CN111356461A - 免疫调节性低聚糖 - Google Patents
免疫调节性低聚糖 Download PDFInfo
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- CN111356461A CN111356461A CN201880073029.9A CN201880073029A CN111356461A CN 111356461 A CN111356461 A CN 111356461A CN 201880073029 A CN201880073029 A CN 201880073029A CN 111356461 A CN111356461 A CN 111356461A
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Abstract
本公开提供了免疫调节性低聚糖及其用途。
Description
相关申请的交叉引用
根据美国法典第35篇第119条,本申请要求2017年10月4日提交的临时申请序列号62/567,865的优先权,该临时申请的公开内容通过引用并入本文。
技术领域
本公开提供了免疫调节性低聚糖及其用途。
背景技术
类风湿性关节炎(RA)是一种终生的全身性自身免疫性疾病,其对女性的影响(通常在其最有生育力和生子的年龄)的是男性的三倍。患有RA女性的怀孕造成了治疗挑战。一些抗风湿药可能会穿过胎盘并伤害胎儿和/或转移到母乳中并伤害母乳喂养的婴儿。应避免致畸性化合物,例如甲氨蝶呤和来氟洛米(leflunamide),并且高剂量甾体可能与胎膜早破有关。药物转移到母乳中的高风险经常导致对女性停止母乳喂养的建议。
2’-岩藻糖基乳糖(2’FL)和乳糖-N-(新)四糖(LNnT),作为医疗食品和成人膳食成分,已被FDA认证为公认安全(GRAS)。而且,这些低聚糖具有良好的耐受性,在胃中保持不被消化,而在下胃肠道中被完整吸收。
发明内容
慢性巨噬细胞炎症在类风湿性关节炎的发生和发展中起关键作用。本文提供的数据表明,基于3’-唾液乳糖(3’SL)和6’-唾液乳糖(6’SL)的低聚糖以及包含3’SL和6’SL或由3’SL和6’SL组成的纯化制剂能减轻巨噬细胞炎症并抑制促炎性细胞因子,例如白介素(IL)-1β和IL-6,的分泌。
在具体的实施方案中,本公开提供了一种用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,所述方法包括向该受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I、I(a)或II的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;R不存在或者是(C1-C5)烷基;并且R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在另一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,其包括向受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I(b)或I(c)的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;R不存在或者是(C1-C5)烷基;并且R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在又一个实施方案中,本公开进一步提供了一种用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,该方法包括向该受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I(d)、I(e)或II(a)的结构:
或其药学上可接受的盐、溶剂化物或前药。在某些实施方案中,本文公开的方法包括向受试者口服施用本公开的低聚糖或包含本公开的低聚糖的药物组合物。在又一个实施方案中,本文公开的方法包括将包含至少一种本公开的低聚糖的营养组合物口服施用给受试者。在某些实施方案中,营养组合物包含3’SL、6’SL或3’SL和6’SL的组合或由其组成。在其它实施方案中,营养组合物以145mg/L或更高的3’SL、6’SL或3’SL和6’SL的组合包含3’SL、6’SL或它们的组合,或者由其组成。在另一个实施方案中,营养组合物中总低聚糖的至少9%(例如10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100%;或任意上述值之间的任何值)包含3’SL、6’SL或其组合。在另一个实施方案中,将包含本公开的低聚糖的药物组合物配制成片剂或胶囊剂。在另一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,其包括向受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物,其中所述自身免疫性病症选自由以下各项组成的组:自身免疫性心肌炎、德雷斯勒综合征、心包切开术后综合征、亚急性细菌性心内膜炎、抗肾小球基底膜肾炎、间质性膀胱炎、狼疮肾炎、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、抗合成酶综合征、斑秃、自身免疫性血管水肿、自身免疫性孕酮性皮炎、自身免疫性荨麻疹、大疱性类天疱疮、瘢痕性类天疱疮、疱疹样皮炎、盘状红斑性狼疮、获得性大疱性表皮松解症、结节性红斑、妊娠类天疱疮、化脓性汗腺炎、扁平苔癣、硬化性苔藓、线状IgA病、硬斑病、寻常天疱疮、急性痘疮样苔藓样糠疹、穆-哈二氏病、银屑病、系统性硬皮病、白癜风、艾迪生氏病、自身免疫性多内分泌综合征1型、自身免疫性多内分泌综合征2型、自身免疫性多内分泌综合征3型、自身免疫性胰腺炎、1型糖尿病、自身免疫性甲状腺炎、奥德甲状腺炎(Ord's thyroiditis)、格雷夫斯氏病、自身免疫性卵巢炎、子宫内膜异位症、综合征、自身免疫性肠病、抗磷脂综合征、再生障碍性贫血、自身免疫性溶血性贫血、自身免疫性淋巴细胞增生综合征、自身免疫性中性粒细胞减少症、自身免疫性血小板减少性紫癜、冷凝集素病、特发性混合性冷球蛋白血症、伊文氏综合征、恶性贫血、纯红细胞再生障碍性贫血、血小板减少症、痛性肥胖症、成人斯蒂尔病(adult-onsetStill's disease)、强直性脊柱炎、CREST综合征、药物性狼疮、与附着点炎症相关的关节炎(enthesitis-related arthritis)、嗜酸性筋膜炎、Felty综合征、IgG4相关的疾病、幼年型关节炎、慢性莱姆病、混合性结缔组织疾病、复发性风湿病、帕罗综合征(Parry Rombergsyndrome)、Parsonage-Turner综合征、银屑病关节炎、反应性关节炎、复发性多发性软骨炎、腹膜后纤维化、风湿热(rhematic fever)、类风湿性关节炎、结节病、施尼茨勒综合征、全身性红斑狼疮、未分化结缔组织病、皮肌炎、纤维肌痛、包涵体肌炎、肌炎、重症肌无力、神经性肌强直、亚急性小脑变性、多肌炎、急性播散性脑脊髓炎、急性运动性轴索型神经病、抗N-甲基-D-天冬氨酸受体脑炎、巴洛同心性硬化、Bickerstaff脑炎、慢性炎症性脱髓鞘性多发性神经病、格林-巴利综合征(Guillain-Barrèsyndrome)、桥本脑病、特发性炎症脱髓鞘疾病、Lambert-Eaton肌无力综合征、多发性硬化症、Oshtoran综合症、与链球菌相关的儿童自身免疫性神经精神障碍、进行性炎症性神经病、不宁腿综合征、僵人综合征、小舞蹈病、横贯性脊髓炎、自身免疫性视网膜病、自身免疫性葡萄膜炎、Cogan综合征、格雷夫斯眼病、中间葡萄膜炎、木样结膜炎、蚕蚀性角膜溃疡、视神经脊髓炎、眼球阵挛-肌阵挛综合征、自身免疫性内耳疾病、美尼尔氏综合症(Ménière's disease)、白塞病(disease)、嗜酸性肉芽肿伴多管炎、IgA血管炎、川崎病、白细胞破碎性血管炎、狼疮血管炎、类风湿性血管炎、显微镜下多血管炎、结节性多动脉炎、风湿性多肌痛、荨麻疹性血管炎、血管炎和原发性免疫缺陷。在又一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,其包括向受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物,其中所述炎性疾病选自由以下各项组成的组:强直性脊柱炎、抗磷脂抗体综合征、痛风、肌炎、类风湿性关节炎、硬皮病、全身性红斑狼疮、血管炎、综合征、哮喘、结核病、慢性牙周炎、慢性鼻窦炎、慢性活动性肝炎、阿尔茨海默病、帕金森氏病、肾炎、纤维肌痛、动脉粥样硬化、骨关节炎、银屑病关节炎、湿疹、胃炎、鼻窦炎、脂溢性皮炎和韦格纳氏肉芽肿病。在另一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,所述方法包括向所述受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物,其中所述炎性疾病由巨噬细胞驱动的慢性炎症引起或与之相关。在又一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,所述方法包括向受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物,其中所述炎性疾病由巨噬细胞驱动的慢性炎症引起或与之相关,所述巨噬细胞驱动的慢性炎症选自由以下各项组成的组:动脉粥样硬化、慢性阻塞性肺疾病、胰岛素抗性、2型糖尿病、肥胖症和全身型幼年特发性关节炎。在具体的实施方案中,本公开还提供了一种用于治疗患有或怀疑患有类风湿性关节炎的受试者的方法,其包括向受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物。在另一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,其包括向受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物与另外的治疗剂。在另一个实施方案中,本公开还提供了用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,所述方法包括向所述受试者施用有效量的本文公开的低聚糖或包含本文公开的低聚糖的药物组合物与非甾体抗炎药、糖皮质激素、生物反应调节剂或阿片样物质(opioid)。
非甾体抗炎药的实例包括但不限于氨基比林、4-氨基安替比林、阿扎丙宗、氯非宗、双苯米唑、泛普法宗、非普拉宗、酮保泰松、安乃近、莫非保松、吗拉宗、尼芬那宗、羟基保泰松、安替比林、苯基丁氮酮、异丙安替比林、磺吡酮、琥保松、阿司匹林、阿洛普令、扑炎痛、卡巴匹林钙、二氟尼柳钙、地匹乙酯、乙水杨胺、胍西替柳、水杨酸镁、水杨酸甲酯、双水杨酯、水杨苷、水杨酰胺、水杨酸(水杨酸盐)、水杨酸钠、醋氯芬酸、阿西美辛、阿氯芬酸、氨芬酸、苄达酸、溴芬酸、布马地宗、丁苯羟酸、双氯芬酸、联苯吡胺、依托度酸、联苯乙酸、芬克洛酸、芬替酸、吲哚美辛、吲哚美辛法呢酯、伊索克酸、酮咯酸、氯那唑酸、奥沙美辛、普罗度酸、丙谷美辛、舒林酸、硫平酸、痛灭定、佐美酸、安吡昔康、屈恶昔康、伊索昔康、氯诺昔康、美洛昔康、吡罗昔康、替诺昔康、阿明洛芬、苯恶洛芬、卡洛芬、右布洛芬、右酮洛芬、苯布芬、非诺洛芬、氟诺洛芬、氟比洛芬、布洛芬、异丁普生、吲哚洛芬、酪洛芬、氯索洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、舒洛芬、Tarenflurbil、替泊沙林、噻洛芬酸、维达洛芬、萘普西诺、阿扎丙宗、氯尼辛、依托芬那酯、氟灭酸、氟尼辛、甲氯芬那酸、甲灭酸、莫尼氟酯、尼氟灭酸、托芬那酸、氟替阿嗪、阿利考昔、塞来昔布、西米考昔、地拉考昔、依托考昔、非罗考昔、罗美昔布、吗伐考昔(Mavacoxib)、帕瑞考昔、罗贝考昔、罗非昔布、伐地考昔、氨基丙腈、炎痛静、硫酸软骨素、双醋瑞因、氟丙喹宗、氨基葡萄糖、糖胺多糖、贯叶金丝桃素、萘丁美酮、尼美舒利、奥沙西罗、普罗喹宗、超氧化物歧化酶/奥古蛋白和替尼达普。糖皮质激素的实例包括但不限于倍他米松和强的松。生物反应调节剂的实例包括但不限于羟化氯喹、来氟米特、甲氨蝶呤、托法替尼、阿巴西普、阿达木单抗、阿达木单抗-atto、阿那白滞素、依那西普、依那西普-szzs、利妥昔单抗、英夫利昔-dyyb、戈利木单抗、妥珠单抗、托珠单抗和sarilumab。阿片样物质的实例包括但不限于曲马多、奥施康定、羟考酮、芬太尼、吗啡、可待因、二氢可待因和actiq。
