CN118001376A - 膜联蛋白a5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品和药物组合物 - Google Patents
膜联蛋白a5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品和药物组合物 Download PDFInfo
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Abstract
本发明提供了一种膜联蛋白A5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品和药物组合物。具体地，本发明提供了一种膜联蛋白A5的用途，用于生发、育发、护发、防脱发和/或治疗脱发。本发明公开的膜联蛋白A5能够有效促进雄激素脱发后的毛发再生，可以作为生发、育发、护法、防脱发产品和治疗脱发的药物组合物的有效成分。
Description
技术领域
本发明属于医药生物技术领域，具体地，涉及一种膜联蛋白A5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品。
背景技术
脱发是临床上的常见疾病，其病因尚未完全阐明，研究显示可能与年龄、机体免疫力、遗传、激素水平、局部炎症反应、神经和环境因素等相关。目前，常见的脱发类型主要有雄性激素脱发、斑秃、休止期脱发、老年性脱发等，其中雄性激素脱发是发病率最高的类型，好发于男性，并呈典型的家族遗传特性。目前，美国FDA批准的雄激素脱发治疗药物仅有非那雄胺和米诺地尔两种，然而患者在接受上述药物治疗后通常会发生较为严重的不良反应或副作用。因此，本领域迫切需要开发新的生发、育发、护发、防脱发产品和对人体无不良反应或副作用的治疗脱发的药物。
发明内容
本发明的目的就是提供一种新的生发、育发、护发、防脱发产品和对人体无不良反应或副作用的治疗脱发的药物。
本发明的第一方面，提供了一种膜联蛋白A5在制备用于治疗脱发的药物组合物或医疗器械中的用途。
在另一优选例中，所述的脱发选自下组：雄性激素脱发、斑秃、休止期脱发、老年性脱发、心理压力性掉发、物理性脱发、化学性脱发、营养代谢性脱发、感染性脱发、内分泌失调性脱发。
在另一优选例中，所述的药物组合物用于(1)促进毛发生长；(2)脱发后的毛发再生；(3)提高毛囊内细胞增殖能力；(4)增加毛乳头周围毛细血管数量；(5)抑制毛囊中雄激素受体(AR)和转化生长因子β1(TGF-β1)的表达。
在另一优选例中，所述的药物组合物用于(1)抑制皮肤中TGF-β1、IL-6、THF-α、IL-1β的表达；(2)降低胞内双羟睾酮(DHT)的含量；和/或(3)提高人毛乳头细胞的体外生长能力。
在另一优选例中，所述的双氢睾酮含量为毛乳头细胞中的双氢睾酮。
在另一优选例中，所述的毛乳头细胞是人原代毛乳头细胞。
本发明的第二方面，提供了一种膜联蛋白A5在制备用于治疗生发和/或防脱发产品中的用途。
在另一优选例中，所述的产品用于(a)提高毛发顺滑程度；(b)减轻毛发脱落；(c)增加毛发生长密度；和/或(d)促进毛发生长。
在另一优选例中，所述的产品用于育发和/或护发。
本发明的第三方面，提供了一种用于治疗脱发的药物组合物，所述的药物组合物包括：(i)膜联蛋白A5；(ii)用于治疗脱发的其他药物；(iii)药学上可接受的辅料。
在另一优选例中，所述的辅料选自下组：稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂。
