LENSES & DRUG DELIVERY

Ophthalmic Drug Delivery Through Contact Lenses

Contact lenses could alleviate patient noncompliance and offer a more efficient drug delivery system.

Anuj Chauhan is a professor and the director of the Graduate Programs in Chemical Engineering at the University of Florida. He is also an adjunct faculty member in the Department of Ophthalmology at the University of Florida. He received a BTech degree in Chemical Engineering from Indian Institute of Technology, Delhi, India, and a PhD in Chemical Engineering from the City University of New York. He has received research funding from Alcon.

By Anuj Chauhan

While eyes are one of the most accessible organs in a human body, ophthalmic drug delivery remains a challenge. Most anterior segment diseases are treated through eye drops, which are an inefficient vehicle for drug delivery due to the rapid clearance of the instilled fluid through canalicular drainage.

Even during the brief residence time in tears of about five minutes, the drug molecules can diffuse both into the cornea and into the conjunctiva. Most of the drug diffuses into the conjunctiva because of its much larger area compared to the cornea, and the drug is then carried into the systemic circulation. The canalicular drainage and conjunctiva uptake account for about 95 percent to 99 percent of the instilled drug, and thus only about 1 percent to 5 percent reaches the target tissues in the anterior eye (Bourlais et al, 1998).

The systemic uptake of the drug can sometimes lead to side effects, thus limiting the amount of drug that can be delivered to the eyes. The rapid clearance of the drug sometimes necessitates instillation of multiple eye drops each day, leading to reduced patient compliance. Further-more, the difficulties of instilling eye drops lead to variations in the mass of the drug reaching the target tissue, further reducing compliance with the desired pharmacokinetic drug profiles.

In spite of all these problems, eye drops continue to be the mainstay of ophthalmic drug delivery because most other replacements could not overcome the limitations of eye drops.

An Optimal Delivery System

An optimal delivery system for the anterior cornea should deliver a large fraction of the drug payload to the cornea. Because the area of the conjunctiva is much larger than that of the cornea, delivery of a larger fraction to the cornea necessitates a device that is preferentially located closer to the cornea. The only device that satisfies this requirement is a contact lens, which sits on the cornea, separated by a thin post-lens tear film of about 2 to 3 micron thickness (Figure 1).

Because of limited tear mixing between the post-lens tear film and the remaining tear fluid, drug molecules released from the contact lens into the post-lens tear film diffuse into the cornea, eventually reaching the target organs. The contact lens also releases the drug into the pre-lens tear film, but the rapid breakup of the film after each blink minimizes this fraction. Consequently, at least 50 percent—and likely as much as 70 percent—of the drug payload of a contact lens diffuses into the cornea, a vast improvement compared to eye drops. The high bioavailability of contact lenses requires use of much less drug amounts, which would lead to cost savings and, more importantly, to reduced systemic drug exposure.

A few recent animal studies conducted by our group in a Beagle dog model of glaucoma demonstrated that contact lenses can achieve the same amount of intraocular pressure (IOP) reduction as eye drops, even though the lenses contained only about one-sixth of the drug loaded in the eye drops.

Figure 1. Schematic illustrating the placement of a contact lens over the cornea.

Other Benefits of Contact Lenses for Delivering Drugs In addition to the significant increase in bioavailability, contact lens use for delivering ophthalmic drugs will likely improve patient compliance. Lack of patient compliance is a major problem, particularly for chronic diseases and also for diseases that require several eye drops to be instilled each day. A daily wear contact lens could be designed to release the drug for the entire day or an extended wear contact lens could be designed to release it for several days. Thus, a single lens application would be adequate for therapy. Additionally, contact lenses can correct vision while they deliver ophthalmic drugs, which makes drug-eluting lenses ideal for patients who require drug delivery in addition to vision correction.

Improved pharmacokinetics is another potential benefit of using contact lenses for drug delivery. When drugs are delivered through eye drops, the drug concentration in the target tissue increases after instillation, but then begins to decrease due to the clearance mechanisms. There are thus periods of non-therapeutic tissue concentrations in between two successive eye drop instillations. A contact lens can deliver the drug continuously at a reasonably constant rate, which could perhaps lead to improved drug efficacy. Use of drug-eluting contact lenses would also eliminate the need for preservatives that are known to cause corneal toxicity.

