CN1139375A - 生物相容性眼睛植入物 - Google Patents
生物相容性眼睛植入物 Download PDFInfo
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- CN1139375A CN1139375A CN94194697A CN94194697A CN1139375A CN 1139375 A CN1139375 A CN 1139375A CN 94194697 A CN94194697 A CN 94194697A CN 94194697 A CN94194697 A CN 94194697A CN 1139375 A CN1139375 A CN 1139375A
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Abstract
用包含活性试剂的植入物引入眼睛的脉络膜上的间隙或无血管区域以达到治疗目的。控制药物的投药并保持长的时期,同时在投药部位以外基本上没有明显的药量。
Description
技术领域
本发明提供用于治疗眼科疾病的生物相容性植入物。
发明背景
眼睛在人们的一生当中是最重要基本器官之一。由于年老、疾病和可对视力有不利影响的其它因素,因此保持眼健康的能力变得十分重要。致盲的原因就是不能导入药物或治疗到眼内,使这些药物或治疗剂以治疗有效的浓度保持在眼睛内。口服吸取或在眼睛以外的某一部位注射是系统的供药方法。但是,这种系统给药,特别对眼睛来说不能使药物达到有效程度,因此为了在眼内达到有效浓度,就不得不投入一般的不能接受的高剂量的药。另一方面,当药物注入眼内时,它很快冲掉或从眼内排除进入一般的循环。从治疗观点出发,这可能与完全未给药的效果相同。由于把药物传送到眼内存在着这些固有的困难,因而目前眼科疾病的医疗方法是不适当的。
现在越来越迫切需要解决在眼科治疗中遇到的这些困难,在这问题上现有许多种眼科疾病都是相同情况。其中许多疾病的治疗是能得到改进的,如果能获得适当的治疗传送手段的活。因而,开发新的治疗手段打破目前治疗手段的限制是具有重大意义的。相关文献
1989年8月1日公告的US4,853,224,公开了一些生物相容性植入物,植入眼前部或后部用于治疗某种眼科疾病。1992年11月17日公告的US5,164,188,公开了一种治疗眼科疾病的方法,它是将包含有效药物的一种可生物降解的植入物植入眼睛脉胳膜上的间隙或睫状环中。
典型的生物相容性的、生物非降解的加成聚合物组合物已在US4,303,637、US4304765、US4190642、US4186184、US4057619、US4052505、US4281654、US4959217、US4014335、US4668506、US4144317中叙述。
Heller(1),Biodegradable Polymer in Controlled DrugDelivery,在CRC Critical Reviews in Therapeatic Drug Carr-ier Systems,卷1,CRC Press,Boca Raton,FL,1987,第39-90页,介绍了一种包囊,它用可生物降解聚合物来控制药物的传送。关于在可生物降解聚合物组合物中可用的一些可生物降解的水凝胶,参见Heller(2),在Hydrogels in Medicine and Pharmacy,N.A.Peppes ed.,卷III,CRC Press,Boca Raton,FL,1987,第137-149页。Heller,J.of Controlled Release(1985)2:167-177;Leong等人,BioMaterials(1986)7:364-371中描述了聚酐微球。Jackanicz等人,Contraception(1973)8:227;Yolles等人,在Controlled Release of Biologically Active Agents,Tanquary等人,eds,Plenum Press,New York,NY,1974,第3章;Liu等人,Opthamology(1987)94:1155-1159和在那里引用的参考资料中报导了关于玻璃体内用的脂质体治疗眼科疾病的研究。也可参见Cutright等人的Oral Surgery,Oral Medicine,and Oral Patho-logy(1974)37:142,和Shindler等人的Contemporary Topicsin Polymer Science(1977)2:251-289。Anderson等人的Contr-aception(1976)13:375和Miller等人的J.Biomed.Materials Res.(1977)11:771叙述了聚(dL-乳酸)的各种性能。
有关的美国专利包括:US3,416,530;3,626,940;3,828,777;3,870,791;3,916,899;3,944,064;3,962,414;4,001,388;4,052,505;4,057,619;4,164,559;4,179,497;4,186,184;4,190,642;4,281,654;4,303,637;4,304,765;4,304,767;4,439,198;4,452,776;4,474,751;4,613,330;和4,617,186。
发明概述
将用作药物传送体系的生物相容性植入物植入玻璃体外的一个部位,包括眼睛脉络膜上的间隙、无血管区域例如睫状环、或外科手术诱导的无血管区域,以提供有效治疗用量的治疗眼科疾病的药剂。该植入物也可以放置在无血管区域的上面,使药物穿过巩膜(transcleral)扩散到所需治疗的部位。该植入物是以斑、片、薄膜、杆、纤维和/或微球或微胶囊形式提供,用于精确传送特定的药剂到眼睛的内部区域。具体实施方案的说明
将包含缓释剂的生物相容性植入物直接植入到主要在眼睛(特别是哺乳类眼睛)玻璃体外的部位,通过这种方法来处理眼睛的各种症状、疾病、肿块和失调。玻璃体外部位包括脉络膜上的间隙、睫状环等等。该脉络膜上就是位于内巩膜壁和对面的脉络膜之间可能有的间隙。植入脉络膜上的植入物可以把药物传送到脉络膜及传送到解剖学上对合的视网膜,这取决于该药物从植入物中的扩散情况、包含在植入物中的药物浓度等。具有特殊意义的是把植入物植入在无血管区域的上面或里面。该无血管区域可以是自然存在的例如睫状环,或者是通过手术产生的无血管区域。可通过本领域已知方法,如激光部分切除术、光凝结、冷疗法、热凝法、烙术等,在眼内产生外科手述诱导的无血管区域。特别希望在需要治疗的部位上面或附近产生这种无血管区域,但特别是在所需治疗部位远离睫状环或远离睫状环的放植入物的地方是不可能产生这种无血管区的。在无血管区域上面引入植入物将使植入物中的药物扩散到眼内部而避免扩散到血流中。
植入物可通过外科方法进入或作用在脉络膜上或无血管的区域,并放在该作用空间的关键地方。或者,也可以把植入物大体上放在眼睛外表面,但要直接放在无血管区域的上面,以便使药物穿过巩膜扩散到眼内的空间。优选的是,该植入物大小应与选择作为植入部位的区域的尺寸和形状相称,而不会在植入后从嵌入部位迁移出。并且植入物最好是至少有点柔软,使它容易嵌入眼睛内并有助于眼睛对植入物的适应。植入物可以是斑、颗粒、薄片、小片、微胶囊等,也可以具有与所选择嵌入部位相应的尺寸或形状。在植入物是生物非降解的情况时,该植入物也可以包含一个可再填充的贮源。配制的植入物中包含一种或多种药剂,它可以释放或在一段延续时间期间内以有效治疗剂量释放到眼睛内部。以此方式,从植入物中释放的药剂可以到达脉络膜、视网膜和玻璃体。
能够进一步控制扩散,使各种药剂精确传送。例如在脉络膜上放置植入物的情况,可通过植入物中的药剂浓度和释放速率来控制某种特定药剂使其恰好传送到其下的脉络膜中。通过增加浓度和扩散速率,药剂将扩散到玻璃体内或者扩散到对合的视网膜内。因此,可使需要药剂的部位得到该药剂并保持有效剂量而不会迅速洗掉。此外,本发明的处理方法不需要很大程度提高对宿主的药物用量以此来达到药物在眼内的有效程度,如系统投药所需要的那种程度。
含有药剂或含有对治眼睛有用的某些试剂的植入物,一般包封式或溶解或分散在一种聚合物试剂中。也可使用能放置在规定部位而不会迁移的材料,如氧化钎维素(oxycel)、明胶、聚硅氧烷等。这些成分是生物相容性的,可以是可生物降解的或非生物降解的,或者是生物降解和非生物降解聚合物的组合,所用的这些聚合物成分的选择可以随着投药部位、治疗所需周期、患者耐受性、要治疗的疾病性质等而变化。
各种生物相容的、非生物降解聚合物成分均可以用于该植入物中。所用的非生物降解聚合物成分必须要能释放药物的,例如通过溶解/扩散或沥滤机理来释放。所用非生物降解聚合物组合物可根据该聚合物与要使用药物或其它活性试剂的相容性、制造容易程度、所需药物释放速率、所需密度或孔隙等而改变。各种可以使用的非生物降解聚合物已公开在US4303637;US4304765;US4190642;US4186184;US4057619;US4052505;US4281654; US4959217;US4014335;US4668506;US4144317中。非生物降解聚合物可以是均聚物、共取物、直链、支链、或交联衍生物。
有用的生物相容性、非生物降解聚合物的具体例子包括聚氨基甲酸酯或聚脲(特别是聚氨酯)、可以交联而生成非生物降解聚合物的聚合物(例如交联聚醋酸乙烯酯)等等。特别有用的还有酯含量为4至80%的乙烯-乙烯基酯共聚物,例如乙烯-乙烯基乙酸酯(EVA)共聚物、乙烯-乙烯基己酸酯共聚物、乙烯-乙烯基丙酸酯共聚物、乙烯-乙烯基丁酸酯共聚物、乙烯-乙烯基戊酸酯共聚物、乙烯-乙烯基三甲基乙酸酯共聚物、乙烯-乙烯基二乙基乙酸酯共聚物、乙烯-乙烯基3-甲基丁酸酯共聚物、乙烯-乙烯基3,3-二甲基丁酸酯共聚物和乙烯-乙烯基苯甲酸酯共聚物。在US4052505和US4144317中描述了用包括乙烯-乙烯基乙酸酯共聚物的乙烯-乙烯基酯共聚物来制造由扩散作用而使药物溶解于聚合物并通过该聚合物扩散的眼药传送装置。
另外典型的天然存在的或合成的非生物降解聚合物材料包括聚甲基丙烯酸甲酯、聚甲基丙烯酸丁酯、增塑聚氯乙烯、增塑聚酰胺类、增塑尼龙、增塑软尼龙、增塑聚对苯二甲酸乙二醇酯、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、聚偏氯乙烯、聚丙烯腈、交联聚乙烯吡咯烷酮、聚三氟氯乙烯、氯化聚乙烯、聚4,4′-异亚丙基二亚苯基碳酸酯、偏氯乙烯-丙烯腈共聚物、氯乙烯-富马酸二乙酯共聚物、聚硅氧烷、硅橡胶(特别是医药级)、聚二甲基硅氧烷、乙丙橡胶、硅氧烷-碳酸酯共聚物、偏氯乙烯-氯乙烯共聚物、氯乙烯-丙烯腈共聚物、偏氯乙烯-丙烯腈共聚物、聚烯烃类、聚乙烯基-烯烃类、聚苯乙烯、聚卤-烯烃类、聚乙烯基类、聚丙烯酸酯、聚甲基丙烯酸酯、聚氧化物类、聚酯类、聚酰胺类和聚碳酸酯类。
可生物降解的或非生物降解的水凝胶也可用于本发明植入物。水凝胶典型的是一种共聚物材料,其特点在于能够浸渗液体。可以使用的典型非生物降解的水凝胶及其制备方法已描述于US4959217和US4668506中,在此引入作为参考。可以使用的典型的可生物降解水凝胶已公开了Heller(2)中,前文。
在使用非生物降解性聚合物的地方,主要通过溶解和扩散作用控制药物释放速率。药物通过非生物降解性聚合物的扩散速率可受药物溶解性、聚合物亲水性、聚合物交联程度、聚合物吸水后的膨胀而使该聚合物更易渗透到药物中等等因素的影响。药物从植入物中的扩散也可由植入物的结构控制。例如,可借助于固定于包含药物的聚合物层的一层膜来控制药物从植入物中的扩散。该膜层放置在含该药物的聚合物层和所需治疗部位的中间。该膜可由上述可生物相容的任何一种材料组成,并可以随着所用药物、除包含在聚合物中药物以外的药物的存在、含该药物的聚合物组成、所需扩散速率等等而改变。例如,该聚合物层通常包含大量药物,一般来说是饱和的。这种饱和药物的聚合物一般以很高速率释放药物。在这种情况下,药物的释放速度可通过选择膜的药物渗透性比聚合物低的一种膜来减慢。由于该膜的较低药物渗透性,药物将集中在聚合物中,并且总扩散速率将由膜的药物渗透性确定。因此,减少了从植入物中药物的释放速率,为该药物向治疗部位释放受到更多的控制和持续更长时间而创造了条件。
