Journal
PHARMACEUTICAL RESEARCH
Volume 24, Issue 8, Pages 1517-1526Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11095-007-9270-z
Keywords
aqueous insulin stability; insulin aggregation; ionic complexation; PEG-b-poly(L-histidine); polymeric stabilizers
Funding
- NIGMS NIH HHS [GM72612] Funding Source: Medline
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Purpose. This study is to investigate whether poly(ethylene glycol) (PEG)-b-poly(L-histidine) [PEG-polyHis] can reduce aggregation of insulin in aqueous solutions on agitation by forming ionic complexes. Materials and Methods. Insulin aggregation on agitation was monitored spectrophotometrically and by fibrillation studies with a dye Thioflavin T. Pluronic F-127 as a control and PEG-polyHis as a novel multifunctional excipient were added to prevent destabilization of insulin. Conformation of insulin was evaluated in a circular dichroism (CD) study. Results. Ionic interactions between insulin and PEG-polyHis were induced in the pH range: 5.5-6.5. pH 5.5 was selected for further evaluation based on particle size/zeta potential studies. Ionic complexation with PEG-polyHis is more effective at pH 5.5 in stabilizing insulin ( 75% of insulin retained versus 0% with no excipient) than Pluronic F-127 (42% retained). PEG-polyHis guards against insulin aggregation in non-complexing pH conditions ( pH 7.4), 64% insulin retained versus 58% with F-127 and 0% with no excipient) pointing to the potential role played by PEG in modulation of insulin surface adsorption. Rate of fibrillation was higher for plain insulin compared with addition of PEG-polyHis and Pluronic F-127 at both pH. Conclusions. Understanding and manipulation of such polyelectrolyte-protein complexation will likely play a role in protein stabilization.
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