CN103096870A - 调节毛发生长的方法和组合物 - Google Patents
调节毛发生长的方法和组合物 Download PDFInfo
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- CN103096870A CN103096870A CN2011800295159A CN201180029515A CN103096870A CN 103096870 A CN103096870 A CN 103096870A CN 2011800295159 A CN2011800295159 A CN 2011800295159A CN 201180029515 A CN201180029515 A CN 201180029515A CN 103096870 A CN103096870 A CN 103096870A
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- alopecia
- oligosaccharide
- hair
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Abstract
在此说明了涉及促进毛发生长的方法和组合物。
Description
发明背景
肝素相关化合物被广泛用作抗凝剂和抗血栓剂。据报道它们还抑制毛发生长。参见Wang(王)和Po(朴)(2006)Enoxaparin-induced alopecia in patients with cerebral venous thrombosis(在患有脑静脉血栓形成的 患者中的依诺肝素诱导的脱发).J Clin Pharm Ther(临床药理学与治疗学杂 志)31(5):513-7;Tsele,(2003),Diffuse alopecia in a hemodialysis patient caused by a low-molecular-weight heparin,tinzaparin(在由低分子量肝素,亭 扎肝素引起的血液透析患者中的弥漫性脱发).Am J Kidney Dis_(美国肾脏病杂志)41:E15;Paus(鲍尔斯)(1991)Hairgrowth inhibition by heparin in mice: a model system for studying the modulation of epithelial cell growth by glycosaminoglycans(在小鼠中通过肝素的毛发生长抑制:用于研究通过葡糖 胺多糖的上皮细胞生长调制的模型系统)?Br J Dermatol(英国皮肤病杂志)124:415-22。
发明概述
本发明至少部分地基于以下发现,即低分子量肝素(例如,一种在此说明的LMWH(低分子量肝素),例如,一种具有降低的抗凝血活力的LMwH)能促进毛发生长。因此,本发明的特点尤其是增加毛发生长的方法,以及相关的药物制剂、兽医和/美容制剂。
如在此所使用的,“毛发”是指头皮、头部、面部和/或身体的毛发,包括但不限于头皮上的毛发、睫毛、眉毛、八字须以及胡须。
如在此所使用的,“诱导毛发生长”是指一个新毛发周期的早期诱导生长(与对照相比)、和/或延长该毛发周期的活性生长期、和/或增加毛发的生长速率、和/或增加毛干的宽度,包括但不限于诱导毛发生长并更能让肉眼可见。
如在此所使用的,将两种或多种药剂“联合使用”是指这些单个药剂被同时给药或在一个时间间隔内给药,这样使得这些药剂对受试者的生理效应重叠。配制品这两种或多种药剂可以在或可以不在同一配制品或制剂中给药。
附图简要说明
图1显示了用带有盐水、法安明、MONC402或MONC202的渗透泵处理16天后的剃毛后小鼠的照片。
详细说明
毛发损失
脱发是指人类头部或身体的毛发损失或变稀薄,或者动物绒毛或羽毛的损失。遗传、激素效应、某些疾病、以及某些药物和治疗都能导致脱发。脱发随年龄的增长更加常见,但毛发损失可以在更年轻时开始。
化学治疗诱导的脱发是临床肿瘤学领域的一个难题。某些化学治疗剂例如抗代谢药(甲氨蝶呤、5-氟尿嘧啶、阿糖胞苷)、烷化剂(环磷酰胺、氮芥、达卡巴嗪、异环磷酰胺)、抗肿瘤抗生素(博来霉素、放线菌素D、道诺霉素、多柔比星、米托蒽醌)、长春花生物碱(长春新碱、长春碱)和紫杉烷类(紫杉醇、泰素帝),产生生长期脱发以诱导脱发,这很可能是通过杀死毛发基质的活性增殖细胞实现的。头皮毛发是特别敏感的。
低分子量肝素
在此说明的LMWH能在多种方法中用于诱导毛发生长。
在一些实施方案中,LMWH可具有以下特点:(a)降低的抗凝剂活性,例如抗-Xa活性和抗-IIa活性各自小于50IU/mg、20IU/mg、10IU/mg、5IU/mg或更小(例如,在0.5IU/mg-10IU/mg之间、0.5IU/mg-5IU/mg之间、1IU/mg-10IU/mg之间、1IU/mg-5IU/mg之间;(b)乙二醇裂解的糖醛酸残基(例如,小于50%、40%、30%、20%的乙二醇分裂的糖醛酸残基);(c)重均分子量在3,500Da与8,000Da之间,例如4,000Da与8,000Da之间。
在一些实施方案中,该LMWH可额外地具有以下特征中的一个或多个(例如2个、3个、4个、5个、6个、7个、8个、或9个、10个、11个)。
(d)大于40%U2SHNS,6S二糖残基;
(e)脱硫度小于40%;
(f)一条或多条多糖链,这些链具有一个4,5-未饱和的非还原端糖醛酸残基;
(g)一条或多条多糖链,这些链在该还原端具有一个2,5-脱水甘露醇残基;
