CN1283992A - 持续释放药物传递装置 - Google Patents
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Abstract
本发明提供了能够得到所需的局部或全身生理学或药理学效果的治疗哺乳动物有机体的方法和装置。该方法包括对需要这类治疗的哺乳动物有机体在需要有效药剂释放的区域上进行持续释放药物传递装置给药,然后允许有效药剂以控制方式通过所述装置。该装置包括包含有效药剂的内部药芯或贮池;第一包覆层,该包覆层可渗透有效药剂的通过;第二包覆层,该包覆层基本上不能渗透有效药剂的通过;以及第三包覆层,该包覆层可渗透有效药剂的通过。第一包覆层覆盖了至少部分内部药芯。第二包覆层覆盖了至少部分第一包覆层和内部药芯;但至少有小部分第一包覆层或内部药芯没有被第二包覆层覆盖。第二包覆层包括不渗透膜和至少一块圆片。第三包覆层基本上完全覆盖了第二包覆层和未被覆盖的第一包覆层和内部药芯。
Description
发明领域
本发明涉及新的持续释放药物传递装置,该装置包括包含能够获得所需的局部或全身生理学或药理学效果的有效药剂的内部药芯或贮池;可渗透通过有效药剂的第一包覆层;包含不渗透聚合物和至少一块基本上不能渗透通过有效药剂的圆片的第二包覆层;以及能够渗透通过有效药剂的第三包覆层。第一包覆层覆盖了至少部分内部药芯。第二包覆层覆盖了至少部分第一包覆层和内部药芯;但至少有小部分第一包覆层或内部药芯没有被第二包覆层覆盖。第三包覆层基本上完全覆盖了第一包覆层和第二包覆层。未被第二包覆层覆盖的部分第一包覆层可允许药剂通过第三包覆层,从而允许控制释放。
发明背景
这些年来,人们研制了各种辅助治疗许多疾痛或疾病的药物。然而,这些药物在许多情况下不能在没有各种有害副作用的条件下经口或经静脉内给药。
例如,在治疗爱滋病患者的CMV视网膜炎中,静脉内注射甘西洛维(ganciclovir)(GCV)是有效的,但是其骨髓毒性却限制了其有效性。在静脉内注射GCV治疗中,嗜中性白血球减少症(嗜中性细胞的绝对数量<1000)的发病率为30至50%。为了防止疾病发展或再发作,连续维持GCV的治疗是必要的,但如果忽视维持性治疗,则在治疗中会有30至50%的患者经历复发。与全身性GCV给药相关的其它问题包括:与永久性留置导管相关的脓毒病危险,以及不能接受与齐多呋定(AZT)同时治疗,所述齐多呋定已表现出可延长生命且改善爱滋病患者的免疫功能。
通过经玻璃体内,每周注射一次或两次200至400μgGCV,可暂时性免除爱滋病患者的CMV视网膜炎。与全身性治疗相比,进行玻璃体内GCV注射可提供更高的眼内药物浓度,也可降低嗜中性白血球减少症的发病率。目前的治疗爱滋病患者的CMV视网膜炎的方法显然不是最满意的。甘西洛维能防止病毒生长,所以抑制疾病需要持续给药。
由于某些药物具有一定的危险性,所以研究者们已经研制出了通过服用这类药物辅助治疗这些疾痛和疾病的系统。许多这些系统均提供了能够降低有害副作用发生的释放速率。
这类传递装置之一是经口服给药的药丸或胶囊,它们包含封在各种组合物层内的药物,所述组合物层在一段时间内于消化道内溶解,因而允许药物渐渐地或慢慢地释放到系统中去。
另一种类型的控制这类药物给药的装置,是通过利用聚合物材料包覆药物而制备的,所述聚合物材料可渗透药物的通过,从而获得所需的作用。这类装置特别适用于在不将患者的整个身体暴露于药物的条件下,在特定的局部区域对患者进行治疗。因为可将药物的任何可能的副作用降低至最低,所以这类装置具有优点。
这种系统特别适用于治疗影响眼睛的疾痛。对眼睛的外表面进行药物给药的方法公开在Arnold的美国专利4,014,335中。为了使药物慢慢地释放到泪液膜中,从而加长释放时间,Arnold描述了多种用作沉积或药物贮池的眼睛插入物。这些插入物由柔性聚合物材料制成,所述聚合物材料为生物惰性、不会引起过敏症且不溶于流出的眼泪。为了启动这些装置的治疗程序,将眼插入物放置在眼球的巩膜与眼皮之间的陷凹处,从而对眼睛进行给药。
由不溶于流出的眼泪的聚合物材料制得的装置在所需的治疗过程中保持其形状和完整性,从而用作对眼睛和周围组织进行连续给药的药物贮池,给药速率以不受聚合物材料溶解或腐蚀的影响为宜。在所需治疗程序的最后,将该装置从所述陷凹处离去。
