CN113143958A - 扩大使用硅酸锆组合物及其使用方法 - Google Patents
扩大使用硅酸锆组合物及其使用方法 Download PDFInfo
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- CN113143958A CN113143958A CN202110531403.9A CN202110531403A CN113143958A CN 113143958 A CN113143958 A CN 113143958A CN 202110531403 A CN202110531403 A CN 202110531403A CN 113143958 A CN113143958 A CN 113143958A
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Abstract
本发明涉及扩大使用硅酸锆组合物及其使用方法。本发明涉及具有低于0.6ppm的铅含量的硅酸锆组合物,以及以超过200‑L的反应器体积制造具有低于1.1ppm的铅含量的硅酸锆的方法。对于给予硅酸锆的剂量要求的扩大使用而言,本发明的硅酸锆的铅含量在被认为可接受的水平范围内。
Description
本申请是申请日为2016年10月10目的中国专利申请201680059460.9“扩大使用硅酸锆组合物及其使用方法”的分案申请。
相关申请的交叉引用
本申请要求名称为“EXTENDED USE ZIRCONIUM SILICATE COMPOSITIONS ANDMETHODS OF USE THEREOF[扩大使用硅酸锆组合物及其使用方法]”并且于2015年10月14日提交的美国专利申请号14/883,428的权益,将其通过引用以其全文清楚地结合在此。
技术领域
本发明涉及配制用来以升高的速率从胃肠道去除毒素(例如钾离子或铵离子)而不引起不希望的副作用的新颖微孔硅酸锆组合物。这些组合物被制备成呈现用于长期给予以治疗或预防某些病症(即高钾血症)的复发或发生所需的特性。
背景技术
急性高钾血症是由升高的血清钾水平引起的严重的危及生命的病症。钾是参与人体中许多过程普遍存在的离子。钾是最丰富的细胞内阳离子,并且对于许多生理过程(包括维持细胞膜电位、细胞体积的稳态、以及动作电位的传递)而言是至关重要的。其主要膳食来源是蔬菜(番茄和马铃薯)、水果(橙子、香蕉)和肉。血浆中的正常钾水平是在3.5mmol/1-5.0mmol/l之间,其中肾脏是钾水平的主调节器官。肾脏排泄钾是被动的(通过肾小球),且在近端小管和亨利袢的升肢中主动再吸收。存在远端小管和集合管中的钾的主动外排,这两个过程都是由醛固酮控制的。
增加的细胞外钾水平导致细胞的膜电位的去极化。这种去极化打开某些电压门控钠通道,但是不足以产生动作电位。在一段短暂时期后,打开的钠通道灭活并且变得不反应,提高了用来产生动作电位的阈值。这导致神经肌肉的、心脏的和胃肠的器官系统的损伤,并且这一损伤造成看上去患有高钾血症的症状。最令人担忧的是对心脏系统的影响,其中心脏传导的损伤会造成致命的心律失常,例如心脏停搏或心室性震颤。由于致命的心律失常的可能性,高钾血症表现为必须立即校正的急性代谢紧急情况。
当过量产生血清钾(口入摄入、组织分解)时,高钾血症会进一步发展。无效消除(它是高钾血症的最常见病因)可以是激素的(如在醛固酮缺乏症中)、药理学的(用ACE抑制剂或血管紧张素受体阻断剂进行治疗),或更常见地,是由于减弱的肾功能或晚期心脏衰竭。高钾血症的最常见病因是肾功能不全,并且在肾衰竭的程度和血清钾(S-K)水平之间存在密切相关。此外,多种不同常用药物引起高钾血症,例如ACE抑制剂、血管紧张素受体阻断剂、保钾利尿剂(例如阿米洛利、安体舒通)、NSAID(例如布洛芬、萘普生、塞来昔布)、肝素以及某些细胞毒性的和/或抗生素的药物(例如环胞素和甲氧苄啶)。最后,β受体阻断剂、地高辛或琥珀胆碱是高钾血症的其他熟知的病因。此外,晚期程度的充血性心脏病、大量损伤、烧伤或血管内溶血引起高钾血症,如可以是代谢性酸中毒,最常见的是作为糖尿病酮症酸中毒的一部分。
