| Objective In order to prolong the effect of the local anesthetic to several days or even weeks, which can ease the pain caused by various diseases, we decide to prepare and optimize the Ropi lactic-glycolic acid polymer nanoparticles(Ropi-PLGA-NPs), and determine its characteristics in vitro. In china, the study about in vivo release characteristics, belong to local anesthetic delivery system,were mostly surrounded in the nerves and subcutaneous. To evaluate the Ropi-PLGA-NPs’ antinociception and safety in epidural, we prepared the lumbar epidural catheter model and study the pharmacodynamic, pharmacokinetic and biocompatibility of epidural ropivacaine in PLGA-nanoparticles.Method The Ropi-PLGA-NPs were prepared by oil-in-water emulsion by the solvent evaporation technique.The formulation was optimized by the Central Composite Desig/Response Surface Method(CCD-RSM), with the encapsulation efficiency(EE), drug loading(DL) and particle size as the indexes. Nanoparticles were evaluated in vitro their drug release mechanism by fitting different model equations. In vivo experiment, 40 healthy New Zealand white rabbits were randomly divided into four groups: normal group(A), ropivacaine hydrochloride(B), Ropi-PLGA-NPs(C), placebo nanoparticles(PLAC-PLGA-NP)(D). The combined evaluating method to hindlimb was used to evaluate the anesthetic effect. In this method, different stages of analgesic time in each group were recorded with T1, T2, T3, while the total anesthesia time with T, and use Integrated score S value(scores plused by the values about each phase duration multiply corresponding value) as the comprehensive index to evaluated the analgesia effect after epidural administration. The HPLC was used to measure the plasma concentrations of Ropi at each time point(0.15, 0.5, 1, 2, 3, 5, 7, 8, 10, 12, 24, 36, 48, 72, 96 h), and the pharmacokinetic parameters was calculated by the non-compartmental model. The microscopic examination of the application site and surrounding tissuewas performed to evaluate the biocompatibility of Ropi-PLGA-NPs. Result The Ropi-PLGA-NPs made by the optimized prescription have smooth and rounding appearance, with the mean particle size was(331.21±2.11) nm. The DL was(13.81 ±1.35)% while the EE was( 74.82±2.53) %, which was expected to be.The accumulative release rate of the Ropi-PLGA-NPs was best fitted the Higuchi function. After epidural administration of PLGA-ropivacaine nanopaticles in the rabbit, different stages of analgesic time T1(9.11±0.88), T2(3.67±0.59), T3(1.53±0.21), while the total anesthesia time T(14.21±2.21), and the Integrated score S value(21.03±1.76) in group C were much longer than that of in group B(1.83±0.22, 0.82±0.13, 0.49±0.19, 3.11±0.19, 4.94±0.67, P <0.001). The Cmax in plasma was around 0.38 mg·L-1 which was lower than that of ropivacaine solution(1.72 mg·L-1, P <0.001), while the mean resistant time was seven times longer than that of ropivacaine solution. The anatomical grade and microscopic examination of the implanted sites were about I-II, revealed that only mild infiltration was found in examined tissues.Conclusion The Ropi-PLGA-NPs made by emulsion solvent evaporation technique have obvious drug-release behaviour in vitro, with high EE, DL and smooth appearance. Compared to ropivacaine solution, epidural administration of Ropi-PLGA-NPs showed prolonged sensory blocks which was expected, and led to a sustained low and safety levels of ropivacaine in plasma. |
PDF Full Text Request