在具体的实施方案中,本公开提供了一种在有需要的受试者中减轻巨噬细胞炎症和/或抑制促炎性细胞因子分泌的方法,所述方法包括向该受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I、I(a)或II的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;R不存在或者是(C1-C5)烷基;并且R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在另一个实施方案中,本公开提供了一种在需要其的受试者中减轻巨噬细胞炎症和/或抑制促炎性细胞因子的分泌的方法,该方法包括向该受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I(b)或I(c)的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;R不存在或者是(C1-C5)烷基;并且R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在又一个实施方案中,本公开提供了一种在有此需要的受试者中减轻巨噬细胞炎症和/或抑制促炎性细胞因子分泌的方法,该方法包括向受试者施用有效量的低聚糖或包含低聚糖的药物组合物,其中所述低聚糖包含式I(d)、I(e)或II(a)的结构:
或其药学上可接受的盐、溶剂化物或前药。在另一个实施方案中,促炎性细胞因子包括白介素(IL)-1β和IL-6。在某些实施方案中,对于本文公开的方法,将本公开的低聚糖或包含本公开的低聚糖的药物组合物施用于5岁或更大年龄(例如6、7、8、9、10、11、12岁或更大)的人类受试者。在一个可选的实施方案中,将包含低聚糖的组合物施用于小于5岁的受试者。在另一个实施方案中,对于本文公开的方法,将本公开的低聚糖或包含本公开的低聚糖的药物组合物施用于18岁或更大年龄的人类受试者。
附图说明
图1A-C证明3’-唾液乳糖(3’SL)降低了LPS激活的巨噬细胞中的IL-6和IL-1βmRNA的表达。使RAW246.7细胞暴露于LPS[单独地或与汇集的人乳低聚糖(HMO)或3’-唾液乳糖(3’SL)或2’-岩藻糖基乳糖(2'FL)组合]。6小时后,通过RT-PCR测量IL-6(A)和IL-1β(B)mRNA的水平,并绘制为相对于仅暴露于LPS的细胞中相应mRNA水平的平均值±标准偏差(n=8)(**p<0.01;***p<0.001)。HMO是一组150多种结构不同的低聚糖,其组成遵循基本结构蓝图(C),包含五个单糖结构单元:葡萄糖(深灰色圆圈)、半乳糖(浅灰色圆圈)、N-乙酰氨基葡萄糖(深灰色方形)、岩藻糖(灰色三角形)和唾液酸(灰色菱形)。3’SL在末端处含有乳糖和唾液酸;2’FL在末端处含有乳糖和岩藻糖。
图2A-C显示3’-唾液乳糖(3’SL)减轻了CAIA小鼠模型中的爪肿胀和软骨损伤。在研究过程中,口服灌胃3’SL(20mg,每天三次,从LPS引发时开始)降低基线校正的足踝肿胀(A)和临床病理评分28(B)。3’SL暴露还显著减少了通过组织学评分测量的后爪关节炎、侵蚀和软骨损伤(C)。(*p<0.05、**p<0.01、***p<0.001)。
具体实施方式
如本文和所附权利要求书中所使用的,单数形式“一个/种(a、an)”和“该/所述(the)”包括复数指代,除非上下文另外明确指出。因此,例如,对“一种低聚糖”的引用包括多种这样的低聚糖,并且对“该治疗剂”的引用包括引用本领域技术人员已知的一种或多种治疗剂及其等同物,等等。
而且,除非另有说明,否则“或”的使用表示“和/或”。类似地,“包含(comprise、comprises、comprising)”和“包括(include、includes、including)”是可互换的,而不意图是限制性的。
应进一步理解的是,在各种实施方案的描述使用术语“包含”的情况下,本领域技术人员应理解,在某些特定情况下,可以使用语言“基本上由…组成”或由…组成”来可替代地描述实施方案。
除非另有定义,否则本文中使用的所有技术和科学术语均具有与本公开所属领域的普通技术人员通常理解的含义相同的含义。尽管许多方法和试剂与本文所述的那些相似或等同,但是本文公开的是示例性的方法和材料。
为了描述和公开可以与本文的描述结合使用的方法的目的,本文中提及的所有出版物均通过引用全文并入本文。此外,对于在本公开中明确定义的术语,即使在出版物、字典、论文等中赋予该术语不同的含义,在所有方仍以在本公开中明确提供的术语的定义为准。
术语“烯基”是指包含碳和氢原子的有机基团,其在两个碳之间包含至少一个共价双键。通常,在本公开中使用的“烯基”是指有机基团,其包含2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或30个碳原子,或包含介于前述值中的任何两个之间的任何范围的碳原子或包括前述值中的任何两个的任何范围的碳原子。尽管C2-烯基可以与母链的碳形成双键,但是具有三个或更多个碳的烯基可以包含一个以上的双键。在某些情况下,烯基将被缀合,在其它情况下烯基将不被缀合,而在其它情况下,烯基可具有缀合区段和非缀合区段。另外,如果存在多于2个碳,则碳可以以直链方式连接,或者可选地,如果存在多于3个碳,则碳也可以以支链方式连接,使得母链包含一个或多个仲碳、叔碳或季碳。除非另有说明,否则烯基可以是取代的或未取代的。
术语“烷基”是指包含碳和氢原子的有机基团,其在碳之间包含共价单键。通常,在本公开中使用的“烷基”是指有机基团,其包含1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或30个碳原子,或包含介于前述值中的任何两个之间的任何范围的碳原子或包括前述值中的任何两个的任何范围的碳原子。在存在多于1个碳的情况下,则碳可以以直链方式连接,或者可选地,如果存在多于2个碳,则碳也可以以支链方式连接,使得母链包含一个或多个仲碳、叔碳或季碳。除非另有说明,否则烷基可以是取代的或未取代的。
术语“炔基”是指包含碳和氢原子的有机基团,其在两个碳之间包含共价三键。通常,在本公开中使用的“炔基”是指有机基团,其包含2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或30个碳原子,或包含介于前述值中的任何两个之间的任何范围的碳原子或包括前述值中的任何两个的任何范围的碳原子。尽管C2-炔基可以与母链的碳形成三键,但是具有三个或更多个碳的炔基可以包含一个以上的三键。在存在多于3个碳的情况下,则碳可以以直链方式连接,或者可选地,如果存在多于4个碳,则碳也可以以支链方式连接,使得母链包含一个或多个仲碳、叔碳或季碳。除非另有说明,炔基可以是取代的或未取代的。
本公开中所用的术语“芳基”指的是具有离域π电子云的共轭平面环系,所述环系仅含有碳作为环原子。用于本公开的目的的“芳基”涵盖了1个至4个芳环,其中当芳基大于1个环时,所述芳环连接,以使得它们被连接、稠合或其组合。芳基可以是取代的或未取代的,或在多于一个芳环的情况下,一个或多个环可以未被取代;一个或多个环可以被取代;或其组合。
如本公开中所用的术语“环烷基”指的是烷基,其含有连接的至少3个碳原子,但不多于12个碳原子,以使它形成环。用于本公开的目的的“环烷基”涵盖了1个至4个环烷基环,其中当环烷基大于1个环时,则所述环烷基环连接,以使得它们被连接、稠合或其组合。环烷基可以是取代的或未取代的,或在多于一个环烷基环的情况下,一个或多个环可以未被取代;一个或多个环可以被取代;或其组合。
为了本公开的目的,术语“杂-”在用作前缀时,如杂烷基、杂烯基、杂炔基或杂烃,指的是一个或多个碳原子被作为母链的一部分的非碳原子置换的指定烃。这样的非碳原子的实例包括但不限于N、O、S、Si、Al、B以及P。如果在杂基母链中存在多于一个非碳原子,则该原子可以是相同元素或可以是不同元素如N和O的组合。在一个特定的实施方案中,“杂”-烃(例如烷基、烯基、炔基)是指具有1至3个C、N和/或S原子(作为母链的一部分)的烃。
如本文所用的术语“杂环”指的是含有至少1个非碳环原子的环结构。用于本公开的目的的“杂环”涵盖了1个至4个杂环的环,其中当杂环大于1个环时,所述杂环的环连接,以使得它们被连接、稠合或其组合。杂环可以是芳族或非芳族的,或在多于一个杂环的环的情况下,一个或多个环可以是非芳族的;一个或多个环可以是芳族的;或其组合。杂环可以被取代或未被取代,或在多于一个杂环的环的情况下,一个或多个环可以未被取代;一个或多个环可以被取代;或其组合。通常,非碳环原子是N、O、S、Si、Al、B或P。在其中存在多于一个非碳环原子的情况下,这些非碳环原子可以是相同元素,或不同元素(如N和O)的组合。杂环的实例包括但不限于:单环杂环,如氮丙啶、环氧乙烷、环硫乙烷、氮杂环丁烷、氧杂环丁烷、硫杂环丁烷、吡咯烷、吡咯啉、咪唑烷、吡唑烷、吡唑啉、二氧戊环、环丁砜、2,3-二氢呋喃、2,5-二氢呋喃、四氢呋喃、噻吩烷、哌啶、1,2,3,6-四氢-吡啶、哌嗪、吗啉、硫代吗啉、吡喃、噻喃、2,3-二氢吡喃、四氢吡喃、1,4-二氢吡啶、1,4-二烷、1,3-二烷、二烷、高哌啶、2,3,4,7-四氢-1H-氮杂高哌嗪(2,3,4,7-tetrahydro-1H-azepinehomopiperazine)、1,3-二氧杂环庚烷、4,7-二氢-1,3-二氧杂环庚(4,7-dihydro-1,3-dioxepin)和环氧己烷;以及多环杂环,如吲哚、吲哚啉、异吲哚啉、喹啉、四氢喹啉、异喹啉、四氢异喹啉、1,4-苯并二烷、香豆素、二氢香豆素、苯并呋喃、2,3-二氢苯并呋喃、异苯并呋喃、苯并吡喃、苯并二氢吡喃、异苯并二氢吡喃、咕吨、吩噻、噻蒽、吲哚嗪、异吲哚、吲唑、嘌呤、酞嗪、萘啶、喹喔啉、喹唑啉、噌啉、蝶啶、菲啶、萘嵌间二氮杂苯、菲咯啉、吩嗪、吩噻嗪、吩嗪、1,2-苯并异唑、苯并噻吩、苯并唑、苯并噻唑、苯并咪唑、苯并三唑、硫代黄嘌呤、咔唑、咔啉、吖啶、吡咯里西啶(pyrolizidine)和喹诺里西啶。除了上文所述的多环杂环之外,杂环还包括这样的多环杂环:其中两个或更多个环之间的环稠合包括多于一个为两个环所共用的键以及多于两个为两个环所共用的原子。这样的桥联杂环的实例包括奎宁环、二氮杂双环[2.2.1]庚烷以及7-氧杂双环[2.2.1]庚烷。
单独或作为后缀或前缀使用的术语“杂环基团”、“杂环部分”、“杂环的”或“杂环”指的是已经被去除了一个或多个氢的杂环。
术语“烃”是指仅包含碳和氢的原子的基团。可以在本公开中使用的烃的实例包括但不限于烷烃、烯烃、炔烃、芳烃和苄基。
如本文所用,术语“非控释赋形剂(non-release controlling excipient)”是指与常规的速释剂型相比,其主要功能不包括改变活性物质从剂型中释放的持续时间或位置的赋形剂。
术语“任选取代的”是指官能团,通常是烃或杂环,其中一个或多个氢原子可以被取代基取代。因此,“任选取代的”是指被取代的官能团(因为一个或多个氢原子被取代基取代),或未取代的官能团(因为氢原子未被取代基取代)。例如,任选取代的烃基是指未取代的烃基或取代的烃基。
如本文所用,术语“药学上可接受的载体”、“药学上可接受的赋形剂”、“生理学上可接受的载体”或“生理学上可接受的赋形剂”是指药学上可接受的材料、组合物或媒介物,例如液体或固体填料、稀释剂、赋形剂、溶剂或封装材料。在与药物制剂的其它成分相容的意义上,每种组分必须是“药学上可接受的”。它也必须适合与人和动物的组织或器官接触使用,而没有过度的毒性、刺激、变态反应、免疫原性或其它问题或并发症、与合理的获益/风险比相称。“药学上可接受的载体”和“药学上可接受的赋形剂”的实例可见于以下出版物:Remington:The Science and Practice of Pharmacy(《雷明顿:药学技术与实践》),第21版;Lippincott Williams&Wilkins:Philadelphia,Pa.,2005;Handbook ofPharmaceutical Excipients(《药用辅料手册》),第5版;Rowe等编辑,The PharmaceuticalPress and the American Pharmaceutical Association:2005;和Handbook ofPharmaceutical Additives(《药物添加剂手册》),第3版;Ash和Ash编辑,GowerPublishing Company:2007;Pharmaceutical Preformulation and Formulation(《药剂处方前和处方研究》),Gibson编辑,CRC Press LLC:Boca Raton,Fla.,2004。
