CN1258221A - 包含聚(环脂族磷酸酯)化合物的可生物降解组合物,制品,及其应用方法 - Google Patents
包含聚(环脂族磷酸酯)化合物的可生物降解组合物,制品,及其应用方法 Download PDFInfo
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- CN1258221A CN1258221A CN98805636A CN98805636A CN1258221A CN 1258221 A CN1258221 A CN 1258221A CN 98805636 A CN98805636 A CN 98805636A CN 98805636 A CN98805636 A CN 98805636A CN 1258221 A CN1258221 A CN 1258221A
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Abstract
本发明公开了生物降解性、流动性或挠性的聚合物组合物,它包含具有式(Ⅰ)所示循环单体单元的聚合物,其中:R和R’各自独立地为直链或支链亚烷基,是未取代的或被一个或多个非干扰性取代基取代;L是二价环脂族基;R”选自H、烷基、烷氧基、芳基、芳氧基、杂坏或杂环氧基;n为5-1,000,其中所述可生物降解聚合物在生物降解前后都是生物相容的。在一个实施方案中,R、R’和R”中的一个或多个是生物活性物质。还公开了除含该聚合物外还含有生物活性物质的无定形组合物,以及利用该组合物控制释放生物活性物质的方法。
Description
发明背景
1.发明领域
本发明涉及在体内降解为无毒残余物的、生物降解性聚(磷酸酯)组合物,特别是在该聚合物主链中含有环脂族结构的那些。本发明组合物特别可用作局部、药物控制释放系统用的挠性或流动性材料。
2.在先技术的描述
生物相容性聚合材料已广泛用于释放治疗药物和医疗植入物应用。如果医疗植入物欲用作药物释放或其他控制释放系统,采用生物降解性聚合载体是一种有效的以局部和可控方式释放治疗剂的方法,参见Langer等,“作为生物活性剂控制释放用载体的聚合物的化学和物理结构”,J.Macro.Science,Rev.Macro.Chem.Phys.,C23(1),61-126(1983)。这样,所需的药物总量较小,且可将毒副作用减至最小。在某些时候聚合物已用作将治疗剂局部和持续释放的载体。参见Leong等,“聚合物控制药物释放”,《先进药物释放评论》(AdvancedDrug Delivery Rev.),1:199-233(1987);Langer,“新的药物释放方法”,《科学》249:1527-33(1990),和Chien等,《新的药物释放系统》(1982)。这样的释放系统提供了增强治疗功效和减小总体毒性的可能性。
当使用非生物降解性聚合物基质时,使治疗剂释放的步骤是水扩散到基质中,治疗剂溶解,和该治疗剂通过该基质的通道扩散出来。结果,以可溶态存在的治疗剂的平均停留时间一般是在非生物降解基质中大于在可生物降解基质中,因为当基质可生物降解时,就不再需要通过该基质通道的通路。
由于许多药剂的半衰期短,在它们释放前,非生物降解基质中的治疗剂就会分解或失活。这个问题对于许多生物大分子例如蛋白质和较小的多肽来说尤其显著,因为这些分子一般是水解不稳定的,且具有显著低的通过多数聚合物基质的渗透性。在非生物降解基质中,许多生物大分子甚至开始聚集并从溶液中沉淀出来,阻断了从该载体基质中扩散出来所需的通道。
这些问题通过使用生物降解性刚性基质得到了部分缓和,除了一些扩散释放外,主要是通过该固体聚合物基质的降解使治疗剂控制释放。已研究作为可能的固体生物降解物质的几类合成聚合物的实例包括聚酯(Pitt等,“基于脂族聚酯的生物降解药物释放系统:用于避孕药和麻醉药拮抗剂”,《生物活性物质的控制释放》,19-44(RichardBaker编,1980);聚氨基酸和伪-聚氨基酸(Pulapura等,“医疗应用的可生物吸收聚合物的发展趋势”,《生物材料应用杂志》6:1,216-50(1992);聚氨酯(Bruin等,“人造皮肤中的生物降解赖氨酸二异氰酸酯基聚(乙交酯-共-ε己内酯)尿烷网状构造”,《生物材料》11:4,291-95(1990);聚(原酸酯)(Heller等,“炔诺酮从聚(原酸酯)的释放”,《聚合物工程科学》21:11,727-31(1981);和聚酐(Leong等,“用于生物活性剂的控制释放的聚酐”,《生物材料》7:5,364-71(1986)。
具有磷酸键的聚合物,叫做聚磷酸酯、聚膦酸酯和聚亚磷酸酯,是已知的。参见Penczek等,《聚合物合成手册》第17章:“含磷聚合物”,(Hans R.Kricheldorf编,1992年)。这三类化合物的结构分别如下所示,每种都带有与该磷原子相连的不同侧链: 聚磷酸酯 聚磷酸酯 聚亚磷酸酯
这些聚合物的多用途来自磷原子的多用途,它们对于反应的多重性是已知的。其键合可涉及3p轨道或各种3s-3p杂化轨道;因为可进入d轨道,因此spd杂化轨道也是可能的。因此,通过改变R或R’基就可容易地改变聚磷酸酯的物理化学性能。该聚合物的生物降解性主要是由于该聚合物主链中的生理不稳定磷酸酯键。通过处理主链或侧链,可得到宽范围的生物降解率。
聚磷酸酯的另一个特性是官能侧基的有效性。由于磷可能是五价的,药物分子或其他生物活性物质可以化学键合到该聚合物上。例如,带有-O-羧基的药物可以经磷酸酯键与该磷原子偶合,它是可水解的。参见Leong,美国专利5,194,581和5,256,765。主链中的P-O-C基也降低了该聚合物的玻璃转化温度,并且重要的是,使之能溶解于常用有机溶剂,这是易于特性描述和加工所期望的。
但是,使用大多数已知生物降解聚合物包括那些磷酸酯的药物释放系统已是刚性物质。在这种情况下,药物被加入到聚合物中,并将该混合物塑造成一定形式,诸如圆筒状,圆盘状,或植入用纤维。
然而,蛋白质和其他大的生物分子仍难以从刚性生物降解物中释放,因为这些较大的分子特别不稳定,且一般与该固体聚合物基质载体一起降解。更特别的是,当给药后聚合物开始降解时,随着该聚合物成为离子化的、质子化的或水解了的,该聚合物的断裂副产物造成高浓度的微环境。在这些条件下,蛋白质容易变性或降解,就不再能用于治疗目的。
另外,在制备刚性药物释放系统的过程中,生物活性物质如蛋白质一般承受极大压力。必需的制造步骤可包括过量接触热,极大pH值,大量有机溶剂,交联剂,冷冻和干燥。制造或制备完后,该药物释放系统在给药前必须储存一定延续时间,关于蛋白质在固体生物降解释放系统中的长期稳定性,可得到的信息很少。
刚性聚合物可以以小颗粒如微球或微胶囊的形式用注射器或导管插入身体里。但是,由于它们仍然是固体颗粒,它们没有形成连续而近乎均匀的整体基质,而这往往是优选释放图所需要的。
此外,用这些聚合物制备并含有将要释放到体内的生物活性物质的微球或微胶囊往往难以大规模生产。大多数微囊包封过程涉及高温并要接触有机溶剂,这些步骤有可能损害蛋白质的生物活性。另外,它们的储存经常存在问题,并且注射后,它们的颗粒性质会引起注射器阻塞和/或注射到软组织中的小颗粒会对该组织产生刺激。
Dunn等人的美国专利5,278,201;5,278,202;和5,340,849中公开了一种热塑性药物释放系统,其中将固态的、直链的、生物降解性聚合物或共聚物溶于溶剂中形成液体溶液。一旦将该聚合物溶液加入到有足够多水的体内,溶剂就从该聚合物中逸散或扩散,从而使该聚合物凝结或固化为固体物质。但是,该系统需要溶剂的存在,并且要找到具有可接受的生物相容性的足够无毒的有机溶剂是困难的。
因此,需要能提供可用于体内释放各种不同生物活性物质、包括疏水性药物和甚至是庞大的大分子化合物如医疗用蛋白质的、挠性或流动性生物降解组合物的组合物和方法,优选不需要存在大量有机溶剂。还需要能提供可以对软组织周围的损伤最小的方式控制释放的生物降解聚合物组合物。
Coover等人的美国专利3,271,329中公开了用二烷基或二芳基亚磷酸氢盐和某些二醇化合物如1,4-环己烷二甲醇制备的有机磷聚合物。参见第1栏,24-31行。Vandenberg等人的美国专利3,655,585中公开了具有至少一个下式表示的循环单元的磷聚合物:
其中R可以是烷基,而Z可以是亚烷基如亚环己基。参见第1栏,28-55行。Herwig等人的美国专利3,875,263中公开了具有环亚烷基部分例如1,4-亚甲基-环己烷的二次膦酸酯。参见第1栏,18-37行,和第2栏,第13行。
然而,所有这些专利都提出,这些物质和用这些物质制备的聚合物组合物应挤压或模塑成制品或纺织成纤维(Coover等人);用作润滑油、汽油、和合成树脂或其他聚合物的添加剂(Vandenberg等人,和Herwig等人);或者用作涂料化合物(Herwig等)。本领域技术人员已知这些化合物主要用于带来高的耐火性和防火性能(Coover等,和Herwig等),或用于提高对氧化和热的稳定性,以及用于改善冲击强度(Vanderberg等)。
发明概述
现已发现,用聚(环脂族磷酸酯)化合物制成的聚合物组合物能为甚至是大和/或庞大的生物大分子,包括疏水性药物和甚至是大和庞大的生物大分子如医疗用蛋白质提供合宜的挠性或可流动载体。本发明的生物降解聚合物组合物包含具有式I显示的循环单体单元的聚合物:其中:
R和R’各自独立地为直链或支链脂族基,是未取代的或被一个或多个非干扰性取代基取代;
L是二价环脂族基;
R”选自H、烷基、烷氧基、芳基、芳氧基、杂环或杂环氧基;和
n为5-1,000其中该生物降解聚合物组合物在生物降解前后都是生物相容的。在一个特别优选的实施方案中,R、R’和R”中的一个或多个是以能在生理学环境中释放的形式存在的生物活性物质。
本发明还包含可用于植入、注射或者可完全或部分置于体内的挠性制品,该制品包含生物降解性、流动性或挠性的聚合物组合物,该组合物包含具有式I所示的循环单体单元的聚合物,其中R、R’、R”、L和n如上定义。
在本发明的另一个实施方案中,提供了用于生物活性物质控制释放的方法,它包含以下步骤:
(a)将生物活性物质与具有式I所示循环单体单元的生物降解聚合物结合:其中R、R’、L、R”和n如上定义,形成可植入或可注射的聚合物组合物;和
(b)将在步骤(a)中形成的聚合物组合物部分或完全置于体内的预选定部位,以便该聚合物组合物至少部分与生物液体接触。由于本发明组合物优选是粘性的、流动性“凝胶样”物质或挠性物质,因此它们可用于释放各种各样的药物,例如,从疏水性药物如紫杉醇到大的水溶性大分子如蛋白质。即使当本发明的组合物是不可流动的时候,它仍然是挠性的,并可允许至少部分大的蛋白质在降解前通过基质扩散。因此,本发明提供了一种释放系统,它使用方便,并能以有效方式释放大的生物大分子。
附图的简要描述
图1显示了用31P-NMR和1H-NMR确定的P(反式-CHDM-HOP)的结构。
图2显示了P(顺式-/反式-CHMD-HOP)的色谱图和分子量分布。
图3A显示了作为P(反式-CHDM-HOP)频率的函数的活性能量图,图3B显示了相应粘度的温度依赖性。
图4A显示了培养72小时后在P(CHDM-HOP)表面生长的HEK293细胞,图4B显示了培养72小时后在TCPS表面生长的HEK293细胞。
图5代表侧链结构对在磷酸盐缓冲溶液中的本发明的三种聚(磷酸酯)的体内降解速率的作用图。
图6显示了从载荷率为33%的聚合物P(CHDM-HOP)中释放的生物大分子FITC-BSA的释放曲线。
图7代表作为30%、10%和1%载荷水平的函数的、FITC-BSA的体外释放动力学图。
图8代表侧链结构对具有10%载荷水平的FITC-BSA的蛋白释放动力学的体外作用图。
图9显示了从P(CHDM-HOP)中释放的低分子量药物(阿霉素、顺铂、和5-氟尿嘧啶)的释放。
图10代表从P(CHDM-HOP)基质中同时释放的顺铂和阿霉素的释放图。
图11代表作为时间函数的从在磷酸盐缓冲液中的P(CHDM-HOP)基质释放的IL-2的累积百分数。
图12显示了从在磷酸盐缓冲液中的P(CHDM-HOP)基质释放的IL-2的累积百分数的校正曲线。
图13对比了作为皮下丸剂给药或分散于P(CHDM-HOP)基质中给药的IL-2的药动学。
