Effect of Ingested Lipids on Drug Dissolution and Release with Concurrent Digestion: A Modeling Approach
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RESEARCH PAPER
Effect of Ingested Lipids on Drug Dissolution and Release with Concurrent Digestion: A Modeling Approach Fulden Buyukozturk & Selena Di Maio & David E. Budil & Rebecca L. Carrier Received: 11 March 2013 / Accepted: 20 October 2013 / Published online: 14 November 2013 # Springer Science+Business Media New York 2013
ABSTRACT Purpose To mechanistically study and model the effect of lipids, either from food or self-emulsifying drug delivery systems (SEDDS), on drug transport in the intestinal lumen. Methods Simultaneous lipid digestion, dissolution/release, and drug partitioning were experimentally studied and modeled for two dosing scenarios: solid drug with a food-associated lipid (soybean oil) and drug solubilized in a model SEDDS (soybean oil and Tween 80 at 1:1 ratio). Rate constants for digestion, permeability of emulsion droplets, and partition coefficients in micellar and oil phases were measured, and used to numerically solve the developed model. Results Strong influence of lipid digestion on drug release from SEDDS and solid drug dissolution into food-associated lipid emulsion was observed and predicted by the developed model. Ninety minutes after introduction of SEDDS, there was 9% and 70% drug release in the absence and presence of digestion, respectively. However, overall drug dissolution in the presence of food-associated lipids occurred over a longer period than without digestion. Conclusion A systems-based mechanistic model incorporating simultaneous dynamic processes occurring upon dosing of drug with lipids enabled prediction of aqueous drug concentration profile. This model, once incorporated with a pharmacokinetic model considering processes of drug absorption and drug lymphatic transport in the presence of lipids, could be highly useful for quantitative prediction of impact of lipids on bioavailability of drugs.
KEY WORDS biorelevant media . colloidal particles . computational modeling . EPR . food effect . mass transport . mechanistic modeling . self-emulsifying drug delivery systems ABBREVIATIONS BS bile salts EPR electron paramagnetic resonance FA fatty acids GI gastrointestinal HPLC high performance liquid chromatography MG monoglycerides NaTDC sodium taurodeoxycholate PC L-alpha-phosphatidylcholine PL phospholipids SEDDS self-emulsifying drug delivery systems TB TEMPOL benzoate
INTRODUCTION Ingested lipids, either originating from food or used as delivery agents, can have significant effects on dissolution, solubility, transport, and bioavailability of orally delivered compounds. The influence of ingested lipids on compound absorption originates from several mechanisms. Colloidal structures
Electronic supplementary material The online version of this article (doi:10.1007/s11095-013-1238-6) contains supplementary material, which is available to authorized users. F. Buyukozturk : S. Di Maio : R. L. Carrier (*) Department of Chemical Engineering, College of Engineering Northeastern University, 360 Huntington Avenue Boston, Massachusetts 02115, USA e-mail: [email protected] F.
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