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Jejunal absorption of aprepitant from nanosuspensions: Role of particle size, prandial state and mucus layer.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-1525-1430
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-5586-2906
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.ORCID iD: 0000-0002-1406-9389
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2018 (English)In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 222-230, article id S0939-6411(18)30760-4Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 132, p. 222-230, article id S0939-6411(18)30760-4
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-363157DOI: 10.1016/j.ejpb.2018.09.022PubMedID: 30266667OAI: oai:DiVA.org:uu-363157DiVA, id: diva2:1255737
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-11-28Bibliographically approved
In thesis
1. Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
Open this publication in new window or tab >>Intestinal absorption of drugs: The impact of regional permeability, nanoparticles, and absorption-modifying excipients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

For successful delivery of orally given drug products, the drug compounds must have adequate solubility and permeability in the human gastrointestinal tract. The permeability of a compound is determined by its size and lipophilicity, and is usually evaluated in various pre-clinical models, including rat models.

This thesis had three major aims: 1) investigate regional permeability in human and rat intestines and evaluate two different rat models, 2) investigate the mechanisms behind absorption in nanosuspensions, and 3) investigate the effect of food on the absorption of drug molecules in solutions and suspensions, and also food’s effect on absorption modifying excipients (AMEs).

Effective human permeability values obtained using regional intra-intestinal dosing and a deconvolution method agreed with values established by perfusion from the jejunum, demonstrating the accuracy and validity of the intra-intestinal bolus-dosing approach. Single-pass intestinal perfusion (SPIP) in rats showed better correlation with human effective permeability than the Ussing chamber, and was therefore deemed the better model for predicting drug permeability in humans.

Absorption of microsuspensions and nanosuspension was investigated using rat SPIP, which showed that microsuspensions are subject to pronounced food effects, probably by partitioning of drug into the colloidal structures formed by bile acids, lecithin, and fatty acids. Nanosuspensions were less affected by food, which was attributed to fewer available nanoparticles in the fed state due to partitioning into colloidal structures, and because nanoparticles are able to cross the aqueous boundary layer on their own, increasing the concentration of drug adjacent to the epithelial membrane.

AMEs had less effect in the fed state than the fasted state when investigated using SPIP. This difference may be caused by AMEs partitioning into luminal colloidal structures, decreasing the AMEs’ effects on the intestinal membrane. It thus seems that AMEs as well as drug compounds are subject to food-drug interactions, which may either increase or decrease the effect or absorption, something that needs to be considered during development of new drug products. 

In summary, this thesis has improved the knowledge of pre-clinical absorption models and the understanding of several biopharmaceutical mechanisms important for drug absorption.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 73
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 260
Keywords
Permeability, intestinal absorption, regional permeability, nanoparticles, nanosuspensions, absorption-modifying excipients, AMEs
National Category
Pharmaceutical Sciences
Research subject
Biopharmaceutics
Identifiers
urn:nbn:se:uu:diva-363908 (URN)978-91-513-0484-7 (ISBN)
Public defence
2018-12-07, A1:107A, Uppsala Biomedical Centre, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2018-11-14 Created: 2018-10-20 Last updated: 2018-11-30

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Roos, CarlDahlgren, DavidSjögren, ErikSjöblom, MarkusHedeland, Mikael

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