CN1230200C - 稳定的酶清创剂 - Google Patents

稳定的酶清创剂 Download PDF

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CN1230200C
CN1230200C CNB018214770A CN01821477A CN1230200C CN 1230200 C CN1230200 C CN 1230200C CN B018214770 A CNB018214770 A CN B018214770A CN 01821477 A CN01821477 A CN 01821477A CN 1230200 C CN1230200 C CN 1230200C
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戴维·W·霍布森
戴维·P·琼斯
卡塔尔兹娜·科斯特尔
皮拉尔·P·杜凯
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Abstract

本发明涉及酶无水亲水性清创剂，该清创剂组合使用蛋白水解酶和无水亲水性泊洛沙姆载体。

Description

稳定的酶清创剂
技术领域
本发明涉及一种组合物，该组合物用于坏死组织的酶促清创和用于急性和慢性创伤中脓液的液化。
技术领域
酶促清创在过去就已知。但是，其仍然具有实质的功效问题。具体而言，现有技术的清创组合物为了稳定的贮存通常需要冷藏，并且因为它们通常含有大量水，因而具有保存期稳定性的问题。一直认为水是必需的，因为水将酶溶解，而酶被认为是获得有效清创所必需的。
热敏蛋白水解酶和大量水基载体的组合已经带来既需要冷藏温度，通常在冷冻温度，还在使用前保存期限短的实际影响。因此，这种组合已经很少使用，并且在商业上不太受欢迎。
因此，可以看出，对于正常室温的、低气味、有效的蛋白酶清创剂存在持续的需求，该清除剂在室温下具有良好的保存期稳定性，而没有牺牲蛋白酶的清创作用的性质。本发明的主要目的是满足上述需求。
本发明的另一目的是提供室温稳定的酶清创剂，其稠度或粘度允许产品保留在坏死和渗出的伤口中。
本发明的另一目的是提供酶清创剂，其类型满足上述目的，可以有效包装并从管中分散。
本发明的另一目的是提供上述类型的组合物，其可以将无水且亲水的组分，和活性酶清创剂，以及其它活性组分合并在独特的半固体软膏敷囊中，以得到一般而言蛋白酶类，特别是木瓜蛋白酶的优异室温稳定性。
实现上述每个目的，以及其它目的的方法和方式将从下面本发明的详细描述中变得明显。
附图说明
图1是显示室温木瓜蛋白酶稳定性研究的图。
发明内容
本发明公开了用于坏死伤口的半固体亲水性无水软膏酶清创组合物，其被设计为具有室温稳定性，并保持蛋白酶的效力。广义上说，该组合物是无水亲水性泊洛沙姆载体与少量但清创有效量的一种或多种蛋白水解酶，优选是木瓜蛋白酶组合的酶清创剂。
具体实施方案
本发明的基质或载体部分可以一般性地描述为无水泊洛沙姆载体，它是环氧乙烷和环氧丙烷的嵌段共聚物，其结构如下：
        HO(C2H4O)x(C3H6O)y(C2H4O)xH
其中x为2～150，且y为15～70。优选x为12～141，且y为20～56。一般而言，满足上述说明的环氧乙烷和环氧丙烷的嵌段共聚物可以从BASF商购，商标为“Pluronic and Lutrol F Block Copolymers”。这些聚合物的详细特性参见关于Pluronic多元醇的BASF CorporationTechnical Data Sheets，copyright 1992，该文献引入本文作参考。
它们通常包括分子量为1000～16000的嵌段共聚物。对于本发明而言重要的是，它们具有水溶性，以乳膏或软膏的形式存在，并且能够在无水条件下长期贮存。
一般而言，本文中有用的环氧乙烷和环氧丙烷的嵌段共聚物的亲水亲油平衡(HLB)值为8～30，且优选为12～25。使用BASF的泊洛沙姆码标，适用于本发明的泊洛沙姆包括，但不限于：Pluronic/Lutrol F 44(泊洛沙姆124)
Pluronic/Lutrol F 68(泊洛沙姆188)
Pluronic/Lutrol F 87(泊洛沙姆237)
Pluronic/Lutrol F 108(泊洛沙姆338)
Pluronic/Lutrol F 127(泊洛沙姆407)
接下来是少量但清创有效量的蛋白水解酶。如本领域技术人员所公知的，蛋白水解酶具有部分或全部水解肽酰胺键的能力。这些酶还可能具有与蛋白水解活性相关的某些固有的分解脂肪和/或分解淀粉的活性。优选的蛋白水解酶是木瓜蛋白酶。其它的适宜蛋白水解酶包括胰蛋白酶、胰凝乳蛋白酶、链激酶、链球菌DNA酶、无花果蛋白酶、胃蛋白酶、羧肽酶、氨肽酶、木瓜凝乳蛋白酶、菠萝蛋白酶和其他蛋白水解酶。
木瓜蛋白酶是源自天然绿色水果热带番木瓜或番木瓜(Caricapapaya)的酶，将它们的澄清多水液体收集、干燥、研磨成粉，并过筛以得到木瓜蛋白酶。它是类似于胃蛋白酶的酶，但是在酸、碱或中性溶液中起作用。它是白至灰色粉末并且适度吸湿。它在碱液中在约5小时内能溶解200倍于其重量的凝固的卵清蛋白。它极易溶于水和甘油，但几乎不溶于乙醇。高活性纯化木瓜蛋白酶(High ActivityPurified Papain)(Belgium)可从Enzyme Development Corporation商购，其是具有50000USP单位/mg效能的高精制木瓜蛋白酶。该物质以低气味的白色至黄褐色粉末提供。
