CN106061520A - 用于刺激骨形成的复合物 - Google Patents

用于刺激骨形成的复合物 Download PDF

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CN106061520A
CN106061520A CN201580011414.7A CN201580011414A CN106061520A CN 106061520 A CN106061520 A CN 106061520A CN 201580011414 A CN201580011414 A CN 201580011414A CN 106061520 A CN106061520 A CN 106061520A
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霍坎·尼格伦
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Elos Medtech Timmersdala AB
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Abstract

本发明涉及用于刺激骨形成的复合物，其中所述复合物由糊状物或具有可在骨组织和其他感兴趣的表面上涂覆和铺展的粘性性质的类似物质组成，其中所述复合物包含Mg和元素Ca、Mn和Zn中的至少一种，且其中Mg构成在复合物中的Mg、Ca、Mn和Zn总量的至少75重量％。本发明还涉及：通过将复合物施用在骨组织上、骨髓腔中或植入物上来刺激骨形成的方法；包括含所述复合物的容器的医疗套件；和用于制备所述复合物的方法。

Description

用于刺激骨形成的复合物
技术领域
用于特异性局部刺激骨形成密质骨和松质骨的复合物(compound)。
背景技术
弱骨、骨脆或骨质疏松症，是在老年人群中常见的病况，在年龄70-80岁的女性中的患病率约30％。骨缺损，例如由于放射疗法，也是一种需要增加形成新分化的骨组织的临床病况。
具有数种类型这样的药物，其当一般地施用时可影响骨组织和矿化作用。二膦酸盐类通过两种不同的机制起作用，通过结合羟磷灰石和通过在破骨细胞的线粒体中摄取随后细胞死亡，其中与羟磷灰石的结合可降低矿物的转换。雷尼酸锶通过其对骨形成细胞的效应而起作用并导致松质骨中的骨密度增加，但不影响密质皮质骨。通常被施用的药物具有不良反应，所述不良反应有时可为非常令人苦恼的。为此，希望得到局部作用试剂以影响骨形成和骨转换。
在这些具有局部效果的试剂中，有通过刺激由间充质干细胞分化骨形成细胞来起作用的骨形态发生蛋白。所述治疗的临床效果是适度的(4％失败的胫骨骨折愈合改进)。氟离子通过与羟磷灰石结合并降低矿物的转化来起作用。
目前，似乎是已知没有引起特异性刺激密质皮质骨形成的刺激骨形成的方法/复合物。
发明内容
本发明的一个方面提供一种复合物/制剂，其提供改进的骨形成特别是密质皮质骨形成。
本发明涉及用于刺激骨形成的复合物，其中所述复合物由糊状物或具有可在骨组织和其他感兴趣的表面上涂覆和铺展的粘性性质的类似物质组成，其中所述复合物包含Mg和元素Ca、Mn和Zn中的至少一种，且其中Mg构成在复合物中Mg、Ca、Mn和Zn总量的至少75重量％。
本发明基于如下知识：镁(Mg)对于骨形成的刺激具有特别有益的效果。由于这个原因，根据本发明的复合物具有高比例的Mg。
本发明也基于如下知识：糊状物或具有粘性性能的类似物质非常适合用于局部施用以由此得到良好的局部效果而无全身施用的药物可引起的效果。
为了研究镁离子对骨组织的效果，在骨髓中进行复合物的植入。使用盐溶液被制成糊状物的MgO的无菌制剂/复合物被植入骨中的骨髓腔中并使其起作用。由此，观察到对密质皮质骨壁的厚度的特定效果。在插入所述试剂3周后观察效果。在2周后，没有可测量的效果。据使用组织学方法的分析，发现皮质密质骨壁的厚度的统计学上显著的(p<0.001)刺激。这是一个重要的发现，因为当骨被负载时是该骨壁承载力。强的骨壁意味着对骨折的保护增加。
进一步地，本发明基于如下知识：复合物中钙(Ca)、锰(Mn)和/或锌(Zn)的存在增加镁对于骨形成刺激的有益效果。由于这个原因，根据本发明的复合物包含控制量的这些元素中的至少一种，优选数种。
Ca、Mn和Zn如何增加镁的有益效果的机制还未被充分研究。然而，有迹象表明，引起该效果的机制是促进新血管生长的生长因子主要是VEGF的激活，这对于新骨的形成是必要的。将Ca、Mn和Zn特别是它们的组合添加至MgO形式的主要组分中产生改进的效果。
因此，在根据本发明的复合物中，Mg+Ca+Mn+Zn总量的至少75％应为Mg，适合的是以MgO的形式。金属Mn和Zn在高浓度下均具有毒性作用，且在复合物中这些金属的浓度不应超过5％。可能地，高达10％可能是可接受的。显着较低的浓度可能是足够的。复合物中Ca的量可构成多达100％的残余量。
