Drug delivery and formulation development of hesperidin: a systematic review

Natural bioflavonoids, particularly hesperidin from citrus fruits, have attracted attention due to their potent antioxidant, anti-inflammatory, anticancer and neuroprotective properties. However, the clinical application of hesperidin is limited by its poor solubility, low bioavailability, and stability issues. Following PRISMA guidelines, we searched PubMed, MEDLINE, Scopus, and Google Scholar from inception to 10 January 2025 using terms combining ‘hesperidin’ with ‘bioavailability,’ ‘solubility,’ ‘absorption,’ and ‘formulation.’ Two reviewers independently screened records against predefined inclusion criteria (original, formulation-focused studies reporting biopharmaceutical or biological outcomes), resolved disagreements through discussion or third-reviewer adjudication, extracted data using a standard template, and assessed the risk of bias across six domains. From 1,625 records, 69 studies met eligibility. Platforms spanned inclusion complexes, solid dispersions, self-microemulsifying drug delivery systems (SMEDDS), microparticles, gels/microemulsions, and diverse nanoformulations (polymeric, lipidic, metallic, exosomal). Most approaches increased dissolution and/or exposure; lipidic and polymeric nanosystems delivered the largest, most consistent improvements, with early clinical signals in vascular, metabolic and oncological indications. Formulation advances can significantly mitigate hesperidin’s biopharmaceutical liabilities, with lipid-based systems, polymeric nanoparticles, and phytosomes emerging as leading strategies. Translation will benefit from stability and immunotoxicity packages, quality-by-design manufacturing, and well-designed, adequately powered clinical trials using harmonised pharmacokinetic and clinical endpoints. INPLASY202550096