高钾血症的症状有一些是非特异性的并且一般包括不适、心悸和肌无力,或心律失常的体征,例如心悸、心搏快慢交替或眩晕/昏倒。通常,然而,在针对医学障碍的常规筛查血液测试期间或在已经发展了严重的并发症(例如心律失常或猝死)后才检测到高钾血症。通过S-K测量,明显地建立了诊断。
治疗取决于S-K水平。在更温和的情况下(S-K在5mmol/l至6.5mmol/l之间),用钾结合树脂进行急性治疗,结合饮食建议(低钾膳食)并且可能地修改药物治疗(如果用药物治疗引起高钾血症)是护理标准;如果S-K高于6.5mmol/l或如果存在心律失常,钾的应急降低并且在医院环境中的密切监控是强制性的。典型地使用以下治疗:
胰岛素IV(+葡萄糖用来预防低血糖),其将钾移入细胞并且离开血液。
钙补充。钙并不降低S-K,但是它降低了心肌兴奋性,并且因此稳定了心肌,减小了心律失常的风险。
碳酸氢盐。碳酸氢盐离子将刺激将K+交换为Na+,因此导致刺激钠钾ATP酶、渗析(在严重情况下)。
使用硅酸锆或硅酸钛微孔离子交换剂来从血液或透析液去除毒性阳离子和阴离子描述于美国专利号6,579,460、6,099,737、6,332,985和美国2004/0105895,将其各自以其全文结合在此。微孔离子交换剂的附加实例发现于美国专利号6,814,871、5,891,417和5,888,472,将其各自以其全文结合在此。
本发明的诸位发明人已经发现,当在高钾血症的治疗中用于体内去除钾时,已知的硅酸锆组合物可以显示出不希望的效果。具体地,本发明的诸位发明人发现,在动物研究中,给予硅酸锆分子筛组合物关系到混合白细胞炎症、极小急性膀胱炎的发病率,并且在肾盂和尿液中观察到未鉴定的晶体,连同尿液pH的升高。本发明的诸位发明人通过控制硅酸锆组合物的粒度和钠含量,解决了这些问题。参见美国专利号8,802,152和8,808,750,将其各自以其全文结合在此。
此外,已知硅酸锆组合物已经具有以下问题:晶体杂质和不希望地低阳离子交换能力。更多可溶形式的硅酸锆的减少对于减少或消除锆或硅酸锆的全身吸收而言是重要的。本发明的诸位发明人通过以从该组合物中基本上消除ZS-8,导致不希望的水平的ZS-8的方式控制生产条件,解决了这一问题。参见美国专利号8,877,255。
本发明的诸位发明人已经发现,某些硅酸锆组合物对于长期使用而言是有用的,例如在治疗与升高水平的血清钾相关的病症时。在长期治疗方案中使用硅酸锆组合物需要小心控制杂质,特别是组合物中的铅。例如,FDA设置了用于以每天5微克扩大使用的组合物中铅的接受标准。本发明的诸位发明人已经发现,使用已知方法按工业量生产的硅酸锆包含大约1ppm至1.1ppm或更多的铅。甚至当以更高纯度以更小批次制备硅酸锆时(即使用可商购自西格玛-奥德里奇(Sigma-Aldrich)的试剂级材料),发现铅的水平是0.6ppm或更多。因为硅酸锆治疗利用范围从5克至45克每天的剂量,所以铅的水平的降低是必需的。本发明涉及具有通过每日剂量的硅酸锆成为必需的可接受范围内的铅含量的硅酸锆的组合物。
发明内容
本发明涉及阳离子交换组合物,其包含具有式(I)的硅酸锆:
ApMxZr1-xSinGeyOm (I)
其中
A是钾离子、钠离子、铷离子、铯离子、钙离子、镁离子、水合氢离子或其混合物,