可能具有可增加镁刺激骨形成的其他物质。然而，Ca、Mn和/或Zn也是适合的，因为添加至少少量的这些元素至旨在放置在人体内的物质中是没有争议的。
在所述复合物的变体中，Mg和Ca、Mn和/或Zn根据下面内容在复合物中分别构成Mg+Ca、Mn和/或Zn的总量的子量：
Mg–至少75重量％且不超过99重量％；和
Ca、Mn和/或Zn–至少1重量％且不超过25重量％。
复合物中Mn或Zn的量应为Mg+Ca和/或Zn总量的至少0.01重量％，优选至少0.1重量％，以使所述元素或所述多种元素的存在产生改进的效果。
复合物中Ca的量应为Mg+Ca、Mn和/或Zn总量的至少1重量％。
在一个合适的实施方案中，所述复合物包含在复合物中的Mg、Ca、Mn和Zn总量的90重量％Mg、5重量％Ca、4重量％Zn和1重量％Mn。
如上所述的复合物由糊状物或具有可在骨组织和其他感兴趣的表面上涂覆和铺展的粘性性质的类似物质组成。因此所述复合物可通过简单将材料铺展在骨组织上而应用和分散在感兴趣的骨组织上。
可通过将MgO粉末或其他基于镁的材料与水溶液例如诸如等渗盐水溶液混合，或通过制备磷酸盐水泥混合物(其在应用前不允许变硬太多)来制备这样的合适的物质。在制备过程中可以多种方式添加Ca、Mn和/或Zn。当然，在植入前，所述复合物也必须是无菌的，且为可植入质量的。
优选地，在所述复合物中Mg主要存在为MgO/MgOH或MgHPO4。
本发明也涉及根据上述的复合物在刺激骨形成中的应用，优选地包括在骨组织上或在骨中的骨髓腔中应用所述复合物，并涉及密质皮质骨的刺激。所述复合物可在植入物放置在体内之前或之后被应用在所述植入物上。
本发明也涉及用于刺激骨生长的方法，其中所述方法包括在骨组织上、骨髓腔中或植入物上应用根据上述的复合物的步骤。
本发明也涉及一种包括含所述复合物的容器的医疗套件(medical kit)。所述容器应为管型，所述容器在容器的一端具有开口，且具有旨在被压缩以由此通过所述开口挤出所述复合物的容器体。该“医疗套件”也可包括其他合适的附件，例如，诸如，抹刀，以将所述复合物施用和铺展在目标表面上或目标腔中。或者，所述医疗套件可包括两个或更多个容器，其在混合时形成所指定的复合物。例如，其可为两组分套件，干的批次和具有液体的批次，以就在骨组织上施用之前形成磷酸盐水泥混合物。
根据本发明的复合物的合适的基础材料是氧化镁，MgO，例如，“纯MgO-粉末99,995痕量金属基础”(Sweden AB,Kista,Sweden)。可通过在高压釜中热处理来对粉末灭菌。可以至少两种方式制备所述复合物。可由MgO粉末和(无菌的)等渗盐水溶液来制备糊状物，并且可通过将MgO粉末与酸性磷酸盐离子例如磷酸或磷酸二氢盐(的溶液)混合来制备磷酸盐水泥。可在制备所述复合物之前或过程中添加例如粉末或在溶液中的离子的形式的Ca、Mn和Zn。
当MgO与水溶液混合时，大部分的镁将为氢氧化镁Mg(OH)x的形式。
根据本发明的制剂/复合物合适地由复合物中的Mg、Ca、Mn和Zn总量的85-95重量％Mg(以MgO/MgOH或MgHPO4的形式)、2-13重量％Ca、1-5重量％Zn和0.1-2重量％Mn(以氧化物/氢氧化物或磷酸氢盐的形式)组成。
基于镁的材料，例如MgO，可溶解在0.1M NaH2PO4中以使pH>6。该制剂导致磷酸盐水泥在变硬前形成或多或少的粘性糊状物。所述溶液可包括约1-2％的透明质酸盐，以调节粘度，和约1％的生物可降解纤维作为加固剂。
或者，基于镁的材料，例如MgO，溶解在例如0.15M NaCl中，即，等渗盐水溶液中，以形成糊状物。所述糊状物可包含约0.5–2％透明质酸盐以调节粘度。
像这样的使用磷酸钙水泥用于愈合骨的机理可能是已知的，但还未注意高浓度的Mg的积极效果。这样的已知水泥是基于土金属磷酸盐或磷酸氢盐(主要是Ca，有时具有少量的Sr或Mg的添加物)，其在添加水或盐水溶液时自发硬化为磷酸盐水泥。
因此，所述复合物可用作用于受损的骨组织的药物，以刺激皮质密质骨的形成。以混状物或具有粘性性质的相似物质的形式制备的复合物被铺展在考虑中的骨组织上并因此提供密质骨中骨生成的特异性局部刺激。所述复合物可用在多种应用中，例如在骨伤康复过程中。所述复合物也可用于填充在牙齿拔出后的洞中。
所述复合物应具有100s Pa量级的动态粘滞度，即，大致与牙膏、室温下的花生酱或新鲜的未硬化的灰浆相同的动态粘滞度。即，这样的糊状物，这样的粘性液体，在已被涂覆或铺展在目标区域上后可保持其形态和位置。一旦已施用所述复合物，所述糊状物可被允许硬化。
所述复合物也可与植入物，例如，钛螺钉一起使用，以使植入物更好地固定。也可在其植入之前在植入物上应用所述复合物。

