CN101027049A - 药物组合物及其用途 - Google Patents
药物组合物及其用途 Download PDFInfo
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- CN101027049A CN101027049A CNA2005800194523A CN200580019452A CN101027049A CN 101027049 A CN101027049 A CN 101027049A CN A2005800194523 A CNA2005800194523 A CN A2005800194523A CN 200580019452 A CN200580019452 A CN 200580019452A CN 101027049 A CN101027049 A CN 101027049A
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Abstract
多不饱和脂肪酸(“PUFA”)或者其药理学可接受的盐或衍生物(比如EPA和/或DHA)和至少一种免疫抑制剂或抗肿瘤剂(所说的药剂具有至少一个氨基酸残基)或者其药理学可接受的盐或衍生物(比如甲氨蝶呤或环孢素)相组合使用，用于治疗包括急性或慢性不适当免疫应答的病症。可治疗的具体病症包括慢性炎症疾病(例如克隆病和溃疡性结肠炎)和肿瘤疾病(例如肠癌和前列腺癌)。本发明优选实施方案的一个优点在于可提高免疫抑制剂或抗肿瘤剂的生物利用度。
Description
本发明涉及至少一种多不饱和脂肪酸(“PUFA”)或者其药理学可接受的盐或衍生物和至少一种免疫抑制剂和抗肿瘤剂或其药理学可接受的盐或衍生物相组合，用于治疗涉及急性或慢性不适当免疫应答的病症，比如炎性肠疾病(“IBD”)、类风湿性关节炎、贝赫切特综合征、银屑病、前列腺癌或肠癌。
根据Martindale(“The Complete Drug Reference”32nded；1999)，IBD包含胃肠(“GI”)道的慢性非特异性炎性病症。IBD的两种主要形式是克隆病和溃疡性结肠炎。
克隆病的特征在于GI壁有增厚区域，炎症蔓延到所有层，深度溃疡和粘膜裂缝，并出现肉芽肿。感染区可能操作于GI道的任何区域，散布着正常组织区域。
溃疡性结肠炎局限于结肠和直肠。炎症是表面的，但是连续分布在感染区，却很少有肉芽肿。轻度疾病中，只有直肠被感染(直肠炎)。在重度疾病中，溃疡广泛存在，可能丧失大量的粘膜，并且结肠毒性扩张的风险增加，这是潜在地威胁生命的并发症。
虽然克隆病和溃疡性结肠炎具有不同性，但是这两种症状可以使用相似的治疗。皮质类固醇被用于治疗较严重的活动性疾病，氨基水杨酸盐衍生物可用于治疗较轻度的活动性疾病。此外，免疫抑制剂疗法已经被用于治疗慢性活动性疾病。例如，硫唑嘌呤(CAS NO446-86-6；6-(1-甲基-4-硝基咪唑-5基硫代)嘌呤)对克隆病患者，尤其是并发瘘病的克隆病患者有益，并且可能对顽固性溃疡性结肠炎有用。
类风湿性关节炎是其中关节(通常包括手和脚的关节)发炎导致肿胀，疼痛和通常关节破坏的炎性关节炎。它被认为是一种自身免疫疾病，其中免疫系统的组分攻击排列在关节旁的软组织。使用非甾体抗炎药(“NSAIDs”)比如布洛芬、皮质类固醇比如醋酸泼尼松和免疫抑制药比如甲氨蝶呤和英夫利昔单抗治疗这种症状。
贝赫切特综合征是慢性复发性炎症失调，能产生复发性疼痛的口腔溃疡、皮肤水泡、生殖器溃疡和关节肿胀。还引起眼睛、血管、神经系统和消化道发炎。它被认为是自身免疫失调。使用皮质类固醇比如泼尼松和免疫抑制剂比如环孢素治疗这种病症。
银屑病是一种慢性、复发性疾病，引起一种或多种具有银色鳞屑的突起的红色斑点，并且斑点和正常皮肤的边界清晰。它是由于皮肤细胞的不正常的快速生长引起的，被认为是免疫系统问题引起的。在过去，这种症状使用光疗法、局部药物比如皮质类固醇和口服药物比如环孢素和甲氨蝶呤进行治疗。
在美国，前列腺癌是男人最常见的癌症和第二常见的癌症死亡原因。目前采用三种治疗形式治疗前列腺癌：手术、放射疗法和激素疗法。
在美国和欧洲西部，肠癌是非常普遍的。约50％的大肠肿瘤发生在直肠，约20％发生在乙状结肠。局部疾病的一线治疗是手术。基于氟尿嘧啶的辅助治疗也被广泛应用。研究表明，与大丸剂给药相比，长期输注氟尿嘧啶能提高辅助治疗的效果。另一种方法是使用生化调节剂，比如叶酸，或免疫调节剂，比如左旋咪唑。
