Stimulus-Responsive Polysaccharide Microgel Particles Prepared by Temperature Induced Aggregation and Electrospraying Techniques

摘要

The field of controlled release is a broad area of study concerned with influencing the location, concentration, and efficacy of administration of active pharmaceutical ingredients (APIs), diagnostics, nutrients, or other bioactive compounds. Among the many constituents used to fabricate controlled-release excipients, polysaccharides are attractive for their inherent biocompatibility and favorable physical properties. The release of bioactive material from polymer networks can be controlled through manipulation of many physical properties of the matrix. Composition, particle size distribution, morphology, crosslinking density, and stimulus responsiveness are some of the factors considered when designing microparticle systems for controlled release. The particle size in particular is an important characteristic that affects the biodistribution and release kinetics. This work investigates two techniques for synthesis of polysaccharide microgel particles intended for oral and pulmonary delivery applications with a focus on controlling particle size.;In the first approach, self-assembled microgel particles were synthesized by covalently crosslinking hydroxypropyl cellulose (HPC) with trisodium trimetaphosphate (TSTMP). HPC is a water-soluble cellulose ether that exhibits a lower critical solution temperature (LCST) in aqueous solution. Microgel particles were synthesized by heating HPC solution above the LCST, resulting in polymer aggregation. Self-assembled aggregates were crosslinked, resulting in hydrated microgel particles upon cooling. The particles were coated with sodium alginate (SA) to present a transport barrier for release of the bioactive compound in the gastric environment, reduce hydrolysis of phosphate linkages, and impart mucoadhesive properties. A phosphate assay was developed to assess the phosphate ester crosslink formation process. Release kinetics experiments and modelling were performed to assess the efficacy of the system as a formulation for the oral delivery of glucose. Controlled release of an ionic diabetes drug, metformin HCl, was also demonstrated with the HPC microgel particle suspension. Electrospraying is a method of forming small uniform droplets by applying high voltage to a liquid flowing from a capillary. The shape of the liquid meniscus at the capillary outlet becomes elongated in the direction of the applied field when sufficient potential is applied between the fluid emitter and counter electrode. The droplets emitted are thus smaller than under ordinary extrusion conditions where gravity and surface tension control droplet size.;An investigation of the effect of various factors on the size and shape of ionically crosslinked sodium alginate (SA) particles for macromolecular drug delivery was conducted. Ionically crosslinked SA particles prepared by electrospraying have been investigated for encapsulation of biological macromolecules and cells 1, however, few studies have reported particles generated from dilute alginate solutions leading to microgel particles < 100 mum in diameter. In this work, particles were prepared using alginate solutions above and below the critical overlap concentration, c.;*, to examine the importance of chainentanglement. The normalized droplet size was found to scale differently for dilute and semi-dilute alginate solutions.