CN1211091C - 治疗高胆固醇血症的聚烯丙胺聚合物 - Google Patents
治疗高胆固醇血症的聚烯丙胺聚合物 Download PDFInfo
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- CN1211091C CN1211091C CNB988071118A CN98807111A CN1211091C CN 1211091 C CN1211091 C CN 1211091C CN B988071118 A CNB988071118 A CN B988071118A CN 98807111 A CN98807111 A CN 98807111A CN 1211091 C CN1211091 C CN 1211091C
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Abstract
从患者体内排出胆汁酸的方法，包括给患者服用治疗上有效量的不可吸收的胺聚合物，其特点在于含有化学式(I)所示的重复单元，和它的盐，其中n是正整数，x是零或1到约4之间的整数。
Description
本发明的背景
肠对胆汁酸的重吸收将脂蛋白胆固醇保存在血流中。相反地，血液胆固醇含量可通过减少胆汁酸的重吸收来降低。
一种减少重吸收的胆汁酸量从而降低血清胆固醇的方法是，口服螯合胆汁酸使胆汁酸不能被吸收的化合物。螯合的胆汁酸从而被排掉。
已提出的与胆汁酸螯合的化合物包括各种离子交换聚合物。一种这样的聚合物是消胆胺，是二乙烯苯/苯乙烯和三甲基铵甲基苯乙烯的共聚物。长久以来认为这种聚合物味道很差，砂质，并会引起便秘。最近，提出了多种聚合物，其特点在于在胺聚合物主链上带有疏水取代基和季铵基(Ahlers等人的美国专利5,428,112和5,430,110及Mctaggert等人的美国专利5,462,730，这些文献的内容都通过在此引述而合并于本文)。
本发明的概述
本发明涉及不可预料地发现了一种新型离子交换树脂，其具有改进的胆汁酸螯合特性，致使剂量减小，这样改善了患者的耐受性和配合性，从而提高了组合物的可口性，并且其可相对容易地制备。使用在本发明中的这种聚合物含有如本文所描述的不可吸收的并还可交联的聚合胺。本发明得出的聚合物特性是在对患有高磷酸盐血症的患者进行使用聚合物结合磷酸盐的临床试验期间发现的。本发明聚合胺的特点在于具有一个或多个下列化学式所示的单体单元和它们的盐，
其中n是正整数，x是0或1到约4的整数。聚合物的特征在于可以基本不含一种或多种烷基化的胺单体和/或基本不含一种或多种三烷基铵烷基基团。在较好的具体实施中，聚合物是通过多官能交联剂交联的。
本发明提供了从患者体内排出胆汁酸的有效治疗(从而降低患者的胆固醇含量)，特别是对于血清LDL含量至少为约130mg/dL的患者。本发明还提供了使用本文描述的聚合物制备治疗高胆固醇血症或与胆汁酸螯合的药剂。
附图简要说明
附图表示基线LDL胆固醇与交联的聚烯丙胺对LDL胆固醇影响的关系。
本发明的详细叙述
如上所述，使用在本发明中的聚合物包括上面化学式所示的任意交联的聚合胺。较好的聚合物是聚烯丙胺或聚乙烯胺。重要的是，聚合物的特点在于单体的氨基基团上基本不含取代的或未取代的烷基，如在胺聚合物的烷基化作用中所获得的聚合物。也就是，聚合物的特点在于聚合物基本不含烷基化的胺单体。
聚合物也可以是一种或多种含胺单体或不含胺单体的均聚物或共聚物。其中共聚物是用上面化学式所示的单体制备的，共聚用单体较好地是具有惰性，无毒和/或与胆汁酸螯合的特性。适用的不含胺单体的实例包括乙烯醇，丙烯酸，和乙烯甲酰胺。含胺单体实例较好地包括含上面化学式1的单体。较好地，单体是脂肪族的。最好的是，聚合物是均聚物，如均聚烯丙胺或均聚乙烯胺。
较好地，聚合物通过交联变成不溶于水的。交联剂具有与单体胺基团反应的官能团。或者，交联剂具有与胺单体进行自由基聚合反应的两个或多个乙烯基团。
适用的交联剂实例包括氯代丙烯酰，表氯醇，丁二醇二环氧甘油醚，乙二醇二环氧甘油醚，和二甲基琥珀酸酯。
较好的交联剂是表氯醇因为其有效性高并且成本低。表氯醇的有利之处还因为它的分子量低并有疏水性，维持了聚合胺凝胶的水溶长性。
