Integrated Optimization, Microencapsulation, and Food Incorporation of Cistus creticus Phenolic Extracts: Simulated Gastrointestinal Digestion and PermeaPad® Passive Membrane Permeation

Cistus creticus L. is a Mediterranean plant rich in phenolic constituents with substantial antioxidant potential. This study developed an integrated experimental approach com-bining ultrasound-assisted extraction (UAE), phenolic profiling, maltodextrin-based mi-croencapsulation, incorporation into a bakery matrix, simulated gastrointestinal digestion, and passive membrane permeation. UAE was optimized using a three-factor Box–Behnken response surface design considering temperature, actual sonication time, and ethanol concentration. The predicted optimum was obtained at 80 °C, 40 min, and 60% (v/v) etha-nol. Experimental verification yielded a total phenolic content of 354.1 ± 0.9 mg GAE/g dry plant material and DPPH antioxidant capacity of 115.6 ± 0.7 mg TE/g dry plant material, closely matching model predictions. UHPLC–QTOF-MS/MS enabled the tentative assign-ment of 19 phenolic compounds, quantified using analyte-specific calibration curves normalized to syringaldehyde as an internal standard. Freeze-drying with maltodextrin at a 1:30 core-to-wall ratio (w/w) resulted in 88.4 ± 0.9% phenolic recovery and 99.4% en-capsulation efficiency. The encapsulated extract showed greater retention of Folin-reactive constituents during storage than the non-encapsulated extract. During modified static INFOGEST digestion, measurable Folin-reactive equivalents increased progressively, with the extent of change depending on formulation and food-matrix incorporation. Passive membrane transport was subsequently assessed using PermeaPad® with donor prepara-tions standardized to an initial total load of 20 mg GAE. After 240 min, cumulative perme-ated fractions were 16.5% for the non-encapsulated extract, 26.0% for the encapsulated ex-tract, 18.5% for grissini containing non-encapsulated extract, and 32.0% for grissini con-taining encapsulated extract. Overall, microencapsulation and incorporation into a bakery matrix modified the stability, gastrointestinal behavior, and passive membrane transport of the C. creticus Folin-reactive fraction demonstrating technological feasibility.