Polymeric Precipitation Inhibitor–Based Solid Supersaturable SMEDD Formulation of Canagliflozin: Improved Bioavailability and Anti-diabetic Activity

Abstract

The current investigation explores the enhanced biopharmaceutical attributes of solid supersaturable self-microemulsifying drug delivery system (Solid SS SMEDDS) for poorly water soluble drug canagliflozin (CFZ). Solid SS SMEDD formulation was prepared by spray drying using Neusilin US2 as an adsorbent. The developed SS SMEDDS were characterized for physicochemical and solid state characterizations. Theoretical molecular simulations were performed by in silico docking. BET measurements were done for evaluating surface area topography. In vitro dissolution, ex vivo permeation, and pharmacokinetics studies were performed to determine release rate, permeability, and absorption behavior, respectively. Anti-diabetic studies and histopathology were done as per standard protocols. The solid SS SMEDD formulation containing 320 mg Lauroglycol FCC, 1200 mg Tween 80, 480 mg Transcutol-P, and 2.24% w/v Poloxamer 188 as polymer-based precipitation inhibitor (PPI) was optimized. The solid state attributes of CFZ in solid SS SMEDDS revealed its molecularly dispersed state. The prepared formulation demonstrated uniform flow properties, nanoparticulate size distribution, and acceptable drug content. Theoretical simulations revealed strong intermolecular hydrogen bonding with a docking score of − 5.184 kJ/mol. In vitro dissolution studies depicted enhanced release of CFZ from solid SS SMEDDS in various dissolution media. Remarkable improvement in ex vivo permeability was observed across the jejunum segment of rat intestine. These studies revealed enhanced absorption of CFZ in rats following oral administration of solid SS SMEDDS, as compared with that of pure drug and marketed product. Pharmacological evaluation of optimized solid SS SMEDDS also revealed enhanced anti-diabetic activity, as evident from urinary glucose excretion studies and SGLT II protein expression in rat kidneys. Accelerated stability study confirmed the stability of the formulation up to 6 months storage period. The designed delivery system indicated promising results in developing an effective formulation of CFZ for diabetes mellitus.