REVIEW URRENT C OPINION
Sustained drug delivery in glaucoma O’Rese J. Knight and Scott D. Lawrence
Purpose of review This article reviews recently published studies and important clinical trials of novel drug delivery systems for glaucoma and evaluates the potential of these systems to provide sustained therapeutic benefits. Recent findings The efficacy of topical medications to lower intraocular pressure (IOP) is limited by poor patient adherence, low bioavailability of drug and the potential for local and systemic side effects. Recent studies highlight the potential for sustained drug delivery through innovative delivery platforms. Nanoparticle-based formulations, drug-eluting contact lenses, punctum inserts and bioadhesive matrices placed in the conjunctival sac can enhance drug delivery by increasing precorneal residence time, enhancing corneal permeation and lowering the systemic absorption of drug. Periocular injections and surgically implanted drug reservoirs could offer even greater duration of drug delivery, particularly when the drug is packaged within stable vehicles. Summary Novel platforms for providing sustained drug delivery in glaucoma continue to evolve. The ability to incorporate effective commercially available drugs into more stable compounds is an important element. Although more research is needed to establish their clinical efficacy, novel delivery systems will allow for more targeted medical therapy and for the opportunity to further explore neuroprotective and gene-based therapies. Keywords drug delivery, glaucoma, implants, nanoparticles, neuroprotection
INTRODUCTION Glaucoma is the leading cause of irreversible blindness and visual impairment in the world. It is expected to affect nearly 80 million people by 2020, with 5.9 million being bilaterally blind [1]. Glaucoma is a neurodegenerative disorder characterized by the death of retinal ganglion cells and is associated clinically with elevated intraocular pressure (IOP), vision loss and optic nerve degeneration [2]. Conventional first-line therapy for glaucoma involves applying one or more topical eye drops designed to lower IOP by at least 25%, accounting for individual patient risk factors and severity of disease [3]. This approach is generally insufficient for two reasons. First, a significant percentage of glaucoma cases are not associated with elevated IOP (normal tension glaucoma). Second, glaucoma progression and vision loss may occur despite significant lowering of IOP. In an effort to improve treatment efficacy and clinical outcomes, recent research has concentrated on developing novel systems for achieving sustained drug delivery in glaucoma. An ideal drug delivery system would achieve a prolonged www.co-ophthalmology.com
duration of drug effect while limiting systemic absorption, ocular tissue toxicity and patient discomfort. New drug platforms with the potential for IOP reduction lasting weeks or even months with a single dose could overcome present barriers to treatment and improve clinical efforts to prevent glaucoma progression and preserve vision. This review describes emerging drug delivery methods for glaucoma related to recent human and animal trials.
BARRIERS TO CONVENTIONAL DRUG DELIVERY IN GLAUCOMA Poor adherence to prescribed medical treatment for glaucoma has been well described [4,5]. Glaucoma patients typically self-administer one or more Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Correspondence to Scott D. Lawrence, MD, Department of Ophthalmology, University of North Carolina at Chapel Hill, 5101 Bioinformatics Bldg, CB 7040, Chapel Hill, NC 27599, USA. Tel: +1 919 966 5296; fax: +1 919 966 1908 Curr Opin Ophthalmol 2014, 25:112–117 DOI:10.1097/ICU.0000000000000031 Volume 25 Number 2 March 2014
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Sustained drug delivery in glaucoma Knight and Lawrence
KEY POINTS Topical medical therapy for glaucoma is inefficient due to poor patient adherence and limited bioavailability in the target tissues. Novel approaches such as nanoparticle-based formulations, drug-eluting contact lenses, bioadhesive polymers and punctal inserts enhance drug delivery by increasing precorneal residence time and corneal permeation. Periocular injections and surgically implanted drug reservoirs offer the potential for extended release of glaucoma drugs targeting both the anterior and posterior segments, particularly when a stable carrier vehicle is used. Novel drug delivery systems could support neuroprotective and gene therapy approaches in patients with glaucoma and ocular hypertension.
topical hypotensive agents at a frequency ranging from one to three times per day. The physical challenges of accurately administering eye drops as well as complex dosing schedules likely contribute to decreased adherence rates in this elderly population [6,7]. The Glaucoma Adherence and Persistency Study [8] demonstrated that 54% of glaucoma patients had a gap in their medication usage, and that one gap increased the likelihood of additional gaps. Even glaucoma patients who intend to persist in their medical treatment may not be able to tolerate certain local or systemic side effects of daily topical formulations. In addition to patient-related barriers, numerous physiologic factors make short-acting topical therapy an inefficient method of drug delivery. Low bioavailability in the eye is a serious problem, with less than 5% of an active topical drug reaching the aqueous humour of the eye. As a result of the normal tear drainage system, almost 50% of a drop is immediately lost upon instillation [9]. The pH and osmolarity of topical solutions can increase reflex tearing and lachrymal drainage as well. As much as 80% of a medication that initially resides in the conjunctival cul-de-sac is absorbed through the nasal mucosa into the systemic circulation. This can lead to undesirable side effects, particularly in the case of nonselective beta-blockers. The cornea represents an additional barrier to drug penetration, particularly at the level of the epithelium, which is composed of five layers of cells connected by tight junctions. Penetration of a medication across the cornea is dependent on a number of factors, including the size, charge and lipophilic nature of the agent. The precorneal residence time of most
glaucoma medications is low, and any improvements of this variable are critical to increasing drug permeation across the cornea [10]. Also, drugs delivered through the anterior segment have little bioavailability to the posterior segment and retina, limiting the potential benefit of future neuroprotective and gene therapy approaches that might target the optic nerve and retinal ganglion cells.
