CN1191492A - 通过组合亲水和疏水剂制备改进的用于可控释放的药物剂型 - Google Patents

通过组合亲水和疏水剂制备改进的用于可控释放的药物剂型 Download PDF

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CN1191492A
CN1191492A CN96195703A CN96195703A CN1191492A CN 1191492 A CN1191492 A CN 1191492A CN 96195703 A CN96195703 A CN 96195703A CN 96195703 A CN96195703 A CN 96195703A CN 1191492 A CN1191492 A CN 1191492A
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弗兰克·科金基
黄振强
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Abstract

公开了包含于生物可降解的缓释埋植剂中以调节彼此的释放速率的亲水和疏水物的组合物。治疗活性剂和调节剂的制剂在一个持续的时间内提供基本上恒定的释放速率。

Description

通过组合亲水和疏水剂制备 改进的用于可控释放 的药物剂型
用于药物控制，缓释的生物可降解埋植剂的配制。
使活性成分持续释放的固体药学活性埋植剂能够在体内提供相对均一浓度的活性成分。埋植剂在持续时间内对特殊靶位点提供高的局部浓度中特别有效。这些持续释放形式减少了给药的剂量，并且避免了传统药物治疗中药物浓度的峰值和最低值。使用生物可降解药物释放系统还有一个好处是余下的埋植剂不需要从靶位点清除。
缓释埋植剂的许多预期益处依赖于在相对恒定水平的持续释放。然而，使用生物可降解基质的疏水药物制剂可能有一个在基质发生浸蚀之前表现很少或没有释放的释放分布，而在那一点则有药物的倾卸。
配制可埋植药物对眼睛特别有益，因为可以减少所需的手术操作，并特异性地提供对眼的有效的药物水平。当直接对眼注射溶液时，药物很快洗出或从眼进入全身循环而耗尽。从治疗观点来看，这与根本不给药一样是无用的。由于这种释放药物到眼睛的固有困难，因此缺乏对眼病的成功药物治疗。
能提供恒定药物释放速率的改进的持续释放制剂对医学和兽医学应用来说相当重要。相关文献
美国专利第4,997,652和5,164,188号中公布了为治疗眼科疾病而引入到眼睛前房或后面部分的生物相容性埋植剂。
Heller在CRC治疗药物载体系统评论(CRC Critical Reviews in Therapeutic Drug Carrier Systems)Vol.1，CRC出版社，Boca Raton，FL，1987，39-90页中的可控制药物释放中的生物可降解聚合物(Biodegradable Polymers inControlled Drug Delivery)一文中描述了用于可控制药物释放的包囊法Heller在医学和药学中的水凝胶(Hydrogels in medicine and Pharmacy)，N.A.Peppes ed.Vol.III，CRS出版社，Boca Raton，FL，1987，137-149页中进一步描述了生物可剥蚀聚合物。
Anderson等在避孕(Contraception)(1976)13：375以及Miller等在生物医学材料研究杂志(J.Biomed.Materials Res.)(1977)11：711中描述了聚(dL-乳酸)的多种特征。美国专利第5,075,115号公布了使用乳酸聚合物和共聚物的持续释放制剂。
Di Colo(1992)生物材料(Biomate rials)13：850-856中描述了来自疏水聚合物的可控制药物释放。
本发明提供了制备用于药物缓释的生物可降解埋植剂的组成和方法。通过把疏水和亲水剂组合入埋植剂来调节释放速率。释放调节剂可能用作加速或延缓释放速率。可任意地，调节剂可以是治疗活性剂。本发明提供了一种持续释放埋植剂，它含有具有确定释放模式的活性剂组合物。
                    附图的简要说明
图1A表示来自一种缓释药物递送系统的疏水药物的释放分布图。图1B表示在使用释放调节剂的药物递送系统中配制的同一药物的释放分布图。
图2A表明了缺少或存在释放修饰物，盐酸环丙氟哌酸(ciproflaxacin HCl)情况下地塞米松(dexamethasone)的释放分布图。图2B表明了地塞米松存在下环丙氟哌酸(cipr of loxacin)的释放。图2C表明了缺乏释放修饰剂时环丙氟哌酸的释放。图2D表明了来自含有组合亲水和疏水药物，并进一步含有非药学活性释放修饰剂的一种药物递送系统的释放分布图。
图3表明眼睛的剖面图。
通过缓慢释放生物可降解埋植剂改进剂型获得了可控制的药物释放。
药物从埋植剂的释放速率通过向埋植剂中添加释放调节剂进行调节。疏水药物的释放可通过在埋植剂中包括加速剂得以增强，而包括迟缓剂则能减小亲水药物的释放速率。释放调节剂可以是生理惰性的，或是治疗活性剂。有价值的制剂包括消炎药物，例如糖皮质激素(glucocorticoids)，NSAIDS等与一种眼科活性药物的组合。
治疗活性药物的释放速率通过在移植多聚体基质中的运输速率及调节剂的作用进行控制。通过调节释放速率。在期间时间内，药物在治疗剂量范围内基本上以恒定速率释放。释放速率在期望时间内的变动通常不超过大约100％，更常见地不超过大约50％。可以使药物到达需要药物的特异位点。并保持在有效剂量。
药物溶解性，聚合物亲水性，聚合物交联度，聚合物吸水膨胀以使聚合物屏障对药物渗透性增强，埋植剂的几何结构以及诸如此类等都可影响药物在聚合物屏障中的运输。在高药物负荷时，例如在负荷浓度超过理论渗漉作用阈值时，渗漉作用原理预示药物从药物传递系统基质沥滤的潜在可能性。在这种情况下，释放调节剂对减缓沥滤过程是有用的。
释放调节剂是一种以确定方式改变药物从一种生物可降解埋植剂释放的试剂。它可能是加速剂或迟缓剂。加速剂是亲水性组合物，它与疏水药物联合使用以加快释放速率。亲水性试剂是指那些在环境温度下于水中至少有大约100微克/毫升溶解度的组合物。疏水性试剂是指那些在环境温度下于水中有少于大约100微克/毫升溶液度度的组合物。
得益于使用一种释放调节剂的治疗活性药物可以来自，但并不局限于，下列治疗类型：Ace-抑制剂；影响基底膜的内源性细胞因子；影响内皮细胞生长的药物；肾上腺素能激动剂或阻滞剂；醛糖还原酶抑制剂；止痛剂；麻醉剂；抗过敏剂；抗细菌剂；抗纤维变性剂；抗真菌，例如两性霉素B；抗青光眼；抗高或低血压；消炎；抗瘤生成剂；抗原生动物剂；抗肿瘤；抗病毒剂；羧酸脱水酶抑制剂；螯合剂；胆碱能的；胆碱酯酶抑制剂；CNS激动剂；避孕药；多巴胺受体激动剂或拮抗剂；雌激素；糖皮质激素；葡糖苷酶抑制剂；释放因子；生长激素抑制剂；生长刺激剂；溶血剂；肝素拮抗剂；免疫调节剂；免疫抑制剂；LH-RH激动剂；缩瞳药；NSAID；黄体酮；溶栓剂；血管扩张剂；加压剂；和维生素。在特征性具有缓慢释放分布图从而可得益于含有释放加速剂的制剂的疏水性药物中，有环孢素，例如环孢素A，环孢素G等；长春花生物碱，例如长春新碱和长春花碱；氨甲蝶呤；视黄酸；一些抗生素，例如安莎霉素类诸如利福平；硝基呋喃类例如硝呋齐特；非甾族消炎药物例如双氯芬酸，Keterolac，氟比洛芬，甲氧萘酸(萘普生)，舒洛芬，布洛芬，阿司匹林；甾族化合物等。
甾族化合物特别重要，特别是具有消炎活性的甾簇组合物，即糖皮质激素。糖皮质激素包括如下：
21-乙酰氧基孕烯醇酮 氟米松 甲泼尼松
阿氯松 氟尼缩松 甲泼尼龙
阿尔孕酮 氟轻松 莫美他松糠酸酯
安西奈德 氟轻松醋酸酯 强的松龙-21-间苯酰磺酸钠
倍氯米松 氟考丁酯 强的松龙硬脂酰乙醇酸钠
倍他米枪 氟可龙 强的松龙叔丁乙酯
布地奈德 氟米龙 强的松龙21-特戊酸酯
氯泼尼松 醋酸甲氟龙 泼尼松
氯倍他索 醋酸氟甲叉龙 强的松龙戊酸酯
氯倍他松 氟泼尼龙 帕拉米松
氯泼尼醇 氟氢缩松 泼尼立定
氯可托龙 醛基缩松 泼尼卡酯
皮质甾醇 哈西缩松 尼立定
可的松 卤米松 泼尼龙
可的伐唑 双醋溴氟龙 21-二乙胺醋强的松龙
地夫可特 氢可他酯 硫氢可的松
羟泼尼缩松 双氟拉松 曲安西龙
去羟米松 氢化可的松 强的松龙磷酸钠
地塞米松 醋酸氢化可的松 曲安奈德
双氟可龙 磷酸氢化可的松 强的松龙琥珀酸钠
diruprednatc 琥钠氢可松 苯曲安奈德
甘草次酸 叔丁醋酸氢化可的松 己曲安奈德
氟扎可松 马泼尼酮
氟氯缩松 甲羟松
可知这些氢化可的松有益于眼炎疾病治疗的重要治疗效果，它们的效能和生物耐受性随其化学取代的官能而有变化。
下面是用于眼炎治疗的糖皮质激素的例子，并且在本发明中的应用比较重要，磷酸钠地塞米松；强的松龙磷酸钠；强的松龙醋酸酯；氟甲孕松醋酸酯；地塞米松；氟米龙；和甲羟松。其中，认为地塞米松是最有效的，并从而是用于眼内药物递送系统的良好候选物，因为一个小的药物释放速率对于在眼内达到治疗浓度水平已经足够。氟羟脱氢皮质醇是另一个重要的缓释眼内给药药物。
加速剂可以是生理惰性的水溶性聚合物，例如低分子量甲基纤维素或羟丙基甲基纤维素(HPMC)；糖，例如单糖诸如果糖和葡萄糖，双糖诸如乳糖，蔗糖或多糖，通常中性或不带电，诸如纤维素，直链淀粉，葡聚糖等。此外，加速剂可以是生理活性剂，可制成一种组合治疗药剂。在这种情况下，将由所需的组合治疗活性决定加速剂的选择。
释放迟滞剂是减慢亲水性药物释放速率的疏水性组合物，从而提供一个更缓释的分布图。可得益于释放调节的重要亲水性药物包括水溶性抗生素，例如如上所述，核苷酸类似物，例如无环鸟苷，9-(1，3-二羟-2-丙氧甲基)鸟嘌呤(gancyclovir)，阿糖腺苷，叠氮胸苷(azidothymidine)，双脱氧肌苷，双脱氧胞嘧啶；肾上腺素；异氟磷(is oflurphate)；亚德里亚霉素；博莱霉素；丝裂霉素；胞嘧啶阿拉伯糖苷(ara-C)；放线菌素D；莨菪胺；以及诸如此类。
作为释放迟滞剂的重要试剂包括非水溶性聚合物，例如高分子量甲基纤维素和乙基纤维素等，低水溶性有机组合物，和如前所述的药学活性疏水剂。
在一种组合物中作为活性成分和/或作为活性释放调节剂的一类重要药物是具有抗细菌活性的药物。成功地治疗感染的眼睛的抗细菌药物类型有：氨基糖甙类，amphenicols，安莎霉素类，内酰胺，lincosamides，大环内酯，多肽，四环素，二氨基嘧啶，呋喃西林，喹诺酮及其类似物，氨磺酰，砜等。当一种组合物不能控制细菌感染范围时，可把多种抗细菌药物联合到一种组合产品中。用于治疗眼部感染的抗生素例子包括：氯霉素；多粘菌素b，新霉素，短杆菌肽；新霉素；杆菌肽；乙酰磺胺钠；艮他霉素；环丙沙星；托普霉素；trimethprim sulfate；氧氟沙星；红霉素；氟哌酸；万古霉素；四环素；和金霉素。
抗病毒药物也很重要。包括许多水溶性核苷酸类似物，例如无环鸟苷，9-(1，3-二羟-2-丙氧甲基)鸟嘌呤阿糖腺苷，叠氮胸苷，双脱氧肌苷和双脱氧胞嘧啶。
作为一种抗细菌组合物特别重要的是喹诺酮，它是一种非常有效，广谱的抗生素。这些药物的高活性使得药物在低水平时即可达到治疗浓度。实例包括环丙沙星；氟哌酸；氧氟沙星；依诺沙星，洛美沙星；氟罗沙星；替马沙星，妥舒沙星和甲氟哌酸。
在本发明的一个优选实施方案中，埋植剂包括一种消炎药物，例如如上所述的非甾类消炎药物或糖皮质激素，以及一种释放调节剂，其中释放调节剂是一种眼科活性剂。一些疾病需要来自不同治疗类型药物的联合给药。联合由需治疗的特定情形决定，例如病毒性感录，肿瘤，细菌性感染等。然后挑选合适的消炎药物优化组合的治疗活性剂的释放分布图。重要的组合物包括消炎药和抗肿瘤剂，例如糖皮质激素和氨甲蝶呤，糖皮质激素和5-氟尿嘧啶，NSAID和氨甲蝶呤；消炎药和抗病毒剂；例如糖皮质激素或NSAID与阿糖腺苷，叠氮胸苷，双脱氧肌苷，双脱氧胞嘧啶，无环鸟苷，膦甲酸(foscarnet)，或9-(1，3二羟-2-丙氧甲基)鸟嘌呤相组合；消炎药和抗细菌剂，例如糖皮质激素和喹诺酮，NSAID和喹诺酮。
来自两个不同治疗类型的治疗剂的共递送的医疗需要的一个例子是眼科手术。眼科手术由于感染和发炎通常十分复杂，因而需要制造同时施有消炎和抗细菌药物的药品。治疗眼睛手术后并发症特别重要的是递送组合有消炎药物和抗细菌药物，例如地塞米松和环丙沙星的一种药物释放制剂。由于它们的高活性，这两种药物是眼内药物递送的良好候选物。
一种组合的消炎药物，以及抗生素或抗病毒剂，可以进一步与一种附加的治疗剂相组合。附加剂可能是一种止痛剂，例如可待因，吗啡，keterolac，萘普生等，一种麻醉剂，例如利度卡因盐酸盐；b-肾上腺素能阻断剂或b-肾上腺素能激动剂，例如麻黄素(ephidrine)，肾上腺素等；醛糖还原酶抑制剂，例如依帕司他，ponalrestat，索比尼尔，托瑞斯他；抗过敏剂，例如色苷酸，氯地米松，地塞米松，以及氟尼缩松；秋水仙素。Anihelminthicagents，例如伊维菌素和舒拉明钠；抗阿米巴药物，例如氯喹和金霉素；以及抗真菌药物，例如两性霉素等可以与一种抗生素和一种消炎药物共同配制。为了眼内使用，把抗青光眼药物例如乙酰唑胺(dimox)，苯呋洛尔，β-阻断剂，钙-阻断剂等与消炎和抗菌药物组合是重要的。为了治疗瘤形成，可以使用组合有抗瘤形成药物，特别是长春花碱，长春新碱，干扰素a，b和g，抗代谢物例如叶酸类似物，嘌呤类似物，嘧啶类似物的组合物。组合中也对免疫抑制剂例如硫唑嘌呤，环孢素和mizoribine感兴趣。有用的组合物还包括缩瞳药，例如碳酰胆碱，散瞳药例如阿托品等，蛋白酶抑制剂例如抑肽酶，卡莫司他，加贝酯，血管扩张剂例如缓激肽，以及各种生长因子，例如表皮生长因子，碱性成纤维细胞生长因子，神经生长因子，诸如此类。
单独或组合用于埋植剂中的活性剂的量依据所需有效剂量以及从埋植剂的释放速率而有很大变化。药物通常至少占埋植剂大约1个重量百分数，更通常至少占埋植剂10个重量百分数，并且通常不超过80，更通常不超过40埋植剂重量百分数，使用释放调节剂的数量依赖于所期望的释放分布图，调节剂活性以及不存在调节剂时活性药物的释放分布图。释放非常慢或非常快的药物需要相对高数量的调节剂。通常调节剂至少会占有10％，更通常至少大约20％的埋植剂重量百分数，并且通常不超过大约50％，更通常不超过40％埋植剂重量百分数。
并用活性药物时，每种活性药物的所需释放分布是确定的。如果需要，加入生理惰性调节剂精确控制释放分布图。药物释放将提供每种活性药物的治疗水平。
调节剂和活性药物的精确比例通过配制含有不同量调节剂的多种埋植剂并由经验确定。使用美国药典(USP)批准的用于溶出或释放试验的方法测定释放速率(USP23；NF18(1995)pp.1790-1798)。例如，使用无限渗透法(infinite sink method)，把定量的药物递送装置样品加入到已测定了体积的溶液，其中含有4份重量的乙醇和6份重量的去离子水，溶液体积将使释放后的药物浓度不超过5％饱和度。混合液置于37℃并缓慢搅拌以保持埋植剂以悬浮液存在。溶出药物对时间函数的出现可通过本技术领域熟知的各种方法进行鉴测，例如分光光度法，高效液相层析(HPLC)，质谱等。1小时后，介质中的药物浓度表示药剂中自由的未包埋药物量，而90％药物释放所需的时间与药物在体内的预期作用时间相关。通常，该释放的一些平均值不会有大的波动，从而提供相对均匀的释放。
正常制备的埋植剂在至少3天的时间内释放活性药物，更通常地至少大约一个星期，并且通常不超过大约一年，更通常不超过大约三个月。在大多数情况下，埋植剂基质在埋植位点的生理使用期限至少等同于给药的预期时间，通常至少两倍于给药的预期时间，并且可能有5倍到10倍于给药的预期时间的寿命。释放的预期时间随治疗情况而变化。例如，设计用于白内障手术后的埋植剂将有大约3天到1周的释放期间；治疗眼色素层炎可能需要超过大约4周到6周时间的释放；而治疗巨细胞病毒感染可能需要超过3到6个月或更长时间的释放。
埋植剂的大小与选择作为埋植位点区域的大小和形状一致并且在埋植后不会从插入位点迁移。埋植剂可能是坚硬的，或有些柔性以有利于埋植剂在靶位点的插入以及埋植剂的调节。埋植剂可能是颗粒，片(sheets)，小块(patchs)，板(plaques)，纤维(fibers)，微囊(microcapsules)诸如此类并且可能是与选择插入位点相容的任何大小或形状。
埋植剂可能是整体的(monolithic)的，即把活性药物均匀分布于聚合物基质，或用胶囊包埋，此处活性药物储存囊用聚合物基质包埋。为了便于制造，整体埋植剂通常优选为胶囊形式。然而，在某些情况下，由胶囊包埋的储存型提供的较强控制可能是有益的，在那里药物的治疗水平降到一个很窄的范围。使用的聚合物组合物的选择随着施药位置，所需治疗时间，病人耐受性，要治疗的疾病特性等等而变化。该聚合物的特性包括在埋植位点的生物可降解性，与有用药物的相容性，易于成囊，在生理环境下至少7天，优选地超过两周的半衰期，水溶性，诸如此类。聚合物通常在含有至少大约10％，更通常至少大约20％的埋植剂重量百分数，并且可包括多至大约70％或更多的重量百分数。
可使用的生物可降解聚合物组合物可以是有机酯或醚，当降解时产生生理可接受降解产物，包括单体。酐，酰胺，正酯或诸如此类，通过其自身或者与其它单体组合，可以找到应用。聚合物将是缩合聚合物。聚合物可以是交联或非交联的，通常不超过轻微交联，一般少于5％，通常少于1％。多数情况下，除了碳和氢，聚合物将包括氧和氮，特别是氧。氧可能以含氧形式出现，例如羟基或醚，羰基，例如非氧代羰基，诸如羧酸酯，诸如此类。氮可能以酰胺，氰和氨基形式出现。在Heller，supra中陈述的聚合物可以应用，其公开内容以参考文献形式特别地并入本发明。
特别重要的是羟基脂肪族羧酸的同聚或共聚聚合物，以及多糖。其中包括的重要聚酯是D-乳酸，L-乳酸，外消旋乳酸，乙醇酸，聚己内酯的聚合物以及它们的组合。使用L-乳酸酯或D-乳酸酯获得了缓慢生物降解的聚合物，而用消旋体时显著增强了降解。乙二醇酸和乳酸的共聚物特别重要，此时生物降解速率可以由乙二醇酸对乳酸的比例控制。最快降解共聚物中有大致相同数量的乙二醇酸和乳酸。具有非等同比率的同聚或共聚物对降解抗性更强。
多糖中有海藻酸钙(calcium alginate)，以及功能化纤维素，特别是特征为水溶性，分子量大约5千道尔顿(KD)到500千道尔顿(KD)的羧甲基纤维素酯等。生物可降解水凝胶也可用于目本发明的埋植剂。典型的水凝胶是共聚物材料，特征为吸收液体的能力。可以使用的生物可降解水凝胶例子描述于Heller的文中：医学和药学中的水凝胶(Hydrogels in Medicine and Pharmacy)，N.A.Peppes ed.，Vo1.III，CRC Press，Boca Raton，FL，1987，pp137-149。
颗粒可制备成中心是一种材料，表面有一层或多层相同的或不同的组分，此处的层可能是交联的，有不同的分子量，不同的密度或孔度，诸如此类。例如，中心可包括是用聚乳酸盐-聚乙二醇酸盐共聚物包被的聚乳酸酯，以增强最初降解的速率。使用的乳酸酯对乙二醇酸酯的多数比率在大约1∶0.1到1∶1的范围。或者，中心可以是用聚乳酸酯包被的聚乙烯醇，从而在聚乳酸酯降解后，中心将会溶出并快速从埋植位点洗出。
埋植剂可应用于便于使用活性药物缓释制剂的各种情形的治疗，此时埋植剂作为一个缓释剂。从而，依赖于要处理的具体情况，可把埋植剂引入到便于使用活性药物缓释制剂的宿主的多种不同位置，包括眼睛，中枢神经系统，血管系统，骨，皮肤，肌肉，耳朵等等…。
用于治疗眼睛状况，疾病，肿瘤或紊乱的埋植剂制剂非常重要。依赖于埋植剂的形状和剂型，要治疗的情况等，可以把生物可降解埋植剂埋移植到不同的位点。适合的位点包括前房，后房，后面部分，包括玻璃体腔，脉络膜前空间，结膜下，巩膜外，角膜内，角膜外以及巩膜。玻璃体外的合适位点包括脉络膜前空间，平面部分(the pars plana)等等。脉络膜前是位于巩膜内壁和并列的脉络膜之间的潜在空间。引入到脉络膜前的埋植剂依赖于药物从埋植剂的扩散，埋植剂中含有的药物浓度等等可把药物递送到脉络膜和解剖学上并列的视网膜。可以将埋植剂引入到无血管区上面或内部。无血管区可以是天然存在的，例如平面部分(the pars plana)，或是通过手术和化学方法造成无血管的区域。手术造成的无血管区可能是通过例如激光切除，光凝结，冷疗，热凝结，烧灼等等本技术领域熟知的方法产生于眼睛中。特别需要在所需治疗位点上或附近产生这样一个无血管区，特别是所需治疗位点远离thepars plana时或不能把埋植剂放到the pars plana时。把埋植剂引入到无血管区将使药物从埋植剂扩散并进入眼内部同时避免了药物扩散到血液。
现在转到图3，显示了眼睛的剖面图，图解说明依据本发明的埋植位点。眼睛包括晶状体16及玻璃体房3。邻近玻璃体房3是视网膜11的视觉部分。埋植可在视网膜中11或视网膜下12。视网膜被脉络膜18环绕。埋植可在脉络膜内或脉络膜前4。在视网膜视觉部分和晶状体之间，邻近玻璃体处是thepars plana 19。环绕脉络膜18的是巩膜8。埋植可在巩膜内8或巩膜外7。眼睛的外部表面是角膜9。埋植可在角膜外9或角膜内10。眼睛的内部表面是结膜6。角膜后面是前房1，它后面是晶状体16。后房2环绕晶状体，如图所示。与外部表面相对的是视神经，以及视网膜的动脉和静脉血管。埋植以脑膜空间13，视神经15和视神经内14可以使药物递送到中枢神经系统，并提供一种机制借此可越过血脑屏障。
其它的埋植位点包括把抗肿瘤药物递送到瘤生成损伤，例如肿瘤，或损伤区域，例如周围组织，或在肿瘤物质已经去除的情况下，与先前去除的肿瘤相近的组织和/或去除肿瘤后进入剩余空腔的组织。埋植剂可使用多种方法给药，包括手术方法，注射，套(管)针等等。
