CN101325973A - 寡聚糖醛酸盐用于治疗粘液高粘度的用途 - Google Patents
寡聚糖醛酸盐用于治疗粘液高粘度的用途 Download PDFInfo
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Abstract
本发明提供一种治疗人或非人类对象以对抗呼吸道粘膜粘度过高的方法，该方法包括向所述对象的所述道的粘膜表面施加有效量的生理学上可容许的寡聚糖醛酸盐。
Description
本发明涉及一种使用寡聚糖醛酸盐(oligouronate)治疗人或非人类动物，特别是哺乳动物，对抗升高的粘膜粘度，例如提高粘液的清除，特别是从呼吸道如在COPD(慢性阻塞性肺病)的情况下，特别是鼻窦和肺，尤其是在治疗囊性纤维化(CF)、慢性阻塞性肺病和鼻窦炎。
囊性纤维化是欧洲人群最普通的致死性遗传病。这种病是由编码囊性纤维化跨膜调节因子(CFTR)的基因中的变异，一种存在于人体分泌和其它细胞中的氯离子通道的变异引起的。该病的特征在于在人体中存在粘稠的、顽固的粘液分泌，其能导致肺病、消化问题和不育症。肺中正常的粘膜纤毛清除率不能清除成为由微生物定居的过度粘稠的粘液而提高了粘液的粘度并导致慢性肺炎和阻塞。因此肺病对于大多数的CF病人来说是最大的健康问题并且是死亡的主要因素。
粘液是整个呼吸道，包括肺的正常分泌物。其主要功能是作为保持肺部清洁并保护肺部免遭感染的粘膜纤毛清除系统的一部分。粘膜纤毛清除系统具有三个主要成分：粘液；纤毛；和气道表面液体。这样上皮表面包含粘液分泌杯状细胞和纤毛上皮细胞，并覆盖有气道表面液体层以及在其上有一层粘液，纤毛尖伸入其中。粘液是一种主要由水(约95％wt.)和粘蛋白组成的粘稠凝胶物质，凝胶形成分子是造成粘液物理性能的原因。纤毛是来自上皮细胞表面的很小头发状的伸出物，在含水的、非粘性气道表面液体中以其浸入粘液层中的尖端有节律地振动。粘液层在捕获细菌、病毒、可吸入颗粒物、环境污染物以及细胞碎屑的肺部表面上形成粘着层。纤毛的振动推动这种粘液层和捕获在其中的任何物质朝向嘴运动而清除出肺部。在正常条件下，粘膜纤毛清除系统有效地作用且保持肺的清洁和无感染。假若该系统失效，则有第二道防线-咳嗽。这样当对于刺激或炎症，例如，由于可吸入颗粒物或感染响应，分泌的粘液程度增加时，粘液借助于咳嗽的反射作用从肺中射出。
在CF病人中肺中的粘液是比正常人的更稠和更粘，因此这种较粘稠的粘液不能轻易地借助纤毛输送。结果损害了粘膜纤毛清除系统而使肺更易于感染。另外，CF病人的肺似乎是处于一种具有持续低水平发炎并且对通常引起发炎的因子(agent)具有高的反应的高炎症状态下。问题是粘液产生增加是对炎症响应的一部分。假若对借助于粘膜纤毛清除系统或咳嗽过于粘稠而不能清除时则积累了增加的粘液，肺容量下降并且氧通过粘膜的交换量也下降。这为细菌的定居提供了理想的环境，由于其也引起发炎和激活免疫应答，因此给CF病人带来严重的问题。这不仅导致粘液分泌的增加，而且还增加免疫应答细胞和因子如巨噬细胞和溶菌酶的存在。当细菌和巨噬细胞死亡后，它们的细胞内含物被释放到粘液中并且这些包括粘性分子如DNA。此外，某些细菌，例如伯克霍尔德氏菌属(Burkholderia sp)和绿脓假单胞杆菌(Pseudomonas aeruginosa)，也分泌高粘性的多糖，后者情况下是藻酸盐(alginates)。这些分子进一步增高粘液的粘度，在藻酸盐的情况下通过与粘液的粘蛋白基质的相互作用而明显，但是在DNA的情况下通过提高粘蛋白基质内的溶胶相的粘度而明显。
