A drug–drug cocrystal of breviscapine and borneol: harnessing natural product synergy for synchronized release and improved pharmacokinetics

A drug–drug cocrystal strategy harnessing natural product synergy was developed to address the oral delivery barriers of breviscapine (BRE), a natural flavonoid with poor solubility and extensive first-pass metabolism. BRE was integrated with the monoterpenoid permeation enhancer borneol (BO) via solvent evaporation to form a stable supramolecular assembly. Comprehensive solid-state characterization and density functional theory calculations confirmed that the cocrystal lattice is stabilized by specific hydrogen bonding between the flavonoid and terpenoid scaffolds. The optimized BRE-BO cocrystal exhibited highly synchronized release of both natural products ( R 2 = 0.86), in contrast to the discordant dissolution of the physical mixture, with kinetics following the Korsmeyer–Peppas model (n = 0.45) indicative of Fickian diffusion. In vivo pharmacokinetic evaluation in rats demonstrated that the synergy conferred by co-delivered BO resulted in a 1.6-fold enhancement in oral bioavailability ( AUC 0-24 ), a prolonged T max (from 2.3 to 3.3 h), and an elevated C max (1.2 vs. 0.8 mg/L) compared to bulk BRE. These findings demonstrate that drug–drug cocrystallization can simultaneously achieve dissolution synchronization and pharmacokinetic optimization, providing a viable strategy for the formulation of poorly bioavailable natural flavonoids without the use of polymeric excipients.