CN1289091C - 治疗炎症的药物组合物和相关用途 - Google Patents
治疗炎症的药物组合物和相关用途 Download PDFInfo
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- CN1289091C CN1289091C CNB998047996A CN99804799A CN1289091C CN 1289091 C CN1289091 C CN 1289091C CN B998047996 A CNB998047996 A CN B998047996A CN 99804799 A CN99804799 A CN 99804799A CN 1289091 C CN1289091 C CN 1289091C
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- tocopherol
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Abstract
通过服用一种甾体抗炎药或非甾体抗炎药并连同多不饱和脂肪酸或其衍生物,还有任选的药物活性抗氧化剂治疗胃肠道和/或全身或局部炎症的方法以及描述了实施这些方法的组合物。
Description
本发明是申请序号为09/022,008(1998年2月11日申请的)的延续部分。
本发明提供了可预防、减轻或治疗胃肠道炎症和全身或局部炎症的组合物,所述组合物含有抗炎药物,并组合多不饱和脂肪酸原料,诸如ω-3、ω-6和ω-9多不饱和脂肪酸,还有任选的药物活性抗氧化剂原料,如生育酚(例如,α-和/或γ-生育酚)。同时也描述了通过口服、局部或其它方式,用本发明组合物对哺乳动物给药来预防、减轻或治疗这类炎症的方法。
发明背景
本发明涉及治疗“胃肠道”(GIT)炎症的方法和组合物;对于那些不是胃肠道的炎症,但却是胃肠道炎症引起的后遗症的炎症;以及不涉及胃肠道炎症的全身或局部(即非肠道)炎症也是适应的。
炎症(定义如下)可以是慢性的或急性的或者介于两者之间的。胃肠道炎症病因学可以归因于各种不同的感染,对药物或其它外源性物质(刺激性的)不同反应或多种病如肠炎病(局限性回肠炎;溃疡性结肠炎)。本发明原来的焦点是肠炎,但是想仅仅是做个例子,并不局限或限制于该病,炎症部位或类型。
作为本发明提到的病的实例,肠炎的特征是有不同的病活动期,即,静止期、中间期和急性(活动)期。从无到轻微和可以忍受到剧烈和需要住院治疗取决于病期。该病的病因学是未知的,但是其主要病理生理学认为这似乎是胃肠道内“过度炎症”的结果。在疾病的中间期和急性期,可发生肠外(全身)连累炎症,即,眼炎,关节炎。全身症状本身是病理生理学中的炎症并且提出分立的处置方法。
肠炎的慢性期和急性期治疗包括但不局限于药物疗法。在静止期,即缓和期时,某些病人不需要医疗,尽管饮食管理常被限定为附加疗法(见下文)。在中间期时,病人经受了以各种低(维持)剂量药物时可以忍受的轻微症状。所使用的药物包括甾体类和非甾体类抗炎药物(即甾体类,如强的松和强的松龙),还有5-氨基水扬酸衍生物(即氨基水扬酸,柳氮磺胺吡啶,奥沙拉秦和巴柳氮)及其它统称为“免疫抑制的”药物(例如,环孢霉素,硝基咪唑硫嘌呤和6-巯基嘌呤)最后,通常要限定附加食疗。
