Shared IVIVR for Five Commercial Enabling Formulations Using the BiPHa+ Biphasic Dissolution Assay

Abstract

The present study intended to confirm the in vivo relevance of the BiPHa+ biphasic dissolution assay using a single set of assay parameters. Herein, we evaluated five commercial drug products formulated by various enabling formulation principles under fasted conditions using the BiPHa+ assay. The in vitro partitioning profiles in the organic phase were compared with human pharmacokinetic data obtained from literature. In the first part, a meaningful in vitro dose of the formulations was assessed by determining the maximum drug concentration in the artificial absorption sink during dissolution (organic 1-decanol layer, Cdec,max). Then, the maximum concentration of the partitioned drug in the organic layer was correlated with the in vivo fraction absorbed, which was derived from published human pharmacokinetic data. Fraction absorbed represents the percentage, which is absorbed from the intestine without considering first pass. It was found that the maximum drug concentration in the organic phase obtained from an in vitro dose of ten milligrams, which is equivalent to 15–25 µmol of the respective drug, led to the highest congruency with the fraction absorbed in vivo. In the second part, the in vivo relevance of the BiPHa+ dissolution data was verified by establishing a shared in vitro/in vivo relationship including all formulations. Based on the in vitro kinetics of the BiPHa+ experiments human in vivo plasma profiles were predicted using convolutional modelling approach. Subsequently, the calculated pharmacokinetic profiles were compared with in vivo performance of the studied drug products to assess the predictive power of the BiPHa+ assay. The BiPHa+ assay demonstrated biorelevance for the investigated in vitro partitioning profiles using a single set of assay parameters, which was verified based on human pharmacokinetic data of the five drug products.

Novel Biphasic In Vitro Dissolution Method Correctly Predicts the Oral Bioavailability of Curcumin in Humans

“…For all of these formulations, the dissolved amount of curcuminoids in the aqueous medium was too low to facilitate pronounced partitioning into the 1-decanol layer. A similar effect was described by Denninger et al for itraconazole . Due to low itraconazole concentrations in the aqueous medium, the partitioning into the organic phase was limited.…”

“…A similar effect was described by Denninger et al for itraconazole. 31 Due to low itraconazole concentrations in the aqueous medium, the partitioning into the organic phase was limited. This might also explain the ineffectiveness of the formulations targeting postabsorptive mechanisms, such as inhibiting phase II enzymes with adjuvants (e.g., piperine) 16,17 or intestinal membrane transporters (e.g., with turmeric oils), 15 as these inhibitors would only affect curcumin that was already absorbed, which, as stated above, was limited by poor dissolution.…”

“…Furthermore, the characterization of formulations containing more than one active ingredient, which is common for plant extracts and dietary supplements, is challenging, and the use of these dissolution approaches might not be feasible . To overcome these limitations, biorelevant testing methods, such as biphasic dissolution approaches − or in vitro digestion models, ,− have been developed. In vitro digestion models typically use sequential mouth, gastric, and intestinal digestion steps to mimic the condition in the human gut.…”

“…32 Denninger et al developed a fully automated small-scale, onevessel biphasic dissolution setup (BiPHa+) and demonstrated its ability to generate biorelevant results for various drugs. 30,31 Compared to in vitro digestion models, the biphasic dissolution setup of Denninger et al represents the human gastrointestinal tract in a more simplified way, but its major advantage is the fully automated design. For example, no manual pH adjustments are required and concentration changes of the substance of interest can be tracked online in both phases.…”

In Vitro–In Vivo Relationship in Mini-Scale—Enabling Formulations of Corallopyronin A

“…The dissolution experiment of neat CorA and CorA-ASD formulations were performed using the biphasic dissolution apparatus BiPHa+ [31,32]. The experimental setup for the aqueous phase was identical to the monophasic setup (Section 2.4.1).…”