CN101217968B - 补骨脂酚的组合物及其制备方法 - Google Patents
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Abstract
本发明提供了具有低杂质水平,尤其是呋喃香豆素杂质的补骨脂酚组合物(UP246)。本发明还提供了用于补骨脂酚组合物的分离、纯化和分析的改良方法。最后,本发明提供了使用纯化的补骨脂酚组合物及其制剂来预防和治疗由环氧合酶(COX)、脂氧合酶(LOX)、轻度炎性病症和各种微生物感染介导的各种疾病和病症的方法。本发明的方法包括向有此需要的主体给药有效量的本发明组合物以及药物学可接受的载体。
Description
技术领域
本发明涉及具有低杂质,尤其是呋喃香豆素杂质水平的补骨脂酚及其相关化合物的组合物。本发明提供了用于补骨脂酚组合物的分离、纯化和分析的改良方法。最后,本发明提供了使用纯化的补骨脂酚组合物及其制剂来预防和治疗由环氧合酶(COX)、脂氧合酶(LOX)、轻度炎性病症和各种微生物感染介导的各种疾病和病症的方法。
背景技术
补骨脂酚的结构如下所示,它是具有在芳环上的单个羟基和不饱和烃链的酚化合物。已经从补骨脂(Psoralea.corylifolia L.)(豆科(Luguminosae))的种子和Psoralea.glandulosa L.(蝶形花科)的地上部分中分离了它。
补骨脂酚
已经显示从植物补骨脂中提取的补骨脂酚具有抗肿瘤、抗氧化剂(Haraguchi等(Sept.2002)Phytother Res.16(6):539-544)、细胞毒性((Dec.1989)Yakugaku Zasshi.109(12):962-965)、抗微生物(Newton等(Jan.2002)J Ethnopharmacol.79(1);57-67)和护肝活性(Cho等(Nov.2001)Planta Med.67(8):750-751)。它还显示是拓扑异构酶II抑制剂(Sun等(Mar.1998)J NatProd.61(3):362-366)。补骨脂酚可以剂量依赖的方式抑制PTPlB活性,其IC50值为20.8±1.9μM(Kim等(Jan.2005)Planta Med.71(1):87-99)。Batap等已经报告了作为抗肿瘤药的放射性碘标记的补骨脂酚的制备和体外评价((Mar.2005)Appl Radiat Isot.62(3):389-393)。已经报告补骨脂酚的萜链对于其抗氧化剂活性很关键(Adhikari等(Sept.2003)Chem ResToxicol.16(9):1062-1069)。
还已经报告补骨脂酚是可用于开发对抗口腔病原体的抗菌药的有用化合物,且对于在食品添加剂和用于预防和治疗龋齿的嗽口剂中应用具有极大潜力(Katsura等(Nov.2001)Antimicrob Agents Chemother.45(11):3009-3013)。抗炎和退热活性导向的补骨脂活性提取物的分级导致分离了补骨脂酚以及三种其它活性化合物:环补骨脂酚A和B以及异补骨脂素(Backhouse等(Nov.2001)J Ethnopharmacol.78(1):27-31)。据报道,补骨脂酚控制白细胞功能如类花生酸在炎性位置的产生、迁移和脱粒,并且是分泌和胞内PLA2的弱抑制剂。它剂量依赖性地减少分别由人嗜中性粒细胞和血小板微粒体形成的LTB4和TXB2(Ferrandiez等(Sept.1996)JPharm Pharmacol.48(9):975-980)。它还通过灭活RAW 264.7巨噬细胞内的核转录因子-κB抑制诱导型一氧化氮合酶基因的表达(Pae等(Sept.2001)International Immunopharmacol.1(9-10):1849-1855)。还报告了补骨脂酚对线粒体脂质过氧化的抑制(Haraguchi等(Aug.2000)Planta Med.66(6):569-571)。Krenisky等在Biol Pharm Bull.(Oct.1999)22(10):1137-1140)中描述了从Otholobium pubescens(豆科)中分离的补骨脂酚的分离和抗高血糖活性。最后,已经报告包含补骨脂酚以及许多其它香豆素型化合物的被称为补骨脂剂的粗提物可促进骨愈合(US2004/0043089A1)。
因此,补骨脂酚是生物学活性的天然产物,具有用于预防和治疗各种疾病和病症的极大潜力。然而,目前关于该化合物的使用存在许多限制,主要由于其在天然来源中的低浓度,以及共存的有毒组分的存在。使用从补骨脂属植物中分离的补骨脂酚组合物涉及的一个主要问题是补骨脂素类的存在,例如补骨脂素和异补骨脂素,其结构如下所列。补骨脂素类也被称为呋喃香豆素类,是植物,包括许多水果和蔬菜中天然存在的第二代谢物。
补骨脂素 异补骨脂素
许多健康危险伴随着包含补骨脂素的植物和合成补骨脂素类的处理、局部施用和摄取。公知补骨脂素类是光毒性剂,其可增加皮肤对紫外线辐射的敏感性并促进皮肤癌(Epstein(1999)Med.Surg.18(4):274-284)。已知补骨脂素可诱导大鼠的生长抑制(Diawara等(1997)CancerLett.114(1-2):159-160)。来自补骨脂属植物的粗提物的性腺毒性直接关联下丘脑-垂体-性腺轴的中断(Takizawa等(2002)J.Toxicological Sciences27(2):97-105)。在雌性大鼠饮食中口服给药补骨脂素类、佛手内酯(5-甲氧基补骨脂素)和花椒毒素(8-甲氧基补骨脂素)以剂量依赖的方式减少出生率、植入位点的数目、幼仔、黄体、充满和空子宫重量、和循环的***水平(Diawara等(1999)J.Biochem.Molecular Toxicology 13(3/4):195-203)。还显示补骨脂素类诱导肝酶CYPlA1和UGTlA6的mRNA,这暗示由补骨脂素类增强的***代谢可以解释生殖毒性和观察到的卵泡功能和***的减少(Diawara等(May-June 2003)Pediatr Pathol Mol Med.22(3):247-58)。补骨脂素和异补骨脂素占补骨脂属种子干重的约0.1-2%和乙醇及其它有机溶剂粗提物重量的约1-20%。为了增强补骨脂酚组合物,尤其是从植物来源分离的补骨脂酚组合物的纯度和安全性,仍然需要用于除去有毒化合物,如补骨脂素和异补骨脂素,以及其它香豆素类的方法。
由细胞膜释放和代谢的花生四烯酸(AA)通过几种不同的途径导致前致炎代谢物的产生。可证明,两种最重要的致炎途径由酶脂氧合酶(LOX)和环氧合酶(COX)介导。这些是平行的途径,分别导致白三烯和***素的产生,它们在炎症反应的引发和进展中具有重要作用。这些血管活性化合物是化学毒素,可促进炎性细胞浸润到组织中并延长炎症反应。
COX酶的抑制是大多数非甾类抗炎药(NSAIDS)的作用机理。有两种不同的COX酶同工型(COX-1和COX-2),它们共有几乎60%的序列同源性,但在表达谱和功能方面不同。COX-1是构成型的酶,它与生理上重要的***素的产生有关,***素帮助调节正常生理功能,例如血小板聚集、保护胃内的细胞功能并维持正常的肾功能(Dannhardt和Kiefer(2001)Eur.J.Med.Chem.36:109-26)。第二种异构体COX-2是可由前致炎细胞因子如白介素-1β(IL-1β)和其它生长因子诱导的酶形式(Herschmann(1994)Cancer Metastasis Rev.134:241-56;Xie等(1992)Drugs Dev.Res.25:249-65)。这种同工型催化由花生四烯酸(AA)产生***素E2(PGE2)。
