Pharmaceutical and Analytical Development, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936, USA.
Int J Pharm. 2011 Oct 31;419(1-2):12-9. doi: 10.1016/j.ijpharm.2011.05.073. Epub 2011 Jul 22.
Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.
由于暴露在高温下，使用热熔挤出工艺制备对熔融降解的水溶性差的化合物的无定形固体分散体仍然是一个挑战。本研究的目的是开发一种对热敏感且在 165°C 熔融时降解的水溶性差的化合物 NVS981 的物理和化学稳定的无定形固体分散体。羟丙基甲基纤维素（HPMC）基聚合物；HPMC 3cps、HPMC 邻苯二甲酸酯（HPMCP）和 HPMC 乙酰琥珀酸酯（HPMCAS）被选择为载体，由于其相对较低的玻璃化转变温度，使用热熔挤出法制备固体分散体。比较了它们的制造难易程度、物理稳定性（如重结晶潜力、相分离、分子迁移率和药物溶解增强）。在每个聚合物系统中研究了两种不同的药物负载量 20%和 50%（w/w）。有趣的是，与所有三种载体中 20%（w/w）药物负载相比，50%（w/w）药物负载的固体分散体在熔融挤出机中更容易加工，这归因于药物的塑化行为。在加速稳定性条件下储存时，在较低和较高药物负载下，HPMC 3cps 和 HPMCAS 固体分散体中未观察到相分离，而对于 HPMCP，在较高药物负载下 3 个月后观察到相分离。通过研究在 pH 6.8 磷酸盐缓冲液中的药物溶解来评估这些固体分散体的药物性能。用于肠包衣的聚合物（即 HPMCP 和 HPMCAS）制备的固体分散体中的药物释放速度比水溶性聚合物 HPMC 3cps 更快。总之，在所研究的 3 种用于使用热熔挤出法制备热敏感化合物的固体分散体的聚合物中，HPMCAS 被发现是最有前途的，因为它易于加工，并提供了具有增强溶解的稳定固体分散体。
