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CN102300587A - 用于伤口愈合的氧化剂和光活化剂的组合物 - Google Patents

用于伤口愈合的氧化剂和光活化剂的组合物 Download PDF

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Publication number
CN102300587A
CN102300587A CN2009801543375A CN200980154337A CN102300587A CN 102300587 A CN102300587 A CN 102300587A CN 2009801543375 A CN2009801543375 A CN 2009801543375A CN 200980154337 A CN200980154337 A CN 200980154337A CN 102300587 A CN102300587 A CN 102300587A
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light
dye
red
acid
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CN102300587B (zh
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R·皮尔加利尼
N·劳皮斯
F·贝利尼
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Kehuan Skin Management Technology Guangdong Co ltd
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Klox Technologies Inc
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Abstract

本发明提供了一种伤口愈合组合物，其包含至少一种氧化剂、至少一种能够活化所述氧化剂的光活化剂，及至少一种选自透明质酸、葡糖胺和尿囊素的愈合因子，以及药学上可接受的载体。此外，本发明公开了局部治疗伤口的方法，其使用至少一种氧化剂和至少一种能够活化所述氧化剂的光活化剂，接着照射所述光敏剂。

Description

用于伤口愈合的氧化剂和光活化剂的组合物
背景
(a)领域
公开的主题主要涉及一种伤口愈合组合物及其治疗方法。
(b)相关现有技术
伤口修复过程对手术程序或跌打损伤后恢复组织完整性和功能是基本的。延迟的伤口愈合和手术伤口开裂代表着重大的临床问题。
如Albrecht等在WO 05/032459和WO 05/021094中所描述，使用光敏染料例如赤藓红B、番红O的光动力学疗法已被用于杀灭细菌。光敏染料被用于直接杀灭细菌。这些专利申请中描述的组合物缺乏氧化剂和愈合因子，并且不将它们直接用于促进伤口愈合。
Neuberger等的美国专利第6,056,548号描述了一种使用光敏染料在口腔中杀灭细菌，并促进口腔卫生的方法。这个专利也描述了使用漂白剂过氧化氢，以光漂白和破坏用于杀灭细菌的光敏染料。但是，所使用的组合物未提及愈合因子且不将它们用于直接促进伤口愈合。
Grafe等的WO 08/013962描述了以下组合物的应用，所述组合物包含胶原和可光活化的分子替莫泊芬(mTHPC)，其用于体内交联胶原以增强和稳定胶原支架的微观结构。这个专利还描述该组合物显示出抗微生物的效果，并消毒治疗部位及抑制微生物生长。但是，这些组合物不包含氧化剂或愈合因子，因而通过强化所形成的胶原支架和细菌杀灭促进伤口愈合。
尽管杀灭存在于受伤部位的细菌对伤口愈合是有利的，但是它不直接促进伤口修复。因此，在病理损害、外伤或创伤形成后，非常有需要提供一种用于愈合皮肤损伤和伤口的新组合物以不仅杀灭细菌，而且还改善和加速愈合过程。
发明概述
根据一个实施方案，公开了一种伤口愈合组合物，其包含至少一种氧化剂、至少一种能够活化所述氧化剂的光活化剂(photoactivator)及至少一种选自透明质酸、葡糖胺和尿囊素的愈合因子，以及药学上可接受的载体。
所述氧化剂可选自过氧化氢、过氧化氢脲和过氧化苯甲酰。
所述伤口愈合组合物还可包含至少一种亲水性胶凝剂。
所述亲水性胶凝剂可选自葡萄糖、改性淀粉、甲基纤维素、羧甲基纤维素、丙基纤维素、羟丙基纤维素、carbopol
Figure BPA00001403368500021
聚合物、藻酸、藻酸钠、藻酸钾、藻酸铵、藻酸钙、琼脂、角叉菜胶、刺槐豆胶、果胶、明胶。
所述光活化剂可选自呫吨衍生物染料、偶氮染料、生物染色剂和类胡萝卜素。
所述呫吨衍生物染料可选自芴染料、荧光酮染料和rhodole染料。
所述芴染料可选自焦宁染料和罗丹明染料。
所述焦宁染料可选自焦宁Y和焦宁B。
所述罗丹明染料可选自罗丹明B、罗丹明G和罗丹明WT。
所述荧光酮染料可选自荧光素和荧光素衍生物。
所述荧光素衍生物可选自焰红染料B、玫瑰红和汞溴红。
所述荧光素衍生物可选自伊红和赤藓红。
所述偶氮染料可选自甲基紫、中性红、对位红、苋菜红、淡红、诱惑红AC(allura red AC)、酒石黄、橘黄G、丽春红4R、甲基红和紫脲酸铵-红紫酸铵。
所述生物染色剂可选自番红O、碱性品红、酸性品红、碘化3，3′-二己基羰花青(3，3′dihexylocarbocyanine iodide)、胭脂红酸和吲哚菁绿。
所述类胡萝卜素可选自藏红花酸、α-藏红花原色素(8，8-双脱辅基-8，8-类胡萝卜素酸(8，8-diapo-8，8-carotenoic acid))、玉米黄素、番茄红素、α-胡萝卜素、β-胡萝卜素、红木素和岩藻黄质。
所述类胡萝卜素可作为选自藏红花红粉、胭脂树橙提取物和褐藻提取物的混合物存在于组合物中。
所述伤口愈合组合物还可包含至少一种螯合剂。
所述螯合剂可选自乙二胺四乙酸(EDTA)和乙二醇四乙酸(EGTA)。
所述伤口愈合组合物还可包含至少一种脂解刺激因子。
所述脂解刺激因子可选自咖啡因和1，7-二甲基黄嘌呤。
根据一个实施方案，公开了一种伤口愈合的方法，其包括以下步骤：a)在患者皮肤上局部施用组合物，所述组合物包含至少一种氧化剂、至少一种能够活化所述氧化剂的光活化剂；及b)将步骤a)所述的皮肤用光化光处理足以使所述光活化剂引起所述氧化剂活化的时间。
所述伤口愈合的方法可包括将皮肤暴露于光化光中达约60秒至约5分钟的时间。
所述伤口愈合的方法可包括将皮肤暴露于光化光中达每cm2待处理区域约60秒至约5分针的时间。
所述伤口愈合的方法可包括将皮肤暴露于在正被处理的区域上连续移动的光化光源中。
所述伤口愈合的方法可包括将皮肤暴露于光化光中，所述光化光可为具有400nm至600nm之间波长的可见光。
以下术语在下面定义。
术语“亲水性胶凝剂”意指稠化和稳定液体溶液、乳剂和悬浮液的物质。当其大部分由液体组成时，亲水性胶凝剂溶于液体中并提供将固体物质外观赋予所得凝胶的结构。亲水性胶凝剂与增稠剂非常相似。
术语“光化光”意指由特定光源(灯、LED或激光)发射并且在与物质(例如以下定义的光活化剂)相互作用时能被该物质吸收并产生可辨别或可测量变化的光能；对于临床可辨别变化，我们可假定使用的光活化剂颜色的变化(例如从红色至透明)。
术语“光活化剂”意指能吸收光化光的化合物。所述光活化剂容易经历光致激发并接着将其能量传递给其它分子，从而增强或加速光的色散，并增强或活化存在于反应混合物中的氧化剂。
术语“氧化剂”意指容易传递氧原子并氧化其它化合物的化合物，或在氧化还原化学反应中获得电子的物质。
术语“螯合剂”意指去除金属离子(例如铁)并将其保存于溶液中的化学制品。
术语“愈合因子”意指促进或增强组织愈合或再生过程的化合物。
术语“脂解”意指脂质被降解成其组成性脂肪酸的过程。
术语“暴露于光化光的时间”意指每次施用光化光时组织、皮肤或伤口暴露于光化光的时间。
术语“暴露于光化光的总时间”意指数次施用光化光后组织、皮肤或伤口暴露于光化光的累积时间。
术语“药学上可接受的载体”意指防腐剂溶液、盐溶液、等渗(约0.9％)盐溶液或约5％的白蛋白溶液、悬浮液、无菌水、磷酸缓冲盐水等。适合递送给患者的其它缓冲剂、分散剂和惰性无毒物质可包含于本发明的组合物中。所述组合物可为溶液剂、悬浮剂或适于给药的任意合适制剂，并通常无菌及不含不需要的颗粒物质。所述组合物可通过常规灭菌技术进行灭菌。
如附图中所描述，本文主题的特点和优点根据以下所选实施方案的详细描述将会变得更显而易见。如会认识到，所公开和要求保护的主题能够在多方面进行改变，所有均不会背离权利要求的范围。因此，认为附图和说明书在本质上是说明性的，而不是限制性的，并且主题的全部范围在权利要求中阐述。
附图简述
图1显示伊红Y不影响细胞的生存力。将Hep G2细胞用渐增浓度(0.001-100μM)的伊红Y处理24小时，或不处理(CTL)。星形孢菌素(STS)被用作引起细胞死亡的阳性对照。较高浓度(0.5和1mM)的伊红Y不可被测试，因为该染料干扰测定。
