Search

The purpose of this study was to validate both existing fasted and fed state simulated intestinal fluids (FaSSIF and FeSSIF), and simpler, alternative media for predicting intraluminal drug solubility during drug discovery and early drug development. For 17 model drugs, the solubilizing capacity of FaSSIF c and FeSSIF c (subscript indicates the use of crude taurocholate) and different concentrations of d -α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in phosphate buffer were correlated with the solubilizing capacity of human intestinal fluids (HIF) in the fasted and the early postprandial state. A good correlation between solubility in fasted HIF and FaSSIF c and between solubility in fed HIF and FeSSIF c was obtained, indicated by R 2 values of 0.91 and 0.86, respectively. Comparable values were obtained for 0.1% TPGS for the fasted state ( R 2 = 0.84) and 2% TPGS for the fed state ( R 2 = 0.84). Direct estimation of intestinal drug solubility by the measured solubilities in FaSSIF c and FeSSIF c was acceptable. However, better estimates were obtained by calculating solubilities based on the equations describing the relationship between solubilities in FaSSIF c and FeSSIF c as function of observed solubilities in HIF. Using this approach, the predictive value of the TPGS-based solvent system was also acceptable and comparable to that of FaSSIF c and FeSSIF c . In conclusion, FaSSIF c and FeSSIF c can be considered biorelevant media for intestinal solubility estimation. A simpler TPGS-based system may be a valuable alternative with improved stability and lower cost.

To explore the effect of the nutritional state on the solubilizing properties of human intestinal fluids (HIF) on a time-after-food administration basis. HIF were collected in fractions of 30 min from five volunteers in the fasted, fed and fat-enriched fed state. In vitro solubility of five BCS class II drugs (danazol, diazepam, nifedipine, ketoconazole, indomethacin) was assessed in the intestinal fractions and simulated intestinal fluids. Solubilities in intestinal fractions were characterized by high time- and subject-dependent variability. For the non-ionized drugs, solubility in early intestinal fractions was higher in both fed states compared to the fasted state, and in the fat-enriched fed state compared to the fed state. Solubility in simulated intestinal fluids did not sufficiently predict the solubilizing capacity of the early postprandial phase. Solubility in HIF was shown to be determined by a complex interplay of various intraluminal parameters. For the ionized drugs, pH played a significant role for indomethacin (R 2 = 0.86); for the partly ionized ketoconazole other intraluminal parameters were also important. Solubilizing capacity of HIF in the fed state is strongly time-dependent. Intraluminal dissolution may, therefore, vary with drug arrival time in the small intestine and constitute a source of variability in intestinal drug absorption.

It was the purpose of this study to explore supersaturation of poorly soluble drugs in human intestinal fluids (HIF), and to assess potential food effects on the creation and maintenance of supersaturation. Duodenal fluids were collected from healthy volunteers and pooled according to three nutritional states (fasted-, fed-, and fat-enriched fed state). Supersaturation was created at a fixed degree of supersaturation (DS=20) using the solvent-shift method. Fasted- and fed-state simulated intestinal fluids (FaSSIF and FeSSIF) were used as intestinal simulation media. Supersaturation in HIF showed to be stable up to a certain degree for different poorly soluble drugs. In HIF as well as in FaSSIF and FeSSIF, supersaturation appeared to be compound and medium specific. Supersaturation stability was found to be inversely proportional to the solubility in the corresponding media. Food intake affected itraconazole supersaturation positively. On the contrary, etravirine and loviride supersaturation decreased upon food intake. Supersaturation experiments in FaSSIF and FeSSIF showed similar results as in HIF for etravirine and loviride, whereas itraconazole supersaturation behaved differently in HIF versus simulation media. The present study illustrates, for the first time, that supersaturation can be created and maintained in HIF, even in the absence of excipients.

The purpose of this study was to assess the changes in duodenal composition in three nutritional states: fasted, fed, and fat-enriched fed state. Two isocaloric meals were administered to healthy subjects on nonconsecutive days. Subsequently, duodenal samples were collected every 30 min after which they were characterized with respect to pH, lipolytic products, bile salts, phospholipids, osmolality, and surface tension. The resulting time profiles displayed fluctuating patterns, which reflect high inter- and intrasubject variability. Duodenal composition was not altered by the higher fat percentage of the fat-enriched liquid meal. Monoglycerides, amounting from 5% to 88% of total lipids, were the dominant lipolytic species, followed by free fatty acids. Within 30 min after meal administration, individual intraduodenal concentrations of lipid products were 0.0-5.5, 1.0-14.9, and 3.1-22.4 mg/mL in fasted, fed, and fat-enriched fed state, respectively. The corresponding values for bile salts were 2.0-9.0, 6.9-9.3, and 4.4-30.3 mM and for phospholipids 0.06-2.4, 2.6-5.7, and 1.4-9.3 mM, respectively. Specific trends though, were not detected. This study illustrates the variable intraluminal conditions that can result after food intake. As intraduodenal events (e.g., intraduodenal dissolution) affect absorption of poorly water soluble and/or highly lipophilic drugs, this variability may possibly contribute to the highly variable drug plasma-time profiles often observed.