Dexamethasone PLGA Microspheres for Sub-Tenon Administration: Influence of Sterilization and Tolerance Studies

Abstract

Many diseases affecting the posterior segment of the eye require repeated intravitreal injections with corticosteroids in chronic treatments. The periocular administration is a less invasive route attracting considerable attention for long-term therapies. In the present work, dexamethasone-loaded poly(lactic-co-glycolic) acid (PLGA) microspheres (Dx-MS) were prepared using the oil-in-water (O/W) emulsion solvent evaporation technique. MS were characterized in terms of mean particle size and particle size distribution, external morphology, polymer integrity, drug content, and in vitro release profiles. MS were sterilized by gamma irradiation (25 kGy), and dexamethasone release profiles from sterilized and non-sterilized microspheres were compared by means of the similarity factor (f2). The mechanism of drug release before and after irradiation exposure of Dx-MS was identified using appropriate mathematical models. Dexamethasone release was sustained in vitro for 9 weeks. The evaluation of the in vivo tolerance was carried out in rabbit eyes, which received a sub-Tenon injection of 5 mg of sterilized Dx-MS (20–53 µm size containing 165.6 ± 3.6 µg Dx/mg MS) equivalent to 828 µg of Dx. No detectable increase in intraocular pressure was reported, and clinical and histological analysis of the ocular tissues showed no adverse events up to 6 weeks after the administration. According to the data presented in this work, the sub-Tenon administration of Dx-MS could be a promising alternative to successive intravitreal injections for the treatment of chronic diseases of the back of the eye.

Long-term corticosteroid-induced chronic glaucoma model produced by intracameral injection of dexamethasone-loaded PLGA microspheres

“…An intraocular PLGA implant loaded with dexamethasone is already available in ophthalmological clinical care (Ozurdex®) (Chang-Lin et al., 2011 ). In addition, it is well known that PLGA Ms can encapsulate and subsequently sustainedly release corticosteroids such as dexamethasone for several months (Barcia et al., 2009 ; Dawes et al., 2012; Barbosa-Alfaro et al., 2021 ). Depending on Ms particle size, among other technical parameters, it is common to find an initial rapid release of the active compound followed by one or several low-rate release phases.…”

“…In our case, as a second injection of the formulation was performed in the in vitro release study to mimic the in vivo administration, the two release profiles overlapped.It has already been shown in many previous works that the degradation of PLGA matrices is a homogeneous degradation, which, unlike the heterogeneous degradation of polymers in the matrices, takes place in the entire polymer chain at the same time. In aqueous media, although partially aggregated, PLGA microspheres maintain a spherical external appearance for weeks, despite the continuous degradation by hydrolysis of PLGA until a moment comes when the structures collapse, becoming polymeric aggregates without definite shape (Checa-Casalengua et al., 2011 ; Barbosa-Alfaro et al., 2021 ). Although a similar behavior can be assumed in vivo , it is very difficult to establish the exact behavior of these PLGA microspheres once injected into the anterior chamber.…”

Long‐Acting Ocular Injectables: Are We Looking In The Right Direction?

“…[ 114 ] PLGA or PLA have also been formulated as nano‐ or micro‐suspensions with drugs, such as triamcinolone acetonide and dexamethasone, and biocompatible solvent and then injected into confined ocular spaces, demonstrating sustained release for specific durations in vivo. [ 115,116 ] Meng et al. formulated long‐acting PLA‐based microparticles for the sustained release of dexamethasone disodium phosphate (DSP) to prevent corneal graft failure.…”

Validation of a Rapid and Easy-to-Apply Method to Simultaneously Quantify Co-Loaded Dexamethasone and Melatonin PLGA Microspheres by HPLC-UV: Encapsulation Efficiency and In Vitro Release

“…Both DX and MEL need to achieve considerable concentrations in the retina to be therapeutically effective. Intraocular drug delivery devices can provide a continuous supply of active substances close to the retina during the long term and represent an ideal system designed for neuroprotectants in chronic neurodegenerative diseases [20,21]. In this study, biodegradable poly(D,L-lactic-co-glycolic) acid (PLGA) microspheres were elaborated as a novel drug delivery system for the co-delivery of DX and MEL to be intravitreally administered.…”