CN100482637C - 用于投递活性剂的化合物和组合物 - Google Patents
用于投递活性剂的化合物和组合物 Download PDFInfo
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- CN100482637C CN100482637C CNB018119182A CN01811918A CN100482637C CN 100482637 C CN100482637 C CN 100482637C CN B018119182 A CNB018119182 A CN B018119182A CN 01811918 A CN01811918 A CN 01811918A CN 100482637 C CN100482637 C CN 100482637C
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Abstract
本发明提供了用于投递活性剂的化合物和组合物,还提供了其施用和制备方法。
Description
发明领域
本发明涉及用于将活性剂诸如生物学或化学活性剂投递至作用靶的化合物。这些化合物很适合与活性剂形成非共价混合物,并通过口服、结肠内、肺部、或其它给药途径施用于动物。本发明还公开了这些组合物的制备和施用方法。
发明背景
投递活性剂的传统方法常常受到生物学、化学和物理屏障的严重限制。通常,这些屏障是由投递经过的环境、投递靶的环境和/或靶自身引起的。生物学和化学活性剂尤其受到这些屏障的影响。
在将具有生物学活性和化学活性的药理学和治疗学试剂投递至动物时,屏障是由机体产生的。物理屏障的范例是某些活性剂相对不能透过但在到达作用靶(诸如循环系统)前必须穿过的皮肤、脂双层和各种器官膜。化学屏障包括但不限于胃肠(GI)道的pH变化和降解酶。
这些屏障在口服投递系统的设计中特别重要。如果没有生物学、化学和物理屏障的话,口服投递是将许多生物学或化学活性剂施用于动物的常规选择。在通常不能进行口服施用的大量试剂中,有生物学或化学活性肽,诸如降钙素和胰岛素;多糖,特别是粘多糖,包括但不限于肝素;类肝素;抗生素;和其它有机物。在胃肠道中,在酸水解、酶、等等的作用下,这些试剂可能迅速失效或遭到破坏。另外,高分子药物的大小和结构可能阻止吸收。
易受影响药物的早期口服施用方法依赖佐剂(如间苯二酚和非离子表面活性剂诸如聚氧乙烯油醚和正十六碳烷基聚乙烯醚)的共施用,从而人为提高肠壁的通透性;以及酶抑制剂(如胰腺胰蛋白酶抑制剂、二异丙基氟磷酸(DFP)和特斯乐(trasylol))的共施用,从而抑制酶促降解。还描述了脂质体作为胰岛素和肝素的药物投递系统。然而,这些药物投递系统不具有广泛的用途,因为:(1)这些系统需要有毒量的佐剂或抑制剂;(2)无法得到合适的低分子量“货物”即活性剂;(3)这些系统稳定性弱和保存期不足;(4)这些系统难以制造;(5)这些系统未能保护活性剂(货物);(6)这些系统会不利的改变活性剂;或(7)这些系统不能容许或促进活性剂的吸收。
最近,类蛋白质微球体已用于投递药物。例如参阅US 5,401,516、US 5,443,841和US RE 35,862。另外,某些经修饰氨基酸已用于投递药物。参阅例如US 5,629,020、US 5,643,957、US 5,766,633、US5,776,888和US 5,866,536。
然而,仍然需要简单、便宜、易于制备且能够通过各种途径投递广泛活性剂的投递系统。
发明概述
本发明提供了可用于投递活性剂的化合物和组合物。本发明涵盖具有如下通式的化合物、或其盐类、或其组合物。
化合物1
本发明的组合物包含至少一种活性剂,优选生物学或化学活性剂,以及至少一种本发明化合物或其盐类。本发明还提供了这些组合物的制备和施用方法。
本发明还提供了包含所述组合物的剂量单位形式。剂量单位形式可以采用固体(诸如片剂、胶囊或颗粒诸如粉剂或囊剂)或液体的形式。
本发明还提供了与本发明组合物一起,尤其是通过口服、结肠内或肺部途径将生物学活性剂施用于需要该试剂的动物的方法,以及使用这些组合物的治疗方法。本发明还提供了在动物中治疗疾病的方法,包括将本发明的组合物施用于需要它的动物。
发明详述
化合物
化合物可以采取羧酸和/或其盐类的形式。盐包括但不限于有机和无机盐,例如碱金属盐,诸如钠、钾和锂;碱土金属盐,诸如镁、钙或钡;铵盐;碱性氨基酸,诸如赖氨酸或精氨酸;和有机胺,诸如二甲胺或吡啶。优选的盐是钠盐。盐可以是单价或多价盐,诸如单钠盐和二钠盐。盐还可以是溶剂化物,包括乙醇溶剂化物。
另外,还可以使用包含一种或多种这类化合物的多氨基酸和肽。
氨基酸指具有至少一个游离氨基的任何羧酸,包括天然存在的和人工合成的氨基酸。多氨基酸指肽(通过肽键相连的两个或多个氨基酸),或通过由其它基团形成的键(它们可以通过例如酯或酸酐键相连)而相连的两个或多个氨基酸。肽的长度可以变化,由两个氨基酸的二肽至几百个氨基酸的多肽。一个或多个氨基酸或肽单位可以是酰化或磺化的。