在另一优选例中，所述的药物组合物的剂型选自下组：擦剂、喷剂、洗剂、膏剂和注射剂。
在另一优选例中，所述的药物组合物通过选自下组的方法导入机体组织：注射、喷射、渗透、吸收、物理介导的方法、化学介导的方法、或被其他物质混合或包裹后导入机体组织。
在另一优选例中，所述的其他药物选自下组：氢万液、米诺地尔、非那雄胺。
本发明的第四方面，提供了一种体外降低细胞内DHT浓度的方法，所述的方法包括步骤：在膜联蛋白A5存在下，培养细胞，从而降低细胞内DHT的浓度。
在另一优选例中，所述方法为非治疗性和非诊断性的。
在另一优选例中，所述的细胞是人毛乳头细胞。
在另一优选例中，所述的膜联蛋白A5是外源添加的。
在另一优选例中，所述的膜联蛋白A5的浓度为1-1000ng/ml。
在另一优选例中，所述的方法还包括步骤：检测细胞内DHT的浓度，并与加入膜联蛋白A5前细胞内DHT的浓度做对比。
本发明的第五方面，提供了一种体外提高毛乳头细胞生长能力的方法，所述的方法包括步骤：在膜联蛋白A5存在下，培养毛乳头细胞，从而提高毛乳头细胞的生长能力。
在另一优选例中，所述方法为非治疗性和非诊断性的。
在另一优选例中，所述的细胞是人毛乳头细胞。
在另一优选例中，所述的膜联蛋白A5是外源添加的。
在另一优选例中，所述的膜联蛋白A5的浓度为1-1000ng/ml。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为膜联蛋白A5对小鼠雄激素性脱发的治疗作用；
图2为膜联蛋白A5对小鼠雄激素性脱发治疗后的组织学HE染色结果图；
图3为膜联蛋白A5对小鼠雄激素性脱发治疗后的免疫组化染色结果图；
图4为膜联蛋白A5对小鼠雄激素性脱发治疗后的小鼠毛囊标本雄激素受体及TGF-β1表达结果。
具体实施方式
本发明人经过广泛而深入的研究，通过大量筛选，首次开发了一种新颖的膜联蛋白A5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品和药物组合物。实验结果有效证实了膜联蛋白A5能够有效提高雄激素脱发模型小鼠毛囊中细胞的增殖能力，促进毛乳头周围的毛细血管数量，并抑制小鼠毛乳头中AR与TGF-β1的表达水平，进一步促进雄激素脱发后的毛发再生能力。因而，膜联蛋白A5可以用于生发、育发、护发、防脱发以及治疗脱发。在此基础上完成了本发明。
膜联蛋白A5
膜联蛋白A5(annexin A5，AnxA5)是由319个氨基酸多肽单链构成的钙磷脂结合蛋白，是人体中一种重要的功能蛋白质分子，广泛分布于人体的细胞和体液中。膜联蛋白A5是膜联蛋白家族中的一员，具有特定结构和独特的生化特性，能够以钙离子依赖方式，可逆、特异性、高效地结合磷脂酰丝氨酸分子，基于此特性，膜联蛋白A5发挥着重要的生物学功能，在诸多人体生理、病理现象中发挥重要作用。早在1985年，研究者首次提出膜联蛋白A5具有抗凝功能，并也称之为抗凝蛋白。在近些年的研究中，随着相关研究的深入热化，膜联蛋白A5还参与炎性反应、凋亡进程、调控肿瘤发展等多方面作用。目前，尚未有相关研究揭示膜联蛋白A5在生发、育发、护发以及治疗脱发方面的应用。
药物组合物和施用方法
膜联蛋白A5可以制备成药物组合物，诸如片剂、胶囊、粉剂、微粒剂、溶液剂、锭剂、胶冻、乳膏制剂、醑剂、悬液、酊、泥敷剂、搽剂、洗剂、注射剂和气雾剂之类的剂型。药物能够由通常已知的制备技术来制备，并且合适的药物添加剂能够被添加到该药物中。
