Corneal Clarity

Update on Ocular Drug Delivery Systems: What’s New and on the Horizon

By Thomas John, MD

In my December column, I reviewed the formidable natural ocular barriers that drug delivery systems must overcome in order to deliver sight-preserving medications to the eye. In this column, we will look at how we meet these therapeutic challenges in the anterior segment.

Topical Still Rules — For Now

Ophthalmic drug delivery systems comprise a long list of therapeutic avenues, yet we are merely using the tip of the iceberg — that is, topical eyedrops and ointments — to treat most anterior segment issues. Topical drug delivery is the most common mode of treating eye diseases. However, once a drop is placed on the ocular surface of the inferior cul-de-sac, the tear film, assisted by the blink reflex, dilutes it and often drains it quickly away from the targeted location, returning to the normal resident volume of about seven.

In this context, to facilitate passive passage via diffusion across the corneal barrier, drug concentration becomes important. Hence, augmented drug absorption needs can accelerate corneal penetration and prolong corneal contact time. Drops (solutions or suspension) are preferred over ointments, because the latter can blur the vision. Drops are convenient, relatively safe, effective and usually well tolerated by patients.

However, other modes of delivery that may be more efficacious have recently arrived or are on the horizon. Let’s examine how those intended for the anterior segment work. The ophthalmic drug delivery systems I will review are:

●  Ophthalmic drops for anterior segment.

●  Cul-de-sac inserts.

●  Therapeutic contact lenses.

●  Punctal plugs.

●  Implants, both subconjunctival and episcleral.

●  Physical devices, such as Iontophoresis.

Ophthalmic Drops For the Anterior Segment

Modifications of eyedrops have been used to increase ocular surface drug residence time or decrease drug elimination, or both, while optimally maintaining clear vision. In recent years, several in situ gel-forming systems such as ion (eg, gellan gum and alginate), pH (eg, Carbopopl, cellulose acetate phosphate), and temperature (eg, Poloxamer) have been shown to sustain ophthalmic drug delivery.^1-3

►  Methylcellulose.  Solutions containing methylcellulose are used as tear substitutes and provide long coverage and protection for the ocular surface.

►  Gellan gum.  Biopolymer gellan is a high-molecular-weight, exocellular bacterial, polysaccharide gum produced as a fermentation product by a pure culture of nonpathogenic Pseudomonas elodea.⁴ It has the salient property of temperature-dependent, cation-induced gelation, forming thermoreversible gels when heated and cooled. It spans the fields of pharmaceuticals, food and environmental bioremediation of contaminated soils. Timoptic XE (timolol maleate, Merck & Co.) contains gellan gum.

►  DuraSite.  This technology incorporates a polymer-based formulation meant to extend drug residence time compared to conventional topical drugs. Polyacrylic acid is cross-linked with divinyl glycol to result in hydrogen-bonding with mucus and the epithelium (corneal and conjunctival), which are negatively charged, and thus extend the drug residence time to hours on the ocular surface. Examples include AzaSite (azithromycin, Merck & Co.) and Besivance (besifloxacin, Bausch + Lomb). Future products may be formulated using the DuraSite 2 platform. Bromfenac in DuraSite is currently being evaluated.

QLT’s investigational punctal plug provides a 90–day supply of IOP-lowering medication.

►  Xantham gum.  This anionic polysaccharide derives from the bacterial coat of Xanthomonas campestris. In TobraDex (tobramycin/dexamethasone, Alcon), the xanthum gum first decreases the viscosity of the suspension via its ionic interaction with tobramycin, and then decreases the sedimentation of dexamethasone particles. However, the viscosity increases on the ocular surface when it comes into contact with tears, where the tear pH and ionic content interrupts the xanthum gum-tobramycin interactions. This increase in viscosity helps increase drug retention and, hence, improves ocular bioavailability of these drugs. It is used as a vehicle in TobraDex ST and Moxeza (moxifloxacin, Alcon).

►  Novasorb.  Nanotechnologies are in the forefront of improving ocular drug delivery systems, although some hurdles still exist in bringing such technologies and their products to market. The Novasorb technology platform uses a novel, cationic, nanoemulsion method for topical drug delivery. Even the cationic emulsion without any active ingredient has shown itself to be of benefit to the ocular surface.⁵ This technology has been tested with cyclosporin A (Cyclokat CyA, Novagali Pharma) for dry eyes and preservative-free latanoprost for glaucoma (Catioprost, Novagali).

Cationorm (Novagali) is a preservative-free, cationic emulsion indicated for dry eye treatment. This example of Novasorb technology has been available in France since 2008. Cationorm is based on electrostatic attraction between the positively charged emulsion and the negatively charged ocular surface; namely, the cornea and conjunctiva. It enhances the absorption of lipophilic drugs, decreases the frequency of drug application, and potentially reduces side effects. NOVA22007, a cationic emulsion containing cyclosporin, is under going study for dry eye and vernal keratoconjunctivitis.

