CN1547474A - 含选择性环加氧酶-2抑制剂及一元醇的可渗透皮肤的组合物 - Google Patents
含选择性环加氧酶-2抑制剂及一元醇的可渗透皮肤的组合物 Download PDFInfo
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- CN1547474A CN1547474A CNA028149467A CN02814946A CN1547474A CN 1547474 A CN1547474 A CN 1547474A CN A028149467 A CNA028149467 A CN A028149467A CN 02814946 A CN02814946 A CN 02814946A CN 1547474 A CN1547474 A CN 1547474A
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Abstract
一种经皮给药的药物组合物,所述组合物包括至少一种溶于药学上可接受的载体(所述载体含有低分子量一元醇)中的选择性环加氧酶-2(COX-2)抑制药物或其前药,且其治疗药物皮肤渗透速率至少等于将所述治疗药物溶于70%乙醇水溶液中的参比溶液所提供的皮肤渗透速率。一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或感染部位的方法,所述方法包括将此种组合物局部给药到所述患者的皮肤,优选在与疼痛和/或感染部位叠加或相邻的区域。一种对患有由COX-2所介导的疾病的患者实施全身治疗的方法,所述方法包括将所述组合物经皮给药,优选将所述组合物与所述患者的不大于大约400cm2的皮肤区域相接触。
Description
发明领域
本发明涉及含有选择性环加氧酶-2(COX-2)抑制药物的药物组合物,具体涉及适合于对皮肤给药以获得局部或全身治疗效果的这类组合物。本发明还涉及制备这类组合物的方法,涉及包括将这类组合物给药到有需要的患者的皮肤的治疗方法。
发明背景
环加氧酶(COX)的抑制作用据信至少是非甾体抗炎药(NSAID)通过抑制前列腺素合成而发挥其特征性抗炎、退热和镇痛效应的主要机制。治疗药物量的常规NSAID,例如酮咯酸、双氯芬酸、萘普生及其盐既抑制组成型表达的COX-1,又抑制环加氧酶的炎症相关或诱导型COX-2同种型。COX-1产生正常细胞功能所需的前列腺素,因此其抑制作用显然可解释与应用常规NSAID有关的某些不良副作用。选择性抑制COX-2与完全抑制COX-1不同,其获得抗炎、退热、镇痛和其它有用的治疗效果的同时,最小化或消除所述不良副作用。因此选择性COX-2抑制药物代表本领域内一大进步。
已报导具有治疗和/或预防作用的选择性COX-2抑制效果的多种化合物,且已公开这些化合物在治疗或预防特定COX-2所介导的疾病或此类常规疾病中的用途。这些化合物中大部分为如美国专利号5,466,823(Talley等)中所报导的取代的吡唑基苯磺酰胺,包括例如化合物4-[5-(4-甲苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺(在本文中也称作塞来考昔(I))和化合物4-[5-(3-氟-4-甲氧基苯基)-3-二氟甲基]-1H-吡唑-1-基]苯磺酰胺(在本文中也称作地拉考昔(II))。
所报导的具有治疗和/或预防作用的选择性COX-2抑制效果的其它化合物有如在美国专利号5,633,272(Talley等)中报导的取代的异噁唑基苯磺酰胺,包括例如化合物4-[5-甲基-3-苯基异噁唑-4-基]苯磺酰胺(在本文中也称作伐地考昔(III))。
所报导的具有治疗和/或预防作用的选择性COX-2抑制效果的其它化合物有如美国专利号5,474,995(Ducharme等)中报导的取代的(甲磺酰)苯基呋喃酮,包括例如化合物3-苯基-4-[4-(甲磺酰基)苯基]-5H-呋喃-2-酮(在本文中也称作罗非考昔(IV))。
美国专利号5,981,576(Belley等)公开了据说可用作选择性COX-2抑制药物的另一系列的(甲磺酰基)苯基呋喃酮,包括3-(1-环丙基甲氧基)-5,5-二甲基-4-[4-(甲磺酰基)苯基]-5H-呋喃-2-酮和3-(1-环丙基乙氧基)-5,5-二甲基-4-[4-(甲磺酰基)苯基]-5H-呋喃-2-酮。
美国专利号5,861,419(Dube等)公开了据说可用作选择性COX-2抑制药物的取代的吡啶,包括例如化合物5-氯-3-(4-甲磺酰基)苯基-2-(2-甲基-5-吡啶基)吡啶(在本文中也称作艾托考昔(V)))。
欧洲专利申请号0 863 134公开了据说可用作选择性COX-2抑制药物的化合物2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮。国际专利公开号WO 99/11605公开了据说为COX-2的选择性抑制剂的5-烷基-2-芳氨基苯乙酸及其衍生物,包括化合物5-甲基-2-(2’-氯-6’-氟苯胺)苯乙酸及其盐。
美国专利号6,034,256(Carter等)公开了一系列据说可用作选择性COX-2抑制药物的苯并吡喃,包括化合物(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸(VI)。
国际专利公开号WO 00/24719公开了据说可用作选择性COX-2抑制药物的取代的哒嗪酮,包括化合物2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮。
选择性COX-2抑制药物已用多种方式进行配制,主要被配制成口服给药剂型。然而,例如在部分上述专利中均建议此类药物采用局部给药。
上述美国专利号5,466,823和专利号5,633,272公开了其主题化合物(包括塞来考昔和伐地考昔)可局部给药。在这些专利中还公开了所述化合物可溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油和苄醇之中。
上述美国专利号5,474,995公开了其主题化合物(包括罗非考昔)可以配制成用于局部给药的乳膏剂、软膏剂、凝胶剂、溶液剂或混悬剂。上述美国专利号5,861,419同样公开了其主题化合物(包括艾托考昔)可制剂成用于局部给药的乳膏剂、软膏剂、凝胶剂、溶液剂或混悬剂,还建议局部制剂通常可包括药物载体、助溶剂、乳化剂、渗透促进剂、防腐剂体系和润滑剂。
上述美国专利号6,034,256公开了其主题化合物(包括(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸及其盐)可以局部软膏剂或乳膏剂的形式使用,以疗外部组织(例如皮肤)发炎。
美国专利号5,932,598(Talley等)公开了一类选择性COX-2抑制药物的水溶性前药,包括化合物N-[[4-(5-甲基-3-苯基异噁唑-4-基)苯基]磺酰基]丙酰胺(在本文中亦称作帕瑞考昔(VII))及其盐,例如钠盐(在本文中亦称作帕瑞考昔钠)。在给药到患者后,帕瑞考昔转化为基本上不溶于水的选择性COX-2抑制药物伐地考昔。帕瑞考昔本身对COX-1和COX-2两者均体现出微弱的体外抑制活性,而伐地考昔(II)对COX-2有强的抑制活性,但对COX-1的抑制性较弱。
由于帕瑞考昔,特别是盐例如帕瑞考昔钠的高水溶性,与大多数选择性COX-2抑制药物如塞来考昔和伐地考昔相比,已有提议将前药帕瑞考昔经肠胃外给药。参见Talley等(2000),
J.Med.Chem.43,1661-1663。
上述美国专利号5,932,598和专利号6,034,256公开了其主题化合物可以局部软膏剂或乳膏剂施用,以治疗外部组织(例如皮肤)发炎。其中还公开了用于此类目的的乳膏基的水相可包含至少30%重量的多羟基醇,如丙二醇、丁-1,3-二醇、甘露糖醇、山梨糖醇、甘油、聚乙二醇及其混合物,并公开了所述局部制剂可包含皮肤渗透促进剂如二甲亚砜。其中还公开了所述主题化合物可用经皮仪器给药,例如采用贮库和多孔薄膜型贴剂或固体基质类贴剂。
美国专利号5,607,690(Akizawa)公开了含有NSAID双氯酚酸(羟乙基吡咯烷盐形式)的外用抗炎和止痛膏药。据报导,与其它类似的含有双氯酚酸钠的制剂相比,这种制剂具有增强的皮肤渗透力。该专利中提到双氯酚酸钠皮肤渗透力低是由于该盐在水中溶解度低的缘故。
国际专利公开号WO 99/62557公开了用于经皮给药的含有吸收促进剂的NSAID组合物,所述吸收促进剂主要由二甘醇醚和脱水山梨糖醇酯,以及粘性基质组成。
国际专利公开号WO 00/41538公开了用于经皮给药的含有两种或多种具有不同官能团的丙烯酸基聚合物的混合物的药物组合物。
国际专利公开号WO 00/51575公开了包含带皮肤渗透促进剂的NSAID组合物的经皮装置,其中皮肤渗透促进剂选自脂肪醇(例如油醇)和脂肪酸酯(例如甘油单油酸酯、肉豆蔻酸异丙酯)。
国际专利公开号WO 97/29735公开了含有皮肤渗透促进剂的经皮药物输送体系,所述皮肤渗透促进剂为酯类防晒剂,优选对氨基苯甲酸、二甲基对氨基苯甲酸、肉桂酸、甲氧基肉桂酸或水杨酸的长链烷基酯,例如二甲基对氨基苯甲酸辛酯或水杨酸辛酯。
因此,将NSAID,更具体地讲,将选择性COX-2抑制药物对皮肤给药,以达到局部或全身治疗效果目的已在本领域引起广泛关注。但是,在本领域仍需要一种能使所述药物具有足够的皮肤渗透率以达此效果的选择性COX-2抑制药物组合物。
当需要获得全身治疗效果时,所述组合物必须能通过皮肤渗透每天输送一定剂量的药物,该剂量至少等于当将所述药物经口或经肠胃外给药时每天的最小治疗有效剂量。此外,既不实用也不方便将某种药物涂布在大面积皮肤之上以达到此结果;通常最大涂布面积为约400cm2,但优选治疗更小面积的皮肤。
例如,对塞来考昔而言,成年人口服给药常用最小每日剂量为大约200mg。因此对塞来考昔来说,为达到最小每日剂量,在400cm2的面积之上的最小渗透速率必须为500μg/cm2·天。通常最好治疗远小于400cm2的面积,因此需求的最小渗透速率甚至需高于500μg/cm2·天。即使只需要局部给药时,高的渗透速率也很重要,因为能局部涂布的皮肤面积通常不大于约140cm2,而常常要小很多。实际中,即使对大多数有疗效的选择性COX-2抑制药物而言,大多数情况下要求至少大约10μg/cm2·天的渗透速率。
因此不管是否需要全身或局部的治疗效果,当对不大于大约400cm2的皮肤面积给药时,仍然难于配制出具有治疗效果的选择性COX-2抑制药物组合物。
发明概述
本发明提供一种经皮给药的药物组合物,所述组合物含有治疗有效量的、溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中:(a)所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,和(b)所述组合物的试样所提供的治疗药物的皮肤渗透速率至少等于将所述治疗药物溶解于70%乙醇水溶液中得到的参比溶液所提供的渗透速率。
本文中“参比溶液”为治疗药物浓度与试样的治疗药物浓度相同的溶液,该浓度最高可达该治疗药物在70%乙醇水溶液中的溶解度极限。这种参比溶液本身也是本发明的一种实施方案。
优选所述试样提供的皮肤渗透速率不小于大约10μg/cm2·天。
本发明还提供一种经皮给药的药物组合物,所述组合物含有溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,且其在所述组合物中的浓度为大约12.5至大约400mg/ml。
本发明还提供一种经皮给药的药物组合物,所述组合物含有溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中所述治疗药物含有伐地考昔和/或其前药,且其在所述组合物中的浓度为大约0.5到大约400mg/ml。
在本发明的一种优选组合物中,所述载体还含有皮肤渗透促进剂。
本发明还提供一种将选择性COX-2抑制药物靶向输送到患者的疼痛和/或发炎部位的方法,所述方法包括将本发明所提供的药物组合物局部给药到所述患者的皮肤表面,优选在与疼痛和/或发炎部位重叠或相邻的区域。
本发明还提供了一种对患有由COX-2介导的疾病的患者进行全身治疗的方法,所述方法包括将本发明所提供的药物组合物经皮给药,优选将所述组合物与所述患者的皮肤接触,其接触面积不大于大约400cm2。
发明详述
本发明的经皮给药的药物组合物含有溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇。例如,所述治疗药物可为不饱和、饱和或过饱和浓度,只要所述治疗药物在贮存于密闭容器内时,在标准环境温度下,在制备至使用期间保持溶解状态达一段可接受的时间即可。
