CN109248167A - 用于减少脱发和/或增加毛发再生的组合物 - Google Patents
用于减少脱发和/或增加毛发再生的组合物 Download PDFInfo
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- CN109248167A CN109248167A CN201811314591.4A CN201811314591A CN109248167A CN 109248167 A CN109248167 A CN 109248167A CN 201811314591 A CN201811314591 A CN 201811314591A CN 109248167 A CN109248167 A CN 109248167A
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Abstract
本发明涉及包含2％至5％的米诺地尔、0.01％至15％的非那雄胺和0.01％至15％的前列腺素类似物的组合物。在一个实施方案中，所述前列腺素类似物为拉坦前列素。在优选实施方案中，所述组合物包含5％的米诺地尔、0.1％的非那雄胺和0.03％的拉坦前列素。本发明还涉及所述组合物用于在人对象中减少脱发和/或增加毛发再生的用途。
Description
发明领域
本发明的发明人发现，当与常规疗法(如局部施用5％的米诺地尔溶液)相比时，包含米诺地尔、非那雄胺和前列腺素类似物的组合物在减少脱发和增加毛发再生方面显示出改善的特性。
发明背景
雄激素性脱发症(AGA)是由毛囊减薄(thinning)引起的脱发(在头皮水平)。它在19至70岁的男性中十分常见。值得注意的是，超过50％的高加索男性在其50多岁时会受脱发的影响。女性的脱发主要是发生在绝经后的问题。
受雄激素性脱发(AGA)影响的个体表现出其自尊的减弱，这会消极地影响他们生活的许多方面。本发明的发明人发现，用于局部施用的包含米诺地尔、非那雄胺和前列腺素类似物的组合物在减少脱发和增加毛发再生方面是有效的。
市面上有数种预防脱发的产品。例如，从20世纪90年代起，米诺地尔就以2％的浓度(无处方)和3％以及5％的浓度(按处方)以局部形式使用。虽然研究证明5％米诺地尔的有效性优于2％浓度的米诺地尔，但是米诺地尔在促进毛发再生方面的有效性低于40％。米诺地尔被认为是可用于治疗脱发的局部黄金标准。
另一种预防脱发的产品是非那雄胺。其通常以1mg/天的剂量口服施用。存在与施用非那雄胺相关的许多副作用，包括性欲降低、阳痿、射精障碍、过敏反应、睾丸疼痛、男性不育、男性乳癌以及抑郁症。在更高浓度(5mg)下，非那雄胺可以引起良性前列腺增生。
拉坦前列素(一种PGF2α前列腺素类似物)在眼科中被广泛用于治疗开角型青光眼和高眼压症。它的副作用之一为眼周多毛增加，包括睫毛粗度、长度和色素沉着的增加，这区别于毛发生长。它的一些其它不良反应为红斑、毛囊炎、烧灼感以及丹毒。拉坦前列素眼用溶液具有0.005％的浓度。应当注意的是，头皮毛囊和睫毛毛囊不同，并且不能简单地从对一种毛发的药物效果来推断对另一种毛发的药物效果。
本发明发现，用于向头皮局部施用的包含米诺地尔、非那雄胺和前列腺素类似物的组合物减少了脱发并增加了毛发再生。此种组合物显示出比单独施用所述组合物的各组分所观察到的更优改进，并且目前为止得到的结果显示所述改进可能优于所述组分之和。
发明概述
本发明涉及包含2％至5％的米诺地尔、0.01％至15％的非那雄胺和0.01％至15％的前列腺素类似物的组合物。在一个实施方案中，所述前列腺素类似物为拉坦前列素。在另一实施方案中，所述组合物包含5％的米诺地尔、0.1％的非那雄胺和0.03％的拉坦前列素。本发明还涉及包含2％至5％的米诺地尔、0.01％至15％的非那雄胺和0.01％至15％的前列腺素类似物的组合物用于在人对象中减少脱发和/或增加毛发再生的用途。
附图说明
图1A至1L是显示在治疗之前和用本发明组合物进行6个月的治疗进程中每隔一段时间，参与者1头皮的一系列照片。图1A和1B显示了在第1个月第一天进行治疗之前的头皮，图1C和1D显示了在第2个月的头皮，图1E和1F为第3个月的头皮，图1G和1H为第4个月的头皮，图1I和1J为第5个月的头皮，以及图1K和1L是第6个月的头皮；
图2A至2L是显示在治疗之前和用本发明组合物进行6个月的治疗进程中每隔一段时间，参与者2头皮的一系列照片。图2A和2B显示了在第1个月第一天进行治疗之前的头皮，图2C和2D显示了第2个月的头皮，图2E和2F为第3个月的头皮，图2G和2H为第4个月的头皮，图2I和2J为第5个月的头皮，以及图2K和2L为第6个月的头皮；
