Engineering Advances in Drug Delivery: Polysorbate 80 and Blood-Brain Barrier Permeation

Polysorbate 80 minor components can selectively increase blood–brain barrier (BBB) permeation, providing a tunable formulation strategy to enhance CNS exposure for compatible drugs.

The study shows that small, defined fractions within this surfactant can differentially modify excipient-driven transport across the BBB—an effect with direct implications for formulation selection and candidate prioritization.

Distinct minor components within Polysorbate 80 altered BBB permeation in vivo, producing variable, drug-specific effects across representative compounds. Isolated fractions such as a PEG/PS/PI mixture produced a 6.9-fold increase in donepezil brain concentrations (to 11.8 ± 1.2 ng/mL). PIM components increased delivery of DiR, donepezil, and nimodipine, while PSM/PSD fractions improved transport for DiR and donepezil; chlorogenic acid and paclitaxel showed no enhancement. These mouse-model comparisons demonstrate both directionality and selectivity across at least two chemotypes and provide quantitative effect-size ranges relevant to formulation decisions.

Brain uptake was assessed in BALB/c mice after intravenous dosing. Lipophilic tracer distribution was measured by fluorescence imaging and therapeutic-drug brain homogenate concentrations were quantified by UPLC–MS/MS to derive brain uptake endpoints. The design included vehicle controls and component-isolated comparisons to distinguish surfactant effects from formulation-matrix influences, with multiple cohorts per comparison to support internal reproducibility. Primary endpoints were absolute brain homogenate concentrations and fold-change versus control, yielding clear pharmacokinetic readouts.

For formulation scientists, these results argue for surfactant-grade selection and component-resolved screening early in development. Systematic testing of isolated minor components, dose-ranging in relevant rodent models, and early assessment of drug–component interaction patterns will help de-risk candidate selection. Documenting component composition and prioritizing fractions that demonstrate favorable brain uptake for the intended chemotype can materially influence translational risk–benefit decisions for Polysorbate 80-containing systems.

Translational interpretation must account for species differences in BBB transport, variability across chemical classes, and potential safety or immunogenicity signals from defined excipient fractions. Bridging studies—PK/PD correlation, expanded safety profiling, and validation of scalable manufacturing for selected fractions—are necessary before clinical progression.

The heterogeneity of responses across drugs underscores the need to integrate component-resolved data into go/no-go criteria and to prioritize PK bridging and safety characterization to streamline the preclinical-to-clinical transition.

Key Takeaways:

• Certain Polysorbate 80 minor components selectively enhance BBB permeation—observed effect sizes reached up to 6.9-fold.
• Formulation scientists and early-phase CNS development teams should prioritize component-resolved surfactant screening paired with PK readouts.
• Prioritize PK/PD bridging, safety profiling, and manufacturability assessment for promising excipient fractions before clinical translation.