因此维持粘液以一种能通过纤毛输送的形式是治疗CF的关键目标。简单地破坏掉其凝胶状结构的药物将导致粘液成为流体，该流体犹如CF病人的高粘度的粘液那样不可转移。因此重要的是任何治疗药物都不应当破坏掉通过糖蛋白粘蛋白形成的凝胶基质。
现在我们已经发现了使用寡聚糖醛酸盐能实现这一点，所述寡聚糖醛酸盐即带有多个羟基的寡聚物，尤其是含有2个到30个单体残基的寡聚物。
在呼吸道的别处，尤其在鼻窦，特别是在鼻旁窦中，过度粘稠的粘液是有问题的。寡聚糖醛酸盐，也可以使用于解决这些问题。
因此，从一方面看到本发明提供了对抗人或非人类(例如哺乳动物)对象呼吸道粘膜粘度过高(mucosal hyperviscosity))的治疗方法，例如治疗慢性阻塞性肺病、鼻窦炎或囊性纤维化疾病，所述方法包括向所述患者的所述道中的粘膜表面施用有效量的生理学上可容许的多元醇寡聚糖醛酸盐(oligouronate polyol)。
从另一方面看到本发明提供了生理学上可容许的寡聚糖醛酸盐在制备用于治疗呼吸道粘膜粘度过高的药物中的用途。
寡聚糖醛酸盐的施用可以通过任何向粘液分泌物，或向病人呼吸道(例如鼻旁窦道或者更优选的是肺)载有粘液的表面给药的方式。一般是通过吸入引入，例如以液滴(例如，气溶胶)或粉末吸入。
对于寡聚糖醛酸根的平衡离子可以是通常使用的使药物带电的生理学上可容许的离子，例如，钠离子、钾离子、铵离子、氯离子、甲磺酸根、葡甲胺离子。然而最好是不使用能促进藻酸盐胶凝(alginate gelation)的离子，例如第2族金属。
当寡聚糖醛酸盐是合成物质时，优选是具有低于100000Da的重均分子量的天然存在的多糖的衍生物。优选的是3-至28-聚体(mer)，尤其是4-至25-聚体，特别是6-至22-聚体，尤其是8-至15-聚体，特别是10-聚体，例如，具有350至6000Da的分子量，特别是750至4500Da的分子量。可以是单一化合物，也可以是例如，一定聚合度范围的寡聚糖醛酸盐化合物的混合物。而且，寡聚糖醛酸盐中的单体残基，例如单糖基，可相同，也可以不同，并且不是所有都必须带有带电基团，尽管优选的是大部分(例如至少60％，优选至少80％，更优选至少90％)带有带电基团。优选的是基本上大部分，例如至少80％，更优选至少为90％的带电基团具有相同极性。在寡聚糖醛酸盐中，羟基与带电基团的比例优选至少为2∶1，更尤其至少是3∶1。
来自天然源的寡聚糖醛酸盐易于得到，因为许多天然的多糖含有带电荷的糖醛酸(uronate)的残基，例如残基如古洛糖醛酸和半乳糖醛酸残基。
使用常规的多糖溶解技术诸如酶消化和酸水解可以完成多糖对寡糖的裂解以产生本发明有用的寡聚糖醛酸盐。之后以色谱法使用离子交换树脂或通过分级沉淀或溶解使寡聚糖醛酸盐从多糖分解产物中分离。
也可对寡聚糖醛酸盐进行化学改性，包括但不限于改性以加入带电荷的基团(如羧基化或羧甲基化的聚糖)，以及以改变柔性而改性的寡聚糖醛酸盐(例如，通过高碘酸氧化)。
例如在“Handbook of Hydrocolloids”，Phillips和Williams编，CRC，Boca Raton，Florida，USA，2000中对合适的多糖进行了讨论。然而使用藻酸盐是特别优选的，因为这些以甘露糖醛酸(manuronic)(M)和古洛糖醛酸(G)的嵌段共聚物和G-嵌段寡聚物天然存在，易于从藻酸盐原料生产。事实上，通常寡聚糖醛酸优选是寡聚古洛糖醛酸，或者稍差点是寡聚半乳糖醛酸。
当把藻酸盐作为制备寡聚糖醛酸盐的起始物料使用时，古洛糖醛酸的含量视需要可通过用来自A.vinelandii的甘露糖醛酸C-5差向异构酶进行差向异构化而提高。
