Study On Preparation And Characterization Of Solid Lipid Nanoparticles Carrying Oxytetracycline And Its Pharmacyokinetics In Rabbits

Oxytetracycline (OTC), a broad-spectrum antibiotics in tetracycline family, is widely used to treat swine enzootic pneumonia,eperythrozoonosis and endometritis of cows, which is often used as a growth promoter and a feed additive. But it is difficult to achieve therapeutic concentrations in the blood,because of instable, irregular and incomplete oral absorption of its solution. Long-term use of Oxytetracycline will result in superinfection,causing poisoning and death.Solid lipid nanoparticles(SLN) is a promising drug delivery system with solid lipid as drug carriers,particle diameters ranging between50and1000nm, which has the advantages of high physical stability, slow speed of drug leakage and good targeting property,etc. Solid lipid nanoparticles carrying Oxytetracycline(OTC-SLN) was prepared by the method of emulsification evaporation-solidifictiotion at low temperature,with non-ionic surfactant poloxamer188as a emulsifier,and glycerin monostearate as a lipid carrier.The related properties and pharmacokinetic in rabbits of OTC-SLN were studied, intending to make it release slowly,prolong biological half-life,tissue distridution and redue the administration times.The analysis method in vitri of OTC was established before prescription-Ultraviolet spectrophotometry,for determining the encapsulation efficiency and drug loading. The regression equation of concentration and absorbance of Oxytetracycline was: A=0.03946C+0.011700(r=0.9999, n=5). The linear range was5～25μg/mL. The intro-day and inter-day precision was0.84%～1.46%and1.75%～2.44%, respectively. The results accord with the drug content determination requirements.The solubility experiments showed that higher solubility of OTC in acid and conditions.The result of partition coefficient in oil/water showed that Oxytetracycline was lipophilic drugs and exisited problems of poor hydrophilicty.Stability determination of Oxytetracycline aqueous showed that OTC was unstable in light and high temperature.The praparation of OTC-SLN was optimized by single factor experimental design and orthogonal experimental design, the optimal technology was as follows:the amount of Oxytetracycline, monostearate,lecithin and poloxamer188are100mg,500mg,75mg and 450mg respectively. OTC-SLN was prepared by the method of emulsification evaporation-solidifictiotion at low temperature.The characteristic data shows that the OTC-SLN was round with mean particle size of345.8nm,dispersion index of0.512, Zeta potential of-34.7mV,the average entrapment efficiency51.25%and loaded drug10.25%. There were no obvious changes of the entrapment efficiency and loaded drug at4℃within one month. The release profile in ivtro was best fitted with distribution with sustained release effect,compared with the active compound.In addition,a freeze-drying method is investigated in order to improve the stability of the OTC-SLN suspension,using3%mannitol as a protector.The OTC-SLN and Oxytetracycline were administrated on health rabbits by peritoneal injection.Using drug concentration in plasma as an indicator,intraperitoneal pharmacokinetic differences between the OTC-SLN and OTC were compared. Plasma drug concentration was determined by HPLC, limit of detection of plasma concentration was0.15μg/mL. Pharmacokinetic parameters were analyzed by DAS3.1.0pharmacokinetic program. Oral pharmacokinetic behaviors of OTC suspension and OTC-SLN were investigated in plasma. The results showed that oral absorption has a markly improvement in OTC-SLN groups. The AUC(0-∞) of OTC-SLN is about2.03-fold higher than that of OTC suspension, Cmax of OTC-SLN is1.01-fold greater than that of OTC suspension, Tmax of OTC-SLN is4-fold later than that of OTC suspension.The results showed OTC-SLN may significantly enhancend the oral absorption and bioavailbility.OTC-SLN was successfully prepared in this experiment. The method was handy and simple, and the quality was adjustable. The quality evaluation, release test in vitro and pharmacokinetic experiment indicated that OTC-SLN obtained targeting,and sustained-release. It is potential to be used as a good carrier in drug delivery system.