在肠炎的活动期,例如,局限性回肠炎,需要强化药物治疗,有时需要在医院环境中进行。应使用比慢性活动期更高剂量的甾体类和免疫抑制类药物。最近人们已开始使用一种新型甾体类药物,布地奈得(Astra)。Rutgeerts在1994年发现布地奈得较强的松在治疗局限性回肠炎(CD)急性期一样有效且副作用更小。布地奈得特别有用,因为它可“局部地”进入到胃肠道腔内侧,该部位在局限性回肠炎中是炎症的部位;这可减少体循环中药物的不良高浓度,其可以出现药物相反的临床表现。此外,给予布地奈得或其它局部活性药物的缓释制剂是优选的治疗方案。
附加疗法通常包括不同类型和范围的饮食改变。对于处于缓和期的病人,通常不用治疗。然而,对于处于活动期病人,我们就要尽力推迟其旧病复发。我们常尽量使用饮食疗法。例如,应该限定病人食用低残渣(纤维)和“温和的”食物。最近的研究表明:一年中每天服用ω-3多不饱和脂肪酸来源的病人比服用安慰剂油的病人复发的可能性要小。对于中间期症状,低剂量疗法可以与上述提到类似的限定饮食结合治疗。
某些病人在急性期病情如此严重以致于整个肠会停止蠕动,因此,病人需要以完全胃肠外营养(TPN)的方式供给营养。另外一些病人情况会好些,或许他们也会用药物及用被称为“医疗食物”的特殊食物进行治疗。医疗食物通常是有规定配方的液体并且是对特别病要进行饮食管理的而且是要在医生监督下服用的食物。因为慢性期的肠炎常常会引起病人部分厌食并可能会产生吸收障碍以及会出现常见的营养不良情况。如此营养不良可以导致必需脂肪酸(EFA)的缺乏。食疗常常是必需脂肪酸(EFA)好的来源。一旦病情稳定,可以安排病人食用限定食物(低残渣;“温和的”)。只有当症状缓解时,才可开始食用“正常”食物。
某些治疗食物的“治疗”(即缓解感应)性质引起了关于鉴别起作用的饮食成分及其作用机理的思考。这种饮食的许多食物成分在这一点上引起了注意。特别是被称为“ω-3多不饱和脂肪酸”(“ω-3”)和如甘油三酸酯和酯衍生物的脂质成分,其本身具有抗炎代谢性质。事实上,ω-3在哮喘,风湿性关节炎及癌症的临床试验中已经显示出具有抗炎作用。最近的临床试验表明ω-3能降低病人“缓和期”局限性回肠炎的复发率(Belluzzi等,1996)。这与ω-3抗炎作用相一致。其它临床研究已经表明了在治疗肠病时补充ω-3的益处(Stenson等,1992;Mate等,1991;和其它参考文献Belluzzi等,1996)。应用富含ω-6和ω-9多不饱和脂肪酸脂质来源的其它研究也进一步表明了患有肠炎的病人可以通过补充合适的食物以缓解症状。同时,本发明的主要中心意思是将抗炎药物与富含ω-3多不饱和脂肪酸精制食用油结合使用,其它富含多不饱和脂肪酸来源的,如ω-6和ω-9多不饱和脂肪酸可以替代ω-3制剂。本发明中一直提到的ω-3的用途仅仅是想作为一个例子而并非对药物和油制剂的规格有所局限或限制。
本发明中提到的加入抗氧化剂对临床和制剂都有益。其仅作为一个例子但并不限于本发明。被明确地称为“维生素E”的营养剂是由一种生育酚异构体混合物组成,其中α和γ形最常见于血液中和大多数食物中。生育酚是体外有效的抗氧化剂并且通常要被加入到多不饱和脂肪酸的制剂中以使其氧化减少到最小。生育酚在动物和人体中也会发挥其有益的作用,可能是因为其抗氧化性质。我们尚未意识到所研究的生育酚与治疗胃肠道炎症有关,但其有效的临床作用可以是作为稳定剂型原因之外加入制剂中的第二个原因。最近研究表明生育酚α和γ异构体在其抗氧化能力特性方面有所不同,也就是两种形的结合理论上会对过氧化起到较好的全面的保护作用。
