CN1969874B - 一种外用复方阿巴芬净药物组合物 - Google Patents
一种外用复方阿巴芬净药物组合物 Download PDFInfo
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Abstract
本发明属于一种外用复方阿巴芬净药物组合物,含有阿巴芬净0.01~20%,肾上腺皮质激素0.005~1%,其余为药用辅料。该组合物还可进一步包含抗细菌物质。该组合物抗菌谱广,不仅能提高治疗真菌的疗效,减轻感染对皮肤的损伤,还能治疗一些真菌和细菌的混合感染,并具有止痒和快速消炎的作用,同时对阴道念珠菌病、外阴阴道炎也有很好的疗效,对局部几无刺激作用。
Description
技术领域
本发明属于药物制剂领域,具体涉及外用复方阿巴芬净药物组合物,包含有效治疗量的阿巴芬净(abafungin)和肾上腺皮质激素,是一种具有广谱抗菌、抗炎和抗瘙痒作用的外用制剂。该组合物用于治疗皮肤真菌感染、瘙痒、真菌和细菌的混合感染、阴道念珠菌病、外阴阴道炎(特别是在细菌也卷入时)、各种皮炎,对局部几无刺激作用。
背景技术
浅部真菌病是一种常见病,多发病。浅部真菌感染由表皮癣菌属、毛癣菌属、小孢子菌属等皮肤癣菌所致感染。三者均可侵犯皮肤,引起手足癣、体癣、股癣、叠瓦癣等;前二者可侵犯指(趾)甲,引起甲癣;后二者可侵犯毛发,引起头癣、黄癣等。浅表真菌病传染性强,发病率极高、顽固而又极易复发,如足癣,即脚气,全国平均发病率达三分之一,在一些高发地区发病率高达60%。
皮肤真菌感染时常伴有炎症和细菌的存在,但是单用抗真菌药效果往往不佳;皮肤炎症不管是感染性和非感染性,单用激素消炎均易诱发真菌或细菌感染。
目前抗真菌药物品种较多,但这些药物抗真菌作用均为单一作用机制,而且这些机制均在真菌生长时才发挥作用,对静止期的真菌效果较差。
阿巴芬净(abafungin)为氨基噻唑类抗真菌药,其特征是抗菌谱广,对生长中和静止中的真菌细胞均具有杀灭作用,具有抑制真菌和杀灭真菌的双重作用,能靶向静止的真菌细胞,有效杜绝感染复发,可以治疗一些真菌和细菌的混合感染,对念珠菌的作用更优。肾上腺皮质激素类药物,具有抗炎等作用,无抑杀真菌作用。两者制成复方后,对真菌感染具有增效作用,同时也能够减轻真菌以及细菌对皮肤的损伤,抑制各种炎症反应,对阴道念珠菌病、外阴阴道炎也有很好的疗效,同时还兼有止痒作用。
发明内容
本发明的目的是提供一种治疗浅部真菌病的含有阿巴芬净、肾上腺皮质激素和药用辅料或载体的外用复方药物组合物,即外用复方阿巴芬净组合物,该组合物能有效的治疗浅部真菌感染和炎症、真菌和细菌的混合感染、阴道念珠菌病、外阴阴道炎(特别是在细菌也卷入时)。
本发明的另一目的是提供外用复方阿巴芬净组合物在制备治疗皮肤真菌感染、各种皮炎、瘙痒、阴道真菌细菌感染和外阴阴道炎药物中的运用。
阿巴芬净的作用机制新颖,具有双重作用机制,即作用于细胞壁又作用于细胞膜,对生长中和静止中的真菌细胞均具有杀灭作用,具有抑制真菌和杀灭真菌的双重作用,有效杜绝感染复发。同时,肾上腺皮质激素能抑制炎症反应、减轻皮损、提高致痒阈。
本发明的外用复方阿巴芬净组合物,其中,阿巴芬净占组合物重量的0.01~20%,优选0.5~5%,更优选1~2%;肾上腺皮质激素占组合物重量的0.005~1%,优选0.01~0.5%。
