(W0930-03-17) Development of Soluplus/TPGS Mixed Micelles Using Hot-Melt Extrusion for Hydrophobic Drug Delivery

Purpose: The poor aqueous solubility is a well-recognized restriction for the clinical application of many drug molecules. Micelles delivery system provides a promising strategy for the solubility enhancement of hydrophobic drugs. Hot-melt extrusion (HME) is one of the most popular techniques for scale-up pharmaceutical manufacturing with distinct advantages. The present study aims to develop and evaluate Soluplus/TPGS mixed micelles prepared using the HME coupled hydration method for extended delivery of poorly water-soluble drugs fenofibrate (FEN).

Methods: FEN-loaded polymeric mixed micelles were prepared using the HME coupled hydration method. Briefly, the physical mixture contained FEN, Soluplus, and TPGS was fed into a co-rotating twin-screw extruder (11 mm Process 11™, ThermoFisher Scientific, Karlsruhe, Germany). Extrusion was performed at 110 °C with a Thermo Fischer standard screw configuration at a speed of 30 rpm. Then, the extrudates were pulverized using a coffee grinder and sieved through ASTM E-11 #60 mesh. Subsequently, the sieved powder was dispersed into deionized (DI) water under continuous stirring conditions at 40 °C for 2 h. The micellar suspension was centrifuged (12,000 rpm, 5 min) to remove unincorporated drugs. The hydrodynamic diameter of the micelles was assessed by dynamic light scattering using a Nano Zetasizer (Malvern Instruments Inc., UK). A reverse-phase HPLC drug quantification methodology (Waters Corp., Milford, MA, USA) was used to determine the encapsulation efficiency. The spherical morphology of the micellar formulations was studied with a JSM-7200FLV scanning electron microscope (SEM) (JEOL, Peabody, MA, USA). The micellar solutions were diluted 10, 50, and 100 folds with DI water and then analyzed for the change of particle size. The release of FEN from the micelles was evaluated using the dialysis method.

Results: The drug-loaded micelles were successfully prepared without obvious precipitation of either polymers or drugs. The encapsulation efficiency (EE%) of the micellar formulations was approximately 90%. The mean particle size of the drug-loaded micelles was around 100 nm with a polydispersity index less than 0.2 (Fig. 1A). The spherical micelles were clearly observed by SEM (Fig. 1B). The in vitro release study showed that the free FEN and FEN-loaded mixed micelles exhibited drug release of 100% and 20% after 12h, separately. This result demonstrated that the drug-incorporated mixed micelles showed extended-release property compared to the free drug (Fig. 2), which had the potential of being used as drug delivery carriers for bioavailability improvement. In dilution study, the particle sizes of the mixed micelles showed no significant change upon dilution, indicating the stable physicochemical property of the micelles (Fig. 3). The performance of mixed micelles against dilution was crucial for the further in vivo delivery evaluation of the loaded drug in physiological environments where the micelles are in non-equilibrium conditions.

Conclusion: The FEN-loaded Soluplus/TPGS mixed micelles could be successfully prepared via the HME paired hydration method with an ideal EE% of around 90%. The mean particle size of the micelles was around 100 nm with a polydispersity index (PDI) less than 0.2. The extended-release of the FEN from the mixed micelles suggested that incorporating the FEN into the micellar system may retain the drug release for a prolonged period. The micellar formulations exhibited stabilizing effect against dilution. The current study demonstrated the feasibility and potential of preparing mixed micelles via the HME coupled hydration method for hydrophobic drug delivery.

Figure 1. Particle size (A) and SEM images (B) of the FEN-loaded micelles.

Figure 2. In vitro release profiles of free FEN and FEN-loaded micelle.

Figure 3. The particle sizes of FEN-loaded mixed micelles in dilution study.