Stability characterization, kinetics and mechanism of tacrolimus degradation in cyclodextrin solutions

• Published in: International Journal of Pharmaceutics
• Main Authors: Prajapati, Manisha, Eiríksson, Finnur Freyr, Loftsson, Thorsteinn
• Other Authors: Lyfjafræðideild (HÍ), Faculty of Pharmaceutical Sciences (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland
• Format: Article in Journal/Newspaper
• Language: English
• Published: Elsevier 2020
• Subjects: Cyclodextrins; Tacrolimus; Stability; Solubility; Kinetics; Sýklódextrín; Lyfjaefnafræði; Ferreira; Iceland
• Online Access: https://hdl.handle.net/20.500.11815/2458; https://doi.org/10.1016/j.ijpharm.2020.119579

Tacrolimus is a macrolide lactone and potent immunosuppressant. It is highly lipophilic and has very limited aqueous solubility. Tacrolimus is highly susceptible to hydrolysis which results in very limited stability in aqueous solutions. Besides this, tacrolimus also undergoes dehydration and epimerization. Cyclodextrin (CD) complexation can increase the solubility and stability of hydrophobic drugs in aqueous solutions through the formation of drug/CD complexes. The aim of this study was to investigate degradation kinetics, mechanism and stability of tacrolimus in aqueous CD solutions, with the ultimate goal of developing an aqueous vehicle for ophthalmic delivery. For this, phase-solubility and kinetic studies in aqueous solutions containing different CDs at different pH values were performed. Mass spectrometry studies were also performed to elucidate the degradation mechanism of the drug in aqueous CD solution. The study showed that the drug has maximum stability between pH 4 and 6 and hydrolysis was the main cause of tacrolimus degradation in aqueous 2-hydroxypropyl-βCD (HPβCD) solutions. βCD and its derivatives were the better CD solubilizers for tacrolimus. The solubility and stability studies were further conducted with CD and surfactants, which is tyloxapol, tween 80 and poloxamer 407, where the combination provided better results compared to individual components. This work was financially supported by the European Union grant no. MSCA-ITN-2017-765441 (transMed) and Faculty of Pharmaceutical Sciences, University of Iceland. Special thanks to Master students Ana Teresa Ferreira Nakov and Beatriz Maria Velez Alves for their help in the lab.