CN105979956A - 用于抑制5-α还原酶的基于植物提取物的组合物 - Google Patents
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Abstract
本发明涉及用于抑制5‑α还原酶的基于来自梨果仙人掌(Opuntia ficus)的花或果实和稻(Oryza sativa)(黑米)的植物提取物的组合的保健品组合物、化妆品组合物或药物组合物。具体地,根据本发明的制剂用于预防或治疗良性前列腺肥大或增生、预防或治疗雄激素性脱发和痤疮。
Description
本发明涉及用于抑制5-α还原酶的基于来自梨果仙人掌(Opuntia ficus indica)和稻(Oryza sativa)(黑米)的花或果实的植物提取物的组合的保健品组合物、化妆品组合物或药物组合物。具体地,根据本发明的制剂用于预防或治疗良性前列腺肥大或增生、预防或治疗雄激素性脱发和痤疮。
睾酮是由睾丸间质细胞(Leydig cell)受下丘脑和脑垂体前叶控制合成的一种雄激素(1)。细胞中的睾酮由血管系统收集,通过5-α-还原酶转化为去氢睾酮(DHT)。由此产生的DHT能够与雄激素受体结合并作用于特定的核基因的转录和表达。产生的DHT作用于前列腺组织的分化和生长、男性生殖器的生长、面部和身体上毛发的青春期生长,并参与若干疾病诸如痤疮、多毛症、良性前列腺肥大(BPH)、雄激素性脱发(AGA)和前列腺癌(1)。
良性前列腺肥大(BPH)和雄激素性脱发(AGA)是雄激素依赖性疾病,其中睾酮通过5-α-还原酶转化为DHT起到了关键作用(2)。在前列腺中,DHT通过两种异形体形式(1型和2型)的5-α-还原酶的作用而产生,并参与前列腺组织的生长。在头皮中,DHT主要通过2型的5-α-还原酶而产生,并负责毛球的小型化(2)。
良性前列腺肥大(BPH)是与衰老相关的病理病况,侵袭多达20%的40岁男性,而在70岁男性中还可以达到80%(3)。相较于低死亡率(0.35/100.000人),良性前列腺肥大是潜在不断发展的疾病,其必然具有若干下尿路症状(LUTS),并且伴随疾病进展,其可能对男性受试者的生活质量具有负面影响(4)。
与BPH相关的最常见症状分为机械和动力梗阻型、和刺激型症状(5,6)。机械梗阻型症状通过前列腺移行带中的上皮组织的过度生长来确定,而动力梗阻型症状源于膀胱颈、前列腺及前列腺囊的平滑肌张力的增大。梗阻型症状包括:开始排尿困难、断续的尿流、膀胱排空不彻底、尿流减少和尽力排尿。定义为具有刺激性来源的症状是:夜尿症(nicturia)、尿急、尿频(排尿频繁)、失禁和排尿过程中灼烧/疼痛(3,7)。目前使用国际前列腺症状评分(IPSS)的调查表来评估此类症状并从而评估疾病的严重度。
如果不能恰当治疗,良性前列腺增大可随时间而发展,导致对于患者健康而言更严重的后果。尿潴留可确定由于膀胱残余尿中细菌的生长导致的前列腺炎的发生,和由于残余尿中盐的形成导致的肾结石。并且,膀胱排空不彻底和慢性尿潴留可显著损害肾功能,并随之出现梗阻型尿路病。
BPH的原因目前仍不完全清楚。然而,可能的是设想此类伴随衰老的疾病与男性受试者中激素状态的改变相关联,尤其是去氢睾酮(DHT)水平的增高相关联。DHT实际上是参与前列腺组织的生长的睾酮的衍生物,从而其积累可产生组织肥大的病况(8)。什么是导致此类DHT的产生增加的原因仍是研究的主题。然而,科学证据阐释了抑制5-α-还原酶如何能起作用并控制这样的疾病,该酶为负责睾酮转化为DHT的酶(8)。良性前列腺肥大的治疗中的药理学疗法基于两类可能的化合物:α-阻滞药和5α-还原酶的抑制剂(8,9,10)。
α-阻滞药(α1-肾上腺素受体拮抗剂)通过放松前列腺和膀胱颈的动脉的平滑肌来起作用,从而减少尿路梗阻并促进尿流速的增大。最常见的α-阻滞药包括:多沙唑嗪、特拉唑嗪、阿夫唑嗪、赛洛多辛和坦洛新。此类药物用于治疗良性前列腺肥大的症状,但它们对疾病的发展并未显示任何作用。α-阻滞药的扩展应用可诱导一些副反应,比如头晕、头痛、不适、疲劳和呼吸困难。较少观察到的其他反应为直立性低血压和逆行射精。
5α-还原酶的抑制剂通过阻断该酶的合成和产生并因而阻断睾酮向DHT的转化而起作用。此类化合物(比如非那雄胺和度特雄胺)能够诱导肥大性前列腺的体积减小并阻止生长进程,为此,在轻度和重度BPH(前列腺体积>40ml)的治疗中指示此类疗法(9)。而且在该情况下,观察到若干副作用,比如性欲减退、男子乳腺发育、逆行射精(异常射精)。
其他药理治疗涉及具有抗毒蕈碱(抗胆碱能)作用的物质和5-磷酸二酯酶的抑制剂,但由于低效率和大量副作用,它们的使用受到限制(9)。
仅在药理治疗(甚至组合的治疗)完全失败的情况下,可能诉诸于外科手术治疗。然而,这样的治疗又将患者暴露于与正常功能和射精力学相关的高水平的术后风险。即使是最近的更少侵入性的技术,比如经尿道针刺消融术(TUNA)或激光前列腺切除术(TURP),表现出一些限制并处于实验中(11,12)。
