CN114057831B - 促进血管增生的短链胜肽及其促进糖尿病伤口愈合的用途 - Google Patents
促进血管增生的短链胜肽及其促进糖尿病伤口愈合的用途 Download PDFInfo
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- CN114057831B CN114057831B CN202010787558.4A CN202010787558A CN114057831B CN 114057831 B CN114057831 B CN 114057831B CN 202010787558 A CN202010787558 A CN 202010787558A CN 114057831 B CN114057831 B CN 114057831B
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Abstract
本发明关于一种促进血管增生的短链胜肽、组合物及其在糖尿病伤口愈合的应用。本发明的短链胜肽组合物具有使血管内皮生长因子增加,导致血管增生,进而促进伤口(尤其是糖尿病患难愈的伤口)的修复愈合的功效。
Description
技术领域
本发明关于一种用于伤口愈合的短链胜肽。更特别地是,本发明关于一种包含一由5~10个氨基酸组成的短链胜肽及其组合物,具有诱发血管增生,并进而促进糖尿病伤口修复、愈合的功效。
背景技术
伤口的愈合过程可分三个阶段:第一个阶段是凝血与止血;第二个阶段是白血球聚集在伤口,用以抵抗感染;而在最后的增生阶段,必须要有新的血管和神经形成,并因此生长出新的肉芽组织。一般伤口瘙痒是发生在增生阶段,此时新的血管和神经等都在积极修复伤口,这些组织因密集增生而挤在一起,由于新生的末梢神经非常敏感,特别容易受到刺激,因此病人会产生瘙痒的感觉。
一般人皆有糖尿病患者的伤口不容易愈合这种概念,主要是因糖尿病导致患者自身免疫力下降所造成的,因此一旦糖尿病患者出现了伤口愈合的周期很长,而不进行及时的处理,就可能造成感染等情况的发生。此外,糖尿病患者当血糖浓度过高时,因细胞外液渗透压升高,导致水从细胞内渗出;而葡萄糖从尿中排出,形成渗透性利尿,通过尿液排出过多的水分和电解质。这样细胞内、外都可能发生脱水,影响伤口处皮肤愈合。
若糖尿病患者的血糖控制不好,除了其身体消灭细菌的能力降低之外,由于高血糖会降低细胞运输氧到组织的能力,也影响伤口愈合。此乃因为糖尿病患者血糖水平升高时,促使葡萄糖氧化物沉积在组织胶原内,出现异常的胶原蛋白,导致血管丧失弹性,微循环变差,体肢末端的代谢废物无法完全清除,容易导致组织坏死。
糖尿病血糖升高易引起微血管病变,损害血管和神经。糖尿病伤口难以愈合的另一个主要原因是,下肢中小动脉的血管壁增厚、血管腔狭窄引起的远端血管阻塞、缺血及血循环不畅,致使新鲜的肉芽无法顺利长出;而且因为血循环不畅,导致药物也难以到达伤口帮助消炎。再加上糖尿病患者富于糖分的伤口,也容易滋生细菌的感染。这样伤口就会越来越大,感染越来越重,最后发生坏疽(即发黑)。
糖尿病患者是足部溃疡的高风险群,而愈合不佳的糖尿病足部溃疡更可能会导致糖尿病患部份或全部的足部、甚至是下肢的截肢。抗微生物制剂(抗菌剂或抗生素)能抑制细菌的生长,所以有时候会用来治疗糖尿病患足部的溃疡伤口。目前一般常用的伤口敷料,有抗生素药膏、银离子抗菌纤维敷料,吸收性泡棉敷料等,视伤口的状况来选择,其目的是维持伤口的保湿、保温与抗菌、制菌来达到伤口愈合。
发明内容
为了解决上述问题,本发明的目的在于提供一种具有能有效诱发血管增生,并进而促进伤口(尤其是糖尿病伤口)修复、愈合的短链胜肽及其组合物。
为了实现上述目的,本发明提供一种具有促进血管增生的短链胜肽,包含一由5~10个氨基酸组成的短链胜肽,且所述的短链胜肽具有分子量为550~1100Da。
