CN102470147A - 适用于血浆的平衡明胶溶液 - Google Patents
适用于血浆的平衡明胶溶液 Download PDFInfo
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- CN102470147A CN102470147A CN2010800330764A CN201080033076A CN102470147A CN 102470147 A CN102470147 A CN 102470147A CN 2010800330764 A CN2010800330764 A CN 2010800330764A CN 201080033076 A CN201080033076 A CN 201080033076A CN 102470147 A CN102470147 A CN 102470147A
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- Prior art keywords
- gelatin
- pharmaceutical preparation
- physiologically acceptable
- described pharmaceutical
- gelatine derivative
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Classifications
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
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Abstract
本发明涉及一种药物制剂，其包括水性组合物，该组合物又包括明胶和/或生理上可接受的明胶衍生物。本发明的药物制剂可以用于预防和治疗血容量不足。本发明还涉及该药物制剂作为容量替代剂的用途和作为保护红细胞的洗涤液的用途。
Description
技术领域
本发明涉及一种药物制剂，其包括含有明胶和/或生理上可接受的明胶衍生物的水性组合物。该药物制剂适合血容量不足的预防与治疗。此外，本发明还涉及该药物制剂作为血容量替代与保护红细胞洗涤液的用途。
背景技术
循环衰竭是最常观察到的临床休克症状之一，其特征是循环血容量的减少(血容量不足)，其中血容量不足的潜在原因包括血液、血浆或细胞外液的绝对减少或相对不足(不均匀分布)。血液或血浆的减少有其自身创伤性原因(出血性创伤)，或是源于外科措施而导致血液损失增加。原发性血管外液不足是由液体摄入的减少或液体的异常损失(例如通过过度盗汗、呕吐、胃肠道丢失)所致；明显的血管外液不足，也可以对循环血容量造成影响。同样源于创伤性事件或严重疾病条件下，血管活性物质以及介质与激素间的不同相互作用，导致血管扩张继而出现血容量相对不足或不均匀分布；此外，这还会导致已存在的休克状态的持续。最后，血管内皮的全身性功能失调导致液体外溢，也会产生血容量不足，即：血浆液体通过内皮屏障渗漏进入外周组织(例如在炎症性疾病如败血症中)。
取决于血容量不足与介质影响的程度，心脏功能也可能随之下降。如果血容量不足持续存在，心肌代偿能力不足，进而则出现循环衰竭；其中心肌代偿时可提高心脏收缩力与心率。
血容量不足或体循环(即大循环)衰竭的后果包括对微循环(即组织与器官灌注)的影响；其结果是，单个或多个器官的局部缺血可导致受影响组织的缺氧与细胞代谢的下降。当缺氧持续足够长的时间，细胞死亡就可导致器官损伤甚至器官衰竭，其最初是可逆的，但最终是不可逆的。
在所有血容量不足型循环衰竭或休克中，恢复循环血容量是在药物与其它治疗之前的首要治疗目的。通过灌注透明或胶体容量替代液体来恢复循环血容量；而在大量失血以及输氧能力相对降低时，则需通过输入血液或血液成分来补充循环血容量。容量替代与相关的体内循环补充增加了回心的静脉回流，并提高了心输出量；增加的组织灌注消除了组织缺血时的缺氧情况，并恢复了代谢。
