CN115029296A - 一种快速自崩解无菌培养基及其制备方法 - Google Patents
一种快速自崩解无菌培养基及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种快速自崩解无菌培养基及其制备方法,快速自崩解无菌培养基包括培养基基质和崩解剂,所述崩解剂由有机酸、碱和润滑剂组成;所述有机酸包括柠檬酸、酒石酸、酸性氨基酸中的一种或多种,所述酸性氨基酸选自谷氨酸或天门冬氨酸;所述碱包括碳酸盐或碳酸氢盐;所述润滑剂选自L‑亮氨酸、月桂醇硫酸镁中的一种或多种。本发明不仅改善培养基存储运输对温湿度的要求,显著提高培养基的货架期,最重要的是保证了大规模生产的稳定性、可靠性和经济性。
Description
技术领域
本发明属于无血清培养基技术领域,具体涉及到一种快速自崩解无菌培养基及其制备方法。
背景技术
目前CHO等哺乳动物细胞被广泛用于单克隆抗体、治疗性蛋白质药物等的工业化生产。此类产品的生产过程中,一个高效、稳定、低成本的生产工艺至关重要。生产过程除了涉及生产用细胞株,还需要大量的培养基。尤为重要的是,生产用培养基显著影响治疗性蛋白质产品的品质和生产成本。
培养基是细胞在体外培养的微环境,为其提供营养物质、合适的酸碱度以及缓冲系统,一般包括多种碳水化合物、氨基酸、维生素、无机盐、微量元素等。培养基根据成分分为含血清培养基、无血清培养基等多个种类。无血清培养基作为单克隆抗体等治疗性蛋白工业化生产行业的关键原材料,直接影响产品的质量、产量和安全性。目前在工业化大规模生产治疗性蛋白质的过程中,商业化的无血清培养基的主流形式为粉末状培养基,该类型培养基与空气接触面大,在存贮过程中容易受潮结块并污染。同时,该类型培养基在使用前的溶解过程中容易漂浮在液面,并成团、结块,引发培养基难于溶解等问题。即使通过持续搅拌促进溶解,也至少需要4h才能较充分溶解。同时,为了去除溶解过程中形成的团块,后续还需要过滤等环节。而且,传统粉末培养基的溶解、过滤环节,需要滤器完整性测试、长时间搅拌等过程。在培养基的溶解、搅拌和过滤过程中,由于培养基暴露在空气中的时间较长,暴露面较大,容易结块、污染。尤其是在工业生产过程中,传统粉末培养基经溶解后只能采用过滤除菌。而过滤除菌的液体培养基发生轻度污染时,很难在后续无菌检测中被检出。一旦这些轻度污染的培养基进入生产环节则会引发大面积生产体系污染,导致生产失败。上述现象提示传统粉末培养基存贮过程中易受潮、结块、污染,溶解过程时间长、容易成团和污染,因此从传统粉末培养基溶解得到的液体培养基的批次稳定性差、容易污染,从而降低蛋白质治疗产品的稳定性甚至引发生产失败。
因此,本领域迫切需要开发新的溶解便捷、灭菌彻底的培养基。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊,而这种简化或省略不能用于限制本发明的范围。
鉴于上述和/或现有技术中存在的问题,提出了本发明。
本发明的其中一个目的是提供一种快速自崩解无菌培养基,无血清、无蛋白、无动物来源,具备崩解迅速、彻底、无菌的优点,缩短培养基溶解时间,溶解过程中无需搅拌,溶解后无需过滤,大幅度缩短生产时间、简化生产工艺,从而避免培养基受潮、结团、溶解不彻底、污染的问题。
为解决上述技术问题,本发明提供了如下技术方案:一种快速自崩解无菌培养基,包括培养基基质和崩解剂,所述崩解剂由有机酸、碱和润滑剂组成;
所述有机酸包括柠檬酸、酒石酸、酸性氨基酸中的一种或多种,所述酸性氨基酸选自谷氨酸或天门冬氨酸;
所述碱包括碳酸盐或碳酸氢盐;
所述润滑剂选自L-亮氨酸、月桂醇硫酸镁中的一种或多种。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述有机酸选自柠檬酸或酒石酸;所述有机酸与所述培养基基质的质量比不超过10:100。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述碱选自碳酸钠、碳酸氢钠中的一种或两种的混合;所述碱与所述培养基基质的质量比不超过25:100。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述润滑剂与所述培养基基质的质量比为0.5~5:100;
