CN101677940A - 一种治疗鼻出血的组合物 - Google Patents
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Abstract
本发明公开了一种凝胶组合物,包括a)一种羧基聚亚甲基聚合物;b)甘氨酸;c)钙离子源;和d)水。本发明还公开了一种干组合物,包括组分a),b)和c)。本发明凝胶组合物可以有效预防和治疗鼻出血,该组合物很容易敷到鼻腔,并且用完之后不必清除。
Description
技术领域
本发明涉及一种新的治疗鼻出血的组合物,具体地说,本发明涉及一种预防和治疗鼻出血的凝胶组合物,该组合物很容易敷到鼻腔,并且用完之后不必清除。
背景技术
鼻出血是一种非常常见的疾病。尽管大多数情况下,出血症状是暂时的,非周期性的,但是有些病人会再次出血,产生严重的症状。处理严重鼻出血最常用的方法是出血血管烧灼术。当出血源不可见时,可以用止血垫或充气的橡皮球填充在鼻内,但是这种方法会令病人感到不方便,也不舒服。止血垫一般宽2cm,长40-100cm。止血垫被挤压进鼻子,它通过对鼻粘膜的压力来止血,将会留在鼻内1-4天。充气的橡皮球也通过对鼻粘膜的压力来止血,将会留在鼻内1-2天。不论是止血垫还是充气的橡皮球插入鼻腔时,都会疼痛,妨碍正常呼吸,也可能导致局部感染。因此,提供一种没有这些缺陷的治疗鼻出血的方法是有必要的。
WO 01/00218公开了一种鼻喷雾剂配方,包括死海盐,浓度为0.5-5g/L无菌水,还包括一种缓冲液,该配方基本不含有毒、有机杂质。该配方用于治疗鼻炎、鼻窦炎、鼻出血和术后感染,但该专利没有公开鼻出血的试验结果。
已有对各种鼻腔凝胶和血管缩小药的试验性研究,可参见文献Bende et al,ActaOtolaryngol(Stockh)88,459-461(1979);Bende et al,Acta Otolaryngol(Stockh)102,488-493(1986);Bende et al,Acta Otolaryngol(Stockh)110,124-127(1990)。早期的临床结果显示在周期性鼻出血中纤维蛋白溶解起了重要作用,可参见文献Petruson et al,Acta Otolaryngol(Stockh)suppl.317(1974)。文献Tibbelin et al,ORL(Basel)57,207-209(1995)通过随即双盲、多中心临床试验来研究局部施用止血剂止血环酸(AMCA)凝胶和安慰剂凝胶的效果。两种凝胶都具有有益效果,令人惊奇的是,安慰剂凝胶的效果比止血环酸(AMCA)凝胶(纤维蛋白溶解系统的一种抑制剂)效果稍好,但是差异不显著。
发明内容
本发明提供了一种改良的用作鼻凝胶的组合物,该组合物具有前述已知安慰剂凝胶的所有优点,同时能更有效治疗鼻出血。
为达到上述目的,本发明采取的技术方案为:
一种凝胶组合物,包含
(a)羧基聚亚甲基聚合物;
(b)甘氨酸;
(c)钙离子源;和
(d)水。
其他现有技术中常规的辅料也可以添加到凝胶组合物中,以下将有详细说明。
本发明还提供了一种制备所述新的凝胶组合物的方法,包括按任意顺序将以上(a)、(b)、(c)干物质与水混合。
另外,本发明还提供了一种预防或治疗鼻出血的方法,所述方法为将有效剂量的本发明的凝胶组合物注入人类或动物的鼻腔。
进一步地,本发明还提供了该凝胶组合物在治疗学中的应用,尤其是在治疗鼻出血中的应用。
更进一步地,本发明还提供了该凝胶组合物在预防或治疗鼻出血中的应用。
