CN110139568A - 用于血糖控制的加强糖的粗制剂的方法和组合物 - Google Patents
用于血糖控制的加强糖的粗制剂的方法和组合物 Download PDFInfo
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- CN110139568A CN110139568A CN201780079270.8A CN201780079270A CN110139568A CN 110139568 A CN110139568 A CN 110139568A CN 201780079270 A CN201780079270 A CN 201780079270A CN 110139568 A CN110139568 A CN 110139568A
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Abstract
用于血糖控制的组合物包括甜味剂、多酚和淀粉。两个制剂的例子包括但不限于i)甜味剂、没食子酸作为多酚和阿糖基木聚糖作为淀粉;和ii)甜味剂、橙皮素或橙皮苷作为多酚的和菊粉作为淀粉。有利地,制剂包括组分的组合,以提供有效的制剂,其缓解或纠正高血糖负荷或摄入的高血糖作用。
Description
技术领域
本发明涉及用于改善的血糖控制的方法和组合物以及尤其用于血糖控制的具有加强糖的改善的制剂的方法和组合物。
背景技术
糖尿病是全球死亡的主要贡献因素,每年导致150万人死亡,另外220万归因于高血糖水平。糖尿病已经在世界范围内从1980年的1.08亿持续增加至2015年的4.22亿。出现糖尿病/代谢综合症的直接原因是高血糖或消耗大量糖的直接副作用。糖的这种快速涌现触发了促炎免疫应答,其缓慢导致出现代谢综合症、肥胖、糖尿病和神经疾病(例如III型糖尿病)。
发明内容
本发明涉及用于血糖控制的加强糖的改善的制剂的方法、制剂和用途。该制剂包括组分的组合,以提供有效的制剂,其缓解或纠正高血糖负荷或摄入的高血糖作用。在一个有利的一般形式中,制剂具有三种不同的组分:甜味剂、多酚和淀粉。两个制剂的例子为:
i)甜味剂、沒食子酸作为多酚和阿糖基木聚糖作为淀粉;和
ii)甜味剂、橙皮素或橙皮苷作为多酚和菊粉作为淀粉。
所述制剂可与待并入食料的其他成分组合,所述其他成分比如饮品、糊状物和医学制剂,仅举几例。可能的酚/多酚化合物的非限制性目录包括但不限于沒食子酸、杨梅黄酮和橙皮素或橙皮苷。
该方法和组合物包括可消耗的糖与另外生物缓冲策略的专门制剂,以获得减轻碳水化合物基础的血糖影响的基于碳水化合物的甜味剂,从而使得血流中的高血糖作用被缓解或明显减轻。所述制剂具有三种主要类型的组分:碳水化合物基础、多酚和多糖淀粉。
碳水化合物基础的目的本身是显而易见的,因为其为制剂的增甜方面,用于其作为甜味剂的传统用途。该制剂的多酚方面作用于经直接抑制tnf-α促炎通路而抑制促炎反应。多酚具有的另外作用在于其下调高血糖的慢性作用,因为其对于峰效率引导碳水化合物管理,但是减少碳水化合物存储为脂肪并且引导碳水化合物用于肌肉组织的即时利用。制剂的多糖部分进一步用于控制血糖影响,可作为碳水化合物转化酶比如α淀粉酶和葡糖苷酶的底物起作用。
三种组分(甜味剂、多酚和淀粉)的组合,当在有利的形式中时,使得当将制剂施用至遭受高血糖的个体比如人或动物时,缓解高血糖的作用。在具体的有利形式中,制剂缓解高血糖,比如代谢综合症、糖尿病和神经疾病。
该制剂在其制造期间,可在适于添加至食品中的干燥状态下组合。这种的例子包括但不限于饮品、面包、糖果、甜点、包衣、医学食品和药学制剂。
该制剂可通过如下来产生:将适当的甜味剂加热,以形成液态的甜料,将其添加至多酚和淀粉中,使得组分嵌入再结晶形式的甜味剂中。这种的例子包括但不限于食糖(table sugar)、饮品、面包、糖果、甜点、包衣、医学食品和药学制剂。
