CN112334142A - 包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮的创伤治疗或皮肤活性用药学组合物 - Google Patents
包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮的创伤治疗或皮肤活性用药学组合物 Download PDFInfo
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- CN112334142A CN112334142A CN201980042003.2A CN201980042003A CN112334142A CN 112334142 A CN112334142 A CN 112334142A CN 201980042003 A CN201980042003 A CN 201980042003A CN 112334142 A CN112334142 A CN 112334142A
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Abstract
本发明涉及包含β‑葡聚糖、甘氨酸(glycitin,4'‑羟基‑6‑甲氧基异黄酮‑7‑D‑葡萄糖苷(4'‑hydroxy‑6‑methoxyisoflavone‑7‑D‑glucoside))及4',6,7‑三甲氧基异黄酮的创伤治疗或皮肤活性用药学组合物。
Description
技术领域
本申请将2018年6月22日申请的韩国专利申请第10-2018-0072306号作为优先权主张,上述说明书全文为本申请的参考文献。
本发明涉及包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮的创伤治疗或皮肤活性用药学组合物。
背景技术
皮肤为从外部刺激中保护人体,执行阻止水分的流失,调节体温,防止细菌侵入等重要的生命保护功能的器官中之一,当皮肤因烧伤或各种外伤而发生缺损时,丧失其保护作用而引起功能的障碍,并引起水分流失等导致的多种副作用和来自外部的细菌感染等,从而难以治疗患处,或引起继发性功能障碍或损伤等的追加的副作用,严重时,则还影响生命延长。因此,为了迅速治疗伤口,并将继发性各种副作用最小化,需要利用适当的敷料来治疗伤口。
创伤为因外部的压力而破坏组织的连续性,或一部分区域发生缺损的状态。单纯的外伤等轻度创伤可通过自我修复功能来进行再生,但重症烧伤或复合创伤、褥疮、外科手术引起的创伤等难治性创伤难以彻底修复。难治性创伤或广泛的创伤有可能在组织本身的功能执行时留下缺陷,因而需要用于迅速治疗创伤部位,并将继发性各种副作用最小化的治疗。众所周知,相比于干燥的状态,当维持湿润状态时,创伤的愈合速度快2倍左右。以往,为了维持湿润状态,使用利用被生理学溶液或包含消毒剂的溶液浸湿的纱布来敷料的方法。但是,此时,敷料的更换周期应频繁,因而存在管理时麻烦,且不仅是创伤部位,周边部也因生理学溶液或消毒剂而维持浸湿的状态,导致引发皮肤的溃烂的问题。近来,多使用由水凝胶或水胶体之类的创伤包覆材料保护患处的同时防止来自体内的水分泄漏,并吸收渗出液来维持湿润环境的方法。
β-葡聚糖为由葡萄糖形成的高分子物质,其来源多样,尤其,众所周知,从酵母的细胞壁中获得的来源于酵母的β-葡聚糖为具有作用于皮肤来调节新陈代谢及生物节律,并向免疫系统给予活性的皮肤保护功能的生物活性物质中之一,广泛用于治疗创伤(韩国授权专利第10-1109146号)。甘氨酸(Glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷(4′-hydroxy-6-methoxyisoflavone-7-D-glucoside))具有在成纤维细胞中增加胶原蛋白的合成,抑制弹性蛋白酶(elastinase)的活性,并显著抑制由过氧化氢诱导的细胞的老化的效果。并且,作为从植物中提取的天然单一物质的4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)和甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)促进皮肤真皮层的增殖和胶原蛋白的合成而皱纹改善效果卓越。但是,还没有有关在以特定比率混合上述三种物质来治疗创伤的过程中是否有协同效果的研究。
对此,研究人员确认到当以特定比率混合β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)来进行处理时,与单独处理上述三种物质时相比,创伤治疗的效果更大的事实,并完成本发明。
