CN105102002A - 用于在消化道中保护伤口、提供止血或预防粘连的药物组合物 - Google Patents
用于在消化道中保护伤口、提供止血或预防粘连的药物组合物 Download PDFInfo
- Publication number
- CN105102002A CN105102002A CN201380071318.2A CN201380071318A CN105102002A CN 105102002 A CN105102002 A CN 105102002A CN 201380071318 A CN201380071318 A CN 201380071318A CN 105102002 A CN105102002 A CN 105102002A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- cellulose
- hydroxyethyl
- composition according
- carboxymethylstach sodium
- 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.)
- Granted
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 44
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- 210000001035 gastrointestinal tract Anatomy 0.000 title claims abstract description 22
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- 208000027418 Wounds and injury Diseases 0.000 title claims description 16
- 239000000843 powder Substances 0.000 claims abstract description 29
- 229920002807 Thiomer Polymers 0.000 claims abstract description 26
- 239000003230 hygroscopic agent Substances 0.000 claims abstract description 25
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- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 25
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- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 25
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 24
- 239000011734 sodium Substances 0.000 claims description 22
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Abstract
本发明提供了用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含某种粘膜粘性聚合物和某种吸湿剂。
Description
技术领域
本发明涉及用于在消化道(gastrointestinaltract)中提供伤口保护、止血或抗粘连的药物组合物。更具体而言，本发明涉及用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含某种粘膜粘性(mucoadhesive)聚合物和某种吸湿剂。
