CN1419438A - 用2-脱羧基-2-磷酸亚基衍生物治疗脱发的组合物和方法 - Google Patents
用2-脱羧基-2-磷酸亚基衍生物治疗脱发的组合物和方法 Download PDFInfo
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- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
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- A—HUMAN NECESSITIES
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Abstract
用含2-脱羧基-2-磷酸亚基前列腺素类似物的组合物治疗哺乳动物脱发的方法。这种组合物可局部施用于皮肤。这种组合物可以制止、逆转脱发并促进毛发生长。还可用含2-脱羧基-2-磷酸亚基前列腺素类似物的组合物降低眼内压和治疗骨病。
Description
发明背景
本发明涉及使用前列腺素的2-脱羧基-2-磷酸亚基衍生物的组合物和方法。具体说,本发明涉及用前列腺素的2-脱羧基-2-磷酸亚基衍生物治疗哺乳动物脱发。本发明还涉及使用前列腺素的2-脱羧基-2-磷酸亚基衍生物降低哺乳动物的眼内压和治疗哺乳动物的骨病。
发明背景
脱发-美容处理
脱发是一种常见病,例如天然的或是因为使用某些用于减轻疾病如癌症的治疗药而由化学机制引起的。通常这种脱发还伴随有毛发再生长的缺失,从而使患者部分或完全秃顶。
头皮上头发的生长并不是连续的,而是以由生长和静止交替阶段构成的循环形式发生的。可以将这种循环分为3个主要阶段:毛发生长初期、毛发生长中期和毛发生长终期。毛发生长初期是循环的生长阶段,其特征为毛囊深入真皮同时细胞迅速增生,这些细胞分化形成头发。随后的阶段为毛发生长中期,这是一个过渡阶段,其特征为细胞分化的停止,在该阶段毛囊通过真皮退回且头发停止生长。随后的阶段,毛发生长终期,其特征为静止期,在该阶段退回的毛囊包含填满真皮乳头细胞的毛芽。在毛发生长终期,由真皮内细胞的迅速增生、真皮乳头的膨胀和基质膜成分的形成引发新一轮的毛发生长初期。当毛发生长停止,大部分毛囊处于毛发生长终期且不接合毛发生长初期,从而引起部分或完全秃顶。
人们已进行了许多引发头发再生长的尝试,例如促进或延长毛发生长初期。最近,美国食品和医药管理局批准了两种用于治疗男性型脱发的药物:局部米诺地尔(Pharmacia&Upjohn的商品ROGAINE)和口服非那司提(Merck&Co.,Inc的商品PROPECIA)。然而,由于一些因素如对安全的考虑和药效不高,对有效的毛发生长诱导剂的研究还在进行中。
脱碘酶I,一种含硒蛋白(selenoprotein),将人皮肤中的甲状腺激素甲状腺素(“T4”)甲状腺原氨酸(“T3”)转化成。硒缺陷会因为脱碘酶I活性的降低导致T3的含量减少;而这种T3含量的减少与脱发极其相关。与这一观察结果一致的是,有关于头发生长是施用T4对的副作用的报道,参见如Berman“L-甲状腺素对牛毛发生长和毛色的外周影响”,Journal of Endocrinology,第20卷,第282-292页(1960);和Gunaratnam,“甲状腺素对狗毛发生长的影响”,J.Small Anim.Pract.,第27卷,第17-29页(1986)。另外,在一些关于脱发治疗的专利出版物中涉及T3和T4。例如参见Fischer等人,DE1,617,477(1970年1月8日出版);Mortimer,GB2,138,286(1984年10月24日出版);和Lindenbaum,WO96/25943(授予Life Medical Science,Inc.,于1996年8月29日出版)。
然而不幸的是,施用T3或T4或这两者来治疗脱发是不切实的,因为这些甲状腺激素引发显著的心脏毒性。参见如Walker等人,美国专利No.5,284,971(授予Syntex,于1994年2月8日出版);和Emmett等人,美国专利No.5,061,798(授予Smith Kline&French Laboratories,于1991年10月29日出版)。
在另一方法中,已用前列腺素来促进毛发生长,因为前列腺素具有与甲状腺激素相似的效益,即增加毛发的长度和色素沉着的改变。天然前列腺素(如PGA2、PGB2、PGE1、PGF2α和PGI2)是C-20不饱和脂肪酸。PGF2α(人体中的天然前列腺素F类似物),其特征为其在脂环的C9和C11位含羟基,在C5和C6间具有顺式-双键,和在C13和C14间包含反式-双键。PGF2α的结构式为:
天然前列腺素F的类似物是本领域已知的。例如,参见美国专利No.4,024,179(1997年5月17日授予Bindra和Johnson);德国专利No.DT-002,460,990(1976年7月1日出版,授予Beck,Lerch,Seeger和Teufel);美国专利No.4,128,720(1978年12月5日授予Hayashi,Kori和Miyake);美国专利No.4,011,262(1977年3月8日授予Hess,Johnson,Bindra和Schaaf);美国专利No.3,776,938(1973年12月4日授予Bergstrom和Sjovall);P.W.Collins和S.W.Djuric,“用于治疗的前列腺素和前列腺环素类似物的合成”,Chem.Rev.第93卷,第1533-1564页(1993);G.L.Bundy和F.H.Lincoln“PG1系列17-苯基-18,19,20-三去前列腺素I.的合成”,Prostaglandin,第9卷,第1号,第1-4页(1975);W.Bartman,G.Beck,U.Lerch,H.Teufel和B.Scholkens,“溶解黄体的前列腺素:合成和生物活性”,Prostaglandin,第17卷,第2号,第301-311页(1979)。
前列腺素一般具有很广泛的生物活性。例如,PGE2具有以下特性:a)细胞增生的调节剂,b)细胞因子合成的调节剂,c)免疫应答的调节剂;d)血管舒张的诱导剂。据信,血管舒张是米诺地尔提供毛发生长益处的机制之一。在体外,文献中的结果也表明前列腺素的某些抗炎性质c.f.;Tanaka,H.Br J.Pharm.,116,2298(1995)。
然而,已有的用前列腺素促进毛发生长的方法并不成功。不同的前列腺素类似物可能以各种浓度结合于多种受体,而产生双相作用。因此,本发明的目的是提供用前列腺素使毛发生长的方法,还涉及促进毛发生长的组合物。本发明的另一目的是选择合适的促进人和低等动物毛发生长的前列腺素类似物。
骨病-药物治疗
除了上述生物活性外,还已知前列腺素能影响骨骼。因此,本发明的另一目的是提供使用前列腺素治疗骨病的组合物和方法。
药物(如皮质醇)的施用、长期卧床休养、肢体的废用和微重力都可能导致骨损失(bone 1oss)的加速。在骨质疏松症中存在骨质重建过程的不平衡,即骨的再吸收速度比其形成的速度快。虽然这种不平衡随着大部分人(男性和女性)年龄的增加都有一定程度的发生,但是对较年轻的骨质疏松症患者而言更严重,尤其对那些患绝经期后期形式该病的患者而言。由于上述原因的骨损失可能导致小梁的完全清除和骨结构的劣化,从而使剩下的骨的强度不均衡地下降。
为了让骨能完全恢复到正常强度,要形成新的小梁以复原结构并增加骨质。由于正常小梁的复原与强度和恢复到正常刚度以及减震能力的增加相关,则骨头不易骨折。患其它骨病(如骨关节炎、Paget病、牙周病和骨折)的患者也可受益于恢复正常的骨骼结构和骨质的这些治疗。
已尝试了多种药剂用于通过减缓骨损失或增加骨质对骨病进行治疗。用于减缓骨损失和重建骨密度的药剂可列举为抗再吸收药,如二膦酸酯。
前列腺素E类似物是骨再吸收和形成的强刺激剂。合成代谢药如某些前列腺素E类似物可能对患骨病(如骨质疏松)的患者而言是有害的,因为增加的再吸收可能会导致小梁的穿孔和损失或可能使存在的小梁结构衰减。同样在皮层质骨中也会发生再吸收的增加,这将会提高一些部位骨折的发生率。
已用合成代谢药(如氟化物或其它前列腺素E类似物)增加骨质。然而,这些药物不能形成与损失掉的骨头的结构和构建类似的骨头。
已知如上所示的天然PGF2α能影响骨再吸收。然而,天然的前列腺素具有一些限制它们用于全身给药的缺陷。天然前列腺素的特征为它们对某些前列腺素受体的活性,但是它们的活性不局限于任何一种受体。因此,全身施用天然前列腺素会带来副作用,如炎症、表面刺激、平滑肌收缩、疼痛和支气管收缩。
因此,本发明的目的是提供使用前列腺素类似物治疗骨病而无显著的不良副作用的组合物和方法。本发明的另一目的是选择合适的、促进哺乳动物和低等动物骨头生长的前列腺素。
眼内压-药物治疗
除了上述药学上的特性外,还已知天然前列腺素能降低眼内压。降低眼内压能有效地治疗疾病如青光眼。参见,C.Iijebris,G.Selen,B.Resul,J.Stenschantz,和U.Hacksell,“17-苯基-18,19,20-三去前列腺素F2α异丙酯的衍生物:潜在的抗青光眼的药物”,Journal of Medicinal Chemistry,第38卷,第2号,第289-304页(1995)。但如上所述,天然前列腺素通常不是对任何一种前列腺素受体是特异性的,因此会引起副作用。
因此,本发明的另一目的是提供用前列腺素降低眼内压而无明显副作用的组合物和方法。本发明的另一目的是选择合适的、降低哺乳动物和低等动物眼内压的前列腺素。
发明概述
本发明涉及用于治疗脱发的组合物和方法。这些方法包括施用包含特定的前列腺素的组合物,这种前列腺素能与毛发选择性受体(如FP受体)强烈相互作用。前列腺素的选择至关重要,因为前列腺素必须选择性地激活FP受体而不激活其它含抵销FP受体活化有作用的受体或导致明显的副作用。本发明所用的前列腺素是前列腺素的2-脱羧基-2-磷酸亚基衍生物。本发明还涉及用前列腺素的2-脱羧基-2-磷酸亚基衍生物制备用于治疗脱发的组合物。该组合物包含:成分A)前列腺素的2-脱羧基-2-磷酸亚基衍生物,成分B)载体,和任选的成分C)活性增强剂。
本发明还涉及治疗骨病的组合物和方法。该方法包括向患骨病(如骨质疏松)的患者施用包含前列腺素的2-脱羧基-2-磷酸亚基衍生物的组合物。本发明还涉及用前列腺素的2-脱羧基-2-磷酸亚基衍生物制备治疗骨病的组合物。
本发明还涉及降低眼内压的组合物和方法。该方法包括向患病(如青光眼)的患者施用包含前列腺素的2-脱羧基-2-磷酸亚基衍生物的组合物。本发明还涉及用前列腺素的2-脱羧基-2-磷酸亚基衍生物制备降低眼内压的组合物。
发明详述
一方面,本发明涉及治疗哺乳动物脱发的组合物。“治疗脱发”包括制止和/或逆转脱发以及促进毛发生长。
在本文中参考许多出版物和专利。本文将所引用的所有美国专利全部纳入作为参考。
除非特别指出,本文中的所有百分比、比率和比率都是以重量计的。
术语的定义和使用
以下列出了本文所用的术语的定义:
“激活”指受体的结合和信号传导。
“酰基”指适合以下酰化的单价基团:酰化氮原子形成酰胺或氨基甲酸酯,酰化醇形成碳酸酯,或酰化氧原子形成酯基团。优选的酰基包括苯甲酰基、乙酰基、叔丁基乙酰基、对苯基苯甲酰基和三氟乙酰基。更优选的酰基包括乙酰基和苯甲酰基。特别优选的酰基是乙酰基。
“芳基”指具有单环结构或稠合双环结构的单价基团。单环芳基的环包含5-10个碳原子,宜为5-7个碳原子,更佳的是5-6个碳原子。双环芳基的环中包含8-12个碳原子,宜为9-10个碳原子。芳基是未取代的。最优选的芳基是苯基。
“碳环基团”指单价饱和的或不饱和的烃环。碳环基团是单环、或稠合的、螺环或桥接的双环系。单碳环基团的环中包含4-10个碳原子,宜为4-7个碳原子,更优选的是5-6个碳原子。双碳环基团的环中包含8-12个碳原子,宜为9-10个碳原子。碳环是未取代的。优选的碳环包含环戊基、环己基、环己烯基、环庚基和环辛基。更优选的碳环包括环己基、环庚基和环辛基。最优选的碳环是环庚基。碳环基团不是芳族的。
“氰基”指包含腈官能团的基团。
“FP促效剂”指激活FP受体的化合物。
“FP受体”指已知的人FP受体、它们的剪接变体和与已知人FP受体具有类似结合和激活性质的未描述过的受体。“FP”指一类对所有天然前列腺素的PGF2α具有最高亲和力的受体。FP指一种已知的蛋白质。
“杂原子”指F、Cl、Br或I。较佳地,杂原子是F、Cl或Br;更优选的是Cl或F;最优选的是F。
“卤化的杂基团”指取代的杂基团或取代的杂环基团,其中至少一个取代基是卤原子。卤化的杂基团可以是直链、支链或环状结构。优选的卤化的杂基团具有1-12个碳原子,更佳地为1-6个碳原子,最优选的是1-3个碳原子。优选的卤原子取代基是Cl和F。
“卤化的烃类基团”指取代的单价烃类基团或取代的碳环基团,其中至少一个取代基是卤原子。卤化的烃类基团是直链、支链或环状结构。优选的卤化的烃类基团具有1-12个碳原子,更佳地为1-6个碳原子,最优选的是1-3个碳原子。优选的卤原子取代基是Cl和F。最优选的卤化的烃类基团是三氟甲基。
“杂芳基”指环中包含碳原子和1-4个杂原子的芳环。杂芳族神经痛单环或稠合双环。单环杂芳基的环中包含5-10个成员原子(即碳原子和杂原子),宜为5-7个,更佳地是5-6个。双环杂芳族环的环中包含8-12个成员原子,宜为9-10个。杂芳基是未取代的。优选的杂芳基包括噻吩基、噻唑基、嘌呤基、嘧啶基、吡啶基和呋喃基。更优选的杂芳基包括噻吩基、呋喃基和吡啶基。最优选的杂芳基是噻吩基。
“杂原子”指杂环基团或杂基团链中除碳以外的原子。较佳地,杂原子选自:氮、硫和氧原子。含有多个杂原子的基团可能包含不同的杂原子。
“杂环基团”指环中包含碳原子和1-4个杂原子的饱和或不饱和环。环中杂原子不相邻。杂环基团不是芳族的。杂环基团是单环或稠合的或桥接的双环系。单杂环基团的环中包含4-10个成员原子(即包含碳原子和至少1个杂原子),较佳地4-7个,更优选的是5-6个。双环杂环基团的环中包含8-12个成员原子,宜为9-10个。杂环基团是未取代的。优选的杂环基团包括胡椒酰(piperzyl)、吗啉基、四氢呋喃基、四氢吡喃基和哌啶基。
“杂基团”指含有1-18个成员原子(即碳原子和至少一个杂原子)的饱和的或不饱和链。杂原子不相邻。较佳地,链包含1-12个成员原子,更佳地为1-6个,最佳的为1-4个。该链是直链或支链的。优选的支链杂基团具有1个或2个支链,较佳地为具有1个支链。优选的杂基团是饱和的。不饱和的杂基团具有1个或多个双键、一个或多个三键或都有。优选的不饱和杂基团包含一个或两个双键或一个三键。更优选的是,不饱和杂基团具有一个双键。杂基团是未取代的。
“单价烃基”指1-18个(较佳地为1-12个)碳原子的链。“低级单价烃基”指具有1-6个(较佳地为1-4个)碳原子的单价烃基。单价烃基可能是直链或支链结构。优选的单价烃基具有1个或2个支链,较佳地为1个支链。优选的单价烃基是饱和的。不饱和单价烃基具有一个或多个双键、一个或多个三键、或这两者。优选的不饱和单价烃基具有1个或2个双键或1个三键;更优选的不饱和单价烃基具有1个双键。
“药学上可接受的”指适用于人或其它哺乳动物的。
“前列腺素”指具有激素的或调节性能的多种强生物活性的脂肪酸衍生物。
“保护基团”指取代羟基中的活泼氢从而防止羟基上的不良副反应的基团。保护基团在有机合成在的用途是本领域所熟知的。保护基团的示例可见Greene,T.W.和Wuts,P.G.M.的“有机合成中的保护基团”,第2版,Wiley&Sons,Inc.,1991中的第二章。优选的保护基团包括甲硅烷基醚、烷氧基甲基醚、四氢吡喃基、四氢呋喃基、酯和取代的或未取代的苄醚。
“安全和有效量”指足以能向待治疗的患者的疾病提供有益改善的前列腺素量,但该量也足够低至避免严重的副作用(合理的益处/风险比)。
“选择性”指对特定受体比对其它受体具有结合或活化优先性,这可以用受体结合或活化试验定量。
“对象”指需要治疗的活的脊椎动物,如哺乳动物(优选人)。
“取代的芳基”指1-4个与环中碳原子结合的氢原子被其它取代基取代的芳基。优选取代基包括:卤原子、氰基、单价烃基、取代的单价烃基、杂基团、芳基、取代的芳基、或它们的组合。更优选的取代包括卤原子、单价烃基和取代的单价烃基。优选的取代的芳基包括萘基。取代基可以是在环的邻位、间位或对位或它们的组合上取代的。环上优选的取代模式是邻位或间位。最优选的取代模式是邻位。
“取代的碳环基团”指1-4个与环中碳原子结合的氢原子被其它取代基取代的碳环基团。优选取代基包括:卤原子、氰基、单价烃基、单价杂基团、取代的单价烃基、芳基、取代的芳基、或它们的组合。更优选的取代包括卤原子和取代的单价烃基。碳环基团不包括芳环。
“取代的杂芳基”指1-4个与环中碳原子结合的氢原子被其它取代基取代的杂芳基。优选的取代基包括:卤原子、氰基、单价烃基、取代的单价烃基、杂基团、取代的杂基团、苯基、苯氧基或它们的组合。更优选的取代包括卤原子、卤化的烃基、卤化的杂基团、单价烃基和苯基。
“取代的杂环基团”指1-4个与环中碳原子结合的氢原子被其它取代基取代的杂环基团。优选的取代基包括:卤原子、氰基、单价烃基、取代的单价烃基、杂基团、取代的杂基团、卤化的烃基、卤化的杂基团、苯基、苯氧基或它们的组合。更优选的取代基包括卤原子和卤化的烃基。取代的杂环基团不是芳族的。
“取代的杂基团”指1-4个与链中碳原子结合的氢原子被其它取代基取代的杂基团。优选的取代基包括卤原子、羟基、烷氧基(如甲氧基、乙氧基、丙氧基、丁氧基和戊氧基)、芳氧基(如苯氧基、氯苯氧基、甲苯氧基、甲氧基苯氧基、苄氧基、烷氧基羰基苯氧基和酰氧基苯氧基)、酰氧基(如丙酸基、苯甲酸基和乙酰氧基)、氨基甲酰氧基、羧基、巯基、烷硫基、硫酰基、芳硫基(如苯硫基、氯苯硫基、烷基苯硫基、烷氧基苯硫基、苄硫基和烷氧基羰基苯硫基)、芳基(如苯基和甲苯基)、取代的芳基(如烷氧基苯基、烷氧基羰基苯基和卤代苯基)、杂环基团、杂芳基和氨基(如氨基、1-3个碳原子的单-和二-烷基氨基、甲基苯基氨基、甲基苄基氨基、1-3个碳原子的烷基(alkanyl)酰氨基、氨基甲酰氨基、脲基和胍基)。
“取代的单价烃基”指1-4个与链中碳原子结合的氢原子被其它取代基取代的单价烃基。优选的取代基包括卤原子、卤化的烃基、卤化的杂基团、烷基(如甲基、乙基、丙基和丁基);羟基、烷氧基(如甲氧基、乙氧基、丙氧基、丁氧基和戊氧基)、芳氧基(如苯氧基、氯苯氧基、甲苯氧基、甲氧基苯氧基、苄氧基、烷氧基羰基苯氧基和酰氧基苯氧基)、酰氧基(如丙酸基、苯甲酸基和乙酰氧基)、氨基甲酰氧基、羧基、巯基、烷硫基、硫酰基、芳硫基(如苯硫基、氯苯硫基、烷基苯硫基、烷氧基苯硫基、苄硫基和烷氧基羰基苯硫基)、芳基(如苯基和甲苯基)、取代的芳基(如烷氧基苯基、烷氧基羰基苯基和卤代的苯基)、杂环基、杂芳基和氨基(如氨基、1-3个碳原子的单-和二-烷基氨基、甲基苯基氨基、甲基苄基氨基、1-3个碳原子的烷基(alkanyl)酰氨基、氨基甲酰氨基、脲基和胍基)。
本发明所用的前列腺素
适用于本发明的前列腺素选自:前列腺素的2-脱羧基-2-磷酸亚基衍生物;2-脱羧基-2-磷酸亚基衍生物的光学异构体、非对映体和对映体;2-脱羧基-2-磷酸亚基衍生物的药学上可接受的盐;和2-脱羧基-2-磷酸亚基衍生物的可生物水解的酰胺、酯和酰亚胺。
适合的2-脱羧基-2-磷酸亚基衍生物可以选自:
式I 式II和
R1选自:氢原子、低级单价烃基、低级取代的单价烃基和低级杂基团。R1宜选自:氢原子;烷基,如甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基;卤化的烃基如三氟甲基或CH2CH2CF3;CH2CH2OH和CH2CH2CH2OH。更佳地,R1是氢原子、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、三氟甲基、CH2CH2CF3、CH2CH2OH或CH2CH2CH2OH。最佳的,R1是氢原子、甲基、乙基、正丙基、异丙基或CH2CH2OH。
R2选自:氢原子、单价烃基、取代的单价烃基、杂基团、取代的杂基团、碳环基团、取代的碳环基团、杂环基团、取代的杂环基团、芳基、取代的芳基、杂芳基和取代的杂芳基。较佳地,R2是H、CH2CO2H、CH2C(O)NHOH、甲基、CF3、乙基、正丙基、异丙基、CH2CH2OH、CH2CH(OH)CH2OH、苄基或叔丁基。更佳地,R2是H、甲基、CF3、乙基、正丙基、异丙基、CH2CH2OH、CH2CH(OH)CH2OH和苄基。最佳的,R2是H、甲基、CF3、乙基、正丙基、异丙基或CH2CH2OH。
R3选自:氧原子、硫原子和NH。较佳地,R3选自氧原子或NH。更佳地,R3是氧原子。
R4选自:氧原子和硫原子。较佳地,R4是氧原子。
R5是二价基团。R5选自:烃基、取代的烃基、杂基团和取代的杂基团。R5可以是饱和的或不饱和的,即R5可含有一个或多个单键、双键、三键或它们的组合。当R5是杂基团时,R5仅包含一个选自氧、氮和硫的杂原子。优选的杂原子是氧。R5宜包含1-5个成员原子,更佳的为3-5个成员原子。
键a选自单键、反式双键和三键。
R6是选自-C(O)-和-C(R9)(OR9)-的二价基团。
R7是选自呈式(CR9(R9))p-X-(CR9(R9))q的二价基团,其中p为0-3的整数,q为0-3的整数,X选自:氧原子、二价烃基、硫原子、SO、SO2和NR9。较佳地,X选自:单键、反式双键、三键、氧原子、硫原子和NR9。
R8选自:甲基、碳环基团、取代的碳环基团、杂环、取代的杂环、芳基、取代的芳基、杂芳基、取代的杂芳基。当R8是单环基团时,其包含5-10个成员原子。当R8是双环基团时,其包含8-12个成员原子。较佳地,R8选自:单碳环基团、取代的单碳环基团、单杂环、取代的单杂环、芳基、取代的芳基、杂芳基和取代的杂芳基。
R9是氢原子或低级单价烃基。较佳地,R9是氢原子。
R10是氢原子或低级单价烃基。较佳地,R10是氢原子。
成分A)也可以是任何上述结构的光学异构体、非对映体和对映体;或任何上述结构的药学上可接受的盐;或任何上述结构的可生物水解的酰胺、酯和酰亚胺。
本发明所用的前列腺素宜为如下式:其中,R1、R2、R3、R4、R5、R6、R7、R8、R9和键a如上所述。更佳地是,R9是氢原子。
可用常规有机合成方法制备成分A)。可用如下反应流程制备适用于成分A)的前列腺素。
流程1
在流程1中,R1、R2、R5、R6、R7、R8、R9和键a如上所述,X是卤素原子,且Q和Q2是保护基团。作为起始物的Corey内酯(S1a)是可购得的(如可以从Aldrich Chemical或Cayman ChemicalCompany购得)。用已知的Wadsworth-Horner-Emmons反应将所需的前列腺素的底链连接于Corey内酯,制得S1b类型的化合物。随后,进行标准的前列腺素ω链操作和官能团的保护(包括任选的烯烃还原),制得S1c型的化合物。此时,改变前列腺素合成的标准过程,用ω-官能化的Witting试剂制备S1d型的2-脱羧基前列腺素衍生物。当可获得含羧酸的前列腺素时,就通过用Hunsdiecker反应的改进法通过一碳降解制得S1d型的化合物。
通过与二乙氧基次膦酸(phosphinite)烷基酯(如所示,可用购得的氯二乙氧基膦试剂制得)的次膦酸偶联反应,可从S1d型化合物制得S1e型化合物。通过任选的除去烯烃并随后除去S1e的保护基团Q和Q2,可从S1e化合物制得呈式III的化合物。
或者,可从中间体S1e制备S1f型的化合物,其中保护基团Q和Q2选自本领域技术人员已知的各种基团(参见,如“有机合成中的保护基团”,Greene,T.W.和P.G.M.,第2版,Wiley&Sons,Inc.,1991)。随后除去C11上的保护基团Q,再氧化,得到S1f的酮前体。通过最终的去保护可以制得S1f型的化合物。
通过与羟胺缩合,可以从S1f的化合物制得式I的化合物。通过在THF∶乙酸(1∶1)中用氰基氢硼化钠处理,随后用HCl淬灭,可以还原式II的化合物制得式I的化合物。本领域技术人员用常规的有机合成方法,可以制备适用于本发明的前列腺素。
适合的式I的前列腺素的实例包括式1A。式1A是其中R1、R7、R8和R9在表1A中定义。
适合的式II的前列腺素的实例包括式2A。
适合的式III的前列腺素的实例包括式3A和3B。
表3A:式3A的取代基
式3B是其中R1、R7和R8在表3B中定义。
表3B:式3B的取代基
本发明的组合物
脱发
本发明还涉及治疗脱发的组合物。“治疗脱发”指制止和/或逆转脱发以及促进毛发生长。本发明的组合物包括成分A)以上所述的PGF和成分B)载体。本发明的组合物还可包含成分C)一种或多种任选地活性增强剂。
本发明的组合物可以是药物或化妆品组合物,用于脱发的治疗和预防。使用标准药物制剂方法,如Remington’s Pharmaceutical Science,MackPublishing Company,Easton,Pa(1990)中公开的那些方法。
本发明的组合物还包含载体成分B)。“载体”指一种或多种适用于给予哺乳动物的相容物质。载体包括固态或液态稀释剂、水溶助长剂(hydrotope)、表面活性剂和胶囊材料。“相容”指组合物的成分能与前列腺素彼此混合,以在常规使用条件下不发生降低组合物效力的相互作用的形式。载体必须有足够高的纯度且毒性也要足够低,使它们适用于给予待治疗的哺乳动物。根据本文所述的预期用途,载体可能是惰性的,或具有药物益处和/或化妆品益处。
成分B)的选择取决于成分A)前列腺素要施用的途径和组合物的形式。组合物可以是多种形式,如适用于全身施用的(如口服、直肠给药、鼻部给药、舌下给药、颊部给药或肠胃外给药)或局部施用(如在皮肤、眼睛,脂质体输送系统,或离子电渗法)。优选的是将药物局部施用于所需生长毛发的位置。
全身施用的载体通常包括一种或多种选自以下的成分:a)稀释剂、b)润滑剂、c)结合剂、d)分散剂、e)色素、f)调味剂、g)加甜剂、h)抗氧剂、j)防腐剂、k)助流剂、m)溶剂、n)悬浮剂、o)表面活性剂和它们的组合等。
成分a)是稀释剂。适合的稀释剂包括:糖,如葡萄糖、乳糖、右旋糖和蔗糖;多元醇,如丙二醇;硫酸钙;碳酸钠;甘油;甘露醇;山梨糖醇和麦芽糊精。
成分b)是润滑剂。适合的润滑剂的实例为固态润滑剂,包括二氧化硅、滑石粉、硬脂酸及其镁盐和钙盐、磷酸钙;和液态润滑剂,如聚乙二醇和植物油如花生油、棉籽油、芝麻油、橄榄油、玉米油和可可豆油。
成分c)是结合剂。适合的结合剂包括:聚乙烯吡咯烷酮;硅酸铝镁;淀粉,如玉米淀粉、马铃薯淀粉;明胶;黄蓍胶;和纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素、甲基纤维素、微晶纤维素和羟丙基甲基纤维素;卡波姆;聚烯吡酮(providone)、阿拉伯树胶、胍尔豆胶和黄原胶。
成分d)是分散剂。适合的分散剂包括:琼脂、海藻酸及海藻酸钠、泡腾混合物、交联甲基纤维素、聚乙烯聚吡咯烷酮、羧甲基淀粉钠、羟乙酸淀粉钠、粘土和离子交换树脂。
成分e)是色素,如FD&C染料。
成分f)是调味剂,如薄荷醇、胡椒薄荷和水果香精。
成分g)是调味剂,如糖精和阿斯巴特。
成分h)是抗氧剂,如丁基化的羟基苯甲醚、丁基化的羟基甲苯和维生素E。
成分j)是防腐剂,如苯酚、对羟基苯甲酸的烷基酯、苯甲酸及其盐、硼酸及其盐、山梨酸及其盐、三氯叔丁醇(chorbutanol)、苯甲醇、硫柳汞、乙酸苯汞和硝酸苯汞、硝甲酚汞、苯扎氯铵、氯化十六烷吡啶、对羟苯甲酸甲酯和对羟苯甲酸丙酯。特别优选的是苯甲酸的盐、氯化十六烷吡啶、对羟基苯甲酸甲酯和对羟苯甲酸丙酯和苯甲酸钠。
成分k)是助流剂,如二氧化硅。
成分m)是溶剂,如水、等渗盐水、油酸乙酯、醇如乙醇、甘油、乙二醇(如聚丙二醇和聚乙二醇)和缓冲液(如磷酸盐、乙酸钾、硼酸、碳酸、磷酸、丁二酸、苹果酸、酒石酸、柠檬酸、乙酸、苯甲酸、乳酸、甘油酸、葡糖酸、戊二酸和谷氨酸)。
成分n)是悬浮剂。合适的悬浮剂包括:FMC Corporation of Philadelphia的AVICELRC-591、Pennsylvania和海藻酸钠。
成分o)是表面活性剂,如卵磷脂、聚山梨醇80、月桂基硫酸钠、聚氧乙烯去水山梨醇糖脂肪酸酯、聚氧乙烯单烷基醚、蔗糖单酯、羊毛脂酯和羊毛脂醚。合适的表面活性剂是本领域已知的且是可以购得的,如Atlas PowderCompany of Wilmington,Delaware的TWEENS。
用于肠胃外施用的组合物通常包含A)0.1-10%前列腺素和B)90-99.9%载体,该载体包含a)稀释剂和m)溶剂。较佳地,成分a)是丙二醇,m)是乙醇或油酸乙酯。
用于口服的组合物可以有多种剂型。例如,固态形式包括片剂、胶囊、粒剂和粉状制剂。这些口服剂型包含安全有效量(通常为至少5%,宜为25%-50%)的A)前列腺素。口服剂型组合物还包含至多95%(宜为50-75%)作为载体的B)。
片剂可以是压制的、研制的、肠溶衣的、糖涂层的、膜涂层的或复压片。片剂涂层包含A)前列腺素和B)载体,载体包括选自以下的成分:a)稀释剂、b)润滑剂、c)结合剂、d)分散剂、e)色素、f)调味剂、g)加甜剂、k)助流剂和它们的组合。优选的稀释剂包括碳酸钙、碳酸钠、甘露醇、乳糖和纤维素。优选的结合剂包括淀粉、明胶和蔗糖。优选的分散剂包括海藻酸和交联羟甲纤维素。优选的润滑剂包括硬脂酸镁、硬脂酸和滑石粉。优选的色素是FD&C染料(用于增加外观)。咀嚼片宜包含g)加甜剂,如阿斯巴特和糖精,或f)调味剂如薄荷醇、胡椒薄荷醇和水果香精。
胶囊(包含缓释和持续释放制剂)通常包含A)前列腺素和B)载体,载体包括一种或多种在上述含明胶的胶囊中所公开的稀释剂。粒剂通常包含A)前列腺素,还宜包含k)助流剂,如二氧化硅以改善其流动特性。
口服制剂中载体的选择取决于次要考虑因素如口味、成本及存储稳定性,这对本发明的目的而言并不关键。本领域技术人员无需进行试验就可最佳化合适的成分。
可用常规方法将固态组合物涂层,通常用pH或时控的涂层,从而能在肠胃道中的不同时间释放前列腺素以延长所需的作用。通常涂层包含一种或多种选自以下的成分:苯二甲酸醋酸纤维素、苯二甲酸聚醋酸乙烯酯、苯二甲酸羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂如EUDRAGIT涂层(可从Rohm&HaasG.M.B.H.of Darmstadt,Germany购得)、蜡、虫胶、聚乙烯吡咯烷酮和其它可购得的膜涂层制剂如Dri-Klear(Crompton&Knowles Corp.,Mahwah,NJ制备)或OPADRY(由Colorcon,Inc.,of West Point,Pennsylvania制备)。
口服给药的组合物还可以是液态形式。例如,合适的液态形式包括水溶液、乳剂、悬浮液、由非泡腾的粒剂重建的溶液、由非泡腾粒剂重建的悬浮液、由泡腾粒剂重建的泡腾剂、酏剂、酊剂、糖浆等。液态口服施用的组合物通常包含A)前列腺素和B)载体,载体包含选自以下的成分:a)稀释剂、e)色素和f)调味剂、g)加甜剂、j)防腐剂、m)溶剂、n)悬浮剂、和o)表面活性剂。糖浆液态组合物宜包含一种或多种选自以下的成分:e)色素、f)调味剂和g)加甜剂。
可用于进行向对象送递目的化合物的其它组合物包括舌下、颊和鼻剂型。这些组合物通常包含一种或多种可溶性填充成分,如a)稀释剂(包括蔗糖、山梨糖醇和甘露醇)、和c)结合剂(如阿拉伯树胶、微晶纤维素、羧甲基纤维素和羟丙基甲基纤维素)。这些组合物还可包含b)润滑剂、e)色素、f)调味剂、g)加甜剂、g)抗氧剂和k)助流剂。
用于治疗脱发的组合物还可包含成分C)任选地活性增强剂。成分C)宜选自:i)(除PGF以外的)毛发生长刺激剂和ii)渗透增强剂。
成分i)是任选的毛发生长刺激剂。成分i)可列举为血管扩张剂、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、甲状腺激素衍生物和甲状腺激素类似物、非选择性前列腺素促效剂或拮抗剂、类视色素、三萜烯和它们的组合等。“非选择性前列腺素”促效剂和拮抗剂与成分A)不同,因为它们不会选择性激活FP受体,而且它们可能会激活其它受体。
血管扩张剂如钾通道促效剂(包括米诺地尔和米诺地尔衍生物,如阿米昔尔(aminexil))以及在美国专利No.3,382,247、5,756,092、5,772,990、5,760,043、5,466,694、5,438,058、4,973,474中所公开的那些和克罗吗宁和二氮嗪可用作组合物中的任选地毛发生长刺激剂。
合适的抗雄激素的实例包括5-α-还原酶抑制剂如非那司提和美国专利No.5,516,779和Nane等人在癌症研究58“C17,20-裂解酶和5α-还原酶的某些新型抑制剂的体外和体内作用以及它们在治疗前列腺癌中的潜在用途”中所公开的那些,以及乙酸环丙孕酮、壬二酸及其衍生物和那些在美国专利No.5,480,913中所公开的化合物,氟他米特和那些在美国专利No.5,411,981、5,565,467和4,910,226中所公开的化合物。
抗菌剂包括硫化硒、酮康唑、三氯卡班、三氯生、硫氧吡啶锌、伊曲康唑、亚细亚酸、扁柏酚、米匹罗星(mipirocin)和EPA0,680,745中所公开的那些、盐酸克林西星(clinacycin)、过氧苯甲酰、过氧化苄和米诺环素。
合适的抗炎药的实例包括糖皮质激素(如氢化可的松、糠酸莫米松和氢化泼尼松)、非甾类抗炎药(包括环加氧酶或脂肪氧化酶,如美国专利No.5,756,092中所公开的那些和苄达明)、水杨酸和那些在EPA0,770,399(1997年5月2日出版)、WO94/06434(1994年3月31日出版)和FR2,268,523(1975年9月21日出版)中所公开的化合物。
3,5,3’-三碘甲腺原氨酸是合适的甲状腺激素的实例。
合适的非选择性前列腺素促效剂和拮抗剂的实例包括那些在WO98/33497(Johnstone,1998年8月6日出版)、WO95/11003(Stjernschantz,1995年4月27日出版)、JP97-100091(Ueno)和JP96-134242(Nakamura)中所公开的化合物。
合适的类视色素包括异维甲酸、依曲替酸和他佐罗汀。
成分i)的其它任选的毛发生长刺激剂包括:苯扎氯铵、苄索氯胺、苯酚、雌二醇、马来酸氯苯吡胺、叶绿酸衍生物、胆固醇、水杨酸、半胱氨酸、甲硫氨酸、红椒酊剂、烟酸苄酯、D,L-薄荷醇、薄荷油、泛酸钙、泛醇、蓖麻油、氢化泼尼松、间苯二酚、蛋白质激酶C的化学活化剂、葡糖胺聚糖链细胞内吸收的抑制剂、糖苷酶活性的抑制剂、葡糖胺聚糖酶抑制剂、焦谷氨酸酯、己糖酸(hexosaccharic acid)或酰化的己糖酸、芳基取代的乙烯、N-酰化的氨基酸、类黄酮(flavinoid)、子囊霉素衍生物和类似物、组胺拮抗剂(如盐酸苯海拉明)、三萜烯(如齐墩果酸和熊果酸)和那些在美国专利No.5,529,769、5,468,888、5,631,282和5,697,705、JP10017431、WO95/35103、JP09067253、WO92/09262、JP62093215和JP08193094;皂素,如EP0,558.509(Bonte等人,1993年9月8日出版)和WO97/01346(Bonte等人,1997年1月16日出版)中公开的皂素;蛋白多糖酶或葡糖胺聚糖酶抑制剂,如美国专利No.5,015,470、5,300,284和5,185,325中公开的;雌激素促效剂和拮抗剂、假特林(pseudoterin)、细胞因子和生长因子刺激剂、类似物或抑制剂如白细胞介素1抑制剂、白细胞介素-6抑制剂、白细胞介素-10刺激剂、和肿瘤坏死因子抑制剂、维生素如维生素D类似物和甲状腺激素拮抗剂、维生素B12类似物和泛醇、干扰素促效剂和拮抗剂、醇酸如美国专利No.5,550,158中公开的那些、二苯甲酮和乙内酰脲抗惊厥药如苯妥英以及它们的组合。
其它毛发生长刺激剂公开于:JP09-157,139(Tsuji等人,1997年6月17日出版);EP0277455A1(Mirabeau,1988年8月10日出版);WO97/05887(CaboSoler等人:1997年2月20日出版);WO92/16186(Bonte等人,1992年3月13日出版);JP62-93215(Okazaki等人,1987年4月28日出版);美国专利No.4,987,150(Kurono等人,1991年1月22日出版);JP29081(Ohba等人,1992年10月15日出版);JP05-286,835(Tanaka等人,1993年11月2日出版);FR2,723,313(Greff,1994年8月2日出版);美国专利No.5.015,470(Gibson,1991年5月14日出版);美国专利No.5,559,092(1996年9月24日出版);美国专利No.5,536,751(1996年7月16日出版);美国专利No.5,714,515(1998年2月3日出版0;EPA0,319,991(1989年6月14日出版);EPA0,357,630(1988年10月6日出版);EPA0,573,253(1993年12月8日出版);JP61-260010(1986年11月18日出版);美国专利No.5,772,990(1998年6月30日出版);美国专利No.5,053,410(1991年10月1日出版);美国专利No.4,761,401(1988年8月2日出版)。
最优选的活性增强剂是米诺地尔和非那司提,其中地诺米尔是最优选的。
成分ii)是可以加到全身给药的所有组合物中的渗透增强剂。组合物中成分ii)的存在量通常为1-5%。渗透增强剂是实例包括2-甲基丙-2-醇、丙-2-醇、乙基-2-羟基-丙酸酯、己-2,5-二醇、聚氧乙烯(2)乙基醚、二(2-羟丙基)醚、戊-2,4-二醇、丙酮、聚氧乙烯(2)甲基醚、2-羟基丙酸、2-羟基辛酸、丙-1-醇、1,4-二噁烷、四氢呋喃、丁-1,4-二醇、丙二醇二壬酸酯、聚氧丙烯15硬脂基醚、辛醇、油醇的聚氧乙烯酯、油醇、月桂醇、己二酸二辛酯、己二酸二辛酯、己二酸二异丙酯、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、癸二酸二辛酯、辛二酸二丁酯、壬二酸二辛酯、癸二酸二苄酯、邻苯二甲酸二丁酯、壬二酸二丁酯、肉豆蔻酸乙酯、壬二酸二甲酯、肉豆蔻酸丁酯、琥珀酸二丁酯、邻苯二甲酸盐二癸酯、油酸癸酯、己酸乙酯、水杨酸乙酯、棕榈酸异丙酯、月桂酸乙酯、壬酸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、2-羟基辛酸、二甲基亚砜、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、磷化氢氧化物、糖酯、四氢糠醇、脲、二乙基-间-甲苯甲酰胺、1-月桂基氮杂环庚-2-酮、ω3脂肪酸和鱼油以及它们的组合。
在本发明的一优选实施例中,局部施用前列腺素。可以局部施用于皮肤的局部化合物可以是任何形式,包括:溶液、涂油、乳膏、油膏、凝胶、洗液、香波、免洗或要清洗的护发素、乳液、清洗剂、保湿剂、喷雾、皮肤贴片等。局部用的组合物包含:上述的成分A)前列腺素和成分B)载体。局部用的组合物的载体宜协助前列腺素渗透入皮肤,到达毛囊的环境。局部用的组合物还宜包含C)一种或多种上述任选地活性增强剂。
局部用的治疗脱发的组合物中各成分的实际量取决于多种因素。成分A)的用量取决于所选用的前列腺素的IC50。“IC50”指抑制50%的浓度。加到局部用的组合物的成分A)的量为:
IC50×10-2≥成分A)的%≥IC50×10-3,
其中IC50以毫微摩尔单位表示。例如,若前列腺素的IC50为1nM,则成分A)的量为0.001-0.01%。若前列腺素的IC50为10nM,则成分A)的量为0.01-0.1%。若前列腺素的IC50为100nM,则成分A)的量为0.1-1.0%。若前列腺素的IC50为1000nM,则成分A)的量为1.0-10%,宜为1.0-5%。如果成分A)的量超出了上述范围(即高于或低于),则可能降低治疗的效力。可以按以下的参考例1的方法计算IC50。无需试验,本领域技术人员可计算IC50。
局部用的组合物还宜包含1-20%成分C),且成分B)的量应足以使成分A)、B)和C)的总量到达100%。与PGF联用的B)载体的量应足以提供实际量的组合物以给予单位剂量化合物。配制用于本发明方法的剂型的方法和组合物在以下文献中有描述:“现代药学”第9和10章,Banker&Rhodes编辑(1979);Lieberman等人,“药物剂型:片剂”(1981);和Ansel,“药物剂型导论”,第2版(1976)。
成分B)载体可包含单种成分或两种或多种成分的组合。在局部用的组合物中,成分B)是局部载体。优选的局部载体包括一种或多种选自以下的成分:水、醇、芦荟胶、尿囊素、甘油、维生素A和E油、矿物油、丙二醇、聚丙二醇-2肉豆寇基丙酸酯、异山梨酸二甲酯和它们的组合等。更优选的载体包括丙二醇、异山梨酸二甲酯和水。
局部载体可以包含一种或多种选自以下的成分:q)乳化剂、r)推进剂、s)溶剂、t)湿润剂、u)增稠剂、v)粉末和w)香精,以补充或替代上述优选的局部载体成分。本领域技术人员无需试验就能最佳化局部用的组合物的载体成分。
成分q)是乳化剂。局部用的组合物中成分q)的量通常为5-95%。适合的乳化剂包括十八烷醇、单蓖麻酸甘油酯、单硬脂酸甘油酯、丙-1,2-二醇、丁-1,3-二醇、貂油、鲸腊醇、异硬脂酸异丙酯、硬脂酸、棕榈酸异丁酯、硬脂酸异鲸腊酯、油醇、月桂酸异丙酯、月桂酸己酯、油酸癸酯、十八烷-2-醇、异鲸腊醇、棕榈酸鲸腊酯、癸二酸二-正-丁酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、硬脂酸丁酯、聚乙二醇、三甘醇、羊毛脂、芝麻油、椰子油、花生油、蓖麻油、乙酰化的羊毛脂醇、矿脂、矿物油、肉豆蔻酸丁酯、异硬脂酸、棕榈酸、亚油酸异丙酯、乳酸月桂酯、乳酸肉豆蔻酯、油酸癸酯、肉豆蔻酸肉豆蔻酯、聚二甲基硅氧烷和它们的组合。优选的乳化剂包括十八烷醇和聚二甲基硅氧烷。
成分r)是推进剂。局部用的组合物中成分r)的量通常为5-95%。适合的推进剂包括丙烷、丁烷、异丁烷、二甲醚、二氧化碳、一氧化二氮和它们的组合。
成分s)是溶剂。局部用的组合物中成分s)的量通常为5-95%。适合的溶剂包括水、乙醇、二氯甲烷、异丙醇、蓖麻油、乙二醇单乙醚、二乙二醇单丁醚、二乙二醇单乙醚、二甲基亚砜、二甲基甲酰胺、四氢呋喃和它们的组合。优选的溶剂是乙醇。
成分t)是湿润剂。局部用的组合物中成分t)的量通常为5-95%。适合的湿润剂包括甘油、山梨糖醇、2-吡咯烷酮-5-羧酸钠、可溶性胶原、邻苯二甲酸二丁酯、明胶和它们的组合。优选的湿润剂包括甘油。
成分u)是增稠剂。局部用的组合物中成分u)的量通常为0-95%。
成分v)是粉末。局部用的组合物中成分v)的量通常为0-95%。适合的粉末包括白垩、滑石粉、漂白土、陶土、淀粉、树胶、胶质二氧化硅、聚丙烯酸钠、四烷基铵绿土、三烷基芳基铵绿土、化学改性的硅酸镁铝、有机改性的蒙脱石粘土、水合硅酸铝、二氧化硅粉末、聚羧乙烯、羧甲基纤维素钠、单硬脂酸乙二醇酯和它们的组合。
成分w)是香精。局部用的组合物中成分w)的量通常为0.001-0.5%,宜为0.001-0.1%。
成分C)任选的活性增强剂如上所述。可以将任何i)毛发生长刺激剂和i)渗透增强剂加到局部用的组合物中。较佳地,局部用的组合物包含0.01-15%成分i)任选的毛发生长刺激剂。更优选的是,组合物包含0.1-10%成分i),最优选的是包含0.5-5%成分i)。较佳地,局部用的组合物包含1-5%成分ii)。
在本发明的另一实施例中,可将局部用的组合物施用于生长毛发和生长毛发部位的皮肤上,使毛发变黑、逆反毛发的泛灰和使毛发变密。例如,可将局部用的组合物施用于长头发的头皮或睫毛上。这种局部用的组合物可以是例如用上述方法制备的化妆品组合物。可施用于睫毛的组合物的实例是睫毛膏。可以在本领域已知的睫毛膏组合物中(例如美国专利No.5,874,072中所公开的睫毛膏,本文将其纳入作为参考)添加前列腺素。睫毛膏还可包含dd)水不溶性材料、ee)水溶性成膜聚合物、ff)蜡、o)表面活性剂、gg)色素和s)溶剂。
成分dd)是水不溶性材料,选自:丙烯酸共聚物;苯乙烯/丙烯酸/甲基丙烯酸共聚物;丙烯酸乳胶;苯乙烯/丙烯酸酯共聚物乳胶;聚乙酸乙烯酯乳胶;乙酸乙烯酯/乙烯共聚物乳胶;苯乙烯/丁二烯共聚物乳胶;聚氨酯乳胶;丁二烯/丙烯腈共聚物乳胶;苯乙烯/丙烯酸酯/丙烯腈共聚物乳胶和它们的混合物,其中丙烯酸酯共聚物和苯乙烯/丙烯酸酯/甲基丙烯酸酯共聚物还可包含氨、丙二醇、防腐剂和表面活性剂。
成分ee)是水溶性、成膜聚合物。成分ee)选自:乙烯醇/聚(烯氧基)丙烯酸酯;乙烯醇/乙酸乙烯酯/聚(烯氧基)丙烯酸酯;聚氧乙烯;聚氧丙烯;丙烯酸酯/辛烷基-丙烯酰胺共聚物和它们的混合物。
成分ff)是蜡。“蜡”指低熔点的有机混合物或高分子量的、室温为固态的化合物,在组合物中通常与脂肪和油类似,但它们不含甘油酯。其中一些是烃类,其它则是脂肪酸和醇的酯。用于本发明的蜡选自:动物蜡、植物蜡、矿物蜡、天然蜡的各种馏分、合成蜡、石油蜡、乙烯型聚合物、烃类(如Fischer-Tropsch)蜡、有机硅蜡和它们的混合物,其中蜡的熔点在55-100℃之间。
成分o)是如上所述的表面活性剂。睫毛膏中的成分o)宜为HLB为3-15的表面活性剂。合适的表面活性剂包括那些在C.T.F.A.Cosmetic IngredientHandbook,第587-592(1992);Remington’s Pharmaceutical Science,第15版,第335-337页(1975);和McCutcheon’s,第1卷,Emulsifiers&Detergents,North American Edition,第236-592页(1994)中公开的表面活性剂。
成分gg)是色素。适合的色素包括无机色素、有机沉淀染料、珠光颜料和它们的混合物。可用于本发明的无机色素包括:金红石或锐钛矿二氧化钛(以颜色指数编码的参考号为CI 77,891);黑、黄、红和棕色氧化铁(编码的参考号为CI 77,499、77,492和77,491);锰紫(CI 77,742);群青(CI 77,007);三氧化二铬(CI 77,288);氢氧化铬(CI 77,289);和铁篮(ferric blue)(CI77,510)和它们的混合。
可用于本发明的有机染料和沉淀染料包括选自以下的染料:D&C红No.19(CI 45,170)、D&C红Nol9(CI 15,585)、D&C红No.21(CI 45,380)、D&C橙No.4(CI 15,510)、D&C橙No.5(CI 45,370)、D&C红No.27(CI 45,410)、D&C红No.(CI 15,630)、D&C红No.7(CI 15,850)、D&C红No.6(CI 15,580)、D&C黄No.5(CI 19,140)、D&C红No.36(CI 12,085)、D&C橙No.10(CI45,425)、D&C黄No.6(CI 15,985)、D&C红No.30(CI 73,360)、D&C红No.3(CI 45,430)和以胭脂虫红为基础的染料和沉淀染料(CI 75,570)和它们的混合物。
可用于本发明珠光颜料包括选自以下的珠光颜料:白色珠光颜料,如用氧化钛、氯氧化铋包涂的云母;有色珠光颜料,如氧化铁包涂的钛云母、铁蓝、氧化锆等包涂的钛云母、用选自上述的有机颜料以及氯氧化铋包涂的钛云母和它们的混合物。
成分s)是如上所述的溶剂,优选水。
添加到睫毛膏中的A)前列腺素的量如上局部用的组合物所述。
还可以脂质体送递系统的形式施用前列腺素,如单层小泡、单层大泡和多层小泡。可以由多种磷脂(如胆固醇、硬脂胺或卵磷脂)制成脂质体。局部送递本发明化合物的优选制剂使用以下文献所述的脂质体:Dowton等人,“脂质体组合物对局部送递胶囊化的环孢菌素A的影响:I.用无毛小鼠皮肤进行的体外研究”,S.T.P.Pharma Sciences,第3卷,第404-407页(1993);Wallach和Philippot,“新型脂类小泡:Novasome”,Liposome Technology,第1卷,第141-156页(1993);Wallach,美国专利No.4,991,928(授予Micro-Pak,Inc.,于1990年3月27日出版);和Weiner等人,美国专利No.5,834,014(授予密西根大学和Micro-Pak Inc.,于1998年11月10日出版)(在Weiner等人的文献中,用本发明的化合物替代或补充米诺地尔)。
还可月离子电渗疗法施用前列腺素。参见,如网址www.unipr.it/arpr/dipfarm/erasmus/erasm14.html;Banga等人,“用于透皮送递肽/蛋白药物的水凝胶-基础的离子电渗疗法送递装置”,Pharm.Res.,第10(5)卷,第697-702页(1993);Ferry,“用于透皮药物送递的离子电渗疗法的治疗模型”,Pharmaceutical Acta Helvetiae,第70卷,第279-287页(1995);Gangarose等人,“局部送递药物的离子电渗疗法”,Int.J.Pharm.第123卷,第159-171页(1995);Green等人,“体外离子电渗疗法送递系列三肽透过皮肤”,Pharm.Res.,第8卷,第1121-1127页(1991);Jadoul等人,“在皮肤中用离子电渗疗法送递芬太尼和TRH的定量和定位”,Int.J.Pharm.,第120卷,第221-8页(1995);O’Breien等人,“对其抗病毒活性、药物动力学特性和治疗效力的最新综述”,第37卷,第233-309页(1989);Parry等人,“阿昔洛韦在人皮肤中的生物可利用性”,J.Invest.Dermatol.第98(6)卷,第856-63页(1992);Santi等人,“在透皮离子电渗疗法中鲑鱼降钙素的药物存储组合物和送递”,Pharm.Res.,第14(1)卷,第63-66页(1997);Santi等人,“逆向离子电渗疗法-确定电渗流的参数:I.pH和离子强度”,J.Control.Release,第38卷,第159-165页(1996);Santi等人,“逆向离子电渗疗法-确定电渗流的参数:II.电极室制剂”J.Control.Release,第42卷,第29-36页(1996);Rao等人,“逆向离子电渗疗法:在人体内的非扩散的葡萄糖监测”,Pharm.Res.,第12(12)卷,第1869-1873页(1995);Thysman等人,“用离子电渗疗法向大鼠送递人的降钙素”,J.Pharm.Pharmacol.第46卷,第725-730页(1994);和Volpato等人“离子电渗疗法增强由电排斥和电渗透向裸鼠皮肤送递阿昔洛韦”,Pharm.Res.,第12(11)卷,第1623-1627页(1995)。
可将前列腺素装入药盒,这种药盒包含前列腺素、上述的全身和/或局部用的组合物;和信息和/或说明书,说明用此药盒能提供对哺乳动物(尤其是人)脱发的治疗。这种信息和说明书可以是文字和/或图片等的形式。此外或代替之,药盒还可包含前列腺素和/或组合物;和信息和/或说明书,说明前列腺素或组合物的施用方法,较佳地还附带治疗哺乳动物脱发的益处。
骨病
除了治疗脱发的益处外,本发明的前列腺素还可用于治疗骨病。不希望束缚于理论,据信通过形成新的小梁、形成骨质(维持正常化的骨更新速率的同时)和形成骨内表面(而不从已存在的皮层除去骨头),前列腺素可用于增加骨量和小梁的数量。
本发明涉及治疗骨病的组合物。可按标准制剂方法(如Remington’sPharmaceutical Science,Mack Publishing Company,Easton,Pa(1990)所述的),用如上所述的成分制备用于骨病的组合物。治疗骨病的优选施用途径是透皮、鼻内、直肠、舌下施用和口服。
适用于治疗骨病的口服组合物通常包含A)上述的前列腺素和B)载体。一般片剂组合物包含A)前列腺素和B)载体,载体包含选自以下的成分:a)稀释剂、b)润滑剂、c)结合剂、d)分散剂、e)色素、f)香精、g)加甜剂、k)助流剂和它们的组合。优选的稀释剂包括碳酸钙、碳酸钠、甘露醇、乳糖和蔗糖。优选的润滑剂包括硬脂酸镁、硬脂酸和滑石粉。优选的结合剂包括微晶纤维素、淀粉和明胶。优选的分散剂包括羟基乙酸淀粉钠、海藻酸和交联羟甲纤维素。
典型的用于治疗骨病的肠胃外药物组合物包含A)前列腺素和B)载体,载体包含以下成分:j)防腐剂和m)溶剂。以下的防腐剂包括对羟基苯甲酸甲酯和对羟基苯甲酸乙酯。优选的溶剂包括电渗盐水。本领域技术人员无需试验就可优化用于治疗骨病的组合物的成分。
前列腺素可任选的与其它对骨损失起有益作用的成分联合使用。因此,其它活性成分如维生素D类似物、激素、钙补充剂、二膦酸酯化合物(如那些在Procter&Gamble Company的文献中广泛描述的)以及它们的组合等也可施用于需要它们与前列腺素联用的患者。施用的剂量浓度和方式包括脉冲剂量,且在文献中已有描述。
眼内压
本发明所用的前列腺素还可用于降低眼内压。因此,这些前列腺素可用于治疗青光眼。本发明还涉及降低眼内压的组合物。优选的降低眼内压的施用方式是局部施用。用于眼睛的局部用的药物组合物包含A)前列腺素;B)载体,如纯化水;和一种或多种选自以下的成分:y)糖,如右旋糖酐,尤其是右旋糖酐70;z)纤维素或其衍生物;aa)盐;bb)EDTA二钠(乙二胺四乙酸二钠);和cc)pH调节剂。
适合施用于眼睛的局部药物组合物中的成分z)纤维素衍生物的实例包括羧甲基纤维素钠、乙基纤维素、甲基纤维素和羟丙基甲基纤维素。羟丙基甲基纤维素是优选的。
适合施用于眼睛的局部药物组合物中的成分aa)盐的实例包括氯化钠、氯化钾和它们的组合。
cc)pH调节剂的实例包括HCl或NaOH,其存在量足以将施用于眼睛的局部药物组合物的pH调节至7.2-7.5。
本发明的方法
脱发
本发明还涉及治疗哺乳动物脱发的方法。这种方法包括对患脱发的哺乳动物(尤其是人)施用上述PGF。例如,可用本发明的方法治疗诊断患有脱发的哺乳动物,包括雄性型脱发和雌性型脱发。较佳地,将包含A)前列腺素和B)载体的全身或局部用的组合物施用于哺乳动物。更佳的是,这种组合物是包含A)前列腺素、B)载体和C)任选的活性增强剂的局部用的组合物。
治疗脱发施用的前列腺素的剂量取决于施用的方法。对全身给药(如口服、直肠给药、鼻部给药、舌下给药、颊部给药或肠胃外给药)而言,通常每天给予0.5mg-300mg,较佳地为0.5mg-100mg,更佳地为0.1mg-10mg的前列腺素。这些剂量只是示范性的,可根据多种因素调节每天的给药剂量。要施用的前列腺素特定剂量、以及治疗的持续时间和治疗是局部的或是全身的都是相互关联的。剂量和疗法也取决于因素如所用的特定前列腺素、治疗的适应性、化合物的效力、对象的个人特征(如,体重、年龄、性别和对象对药物的反应)、疗法的顺应性和治疗的任何副作用的存在情况和严重性。
对局部给药(如在皮肤、眼睛上的局部施用,脂质体送递系统或离子电渗疗法)而言,通常每天施用局部用的组合物一次。每天施用局部用的组合物持续时间相对较短(即几周)。通常,6-12周己足。局部用的组合物宜为免洗组合物。通常,局部用的组合物在施用后的至少几小时内不会清除。
除治疗脱发的益处以外,发明人发现本发明组合物和方法中的前列腺素还能使毛发变黑和变密,且可能逆转毛发泛灰。本发明还涉及用于毛发变黑、变密和逆转泛灰的方法。该方法包括将用于治疗脱发的局部用的组合物施用于毛发和/或毛发生长部位的皮肤。在本发明的一优选实施例中,将局部用的组合物,如上述的睫毛膏组合物,施用于睫毛。
骨病
本发明还涉及用上述前列腺素治疗骨病的方法。该方法包括对患骨病的哺乳动物(宜为人)施用上述前列腺素。例如,可用本发明的方法治疗诊断为患骨质疏松的哺乳动物。较佳地,将包含A)前列腺素和B)载体的全身用组合物施用于哺乳动物。治疗骨病优选的途径是透皮、鼻内、直肠、舌下施用和口服。
治疗骨病的全身施用的前列腺素的剂量范围每天为约0.01-1000μg/kg体重,较佳地为约0.1-100μg/kg体重,最佳的为1-50μg/kg体重。用药物动力学和透皮制剂领域的普通技术人员已知的方法,设计透皮剂量以获得类似的血清或血浆浓度。预计全身施用的血浆浓度范围为0.01-100毫微克/ml,更佳地为0.05-50ng/ml,最佳的是0.1-10ng/ml。这些剂量是以每天施用的比例为基础的,也可用每周或每月的累积剂量来计算临床需要。
根据待治疗的患者、待治疗的疾病、待治疗的疾病严重性、施用的方式等,为达到所需的效果所用的剂量各不相同。
眼内压
本发明的前列腺素还可用于降低眼内压。因此,可将这些前列腺素用于治疗青光眼。本发明还涉及降低哺乳动物眼内压的方法。该方法包括将上述前列腺素施用于哺乳动物(宜为人)。例如,可用本发明的方法治疗诊断为患青光眼的哺乳动物。治疗青光眼的施用方式是局部的。较佳地,每天向哺乳动物施用上述用于眼睛给药的局部用组合物。每天施用局部用的组合物,相对较短的时间(即,将近几周)。通常6-12周已足。
实施例
用这些实施例向本领域技术人员说明本发明,但并非对本发明的范围进行限制,本发明的范围仅受所附权利要求的限制。
参考例1-放射性配体结合试验
用放射性配体结合试验可以确定PGF相对于PGF2α的IC50。作为对照,PGF2 α本身的IC50应不低于1.0nM且不高于5.0nM。