Claims (22)

1.用于刺激骨形成的复合物，其中所述复合物由糊状物或具有可在骨组织和其他感兴趣的表面上涂覆和铺展的粘性性质的类似物质组成，其中所述复合物包含Mg和元素Ca、Mn和Zn中的至少一种，且其中Mg构成在复合物中的Mg、Ca、Mn和Zn总量的至少75重量％。
2.根据权利要求1所述的复合物，其中Mg构成在复合物中的Mg、Ca、Mn和Zn总量的至少85重量％。
3.根据权利要求1所述的复合物，其中Mg构成在复合物中的Mg、Ca、Mn和Zn总量的不多于99重量％。
4.根据前述权利要求任一项所述的复合物，其中所述复合物包含元素Ca、Mn和Zn中的至少两种。
5.根据前述权利要求任一项所述的复合物，其中所述复合物包含Ca、Mn和Zn的混合物。
6.根据前述权利要求任一项所述的复合物，其中Ca构成在复合物中的Mg、Ca、Mn和Zn总量的至少1％且不多于25％。
7.根据前述权利要求任一项所述的复合物，其中Mn构成在复合物中的Mg、Ca、Mn和Zn总量的至少0.01％，优选至少0.1％，且不多于5％。
8.根据前述权利要求任一项所述的复合物，其中Zn构成在复合物中的Mg、Ca、Mn和Zn总量的至少0.01％，优选至少0.1％，且不多于5％。
9.根据前述权利要求任一项所述的复合物，其中Mg以MgO、MgOH或MgHPO4形式存在。
10.根据前述权利要求任一项所述的复合物，其中所述复合物是无菌的且为可植入质量的。
11.根据权利要求1-10任一项所述的复合物，其供在骨形成的刺激中使用。
12.根据权利要求11所述的复合物，其中所述使用包括在骨组织上、在骨中的骨髓腔中或在植入物上应用所述复合物。
13.根据权利要求11或12所述的复合物，其中所述使用涉及刺激密质皮质骨的形成。
14.用于刺激骨生长的方法，其中所述方法包括在骨组织上、骨髓腔中或植入物上应用根据权利要求1-10任一项所述的复合物的步骤。
15.医疗套件，其包括含权利要求1-10任一项所述的复合物的容器。
16.根据权利要求15所述的医疗套件，其中所述容器应为应为管型，所述容器在容器的一端具有开口，且具有旨在被压缩以由此通过所述开口挤出所述复合物的容器体。
17.医疗套件，其包括含混合在一起时形成根据权利要求1-10任一项所述的复合物的组分的两个或更多个容器。
18.用于制备根据权利要求1-10任一项所述的复合物的方法，其中所述方法包括将MgO粉末和元素Ca、Mn和Zn中的至少一种在水溶液中混合在一起的步骤。
19.根据权利要求18所述的方法，其中所述方法包括灭菌MgO粉末的步骤，优选通过在高压釜中热处理进行灭菌。
20.根据权利要求18或19所述的方法，其中所述方法包括将透明质酸盐添加至混合物中以调节粘度的步骤。
21.根据权利要求18-20任一项所述的方法，其中所述水溶液是等渗盐水溶液。
22.根据权利要求18-20任一项所述的方法，其中所述水溶液包含酸性磷酸盐离子。
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