Novel continuous flow technology for the development of a nanostructured aprepitant formulation with improved pharmacokinetic properties

Abstract

The oral bioavailability of Aprepitant is limited by poor dissolution of the compound in the gastrointestinal tract which is more prominent in the fasted state resulting in significant positive food effect. Due to the low aqueous solubility of the active substance the product development has been focused on decreasing the particle size of the active compound down to the submicron range in order to overcome this disadvantageous pharmacokinetic property. The marketed drug consisting of wet-milled nanocrystals exhibits significantly higher oral bioavailability in the fasted state and reduced food effect when compared to the unformulated compound. We have developed a novel process for the production of a nanostructured Aprepitant formulation in which the generation of the nanosized particles takes place at molecular level. The process relies on controlled continuous flow precipitation of the compound from its solution in the presence of stabilizers. The precise control of the production parameters (mixing geometry, flow rates, temperature, etc.) allows to tailor the physicochemical properties and biological performance of the active compound. We have prepared a novel nanostructured Aprepitant formulation using this method and compared its physicochemical and pharmacokinetic properties with the reference compound and the marketed nanoformula. We found that our method produces a stable amorphous solid form comprising novel nanostructured particles having a particle size of less than 100 nm with instantaneous redispersibility characteristics and improved apparent solubility and permeability. In vivo beagle dog pharmacokinetic studies showed that the novel formula exhibited greatly improved pharmacokinetic characteristics when compared to the reference compound, while serum blood concentrations for the nanostructured formula and the wet-milled formula were similar. The marked food effect observed for the reference compound was practically eliminated by our formulation method. These results indicate that the novel continuous flow precipitation technology is a suitable tool to prepare nanostructured formulations with similar, or even superior in vitro and in vivo characteristics when compared to the industrial standard milling technology.

Keywords: Aprepitant; Bioavailability; Continuous flow nanoprecipitation; Food effect; In vitro/in vivo correlation; Solubility.