Scherlund M, Brodin A, Malmsten M
AstraZeneca R&D, SE-151 85, Sodertalje, Sweden.
Int J Pharm. 2000 Dec 15;211(1-2):37-49. doi: 10.1016/s0378-5173(00)00589-5.
A formulation consisting of a eutectic mixture of lidocaine and prilocaine, Lutrol((R)) F68 and Lutrol((R)) F127, suitable for anesthetizing the periodontal pocket has previously been developed. This consists of discrete micelles with a diameter of 20-30 nm and has a suitable gelation temperature, a good release profile and excellent long-term stability. In this study, the unimer/micelle transition and gel formation of the formulation, in its concentrated state, are investigated using differential scanning calorimetry (DSC), dye solubilization, rheology, and nuclear magnetic resonance (NMR) self-diffusion. The critical micellization temperature (cmt) and gelation temperature are found to be interconnected and influenced by cosolutes, such as electrolytes and hydrophobic substances, the latter as found particularly for the eutectic mixture of the local anesthetic agents lidocaine and prilocaine. Both cmt and the gelation temperature decrease with increasing pH of the system, i.e. at reduced solubility of the active ingredients. Moreover, both cmt and the gelation temperature increase upon diluting the system with water. The ratio between the two block copolymers present in the system also has an impact on both cmt and the gelation temperature, resulting in a decrease in onset temperature of both processes with an increase of Lutrol((R)) F127. The amount of the active ingredients present in the micelle phase depends on the pH of the system being approximately 0% w/w at pH 5, 50-60% w/w at pH 7.8 and 80% w/w at pH 9.
先前已开发出一种由利多卡因和丙胺卡因的低共熔混合物、聚氧乙烯蓖麻油((R))F68和聚氧乙烯蓖麻油((R))F127组成的制剂，适用于麻醉牙周袋。该制剂由直径为20 - 30纳米的离散胶束组成，具有合适的胶凝温度、良好的释放曲线和出色的长期稳定性。在本研究中，使用差示扫描量热法(DSC)、染料增溶、流变学和核磁共振(NMR)自扩散研究了该制剂在浓缩状态下的单分子/胶束转变和凝胶形成。发现临界胶束化温度(cmt)和胶凝温度相互关联，并受共溶质影响，如电解质和疏水物质，后者尤其见于局部麻醉剂利多卡因和丙胺卡因的低共熔混合物。cmt和胶凝温度均随体系pH值的升高而降低，即在活性成分溶解度降低时降低。此外，用水稀释体系时，cmt和胶凝温度均升高。体系中存在的两种嵌段共聚物的比例也对cmt和胶凝温度有影响，随着聚氧乙烯蓖麻油((R))F127的增加，这两个过程的起始温度均降低。胶束相中活性成分的量取决于体系的pH值，在pH 5时约为0% w/w，在pH 7.8时为50 - 60% w/w，在pH 9时为80% w/w。
