CN116528846A - 用于皮肤和粘膜的创伤性损伤愈合的制剂 - Google Patents
用于皮肤和粘膜的创伤性损伤愈合的制剂 Download PDFInfo
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- CN116528846A CN116528846A CN202180080430.7A CN202180080430A CN116528846A CN 116528846 A CN116528846 A CN 116528846A CN 202180080430 A CN202180080430 A CN 202180080430A CN 116528846 A CN116528846 A CN 116528846A
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- hydrogen peroxide
- acid
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- trichloroacetic acid
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Abstract
本发明涉及乳膏、软膏、液体或凝胶形式的制剂,并且涉及其在加速粘膜和皮肤的伤口和溃疡愈合中的用途。这些制剂的组分共同作用可以有效治疗多种手术伤口、自发性溃疡、创伤后伤口、未愈合伤口、溃疡和褥疮。本发明的制剂本身可以加速伤口和溃疡的修复,减少炎症和肿胀,减轻疼痛和瘙痒,以及在尽管用抗菌剂和纤维蛋白溶解剂治疗但未修复的情况下加速上皮形成过程。
Description
技术领域
本发明涉及用于修复皮肤和粘膜的手术伤口的乳膏、软膏、液体或凝胶形式的制剂。制剂组分的协同作用允许在口腔医学干预,例如拔牙、根尖切除术、窦底提升、植入学、龈切除术、牙周手术之后以及在缓慢愈合伤口、自发性溃疡、多种来源的疮和坏死性疮包括化脓性肉芽肿、睑板腺囊肿、龈瘤、瘘和脓肿的皮肤病学治疗中的令人惊奇的损伤愈合活性。
发明背景
皮肤和粘膜表面的完整性的破坏导致伤口形成。伤口愈合是恢复组织完整性的复杂生物过程。在生理学方面,伤口愈合可以示意性地分成四个不同阶段:止血、炎症、增殖和组织重塑。损伤后,止血过程立即开始:出血受血小板聚集控制,随后形成纤维蛋白凝块使出血停止并且为细胞附着和增殖提供支架。2-3天后,炎性过程进展至增殖阶段,并且纤维母细胞被吸引至伤口以合成肉芽组织。该肉芽组织允许白细胞进入伤口部位,并且一旦伤口闭合,则未成熟瘢痕可以转入可持续至多一年的最终重塑阶段。纤维母细胞在组织再生中的主要功能是通过产生和重塑细胞外基质来维持结缔组织的物理完整性。无论伤口的病因如何(急性还是慢性),上述修复过程类似,但是急性伤口(例如手术切口)通常相对快速地通过这些阶段,而在最初损伤后经历至多12周的延迟愈合(通常由于长期病理性炎症)的伤口定义为慢性伤口。
几种损伤例如生物膜形成、微生物侵入、反复创伤、局部缺血、水肿、静脉高压和机械力(包括压力)的作用可以引起愈合损害。这些损伤导致角质细胞迁移不良并且上皮形成也被延迟。在这些进展缓慢(indolent)的情况下,伤口床准备仍为疗法标准。
有效伤口床准备可以涉及酶促(J.Ramundo等人,J Wound Ostomy ContinenceNurs Actions.2008年5月-6月;35(3):273-80;McCarty MS;Adv Wound Care(NewRochelle).2013年10月;2(8):438-447)和手术清创、驻留纤维母细胞刺激和生长因子释放的刺激(L.Maddaluno等人,Development(2017)144,4047-4060)、向伤口添加额外的生长因子(M.Yadav等人,Indian Journal of Fundamental