CN116832144A - 血小板衍生生长因子在制备治疗烫伤药物中的应用 - Google Patents
血小板衍生生长因子在制备治疗烫伤药物中的应用 Download PDFInfo
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Abstract
本发明提供了血小板衍生生长因子在制备治疗烧烫伤药物中的应用,所述应用在血小板衍生生长因子被制备为外敷制剂时对烧烫伤动物模型治疗中产生了优异的治疗效果,可以有效提高浅Ⅱ度、深Ⅱ度烫伤模型小型猪的创面愈合率,改善创面损伤的恢复作用,能够促进新生血管的形成,成纤维细胞和纤维细胞增生。
Description
技术领域
本发明涉及一种蛋白质活性因子的医学新用途,属于医药技术领域。
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。
烧伤一般指由热力如沸液(水、油、汤)、炽热金属(液体或固体)、火焰、蒸汽和高温气体等所致的人体组织和器官损伤。烧伤深度的判断国内通常采用三度四分法:I 度、浅II度、深II 度、III 度。一般将I 度和浅II 度烫伤称浅度烫伤,深II 度和III 度烫伤称深度烫伤。浅Ⅱ度烫伤:伤到真皮浅层,部分生发层健在。局部红肿,有大小不一水疱,内含黄色或淡红色血浆样液体或蛋白凝固的胶动冻物。去除水疱腐皮后,可见创面潮红。脉络状或颗粒状扩张充血的毛细血管网,伤后1~2天更明显。创面基地较软,温度较高。若无感染等并发症,约2周可愈。愈合后短期内可有色素沉着,不留瘢痕,皮肤功能良好。深Ⅱ度烫伤:伤到真皮乳头层以下,但仍残留部分网状层。局部肿胀,间或有较小水疱。去除表皮后,创面微湿、微红或红白相间,触之较韧。可见针孔或粟粒般大小红色小点,伤后1~2天更明显。如症状较深,可见扩张充血或栓塞的小血管枝(真皮血管丛充血或栓塞)。若无感染等并发症,约3~4周可愈。愈合后可见瘢痕和瘢痕收缩引起的局部功能障碍。愈合后的上皮多脆弱,缺乏韧性和弹性。
烧烫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,而烧伤是主要是因为外因性高温液体、固体、气体所导致的皮肤创伤,更多是产生与日常工作、生活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烧伤产生优异治疗效果的药物制剂。本发明的目的就是提供PDGF在烧烫伤治疗药物领域中的一种具体应用。
发明内容
基于上述目的,本发明提供了血小板衍生生长因子在制备治疗烧烫伤药物中的应用。
在一个优选的实施方案中,所述血小板衍生生长因子被制备为外敷制剂,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。
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。
在一个尤为优选的实施方案中,所述血小板衍生生长因子由巴氏毕赤酵母表达而成。
在又一个优选的实施方案中,所述外敷制剂还含有透明质酸钠、羧甲基纤维素钠,所述外敷制剂被制备为凝胶制剂。
更为优选地,所述外敷制剂还含有制药学上可接受的载体。
在一个优选的实施方案中,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。
在一个更为优选的实施方案中,所述血小板衍生生长因子在外敷制剂中以3.5×103IU/cm2的浓度分布,所述烧烫伤为浅Ⅱ度烧烫伤。
在另一个更为优选的实施方案中,所述血小板衍生生长因子在外敷制剂中以7×103IU/cm2-14×103IU/cm2的浓度分布,所述烧烫伤为深Ⅱ度烧烫伤。