甲氨蝶呤(CAS No.59-05-2；4-氨基-4-脱氧-10-甲基蝶酰-L-谷氨酸)是一种抗肿瘤剂，作为叶酸的抗代谢物发挥作用。已经被广泛应用治疗大量的恶性疾病包括口腔肿瘤和胃肿瘤，通常和其它抗肿瘤剂联合使用。Martindale没有提及使用甲氨蝶呤治疗结肠或直肠癌。相反，氟尿嘧啶(5-氟嘧啶-2，4-(1H，3H)-二酮)似乎是治疗恶性瘤可选用的抗肿瘤剂。
甲氨蝶呤也是一种用于治疗IBD的免疫抑制剂。以每周肌肉注射1次，剂量为25mg，甲氨蝶呤能改善症状并减少慢性活动性克隆病对皮质类固醇的需求(Feagan et al；N.Engl.J.Med.1995；332；292-7)。低剂量的甲氨蝶呤已被用于在顽固性及皮质类固醇依赖性克隆病中诱导缓解以及甾族化合物节约效应(Egan et al；Mayo Clin.Proc.1996；71；69-80)。本文后面的参考文献公开了肌肉注射相对口服甲氨蝶呤而言副作用更少，复发更低。
环孢素(CAS No.59865-13-3；环{-[4-(E)-丁-2-烯基-N，4-二甲基-L-苏氨酰]-L-高丙氨酰-(N-甲基甘氨酰)-(N-甲基-L-亮氨酰)-L-缬氨酰-(N-甲基-L-亮氨酰)-L-丙氨酰-D-丙氨酰-(N-甲基-L-亮氨酰)-(N-甲基-L-亮氨酰)-(N-甲基-L-缬氨酰)-})是用于治疗被认为具有自身免疫组分的多种疾病的免疫抑制剂，。环孢素已被尝试用作为IBD的二线药物，并获得或多或少的成功。发现静脉内应用大剂量的环孢素对顽固性溃疡性结肠炎有效(Lichtiger et al；N.Engl.J.Med.1994；330；1841-5)，并且若经灌肠施用，也可能是有用的(Sandborn et al；Am.J.Gastroenterol.1993；88；640-5)。然而，对克隆病的益处不是很清楚。虽然据报道静脉内疗法对治疗顽固性瘘病有用，但是口服的较小剂量对成人和儿童活动性克隆病得到令人失望的结果(参见例如Feagan et al；N.Engl.J.Med.1994；330；1846-51)。当口服施用时，环孢素通常以液体灌装胶囊或油性混悬剂施用。
放线菌素D(CAS No.50-76-0；N，N′-(2-氨基-4，6-二甲基-3-氧代-3H-吩噁嗪-1，9-二基二羰基)-双[苏氨酰-D-缬氨酰脯氨酰(N-甲基甘氨酰)(N-甲基缬氨酸)1.5-3.1-内酯)是已被用于治疗妊娠滋养细胞肿瘤和其它实体瘤包括脑瘤、维尔姆斯瘤和多种肉瘤的抗肿瘤剂。它也是一种免疫抑制剂，通常经静脉注射施用。
已知二十碳-5，8，11，14，17-五烯酸(“EPA”)、二十二碳-4，7，10，13，16，19-六烯酸(“DHA”)和其它PUFAs可用于治疗IBD(参见，例如EP-A-0244832，EP-A-0289204，EP-A-0311091和WO-A-93/21912)。
EP-A-0825858(Buser et al；1996年11月21日出版)公开了一种口服剂型，其中包含或是游离酸或其药学可接受盐形式的PUFA作为活性成分。口服剂型用时间依赖性而非pH依赖性释放的包衣材料进行包衣，所述的包衣材料使得在回肠内释放PUFA。口服剂型用于治疗IBD。
Zerouga等(Anti-Cancer Drugs 2002；13；301-311)合成并表征了含有DHA和甲氨蝶呤两种抗肿瘤剂的亲脂性磷脂酰胆碱衍生物，群众DHA和甲氨蝶呤分别在磷脂的sn-1位和sn-2位共价结合。结果显示DHA和甲氨蝶呤在体外抑制鼠白血病细胞的增殖，并且当DHA和甲氨蝶呤作为独立的药剂同时投递时和当通过磷脂酰胆碱部分连接在一起时具有潜在的协同作用。
Ferguson(Proc.Annu.Meet.Am.Assoc.Cancer Res.1995；36；A1722)研究了γ-亚油酸(“GLA”)对人鳞状细胞癌系和多药耐受性及卡铂耐受性变种的细胞毒性和化学调节作用。结果显示，与没有处理过的细胞相比，用GLA预处理的细胞对长春新碱和卡铂的暴露更敏感。取决于GLA的浓度，卡铂对人鳞状细胞癌和卡铂耐受性变异细胞系的毒性提高到50％。此外，可见GLA将长春新碱毒性提高了高达40％。
JP-A-63258816(Imayado et al；1988年10月26日出版)公开了一种含有低选择毒性的抗癌药物(选自长春新碱、柔红霉素、VP-16和顺铂)和高选择毒性的高度不饱和脂肪酸(例如GLA、花生四烯酸或EPA)的抗癌组合物。该文件中公开了组合物可以传统方式在采用所示抗癌剂的应用中使用。该文件举例说明了抗癌剂和高度不饱和脂肪酸之一的多种组合的0.5wt％乙醇溶液的体外作用研究。所有脂肪酸纯度为99％。