在本发明的一些具体实施形式中,所述的短链胜肽是由Xxx-Asn-Pro-Yyy-Thr(SEQ ID No.1)所示的氨基酸序列及0~3个其他任意氨基酸组成,其中Xxx及Yyy各代表一任意氨基酸。较佳地,Xxx代表一碱性氨基酸,Yyy代表一任意氨基酸;最佳地,Xxx代表一碱性氨基酸,Yyy代表一酸性氨基酸。
在本发明的一些具体实施形式中,所述的短链胜肽用于促进糖尿病伤口的血管增生。
在另一方面,本发明关于一种包含一由5~10个氨基酸组成的短链胜肽用于制备糖尿病伤口修复组成物的用途,所述的短链胜肽具有分子量为550~1100Da。
在本发明的一具体实施形式中,所述的短链胜肽是由Xxx-Asn-Pro-Yyy-Thr(SEQID No.1)所示的氨基酸序列及0~3个其他任意氨基酸组成,其中Xxx代表一碱性氨基酸,Yyy代表一任意氨基酸;或者,Xxx代表一碱性氨基酸,Yyy代表一酸性氨基酸。
本发明也提供一种促进血管增生的短链胜肽组合物,包含所述一由SEQ ID No.1:Xxx-Asn-Pro-Yyy-Thr所示的氨基酸序列及0~3个其他任意氨基酸组成的短链胜肽,及一药学上可接受的载体、赋形剂或稀释剂。
在本发明的具体实施形式中,所述的短链胜肽及其组合物用于促进糖尿病伤口的血管生成。所述的伤口,包括(但不限定于)创伤伤口及烫伤伤口。
本发明的有益效果在于:
本发明提供一种促进血管增生的短链胜肽组合物,该短链胜肽具有能有效诱发血管增生,并进而促进伤口(尤其是糖尿病伤口)修复、愈合的短链胜肽及其组合物。
具体实施方式
胜肽是两个以上的氨基酸通过脱水缩合而成的聚合物,由第一个氨基酸分子的羧基与第二个氨基酸分子的氨基缩合,而形成具有两个氨基酸的短链就称为二胜肽;由三个氨基酸缩合而成的肽链称为三胜肽,依此类推。通常,具有小于10个氨基酸的胜肽链称为短链胜肽。
在本发明使用的短链胜肽是由5~10个氨基酸组成,分子量为550~1100Da,较佳地,本发明的短链胜肽包含一由Xxx-Asn-Pro-Yyy-Thr(SEQ ID No.1)所示的氨基酸序列,其中Xxx及Yyy各代表一任意的氨基酸,及0~3个其他任意氨基酸。
在本发明,“其他任意氨基酸”指可依需要,添加于本发明Xxx-Asn-Pro-Yyy-Thr(SEQ ID No.1)氨基酸序列的N-端或C-端,而不会影响该五肽序列的促进血管增生活性的任意氨基酸。
在本发明,“任意氨基酸”指由氨基(-NH2)和羧基(-COOH)的官能团,以及连到每一个氨基酸的侧链所组成的有机化合物。构成天然蛋白质的氨基酸包括:甘氨酸(Glycine)、丙氨酸(Alanine)、缬氨酸(Valine)、亮氨酸(Leucine)、异亮氨酸(Isoleucine)、苯丙氨酸(Phenylalanine)、色氨酸(Tryptophan)、酪氨酸(Tyrosine)、天冬氨酸(Aspartate)、组氨酸(Histidine)、天冬酰胺(Asparagine)、谷氨酸(Glutamate)、赖氨酸(Lysine)、谷氨酰胺(Glutamine)、甲硫氨酸(Methionine)、精氨酸(Arginine)、丝氨酸(Serine)、苏氨酸(Threonine)、半胱氨酸(Cysteine)、脯氨酸(Proline)等。
在本发明,一些较佳的短链胜肽包含一碱性氨基酸,其在正常生理环境下带正电,实施例包括(但不限定于)赖氨酸(Lysine)、精氨酸(Arginine)、组氨酸(Histidine)等。本发明另一些较佳的短链胜肽包含一酸性氨基酸,即侧链带有酸性基团的氨基酸残基,实施例包括(但不限定于)谷氨酸(Glutamate)、天冬氨酸(Aspartate)、γ-氨基丁酸(γ-aminobutyric acid,简称GABA)等。