本文所用的术语“控释赋形剂(release controlling excipient)”是指与常规速释剂型相比,其主要功能是改变活性物质从剂型中释放的持续时间或位置的赋形剂。
如本文所用,术语“受试者”是指动物,包括但不限于灵长类动物(例如人、猴子、黑猩猩、大猩猩等)、啮齿动物(例如大鼠、小鼠、沙鼠、仓鼠、雪貂等)、兔类动物、猪(例如猪、小型猪)、马、犬、猫科动物等。术语“受试者”和“患者”在本文可互换使用。例如、哺乳动物受试者可以指人类患者。
关于给定的低聚糖,本文所用的术语“基本上纯的”是指该低聚糖基本上不含其它生物大分子。以干重计,基本上纯的低聚糖为至少75%(例如,至少80、85、95或99%)纯。可以通过任何适当的标准方法,例如通过柱色谱法、聚丙烯酰胺凝胶电泳或HPLC分析来测量纯度。
术语“取代基”是指取代氢原子的原子或原子的基团。为了本发明的目的,取代基包括氘原子。
关于烃类、杂环等,术语“取代的”是指其中母链含有一个或多个取代基的结构。
术语“治疗上可接受的”是指适合与患者的组织接触使用而没有过度的毒性、刺激、变态反应、免疫原性的那些化合物(或盐、前药,互变异构体、两性离子形式等),其与合理的收益/风险比相称,并且对预期用途有效。
本文所用的术语“治疗(treat、treating和treatment)”是指改善与疾病或病症(例如关节炎)有关的症状,包括预防或延迟疾病或病症症状的发作和/或减轻疾病或病症症状的严重程度或频率。
关于烃类、杂环等,术语“未取代的”是指其中母链不包含取代基的结构。
术语“活性成分”和“活性物质”是指低聚糖或化合物,其被单独施用于受试者或与一种或多种药学上可接受的赋形剂和/或载体组合施用于受试者,以治疗、预防或改善病症的一种或多种的症状。
术语“药物”或“治疗剂”是指被施用于受试者以治疗、预防或改善病症的一种或多种的症状的化合物或其药物组合物。
如本文所用,术语“病症”意图与术语“疾病”、“综合症”和“病状”(如在医学状况中)大体上是同义的且可互换使用,因为它们均反映出身体或其一部分的异常状况,该异常状况损害正常的功能且通常表现为不同的体征和症状。
类风湿性关节炎(RA)是一种终生的全身性自身免疫性疾病,其对女性的影响(常在其最有生育力和生子的年龄)的是男性的三倍。患有RA女性的怀孕造成了治疗挑战。一些抗风湿药可能会穿过胎盘并伤害胎儿和/或转移到母乳中并伤害母乳喂养的婴儿。应避免致畸性化合物,例如甲氨蝶呤和来氟洛米,并且高剂量甾体可能与胎膜早破有关。药物转移到母乳中的高风险经常导致对女性停止母乳喂养的建议。孕妇可以经历RA症状的改善,或者甚至进入完全缓解期。归因于这种现象的机制有几种,包括父系HLA型、激素和T细胞亚型的转变。
本公开证明,3’-和/或6’-唾液乳糖在巨噬细胞中具有抗炎作用,并减轻了小鼠的爪肿胀和软骨损伤。发现3’-和/或6’-唾液乳糖(分别为3’SL和6’SL)是一种抗炎剂,其降低体外活化巨噬细胞中促炎性细胞因子的表达,并且在口服给与时在体内减轻胶原抗体诱导的关节炎(CAIA)小鼠模型的爪肿胀和软骨损伤。
本公开的低聚糖的口服施用提供了婴幼儿和成人中低聚糖的全身循环。与FDA批准的其它药物不同,本文所述的低聚糖不仅可以被施用来治疗成人受试者的疾病或病症,而且还可以被施用于怀孕的雌性、婴幼儿和器官功能受损(例如,肾衰竭)的受试者。本文证明了本公开的低聚糖作为用于治疗RA的疗法的功效。由于本公开的低聚糖对人类几乎没有不良影响或没有不良影响,因此这种治疗形式可以用作预防疗法、用作一线治疗选择或用作任一性别的患者都可以很好耐受的现有疗法的辅助手段。
在具体的实施方案中,本公开提供了具有式I、I(a)或II的结构的低聚糖:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
在某些实施方案中,本公开提供了具有式I(b)或I(c)的结构的低聚糖:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;
R’独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
在具体的实施方案中,本公开提供了本文公开的方法,该方法包括施用本文公开的基于3’-唾液乳糖(3’SL)的低聚糖或包含本文公开的基于3’-唾液乳糖(3’SL)的低聚糖的药物组合物。
在另一个实施方案中,本公开还提供了本文公开的方法,该方法包括施用一种或多种具有式I、I(a)和/或II的结构的低聚糖:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在可选的实施方案中,本公开进一步提供了本文公开的方法,该方法包括施用药物组合物,该药物组合物包含一种或多种具有式I、I(a)和/或II的结构的低聚糖或其药学上可接受的盐、溶剂化物或前药。
在另一个实施方案中,本公开还提供了本文公开的方法,该方法包括施用一种或多种具有式I(b)和/或I(c)的结构的低聚糖:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。在可选的实施方案中,本公开进一步提供了本文公开的方法,该方法包括施用药物组合物,该药物组合物包含一种或多种具有式I(b)和/或I(c)的结构的低聚糖或其药学上可接受的盐、溶剂化物或前药。
在又一个实施方案中,本公开提供了本文公开的方法,该方法包括施用一种或多种具有式I(d),I(e)和/或II(a)的结构的低聚糖:
或其药学上可接受的盐、溶剂化物或前药。在可选的实施方案中,本公开还提供了本文公开的方法,该方法包括施用药物组合物,该药物组合物包含一种或多种式I(d)、I(e)和/或II(a)的低聚糖或其药学上可接受的盐、溶剂化物或前药。
在另一个实施方案中,所述低聚糖基本上是单对映体、按重量计约90%或更多的(-)-对映体和按重量计约10%或更少的(+)-对映体的混合物、按重量计约90%或更多的(+)-对映体和按重量计约10%或更少的(-)-对映体的混合物、基本上单独的非对映体、或按重量计约90%或更多的单独的非对映体和按重量计约10%或更少的任何其它非对映体的混合物。
本文公开的低聚糖可以是对映体纯的(例如单对映体或单非对映体),或者可以是立体异构体混合物,例如对映体的混合物、外消旋混合物或非对映体混合物。这样,本领域技术人员将认识到,对于在体内经历差向异构化的低聚糖,以其(R)形式施用低聚糖等效于以其(S)形式施用低聚糖。用于制备/分离单独的对映体的常规技术包括由合适的光学纯前体进行手性合成或外消旋体拆分,其使用例如手性色谱法、重结晶、拆分、非对映体盐形成或衍生为非对映体加合物,然后进行分离。
当本文公开的低聚糖包含酸性或碱性部分时,它也可以作为药学上可接受的盐公开(参见,Berge等,J.Pharm.Sci.1977,66,1-19;和“Handbook of Pharmaceutical Salts,Properties and Use(《药物盐、性质和使用手册》),”Stah和Wermuth编辑;Wiley-VCH andVHCA,Zurich,2002)。
用于制备药学上可接受的盐的合适的酸包括但不限于乙酸、2,2-二氯乙酸、酰化氨基酸、己二酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸(cyclamic acid)、环己氨磺酸、十二烷基磺酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基-乙磺酸、甲酸、富马酸、粘酸(galactaric acid)、龙胆酸、葡萄庚酸、D-葡糖酸、D-葡萄糖醛酸、L-谷氨酸、α-氧代-戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-苯基乙醇酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸(pamoic acid)、高氯酸、磷酸、L-焦谷氨酸、糖酸(saccharic acid)、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对-甲苯磺酸、十一碳烯酸和戊酸。
用于制备药学上可接受的盐的合适的碱包括但不限于无机碱,例如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌或氢氧化钠;以及有机碱,例如伯胺、仲胺、叔胺和季胺、脂族胺和芳族胺,包括L-精氨酸、苯乙苄胺、苄星青霉素(benzathine)、胆碱、二甲基乙醇胺、二乙醇胺、二乙胺、二甲胺、二丙胺、二异丙胺、2-(二乙氨基)-乙醇、乙醇胺、乙胺、乙二胺、异丙胺、N-甲基-葡糖胺、海巴明(hydrabamine)、1H-咪唑、L-赖氨酸、吗啉、4-(2-羟乙基)-吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟乙基)-吡咯烷、吡啶、喹核碱、喹啉、异喹啉、仲胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇和氨丁三醇。
本文所公开的低聚糖也可以被设计为前药,其是本文所公开的低聚糖的功能性衍生物并且在体内易于转化为母体低聚糖。前药通常是有用的,因为在某些情况下,它们可比母体低聚糖更容易施用。它们例如可以通过口服施用而成为生物可利用的,而母体低聚糖则不是。与母体低聚糖相比,前药在药物组合物中也可具有增强的溶解度。前药可以通过多种机制转化为母体药物,所述机制包括酶促过程和代谢水解。见Harper,Progress in DrugResearch 1962,4,221-294;Morozowich等,在以下中:“Design of BiopharmaceuticalProperties through Prodrugs and Analogs,”Roche编辑,APHA Acad.Pharm.Sci.1977;“Bioreversible Carriers in Drug in Drug Design,Theory and Application,”Roche编辑,APHA Acad.Pharm.Sci.1987;“Design of Prodrugs,”Bundgaard,Elsevier,1985;Wang等,Curr.Pharm.Design 1999,5,265-287;Pauletti等,Adv.Drug.DeliveryRev.1997,27,235-256;Mizen等,Pharm.Biotech.1998,11,345-365;Gaignault等,Pract.Med.Chem.1996,671-696;Asgharnejad,在以下中:“Transport Processes inPharmaceutical Systems,”Amidon等编辑,Marcell Dekker,185-218,2000;Balant等,Eur.J.Drug Metab.Pharmacokinet.1990,15,143-53;Balimane和Sinko,Adv.DrugDelivery Rev.1999,39,183-209;Browne,Clin.Neuropharmacol.1997,20,1-12;Bundgaard,Arch.Pharm.Chem.1979,86,1-39;Bundgaard,Controlled Drug Delivery1987,17,179-96;Bundgaard,Adv.Drug Delivery Rev.1992,8,1-38;Fleisher等,Adv.Drug Delivery Rev.1996,19,115-130;Fleisher等,Methods Enzymol.1985,112,360-381;Farquhar等,J.Pharm.Sci.1983,72,324-325;Freeman等,J.Chem.Soc.,Chem.Commun.1991,875-877;Friis和Bundgaard,Eur.J.Pharm.Sci.1996,4,49-59;Gangwar等,Des.Biopharm.Prop.Prodrugs Analogs,1977,409-421;Nathwani和Wood,Drugs 1993,45,866-94;Sinhababu和Thakker,Adv.Drug Delivery Rev.1996,19,241-273;Stella等,Drugs 1985,29,455-73;Tan等,Adv.Drug Delivery Rev.1999,39,117-151;Taylor,Adv.Drug Delivery Rev.1996,19,131-148;Valentino和Borchardt,DrugDiscovery Today 1997,2,148-155;Wiebe和Knaus,Adv.Drug Delivery Rev.1999,39,63-80;Waller等,Br.J.Clin.Pharmac.1989,28,497-507。