JP-A-8092129(Yazawa et al；1996年4月9日出版)公开了自身免疫疾病引起的眼症状的治疗，其中包含免疫抑制剂和EPA和/或DHA。公开的免疫抑制剂的实例包含地塞米松、环孢素A、瑞帕霉素、FK506、布雷青霉素、环磷酰胺、硫唑嘌呤和甲氨蝶呤。在仅有的举例说明的实施方案中，服用环孢素A的2位患者和服用FK506的另外2位患者给予含有金枪鱼油的明胶软胶囊，所述金枪鱼油包含6％EPA和25％DHA。日剂量是2400mg，分成3份施用。
WO-A-98/09621(Scott et al；1998年3月12日出版)公开了一种治疗和预防抗癌化学疗法的副作用的方法，其中使用碳链长度是14-26并在分子内具有顺式或反式构型的2-6个双键的PUFA。优选的PUFAs包括EPA和DHA。其中公开了该方法尤其适合治疗由于使用甲氨蝶呤、5-氟尿嘧啶、环磷酰胺、顺铂、阿霉素、紫杉醇和长春新碱引起的副作用。PUFAs可以同时和抗癌药物施用或优选在用抗癌药物治疗之前和治疗过程中施用。PUFAs的每日剂量可为1mg-100g，并且PUFAs可以任何合适的方式施用，包括以例如胶囊和片剂形式口服。
WO-A-98/09621中针对使用甲氨蝶呤唯一举例说明的实施方案中，以锂盐形式静脉注射GLA的累积剂量30g后，接着每日口服2g的GLA锂盐继续治疗，1周后，使用“CMF”疗法(环磷酰胺、甲氨蝶呤、5-氟尿嘧啶)治疗患有乳腺癌的女性患者。抗癌治疗的副作用降低。
WO-A-98/09621中治疗GI道病症的唯一举例说明的实施方案中，使用5-氟尿嘧啶治疗患有转移性结肠癌的男性患者。化学治疗之前2周和整个化学治疗过程中，该患者还接受每日3g的EPA纯甘油三酯。同样地，该化学治疗的副作用降低。
Suzuki et al(J.Pharm.Sci.1998；87(10)；1196-202)公开了在大鼠体内使用脂肪酸乳剂提高了结肠和直肠对肽类激素--胰岛素的吸收。在大鼠肠襻原位直接施用该乳剂。测试了饱和、单不饱和和多不饱和脂肪酸，包括EPA和DHA，结果显示胰岛素吸收水平随脂肪酸的不饱和度的增加而增加。
Barichello等(Int.J.Pharm.1999；183(2)；125-32)公开了使用含有不饱和脂肪酸的普流尼克(pluronic)F-127凝胶制剂对大鼠直肠施用胰岛素。
WO-A-03/92671(Krishnan；2003年11月13日出版)公开了抑制血管生成的组合物。该组合物包含烷基-取代的脂肪酸、任选地免疫抑制剂，比如环孢素。该文件中公开了涉及血管生成的多种病症，包括多种癌症、克隆病和溃疡性结肠炎。该文件中举例说明了使用烷基-取代的脂肪酸和环孢素抑制人脐静脉内皮细胞(“HUVEC”)的增殖的体外研究。
对于涉及急性或慢性不适当免疫应答的病症(比如IBD和肠癌)的改进治疗方法存在需求。因此，本发明的目的在于提供这些病症的改进治疗方法。
本发明的优选实施方案的目的是改善免疫抑制剂和抗肿瘤剂，尤其是甲氨蝶呤或环孢素的口服生物利用度。
本发明的优选实施方案的目的还在于提供免疫抑制剂和抗肿瘤剂的施用方法，所述方法能降低通常与通过非肠道途径施用有关的全身副作用(包括恶心和呕吐)。
根据第一方面，提供了PUFA或者其药理学可接受的盐或衍生物在生产用于治疗涉及急性或慢性不适当免疫应答的病症、尤其是肠道病症的药物中的用途，所述药物包含至少一种免疫抑制剂和抗肿瘤剂(所说的药剂具有至少一个氨基酸残基)或者其药理学可接受的盐或衍生物。
本发明的第一方面还提供多不饱和脂肪酸(“PUFA”)或其药理学可接受的盐或衍生物以及至少一种免疫抑制剂和抗肿瘤剂(所说的药剂具有至少一个氨基酸残基)或者其药理学可接受的盐或衍生物在生产用于治疗所述病症的药物中的用途。
本发明的第一方面进一步提供了至少一种免疫抑制剂和抗肿瘤剂(所说的药剂具有至少一个氨基酸残基)或者其药理学可接受的盐或衍生物在生产药物中的用途，所述的药物包含多不饱和脂肪酸(“PUFA”)或其药理学可接受的盐或衍生物，用于治疗所述的病症。
通过对肠粘膜局部应用活性剂，可以治疗这些病症，获得局部或全身效果。若待治疗的病症是肠道病症，则局部应用的活性剂具有局部效果。
“免疫抑制剂”的表达意思是对人类或动物机体具有抑制免疫应答作用的药理学可接受的化合物。“抗肿瘤剂”的表达意思是对肿瘤细胞具有细胞毒作用的药理学可接受的化合物。这些表达容易被领域中的技术人员接受。