药物辅料的例子包括药学上可接受的载体、赋形剂、稀释剂、粘结剂、分解剂、填充剂、粘合剂、湿润剂、润滑剂、流动助剂、崩解剂、吸收促进剂、表面活性剂、悬浮剂、乳化剂、稳定剂、保温(润湿)剂、防腐剂、溶剂、增溶剂、防腐剂、调味剂、增甜剂、染料、香料、推进剂、吸附载体等，这些药物辅料可以进行选择并以在不影响本发明的效果的范围内的合适量添加。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和膜联蛋白A5相互掺和，而不明显降低膜联蛋白A5的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的膜联蛋白A5的剂型包括擦剂、喷剂、洗剂、膏剂、软膏剂、散剂、贴剂、喷射剂和吸入剂。膜联蛋白A5在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
膜联蛋白A5可以单独给药，或者与其他药学上可接受的用于治疗脱发的药物联合给药。
含有膜联蛋白A5的产品
本发明所述的膜联蛋白A5可以制备成多种剂型，如乳剂、液体、膏剂、霜剂、糊剂、饼、粉剂之类的剂型。
在不防碍本发明的效果的范围内，本发明的产品中可以添加通常的生理上可接受的其他组分，例如成膜剂、油溶性凝胶化剂、有机改性粘土矿物、树脂、保湿剂、防腐剂、抗菌剂、香精、盐类、抗氧化剂、pH调节剂、螯合剂、清凉剂、抗炎剂、维生素类、氨基酸类、核酸、激素、包合化合物等。
油溶性凝胶化剂是选自硬脂酸铝、硬脂酸镁、肉豆蔻酸锌等金属皂；N-月桂酰基-L-谷氨酸、α，γ-二-正丁基胺等氨基酸衍生物；环糊精棕榈酸酯、环糊精硬脂酸酯、环糊精2-乙基己酸棕榈酸酯等环糊精脂肪酸酯；蔗糖棕榈酸酯、蔗糖硬脂酸酯等蔗糖脂肪酸酯；一亚苄基山梨醇、二亚苄基山梨醇等山梨醇的亚苄基衍生物；二甲基苄基十二烷基铵蒙脱石粘土、二甲基二十八烷基铵蒙脱石粘土等有机改性粘土矿物等的凝胶化剂，可以根据需要使用一种，或者使用二种或以上。
保湿剂有：甘油、山梨醇、丙二醇、双丙甘醇、1，3-丁二醇、葡萄糖、木糖醇、麦芽糖醇、聚乙二醇、透明质酸、硫酸软骨素、吡咯烷酮羧酸盐、聚氧乙烯甲基葡糖苷、聚氧丙烯甲基葡糖苷等。
抗菌防腐剂有：对羟基苯甲酸烷基酯、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、苯氧基乙醇等，抗菌剂有：苯甲酸、水杨酸、石炭酸、山梨酸、对羟基苯甲酸烷基酯、对氯间甲酚、六氯酚、苯扎氯铵、氯化洗必泰、三氯-N-碳酰苯胺、三氯生、感光素、苯氧基乙醇等。
抗氧化剂有：生育酚、丁基羟基茴香醚、二丁基羟基甲苯、植酸等，pH调节剂有：乳酸、柠檬酸、乙醇酸、琥珀酸、酒石酸、dl-苹果酸、碳酸钾、碳酸氢钠、碳酸氢铵等，螯合剂有丙氨酸、乙二胺四乙酸钠盐、多磷酸钠、偏磷酸钠、磷酸等，清凉剂有：L-薄荷醇、樟脑等，抗炎剂有：尿囊素、甘草亭酸、甘草酸、凝血酸、甘葡环烃(Azulene)等。
氨基酸类有：甘氨酸、缬氨酸、亮氨酸、异亮氨酸、丝氨酸、苏氨酸、苯丙氨酸、精氨酸、赖氨酸、天冬氨酸、谷氨酸、胱氨酸、半胱氨酸、甲硫氨酸、色氨酸等，核酸有脱氧核糖核酸等，激素有雌二醇、乙烯基雌二醇等。
对于产品的形态没有特别限定，可以是液状、乳液状、霜状、固体状、糊状、凝胶状、粉末状、多层状、摩丝状(mousse)、喷雾状等。
本发明的主要优点包括：
(1)本发明首次公开了膜联蛋白A5在生发、育发、护法、防脱发或治疗脱发领域的用途。
(2)本发明公开的膜联蛋白A5可以通过注射或涂抹式外用，施用简便。
(3)本发明公开的膜联蛋白A5够有效提高雄激素脱发模型小鼠毛囊中细胞的增殖能力，促进毛乳头周围的毛细血管数量，并抑制小鼠毛乳头中AR与TGF-β1的表达水平。
