| Objectives:Azithromycin is a broad-spectrum antibacterial drug with a very wide range of clinical applications.It is the first choice for pneumonia and is recommended by the"Clinical Reasonable Use of Antibacterial Drugs".The main dosage forms are injections and oral preparations.There are many types of azithromycin oral preparations on the market,such as granules,dry suspensions,capsules,etc,but their bioavailability is only 37%,the oral dosage is large,and the adverse reactions rate reached 12%.At the same time,during the treatment of children,especially infants and young children,the dosage of existing preparations is not easy to grasp,which affects the safety of medicines.Therefore,it is very necessary to develop an oral administration system of azithromycin that can significantly improve the bioavailability and provide more options for clinical applications.As a nano-level drug carrier,self-microemulsion can effectively solve the problem of low solubility and low permeability of azithromycin,and its preparation process is simple.In this study,an oral azithromycin self-microemulsion delivery system（AZM-SMEDDS）was established through screening and optimization,and the system characteristics and stability were being studied;taked the marketed preparation Xishumei?as the reference preparation,comparative study of the pharmacokinetic behavior of AZM-SMEDDS in rats and mice,tissue distribution in mice,and the antibacterial activity in mice.It is hoped to obtain a new oral azithromycin delivery system with significantly improved bioavailability and improved drug safety.Methods:1.Establishment of AZM-SMEDDSThe basic physical and chemical properties of azithromycin were put into study through apparent oil-water partition coefficient and solubility tests.The types of oil phase and surfactants were preliminarily screened through the solubility test of azithromycin in various excipients,and the proportion of surfactants was determined by compatibility test of excipients.We drawed a pseudo ternary phase diagram to determine the type of co-surfactant,through response surface-star point design,used encapsulation rate,light transmittance and emulsification time as indicators to further determine the oil proportion and Km value,added flavors,and selected the type and dosage of stabilizers based on the results of the 40°C high temperature test.AZM-SMEDDS was successfully established.2.Characteristic study and stability evaluation of AZM-SMEDDSThrough appearance,particle size and distribution,DSC and FTIR,the relevant characteristics of the AZM-SMEDDS were put into study.Taking traits,content,stratification phenomena and related substances as the stability inspection items,the stability of the AZM-SMEDDS was investigated through influencing factors,accelerated and long-term tests.3.Preliminary study on the pharmaceutical behavior of AZM-SMEDDSBy simulating four different physiological p H of the gastrointestinal tract in vitro,we explored the difference between the release of AZM-SMEDDS and the marketed preparation Xishumei?at different physiological p H,and established a plasma azithromycin content detection method——antibiotic microbial assay method,and compared the pharmacokinetic behavior of AZM-SMEDDS and the marketed preparation Xishumei?in rats and mice,then,calculated their relative bioavailability,and studyed its tissue distribution in mice.4.Preliminary study on the antibacterial activity of AZM-SMEDDSStaphylococcus aureus was used as the test strain to study the difference between the self-microemulsion state and the original drug state to the microbial susceptibility test,so as to judge the difference in antibacterial effect in vitro.By establishing a mouse infection model of Staphylococcus aureus,using mouse survival rate,weight change,lung index and lung wet-to-dry ratio（W/D）as inspection indicators,we need to compare the in vivo antibacterial activity of the AZM-SMEDDS and the marketed reference preparation Xishumei?.Results:1.Through the study of the establishment of AZM-SMEDDS,solubility and system composition compatibility tests confirm that MCT was used as the oil phase,and TW80:ELP=1:1 was used as the mixed surfactant,when the co-surfactant was PEG600,the area of the pseudo-ternary phase diagram self-microemulsion was the largest;the star point design test results showed that the Km value of the azithromycin self-microemulsion prescription is 2,and the oil ratio（%）=8.7%,it is the best composition of the system.The addition of 0.2%sucralose could well mask the bitter taste of azithromycin.The best stabilizer was selected as Sta-3 under the high temperature condition of 40℃.When the addition amount is 0.1%,the system produced the least amount of impurities.The optimal prescription is named YPL609.2.YPL609 was in a clear and transparent microemulsion state at room temperature.The particle size was 13.40±0.28 nm,the polydispersity coefficient（PDI）is0.111±0.019,the particle size was small,the distribution range was narrow and the distribution was uniform;DSC and FTIR indicate that the azithromycin drug molecule was contained in the self-microemulsion system,rather than a simple physical mixing state,the stability test results proved that the YPL609 has good stability.3.The in vitro release test results showed that under the conditions of 4 different p H values（p H=1.2,4.5,6.8,7.4）,more than 60%of azithromycin in YPLL609 existed in the form of microemulsion droplets,and a small amount exists as free molecules,and YPL609 had a good drug loading condition.The marketed preparation Xishumei?was used as a reference preparation to compare the pharmacokinetic behavior of YPL609 in rats and mice and the tissue distribution in mice.After a single oral administration,in SD rats,the AUC0→∞=18.23μg*h/m L,and the AUC0→∞=11.31μg*h/m L of Xishumei?,with a relative bioavailability of 161%;in KM mice,the AUC0→∞=43.23μg*h/m L,the AUC0→∞=19.78μg*h/m L of Xishumei?,the relative bioavailability was 219%,the drug concentration of YPL609 in lung tissue was significantly higher than Xishumei?（P<0.05）.4.Staphylococcus aureus was used as the test strain to investigate the difference between the self-microemulsion state and the original drug state to the microbial susceptibility test.The results showed that the self-microemulsion state and the original drug state had the same antibacterial effect.A mouse lung infection model of Staphylococcus aureus was establishing,and the marketed preparation Xishumei?were used as the reference preparation.After the respective administrations,the survival rates of YPL609 and Xishumei?mice were both greater than 80%.The weight of the mice in the YPL609 group decreased first and then increased,The weight of the mice in the Xishumei?group showed a continuous downward trend,but after 48 hours,the downward trend slowed,the lung index and lung wet-to-dry ratio（W/D）of the YPL609group and the Xishumei?group were significantly lower than those of the model group（P<0.01）.The results shows that compared with the reference preparation Xishumei?,YPL609 is supported by the pneumonia model drug data,and both have curative effects.Conclusion:In order to solve the problem of low bioavailability of the marketed azithromycin oral preparations,this article used a self-microemulsifying drug delivery system to solubilize azithromycin,selected and optimized the composition,and successfully established an AZM-SMEDDS that can significantly promote absorption and had good stability.This system significantly improved the oral bioavailability of azithromycin in rats and mice.Its plasma AUC value in rats was 1.61 times that of the reference preparation Xishumei?,and its plasma AUC value in mice was the same as that of Xishumei?.and its plasma AUC value in mice was 2.19 times that of Xishumei?,the lung tissue drug concentration in mice is significantly higher than that of Xishumei?（P<0.05）.A mouse lung infection model of Staphylococcus aureus was established,and the antibacterial effects of the self-made AZM-SMEDDS and the reference preparation Xishumei?were compared,and it is found that the self-made AZM-SMEDDS and the reference preparation Xishumei?supported by the pneumonia model drug data,both have curative effects.Finally,the self-made azithromycin self-microemulsion system can significantly improve the oral bioavailability of azithromycin. |
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