Document Detail

Simulating fasted human intestinal fluids: understanding the roles of lecithin and bile acids.
MedLine Citation:
PMID:  20698569     Owner:  NLM     Status:  In-Process    
The purpose of this work is to evaluate the roles of lecithin and bile salts in a new generation of fasted simulated small intestinal fluid (FaSSIF-II), thus enhancing the closer mimic of simulated fluids to the real human intestinal fluids (HIF) in drug discovery and drug product development. To assess the effects of lecithin in FaSSIF-II, solubility studies were conducted at 37 °C using four media including first generation simulated intestinal fluid (FaSSIF-I), FaSSIF-II, phosphate pH 6.5 buffer, and HIF. A total of 24 model compounds representing a wide range of biopharmaceutic properties were included. The drug solubility values measured in the FaSSIF-II were compared with those in FaSSIF-I, pH 6.5 buffer and HIF. To assess the effects of bile acids, solubility was measured for 4 compounds in the FaSSIF-I containing five different bile acids of various concentrations. The lecithin concentration in the FaSSIF-II is lowered from 0.75 mM to 0.2 mM. The results suggested that the FaSSIF-II is a better medium to reflect HIF, compared with pH 6.5 phosphate buffer and FaSSIF-I. Solubility of neutral compounds including atovaquone, carbamazepine, cyclosporine, danazol, diethylstilbestrol, felodipine, griseofulvin and probucol in FaSSIF-II showed improvement in predicting the in vivo solubility. The relative standard deviation (SD) of solubility measurement in FaSSIF-II is comparable with FaSSIF-I. For the acidic and basic tested compounds, the FaSSIF-II performs similarly to the FaSSIF-I. Experimental results showed that the level of bile salts typically is less than 5 mM under fasted state. Among the five studied bile acids, the conjugation (glycine or taurine) has no impact on the drug solubilization, while there may be a minimal effect of the degree of hydroxylation of the steroid ring system on solubilization. The lecithin concentration of 0.2 mM in FaSSIF-II has been demonstrated to closely represent HIF, for both neutral and ionizable compounds. In the composition of simulated intestinal fluids, the structure of bile acids has minimal effect, providing the flexibility of choosing one bile salt to represent complex in vivo bile acids.
Erik Söderlind; Eva Karlsson; Anders Carlsson; Rui Kong; Anna Lenz; Sara Lindborg; Jennifer J Sheng
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Publication Detail:
Type:  Journal Article     Date:  2010-09-01
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  7     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2013-01-03     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1498-507     Citation Subset:  IM    
Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
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