M是至少一种骨架金属,其中该骨架金属是铪(4+)、锡(4+)、铌(5+)、钛(4+)、铈(4+)、锗(4+)、镨(4+)、铽(4+)或其混合物,
“p”具有从约1至约20的值,
“x”具有从0至小于1的值,
“n”具有从约0至约12的值,
“y”具有从0至约12的值,
“m”具有从约3至约36的值,并且1≤n+y≤12,
其中该组合物显示出低于0.6ppm的铅含量。优选地,该铅含量范围是从0.1ppm至0.6ppm、更优选地从0.3ppm至0.5ppm、和最优选地从0.3ppm至0.45ppm。在一个实施例中,铅含量是0.38ppm。本发明还涉及按200-L或超过此的反应体积制造硅酸锆,其中铅含量低于1.1ppm。在此实施例中,该铅含量范围是从0.1ppm至1.1ppm、更优选地从0.3ppm至0.5ppm、和最优选地从0.3ppm至0.45ppm。
除了具有希望的水平的铅杂质,该组合物可以显示出使其作为口服摄入的离子陷阱是令人满意的一个或多个特性。在一个方面,该硅酸锆组合物可以具有超过2.3meq/g的钾交换能力,优选地范围是从2.3meq/g至3.5meq/g,更优选地是在3.05meq/g和3.35meq/g的范围内,并且最优选地是约3.2meq/g。在一个实施例中,组合物中7%的颗粒具有小于3微米的直径。在其他实施例中,组合物中小于0.5%的颗粒具有小于1微米的直径。优选地,钠含量按重量计低于12%,并且更优选地,按重量计是9%或更少。该硅酸锆优选地显示出具有在大约15.5和28.9处出现的两个最高峰的XRD衍射图,其中最高峰出现在28.9处。该材料优选地是ZS-9,或主要是ZS-9,具有范围从7至9的pH,并且钾负荷量是在2.7mEq/g和3.7mEq/g之间,并且最优选地是大约3.5。
本发明还涉及给予以上硅酸锆组合物的方法。在一个优选实施例中,经超过5个连续日的时期给予该硅酸锆组合物。
附图说明
图1是多面图,显示硅酸锆Na2.19ZrSi3.01O9.11*2.71H2O(MW 420.71)的结构。
图2显示用于生产硅酸锆的具有挡板的反应容器的示意图。
图3显示用于生产硅酸锆的加工设备的图样。
图4显示根据实例3制备的硅酸锆的粒度分布。
图5显示根据实例3制备的硅酸锆的XRD图。
发明详述
本发明的诸位发明人已经发现,解决了对扩大使用具有低杂质谱的组合物的需要的新颖的硅酸锆分子筛吸收剂。这些硅酸锆组合物符合用于上述硅酸锆组合物的性能标准,而且还显示出减少的杂质,特别是铅,这使得该组合物适合扩大使用。
本发明的诸位发明人已经设计了用于高纯度、高KEC ZS-9晶体的更大规模生产的反应器。参见美国专利号8,802,152;8,808,750;和8,877,255。反应器200具有在其侧壁上的挡板结构204,在反应期间,该挡板结构结合搅拌器201提供晶体的显著提升和悬浮,并且产生高纯度、高KEC ZS-9晶体。图2.除了挡板结构204,改进的反应器还包括用于在结晶期间控制反应温度的冷去或加热套。优选地,该反应器具有至少20-L、更优选地200-L、500-L、2000-L、或5000-L,或在200-L至30,000-L的范围内的体积。
用于生产硅酸锆的工艺流程显示在图3中。向该反应器添加硅酸盐源。现有工艺使用硅酸钠作为硅酸盐的来源,能够制造对于口服给予而言具有希望的特征的硅酸锆。该工艺还使用填充至图3中显示的反应器的50%NaOH溶液、水和乙酸锆。还显示的是干燥器,其中进料原硅酸锆产品。在该干燥器中,清洗、质子化并且干燥硅酸锆,以产生与水性废料一起的希望的硅酸锆。
如以下在实例2中讨论,硅酸盐源是胶体二氧化硅而不是硅酸钠。本发明的诸位发明人发现,在用于制造高质量硅酸锆的已知工艺中替换硅酸钠是无效的。本发明是基于本发明的诸位发明人的发现,其中反应器最初不应填充胶体二氧化硅,而是添加先前混合的氢氧化钠和水。此外,在添加胶体二氧化硅后必须提高搅拌速率,持续至少二十分钟,从而破坏硅键,并且获得良好混合的溶液。可以通过参考以下实例2理解本发明工艺的另外的方面。
