The complexation between novel comb shaped amphiphilic polyallylamine and insulin—Towards oral insulin delivery

• Published in: International journal of pharmaceutics Vol. 376; no. 1; pp. 46 - 55
• Main Authors: Thompson, C.J., Tetley, L., Uchegbu, I.F., Cheng, W.P.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 06.07.2009; Elsevier
• Subjects: Administration, Oral; Biological and medical sciences; Caco-2 Cells; Cell Survival - drug effects; Drug Carriers - administration & dosage; Drug Carriers - pharmacokinetics; Drug Delivery Systems - methods; Enzymatic degradation; General pharmacology; Humans; Inactivation, Metabolic; Insulin - administration & dosage; Insulin - pharmacokinetics; Medical sciences; Nano-complexes; Oral delivery; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyamines - adverse effects; Polyamines - chemical synthesis; Polyamines - chemistry; Polymeric self-assemblies; Polymers - chemical synthesis; Proteins and peptides; Surface-Active Agents - adverse effects; Surface-Active Agents - chemical synthesis; Polymeric self-assemblies; Proteins and peptides; Enzymatic degradation; Nano-complexes; Oral delivery; Complexation; Pharmaceutical technology; Peptides; Oral administration; Polymer; Amphiphilic compound; Insulin; Protein; Degradation
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2009.04.014

Novel amphiphilic polyallylamine (PAA) were previously synthesised by randomly grafting palmitoyl pendant groups and subsequent quaternising with methyl iodide. The ability of these self-assembled polymers to spontaneously form nano-complexes with insulin in pH 7.4 Tris buffer was evaluated by transmittance study, hydrodynamic size and zeta potential measurements. The transmission electron microscopy images showed that non-quaternised polymer complexes appeared to form vesicular structures at low polymer:insulin concentrations. However, at higher concentrations they formed solid dense nanoparticles. The presence of quaternary ammonium moieties resulted in insulin complexing on the surface of aggregates. All polymers exhibited high insulin complexation efficiency between 78 and 93%. Incubation with trypsin, α-chymotrypsin and pepsin demonstrated that most polymers were able to protect insulin against enzymatic degradation by trypsin and pepsin. Quaternised polymers appeared to have better protective effect against trypsinisation, possibly due to stronger electrostatic interaction with insulin. Interestingly, non-quaternised polymers significantly enhanced insulin degradation by α-chymotrypsin. All polymers were less cytotoxic than PAA, with the quaternised polymers exhibiting up to 15-fold improvement in the IC 50 value. Based on these results, quaternised palmitoyl graft polyallylamine polymers showed promising potential as oral delivery systems for insulin.