CN1520895A - 利用可植入系统持续释放活性物质 - Google Patents

利用可植入系统持续释放活性物质 Download PDF

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CN1520895A
CN1520895A CNA2004100070640A CN200410007064A CN1520895A CN 1520895 A CN1520895 A CN 1520895A CN A2004100070640 A CNA2004100070640 A CN A2004100070640A CN 200410007064 A CN200410007064 A CN 200410007064A CN 1520895 A CN1520895 A CN 1520895A
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J·R·佩里
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K·E·迪奥尼
F·A·兰德劳
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S·D·拉特巴奇
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J·A·马鲁德
J·C·赖特
J·B·埃克恩霍夫
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M5/1452—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons
    • A61M5/14526—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by means of pistons the piston being actuated by fluid pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142—Pressure infusion, e.g. using pumps
    • A61M5/145—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M2005/14513—Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons with secondary fluid driving or regulating the infusion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61M2206/00—Characteristics of a physical parameter; associated device therefor
    • A61M2206/10—Flow characteristics

Abstract

本发明涉及将活性物质成分在预定给药期间进行释放的装置。将一个不可渗透的储存器划分为一个水－膨胀物质室和一个活性物质成分室。来自环境的液体通过半渗透栓被吸入到水－膨胀物质室并且通过逆扩散调节出口管释放活性物质成分。释放期间高达到两年。

Description

利用可植入系统持续释放活性物质
本发明申请是申请号为97192007.9、发明名称为“利用可植入系统持续释放活性物质”的中国专利申请的分案申请。
技术领域
本发明涉及生物活性物质的缓慢释放。具体地说，是涉及一种可植入的释放系统，用以将活性物质持续释放到一个自然或人工的体腔内的液体环境。
背景技术
将活性物质以控制的速率持续释放治疗疾病一直是药物释放领域的一个目标。为释放活性物质曾采用了各种方法。
一种方法是使用可植入的扩散系统。例如，Philip D.Darney在不孕症和妇产科学今论(Current Opinion in Obstetrics and gynecology)1991，3：470-476中所描述的用于避孕的皮下植入物。Norplant需要在皮下植入6个装有左炔诺孕酮的硅橡胶胶囊。防止受孕可达5年。植入物以简单的扩散形式运作，即，活性物质通过聚合物材料扩散，其速率由活性物质的组成和聚合物材料的性质所控制。Darney还进一步描述了称为CapranorTM和炔诺酮丸的可生物降解的植入物。这些系统被设计成释放避孕药约一年，而后溶化。CapranorTM系统包括其中装有左炔诺孕酮的聚(ε-己内脂)胶囊而小丸是10％纯胆甾醇和90％炔诺酮。
已有报导可植入的输液泵也被用于通过静脉内、动脉内、鞘内、腹膜内、脊柱内和硬膜外的路径释放药物。输液泵通常用手术植入下腹部皮下组织的囊内。在BBI Newsletter，第17卷，第12期，209-211页，1994年12月中描述了用于控制疼痛、化学疗法和胰岛素释放的系统。这些系统可以提供较简单的扩散系统更为精确地控制释放。
一种特别有前景的方法包括如同在美国专利第3987790、4865845、5057318、5059423、5112614、5137727、5234692和5234693号中所描述的渗透驱动装置，这些文献均引入本文以供参考。这些装置可植入动物体内以控制方式以预定给药期限释放活性物质。通常，这些装置是通过由外部环境吸入液体并释放相应量的活性物质进行运作的。
上述装置可用于将活性物质释放到所应用的液体环境中。虽然这些装置已应用于人类和兽医的目的，但仍需要能够释放活性物质，特别是极不稳定物质的装置，以便能够在持续的时间段内以控制的速率可靠地向人类释放。
发明内容
