CN101600420A - 三环二萜及其衍生物用于治疗、辅助治疗或预防炎性病症和/或关节病症的用途 - Google Patents
三环二萜及其衍生物用于治疗、辅助治疗或预防炎性病症和/或关节病症的用途 Download PDFInfo
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- CN101600420A CN101600420A CNA2007800503865A CN200780050386A CN101600420A CN 101600420 A CN101600420 A CN 101600420A CN A2007800503865 A CNA2007800503865 A CN A2007800503865A CN 200780050386 A CN200780050386 A CN 200780050386A CN 101600420 A CN101600420 A CN 101600420A
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Abstract
本发明涉及至少一种三环二萜用于制造营养药物或药物的用途,所述营养药物或药物用于治疗、辅助治疗或预防炎性病症和/或关节病症。
Description
本发明涉及至少一种三环二萜用于制造营养药物或药物的用途,所述营养药物或药物用于治疗、辅助治疗或预防炎性病症和/或关节病症。
炎性病症(Inflammatory disorder)是世界上最重要的健康问题之一。炎症一般是身体组织对外界材料或伤害性刺激的宿主侵入的局部保护性应答。炎症的起因可以是感染性试剂如细菌、病毒和寄生虫;或物理因素如烧灼或辐射;或化学品如毒素、药物或工业试剂;或免疫反应如***反应和自身免疫应答或与氧化应激相关的病症。
炎症的特征在于受影响区域出现疼痛、发红、肿胀、发热和最终丧失功能。这些症状是在免疫***的细胞之间发生的一组复杂的相互作用的结果。细胞的应答导致产生若干组炎症介质的相互作用网络,所述炎症介质为:蛋白质(例如细胞因子、酶(例如蛋白酶、过氧化物酶)、主要碱性蛋白、黏附分子(ICAM,VCAM)),脂质介质(例如类花生酸、***素、白细胞三烯、血小板活化因子(PAF)),活性氧种类(例如过氧化氢、超氧化物阴离子O2 -、一氧化氮(NO)等)。然而,这些炎症介质中的一些也是正常细胞活性的调节子。因此,炎症反应的不足导致产生缺乏抵抗力的宿主(即感染),而不受控制的因此是慢性的炎症导致部分由若干种上述介质的过量生产而介导的炎性疾病。
关节病症是老年人中残疾和功能障碍的主导原因;60岁以上的人中有几乎80%显示这些病症的一些迹象。年龄、遗传因素、肌肉废用(muscledisuse)和虚弱、创伤、肥胖症和解剖学异常会促使该病症的发生。关节病症可例如由关节的(慢性)炎性疾病以及由一个或数个关节的软骨退化或其组合引起。软骨退化在本发明的范围内定义为关节软骨的代谢病症,其特征是软骨降解酶如基质金属蛋白酶的生产增加。
炎性介质过量生物合成导致的急性和慢性炎症涉及大量炎性病症,如关节炎(例如骨关节炎、风湿性关节炎)、哮喘、炎性肠病、炎性皮肤疾病(例如接触性皮炎[尤其是尿布区皮炎]、特应性皮炎、干燥症、湿疹、酒渣鼻、皮脂溢出、银屑病、神经性皮炎、痤疮、热烧伤和辐射烧伤如晒伤、其它类型的皮肤炎症和衰老的组织退化作用)和慢性炎性病症,例如动脉粥样硬化、心脏病、代谢综合征X、骨质疏松、癌症、Alzheimer’s病及其前期阶段(如轻度认知缺损)或由慢性皮肤炎症引起的光老化。
关节炎是关节的慢性(炎性)疾病,其包括许多不同的形式。例如,关节炎包括风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、***性红斑狼疮和幼年型关节炎。与哮喘类似,风湿性关节炎的特征是在分子水平上细胞因子、趋化因子、激肽及其受体、黏附分子及其各自受体以及炎性酶长期失衡表达。
骨关节炎是由一个或多个关节的软骨分解和损失引起的关节疾病,其由于衰老期间关节的磨损消耗(wear and tear)而发生,并导致疼痛和减小的关节功能。骨关节炎的症状包括一个或多个关节疼痛、僵硬和丧失活动性(mobility)。过量的关节负荷提高骨关节炎的风险,因此骨关节炎主要影响负重关节如脊柱、膝盖和髋,但是拇指和指关节也可以受影响。关节病症也可由伤害(即微损伤(microdamage)或钝伤,骨折,对腱、半月板或韧带的损伤)引起,或可以由过度机械应激引起,或由例如损伤或肥胖症造成的其它生物力学不稳定性引起。
银屑病是最常见的皮肤问题之一,其影响1-3%的人群。炎性肠病是用于描述胃肠道疾病的一个通用术语,其包括疾病如溃疡性结肠炎和Crohn’s疾病。
除了血管内脂质沉积的过程之外,内皮(即血管壁)的炎性反应被认为关键性地引起动脉粥样硬化,即粥样斑形成。引发炎症的血管损伤导致动脉粥样硬化。活化的巨噬细胞、T-淋巴细胞和最终的平滑肌细胞存在于动脉粥样硬化斑块中。单核细胞/巨噬细胞和淋巴细胞活化导致类花生酸、细胞因子和基质金属蛋白酶(MMP)的释放,所述类花生酸、细胞因子和基质金属蛋白酶涉及内皮损伤以及动脉粥样硬化斑块的形成和最后破裂。最后,在冠状动脉疾病(CAD)的高风险组中,循环炎性标记物(circulatinginflammatory markers)如C-反应性蛋白(CRP)、血纤蛋白原(fibrinogen)和白细胞介素提高或改变。若干临床试验指出:提高的CRP浓度与提高的冠状和血管事件风险相关。因此,看起来炎症在粥样斑形成的开始和发展中起重要作用。
炎性过程还与Alzheimer’s疾病的病理生理学相关。在患有Alzheimer’s疾病的患者大脑中存在炎症的迹象,因为其特征是细胞因子和活化的小神经胶质细胞水平提高。因此,炎症不仅涉及经典的炎性病症(例如关节炎、哮喘、肠病),而且与许多慢性炎性病症(例如动脉粥样硬化、心脏病、代谢综合征X、骨质疏松、癌症、Alzheimer’s疾病)相关。
炎性事件还与不同类型癌症(例如胃癌、肠癌、黑色素瘤)的病理生理学相关。在人的乳腺、结肠、肺和胰腺的癌中已经发现提高的炎性介质(如***素)水平。
目前两种主要的药物种类-皮质类固醇和非类固醇消炎药(NSAID),被用于治疗炎性病症和/或关节病症。NSAID和皮质类固醇事实上提供了症状缓解。出于对长期使用的严重副作用的越来越多的考虑,皮质类固醇的使用已减少。
NSAID是最广泛使用的药物之一,主要用于治疗疼痛和炎性病症,尤其是用于治疗关节炎(即减轻疼痛),但是也用于治疗软骨退化如骨关节炎。然而在后种情况下,给予药物来控制疼痛和抑制肿胀,而不是来预防或治疗对软骨的损伤。
流行病学研究已提出摄取NSAID的患者具有比不摄取NSAID的患者更低的发生Alzheimer’s疾病的风险。NSAID的保护性作用提示环氧合酶可能涉及神经变性过程。
流行病学研究显示:与不摄取NSAID的人群相比,在摄取NSAID的人群中结肠直肠癌、胃癌、食管癌和乳腺癌的风险显著降低。在动物模型中,NSAID显著降低肿瘤发生。
然而,在治疗慢性疾病如关节炎或骨关节炎时,NSAID的长期使用受到严重副作用(如严重的胃肠并发症、肾毒性或哮喘反应)的限制。
因此,患有炎性疾病和/或关节病症的患者对被认为是“天然的”疗法具有特殊的兴趣,所述疗法具有温和的消炎作用并且不具有大的副作用,所述疗法可以被用于疾病预防和作为辅佐疗法。即使存在具有所示消炎作用的“天然”药剂的例子,但是这些“天然”化合物通常具有不足的生物活性,因而具有不足的抑制活性。
因为上述原因,对新型的治疗关节病症(如由软骨退化引起的)的药剂和消炎剂存在巨大的需求。
令人惊奇地发现,式I和/或II的三环二萜具有消炎活性并适合治疗或预防软骨损失和损伤,因而可以被用作适用于治疗、辅助治疗或预防炎性病症和/或关节病症的药剂。
其中R1为氢或C1-6-烷基;
R2为羟基、C3-5-酰氧基、羟甲基、1,3-二羟丙基或C1-6-烷基;
R3和R4彼此独立地为氢、羟基、羟甲基(-CH2-OH)、C1-5酰氧基或C1-6烷氧基;
R5为C1-6-烷基、羟甲基、羧基(CO2H)或甲氧羰基(CO2CH3);
R6为氢,或R5和R6一起形成双键;
R7和R8彼此独立地为C1-6-烷基、羧基、x-羟基-Cx-烷基(x为从1到6的整数)或C1-6烷氧羰基(-CO2(C1-6-烷基)),条件是R7和R8中的至少一个为C1-6-烷基;
R9为氢、羟甲基、甲氧基、氧代或C1-5酰氧基;
R10是氢或R5和R10一起为-CO-O-、-O-CO-、-CH2-O-或-O-CH2-;
R11和R12二者均为氢或R11和R12一起为氧代;
R13为C1-6-烷基、羟甲基、羧基(CO2H)或甲氧羰基(CO2CH3)或R6和R13一起形成双键;
进一步的条件是,对式I而言,如果R2是羟基,则R1是C1-6-烷基。
因此,本发明涉及至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义)用于制造营养药物或药物的用途,尤其是用于制造下述营养药物或药物的用途,所述营养药物或药物用于治疗、辅助治疗或预防炎性病症,如心脏病、多发性硬化、骨关节炎和类风湿性关节炎、动脉粥样硬化和骨质疏松,优选地用于治疗、辅助治疗或预防关节炎,尤其是骨关节炎和类风湿性关节炎。
本发明的三环二萜还适合用于治疗、辅助治疗和预防关节病症,尤其是用于减轻关节炎症、维护和/或提高关节健康、预防关节僵直、提高关节活动性、提供柔软和/或灵活的关节、润滑关节、减轻与关节炎症相关的疼痛、减轻关节肿胀、减少关节问题并提供关节护理。因此,本发明还涉及至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义)用于制造营养药物或药物的用途,所述营养药物或药物用于治疗、辅助治疗或预防关节病症。
本发明的其它对象是至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义)作为软骨再生剂和维护剂的用途,以及至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义)用于维护和再生关节软骨(用于制造用于维护和再生关节软骨的组合物)的用途。
在本发明的所有实施方案中,优选的是式I和/或II的三环二萜,其中
R1是氢或异丙基;
R2是羟基或异丙基;
R3和R4彼此独立地为氢、羟基或甲氧基;
R5为甲基、羧基(CO2H)或羟甲基;
R6为氢,或R5和R6一起形成双键;
R7和R8彼此独立地为甲基、羧基、羟甲基或甲氧羰基,条件是R7和R8中的至少一个是甲基;
R9是氢、氧代或甲氧基;
R10是氢,或R5和R10一起为-CO-O-、-O-CO-、-CH2-O-或-O-CH2-;
R13是羧基,
进一步的条件是,对式I而言,如果R2是羟基,则R1是异丙基;甚至更优选的是如下三环二萜:7-氧代脱氢松香酸(III)、桃拓酚(IV)、羟基桃拓酚(V)、桃拓酚-19-羧酸甲酯(VI)、鼠尾草酮(sageone)(VII)、8,11,13-松香三烯-11,12,20-三醇(VIII)、扁柄草酸(royleanoic acid)(IX)、铁锈醇(ferruginol)(X)、鼠尾草酸12-甲基醚(carnosic acid 12-methylether)(XI);最优选的是鼠尾草酮(VII)、8,11,13-松香三烯-11,12,20-三醇(VIII)、鼠尾草酸12-甲基醚(XI)和/或7-甲基迷迭香酚(XII);尤其是鼠尾草酸12-甲基醚(XI)。
