CN111971026A - 用于持续释放大分子药物化合物的可植入器件 - Google Patents
用于持续释放大分子药物化合物的可植入器件 Download PDFInfo
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Abstract
提供了一种用于递送大分子药物化合物的可植入器件。所述器件包括具有外表面的芯和与所述芯的外表面相邻的膜层。所述芯包含芯聚合物基质，在所述芯聚合物基质内分散具有约0.5kDa或更大的分子量的药物化合物，所述聚合物基质含有疏水聚合物。此外，所述膜层包含膜聚合物基质，在所述膜聚合物基质内任选地分散所述大分子药物化合物。所述芯中的大分子药物化合物的浓度大于所述膜层中的大分子药物化合物的浓度。
Description
相关申请
本申请要求(2018年5月24日提交的)美国申请序列号62/675,982的优先权，所述专利以其全文引用的方式并入本文。
发明背景
生物大分子药物化合物通常由一个或多个低聚链或聚合链组成，从而形成由非共价力保持在一起的三维结构。尽管这些药物化合物具有实现多种疗效的潜能，但传统上难以在持续时间段内可控地递送这些化合物。例如，多种可植入递送器件是通过使药物化合物溶解在基质聚合物中来形成的。这些被溶解的药物分子可通过植入物扩散并且释放入患者。但不幸的是，药物洗脱高度取决于药物分子的扩散系数，扩散系数又与药物分子的分子量成反比。因此，大分子药物化合物因其更大的分子量而趋向于具有更低的扩散系数。此外，这类化合物通常具有链长缠结，这可能更进一步地降低了有效扩散系数。考虑到这些困难，继续存在对能够在持续时间段内以有效量递送大分子化合物的可植入递送器件的需要。
发明内容
根据本发明的一个实施方案，公开了一种用于递送大分子药物化合物的可植入器件。该器件包括具有外表面的芯和与芯的外表面相邻的膜层。芯包含芯聚合物基质，在该芯聚合物基质内分散分子量约0.5kDa或更大的药物化合物，该聚合物基质含有疏水聚合物。此外，膜层包含膜聚合物基质，在该膜聚合物基质内任选地分散大分子药物化合物。芯中的大分子药物化合物的浓度大于膜层中的大分子药物化合物的浓度。
本发明的其他特征和方面阐述于下文的更多细节中。
附图简述
本发明的完整和实现性公开内容、包括对本领域普通技术人员的最佳模式更具体而言阐述于参考附图的说明书的其余部分，在附图中：
图1是本发明的可植入器件的一个实施方案的透视图；
图2是图1的可植入器件的截面图；
图3是本发明的可植入器件的另一个实施方案的透视图；
图4是图3的可植入器件的截面图；
图5是示出实施例1-4的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图6是示出实施例1-4的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图7是示出实施例5-7的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图8是示出实施例5-7的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图9是示出实施例8-13的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图10是示出实施例8-13的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图11是示出实施例14-18的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图12是示出实施例14-18的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图13是示出实施例19-20的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图14是示出实施例19-20的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图15是示出实施例21-23的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；
图16是示出实施例21-23的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线；
图17是示出实施例24-27的胶原的累积释放比对比释放时间(小时)的图线；
图18是示出实施例24-27的胶原的释放速率(μg/h)对比释放时间(小时)的图线；
图19是示出实施例28-30的菠萝蛋白酶的累积释放比对比释放时间(小时)的图线；并且
图20是示出实施例28-30的菠萝蛋白酶的释放速率(μg/h)对比释放时间(小时)的图线。
本说明书和附图中对附图标记的重复使用意图线示本发明的相同或类似的特征或要素。
发明详述
本领域普通技术人员要理解的是，所呈现的论述仅为对示例性实施方案的描述，并且不意图限制本发明的更广泛方面。
一般而言，本发明涉及一种能够递送大分子药物化合物以阻止和/或治疗患者(例如人、宠物、农场动物、赛马等)中的病症、疾病和/或美容状态的可植入器件。可植入器件可具有各种不同的几何形状，诸如圆柱(棒)、圆盘、环、环状物(doughnut)、螺旋、椭圆、三角、卵形等。例如，在一个实施方案中，器件可具有大体上圆形的截面形状，以使得整体结构呈圆柱(棒)或圆盘的形式。在这类实施方案中，器件将通常具有约0.5至约50毫米、在一些实施方案中约1至约40毫米、和在一些实施方案中约5至约30毫米的直径。器件的长度可有所变化，但通常在约1至约25毫米的范围内。圆柱形器件可例如具有约5至约50毫米的长度，而圆盘形器件可具有约0.5至约5毫米的长度。
