Pre-clinical development of cyclodextrin-based nanoparticles for oral delivery of protein/peptide drugs-in vitro and in vivo evaluation

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dc.contributor.advisor O'Driscoll, Caitriona M. en Presas, Elena 2018-03-06T12:02:37Z 2018 2018
dc.identifier.citation 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. en
dc.description.abstract 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. en
dc.description.sponsorship Trans-int Consortium (281035-2 TRANS-INT CP-IP) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2018, Elena Presas. en
dc.rights.uri en
dc.subject Nanotechnology en
dc.subject Nanomedicine en
dc.subject Oral protein delivery en
dc.subject Nanoparticles en
dc.title Pre-clinical development of cyclodextrin-based nanoparticles for oral delivery of protein/peptide drugs-in vitro and in vivo evaluation en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral Degree (Structured) en
dc.type.qualificationname PhD (Science) en
dc.internal.availability Full text not available en Restricted to everyone for three years en 2021-03-05T12:02:37Z
dc.description.version Accepted Version
dc.contributor.funder Trans-int Consortium en
dc.contributor.funder Seventh Framework Programme en
dc.description.status Not peer reviewed en Pharmacy en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.entireThesis Entire Thesis Restricted
dc.check.embargoformat Hard bound copy in Library only en
dc.internal.conferring Spring 2018 en
dc.relation.project info:eu-repo/grantAgreement/EC/FP7::SP1::NMP/281035/EU/New Oral Nanomedicines: Transporting Therapeutic Macromolecules across the Intestinal Barrier/TRANS-INT en

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© 2018, Elena Presas. Except where otherwise noted, this item's license is described as © 2018, Elena Presas.
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