可以使用基于酶的发酵技术(重组酶或天然酶)或微生物发酵技术通过生物技术手段生产低聚糖。在后一种情况下,微生物可以表达其天然酶和底物,或可以被工程改造以产生相应的底物和酶。可以使用单一微生物培养物和/或混合培养物。可选地,可以通过化学合成从乳糖和其它底物产生低聚糖。
生物技术方法使得有可能大规模、成本有效地生产目标低聚糖。准确地说,可以通过对遗传修饰的细菌、酵母或其它微生物进行发酵而在水介质中高产率地生产本文公开的低聚糖。参见,例如,WO200l04341;WO2007101862;WO2010070104;WO2010142305;WO2012112777;Priem等,Glycobiology 12:235(2002);Drouillard等,Angew.Chem.Int.Ed.45:1778(2006);Han等,Biotechnol.Adv.30:1268(2012);Lee等,Microb.Cell Fact.11:48(2012);Baumgartner等,Microb.Cell Fact.12:40(2013);和WO2014135167A1。可选地,可以基于以下出版物中描述的方法合成本公开的低聚糖:WO2011100980A1;WO2012007588A1;WO2012127410A1;WO2012155916A1;WO2013044928A1;和US9102966B2。可以如WO2012/155916和WO 2013/044928中所述合成LNT,可以如WO 2013/091660中所述制备LNT和LNnT的混合物,可以如WO 2010/115934和WO2010/115935中所述制备2’-FL,可以如WO 2013/139344中所述制备3-FL,可以如WO 2010/100979中所述制备6’-SL及其盐,可以如WO 2012/113404中所述制备唾液酸化低聚糖,以及可以如WO 2012/113405中所述制备人乳低聚糖的混合物。作为酶促生产的实例,可以如WO 2012/007588中所述制备唾液酸化的低聚糖,可以如WO 2012/127410中所述制备岩藻糖基化的低聚糖。关于生物技术方法,WO 2001/04341和WO 2007/101862描述了如何使用转基因大肠杆菌(E.coli)制备任选被岩藻糖或唾液酸取代的低聚糖。
在某个实施方案中,本公开提供了一种营养组合物,其包含本文公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)以及一种或多种食品级试剂。在某些实施方案中,营养组合物包含3’SL、6’SL或3’SL和6’SL的组合或由其组成。在其它实施方案中,营养组合物以145mg/L或更高的3’SL、6’SL或3’SL和6’SL的组合包含3’SL、6’SL或它们的组合或由其组成。在另一个实施方案中,营养组合物中总低聚糖的至少9%(例如10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100%;或任意上述值之间的任意值)包含3’SL、6’SL或其组合。可以与本文公开的低聚糖一起使用的食品级试剂的实例包括但不限于乳(例如,牛奶、杏仁奶、豆浆)、酸奶、麦芽糊精、乳蛋白浓缩物、舒可慢(Sucromalt)、丙三醇、可可粉、大豆分离蛋白、果糖、植物或动物油(例如高油酸红花油、大豆油、菜籽油)、植物固醇酯、HMS/HMO、大豆卵磷脂、角叉菜胶、牛磺酸、L-肉毒碱、维生素和/或矿物质(例如抗坏血酸钠、柠檬酸钾、磷酸钠、柠檬酸钙、氯化胆碱、氯化钾、柠檬酸钠、氧化镁、α-醋酸生育酚、硫酸锌、硫酸亚铁、烟酰胺、泛酸钙、维生素A棕榈酸酯、柠檬酸、硫酸锰、盐酸吡哆醇、维生素D3、硫酸铜、单硝酸硫胺素、核黄素、β-胡萝卜素、叶酸、生物素、碘化钾、氯化铬、硒酸钠、钼酸钠、植物甲萘醌、维生素B12、氯化镁、磷酸钙)。
本文公开了药物组合物,其包含本公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)或其药学上可接受的盐、溶剂化物或前药(作为活性成分)与药学上可接受的媒介物、载体、稀释剂或赋形剂或其混合物;与一种或多种药学上可接受的赋形剂或载体。
本文公开了修饰释放(modified release)剂型的药物组合物,其包含本公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)或其药学上可接受的盐、溶剂化物或前药;以及本文所述的一种或多种控释赋形剂或载体。合适的修饰释放剂型媒介物包括但不限于亲水或疏水基质装置、水溶性隔离层包衣、肠溶衣、渗透装置、多颗粒装置及其组合。药物组合物还可包含非控释赋形剂或载体。
本文进一步公开了肠溶衣包衣剂型的药物组合物,其包含本文公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)或其药学上可接受的盐、溶剂化物或前药;和用于肠溶衣包衣剂型的一种或多种控释赋形剂或载体。药物组合物还可包含非控释赋形剂或载体。
本文进一步公开了泡腾剂型(effervescent dosage form)的药物组合物,其包含本文公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)或其药学上可接受的盐、溶剂化物或前药,所述一种或多种低聚糖为基本上纯的形式(例如,缺乏在乳中可见的其它低聚糖);和用于泡腾剂型的一种或多种控释赋形剂或载体。药物组合物还可包含非控释赋形剂或载体。
另外,公开了某种剂型的药物组合物,其具有即时释放成分和至少一种延迟释放成分,并且能够以在时间上间隔开(例如,在时间上间隔0.1至24小时或几天)的至少两个连续脉冲的形式使本文公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)不连续地释放。药物组合物包含本文公开的低聚糖或其药学上可接受的盐、溶剂化物或前药;以及一种或多种控释和非控释赋形剂或载体,例如适用于可破坏的半透膜的那些赋形剂或载体和可溶胀物质。
本文还公开了用于向受试者口服施用的剂型的药物组合物,其包含本文公开的一种或多种低聚糖(例如3’SL和/或6’SL或其衍生物)或其药学上可接受的盐、溶剂化物或前药;以及包封在中间反应层中的一种或多种药学上可接受的赋形剂或载体,该中间反应层包含用碱部分中和并具有阳离子交换能力的耐胃液聚合物分层材料和耐胃液外层。
本文提供的药物组合物包含约0.1至约1000mg或高达2000mg或高达3000mg(或0.1至3000mg之间的任何值)、约1至约500mg、约2至约100mg、约1mg、约2mg、约3mg、约5mg、约10mg、约15mg、约20mg、约30mg、约40mg、约50mg、约100mg、约500mg的本文公开的一种或多种低聚糖,所述低聚糖为用于口服施用的速释片剂的形式。药物组合物还包含非活性成分,例如调味剂、共聚维酮、乙基纤维素、硬脂酸镁、甘露醇和二氧化硅。
本文提供的药物组合物包含约0.1至约1000mg或高达2000mg或高达3000mg(或其间的任何值)、约1至约500mg、约2至约100mg、约1mg、约2mg、约3mg、约5mg、约10mg、约15mg、约20mg、约30mg、约40mg、约50mg、约100mg、约500mg的本文公开的一种或多种低聚糖,所述低聚糖为用于口服施用的延长释放片剂的形式。药物组合物还包含非活性成分,例如乙基纤维素、癸二酸二丁酯、聚乙烯吡咯烷酮、硬脂富马酸钠、胶体二氧化硅和聚乙烯醇。
本文公开的药物组合物可以以单位剂型或多剂型公开。如本文所用,单位剂型是指适于向人和动物受试者施用并如本领域已知被单独包装的物理上离散的单元。每个单位剂量包含足以产生期望治疗效果的预定量的低聚糖、以及所需的药物载体或赋形剂。单位剂型的例子包括安瓿、注射器以及单独包装的片剂和胶囊剂。单位剂型可以以其分数或倍数施用。多剂型是包装在单个容器中的多个相同的单位剂型,其将以分开的单位剂型被施用。多剂型的例子包括小瓶、瓶装的片剂或胶囊剂或瓶装的品脱或加仑。
本文公开的低聚糖可以单独施用,或与本文公开的一种或多种其它低聚糖和/或一种或多种其它活性成分联合施用。可以将包含本文公开的低聚糖的药物组合物配制成用于口服、肠胃外和局部施用的各种剂型。药物组合物也可以被配制成修饰释放剂型,包括延迟释放、延长释放、拖延释放、持续释放、脉冲式释放、控制释放、加速释放以及快速释放、靶向释放、程序化释放和胃滞留剂型。这些剂型可以根据本领域技术人员已知的常规方法和技术来制备(参见,Remington:The Science and Practice of Pharmacy,同上;Modified-Release Drug Deliver Technology(《修饰-释放药物输送技术》),Rathbone等编辑,Drugsand the Pharmaceutical Science,Marcel Dekker,Inc.:New York,N.Y.,2002;Vol.126)。
本文公开的药物组合物可以一次或以时间间隔多次施用。应当理解,治疗的确切剂量和持续时间可以随所治疗的患者的年龄、体重和状况而变化,并且可以使用已知的测试方案或通过从体内或体外测试或诊断数据推断而凭经验确定。还应理解,对于任何特定的个体,应根据个体需要和施用或指导制剂施用的人员的专业判断,随时间调整具体的剂量方案。
在患者的状况没有改善的情况下,根据医生的判断,低聚糖的施用可以是长期施用,即,施用延长的时间段,包括患者生命的全部存活时间,以便减轻或以其它方式控制或限制患者疾病或状况的症状。
在患者的状况确实得到改善的情况下,根据医生的判断,可以连续进行低聚糖的施用,或在一定时间段内(即“药物假期”)暂时停止低聚糖的施用。
一旦患者的状况发生了改善,则在必要时施用维持剂量。随后,可以根据症状将施用的剂量或频率或两者降低至改善的疾病、病症或病状得以保持的水平。但是,在任何症状复发的情况下,患者可能需要长期间歇性治疗。
本文公开的药物组合物可以被配制为固体、半固体或液体剂型,用于口服施用。如本文所用,口服施用还包括颊、舌和舌下施用。合适的口服剂型包括但不限于片剂、胶囊剂、丸剂、糖剂、锭剂、消食剂(pastime)、扁囊剂、微丸剂、药用口香糖、颗粒剂、散装粉剂、泡腾或非泡腾粉剂或颗粒剂、溶液剂、乳剂、悬浮剂、溶液剂、圆片剂(wafer)、喷剂(sprinkle)、酏剂和糖浆。除低聚糖外,药物组合物还可包含一种或多种药学上可接受的载体或赋形剂,包括但不限于粘合剂、填充剂、稀释剂、崩解剂、润湿剂、润滑剂、助流剂、着色剂、移染剂、甜味剂和调味剂。
粘合剂或造粒剂(granulator)使片剂具有粘结性、以确保片剂在压制后保持完整。合适的粘合剂或造粒剂包括但不限于淀粉,例如玉米淀粉、马铃薯淀粉和预胶化淀粉(例如,STARCH 1500);明胶;糖,例如蔗糖、葡萄糖、右旋糖、糖蜜和乳糖;天然和合成树胶,例如阿拉伯树胶、海藻酸、藻酸盐、爱尔兰藓(Irish moss)提取物、Panwar树胶、印度树胶(ghatti gum)、isabgol外皮的粘物质、羧甲基纤维素、甲基纤维素、聚乙烯吡咯烷酮(PVP)、铝硅酸镁盐(Veegum)、落叶松阿拉伯糖半乳聚糖、粉状黄芪胶和瓜尔胶;纤维素,例如乙基纤维素、醋酸纤维素、羧甲基纤维素钙、羧甲基纤维素钠、甲基纤维素、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC);微晶纤维素,例如AVICEL-PH-101、AVICEL-PH-103、AVICEL RC-581、AVICEL-PH-105(FMC Corp.,Marcus Hook,Pa.);及其混合物。合适的填充剂包括但不限于滑石粉、碳酸钙、微晶纤维素、粉状纤维素、葡萄糖结合剂(dextrates)、高岭土、甘露醇、硅酸、山梨糖醇、淀粉、预胶化淀粉及其混合物。粘合剂或填充剂在本文公开的药物组合物中可以以按重量计约50%至约99%存在。
