Preparation And Formulation Of Novel Drug Nanoparticles Based On High Efficient Solubilization

Many known technologies can be used to improve the solubility of insoluble drugs,which can be divided into two main types: one is to add different kinds of solubilizers,such as organic solvents,Tween 80,etc.;the other is mainly through the change of the principle of physical properties of drugs.The transformation of solid structure and particle size of drugs is an important aspect of the second category above.They will influence the saturation solubility and dissolution of the drug by some technical means.The decrease of crystallinity or amorphous state can improve the solubility of drugs,and the transformation of polymorphism can also lead to the change of drug solubility.According to the Noyes Whitney equation,with the decrease of particle size,the total effective surface area of drug particles increases and the dissolution rate increases.In addition,the decrease of particle size will reduce the thickness of diffusion layer around the drug particles,thus increasing the concentration gradient of drug particles,so the size of nanoparticles can generally greatly improve dissolution.In this project,the preparation method of amorphous nanoparticle is proposed in combination with the amorphous solid state and nanoparticles,aiming to further improve the dissolution of drugs.According to the latest literature reports,amorphous nanosuspension can only be achieved by solvent-antisolvent precipitation(bottom-up process).However,the drug loading of this preparation method is very small,usually far less than 0.1%,which may be difficult to further scale up or be used in downstream processing.Therefore,the first preparation of amorphous solid dispersion was proposed in this paper,and then the "top down" method was used to prepare the nano-amorphous drugs.This topic uses three amorphous technologies combined with high-pressure homogenization(Top-down)to study four model drugs: the combined technology of rotary evaporation and high-pressure homogenization is used to prepare quercetin nano-amorphous drugs,and melt quenching-high-pressure homogenization is used.The combined technology of indomethacin was used to prepare nano-amorphous indomethacin drugs,and the combined technology of freeze-drying and high-pressure homogenization was used to prepare meloxicam and naproxen nano-amorphous drugs,respectively.Study the effect of process parameter stabilizers on the preparation of amorphous(crystallinity,particle structure,etc.);the effect of reduced crystallinity on the efficiency of the "Top-down" process and the effect of the prepared nano-amorphous,and study the particle size and the amorphous Synergistic influence of shape setting on dissolution,etc.The amorphous preparation process shows that the applicable preparation methods and stabilizer ratios of each drug are quite different.After optimization,amorphous drugs with reduced crystallinity can be prepared.Compared with the bulk drug,the particle structure of the amorphous sample drug has changed,and more breaking points are apparently added.Regarding the preparation technology,the freeze-drying method has the largest bulkiness of particles,which is related to the process of its sublimation method.Amorphous drugs can be successfully nano-sized after being prepared by high-pressure homogenization,indicating the feasibility of this combined method.The study on the dissolution rate of the prepared nano-amorphous state shows that the nano-amorphous state can obtain a higher dissolution rate than the nanocrystalline,micro-amorphous,etc.Among them,for quercetin and meloxicam,the advantage of preparing amorphous is more obvious than the modification of particle size.The dissolution results of indomethacin and naproxen indicate the influence of particle size reduction on dissolution Even bigger,these differences are mainly related to the nature of the drug itself.In addition,the particle size test results show that after being prepared into an amorphous shape,the particle size reduction rate during the Top-down process can be effectively accelerated,which is speculated to be related to the change in the particle structure.Quercetin raw materials,nanocrystals,amorphous solid dispersion and nano amorphous were processed downstream to prepare tablets.Through orthogonal experiment,the excipients were selected as soluble starch,sucrose,cross-linked povidone,dextrin,PVP-K25 and magnesium stearate.Wet granulation was selected as the production process.The dissolution curves of all samples were compared,and the similarity and dissolution efficiency were investigated.The results show that the nano-amorphous still has outstanding advantages after the preparation of tablets,and has good release and effectiveness.