The Introduction of a New Flexible In Vivo Predictive Dissolution Apparatus, GIS-Alpha (GIS-α), to Study Dissolution Profiles of BCS Class IIb Drugs, Dipyridamole and Ketoconazole.

The physiological pH changes and peristalsis activities in gastrointestinal (GI) tract have big impact on the dissolution of oral drug products, when those oral drug products include APIs with pH-dependent solubility. It is well documented that predicting the bioperformance of those oral drug products can be challenging using compendial methods. To overcome this limitation, in vivo predictive dissolution apparatuses, such as the transfer model, have been developed to predict bioperformance of oral formulation candidates and drug products. In this manuscript we utilize a new transfer-model dissolution apparatus, the gastrointestinal simulator-α (GIS-α), to characterize its behavior in terms of transfer kinetics and pH, assess its reproducibility and adaptability to mimic different transfer conditions, as well as study dissolution of ketoconazole and dipyridamole as model BCS class IIb compounds. Availability of commercially available dissolution transfer systems with similar configuration to compendial dissolution apparatus, may be helpful to simplify and standardize in vivo predictive dissolution methodologies for BCS class IIb compounds in the future.

The impact of supersaturation level for oral absorption of BCS class IIb drugs, dipyridamole and ketoconazole, using in vivo predictive dissolution system: Gastrointestinal Simulator (GIS).

The development of formulations and the assessment of oral drug absorption for Biopharmaceutical Classification System (BCS) class IIb drugs is often a difficult issue due to the potential for supersaturation and precipitation in the gastrointestinal (GI) tract. The physiological environment in the GI tract largely influences in vivo drug dissolution rates of those drugs. Thus, those physiological factors should be incorporated into the in vitro system to better assess in vivo performance of BCS class IIb drugs. In order to predict oral bioperformance, an in vitro dissolution system with multiple compartments incorporating physiologically relevant factors would be expected to more accurately predict in vivo phenomena than a one-compartment dissolution system like USP Apparatus 2 because, for example, the pH change occurring in the human GI tract can be better replicated in a multi-compartmental platform. The Gastrointestinal Simulator (GIS) consists of three compartments, the gastric, duodenal and jejunal chambers, and is a practical in vitro dissolution apparatus to predict in vivo dissolution for oral dosage forms. This system can demonstrate supersaturation and precipitation and, therefore, has the potential to predict in vivo bioperformance of oral dosage forms where this phenomenon may occur. In this report, in vitro studies were performed with dipyridamole and ketoconazole to evaluate the precipitation rates and the relationship between the supersaturation levels and oral absorption of BCS class II weak base drugs. To evaluate the impact of observed supersaturation levels on oral absorption, a study utilizing the GIS in combination with mouse intestinal infusion was conducted. Supersaturation levels observed in the GIS enhanced dipyridamole and ketoconazole absorption in mouse, and a good correlation between their supersaturation levels and their concentration in plasma was observed. The GIS, therefore, appears to represent in vivo dissolution phenomena and demonstrate supersaturation and precipitation of dipyridamole and ketoconazole. We therefore conclude that the GIS has been shown to be a good biopredictive tool to predict in vivo bioperformance of BCS class IIb drugs that can be used to optimize oral formulations.