化合物(III)到(XII)的结构列于表1中。
表I三环二萜
在本发明的所有实施方案中,术语“式I和/或II的三环二萜”还包括其中至少一种式I和II的三环二萜的含量如下的任何植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地为至少50wt-%(即从50到100wt-%),更优选地为至少70wt-%(即从70到100wt-%),最优选地为至少90wt-%(即从90到100wt-%)。本发明上下文中使用的术语“植物的材料”和“植物材料”表示植物的任何部分。
“鼠尾草酸12-甲基醚”表示,外消旋混合物以及纯净的(4aR,10aS)-鼠尾草酸12-甲基醚或纯净的(4aS,10aR)-鼠尾草酸12-甲基醚或它们的任何混合物或非对映异构体。鼠尾草酸12-甲基醚可分离自植物如鼠尾草、迷迭香、Hyptis martiusii,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中鼠尾草酸12-甲基醚的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“鼠尾草酸12-甲基醚”表示“天然”(经分离的)和“合成”(制造的)鼠尾草酸12-甲基醚。
“7-氧代脱氢松香酸”表示,外消旋混合物以及纯净的(1S,4aS,10aR)-7-氧代脱氢松香酸或纯净的(1R,4aR,10aS)-7-7-氧代脱氢松香酸或它们的任何混合物或非对映异构体。7-氧代脱氢松香酸可分离自以下植物如Cynaracardunculus ssp.cardunculus和Juniperus chinensis,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中7-氧代脱氢松香酸的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“7-氧代脱氢松香酸”表示“天然”(经分离的)和“合成”(制造的)的7-氧代脱氢松香酸。
“桃拓酚”表示,外消旋混合物以及纯净的(4bS,8aS)-桃拓酚((+)-桃拓酚,反式-桃拓酚)或纯净的(4bR,8aR)-桃拓酚或它们的任何混合物或非对映异构体。桃拓酚可分离自以下植物如sage、juniper和podocarpus sp,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中桃拓酚的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“桃拓酚”表示“天然”(经分离的)和“合成”(制造的)的桃拓酚。桃拓酚的合成描述于若干文章中,即Tetrahedron Letters 2003,44(49),8831-8835中。
“16-羟基桃拓酚”表示,外消旋混合物以及纯净的(1S,4αS,10aR)-16-羟基桃拓酚或纯净的(1R,4aR,10aS)-16-羟基桃拓酚或它们的任何混合物或非对映异构体。16-羟基桃拓酚可分离自Podocarpus species和其它植物的木材。因此,该表述还包括这些植物的任何材料或提取物或其中16-羟基桃拓酚的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“16-羟基桃拓酚”表示“天然”(经分离的)和“合成”(制造的)的16-羟基桃拓酚。16-羟基桃拓酚的合成描述于若干文章中,即Journal of theChemical Society,Abstracts 1963,1553-1560和Chemistry & Industry(London,United Kingdom)1963,44,1760-1761中。
“桃拓酚-19-羧酸甲酯”表示外消旋混合物以及纯净的(4aR,10aS)-桃拓酚-19-羧酸甲酯或纯净的(4aR,10aS)-桃拓酚-19-羧酸甲酯或它们的任何混合物或非对映异构体。桃拓酚-19-羧酸甲酯可分离自Podocarpus species和其它植物的木材。因此,该表述还包括这些植物的任何材料或提取物或其中桃拓酚-19-羧酸甲酯的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“桃拓酚-19-羧酸甲酯”表示“天然”(经分离的)和“合成”(制造的)的桃拓酚-19-羧酸甲酯。桃拓酚-19-羧酸甲酯可根据Chemistry& Industry(London,United Kingdom)1963,44,1760-1761中所述工艺制备。
鼠尾草酮可分离自以下植物如鼠尾草和其它salivia sp,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中鼠尾草酮的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“鼠尾草酮”表示“天然”(经分离的)和“合成”(制造的)的鼠尾草酮。鼠尾草酮的合成描述于例如Journal of Organic Chemistry 1997,62(20),6928-6951中。
“8,11,13-松香三烯-11,12,20-三醇”表示,外消旋混合物以及纯净的(4bR,8aS)-8,11,13-松香三烯-11,12,20-三醇或纯净的(4bS,8aR)-8,11,13-松香三烯-11,12,20-三醇或它们的任何混合物或非对映异构体。8,11,13-松香三烯-11,12,20-三醇可分离自植物如Salivia sp,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中8,11,13-松香三烯-11,12,20-三醇的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“8,11,13-松香三烯-11,12,20-三醇”表示“天然”(经分离的)和“合成”(制造的)的8,11,13-松香三烯-11,12,20-三醇。
“扁柄草酸”表示,外消旋混合物以及纯净的(4aR,10aS)-扁柄草酸或纯净的(4aS,10aR)-扁柄草酸或它们的任何非对映异构体或混合物。扁柄草酸可分离自植物如鼠尾草(Salvia sp.),但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中扁柄草酸的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。″扁柄草酸″表示“天然”(经分离的)和“合成”(制造的)的扁柄草酸。
“铁锈醇”表示,纯净的(4bS,8aS)-铁锈醇或纯净的(4bR,8aR)-铁锈醇或它们的任何立体异构体或混合物。铁锈醇可分离自植物如Cryptomeriasp.,Juniperus sp.、Salvia sp.,但不限于此。因此,该表述还包括这些植物的任何材料或提取物或其中铁锈醇的含量如下的任何其它植物材料或提取物,所述含量以植物材料或提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。“铁锈醇”表示“天然”(经分离的)和“合成”(制造的)的铁锈醇。铁锈醇的合成描述于Organic Letters 2001,3(11),1737-1740。
除了(纯净的)化合物鼠尾草酸12-甲基醚、7-氧代澳洲柏酸(7-oxocallitrisic acid)、桃拓酚、16-羟基桃拓酚、桃拓酚-19-羧酸甲酯、20-脱氧代-鼠尾草酚、7-甲基迷迭香酚、鼠尾草酮、8,11,13-松香三烯-11,12,20-三醇、扁柄草酸和铁锈醇以外,特别优选的是以如下含量包含这些化合物的植物材料和植物提取物,所述含量以植物材料/提取物的总重为基础至少为30wt-%(即从30到100wt-%),优选地至少为50wt-%(即从50到100wt-%),更优选地至少为70wt-%(即从70到100wt-%),最优选地至少为90wt-%(即从90到100wt-%)。
在本发明的上下文中,“治疗”还包括辅助治疗以及预防。“预防”可以是预防第一次发生(一级预防)或预防复发(二级预防)。在本发明的上下文中,术语“病症”还包括疾病。
对包括人的动物而言,至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义和偏好)的剂量和比例可根据已知的因素改变,所述因素例如具体组合物的生理特征及其施用模式和途径;接收者的年龄、健康和体重;症状的性质和程度;共存的治疗种类;治疗的频率;和想要的效果,所述剂量和比例可以由本领域的专家使用常规试验确定,或根据营养药物配制的常见考虑决定。对人而言,至少一种式I和/或II的三环二萜(其具有上文给出的R1到R13定义和偏好)的合适的每日剂量可在每天每kg体重0.001mg到每天每kg体重约40mg的范围内。更优选的是每kg体重约0.01到约10mg的每日剂量,特别优选的是每kg体重约0.05到5.0mg的每日剂量。可相应计算包含这类式I和式II三环二萜(其具有上文给出的R1到R13定义和偏好)的植物材料或植物提取物的用量。在人用固体剂量单位制剂中,具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜适当地以下述含量存在,所述含量在每剂量单位约0.1mg到约1000mg的范围内,优选地在每剂量单位约1mg到约500mg的范围内。
在一个不同的方面,本发明还涉及具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜用作药物/组合物的用途,所述药物/组合物用于治疗、辅助治疗或预防炎性病症,如关节炎,尤其是骨关节炎和类风湿性关节炎;和/或治疗、辅助治疗或预防关节病症。
在另一方面,本发明涉及一种营养药物,所述营养药物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜和营养药物可接受的载体。具体地,本发明涉及一种用于治疗、辅助治疗或预防炎性病症(如关节炎,尤其是骨关节炎和类风湿性关节炎)和/或关节病症的营养药物,所述营养药物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜和营养药物可接受的载体。
本发明还涉及一种用于治疗、辅助治疗和预防动物(包括人类)中的炎性病症(如关节炎,尤其是骨关节炎和类风湿性关节炎)和/或关节病症的方法,所述方法包括对有需要的动物(包括人类)施用有效量的至少一种具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜。另外,本发明涉及再生和/或维护哺乳动物中的(关节)软骨的方法,所述方法包括对需要这类再生和/或维护的哺乳动物施用有效量的至少一种具有上文给出的R1到R13的定义的式I和式II的三环二萜。
术语“有效量”是指获得生理效应必需的量。生理效应可通过单一剂量或重复剂量达到。当然,施用的剂量可根据已知的因素变化,如具体组合物的生理学特征及其施用模式和途径;接受者的年龄、健康和体重;症状的性质和程度;共存的治疗种类;治疗频率;以及期望的效果,并且所述剂量可由本领域技术人员调节。
在本发明的框架中,动物表示所有动物,包括哺乳动物,其例子包括人。除人以外,优选的动物例子是非反刍动物或反刍动物,包括猫、犬、单峰骆驼、骆驼、大象和马。
本文使用的术语营养药物包括食物制品、食品、膳食补剂、营养补剂或用于食物制品或食品的补剂组合物。
因此,在另一实施方案中,本发明涉及一种营养药物,所述营养药物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜,尤其用于治疗、共治疗或预防炎性病症(如关节炎,尤其是骨关节炎和类风湿性关节炎)和/或关节病症,其中所述营养药物是食物制品、食品、膳食补剂、营养补剂或用于食物制品或食品的补剂组合物,优选地是膳食补剂、营养补剂或用于食物或食品的补剂组合物。
本文使用的术语“食物制品”是指适用于被人或动物消耗的任何食物或饲料。食物制品可以是经制备和经包装的食物(例如蛋黄酱、色拉酱、面包或乳酪食物)或动物饲料(例如挤压和成粒的动物饲料、粗混饲料或宠物食物组合物)。本文使用的术语“食品”是指适合人或动物消耗的任何物质。术语“膳食补剂”是指用于补充人或动物膳食的小量化合物,其被包装在单个或多个剂量单位中。膳食补剂通常不提供大量的卡路里,但是可含有其它微量营养物(例如维生素或矿物)。术语“营养补剂”是指包含与卡路里来源组合的膳食补剂的组合物。在一些实施方案中,营养补剂是肉替代物或补剂(例如营养或能量棒或营养饮料或浓缩物)。
食物制品或食品为例如饮料(如非酒精饮品和酒精饮品)以及要被添加进饮用水和液体食物中的液体制剂,其中非酒精饮品为例如软饮、运动饮品、果汁(例如橙汁、苹果汁和葡萄汁);柠檬水、茶、接近水的饮品和乳和其它乳制品饮品(例如酸乳饮品)和减肥饮品。在另一实施方案中,食物制品或食品是指包含本发明的组合物的固体或半固体的食物。这些形式可包括但不限于:烘焙的商品如蛋糕和曲奇、布丁、乳制品、糖膏(confection)、点心食物或冷冻糖膏或花式新品(novelties)(例如冰激凌、奶昔);制备的冷冻肉、糖果、点心制品(例如薯片);液体食物如汤、涂抹物、酱、沙拉酱、制备的肉制品、乳酪、酸乳和任何其它含脂肪或油脂的食物;和食物成分(例如小麦粉)。
术语食物制品或食品还包括功能性食物和制备的食物制品,后者是指适合人消耗的任何预先包装的食物。
包括宠物食物组合物的动物饲料有利地包括旨在补充必需膳食需要的食物、调剂物(treats)(例如狗饼干)或其它食物补剂。包含本发明的组合物的动物饲料可以是干燥组合物(例如粗粒)、半潮湿组合物、潮湿组合物或其任何混合物的形式。可供选择的或另外的,动物饲料是补剂,例如肉汤、饮用水、酸乳、粉末、悬浮液、咀嚼物(chew)、调剂物(例如饼干)或任何其它递送形式。
本发明的膳食补剂可以以任何合适的方式被递送。在一些优选的实施方案中,膳食补剂被配制为用于口递送。本发明的膳食补剂的成分包含在用于口消耗的可接受赋形剂和/或载体中。载体和由此产生的膳食补剂自身的实际形式不是关键的。载体可以是液体、凝胶、软胶囊、胶囊、粉末、固体片剂(包衣或非包衣的)、茶等等。膳食补剂优选地以片剂或胶囊的形式,最优选以硬(壳)明胶胶囊的形式。合适的赋形剂和/或载体包括麦芽糖糊精、碳酸钙、磷酸氢钙、磷酸三钙、微晶纤维素、葡萄糖、米粉、硬脂酸镁、硬脂酸、交联羧甲基纤维素钠、淀粉羟乙酸钠、交聚维酮、蔗糖、植物胶、乳糖、甲基纤维素、聚维酮、羧甲基纤维素、玉米淀粉等等(包括其混合物)。优选的载体包括碳酸钙、硬脂酸镁、麦芽糖糊精及其混合物。使用传统的技术将多种成分和赋形剂和/或载体混合并形成想要的形式。本发明的片剂或胶囊可以用肠衣包裹,所述肠衣在约6.0到7.0的pH下溶解。在小肠中溶解而在胃中不溶解的合适肠衣是醋酸纤维素邻苯二甲酸酯(cellulose acetate phthalate)。配制和施用技术的更多细节可见于最新版的Remington′s Pharmaceutical Sciences(Maack Publishing Co.,Easton,PA)。
在其它一些实施方案中,膳食补剂作为适合被消费者添加进食物或饮料中的粉末或液体提供。例如,在一些实施方案中,膳食补剂可以以粉末的形式被施用给个体,例如通过混合进饮料中使用,或通过搅拌进半固体的食物(如例如布丁、点心(topping)、酱、浓汤(puree)、烹调的谷物或沙拉酱)中使用,或通过以其它方式添加进食物(例如封装在食物或饮料容器的盖中,用于在消耗前立即释放)使用。膳食补剂可含有一种或多种惰性成分,特别是在期望限制由膳食补剂添加进食谱中的卡路里数时。例如,本发明的膳食补剂也可以含有任选的成分,包括例如草药、维生素、矿物、强化剂、着色剂、甜味剂、调味剂、惰性成分等等。
在一些实施方案中,膳食补剂还含有维生素和矿物,包括但不限于磷酸三钙(calcium phosphate tribasic)或醋酸三钙(calcium acetatetribasic);磷酸二钾(potassium phosphate dibasic);硫酸镁或氧化镁;盐(氯化钠);氯化钾或醋酸钾;抗坏血酸;原磷酸铁;烟酰胺;硫酸锌或氧化锌;泛酸钙;葡萄糖酸铜;核黄素;β-胡萝卜素;盐酸吡哆醇;硫胺单硝酸酯;叶酸;生物素;氯化铬或chromium picolonate;碘化钾;硒酸钾;钼酸钠;叶绿醌;维生素D3;氰钴铵素;***钠;硫酸铜;维生素A;维生素C;肌醇;碘化钾。维生素和矿物的合适剂量可以通过参考U.S.RDA指南获得。
在其它一些实施方案中,本发明提供了包含本发明的组合物的营养补剂(例如能量棒或肉代替棒或饮料)。营养补剂可以作为正餐或点心替换物使用,并通常提供养分卡路里。优选地,营养补剂以平衡的量提供碳水化合物、蛋白质和脂肪。营养补剂还可包含碳水化合物,单糖、中链长度糖或多糖或其组合。单糖可以针对想要的感觉特性选择。未烹饪的玉米淀粉是复杂碳水化合物的一个例子。如果期望维持其高分子量结构,则食物配制物或其部分中仅应该包含未经烹饪或加热加工的碳水化合物,因为加热会将复杂的碳水化合物分解为单纯的碳水化合物,其中单纯的碳水化合物是单糖或二糖。在一个实施方案中,营养补剂包含三种链长度水平的碳水化合物(简单、适中和复杂;例如蔗糖、麦芽糖糊精和未烹饪的玉米淀粉)来源的组合。
要掺入本发明的营养补剂中的蛋白质来源可以是用在营养配制物中的任何合适的蛋白质,其可包括乳清蛋白、乳清蛋白浓缩物、乳清粉末、卵、大豆粉、大豆乳、大豆蛋白、大豆蛋白分离物、酪蛋白酸盐(例如酪蛋白酸钠、酪蛋白酸钙钠、酪蛋白酸钙、酪蛋白酸钾)、动物和植物蛋白质及其水解产物或混合物。选择蛋白质来源时,首先应当考虑蛋白质的生物学价值,最高的生物学价值在酪蛋白酸盐、乳清、乳清蛋白、卵清蛋白和全卵蛋白中发现。在一个优选的实施方案中,蛋白质是乳清蛋白浓缩物和酪蛋白酸钙的组合。这些蛋白质具有高生物学价值;即它们具有高比例的必需氨基酸。参阅Modern Nutrition in Health and Disease,第八版,Lea& Febiger出版,1986,具体在第1卷,第30-32页。营养补剂可还含有其它成分,如其它维生素、矿物、抗氧化剂、纤维和其它膳食补剂(例如蛋白质、氨基酸、胆碱、卵磷脂、ω-3脂肪酸)的一种或组合。对一种或若干种这些成分的选择是配制、设计、消费者偏好和最终用户的一个问题。添加进本发明的膳食补剂中的这些成分的用量是技术人员容易知道的。对这些用量的指南可以由针对儿童和成人的U.S.RDA提供。可以被添加的其它维生素和矿物包括,但不限于,磷酸三钙或醋酸三钙;磷酸二钾;硫酸镁或氧化镁;盐(氯化钠);氯化钾或醋酸钾;抗坏血酸;原磷酸铁;烟酰胺;硫酸锌或氧化锌;泛酸钙;葡萄糖酸铜;核黄素;β-胡萝卜素;盐酸吡哆醇;硫胺单硝酸酯;叶酸;生物素;氯化铬或chromiumpicolonate;碘化钾;硒酸钾;钼酸钠;叶绿醌;维生素D3;氰钴铵素;***钠;硫酸铜;维生素A;维生素C;肌醇;碘化钾。
营养补剂可以以多种形式和通过多种生产方法提供。在一个优选的实施方案中,为了制造食物棒,液体成分被烹饪;干燥成分与液体成分被添加进混合机中并混合,直到获得生面团相;将生面团放进挤压机中并挤压;将经挤压的生面团切成合适的长度;使产物冷却。除了本文明确列出的成分外,该棒还可含有其它养分和填充剂以加强口味。
本领域技术人员理解:其它成分(例如填充剂、乳化剂、防腐剂等)可以被添加进本文所述的这些中用于加工或制造营养补剂。
另外,调味剂、着色剂、香料、坚果等等可以被掺入营养药物组合物中。调味剂可以是有味的提取物、挥发油、巧克力调味剂、花生酱调味剂、曲奇碎屑、松脆米(crisp rice)、香草或任何可商业获得的调味剂的形式。有用的调味剂的例子包括,但不限于,纯净的茴香提取物、仿造的香蕉提取物、仿造的樱桃提取物、巧克力提取物、纯净的柠檬提取物、纯净的橙提取物、纯净的薄荷提取物、仿造的菠萝提取物、仿造的朗姆提取物、仿造的草莓提取物或纯净的香草提取物;或挥发油,如香蜂叶油(balmoil)、月桂叶油、佛手柑油、柏木油(cedarwood oi)、胡桃油、樱桃油、桂皮油、丁香油或薄荷油;花生酱、巧克力调味剂、香草曲奇碎屑、奶油糖(butterscotch)或太妃糖(toffee)。在一个实施方案中,膳食补剂含有可可或巧克力。
乳化剂可以被添加用于营养药物的稳定性。合适的乳化剂的例子包括,但不限于卵磷脂(例如来自卵或大豆),和/或甘油单酯和甘油二酯。其它乳化剂对技术人员来说是明显的,对合适的乳化剂的选择将部分取决于配制物和最终产物。也可以向营养补剂中添加防腐剂以延长产物的货架寿命。优选地,使用如山梨酸钾、山梨酸钠、苯甲酸钾、苯甲酸钠、或EDTA二钠钙(calcium disodium EDTA)。
除了上述碳水化合物外,营养药物可含有天然或人工的(优选低卡路里的)甜味剂,例如糖类、环己烷氨基磺酸盐(cyclamate)、天冬胺(aspartamine)、天冬甜素(aspartame)、安赛蜜K(acesulfame K)和/或山梨糖醇。如果营养补剂旨在被超重或肥胖的个体或患有II型糖尿病的个体(其易患高血糖症)消耗,则这类人工甜味剂是期望的。
另外,可以向本发明的营养药物中添加多种维生素和矿物补剂,以获得足够量的一些膳食中缺乏的必需养分。多种维生素和矿物补剂也可以适用于疾病预防和防止由生活方式引起的营养丧失和缺乏。
当然,通过营养药物施用的至少一种式I和/或式II的三环二萜(具有上文给出的R1到R13的定义和偏好)的剂量和比例可根据已知的因素改变,所述因素例如具体组合物的生理特征及其施用模式和途径;接收者的年龄、健康和体重;症状的性质和程度;共存的治疗种类;治疗的频率;和想要的效果,所述剂量和比例可以由本领域的专家使用常规试验确定,或使用关于营养药物组合物配制的常见考虑决定。
根据本发明的营养药物可包含至少一种式I和/或式II的三环二萜(具有上文给出的R1到R13的定义和偏好),其含量为每份约0.001mg到1g,优选地每份0.01mg到1g,最优选地在每份2.0mg到300mg的范围内。
在膳食组合物中,特别是在人的食物和饮料中,至少一种式I和/或式II的三环二萜(具有上文给出的R1到R13的定义和偏好)适当地以下述含量存在,所述含量以食物或饮料的总重为基础在约0.0001(1mg/kg)到约5wt-%(50g/kg)、优选地在约0.001%(10mg/kg)到约1wt-%(10g/kg)、更优选地在约0.01(100mg/kg)到约0.5wt-%(5g/kg)的范围内。
在本发明的一个优选的食物和饮品中,具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的含量在每份10到30mg的范围内,即每kg食物或饮料120mg。
对除人之外的动物,就本发明的目的而言,具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的适当每日剂量可以在每天每kg体重0.001mg到约1000mg的范围内。更优选的是每kg体重约0.1mg到约500mg的范围内的每日剂量,特别优选的是每kg体重约1mg到100mg范围内的每日剂量。
如果使用包含至少一种式I和/或式II的三环二萜(具有上文给出的R1到R13的定义和偏好)的植物材料或植物提取物来代替纯化合物,则可相应计算要应用的剂量。
另一方面,本发明涉及一种药物,所述药物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜和药物可接受的载体。具体地,本发明涉及一种用于治疗、辅助治疗或预防炎性病症(如关节炎,尤其是骨关节炎和类风湿性关节炎)和/或关节病症的药物,所述药物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜和药物可接受的载体。
本领域技术人员知道何种载体可以被用作可药用载体。合适的药物载体例如在本领域的标准参考文献-以上Remington′s PharmaceuticalSciences中有所描述。这类可药用载体的例子为适用于口/肠胃外/可注射施用的无机和有机载体材料,其包括水、明胶、***胶、乳糖、淀粉、硬脂酸镁、滑石、植物油等等。
药物可还含有常规的药物添加剂和佐剂、赋形剂或稀释剂,其包括但不限于:水、任何来源的明胶、植物胶、木质素磺酸盐、滑石、糖、淀粉、***胶、植物油、聚亚烷基二醇、调味剂、防腐剂、稳定剂、乳化剂、缓冲液、润滑剂、着色剂、湿润剂、填充剂等等。
在一个优选的实施方案中,药物是粉末、片剂、胶囊、凝胶、液体或固体实施方案的形式。
药物中各个组分的剂量和比例可以由本领域技术人员使用常见的临床前和临床试验确定,或使用关于营养药物组合物配制的常见考虑决定。
药物包括含量优选地为每剂量单位(例如每粒胶囊或片剂)1mg到2000mg的至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜,或包括1mg每日剂量到3000mg每日剂量的液体配制物。在一个优选的实施方案中,以至少0.01mg/kg体重/天的用量,优选地以0.1-50mg/kg体重/天的用量,最优选地以0.3-15mg/kg体重/天的用量,以单一剂量或多次剂量的形式,通过药物组合物施用至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜,优选地施用其形式为至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的含量为至少30wt-%的富集的植物提取物。如果使用包含至少一种具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜的植物材料或植物提取物来代替纯化合物,则可相应计算要应用的剂量。
根据本发明的营养药物和药物可以是适用于施用给动物体(包括人体)的任何盖伦形式(galenic form),更尤其是口施用中常规的任何形式,例如固体形式,例如作为食物或饲料(用的添加剂/补充剂)、食物或饲料预混物、强化的食物或饲料、片剂、丸剂、颗粒剂、锭剂、胶囊和泡腾配制剂(如粉末和片剂);或液体形式,例如溶液、乳剂或悬浮液的形式,例如作为饮料、糊剂和油悬浮液。糊剂可以被填充进硬或软壳胶囊中。其它应用形式的例子是用于经皮、肠胃外、局部或可注射施用的形式。营养药物和药物组合物可以是受控(延迟)释放的配制剂的形式。药物组合物的例子也包括适用于苯酚化合物局部应用和经皮吸收的组合物,如霜剂、凝胶、喷雾、干燥胶棒、粉末等。
另外,可以向本发明的营养药物性组合物中添加多种维生素和矿物补剂,以获得足够量的一些膳食中缺乏的必需养分。多种维生素和矿物补剂也可以适用于疾病预防和防止由生活方式引起的营养丧失和缺乏。
本领域技术人员知道何种载体可以被用作可药用载体。这类可药用载体的例子为适用于口/肠胃外/可注射施用的无机和有机载体材料,其包括水、明胶、***胶、乳糖、淀粉、硬脂酸镁、滑石、植物油等等。
除了至少一种式I和式II的三环二萜和可药用载体外,根据本发明的药物组合物可还含有常规的药物添加剂和佐剂、赋形剂或稀释剂,其包括但不限于:水、任何来源的明胶、植物胶、木质素磺酸盐、滑石、糖、淀粉、***胶、植物油、聚亚烷基二醇、调味剂、防腐剂、稳定剂、乳化剂、缓冲液、润滑剂、着色剂、湿润剂、填充剂等等。
至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜可与本领域技术人员已知的其它营养药物组合物或治疗剂通过如下组合使用从而治疗或预防炎性病症和/或关节病症:在施用至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜之前、同时或之后施用。
根据本发明,具有上文给出的R1到R13的定义和偏好的式I和式II的三环二萜本身,以植物材料或提取物的总重为基础以至少30wt-%(即从30wt-%到100wt-%)的含量、优选地以至少50wt-%(即从50wt-%到100wt-%)的含量、更优选地以至少70wt-%(即从70wt-%到100wt-%)的含量、最优选地以至少90wt-%(即从90wt-%到100wt-%)的含量含有它们的植物材料和提取物,以及含有它们的膳食和药物组合物都可以被用作药物,特别是用作用于治疗、辅助治疗或预防炎性病症(如关节炎,尤其是骨关节炎和类风湿性关节炎)和/或用于治疗、辅助治疗或预防关节病症的药物。
具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜、(特别是以植物材料或提取物的总重为基础以至少30wt-%的含量,优选地以至少50wt-%的含量,更优选地以70wt-%到90wt-%的含量,最优选地以至少90wt-%的含量)含有它们的植物材料和植物提取物(的混合物)以及含有它们的膳食/药物组合物因此适用于治疗动物,包括人。
还在另一方面,本发明还涉及式I和/或式II的三环二萜(具有上文给出的R1到R13的定义和优选定义)用于治疗、辅助治疗或预防皮肤炎性病症(例如晒伤)、不纯皮肤(impure skin)(例如痤疮)或慢性皮肤炎症的结果(例如光老化)的用途。用于治疗、辅助治疗或预防皮肤炎性病症(例如晒伤)、不纯皮肤(例如痤疮)或慢性皮肤炎症的结果(例如光老化)并且包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的组合物可以被设计为用于口服递送,例如作为营养药物或药剂(medicament);或可以被设计为用于局部应用,例如作为霜剂或洗剂,但不仅限于此。
另一方面,本发明涉及化妆品或皮肤病学制剂(后一制剂是特定种类的药物),其包含有效量的至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜或含有它们的组合物(以植物材料或提取物的总重为基础,以至少30wt-%的含量、优选地至少50wt-%的含量、更优选地70wt-%到90wt-%的含量、最优选地至少90wt-%的含量含有它们的植物材料/提取物;膳食/药物组合物)和化妆上或皮肤病学可接受的载体。
化妆品或皮肤病学组合物还可包含常规的化妆品或者皮肤病学佐剂和/或添加剂和/或额外的活性成分。
优选地,化妆品或皮肤病学制剂是下述皮肤护理制剂,其用于治疗、辅助治疗或预防皮肤炎症,尤其是由UV-辐射引起的晒伤、接触性皮炎(尤其是尿布区皮炎)、特应性皮炎、干燥病、湿疹、酒渣鼻、皮脂溢出、银屑病、神经性皮炎、热烧伤、光老化;或用于治疗、辅助治疗或预防不纯皮肤(例如痤疮)。不纯皮肤的例子包括脓疱、痤疮和具有炎性方面的其它皮肤不纯。
还在另一方面,本发明涉及用于治疗、辅助治疗或预防炎性皮肤病症的组合物,所述组合物包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜。用于治疗、辅助治疗或预防炎性皮肤病症并且包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的组合物可以被设计为用于口服施用,例如作为营养药物或药物或药剂;或可以被设计为用于局部引用,例如作为霜剂或洗剂,但不仅限于此。如果用于治疗、辅助治疗或预防皮肤炎性病症并且包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的组合物旨在用于口服施用,则其可以是具有上文给出的所有定义和偏好的营养药物或药物的形式。这类制品也被称为美容食物和补剂。如果用于治疗、辅助治疗或预防皮肤炎性病症并且包含至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜的组合物旨在用于局部应用,则其可以是如本文所述的化妆品或皮肤病学制剂的形式。
术语“炎性皮肤病症”包括皮肤的炎性疾病,例如接触性皮炎[尤其是尿布区皮炎]、特应性皮炎、干燥症、湿疹、酒渣鼻、皮脂溢出、银屑病、神经性皮炎、痤疮、热烧伤和辐射烧伤如晒伤以及任何其它类型的皮肤炎症(例如慢性皮肤炎症引起的光老化)。术语“炎性皮肤病症”还包括术语“不纯皮肤”。“不纯皮肤”可由多种因素引起:多种外源和内源刺激(例如日晒、风吹、寒冷、干燥、对霜剂或其它皮肤护理制品的不相容性或敏感性、过量生产皮脂随后引起脓疱、黑斑和痤疮)引起的皮肤刺激(skin irritation)。普遍被接受的是表皮中的炎性过程涉及导致皮肤刺激、敏感性皮肤和不纯皮肤的过程。进一步充分确立的是在这些机制中,细胞因子起到重要的作用。炎性刺激后表皮中的角质形成细胞释放炎症前期细胞因子(pro-inflammatory cytokine)(Boniface K,Lecron JC,Bernard FX,Dagregorio G,Guillet G,Nau F,Morel F,Keratinocytes as targets forinterleukin-10-related cytokines:a putative role in the pathogenesis ofpsoriasis,Eur.Cytokine Netw,2005年12月;16(4):309-19)。
因此,皮肤细胞对炎症刺激应答的降低可导致不纯或敏感皮肤状况的改善,并可帮助产生具有健康和天然光彩(radiance)和红晕(glow)的纯净皮肤。
因此,本发明还涉及至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜用于促进皮肤的最佳健康、天然光彩和红晕和/或美丽外观的用途。另外,本发明包括至少一种具有上文给出的R1到R13的定义和偏好的式I和/或式II的三环二萜用于维持皮肤的清澈、纯净外观的用途。
术语“有效量”优选地表示每种活性剂占化妆品或皮肤病组合物总重的至少0.001%。优选地,化妆品或皮肤病学制剂以下述含量包含选自上文所列的活性剂,所述含量在0.01wt.-%和20wt.-%之间,更优选地在0.05和10wt.-%之间,进一步更优选地在0.1和5wt.-%之间。
要应用于皮肤的化妆品或皮肤病学制剂的用量取决于制剂中活性成分的浓度和期望的化妆品或药物效果。例如,应用可以是对皮肤应用霜剂。通常以1到2mg霜剂/cm2皮肤的用量应用霜剂。然而,应用于皮肤的组合物用量不是关键性的,如果应用某用量的组合物不能达到期望的作用,则可以使用含有更多活性成分的更高浓度的活性制剂。
本发明还涉及化妆品制剂的下述用途,所述用途用于美容治疗、辅助治疗或预防皮肤炎症,尤其是用于美容治疗、辅助治疗或预防晒伤、接触性皮炎(尤其是尿布区皮炎)、特应性皮炎、干燥病、湿疹、酒渣鼻、皮脂溢出、银屑病、神经性皮炎、热烧伤或光老化,以及用于美容治疗、辅助治疗或预防对环境胁迫(例如风、肥皂、干燥气候)敏感的皮肤。
