CN104135954B - 膜及制造方法 - Google Patents

膜及制造方法 Download PDF

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Publication number
CN104135954B
CN104135954B CN201280070872.4A CN201280070872A CN104135954B CN 104135954 B CN104135954 B CN 104135954B CN 201280070872 A CN201280070872 A CN 201280070872A CN 104135954 B CN104135954 B CN 104135954B
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film
polymer
polymer solution
mould
medical device
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CN104135954A (zh
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D.阿姆布鲁斯特
J.德耶
J.乔姆恩
S.科尔
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Synthes GmbH
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Synthes GmbH
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Abstract

本发明公开了一种柔性体，所述柔性体包括具有第一表面和相对的第二表面的聚合物膜。所述聚合物膜具有从所述第一表面延伸到所述第二表面的多个孔以及从所述第一表面突起的多个升高唇缘，使得所述多个孔中的每一个被所述多个升高唇缘中的一个围绕。本发明公开了一种制备聚合物膜的方法，所述方法包括将聚合物溶液置于具有从模具的底部延伸的多个突起的单面模具中，其中所述聚合物溶液的特征在于抑制所述聚合物无外力流遍所述模具的粘度；促动所述聚合物溶液围绕所述多个突起中的每一个；以及固化所述聚合物溶液。

Description

膜及制造方法
相关申请的交叉引用
本申请要求于2011年12月28日提交的名称为“Films and Methods ofManufacture”的美国临时专利申请No.61/580,679的权益，该临时专利申请据此以引用的方式全文并入。
背景技术
本发明整体涉及膜(例如聚合物膜)及制造方法，并在至少一些实施例中涉及用于医疗用途的穿孔膜及制造方法。
发明内容
在一个实施例中，存在一种柔性体，该柔性体包含具有第一表面和相对的第二表面的膜(例如聚合物膜)，该膜具有从第一表面延伸到第二表面的多个孔以及从第一表面突起的多个升高唇缘，使得多个孔中的每一个被多个升高唇缘中的一个围绕。在一个优选实施例中，膜由聚合材料(即聚合物膜)构成。在一个实施例中，聚合物膜包含生物吸收性聚合物。在一个实施例中，生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、乙交酯、内酯、内酰胺、三亚甲基碳酸酯、环状碳酸酯、环醚、对二氧环己酮、β-羟基丁酸、β-羟基丙酸、β-羟基戊酸，以及它们的组合。在一个实施例中，生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、ε-己内酯、三亚甲基碳酸酯、对二氧环己酮，以及它们的组合。在一个实施例中，生物吸收性聚合物是乙交酯、三亚甲基碳酸酯、丙交酯和己内酯的共聚物。
在一个实施例中，第一表面包括在所述多个升高的突起唇缘之间延伸的邻接平面部分。在一个实施例中，所述多个升高的突起唇缘各自具有比邻接平面部分高约0.1mm至约1.0mm的外边缘。在一个实施例中，聚合物膜包含多种离散的洗脱药物组分，并且其中聚合物膜被配置成在植入柔性体后在不同时间段洗脱所述多种离散的药物组分。在另一个实施例中，柔性体包含被配置成将聚合物膜形成鞘管的至少一个接缝。在一个实施例中，聚合物膜在第一平面方向上具有第一拉伸强度并在垂直于第一平面方向的第二平面方向上具有第二拉伸强度，其中第一拉伸强度基本上等于第二拉伸强度。在一个实施例中，聚合物膜具有不大于0.06mm的标称厚度。在一个实施例中，第一表面具有不同于第二表面的第二触感的第一触感。
在另一个实施例中，存在一种制备聚合物膜的方法，包括：将聚合物溶液置于具有从模具底部延伸的多个突起的单面模具中，其中该聚合物溶液的特征在于抑制聚合物无外力流遍模具的粘度；促动聚合物溶液围绕所述多个突起中的每一个；以及固化聚合物溶液。在一个实施例中，模具包括延伸高度基本上等于所述多个突起中的每一个的高度的围型体(perimeter form)。在一个实施例中，促动包括拉引促动装置(诸如刀片、条、橡皮扫帚或辊)横跨围型体和所述多个突起，以迫使聚合物溶液围绕所述多个突起流动并流遍模具，使得聚合物溶液具有基本上均匀的厚度。在一个实施例中，突起中的每一个的外表面在拉引后基本上不含聚合物溶液。在一个实施例中，放置步骤包括将聚合物溶液沉积在模具中，使得聚合物溶液的一部分在围型体和突起的高度以上。