and Applied Life Sciences(2012),2(2)4月-6月,164-172)、部署生物工程细胞外基质(F.Urciolo等人,J.Clin.Med.2019,8,2083)、胶原蛋白和海藻酸盐(B.A.Aderibigbe等人,Pharmaceutics,2018,10(2),42)、培养的角质细胞悬浮液和甚至生物工程皮肤制剂(G.Schultz.Wound Repair andRegeneration,2003年4月,11增刊1(s1):S1-28)(任何组合),并且干细胞疗法也有希望(N.Kosaric等人,Expert Opinion on Biological Therapy,19(6),2019)。
已知的治疗选择仅保持中度有效并且通常无法促进易感人群,例如老年人和糖尿病患者的非愈合伤口的闭合,或者在由昆虫或蜘蛛咬伤的伤口的情况下代表有限的补救措施(Hindawi Publishing Corporation,Case Reports in Emergency Medicine,第2016卷,文章ID 7640789)。此外,这些方法中的一些,例如生物工程皮肤替代物,虽然代表自体移植的有效替代方案,但诱导皮肤细胞修复伤口而非引导再生过程。
类似地,手术切口后口腔粘膜的手术创伤需要(无并发症)长恢复时间。为了恢复口腔的原始生理学,通常需要至多五周,但伴有一些可延迟伤口完全愈合的可能并发症。特别的是,对拔牙的正常愈合响应导致显著骨损失和周围龈塌陷。在正常愈合中,很大百分比的拔牙部位遭受手术后并发症。
事实上,拔牙后,血凝块填充齿槽,并且一周后,凝块被肉芽组织替代;3周后,肉芽组织被胶原蛋白替代,并且骨形成始于拔牙齿槽的基底和周边。5周时,据估计,平均三分之二的拔牙齿槽被骨填充。发现上皮需要最少三周以完全覆盖拔牙齿槽,其中一些拔牙部位需要至多五周以完全覆盖齿槽(Amler MH等人,J Am Dent Assoc.1960;61(7),32-44;Amler MH Oral Surg Oral Med Oral Pathol,1969,27(3),309-318)。上文所提及的响应于拔牙的正常愈合的手术后并发症可以包括干槽症、感觉迟钝、严重感染、疼痛、肿胀、牙关紧闭和出血。所有这些可能的并发症均显著增加口腔粘膜的手术切口的总愈合时间。
单独或者与其它化合物结合的三氯乙酸可以用作“化学脱皮”(Monheit GD;J.Dermatol.Surg.Oncol.(1989)15(9),945-950)。50%三氯乙酸(TCA)溶液常用作中等深度化学剥脱,其常用于治疗细纹、光化性光损伤、色素沉着过度以及甚至光化相关的恶化前变化,例如光化性角化病。
已经公开氯乙酸用于与细胞外聚合物质溶剂化系统表面活性剂和缓冲剂一起治疗慢性伤口(WO2009152374)。含有三氯乙酸和过氧化氢、pH范围为2.3-2.6的制剂也被提出用于治疗皮肤和粘膜病变,例如痤疮、由日光引起的损伤和日光雀斑(EP1979053),其具有一些限制,因为过氧化氢(已知为温和抗菌剂)可用于皮肤以预防轻微割伤、擦伤和烧伤的感染,但其对组织修复具有潜在负面影响,并且不应当用于治疗深伤口,动物、昆虫或蜘蛛咬伤,或严重烧伤(Agency for Toxic Substances and Disease Registry,Buford HwyNE Atlanta-Hydrogen Peroxide)。
最近,过氧化氢在伤口愈合过程期间的生物效应得到重新考虑:在相对高浓度(即3%)下,过氧化氢显示其强大的氧化和促炎能力以对伤口组织进行消毒(Roy S等人,MolTher 2006;13:211-220);然而,在较低浓度(即1%)下,其显示良好的抗微生物效应和皮肤耐受性(Capizzi R.等人,Br J Dermatol 2004;151:481-484)。相反,三氯乙酸的氧化形式,即三氯过氧乙酸未曾考虑使用于人类,即使体外试验证实了稀释水溶液对于枯草芽孢杆菌(Bacillus subtilis)、大肠杆菌(Escherichia coli)和金黄色葡萄球菌(Staphylococcus aureus)的消毒剂特性(Sita,F.等人,Journal of Hygiene,Epidemiology,Microbiology and Immunology(1968),12(3),370-3)。