“一段可接受的时间”由环境所决定,但通常为至少大约5天,优选至少大约30天,更优选至少大约6个月,还更优选至少大约1年,最优选至少大约2年。
除了本文中所要求的治疗药物的可溶解组分外,任选所述治疗药物还含有第二组分,所述组分以颗粒形式分散于载体之中,例如以稳定悬浮液的形式存在。所述第二组分可作为所述治疗药物的贮藏库,以保持已溶解组分基本饱和。但是,通常优选基本上所有治疗药物均以溶解形态存在。
术语“经皮给药”表示所述组合物适合于直接涂布到皮肤上,可以足够剂量吸收到皮肤内和/或渗透通过皮肤而提供局部和/或全身治疗效果。
所述治疗药物含有至少一种选择性COX-2抑制药物或其前药。可使用任何本领域所知的选择性COX-2抑制药物或前药。
本文可用的一种优选的选择性COX-2抑制药物为式(VIII)的化合物或前药或其药学上可接受的盐:
其中:
A为选自部分不饱和或不饱和杂环基和部分不饱和或不饱和碳环基团,优选选自吡唑基、呋喃酮基、异噁唑基、吡啶基、环戊烯酮基和哒嗪酮基的杂环基的取代基;
X为O、S或CH2;
n为0或1;
R1为至少一种选自杂环基、环烷基、环烯基和芳基的取代基,任选在可取代的位置被一个或多个选自烷基、卤代烷基、氰基、羧基、烷氧基羰基、羟基、羟烷基、卤代烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚磺酰基、卤基、烷氧基和烷硫基的基团取代;
R2为甲基、氨基或氨基羰基烷基;
R3为一个或多个选自氢、卤基、烷基、烯基、炔基、氧代基、氰基、羧基、氰烷基、杂环基氧基(heterocyclyoxy)、烷氧基、烷硫基、烷基羰基、环烷基、芳基、卤代烷基、杂环基、环烯基、芳烷基、杂环基烷基、酰基、烷硫基烷基、羟基烷基、烷氧基羰基、芳基羰基、芳烷基羰基、芳烯基(aralkenyl)、烷氧基烷基、芳硫基烷基、芳氧基烷基、芳烷基硫基烷基、芳烷基氧基烷基、烷氧基芳烷基氧基烷基、烷氧基羰基烷基、氨基羰基、氨基羰基烷基、烷基氨基羰基、N-芳基氨基羰基、N-烷基-N-芳基氨基羰基、烷基氨基羰基烷基、羧基烷基、烷基氨基、N-芳基氨基、N-芳烷基氨基、N-烷基-N-芳烷基氨基、N-烷基-N-芳基氨基、氨基烷基、烷基氨基烷基、N-芳基氨基烷基、N-芳烷基氨基烷基、N-烷基-N-芳烷基氨基烷基、N-烷基-N-芳基氨基烷基、芳氧基、芳烷基氧基、芳硫基、芳烷基硫基、烷基亚磺酰基、烷基磺酰基、氨基磺酰基、烷基氨基磺酰基、N-芳基氨基磺酰基、芳基磺酰基以及N-烷基-N-芳基氨基磺酰基,R3任选在可取代的位置上被一个或多个选自烷基、卤代烷基、氰基、羧基、烷氧基羰基、羟基、羟基烷基、卤代烷氧基、氨基、烷基氨基、芳基氨基、硝基、烷氧基烷基、烷基亚磺酰基、卤基、烷氧基和烷硫基的基团所取代;且
R4选自氢和卤基。
特别可用于本发明的组合物的有具有式(IX)的选择性COX-2抑制药物,或其异构体、互变异构体、药学上可接受的盐或其前药:
其中R5为甲基或氨基,R6为氢或C1-4烷基或烷氧基,X’为N或CR7,其中R7为氢或卤素,且Y和Z独立为五元到六元环上相邻的碳或氮原子,所述五元或六元环优选在一个或多个位置上被氧、卤素、甲基或卤代甲基所取代。优选所述五元或六元环为在不多于一个位置上被取代的环戊烯酮、呋喃酮、甲基吡唑、异噁唑和吡啶环。
可用于本发明组合物的还有具有式(X)的化合物,及其药学上可接受的盐:
其中x”为O、S或N-低级烷基;R8为低级卤代烷基;R9为氢或卤素;R10为氢、卤素、低级烷基、低级烷氧基或卤代烷氧基、低级芳烷基羰基、低级二烷基氨基磺酰基、低级烷基氨基磺酰基、低级芳烷基氨基磺酰基、低级杂芳烷基氨基磺酰基、5元或6元含氮杂环磺酰基;R11和R12独立为氢、卤素、低级烷基、低级烷氧基或芳基。
式(X)的特别有用的化合物为(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸。
可用于本发明组合物的还有选择性抑制COX-2的5-烷基-2-芳基氨基苯乙酸及其衍生物。此类型的特别有用的化合物为5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸及其药学上可接受的盐。
可用于本发明方法和组合物的有例如塞来考昔、地拉考昔、伐地考昔、帕瑞考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮、(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸、2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮、5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸及其盐,更优选塞来考昔、伐地考昔、帕瑞考昔及其盐、罗非考昔及艾托考昔。
在本发明的优选实施方案中,所述治疗药物含有伐地考昔和/或其前体,例如帕瑞考昔和/或其盐,如帕瑞考昔钠。
用于本发明组合物中的伐地考昔可通过任何已知方法,例如前述美国专利号5,633,272中所示的方式制备。用于本发明组合物的帕瑞考昔可通过任何已知方法,例如前述美国专利号5,932,598中所示的方式制备。其它选择性COX-2抑制药物可通过任何已知方法,包括在公开此类药物的专利申请中所示的方法(例如前述美国专利号5,466,823或美国专利号5,892,053(Zhi等)中的塞来考昔的情况,所述专利通过引用结合到本文中来)制备。
根据本发明的第一种实施方案,所述组合物的治疗药物的皮肤渗透速率至少等于溶于70%乙醇水溶液中的治疗药物的参比溶液所提供的渗透速率,优选速率不小于大约10μg/cm2·天。当在本文中指定了皮肤渗透速率或此类速率的范围时,应理解为由标准测试,例如采用人尸体皮肤的标准测试所确定的速率。
作为此类测试的一个实例,可采用在以下实施例中更具体描述的Franz扩散细胞(具有合适面积的尸体皮肤薄膜,例如直径20mm的圆片)和合适的受体流体。本领域的熟练人员能够选择合适的受体流体,但本发明优选的受体流体为1%吐温80溶液和6%聚乙二醇(20)油基醚(oleth-20)溶液。保持受体流体在合适的温度下,优选大约为活人皮肤的温度。将所述膜定位以使其内表面(即与表皮面相反的表面)与受体流体相接触。从受体流体内除去气泡,然后将其与所述膜平衡30分钟。将组合物的试样与所述膜的表皮面接触,放置一段预定的时间,例如24小时。在此期间内分阶段,和/或在此期间结束时,用合适的分析方法(例如高效液相色谱(HPLC))确定受体流体内的一个或多个选择性COX-2抑制药物的浓度。该浓度为在测试期间内已经渗透进皮肤膜内的一种或几种药物的量的度量,可用于计算药物的皮肤渗透速率,单位为例如μg/cm2·天或μg/cm2·小时。
应理解的是来源不同的各种皮肤膜的渗透率明显不同。因此透过此类膜的绝对渗透速率的意义不如与参考组合物进行对比得到的相对渗透速率。本文采用的标准参比组合物为溶于70%乙醇水溶液中的治疗药物溶液。发现其本身即为本发明的一个实施方案,此参比组合物通常提供的皮肤渗透速率为大约10μg/cm2·天或更高,尤其是当所述治疗药物在70%乙醇水溶液中基本上为饱和溶液时更是如此。但是,如果在采用某种皮肤膜的测试中某一组合物提供的皮肤渗透速率小于10μg/cm2·天,只要该速率至少等于采用来源相同的皮肤膜的参比组合物作对比测试所表现的皮肤渗透速率,便不能将其排除出本发明的范围。
优选的皮肤渗透速率某种程度上取决于所选择的药物或前药的治疗效力。例如,对需要相对较高的血液浓度以达到治疗效果的塞来考昔而言,皮肤渗透速率优选不小于大约25μg/cm2·天,更优选不小于大约50μg/cm2·天,还更优选不小于大约75μg/cm2·天,最优选不小于大约100μg/cm2·天。
根据本发明的第二种实施方案,所述组合物中的治疗药物含有至少一种选择性COX-2抑制药物或其前药,在所述组合物中的浓度为大约12.5到大约400mg/ml。低于此浓度范围,例如在10mg/ml(或大约1%重量)的浓度下,对大多数选择性COX-2抑制药物而言,即使有渗透促进剂存在,其皮肤渗透速率都可能太小而达不到治疗效果。高于此浓度范围,例如在大约40%重量(取决于所述组合物的比重,可为大约420到大约500mg/ml的浓度)的浓度下,很可能非常难将大多数选择性COX-2抑制药物、前药或其盐溶解。
优选在此实施方案中,所述治疗药物的浓度为大约12.5到大约375mg/ml,更优选为大约12.5到大约250mg/ml,最优选大约12.5到大约125mg/ml。本领域的熟练人员可以理解,要求较高剂量的药物(例如塞来考昔)的最佳浓度可能高于要求较低剂量的药物(例如伐地考昔)。
本发明的用于经皮涂布而将药物全身输送的塞来考昔组合物优选含有的塞来考昔浓度达到日剂量为大约100mg到大约400mg,例如大约250mg到大约350mg,如大约275mg到大约325mg。优选该浓度使得将所述组合物每天涂布一至四次,涂布皮肤面积最高可达大约400cm2时可达到该剂量。
本发明的用于经皮涂布而将药物全身输送的伐地考昔组合物优选含有的伐地考昔浓度达到日剂量为大约10mg到大约100mg,优选大约20mg到大约80mg,例如大约30mg到大约40mg,如大约32mg到大约38mg,更特别是大约34mg到大约36mg。优选该浓度使得将所述组合物每天涂布一至四次,优选一到两次,涂布皮肤面积最高可达大约400cm2,优选大约1cm2至大约100cm2时可达到该剂量。
本发明的用于经皮涂布而将药物全身输送的帕瑞考昔组合物优选含有的帕瑞考昔浓度达到日剂量为大约10mg到大约100mg,优选大约30mg到大约80mg,例如大约45mg到大约75mg,如大约50mg到大约70mg。优选该浓度使得将所述组合物每天涂布一至四次,优选一到两次,涂布皮肤面积最高可达大约400cm2,优选大约1cm2至大约100cm2时可达到该剂量。
对其它选择性COX-2抑制药物和前药而言,所述浓度应该使提供的日剂量在已知的此类药物和前药的具有疗效的范围之内。优选日剂量在提供等同于刚刚提及的塞来考昔、伐地考昔或帕瑞考昔的日剂量范围的疗效的范围之内。
根据本发明的第三种实施方案,所述组合物中的治疗药物含有伐地考昔和/或其前药,且在所述组合物中的浓度为大约0.5到大约400mg/ml,优选大约0.5到大约125mg/ml。在该实施方案中的治疗药物的浓度优选为大约0.05%重量到大约10%重量,更优选大约0.5%重量到大约5%重量,特别当将所述组合物用于靶向给药到与皮肤表面的疼痛和/或发炎部位相叠加或相邻的部位时更是如此。
在第三种实施方案中,优选的前药为帕瑞考昔或其盐,例如帕瑞考昔钠。
或者,根据第三种实施方案,所述治疗药物可单独为伐地考昔或伐地考昔与另一药物的联合药物。
现已意外发现同时含有帕瑞考昔或其盐以及低水溶解度的选择性COX-2抑制药物(例如塞来考昔或伐地考昔)的组合物,与不含帕瑞考昔的组合物相比,低水溶解度药物的皮肤渗透速率得以极大提高。因此,在一种具体实施方案中,前述组合物中的治疗药物含有帕瑞考昔或其盐,以及低水溶解度的选择性COX-2抑制药物。根据该实施方案,所述低水溶解度的药物可例如选自塞来考昔、地拉考昔、伐地考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮和2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮。
根据以上任何一种实施方案,优选所述治疗药物完全溶解于载体之中。
所述载体含有治疗药物的药学上可接受的溶剂。对由一种或两种水溶性药物或前药(例如帕瑞考昔钠)组成的治疗药物而言,水为优选的溶剂。对低水溶解度的药物或前药而言,需要一种或多种药学上可接受的有机溶剂。此类溶剂例如可选自单-、二-和多羟基醇,例如包括乙醇、异丙醇、正丁醇、1,3-丁二醇、丙二醇、甘油、glycofurol、肉豆寇醇、油醇和聚乙二醇(PEG)(例如,平均分子量为大约200到大约800的PEG)。合适的PEG包括PEG-200、PEG-350、PEG-400、PEG-540和PEG-600,优选PEG-400。上述某些溶剂另外还可用作皮肤渗透促进剂。
或者或另外,可采用药学上可接受的二醇醚溶剂,例如符合式(XI)的溶剂:
R1-O-((CH2)mO)n-R2 (XI)
其中R1和R2独立为氢或C1-6烷基、C1-6烯基、苯基或苄基,但R1和R2不同时为氢;m为2到大约5的整数;n为1到大约20的整数。优选R1和R2中有一个为C1-4烷基,另一个为氢或C1-4烷基;更优选R1和R2中至少有一个为甲基或乙基。优选m为2。优选n为1到大约4的整数,更优选为2。
用于本发明的组合物中的乙二醇醚通常的分子量为大约75到大约1000,优选大约75到大约500,更优选大约100到大约300。重要的是,此类乙二醇醚必须在药学上可接受,且必须满足本文所有其它条件。
