CN1806858A - 植入体用抗生素涂层 - Google Patents
植入体用抗生素涂层 Download PDFInfo
- Publication number
- CN1806858A CN1806858A CNA2005101316568A CN200510131656A CN1806858A CN 1806858 A CN1806858 A CN 1806858A CN A2005101316568 A CNA2005101316568 A CN A2005101316568A CN 200510131656 A CN200510131656 A CN 200510131656A CN 1806858 A CN1806858 A CN 1806858A
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- Prior art keywords
- implant
- coating
- acid
- antibiotic
- host material
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Abstract
本发明涉及一种植入体用抗生素涂层，其特征在于，它们是由至少一种有机饱和、疏水的、熔点在45℃－100℃之间的低分子量基质材料及溶解其中的一种低分子量疏水添加剂组成，而且，在由基质材料和添加剂组成的混合物中悬浮有一种抗生素，或者说该涂层是由能与基质材料、添加剂组成的混合物相混的抗生素溶解在由基质材料和添加剂组成的混合物中。
Description
技术领域
本发明涉及植入体上使用的抗生素涂膜及其制备涂抹方法。
背景技术
植入体的作为一种概念，它既具有物质的特性，又具有器官的特性。在外科手术中，至少有部分材料要被带入人体内。这些植入体会与人体骨骼、运动器官及辅助器官的各部分，以及人体内的血液或结缔组织接触。在Unfallchlrurgle和矫形外科手术中，都要大量使用各种不同的合成骨骼材料、内涵管以及骨骼的代用材料，但问题是植入体与其周边组织之间的边界层附近总会有病菌繁殖，而且还可能引起严重的感染。在骨头组织中因植入体引发的感染是植入材料在骨骼组织中造成的最严重并发症。与植入体相关的感染是非常复杂的症状，诊治需要很长时间，并且消耗很多精力，显然由此所消耗的费用也是十分可观的。有一点是很有用，即保护好植入材料，特别是在植入后关键的第一天内，可以通过在植入体表面上局部释放抗菌剂就能防止细菌繁殖。
在血管外科中，人们发现了PTFE(聚四氟乙烯)及聚酯做成的假体作为各种血管代用品的用途。对这些血管代用品的植入存在有危险，即，在植入后，在1小时到1天之内，替代材料中的细菌就会侵入，并且有可能在替代材料的内表面上繁殖。因此，能临时在替代材料上涂抹抗菌保护剂就很重要，也很有意义。
为保护植入体表面免于细菌感染，有人提出了在可吸收聚合材料的培养基上涂抹一系列抗菌剂涂层的建议。
在EP 0328421专利说明书中就披露了一种化学组分，它们是由聚氨基甲酸乙酯、硅树脂及生物降解聚合物构成的基质聚合材料。在该基质材料中，包含有带氯己定(洗必泰)银盐的协同作用组分。
在EP 0652017专利说明书中阐述了一种生物材料的涂层，据说涂抹这种生物材料就能阻止血液凝固以及阻止血浆和细胞构成的血液组成部分在涂层生物材料附近粘结。在生物材料表面上，这些涂层都是自粘着在其表面上的，并且，能在体内持续降解。这种涂层主要是由聚α羧酸(例如，聚乳酸)构成。
在以下这些专利说明书，WO 00/15273，US 3277003，US 3839297，US5378540，US 5312437，US 5123912，US 5100433，US 5032638，US 4857602，US4711241中也披露了在降解聚酯培养基上相类似的工艺技术材料，问题是，对于这些包含有生物降解聚合物的涂层，聚合物的分解进行得相当缓慢，特别是在那些能向内长入骨头组织内部的植入材料涂层中，对于长入骨骼组织具有阻碍作用。最要紧的是必须注意会产生酸性降解产物：如，乳酸、乙醇酸，在局部积累的情况下，就将可能发炎。此外，在聚合体涂层上还有一个问题是，剪切应力，就好象在压入配合技术中的典型方法，作为膜层的整个涂层也可以被剥离或展开。
在EP0279666说明书中介绍了外科手术缝合线用涂料。这种涂料将涉及到蔗糖脂肪酸酯。
在US4532929专利说明书中介绍了外科手术缝合线的干涂层，它们是以利用碱土金属脂肪酸盐为基础，主要作为修整剂(上涂料剂)。
在WO 0007574专利说明书中建议使用一种不会分解的药物，这种产品中包含有两种物质：物质A和物质B，其中，物质A是亲油(亲脂)的，与物质B不同，并且，物质A在水中是可溶解的，而物质B则不能。物质A和B都能起到很好的药物作用。再有，物质A还是一种非离子表面活性剂。
发明内容