发明内容
技术问题
本发明要解决的问题在于,提供包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤治疗或皮肤活性用药学组合物。
解决问题的方案
本发明提供包含β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤治疗用药学组合物。
本发明提供包含β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤治疗用皮肤外用剂组合物。
并且,本发明提供上述药学组合物还包含羧甲基纤维素(CMC,Carboxy MethylCellulose)的创伤治疗用药学组合物。
本发明提供上述药学组合物还包含聚乙烯醇(Poly vinyl alcohol)的创伤治疗用药学组合物。
本发明提供包含β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤改善用化妆品组合物。
本发明的再一目的在于,提供包括以药学上有效的量将β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)给药到需要其的个体的步骤的创伤治疗方法。
本发明的另一目的在于,提供用于将β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)使用于创伤治疗用组合物的用途。
发明的效果
本发明的皮肤外用剂以特定浓度混合β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮而制成,将上述皮肤外用剂处理于创伤部位,其结果发现具有伤口愈合效果比个别处理各自的组合物时更突出的效果。由此,可促进手术后恢复患者或创伤患者的伤口愈合速度,并提供伤口的保护及湿润环境。进而,开发还包含羧甲基纤维素或聚乙烯醇的皮肤外用剂来提供执行吸收来源于创伤的渗出物的功能的水凝胶管型皮肤外用剂和水胶体贴片型皮肤外用剂。
附图说明
图1为示出根据β-葡聚糖的浓度的人类角质细胞和成纤维细胞的分化及迁移的结果。
图2为通过免疫印迹(western blotting)确认根据0.5%的β-葡聚糖处理的上皮细胞和成纤维细胞的因子表达效果的结果。
图3为通过免疫印迹确认根据甘氨酸和4′,6,7-三甲氧基异黄酮的浓度及混合的上皮细胞和成纤维细胞的分化、迁移及生长因子的表达的结果。
图4为确认根据甘氨酸和4′,6,7-三甲氧基异黄酮的调配比率的角质细胞的分化和迁移的结果。
图5为通过免疫印迹确认上皮细胞及成纤维细胞的单独培养及上皮细胞及成纤维细胞的共培养(co-culture)中甘氨酸及4′,6,7-三甲氧基异黄酮的混合液中的生长因子的表达的结果。
图6为确认包含β-葡聚糖、羧甲基纤维素、4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)及甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)的创伤愈合水凝胶的创伤愈合效果的结果。
图7为确认包含β-葡聚糖、聚乙烯醇、4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)及甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)的水胶体贴片中根据聚乙烯醇的重量的贴片的溶胀度的结果。
图8为确认包含β-葡聚糖、聚乙烯醇、甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)、4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的水胶体贴片的创伤愈合效果的结果。
具体实施方式
确认当以特定比率混合β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)来进行处理时,与单独处理上述三种物质时相比,创伤治疗的效果更大的事实,并完成本发明。
