CN104703583A - 经修饰的透明质酸衍生物及其用途 - Google Patents
经修饰的透明质酸衍生物及其用途 Download PDFInfo
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- CN104703583A CN104703583A CN201380052657.6A CN201380052657A CN104703583A CN 104703583 A CN104703583 A CN 104703583A CN 201380052657 A CN201380052657 A CN 201380052657A CN 104703583 A CN104703583 A CN 104703583A
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Abstract
本发明涉及式I的透明质酸衍生物、它们的合成及其在有需要的受试者中作为化妆品或作为药剂的用途。
Description
技术领域
本发明涉及透明质酸衍生物和它们在医学和化妆品领域中的用途或作为饮食添加物的用途。本发明另外涉及含有这样的衍生物的药物组合物以及得到它们的方法。
背景技术
长久以来，研究人员已经已经做出了大量努力来鉴别新的组织修复医疗装置，以提供克服以前的装置的某些缺点的新工具，或者更加适用于特定组织。近十年来，所述努力甚至已经增加，也因为人们渴望简单地通过改变正常老化进程来改变他们的美学表像的需要日益增加。
公认的是，皮肤是可以被多种天然和非天然因素改变的感觉组织，所述因素诸如紫外线暴露、老化、吸烟、烧伤、痤疮、疾病等…
在健康的受试者中，组织修复或组织再生在伤害所述组织的损伤以后通过愈合过程而发生。在老化过程中，透明质酸和/或胶原在软组织中的产生减少，伴随着加速的降解速率。这样的机制会导致凹陷区(depressed area)诸如纹线、皱纹、纹理和褶皱的形成。
目前可得到的克服软组织缺陷的方法包括外科手术(例如，自体或异种移植)或涉及使用真皮填充剂的更低侵袭性技术的应用。
皮肤是由3个主要层组成的高度机化的结构，每个层具有它自身的功能。被称作表皮的外层主要由角质形成细胞组成，并且担任保护免于外界因素(诸如病原体、由紫外线引起的氧化剂应激、化学试剂的侵害)的作用，同时调节通过经表皮损失从身体释放的水的量。
中层是真皮，且是基本上由3种纤维蛋白蛋白质(即胶原、弹性蛋白和网硬蛋白)以及支持基质组成的致密弹性纤维结缔组织。所述支持基质由糖胺聚糖(即，GAG)组成，所述糖胺聚糖是能够结合大量水的长链多糖。它们一起形成不会泄漏真皮的凝胶。
最后，被称作下皮的内层是纤维脂肪层，其松散地连接至真皮，起隔断层和保护垫的作用。
真皮-表皮连接决定了皮肤的表面。因而，具有锚定结构完整性的真皮-表皮连接会维持折叠，由此增加真皮和表皮之间的接触的表面积，并促进这2种组织之间的可扩散因子的交换，从而强化它们的粘结力和改善皮肤的外观。在改变锚定结构的情况下，特别是由于胶原IV、胶原VII、层粘连蛋白V的合成的缺乏和/或由于老化或疾病，这会造成真皮-表皮连接的扁平化。实际上，已经证实，胶原IV和胶原VII在创伤愈合过程中是非常重要的(Betz P,等人,Int.J.Legal.Med.,1992,105,93)。
组织修复也涵盖了慢性创伤和/或非愈合性创伤。这样的创伤的患病率在年龄相关的疾病中、在受获得性免疫缺陷综合征(AIDS)影响的人中、或在癌症干预以后面临辐射的患者中增加。慢性创伤(诸如静脉腿溃疡)需要长期护理，且花费非常大。此外，这样的创伤经常在愈合的18个月内复发。在过去的40年中，潮湿创伤愈合的概念已经被普遍接受，从而产生了数百种不同的敷料技术，它们的目的在于改善愈合过程的时间和质量。除了传统的纱布以外，大多数目前可得到的敷料属于下述类别之一：泡沫、水胶体、水凝胶、海藻酸盐和膜；前2种代表全球潮湿创伤敷料市场的最大份额。水胶体最常见地由羧甲纤维素、明胶或果胶制成，且可以与海藻酸盐、透明质酸盐或胶原或其混合物相组合。涉及生物材料(诸如胶原、透明质酸、壳聚糖、海藻酸盐或弹性蛋白)的敷料被称作生物敷料。
由于胶原是细胞外基质(ECM)的最丰富蛋白，基于胶原的生物敷料已经被广泛地开发，但是已经逐渐被新生代的敷料替代。
已经证实，基于海藻酸盐的敷料能够促进细胞活性诸如附着和增殖(Thomas S.,J.Wound Care,2000,9,2,56；Thomas S.,J.Wound Care,2000,9,3,115；Thomas S.,J.Wound Care,2000,9,4,163)。
由于假定的成纤维细胞形成的刺激和增加的与愈合有关的早期反应，壳聚糖多糖已经被用于治疗烧伤和创伤(Paul W.,等人,Trends Biomater.Artif.Organs,2004,18,18)。
最后，存在多种含有透明质酸盐的敷料，其中透明质酸已经经过化学修饰，并同时维持它的天然的生物相容性、生物可降解性和免疫原性缺乏。透明质酸是以高浓度存在于皮肤和结缔组织中的内源多糖。在皮肤中，聚合的透明质酸可以结合水，从而形成辅助水合和充盈的粘稠物质。因此，透明质酸随着老化的损失与增加的脱水和皮肤的起皱有关。除了皮肤以外，透明质酸(即，HA)作为细胞内基质的核心组分也天然地存在于身体的不同的其它组织(诸如肌腱、肌肉、软骨和玻璃体液)中，从而使得它非常适合靶向这些组织的生物医学应用。
基于HA的生物材料敷料的例子是这样的，其中HA：
√未经过修饰，如它的钠盐(例如，ialugen,Ibsa)，呈乳膏剂的形式或在含有4g ialugen的纱布垫中，用于局部施用。
√如在专利EP0216453中描述的，经由羧酸部分而完全地或部分地酯化(例如，)，用于药物(例如，外科手术皮肤病学、眼科学、牙医学：Ballini A.,等人,Int.J.Med.Sci.,2009,6,2,65)或化妆品领域中。这些HA-酯可以被挤出以产生膜和纤维，被低压冻干以得到海绵状物，或通过喷雾干燥、提取和蒸发进行加工以产生微球。
√经由羟基部分而酯化(WO2004013182)。
√与其它生物活性成分连接：
o紫杉醇，以防止外科手术后的粘着形成(Jackson J.K.,等人,Pharm.Res.,2002,19,4,411；WO02090390)；
o氨苄西林(GB2207142)；
√与下述物质交联以形成分子网络
oα羟酸的聚合物诸如聚乳酸(WO2006069578)；1,4-丁二醇二缩水甘油基醚；1,3-二胺丙烷；多功能的环氧衍生物(EP0161887)；或可以
o在葡萄糖胺残基的脱乙酰化的氨基部分与葡糖醛酸部分的羧酸基团之间自交联，或在葡糖醛酸部分的羧酸基团与任何单元的羟基基团之间自交联(例如，US5676964B1,其在腹腔-骨盆外科手术以后充当保护和隔开组织的屏障，并由此避免粘着并发症)。