描述在美国专利3,416,530中的另一类用于对眼睛的外表面进行药物持续释放的装置,是由许多毛状开口制成的,这些开口可使得装置外部与腔室内部产生联系,所述腔室一般是由聚合物膜围成的。尽管该结构中的这些毛状对于将某些药物释放到眼睛中去是有效的,但是由于难以在大规模制备中利用聚合物控制这些开口的尺寸,所以对制备这些装置增加了相当的复杂性。
描述在美国专利3,618,604中的另一装置不涉及这类开口,而是通过聚合物膜扩散的方法使得药物释放。正如在该专利中所公开,在一优选的实施方案中,该装置包含在其内部腔室中含有药物的密闭容器。尽管如此,正如美国专利4,014,335中所描述,这类装置已被证明存在一些问题,例如为形成容器而进行的密闭膜的边缘就是非常困难的任务。另外,在制备这些装置中,由于变形而引入到膜壁的应力和应变会导致贮池破裂和渗漏。
描述在美国专利4,014,335中的另一这类装置包含三层叠层,所述叠层含有一对独立且不连续的由不溶于眼泪的材料构成的第一和第三器壁,其中一个器壁由能够渗透药物通过的药物释放材料构成,其它器壁由不能渗透药物通过的材料构成。
上述系统或装置均是试图提供药物的缓慢释放,在所需的局部或全身有效地对患者进行治疗,得到某些生理学或药理学效果;然而它们具有许多与使用相关的缺点,包括经常很难得到所需的药物释放速率。在治疗CMV视网膜炎中,特别重要的是需要一种更好的释放系统。
在研制本发明之前,人们研制出了新的持续释放传递装置,该装置改进了许多上述与药物传递相关的问题。描述在美国专利5,378,475中的装置包括基本上不能渗透通过有效药剂的第一包覆层和能够渗透通过有效药剂的第二包覆层。在该装置中,第一包覆层覆盖了至少部分内部药芯;但至少还有小部分内部药芯没有被第一包覆层覆盖。第二包覆层基本上完全覆盖了第一包覆层和未被覆盖的内部药芯。没有被第二包覆层覆盖的部分内部药芯可允许药剂通过第二包覆层,从而允许控制释放。
尽管美国专利5,378,475中描述的装置解决了许多上述涉及药物传递方面的问题,但该装置及制备该装置的方法并不是没有问题。特别地,适合于包覆内部药芯的聚合物常常相对较软,因此在在制备均质膜中会出现技术困难。当试图包覆带有边缘的非球体(如圆柱形)时更是如此。在这种情况下,为了获得连续的包覆层,必须使用相对较厚的膜。因此,作为封闭内部药芯端部所需的厚度结果,该装置的尺寸要大于所必须的尺寸。
在设计植入到有限的解剖空间(如眼睛)中的装置时,装置的尺寸是一个非常重要的问题。为了植入和取出,更大的装置需要更加复杂的手术。另外,为获得均匀的包覆层所需的额外的聚合物会降低植入物的有效体积,因而限制了能够传递的药物量。
作为所有上述结果,特别是对于在眼中使用,为了获得所需的局部或全身生理学或药理学效果,在本领域中仍需要改进能够对患者提供药物持续释放的装置的设计和制备方法。
发明概要
由此可见,本发明的主要目的是提供一种适合于药物控制和持续释放的装置,所述药物可有效地获得所需的局部或全身生理学或药理学效果。
在一个实施方案中,该装置包括包含能够有效地获得所需效果的药剂的内部药芯或贮池。该装置还包括第一包覆层,所述第一包覆层可渗透通过药剂。另外,该装置包括第二包覆层,该第二包覆层包括至少一块圆片和不渗透性聚合物。第二包覆层基本上不能渗透通过药剂且覆盖部分第一包覆层和内部药芯。第二包覆层在与第一包覆层接触的一侧阻止药剂从内部药芯通过。未被阻止的内部药芯剩余部分允许控制量的药剂从内部药芯经第二包覆层传入第一包覆层,进入第三包覆层。第三包覆层能够渗透通过药剂,基本上覆盖了整个第二包覆层。为了控制药剂渗透第三包覆层的速率,第二包覆层位于内部药芯和第三包覆层之间。
本发明的另一目的是提供一种制备治疗哺乳动物有机体(如人)的方法,从而获得所需的局部或全身生理学或药理学效果。该方法包括将持续释放药物传递系统置于需要药物释放的区域,允许药剂通过第三包覆层到达所需的治疗区域。
本发明的另一目的是提供适合于直接植入到眼睛的玻璃体中去的眼用装置。人们可惊奇地发现,本发明的这种装置提供了各种药物的持续控制释放,从而可在没有有害副作用危险的条件下对眼睛进行治疗。
本发明的目的是使包含在眼内装置中的药物量最大,而使其尺寸最小,从而延长植入时间。
本发明的另一目的是提供一种眼传递系统,该系统可应用于眼内晶体,从而治疗炎症或晚期囊状浑浊化。
鉴于上述目的以及将在下文中变得明显的本发明其它目的、优点、特征等方面,参照本发明的详细描述以及所附的权利要求,本发明的实质将会得到更加清楚的理解。
附图简述
图1为持续释放药物传递装置的一个实施方案的放大视图,显示出了内部药芯、第一包覆层、第二包覆层和第三包覆层。
图2A为不渗透聚合物的放大视图。图2B为包括不渗透膜和不渗透圆片的第二包覆层的放大视图。
发明优选实施方案的详细描述
更具体而言,本发明发现了一种装置及其制备方法,所述装置适用于药剂的控制和持续释放,所述药剂能够有效地获得所需的局部或全身生理学或药理学效果。具体是,本发明发现,通过密封带有不渗透圆片的至少一个表面,可使用更薄的包覆层。与其它可能的方法相比,本发明方法具有能够制备更薄、更短的装置的优点。进一步的优点在于用于制备不渗透圆片的材料可不需要具备延展性(从而便于覆盖弯曲的表面),而是可使用相对较硬的材料,容易地制备均匀的扩散口。该装置包括包含有效地获得所需效果的药剂的内部药芯或贮池。该装置进一步地包括第一包覆层、第二包覆层和第三包覆层。可渗透有效药剂通过的第一包覆层完全覆盖了内部药芯。第二包覆层仅仅覆盖部分第一包覆层和内部药芯,不能渗透通过药剂。第三包覆层覆盖全部第一包覆层和第二包覆层,可渗透通过药剂。未被第二包覆层覆盖的部分第一包覆层和内部药芯可促使药剂通过第三包覆层。特别地,第二包覆层位于内部药芯和第三包覆层之间,因此阻止药剂通过第三包覆层的邻近部分,从而控制药剂传递的释放。
图1表示本发明持续释放药物传递装置的一个实施方案。尽管图1所示的装置为圆柱形,但是该装置可以是任何形状。该装置包括内部药芯或贮池5,能够渗透内部药芯或贮池中的药剂通过的渗透包覆层10,不能渗透内部药芯或贮池5中的药剂通过的不渗透包覆层15,以及能够渗透内部药芯或贮池5中的药剂通过的渗透包覆层20。第二包覆层包括不渗透聚合物17和位于圆柱形内部药芯端部的圆片18和19。图1还显示了缝合标签30。
图2A和2B仅显示第二包覆层,表示了与使用不渗透圆片作为部分第二包覆层相关的好处。图2A显示在内部药芯的边缘具有薄包覆层的不渗透聚合物层17。薄包覆边缘31形成了有效药剂的有效渗漏。
图2B表示了利用不渗透圆片的好处。第二包覆层包含不渗透聚合物17和位于圆柱形内部药芯端部的圆片18和19。不渗透圆片18包含一扩散口。不渗透圆片18和19预防有效药剂向不渗透聚合物的薄边缘31的渗漏。
本发明还涉及治疗哺乳动物有机体的方法,从而得到所需的局部或全身生理学或药理学效果。该方法包括对哺乳动物有机体服用持续释放药物传递系统,允许能够获得所需的局部或全身效果的有效药剂通过第三包覆层,与哺乳动物有机体接触。这里所使用的术语“服用”是指放置、插入、注射、植入或其它使得该装置暴露于哺乳动物有机体的方式。给药路线取决于许多因素,包括应答或治疗的类型、药剂的类型以及优选的给药位置。
某些实施方案中的装置可适用于提供包含能够在涉及至少下列领域中获得所需的局部或全身生理学或药理学效果的有效药剂的控制和持续释放:治疗癌变原发肿瘤(如恶性胶质瘤);慢性疼痛;关节炎;风湿病;激素缺乏症,如糖尿病和矮小症;以及在预防拒绝移植和癌症治疗中调节免疫性应答。利用本发明的药物传递装置也可预防或治疗许多其它病态。这类病态对于本领域普通技术人员是公知的。对于非本领域技术人员,可参见对比文献:Goodman和Gilman,治疗学的药理学基础(The Pharmacological Basis of Therapeutics),第8版Pergamon Press,NY,1990;以及Remington药物学(Remingtos’s Pharmaceutical Science),第18版.,MackPublishing CoEaston,PA,1990。这两篇对比文献在此引作参考。
另外,该装置适用于由AIDS及与AIDS相关的机会性感染疾病(如细胞巨化病毒感染、弓形体病、卡氏肺囊虫和细胞间分支杆菌)感染的哺乳动物有机体。
该装置特别适用于治疗眼病,如青光眼、增殖性玻璃体视网膜病、糖尿病性视网膜病、眼色素层炎和角膜炎。该装置还特别适用于在治疗患有细胞巨化病毒视网膜炎的哺乳动物有机体中用作眼用装置,其中将该装置通过手术植入在眼睛的玻璃体内。
正如上文所描述,内部药芯或贮池包含能够获得所需的局部或全身生理学或药理学效果的有效药剂。下列几类药剂可假如到本发明装置中去:麻醉剂和镇痛剂,如利多卡因及相关化合物和苯并安定及相关化合物;抗癌剂,如5-氟尿嘧啶、阿霉素及相关化合物;抗炎剂,如6-甘露糖磷酸盐;抗真菌剂,如氟康唑及相关化合物;抗病毒剂,如磷酸一甲酸三钠、三氟胸苷、无环鸟苷、甘西洛维、DDI和AZT;细胞传送/迁移逼近剂(impending agent),如秋水仙碱、长春新碱、细胞分裂抑素B和相关化合物;抗青光眼药物,如β-阻滞剂:噻吗洛尔、倍他洛尔、阿替洛尔等;免疫学应答调节剂,如胞壁酰基二肽及相关化合物;肽和蛋白质,如环孢子菌素、胰岛素、生长激素、与有的是相关的生长因子、热冲击蛋白质急相关化合物;甾族化合物,如地塞米松、脱氢皮质甾醇急相关化合物;低溶解度类固醇,如氟轻松及相关化合物;以及碳酸酐酶抑制剂。
