CN104039369B - 疏水性塞拉集宁化合物和包含该化合物的装置 - Google Patents
疏水性塞拉集宁化合物和包含该化合物的装置 Download PDFInfo
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- CN104039369B CN104039369B CN201280045894.5A CN201280045894A CN104039369B CN 104039369 B CN104039369 B CN 104039369B CN 201280045894 A CN201280045894 A CN 201280045894A CN 104039369 B CN104039369 B CN 104039369B
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Abstract
一种疏水性阳离子甾族抗微生物(塞拉集宁ceragenin)化合物形成具有疏水性甾醇表面和亲水性阳离子表面的两性分子化合物。所述疏水性CSA也包括给予所述塞拉集宁化合物至少6.5的CLogP值的疏水性取代基。
Description
相关申请的交叉引用
本申请要求2011年7月20日提交的、发明名称为“用于阻止细菌生物膜形成的含塞拉集宁的水凝胶”的美国临时专利申请号61/572,714和2012年5月3日提交的、发明名称为“包含洗脱塞拉集宁化合物的水凝胶材料”的美国临时专利申请号61/642,431的权益,二者均通过引用并入本文。
背景技术
1.发明领域
本发明涉及疏水性塞拉集宁化合物和掺入该疏水性塞拉集宁化合物的装置。所述塞拉集宁化合物具有给予化合物相对高的CLogP值以允许所述化合物非共价结合聚合材料的疏水性取代基。
2.相关技术
塞拉集宁化合物,本文也称为阳离子甾族抗微生物化合物(CSA),是合成产生的小分子化合物,其包括具有与主链连接的各种带电基团(如胺和阳离子取代基)的甾醇骨架。所述主链可用于将所述胺或胍基团定位在所述甾醇主链的一个表面或平面上。例如,显示在主链的一个表面或平面上有伯氨基的化合物的方案示于以下方案I:
塞拉集宁为阳离子的和两性的,以与所述主链连接的官能基团为基础。它们为表面两性的,具有疏水性表面和多聚阳离子表面。在不希望束缚于任何特定理论的情况下,本文所述抗微生物塞拉集宁化合物起到抗微生物剂(如抗细菌剂、抗真菌剂和抗病毒剂)的作用。例如,据信,本文所述抗微生物塞拉集宁化合物通过结合细菌和其它微生物的外部细胞膜并***所述细胞膜中形成允许对所述微生物的存活起决定性的离子泄漏的孔并导致受感染的微生物死亡而起到抗细菌剂的作用。另外,本文所述抗微生物塞拉集宁化合物也可使细菌对其它抗生素敏感。例如,在所述抗微生物塞拉集宁化合物的浓度低于相应最低抑菌浓度时,所述塞拉集宁化合物通过增加细菌的外膜的渗透性而使细菌变得对其它抗生素更敏感。
所述带电基团负责破坏细菌的细胞膜,并且在没有所述带电基团的情况下,所述塞拉集宁化合物将不能破坏所述膜以引起细胞死亡或敏化。
发明概述
本发明涉及尽管具有亲水的阳离子表面但是仍为相对疏水性的塞拉集宁化合物。已发现高疏水性具有与聚合物结合然后选择性从所述聚合物材料释放以杀灭微生物的令人惊讶和意想不到的能力。
在一个实施方案中,本文公开的疏水性塞拉集宁化合物具有(i)包含四个稠合碳环的甾醇结构;(ii)与所述四个稠合碳环的至少三个的每个连接以便形成具有疏水性甾醇表面和亲水性阳离子表面的两性分子化合物的至少一个阳离子取代基;(iii)与所述稠合碳环的至少一个连接的至少一个疏水性取代基;和(iv)其中所述CSA化合物具有至少6.5的CLogP值。
所述CLogP值通过选择与适当的阳离子取代基组合的适当的疏水性取代基来获得。选择所述阳离子取代基和疏水性取代基以产生6.5或更大、7.5或更大甚至10或更大的CLogP值。为了获得理想的CLogP值,当使用具有较小疏水性的阳离子取代基时,需要疏水性取代基的更大疏水性。
高CLogP值允许所述化合物非共价结合于具有疏水性部分的聚合物。例如,本文所述疏水性化合物可非共价结合水凝胶材料。所述疏水性结合允许塞拉集宁化合物与所述聚合物结合同时对杀灭微生物的能力具有极小影响。