VEHICLES FOR ENHANCED TOPICAL DRUG DELIVERY Topical administration of glaucoma medications remains the preferred mode of delivery due to its noninvasive nature, relative safety and proximity to glaucoma targets in the anterior segment: the trabecular meshwork and ciliary body. One strategy for achieving sustained delivery of commercially available glaucoma drugs utilizes novel delivery platforms to increase precornea residence time of the drug. By creating a more permanent reservoir of drug on or near the cornea, researchers aim to increase drug bioavailability while minimizing unwanted systemic side effects.
Nanoparticle-based topical formulations Recent advances in the field of nanomedicine show promise for application in ophthalmic diseases. Nanoparticles on a scale of 10–1000 nm offer a unique platform for drug delivery. By adjusting particle material and size, nanoparticles possess numerous properties such as mucoadhesion, biocompatibility and biodegradability, all of which can enhance drug permeation across the cornea. Jain et al. [11] studied a nanoparticle-based system containing betaxolol hydrochloride in a dexamethasone-induced glaucoma rabbit model. They found that the nanoparticle-based formulation achieved a 36% reduction in IOP at 5 h that was significantly greater than the marketed formulation. Gupta et al. [12 ] used gamma scintigraphy to study ocular retention of a novel polylactic coglycolic acid (PLGA) nanoparticle that was incorporated into a cationic chitosan gel solution containing radiolabelled Sparfloxacin in a rabbit model. The group found nearly 100% corneal retention at 30 min (measured by percentage radioactivity) of the combined preparation that was significantly greater than the marketed formulation as well as nanoparticle or gel solution alone. Recent in-vivo studies of nanoparticle-based delivery of carbonic anhydrase inhibitors [13–16], brimonidine [17] and pilocarpine [18] have demonstrated superior drug stability and corneal permeation than commercial solutions.
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However, the sustained in-vivo IOP reduction of most of these formulations was less than 24 h.
Contact lens-based delivery With over 120 million contact lens wearers worldwide, researchers are exploring therapeutic uses of these devices for drug delivery [19 ]. Interest in this approach goes back decades, although establishing a drug-eluting contact lens without compromising important lens properties such as transparency, elasticity and permeability has been challenging. Advances in hydrogel technology now allow for drug reservoirs to be released over a longer duration from a polymeric network [19 ]. Drugs loaded on the corneal side of a contact lens diffuse into the post lens tear film and are present for up to 30 min, providing a potential 50% drug bioavailability. This is compared with the 5-min mean precorneal residence time and 1–5% bioavailability of eye drops [20]. In one recent study [21], puerarin, a novel antiglaucoma drug, loaded into soft contact lenses had a mean precorneal residence time of 77.45 compared with 12.88 min of the 1% puerarin eye drop. Peng et al. [22 ] studied the efficacy of timolol-loaded hydrogel contact lenses to lower IOP in dogs. Lenses were applied to one eye and replaced every 24 h, while the fellow eye served as a control. Average IOP reduction was similar to commercial eye drops even when the drug load was reduced by two-thirds, suggesting that the contact lens platform could achieve better bioavailability of drug than conventional therapy. Jung et al. [23 ] incorporated propoxylated glyceryl triacylate nanoparticles containing timolol into silicone-hydrogel contact lenses. They loaded 100 and 200 mm silicone gels with 316 and 713 mg of drug, respectively, and compared drug release profiles in canines. Not surprisingly, the amount of drug released from the 200 mm contact lens was twice that of the thinner lens. However, the authors found that the duration of drug release exceeded 30 days in both models. This study suggests that the combination of platforms could have an additive therapeutic benefit. Ciolino et al. [24 ] studied latanoprost-eluting contact lenses containing drug-polymer films in a rabbit model and found that aqueous levels of drug matched those achieved by commercial formulations for up to 1 month. &&
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Bioadhesive matrix polymers Biodegradable polymers can be used as a platform for delivering glaucoma drugs to the cornea with an advantage of increased residence time compared with gel formulations and conventional eye drops. The matrix materials are chosen to provide a 114
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controlled release of drug over time with the potential for once-weekly or once-monthly dosing. Huang et al. [25] showed that a PLGA film could be placed in the conjunctival cul-de-sac of ocular hypertensive rabbits and could achieve IOP-lowering of approximately 7 mmHg over 7 days without evidence of local side effects. More recently, Kashiwagi et al. [26 ] developed a latanoprost-loaded nanosheet with a chitosan base that is applied directly to the cornea and has been shown to reduce IOP for up to 9 days in normotensive rats. Similarly, Fulgeˆncio Gde et al. [27 ] developed a chitosan-coated timolol maleate film that achieved sustained IOP lowering. Although the drug was released over 4 weeks with 85% released during the first 2 weeks, IOP lowering was sustained over a 10-week period. &
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Ocular inserts Ocular inserts are typically solid or semi-solid polymers designed for placement in the puncta or conjunctival sac wherein they elute medications. The best studied such device was the Ocusert system [28], which consisted of a central reservoir of pilocarpine enclosed within a double microporous membrane. This device was designed for placement in the conjunctival sac and delivered a 20 or 40 mg/h dose rate of drug over 7 days. Advantages of such a device include increased precorneal residence time, more accurate dosing and decreased systemic absorption. Disadvantages include foreign body sensation as well as the potential for movement or loss of the vehicle. Newer insertion devices are under clinical investigation. An experimental punctal plug delivery systems containing a formulation of latanoprost (Mati Therapeutics, Inc., British Columbia, Canada) recently underwent a phase 2 clinical trial with results pending [29]. Also, Forsight Vision5, Inc. (Menlo Park, California, USA) is conducting a phase 2 study [30] comparing duration of IOP lowering by a propriety latanoprost-impregnated silicone ring custom fit to patients’ fornices versus topical timolol in patients with primary open-angle glaucoma (POAG) and ocular hypertension. Ocular Therapeutix, Inc. (Bedford, Massachusetts, USA) is conducting a phase I trial [31] of a hydrogel punctal plug that elutes travoprost in sustained release of 4 mg/day over 2 months or 3 mg/day over 3 months versus timolol maleate (0.5%) drops.
