Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Ta-Hsin Tsung
,
Yu-Chien Tsai
,
Hsin-Pei Lee
,
Yi-Hao Chen
,
Da-Wen Lu

Ocular drug delivery is a challenging field due to the unique anatomical and physiological barriers of the eye. Biodegradable polymers have emerged as promising tools for efficient and controlled drug delivery in ocular diseases.

  • biodegradable polymers
  • nanomedicine in ophthalmology
  • ocular drug delivery
  • controlled drug release
  • sustained drug delivery

1. Introduction

The human eye is a highly intricate organ protected by robust anatomical and physiological barriers, rendering it an immune-privileged organ, and impeding systemic circulation [1]. The eye’s structure can be classified into two primary segments: the anterior segment and the posterior segment. The anterior segment encompasses the cornea, conjunctiva, aqueous humor, iris, ciliary body, and lens, while the posterior segment primarily comprises the vitreous humor, sclera, retina, choroid, and optic nerve. The intricate anatomy and physiology of the eye impose inherent and unique barriers that serve to protect against environmental toxins and microorganisms. However, these barriers also pose significant challenges in achieving effective ocular drug delivery. Traditional methods of drug administration, including topical eye drops and ointments, often exhibit an inadequate bioavailability and limited therapeutic outcomes [2]. These limitations arise from various factors such as tear turnover, tear film dynamics, and the presence of ocular barriers such as the cornea, conjunctiva, and blood–retinal barriers [3][4][5]. Consequently, frequent high-dose administrations are typically required, contributing to patient noncompliance and treatment failure.
These limitations have necessitated the demand for innovative strategies to enhance drug delivery to targeted ocular tissues and improve therapeutic efficacy. Biodegradable polymers have emerged as promising candidates for ocular drug-delivery systems (DDSs) due to their ability to undergo degradation, thereby enabling the controlled and sustained release of drugs at the targeted site. Through their controllable degradation, they enable precise and sustained drug release at the designated site. Moreover, the inherent properties of biodegradable polymers, such as their biocompatibility, adaptability, and versatility in formulation, align effectively with the unique requirements imposed by the eye’s structure and function. Utilizing biodegradable polymer-based DDSs offers the potential for multiple benefits, including enhanced drug stability, an extended residence time in ocular tissues, improved drug bioavailability, a reduced dosing frequency, and the possibility for targeted delivery to specific ocular tissues, thereby bridging the gap between the eye’s natural barriers and therapeutic needs [6].

2. Biodegradable Polymer-Based Drug-Delivery Systems for Ocular Diseases

The eye’s anterior and posterior segments are susceptible to an array of vision-threatening diseases. Notably, disorders like glaucoma, anterior uveitis, and ocular surface conditions such as dry eye disease and keratoconjunctivitis predominantly impact the anterior segment. Conversely, the posterior segment is frequently compromised by conditions like age-related macular degeneration, diabetic retinopathy, and retinal vascular occlusions. The recent upsurge in attention towards biodegradable DDSs highlights their promising role in treating various ocular afflictions. They provide a targeted and prolonged release of therapeutic agents, improve drug stability and bioavailability, and offer possibilities for specific drug delivery. Consequently, this results in the overall enhancement of drug efficacy and a reduction in systemic adverse effects. These beneficial features can notably improve patient compliance and treatment outcomes, particularly in managing chronic ocular diseases that frequently require prolonged treatment. These systems are being leveraged to treat a diverse range of ocular diseases, and their application is discussed in subsequent sections in greater detail.

