Nano Medicine And Carrier Prepared Using Ultrasound Coupling To Supercritical CO₂ And Mechanism Research

Nanomedicine has caused a lot of concern,since it is an attractive alternative to improve the solubility and the bioavailability of insoluble pharmaceutical materials,and can get several medical functions via surface-modifications.The conventional methods for nanomedicine preparation have drawbacks such as uncontrollable particle size,toxic solvent-residue,abundant use of surfactants,and so on.Solution enhanced dispersion by supercritical fluid?SEDS?is the leading method for nanomedicine preparation,showing advantages like environmental-friendly,easy control of particle size,moderate operational conditions,etc.SEDS has made a rapid growth during recent years,however,it still has several problems:?1?complexity of project design due to numerous operating variables,?2?limitation for crystal materials of low molecular weight,?3?inconsistent mechanisms in describing nanoparticle formation,and?4?the present supercritical methods are inadequate in modifying nanocarriers.These problems are severe bottlenecks for the development of supercritical micronization technology.Therefore,in this study,on the basement of the researches on material phase behaviors and mechanisms of variable effects,the ultrasound is used to couple with supercritical CO₂ to prepare curcumin nanoparticle,curcumin proliposome,and chitosan modified graphene oxide nano drug carrier.With these models,the effects of ultrasound are studied.The results show that during the nanomedicine preparation,this method breaks throw the limitation of SEDS in treating small crystal materials,and the ultrasound can help control the particle morphologies,simplify the operation,increase the drug load,and so on.It also presents the possibility of producing modified functional nanomedicine via the ultrasound coupled to the supercritical CO₂.The detail research contents and results are as follows:1)The phase behaviors of glycyrrhizin,hydrogenated phosphatidylcholine?HSPC?,and curcumin in the ternary system made up of the supercritical CO₂,the organic solvent and the solute are studied using a self-made equipment,and the solubility of glycyrrhizin is fitted using several semi-empirical equations.The solubilities of all determined materials increase with the content of organic solvents and pressure,but have complicated relations with temperature.The solubilities are also impacted by the polarity of materials,and decrease with the enhanced polarity.Calculated with the phase behavior data obtained,it proves that the selected materials are practicable for SEDS.The results are significant for the following experimental design.2)HSPC,glycyrrhizin and aescin nanoparticles are prepared using SEDS,separately,to study the mechanisms of operational variables and to pick up the key parameters relating to the nanomedicine formation,as well as to resolve the insoluble problems of aescin.The results show that nanomedicine is formed mainly via the nuclear and growth mode,rather than the droplet and fluid dynamic way.Additionally,the material dependency of SEDS is studied also.It is available to get nano particles for amorphous materials and big molecular materials,but for the small molecular crystal materials,the traditional SEDS needs some improvement,which contributes to the limited supersaturation degree.3)Curcumin nanoparticle is prepared using ultrasound coupled to SEDS,proving its availability of nano-sized treatment for small molecular crystal material.The results show that during the preparation,the ultrasound has effects of increasing supersaturation,enhancing mass transfer,and some heat effect.The supersaturation degree increases with the ultrasound power,and the needle-or rod-like particle,irregular lumpy particle and nano spherical particle are generated.The observation of jet flow indicated ultrasound could accelerate the mixing speed between liquid solution and CO₂,and thus reduce the gaseous region and the local saturation gradient.The introduction of ultrasound greatly simplifies the SEDS process.4)Curcumin proliposome?CPL?was prepared using ultrasound coupled to SEDS.The effects of the process parameters,such as weight ratio of starting material,pressure,temperature,and ultrasound power,on the entrapment efficiency?EE?and the drug load are investigated.When the weight ratio of HSPC to curcumin increases,the morphology of CPL transforms gradually from coprecipitation form to encapsulation form,and the EE also increases.During the CPL preparation,the ultrasound enhances the mass transfer,leading to uniform product;and increases the supersaturation and inhibits the crystal growth of curcumin together with the HSPC molecular effect,rising the drug load.The heating effect should be paid attention for the temperature-sensitive material.In conclusion,the ultrasound coupled to SEDS can produce stable CPL,improve the drug load,and control the drug release via morphology adjusting.5)Ultrasound-induced synthesis of chitosan-modified nano-scale graphene oxide?CS-NGO?hybrid nanosheets,which has a great potential for pharmaceutical applications,in supercritical CO₂ without catalyst was presented for the first time.The preparation process does not require organic solvent and post-processing,and CO₂ easily escapes from the product.The morphology and structure of the CS-NGO,characterized using scanning electron microscopy,transmission electron microscopy,infrared spectroscopy,X-ray photoelectron spectroscopy and thermogravimetric analysis,confirmed it was combined via the amide linkage,and had excellent dispersibility and stability toward acidic and physiological aqueous solution,which implies that it could be used as a drug-carrier.The sonication power played a crucial role in inducing forming amidation,and the conversion rate increased with the sonication time.The mechanism of this reaction was explained.