CN113304253A - 一种辅助预防或辅助治疗新冠肺炎的食物及其应用 - Google Patents
一种辅助预防或辅助治疗新冠肺炎的食物及其应用 Download PDFInfo
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Abstract
本发明公开了溶菌酶或包括溶菌酶的组合用于制备辅助预防或辅助治疗COVID‑19新冠肺炎的食物的应用。本发明提供的溶菌酶或其组合可以有效抑制新冠病毒导致的细胞损伤,抑制新冠病毒诱导的炎性因子表达,改善肺部病变导致的气道阻塞和呼气量下降,改善肠道屏障功能障碍。对于患者高病毒载量、呼吸窘迫、肠道功能受损等具有良好作用,可降低新冠病毒感染率、降低新冠肺炎重症率。另外鉴于溶菌酶的安全性极高,其对于未确诊的新冠病毒高危感染人群预防新冠肺炎而言也具有非常重要的价值。
Description
本申请是分案申请;原申请的申请号为“CN202080000788.X”,申请日为2020年05月09日,发明名称为“一种预防或治疗COVID-19新冠肺炎的药物、食物及其应用”。
技术领域
本发明涉及食品领域,具体涉及一种可以辅助预防或辅助治疗COVID-19新型冠状病毒肺炎的食物及其应用。
背景技术
COVID-19是属于冠状病毒科的一种新病毒。COVID-19与SARS冠状病毒有一定相似性,但也有明显区别。特别是在病毒基因序列、无症状携带者、传染性、临床症状、组织病理学等方面有明显区别。病理学观察表明,新冠肺炎患者肺部纤维化程度低于SARS非典型性肺炎,但肺部增生和阻塞情况则高于SARS非典型性肺炎。
目前全球范围内已经推荐了一些可用于治疗新冠肺炎的药物。但很多属于应急用药或同情用药,仍然存在许多不足。例如广谱抗病毒药物对于COVID-19没有明显的活性,许多对症治疗病毒性肺炎的药物效果也较差。还有不少药物虽然可以抑制病毒但存在明显的毒性。因此,对于安全有效的防控新冠肺炎的产品存在迫切的需求。
发明内容
本发明的目的之一是提供一种制备辅助预防或辅助治疗新冠肺炎的食物的应用。为了实现该目的,本发明所采取的技术方案是:
溶菌酶或包括溶菌酶的组合在制备辅助预防或辅助治疗COVID-19新冠肺炎的食物中的应用。
在一些实例中,所述的食物为保健食品或特殊医学用途食品。
在一些实例中,所述的组合中还包括甘草酸或其盐。
在一些实例中,所述的食物中还包括食物上适用的添加剂。
在一些实例中,所述的添加剂可以是防腐剂、着色剂、调味剂、香料、保鲜剂、抗氧化剂、乳化剂、粘稠剂、碳水化合物、脂肪、维生素、氨基酸、微量元素、蛋白质等等。
在一些实例中,所述组合中的溶菌酶和甘草酸或其盐可以通过各种方式进行组合。可以以各自独立存在于不同食品中的方式进行组合,例如组合包装、联合使用等方式;也可以以共同存在于同一食品中的方式进行组合,例如复合食品的方式等。
在一些实例中,所述组合中溶菌酶和甘草酸或其盐的重量比可以是100:1至1:100,优选100:1至2:1,更优选100:1至5:1,进一步优选100:1至10:1。在一些优选方案中,二者可产生显著的协同作用。
在一些实例中,所述溶菌酶的每日用量可以是0.5g至20g。
在一些实例中,所述溶菌酶的服用次数可以是在非睡眠时间的每1-24小时服用一次,例如每1小时、每2小时、每4小时、每6小时、每8小时、每12小时、每24小时服用一次。
在一些实例中,所述COVID-19新冠肺炎表现为经新冠病毒核酸检测呈阳性。
