CN1420790A - 释放物质和采用该物质的药物释放系统 - Google Patents
释放物质和采用该物质的药物释放系统 Download PDFInfo
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- CN1420790A CN1420790A CN01807467A CN01807467A CN1420790A CN 1420790 A CN1420790 A CN 1420790A CN 01807467 A CN01807467 A CN 01807467A CN 01807467 A CN01807467 A CN 01807467A CN 1420790 A CN1420790 A CN 1420790A
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- phospholipid
- covalent bond
- alkylene glycol
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Abstract
本发明的目的是制备具有优异释放性并且使药物能够长期有效滞留在体内的物质,和利用该物质构成的药物释放系统。该释放物质是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键,当该释放物质全身或局部给药时,该物质长期滞留在机体中的靶部位,由此通过1次给药使药物效力长时间持续成为可能。
Description
技术领域
本发明涉及具有优异释放性的物质,它们是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键,还涉及药物释放系统,它通过全身或局部给以该释放物质,使药物长期滞留于机体特定部位成为可能。
背景技术
眼内疾病例如视网膜、视神经或玻璃体的疾病经常是顽固性的,有效治疗方法的开发是迫切需要的。尽管眼部疾病一般多是通过药物的滴注加以治疗的,不过药物几乎释放不到眼内组织例如视网膜,这使得眼内疾病的治疗更加困难。
有鉴于此,尝试了直接给药至机体特定部位的方法。例如,报道了含有药物的脂质体或微球体给药至眼内组织例如玻璃体的技术(PCT No.508369/1994的日文公开文本,日本未审专利公报No.221322/1992等)。
不过,利用脂质体控制药物的释放并非易事。脂质体和微球体的粒径较大。因此,当它们对眼内组织例如玻璃体给药时,有时不能维持玻璃体的透明性。
另一方面,当药物口服给药时,药物在胃、小肠、大肠、肝内容易被吸收和代谢。因此,难以释放药物至特定部位,以达到表现药物功效的浓度。
这些事实说明,制备具有优异释放性并且使药物能够长期有效地滞留在体内的物质和利用该物质构建药物释放系统是重要的课题。
发明内容
本发明人针对释放物质和采用该释放物质的药物释放系统进行了深入的研究,本发明人制备了具有优异释放性的物质,它们是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键。结果发现,该释放物质和采用该释放物质的全身或局部药物释放系统能够用于治疗机体各种部位的疾病。当该释放物质对玻璃体给药时,该释放物质长期滞留在视网膜和玻璃体内。
本发明提供由聚亚烷基二醇或其反应性衍生物、磷脂和药物通过共价键连接形成的释放物质和全身或局部给以该物质的药物释放系统。本发明还提供一种治疗方法,包括对患者全身或局部单独给以药学上有效量的释放物质,或者与药学上可接受的载体或添加剂组合给药,该释放物质含有通过共价键连接的聚亚烷基二醇或其反应性衍生物、磷脂和药物,本发明还提供该物质的用途。
当本发明的释放物质被全身或局部给药时,该物质长期滞留在机体的靶部位,由此通过1次给药使药物功效长期持续成为可能。
本发明涉及由下列通式[1]代表的释放物质,含有通过共价键连接的聚亚烷基二醇或其反应性衍生物、磷脂和药物,
(A)m-X-Y-(B)n……[1]
其中A和B是相同或不同的药物残基,X是聚亚烷基二醇或其反应性衍生物残基,Y是磷脂骨架或磷脂残基,m是0或1以上的整数,n是0或1,m和n至少有一个不是0,所有A、B、X和Y都是通过共价键连接的,也就是说,式[1]中的“-”代表共价键。
聚亚烷基二醇是含有重复单元[-O-亚烷基-]的聚合物,该亚烷基可以被低级烷基或羟基取代。聚亚烷基二醇的优选实例是亚烷基由2-3个碳链形成,其更优选的实例是聚乙二醇和聚丙二醇。聚亚烷基二醇的反应衍生物是聚亚烷基二醇至少一个末端被化学修饰的衍生物,以便聚亚烷基二醇能够通过共价键与药物或磷脂连接。反应性衍生物的优选实例是向聚亚烷基二醇一个或两个末端引入氨基烷基、羧基烷基、巯基烷基、酰肼基烷基、马来酰亚氨基烷基、磺酰基烷基、乙烯基磺酰基烷基、乙烯基羰基的衍生物。反应性衍生物的更优选实例是向一个或两个末端引入氨基乙基、氨基丙基、羧基甲基、羧基乙基、巯基乙基或酰肼基甲基的衍生物。
当通式[1]中的m是零时,位于聚亚烷基二醇一个末端的OH基可以被烷基、酰基等保护起来。
聚亚烷基二醇或其反应性衍生物可以是任意直链的、星状的和分支的,考虑到释放物质在靶部位的浓度、释放物质滞留于靶部位的时间等,可以适当加以选择。利用星状或分支的聚亚烷基二醇或其反应性衍生物,多种药物可以通过共价键连接于一个释放物质。
关于键合方式,药物、聚亚烷基二醇(包括其反应性衍生物)和磷脂优选地以药物-聚亚烷基二醇-磷脂的方式连接。它们还可以以聚亚烷基二醇-磷脂-药物或药物-聚亚烷基二醇-磷脂-药物的方式连接。
通过选择适合的聚亚烷基二醇,多种药物可以连接于该聚亚烷基二醇。进而,通过连接药物与磷脂,多种药物可以连接于释放物质。
构成本发明释放物质的聚亚烷基二醇或其反应性衍生物的分子量是没有限制的,考虑到机体的药物释放部位、形成共价键的药物的种类与性质、所需释放物质浓度、释放物质滞留的时间等,可以适当加以选择。分子量通常为500至200,000,更优选为1,000至50,000。