药物和营养剂,ω-3及生育酚的结合使用可以提高肠炎和其它炎症的治疗效果,比添加方式更加有效,这是本发明的主题。
发明概述
本发明提供了治疗胃肠道和/或体内非胃肠道部位慢性或急性炎症临床表现的方法和组合物。组合物包括多不饱和脂肪酸来源,诸如ω-3和/或ω-6和/或ω-9脂肪酸,包括其甘油三酯和酯;可用于治疗医学病症的药物及任选的药物活性抗氧化剂来源(优选生育酚α和γ异构体的结合物)。也包括任选的可药用载体,包括其它精制油和非精制油、稀释剂、粘度调节剂、稳定剂、能消化或可吞服基质和穿透增强剂。
发明详述
本发明提供了一种口服、肠溶、或局部制剂,所述制剂含有多不饱和脂肪酸原料或形式,例如ω-3,和任选的药物活性抗氧化剂来源或形式如生育酚以及抗炎非甾体药物或抗炎甾体药物如布地奈得,为治疗体内胃肠道和/或非胃肠道部位的炎症,该制剂将抗炎药剂,如布地奈得与合适的高纯度的多不饱和脂肪酸原料,如ω-3或与高纯化或精制油结合使用,这样可以提供含有完全溶解药物或不同程度悬浮药物的制剂。富集脂肪酸量的变化,油的来源,所用油的类型(例如,游离脂肪酸,乙酯或甘油三酯)和/或加入药用赋形剂,如载体,包括其它精制和非精制油、稀释剂、粘度调节剂、稳定剂、能消化或可吞服基质、穿透增强剂可以用来改进药物在制剂中的溶解度。另外,可以用同样的方法来提高或减少制剂中的药物和/或油的成分的吸收,还可以改变制剂的各种物理特性,如粘度、扩展性及滞留时间。本发明具体讲授了例如肠道内药物释放可以通过加入合适的赋形剂(如上详述)或通过用各种类型或各种类型结合的高纯化多不饱和脂肪酸以改变制剂的特性来控制。此改进会适合于所选定的疾病靶向,即,以实例详述所出现炎症反应的类型、位置和程度。优选但不独有地,该制剂优选应用具有固有抗炎性质的高精制油,例如,ω-3、ω-6和ω-9的多不饱和脂肪酸族。因此,该制剂能有效地防止或减少某些疾病的急性骤发;能减少所需有效药物剂量;及能降低与药物相关的副作用。该制剂也可以减少疾病慢性全身效应的发病率或严重性。最后,该制剂还可减少发病率或治疗药物成分副作用的严重性。ω-3和/或ω-6和/或ω-9的作用及任选的抗氧化剂成分或所有组分的结合物都可以允许以最初较低的剂量或最后“逐渐减少”的剂量或通常规定和有效的药物组分的维持剂量。减少药物剂量又不影响临床疗效的特性是本发明的一部分。
我们还惊奇地发现如富含ω-3多不饱和脂肪酸油的存在,除了其在医疗方面的相当潜在益处外,还可以作为抗炎药物的载体而起作用。在某些例子中,高纯度油,例如ω-3可作为能使药物缓慢释放的悬浮介质而起作用,在其它情况下,它们能部分或全部地溶解药物而使其药物快速释放或药物吸收。制剂中药物溶解度的改变可通过加入如上详述的各种药剂,或应用不同种类的或不同类型高精制油的结合物来实现。
如果使用ω-3油加入到制剂中,其益处包括如下三点,首先,充足精制脂肪酸在某些患有肠炎病人中显示出比正常要低,其次,因为生育酚(维生素E)的作用在营养不良或肠炎情况下也常常要减弱,因此制剂中充满了加入这种维生素是有益的,再次,生育酚作为抗氧化剂来保护多不饱和脂肪酸。