含交联剂使得聚合物不溶解并完全抗吸收和分解，从而限制了聚合物对胃和肠道的活性。这样，组合物对于它们的活性是非内吸收的，这样在患者体内减小了副作用。通常，交联剂的使用量占单体和交联剂总量的约0.5-25％重量比(更好地占约2.5-20％重量比，最好地占1-10％重量比)。
通常，与胺聚合物反应的交联剂的量为足够产生约0.5％到20％胺的量，在一个较好的具体实施中，约0.5％到20％的胺基团与交联剂反应。本发明较好的聚合物在此领域中是众所周知的，在Holmes-Farley等人的美国专利5,496,545中描述了使用脂肪族胺聚合物治疗高磷酸盐血症。这些聚合物也提及可用作治疗铁过载(Mandeville等人的美国专利5,487,888)。这两项专利的内容都通过在此引述而合并于本文。
通常，非交联的和交联的聚合烯丙胺和聚合乙烯胺在此领域中是众所周知的，和/或是可工业制备的。制备聚烯丙胺和聚乙烯胺，及它们交联的衍生物的方法在上面的美国专利中作了描述，其全部内容都通过在此引述而合并于本文。在Harada等人的美国专利编号4,605,701h 4,528,347(其全部内容都通过在此引述而合并于本文)中也描述了制备聚烯丙胺和交联的聚烯丙胺的方法。
如上所述，聚合物可以以盐的形式服用。这里的“盐”是指在重复单元中的氮基团质子化，产生正电氮原子和负电平衡离子。
可选择阳离子的平衡离子以将对患者的不好的作用降到最小，如下面具体描述的。适用的平衡离子包括Cl、Br、CH3OSO3、HSO4、SO4、HCO3、CO3、乙酸盐、乳酸盐、琥珀酸盐、丙酸盐、丁酸盐、抗坏血酸盐、柠檬酸盐、马来酸盐、叶酸盐、氨基酸衍生物、核苷、脂质、或磷酸脂。平衡离子可以是相同的，或彼此不同的。如，反应产物可包含两种不同类型的平衡离子，两种都与排出的胆汁酸交换。
本发明的聚合物可给患者口服，剂量为从约1mg/kg/天到约1g/kg/天，较好的为约5mg/kg/天到约200mg/kg/天(如在约10mg/kg/天到约2000mg/kg/天之间)；具体的剂量取决于个体患者(如患者的体重和所需排出的胆汁酸的量)。聚合物可以以含水方式或以脱水方式服用如果需要，可调味或加到食物或饮料中以增加患者的可接受性。其他组分如其他胆汁酸螯合剂，治疗高胆固醇血症，动脉硬化或其他相关症状的药物，或惰性组分如人造着色剂也可加入。
适用的服用方式实例包括片剂，胶囊，和散剂(如撒在食物上或混在水或果汁中)。片剂，胶囊或散剂可用能保护组合物在食道中不被分解，但当组合物在胃中及与食物混合经过患者小肠时能被分解的物质包裹。聚合物可单独服用或与药用可接受的载体如，碳酸镁，乳糖，或聚合物可与之形成胶束的磷酸脂一起服用。
本发明可用来治疗患者，特别是患有高胆固醇血症的人，特别是治疗血清LDL含量超过约130mg/dL的患者。
本发明由下列实例作更具体地描述。
实施例
A.聚合物制备
1.聚(乙烯胺)的制备
第一步涉及亚乙基双乙酰胺的制备。
将乙酰胺(118g)，乙醛(44.06g)，乙酸铜(0.2g)和水(300mL)加入到装配有冷凝器，温度计，和机械搅拌器的1升三颈口烧瓶内。加入浓HCl(34mL)，混合物搅拌加热到45-50℃持续24小时。然后真空排除水留下浓稠泥状物，冷却到5℃形成晶体。加入丙酮(200mL)搅拌几分钟，之后将固态物滤出并弃掉。冷却丙酮到0℃并将固态物滤出。固态物用500mL丙酮冲洗，风干18小时得到31.5g的亚乙基双乙酰胺。
下一步涉及从亚乙基双乙酰胺制备乙烯乙酰胺。
将亚乙基双乙酰胺(31.05g)，碳酸钙(2g)，硅藻土541(2g)加入到装配温度计，机械搅拌器和顶部加热的维格罗(Vigroux)分馏柱的500毫升三颈口烧瓶内。加热罐到180-225℃，将混合物在25毫米汞柱真空蒸馏。只收集一种馏分(10.8)，其中除产物外(取决于NMR)含有大量的乙酰胺。将固态产物溶解在异丙醇(30mL)中，生成粗制聚合用乙烯乙酰胺溶液。
混合粗制乙烯乙酰胺溶液(15mL)，二乙烯苯(1g，技术级，纯度55％，混有异构体)，和AIBN(0.3g)，在氮氛围下加热回流90分钟，生成固态沉淀物。将溶液冷却，加入异丙醇(50mL)，离心收集固态物。将固态物用丙醇冲洗两次，用水冲洗一次，在真空烤箱中干燥获得0.8g聚(乙烯乙酰胺)，其用作制备聚(乙烯胺)。
