Sokač Katarina, Vrban Lucija, Liović Marin, Škorić Irena, Vianello Robert, Bregović Nikola, Žižek Krunoslav
University of Zagreb, Faculty of Chemical Engineering and Technology, Department of Mechanical and Thermal Process Engineering, Trg Marka Marulića 19, 10 000 Zagreb, Croatia.
Laboratory for the Computational Design and Synthesis of Functional Materials, Ruđer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia.
Int J Pharm. 2025 Apr 30;675:125552. doi: 10.1016/j.ijpharm.2025.125552. Epub 2025 Apr 3.
Dasatinib, a potent tyrosine kinase inhibitor, is widely used to treat chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, its poor aqueous solubility and high first-pass metabolism result in limited oral bioavailability and potentially severe side effects, such as cardiotoxicity, hepatotoxicity, and pulmonary complications, which are intensified by rapid concentration peaks in the bloodstream. To address these challenges, this study examines the development of a controlled-release formulation of dasatinib using cyclodextrins as macrocyclic receptors to form inclusion complexes. Cyclodextrins, known for their ability to form host-guest complexes, enhance drug solubility and stability while enabling controlled drug release and aligning with green chemistry principles when synthesized mechanochemically. Different solid-state and solution-based characterization methods confirmed successful complexation and drug amorphization. Additionally, molecular dynamics simulations provided valuable insights into the binding interactions between dasatinib and cyclodextrins in both gas-phase and aqueous medium, simulating experimental conditions in the absence of a solvent and a physiological environment. Formulated tablets exhibited enhanced solubility and improved in vitro release profiles, suggesting a potential reduction in adverse side effects and improved patient compliance. The results demonstrate the efficacy of cyclodextrins as carriers for dasatinib, highlighting their potential to improve the drug's therapeutic profile in leukemia treatment by facilitating a steady, controlled release and minimizing toxicity.
达沙替尼是一种强效酪氨酸激酶抑制剂，广泛用于治疗慢性髓性白血病和费城染色体阳性急性淋巴细胞白血病。然而，其水溶性差且首过代谢高，导致口服生物利用度有限，并可能产生严重的副作用，如心脏毒性、肝毒性和肺部并发症，而血流中快速的浓度峰值会加剧这些副作用。为应对这些挑战，本研究考察了以环糊精作为大环受体形成包合物来开发达沙替尼控释制剂的情况。环糊精以其形成主客体复合物的能力而闻名，它能提高药物的溶解度和稳定性，同时实现药物的控释，并且在机械化学合成时符合绿色化学原则。不同的固态和基于溶液的表征方法证实了包合作用的成功和药物的无定形化。此外，分子动力学模拟在气相和水介质中模拟了无溶剂和生理环境下的实验条件，为达沙替尼与环糊精之间的结合相互作用提供了有价值的见解。制成的片剂表现出溶解度增强和体外释放曲线改善，这表明副作用可能减少且患者依从性提高。结果证明了环糊精作为达沙替尼载体的有效性，突出了它们通过促进稳定、可控释放并使毒性最小化来改善白血病治疗中药物治疗效果的潜力。