在本发明中,根据对呈现β-葡聚糖的效果的浓度进行实验的结果,确认到0.5%的β-葡聚糖对人类角质细胞的分化、迁移及浸润有效,且对成纤维细胞分化的效果突出(图1)。确认到上述上皮细胞及成纤维细胞的生长诱导因子的表达也在0.5%的β-葡聚糖中有效增加(图2)。本发明人为了确认甘氨酸和4′,6,7-三甲氧基异黄酮的协同效果,单独按不同浓度处理甘氨酸及4′,6,7-三甲氧基异黄酮,并且,以1.43:1混合处理甘氨酸及4′,6,7-三甲氧基异黄酮。其结果,确认到上皮细胞和纤维细胞的生长因子的表达增加(图3)。进而,以1.43:1.2.86:1及1.43:2改变比率来混合上述甘氨酸及4′,6,7-三甲氧基异黄酮,并处理于上皮细胞,其结果,当以1.43:1混合甘氨酸和4′,6,7-三甲氧基异黄酮时,可确认上皮细胞的分化和迁移增加(图4)。共培养上皮细胞及成纤维细胞来以1.43:1将甘氨酸及4′,6,7-三甲氧基异黄酮作为混合液进行处理,其结果,确认到使上皮细胞和成纤维细胞的生长因子的表达增加。
本发明提供包含β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤治疗用药学组合物。
上述β-葡聚糖(β-glucan)可与以下化学式1相同。
化学式1
或者,
上述甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)可与以下化学式2相同。
化学式2
上述4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)可与以下化学式3相同。
化学式3
本发明人确认根据β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮的比率的上皮细胞和成纤维细胞的分化及迁移的效果,其结果,确认到由0.25w/v%的β-葡聚糖、0.00446w/v%的甘氨酸和0.00312w/v%的4′,6,7-三甲氧基异黄酮混合而成的混合液的效果最突出(表1)。
上述β-葡聚糖、甘氨酸(glycitin)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的重量比可以为320.5:1.43::1至1602:1.43:1。
上述药学组合物可包含0.1w/v%至5.0w/v%的β-葡聚糖,优选地,可包含0.1w/v%至0.5w/v%,最优选地,可包含0.25重量百分比。
上述药学组合物能够以0.00223w/v%至0.0223w/v%的浓度包含甘氨酸,优选地,能够以0.00223w/v%至0.00446w/v%的浓度包含,最优选地,能够以0.00446w/v%的浓度包含。
上述药学组合物能够以0.00156w/v%至0.0156w/v%的浓度包含4′,6,7-三甲氧基异黄酮,优选地,能够以0.00156w/v%至0.00312w/v%的浓度包含,最优选地,能够以0.00312w/v%的浓度包含。
上述甘氨酸及4′,6,7-三甲氧基异黄酮可以为1.43:2至2.86:1,优选地,可以为1.43:1。
提供包含β-葡聚糖、甘氨酸(glycitin)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤治疗用皮肤外用剂组合物。
本发明的皮肤外用剂组合物可包含化妆品学或皮肤科学上可接受的介质或基剂来进行剂型化。其为适用于局部的所有剂型,例如,上述皮肤外用剂组合物能够以选自由柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华素、洁面霜、洁面泡沫、卸妆水、面膜、粉饼、润肤露、润肤霜、润肤油及润肤精华素、隔离霜、粉底、染发剂、洗发水、护发素、身体清洁剂、牙膏、漱口液、软膏、管、贴片及喷雾剂组成的组中的一种进行剂型化。这些组合物可通过本领域的常规方法来进行制备。
并且,本发明的组合物可包含脂肪物质、有机溶剂、溶剂、浓缩剂、凝胶剂、软化剂、抗氧化剂、悬浮剂、稳定剂、发泡剂(foaming agent)、芳香剂、表面活性剂、水、离子型或非离子型乳化剂、填充剂、金属离子螯合剂、螯合剂、保鲜剂、维生素、阻隔剂、湿润剂、必要油、染料、颜料、亲水性或亲油性活性剂、脂质小囊或化妆品中通常使用的任意其他成分之类的化妆品学或皮肤科学领域中通常使用的助剂。上述助剂以化妆品学或皮肤科学领域中一般使用的量进行导入。
本发明提供如上所述的皮肤外用剂组合物还包含羧甲基纤维素(CMC,CarboxyMethyl Cellulose)的皮肤外用剂组合物。