除了上述药剂之外,其它药剂也适合于对眼及其周围组织进行给药,从而产生局部或全身生理学或药理学的有益效果。这类药剂的实例包括神经保护剂,如尼莫地平及相关化合物;抗生素,如四环素、氯四环素、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;抗菌药物,如磺胺药物、乙酰磺胺、磺胺甲基硫代二嗪和磺胺异嘧唑;抗病毒药物,包括碘苷;及其它抗菌素,如硝基糖腙和丙酸钠;抗过敏性药物,如安他唑啉、镁沙比林、扑尔敏、美吡拉敏和抗感明;抗炎性药物,如氢化可的松、醋酸氢化可的松、21-磷酸地塞米松、氟轻松、甲羟松、甲泼尼龙、强的松龙21-磷酸酯、强的松龙醋酸酯、氟米龙、倍他米松和triminolone;解充血药,如苯福林、萘甲唑林和四氢唑啉;缩瞳药和抗胆碱酯酶,如毛果芸香碱、水杨酸毒偏豆碱、碳酰胆碱、异氟磷、碘磷灵和地美溴铵;散瞳剂,如硫酸阿托品、环喷托酯、后马托品、东莨菪碱、托品酰胺、尤卡托品和羟苯丙胺;类交感神经药物,如肾上腺素;以及前药,如下述文献中描述的那些前药:前药设计(Design of Prodrugs),HansBundgaard编辑,Elsevier Scientific Publishing CoAmsterdam,1985。再者,判别其它药剂的参考文献可以是任何标准药学课本,如Remington药物学(Remingtos’s Pharmaceutical Science)。
这类化合物的任何可药用形式均可用于本发明实践中,也就是可使用其游离碱或可药用盐或酯。例如,可药用盐包括硫酸盐、乳酸盐、乙酸盐、硬脂酸盐、盐酸盐、酒石酸盐、马来酸盐等。
大量的聚合物可用于构造本发明装置。唯一的要求在于它们必须是惰性、无免疫原且具有所需的渗透性。
可用于构造本发明装置的物质包括与体液和眼组织生物学相容且基本上不溶于与所述物质相接触的体液的天然存在物质或合成物质。由于器壁溶解会影响药物释放的不变性以及系统在较长时间内保持在其位置的能力,所以避免使用迅速溶解的物质和在流出的眼泪中溶解度很高的物质。
与体液和眼组织生物学相容且基本上不溶于与所述物质相接触的体液的天然存在物质或合成物质包括但不局限于:聚乙酸乙烯酯、交联聚乙烯醇、交联聚丁酸乙烯酯、乙烯-丙烯酸乙酯共聚物、聚己基丙烯酸乙酯、聚氯乙烯、聚乙烯乙缩醛、增塑乙烯-乙酸乙烯酯共聚物、聚乙烯醇、聚乙酸乙烯酯、乙烯-氯乙烯共聚物、聚乙烯基酯、聚丁酸乙烯酯、聚乙烯醇缩甲醛、聚酰胺、聚甲基异丙烯酸酯、聚丁基异丙烯酸酯、增塑聚氯乙烯、增塑尼龙、增塑软尼龙、增塑对苯二甲酸乙酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、聚四氟乙烯、聚偏二氯乙烯、聚丙烯腈、交联聚乙烯基吡咯烷酮、聚(1,4’-异亚丙基二联苯碳酸酯)、1,1-二氯乙烯、丙烯腈共聚物、氯乙烯-diethyl fumerale共聚物、硅橡胶(特别是医学级聚二甲基硅氧烷)、乙烯-丙烯橡胶、硅酮-碳酸酯共聚物、二氯乙烯-氯乙烯共聚物、氯乙烯-丙烯腈共聚物和二氯乙烯-丙烯腈共聚物。
具体而言,本发明装置的第二包覆层可由任何上述聚合物或任何其它聚合物制得,所述其他聚合物应当与体液和眼组织生物学相容、基本上不溶于与所述物质相接触的体液且基本上不能渗透通过有效药剂。正如这里所使用的,术语“不能渗透”是指为了获得所需的局部或全身生理学或药理学效果,所述包覆层以所要求的速率不允许有效药剂通过。
正如上文所述,第二包覆层必须选自不渗透物质,从而使得药剂不能从内部药芯传递至第二包覆层的邻近部分。目的在于阻止有效药剂传递至那些部分,由此控制药剂从药物传递装置中的释放。
第二包覆层(即聚合物)的组成必须选择成允许上述控制释放。第二包覆层的优选成分将根据下述因素改变:活性药剂、所需的控制速率以及给药方式。由于如分子大小在确定药剂向第二包覆层传递的速率时起着决定性的作用,所以活性药剂的同一性是很重要的。
圆片基本上不能渗透通过有效药剂,可覆盖没有被第二包覆层的不渗透膜覆盖的部分内部药芯。如图2B所示,圆片可覆盖内部药芯的边缘;与其它可能的方法相比,圆片可在内部药芯上应用更薄的不渗透膜均匀包覆层。在一个实施方案中,不渗透膜可完全覆盖内部药芯和圆片。药物释放可通过圆片中的孔(参见图2B)或通过不渗透膜中的孔进行。用于圆片的聚合物的物理性能可基于其在不会使得孔变形的条件下,能够经受得起接着的操作步骤(如热固化)的能力而选择。用于不渗透膜的聚合物可基于覆盖内部药芯的容易程度而选择。用于圆片的可能的材料包括:特氟龙(Teflon)、聚碳酸酯、聚异丙烯酸甲酯、聚乙二醇、高级乙烯乙酸乙烯酯(乙烯基含量为9%)和聚乙烯醇。
由于第二包覆层基本上不渗透通过有效药剂,所以仅有部分内部药芯或贮池和第一包覆层能够被第二包覆层覆盖。根据所需的装置传递速率,为了使得有效药剂传递更快,第二包覆层可仅覆盖小部分内部药芯表面,或者为使得有效药剂传递更慢,第二包覆层可仅覆盖大部分内部药芯表面。
至少50%的表面可被第二包覆层覆盖。为了降低释放速率,可至少覆盖75%的表面。为了再进一步降低释放速率,可至少覆盖95%的表面。
只要能够获得所需的药剂释放速率,第二包覆层可覆盖任意部分的第一包覆层和内部药芯的表面,但不能高达100%。
包括不渗透膜和不渗透圆片的第二包覆层可位于内部药芯和第一包覆层上方的任何位置,包括但不局限于第一包覆层和内部药芯的顶部、底部及任何一侧。另外,它可位于顶部和侧边,或底部和侧边,或顶部和底部,或对侧,或顶部、底部或侧边的任意组合。
本发明装置的第一和第三包覆层应当与体液和眼组织生物学相容、基本上不溶于与所述物质相接触的体液,且能够渗透通过能够获得所需效果的有效药剂或成分。
有效药剂在低化学势的方向扩散,即沿着装置的外表面扩散。在外表面上再次建立平衡。当第三包覆层两侧的条件维持不变时,将根据Fick扩散定律建立有效药剂的稳态流动。药物通过扩散流经物质的速率一般取决于其中药物的溶解性以及器壁的厚度。这就意味着用于构造器壁的适当材料的选择将取决于所使用的特殊药物。
有效药剂流经本发明聚合物包覆层的扩散速率,可通过在沉降条件下进行的扩散池研究而确定。在于沉降条件下进行的扩散池研究中,当与给体区中的高浓度相比,受体区中的药物浓度基本上为零。在这些条件下,药物释放的速率如下式:
Q/t=(D·K·A·DC)/h其中Q为释放的药物量,t时间,D扩散系数,K为分配系数,A为表面积,DC穿过膜的药物浓度差,以及h为膜的厚度。
在药剂扩散通过充有水的孔流过包覆层的情况下,不存在分配现象。由此可将方程中的K消除掉。在沉降条件下,如果从给体侧释放的速度很慢,那么DC值基本上为常数且等于给体区的浓度。由此可见,释放速率只取决于膜的表面积(A)、厚度(h)和扩散系数(D)。在构造本发明装置中,尺寸(因此,表面积)主要取决于有效药剂的尺寸。
由此,渗透系数可通过Q与时间曲线的斜率得到。渗透系数P可通过下式与扩散系数联系起来:
P=(K·D)/h一旦所建立的包覆层的渗透系数可渗透药剂的通过,则可确定覆盖有必须不渗透药剂通过的包覆层的药剂表面积。这可通过下述方法完成:渐渐地降低可利用的表面积,直至获得所需懂得释放速率。
适用作第一和第三包覆层的实例性多微孔材料,例如描述在美国专利4,014,335中,整个该文献在此引作参考。这些材料包括交联聚乙烯醇、聚烯烃或聚氯乙烯或交联明胶;再生、不溶性、不冲刷纤维素、酰化纤维素、酯化纤维素、乙酸丙酸纤维素、乙酸丁酸纤维素、乙酸对苯二甲酸纤维素、乙酸二乙基-氨基乙酸纤维素;聚氨酯、聚碳酸酯,以及通过由不溶性胶原质改性的聚阳离子和聚阴离子共沉淀形成的多微孔聚合物。优选交联聚乙烯醇。第三包覆层应当选择成能够降低药剂从内部药芯向哺乳动物有机体(如人)释放的速率。第三包覆层不必提供药剂向生物学环境的渐渐或控制释放,但是,第三包覆层可有利地选择成具备那种性能或特征。
本发明的装置可根据许多方法制得,如通过获得有效量的药剂并将药剂压成所需的形状。一旦成型,即可涂覆第一包覆层。可通过将装置浸渍在包含所需聚合物的溶液中一次或多次而涂覆第一包覆层。任意地,可利用聚合物溶液,通过点滴、喷洒、冲刷或其它涂敷装置外层的方法涂覆第一包覆层。当使用聚乙烯醇溶液获得第二包覆层时,所需的厚度可通过应用几次涂层而达到。在涂覆下一层之前,可先干燥各层。最后可加热装置,从而调节外层的渗透系数。
不渗透圆片可在涂敷不渗透聚合物层之前,直接涂覆于第一包覆层上。在圆柱形药芯情况下,在将圆片涂覆于一端或两端之后,可将不渗透膜缠绕在药芯的周围。由此,第二包覆层既包括不渗透膜,又包括不渗透圆片。在利用不渗透圆片封闭至少一个表面时,可使用更薄的包覆层。与其它可能的方法相比,这种方法具有优点,能够制得更薄、更短的装置。
为了预防药物在没有被覆盖的区域(扩散层或扩散口)之外,从不渗透聚合物包覆层内释放出来,所述不渗透聚合物包覆层的厚度必须足够。由于要求植入物的尺寸为最小,所以不渗透膜包覆层的厚度可为0.01至2毫米,优选0.01至小于0.5毫米。
为了预防药物在特别制得的膜或口之外从不渗透圆片中释放出来,所以不渗透圆片的厚度也应当足够。由于要求植入物的尺寸为最小,所以不渗透膜圆片的厚度可为0.01至2毫米,优选0.01至小于1毫米。
一旦将包括不渗透圆片的第二包覆层涂覆于该装置,则可涂覆第三包覆层。第三包覆层可通过将装置浸渍在包含所需聚合物的溶液中一次或多次而涂覆。任意地,可利用聚合物溶液,通过点滴、喷洒、冲刷或其它涂敷装置外层的方法涂覆第三包覆层。当使用聚乙烯醇溶液获得第三包覆层时,所需的厚度可通过应用几次涂层而达到。在施用下一层之前,可先干燥各层。最后可加热装置,从而调节外层的渗透系数。
如何制备本发明装置的上文描述仅仅是举例说明性的,不应当被认为是以任何方式来进行限制本发明的范围,许多配方均是本领域技术人员所公知的。特别地,制备装置的方法取决于所选择的活性药剂和聚合物的一致性。在给定活性药剂以及第一包覆层、第二包覆层(膜和圆片)和第三包覆层的组成的条件下,本领域的技术人员可利用常规的涂层技术,容易地制得本发明装置。
为了获得所需的局部或全身生理学或药理学效果,治疗哺乳动物有机体的方法包括对哺乳动物有机体服用本发明持续释放药物传递装置,允许药剂通过装置与哺乳动物有机体直接接触。
本发明的药物传递系统可通过本领域公知的给药路线对哺乳动物有机体进行给药。这类给药路线包括经眼内、口、皮下、肌内、腹膜内、鼻内、皮肤等。另外,一次可服用一种或多种装置,或者内部药芯中可包含多种药剂。
本发明的药物传递系统特别适用于直接植入到眼睛的玻璃体中或应用于眼内晶体。
对于本领域普通技术人员来讲,这些给药方法及其制备方法是公知的。其制备方法在下述文献中提及:Remington药物学(Remiingtos’sPharmaceutical Science)。
药物传递系统可服用足够的时间,从而允许在这些条件下治疗所述疾病。
对于局部药物传递,该装置可通过手术植入到作用位置或其附近。本发明装置可用于治疗眼疾病、原发性肿瘤、风湿和关节炎疾病及慢性疼痛。
对于全身缓解,该装置可通过皮下、肌内或腹膜内给药。此时,该装置能够得到持续系统水平,可避免早期代谢。另外,这类装置可经口服给药。
在本发明的一个实施方案中,制备了包含预防复制病毒的有效剂量的甘西洛维作为有效药剂的眼用装置。当通过外科手术植入到眼睛的玻璃体中去时,这类装置可用于有效地抵抗或抑制细胞巨化病毒关节炎的复发。这类装置可治疗完成后永久地保留在玻璃体中。用于这些装置中的甘西洛维优选剂量为约0.01mg至约40mg。更优选地,这类装置可包含约15mg至约30mg的甘西洛维。这些优选含量范围可提供甘西洛维在数小时至两年时间内的持续释放。优选的第一包覆层为聚乙烯醇。优选的不渗透圆片为特氟龙或乙基乙烯醇。优选的第三包覆层为聚乙烯醇。当所制得的装置用于植入到眼睛的玻璃体中时,优选该装置在任何方向上均不超过大约7mm。由此,优选图1所示的圆柱形装置的高度不超过7mm,直径不超过3mm。优选的第一包覆层厚度为约0.05mm至约0.5mm。优选的第二包覆层厚度为约0.1mm至约1.0mm。优选的第三包覆层厚度为约0.1mm至约2.0mm。
本发明的另一实施方案制备了包含以尼莫地平作为有效药剂的眼用装置。正如下文实施例所进一步揭示的那样,这类装置可提供数年的尼莫地平长期持续释放。用于这些装置中的尼莫地平优选含量为2mg至15mg。更优选地,这类装置包含大约10-15mg。这种优选的含量范围可提供尼莫地平超过十年的持续释放。作为第一包覆层,优选的材料包括聚乙烯醇,圆柱形装置的一端被一乙烯乙酸乙烯酯(9%)圆片覆盖,另一端未被覆盖;作为不渗透包覆层的乙烯乙酸乙烯酯(19%)覆盖了圆柱的侧面;端部由圆片密封;聚硅氧烷第三包覆层覆盖了整个部件。第一包覆层的优选厚度为0.05mm至0.2mm。不渗透聚合物层的优选厚度为0.05mm至0.15mm,优选0.075mm。圆片的优选厚度为0.05mm至2mm,以及第三包覆层的优选厚度为0.1mm至0.5mm。
本发明的另一实施方案制备了包含以氟轻松作为有效药剂的眼用装置。正如下文实施例所进一步揭示的那样,这类装置可提供数年的氟轻松持续释放。用于这些装置中的氟轻松优选含量为2mg至15mg。更优选地,这类装置包含大约5mg至10mg。这种优选的含量范围可提供氟轻松3年的持续释放。该装置的总直径为2mm,长度为5mm。
作为第一包覆层,优选的材料包括聚乙烯醇,圆柱形装置的一端被一乙烯乙酸乙烯酯(9%)圆片覆盖,另一端未被覆盖;作为不渗透包覆层的乙烯乙酸乙烯酯(19%)覆盖了圆柱的侧面;端部由圆片密封;聚乙烯醇第三包覆层覆盖了整个部件。第一包覆层的优选厚度为0.05mm至0.2mm。不渗透聚合物层的优选厚度为0.05mm至0.15mm,优选0.75mm。圆片的优选厚度为0.05mm至2mm,以及第三包覆层的优选厚度为0.1mm至0.5mm。
尽管本发明上述实施方案描述了有效药剂含量的优选范围和优选的第一和第二包覆层的优选厚度,但是这些优选并不意味着限制本发明。正如本领域技术人员容易理解的那样,优选的含量、材料和尺寸取决于给药方法、所使用的有效药剂、所使用的聚合物、所需的释放速率等。类似地,除了上述因素之外,实际释放速率和释放时间取决于还取决于许多因素,例如所治疗的疾病情况、患者的年龄和病情、给药路线,以及那些对本领域技术人员来讲是非常明显的其它因素。
通过上文描述,本领域普通技术人员可容易地确定本发明的基本特征,并且可在不背离本发明精神范围的条件下对发明进行各种改变和/或改进,使之适应于各种使用及条件。由此,在下述权利要求全部范围内,这些改变和/或改进均是适当、公正和有意识的。
Claims (23)
1、一种为获得所需局部或全身生理学或药理学效果而治疗哺乳动物有机体的方法,该方法包括:
给需要这类治疗的哺乳动物有机体服用持续释放药物传递系统,所述药物传递系统包括:
(1)内部药芯或贮池,所述内部药芯或贮池包括能够有效地获得所需局部或全身生理学或药理学效果的有效剂量的药剂,
(2)能够渗透通过所述药剂的第一包覆层,其中所述第一包覆层覆盖至少部分所述内部药芯,
(3)基本上不渗透通过所述药剂的第二包覆层,而且所述第二包覆层覆盖至少部分内部药芯和第一包覆层,其中至少小部分内部药芯或第一包覆层未被所述第二包覆层覆盖,且所述第二包覆层包含一不渗透膜和至少一块不渗透圆片,和
(4)能够渗透所述药剂通过的第三包覆层,其中所述第三包覆层基本上完全覆盖所述第二包覆层和第一包覆层未被覆盖的部分或内部药芯,由此所述药剂能够以控制的方式通过所述第三包覆层。
2、根据权利要求1治疗哺乳动物有机体的方法,其中所述第三包覆层包含聚乙烯醇。
3、根据权利要求2治疗哺乳动物有机体的方法,其中所述第二包覆层包含乙烯乙酸乙烯酯。
4、根据权利要求3治疗哺乳动物有机体的方法,其中所述第一包覆层包含聚乙烯醇。
5、根据权利要求1治疗哺乳动物有机体的方法,其中所述有效药剂包括氟轻松、尼莫地平或甘西洛维。
6、一种治疗哺乳动物有机体细胞巨化病毒关节炎的方法,该方法包括:
给需要这类治疗的哺乳动物有机体服用持续释放药物传递系统,所述药物传递系统包括:
(1)内部药芯或贮池,所述内部药芯或贮池包括能够有效地获得所需局部或全身生理学或药理学效果的有效剂量的甘西洛维,
(2)能够渗透所述药剂通过的第一包覆层,其中所述第一包覆层基本上完全覆盖所述内部药芯,
(3)基本上不渗透通过所述甘西洛维的第二包覆层,而且所述第二包覆层覆盖至少部分内部药芯和第一包覆层,其中至少小部分内部药芯或第一包覆层未被所述第二包覆层覆盖且所述第二包覆层包含一不渗透膜和至少一块不渗透圆片,和
(4)能够渗透所述甘西洛维通过的第三包覆层,其中所述第三包覆层基本上完全覆盖所述第二包覆层和第一包覆层未被覆盖的部分或内部药芯,由此所述甘西洛维能够以控制的方式通过所述第三包覆层。
7、一种为有效获得所需局部或全身生理学或药理学效果而提供药剂控制和持续给药的方法,该方法包括:
在所需位置上通过外科手术植入持续释放药物传递系统,所述药物传递系统包括:
(1)内部药芯或贮池,所述内部药芯或贮池包括能够有效地获得所需生理学或药理学效果的有效剂量的药剂,
(2)能够渗透通过所述药剂的第一包覆层,其中所述第一包覆层覆盖至少部分所述内部药芯,
(3)第二包覆层,所述第二包覆层基本上不渗透所述药剂的通过,而且所述第二包覆层覆盖至少部分内部药芯和第一包覆层,其中至少小部分内部药芯或第一包覆层未被所述第二包覆层覆盖,且所述第二包覆层包含一不渗透膜和至少一块不渗透圆片,和