背景技术
消化道出血是很常见的医疗问题。约50％的患有胃溃疡的患者被诊断为出血性胃溃疡。在约80％的病例中，消化道出血主要发生在上消化道。在上消化道出血中，出血起始于食道、胃或十二指肠，并导致吐血和黑粪症。上消化道出血中的出血点可以通过内窥镜方法来识别；且其识别率为约90％。进行各种胃或结肠息肉切除术、内窥镜粘膜切除术和内窥镜治疗以治疗胃或结肠癌。然而，在这种治疗期间或之后，有时胃或结肠发生出血，可能需要紧急手术治疗或甚至会导致患者死亡。
最近，正采用内窥镜止血方法来治疗消化道出血。内窥镜止血方法包括例如高渗盐水、肾上腺素或醇的直接局部注射；使用电热、氩气或激光的凝固治疗；和使用夹子的物理止血方法。然而，常规方法旨在通过由向溃疡周围的血管内注射液体剂而产生的压或通过结扎血管本身来减少出血量。相应地，溃疡残留以其粘膜的形式脱落。因而甚至在治疗之后，常会继续出血。根据研究结果，常规内窥镜止血治疗仅在70-80％的情况中是成功的。此外，内窥镜止血治疗3-4天后，在20-25％的情况中重新发生出血。再出血(Re-bleeding)指的是血管出血，且发生于通过溃疡周围组织的再生而完全治愈溃疡之前。因此，对于阻止溃疡粘膜脱落时的出血，存在难以由常规内窥镜止血方法解决的局限性。即在常规内窥镜止血方法中，溃疡或病灶的治愈率太低，且常会发生再出血。为了解决这些问题，韩国专利公开号10-2006-0040329已公开用于体内用途的止血剂和将该止血剂施用到人类体内的溃疡上的方法，其中具有聚合物-溶液形式的涂覆剂(coatingagent)以内窥镜方式分散并涂覆于溃疡上，以阻止溃疡出血并使再出血的可能性最小化。
同时，为了增加溃疡或病灶的治愈率并使再出血的可能性最小化，需要可有效保护伤口(例如溃疡和/或病灶)和预防粘连以及阻止出血(即提供止血)的多功能制剂。即需要通过内窥镜导管施用(或注射)于消化道内的制剂，从而保护伤口，提供止血和/或预防粘连。为了进行消化道内的局部给药，该制剂不仅需要具有适合的粘度和粘膜粘性(即粘膜粘附性)，还需要在靶区域形成提供止血的物理保护罩(physicalprotectiveshield)。
为了预防手术区域中的粘连，已研发凝胶形式或溶胶-凝胶形式的制剂。然而，在对上消化道的施用期间，具有低粘度的凝胶制剂涉及其许多损失，导致物理保护罩的形成受限。而且虽然具有高粘度的凝胶制剂具有优异的粘膜粘性，但其有以下缺点，例如需要高压喷射装置，涉及其许多损失等。溶胶-凝胶制剂指的是在某个温度(例如体温)下由溶胶形式(例如施用至身体之前)变为凝胶形式的制剂。然而，常规溶胶-凝胶制剂的胶凝时间非常短，可能导致施用至身体之前在导管中形成凝胶；且施用过程中仍涉及其许多损失。
发明内容
技术问题
为了研发通过内窥镜施用(或注射)于消化道内从而于消化道中保护伤口、提供止血和/或预防粘连的药物制剂，本发明人进行了各种研究。已通过本发明出人意料地新发现了通过组合某种粘膜粘性聚合物和某种吸湿剂而获得的具有粉末形式的制剂具有适于穿过导管和/或施用于身体的适合的移动性(或流动性)；通过在施用点处立即形成凝胶而形成罩，从而使其任何损失最小化；以及提供快速伤口保护、止血和抗粘连(即预防粘连)。
因此，本发明的一个目的是提供用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含某种粘膜粘性聚合物和某种吸湿剂。
技术方案
根据本发明的一个方面，提供了用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含选自羟乙基纤维素、聚环氧乙烷和其混合物的粘膜粘性聚合物；和选自交联羧甲基纤维素钠、羧甲淀粉钠、交聚维酮和其混合物的吸湿剂。
本发明的药物组合物还可包含选自氯化钙、磷酸钙、氢氧化钙、硅酸钙、硫酸钙和其混合物的无机材料。优选地，本发明的药物组合物可通过内窥镜给药于消化道内。