原则上，透明(等渗电解质溶液)与胶体容量替代液体(在含电解质的介质中，添加了所谓水胶体的高分子量成分的溶液)均可适用于消除急性血容量不足与相对体循环紊乱。一方面，亲水胶体是内源性蛋白如人血白蛋白，或化学改性的蛋白质成分；另一方面，包含在容量替代溶液中的胶体可能是多糖类(右旋糖苷类)或化学改性的多糖类衍生物，通常是羟乙基淀粉(HES)。与透明溶液不同的是，在循环中这些胶体容量替代溶液中的高分子量成分提供了与液体更加显著与更加稳固的结合力，即更强与更长久的量与填充效果。可以认为产生以上效果的关键在于亲水胶体的分子大小，其作用甚至可通过亲水胶体上的电荷载体和/或大水合物外壳的存在而进一步提高。因此，胶体容量替代溶液的分布首先仅限于体内循环(即血管内的部分)，而透明溶液的组分可以自由穿过血管屏障，使得透明溶液从一开始就分布在整个细胞外隙，并且大约是分布在血管内的量的4倍。所以，为达到相同的循环补充量，所使用的透明容量替代溶液大约须是胶体溶液的4倍；并且相对于胶体溶液，透明溶液持续时间短，或者说需要更频繁的后续灌注。当透明溶液灌注时，由于液体同时流入细胞外隙，所以存在于身体某处形成液体蓄积(即水肿)的风险；假如再排泄盐类与液体的能力下降，这种情况通常可能在损伤、手术后或严重疾病下，使用透明液体则可能出现液体过载的风险。鉴于以上原因，以血管内容量替代为目的时，胶体溶液相对于透明溶液是优选的。
在各种胶体容量替代溶液中，含有人造胶体(即羟乙基淀粉与明胶)的溶液，相对天然胶体(白蛋白)在目前临床实践里获得巨大的成功。这是因为，总体上，它的使用相对于白蛋白较为便宜，并且没有血流动力学稳定性上的直接效力与休克治疗疗效的相关缺点。右旋糖酐溶液可影响血液凝固，由于过敏性休克所需预防的复杂性使其非常不受欢迎；这也是为什么只有右旋糖酐溶液渐渐退出视线，几乎从最近几年的临床实践中消失。
尽管灌注的羟乙基淀粉要经受体内复杂的降解和改性过程的影响，其中也包括并发的储存现象，但明胶与明胶衍生物在人体组织中可被现有的酶系统(主要是朊酶类)降解成较小的碎片，并当碎片大小低于肾阈时最终由肾脏排出。在最初的24小时，尿液中的回收率大约是给予量的60％；在1周时间内，可上升到95％以上。所以，明胶的代谢率与清除率优于那些用于容量替代剂的其它人造胶体(例如羟乙基淀粉)。基于现有知识，明胶与明胶衍生物不会储存于人体组织与器官中；因而从这一方面讲，不存在器官并发症。此外，与其它人造胶体相比，由于其对血液凝固影响较少或完全无影响；这使明胶或明胶衍生物，相比其它人造胶体或由此准备的容量替代剂，可由静脉内灌注更高的剂量。
在医学与制药工业中，本领域的技术人员常将明胶或其衍生物用于硬胶囊与软胶囊的制备，以及容量不足型休克的灌注治疗中。例如，下述的具有20,000到35,000的平均分子量的明胶制剂可作为容量替代剂：氧化聚明胶，如
脲交联明胶，
以及琥珀明胶，
(也被称为)、
和
在医学上，含有明胶的容量替代溶液的应用并非没有问题。例如，目前使用的某些明胶溶液中所含氯化物成分过高，后者可增加高氯血症酸中毒的风险。含有明胶或其它胶体的容量替代溶液的主要适应症是低血容量型循环衰竭与休克的治疗。与以上临床症状相关的组织灌注的减少又会必然导致酸中毒，此种酸中毒虽可因容量替代溶液的灌注而快速消除，但组织灌注的减少绝不会因其自身的酸中毒效应而加剧、甚至仅是持续。由于酸中毒的严重性与凝血病的发生相关，所以创伤性或外科手术所致的血液丢失也是低血容量性休克的主要原因。高氯代谢性酸中毒其更加不良后果是电解质紊乱，后者推迟了外伤与手术后多尿期的恢复，或可能与神经机能障碍相关，如多寐或手术后恶心呕吐(PONV)。
考虑到可能增加脑水肿的风险，其它明胶溶液用于头部外伤或神经外科患者的应用受到极严格的限制。其原因在于溶液低张性的存在，后者可因溶液、或因此受影响的血浆与颅内压的重量摩尔渗透压浓度间成反比，而导致占位进程中临床相关的预后恶化。
在这样的背景下，考虑到明胶在其它方面相当有利的属性，例如不存在组织内蓄积、器官应激、对凝血的影响以及剂量限制，因而迫切需要制备出一种明胶溶液，该明胶溶液具有一种组合物，该组合物可用于维持酸碱平衡与电解质平衡的内环境稳定，使得该明胶溶液可应用于之前因溶液低张性所致的特定风险而不能使用的临床中，并且拥有较高的整体应用安全性。
发明内容
令人惊讶的是，本申请的发明人发现现有技术中存在的问题可以通过以下方法解决：在适当的水溶液中，调整与明胶和/或生理上可接受的明胶衍生物、和/或明胶蛋白(gelatineartige Protein)和/或多肽类相关的特定电解质模型。由于它们的等渗性以及与血浆电离图更加接近，因此这样得到的药物制剂相对之前的明胶制剂在应用上更加广泛与安全。严格的等渗性，在整体上特异性地降低了外周水肿与液体过载的风险，并且提高了血液细胞成分的液体耐受性。例如，已证实了红细胞保护效力，该效力增强了明胶本身现有的作用，并使液体与机械式自体输血的红细胞洗涤溶液格外配适。
