莲心碱的固体分散体与包合物的体外溶出度及大鼠药动学研究

Study on the Solubility in vitro of Liensinine Solid Dispersion and Liensinine Inclusion Compound and Rats Pharmacokinetics

目的:比较莲心碱的固体分散体与包合物的体外溶出度及其在大鼠体内的生物利用度。方法:分别制备莲心碱PVP(聚乙烯吡咯烷酮)-K30固体分散体和莲心碱羟丙基-β-环糊精(HP-β-CD)包合物,按《中国药典》桨法考察莲心碱原料药、固体分散体与包合物在0、10、20、30、40、50 min的体外溶出度。取12只SD大鼠随机均分为3组,分别ig给予莲心碱固体分散体、包合物、原料药混悬液(莲心碱的给药量均为8 mg/只);采用高效液相色谱法测定给药前与给药后5 min和0.25、0.5、1、1.5、2、3、4、6、8、10、24 h的血药浓度,用DAS 2.0软件计算药动学参数。对3种莲心碱样品的累积溶出度及药动学参数进行比较。结果:在45 min时莲心碱固体分散体、包合物与原料药的累积溶出度分别为88.02%、73.06%、18.60%。莲心碱固体分散体、包合物与原料药在大鼠体内的药动学参数分别为t1/2a(0.230±0.060)、(0.293±0.091)、(0.365±0.092)h,cmax(28.750±0.832)、(26.330±0.582)、(22.772±1.691)μg/ml,tmax(0.433±0.067)、(0.590±0.108)、(1.361±0.133)h,AUC0-24 h(606.701±34.512)、(489.800±29.181)、(343.900±16.311)μg·ml/h。三者给药后药动学特征均符合二室模型;固体分散体的cmax和AUC0-24 h均高于包合物(P<0.05)。结论:与原料药比较,将莲心碱制成固体分散体与包合物后均能提高其累积溶出度和大鼠体内的生物利用度;且固体分散体在大鼠体内的吸收速度更快,优于包合物。

OBJECTIVE： To compare the solubility in vitro of liensinine solid dispersion and inclusion compound and the rats＇ bioavailability in vivo. METHODS： Liensinine PVP-K30 solid dispersion and liensinine hydroxypropyl-β-cyclodextrin （HP-β-CD） inclusion compound were respectively prepared. Chinese Pharmacopoeia slurry method was used to detect the solubility in vitro of liensinine APIs, solid dispersion and inclusion compound at the time point of 0, 10, 20, 30, 40 and 50 min. 12 SD rats were ran- domly divided into 3 groups, which were respectively given liensinine solid dispersion, inclusion compound and APIs mixed sus- pension, ig; the dose of liensinine was 8 mg/case. HPLC was used to determine the plasma concentration at the time point of be- fore and 5 min and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24 h after administration; and the pharmacokinetic parameters were cal- culated by DAS2,0. The cumulative solubility and pharmacokinetic parameters were compared. RESULTS： The cumulative solubili- ty of liens^nine solid dispersion, inclusion compound and APIs were respectively 88.02%, 73.06% and 18.60% at the time point of 45 min. The pharmacokinetic parameters were respectively t1/2a as （0.230 ± 0.060）, （0,293 ± 0.091） and （0.365 ±0.092） h, Cmas （28.750 ± 0.832）, （26.330 ± 0.582） and （22.772 ± 1.691）μg/ml, tmax as （0.433 ±0.067）, （0.590 v 0.108） and （1.361v 0.133） h and AUC0-24h as （606.701 ± 34.512）, （489.800 ± 29.181） and （343.900 ± 16.311） μg. ml/h. The pharmacokinetic characteristics were in line with the two-compartment model and the Cmax and AUC02-24h of solid dispersion were higher than inclusion compound （P〈0.05）. CONCLUSIONS： Compared with APIs, the solid dispersion and inclusion compound of liens^nine can improve the cu- mulative solubility and rats＇ bioavailability in vivo. Solid dispersion is faster than inclusion compound in aspect of absorption rate.