Montmorillonite-surfactant hybrid particles for modulation of intestinal P-glycoprotein mediated transport

Rasmus Blaaholm Nielsen, Ariane Kahnt, Lieve Dillen, Koen Wuyts, Jan Snoeys, Ulla Gro Nielsen, Rene Holm, Carsten Uhd Nielsen

Publikation: Konferencebidrag uden forlag/tidsskriftPosterForskningpeer review

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P-glycoprotein (P-gp) plays an important role in the absorption of many drugs, as it effluxes substrates, which leads to lowered absorption of the substrate. This poses a challenge in the development of new drugs, as many lead compounds are avoided in drug discovery or even stopped during drug development, because they are P-gp substrates. P-gp is the most extensively studied efflux transporter and there is a vast interest to develop P-gp inhibitors. Three generations of small molecule P-gp inhibitors have been developed, but none have reached the market as viable P-gp inhibitors. Concurrently, pharmaceutical excipients, especially non-ionic surfactants, have been shown to inhibit P-gp in vitro and in vivo. However, large doses are required to observe P-gp inhibition in vivo, and optimisation is needed. Montmorillonite (MMT) is a layered clay material with a high surface area and distinct adsorptive properties, which makes it interesting in the formulation of nanomaterials for drug delivery. Montmorillonite-surfactant hybrid (MSH) particles containing the P-gp probe, digoxin, have been developed to enhance the inhibition properties of the non-ionic surfactant, polysorbate 20 (PS20). It is hypothesised that the association of PS20 and digoxin to the distinct adsorptive and mucoadhesive MMT layer surface will cause simultaneous release of digoxin and PS20. This will lead to intestinal mucosa-localised elevated concentrations of both PS20 and digoxin in vivo, which results in more effective inhibition of P-gp and increased absorption of digoxin.
To characterise MSH particles and investigate if MSH particles can increase digoxin exposure after oral administration.
MSH particles were prepared by lyophilisation of suspensions of MMT and PS20 in a 1:1 ratio with low levels of digoxin (0.02-0.2 % w/w) to yield light, porous powders. MSH particles were characterised by scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry, X-ray powder diffraction, and low angle laser light scattering. To evaluate the ability of MSH particles to increase digoxin exposure in vivo, they were orally administered to Sprague Dawley rats.
PS20 induces extrusion of water from MMT interlayer spaces, stabilisation of MMT aggregates in suspensions, and increasing clay interlayer distance as a result of PS20 intercalation. This confirms the strong interaction between PS20 and MMT in the solid and suspended MSH particle systems. Furthermore, MSH particles tended to increase digoxin exposure in vivo. Administration of 0.2 mg kg-1 digoxin and 0.5 g kg-1 PS20 as MSH particles compared to a simple solution led to a non-significant increase in AUC0-6h and Cmax of 31 and 33 %, respectively. Furthermore, control digoxin-treated montmorillonite with no PS20 decreased AUC0-6h and Cmax by 54 and 52 %, respectively, compared to digoxin administered alone, which suggests that MMT alone retains digoxin from absorption.
MSH particles tended to enhance the P-gp inhibition properties of PS20, which led to slightly increased digoxin exposure. There is a potential for MSH particles for oral drug delivery of P-gp substrate drug substances.
Publikationsdato14. jan. 2019
Antal sider1
StatusUdgivet - 14. jan. 2019
BegivenhedNordic POP 1st Annual Meeting - Holmenkollen, Oslo, Norge
Varighed: 14. jan. 201916. jan. 2019


KonferenceNordic POP 1st Annual Meeting