根据本发明所述的硅酸锆显示出低于1ppm的铅含量。更优选地,该铅含量范围是从0.1ppm至0.8ppm、更优选地从0.3ppm至O.6ppm、和最优选地从0.3ppm至0.45ppm。在一个实施例中,铅含量是0.38ppm。
具体实施方式
1.一种阳离子交换组合物,其包含具有式(I)的硅酸锆:
ApMxZr1-xSinGeyOm (I)
其中
A是钾离子、钠离子、铷离子、铯离子、钙离子、镁离子、水合氢离子或其混合物,
M是至少一种骨架金属,其中该骨架金属是铪(4+)、锡(4+)、铌(5+)、钛(4+)、铈(4+)、锗(4+)、镨(4+)、铽(4+)或其混合物,
“p”具有从约1至约20的值,
“x”具有从0至小于1的值,
“n”具有从约0至约12的值,
“y”具有从0至约12的值,
“m”具有从约3至约36的值,并且1≤n+y≤12,
其中该组合物显示出低于0.6ppm的铅含量。
2.如实施方案1所述的组合物,其中该铅含量范围是从0.1ppm至0.5ppm。
3.如实施方案1所述的组合物,其中该铅含量范围是从0.3ppm至0.5ppm。
4.如实施方案1所述的组合物,其中该铅含量范围是从0.3ppm至0.45ppm。
5.如实施方案1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径。
6.如实施方案1所述的组合物,其中该组合物中小于0.5%的颗粒具有小于1微米的直径。
7.如实施方案1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量低于12%。
8.如实施方案1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量为9%或更小。
9.如实施方案1所述的组合物,其中该组合物显示出具有在大约15.5和28.9处出现的两个最高峰的XRD衍射图,其中最高峰出现在28.9处。
10.如实施方案1所述的组合物,其中pH范围是从7至9。
11.如实施方案1所述的组合物,其中钾负荷量是在2.7mEq/g和3.7mEq/g之间。
12.如实施方案1所述的组合物,其中钾负荷量为大约3.5。
13.一种用于治疗高钾血症的方法,该方法包括向对其有需要的患者给予实施方案1中所定义的组合物。
14.一种用于治疗高钾血症的方法,该方法包括向对其有需要的患者给予具有低于0.6ppm的铅含量的硅酸锆。
15.如实施方案14所述的方法,其中该铅含量范围是从0.1ppm至0.5ppm。
16.如实施方案14所述的方法,其中该铅含量范围是从0.3ppm至0.5ppm。
17.如实施方案14所述的方法,其中该铅含量范围是从0.3ppm至0.45ppm。
18.如实施方案14所述的方法,其中该组合物中小于7%的颗粒具有小于3微米的直径。
19.如实施方案14所述的方法,其中该组合物中小于0.5%的颗粒具有小于1微米的直径。
20.如实施方案14所述的方法,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量低于12%。
21.如实施方案14所述的方法,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量为9%或更小。
22.如实施方案14所述的方法,其中该组合物显示出具有在大约15.5和28.9处出现的两个最高峰的XRD衍射图,其中最高峰出现在28.9处。
23.如实施方案14所述的方法,其中pH范围是从7至9。
