CN1500475A - 可扩散植入的释放系统 - Google Patents
可扩散植入的释放系统 Download PDFInfo
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- CN1500475A CN1500475A CNA200310119897A CN200310119897A CN1500475A CN 1500475 A CN1500475 A CN 1500475A CN A200310119897 A CNA200310119897 A CN A200310119897A CN 200310119897 A CN200310119897 A CN 200310119897A CN 1500475 A CN1500475 A CN 1500475A
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Abstract
本发明提供了一种用于释放有效试剂的持续释放的释放系统。该系统包括含有有效试剂的储器和毛细管，该毛细管将储器和系统外部连通用于从系统中释放有效试剂。毛细管的横截面积和长度经选择以便以预定速率释放有效试剂。该系统还可以包括在释放有效试剂过程中为不透性和密实的外表面。该有效试剂可以配制在玻璃状糖基质中。
Description
本申请是申请日为1998年3月17日、申请号为98803906.0，发明题目为“可扩散植入的释放系统”的分案申请。
本发明一般涉及一种持续释放有效试剂的释放系统。更具体地说，本发明涉及一种带有一毛细管的持续释放有效试剂的释放系统，其用于通过扩散控制有效试剂的释放速率。
在本领域中已知各种用于释放活性剂的释放系统。这些系统一般是通过从包封的胶囊或从多结构装置中扩散释放活性剂，该多结构装置有一由聚合物形成的壁，可以让水和/或该活性剂渗透进入选择的环境中。参见例如美国专利4135514、3760806、3760984和3995631。然而，由于这些装置中至少一个固有特征影响该试剂从装置中释放的速率，因此许多种试剂不能迅速通过这些现有的系统释放出来。例如，由于许多试剂通过系统中控制速率的物质时渗透速率太小而不能产生有益效果，因此这些试剂不能有效地从扩散控制释放系统中释放。
由于其它类活性剂的特定化学特性，因此它们也不能令人满意地通过扩散装置释放。这类试剂包括盐，由于它们的离子特性，它们不易通过聚合物膜扩散。这类试剂也包括不稳定的极性化合物，它们不能配制成适宜贮存并从这类现有的系统中释放的令人满意的组合物。
由于现有技术中扩散释放系统和装置的上述缺陷，因此在本领域需要一种系统，它可以使有效试剂、尤其是不易渗透通过聚合物膜的有效试剂持续释放。
因此，本发明的一个目的是提供一种适宜于控制和持续释放有效试剂的扩散释放系统。
在一个实施方式中，系统包括一含有有效试剂的储器和毛细管，该毛细管将储器与装置外部连通，用于从装置中释放有效试剂。毛细管的横截面积和长度经选择，以便以预定速率释放有效试剂。系统还包括在释放有效试剂过程中为不透性和密实的外表面。
在另一实施方式中，系统包括一含有在玻璃状糖基质中配制的有效试剂的储器和毛细管，该毛细管将储器与装置外部连通，用于从装置中释放有效试剂。毛细管的横截面积和长度经选择，以便以预定速率释放有效试剂。
本发明的另一目的是提供一种使用根据本发明的持续释放的释放系统以预定速率释放有效试剂的方法。该方法包括将持续释放的释放系统放置在需要有效试剂的地方或放置在希望释放有效试剂的地方，并使有效试剂通过释放系统的毛细管以获得所需效果。
本发明的另一目的是提供一种以预定速率释放有效试剂的持续释放的释放系统的制备方法。该方法包括如下步骤：提供一具有在释放有效试剂过程中为不透性(impermeable)和密实(non-porous)的外表面的储器，将有效试剂填充到储器中，以及提供一具有扩散控制器的储器。该扩散控制器包括一横截面积和长度经选择以提供预定速率的毛细管。
本发明的另一目的是提供一种以预定速率释放在玻璃状基质中配制的有效试剂的持续释放的释放系统的制备方法。该方法包括如下步骤：提供一储器，在储器中提供一在玻璃状糖基质中配制的有效试剂，以及提供一具有扩散控制器的储器。该扩散控制器包括一横截面积和长度经选择以提供预定速率的毛细管。
从下面的详细说明和附加权利要求书及附图来看，本发明的其它目的、优点、特性和特征将变得更清楚。
这些附图(不是按比例画的)在于举例说明本发明的不同实施方式。
附图如下：
图1为持续释放有效试剂的释放系统的一个实施方式中显示有效试剂储器和长且窄的毛细管的放大图；
图2为持续释放有效试剂的释放系统的另一实施方式中显示有效试剂储器、长且窄的毛细管和植入物附着体的放大图；
图3为根据本文实施例制备的持续释放的释放系统的放大图；以及
图4为根据本文实施例制备的释放系统的释放速率与时间的函数关系图。
本发明一般涉及一种适宜于控制和持续释放有效试剂的扩散释放系统。
在一个优选实施方式中，该系统包括一含有有效试剂的储器和毛细管，该毛细管将储器和系统外部连通，以从系统中释放有效试剂。毛细管的横截面积和长度经选择以便以预定速率释放有效试剂。该系统还包括在释放有效试剂过程中为不透性和密实的外表面。
本文中使用的术语“有效试剂”是指任意组合物或在哺乳动物机体中产生生理或药理反应的物质。这类组合物和物质包括药物、药剂、维生素、营养素等。术语“有效试剂”也指待释放到其它类环境，例如池、槽、储器等的其它组合物和物质。这些类型的组合物中包括杀虫剂、灭菌剂、营养素、维生素、食品添加剂、避孕药、生育力抑制剂和生育力促进剂。
术语“不透性”是指足以使环境液体和释放系统中所含的组分不能透过的物质，以便这类液体和组分尽可能少地通过不透性物质移入或移出系统，以基本上不对系统的功能产生负面影响。
术语“密实”是指一物质，它本质上没有可以使在释放有效试剂的过程中环境液体和释放系统中所含的组分穿过的洞、孔或管。
此外，本文中使用的术语“毛细管”是指通常为窄且长的管，通过它储器内的组分可以移出释放装置并且系统外的环境液体可以移到储器里面。正如本文下面所解释的，毛细管的长度和横截面积经选择以便通过扩散以希望的速率从系统中释放有效试剂。
图1描述了本发明持续释放有效试剂的释放系统的一个实施方式。尽管图1所示的系统一般为圆柱形，但是系统可以为任意形状。该系统包括含有有效试剂的储器5、不透性且密实的外表面10、以及横截面积和长度经选择以便以预定速率从储器5将有效试剂释放到系统外面区域的毛细管15。毛细管15含有出口20，通过它储器5内的有效试剂离开系统，并且通过它系统外的环境液体可以进入储器5。
图2描述了本发明持续释放有效试剂的释放系统的另一实施方式。同样，尽管图2所示的系统一般为圆柱形，但是系统可以为任意形状。相似地系统包括一含有有效试剂的储器5’、不透性且密实的外表面10’、以及横截面积和长度经选择以便以预定速率从储器5’将有效试剂释放到系统外面区域的毛细管15’。这里，毛细管15’为螺旋结构。图2还显示了与毛细管15’相通的出口20’，通过它储器5’内的有效试剂离开系统，并且通过它系统外的环境液体可以进入储器5’。图2还显示了附着体25，当系统植入哺乳动物受治疗者内时该附着体用于固定系统。这里显示的附着体25为环状。然而，附着体25可以为本领域中已知的任意形状，用于将持续释放的释放系统固定在使用的环境中，例如，用于将植入物固定在哺乳动物体内或用于将装置固定在槽或其它使用的环境中。
根据本发明的系统特别适用于提供有效试剂的控制和持续释放，以在涉及至少以下领域有效地获得所需局部或全身生理或药理效果：癌性原发性瘤(例如：成胶质细胞瘤)、慢性疼痛、关节炎、风湿病、例如糖尿病和矮小的激素缺乏的治疗，和对例如在防止移植排斥和癌治疗的免疫反应的改进。本领域普通技术人员已知有许多其它疾病，例如在Goodman and Gilman，The Pharmacological Basis ofTherapeutics第8版，Pergamon出版社，纽约，1990中和Remington’sPharmaceutical Sciences，第18版，Mack Publ.Co.，Easton，PA，1990中描述的那些，将它们都引用来加入本文中。
除上面的之外，该系统适宜用于治疗被AIDS和AIDS相关的疏忽感染，例如巨细胞病毒感染、弓形体病、卡氏肺囊虫和细胞间鸟型结核分支杆菌所感染的哺乳动物机体。例如，该系统可以用于释放有效试剂，以有效地治疗AIDS患者嘴中的真菌感染。如果需要这样使用，可以将该系统设计成适宜于植入患者牙中的形状。
该系统对治疗例如青光眼、增生玻璃体视网膜病、糖尿病性视网膜炎、眼色素层炎和结膜炎的眼病特别有用。该系统还特别用作眼系统，以治疗患巨细胞病毒视网膜炎的哺乳动物机体，其中将该系统手术植入眼的玻璃体中。
用于本发明系统的适宜有效试剂包括(但不限于此)如下：
1.肽和蛋白质，例如环孢菌素、胰岛素、生长激素、与胰岛素相关的生长因子、热震蛋白质和相关化合物；
2.麻醉剂和镇痛剂，例如利多卡因和相关化合物、以及苯佐地西泮(benzodiazepam)和相关化合物；
3.抗癌剂，例如5-氟尿嘧啶、阿霉素和相关化合物；
4.抗炎剂，例如6-甘露糖磷酸酯；
5.抗真菌剂，例如氟康唑和相关化合物；
6.抗病毒剂，例如磷酸基单甲酸三钠、三氟胸腺嘧啶核甙、阿昔洛韦、昔多氟韦(cidofovir)、更昔洛韦、DDI和AZT；
7.细胞转运/移动悬挂剂，例如秋水仙碱、长春新碱、细胞松弛素B和相关化合物；
8.抗青光眼药物，例如β-阻滞剂：噻吗洛尔、倍他洛尔、阿替洛尔等；
9.免疫反应改进剂，例如孢壁酰基二肽和相关化合物；
10.甾族化合物，例如地塞米松、泼尼松龙和相关化合物；和
11.碳酸酐酶抑制剂。
除上述试剂之外，其它适宜于给药(特别是对眼和其周围组织)以产生局部或全身生理或药理效果的有效试剂可以用于本发明的系统中。这些试剂的例子包括抗生素，例如四环素、金霉素、杆菌肽、新霉素、多粘菌素、短杆菌肽、土霉素、氯霉素、庆大霉素和红霉素；抗菌剂，例如磺胺、磺乙酰胺、磺胺甲噻唑和甘特里辛；例如碘苷的抗病毒剂；以及例如硝呋醛和丙酸钠的其它抗菌剂；抗变态反应药，例如安他唑啉、麦沙吡立伦、氯苯吡胺、吡拉明和非尼腊明；抗炎症药，例如氢化可的松、氢化可的松醋酸酯、地塞米松21-磷酸酯、氟轻松、甲羟松、甲泼尼龙、泼尼松龙21-磷酸酯、醋酸泼尼松龙、氟米龙、倍他米松和triminolone；减充血剂，例如脱羟肾上腺素、萘唑啉和四氢唑啉；缩瞳药和抗胆碱酯酶，例如毛果芸香碱、酯化水杨酸酯、碳酸胆碱、氟磷酸二异丙酯、二乙氧膦酰硫胆碱碘和地美溴铵；扩瞳药，例如硫酸阿托品、环戊通、后马托品、东莨菪碱、托吡卡胺、优加托品和羟苯丙胺；以及例如肾上腺素的拟交感神经药。
在实施本发明时，上述有效试剂可以以任意药理上可接受的形式使用，例如游离碱或药理上可接受的盐或其酯。药理上可接受的盐包括例如硫酸盐、乳酸盐、硬脂酸盐、盐酸盐、酒石酸盐、马来酸盐等。水溶性有效试剂特别适用于本发明。
有效试剂也可以与药理上可接受的载体以及选择性地其它组分一起使用，这些组分例如有抗氧化剂、稳定剂、扩散增强剂等。例如在不希望有效试剂吸水的地方，可以将有效试剂配制在例如蜡或油的疏水载体中，以使有效试剂从系统中充分扩散。
在一个优选实施方式中，可以将如蛋白质的有效试剂配制在倾向于防止有效试剂水解降解的玻璃状糖基质中。
可以将许多物质用于构造本发明的系统。唯一要求是它们适宜是惰性且是上述定义的不透性和密实。当在机体内使用根据本发明的系统时，挑选的物质也应该是生物相容的。适宜于构造本发明的物质包括自然生成或合成的物质，特别是能与体液和眼组织生物相容的那些，并且在一段持续时间内在物质待接触的液体中本质上不溶解。由于系统外表面的溶解或分解将影响恒定控制释放有效试剂及在一段延缓时间内系统要保持在原地的性能，因此应避免使用溶解快的物质、在眼液中溶解度高的物质或在释放有效试剂过程中发展成孔、洞或管的物质。
能适用于本发明与体液和眼组织生物相容的自然生成或合成的物质通常包括金属、陶瓷、玻璃、聚合物和其结合物。这些聚合物的例子包括聚乙烯、聚丙烯、聚对苯二甲酸乙二醇酯、塑化聚氯乙烯、交联聚酯、聚碳酸酯、聚砜、聚苯乙烯、聚(2-戊烯)、聚(甲基丙烯酸甲酯)、聚(1，4-亚苯)、聚四氟乙烯和聚-乙烯-乙酸乙烯酯(EVA)。优选聚合物包括聚乙烯和聚丙烯。可以根据以下选择优选聚合物：生物相容性、不透度、对光的透明度或通过例如超声或X-射线的外部测量检测到的能力。
优选地，该聚合物也可以生物腐蚀。适宜可生物腐蚀的聚合物包括聚(乙醇酸)、聚(乳酸)、乳酸/乙醇酸共聚物、聚原酸酯、聚酐、聚磷腈(polyphosphazones)和聚己内酯。由于这些聚合物的慢的腐蚀性能，因此它们特别优选，而且在有效试剂释放过程中它们不应该经受过度改变。
适宜本发明中使用的金属的例子包括钛、不锈钢、锡和铝。优选地，金属为钛或钛合金。
可以由上面列出的物质或其组合制备系统外表面和毛细管。外表面和毛细管可以由相同物质构成，也可由不同物质构成。例如，系统外表面物质可以是金属，然而构成毛细管的物质可以是聚合物。
可以以不同方法制备本发明的系统。例如，如果系统完全由聚合物制成，那么可以将聚合物注模或压铸成所需形状和大小。然后例如以水溶液制剂获得有效量的有效试剂。可以通过例如注射器或移液管的任意传统装置将有效试剂填充到储器和毛细管中。将有效试剂填充到系统中应小心，以避免在储器或毛细管中出现气泡，由于气泡可能起一把锁的作用，它将阻止有效试剂湿润和/或移到系统外面希望的地方。因此，在该实施方式中，该毛细管至少应该用能将水吸到储器中的介质填充。该介质可以是水本身、有效试剂的水溶液或最初以固态出现的生物相容吸湿剂。
无论如何，上面所述的制备本发明系统的方法仅仅是举例性的，不应该作为限制本发明的范围。对本领域技术人员来说，制备该系统的各种方法应该是显而易见的。特别地，制备该系统的方法取决于有效试剂和外表面材料的性能。只要有效试剂和材料选定，对本领域技术人员来说，可以使用常规制造技术容易地制备本发明的系统。
自然，可以制备根据本发明的系统以容纳任意所需量的有效试剂。也可以改变毛细管的横截面积和长度以获得所需的释放速率，下面将更详细解释。
根据本发明的系统为扩散有效试剂的释放系统，其中通过毛细管对有效试剂的扩散进行控制。
数学上，可以通过菲克定律描述扩散过程：
J＝-D·A·(ΔC/L)
其中，J为来自系统的有效试剂的质量转移，D为有效试剂的扩散系数，A为扩散发生所通过的表面积，ΔC为有效试剂在释放系统内外的浓度差，以及L为扩散路径的长度。
在本领域现有的系统中，用于控制来自含有效试剂的储器的该试剂质量转移J的最基本方法是用一膜包围该储器，有效试剂通过该膜的扩散系数D较低。调整膜的表面积A和厚度L可以获得所需质量转移。
与本领域现有的系统直接对照，为了释放有效试剂，根据本发明的系统特别优选不含有效试剂或环境液体必须通过的渗透膜或半渗透膜。因此，在本发明中，有效试剂的释放速率不受有效试剂通过包围储器的物质的扩散系数的控制。相反，它受扩散发生所通过的选择表面积A(即毛细管的横截面积)和扩散路径长度L(即毛细管长度)的控制。值A越小且值L越大，转移量将越低。
为了获得任意所需释放速率，可以根据上面的菲克定律确定毛细管的特定横截面积A和长度L。在本领域技术人员水平范围内，一旦知道有效试剂的扩散系数D、质量转移J和系统内外有效试剂的浓度差ΔC，就可以确定毛细管的横截面积A和长度L。通常，特定有效试剂(例如药物)通过特定介质的扩散系数D可以通过试验计算出或通过查阅本领域技术人员已知的标准手册或评论文章计算出，参见例如Remington’s，第1680-81页和R.W.Baker & H.K.Lonsdale，Controlled Release：Mechanisms and Rates in ADVANCES INEXPERIMENTAL MEDICINE AND BIOLOGY，第47卷，第15-71页(Tanqaury& Lacey eds.，1974)，全文引用加入本文。
在有效试剂为药物的情况下，根据有效药物剂量选择质量转移J。用于特定疾病的典型药物剂量可以在标准药学手册中找到。参见例如Goodman & Gilman；Physician’s Desk Reference(PDR)和The ExtraPharmacopeia(Royal Pharm.Soc.)。根据系统储器里面的有效试剂的浓度(通常为已知)和系统外面相同有效试剂的浓度(通常为零，但是可能大于零，这取决于具体的有效试剂)可以容易地确定浓度差ΔC。一旦J、D和ΔC的值确定后，可以使用菲克定律确定A和L的可接受的值，这将决定了毛细管所需的横截面积和长度。
显而易见，根据本发明控制质量转移的方法与使用渗透膜是根本不同的。使用这种控制质量转移的方法的一个重要优点是本发明的系统可以用于释放亲水分子，众所周知，这对于由膜控制的扩散系统释放是很困难的。
也要着重指出，本发明的释放方法与通过使用窄出口限制液体流动是不同的。实际上，液体通过该系统的毛细管最好没有粘性流动。在该优选实施方式中，用松散交联且高度膨胀但固定的凝胶填充毛细管，通过它可以发生有效试剂的扩散。这类凝胶包括膨胀聚丙烯酸盐(酯)、聚甲基丙烯酸盐(酯)、交联明胶、例如NaCMC、HPMC和HPC的交联碳酸盐、藻酸盐、硬脂酸铝凝胶和PVP凝胶。
根据本发明系统的另一优点是没有运动部分，因此它比本领域中已知的活塞型渗透释放系统更易制备。
如上所述，可以使用根据本发明的系统治疗哺乳动物机体以获得所需局部或全身的生理或药理效果。可以通过对哺乳动物机体给予持续释放有效试剂的释放系统，并使其中的有效试剂离开系统以直接与哺乳动物机体接触来使用该系统。
可以通过本领域已知的任意给药途径对哺乳动物机体给予本发明的有效试剂释放系统。这些给药途径包括眼内、口、皮下、肌内、腹膜内、鼻内、皮肤、鞘内等。此外，可以一次给予一个或多个系统，或者可以在储器内或内芯包括一种以上的试剂。
本发明的有效试剂释放系统特别适宜于直接植入眼的玻璃体中和用于眼内晶状体。
这些给药方法及其制备技术对本领域普通技术人员来说也是公知的。其制备技术在例如Remington’s Pharmaceutical Sciences中有阐述。
可以在足够长的时间内并在治疗相应疾病条件下在适宜位置给予有效试剂释放系统。
为了局部释放有效试剂，可以手术将本发明的系统植入作用位置或附近。当它用于治疗眼、原生性瘤、风湿性关节炎和慢性疼痛时就是这样。
为了全身缓解，可以通过皮下、肌内或腹膜内植入该系统。当该系统将用于持续全身水平和避免早产代谢时就是这样。
在本发明的一个特别优选的实施方式中，可以制备眼内植入物系统，它含有有效量的昔多氟韦作为有效试剂，以治疗经AIDS诱导的巨细胞病毒视网膜炎眼感染。已经评价，当昔多氟韦被直接释放到玻璃体中时，它在治疗该疾病时的有效药剂量为0.5-2μg/天。昔多氟韦有三个可电离位置，因此不希望通过聚合物膜迅速扩散。它在水中的溶解度高(＞150mg/ml)并且在水溶液中特别稳定。因此，它非常适用于本发明的系统中。
在该实施方式中，用饱和昔多氟韦水溶液填充系统的储器和毛细管。假定昔多氟韦在水中的扩散系数为1×10-6cm2/s，在水中的溶解度ΔC为150mg/ml，那么用长1cm、直径为0.1mm的毛细管可以获得1μg/天的所需药剂量。如果最初用至少约730μg的昔多氟韦填充储器，那么系统可以释放昔多氟韦达两年或更长时间。治疗结束后这类系统可以永久性保留在玻璃体中。
通常，本发明系统中使用的有效试剂的量为约0.01mg约2.5g。优选地，系统所含有效试剂的量为约1mg-约100mg。最优选系统所含有效试剂的量为约1mg-约10mg。这些优选范围可以使有效试剂持续释放几天到一年以上。
优选地，根据本发明系统的毛细管的横截面基本上为环形。在这种情况下，毛细管优选具有约0.01mm-约1mm的直径和约0.1cm-约25cm的长度。作为一个整体，该系统优选具有约0.1mm-约10mm的直径和约1mm-约50mm的长度。当将这样的系统植入眼的玻璃体中时，该系统在任意方向最好不超过5mm。因此，图1和2所示的圆柱形系统的长度或直径最好不超过5mm。
在单个优选实施方式中，本发明的系统包括一含有配制在玻璃状糖基质中的有效试剂的储器和一毛细管，该毛细管连接在储器和用于从系统释放有效试剂的系统外部之间。毛细管的横截面积和长度经挑选以便以预定速率释放有效试剂。
这里，当在上述第一个实施方式中释放有效试剂时，系统的外表面不需要为不透性和密实。然而，经思考本发明的该实施方式在释放有效试剂的过程中系统的外表面可以是不透性和密实的。
优选地，本系统中使用的有效试剂为例如本文上面提到的那些肽或蛋白质。
最近提出过在玻璃介质中配制的有效试剂(特别是蛋白质)可以延长它们的货架寿命并可免去冷藏的要求。见例如F.Franks，Long-TermStabilization of Biologicals，BIO/TECHNOLOGY，第12卷，第253-56页(1994年3月)，全文引用加入本文。
可以通过从其均匀溶液中除去水以将蛋白质配制在玻璃基质中。可以通过蒸发或骤冷溶液除去水。该过程通常称作是玻璃化。随着从溶液中除去水，它渐渐变粘直到获得含蛋白质的“固化”液体。该“固化”液体通常称作玻璃。
玻璃体有许多独特的物理和化学性能，这使它们更理想地用于制造有效试剂制品。在它们中间，最重要的是固化液体使最初溶液的分子混乱。由于阻止了包封其中的蛋白质的结晶和化学反应，该混乱有利于玻璃体的长期稳定性。
糖在稳定蛋白质制剂中也起到了重要作用。在溶液中，公知它们将蛋白质的变性平衡向自然状态移动。大部分糖，特别是低分子量糖类，同样公知易于玻璃化并提供能延缓蛋白质失活反应的玻璃状基质。
为了说明，用于根据本发明系统中的玻璃状糖基质可以通过压缩蛋白质与糖和缓冲剂以及加或不加粘合剂的冻干混合物制成。加入系统时的蛋白质-糖基质所夹带的空气应最小。本领域中已知各种方法用于这种加入。优选通过玻璃化，所选的制剂应具有大于环境温度的玻璃化温度(Tg)。制剂的Tg为制剂组分相对量的函数，并且其测定方法对本领域技术人员来说为已知。
另外，蛋白质可以经玻璃化或直接在释放系统的储器中被包封在玻璃状糖基质中。
在根据本发明的释放系统中配制和使用的蛋白质和蛋白质化合物的例子包括具有生物活性或者可以用于治疗疾病或其它病理情况的那些蛋白质。它们包括(但不限于)生长激素、第八因子、第九因子和其它凝血因子、胰凝乳蛋白酶、trysinogen、α-干扰素、β-半乳糖苷酶、乳酸脱氢酶、生长因子、凝血因子、酶、免疫反应刺激剂、细胞因子、淋巴因子、干扰素、免疫球蛋白、逆病毒(retroviruses)、白介素、肽、促生长素抑制素、生长激素类似物、促生长因子-C、促性腺释放激素、促卵泡成熟激素、促黄体激素、LHRH、例如leuprolide、那法瑞林和戈舍瑞林的LHRH类型物、LHRH促效药和拮抗物、生长激素释放因子、降钙素、秋水仙素、例如绒毛膜促性腺激素的促性腺激素、催产素、奥曲肽、生长激素+氨基酸、后叶加压素、促肾上腺皮质激素、表皮生长因子、促乳素、生长激素+蛋白质、二十四肽促皮质素、赖氨加压素、例如促肾上腺素释放激素的多肽、甲状腺刺激素、分泌素、促胰酶素、脑啡肽、高血糖素、内部分泌和通过血流分配的内分泌剂等。可以被包封和释放的其它试剂包括α1抗胰蛋白酶、胰岛素、和其它肽激素、肾上腺皮质刺激素、甲状腺刺激素、和其它垂体激素、干扰素α、β和δ、红细胞生长素、例如GCSF的生长因子、GM-CSF、胰岛素状生长因子1、组织纤溶酶原激活物、CF4、dDAVP、肿瘤坏死因子受体、胰酶、乳糖酶、白介素-1受体拮抗剂、白介素-2、肿瘤抑制蛋白、细胞毒蛋白、病毒、病毒蛋白、重组抗体和抗体片段等。也可使用上面的类似物、衍生物、拮抗物、激动剂和药用盐。
上面试剂可以用于治疗或预防各种症状，包括(但不限于)血友病和其它血液病症、生长病症、糖尿病、白血病、肝炎、肾衰竭、HIV感染、例如脑甙酶缺乏和腺甙脱氨酶缺乏的遗传性疾病、高血压、脓毒性休克、例如多发性硬化、格雷夫斯氏病、全身性红斑狼疮和类风湿性关节炎的自身免疫疾病、休克和消耗紊乱、膀胱纤维化、乳糖不耐性、克罗恩氏病、炎症性肠疾病、胃肠道和其它癌症。
用于本发明制品的蛋白质化合物可以使用其盐形式，最好是药用盐。有用的盐对本领域技术人员来说为已知，包括与无机酸、有机酸、无机碱或有机碱成的盐。
用于制备玻璃状基质的糖包括(但不限于)：葡萄糖、蔗糖、海藻糖、乳糖、麦芽糖、棉子糖、水苏糖、麦芽糖糊精、环糊精、例如葡聚糖的糖聚合物和它们的衍生物、ficoll和淀粉。
用于配制玻璃状基质的缓冲剂包括(但不限于)：MES、HEPES、柠檬酸盐、乳酸盐、醋酸盐和氨基酸缓冲剂。
含有玻璃状糖基质的该系统最好由透水性低的可生物腐蚀的聚合物构成。这类聚合物包括聚乙醇酸、聚乳酸、乳酸/乙醇酸共聚物、聚原酸酯、聚酐、聚膦腈和聚己内酯。由于这些聚合物的慢的腐蚀性能且吸水性低，因此它们特别优选，而且在有效试剂释放过程中它们不应该经受过度改变。
在实施过程中，具有渗透活性的玻璃状糖蛋白质基质可以通过聚合物吸收一些水。然而，如果适当选择聚合物，可以使通过聚合物壁吸收的水分最小。因此，毛细管应是质量转移的主要路线以及控制蛋白质释放速率主要方法。具体地说，玻璃状糖蛋白质基质溶解的速率主要由通过毛细管吸收水分的速率和释放糖的速率决定的。例如在第一个实施方式中，从在该实施方式中的系统释放蛋白质的速率由其通过毛细管的扩散决定的。而且，对给定浓度的蛋白质来说，该速率可以通过改变毛细管的长度和横截面积来调整。
经简单地放置，毛细管的直径控制吸入储器的水分量，而且因此控制了糖基质溶解的速率。同时，毛细管的直径控制了从系统释放蛋白质的速率。
本发明的该实施方式的优点在于：只要蛋白质在释放系统里面，它就可以受到玻璃状糖基质的保护，或者受到曾经形成的糖基质的溶解稳定剂分子的保护。因此，通过使用根据本发明的系统，可以获得比传统制品保持更多生物活性的蛋白质的持续和控制释放。
根据本发明的该实施方式的系统可以按照上述第一个实施方式的系统的相同方式制造和使用。
下面的实施例仅仅是描述本发明，而不应该被认为是限制本发明的范围，同样地，根据本说明，该实施例和其另外的等同物对本领域技术人员将变得更清楚。
实施例
将四个圆柱形杯标上A、B、C和D用作储器。这些杯由丙烯酸酯制成，并且长为2cm、外直径为8mm、内直径为4mm。在杯的一端开口填充有效试剂。该实施例的释放系统的放大图可以参见图3。将布比卡因盐酸盐的饱和水溶液浆液作为有效试剂。杯30用足够的该浆液填满，以便固定之后，它们都含有一层厚约1cm的固态药物35和在该固态层上部的一层饱和药物溶液40。不必以任意其它方式测量杯中的药物量。
然后将含有毛细管15”的扩散控制器45插入每个杯的开口端。扩散控制器45由丙烯酸酯制成且为圆柱形。扩散控制器45长5mm，直径约为4mm。在将放置毛细管15”的轴线方向将1mm的出口插入每个扩散控制器中。
由于小气泡堵塞扩散控制器中的毛细管从而重复阻碍最初试验，因此必须特别小心以从杯中除去空气。据信，除去小气泡的最好方法是用脱气药物浆液填充杯，然后用扩散控制器覆盖这些杯之前对它们抽几次真空。
然后在垂直位置将每个杯30粘合到闪烁小瓶的底部。用15ml水填充小瓶，定期替换并测定药物含量。在37℃下在Dubnoff型水浴中摇动小瓶。连续试验直到大多数杯中不再含可见量的固态药物。
图4中图示了每个释放系统A、B、C和D的释放速率与时间的函数关系。从图4中看出，每个释放系统释放药物的速率相对恒定且可再生。特别地，尽管在第1天系统稍微有点充满，但是从第2天到第23天释放速率相对恒定。在第24天，系统D中药物耗尽的影响变得明显。在23天内四个系统的平均释放速率范围为第2天的835mcg/天-第23天的530mcg/天。
该实施例的结果说明了通过使用根据本发明的扩散释放系统可以在一段时间内实现相对恒定的释放速率。
尽管参照一些优选实施方式描述和说明本发明，但是对本领域技术人员来说，可以进行改进、变化、删除和替换，而不背离本发明的宗旨和范围。本身，适当且公正地进行这些改变和/或改进都落在以下权利要求书同等的全部范围内。
Claims (19)
1.一种用于以预定速率释放配制在玻璃状糖基质中的有效试剂的持续释放的释放系统，包括：
(a)储器，包括所述有效试剂；和
(b)毛细管，将所述储器和系统外部连通用于从系统释放所述有效试剂，
选择所述毛细管的横截面积和长度以便提供所述预定速率。
2.根据权利要求1的系统，其中所述有效试剂为昔多氟韦。
3.根据权利要求1的系统，其中所述有效试剂为蛋白质或肽。
4.根据权利要求3的系统，其中所述蛋白质被咬合在玻璃状糖基质中。
5.根据权利要求1的系统，其中所述毛细管用所述有效试剂填充。
6.根据权利要求1的系统，其中所述毛细管用能够从所述储器向系统外部扩散所述有效试剂的固定凝胶填充。
7.根据权利要求1的系统，其中所述毛细管用水填充。
8.根据权利要求1的系统，其中所述系统由可生物腐蚀的聚合物制成。
9.根据权利要求8的系统，其中所述可生物腐蚀的聚合物选自聚(乙醇酸)、聚(乳酸)、乳酸/乙醇酸共聚物、聚原酸酯、聚酐、聚磷腈和聚己内酯。
10.根据权利要求1的系统，其中所述毛细管为螺旋状。
11.根据权利要求1的系统，其中所述系统可以植入哺乳动物机体中。
12.根据权利要求11的系统，还包括在其一端的环，用于将所述系统固定在所述哺乳动物机体里面。
13.根据权利要求1的系统，其中所述系统可以以0.5-2μg/天连续释放所述有效试剂。
14.根据权利要求1的系统，其中所述系统可以在至少两年的时间内连续释放所述有效试剂。
15.根据权利要求1的系统，其中所述毛细管的直径为0.01mm-1mm。
16.根据权利要求1的系统，其中所述毛细管的长度为0.1cm-25cm。
17.根据权利要求1的系统，为圆柱型。
18.根据权利要求19的系统，直径为0.1mm-10mm，长度为1mm-50mm。
19.一种以预定速率释放配制在玻璃状糖基质中的有效试剂的持续释放的释放系统的制备方法，所述方法包括以下步骤：
(a)提供储器；
(b)在所述储器中提供一配制在玻璃状糖基质中的有效试剂；和
(c)提供带有扩散控制器的储器，
所述扩散控制器包括一横截面积和长度经选择以便提供所述预定速率的毛细管。
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1998
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- 1998-03-17 ES ES98911690T patent/ES2205462T3/es not_active Expired - Lifetime
- 1998-03-17 CA CA002284058A patent/CA2284058C/en not_active Expired - Fee Related
- 1998-03-17 NZ NZ500018A patent/NZ500018A/en unknown
- 1998-03-17 PT PT98911690T patent/PT973499E/pt unknown
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- 1998-03-17 DE DE69816980T patent/DE69816980T2/de not_active Expired - Fee Related