2.1. Anterior Segment Diseases

2.1.1. Glaucoma

Glaucoma, a group of ocular disorders characterized by progressive optic nerve damage, stands as a leading cause of irreversible blindness globally [7]. Primarily, the condition is associated with elevated intraocular pressure (IOP), often resulting from impaired aqueous humor outflow. Despite its common occurrence, the pathogenesis of glaucoma remains complex and not fully understood. Consequently, the medical and surgical interventions currently available primarily focus on lowering IOP, which is the only modifiable risk factor to date. Pharmacological treatments for glaucoma, which encompass beta blockers, prostaglandin analogs, alpha agonists, and carbonic anhydrase inhibitors, are usually the first-line therapy. However, patient noncompliance often arises due to the inconvenience of frequent dosing, local side effects, and the asymptomatic nature of early-stage glaucoma [8]. Surgical interventions, on the other hand, can lead to complications such as hypotony, infection, and cataracts [9][10]. Laser therapy, a middle ground between pharmacological and surgical treatments, does not always provide long-term IOP control and may need to be repeated or supplemented with medication or surgery [11]. These challenges underscore the need for innovative, effective, and long-lasting glaucoma treatments.
Addressing the shortcomings of current glaucoma therapies, recent scientific focus has been geared towards the development of biodegradable polymer-based DDSs. These offer the targeted, sustained delivery of therapeutic agents to overcome the barriers presented by the eye’s unique anatomy and physiology, facilitating effective drug delivery to the anterior segment. These systems also aim to improve patient compliance by reducing the dosing frequency and minimizing systemic side effects. Numerous antiglaucoma pharmaceuticals, such as latanoprost, dorzolamide, brinzolamide, timolol maleate, brimonidine, and pilocarpine, have been the subject of research in diverse biodegradable DDSs [12]. These include polymeric NPs [13], microneedles [14], inserts [15], and in situ hydrogel systems [16][17][18][19][20][21]. For example, Franca et al. developed a chitosan/hydroxyethyl cellulose insert aimed at facilitating the sustained release of dorzolamide. Administering this ocular insert to male Wistar rats resulted in a notable decrease in the IOP for a two-week period, a change not seen in either the untreated or placebo groups. Moreover, this insert exhibited a protective effect against the death of retinal ganglion cells [15]. In a different study carried out by Pan and colleagues, they employed PLGA NPs to carry both dexamethasone and melatonin. These NPs consistently released both drugs in vitro without a burst, showed no toxicity on the R28 cells, and improved retinal penetration while significantly reducing the IOP in a rabbit eye mode [22]. In situ hydrogels, particularly those derived from gelatin, are the subject of intensive investigation for glaucoma management. A biodegradable in situ gel delivery system intended for the intracameral administration of pilocarpine was proposed by Lai et al. Gelatin-g-poly(N-isopropyl-acrylamide) was employed to produce these copolymeric carriers. The resultant carriers demonstrated a significant reduction in IOP alongside remarkable miotic effects [23]. El-Feky et al. crafted a semisynthetic chitosan–gelatin hydrogel by using oxidized sucrose, providing a sustained release of timolol for ocular hypertension control. This hydrogel, with proven mucoadhesive properties, released timolol slower than conventional eye drops, thereby extending its efficacy in male albino rabbits [19]. These formulations have shown promising results in terms of improved bioavailability and sustained drug release.
In a landmark achievement in March 2020, Durysta®, a PLGA-based, biodegradable, sustained-release, IOP-lowering implant, received FDA approval. Durysta®, a product from Allergan plc, is a rod-shaped polymer matrix housing 10 µg of bimatoprost for gradual ocular release over an extended period. The implant is designed to address nonadherence issues in glaucoma treatment, offering a prolonged, reliable, and convenient therapeutic solution [24]. Evidence for its safety and effectiveness comes from the results of two Phase III clinical studies, known as ARTEMIS 1 and 2 [25][26], and patients reported substantial implant biodegradation within a year and effective IOP control for over three years.
Durysta® stands as the only approved biodegradable drug-delivery system, though many alternatives are under active exploration. For instance, ENV515 travoprost Extended Release, a rod-shaped, biodegradable intracameral implant, is fabricated by using the PRINT® technique and a PLGA-inclusive polymer blend. Designed to deliver a steady supply of travoprost over 6 to 12 months, patients treated with ENV515 demonstrated similar IOP reductions to those treated with either topical travoprost 0.004% or topical timolol 0.5% [27]. Additionally, sustained IOP-reducing effects lasting 8 months after a single implantation were observed in both hypertensive and normotensive Beagle dogs in preclinical studies, affirming its safety and tolerability [28].
Ocular Therapeutix is currently investigating another biodegradable intracameral implant called the OTX-TIC. This implant comprises a soft hydrogel platform encapsulating travoprost-loaded microparticles, all maintained in a meshwork structure. A Phase 1 clinical trial evaluated the safety, effectiveness, durability, and tolerability of the OTX-TIC implant [29].
An innovative biodegradable implant called latanoprost FA SR, shaped like a rod and designed for intracameral use, is being pioneered by PolyActiva, situated in Parkville VIC, Australia. The objective is to utilize this to administer latanoprost, aiming to alleviate primary open-angle glaucoma. Currently, it is under assessment in Phase II clinical trials. The goal of these trials is to achieve a reduction in IOP by 20% within the low-dose patient group. The future trajectory in DDSs for glaucoma therapy could see the incorporation of combination therapies in a long-acting delivery device. Moreover, a ground-breaking extended-release system synchronized with a device that monitors intraocular pressure is considered advantageous.

2.1.2. Anterior Uveitis

Uveitis is an inflammatory condition that affects the uveal tract, which encompasses the iris, ciliary body, and choroid. Symptoms typically include redness, pain, light sensitivity, blurred vision, and floaters. Depending on the part of the uvea affected, uveitis is classified into anterior, intermediate, posterior, and panuveitis. It can occur at any age and can be acute, recurrent, or chronic. The underlying cause can vary widely, including autoimmune disorders, infections, and injury, or it can sometimes be idiopathic. Treatment often entails the use of anti-inflammatory medications, corticosteroids, and other immunosuppressive agents [30]. Despite the availability of effective systemic and topical anti-inflammatory medications, the treatment of uveitis remains a challenge. One reason is the need for frequent dosing, which can lead to poor patient compliance and, consequently, disease recurrence. The frequent application of eye drops can also cause local side effects like cataracts and glaucoma. Moreover, the systemic administration of drugs may cause severe side effects like osteoporosis, hypertension, and gastric ulcers. This is where the potential of biodegradable DDSs comes into the picture.
Various materials are being explored for their applicability in the creation of biodegradable DDSs aimed at treating anterior uveitis. Wu et al. conducted a significant study on the use of micelles made from monomethoxy poly(ethylene glycol)-poly(ε-caprolactone), conjugated with rapamycin. When administered through an intravitreal injection, these micelles demonstrated a prolonged retention of rapamycin within the retinal pigment epithelial cells of rats, lasting for a minimum of two weeks. This prolonged release improved the treatment efficacy for autoimmune uveitis compared to the use of a rapamycin suspension alone [31].
Gonzalez-Pizarro et al. engineered an in situ gel system encapsulating fluorometholone-loaded PLGA nanoparticles. The delivery of this formulation demonstrated a noteworthy enhancement in the precorneal residency duration. This increase subsequently resulted in an amplified ocular bioavailability and deep-tissue penetration, including areas such as the aqueous humor and crystalline lens, as observed in a rabbit model [32].
In another study by Xu et al., the researchers engineered nanomicelles comprising chitosan oligosaccharide-valylvaline-stearic acid amalgamated with dexamethasone. Exhibiting prolonged drug-release characteristics, these nanomicelles additionally demonstrated enhanced adhesion to mucosal surfaces along with improved penetrative properties. Evidencing their potential efficacy, these nanomicelles manifested promising results in both rat and rabbit experimental models [33].

