Clarithromycin Submicron Emulsion For Injection

Parenteral submicro-emulsion,with high biocompatibility,low toxicity and irritation,has been widely used as an excellent drug delivery carrier.Clarithromycin has wide antibacterial spectrum and strong antibacterial activity.However,clarithromycin i.v.can cause serious venous irritation,and thus developing a new preparation i.v.is quite necessary.The aim of this thesis was to prepare thermal sterile stable and lower i.v.irritation clarithromycin submicro-emulsion(ClaE)using high-pressure homogenization technology.An HPLC method was established for the analysis of ClaE in vitro.The solubility,stability and oil phase-water phase partition of clarithromycin were closely related with the pH of mediums.At low pH,the chemical stability was bad.By increasing the pH of mediums,the solubility decreased and oil phase-water phase partition turned higher.The solubility of clarithromycin in LCT,MCT and safflower oil were all below 4mg/mL while it was 52.25mg/mL in V_E.So V_E can be selected as an oil solvent for preparing ClaE.High pressure homogenization was used to prepare ClaE.HPLC,dynamic light scattering and electrophoretic light scattering technology,and ultrafiltration were also employed.Taking physical appearance,pH,particle size distribution(PSD),ζ-potential,content,entrapment efficiency and thermal sterile stability as index,the final formulation and preparation process for ClaE using V_E as oil phase were as follows:as quality percentage,oil phase was composed of 0.25%clarityromycin,10%MCT,5%V_E,1%soybean lecithin;the water phase was composed of 2.5%glycerol,0.2%F-68,0.2%Tween-80,2%EL-40,0.1%sodium oleate and 0.05% L-Cysteine;and the oil phase and water phase were both heated to 55℃;the homogenization pressure and cycles were 600bar and 8 times;the pH was adjusted to 8.0 and then ClaE was sterilized in a rotating water bath at 100℃for 30min.The thermal sterile stability of ClaE using V_E as oil phase were carefully investigated including the effects of different sterile time,sterile methods,drug concentrations and pH values. The results showed that sterilization in a rotating water bath at 100℃for 30min can maintain the stability of ClaE while the pH was adjusted to 8.0 before sterilization.The results of high temperature accelerating test and room temperature stability investigation indicated that after storage at 40℃and 60℃for 10 days or at 25℃for 3 months,the drug content of ClaE were all below 90%of the effective content.In addition,as the safe application for large dose of V_E is unknown and EL-40 has serious adverse effects,therefore,based on more deeply research, preparing clarithromycin-phospholipid complex was employed to prepare ClaE.The reaction solvents,the ratios and types of phospholipids were investigated,and the clarithromycin-phospholipid complex was finally prepared with clarithromycin and soybean lecithin at a ratio of 1:10 in dehydrated alcohol at 65℃for 3h,and then the reaction solvent was evaporated to obtain dry residue.DSC was also employed to identify the formation of the complex and analyze the possible interaction between clarithormyin and phospholipids.The final formulation and preparation process for ClaE using clarithromycin- phospholipid complex were as follows:as quality percentage,oil phase was composed of 0.25% clarityromycin in the form of the complex,16%MCT,4%LCT,1%soybean lecithin;the water phase was composed of 2.5%glycerol,0.2%F-68,0.2%Tween-80,0.1%sodium oleate and 0.02%L-Cysteine;and the oil phase and water phase were heated to 55℃and 80℃, respectively;the homogenization pressure and cycles were 700bar and 7 times;the pH was adjusted to 8.0.and then ClaE was sterilized in a rotating water bath at 100℃for 30min.The characteristics including PSD,ζ-potential,drug content and entrapment efficiency of ClaE using clarithromycin-phospholipid complex were 140.3±47.2nm,-20.99mV,101.1%and 91.4%,respectively.Shaking stability test showed that the particle size of ClaE had no significant variation and there were also no flocculation and coalescence.After accelerating test at 60℃for 10 days,the drug content only reduced 5.7%.In addition,the results of long term stability test at 25±2℃and 10±2℃for 6 months showed that the characteristics of ClaE were nearly unchanged,and therefore,ClaE using clarithromycin-phospholipid complex was stable enough and had the potential for industrial production and clinical application.UPLC/MS/MS method was established to determine clarithromycin concentration in rat plasma.Taking clarithromycin solution(ClaS)as reference,both ClaE using clarithromycinphospholipid complex and ClaS fitted three-compartment model and their pharmacokinetic curves were similar.The main pharmacokinetic parameters of ClaE and ClaS analyzed by statistical moment method showed no statistically differences(n=6,P＞0.05)except Vss.AUC_0-t and MRT of ClaE and ClaS were(44.96±7.222)and(38.52±28.455)mg/L*h,and(4.162±0.653) and(4.896±2.809)h,respectively.