Abstract
Enhancing the oral bioavailability of peptides has received a lot of attention for decades but remains challenging, partly due to low intestinal membrane permeability. Combining a permeation enhancer (PE) with unidirectionally releasing microcontainers (MCs) has previously been shown to increase insulin permeation across Caco-2 cell monolayers. In the present work, this setup was further employed to compare three common PEs—sodium caprate (C10), sodium dodecyl sulfate (SDS), and lauroyl carnitine. The concept was also studied using porcine intestinal tissue with the inclusion of 70 kDa fluorescein isothiocyanate-dextran (FD70) as a pathogen marker. Moreover, a combined proteolysis and Caco-2 cell permeation setup was developed to investigate the effect of soybean trypsin inhibitor (STI) in the MCs. Lastly, in vivo performance of the MCs was tested in an oral gavage study in rats by monitoring blood glucose and insulin absorption. SDS proved to be the most potent PE without increasing the ex vivo uptake of FD70, while the implementation of STI further improved insulin permeation in the combined proteolysis Caco-2 cell setup. However, no insulin absorption in rats was observed upon oral gavage of MCs loaded with insulin, PE and STI. Post-mortem microscopic examination of their gastrointestinal tract indicated lack of intestinal retention and optimal orientation by the MCs, possibly precluding the potential advantage of unidirectional release.
Highlights
Since the discovery of insulin, almost a century ago, there has been a profound pursuit of developing strategies for oral peptide administration in order to improve patient convenience [1,2,3,4]
The commercial potential using permeation enhancer (PE) was further cemented with approval by the U.S Food and Drug Administration of the glucagon-like peptide-1 (GLP-1) agonist, semaglutide, for oral administration based on gastric permeation enhancement by salcaprozate sodium (SNAC) [7]
While commercialization has proved achievable with an oral bioavailability of 0.1–1.2% for peptides such as desmopressin and semaglutide [7,8], there still lies an obvious potential in further improving the fraction of intact peptide absorption
Summary
Since the discovery of insulin, almost a century ago, there has been a profound pursuit of developing strategies for oral peptide administration in order to improve patient convenience [1,2,3,4]. While commercialization has proved achievable with an oral bioavailability of 0.1–1.2% for peptides such as desmopressin and semaglutide [7,8], there still lies an obvious potential in further improving the fraction of intact peptide absorption. This could lead to lower manufacturing expenses or enabling the therapeutic availability of larger macromolecules more prone to degradation in the gastrointestinal (GI) tract. Oral in vivo studies were conducted in rats in order to evaluate whether previously published indications on intestinal retention of MCs [18] were sufficient for creating local intestinal environments of high PE and insulin concentrations, leading to the increased oral bioavailability of insulin. FPDer7m0:eG7e0akrDa(Hfleulolerretsocweinn, isoPtAhi,ocyUaSnAat))e.-deFxDtr7a0n:, E7L0ISAk:Deanzyfmlueo-rleinsckeeidn iimsomthuioncoysaonrabteen-dt eaxstsraayn, ,anEdLISSEAC: : esnizzeyemxec-lluinsikoendchimrommuantoogsorarbpehnyt. (acs)sIany,viavnodorSaEl Cga: vsaigzee setuxcdliuessioonf ccoharotemdaMtoCgsraipnhayg. e(cla)tIinn vcaivposuolrea.l gavage studies of coated MCs in a gelatin capsule
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