无论具体形状或大小，器件均为多层的，因为其包含至少一个与芯的外表面相邻定位的膜层。芯包含芯聚合物基质，芯聚合物基质包括疏水聚合物和分散在芯聚合物基质内的大分子药物化合物。通常，大分子药物化合物将构成芯的约5重量％至约60重量％、在一些实施方案中约10重量％至约50重量％、和在一些实施方案中约15重量％至约45重量％，而芯聚合物基质构成芯的约40重量％至约95重量％、在一些实施方案中约50重量％至约90重量％、和在一些实施方案中约55重量％至约85重量％。一个或多个膜层还包含聚合物基质，在聚合物基质内可任选地分散药物化合物。值得注意的是，芯聚合物基质中的药物化合物的浓度(重量％)大于膜层中的药物化合物的浓度(重量％)。例如，在某些实施方案中，膜层一般可不含这类药物化合物。毫无疑问，在其它实施方案中，膜层可包含药物化合物，使得芯中的药物化合物浓度与膜层中的药物化合物浓度之比大于1，在一些实施方案中约1.5或更大，和在一些实施方案中约1.8至约4。
通过对如上文指出的芯和一个或多个膜层的具体性质和它们形成的方式进行选择性控制，本发明人已发现所得器件可在长时间段内有效地持续释放大分子药物化合物。例如，可植入器件可在约5天或更长、在一些实施方案中约10天或更长、在一些实施方案中约20天至约60天、和在一些实施方案中约25天至约50天(例如约30天)的时间段释放药物化合物。此外，本发明人还已发现可在释放时间段中以受控方式(例如零级或近零级)释放药物化合物。例如，在15天后，可植入器件的累积释放比可为约20％至约70％，在一些实施方案中约30％至约65％，和在一些实施方案中约40％至约60％。同样地，在30天后，可植入器件的累积释放比仍可为约40％至约85％，在一些实施方案中约50％至约80％，和在一些实施方案中约60％至约80％。“累积释放比”可通过将具体时间间隔时释放的药物化合物的量除以初始存在的药物化合物的总量，并随后将该数值乘以100来测定。
毫无疑问，递送的药物化合物的实际剂量水平将视所采用的具体药物化合物和其意图释放的时间段而变化。剂量水平一般足够高以提供治疗有效量的药物化合物来给予所需治疗结果，即，有效地减少或减轻药物所施用病症的症状的水平或量。所需精确量将尤其视受治疗的受试者、递送大分子药物化合物的受试者的年龄和一般状况、受试者免疫系统的能力、所需效果的程度、受治疗病症的严重度、所选具体大分子药物化合物和组合物的施用模式而变化。适当的有效量可容易地由本领域技术人员决定。例如，有效量将通常为约5μg至约200mg，在一些实施方案中每天约5μg至约100mg，和在一些实施方案中每天递送约10μg至约1mg的大分子药物化合物。
现将更详细描述本发明的各种实施方案。
I.芯
如上文所示，芯聚合物基质至少含有在性质上大体为疏水聚合物，以使得其可在被置于含水环境中、诸如哺乳动物体内时在一定时间段保持其结构完整性，并且足够稳定以在使用前存储延长的时段。出于这一目的，合适的疏水聚合物的实例可包括例如有机硅聚合物，聚烯烃，聚氯乙烯，聚碳酸酯，聚砜，苯乙烯丙烯腈共聚物，聚氨酯，有机硅聚醚-聚氨酯，聚碳酸酯-聚氨酯，有机硅聚碳酸酯-聚氨酯等，以及它们的组合。毫无疑问，被疏水聚合物涂布或者以其他方式包封的亲水聚合物也适合用于芯聚合物基质中。通常，如根据ASTM D1238-13在190℃的温度和2.16千克的载荷下测定的，疏水聚合物的熔体流动指数为约0.2至约100g/10min，在一些实施方案中约5至约90g/10min，在一些实施方案中约10至约80g/10min，和在一些实施方案中约30至约70g/10min。
在某些实施方案中，芯聚合物基质可含有半结晶烯烃共聚物。根据ASTM D3418-15测定的，这种烯烃共聚物的熔融温度可为例如约40℃至约140℃，在一些实施方案中约50℃至约125℃，和在一些实施方案中约60℃至约120℃。这类共聚物一般衍生自至少一种烯烃单体(例如乙烯、丙烯等)和至少一种接枝于聚合物骨架上和/或作为聚合物(例如嵌段或无规共聚物)的组分并入的极性单体。合适的极性单体包括例如乙酸乙烯酯，乙烯醇，马来酸酐，马来酸，(甲基)丙烯酸(例如丙烯酸、甲基丙烯酸等)，(甲基)丙烯酸酯(例如丙烯酸酯、甲基丙烯酸酯、丙烯酸乙酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯等)，等等。一般可在聚合物组合物中采用各种各样的这类共聚物，诸如乙烯-乙酸乙烯酯共聚物，乙烯(甲基)丙烯酸聚合物(例如乙烯丙烯酸共聚物和这些共聚物的部分中和的离聚物，乙烯甲基丙烯酸共聚物和这些共聚物的部分中和的离聚物等)，乙烯(甲基)丙烯酸酯聚合物(例如乙烯甲基丙烯酸酯共聚物，乙烯丙烯酸乙酯共聚物，乙烯丙烯酸丁酯共聚物等)，等等。无论所选的具体单体，本发明人已发现可选择性控制共聚物的某些方面以帮助实现所需释放性质。例如，共聚物的极性单体含量可被选择性控制在约10重量％至约60重量％、在一些实施方案中约20重量％至约55重量％、和在一些实施方案中约25重量％至约50重量％的范围内。相反地，共聚物的烯烃单体含量可同样地在约40重量％至约90重量％、在一些实施方案中约45重量％至约80重量％、和在一些实施方案中约50重量％至约75重量％的范围内。
例如，在一个具体实施方案中，芯聚合物基质可含有乙烯-乙酸乙烯酯聚合物，该聚合物为衍生自至少一种乙烯单体和至少一种乙酸乙烯酯单体的共聚物。如根据ASTMD1505-10测定的，乙烯-乙酸乙烯酯共聚物的密度还可为约0.900至约1.00克/立方厘米(g/cm3)，在一些实施方案中约0.910至约0.980g/cm3，和在一些实施方案中约0.940至约0.970g/cm3。可采用的合适的乙烯-乙酸乙烯酯共聚物的实例包括可以名称
(例如
4030AC)购自Celanese的、以名称
(例如
40W)购自DuPont的和以名称