本说明书中和附加权利要求书中所用的下列术语定义如下:“治疗”是指下述的任何一种或全部解释:
●防止复发,即维持缓解
●胃肠道炎症急性期的缓解感应,不管病因学如何。
●对其它治疗方法无效的病人和/或甾体类药依赖型或依赖其它疗法的病人的上述两种解释。
●无论是在胃肠道或是其它什么部位,即,全身性或局部,防止或减少疾病的影响,。
●无论是在急性期还是在非急性期所需药物剂量的减少。
●治疗药物组分副作用的降低。
“炎症”这里是指对传染或对物理或化学损伤有反应,在身体局部内发红、发热、肿胀、疼痛并常伴有疼痛或令人烦乱的症状。与本发明相关的生化介质和炎症效应部还包括“二十烷类”,所述二十烷类是从精制脂肪酸包括ω-3中的白细胞中得到。已知从ω-3产生出的二十烷类能使炎症减少或其有抗炎作用。这些二十烷类也可以是“免疫抑制剂”。从ω-3多不饱和脂肪酸产生出的二十烷类部分地说明了其抗炎作用。然而,ω-3多不饱和脂肪酸其它生理和生化性质有助于其在抗炎方面的有效作用。ω-3和ω-9多不饱和脂肪酸的抗炎性质没有许多文件证明,但是其可提供虽有些不同然而重叠机理相似的潜在好处。
“胃肠道”炎症这里是指胃肠道,从口到肛门任何部分所发生或有发生危险的炎症。
“全身或局部炎症”这里是指除了胃肠道以外的体内任何部位包括皮肤所发生或有发生危险的炎症。
在组合物中出现的和本发明方法中所用的药物是目前可用于治疗肠炎的抗炎药。合适的的抗炎药包括皮质甾类,如强的松、氢化可的松、替可的松、倍他米松、布地奈得;非甾体类抗炎药物(NSAIDs)包括氨基水扬酸类如5-氨基水扬酸(氨基水扬酸)及其衍生物包括柳氮磺胺吡啶和奥沙拉秦。
其它可以考虑的药物包括烟碱和抗生素如灭滴灵和环丙氟派酸。
“ω-3”这里是指含有该化学名称任何或全部多不饱和脂肪酸和其衍生物包括甘油三酯和酯的油,包括但不限于二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)。脂肪酸可以是甘油三酸酯、甘油二酸酯或甘油酯或其“游离”形,如乙基酯。来源包括:动物(如,鱼);植物(如,月见草油、琉璃苣);其它活的来源,如,海藻、细菌、和酵母以及它们“生物工程”衍生形;已被纯化,改进或合成的制品;和“ω-3”前体。也还包括的有水溶性的衍生物。“ω-6”和“ω-9”这里是指含有该化学名称任何或全部多不饱和脂肪酸和其衍生物的油,如ω-3所述。ω-3、ω-6和ω-9的多不饱和脂肪酸可以代表性地以每天1-6克的量服用,可能每天至多30克,但对多数适应症来说,通常每天要服用约3克。然而,因为服用多不饱和脂肪酸的确切量取决于ω-3、ω-6或ω-9来源的纯度、服用药的部位、用于与多不饱和脂肪酸结合使用的抗炎药物的相对量、正在治疗的适应症,所用的多不饱和脂肪酸的实际量会比每天1克的量要低得多。
“抗氧化剂”这里是指已知的或被认为是具有体外和/或体内抗氧化剂作用的,也就是具有药理活性的任何天然产生的或合成的化学品。实例包括几种维生素,诸如生育酚、抗坏血酸盐和β-胡萝卜素。
“生育酚”这里是指任何来源、形式、异构体、或衍生物的生育酚(“维生素E”),特别指α-和γ-异构体的混合物。
