CN114129767B - 表面封闭性软组织创面保护胶及其应用 - Google Patents
表面封闭性软组织创面保护胶及其应用 Download PDFInfo
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- CN114129767B CN114129767B CN202111528196.8A CN202111528196A CN114129767B CN 114129767 B CN114129767 B CN 114129767B CN 202111528196 A CN202111528196 A CN 202111528196A CN 114129767 B CN114129767 B CN 114129767B
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- soft tissue
- wound
- wound surface
- tissue wound
- colloid
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Abstract
本发明提供了一种表面封闭性软组织创面保护胶及其应用，包括胶体液部分和固定液部分，其胶体液部分有效成分为阴离子聚合物、胶体物质、触变剂、促细胞增殖物质、增塑剂，固定液包括阳离子化合物、阳离子聚合物、增稠剂和触变剂。该保护胶可在口腔、食管、胃、肠道和皮肤创面和溃疡表面形成封闭性胶体膜，保护创面避免外部刺激因子的作用，收缩创面，促进损伤溃疡创面的愈合。本发明使创面保护胶产品具有表面封闭性，在创面能牢固结合，解决了保护胶的粘附不强容易脱落问题。动物试验表明本发明的软组织创面保护胶具有更好的粘附性，能明显促进损伤性软组织创面的修复，因此可用于软组织损伤创面的保护和促进愈合。
Description
技术领域
本发明涉及生物医药技术领域，特别是涉及一种适用于通过消化道内窥镜喷涂到消化道损伤粘膜表面的一种具有表面封闭性软组织创面保护胶产品和制备方法。
背景技术
内窥镜下胃粘膜切除手术和胃粘膜剥离术是早期胃癌和胃良性肿瘤切除的微创手术，不仅可达到根治早期胃癌的目的，且具有创伤小、对患者生存质量影响小等优点，已逐渐取代部分传统外科手术。食道和结肠的早期癌变和良性肿瘤切除的微创手术也取代部分的传统外科手术。但是，目前这种手术后创面仅做止血处理，尚无良好的创面保护措施。裸露的创面在消化液的作用下经历溃疡活动期、愈合期和瘢痕期，并且创面的愈合时间也较长。临床研究资料显示病人经内窥镜下胃粘膜切除手术和胃粘膜剥离术6周的愈合率为69％左右。因此，有必要提供一种可以直接通过胃镜应用到胃损伤粘膜表面的产品。
目前申请的消化道粘膜损伤表面的保护胶专利都是通过和创面底部粘附实现贴敷到创面上，虽然具有一定的粘附性，但是粘附强度仍然不是很强，在消化道蠕动的情况下也会出现容易脱落的情况，特别是保护胶在胃酸情况下完全固化后也比较溶液从表面脱落。正常情况下，胃酸的pH值在1-3之间，而胃粘膜损伤的病人通常服用抗胃酸的药物，服用抗胃酸药物后胃液的pH可以达到5.5-6.5之间，而长期使用质子泵抑制剂(PPI)的人群，其胃内pH值可达到6-7，因此酸敏感性材料在这种较高的pH条件下不会形成牢固的凝胶，粘附强度也会减低，因此有必要研究一种粘附性更强的创面保护材料。