将至少一种免疫抑制剂及抗肿瘤剂与PUFA共同施用的一个优点在于通常可提高药剂的口服生物利用度，因此可以施用用与原本必须通过非肠道途径施用的剂量相比更低剂量的该活性剂治疗涉及急性或慢性不适当免疫应答的病症。因此避免了不期望的皮下和静脉内给与药剂，比如甲氨蝶呤或环孢素，从而降低或消除了与高口服剂量或非肠道使用该药剂相关的不需要的副作用。
不希望被任何特殊的理论约束，发明人认为，药剂的摄入增加并非由于PUFA和药剂的交互作用导致的药理作用，而是由于其物理作用。相信药剂可以被“包裹”入和肠粘膜细胞融合的PUFA层内。与不饱和度较低的脂肪酸相比，PUFAs具有较高的流动性，因此改善药剂的投递。
在优选的实施方案中，至少部分在过胃之后释放PUFA和制剂。通常，所有的或基本上所有的释放是过胃之后发生的。可以靶向确定活性剂在肠中的释放位点，这取决于待治疗的病症。
若欲全身性治疗病症，例如慢性炎症或肿瘤疾病，优选在空肠开始释放，并沿着回肠的大部分继续释放。在肠的这一部分观察到活性剂的生物利用度增加。通常，在这些实施方案中，在回肠末端之前释放完全。类似的释放模式可用于局部治疗肠病症，比如小肠的炎性病症(例如小肠克隆病和贝赫切特综合征)和小肠肿瘤。
在其它的实施方案中，释放从小肠开始，并向下延续到大肠。例如，对于结肠病症、例如结肠的炎性病症(例如溃疡性结肠炎)和结肠-直肠癌的局部治疗，优选活性剂的回肠-结肠释放。
据信药剂在和肠粘膜接触时会与PUFA相互作用。PUFA帮助药剂被吸收进入肠壁细胞，导致药剂在粘膜和肠壁的免疫细胞和肿瘤细胞内的局部细胞摄入增加。通常通过提供在肠壁免疫细胞和/或肿瘤细胞可达到的高浓度PUFA和药剂来实现药剂的局部施用，发明人相信这将导致组分的作用效果显著加强。
已知PUFAs具有抗肿瘤和免疫抑制活性(参见以上)。因此，本发明的另一个优点是药剂和PUFAs的共施用导致了制剂的抗肿瘤和/或免疫抑制作用的协同加强。
适宜的PUFA包括Ω-3、Ω-6和Ω-9的PUFAs。但是，无论使用哪一种PUFA，优选未取代形式。适宜的实例包括EPA、DHA和GLA。至少一种PUFA优选EPA或DHA。在优选实施方案中，使用包含EPA和DHA的PUFA混合物。在这些实施方案中，混合物中EPA和DHA的总量优选至少约为混合物的60wt％。混合物可以是浓缩的鱼油产品的形式。在优选的实施方案中，混合物包含约50-60wt％、优选55wt％的EPA，以及约15-25wt％、优选20wt％的DHA。
所述PUFA或至少一种PUFA优选游离酸形式。作为替代，所述PUFA或至少一种PUFA可以是药理学可接受的盐形式(比如锂盐或钠盐)、药理学可接受的酯形式(比如乙酯或甘油三酯)或药理学可接受的n-3磷脂。
免疫抑制剂或抗肿瘤剂优选具有1-15氨基酸残基。适宜的氨基酸衍生的免疫抑制剂包括甲氨蝶呤、放线菌素D、环孢素和单克隆抗体比如英夫利昔单抗(infliximab)、那他珠单抗(natalizumab)、达克珠单抗(daclizumab)或莫罗单抗(muromonab)。适宜的氨基酸衍生的抗肿瘤剂包括甲氨蝶呤和放线菌素D。
其它非氨基酸衍生的药剂可联合用于本发明。这些药剂可具有复杂的化学结构，例如生物碱，或是真菌或细菌起源的物质。其它非氨基酸衍生的免疫抑制剂的实例包括6-巯基嘌呤(6-“MP”)、环磷酰胺、霉酚酸酯、泼尼松、西罗莫司、地塞米松、瑞帕霉素、FK506、布雷青霉素、巯唑嘌呤和藤霉素。其它非氨基酸衍生的抗肿瘤剂的实例包括氟尿嘧啶、博莱霉素、依托泊苷、紫杉醇、长春新碱、阿霉素、顺铂、柔红霉素和VP-16。
药物可包含至少一种口服剂型，所述的口服剂型包含PUFA或其盐或衍生物和至少一种免疫抑制剂和所述抗肿瘤剂或其盐或其衍生物的混合物。在这些实施方案中，或免疫抑制剂或抗肿瘤剂可以和PUFA同时共施用。在这些实施方案中，PUFA独立于其药剂，即不与其它物质相缀合。混合物基本上由所述混合物组成或可进一步包含药理学可接受的赋形剂。
作为替代，该药物可包含至少一种第一口服剂型和至少一种第二口服剂型，所述的第一口服剂型包含PUFA或其盐或衍生物，所述的第二口服剂型包含至少一种所述免疫抑制剂和所述抗肿瘤剂或其盐或衍生物。在这些实施方案中，或免疫抑制剂或抗肿瘤剂可以和PUFA同时或顺序共施用。该第一或第二口服剂型还可包含药理学可接受的赋形剂。
适宜的待治疗病症可以是慢性炎症疾病。例如，该慢性炎症疾病来自于对免疫应答的过度活跃和部分缺陷的控制。这些病症的实例包括IBD(例如克隆病和溃疡性结肠炎)、类风湿性关节炎、贝赫切特综合征和银屑病。