将聚(乙烯乙酰胺)(0.79g)置于内有水(25mL)和浓HCl(25mL)的100mL一颈口烧瓶内。将混合物回流5天，之后滤出固态物，用水冲洗一次，用异丙醇冲洗两次，在真空烤箱中干燥获得0.77g产物。红外线光谱显示有显著量的酰胺(1656cm)保留，没有形成很多胺(1606cm)。将这个反应的产物(约0.84g)悬浮在氢氧化钠(46g)和水(46g)中，加热至沸腾(约140℃)。由于形成泡沫，将温度降低并维持在约100℃2小时。加入水(100mL)，将固态物过滤收集。在水中冲洗一次后，将固态物悬浮在水(500mL)中，用乙酸调节pH到5。将固态物再次滤出，用水冲洗，然后用异丙醇冲洗，在真空烤箱中干燥获得0.51g产物。红外线光谱显示有显著量的胺形成。
2.氢氯化聚(烯丙胺)的制备
在装配有(1)冷凝器，顶部有氮气入口，(2)温度计，(3)机械搅拌器的水套管2升反应锅中加入浓盐酸(360mL)。用反应锅套管中的循环水(水温为0℃)将酸冷却到5℃。维持反应温度在5-10℃，搅拌滴加烯丙胺(328.5mL，250g)。加料完成后，将混合物移出，置于3升一颈口烧瓶内，在60℃通过旋转真空蒸发将206g液态移出。然后加入水(20mL)，液体回到反应釜中。将二氢氯化偶氮(脒丙烷)(0.5g)悬浮在11mL的水中并加入到反应釜中。反应产物混合物在氮氛围下搅拌加热到50℃24个小时。另外加入悬浮在11mL水中的二氢氯化偶氮(脒丙烷)(0.5g)，之后继续搅拌加热14个小时。
这段时间的最后，向反应混合物中加入蒸馏水(100mL)，将液体混合物搅拌冷却。将混合物移出置于2升的分离用漏斗中，之后将其滴加入甲醇(4L)搅拌溶液中，产生固态物。将固态物过滤移出，再悬浮在甲醇(4L)中，搅拌1个小时，过滤收集。然后用甲醇重复冲洗一次，固态物在真空烤箱内干燥获得215.1g的白色粒状的氢氯化聚(烯丙胺)。
3.制备与表氯醇交联的氢氯化聚(烯丙胺)
在5加仑容器中加入如在实例2中描述制备的氢氯化聚(烯丙胺)(1kg)和水(4L)。搅拌混合物溶解氢氯化物，加入固体氢氧化钠(284g)调节pH值。产物溶液冷却到室温，之后搅拌一次加入全部表氯醇交联剂(50mL)，轻轻搅拌产物混合物直至其成凝胶(约35分钟)。可使交联反应在室温下再进行18个小时，之后将聚合物凝胶移出，分批置于有10L水的掺合器中。每份轻轻掺合约3分钟形成粗糙颗粒，然后搅拌1小时过滤收集。通过将固态物悬浮在水中(10L，15L，20L)，将其冲洗三次，搅拌每次的悬浮液1小时，过滤收集每次的固态物。然后将产物固态物悬浮在异丙醇(17L)中冲洗一次，然后过滤收集固态物，之后将固态物在真空烤箱内50℃下干燥18个小时，获得约677g易碎的白色固态粒状交联的聚合物。
4.制备与丁二醇二环氧甘油醚交联的氢氯化聚(烯丙胺)
在5加仑容器中加入如在实例2中描述制备的氢氯化聚(烯丙胺)(500g)和水(2L)。搅拌混合物溶解氢氯化物，加入固体氢氧化钠(134.6g)调节pH值到10。产物溶液在容器内冷却到室温，之后搅拌一次加入全部1，4-丁二醇二环氧甘油醚交联剂(65mL)，轻轻搅拌产物混合物直至其成凝胶(约6分钟)。可使交联反应在室温下再进行18个小时，之后将聚合物凝胶移出，之后在真空烤箱内75℃下干燥24小时。然后将干燥的固态物磨碎，用-30目筛筛过，之后将其悬浮在6加仑水中并搅拌1小时。将固态物滤出，冲洗过程重复两次。然后将产物固态物风干48小时，在真空烤箱内50℃下干燥24小时，获得约415g白色固态交联的聚合物。
5.制备与乙二醇二环氧甘油醚交联的氢氯化聚(烯丙胺)
在100mL有倾口的烧杯内加入如在实例2中描述制备的氢氯化聚(烯丙胺)(10g)和水(40mL)。搅拌混合物溶解氢氯化物，加入固体氢氧化钠调节pH值到10。产物溶液在倾口烧杯内冷却到室温，之后搅拌一次加入全部乙二醇二环氧甘油醚交联剂(2.0mL)，轻轻搅拌产物混合物直至其成凝胶(约4分钟)。可使交联反应在室温下再进行18个小时，之后将聚合物凝胶移出，在500mL甲醇中掺合。将固态物滤出，并悬浮在水(500mL)中，搅拌1小时后，将固态物滤出并重复冲洗过程。将产物固态物在异丙醇(400mL)中冲洗两次，然后将固态物在真空烤箱内50℃下干燥24个小时，获得约8.7g的白色固态交联的聚合物。
6.制备与二甲基琥珀酸酯交联的氢氯化聚(烯丙胺)
