Studies Of Clevidipine Loaded Lipid Emulsion For Intravenous Injection

Clevidipine is a dihydropyridine calcium channel blocker, which can selectivelyinhibit the calcium ions flowing in the vascular smooth muscle cells, thereby reducing thearterial pressure. Due to the drug’s characteristics of soluble in oil to a certain extent, it’s agood choice to use lipid emulsion as the carrier. Despite the clevidipine emulsion has beenstudied by so many reseachers, the quality still need to be improved. It’s difficult tocontrol the particle size uniform and the lipid are easy to be oxidized during the process ofpreparation and store. In this article, clevidipine loaded lipid emulsion for intravenousinjection was developed. The uniformity of the particle size was improved effectively,thus increasing the stability of the emulsion. It also partially solved the problem ofdegradation of the lipid during the process of preparation and store. The major results areas the following:In the preformulation study, HPLC methods were established to determine thecontent of clevidipine in emulsion. We found that the methods’ specificity and linearitywere good （range of5⁸0μg/ml, R²=0.9993）, and the recovery was98.5%, RSD=1.66%.They met the requirements for determination of pharmaceutical preparations. Secondly,the physical and chemical properties of clevidipine were studied. The result showed thatits solubility in MCT was better than soybean oil. Various external factors on clevidipinestability were investigated. Clevidipine was sensitive to light, high temperature andoxidation conditions.Optimization of clevidipine emulsion was achieved by increasing the stability ofclevidipine emulsion. The results showed that the emulsion with VE or Na₂S₂O₃added inwill lead to drops of oil appearing on the emulsion surface; adding0.02%α-lipoic acidinto the emulsion can reduce impurities produced in the process of preparation and store.The final clevidipine emulsion: clevidipine （0.05%）, α-lipoic acid （0.02%）, soybean oil（10%）, MCT （10%）, egg yolk lecithin （1.2%）, glycerol （2.25%）, oleic acid （0.06%）,EDTA-2Na （0.005%）, water for injection.Technological conditions were optimized, they were: oil phase temperature （75℃）, water phase temperature （70℃）, mixed for5min, high shear speed （14500rpm for3min）,adjust the pH of coarse emulsion to9.2with0.1mol/L NaOH, high-pressure microfluidpressure （1000bar for6cycles）, autoclaving （121℃for15min）. The mothod ofpreparing clevidipine emulsion by high-pressure microfluidization is shorttime-consuming and easy to engaging into large scale production. The particle size ofemulsion is more uniform.The final clevidipine emulsion is characterized with the diameter of269.55±1.77（nm）,poly disparity index （PDI） of0.07±0.01, zeta potential of-40.30±0.57（mV）. DSC andXRD analysis showed that clevidipine in lipid emulsion was amorphous probably.Impurity limits: free fatty acids <5mmol/L, peroxide value <2.5mmol/L, anisidine value＜2.2.The stability of clevidipine emulsion was investigated under extreme conditions. Theresults showed that the drug content decreased and the impurities increased under theconditions of60℃and light. Under-20℃, phase separation occurred. The characteristicof clevidipine emulsion hardly changed under4℃. The result of accelerated stabilitystudies showed that the size, PDI, zeta potential of clevidipine lipid emulsion hardlychanged, but the content of clevidipine was slightly decreased and related substancesincreased. In addition, the results of physical stability of clevidipine emulsion in differentdilutions showed that the particle size increased significantly in0.9%NaCl solution, and itwas stable in5%dextrose dilution in48h.