在一个实施方案中，粘膜粘性聚合物和吸湿剂分别以基于组合物的总重量的70-95wt/wt％和5-30wt/wt％的范围的量存在。
在另一个实施方案中，粘膜粘性聚合物、吸湿剂和无机材料可以分别以基于组合物的总重量的40-75wt/wt％、5-30wt/wt％和10-40wt/wt％的范围的量存在。优选地，粘膜粘性聚合物、吸湿剂和无机材料可分别以基于组合物的总重量的50-70wt/wt％、10-20wt/wt％和10-30wt/wt％的范围的量存在。
本发明的药物组合物还可包含选自表皮生长因子、角化细胞生长因子、碱性成纤维细胞生长因子和其混合物的伤口愈合剂；优选表皮生长因子。
有益效果
本发明的药物组合物具有粉末形式，该粉末形式可避免与溶液、凝胶或溶胶-凝胶形式的常规制剂相关的问题。即本发明的粉末形式的药物组合物具有适于穿过导管和/或施用于身体的适合的移动性(或流动性)；通过在施用点处立即形成凝胶而形成罩，从而使其任何损失最小化；并可提供快速伤口保护、止血和抗粘连(即预防粘连)。特别地，相较于简单吸附于出血点的常规止血制剂，本发明的提供即时凝胶形成(immediategel-formation)的组合物显示出更优异的止血和抗粘连潜力。
附图简要说明
图1至图22示出通过评价本发明的粉末制剂的止血潜力而获得的照片。
图23示出本发明的粉末制剂对粘膜切除引起的兔子胃出血模型的止血作用。
图24示出本发明的粉末制剂对内窥镜粘膜切除引起的迷你猪胃出血模型的止血作用。A)治疗前胃出血，B)治疗3分钟后胃溃疡的内窥镜图像和C)治疗6分钟后胃溃疡的内窥镜图像。
图25示出在本发明的粉末制剂治疗后减小的溃疡面积(积累的溃疡治愈(precipitatedulcerhealing))(****p<0.0001)。
图26示出在本发明的粉末制剂治疗后对兔子胃溃疡和出血模型的积累的粘膜治愈(precipitatedmucosalhealing)(厚度)的组织学观察(**p<0.01)。
图27示出本发明的粉末制剂对迷你猪模型的内窥镜粘膜切除术胃出血高达72小时的延伸溃疡覆盖和止血作用的内窥镜观察。
图28示出迷你猪的对照(未治疗的)粘膜和本发明的粉末制剂治疗的粘膜的苏木精和曙红(H&E)染色图像。
最佳实施方式
本发明提供了用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含选自羟乙基纤维素、聚环氧乙烷和其混合物的粘膜粘性聚合物；和选自交联羧甲基纤维素钠、羧甲淀粉钠、交聚维酮和其混合物的吸湿剂。
本文中使用的术语“粉末形式”包含任何和所有粉末形式，包括例如通过常规配制方法获得的药物粉末形式和药物颗粒形式(即颗粒)。
本发明人评价了关于粘膜粘性聚合物和吸湿剂的各种组合的各项性能，包括通过即时胶凝化的保护罩形成能力、凝胶强度和止血潜力。已通过发明出人意料地新发现了通过组合某种粘膜粘性聚合物和某种吸湿剂而获得的具有粉末形式的制剂具有适于穿过导管和/或施用于身体的适合的移动性(或流动性)；通过在施用点处立即形成凝胶而形成罩，从而使其任何损失最小化；以及提供快速伤口保护、止血和抗粘连(即预防粘连)。
本发明的药物组合物可通过内窥镜(即内窥镜导管)给药于消化道内。
在一个实施方案中，本发明的药物组合物可包含粘膜粘性聚合物和吸湿剂，其中该粘膜粘性聚合物和吸湿剂可以分别以基于组合物的总重量的70-95wt/wt％和5-30wt/wt％的范围的量存在。
在另一个实施方案中，除粘膜粘性聚合物和吸湿剂之外，本发明的药物组合物还可包含选自氯化钙、磷酸钙、氢氧化钙、硅酸钙、硫酸钙和其混合物的无机材料。在该实施方案中，粘膜粘性聚合物、吸湿剂和无机材料可分别以基于组合物的总重量的40-75wt/wt％、5-30wt/wt％和10-40wt/wt％的范围的量存在。优选地，粘膜粘性聚合物、吸湿剂和无机材料可分别以基于组合物的总重量的50-70wt/wt％、10-20wt/wt％和10-30wt/wt％的范围的量存在。