2.1.3. Dry Eye Disease

The most recent 2017 update from the Tear Film and Ocular Surface Society’s International Dry Eye Workshop categorizes dry eye disease (DED) as a complex condition involving the ocular surface, which destabilizes the tear film and triggers eye-related symptoms [34]. The report emphasizes the significant role of tear film fluctuations, hyperosmolarity, inflammation, and damage to the ocular surface as well as neurosensory irregularities in causing DED. In some cases, it can also be associated with systemic conditions such as Sjögren’s syndrome, lupus, or rheumatoid arthritis. This condition triggers tear film instability, discomfort in the eye, vision impairments, and could potentially harm the ocular surface. Typical symptoms might manifest as a sensation of burning or stinging, impaired vision, and a feeling akin to having a foreign object or grit in the eye.
Approaches to managing DED target the replenishment or preservation of the eye’s tear volume and quality to lessen the impacts of dryness and associated discomfort. These strategies employ lubricants such as synthetic tears and sodium hyaluronate ocular drops, anti-inflammatory medications like corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs), immune system suppressants including cyclosporine A (CsA), along with other drugs like secretagogues and autologous serum eye drops. Additionally, procedures like punctal occlusion may be applied [35][36].
Corticosteroids, recognized for their potent anti-inflammatory properties, are extensively employed to manage ocular surface inflammation. Efforts are underway to develop biodegradable corticosteroid formulations to improve bioavailability and curtail systemic side effects. Various research has successfully delivered corticosteroids like prednisolone acetate, dexamethasone sodium phosphate, fluorometholone, and triamcinolone acetonide by using delivery systems like polymeric nanoparticles, micelles, and hydrogels [32][37][38][39][40][41][42][43][44]. These systems improve the time the medication remains on the cornea and increase its availability in the eye. As an illustration, Hanafy and colleagues designed a system of self-assembled NPs loaded with prednisolone acetate by using chitosan-deoxycholate. This system managed to double the release of prednisolone after a 24 h period compared to a commercially available micronized drug-loaded gel [37]. A chitosan thermosensitive hydrogel embedded with nanostructured lipid carriers and dexamethasone was fabricated by Tan et al. [45]. The distinct feature of this concoction is its thermosensitivity, which enables it to transform into a hydrogel when interacting with the conjunctival sac upon administration as a solution into the eye. The in vitro release study findings demonstrated that this formulation enables the sustained release of dexamethasone. Beyond corticosteroids, NSAIDs also serve a significant role in managing ocular inflammation. A notable example includes the work of Sánchez-Lopez et al., who developed a dexibuprofen-loaded PLGA NP system. The NPs showed a slow two-phase release, with an initial rapid release for around 150 min followed by sustained drug release over 24 h. This demonstrated the potential for prolonged dexibuprofen delivery, which could reduce the frequency of patient dosing [46].
Topical CsA, a fungal metabolite, has gained attention due to its anti-inflammatory characteristics, which presumably stem from its capability to inhibit T-cell activation through interleukin-2. Several FDA-approved CsA-based eye drop formulations such as Restasis®, Ikervis®, Cequa®, and CyclASol® have proven effective in alleviating symptoms and signs related to DED [47][48][49]. Significant efforts have been dedicated in recent times to leverage biodegradable DDSs to enhance the therapeutic efficacy of CsA. This innovative approach has shown encouraging outcomes. PCL NPs, augmented with penetration-boosting surfactants like benzalkonium chloride, have been employed for ocular CsA delivery [50]. Another study by Liu et al. developed surface-modified PLGA and dextran NPs with phenylboronic acid to enhance their mucoadhesive properties [51]. The findings highlighted this formulation’s enhanced safety, prolonged CsA release, and weekly dosing efficacy for inflammation mitigation and corneal healing. Eudragit RL-coated PLGA particles, known as cationic NPs, exhibited heightened corneal retention and absorption. This formulation showed substantial cellular-uptake and tear-fluid concentrations of CsA [52]. Başaran et al. developed a cationic chitosan solid-lipid NP system for CsA, which exhibited substantial precorneal retention and drug uptake. CsA was detectable in ocular fluid samples for 48 h, indicating successful penetration and prolonged release due to an increased eye residence time [53].
Research is ongoing to improve the current understanding of DED and develop novel therapeutic strategies. Although current treatment options can manage the symptoms in most patients, there are still challenges to be addressed, including identifying the exact etiology in individual patients and designing personalized therapeutic regimens.

2.1.4. Keratoconjunctivitis

The widespread ocular surface disorder conjunctivitis is marked by conjunctiva inflammation and can originate from infectious sources or noninfectious elements such as allergens, toxins, or immune or neoplastic processes [54]. On the other hand, keratitis arises from corneal inflammation and can be categorized into infectious or noninfectious types based on the causative agent. Infectious keratitis can further be divided into bacterial, protozoal (e.g., Acanthamoeba), fungal, and viral forms [55].
Therapeutic strategies for keratoconjunctivitis encompass antibiotics, antivirals, antifungals, and anti-inflammatory medications tailored to address specific causative agents. However, the diminished water solubility and fleeting ocular surface residence time present notable challenges. To enhance the therapeutic efficiency, investigations into biodegradable formulations capable of protracting drug release have been conducted. Ameeduzzafar and colleagues developed chitosan-based NPs designed for the delivery of levofloxacin. These NPs displayed biocompatibility suitable for topical ocular application and exhibited an extended retention period in the ocular region in comparison to a levofloxacin solution [56]. Mudgil et al. developed a PLGA NS containing moxifloxacin. This formulation exhibited superior transcorneal permeation and exhibited a protracted antimicrobial effectiveness against Staphylococcus aureus and Pseudomonas aeruginosa, as contrasted with the commercially available eye drop Moxicip® [57]. Kapanigowda et al. designed ganciclovir-loaded chitosan microspheres, which showcased a substantial amplification in peak concentration as opposed to a ganciclovir solution. The effectiveness and tolerability of the said formulation were underscored by in vivo ocular pharmacokinetic studies paired with histopathology reports [58].
Xie et al. pioneered the design of core-shell-structured HA-based microcapsules by using a one-step in situ drug-encapsulation process for ofloxacin. This unique method facilitated the construction of a resorbable hydrogel punctal plug with an enhanced and extended drug-release feature. When utilized for ofloxacin microencapsulation, it showcased improved and sustained drug release in aqueous environments [59]. Abbas et al. developed an in situ gelling solution infused with oxytetracycline-loaded gelatin-polyacrylic acid NPs [60]. This optimized solution was evaluated for its potential to counteract Pseudomonas aeruginosa through both in vitro trials and an in vivo rabbit eye conjunctivitis model. The findings suggested prolonged efficacy against keratitis and an antibacterial potency comparable to that of an established commercial product.

