CN101977599A - 用于处理细胞环境和离子通道的缓冲水溶液的组合物及其使用方法 - Google Patents
用于处理细胞环境和离子通道的缓冲水溶液的组合物及其使用方法 Download PDFInfo
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- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
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Abstract
本发明涉及一种组合物，该组合物用于局部或体内处理动物组织以缓冲和校准细胞环境的pH，同时还作为影响炎症、蛋白酶、活性氧和自由基的方法对特异性细胞膜离子通道起作用。
Description
相关申请
本申请请求2007年12月11日提交的美国临时专利申请序号US61/007,228的权益。
技术领域
本发明涉及一种组合物，该组合物用于局部或体内处理动物组织以缓冲和校准细胞环境的pH，同时还作为影响炎症、蛋白酶、活性氧和自由基的方法对特异性细胞膜离子通道起作用。
背景技术
许多疾病状态或医学操作导致细胞环境的pH平衡改变。这由此导致细胞开始产生异常类型或数量的代谢产物例如炎性细胞因子、蛋白酶和各种基团种类。这在癌症以及低氧或缺氧状态组织中和对组织破坏或外科手术的响应中是确切的。应激也导致细胞和胞外pH水平改变。
本发明通过合并有细胞膜电位改变阳离子例如钠或钾或铷或铯或其组合而用作缓冲抗衡离子、并以特异性水平缓冲细胞环境，由此寻求治疗细胞状态和引起潜在疾病的作用并且使其受益。可以选择这些阳离子以影响特异性细胞离子通道例如钠离子通道、钾离子通道或依赖于所选离子的其他通道。缓冲剂可以由任意典型缓冲剂组成例如抗坏血酸或柠檬酸或Tris或磷酸盐或乙酸盐或类似的缓冲剂或多种外来的酸或碱例如透明质酸，这取决于期望的缓冲液的pH。
本发明的其他特征在考虑到下列优选实施方案的详细描述时对本领域技术人员是显而易见的，这些优选实施方案举例说明了作为明确可理解的实施本发明的最佳方案。
发明内容
本发明涉及组合物，其用于控制细胞环境pH和细胞膜离子通道，以减少和/或防止可被异常pH环境正向调节的炎性细胞因子、活性氧和蛋白酶的产生；本发明涉及包含所述组合物的药物和化妆品组合物及它们在治疗与炎症、活性氧和蛋白酶相关的疾病中的应用，例如包括但不限于皮肤癌、癌症、炎症、晒伤、伤口、关节炎、眼疾病、龈疾病、银屑病、特应性皮炎、酒渣鼻或其他其中炎症和组织降解是组成部分的疾病。
本发明以独特的组合来组合成分以实现三个不同目的，得到的效果是一种用于帮助控制炎症、组织降解和随后的降解级联的方法。首先，这种独特的组合用于清除、或减少氧自由基、其他自由基和活性氧。其次，这种独特的组合用于预防或减轻组织炎症和防止或减少炎性细胞因子的产生，第三，这种独特的组合用于防止或减少蛋白酶的产生或表达。
炎症是哺乳动物对各种侵袭和各种组织上的应激的正常响应。一般而言，这是一种能够使身体受到保护或自我修复的有益响应。在正常情况下它还受众多其他控制机理紧密控制。当炎症失去控制时，正如在许多疾病尤其是慢性疾病中典型地发现的，它可以对所涉及的组织产生破坏性损害。
一旦炎症失去控制，则恢复内环境稳定是极为困难的，并且直到达到这一点时，大量损害可能已经对所涉及的组织发生。炎症过程本身可以自我强化，有许多不同细胞因子和化学种类正向调节炎症应答。可以通过作用于特异性细胞受体例如使用各种NSAIDS(非甾体抗炎药)、皮质类固醇等，辅助通过外部添加剂控制这一过程。本发明通过多变手段采用了不同方法以找到炎症的一些基本原因并且通过减少其刺激而有助于控制炎症的负面后果。
组织的pH在正常情况下受到极为严格地控制，但会因组织损伤和对组织的其他侵害而受到扰乱。一旦pH从这种平衡状态发生偏离，则各种组织中的细胞表达各种响应，这些响应导致NO、ROS、自由基和其他化学种类生成。它们由此诱导TNF-α、IL-1、IL-2、IL-6等的炎性细胞因子正向调节。然后它们正向调节其他细胞因子和各种组织降解蛋白酶。
具体实施方式
作为本发明的一个方面，通过控制组织的pH，能够减少自由基种类、NO和ROS等生成。这将有助于减少在该组织及其环境中的炎症刺激。作为本发明的第二个方面，通过用适当选择的酸/碱的组合来清除可能存在的自由基，能够进一步减少炎症刺激。此外，作为本发明的第三个方面，证据显示通过细胞膜离子通道的离子转运的改变确实影响炎性细胞因子产生并且由此可以减少炎症。作为本发明的第四个方面，减轻炎症会减少各种损伤组织的蛋白酶受到刺激而产生，这些蛋白酶的片段可以诱导炎症级联。作为本发明的第五个方面，文献显示正确选择所用的离子可以通过调节蛋白酶的mRNA来降低蛋白酶的表达水平。