其中,所述润滑剂为L-亮氨酸,所述润滑剂与所述培养基基质的质量比为1~5:100;优选L-亮氨酸与颗粒半成品质量比为1:100;
所述润滑剂为月桂醇硫酸镁,所述润滑剂与所述培养基基质的质量比为3~5:100;优选月桂醇硫酸镁与颗粒半成品质量比为3:100。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述培养基基质由氨基酸混合物、无机盐和添加物混合物以及维生素混合物按照24.8~36.1:61.3~73:1~2.2的质量比构成;本发明的培养基不仅包括氨基酸、无机盐、微量元素、维生素、碳水化合物等营养成分,还包含促进片剂自崩解的碱性碳酸(氢)盐、有机酸以及润滑剂等组分。其中,碱性碳酸(氢)盐、有机酸以及润滑剂还可以为细胞提供营养、维护渗透压和pH的缓冲体系。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述氨基酸选自20种必须氨基酸(或盐酸盐形式氨基酸),如L-苯丙氨酸、L-甲硫氨酸、L-色氨酸、L-组氨酸、L-赖氨酸、L-亮氨酸、L-苏氨酸、L-缬氨酸、L-异亮氨酸、L-天冬酰胺、L-脯氨酸、L-天冬氨酸、L-丝氨酸、L-谷氨酸、L谷氨酰胺、L-精氨酸、L-络氨酸、甘氨酸、L-半胱氨酸、L-丙氨酸。氨基酸作为细胞生长主要的碳源和氮源,即可用于蛋白质、核酸和脂类的生物合成,也能通过几个主要的中间代谢产物进入糖代谢进行供能;通过实验确定每一种氨基酸的合理用量范围,既满足细胞的营养需求,同时避免代谢溢流的出现;
根据本发明的实施例,所述氨基酸混合物,按质量份数计,包括L-精氨酸29~1000份、L-胱氨酸50~300份、甘氨酸59~497份、L-组氨酸51~720份、L-异亮氨酸109~981份、L-亮氨酸132~1119份、L-赖氨酸盐酸盐212~895份、L-甲硫氨酸20~434份、L-苯丙氨酸24~930份、L-丝氨酸154~941份、L-苏氨酸57~817份、L-丙氨酸9~498份、L-天门冬酰胺5~378份、L-天门冬氨酸5~307份、L-半胱氨酸盐酸盐5~505份、L-谷氨酸51~502份、L-脯氨酸0~352份、L-色氨酸24~1204份、L-酪氨酸79~612份、L-缬氨酸81~870。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:所述无机盐可以是选自本领域中细胞培养基中常用的无机盐:如Na+和K+主要用于维持细胞膜电位;Na+、Cl-和HCO3 -主要用于维持渗透压,HCO3 -和HPO4 2-作为pH缓冲体系,同时作为崩解的碱性组分;PO4 3-可作为核酸、磷脂和ATP等的合成原料;Mg2+与ATP合成耦联,与Ca2+一起参与细胞与细胞、细胞与基质的粘附。各个无机盐浓度的选择还需要同时考虑对渗透压的影响。
微量元素如铁(Fe2+)、铜(Cu2+)、锌(Zn2+)、铯(Se)、锰等主要作为酶的辅基参与细胞生命活动,如Fe2+和Cu2+二者均为线粒体中呼吸链的组成部分,参与电子传递;Zn2+作用时与胰岛素耦联;Se也可以作为氧化剂,是谷胱甘肽过氧化物酶的辅因子,消除氧化应激反应。微量元素细胞所需量微小,但缺乏会对细胞产生严重影响;
根据本发明的实施例,所述无机盐和添加物混合物,按质量份数计,包括氯化钙50~500份、硫酸铜0.001~0.1份、硝酸铁0.01~0.1份、硫酸亚铁0.1~1份、氯化钾100~500份、无水氯化镁10~100份、硫酸镁20~200份、磷酸二氢钠30~300份、磷酸氢二钠30~300份、硫酸锌0.1~1份、氯化钠2000~7000份、D-葡萄糖1000~6000份、次黄嘌呤二钠盐10~100份、Hepes 0~5000份、亚油酸0.1~1份、硫辛酸0.1~2份、腐胺0.1~1份、丙酮酸钠100~500份、胸苷1~5份、PF-68 50~2000份、亚硒酸钠0.001~0.010份、乙醇胺2~10。