在该制剂的另一方面中,将制剂分散并且负载在所述甜味剂的液相中,所述甜味剂比如玉米糖浆。这种的例子包括但不限于饮品、面包、糖果、甜点、包衣、医学食品和药学制剂。
在该制剂的仍另一方面中,在一个有利的形式中,甜味剂为天然的和半合成性质的碳水化合物基础。这种的例子包括但不限于单糖、二糖、低聚糖和人工甜味剂。例子包括:果糖、半乳糖、蔗糖、脱氧核糖、乙糖、丙糖、丁糖、戊糖、己糖、戊糖、醛糖、呋喃糖、吡喃糖、呋喃葡萄糖、吡喃葡萄糖、蔗糖、乳果糖、乳糖、麦芽糖、纤维二糖、壳二糖、曲二糖、黑曲霉二糖(nigerlose)、异麦芽糖、槐糖、昆布二糖、龙胆二糖、松二糖、麦芽酮糖、帕拉金糖、甘露二糖、蜜二糖、车前二糖(melibiulose)、芸香二糖(runtinose)、木二糖、低聚果糖、低聚半乳糖、低聚甘露糖、阿斯巴甜糖、甜蜜素、糖精、甜叶菊、三氯蔗糖、安赛蜜钾、乙酸铅、罗汉果苷、布拉齐因(brazzein)、可鲁可林(curculin)、赤藓糖醇、甘草甜素、甘油、菊粉、异麦芽酮糖醇、乳糖醇、马槟榔甜蛋白(mabinlin)、麦芽糖醇、神秘果素(miraculin)、莫那甜(monatin)、应乐果甜蛋白(monellin)、欧亚水龙骨甜素(osladin)、倍他丁(pentadin)、山梨糖醇、塔格糖(tagetose)、奇异果甜蛋白(thaumatin)、木糖醇、爱德万甜(advantame)、阿力甜(alitame)、甘素(dulcin)、甜素(glucin)、新橙皮苷二氢查尔酮、纽甜、p-4000、糖精、L-鼠李糖、l-葡萄糖、l-甘露糖、l-岩藻糖。
该制剂的一个有利的形式的仍另一方面是,该组分具有生物活性酚性质。这种的例子包括但不限于酚类、flavonals、类黄酮、生物类黄酮、花青苷、黄烷酮、黄烷醇、黄烷、花青素。例子包括:芹菜脑(apiole)、鼠尾草酚(carnosol)、香芹酚、莳萝油脑(dillapiole)、迷迭香酚(rosemarinol)、槲皮素、山奈酚、杨梅黄酮、二氢杨梅素、非瑟酮、芸香苷、异鼠李素、橙皮素、橙皮苷、柚皮苷、柚皮素、水飞蓟宾(silybin)、圣草酚、金合欢素(acacetin)、芹菜素(apigenin)、白杨黄素、香叶木素、柑橘黄酮、木犀草素、菊花、儿茶素、没食子儿茶素、表儿茶素、表没食子儿茶素、表没食子儿茶素没食子酸酯、茶黄素、茶红素、原花色素(proanthocyanodins)、花葵素(pelagonidin)、甲基花青素、花青素、花翠素、二甲花翠素、矮牵牛素、大豆黄素、染料木黄酮、黄豆黄素(glycitien)、异黄烷(isoflavanes)、异黄烷二酚、异黄烯(isoflavenes)、紫檀碱(pterocarpans)、橙酮、查尔酮(chalconoids)、白藜芦醇(reseveratrol)、蝶芪、白皮杉醇、赤松烷(pinosylvan)、鞣花鞣质(ellagictannin)、安石榴苷(punicalagin)、栗木鞣花素(castalagin)、栎木鞣花素(vescalagin)、栗木素(castalin)、木麻黄鞣亭(casuarictin)、大丁香素(grandinin)、石榴皮鞣素(punicalins)、roburin(鞣花单宁)、特里马素(tellimagrandin)、榄仁黄素(terflavin)、沒食子单宁(gallotannin)、原花色素、聚黄酮(polyflavonoid)、pyrocatecolic(焦儿茶酚)、flavolan、水杨酸、香草醛、没食子酸、鞣花酸(elagic