CL DRUG DELIVERY
Contact Lenses in Drug Delivery
A look at mechanisms for and benefits associated with using contact lenses to deliver ocular medications.
By Jason Marsack, PhD
Dr. Marsack completed a PhD in Physiological Optics and Vision Science at The University of Houston, College of Optometry. His research interests include optical aberration of the eye, custom and pseudo-custom correction of optical aberration, visual performance, metrics predictive of visual performance, and ocular drug delivery.
Like medications taken by mouth, eye drops place the burden of treatment plan compliance in the hands of patients. However, instilling eye drops can present a unique compliance challenge compared to taking medications orally.
The Problem With Eye Drops
Yeaw et al (2009) reported on treatment plan adherence of new patients for six drug classes, one of which was medication for treating glaucoma delivered through eye drops. They reported that the glaucoma group had among the lowest adherence rates of those studied. Twelve-month adherences rates were only 37 percent in the glaucoma group, surprising considering the severe nature of vision loss associated with uncontrolled glaucoma.
They hypothesized that the low adherence may be due in part to the mode of drug delivery—eye drops—and reported that patients may be more likely to forget to instill their eye drops compared to those taking orally ingested medication. With oral medications, a patient may have multiple pills to take in a day, with each pill acting as a subtle reminder to ingest other pills. In a study examining patient noncompliance, Rees et al (2010) reported that unintentional (forgetfulness) and intentional (concern about medications) factors both influence non-adherence.
Many strategies have attempted to improve compliance, such as increased patient education, reminder devices, devices to assist with drop instillation, etc. However, a systematic review by Waterman and coauthors (2013) of 16 studies reported that to date, these regimens offer mixed results. Furthermore, a study by Beckers et al (2012) of three such methods to improve adherence to a glaucoma medication regimen delivered through eye drops reported that patients believe that they are more adherent to medication regimens than they actually are. This belief may reduce patients’ perceived threat of noncompliance because in their minds, they are compliant.
Delivering ocular drugs via soft contact lenses loaded with therapeutic agents is clinically appealing and could address issues related to noncompliance. Several lines of investigation are currently assessing a variety of evolving delivery mechanisms for a wide range of ocular therapeutics.
Methods of Contact Lens Drug Delivery
Across the spectrum of potential delivery mechanisms currently under investigation to facilitate drug delivery from contact lenses, the functional goal is the same: to control the release rate of the drug and to regulate its availability at the ocular surface. From a drug delivery standpoint, success of the release mechanisms will require consideration of the structure of the drug being delivered, requirements/dosing regimen of the treatment plan, and individual patient constraints. This article will briefly describe the individual mechanisms of a sub-set of four different techniques currently under investigation for lens-mediated drug delivery.
Diffusion Early on, the idea for utilizing contact lenses in drug delivery was envisioned as simple diffusion from a soft contact lens that had been soaked in the drug. Karlgard and coauthors (2003) performed a comparison of release characteristics for five p-HEMA contact lens models and two silicone hydrogel lens models that were commercially available. The investigators soaked the lenses in four representative ocular medications (two anti-allergy, one nonsteroid anti-inflammatory, and one steroid) and then placed them in release solution. The results demonstrated that drug uptake and release were influenced by factors associated with both the drug and the lens material, but that in general (one drug excluded), drug release was rapid.
This and similar work demonstrates that use of native, drug-soaked lenses does not fully alleviate the dosing problems associated with eye drops and suggests that modification to the native lens material may be necessary to implement a mechanism that can deliver the drug at the correct dosage over time. Research is focused on such alterations to the contact lens, allowing greater control in delivery. As the native, drug-soaked lens released medication too rapidly, these novel approaches attempt to control the drug delivery process by creating additional barriers to drug release from the lens, such that the drug will be delivered more consistently to the ocular surface.
Molecular Imprinting White and Byrne (2010) describe the process of molecular imprinting in the following way: “a polymer synthesis technique exploiting template-mediated polymerization mechanisms to produce synthetic macromolecular networks with tailored affinity, capacity and selectivity for a template molecule.”
This technique results in locations within the lens matrix where the drug can bind to the lens material. These pockets (commonly referred to as memory) are created with template particles during the polymerization process. When worn on the eye, the drug releases from the lens at a reduced rate compared to the case of simple diffusion due to the increased affinity of the drug with the lens material at the binding sites. White and Byrne (2010) explained that the drug delivery rate in a molecularly-imprinted contact lens is limited by three factors: 1) drug size, 2) lens material mesh size, and 3) interactions between the drug and the lens material.
Using the mechanisms of imprinted therapeutic contact lenses, Tieppo et al (2012) demonstrated an increased drug residence time and constant tear film concentration over a duration of 26 hours in-vivo in a rabbit model. In contrast, the non-imprinted, drug-soaked control lenses showed a rapid release over approximately the first two hours, followed by a steady decline over the next 10 hours.