用可植入渗透系统向动物体内释放活性物质是众所周知的。将这些系统适用于人类产生了一系列的难题。用于人类植入的装置的尺寸需减小。装置的强度必须足以保证系统的牢固性。须确保精确的和可重现的释放速率以及持久性，并且由植入到启动释放的时间间隔要缩小到最短。在体腔内遇到升高温度的情况下，活性物质在持续的时间段内必须再现其纯度和活性。
因此，本发明一方面是一种用于将活性物质制剂释放到所应用的液体环境的液体-吸入装置。该装置包括水-膨胀的、半透性的材料，这种材料以与内壁密封的形式被安装在一个不可渗透储存器的一端。该装置还包括当水-膨胀材料膨胀时从装置被排出的活性物质。
另一方面，本发明涉及用于将活性物质释放到所应用液体环境中的可植入装置。该装置包括一个储存器和一个配套的逆扩散调节出口管。活性物质的流动路径包括一个在逆扩散调节出口管的连接面和储存器之间形成的通路。
另一方面，本发明涉及一种用于在预定的给药期间在所应用的液体环境中贮存活性物质的装置，该装置包括一个含有活性物质的储存器。储存器是不可渗透的并且至少部分是由金属材料制成。储存器接触活性物质的部分不与活性物质起反应，并由选自钛及其合金类的材料制成。
再一方面，本发明是一种可植入的、液体-吸入的、活性物质释放系统，系统包括一个不可渗透储存器。储存器带有一个活塞，它将储存器分为一个容纳活性物质的室和一个容纳水-膨胀物质的室。容纳活性物质的室带有一个逆扩散调节出口管。容纳水-膨胀物质的室带有一个半渗透的栓。栓或出口管可以在内部压力下从储存器脱开，该内部压力低于由水-膨胀物质所产生的最大渗透压力。
本发明还涉及一种液体-吸入的、可植入的活性物质释放系统，其释放的启动时间少于预定的给药时段的10％。
另一方面，本发明涉及一种制备可植入的、液体-吸入的活性物质的释放系统的方法。该方法包括在不可渗透的储存器的端部注模一个半渗透的栓从而使栓受到储存器的保护。
另一方面，本发明涉及一种不可渗透的活性物质释放系统用以释放一种易于降解的活性物质。储存器带有一个将储存器分割成一个水-膨胀物质室和一个活性物质室的活塞。水-膨胀物质室的开口端带有一个半渗透的膜而活性物质室的开口端带有一个逆扩散调节出口管。该系统有效地将活性物质室密封并将其与应用环境隔离。
另一方面，本发明涉及用于活性物质释放系统的逆扩散调节出口管。出口管限定了流动路径、其长度、内部横截面的形状和面积，提供了活性物质的平均线性流速，该流速大于所应用的环境内液体向内的线性流动。
本发明还涉及用于活性物质释放系统的半渗透的栓。该栓是水-膨胀的且在释放系统中必须是直线膨胀的以便在系统植入应用的液体环境后开始泵送。
本发明还涉及用于释放亮丙瑞林(Leuprolide)的可植入释放系统。
附图说明
所有的图都不是按比例绘制的，是用于说明本发明的各种实施方案的。相同的结构用相同的数字表示。
图1和2为本发明的释放装置两个实施方案的部分横剖面视图。
图3为图1中逆扩散调节出口管的放大的横剖面视图。
图4为说明管嘴直径和长度对药物扩散的影响的曲线。
图5、6、7和8为根据本发明的储存器的半渗透栓端部的另一个实施方案的放大的横剖面图。
图9、10和11为系统采用亮丙瑞林(图9)和蓝色染料和不同的膜(图10和11)的释放速率曲线。
发明详述
本发明提供了一种用于向应用液体环境释放活性物质的装置，其中活性物质直到其被释放之前必须得到保护以免受到液体环境的影响。实现了持续和受控释放。
定义
术语“活性物质”是指可选择地与可药用载体和可选择地与附加成分例如抗氧化剂、稳定剂、渗透促进剂等结合的活性物质。
“预定的给药时间”表示一个大于7天的时间段，通常在约30天到2年，优选地约大于1个月并通常在1个月到12个月之间。
“启动”释放的时间表示从植入所应用的液体环境中到活性物质真正以不小于预期的稳定状态速率的大约70％的速率释放的时间。
术语“不可渗透”意味着材料对于环境液体以及给药装置中所含的成分是充分不可渗透的，从而通过不可渗透装置进入或移出装置的这些材料的迁移非常之低以致在释放期间对装置的功能基本上没有不利影响。
术语“半渗透”意指材料对于外部液体是可以渗透的但对于给药装置和使用的环境中所含的其它成分基本上是不可渗透的。
本发明采用的术语“治疗有效量”或“治疗有效速率”是指产生预期的生物或药理效果所需要的活性物质的量或速率。
本发明的活性物质释放装置在需要持续和控制释放活性物质的情况下得到应用。在许多情况下，如果活性物质在释放前于使用环境接触就易于降解，而该释放装置避免了这种接触。
图1为本发明装置的一个实施方案。在图1中示出一个液体-吸入系统10，它包括一个不可渗透的储存器12。储存器12被活塞16分成两个室。第一室18适宜于盛装活性物质而第二室20适宜于盛装液体-吸入物质。一个逆扩散调节出口管22被插入第一隔段18的开口端，在第二室20的开口端插进一个水-膨胀半透栓24。图1中逆扩散调节出口管22示为一个凸螺纹部件与储存器12的光滑内表面处于相连接的位置从而在其间形成一个螺旋形通道34。如图3所示的储存器12和逆扩散调节出口管22连接面之间所形成的螺旋形通道34的螺距(x)、幅度(y)和横截面的面积和形状是影响通道34防止外部液体逆扩散进入室18中的成分的效能和装置中的回压的因素。出口管22的几何形状可以防止扩散进入储存器。通常，需选择这些特征值以使螺旋形流动通道34的长度和通过其中的活性物质的流动速率足以防止外部液体通过流动通道34的逆扩散，同时不会明显地增加回压，因而在启动后活性物质的释放速率由渗透泵送的速率控制。
图2为带有储存器12，活塞16和栓26的本发明的装置的第二个实施方案。在该实施方案中，流动通道36是由带螺纹的逆扩散调节出口管40和储存器12内表面上构成的螺纹38之间所形成的。逆扩散调节出口管40和储存器12的螺纹部分的幅度是不相同的因而在储存器12和逆扩散调节出口管40之间形成一个流动通道36。
