Complexação do quimioterápico Docetaxel com Hidroxipropil- gama-ciclodextrina: uma estratégia para aumentar a solubilidade do fármaco

Abstract

Docetaxel (DTX), a chemotherapeutic agent of the taxane class, is recognized as an essential medicine by the World Health Organization (WHO) for the treatment of several types of cancer, including breast cancer. Classified as class IV in the biopharmaceutical classification system, DTX has low water solubility (6 μM) and limited bioavailability. Commercial formulations of DTX use a nonionic surfactant, polysorbate 80, in addition to ethanol to increase its solubility, which can exacerbate the side effects of chemotherapy. To address these limitations, this study explores the complexation of DTX with hydroxypropyl-gamma-cyclodextrin (HP-γ-CD), a promising strategy to improve drug solubility. The DTX:HP-γ-CD inclusion complex was prepared by the co-solubilization method followed by lyophilization, in a stoichiometric ratio of 1:2, with an equilibrium time of 6 hours. Characterization techniques such as scanning electron microscopy (SEM), differential scanning calorimetry (DSC), infrared spectroscopy (FTIR), X-ray diffraction (XRD), and field gradient diffusion nuclear magnetic resonance (1H-NMR) were used. The results revealed that complexation increased the aqueous solubility of DTX by approximately 25-fold (150 μM). DSC demonstrated the disappearance of the endothermic peak of DTX in the complex with HP-γ-CD. SEM micrographs indicated the loss of the crystalline structure of DTX upon complexation, confirmed by XRD, which revealed the loss of the crystalline pattern of the complexed DTX and changes in the dimensions of the complex (D=18.09, d=10.13, and h=8.07 Å) compared to pure HP-γ-CD (D=17.57, d=10.56, and h=8.96 Å). FTIR spectra showed shifts in the carbonyl bands of the drug, suggesting interactions between DTX and HP-γ-CD. 1H-NMR (DOSY) analysis indicated that 17% of DTX interacted with HP-γ-CD, with an intermediate affinity constant (Ka) of 746 L/mol. This study, the first to investigate the association of DTX with HP-γ-CD, suggests that the complex formed is a promising strategy to increase the aqueous solubility of the drug, with the potential to become a new pharmaceutical formulation with reduced side effects and greater therapeutic efficacy against cancer.