因此,需要对皮肤和粘膜上手术伤口的创新药理学治疗,避免上述手术后并发症并且允许最佳伤口床准备。
发明概述
为了解决上述问题,本发明提供了用于修复皮肤和粘膜伤口的制剂。
本发明的伤口愈合组合物包含:
-第一组分,其选自重量浓度范围为0.08%至38%的三氯乙酸或氯乙酸;
-第二组分,其选自重量浓度范围为0.01%至5%的过氧化氢水溶液,或三氯过氧乙酸。
这些制剂的组分在皮肤和粘膜的伤口的治疗中显示协同作用。
三氯乙酸和过氧化氢优选以约4.34-4.74的相对分子比存在。三氯过氧乙酸和三氯乙酸优选以约3.6-4.0的相对分子比存在。本发明的制剂不具有过氧化氢对组织的潜在负面影响。可选择的是,以相同相对分子比4.43-4.74组合使用氯乙酸和过氧化氢代替三氯乙酸和过氧化氢,也可用作上述制剂的组分。
本发明的制剂以乳膏、软膏、液体、凝胶形式或者类似施用形式局部应用。制剂迅速起效,快速减少肿胀和疼痛,促进伤口愈合并且缩短慢性伤口例如慢性溃疡、褥疮的恢复时间。制剂的使用也有效治疗响应于拔牙的正常愈合的手术后并发症,包括干槽症、感觉迟钝、严重感染、疼痛、肿胀、牙关紧闭、出血,以及治疗缓慢愈合伤口、自发性溃疡、多种来源的疮和坏死性疮,包括化脓性肉芽肿、睑板腺囊肿、龈瘤、瘘和脓肿。
发明详述
本发明的制剂的特征在于过氧化氢水溶液的浓度(0.01-5%的5-31%、优选29-31%过氧化氢水溶液)显著低于现有技术公开的,特别是在EP 1979053中所公开的(50-80重量%)。
三氯乙酸的浓度优选范围为0.1-35重量%,更优选0.15-15重量%。
氯乙酸和过氧化氢可选择地代替三氯乙酸和过氧化氢,以相同的相对分子比4.34-4.74和最终浓度0.08-38重量%使用。
本发明的制剂可以使用0.9%w/v NaCl水溶液稀释。经稀释的制剂确保粘膜和皮肤细胞的存活并且可用于加速手术伤口、创伤后伤口、未愈合伤口、溃疡和褥疮的修复。制剂的pH值高于2.6,通常范围为2.6至3.6。可选择地,三氯过氧乙酸可以通过将等摩尔量的过氧化氢添加至三氯乙酸中原位制备。
本发明的液体制剂可以包含范围为38-99重量%的水、范围为0.001-0.5重量%的EDTA二钠盐、范围为0.025-15重量%的甘油、范围为0.03-14重量%的氨水(28%-32%)、范围为0.005-5重量%的增稠剂和调质剂以及任选0.8-0.9%w/v的氯化钠。优选的增稠剂和调质剂包括羟乙基纤维素、瓜尔胶、刺槐豆胶、黄原胶、明胶和丙烯酸羟乙酯/丙烯酰二甲基牛磺酸钠共聚物。更优选增稠剂和调质剂包括丙烯酸羟乙酯/丙烯酰二甲基牛磺酸钠共聚物(SepineoTM d.e.r.m)。可选择地,氯乙酸和过氧化氢可以代替三氯乙酸和过氧化氢使用。
本发明的未稀释的软膏制剂还可以包含范围为5-12重量%的水、范围为0.5-1.5重量%的月桂基硫酸钠、范围为10-15重量%的丙二醇、范围为20-30重量%的硬脂醇、范围为20-30重量%的凡士林、范围为4-6重量%的氨水(28%-32%)以及任选浓度为0.02-0.05%的一种或多种防腐剂。优选的防腐剂包括对羟基苯甲酸丙酯、对羟基苯甲酸甲酯、苯甲酸钠和乙基己基甘油。任选地,制剂不含任何防腐剂。氯乙酸和过氧化氢或者三氯乙酸和三氯过氧乙酸可以选择地代替三氯乙酸和过氧化氢使用。这些制剂可以任选在用等渗0.9%w/v NaCl水溶液稀释后施用。
