CN1026462C - 改进的抗微生物涂层植入物 - Google Patents

改进的抗微生物涂层植入物 Download PDF

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CN1026462C
CN1026462C CN88106341A CN88106341A CN1026462C CN 1026462 C CN1026462 C CN 1026462C CN 88106341 A CN88106341 A CN 88106341A CN 88106341 A CN88106341 A CN 88106341A CN 1026462 C CN1026462 C CN 1026462C
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何塞·L·迪莱昂
托马斯·哈里·费格森
小丹尼尔·史图尔特·斯金纳
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Abstract

在植入物表面施涂抗微生物剂的均匀粘附涂层，包括在植入物表面涂以硅油薄膜，然后使带有硅油膜的表面与抗微生物剂接触，成为薄膜粘附形式。形成具耐久性的抗微生物剂涂层。涂层后的植入物可以采用机械化设备进行包装，而不会给该抗微生物剂带来显著损耗。

Description

本发明涉及改进的植入物。更具体讲，本发明涉及具改进抗感染性能的药物释放植入物。按本发明所施加的涂层，在植入物的机械包装过程中能更好地保留于植入物的表面，以发挥预防感染效能，否则在植入之后会发生感染。
在美国专利4，191，741号中描述了用受控释放的植入物对反刍动物给以雌二醇药物。在这些植入物的植入过程中，卫生条件一般都不够好，将引起感染而导致植入物损失。在英国专利申请2，136，688号中描述了在植入物表面上使用抗生素或杀菌剂层或涂层以减少感染并改进植入物保留效果。此种抗生素涂层便于在非无菌条件下于胃肠外施用植入物;对于植入针、动物体上的植入部位以及植入器械的清洗要求都减至最低，甚至可免去。
已知可将抗微生物剂于植入物表面包覆或涂成一层以防止在植入的部位发生感染。但于实行此种技术时遭遇到某些困难。业已发现，表面施涂的抗微生物剂易于因对于植入物的机械操作，例如当自动式包装操作时，而从植入物表面错动位置。失掉这种抗微生物剂涂层就使抗感染能力大大下降。曾经采用的对策是耗费大量劳力的再涂层步骤以及对经抗微生物剂涂层的植入物采用手工方式包装，用以保证在植入手术时还具有有效的抗微生物涂层。即使在植入物制造和（或）包装时十分小心地操作，也难于控制涂层不均匀性。
使植入物上的抗微生物剂涂层有更高均匀性和对植入物有更强粘附力，即可实现植入物的制造与包装达到更高效率，同时使植入部位具更高抗感染能力。在本技术领域中所需要的是改进的植入物涂层方法，用以在植入物表面得到更均匀和更耐久的抗微生物剂涂层，要在制造、搬运和贮存中具有良好稳定性，要能在植入时直接提供抗微生物剂，并且对植入物的功能没有干扰。
按照本发明，应用一种流动性聚硅氧烷（下称硅油）来促进抗微生物剂在植入物上的均匀粘附。本发明对于抗感染植入物的生产和使用都带来许多优越性，能使植入物的制造和加工操作达到更高效率。所粘附的抗微生剂涂层不容易从植入物表面震摇脱落，使得植入物能经受住自动式包装操作的更苛刻条件，可免去再涂粉或再涂层步骤。采用本发明的方法后，可使抗微生物剂施有量更高并且更为稳定一致，从而使得制造过程中所需品质控制和（或）分析的时间较少。其他优越性包括改进植入物的外观和涂层的稳定一致性。并且抗微生物剂涂层的施涂不受原料正常变化的影响。
本发明的依据是发现可将一种硅油旋涂于植入物的外表面，用以改进其后所施涂的抗微生物主行粘附性。该种硅油与植入物表面有很高亲和性，并且分散于植入物表面形成一薄层。这层膜就在其后施涂抗微生物剂时起到基质状载体的作用，所用抗微生物剂一般是采取薄膜粘附粉末或涂粉形式。抗微生物剂在接触到硅油层时被部分润湿，于是留在植入物的表面。
本发明的优选实施方案是将一种粘附抗微生物剂涂层施涂于植入物，该植入物包含在一种硅氧烷聚合物基质中的一种组成代谢剂，其中该基质的作用是供持续地释放该组成代谢剂。该硅油对于植入物的安全和效能没有不利作用。按本发明施加了涂层之后，组成代谢剂从植入物向外扩散的速率基本不变。
