CN100571792C - 内含缓释抗生素/抗菌素的骨骼替代物 - Google Patents
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Abstract
本发明涉及一种内含缓释抗生素/抗菌素的骨骼替代物,该骨骼替代物是由二水硫酸钙和碳酸钙小颗粒,以及至少一种选自氨基糖甙类抗生素、林可酰胺类抗生素、胍基葡糖肽类抗生素、大环内酯类抗生素、酮内酯类抗生素、硝米特、氟轻松类抗生素、恶唑烷酮类抗生素、类固醇类抗生素、防腐剂、制霉剂/抗真菌抗生素的小颗粒组成的压缩混合物,小颗粒附有甘油三棕榈酸酯和/或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇部分或全部包裹的涂层。包裹层和小颗粒互相结合。
Description
技术领域
本发明涉及一种内含缓释抗生素/抗菌素的骨骼替代物。
背景技术
骨髓炎是一种很难治疗的骨骼组织传染病。通常采用对骨骼感染区进行清创手术的治疗方法。接着采用一种利用不可吸收的-链或者利用含有骨胶原氟盐(Kollagenvilesen)的庆大霉素的局部抗生素治疗法,并证明是可靠有效的。因此,让庆大霉素在一个高位的药盒中局部释放,以便杀死存留的细菌病原菌。但是,最理想的是采用一种骨骼替代物。利用这种替代物,一方面可以局部地释放庆大霉素,另一方面还可以有利于骨骼生长,并且发挥其特有的占位功能。
采用二水硫酸钙作为骨骼替代物的治疗方法早就逐渐为人所熟悉,参见[E.Martin:(Zur Ausfuellung von Knochenhoehlen mit totemMaterial);Zentab Chir 21(1894)193-200;E.Edber:(Some experiencesof filling osteous cateous cavities with plaster),Acata Chir Scand67(1930)313-319;.J.O.Holinger,J.Brekke,E.Kruskin,D.Lee:(Role ofbone substitutes;Clin Orthop 324(1996)55-56)]。
在美国专利US2002110541,US5807567,US2002197315,US6652887,US5756127和US5614206中,报道了一种骨骼替代物。这种替代物基本上是由一种α-和β-硫酸钙混合物组成,并且将其作为药物有效成分的药效释出系列药(Drug-Delivery-Systeme)。这种骨骼替代物在将其注入到水溶液后的第一个小时内就把吸收的绝大部分有效物质释放出来,然后在以后的几天中解释出的只是很少量的剩余有效物质。
在德国专利DE19953771中,公开了一种骨骼替代物。这种骨骼替代物由二水硫酸钙和纳米级的羟磷灰石微粒组成的混合物构成。用这种材料制作的成型体,具有很大的内部表面积,并且可以用水相抗生素溶液进行浸透。经过这种方法处理的成型体,能够或多或少地减缓抗生素的释放。绝大部分抗生素将在开始的几个小时内释放。这种缓慢释放的原因,主要是依赖于成型体的内表面吸收了最大量的有效物质。