本发明通过解决这些炎症正向调节的领域起作用。缓冲剂有助于控制组织环境的pH。添加柠檬酸和其他酸和铷有助于清除自由基和ROS。添加这些酸的盐影响所涉及的特异性离子通道，并且这些效果一起独立地和各自地减量调节炎症和蛋白酶产生。
这种治疗结果将有助于使组织恢复到内环境稳定和正常状态。这将适合于下列实施例，但决不限定于此。就癌症而言，这将有助于预防肿瘤生长并且有可能使其萎缩。就伤口而言，尤其是慢性伤口，它使得组织能够正常愈合。就银屑病、特应性皮炎和其他皮肤病而言，它会预防那些疾病的症状。就关节炎而言，它有助于预防对关节的损害。就牙龈炎和龈疾病而言，它有助于预防牙龈组织降解。就黄斑变性而言，它会预防血管发生和血管增殖。就晒伤而言，它有助于预防对表皮的损伤。就皮肤老化而言，它有助于预防胶原蛋白损伤和随后产生的皱纹。
这些仅是几种可能的应用。全范围的应用适合于任何其中存在组织降解的疾病。
在伤口护理领域中，伤口一般变得比正常组织更具酸性。这种pH改变可以诱导其他事件的级联，例如中性白细胞募集反应，由此由启动炎症级联。这可以从生成氧自由基和产生其他活性氧(ROS)开始，从而导致促炎细胞因子例如TNF-α、IL-1、IL-6，IL-8等的正向调节。由此导致进一步的组织降解，因为蛋白酶被诱导。如果pH不加以控制，则可能的情况是一般的急性伤口变成慢性无响应性伤口。
近期研究(Weindorf，M.等人，Zeitshrift fur Wund Heilung，12(2)：1-4，May 2007，引入本文作参考)显示，欧洲使用的大伤口护理敷料的内部pH基本上未加以控制，从pH 2.2到pH 11.70。由于不控制伤口环境的pH，这些敷料实际上可以通过诱导进一步的炎症和组织分解而促进伤口病理学。Kellum等人(Kellum，J.等人，J Leukoc.Biol，69：522-530，2001，引入本文作参考)显示，适度降低的pH、甚至在pH 6-7下，会正向调节炎性细胞因子。pH从7.4降至7.0会正向调节NO(一氧化氮)，由此正向调节炎症级联。
Kellum还发现了根据所研究的酸性种类不同产生的不同效果。盐酸(HCl)正向调节炎症，甚至是在pH小幅度减低的情况下。相反，乳酸是有效的抗炎剂。
Coakley等人(Coakley，R.等人，Blood 100(9)：3383-91，2002，引入本文作参考)发现pH降低对可以诱导组织坏死的中性白细胞具有强烈影响。他们还发现碱化组织环境可以保护中性白细胞并且有助于预防坏死。Gerwick等人(Gerwick，L.等人，Cancer Res.56：1194-98，1996，引入本文作参考)发现癌症肿瘤一般比正常组成更具有酸性。Xu等人(Xu等人，Cancer Res.60：4610-16，2000，引入本文作参考)发现卵巢癌细胞中的酸性pH产生升高水平的炎性细胞因子IL-8。
Razaq(Razaq，S.等人，European Spine J.12(4)：341-9，2003，引入本文作参考)发现酸性pH显著减少控制组织降解蛋白酶的身体正常系统。在酸性pH下，牛片(bovine disks)显示，金属蛋白酶类组织抑制剂(TIMP)一般控制50％以上，TIMP 1控制90％以上。由于这些抑制剂是控制MMP的关键机制，所以这种TIMP的显著减少将导致MMP的超表达和由此产生的组织降解水平过度。
Qian Shi等人(Qian Shi等人，J.Interferon&Cytokine Res.20(11)：1023-28，2000，引入本文作参考)发现，肿瘤pH达pH 6.4的弱酸中毒导致NF-KB水平增加。这种增加的I L-8由此导致炎症增加，并且促进肿瘤发展。
Martin等人(Martin，P等人，Trends Cell Biol.15：599-607，2005，引入本文作参考)发现，炎症响应对组织修复过程而言并非是必需的。他对PU-1裸鼠所做的研究显示，它们正常愈合，伤口组织与正常小鼠相比无纤维化。PU-1裸鼠缺乏中性白细胞，由此显示仍然能够在没有通过炎症正常正向调节的中性白细胞的情况下愈合伤口。其他研究显示，抑制炎症应答实际上可以加速伤口愈合，减少肉芽组织和瘢痕形成。