本发明提供的血小板衍生生长因子凝胶制剂显示出对烧烫伤优异的治疗效果,血小板衍生生长因子凝胶制剂的2倍临床剂量(14μg/cm2)可明显增加浅Ⅱ度、深Ⅱ度烫伤模型小型猪的创面愈合率,血小板衍生生长因子凝胶制剂的0.5倍临床剂量(3.5μg/cm2)可明显增加浅Ⅱ度烫伤模型小型猪的创面愈合率,血小板衍生生长因子凝胶制剂的 1倍临床剂量(7μg/cm2)可明显增加14天观察期的深Ⅱ度烫伤模型小型猪的创面愈合率。血小板衍生生长因子凝胶制剂的0.5、1、2倍剂量(3.5、7、14μg/cm2)可改善浅Ⅱ度、深Ⅱ度烫伤模型小型猪的创面损伤的恢复作用,能够促进新生血管的形成,成纤维细胞和纤维细胞增生。
附图说明
图1. A组动物脊柱左侧给药21天后皮肤组织病理学图片;
图2. A组动物脊柱右侧给药21天后皮肤组织病理学图片;
图3. B组动物脊柱左侧给药21天后皮肤组织病理学图片;
图4. B组动物脊柱右侧给药21天后皮肤组织病理学图片;
图5. C组动物脊柱左侧给药21天后皮肤组织病理学图片;
图6. C组动物脊柱右侧给药21天后皮肤组织病理学图片;
图7.D组动物脊柱左侧给药21天后皮肤组织病理学图片;
图8. D组动物脊柱右侧给药21天后皮肤组织病理学图片;
图9. E组动物脊柱左侧给药21天后皮肤组织病理学图片;
图10.E组动物脊柱右侧给药21天后皮肤组织病理学图片。
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。
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的不同进行具体调整。
应用实施例 应用TPG-PDGF对皮肤烫伤动物模型的治疗
本实验委托广东莱恩医药研究院有限公司全程评价。
1. 实验动物:巴马小型猪。雌性15只;雄性15只。雄性:8.48~10.70kg;雌性:8.28~11.04kg。
模型构建:试验选用经适应性观察符合要求的小型猪30例,雌雄各半,烫伤造模后按烫伤部位评分和性别均衡随机分为5组,分别为模型对照组(A组)、上市品对照组(B组)、PDGF低剂量组(C组)、PDGF中剂量组(D组)、PDGF高剂量组(E组)。计划先对小型猪进行Ⅱ度烫伤造模,给药前造模1次,每例动物分别做2个烫伤面,分别位于脊柱左侧、右侧,脊柱左侧烫伤面为浅Ⅱ度烫伤,脊柱右侧烫伤面为深Ⅱ度烫伤;每个烫伤面的面积为100cm2。烧烫伤造模操作:小型猪试验前按体重先用4-9mg/kg剂量的丙泊酚对动物静脉注射诱导麻醉,用异氟烷进行气体维持麻醉,使其进入第三期外科麻醉期。将动物保定于恒温手术台,背部进行备皮,备皮面积约为15cm×15cm,用纱布或隔热膜挡隔无需烫伤的部位,选用制备好的约为10cm×10cm的40层纱布两块浸入热水中,待水温恒定于95℃以上时,取出,立即分别平铺于待烫伤区域内,烫伤时间分别为22S(浅Ⅱ度烧伤),28S(深Ⅱ度烧伤)。造模前后均需对烧烫伤部位进行消毒处理,完成造模后造模部位用无菌纱布覆盖,绷带固定。
各组小型猪造模后可见造模部位脊柱右侧创面呈现暗红色、紫红色,各种不同程度的水疱,中度至重度肿胀,创面湿润或有渗出,部分创面可见脉络状或颗粒状扩张充血的毛细血管网,针孔或粟粒般大小红色小点,脊柱左侧创面症状与右侧相似,程度稍轻;后随时间推移于约第2周后出现不同程度焦痂、创面触感变硬,部分如皮革感,有色素沉着,有瘢痕或瘢痕收缩。上述症状分别为明显的深Ⅱ度、浅Ⅱ度烫伤模型临床反应。
2. 受试药物及分组:
本发明制备的TPG-PDGF比活性为1×106IU/mg,实验分组中的PDGF低剂量组(C组)以3.5×103IU/ cm2,PDGF中剂量组(D组)以7×103IU/cm2,PDGF高剂量组(E组)以14×103IU/cm2剂量用药,换算为本发明的PDGF凝胶含量则分别为3.5μg/ cm2,7μg/ cm2,和14μg/ cm2的剂量用药。
表1. 受试药物及分组明细表
。