√沉积在膜/纱布上。
有些敷料可以进一步含有补充性的生物活性成分诸如抗生素、抗炎药、镇痛药或生长因子或它们的混合物。这样的产品的非穷尽列表中的代表可以为：它是含有3％双氯芬酸(在2.5％透明质酸中)的局部用凝胶，最近被批准用于治疗光化性角化病；或Regranex，即含有重组人血小板衍生的生长因子-BB的凝胶，目前处于III期临床试验中，用于神经病的糖尿病性溃疡。
WO2007048522公开了一种由透明质酸钠(sodium hyaluronateacid)、甘氨酸和脯氨酸和可能含有的赖氨酸和亮氨酸组成的乳膏组合物，其在快速的创伤愈合过程中可有效地促进细胞再聚合。
WO2010003797公开了具有不同分子量的基于HA的组合物，其用于治疗角膜创伤。它声称，低分子量HA级分(即，51kDa和320kDa)会增进愈合过程，同时高分子量HA级分(即，1500kDa)可能因为过于粘稠而不会促进的创伤愈合。
WO2008015249公开了由高分子量HA和多胺(例如，腐胺(putrecine))的颗粒制成的组合物，优选胶体，其用作填充剂(即，抗-皱纹填充剂或唇填充剂)，用于治疗创伤愈合和用于保护人皮肤免于紫外(UVA)辐射，但是也用于保护人皮肤对抗自由基的有害作用。公开的唯一实验数据关注不同组合物的吸光度结果，因此被指示用作皮肤保护组合物。
还已经将主要由交联的HA制成的水凝胶报道为聚合基质，其可用于培养细胞(例如，形成软骨的细胞、形成骨的细胞、肌细胞、成纤维细胞和器官细胞)和将所述细胞植入特定器官中(US6129761)。
真皮填充剂是本领域众所周知，且通常由基于胶原和/或透明质酸的衍生物制成。在过去，最广泛地使用的填充剂是基于牛或人胶原，且倾向于持续3-6个月。更近的填充剂类别是基于透明质酸(HA)，它们之间在HA的交联模式(即，类型和程度)、粒度和制剂方面存在差异。对这些参数中的每一种已经进行了大量研究和精细调节，以产生有目的地适合不同身体区域的填充剂。
为了克服HA不稳定性和/或容易被透明质酸酶降解，在过去的十年中出现了具有提高的半衰期的交联HA填充剂。普遍接受的是，具有低粘度的基于HA的真皮填充剂(诸如轻度交联的和/或由低分子量组成的那些)在体内的持续时间短于高度交联的和/或由高分子量HA组成的那些真皮填充剂。从高度修饰的HA衍生出的第二类填充剂通常是优选的，因为所述填充剂不需要象低粘度填充剂那样频繁地注射给患者。
已经于2003年12月得到FDA批准的第一类基于HA的交联的真皮填充剂是RestylaneTM，即它在欧洲被批准以后7年。RestylaneTM也被称作非动物的稳定化的透明质酸(NASHA)，是由具有大约100万分子量的透明质酸组成的可注射填充剂，其已经与两臂交联剂(即，1,4-丁二醇二缩水甘油基醚(BDDE))交联以形成HA分子的2个羟基之间的醚交联。RestylaneTM特别适合用于矫正脸下部和眼下面的纹线以及增加唇大小。对进行的最近组织病理学研究已经证实，它会刺激胶原I和III的合成(Wang F.,等人,Arch.Dermatol.,2007,143,155)。
另一类填充剂以由Hylan B凝胶组成的Hylaform家族为代表。该家族由Hylaform Fine系、Hylaform Plus和Hylaform(Inamed Corporation,California,USA)组成，且源自使用二乙烯基砜(DVS)的交联方法，在该方法中，所述交联也通过HA的羟基而发生，从而形成HA分子之间的磺酰基-二乙基-交联。
基于HA的另一个交联的真皮填充剂家族是由不同成员(即，Juvederm 18、Juvederm 24、Juvederm 24HV和Juvederm 30)组成的Juvederm，并且是借助于BDDE(如Restylane)交联的HA产物。但是，Juvederm被宣称为均匀的凝胶形式而不是颗粒形式。它的用途是，适合用于中间至深层真皮中，用于纠正中等至严重的面部皱纹和褶皱，诸如鼻唇沟。
除了或JuvedermTM以外的、由更大的透明质酸凝胶颗粒组成的被推荐用于更深的注射。临床试验证实，的单次注射可以维持效果多达6个月。
在呈现更深陷入的面部纹线和皱痕的患者中，具有小粒度成分的制剂的应用倾向于更柔软和更光滑，并且因此非常适用于诸如唇等区域。更大的颗粒具有更多的结构，并且最适合用于深褶皱诸如鼻唇沟。
已经在老化皮肤中证实，发生胶原VII表达的减少，所述胶原VII负责将基膜锚定至真皮胶原纤维(Chen Y.Q.,等人,J.Invest.Dermatol.,1994,102,205)。最近已经发现，新的C-吡喃木糖苷衍生物会诱导糖胺聚糖和硫酸类肝素蛋白聚糖的皮肤表达(Pineau N.,等人,Eur.J.Dermatol.,2008,18,1,36)。
但是，除了由不同公司宣称的一种真皮填充剂胜过另一种真皮填充剂的所有潜在优点以外，关于所述优点的科学证据仍然存在一些疑点。根据它们的组成对不同的基于HA的真皮填充剂的优点/缺点进行对比的综述凸显了下述事实：并非所有假定的、宣称的不同填充剂的优点都经过科学地和彻底地评估(Alemman I.B.,等人,Clin.Interv.Aging,2008,3,4,629)。
最近已经公开了有包衣的透明质酸颗粒(WO2008147817)。
针注射是以最小副作用将填充剂递送进靶位置的优选方法。
在下面报告了可以将基于HA的衍生物用于制药领域中的用途的非穷举列表。
(一种由自体角质形成细胞制成的表皮自体移植物复合材料，所述角质形成细胞生长在由100％酯化的HA(即，苄酯)制成的可生物降解的基质上)已经在有利于具有慢性糖尿病足的患者的完全溃疡愈合方面表现出有前途的结果(Lobmann R.,等人,J.Diabetes Complications,2003,17,199)。
一种类似的自体移植物复合材料已经表现出对隐性营养不良性大疱性表皮松解患者的慢性皮肤溃疡创伤愈合的有益效果(Wullina U.,等人,J.Dermatol.,2001,28,4,217)。
已经证实，含有HA的凝胶(即，)的高分子量级分可用于治疗牙周病诸如牙龈炎(Jentsch H.,等人,J.Clin.Periodontol.,2003,30,2,159)。
已经证实，(一种由制成的纺织鼻敷料)会增强针对原发性慢性泪囊炎的鼻内内窥镜泪囊鼻腔吻合术的愈合过程(Wu W.,等人,Eye,2011,25,6,746)，并且已经证实低压冻干的HA的乙酯可用于不同的耳病理学和用于实践耳科的、耳神经外科手术的和牙口腔医学的显微外科手术，诸如鼓膜穿孔的修复(US5503848)。
在下面报告了可以将基于HA的衍生物用于化妆品领域中的用途的非穷举列表。
