Applications of Nanoparticles in HerbalMedicine: Zedoary Turmeric Oil andIts Active Compound ¯-Elemene

Meiwan Chen,a Shengpeng Wang,a Miao Tan and Yitao Wang

State Key Laboratory of Quality Research in Chinese Medicine

Institute of Chinese Medical Sciences

University of Macau, Macau, China

Abstract: Zedoary turmeric oil and its main active ingredient β-elemene are novel plant-derived anticancer agents with long-term clinical application history and low toxicity, whichhave been approved by the Chinese SFDA to treat different tumors including cancers of thebrain, ovary, prostate, breast, lungs, liver, colon, and other tissues. Unfortunately, theirhydrophobic properties, poor stabilities and low bioavailabilities seriously hamper theirapplications in clinic. Therefore, more attention should be paid to develop novel drugdelivery systems for zedoary turmeric oil and β-elemene to enhance their overall quality.Recently, increased research has been carried out on a nanoparticle drug delivery system ofzedoary turmeric oil and β-elemene to solve their poor aqueous solubilities and low bioa-vailabilities in vivo with much remarkable achievements springing up in the last decade. Thisreview presents the novel nanoparticle formulations of zedoary turmeric oil and β-elemeneand introduces the possible future prospects of their further study.

Keywords: Nanoparticle Drug Delivery of Systems; Zedoary Turmeric Oil; β-Elemene;Research Perspectives; Review.

Introduction

Zedoary turmeric oil, which is extracted from Curcuma phaeocaulis Valeton, Curcumakwangsiensis S. G. Lee et C. F. Liang, and Curcuma wenyujin Y. H. Chen et C. Ling, hasbeen linked to protection against liver injury, as well as reported anticancer, anti-throm-botic, and anti-virus effects (You et al., 2006; Sun et al., 2009a). Elemene, curcumol,curdione, germacrone, and pinene are marked as the main biological active components inzedoary turmeric oil. Elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane, Fig. 1) is

Correspondence to: Dr. Yitao Wang, Institute of Chinese Medical Sciences, University of Macau, Av. PadreTomas Pereira S.J., Taipa, Macau, China. E-mail: ytwang@umac.moaThese authors contributed equally to this work.

The American Journal of Chinese Medicine, Vol. 39, No. 6, 1093–1102© 2011 World Scientific Publishing Company

Institute for Advanced Research in Asian Science and MedicineDOI: 10.1142/S0192415X11009421

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an antitumor drug used for different tumors, including glioblastoma (Yao et al., 2008). Theextract of elemene is a mixture of �-, β-, and �-elemene, with β-elemene as the maincomponent, accounting for 60–72% of the three isoforms (Zhang et al., 2010b). Zedoaryturmeric oil and its active ingredient of β-elemene have been shown potent activity for theblockade of cell cycle progression, inducing cell cycle G2/M, G0/G1 arrest, andenhancement of the cytotoxicity effect of cisplatin, decetaxel and taxanes in many cancercells (Sun et al., 2009b). However, the clinical application of zedoary turmeric oil andβ-elemene has been limited by their hydrophobic properties, poor stability and low bioa-vailability, etc. So far, injections, freeze-dried powder, aerosol, and other formulations ofzedoary turmeric oil and β-elemene have been used in the treatment of cervical and livercancer owing to its capability to inhibit tumor proliferation, improve clinical symptoms andquality of life, prevent transfer recurrence, and enhance immune function. β-elemeneinjections, a wide spectrum anticancer drug with the main ingredient of β-elemene, havebeen manufactured by several pharmaceutical companies in China since 1995 (Peng et al.,2006). However, β-elemene injections have been reported as having side effects in clinicalapplications (Wang et al., 2006).

With the ongoing development of nanotechnologies, the novel delivery system ofzedoary turmeric oil and β-elemene has developed. The emergence of nanoscience, whichis the creation and utilization of materials and tools on the nanometer scale, has exerted adeep influence on numerous industries and particularly the pharmaceutical industry(Kumar, 2010). Increasing novel nanoparticulate formulations, such as liposome, micro-emulsion and microcapsules of zedoary turmeric oil and β-elemene have been focused and

Figure 1. Chemical structure of Elemene (1-methyl-1-vinyl-2,4-diisopropenyl-cyclohexane).

