¹Department of Pharmaceutical Chemistry, Bharati Vidyapeeth College of Pharmacy, Kolhapur-416013, MS, India DOI : 10.29228/jrp.530 Lisinopril belongs to BCS class III having high solubility and low permeability. Reportedly, the oral bioavailability of lisinopril is 25 to 30% and its effectiveness is limited due to poor permeability. Hence, the current investigation is aimed to formulate transdermal ion-pair gel using a permeation enhancer for enhanced delivery of lisinopril across the stratum corneum and evaluate pharmacokinetics of lisinopril in rabbits. The formation of ion-pair is corroborated using Fourier Transform Infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), X-ray Diffraction (XRD), zeta potential, particle size analysis, oil/water partition coefficient study, etc. Optimization of the formulation was done using 32 factorial designs. Total nine batches (F1-F9) were prepared and the effect of propylene glycol (mL; Xsub>1) and carbopol 934 (%; X2) was investigated on gel viscosity (Y₁) and permeability through rabbit’s skin at 8h (Y₂). Propylene glycol exhibited a non-significant (p>0.05) effect on both gel viscosity and skin permeability whereas carbopol 934 demonstrated significant (p<0.05) positive and negative effects on both, respectively. The viscosity of all the lisinopril ion-pair gel (F1-F9) was ranging between 17.24 ± 2.16 Pa.s (Batch F9) to 7.54 ± 1.34 Pa.s (Batch F4). Ex-vivo permeability of all the prepared batches (F1-F9) across excised rabbit’s skin was ranging between 85.93 ± 1.26% (Batch F4) to 62.17 ± 1.57% (Batch F9). Remarkably, optimized formulation (F4) exhibited 1.7 folds improvement in skin permeability and 2.4 folds improvement in bioavailability than plain lisinopril gel. These findings demonstrate that ion pair formation is a promising strategy for significantly improving the skin permeability of lisinopril. Keywords : Ion-pair formation; permeation enhancer; topical drug delivery; Carbopol 934; Angiotensin Converting Enzyme.