Surfactants Several additional techniques now under investigation place an additional barrier to drug release within the lens material. One such technique is the addition of surfactant to the lens matrix. Kapoor and coauthors (2009) describe the action of surfactants as follows: “The surfactants can interact with the polymer matrix and form micellar aggregates creating hydrophobic sites inside the gel system where hydrophobic substance will preferentially partition.” Their study described the dispersion throughout the lens of surfactants that have an increased affinity for the targeted therapeutic agents. They reported on bench work with release of cyclosporin A from soft lens materials constructed with several different surfactants at several different concentrations and found that the duration of release can be increased by a factor of 5, as compared to release from the control, pure p-HEMA material.
Recently, Lokendrakumar and coauthors (2013) demonstrated controlled release of drug from commercially available contact lenses that had been modified with a surfactant and then loaded with the drug.
Nanoparticles Another technology that seeks to create an additional barrier to drug diffusion through a contact lens material is the use of nanoparticles. Guzman-Aranguez et al (2013) describe this methodology as follows: “This method is based on incorporation of drug-loaded colloidal particles (nanoparticles, liposomes, microemulsions, etc.) into the matrix of the contact lens. Drug-loaded colloidal particles entrap a large amount of drug, and then are dispersed in the lens matrix during polymerization.”
These particles encapsulate the drug and are themselves encapsulated within the larger bulk of the lens material, with the nanoparticle shell acting as a protective barrier during manufacture (Guzman-Aranguez et al, 2013). Once formed, the nanoparticle serves a second purpose as an impediment to drug delivery, slowing the rate of drug release from the lens. The drug must diffuse across both the nanoparticle shell and through the bulk lens material to reach the ocular surface.
Gulsen and Chauhan (2004) demonstrated that drops of stabilized oil-in-water microemulsions in p-HEMA gels provided release over a period of eight days under controlled, bench conditions. The drug release demonstrated in this study had a two-phase release profile, with approximately 50 percent of the drug being released in the first few hours followed by slower release over days. When extrapolated to the constraints associated with a typical contact lens, the authors state that this method would store enough drug in the lens for release over three to four days.
Jung and coauthors (2012) recently reported on nanoparticle-loaded extended wear contact lenses for the delivery of glaucoma medication. Their experiments showed that at room temperature, the drug can be delivered at therapeutic doses for approximately one month. The authors went on to demonstrate that the system was effective at lowering intraocular pressure in-vivo in Beagle dogs, but cautioned that future studies in larger animals are needed to further demonstrate safety and efficacy.
Challenges Associated With Delivering Drugs via Contact Lenses
In examining the literature, several challenges are commonly identified with delivery of drugs via contact lenses (Bengani and Chauhan, 2012; Sheardown, 2012). Notable among these, when contact lenses are modified from single-purpose devices (refractive correction only) to a combined device (refractive correction and drug delivery), several factors must be considered for the lens to be viable, regardless of the drug delivery mechanism. Clinical suitability is predicated on the assumption that the addition of the drug delivery mechanism will not impede its ability to act as a refractive lens and that it will continue to satisfy basic physiological requirements for prolonged, safe wear. Investigators have identified and are now examining several factors of importance in this topic, including toxicity, optical transmittance, oxygen permeability, protein aggregation, lens comfort, and lens wetting. Simply put, drug delivery from a contact lens must be accompanied by continued satisfactory visual performance and ocular health.
From a practical standpoint, contact lenses have a fairly small volume, and the volume of the lens imposes a fundamental limit on the amount of drug that it can hold. Related to volume, the mechanism utilized to input the drug into the lens, and the mechanisms developed to reload (if possible) more drug into the contact lens over time, may dictate the suitability of the lens for drug delivery.
Potential Benefits of Delivering a Drug via Contact Lenses
The over-arching advantages of delivering ocular therapeutics via contact lenses are increased availability of the drug at the ocular surface and convenience. Time-mediated delivery from a contact lens may ameliorate the unintentional nonadherence discussed by Rees and coauthors (2010). This does assume that patients comply with wearing the contact lenses, which would be less problematic for habitual contact lens wearers who rely on their contact lenses for refractive correction than for emmetropes or habitual spectacle wearers. But even in the latter two cases, the compliance issue is altered from a problem of remembering to instill medication to remembering to wear the contact lenses. And controlled, constant release of drug at the ocular surface via a soft contact lens would provide a mechanism for continual drug delivery as long as the lens is being worn.
On the Horizon
The potential for using soft contact lenses to deliver drugs to the ocular surface is an exciting example of a single device simultaneously addressing two significant problems for patients (refractive correction and drug application). When might such lenses be available for general use? Current research is demonstrating techniques that provide controlled release of drugs from contact lenses over more therapeutically relevant time courses. A wide range of drug delivery mechanisms is under investigation for administration of a wide range of drugs (some of which I’ve described here). Given the evidence in the literature, at least for a sample of drugs, the answer may be “perhaps relatively soon.” CLS
I would like to thank Ms. Suzanne Fermier for support in obtaining reference material for the article.
For references, please visit www.clspectrum.com/references.asp and click on document #213.