Sustained release ocular drug delivery systems for glaucoma therapy

ABSTRACT

Introduction

Glaucoma is a group of progressive optic neuropathies resulting in irreversible blindness. It is associated with an elevation of intraocular pressure (>21 mm Hg) and optic nerve damage. Reduction of the intraocular pressure (IOP) through the administration of ocular hypotensive eye drops is one of the most common therapeutic strategies. Patient adherence to conventional eye drops remains a major obstacle in preventing glaucoma progression. Additional problems emerge from inadequate patient education as well as local and systemic side effects associated with adminstering ocular hypotensive drugs.

Areas covered

Sustained-release drug delivery systems for glaucoma treatment are classified into extraocular systems including wearable ocular surface devices or multi-use (immediate-release) eye formulations (such as aqueous solutions, gels; ocular inserts, contact lenses, periocular rings, or punctual plugs) and intraocular drug delivery systems (such as intraocular implants, and microspheres for supraciliary drug delivery).

Expert opinion

Sustained release platforms for the delivery of ocular hypotensive drugs (small molecules and biologics) may improve patient adherence and prevent vision loss. Such innovations will only be widely adopted when efficacy and safety has been established through large-scale trials. Sustained release drug delivery can improve glaucoma treatment adherence and reverse/prevent vision deterioration. It is expected that these approaches will improve clinical management and prognosis of glaucoma.

KEYWORDS:

• Glaucoma
• IOP
• adherence
• fluctuation in IOP
• sustained-release drug delivery

1. Introduction

Glaucoma is the second most common cause of irreversible blindness worldwide [1]. By 2010, it had affected more than 60 million people around the world, leading to 8.4 million cases of sight loss. The number of glaucoma cases was predicted to exceed 111 million people by the year 2040 [2,3]. Glaucoma is often called ‘the silent thief of sight’ as it is symptomless in the early stages and can cause irreversible damage before vision is affected. However, in advanced glaucoma, patients frequently experience difficulty in night vision, with gradual deterioration of their eyesight, leading to blindness from damage to the optic nerve [4,5]. The primary risk factor for developing glaucoma is high intraocular pressure (IOP). Other predisposing risks include: certain medical conditions such as advanced age, ethnicity, and family history [6,7].

The goal of glaucoma pharmacotherapy is to maintain/control the IOP in a clinically acceptable range by using an ocular hypotensive agent. Currently, topical administration of eye drops is the most common method for treating ocular hypertension. Eye drops are easily formulated and have favorable characteristics, including low manufacturing costs [8,9]. However, precorneal contact time and ocular bioavailability are compromised by the barrier function of the ocular surface, the blinking process, and tear production. As a consequence, topical ophthalmic formulations are typically administered more than once daily at relatively high drug concentrations to maintain the required therapeutic levels of drug at the target site [10].

The major limitations of multi-dose regimens are patient adherence, local and systemic side effects [11,12]. Around 50% of glaucoma patients do not follow the dosing instructions properly, as convenience is a major factor negatively impacting patient adherence [13,14]. Approximately one-third of patients are incapable of effectively self-administering their eye drops [15,16]. Since glaucoma is mainly an elderly disease, conditions like rheumatoid arthritis may compromise dexterity and reduce the patient’s ability instill the medicine from an eye dropper; Parkinson’s tremor can make correct positioning for drop installation difficult [17]. Other noncompliance factors include failure to perceive an immediate treatment effect, cost, and the unavailability of generic medications, leading to a high treatment discontinuation, approaching 50% of the patients [18,19].

Many studies have shown fluctuations in IOP after treatment with eye drops, whereas systemic medications are less effective and tend to increase the risk of visual field deterioration [20,21]. Improving adherence and decreasing the intra- and inter-day variability in IOP is pivotal to improving glaucoma therapy [21,22]. Sustained release technologies or formulations can address many of the aforementioned issues [4,22–26]. In this review, we will critically appraise current glaucoma medications/dosage forms and shed light on the promising role of sustained release drug delivery technologies to improve such therapy. Evaluation of sustained-release formulations, device technologies, and those under preclinical and clinical development, along with potential future trends will be provided.

2. Challenges with current glaucoma medication and sustained release therapy

Prostaglandin analogues (bimatoprost, latanoprost, tafluprost, and travoprost) are considered the first line of therapy for glaucoma because of their efficacy in lowering IOP and fewer systemic adverse effects. However, high doses of prostaglandins may induce stinging, burning, hyperemia, eyelash changes, increased iris pigmentation, and increased periocular skin pigmentation [27,28]. Topical administration of prostaglandin analogues can only reduce visual field progression by about a half when compared with a placebo. This was the outcome of a randomized, controlled study in which glaucoma patients were given latanoprost 0.05% or placebo eye drops. The mean decrease in the IOP after 24 months was 3.8 mm Hg in the latanoprost group and 0.9 mm Hg in the placebo group [29].

Most glaucoma treatments today have been reported to effectively lower IOP [30,31]. However, they are unable to consistently flatten the diurnal curve of IOP. It has been previously shown that an increase in IOP fluctuation is associated with increased risk of visual field deterioration [21,32,33]. Furthermore, IOP fluctuations extended over a period of more than 24 h have been shown to contribute to glaucoma progression [21]. Therefore, continuous IOP monitoring over a 24-h period can provide a better measure for control of factors leading to IOP variability [34]. Ideally, sustained-release drug delivery over a continuous period (weeks, months, or even years) can achieve a desirable drug concentration at the target site over extended time periods. Additionally, limiting systematic side effects and enhancing patient’s adherence to therapy.