本发明人研究提供伤口的保护及湿润环境来执行吸收来源于创伤的渗出物的功能的水凝胶管型皮肤外用剂。提供如上所述的皮肤外用剂组合物还包含聚乙烯醇(Polyvinyl alcohol)的皮肤外用剂组合物。在0.25%的β-葡聚糖溶液中放入4重量百分比的羧甲基纤维素(羧甲基纤维素钠(Sodium carboxymethyl cellulose),Mw.~250000),并在60℃温度下搅拌来进行混合之后,分别以0.00312w/v%和0.00446w/v%的浓度添加4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)和甘氨酸(4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)来将上述混合水溶液放入模具中,以制备创伤愈合水凝胶。在制备上述水凝胶的过程中,根据羧甲基纤维素的重量百分比来测定粘度,其结果,判断为包含4重量百分比的羧甲基纤维素的水凝胶的粘度适当。以上述制备的水凝胶管型确认创伤愈合效果。每个实验组分配5只美国癌症研究所小鼠(ICR Mouse),并利用5mm的活检打孔器(biopsy punch)来使背部受伤之后,区分为两种创伤包覆材料和非处理组(control)、生理盐水处理组来确认14天的伤口的变化,其结果,通过伤口的恢复速度和组织检查评价功效,包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮作为有效成分的羧甲基纤维素组合物呈现最优秀的效果。
在总组合物重量份中,上述羧甲基纤维素可以为0w/v%至8w/v%,优选地,可以为2w/v%至6w/v%,更优选地,可以为4w/v%。
上述组合物能够以选自由柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华素、洁面霜、洁面泡沫、卸妆水、面膜、粉饼、润肤露、润肤霜、润肤油及润肤精华素、隔离霜、粉底、染发剂、洗发水、护发素、身体清洁剂、牙膏、漱口液、软膏、管、贴片、凝胶及喷雾剂组成的组中的一种进行剂型化,最优选地,能够以凝胶型进行剂型化。
本发明的发明人开发提供伤口的保护及湿润环境来执行吸收来源于创伤的渗出物的功能的水凝胶管型皮肤外用剂。进而,研究上述皮肤外用剂组合物包含聚乙烯醇的贴片型皮肤外用剂组合物。在纯化水中放入5、7、10重量百分比的聚乙烯醇(PVA,Mw.85000~124000),并在80℃温度下搅拌来进行混合。将上述混合液成型于直径为120mm的聚苯乙烯皿之后,在-80℃温度下进行冻结,并在常温条件下进行解冻。将此过程反复两次来使聚乙烯醇进行物理交联,以评价物性,并制备水胶体型贴片。之后,将在0.25%的β-葡聚糖溶液中分别以0.00312w/v%和0.00446w/v%的浓度添加4′,6,7-三甲氧基异黄酮和甘氨酸而成的溶液涂敷于水胶体表面,以制备创伤愈合水胶体。测定根据聚乙烯醇的重量百分比的溶胀度,其结果,判断7%的重量的水胶体更容易吸收创伤皮肤的渗出物。对上述制备的水胶体贴片型创伤包覆材料的创伤愈合功效进行比较实验。每个实验组分别分配5只美国癌症研究所小鼠,并利用5mm的活检打孔器来使背部受伤之后,区分为制备的创伤包覆材料贴片和非处理组(control)、生理盐水纱布处理组、一般带处理组来确认14天的伤口的变化。通过伤口的恢复速度评价功效,确认到包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮作为有效成分的聚乙烯醇贴片(PVA patch)组合物呈现最优秀的效果。
在总组合物重量份中,上述聚乙烯醇可以为5w/v%至10w/v%,优选地,可以为6w/v%至8w/v%,更优选地,可以为7w/v%。
上述组合物能够以选自由柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华素、洁面霜、洁面泡沫、卸妆水、面膜、粉饼、润肤露、润肤霜、润肤油及润肤精华素、隔离霜、粉底、染发剂、洗发水、护发素、身体清洁剂、牙膏、漱口液、软膏、管、贴片、凝胶及喷雾剂组成的组中的一种进行剂型化,最优选地,能够以贴片型进行剂型化。
上述创伤可以为烧伤、溃疡、外伤、外科手术(手术后,post-surgical)、生育、慢性伤口(chronic wound)或皮肤炎(dermatitis)引起的损伤,最优选地,可以为创伤。
提供包含β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)的创伤改善用化妆品组合物。
本发明的再一目的在于,提供包括以药学上有效的量将β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)给药到需要其的个体的步骤的创伤治疗方法。
在本发明中,“个体”是指需要治疗疾病的对象,更具体地,是指包括人类的猴、牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠之类的所有动物,可将本发明的药学组合物给药到个体来有效预防或治疗上述疾病。本发明的药学组合物可与现有的治疗剂并行地进行给药。