acid)、鞣酸、咖啡酸、绿原酸、阿魏酸、香豆素、酪醇、羟基酪醇、橄榄油刺激醛(oleocanthol)、橄榄苦苷、辣椒素、姜醇、麦芽糊精、右旋糖、sterubin(圣草酚-7-甲酯)、杜鹃黄苷(azalein)、高良姜精、棉花皮素、金丝桃苷、淫羊藿苷、异槲皮素、异鼠李素、山柰素(kaempferide)、山柰苷(kaempferitrin)、桑色素、杨梅苷(myricitrin)、槲皮苷(quercitrin)、藿香黄酮醇、甲基鼠李黄素、刺槐素、刺槐糖、绣线菊苷(spiraeoside)、spirenoside、曲克芦丁、汉黄芩素(wogonin)、sterubin、枸橘苷(poncirin)、泽兰叶黄素、芹黄素。
该制剂一个有利形式的仍进一步的方面是包含淀粉,例如但不限于聚合碳水化合物或多糖。这种例子为但不限于吡喃葡萄糖、直链淀粉、支链淀粉、糖原、阿糖基木聚糖、纤维素、几丁质、果胶、酸性多糖。
在该制剂的仍另一有利的形式中,酚添加剂起作用以通过下述方法控制高血糖的副作用:抑制促炎的tnf-α、抑制α淀粉酶、抑制葡糖苷酶、抑制glut 2运输至脂肪组织中、刺激glut 4运输至肌肉组织中、刺激肌肉组织中线粒体发生。
在该制剂一个有利形式的仍另一方面中,所述制剂包含适当的淀粉(start)用于通过下述方法抑制糖的血糖影响:直接抑制酶α淀粉酶、直接抑制酶葡糖苷酶、抑制和缓冲胃酸。
在优选制剂的仍另一方面中,所述制剂通过防止或减少来自淀粉酶活性的副产物的珐琅降解酸而防止口部的窝洞形成。改善的糖制剂的酚成分足够充分抑制口腔中的淀粉酶活性。
此外,在该制剂的有利形式的仍另一方面中,所述制剂通过抑制脂肪组织的glut2途径的减少脂肪积聚的直接相互作用和通过激活glut 4途径的增加能量/碳水化合物消耗的直接刺激,而使得重量减少或防止增重。
示例性优选的制剂实施例
一些优选的制剂包括有效量的三种组分的组合,以缓解或纠正高的血糖负荷的高血糖作用。该制剂可从三个不同但是有功能的方面完成。三种不同的组分是甜味剂、多酚和淀粉。所述制剂可作为三种成分的组合存在,所述三种成分以足够用于添加至食料比如饮品、糊状物或药学制剂中的方式组合。在各种有利形式中的所述制剂可再结晶为成形化合物,使用糖作为用于剩余两种化合物的运载介质。进一步,该制剂的各种有利形式组合至液体形式,其中化合物由液体甜料比如玉米糖浆运载。
制剂的有利形式包括但不限于下述两个例子:
i)甜味剂、没食子酸作为多酚和阿糖基木聚糖作为淀粉;和
ii)甜味剂、橙皮素或橙皮苷作为多酚和菊粉作为淀粉。
一些优选制剂的实施例
实施例1:干燥制剂:
70%-95%的蔗糖(甜料)
10%-30%的没食子酸(多酚)
10%-30%的阿糖基木聚糖(淀粉)
实施例2:结晶制剂:
将蔗糖或其他适当的甜料加热至足够的温度以液化。然后将第二成分、然后第三成分添加至所述加热的和液相蔗糖中。使得混合物干燥并且然后最终制粒。
70%-95%的蔗糖(甜料)
10%-30%的没食子酸(多酚)
10%-30%的阿糖基木聚糖(淀粉)
实施例3:液体基制剂:
70%-95%的玉米糖浆(液体甜料基)
10%-30%的没食子酸(多酚)
10%-30%的阿糖基木聚糖(淀粉)
实施例4:干燥制剂:
70%-95%的蔗糖(甜料)
10%-30%的橙皮素或橙皮苷(多酚)
10%-30%的菊粉(淀粉)
实施例5:结晶制剂:
将蔗糖或其他适当的甜料加热至足够的温度,以液化。然后将第二成分、然后第三成分添加至加热的和液相蔗糖中。使得混合物干燥并且然后最终制粒。
70%-95%的蔗糖(甜料)
10%-30%的橙皮素或橙皮苷(多酚)
10%-30%的菊粉(淀粉)
实施例6:液体基制剂:
70%-95%的玉米糖浆剂(液体甜料基)
10%-30%的橙皮素或橙皮苷(多酚)
10%-30%的菊粉(淀粉)
如下提供用于制造的示例性方法和进一步制剂:
该制剂用于1千克或1升的改进的糖质量,组合比例为80%的甜料、10%的酚和10%的淀粉。