From a formulation perspective, sustained-release technologies would offer significant benefits to both patients and clinicians by providing better IOP control for over 24 h, eliminating poor adherence and reducing side effects. However, good efficacy and safety profiles are not always enough to get these products to the market; cost-effectiveness issues must also be addressed. For instance, Ocusert® was the first successful ocular insert introduced commercially (in 1975) with a controlled release system designed to provide zero-order release of pilocarpine over a week [35]. However, it was withdrawn from the market in 1993 due to its inefficiency in lowering IOP and excessive side effects, compared with conventional pilocarpine eye drops [36]. Other shortcomings of Ocusert® included difficulty in its insertion, expulsion from the eye, and drug leakage [37–39]. Usually, when new technologies are to be launched into the market, efficacy and cost are judged against current commercial products. However, to be both medically and commercially viable, sustained release products are required to be superior to what is available, safe, convenient for clinicians and patients, and also competitive in price [4,40]. Broadly speaking, sustained release formulations can be categorized as either extraocular or intraocular systems. Extraocular systems include eye gels, ocular inserts, contact lenses, periocular rings, and punctual plugs. Intraocular systems are considered to be rather invasive and include the likes of intraocular implants [22,41].

3. Extraocular drug delivery systems

An extraocular drug delivery system permits the steady release of IOP-lowering medications, promoting a more stable diurnal IOP with fewer side effects than conventional ophthalmic eye drops formulations. There are several commercially available extraocular drug delivery systems some that are currently being researched, including gel-forming eye drops, ocular inserts, contact lenses, and punctual plugs (Table 1). All are designed for maintenance of therapeutic drug levels on the ocular surface over a prolonged duration with minimal local adverse effects [68].

Table 1. Summary of the sustained release antiglaucoma systems in different stages of development.

Drug delivery system	Drug	Excipients	Drug delivery plat form	Status	References
Gel-forming drops SoliDrop DuraSite ISV-215	Brimonidine Bimatoprost	Poly (lactic-co-glycolic acid) polymer solventPentablock copolymer (polyglycolic acid)	Ocular surfaceOcular surface	Preclinical Preclinical	[42, 43]
Ocular insert Bimatoprost ocular insert	Bimatoprost	Silicone matrix, polypropylene	Conjunctival cul-de-sac/fornix	Phase II clinical trial	[44]
Contact lenses. Soak and release Vitamin E Film impernation in contact lens Enzyme Triggered Molecular imprinting Topical Ophthalmic Drug Delivery Device (TODDD^TM)	Brimonidine and timolol Timolol and dorzolamide Timolol and dorzolamide Latanprost Timolol Timolol	-Vitamin EMethafilconNanodiamond-gel--	Ocular surfaceOcular surfaceOcular surfaceOcular surfaceOcular surfaceOcular surface	Clinical Preclinical Preclinical Preclinical Preclinical Phase I/II clinical trial	[45,46] [47]. [48] [49] [50] [51]
Punctual plag OTX-TP Evolute	Travoprost Latanoprost	Polyethylene glycol–based hydrogel with loaded PLA-	PunctaPuncta	Phase II clinical trial Phase II clinical trial	[52] [53]
Intracameral implant DURYSTA ENV515 or Travoprost XR OTX-TIC iDose Travoprost PA5108 DE-117	Bimatoprost Travoprost Travoprost Travoprost Latanoprost Latanoprost	Navadur-poly (D, L) sustained Lactide-co-glycolic acid(PLAGA)----Polycaprolactone	Intravitreal implantIntracameral implantIntracameral implantIntracameral implantIntracameral implantIntracameral implant	Phase III clinical trial Phase II clinical trial Phase III clinical trial Phase III clinical trial Phase I clinical trial Preclinical trial	[54,55] [56,57] [58,59] [60,61] [62] [63,64]
Subconjunctival injection Durasert ™ POLAT-001	Latanoprost Latanoprost	-	Intravitreal implantSubconjunctival space	Phase I/II clinical trial Clinical II	[65,66] [67]

3.1. Gel forming (in situ gelling) drops

This approach is based on drug delivery from viscous, polymer-based systems that are liquid during instillation onto the eye but would rapidly change to a thin viscoelastic gel once in contact with the tear fluid, or once they are subjected to a physicochemical trigger, such as pH, temperature, or change in ionic strength. This change of the instilled solution from sol-to-gel, referred to as a phase change, extends the drug residence time and favors sustained drug release [68–70]. Using a gel for drug delivery also enhances ocular bioavailability, minimizes side effects, and improves patient compliance by reducing the dosing frequency. The ease of administration, delivery of an accurate and reproducible dose, and simple manufacturing process are additional advantages [68–70]. Specific polymers used in such formulations include: gellan gum, xanthan gum, carbomers, poloxamers, and cellulose derivatives [71–73].

Several ophthalmic gel formulations are available in the market for topical treatment of glaucoma, like Timoptic-XE® (Merck) containing timolol maleate in gellan gum, Pilopine HS® (Alcon Laboratories) of pilocarpine in carbomer, and Timolol® (GFS Alcon) containing timolol maleate in xanthan gum [74]. More recent research has led to the advanced anti-glaucoma ophthalmic gel formulations, SoliDrop, and DuraSite ISV-215.

3.2. SoliDrop

The SoliDrop (Otero Therapeutics, Pittsburgh, PA, U.S.A) is a gel-forming drop that uses poly (lactic-co-glycolic acid) microspheres, which can be loaded with a variety of drugs for long-term release in a topical eye drop formulation. The microspheres are incorporated into a reverse thermal, acrylamide-based hydrogel. After topical administration, the SoliDrop converts from a liquid into a semi-solid gel depot. The gel remains under the lower eyelid and continuously releases the desired drug for up to one month [42,75]. Once the polymer-containing gel comes into contact with the tear fluid, it begins swelling where it is capable of taking on large volumes of water while remaining insoluble [42]. When the therapy period ends, the gel is removed by washing the lower conjunctival fornix with normal saline. The gel expansion which accompanies polymer chain relaxation during swelling, facilitates controlled drug diffusion [76]. Fedorchak et al., examined the efficacy of long-term release of brimonidine from a SoliDrop eye drop formulation in glaucoma therapy [77]. The microspheres released an average of 2.1 ± 0.37 mg brimonidine tartrate per mg microspheres per day. The gel microsphere eye drop had an average volume diameter of 7.46 ± 2.86 μm [77]. At 33.5°C, the gel swells, sheds excess water, and shrinks to its semi-solid form. This gel is held at the ocular surface for 28 days [42]. Studies in rabbits showed a 30% reduction in IOP from baseline after administering a single dose of brimonidine-loaded gel, equivalent to the conventional brimonidine eye drops administered twice daily [42,77]. Single dose of the hydrogel/microsphere formulations (SoliDrop) was retained on the eye for the length of the study with sustained brimonidine in vivo release for over 28 days [42].

