Enhancement of hydrophilic drug loading and release characteristics through micellization with new carboxymethyldextran-PEG block copolymers of tunable charge density

Ghareb Mohamed Soliman and Françoise M. Winnik

International Journal of PharmaceuticsVolume 356, Issues 1-2, 22 May 2008, Pages 248-258


Abstract
The micellization of a model cationic drug, diminazene diaceturate (DIM) and a series of new diblock copolymers, carboxymethyldextran-poly(ethylene glycols) (CMD-PEG), were evaluated as a function of the ionic charge density or degree of substitution (DS) of the carboxymethyldextran block and the molar ratio, [+]/[−], of positive charges provided by the drug to negative charges provided by CMD-PEG. Micelles ([+]/[−] = 2) incorporated up to 64% (w/w) DIM and ranged in hydrodynamic radius (RH) from 36 to 50 nm, depending on the molecular weight and DS of CMD-PEG. The critical association concentration (CAC) was on the order of 15–50 mg/L for CMD-PEG of DS > 60%, and ca. 100 mg/L for CMD-PEG of DS 30%. The micelles were stable upon storage in solution for up to 2 months and after freeze-drying in the presence of trehalose. They remained intact within the 4 < pH < 11 range and for solutions of pH 5.3, they resisted increases in salinity up to 0.4 M NaCl in the case of CMD-PEG of high DS. However, micelles of DIM and a CMD-PEG of low DS (30%) disintegrated in solutions containing more than 0.1 M NaCl, setting a minimum value to the DS of copolymers useful in in vivo applications. Sustained in vitro DIM release was observed for micelles of CMD-PEG of high DS ([+]/[−] = 2).
Keywords: Polyion complex micelles; Dextran; Electrostatic interactions; Polyelectrolytes; Diminazene diaceturate; Hydrophilic drug