CN115151243A - 包含pedf-衍生短肽(pdsp)的组合物及其用途 - Google Patents
包含pedf-衍生短肽(pdsp)的组合物及其用途 Download PDFInfo
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- CN115151243A CN115151243A CN202080084624.XA CN202080084624A CN115151243A CN 115151243 A CN115151243 A CN 115151243A CN 202080084624 A CN202080084624 A CN 202080084624A CN 115151243 A CN115151243 A CN 115151243A
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- Prior art keywords
- pdsp
- histidine
- nicotinamide
- buffer
- sorbitol
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Abstract
一种水性制剂,其包含具有SEQ ID NO:1、2、3、5、6、8或9中之一序列的PEDF‑衍生短肽(PDSP);具有1mM至100mM浓度的组氨酸;和抗氧化剂及任选的非离子性张力剂。pH值为约5至9。该抗氧化剂为烟酰胺,其浓度为50mM至1000mM。非离子性张力剂为山梨糖醇,其浓度为0mM至500mM。PDSP的浓度为0.01%至1%w/v。
Description
发明背景
发明领域
本发明涉及PEDF-衍生短肽的组合物,尤其涉及此类肽的制剂及其用途。
背景
人色素上皮-衍生因子(PEDF)为418个氨基酸的分泌蛋白质,分子量为约50kDa。PEDF是具有许多生物功能的多功能蛋白质(参见美国专利申请公开第2010/0047212号)。发现人PEDF的不同肽区域负责不同功能。例如,已鉴定出34聚体片段(PEDF的残基44至77)具有抗血管生成活性,同时已鉴定出44聚体片段(PEDF的残基78至121)具有神经营养性质。
已发现人类PEDF-衍生短肽(PDSP)是用于治疗或预防各种疾病或病症的有前景的治疗剂。例如,发现PDSP可有效促进肌肉再生或动脉血管生成(arteriogenesis)(美国专利第9,884,012号),治疗秃发和/或毛发脱色(美国专利第9,938,328号),治疗骨关节炎(美国专利第9,777,048号),预防或改善皮肤老化(美国专利第9,815,878号),治疗肝硬化(美国专利第8,507,446号),或治疗各种眼部疾病或症状(例如视网膜变性、睑板腺疾病、干眼症)。还发现相应小鼠PEDF-衍生短肽(moPDSP)具有相同治疗效果。然而,这些肽的制剂缺乏长期稳定性。因此,需要用于这种有前景的生物医药产品的更好制剂。
发明概述
本发明的实施方式涉及PEDF-衍生短肽(PDSP)的制剂,包括SEQ ID NO:1(39聚体)、SEQ ID NO:2(34聚体)、SEQ ID NO:3(29聚体)、SEQ ID NO:5(24聚体)、SEQ ID NO:6(20聚体)、SEQ ID NO:8(mo29聚体)和SEQ ID NO:9(mo20聚体),其中mo29聚体及mo20聚体分别为对应于人类29聚体和20聚体的小鼠PDSP。
本发明一方面涉及一种水性制剂,其包含具有SEQ ID NO:1、2、3、5、6、8或9中之一序列的PEDF-衍生短肽(PDSP);具有1mM至100mM浓度的组氨酸;和抗氧化剂及任选的非离子性张力剂。抗氧化剂为抗坏血酸或烟酰胺。非离子张力剂为山梨糖醇、右旋糖、甘油、甘露醇、氯化钾、氯化钠、乙二醇或丙二醇。