对COX和LOX表现出双重特异性的抑制剂具有抑制花生四烯酸代谢的多重途径的明显好处。这种抑制剂能通过抑制***素(PG)以及多重白三烯(LT)生成阻断它们的炎性作用。这包括PGE2、LTB4、LTD4和LTE4的血管舒张、血管通透性和趋化性作用,它们还公知作为过敏性反应(anaphalaxi)的慢反应物质。其中,LTB4具有最有效的趋化性以及化学增活作用(Moore(1985)in Prostanoids:pharmacological,physiological and clinical relevance,Cambridge University Press,N.Y.,pp.229-230)。
由于COX抑制剂的作用机理与大多数常规NSAID的机理部分相同,所以COX抑制剂被用于治疗许多相同的症状,包括与炎症在其中起关键作用的短期皮肤病症和慢性病中的炎症相关的疼痛和肿胀。因此,负责生成这些炎症介质的酶已成为开发旨在治疗炎症的许多新药的目标,炎症是导致疾病如类风湿性关节炎、骨性关节炎和阿尔茨海默病的发病机制的因素。
短期皮肤病症包括与轻度擦伤或接触性皮炎有关的炎症的治疗,以及与***素和白三烯途径直接相关的皮肤病症,例如皮肤色素沉着过度、老年斑、白癜风(vitilago)、***性红斑狼疮、牛皮癣、癌、黑素瘤、和其它哺乳动物皮肤癌。COX抑制剂的使用已经扩展到包括例如***性红斑狼疮(SLE)的疾病(Goebel等(1999)Chem.Res.Toxicol.12:488-500;Patrono等(1985)J.Clin.Invest.76:1011-1018),以及风湿性皮肤病症,例如硬皮病。COX抑制剂还用于减轻非风湿起因的炎性皮肤症状如牛皮癣,其中减轻由***素过度生成导致的发炎可提供直接的益处(Fogh等(1993)Acta Derm Venerologica 73:191-193)。近期报告了5-脂氧合酶在患有***性硬化症的患者的皮肤中过度表达。这导致暗示LOX途径可能在***性硬化症的发病机制中很重要,并可能是有效的治疗靶标(Kowal-Bielecka(2001)Arthritis Rheum.44(8):1865)。最后,COX-2和5-LOX两者在过敏原注射位置处的酶活性增加暗示使用双重COX/LOX抑制剂治疗皮肤过敏反应的早期和晚期症状的潜力(Church(2002)Clin.Exp.Allergy.32(7):1013)。
***素和白三烯还在创伤、烧伤、烫伤、痤疮、微生物感染、皮炎、和许多其它皮肤疾病和病症的生理和病理过程中起重要作用。在热或化学烧伤后以明显升高的环氧合酶和脂氧合酶活性激活前致炎级联被大量记载,并在随后可能导致多个器官衰竭的严重症状和免疫功能障碍的发展中起重要作用(Schwacha(2003)Burns 29(1):1:He(2001)J.BurnCare Rehabil.22(1):58)。
除了用作抗炎药外,COX抑制剂的另一个潜在作用是治疗癌症。已经在各种人恶性肿瘤中证实了COX的过度表达,显示COX抑制剂可有效地治疗患有皮肤癌的动物。尽管作用机理尚未完全了解,但显示COX的过度表达可抑制凋亡并增加肿瘤发生性细胞类型的侵袭性(Dempke等(2001)J.Can.Res.Clin.Oncol.127:411-17;Moore和Simmons(2000)Current Med.Chem.7:1131-1144)。已经证明在皮肤光化性角化病和鳞状细胞癌产生中涉及COX的产生上调。还在由DNA损伤产生的损伤中发现了升高的COX量(Buckman等(1998)Carcinogenesis 19:723)。因此,控制COX的表达或蛋白质功能似乎将导致炎症反应和最终进展为癌症的降低。事实上,已经发现COX抑制剂如吲哚美辛和CelebrexTM可有效地治疗UV诱导的红斑和肿瘤形成(Fischer(1999)Mol.Carcinog.25:231;Pentland(1999)Carcinogenesis 20:1939)。最近,还显示脂氧合酶的过度表达与表皮肿瘤发展(Muller(2002)Cancer Res.62(16):4610)和黑素瘤癌发生(Winer(2002)Melanoma Res.12(5):429)有关。由脂氧合酶途径产生的花生四烯酸(AA)代谢物在与肿瘤生长相关的信号转导中起重要作用,这暗示脂氧合酶途径的抑制将是预防癌症发展的有效靶标(Cuendet(2000)Drug Metabol Drug Interact 17(4):109:Steele(2003)Mutat Res.523-524:137)。因此,使用具有双重COX/LOX抑制活性的治疗药可在癌症的化学预防中提供明显优点。
痤疮是毛囊皮脂腺单元的慢性疾病,其特征是皮脂腺过度产生皮脂、毛囊上皮脱落、细菌增殖和炎症。激素失衡、微生物感染和炎症是与痤疮发生有关的三个主要因素(Toombs(2005)Dermatol.Clin.23(3):575-581;Nishijima等(2000)J.Dermatol.27(5):318-323)。目前用于预防和治疗痤疮的治疗药包括抗炎药如类视黄醇、抗微生物药和激素药(Leyden(2003)J.Am.Acad.Dermatol.49(3 Suppl):S200)。
与痤疮有关的主要细菌种类是痤疮丙酸杆菌(Propionibacteriumacnes)和革兰氏阳性表皮葡萄球菌(Staphylococcus epidermidis)(Perry和Lambert(2006)Lett.Appl.Microbiol.42(3):185-188)。目前的治疗药包括过氧化苯甲酰和其它抗微生物药如氨苄西林和庆大霉素(Fermandez等(2005)Expert Rev.Anti Infect Ther.3(4):557-591)。不幸的是,已经报告了痤疮丙酸杆菌和表皮葡萄球菌两者的耐药性(Nishijima等(2000)J.Dermatol.27(5):318-323)。
临床上还证实,局部施用抗炎药如类视黄醇(Millikan(2003)J.Am.Acad.Dermatol.4(2):75)和COX抑制剂水杨酸(Lee(2003)Dermatol Surg29(12):1196)是用于痤疮治疗的有效和安全的疗法。此外,大量记载使用非甾类抗炎药(NSAID)作为常见和非常见皮肤病,包括痤疮、牛皮癣、晒伤、结节性红斑、冷球蛋白血症、斯威特综合征(Sweet’s syndrome)、***性肥大细胞增多症、荨麻疹性血管炎、青斑样(liverdoid)血管炎和结节性血管炎的治疗药(Friedman(2002)J.Cutan Med.Surg.6(5):449)。
牙周病是一些或全部牙齿支撑结构(牙龈、牙骨质、牙周膜、牙槽骨和牙齿周围的其它组织)的炎症和感染。牙龈炎(牙龈)和牙周炎(牙龈和骨)是两种主要的牙周病形式。根据由国家牙齿和颅面研究协会(NationalInstitute of Dental and Craniofacial Research)发布的全国口腔信息(National Oral Information),估计目前有80%的美国成年人患有某些形式的牙周病。当在清洁的牙齿上形成菌膜时引起牙周病。这种菌膜吸引需氧革兰氏阳性菌(主要是放线菌和链球菌),它们粘附到牙齿上形成斑块。斑块在几天内变厚,下面的细菌耗尽了氧,厌氧运动型杆菌和螺旋菌开始在牙龈下区域繁殖。由厌氧菌释放的内毒素引起炎症、牙龈组织破坏和甚至骨质疏松。牙周病有四个主要阶段,它们可以表征如下。牙周病的破坏性冲击超出牙齿卫生和健康,因为已经在一些患病者的肝、肾和脑中发现了由牙周病引起的显微损伤。
牙周病的四个阶段
目前用于治疗牙周病的方法局限于以控制感染为主要目标(Genco等(1990)in Contenporary Periodontics,The CV.Mosby Company,St.Louis,pp.361-370)。普通的抗微生物药或抗斑块药包括氯己定、三氯生、氟化亚锡、李施德林(Listerine)、过氧化氢、西吡氯铵(cetylpyridimiun chloride)和血根碱生物碱。抗微生物口腔清洗剂、防腐片(antiseptic chip)、抗生素凝胶/微球和酶抑制剂-多西环素处方药是用于治疗和控制牙周病的优选非机械/物理选择。不幸的是,目前没有既控制炎症又抑制感染的单一的牙周药物。