图14显示了Balb/c小鼠的皮下注射部位的组织学检查结果。
图15显示了在体内黑素瘤肿瘤模型中,肿瘤移植四周后小鼠的肿瘤大小分布。
图16显示了在体内黑素瘤肿瘤模型中,肿瘤移植六周后小鼠的肿瘤大小分布。
图17显示了在体内黑素瘤肿瘤模型中,四个不同治疗组的作为时间函数的存活百分数。
图18显示了本发明的两种聚合物组合物的释放曲线,一个包含在聚合物P(CHDM-EOP)中的化学治疗剂紫杉醇,另一个包含在聚合物P(CHDM-HOP)中的紫杉醇。
图19显示了从三种不同P(CHDM-HOP)/利多卡因混合物样品中释放的利多卡因的体外释放曲线。
图20A显示了作为培养时间的函数的利多卡因的体外释放累积量,图20B显示了作为时间的平方根的函数的利多卡因的释放。
图21描绘了体内注射了在P(CHDM-HOP)中或在盐水溶液中的25mg利多卡因后,最大感受伤害作用对时间的百分数。
图22描绘了注射了在P(CHDM-HOP)中或在盐水溶液中的25mg利多卡因后,最大运动机能作用对时间的百分数。
图23显示了在注射了25mg利多卡因的盐水溶液后,注射了在P(CHDM-HOP)中的25mg利多卡因后,以及注射了在P(CHDM-HOP)中的50mg利多卡因后,血浆中的利多卡因浓度。
发明详述本发明的聚合物组合物
本文中所用的术语“脂族”是指直链、支链或环状烷烃、烯烃或炔烃。本发明的聚(环脂族磷酸酯)组合物中优选具有约1到20个碳原子的直链或支链脂族基。优选的环脂族基可以有一个或多个不饱和部位,即双键或三键,但本质上不是芳族的。
本文中所用的术语“芳基”是指具有4n+2π电子的不饱和环碳化合物。本文中所用的术语“杂环”是指具有一个或多个除了环上碳原子以外的环原子,如氮、氧或硫原子的饱和或不饱和环化合物。
本文中所用的术语“非干扰性取代基”的意思是指不与该单体反应的取代基;不催化、终止或干扰该聚合反应的取代基;以及不通过分子内或分子间反应而与所得聚合物链反应的取代基。
本发明的可生物降解和可注射的聚合物组合物包含具有式I所示循环单体单元的聚合物:其中R和R’各自独立地为直链或支链脂族基,是未取代的或被一个或多个非干扰性取代基取代。R和R’各自可以是任何脂族部分,只要该部分不会对该聚合物的聚合或生物降解反应造成不良干扰。
优选的是,R和R’具有约1到20个碳原子。例如,R和R’各自可以是亚烷基,诸如亚甲基,亚乙基,1,2-二甲基亚乙基,亚正丙基,亚异丙基,2-甲基亚丙基,2,2-二甲基亚丙基,或亚叔丁基,亚正丁基,亚叔戊基,亚正己基,亚正庚基,等等;亚烯基,诸如亚乙烯基,亚丙烯基,亚十二碳烯基,等等;亚炔基,诸如亚丙炔基,亚己炔基,亚十八炔基,等等;被非干扰性取代基取代的脂族基,例如羟基-、卤素-或氮-取代的脂族基。不过,优选的是,R和R’各自为支链或直链亚烷基,更优选的是,为具有1至7个碳原子的亚烷基。最优选的是,R为亚甲基或亚乙基。
在本发明的一个实施方案中,R、R’各自,或者R和R’均为以能释放到生理学环境中的形式存在的生物活性物质。当在此方式中该生物活性物质是该聚(磷酸酯)主链的一部分时,它作为由本发明组合物降解形成的聚合物基质释放。
一般而言,可用于本发明组合物的生物活性物质非常广泛。术语“生物活性物质”非限制性包括:药物;维生素;矿物质添加剂;用于治疗、预防、诊断、治愈或减轻疾病或病情的物质;影响身体结构或功能的物质;或在置于预定生理学环境中后成为生物活性或活性更高的药物前体。这些活性物质可以描述为单一个体或多个个体的混合物。
各个种类的生物活性物质的非限制性实例包括下列扩展的治疗剂:β-肾上腺素能阻滞剂,合成代谢剂,雄性类固醇,抗酸剂,抗哮喘药,抗变态反应药,抗胆固醇血药和抗脂质药,抗胆碱能药和拟交感神经药,抗凝剂,抗惊厥剂,止泻剂,止吐剂,抗高血压药,抗感染药,抗炎药诸如类固醇、非类固醇性抗炎药,抗疟药,抗躁狂药,止恶心药,抗肿瘤药,抗肥胖药,抗震颤麻痹药,退热剂和镇痛剂,镇痉药,抗血栓形成药,抗尿酸血药(anti-uricemic agents),抗心绞痛药,抗组胺药,镇咳药,食欲抑制剂,苯并菲啶生物碱,生物制剂,心脏作用药,大脑扩张药,冠脉扩张药,减充血剂,利尿剂,诊断剂,红细胞生成剂,雌激素,祛痰药,胃肠镇静剂,体液药,高血糖药,安眠药,低血糖药,离子交换树脂,缓泻药,矿物质添加剂,缩瞳药(miotics),粘液溶解剂,神经肌肉药,营养物质,外周血管舒张药,促孕药,前列腺素,精神兴奋药,治疗精神病药,镇静剂,兴奋剂,甲状腺药和抗甲状腺药,安定药,子宫松弛药,维生素,抗原物质,和药物前体。
上述各类中有用的生物活性物质的具体实例包括:(a)抗肿瘤药,如雄激素抑制剂,抗代谢物,细胞毒性剂,和免疫调节剂;(b)镇咳药,如右甲吗喃,氢溴酸右甲吗喃,那可丁,枸环戊酯,和盐酸chlorphedianol;(c)抗组胺药,如马来酸氯苯那敏,酒石酸苯茚达明,马来酸新安特甘,琥珀酸杜克西拉明,和柠檬酸苯托沙敏;(d)减充血剂,如盐酸苯福林,盐酸去甲麻黄碱,盐酸伪麻黄碱,和麻黄碱;(e)各种生物碱,如磷酸可待因,硫酸可待因,和吗啡;(f)矿物质添加剂,如氯化钾,氯化锌,碳酸钙,氧化镁,以及其他碱金属和碱土金属盐;(g)离子交换树脂,如考来烯胺;(h)抗心律失常药,N-乙酰普鲁卡因酰胺;(i)退热剂和镇痛剂,如扑热息痛,阿司匹林,和布洛芬;(j)食欲抑制剂,如盐酸苯丙醇胺或咖啡因;(k)祛痰药,如愈创木酚甘油醚;(1)抗酸剂,如氢氧化铝和氢氧化镁;(m)生物制剂,如肽,多肽,蛋白质和氨基酸,激素,干扰素或细胞因子,以及其他生物活性肽类混合物,诸如hGH,tPA,降钙素,ANF,EPO和胰岛素;(n)抗感染药,如杀真菌剂,抗病毒剂,防腐剂和抗生素;和(m)脱敏药和抗原物质,如用于疫苗应用的那些。
更具体地说,有用的生物活性物质的非限制性实例包括下列治疗剂种类:镇痛剂,如非类固醇性抗炎药,鸦片制剂兴奋剂和水杨酸盐;抗组胺药,如H1-受体阻滞剂和H2-受体阻滞剂;抗感染药,如抗蠕虫药,抗厌氧菌药,抗生素,氨基糖甙类抗生素,抗真菌类抗生素,头孢菌素类抗生素,大环内酯类抗生素,各种β-内酰胺类抗生素,青霉素类抗生素,喹诺酮类抗生素,磺胺类抗生素,四环素类抗生素,抗分支杆菌药,抗结核的抗分支杆菌药,抗原生动物药,抗疟的抗原生动物药,抗病毒剂,抗逆转录病毒剂,杀疥螨药,和抗泌尿感染剂;抗肿瘤药,如烷化剂,氮芥类烷化剂,亚硝基脲类烷化剂,抗代谢物,嘌呤类似物抗代谢物,嘧啶类似物抗代谢物,激素类抗肿瘤药,天然抗肿瘤药,抗生素类天然抗肿瘤药,和长春花生物碱类天然抗肿瘤药;自主神经药,如抗胆碱能药,抗毒蕈碱抗胆碱能药,麦角生物碱,拟副交感神经药,胆碱能兴奋剂类拟副交感神经药,胆碱酯酶抑制剂类拟副交感神经药,抗交感神经药,α-受体阻滞剂类抗交感神经药,β-受体阻滞剂类抗交感神经药,拟交感神经药,和肾上腺素能兴奋剂类拟交感神经药;心血管药,如抗心绞痛药,β-受体阻滞剂类抗心绞痛药,钙通道阻滞剂类抗心绞痛药,硝酸酯类抗心绞痛药,抗心律失常药,强心甙类抗心律失常药,第I类抗心律失常药,第II类抗心律失常药,第III类抗心律失常药,第IV类抗心律失常药,抗高血压药,α-受体阻滞剂类抗高血压药,血管紧张素转化酶抑制剂(ACE抑制剂)类抗高血压药,β-受体阻滞剂类抗高血压药,钙通道阻滞剂类抗高血压药,作用中枢的肾上腺素能类抗高血压药,利尿剂类抗高血压药,外周血管舒张剂类抗高血压药,抗血脂药,胆酸螯合剂类抗血脂药,HMG-CoA还原酶抑制剂类抗血脂药,影响肌收缩力药(inotropes),强心甙类影响肌收缩力药,和溶解血栓药;皮肤病药,如抗组胺药,抗炎药,皮质类固醇类抗炎药,止痒药/局麻药,局部抗感染药,抗真菌类局部抗感染药,抗病毒类局部抗感染药,和局部抗肿瘤药;电解和肾药,如酸化剂,碱化剂,利尿剂,碳酸酐酶抑制剂类利尿剂,环状利尿剂,渗压性利尿剂,钾节制性利尿剂,噻嗪类利尿剂,电解质置换剂,和促尿酸尿药;酶,如胰酶和血栓溶解酶;胃肠药,如止泻剂,止吐剂,胃肠抗炎药,水杨酸酯(盐)类胃肠抗炎药,抗酸性抗溃疡药,胃酸泵抑制剂类抗溃疡药,胃粘膜抗溃疡药,H2-受体阻滞剂类抗溃疡药,胆结石溶解药,助消化药,催吐药,缓泻药和粪便软化药,和促动力药;全身麻醉剂,如吸入型麻醉剂,卤化吸入型麻醉剂,静脉内麻醉剂,巴比妥类静脉麻醉剂,苯并二氮杂类静脉麻醉剂,和鸦片制剂兴奋剂静脉麻醉剂;血液病药,如抗贫血药,生血性抗贫血药,絮凝剂,抗凝剂,止血性絮凝剂,血小板抑制剂类絮凝剂,血栓溶解酶类絮凝剂,和血浆容积膨胀剂;激素和激素调节剂,如堕胎药,肾上腺药,皮质类固醇类肾上腺药,雄激素,抗雄激素,抗糖尿病药,磺酰脲类抗糖尿病药,抗低血糖药,口服避孕药,孕激素类避孕药,雌激素,生育药,催产剂,甲状旁腺素制剂,脑垂体激素,孕激素,抗甲状腺素制剂,甲状腺素,和子宫收缩抑制剂;免疫生物制剂,如免疫球蛋白,免疫抑制剂,类毒素,和疫苗;局部麻醉剂,如酰胺类局部麻醉剂和酯类局部麻醉剂;肌与骨骼药,如抗痛风类抗炎药,皮质类固醇类抗炎药,金化合物类抗炎药,免疫抑制剂类抗炎药,非类固醇性抗炎药(NSAID),水杨酸酯(盐)类抗炎药,骨胳肌松弛药,神经肌肉阻滞剂类骨胳肌松弛药,和反向神经肌肉阻滞剂类骨胳肌松弛药;神经病药,如抗惊厥药,巴比妥类抗惊厥药,苯并二氮杂类抗惊厥药,抗偏头痛药,抗震颤麻痹药,抗眩晕药,鸦片制剂兴奋剂,和鸦片制剂拮抗药;眼用药,如抗青光眼药,β-受体阻滞剂类抗青光眼药,缩瞳类抗青光眼药,散瞳药,肾上腺素能兴奋剂类散瞳药,抗毒蕈碱类散瞳药,眼用麻醉剂,眼用抗感染药,眼用氨基糖甙类抗感染药,眼用大环内酯类抗感染药,眼用喹诺酮类抗感染药,眼用磺胺类抗感染药,眼用四环素类抗感染药,眼用抗炎药,眼用皮质类固醇类抗炎药,和眼用非类固醇性抗炎药(NSAID);精神病治疗药,如抗抑郁药,杂环类抗抑郁药,单胺氧化酶抑制剂(MAOI),选择性5-羟色胺重摄取抑制剂(SSRI),三环类抗抑郁药,抗躁狂药,抗精神病药,吩噻嗪类抗精神病药,抗焦虑药,镇静剂和安眠药,巴比妥类镇静剂和安眠药,苯并二氮杂类抗焦虑药,镇静剂,和安眠药,和精神兴奋药;呼吸疾病治疗药,如镇咳药,支气管扩张药,肾上腺素能兴奋剂类支气管扩张药,抗毒蕈碱类支气管扩张药,祛痰药,粘液溶解药,呼吸系统抗炎药,和呼吸系统皮质类固醇类抗炎药;毒理学药,如解毒剂,重金属拮抗药/螯合剂,物质滥用治疗剂,遏制性物质滥用治疗剂,和戒断性物质滥用治疗剂;矿物质;和维生素,如维生素A,维生素B,维生素C,维生素D,维生素E,和维生素K。
