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

Cistus creticus phenolic extracts offer potential as food ingredients, but their formulation-dependent behavior across processing, digestion, and membrane transport remains insufficiently characterized. This study integrated Box–Behnken optimization of ultrasound-assisted extraction, ultra-high-performance liquid chromatography–quadrupole time-of-flight tandem mass spectrometry (UHPLC–QTOF-MS/MS) profiling, maltodextrin freeze-drying, incorporation into grissini, storage assessment, modified INFOGEST digestion, and PermeaPad® passive permeation. The experimentally verified extraction conditions (80 °C, 40 min, 60% ethanol) yielded 354.1 ± 9.9 mg GAE/g dry plant material and DPPH antioxidant capacity of 115.6 ± 2.7 mg TE/g. Nineteen phenolic constituents were identified and quantified by UHPLC–QTOF-MS/MS. The 1:30 core-to-wall formulation achieved the highest phenolic recovery (88.4 ± 0.9%) and a Folin-based encapsulation efficiency of 99.4%. After 12 days at 25 °C, encapsulated and non-encapsulated extracts retained 95.0 ± 0.4% and 75.9 ± 0.4% of their initial Folin-reactive responses, respectively. Digestion produced formulation-dependent changes in measurable Folin-reactive equivalents, including in control grissini. Under equal initial donor loads (20 mg GAE), cumulative PermeaPad® transfer at 240 min was greater for encapsulated than non-encapsulated extract (26.0% versus 16.5%) and corresponding grissini (32.0% versus 18.5%; Holm-adjusted p < 0.001 for both comparisons). These formulation-dependent in vitro findings motivate compound-specific and biological investigations, without establishing intestinal absorption or systemic bioavailability.