Colloidal phase behavior of pH-responsive, amphiphilic PEGylated poly(carboxylic acid)s and effect on kinetic solubility under acidic conditions.
PEGylated poly(carboxylic acid)s, PEG-b-PCAs, were evaluated as additives for solubilized oral formulations of weakly acidic compounds. Micelles of poly(ethylene glycol)-block-poly(acrylic acid), PEG-b-PAA, and poly(ethylene glycol)-block-poly(methacrylic acid), PEG-b-PMAA, were prepared. Fluorescence spectroscopy and dynamic light scattering revealed that both polymers assemble into nanoscopic structures (< 200 nm) in acidic media and exhibit pH-sensitive colloidal phase behavior. Using a solvent evaporation technique, the block copolymers and corresponding PCA homopolymers were incorporated into PEG3350-based solid dispersions. The kinetic solubility profile of a BMS compound, BMS-A (Seq ~ 12.5 μg/mL at pH 1.1) in 0.1 N HCl was monitored as a function of polymer composition. While BMS-A precipitated rapidly in 0.1 N HCl in the absence of PEG-b-PCAs, a supersaturated level of ca. 400 μg/mL was maintained for variable lengths of time in the presence of PEG-b-PCAs. Although the kinetic solubility of BMS-A was also enhanced in the presence of the PCA homopolymers, the relative magnitude and duration of supersaturation as a function of polymer composition suggests that micellar solubilization, rather than specific interaction, contributes to enhanced solubility of BMS-A in 0.1 N HCl. Under acidic conditions, pH-responsive PEG-b-PCAs may offer the kinetic supersaturation necessary to minimize precipitation of compounds which have limited solubility in acidic milieu.
Biopharmaceutics Research and Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903, USA. monica.adams@bms.com
Monica L
ML
Adams
Venkatramana M
VM
Rao
Ajit
A
Thakur
Munir A
MA
Hussain
D002264:Carboxylic Acids / Q000737:chemistry* / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003102:Colloids; D006863:Hydrogen-Ion Concentration; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry* / Q000493:pharmacokinetics; D014961:X-Ray Diffraction / Q000379:methods
D002264:Carboxylic Acids; D003102:Colloids; D008823:Micelles; D011108:Polymers; D013501:Surface-Active Agents; D011092:Polyethylene Glycols