Study On Preparation And Formulation For Improve Drug Dissolution

Low water solubility was one of the major obstacles faced by many candidate pharmaceutical reparations and their development process,the clinical development and application are limited by its low water solubility.Nanosuspensions and solid dispersions are considered to be effective methods to increase the solubility of poorly soluble drugs.In this study,two-step method was used to improved the solubility of drugs.Preparation of high-efficiency solubilizing drugs by amorphous solid dispersion combined with nanotechnology.The combination of small particle size and amorphous solid state in the system was used to generate a synergistic effect on the dissolution of drugs,significantly improving the dissolution of insoluble drugs.In this study,polyvinylpyrrolidone（PVP）and hydroxypropyl methylcellulose（HPMC）were used as stabilizers,rotary evaporation combined with wet bead milling（WBM）/high pressure homogenization（HPH）was used to improve the solubility of drugs.The polymer type and proportion on the microstructure morphology,intermolecular interaction form,particle size reduction rate,solid state and the dissolution value of drugs were investigated,the parameters in the preparation process were optimized.The solid dispersion of PVP and HPMC were partially or fully amorphous and the drug formed hydrogen bond with the polymer.Response surface methodology was used to screen the optimal conditions for high pressure homogenization: drug concentration 2%,pressure 1500 bar,and 20 cycles.The different combined methods（rotary evaporation+WBM/HPH）had no significant effect on the dissolution of the nanosuspension.The concentration of polymer had no significant effect on the stability of amorphous solid state.However,the type of polymer significantly affected the stability of amorphous solid state in the process of reduction particle size.Besides,the concentration of polymer had no significant effect on the particle size reduction rate and the amorphous stability.However,the type of polymer significantly affected the amorphous stability.When PVP was used as stabilizer,the dissolution value of indomethacin nanosuspension prepared by two-step method could reached more than 85%,which proved that relatively small particle size and amorphous solid state could played an important role.When HPMC was used as stabilizer,the dissolution value of the nanosuspensions prepared by the two-step method was not significantly increased compared to the solid dispersion due to recrystallization of the HPMC solid dispersion in the process of reduction the particle sizes.This study showed the appropriate stabilizers could overcome the influence of water and external forces on the amorphous state of drugs,and maintained the stability of the amorphous state in the process of particle size reduction.Freeze-drying was adopted to solidify the nanosuspension.The effects of freeze-drying protectant,polymer type,polymer concentration and different preparation processes（rotary evaporation+WBM/HPH）on the stability of solid samples were studied.The sample solidified with PVP as stabilizer could maintained stability for 6 months,and its redispersion particle size,PDI,and dissolution value were not changed significantly compared to the initial nanosuspension.The final dissolution value of nano-drug tablets prepared by the combined method could reached 95%,which was much higher than that of other single technologies.It was proved that the optimized tablet preparation technology could retained its dissolution advantages.In addition,the effects of particle size（300-500 nm）and dissolution medium（phosphate buffer with different pH or different concentration of solubilizer）on the dissolution of the nano-sized drugs were investigated.Indomethacin and meloxicam were selected as the pH-dependent drug model.In the sink condition,due to the rapid effect of pH and particle size on the dissolution,the difference in dissolution of two different particle sizes nanosuspensions could not be identified.Dissolution curves and statistics showed that different particle sizes of indomethacin nanosuspensions were significant different in non-sink conditions,but meloxicam had no significant difference,which was due to the difference of physical and chemical properties of the drug itself.Quercetin was used to investigated the effect of particle size and solubilizer（micelle）on dissolution.In the non-sink condition,the dissolution of quercetin nanosuspension could be divided into two phase:（phase1）: a fast dissolution stage,the smaller particle size could achieve a higher dissolution value;phase 2: if the concentration of tween in the dissolution medium was enough,the nano-drugs which are not completely dissolved in phase 1 will be further slowly dissolved to reach the dissolution equilibrium.In the phase 2,nanosuspensions with small particle size could quickly reached the saturation solubility.The response surface showed that when the concentration of tween in the dissolution medium was higher,the influence of particle size on dissolution was not significant.