Sznitowska Malgorzata, Klunder Malgorzata, Placzek Marcin
Department of Pharmaceutical Technology, Medical University of Gdansk, Poland.
Chem Pharm Bull (Tokyo). 2008 Jan;56(1):70-4. doi: 10.1248/cpb.56.70.
The aim of this study was to find a biocompatible, lecithin-based carrier for paclitaxel (PTX) suitable for intravenous infusion and ensuring a soluble PTX concentration of 100 mg/100 ml or higher for at least 24 h. Aqueous dispersions of egg or soya lecithin (water-lecithin dispersions, WLD), mixed micellar (MM) solutions of egg lecithin and sodium deoxycholate, and formulations containing lecithin plus the co-surfactants and co-solvents poloxamer, polysorbate, Span, benzalkonium chloride, and macrogol were investigated. Amorphous PTX was prepared by lyophilization. PTX co-lyophilized with surfactants was also studied. Unlike crystalline PTX, the drug in an amorphous form is easily soluble in 1-5% (w/w) WLD or in MM. The highest solubility (up to 570 mg/100 ml) was achieved in 5% WLD. Dissolved PTX precipitated from all tested formulations over 24 h. Despite this, concentrations of dissolved PTX of 100 mg/100 ml or higher were observed after 24 h in 5% egg WLD, 1-5% soya WLD, and in 5% MM (lecithin : deoxycholate ratio 1 : 1 w/w). When four different batches of 5% egg WLD were prepared, containing PTX in clinically relevant concentration of 100 mg/100 ml, no precipitation of PTX was observed within 24 h and this formulation is the most promising candidate for further in vivo studies. Neither additional surfactants nor co-lyophilization increased PTX solubility in the lecithin-based carriers. The use of parenteral emulsions as solvents for the co-lyophilized PTX also failed to increase the solubility of the drug up to the target concentration.
本研究的目的是找到一种生物相容性好、基于卵磷脂的紫杉醇（PTX）载体，适用于静脉输注，并确保紫杉醇浓度在100 mg/100 ml或更高水平至少维持24小时。研究了鸡蛋卵磷脂或大豆卵磷脂的水分散体（水-卵磷脂分散体，WLD）、鸡蛋卵磷脂与脱氧胆酸钠的混合胶束（MM）溶液，以及含有卵磷脂加辅助表面活性剂和助溶剂泊洛沙姆、聚山梨酯、司盘、苯扎氯铵和聚乙二醇的制剂。通过冻干制备无定形紫杉醇。还研究了与表面活性剂共冻干的紫杉醇。与结晶型紫杉醇不同，无定形药物易溶于1-5%（w/w）的WLD或MM中。在5%的WLD中溶解度最高（可达570 mg/100 ml）。在所有测试制剂中，溶解的紫杉醇在24小时内均会沉淀。尽管如此，在24小时后，在5%的鸡蛋WLD、1-5%的大豆WLD和5%的MM（卵磷脂:脱氧胆酸钠比例为1:1 w/w）中观察到溶解的紫杉醇浓度达到100 mg/100 ml或更高。当制备四批不同的5%鸡蛋WLD，其中紫杉醇浓度为临床相关浓度100 mg/100 ml时，24小时内未观察到紫杉醇沉淀，该制剂是进一步体内研究最有前景的候选者。额外添加表面活性剂或共冻干均未提高紫杉醇在基于卵磷脂的载体中的溶解度。使用肠胃外乳剂作为共冻干紫杉醇的溶剂也未能将药物溶解度提高到目标浓度。
