¹Department of Pharmaceutics, Faculty of Pharmacy, PSG College of Pharmacy, Coimbatore, India DOI : 10.29228/jrp.187 Lisinopril dihydrate (LP) is an FDA approved drug used in the treatment of hypertension. When administered orally it is slowly and incompletely absorbed with a bioavailability of 25–30% only. The aim of the present study is to increase the bioavailability of LP by formulating into nano-spanlastic bio-adhesive gel for intranasal delivery. LP loaded nano-spanlastics (LPSp) were prepared by ethanol injection method according to 23 factorial designs using Design Expert® software, to explore the impact of different independent variables on Particle Size (PS) and Entrapment efficiency (EE%). The optimized LPSp was evaluated for PS, surface morphology, polydispersity index (PDI), zeta potential, EE% and in-vitro drug release. Further, the optimized LPSp was loaded into Carbopol gel base (1%) and evaluated for pH, percentage drug content, texture properties and rheology. The permeation and histopathological studies were carried out using goat nasal mucosa. The optimized LPSp possessed spherical shape with PS and EE% of 320±4.5 nm and 72±2.5% respectively. Drug release studies revealed that the drug enclosed in spanlastic dispersion showed higher drug release compared to niosome dispersion. The LPSp gels exhibited satisfactory results for pH, drug content, texture properties and rheology. The ex-vivo results showed that the permeation rate of LP loaded nano-spanlastic bio-adhesive gel (LPSpG) increased when compared to that of LP loaded niosome gel (LPNiG). The results infer that encapsulating LP into vesicular carriers and formulating into a bio-adhesive gel augments its permeation and increases the residence time in nasal mucosa and therefore enhances its bioavailability. Keywords : Lisinopril dihydrate; spanlastic; edge activator; permeation; intranasal route; bio-adhesive gel