分别示于图1和2中的水-膨胀半渗透的栓24和26被插入储存器以使储存器的壁同心地环绕着并保护着栓。在图1中，栓24的顶部50暴露在使用环境中，可以构成一个覆盖在储存器12端部的带有凸缘的端盖部分56。半渗透的栓24与储存器12的内表面为弹性地啮合，在图1中示出配有螺脊60以起到使半渗透的栓24和储存器12内表面有摩擦地相啮合的作用。另外，螺脊60用以生成附加的环向密封，在半渗透栓24因水化而膨胀之前起到密封的作用。螺脊60和储存器12内表面间的间隙可防止水化膨胀作用在储存器12上的应力，这种应力可以导致储存器12被拉坏或将栓24压坏或剪坏。图2为半渗透栓26的第二个实施方案，其中栓是用注模法注入储存器的顶部并且半渗透栓26的顶部与储存器12的顶部62齐平。在该实施方案中，栓的直径显著小于储存器12的直径。在两个实施方案中栓24和26在暴露于体腔内的液体时将会膨胀从而形成与储存器12间的更为紧密的密封。
上述实施例的部件新颖的构造提供了非常适于植入人体的可植入装置，并保证释放装置能在体温下的长时间贮存不稳定成分，该装置具有小于给药时间段10％的启动时间并可设计成高度可靠的和具有可预知的故障自动保险的形式。
储存器12必须足够坚固以保证其不致于漏渗、断裂、破坏或变形从而在应该不可渗透的使用期间需承受的应力作用下释放出其活性物质。特别是，其应设计成能以抵抗室20中水-膨胀材料所产生的最大渗透压力。储存器20还应该是化学惰性的和生物相容的，即，它必须是不与活性物质成分以及人体起反应的。适合的材料通常包括不起反应的聚合物或生物相容的金属或合金。聚合物包括丙烯腈聚合物，例如丙烯腈-丁二烯-苯乙烯三元共聚物等；卤化聚合物，例如聚四氟乙烯、聚氯三氟乙烯、四氟乙烯和六氟丙烯共聚物；聚酰亚胺；聚砜；聚碳酸酯；聚乙烯；聚丙烯；聚氯乙烯-丙烯酸共聚物；聚碳酸酯-丙烯腈-丁二烯-苯乙烯；聚苯乙烯；等。在下述文献中报告了水气透过用于形成储存器的组成物的速率：药学杂志(J.Pham.Sci.)，第29卷，1634-37页(1970)；Ind.Eng.Chem.，第45卷，2292-2306页(1953)；材料工程学(Materials Engineering)，第5卷，38-45页(1 972)；Ann.Book of ASTMStds.，第8卷第2期，208-211页和584-587页(1984)；和工业与工程化学(Ind.and Eng.Chem.)，第49卷，1933-1936页(1957)。在通用聚合物手册(Handbook of Common Polymers，Scott和Roff，CRC Press，ClevelandRubber Co.，Cleveland，OH)中公开了一些聚合物。本发明中使用的金属材料包括不锈钢、钛、铂、钽、黄金及其合金以及镀金铁合金、镀铂铁合金、钴-铬合金和氮化钛涂覆的不锈钢。由钛或含有高于60％，通常高于85％钛的钛合金制成的储存器特别适用于大多数尺寸要求严格的情况，适用于高负载能力和长期使用的情况和使用在植入部位对机体化学敏感的成分的情况或机体对成分敏感的情况。优选的系统在37C于14个月后至少保留有70％的活性物质并且至少有约9个月的储存稳定性，或者优选在2-8℃至少有约两年的储存稳定性。最优选将系统在室温下贮存。在某些实施方案中，对于不同于特殊说明的液体-吸入装置的使用情况，其中不稳定的成分是在室18之中，特别是蛋白质和/或肽成分，对于与这些成分接触的金属部件必须使用如上所述的钛或其合金制作。
本发明的装置提供了一个密封的室18，该室有效地将活性成分与液体环境隔离。储存器12由一种刚性的、不可渗透的和坚固的材料制成。水-膨胀半渗栓24由低硬度材料构成并与储存器的形状相适应从而在变湿时与储存器12内侧形成一种液体-紧固的密封。流动通道34使室18与环境液体的逆扩散隔开。活塞16将室18与被允许由半渗透栓24和26进入室20的环境液体相隔离，从而在稳-态流动情况下使用时，活性物质自出口管22以相应于通过半渗透栓24和26由环境流入室20中的水-膨胀材料的水的速率排出。因此，栓和活性物质成分即使在储存器变形的情况下也不致受到损害且其功能也不会影响。另外，避免了密封胶和粘结剂的使用同时也解决了附带的生物相容性问题以及便于制造的问题。
制作半渗透栓的材料为半渗透的并在变湿时能与储存器的形状相适应以及能够粘附于储存器的刚性表面上的。当半渗透栓被置于液体环境因其水合作用而膨胀，从而在栓和储存器间的连接面形成密封。所设计的储存器12与出口管22之间以及储存器12与栓24和26之间的密封强度应能承受由装置所产生的最大渗透压力。在另一个优选的方案中，所设计的栓24和26应能承受至少10倍的渗透物质室20的运作压力。在又一个方案中，在一定的内部压力下栓24和26可从储存器脱开，该压力低于使逆扩散调节出口管脱开所需的压力。在此故障自动保险的实施方案中，水-膨胀物质室将被打开并降低压力，从而避免了挤出扩散调节出口管和相伴随的大量活性物质的释放。在其它情况下，其中故障自动保险系统需释放出活性物质成分而不是水-膨胀物质成分，半渗透栓必须在一定的压力下脱开，该压力大于出口管的压力。
不论是那一种情况，半渗透栓必须长得足以在运作的情况下与储存器壁密封地啮合，即，其必须具有1∶10和10∶1之间的长度与直径比，优选地长度直径比至少约1∶2，并通常在7∶10和2∶1之间。栓必须能够吸入约为其重量0.1％和200％之间的水。栓的直径应能使其在作为一个或更多的环形区域密封接触的结果即吸水前密封地安装在储存器内，并能在吸水后就地膨胀从而形成与储存器更为紧密的密封。制作半渗透栓的聚合物材料可依泵送速率和装置构造的要求而不同，可以包括但不限于可塑纤维素材料、增强的聚甲基丙烯酸甲酯例如羟乙基甲基丙烯酸酯(HEMA)和高弹材料例如聚亚胺酯和聚酰胺、聚醚-聚酰胺共聚物、热塑共聚多酯等。
