CN114025768B - 促进毛发生长的药品 - Google Patents
促进毛发生长的药品 Download PDFInfo
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- CN114025768B CN114025768B CN201980098011.9A CN201980098011A CN114025768B CN 114025768 B CN114025768 B CN 114025768B CN 201980098011 A CN201980098011 A CN 201980098011A CN 114025768 B CN114025768 B CN 114025768B
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Abstract
本发明涉及美容学、皮肤学和医学领域,并涉及用于促进哺乳动物毛发生长和/或主要用于预防和/或治疗人类脱发的组合产品以及基于其的组合物的开发和生产,更具体地,涉及基于F‑和E‑型前列腺素衍生物的组合,其特征在于无不良副作用,本发明还涉及包含所述组合的稳定组合物。在单一组合物中使用前列腺素组合使得能够同时激活多个生理过程,包括刺激毛囊产生新头发,增加毛囊附近区域的局部微循环,并减少血小板聚集,从而防止毛细血管网络中的血栓形成。此外,在所述组合或基于所述组合的组合物中存在携带一组氮氧化物供体的修饰的前列腺素能够使所述组合或组合物的其他成分更好地渗透到皮肤中。
Description
技术领域
本发明涉及美容学、皮肤学和医学领域,并涉及一种用于促进哺乳动物(优选为人类)毛发生长的组合的开发和制备,以及基于此的一种组合物。更具体地,本发明涉及用于停止脱发和/或恢复及激活毛发生长的组合,组合物和方法。
背景技术
秃发或脱发是头皮部分或完全毛发减少的过程。前去看毛发学家的10名患者中有9名抱怨脱发。脱发的类型有几种:斑秃,弥漫性,雄激素性,瘢痕性,脂溢性。雄激素性,即所谓的男性型脱发,是该疾病最常见的形式。研究表明,世界上25至55岁的男性人群中有30-35%受到雄激素性脱发的影响。在女性中,诊断为此种脱发的频率较低。
由于医学的进步,目前已经明确了雄激素性脱发的原因。脱发的直接原因是雄性激素(雄激素,androgens)对位于额区和顶区的毛囊的损伤效应。在激素活性的影响下,具有对激素分子敏感的受体的毛球(bulb)逐渐失去生成健康头发的能力并最终死亡,从而导致不可逆转的脱发。
尽管激素活性是所有男性与生俱来的,但如前所述,只有三分之一的人患有秃顶。这是由于秃发发展的第二个关键因素是各人继承自父母的遗传信息。已发现在70-72%的情况下秃发基因是由男性通过母系遗传的:母亲将其从父亲传给儿子。在其他情况下,秃发基因直接从父亲处遗传。非常罕见的情况下,患有雄激素性脱发的男性在其家族中是第一个受到影响的。因此,脱发的原因是两个因素的共生效应:遗传和激素活性。
目前,有很多方法可以对抗脱发。例如,毛发移植是一种非药物方法。毛发移植手术痛苦且昂贵,此外它还有许多同样显著的缺点。例如,患者自己的供体毛球通常不足以覆盖患病区域;毛发轻短,手术后后脑勺上疤痕可见,不能总是被遮盖住;手术通常分几个阶段进行,因为秃发面积趋于增加,而供体面积是有限的。
其他抗秃发的方法包括暴露于紫外线辐射,按摩,精神科治疗等。但是,上述方法均不被认为是有效的。血运重建手术和针灸也被证明抗脱发的效果较差。
因此,解决该问题的最常见和最有希望的方法是开发一种治疗各种病因脱发的治疗剂。男性型脱发被认为是药物治疗的主要适应症。长期以来,有观点认为全身或局部应用抗雄激素能够提供必要的对脱发过程的抑制作用,因为男性型秃发的原因是雄激素过量。然而,研究并不支持这一积极的理论。
睾酮被认为是一种可选药品。例如,已知雄激素睾酮在局部施用于三角肌区域以及施用于下颏和耻骨区域时可刺激毛发生长。有发现即使是口服给药也会导致胡须和耻骨区,以及躯干和四肢的毛发生长增加。虽然即使是局部涂抹在手臂上也会导致毛发生长增加,但这种激素对头皮无效,相反地,会导致头发稀疏。高剂量的睾酮也会导致男性型秃发。
目前,有两种经美国FDA批准用于治疗男性型秃发的药物:外用米诺地尔(WO1999053923A1,WO1988007362α1商标来自法玛西亚普强),口服非那雄胺(W01995010284A1,USP5670643商标/>来自默克公司)。尽管这些药物在毛发学中被广泛使用,但值得注意的是它们的有效性不足。举例而言,可引用临床研究的结果:使用2%米诺地尔的女性中有19%在使用8个月后注意到中等程度的头发生长,而服用安慰剂的女性中有7%具有相同的结果(http://www.americanhairloss.org/women_hair_loss/treatment.asp)。
由于安全问题和现有治疗的有效性有限,对更有效的毛发生长刺激剂的探寻正在进行中。苯妥英就是这样一种药物,其具有抗惊厥作用,广泛用于控制癫痫发作。在癫痫患儿中常见多毛症,并且通常在治疗开始后2-3个月出现,首先明显出现在四肢伸肌侧,然后在躯干和面部。链霉素以类似的方式作用。停药后,毛发密度恢复到先前的水平,仅在极少数情况下保持不变,即多毛症是由应用前述抗生素引发的。