本文描述的化合物可能衍生自氨基酸,而且根据本公开书和WO96/30036、WO 97/36480、US 5,643,957和US 5,650,386中描述的方法,通过本领域从业人员技术范围内的方法,可以容易的由氨基酸进行制备。例如,可以通过单一氨基酸与适当的酰化剂或胺修饰剂的反应来制备该化合物,所述试剂与氨基酸中存在的游离氨基反应而形成酰胺。正如本领域技术人员所知道的,保护基可用于避免不需要的副反应。关于保护基,参考T.W.Greene,《Protecing Groups in OrganicSynthesis》(有机合成中的保护基),Wiley,纽约,1981,将其公开书收入本文作为参考。
可以通过本领域知道的方法来制造本发明化合物的盐类。例如,可以通过将化合物溶于乙醇并添加氢氧化钠水溶液来制造钠盐。
可以通过重结晶或者通过在一种或多种固相层析支持物上单独或先后进行的分级分离来纯化化合物。合适的重结晶溶剂系统包括但不限于乙腈、甲醇和四氢呋喃。可以在合适的层析支持物诸如矾土上使用甲醇/正丙醇混合物作为流动相进行分级分离;反相层析使用三氟乙酸/乙腈混合物作为流动相;而离子交换层析使用水或适当的缓冲液作为流动相。在进行阴离子交换层析时,优选采用0-500mM氯化钠梯度。
依照一个实施方案,采用化合物的无水形式。
活性剂
适用于本发明的活性剂包括生物学活性剂和化学活性剂,包括但不限于杀虫剂、药理学试剂和治疗学试剂。
例如,适用于本发明的生物学或化学活性剂包括但不限于蛋白质、多肽、肽、激素、多糖(特别是粘多糖混合物)、碳水化合物、脂质、其它有机化合物、特别是自身不穿过(或只有施用剂量的一部分穿过)胃肠粘膜和/或在胃肠道中易于受到酸和酶的化学切割影响的化合物、或其任意组合。
详细范例包括但不限于如下各项,包括它们的合成、天然或重组来源:生长激素(包括人生长激素即hGH、重组人生长激素即rhGH、牛生长激素和猪生长激素)、生长激素释放激素、干扰素(包括α-干扰素、β-干扰素和γ-干扰素)、白介素-1、白介素-2、胰岛素(包括猪胰岛素、牛胰岛素、人胰岛素和人重组胰岛素,并任选地具有抗衡离子,包括钠、锌、钙和铵离子)、胰岛素样生长因子(包括IGF-1)、肝素(包括未分级分离肝素、类肝素(heparinoid)、皮肤素、软骨素、低分子量肝素、极低分子量肝素和超低分子量肝素)、降钙素(包括鲑鱼降钙素、猪降钙素、鳗鱼降钙素和人降钙素)、促红细胞生成素、心钠素、抗原、单克隆抗体、抑生长素、蛋白酶抑制剂、促肾上腺皮质激素、促性腺素释放激素、催产素、促黄体素释放激素、促卵泡激素、葡糖脑苷脂酶、血小板生成素、非格司亭(filgrastim)、前列腺素、环孢菌素、加压素、色甘酸钠(克罗莫格利酸钠(sodium chromoglycate)或克罗莫格利酸二钠)、万古霉素、去铁草酰胺(desferrioxamine)即DFO、甲状旁腺激素即PTH(包括其片段)、抗微生物剂(包括抗真菌剂)、维生素;这些化合物的类似物、片段、模拟物或聚乙二醇即PEG修饰衍生物;或其任意组合。胰岛素的其它合适形式包括但不限于胰岛素的合成形式,正如美国专利号4,421,685、5,474,978和5,534,488中所述,将它们的完整内容收入本文作为参考。
投递系统
本发明的组合物包含投递剂和一种或多种活性剂。在一个实施方案中,通过在施用前混合活性剂,将一种或多种投递剂化合物、或这些化合物的盐类、或包含这些化合物或盐类作为一个或多个单元的多氨基酸或肽用作投递剂。
施用组合物可以采取液体的形式。给药载体可以是水(例如用于鲑鱼降钙素、甲状旁腺激素和促红细胞生成素)、25%丙二醇水溶液(例如用于肝素)和磷酸盐缓冲液(例如用于rhGH)。其它给药载体包括聚乙二醇、山梨醇、甘露醇和蔗糖。可以通过临施用前混合投递剂化合物的溶液与活性剂的溶液来制备给药载体。或者,可以混合投递剂(或活性剂)的溶液与活性剂(或投递剂)的固体形式。还可以混合投递剂化合物和活性剂的干粉。还可以在制造过程中混合投递剂化合物和活性剂。
给药溶液可任选包含添加剂,诸如磷酸盐缓冲盐、柠檬酸、乙二醇或其它分散剂。可以向溶液中掺入稳定化添加剂,优选的浓度范围是大约0.1-20%(w/v)。
或者,施用组合物可以采取固体的形式,诸如片剂、胶囊或颗粒,诸如粉剂或囊剂。可以通过混合固体形式的化合物与固体形式的活性剂来制备固体剂量形式。或者,可以通过本领域知道的方法由化合物与活性剂的溶液获得固体,诸如冻干、沉淀、结晶和固体分散体。
本发明的施用组合物还可以包含一种或多种酶抑制剂。这些酶抑制剂包括但不限于诸如放线酰胺素或表放线酰胺素及其衍生物等化合物。其它酶抑制剂包括但不限于抑酶肽(抑肽酶)和Bowman-Birk抑制剂。
本发明施用组合物中活性剂的用量是特定活性剂有效实现目标指示的目的的量。组合物中活性剂的量通常是药理学、生物学、治疗学或化学有效量。然而,在以剂量单位形式使用组合物时,用量可以低于该量,因为剂量单位形式可以包含多种化合物/活性剂组合物,或者可以包含分开的药理学、生物学、治疗学或化学有效量。然后,可以在合计包含有效量活性剂的累计单位中施用总有效量。
可以通过本领域技术人员知道的方法来测定将要使用的活性剂总量。然而,因为组合物可以更有效的投递活性剂而胜过以前的组合物,所以可以对受试者施用比以前的剂量单位形式或投递系统更少量的生物学或化学活性剂,而仍然达到相同血液水平和/或治疗效果。
本文公开的化合物投递生物学或化学活性剂,特别是在口服、鼻内、舌下、十二指肠内、皮下、经颊、结肠内、直肠、阴道、粘膜、肺部、经皮、皮内、胃肠外、静脉内、肌肉内和眼部系统中,以及穿过血脑屏障。
