CN1642503A - 用于药物送递的治疗聚酐化合物 - Google Patents
用于药物送递的治疗聚酐化合物 Download PDFInfo
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- CN1642503A CN1642503A CNA038074877A CN03807487A CN1642503A CN 1642503 A CN1642503 A CN 1642503A CN A038074877 A CNA038074877 A CN A038074877A CN 03807487 A CN03807487 A CN 03807487A CN 1642503 A CN1642503 A CN 1642503A
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Abstract
提供了将低分子量药物连接入聚合药物送递体系的聚酐,所述低分子量药物在它们的结构中包含一个羧酸基和一个氨基、硫羟、醇或酚基。还提供了通过这些聚酐连接基生产聚合药物送递体系的方法,以及经所述聚合药物送递体系给予宿主低分子量药物的方法。还提供了基于本发明的聚合药物送递体系的医疗植入物。
Description
发明背景
在过去广泛地研究了用于多种用途的包括芳族或脂族酐的聚合物。例如,在二十世纪三十年代制备了用于纺织工业的包括脂族聚酐的纤维。在二十世纪五十年代中期,制备了具有改良的成膜和成纤维性能的芳族聚酐。最近,已试图合成具有更大热稳定性和水解稳定性和药物缓释性能的聚酐。
美国专利4,757,128和4,997,904公开了从二元酸和乙酸的纯的、分离的预聚物制备具有改良的药物缓释性能的聚酐。然而,这些生物相容的和生物可降解的芳族聚酐具有自由基或脂族键导致化合物具有缓慢的降解时间和相对不溶的降解产物,除非结合入含有亲水性更大的单体(例如癸二酸)的共聚物。′128专利和′904专利中公开的芳族聚酐也不溶于大多数有机溶剂。美国专利4,888,176中也描述了从具有脂族键、重均分子量大于20,000的聚酐作为均匀的聚合物母体生产的和固有速度大于0.3dL/g的生物可侵蚀的可控释放装置和一种生物活性物质。美国专利4,857,311中公开了另一种用于可控送递生物活性化合物的生物可侵蚀的基体物质,它包含具有均匀的脂族和芳族残基分布的聚酐聚合物。
美国专利5,264,540中公开了从对位取代的二芳族二元羧酸制备的用于创伤愈合装置的生物相容的和生物可降解的芳族聚酐。但是,这些化合物表现出高熔融温度和玻璃化转变温度和降低的溶解度,于是使它们难于加工。这些公开的聚酐还包含不能被水解的自由基或脂族键。
还已经公开了用于矫形外科和牙科用途的聚酐聚合物基质。例如,以其全文并入本文作参考的美国专利4,886,870公开了一种适用于修复术和植入的生物可侵蚀的制品,它包含生物相容的、疏水性的聚酐基质。以其全文并入本文作参考的美国专利5,902,599也公开了适用于各种牙科和修复术用途的生物可降解的聚合物网络,它们是通过酐预聚物的聚合形成的。
现已开发了具有改良的降解、加工和溶解性能以及基于它们的降解产物的效用的生物相容的和生物可降解的聚酐。
发明概述
本发明提供了作为将药物分子连接入聚合药物送递体系的聚合物主链的生物相容的和生物可降解的聚酐。本发明的聚酐聚合物显示了增强的溶解度和加工性,以及降解性质,这是由于不同于自由基或脂族键的可水解的键例如酯、酰胺、尿烷、氨基甲酸酯和碳酸酯的应用。所述聚酐主链具有一个或多个在水解时将提供治疗活性化合物的基。本发明的聚合物主链中包含一个或多个式(I)的单元:
-C(=O)R1-X-R2-X-R1-C(=O)-O- (I)其中,每个R1是在聚合物水解时将提供治疗活性化合物的基;每个X独立地是一个酰胺键,一个硫酯键,或一个酯键;而且R2是一个连接基;条件是,所述治疗活性化合物不是邻羟基芳基羧酸。
本发明的聚酐被用来连接在它们的分子结构中包含一个羧酸基和至少一个氨基、硫羟、醇或酚基的低分子量药物分子。因此,式(I)的聚酐起包含这些低分子量药物的聚合药物送递体系的聚合物主链的作用。
因此,本发明还涉及组合物、生产组合物的方法和应用组合物的方法,所述组合物包含式(I)的聚酐和在它们的分子结构中包含一个羧酸基和至少一个氨基、硫羟、醇或酚基的低分子量药物分子,其中,药物分子通过聚酐彼此连接。这些聚合药物送递体系提供了以控制方式将药物送递到宿主的任意位点的有效方法。“宿主”,它表示包括动物和植物。
本发明还提供了一种药物组合物,它包含本发明的聚合物和药物上可接受的载体。
本发明还提供了一种治疗动物中的疾病的治疗方法,它包括,对需要这种疗法的动物给予有效量的本发明聚合物。
本发明还提供了一种对宿主送递治疗活性化合物的方法,该方法包括,给予宿主一种生物相容的和生物可降解的本发明聚合物,它降解成生物活性化合物。
本发明提供了用于医疗的本发明聚合物,以及本发明的聚合物在生产用于治疗哺乳动物例如人的疾病的药物中的应用。
本发明还提供了适用于制备本发明的聚合物的方法和本文公开的中间体。
本发明还提供了一种包含一种生物活性化合物(活性剂)或本发明的药物分子的聚合物或组合物,可将它形成医疗植入物或微粒或者应用到或涂到医疗植入物或微粒上。
附图简述
图1.Southern研究的连续微囊化方法,通过它将一种药物、聚合物和聚合物溶剂分散体加到机械搅拌的水/表面活性剂混合物中而形成微滴的乳液,然后将它用水提取以除去溶剂和形成硬化的微胶囊或微球供通过离心、过滤等收集。
图2.阐释了几个用于本发明的空心针形载体12。
图3.阐释了本发明的丸、“生物丸”或籽10在生物可侵蚀的针形载体的空心腔或室内的放置。
本发明的详细描述
定义
除非另外描述,应用了如下定义:
如本文应用的冠词“一种”表示冠词的语法对象的一种或一种以上(即至少一种)。例如“一种成分”表示一种成分或多于一种成分。
卤是氟、氯、溴或碘。
烷基、烷氧基等表示直链和支链基;但是关于例如“丙基”这样的单个基只包括直链基,对支链异构体例如“异丙基”具体地提及。
芳基表示苯基或一个具有约9~10个环原子的单边稠合的双环碳环的基,其中,至少一个环是芳族的。
杂芳基包括通过一个含5或6个环原子的单环芳环的环碳连接的基,所述芳环包含碳原子和1~4个各自选自非过氧化物氧、硫和N(X)的杂原子,其中,X不存在或是H、O、(C1-C6)烷基、苯基或苄基,以及它衍生的一个约8~10个环原子的单边稠合的双环杂环的基,特别是苯基衍生物或通过其上稠合1,2-亚丙基、三亚甲基或四亚甲基双基而衍生的一个基。
术语酯键表示-OC(=O)-或-C(=O)O-;术语硫酯键表示-SC(=O)-或-C(=O)S-;而且术语酰胺键表示-N(R)C(=O)-或-C(=O)N(R)-,其中每个R是合适的有机基,例如氢、(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基(C1-C6)烷基、芳基、杂芳基、芳基(C1-C6)烷基、或杂芳基(C1-C6)烷基。术语尿烷或氨基甲酸酯键表示-OC(=O)N(R)-或-N(R)C(=O)O-,其中,每个R是一个合适的有机基,例如氢、(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基(C1-C6)烷基、芳基、杂芳基、芳基(C1-C6)烷基、或杂芳基(C1-C6)烷基,而且术语碳酸酯键表示-OC(=O)O-。
术语“氨基酸”包括呈D型或L型的天然氨基酸(例如Ala、Arg、Asn、Asp、Cys、Glu、Gln、Gly、His、Hyl、Hyp、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr和Val)以及非天然氨基酸(例如磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、羟基脯氨酸、γ羧基谷氨酸、马尿酸、八氢吲哚-2-羧酸、statine、1,2,3,4-四氢异喹啉-3-羧酸、青霉胺、鸟氨酸、瓜氨酸、α-甲基丙氨酸、对-苯甲酰基苯丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸和叔丁基甘氨酸)的残基。该术语还包括带有常规氨基保护基(例如乙酰基或苄氧羰基)的天然的和非天然的氨基酸,以及羧基端被保护的(例如作为(C1-C6)烷基、苯基或苄基酯或酰胺,或者作为α-甲基苄基酰胺)天然的和非天然的氨基酸。其它合适的氨基和羧基保护基是本领域技术人员已知的(参见例如,Greene,T.W.;Wutz,P.G.M.“有机合成中的保护基”(ProtectingGroups In Organic Synthesis)第二版,1991,New York,John Wiley& sons,Inc.,及其中引述的文献)。
术语“宿主”包括动物和植物。
术语“肽”描述了2~35个氨基酸(例如前文定义的那些)的序列或肽基残基。所述序列可能是线形或环状的。例如,环状肽可制备自或可得自序列中两个半胱氨酸残基之间的二硫桥的形成。优选地,一条肽包含3~20个或5~15个氨基酸。肽衍生物可根据美国专利No.4,612,302、4,853,371和4,684,620中公开的或者如下文实施例中描述的那样制备。本文具体引述的肽序列书写时氨基端在左边,而羧基端在右边。
本发明的聚合物
本发明的生物相容的、生物可降解的聚酐适用于需要送递生物活性化合物的各种用途。这样的用途实例包括,但不限于,医疗、牙科的和化妆品的应用。
本发明的聚合物可按常用于生产各种具有有价值的物理和化学性质的产品的合成聚合物领域的方法来制备。这些聚合物容易被加工成糊或溶剂浇铸而形成具有供设计各种医疗植入物的不同几何形状的膜、涂层、微球和纤维,还可通过压模和挤出来加工。
医疗植入物用途包括使用聚酐形成下列形状的物品:例如血管移植物和支架、骨板、缝线、可植入的传感器、可植入的药物送递装置、用于组织再生的支架和可在已知时段分解成无毒成分的其它物品。
还可将本发明的聚合物掺入口服制剂和掺入下列产品:例如皮肤增湿剂、清洁剂、垫、膏药、洗液、乳膏、凝胶、软膏、溶液、洗发剂、局部应用的鞣酸疗法产品和唇膏。
虽然本发明提供了从适当地官能化的生物活性化合物制备的均聚物,但本申请人已发现,包含一种或多种生物活性化合物的聚合物的机械性质和水解性质可通过对聚合物主链中的连接基(R2)改性而控制。
优选地,本发明的聚合物包括这样的主链:其中,生物活性化合物和连接基(R2)通过酯键、硫酯键、酰胺键或其混合物而连接在一起。由于酯键、硫酯键和/或酰胺键的存在,所述聚合物可在生理条件下水解而提供生物活性化合物。所以,本发明的聚合物可能特别适合作为生物活性化合物的控制释放源,或者作为将生物活性化合物定位送递到选定位点的介质。例如,本发明的聚合物可用于将治疗剂定位送递到病人身体内的选定位点(即,肿瘤内或附近),此处,聚合物的降解提供治疗剂的定位的、控制的释放。
现已开发了起低分子量药物分子的连接基作用的生物可降解的、生物相容的聚酐。包含通过本发明的聚酐连接的低分子量药物的组合物适用于需要以控制方式送递药物的各种用途。为本发明,“低分子量药物”表示它包括这样的任何化合物,即,在它的结构中包含一个羧酸基和至少一个氨基、硫羟、醇或酚基,其中,所述化合物具有证实了的药物活性和约1000道尔顿或更小的分子量。
