Microenvironmental PH-modification Based Solid Dispersions Of Poorly Water-soluble And Ionizable GT0918

OBJECTIVE To improve the solution rate and oral absorption of the poorly water-soluble and ionizable model drug (GT0918), a pH-modified solid dispersion (pHM-SD) was designed and evaluated. METHODS Firstly, the ternary solid dispersion powder containing the model drug, polyvinylpyrrolidone (PVP k30) and pH-modifier at a1:2:2weight ratio, were prepared by a solvent evaporation method. Then the SD powders were blended with lactose (as a diluent), low-substituted hydroxypropylcellulose (L-HPC)(as a disintegrant) and magnesium stearate (as a lubricant) for5minutes. Samples of the resultant powder mixture were individually weighed and compressed into190mg tablets equivalent to25mg GT0918using a single punch machine with8.0mm diameter round punches and dies. The hardness was controlled at45±5N. Moreover, the dissolution behavior was investigated in different pH dissolution media to optimize the pH-modifier. Furthermore, to investigate the mechanism of solubility enhancement, the physical state of the model drug in solid dispersion were charactered by a scanning electron microscope, differential scanning calorimeter and X-ray diffraction pattern, respectively. Importantly, molecular interactions of drug and pH modifier were also investigated by the FT-IR spectra. Additionally, the microenvironment pH of tablets was detected by the coloration method. Finally, the in vivo performances of the ternary SD tablets were evaluated by beagle dogs. RESULTS The result of dissolution in vitro indicated that the drug in ternary SD based tablets got a fastest dissolution rate. And, dissolution rate of the drug from ternary SD based tablets were in a decreased order:citric acid, succinic acid, fumaric acid and cinnamic acid. The dissolution of the drug from ternary SD based tablets containing citric acid was almost70%within60mins, while, the dissolution of the drug from physical mixture based tablets was only10%. The study of physical state indicated that GT0918had a amorphous structure in the SD and the molecular interactions of citric acid and GT0918had been demonstrated by the FT-IR spectra. The pharmacokinetic experiment performed in beagle dogs indicted that the maximum plasma concentration Cmax of the ternary SD based tablets containing citric acid (5249.43±102.31ng/mL) was higher than that of the common tablet (2769.31±132.87ng/mL), and the peak time Tmax of the ternary SD based tablet (0.83±0.43h) was quiker than that of the common tablet (2.33±1.03h). The relative bioavailability of the ternary SD based tablet compared to common tablet is about126%. Conclusions the solution rate and oral absorption of the poorly water-soluble and ionizable model drug GT0918could be improved by using a microenvironmental pH-modification based solid dispersions approach. Interestingly, two main mechanisms of the pHM modified technology could be indicated by the presnt research. It can create a microenvironment around particles of the drug which can enhance the solubility of the drug. Meanwhile a interaction between the drug and pH-modifier may exist, which can make the drug in a stable physical stae thus improve the dissolution of the drug. However, because of the difference between in vitro and in vivo dissolution environment, it is the key point that design a dissolution environment in vitro which is more similar with the one in vivo.