示例性干燥制剂:
800g蔗糖
100g没食子酸
100g阿糖基木聚糖
将成分混合在一起,以产生干燥的组合配方。
结晶配方的实施例:
将800g的蔗糖加热至足够的温度,以液化(215℉-320℉或101℃-160℃)。
添加100g的没食子酸和100g的阿糖基木聚糖并且混合至所述液体浆料中。
使加热的浆料冷却,然后再结晶以形成常规的糖晶体,其中没食子酸(酚)和阿糖基木聚糖(淀粉)并入内部。
液体配方的实施例:
将800ml的玉米糖浆加热至高于室温(110℉-320℉或30℃-160℃)
将100g的没食子酸和100g阿糖基木聚糖添加至该液化的浆料中并且混合或搅拌。然后使浆料冷却至室温。
该制剂用于1千克或1升的改进的糖质量,组合比例为70%的玉米糖浆(甜料)、10%的没食子酸(酚)和20%的阿糖基木聚糖(淀粉)。
示例性干燥制剂:
700g蔗糖
100g杨梅黄酮
200g葡甘露聚糖
将成分混合在一起,以形成干燥、组合配方。
结晶配方的实施例:
将800g的蔗糖加热至足够的温度,以液化(215℉-320℉或101℃-160℃)。
添加100g的杨梅黄酮和200g的葡甘露聚糖并且混合至所述液体浆料中。
使加热的浆料冷却,然后再结晶以形成常规的糖晶体,其中杨梅黄酮(酚)和葡甘露聚糖(淀粉)并入内部。
液体配方的实施例:
将800ml的玉米糖浆加热至高于室温(110℉-320℉或30℃-160℃)
将100g的杨梅黄酮和200g葡甘露聚糖添加至所述液化的浆料中并且混合或搅拌。然后使浆料冷却至室温。
该制剂用于1千克或1升的改进的糖质量,组合比例为90%的玉米糖浆剂(甜料)、5%的杨梅黄酮(酚)和5%的葡甘露聚糖(淀粉)。
示例性干燥制剂:
900g果糖
50g橙皮素或橙皮苷
50g果胶
将成分混合在一起,以形成干燥、组合配方。
结晶配方的实施例:
将900g的果糖加热至足够的温度,以液化(215℉-320℉或101℃-160℃)。
添加50g的橙皮素或橙皮苷和50g的果胶并且混合至所述液体浆料中。
使加热的浆料冷却,然后再结晶以形成常规的糖晶体,其中橙皮素或橙皮苷(酚)和果胶(淀粉)并入内部。
液体配方的实施例:
将900ml的玉米糖浆加热至高于室温(110℉-320℉或30℃-160℃)
将50g的橙皮素或橙皮苷和50g果胶添加至所述液化的浆料并且混合或搅拌。然后使浆料冷却至室温。
示例性干燥制剂:
800g蔗糖
100g没食子酸
100g阿糖基木聚糖
将成分混合在一起,以形成干燥、组合配方。
结晶配方的实施例:
将800g的蔗糖加热至足够的温度,以液化(215℉-320℉或101℃-160℃)。
添加100g的没食子酸和100g的阿糖基木聚糖并且混合至所述液体浆料中。
使加热的浆料冷却,然后再结晶以形成常规的糖晶体,其中没食子酸(酚)和阿糖基木聚糖(淀粉)并入内部。
液体配方的实施例:
将800ml的玉米糖浆加热至高于室温(110℉-320℉或30℃-160℃)
将100g的没食子酸和100g阿糖基木聚糖添加至所述液化的浆料中并且混合或搅拌。然后使浆料冷却至室温。
该制剂用于1千克或1升的改进的糖质量,组合比例为70%的玉米糖浆(甜料)、10%的没食子酸(酚)和20%的阿糖基木聚糖(淀粉)。
示例性干燥制剂:
800g蔗糖
100g橙皮素或橙皮苷
100g菊粉
将成分混合在一起,以形成干燥、组合配方。
结晶配方的实施例:
将800g的蔗糖加热至足够的温度,以液化(215℉-320℉或101℃-160℃)。
添加100g的橙皮素或橙皮苷和100g的菊粉并且混合至所述液体浆料中。
使加热的浆料冷却,然后再结晶以形成常规的糖晶体,其中橙皮素或橙皮苷和菊粉并入内部。
液体配方的实施例:
将800ml的玉米糖浆加热至高于室温(110℉-320℉或30℃-160℃)