可用于本发明组合物的乙二醇和乙二醇醚的非限定性实例包括乙二醇单甲醚、乙二醇二甲醚、乙二醇单乙醚、乙二醇二乙醚、乙二醇单丁醚、乙二醇二丁醚、乙二醇单苯醚、乙二醇单苄醚、乙二醇丁基·苯基醚、乙二醇萜品基醚、二甘醇单甲醚、二甘醇二甲醚、二甘醇单乙醚、二甘醇二乙醚、二甘醇二乙烯基醚、乙二醇单丁醚、二甘醇二丁醚、二甘醇单异丁醚、三甘醇二甲醚、三甘醇单乙醚、三甘醇单丁醚、四甘醇二甲醚及其混合物。例如参见Flick(1998):Industrial Solvents Handbook,第5版,Noyes Data Corporation,Westwood,NJ。
本发明优选的乙二醇醚溶剂为二甘醇单乙醚,在本领域有时称作DGME或乙氧基二甘醇。例如可从GattefosséCorporation商标为TranscutolTM获得。
根据本发明,至少一种溶剂或皮肤渗透促进剂为低分子量的一元醇。在上下文中“低分子量”表示与肉豆寇醇相比分子量低很多。优选的低分子量一元醇为C2-6一元醇,例如乙醇、异丙醇、正丁醇或DGME。
现已意外发现将乙醇-水混合物作选择性COX-2抑制药物例如塞来考昔或伐地考昔的溶剂通常得到的皮肤渗透率比单独用乙醇作溶剂更大。乙醇对水的合适重量比为大约50/50到大约90/10。最佳比例为大约65/35到大约75/25,例如70/30。因此单独由乙醇组成载体的组合物通常不能满足本发明的皮肤渗透速率至少等于将所述治疗药物溶于70%乙醇水溶液中得到的参比溶液的皮肤渗透速率的标准。
本发明的组合物任选含有一种或多种药学上可接受的助溶剂。适合用于本发明组合物中的助溶剂的非限定性实例包括任何前面所列溶剂;N-甲基-2-吡咯烷酮(NMP);甘油三油酸酯和甘油三亚油酸酯,例如大豆油;甘油三辛酸酯/甘油三癸酸酯,例如Huls的MiglyolTM812;甘油单-和二-辛酸/甘油单-和二-癸酸酯,例如Abiter的CapmulTMMCM;苯甲酸苄酯;邻苯二甲酸二乙酯;三醋精;甘油聚氧化乙烯辛酸/癸酸酯,如甘油单-和二-聚氧化乙烯(8)辛酸/癸酸酯,例如Gattefossé的LabrasolTM;中链甘油三酯;丙二醇脂肪酸酯,例如月桂酸丙二醇酯;油,例如玉米油,矿物油,棉籽油,花生油,芝麻油和聚氧化乙烯(35)蓖麻油,例如BASF的CremophorTMEL;聚氧化乙烯甘油三油酸酯,例如Goldschmidt的TagatTMTO;聚氧化乙烯脱水山梨糖醇酯,例如吐温80;以及脂肪酸低级烷基酯,例如丁酸乙酯,辛酸乙酯以及油酸乙酯。
优选将包含一种作为皮肤渗透促进剂的载体组分。
在一种实施方案中,在载体中有选自萜烯、类萜、脂肪醇及其衍生物的皮肤渗透促进剂。实例包括油醇、麝香草酚、薄荷醇、香芹酮、香芹醇、柠檬醛、二氢香芹醇、二氢香芹酮、新薄荷醇、异胡薄荷醇、4-萜品醇、薄荷酮、胡薄荷醇、樟脑、香叶醇、-萜品醇、里哪醇、香芹酚、反式-茴香脑,以及它们的异构体和其外消旋混合物。任选可存在多于一种此类渗透促进剂,例如可存在脂肪醇和萜烯或类萜。因此,在一种示例性实施方案中,本发明的组合物含有油醇和麝香草酚作为渗透促进剂。
脂肪酸如油酸和其烷基和甘油基酯,如月桂酸异丙酯、肉豆蔻酸异丙酯、油酸甲酯、甘油单月桂酸酯、甘油单油酸酯、甘油二月桂酸酯、甘油二油酸酯等也可用作渗透促进剂。例如国际专利申请号WO 98/18416(所述专利通过引用而结合到本文中来)中所公开的羟基乙酸的脂肪酸酯及其盐也可用作渗透促进剂。此类酯的实例包括月桂酰基羟乙酸酯、己酰基羟乙酸酯、椰油基羟乙酸酯、异硬脂酰基羟乙酸酯、月桂酰基羟乙酸钠、月桂酰基羟乙酸三甲铵(tromethamine)等。还可用作渗透促进剂的有脂肪醇的乳酸酯,例如乳酸月桂酯、乳酸十四烷酯、乳酸油基酯等。特别优选的渗透促进剂的实例有甘油单月桂酯。
其它渗透促进剂包括六氢-1-十二烷基-2H-氮杂_-2-酮(月桂氮_酮,AzoneTM)及其衍生物、二甲亚砜(DMSO)、正癸基甲基亚砜、水杨酸及其烷基酯(例如水杨酸甲酯)、N,N-二甲基乙酰胺、二甲基甲酰胺、N,N-二甲基甲苯酰胺、2-吡咯烷酮及其N-烷基衍生物(例如NMP和N-辛基-2-吡咯烷酮)、2-壬基-1,3-二氧戊环、桉树脑和脱水山梨糖醇酯。
示例性的载体含有DMSO和水,体积比率为100∶0到大约10∶90。
另一示例性的载体含有油醇和丙二醇,体积比率为大约20∶80到大约5∶95。
还有另一示例性的载体含有月桂氮_酮和丙二醇,体积比率为大约20∶80到大约5∶95。
在一个特别的实施方案中,所述载体含有一种作为皮肤渗透剂遮光剂。如在上述国际专利公开号WO 97/29735(通过引用而结合到本文中来)所描述,该类遮光剂可为酯类遮光剂。根据该实施方案,优选的渗透促进剂为式(XII)的化合物:
其中R1基团独立为氢、低级烷基、低级烷氧基、卤素、羟基或NR5R6基团,其中R5和R6独立为氢或低级烷基,或者R5和R6一起与其相连的氮原子形成5元或6元杂环;R2为C5-18线性、支化或环状烷基;R3为氢或苯基;R4为氢或氰基;n为0或1;且q为1或2。优选在式(XII)的化合物中R2为C5-12烷基,最优选为异戊基,辛基(例如2-乙基己基)、_基或高_基(homomenthyl)。
特别优选的式(XII)的化合物为对-氨基苯甲酸(PABA)、对-二甲基氨基苯甲酸、2-氨基苯甲酸、肉桂酸、对-甲氧基肉桂酸、水杨酸和2-氰基-3,3-二苯基丙烯酸的烷基酯,例如对-二甲基氨基苯甲酸2-乙基己酯(帕地马酯)、对-甲氧基肉桂酸2-乙基己酯、水杨酸2-乙基己酯、水杨酸_基酯、水杨酸高_基酯(胡莫柳酯)、2-氨基苯甲酸_酯和2-氰基-3,3-二苯基丙烯酸2-乙基己酯(奥克立林)。
式(XII)的化合物即使作遮光剂效果不太好,也可用作本发明的渗透促进剂。
或者,所述遮光剂除了为酯遮光剂外,还可为例如苯甲酮遮光剂或其变体,如2-羟基-4-甲氧基苯甲酮(羟苯甲酮)、2,2’-二羟基-4-甲氧基苯甲酮(双羟苯酮)、5-苯甲酰基-4-羟基-2-甲氧基苯磺酸(舒利苯酮)或1-(对叔丁基苯基)-3-(对甲氧基苯基)-1,3-丙二酮(阿伏苯宗)。
所述载体的其它成分可包括一种或多种选自增稠剂、表面活性剂、乳化剂、抗氧剂、防腐剂、稳定剂、着色剂和芳香剂的赋形剂。也可含有皮肤刺激减轻剂,如维生素E、甘草次酸或苯海拉明。
本发明的组合物可为任何适合于局部涂布到皮肤的液态或半固态剂型,且可根据本领域常规方法配制。本发明所考虑到的剂型为其成分不为固体支持物的剂型,然而在将所述组合物涂布到皮肤后,在需要时可将封闭物料如敷料或绷带盖在所治疗的区域上,这样并不使所述组合物或方法偏离本发明的范围。本发明的液态或半固体剂型可包括溶液剂、混悬剂和/或乳液剂。
合适的剂型可为例如乳膏剂、糊剂、凝胶剂、软膏剂、洗剂或喷雾剂。在剂型中的治疗药物的浓度取决于所讨论的选择性COX-2抑制药物或前药、将给药的药物或前药的所需剂量、要求给药的频率、选择的渗透促进剂(如有的话)、剂型的性质和其它因素。
非限定的示例性的糊剂、软膏剂、凝胶剂或乳膏剂为含有至少一种选择性COX-2抑制药物或前药、至少一种溶剂、至少一种皮肤渗透促进剂和至少一种增稠剂的本发明组合物。适用于软膏剂、凝胶剂和乳膏剂的合适的增稠剂包括但不限于羟丙基纤维素、羟丙基甲基纤维素(HPMC)、羟乙基纤维素、乙基纤维素、羧甲基纤维素、右旋糖苷、瓜耳胶、聚乙烯基吡咯烷酮(PVP)、果胶、淀粉、明胶、酪蛋白、丙烯酸、丙烯酸酯、丙烯酸共聚物、乙烯醇、烷氧基聚合物、聚环氧乙烷聚合物、聚醚等。
例如,这样的组合物可含有这些成分的用量如下(全部为重量百分比):
选择性COX-2抑制药物或前药 1.25-10%
溶剂(例如,70%乙醇,30%水) 50-97%
助溶剂和/或表面活性剂 0-15%
皮肤渗透促进剂 2-20%
增稠剂 1-5%
当皮肤渗透促进剂含有脂肪醇和萜烯或类萜,例如油醇和麝香草酚时,在刚刚体积的示例性组合物中它们的合适用量为脂肪醇2-10%重量,萜烯或类萜1-6%重量。在特定的情况下超出此范围的用量也可用。
某些前面所列的作为渗透促进剂的化合物本身也可用作局部止痛剂。例如,当在本发明组合物中包括水杨酸甲酯、薄荷醇或其组合(参见例如Bengay_的Pfizer产品)时,它们可提供补充性的止痛效果。具体地讲,此类化合物可提供发作早、时间短的止痛效果,对选择性COX-2抑制药物或前药的时间长、持续性止痛和抗炎效果形成补充。在本发明的含有水杨酸甲酯和薄荷醇的组合物中,合适的用量为水杨酸甲酯5-30%重量,薄荷醇2-20%重量。在特定的情况下超出此范围的用量也可用。
本发明的一种实施方案为适合于用涂药器的方式涂布到皮肤上的组合物,涂药器例如有气雾器、喷雾器、回抽器(pump-pack)、刷子或药签。优选此类涂药器提供固定或可变计量制剂的涂布,如计量制剂气雾器、储能计量制剂泵或手动计量制剂泵。根据该实施方案,最优选通过局部计量制剂气雾器与活动喷嘴覆盖物(actuator nozzleshroud)一起(一起精确控制涂布制剂的量和/或均匀性)的方式进行涂布。所述覆盖物可有助于控制喷嘴与皮肤的距离,此功能也可通过定位条等的方式实现。所述覆盖物的另一个功能围绕治疗的皮肤区域,以阻止或限制组合物的弹回和/或损失。优选受所述覆盖物限定的涂布面积基本上为圆形。可用回抽器推动组合物,或更优选通过采用气雾推进剂如烃或氢氟烃推进剂、氮气、一氧化二氮、二氧化碳或醚,例如二甲醚来推动。
在一个具体的实施方案中,本发明的乳膏剂、糊剂、凝胶剂、软膏剂、洗剂或气雾剂组合物含有作为皮肤渗透促进剂的遮光剂,例如对二甲基氨基苯甲酸辛酯(辛基二甲基PABA或帕地马酯)。在所述组合物中此类遮光剂的合适用量为1-10%重量,优选2-8%重量。
在该实施方案中,所述遮光剂有双重功能,即是作为遮光剂(即,保护不受晒伤或其它对皮肤的紫外线伤害)和作为选择性COX-2抑制药物或前药的渗透促进剂。在将药物或前药给药以减轻来自此种伤害的疼痛和/或发炎时,该实施方案的组合物特别有用。任选还可包括其它常用的遮光成分,如二氧化钛。
本发明的具体特征在于可对剂型进行设计,以将所述药物渗透皮肤而将治疗有效量的药物输送到靶部位(例如表皮、真皮、皮下、肌肉和关节器官和组织),同时保持所述药物的全身浓度不会大大超过最小治疗有效量。因此前述药物组合物可用于将选择性COX-2抑制药物靶向输送到患者的疼痛和/或发炎部位的外部或内部。根据本发明的一种治疗方法,可将本文提供的组合物局部给药到患者的皮肤表面,优选在与疼痛和/或发炎重叠或相邻的部位。
前述药物组合物还可用于对患者由COX-2介导的疾病的患者进行全身治疗。根据本发明的一种治疗方法,将本文提供的药物组合物经皮给药,优选将所述组合物与患者不超过大约400cm2的皮肤面积进行接触。
在以上任何一种方法中,根据第一种实施方案的组合物为可经皮输送的药物组合物,所述组合物含有溶于药学上可接受的载体(该载体含有C2-6一元醇)中的治疗药物,其中所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,且其中所述组合物表现出来的治疗药物皮肤渗透速率至少等于将所述治疗药物溶于70%乙醇水溶液中的参比溶液所表现出来的渗透速率,优选该速率不低于大约10μg/cm2·天,更优选不低于大约50μg/cm2·天。
在以上任何一种方法中,根据第二种实施方案的组合物为可经皮输送的药物组合物,所述组合物含有溶于药学上可接受的载体(该载体含有C2-6一元醇)中的治疗药物,其中所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,且在载体中的浓度为大约12.5到大约400mg/ml。
在以上任何一种方法中,根据第三种实施方案的组合物为可经皮输送的药物组合物,所述组合物含有溶于药学上可接受的载体(该载体含有C2-6一元醇)中的治疗药物,其中所述治疗药物含有伐地考昔和/或其前药,且在载体中的浓度为大约0.5到大约400mg/ml。
本发明的组合物用于治疗和预防各种各样的由COX-2介导性疾病,包括但不限于特征为炎症、疼痛和/或发热的疾病。所述组合物尤其可用作抗炎药,例如用于治疗关节炎,其额外的好处是有害副作用明显少于缺乏对COX-2的选择性优于对COX-1的选择性的常规NSAID组合物。具体地说,本发明组合物与常规非甾体抗炎药NSAID组合物相比,对胃肠毒性和胃肠刺激的潜力降低,所述胃肠毒性和胃肠刺激包括胃肠上部溃疡和出血;对肾副作用(例如肾功能衰竭引起的液体滞留(fluid retention)和高血压恶化)效力降低;对出血次数(包括抑制血小板功能)作用降低;且可能对对阿斯匹林敏感的哮喘的患者而言,降低了引发哮喘的能力。因此,在禁忌常规NSAID的情况下,本发明组合物尤其可用作所述NSAID的替代物,所述禁忌常规NSAID的情况例如患有消化性溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎或有胃肠损害复发史的患者;患有胃肠出血、凝结疾病的患者,所述胃肠出血、凝结疾病包括贫血,例如血凝血酶原过少、血友病或其它出血问题;肾病患者;或手术前患者或摄入抗凝药的患者。
设想的组合物用于治疗多种关节炎疾病,包括但不限于类风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮以及青少年关节炎。
所述组合物用于治疗哮喘、支气管炎、月经性痉挛、早产、腱炎、粘液囊炎、变应性神经炎、巨细胞病毒感染、细胞凋亡(包括HIV诱导的细胞凋亡)、腰痛、肝病(包括肝炎)、皮肤相关疾病(例如银屑病、湿疹、痤疮、烧伤、皮炎和紫外辐射损伤(包括晒斑))以及术后炎症(包括眼科手术后的炎症,所述眼科手术例如白内障手术或屈光手术)。
所述组合物用于治疗胃肠病症,例如炎性肠病、局限性回肠炎、胃炎、过敏性肠综合征和溃疡性结肠炎。
所述组合物用于治疗下面疾病中的炎症:偏头痛、动脉外膜炎结节、甲状腺炎、再生障碍性贫血、霍奇金病、硬皮病(sclerodoma)、风湿性发热、I型糖尿病、神经肌肉接头病(包括重症肌无力)、白质病(包括多发性硬化)、结节病、肾病综合征、贝赫切特综合征、多肌炎、龈炎、肾炎、过敏反应、损伤后出现的肿胀包括脑浮肿、心肌缺血等等。
所述组合物用于治疗眼病,包括但不限于下面炎症疾病:眼内炎、巩膜外层炎、视网膜炎、虹膜炎、睫状体炎、脉络膜炎、角膜炎、结膜炎和睑炎,眼睛一个部分以上的炎症疾病,如视网膜脉络膜炎、虹膜睫状体炎、虹膜睫状体脉络膜炎(也称为眼色素层炎)、角结膜炎、睑结膜炎等;其它COX-2介导的视网膜病,包括糖尿病性视网膜病;眼畏光;眼睛任何组织的急性损伤,包括术后损伤,如白内障手术或角膜移植手术后的急性损伤;术后眼部炎症;手术中的瞳孔缩小;角膜移植物排斥;眼的新血管形成,例如视网膜新血管形成,包括在损伤或感染后出现的新血管形成;黄斑变性;囊状黄斑水肿;晶状体后纤维组织形成;新血管形成性青光眼(neovascularglaucoma);以及眼痛。
所述组合物用于治疗肺部炎症,例如与病毒感染和囊性纤维变性有关的肺部炎症,以及用于骨吸收,例如与骨质疏松有关的骨吸收。
所述组合物用于治疗某些中枢神经系统疾病,例如皮质痴呆包括阿尔茨海默病、神经变性以及由于中风、局部缺血和创伤导致的中枢神经系统损害。术语“治疗”在本文中包括对痴呆的部分或完全抑制,所述痴呆包括阿尔茨海默病、血管性痴呆、多梗死性痴呆、早老性痴呆、酒精性痴呆和老年性痴呆。
所述组合物用于治疗过敏性鼻炎、呼吸窘迫综合征、内毒素休克综合征和肝病。
所述组合物用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛和癌症引起的疼痛。例如,所述组合物用于缓解多种病症中的疼痛、发热和炎症,所述病症包括风湿性发热、流感和其它病毒感染包括普通感冒、腰背痛和颈痛(low back and neck pain)、痛经、头痛、牙痛、扭伤和劳损、肌炎、神经痛、滑膜炎、关节炎包括类风湿性关节炎、退化性关节病(骨关节炎)、痛风和强直性脊椎炎、粘液囊炎、烧伤以及外科和牙科手术后的损伤。
所述组合物用于治疗和预防炎症相关心血管病,包括血管病、冠状动脉病、动脉瘤、血管排斥、动脉硬化、动脉粥样硬化包括心脏移植物动脉粥样硬化、心肌梗塞、栓塞、中风、血栓形成包括静脉血栓形成、心绞痛包括不稳定心绞痛、冠状动脉斑炎症、细菌引起的炎症包括衣原体引起的炎症、病毒引起的炎症以及与外科手术有关的炎症,所述外科手术例如血管移植包括冠状动脉旁路手术、换血管术手术包括血管成形术、放置斯滕特印模(stent placement)、动脉内膜切除术或其它涉及动脉、静脉和毛细管的侵袭性手术。
所述组合物用于治疗患者的血管生成相关性疾病,例如用于抑制肿瘤血管生成。所述组合物用于治疗瘤形成,包括转移癌;眼科病症例如角膜移植排斥、眼新血管形成、视网膜新血管形成包括损伤或感染后的新血管形成、糖尿病性视网膜病、黄斑变性、晶状体后纤维组织形成和新血管性青光眼;溃疡性疾病如胃溃疡;病理性但非恶性的病症,例如血管瘤,包括幼稚型血管瘤、鼻咽的血管纤维瘤以及骨的无血管性坏死;以及雌性生殖系统的疾病如子宫内膜异位。
所述组合物可用于治疗癌症早期疾病,如光化角化症。
所述组合物用于预防、治疗和抑制良性和恶性肿瘤以及瘤形成,包括新陈代谢中的肿瘤形成,例如结肠直肠癌、脑癌、骨癌、上皮细胞衍生的瘤形成(上皮细胞癌)如基底细胞癌、腺癌、胃肠癌如唇癌、口腔癌、食管癌、小肠癌、胃癌、结肠癌、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌如鳞状细胞癌和基底细胞癌、前列腺癌、肾细胞癌以及其它已知的影响全身上皮细胞的癌症。设想本发明组合物特别有用的瘤形成是胃肠癌、巴特雷食管、肝癌、膀胱癌、胰癌、卵巢癌、前列腺癌、宫颈癌、肺癌、乳腺癌和皮肤癌。所述组合物也可用于治疗放射疗法引起的纤维变性。所述组合物也可用于治疗患有腺瘤性息肉的患者,包括患有家族性腺瘤性息肉病(FAP)的患者。此外,所述组合物可用于预防有FAP风险的患者体内形成息肉。
更具体地讲,所述组合物可用于治疗、预防和抑制肢端着色斑状黑素瘤、光化性角化病、腺癌、囊性腺样癌、腺癌、腺肉瘤、星细胞瘤、前庭大腺癌、基底细胞癌、乳癌、细支气管腺癌、毛细血管瘤、良性肿瘤、癌肉瘤、空洞性血管瘤、胆管癌、软骨肉瘤、脉络膜丛刺瘤(chorioid plexus papilloma)或癌、明细胞癌、皮肤T-细胞淋巴瘤(霉菌)、囊腺瘤、发育不良痣(displastic nevi)、内皮窦瘤、子宫内膜增生、子宫内膜基质肉瘤、子宫内膜腺癌、室鼓膜瘤、上皮血管瘤、尤因肉瘤、纤维瘤、病灶结节性增生、促胃液素瘤、生殖细胞瘤、胶质胚细胞瘤、高血糖素瘤、成血管细胞瘤、血管内皮瘤、血管瘤、肝腺瘤、肝腺瘤病、肝细胞癌、胰岛瘤、上皮瘤形成、上皮扁平细胞瘤形成、入侵性扁平细胞癌、卡波济肉瘤、大细胞癌、平滑肌肉瘤、恶性痣瘤、恶性黑素瘤、恶性间皮瘤、成神经管细胞瘤、髓质口皮瘤、黑素瘤、脑(脊)膜瘤、间皮瘤、粘液表皮样癌、成神经细胞瘤、神经上皮细胞腺瘤、节状黑素瘤、燕麦细胞癌、少突细胞神经胶质瘤、骨肉瘤、乳头状浆液(papillary serous)腺癌、松球状瘤、垂体瘤、血浆细胞瘤、假肉瘤、肺胚细胞瘤、肾细胞癌、眼癌、横纹肌肉瘤、肉瘤、血浆癌、小细胞癌、软组织癌、生长激素抑制素分泌瘤、鳞状细胞癌、扁平细胞癌、亚间皮癌、表面扩散黑素瘤、未分化癌、眼黑素瘤、疣状癌、胰腺瘤、彻底分化癌和Wilm氏瘤。
所述组合物通过抑制收缩性前列腺素类合成而抑制前列腺素类引起的平滑肌收缩,并因此可用于治疗痛经、早产、哮喘和嗜酸粒细胞相关性疾病。它们也可用于减少骨丢失,尤其是经绝后妇女的骨丢失(即治疗骨质疏松),以及用于治疗青光眼。
本发明组合物的优选应用是用于治疗类风湿性关节炎和骨关节炎,用于一般性地控制疼痛(特别是口腔手术后疼痛、全身性手术后疼痛、矫形外科手术后疼痛以及骨关节炎的急性突发),用于预防和治疗头痛和偏头痛,用于治疗阿尔茨海默病以及用于化学预防结肠癌。
将本发明的组合物局部涂布可特别用于治疗任何类型的炎性皮肤病(不管是恶性、非恶性或恶化前),包括结疤和酮病,还包括烧伤和日光损伤,例如晒斑,皱纹等。此类组合物可用于治疗各种皮肤损伤导致的发炎,包括但不限于那些由病毒疾病引起者,包括疱疹感染(例如,感冒疮、生殖器疱疹)、带状疱疹和水痘。其它可用此类组合物治疗的皮肤损害或伤害包括褥疮(褥疮性溃疡)、表皮增生、痱子、牛皮癣、湿疹、痤疮、皮炎、瘙痒、疣和红斑痤疮。此类组合物还有助于外科手术后的治愈方法,包括美容手术如化学去皮、激光治疗、擦皮法、整形、眼睑手术等。
本发明组合物除可以用于人类治疗外,还可用于兽医治疗宠物(companion animal)、不同寻常的动物、家畜等等,尤其是哺乳动物包括啮齿动物。更具体地说,本发明组合物可用于治疗马、狗和猫的COX-2介导性疾病。
本发明组合物可用于与阿片类物质和其它镇痛药的一种或多种药物的联合治疗,所述其它镇痛药其中包括麻醉性镇痛药、μ受体拮抗剂、κ受体拮抗剂、非麻醉性(即非成瘾性)镇痛剂、单胺摄取抑制剂、腺苷调节剂、大麻素衍生物、P物质拮抗剂、神经激肽-1受体拮抗剂和钠通道阻滞剂。优选的联合治疗包括应用本发明组合物以及一种或多种选自以下的化合物:醋氯芬酸、阿西美辛、e-乙酰氨基己酸、对乙酰氨基苯酚、醋氨沙洛、乙酰苯胺、乙酰水杨酸(阿司匹林)、S-腺苷甲硫氨酸、阿氯芬酸、阿芬太尼、烯丙罗定、阿明洛芬、阿洛普令、阿法罗定、二乙酰水杨酸铝、氨芬酸、氨氯苯噁嗪、3-氨基-4-羟丁酸、2-氨基-4-甲吡啶、氨丙吡酮、氨基比林、阿米西群、水杨酸铵、安吡昔康、呱氨托美丁、阿尼利定、安替比林、水杨酸安替比林、安曲非宁、阿扎丙宗、阿斯匹林、巴柳氮、苄达酸、贝诺酯、苯噁洛芬、苄哌立隆、苄达明、苄吗啡、黄连素、柏莫洛芬、贝齐米特、α-没药醇、溴芬酸、p-溴乙酰苯胺、5-溴水杨酸乙酸酯、溴水杨醇、布西丁、布氯酸、布可隆、丁苯羟酸、布马地宗、丁丙诺啡、布他西丁、丁布芬、布托啡诺(butophanol)、乙酰水杨酸钙、卡马西平、卡比芬、卡洛芬、卡沙兰、三氯叔丁醇、氯西诺嗪、水杨酸胆碱、辛可芬、桂美辛、西拉马多、环氯茚酸、氯美辛、氯尼他秦、氯尼辛、氯吡酸、丁香、可待因、溴甲可待因、磷酸可待因、硫酸可待因、克罗丙胺、克罗乙胺、地索吗啡、右奥沙屈、右吗拉胺、地佐辛、地恩丙胺、双氯芬酸、二苯米唑、联苯吡胺、二氯尼柳、双氢可待因、盐酸二氢可待因酮烯醇、双氢吗啡、乙酰水杨酸二羟铝、地沙美多、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、diprocetyl、安乃近、地他唑、屈噁昔康、依莫法宗、恩芬那酸、依匹唑、依他佐辛、依那西普、依特柳酯、乙水杨胺、依索庚嗪、依托沙秦、乙甲噻丁、乙基吗啡、依托度酸、依托芬那酯、依托尼秦、丁香酚、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬太尼、芬替酸、非普地醇、非普拉宗、夫洛非宁、氟芬那酸、氟诺洛芬、氟苯乙砜、氟吡汀、氟丙喹宗、氟比洛芬、磷柳酸、龙胆酸、格拉非宁、葡美辛、水杨酸乙二醇酯、愈创蓝油烃、氢可酮、氢吗啡酮、羟哌替啶、异丁芬酸、布洛芬、异丁普生、水杨酸咪唑、吲哚美辛、吲哚洛芬、英夫利昔单抗、白介素-10、三苯唑酸、isoladol、异美沙酮、异尼辛、伊索克酸、伊索昔康、凯托米酮、酮洛芬、酮咯酸、p-乳酰N-酰乙氧基苯胺、来苯胺、左啡诺、来昔帕泛、洛芬太尼、氯那唑酸、氯诺昔康、洛索洛芬、赖氨酸乙酰水杨酸、乙酰水杨酸镁、甲氧芬那酸、甲芬那酸、哌替啶、美普他酚、5-氨基水杨酸、美他佐辛、美沙酮、左美丙嗪、甲嗪酸、甲氧夫啉、美托酮、莫非布宗、莫苯唑酸、吗拉宗、吗啡、盐酸吗啡、硫酸吗啡、水杨吗啉、麦罗啡、萘丁美酮、纳布啡、水杨酸1-萘酯、萘普生、那碎因、奈福泮、尼可吗啡、尼芬那宗、尼氟酸、尼美舒利、5′-硝基-2′-丙氧基乙酰苯胺、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、奥沙拉秦、阿片、奥沙西罗、奥沙美辛、噁丙嗪、羟考酮、羟吗啡酮、羟布宗、阿片全碱、瑞尼托林、帕沙米特、喷他佐辛、哌立索唑、非那西丁、苯吗庚酮、非那佐辛、盐酸非那吡啶、非诺可、苯哌利定、非诺吡酮、乙酰水杨酸苯酯、保泰松、水杨酸苯酯、非尼拉朵、吡酮洛芬、匹米诺定、哌布宗、哌立酮、吡拉唑酸、哌腈米特、吡罗昔康、吡洛芬、吡拉唑酸、哌腈米特、吡罗昔康、普拉洛芬、丙谷美辛、普罗庚嗪、γ-二甲哌替啶、丙帕他莫、丙吡兰、右丙氧芬、异丙安替比林、普罗喹宗、丙替嗪酸、雷米那酮、瑞芬太尼、甲硫利马唑、醋水杨胺、水杨苷、水杨酰胺、水杨酰胺o-醋酸、水杨基硫酸、双水杨酯、沙维林、西美曲特、水杨酸钠、舒芬太尼、柳氮磺吡啶、舒林酸、过氧化物歧化酶、舒洛芬、琥布宗、他尼氟酯、替尼达普、替诺昔康、特罗芬那酯、粉防已碱、噻唑丁炎酮、噻洛芬酸、噻拉米特、替利定、替诺立定、托芬那酸、托美丁、曲马多、tropesin、维米醇、联苯丁酸、希莫洛芬、扎托洛芬、齐考诺肽和佐美酸(参见The Merck Index,第13版(2001)),Therapeutic Category and BiologicalActivity Index,本文小标题为“镇痛药”、“消炎药”和“退热药”)。
特别优选的联合疗法包括采用本发明的组合物(例如本发明的塞来考昔和伐地考昔组合物),以及阿片样物质,更具体地说其中所述阿片样物质是可待因、度冷丁、吗啡或其衍生物。
与选择性COX-2抑制药物联合给药的化合物可单独配制,并通过任何合适途径给药,包括经口、直肠、肠胃外或局部给药到皮肤或其它部位。或者,可将与选择性COX-2抑制药物联合给药的化合物一起配制成本发明的可经皮输送的组合物。
在本发明的一种实施方案中,特别是当由COX-2所介导的疾病为头痛或偏头痛时,在联合疗法中,将本发明的选择性COX-2抑制药物组合物与血管调节药,优选具有血管调节效果的黄嘌呤衍生物,更优选烷基黄嘌呤化合物一起给药。
本文提供的其中烷基黄嘌呤化合物与选择性COX-2抑制药物组合物辅助给药的联合疗法包括于本发明的实施方案中,无论所述烷基黄嘌呤是否为血管调节药,也无论所述联合疗法的治疗效果是否对血管调节效果有任何程度的帮助。本文中术语“烷基黄嘌呤”包括有一个或多个C1-4烷基取代基(优选甲基)的黄嘌呤衍生物,以及此类黄嘌呤衍生物的药学上可接受的盐。特别优选二甲基黄嘌呤衍生物和三甲基黄嘌呤衍生物,包括咖啡因、可可碱和茶碱。更优选所述烷基黄嘌呤为咖啡因。
选择所述选择性COX-2抑制药物和血管调节药或烷基黄嘌呤的总剂量和相对剂量,使得具有减轻与头痛或偏头痛相关的疼痛的治疗和/或预防效果。合适的剂量取决于具体的选择性COX-2抑制药物和具体所选择的血管调节药或烷基黄嘌呤。例如,在塞来考昔和咖啡因的联合疗法中,通常塞来考昔的日剂量为大约50mg到大约1000mg,优选大约100mg到大约600mg,咖啡因的日剂量为大约1mg到大约500mg,优选大约10mg到大约400mg,更优选大约20mg到大约300mg。
可将联合疗法的血管调节药或烷基黄嘌呤以任何合适的途径(包括口服、直肠、肠胃外或局部给药到皮肤或其它部位)、以任何合适的剂型给药。可任选将所述血管调节药或烷基黄嘌呤与选择性COX-2抑制药物配制成单一经皮给药剂型。因此本发明的经皮给药组合物任选含有选择性COX-2抑制药物和血管调节药或烷基黄嘌呤,例如咖啡因,其总剂量或相对剂量与本文前面所示剂量相符。
用于本发明实施方案的组合物的选择性COX-2抑制药物和血管调节药或烷基黄嘌呤的短语“以可有效减轻疼痛的总剂量和相对剂量”表示这样的剂量使得:(a)总体上这些成分可有效减轻疼痛,(b)每一种成分均能对减轻疼痛作出贡献(在其它成分的剂量不能对减轻疼痛作出贡献的情况下)。
实施例
下面实施例举例说明本发明的各个方面,但不应当认为下面的实施例是限制本发明。除非另有声明,否则在这些实施例中使用的术语“帕瑞考昔”为严格意义上的帕瑞考昔酸;例如“帕瑞考昔钠”表示帕瑞考昔的钠盐。
为衡量可经皮给药的药用组合物中的选择性COX-2抑制药物或前药的皮肤渗透性能,用人体死尸皮肤膜提供的Franz扩散细胞,1%吐温80(TweenTM80)溶液作受体流体。在室温下将冷冻的皮肤解冻,用20mm打孔机冲压成膜。将Franz扩散细胞的受体室用所述受体流体充满,将所述扩散细胞保持在32℃下。将所述膜贴在受体室上面,用夹子盖住并夹紧。从受体流体中去除气泡,平衡30分钟。将测试组合物与所述膜接触。对受体流体进行HPLC分析,测量在24小时时间段内渗透过所述膜的药物量。重复各测试几次。
实施例1
以下述溶剂制备塞来考昔的饱和溶液:70%乙醇(EtOH)水溶液、乙醇、PEG-400和丙二醇(PG)。按上述方法测试溶液的皮肤渗透性能,各测试溶液均用250μl液滴进行测试。结果如表1中所示。
实施例2
完全按实施例1中对塞来考昔溶液所描述的那样制备并测试伐地考昔的饱和溶液。结果如表示1中所示。
表1:饱和塞来考昔和伐地考昔溶液的皮肤通量
药物 | 塞来考昔 | 伐地考昔 | ||||||
溶剂 | 70%EtOH | EtOH | PEG-400 | PG | 70%EtOH | EtOH | PEG-400 | PG |
浓度(mg/ml) | 15.2 | 91.4 | 297 | 33.3 | 12.7 | 7.48 | 210 | 23.6 |
皮肤通量(μg/cm2·天) | 15.7±3.83 | 5.62±1.49 | ud | ud | 12.8±4.96 | 1.44±0.54 | ud | ud |
ud=检测不到
当用PEG-400或丙二醇作溶剂时,在24小时的时间段内没有观察到塞来考昔和伐地考昔的皮肤渗透。
令人惊奇的是,70%乙醇水溶液对塞来考昔和伐地考昔两者皮肤通量都比单独用乙醇大。用此溶剂,塞来考昔和伐地考昔的皮肤渗透率相近(分别为15.7和12.8μg/cm2·天)。
实施例3
完全按实施例1和实施例2中对塞来考昔和伐地考昔溶液所描述的那样制备并测试帕瑞考昔钠在70%乙醇水溶液中的饱和溶液。由于采用不同批量的皮肤测量每一种化合物的皮肤通量,对每一批量的皮肤均采用同一标准,并将数据归一化。将结果与前面对应的塞来考昔和伐地考昔的结果一起列在表2之中。
表2:在70%乙醇水溶液中的饱和溶液的皮肤通量
药物或前药 | 浓度(mg/ml) | 皮肤通量(μg/cm2·天) | 归一化的皮肤通量(μg/cm2·天) |
塞来考昔 | 15.2 | 15.7±3.83 | 34.9 |
伐地考昔 | 12.7 | 12.8±4.96 | 53.4 |
帕瑞考昔钠 | 386 | 254±164 | 120.0 |
实施例4
往实施例3所制备的溶于70%乙醇水溶液中的塞来考昔、伐地考昔和帕瑞考昔钠的饱和溶液中加入5%重量的油醇和3%重量的麝香草酚作为皮肤渗透促进剂,制备塞来考昔、伐地考昔和帕瑞考昔钠。如前所述测试这些溶液的皮肤渗透性能,各测试溶液均用250μl液滴进行测试。与表2中的皮肤通量数据相比,计算促进因子。结果如表3中所示。
表3:溶于70%乙醇水溶液中的含5%油醇和3%麝香草酚的饱和溶液的皮肤通量
药物或前药 | 皮肤通量(μg/cm2·天) | 促进因子 |
塞来考昔 | 21.7±4.6 | 1.4 |
伐地考昔 | 323±21 | 25 |
帕瑞考昔钠 | 1210±58.0 | 4.8 |
对伐地考昔而言,油醇和麝香草酚的联合使用是特别显著地提高了皮肤通量。
实施例5
用不同的溶剂和渗透促进剂作为载体制备伐地考昔的饱和溶液(5-1、5-2和5-3)。如前所述测试溶液的皮肤渗透性能。载体组合物如表4所示,伐地考昔浓度和皮肤通量数据如表5所示。
表4:载体的组成(%重量)
组成 | 5-1 | 5-2 | 5-3 |
水 | 30 | 33 | 30 |
乙醇 | 62 | 62 | 30 |
异丙醇 | - | - | 10 |
1,3-丁二醇 | - | - | 22 |
油醇 | 5 | 5 | 5 |
麝香草酚 | 3 | - | 3 |
表5:伐地考昔浓度和皮肤通量
组合物 | 5-1 | 5-2 | 5-3 |
浓度(mg/ml) | 22.0 | 18.5 | 13.4 |
皮肤通量(μg/cm2·天) | 441±160 | 287±23.9 | 302±48.9 |
实施例6
将塞来考昔和伐地考昔(每一种均为1%重量)的凝胶体组合物制备成溶于70%乙醇水溶液中的溶液,加入3%重量的KlucelTM(羟丙基纤维素)作为增稠剂。将这些组合物作非闭合测试,每一种凝胶体用量为50mg,按前面所述方法进行皮肤渗透。同时测量药物在表皮和真皮的分布。结果列于表6中,与实施例1和2中的溶液组合物进行对比。
表6:溶液和凝胶组合物的皮肤通量
药物 | 塞来考昔 | 伐地考昔 | ||
制剂 | 溶液 | 凝胶体 | 溶液 | 凝胶体 |
浓度(mg/ml) | 15.2 | 10 | 12.7 | 10 |
涂布量 | 250μl | 50mg | 250μl | 50mg |
闭合? | 是 | 否 | 是 | 否 |
皮肤通量(μg/cm2·天) | 15.7±3.83 | 3.82±3.36 | 12.8±4.96 | 11.3±6.48 |
表皮中的药物(μg) | 3.92±0.79 | 2.36±1.06 | 9.27±3.84 | 1.81±1.87 |
真皮中的药物(μg) | 2.50±1.53 | 1.22±0.51 | 0.543±0.525 | ud |
ud=没有检测到
实施例7
在含有5%帕瑞考昔钠的67%乙醇水溶液中,制备塞来考昔和伐地考昔的饱和溶液。如前所述测量帕瑞考昔钠与塞来考昔或帕瑞考昔钠与伐地考昔的皮肤通量。与前面表2中不含帕瑞考昔钠的数据相比,计算塞来考昔和伐地考昔的提高倍数。结果列于表7中。
表7:帕瑞考昔钠与塞来考昔或帕瑞考昔钠与伐地考昔的联合药物组合物的皮肤通量
药物组合物 | 塞来考昔+帕瑞考昔钠 | 伐地考昔+帕瑞考昔钠 | ||
塞来考昔 | 帕瑞考昔 | 伐地考昔 | 帕瑞考昔 | |
浓度(mg/ml) | 15.9 | 49.4 | 19.2 | 49.7 |
皮肤通量(μg/cm2·天) | 183±153 | 74.7±14.7 | 108±16.7 | 64.1±11.3 |
提高倍数 | 11.5 | 8.4 |
令人惊奇的是,在溶液中含有帕瑞考昔钠极大提高了塞来考昔和伐地考昔两者的皮肤渗透性能。
实施例8
将含有2.5%或5%塞来考昔凝胶制剂(组合物8-1到8-3)制备成溶于70%乙醇水溶液中的溶液,加入2%羟丙基纤维素(KlucelTM)和1%吐温80(TweenTM80)。组合物8-1不含有HPMC,组合物8-2和8-3含有3%HPMC(MethocelTME15LV)。如实施例6所述测量所述凝胶的皮肤渗透性能。皮肤渗透性能结果列于表8中。
表8:塞来考昔凝胶组合物的皮肤通量
组合物 | 塞来考昔(%) | HPMC(%) | 重复次数 | 皮肤通量(μg/cm2·天) |
8-1 | 2.5 | 0 | 7 | 5.64±3.38 |
8-2 | 2.5 | 3 | 6 | 9.34±4.70 |
8-3 | 5 | 3 | 8 | 8.90±5.57 |
实施例9
如实施例8那样制备含有2.5%塞来考昔的凝胶制剂,但另外加入0.5%卡波姆和0.4%2-氨基-2-甲基-1-丙醇(AMP-95TM)和不同等级的HPMC(加入量3%)。如实施例6所述方法测量所述凝胶,与溶于70%乙醇水溶液中的饱和塞来考昔溶液和前面制备的不含HPMC的塞来考昔凝胶(组合物8-1)相比。15小时后在受体流体中发现的塞来考昔的平均量列于表9。
表9:塞来考昔凝胶组合物15小时后的皮肤通量
组合物 | HPMC(%) | 皮肤通量(μg/cm2·天) |
70%乙醇水溶液中的饱和溶液 | 1.406±0.086 | |
8-1 | 无 | 1.464±0.246 |
9-1 | 3%MethocelTMF4M | 1.821±0.452 |
9-2 | 3%MethocelTME50LV | 2.511±0.959 |
9-3 | 3%MethocelTME15LV | 1.900±0.260 |
实施例10
如前面实施例中所述,制备塞来考昔、伐地考昔和帕瑞考昔的饱和水溶液并在不同温度下测量皮肤通量,重复3次。结果列于表10。
表10:不同温度下的皮肤通量
化合物 | 浓度(μg/ml) | 皮肤通量(μg/cm2·天) | |
32℃ | 50℃ | ||
塞来考昔 | 0.5 | 4.27±0.84 | 23.71±4.42 |
伐地考昔 | 12.1 | 7.94±0.89 | 42.12±7.82 |
帕瑞考昔 | 50.8 | 8.62±1.94 | 47.16±3.70 |
实施例11
按如下所示制备含有2%帕瑞考昔钠和表11中所示赋形剂成分的凝胶制剂(组合物11-1和11-2)。在第一个容器中将TweenTM80(吐温80)与水混合。将HPMC2910缓慢加入到所得含水混合物中,直到其完全分散。在第二个容器中将乙醇、帕瑞考昔钠、丙二醇、麝香草酚和油醇混合。将所得混合物加入到第一个容器内的含水混合物中,并混合完全。在进一步搅拌下缓慢加入KlucelTM(羟丙基纤维素)。
可以看出组合物11-1和11-2在丙二醇的含量上有所不同。
表11:凝胶制剂的组成(%重量)
组成 | 11-1 | 11-2 |
帕瑞考昔钠 | 2 | 2 |
羟丙基纤维素 | 3 | 3 |
HPMC2910 | 3 | 3 |
吐温80 | 1 | 1 |
丙二醇 | 10 | 20 |
麝香草酚 | 2 | 2 |
油醇 | 5 | 5 |
乙醇 | 50 | 40 |
水 | 24 | 24 |
按前面实施例所述非闭合性地测量组合物11-1和11-2的皮肤渗透性能,重复3次。每种组合物均以100μl体积测试;另外将组合物11-1以50和20μl体积测试。皮肤通量记录于表12中。
表12:帕瑞考昔钠凝胶制剂的皮肤通量
组合物 | 体积(μl) | 皮肤通量(μg/cm2·天) |
11-2 | 100 | 27.3±7.0 |
11-1 | 100 | 27.7±7.6 |
11-1 | 50 | 21.1±11.6 |
11-1 | 20 | 3.6±2.4 |
实施例12
制备简单溶液的液体制剂(组合物12-1和12-2)。组合物12-1含有1%塞来考昔、30%水和69%乙醇,按重量计。组合物12-2含有1%塞来考昔、30%水、59%乙醇及10%脲,按重量计。两种组合物均以500μl的体积进行皮肤通量的闭合性测试。结果列于表13中。
表13:塞来考昔的液体制剂的皮肤通量
组合物 | 重复次数 | 皮肤通量(μg/cm2·天) |
13-1 | 1 | 2.02 |
13-2 | 3 | 5.41±3.45 |
实施例13
按实施例11中所述程序制备如表14中所示的含有2%帕瑞考昔钠和赋形剂成分的凝胶制剂(组合物13-1到13-4)。
表14:凝胶制剂的组成(%重量)
组成 | 14-1 | 14-2 | 14-3 | 14-4 |
帕瑞考昔钠 | 2 | 2 | 2 | 2 |
羟丙基纤维素 | 3 | 3 | 3 | 3 |
HPMC2910 | 0 | 3 | 0 | 3 |
吐温80 | 0 | 0 | 1 | 1 |
油醇 | 5 | 5 | 5 | 5 |
麝香草酚 | 2 | 2 | 2 | 2 |
丙二醇 | 10 | 11 | 11 | 11 |
乙醇 | 50 | 43 | 44 | 42 |
水 | 28 | 31 | 32 | 31 |
按前面所述实施例测试组合物13-1到13-4的皮肤渗透性能,重复3次。将所述制剂以50μl的体积进行非闭合性测试。皮肤通量数据列于表15中。
表15:帕瑞考昔钠的凝胶制剂的皮肤通量
组合物 | 皮肤通量(μg/cm2·天) |
13-1 | 8.92±8.52 |
13-2 | 6.73±6.72 |
13-3 | 20.67±7.48 |
13-4 | 21.11±11.62 |
实施例14
如表16中所示制备帕瑞考昔酸(组合物14-1到14-4)的饱和溶液。加入帕瑞考昔后,将所述溶液在旋转搅拌器上混合3小时。
表16:帕瑞考昔酸制剂的组成(%重量)
组成 | 14-1 | 14-2 | 14-3 | 14-4 |
乙醇 | 7.0 | 6.5 | 6.5 | 6.5 |
水 | 3.0 | 3.0 | 3.0 | 3.0 |
帕瑞考昔酸 | 饱和 | 饱和 | 饱和 | 饱和 |
乳酸月桂酯 | 0.5 | |||
乳酸十四烷酯 | 0.5 | |||
甘油二月桂酸酯 | 饱和 |
按前面实施例所述,以300μl的体积测试组合物14-1到14-4的皮肤渗透性能,重复3次。皮肤通量数据列于表17中。
表17:帕瑞考昔酸溶液的皮肤通量
组合物 | 皮肤通量(μg/cm2·天) |
14-1 | 33.9±19.68 |
14-2 | 104.4±15.36 |
14-3 | 167.0±44.4 |
14-4 | 86.2±15.6 |
实施例15
按实施例11中所述方法制备如表18中所示的含有2%帕瑞考昔钠和赋形剂成分的凝胶制剂(组合物15-1到15-4)。
表18:凝胶制剂的组成(%重量)
组成 | 15-1 | 15-2 | 15-3 | 15-4 |
帕瑞考昔钠 | 2 | 2 | 2 | 2 |
羟丙基纤维素 | 3 | 3 | 3 | 3 |
HPMC2910 | 3 | 3 | 3 | 3 |
吐温80 | 1 | 1 | 1 | 1 |
油醇 | 5 | 5 | 5 | 5 |
麝香草酚 | 2 | 2 | 2 | 2 |
乳酸月桂酯 | 2 | 2.5 | 3 | 0 |
乳酸十四烷酯 | 2 | 2.5 | 0 | 3 |
甘油二月桂酸酯 | 1 | 0 | 2 | 2 |
丙二醇 | 10 | 10 | 10 | 10 |
乙醇 | 40 | 40 | 40 | 40 |
水 | 29 | 29 | 29 | 29 |
按前面实施例中描述的方法测试组合物15-1到15-4的皮肤渗透性能,重复3次。将所述制剂以50μl的体积进行非闭合性测试。皮肤通量数据列于表19中。
表19:帕瑞考昔钠的凝胶制剂的皮肤通量
组合物 | 皮肤通量(μg/cm2·天) |
15-1 | 67.7±47.4 |
15-2 | 31.6±4.0 |
15-3 | 55.3±34.2 |
15-4 | 39.0±3.1 |
实施例16
按实施例11中所述方法制备如表20A和20B中所示的含有2%塞来考昔、2%帕瑞考昔或2%帕瑞考昔钠(每种情形下均有赋形剂成分)的凝胶制剂(组合物16-1到16-13)。
表20A:凝胶制剂的组成(%重量)
组成 | 16-1 | 16-2 | 16-3 | 16-4 | 16-5 | 16-6 | 16-7 |
塞来考昔 | 2 | 2 | 2 | ||||
帕瑞考昔 | 2 | 2 | |||||
帕瑞考昔钠 | 2 | 2 | |||||
卡波姆980 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | 0.5 | |
羟丙基纤维素 | |||||||
HPMC2910 | 3 | 3 | 6 | 3 | 3 | 3 | 3 |
吐温80 | 1 | 1 | 1 | 1 | 1 | 1 | 1 |
2-氨基-2-甲基-1-丙醇 | 0.4 | 0.4 | 0.2 | 0.4 | 0.4 | 0.4 | |
麝香草酚 | 3 | 3 | 3 | 3 | |||
油醇 | 5 | 2.5 | 5 | 5 | |||
甘油油酸酯 | 5 | 2.5 | 5 | ||||
乙醇 | 65 | 58 | 50 | 65 | 58 | 65 | 60 |
水 | 28.1 | 22.1 | 33 | 28.1 | 22.1 | 28.1 | 25.1 |
PH | 7.50 | 8.45 |
表20B:凝胶制剂的组成(%重量)
组成 | 16-8 | 16-9 | 16-10 | 16-11 | 16-12 | 16-13 |
塞来考昔 | ||||||
帕瑞考昔 | 2 | 2 | 2 | 2 | 2 | 2 |
帕瑞考昔钠 | ||||||
卡波姆980 | 0.5 | |||||
羟丙基纤维素 | 3 | 3 | 3 | |||
HPMC2910 | 3 | 6 | 6 | 2 | 2 | 2 |
吐温80 | 1 | 2 | 1 | 1 | 1 | 1 |
2-氨基-2-甲基-1-丙醇 | 0.4 | |||||
麝香草酚 | 3 | 3 | 2 | 2 | ||
油醇 | 5 | 2.5 | 5 | 5 | ||
甘油油酸酯 | 2.5 | 5 | ||||
乙醇 | 58 | 65 | 50 | 65 | 62 | 62 |
水 | 22.1 | 25 | 33 | 27 | 23 | 18 |
PH | 4.40 | 4.44 | 4.71 | 4.31 |
按前面实施例所述方法测试组合物16-1、16-2、16-9和16-11到16-13的皮肤渗透性能,重复3次。将所述制剂以100μl的体积进行非闭合性测试。皮肤通量数据列于表21中。
表21:凝胶制剂的皮肤通量
组合物 | 皮肤通量(μg/cm2·天) |
16-1 | 5.51±2.28 |
16-2 | 2.56±0.69 |
16-9 | 14.0±6.5 |
16-11 | 10.1±1.4 |
16-12 | 80.4±15.1 |
16-13 | 74.7±17.1 |
实施例17
按前面实施例所述方法制备塞来考昔的饱和溶液(组合物17-1到17-6),溶于表22所示溶剂体系中。
表22:塞来考昔溶液的溶剂体系的组成(%重量)
组成 | 17-1 | 17-2 | 17-3 | 17-4 | 17-5 | 17-6 |
乙醇 | 70 | 65 | 65 | 62 | 68 | 65 |
水 | 30 | 30 | 30 | 30 | 30 | 30 |
甘油油酸酯 | 5 | |||||
水杨酸 | 5 | |||||
油醇 | 5 | |||||
麝香草酚 | 3 | |||||
月桂氧基硫酸钠 | 2 | |||||
丙酮 | 5 |
1ArlacelTM186
按前面实施例所述的方法,以300μl的体积测试组合物17-1到17-6的皮肤渗透性能,重复3次。皮肤通量数据列于表23中。
表23:饱和塞来考昔溶液的皮肤通量
组合物 | 皮肤通量(μg/cm2·天) |
17-1 | 2.60±2.02 |
17-2 | 18.21±11.04 |
17-3 | 6.02±2.86 |
17-4 | 14.16±0.48 |
17-5 | 4.05±1.29 |
17-6 | 4.99±1.03 |
实施例18
制备具有表24中所列组成的1%塞来考昔凝胶制剂。在第一个容器中,将水和吐温80混合,然后加入HPMC,直到HPMC完全分散。在第二个容器中,将乙醇、塞来考昔、丙二醇和桉树油混合。将所得混合物倾倒到第一个容器的混合物中,并混合完全。最后,在搅拌下缓慢加入羟丙基纤维素形成凝胶。
表24:塞来考昔凝胶制剂的组成(%重量)
塞来考昔 | 1.0 |
羟丙基纤维素 | 3.0 |
HPMC2910 | 3.0 |
吐温80 | 1.0 |
丙二醇 | 10.0 |
桉树油 | 0.2 |
乙醇 | 56.8 |
水 | 25.0 |
按前面实施例所述的方法测试所述组合物的皮肤渗透性能。以100μl的体积对所述凝胶制剂进行非闭合性测试。得出1%塞来考昔凝胶制剂的皮肤通量为7.58±1.19μg/cm2·天。
实施例19
将塞来考昔和伐地考昔制备成溶于70%乙醇水溶液的饱和溶液。按前面实施例所述方法测试所述溶液的皮肤渗透性能,采用来自不同皮肤捐赠人1-4和6的皮肤。皮肤捐赠人对这些溶液的塞来考昔和伐地考昔的皮肤通量的影响列于表25中。
表25:皮肤捐赠人对塞来考昔和伐地考昔的皮肤通量的影响
皮肤捐赠人 | 皮肤通量(μg/cm2·天) | |
塞来考昔 | 伐地考昔 | |
1 | 15.7±3.8 | |
2 | 12.8±5.0 | |
3 | 73.7±11.8 | 91.9±15.0 |
4 | 31.9±9.6 | 58.3±11.0 |
6 | 50.4±12.7 |
实施例20
按前文所述方法制备原型帕瑞考昔钠的凝胶制剂,其组成列于表26中。
表26:原型帕瑞考昔钠凝胶制剂
成分 | 原型凝胶体(%重量) |
帕瑞考昔钠 | 2 |
羟丙基纤维素 | 3 |
麝香草酚 | 1 |
油醇 | 3 |
乳酸十四烷酯 | 2 |
乳酸月桂酯 | 2.5 |
甘油二月桂酯 | 0.5 |
1,4-丁二醇 | 6 |
丙二醇 | 4 |
乙醇 | 46 |
水 | 30 |
Claims (96)
1.一种经皮给药的药物组合物,所述组合物含有治疗有效量的、溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中:(a)所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,和(b)所述组合物的试样所提供的治疗药物的皮肤渗透速率至少等于将所述治疗药物溶解于70%乙醇水溶液中得到的参比溶液所提供的皮肤渗透速率。
2.权利要求1的组合物,其中基本上所有的治疗药物均以已溶解形态存在。
4.权利要求1的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自塞来考昔、地拉考昔、伐地考昔、帕瑞考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮、(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸、2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮、5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸及其盐。
5.权利要求1的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自塞来考昔、伐地考昔、帕瑞考昔及其盐、罗非考昔和艾托考昔。
6.权利要求1的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自伐地考昔或其前药。
7.权利要求1的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自帕瑞考昔或其盐。
8.权利要求1的组合物,其中所述一元醇为C2-6一元醇。
9.权利要求8的组合物,其中所述C2-6一元醇选自乙醇、异丙醇、正丁醇和二甘醇单乙醚。
10.权利要求1的组合物,所述组合物为液体或半固体剂型。
11.权利要求10的组合物,所述组合物的剂型选自乳膏剂、糊剂、凝胶剂、软膏剂、洗液和气雾剂。
12.权利要求1的组合物,所述组合物的治疗药物皮肤渗透速率不小于大约10μg/cm2·天。