通过共价键与聚亚烷基二醇或其反应性衍生物连接的药物的化学结构是没有限制的,药物可以具有与聚亚烷基二醇或其反应性衍生物连接的官能团。药物的优选实例是具有羟基、羧基、羰基、氨基、链烯基者。药物的种类是没有限制的,只要该药物对各种疾病具有全身或局部的治疗效果或预防效果即可。药物的实例是抗炎剂、免疫抑制剂、抗病毒剂、抗菌剂、抗真菌剂、抗肿瘤剂、神经保护药、血流改善药、抗青光眼药、止痛剂、麻醉剂、血管生成抑制剂、诊断试剂。用于治疗或预防视网膜、视神经、玻璃体的疾病的药物实例是对由各种原因引起的眼内炎症、病毒或细菌感染、伴有血管增生或视网膜细胞的增殖变化的增殖性玻璃体视网膜病、因各种原因而导致的视网膜出血、视网膜脱落、成视网膜细胞瘤等有效的药物。例如,抗炎剂如磷酸倍他米松用于治疗眼内外科手术伴发的炎症。免疫抑制剂如环孢菌素用于治疗自身免疫性眼色素层炎。抗病毒剂如更昔洛韦用于治疗病毒感染。抗微生物剂如氧氟沙星用于治疗术后感染。抗肿瘤剂如盐酸多柔比星、卡莫司汀、抗VEGF与MMP抑制剂、眼科诊断试剂用于治疗增殖性玻璃体视网膜病。
为了通过共价键连接聚亚烷基二醇或其反应性衍生物与药物,考虑到药物的官能团和聚亚烷基二醇或其反应性衍生物的官能团,它们可以彼此发生化学反应,可以利用普遍使用的方法连接它们。尽管聚亚烷基二醇本身可以用来形成共价键,不过其反应性衍生物可以更容易与各种药物形成共价键。由于具有各种官能团例如氨基、硫醇基、羧基、琥珀酰亚氨基羧酸酯、环氧化物、醛、异氰酸酯、马来酰亚胺、丙烯酸酯和乙烯基砜的聚亚烷基二醇反应性衍生物是商业上可得到的,可以通过这些衍生物与具有官能团的药物之间的化学反应形成共价键。
在释放物质中形成的共价键的实例是酯键、酰胺键、醚键、氨基甲酸酯键、脲键、硫脲键、硫醚键、二硫醚键、砜键、碳酸酯键、碳-碳键。考虑到药物的官能团、聚亚烷基二醇或其反应性衍生物的官能团、磷脂的官能团、在体内患病部位的滞留时间,可以合成具有所需共价键的释放物质。
通过共价键与聚亚烷基二醇或其反应性衍生物连接的磷脂是没有特别限制的,例如由下列通式[2]代表的化合物或其盐,
其中R1和R2相同或不同,表示氢、烷基、烷基羰基、链烯基或链烯基羰基,Z是氨基烷基、二氨基烷基、羟基烷基或二羟基烷基。
磷脂是没有限制的,只要该磷脂毒性低和安全性优异即可。磷脂的实例是大豆卵磷脂、蛋黄卵磷脂、磷脂酰乙醇胺、磷脂酰甘油、磷脂酸、合成卵磷脂。由通式[2]代表的化合物中R1和R2的实例是烷基羰基(烷酰基),例如月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基或亚油酰基,或是药物的残基。Z的实例是氨基乙基、羟基乙基、2,3-二羟基丙基。
磷脂优选具有反应活性官能团,目的是通过共价键连接聚亚烷基二醇或其反应性衍生物与磷脂。磷脂的官能团是没有限制的,例如具有反应活性的官能团如磷脂酰乙醇胺中的氨基、磷脂酰甘油中的羟基和磷脂酰丝氨酸中的羧基。特别优选的磷脂是磷脂酰乙醇胺。
用于通过共价键连接聚亚烷基二醇或其反应性衍生物与磷脂的方法实例是采用酸酐的方法、采用氰尿酰氯的方法、采用碳二亚胺的方法、采用戊二醛的方法。在这些方法中可以选择最好的方法,以通过共价键连接具有聚亚烷基二醇或其反应性衍生物的化合物与磷脂。
可以通过共价键与磷脂连接的药物的化学结构是没有限制的,该药物可以具有能够与磷脂连接的官能团。药物的实例是上述通过共价键与聚亚烷基二醇或其反应性衍生物连接的那些。通过共价键与磷脂连接的药物可以相同或不同于通过共价键与聚亚烷基二醇或其反应性衍生物连接的药物,考虑到疾病、症状、药物功效等,可以将药物适当组合。
本发明的释放物质可以通过各种方法制备。例如,如下流程所示,在缩合剂(例如N,N’-二环己基碳二亚胺)的存在下,化合物[A]与N-羟基琥珀酰亚胺反应,得到活性酯化合物[B]。然后,化合物[B]的活性酯部分与具有氨基的磷脂反应,得到酰胺化合物[C]。在酸性条件下除去作为酰胺化合物[C]的保护基团而引入的叔丁氧羰基,以转化化合物[C]为胺化合物[D]。该胺化合物与活性羰基化合物(例如异硫氰酸酯)反应,得到本发明的释放物质[E]。
(其中R1和R2具有上述相同定义,t是1或1以上的整数)
当本发明的释放物质被全身或局部给药时,释放物质滞留在机体的特定部位,几乎不被代谢。因此,药物在该部位逐渐释放,由此长期对疾病表现治疗和预防作用。滞留在机体特定部位的释放物质本身也可以对疾病表现治疗和预防作用。因此,本发明的药物释放系统通过1次给药,特别使长期治疗迄今难以治疗的机体特定部位成为可能。
通过本发明释放物质的全身或局部给药,本发明的药物释放系统可以用于治疗或预防机体特定部位的各种疾病。疾病的具体实例是由各种原因引起的炎症、病毒或细菌感染、免疫缺陷、肿瘤、伴有血管增生或视网膜细胞增殖变化的增殖性玻璃体视网膜病、视神经病、视网膜出血、视网膜脱落、成视网膜细胞瘤。通过含有通过共价键连接的各种诊断试剂的释放物质的全身或局部给药,可以进行各种诊断。
调整释放物质中的药物含量至这样一种程度是优选的,即可以随着时间的流逝维持药物的有效浓度。
下文眼内滞留性试验部分详细描述了本发明的有益效果。以含有通过共价键连接的荧光素的释放物质作为模型药物,研究在注射到玻璃体内后释放物质在眼内组织(玻璃体和视网膜)中的滞留性,证明本发明的释放物质长期(56天或以上)滞留在玻璃体以及视网膜中。将据报道具有视神经保护作用的地佐环平(药物)本身和含有通过共价键连接的地佐环平的释放物质分别注射到玻璃体内,然后比较药物的眼内滞留性,说明本发明的释放物质在玻璃体、视网膜脉络膜和视神经中的浓度比使用地佐环平本身的情况高100倍或以上,消失的半衰期也显著延长了。