在植入物包括一个含药物和/或膜层的聚合物层的情况下,最好是该植入物再有一个背层。该背层与植入物的表面接触而该表面是不与治疗部位接触或不邻接的。例如植入物是薄片的,背层可以位于该薄片离所要治疗部位最远处的侧面上。在这种情况下,在该薄片的边缘,背层是不必要的,因为植入物这部分的表面积相当小,因而可预料在此部位的聚合物中药物的损失最少。此背层的组成可以随植入物中所用药物、植入部位、与用于植入物药物以外的药剂的相容性等因素而变化。具有特殊重要意义的是,所述背层由生物相容性,优选非生物降解的材料组成,此材料对于包含在聚合物层内的药物是不可渗透的。药物从聚合物层中的扩散只允许经过该聚合物和/或膜层及进入眼膜间通到要治疗部位的通道。背层的典型组成包括聚酯类(例如聚酯薄膜)、聚乙烯、聚丙烯、聚四氟乙烯、aclar及其它已知和/或可商购的薄膜材料。
植入物还可以包含粘合层以固定植入物在所要插放的部位,特别在要将植入物基本上放置在经过无血管区域的眼睛表面上。优选的是该粘合层位于植入物直接与眼膜接触的部分上,并位于所要治疗的部位。根据需要,可把该聚合物层固定在剥离衬或剥离条上。该剥离衬可以是对药物不可渗透的任何适宜材料,它将在贮存期间起到防止药物扩散而脱离聚合物的作用。在植入物包含粘合层的情况下,该剥离衬能防止粘合层粘附在包装材料、其它植入物等的上面。具有代表性的剥离衬是涂覆有剥离剂如聚硅氧烷或氟碳试剂的聚酯层。该剥离剂便于将剥离衬在植入物插放到眼睛之前先从聚合物层上除去。
对于大多数情况,非生物降解植入物在眼睛内具有不确定的寿命,并可以在药物已从聚合物中释放完的时候取出,或者在不再需要治疗或不再具有治疗效力的时候取出。药物投药周期可由包含在聚合物植入物内的药物数量、植入物的大小或形状等等而变化。包含非生物降解聚合物的植入物,药物扩散一般至少为2星期,更一般至少为4星期,通常至少为约12星期,也可以是24星期或更长时间。当治疗完成或治疗不再有效力时,可以取出植入物。
例如,当药物分子量、所需剂量、投药周期(如在慢性治疗时)等是在这样的情况下,即包含所需量的药物或药物溶液的植入物的大小与植入部位尺寸不相容,或者妨害患者视觉的情况下,则使用包含可再填充贮源的非生物降解植入物可能是理想的。非生物降解、可再填充的贮源可以含有一个非生物降解外表面和一个空心或基本上空心的中心区,该中心区对活性试剂起着贮藏或贮存器的作用。该活性试剂可以以各种形状存在,包括以最初的干燥形式;以包含生理缓冲剂(例如盐水)、增渗剂(如乙醇)或防腐剂(例如EDTA-乙二胺四乙酸)的悬浮液形式;以包含可生物降解聚合物组合物的悬浮液形式;以包含可生物降解凝胶的悬浮液形式等等。该植入物可以用存在于植入物内的原始活性试剂悬浮液中的任何一种或所有成份再填充。可以把植入物放进所要插入的部位,使其基本上不从插入位置迁移。
可以通过如直接注入活性试剂到植入物贮源的方法来再填充该植入物。特别重要是包含可再填充贮源的植入物的可操作性,也就是植入物的可再填充应不妨害该植入物在所需部位释放活性试剂能力。因而,优选的是植入物的外表面应含有一个自密封层。该自密封层可含有非生物降解材料,也可以是橡胶状材料或其它能再密封的材料。穿过自密封层注入活性试剂或活性试剂悬浮液不会导致在注入部位产生孔洞。或者,可再填充的植入物可以包含一个入口。该入口可以包含空心纤维,以便与植入物外表面交流及与植入物体内的贮源交流。与植入物外表面交流的入口部分是一种自密封成份或者该入口能进行再密封或能另外进行处理,以避免药物从贮源穿过入口而损失。具有这种入口的植入物可以通过使活性试剂穿过中空纤维注入的方法来进行再填充。另外,植入物放在眼睛组织层内(如:在巩膜层之间)的,该植入物的入口可以这样设置,即便于从眼睛外表面能再填充植入物的贮源。
在植入物插放以后,该可再填充的、非生物降解的植入物会使包含在其内的药物扩散时间至少2星期,更长的通常至少4星期,一般至少约8星期,也可以6个月或更长时间。在药物扩散完成以后,可借助于在植入物内注入药物或药物悬浮液的方法而填充该贮源。或者,该植入物可以包含一个与植入物外表面及内部贮源交流的入口。然后可以穿过入口注入药物或药物悬浮液来再填充该植入物。US4300557描述了包含可再填充贮源的植入物的一个实施例。该可再填充的植入物可以在患者眼内使用一个全疗程,可以使用至少2星期,更长的通常至少4星期,一般至少约8星期,还可以6个月或更长时间。当治疗完成或不再具有效力时,取出该植入物。
可使用的可生物降解聚合物成份可以是有机酯或醚,它们在降解时产生生理上可接受降解产物,包括单体。酐、酰胺、原酸酯等本身可以使用或与其它单体结合使用。该聚合物可以是加聚物或缩聚物,特别可以是缩聚物。该聚合物可以是交联的或非交联的,通常不超过轻微交联,一般小于5%,通常小于1%。多半情况,除碳和氢以外,聚合物还包含氧和氟,特别是包含氧。氧可以以氧化的形式存在,例如羟基或醚;以羰基的形式存在,例如非氧代羰基,比如羧酸酯,等等。氮可以以酰胺、氰基和氨基的形式存在。发现可以使用在前述的Heuer(1)中所列的聚合物,在此特别引入作为参考。
特别有用的聚合物是羟基脂族羧酸的聚合物(它的均聚物或共聚物)及多糖。在聚酯中有用的选自以下这些酸的聚合物:D-乳酸、L-乳酸、外消旋乳酸、乙醇酸、聚乙酸丙酯或它们的组合。由于使用L-乳酸,会缓慢地侵蚀聚合物,而用乳酸外消旋物,侵蚀大为增加。
在多糖中,有藻酸钙,和功能化的纤维素,特别是羧甲基纤维素酯,它们具有水不溶、分子量约5KD至500kD等特点。其它有用的聚合物包括聚乙烯醇、聚酯类和聚醚类,它们是生物相容的并可以是可生物降解的或可溶解的。多半情况,此聚合物的特点包括生物相容性、与有用试剂的相容性、包封容易、生理环境中的半衰期至少6小时(优选多于1天)、玻璃体粘度没有明显增加、水不可溶等。
形成植入物的可生物降解的聚合物,要求其对酶或水解是不稳定的。水可溶的聚合物可以用水解交联的或可生物降解的不稳定交联键交联而成为有用的水不可溶聚合物。该稳定的程度能够在宽范围改变,这取决于单体的选择、是否使用均聚物还是共聚物。在聚合物可用作变化层或可混合时,使用共聚物的混合物。