图3A至3L是显示在治疗之前和用本发明组合物进行6个月的治疗进程中每隔一段时间，参与者3头皮的一系列照片。图3A和3B显示了在第1个月第1天进行治疗之前的头皮，图3C和3D显示了第2个月的头皮，图3E和3F为第3个月的头皮，图3G和3H为第4个月的头皮，图3I和3J为第5个月的头皮，以及图3K和3L为第6个月的头皮；
图4A至4L是显示在治疗之前和仅用5％米诺地尔溶液进行6个月的治疗进程中每隔一段时间，参与者4头皮的一系列照片。图4A和4B显示了在第1个月第1天进行治疗之前的头皮，图4C和4D显示了第2个月的头皮，图4E和4F为第3个月的头皮，图4G和4H为第4个月的头皮，图4I和4J为第5个月的头皮，以及图4K和4L为第6个月的头皮；
图5A至5L是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者5头皮的一系列照片。图5A和5B显示了在第1个月第1天进行治疗之前的头皮，图5C和5D显示了第2个月的头皮，图5E和5F为第3个月的头皮，图5G和5H为第4个月的头皮，图5I和5J为第5个月的头皮，以及图5K和5L为第6个月的头皮；
图6A至6L是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者6头皮的一系列照片。图6A和6B显示了在第1个月第1天进行治疗之前的头皮，图6C和6D显示了第2个月的头皮，图6E和6F为第3个月的头皮，图6G和6H为第4个月的头皮，图6I和6J为第5个月的头皮，以及图6K和6L为第6个月的头皮；
图7A至7G是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者7头皮的一系列照片。图7A和7B显示了在第1个月第1天进行治疗之前的头皮，图7C显示了第2个月的头皮，图7D为第3个月的头皮，图7E为第4个月的头皮，图7F为第5个月的头皮，以及图7G为第6个月的头皮；
图8A至8L是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者8头皮的一系列照片。图8A和8B显示了在第1个月第1天进行治疗之前的头皮，图8C和8D显示了第2个月的头皮，图8E和8F为第3个月的头皮，图8G和8H为第4个月的头皮，图8I和8J为第5个月的头皮，以及图8K和8L为第6个月的头皮；
图9A至9L是显示在治疗之前和仅用0.03％拉坦前列素溶液进行6个月的治疗进程中每隔一段时间，参与者9头皮的一系列照片。图9A和9B显示了在第1个月第1天进行治疗之前的头皮，图9C和9D显示了第2个月的头皮，图9E和9F为第3个月的头皮，图9G和9H为第4个月的头皮，图9I和9J为第5个月的头皮，以及图9K和9L为第6个月的头皮；
图10A至10L是显示在治疗之前和仅用0.03％拉坦前列素溶液进行6个月的治疗进程中每隔一段时间，参与者10头皮的一系列照片。图10A和10B显示了在第1个月第1天进行治疗之前的头皮，图10C和10D显示了第2个月的头皮，图10E和10F为第3个月的头皮，图10G和10H为第4个月的头皮，图10I和10J为第5个月的头皮，以及图10K和10L为第6个月的头皮。
图6是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者6头皮的一系列照片；
图7是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者7头皮的一系列照片；
图8是显示在治疗之前和仅用0.1％非那雄胺溶液进行6个月的治疗进程中每隔一段时间，参与者8头皮的一系列照片；
图9是显示在治疗之前和仅用0.03％拉坦前列素溶液进行6个月的治疗进程中每隔一段时间，参与者9头皮的一系列照片；以及
图10是显示在治疗之前和仅用0.03％拉坦前列素溶液进行6个月的治疗进程中每隔一段时间，参与者10头皮的一系列照片。
发明详述
本发明涉及包含米诺地尔、非那雄胺和前列腺素类似物的组合物，当与单独使用米诺地尔、非那雄胺以及拉坦前列素相比时，所述组合物用于在人对象中减少脱发和增加毛发再生显示出改善的特性。
米诺地尔或(6-(1-哌啶基)-2,4-嘧啶二胺3-氧化物)具有下述结构式：
米诺地尔为晶体，其在丙二醇中的溶解度为75mg/ml，在甲醇中为44mg/ml，在乙醇中为29mg/ml，在2-丙醇中为6.7mg/ml，在DMSO中为6.5mg/ml，在水中为2.2mg/ml，在氯仿中为0.5mg/ml，以及在丙酮中为<0.5mg/ml。米诺地尔具有4.61的pKa。
