Fast In Vitro Release and In Vivo Absorption of an Anti-Schizophrenic Drug Paliperidone from Its Soluplus®/TPGS Mixed Micelles

The purpose of this study was to develop a drug delivery system for paliperidone (PPD) in order to provide a more effective therapeutic strategy for patients with acute schizophrenia. PPD-loaded Soluplus^®/TPGS mixed micelles (PPD-S/T-MM) were prepared using the thin-film hydration method. The critical micelle concentration (CMC) of blank S/T-MM was 4.77 × 10⁻² mg/mL. PPD presented much higher solubility in PPD-S/T-MM formulation than that in pure water. The particle size of blank or drug loaded S/T-MM was around 60 nm. The polydispersity index (PDI) was less than 0.1. PPD-S/T-MM presented a nearly spherical shape under transmission electron microscopy. The encapsulation efficiency (EE%) of PPD-S/T-MM was higher than 94%. Based on the analysis of XRD and DSC, it was proved that PPD was incorporated in the core of the mixed micelles as amorphous dispersion or solid solution. PPD-S/T-MM were stable when they were undergoing dilution with water and the change of environmental pH. Although PPD-S/T-MM showed lower rates to release PPD than those from PPD raw material in acidic solution, they provided faster release rates in neutral conditions than those from PPD raw material who only showed modest dissolution in the same neutral condition. This proves that PPD-S/T-MM can release PPD in a more controlled manner. After oral administration of PPD-S/T-MM (dose of PPD, 6 mg/kg) in rats, the plasma concentration of PPD increased rapidly: T_max was 0.83 ± 0.29 h, and C_max was 844.33 ± 93.73 ng/mL. Oral administration of PPD suspension resulted in longer T_max and lower C_max. The relative oral bioavailability was about 158% for PPD-S/T-MM over PPD suspension. These findings confirm that PPD-S/T-MM can provide faster release in neutral conditions and better oral absorption in rats than those from PPD raw material, which should potentially benefit patients with acute schizophrenia.

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About this article: Zhou, Y.; Wang, C.; Liu, W.; Yang, M.; Xu, B.; Chen, Y. Fast In Vitro Release and In Vivo Absorption of an Anti-Schizophrenic Drug Paliperidone from Its Soluplus^®/TPGS Mixed Micelles. Pharmaceutics 2022, 14, 889. https://doi.org/10.3390/pharmaceutics14050889

Materials
PPD raw materials (purity ˃ 98.0%) were purchased from Widely Chemicals (Wuhan, China). Soluplus® (batch No. 66458088Q0) was kindly gifted from BASF (Ludwigshafen, Germany). D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) was purchased from Hongxin Ruiyu Fine Chemicals (Wuhan, China). HPLC-grade methanol was supplied by Merck KGaA (Darmstadt, Germany). All aqueous solutions were prepared using Milli-Q® water (resistivity ˃ 18 MΩ·cm). All other chemicals used were at least of analytical grade.