本发明的主要任务就是要研制一种临时性抗菌植入体用的涂层，而且这种涂层能以价格低廉、具有一定竞争力和发展前景的方法被涂抹在植入体材料的表面上。这些涂层应当具有阵样的性质，即，一方面在植入体和人体组织间的边界层附近能局部释放出有效的抗生素，另一方面在短时间内、在不释放有害或酸性分解物的前提下涂层能从与人体接触的组织中消除或被分解。为了不影响内涵管发挥最佳功效，就要阻止骨骼组织使其既不能通过持续阻碍作用，又不能通过抗生素涂层的有毒分解产物向内长入未粘接内涵管多孔或粗糙的表面组织上。本发明的另一项任务就是，开发出能粘接在植入体表面上的涂层，而且经剪应力作用后(就象植入体置入时通常出现的情况)涂层作为膜脱离或剥落。此外，该涂层在经过剪应力作用后大部分还能保持，并且，保证能继续得到抗生素的保护。
这些任务可通过以下措施来完成，即，开发具有这样一些特点的抗生素涂层：它们内中是由至少包含一种有机饱和、疏水、熔点在45-100℃之间的、能降解的低分子量基质材料以及溶解其中的疏水、低分子量添加剂构成的涂层，并且，一种抗生素悬浮在由以上基质材料和添加剂组成的涂层中，和/或者，一种能与基质材料和添加剂混合的抗生素溶解其中。
这里所指的“饱和”化合物是指，那些不包含有双键或三键的化合物。所谓“低分子量的”是指，那些摩尔质量小于1000克/摩尔的基质材料性能。在这里所说的降解是指，通过人体或动物组织中现成的酶和酶系统(例如，脂肪酶，β-氧化酶系统、糖酵解及香茅酸环)促使基质材料的降解。所谓“疏水低分子量添加剂”是指那些摩尔质量小1000克/摩尔的有机疏水分子添加剂。借助于良好的粘合性它们将影响植入体表面涂层的附着性。
尤其是，这种涂层在20℃-45℃温度范围内将处于坚硬的凝聚状态，而在压力和剪力作用下会发生塑性变形。这种塑性变形特性是这种涂层的一项非常有用的性质，正因如此，涂层上就不可能有小碎片或颗粒脱落(这种情况可能会酿成机械性炎症)。特别是在经受剪切力作用时(例如，当它们被植入无粘合剂的髋内涵管时就会出现的情况)涂层可能会变形，并在假体的粗糙组织表面上被挤缩，并且还会挤压骨骼周围的海绵组织。
基质材料最好使用由包含有甘油三硬脂酸酯、甘油三(十六酸)酯、甘油三(十四酸)酯、甘油三山嵛酸酯、硬脂酸、棕榈酸、肉豆蔻酸、山嵛酸、十六酸蜂花酯、鲸蜡醇十六酸酯、蜡酸蜡酯及甘油三酯，以及其它各种不同偶数原子的脂肪酸构成。甘油三酯是饱和脂肪，它们能极好地粘附在金属和非金属表面上。在人的机体组织中，脂肪主要包含的是棕榈酸、硬脂酸及油酸的甘油酯。此外，在脂肪中还包含有少量的其它脂肪酸。因此，按照本发明所述基质材料是与人体脂肪相类似的。骨骼，特别是海绵组织中也包含有脂肪。本发明中的脂肪能通过人体组织中固有的代谢作用很容易地被分解。这样，就不可能产生有毒的或酸性分解产物(例如，使用聚乳酸和聚乙醇酸就会出现这种情况)。本发明的另一项优点就是，酶的脂解速度显然要比可降解聚酯的水解速度更快。通过采用饱和的甘油三酯在相当大的程度上还能避免分解产物生成(如对于不饱和脂肪的情况就会出现这些产物)的危险。基质材料始终应当以少量、极薄的膜层涂抹在植入体的表面上，以避免出现血管脂肪栓塞的危险。
此外，以下这组材料是符合本发明目的要求的：硬脂酸、棕榈酸、肉豆蔻酸作为低分子量的酸性材料，最好加入疏水型添加剂。这些物质能很好地粘附在金属及合成材料的表面上。
再有最好采用以下物质作为抗生素，硫酸庆大霉素、硫酸妥布霉素、硫酸阿米卡星、硫酸奈替米星、硫酸希索米星、盐酸万古霉素、泰古霉素、雷冒拉宁、盐酸克林霉素、盐酸洁霉素、甲硝唑、替硝唑、棕榈酸庆大霉素、肉豆蔻酸庆大霉素、月桂酸庆大霉素、棕榈酸妥布霉素、肉豆蔻酸妥布霉素、棕榈酸阿米卡星、肉豆蔻酸阿米卡星、月桂酸阿米卡星、莱恩利得(Linezolid)、硬脂酸洗必泰、棕榈酸洗必泰、月桂酸洗必泰、灰黄霉素、制霉素、富康唑(Fuconazol)、莫克唑(Moxifloxazol)、环丙沙星、夫西地酸、利福平、利福霉素、磷霉素、环丝氨酸、聚盐酸己双胍及三氯生(Trichlosan)。所列举的抗生素月桂酸盐、肉豆蔻酸盐及棕榈酸盐都是相应的抗生素的脂肪酸盐，而不是它们的脂肪酸酯。抗生素也可简单理解为如氯己定、聚盐酸己双胍、三氯生的抗菌或防腐剂。按照本发明，同样在抗生素的涂层的抗生素中加入生长因子，如BMP2和BMP7及激素(如降钙素)。同样，在本发明的涂层中还可添加双磷酸化合物，如，Zoledronat或伊本膦酸钠。此外，按照本发明，抗生素涂层最好是由10-98％内中至少包含有一种有机饱和、疏水、熔点在45-100℃的低分子量基质材料、0.1-50％重量百分比的低分子量的疏水添加剂及0.1-50％的抗生素/抗生素组成。
本发明还涉及到抗生素涂层的处理方法，具体来讲，将由基质材料、添加剂及抗生素组成的混合物加热到高于基质材料熔点温度，然后，将植入体浸没在生成的悬浮液或均质的熔体中，在这种情况下，植入体要事先调节温度，使其至少要比基质材料的熔化温度高10℃，紧接着再使涂有一层涂料的植入体冷却到室温。
