The Preparation And Pharmacokinetic Studies Of Injectable Itraconazole Nanosupension

The minimal solubility in water of many poorly soluble drugs lead to their bio-availability be greatly reduced,which reduce their efficacy.The increases of the using dose may cause serious toxic and side effects,limiting the clinical application of many water insoluble drug,such as poorly soluble itraconazole.In recent years,nanosuspensions have become an effective dosage form to increase the solubility of hydrophobic drugs and to improve their efficacy.But its stability is usually poor,meanwhile.An appropriate stabilizer can improve the stability and restrain the aggregation of particles.Amphiphilic poly amino acid compounds with both hydrophilic and hydrophobic used as a stabilizer of the nanosuspensions may improve the stability of nanosuspensions.Because of its advantages of biodegradability and good bio-compatibility,it has a significant advantage in the preparation of nanosuspensions with good stability.So in this paper itraconazole will be prepared for nanosuspensions with amphiphilic poly amino acid compound poly(ethylene glycol)-poly(aspartic acid benzyl ester as the stabilizer to improve the solubility of itraconazole and the stability of the production.Firstly,Poly(ethylene glycol)-poly aspartic acid benzyl ester amphiphilic diblock copolymers with different molecular weight was synthesized by the L-aspartic acid,triphosgene and methoxy polyethylene glycol amine(MPEG-NH2).The structure of the copolymers was characterized by NMR,IR and fluorescence spectrophotometer.And poly(ethylene glycol)-poly aspartic acid benzyl ester with good biological compatibility acted as a stabilizer to prepare itraconazole nanometer suspension with good physical stability by means of microprecipitation-high pressure homogenization.The prescription and technology were screened by the single factor test making particle size and its distribution(PI)as the index.Nano freeze-dried powder was obtained though freeze drying.Then the particle size and distribution,zeta potential,particle morphology and physical state were respectively studied through these technologies of transmission electron microscope,scanning electron microscope,differential scanning calorimetry(DSC)and X-ray powder diffraction.High performance liquid chromatography(HPLC)method for the determination of itraconazole was established and was used to investigate the content and the dissolution in vitro of itraconazole nanosuspensions agent.At the same time,the stability of the nanosuspensions was also investigated.On the basis of evaluation in vitro,we further established the method for the content determination of itraconazole in plasma and evaluated the pharmacokinetic properties and tissue distribution for the itraconazole nanosuspensions.The synthesis of amphiphilic block copolymers of poly ethylene glycol poly aspartate benzyl ester were confirmed by IR and NMR data.The polymer with better stabilizing effect was selected from three kinds of polymers as the stabilizer for preparation of nanosuspensions.The average particle size and PDI of the prepared nanosuspensions was 268 nm and 0.15.The shape of particles were rectangular or square by transmission electron microscope.The DSC and XRD results showed the structure of itraconazole nanosuspension for crystal structure.The results of in vitro dissolution showed a 3.3 fold increase in the dissolution of the nanoparticles compared to the bulk drug,while the accumulated dissolution was comparable to that of the commercially available injection.The stability results showed that the nanosuspensions prepared by using polyethylene glycol poly benzyl ester as stabilizer was stable at 4 ℃ for a week.There was no significant change in the size and content of freeze-dried powder in one month.ITZ-PBLA-Nanosexhibited better stability than ITZ-F68-Nanos.Finally,we studied the pharmacokinetic behavior of rats and the distribution characteristics of mice after intravenous injection of ITZ-Nanos and injection.The results showed that AUC(0-∞)of ITZ-Nanos group decreased compared to the injection group,MRT(0-∞)and t1/2 slightly prolonged.It declared the retention time in vivo of ITZ-Nanos group was longer.The drug concentration in different tissues in mice showed that itraconazole of ITZ-Nanos converged more easily in the liver,lung and spleen than the injection group.Compared with the control group,the drug concentration of the ITZ-Nanos group in heart and kidney was higher than the injection group.The results showed that ITZ-Nanos changed the distribution characteristics of the drug.