Inclusion complexation of the anticancer drug pomalidomide with cyclodextrins: fast dissolution and improved solubility
Zoltán-István Szabó,
György Orbán,
Enikő Borbás,
Dóra Csicsák,
Szabina Kádár,
Béla Fiser,
Máté Dobó,
Péter Horváth,
Eszter Kiss,
Lívia Budai,
Judit Dobos,
Tamás Pálla,
László Őrfi,
Gergely Völgyi,
Gergő Tóth
Affiliations
Zoltán-István Szabó
Department of Pharmaceutical Industry and Management, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, Gh. Marinescu 38, RO-540139, Targu Mures, Romania
György Orbán
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Enikő Borbás
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rakpart 3., Budapest, H-1111, Hungary
Dóra Csicsák
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Szabina Kádár
Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Műegyetem rakpart 3., Budapest, H-1111, Hungary
Béla Fiser
Computational Molecular Design Research Group, Institute of Chemistry, Faculty of Materials Science and Engineering, University of Miskolc, H-3515, Egyetemváros-Miskolc, Hungary; Ferenc Rákóczi II. Transcarpathian Hungarian Institute, Beregszász, Transcarpathia, Ukraine
Máté Dobó
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Péter Horváth
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Eszter Kiss
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Lívia Budai
Department of Pharmaceutics, Semmelweis University, Hőgyes Endre u. 7, Budapest, H-1092 Hungary
Judit Dobos
Vichem Chemie Research Ltd, Hermann O. utca 15, H-1022, Budapest, Hungary
Tamás Pálla
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
László Őrfi
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary; Vichem Chemie Research Ltd, Hermann O. utca 15, H-1022, Budapest, Hungary
Gergely Völgyi
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary
Gergő Tóth
Department of Pharmaceutical Chemistry, Semmelweis University, Hőgyes E. u. 9, Budapest H-1092, Hungary; Corresponding author.
Pomalidomide (POM), a potent anticancer thalidomide analogue was characterized in terms of cyclodextrin complexation to improve its aqueous solubility and maintain its anti-angiogenic activity. The most promising cyclodextrin derivatives were selected by phase-solubility studies. From the investigated nine cyclodextrins – differing in cavity size, nature of substituents, degree of substitution and charge – the highest solubility increase was observed with sulfobutylether-β-cyclodextrin (SBE-β-CD). The inclusion complexation between POM and SBE-β-CD was further characterized with a wide variety of state-of-the-art analytical techniques, such as nuclear magnetic resonance spectroscopy (NMR), infrared spectroscopy (IR), circular dichroism spectroscopy, fluorescence spectroscopy as well as X-ray powder diffraction method (XRD). Job plot titration by NMR and the AL-type phase-solubility diagram indicated 1:1 stoichiometry in a liquid state. Complementary analytical methods were employed for the determination of the stability constant of the complex; the advantages and disadvantages of the different approaches are also discussed. Inclusion complex formation was also assessed by molecular modelling study. Solid state complexation in a 1:1 M ratio was carried out by lyophilization and investigated by IR and XRD. The complex exhibited fast-dissolution with immediate release of POM, when compared to the pure drug at acidic and neutral pH. Kinetic analysis of POM release from lyophilized complex shows that Korsmeyer-Peppas and Weibull model described the best the dissolution kinetics. The cytotoxicity of the complex was tested against the LP-1 human myeloma cell line which revealed that supramolecular interactions did not significantly affect the anti-cancer activity of the drug. Overall, our results suggest that the inclusion complexation of POM with SBE-β-CD could be a promising approach for developing more effective POM formulations with increased solubility.