按照本发明，另一种抗生素涂层处理方法是，可以将由基质材料、添加剂及抗生素组成的混合物溶解在一种有机溶剂中，然后，将该溶液喷洒在植入体上，在这种情况下，喷洒前先要将该基材的温度至少要调节到比基质材料熔化温度高10℃，比有机溶剂的沸点至少高10℃，接着，再将涂抹了涂料层的植入体冷却到室温。观察成为本发明处理方法的基础，可以将由脂肪酸、抗生素-脂肪酸盐组成的混合物溶解在有机溶剂中，然后将该溶液喷洒在植入体的表面上，只有首先将植入体加热到至少比有机溶剂沸点高出10℃后，再进行喷涂才能获得极其坚牢的粘附涂层。此外，还有令人吃惊的，即，可以使脂肪酸和抗生素-脂肪酸盐组成的混合物熔合，然后就能与各种不同材料构成极其牢固的复合体。因此，在涂抹涂料前先将待涂抹涂料的植入体温度调节到比基质材料的熔点高10℃，这点很重要。
此外，本发明的抗生素涂层还有一种处理方法是，对于在植入体表面上涂抹的由基质材料、添加剂及抗生素组成的混合物时，可以通过热处理使其达到至少是基质材料熔点的温度，即可获得混合物部分或整体熔化的涂层。举例来说，在伸展的PTFE-假体上涂抹由抗生素-脂肪酸盐/脂肪酸构成材料就能显示出牢固粘接性涂料层的优点。
再有，本发明中抗生素涂层最后一种处理方法是，能使由基质材料、添加剂及抗生素组成的混合物构成一种坚牢致密的物质，并且，使该物质在植入体表面上磨擦，涂层将沉积在植入体表面上，在这种情况下，再将涂抹了涂层的植入体加热到至少达到基质材料熔点温度。比如说，可以将那些由基质材料、添加剂及抗生素/抗生素组成的混合物所构成一种坚牢致密的物质用于与传统止销相类似的零件上。还可以将该物质涂抹在待镀膜层的表面上，这样的涂层可以通过在基质材料的熔化点以上的温度条件下加热使其部分熔化，然后，就可获得一光滑而又均匀的表面，从而改善涂层与植入体表面结合状态。
具体实施方式
以下将通过实例对本发明作进一步的具体阐述，但本发明内容并不局限于此。
实施例1
将74.60克三棕榈酸甘油酯[一种由甘油三(十六酸)酯和三硬脂酸甘油酯组成的混合物](Fluka)、0.10克棕榈酸(Fluka)和25.30克硫酸庆大霉素(AK640)放在一起仔细研磨。然后将该混合物放在80℃下搅拌并加热使其熔化，使它们变成一种乳白色、流动的悬浮液。然后，将加热到100℃的、经喷砂处理过的钛圆片(TIAI6V4，d＝20mm)浸入该悬浮液中。3秒钟后，取出钛片，待其冷却到室温后，就会在其表面上形成一层透明的蜡状涂层。该涂层质量为32.5毫克(庆大霉素底层重5.1毫克)。
实施例2
将5.00克五(个)棕榈酸庆大霉素(庆大霉素的棕榈酸盐)、0.80克棕榈酸及0.10克硬脂酸溶解在100.00克甲醇中，从而生成一种清澈的溶液，然后，将一只用高级合金钢制成的圆柱体(d＝10mm，h＝100mm)加热到90℃，再将事先由棕榈酸庆大霉素/棕榈酸/硬脂酸制备而成的甲醇溶液喷涂在该圆柱体上，待表面上溶剂蒸发后，即形成了一层玻璃状、透明、牢固附着的涂层(m＝88毫克)。
实施例3
将74.60克三棕榈酸甘油酯[一种由甘油三(十六酸)酯和三硬脂酸甘油酯组成的混合物](Fluka)、0.10克棕榈酸(Fluka)和25.30克硫酸庆大霉素(AK640)放在一起仔细研磨。然后将该混合物放在80℃下搅拌，并加热使其溶化，从而使它们变成一种乳白色、流动的悬浮液。冷却到室温以后，获得一蜡状的白色固体，将其磨碎，并通过压缩空气将这些精细的粉末喷涂在与例2中相同的钢制圆柱体上。粉状的颗粒会很松散地粘附在金属表面上。接着，将该金属圆柱体加热到80℃，此时，喷涂在金属表面上的粉末就会熔化，并因此形成一层很均匀的涂层(m＝96毫克)。
实施例4
先将与实施例2中相同的金属圆柱体加热到80℃，然后，将其放在由25.00克五(个)棕榈酸庆大霉素(庆大霉素的棕榈酸盐)、4.00克纵榈酸、0.50克硬脂酸组成的均匀粉状混合物(它们是粒径小于250微米的粉末颗粒)组成的粉末槽中，浸没3秒钟。将圆柱体从槽中取出后，该圆柱体表面上就会沉积一层熔化的粉末，之后再将该圆柱体放在80℃下进行热处理15分钟，最后会在该圆柱体表面上形成一层牢固粘附的涂层(m＝125毫克)。
实施例5
将5.00克五(个)棕榈酸庆大霉素(庆大霉素的棕榈酸盐)、0.80克棕榈酸及0.10克硬脂酸溶解在100.00克甲醇中，从而获得一清澈的溶液。将一只PTFE-假体(长10厘米)浸入该溶液中，蒸发溶剂后，在其表上就会形成一薄涂层(m＝39.5毫克)。然后，将涂抹有上述溶液的PTFE-假体放在80℃干燥箱中干燥10分钟，此时，涂层中部分被熔化，并由此形成一均匀牢固的涂层。
实施例6
将5.00克五(个)棕榈酸庆大霉素(庆大霉素的棕榈酸盐)、0.80克棕榈酸及0.10克硬脂酸溶解在100.00克甲醇中，从而生成一清澈的溶液。将一正方形的PGA毛毡(30×30mm)浸渍在该溶液中，在将其中溶剂蒸发掉以后，就会形成一薄涂层(m＝35.2毫克)。然后将其放在80℃干燥箱中干燥10分钟，取出后，在起表面上就会形成一均匀牢固的涂层。
实施例7