合适的稀释剂包括但不限于磷酸氢钙、硫酸钙、乳糖、山梨糖醇、蔗糖、肌醇、纤维素、高岭土、甘露醇、氯化钠、干淀粉和糖粉。当某些稀释剂(例如甘露醇、乳糖、山梨糖醇、蔗糖和肌醇)以足够的量存在时,它们可以赋予某些压制片剂允许通过咀嚼在口腔中崩解的特性。这样的压制片剂可以用作咀嚼片。
合适的崩解剂包括但不限于琼脂;膨润土;纤维素,例如甲基纤维素和羧甲基纤维素;木材产品;天然海绵;阳离子交换树脂;海藻酸;树胶,例如瓜尔胶和铝硅酸镁盐HV;柑橘渣;交联纤维素,例如交联羧甲纤维素;交联聚合物,如交聚维酮;交联淀粉;碳酸钙;微晶纤维素,例如羟基乙酸淀粉钠;波拉克林钾;淀粉,例如玉米淀粉、马铃薯淀粉、木薯淀粉和预胶化淀粉;黏土;aligns;及其混合物。本文公开的药物组合物中崩解剂的量根据制剂的类型而变化,其对于本领域普通技术人员而言是容易辨别的。本文公开的药物组合物可以包含按重量计约0.5%至约15%或约1%至约5%的崩解剂。
合适的润滑剂包括但不限于硬脂酸钙;硬脂酸镁;矿物油;轻质矿物油;甘油;山梨糖醇;甘露醇;乙二醇,例如甘油山嵛酸酯(glycerol behenate)和聚乙二醇(PEG);硬脂酸;月桂基硫酸钠;滑石粉;氢化植物油,包括花生油、棉籽油、向日葵油、芝麻油、橄榄油、玉米油和大豆油;硬脂酸锌;油酸乙酯;月桂酸乙酯;琼脂;淀粉;石松粉;二氧化硅或硅胶,例如200(W.R.Grace Co.,Baltimore,Md.)和(Cabot Co.,马萨诸塞州波士顿);及其混合物。本文公开的药物组合物可包含按重量计约0.1%至约5%的润滑剂。
合适的助流剂包括胶体二氧化硅、(Cabot Co.,马萨诸塞州波士顿)和不含石棉的滑石粉。着色剂包括任何批准、认证的水溶性FD&C染料和悬浮在水氧化铝上的水不溶性FD&C染料、以及色淀(color lakes)及其混合物。色淀是借助于吸附而形成的水溶性染料与重金属的水合氧化物的组合,由此形成不溶形式的染料。调味剂包括从植物(例如果实)中提取的天然香料、以及产生令人愉悦的味觉的化合物(例如薄荷和水杨酸甲酯)的合成混合物。甜味剂包括蔗糖、乳糖、甘露醇、糖浆、甘油和人造甜味剂,如糖精和阿斯巴甜。合适的乳化剂包括明胶、阿拉伯胶、黄芪胶、膨润土和表面活性剂,例如聚氧乙烯脱水山梨糖醇单油酸酯(20)、聚氧乙烯脱水山梨糖醇单油酸酯80(80)和三乙醇胺油酸酯。悬浮剂和分散剂包括羧甲基纤维素钠、果胶、黄芪胶、铝硅酸镁盐、阿拉伯胶、羧甲基纤维素钠、羟丙基甲基纤维素和聚乙烯吡咯烷酮。防腐剂包括甘油、对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、苯甲酸、苯甲酸钠和乙醇。润湿剂包括丙二醇单硬脂酸酯、脱水山梨糖醇单油酸酯、二甘醇单月桂酸酯和聚氧乙烯月桂醚。溶剂包括甘油、山梨糖醇、乙醇和糖浆。乳剂中使用的非性水液体的例子包括矿物油和棉籽油。有机酸包括柠檬酸和酒石酸。二氧化碳的来源包括碳酸氢钠和碳酸钠。
应当理解,即使在同一制剂中,许多载体和赋形剂也可以起到多种作用。
本文公开的药物组合物可以被配制成压制片剂、研制片剂(tablet triturate)、可咀嚼的锭剂、快速溶解片剂、多压片或肠溶衣片剂、糖衣或膜衣片剂。肠溶衣片剂是用抗胃酸作用但在肠中溶解或崩解的物质包衣的压制片剂,从而保护活性成分不受胃的酸性环境的影响。肠溶衣包括但不限于脂肪酸、脂肪、水杨酸苯酯、蜡、虫胶、氨化虫胶和邻苯二甲酸乙酸纤维素。糖衣片剂是被糖衣包围的压制片剂,其可有益于掩盖令人讨厌的味道或气味并保护片剂免于氧化。膜衣片剂是用水溶性材料的薄层或薄膜覆盖的压制片剂。膜衣包括但不限于羟乙基纤维素、羧甲基纤维素钠、聚乙二醇4000和邻苯二甲酸乙酸纤维素。膜衣赋予与糖衣相同的一般特性。多压片是通过一个以上压制循环制成的压制片剂,包括分层片剂,包芯片或干包衣片剂。
片剂剂型可以由粉末、结晶或颗粒形式的活性成分(单独地或与本文所述的一种或多种载体或赋形剂,包括粘合剂、崩解剂、控释聚合物、润滑剂、稀释剂和/或着色剂组合)制备。调味剂和甜味剂在可咀嚼的片剂和锭剂的形成中特别有用。
本文公开的药物组合物可以配制成软胶囊或硬胶囊,其可以由明胶、甲基纤维素、淀粉或藻酸钙制成。硬明胶胶囊也称为干填充胶囊(dry-filled capsule,DFC),其由两部分组成,一部分在另一部分上滑移,从而完全包封活性成分。软弹性胶囊(SEC)是柔软的球形壳体(例如明胶壳体),其通过添加甘油、山梨糖醇或类似的多元醇来增塑。明胶软壳体可以包含防腐剂以防止微生物的生长。合适的防腐剂是如本文所述的那些,包括对羟基苯甲酸甲酯和对羟基苯甲酸丙酯以及山梨酸。本文公开的液体、半固体和固体剂型可以被包封在胶囊中。合适的液体和半固体剂型包括在碳酸丙烯酯、植物油或甘油三酸酯中的溶液和悬浮液。含有这类溶液的胶囊可以如以下专利中所述制备:美国专利号4,328,245;4,409,239;和4,410,545。如本领域技术人员已知的,也可以将胶囊包衣,以改变或维持活性成分的溶解。
本文公开的药物组合物可以配制为液体和半固体剂型,包括乳剂、溶液剂、悬浮剂、酏剂和糖浆剂。乳剂是两相体系,其中一种液体以小球形式分散在另一种液体中,其可以是水包油或油包水。乳剂可包括药学上可接受的非水性液体或溶剂、乳化剂和防腐剂。悬浮剂可包括药学上可接受的悬浮剂和防腐剂。醇水溶液可以包括药学上可接受的缩醛,例如低级烷基醛的二(低级烷基)缩醛(术语“低级”是指烷基具有1-6个碳原子),例如乙醛缩二乙醇;以及具有一个或多个羟基的与水混溶的溶剂,例如丙二醇和乙醇。酏剂是澄清、有甜味的水醇溶液。糖浆剂是糖例如蔗糖的浓缩水溶液,其还可以包含防腐剂。对于液体剂型,例如,可以用足够量的药学上可接受的液体载体(例如水)稀释聚乙二醇中的溶液,以方便地测量,从而用于施用。
其它有用的液体和半固体剂型包括但不限于含有本文公开的活性成分以及以下成分的那些液体和半固体剂型:二烷基化的单或聚亚烷基二醇,包括1,2-二甲氧基甲烷、二甘醇二甲醚、三甘醇二甲醚、四甘醇二甲醚,聚乙二醇-350-二甲醚、聚乙二醇-550-二甲醚、聚乙二醇-750-二甲醚,其中350、550和750是指聚乙二醇的近似平均分子量。这些制剂可进一步包含一种或多种抗氧化剂,例如丁羟甲苯(BHT)、丁基羟基苯甲醚(BHA)、没食子酸丙酯、维生素E、对苯二酚、羟基香豆素、乙醇胺、卵磷脂、脑磷脂、抗坏血酸、苹果酸、山梨糖醇、磷酸、亚硫酸氢盐类,焦亚硫酸钠、硫代二丙酸及其酯和二硫代氨基甲酸盐类。
本文公开的用于口服施用的药物组合物也可以配制成脂质体、胶束、微球或纳米系统的形式。胶束剂型可以如美国专利号6,350,458中所述地制备。
本文公开的药物组合物可以被配制成非泡腾或泡腾颗粒剂和粉剂,以被重构为液体剂型。非泡腾颗粒剂或粉剂中使用的药学上可接受的载体和赋形剂可以包括稀释剂、甜味剂和湿润剂。泡腾颗粒剂或粉剂中使用的药学上可接受的载体和赋形剂可包括有机酸和二氧化碳源。
着色剂和调味剂可以用于所有上述剂型中。
本文公开的药物组合物可以配制成口服营养组合物。口服营养组合物可以包含蛋白质、脂质和/或可消化的碳水化合物的来源,并且可以是固体、粉末或液体形式。可以将组合物设计为营养或营养补充剂的唯一来源。合适的蛋白质来源包括完整的、水解的和部分水解的蛋白质,其可以源自任何合适的来源,例如乳(例如酪蛋白、乳清)、动物(例如肉、鱼)、谷物(例如稻、玉米)和蔬菜(例如大豆、土豆、豌豆)、昆虫(例如蝗虫)以及这些来源的组合。蛋白质来源的例子包括乳清蛋白浓缩物、乳清蛋白分离物、乳清蛋白水解物、酸性酪蛋白、酪蛋白酸钠(sodium casemate)、酪蛋白酸钙、酪蛋白酸钾、酪蛋白水解物、乳蛋白浓缩物、乳蛋白分离物、乳蛋白水解物、脱脂奶粉、浓缩脱脂奶、大豆浓缩蛋白、大豆分离蛋白、大豆蛋白水解物、豌豆浓缩蛋白、豌豆分离蛋白、豌豆蛋白水解物、胶原蛋白以及这些来源的组合。
本文公开的药物组合物可以配制成即释剂型或修饰释放剂型,包括延迟释放、持续释放、脉冲式释放、控制释放、靶向释放和程序化释放形式。
本文公开的药物组合物可以与不损害期望的治疗作用的其它活性成分或与补充期望的作用的物质共同配制。
本文公开的药物组合物可以通过注射、输注或植入进行肠胃外施用,以进行局部或全身施用。如本文所用,肠胃外施用包括静脉内、动脉内、腹膜内、鞘内、心室内、尿道内、胸骨内、颅内、肌内、滑膜内和皮下施用。
本文公开的药物组合物可以以适合于肠胃外施用的任何剂型被配制,所述剂型包括溶液剂、悬浮剂、乳剂、胶束、脂质体、微球、纳米系统和适合于注射前在液体中的溶液或悬浮液的固体形式。这样的剂型可以根据药学领域的技术人员已知的常规方法制备(参见,Remington:The Science and Practice of Pharmacy,同上)。
意图用于肠胃外施用的药物组合物可以包括一种或多种药学上可接受的载体和赋形剂,包括但不限于水性媒介物、水混溶性媒介物、非水性媒介物、抗微生物剂或抵抗微生物生长的防腐剂、稳定剂、溶解增强剂、等张剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮剂和分散剂、润湿剂或乳化剂、络合剂、掩蔽剂或螯合剂、冷冻保护剂、冻干保护剂、增稠剂、pH调节剂和惰性气体。
合适的水性媒介物包括但不限于水、盐水、生理盐水或磷酸盐缓冲盐水(PBS)、氯化钠注射液、林格氏(Ringers)注射液、等张右旋糖注射液、无菌水注射液、右旋糖和乳酸林格氏注射液。非水性媒介物包括但不限于植物来源的不挥发油、蓖麻油、玉米油、棉籽油、橄榄油、花生油、薄荷油、红花油、芝麻油、大豆油、氢化植物油、氢化大豆油、以及椰子油和棕榈籽油的中链甘油三酸酯。水混溶性媒介物包括但不限于乙醇、1,3-丁二醇、液态聚乙二醇(例如聚乙二醇300和聚乙二醇400)、丙二醇、甘油、N-甲基-2-吡咯烷酮、二甲基乙酰胺、和二甲基亚砜。
本文公开的药物组合物可以被配制用于单剂量或多剂量施用。单剂量制剂包装在安瓿、小瓶或注射器中。多剂量肠胃外制剂必须含有抑制细菌或抑制真菌浓度的抗微生物剂。如本领域已知和实践的,所有肠胃外制剂必须是无菌的。
药物组合物可以被配制成悬浮液、固体、半固体或触变液体,以作为植入的贮库施用。在一个实施方案中,本文公开的药物组合物分散在固体内部基质中,该固体内部基质被不溶于体液但允许药物组合物中的活性成分扩散通过的外部聚合物膜包围。
合适的内部基质包括聚甲基丙烯酸甲酯、聚丁基丙烯酸甲酯、增塑或未增塑的聚氯乙烯、增塑的尼龙、增塑的聚对苯二甲酸乙二醇酯、天然橡胶、聚异戊二烯、聚异丁烯、聚丁二烯、聚乙烯、乙烯-乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、碳酸硅酮共聚物、亲水性聚合物例如丙烯酸和甲基丙烯酸的酯的水凝胶、胶原、交联的聚乙烯醇和交联的部分水解的聚乙烯乙酸酯。
合适的外部聚合物膜包括聚乙烯、聚丙烯、乙烯/丙烯共聚物、乙烯/丙烯酸乙酯共聚物、乙烯/乙酸乙烯酯共聚物、硅橡胶、聚二甲基硅氧烷、氯丁橡胶、氯化聚乙烯、聚氯乙烯、氯乙烯与乙酸乙烯酯、偏二氯乙烯、乙烯和丙烯的共聚物、离聚物聚对苯二甲酸乙二醇酯、丁基橡胶、氯醇橡胶、乙烯/乙烯醇共聚物、乙烯/乙酸乙烯酯/乙烯醇三元共聚物和乙烯/乙烯氧基乙醇共聚物。
本文公开的药物组合物可以局部施用于皮肤、孔或粘膜。如本文所用,局部施用包括皮肤(皮内)、结膜、角膜内、眼内、眼、耳、经皮、鼻、阴道、输尿管、呼吸道和直肠施用。
本文公开的药物组合物可以配制成适合针对局部或全身作用而局部施用的任何剂型,包括乳剂、溶液剂、悬浮剂、乳膏剂、凝胶剂、水凝胶剂、软膏剂、隔离剂(dustingpowder)、敷料、酏剂、洗剂、悬浮剂、酊剂、糊剂、泡沫、薄膜、气雾剂、灌洗剂、喷雾剂、栓剂、绷带、皮肤贴剂。本文公开的药物组合物的局部制剂还可以包含脂质体、胶束、微球、纳米系统及其混合物。
适用于本文公开的局部制剂的药学上可接受的载体和赋形剂包括但不限于水性媒介物、水混溶性媒介物、非水性媒介物、抗微生物剂或抵抗微生物生长的防腐剂、稳定剂、溶解增强剂、等张剂、缓冲剂、抗氧化剂、局部麻醉剂、悬浮剂和分散剂、润湿剂或乳化剂、络合剂、掩蔽剂或螯合剂、渗透增强剂、冷冻保护剂、冻干保护剂、增稠剂和惰性气体。
