Biopharmaceutical characterization and formulation development of poorly water-soluble phytochemicals using in vivo predictive biphasic dissolution

Abstract

Nature offers a vast variety of different substances, some of which are known to have health-beneficial effects on humans. Thus, many of these compounds are frequently used as dietary supplements or herbal medicinal products. However, biological effects are often limited by low water solubility and resulting insufficient bioavailability. Consequently, a need for the development of bioavailability-enhanced formulations arises. To ensure efficient and cost-effective formulation development, researchers rely on in vivo predictive in vitro methods to determine the impact of different formulation principles on bioavailability. Addressing this issue, human pharmacokinetic data of five phytochemicals and their corresponding bioavailability-enhanced formulations was used to implement an in vivo predictive biphasic dissolution method (BiPHa+). BiPHa+ was applied for the characterization of 19 different curcumin (CUR), resveratrol, coenzyme Q10 (CoQ10), quercetin and astaxanthin (ASX) formulations. Despite analyzing structurally diverse model extracts and regardless of the formulation principles tested, dissolution results in excellent agreement with the human pharmacokinetic data were obtained for all formulations. A comparison with conventional monophasic dissolution methods emphasized the advantages of the BiPHa+ in terms of powerful prediction. For the resveratrol, CoQ10, and ASX formulations the combination of aqueous non-sink dissolution with an overlaying organic absorption sink proved to be the optimal approach, as conventional methods failed to provide in vivo relevant dissolution data.<br /> Upon analyzing commercial formulations of CoQ10 and ASX only slight improvements in bioavailability were found, highlighting the need for further development of improved formulations. Addressing this drawback, BiPHa+ was utilized as an in vivo relevant screening tool for subsequent formulation development. Initially, CoQ10 was used as a model compound, and a screening process was conducted to identify the optimal polymers for manufacturing of solid dispersions. Kollidon® VA64 and hydroxypropyl cellulose (HPC)-SSL were found to be the most effective options. However, the combination of VA64 with Eudragit® EPO in ternary solid dispersions further improved the effect, resulting in 6-7 times higher CoQ10 concentration in the organic absorption sink of BiPHa+ compared to the commercial formulations. Since none of the investigated polymers could stabilize CoQ10 in the amorphous state, the use of Syloid® XDP 3050 and Silsol® 6035 as mesoporous carriers for drug loading was identified as an alternative formulation principle. In order to investigate the effect of loading into silica for different lipophilic compounds, formulations containing CoQ10, ASX, probucol and lumefantrine were produced. Using incipient wetness impregnation, drug loads up to 50% could be achieved. Shake flasks experiments revealed that an increase in drug load led to a significant increase in biorelevant medium solubility. This effect was consistent across all model compounds tested, resulting in an increase by a factor of up to 180. The use of both mesoporous carriers facilitated the stabilization of active ingredients in a non-crystalline form, while BiPHa+ measurements demonstrated a marked increase in the partitioning rate into the organic absorption sink.