非那雄胺或((5α,17β)-N-(1,1-二甲基乙基)-3-氧代-4-氮杂雄-1-烯-17-酰胺)具有下述结构式：
非那雄胺通常以1mg的日剂量口服施用。
非那雄胺为无水晶体。非那雄胺自由溶于氯仿、DMSO、乙醇、甲醇、n-丙醇；少量溶于丙二醇、聚乙二醇400；并且极微溶于0.1N HCl和0.1N NaOH。非那雄胺不溶于水。
拉坦前列素或((5Z)-7-[(1R,2R,3R,5SO-3,5-二羟基-2-[(3R)-3-羟基-5-苯基戊基]环戊基]-5-庚烯酸1-甲基乙基酯)具有下述结构式：
拉坦前列素是一种油。拉坦前列素极易溶于乙腈；自由溶于丙酮、乙醇、乙酸乙酯、异丙醇、甲醇以及辛醇。其特别不溶于水。
前列腺素调节多种生理功能。已经发现，大部分毛发细胞类型被赋予了前列腺素代谢机制，因此能够产生PGE2和/或PGF2α。毛球的上皮部分是前列腺素合成和互相转换的主要来源。通过Colombe等人(Prostaglandin Metabolism in Human Hair Follicle,ExpDermatol.2007Sep.,16(9):762to 769)，并且由于已经发现米诺地尔也可以增强前列腺素内过氧化物合酶-1(PGHS-1)的活性，这表明前列腺素参与毛发的生长和分化控制，并且前列腺素合成与毛发生长之间存在联系。通过分析PGE2产生中的氧耗量，已经证明米诺地尔是纯化的PGHS-1的有效激活剂，表明米诺地尔的毛发生长刺激作用的机制是刺激PGE2的合成(Michelet et al.,Activation of Cytoprotected Prostaglandin Synthase-1byMinoxidil as a Possible Explanation for Its Hair Growth-Stimulating Effect,J.Invest Dermatol 1997:108:205-209)。这已经通过PGHS-2在毛发周期的控制中的作用被证实(Muller-Decker et al.,Expression of Cyclo-Oxygenase Isozymes DuringMorphogenesis and Cycling of Telage Hair Follicles in Mouse Skin,J.InvestDermatol 2003:121:661-668)。已经显示人毛囊可以维持完整的PGE2和PGF2α代谢。人毛囊表达(i)催化来自PGH2的PGE2合成的mPGES-1、mPGES-2和cPGES，(ii)将PGH2转化为PGF2α的AKR1C3/PGFS，以及(iii)能够控制PGE2/PGF2α互相转换的CDR1和AKR1C1醛-酮还原酶。同样地，已经证明人毛囊充分配备有自我进行前列腺素合成和代谢的酶，意味着PGE2和PGF2α可以通过毛囊产生和互相转换。尽管测试的组合物包含拉坦前列素(一种PGF2α前列腺素类似物)，鉴于前列腺素在毛发生长和分化中的作用，推测也可以使用其它的前列腺素类似物。以示例的方式，其它合适的前列腺素类似物包括曲伏前列素、比马前列素、他氟前列素以及乌诺前列酮。
本发明的组合物包含2％至5％的米诺地尔、0.01％至15％的非那雄胺以及0.01％至15％的前列腺素类似物。在优选实施方案中，所述组合物包含2％至5％的米诺地尔、0.01％至5％的非那雄胺以及0.01％至5％的前列腺素类似物。在更优选的实施方案中，所述组合物包含5％的米诺地尔、0.5％的非那雄胺以及0.1％的前列腺素类似物。在其它优选实施方案中，所述前列腺素类似物为拉坦前列素、曲伏前列素、比马前列素、他氟前列素或乌诺前列酮。在更优选的实施方案中，所述前列腺素类似物为拉坦前列素。在更优选的实施方案中，所述组合物包含如下述表1中所列出的5％的米诺地尔、0.1％的非那雄胺以及0.03％的拉坦前列素。
为了证明适合用于局部施用的包含米诺地尔、非那雄胺以及前列腺素类似物拉坦前列素的组合物的改善的特性，将所述组合物与仅包含5％米诺地尔的组合物，仅包含0.1％非那雄胺的组合物以及仅包含0.03％拉坦前列素的组合物进行比较。按如下所述制备各种组合物。
实施例1：
制备包含非那雄胺、拉坦前列素以及米诺地尔的组合物
为了制备所述组合物，将拉坦前列素稀释以获得浓度为10,000mcg/ml的无水乙醇溶解物，将其制备为储备液，并在冰箱中保存以增强稳定性(-20℃)。将无水乙醇与丙二醇混合，并加热至55℃-65℃。然后向乙醇/丙二醇混合物中添加米诺地尔粉末。在密封罩中，向所述溶液中添加非那雄胺，并搅拌直至溶解。将制备物冷却至室温。向冷却的溶液中加入乙氧基二甘醇和拉坦前列素，并充分搅拌直至溶解。用无水乙醇使最终的溶液达到一定的体积。
使用的量如以下表1中所示：
| 组分 | 功能 | 每单位的量 | ％ |
| 丙二醇 | 溶剂 | 30ml | 50 |
| 米诺地尔USP | 活性成分 | 3g | 5 |
| 非那雄胺USP | 活性成分 | 0.06g | 0.1 |
| 乙氧基二甘醇试剂 | 溶剂 | 3ml | 5 |
| 拉坦前列素(10,000mcg/ml) | 活性成分 | 1.8ml | 0.03 |
| 无水乙醇 | 溶剂 | QS 60ml | 39.87 |
| 总共 | 60ml | 100％ |
对本发明组合物的制备进行各种改进，对技术人员而言将是显而易见的。此外，可以添加其它药学可接受的添加剂，如悬浮剂、乳化剂、非水性赋形剂以及防腐剂。用于制备这些组合物的技术在本领域是众所周知的，并且可以参考Remington’s PharmaceuticalSciences,18th(雷氏药学大全第18版)，Mack Publishing Co.,Easton,Pennsylvania,USA18042。
实施例2：
制备包含米诺地尔的组合物
制备包含5％米诺地尔的组合物。将无水乙醇与丙二醇混合，并加热至55℃至65℃。向乙醇/丙二醇混合物中添加米诺地尔粉末。添加乙氧基二甘醇，并搅拌溶液。用无水乙醇使最终的溶液达到一定的体积，以获得包含5％米诺地尔的溶液。
实施例3：
制备包含非那雄胺的组合物
同时制备包含0.1％非那雄胺的组合物。将无水乙醇与丙二醇混合。向乙醇/丙二醇混合物中添加非那雄胺，以获得具有0.1％非那雄胺浓度的溶液。无水乙醇还可以发挥防腐剂的作用。
实施例4：
制备包含拉坦前列素的组合物
制备包含0.03％拉坦前列素的溶液。将无水乙醇与丙二醇混合。向乙醇/丙二醇混合物中添加拉坦前列素。用无水乙醇使最后的溶液达到一定的体积，以获得具有0.03％拉坦前列素浓度的溶液。在该组合物中，无水乙醇还可以发挥防腐剂的功能。
实施例5：
用本发明的组合物和对比剂治疗参与者-分析和测量
对于各参与者，记录鼻基底与发顶(hair crown)中部的距离，以及耳轮的最远端部分与发顶的分开距离。对发顶中间点周围两厘米×两厘米的平面区域(用可洗的毡头蜡笔标记)进行测量。拍摄每一参与者头皮的照片。
在6个月的周期内，以每月间隔对参与者进行观察，并且以上文所述的方式对它们的头发进行分析，并拍照。
结果
A.用包含非那雄胺、拉坦前列素以及米诺地尔的组合物进行治疗
按照上文所述，首先对各参与者的头发进行分析，并拍照。初次分析之后，向各参与者提供按上文实施例1中所述制备的包含0.1％非那雄胺、0.03％拉坦前列素以及5％米诺地尔的溶液。向参与者的头皮施用1ml，清洗之后每天一次。将1ml作为10次0.1ml定量剂量的喷雾施用。
提供了三名参与者的结果。参与者1为61岁的男性(图1)。参与者2为23岁的男性(图2)，而参与者3为29岁的男性(图3)。这三名参与者都患有雄激素性脱发症，比较剂组的参与者也患有雄激素性脱发症。
图1、2和3清楚地显示了在所有三名参与者中，脱发的显著减少和毛发再生的增加。
B.与单独用米诺地尔、非那雄胺和拉坦前列素治疗的比较
如以上A部分中所述，首先对各参与者的头发进行分析，并拍照。初次分析之后，向各参与者提供包含5％米诺地尔、0.1％非那雄胺或0.03％拉坦前列素的溶液。按上文实施例2至4所述的制备所述组合物。向参与者的头皮施用1ml，清洗之后每天一次。将1ml作为10次0.1ml定量剂量的喷雾施用。
提供了各组参与者的结果。
米诺地尔组的参与者为64岁的男性。图4显示了从该参与者获得的结果。仅观察到了毛发再生的轻微增加，并且该结果远次于用本发明的组合物所观察到的结果。
4名参与者使用了仅包含0.1％非那雄胺的溶液。这些参与者分别为30岁(参与者5)、33岁(参与者6)、36岁(参与者7)以及46岁(参与者8)。图5、6、7和8分别显示了参与者5、6、7和8的结果。仅观察到了毛发再生的轻微增加。该结果远次于用本发明的组合物所观察到的结果。
两名参与者使用了仅包含0.03％拉坦前列素的溶液。这些参与者分别为48岁(参与者9)和52岁(参与者10)。图9和10分别显示了参与者9和10的结果。仅观察到了毛发再生的轻微增加。获得的结果远次于用本发明的组合物所观察到的结果。
当单独与5％米诺地尔的溶液、0.1％非那雄胺的溶液或0.03％拉坦前列素的溶液进行比较时，包含米诺地尔、非那雄胺和拉坦前列素的组合物在减少脱发和增加毛发再生方面显示出改善的特性。本发明的组合物在减少脱发和增加毛发再生方面显示出的改善，优于单独使用所述组合物各组分所观察到的改善，并且目前为止获得的结果表明，使用本发明的组合物所观察到的改善可能优于所述组分的总改善。
尽管本发明的组合物已经在男性中进行了测试，由于在两种性别中毛发生长的机制相同，因此可以在女性中期望类似的结果。
尽管参考本发明的具体实施方案和具体用途对本发明进行了描述，但是对本领域技术人员而言，可以进行各种改进。权利要求的范围不应受优选实施方案或实施例的限制，而应当被赋予与整体说明书相一致的最广泛的解释。
Claims (15)
1.组合物，其包含2％至5％的米诺地尔、0.01％至15％的非那雄胺和0.01％至15％的前列腺素类似物。
2.如权利要求1所述的组合物，其包含5％的米诺地尔、0.5％的非那雄胺和0.1％的前列腺素类似物。
3.如权利要求1所述的组合物，其包含5％的米诺地尔、0.1％的非那雄胺和0.03％的前列腺素类似物。
4.如权利要求1、2或3所述的组合物，其中所述前列腺素类似物为拉坦前列素、曲伏前列素、比马前列素、他氟前列素或乌诺前列酮。
5.如权利要求4所述的组合物，其中所述前列腺素类似物为拉坦前列素。
6.权利要求1至5中任一项所述的组合物，其用于在人对象中减少脱发和/或增加毛发再生。
7.如权利要求6所述的组合物，其中所述人对象为男性。
8.如权利要求6所述的组合物，其中所述人对象为女性。
9.如权利要求1至8中任一项所述的组合物，其用于局部施用。
10.如权利要求9所述的组合物，其为喷雾形式。
11.权利要求1至10中任一项所述的组合物在制备用于在人对象中减少脱发和/或增加毛发再生的药物中的用途。
12.如权利要求11所述的用途，其中所述人对象为男性。
13.如权利要求11所述的用途，其中所述人对象为女性。
14.如权利要求11至13中任一项所述的用途，其中所述组合物用于局部施用。
15.如权利要求14所述的用途，其中所述组合物为喷雾形式。
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| US201462002397P | 2014-05-23 | 2014-05-23 | |
| US62/002,397 | 2014-05-23 | ||
| CN201580001707.7A CN105658223B (zh) | 2014-05-23 | 2015-05-22 | 用于减少脱发和/或增加毛发再生的组合物 |
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| CN201580001707.7A Division CN105658223B (zh) | 2014-05-23 | 2015-05-22 | 用于减少脱发和/或增加毛发再生的组合物 |
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| WO (1) | WO2015176161A1 (zh) |
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| CN109248167A (zh) | 2014-05-23 | 2019-01-22 | 特里普海尔公司 | 用于减少脱发和/或增加毛发再生的组合物 |
| US11696883B2 (en) | 2014-05-23 | 2023-07-11 | Triple Hair Inc. | Compositions for reducing hair loss and/or increasing hair regrowth |
| GB201713113D0 (en) * | 2017-08-16 | 2017-09-27 | Eccles Nyjon Karl | Combination therapy |
| PL3494955T3 (pl) * | 2017-12-08 | 2021-09-13 | Escilab Spółka Z Ograniczoną Odpowiedzialnością | Kompozycja kosmetyczna wspomagająca wzrost włosów |
| CN110507661A (zh) * | 2019-06-14 | 2019-11-29 | 唐安平 | 一种秃头治疗组合物 |