唇增大，蜂窝组织，眼周的皱纹和暗圈，在眉毛和前额水平纹之间的皱纹，嘴角皱纹，由痤疮瘢痕、鼻和下巴形成的不规则，面颊、颞颥中的凹陷区，隆乳。
单独的L-肉碱或与透明质酸一起的L-肉碱在化妆品和医学领域中的应用是已知的。
US4839159公开了L-肉碱用于改善或治愈皮肤病症(包括起皱、干燥的或剥脱的皮肤)和烧伤(特别是晒伤)以及用于治愈和预防瘢痕形成(特别是由病原体感染造成)的用途。
US7854939公开了凝胶化妆品用于治疗皮肤障碍(诸如蜂窝组织和皱纹)的用途，所述凝胶由聚合物诸如羧基乙烯基聚合物(例如，聚羧乙烯)、表面活性剂和丙酰基L-肉碱甘氨酸盐酸盐的复合物制成。
US7763655公开了含有肉碱肌酸(creatinate)的局部用组合物用于抑制皮肤中的蜂窝组织形成的用途。
WO2000029030公开了透明质酸和肉碱或其具有2-20个碳原子的酰基衍生物的复合物用于化妆品(例如，美容洗剂或乳膏剂)和医学应用(例如，腿溃疡、干眼综合征)的用途。该专利申请要求保护含有重量比在1:3至3:1范围内、优选等重量比的2种组分(即，HA和肉碱或其一种酰基衍生物)的优选复合物。
尽管有大量产品可用于在医学和化妆品领域中治疗皮肤障碍，无论是从药物观点还是从化妆品观点仍然认识到的需要是，获得可用于预防或治疗皮肤障碍的新活性成分。
我们现在已经令人惊讶地发现，用肉碱或烷酰基肉碱共价地官能化的透明质酸衍生物具有可用于医学和化妆品领域中和作为饮食添加物的生物学特性。所述衍生物已经被证实会激活身体自身胶原的再生。
发明内容
本发明涉及透明质酸衍生物和它们在医学和化妆品领域中和作为饮食添加物的用途。
本发明提供了包含(m+n)个重复单元的式I的化合物；
其中m和n是>0的整数，且
70<(m+n)<5000且m>n；
符号//是指，2个连续单元可以是未被取代的，或二者被取代或二者中仅一个被取代；
R是H或含有2-20个碳原子的烷酰基部分，其中所述烷酰基部分可以是直链或支链；
X是Cl、Br、Ac、MeSO3或H2PO4；
A是H、Na、K或TBA；或者
当X不存在时，A不存在。
式I的透明质酸衍生物的特征在于作为重复单元总数(即，m+n)和取代度(即，SD)的2个参数。后者尽管可借助于HPLC来计算，但是可以由下式表示。
优选的式I的透明质酸衍生物包含70-5000个重复单元。
更优选的式I的透明质酸衍生物被表征为
200<m+n<2000。
甚至更优选的式I的透明质酸衍生物被表征为
400<m+n<1800。
进一步甚至更优选的式I的透明质酸衍生物被表征为
500<m+n<1700。
此外，上述优选的式I的透明质酸衍生物中的每一种具有被包含在0.01至0.6之间的取代度SD。
甚至更优选的式I的透明质酸衍生物具有被包含在0.01至0.6之间的取代度SD。
术语“单元”或“重复单元”是指被取代的或未被取代的、由D-葡糖醛酸部分和D-N-乙酰基葡糖胺部分构成的二聚体，所述D-N-乙酰基葡糖胺部分是被取代的或未被取代的。
表述“摩尔量”和术语“当量”应当关于由图1表示的透明质酸二聚体单元进行解释。
表述“结合的肉碱的摩尔量”与参数n相关联。
表述“聚二糖二聚体的摩尔量”与参数m相关联。
表述“取代度”和它的首字母简略词“SD”表示下面方程式1的结果
表述“透明质酸”在本文中是透明质烷或它的缩写HA的同义词。HA的所有来源是有用的，包括细菌和禽来源。
表述“基于HA的衍生物”表示，由根据本发明的化学修饰的HA制成的化合物。
本发明的一个实施方案涉及用作化妆品领域中的填充剂的式I的化合物。
具体地，本发明涉及式I的化合物和它们的下述用途：
√注射剂的填充剂，所述注射剂可用于修复、增大、强化需要改造的组织。
√预防和/或治疗蜂窝组织、疤痕或皱纹；增大发育不全的乳房、填充面颊的空洞从而恢复天然外观。
√防止老化。
在本发明的一个优选实施方案中，通过给需要的受试者施用式I的化合物，增量调节至少一种细胞外基质组分。
在本发明的一个更优选实施方案中，所述至少一种细胞外基质被增量调节了5-90％。
在本发明的一个更优选实施方案中，所述至少一种细胞外基质被增量调节了10-70％。
在本发明的一个更优选实施方案中，从施用式I的化合物以后6小时到至少施用后第5天，所述至少一种细胞外基质被增量调节了10-70％。
在本发明的另一个更优选实施方案中，被增量调节的至少一种细胞外基质选自：胶原IV型、VII型、透明质烷合酶1和透明质烷合酶2。
在本发明的另一个更优选实施方案中，被增量调节的至少一种细胞外基质选自胶原IV型或VII型。
本发明的另一个主题是，用于恢复或维持皮肤弹力活性的式I的化合物。
本发明的另一个实施方案涉及用于医学领域中的式I的化合物。
具体地，本发明涉及式I的化合物和它们的下述用途：
√饮食添加物和药剂，其用于预防和/或治疗皮肤和关节的障碍、关节病、克罗恩氏病、溃疡性直肠结肠炎和眼病；
√生物敷料，其可用于治疗急性和/或慢性创伤和/或非天然地愈合的创伤。可以导致这些类型的创伤的因素的非穷举列表是：烧伤；辐照(在放射疗法治疗过程中或暴露于日光)；磨损；切割；撕裂；射击；疾病诸如溃疡(例如，腿和静脉溃疡)，特别是由糖尿病引起的溃疡；干眼综合征；外科手术如剖腹产；
√医疗装置，其用于矫正泌尿学障碍诸如尿失禁、胃液回流；或修复骨、软骨或肌肉损伤；
本发明的另一个主题是，用于支持皮下组织的纤维基质层的式I的化合物。
本发明的另一个主题是，用作食品添加物或用作药剂的式I的化合物，所述药剂用于预防和/或治疗关节障碍、由骨关节炎或纤维肌痛引起的肌肉骨骼不适、滑膜炎、膝关节病、克罗恩氏病、溃疡性直肠结肠炎和眼病诸如干眼综合征。
对于化妆品或药物用途，根据本发明的式I的化合物可以适当地以液体、半液体、乳膏剂、固体、在脂质体中或洗剂的形式口服地或胃肠外地施用。胃肠外施用的非限制性途径是：局部地、真皮内地、关节内地或以本领域众所周知的任意其它胃肠外的合适途径。
作为食品添加物，根据本发明的式I的化合物可以适当地口服施用。
对于眼用，根据本发明的式I的化合物可以适当地口服施用；或以局部施用于眼的滴眼剂、凝胶或软膏剂的形式。
根据本发明，式I的化合物的胃肠外施用途径包括、且不限于，在需要治疗的身体的任何部位的局部和胃肠外施用途径。
根据本发明，可以胃肠外地施用呈化妆品或药物组合物的形式的式I的化合物，其含有剂量为0.1-30％(按重量或体积计)、优选1-20％(按重量或体积计)、最优选2-10％(按重量或体积计)的活性成分，任选地与一种或多种合适的常规助剂或其它活性成分混合。
可以以0.2-200mg/天的剂量，口服地施用呈化妆品、食品添加物或药物组合物形式的根据本发明的式I的化合物，优选的剂量是2-100mg/天，最优选的剂量是约25-50mg/天。
用于口服的式I的化合物可以包有肠溶衣以免于胃酸影响进入小肠中，它将在小肠中被吸收。
本发明的药物组合物可以另外包含下述成分中的一种或多种：