剂量单位形式还可以包含如下任何一项或组合:赋形剂、稀释剂、崩解剂、润滑剂、增塑剂、着色剂、香味剂、掩味剂、糖、增甜剂、盐、和给药载体,包括但不限于水、1,2-丙二醇、乙醇、橄榄油、或其任意组合。
本发明的化合物和组合物可用于将生物学或化学活性剂施用于任何动物,包括但不限于鸟类,诸如鸡;哺乳动物,诸如啮齿类、牛、猪、狗、猫、灵长类、特别是人;和昆虫。
该系统特别有利的用于投递在其它情况中将因为在活性剂到达其靶区(即投递组合物中的活性剂将要释放的区域)前和进行施用的动物体内遭遇的条件而遭到破坏或效力降低的化学或生物学活性剂。具体而言,本发明的化合物和组合物可用于口服施用活性剂,尤其是那些通常不能口服投递的活性剂或那些需要改进投递的活性剂。
包含化合物和活性剂的组合物可用于将活性剂投递至选定生物学系统,而且活性剂的生物利用率与不使用该投递剂时施用活性剂相比获得增加或改进。可以通过在一段时间内投递更多活性剂、或者在特定时间(诸如进行更快或延迟的投递)或一段时间内(诸如持续投递)投递活性剂来改进投递。
施用后,组合物或剂量单位形式中存在的活性剂被吸收到循环中。易于通过测量血液中的已知药理学活性来评估试剂的生物利用率,如由肝素引起的血液凝结时间的增长,或由降钙素引起的循环钙水平的降低。或者,可以直接测量活性剂自身的循环水平。
优选实施方案的描述
下列实施例例示而非限制本发明。所有分数指重量,除非特别指明。
实施例1:化合物制备
1a. 化合物1的制备
向装有大约50ml二氯甲烷的250ml单颈圆底烧瓶中加入4-氯水杨酸(10.0g,0.0579mol)。开始搅动,并在反应的剩余时间继续搅动。向烧瓶中分若干份加入固体的偶联剂1,1-羰基二咪唑(9.39g,0.0579mol)。加入所有偶联剂后将反应液于室温搅动大约20分钟,然后一边搅动一边向烧瓶中加入4-氨基丁酸乙酯盐酸盐(9.7g,0.0579mol)。由加液漏斗逐滴加入三乙胺(10.49ml,0.0752mol)。用二氯甲烷冲洗加液漏斗。将反应液于室温搅动过夜。
将反应液倒入分液漏斗,并用2N HCl清洗而形成乳浊液。将乳浊液静置两天。然后将乳浊液滤过多孔玻璃漏斗中的硅藻土。将滤出液倒回分液漏斗以分层。用硫酸钠干燥有机层,然后过滤,并通过旋转蒸发浓缩滤出液。用2N NaOH水解产生的固体材料,冷藏过夜,然后重新水解。用2N HCl酸化溶液,并分离形成的固体,真空干燥,并使用甲醇/水重结晶两次。分离并干燥沉淀过夜产生的固体。将固体溶于2NNaOH,并用2N HCl将样品的pH调至pH5。收集固体,HPLC揭示单峰。然后将这些固体在甲醇/水中重结晶,分离,然后真空干燥,得到4.96g(33.0%)4-(4-氯-2-羟基苯甲酰基)氨基丁酸。C11H12ClNO4,分子量257.67,熔点131-133℃。燃烧分析:%C:51.27(计算值),51.27(实测值);%H:4.69(计算值),4.55(实测值);%N:5.44(计算值);5.30(实测值)。H-NMR分析:(d6-DMSO):δ 13.0,s,1H(COOH);δ 12.1,s,1H(OH);δ 8.9,t,1H(NH);δ 7.86,d,1H(酰胺邻位H);δ 6.98,d,1H(酚OH邻位H);δ 6.96,d,1H(酰胺间位H);δ 3.33,m,2H(NH毗邻CH2);δ 2.28,t,2H(COOH毗邻CH2);δ 1.80,m,2H(NHβ位脂肪族CH2和COOHβ位CH2)。
1b. 化合物1的其它制备
向装有大约75-100ml二氯甲烷的250ml单颈圆底烧瓶中加入4-氯水杨酸(25.0g,0.1448mol)。开始搅动,并在反应的剩余时间继续搅动。向烧瓶中分成几小份加入固体的偶联剂1,1-羰基二咪唑(23.5g,0.1448mol)。加入所有偶联剂后将反应液于室温搅动大约20分钟,然后一边搅动一边向烧瓶中加入4-氨基丁酸乙酯盐酸盐(24.3g,0.1448mol)。由加液漏斗逐滴加入三乙胺(26.0ml,0.18824mol)。用二氯甲烷冲洗加液漏斗。将反应液于室温搅动过夜。
将反应液倒入分液漏斗,并用2N HCl清洗而形成乳浊液。将乳浊液滤过多孔玻璃漏斗中的硅藻土。将滤出液倒回分液漏斗以分层。用水和盐水清洗有机层,然后用硫酸钠干燥,过滤,并通过旋转蒸发浓缩滤出液。将产生的固体材料用2N NaOH水解过夜。用2N HCl酸化溶液,并将形成的棕色固体用甲醇/水重结晶,热过滤除去不溶黑色物质。分离并干燥沉淀产生的白色固体,得到11.68g(37.0%)4-(4-氯-2-羟基苯甲酰基)氨基丁酸。C11H12ClNO4,分子量257.67,熔点129-133℃。燃烧分析:%C:51.27(计算值),51.26(实测值);%H:4.69(计算值),4.75(实测值);%N:5.44(计算值);5.32(实测值)。H-NMR分析:(d6-DMSO):δ 13.0,s,1H(COOH);δ 12.1,s,1H(OH);δ 8.9,t,1H(NH);δ 7.86,d,1H(酰胺邻位H);δ 6.98,d,1H(酚OH邻位H);δ 6.96,d,1H(酰胺间位H);δ 3.33,m,2H(NH毗邻CH2);δ 2.28,t,2H(COOH毗邻CH2);δ 1.80,m,2H(NHβ位脂肪族CH2和COOHβ位CH2)。