雄激素性脱发或秃发(AGA)是既侵袭男性也侵袭女性的皮肤病。在男性情况下,30岁以上者逾30%和50岁以上者逾50%罹患该病。AGA甚至可以较低发生率侵袭女性,虽然普遍为轻度的临床症状,比如头皮整个上部毛发的弥漫性稀疏(13)。雄激素性脱发的主要原因未完全清楚,若干因素可能在该病中起作用,比如年龄和遗传预先倾向性。此外,个体中脱发的发生和雄激素活性之间存在某种关联,尤其是,部分5-α-还原酶导致的DHT的产生。事实上,毛囊中存在的DHT能够与雄激素受体结合并在毛发的生命周期中诱导生长期持续时间的减少和静止期的延长。结果,毛发将遭受其长度和直径的减小(小型化)。静止期(telagen phase)和脱发之后,将观察到生长期恢复的延迟,结果,毛囊在更长一段时间将是空的。这将意味着所涉及的头皮区域中毛发密度的减少和明显的稀疏。不同生命周期中该病(小型化)的复发将导致毛球的最终死亡和毛发的不可逆脱落(13)。
米诺地尔,通过局部或全身途径给药,成为最常见的雄激素性脱发的治疗之一。最初用作高血压治疗中的血管扩张药的米诺地尔似乎能够直接作用于毛囊角质形成细胞的增殖和分化,诱导生长期的延长。米诺地尔常与其他活性物质组合使用,但在治疗中止后,其作用随时间推移而受到限制。另一方面,该药物的扩展应用似乎显著地增高了不想要的副作用的风险,比如刺激、皮疹、还有严重的瘙痒。
5-α-还原酶的选择性抑制剂,例如非那雄胺,也用于AGA的全身性治疗。然而,这些治疗存在一些缺点,比如:需要长期治疗(至少一年)、高剂量和因此其费用高,与该类药物相关的副作用(男子乳腺发育、性功能障碍等)(13)。
因此需要良性前列腺肥大而非雄激素性脱发的替代治疗,该治疗不存在现有技术中所报道的严重副作用。
本发明的作者现已发现梨果仙人掌的花和/或果实的植物提取物和稻(黑米)的植物提取物的组合应用对良性前列腺肥大的细胞系和雄激素依赖的皮脂腺细胞(用于文献中以研究对由于睾酮介导的增殖性作用导致的痤疮和皮肤疾病的作用)产生了协同型的抗增殖作用。同样,该植物提取物的组合显示了对滤泡真皮乳头细胞的永生化细胞系(用于文献中以研究对雄激素性脱发的作用)的协同型的增殖性作用。如来自台盼兰的测定结果所见,两种植物提取物的组合对正常细胞系(即成纤维细胞的细胞系)未显示任何细胞毒性(数据未示出)。
梨果仙人掌(Opuntia Ficus Indica)(胭脂仙人掌(Nopal))是属于原产自墨西哥和美国西南部的仙人掌科(Cactaceae)的植物,但也常见于地中海盆地周围的天然植物中。此外,在民间医学中,该植物的若干部分在大量应用中具有用途:果实被认为是收敛剂,并且由于其含丰富的维生素C,过去为水手用于防止坏血病;幼叶状枝(在炉中加热之后)用作软化剂,以糊剂的形式来涂覆;将叶状枝的果肉直接涂覆在创伤和溃疡上对于皮肤创伤和皮肤溃疡具有良好的抗炎治疗、恢复和愈合作用;花的煎剂具有利尿性质,并且在以色列认为其是用于治疗良性前列腺肥大(BPH)的天然药物。
在Jonas等人进行的研究中(14),已观察到利用水性溶剂和有机溶剂获得的来自仙人掌品种的花的提取物能够用作5-α-还原酶和芳香酶二者的抑制剂。
Ammar等人(15)已获得了梨果仙人掌的花中所含的化合物的定性-定量表征。根据作者所公开的内容,花的己烷提取物主要由以下物质的衍生物构成:羧酸类(29-97%);萜类(0.2-57%),酯类(0.2-27%)和较少量的醇化合物(<1.8%)。
最近,特别关注了植物母体(plant matrix)中存在的黄酮类化合物。De Leo等人(16)已在梨果仙人掌的花的甲醇提取物中鉴定了山柰酚的糖基化的衍生物、槲皮素和异鼠李素的存在,总含量达到81.75mg/1g新鲜花。
在这些化合物中,异鼠李素3-O-刺槐双糖苷是最普遍的化合物,占总黄酮类含量的约52%。
黑米(稻)是米的一个类型,其谷粒呈现黑色的典型果皮(种壳)。
目前,黑米遍布国际市场分布,其也在意大利种植。事实上,从黑米和意大利米系的杂交育种,获得了杂种(维纳斯米),其维持了中国米的特质,但能够适应我们自身的气候。
在中国,黑米被认为是贵重的食品,因为其存在丰富的营养物质(蛋白质和矿物盐比如铁、锰和硒),但主要因为其有利和有益健康的性质。
事实上,在民间医学中,黑米用于治疗贫血、增强肾功能、促进血液循环和治疗糖尿病(17)。目前此类性质主要归因于存在于果皮中的抗氧化活性物质,和赋予其特殊颜色的花色素苷(anthocyanin)。Min-Kyoung等人进行的最近研究(18)已显示黑米含有三种花色素(anthocyanos ide)物质:花青素(cyanidin)-3-葡糖苷;飞燕草色素(delphinidin)-3-葡糖苷和矮牵牛苷(petudin)-3-葡糖苷。然而,其中花青素-3-葡糖苷作为占主要的量的化合物而存在从而我们可认为黑米是这样的花色素化合物的天然来源(18)。