INJECTABLE SYSTEMS FOR PERIOCULAR DELIVERY Periocular injections and depots in the subconjunctival and subtenons space offer the advantage of Volume 25 Number 2 March 2014
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Sustained drug delivery in glaucoma Knight and Lawrence
prolonged efficacy as well as the potential to reach posterior ocular structures. Therapeutics delivered in this way must penetrate the sclera, a tissue that is highly permeable to large molecules such as proteins and peptides [32]. This approach typically requires quarterly administration by an ophthalmologist at the slit lamp but eliminates most of the patient-centred barriers to medication adherence. A recent voluntary survey of glaucoma patients in Singapore noted that 74% of patients would exchange their eye drops for subconjunctival injections delivered every 3 months [33 ]. To achieve sustained delivery on the order of weeks or months, a stable delivery vehicle is advantageous. Previous preclinical animal studies have examined the use of biodegradable synthetic polymers containing IOP-lowering medications, with duration of action ranging from 10 days to over 6 months [34–36]. More recently, Natarajan et al. [37 ] administered latanoprost-loaded liposomes subconjunctivally to normotensive rabbits and observed a greater reduction in IOP (4.8 versus 2.0 mmHg) that was sustained for at least 90 days than commercial latanoprost delivered topically. A human clinical trial (phases 1 and 2) involving this delivery model is underway with Durasert (pSivida Corp., Watertown, Massachusetts, USA), a bioerodible implant applied in the clinical setting that delivers latanoprost into the subconjunctival space [38]. &
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SURGICALLY IMPLANTED DRUG RESERVOIRS Implanted devices for sustained ocular drug delivery have been available for years. These delivery systems have the potential to achieve the longest sustained action. Primary disadvantages of this approach include the invasiveness of implantation, cost and the possible need for secondary surgery if a complication arises. Retisert and Vitrasert (Bausch and Lomb, Rochester, New York, USA) are intravitreal implants that elute fluocinolone acetonide (30-month duration) and gancyclovir (5–8 month duration), respectively [39,40]. Ozurdex (Allergan, Irvine, California, USA) is a dexamethasone implant that delivers intravitreal steroid for a 6-month period [41]. Iluvian (pSivida Corp., Watertown, Massachusetts, USA) utilizes a slightly different and less invasive platform to reach the posterior segment. The system employs an injectable, polyamide tube (containing fluocinolone acetonide, 190 mg eluted over 36 months) that is nonbiodegradable and cylindrical in shape. The device is delivered intravitreally through a 25-gauge needle and is currently marketed for diabetic macular
oedema [42]. The Illuvian system has received marketing authorization in multiple European countries but is not approved for clinical use in the USA. It seems plausible that the delivery platform of these drug implants could be applied to glaucoma as well. For example, a recent phase 2 clinical trial examined the safety and efficacy of a brimonidine intravitreal implant (200 or 400 mg) in patients with glaucomatous optic neuropathy [43]. Also, a recent study [44 ] found that a posterior segment reservoir could achieve substantial, dose-dependent drug levels in the aqueous humour as well. This would suggest the potential for targeting both anterior segment and posterior segment structure via a single procedure. &&
NOVEL APPLICATIONS OF SUSTAINED DRUG DELIVERY SYSTEMS Sustained drug delivery offers a platform to explore innovative therapeutic models for treating glaucoma. Neuroprotective factors delivered via periocular or intravitreal pathways might reduce damage to retinal ganglion cells and stimulate their growth and regeneration [45–47]. The same polymer-based scaffolds used with commercial glaucoma drugs could be applied to neurotrophic factors as well, opening the door for multiple glaucoma targets [48]. The benefits of gene therapy might also be enhanced by nanoparticles that can protect genetic cargo and enhance targeting of specific cell types [49,50]. Finally, the principles of extended drug release could be applied to glaucoma surgery, as in adjustable release of mitomycin C through polymeric or nanoscale carrier vehicles. Such an approach might lead to better inhibition of fibroblast proliferation than can be achieved with a one-time application of the drug [51,52].
