酪氨酸激酶抑制剂(TKIs)作为慢性粒细胞白血病(CML)的靶向治疗有效,能选择性抑制BCR-ABL1激酶活性。TKIs联合治疗CML得到了体外支持,体内,和基于患者的数据,其中尼洛替尼-达沙替尼共同给药具有更高的细胞摄取,对化疗的抵抗力较低,并且没有遇到额外的不良事件。因此,有必要开发一种合适的分析方法来同时评估这些药物在开发的新型脂质纳米载体如脂质体中的含量。实验设计(DoE)已被实施为QbD的工具,以系统地研究HPLC方法属性和分析响应之间的关系,即,色谱检测,量化,达沙替尼和尼洛替尼的峰性质。构造了Ishikawa图,以描述分析性能的可能影响变量。之后,采用4因素2水平全因子设计(FFD)建模并确定初始风险评估后选择的因素之间的主要影响和交互影响。通过QbD分析优化色谱条件的建议设计空间在选定的药物浓度范围内是线性的,准确和精确,敏感,根据ICH指南和健壮的。最佳方法包括在25°C柱温下梯度模式下流动相(ACN和pH7.00的20mMKH2PO4)的流速为1mL/min,样品注射体积为20μL,检测波长固定在297nm。最重要的是,这种新的HPLC方法是简单和选择性足以评估在脂质纳米载体中的达沙替尼和尼罗替尼含量。
Tyrosine kinase inhibitors (TKIs) are effective as a targeted treatment for chronic myeloid leukemia (CML), which can selectively suppress BCR-ABL1 kinase activity. CML therapy with TKIs combination has been supported by in-vitro, in-vivo, and patient-based data where the nilotinib-dasatinib co-administration has exerted superior anticancer efficacy with greater cellular uptake, less resistance to chemotherapy, and no additive adverse events encountered. Therefore, it is essential to develop a suitable analytical method for the simultaneous estimation of these drugs in the developed novel lipid nanocarriers like liposomes. Design of Experiment (DoE) has been implemented as a tool of
QbD to systematically investigate the relation between the HPLC method attributes and analytical responses, i.e., chromatographic detection, quantification, and peak properties for dasatinib and nilotinib. An Ishikawa diagram is constructed to delineate possible influencing variables to the analytical performances. Afterward, 4 factors 2 level full factorial design (FFD) was employed to model and identify the main effects and interaction effects between the factors selected after the initial risk assessment. The suggested design space for optimized chromatographic conditions by
QbD analysis is linear within the selected range of drug concentrations, accurate and precise, sensitive, and robust according to the ICH guidelines. The optimal method is comprised of a 1 mL/min flow rate of mobile phase (ACN and 20 mM KH2PO4 of pH 7.00) in gradient mode at 25 °C column temperature for 20 μL sample injection volume and detection wavelength fixed at 297 nm. Most importantly, this novel HPLC method is simple and selective enough to evaluate dasatinib and nilotinib content in the lipid nanocarriers.