这些试验结果显示,通过适当选择通过共价键与本发明的聚亚烷基二醇或其反应性衍生物和/或磷脂连接的药物,少数几次给药即可有效治疗各种全身或局部疾病。当使用本发明的药物释放系统时,释放物质可以有效滞留在机体的特定部位,例如视网膜、视神经或玻璃体。因此,有可能减少通过共价键与聚亚烷基二醇或其反应性衍生物、磷脂连接的药物的量,还可以表现减少副作用的效果。
由于本发明的释放物质有效滞留在机体的特定部位,这些物质对治疗局部疾病是特别有效的。它们的制剂形式是没有限制的,例如注射剂、输注剂、片剂、软膏剂、乳剂、悬液等。例如,各种剂型和给药方法可以用于眼病,例如滴眼剂、注射、灌流液、离子电渗和无针注射。本发明药物释放系统中的释放物质可以通过普遍使用的方法配制成适合其给药方法(眼那给药等)的制剂形式。例如,在注射剂的情况下,其实际的制剂例如实施例所述。注射剂可以这样制备,将通过上述方法制备的释放物质溶于BSS溶液(BalancedSalt Solution)、甘油溶液、透明质酸溶液。可以可选地向注射剂中加入稳定剂、等渗剂、缓冲剂、pH调节剂、防腐剂。
稳定剂的实例是乙二胺四乙酸、乙二胺四乙酸二钠。等渗剂的实例是甘油、丙二醇、聚乙二醇、氯化钠、氯化钾、山梨糖醇、甘露糖醇。缓冲剂的实例是柠檬酸、硼酸、磷酸氢钠、冰乙酸、氨基丁三醇、ε-氨基己酸等。pH调节剂的实例是盐酸、柠檬酸、磷酸、乙酸、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠等。防腐剂的实例是山梨酸、山梨酸钾、苯扎氯铵、苄索氯铵、对-羟基苯甲酸酯、苯甲酸钠、二丁基羟基甲苯、氯丁醇、葡萄糖酸氯己定等。
附图说明
图1显示玻璃体组织内浓度随时间(21天)的变化。
图2显示视网膜脉络膜组织内浓度随时间(21天)的变化。
图3显示视神经组织内浓度随时间(21天)的变化。
具体实施方式
本发明的实施例如下所示,它们有助于更好地理解本发明,但是不限制本发明的范围。
a、释放物质的制备
可以用于本发明药物释放系统的释放物质的制备实例如下所示。
实施例1
(1)释放物质A,其中
1)化合物,其中聚乙二醇(分子量5,000)的一个末端OH基的氢被硫脲基乙基取代,另一末端OH基的氢被羰基乙基取代,
2)荧光素,和
3)L-α-二硬脂酰基磷脂酰乙醇胺
是通过共价键连接的(化学式6)。
将二氯甲烷(10ml)、氯仿(5ml)和三乙胺(25μl,0.18mmol)加入到活性酯(0.20g,约40μmol)与L-α-二硬脂酰基磷脂酰乙醇胺(61mg,82μmol)的混合物中,该活性酯中聚乙二醇(分子量5,000)的一个末端OH基的氢被荧光素基硫脲基乙基取代,另一末端OH基的氢被琥珀酰亚氨氧基羰基乙基取代(Fluor-NHS-5k)(由Nippon Oils &Fats Co.,Ltd.生产),将混合物在室温下搅拌过夜。然后,向反应混合物中加入对-甲苯磺酸(40mg,0.21mmol),在减压下浓缩。向浓缩物中加入2-丙醇(5ml),将混合物在室温下搅拌30分钟。然后,滤出所沉淀的结晶,向结晶加入甲醇(10ml),滤出不溶物。在减压下浓缩滤液,向残余物加入2-丙醇,滤出沉淀,得到151mg释放物质A,为橙色结晶。
mp:56.5-64.5℃
(2)释放物质B,其中
1)化合物,其中聚乙二醇(分子量5,000)的一个末端OH基的氢被硫脲基乙基取代,另一末端OH基的氢被羰基乙基取代,
2)荧光素,和
3)L-α-二油酰基磷脂酰乙醇胺
是通过共价键连接的。
mp:49.0-51.0℃
IR(KBr,cm-1):2889,1741,1613,1468,1344
(3)释放物质C,其中
1)化合物,其中聚乙二醇(分子量1,000)的一个末端OH基的氢被硫脲基乙基取代,另一末端OH基的氢被羰基乙基取代,
2)荧光素,和
3)L-α-二硬脂酰基磷脂酰乙醇胺
是通过共价键连接的。
mp:55.0-65.0℃
IR(KBr,cm-1):3313,2917,2850,1748,1617,1540,1468,1349
(4)释放物质D,其中
1)化合物,其中聚乙二醇(分子量10,000)的一个末端OH基的氢被硫脲基乙基取代,另一末端OH基的氢被羰基乙基取代,
2)荧光素,和
3)L-α-二硬脂酰基磷脂酰乙醇胺
是通过共价键连接的。
mp:55.0-60.0℃
IR(KBr,cm-1):2885,1745,1614,1468,1343
(5)释放物质E,其中
1)化合物,其中聚乙二醇(分子量5,000)的一个末端OH基的氢被硫脲基乙基取代,另一末端OH基的氢被羰基乙基取代,
2)荧光素,和
3)L-α-二肉豆蔻酰基磷脂酰乙醇胺
是通过共价键连接的。
mp:65.0-75.0℃
IR(KBr,cm-1):2886,1774,1618,1467,1344
实施例2
释放物质F,其中
1)化合物,其中聚乙二醇(分子量5,000)的两个末端OH基的氢都被羰基乙基取代,
2)(±)-3,4-二氢-2-[5-甲氧基-2-[3-[2-(3,4-亚甲二氧基)苯氧基乙基氨基]丙氧基]苯基]-4-甲基-3-氧代-2H-1,4-苯并噻嗪,和
3)L-α-二硬脂酰基磷脂酰乙醇胺
是通过共价键连接的(化学式7)。
向(±)-3,4-二氢-2-[5-甲氧基-2-[3-[2-(3,4-亚甲二氧基)苯氧基乙基氨基]丙氧基]苯基]-4-甲基-3-氧代-2H-1,4-苯并噻嗪一草酸盐(该化合物的制备方法公开在日本未审专利公报No.123181/1987中)(54mg,88μmol)加入氯仿(5ml),在室温下搅拌。向该混合物中加入三乙胺(0.04ml,0.3mmol),然后加入活性酯(DSPE-NHS-5000)(由Nippon Oils & Fats Co.,Ltd.生产)(0.30g,约50μmol),该活性酯中聚乙二醇(分子量5,000)的一个末端OH基的氢被L-α-二硬脂酰基磷脂酰氧基乙基氨基羰基乙基取代,另一末端OH基的氢被琥珀酰亚氨氧基羰基乙基取代。一小时后,向反应混合物中加入对-甲苯磺酸一水合物(0.20g,1.1mmol),在减压下浓缩。向浓缩物加入2-丙醇(20ml),将混合物在室温下搅拌15分钟,然后滤出不溶物,得到0.28g释放物质F,为无色结晶。