维生素E,通常是D-α-生育酚,是在100,400和1,000IU胶囊中以食品添加的方式得到。对本发明来说,通常日剂量约为400IU。然而,因为本发明的目的是能够使组分的任何一种或全部逐渐减小以促进炎症过程的干预,因此抗氧化剂的用量开始可以要比日剂量低得多或没有。而且,生育酚和其它抗氧化剂常常特别地要加到药物制剂中以减少氧化。因此,既然本发明具体涉及一种含有ω-3、ω-6或ω-9多不饱和脂肪酸的制剂,为本发明起见,抗氧化剂用量将通过所加入的抗氧化剂抗氧化活性仅局限于制剂和/或最大忍受剂量。
对人类治疗的方法和组合物在此描述作为参考,然而,它们也可以用于兽医领域,特别是用于治疗家畜和商品家畜。
为了说明起见,考虑用布地奈得作为所使用的抗炎药物,可以以单剂量或等分剂量改变剂量至多每天9mg(推荐日剂量),但通常是在每剂量3mg至每天3个剂量。最大的忍受剂量还不知道,所用的最大剂量将取决于由医疗专业人员做出疗效和不利作用的比较。请参见U.S.5,643,602,其公开物在此引入作为参考,其中列举了说明性的抗炎甾体、剂量和其它资料。
本发明的组合物包括各种介绍和制剂,例如,所有三“组分”都包括在以单一剂型如胶囊或适于口服用的液体或用于食道或胃肠适应症的局部施用制剂。通过pH溶解-依赖包衣的肠衣片或胶囊将固体口服剂型作成制剂使药物释放到需要治疗的部位。局部施用和眼药制剂,经皮片,溶液/悬浮液/乳剂也包括在本发明中的范围。
治疗用组合物的基本成分可分别按不同时间或同一时间,同时、连续或一起以方便的单一剂量给药。
本发明的制剂适合任何常规路径给药,包括但不限于下述路径:口服、小肠内(管饲)、直肠、眼部、经皮、皮下、肌肉内、腹膜内或静脉内。
药物与ω-3的优选相对比例是ω-3的日剂量为每天0.1-30.0克而生育酚和其它活性组分的相对比例是生育酚的日剂量为每天1-1000IU。
组分可以溶解在例如ω-3多不饱和脂肪酸来源的油载体中。
本发明包括几种实施方案,例如由下述说明的但不局限于:在一种实施方案中,组合物是由一种ω-3和/或ω-6和/或ω-9的来源,一种抗氧化剂来源,例如生育酚以及一种药物,如布地奈得组成。
在一种实施方案中,脂质组分是鱼(海产)油或相对富含ω-3的馏分。抗氧化剂来源例如生育酚(例如,α-和/或γ-生育酚)加入到ω-3中。
在一种实施方案中,脂质组分得自于植物来源,其可用于高含量的ω-3或ω-6或ω-9。
在一种实施方案中,脂质组分是合成的、纯化的、或本身富含ω-3、ω-6或ω-9多不饱和脂肪酸(例如,ω-3的EPA,DHA)来源的组分。其可以是甘油酯、甲基/乙基酯形式或其它相似的可生物利用形式。
在一种实施方案中,本发明制剂含有下列物质作为活性成分:多不饱和脂肪酸来源(ω-3和/或ω-6和/或ω-9);药物(例如,布地奈得);以及抗氧化剂,例如生育酚(例如,α-和/或γ-生育酚),也可以用其它类似的药物来替代或与布地奈得结合使用。
在一种实施方案中,在组合物中,所述脂质来源是包含ω-3和/或ω-6和/或ω-9多不饱和脂肪酸并具有至少50%的脂质含量的精制油。
在一种实施方案中,所述组合物是具有高粘度的并且含有部分悬浮的布地奈得或其前药或衍生物。
在一种实施方案中,所述组合物是具有低粘度的并且含有部分悬浮的布地奈得或其前药或衍生物。
在一种实施方案中,将所述组合物制成胶囊和肠溶包衣使约55%的药物释放和/或运送到小肠近端。
在一种实施方案中,将所述组合物制成胶囊和肠溶包衣使约25%的药物释放和/或运送到小肠末梢。
