Ropivacaine Hydrochloride Loaded Microspheres Prepared By Two Drug-Loadinog Modes And Its Pharmacodynamic Evaluation

Ropivacaine Hydrochloride(ROP)reversibly and temporarily blocks nerve impulse conduction by binding to Na+ channels on the nerve membrane,and has been widely used clinically based on its relatively low toxicity compared to other amide local anesthetics.However,ROP has a short half-life(t1/2=1.8 h),and a single injection can only satisfy the analgesic effect of 2-4 hours,while continuous analgesia is needed within 3-5 days after surgery.In order to break through the limitation of ROP,in this study,ROP-PLGA microspheres with uniform particle size,high drug load and sustained release behavior were prepared by two different methods.It includes the following three aspects:(1)ROP-PLGA microspheres were prepared by the premix membrane emulsification technique combined with W/O/W double emulsion solvent evaporation,which was called "pre-loading" mode.The response surface method(RSM)was used to analyze and optimize the factors affecting the preparation of ROP-PLGA microspheres.Finally,ROP-PLGA microspheres with particle size of 8.368 ?m,Span value of 0.852 and drug loading of 1.76%were prepared and the deviation from the model was less than 7%.In addition,in vitro release results showed that the burst release of ROP-PLGA microspheres prepared by "pre-loading" mode at first 0.5 hour was only 1.45%,and the cumulative release rate was about 70%at 5 days.(2)In order to solve the problems of low drug loading of ROP-PLGA microspheres,porous PLGA microspheres with "self-healing" characteristics were prepared,which was called "post-loading" mode.Finally,the porous self-healing ROP-PLGA microspheres were obtained under healed at 44? for 2.5 hours,with particle size of 38.158 ?m,Span value of 0.688,drug loading of 8.72%,the burst release at first 0.5 hour was 33.21%and accumulated release rate at 3 days reached more than 90%.(3)To evaluate the efficacy and safety of the prepared porous self-healing ROP-PLGA microspheres,the sciatic nerve block model of SD rats was established.The pharmacodynamic results showed that porous self-healing ROP-PLGA microspheres showed the longest sensory and motor nerve block time.H&E section showed that after 7 days of injection of porous self-healing ROP-PLGA microspheres,no inflammatory reaction was observed in the sciatic nerve and main organs on the side of the drug administration,and the blood biochemical indicators were normal,suggesting the satisfactory biological safety of porous self-healing ROP-PLGA microspheres.In summary,based on "pre-loading" mode,ROP-PLGA microspheres with uniform particle size were prepared by double emulsion method combined with the premix membrane emulsification technique,which showed relatively stable release behavior.In addition,based on "post-loading" mode,porous self-healing ROP-PLGA microspheres with high drug loading were obtained by using the self-healing properties of porous microspheres.The most important achievement is that a reasonable and effective animal experimental model was successfully established,which layed a foundation for its clinical application.