Prolase 300R蛋白酶可以商购，并且含有源自热带植物番木瓜的活化和精制的蛋白水解酶。Prolase 300R以均一效能的淡黄褐色粉末提供。每克Prolase 300R含有300 Wallerstein木瓜蛋白酶活性单位，这由凝乳测定方法或者由酪蛋白消化方法测定。
另一组适宜的蛋白水解酶包括那些基本上不含巯基或二硫键的酶，并且包括丝氨酸蛋白酶，特别是那些源自芽胞杆菌属(Bacillus)和链霉菌属(Streptomiasis)细菌及曲霉属(aspergilis)霉菌的酶。
在后一组内，更优选的酶是芽胞杆菌源的碱性蛋白酶，一般称作枯草杆菌蛋白酶。参考文献见Deayl，L.，Moser，P.W.和Wildi，B.S.，″Proteases of the Genus Bacillus.II alkaline Proteases.″Biotechnologyand Bioengineering，Vol.XII，pp.213-249(1970)和Keay，L.和Moser，P.W.，″Differentiation of Alkaline Proteases from Bacillus Species″Biochemical and Biophysical Research Comm.，Vol.34，No.5，pp.600-604，(1969)。
枯草杆菌蛋白酶分为两个亚类，枯草杆菌蛋白酶A和枯草杆菌蛋白酶B。在枯草杆菌蛋白酶A组中，酶源自种枯草杆菌(B.subtilis)、地衣芽孢杆菌(B.licheniformis)和短小芽孢杆菌(B.pumilis)。在该亚类中的生物几乎不产生或不产生中性蛋白酶或淀粉酶。
另外，举例来说，其它适宜的酶是胰酶、胰蛋白酶、胶原酶、角蛋白酶、羧化酶、氨肽酶、弹性蛋白酶和曲霉(aspergillo)-肽酶A和B、链霉蛋白酶E(来自灰色链霉菌(S.griseus))和dispase(来自多粘芽胞杆菌(Bacillus polymyxa))。
在本发明的实践中使用有效量的酶。该量就是能有效清除坏死组织并液化急性和慢性伤口中的脓液的量。该量还是在合理的时间内(例如7天的时间内)实现去除基本上所有这些物质的量。用于特定用途的准确量将取决于几个因素，包括酶的固有活性、预期施用于伤口的次数等。作为基本的标准，工作凝胶提供500USP单位/mg～3000USP单位/mg的活性，优选为800USP单位/mg～2200USP单位/mg。但是，也可以使用更低的量。以重量/体积计，酶制剂很少是纯的，预期酶源将以总凝胶配方重量的1％～15％的量使用。准确的量将随酶的纯度而变化。
尽管并未准确地知道为什么本发明的组合优于现有技术，但据信存在以下机理，该机理解释了无水软膏基质和蛋白水解酶之间存在的协同作用。因为基质是无水的，所以当酶与基质混合并不与任何水接触时，它增强酶的稳定性。当混合物接触伤口时，伤口包含多水物质，因此无水亲水基质物质将酶物质释放，使之与位于待清除伤口中的多水物质接触。然后，酶进攻伤口的蛋白物质，剪去氨基酸末端，将蛋白质断裂成更小的单元，然后它可以容易地洗去。所有这些均在水分扩散入无水亲水基质中，使酶溶解时发生。
与现有技术使用水基材料或无水不溶性材料的系统相比，一方面酶不会过早地随水基材料释放，或者，另一方面，不会被如此牢固地保持在基质中以至于不与待清创的伤口接触。因此，本发明的配方在现有酶清创剂一般无效的方面有效。
如本领域技术人员所公知的，本发明的组合物可以含有其它组分，称作少量物质，如酶活化剂、伤口愈合剂、结构形成组分、抗微生物剂、抗生素和/或麻醉剂，所有这些通常来自GRAS安全列表。一般而言，它们的量将在0.01％～25％内变化。
以下体外酶活性研究是为实验室评估目的而进行的，其预测产品的商业行为。制备以下组合物：
                      实施例1
                                   ％w/w
            泊洛沙姆407            9.8
            泊洛沙姆338            16.1
            泊洛沙姆124            66.6
            木瓜蛋白酶             7.5
                      实施例2
                                   ％w/w
            丙二醇                 20.0
            泊洛沙姆               4076.67
            泊洛沙姆               3389.53
            泊洛沙姆124            55.9
            聚乙烯吡咯酮           0.40
            木瓜蛋白酶             7.50
                 实施例3
                                  ％、w/w
            包封的脲               收率10％
            泊洛沙姆407            6.67
            泊洛沙姆338            9.53
            聚乙烯吡咯酮           0.40
            木瓜蛋白酶             7.50
            泊洛沙姆124            适量到100％
进行室温木瓜蛋白酶稳定性研究，结果如图1所示。