将理解的是,前面的一般描述和下列的详细描述都只是示例性和说明性的,并不是对所要求保护的发明的限制。
发明内容
本发明包括含有补骨脂酚的新组合物,其基本上不含杂质,尤其是呋喃香豆素杂质。本文中也将该组合物称为UP256。在一些实施方案中,所述组合物从包括但不限于豆科、蝶形花科、樟科和木兰科的植物科中获得。在其它实施方案中,所述组合物从选自包括但不限于补骨脂属(Psorlea)、檫木属、木兰属和苍术属(Astractylodes)的植物属的一种或多种植物中获得。在优选实施方案中,所述植物选自包括但不限于补骨脂(豆科)或Psoralea glandulosa L.(蝶形花科)。本发明的组合物可以获自全株植物或获自植物的一个或多个单独部分,包括但不限于种子、茎、茎皮、嫩枝、块茎、根、根皮、嫩芽、根茎(rhixomes)、花和其它生殖器官、叶和其它地上部分。
取决于提取方法和粗提物的纯化程度,组合物中补骨脂酚的量可以在约14至100重量%的范围内。在一个实施方案中,组合物中补骨脂酚的量在30%至100%的范围内。在其它实施方案中,组合物中补骨脂酚的量选自:至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%、至少80%、或至少90%。在优选实施方案中,组合物中补骨脂酚的量为约30%。
杂质包括补骨脂酚组合物不需要的任何物质。通常,补骨脂酚组合物中存在的杂质是生产它们所采用的方法的结果,所述方法包括从天然来源中分离和合成方法。例如,在从天然来源中分离补骨脂酚时,杂质包括呋喃香豆素类,例如补骨脂素、异补骨脂素和其它香豆素型组分。
本发明还包括用于分离和纯化获自天然来源的补骨脂酚粗组合物和相关化合物的改良方法。用于分离和纯化这些组合物的改良方法包括如下步骤:从植物来源中提取化合物,用碱性溶液水解粗提物,并通过包括但不限于柱色谱法、提取然后结晶、溶剂分配、重结晶及其组合的方法纯化。如此纯化的粗提物基本上不含呋喃香豆素杂质如补骨脂素和异补骨脂素。因此,基本上消除了与这些化合物相关的可能的光毒性、局部刺激、致癌性(carcenogenecity)和生殖毒性。在通过本发明的方法分离和纯化后,这些组合物的纯度在选自约27%至100%的范围内。
本发明还包括用于分析补骨脂酚组合物的方法,该方法使杂质的检测和定量成为可能。在本发明的该实施方案中,用于分析补骨脂酚组合物的方法包括使用高压液相色谱法(HPLC)分析所述组合物的步骤。使用HPLC分析使混合物中各种组分的定量成为可能,还提供了追踪补骨脂属植物中的补骨脂酚、补骨脂素、异补骨脂素和其它天然组分的方法,以指导提取、水解和纯化方法。
本发明还包括用于预防和治疗COX和LOX介导的皮肤、口腔、牙齿和牙龈疾病和病症的方法。用于预防和治疗COX和LOX介导的皮肤、口腔、牙齿和牙龈疾病和病症的方法包括向有此需要的主体给药(优选局部给药)有效量的包含补骨脂酚以及药物学可接受的载体的组合物,该组合物基本上不含呋喃香豆素杂质。如上所述,组合物中补骨脂酚的量在27%至100%的范围内。在优选实施方案中,组合物中补骨脂酚的量为约30%。同样如上所述,在优选实施方案中,补骨脂酚从补骨脂属植物中的一种或多种植物中分离。
COX和LOX介导的皮肤疾病或病症包括但不限于痤疮,头皮屑,晒伤,热灼伤,局部创伤,由真菌、微生物和病毒感染引起的轻度炎性病症,白癜风,***性红斑狼疮,牛皮癣,癌,黑素瘤,以及其它哺乳动物皮肤癌,由于暴露至紫外线(UV)辐射、化学品、热、风和干燥环境引起的皮肤损伤,皱纹,皮肤松弛,眼周皱纹和黑眼圈,皮炎和其它过敏相关的皮肤病症。COX/LOX介导的口腔、牙齿和牙龈疾病和病症包括但不限于牙周病,口腔癌症前期病症,口腔癌,和其它口腔恶性肿瘤,敏感性牙龈和牙齿,后遗症,牙髓炎,由物理植入假牙、外伤、损伤、夜磨牙症和口腔内、牙龈上或舌头上的其它轻伤引起的刺激、疼痛和炎症,牙斑和结石,牙齿脱钙,蛋白质水解和龋齿(蛀蚀)。
本发明还包括用于预防和治疗其它COX和LOX介导的疾病和病症的方法,所述疾病和病症包括但不限于全身关节疼痛和僵硬,由于骨关节炎和类风湿性关节炎的病理状况引起的运动性缺乏和身体功能的损失,痛经,动脉粥样硬化,肥胖,糖尿病,阿尔茨海默病,呼吸过敏反应,慢性静脉功能不全,牛皮癣,慢性紧张性头疼,偏头痛,炎性肠病,***癌和其它实体瘤。
用于预防和治疗所述COX和LOX介导的疾病和病症的方法包括向有此需要的主体给药有效量的包含补骨脂酚以及药物学可接受的载体的组合物,所述组合物基本上不含呋喃香豆素杂质。如上所述,组合物中补骨脂酚的量在27%至100%的范围内。在优选实施方案中,组合物中补骨脂酚的量为约30%。同样如上所述,在优选实施方案中,补骨脂酚从补骨脂属植物中的一种或多种植物中分离。
本发明还包括用于预防和治疗由微生物感染,包括但不限于细菌、病毒和真菌感染介导的皮肤、口腔、牙齿或牙龈的疾病和病症的方法,所述方法包括向有此需要的主体给药有效量的包含补骨脂酚以及药物学可接受的载体的药物组合物,所述组合物基本上不含呋喃香豆素杂质。由微生物感染介导的皮肤、口腔、牙龈和牙齿的疾病和病症包括但不限于头皮屑,痤疮,脚癣,牙周病,所述牙周病选自龋齿,牙龈炎,牙周炎,牙髓炎,由于物理植入假牙、外伤、损伤、夜磨牙症、肿瘤性和其它退化性过程引起的牙周病症;白垢(material alba),菌膜,牙斑,结石和色斑。
在一个实施方案中,细菌选自痤疮丙酸杆菌或表皮葡萄球菌。
本发明的组合物可以通过本领域普通技术人员已知的任何方法给药。给药的方式包括但不限于肠道(口服)给药,胃肠道外(静脉内、皮下和肌内)给药以及局部施用。在优选实施方案中,局部给药所述组合物。本发明的预防和治疗方法包括体内(internally)或局部向有此需要的患者给药治疗有效量的包含补骨脂酚的组合物,该组合物基本上不含杂质,尤其是呋喃香豆素杂质。
将理解的是,前面的一般描述和下列的详细描述都只是示例性和说明性的,并不是对所要求保护的发明的限制。
附图说明
图1示意来自补骨脂属植物的代表性提取物的HPLC色谱图。两种呋喃香豆素类——补骨脂素和异补骨脂素等量存在于提取物中。
图2示意在氢氧化钠水解反应之前(图2A)和之后(图2B)补骨脂属提取物的HPLC色谱图。
图3图示包含31%补骨脂酚的UP256样品(MH-258-07-01)的HPLC色谱图。
图4图示包含41%补骨脂酚的UP256样品(MH-258-07-02)的HPLC色谱图。
图5图示包含99%补骨脂酚的UP256样品(MH-258-12-08)的HPLC色谱图。
图6图示UP256组合物(#MH-258-12-08-·-)相对于阳性对照——NDGA(-■-)的5-脂氧合酶(5-LO)酶活性抑制的剂量响应曲线。
具体实施方式
本发明包括具有低杂质水平的补骨脂酚组合物(UP246)。本发明包括用于分离和纯化补骨脂酚组合物的改良方法。本发明还包括分析补骨脂酚组合物的方法,该方法使各种杂质的检测和定量成为可能。本发明还包括使用纯化的补骨脂酚组合物及其制剂来预防和治疗由环氧合酶(COX)、脂氧合酶(LOX)、轻度炎性病症和各种微生物感染介导的各种疾病和病症的方法。
在提及本发明的各方面时本文使用了各种术语。为了帮助说明对本发明组分的描述,提供了下列定义:
要注意的是,术语“a”或“an”实体指一个或多个所述实体。同样地,术语“a”或“an”、“one or more”和“at least one”在本文中可互换使用。
本文中使用的“补骨脂酚”指具有下式的化合物:
补骨脂酚
其中中心双键可以是顺式或反式。结构上与补骨脂酚相关的酚化合物也包括在此定义内。
本文中使用的术语“杂质”包括补骨脂酚组合物中不需要的通常由于从天然来源中分离补骨脂酚导致的任何物质。术语“杂质”包括但不限于呋喃香豆素化合物,其选自包括但不限于补骨脂素、异补骨脂素和其它香豆素型杂质。杂质还指用于获得这些组合物的合成方法所致的杂质。
本文中所使用的“治疗”包括治疗和/或预防。当使用时,治疗指人以及其它动物。
“药物学或治疗有效的剂量或量”指足以诱导期望的生物学结果的剂量水平。该结果可能是疾病的病征、症状或原因的缓解或期望的任何其它生物***的变化。
“安慰剂”指用无活性物质代替足以诱导期望的生物学结果的药物学或治疗有效的剂量或量,所述生物学结果可能缓解疾病的病征、症状或原因。
“主体”或“患者”指向其给药本文所述组合物的活的受试者、人或动物。因此,本文所述的发明可兽用以及用于人类,术语“患者”或“主体”不应以限制性的方式理解。在兽用的情况下,剂量范围可考虑动物的体重如下所述确定。
注意在整个本申请中提供了多个引文。每个引文被全部具体地纳入本文作为参考。
本发明包括包含补骨脂酚的新组合物,其基本上不含杂质,尤其是呋喃香豆素杂质。本文中也将该组合物称为UP256。在一些实施方案中,所述组合物从选自补骨脂植物属的一种或多种植物中获得。在优选实施方案中,所述植物选自包括但不限于补骨脂(豆科)或Psoralea glandulosaL.(蝶形花科)。本发明的组合物可以获自全株植物或获自植物的一个或多个单独部分,包括但不限于种子、茎、茎皮、嫩枝、块茎、根、根皮、嫩芽、根茎、花和其它生殖器官、叶和其它地上部分。
取决于提取方法和粗提物的纯化程度,组合物中补骨脂酚的量可以在约14至100重量%的范围内。在一个实施方案中,组合物中补骨脂酚的量在30%至100%的范围内。在其它实施方案中,组合物中补骨脂酚的量选自:至少30%、至少35%、至少40%、至少45%、至少50%、至少60%、至少70%、至少80%、或至少90%。在优选实施方案中,组合物中补骨脂酚的量为约30%。
杂质包括补骨脂酚组合物中不需要的任何物质。通常,补骨脂酚组合物中存在的杂质是生产它们所采用的方法的结果,所述方法包括从天然来源中分离和合成方法。例如,在从天然来源中分离补骨脂酚时,杂质包括呋喃香豆素类,例如补骨脂素、异补骨脂素和其它香豆素型组分。
本发明还包括用于分离、分析和纯化获自天然来源的补骨脂酚粗组合物的改良方法。用于分离和纯化这些组合物的改良方法包括如下步骤:从植物来源中提取化合物,用碱性溶液水解粗提物,并通过包括但不限于柱色谱法、提取然后结晶、溶剂分配、重结晶及其组合的方法纯化。如此纯化的粗提物基本上不含呋喃香豆素杂质如补骨脂素和异补骨脂素。
实施例1(表1)中描述了使用高压液相色谱法(HPLC)分析补骨脂酚组合物的方法。使用HPLC分析使混合物中各种组分的定量成为可能,还提供了追踪补骨脂属植物内的补骨脂酚、补骨脂素、异补骨脂素和其它天然组分的方法,以指导提取、水解和纯化方法。
如实施例2中所述,在两套提取条件下,使用六种不同的有机溶液体系评价从植物来源中提取补骨脂酚的效率。结果列于表2。参考表2,可以看出可以用任何数量(number)的有机溶剂和/或其组合从补骨脂属植物中提取补骨脂酚。各种提取物中补骨脂酚的量的范围为最大值29.1重量%至13.7重量%。确定用石油醚提取以良好的回收率在粗提物中提供了最高纯度的补骨脂酚。图1示意粗提物的代表性HPLC色谱图。参考此图,可以看出粗提物包含补骨脂酚以及呋喃香豆素杂质补骨脂素和异补骨脂素。实施例3描述了在70℃下用石油醚大规模提取。
实施例4说明使用柱色谱法纯化粗补骨脂酚提取物的效率。特别评价了八种不同类型的树脂从呋喃香豆素杂质中分离补骨脂酚的能力。硅胶和CG-161树脂两者均显示令人满意的分离。然而,在工业规模下植物粗提物的柱色谱法分离通常在经济上是不可行的,因为它需要昂贵的设备和试剂以及有经验的人员,更不用说由于植物粗提物的复杂性导致的这些样品的极低的载荷能力。
实施例5-7描述了用于分离呋喃香豆素杂质和补骨脂酚的新型、经济的方法,所述方法包括用碱处理包含所述杂质的组合物。如下面示意图所示,使用NaOH作为示例,用碱处理打开了呋喃香豆素类的内酯环,从而将它们转化为相应的羧酸盐,这些羧酸盐然后可以通过各种方法容易地从其余混合物中分离。
碱溶液可以选自能够用于打开内酯环的任何碱,包括但不限于氢氧化钠、氢氧化钾、氢氧化钙和氢氧化锂。溶液可以选择具有不同的浓度和pH值,以使到酸盐的转化最大化。反应混合物还可以在不同的温度和压力下加热以使反应速率、效率和产率最大化。
反应过程后可以接着HPLC以确保将香豆素类完全转化为它们各自的羧酸盐。图2A和B示意粗组合物在水解之前和之后的HPLC色谱图。在完成反应后(由HPLC确定),可以使用各种方法处理反应溶液,所述方法包括但不限于柱色谱法提取然后结晶,溶剂分配,重结晶或其组合。如此纯化的粗提物基本上不含呋喃香豆素杂质如补骨脂素和异补骨脂素。
参考实施例5-7,在以各种条件水解然后进行溶剂分配时,有效地从补骨脂酚组合物中除去了呋喃香豆素类,即补骨脂素和异补骨脂素。此外,补骨脂酚的纯度从约10-30%升至30%-50%。能够用于溶剂分配的有机溶剂包括但不限于石油醚、乙酸乙酯、***、己烷、氯仿、丙醇、丁醇和二氯甲烷,以及其它水不混溶的有机溶剂。
在实施例7所述的一个实施方案中,将粗反应混合物直接装填到柱上,然后用极性溶剂洗脱。根据此实施方案,可以获得包含70%至100%补骨脂酚的组合物。在实施例7中,在水解后,将粗反应混合物直接装填到CG-161 cd柱上,然后用甲醇洗脱以提供高纯度(约99%)的补骨脂酚。能够用于此实施方案的其它类型的树脂包括但不限于XAD(Amerlite)、CG-71/CG-161或其它类型的聚苯乙烯树脂;离子交换树脂和硅胶。可以用选自包括但不限于水、甲醇/水、乙醇/水、丙酮/水和乙腈/水以及其它极性溶剂的组合的溶剂洗脱柱。值得注意的是,水解后的柱载荷能力远远大于水解前。此外,这些不含呋喃香豆素的高纯度补骨脂酚组合物的颜色是浅棕色,它们在颜色和活性药的组成两方面极为稳定,这使得它们特别适合制剂、贮存和化妆应用。
在替代实施方案中,可以首先用有机溶剂提取粗反应混合物,然后使用色谱法和/或溶剂分配和/或重结晶进一步纯化。如上所述,取决于提取方法和进一步纯化的程度,可容易地获得包含约30%至100%之间的补骨脂酚的组合物。
本发明包括使用纯化的补骨脂酚组合物及其制剂来预防和治疗由环氧合酶(COX)、脂氧合酶(LOX)、轻度炎性病症和各种微生物感染介导的各种疾病和病症的方法。如实施例8-11所述评价了这些独特的不含呋喃香豆素的补骨脂酚组合物(在本文中被称为UP256)的生物学性质和安全性。
在实施例8中,测试了高纯度的UP256组合物(MH-258-12-08,99%纯度)对COX-1和COX-2酶二者的抑制。UP256显示对两种酶均具有强效的抑制活性。对COX-1的IC50测定为2.34μM,而对COX-2的IC50定量为78μM。因此,与常规COX抑制剂相比,该组合物提供了对COX-1和COX-2酶的更平衡的调节。例如,COX-1选择性抑制剂阿司匹林对COX-1比对COX-2更有效超过150倍,它会引起胃肠道副作用。相反,选择性COX-2抑制剂Vioxx、Celebrex和Bextra对COX-2更有效50-200倍,它们不会引起这么多的胃肠道损害,然而这些COX-2选择性药物会增加心血管危险。另一方面,本文公开的新型组合物提供了对类花生酸途径的最佳调节,而不存在由COX-1选择性NSAID引起的胃刺激和由COX-2选择性抑制剂引起的心血管危险。
还显然UP256抑制COX的作用机理完全不同于NSAID的机理。阿司匹林、Vioxx、Celebrex和Bextra通过共价键与COX酶不可逆地结合以形成牢固结合的酶-抑制剂复合物。这种相互作用完全改变了酶的活性部位和侧袋(side pocket)并破坏了酶(Walker和Kurumbal等(2001)Biochem.357:709-718)。另一方面,UP256通过较弱和可逆的结合抑制COX酶。在这种相互作用的过程中,COX酶的结构和功能没有受到不可逆地改变,从而导致远远更好的耐受性和安全特性。