24.如实施方案14所述的方法,其中钾负荷量是在2.7mEq/g和3.7mEq/g之间。
25.如实施方案14所述的方法,其中钾负荷量为大约3.5。
26.如实施方案14所述的方法,其中该给予持续多于5天。
27.一种制造硅酸锆的方法,该方法包括:
将胶体二氧化硅添加至反应器,该反应器具有至少200-L的体积,
使该胶体二氧化硅与乙酸锆反应,以形成硅酸锆;
其中该硅酸锆具有小于1.1ppm的铅含量。
28.如实施方案27所述的方法,其中该铅含量范围是从0.1ppm至1ppm。
29.如实施方案27所述的方法,其中该铅含量范围是从0.1ppm至6ppm。
30.如实施方案27所述的方法,其中该铅含量范围是从0.3ppm至0.5ppm。
31.如实施方案27所述的方法,其中该铅含量范围是从0.3ppm至0.45ppm。
比较实例1
根据以下代表性实例来制备高容量ZS-9晶体。
如下制备反应物。22-L Morton烧瓶装备有顶置搅拌器、热电偶、和平衡加料漏斗。该烧瓶填充有去离子水(8,600g,477.37摩尔)。按大约145rpm至150rpm开始搅拌,并且向该烧瓶添加氢氧化钠(661.0g,16.53摩尔NaOH,8.26摩尔Na2O)。烧瓶内容物经3分钟的时间从24℃放热至40℃,伴随氢氧化钠溶解。搅拌该溶液一个小时,以便允许最初放热至减退。添加硅酸钠溶液(5,017g,22.53摩尔SO2,8.67摩尔Na2O)。硅酸钠可商购自西格玛-奥德里奇(Sigma-Aldrich)。经30min,借助加料漏斗,向此溶液添加乙酸锆溶液(2,080g,3.76摩尔ZrO2)。将所得悬浮液再搅拌30min。
在去离子水(500g,27.75摩尔)的帮助下,将混合物转移至5-G Parr压力容器模型4555。该反应器装有具有蜿蜒的构造的冷却旋管,以便在邻近搅拌器的反应器内提供挡板样结构。冷却旋管并未填充热交换流体,因为它用于此反应,仅是用来提供邻近搅拌器的挡板样结构。
密封盖容器并且以大约230rpm至235rpm搅拌反应混合物,并且经7.5小时,从21℃加热至140℃至145℃,并且保持在140℃至145℃持续10.5小时,然后经6.5小时加热至210℃至215℃,其中获得295psi至300psi的最大压力,然后保持在210℃至215℃,持续41.5小时。随后,经4.5小时的时间,将反应器冷却至45℃。在去离子水(1.0KG)的帮助下,过滤所得白色固体。用去离子水(40L)洗涤固体,直至洗脱滤液的pH小于11(10.54)。在100℃,在真空(25英寸Hg)中干燥代表性部分的湿饼,以给出1,376g(87.1%)呈白色固体的ZS-9。
如在’152名患者中讨论,此实例的特定反应器构造和工艺条件证明,可以实现更高容量的硅酸锆。例如,相对于仅实现处于1.7meq/g至2.3meq/g的范围的容量的现有工艺,实现了范围是从3.8meq/g至3.9meq/g的容量。
本发明的诸位发明人发现,然而,根据此实例生产的材料,显示出0.6ppm的铅含量。使用电感耦合等离子体-质谱分析法(ICP-MS)确定铅含量。如此制备样品:0.1g称重部分与0.5mL氢氟酸、2mL硝酸、1mL盐酸、和1mL纯净水混合。在最高200℃,使用密闭容器微波系统消化样品,直至材料显现溶解。冷却后,添加内标溶液,并且用纯净水稀释至50g生产溶液用于ICP-MS。
硅酸锆产品的铅的主要贡献来自反应物乙酸锆和硅酸钠。此实例说明,即使当试剂级材料(硅酸钠、乙酸锆)用作反应物,铅的水平也会超过它是可接受的水平。
实例2