将74.60克三棕榈酸甘油酯[一种由甘油三(十六酸)酯和三硬脂酸甘油酯组成的混合物](Fluka)、0.10克棕榈酸(Fluka)和25.30克硫酸庆大霉素(AK640)放在一起仔细研磨。然后将该混合物放在80℃下搅拌，并加热使其溶化，使它们变成一种乳白色、流动的悬浮液。将该悬浮液倾倒在一圆柱形模具(d＝10mm，h＝1Omm)上，待其冷却到室温以后，就会在其表面上形成一层白色蜡状涂层。在喷砂处理过的钛圆片(d＝15mm)上打磨圆柱体，此时在其表面上就会形成很不均匀的涂层。之后使其部分熔融就能获得一均匀的涂层。该涂层面的质量为15.8毫克(庆大霉素底材含量为2.55毫克)。
Claims (10)
1、植入体用抗生素涂层，其特征在于，该涂层至少是由一种有机饱和、疏水的、熔点在45℃-100℃之间的低分子量基质材料，以及溶解在其中的一种低分子量疏水添加剂组成，并且，
●抗生素悬浮在由基质材料和添加剂组成的混合物中，和/或
●一种能与基质材料和添加剂组成的混合物混合的抗生素溶解在由基质材料和添加剂组成的混合物中。
2、根据权利要求1所述的植入体用抗生素涂层，其特征在于，该涂层在20-45℃温度范围内处于固体凝聚态，并且在压力和剪力下会发生塑性变形。
3、根据权利要求1或2所述的植入体用抗生素涂层，其特征在于，基质材料组分是由包含有以下材料组的物质所构成：
硬脂酸甘油酯、三棕榈酸甘油酯、甘油三(十四酸)酯、山嵛酸甘油酯、硬脂酸、棕榈酸、肉豆蔻酸、山嵛酸、肉豆蔻酸棕榈酸酯、十六酸十六酯、蜡酸蜡酯及甘油三酯，以及不同偶数碳原子的脂肪酸。
4、根据权利要求1至3所述的植入体用抗生素涂层，其特征在于，以上材料中添加有硬脂酸、棕榈酸及肉豆蔻酸作为添加剂。
5、根据权利要求1至4所述的植入体用抗生素涂层，其特征在于，作为抗生素药物被加入其中的是硫酸庆大霉素、硫酸妥布霉素、硫酸阿米卡星、硫酸奈替米星、硫酸西索米星、盐酸万古霉素、泰古霉素、雷冒拉宁、盐酸克林霉素、盐酸洁霉素、甲硝唑、替硝唑、棕榈酸庆大霉素、肉豆蔻酸庆大霉素、月桂酸庆大霉素、棕榈酸妥布霉素、肉豆蔻酸妥布霉素、棕榈酸阿米卡星、肉豆蔻酸阿米卡星、月桂酸阿米卡星、莱恩利得(Linezolid)、硬脂酸洗必泰、棕榈酸洗必泰、月桂酸洗必泰、灰黄霉素、制霉素、富康唑(Fuconazol)、莫克唑(Moxifloxazol)、环丙沙星、夫西地酸、利福平、利福霉素、磷霉素、环丝氨酸、聚盐酸己双胍及三氯生(Trichlosan)。
6、根据权利要求1至5所述的植入体用抗生素涂层，其特征在于，该涂层最好是使用由1.0-98.0％、内中至少包含有一种有机饱和、疏水、熔点在45-100℃之间的低分子量基质材料、0.1-5.0％重量百分比的低分子量疏水添加剂及0.1-5.0％的抗生素/抗菌素所组成。
7、权利要求1至6所述的植入体用抗生素涂层的处理方法，其特征在于，先将以上所述组成物加热到高于基质材料的熔点温度，然后将植入体浸入生成的悬浮液或均质的熔体中，在这种情况下，应先将植入体的温度调节到至少高于基质材料熔点以上10℃，接着再使涂有涂料的植入体冷却到室温。
8、植入体用抗生素涂层的处理方法，其特征在于，先将权利要求1至6中所述的组成物溶解在一有机溶剂中，接着将该溶液喷涂在植入体表面上，在这种情况下，喷涂前先要将植入体温度调节到至少高于基质材料熔点以上10℃及高于有机溶剂沸点以上10℃，然后再使涂抹有以上混合物的植入体冷却到室温。
9、植入体用抗生素涂层的处理方法，将权利要求1至6中所述由基质材料、添加剂及抗生素组成的混合物作为涂料涂抹在植入体的表面上，其特征在于，要先将要涂抹的混合物加热到至少达到基质材料的熔点温度。
10、植入体用抗生素涂层的处理方法，其特征在于，使权利要求1至6中所述的混合物变成固态致密的物质，并将其放在植入体表面上磨擦，通过这样的方法使涂层沉积在植入体上，然后根据具体情况有选择地将涂抹有上述混合物的植入体加热到至少达到基质材料熔点的温度。
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998458A (zh) * | 2017-12-22 | 2018-05-08 | 鼎科医疗技术（苏州）有限公司 | 球囊药物涂层及药物球囊 |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9452001B2 (en) * | 2005-02-22 | 2016-09-27 | Tecres S.P.A. | Disposable device for treatment of infections of human limbs |
| DE102006016598A1 (de) * | 2006-04-06 | 2007-11-15 | Heraeus Kulzer Gmbh | Beschichtete Vaskulärimplantate |