本发明的另一目的在于,提供用于将β-葡聚糖、甘氨酸(glycitin,4′-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4′,6,7-三甲氧基异黄酮(TMF,4′,6,7-trimethoxyisoflavone)使用于创伤治疗用组合物的用途。
上述化妆品组合物能够以选自由柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华素、洁面霜、洁面泡沫、卸妆水、面膜、粉饼、润肤露、润肤霜、润肤油、润肤精华素、隔离霜、粉底、染发剂、洗发水、护发素、身体清洁剂、牙膏及漱口液组成的组中的一种进行剂型化。
以下,为了有助于理解本发明,提出优选的实施例。但是,以下的实施例仅为了更容易理解本发明而适用,本发明的内容并不局限于实施例。
实验例1:上皮细胞及成纤维细胞中β-葡聚糖的效果
确认到根据β-葡聚糖的单独处理的作为上皮细胞的人类角质细胞的分化、迁移及浸润效果,并在成纤维细胞中确认到分化。β-葡聚糖从株式会社奎真生物技术中自产而使用。人类皮肤成纤维细胞及人类角质细胞从韩国细胞株银行购买而使用。以1×104细胞/孔(cell/well)(HDF)和5×104细胞/孔(HaCaT)的浓度分别将人类皮肤成纤维细胞(Humandermal fibroblast,HDF)和人类角质细胞(Human Keratinocyte cell,HaCaT)接种于具有包含10%的胎牛血清(FBS)的12ml的达尔伯克(氏)改良伊格尔(氏)培养基(DMEM)的6孔板(well plate),并在37℃温度且5%的CO2条件下进行培养。当进行培养时,将β-葡聚糖的浓度直到0~10%浓度依赖性地分别以200μl的方式处理于上皮细胞(HaCaT)和成纤维细胞(Fibroblast)。确认不同浓度的上皮细胞的分化、迁移、浸润来确认0.5%的β-葡聚糖中最佳的结果,对于成纤维细胞分化而言,未观察到具有显著性的变化(图1)。并且,通过免疫印迹(Western-blot)确认处理0.5%的β-葡聚糖溶液的上皮细胞和成纤维细胞中多种生长因子及蛋白质的表达,其结果,确认到上皮细胞中的显著变化(图2)。
实验例2:成纤维细胞中甘氨酸及4′,6,7-三甲氧基异黄酮的效果
利用甘氨酸和4′,6,7-三甲氧基异黄酮来确认上皮细胞和成纤维细胞的分化诱导效果。准备以1:1混合甘氨酸(10μM(0.00446w/v%)及20μM(0.00892w/v%))、4′,6,7-三甲氧基异黄酮(10μM(0.00312w/v%)及20μM(0.006242w/v%))或甘氨酸(10μM(0.00446w/v%))及4′,6,7-三甲氧基异黄酮(10μM(0.00312w/v%))而成的。分别以1×104细胞/孔(HDF)和5×104细胞/孔(HaCaT)的浓度将人类皮肤成纤维细胞(Human dermalfibroblast,HDF)和人类角质细胞(Human Keratinocyte cell,HaCaT)接种于具有包含10%的胎牛血清的12ml的达尔伯克(氏)改良伊格尔(氏)培养基的6孔板,并在37℃温度且5%的CO2条件下进行培养。将上述甘氨酸、4′,6,7-三甲氧基异黄酮及甘氨酸及4′,6,7-三甲氧基异黄酮混合液处理于成纤维细胞和上皮细胞之后,通过免疫印迹观察培养液中的各个细胞表达蛋白质的变化。与单独使用甘氨酸或4′,6,7-三甲氧基异黄酮的情况相比,当以1:1混合使用两种物质时,确认到上皮细胞和成纤维细胞的分化显著地增加,并确认到各个细胞的分化诱导因子增加。为了提高伤口的愈合效果,确认到两种物质的混用有效(图3)。
实验例3:上皮细胞中甘氨酸和4′,6,7-三甲氧基异黄酮的混合比的效果
并且,将甘氨酸和4′,6,7-三甲氧基异黄酮的混合比变为1.43:1、2.86:1、1.43:2来制备试样,以5×104细胞/孔(HaCaT)的浓度将人类角质细胞(Human Keratinocytecell,HaCaT)接种于具有包含10%的胎牛血清的12ml的达尔伯克(氏)改良伊格尔(氏)培养基的6孔板,并在37℃温度且5%的CO2条件下处理试样之后,培养24小时来察看细胞分化和迁移。当以1.43:1混合甘氨酸和4′,6,7-三甲氧基异黄酮时,确认到对上皮细胞的分化和迁移呈现优秀的效果(图4)。改变甘氨酸及4′,6,7-三甲氧基异黄酮的混合比率来制备试样,利用其来在具有包含10%的胎牛血清的12ml的达尔伯克(氏)改良伊格尔(氏)培养基的Transwell侵袭试剂盒(Transwell invasion kit)上端在37℃温度且5%的CO2条件下将5×104细胞/孔的HaCaT培养24小的实验组中,在Transwell侵袭试剂盒上端接种5×104细胞/孔的HaCaT,在下端接种1×104细胞/孔的HDF(HDF),并处理包含10%的胎牛血清的24ml的达尔伯克(氏)改良伊格尔(氏)培养基和试样之后,在37℃温度且5%的CO2条件下培养24小时来确认生长因子的诱导。确认到甘氨酸及4′,6,7-三甲氧基异黄酮混合物促进上皮细胞和成纤维细胞的增殖(图5)。