本发明还涉及下述方法,所述方法用于治疗、辅助治疗或预防皮肤炎症,尤其是治疗、辅助治疗或预防人晒伤、不纯皮肤(例如痤疮)或与慢性皮肤炎症相关的光老化,所述方法包括下述步骤:对有需要的人施用有效量的根据本发明的皮肤病学组合物。本发明还涉及下述方法,所述方法通过本发明的化妆品制剂对皮肤炎症(尤其是晒伤或不纯皮肤例如痤疮)进行美容治疗、辅助治疗或预防。优选地,通过局部应用达成晒伤预防,所述局部应用包含本发明的组合物,优选地与合适的遮光剂组合。
根据本发明的化妆品或皮肤病学组合物可以是溶剂或脂肪物质中悬浮液或分散液的形式,或者是乳剂或微乳剂(尤其是O/W或W/O型,O/W/O或W/O/W-型,其中O表示油相,W表示水相)的形式,如霜剂、糊剂、乳液、增稠的乳液或乳、软膏剂形式的小泡分散液、凝胶、固体管胶棒或气溶胶摩丝,并可以以摩丝、泡沫或喷雾泡沫、喷雾、管棒或气溶胶或擦拭物(wipe)的形式被提供。化妆品或皮肤病学制剂的例子是皮肤护理制剂,尤其是身体油、身体乳液、身体凝胶、治疗霜剂、皮肤保护软膏、保湿凝胶、保湿喷雾、醒肤身体喷雾、晒后制剂或防晒配制物。
用于治疗、辅助治疗或预防皮肤炎症(例如晒伤、光老化或不纯皮肤)的化妆品或皮肤病学组合物可以是用于口施用的常规方式,其例子在上文中描述,其还包括美容食物和补剂。
本发明的化妆品或皮肤病学制剂(例如作为遮光配制物或晒后制剂)可进一步分别包含常用的化妆品或皮肤病学佐剂和/或添加剂,例如防腐剂/抗氧化剂,脂肪物质/油,水,有机溶剂,硅酮,增稠剂,软化剂,乳化剂,其它遮光剂,抗泡剂,湿润剂,香料,表面活性剂,填充剂,掩蔽剂,阴离子、阳离子、非离子或两性聚合物或其混合物,推进剂,酸化或碱化剂,染料,着色剂,色素或纳米色素,光稳定剂,抗虫剂,皮肤美黑剂,皮肤增白剂,抗菌剂,防腐活性成分或通常被配制进化妆品中的任何其它成分。
可被掺入本发明的化妆品或皮肤病学制剂(例如防晒配制剂)中的遮光剂有利地选自IR、UV-A、UV-B、UV-C和/或广谱遮光剂。UV-B或广谱遮光剂(即具有约290和340nm之间吸收最大值的物质)的例子可以是有机或无机化合物。有机UV-B或广谱遮光剂为例如丙烯酸酯,例如2-氰基-3,3-二苯基丙烯酸2-乙基己基酯(奥克立林(octocrylene),340),2-氰基-3,3-二苯基丙烯酸乙酯等等;樟脑衍生物,例如4-甲基亚苄基樟脑(5000)、3-亚苄基樟脑、甲基硫酸樟脑苯甲烷铵(camphor benzalkonium methosulfate)、聚丙烯酰胺基甲基亚苄基樟脑、磺基亚苄基樟脑、磺基甲基亚苄基樟脑、对苯二亚甲基二樟脑磺酸等等;肉桂酸酯衍生物,例如甲氧基肉桂酸乙基己基酯(MCX)、甲氧基肉桂酸乙氧基乙基酯、甲氧基肉桂酸二乙醇胺酯(Hydro)、甲氧基肉桂酸异戊酯等等,以及键合到硅氧烷上的肉桂酸衍生物;对氨基苯甲酸衍生物,例如对氨基苯甲酸、对二甲基氨基苯甲酸2-乙基己基酯、N-氧丙烯基化的对氨基苯甲酸乙酯、对氨基苯甲酸甘油酯;二苯甲酮,例如二苯甲酮-3、二苯甲酮-4、2,2′,4,4′-四羟基-二苯甲酮、2,2′-二羟基-4,4′-二甲氧基二苯甲酮等等;亚苄基丙二酸酯,例如4-甲氧基亚苄基丙二酸二-(2-乙基己基)酯;2-(4-乙氧基-苯胺亚甲基)丙二酸酯,例如欧洲专利公开EP 0895776中所述的2-(4-乙氧基-苯胺亚甲基)丙二酸二乙酯;如欧洲专利公开EP 0358584B1、EP 0538431B1和EP0709080A1中所述的含有苯丙二酸基的有机硅氧烷化合物如聚硅氧烷-15(SLX);甲酚曲唑三硅氧烷(Drometrizole trisiloxane,Mexoryl XL);咪唑衍生物,例如2-苯基苯并咪唑磺酸及其盐(HS)。2-苯基苯并咪唑磺酸的盐为例如碱金属盐(如钠盐或钾盐),铵盐,吗啉盐,伯、仲和叔胺盐(例如单乙醇胺盐、二乙醇胺盐)等等;水杨酸酯衍生物,例如水杨酸异丙基苄酯、水杨酸苄酯、水杨酸丁酯、水杨酸乙基己基酯(EHS,NEO Heliopan OS)、水杨酸异辛酯或水杨酸高薄荷酯(homosalate,HMS,NEO HeliopanOS)等等;三嗪衍生物,例如辛基三嗪酮(UVINUL T-150)、二辛基丁酰胺基三嗪酮(UVASORB HEB)等等。如例如EP 1471995中所述的被封装的UV-遮光剂如被封装的甲氧基肉桂酸乙基己基酯(Eusolex UV-pearls)或装有UV-遮光剂的微胶囊等等。无机化合物为色素,如微粒化的ZnO、TiO2等等。术语“微粒化的”是指从约5nm到约200nm,尤其是从约15nm到约100nm的颗粒尺寸。TiO2颗粒也可用金属氧化物(例如氧化铝或氧化锆)或有机涂层(例如多元醇、甲基硅酮、硬脂酸铝、烷基硅烷)包覆。这类涂层为本领域熟知。
广谱的或UV A遮光剂(即在约320nm到400nm之间有最大吸收的物质)可以是有机或无机化合物,例如二苯甲酰甲烷衍生物,例如4-叔丁基-4′-甲氧基二苯甲酰甲烷(1789)、二甲氧基二苯甲酰甲烷、异丙基二苯甲酰甲烷等等;苯并***衍生物,例如2,2′-亚甲基-二-(6-(2H-苯并***-2-基)-4-(1,1,3,3,-四甲基丁基)-苯酚)(TINOSORB M)等等;二-乙基己基氧代苯酚甲氧基苯基三嗪(Tinosorb S)等等;亚苯基-1,4-二-苯并咪唑磺酸或盐,例如2,2-(1,4-亚苯基)二-(1H-苯并咪唑-4,6-二磺酸)(Neoheliopan AP);经氨基取代的羟基二苯甲酮,例如如欧洲专利公开EP 1046391中所述的2-(4-二乙氨基-2-羟基-苯甲酰基)-苯甲酸己酯(UvinulA plus);如国际专利公开WO2005080341A1中所述的离子UV-A遮光剂。色素,例如微粒化的ZnO或TiO2等等。术语“微粒化的”是指从约5nm到约200nm,尤其是从约15nm到约100nm的颗粒尺寸。颗粒也可用其它金属氧化物(例如氧化铝或氧化锆)或有机涂层(例如多元醇、甲基硅酮、硬脂酸铝、烷基硅烷)包覆。这类涂层为本领域熟知。
因为二苯甲酰甲烷衍生物具有有限的光稳定性,所以其可以适当地光稳定这些UV-A遮光剂。因此,术语“常规的UV-A遮光剂”也指被以下物质稳定的二苯甲酰甲烷衍生物(例如1789):如欧洲专利公开EP 0514491B1和EP 0780119A1中描述的3,3-二苯基丙烯酸酯衍生物;如US专利No.5,605,680中描述的亚苄基樟脑;如欧洲专利公开EP0358584B1、EP 0538431B1和EP 0709080A1中描述的含苯丙二酸酯基的有机硅氧烷。
可以包含在本发明的化妆品或皮肤病学制剂中的活性成分为例如维生素及其衍生物,例如生育酚,醋酸生育酚,抗坏血酸,抗坏血酸磷酸盐,维生素Q、D和K,视黄醇,视黄醛,视黄酸,视黄醇醋酸酯,视黄醇棕榈酸酯,生物素,类胡萝卜素衍生物如β-胡萝卜素,番茄红素,虾青素,植物提取物,抗菌成分,包含二肽、寡肽和多肽的不稳定的氨基酸如甲硫氨酸、半胱氨酸、胱氨酸、色氨酸、苯丙氨酸、酪氨酸,酚类、多酚或类黄酮,没药醇,尿囊素,植烷三醇,泛醇,AHA酸,泛醌如辅酶Q10,神经酰胺酶,假神经酰胺,精油,植物提取物过氧核糖核酸、植烷酸。
化妆品和皮肤病学佐剂、添加剂和/或其它活性成分的必需量可以以期望的产物为基础,由本领域技术人员容易地选择,并将在实施例中阐述,但不仅限于此。
本发明将通过以下的实施例进一步阐述,然而并不仅限于此。
实施例
鼠尾草酮(VII)和8,11,13-松香三烯-11,12,20-三醇(在下文中称作松香三烯三醇)(VIII)得自Analyticon,通过色谱法从迷迭香针叶的亲脂提取物中分离出纯度>95%的鼠尾草酸12-甲基醚(XI)。
实施例1:抗炎效应
通过测定对一氧化氮和/或促炎症反应***素(PG)合成的抑制作用对鼠尾草酸-12-甲基醚、鼠尾草酮和松香三烯三醇(abietatrientriol)在活化的巨噬细胞中的抗炎效应进行评价。PGE2在炎症过程中起关键作用,而一氧化氮(NO)是多种慢性炎性疾病中发炎的标志,所述炎性疾病包括多种形式的关节炎、胃肠疾病和代谢综合征。
将化合物以浓缩的形式溶于DMSO中,其不含干扰测定的副产物。测定中最终运载体(DMSO)浓度不超过0.2%v/v。
使用鼠巨噬细胞指示细胞系RAW267.7,在细胞测定中测试化合物的抗炎效应,所述细胞系购自美国典型培养物保藏所(ATCC),并根据ATCC提供的方案在DMEM中培养。将细胞(~50’000/孔)接种在平底的微量滴定板中并培养一天。然后在含0.25%胎牛血清(FCS)(D-025)的完全培养基中使细胞饥饿。过夜培养后,去除培养基并用100μL下述D-025代替,所述D-025含有两倍终浓度的测试化合物。随后添加100μL含2μg/ml脂多糖(LPS)的D-025(即LPS的终浓度为1mg/ml)并将细胞培养24小时。通常在两倍稀释步骤中在0.2到50μM的浓度范围内测试物质。使用亚硝酸钠作为标准物,通过Griess反应,测定由细胞释放的一氧化氮产生的亚硝酸盐浓度(参见例如Imai等人,Biochem Biophys Res Comm,197,105[1993])。简言之,将50μl上清液与Griess试剂1(25μL)和Griess试剂2(25μL)混合、离心、并测量540nm处的光密度。通过得自CaymanChemicals(Ann Harbor,WI,USA)并根据制造商的说明使用的EIA测定分泌进入细胞培养基的PGE2。使用双参数最小二乘法拟合方程(two-parametricleast-square fitting equation)[y=A+((B-A)/(1+((C-x)^D)))针对最佳拟合曲线(Excel拟合软件程序)计算IC50值。
表2中显示所有的物质特应性地抑制炎性介质的生产。这通过IC50值表明,所述值在表现物质特异性生物效能的物质之间变化。
表2:单种物质的IC50值
物质 | IC50PGE2 | IC50一氧化氮 |
鼠尾草酮(VII) | 16.9±0.8μmol/L | 7.3±2.1μmol/L |
松香三烯三醇(IX) | 7.8±4.6μmol/L | 12.5±4.8μmol/L |
鼠尾草酸-12-甲基醚(XII) | 44.4±6.1μmol/L | 3.8±0.6μmol/L |
实施例2
物质对涉及软骨建成和分解的基因表达的影响
在关节软骨中,需要维持合成代谢(建成)和分解代谢(分解)事件之间的精密平衡,从而分别预防细胞外基质(ECM)的肥大和过度降解。ECM由胶原和蛋白聚糖建成,所述胶原和蛋白聚糖是在合成代谢过程中被活化和被表达的胶原基因(例如人胶原I或聚集蛋白聚糖(aggrecan)基因)的产物。
分解代谢事件由下述基因的表达控制,例如编码最终降解胶原或蛋白聚糖的基质金属蛋白酶(MMP)的那些基因。在MMP中,MMP-1、MMP-3和MMP-13在软骨降解中起分解ECM的主要作用。
用IL-1β处理细胞,所述IL-1β是诱导软骨分解的天然介质之一,并在骨关节炎软骨组织及其衍生的细胞中被大量检测。用IL-1β处理细胞引发涉及分解代谢事件的基因如MMP的表达。用IL-1β处理细胞还降低了胶原表达水平(与未处理的细胞比较)。
根据来自ATCC的说明书,在细胞培养基上培养软骨细胞(SW1353;购自American Tissue Culture Collection[ATCC])。对于实验处理而言,将细胞接种在6孔平板中并培养两天,直到它们达到汇合。然后如Richard等人Mol.Nutr.Food Res.49,431-442,2005所述,从培养的细胞中提取总细胞RNA并进行反转录。如Richard等人在Mol.Nutr.FoodRes.49,431-442,2005中所述,通过定量实时PCR测定不同基因的表达水平。该实验的结果在下表3中展示:
表3.化合物对人软骨细胞中基因表达的影响。百分比表示相对于未经化合物处理的细胞的基因表达水平。
基因 | 0μM化合物 | 12.5μM松香三烯三醇 | 12.5μM鼠尾草酸12-甲基醚 | 12.5μM鼠尾草酮 |
人MMP-1 | 100% | 30% | 94% | 3% |
人MMP-3 | 100% | Not done | 69% | 112% |
人MMP-13 | 100% | 49% | 60% | 36% |
人胶原I | 100% | 257% | 未进行 | 120% |
人胶原II | 100% | 295% | 139% | - |
聚集蛋白聚糖 | 100% | 264% | 123% | 152% |
化合物有力地降低了涉及软骨降解的基因(MMP-1、MMP-3和MMP-13)的表达,但是它们刺激了与软骨建成有关的一些基因(人胶原I、人胶原II、聚集蛋白聚糖)的表达。这些结果表明所示化合物不仅防止软骨降解,而且帮助软骨组织再生。
实施例3:软明胶胶囊
通过常规工序来制备提供下述剂量的软明胶胶囊,所述剂量为10mg式I和/或II的三环二萜如鼠尾草酸12-甲基醚(XI)。合适的每日剂量为1到5粒胶囊。
其它成分:甘油、水、明胶、植物油
实施例4:硬明胶胶囊
通过常规工序来制备提供下述剂量的硬明胶胶囊,所述剂量为20mg式I和/或II的三环二萜如鼠尾草酸12-甲基醚(XI)。合适的每日剂量为1到5粒胶囊。
其它成分:
填料:适量的乳糖、纤维素或纤维素衍生物
润滑剂:如果需要的话,硬脂酸镁(0.5%)
实施例5:片剂
通过常规工序来制备片剂,每片提供20mg式I和/或II的三环二萜如鼠尾草酸12-甲基醚(XI)作为活性成分,并提供微晶纤维素、二氧化硅(SiO2)、硬脂酸镁、交聚维酮NF(一种崩解剂)总计500mg作为赋形剂。
实施例6:软饮
可如下制备软饮,其包含式I和/或II的三环二萜如鼠尾草酸12-甲基醚(XI):
从以下的成分制备软饮:
混合果汁浓缩物和水溶性香料而不掺入空气。将色素溶于去离子水中。将抗坏血酸和柠檬酸溶于水中。将苯甲酸钠溶于水中。果胶在搅拌下被添加并在煮沸时溶解。冷却溶液。预混合橙油和油溶性香料。将F下提到的活性成分搅拌进A的果汁浓缩物混合物中。
为了制备软饮,将所有的组分A-F混合在一起后使用Turrax、随后使用高压匀化器(p1=200bar,p2=50bar)匀化。
实施例7:包含鼠尾草酸12-甲基醚(XI)的干燥狗饲料
用ROPUFA(由DSM Nutritional Products供应)的水溶液对市售的干燥狗粮(狗用Hill’s Science diet“Canine Maintenance dry”,由Hill’s PetNutrition GmbH,Liebigstrasse 2-20,D-22113提供)进行喷雾,所述用量足够施用给受试者每kg体重4mg到120mg ROPUFA的每日剂量。在挤出整体掺合物之前以下述用量掺入额外的L-抗坏血酸-单磷酸盐(来自DSMNutritional Products AG的STAY-35)、维生素E、β-胡萝卜素和鼠尾草酸-12-甲基醚,所述用量足够在最终的食品组合物中提供30mg的STAY-35/kg、300IU的维生素E/kg、280mg的β-胡萝卜素/kg和100mg的鼠尾草酸-12-甲基醚。将食品组合物干燥至含有以重量计约90%的干物质。
实施例8:包含鼠尾草酮(VII)的湿润猫粮
将市售湿润猫粮(猫用Hill’s Science diet“Feline Maintenance wet”,由Hill’s Pet Nutrition GmbH,Liebigstrasse 2-20,D-22113提供)与ROPUFA(由DSM Nutritional Products提供)的水性分散液以下述用量混合,所述用量足够施用给受试者4mg到120mg ROPUFA的每日剂量。在烹调整体掺合物之前以下述用量掺入额外的L-抗坏血酸-单磷酸盐(来自DSMNutritional Products AG的STAY-35)、维生素E、β-胡萝卜素和鼠尾草酮,所述用量足够在最终的食品组合物中提供30mg的STAY-35/kg、300IU的维生素E/kg、280mg的β-胡萝卜素/kg和200mg/kg的鼠尾草酮。将食品组合物干燥至含有以重量计约90%的干物质。
实施例9:制备包含式I和/或II的三环二萜如鼠尾草酸12-甲基醚(XI)的皮
肤病学组合物(治疗霜剂),其可以被用于(美容)治疗晒伤引起的皮肤
炎症
采用如下成分以下述用量制备治疗霜剂:
成分 | INCI术语 | wt.% | |
A | 肉豆蔻酸甘油酯 | 肉豆蔻酸甘油酯 | 2.00 |
式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 | |
十六烷醇 | 十六烷醇 | 0.50 | |
Myritol 318 | 辛酸/癸酸甘油三酯 | 5.00 | |
Crodamol DA | 己二酸二异丙基酯 | 5.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 2.00 | |
丁基化羟基甲苯 | BHT | 0.05 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Edeta BD | EDTA二钠 | 0.10 | |
AMPHISOL K | 十六烷基磷酸钾 | 2.00 | |
B | 去离子水 | 水 | 加至100 |
1,2-丙二醇 | 丙二醇 | 2.00 | |
D-泛醇75L | 泛醇 | 2.00 | |
乙醇 | 乙醇 | 5.00 | |
尿囊素 | 尿囊素 | 0.20 | |
Carbopol ETD 2001 | 卡波姆 | 0.30 | |
C | KOH 10%溶液 | 氢氧化钾 | 1.50 |
D | 香料 | 香料 | 适量 |
步骤:搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至约45℃。添加C)部分。在11000rpm匀化以得到小颗粒尺寸。搅拌下冷却至室温。然后添加D)部分。
实施例10
O/W防晒乳
成分 | INCI命名法 | %w/w | |
A) | PARSOL SLX | 聚硅氧烷-15 | 6.00 |
Neo Heliopan AP | 3.00 | ||
Tinosorb S | 氢化的可可酸甘油酯 | 3.00 | |
Lanette O | 鲸蜡硬脂醇 | 2.00 | |
Myritol 318 | 辛酸/癸酸甘油三酯 | 6.00 | |
矿物油 | 矿物油 | 2.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 1.00 | |
Prisorine 3515 | 异硬脂醇 | 4.00 | |
B) | Edeta BD | EDTA二钠 | 0.10 |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Amphisol K | 十六烷基磷酸钾 | 2.00 | |
去离子水 | 水 | 加至100 | |
1,2-丙二醇 | 丙二醇 | 5.00 | |
Carbopol 981 | 卡波姆 | 0.30 | |
Tinosorb M | 亚甲基二-苯并***基四甲基丁基苯酚 | 6.00 | |
KOH 10%溶液 | 氢氧化钾 | 2.10 | |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酮(VII) | 0.05-2 |
步骤:搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至环境温度并加入C)部分。匀化以得到小颗粒尺寸。
实施例11
防水型防晒乳
成分 | INCI命名法 | %w/w | |
A) | PARSOL SLX | 聚硅氧烷-15 | 6.00 |
PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 2.00 | |
PARSOL 5000 | 4-甲基亚苄基樟脑 | 4.00 | |
Uvinul T 150 | 乙基己基三嗪酮 | 2.00 | |
硅酮DC 200/350cs | 二甲基硅氧烷(Dimethicone) | 1.00 | |
Lanette O | 鲸蜡硬脂醇 | 2.00 | |
Softisan 100 | 氢化可可酸甘油酯 | 3.00 | |
Tegosoft TN | 苯甲酸C12-15烷基酯 | 6.00 | |
Cetiol B | 己二酸二丁酯 | 7.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 2.00 | |
BHT | BHT | 0.05 | |
Edeta BD | EDTA二钠 | 0.10 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Amphisol | 十六烷基磷酸DEA | 2.00 | |
B) | 去离子水 | 水 | 加至100 |
丙二醇 | 丙二醇 | 5.00 | |
Carbopol 980 | 卡波姆 | 0.30 | |
KOH(10%溶液) | 氢氧化钾 | 1.50 | |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
步骤:
搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至环境温度并加入C)部分。匀化以得到小颗粒尺寸。
实施例12
婴儿和儿童用防晒乳
成分 | INCI命名法 | %w/w | |
A) | Tegosoft TN | 苯甲酸C12-15烷基酯 | 5.00 |
硅酮2503化妆品蜡 | 硬脂基二甲基硅氧烷 | 2.00 | |
十六烷醇 | 十六烷醇 | 1.00 | |
丁基化的羟基甲苯 | BHT | 0.05 | |
Estol GMM 3650 | 肉豆蔻酸甘油酯 | 4.00 | |
Edeta BD | EDTA二钠 | 0.10 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Amphisol A | 磷酸十六烷基酯 | 2.00 | |
B) | 去离子水 | 水 | 加至100 |
Carbopol 980 | 卡波姆 | 0.6 | |
甘油 | 甘油 | 3.00 | |
KOH溶液10% | 氢氧化钾 | 2.4 | |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
步骤:
搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至环境温度并加入C)部分。匀化以得到小颗粒尺寸。
实施例13
高保护性防晒乳
成分 | INCI命名法 | %w/w | |
A) | PARSOL SLX | 聚硅氧烷-15 | 6.00 |
PARSOL 1789 | 丁基甲氧基二苯酰甲烷 | 2.00 | |
PARSOL 5000 | 4-甲基亚苄基樟脑 | 4.00 | |
Uvinul T 150 | 2.00 | ||
硅酮DC 200/350cs | 二甲基硅氧烷 | 1.00 | |
Lanette O | 鲸蜡硬脂醇 | 2.00 | |
Softisan 100 | 氢化的可可酸甘油酯 | 3.00 | |
Tegosoft TN | 苯甲酸C12-15烷基酯 | 6.00 | |
Cetiol B | 己二酸二丁酯 | 7.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 2.00 | |
BHT | BHT | 0.05 | |
Edeta BD | EDTA二钠 | 0.10 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Amphisol K | 十六烷基磷酸钾 | 2.00 | |
B) | 去离子水 | 水 | 加至100 |
丙二醇 | 丙二醇 | 5.00 | |
Carbopol 980 | 卡波姆 | 0.30 | |
KOH(10%溶液) | 氢氧化钾 | 1.50 | |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酮(VII) | 0.05-5 |
D) | 香料 | 香料 | 适量 |
步骤:
搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至环境温度并加入C)和D)部分。匀化以得到小颗粒尺寸。
实施例14
无水防晒凝胶
成分 | INCI命名法 | %w/w | |
A) | PARSOL MCX | 甲氧基肉桂酸乙基己酯 | 6.00 |
PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 4.00 | |
PARSOL 5000 | 4-甲基亚苄基樟脑 | 4.00 | |
Uvasorb HEB | 二乙基己基丁酰胺基三嗪酮 | 1.50 | |
Uvinul A plus | 2.00 | ||
维生素E醋酸酯 | 生育酚醋酸酯 | 1.50 | |
Tegosoft TN | 苯甲酸C12-15烷基酯 | 9.00 | |
Elefac I-205 | 新戊酸乙基己基十二烷基酯 | 2.00 | |
醇 | 醇 | 加至100 | |
异丙醇 | 异丙醇 | 20.00 | |
B) | Klucel MF | 羟丙基纤维素 | 2.00 |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
D) | 香料 | 适量 |
步骤:
搅拌下将A)和B)部分混合。均匀时在搅动下加入C)和D)部分。
实施例15
防晒凝胶
成分 | INCI命名法 | %w/w | |
A) | Pemulen TR-2 | 丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物 | 0.60 |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 |
Edeta BD | EDTA二钠 | 0.1 | |
水 | 水 | 加至100 | |
B) | PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 4.00 |
PARSOL 340 | 奥克立林(Octocrylene) | 3.00 | |
Tegosoft TN | 苯甲酸C12-15烷基酯 | 15.00 | |
Antaron V-216 | PVP/十六碳烯共聚物 | 1.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 0.50 | |
丁基化的羟基甲苯 | BHT | 0.05 | |
Cremophor RH 410 | PEG-40氢化的蓖麻油 | 0.50 | |
Tris Amino | 氨丁三醇(Tromethamine) | 0.50 | |
C) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
D) | 香料 | 香料 | 适量 |
步骤:
搅拌下将A)和B)部分加热至85℃。均匀时在搅动下向A)中加入B)部分。搅拌下冷却至环境温度,并加入C)和D)部分。匀化以得到小颗粒尺寸。
实施例16
高保护WO防晒乳
成分 | INCI命名法 | %w/w | |
A) | PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 2.00 |
PARSOL 5000 | 4-甲基亚苄基樟脑 | 4.00 | |
Uvinul T 150 | 乙基己基三嗪酮 | 2.00 | |
Uvinul TiO2 | 二氧化钛和三甲氧基辛酰基硅烷 | 5.00 | |
Arlacel P 135 | PEG-30二多羟基硬脂酸酯 | 2.00 | |
Tegosoft TN | 苯甲酸C12-15烷基酯 | 5.00 | |
Cosmacol EMI | 苹果酸二C12-13烷基酯 | 6.00 |
Miglyol 840 | 二辛酸/二癸酸丙二醇酯 | 6.00 | |
丁基化的羟基甲苯 | BHT | 0.05 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
B) | 去离子水 | 水 | 加至100 |
甘油 | 甘油 | 5.00 | |
Edeta | EDTA二钠 | 0.1 | |
NaCl | 氯化钠 | 0.30 | |
C) | PARSOL HS | 苯基苄基咪唑磺酸 | 4.00 |
水 | 水 | 20.00 | |
三乙醇胺99% | 三乙醇胺 | 2.50 | |
D) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
E) | 香料 | 适量 |
步骤:
搅拌下将A)、B)和C)部分加热至85℃。均匀时在搅动下向A)中加入B)和C)部分。搅拌下冷却至环境温度,并加入D)和E)部分。匀化以得到小颗粒尺寸。
实施例17
含颜料的W/O乳
成分 | INCI命名法 | %w/w | |
A) | Cremophor WO 7 | PEG-7氢化蓖麻油 | 6.00 |
Elfacos ST 9 | PEG-45/十二烷基二醇共聚物 | 2.00 | |
PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 3.00 | |
Tinosorb S | 5.00 | ||
PARSOL 5000 | 4-甲基亚苄基樟脑 | 4.00 |
精细ZnO | 氧化锌 | 2.00 | |
微晶蜡 | 微晶蜡 | 2.00 | |
Miglyol 812 | 辛酸/癸酸甘油三酯 | 5.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 1.00 | |
霍霍巴油 | 霍霍巴树种子油 | 5.00 | |
Edeta BD | EDTA二钠 | 0.10 | |
丁基化的羟基甲苯 | BHT | 0.05 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
B) | 去离子水 | 水 | 加至100 |
甘油 | 甘油 | 5.00 | |
C) | Neo Heliopan AP | 2.00 | |
去离子水 | 水 | 20.00 | |
KOH 10%溶液 | 氢氧化钾 | 4.00 | |
D) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
E) | 香料 | 香料 | 适量 |
步骤:
搅拌下将A)、B)和C)部分加热至85℃。均匀时在搅动下向A)中加入B)和C)部分。搅拌下冷却至环境温度,并加入D)和E)部分。匀化以得到小颗粒尺寸。
实施例18
含有维生素C的保护性日霜
成分 | INCI术语 | %w/w | |
A) | PARSOL SLX | 聚硅氧烷-15 | 4.00 |
PARSOL 1789 | 丁基甲氧基二苯甲酰甲烷 | 1.50 | |
肉豆蔻酸甘油酯 | 肉豆蔻酸甘油酯 | 2.00 | |
十六烷醇 | 十六烷醇 | 0.50 | |
Myritol 318 | 辛酸/癸酸甘油三酯 | 5.00 | |
Crodamol DA | 己二酸二异丙基酯 | 5.00 | |
维生素E醋酸酯 | 生育酚醋酸酯 | 2.00 | |
丁基化的羟基甲苯 | BHT | 0.05 | |
Phenonip | 苯氧乙醇&对羟基苯甲酸甲酯&对羟基苯甲酸乙酯&对羟基苯甲酸丙酯&对羟基苯甲酸丁酯 | 0.60 | |
Edeta BD | EDTA二钠 | 0.10 | |
Amphisol K | 十六烷基磷酸钾 | 2.00 | |
B) | 去离子水 | 水 | 加至100 |
1,2-丙二醇 | 丙二醇 | 2.00 | |
D-泛醇75L | 泛醇 | 2.00 | |
乙醇 | 乙醇 | 5.00 | |
尿囊素 | 尿囊素 | 0.20 | |
Carbopol ETD 2001 | 卡波姆 | 0.30 | |
KOH 10%溶液 | 氢氧化钾 | 1.50 | |
C) | 水 | 水 | 10.00 |
Stay-C 50 | 抗坏血酸磷酸钠 | 0.50 | |
D) | 式I和/或II的三环二萜 | 例如鼠尾草酸12-甲基醚(XI) | 0.05-25 |
E) | 香料 | 香料 | 适量 |
Claims (19)
1.至少一种式I和/或II的三环二萜用于制造营养药物或药物的用途,所述营养药物或药物用于治疗、辅助治疗或预防炎性病症和/或关节病症,所述式I和II为:
其中R1为氢或C1-6-烷基;
R2为羟基、C3-5-酰氧基、羟甲基、1,3-二羟丙基或C1-6-烷基;
R3和R4彼此独立地为氢、羟基、羟甲基(-CH2-OH)、C1-5酰氧基或C1-6烷氧基;
R5为C1-6-烷基、羟甲基、羧基(CO2H)或甲氧羰基(CO2CH3);
R6为氢,或R5和R6一起形成双键;
R7和R8彼此独立地为C1-6-烷基、羧基、x-羟基-Cx-烷基(x为从1到6的整数)或C1-6烷氧羰基(-CO2(C1-6-烷基)),条件是R7和R8中的至少一个为C1-6-烷基;
R9为氢、羟甲基、甲氧基、氧代或C1-5酰氧基;
R10是氢,或R5和R10一起为-CO-O-、-O-CO-、-CH2-O-或-O-CH2-;
R11和R12二者均为氢,或R11和R12一起为氧代;
R13为C1-6-烷基、羟甲基、羧基(CO2H)或甲氧羰基(CO2CH3),或R6和R13一起形成双键;
进一步的条件是对式I而言,如果R2是羟基,则R1是C1-6-烷基。
2.根据权利要求1的用途,其中所述至少一种三环二萜是式I和/或II的化合物,其中R1是氢或异丙基;R2是羟基或异丙基;R3和R4彼此独立地为氢、羟基或甲氧基;R5为甲基、羧基(CO2H)或羟甲基;R6为氢,或R5和R6一起形成双键;R7和R8彼此独立地为甲基、羧基、羟甲基或甲氧羰基,条件是R7和R8中的至少一个是甲基;R9是氢、氧代或甲氧基;R10是氢,或R5和R10一起为-CO-O-、-O-CO-、-CH2-O-或-O-CH2-;R13是羧基,进一步的条件是对式I而言,如果R2是羟基,则R1是异丙基。
