The Optimization Of Membrane Emulsification Settlement Process And Its Verification On The Exenatide Microsphere

With the development of modern pharmaceutical industry,more and more protein and peptide drugs have attracted our attention because of great medicinal value.In 2002,FDA had approved 12 protein drugs.But the structural instability,short half-life and low oral exploitation degree,their clinical application are limited.For long-term injection protein and polypeptide drug,microsphere for long-acting sustained release is one of the important agents in the pharmaceutical industry,not only can reduce the number of injections,also can guarantee stable blood drug concentration with slow release.There are many products in the market such as Bydureon~?and Lupron~?which used to treat diseases such as diabetes,endometriosis.Microsphere preparation technology is multifarious,difficulty of quality control,and so far only a few products come into the market,making microspheres niche preparations.Since the late 80s,the concept of membrane emulsification was raised,and become focus soon because of simple and easy to get high quality uniform microspheres.However,we still need to consider the cost problem of aseptic filling operations for Industrial production.Our laboratory has developed a set of equipment for membrane emulsification subsidence,which can prepare biological macromolecular microspheres under the condition of sterile environmental without collision,shear force and high temperature,and easy to get particle size uniformity,Compared with traditional membrane emulsification method,our particle size uniformity increased from 0.432 to0.221,and more easy to realize fluid filling unit operations.This research adopts the membrane emulsification settlement process,prepared exenatide long-term sustained release microspheres under the condition of SPG membrane of 20 microns,～6kpa nitrogen pressure,150-200times/min vibration frequency,and the particle size distribution in the 40-60 um with a higher uniformity.We investigate the drugs stability of the peptide in p H7.4 PBS buffer at different temperature by HPLC.According to the results,exenatide at 37℃PBS buffer is extremely unstable.This paper has established the HPLC analysis to exenatide with the solution of dimethyl sulfoxide.We used exenatide as model drug and design six kinds of prescription,confirms the feasibility of membrane emulsification settlement process,by inspecting scanning electron microscopy,loading capacity,encapsulation efficiency,particle size distribution and in vitro release study.The results showed he microspheres have encapsulation efficiency as high as 90%,the cumulative release up to 94%in 30 days,and also have smooth surface,uniform size distribution.The process parameters are adjustable and controllable and easy to realize repeat between batch,which have great potential for the future development of the industrialization.We look forward to this method will create greater changes for domestic biological macromolecular microspheres process.