mp:51.7-56.1℃
IR(KBr,cm-1):2887,1742,1467,1113
实施例3
释放物质G,其中
1)化合物,其中聚乙二醇(分子量5,000)的两个末端OH基的氢都被羰基乙基取代,
2)[5R,10S]-(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺,和
3)L-α-二硬脂酰基磷脂酰乙醇胺
是通过共价键连接的(化学式8)。
在氮气氛下,向[5R,10S]-(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺(地佐环平)马来酸盐(0.12g,0.36mmol)加入二氯甲烷(6.4ml),在室温下搅拌所得混合物。向该混合物中加入三乙胺(0.18ml,1.3mmol),然后加入活性酯(DSPE-NHS-5000)(由Nippon Oils & Fats Co.,Ltd.生产)(1.9g,约0.32mmol),该活性酯中聚乙二醇(分子量5,000)的一个末端OH基的氢被L-α-二硬脂酰基磷脂酰氧基乙基氨基羰基乙基取代,另一末端OH基的氢被琥珀酰亚氨氧基羰基乙基取代,将混合物搅拌过夜。在减压下浓缩反应混合物,向浓缩产物加入0.1N盐酸(100ml),用氯仿(100ml)萃取三次。萃取液经无水硫酸钠干燥,在减压下浓缩。残余物经过硅胶柱色谱分离纯化,用乙醚滤出所得晶体,得到0.27g释放物质G,为无色晶体。
mp:52.4-56.9℃
b、制剂例(注射剂)
向释放物质G(30mg)加入无菌的2.6%甘油溶液(10ml),在60℃下加热所得混合物,同时搅拌,得到其中溶解有释放物质G的注射液。通过适当改变本发明释放物质的种类和添加剂的混和比例,可以得到所需的注射剂。
c、用荧光光度测定法进行眼内滞留试验
利用含有荧光的释放物质A和B,按照下列方法进行眼内滞留试验。
释放物质的准备:
向释放物质A和B(36mg)各加入无菌的2.6%甘油溶液(10ml),将所得混合物加热至60℃,同时搅拌,制得其中溶解有释放物质A的注射液和其中溶解有释放物质B的注射液。为进行对比,使用荧光素钠代替释放物质A和B,重复上述相同程序,制得含有荧光素钠的10μg/ml注射液。
给药方法和测量方法
1)向白色家兔肌内给以含有比例为7∶3的盐酸氯胺酮水溶液(50mg/ml)与盐酸赛拉嗪水溶液(50mg/ml)的混和溶液,进行麻醉。
2)向两眼内滴注托吡卡胺(0.5%)/盐酸苯福林(0.5%)滴眼液,导致双眼瞳孔放大。
3)用盐酸奥布卡因(0.5%)滴眼液麻醉双眼表面。
4)用装有30G针头的注射器向眼扁平部玻璃体中心给以上述各注射液。
5)在第1、4、7、15、35和56天对玻璃体给药后,用荧光光度测定仪器经时测量眼内荧光强度。绘制校准曲线,测定玻璃体和视网膜中的浓度变化,计算各自的半衰期。在测量眼内荧光强度之前也进行上述操作1)和2)。
结果:
表1显示释放物质A、B和荧光素钠在玻璃体中的半衰期,表2显示它们在视网膜中的半衰期。表1和2中的数值分别是3例的平均值。表1
(表中的数值是按照瞬间法从向玻璃体内注射后1至35天测量的数据计算而来的)表2
(表中的数值是按照瞬间法从向玻璃体内注射后1至56天测量的数据计算而来的)
供试物质 | 半衰期(天) |
释放物质A | 7.0 |
释放物质B | 5.0 |
荧光素钠 | <0.2 |
供试物质 | 半衰期(天) |
释放物质A | 19.5 |
释放物质B | 16.5 |
荧光素钠 | <0.1 |
考察:
表1清楚地显示,释放物质A和B在玻璃体中的半衰期是5.0至7.0天,而荧光素钠仅不到五小时。这些结果显示,本发明的释放物质显著延长在玻璃体中的滞留时间。表2清楚地显示,释放物质A和B在视网膜中的半衰期是16.5至19.5天,而荧光素钠仅不到2.4小时。这些结果显示,对玻璃体给药的本发明释放物质移行到视网膜,长时间滞留在那里。
d、采用放射性同位素的眼内滞留试验
为了研究释放物质G对在眼内组织(玻璃体、视网膜、视神经等)中滞留的效果,按照下列方法利用放射性同位素进行眼内滞留试验。
药物溶液的制备:
称出释放物质G(9mg),在5ml刻度烧瓶内溶于2.6%甘油水溶液,调节总量至5ml。向另一支试管内加入用氚[3H]标记释放物质G所得化合物(以下称之为“释放物质G[3H]”)在甲苯/乙醇(1∶1)溶液中的37MBq/ml(200μl),在氮气流下蒸馏除去甲苯/乙醇。向该试管内加入前面制备的释放物质G溶液(5ml),搅拌所得混合物,制得给药溶液。
另一方面,称出[5R,10S]-(+)-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐(以下称之为“对比物质X”)(0.96mg),在10ml刻度烧瓶内溶于2.6%甘油水溶液,调节总量至10ml。向另一支试管内加入用氚[3H]标记对比物质X所得化合物(以下称之为“对比物质X[3H]”)在乙醇溶液中的37MBq/ml(400μl),在氮气流下蒸馏除去乙醇。向该试管内加入前面制备的对比物质X溶液(10ml),搅拌所得混合物,制得给药溶液。在制备中全部使用无菌的器具。
向玻璃体内注射:
按照1ml/kg的比率向日本白兔肌内注射含有比例为7∶3的盐酸氯胺酮水溶液与盐酸赛拉嗪水溶液的混和溶液,以麻醉兔子。然后,用盐酸奥布卡因(0.5%)眼用溶液麻醉双眼表面,然后用30G针头向玻璃体内注射每种供试物质的给药溶液(100μl/眼)。注射是利用装有塞子的针头进行的,目的是避免针头插入视网膜。表3显示各给药溶液的浓度、给药量。
表3
予给药溶液 | 浓度(μmol/ml) | 给药量(μl) | 给药放射性(KBq/眼) |
