| Postoperative intestinal adhesion easily leads to intestinal obstruction,infertility,chronic abdominal pain,intestinal necrosis and other diseases,which is one of the urgent problems to be solved in the current clinical field.In this paper,the combination of atorvastatin calcium cationic subemulsion and PLGA-PEG-PLGA thermo-sensitive gel was used to prevent the formation of postoperative intestinal adhesion.The first chapter describes the setting background,significance and research content of this paper.In chapter 2,the ultraviolet spectrophotometry and HPLC of atorvastatin calcium were established.The physical and chemical properties of atorvastatin calcium were investigated,including solubility,stability,oil and water distribution coefficient.The results showed that the solubility of atorvastatin calcium increased with the increase of p H.And it was unstable in an acid,stable relatively in a base,stable at a p H of13.Better lipophilicity was shown at p H6.8-7.4.Therefore,the p H range of 6-8 should be selected as far as possible during preparation.In chapter 3,the formulation and preparation technology of atorvastatin calcium cationic subemulsion were investigated by single factor investigation and response surface optimization.The optimal formulation was as follows: oil phase(soybean oil)was 9%,emulsifier(lecithin:HS15)was 1.7%:1.3%,emulsifier(poloxam 188)was 1.3%,and stabilizer(octylamine)was 0.05%.When the shear temperature is 70?,the shear time is 15 min,the shear speed is 10000 rmp,the homogenization pressure is 900 bar,and the homogenization times is 7,it is the best preparation technology.The three batches of submicroemulsion were prepared according to the best prescription process with milky white appearance and no hanging wall phenomenon,with particle size ranging from 155-162 nm,Zeta potential of about +12mv,small particle size distribution coefficient,and good drug load and encapsulation rate.In chapter 4,the physical and chemical properties of atorvastatin calcium cationic subemulsion,PLGA-PEG-PLGA and its mixed preparation were investigated.The appearance,potential,p H value,particle size,encapsulation rate and drug content of the submicroemulsion were stable for a long time when stored at 4? and room temperature.The atorvastatin calcium submicroemulsion of different concentrations did not produce hemolysis and was safe.The suitable concentration of the thermo-sensitive gel was 16.7w/w%,the phase change temperature was 30?,and the degradation in vitro dissolved about 90% in 21 days.The in vitro degradation of the thermo-sensitive gel containing atorvastatin calcium cationic subemulsion was about 90% within 21 days,which was equivalent to the blank gel with the same mass fraction.In the in vitro release experiment,continuous release was achieved within the range of 40-70 ng /m L within 21 days,showing a good effect of slow and controlled release.The drug content did not decrease and the stability was good.In chapter 5,the cytotoxicity and uptake experiments based on adhesion cells showed that the blank submicroemulsion had no obvious toxicity to adhesion cells.When the calcium concentration of atorvastatin reached 10 ng/m L,it began to show obvious cytotoxicity,and the toxicity of the drug-loaded submicroemulsion was greater than that of the API.The uptake mechanism indicated that the uptake of adhesion cells to submicron milk was mainly dependent on energy,and was then influenced by endocytosis mediated by fossa and clathrin.In chapter 6,a model of intestinal adhesion was established to investigate the pharmacodynamics.The decrease of TNF-? and NF-?B by western blot indicated that the preparation had anti-inflammatory effects.Moreover,atorvastatin calcium can promote the secretion of t-pa and destroy the cytoskeleton to prevent the migration of adhesion cells. |
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