在一些实例中,所述COVID-19新冠肺炎除了表现为经新冠病毒核酸检测呈阳性之外,还表现为气道阻力增加或呼气量下降。
在一些实例中,所述COVID-19新冠肺炎除了表现为经新冠病毒核酸检测呈阳性之外,还表现为肠道屏障功能损伤。
在一些实例中,所述食物可以以不同的方式进行给予,例如可以是口服给予、鼻饲给予、注射给予、吸入给予等。
在一些实例中,所述食物可以是不同的释放形式,例如常释、延释、缓释或控释等。
本发明的目的之二是提供一种辅助预防或辅助治疗新冠肺炎的食物。为了实现该目的,本发明所采取的技术方案是:
一种用于辅助预防或辅助治疗COVID-19新冠肺炎的食物,所述食物中含有溶菌酶。
在一些实例中,所述食物中还含有甘草酸或其盐。
在一些实例中,所述的食物中含有食物上适用的添加剂。
在一些实例中,所述的添加剂可以是防腐剂、着色剂、调味剂、香料、保鲜剂、抗氧化剂、乳化剂、粘稠剂、碳水化合物、脂肪、维生素、氨基酸、微量元素、蛋白质等等。
在一些实例中,所述食物中溶菌酶和甘草酸或其盐的重量比可以是100:1至1:100,优选100:1至2:1,更优选100:1至5:1,进一步优选100:1至10:1。在一些优选方案中,二者可产生显著的协同作用。
在一些实例中,所述COVID-19新冠肺炎表现为经新冠病毒核酸检测呈阳性。
在一些实例中,所述COVID-19新冠肺炎除了表现为经新冠病毒核酸检测呈阳性之外,还表现为气道阻力增加或呼气量下降。
在一些实例中,所述COVID-19新冠肺炎除了表现为经新冠病毒核酸检测呈阳性之外,还表现为肠道屏障功能损伤。
在一些实例中,所述食物可以以不同的方式进行给予,例如可以是口服给予、鼻饲给予、注射给予、吸入给予等。
在一些实例中,所述食物可以是不同的释放形式,例如常释、延释、缓释或控释等。
本发明的有益效果是:
本发明提供的溶菌酶或其组合可以有效抑制COVID-19新冠病毒导致的细胞损伤,抑制COVID-19新冠病毒导致的炎性反应,改善肺部病变导致的气道阻塞和呼气量下降,改善肠道屏障功能。对于COVID-19新冠肺炎患者的高病毒载量、呼吸窘迫、肠道功能受损等具有良好的辅助治疗作用。可降低新冠病毒感染率、降低新冠肺炎重症率。并且鉴于溶菌酶的安全性极高,其对于未确诊的新冠病毒高危感染人群辅助预防新冠肺炎而言也具有非常重要的价值。
具体实施方式
下面用具体实施方式对本发明进行详述。应该理解,具体实施方式部分的内容是属于阐释性的,而非限制性的,即不是对本发明内容的任何限制。
定义:
“溶菌酶”:即lysozyme。本发明的溶菌酶,可以是来源于动物、植物、微生物的溶菌酶,或者是天然溶菌酶的重组物。例如可以是鸡蛋清溶菌酶、人溶菌酶、重组人溶菌酶、噬菌体溶菌酶等。本发明中的溶菌酶包括其药用盐,例如盐酸盐、氯化物、硫酸盐或氨基酸盐等。溶菌酶最早是由弗莱明发现的一种广泛存在于生物体内的内源性酶。溶菌酶已在世界范围内被批准作为食用或药用。在美国被认定为可以安全使用的物质。WHO、欧洲多国、日本和中国允许其作为食物添加剂使用。在中国、日本、新加坡等国被批准药用。目前已知溶菌酶对于疱疹病毒具有较强的抗病毒能力。
“COVID-19新型冠状病毒”即2019新型冠状病毒,是在2019年发现的一种病毒,属于冠状病毒科中的一种新病毒。
“COVID-19新冠肺炎”即因感染COVID-19新型冠状病毒导致的肺炎。国家卫生和健康委员会发布的《新型冠状病毒肺炎诊疗方案》中对COVID-19新冠肺炎的病理特点、临床表现、诊断标准有详细的说明。COVID-19新冠肺炎的诸多特点与细菌性肺炎、病毒性肺炎、非典型性肺炎有明显区别。