进而，本申请的发明人惊讶地发现，当明胶和/或生理上可接受的明胶衍生物的水溶液按本申请所披露的电解质模式(Electrolytmuster)进行灌注时，与其它采用在0.9％氯化钠中所制备的类似的明胶溶液相比，可更加有效地抑制白细胞与血管内皮的暂时结合与稳固结合。这种降低的白细胞/内皮间的相互作用是白细胞活化的砝码；其中白细胞活化是由出血性损伤、休克状态与炎症刺激启动的，并且一旦被可能存在的连续反应(如内皮损伤与活化白细胞渗出)强化，可能出现受累器官的功能衰竭。此外，取决于白细胞/内皮间相互作用降低的程度，明胶-电解质溶液的改善微循环性质可得以加强。
因此，本发明涉及一种水性药物制剂，其包括：
a)20-80g/l的明胶和/或生理上可接受的明胶衍生物和/或明胶蛋白和/或明胶多肽、及其离子成分；
b)150-160mmol/l的钠；
c)4-5mmol/l的钾；
d)1-2mmol/l的钙；
e)1-2mmol/l的镁；
f)82-105mmol/l的氯化物；
g)24-30mmol/l的醋酸盐和/或葡萄糖酸盐。
根据本发明一具体实施方式，除了上述的电解质外，本发明的制剂还包括1-2mmol/l的磷酸盐(酯)。本发明中，磷酸盐包括PO4 3-、磷酸氢盐、磷酸二氢盐以及磷酸盐(酯)衍生物，如甘油磷酸盐。
明胶是哺乳动物中大分子蛋白质即所谓的胶原的降解产物，容易低成本地分离获得，而且可以长时间储存而不会变性。尽管明胶的蛋白属性，但其具有很低的抗原潜力。天然明胶因其较高的分子量，而具有形成高粘性溶液的属性，这种高粘性溶液在低温下会发生凝结，因而并不适合制备肠外制剂。然而，通过对明胶进行化学改性或衍生，就可以回避这种缺点。
这类改性的方法之一是由Tourtelotte于1952年开发的(Tourtelotte，D.和H.E.Williams，in：Stainsby，G.，明胶和胶的研究，1958)。其包括与琥珀酸或其酸酐进行反应，形成琥珀酰明胶(明胶多聚琥珀酸盐(酯)，Gelatinepolysuccinat)。由Schmidt-Thome(Schmidt-Thome，J.，A.Mager和H.H.Schone，Arzneim.-Forsch.12，378(1962))在1962年所开发的另一种方法是基于明胶链被脲桥的交联(脲交联的明胶；多聚明胶)。另外，明胶衍生物可以通过明胶的脱钙、与乙二醛的缩合以及用过氧化氢氧化来制备。这种产物就是所谓的氧化聚明胶，其制备方法见Campbell，D.H.等人于Texas Rep.Biol.Med.9，235(1951)、Bonhard，K.于Arzneim.-Forsch.21，1667(1971)以及Nitschmann和Stoll于Pharm.-Ztg.42，1594(1968)中所描述。最近，明胶和明胶蛋白和多肽也可以通过重组的方法进行合成，并将其用于肠外制剂的制备，特别是作为容量替代剂(DE60207053T2)。
在一优选的实施方式中，本发明的制剂包括利用重组方法制备的明胶蛋白和/或明胶多肽。
脲交联明胶(Harnstoffvernetzte Gelatine)可如此制备：将经碱和热水处理后所得到的分子量在12,000-15,000的明胶链用六亚甲基二异氰酸酯进行处理，这将导致在自由羧基和自由氨基之间发生缩合翻译，从而在各个明胶链之间形成肽键。所得缩合产物的平均分子量(数均)为24,500，范围在5000-50,000道尔顿之间。
琥珀酰明胶的合成是从分子量在20,000以上的多肽链与琥珀酸酐反应开始的。然而，与脲交联明胶不同，其在明胶链之间没有形成交联，因而，其分子量保持不变。由于在化学改性中，碱性的氨基基团被酸性的羧基基团所取代，因而所得到的衍生物具有较低的等电点和较高的负电荷。这种较高的负电荷而不是分子量的增加，以及血管内皮细胞的Donnan效应，是在生理pH值下在循环系统中停留时间延长的原因。另外，电荷的改变导致了改性明胶分子的架构的变化，形成了更开放、更不致密的结构，使其通过血管壁的扩散能力下降，而相应地延长了其在血管内的保留时间。