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:维生素是一类细胞所必需的微量成分,功能多样,通常作为酶的辅酶和辅基,在物质代谢中起重要作用。维生素分为脂溶性和水溶性两大类,如硫胺素(VB1)涉及糖代谢中转酮醇酶和转醛醇酶的羧基转移反应;吡哆醇(VB6)是氨基酸代谢中重要的辅酶,主要参与转氨反应;生物素是活化CO2的载体,参与丙酮酸脱氢酶和丙酮酸羧化酶反应,也参与脂肪酸的合成;钴胺素(VB12)参与分子内部C-C单键的重排,如甲基转移反应;烟酰胺是NADH和NADPH等脱氢酶的辅酶,作为电子载体参与生物氧化体系;核黄素(VB2)构成黄酶的辅基,作为电子载体参与生物氧化体系;泛酸钙是辅酶A和磷酸泛酰巯基乙胺的组成成分,主要起传递酰基的作用,在糖代谢、脂质分解代谢、氨基酸代谢以及脂肪酸合成均起作用;叶酸的活性形式是四氢叶酸,是除了CO2外所有一碳单位的重要受体和供体;硫辛酸是酰基载体,在α-酮酸氧化作用和脱羧作用起到酰基转移和电子转移功能;
根据本发明的实施例,所述维生素混合物,按质量份数计,包括D-泛酸钙4~51份、氯化胆碱21~209份、维生素B6氯化物5~53份、维生素B1氯化物5~56份、叶酸6~50份、肌醇52~506份、烟酰胺5~57份、维生素B2 1~12份、维生素B12 1~18。
作为本发明快速自崩解无菌培养基的一种优选方案,其中:本发明还可以包括碳水化合物,作为主要碳源和能源物质,其中最常用的是葡萄糖,可以额外添加补充丙酮酸钠,补充细胞能量的不足。
本发明还可以包括其它有机物分子,如脂类、抗氧化剂。细胞本身可以合成几乎所有脂类,但是唯一无法合成C9双键脂肪酸,因此需要额外添加C9双键脂肪酸,如亚油酸或者亚麻酸。磷脂主要用于形成生物膜的磷脂双分子层,因此额外添加氯化胆碱、乙醇胺和肌醇。如添加还原性谷胱甘肽作为抗氧化剂,则避免细胞在氧化应激过程中产生的超氧阴离子对细胞本身的严重损伤作用。
本发明的另一个目的是提供如上述所述的快速自崩解无菌培养基的制备方法,包括,
提供培养基基质;
将培养基基质湿法制粒成颗粒半成品;
将有机酸与所述颗粒半成品混合,再依次加入润滑剂、碱混合均匀;
将得到的混合物进行压片,获得快速自崩解培养基;
采用60Co-γ辐射灭菌,获得快速自崩解无菌培养基。
作为本发明快速自崩解无菌培养基的制备方法的一种优选方案,其中:具体包括,称量培养基组分,在球磨机中分别研磨粉碎混匀氨基酸混合物(简称A)、无机盐和添加物的混合物(简称B)、维生素混合物(简称C)三种或者其中一种初混物,各个组份依次放入球磨机中粉碎混匀120~300min,控制物料温度在5~35℃;
三种混合物分别采用20~80目过筛,冷却60~120min,形成初混物A、B、C,并密封避光保存;
按照一定比例,将三种混合物中的一种或者一种以上再次按照一定比例在湿法制粒机中混匀,混匀时间为30~80min,转速50~90rpm,切刀速度900~1200rpm;此时,在制粒锅中喷洒粘合剂进行制粒;
采用湿法制粒对混合完成的原材进行制粒,之后采用30~60℃低温干燥20-30h,控制水分不超过2%,过60目筛,获得颗粒半成品;
将有机酸与颗粒半成品混合,再与润滑剂混合,最后再与碱混匀,之后进行压片,获得快速自崩解培养基。
作为本发明快速自崩解无菌培养基的制备方法的一种优选方案,其中:所述将培养基基质湿法制粒,加入水或乙醇水溶液作为粘合剂进行制粒;
其中,采用乙醇水溶液作为粘合剂,乙醇浓度为20~60%;优选纯水或者30%乙醇水溶液。
作为本发明快速自崩解无菌培养基的制备方法的一种优选方案,其中:将润滑剂低温干燥,并采用60目筛进行过筛,之后用于片剂的制备。
作为本发明快速自崩解无菌培养基的制备方法的一种优选方案,其中:所述压片,采用旋转压片,速度10~50rpm,按照配置0.1L、0.5L、1L培养基的用量,进行三个规格快速自崩解培养基的制备。
与现有技术相比,本发明具有如下有益效果:
本发明快速自崩解无菌培养基技术解决了传统粉末培养基溶解时间长、过程复杂、有团块、批次不稳定和污染等问题。在存贮过程中,片剂培养基相比粉末培养基与空气中水分以及微生物等物质的接触面大幅下降,避免培养基在存贮过程中吸潮、结块、污染等问题。因此,本发明的快速自崩解无菌培养基技术不仅改善培养基存储运输对温湿度的要求,显著提高培养基的货架期,最重要的是保证了大规模生产的稳定性、可靠性和经济性。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。其中:
图1为本发明实施例1得到的快速自崩解无菌培养基和对比例1的传统粉末培养基不同条件下细胞生长效果对比图;
图2为本发明实施例1得到的快速自崩解无菌培养基和对比例1的传统粉末培养基不同条件下细胞活性效果对比图。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合说明书实施例对本发明的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
其次,此处所称的“一个实施例”或“实施例”是指可包含于本发明至少一个实现方式中的特定特征、结构或特性。在本说明书中不同地方出现的“在一个实施例中”并非均指同一个实施例,也不是单独的或选择性的与其他实施例互相排斥的实施例。
如无特别说明,实施例中所采用的原料均为商业购买。
实施例1
(1)按照表1~3的比例称取各组分原材料;
表1
表2
表3
在球磨机中分别研磨粉碎混匀氨基酸混合物A、无机盐和添加物的混合物B以及维生素混合物C,各个组份依次放入球磨机中粉碎混匀240min,控制物料温度在25℃;
三种混合物分别采用60目过筛,冷却120min,形成初混物A、初混物B和初混物C,并密封避光保存;
(2)按照质量比A:B:C=27:72:1,将初混物A、初混物B和初混物C放入湿法制粒机中进行混合,混匀时间为60min,转速75rpm,切刀速度1000rpm;
(3)在湿法制粒机中喷洒25%乙醇作为粘合剂进行制粒,获得潮颗粒;
(4)再放入低温干燥箱中进行干燥,参数为温度35℃干燥24h,控制水分不超过2%,过60目筛,得到颗粒半成品,包装避光储存;
(5)将柠檬酸与颗粒半成品按照0.5:100的比例混合;
(6)将步骤(5)的混合物再与L-亮氨酸混合,L-亮氨酸与颗粒半成品重量比1:100;
(7)最后将碳酸氢钠与步骤(6)的混合物按照1:8混匀,按照配置1L培养基用量进行压片,采用旋转压片,速度30rpm,获得快速溶解片剂培养基;
(8)将片剂培养基按照预定的包装规模进行包装;
(9)将包装好的各种规格培养基进行60Co-γ辐射灭菌,获得快速自崩解无菌培养基。
对比例1
对照培养基(商品化粉末培养基,Hyclone,货号SH30556.02)。
实施例2
将实施例1得到的快速自崩解无菌培养基和对比例1的对照培养基进行溶解测试。
对照培养基的配制:在C级洁净空间中,称量商品化粉末培养基20.3g,碳酸氢钠2.3g;倒进装有1L纯水的试剂瓶中;对照组放入搅拌子,在室温和连续搅拌下溶解4h;在搅拌3.5h时加入碳酸氢钠;4h后,在超净台中采用0.22μm滤器进行无菌过滤,获得无菌状态的液体培养基。
实施例1获得快速自崩解无菌培养基的配置:装有1L无菌纯水的无菌试剂瓶采用高压灭菌的方式进行灭菌;在超净台中(室温),将1L规格快速自崩解无菌培养基片放入装有1L无菌纯水的无菌试剂瓶中,静置5min,即可获得无菌状态的液体培养基。
观察两个培养基溶解过程,记录溶解时间、团块形成以及溶解残留等参数。实验结果见表2。
表2
结果显示,快速自崩解无菌培养基溶解过程中不需要搅拌,溶解过程无团块生成,溶解时间约为5min,且无需过滤;而传统粉末培养基溶解过程中会形成聚集性团块,需要机械搅拌,且后续需要过滤。可见,与传统粉末培养基相比,本发明的快速自崩解无菌培养基无需搅拌即可快速溶解,且无团块和粉尘的产生,溶解完成无需过滤即可使用。
实施例3
根据化工行业标准《哺乳类动物细胞培养基》(HG/T3935-2007)和《中国药典》2020版,进行实施例1得到的快速自崩解无菌培养基和对比例1的对照培养基各项指标的检测。测试结果见表3、图1和图2.