(h)每条多糖链大于过3个乙二醇裂解的糖醛酸残基(UG);
(i)10%至50%(例如,10%至40%、10%至30%、15%至30%或15%至25%)的寡糖,这些寡糖具有<3000Da的分子量;
(j)40%-65%(例如,40%-60%、45%-65%、50%-65%或55%-65%)的寡糖,这些寡糖具有在3000Da至8000Da之间的分子量;
(k)5%-30%(例如,10%-30%、15%-30%、10%-25%或15%-25%)的寡糖,这些寡糖具有>8000Da的分子量;
(1)多分散性为约1.2至1.7(例如,约1.3至1.7、1.4至1.6、或1.3至1.6);
(m)基本上由多糖构成,这些多糖包括式I:[Uw-Hx,y,z]m~[UG-Hx,y,z]n其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m和n是整数,这样使得m=4-16,并且n=1-4;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
并且其中符号~表示m和n标记的单元是沿着该多糖链分布的,并且并非必须按照顺序,其中w、x、y、以及z在每个m标记的单元上各自是相同或不同的,并且其中x、y、以及z在每个n标记的单元上各自是相同的或不同的;
(n)基本上由多糖构成,这些多糖包括式II:[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m至r是整数,这样使得:m=0-10;n=0-3;o=0-10;p=0-3;q=0-10;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
在以上例子中,当[Uw-Hx,y,z]每次出现时,w、x、y、和z中每一个可以相同或不同的,并且当[UG-Hx,y,z]每次出现时,x、y、和z中每一个可以相同或不同的。U每次出现时能独立地是艾杜糖醛酸(I)或一种葡萄糖醛酸(G)。在一些实施方案中,n+p之和小于或等于4(例如,小于或等于3、2、1、或0)。在一些实施方案中,n与p之和是4、3、2或1。在一些实施方案中,m、o和q之和在4与18之间,例如4-8、4-9、4-10、4-11、4-12、4-13、4-14、4-15、4-16或4-17。
在一个实施方案中,在该LMWH制剂中的这些多糖链中至少有一个在该非还原端具有以下结构之一:
其中X是H或Me,并且R是H或SO3。例如,在该制剂或药物组合物中的大约10%、20%、30%、40%、50%、60%、70%、80%、90%、或基本上所有的非还原端具有该结构。
在一个实施方案中,在该制剂或药物组合物中的这些多糖链中至少有一个在该还原端包括一个2,5-脱水甘露醇残基。例如,在该制剂或药物组合物中的大约10%、20%、30%、40%、50%、60%、70%、80%、90%、或基本上所有的多糖链在该还原端包括一个2,5-脱水甘露醇残基。
抗IIa活性使用针对平行线测定的统计方法以每毫克的抗IIa活性的国际单位来计算抗IIa活性。使用以下原理来测量在此说明的抗IIa活性水平。
多糖(PS)+ATIII→[PS·ATIII]
IIa
PS·ATIII→[PS·ATIII·IIa]+IIa(过量)
IIa(过量)+底物→肽+pNA(通过分光光度计测量)
抗因子IIa的活性通过样品在抑制凝血酶时对抗凝血酶(ATIII)的增强效果来测定。凝血酶过量可以间接地通过分光光度计进行测量。可以例如在Diagnostica Stago分析仪上或在ACL Futura3 Coagulation系统上使用来自Chromogenix的试剂(S-2238底物,凝血酶(53nkat/管),以及抗凝血酶)、或在任何等效的系统上测量抗因子IIa活性。使用针对低分子量肝素的第二国际标准来校正分析仪的应答。
抗Xa活性使用针对平行线测定的统计方法以每毫克抗因子Xa活性的国际单位来计算一种制剂的抗Xa活性。使用以下原理来测量在此所说明的制剂的抗因子Xa活性。
PS+ATIII→[PS·ATIII]
FXa
PS·ATIII→[PS·ATIII·FXa]+FXa(过量)
FXa(过量)+底物→肽+pNA(通过分光光度计测量)
抗因子Xa的活性通过样品在抑制已活化的因子Xa(FXa)时对抗凝血酶(ATIII)的增强效果来测定。因子Xa过量可以间接地通过分光光度计进行测量。可以例如在Diagnostica Stago分析仪上用肝素检测试剂盒、在ACL Futura3 Coagulation系统上用来自Chromogenix的肝素试剂盒、或在任何等效的系统上测量抗因子Xa活性。可以使用针对低分子量肝素的NIBSC国际标准来校正分析仪的应答。
分子量和链长度当确定一种制剂的重均分子量时,大约3500Da至8000Da、大约3500Da至6300Da、优选地大约4000Da至6000Da、大约4200Da至5900、或大约4300Da至5800Da的重均分子量,表明在该多糖制剂中显著数目的链是具有足够的链长度的。如在此所使用的,“重均分子量”是指糖醛酸/己糖胺二糖重复体的链的以道尔顿计的重量平均值。非糖醛酸和/或非己糖胺结构单元的存在不包括在测定该重均分子量之中。因此,在该制剂中的一条链或多条链中非糖醛酸以及非己糖胺结构单元的分子量不应该包括在测定该重均分子量之中。从以下等式来计算重均分子量(Mw):Mw=∑(cimi)/∑ci。变量ci是在片层i中聚合物的浓度,而mi是在片层i中聚合物的分子量。对一个色谱峰求和,该总和包含多个片层的数据。一个片层的数据可以在色谱峰对比时间的图上被绘成一条垂直线。因此,该洗脱峰可以被分成多个片层。重均分子量计算是依赖于所有片层的浓度和分子量的总和的平均值。例如使用Wyatt Astra软件或任何合适的软件可以测量重均分子量。通过具有两个串联柱子(例如,一个TSK G3000SWXL以及一个G2000SWXL)的高效液相色谱法,与串联着的一个多角度光散射(MALS)检测器以及一个折射率检测器相偶联来测定在此说明的重均分子量。所使用的洗脱液是0.2M硫酸钠,pH 5.0,并且流速是0.5mL/min。
