Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", 70125 Bari, Italy.
Unity of Pharmacology, Department of Pharmacy-Drug Sciences, University of Bari "Aldo Moro", 70125 Bari, Italy.
Int J Mol Sci. 2019 Jan 30;20(3):591. doi: 10.3390/ijms20030591.
New scientific findings have recently shown that dasatinib (DAS), the first-choice oral drug in the treatment of chronic myeloid leukemia (CML) for adult patients who are resistant or intolerant to imatinib, is also potentially useful in the paediatric age. Moreover, recent preclinical evidences suggest that this drug could be useful for the treatment of Duchenne muscular dystrophy, since it targets cSrc tyrosin kinase. Based on these considerations, the purpose of this work was to use the strategy of complexation with hydroxypropyl-β-cyclodextrin (HP-β-CD) in order to obtain an aqueous preparation of DAS, which is characterized by a low water solubility (6.49 × 10 mg/mL). Complexation studies demonstrated that HP-β-CD is able to form a stable host-guest inclusion complex with DAS with a 1:1 apparent formation constant of 922.13 M, as also demonstrated by the Job's plot, with an increase in DAS aqueous solubility of about 21 times in the presence of 6% / of HP-β-CD (0.014 mg/mL). The inclusion complex has been prepared in the solid state by lyophilization and characterized by Fourier Transform Infrared (FT-IR), Nuclear Magnetic Resonance (NMR), Differential Scanning Calorimetry (DSC) techniques, and its dissolution profile was studied at different pH values. Moreover, in view of potential use of DAS for Duchenne muscular dystrophy, the cytotoxic effect of the inclusion complex has been assessed on C2C12 cells, a murine muscle satellite cell line. In parallel, a one-week oral treatment was performed in wild type C57Bl/6J mice to test both palatability and the exposure levels of the new oral formulation of the compound. In conclusion, this new inclusion complex could allow the development of a liquid and solvent free formulation to be administered both orally and parenterally, especially in the case of an administration in paediatric age.
最近的新科学发现表明，达沙替尼（DAS）是治疗对伊马替尼耐药或不耐受的成人慢性髓性白血病（CML）的首选口服药物，对于儿科患者也可能有用。此外，最近的临床前证据表明，由于该药物可靶向 cSrc 酪氨酸激酶，因此它可用于治疗杜氏肌营养不良症。基于这些考虑，本工作的目的是使用与羟丙基-β-环糊精（HP-β-CD）的络合策略来获得 DAS 的水性制剂，其特征为低水溶性（6.49×10 mg/mL）。络合研究表明，HP-β-CD 能够与 DAS 形成稳定的主客体包合络合物，表观形成常数为 1:1，为 922.13 M，如 Job 图所示，在 6％/ HP-β-CD（0.014 mg/mL）存在下，DAS 的水溶解度增加约 21 倍。包合物已通过冻干法制备成固态，并通过傅里叶变换红外（FT-IR）、核磁共振（NMR）、差示扫描量热法（DSC）技术进行了表征，并研究了其在不同 pH 值下的溶解曲线。此外，鉴于 DAS 用于杜氏肌营养不良症的潜在用途，评估了包含复合物对 C2C12 细胞（一种鼠肌肉卫星细胞系）的细胞毒性作用。同时，在野生型 C57Bl/6J 小鼠中进行了为期一周的口服治疗，以测试新的口服化合物制剂的适口性和暴露水平。总之，这种新的包合物可以开发出一种液体和无溶剂制剂，可通过口服和肠胃外途径给药，特别是在儿科患者给药的情况下。
