Traditionally, excipients utilized for the development of pharmaceutically-marketed drug products have been considered largely inert. Excipients are added to formulations for a variety of reasons that may include assisting processability of the drug product formulation, controlling the disintegration rate to facilitate regional dissolution along the gastrointestinal tract (GIT), bulking up the dosage form to enable the administration of low dose compounds, and in some cases providing a sustained release to balance disposition from the body. In each of these cases, the excipients are considered to be pharmacologically inert.
The pharmacologically inert properties of excipients have been brought into some question as numerous reports throughout the years have linked surface-active and other colloidal excipients with the ability to directly modify multidrug resistant transporter function that was first observed in the treatment of tumors. Regulatory bodies have debated how excipients with these purported effects should be classified and potentially regulated. However, it is still not clear if the reported effects of these excipients are directly modifying the transporter (in some cases enzyme) isoforms or acting through an indirect manner where the contribution of the transporter to the net absorption is minimized in contrast to the other pathways of permeation (e.g., passive transcellular or lipophilicity driven transport). Such an indirect effect raises the possibility that these excipients that act as solubilizing agents can potentially increase the solubility, saturate the counter transporter isoform, and increase bioavailability by increasing solubility limited passive diffusion mechanisms. Alternatively, there can be other effects including changing tonicity or perturbating tight junctional proteins to increase paracellular diffusion between the gastrointestinal epithelial cells. A recent literature review of this area has been published from the Knipp Lab, “Considerations for Determining Direct versus Indirect Functional Effects of Solubilizing Excipients on Drug Transporters for Enhancing Bioavailability”. In summary, the paper demonstrated that there is a significant need to illustrate that excipient-transporter effects are direct in nature (arising from a potential of a transporter/enzyme interaction) or more likely indirect arising from the function of the colligative properties the excipients exert in solution. Predicated on the review, Ravine Pharmaceuticals in partnership with Improved Pharma are initiating collaborative efforts to better delineate, understand and monitor profound effects certain classes of pharmaceutical excipients have on drug performance by characterizing the changes in the solution properties that may lead to obfuscation of transporter contributions.
We are pleased to announce that our colleagues from the Knipp Lab in the Industrial and Physical Pharmacy Department at Purdue University has been recognized by the Journal of Pharmaceutical Sciences for having published this manuscript as a most original and most significant scientific findings. The article can be accessed online here. For further information, please contact us at firstname.lastname@example.org or email@example.com.