图2显示赤藓红B不影响细胞的生存力。将Hep G2细胞用渐增浓度(0.001-100μM)的赤藓红B处理24小时，或不处理(CTL)。星形孢菌素(STS)被用作引起细胞死亡的阳性对照。较高浓度(0.5和1mM)的赤藓红B不可被测试，因为该染料干扰测定。
图3显示最初的伤口闭合在施用伤口愈合组合物后得到改善。将带有切除伤口的大鼠(n＝2/组)用或不用伤口愈合组合物处理，所述组合物包含氧化剂(过氧化氢脲)和光活化剂混合物(伊红Y、赤藓红B和藏红花红粉)。棱形：处理的动物；圆圈：未经处理的动物(对照)。
图4显示伤口闭合在施用伤口愈合组合物后得到改善。将带有切除伤口的大鼠(n＝2/组)用或不用伤口愈合组合物(A)、伤口愈合组合物(B)或伤口愈合组合物(C)处理，所述组合物(A)包含氧化剂(过氧化氢脲)和光活化剂混合物(伊红Y、赤藓红B)，所述组合物(B)包含氧化剂(过氧化氢脲)和光活化剂混合物(伊红Y、赤藓红B和藏红花红粉)，所述愈合组合物(C)包含氧化剂(过氧化氢脲)和光活化剂混合物(伊红Y、赤藓红B、藏红花红粉和吲哚菁绿)。
图5显示伤口闭合在施用伤口愈合组合物后得到改善。将带有切除伤口的大鼠(n＝2/组)用或不用伤口愈合组合物处理，所述伤口愈合组合物包含氧化剂(过氧化氢脲)和光活化剂混合物(伊红Y、赤藓红B)。棱形：处理的动物；三角形：未经处理的动物(对照)。
图6显示伤口闭合在施用伤口愈合组合物后得到改善。
图7显示伤口闭合在施用伤口愈合组合物后得到改善。
优选实施方案的详细描述
根据一个实施方案，提供了一种伤口愈合组合物和在患者皮肤或伤口上使用所述组合物的方法。此产品加速伤口愈合和修复。
根据另一个实施方案，提供了一种使用组合物的方法，即光动力技术，其中通过光将该组合物活化，提供对皮肤或伤口有益的效果并促进愈合。
所述组合物和方法可用于治疗不同皮肤层的创伤，创伤包括切口、撕裂、擦伤、刺伤、穿透伤、枪伤、挫伤、血肿和挤压伤。黏膜损伤也可能用本发明组合物治疗，例如可用于治疗口腔黏膜的病理损害，例如牙周炎、溃疡，和唇疱疹(口面部疱疹)。
所述组合物包含多种选自可能组分组的活性成分。这些多种活性成分每种都具有其作用机制。
氧化剂
所述组合物包含氧化剂作为氧自由基的来源。过氧化物化合物为包含过氧基团(R-O-O-R)的氧化剂，过氧基团为包含两个氧原子的链状结构，每个氧原子与另一个氧原子和基团或某种元素键合。用于制备激活媒质的合适氧化剂包括但不限于：
过氧化氢(H2O2)为制备有机过氧化物的起始材料。H2O2是强氧化剂，而过氧化氢独特的性质在于其降解成水和氧气且不形成任何持久的有毒残留化合物。此组合物中使用的过氧化氢可用在凝胶中，例如用6％的过氧化氢。本发明组合物中可使用的过氧化氢的合适浓度范围为约3.5％至约6％。
脲过氧化氢(也被称为过氧化脲、过氧化氢脲或过碳酰胺)可溶于水并含大约35％过氧化氢。所述组合物中使用的过氧化氢脲可用作凝胶剂，例如用表示5.6％过氧化氢的16％过氧化氢脲。本发明组合物中可使用的过氧化脲的合适浓度范围为约10％至约16％。过氧化脲以可用热或光化学反应加速的缓释方式降解成脲和过氧化氢。释放的脲[尿素，(NH2)CO2)]，高度可溶于水且为强蛋白变性剂。它增加一些蛋白质的溶解度并增强皮肤和/或黏膜的再水合。
过氧化苯甲酰由通过过氧化物基团连接的两个苯甲酰基(羧酸的H被移除的苯甲酸)组成。在痤疮的治疗中发现，浓度在2.5％至10％变化时，释放的过氧化物基团有效杀菌。过氧化苯甲酰也促进皮肤更新并清洁毛孔，这进一步有助于减少细菌数并减少痤疮。过氧化苯甲酰与皮肤接触时降解成苯甲酸和氧气，没有一种是有毒的。本发明组合物中可使用的过氧化苯甲酰的合适浓度范围为约2.5％至约5％。
因为其增加的毒性及其与光动力能量传递不可预见的反应，所以应避免包含其它形式的过氧化物(例如有机或无机过氧化物)。
光活化剂：
光活化剂将光能传递给氧化剂。合适的光活化剂可为荧光染料(或染色剂)，但也可采用其它染料类别或染料(生物学和组织学染料、食品着色剂、类胡萝卜素)。混合光活化剂可通过混合的染料分子增加光吸收并增强吸收和光-生物调节选择性。这创造了产生新的光敏性和/或选择性的光活化剂混合物的多种可能性。
光活化剂的有利特性是增加的荧光性。在本发明中，光在绿至黄光谱的二次放射会是有利的，因为这是深穿透波长范围，具有血液的深吸收。这导致血流强烈的增加、血管舒张和血管舒缩现象。合适的光活化剂包括但不限于：
呫吨衍生物：
呫吨衍生物染料已在全世界长时间使用并测试。它们显示出低毒性和增强的荧光性。呫吨类别由3个亚类组成：a)芴；b)荧光酮；和c)rhodole。
