Controlled release of dasatinib from cyclodextrin-based inclusion complexes by mechanochemistry: A computational and...

Area of Science:

• Pharmaceutical Sciences
• Drug Delivery Systems

Background:

• Dasatinib, a tyrosine kinase inhibitor, faces challenges with poor aqueous solubility and high first-pass metabolism, leading to limited bioavailability and potential toxicity.
• Rapid blood concentration peaks of dasatinib can intensify severe side effects like cardiotoxicity and hepatotoxicity.

Purpose of the Study:

• To develop a controlled-release formulation of dasatinib using cyclodextrins to enhance solubility and bioavailability.
• To investigate the potential of cyclodextrin inclusion complexes to mitigate dasatinib's adverse effects and improve therapeutic outcomes.

Main Methods:

• Formulation of dasatinib-cyclodextrin inclusion complexes using mechanochemical synthesis.
• Characterization of complexation and drug amorphization using solid-state and solution-based methods.
• Molecular dynamics simulations to elucidate dasatinib-cyclodextrin binding interactions.

Main Results:

• Successful complexation and amorphization of dasatinib with cyclodextrins were confirmed.
• Molecular dynamics simulations provided insights into drug-host interactions.
• Formulated tablets demonstrated enhanced solubility and improved in vitro drug release profiles.

Conclusions:

• Cyclodextrins effectively form inclusion complexes with dasatinib, enhancing its solubility and enabling controlled release.
• This formulation approach shows potential for reducing dasatinib's toxicity and improving its therapeutic efficacy in leukemia treatment.
• The study highlights cyclodextrins as promising carriers for improving the pharmacokinetic and safety profile of dasatinib.