| DE102006033312A1 (de) * | 2006-07-17 | 2008-01-31 | Heraeus Kulzer Gmbh | Dentales Implantatsystemteil mit einer Beschichtung |
| WO2008056323A1 (en) * | 2006-11-10 | 2008-05-15 | Sandvik Intellectual Property Ab | Surgical implant composite materials and kits and methods of manufacture |
| EP2018864A1 (en) | 2007-07-23 | 2009-01-28 | Biomet Deutschland GmbH | Pharmaceutical composition, substrate comprising a pharmaceutical composition, and use of a pharmaceutical composition |
| DE102007039871A1 (de) | 2007-08-21 | 2009-02-26 | Friedrich-Baur-Gmbh | Weichgewebe-Implantat mit antibakterieller Wirkung |
| CN102176882A (zh) | 2008-08-07 | 2011-09-07 | 生物活性外科公司 | 医疗器械和植入物的干细胞捕获和固定涂层 |
| US20100069854A1 (en) * | 2008-09-12 | 2010-03-18 | Onajite Okoh | Elastomeric Devices Containing Chlorhexidine/Fatty Acid Salts Made From Fatty Acids of 12 to 18 Carbons |
| DE102010020940B4 (de) * | 2010-05-19 | 2014-09-25 | Heraeus Medical Gmbh | Antibiotische Beschichtung |
| DE102011016277B4 (de) * | 2011-04-06 | 2013-02-21 | Heraeus Medical Gmbh | Plastisch verformbares, biodegradierbares Hämostyptikum und Verfahren zum Formen eines solchen |
| DE102011122752B3 (de) * | 2011-04-06 | 2013-02-21 | Heraeus Medical Gmbh | Medizinisches Implantat enthaltend ein plastisch verformbares,biodegradierbares Hämostyptikum |
| ES2608695T3 (es) | 2011-06-03 | 2017-04-12 | Waldemar Link Gmbh & Co. Kg | Procedimiento para la obtención de un revestimiento de implante e implante correspondiente |
| US8834772B2 (en) | 2011-12-07 | 2014-09-16 | Biomet Manufacturing, Llc | Antimicrobial methacrylate cements |
| US20130288951A1 (en) * | 2012-04-27 | 2013-10-31 | Biomet Manufacturing Corp. | Compositions and methods for coating implant surfaces to inhibit surgical infections |
| EP2841117B1 (en) * | 2012-04-27 | 2019-11-27 | Biomet Manufacturing, LLC | Compositions and methods for coating implant surfaces to inhibit surgical infections |
| US9775853B2 (en) | 2013-03-15 | 2017-10-03 | Biomet Manufacturing, Llc. | Hemostatic compositions and methods |
| WO2015161065A1 (en) * | 2014-04-16 | 2015-10-22 | Biomet Manufacturing, Llc | Methods for coating implant surfaces to treat surgical infections |