在一个实施例中，固化聚合物溶液包括减小聚合物溶液的厚度。在一个实施例中，固化聚合物溶液包括围绕所述多个突起中的每一个形成固化聚合物的弯月面。在一个实施例中，从模具的底部到所述多个突起中的每一个的顶部的距离小于约0.3mm。在一个实施例中，聚合物溶液包含药物。在一个实施例中，聚合物溶液通过在低于90℃的温度下混合溶剂、聚合物和药物而形成。在一个实施例中，围型体限定总模具面积，并且所述多个突起限定总模具面积的至少约15％的面积。在另一个实施例中，该方法包括将药物洗脱膜从模具剥离。
在一个实施例中，聚合物溶液包括可交联的预聚物溶液。在一个实施例中，固化步骤包括通过向聚合物溶液施加UV辐射、温度改变、聚合催化剂、可溶性交联剂或它们的组合而交联聚合物。在一个实施例中，聚合物溶液包括离散的药物单元。在一个实施例中，聚合物溶液包含第一溶剂和聚合物，并且固化步骤包括将聚合物溶液暴露于第二溶剂，在第二溶剂中，第一溶剂是可溶的并且聚合物和药物是不可溶的，使得将第一溶剂至少基本上从聚合物溶液中移除，并且该聚合物固化以包含药物。
附图说明
上文的概述以及下文的聚合物膜及制造方法的实施例的具体实施方式在结合示例性实施例的附图阅读时将更好地理解。然而应当理解，本发明不限于所示的精确布置方式和工具。
在附图中：
图1A是根据本发明的示例性实施例的膜(在此情况下为聚合物膜)的一部分的放大透视示意图；
图1B是根据本发明的示例性实施例的聚合物膜的孔的60倍放大照片；
图2是由图1B的聚合物膜形成的三个示例性鞘管与相应植入式医疗装置结合的顶视图；
图3A是根据本发明的示例性实施例的模具的一部分的透视照片；
图3B是图3A的模具的顶部平面图；
图3C是沿着图3B中的线C-C截取的图3B的模具的横截面侧视图；
图3D是在图3B中所示的模具的放大角落截面图；
图3E是沿着线B-B截取的图3D中所示的模具的放大截面图；
图3F是图3A的模具的放大透视照片；
图3G是根据本发明的另一示例性实施例的模具的放大透视照片；
图4A是添加了聚合物的图3A的模具的示意性侧向截面图；
图4B是图4A中所示的模具的示意性侧向截面图，示出了将聚合物拉引横跨模具的拉引装置；
图4C是图4A中所示的模具的示意性侧向截面图，示出了在被拉引横跨模具并固化以形成聚合物膜后的聚合物；
图5是根据本发明的示例性实施例的自动化浇铸设备的透视图；
图6是图5的自动化浇铸设备的透视图，示出了添加到模具的聚合物；
图7是图5的自动化浇铸设备的透视图，示出了拉引聚合物横跨模具的拉引装置；
图8是添加到根据本发明的另一示例性实施例的模具的聚合物的透视图；
图9是图8的模具的透视图，示出了拉引聚合物横跨模具的拉引装置；
图10是图8的模具的透视图，示出了从模具移除的聚合物膜；
图11A是使用以第一构型所示的图1的聚合物膜形成的鞘管的顶部平面图；
图11B是使用以第二构型所示的图1的聚合物膜形成的鞘管的顶部平面图；
图11C是使用以第三构型所示的图1的聚合物膜形成的鞘管的顶部平面图；
图11D是使用以第四构型所示的图1的聚合物膜形成的鞘管的顶部平面图；
图11E是在图11D中的圆圈B内的区域；
图11F是诸如图11A-11D所示的那些的鞘管的接缝的放大视图；
图12是根据本发明的示例性实施例的聚合物膜的屈服应力图；
图13是根据本发明的示例性实施例的聚合物膜的屈服应变图；
图14是曲线图，示出了当将根据本发明的示例性实施例的套管置于盐水溶液中时药物随着时间的释放速率；
图15是根据本发明的示例性实施例的聚合物膜的体外质量损失图；并且
图16是根据本发明的示例性实施例的聚合物膜的体外分子量损失图。
具体实施方式
在整形外科或创伤手术中，感染是一大挑战。虽然有诸如无菌操作和消毒的预防措施，但是手术部位仍是局部病原体的进入部位使得变成有毒力的并引起感染。
用诸如抗生素的药物涂布植入式装置对于减少感染已是有效的。然而，鉴于植入体和其他医疗装置的大数量、尺寸和形状，对每一装置提供涂层的监管、经济和物流负担是庞大的。若考虑在涂层中使用另外的药物诸如止痛药、抗肿瘤剂和生长促进物质，则该问题会更严重。
本发明的实施例涉及改进的穿孔聚合物膜及其新型浇铸制造方法。在一些实施例中，膜与植入式医疗装置一同使用，但是膜可用于任何应用。
现存的形成穿孔膜的商业方法通常涉及形成固体膜的第一步骤，然后在膜中钻孔或切孔的第二步骤。本文所述的实施例的至少一些中的优点在于：在形成膜的同时，形成膜的孔或穿孔。这在以下情况中可以是有用的：当形成的聚合物膜极薄并且因随后的处理或加工而存在损坏的风险时，或当膜的厚度和/或强度使其难以通过传统方法钻孔或切割而不损坏该膜时。这种方法在以下情况中也可以是有利的：当聚合物溶液包含可受随后的切割或穿孔步骤损坏的药物或其他活性剂时。
本发明的实施例也可用于制备大量的浇铸膜，诸如那些被认为太小而不能通过传统方法(通常为设计用于大量制备的连续方法)经济地制备的膜。本发明的至少一些实施例的额外优点在于：在浇铸片材中形成的穿孔可具有复杂的形状。本发明的至少一些实施例的另一优点在于：膜的至少一侧可被形成为具有不平的表面，其在一些实施例中增加摩擦并给予改善的触感。本发明的这些优点以及其他优点在下文更详细地说明。
详细参考附图，其中相同的附图标记在全文中表示相同的元件，在图1A和1B中示出了根据本发明的示例性实施例的通常标为10的聚合物膜和通常标为18的模具。
参考图1A的实施例，膜10(例如聚合物膜)是具有第一表面10a和相对的第二表面10b的柔性体。
在一个实施例中，膜10可由单个生物相容性材料薄片形成。在一个实施例中，膜10由两个或更多个片材材料构成。在一个优选实施例中，生物相容性材料是生物吸收性的。在与医疗装置12(参见图2)一起使用的实施例中，膜10在一些实施例中当植入体内时将随着时间溶解并被患者吸收，使得仅留下医疗装置12(诸如，如果医疗装置12并非也由生物吸收性材料制成)。医疗装置12在其他实施例中也可由生物吸收性材料制成，在此情况下，医疗装置12和膜10最后将溶解。在一些实施例中，膜10可被配置成以与吸收性医疗装置12不同的速率(例如更快或更慢的速率)吸收。