将100g的橙皮素或橙皮苷和100g菊粉添加至所述液化的浆料并且混合或搅拌。然后使浆料冷却至室温。
该制剂用于1千克或1升的改进的糖质量,组合比例为70%的玉米糖浆(甜料)、10%的橙皮素或橙皮苷(酚)和20%的菊粉(淀粉)。
除了这些实施例。对于本领域普通技术人员显而易见的是,可进行与本公开一致的改变。例如,制剂可包括多于一种甜料、多于一种多酚和多于一种淀粉,使得甜味剂、多酚和/或淀粉的组合可存在于单个制剂中。
Claims (18)
1.一种制剂,其包含甜味剂、多酚和淀粉。
2.根据权利要求1所述的制剂,其中所述制剂当施用至需要其的个体时,缓解高血糖的作用。
3.根据权利要求2所述的制剂,其中该低血糖症病况选自由下述组成的组:代谢综合症、肥胖、糖尿病和神经疾病。
4.根据权利要求1所述的制剂,其进一步包含食料,所述食料包括饮品、面包、糖果、甜点、包衣、医学食品和药学制剂。
5.根据权利要求1所述的制剂,其中所述组合物已经被加热并且所述甜味剂已经被液化,从而所述多酚和淀粉嵌入所述甜味剂的再结晶形式中。
6.根据权利要求5所述的制剂,其中所述制剂已经并入食糖、饮品、面包、糖果、甜点、包衣、医学食品和药学制剂。
7.根据权利要求1所述的制剂,其中所述制剂被分散并且负载在所述甜味剂的液相中,所述甜味剂例如玉米糖浆。
8.根据权利要求7所述的制剂,其中所述制剂并入饮品、面包、糖果、甜点、包衣、医学食品和药学制剂中。
9.根据权利要求1所述的制剂,其中所述甜味剂为天然和半合成性质的碳水化合物基础,包括单糖、二糖、低聚糖和人工甜味剂,包括果糖、半乳糖、蔗糖、脱氧核糖、乙糖、丙糖、丁糖、戊糖、己糖、戊糖、醛糖、呋喃糖、吡喃糖、呋喃葡萄糖、吡喃葡萄糖、蔗糖、乳果糖、乳糖、麦芽糖、纤维二糖、壳二糖、曲二糖、黑曲霉二糖、异麦芽糖、槐糖、昆布二糖、龙胆二糖、松二糖、麦芽酮糖、帕拉金糖、甘露二糖、蜜二糖、车前二糖、芸香二糖、木二糖、低聚果糖、低聚半乳糖、低聚甘露糖、阿斯巴甜糖、甜蜜素、糖精、甜叶菊、三氯蔗糖、安赛蜜钾、乙酸铅、罗汉果苷、布拉齐因、可鲁可林、赤藓糖醇、甘草甜素、甘油、菊粉、异麦芽酮糖醇、乳糖醇、马槟榔甜蛋白、麦芽糖醇、神秘果素、莫那甜、应乐果甜蛋白、欧亚水龙骨甜素、倍他丁、山梨糖醇、塔格糖、奇异果甜蛋白、木糖醇、爱德万甜、阿力甜、甘素、甜素、新橙皮苷二氢查尔酮、纽甜、p-4000、糖精、l-鼠李糖、l-葡萄糖、l-甘露糖、l-岩藻糖。
10.根据权利要求1所述的制剂,其中所述甜味剂、多酚和淀粉中的至少一种具有生物活性酚性质,其包括但不限于酚类、flavonals、类黄酮、生物类黄酮、花青苷、黄烷酮、黄烷醇、黄烷、花青素。例子包括:芹菜脑、鼠尾草酚、香芹酚、莳萝油脑、迷迭香酚、槲皮素、山奈酚、杨梅黄酮、二氢杨梅素、非瑟酮、芸香苷、异鼠李素、橙皮素、橙皮苷、柚皮苷、柚皮素、水飞蓟宾、圣草酚、金合欢素、芹菜素、白杨黄素、香叶木素、柑橘黄酮、木犀草素、菊花、儿茶素、没食子儿茶素、表儿茶素、表没食子儿茶素、表没食子儿茶素没食子酸酯、茶黄素、茶红素、原花色素、花葵素、甲基花青素、花青素、花翠素、二甲花翠素、矮牵牛素、大豆黄素、染料木黄酮、黄豆黄素、异黄烷、异黄烷二酚、异黄烯、紫檀碱、橙酮、查尔酮、白藜芦醇、蝶芪、白皮杉醇、赤松烷、鞣花鞣质、安石榴苷、栗木鞣花素、栎木鞣花素、栗木素、木麻黄鞣亭、大丁香素、石榴皮鞣素、roburin、特里马素、榄仁黄素、沒食子单宁、原花色素、聚黄酮、pyrocatecolic、flavolan、水杨酸、香草醛、没食子酸、鞣花酸、鞣酸、咖啡酸、绿原酸、阿魏酸、香豆素、酪醇、羟基酪醇、橄榄油刺激醛、橄榄苦苷、辣椒素、姜醇、麦芽糊精、右旋糖、sterubin、杜鹃黄苷、高良姜精、棉花皮素、金丝桃苷、淫羊藿苷、异槲皮素、异鼠李素、山柰素、山柰苷、桑色素、杨梅苷、槲皮苷、藿香黄酮醇、甲基鼠李黄素、刺槐素、刺槐糖、绣线菊苷、spirenoside、曲克芦丁、汉黄芩素、sterubin、枸橘苷、泽兰叶黄素、芹黄素。
