| OBJECTIVE: Nimodipine(Nimo)was a dihydropyridine calcium ion antagonist,suitable for cerebral vasospasm after subarachnoid hemorrhage of various reasons,ischemic neuron protection,etc.However,nimodipine injection(Nimotop)(0.2 mg/m L)had limited clinical application due to its low drug loading,easy crystallization after dilution before use,inconvenient use,high vascular irritation,and high toxicity.In order to overcome these defects,in this study,on the basis of cyclodextrin inclusion complex,fat emulsion,liposome,etc.as the drug carrier of nimodipine,liposome was preferred as the modified dosage form of Nimotop.This paper mainly used liposome technology to encapsulate Nimo,and conducted single factor investigation through various factors such as cholesterol to optimize the formulation process,and prepared a new type of nimodipine liposome for injection(Nimo-Lip).On the basis of achieving similar pharmacokinetic parameters and pharmacodynamic effects as Nimotop,the drug loading and drug stability were improved,the vascular irritation and toxicity were reduced,and the drug safety was enhanced.METHODS: Nimo-Lip(0.5 mg/m L)was prepared by thin film hydration method,and the formulation process was optimized by single factor investigation,and an appropriate amount of lyophilization protective agent was added for lyophilization.The particle size,polydispersity index(PDI),encapsulation efficiency(EE%),and in vitro release of liposomes were evaluated.Then,the stability study of Nimo-Lip was carried out,including the influence factor experiment(high temperature,high humidity,light),accelerated stability experiment,reconstitution stability experiment,and comparison of the dilution stability of Nimo-Lip and Nimotop.The pharmacokinetics of rats were investigated,and the pharmacodynamics of Nimo-Lip and Nimotop were evaluated by the rat middle cerebral artery embolism model(MCAO).The safety of Nimo-Lip was evaluated in terms of hemolysis,Osmotic pressuremargina,ear vein irritation and acute toxicity.RESULTS: The optimal formulation and process parameters of Nimo-Lip were as follows: Nimo content was 0.5 mg/m L,drug-lipid ratio was 1:35,cholesterol was 0.8%,DSPE-PEG2000 was 0.1%,hydration temperature was 50℃,and high pressure was uniform at 12000 psi.6 times,and the lyoprotectant was 8% sucrose.The obtained liposomes had a particle size of 123.67±0.92 nm,a PDI of 0.167±0.007,and an EE% of 97.05±0.23(%).The cumulative drug release rate of Nimo-Lip was more than 80% at 8 h,which was similar to the release trend of Nimotop.The results of stability study showed that the preparation discolored at high temperature(60℃),and the EE% of Nimo-Lip was affected by light,so it should be stored in the dark and low temperature,and the accelerated stability was good.The results of the dilution stability investigation of Nimotop show that,compared with the poor stability of Nimotop after 3 h of dilution,Nimo-Lip can be diluted with 5% glucose injection and 0.9%sodium chloride injection remained stable within 24 h,and the dilution stability was significantly improved.In addition,the results of pharmacokinetic and pharmacodynamic studies in rats showed that Nimo-Lip had similar pharmacokinetic parameters and pharmacodynamic effects compared with Nimotop.In the safety evaluation,Nimo-Lip did not undergo hemolysis.Compared with Nimotop,the osmotic pressure was significantly lower,the induced venous irritation was significantly reduced,and the LD50 of Nimo-Lip was 5.003 times that of Nimotop,which greatly improved the safety.CONCLUSION: After encapsulating Nimo with liposome technology,the drug loading and stability were improved,the vascular irritation and toxicity were reduced,the use was convenient,the medication safety was significantly improved,and the patient compliance was enhanced.In this study,Nimotop was improved by liposomes and the drug release was adjusted through prescription optimization,which provided a useful reference for the improvement of drugs or preparations with similar properties to Nimo. |
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