胶塞处理过程对易吸潮类冻干制品的水分有影响 ― 以乳糖为例

I摘要存放过程中，由于胶塞中的水分有可能会转移到冷冻干燥制品中，从而胶塞的水分会对冷冻干燥制品的水分含量造成影响。胶塞中释放的水分可能会对冷冻干燥制品的质量造成不良影响。本研究的目的是评估处理过程和存放条件对胶塞水分含量的影响。胶塞在使用前，会进行清洗和灭菌。这些处理过程，尤其是灭菌处理会增加胶塞的水分含量，增加的幅度与胶塞的材质有密切关系。对于易吸潮类冷冻干燥制品而言，在存放过程中，这些被吸收的水分会从胶塞中释放出来然后转移至产品中。因此，需要一个合适的干燥过程来将胶塞的水分干燥至可以接受的水平。胶塞水分研究的内容包括胶塞的材质，灭菌温度和时间，干燥温度和时间，存放的包装和条件，冷冻干燥对胶塞水分含量的影响以及水分从胶塞中转移至乳糖模型冷冻干燥品。结果证明胶塞在灭菌过程中会吸收大量的水分。为了得到水分较低的胶塞，需要在105ºC条件下干燥至少4小时。干燥结束后，在室温存放条件下，胶塞的水分会迅速重新平衡。胶塞中的水分在冷冻干燥过程不会解吸附出来。在进行水分含量对冷冻干燥制品稳定性影响的风险评估时，制品性质和灌装量都是很重要的因素。对于易吸潮的制品，尤其是低灌装量或小规格的制品，胶塞水分含量的控制尤其重要。最后，胶塞中的水分转移至冷冻干燥制品的多少取决于初始胶塞的水分含量。为了减少水分带来的稳定性问题，有必要选择合适的胶塞以及对胶塞进行合适的处理和保存。关键词：胶塞，处理过程，冷冻干燥制品，乳糖，水分含量IITheConditionsofStopperProcessingCanImplicatetheWaterContentofHygroscopicLyophilizedProducts:AstudywithLactoseStoppermoisturecontentcanhaveasignificantimpactonthewatercontentoflyophilizeddrugproductsduetothepotentialofmoisturetransferfromstoppertoproductduringstorage.Moisturereleasedfromrubberstoppersmayadverselyaffectthequalityoflyophilizedproductduringstorage.Thepurposeofthisstudywastoevaluatetheeffectofprocessingandstorageconditiononthemoisturecontentofrubberstopper.Priortoitsapplication,arubberstopperiswashedandsteamsterilized.Theseprocesses,especiallytheprocessofsteamsterilization,increasethemoisturecontentoftherubberstopperandthemoistureuptakecanvarygreatlydependingontherubberformulation.Asufficientdryingcycleisneededtodrystopperstoanacceptablemoisturelevel.Thestoppermoisturestudiesincludedtheeffectofrubberformulation，steamsterilizationtime,dryingtimeandtemperature,storagemethodandconditions,lyophilizationandmoisturetransferfromstoppertoamodellyophileoflactose.Resultsindicatedthatstoppersabsorbedsignificantamountofmoistureduringsterilization.Toachievefinalmoisturecontentatalowerlevel，stoppersrequiredatleast4hofdryingat105℃.Afterdrying,stoppermoisturelevelsequilibratedrapidlytoambientstorageconditions.Therewasnomoisturedesorptionoftherubberstopperduringthelyophilisationprocess.Bothlyophilizedformulationandproductfillmassareimportantfactorsinassessingtheoverallriskofelevatedmoisturecontentonproductstability.Stoppermoisturecontrolwillbeofgreaterimportancewhendealingwithhygroscopicproducts,especiallyinlowfillmassdosagepresentations.Finally,moisturetransferfromstoppertolyophilizedproductisdependentontheinitialstopperwatercontent.Tominimizetheriskofmoisture-relatedstabilityproblems,thechoiceofanappropriatestopper,processingparameters,andstorageIIIconditionspriortouseareessential.Keywords:stopper,processing,lyophilizedproducts,lactose,moisturecontentIV目录摘要...........................................................................................................................I目录.........................................................................................................................IV第1章绪论...............................................................................................................11引言..........................................................................................................................12研究方案..................................................................................................................22.1模型药物的选择.....................................................................................................22.2胶塞的处理过程对胶塞残留水分的影响.............................................................22.3胶塞中的水分对冻干乳糖水分的影响.................................................................3第2章胶塞处理过程对胶塞残留水分的影响...........................................................51物料与仪器..............................................................................................................51.1物料.........................................................................................................................51.2仪器.........................................................................................................................62胶塞水分含量测定方法..........................................................................................63清洗和蒸汽灭菌对胶塞的残留水分影响..............................................................84干燥过程对胶塞的残留水分影响..........................................................................95存放包装条件对胶塞的残留水分影响................................................................126冷冻干燥对胶塞水分的影响................................................................................14第3章胶塞中的水分对冻干乳糖水分的影响.........................................................171物料与仪器............................................................................................................171.1物料.......................................................................................................................171.2包装材料...............................................................................................................171.3仪器.......................................................................................................................172乳糖水分含量测定方法........................................................................................183容器密封完整性.................................