(例如EVATANE 40-55)购自Arkema的那些。如本领域已知的，一般可使用各种技术中的任何者来形成具有所需性质的乙烯-乙酸乙烯酯共聚物。在一个实施方案中，通过在高压反应中使乙烯单体和乙酸乙烯酯单体共聚来产生聚合物。乙酸乙烯酯可由丁烷氧化以产生乙酸酐和乙醛来产生，乙酸酐和乙醛可一起反应形成乙烯二乙酯。然后，乙烯二乙酯可在酸催化剂的存在下热分解形成乙酸乙烯酯单体。合适的酸催化剂的实例包括芳族磺酸(例如苯磺酸、甲苯磺酸、乙苯磺酸、二甲苯磺酸和萘磺酸)、硫酸和链烷磺酸，诸如Oxley等人的美国专利号2,425,389、Schnizer的2,859,241和Isshiki等人的4,843,170中所描述的。乙酸乙烯酯单体还可通过在催化剂的存在下使乙酸酐与氢气而不是乙醛反应来产生。该过程直接由乙酸酐和氢气转化乙酸乙烯酯，而不需要产生乙烯二乙酯。在又一个实施方案中，乙酸乙烯酯单体可由乙醛和乙烯酮在诸如全氟磺酸树脂或沸石的合适的固体催化剂的存在下反应产生。
能够阻止和/或治疗患者的病症、疾病和/或美容状态的一种或多种药物化合物也被分散在芯聚合物基质内。药物化合物可为系统或局部地预防、治疗和/或美容活性的。无论如何，芯内的至少一种药物化合物就其具有诸如约0.5千道尔顿(“kDa”)或更大、在一些实施方案中约1kDa或更大、在一些实施方案中约5kDa至约250kDa、和在一些实施方案中约20kDa至约200kDa的大分子量而言是“大分子”化合物。通常，这类化合物的生物活性取决于分子的独特三维(例如折叠)结构。这种三维分子结构大致上由特定的非共价键合相互作用维持，诸如原子间的氢键合和疏水键合相互作用(疏水性)。药物化合物可为天然存在的或通过本领域已知的任何方法人造的。通常，还需要药物化合物在高温下稳定，以使得其可在芯聚合物基质中采用的疏水聚合物的熔融温度下或熔融温度附近被并入聚合物基质。例如，药物化合物通常在约25℃至约120℃、在一些实施方案中约40℃至约110℃、在一些实施方案中约40℃至约100℃、在一些实施方案中约40℃至约80℃、和在一些实施方案中约50℃至约70℃的温度下保持稳定。
合适的大分子药物化合物的具体实例可包括例如蛋白质、肽、酶、抗体、干扰素、白细胞介素、血液因子、疫苗、核苷酸、脂质等，以及它们的类似物、衍生物和组合。合适的蛋白质或肽可包括例如促肾上腺皮质激素，血管收缩素，β-内啡肽，铃蟾肽，降钙素，降钙素基因相关多肽，缩胆囊素-8，集落刺激因子，去氨加压素，内皮素，脑啡肽，促红细胞生成素，胃泌素，胰高血糖素，人心房钠尿多肽，干扰素，胰岛素，生长因子，生长激素，促黄体激素释放激素，黑素细胞刺激激素，胞壁酰二肽，神经降压素，催产素，甲状旁腺激素，肽T，胰泌素，生长介素，生长抑素，促甲状腺激素，促甲状腺激素释放激素，促甲状腺激素刺激激素，血管活性肠多肽，后叶加压素等。合适的抗体(例如单克隆抗体)可包括但不限于HIV单克隆抗体2F5，利妥昔单抗，英夫利昔单抗，曲妥珠单抗，阿达木单抗，奥马珠单抗，托西莫单抗，依法利珠单抗和西妥昔单抗。合适的干扰素可包括干扰素α-2b，PEG干扰素α-2b，干扰素α-2b+病毒唑，干扰素α-2a，聚乙二醇化干扰素α-2a，干扰素β-1a和干扰素β。合适的血液因子可包括阿替普酶/替奈普酶和Rh因子VIIa。合适的白细胞介素可包括白细胞介素-2。合适的疫苗可包括全病毒颗粒，重组蛋白，诸如gp41、gp120和gp140的亚基蛋白，DNA疫苗，质粒，细菌疫苗，诸如胞外荚膜多糖的多糖，以及其他疫苗载体。同样地，合适的核酸可包括基于RNA或DNA的分子，诸如寡核苷酸，适体，RNA酶，DNA酶和小干扰RNA，诸如信使RNA(mRNA)、转移RNA(tRNA)、核糖体RNA(rRNA)、干扰RNA(iRNA)、小干扰RNA(siRNA)等。
如果需要，芯还可任选地含有一种或多种赋形剂，诸如放射对比剂、释放改性剂、填充剂(bulking agent)、塑化剂、表面活性剂、交联剂、流动助剂、着色剂(例如叶绿素、亚甲基蓝等)、抗氧化剂、稳定剂、润滑剂、其他类型的抗微生物剂、防腐剂等来增强性质和可加工性。当采用时，任选的一种或多种赋形剂通常构成芯的约0.01重量％至约20重量％、和在一些实施方案中约0.05重量％至约15重量％、和在一些实施方案中约0.1重量％至约10重量％。例如，在一个实施方案中，可采用放射对比剂来帮助确保器件可在基于X射线的成像技术(例如计算机断层摄影术、投影射线摄影术、荧光检查等)中被检测到。这类药剂的实例包括例如钡基化合物、碘基化合物、锆基化合物(例如二氧化锆)等。这种药剂的一个具体实例是硫酸钡。还可采用其他已知的抗微生物剂和/或防腐剂来帮助防止细菌的表面生长和吸附，诸如金属化合物(例如银、铜或锌)、金属盐、季铵化合物等。
不管采用的具体组分如何，芯可通过各种已知技术来形成，诸如通过热熔挤出、注射模塑、溶剂浇注、浸涂、喷涂、微挤出、凝聚等。在一个实施方案中，可采用热熔挤出技术。热熔挤出一般为无溶剂过程，其中芯的组分(例如疏水聚合物、一种或多种药物化合物、任选的赋形剂等)可在连续制造过程中被熔融共混并任选地成形，从而以高通过率实现一致的输出质量。这种技术特别良好地适合于各种类型的疏水聚合物，诸如烯烃共聚物。即，这类共聚物通常展现相对高的长链支化度，具有宽分子量分布。这种性状的组合可导致共聚物在挤出过程中剪切稀化，这有助于促进热熔挤出。此外，极性共聚单体单元(例如乙酸乙烯酯)可通过阻止聚乙烯链段结晶而充当“内部”塑化剂。这可导致烯烃共聚物的熔点更低，其改进所得材料的整体可挠性并且增强其形成为具有各种形状和尺寸的器件的能力。
在热熔挤出过程中，熔融共混可在约40℃至约200℃、在一些实施方案中约60℃至约180℃、和在一些实施方案中约80℃至约150℃的温度范围下发生以形成聚合物组合物。一般可采用各种熔融共混技术中的任何者。例如，可将组分分别或组合地供应至挤出机，挤出机包括至少一个可旋转安装并收纳在机筒(例如圆柱形机筒)内的螺杆。挤出机可为单螺杆或双螺杆挤出机。例如，单螺杆挤出机的一个实施方案可包含外壳或机筒和螺杆，螺杆可在一端由合适的驱动装置(通常包括马达和齿轮箱)旋转驱动。必要时，可采用包含两个分开的螺杆的双螺杆挤压机。螺杆的配置并不特别关键，并且可包含如本领域已知的任何数量和/或定向的螺纹和通道。例如，螺杆通常包含螺纹，螺纹形成绕螺杆芯径向延伸的大体上螺旋的通道。可沿螺杆的长度界定进料段和熔融段。进料段是添加一种或多种烯烃共聚物和/或一种或多种药物化合物的机筒的输入部分。熔融段是共聚物从固体变为类液体状态的相变段。尽管在制造挤出机时不存在对这些段的精确界定的描绘，但在本领域普通技术人员的能力内能可靠地鉴别进料段和发生由固体到液体的相变的熔融段。虽然未必需要，但挤出机还可具有与机筒的输出端相邻并位于熔融段下游的混合段。必要时，在挤出机的混合和/或熔融段内可采用一个或多个分布和/或分散型混合元件。对单螺杆挤出机合适的分布型混合器可包括例如Saxon、Dulmage、腔穴传递式混合器等。同样地，合适的分散型混合器可包括泡形罩环、Leroy/Maddock、CRD混合器等。如本领域众所周知的，可通过在机筒中使用形成聚合物熔体的折叠和再定向的销钉来进一步改进混合，诸如在Buss捏合挤出机、腔穴传递式混合器和旋涡咬合销混合器中使用的那些。