脯氨酸(Proline)对于维持关节及肌腱的正常功能有举足轻重的地位,还可以强化心肌的功能。苏氨酸(Threonine)是人体胶原蛋白及牙齿珐琅质的重要成份,可以防止肝脏脂肪堆积,及促进胃肠道功能更平顺。
用于本发明的实施例,将短链胜肽Met-Lys-Asn-Pro-Glu-Thr-Cys(SEQ ID No.2)溶于生理食盐水,制得浓度为250μg/ml的短链胜肽溶液,再用过滤膜无菌处理后备用,施予(在伤口涂抹)该短链胜肽溶液的实验组,以下称为短链胜肽处理组。
因此,本发明也提供一种促进血管增生的短链胜肽组合物,包含所述一由SEQ IDNo.1:Xxx-Asn-Pro-Yyy-Thr所示的氨基酸序列及0~3个其他任意氨基酸组成的短链胜肽,及一药学上可接受的载体、赋形剂或稀释剂。本文中,“药学上可接受的载体、赋形剂或稀释剂”指,药学上可接受的材料、基底等载剂和赋形剂或稀释剂,例如液体、固体填料、稳定剂、分散剂,悬浮剂、增稠剂、溶剂或包封材料,其作用是运输本发明中的有效成分,使其在患者体能发挥应有的作用。每一个载体必须和组合物中的各个配方成分(包括本发明的短链胜肽)兼容,使其对患者不产生负面影响。药学上可接受的载体包括:糖类,例如乳糖,葡萄糖和蔗糖;淀粉,例如玉米淀粉和马铃薯淀粉;纤维素,例如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;粉末黄蓍胶;麦芽;明胶;滑石。药学上可接受的赋形剂或稀释剂包括可可脂和栓剂蜡;油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,例如丙二醇;多元醇,例如甘油,山梨醇,甘露醇和聚乙二醇;酯,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;表面活性剂;藻酸;无热原水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;以及其它无毒的药学上配方兼容物质。
本发明的其他特色及优点将在下列实施例中被进一步举例与说明,而该实施范例仅作为辅助说明,并非用于限制本发明的范围。
实施例一、短链胜肽组合物促进糖尿病伤口愈合
本实施例使用Sprague-Dawley大鼠(10周龄,350–400g),以链脲佐菌素(Streptozocin,STZ)诱导成糖尿病,以水浴槽维持水温98±2℃造成部分深度的烫伤,占全身表面积的20%背部(20%TBSA)区域烫伤,再涂抹短链胜肽后进行伤口愈合分析评估。
Sprague-Dawley大鼠(10周,350–400g)随机分为四组,其中两组以1%浓度的链脲佐菌素(Streptozocin,STZ),以50mg/Kg的剂量注入大鼠腹腔,共施予2针,1周1针。链脲佐菌素是一种由链球菌产生的天然化合物,对于哺乳动物胰脏中产生胰岛素的胰岛B细胞具有特异的毒性,会破坏生成胰岛素的细胞,引发第I型糖尿病。STZ-诱导糖尿病组,侦测空腹血糖浓度超过250(mg/dL)确认诱导完成(300mg/dL),并维持高血糖2周(肛门上切尾滴血-血糖机测量)。在第16天,先以0.4ml/正常鼠或0.2ml/糖尿病鼠的麻醉药舒泰50(舒泰,动物药入字第05392-05393号)注射后,再进行烫伤处理:以水浴槽维持水温100℃造成部分深度的烫伤(8秒),占全身表面积的20%背部(20%TBSA)区域烫伤。再紧接进行切割采样表皮,固定1×1cm2面积大小的全皮层进行观察。切割采样表皮保留,进一步由台中荣总整形外科,进行切片染色,评估生理变化的机制。
将生理食盐水(无投药对照组)及短链胜肽溶液,分别涂抹于烫伤伤口表面。正常大鼠与糖尿病大鼠,各别区分无投药对照组(涂抹生理食盐水),及短链胜肽处理组(涂抹短链胜肽溶液,250μg/ml),皆在烫伤后第1、5、8、13天进行患部观察与采样切片。
