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oai:cora.ucc.ie:10468/55722023-04-04T07:04:11Zcom_10468_386com_10468_4com_10468_1com_10468_365col_10468_387col_10468_140col_10468_574

Hard bound copy in Library only Entire Thesis Restricted Yes This thesis is due for publication or the author is actively seeking to publish this material O'Driscoll, Caitriona M. Presas, Elena Trans-int Consortium Seventh Framework Programme 2018-03-06T12:02:37Z 2018 2018 Over the past decades, oral protein delivery has become a major research area for pharmaceutical companies. Ideally, once the protein is orally administered, it should remain stable until it reaches the targeted site of absorption in spite of the myriad of factors that could hinder its stability, such as the harsh environment of the gastrointestinal tract, the possible pre-systemic degradation by enzymes, the wide range of pH and the poor permeability of the intestinal mucosa. The application of nanosystems, specifically cyclodextrin-based nanoparticles (NPs) to overcome these barriers is the focus of this project. The overall goal of this thesis has been to design and develop three different nanoparticle formulations including three different drug cargos, two human insulin analogues (insulin glulisine and Lola insulin) and the GLP-1 analogue named as liraglutide. In the first stage of the preclinical development of these formulations, the fabrication process of the three prototypes containing the different cargos was optimized. The resulting formulations showed suitable physico-chemical properties for an oral administration as well as suitable stability profiles, both upon contact with proteolytic enzymes and as a freeze-dried product. In addition, in vitro and ex vivo were carried out to evaluate the intestinal uptake mechanisms of the formulations. In vitro studies using the Caco-2 cell monolayer model and ex vivo (rat intestinal tissue) studies showed that insulin glulisine NPs enhanced the epithelial permeability of insulin. Lastly, the formulations were assessed in different animal models. Best results were obtained with the insulin glulisine NPs, where progressive and significant reduction in the glucose levels was achieved after the in situ instillation (50 IU/kg) to healthy anaesthetized Wistar rats (≈50 % after 45 minutes maintained up to 4 hours). Overall, the insulin glulisine NPs stands out as the most promising for further development of an effective insulin oral dosage form. Trans-int Consortium (281035-2 TRANS-INT CP-IP) Not peer reviewed Accepted Version application/pdf Presas, E. 2018. Pre-clinical development of cyclodextrin-based nanoparticles for oral delivery of protein/peptide drugs-in vitro and in vivo evaluation. PhD Thesis, University College Cork. https://hdl.handle.net/10468/5572 en University College Cork info:eu-repo/grantAgreement/EC/FP7::SP1::NMP/281035/EU/New Oral Nanomedicines: Transporting Therapeutic Macromolecules across the Intestinal Barrier/TRANS-INT © 2018, Elena Presas. http://creativecommons.org/licenses/by-nc-nd/3.0/ Nanotechnology Nanomedicine Oral protein delivery Nanoparticles true Pre-clinical development of cyclodextrin-based nanoparticles for oral delivery of protein/peptide drugs-in vitro and in vivo evaluation Doctoral thesis Doctoral Degree (Structured) PhD (Science)info:eu-repo/semantics/embargoedAccess