2.2. Posterior Segment Disease

2.2.1. Diabetic Retinopathy

Diabetic retinopathy (DR) is a widespread microvascular issue linked to Diabetes Mellitus (DM), accounting for the majority of adult blindness between ages 20–74. Given the global increase in DM, this correlates with a growing incidence of DR. Key risk factors include disease duration, hyperglycemia levels, and hypertension. Diabetic macular edema (DME), a substantial DR subtype, is the leading cause of vision loss in DR patients and is associated with all DR severities, including nonproliferative and proliferative DR [61]. DME develops due to diabetes-induced damage to the blood–retinal barrier, causing fluid leakage into the neural retina and the subsequent thickening and cystoid edema of the macula. Antivascular endothelial growth factor (anti-VEGF) therapies and corticosteroids have a confirmed role in managing DR and DME, with recent research exploring the potential of biodegradable formulations to augment therapeutic effectiveness and bioavailability [62].
Badiee et al. designed a system that entailed the incorporation of bevacizumab-loaded chitosan NPs within a hyaluronic acid ocular implant. The obtained outcomes demonstrated that this unique formulation was capable of sustaining drug release for a duration of two months. Consequently, the utilization of this formulation presents a promising method for achieving the sustained delivery of bevacizumab [63]. Mahaling et al. undertook a study involving the administration of triamcinolone acetonide-loaded NPs, featuring a PCL core and a hydrophilic Pluronic® F68 shell, in a rat model of diabetic retinopathy [64]. A marked reduction in retinal inflammation was observed, as evidenced by a decrease in the expression of NF-κB, ICAM-1, and TNFα following a 20-day treatment period. Moreover, the NP therapy resulted in attenuated glial cell hyperplasia, evidenced by the decreased expression of Glial Fibrillary Acidic Protein (GFAP). It also caused a reduction in microvascular complications, highlighted by decreased VEGF production and fewer microvascular tuft formations, observed after 40 days of therapy. Xu et al. engineered a complex of nanomicelles derived from chitosan oligosaccharide-valylvaline-stearic acid that is capable of self-assembly and the encapsulation of dexamethasone. Utilizing this approach significantly boosted access to the posterior segment of the eye via conjunctival pathways, fostered prolonged release, and heightened penetration attributes. Comparative experimental trials on male rats and albino rabbits showed comparable levels of dexamethasone to those recorded in the FDA-sanctioned NP system loaded with dexamethasone mixed with hydrogenated castor oil-40/octoxynol-40 [33]. Administering periocular injections extends the duration of drug delivery, akin to intravitreal injections, but it comes with the added benefit of a more durable injection site that minimizes the possibility of particle outflow due to tear drainage, despite the necessity for trans-scleral penetration to attain effective drug distribution. Zeng et al. designed PLGA and chitosan NPs encapsulating interleukin-12, a cytokine known for reducing MMP-9 and VEGF-A levels and inhibiting tumor angiogenesis. Despite a modest encapsulation efficiency (34.7%), the formulation demonstrated sustained drug release and a superior efficacy in inhibiting VEGF-A and MMP-9 expression in rat endothelial cells and DR mouse retinas. This formulation significantly reduced retinal damage in DR mice, as evident from the increased retinal thickness and decreased neovascularization after treatment [65].

2.2.2. Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a leading cause of vision loss in industrialized nations, with severe complications like choroidal neovascularization (CNV) and geographic atrophy [66]. The favored approach for delivering anti-VEGF drugs or corticosteroids for AMD is an intravitreal injection. Yet, the permeability of therapeutic small molecules remains suboptimal. Biodegradable drug-delivery systems (DDSs) have been employed to augment the penetration of therapeutic agents across biomembranes, enhancing CNV treatment outcomes.
An innovative technique involving bilayer-dissolving microneedles loaded with ovalbumin-encapsulated PLGA NPs was proposed by Wu et al. for protein transport [67]. This method offers an ex vivo sustained protein release for more than two months and efficiently bypasses the scleral barrier, indicating its potential as a compelling strategy to treat neovascular eye conditions. In a study conducted by Varshochianand and colleagues, albumin PLGA NPs were developed to encapsulate bevacizumab. The resulting NPs offered a prolonged-release formulation of bevacizumab, which maintained a vitreous concentration exceeding 500 g/L for approximately eight weeks in a rabbit model [68]. Badiee et al., in a separate study, embedded bevacizumab into chitosan NPs that were subsequently integrated into a hyaluronic acid-derived ocular implant. While the analysis lacked in vivo testing, the laboratory-based findings revealed a prolonged two-month medication discharge period [63].
Further exploration in the field has suggested that the combined administration of dexamethasone with anti-VEGF agents, such as aflibercept and bevacizumab, in the form of polymeric NPs can exhibit a durable release profile and robust antiangiogenic effects. A case in point is the research conducted by Lui and colleagues, who crafted a unique formulation involving PLGA and polyethylenimine NPs loaded with dexamethasone, with bevacizumab adsorbed onto the surfaces. Their results indicate an enhanced antiangiogenic efficiency compared to monotherapies involving either dexamethasone or bevacizumab alone. Furthermore, this combined formulation showcased an amplified efficacy in inhibiting CNV and exhibited a strong suppressive effect on VEGF secretion [69]. Rudeen et al. innovatively designed a combination DDS that incorporates a hydrogel carrying microparticles loaded with aflibercept and NPs infused with dexamethasone. In vitro examinations of this novel formulation showed a subtle reduction in both the swelling ratio and equilibrium water content when compared to the delivery systems solely containing either aflibercept or dexamethasone. Remarkably, this combined formulation demonstrated an extended release duration, lasting up to 224 days, marking it as a potential advancement in sustained drug-delivery strategies for AMD [70].

