Role of PLGA Variability in Controlled Drug Release from Dexamethasone Intravitreal Implants.

Long-acting injectable formulations based on poly(lactide-co-glycolide) (PLGA) have been commercialized for over 30 years in at least 20 FDA-approved products. These formulations offer several advantages, including reduced dosing frequency, improved patient compliance, and maintenance of therapeutic levels of drug. Despite extensive studies, the inherent complexity of the PLGA copolymer still poses significant challenges associated with the development of generic formulations having drug release profiles equivalent to those of the reference listed drugs. In addition, small changes to PLGA physicochemical properties or the drug product manufacturing process can have a major impact on the drug release profile of these long-acting formulations. This work seeks to better understand how variability in the physicochemical properties of similar PLGAs affects drug release from PLGA solid implants using Ozurdex (dexamethasone intravitreal implant) as the model system. Four 50:50, acid-terminated PLGAs of similar molecular weights were used to prepare four dexamethasone intravitreal implants structurally equivalent to Ozurdex. The PLGAs were extensively characterized by using a variety of analytical techniques prior to implant manufacture using a continuous, hot-melt extrusion process. In vitro release testing of the four structurally equivalent implants was performed in both normal saline and phosphate-buffered saline (PBS), yielding drastically different results between the two methods. In normal saline, no differences in the release profiles were observed. In PBS, the drug release profiles were sensitive to small changes in the residual monomer content, carboxylic acid end group content, and blockiness of the polymers. This finding further underscores the need for a physiologically relevant in vitro release testing method as part of a robust quality control strategy for PLGA-based solid implant formulations.

7 Log Virus Removal in a Simple Functionalized Sand Filter.

Viral contamination of drinking water due to fecal contamination is difficult to detect and treat effectively, leading to frequent outbreaks worldwide. The purpose of this paper is to report on the molecular mechanism for unprecedented high virus removal from a practical sand filter. Sand filters functionalized using a water extract of Moringa oleifera (MO) seeds, functionalized sand (f-sand) filters, achieved a ∼7 log10 virus removal. These tests were conducted with MS2 bacteriophage, a recognized surrogate for pathogenic norovirus and rotavirus. We studied the molecular mechanism of this high removal since it can have important implications for sand filtration, the most common water treatment technology worldwide. Our data reveal that the virus removal activity of f-sand is due to the presence of a chitin-binding protein, M. oleifera chitin-binding protein (MoCBP) on f-sand. Standard column experiments were supported by proteomic analysis and molecular docking simulations. Our simulations show that MoCBP binds preferentially to MS2 capsid proteins demonstrating that specific molecular interactions are responsible for enhanced virus removal. In addition, we simplified the process of making f-sand and evinced how it could be regenerated using saline water. At present, no definitive solution exists for the challenge of treating fecally contaminated drinking and irrigation water for viruses without using technologies that demand high energy or chemical consumption. We propose functionalized sand (f-sand) filters as a highly effective, energy-efficient, and practical technology for virus removal applicable to both developing and developed countries.