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Improved oral bioavailability of anticancer drug tamoxifen through complexation with water soluble cyclodextrins: in vitro and in vivo evaluation

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Abstract

Tamoxifen (TMX), a class II antiestrogen drug consistent with the biopharmaceutical classification system, shows low plasma levels leading to therapeutic failure as a result of poor aqueous solubility. Complexation with multifunctional excipients cyclodextrins (CDs) is an effective technique to increase the bioavailability of low water-soluble drugs in oral dosage forms. In this study, solid complexes were obtained with three cyclodextrins (methyl-beta-cyclodextrin (M-β-CD), hydroxypropyl-beta-cyclodextrin (HP-β-CD) and sulfobutyl ether β-cyclodextrin (SBE7-β-CD)) using co-lyophilization or kneading methods. Physicochemical characterization of solid complexes were performed by differential scanning calorimetry and Fourier transform infrared spectroscopy. The obtained results demonstrated that co-lyophilization method comprises stable inclusion complexes between TMX and cyclodextrins. Dissolution study exhibited that aqueous solubility of TMX was significantly enhanced by complexation with methyl-beta-CD. Consequently, tablet formulation using co-lyophilized complex of TMX and M-β-CD (1:1) with drug dose equivalent to 10 mg was prepared by direct compression method. 99% drug was released from the formulation at the end of 30 min. From the comparative results of dissolution study, it was found that the prepared formulation showed better release properties than commercial TMX tablets. Animal studies were performed with tablet formulation of TMX:M-β-CD and commercial tablet formulation administered to Sprague–Dawley rats by oral gavage. Peak concentration (Cmax) of tablet formulation containing TMX/M-β-CD inclusion complex in mice was efficaciously enhanced twofold over commercial tablet. In conclusion, complexation of TMX with M-β-CD gives a more effective tablet formulation with improved dissolution and enhanced oral bioavailability which can be promising for the formulation of tamoxifen.

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Acknowledgements

Alper B. Iskit has been supported by the Turkish Academy of Sciences, in the framework of the Young Scientist Award Program (EA-TUBA-GEBIP/2001-2-11).

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Authors and Affiliations

  1. Department of Pharmaceutical Technology, Faculty of Pharmacy, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey

    Nazlı Erdoğar & Erem Bilensoy

  2. Department of Analytical Chemistry, Faculty of Pharmacy, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey

    Emirhan Nemutlu

  3. Department of Pharmacology, Faculty of Medicine, Hacettepe University, 06100, Sıhhiye, Ankara, Turkey

    Alper B. İskit & S. Cihan Kara

  4. Division of Pharmacokinetics and Biopharmaceutics, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, 06330, Yenimahalle, Ankara, Turkey

    Zeynep Şafak Teksin

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  1. Nazlı Erdoğar
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Erdoğar, N., Nemutlu, E., İskit, A.B. et al. Improved oral bioavailability of anticancer drug tamoxifen through complexation with water soluble cyclodextrins: in vitro and in vivo evaluation. J Incl Phenom Macrocycl Chem 96, 81–91 (2020). https://doi.org/10.1007/s10847-019-00952-4

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