Fabrication of Spheroidal Microparticles from Biodegradable Polymers for Drug Delivery Application.

Abstract

This work describes the novel fabrication of biodegradable prolate spheroids from poly(lactic-co-glycolic acid) (PLGA) polymers via oil-in-water (O/W) and water-in-oil-in-water (W/O/W) emulsion solvent evaporation methods. Droplet deformation and breakup in mechanically-mixed emulsions are governed by competing viscous and interfacial tension forces that shear the drop apart and hold it together, respectively. The size and shape of fabricated spheroids were manipulated through controlling fabrication process parameters that modulated the viscous and interfacial forces on droplets in the emulsion. These parameters included polyvinyl alcohol, tris(hydroxymethyl)aminomethane and hydrochloric acid (aqueous phase pH) concentrations in the aqueous phase, the mechanical stir speed, the oil-to-aqueous phase volume ratio, the use of acetone and dichloromethane as oil phase solvents, PLGA concentration in the oil phase and PLGA polymer characteristics such as co-monomer ratio, end group and molecular weight. The presented data show that low viscosity ratios and low interfacial tension caused by basic aqueous phase pH, acetone as a co-solvent and hydrophilic polymer side chains and end groups are all conditions that favor the formation of spheroidal particles. Low interfacial tension determined the ability to stretch droplets and form spheroids as well as the aspect ratio of formed particles. However, droplet breakup in the emulsification stage was also critically important; fast stir rates and high continuous phase viscosity led to smaller initial droplet sizes that were unable to be stretched. The polydispersity of fabricated particles was evaluated; low tris concentrations, fast stir rates and high lactic acid concentrations led to monodisperse particle distributions. The flexibility of the described techniques were demonstrated via the loading of a variety of therapeutics including paclitaxel, lovastatin and bovine serum albumin, as well as imaging agents including 6-carboxyfluorescein and cadmium sulfide fluorescent nanospheres into PLGA prolate spheroids. Loaded paclitaxel released faster from spheroid particles than from spheres of the same volume. Non-spherical particles may increase the efficiency of targeted drug delivery carriers in localizing and adhering to the blood vessel wall over spherical particles of the same volume. This technique has the advantages of simplicity in setup, high particle yield and adaptability to a wide range of biodegradable polymers and therapeutics.