CN1156400A - 皮下植入物 - Google Patents
皮下植入物 Download PDFInfo
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- CN1156400A CN1156400A CN95194746A CN95194746A CN1156400A CN 1156400 A CN1156400 A CN 1156400A CN 95194746 A CN95194746 A CN 95194746A CN 95194746 A CN95194746 A CN 95194746A CN 1156400 A CN1156400 A CN 1156400A
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Abstract
本文介绍了一种接近零级动力学延时的，可控制释放的氢化吗啡酮皮下多聚体植入物，它具有不可滥用性、非炎症性、生物相容性、非生物降解性等特点。本文还介绍了通过该植入物减轻癌症疼痛和治疗阿片类药物成瘾的方法。
Description
发明领域
本发明涉及用于经皮下长期施用一种强的阿片样药物的一种独特装置。其使用形式使之难于转化作为非法应用并保证此种药物的长期稳定释放，从而提供长期的疼痛缓解或阿片类药物成瘾的治疗，并防止药物从该装置不平均释放的潜在致死性后果。
本发明背景
近70％癌症患者遭受由于肿瘤或其治疗引起的疼痛。由于在发达和发展中国家中预期寿命已增加，癌症和癌症相关的疼痛已成为重大的社会和医学关注点。全世界阿片类止痛药的易得性，大多数癌症相关疼痛的一线治疗极为不同。在1991年，20个发达国家消耗了全世界吗啡消耗量的86％，而其余14％的吗啡则在占有世界人口大多数的其余国家消耗。(Joranson，D.E.，Journal of Pain and Symptom Management，8(6)：353-360，1993)。
全世界人群的大多数使用很少的阿片类药物用于减轻癌症疼痛是多种原因的结果，包括担心药物转作非法使用和成瘾。而且，很多有癌症相关疼痛的病人需要阿片类止痛药的长期连续给药，这常使1天多次服数片药物成为必需。对这种给药方案的依从性常常是差的。而且，胃肠给药耐受差或在许多有癌症相关疼痛的病人中是被禁止的，而在这些病人中给药又是需要的。然而，阿片类止痛药的连续胃肠外给药费用高，不方便，并需要有冰箱，导管，泵和经训练的人员。
药物成瘾在全世界是重大社会问题。仅在美国，在任何一天，就有数十万成瘾者在治疗门诊登记。他们之中大多数被给予“美散痛维持”作为其治疗的一个基本部分。主要行为和依从问题常使治疗复杂化。
“美散痛维持”治疗的费用是每个病人每个月数百美元。此费用的一个重要部分涉及门诊随诊和监测尿样检测以确保给药的适当依从性，以及涉及美散痛配方的药物收费。
用于药物的控释的给药系统和装置；即控制释放和维持或延长释放，在本领域中是公知的。在文献中已描述多种方法，包括吸收和排泄的生理性改变，溶剂的改变，药物的化学改性，在不可溶性载体上药物的吸收，悬液和植入药丸的使用。其它方法包括将药物与载体如蜡，油，脂，和可溶性多聚体混合，它们被环境逐渐分解导致药物的释放。很多关注已指向储库型装置，即一种药物被包在多聚体容器内的装置，加或不加溶剂或载体，可允许药物从储库中释放出来。
另一型药物给药装置是单块型，其中药物分散于多聚体中，并且通过多聚体的降解和/或药物穿过多聚体而释放药物。乙烯乙酸乙烯酯(EVA)共聚体是无孔多聚体的公知的代表(Rhine，WD，等，Journal ofPharmaceutical Sciences 69：265-270，1980；Sefton，M.V.，等，Journal of Pharmaceutical Sciences，73：1859-1861，1984；Cohen，J.，等，J.Pharm，Sci.，73：1034-7，1973)。药物从多聚体给药系统的释放动力学取决于该药物的分子量，脂溶性，带电量以及多聚体的特性，药物装载百分比，和任何基质包被物的特性。这些因素的重要性加上特定的药理学，毒理学，和治疗目标，要求对特定药物的多聚体植入物的设计必须仔细构建。
Ku等，J.Pharm.Sci.，74，P926(1985)描述了一种多孔方式以获得零级动力学释放。
阿片类拮抗剂和促效剂的持续胃肠外给药已成为一个相当引人关注的领域，因为首先，它提供了治疗阿片类药物滥用的方法，其次，对疼痛的皮下治疗已得到全世界的广泛承认。A.麻醉剂拮抗剂：环丙甲羟二羟吗啡酮
