Dissolving microneedle patches for transdermal delivery of paroxetine: <i>in-vitro, ex-vivo</i> studies and its PBPK modeling

Paroxetine HCl (PRX-HCl), an antidepressant, has poor water solubility and low oral bioavailability with 50% being metabolized in the liver. The oral formulations have multiple side effects. The present work aimed to develop dissolving microneedle patches (MNPs) of PRX-HCl to resolve low bioavailability and side effect issues while achieving enhanced transdermal delivery. Three silicone templates of varying dimensions were used to fabricate 27 blank and nine PRX-HCl MNPs with PVP and PVA through mold casting method. MNPs were evaluated for physicochemical properties, <i>in-vitro release, and ex-vivo permeation</i>. The optimized MNP was further analyzed for FTIR, DSC, skin penetration, <i>in-silico</i> PBPK modeling, and stability. MNPs from the optimized formulation successfully created microchannels in rat skin, demonstrated higher permeation than control MNPs with a flux of 146.18 ± 13.42 µg/cm²/h, presented a decrease in lag phase and an increase in drug plasma C_max and AUC compared to PAXIL CR 12.5 mg oral, and showed higher stability in the room and refrigerator conditions. The prepared MNPs were stable and can deliver PRX-HCl sufficiently across skin barrier with enhanced bioavailability compared to oral administration at similar doses and thus be a better alternative to already available delivery systems for PRX-HCl.