CN107530437A - 止血和伤口愈合剂 - Google Patents
止血和伤口愈合剂 Download PDFInfo
- Publication number
- CN107530437A CN107530437A CN201680020495.1A CN201680020495A CN107530437A CN 107530437 A CN107530437 A CN 107530437A CN 201680020495 A CN201680020495 A CN 201680020495A CN 107530437 A CN107530437 A CN 107530437A
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- China
- Prior art keywords
- chitosan
- acid
- derivative
- calcium
- wound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Classifications
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
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- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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- A—HUMAN NECESSITIES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本发明涉及药物,特别是止血和伤口愈合药物,以及用于停止各种严重程度的出血,包括静脉出血,以及愈合因在上皮和肌肉组织层上的机械作用导致的伤口和切口。为此,利用包含基于壳聚糖和/或其衍生物的活性凝胶组分的止血剂,其特征在于,该药物含有具有三维交联结构的凝胶形式的壳聚糖、其盐和/或其衍生物作为聚合物基质,以及分布于其上的有机钙化合物形式的天然血栓形成组分,有机酸和水,各组分具有一定比例。应用本发明的技术结果是加速停止各种严重程度的出血和产生抗菌效果。
Description
技术领域
本发明涉及一种药物,即止血和伤口愈合剂,可用于阻止各种严重程度的出血,包括静脉的出血,以及可用于治愈组织的表皮和肌肉层上因机械作用导致的伤口和切口。
背景技术
目前,各种止血和伤口愈合剂在医学、兽医学、药剂学等方面正得到积极的开发。
目前,急救中使用了绷带、止血海绵、止血粉等工具。所有可用的工具的主要缺点是,在应用后需要将它们从伤口上移除,从而重新造成机械损伤。这就是为什么创造一种模拟自然止血的与人体活体组织生物相容且同时具有伤口愈合和杀菌性能的无创伤止血剂是一个相关的挑战。
已有一种治疗剂,其受2006年3月20日公布的专利RU2271814,IPC A61 K31/722,A61 K31/785,A61 K31/136,A61 K31/375,A61 K38/43,A61 P17/02保护。
该愈合剂含有壳聚糖、维生素、防腐剂和麻醉剂,此外还含有酶。粉末状壳聚糖是一种天然来源的制剂,最好由蟹壳制成。维生素C或抗坏血酸作为维生素制剂,而来自许多弗斯古(phosphopagues)和匹美卡因(pyromecaines)的聚亚烷基胍作为防腐剂。麻醉剂是从一系列的美索卡因和匹美卡因中选出,酶蛋白水解药是从一系列的胃蛋白酶和胶原酶中选出。
现有试剂的缺点是该药不具有止血特性,不含止血成分,只能用作伤口愈合剂。现有试剂使用二恶英作为杀菌成分。二恶英的一个显著缺点是其致突变活性,胚胎毒性以及破坏肾上腺皮质层的可能性。这种效应是剂量依赖性的。显然,人体中过量的二恶英会引起与糖皮质激素合成受损相关的副作用,这需要立即停用药物和适当的激素替代疗法。