►  Amberlite IRP-69.  This cationic ion exchange resin is present in Betoptic S (betoxolol, Alcon). Betoxolol is positively charged and binds to negatively charged sulfonic acid groups in the resin. When applied to the ocular surface, the Na+ and K+ from tears cause release of betoxolol molecules from the resin into the tear film and then corneal penetration ensues.⁶

Other Drug Delivery Systems

■  Cul-de-sac inserts.  Although in existence since 1974, these have not gained wide clinical acceptance as a drug delivery device. Examples include hydroxypropyl cellulose ophthalmic insert (Lacrisert, Valeant Ophthalmics) and pilocarpine ocular inserts.

■  Contact lenses.  Therapeutic contact lenses have evolved with various modifications but little success. However, interest in this modality seems to have rekindled recently. Ongoing studies are examining the use of presoaked contact lenses to release the antihistamine ketotifen. Other investigations are focusing on the use of disposable soft contact lenses to release sodium cromoglicate for treatment of allergic conjunctivitis.

■  Punctal plugs.  Investigators are studying these devices as a route of drug delivery for latanoprost, bimatoprost and olopatadine. A proprietary drug delivery core is designed to deliver medications over different time periods.

■  Episcleral and subconjunctival implants.  Episcleral implants, made of silicone matrix, are under going investigation for cylosporine A delivery to the ocular surface for the duration of one year. Researchers are also working on the use of such implants as a reservoir to treat posterior segment diseases, including macular degeneration, diabetic retinopathy, endophthalmitis and glaucoma, and malignancies such as retinoblastoma. Also under investigation is a subconjunctival latanoprost insert with two ends, one impermeable and the other permeable, to release the drug over three to six months.

■  Physical devices.  Physical devices have been approved or are being studied to deliver drugs via iontophoresis. Noninvasive iontophoretic drug delivery is being studied for treatment of dry eye and uveitis. This technology also has the potential to treat AMD and other posterior segment diseases.

Typically, iontophoresis is limited to small-size, anionic drugs with low molecular weight. A weak direct current drives the charged molecules of the drug trans-sclerally into the vitreous, retina and choroid.

The future holds promising new technologies that will soon be in testing mode. Some of these include encapsulated cell technology, replenishing mini pumps and nano-structured porous silicon technology.

Durability and Design

Once the drug reaches its target site, its duration may vary depending on the chosen therapeutic avenue. Ophthalmic drops, trans-scleral iontophoresis, and gel-forming solutions usually last from hours to days. Intraocular nanoparticulates and non-viral gene therapy can extend duration from days to weeks. Intraocular liposomes and intraocular microparticles can extend duration to weeks.

If the need for longer duration of drug action arises, biodegradable implants, cell microencapsulation and semi-solid polymeric ocular injection technologies can extend the duration from weeks to months. With non-biodegradable implants, the potential duration of drug action can extend out to years. As we enter a new world of extended drug action, our choices will depend on the ease of application, cost, ease of manufacture, reversibility, decreased toxicity and patient acceptance.

We need to continue our focus on both the active drug and its delivery to move forward to more sophisticated, advanced systems that will overcome the natural physiologic ocular barriers to drug access. This may result in a paradigm shift in ocular drug delivery, with significant use of non-eyedrop systems that may erase the daily ocular drug dosing schedule — rendering compliance a near-nonexistent issue. Further, such regulated drug delivery systems that continue to emerge may diminish drug toxicity. Such an approach will benefit our patients and retain or augment visual quality and vision worldwide, for a better tomorrow. OM

References

1.  Rozier A, Mazuel C, Grove J, Plazonnet B. Gelrite: a novel, ion-activated, in situ-gelling polymer for ophthalmic vehicles effect on bioavailability of timolol. Int J Pharm. 1989;57:163-168.

2.  Lin HR, Sung KC. Carbopol/pluronic phase change solutions for ophthalmic drug delivery. J Contr Rel. 2000; 69:379-388.

3.  Miller SC, Donovan MD. Effect of Poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits. Int J Pharm. 1982;12:147-152.

4.  Jansson, P E, Lindberg B, Sandford P A: Structural studies of gellan gum, an extracellular polysaccharide elaborated by Pseudomonas elodea. Carbohydrate Res. 1983;124:135-139.

5.  Lallemand, F, Daull P, Benita S, Buggage R, Garrigue J-S: Successfully improving ocular drug delivery using the cationic nanoemulsion, Novasorb. J Drug Deliv 2012;2012:604-204, EPub 2012.

6.  Jani R, Gan O, Ali Y, Rodstrom R, Hancock S. Ion exchange resins for ophthalmic delivery. J. Ocul. Pharm. Ther. 1994;10:57-67.

Thomas John, MD,  a world leader in lamellar corneal surgery, is a clinical associate professor at Loyola University at Chicago, and in private practice in Oak Brook, Tinley Park and Oak Lawn, Ill. E-mail him at tjcornea@gmail.com.