Enhancement of oral bioavailability of insulin in humans

Abstract

OBJECTIVE:The purpose of this study is to investigate oral absorption of 1, 2 and 3 U/kg oral insulin five test products with different particle sizes in comparison with 0.1 U/kg subcutaneous reference formulation. METHODS: Twenty five healthy volunteers participated in five studies using a two-phase, two-sequence crossover design with washout period of one day. Mean disposition kinetics was determined by non-compartmental analysis using Kinetica program. Absorption kinetics of insulin products were then determined using SIMCYP simulator utilizing ADAM model. RESULTS & CONCLUSIONS: Dimensional analysis results showed the superiority of formula 4: 2 U/kg oral dose with 57 nm particle size over other oral formulations when compared with subcutaneous route. Optimized intestinal permeability coefficients (×10 -4 ) of insulin best test and reference formulations were 0.084 and 0.179 cm/sec respectively. Total fraction of insulin dose absorbed (Fa) for the test and reference products were 3.0% and 19% respectively. Subcutaneous product exhibited higher absorption rate and extent than oral insulin. Yet that was compensated by the increase in other factors such as Fa*, Peff* and oral dose, leading to similar insulin plasma levels and similar effect on glucose infusion rates. Oral insulin bioavailability was shown promising for the development of oral insulin product.

Insulin-chitosan polyelectrolyte _anocomplexes: preparation, characterization and stabilization of insulin

“…Nanoparticles with specific combinations of molecular weight and degree of deacetylation were dispersed in an oily vehicle and an oral insulin delivery system was developed by our group. In vivo tests were conducted both on animals and humans 40,41 .…”

Using Simcyp to project human oral pharmacokinetic variability in early drug research to mitigate mechanism‐based adverse events

“…However, due to the evolving nature of this nascent technology and the complexities associated with projecting human plasma drug concentration-time curves (let alone human pharmacokinetic parameters), the majority of published PBPK work has used already amassed human pharmacokinetic data to either test the predictive value of certain models [19,20] or, in combination with human in vitro drug metabolism data, to anticipate future clinical pharmacokinetics. The latter is best exemplified by using PBPK models to conduct drug-drug interaction simulations [21][22][23][24][25], to assess bioavailability [26,27], to simulate exposure parameters in particular populations [28][29][30] and to forecast interindividual pharmacokinetic variability [31,32]. For the situation described here, in which it was desired during lead development to estimate the sufficiency of separation between the C max of an expected clinically efficacious oral dose and a primary pharmacology-based AE threshold (C AE ), PBPK modeling was undertaken at an uncharacteristically earlier stage of the drug life cycle to aid in compound selection for preliminary large animal toxicology studies.…”

Oral Delivery of Insulin: Novel Approaches

“…The bioavailability of the preparation versus subcutaneous injection was calculated together with the pharmacokinetic parameters. Moreover, human studies were conducted where twenty-five healthy volunteers participated in five studies using a twophase, two-sequence crossover design with a washout period of one day [102]. Other chitosan fatty acid systems were also formulated, for example chitosan sodium lauryl sulphate nanoparticles [103] and chitosan-oleic acid nanoemulsion (particle size reduced by a high pressure homogenizer) and their hypoglycaemic effects were evaluated and compared to the chitosan-oleic acid-surfactants system.…”

“…These results clearly show that rh-insulin absorption was markedly enhanced by the nanoparticles dispersed in oily vehicle. As a proof of concept, early clinical trials have been performed by Badwan et al [102]. The pharmacokinetic, pharmacodynamic and absorption kinetics of insulin-loaded oily nanosystem preparations of different particle sizes (57-220 nm) were compared with those of subcutaneous formulation in 25 healthy individuals using a euglycaemic clamp technique.…”