Hayden(Hayden，M.等人，Cardiovascular Diabetology 1：3-30，2002，引入本文作参考)注意到pH下降导致所涉及的细胞中的氧化还原应激。由此导致氧自由基净增加，从而导致MMP增加。他还注意到，氧化还原应激增加直接导致ROS增加。
这些观察结果证实了pH作为刺激来自所涉及组织的响应的诱发因素的重要性。
正如Kellum等人(Kellum，J.等人，Critical Care 8：331-336，2004，引入本文作参考)所述：理解酸-碱平衡对炎症应答的影响因各种原因与临床药物高度相关。首先，目前我们对酸中毒对广泛细胞进程的影响的理解上的不足导致了在各种临床环境下如何管理病人的争论。大部分临床医师倾向于忽略外源性CL和pH的影响，但许多人甚至治疗轻度形式的酸血症......第二，我们改变作为操纵细胞进程的工具的酸-碱平衡的能力依赖于对pH与炎性分子合成和释放之间的相关性的改进理解。
这清楚地显示通过不仅使用酸或碱、而且通过正确使用缓冲剂控制组织环境的pH的重要性。
本发明中的第二个因素在于，特异性抗衡离子在诱导由处理所涉及的离子通道和控制细胞膜电位带来的有益效果中的应用。
Eisenhut(Eisenhut，M.，J.of Inflammation 3(5)：1-15，2006，引入本文作参考)报道了离子转运的改变影响炎性细胞因子表达。Hsiau等人(Hsiau，T.Report-Research Science Institute，July2003，引入本文作参考)发现钾离子通道抑制导致planarium中的组织再生破坏。Roger等人(Roger，S.等人，Current PharmaceuticalDesign 12(28)3681-95，2006，引入本文作参考)证实，电压门控钠离子通道涉及癌细胞转移。
Chacon等人(Chacon Cruze，E.等人，J Leucocyte Biology，64：759-66，1998，引入本文作参考)报道了膜去极化通过防止钙诱导的中性白细胞响应而具有抗炎效果。
Van den Berg等人(Van den Berg，A，等人，J.Wound Care 12(10)：1-5，2003，引入本文作参考)报道了金属离子可以抑制多形核中性白细胞(PMN)的补体激活和TOS产生。
Hanley等人(Hanley，P.等人，PNAS 101(25)：9479-84，2004，引入本文作参考)证实，IL-6可以通过膜去极化被诱导。这可能是促炎性的或抗炎性的。钙诱导内向整流钾离子通道，从而诱导膜去极化，由此诱导IL-6增加至多40倍。
炎症和基质金属蛋白酶(MMP)
作为最重要的炎性细胞因子之一，TNF-α长期被视为增加MMP。这导致组织蛋白水解性降解，其片段导致炎性细胞因子在自我强化循环中的进一步表达。
Monroe等人(Monroe，S.等人，海报展示，AAWC，2004，引入本文作参考)证实，四种金属离子组合即钾、铷、钙和锌(K、Rb、Ca和Zn)的组合减少了多种MMP的遗传表达。
本发明教导了如何将通过利用缓冲剂控制pH、通过使用选自钠、钾、铷或铯的抗衡离子影响特异性离子通道、与减少自由基和其他活性氧(ROS)的效果进行组合，以用于正面影响炎症和蛋白酶表达。
本发明的一个实施方案在于利用柠檬酸和柠檬酸钾生成具有有效pH 2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末中。其具有的浓度至多是1000mmol。
本发明的第二个实施方案在于利用柠檬酸和柠檬酸铷生成具有有效pH 2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末中。其具有的浓度至多是1000mmol。
本发明的第三个实施方案在于利用柠檬酸和柠檬酸钠生成具有有效pH 2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末中。其具有的浓度至多是1000mmol。
本发明的第四个实施方案在于利用柠檬酸和柠檬酸铯生成具有有效pH 2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末中。其具有的浓度至多是1000mmol。
本发明的第五个实施方案在于利用柠檬酸和柠檬酸钾、并组合柠檬酸铷，生成具有有效pH 2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末中。其具有的浓度至多是1000mmol。