3.3. DuraSite ISV-215

DuraSite® (InSite Vision, Alameda, CA, U.S.A) is a sustained release technology that uses a synthetic polymer-based formulation (cross-linked polyacrylic acid, polycarbophil) to form a stable mucoadhesive matrix to prolong the precorneal residence time of drugs. Drugs that have been incorporated in DuraSite® platforms include diclofenac, levobunolol, pilocarpine along with numerous antibiotics. At present, two ocular antibiotic formulations using the DuraSite systems are marketed in the US, namely, Besivance® (0.6% besifloxacin) and AzaSite® (1% azithromycin) [43,78,79].

DuraSite ISV-215 uses pentablock copolymers as a mucoadhesive system to deliver 0.03% bimatoprost over a prolonged period [43]. The FDA approved biocompatible pentablock copolymers are composed of polymers such as polyethylene glycol, poly(caprolactone), and polylactic acid/polyglycolic acid [78,80]. Depending on the dose, the duration of release may be as long as two, four, or even six months. Once the drops come into contact with the ocular surface, the thermo-responsive pentablock copolymer(s) transform the drop into a gel [81]. Swelling of the gel leads to a buildup of hydrostatic pressure that squeezes the fluid in the drop, extending drug release over an extended period of time [82].

A study on rabbit’s eye of bimatoprost-loaded DuraSite ISV-215 revealed a 2.2-fold higher drug distribution in the aqueous humor and a 6.1-fold increase in drug concentration to the iris-ciliary body, compared with commercial bimatoprost ophthalmic solution. This improvement in key pharmacokinetic parameters is translated to equivalent efficacy in lowering IOP, enhanced therapeutic index, and decreased ocular side effects related to long-term use of topical bimatoprost [43].

3.4. Ocular inserts

Ocular inserts are sterile solid and semisolid formulations that are placed in the conjunctival sac between the surface of the eye and the lower eyelid. They are fabricated from polymeric systems, and usually contain a drug (although drug-free inserts are also used) and can be manufactured in a variety of sizes and shapes but are usually thin multi-layered cylinders. Normally, the drug is loaded into the polymeric system either in solution or as a dispersion [83]. Ocular inserts are often provided a sustained drug release, prolonged precorneal retention leading to increased ocular absorption [84,85].

Ocular inserts may release a medication by diffusion, osmosis, or bioerosion. Insert A ring on matrix diffusion-baes drug release (Helios™). This ring was developed by ForSight Vision5 Inc. (Menlo Park, California, U.S.A). Its dimensions are (24–29 mm in diameter, 1 mm in thickness) and is made of interior polypropylene support coated in bimatoprost 2.5 mg-loaded silicone [86,87]. Inserts that rely on an osmosis mechanism, usually contain an impermeable elastic membrane that divides the interior of the insert into first and second compartments. The first compartment is surrounded by a semi-permeable membrane made of cellulose acetate derivatives, ethyl vinyl acetate, polyesters of acrylic and methacrylic acids (Eudragit®) and an impermeable elastic membrane. The second compartment (drug containing) comprises water permeable membrane composed of ethylene-vinyl esters copolymers and an elastic membrane.

[88]. After placing the insert into the tear fluid, water diffuses into the first compartment, leading to stretching of the elastic membrane. The resulting expansion of the first compartment leads to a contraction of the second compartment, expelling the drug via a release orifice. With bioerosion, intraocular inserts made from bio-erodible polymers absorb the aqueous tears then undergo erosion, releasing the drug at a controlled rate [89,90].

3.5. Bimatoprost ocular insert

Bimatoprost insert developed by Brandt et al. and marketed as ‘Bimatoprost SR’ (Allergan plc, Dublin, Ireland) is a ring-shaped ocular device containing the ocular hypotensive prostamide bimatoprost covered with a silicone matrix to retard drug release and an inner poly(propylene) core for structural support. The diameter of the ring ranges from 24 mm to 29 mm. The device is inserted between the upper and lower fornix and is replaced after six months (Figure 1). Bimatoprost release into the tear fluid is based on passive diffusion through the silicone matrix, mediated by concentration gradient – driven mass transport of drug molecules. Drug release rate into the tear fluid is determined by factors, including the surface area of the silicone – drug matrix, physical properties of the silicone, and the concentration of bimatoprost in the matrix. Drug release into the tear fluid declined steadily over time, from 35 μg/day to 6 μg/day after six months [86].

Figure 1. (a) Schematic of the bimatoprost SR ocular insert. An internal polypropylene structural ring covered with a silicone-drug matrix for slow release of bimatoprost. (b) Photograph showing the insert outside the eye. (c) Placing the bottom part of the ring in the lower fornix. (d) After the insert is in place only a small part of it is visible in the medial canthus [86].

In a phase II clinical study, 130 glaucoma patients received either placebo ocular inserts, timolol maleate (0.5% ophthalmic solution) twice daily, or 13 mg bimatoprost ocular insert and artificial tears for six months [86]. The results showed that IOP was lowered by 3.2 to 6.4 mm Hg in the bimatoprost ocular insert group, compared with 4.2 to 6.4 mm Hg in the timolol group. Results suggested that the ocular insert was slightly less effective than the timolol topical eye drop. Generally, the ring was well tolerated, with more than 97% of patients reporting that bimatoprost ring was ‘tolerable’ or ‘comfortable.’ Side effects were similar to those of bimatoprost eye drops but with a higher rate of mucous production. The high retention rate exhibited by the ring (more than 90%) over 13 months treatment period indicated that there was little possibility of dislodgement [86].

