CN105209476A - 一种用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法 - Google Patents
一种用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法 Download PDFInfo
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Abstract
本发明涉及一种用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，尤其是细胞生长因子和/或蛋白质，如表皮生长因子(EGF)与成纤维生长因子(bFGF)。本方法包括以下步骤：提供分散相，在常温常压下，蛋白质在所述分散相中并入无水介质中，所述无水介质由油性成分形成，所述油性成分具有亲水性残基，可确保与蛋白质的相互作用，同时保持蛋白质的天然构象，所述油性成分为葡萄籽油、由不同成分组成的基底和丁基羟基甲苯。
Description
发明目的
如题所述，本发明涉及一种用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法。
本发明的目的在于提供一种方法，该方法设想建立一种分散系统，该分散系统作为蛋白质在常温常压下、在油相中的保存、稳定和贮藏手段。具体地，本发明提出的方法基于蛋白质掺入由各成分组成的介质中，例如细胞生长因子(如表皮生长因子EGF和成纤维细胞生长因子bFGF)，但不限于此，所述各成分组成的介质如葡萄籽油、由多种化合物组成的基底(所述多种化合物在本说明书下文中会详细说明)和丁基羟基甲苯(BHT)，形成所述油相。具体地，本发明所提出的方法利用油相成分的某些化学基团促进蛋白质残基的物理-化学作用，使蛋白质天然分子结构维持更长一段时间。因此，本方法简单、经济、具有普适性，对取代通常用于保存蛋白质的复杂保存技术和/或采用水的方法具有潜在的能力。
技术领域
本发明可用于工业化学领域，特别是致力于制造药剂及化妆品的工业，尤其是意在保存生长因子的工业。
背景技术
目前，蛋白质稳定性在化学、药剂和化妆品领域备受关注。蛋白质在许多疾病治疗中作为活性物质，例如糖尿病、癌症、血友病、心肌梗塞等(Krishnamurthy和Manning，2002)。值得注意的是，近年来，利用蛋白质结构已引起化妆品工业的极大兴趣，例如生长因子、表皮生长因子(EGF)。如果蛋白质不能得到恰当的稳定化，会失去其天然结构，以致丧失其生物活性(Krishnamurthy和Manning，2002)。
但问题是蛋白质的稳定化是特别困难的，因为蛋白质非常容易发生降解现象：物理降解、化学降解和酶降解。化学降解涉及脱氨、氧化、还原、水解过程和一些化学相互作用，如二硫键相互作用。物理降解包括表面吸附、聚集、解离、变性和光解过程。此外，还有一些影响与分散介质特性相关的蛋白质聚集的因素，如温度(与蛋白质构象改变的热力学和动力学有关)、pH值(与蛋白质残基与正/负电荷的相互作用有关)、离子强度(与与带电基团相互作用的盐、浓度有关)和表面活性剂(与构象热力学稳定性有关)(Chi等人，2003)。
现有技术工艺可确保蛋白质保持天然构象更长一段时间，这些工艺可以为物理方法，如冷冻(低于-10℃)或冷冻干燥(用于消除蛋白质水溶液的湿气)，但是，通过这些方法得到的产品也会降解；或通过添加共溶剂的化学方法(Chang和PIKAL，2009)。
EGF是首先被分离并被视为生长因子的多肽。EGF具有生物活性，能够刺激角化细胞和成纤维细胞的增殖(随后形成胶原蛋白)，促使血管再生(即，形成新的血管)，并且在它应用的区域形成后续血管，EGF这些生物活性与其天然结构有关。这些特性可促进具有一定厚度的新皮肤的生成，恢复皮肤弹性和紧实度，从而减少细胞氧化带来的影响，并消除皱纹(Tang等人，1994)。这种生长因子最近已开始用于一些制剂中，其中在有关组织再生、加速烧伤愈合、治疗瘢痕疙瘩、痤疮和妊娠纹方面已获得非常良好的效果，甚至可以改善一些治疗效果，如手术、合并植皮，以及剥落后的应用。然而，虽然在医药和化妆品行业正越来越多地使用该蛋白质，但由于其价格高和难以稳定，因此还没有被大量使用(Schouest等人，2012)。
成纤维细胞生长因子(bFGF)是一种生长因子，其作用是增加有丝分裂活性指数及DNA合成，促进各种前体细胞的增殖，如软骨细胞、纤维细胞和成骨细胞等，所述前体细胞形成主体的纤维、结缔组织和支持组织。成纤维细胞生长因子有助于伤口的愈合、造血、血管生成或胚胎发育，因此可表现出截然不同的作用：一)有利于受损组织愈合期间的上皮再形成；二)有血管形成诱导活性；三)参与血细胞系的分化过程；以及四)参与骨骼肌和心肌分化、肺部成熟和内胚层细胞的肝细胞特化。
因此，本发明的目的是提供一种保存和稳定蛋白质的新方法，该方法可用于卫生制剂、医药及化妆品工业发展，且不同于传统的方法。该方法在油相中进行，使得它更简单和经济。需要指出的是，申请人不知晓公开了与本申请提出的用于保存和稳定蛋白质的方法类似的技术特征的任何公开文件或类似发明。
发明内容
一种用于分散蛋白质的介质，所述介质的成分为所述介质提供油性特质。如上所述，EGF、bFGF和其它细胞生长因子和/或蛋白质为大分子，难以稳定化，因为目前多数的分散手段为水性特质，通过采用分散系统可获得短期的稳定，例如乳剂，或一些昂贵、特殊的方法，但是这些方法又不能确保蛋白质天然结构得以长期维持，例如冻干。
本发明中，EGF和其它生长因子和/或蛋白质保存在油性介质，可应用在一些特定的工业过程中，促进蛋白质的稳定性，在这种介质中保存非变性蛋白质是更有效的做法。
更具体地，根据本发明的方法，在制剂中，生长因子由无水介质包围，所述无水介质由其他成分组成，所述成分作为与蛋白质残基相互作用的助剂，包括葡萄籽油，所述葡萄籽油构建介质，保持蛋白质天然构象的同时减少蛋白质残基的静电作用；基底，所述基底由以下物质组成：辛酸/癸酸甘油三酯、PEG－18蓖麻油二油酸酯、丙二醇、季戊四醇四(双-t-苄基羟基氢化肉桂酸)酯、生育酚和三异丙醇胺，这些可促进蛋白质结构域的分子间作用力，使得结构的热力学稳定性更强；以及丁基羟基甲苯(BHT)，其作为一种抗氧化剂，很大程度上避免了蛋白质氧化的化学降解现象。