尽管该组合物在治疗时是以凝胶形式存在的,但也可以先用(a)、(b)、(c)干物质制备组合物,在使用之前制备成凝胶组合物。因此,本发明还提供了一种干组合物,其包括:
(a)羧基聚亚甲基聚合物;
(b)甘氨酸;和
(c)钙离子源。
具体实施方式
以下将对本发明组合物的基本组分的种类和作用做详细说明。
(a)羧基聚亚甲基聚合物
羧基聚亚甲基聚合物(也称卡波姆)是一种聚合物,其由丙烯酸与聚烯基醚或联乙烯乙二醇交联而得到的。卡波姆的基本结构单元是美国俄亥俄州克里夫兰市诺誉(Noveon)公司,有一系列等级的羧基聚亚甲基聚合物出售,它们的商品名为Carbopol(卡波姆)。其等级是根据交联度数和生产条件而定的。天然卡波姆聚合物是白色粉末状,但是它们具有强吸水性,能够吸水膨胀到自身体积的1000倍而形成凝胶。卡波姆本质上是生物惰性的,它在各种外用药中都有很长的安全使用记录。它们吸附于粘膜表面,并从吸附于上皮表面的粘膜层吸水。
当卡波姆进入鼻腔,就能对黏膜和出血血管施压,此时,它的作用与通过对黏膜施压来治疗鼻出血的止血垫的作用是一样的(如背景技术所述)。然而,与止血垫相比,凝胶具有不必清除的优点,因为,凝胶通过黏膜纤毛系统从鼻子向后至喉咙转移,敷用一到两小时后被咽下。
优选地,本发明中的羧基聚亚甲基聚合物为市售的商品,商品名为卡波姆,购买于诺誉(Noveon)公司。卡波姆974P NF和卡波姆971P NF是优选的聚合物。
羧基聚亚甲基聚合物的用量根据聚合物的特性不同而不同。羧基聚亚甲基聚合物的用量一般为干组分总重的5-50wt%,优选为10-35wt%,更优选为15-30wt%,最优选为约20wt%。
本发明凝胶组合物中羧基聚亚甲基聚合物的浓度一般是每升凝胶含羧基聚亚甲基聚合物干重为10-100g,优选为20-50g/L,更优选为30-40g/L,最优选为约35g/L。
(b)甘氨酸
凝胶中的第二种组分为甘氨酸,它是非必须氨基酸,是20种氨基酸中最简单的一种,人体自身能合成甘氨酸。甘氨酸参与了不同类型的代谢反应,并参与了在人体内形成蛋白质的过程。
我们发现,甘氨酸赋予了凝胶高渗透性。水从鼻黏膜流出,这意味着黏膜解除充血,开始收缩,流向血管的血减少,流血可能停止。甘氨酸对人类细胞具有积水性,因此,它可能在鼻黏膜和血管壁的恢复中也起了作用。
甘氨酸是一种可通过商业途径广泛获取的材料。
本发明干组合物中,甘氨酸的含量一般为组分总重的30-90wt%,优选为50-80wt%,更优选为约70wt%。
本发明的凝胶组合物中,甘氨酸的浓度一般为每升凝胶含甘氨酸干重为50-200g,优选为80-150g/L,更优选为110-120g/L,最优选为约117g/L。
(c)钙离子源
第三种基本组成物质为钙离子源(Ca2+)。钙离子参与生物凝血过程,在凝血的最后一步,凝血酶将纤维蛋白原(分子量为340,000)转化为可溶性纤维蛋白。最后,可溶性纤维蛋白转变为不可溶性纤维蛋白,该不可溶性纤维蛋白能更有效抵抗机械力,这样,能够阻止重复流血。不希望受任何理论限制,钙离子的存在,使纤维蛋白能更迅速地转化为不可溶性的形式,由于鼻粘膜变薄,钙离子的吸收增快。
钙离子可以以任何适当的形式存在,但优选为可溶性盐,例如氯化钙,或其他的盐如醋酸盐、磷酸盐、碳酸盐或葡萄糖酸盐。最优选为氯化钙。
钙离子的总量一般为干组分总重的0.005-0.1wt%,优选为0.01-0.05wt%,更优选为0.025-0.040wt%,最优选为约0.035wt%。这个量是基于干组分总重,仅仅表示钙离子的重量。
本发明凝胶组合物中,钙离子的浓度一般为每升凝胶含钙离子10-200mg,优选为20-100mg/L,更优选为40-70mg/L,最优选为约58mg/L。
