| Uric acid is a product of purine metabolism.Excessive uric acid causes gouty arthritis.Uricase(UC)could decrease the concentration of serum uric acid and UC can be used for the treatment of hyperuricemia.In clinical,UC is mainly used for the diagnosis of uric acid level and related diseases and elevated levels of uric acid treatment.However,UC has some shortcomings: short half-life,short active half-life,and poor stability in vivo,thus greatly limits its clinical use.Liposomes(LP)have lipid bilayer thus could encapsulate the drug in bilayer to form ultra micro spherical carrier preparation.LP has advantages of the similarity between biological membranes,improving the drug stability,and reducing drug toxicity.And it also can improve the drug bioavailability,prolong drug half-life,delay drug release,target effects and so on.Hyaluronic acid can be targeted to hyaluronic acid receptor CD44 and CD168,and can reduce the number of inflammatory cells,can adjust the expression of cytokines,can protective effect on gout tissue.Hyaluronic acid also could improve the pathological synovial fluid properties by promoting endogenous hyaluronic acid synthesis,achieve sustained remission of gouty arthritis symptoms and delaying gouty arthritis disease effect.Hyaluronic acid-Uricase liposomes(UHLP)was prepared by reverse evaporation method,and UHLP was used as a new preparation for UC.Not only hope to improve the UC activity and improve the treatment effect of UC;but also hope that UHLP can reducing uric acid levels in the body at the same time,Hope UHLP can target to hyaluronan receptors CD44 and cd168,reduce the number of inflammatory cells,play a role in protecting the joints and anti-inflammatory.Method and results:In Chapter ?,the UHLP was prepared by reverse-phase evaporation method,and evaluated by transmission electron microscope,encapsulation efficiency rate of drug,size and zeta potential.UHLP emerge as spheroids with granular structure under the TEM microscope.UHLP was homogeneous milky white,UHLP were round or oval with uniform size under TEM microscope,the encapsulation efficiency of UHLP was about 60%,the average diameter of them was around 330 nm,and the zeta potential was around-20 mV.In Chapter ?,the optimum temperature,optimum p H of UHLP and free UC were determined by measuring the enzyme activity.The optimum temperature of UHLP and free UC were both 40 ?.And the optimum p H of UHLP was 8.0,and the optimum pH of UC was 8.5.In Chapter ?,the stabilities of UHLP and free UC in vitro were determined by measuring the UC activity.Through measuring the storage stability,thermal stability,p H stability and proteolytic stability of UHLP and UC to compare the stability of free UC and UHLP.The results showed that the influence of the above factors on UHLP was less than that of free UC.In chapter ?,pharmacokinetics of UHLP and UC were studied in SD rats through intravenous injection.DAS2.1.1 pharmacokinetic software was used to processing and statistical results.The main pharmacokinetic parameters of UHLP were AUC(0-7h)(234.39 ± 25.30)U/L·h,MRT(0-7h)(2.03 ± 0.12)h,Cmax(93.91 ± 8.03)U/L,Tmax(0.75 ± 0.00)h.The main pharmacokinetic parameters of free UC were AUC(0-7h)(44.00 ± 5.73)U/L·h,MRT(0-7h)(0.59 ± 0.05)h,Cmax(86.87 ± 8.94)U/L,Tmax(0.17 ± 0.00)h.These results showed that UHLP and free UC were not bioequivalent.Chapter ? mainly focused on the pharmacodynamics of UHLP and free UC in SD rats through intravenous injection.The time needed for UHLP to reach the normal of rats is about 8 h.In comparison,UHLP was remarkably better than free UC when used to catalyze uric. |
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