实施例9描述了LOX抑制测定。LOX的抑制导致与慢性炎症症状直接相关的噬菌细胞性白三烯的积累降低,还减少了潜在的胃肠道副作用。实施例9证实了所述功效。参考实施例9,针对人5-脂氧合酶(5-LO或5-LOX)酶以四个浓度重复测定了高纯度UP256组合物MH-258-12-08(99%纯度)。通过测量剂量响应和IC50(抑制酶活性的50%所需的浓度)证实了COX-2抑制活性。图6图示剂量响应曲线。对LOX抑制的IC50测定为3.41μM。因此,UP256提供了显著减少白三烯产生的额外益处。这种白三烯产生的减少迄今为止优于常规非甾类抗炎药如布洛芬。
实施例10描述了设计用于测定UP256的抗微生物活性的实验。参考实施例10,以八个浓度重复测定UP256对六种不同微生物的抑制。发现在1μg/mL的最低有效浓度下,UP256抑制两种特定的微生物,即痤疮丙酸杆菌和革兰氏阳性表皮葡萄球菌。这两种微生物均直接与痤疮、皮炎、和其它皮肤感染有关。在30μg/mL的浓度下,UP256还显示出对须癣毛癣菌(Trichophyton mentagrophytes)的中度抑制。没有观察到对絮状表皮癣菌(Epidermophyton floccosum)、犬小孢子菌(Microsporum canis)或皮屑芽孢菌(Pityrosporum ovale)的抑制。
如实施例10所述,测定UP256在30%和70%的浓度下在小鼠体内的急性毒性。受试的小鼠在14天中每天口服2g/kg。小鼠在体重增加和血液化学方面没有显示副作用。此外,没有在任何受试的重要器官中观察到毒性。总之,治疗组的重量、血液检测(blood work)和组织学数据与对照组没有不同。在14天的研究中没有观察到副作用。因此,可以推断UP256具有可靠的安全特性。
最后,UP256的分配系数为log P=6.13。化合物的分配系数提供了对其亲水/亲脂平衡值以及从而其潜在的生物利用度的热力学测量。分配系数为6.1 3意味着当配制到给药***中时,此化合物具有高细胞膜渗透和生物利用度。
因此本发明包括用于预防和治疗由COX和LOX介导的皮肤、口腔、牙齿和牙龈疾病和病症的方法。用于预防和治疗COX和LOX介导的皮肤、口腔、牙齿和牙龈疾病和病症的方法包括向有此需要的主体给药(优选局部给药)有效量的包含补骨脂酚以及药物学可接受的载体的组合物,该组合物基本上不含呋喃香豆素杂质。如上所述,组合物中补骨脂酚的量在27%至100%的范围内。在优选实施方案中,组合物中补骨脂酚的量为约30%。同样如上所述,在优选实施方案中,补骨脂酚从补骨脂属植物中的一种或多种植物中分离。
COX和LOX介导的皮肤疾病或病症包括但不限于痤疮,头皮屑,晒伤,热灼伤,局部创伤,由真菌、微生物和病毒感染引起的轻度炎性病症,白癜风,***性红斑狼疮,牛皮癣,癌,黑素瘤,以及其它哺乳动物皮肤癌,由于暴露至紫外线(UV)辐射、化学品、热、风和干燥环境引起的皮肤损伤,皱纹,皮肤松弛,眼周皱纹和黑眼圈,皮炎和其它过敏相关的皮肤病症。COX/LOX介导的口腔、牙齿和牙龈疾病和病症,包括但不限于牙周病,口腔癌症前期病症,口腔癌,和其它口腔恶性肿瘤,敏感性牙龈和牙齿,后遗症,牙髓炎,由物理植入假牙、外伤、损伤、夜磨牙症和口腔内、牙龈上或舌头上的其它轻伤引起的刺激、疼痛和炎症,牙斑和结石,牙齿脱钙,蛋白质水解和龋齿(蛀蚀)。
本发明还包括用于预防和治疗其它COX和LOX介导的疾病和病症的方法,所述疾病和病症包括但不限于全身关节疼痛和僵硬,由于骨关节炎和类风湿性关节炎的病理状况引起的运动性缺乏和身体功能的损失,痛经,动脉粥样硬化,肥胖,糖尿病,阿尔茨海默病,呼吸过敏反应,慢性静脉功能不全,牛皮癣,慢性紧张性头疼,偏头痛,炎性肠病,***癌和其它实体瘤。
用于预防和治疗所述COX和LOX介导的疾病和病症的方法包括向有此需要的主体给药有效量的包含补骨脂酚以及药物学可接受的载体的组合物,所述组合物基本上不含呋喃香豆素杂质。如上所述,组合物中补骨脂酚的量在27%至100%的范围内。在优选实施方案中,组合物中补骨脂酚的量为约30%。同样如上所述,在优选实施方案中,补骨脂酚从补骨脂属植物中的一种或多种植物中分离。
本发明还包括用于预防和治疗由微生物感染,包括但不限于细菌、病毒和真菌感染介导的皮肤、口腔、牙齿或牙龈疾病和病症的方法,所述方法包括向有此需要的主体给药有效量的包含补骨脂酚以及药物学可接受的载体的药物组合物,所述组合物基本上不含呋喃香豆素杂质。由微生物感染介导的皮肤、口腔、牙龈和牙齿的疾病和病症包括但不限于头皮屑,痤疮,脚癣,牙周病,所述牙周病选自龋齿,牙龈炎,牙周炎,牙髓炎,由于物理植入假牙、外伤、损伤、夜磨牙症、肿瘤性和其它退化性过程引起的牙周病症;白垢,菌膜,牙斑,结石和色斑。
在一个实施方案中,所述细菌选自痤疮丙酸杆菌或表皮葡萄球菌。
本发明的组合物可以通过本领域普通技术人员已知的任何方法给药。给药的方式包括但不限于肠道(口服)给药,胃肠道外(静脉内、皮下和肌内)给药以及局部施用。在优选实施方案中,局部给药所述组合物。本发明的预防和治疗方法包括体内或局部向有此需要的患者给药治疗有效量的包含补骨脂酚的组合物,该组合物基本上不含杂质,尤其是呋喃香豆素杂质。
本发明的预防和治疗方法包括向有此需要的主体全身或局部给药治疗有效量的合成和/或从单种植物或多种植物中分离的UP256(补骨脂酚)和药物学可接受的载体。取决于为获得和纯化化合物所使用的方法学,UP256的纯度包括但不限于30%至100%。在优选实施方案中,UP256的剂量为有效、无毒的量,通常选自局部制剂总重量的0.001%至100%的范围内和/或基于主体总体重为0.001-200mg/kg。本领域技术人员使用常规临床实验能够确定用于所治疗的特定疾病的最佳剂量。
本发明包括使用酶、受体、微生物以及其它体外和体内模型评价合成和/或从单种植物或多种植物中分离的UP256(补骨脂酚)与药物学可接受的载体的不同组合物,以优化制剂并获得期望的生理学活性。本发明的组合物可以通过本领域普通技术人员已知的任何方法给药。给药方式包括但不限于肠道(口服)给药,胃肠道外(静脉内、皮下和肌内)给药以及局部施用。本发明的治疗方法包括体内或局部向有此需要的患者给药治疗有效量的合成和/或从单种植物或多种植物中分离的UP256(补骨脂酚),其中所述补骨脂酚基本上不含呋喃香豆素杂质。在一个实施方案中,局部给药所述组合物。用于局部给药的方法包括但不限于牙膏、凝胶剂、软膏剂、嗽口剂、口香糖、酊剂、饮料以及其它已知的药物制剂。当配制到牙膏中时,组合物的含量可以在0.1至2重量%补骨脂酚的范围内。
本发明的组合物可以配制成药物组合物,其包括其它组分例如药物学和/或化妆可接受的赋形剂、佐剂和/或载体。例如,可以将本发明的组合物配制到将治疗主体可忍受的赋形剂中。赋形剂是被用作药物稀释剂或载体的惰性物质。这种赋形剂的实例包括但不限于:水、缓冲液、盐水、甘油、水合二氧化硅、丙二醇、氧化铝、角叉菜胶、纤维素胶、二氧化钛、林格液(Ringer’s solution)、右旋糖溶液、甘露醇、Hank氏溶液(Hank’s solution)、防腐剂以及其他含水生理平衡盐溶液。也可使用非水载体如不挥发性油、芝麻油、油酸乙酯或甘油三酸酯。其他有用的制剂包括含有增粘剂例如羧甲基纤维素钠、山梨醇或右旋糖酐的混悬剂。赋形剂还可含有少量添加剂,如EDTA、DDTA二钠、BHA、BHT、柠檬酸二铵、去甲二氢愈创木酸、没食子酸丙酯、葡萄糖酸钠、焦亚硫酸钠、叔丁基对苯二酚、SnCl2、H2O2和2,4,5-三羟基苯丁酮、维生素C、维生素E和提高等渗性和化学稳定性的其它物质。用于调节制剂的pH的物质的实例包括氢氧化钠、碳酸钠、碳酸氢钠、三磷酸五钠、焦磷酸四钠、十二烷基硫酸钠、过氧化钙、磷酸盐缓冲剂、碳酸氢盐缓冲剂、tris缓冲剂、组氨酸、柠檬酸盐、和甘氨酸及它们的混合物,而芳香剂的实例包括但不限于硫柳汞、间或邻甲酚、***、水果提取物和苯甲醇。标准制剂可以是液体或可溶于合适的液体中作为混悬剂或溶液剂给药的固体。因此,在非液体制剂中,赋形剂可以包括右旋糖、人血清白蛋白、防腐剂等,可在给药之前向其中加入无菌水或盐水。
在本发明的一个实施方案中,组合物还可包括佐剂或载体。佐剂通常为通常提高哺乳动物对特定生物活性剂的生物响应的物质。合适的佐剂包括但不限于:弗氏佐剂(Freund’s adjuvant);其他细菌细胞壁成分;基于铝、钙、铜、铁、锌、镁、锡的盐类;二氧化硅;聚核苷酸;类毒素;血清蛋白;病毒外壳蛋白;其他源自细菌的制剂;γ干扰素;嵌段共聚物佐剂如Hunter′s Titermax佐剂(VaxceL.TM.,Inc.Norcross,Ga.);Ribi佐剂(获自Ribi ImmunoChem Research,Inc.,Hamilton,Mont.);和皂苷及它们的衍生物如Quil A(获自Superfos Biosector A/S,丹麦)。载体通常为提高治疗组合物在被治疗的主体内的半衰期的化合物。合适的载体包括但不限于:聚合物控释制剂、可生物降解的植入物、脂质体、细菌、病毒、油、酯和二醇类。
在一个实施方案中,将组合物制备成控释制剂,其将本发明的组合物缓慢释放至主体内。本文中使用的控释制剂包含处于控释载体内的本发明组合物。合适的控释载体对本领域技术人员将是已知的。优选的控释制剂是可生物降解的(即可生物侵蚀的)。
本发明的治疗药通过本领域技术人员公知的用于局部给药治疗组合物的任何合适的方法局部给药,所述方法包括但不限于作为软膏剂、凝胶剂、洗剂、或乳膏剂基质或作为乳剂、作为贴剂、敷料或面膜(mask)、无粘性纱布、绷带、药签或布擦拭物(cloth wipe)。可以使用公知用于局部给药的任何标准方法将所述局部施用局部给药至任何患病的区域。取决于给药方法,可以以各种单位制剂形式给药治疗组合物。对于特定的给药方式,可以将本发明的治疗组合物配制到本发明的赋形剂中。本发明的治疗药可以给药至任何主体,优选给药至哺乳动物,更优选给药至人。具体给药方式将取决于将治疗的病症。
在一个实施方案中,合适的软膏剂包含:有效、无毒量的所需浓度的UP256(补骨脂酚),所述量通常选自局部制剂总重量的0.001%至100%的范围内,65%至100%(优选75%至96%)的白色软石蜡,0%至15%的液体石蜡,和0%至7%(优选3至7%)的羊毛脂或其合成等价物的衍生物。在另一实施方案中,软膏剂可以包含聚乙烯-液体石蜡基质。
在一个实施方案中,合适的乳膏剂包含乳化体系以及所需浓度的合成和/或从上述单种或多种植物中分离的UP256(补骨脂酚)。乳化体系优选包含2至10%聚氧乙烯醇(例如可以商标CetomacrogolTMl000获得的混合物),10至25%的硬脂醇,20至60%的液体石蜡,和10至65%的水;以及一种或多种防腐剂,例如0.1至1%的N,N″-亚甲基双[N′-[3-(羟基甲基)-2,5-二氧代-4-咪唑烷基]脲](可以名称Imidurea USNF获得),0.1至1%的4-羟基苯甲酸烷基酯(例如可以商标Nipastat获自Nipa Laboratories的混合物),0.01至0.1%的4-羟基苯甲酸丁酯钠(可以商标Nipabutyl sodium获自Nipa Laboratories),和0.1至2%的苯氧乙醇。
在一个实施方案中,合适的凝胶剂包含半固体体系,其中液相被限制在具有高交联度的三维聚合基质中。液相可以包含水,以及所需量的UP256(补骨脂酚),0至20%的可与水混溶的添加剂,例如甘油、聚乙二醇、或丙二醇,和0.1至10%、优选0.5至2%的增稠剂,所述增稠剂可以是天然产物例如黄蓍胶、果胶、角叉菜胶、琼脂和藻酸,或合成或半合成化合物如甲基纤维素和羧聚乙烯(卡波普);以及一种或多种防腐剂,例如0.1至2%的4-羟基苯甲酸甲酯(对羟基苯甲酸甲酯)或苯氧乙醇-分化(differential)。另一种合适的基质包含所需量的UP256(补骨脂酚),以及70至90%的聚乙二醇(例如包含40%聚乙二醇3350和60%聚乙二醇400的聚乙二醇软膏剂,按照美国国家处方集(U.S.National Formulary,USNF)制备),5至20%的水,0.02至0.25%的抗氧化剂(例如丁羟甲苯),和0.005至0.1%的螯合剂(例如乙二胺四乙酸(EDTA))。
上面所用的术语“软石蜡”包括乳膏剂或软膏剂基质白色软石蜡和黄色软石蜡。术语“羊毛脂”包括天然羊毛脂和经纯化的羊毛脂。羊毛脂的衍生物具体包括为了改变其物理或化学性质已经被化学改性的羊毛脂,羊毛脂的合成等价物特别包括公知的并在药物和化妆领域作为羊毛脂替代物使用的可以例如被称为羊毛脂替代品的合成或半合成化合物和混合物。
可以使用的一种合适的羊毛脂合成等价物是可以商标SoftisanTM获得的物质,被称为Softisan 649。获自Dynamit Nobel Aktiengesellschaft的Softisan 649是天然植物脂肪酸、异硬脂酸和脂肪酸的甘油酯;其性质由H.Hermsdorf于Fette,Seifen,Anstrichmittel,Issue No.84,No.3(1982),pp.3-6中论述。
上述的作为合适的软膏剂或乳膏剂基质的成分的其它物质及其性质于权威参考文献中论述,例如药典。Cetomacrogol 1000具有式CH3(CH2)m(OCH2CH2)nOH,其中m可以为15或17,n可以为20至24。丁羟甲苯是2,6-二叔丁基对甲酚。Nipastat是4-羟基苯甲酸甲酯、乙酯、丙酯和丁酯的混合物。
本发明的组合物可以通过常规药物技术制备。因此,可以例如这样方便地制备上述组合物:在高温下,优选在60-70℃下,将软石蜡、任选的液体石蜡、和羊毛脂或其衍生物或其合成等价物混合到一起。然后可以将混合物冷却到室温,并且在添加莫匹罗星的水合晶体钙盐以及皮质甾体和任何其它成分后搅拌以保证充分分散。
无论给药方式如何,具体剂量均根据主体的近似体重计算。确定使用上述各制剂治疗的适当剂量所必需的进一步精确计算可由本领域普通技术人员常规地进行,这处于他们的常规工作范围内,而无需过度的实验,尤其是在参考本文公开的剂量信息和测定的情况下。通过使用用于确定剂量的已建立的测定法并结合适当的剂量-响应数据,可以确定这些剂量。
应注意的是,本文所述的发明可以兽用以及用于人类,术语“主体”不应以限制性的方式理解。在兽用的情况下,剂量范围可以考虑动物的体重如上所述确定。
实施例
下列实施例仅为说明的目的而提供,并非用于限制本发明的范围
实施例1:使用HPLC定量补骨脂酚、补骨脂素和异补骨脂素的方法
使用高压液相色谱法(HPLC),用光电二极管阵列检测器(HPLC/PDA)和Luna苯基-己基柱(250mm×4.6mm)定量如下所述产生的提取物、级分和新组合物中补骨脂酚、补骨脂素和异补骨脂素的量。在12分钟内使用梯度为36%至100%乙腈(ACN)的乙腈-水然后在3分钟内使用100%的ACN从柱中洗脱目标化合物。所用的详细HPLC条件列于表1中。图1图示了HPLC分离的色谱图。基于保留时间和UV峰面积,使用可商购的纯补骨脂酚、补骨脂素和异补骨脂素作为定量标准品,鉴别和定量了目标化合物。补骨脂酚、补骨脂素和异补骨脂素的保留时间分别为18.19分钟、7.33分钟和7.95分钟。
表1:用于补骨脂酚、补骨脂素和异补骨脂素定量的HPLC条件
实施例2:用于从补骨脂属植物中提取补骨脂酚的一般方法
腕式振荡器
向烧瓶中添加溶剂(100mL)和补骨脂种子粉末(10g),在室温下将混合物在腕式振荡器上振荡1小时。然后使混合物通过过滤器并收集滤液。用新鲜溶剂再重复一次提取过程,将滤液合并,在旋转蒸发器中除去溶剂,将残余物在高真空下干燥。
回流
向烧瓶中添加溶剂(50mL)和补骨脂种子粉末(10g),将混合物回流40min。然后过滤溶液,用新鲜溶剂将再重复两次提取过程。将滤液合并并蒸发溶剂以获得干燥的提取物。
在上述提取方法之后,用下列溶剂提取样品植物原料:二氯甲烷(DCM)、EtOAc、丙酮、MeOH、石油醚(沸点35-60℃)和石油醚(沸点60-90℃)。然后如实施例1所述,使用HPLC分析提取物。结果列于表2中。
表2:各种补骨脂提取物的定量
实施例3:从补骨脂属植物中大规模提取补骨脂酚
在70℃于水浴中,在旋转蒸发器上,将补骨脂的种子粉末(2kg)和9升石油(pet.)醚(沸点60-90℃)于20L烧瓶中旋转1小时。然后将溶液倒入独立的容器中,在真空下除去溶剂。向该生物质中添加新鲜溶剂并再重复三次提取过程。合并提取物并蒸发以获得335g具有21重量%的补骨脂酚和3重量%的补骨脂素/异补骨脂素的粗提物(MH-258-01-01),。