通过使用可生物降解聚合物,特别在生物降解比较慢的情况,药物释放速率主要是受控扩散,取决于周围膜的性质或整体的聚合物结构,而不是取决于导致植入物分解的聚合物的降解作用。对于大多数情况,所选颗粒的寿命至少等于投药所需的周期,优选至少二倍于投药所需周期,并可具有所需投药周期5至10倍寿命。投药周期通常至少为3天,更长通常至少为7天,一般至少约15天,也可以是20天或更长时间。
植入的颗粒就组成和物理性能而论可以基本上是均匀的,或者可以是不均匀的。因此,制备的颗粒其中心可以是一种材料,表面有一层或多层有相同或不同成份,这些层的材料可以是交联的、有不同分子量、不同密度或孔隙度等。例如,中心可以是用聚乳酸-聚甘醇酸酯的共聚物涂覆的聚乳酸,由此来提高起始降解速率。所用乳酸与甘醇酸酯的最大比例为约1∶0.1。或者,所述中心可以是用聚乳酸涂覆的聚乙烯醇,这样在聚乳酸降解时,此中心的材料溶解并迅速从眼睛中冲洗走。植入物也可由可生物降解和非生物降解的聚合物组成。例如,植入物包含一个由非生物降解聚合物材料制成的外表面,围绕在可生物降解材料核心的周围。这样,活性试剂的释放速率将受该试剂从生物降价中心释放的影响,也受药物通过非生物降价外层的扩散的影响。
可以使用的能持续释放的任何药理上活性剂,包括药物、药用试剂、细菌试验等。这些试剂能扩散到玻璃体内以有效剂量存在。照这样,药物或药用试剂会充分溶解而以药理上有效剂量存在。可在US4474451,4-6栏中及US4327725,7-8栏中找到可以使用的药用试剂,这些专利在此引入作为参考。
细菌试剂包括耐酸杆菌、(BCG)、短小棒状杆菌(C.parvum)LPS、内毒素等。这些试剂诱发免疫反应,增强肿瘤细胞免疫作用。这些试剂常用作免疫辅药以增强对给药抗原的免疫反应。见Morton等人,Surgery(1970)68:158-164;Nathanson,L.Cancer Chemother.ReP.(1973)56:659-666;Pinsky等人Proc.AACR(1972)13:21;及Zhar等人,J.Nat′l Cancer Inst(1971)46:831-839。
特别有用的药物包括氢化可的松、庆大霉素、5-氟尿嘧啶、山梨糖、醛糖还原酶抑制药、LL-2、TNF、Phakan-a(一种谷胱甘肽的成份)、巯丙酰甘氨酸(thiolathiopronin)、苄吲酸、乙酰水杨酸、三氟胸腺嘧啶脱氧核苷、干挠素(α、β和g)、免疫调制剂例如淋巴细胞活素、单激活素和生长因子、细胞激活素、抗(生长因子)等等。
有用的其它药物包括治疗黄斑变性的药物,例如干挠素,特别是α-干扰素;转化生长因子(TGF),特别是TGF-b;insluinlike生长因子;抗青光眼药物,例如β-受体阻断剂:马来酸噻吗心安、环丙甲氧心安和三甲苯心安;有丝分裂药:毛果芸香碱、氯化乙酰胆碱、异氟磷、溴化癸二胺苯酯、碘化二乙氧膦酰硫胆碱、碘乙磷硫胆碱、卡巴胆碱和毒扁豆碱;肾上腺素和盐,例如地匹福林盐酸化物;和双氯非那胺、乙酰唑胺和甲酰唑胺;抗-白内障和抗-糖尿病的视网膜病药物,例如醛糖还原酶抑制剂、托瑞司他、赖诺普利、埃那拉普利尔和statil;巯基交联药物(除了前面考虑的);抗癌药,例如视黄酸、氨甲喋呤、阿霉素,博菜霉素、去炎松、丝裂霉素、顺一铂、长春新碱、长春碱、放丝霉素-D、阿拉伯糖胞苷、蒽双咪腙、罗氮芥(CCNU)、活化的癌得星、氮烯唑胺(DTIC)、六甲密胺(HMM)、苯丙氨酸氮芥、光辉霉素、甲基苄肼、鬼臼噻吩甙(VM26)、VP16和三苯氧胺;免疫调节剂(除了前面指出的那些);抗凝固剂,例如组织纤维蛋白溶酶原活性剂、尿激酶和链球菌激酶;抗组织损伤试剂,例如过氧化物歧化酶;蛋白质和核酸,例如单-和多无性系的抗体、酶、蛋白激素和基因、基因碎片和质粒;类固醇、特别是抗炎或抗纤维性的药,例如可的松、氢化可的松、强的松龙、强的松、地寒米松、类黄体酮化合物、甲羟松(HMS)和氟甲孕松;非胆固醇抗炎药,例如Ketrolac氨基丁三醇、二氯胺苯乙酸钠和噻丙吩;抗生素,例如头孢噻啶(先锋霉素II)、氯霉素、氯洁霉素、丁胺卡那霉素、妥布霉素、甲氧苯青霉素、林可霉素、氧化霉素(Oxycillin)、青霉素、两性霉素B、多粘菌素B、先锋霉素族、氨苄青霉素、杆菌肽、羧苄青霉素、噻孢霉素、多粘菌素E、红霉素、链霉素、新霉素、磺乙酰胺、万古霉素、硝酸银、磺胺异噁唑二乙醇胺盐、喹诺酮和四环素;其它抗病原体,包括抗真菌的或抗病毒的药剂,例如碘苷、三氟苷、阿糖腺苷(腺嘌呤阿糖腺苷)、无环鸟苷(acycloguanosine)、更昔洛韦(gancyclovir)、乙氨嘧啶、三磺嘧啶合剂-2、氯洁霉素、制霉菌素、氟胞嘧啶、纳他霉素、双氯苯咪唑、酮康唑、芳族二脒(例如二羟基茋脒)和哌嗪衍生物例如二乙基乙胺嗪、睫状肌麻痹剂和扩瞳药,例如阿托品、环凝胶、东茛菪碱、后马托品和托品酰胺。
其它药剂包括抗胆碱药、抗凝血药、抗纤维蛋白溶解剂、抗组胺药、抗疟药、抗毒素、螯合剂、激素、免疫抑制剂、血栓溶解剂、维生素、盐、脱敏剂、前列腺素、氨基酸、代谢产品和抗变应原的药。
在植入物中所用试剂用量在宽范围内变化,取决于所需有效剂量和释放速率。该试剂用量通常为植入物的约1至80%(重量),更通常为植入物的20至40%(重量)。
为了各种目的,可在配方中使用其它试剂。例如,可使用增加药物溶解性的试剂、缓冲剂和防腐剂。植入物的位置如果是没有直接与玻璃体接触的,可用增强剂[即二甲亚砜(DMSO)、洗涤剂、乙醇、异丙基十四烷酸酯(IPM)、油酸、偶氮(azome)等]促进药物扩散到眼内(例如穿过结膜、巩膜和脉络膜到达玻璃体)。增强剂可以增加活性试剂必须扩散穿过眼膜的渗透性,以到达在眼内的所需位置,或者增强剂也起增加药物在玻璃体内溶解性的作用。所用增强剂随在植入物内所用药物以及聚合物的不同而变化。可使用的水可溶防腐剂包括亚硫酸氢钠、硫代硫酸钠、抗坏血酸、氯苄烷铵、氯丁醇、硫柳汞(乙基汞硫代水杨酸钠)、硼酸苯汞、对羟苯甲酸酯类、苄醇和苯乙醇。这些试剂以单独用量为约0.001对约5%(重量),优选为约0.01至约2%(重量)存在。可以使用的适宜的水溶性缓冲剂是碱或碱土金属碳酸盐、磷酸盐、碳酸氢盐、柠檬酸盐、硼酸盐、醋酸盐、琥珀酸盐等,例如磷酸钠、柠檬酸钠、硼酸钠、醋酸钠、碳酸氢钠和碳酸钠。这些试剂用量是能足以保持体系PH值为2至9,优选为4至8。照这样,该缓冲剂用量按总组成计高达5%(重量)。
