Oral insulin delivery system based on chitosan-completed carboxymethylated iota-carrageenan nanoparticles / Pratyusa Sahoo
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 sy...
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| Format: | Thesis |
| Published: |
2019
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| Online Access: | http://studentsrepo.um.edu.my/13839/4/pratyusa.pdf http://studentsrepo.um.edu.my/13839/ |
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| Summary: | 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
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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)
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