上述的肾上腺皮质激素,选自下述化合物(药物)中的一种或多种:氟轻松及其醋酸酯,曲安西龙及其醋酸酯,异丁酸酯与琥珀酸酯,哈西奈德,氢化可的松及其酯酸酯、丁酸酯、丁酸丙酸酯、环戊丙酸酯、叔丁基乙酸酯、戊酸酯与酯酸丙酸酯,地塞米松及其醋酸酯、二异丙基氟磷酸酯、间磺酸苯甲酸酯、叔丁基乙酸酯与2-氯-62-氟酯、三氧-十一酸酯、异烟酸酯与戊酸酯,氟氢可的松及其醋酸酯与琥珀酸酯,曲安奈德及其醋酸酯,倍他米松及其醋酸酯、二丙酸酯、乙丁酯、戍酸酯、琥珀酸酯、安息香酸酯、磷酸酯或戊乙酸酯,倍氯米松及其二丙酸酯,丙酸氯倍他索,氟氢缩松,泼尼松及其醋酸酯或十六酸酯,氢化泼尼松及其醋酸酯、间磺酸苯甲酸酯、十六酸酯、戍酸酯或戊乙酸酯,二氟拉松及其醋酸酯,安西奈德,莫米松及其糠酸酯,甲泼尼龙及其醋酸酯、环戊丙酸酯、磷酸酯或琥珀酸酯,丁酸氯倍他松,氟米松,阿氟米松及其二丙酸酯,二氟可龙,地泼罗酮及其丙酸酯,氟氢缩松,去羟米松。
本发明的复方阿巴芬净组合物,根据用途和剂型的不同需要,还可加入一种或二种抗细菌药物,占组合物重量的0.01%~10%,优选0.1%~2%。
上述的抗细菌药物,包括但不限于红霉素、氯霉素、硫酸新霉素、呋喃西林、乙酰螺旋霉素、氧氟沙星、克林霉素、莫匹罗星等。加入抗细菌物质的复方阿巴芬净组合物可用于治疗皮肤和妇科(妇女的外阴和阴道)的真菌和细菌的混合感染。
本发明所说的外用复方阿巴芬净组合物,其制剂形式为软膏剂、乳膏剂、凝胶剂、霜剂、洗剂、栓剂、油剂或喷剂。
本发明所说的外用复方阿巴芬净组合物,所用的辅料或载体包括油性基质4~55%、水溶性基质0~30%、凝胶基质4~45%、防腐剂0~1%、抗氧剂0~1%和蒸馏水,根据具体制剂形式的需要可选择其中的二种或二种以上(多种)。如制剂形式为乳膏剂可选择油性基质4~45%、水溶性基质0.1~30%、防腐剂0.01~1%、抗氧剂0.01~1%和蒸馏水;为凝胶剂时可选择凝胶基质4~45%、防腐剂0~1%、抗氧剂0~1%和蒸馏水,如需要,还可还包括保湿剂,如甘油、甲基葡萄糖苷、丙二醇等,优选甘油和丙二醇。
上述所说的油溶性基质包括凡士林、羊毛酯、液体石蜡、硬脂酸、单硬脂酸甘油酯、蜂蜡、鲸蜡醇、硬脂醇、十六醇、十八醇、吐温—80、乙酰化单甘油酯在内的任一种或多种。
上述所说的水溶性基质包括聚乙二醇、硅酸镁铝、三乙醇胺、羧乙基纤维素、甘油在内的任一种或多种。
上述所说的防腐剂包括尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、山梨酸、山梨酸钾、山梨酸钙在内的任一种、两种或任两种以上。
上述所说的抗氧剂包括亚硫酸钠、焦亚硫酸钠、乙二胺四乙酸、二叔丁羟基甲苯、亚硫酸氢钠、硫代硫酸钠在内的任一种、两种或任两种以上。
上述所说的凝胶基质包括卡波姆、羟丙纤维素、硅酸镁铝、海藻酸钠、透明质酸、交联聚丙烯酸树脂、丙二醇、乙醇、明胶在内的一种或多种。
上述所说的的制剂形式为乳膏剂或凝胶剂。每天用药1—2次。
具体实施例方式
以下结合实例对本发明做详细描述:
实施例1乳膏
配方:(1)阿巴芬净10g、(2)哈西奈德1g、(3)凡士林10g、(4)硬脂酸110g、(5)液体石蜡60g、(6)单硬脂酸甘油酯35g、(7)尼泊金丙酯0.2g、(8)十八醇50g、(9)三乙醇胺4.5g、(10)尼泊金甲酯1.8g、(11)二叔丁羟基甲苯2g、(12)甘油40g、(13)焦亚硫酸钠10g、(14)乙二胺四乙酸1g、(15)加蒸馏水至1000g。
