Targeting Ocular Topical Penetration with Antibiotics

Though formula improvements have increased effectiveness of anti-infectives, there are crucial factors to consider to get the best outcomes.

By Jesse Pelletier, MD, and Joseph Capriotti, MD

Ophthalmologists are inundated with new products and updates and reformulations of older products all aiming to better serve our patients. This great diversification is no better illustrated than in the field of anti-infectives, where selecting properly for the task at hand can be daunting. We are certainly grateful for all the effective choices at our disposal, as generally speaking, it is rare that ocular surface infections end in a devastating fashion.

Today, topical antibiotics are prescribed for a variety of purposes outside of imminent sight-threatening infection. Though the FDA has approved some for bacterial conjunctivitis and others for infectious keratitis, antibiotics of course serve many other off-label purposes, ranging from prevention of endophthalmitis to the improvement of blepharitis.

The selection of the right anti-infective requires a sound understanding of basic principles and familiarity with more subtle ones. These subtle imprints make each antibiotic unique and useful for a particular situation.

Important features to consider when evaluating an anti-infective include breadth of antibacterial spectrum, bacteriocidal vs. bacteriostatic activity, time vs. concentration dependent effects, and ocular penetration. In this article we will focus on the latter; namely, how the compound we choose gets to its target destination. Traditionally, this has meant penetration into the anterior chamber. However, there are other vital anterior segment antibiotic partition targets that include the cornea, conjunctiva and eyelid.

Before a Drop Touches the Eye

There are three things that have to happen before a drop of any anti-infective can reach potential target tissue: (1) The patient has to remember to take the drop, (2) the drop has to get from the bottle to the exposed ocular surface and (3) the drop has to make it past the tear film. For routine use of a topical anti-infective, (1) and (2) are entirely dependent on patient compliance and patient technique, so the first way to optimize ocular delivery is to make comfortable formulations in easy-to-use packaging that can be dosed as infrequently as possible.

The tear film is then the first anatomical barrier a successfully applied drop meets, and is the most highly variable factor between individual patients. Differences in tear film turnover, osmolarity, protein content, pH, fornix volume, underlying conjunctival vascularity and lacrimal drainage can all affect the amount of any given dose form (drop, gel, ointment, etc.) that makes it through to the conjunctivo-corneal surface. The evolution of mechanisms to isolate the ocular surface from foreign bodies (corneal-blink reflex, reflex tearing, eye lashes, etc.) are of great benefit for protecting the eye but form the first anatomic barriers to drug penetration.

Corneal Anatomy

A basic understanding of penetration involves anatomical comprehension of the anterior segment. The human cornea is a trilaminate structure consisting of a hydrophilic layer or stroma, sandwiched between the two lipophilic layers of the epithelium and endothelium. The epithelium is lipoidal in nature, and contains about 90% of the total cells in the cornea.¹ It poses significant resistance for permeation of topically administered hydrophilic drugs. Moreover, the presence of desmosomes and tight junctional complexes further retard antibiotic permeation.

The corneal stroma comprises about 80-85% of corneal thickness. Anteriorly, Bowman's layer is the cellular condensation of this hydrophilic compartment. In the stroma, a highly organized network of collagen fibrils is responsible for imparting transparency and mechanical strength. It is understood that the anterior stroma, due to its complex associations, is structurally more rigid than the deeper stromal layers. Nonetheless, this hydrophilic layer poses difficulty for the permeation of lipophilic drug molecules.

Besides its vital role in maintaining corneal clarity, the corneal endothelium is also lipophilic. However, in contrast to the tightly bound epithelium, the endothelial junctions are porous and facilitate passage of molecules into the anterior chamber.

As alluded to previously, there also exist other ocular tissues that may be important targets for anti-infectives. The conjunctival epithelium is an irregular, translucent surface that contains goblet cells and numerous microvilli. Similar to the corneal epithelium, it possesses epithelial tight junctions, which can retard hydrophilic molecules. Deep into the epithelium lies the conjunctival stroma. While it is responsible for the robust inflammatory reaction noted in conjunctival insult, the conjunctival stroma also may decrease drug bioavailability via systemic shunting through vascular plexi.²

Optimizing for Delivery

Though most topical drops enter the eye via the cornea, there is a non-corneal route that involves the conjunctiva and sclera; however, this is less effective and aptly named the “non-productive route.”³

With the understanding of key anatomic barriers to overcome, we can turn to properties of the host that may facilitate anti-infective delivery. It sensibly follows that if the corneal epithelium is removed, then the large hurdle of lipophilicity no longer exists. This is particularly true for water soluble or polar compounds, and has been corroborated in animal models. This is also relevant in clinical practice when corneal specialists treating advanced fungal keratitis repeatedly debride the epithelium to facilitate penetration of stubborn, hydrophillic anti-fungal compounds.