1c. 化合物1的其它制备
(4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸)
将22升五颈圆底烧瓶配备高架搅拌器、装有回流冷凝器的1升Dean-Stark阱、热电偶温度读数器、和加热罩。在干燥氮气下进行下列反应。将试剂正丁醇(5000ml)和4-氯水杨酸(2000g,11.59mol)装入反应瓶。将Dean-Stark阱装满正丁醇(1000ml)。加入浓硫酸(50g)。加热反应混合液,回流大约120小时。在此过程中,在阱中收集了大约206ml水。除去加热罩,并让反应混合液冷却至环境温度。排空并除去Dean-Stark阱。注入去离子水(1000ml)。将两相混合液搅动10分钟。停止搅动,让两相分开。虹吸并丢弃底层水相。向反应混合液中注入10%(wt)碳酸氢钠水溶液(1000ml)。将混合液搅动10分钟。用pH试纸测试反应混合液,确保溶液pH高于pH7。向反应混合液中加入水(500ml)。停止搅动,让两相分开。虹吸并丢弃底层水相。用另外500ml去离子水清洗反应混合液。设置常压蒸馏的反应器,接入5升配衡接收器。蒸馏混合液,直至瓶中温度升至140-150℃。将蒸馏由常压蒸馏改成真空蒸馏。蒸馏装置中的压力慢慢降至100mmHg。瓶中温度下降,并将剩余的正丁醇和正丁醚(反应副产物)蒸馏掉。停止加热,让反应混合液冷却至环境温度。用干燥氮气打破真空。将粗制丁酯转移至真空蒸馏装置的5升烧瓶。在0.2-0.5mmHg压力真空蒸馏粗制丁酯。丢弃在低于40℃头温收集的初馏物。在104-112℃头温收集4-氯-2-羟基苯甲酸丁酯级分。该级分称重2559g。产率是96%。
将22升五颈圆底烧瓶配备高架搅拌器、回流冷凝器、热电偶温度读数器、和加热罩。用氮气吹扫反应器。将4-氯-2-羟基苯甲酸丁酯(2559g,11.2mol)和试剂甲醇(10,000ml)装入反应瓶,并搅动内容物直至获得溶液。将反应混合液滤过布氏漏斗,并倒回反应器。加快搅动速率,并向反应器的顶部空间快速通入氨气。持续通入氨气,直至反应器温度达到45℃。暂停通入氨气,并减慢搅动速率。让反应液冷却至环境温度。如上所述重复通入氨气,直至液相层析指示反应完成。完成反应需要5天7次通入氨气。通过常压蒸馏除去大约半数溶剂。让反应混合液冷却至环境温度,并注入去离子水(5L)。向反应器中缓慢加入浓盐酸(大约500ml),直至反应混合液pH达到pH4-5。通过真空滤过大型烧结玻璃漏斗来收集产生的沉淀。用2000ml去离子水清洗产物滤饼,并于50℃干燥32小时,得到1797g4-氯-2-羟基苯甲酰胺。产率94%。
将22升五颈圆底烧瓶配备高架搅拌器、回流冷凝器、加液漏斗、热电偶温度读数器、和加热罩。用氮气吹扫反应器。将乙腈(4700ml)和4-氯-2-羟基苯甲酰胺(1782g,10.4mol)装入反应瓶,并开始搅动。向反应器中注入吡啶(1133ml,14.0mol)。使用冰浴将产生的反应浆液冷却至低于10℃。将氯甲酸乙酯(1091ml,1237g,11.4mol)注入加液漏斗,并缓慢注入搅动中的反应混合液,使得加液过程中反应混合液的温度不超过15℃。完成氯甲酸乙酯加液后,将反应混合液的温度保持在10-15℃达30分钟。除去冰浴,并将反应混合液温热至环境温度。然后将反应混合液缓慢加热至回流,并保持在该温度达18小时。反应混合液的液相层析分析指示反应只完成了80%。通过常压蒸馏除去大约半数溶剂。首先让反应混合液冷却至环境温度,然后用冰浴冷却至低于10℃。向反应混合液中加入额外吡啶(215ml,2.65mol)。通过加液漏斗向冷的反应混合液中缓慢加入氯甲酸乙酯(235g,2.17mol)。完成氯甲酸乙酯添加后,将反应混合液保持在10-15℃达30分钟。除去冰浴,并将反应混合液温热至环境温度。然后将反应混合液缓慢加热至回流,并保持至该温度达18小时,此后液相层析分析指示反应完成了。首先让反应混合液冷却至环境温度,然后用冰浴冷却至低于10℃。通过加液漏斗缓慢加入水(1600ml),并将产生的反应浆液保持在低于10℃达90分钟。通过真空滤过大型烧结玻璃漏斗来收集固体产物。用去离子水清洗产物滤饼,并于50℃真空干燥18小时,得到1914g褐色固体7-氯-2H-1,3-苯并噁嗪-2,4(3H)-二酮。产率83%。
将22升五颈圆底烧瓶配备高架搅拌器、回流冷凝器、热电偶温度读数器、和加热罩。在干燥氮气下进行下列反应。在氮气吹扫下注入7-氯-2H-1,3-苯并噁嗪-2,4(3H)-二酮(1904g,9.64mol)、4-溴丁酸乙酯(1313ml,9.18mol)、和N,N-二甲基乙酰胺(4700ml)。将反应混合液加热至70℃。在大约40分钟内以五等份向澄清溶液中加入碳酸钠(1119g,10.55mol)。将反应混合液保持在70℃过夜。让反应液冷却至55℃。通过真空滤过烧结玻璃漏斗来除去无机固体。用2B-乙醇(2000ml)冲洗反应瓶,并用该冲洗液清洗滤饼。用去离子水清洁反应瓶。将滤出液倒回干净的反应瓶。在冰浴中冷却滤出液。用加液漏斗缓慢加入去离子水(9400ml)。将冷却的混合液搅动过夜。通过真空滤过烧结玻璃漏斗来回收产生的固体。用去离子水清洗产物滤饼。得到2476.0g乙基3-(4-丁酸)-7-氯-2H-1,3-苯并噁嗪-2,4-(3H)-二酮。产率82.2%。