结果:
第1天(实验代号A)
正常SD鼠对照组:(与糖尿病组比较)皮层组织较厚、(截尾)血液颜色鲜红易采血;糖尿病SD鼠组:(与正常组比较)皮层组织较薄、(截尾)血液颜色暗红且采血不易,明显具糖尿病组织与血管并发症。进行切割采样表皮A-1、A-2、A-3、A-4的1×1cm2面积大小的全皮层时,显示全部的SD鼠的伤口都有渗血,参见下表1。
表1.实验第1天观察各组SD鼠的伤口的出血现象
代号 | 组别 | 出血现象 |
A-1 | 正常SD鼠对照组 | 切割采样表皮伤口时,有渗血 |
A-2 | 正常SD鼠+短链胜肽溶液处理组 | 切割采样表皮伤口时,有渗血 |
A-3 | 糖尿病SD鼠对照组 | 切割采样表皮伤口时,有渗血 |
A-4 | 糖尿病SD鼠+短链胜肽溶液处理组 | 切割采样表皮伤口时,有渗血 |
第5天(实验代号B)
正常SD鼠对照组:表皮较干硬且色深,切皮时亦明显厚硬,且无出血现象;正常SD鼠涂抹短链胜肽溶液处理组:表皮较软且色稍浅,切皮时表皮亦较软,且真皮层易有轻微出血。
没有涂抹本发明短链胜肽溶液的正常SD鼠(对照组),进行切割采样表皮(B-1)其伤口没有渗血反应。有涂抹本发明短链胜肽溶液的正常SD鼠(正常SD鼠+短链胜肽溶液处理组),进行切割采样表皮(B-2)时,伤口有轻微渗血反应。糖尿病SD鼠(糖尿病SD鼠对照组),与正常SD鼠对照组比较,其伤口表皮明显较薄,且表皮与真皮容易剥离;而其与有涂抹本发明短链胜肽溶液的糖尿病SD鼠(糖尿病SD鼠+短链胜肽溶液处理组)比较时,显示其表皮层较硬且色深,切皮时亦明显较硬,且无出血现象。糖尿病SD鼠有涂抹短链胜肽溶液的处理组,与糖尿病SD鼠对照组比较时,其表皮层较软且色稍浅,切皮时亦明显较软,且真皮层易有轻微出血。
没有涂抹本发明短链胜肽溶液的糖尿病SD鼠进行切割采样表皮(B-3),显示伤口没有渗血反应,表示已发生血管阻塞、缺血。而伤口经涂抹本发明短链胜肽溶液的糖尿病SD鼠进行切割采样表皮(B-4),与涂抹短链胜肽溶液的正常SD鼠比较,其在第5天的伤口有比较慢的渗血反应,有出血现象表示有血管增生参见下表2。上述的结果显示,有涂抹本发明短链胜肽溶液的糖尿病SD鼠,在第5天已呈现伤口处有血管增生现象,而此修复作用在没有涂抹短链胜肽溶液的SD鼠对照组中皆无发生。
表2.实验第5天观察各组SD鼠的伤口的出血现象
第8天(实验代号C)
正常SD鼠对照组:表皮较干硬且色深,切皮时亦明显厚硬,且真皮层与结缔组织明显分离,较无出血现象。正常SD鼠+短链胜肽溶液处理组:表皮较软且色更浅,切皮时表皮亦较软,且真皮层与结缔组织明显沾粘,且出血明显。由表3的切割伤口出血现象观测结果显示,没有涂抹短链胜肽溶液的正常SD鼠,进行切割采样表皮(C-1)伤口没有渗血反应,表示其伤口处尚未有血管增生。而有涂抹短链胜肽溶液的正常SD鼠,进行切割采样表皮(C-2)伤口有渗血反应,表示本发明的短链胜肽已诱发该处的血管增生。
糖尿病SD鼠对照组:与正常对照组比较时明显较薄,且表皮与真皮容易剥离;而其与有涂抹短链胜肽溶液的糖尿病SD鼠比较,表皮层较硬且色深,切皮时亦明显较硬,真皮层与结缔组织没有沾粘,且无出血现象。糖尿病SD鼠+短链胜肽溶液处理组:与糖尿病SD鼠对照组比较时,其伤口表皮层较软且色稍浅,切皮时亦明显较软,且真皮层易有轻微出血,表示有血管增生。没有涂抹短链胜肽溶液的糖尿病SD鼠,进行切割采样表皮(C-3)的伤口没有渗血反应;而涂抹短链胜肽溶液的糖尿病SD鼠,进行切割采样表皮(C-4)的伤口有明显的渗血反应。参见下表3。上述的结果显示,有涂抹本发明短链胜肽溶液的糖尿病SD鼠,在处理后第8天,本发明短链胜肽促进伤口处血管增生的效果,已相当明显。
表3实验第8天观察各组SD鼠的伤口的出血现象
第13天(实验代号D)