本发明的药物组合物还可包含有利于消化道中伤口(例如溃疡和/或病灶)的伤口愈合剂。例如，本发明的药物组合物还可包含选自表皮生长因子、角化细胞生长因子、碱性成纤维细胞生长因子和其混合物的伤口愈合剂；优选表皮生长因子。该伤愈合剂可按本领域技术人员可容易确定的治疗有效量使用。
在本发明的一个实施方案中，提供了由羟乙基纤维素、交联羧甲基纤维素钠和羧甲淀粉钠组成的药物组合物。例如，本发明的药物组合物可由90wt/wt％的羟乙基纤维素、5wt/wt％的交联羧甲基纤维素钠和5wt/wt％的羧甲淀粉钠组成。而且，本发明的药物组合物可由85wt/wt％的羟乙基纤维素、7.5wt/wt％的交联羧甲基纤维素钠和7.5wt/wt％的羧甲淀粉钠组成。
在本发明的另一个实施方案中，提供了由羟乙基纤维素、交联羧甲基纤维素钠、羧甲淀粉钠和表皮生长因子组成的药物组合物。例如，本发明的药物组合物可由89.99wt/wt％的羟乙基纤维素、5wt/wt％的交联羧甲基纤维素钠、5wt/wt％的羧甲淀粉钠和0.01wt/wt％的表皮生长因子组成。
在本发明的又一实施方案中，提供了由羟乙基纤维素和羧甲淀粉钠组成的药物组合物。例如，本发明的药物组合物可由90wt/wt％的羟乙基纤维素和10wt/wt％的羧甲淀粉钠组成。
在本发明的再一实施方案中，提供了由羟乙基纤维素、聚环氧乙烷、羧甲淀粉钠和氯化钙组成的药物组合物。例如，本发明的药物组合物可由30wt/wt％的羟乙基纤维素、20wt/wt％的聚环氧乙烷、20wt/wt％的羧甲淀粉钠和30wt/wt％的氯化钙组成。
参照以下实施例将进一步详细地描述本发明。这些实施例仅用于说明的目的，并不意图限制本发明的范围。
实施例1：粉末制剂的制备和评价
(1)粉末制剂的制备
对各种类型的粘膜粘性聚合物进行粘膜粘性的初步试验。而且，对各种吸湿剂进行吸湿能力的初步试验。初步试验的结果是羟乙基纤维素(HEC)、海藻酸钠、壳聚糖、羟丙基纤维素(HPC)和聚环氧乙烷(PEO)显示出优异的粘膜粘性；交联羧甲基纤维素钠(Ac-di-sol)、羧甲淀粉钠、硅酸钙和交聚维酮显示出非常优异的吸湿性。从初步试验的结果，下表1中示出的粉末制剂是通过将粘膜粘性聚合物和吸湿剂以及可选的已知止血无机材料(氯化钙)混合而制备的。表1中的量表示制剂中的wt/wt％(重量百分比)。
表1
(2)性质评价
下表2和3中列出了样品的保护罩形成时间、止血潜力和凝胶强度。表2和3中，“O”指的是“适合的”，且“X”指的是“不适合的”。
表2
表3
(2-1)止血潜力
各样品和血液以1:1的比例在有盖培养皿中反应。反应1分钟后，将过量水(10mL)喷洒于其上，以检验是否保持止血。含有氯化钙的样品S6-S9示出良好的止血性。并且不含氯化钙的样品S2、S2-1至S2-4、S2-7、S2-8和S3也示出通过由即时凝胶形成而形成的物理保护罩所获得的止血性。然而，样品S2-5和S2-6未显示止血性，这源于缺少化学止血剂。以及，样品S1、S4和S5未显示止血性，这源于没有形成物理保护罩。
(2-2)凝胶强度
将各样品与水以1:10的重量比反应，以获得凝胶。用流变仪在以下条件下测定凝胶强度。
-转子:No.25
-最大负荷:20N
-拉伸距离:5mm
-十字头速度:120.0mm/分钟
为了比较忍受外部应力的程度，测定了所得凝胶的拉伸强度。根据下式计算各样品的拉伸强度：拉伸强度(MPa)＝最大力(N)/样品横截面积(A)。
其结果是，已确定具有最优异的即时凝胶形成潜力的样品S2显示最高拉伸强度。样品S2-1至S2-4、S2-7、S2-8、S6、S6-1、S6-3、S7、S8和S8-1也显示相对高的拉伸强度。在没有吸湿剂的情况下，由粘膜粘性聚合物和止血无机材料组成的样品S9显示急剧降低的拉伸强度。而且，在既含有粘膜粘性聚合物又含有吸湿剂的样品中，含海藻酸钠或壳聚糖作为粘膜粘性聚合物的样品显示凝胶强度几乎为零(0)。
实施例2：体内研究