释放物质G[3H] | 0.300 | 100 | 148 |
对比物质X[3H] | 0.326 | 100 | 148 |
试样的采集:
在给药后的指定日期,向日本白兔的耳静脉给以戊巴比妥钠水溶液(50mg/ml)(5ml),使其麻醉致死。用生理盐水(约10ml)洗涤眼球,然后用剪子从眼角或外眦剪去眼球外周,摘出眼球。用生理盐水洗涤眼球两次,用纸擦去过量的水。除去眼球结膜,然后用1ml注射器收集房水(约0.2ml)。然后将眼球浸泡在液氮中冻结,将眼球用剃刀沿着中纬线分成两半,从前部收集玻璃体、晶状体、虹膜与睫状体和角膜,从后部收集玻璃体、视网膜脉络膜和视神经。
测量用试样的制备:
测量所收集的玻璃体、视网膜脉络膜和视神经的湿重。测量后,用组织溶解剂溶解它们,然后向所得溶液中加入液体闪烁剂。
标准放射性试样的制备:
分别将释放物质G[3H]给药溶液和对比物质X[3H]给药溶液稀释100倍,制得标准放射性试样。
测定方法:
用液体闪烁计数器测量所制备的测量试样和标准放射性试样的放射性浓度。从每份标准放射性试样的放射性测定每1ng供试化合物的放射性A(dpm/pmol),按照下列方程计算每种组织中的放射性浓度。
组织中的放射性浓度(pmol eq./g)=[{每份组织试样中的放射性(dpm)}/A(dpm/pmol)]/{组织湿重(g)}
药动学参数的计算:
按照瞬间法从每种供试物质在眼内组织中的浓度变化计算消除半衰期,浓度变化是在向玻璃体内注射后1至21天测量的。
结果:
图1、2和3显示在分别向玻璃体内注射后,释放物质G和对比物质X在玻璃体、视网膜脉络膜和视神经中的各自浓度变化。表4和5显示释放物质G和对比物质X分别在玻璃体和视网膜中的半衰期。表4和5中的数值分别是各3例的平均值。
表4
供试物质 | 半衰期(天) |
释放物质G | 3.3 |
对比物质X | 0.5 |
表5
供试物质 | 半衰期(天) |
释放物质G | 7.0 |
对比物质X | 0.6 |
考察:
图1至3清楚地显示当释放物质G对玻璃体给药时,释放物质移行至眼后部如玻璃体、视网膜脉络膜和视神经,长时间保持高浓度。表4和5显示释放物质的半衰期比对比物质X长约6至10倍。
本发明的释放物质是具有优异释放性的物质,它们是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键。采用本发明释放物质的药物释放系统能够长期滞留释放物质于后部,例如玻璃体、视网膜和视神经。因此,用本发明的释放物质向全身或局部给药的药物释放系统通过1次给药使长期治疗或预防各种机体特定部位的疾病成为可能。
本发明提供具有优异释放性的物质,它们是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键,还提供采用该物质的药物释放系统。
Claims (20)
1.释放物质,是由聚亚烷基二醇或其反应性衍生物、磷脂和药物通过共价键连接形成的。
2.由下列通式[1]代表的释放物质,是由聚亚烷基二醇或其反应性衍生物、磷脂和药物通过共价键连接形成的,
(A)m-X-Y-(B)n……[1]
其中A和B是相同或不同的药物残基,X是聚亚烷基二醇或其反应性衍生物残基,Y是磷脂骨架或磷脂残基,m是0或1以上的整数,n是0、1或2,m和n至少有一个不是0,所有A、B、X和Y都是通过共价键连接的。
3.如权利要求1所要求保护的释放物质,其中该聚亚烷基二醇或其反应性衍生物的分子量为500至200,000。
4.如权利要求1所要求保护的释放物质,其中该药物是抗炎剂、免疫抑制剂、抗病毒剂、抗菌剂、抗真菌剂、抗肿瘤剂、神经保护药、血流改善药、抗青光眼药、止痛剂、麻醉剂、血管生成抑制剂或诊断试剂。
5.如权利要求1所要求保护的释放物质,其中磷脂是由下列通式[2]代表的磷化合物或其盐,
其中R1和R2相同或不同,表示氢、烷基、烷基羰基、链烯基或链烯基羰基,Z是氨基烷基、二氨基烷基、羟基烷基或二羟基烷基。
6.如权利要求5所要求保护的释放物质,其中R1和R2至少有一个是月桂酰基、肉豆蔻酰基、棕榈酰基、硬脂酰基、油酰基或亚油酰基。
7.如权利要求5所要求保护的释放物质,其中Z是氨基乙基、羟基乙基或2,3-二羟基丙基。
8.如权利要求1所要求保护的释放物质,其中该释放物质中的共价键是酯键、酰胺键、醚键、氨基甲酸酯键、脲键、硫脲键、硫醚键、二硫醚键、砜键、碳酸酯键或碳-碳键。
9.药物释放系统,以全身或局部给以释放物质为特征,该释放物质是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键。
10.药物释放系统,以向眼内滴注释放物质为特征,该释放物质是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键。
11.用于玻璃体、视网膜或视神经的药物释放系统,以对玻璃体给以释放物质为特征,该释放物质是这样获得的,使聚亚烷基二醇或其反应性衍生物、磷脂和药物彼此反应,形成共价键。
12.如权利要求9所要求保护的药物释放系统,其中该药物是抗炎剂、免疫抑制剂、抗病毒剂、抗菌剂、抗真菌剂、抗肿瘤剂、神经保护药、血流改善药、抗青光眼药、止痛剂、麻醉剂、血管生成抑制剂或诊断试剂。
13.如权利要求10所要求保护的药物释放系统,其中该药物是用于治疗或预防眼病的药物。
14.如权利要求11所要求保护的药物释放系统,其中该药物是用于治疗或预防视网膜、视神经或玻璃体疾病的药物。
15.治疗方法,包含对患者全身或局部单独给以药学上有效量的释放物质,或者将释放物质与药学上可接受的载体或添加剂组合给药,该释放物质包含通过共价键连接的聚亚烷基二醇或其反应性衍生物、磷脂和药物。
16.治疗眼病的方法,包含单独滴注给药药学上有效量的释放物质,或者将释放物质与药学上可接受的载体或添加剂组合给药,该释放物质包含通过共价键连接的聚亚烷基二醇或其反应性衍生物、磷脂和药物。