在一些实施例中，生物吸收性膜10比非吸收性筛网更具优势，筛网例如可变得被致密的纤维组织包裹或嵌入其中，或存在与长期外来物暴露相关的其他问题。在一些实施例中，膜10是仅部分可生物吸收的。
可使用生物吸收性聚合物以便提供具有有限终点的药物(诸如抗生素)的控制释放。抗生素的连续、长期存在通常是不可取的，因为这会形成产生抗生素耐药细菌的条件。在一个实施例中，膜10的完全降解确保药物将在预定的和/或可选的时间完全释放。在一个实施例中，即使在膜10未被完全吸收的情况下，药物释放也可完全释放或基本上完全释放。
膜10的吸收也可影响和/或控制抗生素在连续释放期中的释放。随着膜降解，例如膜的渗透性可增加，并且可释放出更多的药物。在一些实施例中，所用的聚合物对于柔性的结构而言必须具有相对高的拉伸强度，并能通过溶液浇铸而加工。在一个实施例中，膜10由包含以下四种单体中的一种或多种的共聚物构成：乙交酯、丙交酯、己内酯和三亚甲基碳酸酯。乙交酯可包含在内并可具有使膜10的降解加速的效果。丙交酯也可包含在内并可具有增强膜10的机械强度的效果。己内酯和三亚甲基碳酸酯可使用并可具有增加膜10的柔性的效果。
在一个实施例中，生物吸收性聚合物包括PLA、PGA、聚己内酯、聚二氧杂环己酮、TMC以及它们的共聚物中的一者或多者。在一个实施例中，生物吸收性聚合物由乙醇酸、己内酯、乳酸和三亚甲基碳酸酯的共聚物制成。在一个实施例中，生物吸收性聚合物由约60％的乙醇酸、约20％的己内酯、约10％的乳酸以及约10％的三亚甲基碳酸酯的共聚物制成。在一个实施例中，生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、乙交酯、内酯、内酰胺、三亚甲基碳酸酯、环状碳酸酯、环醚、对二氧环己酮、β-羟基丁酸、β-羟基丙酸、β-羟基戊酸，以及它们的组合。在一个实施例中，生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、ε-己内酯、三亚甲基碳酸酯、对二氧环己酮，以及它们的组合。在一个实施例中，生物吸收性聚合物是乙交酯、三亚甲基碳酸酯、丙交酯和己内酯的共聚物。另外或替代地，膜10也可包含天然的生物聚合物，诸如藻酸盐、脱乙酰壳多糖、胶原、明胶、透明质酸盐、玉米蛋白等。
仍参考图1A，膜10可被配置成具有任何优选的尺寸，包括在第一表面10a与第二表面10b之间而排除在图1A和1B中所示的围绕孔14的升高唇缘14a所测得的厚度h3。在一个实施例中，膜10必须足够薄，使得其不干扰在板12与用于固定的螺钉之间的机械互锁(诸如在将膜限制在板与螺钉之间的情况下)。在一些实施例中，厚度h3尽可能最小化。在一个实施例中，选择膜10的厚度，使得膜10的降解不会造成与医疗装置12的连接(诸如板-螺钉构造)的明显松弛。
在一些实施例中，膜10的厚度h3为约0.05mm。在一些实施例中，膜10的厚度h3为约不大于0.05mm。在一些实施例中，膜10的厚度h3小于约0.05mm。在一些实施例中，膜10的厚度h3为约0.06mm。在一些实施例中，膜10的厚度h3为约0.07mm。在一些实施例中，膜10的厚度h3为约0.08mm。在一些实施例中，膜10的厚度h3为约0.09mm。在一些实施例中，膜10的厚度h3为约0.1mm。在一些实施例中，膜10的厚度h3为约0.2mm。在一些实施例中，膜10的厚度h3为约0.3mm。在一些实施例中，膜10的厚度h3为约0.4mm。在一些实施例中，膜10的厚度h3为约0.5mm。
在一个实施例中，膜10的厚度h3在整个膜10中大致均匀。在一些实施例中，膜10朝着沿外周边的一个或多个边缘渐缩。在一些实施例中，膜10的厚度h3在两个或更多个部分中不同，以控制各区域的强度或药物递送。
在一些实施例中，膜10必须具有足够的强度以经受机械力，诸如植入、钻孔和螺钉放置。在一个实施例中，膜10在第一平面方向上具有第一拉伸强度并在垂直于第一平面方向的第二平面方向上具有第二拉伸强度，其中第一拉伸强度基本上等于第二拉伸强度。在一个实施例中，膜10具有如下表1-3所列的强度特性。
表1
表2
表3
膜样品 断裂拉伸应力(标准)(MPa) 模量(自动杨氏)(MPa)
1 15.20147 749.15765
2 21.71590 504.50877
3 19.08817 657.83084
4 18.08469 574.31825
5 18.71550 618.69300
6 21.75346 436.82724
平均值 19.09320 590.22262
标准偏差 2.460 111.150
变异系数 12.885 18.832
在一个实施例中，膜10具有约2％至约4％的屈服拉伸应变(偏置量0.2％)和/或约3％的平均拉伸应变。在一个实施例中，膜10具有约9MPa至约14MPa的屈服拉伸应力(偏置量0.2％)和/或约12.5MPa的平均屈服拉伸应力。在一个实施例中，膜10具有约25MPa至约30MPa的最大负荷下的拉伸应力和/或约27MPa的最大负荷下的平均拉伸应力。在一个实施例中，膜10具有约30％至约215％的断裂拉伸应变(标准)和/或约89％的平均断裂拉伸应变。在一个实施例中，膜10具有约430MPa至约750MPa的自动杨氏模量和/或约590MPa的平均自动杨氏模量。膜10的特征在于以上性质中的一种或多种的组合。