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will present a good perspective in their clinical applications. The application of thesenanoparticle formulations will deliver new approaches for enhancement of their solubility,stability, bioavailability, and pharmacological activity, and the ability to avoid physical andchemical degradation (Ajazuddin and Saraf, 2010).

In this review, we give an overview of the research progression for nanoparticle drugdelivery systems of zedoary turmeric oil and β-elemene including liposomes, micro-emulsion and microcapsules in recent years. It is expected that the research level willimprove and be a scientific foundation for further pharmaceutical studies on zedoaryturmeric oil and β-elemene.

Liposomes

Liposome as a novel drug delivery system has been used to improve the therapeuticactivity and safety of drugs for many years. Compared to the conventional formulations,liposome possesses the advantages of high biocompatibility, ease of preparation,chemical versatility, and simple modulation of pharmacokinetic properties by changingthe chemical composition of the bilayer components (Terreno et al., 2008). Up tonow, various traditional Chinese medicines (TCM) have been made into liposomes,including ginsenosides, tetrandrine, PNS (Panax notoginseng saponins), taxol, and others(Li et al., 2009).

For the formulation study, zedoary turmeric oil liposomes were prepared by a freezedrying method with a tertiary butyl alcohol-water cosolvent system and a single factortest (Yang et al., 2008). These liposomes were spherical with a mean diameter(457:3þ 7:8 nm), entrapment efficiency (92:2� 3:4%), the potential (�23.6 mV), and48 h accumulative release (94.1%). In order to reduce its irritation, prolong its circulationand improve its efficacy, β-elemene liposomes, such as PVP-coated liposomes (Zhanget al., 2006) and long-circulating liposomes (Liu and Li, 2010), were reported in recentyears. A number of studies have been published recently on the preparation methods,content determination, and pharmacokinetic profiles of β-elemene liposomes. Amongthese preparation methods, thin film hydration (TFH), reverse-phase evaporation(REV) and REV plus high-pressure extrusion are the most common techniques. Acomparison of these three methods showed that the diameter of β-elemene liposomeprepared by REV plus high pressure extrusion was smaller and more uniform, and theloading and the envelopment rate was higher than that using the traditional method(Huang et al., 2006).

For quality control of the zedoary turmeric oil and β-elemene liposomes, high per-formance liquid chromatography (HPLC) has been developed to determine β-elemene insterically stabilized liposome (Qi and Liang, 2008). The ultrafiltration-GC method isanother simple, accurate, sensitive, and applicable means to assay the content of zedoaryturmeric oil and β-elemene liposomes (Xie et al., 2009). Cheng et al. (2010) determinedthe contents of curcumol and zedoary turmeric oil (ZTO) in liposomes containingZTO by a HPLC analysis and a spectrophotometric analysis to evaluate their quality.The entrapment efficiency of ZTO was greater than of curcumol, but the yield efficiency

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of ZTO was less than that of curcumol in the liposomes containing ZTO. The percentageof curcumol in the ZTO would change in liposomes with different phospholipid pro-portions. The higher the phospholipid proportion, the higher percentage of curcumol inthe ZTO.

In addition, in vivo studies of β-elemene liposomes showed that its pharmacokineticprofiles changed significantly compared to the conventional forms. To investigate the tissuedistribution of β-elemene liposomes in rats, the HPLC method was established to determinethe drug concentration in plasma and tissue (Song et al., 2007). Compared to the controlgroup treated with elemene injections, β-elemene liposomes were distributed mainly in theliver, spleen, and kidney in rats after intravenous administration.

Solid Lipid Nanoparticles (SLN)

Solid lipid nanoparticles (SLN) are constructed from natural or synthetic lipid or lipoid,such as lecithin and triglycerides, which are solid at room temperature (Pardeike et al.,2009). The advantages of SLN include protecting labile compounds from chemicaldegradation, providing sustained release to improve the availability of the drug, andtargeting effect to improve the efficiency of the drug (Zhu et al., 2009).