上述各类中有用的生物活性物质的优选种类包括:(1)非类固醇性抗炎药(NSAID)类镇痛剂,如双氯芬酸,布洛芬,酮洛芬,和萘普生;(2)鸦片制剂兴奋剂镇痛剂,如可待因,芬太尼,氢吗啡酮,和吗啡;(3)水杨酸酯(盐)类镇痛剂,如阿司匹林(ASA)(肠溶衣型ASA);(4)H1-受体阻滞剂类抗组胺药,如氯马斯汀和特非那定;(5)H2-受体阻滞剂类抗组胺药,如西咪替丁,法莫替丁,尼唑替丁,和雷尼替丁;(6)抗感染药,如莫匹罗星;(7)抗厌氧菌类抗感染药,如氯霉素和克林霉素;(8)抗真菌抗生素类抗感染药,如两性霉素B,克霉唑,氟康唑,和酮康唑;(9)大环内酯抗生素类抗感染药,如阿齐霉素和红霉素;(10)各种β-内酰胺抗生素类抗感染药,如氨曲南和亚胺培南;(11)青霉素抗生素类抗感染药,如萘夫西林,苯唑西林,青霉素G,和青霉素V;(12)喹诺酮抗生素类抗感染药,如环丙沙星和诺氟沙星;(13)四环素抗生素类抗感染药,如多西环素,米诺环素,和四环素;(14)抗结核的抗分支杆菌类抗感染药,如异烟肼(INH),和利福平;(15)抗原生动物类抗感染药,如阿托喹酮和达普宋;(16)抗疟的抗原生动物类抗感染药,如氯喹和息疟定;(17)抗逆转录病毒类抗感染药,如利妥那韦和齐多夫定;(18)抗病毒类抗感染药,如阿昔洛韦,更昔洛韦,干扰素α,和金刚乙胺;(19)烷化剂类抗肿瘤药,如卡铂和顺铂;(20)亚硝基脲类烷化剂类抗肿瘤药,如卡莫司汀(BCNU);(21)抗代谢物类抗肿瘤药,如甲氨蝶呤;(22)嘧啶类似物抗代谢物类抗肿瘤药,如5-氟尿嘧啶(5-FU)和吉西他滨;(23)激素类抗肿瘤药,如高舍瑞林,亮丙瑞林,和他莫昔芬;(24)天然抗肿瘤药,如阿地白介素,白介素-2;docetaxel,依托泊苷(VP-16),干扰素α,紫杉醇,和维A酸(ATRA);(25)抗生素类天然抗肿瘤药,如博莱霉素,更生霉素,柔红霉素,阿霉素,和丝裂霉素;(26)长春花生物碱类天然抗肿瘤药,如长春花碱和长春新碱;(27)自主系统药,如烟碱;(28)抗胆碱能类自主系统药,如苯托品和三己芬迪;(29)抗毒蕈碱的抗胆碱能类自主系统药,如阿托品和奥昔布宁;(30)麦角生物碱类自主系统药,如溴隐亭;(31)胆碱能兴奋剂类拟副交感神经药,如毛果芸香碱;(32)胆碱酯酶抑制剂类拟副交感神经药,如吡斯的明;(33)α-受体阻滞剂类抗交感神经药,如哌唑嗪;(34)β-受体阻滞剂类抗交感神经药,如阿替洛尔;(35)肾上腺素能兴奋剂类拟交感神经药,如沙丁胺醇和多巴酚丁胺;(36)心血管药,如阿司匹林(ASA)(肠溶衣ASA);(37)β-受体阻滞剂类抗心绞痛药,如阿替洛尔和普萘洛尔;(38)钙通道阻滞剂类抗心绞痛药,如硝苯地平和维拉帕米;(39)硝酸酯类抗心绞痛药,如二硝酸异山梨酯(ISDN);(40)强心甙类抗心律失常药,如地高辛;(41)第I类抗心律失常药,如利多卡因,美西律,苯妥英,普鲁卡因胺,和奎尼丁;(42)第II类抗心律失常药,如阿替洛尔,美托洛尔,普萘洛尔,和噻吗洛尔;(43)第III类抗心律失常药,如胺碘酮;(44)第IV类抗心律失常药,如地尔硫和维拉帕米;(45)α-受体阻滞剂类抗高血压药,如哌唑嗪;(46)血管紧张素转化酶抑制剂(ACE抑制剂)类抗高血压药,如卡托普利和依那普利;(47)β-受体阻滞剂类抗高血压药,如阿替洛尔,美托洛尔,纳多洛尔,和普萘洛尔;(48)钙通道阻滞剂类抗高血压药,如地尔硫和硝苯地平;(49)作用中枢的肾上腺素能类抗高血压药,如可乐定和甲基多巴;(50)利尿性抗高血压药,如阿米洛利,呋塞米,二氢氯噻(HCTZ),和螺内酯;(51)外周血管舒张剂类抗高血压药,如肼苯哒嗪和米诺地尔;(52)抗血脂药,如吉非贝齐和普罗布考;(53)胆酸螯合剂类抗血脂药,如考来烯胺;(54)HMG-CoA还原酶抑制剂类抗血脂药,如洛伐他汀和普伐他汀;(55)影响肌收缩力药,如氨力农,多巴酚丁胺,和多巴胺;(56)强心甙类影响肌收缩力药,如地高辛;(57)溶解血栓药,如阿克伐司(TPA),阿尼普酶,链激酶,和尿激酶;(58)皮肤科用药,如秋水仙碱,异维A酸,甲氨蝶呤,米诺地尔,维A酸(ATRA);(59)皮科用皮质类固醇类抗炎药,如倍他米松和地塞米松;(60)抗真菌的局部抗感染药,如两性霉素B,克霉唑,咪康唑,和制霉菌素;(61)抗病毒的局部抗感染药,如阿昔洛韦;(62)局部抗肿瘤药,如5-氟尿嘧啶(5-FU);(63)电解质和肾药,如乳果糖;(64)环状利尿剂,如呋塞米;(65)钾节制性利尿剂,如氨苯蝶啶;(66)噻嗪类利尿剂,如氢氯噻嗪(HCTZ);(67)促尿酸尿药,如丙磺舒;(68)酶如核糖核酸酶和脱氧核糖核酸酶;(69)溶解血栓酶,如阿克伐司,阿尼普酶,链激酶,和尿激酶;(70)镇吐药,如普鲁氯嗪;(71)水杨酸酯(盐)类胃肠抗炎药,如柳氮磺胺吡啶;(72)胃酸泵抑制剂类抗溃疡药,如奥美拉唑;(73)H2-受体阻滞剂类抗溃疡药,如西咪替丁,法莫替丁,尼唑替丁,和雷尼替丁;(74)助消化药,如胰脂肪酶;(75)促动力药,如红霉素;(76)鸦片制剂兴奋剂静脉麻醉剂,如芬太尼;(77)生血性抗贫血药,如红细胞生成素,非尔司亭(G-CSF),和沙莫司亭(GM-CSF);(78)絮凝剂,如抗血友病因子1-10(AHF 1-10);(79)抗凝剂,如华法令;(80)溶解血栓酶类絮凝剂,如阿克伐司,阿尼普酶,链激酶,和尿激酶;(81)激素和激素修饰剂,如溴隐亭;(82)堕胎药,如甲氨蝶呤;(83)抗糖尿病药,如胰岛素;(84)口服避孕药,如雌激素和孕激素;(85)孕激素类避孕药,如左炔诺孕酮和炔诺孕酮;(86)雌激素如缀合雌激素,葡糖醛酸己烯雌酚(DES),雌激素(雌二醇,雌酮,和硫酸雌酮哌嗪);(87)生育药,如氯米芬,人绒毛膜促性腺激素(HCG),和促卵泡激素;(88)甲状旁腺药,如降钙素;(89)脑垂体激素,如去氨加压素,高舍瑞林,催产素,和后叶加压素(ADH);(90)孕激素,如甲羟孕酮,炔诺酮,和孕甾酮;(91)甲状腺激素,如左甲状腺素;(92)免疫生物制剂,如干扰素β-1b和干扰素γ-1b;(93)免疫球蛋白,如免疫球蛋白IM、IMIG、IGIM和免疫球蛋白IV、IVIG、IGIV;(94)酰胺类局部麻醉剂,如利多卡因;(95)酯类局部麻醉剂,如苯佐卡因和普鲁卡因;(96)肌与骨骼的皮质类固醇类抗炎药,如倍氯米松,倍他米松,可的松,地塞米松,氢化可的松,和泼尼松;(97)肌与骨胳的抗炎性免疫抑制剂,如硫唑嘌呤,环磷酰胺和甲氨蝶呤;(98)肌与骨胳的非类固醇性抗炎药(NSAID),如双氯芬酸,布洛芬,酮洛芬,酮咯酸,和萘普生;(99)骨胳肌松弛药,如巴氯芬,环苯扎林,和地西泮;(100)反向神经肌肉阻滞剂类骨胳肌松弛药,如吡斯的明;(101)神经病药,如尼莫地平,利鲁唑,他克林,和噻氯匹定;(102)抗惊厥药,如卡马西平,加巴喷丁,拉莫三嗪,苯妥英,和丙戊酸;(103)巴比妥类抗惊厥药,如苯巴比妥和普里米酮;(104)苯并二氮杂类抗惊厥药,如氯硝西泮,地西泮,和劳拉西泮;(105)抗震颤麻痹药,如溴隐亭,左旋多巴,卡比多巴,和培高利特;(106)抗眩晕药,如美其敏;(107)鸦片制剂兴奋剂,如可待因,芬太尼,氢吗啡酮,美沙酮,和吗啡;(108)鸦片制剂拮抗药,如纳洛酮;(109)β-受体阻滞剂类抗青光眼药,如噻吗洛尔;(110)缩瞳性抗青光眼药,如毛果芸香碱;(111)眼科用氨基糖甙类抗感染药,如庆大霉素,新霉素,和妥布霉素;(112)眼科用喹诺酮类抗感染药,如环丙沙星,诺氟沙星,和氧氟沙星;(113)眼科用皮质类固醇类抗炎药,如地塞米松和泼尼松龙;(114)眼科用非类固醇性抗炎药(NSAID),如双氯芬酸;(115)抗精神病药,如氯氮平,氟哌啶醇,和利螺环酮;(116)苯并二氮杂类抗焦虑药、镇静剂和安眠药,如氯硝西泮,地西泮,劳拉西泮,奥沙西泮,和普拉西泮;(117)精神兴奋药,如苯哌啶醋酸甲酯和匹莫林;(118)镇咳药,如可待因;(119)支气管扩张药,如茶碱;(120)肾上腺素能兴奋剂类支气管扩张药,如沙丁胺醇;(121)呼吸系统的皮质类固醇类抗炎药,如地塞米松;(122)解毒药,如氟马西尼和纳洛酮;(123)重金属拮抗药/螯合剂,如青霉胺;(124)遏制型物质滥用治疗剂,如二硫化四乙秋兰姆,纳曲酮,和烟碱;(125)戒断型物质滥用治疗剂,如溴隐亭;(126)矿物质,如铁,钙和镁;(127)维生素B类化合物,如氰钴胺(维生素B12)和烟酸(维生素B3);(128)维生素C类化合物,如抗坏血酸;(129)维生素D类化合物,如骨化三醇。
除了上述药物以外,也可以使用下列不太常用的药:氯己定;在油中的雌二醇环戊丙酸酯;在油中的雌二醇戊酸酯;氟比洛芬;氟比洛芬钠;伊维菌素;左旋多巴;那法瑞林,和生长激素。
另外,也可以使用下列新药:重组β-葡聚糖;牛免疫球蛋白浓缩物;牛超氧化物歧化酶;包含5-氟尿嘧啶、肾上腺素、和牛胶原的制剂;重组水蛭素(r-Hir),HIV-1免疫原;人抗-TAC抗体;重组人生长激素(r-hGH);重组人血红蛋白(r-Hb);重组人美卡舍明(r-IGF-1);重组干扰素β-1a;来诺拉提(G-CSF);奥氮平;重组促甲状腺素(r-TSH);和托泊替堪。
另外,也可使用下列静脉产品:阿昔洛韦钠;阿地白介素;阿替洛尔;硫酸博莱霉素;人降钙素;鲑鱼降钙素;卡铂;卡莫司汀;更生霉素,盐酸柔红霉素;docetaxel;盐酸阿霉素;依泊丁α;依托泊苷(VP-16);5-氟尿嘧啶(5-FU);更昔洛韦钠;硫酸庆大霉素;干扰素α;醋酸亮丙瑞林;盐酸哌替啶;盐酸美沙酮;甲氨蝶呤钠;紫杉醇;盐酸雷尼替丁;硫酸长春花碱;和齐多夫定(AZT)。
另外,还可使用下列肽、蛋白质、和其他大分子,如白介素1到18,包括突变体和类似物;干扰素α、β和γ;促黄体素释放激素(LHRH)及类似物,促性腺素释放激素(GnRH),转化生长因子-β(TGF-β);成纤维细胞生长因子(FGF);肿瘤坏死因子α&β(TNF-α&β);神经生长因子(NGF);生长激素释放因子(GHRF);上皮生长因子(EGF);成纤维细胞生长因子同源因子(FGFHF);肝细胞生长因子(HGF);胰岛素生长因子(IGF);血小板衍生生长因子(PDGF);侵染抑制因子-2(IIF-2);骨形态发生蛋白1-7(BMP 1-7);生长抑素;胸腺素-α-1;γ-球蛋白;超氧化物歧化酶(SOD);和补体因子。
另一方面,该生物活性物质可以是由用交替戊糖和磷酸酯残基序列组成的骨架将核苷酸连接在一起形成的多核苷酸链组成的核酸。用于避免研制在基因疗法中用于将基因释放到病人体内的细胞基系统时的并发症的一种方式是,将逆转录病毒载体直接释放到靶细胞。例如,该技术已用于感染血管壁内皮细胞。本发明的聚合物和组合物可用于在体内将这种逆转录病毒载体和/或相关基因物质直接输送到其他部位,例如,释放到肺部,以治疗肺部疾病,如囊纤维变性,或用于治疗身体任何局部的肿瘤。
优选的是,该生物活性物质选自以下成员:肽,多肽,蛋白质,氨基酸,多糖,生长因子,激素,抗血管生成因子,干扰素或细胞因子,抗原物质,和药物前体。在一个特别优选的实施方案中,该生物活性物质是治疗用药或药物前体,最优选是选自以下成员的药物:化学治疗药和其他抗肿瘤药,如紫杉醇,抗生素,抗病毒药,抗真菌药,抗炎药,和抗凝剂,用于疫苗应用的抗原或相应的药物前体。
可以使用各种形式的生物活性物质。这些包括但不限于:不带电分子,分子络合物,盐,醚,酯,酰胺,等等,当它们被植入、注射或置于身体内时是具有生物活性的。
本发明的聚合物组合物中的L可以是任何二价环脂族基,只要它不干扰该组合物的聚合物的聚合或生物降解反应就行。有用的L基的具体实例包括未取代和取代的亚环烷基,如亚环戊基,2-甲基-亚环戊基,亚环己基,2-氯代亚环已基,等等;亚环烯基,如亚环己烯基,;具有在一个或多个侧链上的稠合或桥连附加环结构的亚环烷基,如亚四氢化萘基,亚十氢化萘基,和亚降蒎烷基;或类似基团。
本发明的聚合物组合物中的R”是烷基,烷氧基,芳基,芳氧基,杂环或杂环氧基残基。有用的R”烷基的实例包括甲基,乙基,正丙基,异丙基,正丁基,叔丁基,-C8H17,以及类似基团;被非干扰性取代基取代的烷基,如卤代基;相应的烷氧基;和与生物活性物质轭合形成悬垂药物释放系统的烷基。
当R”是烷基或烷氧基时,它优选含有约2至约20个碳原子,更优选含有约6至约15个碳原子。当R”是芳基或相应的芳氧基时,它一般含有约5至约14个碳原子,优选约5至约12个碳原子,并可选地可含有一个或多个彼此稠合的环。特别合适的芳族基的实例包括苯基,苯氧基,萘基,蒽基,菲基等。
当R”是杂环或杂环氧基时,它一般含有约5至约14个环原子,优选约5至约12个环原子,和一个或多个杂原子。合适的杂环基的实例包括呋喃,噻吩,吡咯,异吡咯,3-异吡咯,吡唑,2-异咪唑,1,2,3-三唑,1,2,4-三唑,噁唑,噻唑,异噻唑,1,2,3-噁二唑,1,2,4-噁二唑,1,2,5-噁二唑,1,3,4-噁二唑,1,2,3,4-噁三唑,1,2,3,5-噁三唑,1,2,3-二噁唑,1,2,4-二噁唑,1,3,2-二噁唑,1,3,4-二噁唑,1,2,5-噁三唑,1,3-氧杂噻唑(1,3-oxathiole),1,2-吡喃,1,4-吡喃,1,2-吡喃酮,1,4-吡喃酮,1,2-二噁英(1,2-dioxin),1,3-二噁英,吡啶,N-烷基吡啶鎓,哒嗪,嘧啶,吡嗪,1,3,5-三嗪,1,2,4-三嗪,1,2,3-三嗪,1,2,4-噁嗪,1,3,2-噁嗪,1,3,5-噁嗪,1,4-噁嗪,邻异噁嗪,对异噁嗪,1,2,5-噁噻嗪,1,2,6-噁噻嗪,1,4,2-噁二嗪,1,3,5,2-噁二嗪,氮杂,氧杂,硫杂,1,2,4-二氧杂,茚,异茚,苯并呋喃,异苯并呋喃,硫茚,异硫茚,吲哚,假吲哚,2-异苯唑,1,4-氮茚,吡喃并[3,4-b]-吡咯,异吲唑,吲噁嗪,苯并噁唑,苯甲酰亚氨,1,2-苯并吡喃,1,2-苯并吡喃酮,1,4-苯并吡喃酮,2,1-苯并吡喃酮,2,3-苯并吡喃酮,喹啉,异喹啉,1,2-苯并二嗪,1,3-苯并二嗪,萘吡啶,吡啶并[3,4-b]-吡啶,吡啶并[3,2-b]-吡啶,吡啶并[4,3-b]-吡啶,1,3,2-苯并噁嗪,1,4,2-苯并噁嗪,2,3,1-苯并噁嗪,3,1,4-苯并噁嗪,1,2-苯并异噁嗪,1,4-苯并异噁嗪,咔唑,xanthrene,吖啶,嘌呤,等等。优选的是,当R”为杂环或杂环氧基时,它选自以下成员:呋喃,吡啶,N-烷基吡啶,1,2,3-和1,2,4-三唑,茚,蒽,和嘌呤环。