必要时，可选定螺杆的长度(“L”)与直径(“D”)之比以实现组分的通过量与共混之间的最优均衡。L/D值可为例如约10至约50，在一些实施方案中约15至约45，和在一些实施方案中约20至约40。螺杆的长度可为例如约0.1至约5米，在一些实施方案中约0.4至约4米，和在一些实施方案中约0.5至约2米。同样地，螺杆的直径可为约5至约150毫米，在一些实施方案中约10至约120毫米，和在一些实施方案中约20至约80毫米。除长度和直径以外，还可选定挤出机的其他方面以帮助实现所需共混程度。例如，可选定螺杆的速度以实现所需停留时间、剪切速率、熔融加工温度等。例如，螺杆速度可为约10至约800转/分钟(“rpm”)，在一些实施方案中约20至约500rpm，和在一些实施方案中约30至约400rpm。熔融共混期间表观剪切速率还可为约100秒-1至约10,000秒-1，在一些实施方案中约500秒-1至约5000秒-1，和在一些实施方案中约800秒-1至约1200秒-1。表观剪切速率等于4Q/πR3，其中Q为聚合物熔体的体积流速(“m3/s”)并且R为熔融聚合物所流经的毛细管(例如挤出机模头)的半径(“m”)。
一旦熔融共混到一起，所得聚合物组合物可呈粒料、片材、纤维、长丝等的形式，可使用各种已知的成形技术，诸如注射模塑、压缩模塑、纳米模塑、包覆成型、吹塑、三维打印等来成形为芯。注射模塑可例如在两个主要阶段，即注射阶段和保持阶段中发生。在注射阶段中，用熔融的聚合物组合物填充模具腔。在注射阶段完成后开始保持阶段，其中控制保持压力以将另外的材料填充至腔中并补偿在冷却期间发生的体积收缩。在注料(shot)已成型后，其可随后被冷却。一旦冷却完成，当模具打开并诸如借助模具内的起模杆排出部件时模塑周期完成。一般可在本发明中采用任何合适的注射模塑设备。在一个实施方案中，可采用的注射模塑设备包括第一模具基座和第二模具基座，二者一起界定具有芯的形状的模具腔。模塑设备包括从第一模具半部的外表面经过浇口延伸到模具腔的树脂流动路径。可使用各种技术将聚合物组合物供应至树脂流动路径。例如，可将组合物供应(例如以粒料形式)至附接于包含旋转螺杆(未示出)的挤出机机筒的进料斗。随着螺杆旋转，粒料被向前移动并经受压力和摩擦，这产生热量使粒料熔融。还可提供冷却机构以使树脂在模具腔内固化成芯的所需形状(例如圆盘、棒等)。例如，模具基座可包括一个或多个冷却管线，冷却介质流经该管线以将所需模具温度赋予模具基座的表面，从而使熔融材料固化。模具温度(例如模具表面的温度)可为约50℃至约120℃，在一些实施方案中约60℃至约110℃，和在一些实施方案中约70℃至约90℃。
如上文所示，形成具有所需形状和尺寸的芯的另一种合适的技术是三维打印。在该过程中，可将聚合物组合物并入易适于配合打印机系统使用的打印盒。打印盒可例如包含携带聚合物组合物的线轴或其他类似装置。例如，当以长丝形式供应时，线轴可具有长丝所缠绕的大体上圆柱形的缘。同样地，线轴可限定允许其易于在使用期间安装至打印机的孔或轴。可在本发明中采用各种三维打印机系统中的任何者。特别合适的打印机系统是基于挤出的系统，这通常被称作“熔融沉积建模”系统。例如，可将聚合物组合物供应至包含压板和台架的打印头的构造腔室。压板可基于由计算机操作的控制器提供的信号沿垂直z轴移动。台架是导轨系统，可被配置成基于由控制器提供的信号，在构造腔室内水平x-y平面中移动打印头。打印头由台架支撑，并且被配置为基于由控制器提供的信号，在压板上以逐层方式打印构造结构。例如，打印头可为双尖端挤出头。
II.膜层
如上文所示，可植入器件包含至少一个与芯的外表面相邻定位的膜层。膜层的数量可视器件的具体构造、药物化合物的性质和所需释放分布而变化。例如，器件可包含仅一个膜层。例如，参考图1-2，示出了可植入器件10的一个实施方案，其包含芯40，芯40具有大体上圆形的截面形状，并且是伸长的，以使得所得器件在性质上大体为圆柱形的。芯40界定了外周向表面61，膜层20围绕表面61周向设置。类似于芯40，膜层20也具有大体上圆形的截面形状，并且是伸长的，以使得其覆盖芯40的全长。在器件10使用期间，药物化合物能够从芯40穿过膜层20释放，以使得其从器件的外表面21离开。
毫无疑问，在其他实施方案中，器件可包含多个膜层。例如，在图1-2的器件中，可在膜层20上设置一个或多个另外的膜层(未示出)以帮助进一步控制药物化合物的释放。在其他实施方案中，器件可被配置成使得芯位于或夹在分开的膜层之间。例如，参考图3-4，示出了可植入器件100的一个实施方案，其包含芯140，芯140具有大体上圆形的截面形状，并且是伸长的，以使得所得器件在性质上大体为圆盘形的。芯140界定上外表面161和下外表面163，第一膜层120位于上外表面161上，第二膜层122位于下外表面163上。类似于芯140，第一膜层120和第二膜层122也具有大体上圆形的截面形状，其大体上覆盖了芯140。必要时，膜层120和122的边缘也可延伸超出芯140的外围，以使得它们可密封到一起，从而覆盖芯140的外周向表面170的任何暴露区域。在器件100使用期间，药物化合物能够从芯140穿过第一膜层120和第二膜层122释放，使得其从器件的外表面121和123离开。毫无疑问，必要时，还可在第一膜层120和/或第二膜层122上设置一个或多个另外的膜层(未示出)以帮助进一步控制药物化合物的释放。