(1)粉末制剂的制备
对于体内研究，我们使用由粘膜粘性聚合物(羟乙基纤维素)和吸湿剂(交联羧甲基纤维素钠和羧甲淀粉钠)以及作为伤口愈合剂的表皮生长因子(EGF)组成的粉末制剂。该粉末制剂通过基于1g粉末制剂将羟乙基纤维素(899.99mg)、交联羧甲基纤维素钠(50mg)、羧甲淀粉钠(50mg)和EGF(10μg)混合而制备。在该实施例2中，粉末制剂被称为“制剂”。
(2)方法
<1>动物
实验使用6只重35-40kg的雌性迷你猪(MediKinetics,Pyeongtaeck,韩国)和46只重2-2.5kg的雄兔(NewZealandWhite；OrientBio,Seongnam,韩国)。所有动物照料和实验过程都按照仁荷大学(仁川,韩国)实验动物研究委员会(ExperimentalAnimalResearchCommittee)的指南进行。
<2>用于胃出血的动物模型
在研究中针对兔子和迷你猪制作胃出血模型。按如下制作兔子粘膜切除引起胃出血的模型。在手术之前使兔子禁食24小时，然后通过肌肉注射克他命(4.2mg/kg)和甲苯噻嗪(11.7mg/kg)的混合物麻醉。将兔子随机分为未治疗组、肾上腺素注射组和制剂治疗组。使胃暴露并通过手术沿更大的弧线打开。然后，向胃粘膜下层注入200μl等渗盐水。使用手术切除肿胀的胃粘膜。切除面积直径为约7-10mm。各处理后，测量持续出血时间。
按如下制作迷你猪内窥镜粘膜切除引起胃出血的模型。在内窥镜检查之前使迷你猪禁食36小时。通过肌肉注射替来他明(tiletamine)/唑拉西泮(zolazepam)(VirbacKorea,Seoul,韩国)和甲苯噻嗪(IntervetKoreaLtd.,Seoul,韩国)引起麻醉，并在手术期间吸入异氟烷(HanaPharm.,Gyeonggi-do,韩国)保持麻醉。将内窥镜(GIF-Q260；OlympusMedicalSystems,Tokyo,Japan)插入侧卧位置的动物中。用氩等离子凝结器(APC)标记靶区域，并向粘膜下层注入等渗盐水。进行内窥镜粘膜下层剥离术，以在胃前壁和后壁产生直径为2.0-3.0cm的急性溃疡。
<3>制剂的止血和溃疡治愈作用
评价了制剂对胃粘膜切除的兔模型的止血作用。腹腔镜切除胃粘膜之后，用制剂覆盖出血区域，测量平均出血时间并与其它常规治疗即肾上腺素局部注射的模型比较。在猪模型中，通过内窥镜进行粘膜切除术，然后用制剂覆盖出血点。通过内窥镜经24小时观察治疗后制剂对急性出血和再出血的即时止血作用。如果第一次施药后三分钟内继续出血，按照第一次施药对伤口进行第二次施药。治疗后，观察动物24小时。
通过组织学评估主要观察制剂的溃疡治愈效果。治疗一天后，胃得到恢复，并通过用溃疡面积除以初始溃疡面积来计算相对溃疡面积。对于猪模型，通过内窥镜观察溃疡。治疗三天后，牺牲迷你猪，收集组织并染色用于组织学评估。
<4>组织学研究
将恢复的粘膜组织固定在4％的福尔马林中，嵌入石蜡块，然后使用常规程序用苏木精和曙红(H&E)染色。分析H&E染色的部分以评估胃腺结构并于显微镜下测量溃疡点再生胃粘膜的厚度。
<5>统计分析
所有数据报道为平均±SEM。用T-测试、基于排序(onranks)的单因素方差分析(One-wayANOVA)分析，接着进行Tukey事后测试(Tukey’spost-hoctest)或基于排序的两因素方差分析，接着使用PRISM5软件进行Bonferroni多重比较来分析实验结果。P值<0.05、<0.01、<0.001或<0.0001被认为是统计学上显著的。
(3)结果
<1>制剂的止血功能
观察制剂对兔子和迷你猪的胃粘膜切除引起的出血的止血功能。在兔子模型中，图23中示出各治疗下的平均出血时间。未治疗组和肾上腺素局部注射组分别得到约548秒和约393秒的出血时间。相反地，制剂治疗组显示出显著缩短的出血时间(104秒,p<0.001)。制剂也显示出覆盖出血点的即时止血功能。出血在12分钟至26分钟内停止，并在制剂第一次治疗后保持停止出血72小时(图24)。在该研究中不需要第二次治疗。