In 2019, a phase Ib study assessing the safety and efficacy of an ocular insert containing a combination of bimatoprost and timolol for more significant IOP reduction was completed. The purpose of this study was to determine if a combination of these two drugs delivered to the surface of the eye over 10 weeks is superior at lowering (IOP) than either of the drugs delivered alone [91]. The combination eye drop Ganfort® (bimatoprost 0.03% and timolol 0.5%), caused a superior reduction in IOP with a more rapid onset of action due to the complementary mechanisms of action of each drug [11,92]. However, systemic adverse effects from the β-blocker, including hypotension, bradycardia, irregular pulse, and bronchospasm, resulted in decreased patient compliance. Less serious local adverse reactions related to bimatoprost, including eyelash lengthening, hyperemia, eyelid, and iris pigmentation may also decrease patient compliance.

3.6. Contact lenses

Soft contact lenses are made of chemically cross-linked networks of hydrophilic polymers. While their main use is for vision correction, they could be used for delivery of hydrophilic drugs, such as timolol and dorzolamide, which elute rapidly from the highly hydrated polymer networks [93,94]. Contact lenses are recognized as a promising drug delivery system since they are widely accepted by patients where those used for drug delivery are marketed as ‘smart’ contact lenses [95,96]. Soft contact lenses are made from 2-hydroxyethylmethacrylate (HEMA) [97]. Medicated contact lenses may provide controlled and sustained drug delivery. Passive diffusion is the primary mechanism for sustained drug release and prolonged drug residence time [98,99]. Medicated contact lenses that have been used in glaucoma treatment include: soak and release lenses, vitamin E – loaded lenses, enzyme-triggered release lenses, film impregnation in contact lenses, color contact lenses, and topical ophthalmic drug delivery devices (Figure 2) [96].

Figure 2. Schematic representation of different method used for ocular drug delivery through contact lenses: Soaking of lens in drug solution, vitamin E contact lens, molecular imprinted contact lens, and enzyme triggered contact lens [99,100].

3.6.1. Soak and release

The soaking method is a simple, cost-effective, and convenient way of loading drugs into contact lenses. It involves soaking the contact lens in the drug solution. Such contact lenses may contain cavities or internal channels to accommodate drug molecules. Many researchers have used the soaking method to formulate therapeutic contact lenses, which deliver anti-glaucoma drugs including pilocarpine, brimonidine, and timolol [45,101–103]. Schultz et al. studied the uptake and release of brimonidine tartrate and timolol maleate from contact lenses. In-vitro release demonstrated burst drug release with a plateau after 1 h, however, results in glaucoma patients (30 min use each day for two weeks) demonstrated a similar decrease in IOP to eye drops achieved with a one-tenth (1/10) of the dose. Although the soaking approach is quick and cost-effective, there are limitations. For most ophthalmic drugs, contact lenses have a low affinity. The drug is poorly retained by the contact lens where it is rapidly released (burst release), followed by a steep decrease in drug concentration. Burst release is unsuitable for therapeutic contact lenses in chronic eye diseases, such as glaucoma therapy, where sustained drug delivery is necessary [45,46].

3.6.2. Vitamin E – loaded lenses

Incorporation of vitamin E (tocopherol) into contact lenses can significantly prolong the release of hydrophilic drugs. The anti-oxidant properties of vitamin E can protect the cornea from UV radiation as well as susceptible drugs from oxidation [45]. This method is promising for hydrophilic drugs that do not dissolve in vitamin E, with tocopherol acting as a lipophilic barrier to drug release, prolonging diffusion time into the cornea [99].

Contact lenses loaded with vitamin E were loaded with timolol and dorzolamide, to extend their simultaneous release. The results showed that the incorporation of vitamin E prolonged the release duration for both drugs to around two days, improving IOP reduction compared with an eye drop. More interestingly, continuous use of the lenses for two days, with replacement by a new set of drugs loaded contact lenses for a further two days, resulted in a reduction in IOP over 4 days and for another 8 days after lens removal. These results provide convincing evidence that loading vitamin E into a contact lens is beneficial in glaucoma combination therapy. It controls the release, modulates the duration of action, and may significantly improve patient adherence [47].

3.6.3. Film impregnation in contact lenses

Ciolino et al. reported on latanoprost – poly (lactic-co-glycolic acid) films of varying thickness in Methafilcon A lenses. Results revealed an early burst drug followed by sustained release of latanoprost for one month. Contact lenses with thicker (40–45 mm in thickness) films released more drug after the initial burst drug release. The contact lenses were manufactured in two dosage variations: high (149 g) and low (97 g) latanoprost. The IOP-lowering effectiveness of high-dose and low-dose latanoprost-eluting contact lenses was compared to latanoprost eye drops in adult glaucoma monkeys with a 3-week washout time between the two treatments. Topical latanoprost reduced IOP by 2.9 1.0 to 6.6 1.3 mmHg, 97-g contact lenses by 4.0 1.1 to 7.8 3.8 mmHg, and 149-g contact lenses by 6.0 4.4 to 10.2 2.5 mmHg. In vivo results demonstrated that the lenses provided sustained release of latanoprost for one month with aqueous humor drug concentrations comparable to those obtained with latanoprost eye drops [48].

3.7. Enzyme-triggered timolol release

Kim et al. reported on nanodiamonds of poly(ethyleneimine) that were coated with an enzyme-cleavable polymer, chitosan via a crosslinking process, and loaded with Timolol to produce a nanogel. The nanogel was embedded within a poly(−2-hydroxyethyl) methacrylate (poly HEMA) matrix to produce contact lenses. The system released timolol in the presence of lysozyme while leaving the lens intact. After 24 h in the presence of lysozyme, the cumulative drug release from the lens was 9.41 μg. However, after 48 h of enzyme treatment, variability in the release rate profile was observed because of differences in lysozyme production between patients, especially in diseased ones. Other confounding factors were oxygen permeability, water content, and optical clarity [49].

