Evaluation of Sucrose Laurate as an Intestinal Permeation Enhancer for Macromolecules: Ex Vivo and In Vivo Studies

Abstract

Oral delivery of macromolecules requires permeation enhancers (PEs) adaptable to formulation. Sucrose laurate (SL) (D1216), a food grade surfactant, was assessed in Caco-2 monolayers, isolated rat intestinal tissue mucosae, and rat intestinal instillations. Accordingly, 1 mM SL increased the apparent permeability coefficient (Papp) of [14C]-mannitol and reduced transepithelial electrical resistance (TEER) across monolayers. It altered expression of the tight junction protein, ZO-1, increased plasma membrane potential, and decreased mitochondrial membrane potential in Caco-2 cells. The concentrations that increased flux were of the same order as those that induced cytotoxicity. In rat colonic tissue mucosae, the same patterns emerged in respect to the concentration-dependent increases in paracellular marker fluxes and TEER reductions with 5 mM being the key concentration. While the histology revealed some perturbation, ion transport capacity was retained. In rat jejunal and colonic instillations, 50 and 100 mM SL co-administered with insulin induced blood glucose reductions and achieved relative bioavailability values of 2.4% and 8.9%, respectively, on a par with the gold standard PE, sodium caprate (C10). The histology of the intestinal loops revealed little damage. In conclusion, SL is a candidate PE with high potential for emulsion-based systems. The primary action is plasma membrane perturbation, leading to tight junction openings and a predominant paracellular flux.

Synthesis and In Vivo Evaluation of Insulin-Loaded Whey Beads as an Oral Peptide Delivery System

“…Inclusion of historical data in which C 10 was ad-mixed with native insulin and administered by the i.j. route shows the drop in blood glucose when the two were combined in this rat model [ 37 ]. The % PA calculated for the insulin-dWPI bead prototype, and the prototype + C 10 was 2.4% and 2.3% respectively ( Table 5 ).…”

“…The % relative F calculated for the prototype was 2.2%, and the presence of C 10 increased this to 4.3% ( Table 5 ). The data for insulin + C 10 reported a% F for insulin of 3.3% [ 37 ].…”

“…Insulin solution, PBS, and insulin ad-mixed with C 10 were also injected into closed jejunal loops as controls. The latter (insulin with C 10 ) data was historical data from our group [ 37 ]. This data was obtained with Insuman ® (recombinant human insulin, Sanofi, Frankfurt, Germany) instead of Gibco’s recombinant human insulin.…”

“…To measure the relative pharmacological availability (% PA), and relative bioavailability (% F) one group of animals was dosed with 1 IU/kg insulin by subcutaneous (s.c.) injection. % PA was calculated from the blood glucose levels according to Equation (4) below [ 37 ]. where AAC (inst.)…”

Charge-switchable zwitterionic polycarboxybetaine particle as an intestinal permeation enhancer for efficient oral insulin delivery

“…Although some of these intestinal permeation enhancers have been evaluated in early-stage clinical trials, a relatively poor translation has been achieved until now 23 . The major reasons are that only a small portion of these intestinal permeation enhancers can be used into solid-dose formulations and some have high cytotoxicity 24 , 25 . It is recognized that an ideal intestinal permeation enhancer should be nontoxic, and have strong dosage form assembling ability for protein drug delivery.…”