有一些在男性型脱发毛发修复方面表现出些许前景的治疗方法。方法包括应用含有雌二醇和氧甲氢龙作为活性成分的乳膏微乳液,以及使用有机硅。然而,雌二醇治疗尚未获得明确令人信服的结果:在头皮的不同区域对雌二醇的敏感性不同,并且由于诸如男性乳房发育症的不良副作用,雌二醇绝对不能用于男性,因为需要非常高的局部剂量才能获得明显的毛发生长效应(http://www.follacure.com/t/estrogenB)。
与本文描述的发明最接近的类似物是前列腺素,其具有与甲状腺激素相同的益处,即头发长度的增加和色素沉着的变化。天然存在的前列腺素(例如PGA2、PGB2、PGE1、PGE2、PGD2、PGF2α和PGI2)是C-20不饱和脂肪酸的环氧合酶代谢物。PGF2α天然存在于人体,其特征在于环戊烷上C9和C11位置的羟基,C5和C6之间的顺式双键以及C13和C14之间的反式双键。
天然前列腺素F类似物是本领域已知的。例如,专利文献US4024179(取代的ω-戊醇前列腺素,公开日17.05.1977),US4128720(前列腺素类似物,公开日05.12.1978),US4011262(两个系列的13,14-二氢-15-取代的-ω-戊二醇前列腺素,公开日08.03.1997),US3776938(二氢-pge1,公开日04.12.1973),RU2481339(具有前列腺素活性的取代环戊烷,公开日10.05.2013)。专利US6262105(增强头发生长的方法,公开日17.07.2017)指出,前列腺素及其衍生物可用于促进头发生长。
迄今为止,已经发现比马前列素(RU2363471C2),商品名卢美根(Lumigan)(爱力根公司,Irvine,CA,USA),一种用于治疗青光眼的眼药溶液,能够有效地促进睫毛生长。此外,爱力根公司还进行了男性型脱发使用比马前列素的指征的临床试验。
进行试点双盲临床研究,以探究治疗青光眼的市售药物之一拉坦前列素对头皮毛发生长激活的效果。先前的大量临床观察表明,拉坦前列素促进睫毛生长,这被认为是青光眼治疗的不良反应,其在药物与眼睑接触时表现出来。在一项临床研究中,在施用0.1%拉坦前列素24周后,注意到由于末梢发和绒毛,头发密度显著增加。已经得出结论,拉坦前列素可能有助于刺激毛囊活性和治疗脱发(J Am Acad Dermatol.2012May;66(5):794-800)。
Loreal对各种前列腺素对毛囊活化的效果进行了研究,发现了数种前列腺素参与头发生长的调节,而不仅仅是前列腺素F2α(实验皮肤病学2008;17:63-72)。已注意到PGF2α-FP受体缺陷小鼠没有皮毛问题(科学1997:277:681-683)。事实上,如同PGF2α激动剂一样,PGE2治疗也引起了小鼠(Invest Ophthalmol Vis Sci 2001:42:1134-1145)和人类(Newtopical agents for hair growth.Clin Dermatol 1988:6:119-121)的头发再生。关于这一点,值得注意的是,PGE2 EP1、EP2和EP3受体在真皮中表达(实验皮肤病学2008;17:63-72)。另一方面,促进头发生长的效果可能是间接的,由毛囊周围的环境引起的,这是由于血管生成的激活、细胞外基质的校正,或是由于生长因子的可用率的改变。因此,不仅是PGF2α,其他PG,特别是PGE1、PGE2、PGD2等也可以参与头发生长的调节。毛囊中PG效应的区域可以不同,并且同时激活几个受体会显著增加头发生长的活性。
这一点可以很容易地解释,因为PG通常具有广泛的生物活性。举例而言,PGE2具有以下重要特性:a)通过激活典型的WNT/β-catenin信号通路(任何组织再生的关键)来调节干细胞的增殖,b)调节细胞因子的合成,c)调节免疫反应,以及d)诱导血管舒张。例如,血管舒张被认为是米诺地尔促进头发生长的机制之一。文献中的体外数据也表明了前列腺素的一些抗炎特性(Br.J Pharm.,116,2298,(1995))。然而,以前使用前列腺素刺激头发生长的尝试都没有成功。对研究结果的分析表明,在绝大多数研究中激活头发生长的主要作用归因于PGF2α,后证实这一点并不全对,因为后来明确了,由于对毛球干细胞的激活和分子进一步还原为PGF2a,PGE2具有更强的刺激毛发生长的潜力,从而具有更复杂和有效的功能。不同的前列腺素类似物可以以具有双相效应的不同浓度与各种受体结合。
使用前列腺素,主要是PGF2α衍生物(因为抗青光眼药物是在这些前列腺素的基础上开发的,并且首先观察到睫毛,上眼睑和眼部区域多毛症形式的副作用)来抑制脱发和刺激新头发的生长已成为了既定的事实,申请WO2011/014649提交了关于抑制头发生长或脱毛的方法,该方法不是基于PGF2α-FP受体的激活,而是基于使用特定拮抗剂将其抑制。
因此,前列腺素的广泛应用以及全世界使用它们意愿,表明了这一研究领域是有前景的。尽管上述所有药物都在市场上使用或在进行某阶段的临床试验研究,但显而易见这些药物作为单一疗法的的有效性有限。
发明概述
本发明的目的是开发一种新型有效的,基于前列腺素F和E类似物的增强毛发生长和/或预防和/或治疗对象脱发的医药产品。
