Enhanced oral bioavailability of nintedanib esylate with nanostructured lipid carriers by lymphatic targeting: in vitro, cell line and in vivo evaluation

The present research work was aimed to explore the ability of nanostructured lipid carriers (NLCs) to improve oral bioavailability of Nintedanib esylate (NE) via lymphatic uptake. The NE loaded NLCs (NE-NLCs) were fabricated using high speed homogenization followed by probe sonication method and physiochemically characterized.

Highlights

Lipidic nanocarrier i.e. Nanostructured lipid carriers (NLCs) of Nintedanib esylate (NE) was prepared to get nanosized globules.

Smaller particle size (<200 nm) and high entrapment efficiency was observed with NE-NLCs.

Confocal microscopy across Caco-2 cell line and tissue uptake study using intestine depicted enhanced uptake with FITC loaded NLCs.

NE-NLCs was found to be more toxic as compared to NE suspension on A549 cell line.

Bioavailability was improved by 26.31 fold with NE-NLCs as compared to NE suspension.

Lymphatic uptake study using cycloheximide confirmed the lymphatic transport of NE-NLCs.

The NE-NLCs had particle size of 125.7±5.5 nm, entrapment efficiency of 88.5± 2.50% and zeta potential of -17.3±3.5 mV. DSC and XRD studies indicated that NE was in amorphous form. TEM images showed uniformly distributed spherical shaped particles. In vitro release study of NE-NLCs drug release of 9.23±2.72% in pH 1.2 and 92.09±3.40% in phosphate buffer pH 6.8 in 28 h and obeyed higuchi model. Lipolysis study showed higher amount of drug in aqueous layer in NE-NLCs compared to NE-suspension. Tissue distribution study showed deeper penetration of FITC loaded NLCs compared to FITC solution. The cellular uptake across Caco-2 cells exhibited more uptake of FITC loaded NLCs. Cytotoxicity study using A549 cell line revealed higher potential of NE-NLCs in inhibiting tumor cell growth in comparison to that of suspension.

The oral bioavailability of NE was ameliorated over 26.31 folds after inclusion into NLCs in contrast to NE-suspension. Intestinal lymphatic uptake of cycloheximide treated mice was lower as compared to control without cycloheximide treatment. Thus, the developed NE-NLCs can be an encouraging delivery strategy for elevating oral bioavailability of NE via lymphatic uptake.

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Article information: Priyanshi Patel, Mitali Patel, European Journal of Pharmaceutical Sciences, 2021. https://doi.org/10.1016/j.ejps.2021.105715.