参考图1A、1B、2和11E，在一些实施例中，膜10包括多个穿孔或孔14。在一个实施例中，孔14使流体能穿过或输送通过膜10(例如当植入活体组织附近时)。在一些实施例中，可能重要的是，要使流体能从套管的一侧流向另一侧(内侧至外侧)，以便例如避免在膜10与医疗装置12之间产生“死空间”。另外，相比于无此类穿孔的套管，穿孔14可有利地在药物或生物制剂从聚合物中渗出时将这些物质更均匀地分布到邻近的组织和骨骼。
可将孔14配置成具有任何尺寸和形状。在一个实施例中，孔14由大致圆柱形的侧壁限定。在一些实施例中，孔14具有带有为向内凸表面的区段的侧壁。在一些实施例中，向内凸表面基本上呈抛物线状。孔14的横截面不必是完美的圆形，并在一些实施例中可以是卵形、椭圆形、星形或菱形。在一些实施例中，孔14延伸到一个或多个顶点。在一个实施例中，此类顶点在使用期间促进膜10中的撕裂(例如，其中薄弱区通过孔产生)。在一个实施例中，孔14从内表面10b完全延伸通过片材12至外表面10a(参见图4C)。在一个实施例中，一个或多个孔14仅部分地延伸通过膜10，以控制药物释放或增加膜10的初始强度。
孔14可被配置成使膜10具有任何所需的孔隙度。在一个实施例中，膜10的孔隙度大于约0.01。在一个实施例中，膜10的孔隙度大于约0.02。在一个实施例中，膜10的孔隙度大于约0.03。在一个实施例中，膜10的孔隙度大于约0.04。在一个实施例中，膜10的孔隙度大于约0.05。在一个实施例中，膜10的孔隙度大于约0.06。在一个实施例中，膜10的孔隙度大于约0.07。在一个实施例中，膜10的孔隙度大于约0.08。在一个实施例中，膜10的孔隙度大于约0.09。在一个实施例中，膜10的孔隙度大于约0.10。在一个实施例中，膜10的孔隙度大于约0.11。在一个实施例中，膜10的孔隙度大于约0.12。在一个实施例中，膜10的孔隙度大于约0.13。在一个实施例中，膜10的孔隙度大于约0.15。在一个实施例中，膜10的孔隙度大于约0.15。在一个实施例中，膜10的孔隙度大于约0.16。在一个实施例中，膜10的孔隙度大于约0.17。在一个实施例中，膜10的孔隙度大于约0.18。在一个实施例中，膜10的孔隙度大于约0.19。在一个实施例中，膜10的孔隙度大于约0.20。
参考图11E，在一个实施例中，孔14具有约0.75mm的直径并间隔开约1.75mm。在一个实施例中，孔14排列成规则的阵列(例如，如图11D所示的对齐的行和列)。在一个实施例中，孔14排列成不规则的阵列。
参考图1A、1B和4C，在一些实施例中，每个孔14紧邻从第一表面10a突起的至少一个升高唇缘14a。围绕每个穿孔14的升高唇缘14a的有益效果可包括为每个穿孔14提供强化或索环，从而相对于无升高唇缘14a的类似穿孔膜有效地增加膜10的机械强度。唇缘14a的有益效果可包括在第一表面10a上的纹理化表面。这种纹理可以是触感方面的优点，或当例如第一表面10a与另一表面接触时用于增加(或减小)膜10的第一表面10a摩擦的优点。在一个实施例中，唇缘14a降低膜10粘附至表面(诸如植入物的金属表面)的趋势，从而使得由膜10制成的套管更容易滑到植入物上。在一个实施例中，唇缘14a作为植入物与膜10之间的支座(stand-off)，从而减小膜10与植入物接触的表面积。
在一个实施例中，第一表面10a包括在所述多个升高的突起唇缘14a之间延伸的邻接平面部分。在一个实施例中，唇缘14a基本上呈撞击坑的外表面的形状。在一个实施例中，唇缘14a包括连续凹形表面。在一个实施例中，唇缘14a包括抛物线状凹形表面。在一个实施例中，一个或多个唇缘14a(或在一些实施例中，每个唇缘14a)具有凹形外表面和相对的凸形内表面，其中任一者或两者呈抛物线形状。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.1mm至约1.0mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.1mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.2mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.3mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.4mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.5mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.6mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.7mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.8mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约0.9mm的边缘。在一个实施例中，唇缘14a各自具有在第一表面10a的邻接平面部分上升高约1.0mm的边缘。
在一个实施例中，由于唇缘14a，第一表面10a具有第一触感，该第一触感不同于(例如，可由穿戴手术手套的外科医生所辨别)无唇缘14a的第二表面10b的第二触感。在一个实施例中，在第一表面10a上的一个或多个区域中的孔14各自由升高唇缘14a界定，而在第一表面10a上的一个或多个其他区域中的孔14则无此界定。在一个实施例中，各升高唇缘14a的高度h4(参见图4C)是均匀的。在一个实施例中，至少一个升高唇缘14a具有与至少另一唇缘14a不同的高度h4。在一个实施例中，一个或多个孔14由在第一表面10a和第二表面10b一者或两者上的唇缘14a界定。实施例(诸如图1A所示的实施例)可包括围绕每个唇缘14的单个连续唇缘14a。相对于任一个孔或在各孔之间，连续唇缘在厚度上可为基本上均匀的和/或在高度上可为基本上均匀的。孔14可以在整个或至少一部分聚合物片材上均匀地间隔开。在其他实施例中，聚合物片材的至少一部分的特征在于以至少两种不同的间距构型间隔开的孔。