- 1998-03-17 EP EP98911690A patent/EP0973499B1/en not_active Expired - Lifetime
- 1998-03-17 IL IL13204098A patent/IL132040A/en not_active IP Right Cessation
- 1998-03-17 AU AU65588/98A patent/AU729870B2/en not_active Ceased
- 1998-03-17 KR KR10-1999-7008908A patent/KR100523199B1/ko not_active Expired - Fee Related
- 1998-03-17 DE DE69835305T patent/DE69835305T2/de not_active Expired - Fee Related
- 1998-03-17 DK DK98911690T patent/DK0973499T3/da active
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- 1998-03-17 CN CNB2003101198971A patent/CN1305462C/zh not_active Expired - Fee Related
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- 1998-03-17 WO PCT/US1998/005138 patent/WO1998043611A1/en active IP Right Grant
- 1998-03-17 AT AT03075231T patent/ATE333266T1/de not_active IP Right Cessation
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| IL132040A (en) | 2004-07-25 |
| ES2205462T3 (es) | 2004-05-01 |
| ATE333266T1 (de) | 2006-08-15 |
| DK0973499T3 (da) | 2003-11-17 |
| IL159636A0 (en) | 2004-06-01 |
| NZ500018A (en) | 2001-07-27 |
| KR100523199B1 (ko) | 2005-10-21 |
| IL132040A0 (en) | 2001-03-19 |
| WO1998043611A1 (en) | 1998-10-08 |
| KR20010005834A (ko) | 2001-01-15 |
| ATE246489T1 (de) | 2003-08-15 |
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| HK1027756A1 (en) | 2001-01-23 |
| DE69816980T2 (de) | 2004-07-22 |
| CA2284058C (en) | 2007-02-20 |
| US5972369A (en) | 1999-10-26 |
| EP0973499A1 (en) | 2000-01-26 |
| DE69835305D1 (de) | 2006-08-31 |
| DE69835305T2 (de) | 2007-07-19 |
| JP2001518880A (ja) | 2001-10-16 |
| PT973499E (pt) | 2003-12-31 |
| AU6558898A (en) | 1998-10-22 |
| CN1305462C (zh) | 2007-03-21 |
| EP0973499B1 (en) | 2003-08-06 |
| CN1138579C (zh) | 2004-02-18 |
| AU729870B2 (en) | 2001-02-15 |
| CN1251986A (zh) | 2000-05-03 |
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