本发明的主题是用于预防和治疗与抑制5-α还原酶的酶活性相关的代谢疾病或疾患的保健品组合物或药物组合物,所述保健品组合物或药物组合物包含梨果仙人掌的花和/果实的提取物与稻的提取物组合作为活性成分以及生理学可接受的佐剂和/或赋形剂,所述代谢疾病或疾患选自下组:良性前列腺肥大、雄激素性脱发或痤疮。根据本发明的组合物中存在的梨果仙人掌的花和/或果实和稻(黑米)的提取物的重量比倒数为约1:1至1:25,优选为1:10或1:20。
根据本发明,可使用黑米的某些杂交品种。
来自梨果仙人掌的花或果实的提取物可相互替换或组合使用。
根据本发明的一个优选实施方案,根据本发明的基于梨果仙人掌的花和/或果实和稻(黑米)的植物提取物的组合的药物组合物或保健品组合物专用于良性前列腺肥大的治疗。优选地,此类组合物适用于口服施用,仍优选地为口服溶液、口服乳液、口服混悬液、胶囊、片剂或粉末的形式。在该实施方案中,用于组合的提取物的总浓度占总组合物重量的10-90%。
根据本发明的替代实施方案,根据本发明的基于梨果仙人掌的花和/或果实和稻(黑米)的植物提取物的组合的化妆品组合物或药物组合物专用于雄激素性脱发或痤疮的治疗。
优选地,此类化妆品组合物或药物组合物适用于局部施用、仍更优选地是乳膏、发蜡、软膏、泡沫、洗剂、凝胶剂或喷雾剂的形式。对于局部施用,优选的浓度范围可在最终组合物的以重量计0.5%和5%之间变化(优选2%)。还可能的是以溶液、乳液、口服悬浮液、胶囊、片剂或颗粒的形式提供它们的口服施用。对于口服施用,用于组合物的提取物的优选的总浓度范围可在最终组合物的以重量计10%和90%之间变化。
本发明的另一个主题也是梨果仙人掌的花和/果实与稻(黑米)的提取物的组合,用于同时地、依次地或单独地预防和治疗与抑制5-α还原酶的酶活性相关联的代谢疾病或疾患。所述与5-α还原酶的酶活性的抑制相关联的代谢疾病或疾患选自良性前列腺肥大、雄激素性脱发或痤疮。
根据本发明的梨果仙人掌的花和/或果实和稻(黑米)的植物提取物的组合可适用于化妆品、药物或保健品领域的口服施用或口服应用。
然而将梨果仙人掌的花和/或果实和稻(黑米)的提取物以组合来施用,所述组合维持了1:1和1:25之间的倒数重量比,优选为1:10或1:20的倒数重量比。
对于口服施用,提取物的总浓度的优选范围可在最终组合物的以重量计10%和90%之间变化;对于局部施用,优选的浓度范围可在最终组合物的以重量计0.5%和5%(优选为以重量计2%)之间变化。
现将根据一些优选的实施方案特定参考附图对本发明作出阐释性而非限制性描述,其中:
-图1示出了用梨果仙人掌的花的提取物(O)、黑米的提取物(R)和它们的组合(O/R)处理72小时后获得的BPH-1细胞(良性前列腺肥大的上皮细胞)的细胞活力的百分比值。*p<0.05对比O和R;
-图2示出了用梨果仙人掌的花的提取物(O)、黑米的提取物(R)和它们的组合(O/R)处理72小时后获得的LNCaP细胞(雄激素依赖性肿瘤前列腺细胞)的细胞活力的百分比值。*p<0.05对比O和R;
-图3示出了用梨果仙人掌的花的提取物(O)、黑米的提取物(R)和它们的组合(O/R)处理72小时后获得的DU145细胞(雄激素依赖性肿瘤前列腺细胞)的细胞活力的百分比值。*p<0.05对比O和R;
-图4示出了用维生素C(50μg/mL)、梨果仙人掌的花(O)的提取物、黑米的提取物(R)和它们的组合(O/R)处理24小时之后获得的来自人毛囊的乳头状真皮细胞(papillarydermal cell)(DP细胞)的细胞生长对比对照(未处理)的值。*p<0.05;
-图5显示了用梨果仙人掌的花的提取物(O)、黑米的提取物(R)和它们的组合(O/R)处理9天后获得的人永生化皮脂腺细胞(SZ95皮脂腺细胞系)用睾酮10-6M(测试)处理对比对照(未处理)的细胞生长的值。*p<0.05;
-图6示出了用梨果仙人掌的花(O)的提取物、黑米的提取物(R)和它们的组合(O/R)处理72小时后,BPH-1细胞中获得的5-α-还原酶的抑制百分比。*p<0.05对比O和R;
-图7示出了用梨果仙人掌的花(O)的提取物、黑米的提取物(R)和它们的组合(O/R)处理72小时后,BPH-1细胞中获得的相对于对照(自由基物质ROS的表达)的IF/mg蛋白百分比值。*p<0.05对比O和R。
在仅为阐释性的、而非限制性的本发明的目的下,所报道的由本发明的作者在体外对若干人前列腺细胞系进行的研究显示了根据本发明的含有梨果仙人掌花的提取物和黑米的提取物的组合物的协同的抗增殖作用。
实施例1:仙人掌的花/果实的提取物和稻的提取物的制备
i)梨果仙人掌的花/果实的提取
下文描述了萃取过程:
步骤a:在室温下利用水性溶液(优选酸化至pH 3)或利用水-醇溶液(乙醇含量为10-70%)对新鲜的或干燥的梨果仙人掌(来自地中海盆地的培育)的花/果实进行浸渍。为了有助于萃取,可在接触萃取溶剂之前将花和果实粉碎或切碎。
步骤b:利用新鲜的萃取溶剂对相同的植物母体进行第二次萃取以有利于回收存在的活性物质;
步骤c:在不高于50-60℃的室温下对获得的提取物进行真空下的回收和浓缩。在水-醇提取物的情况下,进行提取物浓缩直至完全去除有机溶剂。
步骤d:通过提取物通过大孔吸收树脂Amberlite XAD-7或其他相似的吸收树脂,利用水-醇溶液(50-90%)洗脱而对活性化合物进行回收和分离。
步骤e:浓缩直至完全去除有机溶剂,然后通过利用合适的技术支持物(例如麦芽糖糊精)通过喷雾干燥或冻干进行干燥。
根据本发明的提取物可以是液体或经干燥的(粉末)。所获得的提取物含有的黄酮类化合物的量不低于0.1%w/p(范围0.1-5%),且异鼠李素3-O-刺槐双糖苷的含量相对于总黄酮类含量不低于20%。
ii)黑米(稻)的提取
下文描述了萃取方法:
步骤a:在室温下在利用盐酸(0.1%,HCl)的酸性pH下利用水-醇溶液(20-60%)对完整的谷粒或通过摩擦谷粒的外表面获得的单独的着色的果皮进行浸渍。
步骤b:利用新鲜萃取溶剂对相同的植物母体进行第二次萃取以促进回收存在的活性物质。
步骤c:在不高于50-60℃的温度下对获得的提取物进行真空下的回收和浓缩直至完全去除有机溶剂。
步骤d:通过提取物通过大孔吸收树脂Amberlite XAD-7或其他相似的吸收树脂,利用水-醇溶液(50-90%)洗脱而对活性化合物进行回收和分离。
步骤e:浓缩直至完全去除有机溶剂,然后通过利用合适的技术支持物(例如麦芽糖糊精)通过喷雾干燥或冻干进行干燥。
本发明涉及液体或经干燥的(粉末)提取物。获得的黑米的提取物存在的花色素含量以作为其主要成分的等价物花青素-3-O-葡糖苷来表达,在1-20%w/p之间。
实施例2:对梨果仙人掌花的提取物和稻的提取物的抗增殖活性的体外研究
该研究的目的是在体外评价彼此分开或相互组合的梨果仙人掌花的植物提取物和稻(黑米)的植物提取物对正常的人前列腺上皮细胞和肿瘤的人前列腺上皮细胞发挥的抗增殖活性。
实验操作方案提供了能够通过MTT比色测定评价细胞活力的体外细胞模型的用途。
材料和方法
良性前列腺肥大或增生是前列腺携带的疾病。该疾病的特征是由于上皮细胞和基质成分(stromal element)的过度生长导致的腺体积的良性增大。这样的组织增生的恶性变性决定了前列腺癌的发展。
已经对来自梨果仙人掌的花的提取物和黑米的提取物及其组合对以下的良性前列腺肥大的模型细胞和前列腺癌的模型细胞的抗增殖活性进行了评价:
-BPH-1:良性前列腺肥大的上皮细胞;
-LNCaP:雄激素依赖性前列腺癌细胞;
-DU145:耐雄激素的前列腺癌细胞。
这些细胞表现了前列腺疾病的不同程度的侵袭性,从良性前列腺肥大(BPH-1)到更严重的癌症类型(LNCaP,DU145)。
在补充有10%胎牛血清、1mM谷氨酰胺和10μl/ml的链霉素/青霉素的RPMI 1640培养基中培养了BPH-1细胞和LNCaP细胞。在补充有10%FCS、1%链霉素-青霉素、1%谷氨酰胺、1%非必需氨基酸的DMEM培养基中培养了DU145细胞。培养维持在37℃下、在5%CO2的气氛中。每2-3天更换培养基。
然后将BPH-1、DU145和LnCap细胞接种到用于MTT测定的孔上,在在37℃下、在5%CO2的气氛中培养24小时后,根据以下表1中报道的内容,用每种提取物单独地和组合地处理72小时。
表1用于对BPH-1、LNCaP和Du145细胞的细胞增殖测定(MTT细胞测定)中的评价的提取物及其组合
样品 | 组合物 | 浓度 |
O | 梨果仙人掌花的提取物 | 10μg/ml |
R | 黑米的提取物 | 200μg/ml |
O/R | 梨果仙人掌花的提取物/黑米的提取物 | 210μg/ml |
O:梨果仙人掌花的提取物;R:黑米的提取物;O/R:两种提取物的组合
通过四唑盐的比色测定测量了处理后的细胞活力,评价了细胞通过线粒体琥珀酸脱氢酶还原3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四氮唑(MTT)的能力。MTT进入细胞并进入线粒体中,在线粒体中它被还原为有颜色的不溶产物甲为了使颜色可见,通过添加DMSO将有颜色的甲颗粒溶解。MTT裂解反应需要完全的细胞完整性,且其与细胞的代谢活性程度成比例。
在37℃、5%CO2下将细胞与溶于培养基的20μl的四唑盐溶液(5mg/ml)和180μl培养基一起孵育三小时之后,除去上清液并添加100μl的DMSO。然后,通过用于微孔板读数的分光光度计(Titertek Multiscan,Flow Laboratories)在570nm的波长下测量了光密度(O.D.)。