根据本发明的一些实施方式,水性制剂的pH值可为约5至9,优选是约6.5至7.5。所述非离子性张力剂为山梨糖醇,其浓度为0mM至500mM。所述抗氧化剂为烟酰胺,其浓度为50mM至1000mM。PDSP的浓度可为0.01%至1%w/v。
根据以下描述和附图可清楚本发明的其他方面。
附图简要说明
图1显示用于评估PDSP溶液的各种制剂的稳定性的测试方案的示意图。根据研究设计制备不同PDSP溶液。用1N HCl或2N NaOH调整PDSP溶液的pH值,用0.2μm针筒过滤器过滤,并放入50ml玻璃瓶中。将过滤的PDSP溶液在室温下以1150RPM搅拌。在不同时间点(每半小时至7或9小时)收集400μl PDSP溶液的等分试样,以13000rpm离心以观测是否出现任何沉淀。继续搅拌PDSP溶液,且在10小时、12小时、18小时和24小时的时间点研究沉淀。记录悬浮物质、沉淀及浑浊出现的时间。
图2显示在连续搅拌条件下,在含有0.85%NaCl的10mM柠檬酸盐缓冲液(pH 6.0)和在含有不同浓度烟酰胺的20mM组氨酸缓冲液(pH 7.0)中制备的PDSP制剂的稳定性测试结果。过滤后,将以这些不同制剂制备的PDSP各放入50mL烧杯中,然后在室温下以1150RPM搅拌溶液。在前7小时里每半小时研究这些溶液,并在搅拌开始后12小时后继续进行连续观测。
图3显示用含有不同浓度山梨糖醇的20mM组氨酸/150mM烟酰胺溶液制备的PDSP制剂的稳定性测试结果。在连续搅拌下进行稳定性测试。过滤后,将以8种不同制剂制备的PDSP放入50mL烧杯中,然后在室温下以1150RPM搅拌溶液。在开始搅拌后的前9小时里每半小时以及第12小时、18小时及24小时研究这些溶液。记录沉淀及混浊出现的时间。
图4显示在连续搅拌条件下用含有不同浓度的山梨糖醇的20mM组氨酸/150mM烟酰胺溶液制备的PDSP制剂中悬浮、沉淀及浑浊出现的时间。曲线1:悬浮物质出现的时间。曲线2:可见沉淀出现的时间。曲线3:浑浊溶液出现的时间。
发明详述
本发明的实施方式涉及具有增强的稳定性的PEDF-衍生短肽(PDSP)的制剂。据发现,各种人类PDSP是用于治疗或预防各种疾病或病症的有前景的治疗剂,所述疾病或病症包括肌肉再生或动脉血管生成、秃发及/或毛发脱色、骨关节炎、皮肤老化、肝硬化或眼部疾病或病症。此类PDSP的示例可包括那些显示于表1中的:
表1:PEDF衍生短肽(PDSP)示例
根据本发明的实施方式,PDSP可为SEQ ID NO:1、2、3、5、6、8或9。另外,这些肽的N端可任选经酰化保护(例如乙酰基或丙酰基保护),并且C端可任选被保护为酰胺。
这些PDSP已在柠檬酸盐缓冲液中制备且在各种临床前研究中发现可有效用于治疗目的。然而,在含有0.85%w/v NaCl的10mM柠檬酸盐缓冲液(pH6.0))中的这些短肽(例如PDSP(SEQ ID NO:3)的制剂缺乏长期稳定性(数月内)。
许多因素,包括化学应力(例如氧化、水解等)及物理应力(例如温度、光照及搅拌),均可影响生物医药产品的品质及稳定性,尤其是在长期储存期间。为研究PDSP在不同制剂中的稳定性,进行加速稳定性测试。具体而言,在应力条件下(尤其是在剪切应力下)测试各种制剂,以鉴定最佳制剂。大量测试后,出人意料地发现某些制剂具有优于原始柠檬酸盐缓冲液制剂的长期稳定性。
以下描述特定实施例以说明本发明的实施方式。然而,本领域技术人员知晓,这些特定实施例仅用于说明且可进行其他修改及变化而不脱离本发明范围。例如,尽管以下实施例使用PDSP(SEQ ID NO:3)进行说明,但可替代使用其他PDSP。