在一些实施例中，膜10包含用于在体内递送的一种或多种药物或其他物质。此类药物包括但不限于抗微生物剂、抗纤维化剂、麻醉剂和抗炎剂以及其他类药物，包括生物制剂，诸如蛋白、生长抑制剂等。
在一个实施例中，膜10包含抗生素。所选的抗生素可具有抗整形外科植入物相关感染中所发现的大部分细菌的活性。这些细菌主要包括葡萄球菌和革兰氏阴性菌。
在一个实施例中，所选的药物在制造植入物所需的制造过程中必需稳定。在一个实施例中，膜10包含庆大霉素。硫酸庆大霉素在100℃以上是热稳定的，并对在一些实施例中用于制造过程的有机溶剂(包括DMSO)是稳定的。
参考图4A-4C，在一个实施例中，膜10包含多种离散的洗脱药物组分30。在一个实施例中，膜10被配置成在植入后在不同的时间段洗脱所述多种离散的药物组分30。在一个实施例中，庆大霉素在体内的洗脱是一个两阶段的过程，即一旦膜10接触水或体液后所发生的破裂释放，以及受聚合物的降解速率控制的第二阶段。在一些实施例中，希望在最初植入时存在庆大霉素的初始破裂释放以减少创伤部位的细菌污染，然后在之后的数天至数周期间存在较低水平的庆大霉素释放以抑制任何存活细菌的生长。在一个实施例中，膜10被配置成在膜10已被植入而与活体组织接触后约1周洗脱出在膜10内所含的药物的约60％。在一个实施例中，粒度和聚合物降解速率的组合控制药物释放特征，并产生所需的2阶段释放。在一个实施例中，药物经2至3周的时间段释放。在其他实施例中，药物经较短或较长的时间范围释放。
在一个实施例中，在这两个阶段中释放的药物的相对量受粒度控制。在一个实施例中，药物组分30均匀分布在整个膜10内，并且相比于不接触膜10的表面的药物组分30，接触膜10的表面的任何药物组分30更快地溶解。在一个实施例中，在植入时接触膜10的表面的药物组分30的量被配置成在植入时破裂释放。在一个实施例中，药物组分30的尺寸越大，则与表面接触的药物组分30的比例越高，并且破裂释放越大。为此，药物组分30的尺寸在一个实施例中保持为直径在10微米以下，该直径使破裂释放降至总药物含量的约20至35％。在一个实施例中，药物组分30的直径在20微米以下。
在一个实施例中，膜10被配置成从一个或多个独立层(其中一些可不含药物)递送多种药物。在其他实施例中，膜10可包含多种药物组分，每一种药物组分的特征在于从膜10释放的速率不同，使得第一药物与不同于第二药物的第二释放特征的第一释放特征相关。
参考图3A-11F，示出了在根据本发明的示例性实施例的制造膜10的方法中所用的装置。
在一个实施例中，开发了聚合物膜10的制造方法以制备用作药物递送膜的聚合物膜10。在一个实施例中，膜10是溶剂浇铸的。在一些实施例中，溶剂浇铸方法在膜10的制造中是有利的，该膜包含可能受熔体方法(诸如吹胀薄膜挤塑)的热和剪切所破坏的药物组分30。使用冲压机(例如，利用数百或数千个孔或具有复杂几何形状的孔)制备膜也是耗时且昂贵的。在一些实施例中，首先将溶剂和药物30混合以形成良好分布的悬浮液，然后将聚合物加入溶液中。
在一些实施例中，在此所述的方法允许薄膜10的形成和孔14的形成在单一步骤中进行。在一些实施例中，本文所述的方法使膜10能具有数千个孔14，具有对几何形状和放置的精确控制以及对膜厚度的精确控制。
参考图3A-3G，在一些实施例中，膜10使用模具18浇铸。在一个实施例中，模具18包括从模具18的底部18a延伸的多个突起或柱状体20以形成孔14。在一个实施例中，模具18由注射成型聚丙烯构成。模具可由其他材料制成，包括聚合物(参见图3F)、玻璃、金属(参见图3G)或陶瓷。在一个实施例中，模具18由两种或更多种材料构成。例如，模具18可具有由金属与聚合物涂层制成的基底以降低浇铸膜对模具的粘附性和/或以形成柱状体20。模具中的腔体可通过浇铸方法、压缩模制方法、注塑方法、化学蚀刻方法或机加工方法形成。
在一个实施例中，模具18包括约0.25mm的腔体深度。在一个实施例中，从模具18a的底部到所述多个柱状体20中的每一个的顶部的距离等于腔体深度(即周壁22的高度)，反之亦然。在一个实施例中，柱状体20长于膜10的所需厚度。在一个实施例中，柱状体20从模具18a的底部延伸0.3mm。在一个实施例中，柱状体20从模具18a的底部延伸0.2mm。在一个实施例中，柱状体20从模具18a的底部延伸0.25mm。在一个实施例中，柱状体20从模具18a的底部延伸0.3mm。在一个实施例中，柱状体20从模具18a的底部延伸0.35mm。在一个实施例中，柱状体20从模具18a的底部延伸0.4mm。在一个实施例中，柱状体20从模具18a的底部延伸0.45mm。在一个实施例中，柱状体20从模具18a的底部延伸0.5mm。
在一个实施例中，柱状体20被布置成产生上述孔14的所选尺寸、形状、图案和布置。在一个实施例中，围型体或周壁22限定总模具面积，并且所述多个柱状体20所限定的面积基本上等于或对应于膜10的开孔面积。
在一个实施例中，模具18包括槽24，其至少部分地围绕模具18的周壁22延伸。在一个实施例中，槽24围绕模具18的整个周壁22延伸。在一些实施例中，槽24保持任何流动或被促动经过周壁22的过量聚合物。在一个实施例中，模具18包括从模具18的至少一个外边缘横向延伸的延伸部40。在一个实施例中，提供延伸部40以抓持和操纵模具18而不与模具18内的聚合物溶液接触。