将12升不锈钢反应器配备高架搅拌器、回流冷凝器、热电偶温度读数器、加液漏斗、和加热罩。在干燥氮气下进行下列反应。向反应器中加入水(3L)和乙基3-(4-丁酸)-7-氯-2H-1,3-苯并噁嗪-2,4-(3H)-二酮(1118g,3.58mol),并开始搅动。向反应浆液中缓慢加入溶于水(2L)的氢氧化钠溶液(574g,14.34mol)。将反应液加热至70℃达6小时,然后让其缓慢冷却至环境温度。将反应混合液滤过布氏漏斗。
将22升五颈圆底烧瓶配备高架搅拌器、回流冷凝器、热电偶温度读数器、和加液漏斗。向反应器中注入去离子水(1880ml)和浓盐酸(1197g,12.04mol)。通过加液漏斗将上述水解液缓慢加到酸液中。通过加入额外的盐酸(160ml,1.61mol)将产生的反应浆液的pH调至3。通过滤过烧结玻璃漏斗收集产物固体,并在真空炉中于50℃干燥24小时,得到1109.3g白色固体4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸。产率是定量的。
1d. 无水4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸钠的制备
将22升五颈圆底烧瓶配备高架搅拌器、回流冷凝器、热电偶温度读数器、和加热罩。在干燥氮气下进行下列反应。向反应器中加入试剂丙酮(13000ml)和4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸(500.0g,1.94mol),并开始搅动。将反应浆液加热至50℃,直至获得混浊的棕色溶液。通过贴有Whatman#1滤纸的温热压滤器,将温热溶液抽入干净的22升反应器。一边搅动一边将澄清的黄色滤出液加热至50℃。一边维持剧烈搅动,一边向反应器中注入氢氧化钠溶液(50%水溶液,155g,1.94mol)。完成加碱后,将反应液加热至回流(60℃)达2.5小时,然后让其缓慢冷却至环境温度。通过真空滤过烧结玻璃漏斗来分离产物,并在真空电炉中于50℃干燥24小时,得到527.3g灰白色固体4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸钠。产率97.2%。
1e. 一水合4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸钠的制备
将22升烧瓶配备高架搅拌器。加入去离子水(2000ml)和4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸(380.0g,1.47mol),并开始搅动。向反应器中加入溶于水(500ml)的氢氧化钠溶液(59.0g,1.48mol)。向反应器中加入水(1500ml),并加热产生的反应浆液,直至完全获得溶液。让反应混合液冷却至环境温度,然后在减压下浓缩至干燥。由烧瓶刮取产生的固体,并于50℃真空干燥,得到401.2g灰白色固体一水合4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸钠。产率96.9%。
1f. 通过异丙醇溶剂化物制备4-[(4-氯-2-羟基苯甲酰基)氨基]丁
酸钠
将1升四颈圆底烧瓶配备高架搅拌器、回流冷凝器、热电偶温度读数器、和加热罩。在干燥氮气下进行下列反应。向反应器中加入异丙醇(400ml)和4-[(4-氯-2-羟基-苯甲酰基)氨基]丁酸(25.0g,0.09mol),并开始搅动。将反应浆液加热至50℃,直至获得混浊的棕色溶液。通过贴有Whatman#1滤纸的温热压滤器,将温热溶液滤入干净的1升反应器。一边搅动一边将澄清的黄色滤出液加热至62℃。一边维持剧烈搅动,一边向反应器中注入氢氧化钠溶液(50%水溶液,7.2g,0.09mol)。完成加碱后,将反应液加热至回流(72℃),然后让其缓慢冷却至环境温度。通过真空滤过烧结玻璃漏斗来分离产物,并于50℃真空干燥24小时,得到23.16g灰白色固体4-[(4-氯-2-羟基苯甲酰基)氨基]丁酸钠。产率92%。
1g. 胶囊制备
如下制备用于灵长类给药的胶囊,它包含化合物1的单钠盐(正如实施例1d中制备的)和胰岛素。首先用35目Tyler标准筛筛选化合物1单钠盐和QA307X锌胰岛素晶体(人:由胰岛素原衍生)(重组DNA起源)(可以由印第安纳州印第安纳波利斯市的Eli-Lilly公司购买),并称取需要的量。在合适大小的玻璃研钵中混合使用几何筛选法筛选得到的化合物1单钠盐和胰岛素。用玻璃杵混匀研钵中的材料。用刮刀刮擦研钵的壁。将产生的制剂转移至塑料称量皿中,用于灌制胶囊。将制剂手工装到#0 Torpac明胶硬胶囊(可以由新泽西州Fairfield市的Torpac公司购买)中。每个胶囊的灌装量取决于动物个体的体重。化合物1的胶囊剂量是100mg/kg、75mg/kg和50mg/kg(作为单钠盐)。胰岛素的胶囊剂量是0.25-0.5mg/kg。
实施例2:胰岛素-口服投递
A.大鼠研究