(4)本发明公开的膜联蛋白A5能够有效提高雄激素脱发后的毛发再生能力，可以有效的作为生发、育发、护法、防脱发产品和治疗脱发的药物组合物的有效成分。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例1.小鼠雄激素性脱发模型的建立及组织切片制备
实验动物：C57BL/6雄性小鼠，5-7周龄，体重20g左右。将其饲养于12小时光照/12小时黑暗的环境中，自由摄食和饮水。实验设置对照组(CTRL)；模型组(DHT)；A5-Low组(膜联蛋白A5治疗，每三天注射给药一次)；A5-High组(膜联蛋白A5治疗，每天注射给药一次)。每组6只小鼠。
造模及给药：双氢睾酮(DHT)诱导形成雄激素脱发小鼠模型。除对照组以外，其余3组小鼠接受颈部皮下注射DHT溶液(5mg/mL)，每只0.01mL，注射持续共计2周，对照组注射同等量的生理盐水。2周后，对全部小鼠进行剃毛处理，用备皮刀将背毛发剃除。接着使用脱毛膏，进一步去除小鼠剃毛区的残留毛发。脱毛完成后，对照组和模型组每天在脱毛区注射PBS 0.2mL，分10点注射，每个点20μL。A5-Low组每三天接受一次膜联蛋白A5治疗，A5-High组每天接受一次膜联蛋白A5治疗，注射方式为在脱毛区域分10个点进行皮下注射，每个点注射20μL浓度为50μg/mL的膜联蛋白A5。每天观察小鼠背部毛发生长情况并拍照记录,16天后进行取材。
组织取材：药物治疗结束后，通过颈椎脱臼处死小鼠。在小鼠毛发新生区域，使用剃毛器及剪刀将小鼠毛发尽可能剔除，然后取脱毛区域中央处约0.5cm×0.5cm小块皮肤的全层组织，浸泡在4％的多聚甲醛中固定24小时。固定使用的多聚甲醛体积与组织的体积比约为4:1。
组织切片制备：皮肤组织固定完成后，使用不同浓度的乙醇进行组织脱水。脱水后，使用无水乙醇及二甲苯作为透明剂，对组织进行透明处理。透明后，将组织置于石蜡中进行浸蜡处理，完成后将组织放置在包埋机的热槽内融化，使用模具包埋蜡块。采用石蜡切片机切厚度为5μm的切片，并放于切片盒中，60℃烘干箱中放置24小时。
结果：如图1，通过对小鼠毛发生长的观察，可见对照组小鼠在第6天时脱毛区域就出现了部分黑色皮肤，在第11天时小鼠皮肤基本已经全部变黑，而DHT注射小鼠黑色皮肤出现较晚，即小鼠进入毛发生长期较慢。采用膜联蛋白A5治疗后的小鼠，其毛发生长的能力显著提升，相比于模型组，均更早地进入了毛发生长期，即膜联蛋白A5能有效促进小鼠毛发的生长。
实施例2.组织学HE染色分析
取切片进行二甲苯脱蜡及梯度乙醇水化，再进行苏木素与伊红染色。染色后再次进行脱水和透明处理。处理结束后，在组织处滴加中性树脂，盖上盖玻片封片，室温下放置过夜，次日使用光学显微镜观察并拍照记录，对毛囊数量进行统计分析。
结果：如图2，通过组织学HE染色观察，发现维持2周的DHT造模注射以及膜联蛋白A5的治疗均不会对小鼠毛囊毛乳头数量、毛囊大小及真皮厚度造成影响。
实施例3.石蜡切片免疫组化分析
取切片进行二甲苯脱蜡及梯度乙醇水化，阻断内源性过氧化物酶，并准备组织切片的抗原热修复处理，随后使用0.2％的TritonX-100溶液进行打孔处理。处理结束后，切片用组化笔在组织周围画圈(防止抗体流走)，在圈内滴加用10％正常兔血清(或其他血清)均匀覆盖组织，置于37℃烘箱内孵育30分钟进行封闭。轻轻甩掉封闭液，以浓度为1:400比例配制CD31(血管生成标志物)、Ki67(细胞增殖标志物)抗体，分别滴于切片上，4℃孵育过夜。次日，PBS(PH7.4)洗涤切片3次，稍甩干后在圈内滴加二抗覆盖组织，37℃孵育45分钟。随后进行DAB显色反应，显微镜下控制显色时间，阳性为棕黄色，蒸馏水冲洗切片终止显色。显色后用苏木素复染细胞核，清洗、脱水、透明后再组织处滴加中性树脂，室温下处理过夜。次日通过显微镜镜检，图像采集分析。
