AAPS PharmSciTech

, 20:153 | Cite as

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

  • Yuan Zhu
  • Wen Xu
  • Jiajia Zhang
  • Youwu Liao
  • Caleb Kesse Firempong
  • Michael Adu-Frimpong
  • Wenwen Deng
  • Huiyun Zhang
  • Jiangnan Yu
  • Ximing XuEmail author
Research Article


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.


self-microemulsifying drug delivery system limonene in vitro release bioavailability in vivo distribution 



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

Authors’ Contribution

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.

Funding Information

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).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.


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Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Yuan Zhu
    • 1
  • Wen Xu
    • 1
  • Jiajia Zhang
    • 1
  • Youwu Liao
    • 1
  • Caleb Kesse Firempong
    • 1
  • Michael Adu-Frimpong
    • 1
  • Wenwen Deng
    • 1
  • Huiyun Zhang
    • 1
  • Jiangnan Yu
    • 1
  • Ximing Xu
    • 1
    Email author
  1. 1.Department of Pharmaceutics, School of Pharmacy, Center for Nano Drug/Gene Delivery and Tissue EngineeringJiangsu UniversityZhenjiangPeople’s Republic of China

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