Alkylated 1,4-diazabicyclo[2.2.2]octane derivatives with an ester moiety: From self-organization to transdermal insulin delivery.

A homologous series of novel cationic surfactants, 1-(2-(alkanoyloxy)ethyl)-1,4-diazabicyclo[2.2.2]octane-1-ium bromides (DAB‑est‑n, where n = 9, 11, 13, 15, 17), bearing an ester fragment between the head group and the hydrophobic tail, was synthesized with overall yields of 68-82% and characterized by IR, 1H NMR spectroscopy, high‑resolution mass spectrometry, and elemental analysis. A DAB-est-15 crystal was characterized by X-ray diffraction analysis. The self‑assembly of surfactants in aqueous solution was investigated using tensiometry, conductometry, fluorimetry, and spectrophotometry. The introduction of the ester group led to a twofold reduction in aggregation thresholds compared to the non‑functionalized analogue (0.5 mM vs. 1 mM). Spectrophotometry revealed a high solubilizing capacity of DAB‑est‑n toward Orange OT and the antidiabetic drug glipizide. The ability to integrate into the lipid bilayer of liposomes was confirmed by turbidimetry and electrophoretic light scattering. The ester‑containing surfactants showed enhanced biodegradability (up to 61%) compared to DAB‑16 and low hemolytic activity for DAB‑est‑9 and DAB‑est‑11. The homologous series of cationic surfactants was used to modify transfersomes for transdermal therapy of type 1 diabetes. Cationic transfersomes modified with DAB‑est‑13 efficiently encapsulated insulin (encapsulation efficiency 58 ± 2%) and were formulated in Carbopol®940 gel. Additionally, in vitro release kinetics revealed a sustained, non-Fickian diffusion profile for insulin-loaded transfersomes. Ex vivo studies on mouse skin demonstrated that modification significantly improved transdermal permeation, yielding an enhancement ratio of 1.8 compared to free insulin. Transdermal delivery of insulin using cationic transfersomes effectively reduced blood glucose levels to values comparable to those in healthy mice in vivo, whereas the gel formulations of free insulin or unmodified transfersomes showed no efficacy.