在一个实施方案中,本发明的聚酐是通过Conix,大分子合成(Macromol.Synth.),2,95~99(1996)中描述的方法制备的。在该方法中,在过量乙酸酐中,在回流温度下将二元羧酸乙酰化,接着在180℃下将所得羧酸酐熔融缩合2~3小时。通过从二氯甲烷沉淀到乙醚中而分离生成的聚合物。所述方法基本上是将二芳族二羧酸酐聚合成芳族聚酐的常规方法。
通过凝胶渗透色谱法(GPC)相对于窄分子量聚苯乙烯标准物计算的,本发明的聚酐具有约1500道尔顿~约100,000道尔顿、至多约100,000道尔顿的平均分子量。通过凝胶渗透色谱法(GPC)相对于窄分子量聚苯乙烯标准物计算的优选的芳族聚酐具有约1500道尔顿、至多约50,000道尔顿的平均分子量。优选的偶氮聚合物具有约1500道尔顿、至多约35,000道尔顿的平均分子量。
生物活性化合物
已发现本发明的聚酐化合物可作为很多低分子量药物的可降解聚合药物送递体系的聚合物主链。可通过聚酐被连接入可降解共聚物的药物具有下列特征。所述药物具有约1,000道尔顿或更小的较低分子量。该药物在其分子结构中必定包含一个羧酸基。此外,该药物在其结构中必定包含至少一个羧酸(-COOH)、胺(-NHR)、硫羟(-SH)、醇(-OH)或酚基(-Ph-OH)。
术语“生物活性化合物”包括当给予动物(例如哺乳动物,诸如人)时提供治疗上所需的效果的治疗剂。可被掺入本发明聚合物的治疗剂包括适当地官能化的止痛药、麻醉剂、抗帕金森病剂、抗感染剂、抗痤疮剂、抗生素、抗胆碱能药、抗凝剂、抗惊厥药、抗糖尿病剂、抗运动障碍剂、抗纤维化剂、抗纤维变性药、抗真菌剂、抗青光眼剂、抗炎剂、抗肿瘤剂、抗骨质疏松剂、抗变形性骨炎剂、抗孢子形成剂、退热剂、防腐剂/消毒剂、抗血栓形成药、骨再吸收抑制剂、钙调节剂、心脏保护剂、心血管剂、中枢神经系统刺激剂、胆碱酯酶抑制剂、避孕药、除臭剂、多巴胺受体兴奋剂、勃起功能障碍剂、致育剂、胃肠剂、痛风剂、激素、安眠药、免疫调节剂、免疫抑制剂、角质层分离剂、偏头痛剂、运动病药、肌肉松弛剂、核苷类似物、肥胖剂、眼药、骨质疏松剂、抗副交感神经药、拟副交感神经药、前列腺素、心理治疗剂、呼吸剂、硬化剂、镇静剂、皮肤和粘膜剂、戒烟剂(smokingcessation agents)、抗交感神经药、合成抗细菌剂、紫外线屏蔽剂、尿道剂、阴道剂和血管舒张药(参见Physicians′Desk Reference,第55版,2001,Medical Economics Company,Inc.,Montvale,NewJersey,pp.201~202)。
在一个优选的实施方案中,在它们的结构中具有所需官能团的低分子量药物的合适的实例可见于几乎所有类别的药物,包括但不限于,止痛药、麻醉剂、抗痤疮剂、抗生素、合成抗细菌剂、抗胆碱能药、抗凝剂、抗运动障碍剂、抗纤维化剂、抗真菌剂、抗青光眼剂、抗炎剂、抗肿瘤剂、抗骨质疏松剂、抗变形性骨炎剂、抗帕金森病剂、抗孢子形成剂、退热剂、防腐剂/消毒剂、抗血栓形成药、骨再吸收抑制剂、钙调节剂、角质层分离剂、硬化剂和紫外线屏蔽剂。
所述生物活性化合物还可包含可用于修饰所述聚合物的性质(例如用于对所述聚合物接枝、交联、悬挂其它分子(例如另一种生物活性化合物),用于改变所述聚合物的溶解性,或者用于实现所述聚合物的生物分布)的其它官能团(包括羟基、巯基、氨基和羧酸,以及其它基)。治疗剂的名单可见于例如:Physicians′Desk Reference,第55版,2001,Medical Economics Company,Inc.,Montvale,New Jersey;USPNDictionary of USAN and International Drug Names,2000,The UnitedStates Pharmacopeial Convention,Inc.,Rockville,Maryland;以及The Merck Index,12版,1996,Merck & Co.,Inc.,WhitehouseStation,New Jersey。本领域技术人员能轻易从这些名单选定具有可供结合入本发明聚合物的必需官能团的治疗剂。
适用于本发明的抗细菌化合物的实例包括,但不限于,4-对氨基苯磺酰氨基水杨酸、氨苯砜乙酸、氨芬酸、阿莫西林、氨苄西林、阿帕西林、阿哌环素、阿扑西林、氨曲南、班贝霉素、比阿培南、羧苄西林、卡芦莫南、头孢羟氨苄、头孢羟唑、头孢曲秦、头孢拉宗、头孢克定、头孢地尼、头孢托仑、头孢平、头孢他美、头孢克肟、头孢甲肟、头孢米诺、头孢地嗪、头孢尼西、头孢哌酮、头孢雷特、头孢氨噻、头孢替坦、头孢替安、头孢唑兰、头孢咪唑、头孢匹胺、头孢匹罗、头孢罗齐、头孢沙定、头孢他啶、头孢特仑、头孢布坦、头孢曲松、头孢唑南、头孢氨苄、头孢来星、头孢菌素C、头孢拉定、环丙沙星、克林沙星、环青霉素、依诺沙星、依匹西林、氟氧头孢、葛帕沙星、海他西林、亚胺培南、洛美沙星、赖甲环素、美罗培南、拉氧头孢、莫匹罗星、那地沙星、诺氟沙星、帕尼培南、哌佐沙星、阿地西林、吡哌酸、喹那西林、利替培南、柳氮磺嘧啶、司帕沙星、琥珀氨苯砜、磺胺柯定、磺胺洛西酸、太古霉素、替马氟沙星、替莫西林、替卡西林、泰格莫南、托氟沙星、曲伐沙星、万古霉素等。
适用于本发明的抗真菌化合物的实例包括,但不限于,两性霉素B、偶氮丝氨酸、克念菌素、鲁斯霉素、那他霉素、制霉菌素等。
适用于本发明的抗肿瘤化合物的实例包括,但不限于,6-重氮-5-氧代-L-正亮氨酸、偶氮丝氨酸、嗜癌霉素A、二甲叶酸、依达曲沙、依洛尼塞、美法仑、甲氨蝶呤、霉酚酸、鬼臼酸乙肼、蝶罗呤、链黑霉素、Tomudex®(N-((5-(((1,4-二氢-2-甲基-4-氧代-6-喹唑啉基)甲基)甲氨基)-2-噻吩基)羰基)-L-谷氨酸)、百士欣等。
适用于本发明的抗血栓形成化合物的实例包括,但不限于,阿加曲班、伊洛前列素、拉米非班、他前列烯、替罗非班等。
适用于本发明的免疫抑制化合物的实例包括,但不限于,布西拉明、霉酚酸、丙考达唑、罗莫肽、百士欣等。
适用于本发明的NSAID化合物的实例包括,但不限于,3-氨基-4-羟基丁酸、醋氯芬酸、阿明洛芬、溴芬那酸、布马地宗、卡洛芬、双氯酚酸、二氟尼柳、因法来酸、依托度酸、芬度柳、氟芬那酸、龙胆酸、甲氯芬那酸、甲芬那酸、美沙拉嗪(mesalamine)、尼氟酸、奥沙拉嗪、奥沙西罗、S-腺苷甲硫氨酸、水杨酸、双水杨酯、柳氮磺吡啶、托芬那酸等。
连接基“R
2
”
本发明的聚合物中的连接基“R2”的性质不是关键性的,只要本发明的聚合物对选定的治疗用途具有可接受的机械性质和释放动力学即可。连接基R2通常是具有约25道尔顿~约400道尔顿分子量的二价有机基。更优选地,R2具有约40道尔顿~约200道尔顿的分子量。
利用标准键长和键角测知连接基R2通常具有约5埃~约100埃的长度。更优选地,连接基L具有约10埃~约50埃的长度。
所述连接基可能是生物惰性的,或者可能自身具有生物活性。连接基还可能包括可用来修饰所述聚合物的性质(例如对所述聚合物接枝、交联、悬挂其它分子(例如另一种生物活性化合物),改变所述聚合物的溶解性,或者实现所述聚合物的生物分布)的其它官能团(包括羟基、巯基、氨基、羧酸和其它基)。
特定的和优选的值
本文关于自由基、取代基、基团和范围列出的特定的和优选的值仅仅是为了阐释,它们不排除其它定义的值或对自由基和取代基定义的范围内的其它值。
具体地说,(C1-C6)烷基可以是甲基,乙基,丙基,异丙基,丁基,异丁基,仲丁基,戊基,3-戊基,或己基;(C3-C6)环烷基可以是环丙基,环丁基,环戊基,或环己基;(C3-C6)环烷基(C1-C6)烷基可以是环丙基甲基,环丁基甲基,环戊基甲基,环己基甲基,2-环丙基乙基,2-环丁基乙基,2-环戊基乙基,或2-环己基乙基;(C1-C6)烷氧基可以是甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,仲丁氧基,戊氧基,3-戊氧基,或己氧基;(C1-C6)烷酰基可以是乙酰基,丙酰基或丁酰基;(C1-C6)烷氧基羰基可以是甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,戊氧羰基,或己氧羰基;(C1-C6)烷硫基可以是甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,戊硫基,或己硫基;(C2-C6)烷酰氧基可以是乙酰氧基,丙酰氧基,丁酰氧基,异丁酰氧基,戊酰氧基,或己酰氧基;芳基可以是苯基,茚基,或萘基;而且杂芳基可能是呋喃基,咪唑基,三唑基,三嗪基,噁唑基,异噁唑基,噻唑基,异噻唑基,吡唑基,吡咯基,吡嗪基,四唑基,吡啶基,(或它的N-氧化物),噻吩基,嘧啶基(或它的N-氧化物),吲哚基,异喹啉基(或它的N-氧化物)或喹啉基(或它的N-氧化物)。
可结合入本发明聚合物中的特定的生物活性化合物是3-氨基-4-羟基丁酸、6-重氮-5-氧代-L-正亮氨酸、醋氯芬酸、氨苯砜乙酸、阿明洛芬、氨芬酸、阿莫西林、两性霉素B、氨苄西林、阿帕西林、阿哌环素、阿扑西林、偶氮丝氨酸、氨曲南、班贝霉素、比阿培南、溴芬那酸、布西拉明、布马地宗、克念菌素、羧苄西林、卡洛芬、卡芦莫南、嗜癌霉素A、头孢羟氨苄、头孢羟唑、头孢曲秦、头孢拉宗、头孢克定、头孢地尼、头孢托仑、头孢平、头孢他美、头孢克肟、头孢甲肟、头孢米诺、头孢地嗪、头孢尼西、头孢哌酮、头孢雷特、头孢氨噻、头孢替坦、头孢替安、头孢唑兰、头孢咪唑、头孢匹胺、头孢匹罗、头孢罗齐、头孢沙定、头孢他啶、头孢特伦、头孢布坦、头孢曲松、头孢唑南、头孢氨苄、头孢来星、头孢菌素C、头孢拉定、环丙沙星、克林沙星、环青霉素、二甲叶酸、双氯芬酸、依达曲沙、依洛尼塞、因法来酸、依诺沙星、依匹西林、依托度酸、氟氧头孢、氟芬那酸、葛帕沙星、海他西林、亚胺培南、洛美沙星、鲁斯霉素、赖甲环素、甲氯芬那酸、甲芬那酸、美法仑、美罗培南、甲氨蝶呤、拉氧头孢、莫匹罗星、霉酚酸、霉酚酸、那地沙星、那他霉素、尼氟酸、诺氟沙星、制霉菌素、奥沙西罗、帕尼培南、哌佐沙星、阿地西林、吡哌酸、鬼臼酸乙肼、丙考达唑、蝶罗呤、喹那西林、利替培南、罗莫肽、S-腺苷甲硫氨酸、柳氮磺嘧啶、司帕沙星、链黑霉素、琥珀氨苯砜、磺胺柯定、磺胺洛西酸、太古霉素、替马氟沙星、替莫西林、替卡西林、泰格莫南、托芬那酸、Tomudex®(N-((5-(((1,4-二氢-2-甲基-4-氧代-6-喹唑啉基)甲基)甲氨基)-2-噻吩基)羰基)-L-谷氨酸)、托氟沙星、曲伐沙星、百士欣或万古霉素。
关于R2的另一个特定的值是二价的、具有1~20个碳原子的支化或非支化的、饱和或不饱和的烃链,其中,该链在碳原子上任选被一个或多个(例如1、2、3或4个)选自下组的取代基取代:(C1-C6)烷氧基、(C3-C6)环烷基、(C1-C6)烷酰基、(C1-C6)烷酰基氧基、(C1-C6)烷氧羰基、(C1-C6)烷硫基、叠氮基、氰基、硝基、卤、羟基、氧代、羧基、芳基、芳氧基、杂芳基和杂芳氧基。
关于R2的另一个特定的值是一种氨基酸。
关于R2的另一个特定的值是一种肽。
关于R2的另一个特定的值是二价的、具有1~20个碳原子的支化或非支化的、饱和或不饱和的烃链,其中,一个或多个(例如1、2、3或4个)碳原子任选被(-O-)或(-NR-)替代。
又一个关于R2的更特定的值是二价的、具有3~15个碳原子的支化或非支化的、饱和或不饱和的烃链,其中,一个或多个(例如1、2、3或4个)碳原子任选被(-O-)或(-NR-)替代,而且其中,该链在碳原子上任选被一个或多个(例如1、2、3或4个)选自下组的取代基取代:(C1-C6)烷氧基、(C3-C6)环烷基、(C1-C6)烷酰基、(C1-C6)烷酰基氧基、(C1-C6)烷氧羰基、(C1-C6)烷硫基、叠氮基、氰基、硝基、卤、羟基、氧代、羧基、芳基、芳氧基、杂芳基和杂芳氧基。
