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Abstract:

Estimates are that around 70% of today’s drug candidates are handicapped by poor aqueous solubility. As gastrointestinal dissolution is a prerequisite for absorption, it is evident that the exposure of these drug candidates will be little to zero after oral administration as such. However, experience with a variety of formulation approaches, so called supersaturating drug delivery systems (SDDS), has shown that intraluminal concentrations of a drug are not necessarily limited by their thermodynamicsolubility in gastrointestinal fluids. Drugs may be in solution at a concentration exceeding the solubility, i.e., in a state of supersaturation. However, the supersaturated state is thermodynamically unstable and, on itself, the driving force for precipitation. As long as supersaturated drugs do not precipitate from this thermodynamic unstable condition, intestinal absorption may be enabled. Considering the vast potential of the supersaturation concept for oral delivery of poorly water soluble drug candidates, industry and academia show a growing interest in studying both induction of supersaturation and subsequent precipitation. Since the added value of gastrointestinal supersaturation will depend on its stability in vivo , efficient exploitation of this strategy requires in vitro evaluation procedures predictive for the behavior of supersaturation inducing formulations in vivo . However, the current knowledge onthe effects of gastrointestinal physiology (including the composition of gastrointestinal fluids, gastrointestinal transit, hydrodynamics and transepithelial transport rate) on drug supersaturation/precipitation is extremely limited, hampering the implementation of biorelevant supersaturation assays in drug and formulation development. The research performed in the framework of this thesis therefore investigated the impact of different biorelevant aspects on drug supersaturation and precipitation to provide the insights needed to advance the biorelevance of the current supersaturation evaluation. As it is extremely difficult to demonstrate drug supersaturation in situ in the intraluminal environment, in a first step, human gastric and intestinal fluids representative for fastedand fed state conditions, were aspirated from healthy volunteers, to serve as biorelevant in vitro test medium for exploring the potential of supersaturation. As such, the supersaturation/precipitation behavior of various poorly soluble drugs (itraconazole, etravirine, loviride, danazol, ritonavir, fenofibrate and glibenclamide) was evaluated in vitro in human gastrointestinal aspirates. The results clearly illustrated that supersaturation of drug compounds with different physicochemical characteristics can be created and maintained up to a certain degree in human gastrointestinal fluids representing different nutritional states, validating the potential of supersaturating drug delivery systems, in vivo . The stability of the induced supersaturation proved to be compound- and medium-dependent. Comparison of the supersaturation stability in human gastric fluids versus fasted state human intestinal fluids indicated inferior supersaturation stability in human gastric fluids. Regarding the effect of food on supersaturation behavior, it was illustrated for allcompounds, except for itraconazole, that supersaturation stability was reduced in postprandial conditions. In addition to the studies performedin human gastrointestinal aspirates, commonly used gastric and intestinal simulation media and simple buffer solutions were benchmarked for their predictive value in a supersaturation/precipitation context. The supersaturation/precipitation behavior in human gastric fluids was adequately predicted using fasted state simulated gastric fluids (FaSSGF). In contrast, SGF overestimated supersaturation stability in 3 out of 5 cases suggesting that the use of FaSSGF is to be preferred for the biorelevant evaluation of drug precipitation in a gastric environment. To predict precipitation kinetics in the intestinal environment, simple aqueous buffer solutions at pH 6.5 should be avoided as they significantly overestimate the stability of supersaturation. The commonly used FaSSIF performs reasonably well in predicting the precipitation behavior in fasted state human fluids. For the fed state, in contrast, fed state simulated intestinal fluid (FeSSIF) may significantly underestimate precipitation. In a second step, the potential of various excipients to inhibit drug precipitation was evaluated in human gastrointestinal aspirates and compared to the excipient mediated precipitation inhibition obtained commonly used artificial media. The extent to which precipitation inhibition could be obtained appeared to be medium, compound and excipientdependent. Experiments using human intestinal fluids from volunteers inthe fasted or fed state evidenced that the nutritional state did not significantly affect the extent of excipient-mediated precipitation inhibition. Achieving substantial excipient-mediated precipitation inhibition in human gastric fluids or FaSSGF proved to be difficult with only modest effects of Eudragit® E PO and HPMC-E5 and no effect of PVP K25. Takinginto account the limited supersaturation stability in human gastric fluids and the modest capacity of excipients to slow down gastric precipitation, one could argue that supersaturation should be targeted to the small intestine. Precipitation inhibition studies performed in human intestinal fluids provide evidence that cellulosic polymers posses the potential to decelerate drug precipitation, possibly resulting in enhanced absorption of low solubility compounds. The usefulness of simple aqueous buffers or simulated intestinal fluids representative for the fasted or fed state as solvent systems to predict excipient-mediated precipitationinhibition in human intestinal fluids appeared to be limited, illustrating the need for further evaluation of media for supersaturation screening. However, since lack of supersaturation stabilization by a given excipient in aqueous buffer or simulated intestinal fluids was always confirmed in human intestinal fluids, elimination of excipients based on screening tests in simple media appears feasible. Since in the intestinal tract, absorption might serve as an alternative for precipitation of supersaturated drug molecules, precipitation kinetics might be altered in an absorption environment compared to a non-absorption environment. Therefore, in a last step, the impact of supersaturation/precipitation on transepithelial transport and vice versa was investigated. The interplaybetween absorption and supersaturation was investigated by comparing classic precipitation assessment in a non-absorption environment with precipitation/permeation assessment in an absorption environment for the poorly soluble drug loviride. While absorption was clearly enhanced when supersaturation was induced, subsequent precipitation also proved to limitthe absorption enhancement. Through comparison of precipitation in absorption versus non-absorption setups, this study explicitly revealed, forthe first time, that, loviride precipitation is overestimated in a non-absorption environment. Consequently, the added value of precipitation inhibitors was also overestimated in a non-absorption setup. These results confirm the hypothesis that absorption in vivo could serve as an alternative for drug precipitation. As such, ignoring permeation is detrimental for accurate prediction of the impact of supersaturation on absorption. Implementing transepithelial permeation into in vitro precipitation assays will therefore be crucial for the efficient development of supersaturating drug delivery systems. In conclusion, this dissertation research has demonstrated that, although very complex, supersaturation and excipient mediated precipitation inhibition are feasible in human gastrointestinal fluids and provides a better understanding of intraluminal supersaturation under biorelevant conditions. Different artificial media were validated for their predictive capacity towards human gastrointestinal fluid and absorption was identified as a precipitation altering factor. Integration of the obtained knowledge in non-clinical evaluation procedures will improve their biorelevance and contribute to the successful exploitation of the supersaturation concept as absorption-enhancing strategy in the future .