可以例如通过确定在该制剂中这些链的平均链长度和/或通过测定在该制剂内多条链的重均分子量来确定一种多糖制剂是否包括多条足够链长度的链。当确定平均链长度时,大约5至22个(例如,大约7至18个,典型地大约7至14个、或8至13个)二糖重复体的平均链长度表明在该制剂中显著数目的链是具有足够的链长度的。
“平均链长度”是指在一条链中发生的糖醛酸/己糖胺二糖重复物的平均链长度。非糖醛酸和/或非己糖胺结构单元(例如,附连的PEG部分)的存在不包括在测定该平均链长度之中。通过将数均分子量(Mn)除以对于一种二糖(500Da)而言的数均分子量测定了平均链长度。
乙二醇裂解的糖醛酸在此说明的一种多糖制剂可以包括一个开口的糖苷环,常规地被称为还原-氧化作用(RO)衍生物。在这些制剂中,具有邻二醇(vicinyl diol)的一个或多个糖苷环例如在C2-C3之间的键通过一个氧化作用、随后通过一个还原作用而被打开。这些化合物在此也被称为“乙二醇裂解”的衍生物。在此所说明的本发明的另一个实施方案中,这些乙二醇裂解的残基使它们自己进行随后的官能化作用。因此,这些化合物还可以带有相等或不同的基团,以代替衍生自乙二醇裂解的伯羟基基团,例如醛基团、甲氧基基团、或寡聚糖或肽基团,其范围是从一个单一的糖或氨基酸到超过一个单元的长度,例如2个或3个单元。
在一些实施方案中,小于50%的糖醛酸残基是乙二醇裂解的糖醛酸残基(例如,小于40%、30%、25%、或20%的糖醛酸残基是乙二醇裂解的糖醛酸残基)。
还原端结构在一些例子中,在此所说明的一种多糖试剂中至少有大约50%的链具有一个经修饰的还原端结构,例如一个2,5-脱水甘露糖残基或已被还原生成醇的一个2,5-脱水甘露糖。在一些实施方案中,在该制剂中至少约55%、60%、65%、70%、75%、80%、85%、90%、或95%的链具有一个经修饰的还原端结构,这样使得该还原端包括一个2,5-脱水甘露糖残基或已被还原生成醇的一个2,5-脱水甘露糖。
多分散性在此提供的多糖制剂的多分散性是约2或更小,例如1.7或更小,例如约1.7或1.6至1.2、约1.4-1.5、以及这之间的数值。术语“多分散的”或“多分散性”是指一种组合物的重均分子量(Mw)除以数均分子量(Mn)。从以下等式来计算数均分子量(Mn):Mn=∑ci/(∑ci/mi)。变量ci是在片层i中多糖的浓度,而Mi是在片层i中多糖的分子量。对一个色谱峰求和,该总和包含多个片层的数据。一个片层的数据可以在色谱峰对比时间的图上被绘成一条垂直线。因此,该洗脱峰可以被分成多个片层。数均分子量是依赖于在每个片层数据的分子量和浓度的一种计算。以上说明了测定重均分子量的方法,并且还将这些方法用于测定多分散性。
制作在此说明的LMWH的方法
一种方法包括提供一种前体肝素制剂(例如UFH)并且处理该前体肝素制剂(例如,通过酶促或化学解聚作用,例如通过亚硝酸解聚作用)来获得一种多糖制剂,该制剂具有大约3000Da至7000Da的重均分子量或大约7至18个二糖的平均链长度。
可以通过一种方法来处理该前体肝素制剂,该方法包括解聚作用(例如,通过亚硝酸处理、水解、或酶促解聚作用),之后任选地进行一个乙二醇裂解的反应。亚硝酸解聚作用可以通过以下方式实现,例如通过用亚硝酸(例如,约0.02至0.04M亚硝酸)在约2至4的pH下、在约10℃至30℃的温度下处理该前体肝素制剂(例如,UFH)一个特定的时间段(例如约1至5小时)。该乙二醇裂解反应涉及使用高碘酸盐(例如,约0.05M至0.2M的高碘酸钠)在约0℃至10℃的温度下将高碘酸盐氧化反应进行10至20小时。在一些实施方案中,残留的杂质例如盐类或二甘醇(DEG)可以依次通过一种色谱方法,例如凝胶过滤色谱法来去除。可任选地,这一氧化的制剂接着通过用一种还原剂(例如,大约0.5至2.0%(w/v)硼氢化钠)在大约6.0至7.0的pH下、并且在大约0℃至10℃的温度下处理大约0.5至3小时而被还原。
可以使用酶促消化、化学消化或其组合来处理一种前体肝素制剂。化学消化的实例包括氧化解聚作用(例如,使用H2O2或Cu+以及H2O2)、脱氨基切割(例如使用硝酸异戊酯或亚硝酸)、β-消除性切割(例如用苄基酯)、和/或通过碱性处理。酶促消化可以包括使用一种或多种降解肝素的酶类。例如,这种或这些降解肝素的酶可以是例如一种或多种肝素酶,肝素裂解酶,硫酸肝素甘油氨基聚糖(HSGAG)裂解酶(一种裂解酶,被描述为甘油氨基聚糖(GAG)裂解酶,它也可以降解肝素)。优选地,该酶在未硫酸化的糖醛酸的一个或多个糖苷键上进行切割。
配制与给药
