Hou Hao, Siegel Ronald A
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharm Sci. 2006 Apr;95(4):896-905. doi: 10.1002/jps.20600.
The present work consists of studies of saturated and supersaturated solutions of diazepam (DZP) in [glycofurol (GF)/water] cosolvent systems, which are a potential dosage form for intranasal administration of DZP in rapid response to epileptic seizure emergencies. Equilibrium solubility of DZP increased in a convex manner with GF content, and also increased with temperature. Rapidly mixed supersaturated 40 mg/mL solutions displayed temporal stability, with long periods before onset of crystallization. Permeation of supersaturated DZP across polydimethylsiloxane (PDMS) membranes, chosen as an in vitro model for nasal mucosa, was shown to be well described by Theeuwes's transference equation, when DZP was formulated up to three times its solubility in a particular cosolvent vehicle. Transference and time lag were independent of vehicle composition, indicating that permeation enhancement was due virtually exclusively to enhanced driving force due to supersaturation. Implications of these results on potential intranasal DZP delivery systems based on supersaturation are discussed.
本研究工作包括对安定（DZP）在[聚乙二醇单甲醚（GF）/水]混合溶剂体系中的饱和溶液和过饱和溶液进行研究，该体系是一种用于鼻内给药DZP以快速应对癫痫发作紧急情况的潜在剂型。DZP的平衡溶解度随GF含量呈凸形增加，且也随温度升高而增加。快速混合的40 mg/mL过饱和溶液表现出时间稳定性，在结晶开始前有较长时间。当DZP在特定混合溶剂载体中的制剂浓度达到其溶解度的三倍时，过饱和DZP透过聚二甲基硅氧烷（PDMS）膜（选为鼻黏膜的体外模型）的渗透情况被证明可用Theeuwes迁移方程很好地描述。迁移和时滞与载体组成无关，这表明渗透增强几乎完全是由于过饱和导致驱动力增强。讨论了这些结果对基于过饱和的潜在鼻内DZP递送系统的影响。