植入物也可以呈任何几何形状,包括纤维、薄片、薄膜、微球、圆片、斑等等。植入物尺寸的上限由多种因素确定,例如眼睛对植入物的耐受性、插放在无血管区的尺寸限度、处理容易程度等。使用薄片或薄膜时,为了处理容易,薄片或薄膜大小至少为约0.5mm×0.5mm,通常为约3-10mm×5-10mm,厚度为约0.25-1.0mm。在使用纤维时,纤维的直径一般为0.1-1mm。纤维长度一般为0.5-5mm。能用植入物的大小和形状来控制药物在治疗期内的释放速率和在眼内的药物浓度。在某些情况下,可以利用植入物的混合物,使用相同或不同药理试剂。以这种方法,一次投药就可达到一个疗程的量,而其中释放方式可以大不相同。
可以使用各种技术生产植入物。有效的技术包括溶剂蒸法、相分离法、界面法、挤出法、模塑法、注塑法、热压法等等。
在制备含药物的聚合物的植入物来说,对于大多数情况,使用溶剂蒸发法。当植入物形状为微胶囊或微颗粒时,将控制实际速率的聚合物溶解于挥发性的、基本上水不混溶的溶剂中,例如氯仿、二氯甲烷或苯。有时用少量水可混溶的有机共溶剂,特别是氧化的溶剂如丙酮、甲醇、乙醇等来改性水不可混溶的溶剂。通常,水可混溶有机共溶剂少于约40%(体积),一般少于约25%(体积)。然后把该试剂加到聚合物-溶剂溶液中。根据试剂的性质,可使试剂分散在粘性聚合物-溶剂混合物中,或分散在已粉碎成细粉末的药物细颗粒固体分散体系中,通常,此药物微细粉末尺寸小于约1mM,一般小于0.5mM,也可以为约0.5μM或更小。在使用聚合物水凝胶,特别是使用非生物降解聚合物水凝胶时,需要加一种催化剂以达到药物-溶剂溶液的聚合。非生物降解水凝胶的制备方法在本领域是众所周知的,并描述在US4668506和US4959217中。
在介质中所使用的聚合物用量随所需植入物的尺寸大小、是否增加另外涂层、溶液粘度、聚合物溶解性等因素而变化。通常,聚合物浓度范围为10至80%(重量)。试剂与聚合物的比例随所需释放速率而改变,一种试剂用量通常为聚合物的1至80%(重量),不包括存在的其它试剂的量。
因为最终产品一般是由初始物的比例得到的,所以可调节药物与聚合物的比例以产生最佳组成。通过控制药物-聚合物-溶剂混合物及水分散介质的起始体积粘度,也可把所溶解的聚合物试剂/混合物加入到快速搅拌的水溶液中。在这种情况时,聚合物混合物在没有分散剂存在下就会凝结,导致形成大的片状或块状胶囊或微胶囊。当水溶液在凝聚期间减慢或停止搅拌时,也可以得到微胶囊。然后把微胶囊成型成可插放到眼内的片。
以另一个可供选择的制造植入物的方法,可在成层溶液周围形成涂膜以提供一种胶囊包封的植入物用来控制、延长活性试剂的释放。为了形成该涂膜,将适当的含水溶液(一般为水)缓慢倒在该表面上。以这种方法,由聚合反应生成的膜包在药物或试剂周围。所得的贴有膜的片可切成能插入眼中的任何尺寸或几何形状。为了制备特殊尺寸薄片,可使溶液在预成型模具内成层,并在表面发生聚合反应。以此方式,得到随时可以使用的植入物,而不必切成所需尺寸大小。或者,可把药物和聚合物混合物挤出成如长条或长纤维。然后可把纤维切成插放所需长度。
可以选择性地把分散液或溶液加到快速搅拌的包含水和分散剂的水溶液中,它们可以是一种保护胶体。为了形成大分子,可以使用分散剂,例如聚乙烯醇(1-5%)或非离子型洗涤剂,例如Span洗涤剂。
植入物也可以通过将试剂与熔融聚合物在适当温度下混合的方法来制备,例如在60至90℃范围内与熔融的聚乳酸聚合物混合。可将所得混合物切割、模压、注射模塑或挤出成能插放到眼内的任何形状或大小尺寸。
形成植入物的方法还可以通过把活性剂分散液或溶液倾倒或成层在一个表面上(如在石质板上)。通过改变与聚合物溶液体积相关的表面积,所形成的层可制成符合任何所需大小的表面积和宽度。为了易处理植入物,可直接将聚合物溶液成层在剥离衬片上。当需要时,该剥离衬片可以包含一个粘合层,该粘合层在该衬的一边,与聚合物溶液相接触。在溶剂蒸发以后,可使用第二层剥离衬来保护植入物暴露部分。使用背层时,可把聚合物溶液直接成层在背层材料上,使溶剂蒸发,或者使剥离衬附在其下面的结构。当需要膜层时,可把成膜聚合物溶液成层在聚合物层上。然后需要时,可以把剥离衬放在聚合物层和/或膜层之上。要使植入物包含粘合层时,在把该剥离衬放在聚合物层和/或膜层上以前,就可将粘合层涂在剥离衬上。若先插入植入物而后取出剥离衬,则粘合层就基本保留在聚合物层和/或膜层上。
需要时,可由上述的一种方法形成植入物,但没有活性试剂。然后给该无药物的植入物装上药物,例如通过把植入物浸入含活性试剂溶液,浸的时间要足以使它吸收药物。或者例如,在植入物包含中空纤维的情况,可把活性剂直接装入该纤维内,随后将该植入物密封。在药物活性不受损害的情况下,可以把填充药物的植入物干燥或部分干燥以贮存供以后使用。在选择的药物活性对暴露于溶剂、热或其它方面的条件(常规的溶剂蒸发,模塑,挤出或上述其它方法方面的条件)是敏感的情况下,发现这种形成植入物的方法特别有实用性。
当需要植入物包含可再填充的贮源的情况下,可把植入物模制成两个分离部分。其中至少一个分离部分基本上是凹面的。然后用生物相容性粘合剂,例如聚硅氧烷粘合剂,可以把包含该植入物在内的那两部分粘合在一起,形成的植入物有基本上中空的中心,可起活性试剂或药物贮存或贮藏作用。或者,可用通常的形成-灌装-封口技术来制造包含贮源的植入物。需要有入口的情况,在封口以前设置好该入口在植入物中的位置。也可用注射模塑技术制造可再填充的植入物。用注射模塑法时,通过改变盛放聚合物混合物的模具来改变植入物形状和尺寸大小、贮源内活性剂所需容积、再填充该植入物用的入口位置等。在非生物降解外层形成以后,用活性试剂或活性试剂悬浮液填充该可再填充的植入物。或者,可共模塑该植入物,因此,例如在注射模塑期间,通过共注射进一个模具内,就基本上同时形成非生物降解外部表面和可生物降解活性剂中心区。
