Paclitaxel/β-cyclodextrin complexes for hyperthermic peritoneal perfusion -: Formulation and stability
Paclitaxel/β-cyclodextrin complexes for hyperthermic peritoneal perfusion -: Formulation and stability
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DOI：
10.1016/j.ejpb.2006.11.025
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发表时间：
2007-06-01
影响因子：
4.9
通讯作者：
Vervaet, Chris
中科院分区：
文献类型：
--
作者：
Bouquet, Wim;Ceelen, Wirn;Vervaet, Chris
由于其低水溶性，紫杉醇目前配制在Cremophor EL（R）/乙醇混合物中。然而，该制剂的载体引起几种副作用。我们的目标是制定一个无表面活性剂和无溶剂的紫杉醇溶液，可用于热腹腔内化疗灌注程序（HIPEC）。研究了化学修饰的β-环糊精与紫杉醇形成复合物的潜力，作为增加紫杉醇水溶性的手段。显示甲基化β-CD（随机甲基化和2，6-二甲基化）。与磺丁基-醚-和羟丙基-β-CD相比，溶解紫杉醇的能力最好。产生100%包合效率的紫杉醇与随机甲基化-β-环糊精（RAME-β-CD）的最小比率为1/20（mol/mol）。通过冷冻干燥制备的紫杉醇/RAME-β-CD包合物在4 ℃下储存时稳定至少6个月。使用紫杉醇/RAME-β-CD-复合物配制5 mg/ml紫杉醇溶液。稀释这些溶液后，未观察到沉淀。在室温下储存24小时或在HIPEC条件（41.5 ℃）下储存2小时后，1/40（mol/mol）比率在0.1和0.5 mg/ml的紫杉醇浓度下显示出最高的稳定性。当将羟丙基甲基纤维素（HPMC）加入到复溶介质中时，稳定性显著增加，从而提供了减少制剂中RAME-β-CD的量的机会。(c)2006 Elsevier B. V.保留所有权利。
Due to its low aqueous solubility paclitaxel is currently formulated in a Cremophor EL (R)/ethanol mixture. However, the vehicle of this formulation causes several side-effects. Our objective was to formulate a tensioactive-free and solvent-free paclitaxel solution, which can be used for a hyperthermic intraperitoneal chemoperfusion procedure (HIPEC). The potential of chemically modified beta-cyclodextrins to form complexes with paclitaxel was investigated as a means to increase the aqueous solubility of paclitaxel. Methylated beta-CDs (randomly methylated and 2,6-dimethylated) showed. the best ability to solubilise paclitaxel compared to sulfobutyl-ether- and hydroxypropyl-beta-CD. The minimal ratio of paclitaxel versus randomly methylated-beta-cyclodextrin (RAME-beta-CD) yielding 100% inclusion efficiency was 1/20 (mol/mol). Paclitaxel/RAME-beta-CD inclusion complexes prepared via freeze drying were stable for at least 6 months when stored at 4 degrees C. A 5 mg/ml paclitaxel solution was formulated using paclitaxel/RAME-beta-CD-complexes. Upon dilution of these solutions, no precipitation was seen. After 24 h storage at room temperature or 2 h at HIPEC conditions (41.5 degrees C) the 1/40 (mol/mol) ratio showed the highest stability at paclitaxel concentrations of 0.1 and 0.5 mg/ml. When hydroxypropyl methylcellulose (HPMC) was added to the reconstitution medium, the stability significantly increased, offering the opportunity to reduce the amount of RAME-beta-CDs in the formulation. (c) 2006 Elsevier B.V. All rights reserved.