现有的受2014年10月4日公布的专利RU2519220,IPC A61 K31/722,A61 K31/155,A61 L15/2,A61 L26/00,A61 P7/04保护的止血剂,旨在停止大量出血。该试剂含有75至95重量%的选自盐酸盐、氢溴酸盐、甲酸盐、乙酸盐、琥珀酸盐、柠檬酸盐、乙醇酸盐或壳聚糖乳酸盐的一系列多分散粉末的壳聚糖盐和4-20%聚六亚甲基胍盐酸盐。壳聚糖盐和聚六亚甲基胍盐酸盐通过1-5重量%的缩水甘油基多功能化合物共价交联。壳聚糖盐选择平均粒径为0.2+2.0mm,壳聚糖脱乙酰度为0.75±0.95,分子量为10+500kDa。该试剂使用丁二醇,二或三甘醇或丙二醇的二缩水甘油醚,低聚二氧化乙烯,以及甘油或三羟甲基丙烷的三缩水甘油醚作为缩水甘油醚的多官能化合物。
现有试剂的缺点是,该试剂是粉末组合物。干组合物需要溶胀和机械作用(压力)以给出期望的效果,其可以导致伤口的不完全填充和施加时的疼痛作用。这些成分的粉状性质可能导致其分布不均匀。一系列的二缩水甘油醚的化合物被用作交联成分。这些化合物是不稳定的,存储时观察到它们的水解,这限制了试剂的持续时间。
就技术实质而言,被选为原型的最接近所要求保护的发明是由2014年8月20日公布的专利RU2526183,IPC A61 K47/36,A61 K9/06,A61 K31/72,A61 F13/02保护的止血烧伤和伤口愈合组合物。
该组合物以水凝胶的形式生产,并且含有活性胶凝剂、增塑剂、活性和辅助组分,即1.0至10.0重量%的壳聚糖盐(chitosonium salt)的水溶性杂聚物,1.0至10.0重量%的右泛醇和/或2-烯丙氧基乙醇物质,0.1至5.0重量%的氨基己酸或氨甲环酸的固定化医药物质和0.05-2.0重量%的氯化钙(CaCl2),0.1至5.0重量%的利多卡因或阿尼卡因的固定化药物和0.005至0.1重量%的氯己定和水。已知组合物的缺点是2-烯丙氧基乙醇和氯己定能引起包括过敏性休克在内的过敏反应。氯己定对皮肤和眼睛有明显的刺激作用。此外,该组合物的主要成分之一是无机化合物CaCl2。无机化合物CaCl2离解为Ca2+和Cl-离子,且由于快速衰减,该物质能迅速渗入细胞,可导致细胞毒性和高渗性。解离成离子后,化合物被迅速处理,因此,迅速从伤口表面区域除去。结果表明,该药作用时间短,止血时间长。此外,该凝胶在组合物的这种结构中没有空间结构网格,因为壳聚糖成为化学上彼此无关的壳聚糖大分子的隔离链。因此,该组合物不能模拟血细胞膜和血管壁的碎片,它们具有提供天然凝血过程的三维基质结构。药物的贮存期短是由于酸性介质中壳聚糖链自发水解所致。
发明内容
本发明的目的是创造一种无创伤的与人体活体组织具有生物相容性的止血剂,该止血剂基于天然止血操作,同时具有杀菌和伤口愈合性能和至少3年的保质期。
本发明的技术成果包括加速停止各种严重程度的出血并产生抗菌效果。
所述技术成果通过开发和获得含有基于壳聚糖和/或其衍生物的活性胶凝剂的止血和伤口愈合剂来实现,这种成果是独特的,因为它包含具有三维交联结构的凝胶形式的壳聚糖、其盐和/或其衍生物作为聚合物基质,和在这些基质上形成配位键的有机钙化合物形式的天然血栓形成组分、有机酸和水,各组分比例如下,%重量:
壳聚糖,其盐或其衍生物-0.2-30;
钙的有机化合物-0,01-10;
有机酸-0,1-10;
水-其余,
此外,嵌段-和接枝共聚物,如壳聚糖-聚乙烯吡咯烷酮,壳聚糖-聚-2-羟乙基甲基丙烯酸酯/聚-2-羟丙基甲基丙烯酸酯,壳聚糖-聚丙交酯,壳聚糖-聚乙交酯用作壳聚糖衍生物,和天冬氨酸、琥珀酸或烟酸用作有机酸。
该试剂还含有甘油磷酸钙、葡萄糖酸钙、琥珀酸钙或烟酸钙作为天然血栓形成组分,与壳聚糖形成络合物的钙的衍生有机化合物形式。
此外,将氨基己酸作为纤维蛋白溶解的抑制剂引入组合物中。为了获得抗菌效果,银纳米粒子被引入到该试剂的组合物中。
在下面的详细描述中公开了本发明的上述和其它方面和优点。
发明详述