为了不同的目的可在药物中使用其它试剂。例如可使用缓冲剂和防腐剂。可能使用的水溶性防腐剂包括亚硫酸氢钠，硫酸氢钠，硫代硫酸钠，苯基苄基二甲基氯化铵(benzalkoniam chloride)，三氯叔丁醇，硫柳汞，乙酸苯汞，硝酸苯汞，羟苯甲酯，聚乙烯醇和苯乙醇。这些试剂可能单独以大从约0.001到大约5％，并优选地大约0.01到大约2％的重量含量存在。可能使用的由美国食品与药物管理局(FDA)批准的对期望给药方法合适的水溶性缓冲剂是碳酸钠，四硼酸钠，磷酸钠，醋酸钠，碳酸氢钠等。这些试剂可能以足够保持制剂pH值在2到9之间并优选地在4到8之间的量存在。这些缓冲剂可能占总组合物重量的多达5％。当缓冲剂或增强剂是亲水性的，它也可用作释放加速剂，并与其它调节剂有累积效应。类似地，一种亲水性缓冲剂也可能用作释放迟滞剂。
埋植剂可以是包括纤维，片，膜，微球，球，圆盘，板等等的任何几何形状。埋植剂大小的上限将由诸如埋植剂耐受性，插入的大小限制，是否容易处理等因素决定。当使用片或膜时，为了易于处理，片或膜将在至少大约0.5毫米×0.5毫米范围，通常大约3-10毫米×5-10毫米，厚度大约0.25到1.0毫米。当使用纤维时，纤维直径将一般在0.05到3毫米范围内。纤维长度将一般在0.5-10毫米范围内。球体将在2微米到4微米直径范围，与其它形成的颗粒有相当的体积。
埋植剂的大小和形式可用于控制释放速率，治疗时期以及在埋植位点的药物浓度。大的埋植剂将释放相应大的剂量，但由于其表面积对质量比，可能释放速率慢。选择特定大小和几保形状的埋植剂以最好的适合埋植位点。房，例如前房，后房和玻璃体房，能够容纳相对较大的直径1到3毫米不同几何形状的埋植剂。而片状或圆盘状的则优选地移植到脉络膜上空间用于视网膜内移植的有限空间需要相对小的，直径从0.05到1毫米的埋植剂。
在有些情况下，可能应用使用相同或不同药理剂的埋植剂混合物。这样，用单一给药获得了具有双相或三相释放的释放分布图的混合，此时的释放模式可能大大改变。
可以使用各种技术生产埋植剂。有用的技术包括溶剂蒸发法，相分离法，界面法，挤压法，模压法，注射模压法，热压法等等。特殊的方法在美国专利4,997,652中讨论，其以参考文献形式并入本发明。在一个优选实施方案中，使用挤压法避免制造中溶剂的需要。使用挤压法时，要选择聚合物和药物以使它们在制造所需的温度下(通常至少大约85℃)能稳定存在。
下面的实施例是为了说明但并非限制的目的而提供。
                        实施例1
    一种不含释放调节剂的药物递送系统(DDS)的制备和检测
测定了疏水性药物地塞米松从一种缓释药物递送系统中的释放。该药物递送系统用地塞米松和聚乳酸/聚乙二醇酸共聚物制成。地塞米松粉剂和聚乳酸聚乙二醇酸(PLGA)共聚物粉剂以50/50的比率充分混合。混合好的粉剂填充到挤压机，在95℃下加热1小时，然后通过20标准孔(gauge orifice)压出。从压出的细丝切下大约100-120微克的6个DDS，以用于药物释放鉴定。
将每个单独的DDS放到充满受体介质(9％氯化钠水溶液)的玻璃瓶中。为了提供“无限渗透(infinite sink)”条件，所选择受体介质体积使浓度不会超过5％饱和度。为了减小次生(secondary)运输现象，例如在不流动的边界层的浓度极化，把每个玻璃瓶放到37℃下的振荡水浴中。在确定的时间点从每一瓶中取出样品用于HPLC检测。HPLC方法如美国药典(USP)23(995)1791-1798页中所述。用浓度值计算累积释放分布图。释放分布图显示于图1A。可以看到用这种DDS，药物释放很慢。在开始四周后开始有明显的药物释放，接近聚合物分解的时间。
        一种含有HPMC释放调节剂的DDS的制备和检测
如上所述制造一种药物递送系统，只是要包括不同浓度的亲水性羟丙基甲基纤维素(HPMC)作为释放调节剂。使用了表1所示的药物，聚合物和HPMC组合。
                     表1
批号# PLGA HPMC 地塞米松 总计
XT014 3.5 1.5 5 10
XT015 2 2 5 9
XT013 1.5 1.5 5 8
如上所述测定药物的释放。数据显示图1B。可以看到随着HPMC的加入，释放速率显著增加。对XT014和XT015观察到接近零级的释放，此处释放调节剂对药物的比率是0.3到0.4。通过选择合适的聚合物和释放调节剂，能够定制药物释放和递送间隔以提供加速的或迟滞的释放分布图。