3.8. Molecular imprinting

Molecular dynamics requires the use of a template drug molecule with functional monomers that can surround it during the contact lens polymerization process. This results in the formation of macromolecular memory binding sites and chemical groups that accommodate the drug, retaining an imprint of the drug’s structure. The molecularly imprinted pockets act like receptors or binding sites, for the drug of interest, or closely related analogues. This tailor-made binding increases drug loading via the imprinted monomers network, while achieving an adequate release rate [99,100,103]. A new contact lens was designed for timolol delivery in which a color change acts as a visual indicator of the extent of medication release. The contact lens was produced from a molecularly imprinted hydrogel with timolol-loaded nanocavities. The imprinted hydrogel was formed by polymerization of 2-hydroxyethyl methacrylate (HEMA) with small amounts of methacrylic acid around the timolol template. The resulting polymer accommodated a higher load (10 mg) timolol. The lens released the medication over 12 h and was then reloaded for a further 12-h release. As timolol diffused out of the contact lens, the iris changed color from yellow to blue, alerting the user to change the lens. Whilst, in vitro results are promising, animal experiments, followed by a human study, are essential to establish efficacy and safety [50].

3.9. Topical ophthalmic drug delivery device (TODDD^TM)

The Topical Ophthalmic Drug Delivery Device (TODDD, Amorphex Therapeutics) is a flexible, non-erodible topical device constructed from a soft elastomeric, non-hydrogel material that is placed in the upper conjunctival fornix (Figure 3). The TODDD is a large (20 mm length, 8 mm width, and 1 mm thickness), yet comfortable device that patients can easily insert and remove. Upon insertion into the eye (on the conjunctiva/sclera below the upper eyelid), the drug diffuses continuously from the device across the conjunctiva and sclera, without changing the shape of the device. TODDD provides sustained release of the drug for over 90 days. A wide range of drugs have been successfully incorporated into TODDD™ matrices including timolol, brimonidine, prostaglandin analogues, ibuprofen, dexamethasone, and prednisolone [51,104–106].

Figure 3. Therapeutics Topical ocular drug delivery device (TODDD^TM) [52].

Leahy et al. examined the effectiveness of a TODDD system loaded with 3 mg of timolol in rabbits. The results showed an optimal reduction in IOP of 5.5 mm Hg, representing a 37% improvement over baseline over 3 months [51]. Crawford, K., et al. evaluated the efficacy of a TODDD system equipped with ocular ring devices holding two latanoprost-drug depots (cylindrical cores, 600 µg latanoprost) in eight dogs over 16 days. The results indicated that the IOP reduction in the treated eye of around 3 mmHg on days 4 (n = 6) and 8 (n = 4), and 7 mmHg on day 16 (n = 3), representing a 37% reduction in IOP from baseline [107]. A human clinical study was conducted to check the safety and retention rate of TODDDs without a drug for one month. The results showed 75% of the subjects retained the device on the eye for one month, with an acceptable safety profile. A smaller, one-day study with a newer design showed over 90% success. A further clinical study indicated that the delivery of timolol from a single device took place in a continuous and uninterrupted manner over six months [108].

3.10. Punctual plugs

Punctual plugs are tiny, biocompatible devices inserted into tear ducts (canaliculi) to block tear drainage and maintain contact between the tears and the ocular surface. Punctual plugs are more comfortable than surface implants, and their insertion is less invasive. Improved efficacy and drug dose reduction are potential advantages of punctual plugs over conventional eye drop formulations. However, common drawbacks of these devices include excessive tearing, displacement, or ejection, bacterial infection from the occlusion, and foreign body sensation [4,96]. Diffusion is the mechanism by which a drug is released from a punctual plug into the tear fluid. Punctual plugs containing both solid and semisolid drug preparations have been developed with sustained-release properties of up to 3–4 months [109]. OTX-TP, Latanoprost punctual plug delivery system (L-PPDS)/Evolute are examples of such punctual plugs [52].

3.11. OTX-TP

The OTX-TP (Ocular Therapeutix, Bedford, MA, U.S.A), is a novel sustained-release travoprost delivery system that made of a rod-shaped, dried polyethylene glycol-based hydrogel. A punctum plug inserted into the superior or inferior canaliculus. Embedded in the punctum plug are poly (lactic acid) microspheres that contain encapsulated travoprost. After placement in the eye, the OTX-TP expands in volume as it hydrates in the tear fluid within the canaliculus. After that, microspheres progressively erode and dissolve by hydrolysis, releasing the medication in a regulated manner over a 30-day period.

In a Phase IIb trial, patients were assigned either an OTX-TP plug with placebo artificial tears or a placebo non-eluting plug containing timolol (0.5% ophthalmic solution). A greater reduction in IOP was observed in the timolol group (6.4–7.6 mm Hg) than in the OTX-TP group (4.5–5.7 mm Hg), possibly from prolonged contact time between the solution and the ocular surface caused by the placebo punctual plug. Retention rates for the plugs were 91% on day 60, 88% on day 75, but only 48% by day 90. Adverse events of hyperemia were not recorded for any of the patients receiving the OTX-TP [52].

In another trial, OTX-TP plugs were inserted onto the ocular surface in glaucoma participants. The retention rate of the plug was 100% and reduction in IOP was comparable with topical travoprost. On day 10, IOP declined to 24% and on day 30, 15.6%. On day 3, 38.5% of patients complained of ocular pain, which dropped to zero by day 20. Other adverse effects, including excessive tearing (3.8%) and itching (15.4%), tended to peak at 3 days and disappeared at day 30 [52,110]. A phase III trial is currently underway to evaluate the efficacy of the OTX-TP.

3.12. Evolute/Latanoprost punctual plug delivery system (L-PPDS)

The Evolute/Latanoprost Punctual Plug Delivery System (L-PPDS) (Mati Therapeutics, Austin, TX, U.S.A) was developed for lowering. The L-shaped punctual plug is composed of a core of latanoprost-polymer (cyanoacrylate) matrix surrounded by silicone. The reservoir matrix has an opening through which the drug is released after coming into contact with the tear film [111,112]. Mati Therapeutics has conducted two open-label phase II clinical trials to evaluate the safety and efficacy of various L-PPDS formulations for the treatment of open-angle glaucoma [111]. The first study included two groups treated with two dosages of latanoprost, 44 μg (group 1), and 81 μg (group 2) for 6 weeks. The punctual plug retention rate was high for both groups 77% (group 1) and 94% (group 2), yet loss of the plug or inadequate IOP control were the main reasons for discontinuation of treatment. The most common adverse effects reported were foreign body sensation and itching. Conjunctival hyperemia was also reported, but this was exclusively in group 2 [113]. In the second clinical study, participants were treated with two different formulations of 95 μg latanoprost for 12 weeks. The results showed a 20% reduction in IOP at three months with 92% plug retention. The punctual plugs had lowered the ocular pressure by 7 mm Hg compared with a 5 mm Hg reduction using latanoprost eye drops [53,113].