另一个实施方案在于利用乳酸和乳酸柠檬酸钾生成具有有效pH2.0-7.0的缓冲剂。可以将其加入到水溶液、软膏剂或粉末。其具有的浓度至多是1000mmol。
再一个实施方案合并了不同缓冲剂的组合以实现特定的效果。例如，柠檬酸是有效的ROS清除剂。透明质酸有助于愈合受损组织，更具体地说，其已经被用于辅助减轻腹部手术后典型的粘连。可以预期，柠檬酸和透明质酸及其缓冲剂的组合将合并两种类型的缓冲剂的有益效果。
本说明书易于进行各种变型和可替代形式，已经通过实施例显示了其具体的典型实施方案并且在本文中进行了详细描述。然而应当理解的是，其目的并不是将本发明限定于公开的具体形式，而是相反，其目的在于覆盖属于权利要求所定义的精神实质和范围的所有变型、等效方案和可替代选择。
多个优点来源于本说明书公开的不同特征。应注意，本说明书各组成部分的可替代选择的实施方案可能不包括所有所述的特征，但仍会得益于这些特征的至少一些优点。本领域技术人员易于设计自己的实施方式，这样的实施方式引入有本说明书的一种或多种特征并且落入本说明书和权利要求的精神实质和范围。
Claims (14)
1.局部用组合物，包含由酸及其与抗衡离子形成的互补碱盐组成的缓冲剂，以药学有效浓度用于通过缓冲细胞环境和影响膜离子通道来治疗其中炎症和/或组织降解是组成部分的疾病。
2.权利要求1的局部用组合物，其中所述抗衡离子包括钠(Na)。
3.权利要求1的局部用组合物，其中所述抗衡离子包括钾(K)。
4.权利要求1的局部用组合物，其中所述抗衡离子包括铷(Rb)。
5.权利要求1的局部用组合物，其中所述抗衡离子包括铯(Cs)。
6.权利要求1的局部用组合物，其中所述抗衡离子包括Na和至少一种选自K、Rb和Cs的其他离子。
7.权利要求1的局部用组合物，其中所述抗衡离子包括K和至少一种选自Rb和Cs的其他离子。
8.权利要求1的局部用组合物，其中所述抗衡离子包括Rb和Cs。
9.权利要求1的局部用组合物，其中所述抗衡离子包括选自Na，K，Rb和Cs的至少一种。
10.缓冲液，包含选自柠檬酸，抗坏血酸，磷酸，透明质酸和熊果酸中的酸及其与包括至少一种选自Na、K、Rb和Cs的抗衡离子形成的互补碱盐，以药学有效浓度用于治疗其中炎症和组织降解是组成部分的疾病。
11.缓冲液，由酸例如柠檬酸、抗坏血酸、磷酸、透明质酸、熊果酸或其他酸及其与选自Na、K、Rb或Cs的单独或组合形式的抗衡离子形成的互补碱盐组成，以药学有效浓度用于治疗皮肤癌、体内癌、炎症、晒伤、伤口、关节炎、眼疾病、龈疾病或其他其中炎症和组织降解是组成部分的疾病。
12.缓冲液，由酸例如柠檬酸、抗坏血酸、磷酸、透明质酸、熊果酸或其他酸与缓冲盐组成，所述缓冲盐由相同酸与单独或组合形式的抗衡离子Na、K、Rb或Cs组成，以药学有效浓度用于美容应用，以减少导致皮肤皱纹和老化的炎症和组织降解。
13.缓冲液，由酸例如柠檬酸、抗坏血酸、磷酸、透明质酸、熊果酸或其他酸与缓冲盐组成，所述缓冲盐由单独或组合形式的Na、K、Rb或C s组成，以药学有效浓度用于治疗皮肤病例如银屑病、特应性皮炎、酒渣鼻和其他皮肤病。
14.缓冲液，以药学有效浓度包含至少一种选自柠檬酸和乳酸的酸和至少一种选自Na、K、Rb和Cs的缓冲盐。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US722807P | 2007-12-11 | 2007-12-11 | |
| US61/007,228 | 2007-12-11 | ||
| PCT/US2008/086477 WO2009076553A1 (en) | 2007-12-11 | 2008-12-11 | Composition of aqueous buffer solution for the treatment of cellular environment and ion channels and methods for using same |
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| Publication Number | Publication Date |
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| CN101977599A true CN101977599A (zh) | 2011-02-16 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008801241455A Pending CN101977599A (zh) | 2007-12-11 | 2008-12-11 | 用于处理细胞环境和离子通道的缓冲水溶液的组合物及其使用方法 |