2.2.3. Retinal Vein Occlusions

Retinal vein occlusions (RVOs) represent the second most common retinal vascular disorder, second only to diabetic retinopathy. This condition includes central retinal vein occlusions (CRVOs); branch retinal vein occlusions (BRVOs); and less commonly, hemiretinal vein occlusions. Notably, BRVOs occur with a four-to-six-fold higher frequency than CRVOs, the latter of which impacts an estimated 2.5 million people globally. The incidence of RVOs is skewed towards men and those aged 65 years and above, with contributing factors encompassing age, hypertension, cardiovascular disease, DM, hyperviscosity syndromes, and glaucoma. The primary driver of progressive vision loss in RVO patients is macular edema. VEGF exacerbates this condition by promoting neovascularization and vascular permeability [71]. Additionally, a widely accepted theory underscores the role of inflammation in the progression and outcomes of vitreoretinal diseases, inclusive of RVOs [72].
In June 2009, the FDA granted approval for Ozurdex®, a biodegradable device manufactured by Allergan in Irvine, CA, designed to deliver 700 μg of dexamethasone to treat macular edema associated with either BRVOs or CRVOs. Data from Phase III clinical trials revealed a significant improvement in visual acuity, quantified as a gain of 15 or more letters, for a larger proportion of patients in the treatment group as compared to the sham group for up to 90 days after the injection [73]. However, this observed advantage seemed to diminish by 180 days, to the point of insignificance. Evaluations after a second round of injections at the six-month mark demonstrated a less pronounced effect by the end of the year.
A novel biodegradable dexamethasone implant, AR-1105, currently under investigation, is developed to treat macular edema resulting from CRVOs. The implant comprises a mixture of dexamethasone and a bioerodible PLGA polymer blend, fabricated by using PRINT® micromolding technology. This design facilitates a more gradual release of dexamethasone at a lower total dose (340 µg) compared to existing therapies. In a multicenter Phase II trial spanning six months, two AR-1105 formulations with identical doses but varied release kinetics were evaluated for their safety and efficacy. The study yielded promising results, with both formulations exhibiting good tolerability and significant, sustained improvements in visual acuity and retinal thickness in patients with RVOs characterized by longstanding edema [74].