| DE102015213855A1 (de) * | 2015-07-22 | 2017-01-26 | Biomet Deutschland Gmbh | Implantat mit einer bioaktiven Beschichtung und Verfahren zur Herstellung desselben |
| CN112966411B (zh) * | 2021-02-07 | 2022-05-24 | 华南理工大学 | 一种基于体代表单元应力的医疗植入件及制备方法与应用 |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL137354C (zh) | 1962-03-15 | |||
| GB1090421A (en) * | 1963-12-13 | 1967-11-08 | Aerosan Ltd | Improvements in surgical dressings |
| US3277003A (en) | 1964-02-17 | 1966-10-04 | Phillips Petroleum Co | Lubricating oils containing amine oxides |
| US3839297A (en) | 1971-11-22 | 1974-10-01 | Ethicon Inc | Use of stannous octoate catalyst in the manufacture of l(-)lactide-glycolide copolymer sutures |
| US4532929A (en) | 1984-07-23 | 1985-08-06 | Ethicon, Inc. | Dry coating of surgical filaments |
| US4857602A (en) | 1986-09-05 | 1989-08-15 | American Cyanamid Company | Bioabsorbable surgical suture coating |
| US4711241A (en) | 1986-09-05 | 1987-12-08 | American Cyanamid Company | Surgical filament coating |
| US5032638A (en) | 1986-09-05 | 1991-07-16 | American Cyanamid Company | Bioabsorbable coating for a surgical device |
| JPS6485660A (en) | 1987-02-19 | 1989-03-30 | Nippon Medical Supply | Suture coated with sugar fatty acid ester |
| US5123912A (en) | 1987-08-26 | 1992-06-23 | United States Surgical Corporation | Absorbable coating composition, coated sutures and method of preparation |
| US5019096A (en) | 1988-02-11 | 1991-05-28 | Trustees Of Columbia University In The City Of New York | Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same |
| EP0573094B1 (en) | 1988-12-29 | 2002-09-18 | Genzyme Corporation | Absorbable blend for controlled release |
| US5641503A (en) * | 1989-04-27 | 1997-06-24 | Mcneil-Ppc, Inc. | Additives to tampons |
| US5100433A (en) | 1990-11-08 | 1992-03-31 | Ethicon, Inc. | Suture coated with a copolymer coating composition |
| US5312437A (en) | 1992-06-12 | 1994-05-17 | United States Surgical Corporation | Absorbable coating composition and suture coated therewith |