Country Status (9)
| Country | Link |
|---|---|
| US (2) | US20100260863A1 (zh) |
| EP (1) | EP2234498A4 (zh) |
| JP (1) | JP2011506470A (zh) |
| CN (1) | CN101977599A (zh) |
| AU (1) | AU2008335083A1 (zh) |
| CA (1) | CA2708611A1 (zh) |
| IL (1) | IL206337A0 (zh) |
| MX (1) | MX2010006300A (zh) |
| WO (1) | WO2009076553A1 (zh) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP6133858B2 (ja) * | 2011-07-28 | 2017-05-24 | スリーエム イノベイティブ プロパティズ カンパニー | 創傷治癒組成物及び使用方法 |
| WO2018042352A1 (en) | 2016-08-31 | 2018-03-08 | Taro Pharmaceutical Industries | Fenoldopam topical formulations for treating skin disorders |
| ES2941241T3 (es) | 2019-03-08 | 2023-05-19 | Taro Pharma Ind | Composiciones tópicas estables de Fenoldopam |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS52128232A (en) * | 1976-04-16 | 1977-10-27 | Meiji Seika Kaisha Ltd | Drugs for alleviating toxicity to kidneys |
| US4579960A (en) * | 1984-05-07 | 1986-04-01 | Schering Corporation | Stable solutions containing thimerosal |
| US4986981A (en) * | 1986-07-07 | 1991-01-22 | Den Mat Corporation | Toothpaste having low abrasion |
| US5250678A (en) * | 1991-05-13 | 1993-10-05 | Merck & Co., Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
| EP1421936A4 (en) * | 2001-04-25 | 2008-11-05 | Mitsubishi Tanabe Pharma Corp | OPENING AGENT FOR THE POTASSIUM CHANNEL |
| JP2005515191A (ja) * | 2001-11-29 | 2005-05-26 | グレイストーン メディカル グループ、インコーポレイテッド | 創傷の治療及び使用する組成物 |
| JP2005527613A (ja) * | 2002-05-24 | 2005-09-15 | グレイストーン メディカル グループ、インコーポレイテッド | 抗癌製剤 |
| US20030228374A1 (en) * | 2002-06-07 | 2003-12-11 | Pesacreta Thomas C. | Topical treatment for skin irritation |
| WO2005065695A1 (en) * | 2003-12-26 | 2005-07-21 | Giles Brian C | Method and formula for suppression of cancer, metastasis, vascularization, and pain suppression |