细胞活力表达为相对于未处理的对照的光密度的百分比。对于每种样品,以三个重复进行实验。
结果
从所进行的MTT测定获得的数据显示了当单独使用仙人掌花的提取物(O)和黑米的提取物(R)时,它们均能够对BPH-1细胞系、LNCaP细胞系和DU145细胞系诱导细胞活力的降低(表2)。利用两种提取物的组合(O/R)处理相同的细胞系,相对于单独的提取物以协同型的抗增殖作用确定了细胞活力的显著下降(参见图1-3和表2)。以下表2示出了处理72小时之后细胞增殖(MTT)的值,表示为相对于良性前列腺肥大的上皮细胞(BPH-1)、雄激素依赖性前列腺癌细胞(LNCaP)和耐雄激素的前列腺癌细胞(DU145)的对照(对照(CTRL))的细胞活力百分比。
表2
*p<0.05对比O和R
实施例3:评价梨果仙人掌的提取物和黑米的提取物对乳头状真皮细胞的活性
乳头状真皮细胞是特殊分化的间充质细胞,其在毛发的生命周期中具有重要作用。
这些细胞的刺激和增殖促进了生长期中的毛发生长。此类细胞用作评价毛球的生长促进剂的模型细胞。
材料和方法
在37℃下、在5%CO2的气氛中,在补充100单位/mL的青霉素和100μg/mL的链霉素的生长培养基(PromoCell)中培养了来自人毛囊的乳头状真皮细胞(DP细胞,PromoCell)。然后将DP细胞接种到用于MTT测定的孔上,在37℃下在5%CO2的气氛中孵育24小时之后,根据表1中所指用每种提取物单独地和组合地处理它们24小时。通过MTT比色测定(根据以上所描述的操作方案)测量处理后的细胞活力。将维生素C用作阳性对照(50μg/mL)。
结果
从对来自人毛囊的乳头状真皮细胞进行的细胞增殖测定获得的结果显示了梨果仙人掌花的提取物(O)和黑米的提取物(R)如何决定中度的增殖作用,低于用作阳性对照的维生素C的作用或与之相当(图4)。然而,当两种提取物组合使用时(O/R),这样的作用变得显著更高,生长细胞增多了约54%。
实施例4:评价梨果仙人掌花提取物和黑米提取物对人皮脂腺细胞的细胞增殖的活性
毛囊皮脂腺单元构成了对于雄激素的作用更敏感的皮肤结构。具体地,皮脂腺细胞具有显著的5-α-还原酶的活性,并且为此它们被认为是那些雄激素依赖性皮肤疾患(诸如痤疮)的靶细胞和模型。
材料和方法
在37℃下在5%CO2的气氛中,在补充10%胎牛血清、5μg/ml的重组人表皮生长因子、1mM Ca2+和50μg/ml庆大霉素的Sebomed培养基(Biochrom)中培养了永生化的人皮脂腺细胞(SZ95皮脂腺细胞系)。随后将SZ95细胞接种到用于MTT测定的孔上,在37℃下、在5%CO2的气氛中孵育24小时后,根据表1中所记录的指示用含终浓度10-6M的睾酮和提取物的新培养基进行处理。
在处理9天之后,通过比色MTT测定(根据以上所描述的操作方案)对每种样品评价细胞活力,表示为相对于对照(0%)和相对于用睾酮进行的处理(测试=100%)的百分比值。每个实验以三个重复进行。
结果
对永生化的人皮脂腺细胞SZ95进行的MTT研究显示了如何用睾酮进行的处理在这些细胞中诱导细胞增殖的增高(图5)。梨果仙人掌的花的提取物和黑米的提取物当单独使用时能够拮抗激素诱导的增殖。该作用通过组合使用的两种提取物所发挥的协同作用而增强。
实施例5:评价梨果仙人掌花的提取物和黑米的提取物对细胞增殖所发挥作用的机制
在本研究中,利用良性前列腺肥大的上皮细胞BPH-1作为模型细胞,在以下测定中对单独使用的或组合使用的梨果仙人掌花的提取物和黑米的提取物发挥的作用所涉及的潜在机制进行了评价:
-通过Western印迹技术测定5-α-还原酶的表达(酶抑制);
-ROS氧的自由基物质的产生(抗氧化活性);
-通过ELISA技术测定Akt/PKB因子的表达(细胞周期调控)。
材料和方法
细胞培养和处理
在补充有10%FCS、1mM谷氨酰胺和10μl/ml的链霉素/青霉素的RPMI 1640培养基中培养了BPH-1细胞并维持在37℃下、在5%CO2的气氛中。每2-3天更换培养基。实验前24小时,对细胞进行胰蛋白酶消化,用血细胞计数器计数,接种到新孔中并根据以下表3中所报道的内容用每种提取物单独地和组合地处理72小时。
表3用于BPH-1细胞培养的5α-还原酶抑制、ROS产生和细胞周期调控的测定中的提取物及其组合
5-α-还原酶的抑制
用PBS冰冷洗涤经处理的BPH-1细胞两次,然后用含10mM Tris-HCl、10mM KCl、2mMMgCl2、0.6mM PMSF和1%SDS的pH 7.4的裂解缓冲液收集。在0℃下冷却10分钟之后,离心后收集蛋白质。在每个泳道中上样存在于上清液中的60微克总蛋白,然后通过在聚丙烯酰胺凝胶中电泳分离。然后,将蛋白质转移到潮湿环境中的硝酸纤维素膜中。
通过在4℃下与含0.01%的Tween-20(TBST)和5%的脱脂牛奶的盐缓冲液孵育整夜将膜的非特异性位点掩蔽。
