TY - JOUR
T1 - Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery
T2 - An in vitro and ex vivo assessment
AU - Arif, Sadia Tabassam
AU - Khan, Muhammad Ayub
AU - Frøslev, Patrick
AU - Zaman, Shahiq uz
AU - Panou, Danai Anastasia
AU - Nielsen, Hanne Mørck
AU - Heade, Joanne
N1 - Funding Information:
This work was financially supported by Higher Education commission (HEC) of Pakistan under International Research support Initiative Program (IRSIP) through grant no. IRSIP 48 PSc 06, I-8/HEC/HRD/2021/1 1299 and by the Novo Nordisk Foundation (Grand Challenge Programme: NNF16OC0021948 for the Center for Biopharmaceuticals and Biobarriers in Drug Delivery).
Publisher Copyright:
© 2024 The Author(s)
PY - 2025
Y1 - 2025
N2 - Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the Papp of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [14C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [3H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.
AB - Oral absorption is limited for many small-molecule drugs due to their poor aqueous solubility as well as, for some, poor membrane permeation. One such is levosulpiride (LSP), used to treat psychotic and other conditions. The present study aims to explore the effect of nanostructured lipid carriers (NLCs) for the delivery of LSP. The permeation of LSP in vitro and ex vivo as well as effects on the epithelium and mucosa was monitored. In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the Papp of LSP respectively, as compared to unformulated LSP applied as a suspension. Transepithelial electrical resistance (TEER) measured in real-time by impedance spectroscopy decreased during exposure yet recovered upon removal of the NLCs. Together with the increased passage of the paracellular markers [14C]-mannitol and FD4 applied together with blank NLCs, but not the transcellular marker [3H]-metoprolol, this indicates permeation of LSP via the paracellular pathway. The reversible effect on integrity was associated with altered cell morphology confirmed by occludin and f-actin localization with insignificant effect on metabolic activity. These results suggest that the NLCs and/or components thereof can mediate improved absorption of drugs by increasing the permeability of the intestinal epithelial membrane, further facilitated by increased drug solubilization.
KW - Caco-2 cell culture model
KW - Levosulpiride
KW - Nanostructured lipid carriers
KW - Real-time transepithelial electrical resistance
KW - Ussing ex vivo model
U2 - 10.1016/j.ijpharm.2024.125047
DO - 10.1016/j.ijpharm.2024.125047
M3 - Journal article
C2 - 39653293
AN - SCOPUS:85211991667
VL - 669
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
M1 - 125047
ER -