本文公开的药物组合物可以以栓剂、阴道栓、探条(bougies)、泥罨剂或巴布剂、糊剂、粉剂、敷料、乳膏剂、膏药、避孕药、软膏剂、溶液剂、乳剂、悬浮剂、棉塞(tampons)、凝胶剂、泡沫、喷雾剂或灌肠剂的形式经直肠、尿道、阴道或经阴道周围施用。这些剂型可使用如Remington:The Science and Practice of Pharmacy,同上,中所述的常规方法制备。
本文公开的药物组合物可以以溶液剂、悬浮剂、软膏剂、乳剂、凝胶形成溶液、用于溶液的粉剂、凝胶剂、眼用膜剂和植入物的形式经眼施用。
本文公开的药物组合物可以经鼻内或通过吸入呼吸道施用。可以将药物组合物配制成气雾剂或溶液形式,以使用加压容器、泵、喷射器、雾化器(例如使用电流体动力学产生细雾的雾化器)或喷雾器——单独地或与合适的推进剂组合——进行递送,所述合适的推进剂例如1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷。药物组合物也可以被配制成用于吹入的干粉(单独地或与惰性载体例如乳糖或磷脂组合);和滴鼻剂。对于鼻内使用,粉末可包含生物粘附剂,包括壳聚糖或环糊精。
本文公开的药物组合物可以被配制成修饰释放剂型。如本文所用,术语“修饰释放(modified release)”是指当通过相同途径施用时活性成分的释放速率或释放位置与立即剂型的释放速率或释放位置不同的剂型。修饰释放剂型包括延迟释放、延长释放、拖延释放、持续释放、脉冲式释放、控制释放、加速释放以及快速释放、靶向释放、程序化释放和胃滞留剂型。可以使用本领域技术人员已知的各种修饰释放装置和方法(包括但不限于基质控释装置、渗透控释装置、多颗粒控释装置、离子交换树脂、肠溶衣、多层衣、微球体、脂质体及其组合)制备修饰释放剂型的药物组合物。活性成分的释放速率也可以通过改变活性成分的粒径和多态性来改变。
修饰释放的实例包括但不限于以下美国专利号中所述的那些:3,845,770;3,916,899;3,536,809;3,598,123;4,008,719;5,674,533;5,059,595;5,591,767;5,120,548;5,073,543;5,639,476;5,354,556;5,639,480;5,733,566;5,739,108;5,891,474;5,922,356;5,972,891;5,980,945;5,993,855;6,045,830;6,087,324;6,113,943;6,197,350;6,248,363;6,264,970;6,267,981;6,376,461;6,419,961;6,589,548;6,613,358;和6,699,500。
本文公开的修饰释放剂型的药物组合物可以通过本领域技术人员已知的方法制备,所述方法包括直接压片;干法或湿法制粒,随后压片;熔融制粒,然后压片。
本文公开的药物组合物还可以被配制成靶向待治疗的受试者的特定组织、受体或身体的其它区域,包括基于脂质体的递送系统、基于重新密封的红细胞的递送系统和基于抗体的递送系统。实例包括但不限于下列美国专利号:6,316,652;6,274,552;6,271,359;6,253,872;6,139,865;6,131,570;6,120,751;6,071,495;6,060,082;6,048,736;6,039,975;6,004,534;5,985,307;5,972,366;5,900,252;5,840,674;5,759,542;和5,709,874。
本文提供的免疫调节性低聚糖提供对受试者免疫系统的调节。特别地,本文公开的低聚糖可用于免疫疗法。免疫疗法是通过诱导、增强或抑制免疫反应而对疾病、病症或医学状况进行的治疗。免疫调节方案通常比现有药物具有更少的副作用,包括在治疗微生物疾病时产生耐药性的可能性更低。特别地,在本文中已经发现人乳的成分,人乳低聚糖,可以有效治疗受试者(包括成人受试者)的类风湿性关节炎。类风湿性关节炎是一种自身免疫性疾病,其引起关节和身体其它部位的慢性炎症。自身免疫性疾病是与受试者体内过度活跃的免疫系统相关的疾病,由此受试者的免疫系统攻击并损害其自身的组织。在类风湿性关节炎的情况下,免疫系统产生附着在关节内部(lining)的抗体。免疫系统细胞然后攻击关节,导致发炎、肿胀和疼痛。如果不治疗,类风湿性关节炎会导致永久性关节损伤。类风湿性关节炎的治疗方法通常包括减少免疫系统过多活性的各种口服或注射药物。
已经在本文中发现,本公开的低聚糖通过显著降低接受本公开的低聚糖(3’SL)的动物的炎症、侵蚀和软骨损伤评分而在体内类风湿性关节炎模型中发挥免疫调节作用。尽管前述内容明确确立了使用本公开的低聚糖治疗类风湿性关节炎的功效,但是应当理解,本公开的低聚糖的免疫调节作用对于用于其它自身免疫性疾病和病症以及炎性病症通常是有效的。鉴于此,本公开提供了治疗怀疑患有或患有炎性或自身免疫性病症的受试者的方法,包括向受试者施用有效量的本公开的低聚糖或其药学上可接受的盐、溶剂化物或前药。在可选的实施方案中,本公开提供了用于治疗、预防或改善自身免疫性病症或炎性病症的一种或多种症状的方法,包括向患有或怀疑患有这类疾病的受试者施用治疗有效量的本文公开的低聚糖或其药学上可接受的盐、溶剂化物或前药。
自身免疫性病症包括但不限于自身免疫性心肌炎、德雷斯勒综合征、心包切开术后综合征、亚急性细菌性心内膜炎、抗肾小球基底膜肾炎、间质性膀胱炎、狼疮肾炎、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、抗合成酶综合征、斑秃、自身免疫性血管水肿、自身免疫性孕酮性皮炎、自身免疫性荨麻疹、大疱性类天疱疮、瘢痕性类天疱疮、疱疹样皮炎、盘状红斑性狼疮、获得性大疱性表皮松解症、结节性红斑、妊娠类天疱疮、化脓性汗腺炎、扁平苔癣、硬化性苔藓、线状IgA病、硬斑病、寻常天疱疮、急性痘疮样苔藓样糠疹、穆-哈二氏病、银屑病、系统性硬皮病、白癜风、艾迪生氏病、自身免疫性多内分泌综合征1型、自身免疫性多内分泌综合征2型、自身免疫性多内分泌综合征3型、自身免疫性胰腺炎、1型糖尿病、自身免疫性甲状腺炎、奥德甲状腺炎、格雷夫斯氏病、自身免疫性卵巢炎、子宫内膜异位症、综合征、自身免疫性肠病、腹腔病、克罗恩病、显微镜下结肠炎、溃疡性结肠炎、抗磷脂综合征、再生障碍性贫血、自身免疫性溶血性贫血、自身免疫性淋巴细胞增生综合征、自身免疫性中性粒细胞减少症、自身免疫性血小板减少性紫癜、冷凝集素病、特发性混合性冷球蛋白血症、伊文氏综合征、恶性贫血、纯红细胞再生障碍性贫血、血小板减少症、痛性肥胖症、成人斯蒂尔病、强直性脊柱炎、CREST综合征、药物性狼疮、与附着点炎症相关的关节炎、嗜酸性筋膜炎、Felty综合征、IgG4相关的疾病、幼年型关节炎、慢性莱姆病、混合性结缔组织疾病、复发性风湿病、帕罗综合征、Parsonage-Turner综合征、银屑病关节炎、反应性关节炎、复发性多发性软骨炎、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施尼茨勒综合征、全身性红斑狼疮、未分化结缔组织病、皮肌炎、纤维肌痛、包涵体肌炎、肌炎、重症肌无力、神经性肌强直、亚急性小脑变性、多肌炎、急性播散性脑脊髓炎、急性运动性轴索型神经病、抗N-甲基-D-天冬氨酸受体脑炎、巴洛同心性硬化、Bickerstaff脑炎、慢性炎症性脱髓鞘性多发性神经病、格林-巴利综合征、桥本脑病、特发性炎症脱髓鞘疾病、Lambert-Eaton肌无力综合征、多发性硬化症、Oshtoran综合症、与链球菌相关的儿童自身免疫性神经精神障碍、进行性炎症性神经病、不宁腿综合征、僵人综合征、小舞蹈病、横贯性脊髓炎、自身免疫性视网膜病、自身免疫性葡萄膜炎、Cogan综合征、格雷夫斯眼病、中间葡萄膜炎、木样结膜炎、蚕蚀性角膜溃疡、视神经脊髓炎、眼球阵挛-肌阵挛综合征、自身免疫性内耳疾病、美尼尔氏综合症、白塞病、嗜酸性肉芽肿伴多管炎、IgA血管炎、川崎病、白细胞破碎性血管炎、狼疮血管炎、类风湿性血管炎、显微镜下多血管炎、结节性多动脉炎、风湿性多肌痛、荨麻疹性血管炎、血管炎和原发性免疫缺陷。
炎性病症的实例包括但不限于强直性脊柱炎、抗磷脂抗体综合征、痛风、肌炎、类风湿性关节炎、硬皮病、全身性红斑狼疮、血管炎、综合征、哮喘、慢性消化性溃疡、结核病、慢性牙周炎、溃疡性结肠炎、克罗恩病、慢性鼻窦炎、慢性活动性肝炎、阿尔茨海默病、帕金森氏病、肾炎、肠道易激综合症、纤维肌痛、憩室炎、结肠炎、动脉粥样硬化、骨关节炎、银屑病关节炎、湿疹、胃炎、鼻窦炎、脂溢性皮炎和韦格纳氏肉芽肿病。
在具体实施方案中,自身免疫性病症和炎性病症不是与消化道密切相关的病症(例如,克罗恩病、腹腔疾病、溃疡性结肠炎、憩室炎和肠道易激综合症)。在另一个实施方案中,自身免疫性病症选自全身性红斑狼疮、类风湿性关节炎、恶性贫血、硬皮病、银屑病、慢性甲状腺炎、格雷夫斯氏病、反应性关节炎、综合征和1型糖尿病。此外,鉴于本文提供的数据,本公开的低聚糖特别适合于治疗巨噬细胞驱动的慢性炎症,包括但不限于动脉粥样硬化、慢性阻塞性肺疾病、胰岛素抗性、2型糖尿病、肥胖症、全身型幼年特发性关节炎。
通常,需要向人施用的本文公开的低聚糖的量可以根据诸如风险和状况的严重性、人的年龄、组合物的形式以及被施用给人的其它药物的因素而变化。可以预期,无论受试者的年龄和状况如何,本文所述的低聚糖都应被很好地耐受。低聚糖的施用剂量可以由医生容易地设定,其通常为每天约10mg至约20g的范围,在某些实施方案中为每天约10mg至约15g、每天约100mg至约10g,在某些实施方案中为每天约500mg至约10g,在某些实施方案中为每天约1g至约7.5g。可以基于几个因素来确定适当的剂量,这些因素包括例如被治疗的患者的体重和/或状况、被治疗的状况的严重程度、人的其它小病和/或疾病、副作用的发生率和/或严重程度以及施用方式。适当的剂量范围可以通过本领域技术人员已知的方法来确定。在初始治疗阶段,剂量可以较高(例如每天200mg至20g、优选每天500mg至15g、更优选每天1g至10g,在某些实施方案中为每天2.5g至7.5g)。在维持阶段,剂量可以减少(例如每天10mg至10g、优选每天100mg至7.5g、更优选每天500mg至5g,在某些实施方案中为每天1g至2.5g)。
取决于待治疗的病症和受试者的状况,本文公开的低聚糖可以通过以下施用途径被施用:口服、肠胃外(例如,肌内、腹膜内、静脉内、ICV、脑池内(intracistemal)注射或输注、皮下注射或植入)、吸入、鼻、阴道、直肠、舌下或局部(例如、经皮或局部),并且可以单独地或与适合每种施用途径的药学上可接受的载体、佐剂和媒介物一起被配制成合适的剂量单元。
剂量可以是每天以适当间隔施用的一个、两个、三个、四个、五个、六个或更多个亚剂量的形式。剂量或亚剂量可以以剂量单元的形式施用,每个剂量单元包含约0.01至约2克、约0.05至约1克或约10至约500毫克活性成分。
在某些实施方案中,合适的剂量水平是每天约0.01至约5g/kg患者体重(mg/kg/天)、每天约0.01至约1g/kg、每天约0.01至约0.5g/kg或每天约0.1至约500mg/kg,其可以以单剂或多剂施用。合适的剂量水平可以是每天约0.1至约500mg/kg、每天约0.1至约250mg/kg或每天约0.1至约100mg/kg。在该范围内,剂量可以是每天约0.01至约0.1、约0.1至约1.0、约1.0至约10或约10至约100mg/kg。
本文公开的低聚糖也可以与可用于治疗、预防或改善自身免疫性病症和/或炎性病症的一种或多种症状的其它药剂组合或组合使用。或者,仅通过举例的方式,本文所述的低聚糖中的一种的治疗效果可以通过佐剂的施用得到增强(即,佐剂本身可仅具有最小的治疗益处,但是与另一种治疗剂组合时,对患者的总体治疗益处得到增强)。
这样的其它药剂、佐剂或药物可以通过其通常使用的途径和量与本文所公开的低聚糖同时或依次施用。当本文公开的低聚糖与一种或多种其它药物同时使用时,则可以使用除了本文公开的低聚糖之外还含有此类其它药物的药物组合物,但不是必需的。因此,本文公开的药物组合物包括除了本文公开的低聚糖之外还包含一种或多种其它活性成分或治疗剂的那些药物组合物。