在500mL园底烧瓶内中加入如在实例2中描述制备的氢氯化聚(烯丙胺)(10g)，甲醇(100mL)和三乙剂胺(10mL)。搅拌加入二甲基琥珀酸酯交联剂(1mL)，加热回流溶液，30分钟后停止搅拌。18个小时后，溶液冷却到室温，滤出固态物并悬浮在400mL的异丙醇中。然后将固态物滤出，悬浮在水中(1L)。搅拌1小时后，将固态物滤出，重复冲洗过程两次。然后将固态物在异丙醇(800mL)中冲洗一次，将固态物在真空烤箱内50℃下干燥24个小时，获得约5.9g白色固态交联的聚合物。
将聚(氢氯化烯丙胺)水溶液(550lb，50.7％水溶液)用水(571lb)稀释，用氢氧化钠水溶液(171lb，50％水溶液)中和。将溶液冷却到约25℃加入乙腈(1340lb)和表氯醇(26.2lb)。剧烈搅拌溶液21个小时。在这期间，反应器内容物从两相变为颗粒在液态中呈泥状。过滤分离固态凝胶产物。在淘析过程中用水(136,708lb)冲洗凝胶。过滤分离凝胶并用异丙醇冲洗。凝胶与异丙醇(1269lb)成为泥状，过滤分离。异丙醇/水湿凝胶在真空干燥器中60℃下干燥。干燥的产物磨碎并用50目筛筛过，获得适合药理用的产物。
7.对人类血清胆固醇含量的影响
服用稳定剂量基于磷酸盐结合剂的钙和/或铵的血液透析患者加入一周的筛查期。停服磷酸盐结合剂。
那些在消除期表现高磷酸盐血症(血清P04＞6.0mg/dL)的患者符合药物治疗的条件。RenaGel结合剂(表氯醇交联的聚烯丙胺，GelTex Pharmaceuticals，Inc.，Waltham，MA)的起始剂量以高磷酸盐血症的程度为依据。起始剂量为随餐每天三次两个，或三个，或四个465mg的胶囊。在三个接着的每两周的最后，如所需RenaGel结合剂的剂量每餐增加一个胶囊，以使血清含磷在2.5到5.5mg/dL之间(包括2.5mg/dL和5.5mg/dL)。如果血清含磷量降到少于2.5mg/dL，那么每天减少一到三个胶囊的RenaGel结合剂剂量，以使血清含磷量提高到2.5mg/dL以上。
在研究期间当血清含钙量降到正常以下(由中心实验室正常范围确定的)，通过晚上睡前空腹加服不超过1,000mg补充钙如碳酸盐的钙元素，或通过提高透析液的钙浓度，使血清含钙量回到正常范围内。可提供含300mg钙元素的TUMS EX 750mg片剂。如果患者更喜欢其他配方，其他品牌的碳酸钙或乙酸钙也可使用。
在治疗阶段终结时，任何剩余的RenaGel胶囊都收回，患者停服磷酸盐结合剂两周。在第二个消除期后，患者停服任何晚上的补充钙，重服他们最初的磷酸盐结合剂。
这段时间的每个星期中，星期一(MWF患者)和星期二(TTS患者)，患者在透析前将血液送实验室化验。同一星期的星期三(MWF患者)和星期四(TTS患者)，调查者询问是否患者有不良反应或已更换了可能显示不良反应的药物治疗，并回顾实验室化验结果。
在第一个消除治疗期和第二个消除期内的所选取的日子中，用24小时检出的方法，由麻萨诸塞医疗中心大学的营养师进行磷摄入量的鉴定。
服用稳定剂量的磷酸盐结合剂的约216名血液透析患者加入研究。患者必须严格控制血清含磷量，并且没有任何显著的临床上不稳定的医疗状况。只有那些在第一消除期患有高磷酸盐血症(血清P04＜6.0mg/dL)的患者(约180名患者)接受治疗。
聚合物以含500mg聚合物的胶囊提供。每个患者开始服用三分之一剂量的聚合物：(i)随餐每天三次两个胶囊(0.93g)；(ii)随餐每天三次三个胶囊(1.4g)；(iii)随餐每天三次四个胶囊(1.86g)。
* Wilcoxon Signed等级测试 ** Kruskal-Wallis精度测试
***剂量含量指研究期间使用的最后实际用量
表
| 全部 | 低量 | 剂量含量***中量 | 高量 | ||||||||||||
| 参数 | 调查 | N | 平均 | 标准偏差 | P-值* | N | 平均 | 标准偏差 | N | 平均 | 标准偏差 | N | 平均 | 标准偏差 | P-值** |
| 胆固醇总量(mg/dL) | -1 | 28 | 214.6 | 41.2 | 13 | 217.0 | 42.4 | 3 | 267.3 | 57.4 | 12 | 198.8 | 23.8 | 0.0978 | |
| 2 | 29 | 221.7 | 35.6 | 12 | 216.5 | 35.0 | 4 | 261.8 | 46.1 | 12 | 214.0 | 25.1 | 0.0790 | ||
| 6 | 28 | 182.2 | 46.2 | 12 | 186.8 | 44.1 | 4 | 234.8 | 63.1 | 12 | 160.1 | 25.6 | 0.0222 | ||