4. Intraocular drug delivery platforms

Intraocular drug delivery is to place drugs directly within ocular tissues by injection into the cornea (intrastromal), anterior segment (intracameral), or vitreous (intravitreal). Despite many advantages, intraocular drug delivery usually involves invasive/surgical interventions, which can cause complications such as hemorrhage, endophthalmitis, retinal detachment, cataract, and ocular hypertension [69,114]. Recently, intraocular drug delivery devices were designed for glaucoma treatment to provide localized controlled drug release over extended periods (Table 1) [41].

4.1. Intraocular implants

Intraocular implants could deliver drugs over a very long period, lasting months to years. They are well suited to a clinical setting and can often be injected via a minimally invasive procedure [115]. They offer many advantages, such as sustained and local drug release and reduced side effects [69]. Biodegradable and non-biodegradable polymers have been investigated for various routes of injection into the eye [69,96,115].

Intracameral implants serve as a reservoir system to provide sustained drug release for glaucoma treatment. Such implants are better accepted by glaucoma patients since a minimal drug concentration is needed and fewer side effects are observed compared with conventional eye drops. Intracameral implants are more invasive than subconjunctival implants. The subconjunctival route requires either injection or insertion of the implant beneath the conjunctiva. To inject (via the subconjunctival route) into the posterior segment of the eye, a bleb is initially formed which acts as a slowly depleting depot. The drug then has only the sclera and choroid to cross to reach its site of action, the retina [116]. The administration of glaucoma drugs from the subconjunctival space provides prolonged delivery for 3–4 months [115]. Biodegradable polymers have a substantial benefit over nondegradable systems because the entire system is eventually absorbed by the body, reducing the need for further removal. Potential complications include intraocular infection, implant migration, and inconsistent or overly prolonged biodegradation. In the latter case, difficulties may arise when implants degrade so slowly that residual material remains in the eye for months or even years [14,109,117]. Examples of intracameral implants used in glaucoma therapy include DURYSTA, ENV515, OTX-TIC, iDose Travoprost, PA5108, and DE-117. Subconjunctival injections or implants utilized in glaucoma therapy are Durasert and P0LAT–001 [36,41].

4.2. Intracameral implants

DURYSTA™ (Allergan plc, Dublin, Ireland) was approved in 2020 as a biodegradable implant for injection into the anterior chamber via a prefilled injector. It delivered 10 μg of bimatoprost to provide an IOP-lowering effect lasting for 4–6 months [118]. DURYSTA™ is based on the NOVADUR technology, which is the only clinically approved biodegradable intravitreal implant. The implant has a solid rod-shaped body that contains bimatoprost embedded within a biodegradable polymer matrix of poly(lactic-co-glycolic acid) (PLGA) (Figure 4) [54]. Lactic and glycolic acids completely converted to carbon dioxide and water leaving no residue in the eye [119]. The intravitreal implant was modified to release bimatoprost in a non-pulsatile, steady-state drug release fashion (zero-order kinetics) [54].

Figure 4. Bimatoprost Sustained Release (Bimatoprost SR) implant. (a) (Right): represents the implant injector system and (left) shows the implant with a dime coin for size comparison. (b) Gonioscopic photographs of Bimatoprost SR implant 10 μg in the anterior chamber of the eye of a glaucoma patient (note the swelling and degradation of the implant during therapy) (Left) 2 weeks, (Centre) 9 months, and (Right) 12 months after injection [54].

In a phase I and II paired eye trial, glaucoma patients received DURYSTA™ in one eye with topical bimatoprost 0.03% administered once daily in the other eye. After 16 weeks’ follow-up, IOP reduction from baseline was 7.2, 7.4, 8.1, and 9.5-mm Hg for eyes receiving 6, 10, 15, and 20 μg doses of implant, respectively, compared with 8.4 mm Hg in the other eye. Adverse effects were mild and transient and had mostly ceased within 2 days of the injection [54].

Patients with glaucoma were treated with either DURYSTA™ (at 2 dose strengths) or topical timolol drops, in a Phase III study to further evaluate the safety and efficacy. After 12 weeks, a reduction in IOP of more than 30% was recorded, with no need for supplementary treatment for 1 year after the insertion. Furthermore, a similar efficacy in IOP reduction compared with the timolol group was achieved [120]. A recent study in beagle dogs indicated that intracameral implantation may also be useful in lowering episcleral venous pressure. Intracameral implantation could therefore be used to exploit an additional mechanism to lower IOP, which is pharmacologically different from topical ocular drops. However, these results must be confirmed in human studies because of the significant anatomical differences between the aqueous humor production and drainage system of humans and dogs (Schlemm’s canal in humans versus venous plexus in dogs) [121].

4.3. ENV515 or travoprost XR

ENV515/Travoprost XR (Envisia Therapeutics, Morrisville, NC, U.S.A) is an implant that is injected into the anterior chamber of the eye. It releases travoprost over a period of 6 months using a biodegradable system that requires a single injection. This implant provides IOP reduction over 6 months and can be manufactured from poly(esteramide) (PEA) using PRINT® technology. The polymer is printed, filled with the active ingredient, and injected or inserted into the appropriate ocular site through a suitably sized needle [56,122,123]. The PEA polymer is used to fabricate ENV515 as a rod-shaped implant to provide sustained drug delivery for the treatment of ophthalmic diseases. PEA degrades intravitreally, following zero-order kinetics, resulting in the slow release of travaprost [122,124,125]. In a preclinical study using normotensive beagle dogs, intracameral insertion of ENV515 resulted in an average decrease in IOP of 35 ± 3% to 6.4 ± 0.6 mm Hg from baseline over 24 weeks, with a favorable safety profile and good implant stability [126]. A further Phase IIa clinical study was carried out, recruiting patients with ocular hypertension who had previously been treated with topical prostaglandins. After a washout period, intracameral implantation of the ENV515 to the study eye and topical timolol ophthalmic solution 0.5% was applied once daily to the contralateral eye. After 11 months of receiving a single dose, a mean reduction in IOP of around 6.7 ± 3.7 mm Hg (25% from baseline) was recorded. The device was well tolerated, without serious adverse effects, although dose-related transient hyperemia and eye redness were noted on occasions [127].

