A drug delivery system for the paranasal sinuses consisting of a freeze-dried thermoresponsive hydrogel with degradable microspheres, called FD-TEMPS (Freeze Dried-Thermogel, Extended-release Microsphere-based delivery to the Paranasal Sinuses), was developed. Glass transition temperatures (Tg') of the maximally freeze concentrated solutions consisting of poly(N-isopropylacrylamide) (pNIPAAm) and polyethylene glycol (PEG) were determined by differential scanning calorimetry, which informed optimization of the thermogel formulation. By replacing low molecular weight (MW) PEG (200 Da) with a higher MW PEG (2000 Da), the resulting freeze-dried gel exhibited a brittle texture, porous structure, and low residual moisture (< 3% measured by thermal gravimetric analysis). When combined with poly(lactic-co-glycolic acid) microspheres (PLGA MSs) and freeze dried, the complete system (FD-TEMPS) exhibited enhanced shelf-stability. Specifically, the smooth, spherical morphology of the MSs and initial release kinetics were maintained following 6 weeks of storage under ambient conditions. Furthermore, FD-TEMPS remained in place after application to a simulated mucosal surface, suggesting that it could be more uniformly distributed along the sinonasal mucosa in vivo. Freeze drying enables this delivery system to be stored as a ready-to-use product for better ease of clinical translation without compromising the thermoresponsive or sustained release characteristics that would enable local delivery of therapeutics to the sinonasal mucosa.
Keywords: Controlled release; Freeze drying; Microspheres; Mucosal drug delivery; Thermoresponsive.
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