令人惊讶和意想不到地,已发现,通过使用疏水性/亲水性相互作用将所述塞拉集宁与聚合材料非共价结合,所述疏水性塞拉集宁化合物在微生物的存在时可从所述聚合物选择性地释放,从而在比所预测的更低的浓度和延长的时间段内具有杀灭效应。这与其中固定阻碍了最初接触后的杀灭率的用共价结合的塞拉集宁进行的研究形成对比。所述疏水性塞拉集宁化合物从聚合物选择性释放以杀灭微生物的能力是非常理想的并且是令人惊讶和意想不到的结果。
另外,已发现,如本发明中所使用的塞拉集宁出人意外地越过正常菌群优先杀灭有害微生物,其意味着所述塞拉集宁可以与其它抗微生物剂相比更低的浓度使用而获得相同或更好的效力。该特征避免了现有技术抗微生物剂(其中许多往往杀灭“好的微生物”)的许多有害效应。
所述疏水的塞拉集宁化合物可掺入或制成医疗装置例如有待植入人体或其它动物的医疗装置。例如,可将所述水凝胶涂覆于医疗装置上或掺入聚合产品例如眼科产品。掺入所述疏水化合物的医疗装置可以足以满足最大细菌负荷的规定要求的浓度可控地释放塞拉集宁化合物数周甚至数月。
本发明的这些及其它特征将从以下描述和所附权利要求书中变得更加显而易见,或者可通过如下文中所述的本发明的实践而领会。
附图简介
为了进一步阐明本发明的上述和其它优点,将参考在附图中示出的其特定实施方案来提供本发明的更具体的描述。应理解,这些附图仅描绘了本发明的实施方案且因此并不认为其限制了本发明的范围。本发明将通过使用附图用附加的特征和细节来描述和说明,在附图中:
图1A示出ClogP值小于6.3的塞拉集宁化合物实例;
图1B示出ClogP值大于6.5的塞拉集宁化合物实例;
图2为具有聚合涂层的基底的示意图;
图3为显示在磷酸盐缓冲液中从水凝胶洗脱塞拉集宁的曲线图;
图4为显示高压灭菌后从水凝胶洗脱塞拉集宁的曲线图;
图5为显示在磷酸盐缓冲液和大豆胰蛋白酶培养基中从水凝胶洗脱塞拉集宁的曲线图;
图6为显示在缓冲液和106CFU的金黄色葡萄球菌(S.aureus)中从水凝胶洗脱塞拉集宁的曲线图;
图7为显示在缓冲液和106CFU的绿脓杆菌(P.aeruginosa)中从水凝胶洗脱塞拉集宁的曲线图。
具体描述
I.疏水性塞拉集宁
在一个实施方案中,本文公开的疏水性塞拉集宁化合物具有(i)包含四个稠合碳环的甾醇结构;(ii)与所述四个稠合碳环的至少三个的每个连接以便形成具有疏水性甾醇表面和亲水性阳离子表面的两性分子化合物的至少一个阳离子取代基;(iii)与所述稠合碳环的至少一个连接的至少一个疏水性取代基;和(iv)其中所述CSA化合物具有至少6.5的CLogP值。
所述CLogP值通过选择与适当的阳离子取代基组合的适当的疏水性取代基来获得。选择所述阳离子取代基和疏水性取代基以产生6.5或更大、7.5或更大甚至10或更大的CLogP值。
所述塞拉集宁化合物可具有式I所示的结构:
其中,环A、B、C和D形成稠合环***并且所述4四个稠合环的2或3个
上的R基的至少一个具有阳离子取代基。图I的其它R基可具有各种各样不
同的功能,从而提供具有理想疏水性能的塞拉集宁化合物。
在优选的实施方案中,p=1且q=0且至少R3、R7和R12独立地包括与所述稠合环***连接的阳离子取代基并且R17为包括为给予所述塞拉集宁化合物以所需疏水/亲水特性而选择的疏水基的疏水性取代基,其允许所述塞拉集宁化合物非共价结合于聚合物并随时间洗脱和/或选择性暴露于微生物。所述R17取代基可为疏水性的,但仍包括一个或多个杂原子(O或N)通过具有与其连接的足够数目的碳原子以形成疏水基。所述疏水基可为分支的、取代的或未取代的并且所述分支可发生在所述杂原子(例如二烃基胺)。所述疏水性取代基当q=0时优选连接在R17,以及当q=1时优选连接在R18,但是也可附接在式I的所述D环上的其它位点或环A、B或C上的位置的R基上。当疏水性取代基具有附接于烃基的杂原子的疏水基时,所述疏水基可具有1-20个碳原子,优选8、9、10、11、12或更多的碳原子以及20、18、16或更少的碳原子或其范围之内。所述疏水基也可包括疏水性部分例如三甲基硅烷。所述疏水基可包括一个或多个烃基,每个具有4个或更多、6个或更多、8个或更多、10个或更多或者12个或更多的碳原子。所述疏水基可通过连接到所述杂原子的烃基与所述甾醇结构附接。所述键合可为酯、***、胺或酰胺。当需要水解作用和/或需要不带电荷以赋予更大的疏水性时优选酯键。在那里所述杂原子包括胺,所述疏水基优选二烃基。如本文所述的具有疏水基的合适的疏水性取代基的实例为C13-烃基氨基-C5-烃基和二-(C1-C20)烃基氨基-(C1-C10)-烃基,其可在R17或R18(式I)与所述D环共价结合。