4.4. OTX-TIC

The OTX-TIC (Ocular Therapeutix, Bedford, MA, U.S.A) is a bioresorbable hydrogel implant that is injected into the anterior chamber. It is designed to release micronized travapost after a single injection of an intracameral implant and lowers IOP for 4–6 months. The OTX-TIC exploits hydrogel depot technology to achieve sustained zero-order release over approximately 6 months. Preclinical data on dogs demonstrated target concentrations of travoprost being reached within the aqueous humor with sustained IOP lowering effect and acceptable safety [58,128]. A study on rabbits was carried out to monitor the release of travoprost from intracameral hydrogel implants over 5 months. The results demonstrated that high levels of travoprost were maintained in the aqueous humor for 4 months compared with travoprost eye drops [129]. Finally, a randomized, double-blind, placebo-controlled Phase III clinical trial was specifically designed to evaluate the safety, durability, tolerability, and efficacy of OTX-TIC in glaucoma patients. The reduction of IOP from baseline ranged from 3.27 to 5.72 mm Hg over all time points. The trial did not achieve its primary endpoint of statistically significant mean reduction of IOP compared with placebo at all nine time points [59,130].

4.5. iDose travoprost

iDose Travoprost (Glaukos, San Clemente, CA, U.S.A) includes a reservoir housed in a titanium implant measuring 1.8 mm × 0.5 mm that is inserted into the anterior chamber and anchored within the trabecular meshwork. This implant is enclosed in a titanium membrane that regulates the release of travoprost into the anterior chamber over one year. When the device is depleted of drug, the reservoir of the implant may be removed and replaced (Figure 5). While iDose Travaprost controls IOP over a year after a single ophthalmic procedure, it requires a more invasive procedure than DURYSTA™, ENV515, or OTX-TIC where gonioscopy is required during insertion [60]. A phase II clinical trial demonstrated an average IOP reduction of around 33% over 12 months with iDose Travaprost. A randomized, double-blind Phase III clinical trial is currently being planned [61].

Figure 5. iDose Travoprost implant (a) the iDose implant device magnified. (b) the device anchored to the sclera.

4.6. Pa5108

The PA5108 (PolyActiva, Melbourne, Australia) is a rod-shaped biodegradable implant for insertion into the anterior chamber using a 27 G needle to provide 6-months release of latanoprost.

Drug release begins immediately upon insertion, and a constant daily dose is delivered continuously over the treatment period. Zero-order release profiles are achieved without any ‘burst’ effect on the first day of treatment. PolyActiva has introduced a technology platform that enables slow drug release, combined with specific drug delivery to the site of action [131]. PolyActiva relies on poly(ester), poly(triazole) or poly(urethane) systems, which biodegrade either alone or in combination to release the active drug. PA5108 composed of latanoprost acid that is covalently attached to a monomeric polymer unit through a labile linker. The precise structure of the polymer or the labile linker to latanoprost acid has not yet been disclosed. Polymerization of the drug-monomer with appropriate co-monomers or polymer segments occurs. The polymer in PA5108 is a polytriazole hydrogel that allows for 20 weeks of medication release before the polymer backbone biodegrades [132]. In a preclinical study on 10 glaucomatous dogs, three different formulations of latanoprost implant including PA5108 were evaluated. IOP was reduced after 10, 19, and 34 weeks compared latanoprost eye drops and placebo implants. The implants were well tolerated with no sign of inflammation [62]. A Phase I safety and tolerance clinical trial is now pending [133].

4.7. DE-117

Santen Pharmaceuticals has developed the novel hypotensive prodrug, omidenepag isopropyl (DE-117), for glaucoma treatment. The active metabolite of this medication (omidenepag) has a unique mechanism of action that is unlike that of other currently available glaucoma medications. Unlike prostaglandin analogues that binds the F2-alpha receptor and can only increase outflow via the uveoscleral pathway, DE-117 is a selective agonist for the prostaglandin receptor EP2 and can increase aqueous humor drainage through both the trabecular and uveoscleral outflow pathways [63,134].

Santen developed a poly(caprolactone) (PCL) intracameral device that is implanted into the anterior chamber through a corneal incision. The device is loaded with DE-117 powder and encapsulated between thin films of PCL that biodegrade in vivo to provide sustained drug release over six months of glaucoma therapy. Thin films of polymer provide better control of drug release over an extended period compared with particle-based drug delivery, by increasing the total quantity of loaded drug while controlling release over the diffusive polymer barrier [63]. In vitro studies have demonstrated zero-order release kinetics with a release rate of 0.5 μg/day of DE-117 over six months. Subsequent implantation of DE-117 in 16 normotensive rabbits’ eyes led to a statistically significant IOP reduction compared with untreated eyes or with placebo PCL devices. Tolerability was good, and rates of iris trauma and hyperemia during the implantation procedure were 19% [63,64]. An ophthalmic solution of omidenepag isopropyl 0.002% (EYBELIS®) received approval in Japan in 2018 for the treatment of glaucoma and ocular hypertension [134,135].

5. Subconjunctival injection

5.1. Durasert™ (Latanoprost)

Durasert™ technology (pSivida Corp., Watertown MA, U.S.) has a drug core with one or more surrounding polymer layers to deliver drugs over predetermined periods varying from days to years. The drug release is controlled by the permeability of the polymer layers. Durasert™ technology comprises a biodegradable implant that is approximately the size of a rice grain (3 to 4 mm in length, 0.4 mm in diameter) with high drug loading capacity (up to 80%) and linear release kinetics. The implant can be inserted into the subconjunctival space using a 25-gauge needle. The Durasert™ has been used to release latanoprost for up to 12 months [65]. Phase I/II trials are being conducted to determine the safety and efficacy of the Durasert™ implants [65,136–139].

