CN116832143A - 一种用于全层皮肤损伤创面愈合的pdgf制剂 - Google Patents
一种用于全层皮肤损伤创面愈合的pdgf制剂 Download PDFInfo
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- CN116832143A CN116832143A CN202210290819.0A CN202210290819A CN116832143A CN 116832143 A CN116832143 A CN 116832143A CN 202210290819 A CN202210290819 A CN 202210290819A CN 116832143 A CN116832143 A CN 116832143A
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明提供了一种用于全层皮肤损伤创面愈合的外敷制剂,所述制剂在对非糖尿病的全层皮肤损伤创面治疗中产生了优异的治疗效果,可以在降低活性因子血小板衍生生长因子的剂量的情况下获得更为优异的愈合效果,对于促进创面愈合,减轻病人负担都具有重要的意义。
Description
技术领域
本发明公开了一种药物制剂,属于医药应用技术领域。
背景技术
血小板衍生生长因子(PDGF)是一种多肽生长因子,PDGF家族由PDGF-A、PDGF-B、PDGF-C、PDGF-D四个成员组成,并构成五个功能同源或异源二聚体的结构相关多肽单元:PDGF-AA,PDGF-BB,PDGF-AB,PDGF-CC,和PDGF-DD, PDGF家族成员与PDGF受体结合并通过PDGF受体发出信号,具有多种生物学功能,是多种细胞的强力丝裂原和趋化物。PDGF可促进皮肤上皮细胞代谢,保护皮肤及预防皮肤由于各种原因导致的损伤。PDGF可有效促进皮下胶原细胞功能,加速皮肤胶原细胞生长,促进创面愈合,目前研究发现PDGF在损伤修复过程中发挥重要作用。它也已被用于治疗压疮,并在各种外科手术中加快了愈合速度。中国发明专利CN100503826C公开了一种可在巴氏毕赤酵母中表达的重组人血小板衍生生长因子Thr6-PDGF-BB(简称TPG-PDGF),TPG-PDGF在慢性神经性下肢糖尿病性溃疡的局部治疗方面也获得本领域的重视。但是在实际应用中,不同的适应症由于病理形成条件、病灶病理环境及迁延状况的不同,导致TPG-PDGF在具体的适应症应用上难以获得理想的治疗效果,一直使得TPG-PDGF难以在临床应用中难以得到广泛应用。
全层皮肤缺损创面损伤是一种在病因和病理表现上均不同于慢性神经性下肢糖尿病性溃疡的适应症,糖尿病性溃疡是一种内因性血糖升高导致神经调节功能受损以及血管功能障碍导致的免疫能力低下产生的溃疡性损伤,而全层皮肤缺损创面损伤是主要是因为外因性机械损伤所导致的,更多是产生与日常工作、劳动和军事训练以及战伤中,患者即使免疫能力健全,但是由于创面开放性大,创伤深,其创伤环境明显与糖尿病性溃疡不同,因此现有技术亟待一种能够充分发挥PDGF的创面修复功能,又能针对具有具体病理特点的全层皮肤缺损创面产生优异治疗效果的药物制剂。
发明内容
基于上述目的,本发明首先提供了一种用于全层皮肤损伤创面愈合的外敷制剂,所述外敷制剂含有有血小板衍生生长因子,所述血小板衍生生长因子在外敷制剂中以5×103IU/cm2-21×103IU/cm2的浓度分布。
在一个优选的实施方案中,所述血小板衍生生长因子在外敷制剂中以7×103IU/cm2的浓度分布。
在一个更为优选的实施方案中,所述血小板衍生生长因子为两条B链组成的二聚体,所述B链的氨基酸残基序列为SEQ ID NO.1。
尤为优选地,所述血小板衍生生长因子由巴氏毕赤酵母表达而成。
在一个优选的实施方案中,所述外敷制剂为凝胶制剂。
更为优选地,所述凝胶制剂中的血小板衍生生长因子的比活性为1×106IU/mg。
尤为优选地,所述外敷制剂还含有透明质酸钠、羧甲基纤维素钠。
再为优选地,,所述外敷制剂还含有制药学上可接受的载体。
其次,本发明还提供了含有上述的用于全层皮肤损伤创面愈合的外敷制剂的外科包扎材料。
在一个优选的实施方案中,外科包扎材料为无纺布。