CONCLUSION Topical medications play an important primary and adjunctive role in the treatment of glaucoma. However, the efficacy of these drugs is limited by poor patient adherence, low intraocular bioavailability and the potential for clinically significant local and systemic side effects. Novel delivery systems allow for a more efficient and targeted therapeutic approach with the potential to incorporate neuroprotective and gene therapy approaches. Topical gel solutions, punctal and conjunctival inserts, and contact lenses can improve the efficiency of drug delivery by increasing precorneal residence time and corneal permeation. Subconjunctival and subtenons injections allow for increased targeting of the posterior segment as well as sustained delivery over
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months with a single dose. Surgically implanted reservoirs offer the potential for an even more prolonged drug release. Patients with mild glaucoma that can be controlled with a single medication may still prefer gel-based formulations or drug-eluting contact lenses, particularly when cost is an issue. Patients with more complex drug regimens or personal limitations might prefer a subconjunctival injection every 3–4 months or a surgically implanted drug reservoir. There should be a reasonable amount of caution regarding the potential for allergy or immune-mediated response to polymers or other compounds in which the drugs are packaged. However, as novel delivery systems become clinically available, the ability to effectively treat glaucoma and preserve vision will be enhanced. Acknowledgements S.D.L. has received speaker fees (honoraria) from Alcon Laboratories, Inc. O.J.K. has nothing to disclose. The authors have no relevant sources of funding with regard to this manuscript. Conflicts of interest The authors have no financial or proprietary interest in materials and/or methods mentioned in this manuscript.
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12. Gupta H, Aqil M, Khar RK, et al. Nanoparticles laden in situ gel for sustained ocular drug delivery. J Pharm Bioallied Sci 2013; 5:162–165. This preclinical study evaluated the combined effects of PLGA nanoparticles incorporated in a chitosan-based gel with a radiolabelled drug on precorneal residence time. Residence time was greater for the nanoparticle-gel combination than either constituent or marketed drug formulation alone. 13. Singh J, Chhabra G, Pathak K. Development of acetazolamide-loaded, pH-triggered polymeric nanoparticulate in situ gel for sustained ocular delivery: in vitro. ex vivo evaluation and pharmacodynamic study. Drug Dev Ind Pharm 2013. [Epub ahead of print] 14. Verma P, Gupta RN, Jha AK, Pandey R. Development, in vitro and in vivo characterization of Eudragit RL 100 nanoparticles for improved ocular bioavailability of acetazolamide. Drug Deliv 2013; 20:269–276. 15. Wu W, Li J, Wu L, et al. Ophthalmic delivery of brinzolamide by liquid crystalline nanoparticles: in vitro and in vivo evaluation. AAPS PharmSciTech 2013; 14:1063–1071. 16. Shinde U, Ahmed MH, Singh K. Development of dorzolamide loaded 6-o-carboxymethyl chitosan nanoparticles for open angle glaucoma. J Drug Deliv 2013; 2013:562727. 17. Singh KH, Shinde UA. Chitosan nanoparticles for controlled delivery of brimonidine tartrate to the ocular membrane. Pharmazie 2011; 66:594–599. 18. Li J, Wu L, Wu W, et al. A potential carrier based on liquid crystal nanoparticles for ophthalmic delivery of pilocarpine nitrate. Int J Pharm 2013; 455:75–84. 19. Peng CC, Burke MT, Carbia BE, et al. Extended drug delivery by contact && lenses for glaucoma therapy. J Control Release 2012; 162:152–158. A comprehensive review of the historical background and emerging trends towards optimizing contact lens-based drug delivery for glaucoma. 20. Li CC, Chauhan A. Modeling ophthalmic drug delivery by soaked contact lenses. 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In vivo performance of a drug&& eluting contact lens to treat glaucoma for a month. Biomaterials 2014; 35: 432–439. This animal study showed that contact lenses containing polymer–drug (latanoprost) films 40–45 mm in thickness provided an initial burst of latanoprost in the aqueous humour followed by a steady-state concentration comparable with the average hourly concentration delivered from a drop of commercially available latanoprost. 25. Huang SF, Chen JL, Yeh MK, Chiang CH. Physicochemical properties and in vivo assessment of timolol-loaded poly(D,L-lactide-co-glycolide) films for long-term intraocular pressure lowering effects. J Ocul Pharmacol Ther 2005; 21:445–453. 26. Kashiwagi K, Ito K, Haniuda H, et al. Development of latanoprost-loaded & biodegradable nanosheet as a new drug delivery system for glaucoma. Invest Ophthalmol Vis Sci 2013; 54:5629–5637. This study evaluated latanoprost loaded at three concentrations into a 40 nm thick biodegradable nanosheet at three drug concentrations and applied to the corneas of rats. IOP reduction of more than 20% in the nanosheet containing latanoprost (2.5 mg/cm) was sustained for 7 days without evidence of local adverse effects. 27. Fulgeˆncio Gde O, Viana FA, Ribeiro RR, et al. New mucoadhesive chitosan && film for ophthalmic drug delivery of timolol maleate: in vivo evaluation. J Ocul Pharmacol Ther 2012; 28:350–358. This study examined a chitosan-coated timolol maleate mucoadhesive film applied to the lower conjunctival sac in rabbits. Although the majority of drug (85%) was released in the first 2 weeks, in-vivo IOP levels were significantly reduced for 10 weeks. 