活塞16将室20中的水-膨胀物质与室18中的活性物质隔离并能够在压力下在储存器12中密封地移动。活塞16优选地与一种较储存器12硬度低的材料制成并能变形以装入储存器的腔内并与储存器12形成一种液体-紧固的压力密封。制作活塞的材料优选地为高弹材料，该种材料是不可渗透的，包括但不限于聚丙烯，橡胶例如EPDM、硅橡胶、丁基橡胶等，以及热塑高弹体例如可塑聚氯乙烯、聚亚胺酯、Santoprene、C-FlexTPE(固化聚合物技术公司(ConsolidatedPolymer Technologies Inc.))等。活塞可以设计成自动-加载或压力-加载的。
逆扩散调节出口管22形成释放通道，通过该通道活性物质由室18流入植入的部位，活性物质在此被吸收。出口管22和储存器12间的密封可以设计成能够承受在装置内生成的最大渗透压力或如上所述的故障自动保险的形式。在一个优选实施方案中，使逆扩散调节出口管22脱开所需的压力至少为10倍移动活塞16所需的压力和/或至少为10倍室18中的压力。
活性物质的流出路径为在逆扩散调节出口管22和储存器12的连接面间形成的通道34。通道的长度，出口管路径34或36的内部横-截面的形状和面积的选择应使流出的活性物质的平均线速度大于所应用的环境中的物质因扩散或渗透而引起的向内的线性通量，从而减少或降低逆扩散及其污染泵的内部、破坏稳定性、稀释或其它改变成分的有害的效果。活性物质的释放速率可以通过改变出口管通道的几何特性加以改变，其间的关系如下所示。
活性物质自出口管22向外的流动是由系统的泵送速率和室20中的活性物质的浓度所限定并可用算式表示如下：
    Qca＝(Q)(Ca)                                (1)其中
    Qca为以mg/日计的向外转运的物质A
    Q为以cm3/日计的向外转运的物质及其稀释液的总量
    Ca为以mg/cm3计的室20中组成成分中物质A的浓度
物质A通过出口管22中的材料的扩散流动为物质浓度、流动路径34或36的横-截面形状、物质扩散能力和流动路径34或36的长度的函数，并可表示如下：
    Qda＝Dπr2ΔCa/L                            (2)其中
    Qda为以mg/日计的扩散转运的物质A
    D为以cm2/日计的通过路径34或36中材料的扩散能力
    r为以cm计的流动路径的有效内半径
ΔCa为以mg/cm3计的储存器中物质A的浓度与出口管22外身体内的浓度之差
    L为以cm计的流动路径的长度
通常，储存器内物质的浓度远大于管口外身体内的物质的浓度，因此其差异，ΔCa可以近似地用储存器内物质的浓度Ca表示。
    Qda＝Dπr2Ca/L                               (3)
通常需要将物质的扩散流量保持在小于向外流动的10％。这可由下式表示：
    Qda/Qca＝Dπr2Ca/QCaL＝Dπr2/QL    0.1           (4)
式4表示相对扩散流量随容量流动速率和路径长度的增加而降低，随扩散能力和通道半径的增加而增加，并与药物浓度无关。将式4作为长度(L)和直径(d)的函数对于D＝2×10-6cm2/秒和Q＝0.36μl/日作图，以图4表示。
在管口开向室18内，水的扩散流量可以近似地表示为：
    Qwd(res)＝C0Qe(-QL/DwA)                        (5)其中
    C0为以mg/cm3计的水的浓度分布
    Q为以mg/日计的质量流动速率
    L为以cm计的流动路径的长度
    Dw为以cm2/日计通过流动路径中材料的水的扩散能力
    A为以cm2计的流动路径的横-截面面积
通过管口的流体动力学压力的降低可由下式计算：
    ΔP＝8QLμ/πr4                                (6)
联立求解式(4)，(5)和(6)所得结果示于表1，其中：
    Q  ＝0.38μl/日
    Ca ＝0.4mg/μl
    L  ＝5cm
    Da ＝2.00E-06cm2/秒
    μ ＝5.00E+02cp
    Cw0＝0mg/μl
    Dw ＝6.00E+06cm2/秒
表1
               药物扩散和泵送             水的注入   压力降低
  有效的     泵送速率 扩散     扩散向外
  管嘴直径     横截面     QCa     QDa     QDa/QCa   QDw   Qdw   ΔP
  (mil)     面积mm2     mg/日     mg/日   mg/日   mg/年   磅/英寸2
    1     0.00051     0.152     0.0001     0.0005   0   0   1.55800
    2     0.00203     0.152     0.0003     0.0018   1.14E-79   4.16E-77   0.09738
    3     0.00456     0.152     0.0006     0.0041   4.79E-36   1.75E-33   0.01923
    4     0.00811     0.152     0.0011     0.0074   8.89E-21   3.25E-18   0.00609
    5     0.01267     0.152     0.0018     0.0115   1.04E-13   3.79E-11   0.00249
    6     0.01824     0.152     0.0025     0.0166   7.16E-10   2.61E-07   0.00120
