Grove Mette, Müllertz Anette, Nielsen Jeanet Løgsted, Pedersen Gitte Pommergaard
Pharmaceutical Formulation, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
Eur J Pharm Sci. 2006 Jun;28(3):233-42. doi: 10.1016/j.ejps.2006.02.005. Epub 2006 May 2.
By constructing ternary phase diagrams it was possible to identify two self-microemulsifying drug delivery systems (SMEDDS) containing either medium chain triglycerides (MC-SMEDDS) or long chain triglycerides (LC-SMEDDS), with the same ratio between lipid, surfactant and co-surfactant. The SMEDDS ended up having a composition of 25% lipid, 48% surfactant and 27% co-surfactant, MC-SMEDDS: viscoleo, cremophor RH40, akoline MCM and LC-SMEDDS: sesame oil, cremophor RH40, peceol. Upon dilution with water both SMEDDS resulted in clear to bluish transparent microemulsions with a narrow droplet size of 30nm. The industrial usefulness of the developed SMEDDS was evaluated with regard to bioavailability and chemical stability using the vitamin D analogue, seocalcitol, as model compound. The absorption and bioavailability of seocalcitol in rats were approximately 45% and 18%, respectively, from both the MC-SMEDDS and LC-SMEDDS indicating similar in vivo behavior of the two formulations, despite the difference in nature of lipid component. There was no improvement in bioavailability by the use of SMEDDS, compared to the bioavailability achieved from simple MCT and LCT solutions (22-24%) (Grove, M., Pedersen, G.P., Nielsen, J.L., Mullertz, A., 2005. Bioavailability of seocalcitol. I. Relating solubility in biorelevant media with oral bioavailability in rats-effect of medium and long chain triglycerides. J. Pharm. Sci. 94, 1830-1838.). After 3 months' storage at accelerated conditions (40 degrees C/75% RH), a decrease in concentration of seocalcitol of 10-11% was found in MC-SMEDDS and LC-SMEDDS compared with a degradation of less than 3% for the simple lipid solutions of MCT and LCT. In this study the simple lipid solutions seem to be a better choice compared with the developed SMEDDS due to a slightly higher bioavailability and a better chemical stability of seocalcitol.
通过构建三元相图，得以确定两种自微乳化药物递送系统（SMEDDS），一种含有中链甘油三酯（MC-SMEDDS），另一种含有长链甘油三酯（LC-SMEDDS），脂质、表面活性剂和助表面活性剂的比例相同。最终，SMEDDS的组成为25%脂质、48%表面活性剂和27%助表面活性剂，MC-SMEDDS：轻质液状石蜡、聚氧乙烯氢化蓖麻油RH40、肉豆蔻酰胆碱MCM，LC-SMEDDS：芝麻油、聚氧乙烯氢化蓖麻油RH40、油酸乙酯。用水稀释后，两种SMEDDS均形成澄清至微蓝色透明微乳液，液滴尺寸狭窄，为30nm。以维生素D类似物司骨化醇作为模型化合物，从生物利用度和化学稳定性方面评估了所开发SMEDDS的工业实用性。司骨化醇在大鼠体内的吸收和生物利用度，从MC-SMEDDS和LC-SMEDDS中分别约为45%和18%，这表明两种制剂在体内的行为相似，尽管脂质成分的性质有所不同。与简单的中链甘油三酯（MCT）和长链甘油三酯（LCT）溶液所达到的生物利用度（22 - 24%）相比，使用SMEDDS并未提高生物利用度（Grove, M., Pedersen, G.P., Nielsen, J.L., Mullertz, A., 2005.司骨化醇的生物利用度。I.生物相关介质中的溶解度与大鼠口服生物利用度的关系——中链和长链甘油三酯的影响。《药物科学杂志》94, 1830 - 1838）。在加速条件（40℃/75%相对湿度）下储存3个月后，发现MC-SMEDDS和LC-SMEDDS中司骨化醇的浓度降低了10 - 11%，而MCT和LCT的简单脂质溶液降解率小于3%。在本研究中，由于司骨化醇的生物利用度略高且化学稳定性更好，与所开发的SMEDDS相比，简单脂质溶液似乎是更好的选择。
