Wednesday, April 6, 2011

New Insights into Ophthalmic Drug Delivery

By Neil Canavan
New Insights into Ophthalmic Drug Delivery
Drug delivery to the eye might seem simple because it is a readily accessible target. However, the structure, function, and biochemistry of the eye render it highly impervious to foreign substances.
The barriers to drug penetration and retention represent significant therapeutic challenges met by less-than-optimal methods. Topical administrations, which often require frequent applications over indefinite periods of time, or direct injection of a drug, which risks adverse events related to the procedure, represent profound obstacles to patient compliance. Noninvasive, depot, and/or targeted therapies are needed. (For a detailed discussion of ocular dynamics in relation to drug delivery, see Das and colleagues.1)

Innovation Starts to Gel

Recently improved topical solutions are gels, used to treat outer-eye infections or irritations. This advance addresses issues of patient comfort—compared with ointments—and greater drug retention relative to liquid drops. These new viscous preparations may be made up of polysaccharides, carbomers, cellulose derivatives, and recently, hyaluronic acid. Optimization efforts for this approach include the addition of tamarind seed polysaccharide to hyaluronic acid, which, in one investigation, was found to result in a 3/2 synergistic enhancement of either extra- or intra-ocular drug availability.2
Hyaluronic acid has also been used in the preparation of dexamethasone nanoparticles intended for intravitreal delivery. Devising a method for enhanced drug entrapment, Gomez-Gaete and colleagues spray dried 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, hyaluronic acid, and different concentrations of dexamethasone-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticle suspensions, producing a so-called Trojan particle.3 In vitro studies of Trojan demonstrated a depot drug release profile, which the investigators hypothesized stems from the properties of the excipient matrix and surface irregularities of the resultant spherical particle.
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Case study: Iontophoresis to the Fore

Iontophoresis, a process long used for transdermal drug delivery, has only recently been adapted for ocular use. “Prototypes of the current model were first created by the ophthalmic scientist David Maurice,” according to Michael Patane, PhD, chief scientific officer, Eyegate
Pharmaceuticals, Waltham, Mass. “Then Jean-Marie Parel, a biophysical engineer at the Bascom Palmer Eye Institute, designed versions of an applicator to encompass the drug and the electrode (for ocular use).”
EyeGate Pharma’s corticosteroid EGP-437. The system, in Phase III trials, delivers drug with a special applicator.
The current optimized device addresses effectiveness of delivery and, perhaps more importantly, patient comfort.1-2 With this successful clinical translation, Dr. Patane and colleagues set out to validate the process for ocular drug delivery, specifically to characterize transport-structure relationships dependant on permeability and selectivity
differentials. Using rabbit sclera, Dr. Patane looked at the electro-transport of model compounds of neutral, cationic, and anionic charges. The transport of vancomycin, a structurally complex positively charged glycopeptide antibiotic, was also explored.3
Having established efficacy of transport—at superior concentrations as compared with eye drops—investigation continued with a focus on antibiotics alone, with EyeGate’s device highlighted in two poster presentations at the 2010 Association for Research in Vision and Ophthalmology meeting. The first investigation used mounts of ocular tissue in in vitro studies. Data collected for these comparisons of electro-transport vs. passive diffusion (a topical eye drop) for six antibiotic drug classes were then correlated with values observed in anesthetized rabbits. Results showed marked differences in transport rates between molecules of like charge and a lesser efficacy overall for cathodic delivery. This suggested the need for protocols tailored to the given agent to be transported. Also demonstrated was the ability of iontophoresis to push drug into the anterior chamber and the vitreous humor of the posterior segment, suggesting this method could replace the need for some ocular injections.4
The special applicator that delivers EyeGate Pharma’s corticosteroid EGP-437.
The special applicator that delivers EyeGate Pharma’s corticosteroid EGP-437.
A second poster discussed a phase 1/2, randomized, dose-ranging study of an iontophoresis-optimized formulation of dexamethasone (EGP-437) in patients with non-infectious anterior uveitis. Results of this trial established an optimum dosing charge of 1.6mA-min at 0.4mA over four minutes, for which a resolution of infection was observed in as few as two weeks after a single treatment—a treatment that did not cause an elevation in intraocular pressure typically seen with standard-of-care injections.5
As progress continues toward the first iontophoresis ocular indication,
Dr. Patane and colleagues are working on the transport of proteins and further device optimization. “We need to trim the reservoir and enhance the buffering capacity of the system. Right now we’re loading almost 0.5 ml of drug product,” which is fine for an antibiotic. But to reach the holy grail of
penetrating the posterior segment to treat macular degeneration, loading 0.5 ml of a drug like Lucentis would be cost-prohibitive.