a)药学上可接受的表面活性剂，诸如稳定剂、填充剂、冷冻保护剂(cryo-protectant)、冷冻保护剂(lyo-protectant)、添加剂、媒介物、载体、稀释剂或助剂。所述表面活性剂是技术人员众所周知的，且报道在任意下述手册中：Pharmaceutical Dosage Forms and Drug DeliverySystems(Ansel H.C.,等人,编,Lippincott Williams&Wilkins Publishers,1999年第7版)；Remington:The Science and Practice of Pharmacy(Gennaro A.R.,编,Lippincott,Williams&Wilkins,2000年第20版)；Goodman&Gilman's The Pharmacological Basis of Therapeutics(Hardman J.G.,等人,编,McGraw-Hill Professional,2001年第10版)；和Handbook of Pharmaceutical Excipients(Rowe R.C.,等人,APhAPublications,2003年第4版)，和
b)选自下述的可用于预防或治疗皮肤障碍的至少一种活性成分：
-支持微循环的试剂，包括、但不限于银杏(Gingko biloba)、假叶树属(ruscus)、草木犀属(melilot)、落葵属(red vine)、荚蒾属(viburnum)的提取物；
-用于活化脂解的试剂，包括、但不限于连钱草(Ground ivy)(活血丹属，Glechoma)的提取物、当归根、瓜拉那属木质藤本植物(Paulinia)的提取物、黄嘌呤类碱或其衍生物(Subdued or of the xanthic bases)(例如，咖啡因、可可碱和茶碱)；
-抗炎化合物，包括、但不限于迷迭香酸、甘草酸酯衍生物、α没药醇、环戊并环庚五烯及其衍生物、积雪草苷、sericoside、鲁斯可皂苷元、七叶素、escolin、槲皮素、芦丁、白桦脂酸及其衍生物、儿茶素及其衍生物；
-皮肤增白化合物，包括、但不限于阿魏酸、氢醌、熊果苷、和曲酸；
-抗氧化剂和抗皱纹化合物，包括、但不限于视黄醇和衍生物、生育酚和衍生物、水杨酸酯类及其衍生物；
-改进常见的抗蜂窝组织剂的皮肤穿透和效力的试剂，包括、但不限于单羧酸类，包括乳酸、羟乙酸、扁桃酸及其混合物；
-通过进入表皮的脂质生物合成并且为表皮的屏障形成提供脂质而在皮肤对抗氧化性应激的防御中发挥重要作用的必需脂肪酸(EFA)；优选的必需脂肪酸选自亚油酸、γ-亚麻酸、高-γ-亚麻酸、多聚乙酰神经氨酸(columbinic acid)、二十碳-(正-6,9,13)-三烯酸、花生四烯酸、γ-亚麻酸、二十碳五烯酸、六烯酸及其混合物；或者
-合适的防晒剂，其选自：对氨基苯甲酸(PABA)的衍生物；肉桂酸酯和二苯甲酮衍生物诸如甲氧基-肉桂酸辛酯、2-羟基-4-甲氧基-二苯甲酮；3-羟基犬尿氨酸O-β-DL-葡萄糖苷或其衍生物，其选自：3-羟基犬尿氨酸O-β-D-葡萄糖苷；3-羟基犬尿氨酸O-β-L-葡萄糖苷；3-羟基犬尿氨酸；4-(2-氨基-3-羟基苯基)-4-氧代丁酸O-β-D-葡萄糖苷；4-(2-氨基-3-羟基苯基)-4-氧代丁酸O-β-DL-葡萄糖苷；4-(2-氨基-3-羟基苯基)-4-氧代丁酸O-β-L-葡萄糖苷；3-HKG的谷胱甘肽加成化合物；或其对映异构衍生物；或其混合物；或其盐。
c)任选的至少一种赋形剂或稀释剂，其选自：
-本领域技术人员公知的任何适合比例的增稠剂；示例性的增稠剂是树胶诸如黄原胶、角叉菜胶、明胶、卡拉牙胶、果胶和刺槐豆荚胶；可以保护所述基于水的化妆用组合物；
-防止微生物生长的防腐剂；合适的防腐剂包括对羟基苯甲酸的烷基酯、乙内酰脲衍生物、丙酸盐、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、咪唑烷基脲、脱羟基乙酸钠、苄醇、和各种季铵化合物。如果存在防腐剂，则以本领域技术人员公知的任何合适的比例添加。
-有机硅聚合物，其以本领域技术人员公知的任何合适的比例添加；
-既作为用于促进活性成分分散的载体又作为皮肤软化剂起作用的润肤剂(emollients)，润肤剂可以以本领域技术人员公知的任何合适的比例掺入到本发明的化妆品组合物中；合适的润肤剂可以在一般化学分类下分类为例如酯、脂肪酸和醇、多元醇和烃类；脂肪酸二酯的例子包括：己二酸二丁酯、癸二酸二乙酯、二聚酸二异丙酯(diisopropyl dimerate)、丙二醇肉豆蔻基醚乙酸酯、己二酸二异丙酯、和琥珀酸二辛酯；支链脂肪酸酯的例子包括肉豆蔻酸-2-乙基-己酯、硬脂酸异丙酯和异硬脂醇棕榈酸酯；三元酸酯的例子包括三亚油酸三异丙酯、柠檬酸三月桂酯、三丁酸甘油酯(tributirrine)、和饱和或不饱和的植物油；直链脂肪酸酯的例子包括月桂醇棕榈酸酯、乳酸肉豆蔻酯、油醇芥酸酯(oleyl eurcate)、油酸硬脂基酯、椰子-辛酸酯/癸酸酯、和辛酸鲸蜡酯(cetyl octanoate)；脂肪醇和酸的例子为C10-C20化合物，诸如鲸蜡基、肉豆蔻基、棕榈基和硬脂基的醇和酸；多元醇的例子是直链和支链的烷基多羟基化合物，例如丙二醇和丁二醇、山梨醇、甘油、以及聚合的多元醇例如聚丙二醇和聚乙二醇；烃类的例子为直链的C12-C30烃链，诸如矿物油、石油胶、角鲨烯和异链烷烃；
-水；
-着色剂，
-遮光剂；
-香料。
本发明的局部用皮肤处理组合物可以配制为用于美容护理的所有局部用形式：洗剂、流体乳膏剂、乳膏剂或凝胶。所述组合物可以根据其粘度和使用者的预定用途而被包装在合适的容器中。例如，洗剂或流体乳膏剂可以被包装在瓶子、滚珠涂布器、胶囊、贴剂、推进剂驱动的气雾剂装置、或配备有适合于手指操作的泵的容器中。
当所述组合物是乳膏剂时，可以简单地将其储存在不变形的瓶子中或储存在挤压容器(例如管或有盖的罐)中。
对于每种具体形式，可以使用合适的赋形剂。
这些赋形剂必须具有所有通常需要的性质。例如，可以举例通常使用的丙二醇、甘油、鲸蜡醇、多元醇、被置于或未被置于脂质体中的磷脂、油类(植物油、动物油、矿物油)、防腐剂、湿润剂(dampener)、增稠剂、稳定剂和乳化剂。
根据本发明的表述“化妆上可接受的成分”是适合于其在化妆处理中的用途的产品，例如被包括在由欧洲化妆用具和香水协会(EuropeanCosmetic Toiletry and Perfumery Association，COLIPA)提出并在96/335/EC“Annexto Commission Decision of 8May 1996”中发表的INCI列表中的那些。
可以首先在细胞培养物测定中或在动物模型(通常是小鼠或大鼠)中估计要施用的式I的化合物的治疗有效剂量。