正常SD鼠对照组:与第5日的正常SD鼠对照组(未涂抹短链胜肽溶液)组比,表皮已软且色稍浅,但切皮时与实验上药组比仍明显较厚硬,且真皮层与结缔组织明显分离,但已稍有出血现象,表示正常SD鼠在烫伤13天后已出现血管增生现象。正常SD鼠+短链胜肽溶液处理组:表皮更软且色更浅,切皮时表皮亦更软,且真皮层与结缔组织明显沾粘,且出血更为明显,伤口已需要加压止血。没有涂抹短链胜肽溶液的正常SD鼠,进行切割采样表皮(D-1)伤口有渗血反应。有涂抹短链胜肽溶液的正常SD鼠,进行切割采样表皮(D-2)伤口有明显的渗血反应。
糖尿病SD鼠对照组:与正常对照组比较时明显较薄,且表皮与真皮更易剥离;而与有涂抹短链胜肽溶液的糖尿病SD鼠比较时,其表皮层较硬且色深,切皮时亦明显较硬厚,真皮层比结缔组织没有沾粘,但也已稍有出血现象,表示有些微的血管增生。糖尿病SD鼠+短链胜肽溶液处理组:与糖尿病SD鼠对照组比较时,表皮与真皮易剥离,表皮更软且色更浅,但真皮层与结缔组织明显沾粘,且出血更为明显。没有涂抹短链胜肽溶液的糖尿病SD鼠,进行切割采样表皮(D-3)的伤口有轻微的渗血反应;而涂抹短链胜肽溶液的糖尿病SD鼠,进行切割采样表皮(D-4)的伤口,有很明显的渗血反应。参见下表4。上述的结果显示,没有涂抹本发明短链胜肽溶液的SD鼠在烫伤13天后,其伤口才出现血管增生现象;而有涂抹短链胜肽溶液的SD鼠,其伤口处的血管增生的现象,相较于未涂抹短链胜肽溶液的对照组已相当明显,在正常SD鼠的促进血管增生作用尤其显著。
表4.实验第13天观察各组SD鼠的伤口的出血现象
伤口愈合天数
下表5为总和记录,各组SD鼠的伤口所需愈合的天数。结果显示,经过本发明短链胜肽处理的正常SD鼠伤口,相较于未经涂抹短链胜肽的正常SD鼠伤口,其愈合天数从30天缩短至12~18天,表示短链胜肽促进伤口愈合的效率可达50%;而对于糖尿病伤口,其愈合天数缩短了15天,显示本发明的短链胜肽促进糖尿病伤口愈合的效率亦可达25%。
表5.各组SD鼠的伤口愈合天数
组别 | 伤口愈合天数(天) |
正常SD鼠对照组 | 30天 |
正常SD鼠+短链胜肽溶液处理组 | 12~18天 |
糖尿病SD鼠对照组 | 60天 |
糖尿病SD鼠+短链胜肽溶液处理组 | 45天 |
从上述实施例可以看出,本发明提供的促进血管增生的短链胜肽可以有效促进正常大鼠及糖尿病大鼠的伤口愈合,说明该短链胜肽具有能有效诱发血管增生,并进而促进伤口(尤其是糖尿病伤口)修复、愈合。
SEQUENCE LISTING
<110> 三凡生技研发股份有限公司
<120> 促进血管增生的短链胜肽及其促进糖尿病伤口愈合的用途
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 5
<212> PRT
<213> 人工序列
<400> 1
Xxx Asn Pro Yyy Thr
1 5
<210> 2
<211> 7
<212> PRT
<213> 人工序列
<400> 1
Met Lys Asn Pro Glu Thr Cys
1 5
Claims (6)
1. 一种促进血管增生的短链胜肽,其特征在于,该短链胜肽的氨基酸序列如SEQ IDNo.2所示。
2.如权利要求1所述的短链胜肽,其特征在于,所述促进血管增生为促进糖尿病伤口的血管增生。
3. 一种包含短链胜肽作为制备用于促进糖尿病伤口愈合的组成物的用途,其特征在于,该短链胜肽的氨基酸序列如SEQ ID No.2所示。
4.如权利要求3所述的用途,其特征在于,所述促进糖尿病伤口愈合为用于促进伤口的血管生成。
5.如权利要求3或4所述的用途,其特征在于,该伤口为烫伤伤口。
6.如权利要求3或4所述的用途,其特征在于,该伤口为创伤伤口。
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