下面用实施例对本发明进行进一步阐述,但并非限制本发明的方案和效果。
实施例1:溶菌酶在新冠肺炎患者和高危感染人群中的应用
在新冠肺炎疫情期间,我公司捐赠了包括溶菌酶含片、溶菌酶肠溶片等产品。我们发现这些产品在抗击新冠疫情中起到了积极作用。
有9名新冠肺炎新确诊患者服用了我们提供的溶菌酶含片和/或溶菌酶肠溶片,服用剂量范围为每日0.5g-2g,每日基本坚持服用,结果仅有1名转化为重症,另外8名均为轻症且随后痊愈。经计算重症转化率为11.1%。
有3名人员,疫情期间在高风险的地区居住和出差,坚持每天服用溶菌酶含片和/或溶菌酶肠溶片,用量为每日1g-1.5g,返回复工期间经过核酸检测未发现感染新冠病毒,感染率0%。
根据《新型冠状病毒肺炎流行病学特征分析》的报道,新冠肺炎患者中的重症和危重症患者的比例高达18.5%,当转化为重症和危重症之后,死亡率更可接近50%。我们经过对比发现,服用溶菌酶制剂可大幅降低重症率,进而降低了死亡率,对于防治新冠疫情具有非常积极的作用。另外溶菌酶制剂对于新冠病毒高感染风险人群还起到了辅助预防感染的作用。这对于控制疫情蔓延和疫情复发具有重要的价值。
实施例2:溶菌酶抗新冠病毒的体外试验
用非洲绿猴肾细胞研究了溶菌酶抗COVID-19新冠病毒的效果。
受试物:溶菌酶、甘草酸单铵。
细胞:非洲绿猴肾细胞(VeroE6细胞)。
病毒:COVID-19,使用的滴度为100TCID50。
培养:无菌96孔培养板,每孔加入100μL浓度为2×105cells/mL的VeroE6细胞,37℃培养24小时。培养板按孔分为空白对照组、病毒对照组、溶菌酶低剂量组、溶菌酶中剂量组、溶菌酶高剂量组、甘草酸单铵低剂量组、甘草酸单铵高剂量组,每组3孔。除空白对照组之外,各组中均加入100TCID50病毒液100μL/孔,37℃下5%CO2培养箱吸附2小时后,弃去培养板中细胞培养液。
加样:按剂量将受试样品溶液加入到下列各组的孔中:溶菌酶低剂量组(500μg/ml)、溶菌酶中剂量组(1000μg/ml)、溶菌酶高剂量组(2000μg/ml)、甘草酸单铵低剂量组(1000μg/ml)、甘草酸单铵高剂量组(2000μg/ml),每孔100μl。之后在37℃下孵育4天。
观测细胞病变:孵育完后在光学显微镜下观察细胞病变(CPE)。细胞出现的病变程度按以下6级标准记录:“-”无病变出现,“±”为细胞病变少于10%,“+”为细胞病变约25%,“++”为细胞病变约50%,“+++”为约75%的细胞出现病变,“++++”为75%以上病变。计算各组受试样品对病毒导致的细胞病变的抑制率。抑制率越高说明效果越好。
结果:试验的主要结果列于表1。试验结果表明溶菌酶可显著抑制COVID-19病毒所致细胞病变。甘草酸盐对COVID-19病毒抑制作用较弱。
表1:溶菌酶对COVID-19病毒所致细胞病变的抑制率
受试样品(浓度) | 抑制率(%) |
溶菌酶(500μg/ml) | 15.00±8.66 |
溶菌酶(1000μg/ml) | 46.67±15.28 |
溶菌酶(2000μg/ml) | 78.33±2.89 |
甘草酸单铵(1000μg/ml) | 23.35±5.43 |
甘草酸单铵(2000μg/ml) | 29.42±7.16 |
实施例3:含溶菌酶的组合抗新冠病毒以及新冠病毒引起的炎症的体外试验
研究含溶菌酶的组合对COVID-19病毒引起的细胞病变的抑制作用,以及对COVID-19病毒引起的炎症的抑制效果。
受试物、细胞、病毒等均与实施例2相同。
培养板分组和加样剂量为:空白对照组、病毒对照组、溶菌酶组(350μg/ml)、溶菌酶甘草酸单铵I组(100μg/ml+1μg/ml)、溶菌酶甘草酸单铵II组(100μg/ml+5μg/ml)、溶菌酶甘草酸单铵III组(100μg/ml+10μg/ml)、溶菌酶甘草酸单铵IV组(100μg/ml+50μg/ml)。
观测细胞病变方法与实施例2相同,试验结果见表2。另外,收集无病变细胞,提取RNA,用定量PCR法测定TNF-α、IL-6等炎性因子的相对表达水平,试验结果见表3。
表2:含溶菌酶的组合对COVID-19病毒所致细胞病变的抑制作用
受试样品(浓度) | 抑制率(%) |
溶菌酶(350μg/ml) | 6.67±1.56 |
溶菌酶+甘草酸单铵(100μg/ml+1μg/ml) | 38.20±8.11## |
溶菌酶+甘草酸单铵(100μg/ml+5μg/ml) | 49.32±9.45## |
溶菌酶+甘草酸单铵(100μg/ml+10μg/ml) | 23.68±4.31## |
溶菌酶+甘草酸单铵(100μg/ml+50μg/ml) | 8.20±2.27 |
注:各受试物组合组与溶菌酶组相比,p<0.05(#),p<0.01(##)。
表3:含溶菌酶的组合对COVID-19病毒诱导的细胞炎性因子表达的影响
注:各受试样品组与病毒对照组相比,p<0.05(*),p<0.01(**)。各受试物组合组与溶菌酶组相比,p<0.05(#),p<0.01(##)。
从表2和表3可以看出,溶菌酶和含溶菌酶的受试物组合对COVID-19病毒所致细胞病变有较好的抑制作用,并且可使COVID-19病毒所致的细胞炎性因子升高得到显著降低。与单独的溶菌酶相比,受试物组合的效果明显更好,表现为抑制率明显提高、炎性因子水平明显降低,以及试验剂量大幅减少。提示甘草酸盐对溶菌酶的强大增效作用,特别是甘草酸盐的用量较少时增效作用更好。
实施例4:溶菌酶及其组合物对吸入烟雾豚鼠的气道阻力和肺功能的影响
烟熏模型是慢性阻塞性肺病的经典动物造模方法。动物长期吸入烟雾后会出现黏液分泌增加、气道阻塞、肺功能下降等。本试验借用该造模方法评估溶菌酶对气道阻塞的影响。
1、受试物
溶菌酶、甘草酸单铵、甘草酸单钾。
2、动物及分组
雄性Hartley豚鼠,体重400-500g,随机分组,空白组、模型组、溶菌酶口服组(200mg/kg)、溶菌酶吸入组(2mg/kg)、溶菌酶+甘草酸单铵吸入组(2mg/kg+0.1mg/kg)、溶菌酶+甘草酸单钾口服I组(200mg/kg+20mg/kg)、溶菌酶+甘草酸单钾口服II组(200mg/kg+40mg/kg),每组8只动物。
3、造模
使用仅经口鼻吸入的烟雾暴露系统,将除空白组外的各组动物暴露于香烟烟雾中,使动物每天在40分钟内吸入5根香烟的烟雾,每周暴露5天,持续12周。
4、受试样品配制和给予
用于吸入给予的溶菌酶和甘草酸单铵分别粉碎成颗粒<10μm的粉末。用于口服给予的溶菌酶和甘草酸单钾分别溶于生理盐水中。
除空白组和模型组以外的各组动物从造模开始后的第8周开始给予受试样品,每天1次,持续给予4周。吸入给予组采用口鼻吸入暴露系统给予受试样品,口服给予组采用灌胃给予受试样品。空白组和模型组每日灌胃生理盐水。
5、测试
样品给予完成后进行气道阻力测量和100毫秒呼气容积测量。