在此试验中,用LipofectAMINE试剂,以hFP重组质粒瞬时转染COS-7细胞。48小时后,用Hanks平衡盐溶液(HBSS,无CaCl2、MgCl2、MgSO4或酚红)冲洗转染的细胞。用依地酸分离细胞,并加入HBSS。在200g离心该混合物10分钟,在4℃让细胞沉淀。将沉淀物重悬浮于磷酸盐缓冲盐水-EDTA缓冲液(PBS;1mM EDTA;pH7.4;4℃)。4℃,用800psi氮气空腔化(Parr model 4639)裂解细胞15分钟。将此混合物在4℃、1000g离心10分钟。将上清液在4℃、100,000离心60分钟。将沉淀物重悬浮成1mg蛋白质/ml TME缓冲液(50mMTris;10mM MgCl2;1mM EDTA;pH6.0;4℃),用Pierce BCA蛋白质试剂盒确定蛋白质的水平。用Kinematica POLYTRON(购自KINEMATICAAG,Luzernerstrasse147A CH-6014 Littau,Switzerland)混合此匀浆10秒。然后将此膜制剂储藏于-80℃直到试验使用时冻融。
以96孔形式进行受体竞争性结合试验。各孔含有100g hFP膜、5mM(3H)PGF2和各种竞争化合物,总量为200L。将这些板在23℃培养1小时。用PackardFiltermate 196采集装置通过用TME缓冲液预湿的Packard UNIFILTERGF/B滤器(购自Packard Instrument Co.,Inc.of Downers Grove Illinois)的快速过滤终止培养。用TME缓冲液冲洗滤器4次。将Packard Microscint 20(一种高效液态闪烁混合物)加到滤板孔中,在计数前让这些平板保持在室温3小时。用Packard TOPCOUNT微板闪烁计数器(同样购自Packard Instrument Co.,Inc)进行这些平板的读数。
参考例2-毛发生长终期的转化试验
用毛发生长终期的转化试验测试前列腺素对毛发生长的潜力。毛发生长终期转化试验测定前列腺素将处于毛发生长周期静止阶段(“毛发生长终期”)的小鼠转变到毛发生长周期的生长阶段(“毛发生长初期”)的潜力。
不希望束缚于理论,毛发生长周期有3个主要阶段:毛发生长初期、毛发生长中期和毛发生长终期。据信,在约40天龄-75天龄、毛发生长同步化的C3H小鼠(Harlan Sprague Dawley,Inc.,Indianapolis,IN)中,毛发生长终期较长。据信,在75天龄后毛发生长就不再同步化。用约40天龄的、暗色毛(褐色或黑色)的小鼠进行毛发生长试验,在毛发(毛)的生长过程中发生黑素形成,在此过程中评估毛发生长刺激剂的局部施用。本文用毛发生长终期的转化试验通过测定黑素形成筛选有潜在毛发生长的前列腺素。
使用3组44天龄的C3H小鼠:载体对照组、阳性对照组和测试前列腺素组,其中对测试前列腺素组施用本发明方法所用的前列腺素。试验的长度为24天,其中15天为处理天(处理从星期一到星期五进行)。第一天为处理的第一天。下表4列出了局部研究的设计。表3列处理典型剂量浓度,当然本领域技术人员易理解这些浓度是可以改变的。
表4-试验参数
组号 | 动物编号 | 化合物 | 浓度 | 施用剂量 | 研究长度 |
1 | 1-10 | 测试化合物 | 用载体**配制成0.01% | 400μl局部 | 26天 |
2 | 11-20 | 阳性对照(T3)* | 用载体**配制成0.01% | 400μ1局部 | 26天 |
3 | 21-30 | 载体** | N/A | 400μl局部 | 26天 |
*T3是3,5,3’-三碘甲腺原氨酸
**载体是60%乙醇、20%丙二醇和20%异山梨酸二甲酯(购自Sigma ChemicalCo.,St.Louis,MO)。
从星期一到星期五,在小鼠的下背(尾巴基部到下肋骨)局部处理小鼠。用移液器和吸头将400μl送递到每只动物的背部。边推开小鼠身上的皮毛边施用400μl试剂,让其到达皮肤。
每次向小鼠进行局部处理时,对每只动物处理区域的皮肤进行目测打分,分级为0-4。当小鼠从毛发生长终期向毛发生长初期转化时,其皮肤的颜色会变得更青黑。如表5所示,0-4的分级表示目测观察到的皮肤从白色到青黑色的变化。
表5-评分标准
目测观察 | 分级 |
白色皮肤颜色 | 0 |
皮肤为淡灰色(表明毛发生长初期开始) | 1 |
出现蓝色斑点 | 2 |
蓝色斑点聚集形成一个大的蓝色区域 | 3 |
皮肤呈深蓝色(接近黑色),其覆盖绝大部分处理的区域(表明小鼠处于完全毛发生长初期) | 4 |
参考例3-卵巢被切除的大鼠试验
可方便地用设计为测试前列腺素增加骨量、骨质或密度的能力的试验,确定前列腺素的骨活性。这种试验的一个实例为卵巢被切除的大鼠试验。
在卵巢被切除的大鼠试验中,切除6个月龄的大鼠卵巢,老化2个月,然后每天皮下施用前列腺素一次。完成该研究后,用双能X-射线吸收仪(DXA)或外周定量计算的分层X射线照相术(pQCT)、或微型计算的分层X射线照相术(mCT)确定骨质和/或密度。或者,可以用静态和动态组织形态测定法确定骨量或形成的增加。
参考例4-用于青光眼的药理活性的试验
用设计成测试目标化合物降低眼内压能力的试验确定对青光眼的药理活性。在如下参考文献中描述了这些试验的实例:C.liljebris,G.Selen,B.Resul,J.Sternschantz,和U.Hacksell,“17-苯基-18,19,20-三去前列腺素F2α异丙酯:潜在的抗青光眼药”,Journal of Medicinal Chemistry,第38卷,第2号(1995),第289-304页。
实施例1
制备局部施用的组合物,其包含:
成分 | 1-1 | 1-2 |
前列腺素(wt%) | 0.42 | 1.14 |
PGF的IC50(nM) | 42 | 114 |
乙醇(wt%) | 59.74 | 59.32 |
丙二醇(wt%) | 19.92 | 19.77 |
异山梨酸二甲酯(wt%) | 19.92 | 19.77 |
局部用的组合物中的前列腺素如下:
用本发明的方法治疗患男性型脱发的男性对象。具体说,每天将上述一种组合物局部施用于对象引发毛发生长,持续6周。
实施例2
按Dowton等人,“脂质体组合物对局部送递胶囊化的环孢菌素A的影响:I.用无毛小鼠皮肤进行的体外研究”,S.T.P.Pharma Science,第3卷,第404-407页(1993)所述的方法,用PGF替代环孢菌素A并用NOVASOME1(购自Micro-Pak,Inc.,of Wilmington,Delaware)(用于非离子的脂质体制剂),制备局部施用的组合物。
用上述组合物治疗患男性型脱发的男性对象。具体说,每天将上述组合物局部施用于对象,持续6周。
实施例3
制备包含以下成分的香波:
Ex.3-1 | Ex.3-2 | Ex.3-3 | Ex.3-4 | |
成分 |
月桂基硫酸铵 | 11.5% | 11.5% | 9.5% | 7.5% |
聚氧乙烯月桂基醚硫酸铵 | 4% | 3% | 2% | 2% |
椰油酰胺MEA | 2% | 2% | 2% | 2% |
乙二醇双硬脂酸酯 | 2% | 2% | 2% | 2% |
鲸腊醇 | 2% | 2% | 2% | 2% |
十八烷醇 | 1.2% | 1.2% | 1.2% | 1.2% |
甘油 | 1% | 1% | 1% | 1% |
聚季铵(polyqaternium)10 | 0.5% | 0.25% | - | - |
聚季铵24 | - | - | 0.5% | 0.25% |
氯化钠 | 0.1% | 0.1% | 0.1% | 0.1% |
棉酸酯(Cottonate)脂肪酸的蔗糖聚酯 | 3% | 3% | - | - |
榆树酸酯(behenate)脂肪酸的蔗糖聚酯 | 2% | 3% | - | - |
聚二甲基硅氧烷 | - | - | 3% | 2% |
椰油剂氨基丙基甜菜碱 | - | 1% | 3% | 3% |
月桂基二甲基氧化胺 | 1.5% | 1.5% | 1.5% | 1.5% |
癸基多聚葡萄糖 | - | - | 1% | 1% |
DMDM乙内酰脲 | 0.15% | 0.15% | 0.15% | 0.15% |
IC50为42nM的PGF | - | 0.42% | 0.42% | - |
IC50为114nM的PGF | 0.11% | - | - | 0.1 1% |
地诺米尔 | 3% | 2% | ||
苯氧乙醇 | 0.5% | 0.5% | 0.5% | 0.5% |
香精 | 0.5% | 0.5% | 0.5% | 0.5% |
水 | q.s. | q.s. | q.s. | q.s. |
前列腺素与实施例1的相同。
用本发明的方法治疗患男性型脱发的人对象。具体说,对象每天使用上述香波,共12周。
实施例4制备睫毛膏组合物。该组合物包含:
成分 | %w/w |
水,去离子的,SUP | q.s. |
微粒型的黑1080 | 10.000 |
单硬脂酸甘油酯(2400型) | 8.500 |
C18-36酸三甘油酯 | 5.500 |
三压硬脂酸,液态 | 4.000 |
乙醇SD40-B,190验证/系列号 | 4.000 |
蜂蜡白,鳞片状 | 3.250 |
虫胶,NF | 3.000 |
卵磷脂,粒状(6450型) | 2.500 |
三乙醇胺99%-罐装 | 2.470 |
石蜡 | 2.250 |
石蜡118/125 | 2.250 |
巴西棕榈蜡,NF | 2.000 |
鲸腊基磷酸钾 | 1.000 |
苯氧乙醇 | 0.800 |
油酸,NF | 0.750 |
DL-泛醇 | 0.350 |
PVP/VA共聚物 | 0.250 |