另外，皮肤创面损伤和溃疡目前采用材料有固体的胶原蛋白、壳聚糖、海藻酸钠海绵和无纺布等敷料和水胶体敷料，液体的有壳聚糖、果胶、海藻酸钠、羧甲基新维素水凝胶等产品，这些产品虽然对创面有一定的保护作用但是不能完全封闭伤口，特别是凝胶类产品还需要在创面反复涂抹。这些产品也不具有直接收缩创面的作用。目前具有封闭伤口的负压引流敷料，结构复杂、使用也不是很方便，因此有必要研究一种完全封闭伤口的新型材料。
发明内容
针对上述技术领域中的不足，本发明提供一种表面封闭性软组织创面保护胶产品及其制备方法，该产品具有很强的将创面封闭的特点，并且不易脱落，起到保护软组织创面，避免污染、感染和刺激。
在以前申请的消化道创面保护胶专利中的胶体液部分含有生物粘附剂，通过和创面粘附而贴敷到创面上，这种粘附有一定的粘附作用，但粘附强度仍然不能完全满足临床的要求，因此本发明采用表面封闭的粘附技术，使得创面保护胶能够非常牢固粘附到创面上并保持较长时间。因此本发明形成的软组织创面保护胶具有更好的粘附性能。本发明主要是采用胶体液中的阴离子聚合物和固定液中的阳离子聚合物发生交联反应在表面形成致密的薄膜层并牢固粘附到创面边沿部位，另外在固定液中增加了粘稠剂，使得固定液和胶体液的接触时间延长，因此粘附的牢固性更好。
另外，本发明的表面封闭性软组织创面保护胶利用胶体液和固定液在交联时聚合物大分子收缩，具有将柔软组织创面缩小的作用。文献报道表明开放性伤口愈合过程中伤口收缩占主要地位，一般可以达到80％，其余为上皮细胞新生、胶原蛋白合成及肉芽组织增殖，可见收缩创面可以明显促进创面闭合。脱水收缩作用是大分子溶液或溶胶胶凝后，凝胶的结构仍在继续形成与发展，随着时间的延续，胶体粒子或大分子会进一步靠近和定向更完全，从而使凝胶骨架收缩，一部分液体从凝胶中分离出来，凝胶结构更加致密、体积缩小。本发明的表面封闭性软组织创面保护胶形成的保护凝胶膜通过本身的物理脱水收缩作用，达到缩小创面的作用。
本发明提供一种表面封闭性软组织创面保护胶，包括胶体液部分和固定液部分，其胶体液部分有效成分为阴离子聚合物、胶体物质、触变剂、促细胞增殖物质、增塑剂。固定液包括阳离子化合物、阳离子聚合物、增稠剂和触变剂。
所述的阴离子聚合物果胶、海藻酸盐、透明质酸钠、结冷胶、聚丙烯酸钠、聚甲基丙烯酸钠、聚苯乙烯磺酸钠、阴离子型聚丙烯酰胺、聚谷氨酸一种或两种。
所述果胶为低甲氧基果胶和酰胺化低甲氧基果胶中的一种或两种，海藻酸盐为海藻酸钠、海藻酸钾的一种或两种。
所述胶体物质为葡甘聚糖、卡拉胶、黄原胶、瓜尔豆胶、胶原蛋白、卡波姆、泊洛沙姆、羧甲基壳聚糖、羟丁基壳聚糖、普鲁兰多糖中的一种或两种。
所述的胶原蛋白为猪胶原蛋白、牛胶原蛋白、鱼胶原蛋白，重组胶原蛋白。
所述的促细胞增殖物质为甘草多糖、β-葡聚糖、党参多糖、索拉胶、杏鲍菇葡聚糖、燕麦葡聚糖、灰树花多糖、谷物葡聚糖、酵母葡聚糖、灵芝多糖、胶原蛋白降解产物。
所述的触变剂为硅酸镁锂，亲水性气相二氧化硅。
所述的增塑剂为甘油、聚乙二醇、聚乙烯醇、甘露醇和山梨醇的一种或两种。
所述的阳离子化合物为氯化钙、葡萄酸钙、乳酸钙、氯化锌一种或两种。
所述的阳离子聚合物为高纯度多聚赖氨酸及其衍生物、三聚赖氨酸、鱼精蛋白、壳聚糖季铵盐、聚二甲基二烯丙基氯化铵、具有季铵基团的强阳离子型淀粉基高分子聚合物、阳离子型聚丙烯酰胺、磷酸胆碱聚合物、聚胺、聚乙烯亚胺、阳离子纤维素、瓜尔胶羟丙基三甲基氯化铵一种或两种。