制备方法:将甘油、焦亚硫酸钠放入研钵里研磨均匀后,加入阿巴芬净和地塞米松,研匀,备用,得主药混合物①;将凡士林、硬脂酸、单硬脂酸甘油酯、十八醇、液体石蜡、尼泊金丙酯混合,置于水浴70~80℃搅拌并使溶解,得油相②;将尼泊金甲酯、二叔丁羟基甲苯、乙二胺四乙酸、蒸馏水混合,置于水浴70~80℃搅拌并使溶解,得水相③;将②缓慢加入到③中,边加边剧烈搅拌使乳化完全,待冷却后,等量递加到①里研匀,分装,即可。
实施2乳膏剂
配方:(1)阿巴芬净15g、(2)醋酸曲安奈德0.15g、(3)醋酸氟氢松0.05g、(4)羊毛酯45g、(5)乙酰化单甘油酯70g、(6)液体石蜡60g、(7)十六醇80g、(8)尼泊金乙酯1.8g、(9)亚硫酸钠2g、(10)硅酸镁铝35g、(11)加蒸馏水至1000g。
制备方法:将羊毛酯、乙酰化单甘油酯、液体石蜡、十六醇混合,置于水浴65~75℃搅拌并使溶解,得油相①;将尼泊金乙酯、亚硫酸钠、硅酸镁铝、蒸馏水置于水浴70~80℃搅拌并使溶解,得水相②;边搅拌②边加入①,冷却;将阿巴芬净、醋酸曲安奈德、醋酸氟氢松混合,得主药混合物③,将上述①②混合物等量递加到③中,混合均匀,装量,即得。
实施例3霜剂
配方:(1)阿巴芬净40g、(2)醋酸倍他米松0.3g、(3)甘油100g、(4)十八醇40g、(5)单硬脂酸甘油酯35g、(6)凡士林100g、(7)吐温—8020g、(8)尼泊金丁酯1.5g、(9)二叔丁羟基甲苯1.8g、(10)加蒸馏水至1000g。
制备方法:将十八醇、单硬脂酸甘油酯、凡士林、吐温—80混合,置于水浴70~80℃搅拌并使溶解,得油相①;将尼泊金丁酯、二叔丁羟基甲苯、加蒸馏水混合,置于水浴70~80℃搅拌并使溶解,得水相②;边搅拌②边加入①;将阿巴芬净、醋酸倍他米松、甘油混合均匀,得主药混合物③;再将上述①②混合物等量递加到③里,混合均匀,装量,即得。
实施例4.凝胶剂
配方:(1)阿巴芬净20g、(2)地塞米松0.5g、(3)丙二醇800g、(4)尼泊金乙酯2g、(5)明胶20g、(6)加蒸馏水至1000g。
制备方法:取明胶,加蒸馏水适量,40℃水浴,浸泡至充分溶胀成凝胶,备用;取地塞米松和尼泊金乙酯,加入丙二醇适量,加热使溶解,放冷,加入阿巴芬净和剩余丙二醇,搅拌均匀,得药液;搅拌下将凝胶加入到药液中,不断均质,至搅匀,加水至1000g,搅拌均匀,装量,即得。
实施例5.凝胶剂
配方:(1)阿巴芬净30g、(2)曲安西龙0.2g、(3)卡波姆5g、(4)甘油11.2g、(5)焦亚硫酸钠1g、(6)山梨酸钾2g、(7)蒸馏水加至1000g。
制备方法:取蒸馏水,加入卡波姆、适量甘油置于水浴50~70℃搅拌并使溶解制成凝胶基质;在剩余甘油中加入阿巴芬净和曲安西龙,混合均匀;将凝胶基质等量递加到含主药的甘油里面,混合均匀,再分别加入焦亚硫酸钠、山梨酸钾,混匀装量,即得。
实施例6.凝胶剂
配方:(1)阿巴芬净15g、(2)氟氢缩松0.15g、(3)交联聚丙烯酸树脂20g、(4)海藻酸钠40g、(5)丙二醇50g、(6)甘油200g、(7)乙醇100g、(8)尼泊金丙酯0.2g、(9)加蒸馏水至1000g。
制备方法:将交联聚丙烯酸树脂、海藻酸钠、甘油、乙醇和部分蒸馏水混合,置于水浴30~40℃搅拌并使溶解,成凝胶基质;将阿巴芬净、氟氢缩松、丙二醇、尼泊金丙酯混合均匀后,等量递加凝胶基质,将其混匀,装量,即得。
