WITHDRAWN: Gastroretentive fibrous dosage forms for prolonged delivery of sparingly soluble tyrosine kinase inhibitors. Part 3: Theoretical models of in vivo expansion, gastric residence time, and drug concentration in blood

Abstract

In the present part, models are developed for in vivo expansion, gastric residence time, and drug concentration in blood after administering a slow-release, gastroretentive fibrous dosage form to dogs. The tyrosine kinase inhibitor nilotinib, which is slightly soluble in low-pH gastric fluid but practically insoluble in high-pH intestinal fluid, is used as a model drug. The models suggest that upon ingestion, the fibrous dosage form expands, is retained in the stomach for prolonged time, and releases drug into the gastric fluid at a constant rate. The released drug molecules continuously flow into the duodenum with the gastric fluid flow, and are absorbed by the blood at the same rate. The absorbed drug molecules are eliminated from the blood by the liver at a rate proportional to the drug concentration in blood. Eventually, the elimination rate and the absorption rate balance out, and the drug concentration in blood plateaus out to a steady state value. After the gastric residence time of the dosage form, drug release and drug absorption stop, and the drug concentration in blood drops to zero. By contrast, after administering an immediate-release particulate dosage form the drug particles are swept out of the stomach rapidly, and drug release and drug absorption stop much earlier. The drug concentration in blood rises and falls without attaining steady state. The gastroretentive fibrous dosage forms enable a constant drug concentration in blood for drugs that are insoluble in intestinal fluids.