所述动物模型也可以用于确定适当的浓度范围和给药途径。然后可以使用这样的信息来确定在人类中有用的剂量和给药途径。
人受试者的精确有效剂量将取决于疾病或病症状态的严重程度、受试者的一般健康、受试者的年龄、重量和性别、饮食、给药时间和频率、药物组合、反应敏感性和对治疗的耐受性/应答。
这暗示着，本领域的专家可以利用标准的临床前试验和临床试验或者利用关于美容用饮食产品的制剂的一般考虑来确定组分的剂量。
下述举例说明的实施例绝非本发明意图保护的穷尽列表。
附图说明
图1：它显示了与对照相比，用本发明的组合物处理组织以后释放的LDH的量。
图2：它显示了通过qRT-PCR测得的HAS-1在不同的时间点的基因表达。
图3：它显示了通过qRT-PCR测得的HAS-2在不同的时间点的基因表达。
图4：它显示了通过qRT-PCR测得的COL7A1在不同的时间点的基因表达。
图5：它显示了通过qRT-PCR测得的COL4A1在不同的时间点的基因表达。
图6：它显示了通过qRT-PCR测得的SPAM1在不同的时间点的基因表达。
图7：它显示了HA-肉碱在pH 7.4的PBS中的释放。
实施例
实施例1
透明质酸钠向四丁基透明质酸铵(TBA-HA/CA)的转化
步骤A:透明质酸
将300mg透明质酸钠(关于二糖单元，0.75mmol)溶解在300ml去离子水中，并以1ml/min的流速穿过装有Amberlite IR 120树脂(H-Form)的4X 40cm柱进行洗脱。
步骤B:四丁基透明质酸铵
然后将357μl四丁基氢氧化铵(55％的在H2O中的溶液)加入步骤A的收集的含有HA的渗滤液中，以产生具有pH 7的HA和TBA的化学计量混合物。然后用5l去离子的H2O将该溶液穿过3kDa截止膜透析7小时。将该过程重复2次。随后，将溶液合并，并使用Amicon系统(使用10kDa截止值纤维素膜，施加2.5巴氮压)借助于超滤进一步纯化。冷冻干燥如此得到的TBA-HA，以得到期望的加合物，为纺织样白色固体。
图1:TBA-HA的NMR谱。
图2:TBA-HA的IR波谱。
实施例2/1
步骤A:(2-羟基-4-咪唑-1-基-4-氧代-丁基)-三甲基-铵
将273mg羰基二咪唑(1.69mmol)加入500mg L-肉碱盐酸盐(2.53mmol,1.5当量)在5ml无水DMSO中的溶液中。将反应混合物在室温在氮气氛下搅拌3小时，直到反应结束。在真空下浓缩溶液样品，并通过NMR进行分析。
1H NMR(400MHz,DMSO)δ:8.48(m,1H)；7.75(m,1H)；7.11(m,1H)；4.441(m,1H)；3.55(m,2H)；3.13(m,9H)；2.41(m,2H)。
步骤B：
将得自步骤A的含有1.69mmol活化的肉碱的溶液加入搅拌的1.05gTBA-HA(1.69mmol)在60ml无水DMSO中的溶液中。将反应混合物在氮气氛下搅拌5天。然后将该溶液倒入乙醇/乙醚(600ml,50/50)中。过滤得到的沉淀物，并用1/1乙醇/乙醚溶液冲洗。
步骤C：
将得自步骤B的TBA-HA-CA盐溶解在5％NaCl水溶液中，并以5-10KDa截止值进行切向流过滤(TFF)透析，其中先使用5％氯化钠溶液，然后使用纯水。冷冻干燥如此得到的TBA-HA-CA，以得到期望的加合物，为纺织样白色固体。
实施例2/2
将得自实施例2/1的步骤A的、含有1.69mmol活化的肉碱的溶液加入搅拌的640mg HA(1.69mmol)在60ml无水甲酰胺中的溶液中。将反应混合物在氮气氛下搅拌5天。然后将该溶液倒入乙醇/乙醚(1l,50:50)中。过滤得到的沉淀物，并用1/1乙醇/乙醚溶液冲洗，最后在真空下干燥，然后根据在实施例2/1步骤C中描述的操作进行纯化。
实施例2/3
按照在实施例2/2中描述的操作，将HA和活化的肉碱之间的比例从1/1改为1:10，合成实施例2/3的被取代的HA/CA。
实施例2/4
按照在实施例2/3中描述的操作，将HA和活化的肉碱之间的比例从1/1改为1:5，合成实施例2/4的被取代的HA/CA。
实施例2/5
按照在实施例2/3中描述的操作，将HA和活化的肉碱之间的比例从1/1改为2/1，合成实施例2/5的被取代的HA/CA。
实施例2/6
按照在实施例2/3中描述的操作，在步骤B中将HA和得自步骤A的活化的肉碱之间的比例从1/1改为5/1，合成实施例2/6的被取代的HA/CA。
实施例3
步骤A：
(3-氯羰基-2-羟基-丙基)-三甲基-铵
将L-肉碱盐酸盐(10.5mmol)在800μl亚硫酰氯(11mmol)中的溶液在氮气氛下搅拌1.5h。然后，在减压下除去亚硫酰氯，以得到透明的油。该粗产物溶解在MeOH中的样品的MS分析证实，从预期的酰基氯与MeOH的反应形成了(2-羟基-3-甲氧基羰基-丙基)-三甲基-铵。
步骤B：
将1.08g(3-氯羰基-2-羟基-丙基)-三甲基-氯化铵(5mmol)在DMSO(5ml)中的溶液加入HA(379mg，关于二糖单元为1mmol)在40ml甲酰胺中的溶液中。将得到的混合物搅拌1h，然后倒入EtOH中。过滤得到的沉淀物，并用EtOH和Et2O冲洗，并随后在减压下干燥，然后根据在实施例2/1步骤C中描述的操作进行纯化。
实施例4
肉碱取代度确定
借助于HPLC定量分析，进行肉碱取代度确定。
溶剂和试剂
H2O：蒸馏，并穿过Millipore Milli-Q过滤器过滤；
AcCN：HPLC级；
KH2PO4：试剂级；
设备
1ml和100ml的玻璃容量瓶；
准确至0.1mg的天平
超声浴槽
HPLC系统，其配有：
√色谱仪:Waters Alliance 2690型或等功能仪器
√注射器系统，其能够注射10μl
√紫外检测器(Waters 2487型或等功能仪器)；
√数据系统(Waters“Empower 2”或等功能仪器)；
√柱：Spherisorb SCX 5μm(250*4.6mm内径)。
色谱条件
流速：0.7ml/min；
注射体积：10μl；
洗脱模式：等度；
总洗脱时间：25min；
柱温度：30℃；
检测器波长：205nm。
流动相
50mM KH2PO4/CH3CN 40/60(v/v)。将400ml 50mM KH2PO4溶液加入600ml AcCN中。通过加入浓H3PO4，将得到的混合物的pH调至pH 4.2。然后，借助于超声浴槽或通过用纯氦气鼓泡，将所述溶液脱气。
样品溶液制备
将10mg被取代的HA-CA的样品溶解在1ml 0.1N NaOH中。30min后，通过加入1ml 0.1N HCl来中和溶液。
参照溶液制备
将10mg L-肉碱样品溶解在100ml流动相(即，50mMKH2PO4/CH3CN 40/60(v/v))中。使用相同的流动相，将1ml该溶液样品进一步稀释至100倍体积，以便达到0.001mg/ml L-肉碱的浓度。
操作
