CN101453982A - 两件式内部通道渗透递送系统流动调节器 - Google Patents

两件式内部通道渗透递送系统流动调节器 Download PDF

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CN101453982A
CN101453982A CNA2007800187567A CN200780018756A CN101453982A CN 101453982 A CN101453982 A CN 101453982A CN A2007800187567 A CNA2007800187567 A CN A2007800187567A CN 200780018756 A CN200780018756 A CN 200780018756A CN 101453982 A CN101453982 A CN 101453982A
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CN101453982B (zh
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S·D·劳滕巴赫
P·E·德拉瑟纳
P·C·赞莫拉
M·A·德斯贾丁
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Intarcia Therapeutics Inc
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    • AHUMAN NECESSITIES
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    • Y10TTECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T137/00Fluid handling
    • Y10T137/0318Processes
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

渗透递送系统流动调节器包括构造和布置用于定位在渗透递送系统的容器的开口中的外壳,插入到所述外壳中的内芯,和在外壳和内芯之间限定的螺旋状的流动通道。所述流动通道适用于从渗透递送系统的容器中递送活性剂制剂。

Description

两件式内部通道渗透递送系统流动调节器
相关申请的交叉引用
[0001]本申请要求2006年5月30日的美国临时申请60/809,451的优先权,所述申请的内容被并入本文作为参考。
发明背景
[0002]本发明一般地涉及用于在流体环境中持续递送活性剂的渗透递送系统。更具体地,本发明涉及用于在流体环境中从渗透递送系统递送活性剂的流动调节器。
[0003]图1说明了现有技术的渗透递送系统40,如Peterson等人的美国专利6,524,305所述的。所述递送系统40包括容纳渗透剂47和活性剂44的壳体42。分离元件46在渗透剂47和活性剂44之间形成隔离物。半渗透性的塞48被插入到壳体42的第一开口45中。半渗透性的塞48选择性地允许流体进入壳体42的内部。流动调节器20被插入到壳体42的第二开口39中。流动调节器20允许活性剂44离开壳体42的内部,而控制流体反扩散到壳体42的内部。在渗透递送系统40被置于流体环境中时,来自壳体42外部的流体通过半渗透性塞48进入壳体42并且渗入渗透剂47,引起渗透剂47膨胀。渗透剂47在膨胀时使分离元件46移动,引起活性剂44通过流动调节器20递送到应用环境。
[0004]在图1中所示的现有技术的渗透递送系统40中,流动调节器20的外表面包括螺旋状的递送通路32,活性剂44通过所述递送通路32从壳体42的内部流通到外部。形成螺旋状递送通路32的螺纹(thread)36抵接壳体42的内表面43,使得活性剂44在通过螺旋状递送通路32时接触壳体42的内表面43。对螺旋状递送通路32的间距、距离、横截面积、和形状进行选择,使得从流体环境到壳体42中的反扩散最小化。在流动调节器20中提供填充孔22和排气孔24。在装配这种渗透递送系统40时,首先将流动调节器20插入到壳体42中。然后通过填充孔22将活性剂44注射到壳体42中,而壳体42中的气体通过排气孔24流出。其后,将端盖26插入到孔22、24中,使得只通过螺旋状递送通路32发生活性剂44的递送。
[0005]从上述内容可见,仍希望在渗透递送系统中提供另外的可靠性和流动调节能力。
发明内容
[0006]在一个方面中,本发明涉及渗透递送系统流动调节器,其包括被构造和布置用于定位在渗透递送系统的容器开口中的外壳,插入到外壳中的内芯,和在所述外壳和内芯之间限定的螺旋状流动通道,所述流动通道适合用于从渗透递送系统的容器递送活性剂制剂。
[0007]在另一个方面中,本发明涉及渗透递送系统,其包括容器;设置在所述容器的第一末端、用于选择性地允许进入容器的流动的半渗透性塞;设置在所述容器的第二末端的流动调节器,所述流动调节器包括适合用于将包含在容器中的活性剂制剂递送到所述渗透递送系统在其中起作用的流体环境中的内部螺旋通道。
[0008]在又一个方面中,本发明涉及用于活性剂制剂的可植入的递送系统,其包括由非渗透性材料制成的容器,在所述容器中的包含渗透动力物质的第一室,在所述容器中的包含活性剂制剂的第二室,设置在容器的第一末端与第一室邻接的半渗透性塞,和设置在容器的第二室与第二室邻接的如上所述的流动调节器。
[0009]从以下的说明书和随后的权利要求显而易见本发明的其它特征和优点。
附图说明
[0010]如下所述的附图说明本发明的典型的实施方案,并且不应将其考虑为限制本发明的范围,因为本发明可以允许其它同样有效的实施方案。附图中不一定是按比例的,并且为了清楚和简明,图中的某些特征和某些视图可能在比例上或示意性地放大。
[0011]图1描述现有技术渗透递送系统的剖视图。
[0012]图2A描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在内芯中的内部螺旋流动通道。
[0013]图2B描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在外壳中的内部螺旋流动通道。
[0014]图2C描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和形成在内芯和外壳中的内部螺旋流动通道。
[0015]图2D描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和流动嵌入物,所述流动嵌入物包括插入在内芯和外壳之间的内部螺旋流动通道。
[0016]图2E描述流动调节器的部分剖视图,所述流动调节器具有插入在外壳中的内芯和内芯和外壳上的接合面,用于防止内芯从外壳排出。
[0017]图3描述具有图2A的流动调节器的渗透递送系统的剖视图。
[0018]图4描述使用图3的渗透递送系统得到的活性剂的体外累计释放。
发明详述
[0019]现在参考如附图中说明的几个优选实施方案详细描写本发明。在描述优选实施方案时,阐述了许多细节以便提供对本发明的充分理解。然而,本领域技术人员可以在不使用一些或全部这些细节的情况下实践本发明。在其它情况中,对公知的特征和/或工艺步骤没有进行详细描述,以便不必要地使本发明不清楚。另外,相似的或相同的参考数字用于表示共用的或类似的元件。
[0020]图2A到2E描述用于从渗透递送系统的容器递送活性剂制剂的流动调节器200的部分剖视图。参考图2A,流动调节器200具有暴露于渗透递送系统的容器中的活性剂制剂的入口侧201,和暴露于渗透递送系统在其中起作用的流体环境的出口侧203。典型地,流体环境是液相环境,也就是说,所述流体包含水。流动调节器200包括外壳202和插入到外壳202中并且通常为圆柱形的内芯204。在外壳202和内芯204之间有螺旋状的流动通道206从流动调节器200的入口侧延伸到出口侧203。流动通道206的所有或显著的部分可为螺旋状。流动通道206在流动调节器200内部。因此,流动调节器200在通过流动通道206的活性剂制剂和渗透递送系统的容器之间形成屏障。
[0021]在图2A-2C中,内芯204的外表面210与外壳202的内表面212配合。流动通道206可以形成在内芯204的外表面210中,如图2A所示,或者流动通道206形成在外壳202的内表面212中,如图2B所示。或者,如图2C所示,流体通道206可以包括形成在内芯204的外表面210中的第一流动通道206a和形成在外壳202的内表面212中的第二流动通道206b,其中第一流动通道206a和第二流动通道206b彼此抵接或连通。每个流动通道206a、206b的所有或显著的部分为螺旋状。或者,如图2D所示,流动嵌入物214可以布置在内芯204的外表面210和外壳202的内表面212之间,其中流动嵌入物214提供流动通道206。流动嵌入物214可为例如盘管,管的各个匝之间的距离起到流动通道206的作用。或者,流动嵌入物214可为其中形成有螺旋凹槽的中空的圆柱体或套管,其中螺旋凹槽起到流动通道206的作用。流动通道206可具有任何所需的横截面,其实例包括环形或D形。在图2A-2E中表示了D形的流动通道。流动通道206的长度取决于渗透递送系统的结构和所需的释放速率。典型地,(流动通道206的(螺旋)长度为10到50mm。典型地,流动通道206的有效截面直径为0.1到0.5mm。这些范围作为实例给出,而不是用于限制本发明,除非另有说明。
[0022]参考图2A-2D,对内芯204的最大外径和外壳202的最大内径进行选择,使得在内芯204的外表面210与外壳202的内表面212之间形成过盈配合或密封。这种过盈配合或密封限制制剂流到通道206中。这种过盈配合或密封足以防止内芯204和/或流动嵌入物214从外壳202排出。另一方面,在图2A-2C中,内芯204和外壳202的表面210、212的配合部分分别可包括例如螺纹连接、粘合连接、焊接连接等特征,以便另外相对于外壳202固定内芯204。在图2D中,可以在分别与内芯204和外壳202的表面210、212配合的流动嵌入物214的内和外表面214a、214b的部分之间形成类似的连接特征。图2E公开了用于防止内芯204从外壳202排出的备选方法,其包括在内芯204的外表面210上的外侧肩部216,其与外壳202的内表面212上的内侧肩部218抵接/啮合。这样防止了内芯204通过流动调节器200的出口侧203排出。肩部216、218的抵接/啮合表面可为平的或可为逐渐缩减的,如图2E中所示。
[0023]使用抵接/啮合肩部216、218防止内芯204从外壳202排出到渗透递送系统在其中起作用的流体环境中可以适用于图2A-2D中所示的任一实施例中。此外,可以将图2A-2E中所示实施例的任何特征互换和组合,以产生流动调节器200的替代实施例。例如,在图2E中,螺旋状的通道也可以如图2C中所示位于外壳202的内表面212中。或者,在图2D中,螺旋状的通道也可以位于外壳202的内表面212中和/或内芯204的外表面210中,分别如图2A和2B中所述,其中外壳202和/或内芯204中的通道与流动嵌入物214中的流动通道206邻接或连通。
[0024]参考图2A-2E,外壳202、内芯204、和流动嵌入物214优选由惰性和生物相容的材料形成。惰性的生物相容的材料的实例包括但不限于非反应性聚合物和金属例如钛、不锈钢、铂和它们的合金、和钴铬合金。非反应性聚合物可用于其中希望在将活性剂制剂递送到渗透递送系统在其中起作用的流体环境中时避免活性剂制剂和金属材料之间的相互作用的情况。适合的非反应性聚合物的实例包括但不限于聚芳醚酮例如聚醚醚酮和聚芳醚醚酮、超高分子量聚乙烯、氟化的乙烯-丙烯、聚甲基戊烯、和液晶聚合物。优选地,至少以下表面由不会对活性剂制剂具有有害作用的材料制成或者涂有所述材料,所述表面包括在活性剂制剂流过流动通道206时暴露于活性剂制剂的外壳202、内芯204、和流动嵌入物214的表面。在优选的实施例中,上述表面由惰性的和生物相容的非金属材料制成。这种非金属材料可以是非反应性聚合物,其实例在上述给出。
[0025]可以对流动通道206的长度、横截面形状、和流通区域进行选择,使得活性剂制剂通过流动通道206的平均线速度比物质由于扩散或渗透从渗透递送系统在其中起作用的流体环境线性向内流入的平均线速度更高。这样可具有衰减或缓和反扩散的作用,所述如果不对反扩散进行控制,则可能污染渗透递送系统中的活性剂制剂。可以通过调节流动通道206的几何形状来调节活性剂制剂的释放速度,如以下所述。
[0026]活性剂通过流动通道206的对流流动由渗透递送系统的泵送速率和渗透递送系统的容器中的活性剂制剂中的活性剂浓度决定。对流流动可以表示为:
Qca=(Q)(Ca)(1)
其中Qca是表示为mg/天的活性剂(beneficial)的对流转运,Q是表示为cm3/天的活性剂制剂的总体对流转运,和Ca是表示为mg/cm3的渗透递送系统的容器内的活性剂制剂中活性剂的浓度。
[0027]活性剂离开流动通道206的扩散流动是活性剂浓度和扩散率以及流动通道206的横截面形状和长度的函数。扩散流动可以表示为:
Q da = Dπ r 2 Δ C a L - - - ( 2 )
其中Qda是表示为mg/天的活性剂的扩散转运,D是表示为cm2/天的通过流动通道206的扩散率,r是表示为cm的流动通道206的有效内径,ΔCa是表示为mg/cm3的渗透递送系统容器内的活性剂制剂的活性剂浓度与流动调节器200的递送孔205外侧的流体环境中的活性剂浓度之差,而L是表示为cm的流动通道206的(螺旋)长度。
[0028]通常,渗透递送系统内活性剂制剂中的活性剂浓度比应用的流体环境中的活性剂浓度大得多,使得所述差ΔCa可接近渗透递送系统中活性剂制剂内的活性剂浓度Ca。因此:
Q da = Dπ r 2 C a L - - - ( 3 )
[0029]通常期望保持活性剂的扩散通量比活性剂的对流流动小得多。这可以表示如下:
Q da Q ca = D&pi; r 2 C a QC a L = D&pi; r 2 QL < 1 - - - ( 4 )
方程(4)表示相对扩散通量随体积流速和通路长度的增加而降低,随扩散率和通道半径的增加而增加,并且与活性剂浓度无关。
[0030]其中流动通道206在渗透递送系统中开口处的水的扩散通量可以近似表示如下:
Q wd ( res ) = C O Q e ( - QL / D w A ) - - - ( 5 )
其中Co是表示为mg/cm3的水的浓度分布,Q是表示为mg/天的质量流速,L是表示为cm的流动通道206的长度,Dw是表示为cm2/天的水通过流动通道206中物质的扩散率,和A是表示为cm2的流动通道206的横截面积。
[0031]跨越递送孔的流体动力压降可以计算如下:
&Delta;P = 8 QL&mu; &pi; r 4 - - - ( 6 )
其中Q是表示为mg/天的质量流速,L是表示为cm的螺旋流动通道长度,μ是制剂的粘度,r是表示为cm的流动通道的有效内径。
[0032]图3表示包括流动调节器200的渗透递送系统300。尽管渗透递送系统300表示为具有图2A的流动调节器200,显而易见,可以将图2A-2E中所示的任何流动调节器200用于渗透递送系统300。渗透递送系统300包括容器302,其大小可为使得可以将其植入在体内。容器302具有开口末端304、306。流动调节器200被插入到开口末端304中。半渗透性塞308被插入到开口末端306中。
[0033]半渗透性塞308是控制来自渗透递送系统在其中起作用的流体环境的流体流动到容器302中的膜。半渗透性塞308允许来自流体环境的流体进入容器302。由于半渗透性塞308的半渗透性性质,使容器302中的组合物被阻止通过半渗透性塞308流出容器302。半渗透性塞308可以部分或完全被插入到开口末端306中。在前一种情况中,半渗透性塞308可包括扩大的末端部分308a,其作为与容器302的末端啮合的止动元件起作用。半渗透性塞308的外表面308b可具有与容器302的内表面310啮合的突起或凸纹308c,从而将半渗透性塞308锁定在容器302上并且允许在容器302和半渗透性塞308之间形成密封。容器302还可以包括底切,用于接受半渗透性塞308上的突起308c。用于半渗透性塞308的半渗透性材料是可以在润湿时符合容器302的形状并且可以粘附容器302的内表面310的材料。典型地,这些材料是聚合物材料,其可以根据泵送速率和系统配置要求进行选择。适合的半渗透性材料的实例包括但不限于增塑的纤维素材料、增强的聚甲基丙烯酸甲酯(PMMA)例如羟乙基甲基丙烯酸酯(HEMA)、和弹性体材料例如聚氨酯和聚酰胺、聚醚-聚酰胺共聚物、热塑塑料共聚多酯等等。通常优选聚氨酯。
[0034]在容器302中限定两个室312、314。室312、314由隔离物316例如滑动的活塞或柔性膜片分隔,所述隔离物配置为在容器302内配合和产生密封接触,和用于在容器302内纵向地移动或变形。优选地,隔离物316由非渗透性的弹性材料形成。例如,隔离物316可为由非渗透性弹性材料制成的滑动活塞并且可以包括与容器302的内表面310形成密封的环形突起316a。渗透动力物质318设置在与半渗透性塞308邻接的室314中,活性剂制剂设置在与流动调节器200邻接的室312中。隔离物316使活性剂制剂320与被允许通过半渗透性塞308进入容器302的环境流体分隔,使得在使用中,在稳态流动时,活性剂制剂320以与流体从流体环境通过半渗透性塞308流入容器302的速率相当的速率被排出通过流动通道206。
[0035]渗透动力物质318可为如所示的片剂形式。可以使用一种或多种这种片剂。或者,渗透动力物质318可具有其它形状、质地、密度、和稠度。例如,渗透动力物质318可为粉末或颗粒形式。渗透动力物质318可包括渗透聚合物(osmopolymer)。渗透聚合物是可以吸收含水流体例如水和生物学流体并且在吸入含水流体时膨胀或扩张到平衡状态并且保留显著部分被吸收流体的亲水聚合物。渗透聚合物膨胀或扩张到非常高的程度,通常表现为2到50倍体积增加。渗透聚合物可以是或不是交联的。优选的渗透聚合物是轻微交联的亲水聚合物,这种交联是由共价键或离子键或膨胀之后的残留结晶区形成的。渗透聚合物可以是植物、动物、或合成来源的。适合用于渗透动力物质318的渗透聚合物或亲水聚合物的实例包括但不限于分子量为30,000到5,000,000的聚(羟基烷基甲基丙烯酸酯);分子量为10,000到360,000的聚乙烯吡咯烷酮(PVP);阴离子型和阳离子型水凝胶;聚电解质复合物;低乙酸根残留、用乙二醛、甲醛、或戊二醛交联并且聚合度为200到30,000的聚乙烯醇,甲基纤维素、交联的琼脂和羧甲基纤维素的混合物;羟丙基甲基纤维素和羧甲基纤维素钠的混合物;羟丙基乙基纤维素和羧甲基纤维素钠盐的混合物;羧甲基纤维素钠;羧甲基纤维素钾盐;由马来酸酐与苯乙烯、乙烯、丙烯、丁烯、或异丁烯的细分散共聚物的分散体形成的不溶于水的、水可膨胀的共聚物,每种共聚物的每摩尔马来酸酐具有0.001到约0.5摩尔的饱和交联剂;N-乙烯基内酰胺的水可膨胀的聚合物;聚氧化乙烯-聚氧化丙烯凝胶;聚氧化丁烯-聚乙烯嵌段共聚物凝胶;角豆树胶;聚丙烯酸凝胶;聚酯凝胶;聚脲凝胶;聚醚凝胶;聚酰胺凝胶;聚纤维素凝胶;聚树胶凝胶(polygumgel);吸收和吸附渗透玻璃状水凝胶并且降低其玻璃化温度的水的最初干燥的水凝胶。渗透聚合物的其它实例包括形成水凝胶的聚合物,例如:CARBOPOL
Figure A200780018756D0014105542QIETU
,酸性的羧基聚合物,一种丙烯酸的聚合物并且用聚烯丙基蔗糖交联的,又名聚丙烯酸和聚羧乙烯,分子量为250,000到4,000,000;
Figure A200780018756D00151
聚丙烯酰胺;交联的水可膨胀的茚-马来酸酐聚合物;分子量为80,000到200,000的
Figure A200780018756D00152
聚丙烯酸;分子量为100,000到5,000,000和更高分子量的
Figure A200780018756D00153
聚环氧乙烷聚合物;淀粉接枝共聚物;由缩合的葡萄糖单元组成的AQUA 
Figure A200780018756D00154
丙烯酸酯聚合物多糖,例如二酯交联的聚糖(polygluran);等等。除了渗透聚合物之外或代替渗透聚合物,渗透动力物质318还可以包括渗透剂(osmagent)。渗透剂包括相对于外部流体表现出跨半渗透性壁的渗透压梯度的无机和有机化合物。渗透剂吸收流体到渗透系统中,从而利用流体推动制剂,用于递送通过流动调节器。渗透剂又名渗透活性化合物或溶质。可用于渗透动力物质318的渗透剂的实例包括硫酸镁、氯化镁、氯化钠、硫酸钾、硫酸钠、硫酸锂、磷酸氢钾、甘露醇、尿素、肌醇、琥珀酸镁、酒石酸、碳水化合物例如棉籽糖(raffmose)、蔗糖、葡萄糖、乳糖、山梨醇及其混合物。
[0036]活性剂制剂320可包括一种或多种活性剂.活性剂可为任何生理学或药理学活性的物质,特别是已知用于递送给人体或动物体的那些,例如药物、维生素、营养素等。可通过流动调节器200用渗透递送系统300递送的活性剂包括但不限于作用于传染病、慢性疼痛、糖尿病、外周神经、肾上腺素能受体、胆碱能受体、骨骼肌、心血管系统、平滑肌、血液循环系统、突触位置、神经效应器接合位置、内分泌和激素系统、免疫系统、生殖系统、骨骼系统、自分泌系统、消化和排泄系统、组胺系统和中枢神经系统。适合的试剂可选自例如蛋白质、酶、激素、多核苷酸、核蛋白、多糖、糖蛋白、脂蛋白、多肽、甾体、镇痛药、局部麻醉药、抗生素、抗炎用皮质类固醇、眼用药物和这些物质的合成类似物。优选的活性剂包括大分子(蛋白质和肽)和高度有效的活性剂。活性剂可以作为多种化学和物理形式存在,例如固体、液体和浆状物。除了一种或多种活性剂之外,制剂320可以任选地包括药学可接受的载体和/或另外的成分,例如抗氧化剂、稳定剂、缓冲剂和渗透增强剂。
[0037]用于容器302的材料应该充分坚硬,以便经得起渗透动力物质318的膨胀而不改变其大小或形状。此外,所述材料应该保证容器302不会在植入过程中所受到的应力下或由于操作过程中产生的压力的应力下渗漏、裂缝、破裂、或变形。容器302可由本领域已知的惰性的、生物相容的、天然的或合成的材料形成。容器302的材料可以是或者不是生物可侵蚀的。生物可侵蚀的材料在其应用的流体环境中至少部分溶解、降解、或者以其它方式腐蚀。优选地,容器302的材料不是生物可侵蚀的。通常,优选的容器302的材料是适用于人类植入的那些。优选地,容器302的材料是非渗透性的,特别是在容器302内的制剂稳定性对应用的流体环境敏感时。适合于容器302的材料的实例包括非反应性聚合物或生物相容的金属或合金。用于容器302的非反应性聚合物的实例包括但不限于丙烯腈聚合物例如丙烯腈-丁二烯-苯乙烯三元共聚物;卤化的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;和聚苯乙烯。容器的金属性材料的实例包括但不限于不锈钢、钛、铂、钽、金、和它们的合金,以及镀金的铁合金、镀铂的铁合金、钴铬合金和氮化钛涂层的不锈钢。对于尺寸决定性应用、高有效载荷能力、长持续时间应用、和其中制剂对植入位置的体内化学敏感的应用,优选容器302由钛、或具有大于60%(通常大于85%)钛的钛合金制成。
[0038]可以对流动调节器200的直径进行选择,使得流动调节器200可以压配合到容器302的开口末端304中。还有可能在外壳202的外表面220和容器302的内表面310上包括特征例如螺纹,用于相对于容器302固定流动调节器200。
[0039]以下实施例用于说明本发明,不应将其看作是限制本发明,除非本文中另有说明。
[0040]图3中说明的包含用于治疗例如丙型肝炎的干扰素-ω(IFN-ω)的渗透递送系统用以下组件装配:(i)由植入级钛合金制成并且在其末端具有底切的容器,(ii)包括两个圆柱形片剂的渗透动力物质,每个片剂主要包括具有纤维素和聚维酮粘合剂的氯化钠盐,(iii)活塞,(iv)由聚氨酯制成并且具有与容器中的底切配合的保持凸纹的半渗透性塞,(v)具有D形横截面的螺旋形内部流动通道的流动调节器,直径0.25mm,螺旋长度为35mm,和(vi)包括悬浮在非水媒介物中的IFN-ω的颗粒制剂的悬浮液制剂。