| DE59408725D1 (de) | 1993-10-07 | 1999-10-14 | Axel Stemberger | Beschichtung für Biomaterial |
| DE4404018A1 (de) | 1994-02-09 | 1995-08-10 | Merck Patent Gmbh | Protrahiert freisetzende Darreichungsformen enthaltend Clindamycin-Palmitat |
| US6251137B1 (en) * | 1994-03-23 | 2001-06-26 | Mcghan Medical Corporation | Synthetic triglyceride filler material for surgically implanted prostheses |
| CA2222567C (en) | 1995-06-07 | 2002-01-29 | Southern Biosystems, Inc. | High viscosity liquid controlled biologically active delivery system |
| US5968542A (en) | 1995-06-07 | 1999-10-19 | Southern Biosystems, Inc. | High viscosity liquid controlled delivery system as a device |
| US5736152A (en) | 1995-10-27 | 1998-04-07 | Atrix Laboratories, Inc. | Non-polymeric sustained release delivery system |
| US6423345B2 (en) | 1998-04-30 | 2002-07-23 | Acusphere, Inc. | Matrices formed of polymer and hydrophobic compounds for use in drug delivery |
| DE19831141C2 (de) | 1998-07-11 | 2003-02-27 | Dmc2 Degussa Metals Catalysts | Edelmetallpräparat und dessen Verwendung zur Herstellung von Edelmetalldekoren durch Direkt- und Indirektdruck |
| ATE315386T1 (de) | 1998-08-06 | 2006-02-15 | Joerg Dr Dr Schierholz | Medizinprodukte mit retardierter pharmakologischer aktivität und verfahren zu ihrer herstellung |
| US6632457B1 (en) | 1998-08-14 | 2003-10-14 | Incept Llc | Composite hydrogel drug delivery systems |
| ES2187195T3 (es) | 1998-09-11 | 2003-05-16 | Gerhard Dr Schmidmaier | Implantes biologicamente activos. |
| DE10114364A1 (de) * | 2001-03-22 | 2002-10-02 | Heraeus Kulzer Gmbh & Co Kg | Verfahren zur Herstellung von antibiotischen Kompositen |
| DE10114245A1 (de) * | 2001-03-22 | 2002-10-02 | Heraeus Kulzer Gmbh & Co Kg | Herstellung und Verwendung einer Antibiotikum-/Antibiotika-Zubereitung |
| DE10114244A1 (de) * | 2001-03-22 | 2002-10-02 | Heraeus Kulzer Gmbh & Co Kg | Antibiotikum-/Antibiotika-Zubereitung mit retardierender Wirkstofffreisetzung |
| CA2466432A1 (en) * | 2001-11-08 | 2003-05-15 | Atrium Medical Corporation | Intraluminal device with a coating containing a therapeutic agent |
