Scale Enlarging Of Membrane Emulsification Sedimentation Microsphere Preparation Method

More and more peptides and chemical drugs must be administered by injection,but the only available dosage form for monthly long-acting injection is degradable polymer microsphere.Nevertheless,microsphere has been applied on only 8 drugs since the first microsphere product came into the market 33 years ago.The main reasons for the contrast between the demand and output of microsphere preparation are the cumbersome and inefficient production progress as well as the low reproducibility.For instance,the current microsphere production process in industry requires5 to 6 steps of aseptic operations and more than 20 quality elements that must be strictly controlled.Therefore,microsphere is referred to as "complex preparation in complex preparation".In response to these problems,our laboratory has invented a self-consistent and simple new process-membrane emulsification sedimentation microsphere preparation method,which greatly simplified the microsphere preparation process and improved the reproducibility.In order to be recognized by the industry,the new formulation technology requires a process from small trials to pilot scales.The purpose of this study was to validate and optimize the membrane emulsification sedimentation microsphere preparation process on a pilot scale.To this end,we selected exenatide(the lowest dose of GLP-1 receptor agonist),which is most suitable for long-acting sustained-release administration,as a model drug,and used the self-made membrane-emulsion sedimentation microsphere preparation machine to optimize the exenatide microsphere preparation.In our study,we developed the preparation technique of exanatide microsphere and investigated the effects of several parameters,including the use of release regulators and treating method of exanatide,on the encapsulation efficiency and in vitro release behavior of microspheres,examined the particle size distribution range of magnesium hydroxide particles,screened for the optimal formulation of exenatide microspheres,tested the long-term stability of exenatide microspheres,optimized the membrane emulsification sedimentation process parameters,and prepared exenatide microspheres according to the scale of the test.The results showed the best prescription was that the concentration of PLGA in methylene chloride solution was 15%(w/w),the loading of exenatide was4%,and the content of magnesium hydroxide was 5%.The magnesium hydroxide is stored in an ethanol dispersion treatment at-80℃,so that the magnesium hydroxide particles have a particle size ranging from 100 nm to 1.5 μm.The content of exenatide microspheres was stable within 6months at 4℃.Other process parameters including 10 mm rocker connection distance,5 r/s rocker speed and 20 μm pore size of SPG membrane were considered to be beneficial to the uniformity of the microspheres.Exenatide microspheres with high encapsulation efficiency(98%),uniform particle size(D50 55.79 μm),and ideal release profile(total release of more than 90% in 30 days)were successfully prepared by pilot-scale equipment.In conclusion,the membrane emulsification sedimentation microsphere preparation method realizes the simplification and quality reproduction of the microsphere preparation on the pilot scale,and verifies the membrane emulsification sedimentation device which can realize self-consistent microsphere preparation.