Labrafac MC60 is an efficacious intestinal permeation enhancer for macromolecules: Comparisons with Labrasol® ALF in ex vivo and in vivo rat studies

Labrafac™ MC60 (glycerol monocaprylocaprate) is a lipid-based excipient used in oral formulations as a solubiliser. Due to the high proportions of established permeability enhancers, caprylate (C₈) and caprate (C₁₀), in Labrafac™ MC60, we hypothesised that it might behave as an intestinal permeation enhancer. We therefore evaluated this using two paracellular markers (ex vivo) and insulin (in vivo) as model molecules. Ex vivo studies were conducted in isolated muscle-stripped rat colonic mucosae mounted in Ussing chambers. Apical addition of Labrafac™ MC60 (8, 12, and 16 mg/ml) enhanced the apparent permeability coefficients (P_app) of [¹⁴C] mannitol and FITC-dextran 4 kDa (FD4) across colonic mucosae.

Similar effects were observed in isolated jejunal mucosae, but at higher concentrations (40 mg/ml). The enhancing capacity of Labrafac™ MC60 was transient due to reversibility of reductions in transepithelial electrical resistance (TEER) upon wash-out and effects on fluxes were molecular weight-dependent (MW) as suggested by fluxes of a set of high MW FITC-dextrans. The permeability enhancing effects of Labrafac™ MC60 ex vivo were maintained in the presence of simulated intestinal fluids, FaSSIF and FaSSCoF, in both jejunal and colonic mucosae, respectively. Following intra-intestinal regional instillations to rats, the relative bioavailability of 50 IU/kg insulin ad-mixed with Labrafac™ MC60 was 5 % in jejunum (40 mg/ml) and 6 % in colon (8 mg/ml).

When Labrafac™ MC60 was combined with PEG-60 hydrogenated castor oil (1 % v/v), this further increased the bioavailability of insulin to 8 % in jejunum. Absorption enhancement was also maintained in the presence of FaSSIF in jejunal instillations. Histology after 120 min exposure to Labrafac™ MC60 in vivo for both jejunum and colon was similar to untreated control. Labrafac™ MC60 therefore acts as a non-damaging intestinal permeation enhancer for macromolecules and can be considered as another excipient in screening programmes to develop orally administered macromolecules.

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Materials

Labrafac™ MC60 (Glycerol monocaprylocaprate or glycerol mono- and dicaprylocaprate,) and Labrasol® ALF (caprylocaproyl polyoxyl-8 glycerides) were gifts from Gattefossé (Saint Priest, France). PEG-60 hydrogenated castor oil (HCO-60) was a gift from Nikko Chemicals. [14C] mannitol was obtained from Perkin Elmer, (Ireland), while FITC-dextran analogues (FD4-FD70) were purchased from Merck (Ireland). Human recombinant insulin was purchased from Biosciences (Ireland); a human insulin ELISA kit was purchased from Mercodia (Sweden). Fasted State Simulated Intestinal Fluid-V2 (FaSSIF) and Fasted State Simulated Colonic Fluid (FaSSCoF) were purchased from Biorelevant Ltd (London, UK). Sodium caprate (C10), sodium taurodeoxycholate (NaTDC), tributyrin, pancreatin (from porcine pancreas, 8 x USP), and L-phosphatidylcholine (lecithin), and carbachol were purchased from Sigma-Aldrich (Ireland). All solvents used were HPLC grade. All other chemicals were reagent grade. The compositions and HLB values of the investigated excipients and PEs are shown in Table 1.

Table 1. Compositions of excipients.

Fiona McCartney, Philippe Caisse, Camille Dumont, David J. Brayden, LabrafacTM MC60 is an efficacious intestinal permeation enhancer for macromolecules: Comparisons with Labrasol® ALF in ex vivo and in vivo rat studies, International Journal of Pharmaceutics, 2024, 124353, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.124353.

Read also our introduction article on Mannitol here: