CN1352550A - 酸性缓冲的鼻用喷雾剂 - Google Patents
酸性缓冲的鼻用喷雾剂 Download PDFInfo
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 12
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Abstract
本文公开了缓冲的可流动的pH为4.0－5.0的鼻用喷雾剂。它们主要是水和柠檬酸盐(或柠檬酸盐/磷酸盐)缓冲液。它们还可含有氯化钠、增稠剂和/或防腐剂。该制剂能在模拟流鼻涕的鼻子的条件下维持上述pH。本文还公开了防止鼻病毒的扩散和/或由鼻病毒引起的疾病而使用这些制剂的方法。
Description
相关申请的交叉参考
没有可适用的。
共同发起的研究的声明
本发明在美国政府的支持下，使用NIH拨款基金A140685进行。
背景技术
本发明涉及用于抑制鼻病毒的可喷雾的鼻用制剂。更具体而言，本发明涉及可被喷到人的鼻子中并在体内维持限定的pH值的酸性缓冲溶液。
医生常常给患者使用鼻用喷雾剂，以治疗多种鼻症状。例如，在A.Talbot等人，107 Laryngoscope 500-503(1997)中，作者讨论了使用标准的或高渗的碱性缓冲盐溶液作为鼻用的喷雾剂。这些喷雾剂一般想要治疗多种鼻病症(如窦炎)的症状。
也已知少数温和的酸性鼻用喷雾剂。Atroven鼻用喷雾剂的pH约为4.7，据认为含有抗胆碱能制剂(异丙托溴铵一水化物)、防腐剂苯扎氯铵和EDTA钠、氯化钠、氢氧化钠、盐酸和水。然而，该溶液不是缓冲液，不能在较长的时间里维持鼻子中的低pH。
类似地，NasalCrom鼻用喷雾剂的pH为4.5-6.0，含有色甘酸钠的水溶液和防腐剂。同样，当使用非常缓和的稀释物(基本上为中性pH溶液)处理该制剂时，它立刻变为中性pH。
目前，一种称为ZICAM的鼻用喷雾剂(Gum Tech Intustries)声称可减少普通感冒的影响和持续时间。它含有非缓冲的pH为6.7的喷雾剂溶液葡萄糖酸锌。该喷雾剂的疗效仍在评估中。然而，不论如何，它需要使用昂贵的组分。
已知还有其它的喷雾剂和口服制剂，它们的设计目的是抑制病毒复制因而减轻感冒症状(如果在暴露之前或之后立刻给予)。然而，这些制剂还是要使用昂贵的组分(如ICAM-1)。
已知引起“普通感冒”大部症状起作用的病毒即鼻病毒对基本上是酸性pH的条件敏感。然而，到目前为止，这个知识还没有产生控制普通感冒传染的实用用治疗方法和技术。
其一，人体许多部分对高度酸性条件敏感，并且不能与这些条件接触较长时间。另外，人也不适合接触许多酸性物质(如许多缓冲液)。例如，乙酸常常产生一种不需要的醋味，谷氨酸常氧化成不需要的颜色，天冬氨酸、谷氨酸和酒石酸盐不具有所需的溶解性能，硼酸盐和邻苯二甲酸酯具有毒性副作用，甲酸盐的pH缓冲范围不在正确的范围之内，丙酸盐和琥珀酸盐产生烧灼的感觉。
而且，且不说已经感染了病毒的人需要暂时的病症缓解，还需要(a)防止此人将病毒传染给别人；(b)给予没有传染病的人以一种制剂，以减少他受有传染病的人传染的可能性；和(c)减少一旦传染上病毒后的感染严重性和持续时间。特别理想的是，这些目标以低成本和使患者对其有很好耐受力的技术实现。
这样，可以看出，需要一种改进的鼻用喷雾剂和使用该喷雾剂的方法。
发明的简短概要
本发明一方面提供一种缓冲的可流动的鼻用喷雾剂制剂，其pH为4.0-5.0。它含有水(较佳95-98wt.％)和柠檬酸盐(较佳有0.02M-0.06M柠檬酸盐阴离子)。“柠檬酸盐”可由柠檬酸或碱金属柠檬酸如柠檬酸钠提供。还可有磷酸盐(较佳有0.03M-0.09M磷酸盐阳离子)。
依照本发明，该制剂具有足够的缓冲能力，以便当进行下面所述的“缓冲能力”试验时能维持低于6.0的pH值。在这个试验中，室温下以3∶1的体积比混合给定体积的制剂与Dulbecco磷酸盐缓冲液(pH7.4，从Fisher Scientific买到，目前为Pittsburgh，Pennsylvania)。测定所得溶液的pH，如果pH低于6.0，则该试验通过。
这个试验模拟了将鼻用喷雾剂喷到流鼻涕的鼻子中时由稀释出现的pH改变。正常的鼻子粘液和鼻涕基本上呈中性pH，这倾向于迅速将现有的鼻用喷雾剂变为中性。
该制剂的较佳方面是含有0-0.5wt.％氯化钠和纤维素类增稠剂的鼻用喷雾剂。一种较佳的纤维素类增稠剂是占该组合物0.25-1.0wt.％的甲基纤维素。其它可能的纤维素类增稠剂是微晶纤维素和羟乙基纤维素。增稠剂有助于该鼻用喷雾剂黏附在鼻子的内部(这样，喷雾剂由于打喷嚏或鼻子的呼吸而被吹走的可能性减少)。
一种特别理想的缓冲系统是同时含有柠檬酸盐和磷酸盐的系统。当仅有磷酸盐时，pH太高，当与柠檬酸盐混合时，所需的缓冲性能增加。还需要包括一种或多种标准的鼻用喷雾剂防腐剂，如苯扎氯铵和/或EDTA/EDTA钠。
本发明一方面提供下述用途的方法：
(a)通过将鼻病毒暴露在上述制剂中而将其杀死；
(b)通过将上述制剂喷到人的鼻子中而杀死其中的鼻病毒；和
(c)通过将上述制剂喷到患有或未患有传染病的人的鼻子中，防止鼻病毒的扩散。
本发明提供改进的可杀死人鼻子中鼻病毒的鼻用喷雾剂。用药后可减少因接近患者而被传染的可能性，因而可给那些使用该喷雾剂且没被传染的人提供了预防治疗。还有，这有希望帮助减少那些已感染的患者的症状的持续时间和严重性。
因此，本发明的目的包括：
(a)提供上述种类的鼻用喷雾剂；
(b)提供可在人鼻子中长时间维持pH在4到5.5之间(较佳为5.0)的鼻用喷雾剂；
(c)提供使用这些鼻用喷雾剂以减少由鼻病毒引起的疾病的扩散、严重性和持续时间的方法。
阅读随后的描述将会明白本发明的这些以及其它的目的和优点。下面的描述仅仅是较佳的实施例。因而，为了了解本发明的全部范围，应该注意权利要求书。
详细的描述
我们开始在权利要求书的范围内测试不同的制剂，以确证它们在体外可杀死鼻病毒。我们将鼻病毒和所要求的制剂混合，监测不同时间和温度时鼻病毒的滴度。我们确定，pH越低，溶液的杀死病毒效果越好，所要求的化合物杀死了鼻病毒，而且，在约人体温度的杀死效果比约室温的效果更明显。
在此，我们测试了低pH缓冲液对鼻病毒RV16生存能力的影响。将107TCID50/ml稀释到室温或35℃时预均衡的缓冲液中。在间隔中，将10μL样品转移到含有1mL的冰冷PBS和0.1％白蛋白(PBSA)的试管中。然后确定病毒滴度。
然后我们测试了我们的制剂在非转化细胞(如从肺分离得到的基本的支气管上皮细胞)中对RV16复制的影响。我们的制剂在减少病毒滴度方面非常有效。
在接下来的试验中，我们测定了各种柠檬酸盐与柠檬酸盐/磷酸盐缓冲液的特性。我们发现，在体内柠檬酸盐缓冲液和柠檬酸盐/磷酸盐缓冲液都提供了所需的酸和缓冲能力，而在体外没有对上皮细胞产生不利的损害。
然后我们对人进行一个临床试验，以评估其耐受力。没有发现主要的副作用。
至此，我们迄今较佳制剂如下(gm/L)：
| 制剂1 | 制剂2 | 制剂3 | |
| 柠檬酸 | 10.46 | 5.23 | 12.68 |
| Na2PO4·7H2O | 24.42 | 12.21 | - |
| 甲基纤维素 | 5.00 | 5.00 | 5.00 |
| 苯扎氯铵 | .01 | .01 | .01 |
| EDTA | 1.00 | 1.00 | 1.00 |
| NaCl | - | 4.38 | - |
| 柠檬酸钠 | - | - | 27.70 |
我们的制剂快速地灭活鼻病毒，即使在被大量稀释之后仍保持低pH，毒性低，在试验中耐受力好，所使用的大多数物质先前已被证明可与人接触，生产费用不多，且使用起来简单。
应该知道，可依现有的感染程度、患者的年龄和制剂是用于预防性的或是治疗现有病情而优化使用这些制剂的方案。然而，对于大多数的病情，我们建议在每个鼻孔中喷0.2-0.3ml的该制剂，每天3-6次，喷5天。
其效果对种类繁多的鼻病毒都起作用，包括与普通感冒相关的鼻病毒。
工业应用性
本发明提供用于防止鼻病毒传染病的扩散和发展的制剂。
Claims (12)
1.一种缓冲的可流动的鼻用制剂，其pH为4.0-5.0，它包括：
水；和
柠檬酸盐；
其中，当进行“缓冲能力”试验时，上述制剂的缓冲能力足以维持在pH6.0以下。
2.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，所述制剂是鼻用喷雾剂。
3.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，所述制剂还包含氯化钠。
4.如权利要求3所述的缓冲的可流动的鼻用制剂，其特征在于，所述氯化钠存在于所述制剂中，其浓度为该制剂的0.5wt.％以下。
5.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，所述制剂还包含纤维素类增稠剂。
6.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，所述制剂还包含磷酸盐。
7.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，所述制剂还包含选自苯扎氯铵和EDTA钠的防腐剂。
8.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，柠檬酸阴离子的浓度至少为0.02M。
9.如权利要求1所述的缓冲的可流动的鼻用制剂，其特征在于，水的浓度至少为所述制剂的95wt.％。
10.一种杀死鼻病毒的方法，其特征在于，所述方法包括将鼻病毒暴露在权利要求1所述的制剂中。
