In vitro method developments for the better prediction of bioavailability
Katona Miklós
Pharmaceutical Sciences
Dr. Zelkó Romána
Semmelweis Egyetem, Egyetemi Gyógyszertár Gyógyszerügyi Szervezési Intézet, Zalai terem
2024-04-29 15:00:00
Modern Trends in Pharmaceutical Scientific Research
Dr. Antal István
Takácsné Dr. Novák Krisztina
Dr. Ludányi Krisztina
Dr. Révész Piroska
Dr. Szökő Éva
Dr. Pálla Tamás
Dr. Kovács-Kiss Dorottya
A novel in vitro dissolution method was developed with the aim of enabling a better understanding of the post-gastric behaviour of enteric-coated formulations, and thus better prediction of in vivo bioavailability. First, the physiological conditions at each tract of the gastrointestinal system in fasted state were determined on the basis of literature data. Then, the theoretical (time-varying) conditions were successfully modelled by adding different phosphate buffer solutions to the initial 0.01M HCl in a “Chinese small volume” apparatus using a multistep procedure. Because of the high variability of gastric residence time, two versions of the method (RGE and SGE) were tested, differing in the length of acid treatment (20 min vs 120 min). The improved discriminatory power of the new method compared to the USP method was demonstrated by investigating six commercially available low-dose ASA formulations. The results pointed out the influence of the plasticizer used in the coating on the onset of drug release, while the rate of dissolution was determined by the wettability of the excipients used in the tablet cores. The observations may explain the negative bioequivalence outcome of ASA Krka and Asactal formulations i.e. advanced predictivity of the new method may also be assumed.
The multi-compartmental Gastrointestinal Simulator was implemented to test its applicability to BCS Class IIa compounds. The method using blank biorelevant media was able to differentiate between rapid-release and conventional-release formulations. The study showed that either the salt formation or pre-dissolving the API in a lipid-based solution resulted in temporary supersaturation in the stomach, which affected the dissolution in the later compartments as well. Moreover, a Level A IVIVC model was developed, and the plasma concentrations were simulated based on the in vitro dissolution in the duodenum and jejunum compartments. Similar to the literature, significant increases in Cmax values were observed.
An IVIVC model was also established to predict the effect of food on Rivaroxaban 20 mg formulations. The correlation was built between the published in vivo fasting clinical results and the measured in vitro dissolution in fasted biorelevant media using USP IV apparatus. Then, the fed plasma concentration profile was predicted based on the in vitro dissolution using the same apparatus with fed biorelevant media. The predicted food-effect, especially for Cmax was significant but below the reported literature results.