芴类别包括焦宁(例如焦宁Y和B)和罗丹明(例如罗丹明B、G和WT)。取决于使用的浓度，焦宁和罗丹明两者可能有毒且其与光的相互作用可能导致毒性增加。rhodole染料类别发生的类似作用是已知的。
荧光酮类别包括荧光素染料和荧光素衍生物。
荧光素是在显微术中常用的荧光团，具有494nm的最大吸收和521nm的最大放射。荧光素的二钠盐被称为D&C Yellow 8。它具有非常高的荧光性但快速光降解。在本发明组合物中，荧光素与其它光活化剂如吲哚菁绿和/或藏红花红粉的混合物将增加这些其它化合物的光吸收。
伊红类别包括伊红Y(四溴荧光素、酸性红87、D&C Red 22)，具有514-518nm的最大吸收，将细胞的细胞质、胶原、肌纤维和红细胞染成强烈的红色；和伊红B(酸性红91、eosin scarlet、二溴-二硝基荧光素)，具有与伊红Y相同的染色特性。因其对使用的光谱：广谱蓝光、蓝至绿光和绿光的敏感性，可使用伊红Y、伊红B或两者的混合物。其组织和生物膜染色性质及其低毒性也是有利的。伊红Y和伊红B均对红细胞染色，因而赋予本发明组合物止血(控制血流或阻挡血流)性质和在施用组合物过程中增加对损伤或伤口软组织的光选择性靶向。
焰红染料B(2，4，5，7-四溴-4，5，6，7-四氯荧光素、D&C Red 28、酸性红92)是荧光素的红色染料衍生物，其通过光氧化作用用于废水的消毒和解毒。它具有535-548nm的最大吸收。它也用作制备光敏染料和药品的中间体。
赤藓红B(酸性红51、四碘荧光素)是樱桃粉红、煤基氟食物染料，用作生物染色剂及生物膜和牙菌斑显示剂，在水溶液中具有524-530nm的最大吸收。它受光降解。由于其对使用光谱的光敏感性及其染色生物膜的能力，赤藓红也用在一些实施方案中。当在感染或污染组织的深口袋(例如在牙周治疗的牙周袋)中使用组合物时，包含赤藓红应为有利的。
玫瑰红(4，5，6，7-四氯-2，4，5，7-四碘荧光素、酸性红94)是具有544-549nm最大吸收的明亮淡蓝粉红(bluish-pink)生物学染料，已被用作染料、生物染色剂和诊断辅助剂。也用在合成化学中以从三线态氧中产生单线态氧。
汞溴红(红汞)是具有508nm最大吸收的荧光素的有机汞二钠盐。它用作防腐剂。
偶氮染料：
偶氮(或重氮)染料共有N-N基团，称为偶氮基团。它们主要用在分析化学中或用作食品着色剂，并且它们是非荧光的。合适的偶氮染料包括：甲基紫、中性红、对位红(颜料红1)、苋菜红(偶氮玉红S)、淡红(偶氮玉红、食品红3、酸性红14)、诱惑红AC(FD&C 40)、酒石黄(FD&C Yellow 5)、橘黄G(酸性橙10)、丽春红4R(食品红7)、甲基红(酸性红2)、紫脲酸铵-红紫酸铵。
生物染色剂：
在对生物材料染色方案中常用的染料分子也可用作光活化剂。合适的生物染色剂包括：
番红(番红O、碱性红2)也是偶氮染料并用在组织学和细胞学中。它在革兰氏染色方案中是标准的复染剂。
品红(碱性或酸性)(盐酸蔷薇苯胺)是洋红生物学染料，其可染色细菌并已用作防腐剂。它具有540-555nm的最大吸收。
碘化3，3′-二己基羰花青(DiOC6)是用于细胞内质网、泡囊膜和线粒体染色的荧光染料。它显示出光动力毒性；当暴露于蓝光时，具有绿色荧光。
胭脂红酸(酸性红4、中性红4)是从胭脂虫中天然获得的红色葡糖苷羟基蒽醌(glucosidal hydroxyanthrapurin)。
吲哚菁绿(ICG)用作血容量确定、心输出量或肝功能的诊断辅助剂。ICG与红细胞强烈结合，当用在与荧光素的混合物中时，ICG增加蓝至绿光的吸收。
类胡萝卜素
类胡萝卜素染料也可充当光活化剂。
藏红花红粉是含天然类胡萝卜素的化合物。藏红花是从番红花获得的香料。其特征在于苦味和碘仿或干草样香味；这些特征是由化合物藏红花苦苷和藏花醛引起的。它也包含赋予其特征性黄-红颜色的类胡萝卜素染料藏红花原色素。
藏红花包含多于150种不同的化合物，其中很多是类胡萝卜素：芒果藏红花原色素(mangicrocin)、reaxanthine、番茄红素，和多种α-和β-胡萝卜素，其显示出良好的光吸收和有益的生物活性。藏红花也可充当光子传递剂和愈合因子。藏红花的颜色主要是α-藏红花原色素(8，8-双脱辅基-8，8-类胡萝卜素酸)的效果。干藏红花红粉对波动的pH水平高度敏感并在光和氧化剂存在下快速化学降解。其更耐热。数据显示藏红花具有抗癌、免疫调节和抗氧化性质。对于吸光度，针对藏红花原色素特定的光子波长440nm(蓝光)来确定。其具有深红色并形成具有186℃熔点的晶体。当溶于水时，形成橙色溶液。
藏红花酸是藏红花的另一种化合物，发现其表现出抗血脂作用和促进氧气在不同组织中渗透。更具体地，观察到毛细血管内皮细胞增加的氧合作用。观察到肌肉和大脑皮层氧合作用的增加，引致在具有诱导的出血性休克或肺气肿的实验动物中存活率增加。
胭脂树橙香料(anatto a spice)含有显示相关抗氧化性质的类胡萝卜素红木素作为主要组分(70％-80％)。
β-胡萝卜素也显示出合适的特性。
岩藻黄质是具有光敏化氧化还原反应的显著能力的褐藻组分。
愈合因子：
愈合因子包括在组合物施用部位促进或增强组织愈合或再生过程的化合物。在组合物光活化过程中，皮肤或黏膜在治疗部位增加分子吸收。在延长的时期内观察到治疗部位处血流的增加。随着愈合因子的加入，由于自由基级联的动态相互作用，淋巴引流的增加和渗透压平衡可能的改变可被增强或甚至强化。合适的愈合因子包括但不限于：
透明质酸(乙酰透明质酸、透明质酸盐)：是非硫酸化的糖胺聚糖，广泛分布于整个结缔组织、上皮组织和神经组织中。它是细胞外基质的主要组分之一，并对细胞增殖和迁移作出重大贡献。乙酰透明质酸是皮肤的主要组分，在皮肤中参与组织修复。它大量存在于细胞外基质中，同时有助于组织流体动力学、细胞运动和增殖及参与大量的细胞表面受体相互作用，特别是包括初级受体CD44的相互作用。透明质酸酶类酶降解乙酰透明质酸。人体中有至少七种类型的透明质酸酶样酶，其中几种是肿瘤抑制剂。透明质酸的降解产物，低聚糖和非常低分子量的透明质酸，显示促血管生成(pro-angiogenic)性质。另外，最近的研究显示，乙酰透明质酸片段但非天然高分子量的乙酰透明质酸，在组织损伤中可诱导巨噬细胞和树突细胞的炎症应答。透明质酸很适合针对皮肤的生物学应用。由于其高生物相容性，透明质酸被用于促进组织再生。目前的研究证明，透明质酸出现在愈合早期以物理地为介导免疫应答的白细胞创造空间。它用在伤口愈合应用的生物支架合成中和皱纹治疗中。
葡糖胺：是人体组织中最丰富的单糖之一及糖基化蛋白质和脂质生物合成中的前体。它通常用在骨关节炎的治疗中。葡糖胺常用的形式是其硫酸盐。葡糖胺显示多种作用，包括抗炎活性、刺激蛋白聚糖合成和蛋白水解酶的合成。葡糖胺可用在本发明组合物中的合适的浓度范围为约1％至约3％。
尿囊素：是glyosilic酸的二酰脲。它具有去角质效果，增加细胞外基质的水含量，增强上层死亡(凋亡)皮肤细胞的脱落，并促进皮肤增殖和伤口愈合。
另外，藏红花可同时充当光子传递剂和愈合因子。
螯合剂：
可以包含螯合剂以在闭合感染口袋和难以到达的损害中促进涂层的去除；螯合剂可充当金属离子淬灭剂和缓冲剂。合适的螯合剂包括但不限于：
乙二胺四乙酸(EDTA)：它是一种氨基酸，用于螯合二价或三价金属离子。EDTA通过4个羧酸基团和2个胺基与金属结合。EDTA与Mn(III)、Fe(III)、Cu(III)、Co(III)形成特别强的络合物，防止血小板聚集和血块形成。它用在齿髓治疗中作为仪器使用中的涂层去除剂。它用来缓冲溶液。
乙二醇四乙酸(EGTA)与EDTA相关，但具有对钙离子比对镁离子高得多的亲和力。它可用于制备类似活细胞内部环境的缓冲溶液，并常用于牙医学，更具体地牙髓病学中去除涂层。
脂解刺激因子：
可包含脂解刺激因子，以将组合物用于美容应用例如皱纹治疗中。
咖啡因和咖啡因的代谢衍生物1，7-二甲基黄嘌呤在脂解过程中可增加以释放甘油和脂肪酸到血流中。
亲水性胶凝剂
伤口愈合组合物也可包含一种或多种亲水性胶凝剂。亲水性胶凝剂增强组合物的稠度并有助于促进组合物应用到皮肤或受伤区域。此外，当与过氧化氢(H2O2)使用时，它可有助于缓慢释放H2O2，并提供更直接的反应，因为纯H2O2可直接使用。合适的亲水性胶凝剂包括但不限于葡萄糖、改性淀粉、甲基纤维素、羧甲基纤维素、丙基纤维素、羟丙基纤维素、carbopol
Figure BPA00001403368500121
聚合物、藻酸、藻酸钠、藻酸钾、藻酸铵、藻酸钙、琼脂、角叉菜胶、刺槐豆胶、果胶和明胶。
组合物的用途
纳入合适的光敏化合物并用适当波长光源活化，引致过氧化物(氧化剂)源的降解过程和通过光动力现象发生的其它反应的加速。纳入的染料被特定波长的光子照射并激发到更高能态。当光活化剂激发的电子返回到较低能态时，它们发射出较低能级的光子，因而引起较长波长的光的发射(Stokes频移)。在合适的环境中，大部分这种能量转移被传递给氧或活性过氧化氢并导致氧自由基的形成，例如单线态氧。
