Novel pH-sensitive supramolecular assemblies for oral delivery of poorly water soluble drugs: preparation and characterization.

The objective of the present study was to synthesize novel pH-sensitive block copolymers forming supramolecular assemblies and to explore their potential as poorly water-soluble drug carriers for oral delivery. Diblock copolymers of polyethylene glycol and t-butyl methacrylate (tBMA), ethyl acrylate (EA) or n-butyl acrylate (nBA) were synthesized by atom transfer radical polymerization (ATRP). The pH-sensitive polymers obtained by hydrolysis of t-butyl groups were characterized for aggregation behaviour. Poorly water-soluble model drugs, i.e., indomethacin (IND), fenofibrate (FNB) and progesterone (PRG), were incorporated in supramolecular assemblies by dialysis or oil-in-water (O/W) emulsion methods. Process parameters for emulsion method were studied to maximize drug loading. Progesterone release was evaluated in vitro as a function of pH. Polymers with controlled molecular weights and low polydispersities were obtained by ATRP. All polymers exhibited pH-dependent aggregation behaviour and their critical aggregation concentration (CAC) decreased with increase in the hydrophobic block length. Drug loadings of <6% and 6-14% w/w were achieved by the dialysis and emulsion methods, respectively. Polymer composition, drug concentration and solubilization of polymer in water or dichloromethane (DCM) affected the loading. Progesterone release from supramolecular assemblies increased when the pH of the release medium was raised from 1.2 to 7.2. The results suggest that these supramolecular assemblies with high drug loadings and pH-dependent release kinetics can potentially enhance the oral bioavailability of poorly water-soluble drugs. Copyright 2004 Elsevier B.V.