College of Pharmacy, University of Iowa, 115 S. Grand Avenue, Iowa City, IA 52242, USA.
Drug Product Development, Celgene, 556 Morris Avenue, Summit, NJ 07901, USA.
Int J Pharm. 2019 Sep 10;568:118189. doi: 10.1016/j.ijpharm.2019.03.007. Epub 2019 Mar 6.
Nanocrystalline suspensions offer a promising approach to improve the dissolution rate of BCS Class II/IV drugs and hence oral bioavailability. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound for the study. The objectives of the study were to formulate Irbesartan nanocrystalline suspension via media milling, study the effects of process and formulation variables on particle size reduction, and evaluate bead layering or spray granulation as drying processes. A Design of Experiment approach was utilized to understand the impact of formulation variables on particle size reduction via media milling. Drug concentration and type of stabilizer were found to be significant in particle size reduction. Optimized Irbesartan nanocrystalline suspension (i.e. at 10% w/w with 1% w/w poloxamer 407) showed superior in vitro dissolution profile compared to unmilled suspension. Optimized Irbesartan nanocrystalline suspension was converted into dried powders either by bead layering (with microcrystalline cellulose) or by spray granulation (either with mannitol or microcrystalline cellulose). DSC and PXRD studies revealed that Irbesartan remained crystalline post drying. Microcrystalline cellulose beads layered with Irbesartan nanocrystals showed about 65% drug dissolution within the first 10 min of dissolution study. Mannitol granules containing Irbesartan nanocrystals were fast dissolving (i.e. >90% drug dissolution within 10 min) compared to microcrystalline cellulose granules (i.e. approx. 46% drug dissolution within 10 min). Irbesartan nanocrystalline suspension had the fastest dissolution rates (i.e. >90% drug dissolution in two minutes) followed by mannitol-based granules containing dried Irbesartan nanocrystals (i.e. >90% drug dissolution in ten minutes).
纳米晶混悬剂为提高 BCS Ⅱ/Ⅳ类药物的溶出速率和口服生物利用度提供了一种很有前途的方法。厄贝沙坦（晶型 B）是一种难溶性药物，被选为该研究的模型化合物。该研究的目的是通过介质研磨来制备厄贝沙坦纳米晶混悬剂，研究工艺和配方变量对粒径减小的影响，并评估珠层或喷雾造粒作为干燥过程。采用实验设计方法来理解配方变量对介质研磨过程中粒径减小的影响。药物浓度和稳定剂类型对粒径减小有显著影响。优化的厄贝沙坦纳米晶混悬剂（即 10%w/w 浓度下含 1%w/w 泊洛沙姆 407）显示出比未研磨的混悬剂具有更优的体外溶出特性。优化的厄贝沙坦纳米晶混悬剂通过珠层（与微晶纤维素）或喷雾造粒（与甘露醇或微晶纤维素）转化为干燥粉末。DSC 和 PXRD 研究表明，干燥后厄贝沙坦仍保持结晶状态。用厄贝沙坦纳米晶层积的微晶纤维素珠在溶出研究的前 10 分钟内显示出约 65%的药物溶出。含有厄贝沙坦纳米晶的甘露醇颗粒比微晶纤维素颗粒（即约 10 分钟内 46%的药物溶解）具有更快的溶出速度（即 10 分钟内 90%以上的药物溶解）。厄贝沙坦纳米晶混悬剂具有最快的溶出速率（即两分钟内超过 90%的药物溶解），其次是含有干燥厄贝沙坦纳米晶的甘露醇基颗粒（即十分钟内超过 90%的药物溶解）。