17.治疗玻璃体、视网膜或视神经疾病的方法,包含对玻璃体单独给以药学上有效量的释放物质,或者将释放物质与药学上可接受的载体或添加剂组合给药,该释放物质包含通过共价键连接的聚亚烷基二醇或其反应性衍生物、磷脂和药物。
18.如权利要求15所要求保护的治疗方法,其中该药物是抗炎剂、免疫抑制剂、抗病毒剂、抗菌剂、抗真菌剂、抗肿瘤剂、神经保护药、血流改善药、抗青光眼药、止痛剂、麻醉剂、血管生成抑制剂或诊断试剂。
19.如权利要求16所要求保护的治疗方法,其中该药物是用于治疗或预防眼病的药物。
20.如权利要求17所要求保护的治疗方法,其中该药物是用于治疗或预防视网膜、视神经或玻璃体疾病的药物。
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Application Number | Title | Priority Date | Filing Date |
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CNB018074677A Expired - Fee Related CN100479862C (zh) | 2000-04-03 | 2001-04-03 | 释放物质和采用该物质的药物释放系统 |
Country Status (7)
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US (1) | US7455855B2 (zh) |
EP (1) | EP1279406A4 (zh) |
KR (1) | KR100777195B1 (zh) |
CN (1) | CN100479862C (zh) |
AU (1) | AU2001244713A1 (zh) |
CA (1) | CA2404737C (zh) |
WO (1) | WO2001074400A1 (zh) |
Families Citing this family (20)
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KR100777195B1 (ko) | 2000-04-03 | 2007-11-19 | 산텐 세이야꾸 가부시키가이샤 | 송달성 물질 및 이를 이용한 약물 송달 시스템 |
KR20040039428A (ko) * | 2001-09-28 | 2004-05-10 | 산텐 세이야꾸 가부시키가이샤 | 약물-폴리에틸렌글리콜 결합체를 함유하는 안조직 내 주입제 |
US7279150B2 (en) * | 2002-01-24 | 2007-10-09 | Barnes-Jewish Hospital | Chelating agents with lipophilic carriers |
AU2003220917A1 (en) | 2002-03-29 | 2003-10-13 | Daiichi Pharmaceutical Co., Ltd. | Phospholipid derivative |
EP1550675B1 (en) | 2002-09-30 | 2008-01-02 | Nof Corporation | Phospholipid derivative |
CA2513144C (en) | 2003-01-06 | 2012-03-13 | Nof Corporation | Phospholipid derivative and method for producing the same |
JP4526479B2 (ja) | 2003-03-20 | 2010-08-18 | 日油株式会社 | リン脂質誘導体 |
CA2705785A1 (en) * | 2006-11-14 | 2008-05-22 | Saul Yedgar | Use of lipid conjugates in the treatment of diseases or disorders of the eye |
JP5591226B2 (ja) | 2008-05-12 | 2014-09-17 | ユニバーシティ・オブ・ユタ・リサーチ・ファウンデイション | 眼内薬物送達装置および関連する方法 |
US9095404B2 (en) | 2008-05-12 | 2015-08-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US10064819B2 (en) | 2008-05-12 | 2018-09-04 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
US9877973B2 (en) | 2008-05-12 | 2018-01-30 | University Of Utah Research Foundation | Intraocular drug delivery device and associated methods |
WO2010074325A1 (en) | 2008-12-25 | 2010-07-01 | Canon Kabushiki Kaisha | Labeling composition for intraocular tissue, labeling method of intraocular tissue, and screening method |
WO2012019121A2 (en) | 2010-08-06 | 2012-02-09 | Board Of Trustees Of The University Of Illinois | Multiplexed supramolecular assemblies for non-viral delivery of genetic material |