适合本发明使用的寡聚古洛糖醛酸通常可通过酸解来自Laminariahyperborea的藻酸方便制备，制备方法为在中性pH下溶解，添加无机酸以降低pH至3.4以沉淀寡聚古洛糖醛酸，用弱酸洗涤，于中性pH下再悬浮并冷冻干燥。
从另一方面观察本发明还提供药物组合物，尤其是可吸入的组合物，例如，溶液、悬浮液、分散液或粉末，所述组合物包含生理学上可容许的寡聚糖醛酸盐和生理学上可容许的载体或赋形剂，并优选还有生理学上可容许的粘膜粘度降低剂，例如，核酸裂解酶(例如，DNase如DNase I)、凝溶胶蛋白、硫醇降低剂、乙酰半胱氨酸、氯化钠、不带电荷的低分子量多糖(例如，葡聚糖)、精氨酸(或其它氧化氮前体或合成的刺激物)、或阴离子聚氨基酸(例如，聚ASP或聚GLU)。使用DNase尤其是优选的。寡聚糖醛酸盐通常对成人的给药剂量为1至10000mg，特别是10至1000mg。最佳剂量可通过常规剂量范围实验很容易确定，任选下列动物模型，例如，狗模型的初步研究。
本发明的组合物可以使用常规的药物载体和赋形剂生产，例如，溶剂(如水)、渗透压改性剂、香料、pH调节剂等。它们可含有另外的活性成分，例如能用于破坏不包含在粘液的粘蛋白基质中的生物聚合物(例如DNase，特别是ruDNase)、抗菌剂以及消炎药。使用这种另外的药物和寡聚糖醛酸盐的组合疗法(分开或一起给药)，是本发明方法特别优选的方面。这种另外的药物可以其正常剂量或者甚至较低的剂量，例如，正常剂量的50％使用。
寡聚糖醛酸盐理想的是以喷雾剂给药，优选由水溶液或粉末形式制成气溶胶喷雾剂，例如按体积大小约为纳米至微米(例如，10至50000nm)形式的粒径的粉末。
从另一方面观察，本发明提供包括储存器(reservoir)和液滴发生器(droplet generator)的喷雾施用器，所述储存器包含生理学上可容许的寡聚糖醛酸盐水性溶液。这种喷雾施用器，当然还有寡聚糖醛酸盐，可以用于治疗鼻窦或鼻堵塞或由于一般的寒冷或其它理由产生的阻塞。
现参考下列非限制性实施例和附图对本发明做进一步的说明，其中包括：
图1a至1f是粘蛋白-藻酸盐凝胶以及分别配有葡聚糖、聚乙二醇、DNA、半乳糖醛酸钠寡聚物和古洛糖醛酸钠寡聚物的相同凝胶的复合模量对时间的曲线；
图2和3是显示同样凝胶在胶凝终点时以相对于对照物的百分数表示的复合模量(G*)和相角的柱状图；
图4是显示同样凝胶的流动应力的柱状图表，也以相对于对照物的百分数表示；
图5a和5b显示来自CF病人的经处理和未经处理的痰样品的复合模量G*，图5b显示以相对于对照物(未经处理的痰)的百分数表示的G*；
图5c至5f显示G*对时间的曲线；
图6a和6b表示经处理和未经处理的痰样品的复合粘度(η*)，图6b显示以相对于对照物的百分数表示的η*；和
图7a和7b表示经处理和未经处理的痰样品的相角δ。图7b显示以相对于对照物的百分数表示的δ。
实施例1
检测5种寡聚物对模型粘蛋白-藻酸盐凝胶的作用：
a)低分子量葡聚糖(6000Da)
b)低分子量PEG(3350Da)
c)低分子量DNA
d)半乳糖醛酸钠寡聚物
e)古洛糖醛酸钠寡聚物(G嵌段)
古洛糖醛酸钠寡聚物按上面说明制备并且具有下列特征：
FG 0.87，FM 0.13，FGG 0.83，FGM＝FGM 0.05，FMM 0.08，FGGM＝FMMG 0.04，FMGM 0.02，FGGG 0.79，DP 19。
材料
对照凝胶由0.05M的NaCl中的18mg/ml粘蛋白+0.6mg/ml藻酸盐组成
待测凝胶(test gels)由0.05M的NaCl中的18mg/ml粘蛋白+0.6mg/ml藻酸盐+4mg/ml待测物组成
流变学检测
胶凝-混合样品后立即于37℃下装入流变仪。把温度冷却至10℃(0.5度/分)并且之后保持在10℃下18小时。连续测量样品行为和凝胶发展。
扫频(Frequency sweep)-胶凝后把样品的温度提高至37℃并作为频率的函数监测流变行为。
应力扫描(stress sweep)-于37℃下，作为提高施加的应力的函数监测凝胶行为。
胶凝
一些研究证明古洛糖醛酸钠寡聚物(G嵌段)能置换粘蛋白中的藻酸盐-通过开始胶凝后凝胶的复合模量(G*)随时间的降低观察藻酸盐的相互作用。5种待测凝胶和对照凝胶分别示于图1a至1f中。
在被检测的其它寡聚物中只有半乳糖醛酸钠寡聚物具有类似的作用，表明模量值随时间的下降。其它物质(DNA、PEG、葡聚糖)能引起胶凝的延缓但是通过复合模量的增加表明凝胶继续随时间发展。
对在胶凝期终结时凝胶的复合模量和相角绘图于图2和3中。复合模量是体系的总应答或强度的量度，而相角有关液体状和固体状行为之间的平衡，具有较高的相角表明液体状行为更大。古洛糖醛酸钠寡聚物(G嵌段)导致G*的最大下降并且相角中的最大增加。
来自扫频的凝胶特性
所有的凝胶都显示典型的弱粘弹性凝胶的扫频行为。
来自应力扫描的流动应力
应力扫描用于测定在体系中诱导流动所需的应力。这以相对于对照凝胶中诱导流动所需的应力的百分数绘制于图4中。这给出加入多少物质弱化凝胶基质的指标。G嵌段(古洛糖醛酸钠寡聚物)对流动应力具有最显著的影响，接着是半乳糖醛酸钠寡聚物。
实施例2
对痰的影响
从具有绿脓假单胞菌感染阳性诊断的囊性纤维化病人处收集痰样品。慢慢地搅拌样品，分成若干份，冷冻并贮存在-40℃。
预实验方法：
从冷冻器中取出痰样品并且放入冷藏箱(4℃)中，1小时后检测，在电磁搅拌器上搅拌约10分钟并分成0.5g的多份。除了1份样品，是纯痰样品外其它所有的样品中加入待测介质。所得到的样品是：
A 0.5g痰(纯)
B 0.5g痰+65μl的350mM NaCl溶液(加入古洛糖醛酸盐寡聚物的离子强度)
C 0.5g痰+75μl的150mg/ml古洛糖醛酸钠寡聚物Dp19
D 0.5g痰+75μl的150mg/ml古洛糖醛酸钠寡聚物Dp10
古洛糖醛酸钠寡聚物Dp10(聚合度)具有下列特征：
FG 0.79，FM 0.11，FGG 0.76，FGM＝FMG 0.03，FMM 0.07，FMGG＝FGGM 0.02，FMGM 0.01，FGGG 0.74，FG(红)0.10，FG(合计)0.89，NG＞137，Dp 10
然后慢慢地搅拌混合样品1分钟随后放入冷藏箱5分钟，之后转移至检测用流变仪。
流变学试验：
10℃下使用Rheologica Stress-Tech通用流变仪在板/锥体(cone)(40mm/1°)上进行纯的和混合痰的流变学测量以使蛋白质分解酶的影响最小化。
纯痰和混合有检测介质的痰的流变性分4个不同的步骤完成：
-在0.03的恒定应变和1Hz频率的情况下振荡应变对照物2分钟。
-在0.03的恒定应变和1Hz的频率情况下在预剪切(pre-shear)后(于20s-1剪切速下1分钟)振荡应变对照物60分钟。
-在恒定应变0.03扫频0.1～5Hz的范围。
-在1Hz下应力扫描0.02～20Pa的范围。
图5a是表示60分钟后痰样品在试验终点时的复合模量(G*)的柱状图。图5b是表示如图5a的同样痰样品的柱状图，但是以对照物(纯痰)的％表示。
图5c至5f是痰样品A至D复合模量对时间的作图。
图6a是表示60分钟后痰样品在试验终点时的复合粘度(η*)的柱状图。图6b是表示与图6a相同痰样品的柱状图，但以对照物的％表示。
图7a是表示60分钟后痰样品在试验终点时的相角(phase angle)(δ)的柱状图。图7b是表明与图3a相同痰样品的柱状图，但以对照物的％表示。
古洛糖醛酸盐寡聚物的加入明显地降低了CF病人体外痰的机械性能。复合动力模量(complex dynamic modulus)以及复合动力粘度(complexdynamic viscosity)两者均显著降低，在有些情况下降低至1/5。Dp10似乎比平均Dp19的样品更有效。从所述制备痰样品获得的结果还说明CF的痰在有Dp10G-嵌段存在的情况下获得平衡状机械性能比在有其它组成存在情况下更快(G*和η*与时间无关)。然而，对相角变化的影响没有对G*和η*的影响大。这一点是最重要的，因为它清楚地说明保持粘蛋白网络的机械性能，因此仍能对空气传播污染物起到第一防御线的作用。
实施例3
气溶胶
借助雾化器给药的无菌气溶胶喷雾，是由具有纯度至少为75％古洛糖醛酸盐且聚合度介于5至20的3-10％古洛糖醛酸钠盐嵌段的液体制成的，任选，含有表面活性化合物以稳定气溶胶液滴的大小。
Claims (17)
1.对抗人或非人类对象的呼吸道粘膜粘度过高的治疗方法，该方法包括向所述对象的所述呼吸道的粘膜表面施加有效量的生理学上可容许的寡聚糖醛酸盐。
2.按照权利要求1所述的方法，其用于治疗囊性纤维化。
3.按照权利要求1和2中的任何一项所述的方法，其用于治疗鼻窦炎。
4.按照权利要求1所述的方法，其用于治疗慢性阻塞性肺病。
5.按照权利要求1～4中的任何一项所述的方法，其中将所述寡聚糖醛酸盐给药入病人的气道。
6.按照权利要求1～5中的任一项所述的方法，其中所述寡聚糖醛酸盐包含古洛糖醛酸单体。
7.按照权利要求1～6中的任一项所述的方法，其中所述寡聚糖醛酸盐是4-至25-聚体。
8.生理学上可容许的寡聚糖醛酸盐在制备用于治疗呼吸道粘膜粘度过高的药物的中用途。
9.按照权利要求8所述的用途，其中所述寡聚糖醛酸盐按权利要求6和7中的任一项定义。
10.按照权利要求8和9中的任一项所述的用途，用于制备用于治疗囊性纤维化的可吸入药物。
11.按照权利要求8～10中的任一项所述的用途，用于制备用于治疗鼻窦炎的可吸入药物。
12.按照权利要求8和9中的任一项所述的用途，用于制备用于治疗慢性阻塞性肺病的可吸入药物。
13.可吸入药物组合物，其包含生理学上可容许的寡聚糖醛酸盐和生理学上可容许的载体或赋形剂。
14.按照权利要求13所述的组合物，其还含有生理学上可容许的粘膜粘度降低剂。
15.按照权利要求13和14中的任一项所述的组合物，其含有权利要求6和7中的任一项所述的寡聚糖醛酸盐。
16.按照权利要求13～15中的任一项所述的组合物，其含有脱氧核糖核酸酶。
17.喷雾施药器，其包括储存器和液滴发生器，所述储存器含有生理学上可容许的寡聚糖醛酸盐的水性溶液。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| GB0520375.7 | 2005-10-06 | ||
| GB0520375A GB2430881B (en) | 2005-10-06 | 2005-10-06 | Oligoelectrolyte polyols for the treatment of mucosal hyperviscosity |
| PCT/GB2006/003720 WO2007039754A1 (en) | 2005-10-06 | 2006-10-06 | Use of oligouronates for treating mucus hyperviscosity |