13.权利要求1的组合物,所述组合物的治疗药物皮肤渗透速率不小于大约25μg/cm2·天。
14.权利要求1的组合物,所述组合物还含有至少一种皮肤渗透促进剂。
15.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂选自萜烯、类萜、脂肪醇及其衍生物、脂肪酸及其烷基和甘油基酯、羟基乙酸的脂肪酸酯及其盐、脂肪醇的乳酸酯、月桂氮_酮及其衍生物、二甲亚砜、正癸基甲基亚砜、水杨酸及其烷基酯、N,N-二甲基乙酰胺、二甲基甲酰胺、N,N-二甲基甲苯酰胺、2-吡咯烷酮及其N-烷基衍生物、2-壬基-1,3-二氧戊环、桉树脑、脱水山梨糖醇酯及遮光剂。
16.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂选自油醇、水杨酸甲酯、NMP、麝香草酚、薄荷醇、香芹酮、香芹醇、柠檬醛、二氢香芹醇、二氢香芹酮、新薄荷醇、异胡薄荷醇、4-萜品醇、薄荷酮、胡薄荷醇、樟脑、香叶醇、α-萜品醇、里哪醇、香芹酚、反式-茴香脑,以及它们的异构体和外消旋混合物。
17.权利要求14的组合物,所述组合物含有脂肪醇和萜烯或类萜作为皮肤渗透促进剂。
18.权利要求14的组合物,所述组合物含有油醇和麝香草酚作为皮肤渗透促进剂。
19.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂选自油酸、月桂酸异丙酯、肉豆蔻酸异丙酯、油酸甲酯、甘油单月桂酸酯、甘油单油酸酯、甘油二月桂酸酯、甘油二油酸酯、月桂酰基羟乙酸酯、己酰基羟乙酸酯、椰油基羟乙酸酯、异硬脂酰基羟乙酸酯、月桂酰基羟乙酸钠、月桂酰基羟乙酸三甲铵、乳酸月桂酯、乳酸十四烷酯和乳酸油基酯。
20.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂为甘油单月桂酸酯。
21.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂为下式的化合物:
其中R1基团独立为氢、低级烷基、低级烷氧基、卤素、羟基或NR5R6基团,其中R5和R6独立为氢或低级烷基,或者R5和R6一起与其相连的氮原子形成5元或6元杂环;R2为C5-18线性、支化或环状烷基;R3为氢或苯基;R4为氢或氰基;n为0或1;且q为1或2。
22.权利要求14的组合物,其中所述至少一种皮肤渗透促进剂选自对-氨基苯甲酸(PABA)、对-二甲氨基苯甲酸、2-氨基苯甲酸、肉桂酸、对-甲氧基肉桂酸、水杨酸和2-氰基-3,3-二苯基丙烯酸的C5-18烷基酯。
23.权利要求1的组合物,其中所述治疗药物在所述组合物中的浓度为大约12.5到大约400mg/ml。
24.一种经皮给药的药用组合物,所述组合物含有溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中所述治疗药物含有至少一种选择性COX-2抑制药物或其前药,且在所述组合物中的浓度为大约12.5到大约400mg/ml。
25.权利要求24的组合物,其中基本上所有的治疗药物均以已溶解形态存在。
27.权利要求24的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自塞来考昔、地拉考昔、伐地考昔、帕瑞考昔、罗非考昔、艾托考昔、2-(3,5-二氟苯基)-3-[4-(甲磺酰基)苯基]-2-环戊烯-1-酮、(S)-6,8-二氯-2-(三氟甲基)-2H-1-苯并吡喃-3-甲酸、2-(3,4-二氟苯基)-4-(3-羟基-3-甲基-1-丁氧基)-5-[4-(甲磺酰基)苯基]-3-(2H)-哒嗪酮、5-甲基-2-(2’-氯-6’-氟苯胺基)苯乙酸及其盐。
28.权利要求24的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自塞来考昔、伐地考昔、帕瑞考昔及其盐、罗非考昔和艾托考昔。
29.权利要求24的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自伐地考昔或其前药。
30.权利要求24的组合物,其中所述至少一种选择性COX-2抑制药物或前药选自帕瑞考昔或其盐。
31.权利要求24的组合物,其中所述一元醇为C2-6一元醇。
32.权利要求31的组合物,其中所述C2-6一元醇选自乙醇、异丙醇、正丁醇和二甘醇单乙醚。
33.权利要求24的组合物,所述组合物为液体或半固体剂型。
34.权利要求33的组合物,所述组合物的剂型选自乳膏剂、糊剂、凝胶剂、软膏剂、洗液和气雾剂。
35.权利要求24的组合物,所述组合物的治疗药物皮肤渗透速率不小于大约10μg/cm2·天。
36.权利要求24的组合物,所述组合物的治疗药物皮肤渗透速率不小于大约25μg/cm2·天。
37.权利要求24的组合物,所述组合物还含有至少一种皮肤渗透促进剂。
38.权利要求37的组合物,其中所述至少一种皮肤渗透促进剂选自萜烯、类萜、脂肪醇及其衍生物、脂肪酸及其烷基和甘油基酯、羟基乙酸的脂肪酸酯及其盐、脂肪醇的乳酸酯、月桂氮_酮及其衍生物、二甲亚砜、正癸基甲基亚砜、水杨酸及其烷基酯、N,N-二甲基乙酰胺、二甲基甲酰胺、N,N-二甲基甲苯酰胺、2-吡咯烷酮及其N-烷基衍生物、2-壬基-1,3-二氧戊环、桉树脑、脱水山梨糖醇酯及遮光剂。
39.权利要求37的组合物,其中所述至少一种皮肤渗透促进剂选自油醇、水杨酸甲酯、NMP、麝香草酚、薄荷醇、香芹酮、香芹醇、柠檬醛、二氢香芹醇、二氢香芹酮、新薄荷醇、异胡薄荷醇、4-萜品醇、薄荷酮、胡薄荷醇、樟脑、香叶醇、α-萜品醇、里哪醇、香芹酚、反式-茴香脑,以及它们的异构体和外消旋混合物。
40.权利要求37的组合物,所述组合物含有脂肪醇和萜烯或类萜作为皮肤渗透促进剂。
41.权利要求37的组合物,所述组合物含有油醇和麝香草酚作为皮肤渗透促进剂。
42.权利要求37的组合物,其中所述至少一种皮肤渗透促进剂选自油酸、月桂酸异丙酯、肉豆蔻酸异丙酯、油酸甲酯、甘油单月桂酸酯、甘油单油酸酯、甘油二月桂酸酯、甘油二油酸酯、月桂酰基羟乙酸酯、己酰基羟乙酸酯、椰油基羟乙酸酯、异硬脂酰基羟乙酸酯、月桂酰基羟乙酸钠、月桂酰基羟乙酸三甲铵、乳酸月桂酯、乳酸十四烷酯和乳酸油基酯。
43.权利要求37的组合物,其中所述至少一种皮肤渗透促进剂为甘油单月桂酸酯。
45.权利要求37的组合物,其中所述至少一种皮肤渗透促进剂选自对-氨基苯甲酸(PABA)、对-二甲氨基苯甲酸、2-氨基苯甲酸、肉桂酸、对-甲氧基肉桂酸、水杨酸和2-氰基-3,3-二苯基丙烯酸的C5-18烷基酯。
46.一种经皮给药的药用组合物,所述组合物含有溶于可致溶量的药学上可接受的载体中的治疗药物,所述载体含有低分子量的一元醇,其中所述治疗药物含有伐地考昔和/或其前药,且在所述组合物中的浓度为大约0.5到大约400mg/ml。
47.权利要求46的组合物,其中所述治疗药物含有帕瑞考昔或其盐。
48.权利要求46的组合物,其中所述一元醇为C2-6一元醇。
49.权利要求48的组合物,其中所述C2-6一元醇选自乙醇、异丙醇、正丁醇和二甘醇单乙醚。
50.权利要求46的组合物,所述组合物为液体或半固体剂型。
51.权利要求50的组合物,所述组合物的剂型选自乳膏剂、糊剂、凝胶剂、软膏剂、洗液和气雾剂。
52.权利要求46的组合物,所述组合物还含有至少一种皮肤渗透促进剂。
53.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂选自萜烯、类萜、脂肪醇及其衍生物、脂肪酸及其烷基和甘油基酯、羟基乙酸的脂肪酸酯及其盐、脂肪醇的乳酸酯、月桂氮_酮及其衍生物、二甲亚砜、正癸基甲基亚砜、水杨酸及其烷基酯、N,N-二甲基乙酰胺、二甲基甲酰胺、N,N-二甲基甲苯酰胺、2-吡咯烷酮及其N-烷基衍生物、2-壬基-1,3-二氧戊环、桉树脑、脱水山梨糖醇酯及遮光剂。
54.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂选自油醇、水杨酸甲酯、NMP、麝香草酚、薄荷醇、香芹酮、香芹醇、柠檬醛、二氢香芹醇、二氢香芹酮、新薄荷醇、异胡薄荷醇、4-萜品醇、薄荷酮、胡薄荷醇、樟脑、香叶醇、α-萜品醇、里哪醇、香芹酚、反式-茴香脑,以及它们的异构体和外消旋混合物。
55.权利要求52的组合物,所述组合物含有脂肪醇和萜烯或类萜作为皮肤渗透促进剂。
56.权利要求52的组合物,所述组合物含有油醇和麝香草酚作为皮肤渗透促进剂。
57.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂选自油酸、月桂酸异丙酯、肉豆蔻酸异丙酯、油酸甲酯、甘油单月桂酸酯、甘油单油酸酯、甘油二月桂酸酯、甘油二油酸酯、月桂酰基羟乙酸酯、己酰基羟乙酸酯、椰油基羟乙酸酯、异硬脂酰基羟乙酸酯、月桂酰基羟乙酸钠、月桂酰基羟乙酸三甲铵、乳酸月桂酯、乳酸十四烷酯、乳酸油基酯。
58.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂为甘油单月桂酸酯。
59.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂为下式的化合物:
其中R1基团独立为氢、低级烷基、低级烷氧基、卤素、羟基或NR5R6基团,其中R5和R6独立为氢或低级烷基,或者R5和R6一起与其相连的氮原子形成5元或6元杂环;R2为C5-18线性、支化或环状烷基;R3为氢或苯基;R4为氢或氰基;n为0或1;且q为1或2。
60.权利要求52的组合物,其中所述至少一种皮肤渗透促进剂选自对-氨基苯甲酸(PABA)、对-二甲氨基苯甲酸、2-氨基苯甲酸、肉桂酸、对-甲氧基肉桂酸、水杨酸和2-氰基-3,3-二苯基丙烯酸的C5-18烷基酯。
61.一种经皮给药的药物组合物,所述组合物为糊剂、软膏剂、凝胶剂或乳膏剂,含有总量为1.25%到10%的至少一种选择性COX-2抑制药物或前药,总量为50%到97%的至少一种溶剂,总量为2%到20%的至少一种皮肤渗透促进剂,以及总量为1%到5%的至少一种增稠剂,含量基于重量计算。
62.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂选自萜烯、类萜、脂肪醇及其衍生物、脂肪酸及其烷基和甘油基酯、羟基乙酸的脂肪酸酯及其盐、脂肪醇的乳酸酯、月桂氮草酮及其衍生物、二甲亚砜、正癸基甲基亚砜、水杨酸及其烷基酯、N,N-二甲基乙酰胺、二甲基甲酰胺、N,N-二甲基甲苯酰胺、2-吡咯烷酮及其N-烷基衍生物、2-壬基-1,3-二氧戊环、桉树脑、脱水山梨糖醇酯及遮光剂。
63.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂选自油醇、水杨酸甲酯、NMP、麝香草酚、薄荷醇、香芹酮、香芹醇、柠檬醛、二氢香芹醇、二氢香芹酮、新薄荷醇、异胡薄荷醇、4-萜品醇、薄荷酮、胡薄荷醇、樟脑、香叶醇、α-萜品醇、里哪醇、香芹酚、反式-茴香脑,以及它们的异构体和外消旋混合物。
64.权利要求61的组合物,所述组合物含有脂肪醇和萜烯或类萜作为皮肤渗透促进剂。
65.权利要求61的组合物,所述组合物含有油醇和麝香草酚作为皮肤渗透促进剂。
66.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂选自油酸、月桂酸异丙酯、肉豆蔻酸异丙酯、油酸甲酯、甘油单月桂酸酯、甘油单油酸酯、甘油二月桂酸酯、甘油二油酸酯、月桂酰基羟乙酸酯、己酰基羟乙酸酯、椰油基羟乙酸酯、异硬脂酰基羟乙酸酯、月桂酰基羟乙酸钠、月桂酰基羟乙酸三甲铵、乳酸月桂酯、乳酸十四烷酯和乳酸油基酯。
67.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂为甘油单月桂酸酯。
68.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂为下式的化合物:
其中R1基团独立为氢、低级烷基、低级烷氧基、卤素、羟基或NR5R6基团,其中R5和R6独立为氢或低级烷基,或者R5和R6一起与其相连的氮原子形成5元或6元杂环;R2为C5-18线性、支化或环状烷基;R3为氢或苯基;R4为氢或氰基;n为0或1;且q为1或2。
69.权利要求61的组合物,其中所述至少一种皮肤渗透促进剂选自对-氨基苯甲酸(PABA)、对-二甲氨基苯甲酸、2-氨基苯甲酸、肉桂酸、对-甲氧基肉桂酸、水杨酸和2-氰基-3,3-二苯基丙烯酸的C5-18烷基酯。
70.一种经皮给药的药物组合物,所述组合物为乳膏剂、糊剂、凝胶剂、软膏剂、洗液或气雾剂,含有至少一种选择性COX-2抑制药物或前药以及遮光剂。
71.权利要求70的组合物,其中所述遮光剂为对-二甲基氨基苯甲酸辛酯,其用量为1%到10%重量。
