| Ligustrazine lipid emulsion(LLE for short)is a kind of sustained-release injection,targeting to decrease the degrees of irritation,based on lipid emulsion drug delivery system.The formulation was established on lipid emulsion,optimized by univariate analysis and orthogonal experimental design.For the preparation of lipid emulsion soybean oil and oleic acid were used as the oil phase,PL-100M egg yolk lecithin and poloxamer188 as surfactants and glycerol as co-surfactant.An optimized formulation consisting of soybean oil(12.0%),oleic acid(0.6%),PL-100M(1.0%),poloxamer188(0.6%),glycerol(2.25%)and ligustrazine hydrochloride(0.5%)was selected.The results showed that the average particle size,polydispersity index(PDI),D50,D90,zeta potential,entrapment efficiency and content of ligustrazine hydrochloride of the optimized formulation were 212.6 ± 2.1 nm,0.085 ± 0.013,136.5 ± 13.1 nm,263.2 ± 15.4 nm,-48.6 ± 3.3 mV,66.5 ± 3.4%and 4.95 ± 0.12 mg·mL-1,respectively.LLE was at room temperature storage for six months,and each index was detected at the 0th,5th,15th,30th,60th,90th and 180th day,respectively,results indicated that all parameters had non-significant difference,meaning that LLE had a good stability.Hemolysis tests in vitro showed that LLE would induce hemolytic reaction compared with ligustrazine hydrochloride for injection(LI for short),but it would not do if it was diluted by more than 750 times,so LLE would be secure,if it was used within the concentration range in clinic.Furthermore,release in vitro was conducted to determine the sustain-release property of LLE.Datum indicated release of LLE and LI were both fitted zero-order kinetics,and LLE had a satisfyingly sustained-release property compared with LI.14 male SD rats were administrated a single intravenous dosage level of 22 mg·kg-1 of LLE,and the same rats were received the same dosage level of LI as check experiment,ligustrazine(calculated by ligustrazine hydrochloride)in plasma of 28 rats at various sampling time were detected by HPLC,respectively.Pharmacokinetic parameters were calculated by a WinnoNlin software version 4.1 and analyzed by statistic analysis.The mean concentration-time curves of LLE and LI were both fitted to two-compartment model.T1/2? were 0.013 ± 0.001 hr and 0.014 ± 0.001 hr,T1/2?were 1.415 ± 0.043 hr and 0.806 ± 0.031 hr;AUC0-10hr were 75.59 ± 1.75 ?g·mL·hr-1 and 46.09 ± 1.28 ?g·mL·hr-1,respectively.Compared with the reference preparation,LLE had a 75.5%longer elimination half life and a 64.01%higher bioavailability.Based on AUC0-10 hr,datum of analysis of variance(P<0.01)and t test(P<0.01)demonstrated that highly significant difference existed between two groups in statistical.In other words,LLE had ameliorated the pharmacokinetics properties of LI.Other 72 male SD rats were divided into two groups randomly,the model group were injected a single intravenous dosage level of 22 mg·kg-1 of LLE,and the check group were received the same dosage of LI.Rats were sacrificed at different sampling time,and plasma,heart,liver,lung,spleen,kidney and brain were taken out for assay.The content of ligustrazine in SD rats was both fitted plasma>liver>kidney>brain>lung>heart>spleen.AUC0-3hr were improved by 24.59%,30.99%,11.86%,29.23%,23.55%,20.82%and 29.71%in plasma,heart,liver,spleen,lung,kidney and brain,respectively,compared with the check group.Based on AUC0-3 hr,datum of analysis of variance(P<0.01)and t test(P<0.01)proved that the difference in statistical between the two groups was highly significant.In other words,the distribution property of ligustrazine has changed by lipid emulsion drug delivery system. |
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