在一种实施方案中,将所述组合物制成胶囊和肠溶包衣使约25%的药物释放和/或运送到升结肠和横断结肠。
因为本发明本意是为治疗胃肠道炎症以及全身和局部炎症,多样制剂对本发明来讲是优选的但不是主要的。多样制剂是指以多不饱和脂肪酸和药物不同比例制成的许多制剂。例如,考虑到稳定性的作用,虽然可以调节比例但所呈现的ω-3对抗氧化剂的比例优选不变。当保持不变剂量的营养物(ω-3,生育酚)时,允许逐渐减少治疗组合物中的药物组分。此外,因为病人对药的反应不同,而且同一病人在不同的时间反应也不同,因此,可以改变“最佳”剂量(即,ω-3:药物比例)。最初要逐个确定。允许选择配制得当剂量的多样制剂以适应这种情况。
多样制剂的另外对策是保持ω-3:药物的比例不变,但是随着时间的过去会减少总剂量。多样的减少的剂量使病人能以逐渐减量的方式继续服用同样数量的药物或单一剂型如胶囊或日常用的剂型。另外,应该注意的是,对于针对特定肠内靶向的制剂来说,可以改进所用油的类型或选择能快速或稍慢吸收的油,因此提供了立即或延迟吸收的药物。
本发明以涉及要治疗炎症的部位的下述一般制剂来进一步说明。
型1:在具高或低粘度的游离脂肪酸中,使完全溶解的布地奈得形成胶囊,能使药释放到小肠近端的肠衣胶囊制剂。
释放后:油和布地奈得立即吸收而对制剂分散没有作用。
病灶部位:全身性炎症。
型2:在具高或低粘度的甘油三酯脂肪酸中,使完全悬浮的布地奈得形成胶囊,使药释放到小肠近端的肠衣胶囊制剂。
释放后:油能立即吸收而布地奈得延迟吸收,一些制剂分散。
病灶部位:全身性炎症或小肠近端炎症。
型3:在具高或低粘度的甘油三酸酯混合物中,使完全溶解的布地奈得形成胶囊,使药释放到小肠末梢的肠衣胶囊制剂。
释放后:某些情况油能延迟吸收而某些情况布地奈得能立即吸收,制剂分散,并且药物滞留时间呈微小变化。
病灶部位:末梢小肠病和升结肠。
型4:在具高粘度的甘油三酸酯脂肪酸中,使完全悬浮的布地奈得形成胶囊,使药释放到小肠末梢的肠衣胶囊制剂。
吸收:某些情况油能延迟吸收,布地奈得也延迟吸收,最大量制剂分散有些药物滞留时间要增加。
病灶部位:末梢小肠、升结肠和横断结肠。
型5:在具有低粘度的游离脂肪酸中,使完全溶解的布地奈得形成胶囊,使药释放到升结肠的肠衣胶囊制剂。
吸收:油和布地奈得立即吸收,制剂分散,并且有短的滞留时间。
病灶部位:升结肠和横断结肠。
型6:在具有高粘度的甘油三酸酯中,使完全悬浮的布地奈得形成胶囊,使药释放到升结肠的肠衣胶囊制剂。
吸收:油和布地奈得延迟吸收,最大量制剂分散并且有长的滞留时间。
病灶部位:升结肠和横断结肠。
应当理解,应用本发明讲授所述病症对制备该制剂的本领域技术人员和治疗此种病症的技术人员来说是显而易见的。
本发明的另外特点和优点在如下优选实施方案中有所描述,所述实施例是想作为例子而非限于此。
优选实施方案
实施例#1:
表
1.赋形剂
2.α-和γ-异构体的混合物,要确定的比例。
3.在U.S.5,643,602中所描述的差向(立体)异构体
下面仔细考虑过的局限性回肠炎临床病例是作为治疗肠炎方法的实例而提出的而非局限于此。其它治疗全身或局部炎症反应的说明没有提出来,因为其所包括的原理相似并且对于基于个别临床表现观察和本发明组合物的优选实施方案熟悉此行的读者来说是清楚的。
实施例#1.