将动物置于双室体积描记系统(double chamber plethysmography)中,等动物安静10分钟后,测定特殊气道阻力(specific airway resistance,sRaw)。动物肌内注射氯胺酮进行麻醉后,向气管中插入导管,使用肺功能检测系统测量动物的100毫秒呼气容积(force dexpiratory volume in 100ms,FEV100)。
6、试验结果和评价
动物气道阻力和100毫秒呼气容积的测量结果如表4所示。
表4:溶菌酶及其组合物对动物气道阻力和100毫秒呼气容积的影响
组别 | 气道阻力(cmH2O·s) | 100毫秒呼气容积(mL) |
空白组 | 1.43±0.24 | 11.86±1.24 |
模型组 | 4.72±0.38 | 4.18±1.26 |
溶菌酶口服组 | 3.79±0.30** | 5.79±2.03 |
溶菌酶吸入组 | 3.10±0.14** | 7.68±1.36** |
溶菌酶+甘草酸单铵吸入组 | 2.52±0.22**&& | 9.04±0.84** |
溶菌酶+甘草酸单钾口服I组 | 2.78±0.17**## | 8.05±1.56**# |
溶菌酶+甘草酸单钾口服II组 | 3.47±0.28** | 5.89±1.01 |
注:各给予受试样品组与模型组相比,p<0.05(*),p<0.01(**)。口服组合组与溶菌酶口服组相比,p<0.05(#),p<0.01(##)。吸入组合组与溶菌酶吸入组相比,p<0.05(&),p<0.01(&&)。
本试验通过长期吸入烟雾造成动物肺部气道阻力显著增加以及肺功能显著下降(呼气容积减少)。从试验结果看出,给予受试样品的各组不同程度地减少了动物肺部气道阻力、增加了呼气容积。通过将受试物组合组与单独的溶菌酶组进行比较发现,甘草酸类物质增强了溶菌酶的效果,特别是当甘草酸类物质用量较少时,增效效果显著。
实施例5:溶菌酶及其组合对脂多糖诱导的小鼠肠道屏障功能障碍的保护作用
脂多糖可引发动物肠道功能受损。本实验研究了溶菌酶及其组合对脂多糖诱导的小鼠肠道屏障功能障碍的保护作用。
受试物:溶菌酶、甘草酸单铵、甘草酸二钾。
试验动物:雄性清洁级C57BL/6小鼠,体重20-25g。
动物分组和受试样品给予:动物随机分为:空白组、模型组、溶菌酶组(100mg/kg)、溶菌酶+甘草酸单铵A组(100mg/kg+2mg/kg)、溶菌酶+甘草酸单铵B组(100mg/kg+10mg/kg)、溶菌酶+甘草酸单铵C组(100mg/kg+20mg/kg)、溶菌酶+甘草酸二钾组(100mg/kg+2mg/kg),每组8只动物。各受试样品组每日分别按剂量灌胃给予受试样品,空白组和模型组给与生理盐水。连续给予30天。
造模:完成受试样品的给予后,除空白组外的各组动物腹腔注射脂多糖15mg/kg,空白组注射生理盐水。注射完成后动物禁食12小时。
肠道通透性测定:各组动物灌胃600mg/kg的FITC-葡聚糖(溶于磷酸盐缓冲液中),4小时后眼球取血,用荧光光谱法(激发波长480nm,发射波长520nm)测定血清中FITC-葡聚糖的含量,结果见表5。
肠道组织紧密连接蛋白表达测定:动物处死后,取空肠组织样品,提取RNA,用定量PCR法检测组织中occludin蛋白、Claudin-1蛋白的相对表达水平,结果见表6。
表5:溶菌酶及其组合对肠道通透性的影响
组别 | FITC-葡聚糖含量(μg/ml) |
