In vitro characterization of PEGylated phospholipid micelles for improved drug solubilization: Effects of PEG chain length and PC incorporation

• Published in: Journal of pharmaceutical sciences Vol. 93; no. 10; pp. 2476 - 2487
• Main Authors: Ashok, Beena, Arleth, Lise, Hjelm, Rex P., Rubinstein, Israel, Önyüksel, Hayat
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.10.2004; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Biological and medical sciences; diazepam; Diazepam - administration & dosage; Diazepam - chemistry; Drug Carriers; General pharmacology; Medical sciences; Micelles; parenteral formulation; Particle Size; PEGylated lipids; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phosphatidylethanolamines - chemistry; Polyethylene Glycols - chemistry; QELS; SANS; Solubility; solubilization; sterically stabilized micelles; sterically stabilized mixed micelles; Structure-Activity Relationship; water-insoluble drug; PEGylated lipids; sterically stabilized mixed micelles; sterically stabilized micelles; diazepam; SANS; solubilization; water-insoluble drug; parenteral formulation; QELS; Water; Drug; Pharmaceutical technology; Psychotropic; Chain length; Mixed micelle; Phospholipid; Hypnotic; Lipids; Anticonvulsant; Solubilization; In vitro; Characterization; Ethylene oxide polymer; Formulation; Benzodiazepine derivatives; Diazepam
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20150

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 (0.5−1.5μM) 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.