| Genipin is an active compound, derived from iridoid glycosides-geniposidic (GENIPOSIDE) in the fruit of Gardenia. Genipin is also intestinal metabolite from geniposide, which plays the main role in vivo pharmacological activities. Genipin has been reported to have different effects such as antimicrobial, anti-tumor, anti-inflammatory, treatment of diabetes, hepatoprotective, and neurotrophic effects. Genipin may also have a significant effect as an anti-depressant through regulating gut microbes, energy metabolism and glycometabolism. In addition, genipin is applied to natural biomaterials as a novel crosslinking agent, with advantage of high biocompatibility and low cell toxicity. Thus, the various uses of genipin are increasingly researched. However, the application of genipin in oral administration is restricted as a result of poor aqueous solubility and low dissolution rate. These are the main barriers for the wide use of genipin in pharmaceutical formulations.In this research, we study a kind of an emulsion solvent evaporation method to prepare genipin nanocrystallized powder. The nanocrystallized drug can increase the specific surface area, promote the dissolution of drugs, thus improving water soluble drug, further improve the bioavailability of drug. In the design of optimizing the emulsion solvent evaporation processes, particle size plays an important role in screening optimal conditions of nanoparticles preparation. This paper mainly studies the kind and dosage of surfactant, the concentration of drug in organic phase, the volume ratio of water and organic phase, homogenates time and homogenate speed, homogenization pressure and times. Characteristics of nanocrystallized genipin such as the drug dissolution and drug bioavailability were studied. The research results are as follows:1According to the results of single-factor experiments above, the optimal conditions were as followed:5%o poloxamer188, volume ratio of water to organic phase of10/1,6homogenizations at a speed of10000rpm for1minute each at a pressure of600bar and proportion of genipin to mannitol of1/1.The subsequent characteristics of the optimum sample were obtained under these conditions.2The particle size of genipin freeze-dried powder(without mannitol) after dissolved with water was279.9nm. Mannitol was chosen as lyoprotectant, joined the amount of one time for drug content. The particle size of genipin freeze-dried powder after dissolved with water was59.8nm.3Under the optimal conditions, the optimal genipin nanoparticles were obtained with MPS of59.8nm. Furthermore, the FTIR analyse demonstrated that genipin nanoparticles had the same chemical structure as raw drug after the emulsion solvent evaporation process. The analysis results of XRD and DSC indicated that the prepared genipin nanoparticles were less crystalline. The residual amount of ethanol and chloroform were0.05318%and0.003883%, respectively, which were less than the ICH limit for class Ⅱ. In addition, the solubility of genipin nanoparticles was9.05times of the raw drug.4Residual Solvent Content Analysis:According to the regression equation, the residual ethanol content in genipin nanoparticles was0.05318%.The ICH limit, for ethanol in class Ⅱ solvents is5000ppm or0.5%, therefore, the genipin nanoparticles fully met the ICH requirements and was suitable for pharmaceutical use; According to the regression equation, the residual chloroform content in genipin nanoparticles was0.003883%. Since the ICH limit for chloroform in class Ⅱ solvents is60ppm or0.006%, the genipin nanoparticles met the ICH requirements and was suitable for pharmaceutical use.5Both genipin nanoparticles without mannitol and genipin nanoparticles showed a more rapid dissolution rate and solubility than raw genipin, especially genipin nanoparticles. The maximum solubility (approximately39.73mg·mL-1) was observed in genipin nanoparticles with an MPS of59.8nm at360min. The maximum solubility of genipin nanoparticles without mannitol was15.90mg·mL-1during the same period. However, the maximum solubility of raw genipin was only4.39mg·mL-1. At the beginning,19.1%,90.6%and93.4%of the drugs were dissolved from the raw genipin, genipin nanoparticles without mannitol and genipin nanoparticles, respectively. Both genipin nanoparticles reached to thier maximum solubility at the2nd minute, which was92.6%(genipin nanoparticles without mannitol) and97.2%(genipin nanoparticles), respectively. However, only56.1%of the raw genipin dissolved during the same period and the raw genipin reached to its maximum solubility after60minutes. Thus, the dissolution rate of genipin nanoparticles without mannitol and genipin nanoparticles were1.65and1.73times of the raw drug at the2nd minute, respectively. In accordance with Noyes-Whitney equation, the drug dissolution rate is linear relationship to the surface area exposed to the dissolution medium. The increased dissolution rate and solubility of genipin nanoparticles could be mainly attributed to the great reduction in particle size due to a greater surface area. Therefore, the less crystalline drugs in smaller size can exert their bioactivity efficiently because of their higher dissolution rate and solubility than the crystals.6The oral relative bioavailability of genipin nanoparticles powder was calculated by comparing the corresponding AUC values of the two groups, and the results demonstrated that oral administration of genipin nanoparticules leaded to799%increase in bioavailability. The significant enhancement of oral bioavailability was also in accordance with the result of the dissolution test and other characterization tests.Through the above experimental results, we proved the prepared genipin nanoparticles powder had uniform particle size distribution,Its physical and chemical properties was stability. The poorly soluble characteristic of original powder was significantly improved, thus improving its bioavailability. |
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