用TBST适当地稀释针对5α-还原酶的抗体,在室温下孵育2小时,然后利用用于化学发光的底物Supersignal West Pico Chemioluminescent(Pierce Chemical Co.,Rockford,IL)用缀合过氧化酶的第二抗体检测。通过放射自显影照片的光密度分析对蛋白质的表达进行定量。将每种样品的单个条带的密度相对于作为参考蛋白的α-微管蛋白来表达,并将所示数值(信号密度的对应物)以任意光密度单位来报道。从这些数据中,已计算了每种样品相对于对照的抑制百分比。每个实验以三个重复进行。
结果
从进行的研究中获得的数据显示了梨果仙人掌的提取物相对于黑米的提取物显示了对5α-还原酶的表达更高的抑制,百分比达约40%(参见表4;图6)。
表4从利用梨果仙人掌花提取物(O)和黑米提取物(R)单独地或组合地(O/R)处理的良性前列腺肥大的上皮细胞(BPH-1)获得的5α还原酶的抑制百分比
*p<0.05对照O和R
然而,当组合使用提取物时,观察到该作用的显著增强,抑制百分比为约75%。
氧的自由基物质(ROS)的测定
为测定自由基物质,使用了非荧光的二氯荧光素二乙酸酯(DCFH-DA)。在ROS存在下,DCFH-DA水解并氧化为DCF,后者为高度荧光分子。利用荧光计Hitachi在λEx=485nm和λE=530nm处使用DCF的细胞内荧光的密度来定量细胞中存在的氧化物质。结果表示为荧光密度/mg蛋白质。
结果
从实验中获得的数据显示了利用黑米的提取物对BPH-1细胞系进行的处理决定了自由基物质ROS的较低表达,且因此抗氧化保护作用高于从梨果仙人掌的花的提取物中所获得的抗氧化保护作用(参见表5和图7)。此外,当用两种提取物处理细胞时,自由基物质的产生显著降低(87%抑制),两种提取物之间的协同作用增强了细胞内抗氧化防御。
表5利用梨果仙人掌花提取物(O)和黑米提取物(R)单独地和组合地(O/R)处理的BPH-1细胞表达的自由基物质ROS的百分比值对比对照
*p<0.05对比O和R
Akt/PKB因子表达的测定
通过STAR(Signal Transduction Assay Reaction)ELISA试剂盒,根据供应商的说明,对BPH-1细胞裂解物进行了fosfo-AKT(Thr308)和fosfo-AKT(Ser473)的表达的测定。通过测量450nm波长处的吸光度进行了比色测定,p-Akt(Thr308)和p-Akt(Ser473)的含量表示为U/ng总Akt。
结果
在用梨果仙人掌花和黑米的提取物处理的细胞样品中,观察到Akt(Thr308)和Akt(Ser473)水平相对于作为对照的未处理的细胞的显著降低(表6)。而当组合使用提取物时(O/R),该作用结果显著增强。
表6利用梨果仙人掌花的提取物(O)和黑米的提取物(R)单独地和组合地(O/R)处理的BPH-1细胞中Akt(Thr308)和Akt(Ser473)的表达
*p<0.05对比O和R
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实施例2-4中采用的几个实验模型允许对单独使用的或组合使用的梨果仙人掌花的提取物和黑米的提取物在以下方面进行评价:通过BPH-1、LNCaP和DU145细胞系对在治疗若干雄激素依赖性疾病诸如良性前列腺肥大(不同侵袭程度)中的作用进行评价,通过来自人毛囊的乳头状真皮细胞(DP细胞)对在治疗雄激素性脱发中的作用进行评价;通过使用人永生化的皮脂腺细胞的SZ95细胞系对在治疗痤疮和其他雄激素依赖性皮肤疾患中的作用进行评价。
对所用的每种细胞系,采用了细胞增殖的MTT测定作为评价和定量方法。所获得的数据显示了单独的提取物如何能够用作所用细胞系的增殖调节剂。它们确实抑制了BPH-1、LNCaP和DU145前列腺细胞系表达的过度增殖,和在SZ59皮脂腺细胞的情况下利用睾酮进行处理所诱导的增殖,并促进了毛发乳头状真皮细胞的活力。当组合使用两种提取物时此类作用以协同型作用对所有细胞系显著增强。
实施例6:配方实例
下文示出了用于口服应用(片剂、胶囊、粉末)和局部应用(凝胶剂、补剂)的包括不同倒数重量比的梨果仙人掌的花/果实的提取物和黑米的提取物的组合的若干配方。
I)用于口服用途的配方实例
-胶囊(1:10比率)
组分 | %w/p |
梨果仙人掌花提取物 | 1% |
黑米提取物 | 10% |
乳糖 | 高达100克 |
制备方法:
根据几何衰减法则将提取物与乳糖混合,然后再分配在胶囊中。
-片剂(1:20比率)
制备方法:
将黑米和梨果仙人掌的花的提取物混合,然后根据实践利用用柠檬酸酸化的颗粒化溶液和阿拉伯胶进行流化床制粒。
将颗粒与抗结剂(滑石、二氧化硅、硬脂酸镁)混合,通过压片机器对混合物进行压片。用虫胶和滑石对片剂进行初级包衣,然后用改良的预胶化淀粉、甘油和滑石进行后续包衣。
-用于口服用途的粉末(1:1比率的实例)
组分 | %w/p |
