With this month’s focus on the topic of research, it seemed an appropriate time to dedicate this column to summarizing some new ocular drug delivery technologies that are on the horizon.

These systems have the potential to revolutionize the way that drugs are delivered—particularly to the anterior segment. Anterior portions of the eye can be reached relatively easily by topical administration but, of course, this method of delivery typically comes with many limitations.

Most medications delivered to the eye tend to come in the form of eye drops. When an eye drop is instilled, bioavailability of the drug suffers. In fact, only approximately 1-5% of the drug is actually absorbed into the eye.¹

The ideal eye drop volume is approximately 5-10 microliters, but most eye drop bottles deliver 30-50 microliters. Most of this volume quickly drains into the nasolacrimal system, although some will spill out onto the lower lid.

This limitation makes eye drops a very inefficient and imprecise method of drug delivery. As such, eye drops require frequent dosing, which is often burdensome for many patients, resulting in poor adherence and persistence.

A number of novel drug delivery systems in various stages of development are being investigated to improve upon these limitations. Some include use of contact lenses, biodegradable polymers, liposomes, iontophoresis, nanoparticles and gene delivery systems.²

These newly developed delivery systems offer patients a number of advantages over topical administration: higher bioavailability, reduced dosing and improved patient adherence.

Iontophoresis
Iontophoresis allows ionized drug molecules to be moved across a biological membrane under the influence of an electrical current. This technique has applications for both anterior and posterior segment drug delivery. The Down on the Pharm column in the October 2013 issue of Review of Cornea & Contact Lenses contains a detailed discussion of this exciting new technology.

Liposomes
Liposomes are vesicles that consist of an aqueous core that is surrounded by an outer phospholipid bilayer. Liposomes are both biodegradable and biocompatible, and are delivered conveniently like an eye drop. They differ from eye drops in their ability to provide a sustained and controlled release of the drug they carry.

These vesicular systems can enhance penetration of poorly absorbed drugs, not only by encapsulating hydrophobic and hydrophilic drugs, but also by binding to the corneal surface, which leads to increased retention time (varies greatly per liposome formulation).

Liposomal formulations are currently being studied in a wide variety of drug classes, including antibiotics, anti-inflammatory drugs and glaucoma medications. Liposomal vesicles containing acetazolamide demonstrated the ability to provide sustained IOP lowering effects in a rabbit model lowering IOP up to 8mm Hg.^3-5

Contact Lenses
Currently, there are several strategies being developed to use contact lenses as a drug delivery system. For example, soaking a preformed contact lens in a wide variety of drugs has been investigated.

A study by Li et al. demonstrated that at least 20% of timolol that was loaded into a soft contact lens by soaking entered the eye, which is a significantly higher amount than the uptake from an eye drop.⁶ This higher bioavailability has been demonstrated in vitro and in vivo.

The initial drug loading into a contact lens depends on numerous factors, such as the water content, lens thickness, drug molecular weight and drug solubility. Soaking a drug in a preformed lens does not provide sufficient binding of the drug to the lens material to allow for the desired sustained release. While this method typically provides a greater degree of bioavailability of the drug than is observed with eye drops, the release of the drug occurs quickly and fails to provide a sustained release system.^6-7

Copolymerization of the contact lens hydrogels with monomers (e.g., methacrylamide propyltrimethylammonium chloride) that are able to interact with the drug is another method that is currently being evaluated. These monomers serve as binding points for the drug molecules.

Nonsteroidals, such as ibuprofen and diclofenac, have successfully been loaded into such lenses, and have demonstrated the ability to release the drug for up to a week.

Another method being evaluated involves incorporating drug-loaded colloidal particles, such as liposomes or nanoparticles, directly into the matrix of the contact lens during polymerization. The colloidal particles are encapsulated, which prevents the drug from interacting with the contact lens polymer and thereby possibly becoming inactive.

When the drug is ready to be released, it must first diffuse through the capsule and penetrate to the surface of the hydrogel matrix.

