Inhibitors of vascular endothelial growth factor (VEGF) have become the standard of care in the treatment of numerous retinal diseases; however, their dosing regimen imposes a significant treatment burden, requiring frequent administration to maintain vision or improve retinopathy results. Adherence to this high injection burden can be challenging, and failure to receive regular treatments is a significant risk factor for vision loss in eyes with macular disease or retinopathy progression in diabetes.^1,2

Sustained-release drug delivery (SRDD) technologies intend to reduce the treatment burden by providing therapeutic drug concentrations to affected tissues while reducing systemic exposure, potentially resulting in improved safety and better long-term disease control. Many SRDD technologies that deliver drugs of various classes are in clinical development for the treatment of retinal diseases. These technologies use a variety of polymers to incorporate and slowly release the active agents over time. Polymers are higher molecular weight linear or branched chains of repeating units called monomers that may be further crosslinked across their units to create a structure and network.

OPTIMAL POLYMER ATTRIBUTES

A key attribute of polymer-based SRDD technologies is bioresorption: as they degrade (biodegradation) or dissolve (bioerosion) in the body, the polymer materials are cleared by biological processes. The use of degradable polymer technologies in combination with a nondegradable device, such as a polyimide tube (Yutiq; Eyepoint Pharmaceuticals) or silicone cup (Retisert; Bausch + Lomb), have been effectively used in the ocular space for long-term SRDD applications with the understanding that these nondegradable components will either persist or require removal after drug release. Ideally, polymer SRDD technologies should erode or degrade completely to allow for repeat dosing without accumulation of empty vehicles that may restrict or limit repeat administration.

Any material placed within the eye should be biocompatible and nontoxic. Specifically, the material should not be proinflammatory or immunogenic. The byproducts liberated through polymer degradation or erosion should also be inert, nontoxic, noninflammatory, and readily cleared. An ideal polymer also has high spatial efficiency to incorporate the necessary amount of active drug required for sustained and durable efficacy while minimizing the implant size. Smaller implants can be delivered via injection, while larger implants may require surgical implantation. Implants that are large or made with rigid materials may pose a greater risk of long-term adverse events than smaller, softer injectable implants. Optimally, a polymer-based SRDD technology would accommodate the incorporation of a variety of types and sizes of drugs and even potentially multiple different drugs for applications where multidrug therapy is indicated.

Polymer choice is a key determinant of drug release that differentiates various SRDD technologies. Polymer-based SRDD technologies should possess appropriate pharmacokinetic and pharmacodynamic properties to ensure the safe administration and delivery of the required amount of drug within the therapeutic index for the targeted duration of therapy. Drug is released from the polymer network as the polymer degrades and/or through the network matrix on the basis of low solubility and diffusion into the surrounding environment. Preferably, the polymer used for retinal therapeutics can deliver drug over extended periods of time at a rate designed to provide therapeutic benefit.

Many different polymers are used for drug delivery systems throughout the body. For the treatment of retinal diseases, the most common polymers being incorporated into SRDD technologies in development include hydrogels, polylactic-co-glycolic acids (PLGAs), and polyvinyl alcohols (PVAs). The attributes of each of these polymers is described below and in Table 1.

HYDROGELS

Hydrogels are polymers composed of various classes of monomers that are physically and/or chemically cross-linked to maintain their 3-dimensional structures while being able to take on large quantities of water. Cross-linked hydrogels are formed through covalent bonds providing stability to the hydrogel structure. Dissolved drugs or particulate drug suspensions are entrapped in the hydrogel network during cross-linking. Hydrogels are customizable to deliver small molecules, peptides, large proteins, or biologics.

Drug release occurs through dissolution and diffusion and/or by gradual biodegradation of the hydrogel. The drug release rate from these hydrogels can be controlled by the type and degree of cross-linking, polymer modification, molecular weight, and other physicochemical properties.³ They are aqueous, soft, and elastic when hydrated. As a class, hydrogels are generally highly biocompatible with little to no immune or inflammation reactions and completely biodegrade into smaller polymer chains through hydrolysis, leaving no harmful byproducts behind. To date, the FDA has approved more than 2 dozen hydrogel-based therapeutics for a wide variety of indications.⁴

Current hydrogel-based ocular SRDD technologies include Elutyx technology (Ocular Therapeutix, Inc) used in the FDA-approved dexamethasone intracanalicular insert (Dextenza) for the treatment of postoperative pain and inflammation and for the treatment of ocular itching associated with allergic conjunctivitis. This hydrogel insert delivers tapered dexamethasone onto the ocular surface for up to 30 days regulated by passive diffusion. Elutyx technology can be designed to release drug across days, weeks, or months. Clinical development is ongoing for OTX-TKI, an SRDD consisting of the highly potent tyrosine kinase inhibitor (TKI) axitinib entrapped within a cross-linked, bioresorbable Elutyx technology matrix, for treatment of age-related macular degeneration (AMD), diabetic retinopathy (DR), and other VEGF-mediated retinal diseases.^5,6 OTX-TKI is a single soft, flexible, hydrogel intravitreal implant injected through a 25-gauge needle. Axitinib has the highest binding affinity for VEGF receptors of all the TKIs currently in development for retinal vascular diseases, thus allowing incorporation of less drug into a single implant.^7,8 In preclinical studies there was no evidence of an inflammatory response⁹ and no histologic changes to ocular tissues.¹⁰ Early-phase clinical evaluation suggests that a single intravitreal OTX-TKI implant bioresorbs within 9 to 10 months.¹¹ In a follow-up clinical trial, 73% of the subjects injected with a single OTX-TKI implant did not require rescue treatment at least up to 10 months.¹² The Elutyx technology is also the polymer platform in investigational products for glaucoma (OTX-TIC),¹³ dry eye disease (OTX-CSI),^14,15 and episodic dry eye disease (OTX-DED).¹⁶