制剂含有三维交联结构的凝胶形式的壳聚糖、其盐和/或其衍生物,特别是嵌段共聚物,以聚合物基质形式并与血栓形成的天然成分形成配位键,使得可以对具有三维基质结构的血细胞膜和血管壁的片段进行建模,在有钙离子存在下提供凝血的天然过程。
由于双功能单体与反应性基团的缩合反应,或在双官能乙烯基单体的自由基聚合过程中,在壳聚糖改性过程中形成具有三维结构的凝胶。各组分的这种复合物可促进凝血过程。
组合物的结构以及因此结构的吸附扩散,弹性-塑性,光学和其它参数在很大程度上取决于其形成方式及其变化(化学,物理-化学)。壳聚糖大分子具有杂链结构,由决定多糖的脱乙酰度(DD)的D-葡糖胺残基的单元和少量由P-1,4-糖苷键键合的D-乙酰基-D-葡糖胺构成。该聚合物的多官能度导致以下事实:根据制备方法,该组合物中的壳聚糖可以具有两种化学形式:盐(C-)和碱(O-),其物理化学和生化特性不同。热处理,聚合物基质中生物活性物质的引入,交联剂的加工等也对组合物的性质有显著的影响。然而,该组合物不仅保留了一系列有价值的性质,而且作为改性的结果,它可以显著改善它们,甚至获得新的有用性质。本研究的目的-基于壳聚糖及其盐的材料以及壳聚糖的嵌段和接枝共聚物可以被认为是这样的组合物。(Mochalova A.E.,Nikishchenkova L.V.,Smirnova N.N.,SmirnovaL.A.,基于壳聚糖的水凝胶的热力学性质,范围为Т->0-350К。//高分子化合物,Biology-2007系列-第49卷第2期。-第371-376页)
三维结构的存在使得组合物长期储存:产品的储存时间增加到3年。
止血和伤口愈合剂制备如下:
在壳聚糖盐和壳聚糖嵌段-聚丙交酯,壳聚糖和/或其衍生物的盐的混合物中加入0.1-10%的有机酸,确保形成稳定的凝胶。在混合期间,以0.01-10重量%的量将有机化合物-烟酸钙,甘油磷酸钙,葡萄糖酸钙,琥珀酸钙的形式的天然血栓形成成分加入基于壳聚糖和壳聚糖嵌段聚丙交酯的凝胶,壳聚糖的盐和/或其衍生物的量为0.2-5.0重量%。
在起始组分的混合阶段,可以向反应混合物中加入各种添加剂如抗菌剂。这种抗菌剂可以是0.0001-1.0重量%的银纳米颗粒,止痛组分,蛋白水解酶,抗氧化剂,用于各种病因的伤口再生的兴奋剂(例如,作为纤维蛋白溶解抑制剂的氨基己酸),其量为0.1-5.0重量%和可帮助愈合伤口和灼伤的其它药物。
实施例1
向壳聚糖盐和壳聚糖嵌段聚丙交酯的混合物补充天冬氨酸,其形成稳定的凝胶。向基于壳聚糖和壳聚糖嵌段-聚丙交酯(5.0重量%)的凝胶补充有机钙化合物,甘油磷酸钙形式的天然血栓形成成分,其量为0.2重量%,并且其余用水补足100重量%。
以类似实施例1的方式进行实施例2-7。
数据归纳在表格中。
表1
壳聚糖的量的增加超过30重量%的将导致体系的显著结构化,并且降低小于0.2重量%将导致难以形成三维结构
Ca有机化合物形式的天然血栓形成成分的量的增加超过10%不会导致组合物的性能进一步改善,不会增加凝血速度,Ca有机化合物的量小于0.01%将显著降低止血效果的有效性。
纤维蛋白溶解抑制剂量的增加超过10重量%和减少小于0.1重量%将导致血栓形成速率的降低。
银纳米粒子的量的增加大于1重量%将导致银对体细胞出现毒性作用。大量的AgNO3增加愈合时间。银纳米粒子的量的减少小于0.01重量%将导致组合物的杀菌作用消失;它将继续表现出只有抑菌性质。
有机酸可以是琥珀酸,烟酸或天冬氨酸;它不影响组合物的性质。这些酸中任何一种的施用量都足以形成均匀的均相体系,并使pH达到与内部环境相适应(pH不超过5.2-5.4)。
凝血时间的研究如下进行。
表玻璃上的体外试验。
将来自实验动物的3-4滴柠檬酸化血液施加到无菌表玻璃上。柠檬酸化血液是含有柠檬酸钠作为抗凝剂的血液。
血液用100μl止血剂覆盖。在整个混合物中观察到立即形成微观血块。
凝血记录仪(hemocoagulographer)N-331的体外试验