所述的增稠剂为羟丙基甲基纤维素、水溶性淀粉、明胶、甲基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮、聚氧乙烯一种或两种。
本发明还提供一种前述的表面封闭性软组织创面保护胶在治疗消化性溃疡创面、胃出血、胃粘膜切除和剥离术、食道粘膜剥离术和十二指肠道粘膜剥离术后的创面和皮肤创面治疗中的应用。
本发明在描述效果时，主要以胃部环境进行描写，但是并不代表本发明仅局限于胃部，本发明可以应用于人体消化道，包括口腔、食道、肠道，也可以用于皮肤等软组织创面。
与现有技术相比，本发明具有以下优点：
本发明采用科学原理，采用表面封闭模式，粘附更加牢固，阻断消化液对粘膜的消化刺激作用,保护创面促进溃疡愈合。
具有表面封闭性软组织创面保护胶产品在使用前，溶液状态下产品不形成凝胶状态。产品具有触变性和可注射性避免了注射后的瞬间流动，更容易粘附到创面。
本发明中的固定液含有高分子和小分子的阳离子，高分子阳离子可以在表面迅速交联固定，小分子阳离子容易渗透到底层发生交联固化胶体液。
本发明的产品在表面涂布形成的保护层可以维持较长时间，不需要频繁更换敷料。
本发明增加了促进细胞迁移材料，能促进创面粘膜细胞增殖和迁移能力，具有促进创面愈合作用。
本发明的表面封闭性软组织创面保护胶在不加触变剂(触变剂体内不能分解吸收，可以采用高浓度降低流动性)的情况下可以用于体内出血创面的止血、组织的固定、创口封闭等方面的应用。
本发明的表面封闭性软组织创面保护胶在创面呈现两种状态，表层为致密的胶膜，具有一定的强度，而底层仍然为胶体液状态，不会和创面形成粘连。因此在体表应用时也可以很方便的去除，不会对创面造成二次损伤。
本发明的表面封闭性软组织创面保护胶还可以添加应用部位相应药物的应用，例如添加抗生素、抗菌杀菌药物、局部营养因子、细胞生长因子等药物。
本发明选择合适的生物安全无毒性的阳离子化合物和阳离子聚合物作为固定剂的成分，特别是本发明固定液中增加了阳离子聚合物和增稠剂，在创面上短时间内将胶体液固定粘附到表面上，明显提高了和创面的粘附性，解决了软组织创面保护胶的粘附问题。
附图说明
图1为使用实施例1保护胶后创面成胶情况。
图2为使用实施例2保护胶后创面成胶情况。
图3为使用实施例3保护胶后创面成胶情况。
图4为使用实施例4保护胶后创面成胶情况。
图5为使用实施例5保护胶后创面成胶情况。
图6为涂胶前创面大小。
图7为使用实施例1保护胶后创面大小。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。
本发明实施例中没有特殊说明，采用的均为一般化学品，市场上购买即可得到。
实施例1
胶体液
组分1：取硅酸镁锂7.5克溶解在生理盐水500ml中混匀，然后将上述成分加入搅拌至完全溶解，每瓶10ml包装,高温蒸汽灭菌。
固定液
1.高纯度多聚赖氨酸 12g
2.氯化钙 5克
3.羟丙基甲基纤维素 6克
组分2：取硅酸镁锂5.0克溶解在生理盐水500ml中混匀，将以上成分溶解在500ml水溶液，每瓶10ml包装,高温蒸汽灭菌。
实施例2
胶体液
组分1：将上述成分加入生理盐水500ml中混匀搅拌至完全溶解，每瓶10ml包装,高温蒸汽灭菌。
固定液
1.高纯度多聚赖氨酸 12g
2.氯化钙 5克
3.羟丙基甲基纤维素 12克
组分2：将以上成分溶解在500ml水溶液，每瓶10ml包装,高温蒸汽灭菌。