5.2. POLAT-001

The POLAT-001 (Peregrine Ophthalmic Pte Ltd, Singapore) is a nanoliposome formulation, containing latanoprost for injection into the subconjunctival space. A single subconjunctival injection of the liposomal formulation into rabbit eyes led to a sustained IOP lowering effect over a period of 50 days with an IOP reduction comparable to daily eye drop administration. In a trial with six ocular hypertensive patients, a single subconjunctival injection of POLAT-001 gave an IOP reduction of more than 20%, which lasted for 3 months [140]. The hydrophobic properties of the latanoprost allow it to concentrate in the liposome within the fatty chains of the lipid bilayer, giving a high drug loading efficiency (94%), corresponding to a total drug load of ~1 mg/ml. Additionally, the hydrophobic properties of the bilayer limit the rate of drug partitioning out of the liposome into the aqueous environment of the subconjunctival space. These properties account for the significant reduction in IOP observed over an extended period in the clinical trial with six patients [140,141]. An open-label Phase II clinical study comparing POLAT-001 with a latanoprost ophthalmic solution is pending [142].

6. Conclusion

The future of glaucoma therapeutic management lies in the improvement of patient adherence to prescribed topical leading to the prevention of vision loss. The development of sustained release platforms for the delivery of ophthalmic drugs has the potential to address both objectives. This review has highlighted a diverse range of sustained-release ophthalmic drug delivery systems that are at different stages of research and development, which collectively represent the beginning of a new era in glaucoma therapy. However, these innovations will only be widely adopted when efficacy and safety has been proven through large-scale trials. Nevertheless, the advantages of sustained-release medications cannot be ignored; firstly, drug release can be prolonged over weeks, months, and even years, while still maintaining therapeutic drug concentration in the eye. This minimizes adverse effects associated with repeated topical administration and helps to preserve vision. Secondly, sustained drug release improves patients’ adherence to the treatment by reducing or even removing the need for daily dosing. The frequency and extent of side effects associated with combination glaucoma therapies decreases. Some of the implants described are biodegradable and hence would not require removal at the end of the therapy. Thirdly, sustained drug release with effective drug delivery will also maximize the efficacy of treatment, decrease drug wastage, and reduce side effects. Intraocular implantation overcomes absorption barriers, enhancing intraocular bioavailability. Finally, sustained release systems have the potential to preserve vision in glaucoma through IOP-lowering and may even lead to the reversal of optic disc damage via neuroprotection. It is expected that these approaches will improve clinical management and prognosis of glaucoma and subsequently improve the lives of many patients.

7. Expert opinion

Adherence to conventional therapy is a significant barrier to the effective management of glaucoma. Most glaucoma patients are non-adherent to their treatment regime, leading to poor control of IOP and loss of vision. Whilst some of the conventional sustained-release glaucoma formulations may improve patient adherence, they are likely to pose a greater risk of serious adverse complications, such as infection, inflammation, retinal detachment, and hemorrhage. Intraocular injections are contraindicated in certain patients; retention of punctal plugs has been problematic [42,143].

Extraocular drug delivery systems enable gradual release of the IOP-lowering-drug, promoting better diurnal control of IOP with fewer side effects, compared to eye drops. They offer the advantage of being less invasive, allowing self-administration, or at most via a simple visit to the clinic for implantation. However, the shorter durations of action, poor efficacy, and side effects associated are limitations that need to be addressed. Conjunctival hyperemia, punctate keratitis, and eye secretion are common side effects of extraocular bimatoprost inserts [86]. High incidence of undesirable effects has been reported in patients wearing the L-PPDS latanoprost-eluting punctual plug [144,145]. Patient education on the correct plug insertion to avoid movement, itching, and wiping is essential [146].

Intraocular drug delivery, on the other hand, promotes anti-glaucoma therapy without ocular side effects and may be used for patients who are either intolerant of or noncompliant with traditional topical therapy. A longer duration of action and more effective therapy is possible than with extraocular systems, but more invasive intervention is required. Intracameral implantation provides sustained drug delivery, which bypasses the corneal and precorneal barriers to reach the target tissues, and it requires minimal patient intervention post implantation [63]. A good example is DURYSTA™, which showed similar efficacy to topical eye drops but with a significant reduction in conjunctival hyperemia and eyelash growth [54]. The most surprising feature of DURYSTA™ is that intracameral implantation was found to act as an additional mechanism in lowering IOP [121].

Two separate subconjunctival systems have been studied in clinical trials including (POLAT-001 and DURYSTA™). They are produced either as a liposomal, microparticle, or nano implanting formulations. In addition to the implantation of the device, the depot formulation offers sustained drug delivery and a significantly reduced dose frequency, providing efficacy with minimal toxicity. The benefits of implanting such a formulation into the subconjunctival space are twofold; firstly, a smaller gauge needle (30 G) is required compared with bimatoprost SR that employs a (28 G) needle size [54]. Secondly, the suspension formulation can be tailored to exploit the high drug loading capacity of the subconjunctival space. By using liposomes as the carrier for a hydrophobic drug such as latanoprost in POLAT-001, a high drug loading efficiency (94%) can be achieved via the large volume of the subconjunctival space, which is far larger than intracameral space [140,141].

The overall advantages of implantable delivery systems in glaucoma are to reduce dosing frequency through sustained drug delivery, ensuring patient adherence. Preventing neuronal loss and disease progression, while highly desirable, is still under investigation.

Article highlights

• Over 55 million people worldwide are affected by primary open-angle glaucoma (POAG) which if untreated would lead to irreversible sight loss

• Ocular hypotensive drugs administered as eye drops are often associated with therapy failure due to systemic and local side effects as well as poor adherence, especially in the elderly population

• Extraocular and intraocular sustained drug delivery systems for glaucoma treatment could provide improved therapies with better patient adherence

• These approaches will improve clinical management and prognosis of glaucoma and subsequently the lives of many patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.