√用流动相调节色谱柱60min。
√注射10μl空白溶液。将该注射重复2次。
√注射10μl参照溶液。将该注射重复2次。
√注射10μl样品溶液。将该注射重复2次。
计算方法
使用下面的方程式1，定量在NaOH水解后从所述聚合物释放出的肉碱的量：
其中：
SD：取代度
As：样品溶液中的肉碱的峰面积(2次注射的平均值)
Ar：参照溶液中的肉碱的峰面积(2次注射的平均值)
Wr：参照样品的重量(mg)
Ws：样品的重量(mg)
S：参照样品的浓度百分比
表2
| 实施例 | TBA-HA | HA | CA-CDI | CA-Cl | SD |
| 2/1 | 1 | 1 | 0.10 | ||
| 2/2 | 1 | 1 | 0.11 | ||
| 2/3 | 1 | 10 | 0.51 | ||
| 2/4 | 1 | 5 | 0.48 | ||
| 2/5 | 2 | 1 | 0.01 |
| 2/6 | 5 | 1 | 0.13 | ||
| 3 | 1 | 5 | 0.06 |
实施例5
将冷冻干燥的上述实施例的HA-CA悬浮于1l无菌水性磷酸钠缓冲溶液(0.1-30％)中，并搅拌至得到凝胶。
实施例5/1
使用10g得自实施例2/2的HA-CA(SD＝0.11,MW＝900KDa)和0.5％水性磷酸钠缓冲溶液，得到含有1％的HA-CA的凝胶。
实施例5/2
使用20g得自实施例2/4的HA-CA(SD＝0.48,MW＝900KDa)和1％水性磷酸钠缓冲溶液，得到含有2％的HA-CA的凝胶。
实施例6
HA-肉碱在PBS(pH7.4)中的释放
将16.8mg实施例2/2的聚合物溶解在3.4ml PBS中，以便得到终浓度为5mg/ml的溶液。将如此得到的溶液放入37℃水浴中。使用与在实施例4中所述相同的实验方案，通过HPLC监测释放。
在图7中报告的结果指示在生理pH时非常好的稳定性。
实施例7
为了评价本发明的药物组合物的效果，已经在全厚度皮肤模型上进行了体外生物学试验。该模型被公认为人全厚度皮肤等同物。借助于注射器，将本发明的组合物(150μl)注射进表皮和真皮之间的组织的3个不同点(即，每次注射50μl)。用未修饰的HA和仅用盐水溶液重复相同的实验方案，同时，在第4个平行实验运行中，仅用盐水溶液局部地处理组织。
膜完整性确定
通过测量细胞外培养基中的乳酸脱氢酶(LDH)的水平，确定膜完整性。实际上，LDH是一种存在于所有细胞中的稳定的细胞质酶。它在细胞外的存在的证据，必然是决定它的快速释放的细胞损伤的结果(Korzeniewski,C.,等人,J.Immunol.Methods,1983,64,313)。借助于商购可得的比色测量试剂盒(即，Cytotoxicity Detection KIT-LDH,Roche,批号1253300)进行所述确定，所述试剂盒是基于甲臢盐(λ492nm，利用在690nm的参照)的检测。收集培养物上清液，并与在试剂盒中包含的反应混合物一起在室温在暗处温育20min。死细胞或质膜受损伤的细胞的量的增加会导致培养基中的LDH酶活性的增加，所述增加与形成的甲臢的量直接相关。以前已经确定了使用8种LDH浓度的标准曲线：500mU/ml、250、125、75、62、5、31、25、15、62、7和8mU/ml。
如图1所示，任一组的LDH值不是统计上不同的，这意味着，在用本发明的组合物处理以后的良好细胞完整性证实了所述组合物的良好生物相容性。
基因表达水平的变化
为了评估用本发明的组合物注射组织的药理学作用，考虑5种不同的靶标(即，HAS1、HAS/2、COL4A1、COL7A1、SPAM1，它们分别编码透明质酸合酶-1、透明质酸合酶-2、胶原IV型α1、胶原VII型α1、透明质酸酶)，运行实时PCR实验。
HAS1基因
在注射HA-CA后直到第5天，HAS1基因表达没有受到显著影响，同时未修饰的HA的注射会引起在36小时时的强烈过表达，随后在第5天快速减量调节(即，图2)。这样的行为证实，未修饰的HA会在培养基中放松效力至长期，同时证实了HA-CA会促进新HA的合成，因此能够实现更快速的愈合过程。
HAS2基因
HAS2基因表达在6h时被增量调节，此后恢复至正常水平。当使用未修饰的透明质酸替代HA-CA时，观察到类似的趋势(即，图3)。
COL7A1基因
证实了COL7A1基因表达从包含HA-CA注射的实验的第5天高度增加，同时它的水平保持对于未修饰的HA而言是明显稳定的(即，图4)。
COL4A1基因
COL4A1基因表达在6h时间点被增量调节，此后恢复至正常水平(即，36h和5天)。有趣的是观察到(即，图5)，未修饰的透明质酸的注射会引起COL4A1与对照组相比在第5天的减量调节，同时在更早的时间点(即，6h)观察到由HA-CA引起的类似的增量调节。
SPAM1
未修饰的透明质酸的注射会导致SPAM1基因在第5天的强增量调节，同时HA-CA在相同时间点的作用强度低得多，并且甚至小于当使用盐水溶液时(即，图6)。
Claims (13)
1.包含(m+n)个重复单元的式I的透明质酸衍生物，
其中m和n是>0的整数，且
70<(m+n)<5000且m>n；
符号//是指，2个连续单元可以是未被取代的，或二者被取代或二者中仅一个被取代；
R是H或含有2-20个碳原子的烷酰基部分，其中所述烷酰基部分可以是直链或支链，只要它含有3-20个碳原子；
X是Cl、Br、Ac、MeSO3或H2PO4；
A是H、Na、K或TBA；或者
当X不存在时，A不存在。
2.根据权利要求1所述的透明质酸衍生物，其中
200<(m+n)<2000。
3.根据权利要求1所述的透明质酸衍生物，其呈现被包含在0.01至0.60之间的取代度SD。
4.组合物，其包含根据权利要求1-3中的任一项所述的式I的化合物作为活性成分，且任选地包含一种或多种稀释剂或赋形剂。
5.可肠内或胃肠外施用的根据权利要求4所述的组合物。
6.用于口服、局部、真皮内、关节内、注射或眼科应用的根据权利要求4所述的组合物。
7.呈液体、半液体、乳膏剂、固体、在脂质体中或洗剂形式的根据权利要求4所述的组合物。
8.用于口服的具有肠溶衣的根据权利要求5所述的组合物。
9.用作注射剂填充剂的根据权利要求1-3中的任一项所述的式I的透明质酸衍生物。
10.用作化妆品的根据权利要求1-3中的任一项所述的式I的透明质酸衍生物。
11.用作食品添加物的根据权利要求1-3中的任一项所述的式I的透明质酸衍生物。
12.用作药剂的根据权利要求1-3中的任一项所述的式I的透明质酸衍生物。
13.用于下述用途的根据权利要求7所述的透明质酸衍生物：
a)修复需要改造的组织的缺陷或损伤；或者
b)增大和强化软组织；或者
c)增大发育不全的乳房；或者
d)矫正由声带麻痹造成的失声或发声困难；或者
e)治疗胃液回流；或者
f)治疗缺陷性肛门括约肌；或者