不管所采用的具体构造如何，一个或多个膜层一般包含含有疏水聚合物的膜聚合物基质，诸如上文所描述的。聚合物基质通常构成膜层的约30重量％至100重量％，在一些实施方案中约40重量％至约99重量％，和在一些实施方案中约50重量％至约90重量％。当采用多个膜层时，通常期望每个膜层包含包括这类疏水聚合物的聚合物基质。例如，第一膜层可包含第一聚合物基质并且第二膜层可包含第二聚合物基质。在这类实施方案中，第一和第二聚合物基质各自含有疏水聚合物，其可以相同或不同。同样地，膜层中使用的疏水聚合物也可与芯中采用的疏水聚合物相同或不同。例如，在一个实施方案中，芯和一个或多个膜层采用相同的疏水聚合物(例如α-烯烃共聚物)。在其他实施方案中，一个或多个膜层可采用具有比芯中采用的聚合物更低的熔体流动指数的疏水聚合物(例如α-烯烃共聚物)。尤其地，此举可进一步帮助控制药物化合物从器件释放。例如，芯中采用的疏水聚合物的熔体流动指数与一个或多个膜层中采用的疏水聚合物的熔体流动指数之比可为约1至约20，在一些实施方案中约2至约15，和在一些实施方案中约4至约12。如根据ASTM D1238-13在190℃的温度和2.16千克的载荷下测定的，一个或多个膜层中的疏水聚合物的熔体流动指数可例如为约1至约80g/10min，在一些实施方案中约2至约70g/10min，和在一些实施方案中约5至约60g/10min。可采用的合适的乙烯-乙酸乙烯酯共聚物的实例包括可以名称
(例如
4030AC或2861A)购自Celanese的那些。
如上文所示，器件中使用的一个或多个膜层可任选地包含分散在聚合物基质内的大分子药物化合物，诸如上文所描述的。一个或多个膜层中的药物化合物可与芯中采用的药物化合物相同或不同。无论如何，当在膜层中采用这种大分子药物化合物时，膜层一般包含使得芯中药物化合物的浓度(重量％)与膜层中药物化合物的浓度(重量％)之比高于1、在一些实施方案中为约1.5或更高和在一些实施方案中约1.8至约4的量的药物化合物。当采用时，药物化合物通常仅构成膜层的约1重量％至约40重量％，在一些实施方案中约5重量％至约35重量％，和在一些实施方案中约10重量％至约30重量％。毫无疑问，在其他实施方案中，在从芯释放之前，膜层一般不含这类大分子药物化合物。当采用多个膜层时，每个膜层可一般包含使得芯中药物化合物的重量百分比与膜层中药物化合物的重量百分比之比高于1、在一些实施方案中为约1.5或更高和在一些实施方案中约1.8至约4的量的药物化合物。
一个或多个膜层和/或芯还可任选地包含如上文所描述的一种或多种赋形剂，诸如放射对比剂、亲水化合物、填充剂、塑化剂、表面活性剂、交联剂、流动助剂、着色剂(例如叶绿素、亚甲基蓝等)、抗氧化剂、稳定剂、润滑剂、其他类型的抗微生物剂、防腐剂等来增强性质和可加工性。当采用时，任选的一种或多种赋形剂通常构成膜层的约0.01重量％至约60重量％、和在一些实施方案中约0.05重量％至约50重量％、和在一些实施方案中约0.1重量％至约40重量％。
为了帮助进一步控制从可植入器件的释放速率，例如，还可将亲水化合物并入一个或多个膜层的聚合物基质，其可溶和/或可溶胀于水中。当采用时，膜聚合物基质内的疏水聚合物与亲水化合物的重量比可为约0.25至约200，在一些实施方案中约0.4至约80，在一些实施方案中约0.8至约20，在一些实施方案中约1至约16，和在一些实施方案中约1.2至约10。这类亲水化合物可例如构成膜聚合物基质的约1重量％至约50重量％、在一些实施方案中约2重量％至约40重量％，和在一些实施方案中约5重量％至约30重量％，而疏水聚合物通常构成膜聚合物基质的约50重量％至约99重量％、在一些实施方案中约60重量％至约98重量％，和在一些实施方案中约70重量％至约95重量％。在这类实施方案中，亲水化合物同样地可构成膜层的约1重量％至约50重量％、在一些实施方案中约2重量％至约40重量％，和在一些实施方案中约5重量％至约30重量％。合适的亲水化合物可包括例如聚合物，非聚合物材料(例如甘油、糖、盐、肽等)，等。合适的亲水聚合物的实例包括例如，藻酸钠、藻酸钾和藻酸钙，羧甲基纤维素，琼脂，明胶，聚乙烯醇，聚亚烷基二醇(例如聚乙二醇)，胶原，果胶，几丁质，壳聚糖，聚1-己内酯，聚乙烯吡咯烷酮，聚(乙烯基吡硌烷酮-共聚-乙酸乙烯酯)，多糖，亲水聚氨酯，聚羟基丙烯酸酯，葡聚糖，黄原胶，羟丙基纤维素，甲基纤维素，蛋白质，乙烯-乙烯醇共聚物，水溶性聚硅烷和有机硅，水溶性聚氨酯等，以及它们的组合。特别合适的亲水聚合物是聚亚烷基二醇，诸如具有约100至500,000克/摩尔、在一些实施方案中约500至200,000克/摩尔和在一些实施方案中约1,000至约100,000克/摩尔的分子量的那些。这类聚亚烷基二醇的具体实例包括例如聚乙二醇、聚丙二醇、聚丁二醇、聚表氯醇等。
还可采用一种或多种非离子、阴离子和/或两性表面活性剂来帮助形成均匀的分散体。当采用时，这样的一种或多种表面活性剂通常构成芯的约0.05重量％至约8重量％，和在一些实施方案中约0.1重量％至约6重量％，和在一些实施方案中约0.5重量％至约3重量％。通常具有疏水基部(例如长链烷基或烷基化芳基)和亲水链(例如含有乙氧基和/或丙氧基结构部分的链)的非离子表面活性剂是特别合适的。可使用的一些合适的非离子表面活性剂包括但不限于乙氧基化的烷基酚，乙氧基化和丙氧基化的脂肪醇，甲基葡萄糖的聚乙二醇醚，山梨醇的聚乙二醇醚，氧化乙烯-氧化丙烯嵌段共聚物，脂肪(C8-C18)酸的乙氧基化酯，氧化乙烯与长链胺或酰胺的缩合产物，氧化乙烯与醇的缩合产物，脂肪酸酯，长链醇的单酸甘油酯或二酸甘油酯，以及它们的混合物。特别合适的非离子表面活性剂可包括脂肪醇的氧化乙烯缩合物，脂肪酸的聚氧乙烯醚，聚氧乙烯山梨醇酐脂肪酸酯，和山梨醇酐脂肪酸酯等。用来形成这类乳化剂的脂肪组分可为饱和或不饱和、取代或未取代的，并且可含有6至22个碳原子、在一些实施方案中8至18个碳原子，和在一些实施方案中12至14个碳原子。已用聚氧乙烯改性的山梨醇酐脂肪酸酯(例如单酯、二酯、三酯等)是一组特别有用的非离子表面活性剂。这些材料通常通过将氧化乙烯添加至1,4-山梨醇酐酯来制备。聚氧乙烯的添加使亲脂的山梨醇酐酯表面活性剂转化为一般可溶或可分散于水中的亲水表面活性剂。这类材料可以名称