11.根据权利要求1所述的制剂,其中所述淀粉选自由下述组成的组:聚合碳水化合物或多糖,包括吡喃葡萄糖、直链淀粉、支链淀粉、糖原、阿糖基木聚糖、纤维素、几丁质、果胶、酸性多糖。
12.根据权利要求1所述的所述的制剂,其中,当所述制剂被施用至个体时,所述多酚适于通过一个或多个下述方法控制高血糖的副作用:抑制促炎的tnf-α、抑制α淀粉酶、抑制葡糖苷酶、抑制glut 2运输至脂肪组织中、刺激glut 4运输至肌肉组织中和/或刺激肌肉组织中线粒体发生。
13.根据权利要求1所述的制剂,其中所述制剂当被施用至个体时,通过一个或多个下述方法抑制糖的血糖影响:直接抑制酶α淀粉酶、直接抑制酶葡糖苷酶、抑制和缓冲胃酸。
14.根据权利要求1所述的制剂,其中所述制剂当被施用至需要其的个体时,通过防止或减少来自淀粉酶活性的副产物的珐琅降解酸而防止口部的窝洞形成。
15.根据权利要求1所述的制剂,其中所述多酚被配制为当所述制剂被施用至需要其的个体时,抑制口腔中的emulase活性。
16.根据权利要求1所述的制剂,其中当被施用至需要其的患者时,产生改善的糖制剂,将通过下述引起重量减少或防止增重:通过抑制脂肪组织的glut 2途径来减少脂肪积聚的直接相互作用和通过激活glut 4途径的增加能量/碳水化合物消耗的直接刺激。
17.根据权利要求1所述的制剂,其中所述多酚为橙皮素或橙皮苷并且所述淀粉为菊粉。
18.根据权利要求1所述的制剂,其中所述多酚为没食子酸并且所述淀粉为阿糖基木聚糖。
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- 2017-11-15 JP JP2019527160A patent/JP2020528042A/ja active Pending
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CN111096986A (zh) * | 2019-12-31 | 2020-05-05 | 江门民康生物科技研究有限公司 | 一种以神秘果果核为原料的提取物及其在制备具有降血糖作用的药物或保健品中的应用 |
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CN112569246A (zh) * | 2020-12-22 | 2021-03-30 | 成都大学 | 用于抗炎镇痛止血的药物及药物活性组分筛选方法 |
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WO2018093830A2 (en) | 2018-05-24 |
KR20190130120A (ko) | 2019-11-21 |
JP2020528042A (ja) | 2020-09-17 |
WO2018093830A3 (en) | 2019-06-06 |
CA3051413A1 (en) | 2018-05-24 |
AU2017361084A1 (en) | 2019-06-06 |
US20180133243A1 (en) | 2018-05-17 |
EP3541207A4 (en) | 2020-05-20 |
BR112019009982A2 (pt) | 2019-08-27 |
EP3541207A2 (en) | 2019-09-25 |
RU2019117451A (ru) | 2020-12-17 |
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