pH检测按照《中国药典》2020版第四部通则0631进行。渗透压(mOsm/kg H2O)检测按照《中国药典》2020版第四部通则0632进行。干燥失重检测按照检测按照《中国药典》2020版第四部通则0831进行。细菌内毒素(EU/mL)检测按照《中国药典》2020版第四部通则1143进行。微生物限度(包括细菌和霉菌数量,CFU/g)检测检测按照《中国药典》2020版第四部通则1105进行进行,检查项目为细菌数和霉菌数。检查法采用平皿法。澄清度检测按照《中国药典》2020版第四部通则0902进行。细胞生长测试(CHO细胞)检测按照化工行业标准《哺乳类动物细胞培养基》(HG/T3935-2007)进行。
表3
结果显示,快速自崩解无菌培养基溶解后培养基渗透压为301,pH为6.9,液体澄清,不含有细菌和霉菌,细菌内毒素含量小于10EU/mL,在该培养基中,细胞生长代谢良好。传统粉末培养基溶解后的渗透压为282,pH为7.0,液体澄清,过滤后不含有细菌和霉菌,细菌内毒素含量小于10EU/mL,细胞生长代谢良好。该实验结果提示本发明快速自崩解无菌培养基的质量远高于行业标准,满足生物制药行业的要求。
图1显示的是快速自崩解无菌培养基和传统粉末培养基不同条件下的细胞生长效果。由图1可以看出,细胞在快速自崩解无菌培养基和传统粉末培养基中,细胞生长代谢趋势基本一致,说明快速自崩解无菌培养基对于细胞是安全的可靠的,未因为添加的润滑剂、崩解剂等成分对细胞生长代谢产生影响。
图2显示的是快速自崩解无菌培养基和传统粉末培养基不同条件下的细胞活性效果。由图2可以看出,细胞在快速自崩解无菌培养基和传统粉末培养基中,细胞活性的变化趋势基本一致,细胞生命周期一致,说明快速自崩解无菌培养基形式和添加物对于细胞活性和细胞生命周期未产生显著影响。
从图1和图2可以看出,快速自崩解无菌培养基在“细胞生长实验”方面符合培养基行业行业标准。
综合评估图1、图2和表3的结果,快速自崩解无菌培养基的各项指标达到甚至高于培养基行业的指标标准。
实施例4
将实施例1得到的快速自崩解无菌培养基和对比例1的对照培养基放置在冰箱(4℃)中,观察长期存放后培养基的外观变化情况。结果见表4。
表4
结果显示,快速自崩解无菌培养基经过24个月的存储,其外观形态没有显著变化,而对照组的商品化培养基存储12个月后开始结团并发黄。该实验结果提示本发明自崩解片状培养基更加耐存储。
实施例5
本实施例5与实施例1基本相同,区别在于对有机酸以及有机酸与碱的比例进行筛选,检测崩解剂的类型和酸碱比例在片剂培养基中崩解效果的影响。筛选试验分组如表5所示。
表5
将柠檬酸、酒石酸和碳酸氢钠按照不同配比组合制备快速自崩解无菌培养基,分别溶解在装有1L水的无菌试剂瓶中,按照实施例1中的溶解测试,观察培养基溶解过程,记录溶解时间、崩解效果等参数。实验结果见表6。
表6
结果显示:柠檬酸组中,快速崩解培养基在水中崩解后液体澄清;酒石酸组,快速崩解培养基在水中崩解后液面有悬浮细微颗粒,这可能是酒石酸遇到钙镁离子从而产生浑浊。
有机酸和碳酸氢钠的比例也显著影响培养基的崩解速度,无论是采用柠檬酸或者酒石酸,柠檬酸在在1:10和1:12.5的比例时,崩解速度随着碳酸氢钠用量的升高;酒石酸在1:10到1:15的比例范围之间时,崩解速度随着碳酸氢钠用量的升高。但当比例达到1:17.5时,其崩解速度不再增加。因此,推荐工艺中首选柠檬酸和碳酸氢钠的酸碱组合,且配比1:12.5。
实施例6
本实施例6与实施例1基本相同,区别在于对润滑剂种类和浓度进行筛选,就润滑剂的类型和含量对培养基片剂生产中粘冲的影响进行比对。筛选试验分组如表7所示。
表7
将L-亮氨酸、硬脂酸镁、月桂醇硫酸镁三种润滑剂的类型和不同浓度制备快速自崩解无菌培养基,分别溶解在装有1L水的无菌试剂瓶中,按照实施例1中的溶解测试,观察培养基溶解过程,记录防粘冲效果、溶解时间、团块形成以及溶解残留等参数。实验结果见表8。
表8
其中,粘冲是指在制备片剂时,一些片剂材料或者一薄片片剂材料粘附在冲头上,造成片剂表面粗糙不平或有凹痕的现象。在本对比试验中规定:少量片剂材料颗粒粘附在冲头表面为少量粘冲;有薄片形状的粘附为粘冲严重。