Challenges in Designing Drug-Eluting Contact Lenses Contact lenses were first explored as potential drug delivery devices a few decades back, but a commercial product was never developed because of the challenges in designing a drug-eluting lens without sacrificing key lens properties including transparency, modulus, ion and oxygen permeability, etc.

The drug release durations from contact lenses depend on both the drug and the lens properties. Generally, silicone hydrogel lenses release hydrophobic drugs for longer durations due to stronger binding with the polymeric network (Peng et al, 2012). The release duration from commercial contact lenses is only a few hours or less for several ophthalmic drugs in the size range of 300 to 500 Dalton. The release duration can be considerably longer for hydrophobic molecules with larger molecular weight such as cyclosporine, which can be released for a few weeks from silicone hydrogel lenses. If the release duration is only a few hours, contact lenses are not optimal for extended drug delivery lasting an entire day to possibly weeks. Extended drug release durations are critical because otherwise multiple contact lenses may be required each day, which will increase cost and reduce compliance.

Approaches for Increasing Drug Release Duration from Contact Lenses

The last decade has seen a renewed interest in using contact lenses for drug delivery, and researchers have used several approaches to increase the release duration of drugs without impacting other properties.

Molecular Imprinting This approach illustrated in Figure 2 is based on the attempt to mimic the “lock and key” interaction between an enzyme and its substrate by creating cavities in the contact lens that have a very high affinity for the drug molecule. To create the high-affinity pockets, the drug is added along with one or more functional monomers to the polymerization mixture followed by curing. During polymerization, the functional monomers assemble around the drug and are then frozen in that arrangement due to crosslinking during polymerization. The drug along with the unreacted monomers is then extracted from the lens, leaving behind a lens containing cavities that have recognition for the drug. The drug can then be reloaded into the lens by soaking in the drug solution. The high-affinity pockets increase the overall partition coefficient of the drug and also slow the transport because the drug bound to the cavities is not available for diffusion. As the free drug diffuses out of the lens, the bound drug desorbs to maintain equilibrium with the free drug and then diffuses.

The net effect of the drug binding to the imprinted pockets is reduced effective diffusivity, which leads to an increase in the total release duration from the contact lenses. Molecularly imprinted lenses have been designed for extended release duration of several drugs including timolol, norfloxacin, ketotifen fumarate, and comfort enhancers such as hyaluronic acid. Most of the molecular imprinting studies have focused on hydrophilic hydrogel lenses, which are suitable only for daily wear lenses (Hiratani and Al-varex-Lorenzo, 2004; Venkatesh et al, 2007).

Figure 2. Schematic illustrating the concept of using molecular imprinting to increase drug partitioning and to retard drug transport.

Animal studies were conducted in rabbits with timolol-imprinted soft contact lenses consisting of N,N-diethylacrylamide, methacrylic acid, and ethylene glycol dimethacrylate (Hiratani et al, 2005). The imprinted contact lenses provided measurable timolol concentrations in the tear fluid for 2.0- and 3.0-fold longer than did the non-imprinted contact lenses and eye drops, respectively. Also, the area under the timolol concentration-time curve (AUC) was 3.3- and 8.7-fold greater for imprinted lenses than for non-imprinted contact lenses and eye drops, respectively.

Nanoparticle-Loaded Contact Lenses Nanoparticles can be dispersed into contact lenses without impacting vision due to their small sizes, which eliminates scattering of visible light. The nanoparticles could be designed to have a high affinity for the drug by tailoring the hydrophobic or the ionic inter-actions of the drug with the particle matrix (Figure 3). The increased affinity for the particles increases the partition coefficient and also reduces the effective diffusivity because the drug partitioned in the particles cannot directly diffuse. In most cases the drug concentration in the particles is in dynamic equilibrium with the contact lens matrix. Thus, the fundamental mechanism for attenuating the drug release rates with nanoparticles is similar to that for molecular imprinting.