另一种适宜的待治疗症状是肿瘤疾病。例如，该肿瘤疾病可来自于对异常细胞的免疫识别和应答的缺陷。这些病症的实例包括肠癌和前列腺癌。
本发明特别应用于局部治疗肠病症。
待治疗的肠病症可以是IBD，例如克隆病或溃疡性结肠炎。在这些实施方案中，所用的药剂通常是免疫抑制剂，比如甲氨蝶呤、放线菌素D、环孢素或单克隆抗体。
待治疗的肠病症可以是肠癌，在这些实施方案中，抗肿瘤剂是甲氨蝶呤或放线菌素D。本发明特别适用于治疗结肠癌和/或直肠癌。
本发明的第一方面还提供了PUFA或其药理学可接受的盐或其衍生物用于提高至少一种免疫抑制剂和抗肿瘤剂的全身生物利用度和在至少部分肠部的局部生物利用度的用途，所述的药剂具有至少一个氨基酸残基，在用于治疗涉及急性或慢性不适当免疫应答的病症的药物中。
根据本发明的第二方面，提供了涉及急性或慢性不适当免疫应答的病症的治疗方法，包括同时或顺序施用PUFA或其药理学可接受的盐或衍生物和至少一种免疫抑制剂和抗肿瘤剂(所说的药剂具有至少一个氨基酸残基)或其药理学可接受的盐或衍生物。药剂通常根据治疗特殊症状中所需的治疗有效量施用。在使用PUFA衍生物的实施方案中，所述衍生物通常是酯或n-3的磷脂。该治疗可以具有上述的任何特征。
如以上所述，PUFA和药剂可以相同的口服剂型或不同的口服剂型共同施用。因此，“口服剂型”这一表述是指包括其中PUFA和药剂以相同的口服剂型共施用的实施方案以及其中PUFA和药剂以分开的口服剂型施用的实施方案。适宜的形式包含胶囊(比如硬或软明胶胶囊)和片剂。在使用明胶胶囊的实施方案中，明胶可以是A型明胶或B型明胶，并且A型明胶是优选的。制备明胶的胶原物质可来源于猪、牛或鱼。猪明胶是优选的，在使用游离酸形式的PUFA的实施方案中尤其如此，因为与使用其它来源的明胶制备的胶囊相比，PUFA和此胶囊壁之间不需要的相互作用水平有所降低，因此能改善制剂的稳定性和有效保存期。
根据本发明的第三方面，提供了包含PUFA或其药理学可接受的盐或其衍生物以及至少一种免疫抑制剂和抗肿瘤剂(所述的药剂具有至少一个氨基酸残基)或者其药理学可接受的盐或衍生物的口服剂型，。优选口服剂型包被了延迟释放的包衣，例如肠溶包衣，用以延迟PUFA和药剂的释放到通过胃部之后。
PUFA可以与制剂不同的口服剂型共施用。EP-0825858中公开了单独口服施用PUFA的合适形式(参见上述)，将其公开内容在此引入作为参考。
根据本发明的第四方面，提供用于独立口服施用药剂的适宜形式，其中口服剂型包含至少一种免疫抑制剂和抗肿瘤剂(所述的药剂具有至少一个氨基酸残基)或其药理学可接受的盐或其衍生物，所述口服剂型包被了延迟释放的包衣，例如肠溶包衣。这种口服剂型可和包含PUFA的独立口服剂型、例如EP-0825858中公开的剂型结合使用，该文献的公开内容在此引入作为参考。
局部治疗肠病症中所用的口服剂型优选会延迟PUFA和药剂的释放，直到到达肠的受感染部位。在这些实施方案中，口服剂型可以包被了允许在胃之后释放所述活性成分或每种活性成分的包衣，从而对肠粘膜局部施用该活性组分或每一种活性组分。适宜的包衣将以pH依赖形式或非pH依赖形式延迟制剂的初始释放。
口服剂型可包被有pH依赖性的释放包衣材料。从十二指肠到结肠，肠内的pH从约6逐渐增加到约7.5。已开发了不同的基于聚丙烯酸酯的包衣材料，它们能溶解于不同pH的肠道内，因此在肠道的不同部位从包被剂型中释放活性物质。适宜的肠溶包被物质包括EudragitTM L，EudragitTM S和EudragitTM F(Rohm Pharma Polymers)。
包衣可以以非pH依赖方式延迟制剂的初始释放。例如，在优选的实施方案中，包衣以时间依赖性而非pH依赖性的形式延迟制剂的初始释放。口服剂型可以包被有时间依赖性而非pH依赖性的释放包衣材料。在这样的实施方案中，根据包衣的厚度，释放的位点可能会改变。例如，随着包衣厚度的增加，初始释放的位点将沿着肠道进一步下移。因此，这种材料的相对较薄的包被可引起在小肠内、例如在十二指肠内初始释放，而相对较厚的包被可能导致在结肠的末端回肠初始释放。
在一些实施方案中，包衣的厚度足以延迟活性物质的初始释放平均约30min-约60min。这样的实施方案适用于回肠释放药剂。在其它实施方案中，包衣厚度将足以延迟活性物质的初始释放平均约60min-约120min，优选平均约90min-约120min。这样的实施方案适用于在末端回肠或结肠内或附近初始释放活性物质。