TPG-PDGF在对非糖尿病的全层皮肤损伤创面治疗效果,并没有显示剂量依赖性关系,片面提高PDGF的剂量,反而会延缓创面愈合,伤后14d, 7μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后21d, 仅7μg治疗组比两个对照组显著减少(0.08vs0.11)(p<0.05),减少的比例高达27%(0.03/0.11)。这一点和CN100356977C公开的 TPG-PDGF治疗糖尿病溃疡所表现的结果不同,其结果显示,各剂量治疗组没有显示明显的差异。这些结果提示,非糖尿病的全层皮肤损伤创面病理与糖尿病溃疡病理不同,使用糖尿病溃疡的治疗方法在治疗非糖尿病的全层皮肤损伤创面难以获得理想的治疗效果,本发明提供的用于全层皮肤损伤创面愈合的外敷制剂通过精准的生物活性制剂的技术方案即PDGF以3.5×103IU/cm2-14×103IU/cm2的浓度对于创面进行治疗,优选7×103IU/cm2,能够获得优于高剂量的治疗效果,对于临床治疗效果,减轻病人负担都具有重要的意义。
附图说明
图1. Wistar大鼠伤后当天各组创面组织统计图;
图2. Wistar大鼠伤后3天各组创面组织统计图;
图3. Wistar大鼠伤后5天各组创面组织统计图;
图4. Wistar大鼠伤后7天各组创面组织统计图;
图5. Wistar大鼠伤后10天各组创面组织统计图;
图6. Wistar大鼠伤后14天各组创面组织统计图;
图7. Wistar大鼠伤后21天各组创面组织统计图。
具体实施方式
下面结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的权利要求所限定的保护范围构成任何限制。
制备实施例
PDGF参照CN100503826C制备,所制备的TPG-PDGF比活性为1×106IU/mg(简称TPG-PDGF)。
PDGF参照CN100356977C中的实施例1的配方制备(TPG-PDGF含量调整),其中:
重组人血小板衍生生长因子 0.1g,
透明质酸钠 0.5g,
羧甲基纤维素钠 24g,
赖氨酸盐酸盐 5g,
磷酸氢二钠 0.6g,
磷酸二氢钠 0.05g,
对羟基苯甲酸甲酯 1.6g,
对羟基苯甲酸丙酯 0.2g,
氯化钠 7.8g,
加注射用水到1000g。
对上述凝胶制剂中的PDGF含量根据在具体的治疗方案中所需求的生物活性浓度的不同进行具体调整。
应用实施例 应用TPG-PDGF对全层皮肤损伤创面动物模型的治疗
本实验委托中国医学科学院药用植物研究所全程评价。
实验动物:本实验选用180-220g的健康雄性Wistar大鼠(购自北京维通利华实验动物技术有限公司)。所有大鼠均饲养于中国医学科学院药用植物研究所动物房中,温度控制在22 ± 2 ℃,湿度控制在60 ± 10%,12小时明暗循环,允许自由饮食和饮水。所有动物实验程序均由中国医学科学院北京协和医学院药用植物研究所动物伦理委员会批准并严格遵守国家针对实验动物护理和使用的指导原则(SLXD-2019)。
受试药物:
TPG-PDGF空白基质凝胶 15g/支
TPG-PDGF凝胶30μg/ml 15g/支
TPG-PDGF凝胶100μg/ml 15g/支
TPG-PDGF凝胶300μg/ml 15g/支
重组牛碱性成纤维细胞生长因子凝胶(贝复新):珠海亿胜生物制药有限公司21000IU/5g/支。
模型制备:在试验前Wistar大鼠单笼喂养1周,自由饮水与摄食。大鼠试验当日禁食,用乙醚吸入麻醉,背部剃毛,75%酒精常规消毒。用直径20mm的环形在Wistar大鼠脊柱两侧各压出1个圆形印迹(3.14cm2),外科手术剪刀沿压痕剪去全层皮肤(达深筋膜),即每只大鼠背部各制成两个圆形全层皮肤缺损创面止血备用,制备全层皮肤缺损创面。
分组:上述Wistar大鼠60只随机分成六组:
(1)模型对照组:致伤后创面组(n=10),仅包扎处理;
(2)基质对照组:致伤后创面给无TPG-PDGF 的凝胶基质(n=10);
(3)低剂量(2.1μg)治疗组1:致伤后创面给2.1μg TPG-PDGF /cm2(n=10);相当于2.1×103IU/cm2;
(4)低剂量(3.5μg)治疗组2:致伤后创面给3.5μg TPG-PDGF /cm2(n=10);相当于3.5×103IU/cm2;