There is a large body of literature on synthesis of nanoparticles for drug encapsulation, and so there is significant flexibility in choosing the optimal nanoparticles to incorporate in the contact lenses. Researchers have successfully dispersed microemulsions, liposomes, cyclodextrins, and polymeric nanoparticles in contact lenses for extended delivery of several drugs including timolol, cyclosporine, diclofenac, etc. (dos Santos et al, 2009; Gulsen and Chauhan, 2004; Jung and Chauhan, 2012; and others. For complete list see www.clspectrum.com/references.asp). The release durations can be increased from a few hours to possibly as long as a few weeks, depending on the choice of the drug and the nanoparticles.

Highly crosslinked polymeric nanoparticles loaded with timolol were dispersed in hydroethyl methacrylate-based lenses and also in silicone hydrogels to obtain release durations of about a month (Jung and Chauhan, 2012). Also, cyclosporine was encapsulated in micelles and microemulsions to develop lenses for extended delivery lasting longer than a month (Kapoor et al, 2009; Kapoor and Chauhan, 2008). Recently, ionic surfactants were utilized to increase the release duration of dexamethasone phosphate to a few weeks (Bengani and Chauhan, 2012).

While nanoparticle incorporation is a flexible approach, it needs to be modified depending on the drug of interest. Furthermore, the sequential approach of first preparing the nanoparticles, then adding the polymerization mixture, followed by lens curing could be tedious. Also, some nanoparticles could get destabilized during polymerization. An alternate, but similar approach is based on adding the surfactant to the polymerization mixture. The surfactant self-assembles into aggregates such as micelles or vesicles during polymerization, and hydrophobic drugs could be partitioned in the hydrophobic regions of these aggregates. Alternatively, ionic drugs could interact with the head group of the ionic surfactants to increase the partitioning, thereby reducing the effective diffusivity.

Figure 3. Schematic illustrating the concept of using nanoparticles in contact lenses for extended drug delivery.

Surfactant-loaded contact lenses have been designed for extended release of cyclosporine and dexamethasone phosphate. The surfactant loaded into the lenses could potentially diffuse during lens wear as well, but the rate of surfactant release could be minimized by tailoring the interactions of the surfactant with the contact lens matrix.

Animal studies were conducted with nanoparticle-loaded contact lenses in Beagle dogs to show that extended release of timolol could significantly reduce IOP for about four days (Jung et al, in press). There was a good correlation between the in vitro release rates and the in vivo IOP reduction.

Contact Lenses With Nanobarriers All approaches previously described have to be tailored to the specific drug of interest. An approach that could be applicable to many drugs would be useful as it could reduce the developmental work required for commercialization and could allow simultaneous extended delivery of multiple drugs from the same lens.

Chauhan and coworkers have developed extended wear contact lenses loaded with nanobarriers of vitamin E to facilitate extended delivery of several ophthalmic drugs. Vitamin E is very hydrophobic, so ionic drugs are forced to diffuse in a tortuous path around the vitamin E barriers, leading to an increase in the effective path length that in turn increases the release duration (Figure 4). Because the mechanism for increasing the release duration is purely an increase in path length, the relative increase in the release duration is identical for all hydrophilic drugs. Vitamin E is particularly effective at increasing drug release durations because of a quadratic relationship between vitamin E loading and drug release durations, i.e., a two-fold increase in vitamin E loading leads to a four-fold increase in drug release duration. This quadratic dependency is a characteristic of the “barrier-effect” because the barriers act by increasing the diffusion distance and diffusion time increases as square of the diffusion distance. Silicone hydrogel contact lenses loaded with vitamin E have been shown to significantly increase the release duration of several ophthalmic drugs including timolol, dexamethasone phosphate, fluconazole, and cysteamine (Peng et al, 2010). For each of the drugs, vitamin E loadings of 10 percent and 40 percent increase the release time of the hydrophilic drugs by a factor of about 5 and 400, respectively. The hydrophobic drugs can partition into the vitamin E barriers, but that transport is also attenuated due to the high viscosity of vitamin E. The vitamin E-loaded lenses are also shown to be effective at extended delivery of several hydrophobic drugs including dexamethasone and cyclosporine (Kim et al, 2010; Peng and Chauhan, 2011).