(例如
80或聚乙烯(20)山梨醇酐单油酸酯)商购获得。
一个或多个膜层可使用与用来形成芯的相同或不同的技术来形成，诸如通过热熔挤出、注射模塑、溶剂浇注、浸涂、喷涂、微挤出、凝聚等。在一个实施方案中，可采用热熔挤出技术。还可分别或同时形成芯和一个或多个膜层。例如，在一个实施方案中，分别形成芯和一个或多个膜层，并且然后使用已知的结合技术，诸如通过冲压、热密封、粘结结合等组合到一起。
III.器件的使用
本发明的可植入器件可以各种不同的方式使用来阻止和/或治疗患者中的病症、疾病或美容状态。可使用标准技术，经皮下、口服、粘膜等植入器件。递送路线可为肺内、胃肠、皮下、肌肉内，或引入中枢神经系统、腹膜内，或器官内递送。必要时，可在使用前将器件密封在包装(例如无菌泡罩包装)内。密封包装的材料和方式可如本领域已知来改变。例如，在一个实施方案中，包装可包含基材，基材包括实现所需保护性质程度所需要的任何层数，诸如1或更多、在一些实施方案中1至4层、和在一些实施方案中1至3层。通常，基材含有聚合物膜，诸如由聚烯烃(例如乙烯共聚物、丙烯共聚物、丙烯均聚物等)、聚酯(例如聚对苯二甲酸乙二醇酯、聚萘二甲酸乙二醇酯、聚对苯二甲酸丁二醇酯等)、氯乙烯聚合物、乙烯基乙胺嘧啶(chloridine)聚合物、离聚物等、以及它们的组合形成的那些。膜的一个或多个板可诸如在外周边缘处密封到一起(例如热封)，以形成可存储器件的腔。例如，单一膜可在一个或多个点折叠并且沿其外围密封以界定器件所处的腔。为了使用器件，可诸如通过破坏密封来打开包装，并且然后可将器件移出并植入患者中。
参考以下实施例可更好地理解本发明。
试验方法
药物释放：可使用体外法测定药物化合物(例如菠萝蛋白酶)的释放。更具体而言，可将可植入器件样品置于150毫升叠氮化钠水溶液中。溶液被封闭于防UV的250ml
烧瓶中。然后将烧瓶置于控温水浴中并以100rpm不断摇晃。在释放实验中维持37℃的温度以模拟体内条件。通过完全交换叠氮化钠水溶液以有规律的时间间隔取出样品。使用Cary 1分裂波束仪，经由UV/Vis吸收光谱法测定溶液中药物化合物的浓度。由该数据计算每个采样间隔所释放药物化合物的量(微克/小时)并且随时间(小时)绘图。此外，药物化合物的累积释放比也通过将每个采样间隔所释放的药物化合物的量除以初始存在的药物化合物的总量，并随后将该数值乘以100计算为百分比。然后随时间(小时)绘制该百分比。
实施例1-4
以不同浓度的疏水聚合物(
4030AC)和大分子生物制剂(菠萝蛋白酶)形成了四种(4)不同类型的芯层。为了形成样品，使用Haake Rheomix 600p，将菠萝蛋白酶粉末初始熔融配混入
4030AC。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有25毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。
不同芯层内菠萝蛋白酶和
4030AC含量在表1中给出。
表1
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图5-6中。
实施例5-7
使用含有20重量％疏水聚合物和80重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了三种(3)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有23毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
4030AC和
VA64来形成膜层，不同之处在于所得圆盘具有25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。表2示出每个实施例中使用的芯和膜层的含量。
表2
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图7-8中。
实施例8-13
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了六种(6)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有23毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
2861A和具有100,000克/摩尔的分子量的聚乙二醇(“PEG”)来形成膜层，不同之处在于配混在170℃的温度下发生，并且所得圆盘具有0.5毫米的厚度和25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。表3示出每个实施例中使用的芯和膜层的含量。
表3
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图9-10中。
实施例14-18
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了五种(5)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有23毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
2861A和
VA64来形成膜层，不同之处在于配混在170℃的温度下发生，压制期间使用的温度为100℃，并且所得圆盘具有0.5毫米的厚度和25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。表4示出每个实施例中使用的芯和膜层的含量。
表4
