Controlled Release and Enhanced Bioavailability of Spray-Dried Microparticles Loaded with Liposoluble Vitamins and Natural Flavonoids Quercetin and Fisetin

Lipophilic bioactive compounds often exhibit poor aqueous solubility, chemical instability and low intestinal absorption, limiting their effectiveness in nutraceutical and pharmaceutical formulations. This study aimed to develop gastro-resistant spray-dried microparticles (MPs) capable of encapsulating and modulating the release of selected liposoluble molecules (fisetin, quercetin, β-carotene, vitamin A acetate and vitamin E). Five formulations (MILC-Fis, MILC-Q, MILC-β-car, MILC-Vit.A and MILC-Vit.E) were prepared within the innovative MILC® matrix (Micro Intelligent Lite Carrier), composed of milk and whey proteins (WPs), to obtain microparticles prepared exclusively with food-based materials. Scanning electron microscopy (SEM) analysis confirmed the formation of predominantly spherical particles with a mean diameter of approximately 15 ± 5 μm. MPs showed high encapsulation efficiencies, up to 79.6% for MILC-Q and 75.7% for MILC-Fis, exhibited pH-dependent release profiles with minimal release under gastric conditions (pH 1–2) and enhanced release at intestinal pH (6.8). In vitro studies demonstrated a significant increase in bioaccessibility, while in vivo pharmacokinetic evaluation revealed an improvement in bioavailability, with MILC-Q and MILC-Fis increasing the AUC by 8.2-fold and 2.47-fold, respectively, compared with the non-encapsulated compounds. These results highlight the potential of the MILC® protein matrix to protect lipophilic bioactives during gastric transit and enhance their intestinal availability and systemic exposure, supporting its applicability as a food-grade delivery platform for poorly soluble nutraceuticals and functional food formulations.