可在本文所述实施方案中使用的式I化合物的许多实例示于图1B中。用于产生将有选择地从聚合物洗脱的组合物的疏水性塞拉集宁的合适的实例包括但不限于CSA-131、CSA-132、CSA-133、CSA-134、CSA-135、CSA-137、CSA-138、CSA-144和CSA-145。前述化合物具有大于6.5、7.5、8.5并且在某些情况下大于10的CLogP值。图1A示出具有小于6.5的CLogP值的化合物。当与图1B的化合物进行对比时,图1A的化合物示出赋予大于6.5、7.5、8.5或10的CLogP值所期望的疏水性的变化的类型。例如,当所述杂原子为酯基的一部分时,9个或更大的碳氢链长度足以赋予所需要的疏水性。当胺基团为所述杂原子时,11个碳原子更为足够。可加入其它部分例如三甲基硅烷以允许胺基团以更短的链长度使用或提供额外的疏水性。
再次参照式I,更具体地说,稠合环A、B、C和D的每一个独立地为饱和的,或为完全或部分不饱和的,条件是A、B、C和D的至少两个为饱和的,其中环A、B、C和D形成环***;m、n、p和q的每一个独立地为0或1;R1直至R4、R6、R7、R11、R12、R15和R16的每一个独立地选自由氢、羟基、取代或未取代的(C1-C10)烃基、(C1-C10)羟烃基、(C1-C10)烃氧基-(C1-C10)烃基、(C1-C10)烃基羧基-(C1-C10)烃基、(C1-C10)烃基氨基-(C1-C10)烃基、(C1-C10)烃基氨基-(C1-C10)烃基氨基、(C1-C10)烃基氨基-(C1-C10)烃基氨基-(C1-C10)烃基氨基、取代或未取代的(C1-C10)氨基烃基、取代或未取代的芳基、取代或未取代的芳氨基-(C1-C10)烃基、(C1-C10)卤代烃基、C2-C6烯基、C2-C6炔基、氧代、附接于第二类固醇的连接基团、取代或未取代的(C1-C10)氨基烃氧基、取代或未取代的(C1-C10)氨基烃氧基-(C1-C10)烃基、取代或未取代的(C1-C10)氨基烃基羧基、取代或未取代的(C1-C10)氨基烃基氨基羰基、取代或未取代的(C1-C10)氨基烃基甲酰胺基、H2N-HC(Q5)-C(0)-0—、H2N—HC(Q5)-C(0)—N(H)—、(C1-C10)叠氮烃氧基、(C1-C10)氰基烃氧基、P.G.-HN—HC(Q5)-C(0)—0—、(C1-C10)胍基烃氧基、(C1-C10)季铵盐烃基羧基和(C1-C10)胍基烃基羧基组成的组,其中Q5为任何氨基酸的侧链(包括甘氨酸的侧链,即H),P.G.为氨基保护基,并且当稠合环A、B、C或D的其中之一为不饱和时R5、R8、R9、R10、R13和R14的每一个独立地被缺失以便完成该位点的碳原子的化合价,或者选自由氢、羟基、取代或未取代的(C1-C10)烃基、(C1-C10)羟烃基、(C1-C10)烃氧基-(C1-C10)烃基、取代或未取代的(C1-C10)氨基烃基、取代或未取代的芳基、(C1-C10)卤代烃基、C2-C6烯基、C2-C6炔基、氧代、附接于第二类固醇连接的连接基团、取代或未取代的(C1-C10)氨基烃氧基、取代或未取代的(C1-C10)氨基烃基羧基、取代或未取代的(C1-C10)氨基烃基氨基羰基、H2N—HC(Q5)-C(0)—0—、H2N—HC(Q5)-C(0)—N(H)—、(C1-C10)叠氮烃氧基、(C1-C10)氰基烃氧基、P.G.-HN—HC(Q5)-C(0)—0—、(C1-C10)胍基烃氧基和(C1-C10)胍基烃基羧基组成的组,其中,Q5为任何氨基酸的侧链,PG.为氨基保护基,条件是R1-4、R6、R7、R11、R12、R15、R16、R17和R18中的至少两个或三个独立地选自由取代或未取代的(C1-C10)氨基烃基、取代或未取代的(C1-C10)氨基烃氧基、(C1-C10)烃基羧基-(C1-C10)烃基、(C1-C10)烃基氨基-(C1-C10)烃基氨基、(C1-C10)烃基氨基-(C1-C10)烃基氨基(C1-C10)烃基氨基、取代或未取代的(C1-C10)氨基烃基羧基、取代或未取代的芳氨基(C1-C10)烃基、取代或未取代的(C1-C10)氨基烃氧基(C1-C10)氨基烃基氨基羰基、取代或未取代的(C1-C10)氨基烃基氨基羰基、取代或未取代的(C1-C10)氨基烃基羧酰胺、(C1-C10)季铵盐烃基羧基、H2N-HC(Q5)-C(0)-0—、H2N-HC(Q5)-C(0)—N(H)—、(C1-C10)叠氮烃氧基、(C1-C10)氰基烃氧基、P.G.-HN-HC(Q5)-C(0)—O—、(C1-C10)胍基烃氧基和(C1-C10)胍基烃基羧基组成的组;或者它们的药学上可接受的盐。具体CSA化合物的另外的实例在2012年11月3日提交的申请人同时待审的美国专利申请第13/288,902号中有公开,其通过引用并入本文。