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图11-12中。
实施例19-20
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了两种(2)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有23毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
4030AC、具有100,000克/摩尔的分子量的聚乙二醇(“PEG”)和菠萝蛋白酶粉末来形成膜层，不同之处在于所得圆盘具有25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。表5示出每个实施例中使用的芯和膜层的含量。
表5
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图13-14中。
实施例21-23
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了三种(3)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将菠萝蛋白酶粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-菠萝蛋白酶片材冲压出具有23毫米直径的圆盘，以产生含菠萝蛋白酶的芯层/整料式菠萝蛋白酶植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
4030AC和具有100,000克/摩尔的分子量的聚乙二醇(“PEG”)来形成膜层，不同之处在于配混在50℃的温度下发生，压制期间使用的温度为80℃，并且所得圆盘具有0.5毫米的厚度和25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。
表6
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图15-16中。
实施例24-27
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了四种(4)不同类型的芯-膜可植入器件。使用Haake Rheomix 600p，通过将胶原粉末熔融配混入
4030AC来形成芯层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将胶原粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。为了避免熔融的EVA膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于EVA共混物与压板之间。冷却后，移除聚酯膜。使用冲压机由EVA-胶原片材冲压出具有23毫米直径的圆盘，以产生含胶原的芯层/整料式胶原植入物。以与上文所述相同的方式，使用Haake Rheomix 600p通过熔融配混
4030AC和
VA64来形成膜层，不同之处在于配混在50℃的温度下发生，压制期间使用的温度为50℃，并且所得圆盘具有1.0毫米的厚度和25毫米的直径。为了形成芯-膜植入物，采用了溶剂粘合技术。即，使用漆刷将少量的甲苯施加于圆盘的侧面上，并且然后夹心层稍后立即被粘合并压制到一起。由于甲苯蒸发，维持压力24小时。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封芯层的边缘。使边缘干燥排掉甲苯至少48小时。表7示出每个实施例中使用的芯和膜层的含量。
表7
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图17-18中。
实施例28-30
使用含有40重量％疏水聚合物和60重量％生物制剂的芯层与膜层中不同浓度的组分组合，形成了三种(3)不同类型的芯-膜可植入器件。使用具有锥形咬合螺杆的DSM台式双螺杆挤出机，通过将菠萝蛋白酶粉末熔融配混入
4030AC来形成芯棒。首先，
4030AC(1mm细粉)与菠萝蛋白酶干式共混。然后将共混的混合物进料至DSM挤出机中。挤出温度为60℃并且螺杆速度为50rpm。使挤出的长丝冷却至室温并且然后切成30mm长棒。挤出长丝的直径为3.4mm。使用Haake Rheomix 600p，通过将
VA64粉末熔融配混入
4030AC来形成膜层。首先，用
4030AC粒料填充Rheomix 600p腔室并在50℃配混8分钟。使用辊型转子以50rpm在Rheomix 600p中进行配混。8分钟后，将
VA64粉末加入
4030AC熔体，并且在50℃继续熔融混合3分钟。熔融混合后，从Rheomix 600p中取出共混物，并且使用热压机压制成1mm厚的片材。压制期间的温度为50℃，压制时间为3分钟，并且压力为100巴。
为了避免熔融的
4030AC膜粘附至压机的表面，将低粘附、耐温的聚酯箔(
RNK 23)置于
4030AC共混物与压板之间。冷却后，移除聚酯膜。为了形成芯-膜植入物，采用了温度粘合技术。即，将膜层和芯棒加热至55℃达30分钟。然后，通过施加温和的压力并同时长时段滚动试样，手动地将单个膜层附接至单个芯棒。此后，使用由塑料移液管施加的
4030AC的高浓度甲苯溶液密封柱体的两端和膜层端之间的接缝。使边缘和接缝干燥排掉甲苯至少48小时。表8示出每个实施例中使用的芯和膜层的含量。
表8
一旦形成，如上文所描述，测试样品的释放速率。结果阐述于图19-20中。
在不脱离本发明的精神和范围的情况下，本发明的这些和其他修改和变化可由本领域普通技术人员实践。另外，应理解各种实施方案的方面可整体或部分地互换。此外，本领域普通技术人员将理解前文描述仅以举例的方式，并且不意图限制进一步描述于随附权利要求书中的本发明。
Claims (37)
1.用于递送大分子药物化合物的可植入器件，所述器件包括：