11.一种杀死人鼻子中鼻病毒的方法，其特征在于，所述方法包括将权利要求1所述的制剂喷到鼻子中。
12.一种防止鼻病毒传染病扩散的方法，其特征在于，所述方法包括将权利要求1所述的制剂喷到人的鼻子中。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/332,340 | 1999-06-14 | ||
| US09/332,340 US6187332B1 (en) | 1999-06-14 | 1999-06-14 | Acidic buffered nasal spray |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1352550A true CN1352550A (zh) | 2002-06-05 |
Family
ID=23297793
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99816727A Pending CN1352550A (zh) | 1999-06-14 | 1999-12-21 | 酸性缓冲的鼻用喷雾剂 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US6187332B1 (zh) |
| EP (1) | EP1183009A1 (zh) |
| CN (1) | CN1352550A (zh) |
| AU (1) | AU2592000A (zh) |
| CA (1) | CA2293162A1 (zh) |
| MX (1) | MXPA01012922A (zh) |
| WO (1) | WO2000076474A1 (zh) |
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| CN111686242A (zh) * | 2020-07-28 | 2020-09-22 | 沈阳眼产业技术研究院有限公司 | 含有il-18和il-2的喷雾剂及其在提高免疫力中的应用 |
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-
1999
- 1999-06-14 US US09/332,340 patent/US6187332B1/en not_active Expired - Fee Related
- 1999-12-21 MX MXPA01012922A patent/MXPA01012922A/es unknown
- 1999-12-21 AU AU25920/00A patent/AU2592000A/en not_active Abandoned
- 1999-12-21 EP EP99968524A patent/EP1183009A1/en not_active Withdrawn
- 1999-12-21 CN CN99816727A patent/CN1352550A/zh active Pending
- 1999-12-21 WO PCT/US1999/030589 patent/WO2000076474A1/en not_active Application Discontinuation
- 1999-12-24 CA CA002293162A patent/CA2293162A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111686242A (zh) * | 2020-07-28 | 2020-09-22 | 沈阳眼产业技术研究院有限公司 | 含有il-18和il-2的喷雾剂及其在提高免疫力中的应用 |
| CN111686242B (zh) * | 2020-07-28 | 2023-08-01 | 沈阳眼产业技术研究院有限公司 | 含有il-18和il-2的喷雾剂及其在提高免疫力中的应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2293162A1 (en) | 2000-12-14 |
| US6187332B1 (en) | 2001-02-13 |
| WO2000076474A1 (en) | 2000-12-21 |
| MXPA01012922A (es) | 2002-09-18 |
| EP1183009A1 (en) | 2002-03-06 |
| AU2592000A (en) | 2001-01-02 |
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