A novel formulation based on nanostructured lipid carriers (NLCs) was developed to increase solubility and intestinal absorption of khellin. K-NLCs were prepared with stearic acid, hempseed oil, Brij S20, and Labrafil M 1944 CS, using the emulsification-ultrasonication method. Developed nanoparticles were chemically and physically characterized by liquid chromatography, light scattering techniques, and electron microscopy. The size, about 200 nm, was optimal for oral delivery, and the polydispersity index (around 0.26), indicated high sample homogeneity. Additionally, K-NLCs showed a spherical morphology without aggregation by microscopic analysis. The encapsulation efficiency of khellin was about 55%. In vitro release studies were carried out in media with different pH to mimic physiological conditions. K-NLCs were found to be physically stable in the simulated gastric and intestinal fluids, and they preserved about 70% of khellin after 6 h incubation. K-NLCs were also successfully lyophilized testing different lyoprotectants, and obtained freeze-dried K-NLCs demonstrated good shelf life over a month. Lastly, permeability studies on Caco-2 cells were performed to predict khellin passive diffusion across the intestinal epithelium, demonstrating that nanoparticles increased khellin permeability by more than two orders of magnitude. Accordingly, developed NLCs loaded with khellin represent a versatile formulation with good biopharmaceutical properties for oral administration, possibly enhancing khellin’s bioavailability and therapeutic effects.

Pistacia lentiscus L., commonly known as the mastic tree or lentisk, is a woody Mediterranean plant revered for its ecological relevance as well as for its extensive ethnobotanical heritage. Historically, the fruits and the resin of P. lentiscus have been widely utilized in traditional medicine, underscoring its important role in local healing practices. Given these properties, this study explored an innovative approach to efficiently extract anthocyanins and flavonols from P. lentiscus oilcakes utilizing ultrasound-assisted extraction (UAE) as an alternative to conventional solvent extraction. Liquid chromatography–mass spectrometry (LC-MS) and high-performance liquid chromatography with diode-array detection (HPLC-DAD) were used to identify and quantify the anthocyanins and flavonols, revealing the successful extraction of eight distinct anthocyanins and twenty flavonols. A Fractional Factorial Design (FFD) followed by a Box–Behnken design (BBD) were applied to optimize the yield of anthocyanins and flavonols. The optimal extraction conditions found were to be an extraction time of 15 min with 70% ethanol as the solvent and a liquid-to-solid ratio of 0.012 L g⁻¹, which resulted in a maximum extraction yield of 19.78 mg g⁻¹ dry extract for the Total Flavonol Content and over 25.4 mg g⁻¹ dry extract for the Total Flavonol and Anthocyanin Content. By elucidating the optimal conditions for extracting anthocyanins and flavonol glycosides, this study opens promising avenues for utilizing P. lentiscus oilcake by-products, supporting sustainable practices, and advancing the valorization of Mediterranean bio-resources for health-promoting applications.