蓓萨罗丁-聚乙烯吡咯烷酮共无定型物制备及在SD大鼠体内评价

蓓萨罗丁是一种新型维甲酸类似物,大量研究表明其具有神经保护作用。其晶I型的溶解度和生物利用度较低,严重限制了蓓萨罗丁的临床应用。本文首次制备蓓萨罗丁-聚乙烯吡咯烷酮共无定型物样品,基于X射线衍射及红外光谱分析表征了共无定型物结构。同时,利用LC-MS建立SD大鼠血浆及组织中蓓萨罗丁检测方法。体外溶出结果表明共无定型物使蓓萨罗丁在纯水中溶出度提高了4.17倍。SD大鼠分别给予30 mg·kg^-1蓓萨罗丁和共无定型物后,共无定型给药组的蓓萨罗丁血浆AUC从7 034.89μg·L^-1·h提高至10 174.03μg·L^-1·h,达峰时间从7.33 h显著提前至0.9 h,同时Cmax由627.76μg·L^-1显著提升至3 011.88μg·L^-1。各个组织中的蓓萨罗丁含量都有提升,其中以脑、肝和肾组织中提升最为显著。动物福利和实验过程均遵循中国医学科学院药物研究所动物伦理委员会的规定。结果表明蓓萨罗丁-聚乙烯吡咯烷酮共无定型物改变了原药药物代谢动力学特征,为蓓萨罗丁共无定型物治疗脑...

Preparation of a co-amorphous form of bexarotene-PVP-K30 and evaluation in rats

Bexarotene is a synthetic analogue of retinoic acid and exerts protective effects on the nervous system. However, low bioavailability and poor solubility of the crystal type I form severely limits the application of bexarotene in the clinic. A co-amorphous sample of bexarotene-PVP-K30 was prepared and the structure was characterized by X-ray diffraction and infrared spectroscopy. To determine the pharmacokinetics and tissue distribution of bexarotene, an LC-MS method was established to profile and quantify bexarotene in plasma and tissues of SD rats. In vitro dissolution indicated that the co-amorphous form improved the dissolution of bexarotene in pure water 4.17-fold. After rats were orally administered bexarotene or bexarotene-PVP-K30 co-amorphous(equivalent to 30 mg·kg^-1 bexarotene) the AUC of bexarotene was 7 034.89 and 10 174.03 μg·L^-1·h respectively,the peak time was advanced from 7.33 h to 0.9 h with the amorphous form, and Cmaxwas enhanced from 627.76 to3 011.88 μg·L^-1. The co-amorphous form yielded higher concentrations of bexarotene in various tissues, especially brain, liver and kidney. Animal welfare and experimental procedures complied with the rules of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Sciences. The results indicate that bexarotene-PVP-K30 co-amorphous improves the pharmacokinetic characteristics of bexarotene and provides preclinical data in support of bexarotene-PVP-K30 for the treatment of brain diseases.