<2>制剂的溃疡治愈活性
经一天治疗后，肌肉注射克他命/甲苯噻嗪(10/3mg/kg)以牺牲兔子。收集胃组织并进一步处理用于组织学研究。胃粘膜的直接可视化显示了用制剂治疗积累的溃疡治愈(图25)。相较于未治疗组，相对溃疡大小显著降低(56.8％对26.0％,p<0.00001)。组织学研究结果也支持了制剂对胃粘膜结构的积累的恢复。迷你猪中内窥镜粘膜切除引起的溃疡也显示了通过制剂治疗的增强的溃疡治愈以及恢复的粘膜结构(图26-28)。制剂在溃疡病灶上形成覆盖水凝胶(图28)。
Claims (17)
1.用于在消化道中提供伤口保护、止血或抗粘连的粉末形式的药物组合物，其包含选自羟乙基纤维素、聚环氧乙烷和其混合物的粘膜粘性聚合物；和选自交联羧甲基纤维素钠、羧甲淀粉钠、交聚维酮和其混合物的吸湿剂。
2.根据权利要求1所述的药物组合物，还包含选自氯化钙、磷酸钙、氢氧化钙、硅酸钙、硫酸钙和其混合物的无机材料。
3.根据权利要求1或2所述的药物组合物，其中所述组合物通过内窥镜给药于消化道内。
4.根据权利要求1所述的药物组合物，其中所述粘膜粘性聚合物和所述吸湿剂分别以基于所述组合物的总重量的70-95wt/wt％和5-30wt/wt％的范围的量存在。
5.根据权利要求2所述的药物组合物，其中所述粘膜粘性聚合物、所述吸湿剂和所述无机材料分别以基于所述组合物的总重量的40-75wt/wt％、5-30wt/wt％和10-40wt/wt％的范围的量存在。
6.根据权利要求5所述的药物组合物，其中所述粘膜粘性聚合物、所述吸湿剂和所述无机材料分别以基于所述组合物的总重量的50-70wt/wt％、10-20wt/wt％和10-30wt/wt％的范围的量存在。
7.根据权利要求1或2所述的药物组合物，其还包含选自表皮生长因子、角化细胞生长因子、碱性成纤维细胞生长因子和其混合物的伤口愈合剂。
8.根据权利要求7所述的药物组合物，其中所述伤口愈合剂是表皮生长因子。
9.根据权利要求1所述的药物组合物，其由羟乙基纤维素、交联羧甲基纤维素钠和羧甲淀粉钠组成。
10.根据权利要求9所述的药物组合物，其由90wt/wt％的羟乙基纤维素、5wt/wt％的交联羧甲基纤维素钠和5wt/wt％的羧甲淀粉钠组成。
11.根据权利要求9所述的药物组合物，其由85wt/wt％的羟乙基纤维素、7.5wt/wt％的交联羧甲基纤维素钠和7.5wt/wt％的羧甲淀粉钠组成。
12.根据权利要求8所述的药物组合物，其由羟乙基纤维素、交联羧甲基纤维素钠、羧甲淀粉钠和表皮生长因子组成。
13.根据权利要求12所述的药物组合物，其由89.99wt/wt％的羟乙基纤维素、5wt/wt％的交联羧甲基纤维素钠、5wt/wt％的羧甲淀粉钠和0.01wt/wt％的表皮生长因子组成。
14.根据权利要求1所述的药物组合物，其由羟乙基纤维素和羧甲淀粉钠组成。
15.根据权利要求14所述的药物组合物，其由90wt/wt％的羟乙基纤维素和10wt/wt％的羧甲淀粉钠组成。
16.根据权利要求2所述的药物组合物，其由羟乙基纤维素、聚环氧乙烷、羧甲淀粉钠和氯化钙组成。
17.根据权利要求16所述的药物组合物，其由30wt/wt％的羟乙基纤维素、20wt/wt％的聚环氧乙烷、20wt/wt％的羧甲淀粉钠和30wt/wt％的氯化钙组成。
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| DK2950822T3 (da) | 2019-07-22 |
| ES2725879T3 (es) | 2019-09-30 |
| US9918937B2 (en) | 2018-03-20 |
| KR20160006642A (ko) | 2016-01-19 |
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