实施例3
胶体液
1.酰胺化低甲氧基果胶 15克
2.黄原胶 2.5克
3.谷物葡聚糖 1.0g
4.甘油 10g
组分1：取硅酸镁锂7.5克溶解在生理盐水500ml中混匀，然后将上述成分加入搅拌至完全溶解，每瓶10ml包装,高温蒸汽灭菌。
固定液
1.高纯度多聚赖氨酸 12g
2.氯化锌 5克
3.羟丙基甲基纤维素 10克
组分2：取硅酸镁锂5.0克溶解在生理盐水500ml中混匀，将以上成分溶解在500ml水溶液，每瓶10ml包装,高温蒸汽灭菌。
实施例4
胶体液
组分1：取亲水性气相二氧化硅7.5克溶解在生理盐水500ml中混匀，然后将上述成分加入搅拌至完全溶解，每瓶10ml包装,高温蒸汽灭菌。
固定液
1.聚二甲基二烯丙基氯化铵 10g
2.氯化钙 5克
3.羟丙基甲基纤维素 10克
组分2：取亲水性气相二氧化硅7.5克溶解在生理盐水500ml中混匀，将以上成分溶解在500ml水溶液，每瓶10ml包装,高温蒸汽灭菌。
实施例5
胶体液
组分1：取硅酸镁锂7.5克溶解在生理盐水500ml中混匀，然后将上述成分加入搅拌至完全溶解，每瓶10ml包装,高温蒸汽灭菌。
固定液
1.壳聚糖季铵盐 12g
2.葡萄糖酸钙 10克
3.羟乙基纤维素 12克
组分2：取硅酸镁锂7.5克溶解在生理盐水500ml中混匀，将以上成分溶解在500ml水溶液，每瓶10ml包装,高温蒸汽灭菌。
对照例1
组分1：取硅酸镁锂7.5克溶解在采用1mol氢氧化钠调pH8.0的生理盐水500ml中混匀，然后将上述成分加入搅拌至完全溶解，每瓶5ml包装,高温蒸汽灭菌。
组分2：固化液采用氯化钙配制成1.1％的水溶液，每瓶5ml包装,高温蒸汽灭菌。
实验例效果评价
以上实施例的液体的直接用于试验。
1体外胶体膜形成和创面收缩试验
分别取上述液体1ml-2ml涂布在新鲜的猪皮内侧面人工创面上，创面的直径2cm的圆形，然后再涂布固化液，观察胶体膜形成的情况，并测量涂布前和涂布后60分钟后创面的直径，计算创面缩小的百分比{[(涂胶前-涂胶后)/涂胶前]×100％}。结果是实施例1到实施例5均形成胶体膜。创面成胶情况见表1和图1-图5。创面收缩情况见表1和图6和图7。涂胶成膜后能明显缩小创面的大小。
表1涂胶后成膜和创面缩小率
2触变性能测试：
用博力飞DV－Ⅱ型粘度计进行粘度测定。并按照公式(1)计算假塑比值进行比较，选用50rpm和200rpm转速下的粘度进行计算。以羧甲基纤维素溶液作为参照。
假塑比值＝高转速下的粘度/低转速下的粘度(1)。
结果：2％羧甲基纤维素溶液假塑比值0.626，样品1胶体液假塑比值0.235，固定液假塑比值0.321；样品2胶体液假塑比值0.452，固定液假塑比值0.561；样品3胶体液假塑比值0.233，固定液假塑比值0.323；样品4胶体液假塑比值0.231，固定液假塑比值0.332；样品5胶体液假塑比值0.299，固定液假塑比值0.389。
3安全性研究试验
将实施例1-5进行以下生物学试验
1)口腔粘膜刺激：将12ml胶体液倒入直径15cm的无菌培养皿中，然后倒入固定液后30分钟，用生理盐水冲吸收掉多余的固定液，然后按照3cm2/ml比例加入生理盐水，在37摄氏度浸提72小时制备试验液。将样品的实验液制成直径不大于5mm棉球浸透置于3只金黄地鼠一侧颊囊中。接触时间每次最少5min，每天一次，共4次，末次接触后24h肉眼观察颊囊,无痛处死地鼠,取颊囊有代表性部位的组织样品放入4％甲醛溶液中固定后并制作组织切片后进行组织学评价。结果刺激指数均为0，被试样品无口腔粘膜刺激性。
