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Investigation of excipients to improve oral delivery of peptides Saxena, Tanya
Abstract
Oral delivery of drugs provides a patient compliant & cost-effective method of treating multiple diseases. However due to physiological and mechanical barriers like gastric pH (~1.2), pyloric sphincter, enzymatic degradation in gut, mucosal lining, and selective permeability of molecules across the intestinal membrane, most drugs do not reach systemic circulation after oral administration. These hurdles become bigger when peptides are delivered orally, since they have sensitive 3D structures that breakdown easily. The aim of this dissertation is to overcome these hurdles using excipients that protect the peptide from degradation as well as increase their permeability across the intestinal lining. We hypothesized that sub-millimeter sized gelatin microparticles (named sorbops) generated using a novel microfluidic setup, can be loaded with drugs through absorption/adsorption, and enterically coated to bypass the acidic pH of the stomach along with easy transit from the stomach to the intestine. Furthermore, we hypothesized that a model peptide like Glucagon-Like-Peptide-1 (GLP-1), which shows a short half-life of 2 min due to enzymatic degradation, can have longer retention in gut when substituted with more stable chemical analogs pGLP-1 (derived from platypus). Finally, to overcome the last hurdle, we hypothesized that a biocompatible and multi-functional dendrimer like hyperbranched polyglycerol (HPG), after conjugation with GLP-1 using an enzyme sensitive linker, can be released in the intestine to increase the oral bioavailability of the peptide. The hypotheses were tested using in vitro dissolution and permeability studies along with in vivo SPECT/CT imaging and blood sampling for pharmacokinetic and pharmacodynamic studies. Enterically coated sorbops loaded with radiolabeled drugs showed a safe and smooth transit to the intestine within 3 h after oral gavage in mice. Furthermore, GLP-1-HPG conjugates showed 10x higher efficacy compared to free peptide in the systemic circulation. Thus, excipients like sorbops and HPG have the potential to improve the oral bioavailability of peptides.
Item Metadata
Title |
Investigation of excipients to improve oral delivery of peptides
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Creator | |
Supervisor | |
Publisher |
University of British Columbia
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Date Issued |
2023
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Description |
Oral delivery of drugs provides a patient compliant & cost-effective method of treating multiple diseases. However due to physiological and mechanical barriers like gastric pH (~1.2), pyloric sphincter, enzymatic degradation in gut, mucosal lining, and selective permeability of molecules across the intestinal membrane, most drugs do not reach systemic circulation after oral administration. These hurdles become bigger when peptides are delivered orally, since they have sensitive 3D structures that breakdown easily. The aim of this dissertation is to overcome these hurdles using excipients that protect the peptide from degradation as well as increase their permeability across the intestinal lining. We hypothesized that sub-millimeter sized gelatin microparticles (named sorbops) generated using a novel microfluidic setup, can be loaded with drugs through absorption/adsorption, and enterically coated to bypass the acidic pH of the stomach along with easy transit from the stomach to the intestine. Furthermore, we hypothesized that a model peptide like Glucagon-Like-Peptide-1 (GLP-1), which shows a short half-life of 2 min due to enzymatic degradation, can have longer retention in gut when substituted with more stable chemical analogs pGLP-1 (derived from platypus). Finally, to overcome the last hurdle, we hypothesized that a biocompatible and multi-functional dendrimer like hyperbranched polyglycerol (HPG), after conjugation with GLP-1 using an enzyme sensitive linker, can be released in the intestine to increase the oral bioavailability of the peptide.
The hypotheses were tested using in vitro dissolution and permeability studies along with in vivo SPECT/CT imaging and blood sampling for pharmacokinetic and pharmacodynamic studies. Enterically coated sorbops loaded with radiolabeled drugs showed a safe and smooth transit to the intestine within 3 h after oral gavage in mice. Furthermore, GLP-1-HPG conjugates showed 10x higher efficacy compared to free peptide in the systemic circulation. Thus, excipients like sorbops and HPG have the potential to improve the oral bioavailability of peptides.
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Genre | |
Type | |
Language |
eng
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Date Available |
2024-09-30
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Provider |
Vancouver : University of British Columbia Library
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Rights |
Attribution-NonCommercial-NoDerivatives 4.0 International
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DOI |
10.14288/1.0435935
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2023-11
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Campus | |
Scholarly Level |
Graduate
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Rights URI | |
Aggregated Source Repository |
DSpace
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Rights
Attribution-NonCommercial-NoDerivatives 4.0 International