Claims (13)

1.一种酶清创剂，其基本上由以下物质组成：
无水亲水性泊洛沙姆载体，和
足以具有500USP单位/mg～3000USP单位/mg的活性的量的一种或多种蛋白水解酶。
2.权利要求1的酶清创剂，其中泊洛沙姆载体是环氧乙烷和环氧丙烷的嵌段共聚物，其结构如下：
                HO(C2H4O)x(C3H6O)y(C2H4O)xH
其中x为2～150，且y为15～70。
3.权利要求2的酶清创剂，其中x为12～141，且y为20～56。
4.权利要求1的酶清创剂，其中酶活性为800USP单位/mg～2200USP单位/mg。
5.权利要求1的酶清创剂组合物，其中蛋白水解酶选自木瓜蛋白酶、胰蛋白酶、胰凝乳蛋白酶、链激酶、链球菌DNA酶、无花果蛋白酶、胃蛋白酶、羧肽酶、氨肽酶、木瓜凝乳蛋白酶、菠萝蛋白酶和基本上不含巯基或二硫键的蛋白水解酶。
6.权利要求5的酶清创剂组合物，其中蛋白水解酶是木瓜蛋白酶。
7.无水亲水性泊洛沙姆凝胶和一种或多种蛋白水解酶在药物生产中的用途，所述药物用于酶促清创。
8.权利要求7的用途，其中泊洛沙姆载体是环氧乙烷和环氧丙烷的嵌段共聚物，其结构如下：
            HO(C2H4O)x(C3H6O)y(C2H4O)xH
其中x为2～150，且y为15～70。
9.权利要求8的用途，其中x为12～141，且y为20～56。
10.权利要求9的用途，其中所述药物含有足以具有500USP单位/mg～3000USP单位/mg的活性的量的蛋白水解酶。
11.权利要求10的用途，其中酶活性为800USP单位/mg～2200USP单位/mg。
12.权利要求7的用途，其中蛋白水解酶选自木瓜蛋白酶、胰蛋白酶、胰凝乳蛋白酶、链激酶、链球菌DNA酶、无花果蛋白酶、胃蛋白酶、羧肽酶、氨肽酶、木瓜凝乳蛋白酶、菠萝蛋白酶和基本上不含巯基或二硫键的蛋白水解酶。
13.权利要求12的用途，其中蛋白水解酶是木瓜蛋白酶。
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