在过去20年中，已试尝多种方法使用含麻醉剂拮抗剂的多聚体从防止药物滥用。这些拮抗剂的释放特性优于那些纯的促效剂，已在文献中记载证实为一级动力学。
1.甘油植入物
2.胆固醇-甘油三酯盐在大鼠中证实为一级动力学
3.谷氨酸和亮氨酸-生物可降解
4.聚乳酸/羟基乙酸(PLGA)珠B.麻醉剂混合性促效剂/拮抗剂：叔丁啡
慢性疼痛的治疗不优选使用具有一级动力学释放的药物。
1.胆固醇-甘油三酯盐在大鼠中证实一级动力学C.麻醉剂促效剂：吗啡
吗啡是治疗疼痛的一种极好药物，但药效比氢化吗啡酮弱7倍，因而更不适合长期皮下植入。这些植入药物中很多已被证实为一级动力学释放，这将威胁接受含有致死量阿片类的植入物的病人的生命。
1.多聚硅氧烷弹性体
2.含藻酸钠的聚硅氧烷(与水接触后溶胀以释放药物)
3.丸粒
4.聚酐配制剂D.EVA植入物
EVA(乙烯乙酸乙烯酯)多聚物已被用于释放许多类药物：激素(即，强的松龙，胰岛素)，抗肿瘤剂(即，5FU，阿霉素)，蛋白质(即，白蛋白，免疫球蛋白)，神经递质(即，多巴胺)，和抗生素。这些药物的突破与强效阿片类的突破相比是微不足道的。
1.强的松龙(Miyazaki，S.，等，Chem.Pharm，Bull(东京)，29：2714-7，1981)
2. 5FU(Wyszynski，R.E.，等，J.Ocul.Pharmacol.，5：141-6，1989)
3.Adriamycin(Lin，S.Y.，等，Biomat Art Cell Art Org.17：189-203，1989)
4.Insulin(Brown，L.等，Diabetes，35：692-7，1986；Brown，L.等，Diabetes，35：684-91，1986)-EVA包被的并在多聚体的一面带有孔给出接近恒定的释放率。
5.神经生长因子(Hofman，D.，等，Bxp Neurol，110：39-44，1990)
6.免疫球蛋白(Radomsky，M.L.，等，Biomaterials，11：619-24，1990)
7.白蛋白(Niemi，S.M.，等，Lab Anim.Sci.，35：609-12，1985)
8.多巴胺/左旋多巴(During，M.J.，等，Ann，Neurol.，25：351-356，1989；Sabel，B.A.，等，Ann.Neurol.，28：714-717，1990)
文献中已描述制作EVA多聚体和测试它们的生物相容性和非炎症特性的机制。Brown，L.R.，等，J.Pharm.Sci.，72：1181-5，1983；Langer，R.，等，J.Biomed.Mater.Res.，15：267-77，1981；和Niemi，S.M.，等，Lab.Anim.Sci.，35：609-12，1985，都描述了多聚体的非炎症特性和多聚体制造技术。
改变药物从EVA多聚体释放特性中涉及的重要因素已被描述(Brook，I.M.，等，Br.Den，J.，157：11-15，1984)。
美国专利5153002，在此引入作为参考，描述了一种5面包被有不可透层的立方体和一种除一个平面外均被包被的柱体。一种除在中心面的暴露腔外包被有不可透包被物(石蜡)的半球体提供白蛋白释放的零级动力学(Hsieh，D.S.，等，J：Pharm.Sci.，72：17-22，1982)。带有不可透多聚体包被，在一面的中央有孔的EVA可为胰岛素释放提供零级动力学。药物颗粒大小，药物装载量，和基质包被均显著影响释放动力学(Rhine，W.D.，等，J.Pharm，Sci.，69：265-70，1980)。
Grossman等(Proceedings ASCO，Vol.19，P337(1991))描述了将氢化吗啡酮埋藏入由聚乙烯乙酸乙烯酯制成的控释基质中的给药系统。
发明目的
本发明的目的是提供一种可植入的，生物相容的多聚体，它能持续地皮下释放稳定浓度的阿片类止痛药达2周至6个月以上。
本发明的另一目的是以一种难于转化为非法使用的形式提供施用疼痛缓解剂氢化吗啡酮的一种方法。发明概要
本发明涉及一种皮下给药系统，它包含：i)一种多聚体基质材料，ii)包埋于所述基质中的一种治疗学制剂，和，iii)包围所述基质的一种包被物，其中所述给药系统用于提供接近恒定的氢化吗啡酮释放。
本发明还包括提供一种给药系统的方法，它包含i)将一种治疗学制剂埋藏入聚乙烯乙酸乙烯酯基质，ii)将所述基质成形为圆柱形，iii)用聚(甲基丙烯酸甲酯)包被所述基质，和iv)沿圆柱形基质的轴开一个圆柱形的开口，在所述基质中开一个内壁，其中所述基质的所述内壁无包被物。
本发明还涉及一种在遭受疼痛的哺乳类中提供疼痛的长时间缓解的方法，它包含向所述哺乳类施用至少一种装置(当施用2或多种装置时，它们结合在一起或分开)，并且还涉及在具有药物成瘾的哺乳类中治疗阿片类药物成瘾的一种方法，它包含向所述哺乳类经皮下施用至少一种装置。
附图简述
图1是按照本发明的给药装置的透视图。
图2是沿图1的直线2-2给出的给药装置的断面图。为阐述目的，包被物的厚度被夸大了。
图3是本发明的半球体实施方案的透视图。
图4是本发明的立方体实施方案的透视图。
图5是本发明的多单位体(前后排列)实施方案的透视图。
图6显示带有或不带有中央未包被全厚度开口的聚(甲基丙烯酸甲酯)对体外氢化吗啡酮从该装置上的释放的作用。
图7显示具有恒定孔和装置直径的圆柱形装置的高度的改变对氢化吗啡酮从聚(甲基丙烯酸甲酯)包被的装置上的体外释放的作用。
图8证实氢化吗啡酮从本发明的给药装置的释放在体外表现接近零级动力学达4周。使很多控释给药装置复杂化的最初释放“突发”得到了消除。
图9显示通过简单地改变给药装置可很容易获得体外氢化吗啡酮每小时释放量的氢化吗啡酮给药持续时间的灵活性。
图10显示将2种给药装置皮下埋入各5只大白兔产生稳定，持续的血浆氢化吗啡酮浓度达4周。这些血浆浓度在人类治疗浓度范围内。
图11显示从多个植入给药装置的预期氢化吗啡酮释放，及观察到的在兔中血浆氢化吗啡酮浓度随时间的变化。增加皮下植入的给药装置个数使兔血浆氢化吗啡酮浓度产生持续和预期的增加。给予6个植入物(约900μg/hr氢化吗啡酮)的全身毒性限于短暂的增强的镇静和食欲下降。
图12显示皮下植入能给予接近于两个本发明的给药装置的每小时氢化吗啡酮总量的渗透泵，产生相似的兔血浆氢化吗啡酮浓度。
图13显示静脉内给予相当于由2个给药装置4小时(一种典型的人类给药间隔时间)释放的氢化吗啡酮累积量的50％(600μg)和100％(1200μg)的静脉推注剂量，在1分钟后即产生峰值兔血浆浓度，随后经数小时快速下降至基线。峰值血浆氢化吗啡酮浓度被良好耐受，且至少高于用本发明的装置得到的稳态浓度4倍。
发明详述
本发明涉及通过皮下植入使得强效阿片类药物得以控释的装置2，其具有生物相容性，非炎症性和非生物可降解的特性。将如氢化吗啡酮的一种药物包埋入如聚乙烯乙酸乙烯酯的控释基质14，并且此多聚体包被以生物相容性的和氢化吗啡酮不可透过的多聚体12如聚(甲基丙烯酸甲酯)。植入物典型地具有圆柱体形状，圆柱体顶4或底6的直径，大大超出圆柱体外壁8的高度。植入物被穿孔，在装置2的顶4和底6中产开口并产生一层未包被的内部圆柱形壁16。这种结构允许氢化吗啡酮的稳定释放。
本发明的给药装置使药物转作它用的机会最小化，提高了依从性，并减少了需要持续阿片药物施用的癌症相关疼痛病人中对昂贵的支持人员和设备的需要，以及对昂贵和通常不方便的外部导管和泵的需要。该装置在体内和体外给予稳定量的氢化吗啡酮达长时间。本发明产物达到的血浆氢化吗啡酮水平无显著毒性。获得的稳定水平减小了毒性并提高了有效性。用植入物获得的血浆氢化吗啡酮水平和那些水平的变化与用渗透泵获得者相常接近。
EVA多聚体的外包被物12有效地消除在很多其它装置中见到的药物释放的最初“突发”。与静脉内丸粒式给药不同，装置植入后取得的血浆氢化吗啡酮水平在整个给药期间维持稳定并在治疗学范围内。
这些装置的高度的变化(即，壁8的高度)和直径(即顶4和底6的直径)的变化以及植入装置个数的变化提供了每小时释放氢化吗啡酮量，氢化吗啡酮释放持续时间和获得的血浆氢化吗啡酮水平的强度的灵活性。
本发明解决了氢化吗啡酮“突发效应”的问题，消除了氢化吗啡酮的重复注射，提供了一种对稳定和/或慢性癌症疼痛的长期治疗，提供了一种治疗阿片类药物成瘾的方法，并防止了麻醉剂的滥用，即药物转作它用，因为本技术使从本发明的装置提取氢化吗啡酮极为困难。阿片类
氢化吗啡酮(包括盐酸氢化吗啡酮)是一种水溶性，强效(比吗啡强6-7倍)阿片类，用于皮下使用并通常用于有癌症相关疼痛的病人。Vallner等，J.Clin.Pharmacol 21：152-6，1981，Bruera等，J.Natl.Cancer Inst.80：1152-4，1988，Reidenberg等，Clin.Pharmacol Ther.，44：376-82，1988，Moulin等，Can，Med.Assoc.J.146.891-7，1992.，Moulin等，Lancet，337：465-8，1991。对皮下给药装置大小的强制要求有利于选用这种阿片类。氢化吗啡酮具有极好的水溶性并从疏水性EVA多聚体上给出释放的满意形式。基质
乙烯乙酸乙烯酯(EVA)共聚体是一种生物相容性，非炎症性，和非生物可降解性多聚体。一种非生物可降解多聚体被用于本发明以使之局部化。而且，如果有任何不利情况迫使医师从病人取出植入物12，它可被完整取出。一种生物可降解植入物将随时间而变软并失去其结构完整性，使紧急取出的任务变困难，甚至不可能。
装载药物的EVA基质通过溶剂成形技术有利地制造。将多聚体先溶于有机溶剂中，优选一种低沸点溶剂如二氯甲烷或氯仿以利于最终通过蒸发去除溶剂。多聚体溶液的浓度最有利为5～15％(重量)。浓度过稀在塑型过程中导致气泡形成而过浓则使药物颗粒难于在溶液中分散。
将被埋藏入EVA基质的药物溶解于，或在高装载量药物水平情况下，分布入多聚体溶液。药物可通过渗透从多聚体相释放，或者如果药物在多聚体中溶解度低，可通过经孔或通道弥散而释放。由于接近基质表面的药物颗粒被溶解和释放，它们留下孔和通道，正是通过这些孔和通道埋藏的药物颗粒被释放。优选地，药物颗粒被筛选，因为药物颗粒的大小决定着孔和通道的大小。然而，这不是绝对必须的，除非药物颗粒聚集形成大的团块，例如，数百微米大小。使用已被降低颗粒体积至微米级的商购药物颗粒可获得合理的可重复的释放动力学(即，接近恒定的给药)。
然后将带有药物的多聚体溶液塑型为希望的形状和大小。在慢慢蒸发溶剂(以防气泡形成)后，药物分子或药物颗粒被埋藏入多聚体基质中。该塑型通常在低温下进行，以防止药物颗粒在溶剂蒸发过程中沉积。典型地，带有药物的多聚体溶液被浇入已被冷却至低于溶剂的熔点的温度的模型中。因此该溶液快速冷结以便形成药物颗粒在最终基质中的均一分散体。
其它适合用作基质的材料包括聚硅氧烷橡胶，水凝胶如交联聚(乙烯醇)和聚(羟基甲基丙烯酸乙酯)。包被物
包被EVA多聚体基质消除了通常见于控释装置的潜在致死性“突发效应”。未包被的多聚体在给药后前两天达到氢化吗啡酮的突发或高峰，并在随后的几天日逐渐降至最小量(见图6)。这是使用皮下植入物用于药物给药的关键问题，本发明解决了关于氢化吗啡酮的这一问题。为消除突发效应和获得更稳定或恒定的释放动力学而不必处理基质中非均一药物分布，除在中部的一个小开口外，含药物14的EVA多聚体用对药物不可透的和组织相容的包被物12包被，以使植入物2产生最少的纤维组织包裹。有利地，骨胶接剂聚(甲基丙烯酸甲酯)与氢化吗啡酮一起使用。包被物应足够厚以维持植入物期望的寿命，典型地约100微米。
基质的包被物有利地通过浸涂技术获得。例如，通过选定直径的注射器针头穿刺盘状物并浸入多聚体溶液而施用一种包被物。在经反复浸入包被和干燥应用数层包被物后，去除针头以暴露未包被的圆柱状孔。替代地，沿基质轴的开口在包被该基质后产生。药物只通过此开口释放。通过此种构型，获得接近恒定的药物释放，而没有在EVA多聚体中的药物浓度梯度。
该包被材料对氢化吗啡酮不可透，非生物可降解(在2个月内多聚体骨架破裂或质量丢失可忽略)，并溶于一种对于所选择的基质为不良溶剂的溶剂中。否则基质在浸入包被过程中可部分溶解并且一些药物分子或颗粒可埋藏于包被物中。聚(甲基丙烯酸甲酯)的溶度参数是9-9.5[cal/cm3]0.5。其它对于氢化吗啡酮不可透的具有这种溶度参数的多聚体适合包被EVA-氢化吗啡酮多聚体。药物装载
氢化吗啡酮对EVA多聚体的比例是氢化吗啡酮重量占10-90％，优选30-70％。药物/EVA混合物是均质的。氢化吗啡酮浓度的较高水平通常用于开口10非常小时(见下文)。植入物几何形状
植入物形状为圆柱形最有利(见图1和2)。沿整个植入物未包被的壁和包被的壁(相对于未包被的壁)之间的距离保持恒定或基本(±20％)恒定的其它几何形状可被使用，如，一种未包被的壁为半球形的半球(图3)，或具有延伸立方体全高度(厚度)的方形开口的立方体(图4)。这些几何形状在植入物的整个存在期提供接近恒定的释放速度。
圆柱形植入物直径为5-100mm，优选10-25mm和高(厚)1-20mm，优选1-2mm。
沿着圆柱形装置的轴延伸的单个50微米至3mm直径，优选0.5-1.5mm直径，圆形或基本圆形的开口10，产生一个内部圆柱形未包被区16，沿此区药物被释放。圆柱形，立方形、半球形或其它形状装置开口的面积小于装置顶部表面积的10％，优选小于1％。
本发明的多单位装置通过并列放置圆柱形植入物(或其它形状)形成，即，单个装置的轴垂直于多单位装置的轴。(见图5)。在并列放置的情况，单个成员(即，单个圆柱形或立方体)间的接触区(即，单位相连的部位)可被包被或不包被。
在另一实施例中，形成多单位装置，其单个装置(如圆柱形或立方体)的轴与多单位装置的轴相同。为以此种方式连接单个装置并允许药物释放，单个装置被间隔开并通过间隔物连接。在一项实施方案中，间隔物是与多单位轴平行排列的一或多个成员；这种间隔物的每一个连接于每个单个装置的外壁。另外，多孔的成员交替用于单个装置间(并连接所有的装置)。在另一项实施方案中，接触(并连接)一个单个装置的底和相邻装置的顶的小间隔物被用于形成多单位装置。优选使用包被材料，如聚(甲基丙烯酸甲酯)制造间隔物。在另一项实施方案中，包被有包被材料的线被用作间隔物。植入物的施用
本发明的装置12被植入皮下，优选于上臂或腹部区域，使用本领域技术人员公知的步骤。给药剂量选择对特定病人安全而有效者。剂量过低不能缓解疼痛，剂量过大导致镇静继以呼吸抑制。例如，在癌症疼痛治疗中，使用直观模拟定标用于测定疼痛，并确定相对于病人主观疼痛水平的氢化吗啡酮，为一个病人选择一个合适剂量速度的盘。
为治疗癌症疼痛，典型地设计植入物以产生0.1～25mg/hr，优选0.1至10mg/hr(如，25mg/hr，1mg/hr和4mg/hr)。典型地1至3种植入物被置入病人中。剂量(mg/hr)主要通过圆柱状盘的高度或开口直径调节，即，增加高度或开口直径意谓着更大的释放速度(一个更大的未包被表面区16保持暴露于外周)。见图7。多个植入物的给药，不管是单个地还是如上所述并排地，增加剂量速度。而且，增加药物装载量增加剂量速度。
为治疗阿片类依赖，植入物被典型地设计以产生皮下0.1-0.5mg/hr氢化吗啡酮。关于美散痛维持的讨论见Strain等，Ann.Intern.Med.119，23-27(1993)，和Gerstein及Lewin，N，Engl.J.Med.，323，844-848(1990)。
该装置可控制氢化吗啡酮释放达希望的血液水平达2周至超过6个月时间。植入物的寿命有利地受其直径的调节(增加直径增加寿命)。药物装载，开口大小和高度也对植入物的寿命有影响。持续4周的植入物对于癌症疼痛的治疗是有利的，因为肿瘤专家通常至少每个月随诊其有慢性疼痛的癌症病人1次。疼痛的程度可因肿瘤进展而增加，从而需要更大的剂量。而且，对氢化吗啡酮有耐受，因而在随后的月中，可能需要更高的剂量以控制相同程度的疼痛。
本发明的装置通过接近恒定的氢化吗啡酮给药。“接近恒定”定义为在目标给药速度中(在体内或体外)±5倍(500％)，优选±2倍(200％)变化，最优选±1倍(100％变化)。大于5倍的变化导致“突发效应”，它可引起接受者的损害或甚至死亡。
在本发明的一项实施方案中，当病人经受严重疼痛时，除通过植入物释放药物外，还可通过补充一些阿片药物以缓解症状(经口服、直肠等)。治疗疼痛
本发明的植入物可用于任何有指征应用口服阿片类的病历。在约85％具有癌症疼痛的病人中，有指征使用口服阿片类。当口服用药不适合或无效或间断服药有毒性时本发明特别有利。本发明的植入物可用于治疗人类或其它动物中的癌症疼痛。本植入物可用于治疗其它类型的慢性疼痛，如由退行性肌肉骨骼或神经系统疾病导致的慢性严重的疼痛。治疗阿片类依赖
本发明的植入物可用于治疗阿片类药物(如，海洛因)成瘾。以低剂量长时期给予氢化吗啡酮在药物成瘾的治疗中是有效的。本发明的植入物可用于任何计划可使用美散痛维持的情况。本植入物保证低剂量速度的药物可维持长时间而不依赖于病人对口服给药计划的依从性。而且，本植入物的使用以一种基本消除非法使用可能性的方式提供药物。
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下列实施例是阐明性的，而不是本发明的组合物和方法的限制。其它对于本领域工作人员显见的，临床治疗中通常遇到的对许多条件和参数的适当修改和改变包括在本发明的实质和范围内。
实施例
实施例1多聚体配方
低温度溶剂塑型技术被用于配方这些实验中使用的氢化吗啡酮植入物。EVA(分子量约为25000)(Elvax-40W.Dupont)带有40％重量的乙酸乙烯酯，在水中清洗并溶解于二氯甲烷(CH2Cl2)以产生10％溶液。多聚体可通过在Soxhlet提取器中用蒸馏水提取3天，随后用丙酮再提取4天以去除杂质和抗氧化剂而提纯。掺入氢化吗啡酮的基质通过溶剂塑型制备。通过将2克纯EVA溶于20ml二氯甲烷制备EVA的10％(w/v)溶液。
将未过筛的盐酸氢化吗啡酮粉(Knoll Pharmaceuticals)在室温加至10％EVA中以产生50重量百分比溶液，随后将它磁力搅拌约10分钟。氢化吗啡酮粉可被机械地过筛以预定颗粒大小范围并悬于EVA溶液中。在此溶液中任何肉眼可视的团块均用玻璃搅棒打碎。
将该均质溶液迅速浇入在干冰上预冻至-78℃的直径14cm的重结晶盘中。将盘盖上以使凝聚作用最小。固化后(此固化在15分钟内发生)，将样本在2个48小时阶段中干燥：第一个在-20℃，而后是在室温在真空中。
氢化吗啡酮多聚体盘用7号软木塞钻孔器从干燥的圆形厚片切割以产生约0.27cm厚和1.05cm直径的约15个多聚体。对于设计用来证实每小时释放的氢化吗啡酮量的灵活性的那些实验，通过使置于模子中的EVA-氢化吗啡酮量加倍或增加3倍而制备2或3倍厚度的多聚体(分别为0.55-0.65cm和0.83cm厚)。还使用15号软木塞钻孔器从干燥的EVA-氢化吗啡酮厚片切割2.13cm直径的多聚体以证实药物释放时间的灵活性。
实施例2多聚体包被
在包被前，将1个18号空心不锈钢针头在接近多聚体圆面中心处穿过EVA-氢化吗啡酮多聚体的全厚度。随后每个多聚体在丙酮中的10％聚(甲基丙烯酸甲酯)(分子量约996000)(Aldrich)溶液中浸入包被约10秒钟。该聚(甲基丙烯酸甲酯)包被物在室温中空气干燥工作24小时后去除针头，将多聚体翻转，将针头在相反方向再穿过多聚体中的中央孔。此过程随后重复两遍以产生除穿过每个多聚体中心的18号口径圆柱体(约1.25mm直径)外完全包被每个多聚体的聚(甲基丙烯酸甲酯)的厚度增加三倍，很象钮扣中带有一个孔。该包被物厚度为约100-200μm。该包被物材料的溶度参数是9-9.5[cal/cm3]0.5。
实施例3体外释放测定
氢化吗啡酮从包被的EVA-氢化吗啡酮多聚体的释放在体外通过将每个多聚体置于含10ml pH7.40.1M磷酸盐缓冲液，加温至37℃的玻璃闪烁管中进行测定。所有的管被置于37℃水浴中。在适当的间隔，将每管中的缓冲液收集并在约4℃贮存在离心管中并将10ml 37℃的新鲜磷酸盐缓冲液加回至每个管中。样本成批定期测定，使用254mm处的紫外线分光光度计，成对的比色杯，零点相对于空白0.1M pH7.4磷酸盐缓冲液。氢化吗啡酮标准品被包括在每个测定中，并且，如果需要，将样本在缓冲液中稀释以使它们的吸光度可在标准曲线的线性部分进行测定。
包被的EVA-氢化吗啡酮多聚体在体外释放后4天开始以恒定的164μg/hr的平均速度释放氢化吗啡酮并持续4周以上。用不可通过的聚(甲基丙烯酸甲酯)层包被这些多聚体，只留下中心全厚度孔未包被，清除了使很多其它控释装置复杂化的最初“突发”。通过改变包被的EVA-氢化吗啡酮多聚体的厚度和直径可容易地获得每小时释放氢化吗啡酮量及药物给予持续时间的不同值。见图9。体内实验
实施例4A多聚体释放
在全身麻醉下，将2个包被的EVA氢化吗啡酮多聚体置于5只成年兔每一只的一个皮下袋中。每只兔养在一只笼中，随意喂给兔草和水。在植入前和植入后6周内的适当间隔从每只动物抽取血样。将血样离心并取得血浆，贮存于-20℃冰箱中。血浆样本使用商购的放射免疫测定法阿片药物筛选和氢化吗啡酮标准成批进行测定。为试图证实植入的氢化吗啡酮量与所产生的血浆药物水平的关系，另取2只兔每只间隔1周顺次植入3套2单位多聚体。先植入的包被的多聚体被留在原位，从而这些兔在相同时间可有2然后是4然后是6个多聚体在释放氢化吗啡酮。如上所述取血并测定血浆。
在兔皮下置入2个装置产生23-37ng/ml的稳定而持续的血浆氢化吗啡酮水平达4周(见图10)。在单个兔中增加皮下植入物的数量可使该兔的血浆氢化吗啡酮浓度产生持久而可预料的增加(见图11)。在这些动物实验中未观察到显著的毒性，只是在植入2个装置后有轻微短暂的镇静，而且在植入更多的装置后镇静加强并伴有进食减少也表现为短暂的。
实施例4B渗透泵释放
为证实装置植入后测定的兔血浆氢化吗啡酮水平，制备释放接近于2个本发明的装置每小时氢化吗啡酮量的Alzet渗透泵。在全身麻醉下，将Alzet渗透泵(平均泵速＝2.08μl/hr，平均充量＝2073μl)经皮下置于4只兔中并按照上述收集血样。血浆也按照上述制备和测定。
设计为释放297μg/hr氢化吗啡酮的Alzet渗透泵产生平均兔血浆氢化吗啡酮水平28至51ng/ml达2周以上(见图12)。
实施例4C氢化吗啡酮静脉推注
向另外两只兔静脉内施予单一的600μg和1200μg推入剂量(相当于通过多聚体或泵皮下4小时给予的累积量的1/2至1倍，这是人类中典型给药间隔)，并在0，1，2，5，10，20，30，45，60，90，120，150，180，210和240分钟收集样本。
静脉推注600和1200μg氢化吗啡酮在1分钟时产生约200至大于250ng/ml的峰值兔血浆氢化吗啡酮水平，在4小时时快速降回基线(见图13)。
