Oral insulin delivery system based on chitosan-completed carboxymethylated iota-carrageenan nanoparticles / Pratyusa Sahoo

Pratyusa, Sahoo (2019) Oral insulin delivery system based on chitosan-completed carboxymethylated iota-carrageenan nanoparticles / Pratyusa Sahoo. PhD thesis, Universiti Malaya.

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    Acidic environment of the stomach, poor permeability across intestinal membrane and the mucin barrier are among the major limitations in oral delivery of peptide drugs such as insulin. Thus, different nanostructures using mucoadhesive and pH responsive polymers have been proposed as carrier systems for oral insulin delivery. This study focused on designing insulin nanoparticles from chitosan (CS) and carboxymethylated iota-carrageenan (CMCi), based on response surface methodology together with multivariate spline interpolation (RSMMSI). The resulting optimised nanoparticles gave a zeta potential, mean particle size, loading capacity and entrapment efficiency of 52.5 ± 0.5 mV, 613 ± 41 nm, 10.7 ± 0.6%, and 86.9 ± 2.6%, respectively. The pH responsive CMCi protected insulin in an acidic environment and retained its activity as the sulfate moieties of iota-carrageenan interacted with the amino group of insulin via ionic interaction, and the mucoadhesive chitosan adhered to the intestinal mucosa in ex vivo studies. The release of insulin was low (4.91 ± 0.2%) in simulated gastric fluid (SGF) and high (86.64 ± 2.2%) in simulated intestinal fluid (SIF) in a 12-h release study, showing a pH-responsive drug release property. The insulin entrapped in the CS/CMCi nanoparticles retained their bioactivity and was stable in simulated enzymatic environment of the gastrointestinal tract (GIT). The nanoparticles were stable up to 3 months at 4 and −20°C, and up to 7 days at room temperature (25°C). The results of cellular membrane permeability experiments suggested that insulin nanoparticles were transported across Caco-2 cell monolayers mainly via the paracellular pathway, as inferred by the transepithelial electrical resistance (TEER) and apparent permeability coefficients (Papp) of the nanoparticles (22 times higher than control insulin solution), suggesting that the opening of tight junctions (TJs) was involved. The in vivo study using diabetic Sprague Dawley (SD) rats showed a bioavailability of 16.1 ± 1.6% with an iv extended blood glucose lowering effect lasting up to 24–30 h (Cmax: 175.1 ± 23.7 mIU/L, Tmax: 5 h, AUC: 1789.4 ± 158.6). The results support the effectiveness of chitosan�complexed carboxymethylated iota-carrageenan nanoparticles as an oral insulin delivery system for extended glycemic control in basal insulin therapy. Further studies such as cellular uptake of entrapped insulin by confocal laser scanning microscope and site specific intestinal insulin release by an in vivo imaging system, are required to explore its precise release mechanism. Keywords: Nanoparticle, Insulin, Chitosan, Carrageenan, Response surface methodology (RMS)

    Item Type: Thesis (PhD)
    Additional Information: Thesis (PhD) - Faculty of Medicine, Universiti Malaya, 2019.
    Uncontrolled Keywords: Nanoparticle; Insulin; Chitosan; Carrageenan; Response surface methodology (RMS)
    Subjects: R Medicine > R Medicine (General)
    Divisions: Faculty of Medicine
    Depositing User: Mrs Nur Aqilah Paing
    Date Deposited: 11 Oct 2022 02:36
    Last Modified: 11 Oct 2022 02:36
    URI: http://studentsrepo.um.edu.my/id/eprint/13839

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