梨果仙人掌果实提取物 | 5% |
黑米提取物 | 5% |
二氧化硅 | 0.67% |
三氯蔗糖 | 0.17% |
麦芽糖糊精 | 高达100克 |
制备方法:
根据几何衰减法则,将单独的组分和麦芽糖糊精混合,然后再分配到囊或袋中。
II)用于局部用途的配方实例
-抗脱发补剂
制备方法:
在机械搅拌和室温下,将提取物溶解到用柠檬酸酸化的水中,添加乙醇和其他组分。过滤以去除可能的悬浮颗粒。
-凝胶剂
组分 | %w/p |
羟乙基纤维素(Natrosol) | 1.5% |
梨果仙人掌果实提取物 | 0.1% |
黑米提取物 | 2% |
丙二醇 | 10% |
柠檬酸钠 | 0.35% |
焦亚硫酸钠 | 0.50% |
EDTA二钠 | 0.10% |
对羟基苯甲酸甲酯 | 0.20% |
对羟基苯甲酸丙酯 | 0.05% |
去离子水 | 高达100克 |
制备方法:
将柠檬酸钠溶于水中并随后溶解除羟乙基纤维素(Natrosol)之外的全部其他成分。向所获得的溶液添加成比例的羟乙基纤维素以促进其分散,留置搅拌约12小时以形成凝胶。确定制剂的pH不超过5的值。
-抗痤疮乳膏
制备方法:
在75℃下加热A相和B相。将C相添加到B相,并且在缓慢机械搅拌下将所得的溶液添加到A相中。用涡轮式乳化器(turbo-emulsifier)匀化约5分钟并在搅拌下冷却。当乳液达40℃时,添入D相,然后E相,再匀化3分钟。保持搅拌乳液直至完全冷却。
参考文献目录
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权利要求书(按照条约第19条的修改)
1.保健品组合物或药物组合物,包含作为活性成分的梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物的组合,以及药学上可接受的佐剂和/或赋形剂,其用于预防和治疗与5-α还原酶的酶活性的抑制相关的疾病或疾患,所述疾病或疾患选自良性前列腺增生、雄激素性脱发或痤疮。
2.用于根据权利要求1所述用途的保健品组合物或药物组合物,其中所述梨果仙人掌的花和/或果实的提取物和稻(黑米)提取物的倒数重量比在1:1和1:25之间,优选为1:10或1:20。
3.用于根据权利要求1-2中任一项所述用途的保健品组合物或药物组合物,用于预防和治疗良性前列腺,其适用于口服施用。
4.用于根据权利要求3所述用途的保健品组合物或药物组合物,其形式为口服溶液、口服乳液、口服悬浮液、胶囊、片剂、粉末或颗粒。
5.用于根据权利要求1-2中任一项所述用途的化妆品组合物或药物组合物,用于预防或治疗雄激素性脱发或痤疮,其适用于局部施用或口服施用。
6.用于根据权利要求5所述用途的化妆品组合物或药物组合物,其适用于形式为乳膏、发蜡、软膏、泡沫、洗剂、凝胶剂或喷雾剂的局部应用。
7.用于根据权利要求3-5中任一项所述用途的组合物,其适用于口服施用,其中所述提取物的总浓度占最终组合物的重量百分比的10%-90%。
8.用于根据权利要求5-6中任一项所述用途的化妆品组合物或药物组合物,其适用于局部应用,其中所述提取物的总浓度占最终组合物的重量百分比的0.5%-5%。
9.梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物的组合制剂,该梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物用于同时地或分开地用于预防或治疗与5-α还原酶的酶活性的抑制相关的疾病或疾患,所述疾病或疾患选自良性前列腺增生、雄激素性脱发或痤疮。
10.用于根据权利要求9所述用途的组合制剂,其适用于局部施用或口服施用。
Claims (10)
1.保健品组合物或药物组合物,包含作为活性成分的梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物的组合,以及药学上可接受的佐剂和/或赋形剂,其用于预防和治疗与5-α还原酶的酶活性的抑制相关的疾病或疾患,所述疾病或疾患选自良性前列腺增生、雄激素性脱发或痤疮。
2.根据权利要求1所述的保健品组合物或药物组合物,其中所述梨果仙人掌的花和/或果实的提取物和稻(黑米)提取物的倒数重量比在1:1和1:25之间,优选为1:10或1:20。
3.根据权利要求1-2中任一项所述的保健品组合物或药物组合物,用于预防和治疗良性前列腺,其适用于口服施用。
4.根据权利要求3所述的保健品组合物或药物组合物,其形式为口服溶液、口服乳液、口服悬浮液、胶囊、片剂、粉末或颗粒。
5.根据权利要求1-2中任一项所述的化妆品组合物或药物组合物,用于预防或治疗雄激素性脱发或痤疮,其适用于局部施用或口服施用。
6.根据权利要求5所述的化妆品组合物或药物组合物,其适用于形式为乳膏、发蜡、软膏、泡沫、洗剂、凝胶剂或喷雾剂的局部应用。
