Poloxamer 407 (P407) is an ABA triblock polymer widely used in therapeutic delivery due to its temperature-dependent micellization and ordering behavior. However, using P407 to deliver therapeutics across biological barriers remains difficult, as additives that enhance drug flux often hinder formulation stability and mechanical properties. Methyl laurate (ML)─a methyl ester oil─was recently identified as a promising additive for delivery across the eardrum; however, P407/ML easily phase-separates due to poor emulsion stability. Accordingly, we explore adding reverse poloxamers (RPs)─BAB triblock polymers with the same blocks as P407 but in reverse order─to aqueous P407 as a strategy for controlling self-assembly, ordering, and formulation stability. Differential scanning calorimetry (DSC), rheology, and small-angle X-ray scattering (SAXS) reveal that ML induces ordering at low P407 concentrations due to ML encapsulation within micelles. While adding ML challenges formulation stability at both low and high temperatures, adding RPs (17R2 or 17R4) enhances emulsion stability and raises the maximum modulus. However, only the more hydrophilic 17R4 significantly alters self-assembly and rheological transitions in P407/ML. As P407 micellization is well separated from dehydration of 17R4 with increasing temperature, 17R4 chains remain soluble for a wide temperature range, effectively delaying ordering in P407/ML by obstructing contact between micelle coronas. Following dehydration, 17R4 localizes in the micelle corona, altering the P407 aggregation number. In contrast, the low aqueous solubility of 17R2 leads to localization near the micelle core-corona interface; such localization drives cubic ordering in the absence of ML but has little impact on self-assembly when ML is present. These differences in RP solubility and incorporation mechanism─and their impact on P407 rheology, self-assembly, and ordering─provide a framework for selecting the optimal RP type and quantity to produce P407 drug delivery vehicles with well-controlled properties for target applications.
Knisely et al. (Mon,) studied this question.