Menon A, Ritschel W A, Sakr A
University of Cincinnati, College of Pharmacy, OH 45267-0004.
J Pharm Sci. 1994 Feb;83(2):239-45. doi: 10.1002/jps.2600830225.
The poor bioavailability of orally dosed furosemide (60%), a weakly acidic drug, is due to the presence of a biological window comprised of the upper gastrointestinal tract. The purpose of the present study was to develop and optimize in vitro a monolithic modified-release dosage form (MMR) for furosemide with increased gastric residence time and to evaluate the in vivo performance of the dosage form. The principle of floatation was used to restrict the MMR to the stomach. A two-factor three-level full factorial experimental design was employed for formulation development. A flow-through cell was designed to evaluate in vitro dissolution parameters. Quadratic regression models indicated the polymer viscosity and polymer:drug ratio to be significant (p < 0.05) formulation factors in determining the duration of buoyancy and the release profile. Statistical optimization using response surface methodology with certain physiological constraints relating to gastric emptying time predicted an optimal MMR. In vivo evaluation of the optimized MMR in beagle dogs resulted in a significant increase (p < 0.05) in the absolute bioavailability for the MMR dosage form (42.9%) as compared to the commercially available tablet (33.4%) and enteric product (29.5%). Significant in vitro/in vivo correlations (p < 0.05) were obtained for the MMR using deconvolution analysis normalized for bioavailability. The floating dosage form was found to be a feasible approach in delivering furosemide to the upper gastrointestinal tract to maximize drug absorption.
口服给药的呋塞米生物利用度较差（60%），它是一种弱酸性药物，这是由于上消化道存在一个生物窗。本研究的目的是在体外开发并优化一种胃滞留时间延长的呋塞米整体型缓释剂型（MMR），并评估该剂型的体内性能。利用漂浮原理将MMR限制在胃内。采用两因素三水平全因子实验设计进行制剂研发。设计了一个流通池来评估体外溶出参数。二次回归模型表明，聚合物粘度和聚合物与药物的比例是决定漂浮持续时间和释放曲线的显著（p < 0.05）制剂因素。使用响应面法并结合与胃排空时间相关的特定生理约束进行统计优化，预测出了一种最佳的MMR。在比格犬体内对优化后的MMR进行评估，结果显示与市售片剂（33.4%）和肠溶产品（29.5%）相比，MMR剂型的绝对生物利用度显著提高（p < 0.05），达到42.9%。使用经生物利用度归一化的反卷积分析，MMR获得了显著的体外/体内相关性（p < 0.05）。发现漂浮剂型是将呋塞米递送至胃肠道上部以最大化药物吸收的一种可行方法。
