Chair and Department of Pharmaceutical Technology, Faculty of Pharmacy, Poznan University of Medical Sciences, 6 Grunwaldzka Street, 60-780 Poznan, Poland.
Int J Mol Sci. 2021 Nov 17;22(22):12406. doi: 10.3390/ijms222212406.
Nanosizing is an approach to improve the dissolution rate of poorly soluble drugs. The first aim of this work was to develop nanosuspension of cilostazol with liquid antisolvent precipitation (LASP) and its combination with ultrasound. Second, to systematically study the effect of bottom-up processing factors on precipitated particles' size and identify the optimal settings for the best reduction. After solvent and stabilizer screening, in-depth process characterization and optimization was performed using Design of Experiments. The work discusses the influence of critical factors found with statistical analysis: feed concentration, stabilizer amount, stirring speed and ultrasound energy governed by time and amplitude. LASP alone only generated particle size of a few microns, but combination with ultrasound was successful in nanosizing (d10 = 0.06, d50 = 0.33, d90 = 1.45 µm). Micro- and nanosuspension's stability, particle morphology and solid state were studied. Nanosuspension displayed higher apparent solubility than equilibrium and superior dissolution rate over coarse cilostazol and microsuspension. A bottom-up method of precipitation-sonication was demonstrated to be a successful approach to improve the dissolution characteristics of poorly soluble, BCS class II drug cilostazol by reducing its particle size below micron scale, while retaining nanosuspension stability and unchanged crystalline form.
纳米化是一种提高难溶性药物溶解速率的方法。本工作的首要目标是开发西洛他唑的纳米混悬液，采用液相反溶剂沉淀（LASP）法及其与超声的联合应用。其次，系统研究底向上加工因素对沉淀颗粒粒径的影响，确定最佳条件以实现最佳减小效果。在筛选出溶剂和稳定剂后，使用实验设计进行深入的工艺特性研究和优化。本文讨论了通过统计分析发现的关键因素的影响：进料浓度、稳定剂用量、搅拌速度和超声能量（由时间和幅度控制）。单独使用 LASP 只能得到几微米的粒径，但与超声联合使用成功地实现了纳米化（d10 = 0.06，d50 = 0.33，d90 = 1.45 µm）。研究了微纳米混悬液的稳定性、颗粒形态和固体状态。纳米混悬液的表观溶解度高于平衡溶解度，且比粗西洛他唑和微混悬液具有更高的溶解速率。沉淀-超声的底向上方法被证明是一种成功的方法，可以通过将难溶性 BCS 类 II 药物西洛他唑的粒径减小到亚微米以下，同时保持纳米混悬液的稳定性和不变的晶体形态，来改善其溶解特性。