                        实施例2
        一种含有药学活性释放调节剂的DDS的制备和检测
如实施例1所述制造一种药物递送系统，只是要包括环丙沙星，一种药学活性亲水化合物作为释放调节剂。使用表2所示的药物，聚合物和HPMC组合物。
                         表2
  批号#     PLGA 释放调节剂   药物
  XT029     5     -  5地塞米松
  XT032     4  2环丙沙星  4地塞米松
  XT030     5     -  5环丙沙星
如图2A中数据所示，地塞米松的释放由于环丙沙星的加入而增加。与不含调节剂的DDS相比，实际的药物释放几乎增加一倍。除了得益于增加的药物传递之外，还有由于引入环丙沙星抗生素活性而获得的治疗好处。环丙沙星从同一DDS的释放显示于图2B。释放速率高于地塞米松。然而，环丙沙星总体的释放在与地塞米松共配制时比如图2C中所示不含地塞米松时要慢。
                        实施例3
        一种含有多个释放调节剂的DDS的制备和检测
使用羟甲基纤维素，环丙沙星和地塞米松配制了依据表3的一种药物递送系统。
                   表3
批号# PLGA HPMC 环丙沙星 地塞米松
XT035 3.4 0.4 2.4 3.8
数据表明在第一天一个初始的较高释放之后，可观察到其后几乎零级的释放。从治疗有效性方面来讲，总体释放特征是治疗可接受的。
                        实施例4一种含有糖皮质激素和用于治疗巨细胞病毒感染的9-(1，3-二羟-2-丙氧甲基)鸟嘌呤的药物递送系统(DDS)的制备和检测
如实施例1中所述制造一种药物递送系统，只是要包括9-(1，3-二羟-2-丙氧甲基)鸟嘌呤，一种药学活性的亲水性化合物作为释放调节剂。药物和聚合物的组合如下：
                         表4
 PLGA     抗病毒药物     消炎药物
50％          -     50％地塞米松
20％ 40％9-(1，3-二羟-2-丙氧甲基)鸟嘌呤     40％地塞米松
40％ 20％9-(1，3-二羟-2-丙氧甲基)鸟嘌呤     40％地塞米松
40％ 30％9-(1，3-二羟-2-丙氧甲基)鸟嘌呤     30％地塞米松
50％           - 50％9-(1，3-二羟-2-丙氧甲基)鸟嘌呤
随着9-(1，3-二羟-2-丙氧甲基)鸟嘌呤的加入，地塞米松的释放增加。除了得益于增加的药物递送外，还有由于引入抗病毒活性的9-(1，3-二羟-2-丙氧甲基)鸟嘌呤而获得的治疗好处。
                        实施例5一种含有糖皮质激素和用于抗肿瘤治疗的5-氟尿嘧啶的药物递送系统(DDS)的制备和检测
如实施例1中所述制造一种药物递送系统，只是要包括5-氟尿嘧啶，一种药学活性的亲水性化合物作为释放调节剂。药物和聚合物的组合如下：
                            表5
PLGA 抗肿瘤药物 消炎药物
50％     - 50％地塞米松
20％ 40％5-氟尿嘧啶 40％地塞米松
40％ 20％5-氟尿嘧啶 40％地塞米松
40％ 30％5-氟尿嘧啶 30％地塞米松
50％    - 50％5-氟尿嘧啶
伴随5-氟尿嘧啶的加入，地塞米松的释放增加。除了得益于增加的药物传递外，还有由于引入抗肿瘤活性的5-氟尿嘧啶而获得的治疗好处。
                        实施例6
一种含有NSAID和喹诺酮的药物递送系统(DDS)的制备和检测
如实施例1中所述制造一种药物递送系统，只是要包括5-氟尿嘧啶，一种药学活性的亲水性化合物作为释放调节剂。药物和聚合物的组合如下：
                        表6
PLGA 喹诺酮 消炎药物
50％      - 50％萘普生
20％ 40％环丙沙星 40％萘普生
40％ 20％环丙沙星 40％萘普生
40％ 30％环丙沙星 30％萘普生
50％ 50％环丙沙星      -
随萘普生的加入，环丙沙星的释放减少。除了得益于增加的药物释放外，还有引入组合药剂的治疗上的益处。
