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 cancer therapies employing a sparingly-soluble tyrosine kinase inhibitor (TKI) are compromised by excessive fluctuations in the drug concentration in blood. To mitigate this limitation, in this four-part study expandable, gastroretentive fibrous dosage forms that deliver drug into the gastric fluid (and into the blood) at a controlled rate for prolonged time are presented. The dosage form comprises a cross-ply structure of water-absorbing, high-molecular-weight hydroxypropyl methylcellulose (HPMC) based fibers coated with a strengthening, enteric excipient. The intervening spaces between the coated fibers are solid annuli of dispersed drug particles in a low-molecular-weight HPMC-based excipient matrix. The central regions of the annuli are open channels. In this part, models are developed for dosage form expansion, post-expansion mechanical strength, and drug release. The models suggest that upon immersing in a dissolution fluid, the fluid percolates the open channels, diffuses into the annuli and the coated fibers, and the dosage form expands. The expansion rate is inversely proportional, and the post-expansion mechanical strength proportional to the volume fraction of the coating. Drug particles are released from the annuli as the surrounding excipient dissolves. The drug release rate is proportional to the concentration of low-molecular-weight HPMC at the annulus/dissolution fluid interface. The dosage forms can be readily designed for expansion in a few hours, formation of a high-strength viscoelastic mass, and drug release at a constant rate over a day.