CESCO-CANCIAN, Sergio,HOY, Thomas,TRAPPLER, Edward,THOMAS, Michael
申请号：
ES13716655
公开号：
ES2557805T3
申请日:
2013.03.28
申请国别(地区):
ES
年份:
2016
代理人:
摘要：
A method of manufacturing a lyophilized synthetic pulmonary surfactant having a reduced or eliminated cake levitation during the process, the process comprising: providing a lyophilization chamber with a pre-lyophilization mixture comprising dipalmitoyl phosphatidylcholine (DPPC), palmitoyloleoyl phosphatidylglycerol (POPG), palmitic acid and a synthetic peptide with SEQ ID NO: 1 (KL4 polypeptide) dispersed in a solvent having an organic solvent in a range of between 3% (v / v) and below 20% ( v / v) of the total volume of the pre-lyophilization mixture, the remainder being water and / or a buffer, wherein the pre-lyophilization mixture is filled in a container； reduce the temperature inside the lyophilization chamber to begin cooling and solidification of the pre-lyophilization mixture in a freezing phase； wherein the freezing phase comprises cooling the pre-lyophilization mixture to a first temperature of -45 ° C or below -45 ° C at a speed between 0.1 and 1.0 ° C / min and maintaining the pre-lyophilization mixture at the first temperature for a first period of time sufficient to solidify at least 76% of the solvent to form a first solidified mixture； carrying out the annealing phase before a primary drying phase and reducing or eliminating by this means the levitation of the cake of the first solidified mixture and in the lyophilized synthetic pulmonary surfactant, wherein the annealing phase comprises (i) heating the first solidified mixture at a second temperature selected to reduce or eliminate the levitation of the first solidified mixture, (ii) keep the first solidified mixture at the second temperature for a second period of time sufficient to reduce or eliminate the levitation of the first mixture solidified, and (iii) cooling the first solidified mixture to a third temperature of -45 ° C or below -45 ° C at a rate between 0.1 to 1.0 ° C / min to form a second solidified mixture, wherein the second solidified mixture is maintained at the third temperature
