Exploiting supercooled medium-chain lipids and surfactant combinations for solid-phase dominant nanostructured lipid carrier production

Nanostructured lipid carriers (NLCs) are a promising delivery system for poorly water-soluble drugs, including lipophilic peptides. However, NLCs often display unpredictable drug partitioning between solid and liquid lipid phases, potentially compromising controlled release profiles. Here, we demonstrate a novel hybrid NLC approach that directs drug loading primarily to the solid phase while maintaining the structural advantages of established NLCs. Using cyclosporine A (CsA) as a model peptide, we exploited the significant solubility differential between medium-chain solid lipids (glyceryl caprylate: 338.95 ± 77.68 mg mL^-1; glyceryl caprate: 88.63 ± 8.80 mg mL^-1) and the liquid lipid component (soy liquid lecithin: 1.39 ± 0.09 mg mL^-1) to create a natural concentration gradient favouring a solid phase loading. By strategically combining these medium-chain lipids with selective surfactants, particularly PEG-100 stearate, we enabled the controlled transformation of initially supercooled melts into organised type I imperfect crystal structures that effectively encapsulate CsA within the solid lipid matrix. This approach allowed single-step hybrid NLC production at temperatures up to 20 °C lower than conventional methods while reducing homogenisation power requirements by 38%. Our optimised formulations maintained particle size (<200 nm), polydispersity (<0.3), and spherical morphology during four-week storage at 4 °C, room temperature, and 40 °C. Most notably, the controlled CsA release profiles in simulated intestinal fluid confirmed successful drug entrapment within the solid lipid matrix rather than the liquid phase. This work presents a robust strategy for producing stable, solid-phase dominant NLCs at reduced processing temperatures, with significant implications for controlled drug delivery and continuous manufacturing processes.