实施例4:用于纯化补骨脂酚提取物的各种色谱方法的评价
评价了用于纯化使用实施例2所述的方法从补骨脂种子中分离的粗溶剂提取物(MH-206-70-1)的各种色谱方法,以确定使用柱色谱法作为获得无呋喃香豆素类尤其是补骨脂素/异补骨脂素杂质的高纯度补骨脂酚的方法的可能性。简言之,用不同的填料填充各空柱筒(1.3cm ID和20mL容量,来自Bio-Rad),并用不同的溶剂洗脱以试图将呋喃香豆素杂质与补骨脂酚分离。将级分(每级分10mL)收集到试管中,并用硅胶TLC板分析,以20%EtOAc/石油醚展开。基于使用标准溶液确定的保留时间鉴别目标化合物补骨脂酚、补骨脂素和异补骨脂素。结果列于表3中。
表3:用于从补骨脂粗提物中将呋喃香豆素类
与补骨脂酚分离的柱色谱法总结
实施例5:从补骨脂种子中分离的石油醚提取物的水解
在1L圆底烧瓶中,将如实施例3所述从补骨脂种子中分离的石油醚提取物(25g;MH-258-01-01)与500mL NaOH溶液(56.5mM)混合。将溶液在加热套内回流1小时。定期从烧瓶中取出少部分溶液并如实施例1所述使用HPLC分析。在HPLC分析显示补骨脂素和异补骨脂素的峰完全消失后停止反应。然后将反应混合物冷却到室温,以获得暗棕色的溶液,其固含量为约36mg/mL(MH-258-10-01)。
向分液漏斗(150mL)内的20mL水解溶液(MH-258-10-01)中添加DCM(20mL)。将混合物振荡10min,使各层分离。从分液漏斗底部除去DCM层,用20mL新鲜DCM再重复一次提取过程。将有机层合并,通过在真空下旋转蒸发除去溶剂,以获得118mg组合物(MH-258-07-01),其包含31%补骨脂酚并且不含呋喃香豆素杂质(图3)。
向分液漏斗(150mL)内的20mL水解溶液(MH-258-10-01)中添加石油醚(20mL)。将混合物振荡10min,使各层分离。从分液漏斗顶部除去石油醚层,用20mL新鲜石油醚再重复一次提取过程。将有机层合并,通过在真空下旋转蒸发除去溶剂,以获得136mg组合物(MH-258-07-02),其包含41%补骨脂酚并且不含呋喃香豆素杂质(图4)。
实施例6:从补骨脂种子中分离的甲醇提取物的水解
在搅拌器/加热板上的2 L烧杯中,将如实施例2所述从补骨脂种子分离的干燥甲醇提取物(MH-293-68-01)与1L NaOH溶液(44g NaOH的去离子水溶液)混合。将溶液在沸腾下搅拌2小时。在必要时向烧杯中添加水以保持总体积为约1200mL。在2小时后,使溶液冷却到室温,然后将600mL转移到分液漏斗中。加入石油醚(250mL)并将混合物振荡10min,使各层分离。从分液漏斗顶部除去石油醚层,用新鲜溶剂重复提取过程(3×)。将有机提取物合并,通过在真空下旋转蒸发除去溶剂,以获得2.25g组合物(MH-293-74-01),其包含51%补骨脂酚并且不含呋喃香豆素杂质。
实施例7:水解从补骨脂种子中分离的石油醚提取物然后使用柱色谱法纯化
在1L圆底烧瓶中,将如实施例3所述从补骨脂种子中分离的石油醚提取物(25g;MH-258-01-01)与500mL NaOH溶液(56.5mM)混合。将溶液回流1小时。定期从烧瓶中取出少部分溶液并如实施例1所述使用HPLC分析。使反应继续,直到HPLC分析显示补骨脂素和异补骨脂素的峰完全消失为止。然后将反应混合物冷却到室温,以获得暗棕色的溶液,其固含量为约36mg/mL(MH-258-10-01)。
将150mL此溶液(MH-258-10-01)装填到预制备的CG-161cd柱上。此预制柱(5×13cm)包含300mL CG-161cd树脂,该树脂已经用4倍柱体积的去离子水平衡过。将载样(MH-258-10-01)装填到柱顶部,用2500mL去离子水洗脱以使柱达到pH 7,然后用2500mL 70%MeOH/水和4500mL 90%MeOH/水洗脱补骨脂酚。使用TLC监测洗脱液,直到补骨脂酚从柱上完全洗脱为止。将只包含补骨脂酚的级分(2L)合并并在真空下蒸发以除去溶剂。使用此方法获得了不含呋喃香豆素杂质的高纯度补骨脂酚(2.3g)(99%纯度,MH-258-12-08和-09)(参见图5)。还收集了较前和较后的补骨脂酚级分,将其合并并在真空下蒸发。从这些级分中获得了2.4克组合物(MH-258-12-07和-10),其包含70%补骨脂酚并且不含呋喃香豆素杂质。CG-161 cd柱的载荷能力估计为每升CG-161 cd树脂400mL粗水解溶液。在分离后,通过用Clorox、然后用MeOH和4倍柱体积的去离子水洗涤来再生CG-161 cd柱。它可以再生使用许多年。
实施例8:纯化的补骨脂酚对COX-1和COX-2的抑制
为了筛选抑制COX-1和COX-2活性的化合物,开发了利用两种酶对过氧化物酶活性的抑制的高通量、体外测定法(Needleman等(1986)Annu Rev Biochem.55:69)。简言之,用固定量的COX-1和COX-2酶滴定所检查的组合物或化合物。该测定法包括可裂解的过氧化物生色团,以在作为辅因子的花生四烯酸存在时显现各酶的过氧化物酶活性。通常,测定在96孔模板中进行。使用下列浓度范围,在室温下将取自10mg/mL100%DMSO中的贮备液的各抑制剂测定三次:0、0.1、1、5、10、20、50、100和500μg/mL。向各孔中加入150μL的100mM Tris-HCl(pH 7.5)以及在tris缓冲液中稀释的10μL 22μM血色素、在DMSO中稀释的10μL抑制剂和25单位的COX-1或COX-2酶。将各组分在旋转平台上混合10秒,然后加入20μL 2 mM N,N,N′N′-四甲基-对苯二胺二盐酸盐(TMPD)和20μL 1.1mM花生四烯酸以引发反应。将平板振荡10秒,然后温育5分钟,然后在570nm读取吸光度。将抑制剂浓度对抑制%绘图,通过沿着等温线确定半极大值点并与X-轴上的浓度相交,确定IC50。然后将IC50归一化为测定中酶单位的数目。测定高纯度(99%)补骨脂酚样品(MH-258-08)对COX-1和COX-2两者的抑制。结果总结于下面的表4中。
表4:补骨脂酚对COX活性的抑制
实施例9:纯化的补骨脂酚(MH-258-12-08)对5-脂氧合酶的抑制
如上所述,参与炎症反应的最重要的途径之一是由非血红素含铁脂氧合酶(5-LOX、12-LOX和15-LOX)产生的,它们催化脂肪酸如AA的氧化以产生氢过氧化物5-、12-和15-HPETE,这些物质然后转化为白三烯。使用已公开发表的方法(Carter等(1991)J.Pharmacol.Exp.Ther.256(3):929-937,Safayhi等(2000)Planta Medica.66:110-113)进行脂氧合酶抑制测定。5-LOX从人PBML细胞中分离,并利用花生四烯酸作为底物。将受试物和阳性对照溶于1%DMSO中。使用HBSS(Hank氏平衡盐溶液)作为温育缓冲液。在37℃下预温育时间为15分钟,然后在相同的温度下温育15分钟。该测定用EIA定量检测LTB4的形成。相对于5个浓度的阳性对照——NDGA,以10μM、1μM、0.1μM和10nM的浓度重复测定高纯度补骨脂酚(99%补骨脂酚,#MH-258-12-08)。图6示意剂量响应曲线。补骨脂酚(纯度99%)对5-LOX抑制的IC50为3.41μM。
实施例10:纯化的补骨脂酚的抗微生物活性