由组合物活化产生的单线态氧和其它活性氧类被认为以策动力方式(hormetic fashion)运作。也就是说，健康有益的效果通过低暴露于一般有毒刺激(例如活性氧)，通过刺激和调节目标组织细胞中的应激反应途径而带来。对外源产生的自由基(活性氧类)的内源性反应在对外源自由基提高的防御能力中被调节，并引起愈合和再生过程的加速。另外，组合物的活化也将产生抗菌效果。细菌对暴露于自由基的极端敏感使本发明组合物成为实际上的杀菌组合物。
可能的作用机制应为强化的氧化还原信号传递现象，导致产生突出的信号传导过程，在所述过程中细胞将一种信号转化为另一种信号；活化的“第二信使”引起以较小刺激开始的“信号级联”，所述较小刺激通过这些信号的生物监控放大引出大的反应。这些复杂的机制可能通过生长因子活化涉及血管生成现象而作用。
这种方法可描述成光动力学疗法的形式。但是，不像其中光活化激活剂(photoactoactivator)掺于组织结构中的其它光动力技术，在本发明方法中，光活化材料与组织处于简单接触且当被光活化时，充当与组织化学地相互作用的“光动力装置”。另外，光化光穿透组织，而由光活化剂发射的光(较长波长的光)也被组织吸收。
可使用任何光化光源。任何类型的卤素灯、LED或等离子弧灯，或激光可能是合适的。合适的光化光源的主要特征将会是其以适于活化组合物中存在的一种或多种光活化剂的一种或多种波长发射光。在一个实施方案中，使用氩激光。在另一个实施方案中，使用磷酸钛氧钾(KTP)激光(例如GreenLightTM激光)。在又一个实施方案中，LED光固化装置是光化光源。在再一个实施方案中，光化光源是具有400和600nm之间波长的可见光源。另外，光化光源应具有合适的能量密度。非准直光源(LED、卤素灯或等离子灯)合适的能量密度在约900mW/cm2至约2000mW/cm2范围内。激光光源合适的能量密度在约0.5mW/cm2至约0.8mW/cm2范围内。
暴露于光化光的持续时间将依赖于治疗区域表面，和进行治疗的损害、外伤或损伤的类型。组合物的光活化可发生在数秒内或甚至毫秒内，但延长的暴露时间有利于充分利用吸收光、反射光和再发射光对本发明组合物的协同作用及其与治疗中的组织的相互作用。在一个实施方案中，已施用伤口愈合组合物的组织、皮肤或伤口暴露于光化光的时间为60秒至5分钟的时间。在另一个实施方案中，已施用伤口愈合组合物的组织、皮肤或伤口暴露于光化光的时间为每cm2治疗区域60秒至5分钟，以致使10cm2暴露的总时间将为10分钟至50分钟之间。在又一个实施方案中，光化光源在治疗区域上连续移动，持续合适的暴露时间。在再一个实施方案中，施行伤口愈合组合物和光化光的多次施用。在一些实施方案中，组织、皮肤或伤口暴露于光化光至少2、3、4、5、或6次。在一些实施方案中，暴露于光化光前进行伤口愈合组合物的新鲜施用。
备选实施方案
实施例I
通过混合以下组分制备示例性的伤口愈合组合物：
Figure BPA00001403368500141
将氧化剂(4mL)和愈合因子(1.5mL)混合，接着与光活化剂(1mL)混合。将由此得到的组合物施用于受伤患者皮肤上，并用由LED光固化装置(蓝光)提供的光化光活化。治疗后移除组合物。
实施例II
通过混合以下组分制备第二种示例性伤口愈合组合物：
Figure BPA00001403368500142
将氧化剂(4mL)和愈合因子(1.5mL)混合，接着与光活化剂(1mL)混合。将由此得到的组合物施用于受伤患者皮肤，并用由LED光固化装置(蓝光)提供的光化光活化。治疗后移除组合物。
第二种示例性组合物使用荧光素染料作为组合物中存在的其它染料(吲哚菁绿和藏红花红粉)的光活化剂。将少量荧光素添加到吲哚菁绿和藏红花红粉溶液中引起处于活化其它染料化合物波长的光的再发射，并通过增加建立的临床吸收/再发射标准改善治疗。
吲哚菁绿很好地结合血红蛋白并有助于组织的选择性能量吸收，还有助于用产生的自由基级联靶向这些组织。另外，这种光活化剂混合物能使藏红花呈现红色荧光，而这又改善光动力和生物刺激两种现象。
实施例III
光活化剂伊红Y和赤藓红B的毒性通过测定这些化合物对人体细胞的细胞毒性来评价。具有上皮细胞形态的Hep G2人肝细胞癌细胞用浓度渐增(0.001至100μM)的伊红Y或赤藓红B处理24小时，并评价细胞存活。当与未处理细胞相比较时，渐增浓度的伊红Y(图1)或赤藓红B(图2)不影响细胞生存力。星形孢菌素(STS)被用作诱导细胞死亡的阳性对照并引起剂量依赖作用(图1和2)。类似的结果通过用乳酸脱氢酶(LDH)的释放测量细胞死亡获得。因此，既不是伊红Y也不是赤藓红B导致细胞死亡率增加。
实施例IV
大鼠切除伤口模型
用大鼠的随机皮瓣研究伤口愈合过程，以评价缺血预适应和药理性预适应方法对皮瓣存活的益处，对皮瓣应用血流评估技术，展示血管分流术和研究对皮瓣生存力的影响。用随机皮瓣模型研究本发明组合物对皮瓣存活率和有助于愈合过程的相关调节的影响。
