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The effects of food on the dissolution of poorly soluble drugs in human and in model small intestinal fluids.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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2005 In: Pharmaceutical Research, Vol. 22, no 12, 2141-2151 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 22, no 12, 2141-2151 p.
Identifiers
URN: urn:nbn:se:uu:diva-94996OAI: oai:DiVA.org:uu-94996DiVA: diva2:169040
Available from: 2006-10-19 Created: 2006-10-19Bibliographically approved
In thesis
1. Drug Dissolution under Physiologically Relevant Conditions In Vitro and In Vivo
Open this publication in new window or tab >>Drug Dissolution under Physiologically Relevant Conditions In Vitro and In Vivo
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The general aim of the present project was to increase the understanding of the in vivo dissolution of poorly soluble drugs and thereby improve possibility to predict in vivo solubility from substance properties. Increased understanding of the in vivo limitations of drug solubility could potentially also generate ideas for improved formulation principles for poorly soluble compounds and more relevant in vitro dissolution test methods used in formulation development.

The dynamic gastrointestinal secretory and enzymatic responses to a liquid meal were studied in human intestinal fluid (HIF) by in vivo perfusion of a nutritional drink. The main diversity found compared to simulated intestinal fluids was the presence of dietary lipids in fed human intestinal fluid. This difference was showed to be of importance in the solubility of low soluble drugs, since this parameter was underestimated in the simulated fluid. Thus suggesting that simulated intestinal fluids should be prepared with the addition of dietary lipids for better in vitro in vivo predictions.

Solubility and dissolution determinations in fasted and fed HIF showed that the solubility was higher in fed state fluid, probably owing to the higher concentration of lipids in this media. The higher solubility was correlated to both the lipophilicity and aqueous solubility of the drug. The dissolution rate also increased, but not to the same extent as the solubility. These findings need to be considered in the design of in vitro models and in the prediction of food effects on oral bioavailability of poorly soluble drugs.

In addition, an in vivo porcine perfusion study was performed to investigate importance of different mechanisms in food-drug interactions. The results showed that solubilisation might be a more important factor than P-gp inhibition for food-related effects on the intestinal absorption kinetics of Class II drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 65 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 39
Keyword
Biopharmacy, solubility, drug dissolution, food effects, poorly soluble drugs, P-gp inhibition, drug absorption, pemeability, bile acids, phospholipids, human intestinal fluid, simulated intestinal fluid, neutral lipids, solid phase extraction, HPLC, Efflux, Biofarmaci
Identifiers
urn:nbn:se:uu:diva-7195 (URN)91-554-6684-2 (ISBN)
Public defence
2006-11-10, B41, Uppsala Biomedicinska Centrum, Husargatan 3, Uppsala, 10:15
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Available from: 2006-10-19 Created: 2006-10-19Bibliographically approved

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