对羟基苯甲酸甲酯,NF | 0.200 |
二偶氮利定脲 | 0.200 |
二甲基硅油 | 0.200 |
对羟基苯甲酸乙酯,NF | 0.150 |
季戊四醇氢化的松香 | 0.150 |
对羟基苯甲酸丙酯,NF | 0.100 |
EDTA三钠 | 0.100 |
IC50为114nM的前列腺素 | 0.114 |
该前列腺素与实施例1-2所用的相同。
女性对象每天使用此组合物。具体说,将上述组合物局部施用于对象6周,使睫毛变黑变密。
实施例5
用常规方法,如混合和直接压制,制备片剂形式的药物组合物,其成分如下:
成分 量(mg/片剂)
前列腺素 5
微晶纤维素 100
羟基乙酸淀粉钠 30
硬脂酸镁 3
本实施例的前列腺素与实施例1-2所用的相同。
当每天口服一次时,上述组合物能基本增加患骨质疏松患者的骨量。
实施例6
用常规方法制备液态形式的药物组合物,其成分如下:
成分 量
前列腺素 1mg
磷酸盐缓冲的生理盐水 10ml
对羟基苯甲酸甲酯 0.05ml
本实施例的前列腺素与实施例1-2所用的相同。
将1.0ml上述组合物每天一次皮下施用,上述组合物基本能增加患骨质疏松患者的骨量。
实施例7
用常规方法制备用于降低眼内压的局部用药物组合物,其成分如下:
成分 量(wt%)
前列腺素 0.004
葡聚糖70 0.1
羟丙基甲基纤维素 0.3
氯化钠 0.77
氯化钾 0.12
EDTA二钠(乙二胺四乙酸二钠) 0.05
苯扎氯铵 0.01
HCl和/或NaOH pH7.2-7.5
纯化水 q.s.至100%
本实施例的前列腺素与实施例1-2所用的相同。
每天一次使用上述组合物,6-12周,能降低青光眼患者的眼内压。
发明效果
本发明的组合物和方法能向需要这种治疗的对提供毛发生长及外观美感的益处。本发明的组合物和方法还能向需要这种治疗的患者提供治疗骨病和降低眼内压的药物益处。
Claims (9)
1.一种治疗脱发的组合物,其特征在于,所述的组合物包含:
A)活性成分,选自:前列腺素的2-脱羧基-2-磷酸亚基衍生物;2-脱羧基-2-磷酸亚基衍生物的光学异构体、非对映体和对映体;2-脱羧基-2-磷酸亚基衍生物的药学上可接受的盐;2-脱羧基-2-磷酸亚基衍生物的可生物水解的酰胺、酯和酰亚胺;和它们的组合;和
B)载体。
2.如权利要求1所述的组合物,其特征在于,所述的2-脱羧基-2-磷酸亚基衍生物选自如下结构:
式I 式II和
R2选自:氢原子、单价烃基、取代的单价烃基、杂基团、取代的杂基团、碳环基团、取代的碳环基团、杂环基团、取代的杂环基团、芳基、取代的芳基、杂芳基和取代的杂芳基;
R3选自:氧原子、硫原子和NH;
R4选自:氧原子和硫原子;
R5是选自以下的二价基团:烃基、取代的烃基、杂基团和取代的杂基团;条件是当R5是杂基团时,R5仅包含一个选自氧、氮和硫的杂原子;
键a选自单键、反式双键和三键;
R6是选自-C(O)-和-C(R9)(OR9)-的二价基团;
R7是选自呈式-(CR9(R9))p-X-(CR9(R9))q的二价基团,其中p为0-3的整数,q为0-3的整数,X选自:氧原子、二价烃基、硫原子、SO、SO2和NR9;
R8选自:甲基、碳环基团、取代的碳环基团、杂环基团、取代的杂环基团、芳基、取代的芳基、杂芳基、取代的杂芳基;
R9是氢原子或低级单价烃基;和
R10是氢原子或低级单价烃基。
3.如权利要求1或2所述的组合物,其特征在于,所述的R1选自:氢原子、烷基、卤化的烃基、CH2CH2OH和CH2CH2CH2OH;R2选自:H、CH2CO2H、CH2C(O)NHOH、甲基、CF3、乙基、正丙基、异丙基、CH2CH2OH、CH2CH(OH)CH2OH、苄基和叔丁基;R3选自:氧原子或NH;和R4是氧原子。
4.如权利要求1、2或3所述的组合物,其特征在于,所述的R5有1-5个成员原子。
5.如权利要求1、2、3或4所述的组合物,其特征在于,所述的R6是-C(H)(OH)-;X选自:单键、反式双键、三键、氧原子、硫原子和NR9;和R8选自:单环碳环基团、取代的单环碳环基团、单杂环基团、取代的单杂环基团、芳基、取代的芳基、杂芳基和取代的杂芳基。
6.如权利要求1、2、3、4或5所述的组合物,其特征在于,所述的R9是氢原子和R10为氢原子。
7.如权利要求1、2、3、4、5或6所述的组合物,其特征在于,所述的成分B)包含选自以下的成分:q)乳化剂、r)推进剂、s)溶剂、t)湿润剂、u)增稠剂、v)粉末、w)香精、水、醇、芦荟胶、尿囊素、甘油、维生素A和E油、矿物油、丙二醇、聚丙二醇-2肉豆寇基丙酸酯、异山梨酸二甲酯和它们的组合。
8.如权利要求1、2、3、4、5、6或7所述的组合物,其特征在于,所述的组合物还包含成分C)活性增强剂,所述的成分C)选自i)毛发生长刺激剂、ii)渗透增强剂和它们的组合。
9.如权利要求1、2、3、4、5、6、7或8所述的组合物,其特征在于,所述的成分A)的存在量为:IC50×10-2≥成分A)的%≥IC50×10-3,其中成分A)的IC50以毫微摩尔单位表示;所述的成分C)的存在量为1-20%,且加入足够量的成分B)使成分A)、B)和C)的总量为100%。
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2001
- 2001-01-31 US US09/774,558 patent/US20020013294A1/en not_active Abandoned
- 2001-03-30 WO PCT/US2001/010369 patent/WO2001074314A2/en active IP Right Grant
- 2001-03-30 AT AT01926505T patent/ATE311849T1/de not_active IP Right Cessation
- 2001-03-30 AU AU2001253038A patent/AU2001253038A1/en not_active Abandoned
- 2001-03-30 EP EP01926505A patent/EP1267806B1/en not_active Expired - Lifetime
- 2001-03-30 DE DE60115618T patent/DE60115618T2/de not_active Expired - Fee Related
- 2001-03-30 CN CN01807354A patent/CN1419438A/zh active Pending
- 2001-03-30 CA CA002401888A patent/CA2401888A1/en not_active Abandoned
- 2001-03-30 JP JP2001572060A patent/JP2003528898A/ja active Pending
- 2001-03-30 ES ES01926505T patent/ES2254401T3/es not_active Expired - Lifetime
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2006
- 2006-06-28 US US11/476,246 patent/US20060247214A1/en not_active Abandoned
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2013
- 2013-12-06 US US14/099,756 patent/US9346837B2/en not_active Expired - Lifetime
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2016
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US20020013294A1 (en) | 2002-01-31 |
US20060247214A1 (en) | 2006-11-02 |
AU2001253038A1 (en) | 2001-10-15 |
WO2001074314A2 (en) | 2001-10-11 |
DE60115618T2 (de) | 2006-06-22 |
EP1267806B1 (en) | 2005-12-07 |
DE60115618D1 (de) | 2006-01-12 |
CA2401888A1 (en) | 2001-10-11 |
US20160220467A1 (en) | 2016-08-04 |
US9346837B2 (en) | 2016-05-24 |
ATE311849T1 (de) | 2005-12-15 |
US9675539B2 (en) | 2017-06-13 |
US9877908B2 (en) | 2018-01-30 |
EP1267806A2 (en) | 2003-01-02 |
US20140099268A1 (en) | 2014-04-10 |
JP2003528898A (ja) | 2003-09-30 |
US20170239160A1 (en) | 2017-08-24 |
WO2001074314A3 (en) | 2002-02-21 |
ES2254401T3 (es) | 2006-06-16 |
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