Al Kurdi, Zakieh (2015) Subcutaneous and oral delivery of insulin. PhD thesis, University of Greenwich.

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Abstract

The aim of this project was to prepare, optimize, characterize and compare a subcutaneous/oral delivery system for insulin.
The effect of various low molecular weight chitosans (LMWCs) on the stability of insulin, using USP HPLC methods, was investigated. Insulin was found to be stable in a polyelectrolyte complex (PEC) consisting of insulin and LMWC in the presence of Tris-buffer at pH 6.5. In the presence of LMWC, the stability of insulin increased with decreasing molecular weight of LMWC; 13 kDa LMWC was the most efficient molecular weight for enhancing the physical and chemical stability of insulin. The bioactivity of insulin in the PEC was assessed using enzyme-linked immunosorbent assay (ELISA) testing; results showed that insulin is still functionally active in the presence of chitosan. Solubilization of the PEC in a reverse micelle formulation (RMF) and administration to diabetic rats resulted in an oral delivery system for insulin with acceptable bioactivity.
The effect of reduced (GSH) and oxidized (GSSG) glutathione on the bioactivity of insulin was studied. A PEC of insulin with low molecular weight chitosan (13 kDa) was prepared and characterized. The PEC was then solubilized, in the presence and absence of GSH and GSSG, in a reverse micelle consisting of oleic acid and two surfactants (labrasol and plurol). The in vitro and in vivo performances of the reverse micelle formulations (RMFs) were evaluated in rats. At pH 6.5 the association efficiency of the PEC was 76.2%. In vitro insulin release from the RMs was negligible at pH 1.2 and was markedly increased at pH 6.8. The hypoglycemic activity of insulin in the PEC was reduced when administered via the subcutaneous route, regardless of the GSH content. On the other hand, the presence of GSSG significantly enhanced hypoglycaemia. When the RMF was administered via the oral route, the presence of GSH had no effect on the hypoglycemic activity of insulin compared with the GSH free system. However, the presence of GSSG in the oral preparation increased the hypoglycemic activity of insulin; probably by inhibiting insulin degradation, thereby prolonging its effect. Thus, incorporation of GSSG in the RMF reduces blood glucose levels in rats and protects insulin from degradation.
The effect of glucosamine HCl (GlcN⋅HCl) on the bioactivity of insulin, administered via subcutaneous (SC) and oral routes, in rats was also investigated. The oral insulin delivery system (IC-RM) was prepared by solubilizing insulin-chitosan (13 kDa) polyelectrolyte complex (IC-PEC) in a RM system consisting of oleic acid, PEG-8 caprylic/capric glycerides and polyglycerol-6-dioleate. The blood glucose levels were measured using a blood glucose meter. The results revealed that the extent of hypoglycemic activity of SC insulin was GlcN⋅HCl dose dependent when they were administered simultaneously. A significant reduction in blood glucose level (p < 0.05) was found for the insulin:GlcN⋅HCl at mass ratios of 1:10 and 1:20, whereas lower ratios (e.g. 1:1 and 1:4) showed no significant reduction. Furthermore, enhancement of the action of SC insulin was achieved by oral administration of GlcN⋅HCl for five consecutive days prior to insulin injection (p < 0.05). For oral insulin administration via the IC-RM system, the presence of GlcN-HCl increased the hypoglycemic activity of insulin (p < 0.05). The relative pharmacological availabilities (PA) were 6.7% and 5.4% in the presence and absence of GlcN⋅HCl (i.e. the increase in the relative PA was about 23% due to the incorporation of GlcN⋅HCl in the IC-RM system), respectively. The aforementioned findings offer an opportunity to incorporate GlcN⋅HCl in oral insulin delivery systems in order to enhance a reduction in blood glucose levels.

Item Type:	Thesis (PhD)
Uncontrolled Keywords:	Drug delivery systems; oral delivery system; insulin;
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science Faculty of Engineering & Science > School of Science (SCI)
Last Modified:	24 Nov 2017 12:05
URI:	http://gala.gre.ac.uk/id/eprint/18146

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