在德国专利DE10114244,DE10114245,DE10114364,DE10227914或DE10227938中,介绍了一种有效物质的剂型及其制作这种有效物质剂型的方法。这种有效物质的剂型,其主要优点是生成或应用了少量溶于水的有效物质的盐。继而在德国专利DE10227914中又发布了一个缓慢释放活性物质的药物制备方法。这种药物由粉状体考拉宁和最少量的粉状水溶性庆大霉素,克林霉素,万古霉素,莫西沙星,环丙沙星的盐类以及一种无机和/或有机辅料组成的混合物构成。另外,该专利还建议采用碳酸钙,二水硫酸钙,磷酸三钙和羟磷灰石作为辅料使用。这种药物配方,可适用于以片剂,模压制剂,丝状制剂和粒状剂植入体内的有效物质的制备。
在德国专利DE10227935中推出了一种多孔体抗生素涂层及其应用的方法。根据该专利,把至少由脂肪酸酯和奈替米星(乙基西梭霉素),西索米星,庆大霉素,克林霉素,阿米卡星,卡那霉素,妥布霉素,环丙沙星和万古霉素的十二烷基硫酸盐组成的多组药物中的一组少量溶解于水的抗生素盐涂层,掺和到非金属和金属多孔体构成的孔隙系统中去。这种涂层也可以附着在多孔粉末,多孔丸粒,多孔成型体和紧密体多孔层上。抗生素涂层体必须以植入物方式使用。
在美国专利US 5055307中,建议以丸粒药物作为缓慢释放活性物质的方式。这种丸粒由一种钙对磷质量比为1.3至1.8的磷酸钙构成。这种磷酸钙的空隙率为0.1%至70%,比表面积为0.1m2/g至50m2/g。空隙大小在1nm至10μm。丸粒在200摄氏度至1400摄氏度的温度范围内的钙化过程中形成。然后将丸粒置于一种有效物质中进行浸渍。同样也可以使丸粒吸收一种聚合体溶液并在丸粒上形成一层聚合体层。
发明内容
完成本发明任务的手段是,开发一种价格低廉、生产简单并含有能够缓慢释放抗生素/抗菌素的骨骼替代物。
按照本发明技术,此项任务是通过权利要求1中特殊措施完成的。其延伸的用途将在从属权利要求中作专门介绍。本发明提供一种内含缓释抗生素/抗菌素的骨骼替代物,其特征在于,骨骼替代物是由二水硫酸钙和碳酸钙小颗粒,以及至少一种选自氨基苷糖类抗生素、林可酰胺类抗生素、胍基葡糖肽类抗生素、大环内酯类抗生素、酮内酯类抗生素、硝米特、氟轻松类抗生素、恶唑烷酮类抗生素、类固醇类抗生素、抗真菌抗生素的小颗粒组成的压缩混合物,并且小颗粒附有甘油三棕榈酸酯和/或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇部分或全部包裹的涂层。小颗粒包裹层和小颗粒互相结合。这就是说,每一颗微粒都附有甘油三棕榈酸酯和或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇部分或全部包裹的涂层。小颗粒外涂层最好以小于100μm的厚度为宜。
令人惊奇的是,按照本发明制备的成型体,其抗生素缓慢释放有效物质的时间可长达几天到两个星期。根据这个概念制成的压缩混合物,可以理解成是把小颗粒压缩为不存在孔径大于50μm微小空隙的致密物体。由此需要用至少30kN的大作用力(例如对一个直径约为6mm的成型体)进行压缩。这种压缩结构影响到有效物质从物质的内部向物质的外表面扩散的速度。
也可用甘油二月桂酸酯,甘油三肉豆蔻酸酯,甘油二肉豆蔻酸酯,甘油二棕榈酸酯,甘油二硬脂酸酯,蜂蜡,油脂或加氢植物油,代替甘油三月桂酸酯,甘油三棕榈酸酯和甘油三硬酸酯使用。