ES2908479T3 (es) | 2015-08-26 | 2022-04-29 | Achillion Pharmaceuticals Inc | Compuestos para el tratamiento de trastornos inmunitarios e inflamatorios |
AR106018A1 (es) | 2015-08-26 | 2017-12-06 | Achillion Pharmaceuticals Inc | Compuestos de arilo, heteroarilo y heterocíclicos para el tratamiento de trastornos médicos |
RU2018145364A (ru) | 2016-06-27 | 2020-07-28 | Ачиллион Фармасьютикалс, Инк. | Хиназолиновые и индольные соединения для лечения медицинских нарушений |
WO2019191112A1 (en) | 2018-03-26 | 2019-10-03 | C4 Therapeutics, Inc. | Cereblon binders for the degradation of ikaros |
JP2021535112A (ja) | 2018-08-20 | 2021-12-16 | アキリオン ファーマシューティカルズ,インコーポレーテッド | 補体d因子の医学的障害の治療のための医薬化合物 |
EP3866773A4 (en) | 2018-10-16 | 2022-10-26 | Georgia State University Research Foundation, Inc. | CARBON MONOXIDE PRODRUGS FOR THE TREATMENT OF MEDICAL CONDITIONS |
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FR2660193B1 (fr) * | 1990-04-03 | 1994-11-04 | Philippe Maincent | Produit opthalmique comportant des nanocapsules, son procede de preparation et utilisation des nanocapsules. |
DE4120760A1 (de) | 1991-06-24 | 1993-03-04 | 3 M Medica Gmbh | Traegersysteme fuer arzneimittel |
AU4406793A (en) | 1992-06-04 | 1993-12-30 | Clover Consolidated, Limited | Water-soluble polymeric carriers for drug delivery |
US5540935A (en) * | 1993-12-06 | 1996-07-30 | Nof Corporation | Reactive vesicle and functional substance-fixed vesicle |
NZ283658A (en) * | 1994-04-04 | 1999-09-29 | William R Freeman | Compositions and treatment of increased intraocular pressure with phosphonyl-alkyloxy-pyrimidines/purines (nucleosides) |
JP3525516B2 (ja) | 1994-10-27 | 2004-05-10 | 日本油脂株式会社 | 反応性小胞体、小胞体修飾剤および製造方法 |
KR19990063632A (ko) * | 1995-09-21 | 1999-07-26 | 디 헤이쓰, 산드라 우드 | 약물 운송용 트란스사이토시스 매개체 및 상승제 |
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US6071532A (en) * | 1996-10-15 | 2000-06-06 | Emory University | Synthesis of glycophospholipid and peptide-phospholipid conjugates and uses thereof |
NZ336035A (en) * | 1996-11-05 | 2002-03-28 | Childrens Medical Center | Angiogenesis inhibitory composition comprising an inhibitory compound and antiinflammatory drug |
US6258351B1 (en) * | 1996-11-06 | 2001-07-10 | Shearwater Corporation | Delivery of poly(ethylene glycol)-modified molecules from degradable hydrogels |
ES2203072T3 (es) | 1998-02-09 | 2004-04-01 | Enzon Pharmaceuticals, Inc. | Composiciones farmaceuticas que comprenden peg-asparaginasa para el tratamiento de infecciones por vih. |