在一个特别优选的实施方案中,R”是烷基,烷氧基,苯基,苯氧基,或杂环氧基,更优选是具有1至10个碳原子的烷氧基。最优选R”为乙氧基或己氧基。
另外,该侧链R”可以是悬垂附着在该聚合物主链上的生物活性物质,例如通过离子或共价键。在此悬垂系统中,该生物活性物质随着连接R”和磷原子的键在生理学条件下断开而释放。
数目“n”根据该聚合物的预期生物降解能力和释放特性,可在非常宽的范围内变化,但一般在约5至1,000之间变化。优选的是,n为约5至约500,最优选从约5至约200。
本发明组合物中所用的聚合物的分子量可以在宽范围内变化,但必须使该聚合物的分子量保持足够低,以维持其可流动或挠性状态。例如,重量平均分子量(Mw)一般在约2,000至约400,000道尔顿之间变化,优选从约2,000至约200,000道尔顿,最优选从约2,000至50,000道尔顿。数均分子量(Mn)也可在宽范围内变化,但一般在约1,000至约200,000道尔顿范围内,优选从约1,000至约100,000道尔顿,最优选从约1,000至约25,000道尔顿。
生物降解聚合物与非生物降解聚合物的不同在于它们可在体内治疗过程中降解。此过程一般涉及聚合物分解为其单体亚单元。原则上,本发明中所用的聚合物的最后水解断裂产物是环脂族二醇,脂族醇和磷酸酯。所有这些降解产物是潜在无毒的。但是,该水解的中间寡聚产物可以具有不同性能。因此,计划用于注射或完全或部分置于体内的生物降解聚合物,甚至是用明显无害的单体结构合成的,它们的毒理学一般也要在一个或多个毒性分析后确定。
对本领域普通技术人员来说,有许多不同的测试毒性和/或生物相容性的方法。不过,典型的体外毒性测定将用活性癌细胞如GT3TKB肿瘤细胞,按照以下方式进行:
将200微升各种浓度的降解聚合物产物置于接种了密度为104/孔的人胃癌细胞(GT3TKB)的96孔组织培养板中。这些降解聚合物产物和GT3TKB细胞一起培养48小时。测定结果可绘图为该组织培养孔中相对生长百分数对降解聚合物的浓度的曲线。
用于医疗用途例如用于药物释放系统的聚合物也可以通过公知的体内生物相容性试验来进行评价,例如通过皮下植入或注射至大鼠体内,以证实该系统产生水解但在植入部位没有明显的刺激或炎症反应发生。
本发明所用的生物降解聚合物最好是有足够的纯度使其本身具有生物相容性并且在生物降解时仍然保持生物相容性。术语“生物相容性”是指该生物降解产品或该聚合物本身是无毒的并且在注射或与血管组织密切接触时仅仅导致最小限度的组织刺激。由于本发明的聚合物组合物不需要有机溶剂的存在,因此可以更容易满足生物相容性的需要。
然而,为了容易合成、纯化和处理,本发明所用的聚合物优选能溶于一种或多种普通有机溶剂。普通的有机溶剂包括这样的溶剂如乙醇、氯仿、二氯甲烷、丙酮、乙酸乙酯、DMAC、N-甲基吡咯烷酮、二甲基甲酰胺和二甲亚砜。该聚合物优选能溶于至少一种上述溶剂。
本发明的聚合物还可包括其它生物相容性单体单元,只要这些单体单元不影响本发明的生物降解特性和所需要的流动特性。在设计定向药物释放所需要的精确释放特性,这些附加的单体单元可以赋予聚合物更大的挠性或者其它用途所需要的生物降解性精确速率。当应用这些附加的单体单元时,其用量必须足够小以确保生产的生物降解聚合物具有所需要的物理性质如粘度、流动性、挠性或形状。
这些附加的生物相容性单体的例子包括在下列其它聚合物中发现的循环单元:聚磷酸酯、聚丙交酯、聚乙交酯、聚己内酯、聚酸酐、聚酰胺、聚氨酯、聚酯酰胺、聚原酸酯、poly(dioxanones)、聚缩醛、聚缩酮、聚碳酸酯、聚原碳酸酯、poly(phosphazene)、聚羟丁酸酯、聚羟戊酸酯、聚(亚烷基乙二酸酯)、聚(亚烷基琥珀酸酯)、聚苹果酸、聚氨基酸、聚乙烯基吡咯烷酮、聚乙二醇、聚羟基纤维素、壳多糖、脱乙酰壳多糖和二元共聚物、三元共聚物或上述物质的组合物或混合物。
当应用附加的单体单元时,优选那些结晶程度较低和亲水性较高的物质。特别优选的具有所需要物理性质的循环单元是那些来源于下列物质的循环单元:聚丙交酯、聚己内酯和这些物质与乙交酯的共聚物,在这些物质中有更多的无定形区域。聚(环脂族磷酸酯)聚合物的合成
制备聚磷酸酯最通常的反应是二氯磷酸酯与二元醇之间脱盐酸的反应,反应式如下:许多聚磷酸酯也可通过经含合适取代的二氯化物和二元醇之间的缩合反应得到。
聚磷酸酯可以从二元醇经两步缩合反应制备。用20%摩尔过量的二甲基亚磷酸酯和乙二醇反应,然后高温除去低聚物的甲氧基磷酰基末端基团。
熔融缩聚反应的优点是它避免应用溶剂和添加大量的其它物质,从而使纯化更简单直接。它提供的聚合物分子量也适当。但常常需要在较严格的条件下进行,并且能引起链酸解反应(或者当水存在时发生水解反应)。如果聚合物骨架容易脱氢或氧化并接下来发生大基团重组,还可能发生不需要的由热引起的副反应如交联反应。
为了减少这些副反应的发生,聚合反应也可在溶液中进行。溶液聚缩合反应要求预聚合物和含磷组份能溶于一种共同的溶剂中。通常应用氯化有机溶剂如氯仿、二氯甲烷或二氯乙烷。
溶液聚合反应优选在等摩尔量反应物和化学计量量的酸接受体存在下进行,所述的酸接受体通常为叔胺如吡啶或三乙胺。得到的产品通常通过在非溶剂中沉淀来分离,再通过本领域一般技术人员已知的常规技术(例如用酸的水溶液如稀盐酸洗涤)来纯化以除去盐酸盐。
与熔融聚合反应相比,溶液聚合反应的反应时间一般更长一些,但由于整个过程可应用更温和的反应条件,减少了副反应的发生,还可在聚合物中加入较多的敏感性官能团。而且,溶液聚合反应不太可能达到不需要的高分子量物质。
当需要高反应速率时,可以应用界面缩聚反应。所用的温和反应条件最大减少了副反应的发生,因此在溶液方法中二元醇和二氯化物起始原料不需要应用化学计量量。然而,在碱性水相中可能发生酰氯化合物的水解反应。具有一定水溶性的敏感的二氯化物更容易发生水解反应而不是发生聚合反应。可采用相转移催化剂如冠醚或叔铵氯化物将离子化二醇带至界面以促成缩聚反应。影响界面缩聚反应后所得产率和所得聚合物分子量的因素有:反应时间、单体的摩尔比、不混溶溶剂的体积比、酸受体的类型以及相转移催化剂的类型和浓度。
在本发明的优选实施方案中,式I的生物降解性聚合物的制备方法包括以下步骤:R、R′和L如上所述的下式二元醇:
当R或R′是生物活性物质时,则该生物活性物质优选它本身是二元醇,例如甾族化合物如雌二醇。或者,该生物活性物质可以是能够与羧酸的羧基反应产生对生成该聚磷酸酯结构有用的末端羟基基团的二氨基化合物。
聚合反应的目的是形成包括(i)环脂族循环单元和(ii)磷酸酯循环单元的聚合物。其结果可以是均聚物、相对均匀的共聚物和具有一定非均匀微晶结构的嵌段共聚物。这三种方案的任意一种均非常适合用作控释介质。
本发明所用聚合物的制备方法可以在较宽的温度范围下进行,这主要取决于是否应用溶剂和哪种溶剂(如果含有溶剂)、所需要的分子量、所需要的溶解性、产生副反应的反应物的敏感性和催化剂的存在。但对于熔融条件反应优选在约0-235℃温度范围下进行,对于溶液聚合或者应用阳离子或阴离子催化剂的情况下,也可能应用较低的温度如约-50-100℃。
该方法所需要的时间也可以有较宽的变化范围,这取决于以下因素:所用的反应类型、所需要的分子量和为了达到反应所需完成程度通常对较严格或较不严格条件的需要。但该方法通常的时间范围约30分钟-4天。
本发明的方法可以本体、在溶液中、通过界面缩聚反应或任何其它合适的聚合方法进行,但该方法优选在溶液条件下进行。特别有用的溶剂包括二氯甲烷、氯仿、四氢呋喃、二甲基甲酰胺、二甲亚砜、甲苯或者许多其它惰性有机溶剂的任意一种。
特别地,当应用溶液聚合反应时,在聚合反应期间最好存在酸接受体。特别合适的酸接受体物质包括叔胺如吡啶、三甲胺、三乙胺、取代的苯胺和取代的氨基吡啶。最优选的酸接受体是取代的氨基吡啶4-二甲基氨基吡啶(“DMAP”)。
溶液聚合的反应物加入顺序可以有较大变化,这取决于以下因素:二元醇的相对活性、式II的二卤磷酸酯、这些反应物的纯度、聚合反应进行的温度和聚合反应应用的搅拌程度等。然而优选二元醇和溶剂以及酸接受体混合,再缓缓加入二卤磷酸酯。例如,在二元醇、溶剂和酸接受体的冷却反应混合物中细细流入或滴入溶于溶剂中的二卤磷酸酯溶液来控制聚合反应的速率。
式I聚合物从反应混合物中的分离可以应用传统方法例如沉淀、用非混溶溶剂提取、蒸发、过滤和结晶等。但通常应用非溶剂或部分可溶的溶剂如乙醚或石油醚冷却该聚合物溶液来分离和纯化式I聚合物。生物降解性和释放特性
式I聚合物的特征通常为:至少被部分控制的生物降解速率作为聚合物磷酸酯键水解的一个函数。其它因素也很重要。例如,生物降解聚合物的体内寿命还取决于其分子量、结晶度、生物稳定性和交联度。通常地,分子量越大,结晶度越高、生物稳定性越好,则生物降解越慢。另外,还可通过选择不同长度的侧链控制该聚合物的降解速率。因此,降解时间变化较大,优选小于一天至数月。
因此,侧链的结构可以影响包括生物活性物质的组合物的释放行为。例如,希望磷酸酯侧链转变成更亲脂性的或更疏水性的或体积更大的基团时,可以减慢降解过程。因此,与大芳香基侧链相比,具有小脂肪基侧链的聚合物组合物,其释放通常更快些。而且,当式I骨架部分的R和/或R′本身是生物活性物质时,则该生物活性物质的体内释放速率主要由生物降解速率所控制。当要释放的生物活性物质与含磷侧链R″轭合形成悬垂药物给药系统时,释放特性在很大程度上由磷-R′键的不稳定性来控制。
对于含有该聚合物的组合物的流动性或挠性来说,该聚合物的机械性质也很重要。例如,通常优选足够低的玻璃转化温度以使本发明的组合物在体内能保持流动。本发明聚合物的玻璃转化温度更优选约0-37℃,最优选约0-25℃。聚合物组合物
本发明的聚合物组合物可以是挠性或流动性物质。“流动性”是指在体温下能够在整个时间内呈现含有该物质的空间的形状。这包括,例如能够喷至一个部位、能用用装有例如23号针头的人工注射器注射或者通过导管给药的液体组合物。
但术语“流动性”还包括在室温下高粘度、“凝胶样”物质,它们可以通过从管中挤压、倾注或者应用比单独手动对高粘度流动性物质更大压力的任何一个市售泵注射设备来释放至所需要的部位,但仍为流动性物质。当所用的聚合物本身具有流动性时,本发明的聚合体组合物即使是粘性的也不需要包括流动性生物相容性溶剂,尽管仍然可存在微量或残余量生物相容性溶剂。可以通过聚合物的分子量以及通过混合该聚合物主链中环己烷二甲醇的顺式和反式异构体来调整聚合物的粘度。
即使不存在生物活性物质,本发明的聚合体组合物也在医药上具有广泛应用。例如,可以注射该组合物,从而注射之后形成暂时的生物机械屏障以覆盖或包裹内部器官或组织,例如形成用来阻止腹部手术后粘结的屏障。还可应用本发明的聚合物组合物来产生骨蜡和充填剂用于修复骨组织或结缔组织的损伤、或者产生暂时的内部“绷带”以防止进一步的内部损伤或促进内部伤口愈合或者用于为固体植入设施包膜。
甚至可以皮下注射该生物降解性组合物以增大组织或填充至缺损部位。该聚合物组合物注射后在体内逐渐生物降解,从而体内自然组织生长,当聚合物消失时,自然组织替换聚合物基质。因此,当该物质注射至软组织缺损部位后,它能填充该缺损部位并提供台架(scaffold)用于自然胶原蛋白生长。该胶原组织会逐渐替代该生物可降解聚合物。然而,优选地,本发明的聚合物组合物确实含有生物活性物质并使该生物活性物质随时间得到可控制的和有效的释放,即使对于大的生物大分子也是如此。因此,在优选的实施方案中,生物降解性聚合物组合物包括:
(a)至少一种生物活性物质和
(b)具有式(I)所示循环单体单元的聚合物,在式(I)中R、R′、L、R″和n如上所述。
生物活性物质的用量是治疗上的有效量,其有较大的变化范围,主要取决于所用的具体生物活性物质。加入到组合物中的生物活性物质量还取决于所需要的释放特性、生物效应所需的物质浓度以及用于治疗时该生物活性物质必须的释放时间。优选地,在室温和不需要有机溶剂的情况下,生物活性物质容易与本发明的聚合物基质以不同装载程度混合。然而,为了混合迅速和充分,混合期间也可能应用溶剂,在混合充分后再蒸发掉溶剂。
