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Flow field-flow fractionation (FlFFF) was used to characterize the aggregation of a charged, amphiphilic copolymer, MMA 550, prepared from poly(styrene-co-methyl methacrylate-co-maleic anhydride) and poly(ethylene oxide) monomethyl ether. MMA 550 has a charged hydrophobic backbone and hydrophilic grafts which give the polymer a complex behavior in aqueous solution. FlFFF turned out to be a powerful tool for separation and size determination of different polymer aggregate populations in various media. The hydrodynamic diameter of the polymer was obtained from FlFFF measurements in water and pH-adjusted solutions. In pure water, the majority of the polymer molecules had a hydrodynamic diameter of 3-4 nm, which was also found at higher pH values (pH 9). When the pH was lowered, the hydrodynamic diameter increased rapidly. This suggested the formation of large micelles, probably polymolecular, as an effect of the reduced charge repulsion.

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Anionic graft copolymers were synthesized through grafting of poly(ethylene glycol) monomethyl ether (MPEG) onto terpolymers containing succicinic anhydride groups. The backbone polymers were prepared through radical terpolymerization of maleic anhydride, styrene, and one of the following monomers: methyl methacrylate, ethylhexyl methacrylate, and diethyl fumarate. MPEG of different molecular weights were grafted onto the backbone through reactions with the cyclic anhydride groups. In this reaction one carboxylic acid group is formed together with each ester bond. The molecular weights of MPEG were found to influence the rate of the grafting reaction and the final degree of conversion. The graft copolymers were characterized by IR, GPC, and 1H‐NMR. Thermal properties were examined by DSC. Graft copolymers containing 50% w/w of MPEG 2000 grafts were found to be almost completely amorphous, presumably because of crosslinking, and hydrogen bonding between carboxylic acid groups in the backbone and the ether oxygens in MPEG grafts. © 1995 John Wiley & Sons, Inc.

PurposeA versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs).MethodsThe approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated.ResultsThe hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC0–24h was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs.ConclusionsHybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1191-4) contains supplementary material, which is available to authorized users.