在某些实施方案中,本文公开的低聚糖可以与本领域已知的一种或多种抗炎药组合,所述抗炎药包括但不限于非甾体抗炎药(例如,氨基比林、4-氨基安替比林、阿扎丙宗、氯非宗、双苯米唑、泛普法宗、非普拉宗、酮保泰松、安乃近、莫非保松、吗拉宗、尼芬那宗、羟基保泰松、安替比林、苯基丁氮酮、异丙安替比林、磺吡酮、琥保松、阿司匹林、阿洛普令、扑炎痛、卡巴匹林钙、二氟尼柳钙、地匹乙酯、乙水杨胺、胍西替柳、水杨酸镁、水杨酸甲酯、双水杨酯、水杨苷、水杨酰胺、水杨酸(水杨酸盐)、水杨酸钠、醋氯芬酸、阿西美辛、阿氯芬酸、氨芬酸、苄达酸、溴芬酸、布马地宗、丁苯羟酸、双氯芬酸、联苯吡胺、依托度酸、联苯乙酸、芬克洛酸、芬替酸、吲哚美辛、吲哚美辛法呢酯、伊索克酸、酮咯酸、氯那唑酸、奥沙美辛、普罗度酸、丙谷美辛、舒林酸、硫平酸、痛灭定、佐美酸、安吡昔康、屈恶昔康、伊索昔康、氯诺昔康、美洛昔康、吡罗昔康、替诺昔康、阿明洛芬、苯恶洛芬、卡洛芬、右布洛芬、右酮洛芬、苯布芬、非诺洛芬、氟诺洛芬、氟比洛芬、布洛芬、异丁普生、吲哚洛芬、酪洛芬、氯索洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、舒洛芬、Tarenflurbil、替泊沙林、噻洛芬酸、维达洛芬、萘普西诺、阿扎丙宗、氯尼辛、依托芬那酯、氟灭酸、氟尼辛、甲氯芬那酸、甲灭酸、莫尼氟酯、尼氟灭酸、托芬那酸、氟替阿嗪、阿利考昔、塞来昔布、西米考昔、地拉考昔、依托考昔、非罗考昔、罗美昔布、吗伐考昔、帕瑞考昔、罗贝考昔、罗非昔布、伐地考昔、氨基丙腈、炎痛静、硫酸软骨素、双醋瑞因、氟丙喹宗、氨基葡萄糖、糖胺多糖、贯叶金丝桃素、萘丁美酮、尼美舒利、奥沙西罗、普罗喹宗、超氧化物歧化酶/奥古蛋白和替尼达普);糖皮质激素(例如,倍他米松、强的松);生物反应调节剂(例如,羟化氯喹、来氟米特、甲氨蝶呤、托法替尼、阿巴西普、阿达木单抗、阿达木单抗-atto、阿那白滞素、依那西普、依那西普-szzs、利妥昔单抗、英夫利昔-dyyb、戈利木单抗、妥珠单抗、托珠单抗和sarilumab);和阿片样物质(例如,曲马多、奥施康定、羟考酮、芬太尼、吗啡、可待因、二氢可待因、actiq)。
本文公开的低聚糖也可以与其它类型的化合物或药物组合施用,所述其它类型的化合物或药物包括但不限于败血症治疗,例如drotrecogin-α;抗微生物剂,例如氨苄西林;抗真菌剂,如特比萘芬;抗凝剂,例如比伐卢定;溶栓剂,例如链激酶;非甾体类抗炎药,例如阿司匹林;抗血小板药,例如氯吡格雷;去甲肾上腺素再摄取抑制剂(NRI),如托莫西汀;多巴胺再摄取抑制剂(DARI),例如哌醋甲酯;血清素-去甲肾上腺素再摄取抑制剂(SNRI),例如米那普仑;镇静剂,例如安定(diazepham);去甲肾上腺素-多巴胺再摄取抑制剂(NDRI),安非他酮;血清素-去甲肾上腺素-多巴胺再摄取抑制剂(SNDRI),如文拉法辛;单胺氧化酶抑制剂,例如司来吉兰;下丘脑磷脂;内皮素转化酶(ECE)抑制剂,例如膦酰二肽;阿片样物质,例如曲马多;血栓素受体拮抗剂,如伊非曲班(ifetroban);钾通道开放剂;凝血酶抑制剂,例如水蛭素;生长因子抑制剂,例如PDGF活性的调节剂;血小板活化因子(PAF)拮抗剂;抗血小板药物,例如GPIIb/IIIa阻滞剂[例如阿巴西单抗(abdximab)、依替巴肽和欣维宁]、P2Y(AC)拮抗剂(例如氯吡格雷,噻氯匹定和CS-747)和阿司匹林;阻凝剂,如华法林;低分子量肝素,例如依诺肝素;VIIa因子抑制剂和Xa因子抑制剂;肾素抑制剂;中性内肽酶(NEP)抑制剂;血管肽酶抑制剂(双重NEP-ACE抑制剂),例如奥帕曲拉(omapatrilat)和格莫曲拉(gemopatrilat);HMG CoA还原酶抑制剂,例如普伐他汀、洛伐他汀、阿托伐他汀、辛伐他汀、NK-104[又称伊他伐他汀(itavastatin)、尼伐他汀或尼巴他汀(nisbastatin)]和ZD-4522[也称为瑞舒伐他汀或阿塔伐他汀(atavastatin)或维伐他汀(visastatin)];角鲨烯合成酶抑制剂;贝特类(fibrates);胆汁酸螯合剂,例如考来烯胺(questran);烟酸;抗动脉粥样硬化剂,例如ACAT抑制剂;MTP抑制剂;钙通道阻滞剂,如苯磺酸氨氯地平;钾通道激活剂;甲型肾上腺素阻断剂;利尿剂,如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟噻嗪、苄氟噻嗪、甲氯噻嗪、三氯噻嗪、泊利噻嗪、苯并噻嗪(benzothlazide)、依他尼酸、tricrynafen、氯噻酮、furosenilde、musolimine、布美他尼、氨苯蝶啶、阿米洛利和螺内酯;血栓溶解剂,例如组织纤溶酶原激活物(tPA)、重组tPA、链激酶、尿激酶、原尿激酶和茴香酰化纤溶酶原链激酶激活物复合物(APSAC);抗糖尿病药,例如双胍类药物(如二甲双胍)、葡糖苷酶抑制剂(如阿卡波糖)、胰岛素,美格替尼类药物(如瑞格列奈)、磺脲类药物(如格列美脲、格列本脲和格列吡嗪)、噻唑烷二酮类药物(如曲格列酮、罗格列酮和吡格列酮)和PPAR-γ激动剂;盐皮质激素受体拮抗剂,例如螺内酯和依普利酮;生长激素促分泌素;aP2抑制剂;磷酸二酯酶抑制剂,例如PDE III抑制剂(例如西洛他唑)和PDE V抑制剂(例如西地那非、他达拉非,伐地那非);蛋白酪氨酸激酶抑制剂;抗炎药;抗增殖药,例如甲氨蝶呤、FK506[他克莫司、普乐可复(Prograf)]、霉酚酸酯;化疗药物;免疫抑制剂;抗癌剂和细胞毒性剂(例如烷化剂,例如氮芥、烷基磺酸盐、亚硝基脲、乙烯亚胺和三氮烯);抗代谢药,例如叶酸拮抗剂,嘌呤类似物和嘧啶(pyrridine)类似物;抗生素,例如蒽环类、博莱霉素、丝裂霉素、放线菌素D和普卡霉素;酶,例如L-天冬酰胺酶;法呢基蛋白转移酶抑制剂;激素药,例如糖皮质激素(例如可的松)、雌激素/抗雌激素、雄激素/抗雄激素、释放孕酮和促黄体激素的拮抗剂以及醋酸奥曲肽;微管破坏剂,例如海鞘素;微管稳定剂,例如紫杉醇、多西紫杉醇和埃博霉素A-F;植物来源的产物,例如长春花生物碱、表鬼臼毒素和紫杉烷类;和拓扑异构酶抑制剂;含异戊二烯基的蛋白转移酶抑制剂;和环孢菌素;甾体类,如强的松和地塞米松;细胞毒性药物,例如硫唑嘌呤和环磷酰胺;TNF-α抑制剂,如替尼达普;抗TNF抗体或可溶性TNF受体,例如依那西普、雷帕霉素和米特(leflunimide);和环氧酶2(COX-2)抑制剂,如塞来昔布和罗非昔布;以及各种其它药剂,例如羟基脲、丙卡巴肼、米托坦、六甲基三聚氰胺、金化合物、铂配合物例如顺铂、沙铂和卡铂。
为了用于本文所述的治疗应用,本文还描述了试剂盒和制品。这样的试剂盒可以包括载体、包装或容器,该载体、包装或容器被分隔开以容纳一个或多个容器,例如小瓶、管等,每个容器包含用于本文所述方法的单独元件之一。合适的容器包括例如瓶、小瓶、注射器和试管。容器可以由各种材料例如玻璃或塑料形成。
例如,容器可以包含一种或多种本文所述的低聚糖,所述低聚糖任选地为组合物的形式或与本文公开的另外的药剂组合。所述容器任选地具有无菌进入口(例如,所述容器可以是静脉输液袋或具有可被皮下注射针刺穿的塞子的小瓶)。这样的试剂盒任选地包含低聚糖以及与其在本文所述的方法中的使用有关的标识性描述或标签或说明书。在某些实施方案中,容器由3’SL、6’SL或3’SL和6’SL的组合组成。在其它实施方案中,容器包含145mg/L或更高的3’SL、6’SL或其组合或由其组成。在另一个实施方案中,容器包含组合物,所述组合物中的总低聚糖的至少9%(例如10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100%;或任意前述数值之间的任何值)包含3’SL、6’SL或其组合。
试剂盒通常包含一个或多个另外的容器,每个容器均含有从商业和用户的角度来看对于使用本文所述的低聚糖所期望的各种材料(例如试剂,任选地为浓缩形式,和/或装置)中的一种或多种。此类材料的非限制性实例包括但不限于缓冲剂、稀释剂、过滤器、针、注射器;载体、包装、容器、小瓶和/或列出内容物的管标签和/或使用说明书以及具有使用说明书的包装插件。通常还将包括一组说明。
标签可以在容器上或与容器相关联。当将形成标签的字母、数字或其它字符被贴附、模制(molded)或蚀刻到容器本身中时,则标签可以在容器上;当标签存在于也保持容器的接受器或载体中时,则标签可以与容器相关联,例如作为包装插件。标签可用于指示将用于特定治疗应用的内容物。标签还可以指示内容物的使用(例如在本文所述的方法中)说明。这些其它治疗剂可以以例如以《医师案头参考》(Physicians'Desk Reference,PDR)中指示的量或本领域普通技术人员另外确定的量使用。
以下实施例旨在说明而非限制本公开。尽管它们是可能被使用的那些中的典型,但也可以可选地使用本领域技术人员已知的其它方法。
实施例
低聚糖减少受刺激的巨噬细胞中促炎性细胞因子mRNA的表达。首先通过使用多粘菌素B亲和层析法从汇合的人供体乳(pHMO)中分离并纯化HMO,以去除任何脂多糖(LPS)污染。然后将RAW 264.7细胞(一种鼠类巨噬细胞系)与LPS(10ng/mL)和pHMO(500μg/mL)一起孵育6小时。RT-PCR用于测量细胞因子mRNA表达。与仅接受LPS的细胞相比,暴露于LPS和pHMO二者的细胞的IL-6(见图1A)和IL-1β(见图1B)这两种促炎性细胞因子的mRNA水平均显著降低,这两种促炎性细胞因子在诸如风湿性关节炎(RA)的慢性炎性病症中具有重要的病因学意义。
显著降低受刺激的巨噬细胞中促炎性细胞因子mRNA的表达的低聚糖的鉴定。使用了多维色谱方法,该方法首先通过电荷然后通过大小将pHMO分离。特定的低聚糖3’唾液乳糖(3’SL)被鉴定为在降低IL-6和IL-1βmRNA表达方面最有效。为了排除观察到的效果是由于分离过程中的杂质或污染引起的,使用合成的商售3’SL确认了结果。剂量测距研究确定3’SL的IC50值约为15μg/mL。其它低聚糖如2’-岩藻糖基乳糖(2’FL)(其中末端单糖是岩藻糖而不是唾液酸)(见图1C)没有作用,强调了3’SL在巨噬细胞中的抗炎作用对3’SL的结构是特异性的。
3’SL不仅降低了鼠细胞系(RAW 264.7)中的促炎性细胞因子的表达,而且还降低了原代小鼠细胞(骨髓来源的巨噬细胞)中的促炎性细胞因子的表达,而且显著降低了人THP-1单核细胞系中的促炎性细胞因子的表达,这表明这些影响不仅仅是小鼠细胞系假象(artifact)。因此,通过3’SL得到的结果转化为原代细胞以及人类巨噬细胞的。
类风湿性关节炎体内实验设计。已知巨噬细胞和促炎性细胞因子IL-6和IL-1β在RA动物模型和RA患者的关节破坏的发生和发展中起主要作用。如上所述,3’SL在体外显著降低了活化巨噬细胞中IL-6和IL-1β的表达。接下来,询问体外结果是否转化为体内模型的。在小鼠中测试了3’SL在胶原抗体诱导的关节炎(CAIA)模型中的功效。在CAIA模型中,通过如下手段诱发关节炎:全身施用靶向II型胶原(其是关节软骨基质蛋白的主要成分之一)的各个区域的单克隆抗体的混合物,然后在第3天施用内毒素(LPS)。CAIA模型的高摄取率以及从抗体注射之时起使关节炎的发生同步化的能力,使其成为用于解决致病机制问题和筛选候选治疗剂的相对简单直接的模型。
向8周龄雌性BALB/c小鼠注射1.5mg的Arthrogen-CIA单克隆抗体混合物(Chondrex,Inc.)。三天后,给小鼠注射25μg的LPS。从LPS施用的时间开始,随后在接下来的连续11天,向小鼠经口灌胃3’SL(20mg,在盐水中)或仅盐水(作为对照),每天三次。在测试人员对研究组不知情的情况下,确定每一肢的关节炎,每天一次。通过为每个受影响的腕或足踝的显示关节炎迹象的每个解剖关节累计分配2分,对疾病发病率进行评分,并为每个足趾分配1分。通过将所有四肢的分数相加,每只小鼠的最大分数为28。此外,将卡尺放在踝关节的最宽处,以测量两个后肢的足踝厚度,每天一次。施用抗体混合物后14天,对小鼠实施安乐死,然后收集后爪并处理,用于组织学。根据先前验证的评分系统,针对炎症、骨侵蚀和软骨消耗,对H&E染色和甲苯胺蓝染色切片从0到4进行评分。
RA体内模型的结果:在接受3’SL的组中,基线校正的足踝厚度(爪肿胀)(图2A)以及临床指数评分28(图2B)显著降低。组织学分析表明,接受3’SL的动物的炎症、侵蚀和软骨损伤得分明显降低(图2C)。在整个14天的研究期内,对于3’SL暴露均未观察到不良反应。
应当理解,在不脱离本公开的精神和范围的情况下可以进行各种修改。因此,其它实施方案在所附权利要求书的范围内。
Claims (31)
1.一种用于治疗患有或怀疑患有炎性疾病或自身免疫性病症的受试者的方法,所述方法包括向所述受试者施用有效量的至少一种低聚糖或包含所述至少一种低聚糖的药物组合物,其中所述低聚糖包含式I、I(a)和/或II的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;以及
