Fluorouracil Gelatin-plga Microsphere Composite Gel Preparation And Evaluation

5-Fluorouracil is an antimetabolite of the pyrimidine analog type which was synthesized by Duschinsky in 1957.5-Fu has been widely used for colon carcinoma, mammary cancer and skin cancer and so on,especially used as the first line drug of intraperitoneal chemotherapy(IPC)for gastroenteric tumor.It is administered as a solution intravenously and in vivo it is eliminated in 3-5 hours because of short biological half-life.Therefor it is an appropriate candidate for microencapsulation.In this study,we prepare 5-Fu gelatin-PLGA microspheres.With combined gelatin and PLGA,we create a hydrophilic micro-environment,which is good for the envelopment of 5-Fu,and decrease initial burst compared with low entrapment and high burst release of single PLGA micropsheres.On the basis of this,chitosan/PVA hydrogels were prepared by simple freeze- thaw method and gelatin microspheres then entrapped into the hydrogels.The combination of hydrophilic and hydrophobic polymer could be used as drug delivery system for intraperitoneal chemotherapy.In this study,our work includes three parts:1.Preparation of 5-Fu-loaded PLGA microspheres5-Fu was encapsulated into PLGA by W/O/O emulsion solvent evaporation method.The process variables including the volume ratio of acetonitrile/ dichlormethane,polymer concentration,emulsifier type,the power of ultrasonic and temperature on drug encapsulation efficiency were investigated,we choosed the concentration of polymer,initial drug loading and the concentration of span-80 for three aspects for the orthogonal design.When the acetonitrile/ dichlormethane ratio is 4:1,clear and steady W/O emulsion was obtained.Improve the polymer concentration can increase the viscosity of the inter-oil phase resulting in increase encapsulation efficiency and the mean diameter of the microspheres.The of orthogonal design is:concentration of 5-Fu is 25 mg/mL,concentration of span-80 is 2%,PLGA concentration is 5%.The obtained microspheres used optimization formulation appears cyclo-whole,encapsulation efficiency is(68.89±1.82)%,and mean diameter is 18.67μm,loading quantity is 2.55%.The burst release of microspheres is 51.21%within 24 h.we also prepared PLGA microspheres which the molar ratio of Lactic Acid and glycolic acid 90:10,80:20,70:30.In vitro release studies indicated that the burst release of PLGA(90:10),PLGA(80:20),PLGA(70:30)are 41.98%,64.51%,57.46%, relatively.After 15 w,the cumulative release are 27.48%,36.51%,47.46% possessing evident delayed release effect.2.Preparation of the composite of gelatin and PLGA microspheres5-Fu gelatin microspheres was first preparation by emulsification-chemical crosslinking method.Anhydration way,gelatin concentration,initial drug loading etc that influence the encapsulation efficiency were emphasizely investigated The test result indicated,vacuum dehydration superseded the dimethylcarbinol can improve the entrapment of drug.Gelatin concentration below 20%is suitable.When increase the initial drug feed,the entrapment efficicncy will increase.Gelatin-PLGA microspheres were obtained by O/O emulsification extraction method with the material is PLGA(70:30).The ratio of PLGA and gelatin microspheres,drug loading of gelatin microspheres were investigated.Improve the ratio of PLGA/gelatin,the mean diameter will increase,but has little influence to entrapment efficicncy.The initial release of composite microspheres decreased with increasing the PLGA/gelatin ratio while increased with the loading rate of gelatin microspheres.In vitro release studies indicated that composite microspheres has delayed release effect.The composite miccrospheres release curve fit zero-order equition with lower drug loading rate and Higuich model was used to fit that with high drug loading rate.The release rate became much higher result in PLGA erosion and gelatin microspheres swelled.3.Preparation chitosan/PVA hydrogelChitosan and PVA hydrogels(10:90,20:80,30:70 and 40:60)were preparated by freeze- thaw circle method.Swelling rate and dissolve rate in water and PBS,swelling kinetics and internal structure were investigated.The results indicated that the swelling rate of chitosan/PVA was higher in water than in PBS.Reswelling kinetics experiment indicated,when increased the content of chitosan which decreased the PVA crystallinity,the time reach swelling balance will shorter.The scanning electron microscope of the chitosan/PVA hydrogels indicated that containing 20%of chitosan have the most regular structure and at the same time the lowest total porosity.On the contrary samples with the highest content of natural polymer(40%)show the less regular structure and the highest total porosity.The release studiesof 5-Fu from chitosan/PVA(10:90,20:80)indicated,the content of drug and chitosan influence the release rate.In the case of Gelatin-PLGA microspheres enveloped into chitosan/PVA hydrogel,when increase the chitosan content,the release within 0.5 h and 12 h release will decreased.During the process of release,PVA released from the hydrogels resulting in weightlessness,and the weightlessness rate is related to chitosan content.