| US8197797B2 (en) * | 2004-04-12 | 2012-06-12 | Mineral Science Co. | Compositions for oral hygiene and method for using same |
| US7323184B2 (en) * | 2005-08-22 | 2008-01-29 | Healagenics, Inc. | Compositions and methods for the treatment of wounds and the reduction of scar formation |
| EP1951261A4 (en) * | 2005-10-31 | 2009-06-24 | Rigel Pharmaceuticals Inc | PREPARATIONS AND METHODS FOR THE TREATMENT OF INFLAMMATORY DISORDERS |
| CN101299993A (zh) * | 2005-11-04 | 2008-11-05 | 伊士曼化工公司 | 用于给药难溶的药学活性剂的羧烷基纤维素酯 |
| EP2026657A4 (en) * | 2006-05-24 | 2009-12-09 | Pharmaionix Inc | ANTICANCER COMPOSITION AND METHOD OF USE |
-
2008
- 2008-12-11 MX MX2010006300A patent/MX2010006300A/es not_active Application Discontinuation
- 2008-12-11 EP EP08859438A patent/EP2234498A4/en not_active Withdrawn
- 2008-12-11 AU AU2008335083A patent/AU2008335083A1/en not_active Abandoned
- 2008-12-11 WO PCT/US2008/086477 patent/WO2009076553A1/en active Application Filing
- 2008-12-11 US US12/747,890 patent/US20100260863A1/en not_active Abandoned
- 2008-12-11 CN CN2008801241455A patent/CN101977599A/zh active Pending
- 2008-12-11 CA CA2708611A patent/CA2708611A1/en not_active Abandoned
- 2008-12-11 JP JP2010538166A patent/JP2011506470A/ja active Pending
-
2010
- 2010-06-13 IL IL206337A patent/IL206337A0/en unknown
-
2013
- 2013-11-06 US US14/073,153 patent/US20140135284A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20140135284A1 (en) | 2014-05-15 |
| MX2010006300A (es) | 2011-08-17 |
| IL206337A0 (en) | 2010-12-30 |
| US20100260863A1 (en) | 2010-10-14 |
| EP2234498A1 (en) | 2010-10-06 |
| EP2234498A4 (en) | 2011-02-16 |
| WO2009076553A8 (en) | 2010-10-28 |
| AU2008335083A1 (en) | 2009-06-18 |
| JP2011506470A (ja) | 2011-03-03 |
| CA2708611A1 (en) | 2009-06-18 |
| WO2009076553A1 (en) | 2009-06-18 |
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Application publication date: 20110216 |