时间依赖性而非pH依赖性的释放包衣材料可以是中性聚丙烯酸酯物质，比如聚(丙烯酸乙酯-甲基丙烯酸甲酯)物质。适宜的物质的实例包括平均分子量约800,000的Eudragit NE 30 D(Rohm Pharma GmbH)，它通常被用于制备缓释基质。
另一种适宜的非pH依赖性释放包衣是在结肠中细菌酶的作用下能进行生物降解的包衣。适宜的包衣的实例是由乙基纤维素和直链淀粉制成的非pH依赖性的、在结肠细菌酶作用下降解从而在结肠内释放药剂的包衣。以同样方式起作用的其它聚合物也是适宜的。
所述活性组分或每一种活性组分的释放优选沿着肠道的至少部分持续进行。可以使用本领域内已知的持续释放活性成分的任何合适的方法。然而，如果使用时间依赖性而非pH依赖性的释放包衣材料、尤其是Eudragit NE 30 D包被的明胶软胶囊，则沿着肠部分以微滴方式释放活性物质。发明人认为这种持续释放模式是独一无二的。
不希望被任何特殊的理论约束，发明人认为包衣膨胀并穿孔，使得肠液通过包衣。当肠液和明胶接触时，胶囊膨胀到胶囊壁的完整性被破坏、胶囊的组分以微滴形式穿过包衣内的孔出来的程度。胶囊继续沿肠道下行，因此胶囊内容物沿肠部分持续释放。
根据本发明的第三或第四方面，口服剂型通常适于通过诊断或治疗用于治疗人体或动物体。
在优选的实施方案中，药物包含双重的口服剂型。第一口服剂型是含有或400mg或800mg药物组合物的明胶软胶囊，所述药物组合物包含约55wt％的EPA和约20wt％的DHA，都是游离酸形式。胶囊由A型猪明胶制成，包被了Eudragit NE 30 D。第二口服剂型可以是例如2.5mg甲氨蝶呤片剂或25mg环孢素的明胶软胶囊。第二口服剂型优选包被了Eudragit NE 30 D。
根据本发明的第五方面，提供包含至少一种第一口服剂型和至少一种第二口服剂型的药物产品，所述第一口服剂型包含PUFA或其药理学可接受的盐或衍生物，所述第二口服剂型包含至少一种免疫抑制剂和抗肿瘤剂(所述的药剂具有至少一个氨基酸残基)或其药理学可接受的盐或衍生物。优选至少一种第一和第二口服剂型以上述的任何一种形式进行包被。
下面是本发明目前优选的实施方案的描述，这仅仅是举例说明。
实施例-双重口服剂型
第一口服剂型(PUFA)
每个透明的明胶软胶囊填充1000mg鱼油浓缩物，所述的浓缩物包含至少60％重量的DHA和EPA(Incromega 3F60；Croda Universal Ltd，UK)。通过在压力0.8巴，温度25℃下，以35ml/min用薄膜包衣组合物(见下面)对胶囊进行喷雾，在25℃空气干燥至少30min，用EudragitNE 30-D对填充的明胶胶囊进行薄膜包衣，以便提供在pH5.5中保持30-60min的抗性。
通过缓慢将硅消泡乳剂(0.36mg)，棕色氧化铁(E172，3.00mg)，二氧化钛(2.35mg)和滑石(10mg)连续加入到水(75mg)中，搅拌l-2h，得到非常微细的分散体，制备薄膜包衣组合物(用于50,000个胶囊)。将平均分子量约800,000的聚(丙烯酸乙酯-甲基丙烯酸甲酯)(EudragitNE 30D；60mg)的30％水性分散体加入到处于少量水中的polysorbate 80(MO 55 F；0.2mg)内，搅拌所得的混合物。加入硅消泡乳剂(2或3滴)，破坏形成的泡沫，然后缓慢加入上述的分散体。器皿用水(25mg)洗涤，在过滤(150μm)之前，将分散体搅拌30min。
第二口服剂型(甲氨蝶呤)
包含2.5mg甲氨蝶呤钠和药理学可接受的赋形剂的至少一种片剂。
应当理解，本发明不局限于上述的优选实施方案的描述，可进行许多改进和变动，而不背离所附权利要求限定的本发明的精神或范围。
Claims (23)
1.多不饱和脂肪酸(“PUFA”)或其药理学可接受的盐或衍生物在生产药物中的用途，所述药物包含至少一种免疫抑制剂和抗肿瘤剂或者其药理学可接受的盐或衍生物，所说的药剂具有至少一个氨基酸残基，该药物用于治疗涉及急性或慢性不适当免疫应答的病症。
2.权利要求1的用途，其中至少一种PUFA是二十碳-5，8，11，14，17-五烯酸(“EPA”)。
3.权利要求1或2的用途，其中至少一种PUFA是二十二碳-4，7，10，13，16，19-六烯酸(“DHA”)。
4.前述权利要求中任一项的用途，其中至少一种PUFA是游离酸形式。
5.前述权利要求中任一项的用途，其中所说的免疫抑制剂或抗肿瘤剂具有1-15个氨基酸残基。
6.前述权利要求中任一项的用途，其中所说的抗肿瘤剂选自甲氨蝶呤和放线菌素D。
7.权利要求1-4中任一项的用途，其中所说的免疫抑制剂选自环孢素、甲氨蝶呤、放线菌素D和单克隆抗体。
