Further enhanced dissolution and oral bioavailability of docetaxel by coamorphization with a natural P-gp inhibitor myricetin

The current study aims to improve the dissolution and oral bioavailability of a BCS IV drug docetaxel (DOC) by coamorphization with a natural P-gp inhibitor myricetin (MYR). A single-phase coamorphous form of DOC with MYR in a 1:1 molar ratio was prepared by solvent-evaporation method and characteri...

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Bibliographic Details
Published in:European journal of pharmaceutical sciences 2019-03, Vol.129, p.21-30
Main Authors: Wei, Yuanfeng, Zhou, Shengyan, Hao, Tianyun, Zhang, Jianjun, Gao, Yuan, Qian, Shuai
Format: Article
Language:English
Subjects:
Coamorphous
Dissolution
Docetaxel
Myricetin
Oral bioavailability
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Summary:The current study aims to improve the dissolution and oral bioavailability of a BCS IV drug docetaxel (DOC) by coamorphization with a natural P-gp inhibitor myricetin (MYR). A single-phase coamorphous form of DOC with MYR in a 1:1 molar ratio was prepared by solvent-evaporation method and characterized by differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction. In comparison to crystalline DOC, amorphous DOC showed similar equilibrium aqueous solubility, temporary improvement in the intrinsic dissolution rate (IDR) and supersaturated dissolution; while coamorphous DOC-MYR exhibited a persistent enhanced IDR and prolonged highly supersaturated dissolution. In addition, coamorphous DOC-MYR demonstrated significantly superior physical stability compared to amorphous DOC under the long-term storage condition and accelerated condition. Compared with oral administration of crystalline DOC to rats, amorphous DOC showed a significant increase in Cmax (2.6-fold) and a marginal increase in AUC (1.3-fold) of DOC; but coamorphous DOC-MYR performed a 3.9-fold higher Cmax and 3.1-fold higher AUC. In conclusion, coamorphization of DOC with MYR was a promising approach to enhance both dissolution and oral absorption of poorly soluble and permeable DOC. [Display omitted]
ISSN:0928-0987
1879-0720
DOI:10.1016/j.ejps.2018.12.016