5个试验组,分别为模型对照组(A组)、上市品对照组(B组)、PDGF低剂量组(C组)、PDGF中剂量组(D组)、PDGF高剂量组(E组),6只/组,雌雄各半。
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。
3. 给药过程:于造模第2天开始对小型猪进行涂皮给药,给药面积涵盖烧伤部位(覆盖于创面及创面边缘1cm位置)。动物给药21天,每次给药后于下一次给药时除药;A组动物不给药,仅每天拆开包扎对背部皮肤(或烧伤部位)消毒及观察。烧伤部位每天换药时只需将原来药物擦干净,用过氧化氢消毒水消毒烧伤部位及周边部位以防止感染(坏死组织用无菌镊子或剪刀清除,再用无菌生理盐水彻底冲洗干净),再重新涂抹新药,用无菌纱布覆盖,绷带包扎固定。
给药后每天进行临床观察,持续21天,试验期每天进行给药部位评分;对体重进行测定,给药前2次,试验期每周1次,共5次。分别于给药后第3、6、9、14、22天考察受试物对浅Ⅱ度烫伤模型、深Ⅱ度烫伤模型的创面愈合率。末次给药后,测量创面面积,动物麻醉处死,取下烫伤部位皮肤,2-8℃生理盐水漂洗去除血液,分别取浅Ⅱ度烫伤模型、深Ⅱ度烫伤模型靠近脊柱侧边缘皮肤,-80℃保存备用。创伤皮肤组织钉在硬纸片上,10%甲醛溶液中固定,选取靠近边缘部位进行制片,HE染色后,进行组织病理学检查,观察皮肤愈合情况。
4. 烧烫伤部位皮肤观察评估结果(表2)
脊柱左侧烫伤皮肤(浅Ⅱ度烫伤模型):上市品对照组(B组)于给药期D14(第14天,以下同理)、D15、D16、D19、D20时间点创面平均评分值比模型对照组(A组)低,差异具有统计学意义(P<0.05或0.01)。PDGF低剂量组(C组)于给药期D15时间点创面平均评分值比模型对照组(A组)低,差异具有统计学意义(P<0.05)。
表2. 小型猪烫伤部位左侧评分结果(`x±S)
。
备注:①“*”表示与模型对照组(A组)比较,差异具有显著性意义(P<0.05);“**”表示与模型对照组(A组)比较,差异具有非常显著性意义(P<0.01)。②A组、B组、C组、D组、E组分别表示模型对照组、上市对照品组、血小板源生长因子(PDGF)低、中、高剂量组。
表3. 小型猪烫伤部位右侧评分结果(`x±S)
。
备注:①“*”表示与模型对照组(A组)比较,差异具有显著性意义(P<0.05);“**”表示与模型对照组(A组)比较,差异具有非常显著性意义(P<0.01)。②A组、B组、C组、D组、E组分别表示模型对照组、上市对照品组、PDGF低、中、高剂量组。
脊柱右侧烫伤皮肤(深Ⅱ度烫伤模型):上市品对照组(B组)于给药期D16、D19、D20、D21、D22时间点创面平均评分值比模型对照组(A组)低,差异具有统计学意义(P<0.05或0.01)。
5. 创面愈合率结果
给药前将创面边缘描绘在质地均匀的透明膜上,用剪刀将描绘出的透明膜区域剪下,用分析天平称重,分别以左侧、右侧2个创面的透明膜的重量代表总初始创面面积。于给药后第3、6、9、14、22天以相同方法测定2个创面的透明膜总重代表第n天创伤面积,小型猪创面拍照记录。创面愈合率=(初始面积-第n天创面面积)/初始面积×100%,n=3、6、9、14、22。
上市品对照组(B组)左侧(浅Ⅱ度)烫伤皮肤创面愈合率于给药D14、D22比模型对照组(A组)高,右侧(深Ⅱ度)烫伤皮肤创面愈合率于给药D9、D14、D22比模型对照组(A组)高,差异具有统计学意义(P<0.05或0.01)。
PDGF低剂量组(C组)左侧(浅Ⅱ度)烫伤皮肤创面愈合率于给药D22比模型对照组(A组)高,右侧(深Ⅱ度)烫伤皮肤创面愈合率于给药D14比模型对照组(A组)高,差异具有统计学意义(P<0.05或0.01)。
PDGF中剂量组(D组)右侧(深Ⅱ度)烫伤皮肤创面愈合率于给药D9、D14比模型对照组(A组)高,差异具有统计学意义(P<0.05)。
