Solid lipid nanoparticles (SLN) is a new colloid drug delivery system, which simutanously combines the advantages of both polymer nanoparticles system and liposome system and avoids the disadvantages of them. The solid matrix of polymer nanoparticles could make the SLN system more stable. While the lipid carrier makes SLN physical tolerable, bio-compatible and less toxcic. SLN could improve the solubility of lipophlic compounds, protect drug from degradation or biotransformation and provide the sustained release of the drug. Curcumin is a polyphenol derived from Chinese herb Curcuma longa. It possesses diverse pharmacological activities, such as anti-oxidant, anti-inflammation and anti-cancer activities. Poor solubility and stability, rapid metabolism, biotransformation and systemic elimination attributed to the low bioavailability of curcumin and limits its clinical application. The purpose of this research is to encapsulate curcumin into SLN to improve its solubility and stability in aqueous system. Firstly, the parameters for preparation of SLN were optimized, including the concentration of lipid, surfactant, drug and lyophilized protectant. The morphology, physical stability and release profile of curcumin in the optimized formula of SLN were investigated. Subsequently, the anti-cancer effect of formulation was carried out on a human breast cancer cell line MCF-7. The intracellular uptake of curcumin in SLN was monitored by fluorescence microscrope. Finally, the pharmacokinetic profiles of curcumin in SLN in rats after intravenous administration was studied and compred to the unformulated drug. Based on the particle size, zeta potential and entrapment efficiency, an optimized formulation consisting of Dynasan 114®, Sefsol-218®, Pluronic F68®, drug (630∶70∶300∶8, mass ratio), mixture of sucrose and trehalose as lyophilized protectant and loaded with 0.8% drug was prepared. The The optimized lyophilized SLN could be re-dispersed into water with a spherical shape without apparent crystalline drug, mean particle size of 152.8±4.7 nm, high entrapment efficiency (~ 90%) and improved chemical stability in phosphate buffer and cell culture medium. The formulation exhibited a prolonged inhibition to MCF-7 cell but the inhibition rate was close to or lower than that of free drug. An time-depended intracellular uptake of curcumin in SLN could be observed under the fluorescence microscope. The bioavailability of curcumin in SLN was 124.92% to that of unformulated drug, and the elimination of curcumin in SLN was slower than unformulated drug after intravenous administration to rats. Conclusion：As a summary, a formulation of SLN containing Curcumin with improved drug dispersibility and stability in aqueous system has been successfully developed. The curcumin in SLN exhibited a prolonged inhibition to breast cancer cell and higher plasma concentration in rats than those of the free drug after intravenous administration. Key words: Solid lipid nanoparticles, Curcumin, Dissolution, Stability, Sustained release, Anti-cancer, Pharmacokinetics

固體脂質納米粒是一種相對較新的膠體給藥系統，可以看做是聚合物納米給 藥系統和脂質體給藥系統結合的產物，它兼具了二者優點，既有固體基質良好的 穩定性，又有脂質載體良好的生理耐受性和生物相容性。同時又避免了各自在應 用中的缺點，如脂質體穩定性問題和聚合物材料潛在的毒性。固體脂質納米粒可 以起到提高難溶藥物溶解性、防止藥物降解和使藥物達到緩釋的作用。 薑黃素是從中藥薑黃中提取出的一種多酚類化合物，具有廣泛的藥理活性， 如抗氧化、抗腫瘤、抗炎等。但它在水中的溶解度差、易降解、容易發生生物轉 化。它的低口服生物利用度和在生物體內快速的清除速率等成爲了限制薑黃素應 用的因素。本研究欲通過製備薑黃素固體脂質納米粒來解決上述薑黃素在應用中 存在的問題。 本研究首先建立了應用高壓乳勻法製備空白固體脂質納米粒的方法,並優化 了相關製備參數。通過單因素試驗，篩選了脂質種類、含量、乳化劑含量和投藥 量對製劑粒徑大小、分佈、表面電位，藥物包封率和體系穩定性的影響，優化了 薑黃素固體脂質納米粒處方。研究中還篩選了應用凍乾保護劑將脂質納米粒固化 的方法。製劑學性質方面,主要考察了製劑的形態、藥物在固體脂質納米粒中的 化學穩定性和藥物釋放。利用人乳癌細胞 MCF-7，在體外比較了原藥和製劑的 體外抗腫瘤藥效,並通過螢光顯微鏡比較了細胞對原藥和製劑中藥物攝取的區 別。最後，研究還比較了靜脈注射製劑和原藥後大鼠體內的藥動學行為。 結果表明，本研究成功製備了薑黃素固體脂質納米粒，优化后的处方含有固 體脂質 Dynasan 114®，液態脂質 Sefsol-218®，乳化劑 Pluronic F68®和凍乾保護 劑蔗糖和海藻糖混合物。粒徑為 152.8±4.7 nm、分佈均勻、包封率在 90%以上、 物理性質穩定的薑黃素固體脂質納米粒，其凍乾製劑可以在水中複分散。納米粒 水溶液在透射電子顯微鏡下呈圓形或類圓形,分散均勻，無明顯藥物結晶。和原 藥相比，製劑顯著提高了薑黃素在磷酸緩衝溶液和細胞培養液中的穩定性。在 pH=7.4 的磷酸緩衝液中，製劑中藥物呈緩釋行為。體外細胞實驗表明，雖然製 劑對腫瘤的抑制率不如或和遊離原藥相近，但體現了對腫瘤細胞更長時間的持續 抑制作用。製劑中薑黃素可以被腫瘤細胞攝取，攝取量隨孵育時間延長而增加。 藥動學實驗表明，靜脈注射後，製劑在大鼠體內生物利用度是原藥的 124.92%， 製劑在體內的清除率慢於原藥。 結論：本研究成功製備了薑黃素固體脂質納米粒，改善了薑黃素在水中的分 散性和穩定性。製劑表現出持續的腫瘤抑製作用，靜脈注射在大鼠體內的血藥濃 度高於原藥。 關鍵詞：固體脂質納米粒；薑黃素；溶出度，穩定性；緩釋；腫瘤抑制；藥物動 力學