本发明经改进的植入物涂层包括与植入物表面接触的一层硅油，以及与该硅油接触的抗微生物剂。在本发明中对植入物本身特性的要求并不严格，但这种经改进的涂层特别适用于具有生物适合性的硅氧烷聚合物所形成表面的植入物。可以设定该植入物为多种不同结构中的任一种，并可用于修复目的，或作为持续释放生物活性化合物的贮存体或基质。它们可以完全由硅氧烷聚合物制成，例如采用挤型、模制和/或机加工制成，或者可以由本技术领域准用的具有生物适合性植入物材料或复合材料制成植入物芯，再施加硅氧烷聚合物覆层而制成。
适用于植入物结构的代表性硅氧烷聚合物有聚二苯基硅氧烷、聚二甲基硅氧烷（dimethicone）、聚苯基甲基硅氧烷、聚三氟丙基甲基硅氧烷、与聚环氧乙烷共聚的聚二甲基硅氧烷、聚二甲基硅氧烷与聚甲基丙烯酸甲酯的共聚物，以及它们的混合物。
按1980年3月4日颁发的美国专利4，191，741号所披露而制成的植入物可为按本发明进行涂层的优选植入物，其披露的内容作为本发明的参考资料。该专利中所述的植入物是准备用于对反刍动物进行组成代谢剂的受控释放给药。可由这种植入物释放的组成代谢剂实例有雌二醇、组成代谢雌二醇衍生物，包括二丙酸雌二醇酯、苯甲酸雌二醇酯、戊酸雌二醇酯等等、乙酸trenbolone酯以及某些间苯二酚内酯，包括玉米赤霉醇和玉米赤霉烯酮。
按本发明经改进的抗微生物剂涂层施涂于植入物表面的方法是首先施涂硅油，形成一层与植入物表面接触的薄膜，然后将带有该薄膜的植入物表面与抗微生物剂接触。该抗微生物剂最好是呈薄膜粘附粉末或涂粉形式。该层硅油薄膜对于植入物表面和抗微生物剂都有很高亲和性，并作为一种流动性基质把抗微生物剂润湿并有效地粘附于植入物表面。该种硅油能为本发明的抗微生物剂涂层提供均匀粘附基础的效能，是来自于对植入物表面和其本身抗微生物剂的有极高亲和性。
已发现二甲基硅油和硫化二甲基硅油体系特别适用于本发明，用于形成涂层。此种流动性物质与制造该植入物优选使用的硅氧烷聚合物是化学等效物质。因此该种流动性物质既不会干扰或影响植入物的安全性或效能，也不会影响该抗微生物剂在植入部位的发挥效用。
概言之，二甲基硅油为低挥发性液体，所具粘度使之能于室温在植入物表面形成薄的硅油涂层。在数种市售的硅油中，优选的是DowCorning
Figure 88106341X_IMG1
公司所售名为360Medical Fluid的高稠度医药级流动性产品。Dow Corning 360Medical Fluid可供的粘度范围在（77°F测定）20至12500厘沲。优选的硅油粘度范围为约200-500厘沲。一种粘度约350厘沲的硅油已得到极优结果。具有如此高粘度的硅油于室温的挥发性很低，并很容易遍铺于植入物表面，形成与植入物表面接触的很薄液膜。
可采用本技术领域公认的涂布技术，例如浸涂或喷涂将植入物涂以二甲基硅油。使用一种涂布盘，在一次中涂布若干个相同的植入物是很方便的。硅油在植入物表面的涂量为每cm2植入物表面涂上约0.1-0.6mg。优选的涂布量取决于所涂液体的粘度和植入物表面的特性和状况。。当硅油的粘度为350厘沲左右时，植入物表面的涂布量为每cm2约0.2-0.5mg。在使用涂布盘的情况下，可将硅油加到一批植入物上，例如一批尺寸一致的圆柱形植入物上，并且能很快在植入物表面铺展并覆盖一层硅油薄膜。
然后将带有硅油薄膜的植入物与同硅油薄膜有亲和性的抗微生物剂接触。该抗微生物剂较好是细粉或粉末状，当与带有硅油膜的植入物表面接触时，就被硅油膜部分地润湿，从而有效地粘结到植入物表面。
为了给本发明规定范围的目的，术语抗微生物剂应包括抗生素、抗微生物剂、抗菌剂、杀菌剂等等。该种抗微生物剂涂层可以包括各种抗微生物剂的组合物。本发明可用的典型抗生素包括：氨基糖甙类，例如庆大霉素、卡那霉素、新霉素、巴龙霉素、链霉素或妥布霉素;桥环类抗菌素，如利福霉素或利福平;头孢菌素，如先锋菌素Ⅳ、先锋霉素Ⅱ、先锋霉素Ⅰ、defazolin、头孢匹林、头孢雷定或先锋霉素Ⅲ、氯霉素;大环内酯族，如红霉素、太乐菌素、竹桃霉素或螺旋霉素;青霉素类，例如青霉素G和V、青霉素B、甲氧苯青霉素、苯唑青霉素、邻氯青霉素、双氯青霉素、氟氯青霉素、乙氧萘青霉素、氨苄青霉素、羟氨苄青霉素或羧苄青霉素;磺胺类;四环素类，如四环素、土霉素、金霉素、甲烯土霉素、去甲金霉素、吡甲四环素、强力霉素或二甲胺四环素;甲氧苄氨嘧啶-磺胺甲基异噁唑;多肽，例如杆菌肽、多粘菌素、短杆菌素或万古霉素;还有其他抗生素，例如洁霉素、氯洁霉素或放线壮观素。优选的抗生素是土霉素盐酸盐（OTC）。