  1. Behar-Cohen FF, El Aouni A, Gautier S, et al. Transscleral Coulomb-controlled iontophoresis of methylprednisolone into the rabbit eye: influence of duration of treatment, current intensity and drug concentration on ocular tissue and fluid levels. Exp Eye Res. 2002;74(1):51-59. Available at: Accessed February 12, 2011.
  2. Hughes L, Maurice DM. A fresh look at iontophoresis. Arch Ophthalmol. 1984;102(12):1825-1829. Available at: Accessed February 12, 2011.
  3. Güngör S, Delgado-Charro MB, Ruiz-Perez B, et al. Trans-scleral iontophoretic delivery of low molecular weight therapeutics. J Control Release. 2010;147(2):225-231. Available at: Accessed February 12, 2011.
  4. Ruiz-Perez B, Dowie T, Schubert W, Isom P, Moslemy P, Patane M.. A non-invasive ocular drug delivery system that delivers substantially greater antibiotic levels than topical administration. Abstract presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 6, 2010; Fort Lauderdale, Fla. Abstract #5713. Available at: Accessed February 13, 2011.
  5. Patane MA, Cohen A, Sugarman J, From S. Randomized, double-masked study of four iontophoresis dose levels of EGP-437 in non-infectious anterior segment uveitis subjects. Abstract presented at: Association for Research in Vision and Ophthalmology Annual Meeting; May 6, 2010; Fort Lauderdale, Fla. Abstract #5263. Available at: Accessed February 13, 2011.
Indeed, the promise of a nanoparticle approach is being aided by collaborations between the physiochemical bench and the bedside. A case in point: the co-development of a depot functioning, biodegradable delivery system by Tueng Shen, MD, associate professor of ophthalmology, and Buddy Ratner, PhD, a biomaterials pioneer and professor of bioengineering and chemical engineering, both at the University of Washington, Seattle.
“Dr. Shen related to me a need for such a polymer,” said Dr. Ratner. “My group had been working with the NIPAM (N-isopropyl acrylamide) polymer, a thermosensitive material. But it wasn’t degradable. Then, recently, we developed a strategy to make another well-known biostable polymer into a degradable form. We applied this strategy to the polyNIPAM.”4 The result is a biodegradable particle that self-constructs at body temperature after injection into the eye.
“The injectable is a viscous liquid, and when it hits a 37 degrees C surface (the body), it becomes a solid,” Dr. Ratner said.
Over time, via hydrolysis and possibly enzymatic activity, the polyNIPAM solid breaks down into minute, oligomer fragments that are soluble and nontoxic and can be cleared by the kidney. In principle, according to Dr. Ratner, any molecule can be carried in the polyNIPAM. It is electrically neutral and can accommodate hydrophobic molecules if they are emulsified. For varied depot formulation needs, the degradation time of polyNIPAM can be tuned from days to months.
To demonstrate proof of principle for this sustained ocular drug delivery strategy, Drs. Ratner, Shen, and colleagues incorporated the antibiotic norfloxicin within polyNIPAM. For in vivo assays using 3T3 NIH cells, spectrophotometry revealed that the polymer-drug solution exhibited rapid reversible phase transition at body temperature from liquid to solid, and that after an initial burst of drug release over 48 hours, gradual release persisted over two weeks. Results of in vivo rabbit studies were consistent with these observations, while at the same time exhibiting no significant toxicity. The investigators concluded that the delivery platform has the potential to be customized for a wide range of ocular treatment needs.5

Eye Cells, Micelles

No less exotic than phase-shifting polyNIPAM are drug encompassing micelles, developed by Ashim Mitra, PhD, vice provost for interdisciplinary research and director of translational research at the University of Missouri-Kansas City, in collaboration with Lux Biosciences of Jersey City, N.J. The project began with the goal of developing a formulation for treating dry-eye symptoms caused by an inflammatory response, and the drug candidate under consideration was voclosporin, a novel immunosuppressive compound.6 “My idea was to develop a topical aqueous eye drop,” said Dr. Mitra, “but it’s very difficult to do that because voclosporin is completely water insoluble—like a brick.” Dr. Mitra decided to try to deliver it in an outwardly hydrophobic, inwardly hydrophilic micellular package.
Once in the choroidal area, says Dr. Mitra, micelles reach the Bruch’s membrane, fuse with it, and release the therapeutic cargo.
The resulting mixed nanomicelles comprise two non-ionic surfactants, D-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) stabilized with octyl phenol ethoxylate (octoxynol-40) in a defined ratio.7 “This is a highly stable particle and is not temperature or pressure sensitive,” said Dr. Mitra, adding that it has a shelf life as long as two years. The stability of the drug formulation, now known as LUX 214, was not entirely unexpected. However, during pharmacokinetic (PK) studies of topical administration in a rabbit model, the micelles exhibited rapid voclosporin distribution in both the anterior and, much to Dr. Mitra’s surprise, the posterior ocular segment.8
“We found that a reasonable quantity of drug—higher than therapeutic levels—are achieved in retina and on the choroid in the back of the eye,” said Dr. Mitra. “We never expected that. With cyclosporine you don’t see that.” Other laboratories later validated these observations. In explaining the mechanism, Dr. Mitra has surmised that the drug is traversing a conjunctival, scleral pathway to the back of the eye. “We see very little drug in the vitreous humor.” Once in the choroidal area, micelles reach the Bruch’s membrane, fuse with it, and release its therapeutic cargo into the cell.
This observation is tantalizing to Dr. Mitra, as it may be the answer to the elimination of some, if not all, ocular injections. Such an application is not a near-term goal, however. In focus for the moment is the recent clinical data for LUX 214, a first-in-man study of 25 healthy individuals and five subjects with keratoconjctivitis sicca (KCS), which demonstrated overall safety of the voclosporin formulation, and, though not controlled or powered for significance, a documented improvement in both sign and symptom for the KCS cohort.
Progress in ocular drug delivery is somewhat reined in by lack of accurate PK measures. Attaining drug levels in the various compartments of the eye is problematic at best. Dr. Mitra is eager to at least provide would-be formulators with methods for drug detection in ocular delivery in rabbits without the need to sacrifice the animal; recent approaches include LC-MS/MS and microdialysis.9-10


  1. Das S, Suresh P. Drug delivery to eye: special reference to nanoparticles. Int J Drug Deliv. 2010;2:12-21.

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