本发明中所使用的生理上可接受的明胶衍生物可以是脲交联的明胶衍生物，或者优选为琥珀酰明胶衍生物。或者也被称为“改性的液体明胶”(MFG)或“明胶多聚琥珀酸盐(酯)”；其平均分子量如从20,000至32,000(Mw＝重均)或者从18,000至28,000(Mn数均)。在德国，相应的B.Braun Melsungen制品可从市场上购得，其商标名为“Gelafundin”，而在大多数其它的国家，其商品名为“Gelofusine”。用于琥珀酰化或者与尿素交联的起始原料是从牛骨制备的明胶，其可从市场上购得，如在德国可从Ebersbach的Gelita公司购得，在法国可从Isle sur la Sorgue的RousselotSAS公司购得。
在本发明优选的实施方式中，其包括生理上可接受的明胶衍生物，如琥珀酰明胶衍生物、非琥珀酰明胶衍生物、脲交联明胶衍生物、氧化聚明胶(Oxypolygelatine)和明胶多聚琥珀酸盐(Gelatinepolysuccinat)以及重组的明胶蛋白(gelatineartige Protein)和/或多肽。
在一优选的实时方式中，本发明的药物制剂包括20-80g/l的明胶和/或生理上可接受的明胶衍生物和/或明胶单被和/或明胶多肽，优选为30-60g/l，更优选为40-50g/l，例如40g/l。
本发明的等渗(等张)水性药物制剂可以静脉灌注，因而在一优选的实施方式中，其为灌注液的形式。
由于给药适于血浆的溶液的目的是维持血浆电解质浓度的动态平衡，因而其也称为“平衡”的溶液。如果生产技术满足特定的要求(其对本领域技术人员是已知的)，也可以用丙酮酸盐或碳酸氢盐(而不是乙酸盐和/或葡萄酸盐)来部分取代氯化物，而且在本发明的一药物制剂中是优选的。
根据本发明，优先利用那些在相关药典如欧洲药典、美国药典等专著中所推荐和包括的盐。
因而，在一优选的实施方式中，所利用的盐选自如下一组：氯化钠、醋酸钠×3H2O、钠磷酸氢钙×2H2O、氢氧化钠、D-葡萄糖酸钠、氯化钾、醋酸钾、D-葡萄糖酸钙×H2O、氯化钙×2H2O以及氯化镁×6H2O。
为了避免静脉灌注中的感染，本发明的药物制剂优选采用无菌过滤或者热灭菌。特别地，为了进行无菌过滤，可以使用从各制造商处购得的细孔滤芯。例如，孔径在0.2-3.0μm的滤芯是适当的。另外，本发明的药物制剂可以使热灭菌的而不会导致组分的分解。优选地，热灭菌是在高于100℃的温度下进行的，更优选的是在105-150℃下进行的，特别优选的是在110-130℃下进行的；例如，在121℃进行最多30分钟的灭菌，优选最多28分钟，特别优选23-25分钟，或者在112℃进行最多100分钟的灭菌，特别优选70to 90分钟；具体条件可根据容器进行选择。
容量替代剂用于补充人类和动物的血管内液体损失。其一特别的用途是预防与治疗血容量不足，并与血容量不足是源于血液或体液的直接损失如急性出血、创伤、手术、烧伤等，还是源于大循环和微循环之间的分布不平衡如败血症是无关的，也与是否是区域限制无关，如人为中断流血，如在血管段结扎或应用止血带。
进一步地，本发明还涉及上述药物制剂作为容量替代剂的用途。
因而，在另一实施方式中，本发明的药物制剂特别适用于血容量不足的预防与治疗。
已经发现，本发明的药物制剂能够明显地增强微循环。
因而，本发明还涉及本发明的药物制剂用于改善微循环。
由于本发明药物制剂的特殊性质，其特别适用于作为保护红细胞的洗涤液。
本发明还涉及将本发明的药物制剂作为保护红细胞的洗涤液的用途。
实施例
Table 1是本发明药物制剂的组合物：
| 组分 | 浓度 |
| 明胶多聚琥珀酸盐 | 40g/l |
| 钠 | 153mmol/l |
| 钾 | 4mmol/l |
| 钙 | 1.5mmol/l |
| 镁 | 1.25mmol/l |
| 氯化物 | 99mmol/l |
| 醋酸盐 | 24mmol/l |
| 磷酸盐 | 1.5mmol/l |
| 葡萄酸盐 | 2.75mmol/l |
表1所示的组合物可通过秤取下列组分并将其溶解在注射用水中加量至1000ml而得到：40g明胶多聚琥珀酸盐、95mmol氯化钠、24mmol醋酸钠、4mmol氯化钾、1.5mmol葡萄糖酸钙、1.25mmol葡萄糖酸镁、1.5mmol甘油磷酸钠(甘油-1(2)-磷酸二氢盐-二钠盐的混合物)和约35mmol氢氧化钠溶液(氢氧化钠溶液的精确数量取决于调节pH值到7.4(7.1-7.7)所需的量)。
Claims (15)
1.一种水性药物制剂，其包括：
a)20-80g/l的明胶和/或生理上可接受的明胶衍生物和/或明胶蛋白和/或明胶多肽、及其离子成分；
b)150-160mmol/l的钠；