又一个关于R2的更特定的值是二价的、具有3~15个碳原子的支化或非支化的、饱和或不饱和的烃链,其中,一个或多个(例如1、2、3或4个)碳原子任选被(-O-)或(-NR-)替代。
又一个关于R2的更特定的值是二价的、具有3~15个碳原子的支化或非支化的、饱和或不饱和的烃链。
又一个关于R2的更特定的值是二价的、具有3~15个碳原子的支化或非支化的烃链。
一个关于R2的优选的值是二价的、具有6~10个碳原子的支化或非支化的烃链。
一个关于R2的更优选的值是具有7、8或9个碳原子的二价烃链。
一个关于R2的最优选的值是具有8个碳原子的二价烃链。
本发明的一个特定的聚酐连接基包含式(I)的结构:
其中,R1选自下组:烷基,环烷基,取代烷基,芳基,取代芳基,内酰胺,和内酯;X选自下组:酰胺,硫酰胺,酯和硫酯;而且R2是-(CH2)n-表示的烷基,其中,n是1~20。
本发明一种特定的聚酐聚合物包括生物活性化合物,条件是,该生物活性化合物不是α-羟基羧酸。
本发明一种特定的聚酐聚合物包括生物活性化合物,条件是,该生物活性化合物不是邻羟基芳基羧酸。
这种聚合物,其中每个R1是一个将在该聚合物水解时提供不同的生物活性化合物的基,特别适用于给予动物两种治疗剂的组合。
一组优选的聚酐化合物包括由这样的化合物构成的聚合物,即,该化合物包含至少一个游离的羧酸基,以及至少一个可自身聚合或者与羧酸、醇或胺基或双(酰)氯进行共聚反应的醇基、羧酸或胺基。
配方
本发明的聚合物可作为药物组合物配制并且以适合下列选定的给药途径的各种形式给予哺乳动物宿主(例如人患者),即,经口、经直肠、或肠胃外,通过静脉内、肌内、腹膜内、脊柱内、颅内、局部的、眼的或皮下的途径。就某些给药途径来说,所述聚合物可方便地作为微粉化颗粒配制。
于是,本发明的化合物可以与药物上可接受的载体例如惰性稀释剂或可同化的可食载体组合在一起全身给药,例如经口。可将它们包封于硬或软壳明胶胶囊中,可压成片,或者可直接与患者饮食的食物掺合。至于口服治疗给药,可将所述活性化合物与一种或多种赋形剂组合并呈下列形式应用:可摄食的片、含片、锭剂、胶囊、酏剂、悬浮液、糖浆剂、糯米纸囊剂等。这样的组合物和制剂优选包含至少0.1wt%聚合物。组合物和制剂的百分数当然可以改变,而且可以就便是给定的单元剂型的约2~约80wt%,而优选是2~约60wt%。这类治疗上有用的组合物中聚合物的量应使有效的剂量水平得以获得。
片剂、锭剂、丸剂、胶囊等还可包含下列物质:粘合剂例如黄蓍树胶,阿拉伯胶,玉米淀粉或明胶;赋形剂例如磷酸二钙;崩解剂例如玉米淀粉,马铃薯淀粉,藻酸等;润滑剂例如硬脂酸镁;以及甜味剂例如蔗糖,果糖,乳糖或天冬甜素或者可添加调味剂例如薄荷,冬青油,或樱桃香精。当单元剂型是胶囊时,除了上述类别的原料以外,它还可包含液态载体,例如植物油或聚乙二醇。可作为包衣存在各种其它物质或者修饰固体单元剂型的物理形式。例如,可用明胶、蜡、紫胶或糖等包被片剂、丸剂或胶囊。糖浆剂或酏剂可能包含所述活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的羟苯甲酸甲酯和羟苯甲酸丙酯、色素和调味剂例如樱桃香精或橙香精。当然,用于制备任何单元剂型的任何物质都应当是药物上可接受的而且呈应用的量时基本是无毒的。此外,可将所述活性化合物结合入缓释制剂和装置。
还可通过输注或注射在静脉内、脊柱内、颅内或腹膜内给予所述聚合物。可用合适的溶剂例如酒精配制聚合物的溶液,任选与无毒的表面活性剂混合。还可用甘油、液态聚乙二醇、三醋精及其混合物和用油配制分散液。在一般贮存和应用条件下,这些制剂包含防腐剂以防微生物的生长。
适合注射或输注的药物剂型可包括包含含活性组分的聚合物的无菌溶液或分散液或无菌粉末,它们适合临时配制无菌可注射的或可输注的溶液或分散液,任选包封于脂质体中。在所有情况下,最后的剂型在生产和贮存条件下应当是无菌的、液态和稳定的。液态载体或介质可以是溶剂或液态分散介质,它包含,例如乙醇,多元醇(例如甘油、丙二醇、液态聚乙二醇等),植物油,无毒的甘油酯,及其合适的混合物。合适的流动性可通过下列方法保持,例如通过脂质体的形成,对分散体来说通过保持所需的粒径或者通过应用表面活性剂。微生物作用的预防可通过各种抗细菌剂和抗真菌剂来实现,例如对羟基苯甲酸酯、氯代丁醇、苯酚、山梨酸、乙基汞硫代水杨酸钠等。在很多情况下,应当优选的是包含等渗剂,例如糖、缓冲剂或氯化钠。可注射组合物的延长吸收可通过在组合物中应用延迟吸收的作用剂(例如单硬脂酸铝和明胶)来实现。
无菌注射液可这样配制:将需要量的聚合物掺入含有所需的上文列举的各种其它组分的溶剂中,随后无菌过滤。对用来配制无菌注射液的无菌粉末来说,优选的制备方法是真空干燥和冷冻干燥技术,它形成活性组分加存在于预先无菌过滤的溶液中的任何另外的所需组分的粉末。
至于局部给药,本发明的聚合物可呈纯形式应用。但是,一般将希望作为组合物或制剂施用它们,与皮肤病方面可接受的载体(它可能是固体或液体)组合。
适用的固态载体包括细分的固体,例如滑石粉、粘土、微晶纤维素、硅石、氧化铝等。适用的液态载体包括醇或多元醇或醇/多元醇混合物,其中,可任选借助于无毒的表面活性剂在有效水平溶解或分散本发明的化合物。可添加辅剂例如香料和另外的抗微生物剂以优化特定用途的性能。所得液体组合物可从吸收垫应用,用来浸渍绷带和其它敷料,或者利用泵型喷雾器或气溶胶喷雾器喷到受感染的区。
增稠剂例如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性无机原料也可与液态载体一起应用而形成可铺展的糊、凝胶、软膏、皂等,供直接用于使用者的皮肤。
可用来对皮肤送递本发明的聚合物的适用的皮肤用组合物实例是本领域已知的,例如参见,Jacquet等(美国专利No.4,608,392),Geria(美国专利No.4,992,478),Smith等(美国专利No.4,559,157)和Wortzmsan(美国专利No.4,820,508)。
剂量
所述聚合物的适用剂量可通过将它们的体外活性与治疗剂在动物模型中的体内活性比较来确定。将小鼠和其它动物中的有效剂量外推到人的方法是本领域已知的;例如,参见美国专利No.4,938,949。另外,适用的剂量可通过测定给定的聚合物在各种生理条件下的水解速率来确定。治疗中的应用所需的聚合物量不但将随选定的特定聚合物而变,还随给药途径、治疗的病情性质与患者的年龄和状态而变,而且最后将由主治医师或临床医师决定。
所需剂量可就便以单剂量或者作为在适当间隔给药的分次剂量提供,例如作为每天两次、三次、四次或更多次子剂量。子剂量本身可进一步细分,例如细分成一些分开的松散地间隔的给药。
组合疗法
本发明的聚合物还适用于对动物给予治疗剂的组合。这种组合治疗可按下列方法进行:1)可将第二种治疗剂分散在本发明聚合物的聚合物母体中,而且可在聚合物降解时释放;2)可将第二种治疗剂通过键悬挂在本发明的聚合物上(即,不在聚合物主链中),所述键在生理条件下水解而释放第二种治疗剂;3)本发明的聚合物可将两种治疗剂结合入聚合物主链(例如包含一个或多个式(I)的单元的聚合物)或者4)可以一起(或在短时间内)给予两种各自含有不同的治疗剂的本发明聚合物。
于是,本发明还提供了一种药物组合物,它包含一种本发明的聚合物和分散在本发明聚合物的聚合物母体中的第二种治疗剂。本发明还提供了一种包含本发明聚合物的药物组合物,所述聚合物上悬挂了第二种治疗剂(例如通过将在生理条件下水解而释放第二种治疗剂的化学键)。
本发明的聚合物还可与有效地治疗给定病情的其它治疗剂组合给药而提供一种组合疗法。所以,本发明还提供了一种治疗哺乳动物的疾病的方法,它包括,给予有效量的本发明聚合物和另一种治疗剂的组合。本发明还提供了一种药物组合物,它包含一种本发明的聚合物、另一种治疗剂和一种药物上可接受的载体。
本发明聚合物的制备
作为本发明进一步的实施方案提供了并通过下列方法阐述了制备本发明的聚合物的方法,其中,通用的基的含义如上文给定的那样,除非另外说明。
例如,本发明的聚合物可按方案I中阐述的那样,从式(Z1-R1-Z2)的生物活性化合物和式Y1-R2-Y2的连接基母体制备,其中,Z1和Z2中的一个是羧酸基,而其它基Y1、Y2、Z1和Z2都独立选自下表中的值。
方案I
(I)
所述生物活性化合物和连接基母体可利用人们熟知的合成技术(例如通过缩合)聚合而提供本发明的聚合物(I),其中,每个X独立地是一个酯键、硫酯键或酰胺键。
取决于所述生物活性化合物的反应性官能团(Z1和Z2),相应的官能团(Y1或Y2)可选自下表,从而提供所述聚合物主链中的酯键、硫酯键或酰胺键。
生物活性化合物上的官能团(X1或X2) | 连接基母体上的官能团(Z1或Z2) | 聚合物中形成的键 |
-COOH | -OH | 酯 |
-COOH | -NHR | 酰胺 |
-COOH | -SH | 硫酯 |
-OH | -COOH | 酯 |
-SH | -COOH | 硫酯 |
-NHR | -COOH | 酰胺 |
本领域技术人员将明白,在方案I阐述的反应过程中(以及在下文方案II~XV中阐述的反应中)可应用合适的保护基。例如,可在聚合反应过程中保护所述生物活性化合物或连接基母体中存在的其它官能团,而在随后可除去保护基以提供本发明的聚合物。合适的保护基及其接入和除去的方法是本领域熟知的(参见例如Greene,T.W.;Wutz,P.G.M.“Protecting Groups In Organic Synthesis”第二版,1991,New York,John Wiley & sons,Inc.)。
另外,当羧酸与羟基、巯基或氨基反应而提供一个酯键、硫酯键或酰胺键时,可在反应前活化所述羧酸,例如通过形成相应的酰氯。关于活化羧酸,以及关于制备酯键、硫酯键和酰胺键的很多方法都是本领域已知的(参见例如Advanced Organic Chemistry:ReactionMechanisms and Structure,第4版,Jerry March,John Wiley &Sons,pp.419~437和1281)。
如方案2中所述,本发明的聚酐/聚酯可从含羟基/羧酸的式(HOOC-R1-OH)的化合物和从式HOOC-R2-COOH的连接基母体形成。
方案2
(II)
本发明的聚酐/聚酰胺可利用与方案2中阐释的相似方法通过用合适的生物活性胺/羧酸化合物代替方案2中的生物活性羟基/羧酸化合物来制备。
本发明的聚酐/聚硫酯可利用与方案2中阐释的相似方法通过用合适的巯基/羧酸化合物代替方案2中的生物活性羟基/羧酸化合物来制备。
本发明的聚酐/聚酯也可如方案3中所述从含二羧酸的式HOOC-R1-COOH的化合物和从式(HO-R2-OH)的二醇连接基母体形成。
方案3
(III)
本发明的聚酐/聚酰胺可利用与方案2中阐释的相似方法通过用合适的二胺化合物代替方案3中的二醇连接基化合物来制备。
本发明的聚酐/聚硫酯可利用与方案2中阐释的相似方法通过用合适的二巯基化合物代替方案3中的二醇连接基化合物来制备。
本发明的其它聚合物可利用本文描述的反应,应用具有制备所需聚合物的适当基的原料来形成。
本发明的聚合药物送递体系可通过质子核磁共振(NMR)光谱、红外(IR)光谱、凝胶渗透色谱(GPC)、高效液相色谱(HPLC)、差示扫描量热法(DSC)和热重分析(TGA)来表征。至于红外光谱,可通过在NaCl片上溶剂浇铸来制备样品。1H和13C NMR光谱是用溶剂作为内标在CDCl3或DMSO-d6的溶液中测得的。