28. Macoul KL, Pavan-Langston D. Pilocarpine ocusert system for sustained control of ocular hypertension. Arch Ophthalmol 1975; 93:587–590. 29. Mati Therapeutics, Inc. A safety study of the latanoprost punctal plug delivery system (L-PPDS) in subjects with ocular hypertension or open angle glaucoma. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 1 October 2013]. Available from: http://clinical trials.gov/show/NCT00820300 NLM Identifier: NCT00820300. 30. ForSight Vision5, Inc. VISION5 product compared to topical timolol solution in patients with glaucoma or ocular hypertension. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 5 October 2013]. Available from: http://clinicaltrials.gov/show/NCT01915940 NLM Identifier: NCT01915940. 31. Ocular Therapeutix, Inc. Multi-arm feasibility study evaluating OTX-TP compared to timolol in treatment of subjects with open angle glaucoma. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 5 October 2013]. 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Sustained drug delivery in glaucoma Knight and Lawrence 32. Ambati J, Canakis CS, Miller JW, et al. Diffusion of high molecular weight compounds through sclera. Invest Ophthalmol Vis Sci 2000; 41:1181– 1185. 33. Chong RS, Su DH, Tsai A, et al. Patient acceptance and attitude toward an & alternative method of subconjunctival injection for the medical treatment of glaucoma. J Glaucoma 2013; 22:190–194. In total, 151 glaucoma patients completed a 30-item questionnaire. Over 74% of respondents were willing to exchange topical medications for a subconjunctival injection given every 3 months. Most of these patients were willing to do so at equal or higher cost. 34. Wang Y, Challa P, Epstein DL, Yuan F. Controlled release of ethacrynic acid from poly(lactide-co-glycolide) films for glaucoma treatment. Biomaterials 2004; 25:4279–4285. 35. Natu MV, Gaspar MN, Fontes Ribeiro CA, et al. In vitro and in vivo evaluation of an intraocular implant for glaucoma treatment. Int J Pharm 2011; 415:73–82. 36. Bertram JP, Saluja SS, McKain J, Lavik EB. Sustained delivery of timolol maleate from poly(lactic-co-glycolic acid)/poly(lactic acid) microspheres for over 3 months. J Microencapsul 2009; 26:18–26. 37. Natarajan JV, Ang M, Darwitan A, et al. Nanomedicine for glaucoma: lipo&& somes provide sustained release of latanoprost in the eye. Int J Nanomedicine 2012; 7:123–131. This study evaluated the efficacy of latanoprost-loaded liposomes injected in the subconjunctival space of rabbit eyes and found a sustained decrease in IOP of 4.8 mmHg over 90 days with no signs of ocular inflammation. 38. pSivida Corp, 2013. http://www.psivida.com/products-durasert.html 39. Schwartz SG, Flynn HW Jr. Fluocinolone acetonide implantable device for diabetic retinopathy. Curr Pharm Biotechnol 2011; 12:347–351. 40. Wang J, Jiang A, Joshi M, Christoforidis J. Drug delivery implants in the treatment of vitreous inflammation. Mediators Inflamm 2013; 2013:1–8. 41. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117:1134–1146. 42. Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012; 119:2125– 2132.
43. Allergan. Safety and effects of brimonidine intravitreal implant in patients with glaucomatous optic neuropathy. In ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 [cited 24 November 2013]. Available from: http://clinicaltrials.gov/show/NCT00693485 NLM Identifier: NCT00693485. 44. Campochiaro PA, Nguyen QD, Hafiz G, et al. Aqueous levels of fluocinolone && acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants. Ophthalmology 2013; 120:583–587. This study measured aqueous levels of fluocinolone acetonide (FAc) in patients who received 0.2 mg/day (low dose) versus 0.5 mg/day (high dose) Illuvian or the Retisert implant. Aqueous levels of FAc in all groups were elevated during the first 3 months before reaching a steady state. For patients receiving the Illuvian insert, drug levels in the aqueous maintained a steady state for 36 months in the low-dose group and 24 months in the high-dose group. 45. Carmignoto G, Maffei L, Candeo P, et al. Effect of NGF on the survival of rat retinal ganglion cells following optic nerve section. J Neurosci 1989; 9:1263– 1272. 46. Mey J, Thanos S. Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 1993; 602:304–317. 47. Cohen-Cory S, Fraser SE. Effects of brain-derived neurotrophic factor on optic axon branching and remodeling in vivo. Nature 1995; 378:192–196. 48. Checa-Casalengua P, Jiang C, Bravo-Osuna I, et al. Retinal ganglion cells survival in a glaucoma model by GDNF/Vit E PLGA microspheres prepared according to a novel microencapsulation procedure. J Control Release 2011; 156:92–100. 49. Borras T. Advances in glaucoma treatment and management: gene therapy. Invest Ophthalmol Vis Sci 2012; 53:2506–2510. 50. Pita-Thomas DW, Goldberg JL. Nanotechnology and glaucoma: little particles for a big disease. Curr Opin Ophthalmol 2013; 24:130–135. 51. Merritt SR, Velasquez G, von Recum HA. Adjustable release of mitomycin C for inhibition of scar tissue formation after filtration surgery. Exp Eye Res 2013; 116:9–16. 52. Wu Z, Li S, Wang N, et al. A comparative study of the safety and efficacy effect of 5-fluorouracil or mitomycin C mounted biological delivery membranes in a rabbit model of glaucoma filtration surgery. Clin Ophthalmol 2013; 7:655–662.