该研究使用来自非线性白大鼠的血液。研究了加入止血剂的总凝固时间。为了做到这一点,将200μl血液从实验动物的舌下静脉中提取到比色皿中,并加入100μl止血剂。之后,取得仪器读数。
凝血开始的平均时间为23秒。
凝结结束的平均时间为43秒。
原始的血液。凝血开始的平均时间为85s。凝血结束的平均时间为153s。
实验动物的体内试验
对预麻醉后的非线性白大鼠进行体内试验。
进行原始血液凝血时间的初步研究。为此,从每只动物中制备大约2×2cm左右的左髋部的皮瓣,以便暴露股静脉,然后将其切开;使用秒表记录出血时间。在切口部位形成血栓并停止血流被认为是止血的时候。
原始血液的平均止血时间为100秒。
此外,检查了将止血剂应用于切口后的止血时间。在静脉切开后立即施用该药物。登记血液凝固时间。
将药物施用于切口后的平均止血时间为40秒。
通过吸附血小板固定在壳聚糖上,凝血时间达到30-40秒。
所要求药物的测试在下诺夫哥罗德州的Lobachevsky州立大学生物学系的动物与人体的生理和解剖系进行。这个药物的测试开始于2年前。在每个实验中使用十只非线性大鼠,5只为原始的(标准)和5只为实验的。每只动物先用乙醚麻醉。从每只动物中制备2×2cm厚的皮瓣,以便暴露大股骨血管。然后进行整齐的切口引起出血,然后将止血剂施用于动物的伤口。应用的凝胶快速停止出血并在伤口上形成表面膜。实验动物的进一步观察表明,用溶液处理的伤口形成上皮覆盖物且没有感染伤口,比对照动物快2倍。
为了测试止血剂的有效性及其组成的最优性,进行了一些对照试验,其中,从制剂中排除一个关键组分,并且研究了这一组分的缺失对凝血时间的影响:
·当钙的水性溶液施加于静脉出血切口时,血液的凝血时间为
·当壳聚糖盐的溶液施加于静脉出血切口时,血液的凝血时间为
·当钙盐在酸性水溶液中的溶液施加于静脉出血切口时,血液的凝血时间为
当皮肤和组织的完整性受损时,经常发生伤口表面感染。因此,开发具有有效止血性能的产品需要引入具有高杀菌效果的成分。为此,将银纳米颗粒引入组合物中。表2显示了杀菌试验的结果
表2
因此,与原型相比,建议的止血和伤口愈合剂在与出血来源接触时会影响止血并加速血液凝固的自然过程。通过吸附血小板固定在壳聚糖上,凝血时间达到30-40秒。
此外,所要求保护的药物在整个伤口表面具有弹性、吸附和深度一致性。使用所要求保护的药物的另外效果是组合物在可见光和UV波长下的透明度,其允许用UV辐射进行额外的处理。
上述独特的基本特征是必要和充分的,并且在所要求保护的组合中表现出本领域现有技术状态中不能清楚地得出并且对于专家来说并不明显的新性质。在分析的文献中没有发现相同的特征组合。
如本文所公开的,专家们可以发现不改变本发明的本质的其他实施例。因此,本发明的范围应仅由所附权利要求限定。
Claims (5)
1.一种止血和伤口愈合剂,其包含基于壳聚糖和/或其衍生物的活性胶凝剂,其独特之处在于其包含具有三维交联结构的凝胶形式的壳聚糖、其盐和/或其衍生物作为聚合物基质和在该基质上形成配位键的有机钙化合物形式的天然血栓形成组分,有机酸和水,各组分比例如下,%重量:
壳聚糖,其盐和/或其衍生物-0.2-30;
钙的有机化合物-0,01-10;
有机酸-0,1-10;
水-补足余量,
此外,嵌段和接枝共聚物,例如壳聚糖-聚乙烯吡咯烷酮,壳聚糖-聚-2-羟乙酯甲基丙烯酸/聚甲基丙烯酸2-羟丙酯,壳聚糖-聚乳酸,壳聚糖-聚乙醇酸,用作壳聚糖衍生物,和天冬氨酸、琥珀酸或烟酸用作有机酸。
2.如权利要求1的药剂,其包含甘油磷酸钙、葡萄糖酸钙、琥珀酸钙或烟酸钙作为天然血栓形成组分,与壳聚糖、其有机钙化合物的盐和/或衍生物形成配位键。
3.如权利要求1的药剂,其特征在于,其额外包含纤维蛋白溶解抑制剂。
4.如权利要求3的药剂,其特征在于,所述纤维蛋白溶解抑制剂是氨基己酸。
5.如权利要求1的药剂,其特征在于,其额外包含银纳米颗粒。
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Application publication date: 20180102 |