PDGF高剂量组(E组)左侧(浅Ⅱ度)烫伤皮肤创面愈合率于给药D22比模型对照组(A组)高,右侧(深Ⅱ度)烫伤皮肤创面愈合率于给药D22比模型对照组(A组)高,差异具有统计学意义(P<0.05)。
表4. 小型猪烫伤皮肤愈合率结果(`x±S)
。
上市对照品重组牛碱性成纤维细胞生长因子凝胶的1倍临床剂量(300IU/cm2)、受试物PDGF的2倍临床剂量(14μg/cm2)可明显增加浅Ⅱ度、深Ⅱ度烫伤模型小型猪的创面愈合率,受试物PDGF的0.5倍临床剂量(3.5μg/cm2)可明显增加浅Ⅱ度烫伤模型小型猪的创面愈合率,受试物PDGF的 1倍临床剂量(7μg/cm2)可明显增加14天观察期的深Ⅱ度烫伤模型小型猪的创面愈合率。
6. 病理学检查结果
各组(N=6,雌雄各半,共12块皮肤)动物皮肤组织学检查(H-E染色 100×)结果如下:
模型对照组:左侧和右侧背部皮肤均可见真皮层或真皮浅层轻度至重度炎细胞浸润,胶原纤维变性/坏死,轻度至中度成纤维细胞和纤维细胞增生,轻微至中度血管新生(图1:模型对照组 A♀1左,皮肤:真皮浅层轻度炎细胞浸润,中度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,血管新生;图2:模型对照组A♀1右,真皮层中度炎细胞浸润,重度胶原纤维变性/坏死,中度成纤维细胞和纤维细胞增生,血管新生)。
上市品对照组:左侧和右侧背部皮肤均可见真皮层或真皮浅层轻度至重度炎细胞浸润,轻度至中度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,血管新生(图3: 上市品对照组B♀3左,皮肤:真皮浅层中度炎细胞浸润,胶原纤维变性/坏死,重度成纤维细胞和纤维细胞增生,血管新生;图4:上市品对照组B♀3右,皮肤:真皮层轻度炎细胞浸润,中度胶原纤维变性/坏死,重度成纤维细胞和纤维细胞增生,血管新生)。
PDGF低剂量组(C组):左侧和右侧背部皮肤均可见真皮层或真皮浅层轻微至重度炎细胞浸润,轻度至中度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,轻度至重度血管新生(图5:PDGF低剂量组C♂6左,真皮浅层轻微炎细胞浸润,轻度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,中度血管新生;图6:PDGF低剂量组C♂6右,皮肤:真皮层重度炎细胞浸润,中度胶原纤维变性/坏死,轻度成纤维细胞和纤维细胞增生,中度血管新生)。
PDGF中剂量组(D组):6例动物(D♀1、D♀2、D♀3、D♂4、D♂5、D♂6;6/6)左侧和右侧背部皮肤均可见真皮层或真皮浅层轻微至重度炎细胞浸润,轻度至重度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,血管新生(图7:PDGF中剂量组D♂5左,真皮浅层轻微炎细胞浸润,轻度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,血管新生;图8:PDGF中剂量组D♂5右,皮肤:真皮层轻度炎细胞浸润,中度胶原纤维变性/坏死,轻度成纤维细胞和纤维细胞增生,中度血管新生)。
PDGF高剂量组(E组):左侧和右侧背部皮肤均可见真皮层或真皮浅层轻度至重度炎细胞浸润,轻度至中度胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,血管新生(图9:PDGF高剂量组E♀2左,皮肤:真皮浅层中度炎细胞浸润,胶原纤维变性/坏死,成纤维细胞和纤维细胞增生,重度血管新生;图:10:PDGF高剂量组E♀2右,皮肤:真皮层中度炎细胞浸润,胶原纤维变性/坏死,重度成纤维细胞和纤维细胞增生,血管新生)。
