Enhancement of hydrophilic drug loading and release characteristics through micellization with new carboxymethyldextran-PEG block copolymers of tunable charge density.
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 (R(H)) 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 15-50mg/L for CMD-PEG of DS>60%, and ca. 100mg/L for CMD-PEG of DS approximately 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 approximately 0.4M 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 0.1M 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).
Soliman
Ghareb Mohamed
GM
Faculty of Pharmacy and Department of Chemistry, Université de Montréal, CP 6128, Succursale Centre Ville, Montréal, QC H3C 3J7, Canada.
Winnik
Françoise M
FM
D002626:Chemistry, Pharmaceutical; D003911:Dextrans / Q000737:chemistry*; D004133:Diminazene / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry; D004355:Drug Stability; D004356:Drug Storage; D005612:Freeze Drying; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D054712:Salinity; D012965:Sodium Chloride / Q000737:chemistry; D014199:Trehalose / Q000737:chemistry
D003911:Dextrans; D004337:Drug Carriers; D008823:Micelles; D011108:Polymers; D011092:Polyethylene Glycols; D012965:Sodium Chloride; C014392:carboxymethyl dextran; D014199:Trehalose; C003915:diminazene aceturate; D004133:Diminazene