实施例7.油剂
配方:(1)阿巴芬净100g、(2)曲安西龙0.1g、(3)甘油500g、(4)乙醇300g、(5)尼泊金丁酯2g。
制备方法:将阿巴芬净、曲安西龙、甘油、尼泊金丁酯混合均匀后,加入乙醇混匀,装量,即得。
实施例8.喷剂
配方:(1)阿巴芬净200g、(2)氢化可的松9.5g、(3)甘油200g、(4)山梨酸3g、(5)乙醇200g、(6)加蒸馏水至1000g。
制备方法:将阿巴芬净、氢化可的松、山梨酸、甘油混合均匀,再加入乙醇、蒸馏水混合均匀,装量,即得。
实施例9.栓剂
配方:(1)阿巴芬净2g、(2)氟氢松0.5g、(3)甘油700g、(4)明胶140g、(5)尼泊金甲酯2g、(6)加蒸馏水至1000g。
制备方法:将明胶、甘油和蒸馏水混合,水浴60℃加热熔化;呈糊状时,加入阿巴芬净、氟氢松,搅拌均匀,接近凝固时,倒入适宜的阴道栓模具中,稍溢出,冷却凝固后刮平,取出包装即得。
实施例10.洗剂
配方:(1)阿巴芬净40g、(2)地塞米松0.95g、(3)甘油40g、(4)尼泊金乙酯1.5g、(6)加蒸馏水至1000g。
制备方法:将蒸馏水置于水浴上40~50℃加热;另将甘油和阿巴芬净、地塞米松、尼泊金乙酯混合均匀后加入到上述水浴的蒸馏水里和甘油,混合均匀,装量即得。
实施例11.软膏剂
配方:(1)阿巴芬净10g、(2)氟氢可的松0.05g、(3)红霉素0.8g、(4)凡士林200g、(5)乙酰化单甘油酯80g、(6)液体石蜡200g、(7)甘油500g、(8)尼泊金丙酯0.2g。
制备方法:将凡士林和乙酰化单甘油酯混合,置于水浴上40~50℃加热,得油相①;将液体石蜡和甘油混合,置于水浴上40~50℃加热,得水相②;在②搅拌的情况下加入①,再分别加入尼泊金丙酯、阿巴芬净、氟氢可的松、红霉素,搅拌均匀,装量即得。
药理试验
1、抑制豚鼠皮肤真菌感染作用
药物:按实施例1配方及实施例2配方分别制备的制剂1及制2。
含2%阿巴芬净洗剂。
生理盐水。
实验动物:豚鼠,250-300g,雄性,重庆中药研究院实验动物中心提供,合格证号:SCXK(渝)20020004。
豚鼠40只双后足和背部左右两侧约3cm×3cm剃毛,用砂纸反复磨擦豚鼠去毛皮肤,以皮肤有渗出液但又不出血为准,用玻棒将制备的须癣毛癣菌种混悬液105/mL涂擦于损伤皮肤,每1cm2接种1mL。室温保持30C°,10d后动物接种真菌处皮肤出现红斑、红肿、皮疹、鳞屑或痂皮。将感染须癣毛癣菌豚鼠随机分为4组,每组10只,分别为制剂1组、制剂2组、2%阿巴芬净组,生理盐水阴性对照组。将受试物涂于患处,使每次接触时间为30min,每日1次,共7d。对治疗前后皮肤感染症状进行评分,0分表示无皮肤损害,1分为点状红斑,2分为全范围红斑,3分为红肿、鳞屑,4分为超过范围的红斑、结痂。
结果:
治疗前后豚鼠须癣毛癣菌感染足癣、体癣皮肤感染变化情况评分,统计分析显示各组药前无差异;药后与药前相比各组均有显著性差异,对照组显著加重(P<0.05),各治疗组均有减轻(P<0.05),药后制剂1组、制剂2组、阿巴芬净组与对照组比较差异有显著性(P<0.05);药后制剂1、制剂2与阿巴芬净组相比有显著性差异(P<0.05)。结果提示,制剂1、制剂2及阿巴芬净治疗豚鼠须癣毛癣菌感染足癣、体癣有很好治疗作用,并且制剂1及制剂2的疗效显著优于单用阿巴芬净(见表1)。