    7     0.02483     0.152     0.0034     0.0226   1.48E-07   5.4E-05   0.00065
    8     0.03243     0.152     0.0045     0.0295   4.7E-06   0.001715   0.00038
    9     0.04105     0.152     0.0057     0.0373   5.04E-05   0.018381   0.00024
    10     0.05068     0.152     0.0070     0.0461   0.000275   0.100263   0.00016
    11     0.06132     0.152     0.0085     0.0558   0.000964   0.351771   0.00011
    12     0.07298     0.152     0.0101     0.0664   0.002504   0.913839   0.00008
    13     0.08564     0.152     0.0118     0.0779   0.005263   1.921027   0.00005
    14     0.09933     0.152     0.0137     0.0903   0.00949   3.463836   0.00004
    15     0.11402     0.152     0.0158     0.1037   0.015269   5.573195   0.00003
    16     0.12973     0.152     0.0179     0.1180   0.022535   8.225224   0.00002
    17     0.14646     0.152     0.0202     0.1332   0.031114   11.35656   0.00002
    18     0.16419     0.152     0.0227     0.1493   0.040772   14.88166   0.00001
    19     0.18295     0.152     0.0253     0.1664   0.051253   18.70728   0.00001
    20     0.20271     0.152     0.0280     0.1844   0.062309   22.7427   0.00001
计算表明管嘴直径在约3和10mil之间和长为2到7cm对于具有上述运行条件的装置是最佳的。在一个优选实施方案中，经过管口的压力降低小于将逆扩散调节出口管22脱开所需压力的10％。
逆扩散调节出口管22优选地形成一个螺旋形通道34或36包括一个长的流动路径，通过一种装置将出口管机械地连接在储存器中而不用粘结剂或其它密封胶。逆扩散调节出口管由一种惰性的和生物相容的材料制成，材料选自但不限于金属，包括但并不限于钛、不锈钢、铂及其合金以及钴-铬合金等；聚合物包括但不限于聚乙烯、聚丙烯、聚碳酸酯和聚甲基丙烯酸甲酯等。流动路径的长度通常在约0.5和20cm之间，优选地长度在约1和10cm之间，直径在约0.001和0.020英寸之间，优选地在约0.003和0.015英寸之间，以便使流动在约0.02和50μl/日之间，通常是0.2到10μl/日而时常为0.2到2.0μl/日。另外，可将一个导管或其它系统连接在逆扩散调节出口管的端部以便对释放的活性物质成分提供一个从植入物取出的位置。这种系统在本领域中是熟知的，并在例如美国专利第3,732,865和4,340,054中作了描述，这些文献均引入本文以供参考。另外，流动路径的设计对于在这里具体叙述的液体-吸入装置以外的系统可能也是有用的。
上述的本发明装置的构造同样也适用于由启动到稳-态流动速率的最小滞后时间段的情况。这部分地是由半透栓24或26的构造实现的。当水被半透栓吸入时，栓膨胀了。其径向膨胀为刚性的储存器12所限，所以膨胀必定沿直线发生，从而推动室18中的水-膨胀物质，物质又推动活塞16。这将使泵送在水到达水-膨胀物质之前就开始，否则在开始泵送之前是要求水到达膨胀介质的。为便于可靠地启动，流动路径34可预先用室18中的活性物质充填。另外，出口管22的几何特性为初始释放提供了方便，它受到药物沿出口管的长度的浓度梯度的影响。启动时间段小于预定的释放时间的约25％，时常是小于约10％，通常小于预定的释放时间的约5％。在一个一年用的系统的优选实施方案中，至少达到稳-态流动速率70％的时间是14天。
室20中的水-膨胀物质成分优选地为一种组织耐受性成分，其高渗透压力和高可溶性可在一个较长的时间段内推动活性物质同时在半透膜所容许的水中保持为饱和溶液。水-膨胀物质优选选择皮下组织所耐受的，至少以泵送速率和推测浓度能够允许自比标记时间更长地保留在患者体内的植入装置中的偶然送药。在优选实施方案中，水-膨胀物质在正常运作条件下不通过半渗栓24或26产生任何显著的渗滤或渗透(例如小于8％)。渗透物质，例如带有适量的压片剂(润滑剂和黏合剂)和粘度调节剂的NaCl，例如羧甲基纤维素钠或聚丙烯酸钠都是优选的水-膨胀物质。其它用作水-膨胀物质的渗透物质包括易渗聚合物和易渗剂并在例如美国专利第5,413,572号中进行了叙述，这些文献均引入本文以供参考。水-膨胀物质成分可以是一种浆状物、小片、铸模或挤压材料或本领域中所熟知的其它形式。可将一种液体或凝胶添加剂或填充剂加入室20中以便排除渗透机械周围空间的空气。从装置排除空气意在减少标定的外部压力改变(例如，±7磅/英寸2(±5标准大气压))对释放速率的影响。