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Sustained drug delivery in glaucoma O’Rese J. Knight and Scott D. Lawrence
Purpose of review This article reviews recently published studies and important clinical trials of novel drug delivery systems for glaucoma and evaluates the potential of these systems to provide sustained therapeutic benefits. Recent findings The efficacy of topical medications to lower intraocular pressure (IOP) is limited by poor patient adherence, low bioavailability of drug and the potential for local and systemic side effects. Recent studies highlight the potential for sustained drug delivery through innovative delivery platforms. Nanoparticle-based formulations, drug-eluting contact lenses, punctum inserts and bioadhesive matrices placed in the conjunctival sac can enhance drug delivery by increasing precorneal residence time, enhancing corneal permeation and lowering the systemic absorption of drug. Periocular injections and surgically implanted drug reservoirs could offer even greater duration of drug delivery, particularly when the drug is packaged within stable vehicles. Summary Novel platforms for providing sustained drug delivery in glaucoma continue to evolve. The ability to incorporate effective commercially available drugs into more stable compounds is an important element. Although more research is needed to establish their clinical efficacy, novel delivery systems will allow for more targeted medical therapy and for the opportunity to further explore neuroprotective and gene-based therapies. Keywords drug delivery, glaucoma, implants, nanoparticles, neuroprotection
INTRODUCTION Glaucoma is the leading cause of irreversible blindness and visual impairment in the world. It is expected to affect nearly 80 million people by 2020, with 5.9 million being bilaterally blind [1]. Glaucoma is a neurodegenerative disorder characterized by the death of retinal ganglion cells and is associated clinically with elevated intraocular pressure (IOP), vision loss and optic nerve degeneration [2]. Conventional first-line therapy for glaucoma involves applying one or more topical eye drops designed to lower IOP by at least 25%, accounting for individual patient risk factors and severity of disease [3]. This approach is generally insufficient for two reasons. First, a significant percentage of glaucoma cases are not associated with elevated IOP (normal tension glaucoma). Second, glaucoma progression and vision loss may occur despite significant lowering of IOP. In an effort to improve treatment efficacy and clinical outcomes, recent research has concentrated on developing novel systems for achieving sustained drug delivery in glaucoma. An ideal drug delivery system would achieve a prolonged www.co-ophthalmology.com
duration of drug effect while limiting systemic absorption, ocular tissue toxicity and patient discomfort. New drug platforms with the potential for IOP reduction lasting weeks or even months with a single dose could overcome present barriers to treatment and improve clinical efforts to prevent glaucoma progression and preserve vision. This review describes emerging drug delivery methods for glaucoma related to recent human and animal trials.
BARRIERS TO CONVENTIONAL DRUG DELIVERY IN GLAUCOMA Poor adherence to prescribed medical treatment for glaucoma has been well described [4,5]. Glaucoma patients typically self-administer one or more Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Correspondence to Scott D. Lawrence, MD, Department of Ophthalmology, University of North Carolina at Chapel Hill, 5101 Bioinformatics Bldg, CB 7040, Chapel Hill, NC 27599, USA. Tel: +1 919 966 5296; fax: +1 919 966 1908 Curr Opin Ophthalmol 2014, 25:112–117 DOI:10.1097/ICU.0000000000000031 Volume 25 Number 2 March 2014
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KEY POINTS Topical medical therapy for glaucoma is inefficient due to poor patient adherence and limited bioavailability in the target tissues. Novel approaches such as nanoparticle-based formulations, drug-eluting contact lenses, bioadhesive polymers and punctal inserts enhance drug delivery by increasing precorneal residence time and corneal permeation. Periocular injections and surgically implanted drug reservoirs offer the potential for extended release of glaucoma drugs targeting both the anterior and posterior segments, particularly when a stable carrier vehicle is used. Novel drug delivery systems could support neuroprotective and gene therapy approaches in patients with glaucoma and ocular hypertension.
topical hypotensive agents at a frequency ranging from one to three times per day. The physical challenges of accurately administering eye drops as well as complex dosing schedules likely contribute to decreased adherence rates in this elderly population [6,7]. The Glaucoma Adherence and Persistency Study [8] demonstrated that 54% of glaucoma patients had a gap in their medication usage, and that one gap increased the likelihood of additional gaps. Even glaucoma patients who intend to persist in their medical treatment may not be able to tolerate certain local or systemic side effects of daily topical formulations. In addition to patient-related barriers, numerous physiologic factors make short-acting topical therapy an inefficient method of drug delivery. Low bioavailability in the eye is a serious problem, with less than 5% of an active topical drug reaching the aqueous humour of the eye. As a result of the normal tear drainage system, almost 50% of a drop is immediately lost upon instillation [9]. The pH and osmolarity of topical solutions can increase reflex tearing and lachrymal drainage as well. As much as 80% of a medication that initially resides in the conjunctival cul-de-sac is absorbed through the nasal mucosa into the systemic circulation. This can lead to undesirable side effects, particularly in the case of nonselective beta-blockers. The cornea represents an additional barrier to drug penetration, particularly at the level of the epithelium, which is composed of five layers of cells connected by tight junctions. Penetration of a medication across the cornea is dependent on a number of factors, including the size, charge and lipophilic nature of the agent. The precorneal residence time of most
glaucoma medications is low, and any improvements of this variable are critical to increasing drug permeation across the cornea [10]. Also, drugs delivered through the anterior segment have little bioavailability to the posterior segment and retina, limiting the potential benefit of future neuroprotective and gene therapy approaches that might target the optic nerve and retinal ganglion cells.
VEHICLES FOR ENHANCED TOPICAL DRUG DELIVERY Topical administration of glaucoma medications remains the preferred mode of delivery due to its noninvasive nature, relative safety and proximity to glaucoma targets in the anterior segment: the trabecular meshwork and ciliary body. One strategy for achieving sustained delivery of commercially available glaucoma drugs utilizes novel delivery platforms to increase precornea residence time of the drug. By creating a more permanent reservoir of drug on or near the cornea, researchers aim to increase drug bioavailability while minimizing unwanted systemic side effects.