如本文使用的“环”可为杂环或碳环。如本文使用的术语“饱和的”指的是稠合环中的各原子被氢化或被取代由此填满各原子的化合价的式I的稠合环。如本文使用的术语“不饱和的”指的是其中稠合环的各原子的化合价未被氢或其它取代基填满的式I的稠合环。例如,所述稠合环中的相邻碳原子可彼此双键结合。不饱和性还可包括缺失以下对中的至少一个并且在这些缺失的位点用双键完成所述环碳原子的化合价;例如R5和R9;R8和R10;以及R13和R14。
如本文使用的术语“未取代的”指的是各原子被氢化由此填满各原子的化合价的部分。
如本文使用的术语“卤代”指的是卤素原子例如氟、氯、溴或碘。
氨基酸侧链的实例包括但不限于H(甘氨酸)、甲基(丙氨酸)、—CH2—(C=0)—NH2(天冬酰胺)、—CH2—SH(半胱氨酸)和-CH(OH)-CH3(苏氨酸)。
烃基为可被取代或未被取代的分支或未分支的碳氢化合物。分支的烃基的实例包括异丙基、仲丁基、异丁基、叔丁基、仲戊基、异戊基、叔戊基、异己基。取代烃基可具有一个、两个、三个或更多的取代基,其可相同或不同,每个替代氢原子。取代基为卤素(例如F、Cl、Br和I)、羟基、受保护的羟基、氨基、受保护的氨基、羧基、受保护的羧基、氰基、甲基磺酰基、烃氧基、酰氧基、硝基和低级卤代烃基。
本文使用的术语“取代的”是指具有一个、两个、三个或更多取代基的部分,其可为相同的或不同的,每个替代氢原子。取代基的实例包括但不限于卤素(例如F、Cl、Br和I)、羟基、受保护的羟基、氨基、受保护的氨基、羧基、受保护的羧基、氰基、甲基磺酰基、烃氧基、烃基、芳基、芳烃基、酰氧基、硝基和低级卤代烃基。
芳基为C6_20芳环,其中所述环由碳原子组成(例如C6-C14,C6_10芳基)。卤代烃基的实例包括氟甲基、二氯甲基、三氟甲基、1,1-二氟乙基和2,2-二溴乙基。
芳烃基为含6-20个碳原子的基团,其具有至少一个芳环和与该环连接的至少一个烃基或亚烃基链。芳烃基的实例为苄基。
连接基团为用于将一个化合物连接到另一个化合物上的二价部分。例如,连接基团可将第二化合物连接到式I的化合物上。连接基团的实例为(C1-C10)烃氧基-(C1-C10)烃基。
氨基保护基是本领域技术人员所已知的。通常,保护基的种类并非决定性的,条件是它对于在所述化合物的其它位点上的任何后续反应的条件来说是稳定的,并且可在适当的点脱除而未不利地影响所述分子的其余部分。此外,保护基可在实质性合成转化完成后被另一个基团取代。明显地,当一种化合物与本文所公开的化合物的区别仅在于本文所公开的化合物的一个或多个保护基被不同的保护基所代替时,那么那个化合物在本发明的范围之内。进一步的实例和条件参见T.W.Greene,《有机化学中的保护基》(第1版,1981,第2版,1991)。
技术人员将认识到,本文所述各种塞拉集宁化合物保留存在于类固醇的某些立体化学特性和电子特性。如本文使用的术语“单面”指的是具有相同立体化学取向使得它们从所述分子的一侧突出的稠合甾醇主链上的取代基。例如,结合在式I的R3、R7和R12的取代基可以全部为13-取代的或a-取代的。所述部分R3、R7和R12的构型对于与细胞膜的相互作用来说可能是重要的。
化合物包括但不限于具有在任何碳位点共价附接于甾醇主链或骨架的阳离子取代基(例如胺或胍基团)的化合物,例如胆酸。在各种实施方案中,基团共价附接于所述甾醇主链的R3、R7和R12位点的任何一个或多个。在另外的实施方案中,基团不存在于所述甾醇主链的R3、R7和R12位点中的任何一个或多个缺失。
还可使用其它环***,例如5-元稠合环。还涉及具有5元环和6-元环的组合的主链的化合物。阳离子官能团(例如胺或胍基团)可通过至少一个、两个、三个、四个或更多的原子与所述主链分离。
具有疏水性取代基的塞拉集宁可使用申请人的美国专利6,767,904中描述的技术来制备,经过使用更长链的烃基的修改以形成更疏水的取代基。例如,代替使用辛基胺以形成在R17的官能团,可使用相应的更长链的胺。
II.塞拉集宁非共价掺入聚合物