| 10 | 25 | 184.7 | 48.5 | 12 | 195.5 | 47.7 | 4 | 223.5 | 52.9 | 9 | 153.1 | 29.0 | 0.0181 | ||
| 10/最终 | 25 | 184.7 | 48.5 | 12 | 195.5 | 47.7 | 4 | 223.5 | 52.9 | 9 | 153.1 | 29.0 | 0.0181 | ||
| 改变(10/最终-2) | 25 | -37.2 | 29.0 | ＜0.0001 | 12 | -22.3 | 2 | 4 | -38.3 | 25.3 | 9 | -56.7 | 22.3 | 0.0098 | |
| 12 | 25 | 208.1 | 42.1 | 12 | 202.6 | 38.4 | 4 | 267.3 | 45.6 | 9 | 189.2 | 18.0 | 0.0291 | ||
| 改变(12-10) | 24 | 23.1 | 34.2 | 0.0006 | 12 | 7.1 | 40.7 | 4 | 43.8 | 12.9 | 8 | 36.8 | 16.2 | 0.0306 | |
| LDL胆固醇(mg/dL) | -1 | 27 | 145.0 | 34.1 | 13 | 147.2 | 32.2 | 3 | 191.1 | 40.2 | 12 | 131.2 | 24.9 | 0.0494 | |
| 2 | 29 | 154.6 | 27.4 | 12 | 147.4 | 16.3 | 4 | 184.6 | 46.2 | 12 | 152.3 | 25.3 | 0.1441 | ||
| 6 | 28 | 110.5 | 33.4 | 12 | 113.3 | 32.4 | 4 | 150.5 | 43.9 | 12 | 94.5 | 17.3 | 0.0085 | ||
| 10 | 25 | 109.0 | 37.7 | 12 | 109.5 | 34.6 | 4 | 141.0 | 45.6 | 9 | 94.2 | 32.7 | 0.1750 | ||
| 10/最终 | 25 | 109.0 | 37.7 | 12 | 109.5 | 34.6 | 4 | 141.0 | 45.6 | 9 | 94.2 | 32.7 | 0.1750 | ||
| 改变(10/最终-2) | 25 | -45.7 | 29.3 | ＜0.0001 | 12 | -38.0 | 29.0 | 4 | -43.6 | 28.0 | 9 | -56.8 | 29.9 | 0.2972 | |
| 12 | 25 | 141.0 | 33.6 | 12 | 132.3 | 20.9 | 4 | 194.2 | 37.9 | 9 | 129.0 | 23.8 | 0.0221 | ||
| 改变(12-10) | 24 | 33.0 | 24.8 | ＜0.0001 | 12 | 22.8 | 23.6 | 4 | 53.2 | 17.9 | 8 | 38.2 | 23.9 | 0.0503 | |
| 全部 | 低量 | 剂量含量***中量 | 高量 | ||||||||||||
| 参数 | 调查 | N | 平均 | 标准偏差 | P-值* | N | 平均 | 标准偏差 | N | 平均 | 标准偏差 | N | 平均 | 标准偏差 | P-值** |
| 胆固醇总量(mg/dL) | -1 | 27 | 37.6 | 9.4 | 12 | 39.6 | 10.1 | 3 | 32.7 | 4.7 | 12 | 36.8 | 9.6 | 0.5108 | |
| 2 | 29 | 36.4 | 9.2 | 13 | 37.8 | 9.8 | 4 | 31.3 | 5.0 | 12 | 36.5 | 99.6 | 0.4077 | ||
| 6 | 28 | 38.5 | 10.5 | 12 | 40.3 | 13.1 | 4 | 37.0 | 7.4 | 12 | 37.3 | 8.6 | 0.6622 | ||
| 10 | 25 | 36.5 | 11.1 | 12 | 41.3 | 12.0 | 4 | 34.5 | 6.1 | 9 | 30.9 | 9.3 | 0.1053 | ||
