Phosphate decorated lipid-based nanocarriers providing a prolonged mucosal residence time

The aim of this study was to develop phosphate decorated lipid-based nanocarriers including self-emulsifying drug delivery systems (SEDDS), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) to extend their mucosal residence time. All nanocarriers contained tetradecyltrimethylammonium bromide (TTAB) and polyoxyethylene (9) nonylphenol monophosphate ester (PNPP) for surface decoration. Zeta potential, cytotoxicity, charge conversion and phosphate release studies using isolated intestinal alkaline phosphatase (IAP) and Caco-2 cells were performed. Moreover, the residence time of nanocarriers was determined on porcine intestinal mucosa.

Highlights

• Phosphate decorated lipid-based nanocarriers were successfully developed via the introduction of TTAB and PNPP.
• SEDDS, SLN and NLC were selected as lipid-based nanocarriers.
• Phosphate modified lipid-based nanocarriers displayed higher mucosal residence time compared to the blank formulation.

Results showed a shift from negative to positive zeta potential due to the addition of TTAB and charge conversion back to a negative zeta potential when also PNPP was added. Up to a concentration of 0.3 %, lipid-based nanocarriers were not toxic. Charge conversion studies with IAP revealed the highest zeta potential shift for NLC_TTAB-PNPP with almost Δ22 mV. Phosphate release studies using isolated IAP as well as Caco-2 cells showed a fast phosphate release for SEDDS_TTAB-PNPP, SLN_TTAB-PNPP and NLC_TTAB-PNPP. SLN _TTAB-PNPP and NLC _TTAB-PNPP provided the highest increase in mucosal residence time that was 4-fold more prolonged than that of blank formulations. In conclusion, phosphate modified lipid-based nanocarriers can essentially prolong the intestinal residence time of their payload.

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Materials

Captex 8000 (glyceryl tricaprylate) and Captex 300 EP (caprylic/capric triglycerride) were supplied by Abitec, USA. Dynasan 116 (glycerol tripalmitate) was obtained from IOI Oleo GmbH, Germany. Transcutol HP (diethylene glycol monoethyl ether) was received from Gattefosse, France. Cremophor EL (polyoxyl 35 castor oil), Kolliphor RH 40 (polyoxyl 40 hydrogenated castor oil), propylene glycol, oleic acid, Brij 93 (polyethylene glycol oleyl ether), trimethyl tetradecyl ammonium bromide (TTAB), fluorescein dilaurate (FDL), bovine intestinal alkaline phosphatase (IAP, ≥10 DEA units/mg protein) and phosphatase inhibitor cocktail 2 (PIC2) were provided by Sigma-Aldrich, Germany. Polyoxyethylene (9) nonylphenol monophosphate ester (PNPP) was obtained from Ashland Inc, Switzerland. Porcine intestine was supplied by slaughterhouse, Innsbruck, Austria.

Nuri Ari Efiana, Andrea Fürst, Ahmad Saleh, Iram Shahzadi, Andreas Bernkop-Schnürch, Phosphate decorated lipid-based nanocarriers providing a prolonged mucosal residence time, International Journal of Pharmaceutics, Volume 625, 2022, 122096, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2022.122096.