Self-microemulsifying Drug Delivery System for Improved Oral Delivery of Limonene: Preparation, Characterization, in vitro and in vivo Evaluation
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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.
KEY WORDSself-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.
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.
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.
- 4.Hao C-W, Lai W-S, Ho C-T, Sheen L-Y. Antidepressant-like effect of lemon essential oil is through a modulation in the levels of norepinephrine, dopamine, and serotonin in mice: use of the tail suspension test. J Funct Foods. 2013;5:370–9. https://doi.org/10.1016/j.jff.2012.11.008.CrossRefGoogle Scholar
- 5.Lima NGPB, De Sousa DP, Pimenta FCF, Alves MF, De Souza FS, Macedo RO, et al. Anxiolytic-like activity and GC–MS analysis of (R)-(+)-limonene fragrance, a natural compound found in foods and plants. Pharmacol Biochem Behav. 2013;103:450–4. https://doi.org/10.1016/j.pbb.2012.09.005.CrossRefPubMedGoogle Scholar
- 7.Moraes TM, Kushima H, Moleiro FC, Santos RC, Machado Rocha LR, Marques MO, et al. Effects of limonene and essential oil from Citrus aurantium on gastric mucosa: role of prostaglandins and gastric mucus secretion. Chem Biol Interact. 2009;180:499–505. https://doi.org/10.1016/j.cbi.2009.04.006.CrossRefPubMedGoogle Scholar
- 10.Costa MDS, Rocha JE, Campina FF, Silva ARP, Da Cruz RP, Pereira RLS, et al. Comparative analysis of the antibacterial and drug-modulatory effect of Dlimonene alone and complexed with β-cyclodextrin. Eur J Pharm Sci. 2019;128:158–61. https://doi.org/10.1016/j.ejps.2018.11.036.CrossRefPubMedGoogle Scholar
- 13.Yeom DW, Son HY, Kim JH, Kim SR, Lee SG, Song SH, et al. Development of a solidified self-microemulsifying drug delivery system (S-SMEDDS) for atorvastatin calcium with improved dissolution and bioavailability. Int J Pharm. 2016;506(1–2):302–11. https://doi.org/10.1016/j.ijpharm.2016.04.059.CrossRefPubMedGoogle Scholar
- 22.Sermkaew N, Ketjinda W, Boonme P, Phadoongsombut N, Wiwattanapatapee R. Liquid and solid self-microemulsifying drug delivery systems for improving the oral bioavailability of andrographolide from a crude extract of Andrographis paniculata. Eur J Pharm Sci. 2013;50:459–66. https://doi.org/10.1016/j.ejps.2013.08.006.CrossRefPubMedGoogle Scholar
- 23.Nilsson U, Magnusson K, Karlberg O, Karlberg A-T. Are contact allergens stable in patch test preparations? Investigation of the degradation of d-limonene hydroperoxides in petrolatum. Contact Dermatitis. 1999;40:127–32. https://doi.org/10.1111/j.1600-0536.1999.tb06009.x.CrossRefPubMedGoogle Scholar
- 29.Kang JH, Oh DH, Oh Y-K, Yong CS, Choi H-G. Effects of solid carriers on the crystalline properties, dissolution and bioavailability of flurbiprofen in solid self-nanoemulsifying drug delivery system (solid SNEDDS). Eur J Pharm Biopharm. 2012;80:289–97. https://doi.org/10.1016/j.ejpb.2011.11.005.CrossRefPubMedGoogle Scholar
- 32.Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R, et al. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm. 2014;460:131–43. https://doi.org/10.1016/j.ijpharm.2013.10.055.CrossRefGoogle Scholar
- 33.Zhao Y, Wang C, Chow AHL, Ren K, Gong T, Zhang Z, et al. Self-nanoemulsifying drug delivery system (SNEDDS) for oral delivery of Zedoary essential oil: formulation and bioavailability studies. Int J Pharm. 2009;383(1–2):170–7. https://doi.org/10.1016/j.ijpharm.2009.08.035.CrossRefPubMedGoogle Scholar
- 41.Elgart A, Cherniakov I, Aldouby Y, Domb AJ, Hoffman A. Improved oral bioavailability of BCS class 2 compounds by self nano-emulsifying drug delivery systems (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm Res. 2013;30:3029–44. https://doi.org/10.1007/s11095-013-1063-y.CrossRefPubMedGoogle Scholar
- 42.Joshi RP, Negi G, Kumar A, Pawar YB, Munjal B, Bansal AK, et al. SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection. Nanomed-Nanotechnol. 2013;9:776–85. https://doi.org/10.1016/j.nano.2013.01.001.CrossRefGoogle Scholar