This entry is adapted from the peer-reviewed paper 10.3390/ijms241612976

References

  1. Zhou, R.; Caspi, R.R. Ocular immune privilege. F1000 Biol. Rep. 2010, 2, 3.
  2. Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A.K. Ocular drug delivery systems: An overview. World J. Pharmacol. 2013, 2, 47–64.
  3. Mannermaa, E.; Vellonen, K.S.; Urtti, A. Drug transport in corneal epithelium and blood-retina barrier: Emerging role of transporters in ocular pharmacokinetics. Adv. Drug Deliv. Rev. 2006, 58, 1136–1163.
  4. Bachu, R.D.; Chowdhury, P.; Al-Saedi, Z.H.F.; Karla, P.K.; Boddu, S.H.S. Ocular Drug Delivery Barriers—Role of Nanocarriers in the Treatment of Anterior Segment Ocular Diseases. Pharmaceutics 2018, 10, 28.
  5. Runkle, E.A.; Antonetti, D.A. The blood-retinal barrier: Structure and functional significance. Methods Mol. Biol. 2011, 686, 133–148.
  6. Allyn, M.M.; Luo, R.H.; Hellwarth, E.B.; Swindle-Reilly, K.E. Considerations for Polymers Used in Ocular Drug Delivery. Front. Med. 2021, 8, 787644.
  7. Flaxman, S.R.; Bourne, R.R.A.; Resnikoff, S.; Ackland, P.; Braithwaite, T.; Cicinelli, M.V.; Das, A.; Jonas, J.B.; Keeffe, J.; Kempen, J.H.; et al. Global causes of blindness and distance vision impairment 1990–2020: A systematic review and meta-analysis. Lancet Glob. Health 2017, 5, e1221–e1234.
  8. Lavik, E.; Kuehn, M.H.; Kwon, Y.H. Novel drug delivery systems for glaucoma. Eye 2011, 25, 578–586.
  9. Patel, H.Y.; Danesh-Meyer, H.V. Incidence and management of cataract after glaucoma surgery. Curr. Opin. Ophthalmol. 2013, 24, 15–20.
  10. Poulsen, E.J.; Allingham, R.R. Characteristics and risk factors of infections after glaucoma filtering surgery. J. Glaucoma 2000, 9, 438–443.
  11. Gazzard, G.; Konstantakopoulou, E.; Garway-Heath, D.; Adeleke, M.; Vickerstaff, V.; Ambler, G.; Hunter, R.; Bunce, C.; Nathwani, N.; Barton, K. Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial: Six-Year Results of Primary Selective Laser Trabeculoplasty versus Eye Drops for the Treatment of Glaucoma and Ocular Hypertension. Ophthalmology 2023, 130, 139–151.
  12. Tsung, T.-H.; Chen, Y.-H.; Lu, D.-W. Updates on Biodegradable Formulations for Ocular Drug Delivery. Pharmaceutics 2023, 15, 734.
  13. Salama, H.A.; Ghorab, M.; Mahmoud, A.A.; Abdel Hady, M. PLGA Nanoparticles as Subconjunctival Injection for Management of Glaucoma. AAPS PharmSciTech 2017, 18, 2517–2528.
  14. Roy, G.; Galigama, R.D.; Thorat, V.S.; Garg, P.; Venuganti, V.V.K. Microneedle ocular patch: Fabrication, characterization, and ex-vivo evaluation using pilocarpine as model drug. Drug Dev. Ind. Pharm. 2020, 46, 1114–1122.
  15. Franca, J.R.; Foureaux, G.; Fuscaldi, L.L.; Ribeiro, T.G.; Castilho, R.O.; Yoshida, M.I.; Cardoso, V.N.; Fernandes, S.O.A.; Cronemberger, S.; Nogueira, J.C.; et al. Chitosan/hydroxyethyl cellulose inserts for sustained-release of dorzolamide for glaucoma treatment: In vitro and in vivo evaluation. Int. J. Pharm. 2019, 570, 118662.
  16. Agibayeva, L.E.; Kaldybekov, D.B.; Porfiryeva, N.N.; Garipova, V.R.; Mangazbayeva, R.A.; Moustafine, R.I.; Semina, I.I.; Mun, G.A.; Kudaibergenov, S.E.; Khutoryanskiy, V.V. Gellan gum and its methacrylated derivatives as in situ gelling mucoadhesive formulations of pilocarpine: In vitro and in vivo studies. Int. J. Pharm. 2020, 577, 119093.
  17. Bhalerao, H.; Koteshwara, K.B.; Chandran, S. Brinzolamide Dimethyl Sulfoxide In Situ Gelling Ophthalmic Solution: Formulation Optimisation and In Vitro and In Vivo Evaluation. AAPS PharmSciTech 2020, 21, 69.
  18. Orasugh, J.T.; Sarkar, G.; Saha, N.R.; Das, B.; Bhattacharyya, A.; Das, S.; Mishra, R.; Roy, I.; Chattoapadhyay, A.; Ghosh, S.K.; et al. Effect of cellulose nanocrystals on the performance of drug loaded in situ gelling thermo-responsive ophthalmic formulations. Int. J. Biol. Macromol. 2019, 124, 235–245.
  19. El-Feky, G.S.; Zayed, G.M.; Elshaier, Y.A.M.M.; Alsharif, F.M. Chitosan-Gelatin Hydrogel Crosslinked with Oxidized Sucrose for the Ocular Delivery of Timolol Maleate. J. Pharm. Sci. 2018, 107, 3098–3104.
  20. Sun, J.; Zhou, Z. A novel ocular delivery of brinzolamide based on gellan gum: In vitro and in vivo evaluation. Drug Des. Dev. Ther. 2018, 12, 383–389.
  21. Lai, J.-Y.; Luo, L.-J. Chitosan-g-poly(N-isopropylacrylamide) copolymers as delivery carriers for intracameral pilocarpine administration. Eur. J. Pharm. Biopharm. 2017, 113, 140–148.
  22. Pan, X.; Liu, X.; Zhuang, X.; Liu, Y.; Li, S. Co-delivery of dexamethasone and melatonin by drugs laden PLGA nanoparticles for the treatment of glaucoma. J. Drug Deliv. Sci. Technol. 2020, 60, 102086.
  23. Lai, J.-Y. Biodegradable in situ gelling delivery systems containing pilocarpine as new antiglaucoma formulations: Effect of a mercaptoacetic acid/N-isopropylacrylamide molar ratio. Drug Des. Dev. Ther. 2013, 7, 1273–1285.
  24. Shirley, M. Bimatoprost Implant: First Approval. Drugs Aging 2020, 37, 457–462.
  25. Medeiros, F.A.; Walters, T.R.; Kolko, M.; Coote, M.; Bejanian, M.; Goodkin, M.L.; Guo, Q.; Zhang, J.; Robinson, M.R.; Weinreb, R.N.; et al. Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1). Ophthalmology 2020, 127, 1627–1641.
  26. Bacharach, J.; Tatham, A.; Ferguson, G.; Belalcázar, S.; Thieme, H.; Goodkin, M.L.; Chen, M.Y.; Guo, Q.; Liu, J.; Robinson, M.R.; et al. Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2). Drugs 2021, 81, 2017–2033.
