Extraocular Drug Delivery: A Revolution in Progress
Noninvasive extended-release devices are on the horizon.
In 2013, the global prevalence of open-angle glaucoma in people
40 to 80 years of age was 3.5%, equivalent to an astounding
64 million people worldwide.1 As life expectancy and diagnostic detection improve, this number is expected to rise to 76 million by 2020.
Topical medication remains the first line of therapy for glaucoma, despite generally poor compliance with drop regimens. A minority of patients take their drops consistently and correctly, but many more are stymied by the high cost, difficulty of administration, and need for frequent administration. More than 40% of open-angle glaucoma patients require combination therapy, and many juggle multiple medications with different administration frequencies and a host of bothersome adverse effects.2 One study found that only 71% of patients were able to get a drop into the eye, and only 39% did so without touching the bottle to the surface of the eye.3
In addition to patient-related factors that influence compliance, drug delivery to the ocular tissues poses unique challenges. Much of the administered drug is removed by lacrimal and precorneal clearance. The cornea itself imposes structural and dynamic biologic barriers that restrict intraocular absorption, including the hydrophobic corneal endothelium and epithelium, conjunctival blood circulation, and enzymatic degradation prior to absorption into the aqueous humor. Overall, ocular bioavailability from topical drug administration is poor (<5%), with more than 95% of the drug lost due to all these barriers combined.4
New Drug Carriers
In efforts to diminish the frequency of drops and improve bioavailability of antihypertensive drugs, researchers are developing several new drug carriers. One approach is to encapsulate drugs in liposomes or polymeric nanoparticles that easily cross the hydrophobic cellular layers of the cornea. These carriers have several advantages:
- The active macromolecule is protected by encapsulation within the carrier;
- The carriers allow significant dose reduction and therefore have fewer associated systemic side effects; and
- The carrier-drug combinations
demonstrate high stability in ocular fluids and essentially act as extended-release drugs that reduce the overall drop burden on patients.
Unfortunately, use of these medications is still patient-dependent, mitigating potential improvement on patient compliance. Several research groups have tested these delivery systems using timolol in rabbits5 and timolol and brinzolamide ex vivo6 with success; however, the bulk of this research remains in the preclinical phase and awaits human testing.
Contact Lens Delivery Systems
Contact lenses are familiar to many patients, and this platform could serve as a relatively safe and acceptable modality for drug delivery. While investigations regarding contact lens drug delivery are largely preclinical, studies in animal models hold promise.7,8 In a recent study involving glaucomatous monkeys, researchers concluded that a latanoprost-eluting contact lens was as efficacious as topically administered latanoprost and resulted in less variability in IOP fluctuation.8 To provide extended, continuous release of drug, these contact lenses would have to be used nearly constantly, making local tolerance of the ocular surface to the lens material imperative. The small yet real risk of infection posed by constant lens use is a significant downside to this potential method of drug delivery—one which many patients and practitioners may deem unacceptable.
On the horizon are conjunctival inserts, noninvasive devices inserted under the eyelids that would allow continuous drug delivery. Several prototypes are undergoing investigation, and one of the furthest developed thus far is a bimatoprost eluting ocular insert (Allergan). This device contains a bimatoprost-polymer matrix, measures between 24 and 29 mm in diameter, and sits in the conjunctival fornices. It is placed by the ophthalmologist in the clinic with the aid of a scleral depressor and is designed to be replaced every
In a recent phase 2 noninferiority trial, the insert demonstrated tolerability (although dislodgement of the device was a concern, with 28 dislodgements in 15 patients over 6 months) and an IOP-lowering effect of greater than 20% from baseline. It did not, however, meet criteria to establish noninferiority compared with topical timolol.9 It was postulated that a paradoxical response to agonist desensitization associated with continuous elution of a prostaglandin analogue and the small sample size contributed to the failure to show noninferiority. This option, however, may still be a useful alternative for patients who are unable to tolerate topical drop therapy.10
Drug-Eluting Punctal Plugs
Punctal occlusion with drug-eluting plugs is another technology that could obviate frequent drop administration. These small, biocompatible devices can achieve a clinically significant IOP lowering effect with significant dose reduction. However, some patients have reported discomfort with these devices, and, like the plugs used to treat dry eye, the devices are subject to an unacceptably high extrusion rate.
One promising example of this modality is the OTX-TP (Ocular Therapeutix), which allows intracanalicular placement of preservative-free travoprost. The device resorbs within
2 to 3 months, eliminating the need for manual removal. It contains fluorescein for easy monitoring of retention, and the company has reported a retention rate of 90% over 60 days (dropping to 48% by day 90). In a double-dummy phase 2b clinical trial of OTX-TP plus placebo artificial tears compared with topically administrated timolol plus placebo noneluting punctal plugs, the company reported 90-day interim results demonstrating significant IOP reduction in both treatment groups.11 The timolol group achieved a higher level of IOP lowering than expected, greater than that of OTX-TP, possibly due to the effect of the placebo punctal plugs. The insert was well tolerated with no hyperemia-related adverse events. This device is currently in phase 3 trials.
Patients and physicians deserve to have better alternatives to a purely patient-dependent and inconvenient topical ocular antihypertensive regimen. To be accepted by the growing number of patients with glaucoma globally, a successful product will have to demonstrate efficacy, comfort, ease of use, and affordability. n
1. Tham YC, Li X, Wong TY, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. Ophthalmology. 2014;121:2081-2090.
2. Collaborative Normal Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol. 1998;126(4):498-505.
3. Hennessy AL, Katz J, Covert D, et al. Videotaped evaluation of eyedrop instillation in glaucoma patients with visual impairment or moderate to severe visual field loss. Ophthalmology. 2010;117(12):2345-2352.
4. Bachu RD, Chowdhury P, Zahraa HF, et al. Ocular drug delivery barriers–role of nanocarriers in the treatment of anterior segment ocular diseases. Pharmaceutics. 2018;10(1):28.
5. Huang J, Peng T, Li Y, et al. Ocular cubosome drug delivery system for timolol maleate: preparation, characterization, cytotoxicity, ex vivo, and in vivo evaluation. AAPS PharmSciTech. 2017;18:2919.
6. Shrivastava N, Khan S, Baboota S, Ali J. Fabrication and characterization of timolol maleate and brinzolamide loaded nanostructured lipid carrier system for ocular drug delivery [published online ahead of print November 29, 2017]. Curr Drug Deliv. PMID:29189155.
7. 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.
8. Ciolino JB, Ross AE, Tulsan R, et al. Latanoprost-eluting contact lenses in glaucomatous monkeys. Ophthalmology. 2016;123:2085-2092.
9. Brandt JD, DuBiner HB, Benza R, et al. Long-term safety and efficacy of a sustained-release bimatoprost ocular ring. Ophthalmology. 2017;124(10):1565-1566.
10. Aref AA. Sustained drug delivery in glaucoma: current data and future trends. Curr Opin Ophthalmol. 2017;28(2):169-174.
11. Ocular Therapeutix reports on topline results of phase 2b glaucoma clinical trial [press release]. Ocular Therapeutix. October 22, 2016. http://investors.ocutx.com/phoenix.zhtml?c=253650&p=irol-newsArticle&ID=2100516. Accessed May 16, 2018.
Sarwat Salim, MD | Section Editor
• Professor of Ophthalmology and Chief of the Glaucoma Service, Medical College of Wisconsin, Milwaukee
•Financial disclosure: None
Sriranjani P. Padmanabhan, MD
• Clinical Assistant Professor of Ophthalmology, Department of Ophthalmology, University of California, San Francisco
• Financial disclosure: None