Corneal Clarity

Ophthalmic Drug Delivery Systems Fight the Barriers of the Body and Eye

By Thomas John, MD

Ophthalmic therapeutics play a major role in vision preservation and globe retention, especially when one is dealing with serious ocular infectious processes. Therapeutic coverage needs to extend beyond infections to inflammatory processes and other ocular conditions as well. To attain optimal outcomes, both the drug and the ophthalmic drug delivery systems that can overcome natural ocular barriers are equally important.

In this column, I’ll examine the significant barriers ophthalmic drug delivery systems must overcome if our therapies are to become more efficacious. My next column will delve into the various ophthalmic drug delivery systems and their impact on eye care.

The Eye’s Defenses

The eye possesses a range of barriers, both static and dynamic, besides the efflux pumps. In combination or singularly, they pose significant challenges for optimal drug delivery when we try to treat either anterior- and posterior-segment diseases. Static barriers relate to ocular tissue layers such as the cornea, sclera and retina, and the well-known barriers such as the blood-retinal and blood-aqueous barriers. Dynamic barriers include ocular surface tear dilution, blood flow within the conjunctival and choroidal tissues, and the lymphatic flow.

Overcoming these barriers and designing novel ocular delivery systems without causing any permanent tissue damage will take the therapeutic delivery scene from the current topical medications and somewhat less appealing repeated intravitreal injections to a whole different level.

What Drug Delivery Systems Are Up Against

First, let’s look at how these barriers impede drug access to the interior of the eye. The following properties compromise the bioavailability of topically applied ocular drugs: blink-assisted drainage (at a blink rate of 15-20/min.) via the lacrimal drainage routes; tear dilution effect; tear-turnover effect (about 1 μL/min.); drug-molecule binding to tear protein; and reflex lacrimation. Also, a disconnect exists between the amount of volume instilled to the amount retained; namely, the installation volume is usually 20-50 μL, while total resident volume (lacrimal lake) is about 7-10 μL, with any excess volume spilling over the cheek or exiting via the nasolacrimal duct.¹

Although the natural lacrimal lake is only about 7-10 μL, it can usually hold 25-30 μL before tearing results. Age-related eyelid laxity can result in the lacrimal lake holding even more fluid. However, one study estimated less than 5% of topically applied drug dose reaches the intraocular tissues.²

Topically applied medications do not easily enter the anterior chamber, because they usually have to cross the corneal barrier. The surface corneal epithelium contains 90% of the total corneal cells, and offers an imposing barrier effect on topical, hydrophilic drugs. This is because the corneal epithelium is lipoidal, or resembles fat. So a drug must have a “lipophilic-passport” so to speak, to penetrate the epithelium. In other words, the epithelium is lipophilic drug-friendly. To add to this effect, desmosomes attach the epithelial cells to one another, and they posses ribbon-like tight junctions called zonula occludens. These tight junctional complexes dampen any paracellular drug transport.

Corneal Stroma Layer

The next layer, the corneal stroma, is hydrophilic, so it has a barrier effect on lipophilic drugs. Thus, to pass through the corneal barrier a drug has to be both lipophilic and hydrophilic — that is, amphiphilic or amphipathic. The innermost endothelial layer offers carrier-mediated transport and is leaky, with the endothelial junctions allowing macromolecules to pass between aqueous humor and stroma.

The adjacent conjunctiva with its blood vessels and lymphatics bypass the drugs for the most part to systemic circulation. The conjunctiva is two to 30 times more permeable to drugs than the cornea.³ The barrier function of corneal epithelium is much stronger than the conjunctival epithelium, perhaps due to the presence of claudin-10 transmembrane protein and goblet cells in the latter.⁴

One may view scleral barrier function as comparable to corneal stroma. However, sclera is more permeable than the cornea. Scleral rate-limiting factors include the molecular radius.⁵ The sclera is independent of lipophilicity, thus differing from corneal and conjunctival layers. Also, positively charged molecules are less likely to pass through sclera because it binds with negatively charged scleral proteoglycan matrix.⁶

The Route(s) of the Issue

When one chooses the systemic route for ophthalmic drug administration, two barriers take center stage as impediments for drug entry into the ocular space: the blood-aqueous barrier anteriorly with the vascular endothelium of iris and ciliary body; and the blood-retinal barrier posteriorly with the retinal capillary endothelial cells and the retinal pigment epithelial (RPE) cells.

Tight RPE junctions limit intercellular passage. Thus, it is necessary to penetrate these barriers to gain intraocular entry via systemic drug administration. The good news is that nanotechnology can overcome the blood-retinal barrier — that is, 20-nm gold nanoparticles can penetrate this barrier and enter all the retinal layers. Nanoparticles can also enter a neovascular eye because of the leaky nature of the blood-retinal barrier.

The oral route usually fails to attain therapeutic drug concentration in the posterior segment, but increasing the dosage to attain a therapeutic effect introduces unwanted drug toxicity. Also, the oral route, similar to the systemic parenteral route, has to deal with the same barriers within the eye. For example, oral acetazolamide is largely not used due to often-associated systemic toxicity.

Patients don’t necessarily like the periocular (subconjunctival, retrobulbar, peribulbar and subtenon) or intravitreal routes for obvious reasons. Drugs delivered via periocular route can pass through three different avenues to the posterior segment: the transcleral route; the anterior segment via tears, cornea, aqueous and vitreous humor; and systemic circulation via the choroid.

Challenges Remain Formidable

On the other hand, subconjunctival injection bypasses the conjunctival epithelial barrier, and going through the transcleral avenue still has limitations to entering the posterior segment due to static, dynamic and metabolic barriers. Thus, drug delivery into the ocular space entails bypassing or passing through these natural roadblocks or barriers — a true therapeutic challenge. My next column will examine the ocular drug delivery systems at our disposal and how they meet these challenges. OM

References

1. Mishima S, Gasset A, Klyce SD Jr, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966;5:264–276.

2. Ahmed I. The noncorneal route in ocular drug delivery. In: Mitra AK, editor. Ophthalmic drug delivery systems. New York, NY: Marcel Dekker. 2003:335–63.

3. Padma B, Natuva DP, Brahmani S, et al. Ocular drug delivery system and developments. Int J Chem Analyt Sci. 2012;3:1413–1418.

4. Yoshida Y, Ban Y, Kinoshita S. Tight junction transmembrane protein claudin subtypes expression and distribution in human corneal and conjunctival epithelium. Invest Ophthalmol Vis Sci. 2009; 50:2103–2108.

5. Prausnitz MR, Noonan JS. Permeability of cornea, sclera, and conjunctiva: a literature analysis for drug delivery to the eye. J Pharm Sci. 1998;87:1479–1488.

6. Kim SH, Lutz RJ, Wang NS, Robinson MR. Transport barriers in transscleral drug delivery for retinal diseases. Ophthalmic Res. 2007;39:244–254.

Thomas John, MD, a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. E-mail him at tjcornea@gmail.com.