本发明的装置适用于各种各样的活性物质。这些物质并非限定地包括药理学的活性肽和蛋白质、基因和基因制品、其它基因治疗物质及其它小分子。多肽并非限定地包括生长激素、生长激素类似物、生长调节素-C、促性腺激素释放激素、促卵泡成熟激素、促黄体生成素、LHRH、LHRH类似物(例如亮丙瑞林、那法瑞林和戈舍瑞林)、LHRH激动剂和拮抗剂、生长激素释放因子、降钙素、秋水仙素、促性腺激素(例如绒膜促性腺激素)、催产素、奥曲肽、生长激素加氨基酸、后叶加压素、促肾上腺皮质激素、表皮生长因子、催乳激素、生长抑素、生长激素加蛋白质、α1-24促肾上腺皮质激素(osyntropin)、赖氨酸加压素；多肽例如促甲状腺激素释放激素、促甲状腺激素、肠促胰液肽、肠促胰酶素、脑啡肽、高血糖素、内分泌的和血流中分布的内分泌物质等。其它可释放的物质包括α1抗胰蛋白酶、凝血因子VIII、凝血因子IX和其它凝结因子，胰岛素和其它肽激素、促肾上腺皮质激素、促甲状腺激素和其它垂体激素，干扰素α、β、和δ，促红细胞生成素，生长因子例如GCSF、GMCSF、胰岛素样生长因子1、组织血浆酶原激活剂、CD4、dDAVP、白细胞介素-1受体拮抗剂、肿瘤坏死因子、胰酶、乳糖酶、细胞激动素、白细胞介素-1受体拮抗剂、白细胞介素-2、肿瘤坏死因子受体、肿瘤抑制剂蛋白质、细胞毒性蛋白质以及重组抗体和抗体片断等。
上述物质适用于治疗各种适应症，包括但不限于血友病和其它血液病、生长障碍、糖尿病、白血病、肝炎、肾衰、HIV感染、遗传疾病(例如脑甙脂酶缺损和腺甙脱氨酶缺乏)、高血压、败血性休克、自体免疫疾病(例如多发性硬化症、格雷夫斯病、全身性红斑狼疮和类风湿关节炎)、休克和消耗性障碍、膀胱纤维化、不耐乳糖、节段性回肠炎、炎性肠疾病、胃肠和其它癌症。
活性物质可以是无水的或含水的溶液，悬浮液或是与可药用赋形剂或载体的配合物从而形成一种可流动的成分，并可搁置或冷藏储存很长的时间，以及储存在植入释放系统中。所述成分可以包括可药用载体和其它惰性成分。活性物质可以是各种形式的，例如不带电的分子、分子配合物成分或可药用盐。同样，也可使用易于在身体pH、酶等条件下水解的物质的简单衍生物(例如前药、醚、酯、酰胺等)。
应该理解可以将多于一种的活性物质加入到本发明装置的活性物质成分中，使用术语“物质”并不排除使用两种或多种这样的活性物质。本发明的给药装置可应用于例如人类或其它动物。所应用的环境为液体环境并可包括任何皮下位置或体腔，例如腹膜或子宫，但这可以是也可不等同于活性物质成分最终释放点。在一个治疗过程中可以采用单个给药装置或数个给药装置向被治疗对象给药。装置被设计成在一个预定的给药时间内保持植入状态。如果在给药后装置未被取出，它将被设计成能够抵抗水-膨胀物质的最大渗透压力或被设计成带有一个分流通路以释放装置内所产生的压力。
本发明的装置在使用前优选地应该是无菌的，特别是当这种应用是植入时。这可以通过分别对每个部件进行消毒来完成，例如用γ辐射、蒸汽消毒或无菌过滤，然后组装成最终的系统。或者先组装装置，然后利用适合的方法最终进行消毒。
本发明装置的制造
储存器12优选地通过机械加工一个金属棒或压铸或注模聚合物进行制造。储存器的顶部可以是开敞的如图1所示或带有一个空腔如图2所示。
在储存器12如图1所示为敞开时，由储存器外部机械地插入一个水-膨胀半透栓24，并在放入活塞和水-膨胀物质成分之前或之后都不采用粘结剂。储存器12可以带有与栓24上的棱或螺纹相啮合的槽或螺纹。
在储存器12如图2所示带有一个空腔时，空腔的形状可以是圆柱形的，如图5所示；可以是阶梯状的，如图6所示；可以是螺旋状的，如图7所示；或可以是留有空间的形状，如图8所示。然后将半透栓26注入，插入，或用其它方法组装进入空腔从而与储存器壁形成密封。
在机械地或通过焊接或注入的方式将栓26插入以后，将水-膨胀物质装入储存器，接下来插入活塞，采取适当的步骤排除裹进的空气。活性物质用注射器或精密的送药泵充入装置。通常用转动或螺旋的动作，或用轴向压力将扩散减速器插入装置中。
以下的例子是用来说明本发明的。这些例子并不构成对本发明范围的限制。按照本发明公开以及本文附图和权利要求，这些例子的改变和等同对于本领域普通技术人员来讲是很明显的。
具体实施方式
                             实施例
例1-带有HDPE储存器的装置的制造
一个含有用于治疗前列腺癌的醋酸亮丙瑞林的系统是由以下部件组装而成的：
储存器(HDPE)(外径5mm，内径3mm)
活塞(Santoprene)
润滑剂(硅酮药用液)
压缩的渗透起动部件(60％NaCl、40％羧甲基纤维素钠)
膜栓(Hytrel聚醚-酯块状共聚物，注塑成所需的形状)
逆扩散调节出口管(聚碳酸酯)
活性物质(60％丙二醇和40％醋酸亮丙瑞林0.78g)
组装
活塞和储存器内径用硅酮药用液稍加润滑。活塞16被插入室20的开口端。然后将两个渗透起动片(40mg每片)插入在活塞16顶部。在植入后，渗透起动部件与储存器端部齐平。膜栓24是通过将其与储存器对准并轻轻推动植入直到栓完全啮合在储存器中。活性物质被装入一个注射器，而后由开口端将材料注入开口管而充入室18中直到制剂成分距端部为约3mm。填满的储存器进行离心分离(出口管端在“上”)以便将在充填时裹进制剂成分中的气泡排出。出口管22是拧入储存器开口端的直至其完全啮合。当出口管被拧进时，多余的制剂成分由管口逸出以保证标准的充填。
例2-例1中装置的插入
例1中装置的插入是在无菌条件下用一个与植入Norplant避孕植入物时所用的相似的套针将装置放入皮下。插入的部位典型地在上臂内侧，在肘上8到10cm。