本发明中可用的典型杀菌剂包括苯酚;甲酚;间苯二酚;取代的苯酚;醛类，苯甲酸;水杨酸;碘;各种碘递体，例如聚乙烯吡咯酮碘;各种氯递体，例如次氯酸盐;过氧化物，例如过氧化氢和过氧化锌;重金属及其盐，例如红汞、硝酸银、硫酸 锌;表面活性剂，如新洁尔灭，呋喃衍生物，例如呋喃西林，硫及硫代硫酸盐;水杨酰苯胺，还有二苯脲。优选的杀菌剂包括聚乙烯吡咯酮碘、碘、硝酸银以及呋喃衍生物，例如呋喃西林。
本发明的涂层中抗生素或杀菌剂用量取决于所用抗生素或杀菌剂的特性，并在一定程度上取决于施涂的方法。例如，抗生素用量范围约0.1-2.1mg/cm2，较好为约0.2-0.8mg/cm2。杀菌剂的典型用量，以聚乙烯吡咯酮碘为例，为约0.5-5.2mg/cm2，以呋喃西林为例，为约2.0-8.3微克/cm2。聚乙烯吡咯酮碘和呋喃西林的优选用量分别为约0.5-1.0mg/cm2和约2.1-4.1微克/cm2。土霉素盐酸盐的有效用量范围为约0.1-2.1mg/cm2，较好为约0.1-1.0mg/cm2，最好为0.14-0.5mg/cm2。
该抗生素或杀菌剂较好为颗粒或粉末形式，粒径范围约325筛目（45微米）至约60筛目（250微米），更好为约325筛目（45微米）至约200筛目（75微米）。可以将市售的抗生素粉末磨碎，使之达到所要求的粒度分布。
实例1
使用市售商标为COMPUDOSE
Figure 88106341X_IMG3
200的植入物以评价二甲基硅油为基础的土霉素盐酸盐（OTC）涂层的施用效果。COMPUDOSE
Figure 88106341X_IMG4
200植入物的长度为3cm，直径4.76mm。这个直径中包括一个惰性的内芯和含有约24mg活性成分一雌二醇的250微米涂层。其表面面积为4.84cm2，该植入物持续释放雌二醇约200天。此种植入物为EliLilly公司一个分部-Elanco Products Company所出售。
评价结果汇总于表1。全部植入物均于一个涂层盘中用土霉素盐酸盐（OTC）涂粉，涂粉量为每个植入物2.5mg土霉素盐酸盐。预涂粉处理有如下不同：试验1和2未用预处理;试验3用1%烘制二氧化硅（Aerosil
Figure 88106341X_IMG5
）预处理，试验4-6用Dow Corning
Figure 88106341X_IMG6
360Medical Fluid（粘度＝350厘，77°F）预处理。（表1见文后）
以上结果明确地显示出，在用抗生素涂粉之前将植入物用成膜硅油预处理具有优越性。它不仅能提高抗生素在植入物表面的总保留率，同时也提高一批经涂层植入物的涂层均匀性。此外，用肉眼检查看到具有均匀涂层;另外还表明，当在自动包装设备上应用振动杯状植入物排齐并分装到每一个包装内腔的操作过程中，仍能保留它们的均匀涂层。
实例2
按本发明的方法将三批COMPUDOSE
Figure 88106341X_IMG7
200的植入物涂层（每一批约26000件植入物）。处理的方法包括将植入物置于涂布盘或涂粉盘中，加入50g二甲基硅油（dimethicone）（每个植入物2mg二甲基硅油），然后加入65g土霉素盐酸盐，然后翻滚混合，直至植入物的外表已经均匀涂层为止。从这三批的每一批中随机选出植入物进行包装并送去评价。所得结果汇总于表2中。
表2
土霉素盐酸盐（OTC）在COMPUDOSE
Figure 88106341X_IMG8
200植入物上的保留情况
mg OTC/植入物1
批号1    1.64
批号2    1.61
批号3    1.52
10个植入物的平均值
表1
土霉素盐酸盐（OTC）保留结果
试验    预涂粉处理    OTC涂层，    平均值
肉眼观察 mgOTC/植入物 SD2
1 无 OTC涂层 -1-1
不平均
2    无    OTC涂层    0.8    0.19
不平均
3    1%烘制二氧    OTC涂层    0.8    0.41
化硅    不平均
4    2mg/植入物    OTC涂层    1.6    0.15
喷涂硅油    极平均
5    2mg/植入物    OTC涂层    2.7    0.19
喷涂硅油    极平均
6    2mg/植入物    OTC涂层    1.8    0.31
喷涂硅油    极平均
（加入到空盘）
随后加入植入物
1-表示无数值报告
2-与平均值的标准偏差

