Abstract：
At present, the efficacy and safety of many sparingly-soluble tyrosine kinase inhibitors (TKIs) delivered by the prevalent oral dosage forms are compromised by 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 gastric fluid (and into the blood) at a controlled rate for prolonged time are presented. The dosage form comprises a cross-ply structure of expandable, 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 drug particles, and low-molecular-weight HPMC and enteric excipients. 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 thickness of the strengthening 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.
摘要：
目前,许多微溶的酪氨酸激酶抑制剂(TKIs)的有效性和安全性受到血液中药物浓度过度波动的影响。为了减轻这种限制，在这项由四部分组成的研究中，介绍了胃滞留纤维剂型，该剂型以受控的速率长时间将药物输送到胃液（和血液）中。该剂型包括可膨胀的交叉层结构，吸水,高分子量羟丙基甲基纤维素（HPMC）基纤维涂有增强，肠溶赋形剂。涂层纤维之间的中间空间是药物颗粒的固体环，和低分子量HPMC和肠溶赋形剂。环的中心区域是明渠。在这一部分,为剂型扩展开发了模型，膨胀后机械强度，和药物释放。这些模型表明，在浸入溶解流体中时，流体渗入开放的通道，扩散到环形和涂层纤维中，并且剂型膨胀。膨胀率成反比，膨胀后的机械强度与强化涂层的厚度成正比。当周围的赋形剂溶解时,药物颗粒从环中释放。药物释放速率与环空/溶解流体界面处的低分子量HPMC浓度成正比。该剂型可以很容易地设计为在几个小时内膨胀，形成高强度粘弹性物质，药物在一天内以恒定的速度释放。
