Wang Chen-Chao, Tejwani Motwani Monica R, Roach Willie J, Kay Jennifer L, Yoo Jaedeok, Surprenant Henry L, Monkhouse Donald C, Pryor Timothy J
McNeil Consumer and Specialty Pharmaceuticals, Fort Washington, Pennsylvania 19034, USA.
Drug Dev Ind Pharm. 2006 Mar;32(3):367-76. doi: 10.1080/03639040500519300.
Three near zero-order controlled-release pseudoephedrine hydrochloride (PEH) formulations demonstrating proportional release rates were developed using 3-Dimensional Printing (3-DP) technology. Mixtures of Kollidon SR and hydroxypropylmethyl cellulose (HPMC) were used as drug carriers. The release rates were adjusted by varying the Kollidon SR-HPMC ratio while keeping fabrication parameters constant. The dosage forms were composed of an immediate release core and a release rate regulating shell, fabricated with an aqueous PEH and an ethanolic triethyl citrate (TEC) binder, respectively. The dosage form design called for the drug to be released via diffusional pathways formed by HPMC in the shell matrix. The release rate was shown to increase correspondingly with the fraction of HPMC contained in the polymer blend. The designed formulations resulted in dosage forms that were insensitive to changes in pH of the dissolution medium, paddle stirring rate, and the presence/absence of a sinker. The near zero-order release properties were unchanged regardless of the dissolution test being performed on either single cubes or on a group of eight cubes encased within a gelatin capsule shell. The chemical and dissolution properties of the three formulations remained unchanged following 1 month's exposure to 25 degrees C/60% RH or 40 degrees C/75% RH environment under open container condition. The in vivo performance of the three formulations was evaluated using a single-dose, randomized, open-label, four-way crossover clinical study composed of 10 fasted healthy volunteers. The pharmacokinetic parameters were analyzed using a noncompartmental model. Qualitative rank order linear correlations between in vivo absorption profiles and in vitro dissolution parameters (with slope and intercept close to unity and origin, respectively) were obtained for all three formulations, indicating good support for a Level A in vivo/in vitro correlation.
采用三维打印（3-DP）技术研发了三种具有成比例释放速率的近零级控释盐酸伪麻黄碱（PEH）制剂。聚乙烯吡咯烷酮缓释剂（Kollidon SR）和羟丙基甲基纤维素（HPMC）的混合物用作药物载体。在保持制备参数不变的情况下，通过改变Kollidon SR-HPMC比例来调整释放速率。剂型由速释核心和释放速率调节包衣组成，分别用水性PEH和乙醇柠檬酸三乙酯（TEC）粘合剂制备。剂型设计要求药物通过包衣基质中HPMC形成的扩散途径释放。结果表明，释放速率随聚合物共混物中HPMC的比例相应增加。所设计的制剂对溶出介质的pH值变化、桨叶搅拌速率以及是否存在沉降片不敏感。无论对单个立方体还是对封装在明胶胶囊壳中的一组八个立方体进行溶出试验，近零级释放特性均保持不变。在开放容器条件下，将三种制剂在25℃/60%相对湿度或40℃/75%相对湿度环境中暴露1个月后，其化学和溶出特性保持不变。使用由10名空腹健康志愿者组成的单剂量、随机、开放标签、四交叉临床研究评估了三种制剂的体内性能。使用非房室模型分析药代动力学参数。所有三种制剂均获得了体内吸收曲线与体外溶出参数之间的定性等级线性相关性（斜率和截距分别接近1和原点），表明对A级体内/体外相关性有良好支持。