在去离子水中制备投递剂化合物(如下文所示,依照实施例1a或1b制备)和锌人重组胰岛素(可以由加利福尼亚州La Jolla市的Calbiochem-Novabiochem公司购买,产品目录#407694)的口服给药(PO)组合物。通常,向1.5ml水中加入500mg投递剂化合物。搅动产生的溶液并添加一个当量的氢氧化钠,将投递剂化合物的游离酸转变成钠盐。振荡溶液,然后加热(大约37℃)并超声处理。用NaOH或HCl将pH调至大约7-8.5。如果需要,加入额外的NaOH,以获得统一的溶解度,并再次调整pH。(例如,对于化合物1a,向加入了501mg化合物的1.5ml水中总计添加了258.5μl 10N NaOH,最终pH7.73)。然后加水至总体积大约2.4ml并震荡。向溶液中加入来自胰岛素原液(用0.5409g胰岛素和18ml去离子水配制成15mg/ml,用HCl或NaOH调至pH8.15,使用40μl浓HCl、25μl 10N NaOH和50μl 1N NaOH获得澄清溶液)的大约1.25mg胰岛素,并震荡混匀。下文表1列出了最终的投递剂化合物剂量、胰岛素剂量和剂量体积。
给药和取样方案如下。将体重为大约200-250g的雄性
Sprague-Dawley大鼠禁食24小时,并在给药前15分钟施用氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg),需要维持麻醉时再次进行施用。给服药组的五只动物施用给药溶液之一。对于口服,将11cm Rusch 8French导管连接装有移液枪头的1ml注射器。通过导管吸入溶液,使注射器充满给药溶液,然后将导管擦干。将导管插入食道,越过门牙剩下1cm。推动注射器柱塞而施用溶液。
由尾动脉连续采集血液样品,通常在给药后15、30、60、120和180分钟进行。使用胰岛素ELISA测试试剂盒(购自德克萨斯州Webster市的Diagnostic Systems Laboratories公司的试剂盒#DSL-10-1600)测定血清胰岛素水平,修改标准方案,从而为本方案中所用样品的体积和浓度优化标准曲线的灵敏度和线形范围。对每个服药组中五只动物,在每个时间点测量血清人胰岛素浓度(μU/ml)。对每个时间点的五个值取平均值,并将结果作为血清胰岛素浓度对时间作图。下文表1报告了最大值(峰)和曲线下的面积(AUC)。以前的实验揭示,在单独口服人胰岛素后,没有可测量水平的人胰岛素。
B.猴研究
所有动物方案都遵守“实验动物护理原则”,而且得到“实验动物护理和使用委员会(IACUC)”的批准。
用于将胶囊施用于每只动物的给药方案如下。给药前由动物采集基线血浆样品。给药前将每组四只(两雄两雌)体重2-3kg的猕猴禁食4小时,并持续至给药后2小时。临给药前通过肌肉内注射10mg/kg盐酸氯胺酮来麻醉动物。对每只动物施用一粒,其中是不同剂量的化合物1(25-100mg/kg)与不同剂量的胰岛素(0.25-0.5mg/kg)的组合。在整个给药期间提供水,并在给药前夜和整个给药期间提供400ml果汁。用弹性限制器约束动物。将胶囊置于丸药枪中,这是具有放行柱塞和裂口橡胶尖、用来提供胶囊的一种塑料工具。将丸药枪插入动物的食道。推动丸药枪的柱塞,使胶囊通过橡胶尖而进入食道。然后收回丸药枪。紧闭动物的嘴,并由侧面将大约5ml反渗透水施用至口中,以诱导吞咽反射。摩擦动物的咽喉,以进一步诱导吞咽反射。
通过适当静脉的穿刺,在给药前1小时和给药后10、20、30、40和50分钟及1、1.5、2、3、4和6小时,采集含柠檬酸血液样品(每份1ml)。将采集的每份血浆样品分成两份。将一份于-80℃冷冻,并运至另一地点进行胰岛素测定。将另一份用于血糖测定。还有四只猴皮下接受胰岛素(0.02mg/kg)。如上所述采集并分析血液样品。
胰岛素测定
使用胰岛素ELISA测试试剂盒(德克萨斯州Webster市的DSL)测量血清胰岛素水平。
葡萄糖测定
下文表1显示了结果。
实施例3:色甘酸-口服投递
在去离子水中制备包含投递剂化合物(依照实施例1b制备)和色甘酸二钠盐(色甘酸)(威斯康星州密尔沃基市的Si gma)的给药溶液。用一个当量的氢氧化钠将投递剂化合物的游离酸转变成钠盐。震荡该混合液,并置于超声处理器(大约37℃)中。用NaOH水溶液将pH调至大约7-7.5。如果需要,加入额外的NaOH,以获得均一的溶解度,并再次调整pH。震荡混合液以生成均一溶液,如果需要,还使用超声处理和加热。将投递剂化合物溶液混合来自色甘酸原液(175mg/ml,溶于去离子水,如果需要,用NaOH或HCl将pH调至大约7.0,将原液用箔包裹并冻存,然后在使用前融化并加热至大约30℃)的色甘酸。震荡混合液以生成均一溶液,如果需要,还使用超声处理和加热。用NaOH水溶液将pH调至大约7-7.5。然后用水将溶液稀释至期望体积(通常是2.0ml)和浓度,并用箔包裹、保存至使用。下文表2列出了最终的投递剂化合物和色甘酸剂量及剂量体积。
典型的给药和取样方案如下。将体重为大约200-250g的雄性Sprague-Dawley大鼠禁食24小时,并在给药前15分钟用氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg)麻醉,需要维持麻醉时再次进行施用。给药组的五只动物施用给药溶液之一。将11cm Rusch 8 French导管连接装有移液枪头的1ml注射器。通过导管吸入溶液,使注射器充满给药溶液,然后将导管擦干。将导管插入食道,越过门牙剩下1cm。推动注射器柱塞而施用溶液。
