(492d) Fabrication of Drug Loaded PLGA Microparticles Using a Microfluidic Flow-Focusing Device for Sustained Release Formulations

Long acting injectables aim to improve the current standard of care for various infectious diseases and neurological disorders, by eliminating the oral dose. As a result, decreasing dosing frequency with highly active, well-tolerated medications offers an avenue by which the challenges of pill/treatment fatigue, and desire for anonymity can be addressed, while also improving outcomes. To further simplify the dosing schedule and improve adherence, we aim to develop a pulsatile release formulation that enables long-acting delivery of API through either a subcutaneous or intramuscular administration.

A microfluidic approach is proposed to fabricate biodegradable, biocompatible PLGA drug loaded microparticles to enable high drug loading, sustained-release formulations. A glass focus-flow microfluidic design was used to form single oil-in-water emulsions and fabricate PLGA drug loaded microparticles. The dispersion, or oil phase, consists of the drug, organic solvents, and polymer. The continuous, or water phase, consists of a water miscible surfactant. The drug loaded (API_A), single emulsions formed droplets ranging from 150 um to 300 um. The size of the diameter has been shown to be tunable to a desired value based on the capillary number and the relative fluid velocities ratio.

A solvent evaporation step is incorporated to remove two organic solvents. As a result, a 73% reduction in drug loaded (API_A) microparticle size is observed after a timeframe of two days. Gas chromatography confirmed there to be no residual organic solvents detected in washing steps or in dissolved drug loaded (API_A) microparticles. SEM images showed a spherical shape maintained after mixing and washing steps. However, some large pores were captured on the microparticles based on the SEM images, perhaps due to one of the organic solvents, which is also miscible in water, leaving the PLGA polymer upon droplet formation.

A lyophilization step was incorporated after the washing step of the microparticles, to improve drug loading efficiency assessment using UV spectrometry. Furthermore, drug loading efficiency increased, from 2% to 7%, by increasing the polymer to API_A ratio. Due to one of the organic solvents forming a stream upon droplet formation on a chip, as the possible root cause to our low drug loading efficiency, a different API (API_B) was assessed. Furthermore, prodrugs of API_A, are also currently being investigated to improve its hydrophobicity and therefore increase its drug loading efficiency.

API_B, with its lower solubility in water, was also investigated and showed significant improvement to drug loading efficiency, in comparison to API_A, and eliminated the need of one of the organic solvents. The control release functionality of API_B, using a USP-4 apparatus is currently being investigated. An exploratory PK/PD study will also be conducted to test the microfluidic technology.