| Curcumin is a natural active ingredient that extracted from the Carcuraa longa, and the other plants with the carcuma species. Curcumin had been widely used as pigment, food additives and spices, which proved to be sufficient and safe. In recent years, the research had shown that curcumin had extensive pharmacological effects, such as anti-tumor, improving cardiovascular function, anti-inflammatory, antiviral,liver protection, boosting immunity, etc. In spite of the good pharmacological activity and application prospects, the curcumin had the problems, such as hydrophobic, oral absorption, poor stability and low bioavailability in vivo,which exerted a serious influence on its clinical use.Cubic liquid crystalline nanoparticles (LCXP), was spontaneously formed by the amphiphilic lipids and surfactants in the water, which had lots of advantages, such as encapsulation of different polarity and dose of the drug, improvement of the stability of the drug against from the influence of the enzymes and the immune system, good biological affinity and adhesivity, the characteristic of drug controlled release, improvement of drug bioavailability, etc.This paper was aimed to improve the bioavailability of curcumin from two aspects:based on the piperine was natural inhibitors of glucuronic acid, the curcumin was used with piperine to decrease the biological transformation of curcumin in the body. For the low solubility in the water, poor stability, and low bioavailability, the curcumin with piperine cubic liquid crystalline nanoparticles was established. The content of the paper mainly included: physical and chemical properties of the compound curcumin, preparation and stability of compound curcumin lipid cubic liquid crystalline nanoparticles, characterization of structure, features of pharmaceutics, pharmacokinetic and the absorption mechanism of transmembrane and so on, details as below:1.The study on the physical and chemical properties and stability of the compound curcumin. High performance liquid chromatography (HPLC) method was established to determine the content of curcumin and piperine. And then, saturated solubility in organic solvent, apparent solubility and oil/water partition coefficient of the curcumin and piperine were investigated. The results showed that both curcumin and piperine were fat soluble drugs, and had the highest saturated solubility in the PEG400. The curcumin was insoluble in different pH phosphate buffer, and the solubility of piperine gradually improved with the increase of pH. From the study on the thermal stability of curcumin and piperine, the results showed that curcumin and piperine was not stable in water, but the content of drugs had no significant change in ethanol solution.2. Preparation and characterization of compound curcumin lipid cubic liquid crystalnanoparticles. On the basis of screening different coating rate measurement method of compound curcumin lipid cubic liquid crystalline nanoparticles, ethanol injection was selected for the preparation of the compound curcumin lipid cubic liquid crystalline nanoparticles.The influence of stirring temperature, speed, time and ultrasonic frequency on the encapsulation efficiency of the compound curcumin lipid cubic liquid crystalline nanoparticles was investigated by single factor experiment.the optimum preparation technology parameters of compound curcumin lipid cubic liquid crystalline nanoparticles were identified. Finally, the prescription process of compound curcumin lipid cubic liquid crystalline nanoparticles was also studied. With encapsulation efficiency and drug loadings as evaluation index, the prescription was optimized by using uniform design process, and compound curcumin lipid cubic liquid crystalline nanoparticles was achieved with the optimal encapsulation efficiency and drug loadings. And then the polarizing microscope,scanning electron microscopy, laser particle size instrument, small Angle X-ray scattering, infrared spectroscopy and differential scanning calorimetric analysis was adopted to the characterization of Compound curcumin lipid cubic liquid crystalline nanoparticles by the optical properties,morphology, crystalline structure, molecular interaction and heat changes.3. Characteristic study in pharmacy of Compound curcumin lipid cubic liquid crystalline nanoparticles. The research was conducted mainly including the pH value, leakage,the release rate in vitro,biological adhesion and stability of compound curcumin lipid cubic liquid crystalline nanoparticles. And the results showed that the pH and the leakage rate of compound curcumin lipid cubic liquid crystalline nanoparticles is relatively stable. Compared with the crude ingredients, compound curcumin lipid cubic liquid crystalline nanoparticles had better biological adhesion and stability and in terms of in vitro release, compound curcumin lipid cubic liquid crystalline nanoparticles had the feature of controlled release consistent with Higuchi equation, and would not be impacted by the pH and inorganic salt on the in vitro release.4. pharmacokinetic and tissue distribution in mice of compound curcumin lipid cubic liquid crystalline nanoparticles. The sample concentrations at different time points was conducted by atrioventricular model fitting using pharmacokinetic software, and the pharmacokinetic parameters of the best atrioventricular models was determined. According to the results of two groups of the drug, the blood and the tissues distributed in accordance with2rooms open model (C=Ae-αt+Be-βt). The peak concentration of compound curcumin lipid cubic liquid crystalline nanoparticles was significantly higher than the crude drug. and tmax was delayed as well. In addition, the relative bioavailability of compound curcumin lipid cubic liquid crystalline nanoparticles increased nearly by15times, which reached the expectation of the cubsomes. Compound curcumin lipid cubic liquid crystalline nanoparticles mainly distributed in the spleen, liver and lung tissues, especially the spleen. The tissue uptake rate increased by nearly20times compared to other groups.5. The absorption mechanism of compound curcumin cubic liquid crystal. Caco-2monolayer cell model was established and the effect on the cell survival rate of compound curcumin lipid cubic liquid crystalline nanoparticles was investigated to identify the range of the safe concentration. During the cell uptake test, we found that the intake of compound curcumin lipid cubic liquid crystalline nanoparticles gradually increased with the enhancement of concentration, however, the intake of the crude drug showed phenomenon of saturation. After joined verapamil, the intake rate of crude drug had increased to a certain extent. Finally, the influence of the different incubation time and verapamil on the cell membrane was consistent with the results above.In conclusion, the compound curcumin lipid cubic liquid crystalline nanoparticles was prepared by the ethanol precursor.The method proved to be high efficiency, stable, good reproducibility, quality controlled,and good biological adhesive. The compound curcumin lipid cubic liquid crystalline nanoparticles could obviously increase the bioavailability of curcumin in the body and achieve the aim of the trial. Meanwhile, it also provided a good reference to the other drugs for lipid cubic liquid crystalline nanoparticles.The innovation of the paper mainly including:1. The compound curcumin lipid cubic liquid crystalline nanoparticles was prepared for the first time, which not only solved water-soluble problem, poor stability and bioavailability of the curcumin and also provided a new idea for lipid cubic liquid crystalline nanoparticles as drug carrier.2. A variety of methods and technology was adopted for the evaluation in vivo and in vitro of compound curcumin lipid cubic liquid crystalline nanoparticles for the first time. The structure characterization of compound curcumin lipid cubic liquid crystalline nanoparticles was carried out by the spectroscopy, chromatography, DSC, SAXS, and so on. In addition, in vitro release, in vivo bioavailability, cell absorption and transport mechanism was also been studied systematically and comprehensively. |
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