POLYLACTIDE AND POLYLACTIC-CO-GLYCOLIC ACIDS

Polylactide (PLA) and PLGA are used in numerous medical and pharmaceutical devices. PLGA polymers consist of copolymerized lactic and glycolic acid monomers forming a polyester backbone. PLGAs are completely bioerodible through hydrolytic cleavage of the polyester backbone into lactic and glycolic acids. Although these are each nontoxic and readily metabolized, they can create an acidic milieu in the locale of the depot that has the potential to damage nearby tissue.¹⁷ The ratio of lactic to glycolic acid can be varied in PLGAs to control the degradation rate, with more lactic acid for a more hydrophobic polymer (slower degrading) and more glycolic acid for a more hydrophilic polymer (faster degrading).¹⁸

Polylactic-co-glycolic acids can incorporate many types of molecules, including vaccines, proteins, DNA, RNA, and peptides.¹⁹ Drug release is controlled by the degradation rate as well as water penetration/solubilization, erosion, and diffusion of polymer fragments, and the rate of diffusion of the drug being released.¹⁸ Three phases of drug release have been described: an initial burst from surface erosion of the implant, a diffusion phase during biodegradation, and a final burst from disintegration of the implant.²⁰ Such a release pattern favors drugs that benefit from a loading dose followed by a taper, while the trade-off is early and late peak concentrations with potential toxic effects.

Examples of currently approved PLGA-based SRDDs for ocular use include the dexamethasone intravitreal implant (Ozurdex; Allergan/AbbVie) as well as the bimatoprost anterior chamber intraocular implant for glaucoma therapy (Durysta; Allergan/AbbVie). Local acidity arising from PLGA degradation has been proposed as a potential explanation for the corneal injury seen after anterior migration of the dexamethasone intravitreal implant.^17,21 The bimatoprost SRDD, which is intended for anterior-chamber placement, is indicated for single use only due to the increased risk of progressive corneal endothelial cell loss with repeated administration. The mechanism for this is unknown,²² and local mechanical abrasion may play a role due to the rigid nature of the PLGA structure. Development of a TKI-based SRDD technology formulated as self-aggregating sunitinib malate PLGA microspheres (GB-102; Graybug Vision) has ceased.

POLYVINYL ALCOHOL

Polyvinyl alcohol (PVA) is a partially or fully hydrolyzed polymer of vinyl acetate. PVAs are permeable polymers that regulate drug diffusion and may be coupled with less permeable ethylene vinyl alcohol (EVA) to control the diffusion area.²³ SRDD technologies made with PVA can release drug over weeks, months, or years. PVA will generally be bioerodible, but it may be combined with reservoir structures that are not bioerodible to modulate the surface area and the drug release rate. Polyvinyl alcohol polymers can deliver a wide array of different molecule types. The PVA cylindrical forms are injectable, whereas other shapes require surgical implantation and potentially removal with redosing.

Polyvinyl alcohol–based SRDD technologies for ocular drug delivery have been developed and commercialized. Durasert (EyePoint Pharmaceuticals) is used as the delivery platform of 3 different fluocinolone acetonide products, including Retisert (Bausch + Lomb) and Yutiq (EyePoint Pharmaceuticals) for noninfectious posterior uveitis, and Iluvien (Alimera) for diabetic macular edema. Retisert must be surgically implanted, whereas Iluvien and Yutiq can be injected using a 25-gauge needle. A PVA implant currently in development is EYP-1901, a TKI (vorolanib; EyePoint Pharmaceuticals) being evaluated in AMD and DR.^24,25 Unlike the other Durasert SRDDs, EYP-1901 does not contain a nonerodible component to enclose the drug reservoir and is thus completely erodible.²⁶ EYP-1901 is injected through a 22-gauge needle.²⁷ This delivery system is designed to last approximately 6 months or longer, and in an early-phase trial, 53% of eyes with AMD receiving EYP-1901 did not require rescue therapy at 6 months.²⁶

SUMMARY

Polymers are an integral component of SRDD technologies targeting diseases of the posterior segment of the eye. Ideal polymers create soft SRDD structures that are completely biocompatible and bioresorbable. In addition, their degradation byproducts should be metabolized or otherwise eliminated from the body. These polymers can be designed as needed to control the rate and duration of drug delivery. Common polymers incorporated into ocular SRDD platforms include hydrogels, PLGAs, and PVAs. Ongoing research into materials science and bioengineering are likely to produce SRDDs capable of delivering therapeutics to all tissues and compartments of the eye, improving outcomes for patients with a variety of ocular diseases. RP

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