需要注意的是，蛋白质介入油相成分的过程中，应当有适当的质量保证。优选地，该过程在无尘室中、层流条件下进行，应保证对环境的质量控制与微生物控制，以确保产品的无菌性。
简而言之，本发明提出了一种保存、贮藏和稳定蛋白质的方法，采用具有环境和微生物质量的无水分散相(即，不存在水)，通过应用具有亲水性残基的油性物质，保证了与蛋白质的相互作用，保持其天然构象，因此构成了一种相对于需要使用设备的、复杂的和需要有资格的人员的其他方法来说，更简单、更经济、可重复的方法。
经过充分描述本发明的性质、实施方式后，本领域技术人员可理解其范围与有益效果，因此没有必要再作更广泛的解释。应当了解，本发明在实际应用的其他实施方式中，可能不同于本实施例列举的细节，但在不脱离本发明原理的前提下，这些实施方式也视为本发明的保护范围。
参考文献
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ChiEY,KrishnanS,RandolphTW,CarpenterJF.Physicalstabilityofproteinsinaqueoussolution:mechanismanddrivingforcesinnonnativeproteinaggregation.PharmRes.2003；20:1325-36.
KrishnamurthyR,ManningMC.Thestabilityfactor:importanceinformulationdevelopment.CurrPharmBiotechnol.2002；3:361-71.
SchouestJM,LunTK,MoyRL.Improvedtextureandappearanceofbarleyproduced,synthetic,human-likeepidermalgrowthfactor(EGF)serum.J.DrugsDermatol.2012；11(5):613-620.
TangZ,ZhangZ,ZhengYetal.CellagingofhumandiploidfibroblastsisassociatedwithchangesinresponsivenesstoepidermalgrowthfactorandchangesinHER-2expression.MechanismsofAgeingandDevelopment1994；73(1):57-67.
Claims (5)
1.一种用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，尤其是细胞生长因子和/或蛋白质，如表皮生长因子与成纤维生长因子，其特征在于，包括以下步骤：提供分散相，在常温常压下，蛋白质在所述分散相中并入无水介质中，所述无水介质由油性成分形成，所述油性成分具有亲水性残基，可确保与蛋白质的相互作用，同时保持蛋白质的天然构象。
2.如权利要求1所述的用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，其特征在于，所述油性成分包括葡萄籽油。
3.如权利要求1或2所述的用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，其特征在于，所述油性成分包括基底，所述基底由以下物质组成：辛酸/癸酸甘油三酯、PEG－18蓖麻油二油酸酯、丙二醇、季戊四醇四(双-t-苄基羟基氢化肉桂酸)酯、生育酚和三异丙醇胺。
4.如权利要求1-3任一项所述的用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，其特征在于，所述油性成分包括丁基羟基甲苯。
5.如权利要求1所述的用于卫生制剂、医药及化妆品工业发展的保存和稳定蛋白质的方法，其特征在于，所述油性成分为葡萄籽油、丁基羟基甲苯和基底，所述基底由以下物质组成：辛酸/癸酸甘油三酯、PEG－18蓖麻油二油酸酯、丙二醇、季戊四醇四(双-t-苄基羟基氢化肉桂酸)酯、生育酚和三异丙醇胺。
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| BR112015020658B1 (pt) | 2023-12-05 |
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| BR112015020658A2 (pt) | 2017-07-18 |
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| JP6959002B2 (ja) | 2021-11-02 |
| US11147882B2 (en) | 2021-10-19 |
| MX2016001476A (es) | 2016-07-12 |
| US20160030584A1 (en) | 2016-02-04 |
| EP3050894A1 (en) | 2016-08-03 |
| CA2913394A1 (en) | 2015-01-29 |
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| RU2642277C2 (ru) | 2018-01-24 |
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| EP3050894A4 (en) | 2017-04-19 |
| US20190290770A1 (en) | 2019-09-26 |
| ES2502691A1 (es) | 2014-10-03 |
| RU2016107313A (ru) | 2017-09-04 |
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Application publication date: 20151230 |