在一个实施例中，形成用于添加到模具18的聚合物溶液28。在一个实施例中，将聚合物材料在升高的温度下以4:1的溶剂与聚合物比率溶解在二甲基亚砜(DMSO)中并以13重量％添加药物硫酸庆大霉素。在一个实施例中，聚合物溶液28通过在低于90℃的温度下将药物单元30引入聚合物/溶剂共混物而形成。在一个实施例中，聚合物溶液28包含可交联的预聚物，诸如聚氨酯、聚富马酸酯、聚甲基丙烯酸酯等。
参考图4A、6和8，一旦制备好聚合物溶液28后，即将聚合物溶液28置于单面模具18中。在一些实施例中，聚合物溶液28的粘度和/或柱状体20的密度显著地抑制聚合物28在无外力下流遍模具18。在一个实施例中，在向模具18添加聚合物溶液28后，聚合物溶液28的顶部表面是在模具18的基部18a以上的高度h2，其大于模具腔体和柱状体20的高度h1。
参考图4B、7和9，在向模具18添加聚合物溶液28后，在一个实施例中，使用促动装置26以促动聚合物溶液围绕所述多个柱状物20中的每一个。在一个实施例中，促动装置26包括滑动的刀片、条、橡皮扫帚或辊，或使模具18相对于促动装置26移动横跨围型体22和柱状体20的顶部以迫使聚合物溶液28围绕柱状体20流动并流遍整个模具18，使得聚合物溶液28具有基本上均匀的厚度。在一个实施例中，将促动装置26拉引横跨模具18会使过多的材料从柱状体20的顶部表面移除。在一个实施例中，每个柱状体20的外表面在拉引后基本上不含聚合物溶液28。
参考图4C，一旦使聚合物溶液28拉引横跨或遍布整个模具18，则使聚合物溶液28固化以形成膜10。在一个实施例中，将模具18置于升高的温度下的溶剂干燥炉中以移除溶剂，从而留下薄的浇铸膜。在一个实施例中，聚合物溶液28通过向聚合物溶液28施加UV辐射、温度改变、聚合催化剂、可溶性交联剂或它们的组合以使聚合物交联而固化。在一个实施例中，固化步骤包括将包含聚合物溶液28的模具18暴露于第二溶剂。在一个例如聚合物溶液28包含聚合物、药物和第一溶剂的实施例中，第一溶剂可溶于第二溶剂，但聚合物和药物组分不可溶于第二溶剂。因此，通过将聚合物溶液28暴露于第二溶剂，第一溶剂被从聚合物溶液中移除，从而留下聚合物和药品以固化而形成例如膜。
在一个实施例中，固化聚合物溶液将聚合物溶液的厚度从厚度h1降至厚度h3。在一个实施例中，固化聚合物溶液将在柱状体20近侧的聚合物溶液的厚度从厚度h1降至厚度h4。在一个实施例中，在柱状体20近侧的膜10的厚度h4大于在柱状体20之间的膜10的厚度h1。在一个实施例中，唇缘14a通过聚合物溶液在聚合物溶液28固化成膜10期间在柱状体20中的每一个的周围形成弯月面而形成。在一个实施例中，弯月面或唇缘14a与模具18的高度或深度h1具有大约相同的高度h4。在一个实施例中，唇缘14a的高度h4可以通过小心选择柱状体20的材料和几何形状或通过用例如润滑材料诸如含氟聚合物或硅树脂脱模剂涂布柱状体20来控制。在一个实施例中，唇缘14a的高度h4通过聚合物溶液的浓度控制。
参考图10，一旦聚合物溶液28固化后，则将模具18和膜从炉中取出，使之冷却，并将浇铸的穿孔膜10从模具18剥离。
参考图5-7，膜10的制备方法可包括自动化或部分自动化的浇铸机42。在一个实施例中，自动化的浇铸设备包括具有一个或多个处理器和存储器(例如一个或多个非易失性存储装置)的一台或多台计算机44。在一些实施例中，存储器或存储器的计算机可读存储介质存储处理器的程序、模块和数据结构或其子集以控制和运行本文所公开的各种系统和方法。在一个实施例中，计算机可读存储介质在其上存储有计算机可执行指令，该指令在由处理器执行时执行本文所公开的方法中的一种或多种。
膜10可通过其它方法制造。在一个实施例中，可将聚合物溶液28浇铸到具有背衬吸收层的穿孔膜材料上，然后将穿孔膜从吸收层移除，从而移除浇铸溶液，其中在浇铸片材中存在孔。这种方法与上述方法的一个差异在于：在一些实施例中，不在孔14的周围形成升高唇缘。
在另一个实施例中，多孔膜也可通过冻干或冷冻干燥方法形成。在一个实施例中，将聚合物溶液的薄固体膜浇铸在模具中，然后将模具冷冻至低于溶液的冰点的温度，然后置于真空下以从膜中移除溶剂。在一些实施例中，该方法还将产生远小于上文一些实施例中所述的细孔。
在一个实施例中，用于形成浇铸膜的聚合物材料可以是可交联的预聚物液体，将其浇铸到如所本文述的膜模具中，滚压以填充模具并移除多余的材料，然后在原位通过UV辐射、温度、催化剂或其他方式交联。在一个实施例中，该方法可产生与如上所述的非常相似的最终产品，不同的是浇铸膜的最终厚度将会接近或等同于模具深度，并且在孔14的周围将会存在很少的或不存在弯月面或唇缘14a。
在另一个实施例中，可以通过丝网印刷方法形成薄多孔膜。在一个实施例中，以最终图案进行溶液层的丝网印刷，然后干燥。在一个实施例中，这产生非常薄的层，然而可一层接一层地丝网印刷并干燥多个聚合物层，以构造所需的膜厚度。
在另一个实施例中，可如上述，使用具有由疏水性聚合物(诸如硅树脂)以所需穿孔形状制成的图案的玻璃板进行相似的浇铸方法。在一个实施例中，当将薄的聚合物溶液层浇铸到板上时，在玻璃与图案化聚合物之间的表面张力差使溶液在玻璃表面上浓缩，并从图案化疏水性聚合物表面拉离。在一个实施例中，然后将溶液干燥以形成具有与硅树脂聚合物相同图案的穿孔的固体膜。在一个实施例中，也可利用如上所述的可交联预聚物液体进行此方法。
在另一个实施例中，使用双面模具制备薄的多孔聚合物膜，其中将聚合物溶剂溶液注入模具中，并冷冻以固化溶液。在一个实施例中，然后将模具打开并将一面移除，从而在腔体面中留下冷冻溶液。在一个实施例中，将冷冻溶液侧置于炉中以干燥聚合物溶液并形成膜10。
参考图2和11A-11D，在产生膜10后，将膜10成形并形成所需的形式。在一个实施例中，将膜10成形并形成通常符合医疗装置12的尺寸和形状。在一些实施例中，将膜10成形并形成鞘管或套管32、34、36、38。
