(M1430-03-14) Intravitreal Delivery of Anti-Inflammatory Agents via Thermo-Responsive Gel-Forming Biodegradable Triblock Copolymers

Purpose: Age-Related Macular Degeneration (AMD) is a leading cause of disease that affects a person’s central vision and can result in severe loss of vision. Current estimations suggest that around 200 million individuals globally are affected by AMD, with projections indicating a surge to nearly 300 million by the year 2040 (2). Furthermore, reports from the Centers for Disease Control and Prevention (CDC) suggest that approximately 19.8 million Americans, constituting 12.6% of the population, are affected by AMD. As per the National Eye Institute (NEI), AMD is characterized by a deterioration of retina in central vision clarity. Anti-vascular endothelial growth factor (anti-VEGF) therapy is established as an approach in treatment of AMD. However, research indicates that combining therapies yields superior clinical outcomes compared to singular administration of anti-VEGF agents. Various studies have demonstrated the efficacy of integrating dexamethasone (DXM) with anti-VEGF agents to address choroidal neovascularization (CNV) lesions associated with AMD (3). Dexamethasone (DXM) is a potent corticosteroid that has anti-inflammatory properties, and ability to attenuate the permeability of choroidal endothelial cells and the outer blood-retina barrier. Furthermore, it suppresses the expression of vascular endothelial growth factor (VEGF) (3). Ocular bioavailability of topical dexamethasone (DXM) eyedrops is hindered by the intricate anatomy of the eye and various physiological barriers, resulting in less than 7% bioavailability. Intravitreal injection of DXM is a viable strategy for circumventing these barriers and delivering therapeutic agents directly to the target region, thereby mitigating potential side effects. However, conventional injections require repeated administration and decreases patient compliance. Consequently, development of a long-acting intravitreal formulation appears to be a rational proposition. This may alleviate patient discomfort, minimize complications associated with repeated intravitreal administrations, and ultimately enhance treatment outcomes. Intravitreal implants currently available (i.e. Ozurdex® and Retisert®) require a surgical procedure or specialized device for implantation into the eye (4). Biodegradable thermo-responsive hydrogels, based on PLGA-PEG-PLGA triblock copolymers, have undergone extensive research owing to their numerous advantages, including depot delivery for sustained drug release, biodegradability, and non-toxicity. These attributes collectively make them viable system for ocular delivery. This study aims to develop and optimize a DXM-delivery formulation utilizing PLGA-PEG-PLGA thermo-responsive biodegradable triblock copolymers. The system is intended for intravitreal (IVT) administration, with the goal of achieving sustained release

Methods: The copolymer solution was prepared and assessed via ¹HNMR, Gel Permeation Chromatography (GPC), and Dynamic Oscillatory Rheology. The sol-gel transition was characterized using the test tube inversion method. Two DXM+β-cyclodextrin solutions at 4 mg/ml, containing 30%(F1) and 15%w/w (F2) PLGA–PEG–PLGA copolymer were prepared. From these solutions 2 ml was added to glass vials and upon phase transition from sol to get at 37°C, 15 ml of phosphate buffer (pH 7.4) +1% Tween-80 was added to perform dissolution study at 37 C° under sink conditions at 20 rpm back and forth motion. The amount of released DXM was determined by a high-performance liquid chromatography (HPLC).

Results: The molecular composition of PLGA– PEG–PLGA triblock copolymer was confirmed by ¹H NMR measurements. GPC determined the copolymer's polydispersity (approximately 1.30) with a symmetric unimodal peak and narrow molecular weight distribution. The sol–gel transition of the triblock copolymer from liquid phase to a gel confirmed at approximately 37°C, the DXM-loaded thermogel was a low-viscous liquid at low temperature and formed a non-flowing gel at body temperature. Dynamic Oscillatory Rheological properties as a function of temperature and oscillation was performed to determine storage modulus (G') and loss modulus (G"). Sol–gel transition temperature was 30.75 °C and 31.56 °C for 15% w/w and 30% w/w polymer solution respectively, through observation of G" and G' curves intersection. In vitro release experiments demonstrated sustained release of DXM over 15 days.

Conclusion: The results reveal that sustained release formulation developed could serve as a promising thermo-responsive platform for long-acting ocular delivery of DXM. This approach may stimulate research scientists to further investigate therapy in AMD.

References: 1. Butt F, Devonport H. Treatment of Non-Infectious Posterior Uveitis with Dexamethasone Intravitreal Implants in a Real-World Setting. Clin Ophthalmol. 2023;17(January):601–11.
2. Vyawahare H, Shinde P. Age-Related Macular Degeneration: Epidemiology, Pathophysiology, Diagnosis, and Treatment. Cureus. 2022;14(9):7–12.
3. Wang Y, Wang VM, Chan CC. The role of anti-inflammatory agents in age-related macular degeneration (AMD) treatment. Eye [Internet]. 2011;25(2):127–39. Available from: https://dx.doi.org/10.1038/eye.2010.196
4. Zhang L, Shen W, Luan J, Yang D, Wei G, Yu L, et al. Sustained intravitreal delivery of dexamethasone using an injectable and biodegradable thermogel. Acta Biomater [Internet]. 2015;23:271–81. Available from: https://dx.doi.org/10.1016/j.actbio.2015.05.005

Acknowledgements: One author, Bayan Alshahrouri, would like to thank Ashland Specialty Ingredients R&D Pharma (Wilmington, DE) for their technical support, financial aid, and expertise with valuable input during the study.


Figure 1. Characterization of PLGA-PEG-PLGA copolymer. A) Typical 1H-NMR spectra. B) GPC dwt/d (log M) vs. log MW showing the molecular weight distribution for copolymer solution.


Figure 2. A) Viscoelastic profile of PLGA–PEG–PLGA copolymer aqueous solution at different concentrations. G' and G" as a function of temperature for copolymer 15% (w/w) and 30% (w/w) aqueous solution. B) PLGA-PEG-PLGA chemical structure and Sol–gel transition behavior observed as temperature gradually increased.


Figure 3. In vitro release profile for Dexamethasone-based thermogel (at 37 C° and 20 rpm horizontal movement). Blue line represents F1 (30 %w/w of PLGA–PEG–PLGA copolymer). Orange line represents F2 (15 %w/w of PLGA–PEG–PLGA copolymer). Data are represented as mean± standard deviation (SD) from 3 different batches (n = 3).