An Investigation On Liver-targeting Microemulsion Of Norcantharidin

Extensive efforts have been conducted to stress investigation on effective anticancer drugs against hepatogenic cancer, hepatocirrhosis and hepatitis in recent years. It can improve eiBciency on liver-targeting that preparations with special carriers ,such as liposomes, microspheres, micrormulsions and so on. Microemulsions have become the hot subject of applied study in pharmacy domain and could improve the bioavailability of drug absorbed in vivo. The different types of microemulsion can transform each other in them with objective condition because of the changeable internal structure of microemulsion. The carrier potential of microemulsion formation has sparked great interest in a new pattern preparation. Such as the w/o microemulsion afford the unique possibility for the organism activities to localize in a intracellular conformation required to maintain their activities. In addition w/o microemulsion can be applied to the cell modeling film and prepare also superpartical for biological molecule. In recent years, the drugs were entrapped in microemulsion with microemulsion technology in pharmaceutic industry, and entered into the body by injection or oral administration. The high stability of microemulsion can extend quality deadline and accelerate diffusion and absorption. Therefore, the drug delivery systems of microemulsion offer considerable potential study for pharmaceutics industry.Microemulsions are thermodynamically stable, isotropic, transparent or semitransparent, microstructured solutions of surfactant,oil,and water which havecharacteristic dimensions of 10-100 ran. In the present work, microemulsion systems have been proposed to enhance the bioavailability of drugs and developed time-release, fast-release,and targeting administration. The present study in abroad are mostly the microemulsion preparations binding cytotoxic chemicals and LDL's acceptor by acceptor activity of low density lipoprotein(LDL)on the tumor cells being higher than normal tissue cell. The experiment showed that the affinity of tumor cell for microemulsion preparation was significantly higher than free drugs.Injection microemulsion can pass through micropore filter, stand heat pressure sterilization and possess lymphatic metastasis. In this study, we choosed biocompatible ethyl oleate as oil phase,soybean lecithin as surfactant,and having bioactivity ethanol as cosurfactant. The stability and condition for microemulsion formation were investigated.As lecithin is a naturally occurring nontoxic and safe material. Lecithin is slightly too lipophilic to spontaneously form the zero mean curvature lipid layers needed for balanced microemulsions, but different ways of adjusting the hydrophilic-lipophilic balance or spontaneous curvature can be envisaged. In the present study we achieved the formation of microemulsions by introducing short-chain alcohols,ethanol which have the effect of making the polar solvent less hydrophilic. Furthermore,these very weakly amphiphilic cosolvents will also be partially incorporated in the polar parts of the lipid layers,thereby both increasing the area per lipid polar head group,and thus changing the spontaneous curvature of the lipid layers from being slightly curved toward water to becoming more plannar or curved toward oil,and decreasing the stability of the lamellar liquid crystalline phase. We report here on the stability ranges of microemulsions in systems of soy bean lecithin,alcohol,water,and ethyl oleate as well as on the microemulsion preparation procedure.Microemulsions become thermodynamically stable systems,which are able to form spontaneously without requiring any additional external energy. Very often,thepresence of a cosurfactant,usuaUy an alcohol,is required to get an optimal formation,also for the purpose of reducing the amount of surfactant. We observed that stirring speed addition and extension time could decreace weighes of surfactant and cosurfactant^neanwhile,attention to addinning sequence and speed.In preparing procedures for microemulsion, in order to enhance liver targeting of norcantharidin microemulsion, we layed particular emphasis on viscosity,conductive rate^efractive rate,diameter size and doses of applied surfactants with considering physicochemicals of norcantharidin and pharmacology. Quality evaluation for microemulsion were studied by GC.What makes microemulsions fundamental in the pharmaceutical field,apart from their high stability and ease of preparation's their ability to increase considerably the bioavailability of sparingly water-soluble drugs and speed up the drug uptake by the living tissues as for loading process of a lipophilic drug into hydrophilic carriers. This great variety of applications gave rise to numerous studies on the microemulsions properties such as the mechanism ruling of the drug release. One of the most important properties of a microemulsion drug delivery system is the release profile,which describes how the drug diffuses out of the microemulsion carrier after administration,not only in close correlation to drug transport and metabolism in vivo but also profoundly reflecting the stability of microemulsion. The mechanism of drug release for microemulsion is very complicated. It is a very difficult to propose completely quantitative theoretical formula about drug release form microemulsions. A number of experiment methods for the determinative of release profiles from disperse systems have been used in the past. All have their advantages and disadvantages. Generally,drug release from microemulsion give inverse ratio with the stability of microemulsion. It can be obtained different types of drug release by adjusting osmotic pressur gradient inside and outside water phase. These models resemble the drug diffusion and drug release from polymer frame. The release rates are determined by surfactant types and concentration. In this paper,proposingexperimental study about drug release from microemulsions,evidences show the interaction between the drug and the surfactant micelles infers a index characteristic to the release kinetics.Norcantharidin(NCTD), a derivative of cantharidin> is one of the most effective anticancer drugs against hepatogenic cancer, hepatocirrhosis, hepatitis carrier, esophageal carcinoma, gastric carcinoma, breast cancer, lung cancer. One of the advantages of NCTD is that it can promote the growth of leukocyte, which is different from other anticancer drugs. However, the successful treatment with NCTD of conventional formulation remains difficult because of several pharmacokinetic and formulation factors that affect its disposition and toxicily, especially kidneys. The high concentration of NCTD was attributed to the presence of the renal damage. Despite its side effects, NCTD is still largely used in advanced life-threatening tumors because of its high efficacy and low cost.Based on the clinical fact that norcantharidin injection frequently causes urinary organ damnification, we prepared an alternative norcantharidin microemulsion to reduce the adverse effects of NCTD. NCTD is an either hydrophilic or lipophilic compound. The solubility of NCTD is very low in ethanol and cold water, but relatively high in acetone and warm water. To improve the therapeutic index and in vivo applications, the utilization of novel drug delivery systems holds great promise. In the present work, water-in-oil microemulsion (ME) systems have been developed using commercially available and pharmaceutically acceptable components. Lipid-based microemulsions have been proposed to enhance the bioavailability of drugs. In this study,we compare the pharmacokinetic characteristics of NCTD-loaded ME and NCTD injection and evaluate tissue distribution of NCTD for NCTD-loaded microemulsion and NCTD injection in mice.The levels of norcantharidin in plasma and tissues were determined using Gas chromatography. The liver area under the concentration-time curve (AUC)of norcantharidin-loaded microemulsion was 2-fold higher than that of norcantharidininjection after 0.5 h. It appeared that the circulation lifetime of norcantharidin-loaded microemulsion was longer than that of the drug in the injection. NCTD-loaded ME could also reduce the uptake by kidneys,which can decrease the side effects,such as renal toxicity, having been associated with NCTD iv injection. These results indicated that norcantharidin-loaded microemulsion had a good liver targeting efficiency in vivo. The microemulsion delivery systems configure pharmacokinetic profiles that differ from those of free drug. These differences are related to the characteristics of the vehicle, which affect the extent of the tissue distribution and thereafter the disposition profile and efficacy of the drug.The effects of biological reliability was not significance difference between NCTD ME and NCTD injection in vivo.