本发明优选庆大霉素、妥布霉素、奈替米星(乙基西梭霉素)、西索米星、阿米卡星、林可酰胺、克林霉素、替卡拉宁、万古霉素、雷莫拉宁、红霉素、泰利霉素、阿奇霉素、环丙沙星、莫西霉素、利奈唑胺、甲硝唑、替硝唑、氯霉素、氯己定、聚己胍(苷)中的单一物质或其混合物作为本发明骨骼替代物中的有效物质组分。有效物质可以做成微溶于水的盐或少量溶于水的盐使用。因此,根据本发明中的应有之义,水中溶解的少量抗生素盐,被吸收到按照本发明制得的骨骼替代物中。这里以庆大霉素十六烷酸盐,妥布霉素十六烷酸盐和庆大霉素十二烷基硫酸盐为例加以说明。
此外,本发明还具有这样的优点,即骨骼替代物是粒径在100μm-2500μm小颗粒组成的颗粒状或圆柱体状或片状制剂,小颗粒表面包有甘油三硬脂十六烷酸盐和/或甘油三硬脂酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇涂层。
用β-磷酸三钙、磷酸氢钙、二水磷酸氢钙、碳酸镁、酸三镁、氢氧化镁或氧化镁部分或全部替代碳酸钙,是非常实用而有益的。
此外,还要首选具有下列质量百分比组成的配方:
50.0%-90.0%二水硫酸钙;
1.0%-40.0%碳酸钙;
1.0%-40.0%甘油三棕榈酸酯和/或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇以及
0.1%-10.0%的至少一种选自氨基糖苷类抗生素、林可酰胺类抗生素、大环内酯类抗生素、酮内酯类抗生素、硝咪唑、氟醌醇酮(Fluorchinolon)类抗菌素、恶唑烷酮类抗菌素、类固醇类抗菌素、防腐剂、制霉菌素/杀真菌类抗生素。
按照本发明,用骨骼替代物制作的成型体,首选形状是丸状,球体状,环状或圆筒状,必要时采用中空式形状。
具体实施方式
本发明将通过下列实施例加以说明,但是不仅仅局限于这些实施例。
实施例1
用滚磨机研磨179.91克二水硫酸钙(Merck牌),44.98克碳酸钙(Fluka牌)和6.88克庆大霉素硫酸盐(AK545,相当于3.75克庆大霉素基质)混合物。然后把这种混合物和加热到摄氏60度的18.23克三棕榈精(Fluka牌甘油三棕榈酸酯)乙醇溶液进行混合。得到一种糊状的粘稠物。用乙醇进行稀释后,将硬化的混合物粉碎成颗粒状,并加以过筛。将所得粒状物(筛下粒度为63-500μm)送入一台挤压式制片机制成质量为250mg的制剂,其直径为6mm,厚度为4.5mm.
实施例2
用滚磨机研磨176.51克二水硫酸钙(Merck牌),44.13克碳酸钙(Fluka牌)和11.47克庆大霉素硫酸盐(AK545,相当于6.25克庆大霉素基质)混合物。然后把这种混合物和加热到摄60度的17.89克三棕榈精(Fluka牌甘油三棕榈酸酯)乙醇溶液进行混合。得到一种糊状的粘稠物。用乙醇进行稀释后,将硬化的混合物粉碎成颗粒状,并加以过筛。将所得粒状物(筛下粒度为63-500μm)送入一台挤压式制片机制成质量为250mg的制剂,其直径为6mm,厚度为4.5mm.
实施例3
用滚磨机研磨172.11克二水硫酸钙(Merck牌),43.03克碳酸钙(Fluka牌)和7.81克庆大霉素硫酸盐(福建,AK640,相当于5.0克庆大霉素基质)以及5.77克克林霉素氢氯化物(Upjohn,AK 640,相当于5.0克克林霉素基质)混合物。然后把这种混合物和加热到摄氏60度的21.28克三棕榈精(Fluka牌甘油三棕榈酸酯)乙醇溶液进行混合。得到一种糊状的粘稠物。用乙醇进行稀释后,将硬化的混合物粉碎成颗粒状,并加以过筛。将所得粒状物(筛下粒度为63-500μm)送入一台挤压式制片机制成质量为250mg的制剂,其直径为6mm,厚度为4.5mm.
