In vitro Evaluation of Hydroxypropyl-β-cyclodextrin Effects on Rhein Flux Across Microneedle-pretreated Skin

Solid drug-hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes are used to enhance drug solubility and microneedle (MN)-mediated delivery efficiency. However, mechanistic understanding of HPβCD effects in solution on drug transport across pathways in MN-pretreated skin remains limited. This study investigated the in vitro permeation of rhein (RN) across MN-pretreated neonatal porcine skin from saturated RN solutions containing 0-200 mM HPβCD. Phase solubility, total flux (J_total), and permeability coefficient through the microchannel pathway (P_MCP) were determined, along with dermal transport at varying HPβCD concentrations. Permeation experiments under asymmetric and symmetric donor-receiver HPβCD conditions were conducted to elucidate potential interactions between HPβCD and skin transport pathways. RN solubility increased from 241.9 ± 16.4 µg/mL (0 mM HPβCD) to 1,092.5 ± 54.9 µg/mL (200 mM HPβCD), showing a linear trend up to 50 mM. MN permeation studies confirmed that RN transport occurred predominantly through microchannels. The highest J_total (3.87 ± 0.40 μg/cm²/h) was achieved at 25 mM HPβCD, with no further enhancement at higher concentration. Although increasing HPβCD concentration improved RN solubility, P_MCP and dermal transport decreased. Identical permeation profiles under symmetric and asymmetric conditions at 50 mM HPβCD indicated no direct interaction between HPβCD and MN-pretreated skin. In summary, HPβCD-mediated solubility enhancement increased RN flux across MN-pretreated skin, but not microchannel permeability or dermal diffusion.