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Enhancement of dissolution and oral bioavailability by adjusting microenvironment pH in crocetin ternary solid dispersions: Optimization, characterization, in vitro evaluation, and pharmacokinetics

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Abstract

The most promising active ingredient of Crocus sativus L., crocetin (CCT), has been demonstrated to possess many biological activities. However, only a few studies have been conducted on CCT formulation, especially in oral formulation, mainly due to its insolubility in water, which limits its application for oral administration. This article reports an equilibrium saturation solubility and single-pass intestinal perfusion studies conducted to classify the biopharmaceutics classification system (BCS) of CCT. To enhance in vitro dissolution and in vivo oral bioavailability, ternary solid dispersions of CCT (CCT-SDs) with soluplus (SOL) as hydrophilic carrier and meglumine (MEG) as alkalizer were optimized using response surface methodology (RSM) with central composite design (CCD) experiments. Four different preparation methods were evaluated using the optimal formulation, including solvent evaporation, ball milling, spray drying, and freeze-drying. Prepared formulations were characterized by TG-DSC, FTIR, X-RPD, and SEM; the pharmacokinetic studies were performed in rats after oral administration. The cumulative dissolution rate of CCT-SDs containing SOL and MEG prepared by the ball milling method was 97.1% at 15 min and remained at 95.6% at 480 min, which was significantly higher than that of untreated CCT. The lower crystallinity, smaller particle size, and higher microenvironment pH (pHM) were observed in CCT-SDs prepared by the ball milling method. In vivo absorption of CCT-SDs (Cmax = 52.789 ± 12.441 μg/mL and AUC0-12 = 191.748 ± 35.043 μg/mL·h) was greater than untreated CCT (Cmax = 5.918 ± 1.388 μg/mL and AUC0-12 = 44.309 ± 7.264 μg/mL·h). In conclusion, the current study provides ternary solid dispersion formulation of CCT to increase the in vitro dissolution and in vivo bioavailability, which will benefit the commercial production and future clinical applications of CCT.

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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This research has been supported financially by the Key Research and Development Project of Zhejiang Province (No. 2022C03050) and the Science and Technology Research Project of Education Department of Jiangxi Province (No. GJJ171211).

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Author notes

  1. Zheren Tong and Xianyin Liu contributed equally to this work and are considered to be co-first authors.

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China

    Zheren Tong, Yi Tao, Peishi Feng, Xiaolu Jie & Ping Wang

  2. College of Pharmaceutical Sciences, Jiangxi Medical College, Shangrao, 334000, China

    Xianyin Liu, Fujia Luan & Zijin Xu

  3. Zhejiang Suichang Liming Pharmaceutical Co., LTD, Suichang, 323300, China

    Zhangfu Xie & Faxiang Pu

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Contributions

ZT: conceptualization, methodology, formal analysis, investigation, writing original draft. XL: methodology, formal analysis, investigation. YT: methodology, investigation. PF: methodology, investigation. FL: methodology, investigation. XJ: methodology, investigation. ZX: methodology, investigation. FP: methodology, investigation. ZX: conceptualization, formal analysis, writing—review and editing, project administration. PW: conceptualization, formal analysis, resources, writing—review and editing, supervision.

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Correspondence to Zijin Xu or Ping Wang.

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Tong, Z., Liu, X., Tao, Y. et al. Enhancement of dissolution and oral bioavailability by adjusting microenvironment pH in crocetin ternary solid dispersions: Optimization, characterization, in vitro evaluation, and pharmacokinetics. Drug Deliv. and Transl. Res. (2023). https://doi.org/10.1007/s13346-023-01497-3

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