在此说明的LMWH可以被配制成药物或美容组合物用于促进身体显示毛发稀薄或毛发缺失(脱发)区域上的毛发生长。此类组合物典型地包括适宜的药学或美容学可接受的载体(例如缓冲剂、辅助剂、润滑剂、溶剂、缓和剂),以及可任选地其他药物或美容剂,使用熟知的配制方案制得。可以使用一种适宜的运载体,例如可注射的溶液、口服剂型、局部剂型完成这些组合物的给药。给药可以是例如经静脉内、皮下、口服或局部。在该组合物中所使用的LMWH配制品的精确量值将基于该配制品的特性以及给药方案来确定。剂量可以是25mg-1g/天,但是该剂型将取决于给药途径。例如,对于肠胃外剂量,0.5-5mg/kg(例如1-2mg/kg)可以是适宜的,而若是局部给药,该剂型可以是约0.1-10mg/mL(例如,约1mg/mL)。给药将典型地是长期的,即在一段时间内多次给药,例如,每天一次或两次持续至少4、7、10、15、21、30、45、60、90天或更长;或者例如每隔一天至少4、7、10、15、21、30、45、60、90天或更长。在此说明的LMWH组合物可诱导希望或需要毛发生长的身体区域的毛发生长。
对于肠胃外给药(例如,静脉内或皮下给药),该LMWH可以被整合入一种溶液或悬浮液中,该溶液或悬浮液还可含有一种或多种辅助剂,例如无菌稀释液如注射用水、盐水、抗菌剂、抗氧化剂、螯合剂、缓冲剂以及用于调节张力的试剂。该肠胃外制剂可以在小瓶、安瓶、注射器中提供或提供成输液。肝素以及基于肝素的药剂的肠胃外制剂的制作在本领域内是常规的。
制作基于肝素的组合物的口服配制品的方法在本领域内是已知的。例如,Baughman(鲍曼)等人(Oral Delivery of Anticoagulant Doses of Heparin:A randomized,double blind,controlled study in humans(抗凝剂量的肝 素的口界递送:一种人类中的随机化的、双盲的、对照研究)(1998)Circulation(循环)98:1610-1615)描述了肝素与递送剂N-[8(-2-羟基苯甲酰基)氨基]辛酸钠(SNAC)联合口服给药。Kim(金姆)等人(A newly developed oral heparin derivative for deep vein thrombosis:Non-human primate study(用于深部静脉血栓形成的新开发的口服肝素衍生物:非人类灵长目动物研究)(2007)J Controlled Release(控释杂志)123:155-163)描述了一种处于固体剂型的活性口服活性肝素Db-LHD。US 2010-0081708说明了可供口服的多种LMWH。因此,在此说明的LMWH可以使用常规方法提供为一种口服配制品。
对于口服给药,在此说明的LMWH可以提供成片剂、胶囊、水性溶剂、明胶或悬浮液。这样,活性成分可以与药学或美容学可接受的赋形剂相混合,这些辅料例如惰性稀释剂、粘合剂、润滑剂、甜味剂、色素、增味剂、着色剂以及防腐剂。惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙以及乳糖。润滑剂包括油类、硬脂酸镁、硬脂酸或滑石。片剂或胶囊可以用一种材料包被,以延迟胃肠道内的吸收,例如单硬脂酸甘油酯(lycerylmonostearate)或二硬脂酸甘油酯。缓慢释放配制品,例如脂质体、微球、聚乙二醇化LMWH也包括在内。此类口服形式通常包括约1%、2%、3%、4%、5%、10%、15%、20%、30%、40%、50%或更多的LMWH化合物。用于口服给药的典型剂量方案可以是25-100mg/天,但可达到1g或更多。在一个实施方案中,在此说明的LMWH组合物通过一种胶囊、片剂或水性溶液作为饮食补充剂给药,例如每日一次、每日两次、每周一次、每两周、每半周、或每月服用。
基于肝素的化合物的局部配制品的制作在本领域内也是常规的。例如,局部肝素凝胶(或)在欧洲广泛使用,用于预防和治疗与外周血管紊乱有关的局部症状。美国专利5888984和美国专利5668119说明了肝素和其他葡糖胺多糖的局部制剂。Vecchio(韦奇奥)与Frisinghelli(弗里星盖利)(Topically applied heparins for the treatment of vasculardisorders:a comprehensive review(局部施用肝素用于治疗血管疾病:综述).Clin Drug Investig(临床药物调查)(2008)28:603-14)以及Cesarone(塞萨尔容)等人(Topical Heparin:New Observations(局部肝素:新观察)(2007)Angiology(血管学)58:16S-20S)描述了肝素凝胶以及其他基于肝素的局部产品。Song(宋)和Kim(金姆)(Topical delivery of low-molecular-weight heparin with surface-charged flexible liposomes(低分子量肝素与表面带电荷的 柔性脂质体的局部递送)(2006)Biomaterials(生物材料)27:271-280)说明LMWH的局部制剂。因此,在此说明的一种LMWH可以使用常规方法提供为一种局部配制品,即可以根据常规药学或美容学操作,采用常规用于局部施用的药学或美容学赋形剂进行配制的一种制剂。在任何具体组合物的配制过程中所采用的运载体的特性将取决于旨在用于对该组合物进行给药的方法。