8.前述权利要求中任一项的用途，其中药物包含至少一种口服剂型，所述口服剂型包含PUFA或其盐或衍生物和至少一种所述免疫抑制剂和抗肿瘤剂或其盐或衍生物的混合物。
9.权利要求1-7中任一项的用途，其中药物包含至少一种第一口服剂型和至少一种第二口服剂型，所述的第一口服剂型包含PUFA或其盐或衍生物，所述的第二口服剂型包含至少一种免疫抑制剂和抗肿瘤剂或其盐或衍生物，该第一口服剂型和第二口服剂型可同时或顺序施用。
10.前述权利要求中任一项的用途，其中病症是慢性炎性疾病。
11.前述权利要求中任一项的用途，其中病症选自炎性肠疾病(“IBD”)、克隆病、溃疡性结肠炎、类风湿性关节炎、贝赫切特综合征和银屑病。
12.权利要求1-9中任一项的用途，其中病症是肿瘤疾病。
13.权利要求12的用途，其中病症选自肠癌和前列腺癌。
14.涉及急性或慢性不适当免疫应答的病症的治疗方法，包括同时或顺序施用PUFA或者其药理学可接受的盐或衍生物以及至少一种免疫抑制剂和抗肿瘤剂或者其药理学可接受的盐或衍生物，所说的药剂具有至少一个氨基酸残基。
15.一种口服剂型，其中包含PUFA或其药理学可接受的盐或衍生物以及至少一种免疫抑制剂和抗肿瘤剂或者其药理学可接受的盐或衍生物，所说的药剂具有至少一个氨基酸残基。
16.权利要求15的口服剂型，其中口服剂型包被了能延迟活性剂的释放直到通过胃之后的包衣。
17.一种口服剂型，其中包含至少一种免疫抑制剂和抗肿瘤剂或者其药理学可接受的盐或衍生物，所说的药剂具有至少一个氨基酸残基，其中口服剂型包被了时间依赖性而非pH依赖性的释放包衣材料，所述的包衣材料能延迟活性剂的释放直到通过胃之后。
18.权利要求15-17中任一项的口服剂型，其可通过诊断或治疗，用于治疗人体或动物体。
19.一种药物产品，其中包含至少一种第一口服剂型和至少一种第二口服剂型，所述的第一口服剂型包含PUFA或者其药理学可接受的盐或衍生物，所述的第二口服剂型包含至少一种免疫抑制剂和抗肿瘤剂或者其药理学可接受的盐或衍生物，所述的药剂具有至少一个氨基酸残基。
20.权利要求19的药物产品，其中至少一种第一和第二口服剂型包被了能延迟活性剂的释放直到通过胃之后的包衣。
21.权利要求1的用途，其基本上如前文参照附属的实施例所述。
22.权利要求15或17的口服剂型，其基本上如前文参照附属的实施例所述。
23.权利要求19的药物产品，其基本上如前文参照附属的实施例所述。
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| GB8729153D0 (en) * | 1987-12-14 | 1988-01-27 | Efamol Ltd | Fatty acid compositions |
| CH679119A5 (zh) * | 1988-05-13 | 1991-12-31 | Sandoz Ag | |
| IE75744B1 (en) * | 1995-04-03 | 1997-09-24 | Elan Corp Plc | Controlled release biodegradable micro- and nanospheres containing cyclosporin |
| GB9509764D0 (en) * | 1995-05-15 | 1995-07-05 | Tillotts Pharma Ag | Treatment of inflammatory bowel disease using oral dosage forms of omega-3 polyunsaturated acids |
| US5795909A (en) * | 1996-05-22 | 1998-08-18 | Neuromedica, Inc. | DHA-pharmaceutical agent conjugates of taxanes |
| GB9618420D0 (en) * | 1996-09-04 | 1996-10-16 | Scotia Holdings Plc | Fatty acid treatment |
| EP1214067A1 (en) * | 1999-09-09 | 2002-06-19 | EFA Sciences Llc | Methods for treating cell proliferative disorders including cancer |