此实例说明,在500-L反应器中,从硅酸钠和乙酸锆的反应生产硅酸锆。将硅酸钠(148.8kg)和水(100.1kg)添加至500-L反应器,并且以200rpm的速率搅拌。添加氢氧化钠(37.7kg)并且添加剩余的水(100.2kg)。搅拌速率降低至80rpm并且添加乙酸锆(62.0kg)和水(49.4kg),并且允许反应器混合25分钟至35分钟。在210±5℃,以140rpm,加热该反应器从而使材料反应,持续≥48小时。将生成物材料质子化至4.75至5.25的pH,并且干燥至≤5.0%的水分含量。
该组合物具有21.8微米的体积加权平均数,并且具有13.56微米的表面加权平均数。该材料包含1微米以下的小于0.05%的其体积,并且在3微米以下小于1.41%。生成物材料显示出ZS-9的特征XRD图。5至10的2-θ范围内不存在峰值表示没有可检测水平的ZS-8。如在本发明的诸位发明人的现有专利中描述,具有减少量的颗粒状细料并且缺乏可溶形式的硅酸锆(ZS-8)的此材料适合口服给予,例如在高钾血症的治疗中。
然而,本发明的诸位发明人已经发现,根据此实例生产的材料显示出高于提供药物的所需给药的适合水平的铅水平。参见下表2。具体地,发现所得产品具有1.0ppm的铅水平。硅酸锆产品的铅的主要贡献来自反应物乙酸锆(0.28ppm)和硅酸钠(0.38ppm)。在商业规模上,具有更低铅水平的乙酸锆的形式是不可得的。尽管发现其他形式的硅酸盐、胶体二氧化硅具有不可检测的铅水平,但是在用于与乙酸锆反应来形成硅酸锆的以上工艺中,胶体二氧化硅是不适合的。本发明的诸位发明人已经发现,当在试剂中的铅水平不受控制时,在最终产品中的铅水平倾向于更高,这会是这些试剂的批量供应商的问题。当以200-L以及500-L的反应器体积的规模进行反应时,观察到1ppm至1.1ppm级别的类似铅水平。
实例3
此实例说明,在500-L反应器中,从胶体二氧化硅和乙酸锆的反应生产硅酸锆。本发明的诸位发明人发现,为了使胶体二氧化硅与乙酸锆反应,该工艺必须包括另外的步骤和不同搅拌速率。例如,胶体二氧化硅工艺需要增加的搅拌(200rpm)持续≥20分钟的步骤,以便破坏硅键并且获得良好混合的溶液。本发明的诸位发明人发现,在500-L反应器中,通过此工艺,铅水平可以被降低至低于1ppm,并且如以下所示,可以被降低至0.38ppm。
将氢氧化钠(97.2kg)与84.5kg的水混合并且以150rpm搅拌,同时添加108.8kg胶体二氧化硅以相同速率继续搅拌,同时使用10.5kg水来将胶体二氧化硅从加料管线清洗至反应器中。一旦胶体二氧化硅被填充至反应器中,将搅拌增加至200rpm,持续至少20分钟,以便破坏硅键并且获得良好混合的溶液。将搅拌减慢至100rpm,同时添加另外的52.9kg水,并且然后加速至200rpm,持续至少五分钟或更长时间。
然后,将搅拌减慢至150rpm,同时经大约30分钟的时间,添加81.0kg的乙酸锆。在加热前,添加水(62.8kg),并且继续搅拌,持续约30分钟。
尽可能快地将反应器加热至210℃,同时在150rpm混合。将该反应器维持在210±5℃,持续至少36小时。完成时,将材料质子化两次,从而使pH在4.75至5.25的范围内。通过在160℃加热30分钟,将材料干燥,以使水分含量小于5%。
根据此实例制备的所得硅酸锆的粒度分布在图4中显示。该组合物显示出约2%低于3微米的粒度分布。XRD图显示ZS-9的特征,包括在大约15.5和28.9出现的两个最高峰,其中最高峰出现在大约28.9。5至10的2-θ范围内不存在峰值表示没有可检测水平的ZS-8。参见图5。生成物硅酸锆为白色自由流动粉末,基本上不合碎屑和粒子。FTIR图谱显示,在大约799cm-1和917cm-1的条带,这与先前可接受的批次一致。在本发明的诸位发明人的现有专利中显示了适合的FTIR图谱。所得材料的pH为9。测量的钾负荷量为3.5mEq/g。锆含量为约21.7%,硅含量为大约17%,并且钠含量为大约7.3%。最终产品的水分含量为5%。