本发明的技术效果是开发和生产了一种新型有效且无毒的前列腺素F和E衍生物的组合,用于促进毛发生长和/或预防和/或治疗脱发,其特征在于无不良副作用,以及包含所述组合的稳定组合物。组合物中前列腺素组合的使用使得多个生理过程同时激活,包括刺激毛囊形成新毛发,增强毛囊附近区域的局部微循环并减少血小板的聚集,从而防止毛细血管网络中的血栓形成。此外,在该组合或组合物中,带有一组一氧化氮供体的改良前列腺素的存在促进了该组合或组合物的其它成分更好地渗透到皮肤中。
通过开发和创造一种用于增强毛发生长和/或预防和/或治疗受试者脱发的组合,其至少包含式(I)化合物和式(II)和/或式(III)化合物,获得了所述的技术结果。
其中所述的式(I)化合物是:
所述的式(II)化合物是:
所述的式(III)化合物是:
在本发明的具体实施方式中,本发明的组合包含式(I)、式(II)和式(III)化合物。
在本发明的具体实施方式中,本发明的组合包含式(I)和式(II)化合物。
在本发明的具体实施方式中,本发明的组合包含式(I)和式(III)化合物。
在本发明的具体实施方式中,脱发为弥漫性(女性型)、雄激素性或斑秃性。
本发明还提供了一种用于增强生长和/或预防和/或治疗脱发的组合物,其包括本发明的组合和至少一种赋形剂。而且,该组合包含有效数量的组分。
在本发明的具体实施方式中,所述赋形剂为载体、填充剂和/或溶剂。
在本发明的具体实施方式中,通式(I)化合物在组合物中的含量为每1mL的本发明的成品组合物含50-300μg。
在本发明的具体实施方式中,通式(II)化合物在组合物中的含量为每1mL的本发明的成品组合物含50-300μg。
在本发明的具体实施方式中,通式(III)化合物在组合物中的含量为每1mL的本发明的成品组合物含50-200μg。
本发明还包括本发明组合物的用途,用于增强毛发生长和/或预防和/或治疗受试者的脱发。在本发明的具体实施方式中,脱发为雄激素性、弥漫性或斑秃性。
在本发明的具体实施方式中,所述组合物为局部施用。
在具体实施方式中,所述组合物为每日使用或隔日使用。
在本发明的具体实施方式中,所述受试者为人。
本发明还包括基于此的组合和/或组合物的制备。
本发明还涉及增强毛发生长和/或预防和/或治疗受试者的脱发的方法。
进行研究的结果是,发现了包含在本发明的组合中的前列腺素衍生物(其包含NO供体和比前列腺素本身更能有效激活NO合成酶的化学结构)具有针对激活头皮和毛发(睫毛,眉毛等)毛囊的活性,并显示出难以置信的效果。在研究中偶然地发现,除了加强和刺激头发生长的有效作用外,以这种方式合成的分子还促进了药物产品渗透到真皮层,真皮层是毛囊及其调节受体所在之处,其激活会导致毛发生长。带有NO供体的前列腺素衍生物激活毛囊上的数种作用机制,例如激活毛球乳头干细胞,激活生理血管生成,激活细胞外基质,改善血液流变以及通过恢复的毛囊的毛细血管网络促进生长因子和其他微量元素和维生素的输送。整体而言,这整个作用机制产生了促进头发生长的有力效果。
前列腺素F和E的改良衍生物的复合物(组合)已被开发为一种有效制剂,其可增强再生和毛发生长,以防止秃发,并在脱发的不同阶段部分或完全地恢复毛发。本发明使得在人类和动物中促进毛发生长,并且所开发的促进毛发生长的方法与各种类型的治疗剂或载体相容,因此,其可以结合自身表现出一些治疗活性的药物或载体,例如微乳剂,含有雌二醇和氧甲氢龙、米诺地尔或阻断睾酮转化为二氢睾酮的药物、阻断雄激素受体、肽和其他生长因子的抗雄激素药物的乳霜或局部组合物。此外,本发明旨在治疗秃发和促进毛发生长,对其预期目的有效的同时,无毒且不会引起不良副作用。本申请提供了一种治疗男性或女性脱发的方法,患者可在医生的监督下使用该方法,其要求不比其他局部施用的治疗剂更严格。与上述类似物不同,本发明提供了一种女性型脱发和雄激素性脱发的脱发治疗方法,该脱发发生在男性和女性身上,也可用于斑秃的综合治疗,且安全、易用、无痛,便于化妆品使用(不会对受试者造成不适,也不会留下痕迹)。
发明详述
附图简述
图1临床和实验室研究的比较结果,通过分析毛发图像来评估本发明组合物的功效:组合物1的毛发生长剂;组合物2的毛发生长剂,开始使用和3个月后获得。
定义和术语
为了更好地理解本发明,以下是本发明说明书中使用的一些术语。
如在本发明的描述中所使用的,术语“包括”和“包括的”被解释成意为“包括但不限于”。这些术语不应被解释为“仅由……组成”。
本文中使用的术语“载体”是指一种或多种适于给哺乳动物(优选人类)施用的相容物质。例如,载体包括固体或液体稀释剂、助水溶物、表面活性剂和包封剂。本文中使用的术语“相容性”是指该组合物的组分与前列腺素衍生物混溶并且彼此混溶,使得在正常使用条件下不会发生会显著降低该组合物有效性的相互作用。所述载体必须具有足够高的纯度和足够低的毒性,以适合被受治疗的人使用。载体可以是惰性的,具有医药或化妆品的优点,或两者兼有。
载体的选择取决于活性成分的使用方法和组合物的形式。所述组合物可以以适合于局部施用的各种形式呈现(例如,通过脂质体系统,聚合生物降解(纳米)颗粒或离子电渗疗法输送,局部应用于眼部区域的头皮和皮肤,不包括粘膜)。优选地直接在所需的毛发生长部位局部给药。