参考图11A-11F，套管32、34、36、38包括被配置成将膜10形成鞘管的至少一个接缝16。在一个实施例中，套管32、34、36、38通过围绕外周边将第一膜10附接至第二膜10而形成。在一个实施例中，将膜10折叠并至少部分地固定到其本身。例如，可将膜10成形为圆柱体以接合两个相对的边缘。在一个实施例中，第二表面10b与第一表面10a重叠以形成接缝16。在一个实施例中，第二表面10b与第二表面10b重叠以形成接缝16。在一个实施例中，接缝16通过加热膜10的重叠部分并使之再固化而固定。在一个实施例中，套管32、34、36、38的两个端部仍开放以供医疗装置12的插入。在一个实施例中，一个或多个端部是封闭的。在一个实施例中，聚合物片材在形成套管32、34、36、38之前首先形成所需的尺寸和形状。
除了套管32、34、36、38之外，膜10在一些实施例中还可用于其他医疗应用，诸如疝修复网、粘连屏障、软组织填充、过滤膜、药物递送膜、骨移植物固定(例如，在例如脊柱融合术或在长骨的节段性缺损移植中使骨移植物保持就位)或伤口护理产品，诸如绷带。
实例1：
在一个示例性实施例中，植入物通过植入绵羊体内而进行测试。植入物为金属板，其中将管状、薄(0.05-0.08mm)而透明的聚合物套管在即将通过外科手术插入并附接到骨骼前小心地滑动到金属板上。套管紧密配合，在整个长度上完全覆盖金属板，然而套管在板的两个端部是开放的。套管由合成的共聚酯(乙交酯、己内酯、三亚甲基碳酸酯、丙交酯)构成，1.5mm直径的穿孔在整个套管中等距间隔开。一组套管包含1％浓度的三氯生(2,4,4’-三氯-2’-羟基二苯醚)，一组套管包含10％浓度的庆大霉素，并且一组套管包含三氯生(1％)和庆大霉素(10％)的组合。基于体外测试选择庆大霉素和三氯生的浓度以测定每种化合物的治疗窗。
疏水性三氯生在聚合物内为完全溶液形式，与亲水性庆大霉素相反，庆大霉素仍以10-20μm的小粒子悬浮。体外测试已表明，由于三氯生的水中溶解性较差，伴随微弱的初始破裂释放，其在1至3周期间仅缓慢地从这些膜释放。
暴露于套管的表面的水溶性更高的庆大霉素的约50％在插入后24小时内释放到相邻组织中。包封在聚合物深处的其余的庆大霉素更缓慢地溶解并在植入后2至3周的期间释放。聚合物被设计成在手术后60天内通过水解作用而降解。
包含或不包含抗微生物剂的套管经证实是生物相容性的，对软组织和骨愈合的影响甚微并且对金属植入物不具腐蚀性。实验的额外细节可见于Vet Surg.，2012年1月12日，Biodegradable Sleeves for Metal Implants to Prevent Implant-AssociatedInfection:An Experimental In Vivo Study in Sheep.von Plocki SC,Armbruster D,Klein K,Zlinszky K,Hilbe M,Kronen P,GruskinE,von Rechenberg B.，该参考文献全文据此以引用的方式并入。
实例2：
在一个示例性实施例中，膜10通过以下方法制造：
庆大霉素含水量的测定：
硫酸庆大霉素粉末的含水量通过干燥失重方法测量。在玻璃罐中称取约0.5克的庆大霉素，然后在真空下加热到110℃维持3小时，然后再次称重。将重量损失记录为含水量，将其用于计算水分百分比。
溶液混合：
称取14.69克的硫酸庆大霉素粉末，以补偿如上所计算的含水量百分比。使用桨式搅拌器将其在1升的容器内混合到400g的DMSO溶剂中。将混合物搅拌30分钟，直到庆大霉素均匀分布。将100克的包含乙醇酸、己内酯、乳酸和三亚甲基碳酸酯单体的共聚物添加至悬浮液，并将混合容器加热到65℃。持续混合2小时，直至聚合物完全溶入溶液，然后将溶液温度降至55℃。
膜浇铸和溶剂干燥：
使用浇铸模具以及由高密度聚乙烯制成的拉引刀片来从聚合物溶液浇铸薄的穿孔膜。使用碱性洗涤剂溶液预先清洗浇铸模具和拉引刀片，并装载到自动化CNC浇铸夹具中。将15毫升的聚合物溶液抽入聚丙烯注射器中，将注射器装载到浇铸夹具中。浇铸夹具将溶液自动分配到浇铸模具上，并将刀片拉引横跨模具的表面。将填充了聚合物溶液的模具放入85℃下的溶剂干燥炉中约90分钟以使膜干燥。将模具从干燥炉中取出并在2分钟内将膜从模具剥离。
套管密封：
使用具有专门成形的模具的脉冲热密封压机来密封并将浇铸膜切成套管形状。将两个浇铸膜放入压机中，然后将压机以80psi的压力关闭并加热至200℃下维持4秒。将套管从过量的膜材料移除并切成合适的长度。可将密封的套管在50℃下真空干燥并密封在防水包装物中以防止生物吸收性聚合物降解。
本领域的技术人员将认识到，在不脱离本发明的广义发明构思的情况下，可对上文所示和所述的示例性实施例作出修改。因此，应当理解，本发明不限于所示和所述的示例性实施例，而是旨在涵盖如权利要求书所限定的本发明的实质和范围内的修改。例如，示例性实施例的具体特征可以是或可以不是受权利要求书保护的发明的一部分，并且可将所公开的实施例的特征加以组合。除非在本文具体示出，否则术语“一个/种”和“该/所述”不限于一个元件，而相反应被解读为意指“至少一个/种”。
应当理解，为清楚理解本发明，本发明的附图和说明中的至少一些已经简化以专注于相关的元件，同时为清楚起见，省去本领域普通技术人员将认识到也可构成本发明一部分的其他元件。然而，由于此类元件是本领域熟知的，并且由于它们不必然地有利于更好地理解本发明，所以本文不提供对此类元件的说明。
