Yusuke Tanaka1,2, Erin Tay1, Tri-Hung Nguyen1, Christopher J H Porter3,4. 1. Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. 2. Laboratory of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hiro-koshingai, Kure, Hiroshima, 737-0112, Japan. 3. Drug Delivery Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, Australia. chris.porter@monash.edu. 4. ARC Centre of Excellence in Convergent Bio Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. chris.porter@monash.edu.
Abstract
PURPOSE: To evaluate the role of supersaturation in the in vivo absorption of fenofibrate (FFB), after oral administration in a medium-chain lipid-based formulation (MCLBF). METHODS: FFB was loaded at 90% and 20% w/w of saturated solubility in MCLBF. The two formulations were pre-dispersed in purified water at 5% w/w (ME90% and 20%, respectively) and orally administered to rats to measure in vivo luminal drug concentrations. RESULTS: FFB precipitated in the stomach due to lipid digestion by gastric lipases and loss of solubilization capacity. This was most significant for ME90%. For ME90%, a high degree of supersaturation was also observed in the duodenum, however, precipitated FFB crystals rapidly re-dissolved. The combination of supersaturation and rapid re-dissolution appeared to drive effective absorption in the upper intestine. For ME20%, FFB precipitated in the stomach but not in the crystalline form and rapidly re-dissolved. Supersaturation in the duodenum again appeared to be the major driver of oral absorption. CONCLUSIONS: The data provide one of the first studies of in vivo luminal drug concentration, supersaturation and absorption from lipid based formulations and suggests that for FFB, whilst very high supersaturation may drive in vitro and in vivo precipitation, re-dissolution and drug absorption is rapid and efficient.
PURPOSE: To evaluate the role of supersaturation in the in vivo absorption of fenofibrate (FFB), after oral administration in a medium-chain lipid-based formulation (MCLBF). METHODS:FFB was loaded at 90% and 20% w/w of saturated solubility in MCLBF. The two formulations were pre-dispersed in purified water at 5% w/w (ME90% and 20%, respectively) and orally administered to rats to measure in vivo luminal drug concentrations. RESULTS:FFB precipitated in the stomach due to lipid digestion by gastric lipases and loss of solubilization capacity. This was most significant for ME90%. For ME90%, a high degree of supersaturation was also observed in the duodenum, however, precipitated FFB crystals rapidly re-dissolved. The combination of supersaturation and rapid re-dissolution appeared to drive effective absorption in the upper intestine. For ME20%, FFB precipitated in the stomach but not in the crystalline form and rapidly re-dissolved. Supersaturation in the duodenum again appeared to be the major driver of oral absorption. CONCLUSIONS: The data provide one of the first studies of in vivo luminal drug concentration, supersaturation and absorption from lipid based formulations and suggests that for FFB, whilst very high supersaturation may drive in vitro and in vivo precipitation, re-dissolution and drug absorption is rapid and efficient.
Entities:
Keywords:
in vitro digestion; lipid based formulation; luminal concentration; oral absorption; supersaturation
Authors: Matthew F Crum; Natalie L Trevaskis; Hywel D Williams; Colin W Pouton; Christopher J H Porter Journal: Pharm Res Date: 2015-12-24 Impact factor: 4.200
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