  27. Belamkar, A.; Harris, A.; Zukerman, R.; Siesky, B.; Oddone, F.; Verticchio Vercellin, A.; Ciulla, T.A. Sustained release glaucoma therapies: Novel modalities for overcoming key treatment barriers associated with topical medications. Ann. Med. 2022, 54, 343–358.
  28. Navratil, T.; Garcia, A.; Tully, J.; Maynor, B.; Ahmed, I.I.K.; Budenz, D.L.; Lewis, R.A.; Mansberger, S.L.; Gilger, B.C.; Yerxa, B.R. Preclinical Evaluation of ENV515 (travoprost) Intracameral Implant—Clinical Candidate for Treatment of Glaucoma Targeting Six-Month Duration of Action. Investig. Ophthalmol. Vis. Sci. 2014, 55, 3548.
  29. Goldstein, M.H.; Goldberg, D.; Walters, T.R.; Vantipalli, S.; Braun, E.; Metzinger, J.L. Evaluating Safety, Tolerability and Efficacy of an Intracameral Hydrogel-Based Travoprost Implant in Subjects with Glaucoma—Phase 1 Trial. Investig. Ophthalmol. Vis. Sci. 2020, 61, 4266.
  30. Muñoz-Fernández, S.; Martín-Mola, E. Uveitis. Best Pract. Res. Clin. Rheumatol. 2006, 20, 487–505.
  31. Wu, W.; He, Z.; Zhang, Z.; Yu, X.; Song, Z.; Li, X. Intravitreal injection of rapamycin-loaded polymeric micelles for inhibition of ocular inflammation in rat model. Int. J. Pharm. 2016, 513, 238–246.
  32. Gonzalez-Pizarro, R.; Carvajal-Vidal, P.; Bellowa, L.H.; Calpena, A.C.; Espina, M.; García, M.L. In-situ forming gels containing fluorometholone-loaded polymeric nanoparticles for ocular inflammatory conditions. Colloids Surf. B Biointerfaces 2019, 175, 365–374.
  33. Xu, X.; Sun, L.; Zhou, L.; Cheng, Y.; Cao, F. Functional chitosan oligosaccharide nanomicelles for topical ocular drug delivery of dexamethasone. Carbohydr. Polym. 2020, 227, 115356.
  34. Craig, J.P.; Nichols, K.K.; Akpek, E.K.; Caffery, B.; Dua, H.S.; Joo, C.K.; Liu, Z.; Nelson, J.D.; Nichols, J.J.; Tsubota, K.; et al. TFOS DEWS II Definition and Classification Report. Ocul. Surf. 2017, 15, 276–283.
  35. O’Neil, E.C.; Henderson, M.; Massaro-Giordano, M.; Bunya, V.Y. Advances in dry eye disease treatment. Curr. Opin. Ophthalmol. 2019, 30, 166–178.
  36. Messmer, E.M. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch. Arztebl. Int. 2015, 112, 71–81.
  37. Hanafy, A.F.; Abdalla, A.M.; Guda, T.K.; Gabr, K.E.; Royall, P.G.; Alqurshi, A. Ocular anti-inflammatory activity of prednisolone acetate loaded chitosan-deoxycholate self-assembled nanoparticles. Int. J. Nanomed. 2019, 14, 3679–3689.
  38. Wang, B.; Tang, Y.; Oh, Y.; Lamb, N.W.; Xia, S.; Ding, Z.; Chen, B.; Suarez, M.J.; Meng, T.; Kulkarni, V.; et al. Controlled release of dexamethasone sodium phosphate with biodegradable nanoparticles for preventing experimental corneal neovascularization. Nanomedicine 2019, 17, 119–123.
  39. Ryu, W.M.; Kim, S.-N.; Min, C.H.; Choy, Y.B. Dry Tablet Formulation of PLGA Nanoparticles with a Preocular Applicator for Topical Drug Delivery to the Eye. Pharmaceutics 2019, 11, 651.
  40. Tatke, A.; Dudhipala, N.; Janga, K.Y.; Balguri, S.P.; Avula, B.; Jablonski, M.M.; Majumdar, S. In Situ Gel of Triamcinolone Acetonide-Loaded Solid Lipid Nanoparticles for Improved Topical Ocular Delivery: Tear Kinetics and Ocular Disposition Studies. Nanomaterials 2018, 9, 33.
  41. García-Millán, E.; Quintáns-Carballo, M.; Otero-Espinar, F.J. Improved release of triamcinolone acetonide from medicated soft contact lenses loaded with drug nanosuspensions. Int. J. Pharm. 2017, 525, 226–236.
  42. Soiberman, U.; Kambhampati, S.P.; Wu, T.; Mishra, M.K.; Oh, Y.; Sharma, R.; Wang, J.; Al Towerki, A.E.; Yiu, S.; Stark, W.J.; et al. Subconjunctival injectable dendrimer-dexamethasone gel for the treatment of corneal inflammation. Biomaterials 2017, 125, 38–53.
  43. Tan, G.; Yu, S.; Li, J.; Pan, W. Development and characterization of nanostructured lipid carriers based chitosan thermosensitive hydrogel for delivery of dexamethasone. Int. J. Biol. Macromol. 2017, 103, 941–947.
  44. Kesavan, K.; Kant, S.; Singh, P.N.; Pandit, J.K. Mucoadhesive chitosan-coated cationic microemulsion of dexamethasone for ocular delivery: In vitro and in vivo evaluation. Curr. Eye Res. 2013, 38, 342–352.
  45. Tan, G.; Yu, S.; Pan, H.; Li, J.; Liu, D.; Yuan, K.; Yang, X.; Pan, W. Bioadhesive chitosan-loaded liposomes: A more efficient and higher permeable ocular delivery platform for timolol maleate. Int. J. Biol. Macromol. 2017, 94, 355–363.
  46. Sánchez-López, E.; Esteruelas, G.; Ortiz, A.; Espina, M.; Prat, J.; Muñoz, M.; Cano, A.; Calpena, A.C.; Ettcheto, M.; Camins, A.; et al. Dexibuprofen Biodegradable Nanoparticles: One Step Closer towards a Better Ocular Interaction Study. Nanomaterials 2020, 10, 720.
  47. Wang, T.-Z.; Liu, X.-X.; Wang, S.-Y.; Liu, Y.; Pan, X.-Y.; Wang, J.-J.; Nan, K.-H. Engineering Advanced Drug Delivery Systems for Dry Eye: A Review. Bioengineering 2022, 10, 53.
  48. De Paiva, C.S.; Pflugfelder, S.C.; Ng, S.M.; Akpek, E.K. Topical cyclosporine A therapy for dry eye syndrome. Cochrane Database Syst. Rev. 2019, 9, Cd010051.
  49. Gao, D.; Da, Z.; Yang, K.; Shi, Y. Comparison of seven cyclosporine A formulations for dry eye disease: A systematic review and network meta-analysis. Front. Pharmacol. 2022, 13, 882803.
  50. Yenice, I.; Mocan, M.C.; Palaska, E.; Bochot, A.; Bilensoy, E.; Vural, I.; Irkeç, M.; Hincal, A.A. Hyaluronic acid coated poly-epsilon-caprolactone nanospheres deliver high concentrations of cyclosporine A into the cornea. Exp. Eye Res. 2008, 87, 162–167.