进行了GPC以测定分子量和多分散性。在该方法中,将样品溶于四氢呋喃和通过混合床柱(PE PL凝胶,5μm混合床)以0.5mL/min的流速洗脱。优选的是,将样品(约5mg/mL)溶于四氢呋喃并在柱注射以前用0.5μm PTFE注射过滤器过滤。相对于窄分子量聚苯乙烯标准物(Polysciences,Inc.)测定分子量。
还可应用一个系统,例如由装有PE AD-4自动天平的TGA 7热重分析仪和Pyris 1 DSC分析仪构成的Perkin-Blmer系统进行热分析。在该系统中,应用Pyris软件在DEC Venturis 5100计算机上进行数据分析。至于DSC,在10℃/分钟和30psi N2流速下加热5~10mg平均重量的样品。至于TGA,在20℃/分钟和8psi N2流速下加热10mg平均重量的样品。利用NRL Goniometer(Rame-hart)应用蒸馏水获得了固定液滴接触角测定值。在5,000rpm下将聚合物的二氯甲烷溶液(10% wt/vol)旋涂在玻璃载片上达30秒。
也可按常规方法测定本发明的聚合药物送递体系的降解和药物释放分布。就这些试验来说,将聚合物加工成膜、丸、微球、纳米球或纤维(取决于它们的性质)。加工后,将材料进行表征以测定在加工过程中是否发生了任何物理化学变化。然后一式三份在酸性、中性和碱性磷酸盐缓冲液(选定条件以模拟生理范围)中使均匀加工的、称量的和表征了的样品降解。定期地取出缓冲液并用新鲜的介质补充以模拟“浓度差大”的条件。通过HPLC分析用过的缓冲液以测定药物的累积释放。在规定的时段,从缓冲液中取出样品并使表面干燥(吸干)。然后称量它们以测定吸水量。此时,还测量接触角(含水的)以测定降解过程中疏水性的变化。然后在真空中充分干燥样品并称量以测定它们的质量损失。再次测量接触角(干燥的)以测定干物质的疏水性,以及它如何比得上含水物质的疏水性。通过将降解产品的累积释放量随时间描点,就可确定降解动力学。湿的和干燥的聚合物重量随时间的变化表明了物质是整体侵蚀还是表面侵蚀。如果吸水量增大了,就可确定该聚合物是整体侵蚀,而如果只有很少的或没有水的吸收,就认为该物质被表面侵蚀。通过将干重量变化对时间描点,就可确定侵蚀时聚合物的质量损失。该信息将使人们进一步深入了解该物质是如何降解的。还检测了分子量随时间的变化以补充降解结果。
本发明的聚酐化合物可通过常用于合成聚合物领域和用来生产各种具有有价值的物理和化学性质的药物送递产品的已知方法来分离。包含本发明的聚酐化合物的聚合药物送递体系可轻易地加工成糊或溶剂浇铸而形成具有供设计各种医疗植入物的不同几何形状的膜、涂层、微球和纤维,还可通过压模和挤出来加工。医疗植入物用途包括使用聚酐形成下列的成型物品:例如血管移植物和支架、骨板、缝线、可植入的传感器、可植入的药物送递装置、用于组织再生的支架、以及在植入部位送递选定的低分子量药物时在已知时段内无害地分解的其它物品。还可将通过这些本发明的聚酐连接的药物掺入口服制剂和掺入下列产品:例如皮肤增湿剂、清洁剂、垫、膏药、洗液、乳膏、凝胶、软膏、溶液、洗发剂、局部应用的鞣酸疗法产品和唇膏。
不用过多的试验就可轻易由本领域普通技术人员确定给予宿主的、对选定的用途有效的聚合药物的量。该量实际上在化学计量上对应于已知对选定的用途产生有效的治疗的药物量。
本发明还涉及在需要送递低分子量药物的任何用途中应用包含这些通过聚酐连接的低分子量药物的组合物的方法。送递的途径是根据被给予的药物和被治疗的病情选定的。例如,包含连接低分子量药物例如阿莫西林或头孢氨苄的式(I)聚酐的本发明组合物可经口或局部给予以治疗细菌感染。同样,包含连接低分子量药物例如卡比多巴或左旋多巴的式(I)聚酐的本发明组合物可经口给予患有帕金森病的患者以减轻该疾病的症状。
在本发明一个实施方案中,式(I)的聚酐被用来将两种不同的低分子量药物连接入单一的聚合药物送递体系。例如,可应用式(I)的聚酐连接卡比多巴的药物分子与左旋多巴的药物分子,于是可通过单一的聚合药物送递体系同时送递两种药物。
本发明另一个实施方案包括一种将在它们的结构中包含一个羧酸基和至少一个胺、硫羟、醇或酚基的低分子量药物分子连接入聚合药物送递体系的方法,它包括:(a)保护所述低分子量药物分子的羧酸基;(b)在所述低分子量药物分子中添加式(IV)的氯化聚酐连接基
其中,n是1~20,于是药物分子替换式(IV)的聚酐连接基的氯基并且通过它们的氨基、硫羟、醇或酚基与连接基结合;以及(c)将连接的药物分子暴露于热或真空中以至除去保护基。在式(IV)的优选的化合物中,n是6~8。
下列方案示出了药物在本发明的酐聚合物中的连接。优选通过乙酰化保护了低分子量药物分子的羧酸基。然后,将被保护的药物分子暴露于任选呈活化形式(例如氯化形式)的式(IV)连接基的连接基并通过药物分子的氨基、硫羟、醇或酚基与连接基(R2)结合。随后使药物和连接基暴露于热和/或真空以除去保护基,于是产生一个聚合药物送递体系。本发明的聚合物将具有约10~约30个重复单元。
在如下实施例1和2中举例说明了满足在它的结构中一个羧酸基和至少一个氨基、硫羟、醇或酚基的结构要求的低分子量药物的连接。
实施例1阿莫西林聚合物的合成
方案1中示出了在本发明的聚酐中连接阿莫西林。优选通过乙酰化保护低分子量药物分子的羧酸基。然后,使被保护的药物分子暴露于式(IV)的氯化形式连接基,其中,n是8。来自药物分子的氨基替换二酰氯式(IV)的氯基并通过药物分子的氨基与连接基(R2)结合。随后使连接的药物暴露于热和/或真空以除去保护基,于是产生一个聚合药物送递体系。
方案1
实施例2头孢氨苄聚合物的合成
如方案2中所示制备头孢氨苄聚合物。首先例如用苄基保护头孢氨苄的羧酸基。然后将药物与癸二酰氯(式(IV),此时n是8)连接。该连接后,除去保护基而生成羧酸,再将它们乙酰化而产生单体。将该单体熔融聚合。
方案2
实施例3
可按该方法通过本发明的式(I)聚酐连接基制备的其它聚合药物送递体系包括,但不一定限于,卡比多巴送递体系、左旋多巴送递体系和amtenac送递体系。分别在式(V)和(VI)中描绘了卡比多巴和左旋多巴药物送递体系的均聚物。
虽然这些结构描绘了均聚物,这些药物的共聚物也可基于本文提供的教导常规地制备。此外,包含式(I)的聚酐和满足结构要求的其它药物的聚合药物送递体系也可由公开的方法常规地制备,所述结构要求即,一个羧酸基,至少一个氨基、硫羟、醇或酚基,而且具有约1000道尔顿或更低的分子量。
包含一种生物活性剂或化合物、或者本发明的药物分子的上文标识的聚合物、化合物和/或组合物可加工成医疗植入物(例如医疗的、牙科的和手术的植入物)或者应用到或涂敷到医疗植入物上。例如,除了上述植入物以外,还可从上文标识的聚合物、化合物和/或组合物形成下列用途的医疗植入物或者将这些物质应用到或涂敷到下列用途的医疗植入物上:血管的、心血管的、冠状的、外周血管的、矫形外科的、牙科的、口上颌的、胃肠的、泌尿生殖的、眼的、妇科的、肺的、外科的、生理的、代谢的、神经的、诊断和治疗的应用。这样的植入物包括,但不限于,支架、导管、气囊、导线、移植物、缝线、网孔、假关节、假乳房、骨折治疗装置、给药装置、起博器、机械泵、牙科植入物(例如牙的、口上颌的和牙槽的)、去纤颤器和滤器。合适的医疗植入物还包括,但不限于:
下列Boston Scientific(Boston Scientific Corporation,Natick,MA)产品:Polaris(TM),NIR® Elite OTW Stent System,NIR®Elite Monorail(TM),Stent System,Magic WALLSTENT® Stent System,Radius®Self Expanding Stent,NIR® Biliary Stent System,NIROYAL(TM)Biliary Stent System,WALLGRAFT® Endoprosthesis,WALLSTENT® Endoprosthesis,RX Plastic Biliary Stents,UroMaxUltra(TM)High Pressure Balloon Catheter,Passport(TM)Balloon ona Wire Catheter,Excelsior(TM)1018(TM)Microcatheter,Spinnaker®Elite(TM)Flow-Directed Microcatheter,Guider Softip(TM)XF GuideCatheters,Sentry(TM)Balloon Catheters,Flexima(TM)APD(TM)Drainage Catheters with Twist Loc(TM)Hub,Vaxce1(TM)ChronicDialysis Catheter,PASV®PICC Peripherally Inserted CentralCatheters,Chilli® Cooled Ablation Catheters,和Constellation® Catheters;
下列Cordis(Cordis,a Johnson & Johnson Company,Piscataway,N.J.)产品:BX Velocity(TM)Coronary Stents,Ninja FX(TM)BalloonCatheters,Raptor(TM)Balloon Catheters,NC Raptor(TM)BalloonCatheters,Predator(TM)Balloon Catheters,Titan Mega(TM)BalloonCatheters,Checkmate(TM)Brachytherapy Catheters,Infiniti(TM)Diagnostic Catheters,Cinemayre(TM)Diagnostic Catheters,SuperTorque Plus(TM)Diagnostic Catheters,和High Flow(TM)Diagnostic Catheters;
下列Medtronics(Medtronics,Inc.,Minneapolis,MN)产品:Aneurx Stentgraft,S7 Coronary Stents,S670 Coronary Stents,S660 Coronary Stents,BeStent 2 Coronary Stents,D1 BalloonCatheters,和D2 Balloon Catheters;
下列Avantec Vascular(Avantec Vascular,San Jose,CA)产品:Duraflex(TM)Coronary Stent System,和Apollo(TM)CoronaryDilatation Catheter;
下列B.Braun(B.Braun Medical Ltd.,Sheffield,England)产品:Coroflex(TM)Coronary Stent,Cystofix(TM)Urogenital Catheters,和Urecath(TM)Urogenital Catheters;
下列Cook(Cook Group Inc.,Bloomington,IN.)产品:V-FlexPlus(TM)Coronary Stent,和CR II®Coronary Stent;
下列Guidant(Guidant Corporation,Indianapolis,IN)产品:Multilink Penta(TM)Coronary Stents,Multilink Pixel(TM)CoronaryStents,Multilink Ultra(TM)Coronary Stents,Multilink Tetra(TM)Coronary Stents,Multilink Tristar(TM)Coronary Stents,Ancure(TM)Stentgraft,Dynalink(TM)Biliary Stents,Rx Herculink(TM)Biliary Stents,Omnilink(TM)Biliary Stents,Megalink(TM)Biliary Stents,Rx Crosssail(TM)Balloon Dilatation Catheters,Rx Pauersail(TM)Balloon Dilatation Catheters,OTW Opensail(TM)Balloon Dilatation Catheters,OTW Highsail(TM)BalloonDilatation Catheters,Rx Esprit(TM)Balloon DilatationCatheters,Rx Viatrac(TM)Peripheral Catheters,和OTWViatrac(TM)Peripheral Catheters;
下列Ethicon(Ethicon,a Johnson & Johnson Company,Piscataway,N.J.)产品:VicrylTM(resorbable braided coated),PronovaTM,和PanacrylTM;
下列USS/DG Sutures(U.S.Surgical,a division of TycoHealthcare Group LP,Norwalk,CT)产品:Decon IITM(包被的,编织的合成的,可吸收的),PolySorbTM(包被的,编织的合成的,可吸收的),Dexon STM(非包被的,编织的合成的,可吸收的),肠线(可吸收的),BiosynTM(合成单丝,可吸收的),MaxonTM(合成单丝,可吸收的),SurgilonTM(编织尼龙,不可吸收的),Ti-CronTM(包被的,编织聚酯,不可吸收的),SurgidacTM(包被的,编织聚酯,不可吸收的),SofSilkTM(包被的,编丝,不可吸收的),DermalonTM(尼龙单丝;不可吸收的),MonosofTM(尼龙单丝,不可吸收的),NovafilTM(聚丁酯(polybutester)单丝,不可吸收的),VascufilTM(包被的聚丁酯单丝,不可吸收的),SurgileneTM(聚丙烯单丝,不可吸收的),SurgiproTM(聚丙烯单丝,不可吸收的),FlexonTM(不锈钢单丝,不可吸收的),SURGALLOYTM针和SURGALLOYTM OptiVisTM针;
下列Surgical Dynamics(Surgical Dynamics,Inc.,NorthHaven,Connecticut)产品:S*D*SorbTM(suture anchor,AnchorSewTM(suture anchor),S*D*Sorb E-Z TacTM(生物可再吸收的,implant w/osutures),S*D*Sorb Meniscal StaplerTM(送递装置,生物可吸收的修复植入物),Ray Threaded Fusion CageTM(脊柱),AlineTM(颈固定系统),SecureStrandTM(脊柱再造索)和Spiral Radius 90DTM(脊柱系统);
下列Zimmer(Zimmer,Warsaw,Indiana)产品:VerSysTM cementedstem hip system,VerSys HeritageTM Hip cemented stem hipsystem,VerSysTM LD/Fx cemented stem hip system,CPTTM Hipcemented stem hip system,VerSysTM Cemented Revision/Calcarcemented stem hip system,MayoTM Hip porous stem hip system,VerSysTM Beaded MidCoat porous stem hip system,VerSysTM BeadedFullCoat Plus porous stem hip system,VerSysTM Fiber MetalMidCoat porous stem hip system,和VerSysTM Fiber Metal Taperporous stem hip system,VerSysTM LD/Fx press-fit hip system,VerSysTM Cemented Revision/Calcar revision stem hip system,ZMRTMhip revision stem hip system,TrilogyTM Cup acetabular cup hipsystem,ZCATM cup acetabular cup hip system,LongevityTMpolyethylene hip system,CalcicoatTM coating hip system,NexGenTMImplant knee system,NexGenTM Instruments knee system,NexGenTMRevision Instruments knee system,IMTM Instruments knee system,MICRO-MILLTM 5-in-1 Instruments knee system,Multi-ReferenceTM4-in-1 knee system,V-STATTM Instruments kneesystem,Coonrad/MorreyTM elbow,Bigliani/FlatowTM shoulder,Cable ReadyTM Cable Grip System,CollagraftTM Bone Graft Matrix,HerbertTM Bone Screw,M/DNTM Intramedullary Fixation,MiniMagna-FxTM Screw Fixation,Magna-FxTM Screw Fixation,PeriarticularTM Plating System,Versa-FxTM Femoral Fixationsystem,Versa-Fix IITM Femoral Fixation System,和TrabecularTMMetal;
以及下列Alza technologies(ALZA Corporation,Mountain View,CA)产品:DUROS® Implant,OROSTM osmotic,D-TRANSTMtransdermal,STEALTHTM liposomal,E-TRANSTM electrotransport,MacrofluxTM,和ALZAMER depot;
还有下列文献中描述的:Stuart,M.,“Technology Strategies,Stent and Deliver,”
Start-Up,Windhover′s Review of Emerging Medical Ventures,pp.34-38,2000年6月);van der Giessen,WillemJ.等,“Marked Inflammatory Sequelae to Implantation ofBiodegradable and Nonbiodegradable Polymers in PorcineCoronary Arteries,”Circulation,Vol.94,No.7,pp.1690-1697(1996年10月1日);Gunn,J.等,“Stent coatings and local drugdelivery,”
European Heart Journal,20,pp.1693-1700(1999);
欧洲专利申请;01301671、00127666、99302918、95308988、95306529、95302858、94115691、99933575、94922724、97933150、95308988、91309923、91906591和112119841;
PCT发布:WO 00/187372、WO 00/170295、WO 00/145862、WO00/143743、WO 00/044357、WO 00/009672、WO 99/03517、WO 99/00071、WO 98/58680、WO 98/34669、WO 98/23244和WO 97/49434;
美国申请Nos.061568、346263、346975、325198、797743、815104、538301、430028、306785和429459;以及
美国专利Nos.6,325,825,6,325,790,6,322,534,6,315,708,6,293,959,6,289,568,6,273,913,6,270,525,6,270,521,6,267,783,6,267,777,6,264,687,6,258,116,6,254,612,6,245,100,6,241,746,6,238,409,6,214,036,6,210,407,6,210,406,6,210,362,6,203,507,6,198,974,6,190,403,6,190,393,6,171,277,6,171,275,6,165,164,6,162,243,6,140,127,6,134,463,6,126,650,6,123,699,6,120,476,6,120,457,6,102,891,6,096,012,6,090,104,6,068,644,6,066,125,6,064,905,6,063,111,6,063,080,6,039,721,6,039,699,6,036,670,6,033,393,6,033,380,6,027,473,6,019,778,6,017,363,6,001,078,5,997,570,5,980,553,5,971,955,5,968,070,5,964,757,5,948,489,5,948,191,5,944,735,5,944,691,5,938,682,5,938,603,5,928,186,5,925,301,5,916,158,5,911,732,5,908,403,5,902,282,5,897,536,5,897,529,5,897,497,5,895,406,5,893,885,5,891,108,5,891,082,5,882,347,5,882,335,5,879,282,RE36,104,5,863,285,5,853,393,5,853,389,5,851,464,5,846,246,5,846,199,5,843,356,5,843,076,5,836,952,5,836,875,5,833,659,5,830,189,5,827,278,5,824,173,5,823,996,5,820,613,5,820,594,5,811,814,5,810,874,5,810,785,5,807,391,5,807,350,5,807,331,5,803,083,5,800,399,5,797,948,5,797,868,5,795,322,5,792,415,5,792,300,5,785,678,5,783,227,5,782,817,5,782,239,5,779,731,5,779,730,5,776,140,5,772,590,5,769,829,5,759,179,5,759,172,5,746,764,5,741,326,5,741,324,5,738,667,5,736,094,5,736,085,5,735,831,5,733,400,5,733,299,5,728,104,5,728,079,5,728,068,5,720,775,5,716,572,5,713,876,5,713,851,5,713,849,5,711,909,5,709,653,5,702,410,5,700,242,5,693,021,5,690,645,5,688,249,5,683,368,5,681,343,5,674,198,5,674,197,5,669,880,5,662,622,5,658,263,5,658,262,5,653,736,5,645,562,5,643,279,5,634,902,5,632,763,5,632,760,5,628,313,5,626,604,5,626,136,5,624,450,5,620,649,5,613,979,5,613,948,5,611,812,5,607,422,5,607,406,5,601,539,5,599,319,5,599,310,5,598,844,5,593,412,5,591,142,5,588,961,5,571,073,5,569,220,5,569,202,5,569,199,5,562,632,5,562,631,5,549,580,5,549,119,5,542,938,5,538,510,5,538,505,5,533,969,5,531,690,5,520,655,5,514,236,5,514,108,5,507,731,5,507,726,5,505,700,5,501,341,5,497,785,5,497,601,5,490,838,5,489,270,5,487,729,5,480,392,6,325,800,6,312,404,6,264,624,6,238,402,6,174,328,6,165,127,6,152,910,6,146,389,6,136,006,6,120,454,6,110,192,6,096,009,6,083,222,6,071,308,6,048,356,6,042,577,6,033,381,6,032,061,6,013,055,6,010,480,6,007,522,5,968,092,5,967,984,5,957,941,5,957,863,5,954,740,5,954,693,5,938,645,5,931,812,5,928,247,5,928,208,5,921,971,5,921,952,5,919,164,5,919,145,5,868,719,5,865,800,5,860,974,5,857,998,5,843,089,5,842,994,5,836,951,5,833,688,5,827,313,5,827,229,5,800,391,5,792,105,5,766,237,5,766,201,5,759,175,5,755,722,5,755,685,5,746,745,5,715,832,5,715,825,5,704,913,5,702,418,5,697,906,5,693,086,5,693,014,5,685,847,5,683,448,5,681,274,5,665,115,5,656,030,5,637,086,5,607,394,5,599,324,5,599,298,5,597,377,5,578,018,5,562,619,5,545,135,5,544,660,5,514,112,5,512,051,5,501,668,5,489,271,6,319,287,6,287,278,6,221,064,6,113,613,5,984,903,5,910,132,5,800,515,5,797,878,5,769,786,5,630,802,5,492,532,5,322,518,5,279,563,5,213,115,5,156,597,5,135,525,5,007,902,4,994,036,4,981,475,4,951,686,4,929,243,4,917,668,4,871,356,6,322,582,6,319,445,6,309,202,6,293,961,6,254,616;6,206,677,6,205,748,6,178,622,6,156,056, 6,128,816,6,120,527,6,105,339,6,081,981,6,076,659,6,058,821,6,045,573,6,035,916,6,035,751,6,029,805,6,024,757,6,022,360,6,019,768,6,015,042,6,001,121,5,987,855,5,975,876,5,970,686,5,956,927,5,951,587,RE36,289, 5,924,561,5,906,273,5,894,921,5,891,166,5,887,706,5,871,502,5,871,490,5,855,156,5,853,423,5,843,574,5,843,087,5,833,055,5,814,069,5,813,303,5,792,181,5,788,063,5,788,062,5,776,150,5,749,898,5,732,816,5,728,135,5,709,067,5,704,469,5,695,138,5,692,602,5,683,416,5,681,351,5,675,961,5,669,935,5,667,155,5,655,652,5,628,395,5,623,810,5,601,185,5,571,469,5,555,976,5,545,180,5,529,175,5,500,991,5,495,420,5,491,955,5,491,954,5,487,216,5,487,212,5,486,197,5,485,668,5,477,609,5,473,810,5,409,499,5,364,410,5,358,624,5,344,005,5,341,922,5,306,280,5,284,240,5,271,495,5,254,126,5,242,458,5,236,083,5,234,449,5,230,424,5,226,535,5,224,948,5,213,210,5,199,561,5,188,636,5,179,818,5,178,629,5,171,251,5,165,217,5,160,339,5,147,383,5,102,420,5,100,433,5,099,994,5,089,013,5,089,012,5,080,667,5,056,658,5,052,551,5,007,922,4,994,074,4,967,902,4,961,498,4,896,767,4,572,363,4,555,016,4,549,649,4,533,041,4,491,218,4,483,437,4,424,898,4,412,614,D260,955,4,253,563,4,249,656,4,127,133,D245,069,3,972,418,3,963,031,3,951,261,3,949,756,3,943,933,3,942,532,3,939,969,6,270,518,6,213,940,6,203,564,6,191,236,6,138,440,6,135,385,6,074,409,6,053,086,6,016,905,6,015,427,6,011,121,5,988,367,5,961,538,5,954,748,5,948,001,5,948,000,5,944,739,5,944,724,5,939,191,5,925,065,5,910,148,5,906,624,5,904,704,5,904,692,5,903,966,5,891,247,5,891,167,5,889,075,5,865,836,5,860,517,5,851,219,5,814,051,5,810,852,5,800,447,5,782,864,5,755,729,5,746,311,5,741,278,5,725,557,5,722,991,5,709,694,5,709,692,5,707,391,5,701,664,5,695,879,5,683,418,5,669,490,5,667,528,5,662,682,5,662,663,5,649,962,5,645,553,5,643,628,5,639,506,5,615,766,5,608,962,5,584,860,5,584,857,5,573,542,5,569,302,5,568,746,5,566,822,5,566,821,5,562,685,5,560,477,5,554,171,5,549,907,5,540,717,5,531,763,5,527,323,5,520,702,5,520,084,5,514,159,5,507,798,5,507,777,5,503,266,5,494,620,5,480,411,5,480,403,5,462,558,5,462,543,5,460,263,5,456,697,5,456,696,5,442,896,5,435,438,5,425,746,5,425,445,5,423,859,5,417,036,5,411,523,5,405,358,5,403,345,5,403,331,5,394,971,5,391,176,5,386,908,5,383,905,5,383,902,5,383,387,5,376,101,D353,672,5,368,599,D353,002,5,359,831,5,358,511,5,354,298,5,353,922,5,350,373,5,349,044,5,335,783,5,335,775,5,330,442,5,325,975,5,318,577,5,318,575,5,314,433,5,312,437,5,310,348,5,306,290,5,306,289,5,306,288,5,294,389,5,282,832,5,282,533,5,280,674,5,279,783,5,275,618,5,269,807,5,261,886,5,261,210,5,259,846,5,259,845,5,249,672,5,246,104,5,226,912,5,225,485,5,217,772,5,217,486,5,217,485,5,207,679,D334,860,5,197,597,5,192,303,D333,401,D333,400,5,181,923,5,178,277,5,174,087,5,168,619,5,163,946,5,156,615,5,154,283,5,139,514,5,133,738,5,133,723,5,131,534,5,131,131,5,129,511,5,123,911,5,121,836,5,116,358,5,102,418,5,099,676,5,092,455,5,089,011,5,089,010,5,087,263,5,084,063,5,084,058,5,078,730,5,067,959,5,059,213,5,059,212,5,051,107,5,046,513,5,046,350,5,037,429,5,024,322,5,019,093,5,002,550,4,984,941,4,968,315,4,946,468,4,932,963,4,899,743和4,898,156;