使该部位麻醉并通过皮肤作一切口。切口约4mm长。将套针插入切口直到套针的尖端位于距切口4到6cm的距离。而后将塞子从套针移开并将例1中的装置插入套针。装置随即用塞子推进到套针的开口端。然后塞子固定在适当的位置上，从而使例1中的装置保持不动同时将套针自装置和塞子上拉出。将塞子移开从而将植入物留在得到很好地控制的部位。开口的边缘用皮肤闭合罩固定。该部位被覆盖并保持干燥2到3天。
例3-例1中装置的取出
例1中的装置以如下方式取出：通过触摸上臂部位以探明装置的位置。在植入物一端的部位实行麻醉并通过皮肤和所有环绕植入物区域的纤维包膜组织作一个约4mm的垂直切口。推动装置相对切口相反的一端从而将装置相对于切口的近端自切口被推出。用手术刀切断其它纤维组织。取出后，可以接着按例2的过程植入一个新的装置。
例4-例1中装置的释放速率
在一些玻璃试管中装入35ml蒸馏水，然后放入37℃的水浴中。将如例1所述的单个装置放入每个试管中，这些试管周期地进行改换。自系统中释放的速率曲线示于图9。系统没有任何启动时间，因为系统显示一个初始高释放时间段随后是一个约为200天时间段的较低的稳定释放状态。
例5-释放速率曲线
在一些玻璃试管中装入35ml蒸馏水，然后放入37℃的水浴中。在试管达到温度后，如图1所示的单个装置被放入每个试管中，该装置还带有如下所述的膜材料，并含有1％FD&C蓝色染料水溶液作为药物成分。来自试管中的水通过膜的渗透导致系统将成分(蓝色染料)泵送进入试管里周围的水中。在固定的时间间隔，系统被转换到新的试管中。释放的染料的量利用分光光度计测定每个试管中蓝色染料的浓度来确定。泵送速率可由总的染料释放量，试管中水的体积，染料的初始浓度和系统在试管中的时间间隔计算出来。两组不同的试验结果示于图10和11。图10表示3个具有不同栓材料(Hytrel2、3和12个月的系统)的不同的系统，图11表示4个具有不同栓材料的系统。这些材料是：
     膜                                材料
    1个月                              Pebax 25(聚酰胺)
    2个月                       Pebax 22(聚酰胺)
    3个月                       聚亚胺酯(HP60D)
    12个月                      Pebax 24(聚酰胺)
这些系统的释放时间段可以是由2到12个月，这依赖于所应用的膜。
例6-具有钛储存器的释放装置的制造
一个含有用于治疗前列腺癌的含醋酸亮丙瑞林系统是由以下部件组装而成的：
储存器(钛，Ti6A14V合金)(外径4mm，内径3mm)
活塞(C-Flex)
润滑剂(硅酮药用液)
压缩的渗透起动部件(76.4％NaCl、15.5％羧甲基纤维素钠、6％聚乙烯吡咯烷酮、0.5％硬脂酸镁、1.6％水)
PEG 400(8mg，添加于渗透起动工具中以充填空气空间)
膜栓(聚亚胺酯聚合物，注塑成所需的形状)
逆扩散调节出口管(聚乙烯)
药物成分(0.150g的60％水和40％醋酸亮丙瑞林)
组装
活塞和储存器内径稍加润滑。活塞在膜的端部插入储存器约0.5cm。将PEG400加入储存器。然后将两个渗透起动片(每个40mg)由膜的端部插入储存器。插入后，渗透起动部件与储存器端部齐平。膜栓是通过将其与储存器对准并轻轻推进直到栓的保持形状是完全啮合于储存器中。剂型成分被装入注射器中，而后用其由出口管的端部通过将剂型成分注入开口管从而充入储存器，直到成分距离端部为约3mm处。充满的储存器进行离心过滤(出口管端在“上”)以将在充填时裹进制剂成分中的气泡排出。将出口管拧进储存器开口端直至完全啮合。当拧进出口管后，多余的制剂成分将自管嘴逸出以保证标准的充填。
例7-具有钛储存器的醋酸亮丙瑞林释放装置的制造
一种含有用于治疗前列腺癌的醋酸亮丙瑞林的系统是由以下部件组装而成的：
储存器(钛Ti6A14V合金)(外径4mm，内径3mm，长4.5cm)
活塞(C-FlexTPE高弹体，可由Consolidated PolymerTechnologies，Inc.购得)
润滑剂(硅酮药用液360)
压缩的渗透起动片(76.4％NaCl、15.5％羧甲基纤维素钠、6％聚乙烯吡咯烷酮、0.5％硬脂酸镁、1.5％水，总计50mg)
PEG 400(8mg，添加到渗透起动部件以充填空气空间)
膜栓(聚亚胺酯聚合物摄入20％的水，注塑成所需的形状3mm直径×4mm长)
逆扩散调节出口管(聚乙烯，带有6mil×5cm通道)
药物成分(将醋酸亮丙瑞林溶进DMSO直到所量测的亮丙瑞林含量为65mg)
组装
如例6所示，利用无菌操作组装经γ-辐射的部件组装系统，并无菌地充入经无菌过滤的亮丙瑞林DMSO制剂成分。
释放速率
系统释放亮丙瑞林成分约0.35μl/日，其中平均每日释放总量为150μg亮丙瑞林。装置可以这一速率释放亮丙瑞林至少一年。该系统经14天可达到稳态释放量的约70％。
植入与取出
系统的植入将如例2中对晚期前列腺癌患者在局部麻醉下利用切口和套针进行。
一年后，系统将如例3所述在局部麻醉下取出。
例8-前列腺癌的治疗
醋酸亮丙瑞林，一种LHRH兴奋剂，在连续地并按治疗剂量给药时可起到一种促性腺激素分泌的有效抑制剂作用。对动物和人类的研究表明，在一个初始刺激之后长期释放醋酸亮丙瑞林导致抑制睾丸甾类物的产生。这一效果在停止药物治疗以后是可以逆转的。施用醋酸亮丙瑞林可导致抑制某些激素-依赖型肿瘤的生长(Noble和Dunning雄鼠中的前列腺肿瘤和雌鼠中DMBA-引发的乳房肿瘤)以及生殖器官的萎缩。在人类中，施用醋酸亮丙瑞林导致初始的促黄体生成素(LH)和促卵泡成熟激素(FSH)循环水平的增加，引起性腺类固醇(男性中的睾酮和二氢睾酮)水平的瞬时增加。然而，连续使用醋酸亮丙瑞林导致LH和FSH水平的降低。在男性中，睾酮减至阉割的水平。这种降低发生在开始治疗之后的二至六周之内，在前列腺癌的患者中睾酮的阉割水平曾显示可达多年之久。口服时醋酸亮丙瑞林没有活性。