由尾动脉采集血液样品,通常在施用后0.25、0.5、1.0和1.5小时进行。通过HPLC测量血清色甘酸浓度。如下制备样品:在Eppendorf管中混合100μl血清与100μl 3N HCl和300μl乙酸乙酯。将离心管震荡10分钟,然后以10,000rpm离心10分钟。将200μl乙酸乙酯层转移至装有67μl 0.1M磷酸盐缓冲液的Eppendorf管。将离心管震荡10分钟,然后以10,000rpm离心10分钟。然后将磷酸盐缓冲液层转移至HPLC瓶,并注入HPLC(柱=Keystone Exsil Amino 150X2mm i.d.,5μm,Keystone Scientific Products公司;流动相=35%缓冲液(68mM KH2PO4,用85%H3PO4调至pH3.0)/65%乙腈;注射体积=10μl;流速=0.30ml/min;色甘酸保留时间=5.5min;检测240nm的吸收)。以前的研究指示,基线值在零左右。
对每个时间点每组动物的结果取平均值。下文表2报告了这些平均值的最高值(即血清色甘酸浓度均值峰水平)。
实施例4:重组人生长激素(rhGH)-口服投递
在磷酸盐缓冲液中制备投递剂化合物(如下文表3所示,依照实施例1a或1b制备)和rhGH的口服强饲法(PO)给药溶液。用一个当量的氢氧化钠将投递剂化合物的游离酸转变成钠盐。通常,在磷酸盐缓冲液中制备投递剂化合物的溶液,搅动,并在制备钠盐时加入一个当量的氢氧化钠(1.0N)。如果需要,加入额外的NaOH,以获得均一的溶解度,并再次调整pH。混合化合物溶液与rhGH原液(混合15mgrhGH粉剂、75mg D-甘露醇、15mg甘氨酸和3.39mg Na2HPO4,然后用2%甘油稀释至15mg rhGH/ml),并稀释至期望体积(通常3.0ml),从而得到最终给药溶液。下文表3列出了化合物和rhGH剂量及剂量体积。
典型的给药和取样方案如下。将体重为大约200-250g的雄性Sprague-Dawley大鼠禁食24小时,并在给药前15分钟施用氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg),需要维持麻醉时再次进行施用。给服药组的五只动物施用给药溶液之一。将11cm Rusch 8 French导管连接装有移液枪头的1ml注射器。通过导管吸入溶液,使注射器充满给药溶液,然后将导管擦干。将导管插入食道,越过门牙剩下1cm。推动注射器柱塞而施用溶液。
由尾动脉连续采集血液样品,通常在施用后15、30、45和60分钟进行。使用rhGH免疫测定法测试试剂盒(购自马萨诸塞州剑桥市的Genzyme Corporation公司的试剂盒#K1F4015)量化血清rhGH浓度。以前的研究指示,基线值在零左右。
对每个时间点每组动物的结果取平均值。下文表3报告了这些平均值的最大值(即血清rhGH浓度均值峰水平)。(在下文未提供标准偏差(SD)或标准误差(SE)的情况中,在测定前合并每个时间点的五个样品。)
实施例5:干扰素-口服投递
在去离子水中制备投递剂化合物(依照实施例1b制备)和人干扰素(IFN)的给药溶液。用一个当量的氢氧化钠将投递剂化合物的游离酸转变成钠盐。通常,在水中制备投递剂化合物的溶液,搅动,并在制备钠盐时加入一个当量的氢氧化钠(1.0N)。震荡该混合液,并置于超声处理器(大约37℃)中。用NaOH水溶液将pH调至大约7.0-8.5。震荡混合液以生成均一悬浮液或溶液,如果需要,还使用超声处理和加热。如果需要,加入额外的NaOH,以获得均一的溶解度,并再次调整pH。将投递剂化合物溶液混合IFN原液(大约22.0-27.5mg/ml,溶于磷酸盐缓冲液),并稀释至期望体积(通常3.0ml)。下文表4列出了最终的投递剂化合物和IFN剂量及剂量体积。
典型的给药和取样方案如下。将体重为大约200-250g的雄性Sprague-Dawley大鼠禁食24小时,并在给药前15分钟施用氯胺酮(44mg/kg)和氯丙嗪(1.5mg/kg),需要维持麻醉时再次进行施用。给服药组的五只动物施用给药溶液之一。将11cm Rusch 8 French导管连接装有移液枪头的1ml注射器。通过导管吸入溶液,使注射器充满给药溶液,然后将导管擦干。将导管插入食道,越过门牙剩下1cm。推动注射器柱塞而施用溶液。
由尾动脉连续采集血液样品,通常在给药后0、15、30、45、60和90分钟进行。使用针对人IFN-α的细胞筛选免疫测定法试剂盒(购自加利福尼亚州卡马里奥市的Biosource International的试剂盒,产品目录#KHC4012)量化血清IFN浓度。以前的研究指示,基线值在零左右。对每个时间点每组动物的结果取平均值。下文表4报告了这些平均值的最大值(即血清IFN浓度均值峰水平)。
将上文提及的专利、申请、测试方法、和发表物完整收入本文作为参考。
本领域技术人员根据上文详述将提出本发明的许多变化。所有这些明显变化都属于所附权利要求书完全要求的范围之内。
Claims (31)
2.权利要求1的化合物,其中所述盐是一钠盐。
3.包含如下成分的组合物:
(1)至少一种蛋白质、多肽、碳水化合物或脂质作为生物学活性剂;和
(2)具有下式的化合物,
其盐类,或其混合物,
所述生物学活性剂选自下组:生长激素、生长激素释放激素、干扰素、白介素-1、白介素-2、胰岛素、胰岛素样生长因子、肝素、类肝素、皮肤素、软骨素、降钙素、促红细胞生成素、心钠素、抗原、单克隆抗体、抑生长素、蛋白酶抑制剂、促肾上腺皮质激素、促性腺素释放激素、催产素、促黄体素释放激素、促卵泡激素、葡糖脑苷脂酶、血小板生成素、非格司亭、前列腺素、环孢菌素、加压素、色甘酸钠、克罗莫格利酸钠、克罗莫格利酸二钠、万古霉素、去铁草酰胺、甲状旁腺激素、抗微生物剂、抗真菌剂、维生素;及其任意组合。
4.权利要求3的组合物,其中生物学活性剂选自下组:人生长激素、重组人生长激素、牛生长激素、猪生长激素、α-干扰素、β-干扰素、γ-干扰素、猪胰岛素、牛胰岛素、人胰岛素、人重组胰岛素、胰岛素样生长因子-1、未分级分离肝素、低分子量肝素、极低分子量肝素、超低分子量肝素、鲑鱼降钙素、鳗鱼降钙素或人降钙素。
5.权利要求4的组合物,其中所述生物活性剂是低分子量肝素。
6.权利要求4的组合物,其中所述生物活性剂是极低分子量肝素。
7.权利要求4的组合物,其中所述生物活性剂是超低分子量肝素。
8.权利要求3的组合物,其中生物学活性剂为胰岛素、人生长激素、干扰素、色甘酸钠或其组合。
9.权利要求3的组合物,其中生物学活性剂为胰岛素。
10.权利要求3的组合物,其中生物学活性剂为干扰素。
11.包含如下成分的剂量单位形式:
(1)权利要求3的组合物;和
(2)(a)赋形剂、
(b)稀释剂、
(c)崩解剂、
(d)润滑剂、
(e)增塑剂、
(f)着色剂、
(g)给药载体,或
(h)其任意组合。
12.权利要求11的剂量单位形式,其中生物学活性剂选自下组:人生长激素、重组人生长激素、牛生长激素、猪生长激素、α-干扰素、β-干扰素、γ-干扰素、猪胰岛素、牛胰岛素、人胰岛素、人重组胰岛素、胰岛素样生长因子-1、未分级分离肝素、低分子量肝素、极低分子量肝素、超低分子量肝素、鲑鱼降钙素、鳗鱼降钙素或人降钙素。
13.权利要求12的剂量单位形式,其中所述生物活性剂是低分子量肝素。
14.权利要求12的剂量单位形式,其中所述生物活性剂是极低分子量肝素。
15.权利要求12的剂量单位形式,其中所述生物活性剂是超低分子量肝素。
16.权利要求11的剂量单位形式,其中生物学活性剂为胰岛素、人生长激素、干扰素、色甘酸钠或其组合。
17.权利要求11的剂量单位形式,其中活性剂为胰岛素。
18.权利要求11的剂量单位形式,其中活性剂为干扰素。
19.权利要求11的剂量单位形式,其中剂量单位形式采取片剂、胶囊、颗粒、粉剂、囊剂或液体的形式。
20.权利要求11的剂量单位形式,其中给药载体是选自下组的液体:水、25%丙二醇水溶液、磷酸盐缓冲液、1,2-丙二醇、乙醇及其任意组合。
21.制备组合物的方法,包括混合如下成分:
(1)至少一种蛋白质、多肽、碳水化合物或脂质作为生物学活性剂;
(2)权利要求1的化合物;和
(3)任选地给药载体;
所述的生物学活性剂选自:生长激素、生长激素释放激素、干扰素、白介素-1、白介素-2、胰岛素、胰岛素样生长因子、肝素、类肝素、皮肤素、软骨素、降钙素、促红细胞生成素、心钠素、抗原、单克隆抗体、抑生长素、蛋白酶抑制剂、促肾上腺皮质激素、促性腺素释放激素、催产素、促黄体素释放激素、促卵泡激素、葡糖脑苷脂酶、血小板生成素、非格司亭、前列腺素、环孢菌素、加压素、色甘酸钠、克罗莫格利酸钠、克罗莫格利酸二钠、万古霉素、去铁草酰胺、甲状旁腺激素、抗微生物剂、抗真菌剂、维生素;及其任意组合。
22.一种组合物,其中包含:
(a)至少一种蛋白质、多肽、碳水化合物或脂质作为生物学活性剂;和
(b)权利要求2的化合物;
所述生物学活性剂选自下组:生长激素、生长激素释放激素、干扰素、白介素-1、白介素-2、胰岛素、胰岛素样生长因子、肝素、类肝素、皮肤素、软骨素、降钙素、促红细胞生成素、心钠素、抗原、单克隆抗体、抑生长素、蛋白酶抑制剂、促肾上腺皮质激素、促性腺素释放激素、催产素、促黄体素释放激素、促卵泡激素、葡糖脑苷脂酶、血小板生成素、非格司亭、前列腺素、环孢菌素、加压素、色甘酸钠、克罗莫格利酸钠、克罗莫格利酸二钠、万古霉素、去铁草酰胺、甲状旁腺激素、抗微生物剂、抗真菌剂、维生素;及其任意组合。
23.权利要求22的组合物,其中所述活性剂是胰岛素。
24.权利要求22的组合物,其中所述活性剂是人生长激素。
25.权利要求22的组合物,其中所述活性剂是重组人生长激素。
26.权利要求22的组合物,其中所述活性剂是色甘酸钠。
27.权利要求22的组合物,其中所述活性剂是肝素。
28.权利要求22的组合物,其中所述活性剂是降钙素。
29.权利要求22的组合物,其中所述活性剂是甲状旁腺激素。
30.一种固体口服剂型,其中包含:
(A)权利要求22-29中任一项的组合物;以及
(B)(a)赋形剂;
(b)稀释剂;
(c)崩解剂;
(d)润滑剂;
(e)增塑剂;
(f)着色剂;
(g)给药载体;或
(h)其任何组合。
31.权利要求30的固体口服剂型,其中所述固体单位剂型是片剂或胶囊。
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