Preparation And Research Of Acetaldehyde Dehydrogenase Agonist 2 Alda-1 Nanoemulsion

Acute myocardial infarction often causes severe myocardial damage and leads to the death of myocardial cells.Clinically,the rescue measure after myocardial infarction is reperfusion to restore myocardial blood flow.But after myocardial infarction reperfusion(I/R),ROS and reactive aldehydes will be released explosively,causing cardiac glucose metabolism disorders,calcium overload,and myocardial fibrosis,which lead to accumulation of harmful products,apoptosis and necrosis and cause cardiac dysfunction or even death.Reactive aldehydes can react with proteins to form various adducts,resulting in protein dysfunction which further leads to cell damage.However,the current clinical methods for myocardial protection are extremely scarce.ALDH2 is an important cardioprotective enzyme,which plays a central role in the detoxification of active aldehydes.Studies show that ALDH2 mediated detoxification of reactive aldehydes may be an endogenous mechanism solve myocardial ischemia-reperfusion injury.Alda-1 is an acetaldehyde dehydrogenase agonist.It can activate ALDH2,catalyze the degradation of active aldehydes by ALDH2.The accumulation of aldehydes in the body reduces,which also reduces its damage to the myocardium.However,there is no clinical preparation of Alda-1 now.Therefore,this study aims to prepare Alda-1 into the nanoemulsion preparation which can reduce myocardial damage after I/R.The specific research content and results show as follows:1 First,the excipients used for Alda-1 nanoemulsion preparation were screened depending on maximum water ratio,equilibrium solubility,safety,and pre-experiment observation.Finally ester was MCT,emulsifier was polyoxyethylene 40 hydrogenated castor oil(RH-40),Tween-80,soy liquid lecithin,the co-emulsifier was polyethylene glycol 400(PEG-400).And then according to light transmission,the ratio of the immersion region area was 3:7,and the ratio of the emulsifier and the co-emulsifier is 1:1,The ratio of RH-40 and lecithin was 5:1,and the final concentration of Tween-80 was about 0.3%by the lysmia experiment.By the response surface method,the best prescription was screened,per 1g mixed system containing MCT 0.2834 g,the emulsifier was 0.3526 g,of which RH-40:lecithin was 6:1,the co-emulsifier PEG-400 was 0.3640 g,Tween-80 was about 0.0300g Alda-1 was 4.6mg.The low energy emulsification method was mixed with 9 mL of 5%glucose solution.At last,nanoemulsion presented uniform,pale yellow,and translucent.2 This chapter mainly studied the physicochemical properties of nanoemulsion.The morphology of dispersion system was observed by TEM.The Zeta potential and particle size were analyzed by Marvin particle detector.The particle size was 69.77±3.21 nm,Zeta potential was-12.61±1.94 mV,The drμg content was detected by high performance liquid chromatograph 472.71±19.08 μg/mL,and then the stability of nanoemulsion was investigated.The particle size and content of the nanoemulsion after 20 times,100 times,500 times dilution within 3h were detected.When the preparation was diluted 100 times,20 times,the particle size remain stable.When diluted 500 times,the variation of the particle size compared to other multiple,but the RSD in 3 hours is 10%,which was basically stable.The results show that the stability and dilution stability of nanoemulsion can be substantially stable in 3 hours.The release of nanoemulsion showed that free preparations was basically released,but the nanoemulsion was totally released until 48h.The Alda-1 nanoemulsion showed a good sustained release effect,prolonging the action time of the drμg in the vivo.3 To confirm the safety of Alda-1 nanoemulsion,hemolysis and vascular irritation of the blank nanoemulsion have been shown.The hemolysis rate of the blank nanoemulsion was 3.2%±1%,the result was qualified.The results of vascular stimulation experiments was showed according to the apparence or by H&E dye.No vascular tissue damage was observed in all cases.The inner wall of blood vessels was intact,and the blank nanoemulsion showed no significant irritation.4 In order to investigate the metabolism of the drμg in vivo,the metabolic kinetics of the drμg was investigated.The results showed that the Alda-1 nanoemulsion preparation and the free preparation showed significant differences in terms of retention time,half-life,or maximum blood concentration,speed of the clearance.The nanoemulsion showed the obvious advantages.In order to confirm the therapeutic effect of the nanoemulsion preparation,the study examined the size of the myocardial death area and the echocardiogram in the direction of PSLAX and SAX in the case of the drug concentration high,medium,and low(4h after I/R).EF represented the left ventricular wall myocardial fibers shorten the fraction.FS standed for left ventricular ejection fraction.The results showed the group injected high-dose showed the better protective effect of myocardial cells,the smaller area of myocardial death,and the increased of the left ventricular FS and EF.The myocardial function was significantly restored.The levels of myocardial injury markers LDH and CK-MB were further detected.The results showed that after the application of Alda-1 nanoemulsion,the content of LDH and CK-MB was significantly reduced.All studies indicated that Alda-1 nanoemulsion could effectively protect myocardial cells after myocardial reperfusion.It could reduce myocardial damage caused by reperfusion and restore the myocardial function.