1、柠檬酸盐缓冲液(含有0.85%w/v NaCl的10mM柠檬酸盐操作缓冲液,pH 6.0)
由柠檬酸和柠檬酸三钠制备柠檬酸盐缓冲液以实现所需缓冲液能力和pH。例如,分别使用柠檬酸单水合物(MW 210.14kDa)(Merck)及柠檬酸三钠二水合物(MW 294.12kDa)(BioShop)制备溶液A和溶液B。然后将这两种溶液用于制备具有所需浓度和pH值的柠檬酸盐缓冲液。溶液A和B的配方如下所示:
溶液A(0.1M柠檬酸单水合物)(10ml):210.14kDa×10/1000×0.1=0.21g柠檬酸单水合物。称取0.21g柠檬酸单水合物,溶解于10ml ddH2O中,产生10ml溶液A储液。
溶液B(0.1M柠檬酸三钠二水合物)(10ml):294.12kDa×10/1000×0.1=0.294g柠檬酸三钠二水合物。称取0.294g柠檬酸三钠二水合物,溶解于10ml ddH2O中,产生10ml溶液B储液。
为了制备10X柠檬酸盐缓冲液储液(pH 6.0),将1.15ml溶液A和8.85ml溶液B混合,获得0.1M柠檬酸盐缓冲液10mL。然后,用90ml ddH2O稀释所述10ml,0.1M柠檬酸盐缓冲液储液,产生10mM柠檬酸盐操作缓冲液,100ml(1X溶液)。
为制备含有0.85%w/v NaCl的10mM柠檬酸盐缓冲液,将0.85g NaCl加入所述10mM柠檬酸盐操作缓冲液,100ml中。使用前,应基于研究设计来测量并调整pH。
2、组氨酸缓冲液(含有0至260mM山梨糖醇和/或150至350mM烟酰胺的20mM组氨酸缓冲液,pH 7.0)
为了制备用于测试的20mL 20mM组氨酸缓冲液(pH 7.0),将0.062g组氨酸和不同重量的山梨糖醇和/或烟酰胺溶解于15mL ddH2O中。用表2所示的组成制备具有不同山梨糖醇和烟酰胺浓度的各种制剂实例:
表2:各种组氨酸缓冲液组成
20mM组氨酸/150mM烟酰胺:0.37g/20ml |
20mM组氨酸/300mM烟酰胺:0.73g/20ml |
20mM组氨酸/350mM烟酰胺:0.86g/20ml |
20mM组氨酸/120mM山梨糖醇:0.44g/20ml |
20mM组氨酸/140mM山梨糖醇:0.51g/20ml |
20mM组氨酸/160mM山梨糖醇:0.58g/20ml |
20mM组氨酸/180mM山梨糖醇:0.66g/20ml |
使用2N NaOH或1N HCl将缓冲液的pH值调整至pH 7.0。记录用于pH值调整的2NNaOH或1N HCl的体积,然后加入ddH2O以使得总体积为20ml。
3、在不同制剂中制备PDSP
用于这些实施例中的PDSP为在NH2端乙酰化并在COOH端具有酰胺的短合成肽(29聚体)。PDSP的分子量为3243.6kDa。将PDSP以特定浓度溶解于上述各溶液中。
例如,为制备在组氨酸/烟酰胺或柠檬酸盐缓冲液中的20ml PDSP溶液,将6.772mg肽产品添加至20ml组氨酸/烟酰胺缓冲液或柠檬酸盐缓冲液。
在PDSP完全溶解于溶液中后,测定PDSP溶液的pH值,然后根据研究设计将pH值调整至7.0或6.0。使用前,将PDSP溶液各滤过0.2μm针筒过滤器。
4、不同制剂中PDSP的稳定性评估
我们注意到,较早的PDSP在柠檬酸盐缓冲液中的制剂在长期储存(数月内)期间不稳定。为测试不同制剂对于稳定性的影响,使各种PDSP制剂经受应力条件(例如剪切应力)以加速变化。