Film ultrasonic wave dissolving techniques are an important method of preparation forSLN. Using this method, the optimum formula was selected using an orthogonal designtest to prepare β-elemene SLN: β-elemene (20�l), stearic acid (90mg), lecithin (90mg),Tween80 (2.5%, 5ml) and Poloxamer 188 (2.5%, 5ml) (Liu et al., 2007). Another methodis sonication and membrane extrusion (Wang et al., 2008). The result for the effects oftechnological factors on a mean particle size of β-elemene SLN show that sonicationstrength, total length of the sonication period, and preparation temperature can influencethe particle size.

SLN can be modified by folate receptors to achieve the targeted delivery of a drug totumor tissues. Wang et al. (2009) used the supersonic and membrane-extrusion methodto prepare a folate receptor-targeted SLN for β-elemene. In vivo study has shown thatfolate receptor-targeted SLN circulates in the blood for a longer time and reach higherconcentration in many tissues compared to common SLN.

Microcapsule

Microcapsule has been widely applied over the past decades. It is used not only in thefood-making and cosmetics industries, but also in biomedical fields such as drug delivery(Yow et al., 2009). Due to the protection and selective permeation properties of the semi-permeable membrane (Yu et al., 2010), microcapsule as a new form of drug delivery isgetting increased attention. The diameters of microcapsules can be reduced to between afew micrometers and a few millimeters.

Zedoary turmeric oil and β-elemene can be encapsulated in microcapsules to improvetheir therapeutic efficiency. Zhao et al. (2008) investigated the best formulation and

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technique to prepare zedoary turmeric oil microcapsules. The best weight ratio for AG(Acacia gum)/MD (maltodextrin) was 4:1, with 1ml of span-80, 40% DM, at a ratio ofcore to capsule wall material being 4ml:10 g. The best condition for a spray dry techniqueis inlet temperature at 160�C; feeding rate as 2.5ml/min; and aspiration as 100%. Thezedoary turmeric oil microcapsules prepared by established methods are round and fullwith a tight surface, the average size is 5.2�m and the ratio of embed (ER) can reach94.2% with a stable quality. Li et al. (2004) prepared β-elemene calcium alginate gelmicrospheres using the emulsification-internal gelatification technology and then reactedthem with chitosan to obtain calcium alginate-chitosan microcapsules. Their shape,diameter and size distribution were investigated with a confocal laser scanning microscopeand a laser diffraction particle size analyzer, respectively; the results showed uniformmembrane thickness and diameters.

Microspheres (Microballoon)

Microspheres with a diameter in micrometer range are small spherical particles,sometimes called microballoons. They can be manufactured from natural and syntheticmaterials and are characterized in terms of their size, morphology, and encapsulationefficiency.

Zhang et al. (2007) used the orthogonal method and the diameter of the microballoon,its distribution, drug bearing amount, envelop rate, etc. as the indexes to find the optimalpreparation technique for oleum curcumae wenchowensis. The microballoons were pre-pared according to the optimal technique parameters with an average drug-bearing rate of9.45%, envelop rate of 32.34%, average yield rate of 85.19%, and good reproducibility.Therefore, it was assumed that good appearance and the diameter conform to therequirement for hepatic artery embolism. In an in vitro study, the therapeutic effects ofhepatic artery infusion with compound zedoary turmeric oil microsphere on transplantedhepatoma in rats was carried out (Shi et al., 2009). In the treatment of transplantedhepatoma with hepatic artery infusion, the compound zedoary turmeric oil microsphere hadbetter antitumor activity when compared to the zedoary turmeric oil microsphere ormito-mycin microsphere, and will alleviate the abnormality of blood cell count caused bymitomycin.

Microemulsion and Self-Emulsifying Drug Delivery Systems (SEDDS)

Among the various drug delivery systems, the microemulsion system is considered an idealalternative for oral delivery of poor water-soluble compounds (Yin et al., 2009). The majoradvantages include ease of preparation, low viscosity, thermodynamic stability, enhanceddissolution of lipophilic drugs, and bioavailability improvement (Zhang et al., 2010a;Zoumpanioti et al., 2010). Self-emulsifying drug delivery systems (SEDDS) made up ofoils and surfactants, are ideally isotropic, sometimes including co-solvents, which candisperse in the aqueous environment of the gastrointestinal tract to form a fine oil-in-water

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emulsion that improves the oral bioavailability of poor water-soluble drugs (Zhao et al.,2010). It is easy to prepare and can enhance oral bioavailability of poorly absorbed drugs(Hong et al., 2006).

