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Eur J Pharm Biopharm. 2018 Nov;132:222-230. doi: 10.1016/j.ejpb.2018.09.022. Epub 2018 Sep 25.

Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.

Author information

1
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden.
2
Department of Neuroscience, Division of Physiology, Uppsala University, 752 36 Uppsala, Sweden.
3
Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute (SVA), 751 89 Uppsala, Sweden; Department of Medicinal Chemistry, Analytical Science, Uppsala University, Box 574, 751 23 Uppsala, Sweden.
4
Department of Pharmacy, Uppsala University, Box 580, 751 23 Uppsala, Sweden. Electronic address: hans.lennernas@farmaci.uu.se.

Abstract

The number of highly lipophilic active pharmaceutical ingredients (APIs) in pharmaceutical development has been constantly increasing over recent decades. These APIs often have inherent issues with solubility and dissolution, limiting their oral bioavailability. Traditionally, a reduction in particle size to the micrometer range has been used to improve dissolution. More recently, size reduction to the nanometer range has been introduced, which further increases the dissolution rate, but may also involve other mechanisms for increasing bioavailability. The effect of particle size on the absorption of aprepitant was investigated using the single-pass intestinal perfusion (SPIP) model in the rat jejunum. Phosphate buffer, fasted-state simulated intestinal fluid (FaSSIF), and fed-state simulated intestinal fluid (FeSSIF) were used as perfusion media to increase understanding of the processes involved and the effects of colloidal structures. The role of mucus on intestinal absorption was investigated by adding the mucolytic agent N-acetyl-cysteine (NAC). The absorption of aprepitant from the nanosuspensions was similar with all perfusion media (buffer = FaSSIF = FeSSIF), whereas food had a pronounced effect on absorption from the microsuspensions (FeSSIF > FaSSIF > buffer). The colloidal structures hence contributed to absorption from the microsuspensions. Partitioning of aprepitant from the nanosuspension into the colloidal structures decreased the amount of nanoparticles available, which offset the effect of food. The appearance flux of aprepitant in blood was non-significantly decreased for nanosuspensions of aprepitant with NAC versus without NAC in buffer (ratio of 2:1), indicating that particle deposition in the mucus may have been decreased as the layer thinned, with subsequently reduced intestinal absorption. The study also showed that the SPIP model is suitable for investigating detailed absorption mechanisms using complex perfusion media, which increase the biorelevance of the model.

PMID:
30266667
DOI:
10.1016/j.ejpb.2018.09.022
[Indexed for MEDLINE]

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