| 10/最终 | 25 | 36.5 | 11.1 | 12 | 41.3 | 12.0 | 4 | 34.5 | 6.1 | 9 | 30.9 | 9.3 | 0.1053 | ||
| 改变(10/最终-2) | 25 | 0.8 | 9.0 | 0.2823 | 12 | 2.8 | 10.3 | 4 | 3.3 | 3.0 | 9 | -3.0 | 8.2 | 0.1000 | |
| 12 | 25 | 38.6 | 11.3 | 12 | 42.0 | 10.1 | 4 | 35.5 | 5.3 | 9 | 35.6 | 14.2 | 0.1986 | ||
| 改变(10-12) | 24 | 0.9 | 8.5 | 0.8018 | 12 | 0.7 | 7.7 | 4 | 1.0 | 2.7 | 8 | 1.3 | 11.8 | 0.7914 | |
| LDL胆固醇(mg/dL) | -1 | 28 | 165.8 | 80.5 | 13 | 164.7 | 93.9 | 3 | 21.7 | 113.0 | 12 | 153.9 | 55.3 | 0.5796 | |
| 2 | 29 | 153.9 | 92.3 | 13 | 156.3 | 103.7 | 4 | 229.5 | 104.0 | 12 | 126.2 | 64.0 | 0.2165 | ||
| 6 | 28 | 165.5 | 89.5 | 12 | 165.7 | 80.8 | 4 | 236.5 | 123.4 | 12 | 141.7 | 80.7 | 0.2408 | ||
| 10 | 25 | 196.2 | 165.3 | 12 | 223.4 | 222.6 | 4 | 240.0 | 65.1 | 9 | 140.3 | 81.8 | 0.0994 | ||
| 10/最终 | 25 | 196.2 | 165.3 | 12 | 223.4 | 222.6 | 4 | 240.0 | 65.1 | 9 | 140.3 | 81.8 | 0.0994 | ||
| 改变(10/最终-2) | 25 | 38.2 | 150.6 | 0.3161 | 12 | 64.3 | 214.4 | 4 | 10.5 | 55.2 | 9 | 15.8 | 41.0 | 0.9199 | |
| 12 | 25 | 142.5 | 91.2 | 12 | 141.7 | 107.2 | 4 | 188.0 | 76.3 | 9 | 123.4 | 74.3 | 0.2964 | ||
| 改变(10-12) | 24 | -54.0 | 151.3 | 0.0135 | 12 | -81.8 | 209.6 | 4 | -52.0 | 34.7 | 8 | -13.4 | 49.7 | 0.2320 | |
8.对健康的年轻、年老、男性及女性志愿者的影响
八个年轻的(19-40岁)和八个年老的(65岁或更年长)健康的志愿男性和女性受试者，接受随餐每天三次2.325克的RanaGel结合剂(表氯醇交联的聚烯丙胺)持续32天。在整个32天研究期间，全部药物在临床研究中心随餐服用。在第0天，在早餐前抽取10ml血样，进行血浆胆固醇含量分析。在第32天，在早餐前抽取第二个10ml血样。受试者在第32天早餐后脱离研究。检测血浆甘油三酸酯和HDL含量，用Friedewald公式计算LDL胆固醇含量。
示图表示基线LDL胆固醇与交联的聚烯丙胺对LDL胆固醇影响的关系。在这些正常的志愿者中基线胆固醇越高，LDL胆固醇的降低越大。全部16个患者LDL胆固醇降低量平均为42mg/dL。研究中五个患者的基线LDL胆固醇低于100mg/dL。对于基线LDL胆固醇高于120mg/dL的11个患者LDL胆固醇降低量为52.5mg/dL。
等同物
虽然本发明已对于其较好的具体实施作了特别演示和声明，但在没有背离本发明精神和范围的情况下可能作出的各种形式和细节的变通，对于此领域中的技术人员是显而易见的，本发明的范围如所附权利要求书所规定。
Claims (15)
1.一种或多种交联的聚合物或其盐在制备从具有至少130mg/gL的血清LDL水平的患者体内排出胆汁酸的药物中的应用，其特征在于所述的聚合物具有下列化学式所示的重复单元：
