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

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.