Ain-Ai Anchalee, Gupta Pardeep K
Department of Pharmaceutical Sciences, University of the Sciences in Philadelphia, 600 S, 43rd Street, Philadelphia, PA 19104, USA.
Int J Pharm. 2008 Mar 3;351(1-2):282-8. doi: 10.1016/j.ijpharm.2007.09.029. Epub 2007 Sep 29.
The objective of the present study is to formulate Naproxen nanosuspensions at high drug concentrations of up to 300 mg/ml using ball milling and is to investigate the additive effect between hydroxypropyl cellulose (HPC) and arginine hydrochloride as stabilizers. The nanosuspensions were obtained at different arginine hydrochloride/polymer weight ratios. Stability of Naproxen suspensions at 100 and 300 mg/ml was determined over a period of 14 days by measuring the particle size. The control, which contained only drug and buffers without the stabilizers agglomerated immediately after preparation. The study of the effect of arginine hydrochloride as a primary stabilizer indicated that arginine hydrochloride levels of up to 0.8% (w/v) were not able to help reduce particle size below one micron, and were also not able to provide stabilization to the suspensions on storage. Therefore, HPC was also added to the system to increase suspensions stability, presumably by a steric repulsion mechanism. When the Naproxen concentration was increased to 300 mg/ml, 1% (w/v) HPC was not able to provide good stabilization and it was found that arginine hydrochloride increased the stabilization efficiency of 1% (w/v) HPC by preventing flocculation. When HPC level was increased to 4% (w/v), HPC was high enough to sufficiently stabilize the nanosuspensions for 2 weeks and thereby could maintain the mean size diameter of the suspensions without the presence of arginine hydrochloride. Furthermore, stable nanosuspensions were successfully lyophilized without the use of additional cryoprotectants.
本研究的目的是使用球磨法制备药物浓度高达300mg/ml的萘普生纳米混悬液，并研究羟丙基纤维素（HPC）和盐酸精氨酸作为稳定剂之间的协同作用。在不同的盐酸精氨酸/聚合物重量比下获得纳米混悬液。通过测量粒径，在14天的时间内测定了100mg/ml和300mg/ml萘普生混悬液的稳定性。仅含有药物和缓冲液而没有稳定剂的对照制剂在制备后立即聚集。对盐酸精氨酸作为主要稳定剂的作用研究表明，高达0.8%（w/v）的盐酸精氨酸水平无法将粒径减小至1微米以下，也无法在储存时为混悬液提供稳定性。因此，向体系中加入HPC以提高混悬液稳定性，推测是通过空间排斥机制。当萘普生浓度增加到300mg/ml时，1%（w/v）的HPC无法提供良好的稳定性，并且发现盐酸精氨酸通过防止絮凝提高了1%（w/v）HPC的稳定效率。当HPC水平增加到4%（w/v）时，HPC足以使纳米混悬液稳定2周，从而在没有盐酸精氨酸的情况下也能维持混悬液的平均粒径。此外，在不使用额外冷冻保护剂的情况下成功冻干了稳定的纳米混悬液。