实验例4:β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮复合剂型
将β-葡聚糖作为A液,将甘氨酸/4′,6,7-三甲氧基异黄酮作为1.43:1混合液B液,并以如下列表1所示的浓度组成单独或混合来制备各个试液。在Transwell侵袭试剂盒上端接种5×104细胞/孔的HaCaT,在下端接种1×104细胞/孔的HDF(HDF),并分别处理包含10%的胎牛血清的24ml的达尔伯克(氏)改良伊格尔(氏)培养基和实验液三种之后,在37℃温度且5%的CO2条件下培养24小时来确认最佳的浓度条件。
表1
根据β-葡聚糖/甘氨酸/4′,6,7-三甲氧基异黄酮混合液的组成的伤口愈合效果(相对于对照组磷酸盐缓冲液(PBS)的改善率(%))
对于制药复合物而言,当以单一物的最佳(optimal)的组成条件进行调配时,阻止伤口组织的过大增殖等,且用于维持恒常性的组织内机制(mechanism)启动。因此,需要确立次优条件(sub-optimal condition)中的最佳组成条件,并对此确认最佳的组成。尤其,混合0.25%的β-葡聚糖及0.00312%(10μM)的4′,6,7-三甲氧基异黄酮、0.00446%(10μM)的甘氨酸的组成呈现比分别个别地使用时更大的增殖及迁移的协同效果。
实验例5:包含β-葡聚糖、4′,6,7-三甲氧基异黄酮及甘氨酸的创伤愈合水凝胶的
粘度测定
将在实施例4中制备的水凝胶填充于100ml的烧杯中,并利用粘度计来测定粘度。以64号转子(Spindle)进行测定,并以12rpm在53.5%的扭矩(torque)中确认测定值。相比于羧甲基纤维素含量为0重量百分比时,当羧甲基纤维素含量为4重量百分比时,cP值呈现更高,判断4重量百分比的cP值适当(表2)。
表2
实验例6:包含β-葡聚糖、4′,6,7-三甲氧基异黄酮及甘氨酸的创伤愈合水凝胶的
创伤治疗效果
利用在实施例4中制备的各个水凝胶创伤包覆材料来比较创伤愈合功效。每个实验组分别分配5只美国癌症研究所小鼠,并利用5mm的活检打孔器来使背部受伤之后,区分为两种创伤包覆材料和非处理组(control)、生理盐水处理组来确认14天的伤口的变化。通过伤口的恢复速度和组织检查评价功效,确认到包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮作为有效成分的羧甲基纤维素组合物呈现最优秀的效果(图6)。
实施例5:包含β-葡聚糖、4′,6,7-三甲氧基异黄酮及甘氨酸的创伤愈合水胶体贴 片的制备
在纯化水中放入5、7、10重量百分比的聚乙烯醇(PVA,Mw.85000~124000),并在80℃温度下搅拌来进行混合。将上述混合液成型于直径为120mm的聚苯乙烯皿之后,在-80℃温度下进行冻结,并在常温条件下进行解冻。将此过程反复两次来使聚乙烯醇进行物理交联,以评价物性,并制备水胶体型贴片。之后,将在0.25%的β-葡聚糖溶液中分别以0.00312%(10μM)和0.00446%(10μM)的浓度添加4′,6,7-三甲氧基异黄酮和甘氨酸而成的溶液涂敷于水胶体表面来制备创伤愈合水胶体。
实验例6:包含上述β-葡聚糖、4′,6,7-三甲氧基异黄酮及甘氨酸的创伤愈合水胶 体贴片的溶胀度测定
将在上述实施例5中制备的水胶体切割成5×5cm大小,放入称量皿(weighingdish)中,并测定重量(W1)。在测定初始重量的水胶体中考虑吸收力来添加37℃温度的磷酸盐缓冲液。搁置30分钟之后,测定样品的最后重量(W2)。水胶体的溶胀度(Degree ofswelling)根据以下数学式来进行计算。
如图8所示,当5重量百分比时,聚乙烯醇水胶体的溶胀度为约47%,当7重量百分比时,聚乙烯醇水胶体的溶胀度为约80%,呈现更高的溶胀度,从而判断7%重量的水胶体更容易吸收创伤皮肤的渗出物(图7)。
实验例7:包含上述β-葡聚糖、4′,6,7-三甲氧基异黄酮及甘氨酸的创伤愈合水胶 体贴片的创伤愈合效果