在此说明的一种局部制剂可被配制成多种产品形式,例如涂剂、霜剂、精华素、喷雾、气雾剂、乳液、粉饼、油膏、精油、凝胶、摩丝、遮瑕膏、贴剂、眉笔、化妆棉、面膜、唇膏、泡沫、化妆水、或精华露、以及类似物。这些制剂可包括以下各项中的一种或多种:一种溶剂、一种乳化剂、一种缓和剂、一种滑动助剂(例如,一种硅酮)、一种保湿剂、一种香料、一种色素或着色剂、一种防腐剂、一种表面活性剂、一种增稠剂、一种隔离剂、一种蜡、一种油、一种胶凝剂、一种珠光剂、一种pH调节剂。在此说明的局部组合物还可以处于以下形式:香波、护发素产品、免洗发膜、毛发摩丝、发胶、喷发定型剂,可任选地与一种染料和/或其他发毛护理产品合用,用于清洁、定型、处理、护发或染色这些毛发,同时局部使用在此说明的LMWH。可接受的运载体包括水(例如,去离子水);油类例如植物油类或矿物油类;酯类例如棕榈酸辛酯、肉豆蔻酸异丙酯以及棕榈酸异丙酯;醚类例如二癸醚以及异山梨醇二甲基醚;醇类例如乙醇和异丙醇;脂肪醇类例如鲸蜡醇、鲸蜡硬脂醇、硬脂醇以及二苯醇;异链烷烃例如异辛烷、异十二烷以及正十六烷(is hexadecane);硅酮油例如环聚二甲基硅氧烷、二甲基硅油、二甲基硅油交联聚合物、聚硅氧烷以及它们的衍生物,优选有机修饰的衍生物;聚乙二醇类;烃油类例如矿物油、石油、异二十烷以及聚异丁烯;多元醇例如丙二醇、甘油、丁二醇、戊二醇以及乙二醇;蜡类例如蜂蜡和植物蜡类;或以上各项的任意组合或混合物。
在此说明的局部LMWH制剂可以包括在0.01%-50%w/w的LMWH。例如,一种局部制剂可包括在0.5%-30%w/w之间的LMWH、在1%-20%重w/w之间的LMWH、在1%-10%w/w之间的LMWH。然后将局部配制品适用至所希望的身体区域(例如,头皮或眉毛区域)例如每天1至4次。可替代地,这些配制品可频率更低地被施用至所希望的区域,即每周1至5次。在一个实施方案中,该LMWH制剂被局部施用至所希望的身体区域,至少每日一次持续至少三周、四周、十二周或更长,例如不确定。
组合
在此说明LMWH还可以与其他活性化合物联合使用,例如其他促进毛发生长的药剂,例如非那雄胺(保法止)、米诺地尔(落健);维生素类(例如维生素A、维生素B3、维生素B5、以及维生素B12、维生素C、维生素K、维生素E以及它们的混合物);羟基酸类(例如乙醇酸、乳酸、苹果酸、水杨酸、柠檬酸、以及酒石酸);化学性或物理性防晒霜(例如阿伏苯宗(avobenzene)、桂皮酸盐、水杨酸盐、氧苯酮、二氧化钛、氧化锌);抗氧化剂类(例如,硫氢基化合物以及它们的衍生物,例如焦亚硫酸钠以及N-乙酰半胱氨酸、硫辛酸以及二氢硫辛酸、白藜芦醇、乳铁蛋白、以及抗坏血酸以及抗坏血酸衍生物、丁羟甲苯);维甲酸类例如维甲醇以及维生素A棕榈酸酯;生育酚以及它们的醚类;孕酮类以及具有孕酮样活性的自然衍生的成分;染黑剂(例如褪黑素或合成的褪黑素衍生物,或褪黑素样分子、香兰素聚合物、自然提取物或色素例如来自姜花属或熊果属植物的棕色色素或来自含有胡萝卜素或角黄素的植物的黄色、橙色以及红色色素;去屑剂例如煤焦油或酮康唑;肽类例如棕榈酰五肽(palmitoylpentapapeptide)此类额外试剂可能与在此说明的一种LMWH制剂分开提供,或可能存在于同一制剂中,例如以按重量计从约0.001%至约10%的一个量值,特别是以按重量计从约0.01%至约5%的一个量值。
实例
实例1:LMWH的配制
由未分段的肝素(UFH)通过受控的亚硝酸解聚作用之后跟随氧化性乙二醇裂解以及随后的还原反应成为一种醇,产生乙二醇裂解的低分子量肝素醇(GS-LMWH-CH2-OH)。在第一步中,UFH被解聚以获得解聚的肝素(DPH-CHO),这种肝素在该多糖的还原端具有一个脱水甘露糖部分。随后是步骤II,用高碘酸钠对在已解聚的肝素中存在的2,3-二醇的氧化切割,以便沿着该肝素链(GS-DPH-CHO)产生开环的乙二醇裂解残基。步骤III涉及一个还原步骤,其中使用硼氢化钠将这些醛部分转化成醇类以产生乙二醇裂解的低分子量肝素醇。以下段落更详细地描述了制备中的步骤。
解聚作用:将UFH溶解于10倍体积的平衡至室温的去离子水中。该溶液的pH被调节至pH 3.1,并且加入亚硝酸钠(0.03M)。允许该反应溶液被搅拌数小时,随后在加入氯化钠(与起始UFH材料的量值相同)之前将pH中和。盐全部溶解后,持续搅拌下加入至少2倍体积的甲醇。所获得的沉淀在约室温下熟化约1小时。然后将该沉淀过滤并干燥,以获得80%至85%典型产率的DPH。
高碘酸盐氧化作用:在步骤I中获得的醛溶解于约10倍体积的在5℃平衡的水中。向该溶液加入等量体积的经冷却的NaIO4溶液(0.1M),并且将反应混合物搅拌16小时。一旦完成,通过加入一种醇使该反应淬灭,之后升高温度回到室温。然后将氯化钠(量值为起始的醛材料的两倍)加入该溶液中,之后加入至少3倍体积的甲醇以沉淀出肝素。允许将该沉淀在约室温下熟化2小时,之后过滤并干燥,以获得一种乙二醇裂解的聚多糖(典型地产率为约95%至98%)。
还原反应:在步骤II中获得的乙二醇裂解的多糖溶解于约10倍体积的维持在5℃的水中。向该溶液加入硼氢化钠(起始GS多糖量值的十分之一),并且接着将反应混合物搅拌1小时。然后将反应混合物恢复至室温,之后加入氯化钠(与起始GS多糖的量值相同)盐溶解后,向该溶液加入2体积的甲醇,伴随持续搅拌。由此获得的沉淀在约室温下熟化,之后过滤并干燥,以获得所希望的产品。由此获得了具有以下特征的MONC402 LMWH-钠制剂,产率大约为55%至60%:
Mw:5000至7800道尔顿
Mw分布:(i)<3000道尔顿:15%-25%
(ii)3000至8000道尔顿55%-65%
(iii)>8000道尔顿15%-25%
抗Xa活性1IU/mg至20IU/mg
抗IIa活性1IU/mg至20IU/mg
实例2:MONC402对毛发生长的作用
在很多实验性癌症动物模型中,常规方式是将动物的某些区域剃毛,如腹部或背部,以便促进癌细胞的接种或移植,注射,泵的植入等等。在分析MONC402在此类小鼠肿瘤模型中的效果时,我们意外地观察到用MONC402处理的荷瘤小鼠其剃毛部位的毛发再生长速度总是比用盐水做对照处理的小鼠更快。