[0041]将上述几个渗透递送系统的容器填充150μL的悬浮液制剂。将渗透递送系统的半渗透性塞末端置于充满磷酸盐缓冲液(PBS)的小玻璃管中,将渗透递送系统的流动调节器末端置于充满含水释放介质的小玻璃管中。将系统分别在5℃和30℃存储或保温。在特定的时间点,可以将释放介质除去并且更换新的溶液。使用反相高效液相色谱法(RP-HPLC)对取样的释放介质分析活性剂含量。图4表示在6月内的IFN-ω体外累计释放。
[0042]本发明可提供以下优点。两件式流动调节器使得流动调节器的设计具有灵活性并且允许流动调节器的可制造性。外壳与容器不是整体的,并且使得能够在将流动调节器插入到容器中之前检查流动调节器的通道。两件式流动调节器使得在将流动调节器插入到容器中的过程中对通道的另外的机械力最小化。两件式流动调节器允许在保持共用的外套管的同时通过改变内芯或流动嵌入物上的通道而优化流动通道尺寸的灵活性。
[0043]尽管已经参考有限的实施方案描述了实施方案,但是本领域技术人员在了解本发明之后应该理解,可以设计其它实施方案而不脱离本文公开的本发明的范围。因此,本发明的范围仅由随附的权利要求限制。

Claims (20)

1.渗透递送系统流动调节器,包括:
构造和布置用于定位在渗透递送系统的容器的开口中的外壳;
插入到所述外壳中的内芯;和
在所述外壳和内芯之间限定的螺旋状流动通道,所述流动通道适合于从渗透递送系统的容器递送活性剂制剂。
2.权利要求1的流动调节器,其中流动通道形成在与外壳的内表面配合的内芯的外表面上。
3.权利要求1的流动调节器,其中流动通道形成在与内芯的外表面配合的外壳的内表面上。
4.权利要求1的流动调节器,另外包括设置在外壳和内芯之间的流动嵌入物,其中在所述流动嵌入物中形成流动通道。
5.权利要求4的流动调节器,其中外壳、内芯、和流动嵌入物由惰性材料形成。
6.权利要求5的流动调节器,其中惰性材料是非金属材料。
7.权利要求1的流动调节器,其中外壳和内芯由惰性材料形成。
8.权利要求7的流动调节器,其中惰性材料是非金属材料。
9.权利要求1的流动调节器,其中外壳密封啮合所述内芯。
10.权利要求1的流动调节器,其中所述内芯包括外侧肩部,所述外壳包括内侧肩部,其中所述外侧肩部和内侧肩部啮合,以防止在使用中内芯从外壳排出。
11.权利要求1的流动调节器,其中流动通道的长度为10到50mm。
12.权利要求1的流动调节器,其中流动通道的有效截面直径为0.1到0.5mm。
13.渗透递送系统,包括:
容器;
设置在所述容器的第一末端、用于选择性地允许流体流动进入容器的半渗透性塞;和
设置在所述容器的第二末端的流动调节器,所述流动调节器包括适合用于将包含在容器中的活性剂制剂递送到所述渗透递送系统在其中起作用的流体环境中的内部螺旋通道。
14.权利要求13的渗透递送系统,其中流动调节器包括外壳和插入到所述外壳中的内芯,其中在所述外壳和内芯之间限定螺旋通道。
15.权利要求14的渗透递送系统,其中流动调节器被压配合到容器的第二末端中。
16.权利要求14的渗透递送系统,另外包括设置在容器内并且可以在其中移动的隔离物,所述隔离物限定包含渗透动力物质的第一室和包含活性剂制剂的第二室,其中所述第一室与半渗透性塞邻接,第二室与流动调节器邻接。
17.权利要求13的渗透递送系统,其中活性剂制剂包括干扰素-ω。
18.用于活性剂制剂的可植入递送系统,包括:
由不可渗透材料制成的容器;
在容器中的包含渗透动力物质的第一室;
在容器中的包含活性剂制剂的第二室;
设置在容器的第一末端的、与第一室邻接的半渗透性塞;和
设置在容器的第二末端的、与第二室邻接的权利要求1-12中任一项的流动调节器。
19.权利要求18的可植入的递送系统,其中活性剂制剂包括干扰素-ω。
20.权利要求18的可植入递送系统,另外包括在渗透动力物质和活性剂制剂之间的隔离物。
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