Nanoparticle-based topical formulations Recent advances in the field of nanomedicine show promise for application in ophthalmic diseases. Nanoparticles on a scale of 10–1000 nm offer a unique platform for drug delivery. By adjusting particle material and size, nanoparticles possess numerous properties such as mucoadhesion, biocompatibility and biodegradability, all of which can enhance drug permeation across the cornea. Jain et al. [11] studied a nanoparticle-based system containing betaxolol hydrochloride in a dexamethasone-induced glaucoma rabbit model. They found that the nanoparticle-based formulation achieved a 36% reduction in IOP at 5 h that was significantly greater than the marketed formulation. Gupta et al. [12 ] used gamma scintigraphy to study ocular retention of a novel polylactic coglycolic acid (PLGA) nanoparticle that was incorporated into a cationic chitosan gel solution containing radiolabelled Sparfloxacin in a rabbit model. The group found nearly 100% corneal retention at 30 min (measured by percentage radioactivity) of the combined preparation that was significantly greater than the marketed formulation as well as nanoparticle or gel solution alone. Recent in-vivo studies of nanoparticle-based delivery of carbonic anhydrase inhibitors [13–16], brimonidine [17] and pilocarpine [18] have demonstrated superior drug stability and corneal permeation than commercial solutions.
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However, the sustained in-vivo IOP reduction of most of these formulations was less than 24 h.
Contact lens-based delivery With over 120 million contact lens wearers worldwide, researchers are exploring therapeutic uses of these devices for drug delivery [19 ]. Interest in this approach goes back decades, although establishing a drug-eluting contact lens without compromising important lens properties such as transparency, elasticity and permeability has been challenging. Advances in hydrogel technology now allow for drug reservoirs to be released over a longer duration from a polymeric network [19 ]. Drugs loaded on the corneal side of a contact lens diffuse into the post lens tear film and are present for up to 30 min, providing a potential 50% drug bioavailability. This is compared with the 5-min mean precorneal residence time and 1–5% bioavailability of eye drops [20]. In one recent study [21], puerarin, a novel antiglaucoma drug, loaded into soft contact lenses had a mean precorneal residence time of 77.45 compared with 12.88 min of the 1% puerarin eye drop. Peng et al. [22 ] studied the efficacy of timolol-loaded hydrogel contact lenses to lower IOP in dogs. Lenses were applied to one eye and replaced every 24 h, while the fellow eye served as a control. Average IOP reduction was similar to commercial eye drops even when the drug load was reduced by two-thirds, suggesting that the contact lens platform could achieve better bioavailability of drug than conventional therapy. Jung et al. [23 ] incorporated propoxylated glyceryl triacylate nanoparticles containing timolol into silicone-hydrogel contact lenses. They loaded 100 and 200 mm silicone gels with 316 and 713 mg of drug, respectively, and compared drug release profiles in canines. Not surprisingly, the amount of drug released from the 200 mm contact lens was twice that of the thinner lens. However, the authors found that the duration of drug release exceeded 30 days in both models. This study suggests that the combination of platforms could have an additive therapeutic benefit. Ciolino et al. [24 ] studied latanoprost-eluting contact lenses containing drug-polymer films in a rabbit model and found that aqueous levels of drug matched those achieved by commercial formulations for up to 1 month. &&
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Bioadhesive matrix polymers Biodegradable polymers can be used as a platform for delivering glaucoma drugs to the cornea with an advantage of increased residence time compared with gel formulations and conventional eye drops. The matrix materials are chosen to provide a 114
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controlled release of drug over time with the potential for once-weekly or once-monthly dosing. Huang et al. [25] showed that a PLGA film could be placed in the conjunctival cul-de-sac of ocular hypertensive rabbits and could achieve IOP-lowering of approximately 7 mmHg over 7 days without evidence of local side effects. More recently, Kashiwagi et al. [26 ] developed a latanoprost-loaded nanosheet with a chitosan base that is applied directly to the cornea and has been shown to reduce IOP for up to 9 days in normotensive rats. Similarly, Fulgeˆncio Gde et al. [27 ] developed a chitosan-coated timolol maleate film that achieved sustained IOP lowering. Although the drug was released over 4 weeks with 85% released during the first 2 weeks, IOP lowering was sustained over a 10-week period. &
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Ocular inserts Ocular inserts are typically solid or semi-solid polymers designed for placement in the puncta or conjunctival sac wherein they elute medications. The best studied such device was the Ocusert system [28], which consisted of a central reservoir of pilocarpine enclosed within a double microporous membrane. This device was designed for placement in the conjunctival sac and delivered a 20 or 40 mg/h dose rate of drug over 7 days. Advantages of such a device include increased precorneal residence time, more accurate dosing and decreased systemic absorption. Disadvantages include foreign body sensation as well as the potential for movement or loss of the vehicle. Newer insertion devices are under clinical investigation. An experimental punctal plug delivery systems containing a formulation of latanoprost (Mati Therapeutics, Inc., British Columbia, Canada) recently underwent a phase 2 clinical trial with results pending [29]. Also, Forsight Vision5, Inc. (Menlo Park, California, USA) is conducting a phase 2 study [30] comparing duration of IOP lowering by a propriety latanoprost-impregnated silicone ring custom fit to patients’ fornices versus topical timolol in patients with primary open-angle glaucoma (POAG) and ocular hypertension. Ocular Therapeutix, Inc. (Bedford, Massachusetts, USA) is conducting a phase I trial [31] of a hydrogel punctal plug that elutes travoprost in sustained release of 4 mg/day over 2 months or 3 mg/day over 3 months versus timolol maleate (0.5%) drops.
