冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体及其大鼠药动学评价

目的用冷冻干燥技术制备甲苯磺酸拉帕替尼固体分散体,以提高其生物利用度。方法以PVPS630和soluplus^■为载体,采用冷冻干燥法制备甲苯磺酸拉帕替尼固体分散体,通过SEM、DSC、XRPD等手段对固体分散体进行表征,通过表观溶解度、溶出度和大鼠体内药动学测定,评价固体分散体的增溶效果和生物利用度的改善情况。结果在相同药载比的条件下,PVPS630组的溶出度和表观溶解度均优于soluplus^■组。DSC、XRPD、SEM等表征结果显示,PVPS630为载体的固体分散体中,原料均以非晶态存在,而以soluplus^■为载体时,只有药载比为1∶3条件下,原料才呈现非晶态特征。大鼠药动学测定结果表明,固体分散体(甲苯磺酸拉帕替尼-PVPS630为1∶3)较上市药品AUC提高23.64%。结论载体PVPS630与甲苯磺酸拉帕替尼的相容性更理想;固体分散技术有助于本品提高生物利用度。

Preparation of Lapatinib Ditosylate Solid Dispersions by Freeze-drying Technology and Its Pharmacokinetic Evaluation in Rats

OBJECTIVE To improve lapatinib ditosylate''s bioavailability by preparation of its solid dispersion with freeze-drying mothod. METHODS The solid dispersion was prepared by freeze-drying method using PVPS630 and soluplus^® as carriers, respectively. The solid dispersion was characterized using SEM, DSC and XRPD. The apparent solubility, dissolution and pharmacokinetics in rats were determined to evaluate the solubilization effect and the improvement of bioavailability of the solid dispersion. RESULTS With the same drug loading ratio, the dissolution and solubility of the PVPS630 group were both better than those of the soluplus^® group. DSC, XRPD, SEM characterization results also exhibited that raw material was amorphous in all proportion groups when the carrier was PVPS630. While the raw material exhibited amorphous characteristic only when the drug loading ratio was 1:3 (lapatinib ditosylate-soluplus^®) in the soluplus^® groups. The results of rat pharmacokinetic showed that the AUC of solid dispersion (lapatinib ditosylate-PVPS630 1:3) was 23.64% higher than that of reference drug. CONCLUSION The compatibility of PVPS630 with lapatinib ditosylate is better than soluplus^®; and the solid dispersion technology is useful to improve the bioavailability of lapatinib ditosylate.