其中n是正整数，x是零或1到4之间的整数，所说的聚合物与具有与重复单元的胺基基团反应的官能基团的交联剂交联，交联剂的量为单体和交联剂总量的0.5-25％重量比，聚合物不含烷基化的胺单体。
2.根据权利要求1的应用，其中所说的聚合物是通过多官能交联剂交联的聚合物，所说的交联试剂的使用量为占单体和交联剂总量的0.5-25％重量比。
3.根据权利要求2的应用，其中所说交联剂使用量为占单体和交联剂总量的2.5-20％重量比。
4.根据权利要求2的应用，其中所说交联剂包括表氯醇。
5.根据权利要求1的应用，其中所说聚合物是均聚物。
6.根据权利要求5的应用，其中x是1。
7.根据权利要求5的应用，其中x是0。
8.交联的均聚聚烯丙胺在制备从具有至少130mg/dL的血清LDL水平的患者体内排出胆汁酸的药物中的应用，所说的均聚聚烯丙胺与具有与重复单元的胺基基团反应的官能基团的交联剂交联，交联剂的量为单体和交联剂总量的0.5-25％重量比。
9.根据权利要求8的应用，其中所说的交联的均聚聚烯丙胺是通过多官能交联剂交联的聚合物，所说的交联试剂的使用量为占单体和交联剂总量的1-25％重量比。
10.根据权利要求9的应用，其中所说交联剂使用量为占单体和交联剂总量的2.5-20％重量比。
11.根据权利要求10的应用，其中所说交联剂包括表氯醇。
12.交联的均聚聚乙烯胺在制备从具有至少130mg/dL的血清LDL水平的患者体内排出胆汁酸的药物中的应用，所说的均聚聚烯丙胺与具有与重复单元的胺基基团反应的官能基团的交联剂交联，交联剂的量为单体和交联剂总量的0.5-25％重量比。
13.根据权利要求12的应用，其中所说的交联的均聚聚乙烯胺是通过多官能交联剂交联的聚合物，所说的交联试剂的使用量为占单体和交联剂总量的1-25％重量比。
14.根据权利要求13的应用，其中所说交联剂使用量为占单体和交联剂总量的2.5-20％重量比。
15.根据权利要求14的应用，其中所说交联剂包括表氯醇。
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| KR20150127599A (ko) | 2013-03-15 | 2015-11-17 | 모치다 세이야쿠 가부시키가이샤 | 비알코올성 지방간염을 치료하기 위한 조성물 및 방법 |
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-
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- 1997-11-26 US US08/979,096 patent/US6423754B1/en not_active Expired - Lifetime
-
1998
- 1998-06-15 EP EP98930234A patent/EP0996454B1/en not_active Expired - Lifetime
- 1998-06-15 KR KR1019997011968A patent/KR100567751B1/ko not_active IP Right Cessation
- 1998-06-15 MX MXPA99011826A patent/MXPA99011826A/es active IP Right Grant
- 1998-06-15 WO PCT/US1998/012422 patent/WO1998057652A1/en active IP Right Grant
- 1998-06-15 IL IL13343498A patent/IL133434A/xx not_active IP Right Cessation
- 1998-06-15 NZ NZ501719A patent/NZ501719A/en not_active IP Right Cessation
- 1998-06-15 AU AU79675/98A patent/AU735260C/en not_active Expired
- 1998-06-15 AT AT98930234T patent/ATE249228T1/de not_active IP Right Cessation