掺入聚合物的疏水性塞拉集宁化合物可与所述聚合物非共价连接。一旦与水分接触,所述塞拉集宁可从所述聚合物浸出或洗脱。塞拉集宁通常可溶于水中,并且塞拉集宁可与聚合物连接以控制释放速率。适当的对聚合物和塞拉集宁结构的选择允许塞拉集宁的延长时间的释放。
例如,可调整从R17(式I)上的杂原子(例如N)伸出的链以允许从水凝胶聚合物的不同的洗脱速率。示例性的链包括脂类、疏水性链(例如脂肪族的)、亲水性(例如聚氧化乙烯)的,或者与所述聚合物相互作用的任何链为允许改变洗脱速率的方式。较长的链长会将所述塞拉集宁保持在所述聚合物基质内(尤其是疏水性区域)。在一个实施方案中,所述塞拉集宁化合物可具有附接于所述甾醇基(式I)的D环的至少9个碳原子。例如,至少9个碳原子的碳链可附接于式I的R17基,或者甾醇主链的C24碳或其它类似的碳。
掺入所述聚合物的特定塞拉集宁可为水溶液中可溶的或部分可溶的。此外,当与水和适当的表面活性剂混合时塞拉集宁可以凝胶或乳剂的形式使用。基于氧化乙烯和/或氧化丙烯的嵌段共聚物,尤其是普朗尼克(Pluronic)型表面活性剂,特别用于此目的。普朗尼克为BASF(在美国德克萨斯州阿瑟港有办事处的企业)的产品。
塞拉集宁化合物可在水凝胶材料或产品制造期间的任何合适的步骤掺入聚合物中。例如,在一个实施方案中,聚合物可通过沉浸、喷涂、印刷或涂覆等接触到塞拉集宁的溶液。合适的溶剂包括短链醇类例如乙醇、甲醇、异丙醇等等。若需要,用于掺入所述塞拉集宁的溶剂可被去除,例如,通过蒸发。如果必要的话,所述聚合物可通过利用强制热风、烘炉干燥、室温下空气干燥、微波干燥、或者使用加热的干燥鼓、真空室等进行干燥。在一些制造***中,正常的空气流动和温度可在充分地干燥所述基底而无需独立的干燥过程。
已知塞拉集宁化合物可溶于水。或者,塞拉集宁化合物也可溶于这样的材料,如乙醇(以及其它醇类)、丙二醇、丙三醇和多元醇,或者它们的混合物,可与水或不与水一起用于将塞拉集宁化合物掺入聚合材料。此外,塞拉集宁可作为凝胶、乳剂、悬浮液和以干燥的形式掺入。
在另一个实施方案中,塞拉集宁在单体聚合期间掺入聚合物。在这些过程中,所述塞拉集宁可在聚合期间被包括在单体混合物中。在最终聚合物中的所述塞拉集宁可非共价掺入所述聚合物并在与溶剂例如水接触时将相应地洗脱。
III.洗脱
当所述塞拉集宁化合物掺入聚合材料时,选择所述聚合物和所述塞拉集宁化合物的疏水性/亲水性以使所述塞拉集宁化合物与所述水凝胶聚合物非共价结合。所述非共价结合防止所述塞拉集宁化合物在溶剂的存在下立即全部释放。不如说,所述结合允许所述塞拉集宁化合物在溶剂的存在下随时间释放。
所述非共价结合取决于所述聚合物和所述塞拉集宁两者的组合物,并因此需要一起选择以产生想要的洗脱。所述选择通常通过选择具有特定应用所需化学和机械性能的特定聚合物来进行。例如,如果所述聚合物涂覆于有待植入血管组织医疗装置,那么可选择与血管组织和血液相容的聚合物。如果所述聚合物用于制成接触镜片,那么可选择与眼睛相容并且与将所述聚合物制成能矫正视力的形状的需要相容的聚合物。所述聚合材料的疏水性/亲水性因此在某种程度上受所述特定应用的约束。
所述塞拉集宁化合物具有选择的疏水性以提供与特定聚合物的非共价结合。可选择所述塞拉集宁为具有非共价结合所述聚合物的官能团的R基团。例如,基于聚合物的聚丙烯酸酯可在聚合物基质中具有一定百分比的疏水基和亲水基并且可选择所述塞拉集宁化合物为具有与所述聚合物的疏水基非共价结合的疏水性R17取代基(当式I中q=0时)以产生数天或数周的一段时间内相对一致的洗脱。
在某些情况下,所述溶剂也可影响洗脱。在一个实施方案中,所述溶剂为水。在一些实施方案中,所述溶剂可为盐水。
在一个实施方案中,选择所述水凝胶聚合物和塞拉集宁化合物以产生在水或盐水中提供三天、一周或一个月时的0.1-100μg/ml、0.5-50μg/ml或1-10μg/m1的释放速率的非共价结合。在一个实施方案中,前述洗脱速率保持在前述范围内至少3天、一周或一个月。这些洗脱速率部分通过阻止所述化合物快速释放的非共价结合而取得,其产生更多的在后来的时间可得的化合物。
如上所述,已意外地发现,水凝胶中非共价结合的塞拉集宁在微生物存在时选择性洗脱。这是出人意料和意想不到的结果,其使得与其它材料例如共价结合于聚合物表面的塞拉集宁相比使用聚合物-塞拉集宁化合物特别有利。
本领域的技术人员将认识到,特定聚合物和塞拉集宁化合物的选择将取决于特定的应用并且本领域的技术人员可使用本文提供的教导和实施例做出适当的选择。