7.根据权利要求3-5中任一项所述的组合物,其适用于口服施用,其中所述提取物的总浓度占最终组合物的重量百分比的10%-90%。
8.根据权利要求5-6中任一项所述的化妆品组合物或药物组合物,其适用于局部应用,其中所述提取物的总浓度占最终组合物的重量百分比的0.5%-5%。
9.梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物的组合制剂,该梨果仙人掌的花和/或果实的提取物和稻(黑米)的提取物用于同时地或分开地用于预防或治疗与5-α还原酶的酶活性的抑制相关的疾病或疾患,所述疾病或疾患选自良性前列腺增生、雄激素性脱发或痤疮。
10.根据权利要求9所述的组合制剂,其适用于局部施用或口服施用。
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ITMI20140351 | 2014-03-06 | ||
ITMI2014A000351 | 2014-03-06 | ||
PCT/IB2015/051621 WO2015132755A1 (en) | 2014-03-06 | 2015-03-05 | Compositions based on plant extracts for inhibition of the 5-alpha reductase |
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EP (1) | EP3113784B3 (zh) |
KR (1) | KR20160120717A (zh) |
CN (1) | CN105979956A (zh) |
AU (1) | AU2015225767B2 (zh) |
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CN108531543A (zh) * | 2018-03-12 | 2018-09-14 | 黄健聪 | 一种评价生发/防脱发功效的体外组合方法 |
CN113398263A (zh) * | 2021-08-06 | 2021-09-17 | 宜春希宇生物制品有限公司 | 一种治疗脱发的洗发水 |
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EP3389624B1 (en) | 2015-12-18 | 2023-07-26 | Mary Kay Inc. | Topical cosmetic compositions |
TN2018000306A1 (fr) * | 2018-09-03 | 2020-01-16 | Ghidhaoui Abir | Comprimé pelliculé sécable pour le traitement définitif de la calvitie par inhibition de la 5- alpha réductase. |
CN109432319A (zh) * | 2018-12-16 | 2019-03-08 | 王殿玲 | 一种治疗前列腺增生的中药药物 |
WO2023129540A1 (en) * | 2021-12-29 | 2023-07-06 | Jrs Pharma Gmbh & Co. Kg | Lubricant for pharmaceuticals and nutraceuticals |
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US20190117723A1 (en) | 2019-04-25 |
PL3113784T3 (pl) | 2018-02-28 |
MA39500A (fr) | 2017-08-15 |
WO2015132755A1 (en) | 2015-09-11 |
PL3113784T6 (pl) | 2020-10-19 |
KR20160120717A (ko) | 2016-10-18 |
AU2015225767A1 (en) | 2016-07-07 |
AU2015225767B2 (en) | 2020-07-02 |
ES2644469T3 (es) | 2017-11-29 |
EP3113784B1 (en) | 2017-08-16 |
EP3113784B3 (en) | 2020-07-15 |
ES2644469T7 (es) | 2021-03-17 |
US20170100447A1 (en) | 2017-04-13 |
EP3113784A1 (en) | 2017-01-11 |
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