表1 各组对须癣毛癣豚鼠体表感染治疗作用
注:与对照组比:*P<0.05,与阿巴芬净组比较:ΔP<0.05
2、本品的止痒作用
豚鼠40只,随机分为4组,每组10只,即生理盐水阴性对照组、阿巴芬净组、制剂1组、制剂2组。各实验组豚鼠右后足背剃毛,将受试物涂于患处,使每次接触时间为30min,每日1次,连续3d。末次给药后1h,用粗砂纸擦伤右后足背剃毛处,面积1cm×1cm,开始在创面处滴0.01%磷酸组织胺0.05ml/只。此后磷酸组织胺的浓度每隔3min按0.1、0.2、0.4、0.8、1.6、3.2、6.4、12.8、25.6、51.2mg/ml递增,每次均为0.05ml/只。直至豚鼠出现回头舔后足,以最后出现豚鼠舔后足时所给予的磷酸组织胺浓度为致痒阈,记录并比较各组致痒阈。
结果:阿巴芬净组及制剂1、制剂2组的致痒阈显著提高(P<0.05),且制剂1与制剂2的致痒阈显著高于单用阿巴芬净(P<0.05)。结果提示本发明的复方制剂具有明显的止痒作用(见表2)。
表2 各组致痒阈值的影响
注:与对照组比:*P<0.05,与阿巴芬净组比较:ΔP<0.05
3、皮肤局部刺激性实验
为研究本发明复方制剂的局部刺激作用,实验采用同体左右侧自身对比。取豚鼠6只背部左右两侧约3cm×3cm剃毛。将剃毛后豚鼠随机分为2组,每组3只,即制剂1组和制剂2组。左侧去毛区涂受试物1ml,右侧涂生理盐水作为对照,用纱布固定。每只动物分笼饲养,给药24小时后,用温水洗去除留受试物,进行观察。去除受试物后1小时、24小时、48小时、72小时肉眼观察和病理组织学检查,并记录涂抹部位有无红斑和水肿等情况,以及上述情况的恢复情况和时间。
结果显示,每组动物左右受试区均无红斑、水肿等局部刺激表现;组织学切片显示,每组动物左右受试区均未发现有刺激性病理改变。表明本发明的复方制剂无局部刺激性。
以上结果表明,阿巴芬净与肾上腺糖皮质激素合用的复方制剂,不仅能提高疗效,还能减轻感染对皮肤的损伤,并具有快速止痒、消炎作用,对局部几无刺激作用,同时对阴道念珠菌病、外阴阴道炎也有很好的疗效。
Claims (14)
1.一种外用复方阿巴芬净组合物,其特征在于:包含有效治疗量的阿巴芬净、肾上腺皮质激素和药用辅料或载体,其中,阿巴芬净占组合物重量的0.01~20%,肾上腺皮质激素占组合物重量的0.005~1%。
2.如权利要求1所述的外用复方阿巴芬净的组合物,阿巴芬净占组合物重量的1~5%,肾上腺皮质激素占组合物重量的0.01~0.5%。
3.如权利要求1所述的外用复方阿巴芬净组合物,所说的肾上腺皮质激素,选自下述化合物中的一种或多种:氟轻松及其醋酸酯,曲安西龙及其醋酸酯,异丁酸酯与琥珀酸酯,哈西奈德,氢化可的松及其酯酸酯、丁酸酯、丁酸丙酸酯、环戊丙酸酯、叔丁基乙酸酯、戊酸酯与酯酸丙酸酯,地塞米松及其醋酸酯、二异丙基氟磷酸酯、间磺酸苯甲酸酯、叔丁基乙酸酯与2-氯-62-氟酯、三氧-十一酸酯、异烟酸酯与戊酸酯,氟氢可的松及其醋酸酯与琥珀酸酯,曲安奈德及其醋酸酯,倍他米松及其醋酸酯、二丙酸酯、乙丁酯、戍酸酯、琥珀酸酯、安息香酸酯、磷酸酯及戊乙酸酯,倍氯米松及其二丙酸酯,丙酸氯倍他索,氟氢缩松,泼尼松及其醋酸酯及十六酸酯,氢化泼尼松及其醋酸酯、间磺酸苯甲酸酯、十六酸酯、戍酸酯及戊乙酸酯,二氟拉松及其醋酸酯,安西奈德,莫米松及其糠酸酯,甲泼尼龙及其醋酸酯、环戊丙酸酯、磷酸酯及琥珀酸酯,丁酸氯倍他松,氟米松,阿氟米松及其二丙酸酯,二氟可龙,地泼罗酮及其丙酸酯,氟氢缩松,去羟米松。