2)细胞毒性：将12ml胶体液倒入直径15cm的无菌培养皿中，然后倒入固定液后30分钟，用生理盐水冲吸收掉多余的固定液，然后按照3cm2/ml比例加入培养基，在37摄氏度浸提24小时制备试验液。然后按GB/T16886.5中规定的细胞毒性试验采用MTT法测定，细胞增殖率在95％-105％范围内。
3)致敏试验：将12ml胶体液倒入直径15cm的无菌培养皿中，然后倒入固定液后30分钟，用生理盐水冲吸收掉多余的固定液，然后按照3cm2/ml比例加入生理盐水，在37摄氏度浸提72小时制备试验液。然后按GB/T16886.10中规定的方法进行皮肤致敏试验，均未观察到致敏作用。
4组织粘附力的测定(组织留存量法)：
将实施例1-5分别进行以下试验
取SD大鼠,禁食24h用戊巴比妥钠溶液(40mg/kg)经腹腔注射麻醉,解剖取出胃置生理盐水(37℃)中切取胃,用生理盐水将胃内壁清洗干净，清洗的胃在2小时内使用。剪取一定面积的胃组织(2cm×2cm),固定于聚乙烯薄膜上，将0.5ml保护胶均匀涂布于胃黏膜创面上，然后喷涂固化液。胃组织在相对湿度为92.5％的恒湿密闭容器中放置20分钟，将经上述处理的胃组织固定于冲洗斜槽上,将斜槽的角度调至60度，调节蠕动泵流速为20ml/min,将胃组织用0.1mol/L盐酸冲洗5mins,冲洗液收集于一已知重量的烧杯中,在70℃烘干,称重,组织粘附力用粘附百分率表示。
计算方法如下:
胃组织粘附百分率(Bg/％)Bg/％＝{[M-(G-g-m)]/M}x100％
式中M为黏膜保护胶的重量(0.5ml同条件下烘干)；g为空烧杯重；G为烧杯与烘干后残渣总重；m为同体积冲洗液所含固体物质的量(空白对照)。B值越大表示粘附力越大。
结果显示：实施例1：99％，实施2：99％，实施例3：99.5％，实施例4：99.5％，实施例5：99％。试验表明实施例1-5的双组分自粘性胃黏膜保护胶对组织的粘附力较强，不易脱落。
5.动物试验
动物分两组，体重3kg左右。实验组10只，对照组10只。
手术前24小时禁食，不禁水。
麻醉方法：推荐家兔用质量浓度30g/L戊巴比妥钠静脉注射1.0ml/kg。
家兔仰面固定手术台上，腹部去毛。按外科常规手术要求以2％碘酊和75％乙醇溶液消毒试验区域。
在上腹部逐层切开皮肤、肌肉层和腹膜，如有出血结扎止血。暴露胃部，在胃大弯处切开胃，用生理盐水清洗胃部，在胃体内的胃大弯侧面的黏膜下，1：10000肾上腺素生理盐水进行黏膜下注射，注射1ml生理盐水形成胃黏膜突出，然后用环套器切除直径1cm的黏膜形成创面，用电刀电凝止血完全，测量创面的直径。实验组涂布0.5ml保护胶，再喷涂固化液后形成固体化的保护膜，对照组涂布对照例1样品处理，然后缝合胃部。再逐层缝合腹壁。放饲养笼中，禁食一天。
结果观察：与手术后5天和10天安乐死动物实验组和对照组个5只，沿原来的切口切开胃壁，观察创面保护胶覆盖和愈合情况，测量创面的直径，用软件计算创面覆盖和愈合面积。结果发现实验组手术后5天溃疡保护胶覆盖率95.5％，创面愈合率85％；对照组保护胶覆盖率56.5％，部分创面完全脱落，愈合率65％。实验组手术后10天溃疡表面的保护胶完全脱落，创面面积愈合率99.5％；对照组保护胶完全脱落，愈合率85.6％。以上结果可以看出,按实施例1本发明的产品能覆盖创面的时间更长粘附能牢固，更能明显促进黏膜损伤性溃疡愈合，对溃疡创面有明显的治疗作用。