72.一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或发炎部位的方法,所述方法包括将权利要求1的组合物局部给药到所述患者的皮肤。
73.权利要求72的方法,其中将所述组合物给药到皮肤上与疼痛和/或发炎部位相重叠或相邻的部位。
74.权利要求72的方法,其中所述疼痛和/或发炎部位位于表皮、真皮、皮下、肌肉或关节组织。
75.一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或发炎部位的方法,所述方法包括将权利要求24的组合物局部给药到所述患者的皮肤。
76.权利要求75的方法,其中将所述组合物给药到皮肤上与疼痛和/或发炎部位相重叠或相邻的部位。
77.权利要求75的方法,其中所述疼痛和/或发炎部位位于表皮、真皮、皮下、肌肉或关节组织。
78.一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或发炎部位的方法,所述方法包括将权利要求46的组合物局部给药到所述患者的皮肤。
79.权利要求78的方法,其中将所述组合物给药到皮肤上与疼痛和/或发炎部位相重叠或相邻的部位。
80.权利要求78的方法,其中所述疼痛和/或发炎部位位于表皮、真皮、皮下、肌肉或关节组织。
81.一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或发炎部位的方法,所述方法包括将权利要求61的组合物局部给药到所述患者的皮肤。
82.权利要求81的方法,其中将所述组合物给药到皮肤表面与疼痛和/或发炎部位相重叠或相邻的部位。
83.权利要求81的方法,其中所述疼痛和/或发炎部位位于表皮、真皮、皮下、肌肉或关节组织。
84.一种将选择性COX-2抑制药物靶向给药到患者的疼痛和/或发炎部位的方法,所述方法包括将权利要求70的组合物局部给药到所述患者的皮肤。
85.权利要求84的方法,其中将所述组合物给药到皮肤表面与疼痛和/或发炎部位相重叠或相邻的部位。
86.权利要求84的方法,其中所述疼痛和/或发炎部位位于表皮、真皮、皮下、肌肉或关节组织。
87.一种对患有由COX-2所介导的疾病的患者进行全身治疗的方法,所述方法包括将权利要求1的组合物经皮给药。
88.权利要求87的方法,其中将所述组合物与所述患者的不大于大约400cm2的皮肤面积相接触。
89.一种对患有由COX-2所介导的疾病的患者进行全身治疗的方法,所述方法包括将权利要求24的组合物经皮给药。
90.权利要求89的方法,其中将所述组合物与所述患者的不大于大约400cm2的皮肤面积相接触。
91.一种对患有由COX-2所介导的疾病的患者进行全身治疗的方法,所述方法包括将权利要求46的组合物经皮给药。
92.权利要求91的方法,其中将所述组合物与所述患者的不大于大约400cm2的皮肤面积相接触。
93.一种对患有由COX-2所介导的疾病的患者进行全身治疗的方法,所述方法包括将权利要求61的组合物经皮给药。
94.权利要求93的方法,其中将所述组合物与所述患者的不大于大约400cm2的皮肤面积相接触。
95.一种对患有由COX-2所介导的疾病的患者进行全身治疗的方法,所述方法包括将权利要求70的组合物经皮给药。
96.权利要求95的方法,其中将所述组合物与所述患者的不大于大约400cm2的皮肤面积相接触。
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MX (1) | MXPA03010991A (zh) |
NO (1) | NO20035325D0 (zh) |
OA (1) | OA12613A (zh) |
PL (1) | PL367337A1 (zh) |
SK (1) | SK14762003A3 (zh) |
TN (1) | TNSN03127A1 (zh) |
WO (1) | WO2002096435A2 (zh) |
ZA (1) | ZA200309298B (zh) |
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CN102939075A (zh) * | 2010-06-16 | 2013-02-20 | 高砂香料工业株式会社 | 经皮吸收促进剂及其外部皮肤制剂 |
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CN105663032A (zh) * | 2016-02-23 | 2016-06-15 | 青岛科技大学 | 一种维他昔布软膏剂的制备方法 |
CN105848730A (zh) * | 2013-12-24 | 2016-08-10 | 宝洁公司 | 提供增强的护肤活性物质渗透的化妆品组合物和方法 |
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-
2002
- 2002-05-30 PL PL02367337A patent/PL367337A1/xx not_active Application Discontinuation
- 2002-05-30 TN TNPCT/US2002/017067A patent/TNSN03127A1/fr unknown
- 2002-05-30 AP APAP/P/2003/002922A patent/AP2003002922A0/en unknown
- 2002-05-30 KR KR10-2003-7015581A patent/KR20040033286A/ko not_active Application Discontinuation
- 2002-05-30 BR BR0210104-1A patent/BR0210104A/pt not_active IP Right Cessation
- 2002-05-30 CZ CZ20033241A patent/CZ20033241A3/cs unknown
- 2002-05-30 EP EP02774123A patent/EP1404345A2/en not_active Withdrawn
- 2002-05-30 EA EA200301200A patent/EA200301200A1/ru unknown
- 2002-05-30 OA OA1200300310A patent/OA12613A/en unknown
- 2002-05-30 IL IL15910002A patent/IL159100A0/xx unknown
- 2002-05-30 CA CA002448627A patent/CA2448627A1/en not_active Abandoned
- 2002-05-30 SK SK1476-2003A patent/SK14762003A3/sk unknown
- 2002-05-30 US US10/158,342 patent/US20030161867A1/en not_active Abandoned
- 2002-05-30 CN CNA028149467A patent/CN1547474A/zh active Pending
- 2002-05-30 MX MXPA03010991A patent/MXPA03010991A/es unknown
- 2002-05-30 JP JP2002592944A patent/JP2004532871A/ja not_active Withdrawn
- 2002-05-30 HU HU0600294A patent/HUP0600294A2/hu unknown
- 2002-05-30 WO PCT/US2002/017067 patent/WO2002096435A2/en not_active Application Discontinuation
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- 2003-11-28 NO NO20035325A patent/NO20035325D0/no not_active Application Discontinuation
- 2003-11-28 CO CO03105192A patent/CO5640125A2/es not_active Application Discontinuation
- 2003-11-28 MA MA27417A patent/MA27030A1/fr unknown
- 2003-11-28 EC EC2003004869A patent/ECSP034869A/es unknown
- 2003-11-28 CR CR7173A patent/CR7173A/es not_active Application Discontinuation
- 2003-11-28 ZA ZA200309298A patent/ZA200309298B/xx unknown
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102939075A (zh) * | 2010-06-16 | 2013-02-20 | 高砂香料工业株式会社 | 经皮吸收促进剂及其外部皮肤制剂 |
CN104188942A (zh) * | 2010-06-16 | 2014-12-10 | 高砂香料工业株式会社 | 经皮吸收促进剂及其外部皮肤制剂 |
CN105073109A (zh) * | 2013-03-29 | 2015-11-18 | 株式会社AskAt | 眼部疾病用治疗剂 |
CN105073109B (zh) * | 2013-03-29 | 2019-03-22 | 株式会社AskAt | 眼部疾病用治疗剂 |
CN105848730A (zh) * | 2013-12-24 | 2016-08-10 | 宝洁公司 | 提供增强的护肤活性物质渗透的化妆品组合物和方法 |
CN105663032A (zh) * | 2016-02-23 | 2016-06-15 | 青岛科技大学 | 一种维他昔布软膏剂的制备方法 |
CN106267218A (zh) * | 2016-10-18 | 2017-01-04 | 华北理工大学 | 4‑萜品醇脂肪酸酯衍生物及其应用和制备方法 |
Also Published As
Publication number | Publication date |
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JP2004532871A (ja) | 2004-10-28 |
WO2002096435A3 (en) | 2003-05-01 |
US20030161867A1 (en) | 2003-08-28 |
CR7173A (es) | 2004-04-22 |
TNSN03127A1 (fr) | 2005-12-23 |
NO20035325D0 (no) | 2003-11-28 |
MA27030A1 (fr) | 2004-12-20 |
HUP0600294A2 (en) | 2007-02-28 |
CA2448627A1 (en) | 2002-12-05 |
ECSP034869A (es) | 2004-07-23 |
MXPA03010991A (es) | 2004-02-27 |
CO5640125A2 (es) | 2006-05-31 |
AP2003002922A0 (en) | 2003-12-31 |
CZ20033241A3 (cs) | 2004-08-18 |
ZA200309298B (en) | 2004-05-12 |
IS7055A (is) | 2003-11-27 |
WO2002096435A2 (en) | 2002-12-05 |
BR0210104A (pt) | 2004-06-08 |
IL159100A0 (en) | 2004-05-12 |
KR20040033286A (ko) | 2004-04-21 |
SK14762003A3 (sk) | 2004-08-03 |
EP1404345A2 (en) | 2004-04-07 |
EA200301200A1 (ru) | 2004-06-24 |
PL367337A1 (en) | 2005-02-21 |
OA12613A (en) | 2006-06-09 |
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