除了以上文所定义的比例的三氯乙酸和过氧化氢的组合或者三氯过氧乙酸和三氯乙酸的组合之外,本发明的未稀释的乳膏制剂还可以包含范围为20-25重量%的水、范围为5-12重量%的液体石蜡、范围为3-7重量%的丙二醇、范围为8-12重量%的甘油、范围为10-14重量%的氨水(28%-32%)以及范围为1-2重量%的聚山梨酯60。可选择地,氯乙酸和过氧化氢或者三氯乙酸和三氯过氧乙酸可以代替三氯乙酸和过氧化氢使用。这些制剂可以任选在用等渗0.9%w/v NaCl水溶液稀释后施用。
本发明的未稀释的凝胶制剂可以包含范围为25-35重量%的乙醇、范围为11-15重量%的丙二醇、范围为10-14%的氨水(28-32%w/v)、范围为2-5重量%的二乙二醇单乙醚以及范围为1-4%的肉豆蔻醇。可选择地,氯乙酸和过氧化氢或者三氯乙酸和三氯过氧乙酸可选择地代替三氯乙酸和过氧化氢使用。这些制剂可以任选在用等渗0.9%w/v NaCl水溶液稀释后施用。
试验部分
实施例1
用于修复皮肤和粘膜伤口的软膏具有以下组成:
组分 | %(w/w) |
纯化水 | 11.59 |
对羟基苯甲酸丙酯 | 0.02 |
月桂基硫酸钠 | 1.05 |
丙二醇 | 12.63 |
硬脂醇 | 26.32 |
对羟基苯甲酸甲酯 | 0.03 |
三氯乙酸 | 14.60 |
过氧化氢29-31% | 2.21 |
氨水28-32% | 5.22 |
白凡士林 | 26.32 |
该浓缩软膏制剂可以使用0.9%w/v NaCl水溶液稀释以获得pH值≥2.6的最终液体制剂。
实施例2
用于修复皮肤和粘膜伤口的液体具有以下组成(制剂14-03-01:1/400稀释)
浓缩液体溶液可以使用0.9%w/v NaCl水溶液稀释至多1:400以获得pH值≥2.6的最终液体制剂。
实施例2a
用于修复皮肤和粘膜伤口的液体具有以下组成:
组分 | %(w/w) |
纯化水 | 41.5 |
EDTA二钠 | 0.2 |
三氯过氧乙酸 | 28.3 |
三氯乙酸 | 7 |
甘油 | 10 |
氨水28-32% | 11.8 |
SepineoTM d.e.r.m. | 2 |
该浓缩液体溶液可以使用0.9%w/v NaCl水溶液稀释以获得pH值≥2.6的最终液体制剂。可选择地,三氯过氧乙酸可以通过将等摩尔量的过氧化氢添加至三氯乙酸中原位制备。
实施例3
用于修复皮肤和粘膜伤口的乳膏具有以下组成
组分 | %(w/w) |
纯化水 | 23.9 |
液体石蜡 | 10.0 |
三氯乙酸 | 33.0 |
丙二醇 | 5.0 |
过氧化氢29-31% | 5.0 |
氨水28-32% | 11.8 |
甘油 | 10.0 |
聚山梨酯60 | 1.3 |
该浓缩制剂可以使用0.9%w/v NaCl水溶液稀释以获得pH值≥2.6的最终液体制剂。
实施例4
用于修复皮肤和粘膜伤口的凝胶具有以下组成:
该浓缩制剂可以使用0.9%w/v NaCl水溶液稀释以获得pH值≥2.6的最终液体制剂。
比较实施例1
与实施例2(制剂14-03-01)的唯一差异为组分不含过氧化氢。
该浓缩制剂使用0.9%w/v NaCl溶液1:400稀释以获得pH值≥2.6的最终液体制剂。
比较实施例2
该浓缩液体溶液使用0.9%w/v NaCl水溶液1:400稀释以获得pH值≥2.6的最终液体制剂。
随后将液体制剂14-03-01(TCA加H2O2)、14-04-03(仅TCA)和14-04-05(仅H2O2)在体内和体外测试中进行生物学评估。这些测试证实三氯乙酸和过氧化氢在加速粘膜和皮肤的伤口和溃疡愈合方面的协同作用,即使在用0.9%NaCl水溶液稀释至多400倍后并且在pH值≥2.6也是如此。
试验体外和体内测试
试验方案
该研究分为两个步骤:第一步,溶液的有效性使用NHEK细胞(正常人表皮细胞)在体外细胞模型上进行验证;第二步,溶液的有效性在模拟缓慢愈合人伤口的小鼠动物模型上进行。两个步骤中所测试的溶液包括以下组合:
·14-03-01(TCA加H2O2)
·14-04-03(仅TCA)
