Studies Of A Novel Drug Carrier Based On Lipid Emulion For Curcumin Intravenous Delivery

In recent years, the application of curcumin attracts more and more attention of pharmaceutical researchers. Curcumin, a naturally active constituent extracted from the plants of the Curcuma longa, has a variety of biological activities and pharmacological actions, such as anti-oxidation, anti-inflammatory, anti-tumor and anti-virus. To date, no studies either in animals or humans have discovered any toxicity associated with the use of curcumin even at very high doses. Despite the promising pharmacological effects and safety of curcumin, extremely low aqueous solubility and rapid metabolism result in very low oral systemic bioavailability, thus limiting its clinical use. Based on the structure of curcumin and foundation of our research group, we take a novel method to prepare curcumin lipid emulsion for intravenous injection. There are two parts in this formulation including curcumin PEG400solution and blank commercial lipid emulsion. Mix them together before clinical application.In this research, solubility and dispersed stability in lipid emulsion were measured as indexes, we choosed the PEG400as optimum injection vehicle, at the same time, investigated the stability of curcumin in curcumin PEG400solution during sterilization. The results showed that propylgallate as stabilitier could solve the problem of curcumin degradation. The preparation of curcumin lipid emulsion as follows:curcumin (100mg or200mg) was dissolved in PEG400(4mL) and the pH value of the solution was adjusted to3.0by appropriate amount of citric acid. Then the resulting curcumin PEG400solution (25or50mg/mL) was sterilized at121℃for15min and would be diluted with a commercially aqueous injectable lipid emulsion to form curcumin lipid emulsion (1.0or2.0mg/mL) prior to use. Based on the preparation of curcumin lipid emulsion, we evaluate the in vitro and in vivo characteristics of this novel lipid emulsion drug delivery system. Drug content, particle size and pH were measured as the stability indexes of curcumin lipid emulsion in the stability study. The results showed that the maximum stability time of1.0mg/mL and2.0mg/mL curcumin lipid emulsion was20h and14h, respectively. During the stability study, there were no significant changes and differences in terms of pH and particle size both of these two concentrations. Due to the preparation of curcumin lipid emulsion prior to use, the stability time of the two concentrations absolutely meets the clinical use. Secondly, the factors experiment, accelerated stability study and long term stability of curcumin PEG400were carried out according to Chinese pharmacopoeia. The results showed that under condition of high temperature and powerful light, the content of curcumin in curcumin PEG400solution reduced to different degrees. The above results pointed out that the application of curcumin PEG400should avoid high temperature and powerful light. In the study of accelerated stability study, and long term stability, the stability of curcumin PEG400solution is fine.Furthermore, the in vitro release of curcumin from curcumin lipid emulsion was carried out by dialysis membrane method. The results showed that, at the determined time intervals, the cumulative release was71.90±0.44%.The phase distribution of curcumin was detected in the three phases of emulsion system. The aqueous and oil phased of emulsions were separated by the methods of ultracentrifugation,then the distributions of drugs in aqueous and oil phase and O/W interface of emulsions were determined. The result showed that curcumin was mainly dissolved in the oil phase and O/W interface, there was a part of the curcumin distribution in water phase. With the increase of curcumin concentration, the curcumin distribution in the phase presented a certain differences.In order to investigate the metabolism and distribution of curcumin lipid emulsion in vivo, we studied the pharmacokinetics and tissue distribution. In pharmacokinetic study, we compared curcumin lipid emulsion pharmacokinetic parameters with curcumin-Injection’s. The results showed that curcumin lipid emulsion could prolong the CUR half-life in vivo, improve concentrations of curcumin in blood, increase AUC and so on. In the tissue distribution research, the results showed that curcumin mainly distributed in the liver and spleen, whereas less in other tissues distribution. The results told us that this formulation was more suitable for diseased organs of liver and spleen.Finally, based on the results of pharmacokinetics and tissue distribution, we studied effects of curcumin lipid emulsion on carbon tetrachloride-induced liver injury in rats. ALT and AST activity in the plasma, pathological biopsy of livers and various enzymes in oxidative stress condition as indexes, we evaluated the effects of curcumin lipid emulsion on carbon tetrachloride-induced liver injury. The results showed that curcumin lipid emulsion could suppress the activity of ALT and AST in plasma, elevate the activity of SOD and concentration of GSH in liver homogenates. reduce the concentration of MDA. From the results of histological examinations, every doses of curcumin lipid emulsion could ameliorate the injury of livers.Overall, this study evaluated the in vitro and in vivo characteristics of curcumin lipid emulsion. From the results of the study, we believe curcumin lipid emulsion will apply in clinic in the near future.