(5)中剂量(7.0μg)治疗组:致伤后伤面给7.0μg TPG-PDGF /cm2(n=10);相当于7.0×103IU/cm2;
(6)高剂量(14μg)治疗组1:致伤后创面给14μg TPG-PDGF /cm2(n=10);相当于14×103IU/cm2;
(7)高剂量(21μg)治疗组2:致伤后伤面给21μg TPG-PDGF /cm2(n=10);相当于21×103IU/cm2;
(8)阳性药(贝复新)治疗组:使用重组牛碱性成纤维细胞生长因子凝胶(购自珠海亿胜生物制药有限公司,生产批号:04210508)。致伤后伤面给300IU/cm2(n=10)。
给药:
Wistar大鼠随机分成上述6组。将凝胶基质、含TPG-PDGF 三种不同浓度的凝胶基质、阳性药分别吸入1ml无菌注射器内,每个创面滴注0.2ml凝胶剂,并涂布均匀(直径10mm的动物,每个创面0.05ml)。用单层油纱布和无菌敷贴覆盖,再用3M胶带固定。动物单笼喂养,自由饮水进食,每天给药1次,至伤后21d。
疗效评价:
1.创面面积
伤后0、3、5、7、10、14、21d用透明载玻片覆盖创面,用记号笔沿创面边缘描绘出创面,再用扫面透明塑料膜图样的质量,并换算成相应创面的面积(首先扫描透明塑料膜单位面积的像素,像素/cm2)。
2.创面定时拍照
创面于0、3、7、10、14、21d定期照相,观察了解各组在不同时间创面的愈合情况。
3. 实验结果
用SPSS 17统计软件对数据进行统计学处理,组间比较选用方差分析,P<0.05和P<0.01为有统计学意义。
(1) 创面大体观察
Wistar大鼠全层皮肤缺损创面伤后1-2d各组伤腔均逐渐变浅,但肉芽组织增生均不明显。伤后3d治疗组(尤其是21μg剂量组)创面收缩,伤腔变浅,揭起油纱布时创面鲜红、易出血,表明伤腔已有肉芽组织生长形成,对照组创面收缩,结痂面较干燥。伤后7d,治疗组肉芽组织明显增多,创面也有收缩,伤腔逐渐被肉芽组织填平,高剂量组创面肉芽组织略高于创面;对照两组肉芽样组织较少,部分创面仍存在一定伤腔。伤后7d,各组创面均收缩明显,但治疗组比对照组创面收缩明显。伤后10d治疗组创面肉芽组织基本与创面持平。到伤后14d各组创面收缩都很明显,上皮继续增生逐渐覆盖整个创面,到伤后21d各组创面收缩都很明显,仅有部分创面残留少许创面未愈,但对照组未愈创面面积仍比治疗组显著大
(2) 创面面积
各时间及各组的创面面积如图1-7和表1所示。
从伤后3d起,Wistar大鼠创面面积即开始减少。伤后3d,2.1、7μg和21μg治疗组均仍保持较大的伤腔,与基质对照组无显著差异,阳性药组比基质对照组显著减少(p<0.05);伤后5d,基质组仍保持较大的伤腔,7、21μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后7d, 7μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后10d, 7,21μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后14d, 7μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后21d, 仅7μg治疗组比两个对照组显著减少(p<0.05);另外此时的基质对照组相对于模型对照组也有显著差异(p<0.01)。
表1. TPG-PDGF凝胶制剂对大鼠全层皮肤缺损创面愈合的影响(cm2, ±SD)
TPG-PDGF在对非糖尿病的全层皮肤损伤创面治疗效果,并没有显示剂量依赖性关系,片面提高PDGF的剂量,反而会延缓创面愈合,伤后14d, 7μg治疗组和阳性药组比两个对照组显著减少(p<0.05);伤后21d, 仅7μg治疗组比两个对照组显著减少(0.08vs0.11)(p<0.05),减少的比例高达27%(0.03/0.11)。这一点和CN100356977C公开的 TPG-PDGF治疗糖尿病溃疡所表现的结果不同,其结果显示,各剂量治疗组没有显示明显的差异。这些结果提示,非糖尿病的全层皮肤损伤创面病理与糖尿病溃疡病理不同,使用糖尿病溃疡的治疗方法在治疗非糖尿病的全层皮肤损伤创面难以获得理想的治疗效果,本发明提供的用于全层皮肤损伤创面愈合的外敷制剂通过精准的生物活性制剂的技术方案即PDGF以3.5×103IU/cm2-14×103IU/cm2的浓度对于创面进行治疗,优选7×103IU/cm2,能够获得优于高剂量的治疗效果,对于临床治疗效果,减轻病人负担都具有重要的意义。