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对于本领域技术人员显见可对本发明、所公开的装置和相关系统进行多种修改和增加，而不离开在此公开的本发明范围。
Claims (21)
1.一种皮下给药装置，它包括：
i)一种包含聚(乙烯-乙酸乙烯酯)的基质，
ii)均匀地包埋在所述基质中的氢化吗啡酮，
iii)包被所述基质的聚(甲基丙烯酸甲酯)，
其中所述给药装置适合以接近恒定的速度释放所述氢化吗啡酮。
2.按照权利要求2的给药系统，其中该给药系统具有一定的几何形状，能使未包被的壁和包被的壁间的距离沿整个装置基本保持恒定。
3.权利要求1中的给药系统，其中所述给药系统形状为圆柱状，并且沿所述给药系统的中轴有一个圆柱状的开口，形成所述装置的内壁。
4.按照权利要求1中的给药系统，其中所述包被物的厚度是0.1-1mm。
5.权利要求1中的给药系统，其中所述基质含50％重量的氢化吗啡酮和50％重量的聚(乙烯-乙酸乙烯酯)。
6.权利要求5中的给药系统，其中所述氢化吗啡酮均匀地分布于所述基质中。
7.权利要求3中的给药系统，其中高度为1-20mm并且直径为5-100mm。
8.权利要求3中的给药系统，其中所述圆柱形开口直径为0.05-3mm。
9.一种提供给药系统的方法，它包含：
i)在聚乙烯-乙酸乙烯酯基质中包埋治疗剂，
ii)将所述基质形成圆柱形，
iii)用聚(甲基丙烯酸甲酯)包被所述基质，和
iv)沿圆柱形基质中轴制成圆柱形开口，在所述基质中制成一道内壁。
10.一种皮下给药装置，它包含：
i)一种多聚体基质材料，
ii)包埋在所述基质中的治疗剂，和
iii)围绕所述基质的包被物。
其中所述给药系统为圆柱形并有沿所述给药系统中轴的圆柱形开口，在所述给药系统中形成内壁。
11.权利要求10中的给药系统，其中所述多聚体基质材料是聚乙烯-乙酸乙烯酯。
12.权利要求10中的给药系统，其中所述治疗剂是氢化吗啡酮。
13.权利要求19中的给药系统，其中所述包被物是聚(甲基丙烯酸甲酯)。
14.权利要求10中的给药系统，其中所述包被物的厚度是0.1-1mm。
15.权利要求10中的给药系统，其中所述基质含50％重量的氢化吗啡酮和50％重量的聚乙烯乙酸酯。
16.权利要求15中的给药系统，其中所述氢化吗啡酮均匀地分布于所述基质中。
17.权利要求10中的给药系统，其中高度为1-20mm并且直径为5-100mm。
18.包含至少两个权利要求1中的给药装置的多单位给药系统，其中所述装置并列排列。
19.一种在遭受疼痛的哺乳类中提供疼痛长时间缓解的方法，它包含向所述哺乳类经皮下施用权利要求1的装置。
20.权利要求19中的方法，其中所述疼痛为癌症疼痛。
21.一种在具有阿片类药物成瘾性的哺乳类中治疗阿片类药物成瘾的方法，它包含向所述哺乳类施用权利要求1的装置。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/264,689 | 1994-06-23 | ||
| US08/264,689 US5633000A (en) | 1994-06-23 | 1994-06-23 | Subcutaneous implant |
| US264689 | 1994-06-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1156400A true CN1156400A (zh) | 1997-08-06 |
| CN1212809C CN1212809C (zh) | 2005-08-03 |
Family
ID=23007180
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB95194746XA Expired - Fee Related CN1212809C (zh) | 1994-06-23 | 1995-06-20 | 皮下植入物 |
Country Status (16)
| Country | Link |
|---|---|
| US (3) | US5633000A (zh) |
| EP (1) | EP0766538B1 (zh) |
| JP (1) | JP3964933B2 (zh) |
| CN (1) | CN1212809C (zh) |
| AT (1) | ATE309761T1 (zh) |
| AU (1) | AU711323B2 (zh) |
| BR (1) | BR9508124A (zh) |
| CA (1) | CA2193627C (zh) |