利用上述制备的水胶体贴片型创伤包覆材料来比较创伤愈合功效。每个实验组分别分配5只美国癌症研究所小鼠,并利用5mm的活检打孔器来使背部受伤之后,区分为制备的创伤包覆材料贴片和非处理组(control)、生理盐水纱布处理组、一般带处理组来确认10天的伤口的变化。通过伤口的恢复速度评价功效,确认到包含β-葡聚糖、甘氨酸及4′,6,7-三甲氧基异黄酮作为有效成分的聚乙烯醇贴片组合物呈现最优秀的效果(图8)。
Claims (14)
1.一种创伤治疗用药学组合物,其特征在于,包含β-葡聚糖、甘氨酸及4',6,7-三甲氧基异黄酮。
2.根据权利要求1所述的创伤治疗用药学组合物,其特征在于,上述β-葡聚糖、甘氨酸及4',6,7-三甲氧基异黄酮的重量比为320.5:1.43:1至1602:1.43:1。
3.根据权利要求1所述的创伤治疗用药学组合物,其特征在于,上述β-葡聚糖为0.1重量百分比至5.0重量百分比。
4.根据权利要求1所述的创伤治疗用药学组合物,其特征在于,上述甘氨酸为0.00223重量百分比至0.0223重量百分比。
5.根据权利要求1所述的创伤治疗用药学组合物,其特征在于,上述4',6,7-三甲氧基异黄酮为0.00153重量百分比至0.0156重量百分比。
6.一种创伤治疗用皮肤外用剂组合物,其特征在于,包含β-葡聚糖、甘氨酸及4',6,7-三甲氧基异黄酮。
7.根据权利要求6所述的创伤治疗用皮肤外用剂组合物,其特征在于,上述皮肤外用剂组合物以选自由软膏、管、贴片、凝胶及喷雾剂组成的组中的一种进行剂型化。
8.根据权利要求1至5中任一项所述的创伤治疗用药学组合物,其特征在于,上述药学组合物还包含羧甲基纤维素。
9.根据权利要求1至5中任一项所述的创伤治疗用药学组合物,其特征在于,上述药学组合物还包含聚乙烯醇。
10.根据权利要求9所述的创伤治疗用药学组合物,其特征在于,上述创伤为烧伤、溃疡、外伤、外科手术(手术后)、生育、慢性伤口或皮肤炎引起的损伤。
11.一种创伤改善用化妆品组合物,其特征在于,包含β-葡聚糖、甘氨酸(4'-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4',6,7-三甲氧基异黄酮。
12.根据权利要求11所述的创伤改善用化妆品组合物,其特征在于,上述化妆品组合物以选自由柔软化妆水、收敛化妆水、营养化妆水、营养霜、按摩霜、精华素、眼霜、眼部精华素、洁面霜、洁面泡沫、卸妆水、面膜、粉饼、润肤露、润肤霜、润肤油、润肤精华素、隔离霜、粉底、染发剂、洗发水、护发素、身体清洁剂、牙膏及漱口液组成的组中的一种进行剂型化。
13.一种创伤治疗方法,其特征在于,包括以药学上有效的量将β-葡聚糖、甘氨酸(4'-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4',6,7-三甲氧基异黄酮给药到需要其的个体的步骤。
14.一种用途,其特征在于,用于将β-葡聚糖、甘氨酸(4'-羟基-6-甲氧基异黄酮-7-D-葡萄糖苷)及4',6,7-三甲氧基异黄酮使用于创伤治疗用组合物。
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KR101547996B1 (ko) * | 2014-06-30 | 2015-08-27 | 제주대학교 산학협력단 | 상처 치료, 상처 회복 또는 흉터 생성 억제용 피부 외용제 조성물 |
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TW200711666A (en) * | 2005-09-20 | 2007-04-01 | Taiwan Textile Res Inst | Glucan film and applications thereof |
US20130309286A1 (en) * | 2010-11-29 | 2013-11-21 | Biotec Pharmacon Asa | Glucan Compositions |
KR101547996B1 (ko) * | 2014-06-30 | 2015-08-27 | 제주대학교 산학협력단 | 상처 치료, 상처 회복 또는 흉터 생성 억제용 피부 외용제 조성물 |
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WO2019245332A1 (ko) | 2019-12-26 |
JP2021531244A (ja) | 2021-11-18 |
US20210260096A1 (en) | 2021-08-26 |
KR20200000243A (ko) | 2020-01-02 |
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