Memantine‐Loaded PEGylated Biodegradable Nanoparticles for the Treatment of Glaucoma

Abstract

Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N-methyl-d-aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate-induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine-loaded PLGA-PEG nanoparticles (MEM-NP) and investigates the efficacy of this formulation using a well-established glaucoma model. MEM-NPs <200 nm in diameter and incorporating 4 mg mL of memantine were prepared with 0.35 mg mL localized to the aqueous interior. In vitro assessment indicated sustained release from MEM-NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM-NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM-NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.

Deleterious Effect of NMDA Plus Kainate on the Inner Retinal Cells and Ganglion Cell Projection of the Mouse

“…This cell loss is dependent on the inoculated dose of NMDA, since, while a dose of 10 nmol did not cause any cell loss, the intraocular injection of 160 nmol may have induced a cell loss of ca. 70% [6], resembling these models to those obtained by crushing the optic nerve [14,15].…”

“…It has been reported that the loss of RGCs, or just their functional lesion, may affect the transmission of the light signal to higher centers of the visual pathway. Frequently, the administration of glutamate receptor antagonists provides protection of these retinal cells, suggesting that a toxic effect of glutamate triggered by different etiologies might be involved [3][4][5][6].…”

Dexibuprofen Biodegradable Nanoparticles: One Step Closer towards a Better Ocular Interaction Study

“…Instilled in the conjunctival sac of the eye was 50 µL of sample and the appearance of irritation was observed at the time of administration and after 1 h. The evaluation was undertaken by direct observation of the anterior segment of the eye calculating the injuries of the conjunctiva, iris and cornea. The punctuation applied has been described elsewhere [20] and the ocular irritation index has been calculated according to Equation (3). Langmuir monolayers were obtained by spreading a lipid solution at the air/water interface.…”

Nanopharmaceutics: Part II—Production Scales and Clinically Compliant Production Methods

“…Polymeric nanoparticles can be obtained from natural, semi-synthetic or synthetic polymers (e.g., chitosan [37][38][39], polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) [40][41][42][43]), which will then govern the way the drugs are encapsulated inside the matrix (dissolved or dispersed) or attached onto the nanoparticle' surface (chemically bound or adsorbed), and how the drug is released [44]. Polymeric nanoparticles can be produced with a variety of sizes and shapes, with high drug payload for both hydrophilic and lipophilic molecules, can be surface-modified to increase the plasma half-life (e.g., PEGylation [45,46]) to have site-specific targeted delivery [47], and release the drug in a controlled fashion [48][49][50].…”