WITHDRAWN: Gastroretentive fibrous dosage forms for prolonged delivery of sparingly-soluble tyrosine kinase inhibitors. Part 1: Dosage form design, and models of expansion, post-expansion mechanical strength, and drug release

Abstract

At present, the efficacy and safety of many sparingly soluble tyrosine kinase inhibitors (TKIs) are compromised due to the drug's pH-dependent solubility, and the associated excessive fluctuations in the drug concentration in blood. To mitigate this limitation, in this four-part study gastroretentive fibrous dosage forms that deliver drug into the low-pH gastric fluid (and into the blood) for prolonged time are presented. The dosage form comprises a cross-ply fibrous structure of water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) fibers coated with a strengthening, enteric excipient. The intervening spaces between the coated fibers are solid annuli that contain drug particles, low-molecular-weight HPMC, and an enteric excipient. There are open channels in the central regions of the annuli. In this first part, models are developed for in vitro dosage form expansion, post-expansion mechanical strength, and drug release. The models suggest that the expansion rate and the post-expansion mechanical strength can be varied by changing the thickness of the enteric coating over the fibers. The drug particles in the annulus are released as the surrounding excipient erodes. The drug release rate is proportional to the concentration of low-molecular-weight HPMC at the interface between the annulus and the dissolution fluid in the channels. The dosage forms can be readily tailored for expansion in a few hours, formation of a high-strength viscoelastic mass, and drug release at a constant rate over a day.