载体通常包含一种或多种选自以下组的成分:a)稀释剂、b)润滑剂、c)粘合剂、d)崩解剂、e)着色剂、f)矫味剂、g)甜味剂、h)抗氧化剂、i)防腐剂、j)助溶剂、k)溶剂、l)悬浮剂、表面活性剂、m)渗透促进剂、n)其组合,等。
本发明中要求保护的组合物包含本发明与药学上可接受的载体的组合,其可包括适用于特定剂型的任何溶剂、稀释剂、分散液或悬浮液、表面活性剂、等渗剂、增稠剂和乳化剂、防腐剂、粘合剂、润滑剂等。
本发明的组合物还可任选地包括活性增强成分。所述指定成分优选地选自下组:毛发生长促进剂I)(除含有NO供体的改良PGF2α和PGE1/PGE2外),包括生理活性物质、矿物质和植物及动物组织的提取物,以及II)活性物质通过皮肤渗透的促进剂,以及各种填充剂、稳定剂和防腐剂。
组分I)是额外的毛发生长促进剂,可包括但不限于血管扩张剂、抗雄激素、环孢菌素、环孢菌素类似物、抗菌剂、抗炎药、甲状腺激素、甲状腺激素衍生物、以及甲状腺激素类似物,用于校正绝经后妇女激素状态的性激素类似物制剂、非选择性前列腺素激动剂或拮抗剂、维甲酸、三萜、及其组合。非选择性前列腺素激动剂或拮抗剂不选择性激活FP受体,可激活其他受体如前列腺素EP1-4、IP受体,或阻断DP1、DP2、TP受体。组分I)的其它合适的替代品可包括但不限于雌二醇、马来酸氯苯那敏、叶绿素衍生物、胆固醇、水杨酸、半胱氨酸、甲硫氨酸、红辣椒酊剂或辣椒素、苄基烟酸、D,L-薄荷醇、薄荷油、泛酸钙、泛醇、蓖麻油、泼尼松龙、间苯二酚、蛋白激酶C的化学激活剂、糖胺聚糖链细胞摄取抑制剂、糖苷酶活性抑制剂、葡萄糖胺糖苷酸酶抑制剂、焦谷氨酸酯、六碳糖酸或酰化六碳糖酸、芳代乙烯、N-酰化氨基酸、类黄素、子囊素衍生物和类似物、组胺拮抗剂(如盐酸苯海拉明)、三萜(如加丽素(carophylline)和熊果酸)、蛋白聚糖酶或氨基葡萄糖聚糖酶抑制剂、雌激素激动剂,以及细胞因子和生长因子的拮抗剂、促进剂、类似物或抑制剂,如白介素-1和白介素-6抑制剂、白介素-10促进剂、肿瘤坏死因子抑制剂、维生素如维生素D类似物和甲状旁腺激素拮抗剂、维生素B12类似物和泛醇、激动剂和二苯甲酮、以及乙内酰脲、抗惊厥药,如苯妥英、及其组合、干扰素拮抗剂、羟基酸。
如果适用于化妆品的话,最优选的毛发生长活性增强剂是米诺地尔,非那雄胺,度他雄胺,抗雄激素药物如雄激素受体阻滞剂,性激素类似物制剂和一些肽生长因子。
组分II)是一种渗透增强剂,其可以添加到所有组合物中。当组合物中存在组分II)时,其含量通常为1%至5%。渗透增强剂的实例包括但不限于,2-甲基丙烷-2-醇、丙烷-2-醇、2-羟基丙酸乙酯、己烷-2,5-二醇、聚氧乙烯(2)乙酯、二(2-羟丙基)酯、戊烷-2,4-二醇、丙酮、2-羟基丙酸、2-羟基辛酸、1-丙醇、1,4-二氧己环、四氢呋喃、丁烷-1,4-二醇、丙二醇二壬酸酯、油醇、月桂醇、己二酸二辛酯、己二酸二异丙酯,癸二酸二异丙酯,癸二酸二异丙酯,癸二酸二丁酯,癸二酸二乙酯,癸二酸二甲酯,邻苯二甲酸二辛酯,癸二酸二苄酯,邻苯二甲酸二丁酯,矽二酸二丁酯,肉豆蔻酸丁酯,琥珀酸二丁酯,邻苯二甲酸二十二烷基酯,油酸癸酯,己酸乙酯,水杨酸乙酯,棕榈酸异丙酯,月桂酸乙酯,天竺葵酸2-乙基己酯,异硬脂酸异丙酯,月桂酸丁酯,苯甲酸苄酯,苯甲酸丁酯,月桂酸己酯,癸酸乙酯,辛酸乙酯,硬脂酸丁酯,水杨酸苄酯,2-羟基丙酸,N,N-二甲基乙酰胺,N,N-二甲基甲酰胺,2-吡咯烷酮,1-甲基-2-吡咯烷酮,5-甲基-2-吡咯烷酮,1,5-二甲基-2-吡咯烷酮,1-乙基-2-吡咯烷酮,1-乙基-2-吡咯烷酮,氧化膦,糖酯,四氢糠基乙醇,尿素,二乙基间甲苯胺,1-十二烷基氮杂环庚烷-2-酮、ω-3脂肪酸和鱼油及其组合。
填充剂、稳定剂和防腐剂包括但不限于苯扎氯铵、苯甲索氯铵、苯酚、聚氧乙烯(2)甲酯、丙二醇二壬酸酯、聚氧丙烯15硬脂酸酯、辛醇、聚氧乙烯油醇酯。
本发明组合或组合物的组分的有效量是指给予到患者,使得患者最有可能表现出对治疗的所需反应(预防)的化合物的量。所需的确切量可能因受试者而异,取决于患者的年龄、体重和一般状况、疾病/病症的严重程度、与其他药物的联合治疗等。
基于此的组合或组合物可以以任何能有效治疗或预防脱发和/或促进毛发生长的量施用于患者。当本发明的组合用作联合治疗方案的一部分时,在所需治疗期间施用联合治疗中每种成分的量。包含联合疗法的化合物施用于患者时可以同时作为含有所有组分的量和作为组分的单独量。
本发明对象的用途
使用本发明对象的方法包括对患有脱发的哺乳动物(优选人类)施用包含本发明改良的前列腺素衍生物的组合的组合物。优选局部施用包含改良的前列腺素衍生物组合的组合物。更优选地,该组合物是包含下列的组合物:A)改良的前列腺素衍生物的复合物(组合)、B)载体和C)额外的活性增强剂。
令人惊讶的是,已经发现,由于在本发明的组合物和方法中使用改良的前列腺素衍生物,头发趋向于变厚和变黑,而头发变灰可能被逆转。该方法包括将局部组合物施用于生长的毛发和毛发生长部位的皮肤。在本发明的特定实施例中,局部组合物,特定地为睫毛和眉毛用剂,被施用于睫毛和眉毛。