g)治疗泌尿学障碍诸如膀胱输尿管回流或尿失禁；或者
h)修复唇缺陷或面颊空洞缺陷；或者
i)预防或治疗蜂窝组织或皱纹；
j)预防或治疗关节障碍、骨关节炎、纤维肌痛、滑膜炎、膝关节病、克罗恩氏病、溃疡性直肠结肠炎和眼病。
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| WO2017116273A1 (en) * | 2015-12-30 | 2017-07-06 | Asafov Alexander Vilenovich | Formulation for treatment of peripheral joints, spinal joints and/or extracellular matrix elements of connective tissue, method of manufacture and uses |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000029030A1 (en) * | 1998-11-13 | 2000-05-25 | Continental Projects Limited | Complexes of hyaluronic acid/carnitines and pharmaceutical and cosmetic compositions |
| CN101277675A (zh) * | 2005-09-30 | 2008-10-01 | 昭和电工株式会社 | 肉碱衍生物、其盐、皮肤外用制剂和化妆品材料 |
| US20110027357A1 (en) * | 2004-02-18 | 2011-02-03 | Isaac Gilinski | Compositions and methods for timed release of water-soluble nutritional supplements |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4716224A (en) | 1984-05-04 | 1987-12-29 | Seikagaku Kogyo Co. Ltd. | Crosslinked hyaluronic acid and its use |
| US4851521A (en) | 1985-07-08 | 1989-07-25 | Fidia, S.P.A. | Esters of hyaluronic acid |
| GB8713662D0 (en) | 1987-06-11 | 1987-07-15 | Skandigen Ab | Hyaluronic acid derivatives |
| US4839159A (en) | 1988-02-08 | 1989-06-13 | Topicarn, Inc. | Topical L-carnitine composition |
| IT1219587B (it) | 1988-05-13 | 1990-05-18 | Fidia Farmaceutici | Polisaccaridi carbossiilici autoreticolati |
| IT1251151B (it) | 1991-08-05 | 1995-05-04 | Fidia Spa | Materiale spugnoso essenzialmente costituito da acido ialuronico,o suoi derivati |
| US6129761A (en) | 1995-06-07 | 2000-10-10 | Reprogenesis, Inc. | Injectable hydrogel compositions |
| CA2445985A1 (en) | 2001-05-04 | 2002-11-14 | University Of Utah Research Foundation | Hyaluronic acid containing bioconjugates: targeted delivery of anti-cancer drugs to cancer cells |
| ITMI20021666A1 (it) | 2002-07-26 | 2004-01-26 | Jasper Ltd Liability Co | Derivati dell'acido ialuronico |
| US20060134147A1 (en) | 2004-12-21 | 2006-06-22 | Avon Products, Inc. | Cosmetic compositions having carnitine creatinate and methods for using |
| EP1833882A1 (en) | 2004-12-30 | 2007-09-19 | Novozymes Biopolymer A/S | Hyaluronic acid linked with a polymer of an alpha hydroxy acid |
| ITMI20052035A1 (it) | 2005-10-26 | 2007-04-27 | Professional Dietetics Srl | Composizioni farmaceutiche cicatrizzanti sotto forma di crema a base di amminoacidi e sodio ialuronato |
| EP1884231A1 (en) | 2006-08-01 | 2008-02-06 | Auriga International S.A. | Cosmetic or pharmaceutical composition containing hyaluronic acid |
| CN101677912B (zh) | 2007-05-11 | 2013-06-12 | 希格马托制药工业公司 | 可用于递送化妆品活性成分的凝胶 |
| EP2162158A2 (en) | 2007-05-23 | 2010-03-17 | Allergan, Inc. | Coated hyaluronic acid particles |
| WO2010003797A1 (en) | 2008-07-09 | 2010-01-14 | Novozymes Biopharma Dk A/S | Hyaluronic acid for corneal wound healing |
-
2013