Lidocaine has demonstrated the ability to release in such a manner over a period of seven days. Kapoor et al. studied the release of cyclosporine A, demonstrating therapeutic levels of the drug for a period of approximately 20 days. When liposomes are dispersed in a contact lens, the transparency is slightly reduced from 90% transmittance to 80%.^6,8

A third area of development using contact lenses for drug delivery is molecular imprinting. This complex technology involves arranging the hydrogel contact lens material in a manner that creates high-affinity binding sites for drugs.

Prior to polymerization, the drug is added, and monomers then interact with the drug molecules. After polymerization, drug molecules that have acted as templates are removed. The remaining polymer network results in imprinted, active sites that can then be developed with respect to drug loading and release characteristics.

Timolol has been studied and was released over a period of three days. Transmittance has been shown to be similar to conventional lenses.⁶

Ocular Implants (Punctal Plug Delivery System)
A number of punctal plug delivery systems (PPDS), consisting of a drug-eluting device of several different designs, are currently being investigated by several companies.

QLT, Inc. has been developing and studying a PPDS that consists of a surface punctal plug containing a core of active drug for several years. The technology was sold to Mati Therapeutics of Austin, TX, who plans to continue to pursue this drug delivery system.

The company currently has two formulations that have entered into clinical trials: latanoprost for the lowering of IOP, and olopatadine for the management of ocular allergies. Currently, work is also being conducted to formulate an NSAID into this PPDS. The early designs had some difficulty with punctal plug extrusion, but recent modifications have improved this aspect.

Phase II clinical trials of a PPDS with latanoprost have demonstrated significant lowering of IOP with good patient tolerability, with a mean IOP from baseline at 12 weeks being -5.4mm Hg, -4.8mm Hg and -4.9mm Hg for the low, medium and high concentrations of latanoprost, respectively.

Just recently (October 28, 2013), Mati Therapeutics announced the commencement of a Phase II clinical trial comparing latanoprost-PPDS to timolol eye drops. One hundred patients will be enrolled in this randomized, multi-center trial that will last for 14 weeks.

Ocular Therapeutix is also developing a PPDS, but the plug is of the intracanalicular design, and is resorbed over time, so there is no need for removal. As the plug dissolves, drug is steadily released over time. Over a two-month period, Travoprost sustained-release punctal plugs have demonstrated a reduction in IOP greater than 20%.

The company is also evaluating a corticosteroid to be delivered over a period of four weeks for the management of post-operative pain and inflammation after ophthalmic surgery.

The company’s punctal plug, although intracanalicular, contains a visualization aid for patients and eye care providers to easily monitor retention.⁶

With all of the novel technologies that are currently being tested and investigated, the future of ophthalmic drug delivery is bright. New technologies and innovations provide us with creative methods to deliver drugs more consistently, while at the same time improving convenience for patients. 

1. Novack GD. Ophthalmic drug delivery: development and regulatory considerations. Clin Pharmacol Ther. 2009;85(5):539-543.
2. Eljarrat-Binstock E, Pe’er J, Domb AJ. New techniques for drug delivery to the posterior eye segment. Pharm Res. 2010; 27(4):530-543.
3. Rawas-Qalaji M, Williams C. Advances in ocular drug delivery. Curr Eye Res. 2012;37(5):345-356.
4. Mishra GP, Bagui M, Tamboli V et al. Recent applications of liposomes in ophthalmic drug delivery. J Drug Deliv. 2011; e1-14.
5. Haghjou N, Soheilian M, Abdekhodaie MJ. Sustained release intraocular drug delivery devices for treatment of uveitis. J Ophthalmic Vis Res. 2011;6(4):317-329.
6. Guzman-Aranguez A, Colligris B, Pintor J. Contact lenses: promising devices for ocular drug delivery. J Ocul Pharmacol Ther. 2013;29(2):189-99.
7. Phan C, Subbaraman LN, Jones L. In vitro uptake and release of natamycin from conventional and silicone hydrogel contact lens materials. Eye Contact Lens. 2013;39(2):162-168.
8. Jung HJ, Abou-Jaoude M, Carbia BE, et al. Glaucoma therapy by extended release of timolol from nanoparticle loaded silicone-hydrogel contact lenses. J Control Release. 2013;165(1):82-89.