Improving maraviroc oral bioavailability by formation of solid drug nanoparticles

Oral drug administration remains the preferred approach for treatment of HIV in most patients. Maraviroc (MVC) is the first in class co-receptor antagonist, which blocks HIV entry into host cells. MVC has an oral bioavailability of approximately 33%, which is limited by poor permeability as well as affinity for CYP3A and several drug transporters. While once-daily doses are now the favoured option for HIV therapy, dose-limiting postural hypotension has been of theoretical concern when administering doses high enough to achieve this for MVC (particularly during coadministration of enzyme inhibitors). To overcome low bioavailability and modify the pharmacokinetic profile, a series of 70 wt% MVC solid drug nanoparticle (SDN) formulations (containing 30wt% of various polymer/surfactant excipients) were generated using emulsion templated freeze-drying. The lead formulation contained PVA and AOT excipients (MVCSDNPVA/AOT), and was demonstrated to be fully water-dispersible to release drug nanoparticles with z-average diameter of 728 nm and polydispersity index of 0.3. In vitro and in vivo studies of MVCSDNPVA/AOT showed increased apparent permeability of MVC, compared to a conventional MVC preparation, with in vivo studies in rats showing a 2.5-fold increase in AUC (145.33 vs. 58.71 ng.h ml-1). MVC tissue distribution was similar or slightly increased in tissues examined compared to the conventional MVC preparation, with the exception of the liver, spleen and kidneys, which showed statistically significant increases in MVC for MVCSDNPVA/AOT. These data support a novel oral format with the potential for dose reduction while maintaining therapeutic MVC exposure and potentially enabling a once-daily fixed dose combination product.


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Production verview and analytic results for the formation of solid drug nanoparticles
Formation of solid drug nanoparticles and results