The influence of liquid intake on the performance of an amorphous solid dispersion in rats.

The aim of this rat study was to investigate the effect of liquid intake on the oral bioavailability of an amorphous solid dispersion (ASD) containing the poorly water-soluble compound ABT-869. To this end, an ASD was prepared by hot-melt extrusion and administered in form of powder in an open gelatin capsule. The study consisted of three arms: (1) administration of the ASD without any liquid, (2) administration of the ASD with 1.5 mL of water, and (3) administration of a suspension of crystalline drug in water. Administration of the ASD without water resulted in a 4-fold higher exposure as compared to the suspension of crystalline drug. When administered together with water, the in vivo performance of the ASD was dramatically affected and not superior to that of the suspension of crystalline drug. The observed phenomena could not be explained mechanistically, but may be related to the following effects: (I) a faster dissolution in a larger volume of fluid and subsequent precipitation, (II) a change in gastrointestinal transit time that caused a mismatch between dissolution rate and absorption rate, and/or (III) a difference in the mucosal adherence/distribution pattern caused by the gelatin capsule. It remains to be investigated whether the phenomena observed in this study are exceptionally pronounced or even unique for this particular formulation. Yet, our findings emphasize that the amount of liquid co-administered with oral enabling formulations can have an impact on the bioavailability. The administration regime used in animal studies should therefore be considered carefully.

PermeaLoop™, a novel in vitro tool for small-scale drug-dissolution/permeation studies.

Here we report first experiences with the novel in vitro dissolution/permeation setup PermeaLoop™. It was designed to overcome current limitations of in vivo predictive dissolution testing of enabling formulations, such as lack of relevant absorptive drag to allow for meaningful interplay between dissolution and permeation, as it is occurring in vivo. We propose a novel setup with a high area-to-volume ratio and report as a model case the dissolution/permeation behavior of an enabling formulation of the poorly soluble and poorly permeable drug ABT-869. Mini tablets consisting of an amorphous solid dispersion were tested at a downscaled clinically relevant dose. At room temperature, release was fast, and more than 35% of the employed dose permeated within 6 h. In consequence, the amount in the donor decreased significantly. By contrast, only 9% of the employed dose was released when performing the experiment at 35 °C. Still, most of the released drug permeated into the acceptor (>80%), and the permeation rate was release-dependent and vice versa, i.e. the scenario was highly dynamic. Hence, due to a sufficiently large permeation area the dissolution step became rate-limiting. Therefore, PermeaLoop™ is regarded a promising tool for evaluating enabling formulations.

Evaluation of a dynamic dissolution/permeation model: Mutual influence of dissolution and barrier-flux under non-steady state conditions.

Combined dissolution/permeation testing is gaining increasing attention as an in vitro tool for predictive performance ranking of enabling oral formulations. The current aim was to study how in vitro drug permeation evolves under conditions, where the donor concentration is changing (non-steady state). To this end, a model case was construed: compacts of pure crystalline hydrocortisone methanolate (HC·MeOH) of slow release rates were prepared, and their dissolution and permeation determined simultaneously in a side-by-side setup, separated by a biomimetic barrier (Permeapad®). This was compared to a corresponding setup for a suspension of micronized hydrocortisone (HC). The HC suspension showed constant dissolved HC concentration and constant flux across the barrier, representing the permeation-limited situation. For the HC·MeOH compacts, various dynamic scenarios were observed, where dissolution rate and flux influenced each other. Interestingly, for all the dynamic scenarios, the incremental flux values obtained correlated nicely with the corresponding actual donor concentrations. Furthermore, donor depletion was tested using a HC solution. The dynamic interplay between decrease in donor concentration (down to less than 10% of the initial concentration) and flux was studied. The experiences gained are discussed in terms of further developing combined dissolution/permeation setups.

Dynamic dissolution-/permeation-testing of nano- and microparticle formulations of fenofibrate.

The aim of the current study was to evaluate a dynamic dissolution-/permeation-system for prediction of gastrointestinal and absorption-behavior of two commercial fenofibrate formulations. To this end, both dissolution and barrier-flux were followed simultaneously for fenofibrate powder, a microparticle formulation (Lipidil® 200mg) and a nanoparticle formulation (LIPIDIL 145 ONE®) using a pair of side-by side diffusion cells separated by a cellulose hydrate membrane. Under such dynamic conditions, transient supersaturation arising from the nanoparticle formulation could be demonstrated for the first time. Furthermore, the dissolution-/permeation-system introduced here allowed for in-depth mechanistic insights: Biomimetic media, despite enhancing the apparent solubility of fenofibrate via micellar solubilization, did not increase permeation rate, irrespective whether the micro-/ or nanoparticle-formulation was tested. Nondissolved nano-/microparticles served as a reservoir helping to maintain high levels of molecularly dissolved drug, which in turn caused high and constant permeation rates. The micelle-bound drug may also serve as a drug-reservoir, yet of subordinate importance as long as there are nano-/microparticles present. Despite the limitations of the current experimental set-up, combined dissolution-/permeation-testing appears a valuable new tool to promote mechanistic understanding during formulation development. Last but not least, the in vitro dissolution and permeation behavior revealed here was in good qualitative agreement with human duodenal and plasma values reported in literature for the same formulations.