Exenatide is a potent glucagon-like peptide-1 receptor agonist used in clinical practice for the management of type 2 diabetes. Exenatide is administered subcutaneously twice daily, or once weekly in the form of poly (Iactide-coglycolide) PLGA microspheres. This study investigated the benefit of using encapsulated nanoparticulate exenatide as an intraperitoneal and oral treatment compared to native peptide. To optomise the encapsulation process and determine its suitability to other peptide or protein formulations, ovalbumin and glucose-dependent insulinotrophic polypeptide (GIP) were used. The intial formulation data was collected using ovalbumin as the encapsulant and further optomised using GIP. Following method development with the model protein and peptide, exenatide was successfully encapsulated within the polymeric nanoparticles using the double emulsion/solvent evaporation method, resulting in particles of 122.98 ± 1.65 nm in mean diameter, with a 25.0 ± 1.76% encapsulation efficiency of exenatide. Analysis of the peptide using MALDI-MS confirmed the encapsulated peptide to be the same as the native peptide. Stability analysis determined that the material was stable for a period of 12 weeks, the duration of the trails. In vitro drug release in simulated physiological environments representative of the stomach, small and large intestines suggests that the formulation is most suited to drug delivery in the large intestine. In vitro analysis in BRIN-BD11 cells showed exenatide-Ioaded nanoparticles to have limited cytotoxicity and an ability to produce more insulin than native exenatide. In vivo glucose homeostasis results revealed that the oral administration of exenatide-loaded nanoparticles was superior to intraperitoneal administration and native exenatide in reducing blood glucose. Orally administered exenatide was released from nanoparticles in an environment representative of the small intestine over a period of 96 hours, remaining in the blood at low concentrations over the same period of time. The aforementioned results prove that this delivery system has the potential to change diabetes treatment, allowing for the administration of an oral anti-diabetic peptide. Collectively, these results indicate the need for further investigation of the oral administration and release of anti -diabetic peptides from orally administered nanoparticles.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:650084 |
| Date | January 2014 |
| Creators | Craythorne, Natalie Louise |
| Publisher | Ulster University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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