为了确定植入物在体内可能的药物释放行为,可把已称重的植入物放入已测出体积的含4重量份乙醇和6重量份水的溶液。将该混合物保持在37℃温度下,并缓慢搅拌以保持植入物呈悬浮液。用分光光度法随时观察溶解的药物作为时间的函数,直到吸收变得恒定或者直到90%以上的药物已释放。在该介质内一小时以后的药物浓度来表示在剂量中无包封药物数量,而释放90%药物所需的时间与该剂量在体内的作用所预计的时间有关。作为一般的规则,1天的药物释放大约等于在体内释放35天。尽管释放可能不均匀,但一般来说,通常随着药物快速释放的短暂起始阶段之后该释放与相对均匀释放的平均值没有较大的变动。
可以各种方式将植入物放入眼睛内,包括外科手段、注入、套针等。
植入物可基本上放在无血管区域上方眼睛外表层的泪液内,并可锚凹在结膜或巩膜内;在无血管区域上方的巩膜外层或巩膜内层;基本上在无血管区域上方的脉络膜上间隙内,例如睫状环或外科诱导无血管区域;或与玻璃体(vitreal)腔或玻璃体直接相通以免药物扩散在血流内。穿过与植入物下方的要治疗部位相通或基本上相通的巩膜层或其它组织而形成的孔或通道,可用来促进药物扩散到所需部位。结果,孔道位于植入物下方并使植入物中的药物基本上直接流到所要治疗部位。这些孔的形成可通过本领域已知的外科方法或通过使用上述增渗剂的方法,例如用乙醇、油酸、异丙基肉豆蔻酸酯等。
外科方法,例如本领域公知的那些方法,可能对放置大的微胶囊或片是必要的。例如,可用巩膜切开术把植入物放入脉络膜上。在这种情况下,切开巩膜而暴露脉络膜。然后把植入物放在切口两边。或者,可在脉络膜上或无血管区域上方形成一个部分巩膜捕集口。然后把植入物插入,并把巩膜片缝回到适当位置以固定植入物。
另一种方法,可把植入物插入使其直接与玻璃体(vitreal)腔相通。为了实现这方法,在无血管区域上方切割一个部分厚度巩膜捕集口的片,像一个睫状环一样,以移动眼膜。使穿过巩膜床底部做成1个孔(或几个孔),与通过睫状环的玻璃体的基体相通。植入物位于巩膜床内的孔的上方,并且把捕集口的片缝回到适当位置。该植入物这样的放置为药物扩散到玻璃体内和眼内结构作好准备。
以下实施倒是用来说明本发明,而不是限制本发明。
实验
脉络膜植入
将Brown-Pierce(BP)癌植入6个兔子中每1个兔子的一只眼睛的脉络膜床内。在3至6周内肿瘤生长成适当的大小,模拟在人眼睛中生长,在60至90℃范围内,使结节杆菌(BCG-Bacille Calmette-Guerin)1.0×108完全混合于2ml熔化的可生物降解聚乳酸聚合物(polylactic polymer)中。把熔化混合物铺平,并在室温下冷却形成厚度为0.5至0.75mm的薄片。将该变硬的聚乳酸酯-BCG混合物用圆锯锯成4至5mm圆片(或斑)。然后将此圆片或斑用外科方法植入该肿瘤基质中。在7至10天以后,肿瘤的尺寸没有长大,而且肿瘤褪色。在下一个6至8周期间,肿瘤再继续吸收,3个月完全消退。
肿瘤再植入6个动物的每1个动物的前房(在对照眼睛的脉络膜床),接着静脉输注1×107个肿瘤细胞,此后没有肿瘤生长,并且没有动物发病,尸体剖检时,在所有主要器官,包括曾经承受肿瘤的眼睛没有观察到肿瘤浸润。
在6个对照动物的每1个中,浸渗聚乳酸的片诱发相应的局部脉络膜视网膜炎,而该眼睛没有出现进一步的障碍。将The Brown-Pierce肿瘤植入到前房(AC)和脉络膜床内,观察肿瘤生长。随后输注1×107个恶性细胞后每个动物死于扩散性转移。
耐酸杆菌(tbc)掺入聚乳酸内,根除眼内的BP肿瘤并局部和系统地对植入的眼内肿瘤建立特殊免疫性。
掺入Corynebacterium parvum(C.parvum)的聚乳酸得到的结果与掺入耐酸杆菌聚乳酸所观察到的结果相同。将100mgC.parvum与溶解在2ml氯仿和0.25ml乙醇内的1000mg聚乙酸酯混合。把此混合物在水薄层上铺成约0.5mm厚的平片,然后用圆锯从成片的混合物中部锯成5mm圆片或斑。用另外的水在低真空下覆盖此成片的混合物,8小时后完全凝聚。除去水,将该制剂真空干燥,然后再另外干燥24小时。用外科方法把用圆锯锯成的凝聚C.parvum圆片植入肿瘤基质内。在每种情况下,证明了带有聚乳酸的tbc和C.parvum有特殊的抗癌活性、辅助和免疫性能。
长春新碱和VX2腺癌
在6只兔子双眼的脉络膜床内植入VX2腺癌。模拟该肿瘤在人眼内的增长,该肿瘤不治疗时无控制地生长造成远距离转移和眼破裂。
长春新碱,一种长春生物碱(在玻璃试管内用IC50在0.002-0.003Mg/ml范围内,对抗VX2腺癌有效,这是已知的)与聚乳酸掺混。当VX2植入和生长到眼内的适当尺寸为6.5mm×6.5mm(范围在5.5至7.5mm)时,把掺混长春新碱的聚乳酸埋在脉络膜肿瘤基质处。使10mg长春新碱与约500mg己熔化的聚乳酸聚合物混合,然后倾倒成厚度为0.4至0.5mm的薄层,并在室温下冷却过夜。从变硬的混合物用圆锯锯成5mm圆片,并放入脉络膜肿瘤的基质内。对照眼只接收乳酸聚合物。临床注意到肿瘤在6至9天内退化,7至9周完全消退。在未治疗的对照眼内的肿瘤生长并引起肿瘤扩散随后眼球破裂。
睫状环药物传送
睫状环处玻璃体基质的暴露,可通过形成全厚度巩膜片,或者通过在透明层玻璃体收集口用圆锯穿过巩膜床来实现。穿过用圆锯锯成的孔可把封装好的微球放入玻璃体基质内。或者,掺混药物的聚乳酸形成厚度为0.25至1.0mm的3至5×7至9mm的片,把它们放在收集口,紧靠巩膜片的位置。
药物通过睫状环扩散
在六只兔子中每只兔子的一只眼睛的睫状环处植入氨甲蝶呤(MTX)-乳酸微球,并在另外六只兔子的一个眼睛内植入氢化可的松醋酸乙酯-乳酸微球。
在氯仿和乙醇中溶解40%(重量)的MTX和氢化可的松与聚乳酸聚合物的混合物(表1)。在500ml浓度为5%聚乙烯醇水溶液中,在缓慢搅拌至高速搅拌下凝聚成微胶囊。在微真空条件下再持续搅拌8小时完成蒸发。选择尺寸为0.1至0.5mm的所得微球,并在真空下再干燥24至48小时。在将大约25个微胶囊植入睫状环。
在熔化条件下混合40%(重量)的MTX和氢化可的松及聚乳酸聚合物(表2)。将所得混合物铺平成约0.4至0.5mm厚度的薄层,并在室温下冷却过夜。从此薄层中制成尺寸约为3×4mm的片,然后用外科手术把此片放在睫状环内。实验结果如下:
表1