其他组分
调配凝胶组合物时加入水,例如在对病人施药之前加入水。当水与其他组分混合时,水的用量根据凝胶的粘度来确定。而凝胶的粘度随所用的羧基聚亚甲基聚合物的特性不同而不同。一般来说,每千克凝胶含水750-950g,优选为800-900g/kg,更优选为约850g/kg。
除了上述的三种基本成分外,其他现有技术中常规的辅料也可以添加到凝胶组合物中,如pH调节物(酸、碱、缓冲液),防腐剂(如双萘磺酸银、对羟基甲酸丙酯)、抗氧化剂、色素和染料,芳香物质,赋形剂、载体等等。
工艺条件
为了制备本发明所述的用于临床应用的凝胶组合物,采取了以下步骤。
将钙离子,如氯化钙溶解于水中。在与钙离子混合之前或之后,可以在水中加入适量酸、碱或缓冲物质,以确保最终凝胶的pH适宜,如pH6.5-7.5范围内。然后边搅拌边加入甘氨酸,直至甘氨酸溶解完全。然后一边搅拌一边小心缓慢地加入羧基聚亚甲基聚合物(例如逐渐将粉末洒在水溶液中)。继续搅拌直到所有的聚合物完全溶解。测定凝胶的pH,确保其在要求的pH范围内,即pH6.5-7.5。
凝胶组分混合的顺序可以与前述顺序不同。例如,首先可以将干组分混合,然后加入一定量的水形成适当粘度的凝胶。对于任何干组分的组合,本领域技术人员可以采用试误法等方法来确定形成适当粘度的凝胶所需要的水量。
凝胶的制备可以在任何适宜的温度下进行。但是,在室温条件下制备最方便。
可以根据所属领域技术人员熟悉的方式改变和优化前述步骤的工艺条件。
施药方式
本发明组合物以凝胶形式使用。在敷药之前,患者应当清理鼻涕。最好轻轻将鼻内表面清理干净,以使凝胶和鼻黏膜之间的接触最大化。然后,利用预填充的注射器将凝胶注入流血的鼻孔中。优选地,将整个鼻腔都填满凝胶(这可以通过不断施用凝胶直至患者开始感觉凝胶从鼻腔的后部流向喉咙为止来实现)。然而,如果在填充完成之前,流血已经彻底停止了,就没必要填充满整个鼻腔了。这时,可以在患者的鼻孔内放置一小块棉花或其他适当的塞子。
患者应该一定时间内,例如30分钟内,避免擤鼻涕,使凝胶能发挥作用。
实施例:
以下关于本发明制备和应用的实施例仅用来阐述本发明,本发明保护范围不受该实施例限制。
将504g纯水和352ml(366g)1M氢氧化钠溶液置于同一玻璃容器中。再加入185mgCaCl2·2H2O,搅拌混合物直到CaCl2·2H2O溶解。边搅拌边加入100g甘氨酸直到完全溶解。然后边搅拌边加入15g卡波姆PNF 974和卡波姆PNF971。搅拌速度不断加快,凝胶越来越稠。继续搅拌直到所有卡波姆完全溶解。所有步骤都在室温下进行。测定凝胶,确保pH值在6.5-7.5之间。
Claims (22)
1.一种凝胶组合物,其特征在于:包括:
(a)羧基聚亚甲基聚合物;
(b)甘氨酸;
(c)钙离子源;和
(d)水。
2.根据权利要求1所述的凝胶组合物,其特征在于:所述羧基聚亚甲基聚合物为卡波姆974P NF和/或卡波姆971P NF。
3.根据权利要求1或2所述的凝胶组合物,其特征在于:所述羧基聚亚甲基聚合物的浓度为每升凝胶含羧基聚亚甲基聚合物干重10-100g。
4.根据权利要求3所述的凝胶组合物,其特征在于:所述羧基聚亚甲基聚合物的浓度为每升凝胶含羧基聚亚甲基聚合物干重20-50g。
5.根据权利要求4所述的凝胶组合物,其特征在于:所述羧基聚亚甲基聚合物的浓度为每升凝胶含羧基聚亚甲基聚合物干重30-40g。
6.根据权利要求5所述的凝胶组合物,其特征在于:所述羧基聚亚甲基聚合物的浓度为每升凝胶含羧基聚亚甲基聚合物干重35g。
7.根据以上任一项权利要求所述的凝胶组合物,其特征在于:所述甘氨酸的浓度为每升凝胶含甘氨酸干重50-200g。