从上述结果明显看出，使用活性药物和释放调节剂配制的生物可降解埋植剂为长时间内药物以恒定速率释放提供了释放动力学，避免了病人需要用诸如局部给药等比较低效的方法给药。埋植剂通过避免药物释放的峰值和谷值，提供了一种改进的治疗眼和其它病情的方法。
此说明书中提及的所有发表文章和专利申请表示出那些与本发明相关领域熟练技术人员的技术水平。所有发表文章和专利申请，就如每一单独的发表文章或专利申请是特定地和个别地表示以参考文献合并于本发明一样，以同等程度作为参考文献并于本发明。
虽然为了清楚理解的目的，已通过图示和实施例对前述的发明进行了比较详细的描述，显而易见，可以在附加的权利要求书范围内进行某些变化和改进。

Claims (23)

1.一种用于药物缓释的埋植剂，包括：
一种在埋植部位降解的药学可接受的生物可降解的聚合物，其中该生物可降解聚合物至少包括埋植剂重量的大约百分之二十；
一种浓度占埋植剂重量的百分之十到五十的治疗活性剂；
一种浓度占埋植剂重量的百分之十到五十的释放调节剂；
其中所述的治疗活性剂在治疗剂量范围内释放，并至少在大约3天的时期内变化不超过100％。
2.根据权利要求1所述的埋植剂，其中所述的释放调节剂是一种亲水物并且所述的治疗活性剂是一种疏水性物。
3.根据权利要求2所述的埋植剂，其中所述的释放调节剂是羟丙基甲基纤维素。
4.根据权利要求1所述的埋植剂，其中所述的释放调节剂是一种疏水物并且所述的治疗活性剂是一种亲水物。
5.根据权利要求1所述的埋植剂，其中所述的释放调节剂是一种治疗活性剂。
6.根据权利要求5所述的埋植剂，其中所述的活性剂是一种甾族化合物并且所述的释放调节剂是一种水溶性抗生素。
7.根据权利要求5所述的埋植剂，其中所述的活性剂是一种非甾族消炎药物并且所述的释放调节剂是一种水溶性抗生素。
8.根据权利要求1所述的埋植剂，其中所述的生物可降解聚合物是聚-乳酸乙二醇酸共聚物。
9.一种用于药物缓释的埋植剂，包括：
聚乳酸二乙醇酸共聚物，其浓度至少占埋植剂重量的百分之二十；
一种浓度占埋植剂重量百分之十到五十的治疗活性消炎药物；
一种浓度占埋植剂重量百分之十到五十的释放调节剂；
其中所述的治疗活性消炎药物在治疗剂量范围内释放，在至少大约3天的时期内变化不超过100％。
10.根据权利要求9所述的埋植剂，其中所述的释放调节剂是羟丙基甲基纤维素。
11.根据权利要求9所述的埋植剂，其中所述的消炎药物是一种糖皮质激素。
12.根据权利要求11所述的埋植剂，其中所述的糖皮激素是地塞米松。
13.根据权利要求9所述的埋植剂，其中所述的消炎药物是一种非甾族消炎药物。
14.根据权利要求9所述的埋植剂，其中所述的释放调节剂是一种治疗活性剂。
15.根据权利要求14所述的埋植剂，其中所述的释放调节剂是一种水溶性抗生素。
16.根据权利要求15所述的埋植剂，其中所述的水溶性抗生素是一种喹诺酮。
17.根据权利要求14所述的埋植剂，其中所述的释放调节剂是一种水溶性抗肿瘤药物。
18.根据权利要求14所述的埋植剂，其中所述的释放调节剂是一种抗病毒药物。
19.根据权利要求18所述的埋植剂，其中所述的抗病毒药物是一种水溶性核苷酸类似物。
20.根据权利要求14所述的埋植剂，其中所述的消炎药物是地塞米松并且所述的释放调节剂是环丙沙星。
21.根据权利要求14所述的埋植剂，其中所述所述的消炎药物是地塞米松并且所述的释放调节剂是9-(1，3-二羟-2-丙氧甲基)鸟嘌呤。
22.根据权利要求14所述的埋植剂，其中所述的消炎药物是地塞米松并且所述的释放调节剂是5-氟尿嘧啶。
23.根据权利要求14所述的埋植剂，其中所述的消炎药物是萘普生并且所述的释放调节剂是环丙沙星。
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CN100364514C (zh) * 2003-01-09 2008-01-30 阿勒根公司 可生物降解的眼植入体
CN1972678B (zh) * 2004-04-30 2012-02-29 阿勒根公司 延长缓释超过2个月的类固醇眼内植入物
CN101188989B (zh) * 2005-03-01 2010-06-23 阿勒根公司 用于眼部给药的微植入物
CN104812397A (zh) * 2012-09-27 2015-07-29 阿勒根公司 用于持续释放蛋白质的生物可降解的药物递送系统

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