为了进一步研究该观察现象,我们进行了一次实验来评估MONC402对正常小鼠毛发生长的作用。将8周龄雌性BALB/c小鼠的背部剃毛。将含有盐水、法安明、MONC402或MONC202(由UFH的亚硝酸解聚作用衍生的N-脱硫的LMWH)的渗透泵植入每个处理组的四只剃毛的小鼠。七天后将用于封闭移植伤口的钉子去除。在移植渗透泵16天后处死小鼠。(实验结束之前一只接受法安明的小鼠死亡)。对小鼠拍照(见图1)并且确定每只小鼠在处死前其剃毛区域毛发生长的得分(表1)。
如表1所示,对照组、盐水处理的动物在测试期间均未展示出可见的毛发再生长。用MONC202对照(亚硝酸解聚处理的,N-脱硫的LMWH)处理的4只小鼠中有2只在16天时仅显示轻微(非常稀薄或稀薄)的毛发生长。相比之下,MONC402处理的小鼠展示出更高水平的毛发再生长。用20和30mg/kg/天的MONC402处理的小鼠显示出的效果超过(4只小鼠中有3只具有中度毛发生长)10mg/kg/天,显示一种计量依赖反响。
实例3:MONC402与化学治疗联合对毛发生长的作用
该实例显示了当MONC402与一种化学治疗剂联合给药时MONC402对毛发生长的作用。
将8周龄雌性BALB/c小鼠的背部剃毛。将含有盐水亦或MONC402的渗透泵移植到64只小鼠体内(32只盐水,32只MONC402)。小鼠被进一步分成以下组:接受盐水或多西他赛(10mg/kg),从泵移植13天后每周腹腔注射一次。额外地,还有一个空白小鼠组(n=4)以及一个接受仅接受化学治疗的组(多西他赛,10mg/kg,植入泵后6天起,每周腹腔注射一次,n=16),它们并不接受剃毛或泵移植。七天后将用于封闭移植伤口的钉子去除。植入泵27天后,对小鼠剃毛区域的毛发生长评分。
如表2中所示,单独用MONC402处理的小鼠或MONC402与多西他赛联合处理的小鼠在第27天时展示出的毛发再生长比对照组更完全。
实例4:LMWH的局部制剂
本实例说明了一种LMWH凝胶霜剂的制剂,正如所说明的主要是按照Handbook of Pharmaceutical Manufacturing Formulations:Semisolid Products(药学制造的配制品手册:半固体产品).Niazi(尼亚兹),Ed(编辑).第二版,2009的肝素钠凝胶霜剂。
,每100g制造规模,提供以下各项:如在实例1中所说明而制造的0.2g LMWH-钠;15.0g Lutrol E(聚乙二醇400);10.0g液体石蜡;23.0g Lutrol F(泊洛沙姆407);QS(至100g)纯净水。
局部制剂的制备如下:将LMWH钠溶解于水中。加入Lutrol E400和液体石蜡。将混合物搅拌并冷却至6℃。将Lutrol F 127缓慢加入至该混合物中,并且将混合物搅拌直至溶解。当空气气泡溢出时,将得到的混合物加热至室温。
Claims (21)
1.一种诱导受试者毛发生生长的方法,该方法包括:(a)识别一位需要毛发生长的受试者;并且(b)向该受试者给予在此说明的一种LMWH一段时间以及一个量值,使得足以诱导毛发生长。
2.如权利要求1所述的方法,其中该毛发选自下组,其构成为:头皮毛发、面部毛发、身体毛发、睫毛以及眉毛。
3.如以上任何一项权利要求所述的方法,进一步包括在以下条件中的一个或全部两个中来评价毛发生长的步骤,在给药步骤之前以及在给药步骤之后。
4.如以上任何一项权利要求所述的方法,其中该患者患有脱发。
5.如以上任何一项权利要求所述的方法,其中该受试者患有一种病况,该病况选自下组,其构成为:雄激素源性脱发、斑秃、全秃、普秃、休止期脱发、生长期脱发、创伤性脱发、来自美发途径的机械“牵引型脱发”、化学诱导性脱发、热诱导性脱发、放射诱导性脱发、化学治疗诱导性脱发、瘢痕性脱发、自身免疫疾病诱导的脱发(例如,来自盘状红斑狼疮或慢性皮肤型红斑狼疮)、疾病相关性脱发(例如,来自甲状腺功能亢进症或甲状腺功能减退、铁缺乏)、药物诱导性脱发(例如,由以下药物诱导的脱发:抗生素和抗真菌药物、抗抑郁药、抗惊厥药、抗凝血药比如肝素以及一些LMWH、NSAID类药物比如阿司匹林(asprin)、抗高血压药、激素替代疗法)以及梅毒性脱发。
6.如权利要求1至3中任何一项所述的方法,其中该受试者不患有脱发。
7.如以上任何一项权利要求所述的方法,其中该LMWH与一种第二药剂联合给药以便促进毛发生长。
8.如以上任何一项权利要求所述的方法,其中该LMWH与非那雄胺(保法止)或米诺地尔(落健)联合给药。
9.如以上任何一项权利要求所述的方法,其中该LMWH与选自下组的一种或多种药剂联合给药,该组的构成为:促进毛发生长的药剂、维生素类、羟基酸类、化学性或物理性防晒霜、抗氧化剂、维甲酸类、孕酮类、毛发染黑剂或着色剂、毛发润湿剂、以及肽类。
10.如以上任何一项权利要求所述的方法,其中该LMWH是局部给药的。
11.如权利要求10所述的方法,其中该LMWH被配制成一种涂剂、霜剂、精华素、喷雾、摩丝、气雾剂、乳液、粉饼、油膏、凝胶、遮瑕膏、贴剂、眉笔、化妆棉、面膜、唇膏、泡沫、化妆水、或精华露。
12.如权利要求10或11所述的方法,其中该局部配制品进一步包括选自下组的一种药剂,该组的构成为:一种泡沫表面活性剂、一种润湿剂、一种去屑剂、一种促进毛发生长的第二药剂、一种维生素、一种羟基酸、一种化学性或物理性防晒霜、一种抗氧化剂、一种维甲酸、一种孕酮、一种毛发染黑剂或着色剂、一种毛发润湿剂、以及一种肽。
13.如权利要求1至9中任何一项所述的方法,其中该LMWH经口服给药。
14.如权利要求13所述的方法,其中该LMWH被配制为一种片剂、胶囊、水性溶液、明胶固体或半固体、或悬浮液。