·14-04-05(仅H2O2)
并且其效果与未处理的对照样品进行比较。
在体外模型中,NHEK细胞用于在剂量-响应研究中测试溶液的功效以排除任何细胞毒性作用,通过MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物)测试分析细胞存活。由于物质的组合未曾描述于文献中,因此所测试的范围基于文献中所报导的TCA浓度[Yang H等人,Toxicol In Vitro.2011年12月;25(8):1638-43]。特别的是,测试用无菌生理溶液(0.9%NaCl)1:100(20mM);1:200(10mM);1:400(5mM)和1:800(2.5mM)稀释。选择3种不同的刺激方案,如下文所述:
·仅1次处理,保持至多6天(总共1次刺激),方案A
·1次处理/天,进行至多6天(总共5次刺激),方案B
·1次处理/隔天,进行至多6天(总共3次刺激),方案C。
由于数据突出显示最小有效剂量和施用足够剂量的重要性,因此在后续试验中,仅使用方案A和C测试仅5mM浓度。随后,进行测试以评估细胞增殖(结晶紫分析)、迁移(伤口分析)和活性氧簇(ROS)的产生。
迁移和再上皮形成使用雄性C57BL/6JOlaHsd小鼠在体内模型中进行研究,排除方案A和C中测试的物质诱导的任何毒性作用。施用之前,将小鼠在背脊右侧脱毛。脱毛区域为约2×2cm。褥疮模型通过间歇性机械挤压在脱毛区域中挤压,以模拟褥疮的天然形成过程。
特别的是,
·14-03-01(TCA加H2O2)
·14-04-03(仅TCA)
·14-04-05(仅H2O2)
以在无菌生理溶液(0.9%NaCl)中制备的1:400稀释液使用以治疗皮肤伤口。每次治疗结束时,对伤口进行平面测量分析并且收集伤口区域以进行组织学分析,例如E/E(苏木精/伊红)和马森染色。
方法:体外模型
细胞培养
购自Lonza(Basel,Switzerland)的正常人表皮角质细胞(NHEK)在5%CO2温育箱(Thermo Fisher Scientific)中在37℃在含有60μM Ca2+和HKGS(Gibco,Thermo FisherScientific)的EpiLife培养基(Gibco,Thermo Fisher Scientific,Waltham,MA,USA)中培养。培养基每两天更换,并且细胞以70%至80%汇合度使用[Jia,T等人,Molecules 2019,24,3156]。试验在第3-6代进行。
细胞存活率
每次刺激后,将NHEK细胞用无菌PBS 1×洗涤,并且与不含酚红和FBS(胎牛血清)、含有1%MTT染料(基于MTT的体外毒理学分析试剂盒;Sigma-Aldrich)的DMEM(Dulbecco改进的eagle培养基)一起在37℃和5%CO2下温育2小时[Uberti,F等人,J CardiovascPharmacol 57:246-258]。细胞存活率通过使用光谱仪(VICTORX4多标记盘读取器)在570nm测量吸光度并且用690nm校正来确定,并且通过将结果与对照细胞(100%存活)进行比较来计算。
结晶紫
每次处理后,将细胞在室温用1%戊二醛(Sigma-Aldrich)固定15分钟,洗涤,并且在室温用100μL 0.1%结晶紫水溶液(Sigma-Aldrich)染色20分钟。将100μL 10%乙酸添加至多孔盘中并且混合,随后使用光谱仪(VICTORX4多标记盘读取器)在595nm读取吸光度。估计的细胞数目通过将结果与对照细胞(对照T0)进行比较来计算,在第一次处理时检查,并且也报告了未处理的细胞的变化[Uberti F,Cells Tissues Organs.2017;203(4):215-230.Epub 2016年11月25日]。
体外伤口分析