浅Ⅱ度烫伤部位皮肤病变程度比较如下:
各组间真皮浅层炎细胞浸润程度比较,上市品对照组(B)≈PDGF高剂量组(E)>PDGF低剂量组(C)≈PDGF中剂量组(D)>模型对照组(A)。
各组间真皮浅层成纤维细胞和纤维细胞增生程度比较,上市品对照组(B)>PDGF高剂量组(E)≈PDGF中剂量组(D)>PDGF低剂量组(C)≈模型对照组(A)。
各组间真皮浅层血管新生程度比较,上市品对照组(B)>PDGF高剂量组(E)≈PDGF中剂量组(D)>PDGF低剂量组(C)≈模型对照组(A)。
各组间真皮浅层胶原纤维变性/坏死程度无明显差异。
深Ⅱ度烫伤部位皮肤病变程度比较如下:
各组间真皮层炎细胞浸润程度无明显差异。
各组间真皮层成纤维细胞和纤维细胞增生程度比较,上市品对照组(B)>PDGF高剂量组(E)>PDGF中剂量组(D)>PDGF低剂量组(C)≈模型对照组(A)。
各组间真皮浅层血管新生程度比较,上市品对照组(B)≈PDGF高剂量组(E)≈PDGF中剂量组(D)≈PDGF低剂量组(C)>模型对照组(A)。
各组间真皮层胶原纤维变性/坏死程度比较,模型对照组(A)>上市品对照组(B)≈PDGF高剂量组(E)≈PDGF中剂量组(D)≈PDGF低剂量组(C)。
在本试验条件下,上市对照品重组牛碱性成纤维细胞生长因子凝胶1倍剂量(300IU/cm2)、受试物PDGF的0.5、1、2倍剂量(3.5、7、14μg/cm2)可改善浅Ⅱ度、深Ⅱ度烫伤模型小型猪的创面损伤的恢复作用,能够促进新生血管的形成,成纤维细胞和纤维细胞增生,对于浅Ⅱ度、深Ⅱ度烫伤模型愈合的改善程度:上市对照品重组牛碱性成纤维细胞生长因子凝胶1倍临床剂量(300IU/cm2)>PDGF的2倍临床剂量(14μg/cm2)>PDGF的1倍临床剂量(7μg/cm2)>PDGF的0.5倍临床剂量(3.5μg/cm2)。
序列表
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<120>血小板衍生生长因子在制备治疗烫伤药物中的应用
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Claims (9)
1.血小板衍生生长因子在制备治疗烫伤药物中的应用。
2.根据权利要求1所述的应用,其特征在于,所述血小板衍生生长因子被制备为外敷制剂,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。
3.根据权利要求2所述的应用,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所述的应用,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任一所述的应用,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,所述外敷制剂被制备为凝胶制剂。
6.根据权利要求5所述的应用,其特征在于,所述外敷制剂还含有制药学上可接受的载体。
7.根据权利要求5所述的应用,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。
8.根据权利要求7所述的应用,其特征在于,所述血小板衍生生长因子在外敷制剂中以3.5×103IU/cm2的浓度分布,所述烧烫伤为浅Ⅱ度烧烫伤。
9.根据权利要求7所述的应用,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/cm2-14×103IU/cm2的浓度分布,所述烧烫伤为深Ⅱ度烧烫伤。
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