IV.水凝胶聚合物
特别用于掺入疏水性塞拉集宁化合物的一种类型的聚合物为水凝胶聚合物。
合适的水凝胶聚合物的实例包括但不限于聚乙烯醇、聚丙烯酸钠、丙烯酸盐聚合物、聚氧化乙烯、聚(2-丙烯酰胺-2-甲基-1-丙磺酸)(polyAMP S)、聚乙烯吡咯烷酮、聚丙烯酰胺、硅酮、琼脂糖、甲基纤维素、透明质酸、水解聚丙烯腈、这些的组合。所述水凝胶可为共聚物。所述共聚物可包括疏水性和亲水性单元。
在一个实施方案中,所述水凝胶适合于制造接触镜片。亲水性接触镜片可由基于丙烯酸或甲基丙烯酸的亲水性衍生物、亲水性乙烯单体例如乙烯吡咯烷酮等等的交联聚合物制成。所述水凝胶优选包括由疏水性的嵌段或单体做成的疏水区。
合适的接触镜片水凝胶的实例在美国专利8,011,784中有公开,其通过引用并入本文。
所述水凝胶聚合物可制成具有适合校正视力的形状和结构的接触镜片。本领域的技术人员熟悉可提供视力矫正的水凝胶聚合物的形状和结构。也可由所述水凝胶制成的其它装置包括伤口愈合装置例如组织支架和伤口敷料。
V.医疗装置和涂层
本文所述聚合物可用于各种应用中,包括但不限于医疗装置、涂层、绷带、植入物、组织支架等等。图2为包括基底110和聚合涂层120的医疗装置100的示意图。
所述基底110可由适于支撑和/或粘附水凝胶材料的任何材料制成。所述基底可为聚合的、金属的、合金、无机的和/或有机的。在一个实施方案中,所述基底为生物可相容的或生物可吸收的材料。合适的生物可相容的金属材料包括但不限于不锈钢、钽、钛合金(包括镍钛合金)和钴合金(包括钴-铬-镍合金)。合适的非金属的生物可相容的材料包括但不限于聚酰胺、聚烯烃(即聚丙烯、聚乙烯等)、不能吸收的聚酯(即聚对苯二甲酸乙二酯)和生物可吸收的脂肪族聚酯(即乳酸、乙醇酸、丙交酯、乙交酯、对-二氧环己酮、三亚甲基碳酸酯、ε-己内酯等等和这些的组合的均聚物和共聚物)。
所述基底的厚度将取决于所述装置和材料但是可为0.1、1.0、10mm或更大和/或100、10或1mm或更小和/或其范围之内。
聚合涂层120的厚度通常小于基底110的厚度。聚合涂层120可具有0.01、0.1、1.0或10mm或更大和100、10、1.0或0.1mm或更小或其范围之内的厚度。
所述聚合涂层120可为连续的或不连续的。所述涂层可使用诸如浸渍涂覆、旋转涂覆等等的技术施加于所述基底。
可由包含疏水性塞拉集宁化合物的聚合物制成的或可有聚合物涂覆其上的医疗装置的实例包括但不限于骨植入物、骨针、骨螺钉、组织移植物、气道装置例如气管内管、可植入装置例如冠状动脉支架、末梢支架、导管、动-静脉移植物、旁路移植物、起搏器和除纤颤器导线、吻合夹、动脉闭合装置、卵圆孔未闭闭合装置和药物输送球囊。所述聚合物可涂覆其上或形成该装置的结构的任何部分,并且优选在外表面上,更优选在接触组织的外表面或组织空气界面上(当所述装置被植入时)。
VI.通过pH稳定塞拉集宁
在一个实施方案中,塞拉集宁化合物可具有将阳离子取代基附接到甾醇基的可水解键合(例如酯键)。这些键合的水解使所述塞拉集宁失去活性。为了使所述塞拉集宁稳定,可加入酸以取得小于6、5.5、5或4.5且可选地大于2、2.5或3或其范围的pH值。使用之前的稳定性对于产生理想的保存期限来说很重要,并且使用期间和使用后的不稳定可能是防止塞拉集宁在生物***中长期积累所期望的。
调节所述聚合物的中和程度以提高所述塞拉集宁的稳定性可能是有利的。所述聚合物的中和程度可在其制造工艺期间或其后调节。作为选择,所述塞拉集宁可悬浮或溶解于酸性溶液中;并且当将所述塞拉集宁悬浮液或溶液加入所述水凝胶聚合物时,所述水凝胶的中和程度将因此而被调节。
VII.实施例
为了更好地理解疏水性塞拉集宁化合物可以防止细菌定植的机制,评估了CSA-138和接触镜片中使用的水凝胶之间的结合。在第一个实施例中,我们测定了CSA-138从适于在接触镜片中使用的水凝胶洗脱的速率。为了定量从所述水凝胶洗脱的塞拉集宁的量,我们使用了使用质量标记内标的LC/MS。然而,该方法仅给出约2μg/ml的检测极限,并且我们能以低于所述检测极限的恒定的洗脱速率有效地杀灭细菌。例如,所述洗脱在从CSA-138已以1%掺入其中的镜片洗脱的五天内降到检测极限以下,然而所述塞拉集宁似乎仍然在提供合适的杀灭率。
为了降低CSA-138的检测极限,我们制备了CSA-138的放射性标记变体(CSA-138T2),将其掺入接触镜片,并且使用闪烁计数定量其从镜片的洗脱。