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| CN101325973A true CN101325973A (zh) | 2008-12-17 |
| CN101325973B CN101325973B (zh) | 2013-02-13 |
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| US (2) | US8673878B2 (zh) |
| EP (4) | EP3403657B1 (zh) |
| JP (1) | JP5313677B2 (zh) |
| KR (1) | KR101144576B1 (zh) |
| CN (1) | CN101325973B (zh) |
| AU (1) | AU2006298544B2 (zh) |
| BR (1) | BRPI0616982B8 (zh) |
| CA (1) | CA2624568C (zh) |
| DK (3) | DK3403657T3 (zh) |
| EA (1) | EA015436B1 (zh) |
| ES (3) | ES2390974T3 (zh) |
| GB (1) | GB2430881B (zh) |
| HK (1) | HK1125855A1 (zh) |
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| CN106029079A (zh) * | 2014-02-28 | 2016-10-12 | 阿尔吉法玛公司 | 藻酸盐低聚物在治疗囊性纤维化和与缺陷性cftr离子通道功能相关的其它疾病中的应用 |
| CN106659689A (zh) * | 2014-08-29 | 2017-05-10 | 阿尔吉法玛公司 | 海藻酸盐寡聚物的可吸入粉末配制品 |
| CN115005447A (zh) * | 2022-06-16 | 2022-09-06 | 青岛海关技术中心 | 低聚古罗糖醛酸在制备抗疲劳产品中的应用 |
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| CN107050047B (zh) | 2007-11-27 | 2021-06-11 | 阿尔吉法玛公司 | 无菌水类或无菌油类清创组合物和包含组合制剂的产品 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029079A (zh) * | 2014-02-28 | 2016-10-12 | 阿尔吉法玛公司 | 藻酸盐低聚物在治疗囊性纤维化和与缺陷性cftr离子通道功能相关的其它疾病中的应用 |
| CN106659689A (zh) * | 2014-08-29 | 2017-05-10 | 阿尔吉法玛公司 | 海藻酸盐寡聚物的可吸入粉末配制品 |
| CN115005447A (zh) * | 2022-06-16 | 2022-09-06 | 青岛海关技术中心 | 低聚古罗糖醛酸在制备抗疲劳产品中的应用 |
| CN115005447B (zh) * | 2022-06-16 | 2024-02-06 | 青岛海关技术中心 | 低聚古罗糖醛酸在制备抗疲劳产品中的应用 |
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