c)4-5mmol/l的钾；
d)1-2mmol/l的钙；
e)1-2mmol/l的镁；
f)82-105mmol/l的氯化物；
g)24-30mmol/l的醋酸盐和/或葡萄糖酸盐。
2.如权利要求1所述的药物制剂，其中，所述的明胶和/或生理上可接受的明胶衍生物和/或明胶蛋白和/或明胶多肽的数均分子量为18,000-30,000。
3.如前述权利要求中至少一项所述的药物制剂，其中，所述的生理上可接受的明胶衍生物是琥珀酰明胶。
4.如权利要求1或2中至少一项所述的药物制剂，其中，所述的生理上可接受的明胶衍生物是非琥珀酰明胶。
5.如权利要求1或2中至少一项所述的药物制剂，其中，所述的生理上可接受的明胶衍生物是脲交联明胶。
6.如权利要求1或2中至少一项所述的药物制剂，其中，所述的生理上可接受的明胶衍生物是氧化聚明胶。
7.如权利要求1或2中至少一项所述的药物制剂，其中，所述的生理上可接受的明胶衍生物是明胶多聚琥珀酸盐。
8.如前述权利要求中至少一项所述的药物制剂，其包括30-60g/l的明胶和/或生理上可接受的明胶衍生物。
9.如前述权利要求中至少一项所述的药物制剂，其包括40-50g/l的明胶和/或生理上可接受的明胶衍生物。
10.如前述权利要求中至少一项所述的药物制剂，其中，该药物制剂包括重组制得的明胶蛋白和/或明胶多肽。
11.如前述权利要求中至少一项所述的药物制剂，其中，该药物制剂为注入液的制剂形式。
12.如前述权利要求中至少一项所述的药物制剂作为容量替代剂的用途。
13.如权利要求1-11中至少一项所述的药物制剂用于预防和治疗血容量不足。
14.如权利要求1-11中至少一项所述的药物制剂用于改善微循环。
15.如权利要求1-11中至少一项所述的药物制剂作为保护红细胞的洗涤液的用途。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102009034132.3 | 2009-07-20 | ||
| DE102009034132A DE102009034132A1 (de) | 2009-07-20 | 2009-07-20 | Plasmaadaptierte und balancierte Gelatinelösung |
| PCT/EP2010/060210 WO2011009797A2 (de) | 2009-07-20 | 2010-07-15 | Plasmaadaptierte und balancierte gelatinelösung |
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| EP (1) | EP2456446A2 (zh) |
| KR (1) | KR20120046160A (zh) |
| CN (1) | CN102470147A (zh) |
| BR (1) | BR112012001229A2 (zh) |
| DE (2) | DE102009034132A1 (zh) |
| IN (1) | IN2012DN00419A (zh) |
| MX (1) | MX2012000957A (zh) |
| RU (1) | RU2012105925A (zh) |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1313164A (en) * | 1969-04-28 | 1973-04-11 | Knox Gelatine Inc | Blood plasma substitute |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP0223906A3 (en) * | 1982-10-29 | 1989-02-01 | Synthetic Blood Corporation | Gelatin based synthetic whole blood and a process for preparing the same |
| EP1238675A1 (en) | 2001-03-06 | 2002-09-11 | Fuji Photo Film B.V. | Recombinant gelatin-like proteins for use as plasma expanders |