系统按例7中所述进行制造，然后如所描述的予以植入。使用这种系统连续释放亮丙瑞林一年，将使睾酮降至阉割的水平。
以上所进行的描述仅是为了便于理解。不应从中理解出不必要的限制，因为修饰对于本领域的普通专业人员来讲是显而易见的。

Claims (30)

1.一种用于将活性物质释放到所应用的液体环境中的液体-吸入装置，所说的装置包括一种水-膨胀半渗透材料，该材料以密封的形式放置在一个不可渗透的储存器一端的内表面，还包括当水-膨胀材料膨胀时从该装置释出的活性物质。
2.根据权利要求1的装置，其特征在于栓的长度与直径之比为1∶10到10∶1。
3.根据权利要求1的装置，其特征在于半渗透材料是装配进储存器的一个开口端的。
4.根据权利要求1的装置，其特征在于半渗透材料是装配进所说的储存器的一个腔内。
5.根据权利要求4的装置，其特征在于腔的形状是选自包括圆柱形，阶梯形，螺旋形和具有间隔的一组形状中。
6.一种用于将活性物质释放到所应用的液体环境的可植入的装置，所说的装置包括一个储存器和一个相连接的逆扩散调节出口管，其中活性物质的流动路径包括一个在储存器和逆扩散调节出口管连接面间形成的通道。
7.根据权利要求6的装置，其特征在于活性物质以0.02到50μl/目的速率释放。
8.一种用于将活性物质在预定的给药期间储存在所应用的液体环境中的装置，该装置包括一个含有活性物质的储存器，所说的储存器至少应部分地由金属材料制成，所述储存器与所述活性物质接触的部分与活性物质应是不起反应的，与活性物质接触的所说的金属材料选自钛及其合金。
9.根据权利要求8的装置，其特征在于钛合金至少含有60％的钛。
10.一种可植入的液体-吸入的活性物质释放系统，该系统包括一个不可渗透的储存器并带有一个活塞，活塞将储存器划分成一个容纳活性物质的室和一个容纳水-膨胀物质的室，其中容纳活性物质的室带有一个逆扩散调节出口管而容纳水-膨胀物质的室带有一个半渗透的栓；其中栓在一定的内部压力下是可以从储存器脱开的，此压力低于由水-膨胀物质所产生的最大渗透压力。
11.一种可植入的液体-吸入的活性物质释放系统，该系统包括一个不可渗透的储存器并带有一个活塞，活塞将储存器划分成一个容纳活性物质的室和一个容纳水-膨胀物质的室，其中容纳活性物质的室带有一个逆扩散调节出口管而容纳水-膨胀物质的室带有一个半渗透的栓；其中出口管在一定的内部压力下是可以从储存器脱开的，此压力低于由水-膨胀物质所产生的最大渗透压力。
12.一种液体-吸入的可植入的活性物质释放系统，用以将活性物质在预定的给药期间内释放到所应用的液体环境中，其中启动时间少于预定的给药时间的10％。
13.一种制造液体-吸入的可植入的活性物质释放系统的方法，该系统用于在预定的给药时间内将活性物质释放到所应用的液体环境，所说的方法包括注塑一个半渗透的栓到不可渗透的储存器的端部中从而使半渗透的栓得到储存器的保护。
14.一种可植入的亮丙瑞林释放系统，包括∶
(a)一个可植入的储存器；
(b)一个活塞，该活塞将储存器划分为第一和第二室，第一和第二每个室都有一个开口端；
(c)在第一室中的水-膨胀物质成分；
(d)在第二室中的亮丙瑞林成分；
(e)在第一室开口端中的一个半渗透的栓；和
(f)在第二室开口端中的一个逆扩散调节出口管；
其中系统有效地密封住第二室并将亮丙瑞林成分与所应用的环境隔离。
15.根据权利要求14中所说的系统，其特征在于储存器是钛或钛合金的。
16.根据权利要求14中所说的系统，其特征在于活塞是由C-FlexTPE制成的。
17.根据权利要求14中所说的系统，其特征在于水-膨胀物质成分包含至少约64mg氯化钠。
18.根据权利要求14中所说的系统，其特征在于水-膨胀物质成分包含NaCl、胶凝渗透聚合物及制粒和加工助剂。
19.根据权利要求14中所说的系统，还包括在第一室中的添加剂。
20.根据权利要求19中所说的系统，其特征在于添加剂为PEG 400。
21.根据权利要求14中所说的系统，其特征在于亮丙瑞林成分为溶在DMSO中的醋酸亮丙瑞林，且亮丙瑞林的测定含量为37％。
22.根据权利要求14中所说的系统，，该系统包含65mg亮丙瑞林。
23.根据权利要求14中所说的系统，其特征在于半渗透的栓是由吸收了20％的水的聚亚胺酯材料制成。
24.根据权利要求14中所说的系统，其特征在于逆扩散调节出口管是由聚乙烯制成的并具有形状为螺旋状的流动路径，其直径在0.003和0.020英寸之间且长度为2到7cm。
25.根据权利要求14中所说的系统，该系统每日释放约0.35μL亮丙瑞林成分。
26.根据权利要求25中所说的系统，该系统可持续释放亮丙瑞林成分约一年。
27.根据权利要求14中所说的系统，该系统第14天达到稳态释放的至少约70％。
28.根据权利要求14中所说的系统，该系统每日释放亮丙瑞林约150μg。
29.一种治疗前列腺癌患者的方法，该方法包括施用至少一个权利要求14中的系统。
30.一种可植入的亮丙瑞林释放系统，包括：
(a)一个钛合金储存器；
(b)一个C-Flex TPE活塞，该活塞将储存器划分为第一和第二室，第一和第二每个室都有一个开口端；
(c)在第一室中的一个压缩的NaCl-基的渗透起动部件和一种PEG添加剂；
(d)在第二室中为溶于DMSO的醋酸亮丙瑞林溶液形式的65mg亮丙瑞林。
(e)在第一室开口端中的一个吸收了20％水的半渗透的聚亚胺酯栓；和
(f)在第二室开口端中的一个带有螺旋形流动路径的聚乙烯逆扩散调节出口管；
在皮下植入以后，该系统可持续地每日释放约150μg亮丙瑞林，释放约一年。
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