空白组 | 9.40±1.45 |
模型组 | 35.06±5.75 |
溶菌酶组(100mg/kg) | 27.53±3.21** |
溶菌酶+甘草酸单铵A组(100mg/kg+2mg/kg) | 15.31±2.08**## |
溶菌酶+甘草酸单铵B组(100mg/kg+10mg/kg) | 20.25±2.44**## |
溶菌酶+甘草酸单铵C组(100mg/kg+20mg/kg) | 23.89±2.52** |
溶菌酶+甘草酸二钾(100mg/kg+2mg/kg) | 13.17±1.14**## |
注:各受试样品组与模型组相比,p<0.05(*),p<0.01(**)。各受试物组合组与溶菌酶组相比,p<0.05(#),p<0.01(##)。
表6:溶菌酶及其组合对肠道组织紧密连接蛋白表达的影响
注:各受试样品组与模型组相比,p<0.05(*),p<0.01(**)。各受试物组合组与溶菌酶组相比,p<0.05(#),p<0.01(##)。
本实验研究了溶菌酶及其组合物对脂多糖诱导的小鼠肠道屏障功能障碍的保护作用。模型组注射脂多糖后,发现与空白组相比血清葡聚糖含量显著升高,说明大量葡聚糖通过肠道入血,即肠道通透性增加;模型组肠道中两种紧密连接蛋白的表达下降,进一步说明肠道屏障功能受损。本实验发现溶菌酶及其组合物能显著降低脂多糖诱导的肠道通透性升高,显著增加肠道组织紧密连接蛋白的表达,对肠道屏障功能障碍具有明显的保护作用。还发现受试物组合组的效果明显优于单独使用溶菌酶。
结合以上多个实施例,可以看出溶菌酶及其组合可抑制新冠病毒造成的细胞损伤、抑制新冠病毒诱导的炎性因子表达,改善肺部气道阻塞,增加呼气容积,以及改善肠道屏障功能障碍,可降低新冠病毒感染率和新冠肺炎重症转化率。新冠肺炎对于医药界还是一个新生事物,根据目前临床认识表明,患者前期病毒载量很高,中后期具有非常明显的呼吸窘迫症状,肠道屏障功能障碍导致患者持续和继发感染、康复困难、传染性增加,重症患者死亡率高等,因此本发明的溶菌酶及其组合有望通过多种方式辅助预防和辅助治疗新冠肺炎,并且由于其安全性好,用量剂量可加大,有望成为一种辅助预防或辅助治疗新冠肺炎的较好选择。
Claims (10)
1.溶菌酶或包括溶菌酶的组合在制备辅助预防或辅助治疗COVID-19新冠肺炎的食物中的应用。
2.根据权利要求1所述的应用,所述的食物为保健食品或特殊医学用途食品。
3.根据权利要求1所述的应用,所述的组合中还包括甘草酸或其盐。
4.根据权利要求3所述的应用,所述的组合中的溶菌酶和甘草酸或其盐分别存在于不同食品中,或者共同存在于同一食品中。
5.根据权利要求3所述的应用,所述的组合中溶菌酶和甘草酸或其盐的重量比为100:1至1:100,优选100:1至2:1,更优选100:1至5:1,进一步优选100:1至10:1。
6.根据权利要求1所述的应用,所述的食物中还包括食物上适用的添加剂。
7.一种用于辅助预防或治疗COVID-19新冠肺炎的食物,所述食物中含有溶菌酶。
8.根据权利要求7所述的食物,所述食物中还含有甘草酸或其盐。
9.根据权利要求8所述的食物,所述食物中溶菌酶和甘草酸或其盐的重量比为100:1至1:100,优选100:1至2:1,更优选100:1至5:1,进一步优选100:1至10:1。
10.根据权利要求7所述的食物,所述食物中还含有食物上适用的添加剂。
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