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A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect

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Abstract

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.

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Abbreviations

SNEDDS:

Self-nanoemulsifying drug delivery system

HME:

Hot-melt extrusion

ZH:

Ziprasidone hydrochloride

BSC :

Biopharmaceutical classification system

ZH-SD:

Ziprasidone hydrochloride solid dispersion

ZH-PM:

Ziprasidone hydrochloride physical mixture

CCD:

Central composite design

NaAc-HAc:

Acetate buffered

RH:

Relative humidity

Q10:

Cumulative dissolution of drugs in 10 min

DC:

Drug content

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Authors and Affiliations

  1. Nanjing Tech University, Nanjing, Jiangsu Province, China

    Xu Xue, Guoguang Chen, Xiaoqing Xu, Jin Wang, Jingjing Wang & Lili Ren

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  1. Xu Xue
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  2. Guoguang Chen
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  3. Xiaoqing Xu
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Correspondence to Lili Ren.

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Xue, X., Chen, G., Xu, X. et al. A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect. AAPS PharmSciTech 20, 37 (2019). https://doi.org/10.1208/s12249-018-1216-8

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