结果：如图3，免疫组化染色检测Ki67用于评估毛囊中细胞的增殖情况，检测CD31用于评估毛乳头周围的毛细血管数量。连续注射DHT后，相比于对照组的小鼠，雄激素脱发造模的小鼠毛囊中细胞的增殖能力显著下降，且毛乳头周围的毛细血管数量明显减少，但在接受膜联蛋白A5治疗后，毛囊内细胞的增殖存活能力有所提高，毛细血管数量增加,
实施例4.毛囊标本雄激素受体及TGF-β1表达分析
样品处理：小鼠处死后，收集1cm2的皮肤组织，用剪刀尽可能去除表面毛发。分离皮肤上的毛乳头，收集于冰盒中，加入裂解液并进行破碎匀浆及样品裂解。通过高速离心收集上清液，利用BCA法测定蛋白浓度，并根据Western Blot要求制备蛋白样品。
Western Blot检测蛋白表达水平：根据蛋白分子量配制SDS-聚丙烯酰胺分离胶，待胶凝后，加入电泳缓冲液，拔去梳子按照设定好的样品顺序进行上样，利用恒压跑胶使蛋白样品按照分子量大小彻底分开(具体时间根据实际情况调整)。电泳后小心取下胶，制备好转膜夹，放入转膜架中，以200mA，2小时的条件进行转膜(具体可根据蛋白分子量进行调整)，转膜槽外需加冰水混合物，以达到降温的作用，避免温度过高影响转膜效果。转膜结束后取下PVDF膜，置于5％的牛奶中进行封闭，室温摇床上轻摇2小时。随后，裁剪PVDF膜，放入对应的一抗中，4℃条件下孵育过夜。次日，用1×TBST洗膜三次，每次5分钟，再在室温条件孵育二抗2小时，同样洗膜三次，每次5分钟。配置新鲜的显影液，用化学发光仪对膜进行曝光显影，曝光时间需根据不同抗体进行调整，完成后保存胶图。
结果：如图4，将小鼠中的毛乳头进行分离，利用Western Blot实验分析检测雄激素受体(AR)与转化生长因子β1(TGFβ-1)的表达水平。雄激素受体及TGF-β1在正常毛囊中(CTRL组)有所表达，经DHT处理后，小鼠体内的AR及TGF-β1的表达显著升高(DHT组)。而造模后又接受膜联蛋白A5治疗的小鼠(A5-Low/A5-High组)，其体内的AR与TGF-β1表达被明显抑制。
根据上述方案开展实验，获得的实验结果均可有效证实膜联蛋白A5能够有效促进小鼠雄激素脱发后的毛发再生，具体表现为：构建雄激素脱发小鼠模型，并使用膜联蛋白A5进行治疗，实验组小鼠脱毛后的皮肤从粉红色转为黑色出现的时间更早，提示膜联蛋白A5治疗后，有助于小鼠毛发进入生长期，促进毛发生长，并增加毛发覆盖率。通过组织学HE染色观察小鼠毛囊数量，发现造模或是药物治疗均不会影响毛囊毛乳头的数量。采用Ki67免疫组化评估毛囊内细胞增殖的情况，可见在连续注射DHT后，毛囊内细胞的增殖能力显著降低，经膜联蛋白A5治疗后，毛囊内细胞增殖水平发生上调。采用CD31免疫组化染色，评估毛乳头周围毛细血管数量，可见在连续注射DHT后，小鼠毛乳头周围的毛细血管数量明显减少，而膜联蛋白A5治疗后，其毛细血管数量有所增加。分离小鼠中的毛乳头，检测发现膜联蛋白A5治疗后，相比于造模组，其体内的雄激素受体及转化生长因子β1的表达发生下调，从而有助于发毛的生长。因此，膜联蛋白A5可以成为治疗脱发、提高毛发生长质量的有效成分，可以作为治疗脱发的有效方法。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种膜联蛋白A5在制备用于治疗脱发的药物组合物或医疗器械中的用途。
2.如权利要求1所述的用途，其特征在于，所述的脱发选自下组：雄性激素脱发、斑秃、休止期脱发、老年性脱发、心理压力性掉发、物理性脱发、化学性脱发、营养代谢性脱发、感染性脱发、内分泌失调性脱发。