INJECTABLE SYSTEMS FOR PERIOCULAR DELIVERY Periocular injections and depots in the subconjunctival and subtenons space offer the advantage of Volume 25 Number 2 March 2014
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Sustained drug delivery in glaucoma Knight and Lawrence
prolonged efficacy as well as the potential to reach posterior ocular structures. Therapeutics delivered in this way must penetrate the sclera, a tissue that is highly permeable to large molecules such as proteins and peptides [32]. This approach typically requires quarterly administration by an ophthalmologist at the slit lamp but eliminates most of the patient-centred barriers to medication adherence. A recent voluntary survey of glaucoma patients in Singapore noted that 74% of patients would exchange their eye drops for subconjunctival injections delivered every 3 months [33 ]. To achieve sustained delivery on the order of weeks or months, a stable delivery vehicle is advantageous. Previous preclinical animal studies have examined the use of biodegradable synthetic polymers containing IOP-lowering medications, with duration of action ranging from 10 days to over 6 months [34–36]. More recently, Natarajan et al. [37 ] administered latanoprost-loaded liposomes subconjunctivally to normotensive rabbits and observed a greater reduction in IOP (4.8 versus 2.0 mmHg) that was sustained for at least 90 days than commercial latanoprost delivered topically. A human clinical trial (phases 1 and 2) involving this delivery model is underway with Durasert (pSivida Corp., Watertown, Massachusetts, USA), a bioerodible implant applied in the clinical setting that delivers latanoprost into the subconjunctival space [38]. &
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SURGICALLY IMPLANTED DRUG RESERVOIRS Implanted devices for sustained ocular drug delivery have been available for years. These delivery systems have the potential to achieve the longest sustained action. Primary disadvantages of this approach include the invasiveness of implantation, cost and the possible need for secondary surgery if a complication arises. Retisert and Vitrasert (Bausch and Lomb, Rochester, New York, USA) are intravitreal implants that elute fluocinolone acetonide (30-month duration) and gancyclovir (5–8 month duration), respectively [39,40]. Ozurdex (Allergan, Irvine, California, USA) is a dexamethasone implant that delivers intravitreal steroid for a 6-month period [41]. Iluvian (pSivida Corp., Watertown, Massachusetts, USA) utilizes a slightly different and less invasive platform to reach the posterior segment. The system employs an injectable, polyamide tube (containing fluocinolone acetonide, 190 mg eluted over 36 months) that is nonbiodegradable and cylindrical in shape. The device is delivered intravitreally through a 25-gauge needle and is currently marketed for diabetic macular
oedema [42]. The Illuvian system has received marketing authorization in multiple European countries but is not approved for clinical use in the USA. It seems plausible that the delivery platform of these drug implants could be applied to glaucoma as well. For example, a recent phase 2 clinical trial examined the safety and efficacy of a brimonidine intravitreal implant (200 or 400 mg) in patients with glaucomatous optic neuropathy [43]. Also, a recent study [44 ] found that a posterior segment reservoir could achieve substantial, dose-dependent drug levels in the aqueous humour as well. This would suggest the potential for targeting both anterior segment and posterior segment structure via a single procedure. &&
NOVEL APPLICATIONS OF SUSTAINED DRUG DELIVERY SYSTEMS Sustained drug delivery offers a platform to explore innovative therapeutic models for treating glaucoma. Neuroprotective factors delivered via periocular or intravitreal pathways might reduce damage to retinal ganglion cells and stimulate their growth and regeneration [45–47]. The same polymer-based scaffolds used with commercial glaucoma drugs could be applied to neurotrophic factors as well, opening the door for multiple glaucoma targets [48]. The benefits of gene therapy might also be enhanced by nanoparticles that can protect genetic cargo and enhance targeting of specific cell types [49,50]. Finally, the principles of extended drug release could be applied to glaucoma surgery, as in adjustable release of mitomycin C through polymeric or nanoscale carrier vehicles. Such an approach might lead to better inhibition of fibroblast proliferation than can be achieved with a one-time application of the drug [51,52].
CONCLUSION Topical medications play an important primary and adjunctive role in the treatment of glaucoma. However, the efficacy of these drugs is limited by poor patient adherence, low intraocular bioavailability and the potential for clinically significant local and systemic side effects. Novel delivery systems allow for a more efficient and targeted therapeutic approach with the potential to incorporate neuroprotective and gene therapy approaches. Topical gel solutions, punctal and conjunctival inserts, and contact lenses can improve the efficiency of drug delivery by increasing precorneal residence time and corneal permeation. Subconjunctival and subtenons injections allow for increased targeting of the posterior segment as well as sustained delivery over
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months with a single dose. Surgically implanted reservoirs offer the potential for an even more prolonged drug release. Patients with mild glaucoma that can be controlled with a single medication may still prefer gel-based formulations or drug-eluting contact lenses, particularly when cost is an issue. Patients with more complex drug regimens or personal limitations might prefer a subconjunctival injection every 3–4 months or a surgically implanted drug reservoir. There should be a reasonable amount of caution regarding the potential for allergy or immune-mediated response to polymers or other compounds in which the drugs are packaged. However, as novel delivery systems become clinically available, the ability to effectively treat glaucoma and preserve vision will be enhanced. Acknowledgements S.D.L. has received speaker fees (honoraria) from Alcon Laboratories, Inc. O.J.K. has nothing to disclose. The authors have no relevant sources of funding with regard to this manuscript. Conflicts of interest The authors have no financial or proprietary interest in materials and/or methods mentioned in this manuscript.
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