Formulation, Preparation and Evaluation of an Intravenous Emulsion Containing Brucea Javanica Oil and Coix Seed Oil for Anti-tumor Application
Biological and Pharmaceutical Bulletin
Fat emulsion is a special drug delivery system, which is employed to supply calories to patients or as a vehicle for lipid soluble drugs. Since the development of Intralipid ® as an intravenous nutrition emulsion in 1962, fat emulsions loaded drugs have also been studied in detail in the last 40 years for their inherent advantages such as sustained release and targeting applications in the endothelial system and mononuclear phagocyte system. In addition, intravenous emulsions are now widely
... in anticancer therapy because of the advantages described above. 1, 2) Malignant tumors are one of the most serious conditions posing a great threat to patients' lives. There are many commercially available anti-tumor drugs for their treatment. Brucea javanica oil emulsion (BJOE) and Coix seed oil emulsion (CSOE) have already been developed for antitumor clinical applications. 3) BJO is extracted from the nucleoli of Brucea javanica (L.) MERR. (Simaroubaceae) which is widely distributed from southeast Asia to northern Australia. 4) CSO is obtained from the seed of Coix lacryma-jobi L. var. mayuen STAPF by supercritical fluid extraction with CO 2 (SFECO 2 ). Both oleic acid and linoleic acid are the active components of BJO and CSO, and they play an important role in anti-tumor treatment. 5,6) BJOE and CSOE are used to treat primary malignant tumors, including lung cancer, liver cancer, gastric cancer, and breast cancer, because of their wide anti-tumor spectra and good therapeutic effects. They enhance immunocompetence and the effect of natural killer cells on tumor cells. As for CSOE, it has no adverse effects on heart, liver, kidney and hemopoietic system, which encourages improved patient compliance. Furthermore, the mechanism of anti-tumor activity had been thoroughly investigated for both oils. The anti-tumor effect of BJO involves inhibiting the synthesis of DNA, RNA and protein in tumor cells, inducing tumor apoptosis and reversing multidrug resistance, while the anti-tumor effect of CSO involves holding up caryocinesia in tumor cells, inducing tumor apoptosis, inhibiting the formation of new tumor vessels, influencing oncogene expression, modifying cytokine levels and reversing multidrug resistance. 7, 8) In this paper, the formulation and preparation of an intravenous emulsion involving combined BJO and CSO were systematically investigated. The combined use of BJO and CSO to prepare Brucea javanica oil and Coix seed oil emulsion (BCOE) showed the better therapeutic effect. The most valuable aspect of BCOE is that the use of a combined prescription of the two oils improves the anti-tumor activity of CSOE and increases the tolerated dose of BJO while clearly reducing its toxicity. Furthermore, pharmacokinetics and anti-tumor activity studies were also carried out. All the results obtained strongly supported the development of BCOE because of its improved anticancer effect and lower toxicity. The purpose of this study was to prepare and evaluate the intravenous emulsion (BCOE) containing Brucea javanica oil (BJO) and Coix seed oil (CSO), which is used in anti-tumor treatment. The formulation and preparation of BCOE were systematically investigated. High-pressure homogenization, particle size distribution, z z-potential and HPLC were carried out. The pharmacokinetics of the main component, oleic acid, and anti-tumor activity studies about the tumor growth inhibitory ratios (TGIR) and the mortality experiments were also employed to evaluate BCOE in vivo compared with BJO emulsion (BJOE) and CSO emulsion (CSOE) using S 180 sarcoma-bearing mice. The final BCOE formulation was 10% (w/v) oils with BJO and CSO 3 : 1, 0.6% (w/v) Lipid E 80, 0.3% (w/v) Pluronic F-68 (F-68), 0.1% (w/v) sodium oleate and 2.5% (w/v) glycerin in water. The preparation conditions involved 70°C for preparing the crude emulsion, 6 cycles for high-pressure homogenization at 500 bar, pH value was adjusted to 8.5 after high-pressure homogenization and 115°C for 30 min in a rotating water bath for sterilization. The pharmacokinetics parameters showed the combination of BJO and CSO may not influence the elimination of BCOE and have no significant difference between BCOE and BJOE or CSOE. The data of TGIR and mortality indicated that BCOE could increase the anti-tumor activity of CSOE and reduced the toxicity of BJOE. The mortality study (BCOE 0, BJOE 63.3%, CSOE 13.3%) showed that BCOE greatly reduced the toxicity of BJOE and CSOE. Therefore, the development and application of BCOE will make an important contribution to anti-tumor therapy.