- 1998-06-15 CN CNB988071118A patent/CN1211091C/zh not_active Expired - Lifetime
- 1998-06-15 JP JP50464599A patent/JP4420143B2/ja not_active Expired - Lifetime
- 1998-06-15 CA CA002294036A patent/CA2294036C/en not_active Expired - Lifetime
- 1998-06-15 DE DE69818058T patent/DE69818058T2/de not_active Expired - Lifetime
- 1998-06-17 MY MYPI98002704A patent/MY125874A/en unknown
- 1998-07-09 TW TW087109749A patent/TW526063B/zh not_active IP Right Cessation
-
2001
- 2001-01-22 HK HK01100549A patent/HK1029920A1/xx not_active IP Right Cessation
-
2002
- 2002-05-29 US US10/158,207 patent/US20030086898A1/en not_active Abandoned
-
2006
- 2006-02-01 US US11/344,862 patent/US20060239959A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112047854A (zh) * | 2020-10-20 | 2020-12-08 | 中国科学院长春应用化学研究所 | 一种n-乙烯基烷基酰胺的制备方法 |
| CN112047854B (zh) * | 2020-10-20 | 2021-07-02 | 中国科学院长春应用化学研究所 | 一种n-乙烯基烷基酰胺的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| US6423754B1 (en) | 2002-07-23 |
| TW526063B (en) | 2003-04-01 |
| EP0996454A1 (en) | 2000-05-03 |
| AU735260C (en) | 2002-03-28 |
| KR20010013943A (ko) | 2001-02-26 |
| KR100567751B1 (ko) | 2006-04-05 |
| CN1263468A (zh) | 2000-08-16 |
| HK1029920A1 (en) | 2001-04-20 |
| ATE249228T1 (de) | 2003-09-15 |
| DE69818058T2 (de) | 2004-07-08 |
| MXPA99011826A (es) | 2002-07-02 |
| NZ501719A (en) | 2001-10-26 |
| MY125874A (en) | 2006-08-30 |
| EP0996454B1 (en) | 2003-09-10 |
| DE69818058D1 (de) | 2003-10-16 |
| IL133434A (en) | 2005-09-25 |
| JP2002516613A (ja) | 2002-06-04 |
| AU735260B2 (en) | 2001-07-05 |
| WO1998057652A1 (en) | 1998-12-23 |
| AU7967598A (en) | 1999-01-04 |
| US20060239959A1 (en) | 2006-10-26 |
| CA2294036A1 (en) | 1998-12-23 |
| JP4420143B2 (ja) | 2010-02-24 |
| CA2294036C (en) | 2007-08-21 |
| US20030086898A1 (en) | 2003-05-08 |
| IL133434A0 (en) | 2001-04-30 |
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