序列表
<110>北京华芢生物技术有限公司
<120>一种用于全层皮肤损伤创面愈合的PDGF制剂
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<170> SIPOSequenceListing 1.0
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<213> Homo sapiens
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Val Phe Glu Ile Ser Arg Arg Leu Ile Asp Arg Thr Asn Ala Asn Phe
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Leu Val Trp Pro Pro Cys Val Glu Val Gln Arg Cys Ser Gly Cys Cys
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Asn Asn Arg Asn Val Gln Cys Arg Pro Thr Gln Val Gln Leu Arg Pro
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Val Gln Val Arg Lys Ile Glu Ile Val Arg Lys Lys Pro Ile Phe Lys
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aaggccacgg tgacgctgga agaccacctg gcatgcaagt gtgagacagt ggcagctgca 300
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Claims (10)
1.一种用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述外敷制剂含有有血小板衍生生长因子,所述血小板衍生生长因子在外敷制剂中以3.5×103IU/cm2-14×103IU/cm2的浓度分布。
2.根据权利要求1所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述血小板衍生生长因子在外敷制剂中以7×103IU/cm2的浓度分布。
3.根据权利要求2所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述血小板衍生生长因子为两条B链组成的二聚体,所述B链的氨基酸残基序列为SEQ ID NO.1。
4.根据权利要求3所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述血小板衍生生长因子由巴氏毕赤酵母表达而成。
5.根据权利要求1-4任一所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述外敷制剂为凝胶制剂。
6.根据权利要求5所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述凝胶制剂中的血小板衍生生长因子的比活性为1×106IU/mg。
7.根据权利要求6所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述外敷制剂还含有透明质酸钠、羧甲基纤维素钠。
8.根据权利要求7所述的用于全层皮肤损伤创面愈合的外敷制剂,其特征在于,所述外敷制剂还含有制药学上可接受的载体。
9.一种含有权利要求1-4任一所述的用于全层皮肤损伤创面愈合的外敷制剂的外科包扎材料。
10.根据权利要求9所述的外科包扎材料,其特征在于,外科包扎材料为无纺布。
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