1mL成品化妆品或局部剂型中各种修饰前列腺素衍生物的组合的施用剂量,对于前列腺素F2α衍生物的局部给药通常为0.01mg至0.3mg,优选0.1mg至0.2mg,更优选0.075mg至0.15mg;对于前列腺素E1衍生物为0.01mg至0.15mg,优选0.025mg至0.125mg,更优选0.05mg至0.1mg;对于前列腺素E2衍生物为0.01mg至0.3mg,优选0.025mg至0.15mg,更优选0.05mg至0.15mg。前列腺素衍生物在一系列前列腺素F2α-E2-E1衍生物中的比例优选为3-3-1。
包含前列腺素衍生物组合的本发明组合物在相对较短的时间内(例如,几周)每天或每隔一天局部施用。通常情况下,10到12周就足以产生首次可见的效果,通常表现在毛发照片上。一个完整的疗程可以持续几个月,通常长达6个月。用于局部施用的组合物优选不易洗去的。局部组合物施用后的至少几个小时内,不应将其从治疗区域去除。上述实施例(包括剂量范围)仅为示例性实施例,并且可根据各种因素调整每日给药。局部应用前列腺素衍生物的具体剂量、治疗持续时间、局部或额外全身治疗的相关性是相互依赖的。强度和治疗方案还取决于所使用的前列腺素衍生物的特定组合、治疗适应症、个体特征(受试者的体重、年龄、性别和医疗状况)、对治疗方案的依从性以及治疗副作用的存在和严重性等因素。
本发明的对象包含的两到三种在组合物中的基本化合物(前列腺素衍生物),即,分子中含有NO供体的前列腺素F2α衍生物、前列腺素E2衍生物和/或前列腺素E1衍生物。该组合物还可包括相容的组分,例如载体和/或一种或多种额外的活性增强剂。
在本发明的优选实施例中,前列腺素衍生物的组合被局部施用。可局部施用于皮肤的局部组合物可以是任何形式的,包括溶液、油、精华液、乳霜、软膏、凝胶、乳液、洗发水、护发素、牛奶、清洁剂、保湿剂、喷雾等。
局部组合物包括:组分A)上述天然前列腺素的改良衍生物和组分B),特定地为载体。局部组合物的载体优选地促进前列腺素渗入皮肤以进入毛囊环境。如上文所述,用于局部施用的组合物可优选地进一步包含组分C),一种或多种额外活性增强组分。
局部组合物优选进一步包含1%至20%的组分C)以及足量的组分B),以使组分A)、B)和C)的量组合到100%。与前列腺素联合使用的载体的量B)足以提供每标准剂量化合物施用的组合物的实际量。
组分C)是如上所述的可选活性增强剂。可将任何毛发生长刺激剂I)和II)渗透增强剂添加到局部组合物中。优选地,局部组合物包含0.01%至15%量的组分I)额外毛发生长刺激剂。更优选地,该组合物包含0.1%至10%,且最优选0.5%至5%的组分I)。优选地,局部组合物包含1%至5%的组分II)。
前列腺素衍生物可包含在试剂盒中,该试剂盒含有本发明对象组合的局部组合物;说明如何使用该试剂盒促进哺乳动物(最好是人类)毛发生长和/或治疗和/或预防脱发的信息和/或说明。信息和说明可以是文字说明和/或图片和/或图表。此外,在替代的实施例中,所述试剂盒可包括前列腺素衍生物和/或组合物,以及关于用于促进毛发生长和/或治疗和/或预防受试者脱发的组合物和/或组合物的施用方法的信息和/或说明。
因此,本发明提供了上述组合的新型高效制剂,用于促进毛发生长和/或治疗和/或预防脱发,尤其是男性型脱发。本发明促进新陈代谢增加,改善血液循环,使发根处维生素饱和。在本发明的一些特定实施例中,本发明的制剂优选地具有凝胶状稠度,其有助于其有效分布和穿透皮肤屏障,并且对皮肤表层和深层的代谢过程都具有积极影响。
本发明的使用使得用于刺激头发生长和/或治疗和/或预防脱发的药物和化妆品制剂的阵容扩大了。
实施方式描述
式(I)化合物-前列腺素F2α酰胺和L-丝氨酸异丙酯((R)-异丙基2-((Z)-7-((1R,2R,3R,5S)-3,5-二羟基-2-((8,E)-3-羟基辛-1-烯-1-基)环戊基)庚-5-烯酰胺)-3-羟基丙酸)的制备方法。
在室温下,将1880μL三乙胺(13.6mmol)加入3750mg(10.6mmol)前列腺素F2α在50mL乙腈的溶液中,搅拌5分钟,然后加入1769μL(13.6mmol)异丁基氯甲酸酯。室温下搅拌40分钟。将2600mg(13.6mmol)L-丝氨酸异丙酯盐酸盐溶解于8mg水中,加入2900μL(21mmol)三乙胺,随后将所得溶液滴加到上述混合酸酐溶液中,搅拌冷却至4-8℃。将反应混合物搅拌40分钟,同时冷却至4-8℃。在旋转蒸发器上小心地从溶剂混合物中除去乙腈,用乙酸乙酯(500mL)稀释残余物,用水(2×50mL)和饱和氯化钠溶液(1×50mL)洗涤。将有机提取物汇集在无水硫酸钠上干燥,然后在旋转蒸发器上蒸发并在油泵真空中干燥。
产率为4730mg(92%),为在低温(+4℃)下固化的油。
1H-NMR(CDCl3):0.89(3Н),1.22(6Н),1.3(9Н),1.76(3Н),2.04(6Н),2.39(2Н),3.9(2Н),4.03(2Н),4.13(1Н),4.63(1Н),5.08(1Н),5.45(4Н),6.83(1Н).[α]D 25=28.4°,c=1,EtOH.
IR光谱(物质膜):1732cm-1(羰基酯),1653(酰胺羰基),2935,2980和1455cm-1,(烷基的拉伸和变形振动),3360cm-1(br.OH基团的拉伸振动)。
