Title : Polyphenols as pharmaceutical active ingredients: Current challenges in bioavailability and novel drug delivery
Abstract:
Plant polyphenols comprise several major classes, including flavonoids, phenolic acids, stilbenes, lignans, and related compounds. Beyond their classical role as antioxidants, they act as pleiotropic modulators of interconnected signaling, metabolic, and epigenetic pathways, including the Nrf2/Keap1/ARE, NF-κB/NLRP3, and AMPK/SIRT1 signaling axes, as well as microRNA-mediated regulatory networks. By influencing oxidative stress, inflammation, apoptosis, mitochondrial function, and cellular signaling, polyphenols have emerged as promising candidates for multitarget (network-targeted) therapeutics, with considerable neuroprotective, geroprotective, senomorphic, and immunomodulatory, as well as immuno-oncological, potential.
Despite extensive pharmacological evidence, however, only a limited number of polyphenol-based medicines have successfully reached clinical practice, primarily because of poor aqueous solubility, low membrane permeability, extensive first-pass metabolism, chemical instability, and considerable interindividual variability in absorption associated with gut microbiota metabolism. Nevertheless, this metabolic transformation also highlights their potential as microbiota-mediated natural prodrugs, which are converted into highly bioactive postbiotic metabolites, including urolithins and enterolactones.
Successful translation of polyphenols into clinically effective phytopharmaceuticals begins with the quality of medicinal plant raw materials. Botanical authentication, compliance with Good Agricultural and Collection Practices (GACP), chromatographic fingerprinting, quantitative determination of pharmacologically relevant marker compounds, and control of contaminants remain essential prerequisites for producing reproducible standardized extracts. Particular importance is attributed to pharmacopoeial markers of polyphenolic structure, including rosmarinic acid, echinacoside, acteoside, resveratrol, hyperoside, rutin, isoquercitrin, luteolin, luteolin-7-O-glucoside, epigallocatechin-3-O-gallate, silybin, cyanidin-3-O-glucoside, violanthin and vitexin derivatives, and certain lignans. These constituents serve not only as analytical markers for quality control in monographs for several herbal substances of European Pharmacopoeia and State Pharmacopoeia of Ukraine but also as pharmacologically active compounds linking herbal raw materials, standardized extracts, pharmaceutical quality assurance, and therapeutic efficacy.
Recent advances in pharmaceutical sciences have substantially expanded opportunities to overcome the intrinsic biopharmaceutical limitations of polyphenols. Innovative delivery platforms—including liposomes, phytosomes, polymeric and lipid nanoparticles, cyclodextrin inclusion complexes, polymeric micelles, nanoemulsions, lipid-based nanovesicles, self-emulsifying drug delivery systems (SEDDS), plant-derived extracellular vesicles (PDEVs; exosome-like nanoparticles), and stimulus-responsive ("smart") nanosystems—significantly improve aqueous solubility, stability, controlled release, targeted tissue delivery, and systemic bioavailability.
At the same time, modern dosage forms are increasingly being developed for standardized polyphenol-rich botanical extracts, rather than isolated compounds, thereby preserving synergistic interactions among multiple phytoconstituents and reflecting the principles of network pharmacology ("multi-compound–multi-target") and phytochemical synergy. Gastro-resistant capsules, multiparticulate pellet systems, mucoadhesive films, nanoemulgels, hydrogels, electrospun nanofibers, transdermal patches, inhalable powders, and injectable nanoformulations exemplify the transition toward patient-centric phytopharmaceutical dosage forms.
Future pharmaceutical development is expected to integrate standardized botanical extracts, advanced biomaterials, artificial intelligence-assisted formulation design, physiologically based pharmacokinetic (PBPK) modeling, and personalized drug delivery strategies. Equally important will be the establishment of interoperable FAIR-compliant knowledgebases integrating pharmacopoeial information, phytochemical composition, analytical methods, physicochemical properties, pharmacokinetics, molecular targets, biological activities, and formulation technologies for pharmacologically relevant individual polyphenols and their botanical sources. Such resources will facilitate the rational selection of medicinal plant raw materials and their pharmacopoeial marker compounds, accelerate the design of innovative dosage forms, and support data-driven development of next-generation phytopharmaceuticals.