通过使用胶体二氧化硅的以上工艺生产的最终产品中的铅水平为0.38ppm,这是对于长期给予此组合物而言,适合的水平。
在考虑了在此披露的本发明的说明书和实践之后,本领域技术人员将了解本发明的其他实施例和用途。在此引用的所有参考文献,包括美国和外国专利以及专利申请,都通过引用完整地结合在此。说明书和实例旨在被视为仅是示例性的,本发明的真实范围和精神由以下权利要求书指出。
Claims (21)
1.一种阳离子交换组合物,其包含式 (I) 的硅酸锆:
ApMxZr1-xSinGeyOm (I)
其中
A是钾离子、钠离子、铷离子、铯离子、钙离子、镁离子、水合氢离子或其混合物,
M是至少一种骨架金属,其中该骨架金属是铪(4+)、锡(4+)、铌(5+)、钛(4+)、铈(4+)、锗(4+)、镨(4+)、铽(4+)或其混合物,
“p”具有从1至20的值,
“x”具有从0至小于1的值,
“n”具有从0至12的值,
“y”具有从0至12的值,
“m”具有从3至36的值,并且1 ≤ n + y ≤ 12,
其中该硅酸锆显示出低于0.6 ppm的铅含量。
2.如权利要求1所述的组合物,其中该铅含量范围是从0.1 ppm至0.5 ppm。
3.如权利要求1所述的组合物,其中该铅含量范围是从0.3 ppm至0.5 ppm。
4.如权利要求1所述的组合物,其中该铅含量范围是从0.3 ppm至0.45 ppm。
5.如权利要求1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径。
6.如权利要求1所述的组合物,其中该组合物中小于0.5%的颗粒具有小于1微米的直径。
7.如权利要求1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量低于12%。
8.如权利要求1所述的组合物,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量为9%或更小。
9.如权利要求1所述的组合物,其中该组合物显示出具有在大约15.5和28.9处出现的两个最高峰的XRD衍射图,其中最高峰出现在28.9处。
10.如权利要求1所述的组合物,其中pH范围是从7至9。
11.如权利要求1所述的组合物,其中钾负荷量是在2.7 mEq/g和3.7 mEq/g之间。
12.如权利要求1所述的组合物,其中钾负荷量为3.5。
13.根据权利要求1所述的组合物在制备用于治疗有需要的患者中的高钾血症的药物中的用途,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量低于12%。
14.如权利要求13所述的用途,其中该铅含量范围是从0.1 ppm至0.5 ppm。
15.如权利要求13所述的用途,其中该铅含量范围是从0.3 ppm至0.5 ppm。
16.如权利要求13所述的用途,其中该组合物中小于0.5%的颗粒具有小于1微米的直径。
17.如权利要求13所述的用途,其中该组合物中小于7%的颗粒具有小于3微米的直径,并且钠含量为9%或更小。
18.如权利要求13所述的用途,其中该组合物显示出具有在大约15.5和28.9处出现的两个最高峰的使用铜K-α辐射源生成的XRD衍射图,其中最高峰出现在28.9处。
19.如权利要求13所述的用途,其中pH范围是从7至9。
20.如权利要求13所述的用途,其中钾负荷量是在2.7 mEq/g和3.7 mEq/g之间。
21.如权利要求13所述的用途,其中钾负荷量为3.5。
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