实施例1
在测试前将包含1%CSA-138的镜片存放于0.5mL的磷酸盐缓冲液(PBS)中。在进行洗脱研究前,将一副镜片高压灭菌处理45min。为了洗脱研究,将镜片悬浮于2ml等份的PBS、10%TSB生长培养基、含106CFU金黄色葡萄球菌的10%TSB生长培养基或者含106CFU绿脓杆菌的10%TSB生长培养基中。相应的等份试样(包括细菌接种物)每24h进行更换。每24h取出样品并使用闪烁计数分析CSA-138的存在。生成标准曲线以将每分钟计数与CSA-138的浓度相关联。所有实验一式三份地进行。
尽管每天观察到一些变化,但是在悬浮于PBS的镜片的洗脱概况中观察到了可辨认的趋势(图3)。正如预期的,在第一天的洗脱相当高(大约2.2μg/ml)。在接下来的19天的过程中,每日洗脱从每天将近1.6μg/ml变化至1.4μg/ml。
用在研究开始前进行高压灭菌处理的镜片观察到类似的洗脱曲线,只是洗脱的材料的起始量稍微下降(图4)。这种洗脱的下降可能归因于在高压灭菌过程中向存储溶液的增强的洗脱。在所述研究的进程中(从第2天到第20天),洗脱的CSA-138的量从每天将近1.4μg/ml变化至1.2μg/ml。
据预计,水溶液的渗透度的增加将降低CSA-138的溶解度并减慢洗脱。我们测定了在PBS中的10%TSB中的洗脱概况,并且正如预期的洗脱降低(图5),符合用已高压灭菌的镜片所看到的。
因为杀灭率似乎发生在如此低的浓度,所以我们假设细菌的存在影响CSA-138从镜片的洗脱。为了测试这种假设,将镜片与金黄色葡萄球菌或绿脓杆菌一起孵育,并监测洗脱。这些实验分别进行9天和8天。CSA-138的洗脱大幅度波动并到了比细菌不存在时高得多的程度(图6和7)。由于这些变化,所述实验相对于没有细菌的洗脱实验缩短。尽管在细菌存在下的洗脱有着很大的变化,但是对比有和没有细菌的样品来测定洗脱差异的显著性是可能的。在第一天后,差异产生0.05的p值,并且有许多天所述p值低于0.01。这些结果证明细菌影响CSA-138从镜片的洗脱。
金黄色葡萄球菌和绿脓杆菌的CSA-138的MIC值分别为0.5和1.0μg/ml。CSA-138从镜片的洗脱产生正好能消除引入的所述接种物的浓度。高压灭菌所述镜片,周围溶液的渗透度增加,以及细菌的存在适度地影响洗脱概况。
如果采取图5所给出的洗脱概况并延伸所述趋势直到CSA-138的洗脱下降至低于1μg/ml,那么这将需要大约40天(在第二天到第20天之间,洗脱从每天1.4μg/ml降低至每天1.2μg/ml;从每天1.2至1.0μg/ml的降低预计将需要另外19天)。因此,预计CSA-138的洗脱将足以消除细菌的合理接种物多达40天。正如以前的报道中提到的,CSA-138从镜片的洗脱可连续30天防止金黄色葡萄球菌的定植以及19天防止绿脓杆菌的定植。这些研究用相对高水平的接种物(106CFU)进行,并且预期30天后的CSA-138的洗脱将足以消除较小的接种物。
CSA-138的结构优化已产生了有效的抗微生物剂,其与接触镜片的材料连接并以消除革兰氏阳性和阴性细菌的大量接种物所必需的浓度洗脱。考虑到镜片通常接触的细菌数目,有可能使用较低浓度的CSA-138同时持续防止镜片上的细菌生长。
为了本发明的目的,“生理条件”为其中所述pH值、温度和盐浓度通常适合于维持生命的含水条件(例如,对于许多但不是所有装置来说,生理条件常为pH值接近7,温度接近37℃,以及盐浓度接近150mM)。
本发明可在不脱离其精神或本质特征的情况下以其它具体形式呈现。所述实施方案在所有方面都应被认为仅是说明性的而不是限制性的。因此,本发明的范围由所附权利要求而不是前面的描述来表示。在所述权利要求的等同物的含义和范围内的所有变化都在其范围之内。
Claims (24)
1.一种疏水性阳离子甾族抗微生物(CSA)化合物,其包含:
包含四个稠合碳环的甾醇结构;
附接于所述四个稠合碳环的至少三个的每个以便形成具有疏水性甾醇表面和亲水性阳离子表面的两性分子化合物的至少一个阳离子取代基;
附接于所述稠合碳环的至少一个的至少一个疏水性取代基;
其中,所述CSA化合物具有至少6.5的CLogP值和如式I所示的结构:
其中,
q=0并且p=1;
R3、R7和R12独立地包括阳离子基团;
R17为疏水性取代基,所述疏水性取代基包括杂原子和所述杂原子远侧的至少9个碳原子的至少一个碳氢基;以及