将它们各自以其全文并入本文作参考。
除了前文列出的以外,供包含于或添加到生物相容的和生物可降解的聚合物或组合物中的适当类别的生物活性剂或化合物或药物分子实例还包括,但不限于,抗肿瘤剂或抗代谢物剂(例如克拉屈滨、喜树碱、伊立替康、拓扑替康、紫杉醇、甲氨蝶呤、长春新碱、放线菌素D),免疫抑制剂(例如瑞帕霉素、沙利度胺),抗血栓形成剂或抗凝剂(例如血纤蛋白、肝素结合生长因子、肝素钠、低分子量肝素、水蛭素、阿戈托班、伐哌前列素、D-phe-pro-arg-氯甲基酮、双嘧达莫、糖蛋白IIb/IIIa抑制剂、血小板膜受体抗体、基因重组因子VIII水蛭素、凝血酶抑制剂、葡聚糖、活化蛋白质C),抗炎剂(例如水杨酸酯(例如水杨酸、阿司匹林、4-氨基水杨酸酯、5-氨基水杨酸酯)、酮基布洛芬、类固醇(例如地塞米松、糖皮质素、甲泼尼龙、泼尼松(prednasone)、甲基泼尼松(methylprednasone)、氢化可的松)、萘普生(naproxyn)、布洛芬、flurbuprofin),抗真菌剂,抗细菌剂,抗病毒剂,抗感染剂或抗生素(例如阿莫西林、青霉素、环丙沙星),前列腺素或前列腺素抑制剂,血管紧张肽转化酶抑制剂,钙通道封阻剂,油(例如鱼油、ω3-脂肪酸),组胺拮抗剂,HMG-CoA还原酶抑制剂,单克隆抗体,5-羟色胺封阻剂,磷酸二酯酶抑制剂,α干扰素,基因工程上皮细胞及其组合,喹唑啉酮衍生物,编码内皮细胞促细胞分裂原的核酸,例如血管内皮生长因子(VEGF),维生素(例如α生育酚、维生素D),生长因子(例如成纤维细胞生长因子拮抗剂、血小板衍生的生长因子和拮抗剂、骨生长因子(例如骨桥蛋白、二膦酸酯(例如利塞膦酸盐、etidonate、阿仑特罗)和雌激素受体调节剂(例如雷洛昔芬)),抗氧化剂,内皮缩血管肽受体拮抗剂,angiopeptin,DNA和DNA酶,酪氨酸激酶抑制剂ST638,多亚硝基化白蛋白NO供体,天然的、半合成的或合成的激素(例如促卵泡激素(F.S.H.)和黄体生成素(lutenizing hormone)(L.H.)),和对受上文列出的药物影响的靶反义,以及一种或多种上述生物活性剂或化合物或药物分子的混合物。
术语“形成”在其含义中包括可通过物理方法将本发明的聚合物、化合物和/或组合物加工成型为各种形状、几何形状、结构和构型,包括但不限于,薄膜、纤维、棒、盘圈、螺旋形、钩形物、锥形、丸、片、管(光滑或有槽纹的)、盘、膜、微粒、“生物弹”(即,弹形的)、籽(即,弹形的或靶向的籽),以及前述标识的产品、专利和文献中描述的那些,在某些情况下包括形成这样的医疗植入物,即,具有与前述标识的产品、专利和文献中描述的医疗植入物的那些功能特性相比相同的、相似的或完全不同的功能特性。上述形状、几何形状、结构和构型可能包含将进一步增强所需应用或用途的另外的特征。例如,呈棒状、盘圈或锥形的本发明的聚合物、化合物和/或组合物可能具有毛刺,这些毛刺在从针或插管插入时或者当加热到体温以减少运动和/或挤出时可弹出。
本发明的医疗植入物的形状、几何形状、结构或构型将随植入物的用途而改变。例如,至于脊髓损伤或脑震荡的治疗,可使本发明的聚合物、化合物和/或组合物形成盘形医疗植入物供放在硬膜下方。在另一个实例中,可使本发明的聚合物、化合物和/或组合物形成膜或管状医疗植入物而用来治疗外周神经系统的损伤或者加工成含有钻孔的或其它方式形成的通道的一大块固态或发泡的组合物以促进神经生长或骨生长。在另一个实例中,在癌的治疗中,可使本发明的聚合物、化合物和/或组合物形成具有或没有毛刺的丸、微球、棒、膜、盘、弹、钩、杆或锥形医疗植入物,供插入肿瘤切除部位或插入肿瘤内。在上述情况下,医疗植入物的生物侵蚀将产生活性剂。
本发明还预期了,本发明的医疗植入物的形状、几何形状、结构或构型可随送递或给药模式而变并且可增强医疗植入物的疗效。例如,本发明的医疗植入物当插入针状物并贮存时可呈线性棒形但在用冲头(trochar)冲出针状物时可变成盘圈状或者形成很多盘圈或螺旋形状。由于医疗植入物的形状、几何形状、结构或构型改变的结果,可避免因液压或身体运动而从肿瘤或肿瘤切除部位挤出而且大量活性组分可被送递到尽可能小直径针状物的小区域。
本发明的医疗植入物的送递或给药方式可随所需用途而变并且包括本领域已知的和本文给出的那些。
可通过本领域已知的任何方法使本发明的聚合物、化合物和/或组合物形成医疗植入物,这些方法包括,但不限于,模制(例如模压或吹模)和挤出。可从一种或多种相同或不同的本发明的聚合物、化合物和/或组合物形成医疗植入物。
还可通过本领域已知的任何方法将本发明的聚合物、化合物和/或组合物应用于或涂敷到医疗植入物上,这些方法包括,但不限于,溶剂法,例如浸渍和喷雾干燥,以及非溶剂法,例如化学气相淀积、挤压涂敷或浸渍在本发明熔融的聚合物、化合物和/或组合物中。制备方法可根据所述聚合物、化合物和组合物和/或医疗植入物而变。可从一层或多层相同或不同的本发明的聚合物、化合物和/或组合物形成或用它们涂布医疗植入物。
在另一个实例中,可将本发明的聚合物、化合物和/或组合物涂在医疗植入物上,所述植入物呈膜或管状,用来治疗外周神经系统的损伤,或者呈含有钻孔的或其它方式形成的通道的一大块固态或发泡的组合物的形式以促进神经生长或骨生长。在上述情况下,盘、膜、管或块的生物侵蚀将产生含于所述聚合物或组合物中的活性剂。
作为医疗植入物本身或者作为应用到或涂覆在医疗植入物上的聚合物、化合物和/或组合物的厚度将随一个或多个因素而变,例如所述聚合物、化合物和/或组合物的物理和/或化学特性,所述医疗植入物和/或用途或应用。
例如,可从本发明的聚合物、化合物和/或组合物形成或用它们应用或涂布冠状动脉支架到约≤30~50μm的厚度,而应用或涂布了本发明的聚合物、化合物和/或组合物的血管支架可到约≤100μm的厚度,应用或涂布了本发明的聚合物、化合物和/或组合物的药物送递装置可到约≤2mm的厚度。在另一个实例中,用来经颊(舌下)给药(例如放在面颊内,舌下)的圆形薄膜/膜将具有至多约10mm(2cm)的直径和约0.5~2.0mm的厚度。
另外,可使本发明的聚合物、化合物和/或组合物形成微小颗粒或微粒(例如微球和/或微胶囊)。本发明的聚合物、化合物和/或组合物的微粒可通过本领域已知的任何方法制备并且可能包含一种或多种相同或不同的本发明的聚合物、化合物和/或组合物。例如,可利用水包油乳液法制备微粒,于是将本发明的聚合物溶于有机溶剂。然后将该聚合物溶液加到水和PVA(聚乙烯醇,它使微粒稳定)的搅拌溶液中,导致所需微粒的沉淀。任选地,可利用一个均化器。然后让溶液沉降,从溶液中滗去溶剂后将微粒干燥。
在另一个水包油乳液法中,将聚合物溶液加到水和表面活性剂(例如PVA)的溶液中,应用例如一个均化器或分散器在高剪切速率下快速搅拌。添加聚合物溶液以后,在继续搅拌下使溶剂蒸发。通过滗析、过滤或离心回收形成的微粒并干燥。
本发明的微粒还可通过美国专利5,407,609中给出的SouthernResearch的(Southern Research Institute,Birmingham,AL)连续微胶囊化方法制备,将该专利以其全文并入本文作参考,并在附图1中描述了该方法。
根据图1中描述的Southern Research的连续微胶囊化方法,可将蛋白质、肽、小分子、水溶性药物、疏水性药物和包封于丙交酯/乙交酯聚合物中的药物以最少暴露于聚合物溶剂、高包封效率和良好的产率微囊包封到约1~250μm、优选<100μm、更优选<10μm的尺寸。如图1中所示,将药物、聚合物和聚合物溶剂分散液加到机械搅拌的水/表面活性剂混合物中而形成微滴的乳液,然后用水提取以除去溶剂而产生硬化的微胶囊或微球供通过离心、过滤等收集。
可使本发明的微粒形成各种形状和几何形状(例如球形,和规则的或不规则的球形)以及掺入各种制剂或组合物(例如明胶胶囊、液体制剂、喷雾干燥制剂、为与干粉或气溶胶吸入器一起应用的制剂、压制片、局部凝胶、局部软膏、局部散剂)中。
本领域技术人员应懂得,本发明的微粒的所需尺寸将取决于所需的用途和送递方式。给予或送递本发明的微粒的方式包括本文给出的那些,包括经口、通过吸入和局部给药。本发明预期到给予本发明的微粒,它在降解或生物侵蚀时产生更小的颗粒和/或活性剂供有效地治疗靶向的器官。本发明还预期到给予一种或多种或者具有完全相同的尺寸或者具有两种或多种不同尺寸的混合物的本发明相同或不同的微粒。通过改变微粒的尺寸,可控制生物侵蚀的速率和/或活性药物的产生速率和/或活性药物产生的场所。结果,可实现活性药物的定时(例如延迟的和/或持续的)产生。
例如,结肠发炎的壁的治疗(例如,炎性肠病、感染等的治疗)可通过口服包含作为活性剂的抗炎药的本发明微粒来实现。可给予尺寸约1~10μm的这种微粒,以致在到达小肠的回肠区段时,微粒的尺寸约为0.1~1.0μm,而在到达结肠时尺寸约为0.01~0.1μm。参见例如,A.Lamprecht等,
Abstracts/Journal of Controlled Release,Vol.72,pp.235~237(2001)。一旦在肠内,微粒就可能被肠壁的绒毛和/或微绒毛和/或被分泌粘液的肠壁衬里物理截留,于是延迟排出,并且延长胃肠滞留时间和能使在肠壁附近发生聚合物的生物侵蚀时定时缓慢地产生活性剂。
同样,可口服约0.1~100μm、优选约0.1~10μm、更优选约0.1~1μm的本发明的微粒,以至微粒的血液水平能在生物侵蚀时使活性剂遍布周围的组织。在又一个实例中,可利用口服约≤0.6μm、优选约≤0.3μm、更优选约0.1μm本发明的微粒来送递活性药物通过肠道而最终经由淋巴系统到达肝脏。参见例如,P.Jani等,Pharm.Pharmacol.,Vo.42,pp.821~826(1990);M.Desai等,Pharmaceutical Research,Vol.13,No.12,pp.1838~1845(1996)。
约≤10μm的本发明的微粒可局部应用或眼用。
至于皮肤渗透,可应用约1~70μm本发明的微粒。在一个优选的实施方案中,约10~70μm本发明的微粒被用于皮肤渗透。在另一个优选的实施方案中,当应用于人皮肤时,≤10μm本发明的微粒被用来产生感觉光滑的产品。在又一个优选的实施方案中,约1~3μm本发明的微粒被用于皮肤渗透。然而,在似乎更依赖于微粒的形状和强度而不是尺寸的组织(例如皮肤、粘膜)渗透应用中,可利用各不相同的微粒尺寸,如PowderJect的Smart ParticleTM(PowderJectPharmaceuticals,England,U.K.,包括美国专利No.6,328,714、6,053,889和6,013,050中描述的那些)中所例举的。
