Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery: An in vitro and ex vivo assessment

Abstract

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.

Highlights

Levosulpiride permeation is improved by NLCs in vitro and ex vivo.

Enhanced permeation is likely through improved drug solubilization and paracellular pathway modulation.

NLCs formulation is biocompatible.

In vitro and ex vivo permeation studies exhibited an 8-fold and 1.6-fold increase in the P_app 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.

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Materials

Levosulpiride (purity 99.6 %) was obtained as a kind gift from Bio-Labs (Pvt) Ltd. Islamabad, Pakistan. Precirol® ATO5 [glyceryl palmitostreate, consisting of esters of palmitic acid (C16) and stearic acid (C18)] and Labrasol® [caprylocaproyl polyoxyl-8 glycerides, consists of a small fraction of mono-, di- and triglycerides and mainly polyethylenglycol (PEG)-8 (MW 400 g/mol) mono- and diesters of caprylic (C8) and capric (C10) acids] were received from Gattefossé (Cedex, France). Tween® 80 (polysorbate 80) and Span® 80 (sorbitan monooleate 80), Hank’s balanced salt solution (HBSS), phenazine methosulfate (PMS), bovine serum albumin (BSA), 2-[4-(2,4,4-trimethylpentan-2-yl) phenoxy] ethanol (Triton® X-100), fluorescein isothiocyanate–labelled dextran 4 kDa (FD4), Dulbecco’s modified Eagle’s medium (DMEM), penicillin/streptomycin, L-glutamine, non-essential amino acid (NEAA) solution, and trypsin-EDTA were purchased from Sigma Aldrich (Merck KGaA, Darmstadt, Germany). 4-(2-hydroxyethyl)-1-piperazine-1-ethanesulfonic acid (HEPES) was purchased from PanReac AppliChem (Darmstadt, Germany). Fetal bovine serum (FBS) was obtained from GE Healthcare (Cardiff, UK). [14C]-mannitol (0.057 Ci/mmol) and was obtained from Perkin Elmer (Waltham, MA, USA). [3H]-metoprolol (27.6 Ci/mmol) was from Vitax (Placentia, CA, USA). 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxy-methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) was purchased from Promega (Madison, WI, USA). Phosphate-buffered saline (PBS) was from VWR (Radnor, PA, USA). Rabbit polyclonal occludin antibody (cat. no. 711500), goat anti-rabbit IgG (H + L) cross-adsorbed secondary antibody Alexa Fluor™ 555 (cat. no. #A32732), Alexa Fluor® 488 phalloidin, DAPI (4,6-diamidino-2-phenylindole) and 4 % (w/v) paraformaldehyde was purchased from Thermo Fisher Scientific (Waltham, MA, USA). Ultrapure water was purified by a PURELAB flex (ELGA, High Wycombe, UK). Salts used to prepare Krebs-Henseleit buffer (KBS), Mayer’s hematoxylin, Eosin Y alcoholic solution, and all other reagents and chemicals were of analytical grade and obtained from Sigma Aldrich unless stated otherwise.

Sadia Tabassam Arif, Muhammad Ayub Khan, Patrick Frøslev, Shahiq uz Zaman, Danai Anatasia Panou, Hanne Mørck Nielsen, Joanne Heade, Nanostructured lipid carriers as a strategy to enhance oral levosulpiride delivery: An in vitro and ex vivo assessment, International Journal of Pharmaceutics, 2024, 125047, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2024.125047.