式(II)((Z)-1,3-双(硝基)丙烯酰-2-7-(1R,2R,3R)-3-羟基辛烯-1-基-1)-5-氧代环戊烯基-5-庚烯酸酯)和式(III)((Z)-1,3-双(硝基)丙-2-基-7-(1R,2R,3R)-3-羟基-2-(S,E)-3-羟基-1-烯-1-基)-5-氧代环戊基)庚酸酯)的化合物可按照US5,625,083(公告日:29.04.1997)中描述的步骤制备。
基于本发明前列腺素的组合(组合1)的制备实施例
为了制备本发明的组合,取适当量的每种前列腺素:前列腺素F2α酰胺和L-丝氨酸异丙酯(式(I)化合物)、前列腺素E2二硝基甘油酯(式(II的化合物)、前列腺素E1二硝基甘油酯(式(III)化合物)-按以下比例(重量)3:3:1。
为制备20kg用于刺激头发生长的化妆品组合物,取3g前列腺素F2α酰胺和L-丝氨酸异丙酯,3g前列腺素E2二硝基甘油酯和1g前列腺素E1二硝基甘油酯。将这些溶解在异丙醇(前列腺素F2)或95%乙醇(前列腺素E)中的前列腺素以100mg/mL浓度储存。将计算量的各组分溶液放入称重的烧瓶中,并在真空下除去溶剂至残留物为恒定重量。如有不足,添加所需量的初始前列腺素溶液。在每个烧瓶中加入50mL乙醇使组分完全溶解,并将溶液定量转移至250mL烧瓶中。真空下蒸发至干燥。将残留物溶解在600mL乙氧基二甘醇中。使用所得的含有组合1的清液来制备用于刺激毛发生长的组合物。
本发明的组合物实施例
除修饰的前列腺素衍生物外,所述护发精华(本发明组合1的实施例)的配方的形式为:
·前列腺素F2α酰胺和L-丝氨酸异丙酯(式(I)化合物)-0.015%,
·前列腺素E2二硝基甘油酯(式(II)化合物)-0.015%,
·前列腺素E2二硝基甘油酯(式(III)化合物)-0.005%,
在3:3:1的比例中,还可以包括,例如,载体形式的以下组分,%w/w:
用于睫毛强化和生长的精华液(本发明组合2的实施例)的配方除以下修饰的前列腺素衍生物外还包括:
·前列腺素F2α酰胺和L-丝氨酸异丙酯(式(I)化合物)-0.015%,
·前列腺素E2二硝基甘油酯(式(III)化合物)-0.005%,
在3:1的比例中,还可以包括,例如,载体形式的以下组分,%w/w:
用于眉毛强化和生长的精华液(本发明组合3的实例)的配方除以下修饰的前列腺素衍生物外还包括:
··前列腺素F2α酰胺和L-丝氨酸异丙酯(式(I)化合物)-0.015%,
··前列腺素E2二硝基甘油酯(式(III)化合物)-0.005%,
还可以包括,例如,载体形式的以下组分,%w/w:
本发明的各种配方化妆品组合物在室温加速储存期间的稳定性分析
将用于刺激毛发生长的化妆品组合物(根据本发明的组合物1的示例,见上文)维持在+25-27℃下2个月。每周采集样本,并通过HPLC分析组合中成分的含量。为了制备用于分析的样品,从化妆品组合物中提取1g凝胶到圆底玻璃离心管中,并添加2g蒸馏乙酸乙酯。在Multi-Vortex V32上摇动混合物至液体完全混合3分钟。所得悬浮液在6000rpm下离心5分钟,以使各层完全分离。用玻璃移液管小心地除去上层(乙酸乙酯层)并转移到锥形底烧瓶(V25 mL)中。另添加2g蒸馏乙酸乙酯到试管中的剩余溶液中,并再次重复提取程序。用玻璃移液管小心地除去上层(乙酸乙酯层),并将其加入到先前收集的溶液中。有机层在旋转蒸发器上蒸发,并在油泵真空中干燥。将残留物溶解在乙醇中,以得到乙醇浓度为26mg/100μL的溶液。在乙腈-水梯度系统(线性梯度,5→100%乙腈))中,通过微柱反相HPLC分析提取物。通过与参考标准品进行比较,确定本发明组合的成分。根据色谱图中的信号面积估计各组分的量。
结果如表所示。
表1在室温下储存时,用于刺激毛发生长的化妆品组合物中修饰前列腺素F2的含量(相对于初始量的%)。
上述数据表明,在室温下(这比储存成品化妆品组合物的推荐温度范围(+4-+8℃)高20度)储存时,如实施例1所述获得的修饰的前列腺素F2的含量在加速储存期间下降非常缓慢。然而,前列腺素E2和E1的含量随着时间的推移而减少,因为它们转化为了其他产物。应注意的是,如果在用于促进头发生长的化妆品组合物中,取代本发明的前列腺素F2(如实施例1所述获得前列腺素F2)而使用前列腺素F2的另一种衍生物(特别是硝基前列素F2),则后者不能承受在室温下储存2周并且会在上述条件下完全转化为另一种产物。
因此,所获得的实验数据表明,基于本发明前列腺素衍生物组合的组合物具有高稳定性。
用于毛发生长的本发明组合物的临床实验室研究
对具有基于三种毛发用修饰的前列腺素(参见上述组合物实施例)的化妆品配方的毛发生长剂进行临床实验室研究,特别是使用两种包括本发明的不同组合的组合物:
-组合物1包括两种修饰的前列腺素的组合,包括:
150μg/mL(0.015%)式I)化合物;
50μg/mL(0.005%)式III)化合物;
比例为3:1。
-组合物2包括三种修饰的前列腺素的组合,包括:
150μg/mL(0.015%)式I)化合物;
150μg/mL(0.015%)式II)化合物;
50μg/mL(0.005%)式III)化合物;
比例为3:3:1。
实验在22名年龄在25至62岁之间的女性志愿者身上进行,其具有不同严重程度的女性型脱发。
在进行研究时,在使用这些配方之前,所有志愿者都签署了同意进行此类研究并将所获的结果用于科学目的的知情同意书。
