Understanding topical ophthalmic drug delivery: How much gets in?
Several obstacles stand in the way of effective ocular drug penetration.
In understanding how much of an artificial tear or a prescription eye drop actually reaches its target tissue, it is helpful to appreciate the significant obstacles to drug penetration that the eye presents.
The average size of a topical drop is 50 µL and is dropped into a 30 µL “reservoir,” ie, the ocular surface. There is some spillage and nasolacrimal drainage. Tearing and blinking cause dilution and increase the spillage and nasolacrimal clearance.
The volume of the tear film is 7 µL to 10 µL; it turns over at a rate of 0.5 µL to 2.2 µL per minute. The conjunctiva and underlying sclera have a greater surface area than the cornea and are conduits to systemic absorption.
The cornea is the primary route of topical ocular drug absorption and offers significant anatomical barriers. There is less than 5 minutes of ocular surface contact time for any drop; for this reason and the above considerations, approximately 5% of the original dose reaches the target.
To improve ocular topical drug delivery, drug designers have developed strategies that minimize precorneal drug loss and maximize corneal drug absorption. They use three main approaches to deal with the aforementioned challenges:
- increasing the effective dose by increasing the dose and/or the frequency of administration;
- enhancing the molecular design by increasing lipophilicity and/or solubility; and
- altering formulation science by increasing viscosity, corneal penetration and residence time.
Unfortunately, due to patient involvement in the drug delivery process, strategies that may enhance drug absorption may also contribute to noncompliance or suboptimal dosing of the administered drug.
For instance, low drug bioavailability usually requires a higher frequency of administration, a common reason for poor compliance.
Some molecular characteristics, such as lipophilicity, affect the formulation and often require shaking, which may result in variability of the drug administered. This is particularly true of suspensions, which are dependent on resuspension, ie, shaking. When a patient does not shake the bottle as instructed, most of the drug sinks to the bottom and is delivered to the eye at the end of the course of treatment, when it is often less needed.
Poor compliance with shaking of prescription eye drop bottles is legendary. In a classic study by Apt and colleagues in American Journal of Ophthalmology in 1979, 100 adult patients were given a bottle of an ophthalmic suspension medication labeled “Instill one drop in each eye four times daily. Shake well.” “Shake well” was labeled in red to emphasize the point. The number of times the bottle was shaken by each patient was observed and recorded. Of the 100 patients in the study, 63 did not shake the bottle even once.
Sometimes, certain formulation characteristics, such as pH and excipients, are needed for drug delivery; these can result in low tolerability due to discomfort, blurred vision, etc.
Adding to these challenges, there has been variability documented in drop-to-drop volume from some bottles. Nascimento and colleagues published a study in which they concluded that their documented lack of uniformity of drops dispensed by eye drop bottles was inadequate to the real need, especially when it comes to long treatment periods, ie, with expensive drops such as indicated for glaucoma therapy.
In summary, the challenges presented by topical ophthalmic drug therapy are daunting. Nevertheless, having a technician or scribe stay behind in the exam lane for a minute or two to demonstrate the proper technique and to emphasize compliance is invaluable. Even a few quick tips (refrigerating drops that sting, shaking suspensions 20 times before each dose, etc) are immensely helpful and can spell the difference between a successful treatment regimen and one that fails.
- Apt L, et al. Am J Ophthalmol. 1979;doi:10.1016/0002-9394(79)90145-4.
- Nascimento VS, et al. Rev Bras Oftalmol. 2017;doi:10.5935/0034-7280.20170005.
- For more information:
- Marguerite B. McDonald, MD, FACS, can be reached at Ophthalmic Consultants of Long Island, 360 Merrick Road, Lynbrook, NY 11563; email: firstname.lastname@example.org.
Disclosure: McDonald reports no relevant financial disclosures.