R1、R2、R4-R6、R8-R16为任意取代基。
2.如权利要求1中所述的疏水性CSA化合物,其中,所述CLogP值为至少7.5。
3.如权利要求1中所述的疏水性CSA化合物,其中,所述CLogP值为至少8.5。
4.如权利要求1至3中任一项所述的疏水性CSA化合物,其中,所述疏水性取代基包括三甲基硅烷。
5.如权利要求1-3中任一项所述的疏水性CSA化合物,其中,所述至少9个碳原子的至少一个碳氢基团为直链碳氢。
6.如权利要求1-3中任一项所述的疏水性CSA化合物,其中,所述至少9个碳原子的至少一个碳氢基团包括至少11个原子。
7.一种具有至少6.5的CLogP值并具有如式I所示结构的疏水性阳离子甾族抗微生物(CSA)化合物:
其中,
q=0并且m、n和p=1;
R3、R7和R12独立地包括阳离子基团;
R17为疏水性取代基,所述疏水性取代基包括杂原子和所述杂原子远侧的至少9个碳原子的至少一个直链碳氢基;以及
R1、R2、R4-R6、R8-R16为任意取代基。
8.如权利要求7中所述的疏水性CSA,其中,所述CSA化合物选自由以下组成的组:
9.一种具有选自由以下组成的组的结构的疏水性阳离子甾族抗微生物(CSA)化合物:
10.一种装置,其包含聚合物结构和以非共价相互作用掺入所述聚合物结构中或涂覆于所述聚合物结构上的如权利要求1、7或9中任一项的阳离子甾族抗微生物(CSA)化合物。
11.如权利要求10所述的装置,其中,所述聚合物结构包括聚乙烯醇、丙烯酸盐聚合物、聚氧化乙烯、polyAMPS、聚乙烯吡咯烷酮、聚丙烯酰胺、硅树脂、琼脂糖、甲基纤维素、透明质酸或它们的组合。
12.如权利要求11所述的装置,其中,所述丙烯酸盐聚合物为聚丙烯酸钠。
13.如权利要求10所述的装置,其中,所述装置选自由骨针、骨螺钉、末梢支架、导管、动-静脉移植物、旁路移植物、起搏器或除纤颤器导线、吻合夹、动脉闭合装置、卵圆孔未闭闭合装置和药物输送球囊组成的组。
14.如权利要求10所述的装置,其中,所述装置选自骨植入物、气管内管或冠状动脉支架。
15.如权利要求11所述的装置,其中,所述装置为组织移植物。
16.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在3天时和/或在3天的时间段内在过量的盐水中以0.1-100μg/ml的速率从所述聚合物结构洗脱。
17.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一周时和/或在一周的时间段内在过量的盐水中以0.1-100μg/ml的速率从所述聚合物结构洗脱。
18.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一个月时和/或在一个月的时间段内在过量的盐水中以0.1-100μg/ml的速率从所述聚合物结构洗脱。
19.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在3天时和/或在3天的时间段内在过量的盐水中以0.5-50μg/ml的速率从所述聚合物结构洗脱。
20.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一周时和/或在一周的时间段内在过量的盐水中以0.5-50μg/ml的速率从所述聚合物结构洗脱。
21.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一个月时和/或在一个月的时间段内在过量的盐水中以0.5-50μg/ml的速率从所述聚合物结构洗脱。
22.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在3天时和/或在3天的时间段内在过量的盐水中以1-10μg/ml的速率从所述聚合物结构洗脱。
23.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一周时和/或在一周的时间段内在过量的盐水中以1-10μg/ml的速率从所述聚合物结构洗脱。
24.如权利要求10-15任一项所述的装置,其中,所述CSA化合物在一个月时和/或在一个月的时间段内在过量的盐水中以1-10μg/ml的速率从所述聚合物结构洗脱。
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