Development of Piperine-Loaded Soft Binary Ethosomal Gel to Improve Transdermal Delivery: Box-Bhekhen Design Optimization, Ex-Vivo Permeation, and Antimicrobial Evaluation

Natural bioactive compounds have been used to treat various diseases but have some limitations like poor solubility as well as low bioavailability. Piperine (PE) is a natural alkaloid and poor water-soluble compound. The present research work aims to develop PE-loaded binary ethosomes gel (PEES-gel) for the improvement of transdermal delivery. ES was prepared by the hot method and optimized by experimental design software. The phospholipid, cholesterol, and the mixture of alcohols (ethanol and propylene glycol) were taken as independent variables and determined their effect on vesicle size (VS) and entrapment efficiency (EE, %). The optimized PEES (PEESopt) has 187.7 ± 4.63 nm of VS, PDI of 0.253, − 37.3 mV of zeta potential, and 75.12 ± 0.85% of EE. Infrared spectra showed there is no interaction between the drug and excipients. PEESopt was successfully converted into carbopol and HPMC-K100gel. Optimized PEESopt gel (PEESopt-gel2) had excellent viscosity and good spreadability as well as biocompatible with skin pH. PEESopt-gel2 exhibited significantly high and sustained release (86.81 ± 3.12% in 24 h) than PE-gel (51.20 ± 3.63% in 24). PEESopt-gel2 showed high ex-vivo skin permeation (1.99-fold flux) than PE-gel. PEESopt-gel2 exhibited significantly (P < 0.05) high antimicrobial activity than pure PE and PE-gel against tested bacteria. Antioxidant activity results exposed that PEESopt-gel2 displayed a significant (P < 0.05) greater activity than pure PE at each concentration. The findings concluded that PEES-gel is an alternative to synthetic drugs for the topical delivery of PE.