Nuijen B, Bouma M, Talsma H, Manada C, Jimeno J M, Lopez-Lazaro L, Bult A, Beijnen J H
Department of Pharmacy and Pharmacology, Slotervaart Hospital, The Netherlands Cancer Institute, Amsterdam.
Drug Dev Ind Pharm. 2001 Sep;27(8):767-80. doi: 10.1081/ddc-100107240.
Kahalalide F is a novel antitumor agent isolated from the marine mollusk Elysia rufescens; it has shown highly selective in vitro activity against androgen-independent prostate tumors. The purpose of this study was to develop a stable parenteral formulation of kahalalide F to be used in early clinical trials. Solubility and stability of kahalalide F were studied as a function of polysorbate 80 (0.1%-0.5% w/v) and citric acid monohydrate (15-15 mM) concentrations using an experimental design approach. Stabilities of kahalalide F lyophilized products containing crystalline (mannitol) or amorphous (sucrose) bulking agents were studied at +5 degrees C and +30 degrees C +/- 60% relative humidity (RH) in the dark. Lyophilized products were characterized by infrared (IR) spectroscopy and differential scanning calorimetry (DSC). Recovery studies after reconstitution of kahalalide F lyophilized product and further dilution in infusion fluid were carried out to select an optimal reconstitution vehicle. It was found that a combination of polysorbate 80 and citric acid monohydrate is necessary to solubilize kahalalide F. Lyophilized products were considerably less stable with increasing polysorbate 80 and citric acid monohydrate concentrations, with polysorbate 80 being the major effector. A combination of 0.1% w/v polysorbate 80 and 5 mM citric acid monohydrate was selected for further investigation. Lyophilized products containing sucrose as a hulking agent were more stable compared to the products containing mannitol. The glass transition temperature of the sucrose-based product was determined to be + 46 degrees C. The amorphous state of the product was confirmed by IR analysis. A solution composed of Cremophor EL, ethanol, and water for injection (5%/5%/90% v/v/v CEW, kept kahalalide F in solution after reconstitution andfurther dilution with 0.9% w/v sodium chloride (normal saline) to 1.5 microg/m. A stable lyophilized formulation was presented containing 100 microg of kahalalide F, 100 mg sucrose, 2.1 mg citric acid monohydrate, and 2mg polysorbate 80 to be reconstituted with a vehicle composed of 5%/5%/90% v/v/v CEW and to be diluted further using normal saline.
卡哈拉利德F是一种从海洋软体动物红海天牛中分离出的新型抗肿瘤药物；它已显示出对雄激素非依赖性前列腺肿瘤具有高度选择性的体外活性。本研究的目的是开发一种稳定的卡哈拉利德F肠胃外制剂，用于早期临床试验。采用实验设计方法，研究了聚山梨酯80（0.1%-0.5% w/v）和一水柠檬酸（15-15 mM）浓度对卡哈拉利德F溶解度和稳定性的影响。研究了含有结晶性（甘露醇）或无定形（蔗糖）填充剂的卡哈拉利德F冻干产品在+5℃和+30℃、相对湿度（RH）为+/-60%的黑暗条件下的稳定性。通过红外光谱（IR）和差示扫描量热法（DSC）对冻干产品进行表征。进行了卡哈拉利德F冻干产品复溶后再用输液稀释的回收率研究，以选择最佳的复溶载体。发现聚山梨酯80和一水柠檬酸的组合对于溶解卡哈拉利德F是必要的。随着聚山梨酯80和一水柠檬酸浓度的增加，冻干产品的稳定性显著降低，其中聚山梨酯80是主要影响因素。选择0.1% w/v聚山梨酯80和5 mM一水柠檬酸的组合进行进一步研究。与含有甘露醇的产品相比，含有蔗糖作为填充剂的冻干产品更稳定。基于蔗糖的产品的玻璃化转变温度测定为+46℃。通过红外分析证实了产品的无定形状态。由聚氧乙烯蓖麻油、乙醇和注射用水组成的溶液（5%/5%/90% v/v/v CEW），在复溶后并进一步用0.9% w/v氯化钠（生理盐水）稀释至1.5 μg/mL时，能使卡哈拉利德F保持在溶液中。提出了一种稳定的冻干制剂，其含有100 μg卡哈拉利德F、100 mg蔗糖、2.1 mg一水柠檬酸和2 mg聚山梨酯80，要用由5%/5%/90% v/v/v CEW组成的载体进行复溶，并进一步用生理盐水稀释。
