PDF(Pubmed)
Abstract：
BACKGROUND: Pazopanib hydrochloride (PZB) is a protein kinase inhibitor approved by the United States Food and Drug Administration and European agencies for the treatment of renal cell carcinoma and other renal malignancies. However, it exhibits poor aqueous solubility and inconsistent oral drug absorption. In this regard, the current research work entails the development and evaluation of the extrudates of pazopanib hydrochloride by the hot-melt extrusion (HME) technique for solubility enhancement and augmenting oral bioavailability.
RESULTS: Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.
RESULTS: Solid dispersion of the drug was prepared using polymers such as Kollidon VA64, hydroxypropylmethylcellulose (HPMC), Eudragit EPO, and Affinisol 15LV in a 1:2 ratio by the HME process through a lab-scale 18 mm extruder. Systematic optimization of the formulation variables was carried out with the help of custom screening design (JMP Software by SAS, Version 14.0) to study the impact of polymer type and plasticizer level on the quality of extrudate processability by measuring the torque value, appearance, and disintegration time as the responses. The polymer blends containing Kollidon VA64 and Affinisol 15LV resulted in respective clear transparent extrudates, while Eudragit EPO and HPMC extrudates were found to be opaque white and brownish, respectively. Furthermore, evaluation of the impact of process parameters such as screw rpm and barrel temperature was measured using a definitive screening design on the extrude appearance, torque, disintegration time, and dissolution profile. Based on the statistical outcomes, it can be concluded that barrel temperature has a significant impact on torque, disintegration time, and dissolution at 30 min, while screw speed has an insignificant impact on the response variables. Affinisol extrudates showed less moisture uptake and faster dissolution in comparison to Kollidon VA64 extrudates. Affinisol extrudates were evaluated for polymorphic stability up to a 3-month accelerated condition and found no recrystallization. PZB-Extrudates using the Affinisol polymer (Test formulation A) revealed significantly higher bioavailability (AUC) in comparison to the free Pazopanib drug and marketed formulation.
摘要：
背景：盐酸帕唑帕尼（PZB）是一种蛋白激酶抑制剂，已被美国食品和药物管理局和欧洲机构批准用于治疗肾细胞癌和其他肾脏恶性肿瘤。然而,它表现出差的水溶性和不一致的口服药物吸收。在这方面,目前的研究工作需要通过热熔挤出（HME）技术开发和评估盐酸帕唑帕尼的挤出物，以提高溶解度和增加口服生物利用度。
结果：使用诸如KollidonVA64，羟丙基甲基纤维素（HPMC），EudragitEPO,和Affinisol15LV以1:2的比例通过HME工艺通过实验室规模的18mm挤出机。借助自定义筛选设计（SAS的JMP软件，版本14.0）通过测量扭矩值来研究聚合物类型和增塑剂水平对挤出物加工性能质量的影响，外观,和崩解时间作为反应。含有KollidonVA64和Affinisol15LV的聚合物共混物产生相应的透明挤出物，虽然发现EudragitEPO和HPMC挤出物是不透明的白色和褐色，分别。此外，对工艺参数如螺杆转速和机筒温度的影响进行评估，使用确定的筛选设计对挤出物外观进行测量，扭矩,崩解时间,和溶解曲线。根据统计结果，可以得出结论，机筒温度对扭矩有显著影响，崩解时间,并在30分钟时溶解，而螺杆转速对响应变量影响不大。与KollidonVA64挤出物相比，Affinisol挤出物显示出较少的水分吸收和较快的溶解。在长达3个月的加速条件下，评估了Affinisol挤出物的多晶型稳定性，未发现重结晶。与游离帕唑帕尼药物和市售制剂相比,使用Affinisol聚合物的PZB-挤出物(测试制剂A)显示出显著更高的生物利用度(AUC)。
结果：使用诸如KollidonVA64，羟丙基甲基纤维素（HPMC），EudragitEPO,和Affinisol15LV以1:2的比例通过HME工艺通过实验室规模的18mm挤出机。借助自定义筛选设计（SAS的JMP软件，版本14.0）通过测量扭矩值来研究聚合物类型和增塑剂水平对挤出物加工性能质量的影响，外观,和崩解时间作为反应。含有KollidonVA64和Affinisol15LV的聚合物共混物产生相应的透明挤出物，虽然发现EudragitEPO和HPMC挤出物是不透明的白色和褐色，分别。此外，对工艺参数如螺杆转速和机筒温度的影响进行评估，使用确定的筛选设计对挤出物外观进行测量，扭矩,崩解时间,和溶解曲线。根据统计结果，可以得出结论，机筒温度对扭矩有显著影响，崩解时间,并在30分钟时溶解，而螺杆转速对响应变量影响不大。与KollidonVA64挤出物相比，Affinisol挤出物显示出较少的水分吸收和较快的溶解。在长达3个月的加速条件下，评估了Affinisol挤出物的多晶型稳定性，未发现重结晶。与游离帕唑帕尼药物和市售制剂相比,使用Affinisol聚合物的PZB-挤出物(测试制剂A)显示出显著更高的生物利用度(AUC)。