在使用这种化妆品之前和之后进行了客观的实验性临床研究,使用Courage+Khazaka电子有限公司(德国)制造的VISIOSCAN VC 98轮廓仪评估单位面积的头发数量,对头皮进行了轮廓测量(对头部和要治疗的特定区域进行全面检查)。
在第一次测量之前和在应用本发明的毛发生长剂之后,在相同的条件下进行头皮轮廓测量,并评估每单位面积的头发数(密度)。每个志愿者的头发密度在顶区严格定义的标记点处进行评估,其在研究开始之前、应用本发明的制剂之前和之后进行两次,反映在每个患者的病例报告表中。在设备上使用16mm2区域来计算头发密度和头皮照片(用于分析的区域的照片)。
本发明的所述制剂按以下方案使用:以约1mL组合物的量施用在头皮的选定区域上,每天一次。施用期为3个月。
本发明的组合物1和2均制备为洗剂形式,并具有均匀的稠度,易于均匀地施用于皮肤,吸收良好,不具有刺激性和致敏作用。在施用毛发生长组合物1和2后观察到显著的主观结果:头发产生光泽并且脱发减少。研究结果如图1所示。
数据分析和统计处理如下所示。在将毛发生长剂的两种配方(组合物)与基线水平进行比较后,与仅含有两种修饰的前列腺素的配方1相比,当应用具有三种修饰的前列腺素的配方2时,注意到毛发密度显著增加,不过,制剂1也显示出了良好的疗效。
因此,在研究过程中,出乎意料地发现,本发明和基于其的组合物的组合可以显著增加受试者毛发的总数。因此,特别是,基于毛发图像分析技术的的分析,女性使用本发明组合物3个月后,头发总数从13%增加到近30%。
尽管本发明已经参照所公开的实施例进行了描述,但本领域技术人员来说,很明显详细描述的具体实验仅用于说明目的,不应被解释为以任何方式限制本发明的范围。应理解,在不脱离本发明本质的情况下,可以进行各种改动。
Claims (17)
1.一种用于增强毛发生长和/或预防和/或治疗受试者脱发的组合产品,其至少包含式(I)化合物和式(II)和/或式(III)化合物,
其中所述的式(I)化合物是:
所述的式(II)化合物是:
所述的式(III)化合物是:
2.如权利要求1所述的组合产品,其包含式(I)、式(II)和式(III)化合物。
3.如权利要求1所述的组合产品,其包含式(I)和式(II)化合物。
4.如权利要求1所述的组合产品,其包含式(I)和式(III)化合物。
5.如权利要求1所述的组合产品,其中脱发为雄激素性、弥漫性或斑秃性。
6.一种用于增强头发生长和/或预防和/或治疗脱发的组合物,包括权利要求1所述的组合产品和至少一种赋形剂。
7.如权利要求6所述的组合物,其中所述组合产品的组分是有效量的。
8.如权利要求6所述的组合物,其中所述赋形剂为载体。
9.如权利要求6所述的组合物,其中所述赋形剂为填充剂和/或溶剂。
10.如权利要求6所述的组合物,其中通式(I)化合物在组合物中的含量为每1mL成品组合物中含50-300μg。
11.如权利要求6所述的组合物,其中通式(II)化合物在组合物中的含量为每1mL成品组合物中含50-300μg。
12.如权利要求6所述的组合物,其中通式(III)化合物在组合物中的含量为每1mL成品组合物中含50-200μg。
13.权利要求6的组合物在制备用于增强毛发生长和/或预防和/或治疗受试者的脱发的药物中的用途。
14.如权利要求13所述的用途,其中脱发为雄激素性、弥漫性或斑秃性。
15.如权利要求13所述的用途,其中所述组合物为局部施用。
16.如权利要求15所述的用途,其中所述组合物为每日施用或隔日施用。
17.如权利要求13所述的用途,其中所述受试者为人。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5625083A (en) * | 1995-06-02 | 1997-04-29 | Bezuglov; Vladimir V. | Dinitroglycerol esters of unsaturated fatty acids and prostaglandins |
WO2014158373A1 (en) * | 2013-03-14 | 2014-10-02 | Allergan, Inc. | Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith |
RU2662099C1 (ru) * | 2017-10-16 | 2018-07-23 | Общество с ограниченной ответственностью "Гурус БиоФарм" | Фармацевтические композиции для ингаляций, содержащие нитропростон |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3776938A (en) | 1958-05-28 | 1973-12-04 | S Bergstrom | Dihydro-pge1 |
US4011262A (en) | 1972-07-13 | 1977-03-08 | Pfizer Inc. | 13,14-Dihydro-15-substituted-ω-pentanorprostaglandins of the two series |
