Study On The Preparation Of Nanomaterials And Poorly Water-soluble Drug Mesoporous Materials Drug Delivery Based On Supercritical Fluid Technique

In this thesis,the preparation of poorly water-soluble drug loaded mesoporous materials drug delivery system based on supercritical fluid technique was studied.Ibuprofen and HL were used as model drugs.MCM-41,HAP and CMK-3 were used as drug carriers,respectively.The solvent method and the supercritical fluid method were both used to prepare the complex of drug and carrier.The laws of the drug loading and releasing were investigated systematically.Then,the study of the stability of the complex of drug and carrier and in vivo pharmaokinetics study were carried out.There were two acdemic aims in this thesis.One was to develop a novel method to prepare nanoscaled materials with controllable shape,good dispersity and acceptable stability.The other was to develop a new drug loading strategy to prepare poorly water-soluble drug loaded mesoporous microparticles with high drug loading capacity,acceptable stability and sustained releasing property.At first,the physicochemical properties of drugs and carriers were investigated.After the establishment of the UV and HPLC analysis methods,the solubility,pKa and oil-water partition coefficient of the drugs were determined,respectively.Then,a special supercritical fluid device was designed and assembled order to determine the solubility of the drugs in SCF-CO2 by single channel dynamic method.The results showed that the device was a simple,accurate and convenient measurement.Finally,the hydrophilicity and wettability of the carriers,MCM41,HAP and CMK-3,were also measured.At second,the factors,such as time,concentration,pressure,temperature and kinds of entrainment that would influence the drug loading and releasing were investigated,respectively.Based on the response surface methodology,the optimized drug loading capacity for ibuprofen was 37.50%,at 27.63 MPa and 47.87 ℃ for 74 min in drug loading process.Similarly,the optimized drug loading capacity for HL was 13.41%,at 31.62 MPa and 48.62℃ for 10 h in drug loading process.The results showed that supercritical fluid technique has more variables parameters,high drug loading,the product has no pollution.At third,the HAP was prepared by two steps.On the first step,the n-HAP were prepared by liquid phase precipitation method and supercritical fluid method,respectively.On the second step,F127 was used as pore-forming agent to prepare mesoporous HAP microspheres by spray drying.Compared with the liquid phase precipitation method,the n-HAP prepared by the supercritical fluid method had higher crystallinity,better dispersity and more uniform size.The HAP microspheres sprayed were sphere with uniform shape distributed in the range of 5-12 μm.The safe experiments of hypodermic injection and muscle implantation for HAP prepared previously were carried out to test the safty of the materials.The drug distribution in HAP particles was determined by comparing the releasing curves between drug-loaded solid HAP particles and drug-loaded mesoporous HAP particles.The mechanism of sustained release of drugs from mesoporous HAP particles was concluded based on the drug distribution in HAP particles.At fourth,the morphology and polymorphism of the samples were characterized by some usual methods,such as SEM,DSC,X-ray,IR and N2 adsorption desorption isotherms.The result of dissolution study showed that the solubility and dissolution of the drugs loaded into the materials were obviously increased and the samples prepared by supercritical fluid method had a remakable sustained releasing effect.Finally,in vivo study of the ibuprofen-MCM41 complexes and the physical mixture of ibuprofen and MCM41 was carried out.The concentration of ibuprofen in plasma was analyzed by HPLC.The C,x and Tmax of the complexes prepared by solvent method and SCF-CO2 method were 2.573±0.156 μg·mL-1 and 1.923±0.164 μg mL-1 and 33±6.708 min and 96±13.416 min,respectively.The relative bioavailability of the complexes prepared by solvent method and SCF-CO2 method were 214.531±25.207%and 272.349±37.257%,respectively.In conclusion,the supercritical fluid technique is a potential technique in preparing nanoscaled materials and drug loaded mesoporous material drug delivery systems.The nanoscaled materials with controllable shape,good dispersity and acceptable stability.The drug loaded mesoporous particle prepared by supercritical fluid method has many advantages,such as short time in drug loading,high capacity of drug loading,controllable releasing rate,no solvent residue.Especially,using this method to prepare drug loaded mesoporous material drug delivery system is a ideal alternative for heat sensitive and oxidation sensitive drugs.