Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, Av. Ipiranga, 2752, CEP 90.610-000, Porto Alegre, RS, Brazil.
Eur J Pharm Sci. 2011 Feb 14;42(3):238-45. doi: 10.1016/j.ejps.2010.11.014. Epub 2010 Dec 2.
This study reports the development of nanoemulsions intended for intravenous administration of thalidomide (THD). The formulations were prepared by spontaneous emulsification method and optimized with respect to thalidomide (0.01-0.05%, w/w), and hydrophilic emulsifier (polysorbate 80; 0.5-4.0%, w/w) content. The formulations were evaluated concerning physical appearance and drug crystallization; droplet size; zeta potential and drug assay. Only the formulation containing 0.01% THD and 0.5% polysorbate kept its properties in a satisfactory range over the evaluated period (60 days), i.e. droplet size around 200nm, drug content around 95% and zeta potential around -30mV. The transmission electron microscopy revealed emulsion droplets almost spherical in shape confirming the results obtained by photon correlation spectroscopy. Drug crystallization observed for higher content (THD 0.05%, w/w) nanoemulsions was investigated. The crystals observed at optical microscopy presented a different crystal habit compared to that of the raw material used. It was speculated whether the kind of THD polymorph employed could influence nanoemulsion formulation. Formulations were prepared with either one of THD polymorphs (β- or α-) and crystals were characterized by fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). It was observed that regardless of the polymorph employed (β- or α-), drug crystallization occurs in the α-form. THD solubility in oils was not influenced by the polymorphic form. In addition, the in vitro dissolution profile of the selected formulation (THD 0.01%, w/w; polysorbate 0.5%, w/w) was assessed by bulk-equilibrium reverse dialysis sac technique and demonstrated a release profile similar to that of a THD acetonitrile solution, with around 95% THD being dissolved within 4h. Finally, a pharmacokinetic simulation of an intravenous infusion of 250mL of the selected nanoemulsion suggests that the parenteral administration of a dose as low as 25mg might lead to therapeutic plasma concentrations of thalidomide.
本研究报告了用于静脉注射沙利度胺（THD）的纳米乳剂的开发。该制剂通过自发乳化法制备，并针对 THD（0.01-0.05%，w/w）和亲水性乳化剂（聚山梨酯 80；0.5-4.0%，w/w）的含量进行了优化。制剂的物理外观和药物结晶、粒径、Zeta 电位和药物含量进行了评价。只有含有 0.01%THD 和 0.5%聚山梨酯 80 的制剂在评估期（60 天）内保持了其性质处于令人满意的范围内，即粒径约为 200nm，药物含量约为 95%，Zeta 电位约为-30mV。透射电子显微镜显示，乳化液滴呈近球形，证实了光子相关光谱法得到的结果。还研究了含有较高含量（THD 0.05%，w/w）纳米乳剂的药物结晶情况。光学显微镜下观察到的晶体与所用原料的晶体形态不同。推测所使用的 THD 多晶型物的种类是否会影响纳米乳剂的配方。使用 THD 的一种多晶型物（β-或 α-）制备了制剂，并通过傅里叶变换红外光谱（FTIR）和 X 射线衍射（XRD）对晶体进行了表征。结果表明，无论使用哪种多晶型物（β-或 α-），药物都会结晶成α-型。THD 在油中的溶解度不受多晶型物的影响。此外，通过 bulk-equilibrium 反向透析囊技术评估了选定制剂（THD 0.01%，w/w；聚山梨酯 0.5%，w/w）的体外溶解曲线，结果表明，该制剂的释放曲线与 THD 乙腈溶液的释放曲线相似，约 95%的 THD 在 4 小时内溶解。最后，对 250mL 选定纳米乳剂静脉输注的药代动力学模拟表明，低至 25mg 的给药剂量可能导致沙利度胺的治疗血浆浓度。
