Van Drooge D J, Hinrichs W L J, Frijlink H W
Department of Pharmaceutical Technology and Biopharmacy, Groningen University Institute of Drug Exploration, Antonius Deusinglaan 1, 9713AV Groningen, The Netherlands.
J Pharm Sci. 2004 Mar;93(3):713-25. doi: 10.1002/jps.10590.
In this study, a new and robust method was evaluated to prepare physically stable solid dispersions. Trehalose, sucrose, and two inulins having different chain lengths were used as carrier. Diazepam, nifedipine, Delta(9)-tetrahydrocannabinol, and cyclosporine A were used as model drugs. The sugar was dissolved in water and the drug in tertiary butyl alcohol (TBA). The two solutions were mixed in a 4/6 TBA/water volume ratio and subsequently freeze dried. Diazepam could be incorporated at drug loads up to 63% w/w. DSC measurements showed that, except in some sucrose dispersions, 97-100% of the diazepam was amorphous. In sucrose dispersions with high drug loads, about 10% of the diazepam had crystallised. After 60 days of exposure at 20 degrees C and 45% relative humidity (RH), diazepam remained fully amorphous in inulin dispersions, whereas in trehalose and sucrose crystallization of diazepam occurred. The excellent physical stability of inulin containing solid dispersions can be attributed to the high glass transition temperature (T(g)) of inulin. For the other drugs similar results were obtained. The residual amount of the low toxic TBA was only 0.1-0.5% w/w after freeze drying and exposure to 45% RH and 20 degrees C. Therefore, residual TBA will not cause any toxicity problems. This study provides a versatile technique, to produce solid dispersions. Inulin glasses are preferred because they provide an excellent physical stability of the incorporated amorphous lipophilic drugs.
在本研究中，对一种制备物理稳定固体分散体的新的稳健方法进行了评估。使用海藻糖、蔗糖和两种不同链长的菊粉作为载体。地西泮、硝苯地平、Δ⁹-四氢大麻酚和环孢素A用作模型药物。将糖溶解于水中，药物溶解于叔丁醇（TBA）中。将两种溶液按4/6的TBA/水体积比混合，随后进行冷冻干燥。地西泮的载药量可达63%（w/w）。差示扫描量热法（DSC）测量表明，除了一些蔗糖分散体，97 - 100%的地西泮为无定形。在高载药量的蔗糖分散体中，约10%的地西泮已经结晶。在20℃和45%相对湿度（RH）下放置60天后，地西泮在菊粉分散体中仍完全为无定形，而在海藻糖和蔗糖分散体中地西泮发生了结晶。含菊粉固体分散体优异的物理稳定性可归因于菊粉的高玻璃化转变温度（T(g)）。对于其他药物也获得了类似结果。冷冻干燥并暴露于45%RH和20℃后，低毒TBA的残留量仅为0.1 - 0.5%（w/w）。因此，残留的TBA不会引起任何毒性问题。本研究提供了一种制备固体分散体的通用技术。菊粉玻璃是优选的，因为它们能为包载的无定形亲脂性药物提供优异的物理稳定性。