一家医院急诊室两位成人患者,每位检查出有过急性局限性回肠炎复发。每位都有5年以上的局限性回肠炎病史并且每8-10个月有过急性发作。病人#1的CDAI分值为410,指示出严重的疾病发作(CDAI一般是用于表示疾病严重性的指标;分值直接涉及其严重性)。病人开始服用布地奈得,9mg/天,一天两次。如果病情充分改善,计划将剂量在第8-10周内逐渐减量到6mg,然后到3mg。
病人#2的CDAI分值为450,至少与病人#1的病情一样严重。该病人也开始服用布地奈得制剂,9mg/天,所不同是该制剂含有ω-3/生育酚(见表)。也计划在第8周内逐渐减量。两名受试者都不知道他们正在服用的是那种制剂。两名受试者开始吃简单的治疗食物以获得100%的营养,所述医疗食物在其内容物上不是“基本的”而是含有少量的ω-3。
病人#1(服用布地奈得的病人)显示出CDAI分值的逐渐下降,从410基线降到第二周时的290;第四周时220;在服用6周时逐渐稳定在145。将布地奈得用量在第8周时降低到6mg/天,及3mg/天;在第12周停止用药。在6周内病人严格限制饮食。在第10周,患者逐渐吃“温和的”,低残渣的食物,在第12周,可以吃“正常”食物。在第14周,病人被认定为完全康复。
病人#2(服用布地奈得+ω-3的病人)显示出CDAI分值的下降,从450基线降到第二周时的220;第四周时进一步下降到170;在服用第6周时稳定在120,该病人在第6周时开始吃“温和的”,低残渣的食物,在第8-9周,可以吃“正常”食物。在第10周,病人被认定为完全康复。
实施例II.
两位患有局限性回肠炎(CD)的病人,在上10个月内,处于症状缓解期,拍片发现复发的可能性很大。该认定基于炎症生化制造物的提高,即C-反应蛋白质(CRP)、α-1酸醣蛋白和红血球沉降率(ESR)。病人#1开始服用布地奈得“预防”剂量,2mg/天,BID,病人#2开始服用一种布地奈得制剂,日剂量为1.0mg/天;ω-3,剂量为3.0g/天;以及生育酚,剂量为75IU/天。两位病人也碰巧都出现肠外(全身)炎症,包括关节炎和结膜炎。病人和医生都不知道其药方的成分。继续服用每种制剂直至病人康复或一年时间。
病人#1(服用布地奈得的病人)服用后2个月时,显示出炎症制造物值的增加,在第4个月时,增加更多。服用第4个月后不久,分析血样,病人的胃肠道炎症临床症状开始恶化,在第5个月之前,病人被认定为完全复发。允许病人住院度过稳定期,并开始服用含有布地奈得+ω-3的制剂;在治疗的第8周进入缓解期。病人的全身症状没有变化。
病人#2在服用2个月时显示出稳定的生化危险因子,在第4个月时,其危险因子出现明显的降低,在第6个月时,出现完全正常值。病人在第12个月时,终止治疗研究,病人病情没有复发。病人的全身症状在6个月内有显著改善。病人这时可以停止服用布地奈得,但随后可选择继续服用ω-3的商品制剂。
Claims (18)
1.布地奈得或其前药或衍生物、选自ω-3、ω-6、或ω-9多不饱和脂肪酸或其衍生物的一种或多种、和有效量的生育酚在制备用于治疗动物胃肠道和/或全身或局部炎症的药物中的用途。
2.权利要求1的用途,其中生育酚是α-和γ-异构体的混合物。
3.根据权利要求1的用途,其中选自ω-3、ω-6、或ω-9多不饱和脂肪酸或其衍生物的一种或多种是甘油三酸酯、甘油二酸酯或甘油酸酯、甲基酯或乙基酯、游离脂肪酸的形式或其它可生物利用形式。
4.治疗哺乳动物炎症的药物组合物,所述组合物主要由布地奈得或其前药或衍生物、选自ω-3、ω-6、或ω-9多不饱和脂肪酸或其衍生物或其脂质来源的一种或多种和生育酚组成,也包括或不包括可药用载体。
5.权利要求4的药物组合物,其中可药用载体选自稀释剂、粘度调节剂、稳定剂、能消化或可吞服基质、穿透增强剂。
6.权利要求4的药物组合物,其中生育酚是α-和γ-异构体的混合物。
7.权利要求4的药物组合物,其中所述脂质来源是包含选自ω-3、ω-6、或ω-9多不饱和脂肪酸的一种或多种并具有至少50%的脂质含量的精制油。
8.权利要求4的药物组合物,其中选自ω-3、ω-6、或ω-9多不饱和脂肪酸或其衍生物的一种或多种是甘油三酸酯、甘油二酸酯或甘油酸酯、甲基酯或乙基酯、游离脂肪酸的形式或其它可生物利用形式。
9.权利要求4的药物组合物,其中布地奈得或其前药或衍生物是完全溶解的。
10.权利要求4的药物组合物,其中布地奈得或其前药或衍生物是完全悬浮的。
11.权利要求4的药物组合物,其中布地奈得或其前药或衍生物是部分悬浮的。