具有外表面的芯，其中所述芯包含芯聚合物基质，具有约0.5kDa或更大的分子量的药物化合物分散在所述芯聚合物基质内，所述聚合物基质含有疏水聚合物；和
与所述芯的外表面相邻的膜层，其中所述膜层包含膜聚合物基质，在所述膜聚合物基质内任选地分散所述大分子药物化合物，其中所述芯中的大分子药物化合物的浓度大于所述膜层中的大分子药物化合物的浓度。
2.根据权利要求1所述的可植入器件，其中所述器件具有大体上圆形的截面形状。
3.根据权利要求2所述的可植入器件，其中所述器件具有约0.5至约50毫米的直径。
4.根据权利要求1所述的可植入器件，其中所述器件呈圆柱的形式。
5.根据权利要求1所述的可植入器件，其中所述器件呈圆盘的形式。
6.根据权利要求1所述的可植入器件，其中大分子药物化合物构成所述芯的约5重量％至约60重量％，并且所述芯聚合物基质构成所述芯的约40重量％至约95重量％。
7.根据权利要求1所述的可植入器件，其中所述器件能够释放所述大分子药物化合物持续约5天或更长的时间段。
8.根据权利要求1所述的可植入器件，其中在15天的时间段后，所述器件展示约20％至约70％的所述大分子药物化合物的累积释放比。
9.根据权利要求1所述的可植入器件，其中在30天的时间段后，所述器件展示约40％至约85％的所述大分子药物化合物的累积释放比。
10.根据权利要求1所述的可植入器件，其中所述芯聚合物基质的疏水聚合物包含半结晶烯烃共聚物。
11.根据权利要求10所述的可植入器件，其中所述半结晶共聚物衍生自至少一种烯烃单体和至少一种极性单体。
12.根据权利要求11所述的可植入器件，其中所述烯烃单体包括乙烯。
13.根据权利要求11所述的可植入器件，其中所述极性单体包括乙酸乙烯酯、乙烯醇、马来酸酐、马来酸、丙烯酸、甲基丙烯酸、丙烯酸酯、甲基丙烯酸酯、丙烯酸乙酯、甲基丙烯酸甲酯、甲基丙烯酸乙酯，或它们的组合。
14.根据权利要求11所述的可植入器件，其中所述极性单体构成所述共聚物的约10重量％至约45重量％。
15.根据权利要求10所述的可植入器件，其中所述烯烃共聚物具有根据ASTM D3418-15测定的约40℃至约140℃的熔融温度。
16.根据权利要求10所述的可植入器件，其中所述烯烃共聚物包括乙烯-乙酸乙烯酯共聚物。
17.根据权利要求1所述的可植入器件，其中所述疏水聚合物具有根据ASTM D1238-13在190℃的温度和2.16千克的载荷下测定的约0.2至约100克/10分钟的熔体流动指数。
18.根据权利要求1所述的可植入器件，其中所述聚合物基质完全由疏水聚合物形成。
19.根据权利要求1所述的可植入器件，其中所述大分子药物化合物为蛋白质、肽、酶、抗体、干扰素、白细胞介素、血液因子、疫苗、芯苷酸、脂质，或它们的组合。
20.根据权利要求1所述的可植入器件，其中所述膜层包含含有疏水聚合物的膜聚合物基质。
21.根据权利要求20所述的可植入器件，其中所述膜聚合物基质构成所述膜层的约30重量％至100重量％。
22.根据权利要求20所述的可植入器件，其中所述膜层不含所述大分子药物化合物。
23.根据权利要求20所述的可植入器件，其中所述大分子药物化合物构成所述膜层的约1重量％至约40重量％。
24.根据权利要求20所述的可植入器件，其中所述芯中所述大分子药物化合物的浓度与所述膜层中所述大分子药物化合物的浓度之比为约1.5或更高。
25.根据权利要求20所述的可植入器件，其中所述芯中所述疏水聚合物的熔体流动指数与所述膜层中所述疏水聚合物的熔体流动指数之比为约1至约20，根据ASTM D1238-13在190℃的温度和2.16千克的载荷下测定。
26.根据权利要求20所述的可植入器件，其中所述膜聚合物基质还包含亲水化合物。
27.根据权利要求26所述的可植入器件，其中亲水化合物构成所述膜聚合物基质的约1重量％至约50重量％，并且疏水聚合物构成所述膜聚合物基质的约50重量％至约99重量％。
28.根据权利要求20所述的可植入器件，其中所述亲水化合物包括亲水聚合物。
29.根据权利要求28所述的可植入器件，其中所述亲水聚合物包括藻酸钠、藻酸钾或藻酸钙，羧甲基纤维素，琼脂，明胶，聚乙烯醇，聚亚烷基二醇，胶原，果胶，几丁质，壳聚糖，聚1-己内酯，聚乙烯吡咯烷酮，聚(乙烯基吡硌烷酮-共聚-乙酸乙烯酯)，多糖，亲水聚氨酯，聚羟基丙烯酸酯，葡聚糖，黄原胶，羟丙基纤维素，甲基纤维素，蛋白质，乙烯-乙烯醇共聚物，水溶性聚硅烷，水溶性有机硅，水溶性聚氨酯，或它们的组合。
30.根据权利要求1所述的可植入器件，其中所述芯、膜层或两者包含放射对比剂。
31.根据权利要求1所述的可植入器件，其中所述芯界定外周向表面，所述膜层围绕所述外周向表面周向设置。
32.根据权利要求1所述的可植入器件，其中所述芯界定上外表面和下外表面，所述膜层与所述上外表面相邻设置。
33.根据权利要求32所述的可植入器件，其进一步包括与所述下外表面相邻设置的第二膜层。
34.根据权利要求33所述的可植入器件，其中所述第二膜层包含第二聚合物基质，在所述第二聚合物基质内任选地分散大分子药物化合物，其中所述芯聚合物基质中的大分子药物化合物的浓度大于所述第二膜层中的大分子药物化合物的浓度。
35.根据权利要求32所述的可植入器件，其中所述第二膜层不含所述药物化合物。
36.根据权利要求1所述的可植入器件，其中所述芯、膜层或两者由热熔挤出法形成。
37.阻止和/或治疗患者的病症、疾病和/或美容状态的方法，所述方法包括将根据前述权利要求任一项所述的器件皮下植入所述患者中。
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| US20190358167A1 (en) | 2019-11-28 |
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| BR112020023983A2 (pt) | 2021-02-23 |
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