宽1cm乘长2cm的切除伤口在背部中线背侧切出，低于肩胛骨下角2cm。用手术刀片切除皮肤，从伤口边缘切除肉膜和0.5cm的肉膜皮下层。伤口接着与8cm乘8cm大小的标记拍照。将1克伤口愈合组合物施用于伤口(0.5g/cm2)并用蓝色LED光照射3分钟。
实施例V
如上述实施例IV中的描述在大鼠(n＝2/组)上进行切除，将切口用或不用1克伤口愈合组合物的单次施用处理，所述伤口愈合组合物包含氧化剂(过氧化氢脲)和含伊红Y、赤藓红B和藏红花红粉的光活化剂混合物。将切口用LED灯(蓝光)照射3分钟。处理后在10天的时间内评价伤口闭合百分比(图3)。用组合物处理的动物在处理后最初3天的时间段里显示较快的伤口闭合。
实施例VI
如上述实施例IV中的描述在大鼠(n＝2/组)上进行切除，将切口用或不用1克伤口愈合组合物的单次施用处理，所述组合物包含：(A)氧化剂(过氧化氢脲)及含伊红Y和赤藓红B的光活化剂混合物；(B)氧化剂(过氧化氢脲)和含伊红Y、赤藓红B和藏红花红粉的光活化剂混合物；或(C)氧化剂(过氧化氢脲)及含伊红Y、赤藓红B、藏红花红粉和吲哚菁绿的光活化剂混合物。将切口用LED灯(蓝光)照射3分钟。每日评价伤口闭合百分比，评价4天(图4)。用组合物(A)和(B)处理的动物在处理后4天的时间段里显示出改善的伤口闭合。在组合物(C)中加入吲哚菁绿抑制对组合物(A)和(B)观察到的伤口愈合作用。
实施例VII
如上述实施例IV中的描述在大鼠(n＝2/组)上进行切除，将切口用或不用1克包含氧化剂(过氧化氢脲)及包含伊红Y和赤藓红B的光活化剂混合物的伤口愈合组合物的单次施用处理。将切口用LED灯(蓝光)照射3分钟。在12天的时间段里评价伤口闭合百分比(图5)。用组合物处理的动物在处理后最初7天的时间段里显示较快的伤口闭合。
实施例VIII
使用3cm乘9cm(3×9)树脂玻璃模板，在背部皮肤上用手术标记追踪皮瓣，将肩胛骨下角和骨盆上骨作为界限。使用无菌技术将带颅底的纯随机形态皮瓣切下，并通过深筋膜(包括浅筋膜、肉膜、皮下组织和皮肤)被架起。为尽量减少伤口收缩和模拟人体条件，将肉膜的0.5cm皮下层从伤口边缘移除。在1小时内，将不渗透屏障(例如硅酮薄膜)置于皮瓣及其供皮区之间以消除伤口床支持的可能性。然后移除该薄膜，将皮瓣返回到原来的位置并用4/0尼龙缝线以间断方式手术闭合皮瓣边缘。紧随皮瓣的闭合，在皮瓣蒂部外涂13.5g凝胶制剂(0.5g/cm2)并进行辐照。对照不接收任何处理。小心将软膏均匀分布于整个皮瓣。在试验当天制备凝胶制剂。对凝胶+光组别，将动物用凝胶制剂处理，将皮瓣用LED灯辐照3分钟。
实施例IX
如上描述在大鼠(n＝2/组)上进行切除，将切口用或不用凝胶制剂处理，并如实施例VIII所述用LED灯(蓝光)照射。
结果显示因荧光素注射和直接可视化的坏死的直接相关性。针对组织学变化评价活检。处理组的数据显示坏死临床上显著减少1.5倍(在对照和处理组中的坏死百分率分别为45.7(±17.36)对比30.42(±20.18)的平均值，SD)。现在参考图7A，在对照和处理组中皮瓣手术后坏死的临床评价显示，对照组相对于处理组被观察到较高的坏死。
来自对照和处理组活检的苏木精和伊红染色(图7B)表明较多的血管募集(vascular recruitment)发生在处理组中(见其中的黑色箭头)。用于评估胶原原纤维沉积的Masson Trichrome染色(图7C)在放大40倍时显示，相对于对照组，新胶原沉积正发生在处理组中。使用光活化剂和波长特定的光的光动力学治疗，旨在通过刺激皮瓣侧枝的血管募集改善新伤口的局部区域状态(包括其中新胶原的形成)，来增加皮瓣的存活率。
本文描述的实施方案和实施例是对要求保护主题的一般性说明并非限制。本领域技术人员会理解的是，在不背离所要求保护的公开主题的精神和范围的情况下，这些实施方案可如何容易地针对各种应用和以各种方式进行修改和/或调整。在本文中权利要求应理解为包括而不限于所有备选实施方案和本文主题的等同物。本文所用的短语、措词和术语是说明性的并非限制性的。在法律允许范围内，本文引用的所有参考文献均通过引用以其整体结合。会认识到，本文公开的不同实施方案的任何方面可在可能的备选实施方案及特征的备选组合范围内进行组合，所有不同的特征组合应理解为形成所要求保护主题的一部分。

Claims (23)

1.一种伤口愈合组合物，其包含：
至少一种氧化剂；
至少一种能够活化所述氧化剂的光活化剂；及
至少一种选自透明质酸、葡糖胺和尿囊素的愈合因子；
以及药学上可接受的载体。