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
2.根据权利要求1所述的方法,其中所述低聚糖包含式I(b)或I(c)的结构:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;以及
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
4.根据前述权利要求中任一项所述的方法,其中所述低聚糖或包含所述低聚糖的药物组合物被口服施用给所述受试者。
5.根据权利要求4所述的方法,其中所述低聚糖作为营养组合物的一部分被口服施用给所述受试者。
6.根据权利要求4所述的方法,其中包含所述低聚糖的药物组合物被配制成片剂或胶囊剂。
7.根据权利要求5所述的方法,其中所述营养组合物包含至少一种式I、I(a)、I(b)、I(c)、I(d)、I(e)、II和/或II(a)的低聚糖或由其组成。
8.根据权利要求5所述的方法,其中所述营养组合物包含145mg/L或更高的至少一种式I、I(a)、I(b)、I(c)、I(d)、I(e)、II和/或II(a)的低聚糖或由其组成。
9.根据权利要求5所述的方法,其中所述营养组合物中总低聚糖的至少9%包含至少一种式I、I(a)、I(b)、I(c)、I(d)、I(e)、II和/或II(a)的低聚糖。
10.根据权利要求1所述的方法,其中所述自身免疫性病症选自由以下各项组成的组:自身免疫性心肌炎、德雷斯勒综合征、心包切开术后综合征、亚急性细菌性心内膜炎、抗肾小球基底膜肾炎、间质性膀胱炎、狼疮肾炎、自身免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、抗合成酶综合征、斑秃、自身免疫性血管水肿、自身免疫性孕酮性皮炎、自身免疫性荨麻疹、大疱性类天疱疮、瘢痕性类天疱疮、疱疹样皮炎、盘状红斑性狼疮、获得性大疱性表皮松解症、结节性红斑、妊娠类天疱疮、化脓性汗腺炎、扁平苔癣、硬化性苔藓、线状IgA病、硬斑病、寻常天疱疮、急性痘疮样苔藓样糠疹、穆-哈二氏病、银屑病、系统性硬皮病、白癜风、艾迪生氏病、自身免疫性多内分泌综合征1型、自身免疫性多内分泌综合征2型、自身免疫性多内分泌综合征3型、自身免疫性胰腺炎、1型糖尿病、自身免疫性甲状腺炎、奥德甲状腺炎、格雷夫斯氏病、自身免疫性卵巢炎、子宫内膜异位症、综合征、自身免疫性肠病、抗磷脂综合征、再生障碍性贫血、自身免疫性溶血性贫血、自身免疫性淋巴细胞增生综合征、自身免疫性中性粒细胞减少症、自身免疫性血小板减少性紫癜、冷凝集素病、特发性混合性冷球蛋白血症、伊文氏综合征、恶性贫血、纯红细胞再生障碍性贫血、血小板减少症、痛性肥胖症、成人斯蒂尔病、强直性脊柱炎、CREST综合征、药物性狼疮、与附着点炎症相关的关节炎、嗜酸性筋膜炎、Felty综合征、IgG4相关的疾病、幼年型关节炎、慢性莱姆病、混合性结缔组织疾病、复发性风湿病、帕罗综合征、Parsonage-Turner综合征、银屑病关节炎、反应性关节炎、复发性多发性软骨炎、腹膜后纤维化、风湿热、类风湿性关节炎、结节病、施尼茨勒综合征、全身性红斑狼疮、未分化结缔组织病、皮肌炎、纤维肌痛、包涵体肌炎、肌炎、重症肌无力、神经性肌强直、亚急性小脑变性、多肌炎、急性播散性脑脊髓炎、急性运动性轴索型神经病、抗N-甲基-D-天冬氨酸受体脑炎、巴洛同心性硬化、Bickerstaff脑炎、慢性炎症性脱髓鞘性多发性神经病、格林-巴利综合征、桥本脑病、特发性炎症脱髓鞘疾病、Lambert-Eaton肌无力综合征、多发性硬化症、Oshtoran综合症、与链球菌相关的儿童自身免疫性神经精神障碍、进行性炎症性神经病、不宁腿综合征、僵人综合征、小舞蹈病、横贯性脊髓炎、自身免疫性视网膜病、自身免疫性葡萄膜炎、Cogan综合征、格雷夫斯眼病、中间葡萄膜炎、木样结膜炎、蚕蚀性角膜溃疡、视神经脊髓炎、眼球阵挛-肌阵挛综合征、自身免疫性内耳疾病、美尼尔氏综合症、白塞病、嗜酸性肉芽肿伴多管炎、IgA血管炎、川崎病、白细胞破碎性血管炎、狼疮血管炎、类风湿性血管炎、显微镜下多血管炎、结节性多动脉炎、风湿性多肌痛、荨麻疹性血管炎、血管炎和原发性免疫缺陷。
12.根据权利要求1所述的方法,其中所述炎性疾病由巨噬细胞驱动的慢性炎症引起或与巨噬细胞驱动的慢性炎症相关。
13.根据权利要求12所述的方法,其中所述炎性疾病选自由以下各项组成的组:动脉粥样硬化、慢性阻塞性肺疾病、胰岛素抗性、2型糖尿病、肥胖症和全身型幼年特发性关节炎。
14.根据权利要求1所述的方法,其中所述自身免疫性病症或炎性疾病是类风湿性关节炎。
15.根据权利要求1所述的方法,其中所述至少一种低聚糖或包含所述至少一种低聚糖的药物组合物与另外的治疗剂一起施用。
16.根据权利要求15所述的方法,其中所述治疗剂是非甾体抗炎药、糖皮质激素、生物反应调节剂和阿片样物质。
17.根据权利要求16所述的方法,其中所述非甾体抗炎药选自由以下各项组成的组:氨基比林、4-氨基安替比林、阿扎丙宗、氯非宗、双苯米唑、泛普法宗、非普拉宗、酮保泰松、安乃近、莫非保松、吗拉宗、尼芬那宗、羟基保泰松、安替比林、苯基丁氮酮、异丙安替比林、磺吡酮、琥保松、阿司匹林、阿洛普令、扑炎痛、卡巴匹林钙、二氟尼柳钙、地匹乙酯、乙水杨胺、胍西替柳、水杨酸镁、水杨酸甲酯、双水杨酯、水杨苷、水杨酰胺、水杨酸(水杨酸盐)、水杨酸钠、醋氯芬酸、阿西美辛、阿氯芬酸、氨芬酸、苄达酸、溴芬酸、布马地宗、丁苯羟酸、双氯芬酸、联苯吡胺、依托度酸、联苯乙酸、芬克洛酸、芬替酸、吲哚美辛、吲哚美辛法呢酯、伊索克酸、酮咯酸、氯那唑酸、奥沙美辛、普罗度酸、丙谷美辛、舒林酸、硫平酸、痛灭定、佐美酸、安吡昔康、屈恶昔康、伊索昔康、氯诺昔康、美洛昔康、吡罗昔康、替诺昔康、阿明洛芬、苯恶洛芬、卡洛芬、右布洛芬、右酮洛芬、苯布芬、非诺洛芬、氟诺洛芬、氟比洛芬、布洛芬、异丁普生、吲哚洛芬、酪洛芬、氯索洛芬、咪洛芬、萘普生、奥沙普秦、吡洛芬、舒洛芬、Tarenflurbil、替泊沙林、噻洛芬酸、维达洛芬、萘普西诺、阿扎丙宗、氯尼辛、依托芬那酯、氟灭酸、氟尼辛、甲氯芬那酸、甲灭酸、莫尼氟酯、尼氟灭酸、托芬那酸、氟替阿嗪、阿利考昔、塞来昔布、西米考昔、地拉考昔、依托考昔、非罗考昔、罗美昔布、吗伐考昔、帕瑞考昔、罗贝考昔、罗非昔布、伐地考昔、氨基丙腈、炎痛静、硫酸软骨素、双醋瑞因、氟丙喹宗、氨基葡萄糖、糖胺多糖、贯叶金丝桃素、萘丁美酮、尼美舒利、奥沙西罗、普罗喹宗、超氧化物歧化酶/奥古蛋白和替尼达普。
18.根据权利要求16所述的方法,其中所述糖皮质激素选自倍他米松或强的松。
19.根据权利要求16所述的方法,其中所述生物反应调节剂选自由以下各项组成的组:羟化氯喹、来氟米特、甲氨蝶呤、托法替尼、阿巴西普、阿达木单抗、阿达木单抗-atto、阿那白滞素、依那西普、依那西普-szzs、利妥昔单抗、英夫利昔-dyyb、戈利木单抗、妥珠单抗、托珠单抗和sarilumab。
20.根据权利要求16所述的方法,其中所述阿片样物质选自由以下各项组成的组:曲马多、奥施康定、羟考酮、芬太尼、吗啡、可待因、二氢可待因和actiq。
21.一种在有需要的受试者中减轻巨噬细胞炎症和/或抑制促炎性细胞因子分泌的方法,所述方法包括向所述受试者施用有效量的至少一种低聚糖或包含所述至少一种低聚糖的药物组合物,其中所述至少一种低聚糖包含式I、I(a)和/或II的结构:
或其药学上可接受的盐、溶剂化物或前药,其中
R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;以及
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
22.根据权利要求21所述的方法,其中所述至少一种低聚糖包含式I(b)或I(c)的结构:
或其药学上可接受的盐、溶剂化物或前药,其中
R1-R6独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;以及
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
24.根据权利要求21所述的方法,其中所述促炎性细胞因子包括白介素(IL)-1β和IL-6。
25.根据权利要求1或21所述的方法,其中所述受试者是5岁或更大的人类受试者。
26.根据权利要求25所述的方法,其中所述受试者是18岁或更大的人类受试者。
27.一种营养补充剂,其包含至少一种式I、I(a)或II式I、I(a)和/或II的低聚糖式:
或其药学上可接受的盐、溶剂化物或前药,其中,
R1-R18独立地选自H、D、卤代、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环、未取代的或取代的芳基、-ROR'、-RN(R')2、-RSSR'、-SH、-RSOR'、-RSO2R'、-RSO2H、-RSO3H、-RC(=S)-R'、-ROH、-RC(=O)R'、-RNO2、-RSR'、-RCN、-RNC、-RNNR'、-RC(=O)OR'、-ROC(=O)R'、-RC(=O)H、-RC(=O)OH、-RC(=O)N(R')2、-RN3、-ROCN、-RNCO、-RONO2、-RNO、-ROP(=O)(OH)2和-RB(OH)2;
R不存在或者是(C1-C5)烷基;以及
R'独立地选自H、D、未取代的或取代的(C1-C6)烷基、未取代的或取代的(C1-C6)杂烷基、未取代的或取代的(C2-C6)烯基、未取代的或取代的(C2-C6)杂烯基、未取代的或取代的(C3-C6)炔基、未取代的或取代的(C3-C6)杂炔基、未取代的或取代的(C4-C8)环烷基、未取代的或取代的杂环和未取代的或取代的芳基。
28.根据权利要求27所述的营养补充剂,其中所述营养补充剂由所述至少一种式I、I(a)、I(b)、I(c)、I(d)、I(e)、II和/或II(a)的低聚糖和其它非低聚糖成分组成。
29.根据权利要求27所述的营养补充剂,其中所述营养补充剂包含145mg/L或更高的至少一种式I、I(a)、I(d)、I(e)、II和/或II(a)的低聚糖或由其组成。
30.根据权利要求27所述的营养补充剂,其中所述营养补充剂其中所述营养补充剂中的总低聚糖的至少9%包含至少一种式I、I(a)、I(d)、I(e)、II和/或II(a)的低聚糖。
31.一种组合物,其由3’SL和/或6’SL之一或二者和药学上可接受的载体组成。
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CN113924101A (zh) * | 2019-04-09 | 2022-01-11 | 因特因思克医药物公司 | 用于治疗疼痛的免疫调节寡糖 |
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CN116115623A (zh) * | 2022-12-12 | 2023-05-16 | 天津市肿瘤医院(天津医科大学肿瘤医院) | 2'-岩藻糖基乳糖作为一种抗肿瘤辅助药物的应用 |
CN116115623B (zh) * | 2022-12-12 | 2024-02-23 | 天津市肿瘤医院(天津医科大学肿瘤医院) | 2'-岩藻糖基乳糖作为一种抗肿瘤辅助药物的应用 |
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EP3691658A4 (en) | 2021-06-23 |
SG11202002687UA (en) | 2020-04-29 |
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AU2018346500A1 (en) | 2020-04-02 |
WO2019071021A3 (en) | 2020-04-02 |
MX2023006458A (es) | 2023-06-14 |
CA3076920A1 (en) | 2019-04-11 |
US20210236527A1 (en) | 2021-08-05 |
US20230201228A1 (en) | 2023-06-29 |
WO2019071021A2 (en) | 2019-04-11 |
EP3691658A2 (en) | 2020-08-12 |
US20210236526A1 (en) | 2021-08-05 |
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