另外，在方法不依赖于本文所示的步骤的特定顺序的程度上，步骤的特定顺序不应视为对权利要求书的限制。涉及本发明方法的权利要求不应限于以书写的顺序执行其步骤，并且本领域的技术人员可容易地认识到这些步骤可以变化并仍在本发明的实质和范围内。

Claims (32)

1.一种用于药物释放的植入式医疗装置，包括：
具有第一表面和相对的第二表面的柔性聚合物膜，所述柔性聚合物膜具有从所述第一表面延伸到所述第二表面的多个孔以及从所述第一表面突起的多个升高唇缘，使得所述多个孔中的每一个被所述多个升高唇缘中的一个围绕；
其中所述膜包含聚合物并包含一种或多种药物，该药物配置为从所述柔性聚合物膜释放。
2.根据权利要求1所述的植入式医疗装置，其中所述柔性聚合物膜包含生物吸收性聚合物。
3.根据权利要求2所述的植入式医疗装置，其中所述生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、乙交酯、内酯、内酰胺、三亚甲基碳酸酯、环状碳酸酯、环醚、对二氧环己酮、β-羟基丁酸、β-羟基丙酸、β-羟基戊酸，以及它们的组合。
4.根据权利要求2所述的植入式医疗装置，其中所述生物吸收性聚合物包含选自以下的重复单元：L-乳酸、D-乳酸、L-丙交酯、D-丙交酯、D,L-丙交酯、ε-己内酯、三亚甲基碳酸酯、对二氧环己酮，以及它们的组合。
5.根据权利要求2所述的植入式医疗装置，其中所述生物吸收性聚合物是乙交酯、三亚甲基碳酸酯、丙交酯和己内酯的共聚物。
6.根据权利要求1所述的植入式医疗装置，其中所述第一表面包括在所述多个升高唇缘之间延伸的邻接平面部分。
7.根据权利要求6所述的植入式医疗装置，其中所述多个升高唇缘各自具有比所述邻接平面部分高0.1mm至1.0mm的外边缘。
8.根据权利要求1所述的植入式医疗装置，其中所述一种或多种药物包含多种离散的洗脱药物组分，并且其中所述柔性聚合物膜被配置成在植入所述医疗装置后在不同时间段洗脱所述多种离散的药物组分。
9.根据权利要求1所述的植入式医疗装置，还包括被配置成将所述柔性聚合物膜形成鞘管的至少一个接缝。
10.根据权利要求1所述的植入式医疗装置，其中所述柔性聚合物膜在第一平面方向上具有第一拉伸强度并在垂直于所述第一平面方向的第二平面方向上具有第二拉伸强度，其中所述第一拉伸强度基本上等于所述第二拉伸强度。
11.根据权利要求1所述的植入式医疗装置，其中所述柔性聚合物膜具有不大于0.06mm的标称厚度。
12.根据权利要求1所述的植入式医疗装置，其中所述第一表面具有不同于所述第二表面的第二触感的第一触感。
13.根据权利要求8所述的植入式医疗装置，其中所述多种离散的洗脱药物组分包含与所述膜的表面接触的第一量的药物组分和不与所述膜的表面接触的第二量的药物组分。
14.根据权利要求8所述的植入式医疗装置，其中所述多种离散的洗脱药物组分具有低于20微米的直径。
15.根据权利要求8所述的植入式医疗装置，其中所述多种离散的洗脱药物组分具有低于10微米的直径。
16.根据权利要求8所述的植入式医疗装置，其中所述多种离散的洗脱药物组分配置为在两阶段释放过程中洗脱，所述两阶段释放过程包括植入时破裂释放。
17.根据权利要求1所述的植入式医疗装置，其中所述孔提供0.1至0.2的柔性聚合物膜的孔隙度。
18.一种制备权利要求1中所述的柔性聚合物膜的方法，包括：
制备包含聚合物、溶剂和药物的聚合物溶液；
将所述聚合物溶液放置于具有从模具的底部延伸的多个突起的单面模具中，其中所述聚合物溶液的特征在于抑制所述聚合物无外力流遍所述模具的粘度；
促动所述聚合物溶液围绕所述多个突起中的每一个；以及
固化所述聚合物溶液。
19.根据权利要求18所述的方法，其中所述模具包括延伸高度基本上等于所述多个突起中的每一个的高度的围型体。
20.根据权利要求19所述的方法，其中所述促动包括拉引促动装置横跨所述围型体和所述多个突起，以迫使所述聚合物溶液围绕所述多个突起流动并流遍所述模具，使得所述聚合物溶液具有基本上均匀的厚度。
21.根据权利要求20所述的方法，其中所述突起中的每一个的外表面在所述拉引后基本上不含聚合物溶液。
22.根据权利要求19所述的方法，其中所述放置步骤包括将所述聚合物溶液沉积在所述模具中，使得所述聚合物溶液的一部分在所述围型体和所述突起的高度之上。
23.根据权利要求18所述的方法，其中所述聚合物溶液在低于90℃的温度下形成。
24.根据权利要求18所述的方法，其中所述药物包括离散的药物单元。
25.根据权利要求18所述的方法，其中固化所述聚合物溶液包括减小所述聚合物溶液的厚度。
26.根据权利要求18所述的方法，其中固化所述聚合物溶液包括围绕所述多个突起中的每一个形成固化聚合物的弯月面。
27.根据权利要求18所述的方法，其中从所述模具的底部到所述多个突起中的每一个的顶部的距离小于约0.3mm。
28.根据权利要求19所述的方法，其中所述围型体限定总模具面积并且所述多个突起限定所述总模具面积的至少15%的面积。
29.根据权利要求18所述的方法，还包括将所述药物洗脱膜从所述模具剥离。
30.根据权利要求18所述的方法，其中所述聚合物溶液包括可交联的预聚物溶液。
31.根据权利要求18所述的方法，其中所述固化步骤包括通过向所述聚合物溶液施加UV辐射、温度改变、聚合催化剂、可溶性交联剂或它们的组合而交联所述聚合物。
32.根据权利要求18所述的方法，其中所述聚合物溶液的溶剂包含第一溶剂，并且所述固化步骤包括将所述聚合物溶液暴露于第二溶剂，在所述第二溶剂中，所述第一溶剂是可溶的并且所述聚合物和所述药物是不可溶的，使得所述第一溶剂至少基本上从所述聚合物溶液中移除，并且所述聚合物固化以包含所述药物。
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