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Self-microemulsifying Drug Delivery System for Improved Oral Delivery of Limonene: Preparation, Characterization, in vitro and in vivo Evaluation

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Abstract

The current investigation aimed at formulating self-microemulsifying drug delivery system (SMEDDS) to ameliorate oral bioavailability of a hydrophobic functional ingredient, limonene. Solubility test, compatibility test, and pseudo-ternary phase diagrams (PTPD) were adopted to screen the optimal compositions of limonene-SMEDDS (L-SMEDDS). The characteristics of this system assessed in vitro, mainly included determination of particle size distribution, observation of morphology via transmission electron microscopy (TEM), testing of drug release in different dissolution media, and evaluation of stability. The oral bioavailability study in vivo of the formulated limonene was performed in rats with the free limonene as the reference. Compared with the free limonene, the distribution study of L-SMEDDS was conducted in Kunming mice after oral administration. The optimized SMEDDS (ethyl oleate, 14.2%; Cremophor EL, 28.6%; isopropanol, 28.6%; and loaded limonene, 28.6%) under the TEM (about 100 nm) was spherical with no significant variations in size/appearance for 30 days at 4, 25, and 60°C. In comparison with free limonene, higher than 89.0% of limonene was released from SMEDDS within 10 min in different dissolution media. An in vivo study showed a 3.71-fold improved oral bioavailability of the formulated limonene compared to the free limonene. The tissue distribution results showed that limonene predominantly accumulated in the various tissues for the L-SMEDDS compared with the free limonene. Hence, L-SMEDDS could remarkably improve the concentration of limonene in the various organs. These findings hinted that the oral bioavailability of limonene could be improved via an effectual delivery system like SMEDDS.

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Acknowledgements

The authors also thank the Jiangsu University Ethics Committee for the kind guidance in the animal experiments.

Funding

This work was supported by the National Natural Science Foundation of China (grants 81720108030 and 31871810), China Postdoctoral Science Foundation funded project (2015M571700), Research Foundation for Distinguished Scholars of Jiangsu University (15JDG074), and Key Laboratory financial support of Zhenjiang (SS2018004).

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  1. Yuan Zhu, Wen Xu and Jiajia Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, 212013, People’s Republic of China

    Yuan Zhu, Wen Xu, Jiajia Zhang, Youwu Liao, Caleb Kesse Firempong, Michael Adu-Frimpong, Wenwen Deng, Huiyun Zhang, Jiangnan Yu & Ximing Xu

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  1. Yuan Zhu
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  2. Wen Xu
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Contributions

Xi-Ming Xu and Jiang-nan Yu conceived and designed the research. Yuan Zhu and Jia-Jia Zhang performed the majority of the experiments and analyzed the data; Wen Xu wrote the manuscript. Caleb-Kesse Firempong, Youwu Liao, Huiyun Zhang, Michael Adu-Frimpong, and Wenwen Deng modified the manuscript.

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Correspondence to Ximing Xu.

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Zhu, Y., Xu, W., Zhang, J. et al. Self-microemulsifying Drug Delivery System for Improved Oral Delivery of Limonene: Preparation, Characterization, in vitro and in vivo Evaluation. AAPS PharmSciTech 20, 153 (2019). https://doi.org/10.1208/s12249-019-1361-8

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