[Preparation and in vitro quality evaluation of curcumin supersaturated self-nanoemulsion].

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.

Improvement of the bioavailability of curcumin by a supersaturatable self nanoemulsifying drug delivery system with incorporation of a hydrophilic polymer: in vitro and in vivo characterisation.

OBJECTIVES: The current study was focused on preparing curcumin (CUR) supersaturated self-nano-emulsion (PI-CUR-SNEDDS) using hydrophilic polymer and to study the influence of polymer precipitation inhibitor on the physicochemical and biopharmaceutical properties of the PI-CUR-SNEDDS. METHODS: PI-CUR-SNEDDS were prepared using hydrophilic polymer in order to maintain the supersaturation of CUR in nano-emulsion solution, artificial gastrointestinal fluid (AGF), and the precipitates formed, and characterised by in vitro dispersion tests, in vitro intestinal absorption and in vivo pharmacokinetic and compared with CUR-SNEDDS. KEY FINDINGS: PI-CUR-SNEDDS prepared with 2% hydroxypropyl methylcellulose 55-60 (HPMC55-60) as precipitation inhibitor (PI) significantly improved the viscosity, physical stability and CUR's equilibrium solubility of nanoemulsion. HPMC55-60 and CUR interact in AGF through intermolecular interactions, form hydrogen bonds, and produce amorphous precipitates. Compared with CUR-SNEDDS, the proportion of CUR in the hydrophilic phase increased by about 3-fold, and apparent permeability coefficient (Papp) in duodenum, jejunum, ileum, and colon increased by 2.30, 3.65, 1.54 and 2.08-fold, respectively, and the area under the plasma concentration-time curve0-12h of PI-CUR-SNEDDS also increased by 3.50-fold. CONCLUSIONS: Our results suggested that HPMC55-60 maintained the CUR supersaturation state by forming hydrogen bonds with CUR, increasing the solution's viscosity and drug solubilisation, thus improving the absorption and bioavailability of CUR.

Investigation on Correlation of Phase Behavior and Stability of Curcumin Self-nanoemulsion with Different Drug Loading After in Vitro Dispersion / 中国实验方剂学杂志

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%.

Preparation and in vitro quality evaluation of curcumin supersaturated self-nanoemulsion / 中国中药杂志

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.

Effect of existing form of curcumin on intestinal absorption after Cur-SNEDDS dispersion / 中草药

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.