本文中所描述的具体实施例仅仅是对本发明精神作举例说明。本发明所属技术领域的技术人员可以对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代，但并不会偏离本发明的精神。
Claims (10)
1.一种表面封闭性软组织创面保护胶，其特征在于，包括胶体液部分和固定液部分，其胶体液部分有效成分为阴离子聚合物、胶体物质、触变剂、促细胞增殖物质、增塑剂；固定液包括阳离子化合物、阳离子聚合物、增稠剂和触变剂；
所述阴离子聚合物为果胶、海藻酸盐、透明质酸钠、结冷胶、聚丙烯酸钠、聚甲基丙烯酸钠、聚苯乙烯磺酸钠、阴离子型聚丙烯酰胺、聚谷氨酸一种或多种；
胶体物质为葡甘聚糖、卡拉胶、黄原胶、瓜尔豆胶、胶原蛋白、卡波姆、泊洛沙姆、羧甲基壳聚糖、羟丁基壳聚糖、普鲁兰多糖中的一种或多种；
阳离子化合物为氯化锌。
2.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，果胶为低甲氧基果胶和酰胺化低甲氧基果胶中的一种或两种，海藻酸盐为海藻酸钠、海藻酸钾的一种或两种。
3.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，胶原蛋白为猪胶原蛋白、牛胶原蛋白、鱼胶原蛋白，重组胶原蛋白中的一种或多种。
4.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，促细胞增殖物质为甘草多糖、β-葡聚糖、党参多糖、索拉胶、杏鲍菇葡聚糖、燕麦葡聚糖、灰树花多糖、谷物葡聚
糖、酵母葡聚糖、灵芝多糖、胶原蛋白降解产物中的一种或多种。
5.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，触变剂为硅酸镁锂，亲水性气相二氧化硅中的一种或两种。
6.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，增塑剂为甘油、聚乙二醇、聚乙烯醇、甘露醇和山梨醇的一种或多种。
7.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，阳离子聚合物为多聚赖氨酸及其衍生物、三聚赖氨酸、鱼精蛋白、壳聚糖季铵盐、聚二甲基二烯丙基氯化铵、具有季铵基团的强阳离子型淀粉基高分子聚合物、阳离子型聚丙烯酰胺、磷酸胆碱聚合物、聚胺、聚乙烯亚胺、阳离子纤维素、瓜尔胶羟丙基三甲基氯化铵一种或多种。
8.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，增稠剂为羟丙基
甲基纤维素、水溶性淀粉、明胶、甲基纤维素、羟乙基纤维素、聚乙烯吡咯烷酮、聚氧乙烯一种或两种。
9.根据权利要求1所述表面封闭性软组织创面保护胶，其特征在于，还包括抗生素、抗菌杀菌药物、局部营养因子、细胞生长因子中的一种或多种。
10.一种如权利要求1－9任意一项所述的表面封闭性软组织创面保护胶在制备消化性溃疡创面、胃出血创面、胃粘膜切除和剥离术、食道粘膜剥离术、肠道粘膜剥离术后的创面以及皮肤开放性创面和溃疡创面医疗器械中的应用。
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