Self-assembling polyether-b-polymethacrylate graft copolymers loaded with indomethacin

ABSTRACT

The amphiphilic graft copolymers containing polyether-b-polymethacrylate side chains are proposed as carriers for a nonsteroidal anti-inflammatory drug, indomethacin (IMC). Two series of copolymers, poly((methyl methacrylate)-co-(poly(ethylene glycol methacrylate)-graft-poly((methacrylic acid)-co-(tert-butyl methacrylate)))) (P(MMA-co-(PEGMA-graft-P(MAA-co-tBMA)))) and poly((methyl methacrylate)-co-(poly(propylene glycol methacrylate)-graft-poly((methacrylic acid)-co-(tert-butyl methacrylate)))) (P(MMA-co-(PPGMA-graft-P(MAA-co-tBMA)))) were applied in the micellization process. The effects of grafting degree (5–15%), length of the graft polymethacrylic segments (29–186 units), composition (PEG vs. PPG), and content of acidic fraction (52–89%) were verified in the design of two different types of micelles (depending on polyether nature) with proper stability and controlled release of the drug. The methacrylic segment with MAA units resulted in negatively charged layer as it was indicated by measurements of zeta potential (from −2 to −44 mV) The sizes of particles were in the range of 160–225 nm. The type of polyether segment influenced on the content of the drug encapsulation (PEG 39% vs. PPG 93% at 48% of hydrophobic fraction). In vitro experiments demonstrated significantly larger IMC releasing at pH 7.4 than in acidic conditions. The lower drug release rates were monitored for copolymers with long side chains containing large content of acidic units, what enhanced particle stabilization and drug-polymer interactions. The drug release profiles were well fitted to the Higuchi model, suggesting diffusion mechanism. The results confirmed that the graft copolymers might be applied as the carriers releasing a various doses of drug with the rate, which can be adjusted by wider sort of structural parameters than is possible in linear amphiphilic copolymers.

GRAPHICAL ABSTRACT

KEYWORDS:

• Drug delivery
• graft copolymers
• indomethacin
• particles
• PEGMA
• PPGMA
• self-assembly

Acknowledgments

The authors also thank Professor Andrzej Dworak and MSc. Katarzyna Łaba for possibility to use the fluorescence spectrophotometer in the Centre of Polymer and Carbon Materials (Polish Acad. Sci.).