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2009
- 2009-07-20 DE DE102009034132A patent/DE102009034132A1/de not_active Withdrawn
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2010
- 2010-07-15 RU RU2012105925/15A patent/RU2012105925A/ru unknown
- 2010-07-15 DE DE202010018349.9U patent/DE202010018349U1/de not_active Expired - Lifetime
- 2010-07-15 MX MX2012000957A patent/MX2012000957A/es not_active Application Discontinuation
- 2010-07-15 WO PCT/EP2010/060210 patent/WO2011009797A2/de active Application Filing
- 2010-07-15 BR BR112012001229A patent/BR112012001229A2/pt not_active IP Right Cessation
- 2010-07-15 KR KR1020127000796A patent/KR20120046160A/ko not_active Ceased
- 2010-07-15 EP EP10734480A patent/EP2456446A2/de not_active Withdrawn
- 2010-07-15 CN CN2010800330764A patent/CN102470147A/zh active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1313164A (en) * | 1969-04-28 | 1973-04-11 | Knox Gelatine Inc | Blood plasma substitute |
Non-Patent Citations (2)
| Title |
|---|
| 《ANNALS OF SURGERY》 19710101 D.V.Habif等 A Blanced Fluid Gelatin for the Treatment of Hemorrhage 第85-90页 12-15 第173卷, 第1期 * |
| D.V.HABIF等: "A Blanced Fluid Gelatin for the Treatment of Hemorrhage", 《ANNALS OF SURGERY》, vol. 173, no. 1, 1 January 1971 (1971-01-01), pages 85 - 90, XP002638063, DOI: 10.1097/00000658-197101000-00012 * |
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| Publication number | Publication date |
|---|---|
| IN2012DN00419A (zh) | 2015-05-15 |
| RU2012105925A (ru) | 2013-08-27 |
| DE202010018349U1 (de) | 2015-10-28 |
| DE102009034132A1 (de) | 2011-01-27 |
| MX2012000957A (es) | 2012-03-06 |
| EP2456446A2 (de) | 2012-05-30 |
| KR20120046160A (ko) | 2012-05-09 |
| BR112012001229A2 (pt) | 2016-03-01 |
| WO2011009797A3 (de) | 2011-08-25 |
| WO2011009797A2 (de) | 2011-01-27 |
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