- 2013-10-07 AR ARP130103624A patent/AR092922A1/es unknown
- 2013-10-07 JP JP2015535043A patent/JP2015533190A/ja active Pending
- 2013-10-07 TW TW102136212A patent/TW201414478A/zh unknown
- 2013-10-07 CA CA2886144A patent/CA2886144A1/en not_active Abandoned
- 2013-10-07 WO PCT/EP2013/070814 patent/WO2014056841A1/en active Application Filing
- 2013-10-07 SG SG11201501992XA patent/SG11201501992XA/en unknown
- 2013-10-07 AU AU2013328842A patent/AU2013328842A1/en not_active Abandoned
- 2013-10-07 CN CN201380052657.6A patent/CN104703583A/zh active Pending
- 2013-10-07 EA EA201590708A patent/EA201590708A1/ru unknown
- 2013-10-07 US US14/433,539 patent/US20150252120A1/en not_active Abandoned
- 2013-10-07 MX MX2015004386A patent/MX2015004386A/es unknown
- 2013-10-07 EP EP13773263.2A patent/EP2906193B1/en active Active
- 2013-10-07 BR BR112015007823A patent/BR112015007823A2/pt not_active IP Right Cessation
- 2013-10-07 PE PE2015000465A patent/PE20150713A1/es not_active Application Discontinuation
- 2013-10-07 KR KR1020157011845A patent/KR20150065861A/ko not_active Application Discontinuation
- 2013-10-07 IN IN2358DEN2015 patent/IN2015DN02358A/en unknown
-
2015
- 2015-03-17 PH PH12015500585A patent/PH12015500585A1/en unknown
- 2015-03-31 CL CL2015000803A patent/CL2015000803A1/es unknown
- 2015-04-01 IL IL238103A patent/IL238103A0/en unknown
- 2015-05-08 ZA ZA2015/03171A patent/ZA201503171B/en unknown
- 2015-11-27 HK HK15111712.7A patent/HK1210941A1/zh unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000029030A1 (en) * | 1998-11-13 | 2000-05-25 | Continental Projects Limited | Complexes of hyaluronic acid/carnitines and pharmaceutical and cosmetic compositions |
| US20110027357A1 (en) * | 2004-02-18 | 2011-02-03 | Isaac Gilinski | Compositions and methods for timed release of water-soluble nutritional supplements |
| CN101277675A (zh) * | 2005-09-30 | 2008-10-01 | 昭和电工株式会社 | 肉碱衍生物、其盐、皮肤外用制剂和化妆品材料 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112154158A (zh) * | 2018-03-22 | 2020-12-29 | 持田制药株式会社 | 连接有非甾体抗炎化合物的海藻酸衍生物 |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2015533190A (ja) | 2015-11-19 |
| IN2015DN02358A (zh) | 2015-09-04 |
| AR092922A1 (es) | 2015-05-06 |
| EA201590708A1 (ru) | 2015-07-30 |
| EP2906193B1 (en) | 2016-09-28 |
| EP2906193A1 (en) | 2015-08-19 |
| IL238103A0 (en) | 2015-05-31 |
| PH12015500585A1 (en) | 2015-05-04 |
| US20150252120A1 (en) | 2015-09-10 |
| WO2014056841A1 (en) | 2014-04-17 |
| BR112015007823A2 (pt) | 2017-07-04 |
| MX2015004386A (es) | 2015-06-10 |
| CA2886144A1 (en) | 2014-04-17 |
| CL2015000803A1 (es) | 2015-08-07 |
| PE20150713A1 (es) | 2015-05-16 |
| KR20150065861A (ko) | 2015-06-15 |
| AU2013328842A1 (en) | 2015-04-09 |
| ZA201503171B (en) | 2016-11-30 |
| SG11201501992XA (en) | 2015-04-29 |
| HK1210941A1 (zh) | 2016-05-13 |
| TW201414478A (zh) | 2014-04-16 |
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