  51. Liu, S.; Chang, C.N.; Verma, M.S.; Hileeto, D.; Muntz, A.; Stahl, U.; Woods, J.; Jones, L.W.; Gu, F.X. Phenylboronic acid modified mucoadhesive nanoparticle drug carriers facilitate weekly treatment of experimentallyinduced dry eye syndrome. Nano Res. 2015, 8, 621–635.
  52. Wagh, V.D.; Apar, D.U. Cyclosporine a loaded PLGA nanoparticles for dry eye disease: In vitro characterization studies. J. Nanotechnol. 2014, 2014, 683153.
  53. Başaran, E.; Demirel, M.; Sırmagül, B.; Yazan, Y. Cyclosporine-A incorporated cationic solid lipid nanoparticles for ocular delivery. J. Microencapsul. 2010, 27, 37–47.
  54. Azari, A.A.; Barney, N.P. Conjunctivitis: A systematic review of diagnosis and treatment. JAMA 2013, 310, 1721–1729.
  55. Austin, A.; Lietman, T.; Rose-Nussbaumer, J. Update on the Management of Infectious Keratitis. Ophthalmology 2017, 124, 1678–1689.
  56. Ameeduzzafar; Imam, S.S.; Abbas Bukhari, S.N.; Ahmad, J.; Ali, A. Formulation and optimization of levofloxacin loaded chitosan nanoparticle for ocular delivery: In-vitro characterization, ocular tolerance and antibacterial activity. Int. J. Biol. Macromol. 2018, 108, 650–659.
  57. Mudgil, M.; Pawar, P.K. Preparation and In Vitro/Ex Vivo Evaluation of Moxifloxacin-Loaded PLGA Nanosuspensions for Ophthalmic Application. Sci. Pharm. 2013, 81, 591–606.
  58. Kapanigowda, U.G.; Nagaraja, S.H.; Ramaiah, B.; Boggarapu, P.R. Improved intraocular bioavailability of ganciclovir by mucoadhesive polymer based ocular microspheres: Development and simulation process in Wistar rats. DARU J. Pharm. Sci. 2015, 23, 49.
  59. Xie, J.; Wang, C.; Ning, Q.; Gao, Q.; Gao, C.; Gou, Z.; Ye, J. A new strategy to sustained release of ocular drugs by one-step drug-loaded microcapsule manufacturing in hydrogel punctal plugs. Graefes Arch. Clin. Exp. Ophthalmol. 2017, 255, 2173–2184.
  60. Abbas, M.N.; Khan, S.A.; Sadozai, S.K.; Khalil, I.A.; Anter, A.; Fouly, M.E.; Osman, A.H.; Kazi, M. Nanoparticles Loaded Thermoresponsive In Situ Gel for Ocular Antibiotic Delivery against Bacterial Keratitis. Polymers 2022, 14, 1135.
  61. Lee, R.; Wong, T.Y.; Sabanayagam, C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis. 2015, 2, 17.
  62. Ting, D.S.; Cheung, G.C.; Wong, T.Y. Diabetic retinopathy: Global prevalence, major risk factors, screening practices and public health challenges: A review. Clin. Exp. Ophthalmol. 2016, 44, 260–277.
  63. Badiee, P.; Varshochian, R.; Rafiee-Tehrani, M.; Abedin Dorkoosh, F.; Khoshayand, M.R.; Dinarvand, R. Ocular implant containing bevacizumab-loaded chitosan nanoparticles intended for choroidal neovascularization treatment. J. Biomed. Mater. Res. Part A 2018, 106, 2261–2271.
  64. Mahaling, B.; Srinivasarao, D.A.; Raghu, G.; Kasam, R.K.; Bhanuprakash Reddy, G.; Katti, D.S. A non-invasive nanoparticle mediated delivery of triamcinolone acetonide ameliorates diabetic retinopathy in rats. Nanoscale 2018, 10, 16485–16498.
  65. Zeng, L.; Ma, W.; Shi, L.; Chen, X.; Wu, R.; Zhang, Y.; Chen, H.; Chen, H. Poly(lactic-co-glycolic acid) nanoparticle-mediated interleukin-12 delivery for the treatment of diabetic retinopathy. Int. J. Nanomed. 2019, 14, 6357–6369.
  66. Gehrs, K.M.; Anderson, D.H.; Johnson, L.V.; Hageman, G.S. Age-related macular degeneration—Emerging pathogenetic and therapeutic concepts. Ann. Med. 2006, 38, 450–471.
  67. Wu, Y.; Vora, L.K.; Wang, Y.; Adrianto, M.F.; Tekko, I.A.; Waite, D.; Donnelly, R.F.; Thakur, R.R.S. Long-acting nanoparticle-loaded bilayer microneedles for protein delivery to the posterior segment of the eye. Eur. J. Pharm. Biopharm. 2021, 165, 306–318.
  68. Varshochian, R.; Riazi-Esfahani, M.; Jeddi-Tehrani, M.; Mahmoudi, A.R.; Aghazadeh, S.; Mahbod, M.; Movassat, M.; Atyabi, F.; Sabzevari, A.; Dinarvand, R. Albuminated PLGA nanoparticles containing bevacizumab intended for ocular neovascularization treatment. J. Biomed. Mater. Res. A 2015, 103, 3148–3156.
  69. Liu, J.; Zhang, X.; Li, G.; Xu, F.; Li, S.; Teng, L.; Li, Y.; Sun, F. Anti-Angiogenic Activity of Bevacizumab-Bearing Dexamethasone-Loaded PLGA Nanoparticles for Potential Intravitreal Applications. Int. J. Nanomed. 2019, 14, 8819–8834.
  70. Rudeen, K.M.; Liu, W.; Mieler, W.F.; Kang-Mieler, J.J. Simultaneous Release of Aflibercept and Dexamethasone from an Ocular Drug Delivery System. Curr. Eye Res. 2022, 47, 1034–1042.
  71. Laouri, M.; Chen, E.; Looman, M.; Gallagher, M. The burden of disease of retinal vein occlusion: Review of the literature. Eye 2011, 25, 981–988.
  72. Yoshimura, T.; Sonoda, K.-H.; Sugahara, M.; Mochizuki, Y.; Enaida, H.; Oshima, Y.; Ueno, A.; Hata, Y.; Yoshida, H.; Ishibashi, T. Comprehensive Analysis of Inflammatory Immune Mediators in Vitreoretinal Diseases. PLoS ONE 2009, 4, e8158.
  73. Haller, J.A.; Bandello, F.; Belfort, R., Jr.; Blumenkranz, M.S.; Gillies, M.; Heier, J.; Loewenstein, A.; Yoon, Y.H.; Jiao, J.; Li, X.Y.; et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011, 118, 2453–2460.
  74. Singer, M.A.; Boyer, D.S.; Williams, S.; McKee, H.; Kerr, K.; Pegoraro, T.; Trevino, L.; Kopczynski, C.C.; Hollander, D.A. Phase 2 Randomized Study (Orion-1) of A Novel, Biodegradable Dexamethasone Implant (Ar-1105) for the Treatment of Macular Edema Due to Central or Branch Retinal Vein Occlusion. Retina 2023, 43, 25–33.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback