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Keywords:

  • water-insoluble drug;
  • PEGylated lipids;
  • sterically stabilized mixed micelles;
  • sterically stabilized micelles;
  • diazepam;
  • SANS;
  • QELS;
  • parenteral formulation;
  • solubilization

Abstract

Sterically stabilized micelles (SSM) composed of poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) and sterically stabilized mixed micelles (SSMM) composed of DSPE-PEG and egg-phosphatidyl choline (PC) have recently been introduced as novel lipid based carriers for water-insoluble drugs. However, factors that affect the solubilization behavior of these phospholipid micelles are not well understood. This study investigates the effect of PEG chain length and PC content on physical properties and solubilization potential of PEGylated phospholipid micelles. Critical micelle concentrations (CMC) determined for DSPE-PEG with different PEG chain lengths (2000, 3000, and 5000) using a fluorescent probe were in the micromolar range (0.5–1.5 μM) with higher CMC for longer PEG chain length. The size of micelles determined by quasi-elastic light scattering (QELS) showed that micellar systems became heterogeneous when PC was added at ≥25% for DSPE-PEG 2000 and ≥ 40% for DSPE-PEG 5000, respectively. Above these critical PC ratios a significant increase in aggregation number and formation of rodlike particles were observed by small angle neutron scattering (SANS). Solubilization of diazepam was greater with DSPE-PEG 2000 than DSPE-PEG 5000 simple micelles as determined by RP-HPLC. However, DSPE-PEG 5000 micelles showed greater improvement in solubilization of the water-insoluble drug with an increase in PC content. In conclusion, phospholipid micelle size and solubilization potential varied with PEG chain length and PC content in the mixed micelle. Aggregation number and shape of the micelles did not significantly change until the critical PC concentrations. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:2476–2487, 2004