对于这些测试,在过滤后,将在不同缓冲液和赋形剂中制备的二十(20)毫升PDSP(如表3所示)各放入50mL烧杯中。然后,将溶液在室温下以1150RPM搅拌。在7或9小时中每半小时将400μl PDSP溶液的等分试样各收集于1.5ml Eppendorf管中。将收集的样品以13,000rpm离心5分钟以评估是否发生任何沉淀。连续观测后,继续搅拌PDSP溶液直至24小时。在10小时、12小时、18小时及24小时搅拌后,研究溶液外观以及可能的沉淀。记录悬浮物质、沉淀及浑浊出现之时间。实验程序示于图1中。
表3.本研究中测试的制剂清单。
赋形剂 | 基础缓冲液 | pH值 |
0.85%NaCl | 10mM柠檬酸盐缓冲液 | 6.0 |
150mM烟酰胺 | 20mM组氨酸缓冲液 | 7.0 |
300mM烟酰胺 | 20mM组氨酸缓冲液 | 7.0 |
350mM烟酰胺 | 20mM组氨酸缓冲液 | 7.0 |
260mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,120mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,125mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,130mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,140mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,150mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,160mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,170mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
150mM烟酰胺,180mM山梨糖醇 | 20mM组氨酸缓冲液 | 7.0 |
结果
1、在含有0.85%w/v NaCl的10mM柠檬酸盐缓冲液(pH 6.0)中制备的PEDF-衍生短肽(PDSP)的抗剪切力的能力
PDSP制备的原始制剂为含有0.85%w/v NaCl的10mM柠檬酸盐缓冲液(pH 6.0)。此制剂适合各种临床前研究。然而,此制剂在长期储存(数月)内形成浑浊。因此,使用受迫聚集法来研究其稳定性以阐明其抗剪切力的能力。如图2中所显示,溶液在搅拌之前为澄清且透明(图2,上图)。在开始搅拌后约1小时,在该制剂中看到悬浮物质(图2,左图及表4)。开始搅拌后1.5和2.5小时分别观测到沉淀及浑浊溶液。这些观测结果将用作与其他制剂进行比较的基线。
表4.在搅拌条件下在不同制剂中制备的PDSP的稳定性
2、在含有烟酰胺的组氨酸缓冲液中制备的PEDF-衍生短肽(PDSP)的抗剪切力的能力。
为了研究烟酰胺(其为抗氧化剂)对于PDSP在基于组氨酸的缓冲液中的稳定性的影响,选择在含有150mM、300mM或350mM烟酰胺的20mM组氨酸缓冲液(pH 7.0)中制备的PDSP用于比较。如图2和表4所示,对于在含有150-mM、300-mM及350-mM烟酰胺的20mM组氨酸缓冲液中制备的PDSP,分别在开始搅拌后的5、4.5和14小时观测到悬浮物质(表4)。与柠檬酸盐缓冲液中的制剂相比,在含有组氨酸/烟酰胺缓冲液的制剂中的悬浮物质显著更晚形成。
在一项研究中,发现在含有0.85%NaCl的10mM柠檬酸盐缓冲液中制备的PDSP中的悬浮物质为粗粒,并且在解剖显微镜下可观测到小颗粒或纤维。然而,在组氨酸/烟酰胺缓冲液中制备的PDSP制剂中的悬浮物质极细,这仅降低溶液透明度而在解剖显微镜下没有可见颗粒。