擦伤伤口愈合分析如先前描述[Uberti F等人,Cells Tissues Organs.2017;203(4):215-230.Epub 2016年11月25日]使用无菌p200移液管尖端在汇合单层细胞中进行。之后,将细胞在不同方案(A和C)中用不同制剂刺激并且监测6天。每个时间点后,受伤区域的再生在相差显微镜(Leitz,Germany)进行观察。使用ImageJ图像处理程序,裸露区域的大小在每个时间点自6个不同区域处拍摄的数字影像确定。结果表示为迁移细胞的平均值±SD(%)。
ROS产生
超氧阴离子释放速率使用基于细胞色素C还原的标准方案来测量。在处理和未处理的细胞两者中,添加100μL细胞色素C,并且在另一样品中,100μL超氧化物歧化酶特在温育箱中添加30分钟(所有物质均来自Sigma-Aldrich)。培养物上清液中的吸光度使用光谱仪(VICTORX4多标记盘读取器)在550nm测量,并且O2表示为与对照相比,每微克蛋白质每还原细胞色素C的纳摩尔的平均值±SD(%)[Uberti F等人,Cells Tissues Organs.2017;203(4):215-230.Epub 2016年11月25日]。
体外测试的结果
对NHEK细胞的细胞存活率的剂量-响应研究。
进行剂量-响应研究,评估文献中发现的范围内的最佳浓度。该测试允许通过分析施用方案来确定线粒体的代谢。如图1中所示,方案A显示所有物质的剂量响应效果,其中峰值在刺激三天左右;该效果仅可以对14-03-01稳定并且主要效果在5mM(1:400稀释)观察到。
相同测试也用方案B(图2)进行,其中测试组合物每天施用一次处理,持续6天。此外,在此情况下,对于所有测试溶液,最佳结果通过5mM获得(p<0.05)。考虑到结果“低于”方案A中观察到的那些,假定每日刺激过量但无毒性。平台期往往会略微下降,表明方案B过量,并且出于此原因,方案B在后续试验中由方案C(1次处理/隔天,进行最多6天)代替。
增殖分析
增殖分析在根据方案A和C用物质处理的NHEK细胞上使用结晶紫来进行。如图3中所示,与其它组合物相比,14-03-01显著增加细胞增殖(p<0.05),特别是与14-04-03相比多一倍并且与14-04-05相比增加约33%。另外,这些效果在两种方案中均是明显的,但主要效果通过方案C获得(相对于A,p<0.05)。这很重要,因为通过增加细胞数目,有可能这些细胞也可迁移;另外,这些数据表明14-03-01的活性高于单个组分的活性(p<0.05)。
14-03-01、14-04-03和14-04-05对NHEK迁移的影响
评估不同制剂对伤口愈合中NHEK迁移的影响(图4)。我们的结果展现,用14-03-01(方案A和C两者)处理的NHEK细胞中迁移活性相比于对照,以及相比于14-04-03(高约3倍)和14-04-05(约60%)的改善(p<0.05)。这是用以表征迁移中所涉及的多种因素的经验证的方法。数据证实了在增殖分析期间观察到的情况。
制剂对ROS产生的影响
由于文献中报导了关于ROS对愈合的作用的相反的数据,因此进行进一步试验以探究ROS在此情形下的作用。如图5中所示,尽管存在H2O2,但ROS产生并未增加超过测试物质的生理份额(share);这对于确保先前测试中观察到的有效性当然很重要。显然,在两种方案中,与其它物质相比,化合物与过氧化氢一起具有更高的ROS产生,但14-03-01能够相比于对照以及相比于14-04-03(约35%)和相比于14-04-05(约23%),保持低于ROS的生理水平,再次证实TCA和过氧化氢中和单独施用两种组分的负面结果的协同作用。ROS产生是剂量依赖性的,因为方案C提供比方案A更高的结果,但仍为生理性的。
体内测试的方法和结果
为了验证体外获得的数据,体内测试使用60只体重20-25g的8周动物(C57BL/6JOlaHsd小鼠)进行。该方法允许通过监测伤口愈合面积将不同制剂与特定对照进行比较。
伤口愈合面积的评估