生物活性物质加入的量没有临界上限值,但其可接受的溶液或分散液粘度有一个临界上限值以保持组合物所需要的物理特性。加入到释放系统的物质的下限值取决于药物的活性以及治疗所需要的时间。因此,生物活性物质的量不能太小以致其不能产生所需要的生理效应,加入的量也不能太大以致生理活性物质以非控释方式释放。
在这些范围内,生物活性物质的量一般约以1-65%的比例加入到本发明释放系统中。然而,对于特别有效的生物活性物质来说,也可以应用更低的量来达到有效的治疗。
另外,本发明的聚合物组合物也可以包括本发明聚合物和其它生物相容性聚合物或共聚物的混合物,只要这些附加的聚合物或共聚物对该组合物的生物降解性或机械特性不产生不需要的影响。本发明聚合物和这些其它聚合物的混合物甚至可以在设计靶向给药所需的精确释放特性或所需生物降解精确速率中提供明显更大的挠性。这些附加生物相容性聚合物的例子包括其它的聚磷酸酯、聚碳酸酯、聚酯、聚原酸酯、polyphosphazene、聚酰胺、聚氨酯、聚亚胺碳酸酯和聚酸酐。
可药用聚合物载体还可包括宽范围的其它物质,这些物质包括但并不局限于稀释剂、粘合剂和粘结剂、润滑剂、崩解剂、着色剂、膨胀剂、矫味剂、甜味剂和各种物质如缓冲剂和吸附剂。为了制备一种特定的药物组合物,前提是这些附加的物质均不能影响本发明聚合物组合物的生物相容性、生物降解性和流动性或挠性。
为了生物活性物质的释放,该生物活性物质加入到聚合物组合物中。该生物活性物质或者溶解在聚合物组合物中形成适当恒定浓度的均相溶液,或者以所需要的“载荷”水平分散在聚合物组合物中形成悬浮液或分散液(“载荷”水平即每克含生物活性物质的总组合物中生物活性物质的克数,通常以百分比表示)。
为了更有效地使生物活性试剂在挠性或流动性组合物中形成一种均相的、整体的分散液或者均细的分散液,也可能把生物降解性聚合物或生物活性物质溶解在少量非毒性溶剂中,本发明的优点在于在优选的实施方案中形成流动性组合物不需要溶剂。而且,优选避免使用溶剂,因为一旦含溶剂的聚合物组合物全部或部分进入体内后,该溶剂从聚合物中消散开或分散开以及必须在体内被处理或消除,这样在一定时间内增加了身体清除能力的额外负担,而此时疾病或损伤可能已经损害了身体的清除能力。
然而,当应用溶剂促进混合以及维持本发明聚合物组合物的流动性时,该溶剂必须是非毒性的,或者生物相容性的,并且必须是最小量应用。任何即使部分置于体内的物质也不能应用明显毒性的溶剂。这样的溶剂还必须不能在给药部位引起组织刺激或坏死。
当应用溶剂时,合适的生物相容性溶剂的例子包括:N-甲基-2-吡咯烷酮、2-吡咯烷酮、乙醇、丙二醇、丙酮、乙酸甲酯、乙酸乙酯、甲基乙基酮、二甲基甲酰胺、二甲亚砜、四氢呋喃、己内酰胺、二甲基亚砜、油酸或1-十二烷基氮杂环庚烷-2-酮。优选的溶剂包括N-甲基-2-吡咯烷酮、2-吡咯烷酮、二甲亚砜和丙酮,这是由于这些溶剂的溶解能力和生物相容性所决定的。流动性或挠性释放系统
生物降解性治疗试剂释放系统的简单形式包括生物活性物质在聚合物基质中的溶液或分散液,所述聚合物基质具有不稳定(生物可降解)键与聚合物主链相连。该键的裂解把水不溶性聚合物转变成水可溶性的低分子量聚合物片断,该片断可从体内排出。
生物活性物质通常从聚合物基质中释放,其速率至少与该基质的体内降解速率相同。对于某些生物活性物质,只有在该聚合物降解至非分散物质已经与体液接触的某一处后,它们才释放。当聚合物开始降解后,完全被聚合物包围的生物活性物质被释放。然而,关于这个机理,物理性卷入到刚性固体植入结构的长链肽类可能会与基质同时降解,并且与肽链的其余部分脱离,从而释放出不完全的分子片断。
然而对于本发明的聚合物组合物,该聚合物一般在肽或蛋白质部分释放后才降解。在一个特别优选的机理中,当肽链从本发明组合物中释放时,组合物保持挠性,因此在它本身或其聚合物生物降解之前至少部分允许大分子蛋白质扩散通过基质。
组合物中蛋白质的开始释放速率一般可控制地分散通过基质结构的通道,释放速率与蛋白质的分子量成反比。一旦聚合物降解开始后,其侵蚀力也可以使存留在基质中的蛋白质释放。
本发明的生物降解性无定形基质一般包括与其它链相连结的聚合物链。这些连结可以通过基质中聚合物链的简单缠结产生,这是与氢键或范德华力或聚合物晶体区域间的相互作用或者天然离子相互作用完全不同的。或者,可以应用嵌段共聚物的合成或两种不同聚合物的混合来产生具有较宽变化范围物理和机械特性的粘性“油灰”状物质。
当生物活性物质是蛋白质时,特种蛋白质和聚合物物质间的相互作用也经常影响组合物的特性。重要的因素包括:(i)蛋白质的分子量,它是分散特性的一个重要参数;(ii)蛋白质的等电点,它支配电荷-电荷之间的相互作用;(iii)蛋白质中半胱氨酸的存在,它可以参与分子间二硫键的形成;(iv)蛋白质的一级氨基酸序列,其可能容易受到与聚合物物质有关的化学改性;(v)蛋白质中是否有碳水化合物的存在,其能增强或防止聚合物物质的相互作用;(vi)蛋白质的相对疏水性,其能与聚合物上的疏水部位相互作用;和(vii)蛋白质的不均匀度,当蛋白质是通过基因重组方法制备时这是经常存在的。
在一个特别优选的实施方案中,本发明的组合物具有足够的流动性以便注射至体内。注射用组合物在注射后或者直接与血管组织接触后引起轻微组织刺激是非常重要的。
组合物的生物活性物质或本发明的聚合物可以形成均相基质,或者生物活性物质可通过某种方式包覆于聚合物中。例如,生物活性物质首先包覆入微球中然后通过一种至少能部分维持微球结构的方式与聚合物组合。或者,生物活性物质可能与本发明聚合物充分不混溶,它以微滴形式分散在聚合物中,而不是溶解在聚合物中。上面任意一种形式均是可行的,但是优选的方式是,不管组合物的均匀度如何,在聚合物通过磷酸酯键水解降解之前,生物活性物质的主要部分在体内被释放。
在一个实施方案中,本发明组合物用来产生一个柔软的递送药物的“仓库”,其可作为液体形式给药,例如,注射给药,但其需保持足够的粘度以使药物维持在注射部位周围的局部区域。这样形成的“仓库”的降解时间可以从几天至数年,这主要取决于所选择的聚合物及其分子量。通过应用流动形式的聚合物组合物,甚至不需要开切口。在任一情况下,该挠性和流动性递送“仓库”会调整至其在体内所占空间的形状,并且只对周围组织有轻微的损伤。
本发明的挠性或流动性聚合物组合物可以置于体内的任何部位包括:软组织如肌肉或脂肪;硬组织如骨或软骨;空腔如牙周、口腔、阴道、直肠或鼻腔;或者囊袋如牙周袋或眼盲管。该组合物还可以喷雾或倾注至开放性伤口上或者在外科期间用作位置递送系统。
当组合物具有流动性时,其可注射至较深的伤口例如烧伤以防止厚层疤痕。该组合物还可用作暂时性屏障以防止例如腹部手术后不同类型组织相互直接粘附,这是因为其能够包覆组织、器官和假体装置。
基因治疗中,本发明的挠性或流动性组合物可以用于提供一种不包括基于细胞系统的把基因递送至病人的方式。具体地说,本发明组合物可以注射至其它递送基因载体的方式不能直接到达的部位。另外,根据持续基因治疗的需要,本发明组合物生物活性物质的缓释能力不需要重复侵入步骤以使基因载体重新引入到有关部位。
在整形学应用中,可以应用本发明的流动性或挠性组合物修补骨缺损以及结缔组织损伤。例如,当骨被固定或支撑时,把生物降解性组合物充填至骨形态发生蛋白以产生骨植入物用于甚至较大的断节缺损。还可注射该组合物至合适的整形空间,在聚合物基质降解至非毒性残留物之前促进细胞粘附及增生。
一旦注射后,本发明的聚合物组合物应该至少部分地与生物流体如血液、内部器官分泌液、粘膜和脑脊髓液等保持接触。对于药物释放系统,该植入的或注射的组合物会以控制的速度释放包括在基质中的生物活性物质直至该物质耗尽为止,该过程遵循生物活性物质从生物降解性聚合物基质中分散或溶解的普遍规律。
下面的实施例是阐明本发明的优选实施方案,而不是限制本发明的解释。所有的聚合物分子量是指平均分子量。除非特别指出,所有百分比是基于最终释放系统或所制制剂的重量百分比,所有总量为100%重量。实施例实施例1:聚磷酸酯-P(反式-CHDM-HDP)的合成
在氩气保护下,把10g反-1,4-环己烷-二甲醇(CHDM)、1.794g的4-二甲氨基吡啶(DMAP)、15.25ml(14.03g)N-甲基吗啉(NMM)和50ml二氯甲烷转移到装有漏斗的250ml烧瓶中。烧瓶中溶液在搅拌下冷却到-15℃,通过漏斗加入15.9g二氯磷酸己酯(HOP)在30ml二氯甲烷中的溶液。把反应混合物的温度逐渐提高到沸点温度,维持回流温度过夜。
过滤反应混合物,滤液蒸发至干。残余物重新溶解在100ml氯仿中。用0.1M的盐酸和氯化钠的混合物溶液洗涤上述溶液,无水硫酸钠干燥,骤冷状态下加入到500ml乙醚中。收集得到的流动性沉淀,真空干燥得到具有粘浆流动性的透明淡黄色凝胶样聚合物。该聚合物的产率为70-80%。通过如图1所示的31P-NMR和1HNMR光谱以及FT-IR光谱确证了聚(反式-CHDM-HOP)的结构,其分子量(Mw=8584;Mn=3076)通过凝胶渗透色谱法(GPC)确定,如图2所示,应用聚苯乙烯作为测量标准。实施例2:聚磷酸酯-聚(顺式和反式CHDM-HOP)的合成
聚磷酸酯P(顺式/反式1,4-环己烷二甲醇己基磷酸酯)按照如上面实施例1所描述的步骤制备,但应用顺式和反式1,4-环己烷二甲醇作为起始原料。不出所料,顺式/反式P(CHDM-HOP)比实施例1得到的反式异构体粘度小。实施例3:低分子量P(CHDM-HDP)的合成
在氩气保护下,把10g反式1,4-环己烷二甲醇(CHDM)、15.25mL(14.03g)N-甲基吗啉(NMM)和50mL的二氯甲烷转移到装有漏斗的250mL烧瓶中。搅拌下把烧瓶中溶液冷却到-40℃。通过漏斗加入15.19g二氯磷酸己酯(HOP)在20mL二氯甲烷中的溶液,再通过漏斗把10mL二氯甲烷加入到烧瓶中。然后把混合物逐渐升至室温,搅拌4小时。
过滤反应混合物,蒸发滤液至干。残余物重新溶解在100ml氯仿中。用0.5M的HCl-NaCl混合物溶液洗涤,再用饱和NaCl溶液洗涤,无水Na2SO4干燥,冷却状态下加入到1∶5的乙醚-石油醚混合物中。收集得到的油状沉淀物,真空干燥得到透明的淡黄色粘性物质。产品结构通过1HNMR、31PNMR和FT-IR光谱证实。实施例4:聚磷酸酯P(反式CHDM-HDP)的合成
在氩气保护下,把10g反式1,4-环己烷二甲醇(CHDM)、0.424g(5%)的4-二甲氨基吡啶(DMAP)、15.25mL(14.03g)N-甲基吗啉(NMM)和50mL的二氯甲烷转移到装有漏斗的250mL烧瓶中。搅拌下把烧瓶中溶液冷却到-40℃。通过漏斗加入13.24g二氯磷酸丁酯(BOP)在20mL二氯甲烷中的溶液,再通过漏斗把10mL二氯甲烷加入到烧瓶中。然后把混合物逐渐升至沸点,回流4小时。过滤反应混合物,蒸发滤液至干,注意温度不得超过60℃。残余物重新溶解在100ml氯仿中。用0.5M的HCl-NaCl混合物洗涤溶液,再用饱和NaCl溶液洗涤,无水Na2SO4干燥,冷却状态下加入到1∶5的乙醚-石油醚混合物中。收集得到的油状沉淀物,真空干燥得到透明的淡黄色粘性物质。实施例5:聚磷酸酯P(反式CHDM-EOP)的合成
应用反式1,4-环己烷二甲醇(CHDM)和二氯磷酸乙酯(EOP)作为起始原料按照实施例1中的方法制备聚(CHDM-EOP)聚合物。实施例6:P(反式CHDM-HOP)的流变性能
室温下P(反式CHDM-HOP)呈流动性凝胶样状态。该聚合物在25℃下显示237Pa·S的稳定粘度(如图3B所示),流动活化能为67.5KJ/mol(如图3A所示)。实施例7:P(反式CHDM-HOP)的体外细胞毒性
通过旋转涂敷法把盖玻片涂上一层P(反式CHDM-HOP)。然后干燥该涂好的盖玻片,置于防护罩下用紫外线消毒过夜。在6孔培养板的每个孔底部放上一块涂敷聚(反式CHDM-HOP)的盖玻片。把5×105HEK293(人胚胎肾)细胞放入每个孔中,37℃下培养72小时。应用组织培养聚苯乙烯(TCPS)作为阳性对照,检查得到的细胞形态。在P(CHDM-HOP)表面生长的细胞以较慢的速度增生。然而,聚合物表面生长的细胞形态与TCPS表面生长的细胞形态类似。图4A为培养72小时后在聚合物表面生长的HEK293细胞形态,图4B为培养72小时后在TCPS表面生长的HEK293细胞形态。实施例8聚(CHDM-烷基磷酸酯)的体外降解