实验结果显示三个润滑剂表现差异明显。亮氨酸在1%含量即可是实现压片过程不沾冲,达到较好的润滑效果,且继续增加含量防止粘冲的润滑效果基本一致,没有显著增加;月桂醇硫酸镁浓度达到4%时,不粘冲,达到较好对片剂压冲的润滑效果;而1~4%不同浓度的硬脂酸镁制备的泡腾片,在片剂的制备中均能很好地解决粘冲问题,达到润滑效果,但崩解速度和气泡上升速度较同浓度的L-亮氨酸组慢,崩解时间变长,且溶解后出现浮沫,且无法满足培养基澄清透明的质量标准;因此,在压片生产阶段,可以使用L-亮氨酸或者月桂醇硫酸镁,考虑到L-亮氨酸同时是培养基的组成成分,因此,优先推荐1%的L-亮氨酸作为润滑剂。
本发明快速自崩解无菌培养基技术解决了传统粉末培养基溶解时间长、过程复杂、有团块、批次不稳定和污染等问题。在存贮过程中,片剂培养基相比粉末培养基与空气中水分以及微生物等物质的接触面大幅下降,避免培养基在存贮过程中吸潮、结块、污染等问题。因此,本发明的快速自崩解无菌培养基技术不仅改善培养基存储运输对温湿度的要求,显著提高培养基的货架期,最重要的是保证了大规模生产的稳定性、可靠性和经济性。
应说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的精神和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
1.一种快速自崩解无菌培养基,其特征在于:包括培养基基质和崩解剂,所述崩解剂由有机酸、碱和润滑剂组成;
所述有机酸包括柠檬酸、酒石酸、酸性氨基酸中的一种或多种,所述酸性氨基酸选自谷氨酸或天门冬氨酸;
所述碱包括碳酸盐或碳酸氢盐;
所述润滑剂选自L-亮氨酸、月桂醇硫酸镁中的一种或多种。
2.如权利要求1所述的快速自崩解无菌培养基,其特征在于:所述有机酸选自柠檬酸或酒石酸;所述有机酸与所述培养基基质的质量比不超过10:100。
3.如权利要求1或2所述的快速自崩解无菌培养基,其特征在于:所述碱选自碳酸钠、碳酸氢钠中的一种或两种的混合;所述碱与所述培养基基质的质量比不超过25:100。
4.如权利要求3所述的快速自崩解无菌培养基,其特征在于:所述润滑剂与所述培养基基质的质量比为0.5~5:100;
其中,所述润滑剂为L-亮氨酸,所述润滑剂与所述培养基基质的质量比为1~5:100;
所述润滑剂为月桂醇硫酸镁,所述润滑剂与所述培养基基质的质量比为3~5:100。
5.如权利要求1、2、4中任一项所述的快速自崩解无菌培养基,其特征在于:所述培养基基质由氨基酸混合物、无机盐和添加物混合物以及维生素混合物按照24.8~36.1:61.3~73:1~2.2的质量比构成。
6.如权利要求5所述的快速自崩解无菌培养基,其特征在于:所述氨基酸混合物,按质量份数计,包括L-精氨酸29~1000份、L-胱氨酸50~300份、甘氨酸59~497份、L-组氨酸51~720份、L-异亮氨酸109~981份、L-亮氨酸132~1119份、L-赖氨酸盐酸盐212~895份、L-甲硫氨酸20~434份、L-苯丙氨酸24~930份、L-丝氨酸154~941份、L-苏氨酸57~817份、L-丙氨酸9~498份、L-天门冬酰胺5~378份、L-天门冬氨酸5~307份、L-半胱氨酸盐酸盐5~505份、L-谷氨酸51~502份、L-脯氨酸0~352份、L-色氨酸24~1204份、L-酪氨酸79~612份、L-缬氨酸81~870。
7.如权利要求5所述的快速自崩解无菌培养基,其特征在于:所述无机盐和添加物混合物,按质量份数计,包括氯化钙50~500份、硫酸铜0.001~0.1份、硝酸铁0.01~0.1份、硫酸亚铁0.1~1份、氯化钾100~500份、无水氯化镁10~100份、硫酸镁20~200份、磷酸二氢钠30~300份、磷酸氢二钠30~300份、硫酸锌0.1~1份、氯化钠2000~7000份、D-葡萄糖1000~6000份、次黄嘌呤二钠盐10~100份、Hepes 0~5000份、亚油酸0.1~1份、硫辛酸0.1~2份、腐胺0.1~1份、丙酮酸钠100~500份、胸苷1~5份、PF-68 50~2000份、亚硒酸钠0.001~0.010份、乙醇胺2~10。