3.如权利要求1所述的用途，其特征在于，所述的药物组合物用于(1)促进毛发生长；(2)脱发后的毛发再生；(3)提高毛囊内细胞增殖能力；(4)增加毛乳头周围毛细血管数量；(5)抑制毛囊中雄激素受体(AR)和转化生长因子β1(TGF-β1)的表达。
4.一种膜联蛋白A5在制备用于治疗生发和/或防脱发产品中的用途。
5.如权利要求4所述的产品，其特征在于，所述的产品用于(a)提高毛发顺滑程度；(b)减轻毛发脱落；(c)增加毛发生长密度；和/或(d)促进毛发生长。
6.如权利要求4所述的产品，其特征在于，所述的产品用于育发和/或护发。
7.一种用于治疗脱发的药物组合物，所述的药物组合物包括：(i)膜联蛋白A5；(ii)用于治疗脱发的其他药物；(iii)药学上可接受的辅料。
8.如权利要求7所述的药物组合物，其特征在于，所述的其他药物选自下组：氢万液、米诺地尔、非那雄胺。
9.如权利要求7所述的药物组合物，其特征在于，所述的药物组合物通过选自下组的方法导入机体组织：注射、喷射、渗透、吸收、物理介导的方法、化学介导的方法、或被其他物质混合或包裹后导入机体组织。
10.如权利要求7所述的药物组合物，其特征在于，所述的药物组合物的剂型选自下组：擦剂、喷剂、洗剂、膏剂和注射剂。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2024/077422 WO2024179309A1 (zh) | 2023-02-27 | 2024-02-18 | 膜联蛋白a5在生发、育发、护发、防脱发以及治疗脱发中的用途和相关产品和药物组合物 |
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| CN202310170435 | 2023-02-27 | ||
| CN202310170435X | 2023-02-27 |
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| CN118001376A true CN118001376A (zh) | 2024-05-10 |
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| WO (1) | WO2024179309A1 (zh) |
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| GB2542391A (en) * | 2015-09-17 | 2017-03-22 | Annexin Pharmaceuticals Ab | Process of manufacture |
| CN109219444A (zh) * | 2016-06-06 | 2019-01-15 | 临床干细胞有限公司 | 用于毛发生长的肽 |
| WO2021147922A1 (zh) * | 2020-01-20 | 2021-07-29 | 医微细胞生物技术(广州)有限公司 | 细胞外囊泡及其在皮肤产品的用途 |
| EP4347027A1 (en) * | 2021-05-26 | 2024-04-10 | Figene, LLC | Methods and compositions for alopecia treatment using fibroblasts and fibroblast-derived products |
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