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The effect of digestion and drug load on absorption of poorly water soluble drugs from self-nanoemulsifying drug delivery systems (SNEDDS)

University of British Columbia

The rising numbers of poorly water soluble drugs found in the pipelines of the pharmaceutical industry elicit the need for the development of enabling formulations. Lipid-based drug delivery systems (LbDDS) are a versatile group of formulations including self-nanoemulsifying drug delivery systems (SNEDDS). The advantage of using LbDDS, such as SNEDDS, for poorly water soluble drugs is that typically the oral bioavailability is increased compared to traditional solid dosage forms. In order to examine the effect of lipid digestion on absorption of poorly water soluble drugs from SNEDDS the lipase inhibitor orlistat (tetrahydrolipstatin) was used. Halofantrine and fenofibrate were chosen as model drugs and for neither halofantrine nor fenofibrate digestion appeared to have an effect on the oral bioavailability in rats. The administration of halofantrine and fenofibrate in super-SNEDDS led to increasedbioavailability compared to SNEDDS when evaluated in a rat model in vivo. For both halofantrine and fenofibrate there was a significant increase of Cmax for the super-SNEDDS compared to the SNEDDS. For halofantrine no significant increase was seen in the bioavailability for the super-SNEDDS however, for fenofibrate the AUC of the super-SNEDDS was significantly larger than for the SNEDDS. The dynamic in vitro lipolysis model is typically used in the evaluation of digestibility and solubilization capacity of SNEDDS and other LbDDS. The traditional interpretation of data from the lipolysis model is that the solubilized fraction of drug is available for absorption, whereas the precipitated fraction needs to be re-dissolved in order to be absorbed which is believed to lower the bioavailability. However, for super-SNEDDS precipitation seems to be inversely correlated with oral absorption when comparing the in vitro data with the in vivo data. In order to examine precipitation of poorly water soluble drugs dosed in LbDDS in vivo the gastric and intestinal content of rats was examined for precipitated crystalline drug using XRPD and PLM. The study revealed that precipitation only was evident in the stomach, thus precipitation in the intestinal in vitro model may be an artifact and may require the addition of an in vitro gastric digestion step to be predictive in vivo.

Text

2018-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/59178

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/