Organic solvent-free nimodipine-loaded mixed nanomicelles for safe intravenous delivery

Nimodipine (Nimo) is a first-line calcium channel blocker for preventing cerebral vasospasm post-subarachnoid hemorrhage. However, its clinical formulations depend on high concentrations of organic solvents to improve solubility, frequently causing vascular irritation and dilution-induced precipitation that limits safe use. Herein, we developed organic solvent-free Nimo-loaded mixed nanomicelles (Nimo-PGH-MNMs) through a direct dispersion-thermal approach, using soybean phospholipids (SPC), sodium glycocholate (SGC) as primary carriers, and 15-hydroxystearic acid polyethylene glycol ester (HS-15) as a stabilizer. Single-factor screening and modified Box-Behnken-type response surface methodology were subsequently applied for formulation optimization. The optimized Nimo-PGH-MNMs have a uniform diameter of 2.41 ± 0.39 nm, high encapsulation efficiency of 99.8 ± 0.2%, and low critical micelle concentration of 0.38 mg/mL, maintaining stability for 24 h after clinical dilution and tolerating autoclaving at 121 °C for 15 min. In vitro profiles of Nimo-PGH-MNMs are highly similar to that of commercial Nimotop® (similarity factor 85.7 ± 1.5). Additionally, beagle dog pharmacokinetics confirm pharmacokinetic bioequivalence to the commercial formulation, and rat tissue distribution was highly comparable, with only a transient difference in gastric tissue at 2 h that did not alter the overall distribution pattern. Moreover, New Zealand rabbit safety evaluation shows minimal vascular irritation, significantly less than that caused by the ethanol-containing Nimotop®, and no hemolytic reaction, with high biocompatibility. This organic solvent-free and sterilizable system eliminates organic solvent-related risks, resolves conventional formulation limitations, and provides a clinically feasible, scalable strategy for intravenous Nimo delivery, establishing a paradigm for injections of poorly water-soluble drugs.