使用已公开发表的方法(Modugno等(1994)Antimicrobial Agents &Chemotherapy 38:2362-2368;Misiek等(1973)Antimicrobial Agents &Chemotherapy 3:40-48)评价高纯度补骨脂酚样品(99%纯度;#MH-258-12-08)的抗微生物活性。简言之,在37℃下将表皮葡萄球菌(革兰氏阳性,ATCC 12228)在Mueller-Hinton肉汤培养基中培养20小时。在37℃下将痤疮丙酸杆菌(ATCC 6919)在强化梭菌培养基中培养2天。以1mL的温育体积将受试品和阳性对照溶于1%DMSO中。评价时间为1天。使用浊度测量作为定量方法。相对于阳性对照——分别为0.1μg/mL庆大霉素对表皮葡萄球菌和0.1μg/mL氨苄西林对痤疮丙酸杆菌,以100μg/mL、30μg/mL、10μg/mL、3μg/mL、1μg/mL、0.3μg/mL、0.1μg/mL和0.03μg/mL的浓度重复测定高纯度补骨脂酚样品(99%;#MH-258-12-08)。在1μg/ml时,补骨脂酚对表皮葡萄球菌和痤疮丙酸杆菌两者均表现出明显的抑制。在30μg/mL的中等浓度下,高纯度的补骨脂酚样品还抑制了须癣毛癣菌(ATCC 9533)的活性。最后,没有观察到对絮状表皮癣菌(ATCC 18397)、犬小孢子菌(ATCC 36299)和皮屑芽孢菌(ATCC 38593)的抑制。
实施例11:纯化的补骨脂酚的急性毒性评价
通过测定两种纯度水平的补骨脂酚(UP256)(约20%纯度的样品和99%纯度的样品)完成急性毒性研究。在14天的研究中使用40只4-5周龄的雌性ICR小鼠(Harlan)。每天向小鼠给药100mL急性毒性剂量,约每受试品每天2g/kg重量。第一组10只小鼠接受包含20.7%补骨脂酚的组合物,而第二组10只小鼠接受包含99%补骨脂酚的组合物。将UP256组合物混悬在水中并通过注射器给药。向20只小鼠给药水作为对照组。测量所有小鼠的重量,包括基线、3个中点和终点。而且,观察所有组的食物和水消耗。在2周期间记录任何异常的健康状况或行为。在第14天完成所有小鼠的尸体剖检,收集所有组的血液用于全血筛选。还随机从各组中取2只小鼠取出肾和肝组织用于组织病理学检查。通过Antech诊断法完成所有血液检测和病理学检测。
所有组,包括对照组的平均计算体重在2周研究期间持续上升。没有小鼠显示体重下降,所有组的食物/水消耗保持相同。对研究者的攻击(即咬)和相互攻击(即在笼中打斗)是治疗组小鼠与对照小鼠之间唯一的明显行为差异。这种行为可能在接受雄性激素雄激素的小鼠中发生。所有小鼠的尸体剖检没有显示总体异常或任何器官变化。血液检测显示治疗组相对于对照组是正常的。蛋白质、酶和离子水平处于ICR小鼠的正常值内。将肾和肝组织送去做组织病理学检查以评价器官的任何微变化,报告表明肾内不存在明显变化,肝的肝细胞核处于小鼠的正常范围内。在所检查的任一组织切片内不存在实质的炎症或瘤形成的证据。
总之,治疗组小鼠相对于对照组的所有重量、血液检测和组织学数据均相同。对于任一UP256样品,在14天的研究中没有观察到副作用。因此,可以推断出处于两种纯度水平(20%和99%纯度)的UP256均具有可靠的安全特性。
Claims (19)
1.用于制备包含补骨脂酚并且基本上不含呋喃香豆素杂质的组合物的方法,所述方法包括下列步骤:
a)用有机溶剂提取包含补骨脂酚的植物部分,以获得包含补骨脂酚和呋喃香豆素杂质的有机提取物;
b)用碱将步骤a)中获得的有机提取物水解以打开所述呋喃香豆素杂质的内酯环,从而将所述呋喃香豆素杂质转化为相应的羧酸盐;和
c)将步骤b)中获得的水解的呋喃香豆素杂质与补骨脂酚分离,以获得所述包含补骨脂酚并且基本上不含呋喃香豆素杂质的组合物。
2.权利要求1的方法,其还包括以下步骤:柱色谱法、提取然后结晶、溶剂分配、或重结晶或其组合。
3.权利要求1的方法,其中步骤b)包括回流。
4.权利要求1的方法,其中所述碱是氢氧化钠、氢氧化钾、氢氧化钙、或氢氧化锂。
5.包含补骨脂酚并且基本上不含呋喃香豆素杂质的组合物,其中所述组合物根据权利要求1所述方法制备。
6.权利要求5所述的组合物在制备用于预防和治疗环氧合酶(COX)或脂氧合酶(LOX)介导的皮肤或口腔疾病和病症的药物中的应用,其中所述组合物被配制为用于局部给药。
7.权利要求6所述的应用,其中所述COX或LOX介导的口腔疾病和病症是牙齿疾病和病症。
8.权利要求6所述的应用,其中所述COX或LOX介导的口腔疾病和病症是牙龈疾病和病症。
9.权利要求6的应用,其中所述COX或LOX介导的皮肤疾病或病症选自:晒伤,热灼伤,痤疮,头皮屑,局部创伤,由真菌、微生物和病毒感染引起的轻度炎性病症,白癜风,***性红斑狼疮,牛皮癣,癌,由于暴露至紫外线(UV)辐射、化学品、热、风和干燥环境引起的皮肤损伤,皱纹,皮肤松弛,和黑眼圈和皮炎。
10.权利要求9的应用,其中所述癌为黑素瘤。
11.权利要求9的应用,其中所述癌为哺乳动物的皮肤癌。
12.权利要求9的应用,其中所述皱纹为眼周皱纹。
13.权利要求6的应用,其中所述COX或LOX介导的口腔疾病和病症选自:牙周病,口腔癌,敏感性牙龈和牙齿,牙髓炎,由物理植入假牙、外伤、损伤、夜磨牙症和口腔内、牙龈上或舌头上的其它轻伤引起的刺激、疼痛和炎症,牙斑和结石,牙齿脱钙,蛋白质水解和龋齿。
14.权利要求6的应用,其中所述COX或LOX介导的口腔疾病和病症为口腔癌症前期病症。
15.权利要求6的应用,其中所述药物被配制为通过使用无粘性纱布、绷带、药签、布擦拭物、贴剂、面膜、清洁剂、杀菌剂、溶液剂、乳膏剂、软膏剂、凝胶剂或乳剂、糊剂、肥皂或散剂给药的形式。
16.权利要求6的应用,其中所述药物被配制为洗剂。
17.权利要求6的应用,其中所述药物还包含药物学、皮肤学和化妆上适合局部施用的常规赋形剂和任选地还包含佐剂、载体、或其组合。
18.权利要求17的应用,其中所述载体为普通或控释载体。
19.权利要求5所述的组合物在制备用于预防和治疗COX或LOX介导的疾病和病症的药物中的应用,所述疾病和病症选自全身关节疼痛和僵硬,由于骨关节炎和类风湿性关节炎的病理状况引起的运动性缺乏和身体功能的损失,痛经,动脉粥样硬化,肥胖,糖尿病,阿尔茨海默病,呼吸过敏反应,慢性静脉功能不全,牛皮癣,慢性紧张性头疼,偏头痛,炎性肠病和***癌。
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Also Published As
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US20160022602A1 (en) | 2016-01-28 |
JP5443754B2 (ja) | 2014-03-19 |
EP1881839A4 (en) | 2009-05-20 |
KR101802415B1 (ko) | 2017-11-28 |
BRPI0608796B8 (pt) | 2021-05-25 |
KR20130125411A (ko) | 2013-11-18 |
WO2006122160A2 (en) | 2006-11-16 |
CN101217968A (zh) | 2008-07-09 |
EP1881839A2 (en) | 2008-01-30 |
KR101431060B1 (ko) | 2014-08-21 |
KR20080016609A (ko) | 2008-02-21 |
JP2008540551A (ja) | 2008-11-20 |
US20060251749A1 (en) | 2006-11-09 |
US20210154155A1 (en) | 2021-05-27 |
BRPI0608796A2 (pt) | 2010-01-26 |
US10905654B2 (en) | 2021-02-02 |
HK1120743A1 (zh) | 2009-04-09 |
US20110223267A1 (en) | 2011-09-15 |
WO2006122160A3 (en) | 2007-02-08 |
BRPI0608796B1 (pt) | 2019-04-30 |
KR20160055972A (ko) | 2016-05-18 |
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