| US20040052837A1 (en) * | 2002-06-27 | 2004-03-18 | William Stillwell | Lipid conjugated anti-cancer drugs and methods of use thereof |
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- 2005-06-15 AU AU2005253719A patent/AU2005253719A1/en not_active Abandoned
- 2005-06-15 JP JP2007515865A patent/JP2008502630A/ja active Pending
- 2005-06-15 US US11/629,093 patent/US20090018125A1/en not_active Abandoned
- 2005-06-15 CN CNA2005800194523A patent/CN101027049A/zh active Pending
- 2005-06-15 CA CA002569697A patent/CA2569697A1/en not_active Abandoned
- 2005-06-15 EP EP05750805A patent/EP1758573A1/en not_active Withdrawn
- 2005-06-15 WO PCT/EP2005/006412 patent/WO2005123060A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10028928B2 (en) | 2009-03-09 | 2018-07-24 | Pronova Biopharma Norge As | Compositions comprising a fatty acid oil mixture and a free fatty acid, and methods and uses thereof |
| US11395811B2 (en) | 2009-03-09 | 2022-07-26 | Pronova Biopharma Norge As | Compositions comprising a fatty acid oil mixture comprising EPA and DHA in free acid form and a surfactant, and methods and uses thereof |
| CN102724972A (zh) * | 2009-10-23 | 2012-10-10 | 普罗诺瓦生物医药挪威公司 | 脂肪酸油混合物的包衣胶囊和包衣片剂 |
| US9370493B2 (en) | 2009-10-23 | 2016-06-21 | Pronova Biopharma Norge As | Coated capsules and tablets of a fatty acid oil mixture |
| CN113382733A (zh) * | 2019-02-04 | 2021-09-10 | 帝斯曼知识产权资产管理有限公司 | 用于治疗炎性肠病的治疗性组合和组合物 |
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| GB0413729D0 (en) | 2004-07-21 |
| WO2005123060A1 (en) | 2005-12-29 |
| US20090018125A1 (en) | 2009-01-15 |
| EP1758573A1 (en) | 2007-03-07 |
| NO20070338L (no) | 2007-03-09 |
| CA2569697A1 (en) | 2005-12-29 |
| BRPI0512099A (pt) | 2008-02-06 |
| AR049358A1 (es) | 2006-07-19 |
| MXPA06014294A (es) | 2007-05-04 |
| JP2008502630A (ja) | 2008-01-31 |
| IL179795A0 (en) | 2007-05-15 |
| AU2005253719A1 (en) | 2005-12-29 |
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