15.如权利要求1至9中任何一项所述的方法,其中该LMWH通过注射给药。
16.如权利要求14所述的方法,其中该LMWH被配制为用于皮下或静脉内注射。
17.如以上任何一项权利要求所述的方法,其中该LMWH具有以下(a)至(c)特征中的一项或多项:
(a)抗Xa活性以及抗IIa活性,各自小于50IU/mg、20IU/mg、10IU/mg、5IU/mg或更小;
(b)乙二醇裂解的糖醛酸残基(例如,小于50%、40%、30%、20%的乙二醇裂解的糖醛酸残基);
(c)重均分子量在3,500Da与8,000Da之间,例如4,000Da与8,000Da之间;
并且任选地具有以下(d)至(m)特征中的一项或多项:
(d)大于40%U2SHNS,6S二糖残基;
(e)脱硫度小于40%;
(f)一条或多条多糖链,这些链具有一个4,5-未饱和的非还原端糖醛酸残基;
(g)一条或多条多糖链,这些链在还原端具有一个2,5-脱水甘露醇残基;
(h)每条多糖链不超过3个乙二醇裂解的糖醛酸残基(UG);
(i)10%至50%(例如,10%-40%、10%-30%、15%-30%或15%-25%)的寡糖,这些寡糖具有<3000Da的分子量;
(j)40%-65%(例如,40%-60%、45%-65%、50%-65%/或55%-65%)的寡糖,这些寡糖具有在3000Da至8000Da之间的分子量;
(k)5%-30%(例如,10%-30%、15%-30%、10%-25%/或15%-25%)的寡糖,这些寡糖具有>8000Da的分子量;
(1)多分散性为约1.2至1.7(例如,约1.3至1.7、1.4至1.6、或1.3至1.6);
(m)基本上由多糖构成,这些多糖包括式I:[Uw-Hx,y,z]m~[UG-Hx,y,z]n其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m和n是整数,这样使得m=4-16,并且n=1-4;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
并且其中符号~表示m和n标记的单元是沿着该多糖链分布的,并且并非必须按照顺序,其中w、x、y、以及z在每个m标记的单元上各自是相同或不同的,并且其中x、y、以及z在每个n标记的单元上各自是相同的或不同的;
(n)基本上由多糖构成,这些多糖包括式II:[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m至r是整数,这样使得:m=010;n=03;o=010;p=03;q=010;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
18.一种包括LMWH的局部配制品,其中该LMWH具有以下(a)至(c)特征中的一项或多项:
(a)抗-Xa活性和抗-IIa活性,各自小于50IU/mg、20IU/mg、10IU/mg、5IU/mg或更小;
(b)乙二醇裂解的糖醛酸残基(例如,小于50%、40%、30%、20%的乙二醇裂解的糖醛酸残基);
(c)重均分子量在3,500Da与8,000Da之间,例如4,000Da与8,000Da之间;
并且任选地具有以下(d)至(m)特征中的一项或多项:
(d)大于40%U2SHNS,6S二糖残基;
(e)脱硫度小于40%;
(f)一条或多条多糖链,这些链具有一个4,5-未饱和的非还原端糖醛酸残基;
(g)一条或多条多糖链,这些链在该还原端具有一个2,5-脱水甘露醇残基;
(h)每条多糖链不超过3个乙二醇裂解的糖醛酸残基(UG);
(i)10%-50%(例如,10%-40%、10%-30%、15%-30%或15%-25%)的寡糖,这些寡糖具有<3000Da的分子量;
(j)40%-65%(例如,40%-60%、45%-65%、50%-65%或55%-65%)的寡糖,这些寡糖具有在3000Da至8000Da之间的分子量;
(k)5%-30%(例如,10%-30%、15%-30%、10%-25%或15%-25%)的寡糖,这些寡糖具有>8000Da的分子量;
(1)多分散性为约1.2至1.7(例如,约1.3至1.7、1.4至1.6、或1.3至1.6);
(m)基本上由多糖构成,这些多糖包括式I:[Uw-Hx,y,z]m~[UG-Hx,y,z]n其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m和n是整数,这样使得m=4-16,并且n=1-4;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
并且其中符号~表示m和n标记的单元是沿着该多糖链分布的,并且并非必须按照顺序,其中w、x、y、以及z在每个m标记的单元上各自是相同或不同的,并且其中x、y、以及z在每个n标记的单元上各自是相同的或不同的;
(n)基本上由多糖构成,这些多糖包括式II:[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m至r是整数,这样使得:m=0-10;n=0-3;o=0-10;p=0-3;q=0-10;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
19.如权利要求18所述的局部配制品,进一步包括选自下组的一种药剂,该组的构成为:一种促进毛发生长的第二药剂、一种泡沫表面活性剂、一种润湿剂、一种去屑剂、一种维生素、一种羟基酸、一种化学性或物理性防晒霜、一种抗氧化剂、一种维甲酸、一种孕酮、一种毛发染黑剂或着色剂、一种毛发润湿剂、一种香料、一种蜡、一种油、一种抗氧化剂、以及一种肽。
20.如权利要求18或19所述的局部配制品,其中该配制品是一种香波、一种霜剂、一种精华素、一种泡沫、一种凝胶、一种精华素、一种喷雾、一种摩丝、一种气雾剂、一种乳液、一种粉饼、一种油膏、一种遮瑕膏、一种贴剂、一种眉笔、一种化妆棉、一种面膜、一种唇膏、一种化妆水、或一种精华露。
21.一种药物、兽医或美容制剂,该制剂经包装并识别用于有诱导受试者毛发生长的方法,其中该制剂包括一种LMWH,它具有以下(a)至(c)特征中的一项或多项:
(a)抗-Xa活性和抗-IIa活性,各自小于50IU/mg、20IU/mg、10IU/mg、5IU/mg或更小;
(b)乙二醇裂解的糖醛酸残基(例如,小于50%、40%、30%、20%的乙二醇分裂的糖醛酸残基);
(c)重均分子量在3,500Da与8,000Da之间,例如4,000Da与8,000Da之间;
并且任选地具有以下(d)至(m)特征中的一项或多项:
(d)大于40%U2SHNS,6S二糖残基;
(e)脱硫度小于40%;
(f)一条或多条多糖链,这些链具有一个4,5-未饱和的非还原端糖醛酸残基;
(g)一条或多条多糖链,这些链在还原端具有一个2,5-脱水甘露醇残基;
(h)每条多糖链不超过3个乙二醇裂解的糖醛酸残基(UG);
(i)10%-50%(例如,10%-40%、10%-30%、15%-30%或15%-25%)的寡糖,这些寡糖具有<3000Da的分子量;
(j)40%-65%(例如,40%-60%、45%-65%、50%-65%或55%-65%)的寡糖,这些寡糖的分子量在3000Da至8000Da之间;
(k)5%-30%(例如,10%-30%、15%-30%、10%-25%或15%-25%)的寡糖,这些寡糖具有>8000Da的分子量;
(1)多分散性为约1.2至1.7(例如,约1.3至1.7、1.4至1.6、或1.3至1.6);
(m)基本上由多糖构成,这些多糖包括式I:[Uw-Hx,y,z]m~[UG-Hx,y,z]n其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m和n是整数,这样使得m=4-16,并且n=1-4;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
并且其中符号~表示m和n标记的单元是沿着该多糖链分布的,并且并非必须按照顺序,其中w、x、y、以及z在每个m标记的单元上各自是相同或不同的,并且其中x、y、以及z在每个n标记的单元上各自是相同的或不同的;
(n)基本上由多糖构成,这些多糖包括式II:[Uw-Hx,y,z]m-[UG-Hx,y,z]n-[Uw-Hx,y,z]o-[UG-Hx,y,z]p-[Uw-Hx,y,z]q其中U表示一个糖醛酸残基,而H表示一个己糖胺残基;其中m至r是整数,这样使得:m=0-10;n=0-3;o=0-10;p=0-3;q=0-10;w=-2OS或-2OH;x=-NS或-NAc;y=-3OS或-3OH;z=-6OS或-6OH;
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- 2011-06-15 JP JP2013515473A patent/JP5905455B2/ja not_active Expired - Fee Related
- 2011-06-15 AU AU2011268470A patent/AU2011268470B2/en not_active Ceased
- 2011-06-15 CN CN201180029515.9A patent/CN103096870B/zh not_active Expired - Fee Related
- 2011-06-15 BR BR112012031906A patent/BR112012031906A2/pt not_active Application Discontinuation
- 2011-06-15 WO PCT/US2011/040470 patent/WO2011159770A2/en active Application Filing
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Also Published As
Publication number | Publication date |
---|---|
AU2011268470B2 (en) | 2017-02-02 |
JP5905455B2 (ja) | 2016-04-20 |
JP2013528653A (ja) | 2013-07-11 |
CA2795868A1 (en) | 2011-12-22 |
CN103096870B (zh) | 2017-04-19 |
BR112012031906A2 (pt) | 2016-08-23 |
AU2011268470A1 (en) | 2013-01-24 |
WO2011159770A2 (en) | 2011-12-22 |
WO2011159770A3 (en) | 2012-12-27 |
EP2582355A2 (en) | 2013-04-24 |
US20130183254A1 (en) | 2013-07-18 |
US10017585B2 (en) | 2018-07-10 |
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