A microfluidic and mechanistic modeling approach to enhance oral bioavailability of cannabidiol via poloxamer-coated camel milk exosomes.

Cannabidiol (CBD) has significant therapeutic potential, but its oral delivery remains limited by poor aqueous solubility, variable intestinal absorption, and extensive first-pass metabolism. This study evaluated Poloxamer 407-coated camel milk-derived exosomes (CBD-CMDE-P407) as an oral nanocarrier system for improving CBD delivery. The relationship between in vitro release, epithelial permeability, in vivo pharmacokinetics, and GastroPlus® PBPK-based absorption prediction was also examined. CBD-loaded CMDE were successfully prepared with a particle size of 126.11 ± 0.75 nm, while P407 coating increased the hydrodynamic diameter to 142.3 ± 2.1 nm without evidence of major vesicle destabilization. CBD-CMDE-P407 reduced premature CBD release under simulated gastric conditions and supported sustained CBD release under intestinal pH, indicating improved gastric protection and controlled intestinal drug availability. In MDCK monolayers, CBD-CMDE-P407 showed higher apparent permeability than the control formulation, with a Papp of 29.56 × 10-6 ± 0.78 cm/s. Following oral administration in rats, CBD-CMDE-P407 increased systemic CBD exposure compared with the control formulation, with Cmax of 719.58 ± 27.63 ng/mL and AUC0-24 h of 2947.88 ± 124.03 h·ng/mL. A custom microfluidic dissolution chip reproduced the formulation rank order observed with conventional USP dissolution testing and may serve as a complementary low-volume platform for evaluating nanocarrier release behavior. GastroPlus® PBPK modeling further supported the experimental trends, predicting improved absorption for exosome-based formulations, mainly in the proximal small intestine. Overall, these findings provide proof-of-concept evidence that P407-coated CMDE may improve oral CBD delivery through gastric protection, controlled intestinal release, and enhanced epithelial transport. Further studies are needed to establish long-term stability, safety, reproducibility, and pharmacodynamic relevance.