Dawoud, Marwa H. SZaafan, Mai ASaleh, Sarah SMannaa, Islam MSweed, Nabila M2023-04-092023-04-092023-04https://doi.org/10.1007/s13346-023-01315-whttp://repository.msa.edu.eg/xmlui/handle/123456789/5531Vanillic acid (VA) is a phenolic compound with potential antioxidant activity, which improves ischemia-induced myocardial degeneration, by reducing oxidative stress; however, it sufers poor bioavailability owing to its poor solubility. VA-loaded pharmacosomes were optimized using a central composite design, where the efect of phosphatidylcholine:VA molar ratio and the precursor concentration were studied. An optimized formulation (O1) was prepared and tested for the release rate of VA, in vivo bioavailability, and cardioprotective potential on myocardial infarction-induced rats. The optimized formulation showed a particle size of 229.7 nm, polydispersity index of 0.29, and zeta potential of−30 mV. O1 showed a sustained drug release for 48 h. The HPLC–UV method was developed for the determination of VA in plasma samples using protein pre- cipitation. The optimized formulation showed a great improvement in the bioavailability as compared to VA. The residence time of the optimized formula was 3 times longer than VA. The optimized formulation showed a more potent cardioprotec- tive efect as compared to VA, via inhibition of the MAPK pathway with subsequent inhibition of PI3k/NF-κB signaling, in addition to its antioxidant efect. The optimized formulation showed normalization of many oxidative stress and infamma- tory biomarkers. Thus, a VA-loaded pharmacosome formulation with promising bioavailability and cardioprotective activity potential was prepared.en-USVanillic acid ·Bioavailability ·Optimization ·Release rateCentral composite designCardioprotective activityArticlehttps://doi.org/10.1007/s13346-023-01315-w