Another important host factor may be the disease model itself. Some research has shown that various inflammatory conditions such as ulceration, infection, alkali-burn, etc., may be responsible for pathologic changes that enhance drug penetration.⁴ These changes are real and lay outside of the uptake imparted by the epithelial defect alone, but remain poorly understood.

In uninflamed eyes, we cannot rely on the above-mentioned host characteristics to assist in penetration. Therefore, optimization of the anti-infective is necessary to achieve the desired effect. As mentioned previously, lipophilicity has been viewed as cornerstone to solubility for many years. Only recently has the importance of aqueous solubility been truly appreciated. Having balance between these two physiochemical properties theoretically optimizes penetration of an anti-infective compound. The ratio of lipid to water solubility of a compound is often described as the PC or partition coefficient.

Another important physical property is molecular weight. Typically, compounds with molecular weight less than 500 will diffuse through biologic membranes, and fortunately most of our armamentarium is below this critical threshold. However, larger compounds such as bacitracin (1411) and Polymixin (1200) may be impeded by their size.⁴

There are also formulation enhancements that may be made to anti-infectives to increase efficacy. The pH of a particular compound is important. Ionizable organic compounds penetrate epithelium in their unionized form. Therefore, the formulation with a pH that yields the greatest amount of unionized drug is typically the most soluble; however, this system is subject to tear buffering. Another caveat to this may be when anti-infective stability is achieved at a non-optimal pH (for penetration purposes).

Another well-described formulation enhancement is concentration. We have seen this recently with gatifloxacin 0.3% (Zymar), now distributed at 0.5% (Zymaxid). To an extent, the amount of drug that penetrates the cornea increases as the concentration peaks. Formulation additives are also important; specifically, preservatives and vehicles. Quaternary ammonium compounds like BAK, mercurials (thimerosol), and the like frequently receive attention in the literature due to their propensity for ocular surface disturbance. However, in addition to preventing contamination of the anti-infectious compound, these preservatives have been shown to increase epithelial permeability and transscleral drug delivery.⁵

Recently, ophthalmologists have noted change in another formulation modification—the vehicle. Traditional vehicles have been aqueous, as well as various ointments and gels. Azasite and Besivance now employ the vehicle DuraSite, which acts as a polymeric bioadhesive that slowly releases active ingredients from a formed matrix. Benefits of such a strategy include optimization of pharmacodynamic (PD) and pharmacokinetic (PK) parameters which, for our concerns, would theoretically increase corneal penetration.

Interestingly, as we come to better understand PD/PK interactions with respect to antibiotic class we can see that all of the aforementioned enhancements are sound strategy for not only increasing penetration, but also maximizing other important parameters such as tissue concentrations, decreasing MICs, and maintaining our agent above MIC targets for longer periods of time. Today, many pharmaceutical companies are employing these enhancement trends to increase product efficacy.

Conclusion

Anti-infective penetration depends on a variety of factors relating to innate host and drug properties. We have also seen how penetration enhancements can be achieved with sound understanding of the aforementioned properties. Future applications of drug delivery involving advanced technologies such as colloidal dosage (nanomolecules, liposomes, etc.) and iontophoresis will also be built upon the same basic scientific tenets. Penetration, while a vital part of an ideal anti-infective, still only comprises part of the story. Understanding the remaining salient features, the penetration target, and therapeutic goals make us better equipped to successfully use these powerful agents. OM

References

1. Delmonte D, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg 2011;37:588-598.
2. Guadana R, Ananthula HK, Perenky A, et al. Ocular drug delivery. AAPS J 2010;12(3):348-360.
3. Lee V. Mechanisms and facilitation of corneal drug penetration. J Control Release 1990;11:79-90.
4. Benson H. Permeability of the cornea to topically applied drugs. Arch Ophthalmol 1974;91:313-327.
5. Okabe K, Kimura H, Okabe J, et. al. Effect of benzalkonium chloride on transscleral drug delivery. Invest Ophthalmol Vis Sci 2005;46(2):703-708.