Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation: towards oral insulin delivery.

Ibie, C.O.; Knott, R.M.; Thompson, C.J.

Abstract

A significant barrier to oral insulin delivery is its enzymatic degradation in the gut. Nano-sized polymer-insulin polyelectrolyte complexes (PECS) have been developed to protect insulin against enzymatic degradation. Poly(allylamine) (Paa) was trimethylated to yield QPaa. Thiolation of Paa and QPaa was achieved by attaching either N-acetylcysteine (NAC), or thiobutylamidine (TBA) ligands (Paa-NAC/QPaa-NAC and Paa-TBA/QPaa-TBA thiomers). PEC formulations were prepared in Tris buffer (pH 7.4) at various polymer:insulin mass ratios (0.2:1-2:1). PECS were characterised by %transmittance of light and photon correlation spectroscopy. Insulin complexation efficiency and enzyme-protective effect of these complexes was determined by HPLC. Complexation with insulin was found to be optimal at mass ratios of 0.4-1:1 for all polymers. PECS in this mass range were positively-charged (20-40 mV), nanoparticles (50-200 nm), with high insulin complexation efficiency (> 90 %). Complexation with TBA polymers appeared to result in disulphide bridge formation between the polymers and insulin. In vitro enzymatic degradation assays of QPaa, Paa-NAC, and QPaa-NAC PECS showed that they all offered some protection against insulin degradation by trypsin and {esc}ga{esc}s-chymotrypsin, but not from pepsin. QPaa-NAC complexes with insulin are the most promising formulation for future work, given their ability to offer protection against intestinal enzymes. This work highlights the importance of optimising polymer structure in the delivery of proteins.

Citation

IBIE, C.O., KNOTT, R.M. and THOMPSON, C.J. 2019. Complexation of novel thiomers and insulin to protect against in vitro enzymatic degradation: towards oral insulin delivery. Drug development and industrial pharmacy [online], 45(1), pages 67-75. Available from: https://doi.org/10.1080/03639045.2018.1517776

• Journal Article Type: Article
• Acceptance Date: Aug 24, 2018
• Online Publication Date: Sep 25, 2018
• Publication Date: Jan 31, 2019
• Deposit Date: Sep 3, 2018
• Publicly Available Date: Sep 26, 2019
• Journal: Drug developement and industrial pharmacy
• Print ISSN: 0363-9045
• Electronic ISSN: 1520-5762
• Publisher: Taylor and Francis
• Peer Reviewed: Peer Reviewed
• Volume: 45
• Issue: 1
• Pages: 67-75
• DOI: https://doi.org/10.1080/03639045.2018.1517776
• Keywords: Thiomers; Insulin; Polymerprotein complexes; Enzymatic degradation; Oral protein delivery
• Public URL: http://hdl.handle.net/10059/3109