General considerations in designing a drug-eluting contact lens

Ophthalmologists are generally limited to three options in delivering drugs to the eye while minimizing systemic side effects: drops (solutions or suspensions), ointments or injections. Injections are obviously not a practical option for most circumstances where repeated outpatient dosing is desired, and are also not a prospect that most patients would welcome. Patient enthusiasm for ointments is also limited since they blur vision and their thick and sticky consistency is uncomfortable. Consequently, 90% of ocular medications are delivered via drops. However, eye drops have substantial limitations. For example, patients frequently have difficulty administering them correctly [1–3]. When applied properly, only 1–7% of the medication in a drop is absorbed by the eye [4]. Even if all problems with formulation and efficiency were resolved, there remains the enormous problem of patient compliance, particularly with chronic conditions, such as glaucoma, which have notoriously poor compliance rates [5,6].

Sustained-release systems lend themselves naturally to problems of this sort, namely continuous local drug delivery from a depot over extended periods. They are particularly advantageous in contexts where compliance is poor [7]. Injectable microspheres have been used to provide sustained release over extended periods in populations at high risk of noncompliance, for example, dosage of naltrexone in alcoholic patients [8], or risperidone in schizophrenic patients [9]. Drug delivery systems can be applied by a wide range of routes, including injection, implantation and topical application. Even when applied locally (e.g., intramuscular injection and transdermal patches), the intention is frequently systemic delivery. In the case of the eye, however, systemic delivery is not desirable: drugs should achieve levels high enough for effectiveness in the eye without systemic distribution potentially causing toxicity. There are numerous instances of drug-release systems being used in this manner for nonocular applications. For example, microparticles containing concentrations of local anesthetic compounds, high enough to block sensation when injected at the nerve, can produce no systemic toxicity, even though they contain potentially lethal quantities of the drug [10,11]. Similarly, hydrogels containing quantities of tissue plasminogen activator (t-PA), sufficient to prevent adhesions when applied in the peritoneum, do not result in significant systemic blood levels of t-PA [12].

A number of devices and anatomical locations in the eye have been proposed for a drug depot [13]. At least as far as the anterior portions of the eye are concerned, contact lenses have been the device of choice for many investigators (see review [14]). They are widely used, biocompatible, comfortable and optically clear. They are easy to place – either by the patient, or by a physician, nurse or, in fact, an untrained third party. One of their most attractive features from a drug-delivery standpoint is that they are fairly large and thus could, in principle, house large quantities of drug.

There are a number of generic design criteria that are crucial in designing a contact lens-based drug delivery system. The drug – or its means of storage within the lens – must not compromise the optical properties of the lens, for example, by introducing cloudiness or color within the optical axis. The drug and/or its delivery system must not compromise biocompatibility. Extended release of high concentrations of drugs can cause local tissue toxicity even if the delivery system itself does not [15]. Furthermore, a drug delivery system could cause problems even if completely contained by the lens and not in direct contact with the eye. For example, some polymers could cause local acid release as they degrade [16]; it remains to be demonstrated that this does not adversely affect the eye. All the other desirable properties of contact lenses would have to be preserved, including oxygen permeability, reasonable overall bulk and comfort, among others. Drug release from the lens cannot be so rapid as to cause systemic toxicity or side effects, which can happen with many drugs used in ophthalmic practice.

A major design issue arises from the related criteria of how much drug the contact lens should contain and how long release should last. All other factors being equal, the more drug in a device, the longer release could potentially last (assuming that drug content is not increased at the expense of the polymer or other material that prevents the drug’s release). In general – this is a reasonable oversimplification – the drug content of hydrogels, the material from which contact lenses are made, tends to be relatively low, and release tends to be rapid, compared with what can be achieved with more hydrophobic systems. It is, therefore, not surprising that most published prototypes that depended primarily on a hydrogel matrix had low drug contents and released drugs rapidly and for a short period. This is not necessarily a bad thing – it all depends on the intended application and the circumstances in which the device is intended to be used. On the other hand, a drug-eluting contact lens that could provide therapeutic drug concentrations over many weeks could have a significant impact on compliance-related outcomes in chronic diseases. This becomes clear when one considers that, in the case of a fairly advanced regimen for glaucoma, a patient would need to apply a combination of several different eye drops several times per day, spaced a minimum of 5 min apart. It could also be useful in settings and populations where there is limited access to medical care, such as in parts of the developing world. It bears mentioning that a lens containing a large amount of drug would have to be designed so that there were no circumstances that could result in the release of a fraction of the total drug load large enough to do harm.

Another issue is the shape of the release kinetics curve to be obtained for the drug contained in the lens. Much is made of whether the release follows ‘zero-order’ kinetics, which basically means that the same amount of drug is released over time, rather like a constant intravenous infusion. One important deviation from zero-order release is ‘burst’ release – a somewhat arbitrarily defined multifactorial phenomenon that is seen with many drug delivery systems, and that consists of a relatively brief period of rapid drug release preceding a longer period of slower release. (In some drug-releasing contact lenses, the burst release comprises the entirety of the release kinetics). Burst release is wasteful and restricts the total duration of drug release but, more importantly, can result in local or systemic toxicity, depending on the therapeutic index of the drug. In general, larger and more hydrophobic systems show less burst release than smaller, more hydrophilic ones. Deviations from zero-order kinetics after the burst are also undesirable. Fluctuations above the therapeutic level are wasteful, deplete the device unnecessarily, and could result in toxicity. Fluctuations that result in underdosing will result in therapeutic failure. There are many methods of modulating release kinetics, depending on the nature of the drug delivery system.

Aside from the fact that drug-eluting contact lenses could ensure compliance (which would be a major contribution in itself), it remains to be seen whether sustained drug delivery to the eye increases drug flux into the eye and/or results in improved outcomes. It is reasonable to suppose that drugs from such devices could reach all parts of the eye that could be reached by drops. Whether deeper structures could be reached remains to be seen. Similar to all such circumstances, it will, at least in part, depend on the characteristics of the drug (e.g., molecular weight and charge).

The specific composition of matter is important for reasons mentioned earlier. Ideally, the lens itself, and all components, would be composed of materials that are well known and understood in the art, including the drug(s) to be delivered. This will accelerate the pace of research, regulatory issues and penetration into clinical practice. On the other hand, it could be argued that the more novel the materials, the more easily a new drug-delivering contact lens could be patented and, therefore, the more readily it could be commercialized. It bears mentioning that, at this point, the intellectual property space concerning drug-eluting contact lenses is encompassed by a thicket of patents four decades deep. New materials can also enhance performance. For example, highly oxygen-permeable hydrogels may allow the devices to be thicker (enhancing loading and perhaps slowing release), and facilitating their use for an extended period of time.

Effective drug-eluting contact lenses could complicate issues of storage. The lenses must not release their drug load while in storage, nor, ideally, must the lens component that controls drug release degrade in storage, or require special precautions to prevent degradation, such as refrigeration.

Finally, it will be important to determine the cost–effectiveness of drug-eluting contact lenses compared with conventional therapy.

Drug-eluting contact lenses offer the possibility of prolonged treatment or relief from symptoms from a single application. There is a broad range of potential technologies that could be deployed. These could provide the ophthalmologist with new and more effective means of treating patients.

Financial & competing interests disclosure

This research was funded by NIGMS GM073626 (DSK) and NEI 1K08EY019686–01 (JBC). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.