下面是按照上述方法制备的各个聚磷酸酯化合物:
表I聚合物 侧链聚(CHDM-HOP) -O-己烷基聚(CHDM-BOP) -O-丁烷基聚(CHDM-EOP) -O-乙烷基
把50mg的各个聚合物样品在5mL 0.1M、pH7.4磷酸盐缓冲液(PBS)中37℃下培养。在各个时间点倾出上清液,用蒸馏水洗涤上清液三次。聚合物样品然后用氯仿提取,将氯仿溶液蒸发至干。通过与原来的50mg样品相比较对残余物进行失重分析。图5表示侧链结构对PBS中聚磷酸酯体外降解速率的影响。实施例9聚(CHDM-HOP)的蛋白质的体外释放特性
聚(CHDM-HOP)聚合物和蛋白质FITIC-BSA(牛血清白蛋白,一种蛋白质,用荧光标志FITC标记;“FITC-BSA”)以2∶1的比例(重量比)混合(33%装载)。把测量量(66mg或104mg)的聚合物-蛋白质混合物置于10mL的磷酸盐缓冲液PBS(0.1M,pH7.4)中。在固定的时间间隔(约每天),离心该样品,取出上清缓冲液进行吸收光谱测定(501nm),再把新鲜的缓冲液加入到样品中。图6表示得到的释放曲线,即用累积释放FITC-BSA的百分比对时间作图。两种情况下蛋白质的载荷水平为33%重量比。实施例10:不同载荷水平的蛋白质体外释放特性
室温下,FITC-BSA与P(CHDM-HOP)以不同载荷水平(1%,10%和30%)混合直至混合物形成均相糊剂。在37℃下持续震摇下,把60mg装有蛋白质的聚合物糊剂置于6mL的0.1M磷酸盐缓冲液中。在不同的时间点离心样品,用新鲜的缓冲液置换上清液。用UV分光光度法在501nm处测定上清液中释放的FITIC-BSA。图7表示作为载荷水平函数的FITIC-BSA的体外释放动力学。实施例11:侧链结构对FITC-BSA的体外蛋白质释放动力学的影响
下面三种聚合物按照上面的方法制备:
聚(CHDM-EOP)
聚(CHDM-BOP)
聚(CHDM-HOP)
这三种聚合物以每种聚合物10%的载荷水平在室温下与FITC-BSA混合形成均相糊剂。在37℃下持续震摇下,把60mg的装有蛋白质的聚合物糊剂加入到6mL的0.1M磷酸盐缓冲液中。在不同的时间点离心样品,用新鲜的缓冲液替换上清液。在501nm处用UV分光光度法测定上清液中释放的FITC-BSA。图8表示侧链的变化对体外10%载荷水平的FITIC-BSA蛋白质释放动力学的影响。实施例12:聚(CHDM-HOP)中小分子量药物的体外释放
把100mg聚(CHDM-HOP)分别与1mg阿霉素、顺铂或5-氟尿嘧啶在室温下混合来制备含有这些药物的聚(CHDM-HOP)糊剂。在37℃持续震摇下,把等分量的60mg装有药物的聚合物糊剂加入到6mL的0.1M磷酸盐缓冲液中。完成三个样品后,测试每种药物。在不同的时间点,用新鲜的缓冲液替换上清液。上清液中阿霉素和5-氟尿嘧啶的含量用UV分光光度法分别在484nm和280nm处作定量分析。顺铂含量用原子吸收分光光度法测定。图9表示聚(CHDM-HOP)中低分子量药物的释放。实施例13:聚(CHDM-HOP)中阿霉素和顺铂在体外的同时释放特性
把300mg聚(CHDM-HOP)和6mg阿霉素以及6mg顺铂在室温下混合形成一种均匀的分散体来制备糊剂。在37℃持续震摇下,把100mg的糊剂样品加入到10mL的磷酸盐缓冲液(pH7.4)中。在不同的时间点离心样品,取出9ml上清液,用新鲜的缓冲液替换上清液。取出的上清液在484nm处用分光光度法测定所取出的上清液中阿霉素的释放量。用原子吸收分光光度法测定释放的顺铂量。图10表示聚(CHDM-HOP)中阿霉素和顺铂的同时释放。实施例14:聚(CHDM-HOP)中白介素-2的体外释放
用小勺把330mg聚(CHDM-HOP)与3mg白介素-2(IL-2)在室温下混合形成均匀的分散体来制备一种糊剂。在37℃下,把95mg聚(CHDM-HOP)/白介素-2糊剂加入到5mL的0.1M磷酸盐缓冲液(pH7.4)中。在不同的时间点离心样品,取出4mL上清液,替换该上清液。通过应用上面描述的CTLL-2培养物来分析所取出上清液中的IL-2。以混入到糊剂中的起始IL-2总量为基础,计算出IL-2释放的累积百分比。在最后的时间点,样品中仍然还有IL-2的存在。图11表示不同时间(以天为单位)聚(CHDM-HOP)基质中释放的IL-2的累积百分数。实施例15:在组织培养物中聚(CHDM-HOP)中白介素-2的体外释放
用小勺把冻干的人白介素-2(“IL-2,18×106IU)与240mg聚(CHDM-HOP)在室温下混合均匀来制备一种糊剂。在37℃持续震摇下,把三份80mg的聚(CHDM-HOP)/白介素-2糊剂加入到1.5mL的组织培养物(含10%FCS的RPMI1640培养基)中。在不同的时间点离心样品,取出上清液,并用新鲜的培养基替换。通过ELISA分析确定所取出上清液中的IL-2量。
通过下面CTLL细胞培养方法分析所释放的生物活性IL-2的量:把CTLL细胞以每孔2×104细胞的密度置于96孔培养板中,并与等分量所取出的上清液一起培养。培养两天后,应用WST-1分析评估细胞生长速率。与组织培养基的聚(CHDM-HOP)中释放的IL-2分析相平行,作出校准曲线。图12表示用缓释的IL-2作出的校准曲线。所有数据表明:在任意时间点内具有30%以上的生物活性保持。实施例17体内聚(CHDM-HOP)中白介素-2的释放
在2.5MRads处用γ-射线消毒聚(CHDM-HOP)样品,在无菌条件下按照实施例15所述方式与白介素-2混合。把50g含有3.5×105IU IL-2的该IL-2聚合物糊剂样品皮下注射至6只6-8周的雌性Balb/c小鼠体内。另外两只小鼠以丸剂注射(bolus injection)方式接受同样剂量的IL-2,还有另外两只小鼠注射空白的聚(CHDM-HOP)作为对照。
在不同时间点,从尾部静脉中收集50μl血样品。合并每组的血样品并用含有1%BSA的HBSS稀释。分离血浆后按照上面的方法分析IL-2。在直至注射含有聚(CHDM-HOP)/IL-2的糊剂后的三星期,血清中仍可检测出IL-2,因此在体内达到了IL-2的缓释。与之相反,对于注射IL-2丸剂的小鼠,48小时后已经不能检测出IL-2。图13表示以丸剂形式给药IL-2或者将其分散在聚(CHDM-HOP)基质中给药IL-2的药物动力学比较。图14描述了该体内试验皮下注射部位的组织学检查。实施例18 聚(反式CHDM-HOP)的体内生物相容性
按照实施例1中描述的方法合成聚(反式CHDM-HOP)聚合物。为了有助于注射,为了降低粘性,在聚合物中加入10%和20%体积的乙醇以降低粘性。把25μL不含乙醇的聚合物、25μL含10%乙醇的聚合物和25μL含20%乙醇的聚合物注射至Sprague Dawley大鼠的背部肌肉中。在注射3天或13天后收集注射部位的组织,用石蜡组织学方法处理、用heamatoxylln和曙红染料染色并分析。在对照组大鼠中注射医用硅油。
注射乙醇稀释的聚合物时,大鼠背部肌肉部分的组织学检查显示没有急性炎症反应。巨嗜细胞的含量与注射医用硅油的对照组相当,在注射3天或13天后,上面任何一种样品均没有中性细胞的存在。实施例18体外肿瘤模型的药物敏感性
应用阿霉素(“DOX”)、顺铂或5-氟尿嘧啶(“5-FU”)作为药物,对B16/F10黑素瘤细胞系进行了体外研究。在不同浓度DOX、顺铂和5-FU存在下培养该B16/F10细胞。根据得到的数据,即使在0.1μg/ml的浓度下,DOX对细胞培养物也显示最大的抑制效应。实施例19体内肿瘤模型中聚(CHDM-HOP)中白介素-2和阿霉素的控制释放
冻干的白介素(“IL-2”)购自Chiro;小鼠γ-干扰素(“mIFN-γ”)来自Boehringer Mannheim;盐酸阿霉素(“DOX”)来自Sigma。6-8周的C57BL/6小鼠来自Charles River。用攻击性B16/F10黑素瘤细胞系在小鼠体内产生肿瘤,并每周传代一次来维持该细胞。按照实施例1的描述合成该聚(CHDM-HOP)聚合物。
如下面表II所示将小鼠随机分组。在肿瘤注射黑素瘤细胞系细胞的那一天称为第0天。每只小鼠左侧皮下注射50μl(105)磷酸盐缓冲液溶液(PBS)中的肿瘤细胞。在第三天或第七天,选择性地在肿瘤小鼠右侧注射下列物质的一种:(1)IL-2的丸剂,(2)DOX的丸剂,(3)IL-2的聚合物糊剂,(4)DOX的聚合物糊剂,(5)含有IL-2和DOX的聚合物糊剂,或(6)含有IL-2和γ-m IFN的聚合物糊剂。在第3天或第7天,对照组和阴性组不再注射。
IL-2或DOX的丸剂制备如下:把合适量的IL-2或DOX溶于50μl等渗溶液中然后立即注射。IL-2、DOX、IL-2和DOX的混合物或者IL-2和γ-mIFN的混合物的聚合物糊剂是通过把50μl的无菌聚P(CHDM-HOP)和这些药物混合成均相来制备的。表II:体内肿瘤模型小鼠组的分配
组别 | 小鼠数 | 注射后天数 | 制剂 |
对照组 | 5 | - | 无 |
阴性对照组 | 5 | - | 无 |
IL-2丸剂组 | 8 | 3 | 0.8×106IU |
DOX丸剂组 | 8 | 3 | 0.5mg |
DOX丸剂组 | 8 | 7 | 0.5mg |
IL-2糊剂组 | 10 | 3 | 0.8×106IU |
IL-2糊剂组 | 10 | 7 | 0.8×106IU |
DOX糊剂组 | 10 | 3 | 0.5mg |
DOX糊剂组 | 10 | 7 | 0.5mg |
(IL-2+DOX)糊剂组 | 10 | 3 | 0.8×106IU+0.5mg |
(IL-2+DOX)糊剂组 | 10 | 7 | 0.8×106IU+0.5mg |
IL-2+mIFN-γ)糊剂组 | 10 | 3 | 106 IU |
在肿瘤生长第28天和第42天,测量各个小鼠肿瘤大小。结果如下列表III所示,该表显示第28天和第42天肿瘤体积的生长数据以及每个药物组试验后存活的小鼠数。按照长度与宽度平方的乘积的一半计算出肿瘤体积,这可按照1981年Osieka等记载的方法进行。
表III:CHDM-HOP聚合物作为载体用于黑素瘤模型的细胞因子和药物输送
*平均标准偏差
组别 | 开始小鼠数 | 肿瘤注射后肿瘤体积(mm3+SEM*) | |
28天 | 42天 | ||
存活鼠数目 | |||
对照组 | 5 | 无肿瘤 | 无肿瘤 |
阴性对照组 | 5 | 2458±1070.7 | 5656 |
4 | 1 | ||
IL-2丸剂组(3天) | 8 | 1946±505.6 | 3282±1403.3 |
8 | 4 | ||
DOX丸剂组(3天) | 8 | 1218.9±304.1 | 3942.5±1818 |
8 | 5 | ||
DOX丸剂组(7天) | 8 | 1661.2±301.8 | 4394.3±741.3 |
8 | 3 | ||
IL-2糊剂组(3天) | 10 | 934.1±230 | 3183±1223.4 |
10 | 5 | ||
IL-2糊剂组(7天) | 10 | 2709.8±397.3 | 10491±2485.5 |
10 | 3 | ||
DOX糊剂组(3天) | 10 | 1410±475.3 | 4648.9±1202.2 |
8 | 7 | ||
DOX糊剂组(7天) | 10 | 1480±287 | 3915±1739.7 |
9 | 4 | ||
(IL-2+DOX)糊剂组(3天) | 10 | 657.3±248.9 | 3362.8±1120.1 |
8 | 7 | ||
(IL-2+DOX)糊剂组(7天) | 10 | 857.2±243.6 | 3449.8±1285.9 |
8 | 5 | ||
(IL-2+mIFN-γ)糊剂组(3天) | 10 | 1217.9±168.4 | 4469.8±2018.7 |
9 | 4 |
基于这些测量,图15代表第28天(肿瘤移植四星期后)的肿瘤体积分布,图16代表第42天(肿瘤移植6星期后)的肿瘤体积分布。根据对肿瘤小鼠不同的处理,这些图分成若干部分。
第28天的结果表明:与对照组(肿瘤不作处理)和IL-2丸剂注射组相比,接受聚合物/IL-2糊剂小鼠组能成功地延迟肿瘤的生长。然而,对于第7天后才接受聚合物/IL-2糊剂注射的小鼠,肿瘤在第7天时已经有相当大了,因此,肿瘤体积不能观察出有显著的减小。
IL-2和DOX结合可以明显缩小肿瘤体积。注射含IL-2和DOX的聚合物糊剂处理组的肿瘤平均体积明显比对照组的肿瘤体积小。具体地说,在第三天,接受IL-2和DOX/聚合物糊剂的小鼠,其平均肿瘤体积为657.3mm3,而对照组为2458mm3。即使到肿瘤生长第7天时才进行处理,对于含IL-2和DOX的聚合物糊剂,仍然能看出治疗效果。
肿瘤生长第42天的结果也证实了第3天注射含IL-2和DOX的聚合物糊剂对延迟肿瘤生长有最佳效果。在本发明的聚合物糊剂中,DOX和IL-2的联合治疗在更多的试验动物中产生较小体积的肿瘤。根据图15的分布数据,应用组合IL-2和DOX的聚合物糊剂治疗时,有四只小鼠的肿瘤体积小于1000mm3;而对于注射只有DOX的聚合物糊剂时,只有一只小鼠的肿瘤体积在该范围。同样非常明显的是,按照肿瘤生长第42天的评价,单独用IL-2并不能达到最理想的效果。尽管在第28天时小肿瘤体积分布良好,该时间肿瘤生长的进展以及长时间对IL-2缺乏长期可控制的释放都对其长期存活数据产生有害的影响。对于含有IL-2和DOX的聚合物糊剂,聚合物缓慢降解,因此治疗试剂的扩散速率随时间逐渐减少。
然而,由于每组肿瘤体积分布明显不同,表III中看到的平均肿瘤体积并不能代表一种完整的描述。通过对图16分布图中的数据(表示肿瘤移植6星期后肿瘤体积的分散度)和图17中显示的存活曲线(表示除在第3天接受注射单独含DOX的糊剂或者含有组合IL-2和DOX的糊剂外,在第42天的测量前其它各组小鼠的大量死亡)进行比较,可以对本发明治疗的显著效果有更充分的理解。因此,把这些数据作为一个整体考虑,显示糊剂中IL-2和DOX的联合治疗既能显著延迟肿瘤生长又能延长寿命。
注射含DOX的聚合物糊剂后3-4天时的早期死亡被认为至少部分归因于DOX引起体弱动物死亡的毒性效果。相应注射DOX丸剂不会产生早期死亡,可能是由于丸剂注射的DOX从体内的快速分散及清除。实施例20在聚(CHDM-HOP)或聚(CHDM-EOP)中加入紫杉醇
把100g实施例1中聚(CHDM-HOP)和实施例5中聚(CHDM-EOP)中的各个聚合物以约50%的浓度溶于乙醇中。当聚合物完全溶解后,把5mg的紫杉醇粉末(化疗药)加入到该溶液中,搅拌直至粉末完全溶解为止。把该溶液倾入到冰水中使该聚合物组合物沉淀。得到的悬浮液离心,倾出上清液,冷冻干燥过夜,得到粘性的凝胶样产品。实施例21:聚(CHDM-HOP)和聚(CHDM-EOP)中紫杉醇的体外释放
在1.7mL的微型塑料离心管中,把5mg需要测试的实施例20中的这两种紫杉醇聚合物制剂用1mL 80%PBS和20%PEG400的缓冲液混合物在37℃下温育。制备需要测试的每种制剂的四个样品。在特定的时间点,大约每天,倒出PBS:PEG缓冲液,通过HPLC分析紫杉醇。把新鲜的缓冲液加入到该微型离心管中。在第26天时结束该释放研究,此时用溶剂提取聚合物中的紫杉醇,以维持紫杉醇的质量平衡。
图18表示这两种聚合物中得到的紫杉醇释放曲线。在聚(CHDM-HOP)制剂中紫杉醇的总回收率为65%,在聚(CHDM-EOP)制剂中其总回收率为75%。实施例22聚(CHDM-HOP)/利多卡因糊剂的制备
聚(CHDM-HOP)和利多卡因(碱,Sigma,Cat.#L-7757)的糊剂通过机械搅拌法制备,其过程如下:60mg聚(CHDM-HOP)和16mg利多卡因在显微镜载玻片上秤重,用勺将该聚合物和利多卡因充分混合直至得到均匀的混合物。得到的利多卡因/聚合物混合物形成一种24%w/w的利多卡因糊剂,其中的利多卡因以固体形式存在。实施例23聚(CHDM-HOP)中利多卡因的体外释放
将在实施例22中制备约10mg的利多卡因/聚合物混合物在37℃下置于摇动器上的2.0ml磷酸盐缓冲液(PBS)(0.1M,pH7.4)中。该缓冲液在特定的时间点被取代,并取出样品。从聚合物释放到样品中的利多卡因用HLPC分析。图19表示利多卡因/聚合物混合物的三种不同样品的结果。图20A显示释放的利多卡因作为温育时间的函数的累积量,图20B表示释放利多卡因的累积量随时间平方根的变化,该图表明在一个星期内约有90%的药物被释放。利多卡因的释放量与时间平方根的线性关系表明药物的释放在测试时间内主要是通过扩散的机理进行。实施例24大鼠坐骨神经模型中聚(CHDM-HOP)中的利多卡因体内释放
在体重约150-200g的雄性Sprague-Dawley大鼠中插入一根颈静脉插管。腹腔注射约0.3-0.4ml麻醉药合剂(25mg/ml氯胺酮、2.5mg/ml甲苯噻嗪和14.5%200的标准酒精)。识别该动物的坐骨神经。把含25mg或50mg利多卡因的P(CHDM-HOP)或含上述量利多卡因的生理盐水溶液,一次注射到每只动物的坐骨神经中以阻滞神经。把等量的空白聚合物注射至对照组大鼠的坐骨神经中。
期间观测这些大鼠,按照下面的运动原反应和感受伤害反应指定得分:
运动原反应和机能
正常的运动原机能=0,
轻微的拖腿=1,
中度拖腿=2,和
无运动原机能=3;
感受伤害反应和机能
正常感受伤害反应=0,
略微延迟的感受伤害反应=1,
延迟的感受伤害反应=2,和
没有感受伤害反应=3。
也可在特定时间点收集血样品,用HLPC分析利多卡因的血浆浓度。
图22显示注射聚(CHDM-HOP)或生理盐水中的25mg利多卡因后,最大运动原机能效应对时间的关系图。在该图中,100%的最大百分比效应表示得分为“3”的“无运动原反应”。在注射后的第1小时内,所有注射利多卡因制剂的大鼠显示完全的运动原阻滞。下面的表IV总结了注射生理盐水中或聚(CHDM-HOP)中的利多卡因后利多卡因阻滞效应的持续时间。
表IV:注射生理盐水或聚(CHDM-HOP)中的利多卡因后
利多卡因反应的持续时间利多卡因制剂 感觉功能 运动原机能
完全阻滞 部分阻滞 完全阻滞 部分阻滞空白的 0 0 0 0P(CHDM-HOP)25mg在生理 2小时 48小时 1小时 27小时盐水溶液中25mg在聚 54小时 198小时 1小时 198小时(CHDM-HOP)中50mg在聚 119小时 265小时 2小时 240小时(CHDM-HOP)中
聚(CHDP-HOP)中利多卡因引起运动原功能阻滞的持续时间明显长于由利多卡因生理盐水引起的持续时间。然而,仅仅引起部分的运动原功能阻滞,因为即使有略微的拖腿动作,大鼠仍然能够运动。还应该注意到,即使把利多卡因的浓度提高到50mg,完全运动阻滞也只有最小限度的增加。
表V表示给药生理盐水中或聚(CHDM-HOP)中的25mg利多卡因后显示对受伤害反应完全阻滞的大鼠百分比。表V:完全感受伤害反应大鼠的百分比时间 感受伤害反应完全阻滞的大鼠百分比
在P(CHDM-HOP)中的 25mg利多卡因的
25mg利多卡因 生理盐水溶液0.5小时 100 1003小时 100 786小时 100 5024小时 100 030小时 78 048小时 100 051小时 100 054小时 100 072小时 78 099小时 78 0119小时 50 0125小时 78 0143小时 50 0149小时 50 0
与利多卡因生理盐水溶液相比,利多卡因/聚(CHDP-HOP)明显延长了利多卡因的感觉阻滞效应。
图21表示注射聚(CHDP-HOP)或生理盐水中25mg利多卡因后最大感受伤害效应百分比对时间的作图。该图中,100%的最大百分比效应代表得分为“3”即“无感受伤害反应”。同样,与利多卡因的生理盐水溶液相比,在利多卡因/聚(CHDM-HOP)组中观察到明显延长的局部麻醉效应。
应该注意,在利多卡因/生理盐水溶液和利多卡因/聚(CHDM-HOP)制剂引起的感觉阻滞完全恢复之前,其引起的运动阻滞都已很好恢复。大鼠可以经常用后肢运动,但对疼痛刺激没有明显的反应。因为在运动机能恢复之后,感受伤害的完全反应才完全恢复,因此本发明的药物组合物被认为非常适合用于局部麻醉的临床给药和慢性疼痛的处理。
图23表示注射25mg利多卡因的生理盐水溶液、在聚(CHDM-HOP)中的25mg利多卡因和在聚(CHDM-HOP)中的50mg利多卡因后利多卡因的血浆浓度。通过增加聚合物制剂中利多卡因的浓度,体循环中利多卡因浓度只有最小量的增加,但麻醉作用的持续时间延长,这表明大部分药物的扩散只局限于局部区域。
本发明已经这样进行了描述,很明显可以通过多种途径对这同一种方式进行改变。这样的改变被认为并没有脱离本发明的精神和范围,下列权利要求所概括的范围将包括所有这些改变。
Claims (59)
2、如权利要求1所述的聚合物组合物,其中R和R’各自为具有1至7个碳原子的支链或直链亚烷基。
3、如权利要求1所述的聚合物组合物,其中R和R’各自为亚甲基或亚乙基。
4、如权利要求1所述的聚合物组合物,其中R”是烷基,烷氧基,苯基,苯氧基,或杂环氧基。
5、如权利要求1所述的聚合物组合物,其中R”是烷氧基。
6、如权利要求1所述的聚合物组合物,其中n为5至500。
7、如权利要求1所述的聚合物组合物,其中L是环脂族基,未取代或被非干扰性取代基取代。
8、如权利要求7所述的聚合物组合物,其中L是亚环己基。
9、如权利要求1所述的聚合物组合物,其中所述聚合物包含附加的生物相容性单体单元或与其他生物相容性聚合物混合。
10、如权利要求1所述的聚合物组合物,其中所述聚合物的分子量(Mw)为约2,000至400,000道尔顿。
11、如权利要求1所述的聚合物组合物,其中所述组合物还包含至少一种生物活性物质。
12、如权利要求11所述的聚合物组合物,其中所述生物活性物质选自肽,多肽,蛋白质,氨基酸,多糖,生长因子,激素,抗血管生成因子,干扰素或细胞因子,抗原物质,和这些物质的药物前体。
13、如权利要求11所述的聚合物组合物,其中所述生物活性物质是治疗药物或药物前体。
14、如权利要求13所述的聚合物组合物,其中所述药物选自抗肿瘤药,局部麻醉药,抗生素,抗病毒药,抗真菌药,抗炎药,抗凝剂,适于疫苗应用的抗原物质,和这些物质的药物前体。
15、如权利要求11所述的聚合物组合物,其中所述生物活性物质和所述聚合物形成无定形的整体基质。
16、如权利要求1所述的聚合物组合物,其中所述聚合物组合物是无毒的,且当其注射或置于体内与脉管组织紧密接触时产生的组织刺激最小。
17、一种用于防止某一组织与另一组织粘着或包封器官或组织的临时隔离膜,其中所述隔离膜包含权利要求1所述的聚合物组合物。
19、如权利要求18所述的聚合物组合物,其中R和R’各自为具有1至7个碳原子的支链或直链亚烷基。
20、如权利要求18所述的聚合物组合物,其中R和R’各自为亚甲基或亚乙基。
21、如权利要求18所述的聚合物组合物,其中R”是烷基,烷氧基,苯基,苯氧基,或杂环氧基。
22、如权利要求18所述的聚合物组合物,其中R”是烷氧基。
23、如权利要求18所述的聚合物组合物,其中n为5至500。
24、如权利要求18所述的聚合物组合物,其中L是环脂族基,未取代或被非干扰性取代基取代。
25、如权利要求24所述的聚合物组合物,其中L是亚环己基。
26、如权利要求18所述的聚合物组合物,其中所述聚合物包含附加的生物相容性单体单元或与其它生物相容性聚合物混合。
27、如权利要求18所述的聚合物组合物,其中所述聚合物的分子量(Mw)为约2,000至400,000道尔顿。
28、如权利要求18所述的聚合物组合物,其中R”是生物活性物质。
29、如权利要求18所述的聚合物组合物,其中R或R’是生物活性物质。
30、如权利要求18所述的聚合物组合物,其中所述生物活性物质选自肽,多肽,蛋白质,氨基酸,多糖,生长因子,激素,抗血管生成因子,干扰素或细胞因子,抗原物质,和这些物质的药物前体。
31、如权利要求18所述的聚合物组合物,其中所述生物活性物质是治疗药物或药物前体。
32、如权利要求31所述的聚合物组合物,其中所述药物选自抗肿瘤药,局部麻醉药,抗生素,抗病毒药,抗真菌药,抗炎药,抗凝剂,适于疫苗应用的抗原物质,和这些物质的药物前体。
