Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.754997
Title: Oral delivery of insulin for diabetes therapy : the design, fabrication and characterisation of a modified-chitosan based nanoparticle system
Author: Rayasam, Revanth
ISNI:       0000 0004 7428 0113
Awarding Body: Kingston University
Current Institution: Kingston University
Date of Award: 2017
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Abstract:
A number of innovative techniques were developed for the extra-vascular delivery of insulin, of which oral delivery of insulin being one of the most active fields of study in pharmaceutics. Interest in this domain is due to two factors: the therapeutic potential of the approach and lack of delivery systems which demonstrate promising results for clinical implementation. Oral delivery of insulin is of a particular challenge due to highly evolved and complex barriers presented by the gastrointestinal tract (GIT). Long-term s.c. injections are invasive and are associated with major drawbacks such as pain, weight gain, hypoglycaemia, hyperinsulinemia, leading to low patient compliance and adherence. The present work aims to develop novel insulin-loaded chitosan (CS) and pegylated chitosan (CS-O-mPEG) based nanoparticles (NPs) and investigate them for potential colonic delivery. PEG-Chitosan was chemically conjugated using low molecular weight chitosan and mPEG-2000. Insulin loaded pegylated chitosan (CS-O-mPEG) NPs were prepared via the iontropic gelation technique by cross-linking with tripolyphosphate (TPP). The characteristics of the NPs i.e. particle morphology, particle size and zeta potential was evaluated. The effect of pH and the polymer:TPP wieght ratios on NP characteristics was also evaluated. An HPLC analytical method to quantify insulin was developed and validated. In vitro release and entrapment studies of the nanoparticles were conducted using the Franz diffusion cells. Prepared nanoparticle formulations were assessed for biocompatibility using the MTT (Tetrazolim dye) assay and permeability studies on the Caco-2 and MDCK monolayers. Successful CS-O-mPEG conjugation was confirmed by FTIR and 1H NMR spectroscopy. SEM revealed the spherical nature of CS and CS-O-mPEG NPs. A mean diameter ranging from 50 - 250 nm was recorded for the NPs. Characterisation of NPs for zeta potential was carried out for both the CS and CS-O-mPEG formulations. Particle size measurements for the NPs revealed size ranges between 110-250 nm, in accordance to the hydradynamic diameter measured by DLS. RP- HPLC analytical method was developed and validated according to ICH guidelines to quantify Insulin. The data showed presence of well-defined single insulin peak, being successfully recovered at retention time between 7.5 - 9 minutes. CS-O-mPEG NPs demonstrated maximum release in simulated intestinal fluids (SIF). There was some encouraging data obtained in regard to the biocompatibility studies for the prepared Insulin loaded NP formulations using MTT assay. Permeability studies were also conducted for the prepared NP formulations on Caco-2 and MDCK monolayers, revealing better permeation of insulin through the CS-O-mPEG NPs. Insulin-loaded NPs of CS and CS-O-mPEG were successfully formulated. CS-O-mPEG NPs demonstrated superior in vitro characteristics over the conventional CS NPs in terms of aqueous solubility, particle size, entrapment efficiency and drug release profile, In addition, permeation studies revealed that CS-O-mPEG NPs enabled a significantly higher insulin transfer across Caco-2 and MDCK cell monolayer models compared to the CS NPs making the former a promising candidate for oral delivery of insulin.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.754997  DOI: Not available
Keywords: Pre-clinical and human biological sciences
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