伤口愈合的试验模型在使用14-03-01、14-04-03和14-04-05治疗8天的雄性小鼠中进行。如图6中所报告,在方案A中,14-03-01诱导闭合面积大于对照(p<0.05),并且随后与14-04-03和14-04-05相比(分别14%和33%)。该效果与未治疗伤口相比也是统计学显著的(p<0.05)。在方案C中,14-03-01的存在相比于对照(约98%)、14-04-03(约2%)和14-04-05(约4%)诱导更快的闭合。
这些发现已通过利用E/E和马森分析的形态分析证实,其中制剂14-03-01似乎为更好的选择。在方案A的所有治疗中,肉芽组织似乎仍极具活性,并且愈合处于早期阶段。特别的是,14-03-01显示非常明显的修复伤口的能力,并且再上皮形成是几乎完全的。相比之下,方案C显示,用14-03-01治疗的小鼠分别相比于对照、14-04-03和14-04-05呈现伤口的完全上皮形成。上皮形成出现而无任何溃疡,存在无活性肉芽组织,伴随胶原蛋白重塑和血管生成;出于此原因,有可能设想恢复原状(restitutio ad integrum)。
Claims (17)
1.乳膏、软膏、液体或凝胶形式的伤口愈合组合物,其包含:
第一组分,其选自重量浓度范围为0.08-38%的三氯乙酸或氯乙酸;
第二组分,其选自重量浓度范围为0.01-5%的过氧化氢水溶液,或三氯过氧乙酸。
2.根据权利要求1所述的组合物,其包含三氯乙酸和过氧化氢。
3.根据权利要求1所述的组合物,其包含三氯乙酸和三氯过氧乙酸。
4.根据权利要求1所述的组合物,其包含氯乙酸和过氧化氢。
5.根据权利要求2所述的组合物,其中三氯乙酸和过氧化氢的相对摩尔比为4.34-4.74。
6.根据权利要求3所述的组合物,其中三氯过氧乙酸和三氯乙酸的相对分子比为3.6-4.0。
7.根据权利要求4所述的组合物,其中氯乙酸和过氧化氢的相对摩尔比为4.34-4.74。
8.根据权利要求1、2、4、5和7中任一项所述的组合物,其中过氧化氢水溶液为5-31%水溶液,优选29-31%水溶液。
9.根据权利要求1-8中任一项所述的组合物,其pH值为2.6-3.6。
10.根据权利要求1-9中任一项所述的组合物,其是乳膏形式,包含20-25%w/w水、5-12%w/w液体石蜡、3-7%w/w丙二醇、8-12%w/w甘油、10-14%w/w的28-32%w/w氨水溶液和1-2%w/w聚山梨酯60。
11.根据权利要求1-9中任一项所述的组合物,其是软膏形式,包含5-12%w/w水、0.5-1.5%w/w月桂基硫酸钠、10-15%w/w丙二醇、20-30%w/w硬脂醇、20-30%w/w白凡士林、4-6%w/w氨水(28-32%)和任选0.02-0.05%浓度的一种或多种防腐剂。
12.根据权利要求11所述的组合物,其中不使用防腐剂。
13.根据权利要求1-9中任一项所述的组合物,其是液体形式,包含38-99%w/w水、0.001-0.5%w/w EDTA二钠盐、0.025-15%w/w甘油、0.03-14%w/w氨水(28-32%)、0.005-5%w/w增稠剂和调质剂。
14.根据权利要求1-9中任一项所述的组合物,其是凝胶形式,包含25-35%w/w乙醇、11-15%w/w丙二醇、10-14%w/w氨水(28-32%w/v)、2-5%w/w二乙二醇单乙醚和1-4%肉豆蔻醇。
15.根据权利要求1-9中任一项所述的组合物,其用0.9%NaCl水溶液稀释。
16.根据权利要求1、3和6中任一项所述的组合物,其中三氯过氧乙酸通过将过氧化氢添加至三氯乙酸中原位制备。
17.根据权利要求1-15中任一项所述的组合物,其用于治疗未愈合伤口、溃疡和褥疮,治疗拔牙的手术后并发症,包括干槽症、感觉迟钝、严重感染、疼痛、肿胀、牙关紧闭和出血,治疗缓慢愈合伤口、自发性溃疡、多种来源的疮和坏死性疮,包括化脓性肉芽肿、睑板腺囊肿、龈瘤、瘘和脓肿。
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