33、如权利要求18所述的聚合物组合物,其中所述聚合物组合物是无毒的,且当其注射或置于体内与脉管组织紧密接触时产生的组织刺激最小。
34、一种用于植入、注射、或完全或部分置于体内的挠性制品,所述制品包含一种生物降解性、流动性或挠性的聚合物组合物,该聚合物组合物包含具有式I所示循环单体单元的聚合物:其中:
R和R’各自独立地为直链或支链脂族基,是未取代的或被一个或多个非干扰性取代基取代;
L是二价环脂族基;
R”选自H、烷基、烷氧基、芳基、芳氧基、杂环或杂环氧基;和
n为5-1,000,其中所述生物降解聚合物组合物在生物降解前后都是生物相容的。
35、如权利要求34所述的制品,其中R和R’各自为具有1至20个碳原子的支链或直链亚烷基。
36、如权利要求34所述的制品,其中R”是烷氧基。
37、如权利要求34所述的制品,其中L是具有1至20个碳原子的环脂族基,未取代或被非干扰性取代基取代。
38、如权利要求34所述的制品,其中n为5至500。
39、如权利要求34所述的制品,其中所述聚合物包含附加的生物相容性单体单元或所述聚合物组合物包含一种或多种附加的生物相容性聚合物。
40、如权利要求34所述的制品,其中所述生物活性物质选自肽,多肽,蛋白质,氨基酸,多糖,生长因子,激素,抗血管生成因子和其它抗肿瘤剂,干扰素或细胞因子,抗原物质,和这些物质的药物前体。
41、如权利要求34所述的制品,其中所述生物活性物质是治疗药物或药物前体。
42、如权利要求41所述的制品,其中所述药物选自化学治疗剂,局部麻醉药,抗生素,抗病毒药,抗真菌药,抗炎药,抗凝剂,适于疫苗应用的抗原物质,和这些物质的药物前体。
43、如权利要求34所述的制品,其中所述生物活性物质与所述聚合物形成无定形的整体基质。
44、如权利要求34所述的制品,其中所述组合物是无毒的,且当其注射或置于体内与脉管组织紧密接触时产生的组织刺激最小。
46、如权利要求45所述的方法,其中R和R’各自为具有1至20个碳原子的支链或直链亚烷基。
47、如权利要求45所述的方法,其中R”是烷氧基。
48、如权利要求45所述的方法,其中L是具有1至20个碳原子的环脂族基,未取代或被非干扰性取代基取代。
49、如权利要求45所述的方法,其中n为5至500。
50、如权利要求45所述的方法,其中所述聚合物包含附加的生物相容性单体单元或所述聚合物组合物包含一种或多种附加的生物相容性聚合物。
51、如权利要求45所述的方法,其中所述生物活性物质选自肽,多肽,蛋白质,氨基酸,多糖,生长因子,激素,抗血管生成因子和其它抗肿瘤剂,干扰素或细胞因子,抗原物质,和这些物质的药物前体。
52、如权利要求45所述的方法,其中所述生物活性物质是治疗药物或药物前体。
53、如权利要求52所述的方法,其中所述药物选自化学治疗剂,局部麻醉药,抗生素,抗病毒药,抗真菌药,抗炎药,抗凝剂,适于疫苗应用的抗原物质,和这些物质的药物前体。
54、如权利要求45所述的方法,其中所述生物活性物质与所述聚合物形成无定形的整体基质。
55、如权利要求45所述的方法,其中所述组合物是无毒的,且当其注射或置于体内与脉管组织紧密接触时产生的组织刺激最小。
56、如权利要求13所述的聚合物组合物,其中所述药物选自以下成员:β-肾上腺素能阻滞剂,合成代谢剂,雄性类固醇,抗酸剂,平喘药,抗变态反应药,抗心律失常药,抗胆固醇血药和抗脂质药,抗胆碱能药和拟交感神经药,抗惊厥剂,止泻剂,止吐剂,抗高血压药,抗感染药,抗疟药,抗躁狂药,止恶心药,抗肥胖药,抗震颤麻痹药,退热剂和镇痛剂,镇痉药,抗血栓形成药,抗尿酸血药,抗心绞痛药,抗组胺药,镇咳药,食欲抑制剂,苯并菲啶生物碱,生物制剂,心脏作用药,大脑扩张药,冠脉扩张药,减充血剂,利尿剂,诊断剂,红细胞生成剂,雌激素,祛痰药,胃肠镇静剂,体液药,高血糖药,安眠药,低血糖药,离子交换剂,缓泻药,矿物质添加剂,缩瞳药,粘液溶解剂,神经肌肉药,营养物质,外周血管舒张药,促孕药,前列腺素,精神兴奋药,治疗精神病药,镇静剂,兴奋剂,甲状腺药和抗甲状腺药,安定药,子宫松弛药,维生素,和这些物质的药物前体。
57、如权利要求31所述的聚合物组合物,其中所述药物选自以下成员:β-肾上腺素能阻滞剂,合成代谢剂,雄性类固醇,抗酸剂,抗哮喘药,抗变态反应药,抗心律失常药,抗胆固醇血药和抗脂质药,抗胆碱能药和拟交感神经药,抗惊厥剂,止泻剂,止吐剂,抗高血压药,抗感染药,抗疟药,抗躁狂药,止恶心药,抗肥胖药,抗震颤麻痹药,退热剂和镇痛剂,镇痉药,抗血栓形成药,抗尿酸血药,抗心绞痛药,抗组胺药,镇咳药,食欲抑制剂,苯并菲啶生物碱,生物制剂,心脏作用药,大脑扩张药,冠脉扩张药,减充血剂,利尿剂,诊断剂,红细胞生成剂,雌激素,祛痰药,胃肠镇静剂,体液药,高血糖药,安眠药,低血糖药,离子交换剂,缓泻药,矿物质添加剂,缩瞳药,粘液溶解剂,神经肌肉药,营养物质,外周血管舒张药,促孕药,前列腺素,精神兴奋药,治疗精神病药,镇静剂,兴奋剂,甲状腺药和抗甲状腺药,安定药,子宫松弛药,维生素,和这些物质的药物前体。
58、如权利要求41所述的聚合物组合物,其中所述药物选自以下成员:β-肾上腺素能阻滞剂,合成代谢剂,雄性类固醇,抗酸剂,抗哮喘药,抗变态反应药,抗心律失常药,抗胆固醇血药和抗脂质药,抗胆碱能药和拟交感神经药,抗惊厥剂,止泻剂,止吐剂,抗高血压药,抗感染药,抗疟药,抗躁狂药,止恶心药,抗肥胖药,抗震颤麻痹药,退热剂和镇痛剂,苯并菲啶生物碱,生物制剂,心脏作用药,大脑扩张药,冠脉扩张药,减充血剂,利尿剂,诊断剂,红细胞生成剂,雌激素,祛痰药,胃肠镇静剂,体液药,高血糖药,安眠药,低血糖药,离子交换剂,缓泻药,矿物质添加剂,缩瞳药,粘液溶解剂,神经肌肉药,营养物质,外周血管舒张药,促孕药,前列腺素,精神兴奋药,治疗精神病药,镇静剂,兴奋剂,甲状腺药和抗甲状腺药,安定药,子宫松弛药,维生素,和这些物质的药物前体。
59、如权利要求52所述的聚合物组合物,其中所述药物选自以下成员:β-肾上腺素能阻滞剂,合成代谢剂,雄性类固醇,抗酸剂,抗哮喘药,抗变态反应药,抗心律失常药,抗胆固醇血药和抗脂质药,抗胆碱能药和拟交感神经药,抗惊厥剂,止泻剂,止吐剂,抗高血压药,抗感染药,抗疟药,抗躁狂药,止恶心药,抗肥胖药,抗震颤麻痹药,退热剂和镇痛剂,镇痉药,抗血栓形成药,抗尿酸血药,抗心绞痛药,抗组胺药,镇咳药,食欲抑制剂,苯并菲啶生物碱,生物制剂,心脏作用药,大脑扩张药,冠脉扩张药,减充血剂,利尿剂,诊断剂,红细胞生成剂,雌激素,祛痰药,胃肠镇静剂,体液药,高血糖药,安眠药,低血糖药,离子交换剂,缓泻药,矿物质添加剂,缩瞳药,粘液溶解剂,神经肌肉药,营养物质,外周血管舒张药,促孕药,前列腺素,精神兴奋药,治疗精神病药,镇静剂,兴奋剂,甲状腺药和抗甲状腺药,安定药,子宫松弛药,维生素,和这些物质的药物前体。
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CN105188741A (zh) * | 2013-04-03 | 2015-12-23 | 阿勒丁医疗公司 | 新型纳米颗粒组合物 |
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-
1998
- 1998-04-30 WO PCT/US1998/009185 patent/WO1998048859A1/en not_active Application Discontinuation
- 1998-04-30 HU HU0001299A patent/HUP0001299A3/hu unknown
- 1998-04-30 KR KR1019997010061A patent/KR20010020432A/ko not_active Application Discontinuation
- 1998-04-30 BR BR9809017-8A patent/BR9809017A/pt not_active IP Right Cessation
- 1998-04-30 CA CA002288014A patent/CA2288014A1/en not_active Abandoned
- 1998-04-30 TR TR1999/02693T patent/TR199902693T2/xx unknown
- 1998-04-30 CN CN98805636A patent/CN1258221A/zh active Pending
- 1998-04-30 NZ NZ501184A patent/NZ501184A/xx unknown
- 1998-04-30 AU AU71771/98A patent/AU749644B2/en not_active Ceased
- 1998-04-30 IL IL13248798A patent/IL132487A0/xx unknown
- 1998-04-30 EP EP98918959A patent/EP0980269A1/en not_active Withdrawn
- 1998-04-30 US US09/070,204 patent/US6403675B1/en not_active Expired - Lifetime
- 1998-04-30 JP JP54746098A patent/JP2002500640A/ja active Pending
- 1998-04-30 PL PL98336596A patent/PL336596A1/xx unknown
-
1999
- 1999-10-29 NO NO995301A patent/NO995301L/no not_active Application Discontinuation
-
2001
- 2001-12-04 US US10/011,570 patent/US6800672B2/en not_active Expired - Lifetime
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101125916B (zh) * | 2007-06-26 | 2010-06-23 | 天大药业(珠海)有限公司 | 一种生物降解聚合物及其制备方法和应用 |
CN105188741A (zh) * | 2013-04-03 | 2015-12-23 | 阿勒丁医疗公司 | 新型纳米颗粒组合物 |
Also Published As
Publication number | Publication date |
---|---|
AU749644B2 (en) | 2002-06-27 |
HUP0001299A2 (hu) | 2001-05-28 |
NZ501184A (en) | 2002-08-28 |
AU7177198A (en) | 1998-11-24 |
NO995301D0 (no) | 1999-10-29 |
US6800672B2 (en) | 2004-10-05 |
CA2288014A1 (en) | 1998-11-05 |
NO995301L (no) | 1999-12-30 |
KR20010020432A (ko) | 2001-03-15 |
US20020137814A1 (en) | 2002-09-26 |
IL132487A0 (en) | 2001-03-19 |
PL336596A1 (en) | 2000-07-03 |
TR199902693T2 (xx) | 2000-04-21 |
BR9809017A (pt) | 2002-01-02 |
EP0980269A1 (en) | 2000-02-23 |
WO1998048859A1 (en) | 1998-11-05 |
US6403675B1 (en) | 2002-06-11 |
HUP0001299A3 (en) | 2001-09-28 |
JP2002500640A (ja) | 2002-01-08 |
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