Claims (2)

1、制备受控释放组成代谢剂的植入物的一种方法，包括用一种抗微生物剂涂层物去涂布含有组成代谢剂的硅氧烷聚合物基质，其中该涂层物包括一种硅油和与该硅油相接触的抗微生物剂。
2、按权利要求1的一种方法，包括在该硅氧烷聚合物基质表面施涂一种硅油以形成与该表面接触的硅油膜，然后使载有该种膜的表面与一种抗微生物剂接触，成为粘附于液膜上的粉末形式。
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IL87568A (en) 1992-08-18
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CN1031650A (zh) 1989-03-15
ES2035926T3 (es) 1995-04-01
DE3871039D1 (de) 1992-06-17
EP0306212A3 (en) 1990-03-07
HUT48456A (en) 1989-06-28
IL87568A0 (en) 1989-01-31
JPH01113058A (ja) 1989-05-01
PH25569A (en) 1991-08-08
MX168615B (es) 1993-06-01
DK480988A (da) 1989-03-01
DOP1988004632A (es) 2000-01-05
EG18678A (en) 1993-10-30
IE61171B1 (en) 1994-10-05
KR890003358A (ko) 1989-04-14
GR3005376T3 (zh) 1993-05-24
ZA886334B (en) 1990-04-25
ATE75935T1 (de) 1992-05-15
PT88361B (pt) 1995-06-30
NZ225935A (en) 1989-12-21
EP0306212B1 (en) 1992-05-13
PT88361A (pt) 1989-06-30
JP2724166B2 (ja) 1998-03-09
KR960009412B1 (en) 1996-07-19
US4846844A (en) 1989-07-11
IE882636L (en) 1989-02-28
US4952419A (en) 1990-08-28
AU603481B2 (en) 1990-11-15
CY1841A (en) 1996-03-08
AU2164188A (en) 1989-05-25
CA1328073C (en) 1994-03-29
SG28371G (en) 1995-09-01
HU208786B (en) 1994-01-28

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