US4024179A (en) | 1972-11-08 | 1977-05-17 | Pfizer Inc. | Substituted ω-pentanorprostaglandins |
GB1507211A (en) | 1975-02-14 | 1978-04-12 | Ono Pharmaceutical Co | Prostaglandin analogues |
US4828837A (en) | 1987-03-30 | 1989-05-09 | Liposome Technology, Inc. | Non-crystalline minoxidil composition, its production and application |
TW382595B (en) | 1993-10-15 | 2000-02-21 | Merck & Co Inc | Pharmaceutical composition for use in arresting and reversing androgenic alopecia |
US5670643A (en) | 1995-03-16 | 1997-09-23 | Glaxo Wellcome Inc. | Method for preparing finasteride |
DE69823852T2 (de) | 1997-02-04 | 2005-05-19 | Johnstone, Murray A., Seattle | Verfahren zur förderung des haarwuchses und entwicklung des haarsystems |
AUPP310798A0 (en) | 1998-04-22 | 1998-05-14 | Soltec Research Pty Ltd | Vehicle system for a composition comprising a piperidinopyrimidine derivative |
US7851504B2 (en) | 2005-03-16 | 2010-12-14 | Allergan, Inc. | Enhanced bimatoprost ophthalmic solution |
KR20100101097A (ko) | 2007-11-09 | 2010-09-16 | 알러간, 인코포레이티드 | 프로스타글란딘 활성을 갖는 치환된 사이클로펜탄 |
CA3045407C (en) | 2009-07-29 | 2024-03-12 | Elise A. Olsen | Compositions and methods for inhibiting hair growth |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5625083A (en) * | 1995-06-02 | 1997-04-29 | Bezuglov; Vladimir V. | Dinitroglycerol esters of unsaturated fatty acids and prostaglandins |
WO2014158373A1 (en) * | 2013-03-14 | 2014-10-02 | Allergan, Inc. | Topical compositions comprising bimatoprost and methods for stimulating hair growth therewith |
RU2662099C1 (ru) * | 2017-10-16 | 2018-07-23 | Общество с ограниченной ответственностью "Гурус БиоФарм" | Фармацевтические композиции для ингаляций, содержащие нитропростон |
Non-Patent Citations (1)
Title |
---|
1,3-Dinitrates of Cyclooxygenase Metabolites of Endocannabinoid 2-Arachidonoylglycerol. Synthesis and Properties;I. V. Serkov a and V. V. Bezuglov;Russian Journal of Bioorganic Chemistry;第35卷(第2期);245-252 * |
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EA202290013A1 (ru) | 2022-03-18 |
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EP3991734A1 (en) | 2022-05-04 |
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