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|Title:||Studies of insulin transport across intestinal epithelium using nano-encapsulation for oral delivery||Authors:||Zhang, Yiming||Keywords:||DRNTU::Engineering::Materials
|Issue Date:||2018||Source:||Zhang, Y. (2018). Studies of insulin transport across intestinal epithelium using nano-encapsulation for oral delivery. Doctoral thesis, Nanyang Technological University, Singapore.||Abstract:||Diabetes Mellitus is a chronic metabolic disease characterized by abnormally high blood glucose level. Conventional subcutaneous insulin injection has been the dominant treatment option for the diabetic patients due to its immediate glucose lowering effect. However, its long term application has generated a plethora of problems, relating to the complications and compliance issues. Great efforts have been devoted to the development of an effective alternative treatment but none of them has been turned into a solution to date. The discovery of insulin in the early 1920s brought promising hopes to pharmaceutical industries as increasing number of them have been attempting to load the drug in a capsule for the conventional oral route. However, the nature of the protein renders huge difficulties as it attempt to overcome the defensive barriers of the body. The bioavailability of the orally ingested protein drug is too low to achieve the desired glycemic control because of the degradation by proteolytic enzymes and low permeability through the small intestine. These shortcomings have limited the application of oral tablets and discouraged the diabetic patients to switch from the current dominant subcutaneous injection to oral treatment. However, this does not stop the research towards the oral route of delivery because of its promising future. An oral route not only minimizes the patient compliance issue by eliminating the use of invasive needles, more importantly, it offers hepatic glucose regulation as the orally administered insulin would potentially be carried by hepatic portal vein to reach the liver, where glucose homeostasis take place. This made the oral pathway extremely advantageous because it lowers the risk of hypoglycemia and hyperinsulinmeia which are often associated with improper control of injected insulin dose. Hence, the aim of this study is to investigate the transport of insulin across intestinal epithelium using nano-encapsulation for oral delivery. Liposomes has been the most translatable and extensively studied vesicles in the field of oral drug delivery. The studies of insulin transport across intestinal epithelial cells were investigated from three general areas; interaction of empty liposomes with intestinal epithelial Caco-2 cells, cellular interaction and transport of insulin loaded liposomes with appropriated surface modifications across Caco-2 cells, loading of insulin onto surface of liposomes for enhanced transport, improved loading, and sustained release. Liposomes fabricated from lipids of different acyl chain length, degree of saturation, and, cholesterol content has been investigated for their capability to generate high cellular association. Rigid HSPC/DOTAP liposomes demonstrated higher cellular association compared to the softer ones. Eudragit S100 coating was performed on rigid HSPC/DOTAP liposomes with the help of Tween 80. In the presence of free Eudragit S100 and Tween 80, cellular uptake and transport was observed in Eudragit S100-coated insulin-loaded HSPC/DOTAP liposomes. With a modified rehydration protocol, insulin transport was further improved from to 3.9ng/ml to 35.7ng/ml. Subsequently, a Layer-by-Layer approach was developed to load insulin onto the surface of HSPC/DPPG liposomes with the help of oppositely charged chitosan. The multilayer coated liposomes exhibited significant improvement in insulin loading, cellular uptake and transport, and sustained the release of insulin for up to 3 months. With only 1 layer of insulin loaded on the surface of liposomes, the transport of insulin across Caco-2 cells was enhanced by 2.6 fold from 5.7ng/ml to 15ng/ml. An enhancement factor of more than 8x was observed with just 2 layers of insulin coating. This thesis has demonstrated a novel approach to deliver oral insulin via the Layer-by-Layer approach. This approach based on simple electrostatic interaction generated particles with long sustained release window, therefore serve as a potential alternative to the current subcutaneous injection.||URI:||https://hdl.handle.net/10356/88857
|DOI:||10.32657/10220/47649||Fulltext Permission:||open||Fulltext Availability:||With Fulltext|
|Appears in Collections:||IGS Theses|
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