The vitamin E-loaded lenses have been extensively characterized to measure the effect of vitamin E incorporation on transparency, ultraviolet blocking, haze, oxygen and ion permeabilities, modulus, protein binding, water transport, and drug transport. Most of the properties improve with vitamin E incorporation except oxygen and ion permeabilities, which both decrease but are still adequate for extended wear applications (Peng and Chauhan, 2010).

In vivo animal studies were conducted in Beagle dogs to show safety and efficacy of vitamin E-loaded contact lenses for glaucoma therapy (Peng et al, 2012). The study, which focused on daily replacement of vitamin E-loaded drug-eluting contact lenses, showed that the contact lenses can be worn safely and achieve IOP reduction comparable to eye drops.

In the next study, lenses were designed to release drug for four days, and this study proved that continuous wear of the vitamin E-loaded contact lenses is also safe and can lower IOP during the entire wear duration (Peng et al, 2012). Eye drops administered daily can also reduce IOP, but the amount of drug delivered through the eye drops is about six times that delivered through the vitamin E-loaded contact lenses. Contact lenses without vitamin E replaced daily can also achieve therapeutic IOP reduction, but if lenses without vitamin E are worn for four days there is no significant IOP reduction after the second day (Peng et al, 2012).

Figure 4. Schematic illustrating the concept of using transport barriers (yellow ellipses) to retard drug (red circles) transport.

The release profiles of ophthalmic drugs could also be controlled by designing a sandwich contact lens comprised of PLGA (poly[lactic-co-glycolic acid]) coated by pHEMA (poly[hydroxyethyl methacrylate]) films on both sides. Several compounds could be loaded into the PLGA layer and released for extended periods at relatively zero-order release rates. These lenses have not been tested in animals, but extended release of ciprofloxacin has been shown to inhibit ciprofloxacin-sensitive Staphylococcus aureus (Ciolino et al, 2009).

Future Challenges and Opportunities

In spite of the potential benefits of contact lenses for drug delivery, no such product has been commercialized. There are major hurdles to commercialization including processing and storage issues, regulatory issues, high costs of clinical studies, and cost-benefit analysis. To successfully address these challenges, it is critical to identify the diseases that benefit the most by contact lens-based drug delivery. Diseases that require a very high frequency of eye drop instillation are particularly suited for contact lens-based therapies (e.g. infections and cystinosis). Also, drugs that are highly efficacious but also have side effects could be suitable for delivery by contact lenses (e.g. beta blockers and fluoroquinolones).

Patients who prefer to use contact lenses for vision correction could be excellent candidates for lens-based therapy. Dry eyes, corneal injury, glaucoma, and cataract prevention are some other indications that might be suited for contact lenses. There are also several niche applications such as drug delivery after cataract surgery or intravitreal injections that could be successfully implemented through contact lenses.

A phase III study on release of ketotifen fumarate for allergy treatment was recently completed, which is proof of the growing interest in using drug-eluting contact lenses for treating ophthalmic diseases (http://clinicaltrials.gov/ct2/show/NCT00446056). This study has helped lay down the potential landscape for the regulatory route for future products based on drug-eluting contact lenses.

Drug-eluting contact lenses are currently classified by the U.S. Food and Drug Administration as “Combination Products,” which has raised the regulatory hurdle for commercialization. Additional issues that may play an important role in getting these products to market concern the cost that patients or insurance companies are willing to pay. It is also not clear whether drug-releasing contact lenses are suited to be sold in pharmacies or directly by healthcare professionals such as ophthalmologists and optometrists.

Summary

In summary, contact lenses could potentially alleviate several problems associated with delivery of drugs by eye drops. Contact lenses offer a significant increase in bioavailability and potential improvements in efficacy due to improved pharmacokinetics. It may also be possible to achieve improved compliance, particularly for patients who also require contact lenses for vision correction.

There are still several technical, regulatory, and market-related issues that pose hurdles to commercialization, but based on the growing interest from both researchers and industry in drug-eluting contact lenses, it should only be a matter of a few years before we see multiple products based on treating diseases with contact lenses. CLS

For references, please visit www.clspectrum.com/references.asp and click on document #204.