8.根据权利要求7所述的凝胶组合物,其特征在于:所述甘氨酸的浓度为每升凝胶含甘氨酸干重80-150g。
9.根据权利要求8所述的凝胶组合物,其特征在于:所述甘氨酸的浓度为每升凝胶含甘氨酸干重110-120g。
10.根据权利要求9所述的凝胶组合物,其特征在于:所述甘氨酸的浓度为每升凝胶含甘氨酸干重117g。
11.根据以上任一项权利要求所述的凝胶组合物,其特征在于:所述钙离子的浓度为每升凝胶含钙离子10-200mg。
12.根据权利要求11所述的凝胶组合物,其特征在于:所述钙离子的浓度为每升凝胶含钙离子20-100mg。
13.根据权利要求12所述的凝胶组合物,其特征在于:所述钙离子的浓度为每升凝胶含钙离子40-70mg。
14.根据权利要求13所述的凝胶组合物,其特征在于:所述钙离子的浓度为每升凝胶含钙离子58mg。
15.一种制备如权利要求1-14任一项所述的组合物的方法,其特征在于:包括以下步骤:按任意顺序,将干物质(a)、(b)、(c)与水混合。
16.一种预防或治疗鼻出血的方法,其特征在于:将有效剂量的权利要求1-14任一项所述的凝胶组合物注入人类或动物的鼻腔。
17.用于治疗的权利要求1-14任一项所述的凝胶组合物。
18.用于预防或治疗鼻出血的权利要求1-14任一项所述的凝胶组合物。
19.一种干组合物,其特征在于:包括:
(a)羧基聚亚甲基聚合物;
(b)甘氨酸;和
(c)钙离子源。
20.权利要求1-19任一项所述的组合物在制备预防或治疗鼻出血的药物中的应用。
21.一种如实施例所述的凝胶组合物。
22.一种如实施例所述的凝胶组合物的制备方法。
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AU2008217608B2 (en) | 2013-01-10 |
BRPI0807732A2 (pt) | 2014-06-03 |
EP2117502B1 (en) | 2016-11-09 |
RU2009134086A (ru) | 2011-03-27 |
AU2008217608A1 (en) | 2008-08-28 |
IL200277A0 (en) | 2010-04-29 |
KR20090130001A (ko) | 2009-12-17 |
GB2447012B (en) | 2011-03-16 |
GB2447012A (en) | 2008-09-03 |
RU2473327C2 (ru) | 2013-01-27 |
HRP20161626T1 (hr) | 2017-03-10 |
US9138406B2 (en) | 2015-09-22 |
ES2606947T3 (es) | 2017-03-28 |
DK2117502T3 (en) | 2017-01-23 |
CA2678706A1 (en) | 2008-08-28 |
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CA2678706C (en) | 2014-11-18 |
WO2008102150A3 (en) | 2009-04-30 |
EP2117502A2 (en) | 2009-11-18 |
ZA200905519B (en) | 2010-10-27 |
PL2117502T3 (pl) | 2017-08-31 |
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