient impact on vision. Other polymers tested for use in the eye are designed to interact with native mucins. The residence time of formulations using these muco-adhesive polymers is governed by the turnover rate of the tear mucin layer, which is slower than that of the bulk tear film.^1,13

In addition to properties that promote solubility and drug penetration, some nanoparticle, liposome, nano-emulsion and dendrimer formulations also prolong duration. As a drug is attached to the matrix or encapsulated within a nanoparticle delivery system, the system protects the drug from degradation and slows diffusion into the bulk solution, prolonging overall residence time.¹⁴ Drug release is then controlled by the degradation rate of the delivery system, the solubility of the drug and the diffusion of the drug within the nanoparticle delivery system.¹⁵

Punctal plugs can be considered one of the simplest pharmacokinetic-modifying strategies, slowing tear drainage and prolonging the action of artificial tears by physical occlusion of the lacrimal drainage. More recently, plugs have become important sustained-release delivery systems. The plug is usually coated to render all sides but the head impermeable to the drug and tear fluid. Drug diffuses over time into the tear film from the head of the device.¹⁶ The combination of depot drug delivery and slowing of tear drainage provides a one-two punch of therapeutic enhancement. Trials are under way to evaluate the use of punctal plugs for the extended release of travoprost or latanoprost to treat glaucoma.

An approach similar to the punctal plug is the intracanalicular depot. This device slows drainage while at the same time delivering a sustained dosing of dexamethasone (the approach of Ocular Therapeutix), and may also work with other drugs. The steroid depot has shown promise as a treatment for chronic allergic conjunctivitis, and is being tested for treatment of dry eye and ocular inflammation as well.¹⁷

As the progression of polymers to be evaluated for their suitability as prolonged-release drug delivery systems marches on, an alternative—drug-loaded ocular inserts as delivery modalities—is also on the rise. One polymer unique in its combination of qualities is chitosan. Chitosan is a biodegradable, biocompatible and nontoxic natural carbohydrate polymer that has mucoadhesive properties. Chitosan-based ocular inserts enhance precorneal residence time of the co-applied drug, with promising initial results in studies with various drugs.¹⁸

Biodegradable and non-biodegradable implants are emerging as a method for effective long-term delivery of drug to the posterior chamber. As with intravitreal injections, the approach, while invasive, avoids several of the ocular barriers to drug delivery while enabling sustained-release kinetics over a period of years. In 2014, Iluvien (Alimera Sciences) was granted Food and Drug Administration approval as an injectable intravitreal device for treatment of diabetic macular edema in patients who have previously been  treated with a course of corticosteroids and did not have a clinically significant rise in IOP. Iluvien is a non-biodegradable, cylindrical polyimide implant that releases 0.23 to 0.45 μg/day of fluocinolone acetonide for 18 to 36 months. The device is small enough to be implanted into the back of the eye using a 25-gauge needle. Iluvien was developed using the Durasert technology platform (pSivida), which also is currently being investigated by Pfizer for a fully bioerodible, sustained-release delivery system for latanoprost.

The last two decades have seen remarkable innovation in the development of ophthalmic drug delivery systems. Improvements have been driven in large part by considerations of patient compliance, as technologies that increase drug concentrations, penetration and duration should result in reduced dosing requirements and improved efficacy. Research under way in this area pushes boundaries and involves contributions from clinicians, pharmacologists and materials scientists. As this consortium works its magic, we can expect to see a host of new therapeutic modalities materialize in the near future.  REVIEW


Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School, emeritus surgeon at the Massachusetts Eye and Ear Infirmary and chief scientific officer at Ora Inc. Dr. McLaughlin is a senior regulatory writer at Ora.



<sup>1. Morrison PW, Khutoryanskiy VV. Advances in ophthalmic drug delivery. Ther Deliv 2014;5:12:1297-315.
2. Lipinski C, Hopkins A. Navigating chemical space for biology and medicine. Nature 2004;432:7019:855-61.
3. Kim JY, Kim S, Papp M, et al. Hydrotropic solubilisation of poorly water-soluble drugs. J Pharm Sci 2010;99:9:3953-65.
4. Almeida H, Amaral MH, Lobão P, et al. Applications of polymeric and lipid nanoparticles in ophthalmic pharmaceutical formulations. J Pharm Pharm Sci 2014;17:3:278-93.
5. Cholkar K, Patel SP, Vadlapudi AD, et al. Novel strategies for anterior segment ocular drug delivery. J Ocul Pharmacol Ther 2013;29:2:106-23.
6. Cholkar K, Patel A, Vadlapudi AD, et al. Novel nanomicellar formulation approaches for anterior and posterior segment ocular drug delivery. Recent Pat Nanomed 2012;2:2:82-95.
7. Stella VJ. Prodrugs: Some thoughts and current issues. J Pharm Sci 2010;99:12:4755-65.
8. Huttunen KM, Raunio H, Rautio J. Prodrugs—from serendipity to rational design. Pharmacol Rev 2011;63:3:750-71.
9. Kaur IP, Smitha R. Penetration enhancers and ocular bioadhesives: Two new avenues for ophthalmic drug delivery. Drug Dev Ind Pharm 2002;28:4:353-69.
10. Burgalassi S, Chetoni P, Monti D, et al. Cytotoxicity of potential ocular permeation enhancers evaluated on rabbit and human corneal epithelial cell lines. Toxicol Lett 2001;122:1:1-8.
11. Liu R, Liu Z, Zhang C, et al. Gelucire44/14 as a novel absorption enhancer for drugs with different hydrophilicities: In vitro and in vivo improvement on transcorneal permeation. J Pharm Sci 2011;100:8:3186-95.
12. Adelli GR, Balguri SP, Majumdar S. Effect of cyclodextrins on morphology and barrier characteristics of isolated rabbit corneas. AAPS PharmSciTech 2015;16:1220-1226.
13. Agrawal AK, Das M, Jain S. In situ gel systems as ‘smart’ carriers for sustained ocular drug delivery. Expert Opin Drug Deliv 2012;9:4:383-402.
14. Kim NJ, Harris A, Gerber A, et al. Nanotechnology and glaucoma: A review of the potential implications of glaucoma nanomedicine. Br J Ophthalmol 2014;98:4:427-31.
15. Mudshinge SR, Deore AB, Patil S, et al. Nanoparticles: Emerging carriers for drug delivery. Saudi Pharm J 2011;19:3:129-41.
16. Gooch N, Molokhia SA, Condie R, et al. Ocular drug delivery for glaucoma management. Pharmaceutics 2012;4:1:197-211.
17. Walters T, Endl M, Elmer TR, et al. Dexamethasone punctum plug for the treatment of ocular inflammation and pain after cataract surgery. J Cataract Refract Surg 2015 (in press).
18. Franca JR, Foureaux G, Fuscaldi LL, et al. Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: In vitro and in vivo evaluation. PLoS One 2014;9:4:e95461.</sup>