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 −4 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 −1 , as also demonstrated by the Job’s plot, with an increase in DAS aqueous solubility of about 21 times in the presence of 6% w/v 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.

Dasatinib/HP-β-CD inclusion complex based aqueous formulation as a promising tool for the treatment of paediatric neuromuscular disorders

Cutrignelli, Annalisa
;
Sanarica, Francesca;Lopalco, Antonio;Lopedota, Angela;Laquintana, Valentino;Franco, Massimo;Boccanegra, Brigida;Mantuano, Paola;De Luca, Annamaria;Denora, Nunzio
2019

Abstract

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 −4 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 −1 , as also demonstrated by the Job’s plot, with an increase in DAS aqueous solubility of about 21 times in the presence of 6% w/v 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/227201
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