| DE10254215B4 (de) * | 2002-11-20 | 2014-10-09 | Johnson & Johnson Medical Gmbh | Chirurgisches Implantat |
| US6852122B2 (en) | 2003-01-23 | 2005-02-08 | Cordis Corporation | Coated endovascular AAA device |
| US20040167572A1 (en) | 2003-02-20 | 2004-08-26 | Roth Noah M. | Coated medical devices |
-
2005
- 2005-01-19 DE DE102005002703A patent/DE102005002703C5/de not_active Expired - Fee Related
- 2005-12-07 CA CA2529375A patent/CA2529375C/en not_active Expired - Fee Related
- 2005-12-13 CN CNB2005101316568A patent/CN100460022C/zh not_active Expired - Fee Related
- 2005-12-14 AU AU2005256092A patent/AU2005256092B2/en not_active Ceased
- 2005-12-24 EP EP05028458A patent/EP1683531B1/de not_active Not-in-force
- 2005-12-24 ES ES05028458T patent/ES2397955T3/es active Active
- 2005-12-24 PT PT50284587T patent/PT1683531E/pt unknown
- 2005-12-24 DE DE202005021979U patent/DE202005021979U1/de not_active Expired - Lifetime
-
2006
- 2006-01-16 BR BRPI0600050-9A patent/BRPI0600050A/pt active Search and Examination
- 2006-01-16 ZA ZA2006/00403A patent/ZA200600403B/en unknown
- 2006-01-18 JP JP2006009918A patent/JP4575303B2/ja not_active Expired - Fee Related
- 2006-01-19 US US11/335,323 patent/US8092824B2/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107998458A (zh) * | 2017-12-22 | 2018-05-08 | 鼎科医疗技术（苏州）有限公司 | 球囊药物涂层及药物球囊 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2005256092A1 (en) | 2006-08-03 |
| US20060171986A1 (en) | 2006-08-03 |
| ZA200600403B (en) | 2006-12-27 |
| BRPI0600050A (pt) | 2006-09-19 |
| PT1683531E (pt) | 2013-01-28 |
| US8092824B2 (en) | 2012-01-10 |
| DE102005002703C5 (de) | 2013-07-04 |
| CA2529375A1 (en) | 2006-07-19 |
| DE102005002703B4 (de) | 2009-06-04 |
| JP2006198408A (ja) | 2006-08-03 |
| EP1683531A1 (de) | 2006-07-26 |
| CA2529375C (en) | 2010-09-14 |
| DE102005002703A1 (de) | 2006-07-27 |
| CN100460022C (zh) | 2009-02-11 |
| DE202005021979U1 (de) | 2012-01-10 |
| ES2397955T3 (es) | 2013-03-12 |
| AU2005256092B2 (en) | 2008-01-10 |
| EP1683531B1 (de) | 2012-12-12 |
| JP4575303B2 (ja) | 2010-11-04 |
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