2.权利要求1的组合物，其中所述氧化剂选自过氧化氢、过氧化氢脲和过氧化苯甲酰。
3.权利要求1的组合物，其还包含至少一种亲水性胶凝剂。
4.权利要求3的组合物，其中所述亲水性胶凝剂选自葡萄糖、改性淀粉、甲基纤维素、羧甲基纤维素、丙基纤维素、羟丙基纤维素、carbopol
Figure FPA00001403368400011
聚合物、藻酸、藻酸钠、藻酸钾、藻酸铵、藻酸钙、琼脂、角叉菜胶、刺槐豆胶、果胶和明胶。
5.权利要求1的组合物，其中所述光活化剂选自呫吨衍生物染料、偶氮染料、生物染色剂和类胡萝卜素。
6.权利要求5的组合物，其中所述呫吨衍生物染料选自芴染料、荧光酮染料和rhodo1e染料。
7.权利要求6的组合物，其中所述芴染料选自焦宁染料和罗丹明染料。
8.权利要求7的组合物，其中所述焦宁染料选自焦宁Y和焦宁B。
9.权利要求7的组合物，其中所述罗丹明染料选自罗丹明B、罗丹明G和罗丹明WT。
10.权利要求6的组合物，其中所述荧光酮染料选自荧光素和荧光素衍生物。
11.权利要求10的组合物，其中所述荧光素衍生物选自焰红染料B、玫瑰红和汞溴红。
12.权利要求10的组合物，其中所述荧光素衍生物选自伊红和赤藓红。
13.权利要求5的组合物，其中所述偶氮染料选自甲基紫、中性红、对位红、苋菜红、淡红、诱惑红AC、酒石黄、橘黄G、丽春红4R、甲基红和紫脲酸铵-红紫酸铵。
14.权利要求5的组合物，其中所述生物染色剂选自番红O、碱性品红、酸性品红、碘化3，3′-二己基羰花青、胭脂红酸和吲哚菁绿。
15.权利要求5的组合物，其中所述类胡萝卜素选自藏红花酸、α-藏红花原色素(8，8-双脱辅基-8，8-类胡萝卜素酸)、玉米黄素、番茄红素、α-胡萝卜素、β-胡萝卜素、红木素和岩藻黄质。
16.权利要求5的组合物，其中所述类胡萝卜素作为选自藏红花红粉、胭脂树橙提取物和褐藻提取物的混合物存在于所述组合物中。
17.权利要求1-16中任一项的组合物，其还包含至少一种选自乙二胺四乙酸(EDTA)和乙二醇四乙酸(EGTA)的螯合剂。
18.权利要求1-17中任一项的组合物，其还包含至少一种选自咖啡因和1，7-二甲基黄嘌呤的脂解刺激因子。
19.一种伤口愈合的方法，其包括以下步骤：
a)在患者皮肤上局部施用组合物，所述组合物包含至少一种氧化剂、至少一种能够活化所述氧化剂的光活化剂；及
b)将步骤a)所述的皮肤用光化光处理足以使所述光活化剂引起所述氧化剂活化的时间。
20.权利要求19的方法，其中所述皮肤暴露于光化光中达约60秒至约5分钟的时间。
21.权利要求20的方法，其中所述皮肤暴露于光化光中达每cm2待处理区域约60秒至约5分钟的时间。
22.权利要求19-21中任一项的方法，其中所述光化光源在待处理区域上连续移动。
23.权利要求19-22中任一项的方法，其中所述光化光为具有约400nm至约600nm之间波长的可见光。
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CN106573055A (zh) * 2014-06-09 2017-04-19 克洛克斯科技公司 基于硅酮的生物光子组合物及其用途
CN113766832A (zh) * 2019-01-31 2021-12-07 帕尔斯希拉公司 杀菌方法和组合物
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CN115054539A (zh) * 2021-08-27 2022-09-16 湖南科洛克医药有限公司 一种消炎祛疤凝胶的制备工艺
CN115054539B (zh) * 2021-08-27 2024-06-18 湖南科洛克医药有限公司 一种消炎祛疤凝胶的制备工艺
CN115054567A (zh) * 2021-08-30 2022-09-16 湖南科洛克医药有限公司 一种皮肤创口修护凝胶及其使用方法和应用
CN115054567B (zh) * 2021-08-30 2024-10-01 湖南科洛克医药有限公司 一种皮肤创口修护凝胶及其使用方法和应用
CN115487340A (zh) * 2022-10-31 2022-12-20 振德医疗用品股份有限公司 一种负载活性氧的细菌纤维素敷料及其制备方法
CN115487340B (zh) * 2022-10-31 2023-11-17 振德医疗用品股份有限公司 一种负载活性氧的细菌纤维素敷料及其制备方法

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