ABSTRACT
Objective:To investigate the relationship between phase behavior of curcumin （CUR） from self-nanoemulsion drug delivery system （SNEDDS） and stability of the formed nanoemulsion in artificial gastrointestinal fluid. Method:The growth rate of precipitation after dispersion of CUR-SNEDDS was expressed by the change tendency of CUR supersaturation-time curve. The effect of drug loading on crystal nucleation and growth was investigated by ultraviolet-visible spectrometry and polarized light microscope， respectively. X-ray powder diffraction （XRD） and differential scanning calorimetry （DSC） were used to analyze the precipitation forms of CUR-SNEDDS with different drug loading in artificial gastrointestinal fluid. At the same time， the effect of drug loading on the quality stability of nanoemulsion formed by CUR-SNEDDS in artificial gastrointestinal fluid was investigated. Result:In the artificial gastrointestinal fluid， with the increase of drug loading， the area under the supersaturation-time curve of CUR was increased （100% drug loading≈90% drug loading>75% drug loading）， the crystallization nucleation and growth rate were accelerated （100% drug loading>90% drug loading>75% drug loading）， the amorphous proportion in the precipitation composition decreased， the nanoemulsion droplets adhered and distributed unevenly， the particle size and dispersivity were increased. Conclusion:High drug loading promotes the nucleation and growth of crystals， and increases the proportion of crystal forms in the precipitation composition， which leads to the decrease in the stability of the formed nanoemulsion. Therefore， it is suggested that the drug loading of CUR-SNEDDS needs to be controlled below 90%.
ABSTRACT
Objective: To study the relationship between the drug form of curcumin self-nano-emulsion (Cur-SNEDDS) after being dispersed in artificial gastrointestinal fluid and intestinal absorption in rats. Methods: The change trend of curcumin concentration-time curve was used to express the change of precipitation growth. The content and existing form of precipitation were studied by polarized light microscope (PLMC), HPLC, UV full-wavelength (UV) scanning, X-ray powder diffraction (XRD), differential scanning calorimeter (DSC), infrared spectrum (FT-IR), Raman spectrum and nuclear magnetic resonance hydrogen spectrum (1H-NMR). At the same time, the rat valgus intestinal sac model was used to investigate the effect of SNEDDS on the apparent permeability coefficient (Papp) of curcumin. Results: The content of curcumin in the precipitation produced by Cur-SNEDDS dispersion was about 95% of that of curcumin API, and the chemical structure did not change, but the crystal form changed, resulting in amorphous precipitation. Curcumin intermolecular interaction occurred in the dispersion system, and hydrogen bonds were formed. Compared with curcumin, Cur-SNEDDS significantly increased the release rate and degree of curcumin in vitro, and enhanced the absorption of curcumin in duodenum, jejunum, ileum and colon, and the Papp value increased by 6.22, 12.97, 25.71 and 36.75 times, respectively. Conclusion: After Cur-SNEDDS dispersion, the crystal structure of curcumin is changed, which exists in free, amorphous and crystal form, so as to significantly improve the in vitro release and intestinal absorption of curcumin.
ABSTRACT
In order to improve the supersaturation and maintenance time of drug dispersion in curcumin self-nanoemulsion(CUR-SNEDDS), precipitation inhibitors(PPIs) were introduced to prepare curcumin supersaturated self-emulsion(CUR-SSNEDDS). The composition of CUR-SNEDDS prescriptions was selected through the solubility test, the compatibility of oil phase and surfactant, the investigation of the emulsifying ability of the surfactant and the drawing of the pseudo-ternary phase diagram. Analytic hierarchy process was used in combination with central composite design-response surface method to optimize the prescription. The type and dosage of precipitation inhibitors(PPIs) were selected to maintain the supersaturated concentration and duration of CUR in artificial gastrointestinal fluids. At the same time, polarizing microscope was used to evaluate the crystallization inhibition effect and the quality and in vitro release behavior of CUR-SSNEDDS. The prepared CUR-SSNEDDS prescription was capryol 90-kolliphor RH40-transcutol HP-Soluplus(7.93∶66.71∶25.36∶5), with the drug loading of(65.12±1.25) mg·g~(-1). CUR-SSNEDDS was transparent yellow, and the nanoemulsion droplets were spherical with uniform distribution. The emulsification time was(21.02±0.13) s, the average particle size was(57.03±0.35) nm, the polydispersity index(PDI) was(0.23 ± 0.01), and the Zeta potential was(-18.10±1.30) mV. CUR-SSNEDDS significantly inhibited the generation and growth of crystals after in vitro dilution. The supersaturation could be maintained above 10 within 2 h, and the dissolution rate and degree of CUR in artificial gastrointestinal fluid were significantly increased. Soluplus could effectively maintain the supersaturated state of CUR and enhance CUR dissolution in vitro.