8.如权利要求6或7所述的快速自崩解无菌培养基,其特征在于:所述维生素混合物,按质量份数计,包括D-泛酸钙4~51份、氯化胆碱21~209份、维生素B6氯化物5~53份、维生素B1氯化物5~56份、叶酸6~50份、肌醇52~506份、烟酰胺5~57份、维生素B2 1~12份、维生素B12 1~18。
9.如权利要求1~8中任一项所述的快速自崩解无菌培养基的制备方法,其特征在于:包括,
提供培养基基质;
将培养基基质湿法制粒成颗粒半成品;
将有机酸与所述颗粒半成品混合,再依次加入润滑剂、碱混合均匀;
将得到的混合物进行压片,获得快速自崩解培养基;
采用60Co-γ辐射灭菌,获得快速自崩解无菌培养基。
10.如权利要求9所述的快速自崩解无菌培养基,其特征在于:所述将培养基基质湿法制粒,加入水或乙醇水溶液作为粘合剂进行制粒;
其中,采用乙醇水溶液作为粘合剂,乙醇浓度为20~60%。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0155427A1 (fr) * | 1984-02-09 | 1985-09-25 | Societe D'applications Pharmaceutiques Et Biologiques Hoechst-Behring | Nouveau milieu de culture, solide, à délitement rapide, prêt à l'emploi et procédé pour le préparer |
CN103443287A (zh) * | 2010-12-31 | 2013-12-11 | 3M创新有限公司 | 泡腾组合物及其用途 |
CN112795531A (zh) * | 2021-04-11 | 2021-05-14 | 依科赛生物科技(太仓)有限公司 | 一种cho细胞无血清无蛋白培养基及其用途 |
CN114555776A (zh) * | 2019-09-19 | 2022-05-27 | 生命技术公司 | 细胞培养基片剂和制造方法 |
-
2022
- 2022-05-31 CN CN202210606638.4A patent/CN115029296A/zh active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0155427A1 (fr) * | 1984-02-09 | 1985-09-25 | Societe D'applications Pharmaceutiques Et Biologiques Hoechst-Behring | Nouveau milieu de culture, solide, à délitement rapide, prêt à l'emploi et procédé pour le préparer |
CN103443287A (zh) * | 2010-12-31 | 2013-12-11 | 3M创新有限公司 | 泡腾组合物及其用途 |
CN114555776A (zh) * | 2019-09-19 | 2022-05-27 | 生命技术公司 | 细胞培养基片剂和制造方法 |
CN112795531A (zh) * | 2021-04-11 | 2021-05-14 | 依科赛生物科技(太仓)有限公司 | 一种cho细胞无血清无蛋白培养基及其用途 |
Non-Patent Citations (3)
Title |
---|
奉建芳等: "现代中药制剂设计", 31 May 2020, 中国医药科技出版社, pages: 360 * |
李正平等: "口服补液盐散(Ⅱ)泡腾片的研制及其质量控制分析", 中国医药指南, vol. 10, no. 12, pages 479 - 480 * |
赖菁华等: "响应面法优化乌梅泡腾片的配方", 食品工业, vol. 41, no. 4, pages 91 - 94 * |
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