4.如权利要求1所述的外用复方阿巴芬净组合物,其制剂形式为乳膏剂、凝胶剂、霜剂、洗剂、栓剂、油剂或喷剂。
5.如权利要求1所述的外用复方阿巴芬净组合物,还可进一步包含抗细菌物质。
6.如权利要求5所述的外用复方阿巴芬净组合物,所说的抗细菌物质选自以下物质中的一种或2种:硫酸新霉素、克林霉素、氧氟沙星、莫匹罗星、醋酸氯己定、氯霉素和呋喃西林。
7.如权利要求1~6所述的任一外用复方阿巴芬净组合物,所说的药用辅料或载体包括油性基质4~55%、水溶性基质0~30%、凝胶基质4~45%、防腐剂0~1%、抗氧剂0~1%和蒸馏水中的至少二种,均为重量百分比。
8.如权利要求7所述的外用复方阿巴芬净组合物,所述的油溶性基质包括凡士林、羊毛酯、液体石蜡、硬脂酸、单硬脂酸甘油酯、吐温-80、蜂蜡、鲸蜡醇、硬脂醇、十六醇、十八醇、乙酰化单甘油酯在内的任一种或多种。
9.如权利要求7所述的外用复方阿巴芬净组合物,所述的水溶性基质包括聚乙二醇、硅酸镁铝、三乙醇胺、羧乙基纤维素、甘油在内的任一种或多种。
10.如权利要求7所述的外用复方阿巴芬净组合物,所述的防腐剂包括尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、山梨酸、山梨酸钾、山梨酸钙在内的任一种、两种或任两种以上。
11.如权利要求7所述的外用复方阿巴芬净组合物,其特征在于所述的抗氧剂包括亚硫酸钠、焦亚硫酸钠、乙二胺四乙酸、二叔丁羟基甲苯、亚硫酸氢钠、硫代硫酸钠在内的任一种、两种或任两种以上。
12.如权利要求7所述的外用复方阿巴芬净组合物,所述的凝胶基质包括卡波姆、羟丙纤维素、硅酸镁铝、海藻酸钠、透明质酸、交联聚丙烯酸树脂、丙二醇、乙醇、明胶在内的一种或多种。
13.如权利要求4所述的外用复方阿巴芬净组合物,所述的制剂形式为乳膏剂或凝胶剂。
14.权利要求1所述的外用复方阿巴芬净组合物在制备治疗皮肤真菌感染、瘙痒、真菌性皮炎药物中的运用。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4956370A (en) * | 1988-10-24 | 1990-09-11 | Bayer Aktiengesellschaft | Antimycotically active substituted 2-aminothiazoles |
WO2005034956A1 (de) * | 2003-09-11 | 2005-04-21 | York Pharma Plc | Antimykotisch wirksame nagellackformulierungen mit substituierten 2-aminothiazolen als wirkstoff |
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WO2008067774A1 (fr) | 2008-06-12 |
CN1969874A (zh) | 2007-05-30 |
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