| CN114025768B (zh) * | 2019-06-28 | 2023-12-22 | 古鲁生物制药有限公司 | 促进毛发生长的药品 |
| US11253518B2 (en) | 2019-08-07 | 2022-02-22 | Aneira Pharma, Inc. | Methods and compositions for the treatment of hair loss |
| US20230143752A1 (en) * | 2020-03-05 | 2023-05-11 | University Of Miami | Cannabidiol nanodrug formulations and methods for use of the same |
| CA3091554A1 (en) * | 2020-08-28 | 2022-02-28 | Triple Hair Inc. | Formulations for reducing hair loss and/or increasing hair regrowth |
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| DE19509354A1 (de) | 1994-12-08 | 1996-06-13 | Klett Loch Lore M | Kombinationspräparat zur Förderung des Haarwachstums und ggf. des Haut- und Nagelwachstums sowie zur Verhinderung bzw. zur Beseitigung von Haarausfall |
| AUPN814496A0 (en) | 1996-02-19 | 1996-03-14 | Monash University | Dermal penetration enhancer |
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| CN109248167A (zh) | 2014-05-23 | 2019-01-22 | 特里普海尔公司 | 用于减少脱发和/或增加毛发再生的组合物 |
| US11696883B2 (en) | 2014-05-23 | 2023-07-11 | Triple Hair Inc. | Compositions for reducing hair loss and/or increasing hair regrowth |
-
2015
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- 2015-05-22 CN CN201580001707.7A patent/CN105658223B/zh active Active
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2021
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| PL3062797T3 (pl) | 2020-08-24 |
| EP3062797B1 (en) | 2019-08-28 |
| ES2754353T3 (es) | 2020-04-17 |
| US20170100319A1 (en) | 2017-04-13 |
| US20210283038A1 (en) | 2021-09-16 |
| WO2015176161A1 (en) | 2015-11-26 |
| CA2903734A1 (en) | 2015-11-23 |
| CA2903734C (en) | 2016-03-01 |
| EP3062797A4 (en) | 2016-11-23 |
| CN105658223B (zh) | 2018-12-04 |
| EP3062797A1 (en) | 2016-09-07 |
| US20160213590A1 (en) | 2016-07-28 |
| US10470992B2 (en) | 2019-11-12 |
| US12053541B2 (en) | 2024-08-06 |
| CN105658223A (zh) | 2016-06-08 |
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