LE RE# 药物μg/ml 测定 时间周 AC PC AC PC1* MTX EMIT 1 - 0.8 - 02* " " 2 - 1.2 - 03* " " 3 - 1.4 - 04* " " 4 - 0.7 - 05* " " 5 - 1.0 - 06* " " 6 - 0.9 - 07* 氢化可的松 HPLC 1 - 0 - 1.3
表1(续)
LE RE# 药物μg/ml 测定 时间周 AC PC AC PC8* " " 2 - 0 - 2.09* " " 3 - 0 - 2.410* " " 4 - 0 - 1.111* " " 5 - 0 - 0.912* " " 6 - 0 - 2.0#=动物=兔子*=睫状环内的微胶囊+=睫状环内的片RE=右眼LE=左眼AC=前房PC=后房
把MTX和氢化可的松的片放入三只动物中每一只动物一只眼睛的睫状环处和切除巩膜的玻璃体基质上。其结果列于表2中。
表2
LE RE# 药物μg/ml 测定 时间周 AC PC AC PC1+ MTX EMIT 1 - 1.5 - 02+ " " 2 - 4.0 - 03+ " " 3 - 2.0 - 04+ 氢化可的松 HPLC 1 - 0 - 1.35+ " " 2 - 0 - 1.96+ " " 3 - 0 - 2.3#=动物=兔子*=睫状环内的微胶囊+=睫状环内的片RE=右眼LE=左眼AC=前房PC=后房
包含地塞米松的甲基纤维素植入物
在室温时,将2g甲基纤维素溶解在5g磷酸盐缓冲盐水(PBS)中。溶解聚合物以后,加入2g地塞米松并充分混合溶液。然后把聚合物-药物混合物涂覆在3M1022剥离衬上,并用1mm涂覆棒拉延成薄膜,在真空下干燥此薄膜过夜。然后从固定在剥离衬的填充药物聚合物的薄片中切割植入物成所需形状和尺寸。除去剥离衬以后,将一个2.2mg重的植入物植入兔子眼睛的脉络膜上。通过24、96、120和168小时的HPLC分析玻璃体样品,控制释放到玻璃体内药物的浓度,释放时间为1周。24小时以后,在玻璃体内地塞米松的存在量为约1.5ppm。168小时以后,玻璃体内地塞米松的浓度保持程度在约1.0ppm。
非生物降解植入物的制备实施例1
在室温下把2g聚氨基甲酸酯(Pellethane2363-80AE)溶解在8g 1,2,3,4-四氢-9-芴酮(THF)中混合。在聚氨基甲酸酯溶解以后,加入2g地塞米松并充分混合。然后把药物-聚合物混合物涂覆在3M1022剥离衬材料上。所得聚合物薄膜的厚度为250mm至1000mm。在混合物干燥以后,从固定到剥离衬上所得的填充药物的聚合物薄片切出植入物。测试包含药物的聚合物薄片的药物释放行为。从植入物薄片中除去剥离衬,然后在37℃温度,缓慢搅拌条件下,把已称重的薄片样品加到包含4重量份乙醇和6重量份去离子水的溶液中。用分光光度计跟踪所溶药物作为时间的函数。对于装药多的聚合物薄片希望在4小时内释放包含在该薄片内的50%以上的药物。因而当把这类植入物放在眼睛内的时候,药物从该植入物中释放的限速阶段,由该药物在与植入物和接触的膜中的溶解度来确度。实施例2
如上所述,使0.5g聚氨基甲酸酯(Pellethane 2363-80AE)溶解在29THF中。随后加入0.5g更昔洛韦(gancyclovir),并充分混合溶液。在3 M1022剥离衬上使药物-聚合物溶液成层。干燥以后,从所得固定在剥离衬上的填充药物聚合物的薄片切成植入物。除去剥离衬,并如上所述测试药物在体内的释放行为。在最初的2小时以后,60%以上包含在该薄片内的药物释放到介质内。因而药物从该植入物传送的限速阶段不是由该聚合物成分来确定而是由药物在治疗期间溶解在固定植入物的眼膜内的溶解性来确定。
使用非生物降解植入物的睫状环传送药物
使更昔洛韦从无菌更昔洛韦钠的粉末(CryoveneTM,Syntex)中脱离基质,并掺混到上述的聚氨酯薄膜中,药物最终装填量为50%。把一片3mg重的更昔洛韦/聚氨酯植入物放到兔子眼睛的睫状环内。在确定时间点,通过检验从玻璃体取出的50ml样品来控制药物释放。由HPLC法测定这些样品的药物含量并计算在玻璃体内药物的浓度。结果列于表3中。
表3植入后的时间 玻璃体部分更昔洛韦的浓度(mg/ml)
3小时 0.34
24小时 0.25
36小时 0.18
96小时 0.18
从上面结果明显看出用生物相容性植入物可有效地治疗各种各样的眼病。植入物在长时期内连续投药,使病人不必以效果很差的方法用药,例如局部投药。此外,在眼内维持药物适当治疗水平,保持该药物在适当部位并在可能具有有害效果的整个宿主体系中减少高的浓度,以此方法来达到治疗目的。平衡量迅速达到并保持长的时期。此外,在长持续时间内的治疗可以只要求一次或少数几次投药,减少了对患者自身投药的负担;确保实行连续控制投药法,并减少对患者活动的干扰。
药物的聚合物包封和/或掺混而制成的植入物,能保护药理试剂不会在体循环中稀释或降解。该药剂可以各种浓度截留,而不发生任何变化。包封的药物比无包封药物提供了更有效的和毒性更小的高剂量投药法,而同时避免药物受酶侵蚀或免疫识别,把植入物放在眼睛无血管区域上方或之内避免了药物扩散到血流内,并使药物更直接和定位的投药到需要用的部位,在此情况下投在后房内的一个部位。直接投药到后部,因此避免了系统投药所需的高药物浓度和可能与这样的系统投药有关的副作用。
本发明的方法为眼科疾病提供有效的治疗。此方法以非侵害的方式避免了对眼睛内部的注射,但能给有病部位提供治疗有效的药剂。
所有在此说明书中提及的出版物和专利申请都是表示与本发明有关的技术领域中熟练技术人员的技术水平。所有出版物和专利申请在此引作参考的范围,如在所引用的每一个单独的出版物或专利申请中具体指出的范围一样。
尽管为达到更清楚了解的目的,已通过说明和举例对上述发明作了较详细的描述,但某些变化和改进在所附权利要求范围内显然都是可以实施的。
Claims (15)
1、一种处理眼睛疾病的方法,该方法包括:
在眼睛玻璃体外的某一部位,引入一个不会从所述部位迁移的植入物,该植入物包含至少一种选自药物、药用试剂和细菌试剂的药剂,所述药剂被包封在药理上可接受的生物相容性聚合物胶囊中,其中所述植入物能在长时期内提供有效剂量的所述药剂。
2、按权利要求1的方法,其中所述生物相容性聚合物是非生物降解的。
3、按权利要求2的方法,其中所述聚合物是聚氨酯。
4、按权利要求2的方法,其中所述聚合物是乙烯-乙烯基酯共聚物。