为了评估沉淀是否也可随着悬浮物质的存在而出现,将400μl各PDSP溶液的等分试样收集于1.5ml Eppendorf管中进行离心(13000rpm,5分钟)。如图2(中图)及表4所示,对于在含有150-mM、300-mM和350-mM烟酰胺的20mM组氨酸缓冲液中制备的PDSP,分别在开始搅拌后的5.5小时、4.5小时和14.5小时观测到可见沉淀。
观测到悬浮物质或沉淀后,继续搅拌PDSP溶液直至其变为浑浊。图2(下图)及表4显示在含有150-mM、300-mM及350-mM烟酰胺的20mM组氨酸缓冲液中制备的PDSP制剂分别在开始搅拌后的13.5小时、7至24小时及16.5小时变为浑浊。
与在柠檬酸盐缓冲液中制备的PDSP制剂相比,在组氨酸/烟酰胺缓冲液中制备的PDSP制剂可更好地承受剪切应力。此外,在这些组氨酸/烟酰胺制剂中,与含有150mM及300mM烟酰胺的溶液相比,含有350mM烟酰胺的溶液需要更长时间才会出现沉淀,表明较高的烟酰胺浓度可增加PDSP在基于组氨酸的缓冲液中制备的制剂中的稳定性。
3、在含有不同浓度山梨糖醇的组氨酸/烟酰胺缓冲液中制备的PEDF-衍生短肽(PDSP)的抗剪切力的能力
据报导,眼施用烟酰胺可引起眼睛刺激(Keri,G.2005.从烟酰胺耐受性要求重新评价一个实验(Reassessment of the one experiment from the requirement of thetolerance for nicotinamide.)United State Environmental Protection AgencyWashington,D.C.20460.1-12)。因此,山梨糖醇用于代替基于组氨酸的缓冲液中的全部或部分烟酰胺。如表4所示,在仅20mM组氨酸/260mM山梨糖醇制剂中搅拌刚3小时后观测到悬浮物质。并且,在含有120-mM、125-mM、130-mM、140-mM、150-mM、160-mM、170-mM及180-mM山梨糖醇的20mM组氨酸/150mM烟酰胺缓冲液中制备的PDSP中,分别在开始搅拌后的3小时、4.5小时、4小时、13小时、13.5小时、6小时、5小时及4.5小时发现悬浮物质(图3、图4及表4)。
在这些组氨酸/烟酰胺制剂当中,在含有140-mM和150-mM山梨糖醇的20mM组氨酸/150mM烟酰胺中制备的PDSP中,在连续搅拌13小时后观测到悬浮物质、沉淀和浑浊,表明约140mM至150mM的范围可作为山梨糖醇在组氨酸/烟酰胺制剂中的最佳浓度。(图3、图4及表4)。此外,在20mM组氨酸/150mM烟酰胺/140或150mM山梨糖醇缓冲液中和在仅20mM组氨酸/350mM烟酰胺缓冲液中制备的PDSP的稳定性相当,表明山梨糖醇可用于替代部分烟酰胺。
这些结果和以上所述的资料一起表明,与柠檬酸盐/NaCl制剂相比,含有组氨酸/烟酰胺的制剂的PDSP稳定性更好。对于在10mM柠檬酸盐与0.85%NaCl中制备的PDSP,在开始搅拌后的1小时出现沉淀,而对于在含150mM至350mM烟酰胺的20mM组氨酸中制备的PDSP,在5小时搅拌后观测到沉淀。与柠檬酸盐/NaCl制剂相比,组氨酸/烟酰胺制剂形成沉淀所需的时间长5倍,表明PDSP在组氨酸/烟酰胺制剂中显著更稳定。此外,在含有不同浓度的烟酰胺的制剂中,连续搅拌后直至14.5小时才观测到沉淀,表明较高浓度的烟酰胺更适合作为赋形剂用于维持PDSP的稳定性。
与在柠檬酸盐缓冲液中制备的PDSP制剂相比,在仅组氨酸/山梨糖醇缓冲液中制备的PDSP制剂显示出更好的维持PDSP稳定性的能力。然而,当与仅组氨酸/烟酰胺制剂相比时,仅组氨酸/山梨糖醇制剂的维持PDSP稳定性的能力仍旧不够好,这表明烟酰胺可作为在基于组氨酸的缓冲液中维持PDSP稳定性的重要组分。