12.权利要求4的药物组合物,其中组合物提供选自ω-3、ω-6、或ω-9多不饱和脂肪酸或其衍生物的一种或多种的剂量是0.1-30g/天。
13.权利要求4的药物组合物,其中所说的组合物是通过口服用药的,其中炎症是胃肠道炎症,其中脂质来源是高精制油来源。
14.权利要求4的药物组合物,其中所说的组合物是通过口服用药的,并且其中炎症是全身或局部炎症,脂质来源是高精制油来源。
15.权利要求13或14的药物组合物,其中将所述组合物制成胶囊和肠溶包衣使约55%的药物释放和/或运送到小肠近端。
16.权利要求13的药物组合物,其中将所述组合物制成胶囊和肠溶包衣使约25%的药物释放和/或运送到小肠末梢。
17.权利要求13的药物组合物,其中将所述组合物制成胶囊和肠溶包衣使约25%的药物释放和/或运送到升结肠和横断结肠。
18.权利要求4的药物组合物,其中所说的组合物是通过局部用药的,并且其中炎症是全身或局部炎症。
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-
1999
- 1999-02-10 ES ES99906801T patent/ES2201673T3/es not_active Expired - Lifetime
- 1999-02-10 WO PCT/US1999/002671 patent/WO1999040906A2/en active IP Right Grant
- 1999-02-10 CA CA2320807A patent/CA2320807C/en not_active Expired - Fee Related
- 1999-02-10 EP EP99906801A patent/EP1054678B1/en not_active Expired - Lifetime
- 1999-02-10 DE DE69908304T patent/DE69908304T2/de not_active Expired - Lifetime
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- 1999-02-11 TW TW088102197A patent/TW568783B/zh not_active IP Right Cessation
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2002
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2007
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ATE241363T1 (de) | 2003-06-15 |
HK1039281A1 (en) | 2002-04-19 |
DE69908304D1 (de) | 2003-07-03 |
EP1054678A2 (en) | 2000-11-29 |
DE69908304T2 (de) | 2004-02-19 |
EP1054678B1 (en) | 2003-05-28 |
ES2201673T3 (es) | 2004-03-16 |
HK1039281B (zh) | 2007-08-03 |
CN1307477A (zh) | 2001-08-08 |
US20070259037A1 (en) | 2007-11-08 |
WO1999040906A2 (en) | 1999-08-19 |
WO1999040906A3 (en) | 2000-04-06 |
CA2320807A1 (en) | 1999-08-19 |
AU2662599A (en) | 1999-08-30 |
TW568783B (en) | 2004-01-01 |
CA2320807C (en) | 2011-01-18 |
IL137734A0 (en) | 2001-10-31 |
SE0002843L (sv) | 2000-10-03 |
SE0002843D0 (sv) | 2000-08-08 |
US20030013693A1 (en) | 2003-01-16 |
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