Effect of Coadministered Water on the In Vivo Performance of Oral Formulations Containing N‑Acetylcysteine: An In Vitro Approach Using the Dynamic Open Flow-Through Test Apparatus

• Published in: Molecular pharmaceutics 2017-12, Vol.14 (12), p.4272-4280
• Main Authors: Sager, Maximilian, Schneider, Felix, Jedamzik, Philipp, Wiedmann, Markus, Schremmer, Ellen, Koziolek, Mirko, Weitschies, Werner
• Format: Article
• Language: English
• Subjects: Absorption, Physiological - physiology; Acetylcysteine - administration & dosage; Acetylcysteine - pharmacokinetics; Administration, Oral; Adult; Biopharmaceutics - instrumentation; Biopharmaceutics - methods; Chemistry, Pharmaceutical; Cross-Over Studies; Drug Delivery Systems; Drug Liberation; Female; Food-Drug Interactions - physiology; Gastric Emptying - physiology; Healthy Volunteers; Humans; In Vitro Techniques - instrumentation; In Vitro Techniques - methods; Male; Middle Aged; Solubility; Tablets; Water - physiology; Young Adult
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00763

The drug plasma profile after oral administration of immediate release dosage forms can be affected by the human gastrointestinal physiology, the formulation, and the drug itself. In this work, we investigated the in vivo and in vitro performance of two formulations (granules vs. tablet) containing the highly soluble drug N-Acetylcysteine (BCS class I). Thereby, special attention was paid to the effect of the dosage form and the coadministration of water on drug release. Interestingly, the in vivo results from a pharmacokinetic study with 11 healthy volunteers indicated that the drug plasma concentrations were comparable for the tablet given with water as well as for the granules given with and without water. In order to mechanistically understand this outcome, we used a biorelevant dissolution test device, the dynamic open flow-through test apparatus. With the aid of this test apparatus, we were able to simulate biorelevant parameters, such as gastric emptying, hydrodynamic flow as well as physical stress. By this, it was possible to mimic the intake conditions of the clinical trial (i.e., drug intake with and without water). Whereas the experiments in the USP paddle apparatus revealed differences between the two formulations, we could not observe significant differences in the release profiles of the two formulations by using the dynamic open flow-through test apparatus. Even by considering the different intake conditions, drug release was slow and amounted to around 30% until simulated gastric emptying. These results suggest that dissolution was irrespective of coadministered water and the formulation. Despite the high aqueous solubility of N-Acetylcysteine, the limiting factor for drug release was the slow dissolution rate in relation to the gastric emptying rate under simulated gastric conditions. Thus, in case of administration together with water, large amounts of the drug are still present in the stomach even after complete gastric emptying of the water. Consequently, the absorption of the drug is largely controlled by the nature of gastric emptying of the remaining drug. The data of this study indicated that the water emptying kinetics are only determining drug absorption if drug release is rapid enough. If this is not the case, physiological mechanisms, such as the migrating motor complex, play an important role for oral drug delivery.