当使用张力剂(例如山梨糖醇)代替部分烟酰胺时,对于在20mM组氨酸/350mM烟酰胺中制备的PDSP(14.5小时)和在20mM组氨酸/150mM烟酰胺/140或150mM山梨糖醇中制备的PDSP(分别为13小时及14小时),沉淀出现的时间相似。这些数据进一步证实,对于在20mM组氨酸/150mM烟酰胺缓冲液中制备的PDSP制剂,约140至150mM的浓度是山梨糖醇的较好浓度。
总而言之,本文所测制剂表明,对于含有PDSP(例如PDSP;SEQ ID NO:3)的制剂,组氨酸/烟酰胺是比柠檬酸盐缓冲液好得多的基础缓冲液。根据本发明的实施方式,PDSP可为任何适宜浓度(例如0.01%至5%w/v,优选0.01%至1%w/v),并且组氨酸缓冲液可以任何适宜浓度使用,例如1mM至100mM,优选5mM至60mM,更优选10mM至40mM,进一步优选15mM至30mM。制剂的pH值可在5至9之范围内,优选地,pH值为约中性,例如6.5至7.5,最佳约7.0。所述制剂包含适宜浓度,例如50mM至1000mM,优选100mM至700mM,更优选200mM至500mM,进一步优选300mM至400mM的抗氧化剂,优选是烟酰胺。例如,PDSP溶液的优选制剂可包含20mM组氨酸与350mM烟酰胺,pH 7.0。所述制剂亦可包含适宜浓度,例如0mM至500mM,优选10mM至400mM,更优选50mM至300mM,进一步优选100mM至200mM的非离子张力剂,优选是山梨糖醇。例如,PDSP溶液的优选制剂可包含20mM组氨酸与150mM烟酰胺及150mM山梨糖醇,pH 7.0。
本发明的制剂可用于治疗各种疾病及病症,例如视网膜变性、睑板腺疾病、干眼症等。对于眼部施用,所述制剂可为眼用溶液。
已利用有限数目的实施例来说明本发明的实施方式。本领域技术人员应理解,这些实施例仅用于说明而并非意在限制本发明的范围,因为可进行其他修改及变化而不脱离本发明范围。因此,本发明的范围应仅由所附权利要求书限定。
序列表
<110> 全福生物科技股份有限公司
<120> 包含PEDF-衍生短肽(PDSP)的组合物及其用途
<130> PPD12PCT-formulations
<150> US 62/911,367
<151> 2019-10-06
<160> 9
<170> PatentIn version 3.5
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Claims (11)
1.一种水性制剂,其包含:
PEDF-衍生短肽(PDSP),其具有SEQ ID NO:1、2、3、5、6、8或9的序列;
抗氧化剂;和
组氨酸,其具有1mM至100mM的浓度。
2.如权利要求1所述的水性制剂,其特征在于,pH值为约5至9。
3.如权利要求1所述的水性制剂,其特征在于,所述抗氧化剂为烟酰胺。
4.如权利要求3所述的水性制剂,其特征在于,烟酰胺的浓度为50mM至1000mM。
5.如权利要求1所述的水性制剂,进一步包含非离子张力剂。
6.如权利要求5所述的水性制剂,其特征在于该非离子张力剂为山梨糖醇。
7.如权利要求6所述的水性制剂,其特征在于,山梨糖醇的浓度为0mM至500mM。
8.如权利要求1所述的水性制剂,其特征在于,所述组氨酸的浓度为5mM至60mM。
9.如权利要求1所述的水性制剂,其特征在于,所述组氨酸的浓度为10mM至40mM。
10.如权利要求1-9中任一项所述的水性制剂,其特征在于,所述PDSP具有SEQ ID NO:3的序列。
11.如权利要求10所述的水性制剂,其特征在于,所述PDSP的浓度为0.01%至1%w/v。
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