有效物质释放试验
将6片由实施例1和实施例2制得的制剂置于20毫升37摄氏度的精馏水中。每天取出15毫升含有释放有效物质的介质,并换入新鲜的精馏水。在取出的含有有效物质的介质中测出释放的庆大霉素。用ABBOTT公司生产的TDX型分析仪测定释放的庆大霉素。在计算释放的庆大霉素量时,要同时考虑从第一天开始没有全部取出的含有释放药物的介质的量。现将6片庆大霉素基质的释放的质量,相应于试样体在释放介质中存留的时间,分别列表如下。经过11天后,释放试验结束。
Claims (6)
1.内含缓释抗生素的骨骼替代物,其特征在于,骨骼替代物是由二水硫酸钙小颗粒和至少一种选自碳酸钙、β-磷酸三钙、磷酸氢钙、二水磷酸氢钙、碳酸镁、磷酸三镁、氢氧化镁或氧化镁的小颗粒,以及氨基糖苷类抗生素的小颗粒组成的压缩混合物,同时小颗粒附有甘油三棕榈酸酯和/或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇部分或全部包裹的涂层,包裹层和每一颗小颗粒互相结合,同时将其中的小颗粒压缩为不存在孔径大于50微米微小空隙的致密物体。
2.根据权利要求1的内含缓释抗生素的骨骼替代物,其特征在于,骨骼替代物是由粒径在100μm~2500μm的小颗粒组成的颗粒状或片状制剂;小颗粒表面附有甘油三硬脂十六烷酸盐和/或甘油三硬脂酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇部分或全部包裹的涂层。
3.根据权利要求2的内含缓释抗生素的骨骼替代物,其特征在于,骨骼替代物是呈圆柱体状或磨成小平面状的片状制剂。
4.根据权利要求1至3中任一权利要求所述的内含缓释抗生素的骨骼替代物,其特征在于,具有下列质量百分比组成的配方:50.0%-90.0%的二水硫酸钙;
1.0%-40.0%的碳酸钙;
1.0%-40.0%的甘油三棕榈酸酯和/或甘油三硬酸酯和/或甘油三月桂酸酯和/或一到十六烷基醇;以及
0.1%-10.0%的氨基糖苷类抗生素。
5.根据权利要求1至3中任一权利要求所述的内含缓释抗生素的骨骼替代物,其特征在于,所述的抗生素是庆大霉素、妥布霉素、奈替米星、西索米星或阿米卡星。
6.根据权利要求4所述的内含缓释抗生素的骨骼替代物,其特征在于,所述的抗生素是庆大霉素、妥布霉素、奈替米星、西索米星或阿米卡星。
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DE102004060666A DE102004060666B3 (de) | 2004-12-15 | 2004-12-15 | Antibiotikum/Antibiotika enthaltendes Knochenersatzmaterial mit retardierender Wirkstofffreisetzung |
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DE102011122752B3 (de) * | 2011-04-06 | 2013-02-21 | Heraeus Medical Gmbh | Medizinisches Implantat enthaltend ein plastisch verformbares,biodegradierbares Hämostyptikum |
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CN103816565A (zh) * | 2012-07-20 | 2014-05-28 | 赫罗伊斯医疗有限责任公司 | 糊状骨替换材料 |
US9186437B2 (en) | 2012-07-20 | 2015-11-17 | Heraeus Medical Gmbh | Pasty bone replacement material |
CN103816565B (zh) * | 2012-07-20 | 2017-03-01 | 赫罗伊斯医疗有限责任公司 | 糊状骨替换材料 |
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EP1671661B1 (de) | 2009-07-15 |
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CA2526954C (en) | 2009-06-02 |
ES2330015T3 (es) | 2009-12-03 |
EP1671661A2 (de) | 2006-06-21 |
CA2526954A1 (en) | 2006-06-15 |
JP2006167469A (ja) | 2006-06-29 |
BRPI0505586B1 (pt) | 2018-05-08 |
AU2005239648A1 (en) | 2006-06-29 |
SI1671661T1 (sl) | 2010-01-29 |
DK1671661T3 (da) | 2009-11-16 |
ZA200510166B (en) | 2006-11-29 |
PT1671661E (pt) | 2009-10-22 |
AU2005239648B2 (en) | 2007-08-16 |
US7923019B2 (en) | 2011-04-12 |
BRPI0505586A (pt) | 2006-09-12 |
DE102004060666B3 (de) | 2006-03-30 |
PL1671661T3 (pl) | 2010-01-29 |
DE502005007699D1 (de) | 2009-08-27 |
US20060127444A1 (en) | 2006-06-15 |
JP4523544B2 (ja) | 2010-08-11 |
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