TWI243057B (en) | 1998-03-26 | 2005-11-11 | Schering Corp | Formulations for protection of peg-interferon alpha conjugates |
JP5183836B2 (ja) | 1998-08-06 | 2013-04-17 | マウンテン ビュー ファーマシューティカルズ,インコーポレイテッド | Peg−尿酸酸化酵素結合体およびその使用 |
WO2000035422A2 (en) * | 1998-12-18 | 2000-06-22 | Hadasit Medical Research Services & Development Ltd. | Method of administering a compound to multi-drug resistant cells |
DE60039416D1 (de) | 1999-02-08 | 2008-08-21 | Human Genome Sciences Inc | Verwendung vom vaskulären endothelialen wachstumsfaktor 2 (vegf-2) |
EP1173221A2 (en) * | 1999-04-23 | 2002-01-23 | Alza Corporation | Releasable linkage and compositions containing same |
US20020064520A1 (en) * | 1999-08-19 | 2002-05-30 | Yanina Rozenberg | Targeted artificial gene delivery |
WO2001051003A2 (en) * | 2000-01-10 | 2001-07-19 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Use of lipid conjugates in the treatment of disease |
US6602498B2 (en) * | 2000-02-22 | 2003-08-05 | Shearwater Corporation | N-maleimidyl polymer derivatives |
KR100777195B1 (ko) | 2000-04-03 | 2007-11-19 | 산텐 세이야꾸 가부시키가이샤 | 송달성 물질 및 이를 이용한 약물 송달 시스템 |
KR20040039428A (ko) * | 2001-09-28 | 2004-05-10 | 산텐 세이야꾸 가부시키가이샤 | 약물-폴리에틸렌글리콜 결합체를 함유하는 안조직 내 주입제 |
DE10161149B4 (de) * | 2001-12-12 | 2007-03-08 | Ursapharm Arzneimittel Gmbh & Co. Kg | Verwendung von Heparin-haltigem Ophthalmikum |
-
2001
- 2001-04-03 KR KR1020027013171A patent/KR100777195B1/ko not_active IP Right Cessation
- 2001-04-03 AU AU2001244713A patent/AU2001244713A1/en not_active Abandoned
- 2001-04-03 CN CNB018074677A patent/CN100479862C/zh not_active Expired - Fee Related
- 2001-04-03 US US10/240,438 patent/US7455855B2/en not_active Expired - Fee Related
- 2001-04-03 EP EP01917801A patent/EP1279406A4/en not_active Withdrawn
- 2001-04-03 CA CA2404737A patent/CA2404737C/en not_active Expired - Fee Related
- 2001-04-03 WO PCT/JP2001/002882 patent/WO2001074400A1/ja active Application Filing
Also Published As
Publication number | Publication date |
---|---|
CA2404737A1 (en) | 2001-10-11 |
US7455855B2 (en) | 2008-11-25 |
EP1279406A1 (en) | 2003-01-29 |
EP1279406A4 (en) | 2007-10-24 |
AU2001244713A1 (en) | 2001-10-15 |
KR100777195B1 (ko) | 2007-11-19 |
CN100479862C (zh) | 2009-04-22 |
US20030144247A1 (en) | 2003-07-31 |
WO2001074400A1 (fr) | 2001-10-11 |
KR20030009414A (ko) | 2003-01-29 |
CA2404737C (en) | 2010-06-29 |
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