Study On The Aprepitant Submicron Emulsion Injection

As the first NK-1RA,Aprepitant（APT）is used to prevent acute or delayed Chemothrapy Induced Nausea and Vomiting（CINV）associated with highly emetogenic cancer chemotherapy.CINVANTI^?,an APT emulsion for intravenous injection with a dose（7.2mg/m L）,was manufactured by Merck&Co Inc.However,the ultimate emulsion used filtration sterilization rather than thermal sterilization.A safe and stable Aprepitant submicron emulsion injection that can withstand thermal sterilization is presented in this thesis based on some shortcomings of filtration sterilization technology.The main research contents of this thesis are as follows:Study on pre-formulation research of Aprepitant submicron emulsion injection.The solubility,stability and oil-water partition coefficient of Aprepitant were investigated utilizing a HPLC method that was first established.It was shown that the solubility of Aprepitant was increased while the p H of the solvent was increased.Aprepitant was stable in the medium with high p H.The partition coefficient（P）of Aprepitant was decreased while the p H of the solvent was increased.Study on formulation design and preparation techniques of Aprepitant submicron emulsion injection.Using a combination of single factor and orthogonal experiment,the investigation of formulation design and preparation techniques were elaborated.The optimal formulation of submicron emulsion was presented as follows:oil phase:Aprepitant was0.72%,HS15 was 2.16%,egg yolk lecithin E80 was 2.88%,soybean oil was 8.0%.Aqueous phase:glycerol was 2.5%,HS15 was 1.0%,egg yolk lecithin E80 was 2.5%,Tween80 was 1.0%,poloxamer 188 was 1.6%,arginine was 0.1%,sodium oleate was 0.05%.Optimal preparation techniques conditions:shear temperature was 70℃,shear speed was 10000rpm,shear time was 10min,homogenization temperature was 20℃,homogenization pressure was 800 bar,homogenization times were 7 times,sterilization temperature was 121℃,sterilization time was 15min.The submicron emulsion we prepared has a uniform milky white appearance,without wall hanging and the stability was good.Study on physicochemical properties and stability of Aprepitant submicron emulsion injection.The three batches of submicron emulsion are all milky white in appearance,without wall hanging,and fluidity were excellent.The average particle size,PDI,p H value,Zeta potential,drug content and encapsulation efficiency were 156.9nm,0.106,8.38,-34.97m V,99.15%and 97.73%.Observed by TEM,the emulsion was uniform in size,showing a relatively complete and uniform spherical shape,with a particle size of about 150nm.The drug content of APT emulsion and Aprepitant submicron emulsion injection reached 43.72±1.97%at 12 h and 90.84±1.42%at 96 h in Aprepitant submicron emulsion injection and38.05±1.43%at 12 h and 88.75±1.70%at 96 h in APT emulsion,which indicated that the release of Aprepitant was slower.The stability of the submicron emulsion under high temperature,low temperature,light,and freezing conditions was investigated for 10 days.The stability under high temperature and freezing conditions was poor.The emulsion should be refrigerated and protected from light.The stability of the emulsion after storage at 6±2°C and 25±2°C for 6 months was investigated.There is no significant change in various physicochemical properties,which are all within the qualified range.The results showed that the emulsion was stable.Study on quality standards and preliminary safety evaluation of Aprepitant submicron emulsion injection.The quality of submicron emulsion was evaluated by the drug content,the mean particle size,p H value,peroxide value,free fatty acid value,anisidine value and glycerol value of emulsion.The measurement results showed that the indicators of Aprepitant submicron emulsion injection were qualified.Preliminary safety evaluation of submicron emulsion was carried out through hemolysis test,vascular irritation test and rat paw lick test.The security test showed that the submicron emulsion causes no hemolysis and had no irritation on vein and muscle irritation.Study on pharmacokinetics and tissue distribution of Aprepitant submicron emulsion.Atorvastatin calcium was selected as the internal standard to establish an HPLC in vivo analysis method,which has strong specificity,good reproducibility and high accuracy.Using APT emulsion as a reference,the pharmacokinetics of Aprepitant submicron emulsion injection in rats and tissue distribution in mice were studied.The results of pharmacokinetic experiments showed that APT emulsion and Aprepitant submicron emulsion injection have similar metabolic characteristics in vivo,with AUC_0-24h of 110.54±21.89mg/L·h and 104.70±11.87mg/L·h,the former is 1.06 times the latter.T_1/2are 4.51±0.48h and 4.31±0.41h,the former is 1.05 times the latter.C_max is 37.18±1.79μg/m L and37.22±1.62μg/m L,the former is 0.99 times the latter.The results of tissue distribution experiments showed that the drug concentration in the tissues of the APT emulsion group at each time point was higher than that of the Aprepitant submicron emulsion injection group.And the order of drug concentration in tissues was liver>spleen>kidney>Lung>heart at each time point.