Study On In Vitro–in Vivo Correlation And Stability Of Thienorphine Microspheres For Injection

Opioid drug dependence is one of the major problems of drug dependence worldwide.Drug users’physical dependence on drugs can be effectively curbed through opioid or non-opioid treatment programs,but psychological cravings often drive many addicts back to drug use and relapse.At present,the clinical application of anti-relapse drugs include opioid receptor agonists methadone,dexpropoxifen,opioid tincture,etc.However,agonists are"little poison instead of big drug",but easy to addiction,lax control or improper use will become a new drug.Antagonists have poor compliance and are difficult to suppress patients’subjective desire for drugs.Therefore,the development of new,less addictive opioid receptor partial agonists.Through the drug delivery system,the drug can be released slowly within the body,allowing the drug concentration of the blood or specific parts to be maintained within a long period of time,thereby reducing the number of drugs and reducing the risk of producing a toxic side.Poly（lactic-co-glycolic acid）（PLGA）is a commonly used polyester type control carrier,which has a clinical advantage,and this paper has carried out the study of the in vitro and in vivo correlation and the stability of the long-term and sustained release microspheres of thienorphine.The content and results of this research are summarized as follows:1.Scale up the pilot test based on the test results in the laboratory production stage.The drug load,particle size,Span value and encapsulation rate of microspheres prepared in the laboratory production stage can stabilize the production.Based on the previous research,the oil-water phase pump speed,uniform speed and cleaning method of microspheres were screened after the oil-water equal proportion amplification,in order to reach the target particle size D₅₀:28μm～32μm and Span value in the laboratory production stage:1.14～1.40.The dose of irradiation sterilization after microsphere production was screened to provide reliable basis for product sterilization.2.The quality of the pilot-scale production of thienorphine microspheres was studied,and the content,release,related substances,polymer molecular weight,particle size and other determination methods were verified.The stability of the prepared three batches of pilot-scale microspheres was studied.It was found that the microspheres were unstable in high temperature and high humidity environment,and their release behavior was easily affected.Therefore,it was necessary to preserve the microspheres at low temperature and sealed.Accelerated and long-term tests showed that thienorphine long-acting sustained release microspheres should be stored at 5℃±3℃for a long time,short-term storage at room temperature,stability test provides reference for the packaging,transportation,storage of microspheres.3.The use of solvent in thienorphine microspheres was also investigated.First of all,Lupron Depot?is selected from the solvents used in the market microspheres,which is closer to the osmotic pressure and p H of the human body.Then,the compatibility experiment of raw materials and auxiliary materials was conducted to find that Tween-80 and CMC-Na would cause a decrease in p H value.Later,Tween-80 or CMC-Na would be replaced for another test to obtain a stable solvent.4.The bioavailability of thienorphine long-acting sustained release microspheres was also screened,and the bioavailability of subcutaneous injection was higher than that of intramuscular injection.Based on this,A class in vitro and in vivo correlation model was established.