In recent years, elemene emulsion as the main application form of β-elemene has beenwidely used in clinical treatment for several malignant neoplasms, such as lung cancer,gastrointestinal cancer, gynecological cancer, breast cancer, and skin cancer (Ju et al.,2008). However, as a hydrophobic component with poor oral absorption and low bioa-vailability (Lin et al., 2010; Wang et al., 2011), practical applications of elemene emul-sions are still hindered. Hence, many studies have focused on the application ofmicroemulsion as a promising delivery of elemene to achieve sustained release in a tar-geted manner in vivo and thus improve its bioavailability. An elemene oil/water (o/w)microemulsion was prepared by mixing, and ultrasonication methods using elemene as theoil phase and the drug, polysorbate 80, as the surfactant, along with ethanol, propyleneglycol, and glycerol as the cosurfactants (Zeng et al., 2010). The study demonstrated thatthis elemene o/w microemulsion has good clarity, excellent stability, high entrapmentefficiency, and improved bioavailability. In addition, the optimum formulation with a goodapplicable prospect for zedoary turmeric oil SEDDS was composed of ZTO, Tween 80,ethyl oleate, and PEG 400 at the best ratio of 2.5:3:5:2 (Ding et al., 2007). The dissolutionof the optimum formulations of ZTO SEDDS in artificial gastric juice was >95% in 17minand higher than the self-prepared ZTO oil solution capsules; the particle size of ZTOSEDDS was 66.7 nm.

Submicron Emulsion

Submicron emulsion has received increased attention in several fields, including phar-maceutical, cosmetic and food (Nicolaos et al., 2003). At least two nearly immiscible fluidswere dispersed one into the other in the form of droplets with a diameter well below themicronform submicron emulsion system (Cortes-Munoz et al., 2009). This emulsion can beexpected to improve the uptake efficiency of lipophilic substances and be used as colloidaldrug carriers for various therapeutic applications (Grohganz et al., 2005).

Multiple parameters of steam sterilization according to mean droplet size, particle sizedistribution, and zeta potential were applied to identify and study the dispersed phase,the stabilizer, and the co-surfactant of the submicron emulsion of zedoary turmeric oil(Lin et al., 2007). The typical formulation is: zedoary turmeric oil 2.0%, purified soybeanoil 2.0%, purified egg yolk phospholipids 1.2%, purified oleic acid 0.04%, poloxamer1880.8%, and bidistilled water to 100ml. This submicron emulsion possesses a high loadcapacity of the drug and can stay stable under high temperature, pressure sterilization, andat room temperature for six months.

Emulsion phase inversion-ultrasound technology and high-pressure emulsionizingtechnology are two preparation methods for zedoary turmeric oil. Compared to the high-pressure emulsionizing technology, phase inversion-ultrasound technology is bothstable and easily prepared and does enhance the stability and targeting of a zedoaryturmeric oil submicron emulsion (You et al., 2008), since the particle diameter distributions

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and the drug content of the emulsion prepared by the this technology are lower andhigher, respectively.

Conclusion

Nanotechnology is an innovative method that can be used to solve many of the problemsassociated with zedoary turmeric oil and its active ingredient β-elemene. Increased researchhas been carried out on the nanoparticle drug delivery system of zedoary turmeric oil andβ-elemene to solve their hydrophobic properties, poor stability, and low bioavailability.Development of nanoparticle dosage forms of zedoary turmeric oil and β-elemeneincluding polymeric nanoparticles and nanocapsules, liposomes, solid lipid nanoparticles,and nanoemulsions, has many strengths and can have great influence on a number ofindustries, particularly the pharmaceutical industry (Fig. 2). Although the nanoparticledrug delivery systems for zedoary turmeric oil and β-elemene have achieved great progress,more attention should be paid to research the excipients and preparation technology toreduce their toxicity, enhance their activity, and provide more suitable dosage forms tosatisfy the needs of clinical application.

Figure 2. Nanoparticle formulation for zedoary turmeric oil and its active ingredient β-elemene.

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Acknowledgments

This study was supported by the Research Fund of the University of Macau (MYRG 208(Y1-L4)-ICMS11-WYT).

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