(4)能够渗透所述药剂通过的第三包覆层,其中所述第三包覆层基本上完全覆盖所述第二包覆层和第一包覆层未被覆盖的部分或内部药芯,由此所述药剂能够以控制的方式通过所述第三包覆层。
8、根据权利要求7的方法,其中所述装置通过外科手术植入眼睛的玻璃体中。
9、根据权利要求7的方法,其中所述第一和第三包覆层包含聚乙烯醇。
10、根据权利要求7的方法,其中所述第三包覆层为聚硅氧烷。
11、根据权利要求9的方法,其中所述第二包覆层包含乙烯乙酸乙烯酯。
12、根据权利要求11的方法,其中所述有效药剂为甘西洛维或5-氟尿嘧啶。
13、根据权利要求11的方法,其中所述有效药剂为低溶解度类固醇。
14、根据权利要求13的方法,其中所述低溶解度类固醇为氟轻松。
15、根据权利要求11的方法,其中所述有效药剂为一种神经保护剂。
16、根据权利要求15的方法,其中所述神经保护剂为尼莫地平。
17、一种持续释放药物传递系统,该持续药物释放传递系统包括:
(A)内部药芯或贮池,所述内部药芯或贮池包括能够有效地获得所需局部或全身生理学或药理学效果的有效剂量的药剂,
(B)能够渗透通过所述药剂的第一包覆层,所述第一包覆层覆盖至少部分所述内部药芯,
(C)第二包覆层,所述第二包覆层基本上不渗透通过所述药剂的,而且所述第二包覆层覆盖至少部分内部药芯和第一包覆层,其中至少小部分内部药芯或第一包覆层未被所述第二包覆层覆盖且所述第二包覆层包含一不渗透膜和至少一块不渗透圆片,和
(D)第三包覆层,所述第三包覆层能够渗透通过所述有效药剂的,其中所述第三包覆层基本上完全覆盖所述第二包覆层和第一包覆层未被覆盖的部分或内部药芯。
18、根据权利要求17的持续释放药物传递系统,其中所述第三包覆层包含聚乙烯醇。
19、根据权利要求18的持续释放药物传递系统,其中所述第二包覆层包含乙烯乙酸乙烯酯。
20、根据权利要求19的持续释放药物传递系统,其中所述第一包覆层包含聚乙烯醇。
21、根据权利要求20的持续释放药物传递系统,其中所述有效药剂为甘西洛维或氟轻松。
22、根据权利要求17的持续释放药物传递系统,其中所述有效药剂为尼莫地平。
23、根据权利要求17的持续释放药物传递系统,其中第三包覆层包含聚硅氧烷。
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- 1998-08-28 IL IL13456898A patent/IL134568A/xx not_active IP Right Cessation
- 1998-08-28 AU AU90291/98A patent/AU741846B2/en not_active Ceased
- 1998-08-28 CZ CZ20000604A patent/CZ302339B6/cs not_active IP Right Cessation
- 1998-08-28 RS YU11100A patent/RS52096B/sr unknown
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2000
- 2000-02-14 NO NO20000735A patent/NO327752B1/no not_active IP Right Cessation
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2001
- 2001-08-13 HK HK01105631.3A patent/HK1035135A1/xx not_active IP Right Cessation
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2002
- 2002-03-11 NZ NZ517736A patent/NZ517736A/en not_active IP Right Cessation
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2010
- 2010-03-01 JP JP2010044187A patent/JP2010168388A/ja active Pending
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