5、按权利要求4的方法,其中所述乙烯-乙烯基酯共聚物是乙烯-乙烯基乙酸酯共聚物。
6、按权利要求1的方法,其中所述部位是脉络膜上一个间隙。
7、按权利要求1的方法,其中所述部位是一个无血管区域。
8、按权利要求7的方法,其中所述无血管区域是外科手术诱导的无血管区域。
9、一种处理眼睛疾病的方法,该方法包括:
在眼睛的睫状环内引入一个不能从所述睫状环中迁移的植入物,其中所述植入物包含至少一种选自药物、药用试剂和细菌试剂的试剂,所述试剂被药理上可接受的生物相容性聚合物包封,其中所述植入物在长时期内提供有效剂量的所述试剂。
10、一种处理眼睛疾病的方法,该方法包括:
在眼睛的睫状环内引入一个不能”所述睫状环迁移的植入物,其中所述植入物含有第一种活性剂和第二种增渗剂,所述第一种活性剂选自至少一种药物、药用试剂和细菌试剂,及所述第一和第二种试剂被药理上可接受的生物相容性聚合物包封,其中所述植入物在长时期内提供有效剂量的所述第一种试剂。
11、按权利要求10的一种方法,其中所述增透剂选自异丙基十四酸酯、乙醇或油酸中至少一种。
12、一种处理眼睛脉络膜上肿瘤的方法,该方法包括:
在所述的眼睛的脉络膜上间隙内引入一个不能从所述间隙或区域迁移的植入物,其中所述植入物包含至少一种抗肿瘤药剂和药理上可接受的生物相容性聚合物。
13、按权利要求12的方法,其中所述植入物的长和宽尺寸为约0.5至10mm×0.5至10mm、厚度为约0.25至10mm的小片。
14、按权利要求13的方法,其中所述抗肿瘤试剂是氨甲喋呤、长春新碱或一种细菌试剂。
15、按权利要求14的方法,其中所述细菌试剂是耐酸杆菌或短小棒状杆菌。
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-
1993
- 1993-11-15 US US08/153,184 patent/US5443505A/en not_active Expired - Lifetime
-
1994
- 1994-11-09 DE DE69433981T patent/DE69433981T2/de not_active Expired - Lifetime
- 1994-11-09 EP EP95901829A patent/EP0729324B1/en not_active Expired - Lifetime
- 1994-11-09 CN CN94194697A patent/CN1139375A/zh active Pending
- 1994-11-09 AU AU10924/95A patent/AU1092495A/en not_active Abandoned
- 1994-11-09 ES ES95901829T patent/ES2231781T3/es not_active Expired - Lifetime
- 1994-11-09 JP JP7514491A patent/JPH09505300A/ja active Pending
- 1994-11-09 WO PCT/US1994/012898 patent/WO1995013765A1/en active IP Right Grant
- 1994-11-09 AT AT95901829T patent/ATE274872T1/de active
- 1994-11-09 KR KR1019960702428A patent/KR960705512A/ko active IP Right Grant
- 1994-11-25 TW TW083110991A patent/TW368411B/zh active
-
1996
- 1996-03-13 US US08/615,640 patent/US5766242A/en not_active Expired - Lifetime
- 1996-08-14 US US08/698,238 patent/US5824072A/en not_active Expired - Lifetime
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN100345528C (zh) * | 2001-07-12 | 2007-10-31 | 克里斯·P.·洛曼 | 用于治疗干眼的置入物 |
CN1615120B (zh) * | 2001-12-18 | 2012-09-19 | 希亚实验室公司 | 用于眼部给药活性成分的固体盖仑制剂、可溶性固体眼用植入剂及其制备方法 |
CN100428958C (zh) * | 2004-09-06 | 2008-10-29 | 段亚东 | 一种治疗眼病的植入剂 |
Also Published As
Publication number | Publication date |
---|---|
AU1092495A (en) | 1995-06-06 |
EP0729324B1 (en) | 2004-09-01 |
JPH09505300A (ja) | 1997-05-27 |
DE69433981D1 (de) | 2004-10-07 |
KR960705512A (ko) | 1996-11-08 |
DE69433981T2 (de) | 2005-09-01 |
TW368411B (en) | 1999-09-01 |
EP0729324A1 (en) | 1996-09-04 |
EP0729324A4 (en) | 1997-09-03 |
US5443505A (en) | 1995-08-22 |
WO1995013765A1 (en) | 1995-05-26 |
ATE274872T1 (de) | 2004-09-15 |
ES2231781T3 (es) | 2005-05-16 |
US5824072A (en) | 1998-10-20 |
US5766242A (en) | 1998-06-16 |
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