本发明的微粒还可用于对肺(包括肺部深处或肺区)的吸入送递(例如,以一定的速率直接吸入,或者通过气溶胶喷洒)。例如,约0.5~10μm、优选约1~5μm、更优选约1~3μm、更进一步优选约1~2μm的本发明的微粒可配制成气溶胶。至于直接吸入,可利用约0.5~6μm、更优选约1~3μm的微粒。参见例如,ARADIGM的(AradigmCorporation,Hayward,CA)AERx® System和下列美国专利中描述的那些:Nos.6,263,872、6,131,570、6,012,450、5,957,124、5,934,272、5,910,301、5,735,263、5,694,919、5,522,385、5,509,404和5,507,277,以及MicroDose的(MicroDose TechnologiesInc.,Monmouth Junction,NJ)MicroDose DPI吸入器和美国专利Nos.6,152,130、6,142,146、6,026,809和5,960,609中描述的那些。
约≤10μm的本发明的微粒可用于关节内注射而治疗例如关节炎。
约0.1~100μm、优选约0.1~10μm、更优选约0.1~1μm的本发明的微粒可与栓剂(例如甘油栓剂)掺合。
还可使本发明的聚合物、化合物和/或组合物形成丸、“生物弹”(即,弹形的)或籽(例如弹形籽)供包含于如图2和3中列举的可植入和/或可注射的生物可侵蚀的空心载体12(例如筒、弹、胶囊、注射器或针)中。动物和人的应用都是预期的。图2阐释了在本发明中应用的几个空心针形载体12。在一个实施方案中,空心载体12具有在约0.5~10mm范围内的直径。
图3阐释了本发明的丸、“生物弹”或籽10在生物可侵蚀的针形载体的空心腔或室内的放置。根据本发明,可将一个或多个相同或不同的本发明的丸、“生物弹”或籽10放入空心载体12或送递装置内部。所述丸、“生物弹”或籽10可以是将能放入空心载体12内部的任何尺寸。
根据本发明,在发生所述丸、“生物弹”或籽10的生物侵蚀时,产生了一种活性剂。
本发明还预期,空心载体12还可从本发明的聚合物、化合物和/或组合物形成,以至在空心载体12的生物侵蚀时可释放一种活性剂和/或可释放它的内含物(例如,本发明的丸、“生物弹”或籽)。
在一个优选的实施方案中,丸、“生物弹”或籽10是从含有与促卵泡激素(F.S.H.)和/或黄体生成素(L.H.)掺合的水杨酸的本发明聚合物制备的,然后将它们放入生物可侵蚀空心载体12的空心腔或室内或者作为延效型制剂(例如Lupron Depot®)的部分供定时释放送递激素至多约96小时以便刺激排卵。
根据本发明,可将本发明的丸、“生物弹”或籽10和/或一个或多个含有本发明的丸、“生物弹”或籽10的空心载体12放在一个送递装置(例如注射器、气动放样器)中。可进一步给该送递装置装备一个可轴向滑动的套(例如柱塞)、防止送递装置在使用中移动的突出物(例如倒角的突出物)和柄。合适的载体和/或送递装置的实例包括,但不限于,美国专利Nos.6,001,385、5,989,214、5,549,560,WO 96/13300、WO 96/09070、WO 93/23110和EP 068053中描述的那些,将它们以其全文并入本文作参考。
例如,美国专利No.5,989,214和WO 96/133000描述了一种用来对人体或动物体注射药剂的装置,其中,将药剂放置在刚性载体中,其中,所述装置包括:一个可在其中运送载体的室,以及一条连接到该室用来将载体送入体内的通道,它包括固定器,用来相对于身体的皮肤固定所述通道的端头以防通道朝筒轴向的垂直方向移动,而且其中,根据一个实施方案,所述固定器是由在适合与身体皮肤接触的部分上形成的并且基本沿通道轴向延伸的倒角突出物构成的。美国专利No.5,549,560、WO 93/23110和EP 068053描述了一种用来对人和动物注射药剂的装置,其中,将药剂保持在刚性载体中,并且利用气压将所述载体透过皮肤带入体内,而且其中,在利用气压将所述刚性载体带入体内的过程中,相对身体保持将载体带入体内的装置。美国专利No.5,549,560、WO 93/23110和EP 068053还描述了一种用来对动物或人注射药剂的装置,其中,给出一个可放置含药剂的载体的室,一个连接到该室的筒和用来利用气压将载体通过该筒带入体内供注射的装置,其中,给出了当不压在身体上时阻止所述装置使用的装置。美国专利No.6,001,385和WO 96/09070描述了至少部分地从实质上完全变性的淀粉生产的“弹”,特别是植入物,适合作为以经皮方式将活性剂导入人体或动物体的载体。
本发明的微粒的治疗上有效剂量的范围(即,达到所需结果的必需剂量水平)将受给药途径、治疗对象和患者的状态的影响。这样,根据剂量要求,可作为每天一次剂量、每天几次、隔天一次、每周一次等给予本发明的微粒。将需要进行个体测定以确定所需的最佳剂量。
在形成医疗植入物或微粒或者涂到医疗植入物或微粒上或者形成用于医疗植入物的特定包衣以前或同时,可将本发明的聚合物、化合物和/或组合物与其它配料组合或掺合。合适的添加剂实例包括,但不限于,稳定剂,机械稳定剂,增塑剂,固化剂,乳化剂,其它聚合物,包括其它生物相容性和生物可降解的聚合物(例如,美国专利申请No.09/917,231和PCT申请No.US/01/23740中给出的生物相容性和生物可降解的聚酐,美国专利申请No.09/917,595和PCT申请No.US/01/23748中给出的生物相容性和生物可降解的聚偶氨化合物,美国专利申请No.09/917,194和PCT申请No.US/01/23747中给出的生物相容性和生物可降解的聚酯、聚硫酯和聚酰胺,将它们各自以其全文并入本文作参考),射线不透性物质和/或放射同位素物质(例如硼、碘等),栓剂,以及其它诊断剂或治疗剂或药物。
添加的组分可能增强所述聚合物、化合物和/或组合物自身、医疗植入物自身的稳定性和/或可能增强诊断或治疗效果和/或可能增强或赋予诊断活性。例如,如果添加的组分是一种诊断剂或治疗剂或药物,聚合物的生物侵蚀不但产生活性剂,而且还释放诊断剂或治疗剂。在另一个实例中,通过添加射线不透性物质,在插入医疗植入物期间和/或以后(例如血管成形术、牙科应用、关节注射等)应当能目视观察靶向区(例如肿瘤位点、肿瘤)和医疗植入物(例如导管)。在另一个实例中,射线不透性物质还可用来控制和/或增强医疗植入物的生物侵蚀,从而控制和/或增强通过捕获中子产生热而产生活性剂。
添加的组分还可能增强医疗植入物(例如碳纤维)的总机械稳定性。应用的添加剂类别将会随之而变和取决于所需性能和用途。
活性
本发明的聚合物产生特定的治疗效果的能力可应用本领域技术人员熟知的体外和体内药物模型来确定。
将所有公布、专利和专利文献都犹如各自并入本文作参考那样并入本文作参考。已参照各特定的和优选的实施方案描述了本发明。然而,应懂得,可进行很多改变和修饰而保持在本发明的精神和范围内。LH/FSH→释放
96小时刺激动物排卵(混入多聚体阿司匹林)
无针注射—例如PowerJect
代替,解决如何用能被作为固体形式注射的治疗剂(例如疫苗)制备丸—“生物弹”—可生物降解丸
用聚乳酸酯聚合物制备中空“针”
实际尺寸
能填充w/疫苗???等
实际尺寸
气动放样器—药筒装有数以百计的“针”—还自动消毒注射部位(w/局部抗菌喷雾)
药丸—
我们的聚合物药物(例如在
它们的“针”内的多聚体阿司匹林针针快速生物降解(小时)
Claims (2)
1.一种包含一种聚合物的医疗装置,所述聚合物包含一条主链,其中,所述主链包含一个酸酐键,而且其中,所述主链包含一个或多个将在所述聚合物水解时产生生物活性化合物的基;条件是,该生物活性化合物不是邻羟基芳基羧酸。
2.一种包含一个医疗装置和一种聚合物的医疗植入物,所述聚合物包含一条主链,其中,所述主链包含一个酸酐键,而且其中,所述主链包含一个或多个将在所述聚合物水解时产生生物活性化合物的基;条件是,该生物活性化合物不是邻羟基芳基羧酸,其中,所述聚合物被应用到所述医疗装置上。
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WO1999012551A1 (en) * | 1997-09-09 | 1999-03-18 | The Procter & Gamble Company | Method of increasing bone volume using non-naturally-occurring fp selective agonists |
US6200974B1 (en) * | 1997-10-24 | 2001-03-13 | Zeneca Limited | Phenanthroline derivatives |
US6685928B2 (en) * | 1999-12-07 | 2004-02-03 | Rutgers, The State University Of New Jersey | Therapeutic compositions and methods |
-
2003
- 2003-02-06 EP EP03731002A patent/EP1478314A2/en not_active Withdrawn
- 2003-02-06 JP JP2003570767A patent/JP2006501138A/ja active Pending
- 2003-02-06 WO PCT/US2003/003728 patent/WO2003072020A2/en not_active Application Discontinuation
- 2003-02-06 US US10/504,121 patent/US20060013851A1/en not_active Abandoned
- 2003-02-06 CA CA002475253A patent/CA2475253A1/en not_active Abandoned
- 2003-02-06 KR KR10-2004-7012248A patent/KR20050013529A/ko not_active Application Discontinuation
- 2003-02-06 AU AU2003241273A patent/AU2003241273A1/en not_active Abandoned
- 2003-02-06 CN CNA038074877A patent/CN1642503A/zh active Pending
Also Published As
Publication number | Publication date |
---|---|
CA2475253A1 (en) | 2003-09-04 |
WO2003072020A2 (en) | 2003-09-04 |
WO2003072020A9 (en) | 2004-03-11 |
KR20050013529A (ko) | 2005-02-04 |
AU2003241273A1 (en) | 2003-09-09 |
WO2003072020A3 (en) | 2004-02-05 |
EP1478314A2 (en) | 2004-11-24 |
JP2006501138A (ja) | 2006-01-12 |
US20060013851A1 (en) | 2006-01-19 |
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