Dual Level Statistical Investigation of EquilibriumSolubility in Simulated Fasted and Fed Intestinal Fluid

摘要

The oral route is the preferred option for drug administration but contains the inherent issue of drug absorption from the gastro-intestinal tract (GIT) in order to elicit systemic activity. A prerequisite for absorption is drug dissolution, which is dependent upon drug solubility in the variable milieu of GIT fluid, with poorly soluble drugs presenting a formulation and biopharmaceutical challenge. Multiple factors within GIT fluid influence solubility ranging from pH to the concentration and ratio of amphiphilic substances, such as phospholipid, bile salt, monoglyceride, and cholesterol. To aid in vitro investigation simulated intestinal fluids (SIF) covering the fasted and fed state have been developed. SIF media is complex and statistical design of experiment (DoE) investigations have revealed the range of solubility values possible within each state due to physiological variability along with the media factors and factor interactions which influence solubility. However, these studies require large numbers of experiments (>60) and are not feasible or sensible within a drug development setting.In the current study a smaller dual level, reduced experimental number(20) DoE providing three arms covering the fasted and fed states alongwith a combined analysis has been investigated. The results indicatethat this small scale investigation is feasible and provides solubilityranges that encompass published data in human and simulated fastedand fed fluids. The measured fasted and fed solubility ranges arein agreement with published large scale DoE results in around halfof the cases, with the differences due to changes in media compositionbetween studies. Indicating that drug specific behaviors are beingdetermined and that careful media factor and concentration level selectionis required in order to determine a physiologically relevant solubilityrange. The study also correctly identifies the major single factoror factors which influence solubility but it is evident that lowersignificance factors (for example bile salt) are not picked up dueto the lower sample number employed. A similar issue is present withfactor interactions with only a limited number available for studyand generally not determined to have a significant solubility impactdue to the lower statistical power of the study. The study indicatesthat a reduced experimental number DoE is feasible, will provide solubilityrange results with identification of major solubility factors howeverstatistical limitations restrict the analysis. The approach thereforerepresents a useful initial screening tool that can guide furtherin depth analysis of a drug’s behavior in gastrointestinalfluids.