3.根据权利要求1或2的用途,其中所述至少一种式I和/或II的三环二萜是7-氧代脱氢松香酸、桃拓酚、羟基桃拓酚、桃拓酚-19-羧酸甲酯、鼠尾草酮、8,11,13-松香三烯-11,12,20-三醇、扁柄草酸、铁锈醇、鼠尾草酸12-甲基醚和/或7-甲基迷迭香酚。
4.根据权利要求1到3中任一项的用途,其中所述至少一种式I和/或II的三环二萜以至少30wt-%的量包含在植物提取物中。
5.根据权利要求1到4中任一项的用途,其中所述炎性病症是关节炎。
6.一种用于治疗、辅助治疗或预防炎性病症和/或关节病症的营养药物,所述营养药物包含权利要求1到3中任一项定义的至少一种式I和/或II的三环二萜和营养药物可接受的载体。
7.根据权利要求6的营养药物,所述营养药物为食物制品、食品、膳食补剂、营养补剂或用于食物制品或食品的补剂组合物。
8.根据权利要求6或7的营养药物,所述营养药物中,所述至少一种式I和/或II的三环二萜的含量在每份0.01mg到1000mg的范围内,优选地在每份2.0mg到300mg的范围内。
9.一种用于治疗、辅助治疗或预防炎性病症和/或关节病症的药物,所述药物包含权利要求1到3中任一项定义的至少一种式I和/或II的三环二萜和药物可接受的载体。
10.一种化妆品或皮肤病学组合物,其包含权利要求1到3中任一项定义的至少一种式I和/或II的三环二萜和化妆品可接受的载体。
11.根据权利要求10的化妆品组合物或皮肤病学组合物,其为皮肤护理制剂。
12.根据权利要求10或11的化妆品或皮肤病学组合物,其用于治疗、辅助治疗或预防晒伤和/或不纯皮肤。
13.权利要求1到3中任一项中定义的式I和/或II的三环二萜,其用作治疗、辅助治疗或预防炎性病症和/或关节病症的药物。
14.权利要求1到3中任一项定义的至少一种式I和/或II的三环二萜用于治疗、辅助治疗或预防皮肤炎性病症的用途,所述皮肤炎性病症例如晒伤、不纯皮肤或慢性皮肤炎症的结果如光老化。
15.权利要求1-3中任一项定义的至少一种式I和/或II的三环二萜的下述用途:用于治疗、辅助治疗或预防关节中的软骨退化或软骨损伤,用于软骨再生或软骨维护,或用于维护关节健康。
16.一种用于治疗、辅助治疗或预防动物中的炎性病症和/或关节病症的方法,所述方法包括对有需要的动物施用有效量的根据权利要求1-3中任一项的至少一种式I和/或II的三环二萜的步骤,所述动物包括人。
17.根据权利要求16的方法,其中所述炎性病症是关节炎。
18.根据权利要求16的方法,其中所述炎性病症是皮肤炎症,尤其是晒伤或不纯皮肤。
19.根据权利要求16到18中任一项的方法,其中权利要求1-3中任一项定义的至少一种式I和/或II的三环二萜以至少30wt-%的量包含于植物提取物中。
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EP06024382A EP1925301A1 (en) | 2006-11-24 | 2006-11-24 | Use of tricyclic diterpenes and their derivatives for the treatment, co-treatment or prevention of inflammatory disorders and/or joint disorders |
EP06024382.1 | 2006-11-24 |
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CN200780050450XA Expired - Fee Related CN101594859B (zh) | 2006-11-24 | 2007-11-21 | 包含鼠尾草酸12-甲基醚的组合物 |
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US (2) | US8680147B2 (zh) |
EP (3) | EP1925301A1 (zh) |
JP (4) | JP5487520B2 (zh) |
KR (2) | KR101550073B1 (zh) |
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WO (2) | WO2008061724A2 (zh) |
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CN102532250A (zh) * | 2011-11-07 | 2012-07-04 | 中国科学院昆明植物研究所 | 具有抗肿瘤活性的化合物甘西鼠尾草酮a,其制备方法和其应用 |
CN105017155A (zh) * | 2014-04-16 | 2015-11-04 | 华东师范大学 | 类三环二萜并吡唑衍生物及其制备方法和应用 |
CN107823196A (zh) * | 2017-11-24 | 2018-03-23 | 广西医科大学 | 鼠尾草酸在制备治疗类风湿性关节炎药物方面的应用 |
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EP1925301A1 (en) * | 2006-11-24 | 2008-05-28 | DSMIP Assets B.V. | Use of tricyclic diterpenes and their derivatives for the treatment, co-treatment or prevention of inflammatory disorders and/or joint disorders |
ES2366865T3 (es) * | 2008-07-08 | 2011-10-26 | Cognis Ip Management Gmbh | Método para la preparación de (+)-totarol. |
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WO2012168278A2 (en) * | 2011-06-08 | 2012-12-13 | Dsm Ip Assets B.V. | Cosmetic compositions |
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-
2006
- 2006-11-24 EP EP06024382A patent/EP1925301A1/en not_active Ceased
-
2007
- 2007-11-21 WO PCT/EP2007/010076 patent/WO2008061724A2/en active Application Filing
- 2007-11-21 KR KR1020097013050A patent/KR101550073B1/ko not_active IP Right Cessation
- 2007-11-21 CN CNA2007800503865A patent/CN101600420A/zh active Pending
- 2007-11-21 CN CN200780050450XA patent/CN101594859B/zh not_active Expired - Fee Related
- 2007-11-21 JP JP2009537532A patent/JP5487520B2/ja not_active Expired - Fee Related
- 2007-11-21 US US12/515,332 patent/US8680147B2/en not_active Expired - Fee Related
- 2007-11-21 EP EP07846706A patent/EP2083805A2/en not_active Withdrawn
- 2007-11-21 KR KR1020097013051A patent/KR101526611B1/ko not_active IP Right Cessation
- 2007-11-21 US US12/515,329 patent/US20100056615A1/en not_active Abandoned
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102532250A (zh) * | 2011-11-07 | 2012-07-04 | 中国科学院昆明植物研究所 | 具有抗肿瘤活性的化合物甘西鼠尾草酮a,其制备方法和其应用 |
CN105017155A (zh) * | 2014-04-16 | 2015-11-04 | 华东师范大学 | 类三环二萜并吡唑衍生物及其制备方法和应用 |
CN105017155B (zh) * | 2014-04-16 | 2017-06-16 | 华东师范大学 | 类三环二萜并吡唑衍生物及其制备方法和应用 |
CN107823196A (zh) * | 2017-11-24 | 2018-03-23 | 广西医科大学 | 鼠尾草酸在制备治疗类风湿性关节炎药物方面的应用 |
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JP2010510267A (ja) | 2010-04-02 |
JP5633856B2 (ja) | 2014-12-03 |
JP2013255495A (ja) | 2013-12-26 |
KR20090089883A (ko) | 2009-08-24 |
US20100056615A1 (en) | 2010-03-04 |
JP2013227328A (ja) | 2013-11-07 |
KR101550073B1 (ko) | 2015-09-03 |
WO2008061724A3 (en) | 2008-08-21 |
JP5517124B2 (ja) | 2014-06-11 |
EP2083805A2 (en) | 2009-08-05 |
WO2008061720A2 (en) | 2008-05-29 |
KR101526611B1 (ko) | 2015-06-05 |
US8680147B2 (en) | 2014-03-25 |
US20100056634A1 (en) | 2010-03-04 |
JP5633855B2 (ja) | 2014-12-03 |
JP5487520B2 (ja) | 2014-05-07 |
CN101594859A (zh) | 2009-12-02 |
EP2083810A2 (en) | 2009-08-05 |
EP1925301A1 (en) | 2008-05-28 |
JP2010510266A (ja) | 2010-04-02 |
CN101594859B (zh) | 2012-08-08 |
WO2008061724A2 (en) | 2008-05-29 |
KR20090083478A (ko) | 2009-08-03 |
WO2008061720A3 (en) | 2008-10-23 |
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