| DE (1) | DE69534622T2 (zh) |
| IL (1) | IL114244A (zh) |
| MX (1) | MX9606582A (zh) |
| NZ (1) | NZ288988A (zh) |
| RU (1) | RU2157246C2 (zh) |
| TW (1) | TW421597B (zh) |
| WO (1) | WO1996000047A1 (zh) |
| ZA (1) | ZA955168B (zh) |
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| CN102481370A (zh) * | 2009-04-17 | 2012-05-30 | 阿克西亚制药有限责任公司 | 聚合物药物传递系统及生产所述系统的方法 |
| CN106999303A (zh) * | 2014-07-25 | 2017-08-01 | 罗伯特·W·亚当斯 | 改进的医疗植入物 |
| CN111989068A (zh) * | 2018-05-24 | 2020-11-24 | 塞拉尼斯伊娃高性能聚合物公司 | 用于持续释放大分子药物化合物的可植入器件 |
| CN112638400A (zh) * | 2018-06-25 | 2021-04-09 | 泰坦医药品公司 | 用于释放亲脂性或两亲性药用物质的植入物 |
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| US10993906B2 (en) | 2014-07-25 | 2021-05-04 | Robert W. Adams | Medical implant |
| US11857671B2 (en) | 2014-07-25 | 2024-01-02 | Robert W. Adams | Medical implant |
| CN111989068A (zh) * | 2018-05-24 | 2020-11-24 | 塞拉尼斯伊娃高性能聚合物公司 | 用于持续释放大分子药物化合物的可植入器件 |
| CN112638400A (zh) * | 2018-06-25 | 2021-04-09 | 泰坦医药品公司 | 用于释放亲脂性或两亲性药用物质的植入物 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1212809C (zh) | 2005-08-03 |
| JPH10503757A (ja) | 1998-04-07 |
| NZ288988A (en) | 1999-05-28 |
| WO1996000047A1 (en) | 1996-01-04 |
| MX9606582A (es) | 1997-05-31 |
| US6126956A (en) | 2000-10-03 |
| US5858388A (en) | 1999-01-12 |
| DE69534622D1 (de) | 2005-12-22 |
| TW421597B (en) | 2001-02-11 |
| IL114244A (en) | 2004-02-19 |
| IL114244A0 (en) | 1995-10-31 |
| ZA955168B (en) | 1996-01-24 |
| EP0766538B1 (en) | 2005-11-16 |
| AU2869295A (en) | 1996-01-19 |
| BR9508124A (pt) | 1997-08-12 |
| US5633000A (en) | 1997-05-27 |
| EP0766538A4 (en) | 1997-12-03 |
| RU2157246C2 (ru) | 2000-10-10 |
| ATE309761T1 (de) | 2005-12-15 |
| CA2193627A1 (en) | 1996-01-04 |
| DE69534622T2 (de) | 2006-08-10 |
| AU711323B2 (en) | 1999-10-14 |
| EP0766538A1 (en) | 1997-04-09 |
| CA2193627C (en) | 2009-03-31 |
| JP3964933B2 (ja) | 2007-08-22 |
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