CN107252488A - 口服给予的皮质类固醇组合物 - Google Patents
口服给予的皮质类固醇组合物 Download PDFInfo
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- CN107252488A CN107252488A CN201710261488.7A CN201710261488A CN107252488A CN 107252488 A CN107252488 A CN 107252488A CN 201710261488 A CN201710261488 A CN 201710261488A CN 107252488 A CN107252488 A CN 107252488A
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Abstract
在此披露了口服给予的皮质类固醇组合物及其在个体中用于对与胃肠道炎症相关联的病况进行治疗的方法,包括给予一位个体所述口服给予的皮质类固醇组合物。
Description
本申请是申请号为“201080047016.8”,申请日为2010年9月30日,发明名称为“口服给予的皮质类固醇组合物”的申请的分案申请。
技术领域
本发明涉及口服给予的皮质类固醇组合物,对于治疗胃肠道炎症相关联的病况有用。
背景技术
对于治疗与胃肠道上部炎症相关联的病况,目前没有被批准的局部给予的抗炎症药物。这类病况之一嗜酸性食管炎(EE)是食管的一种炎症病况。其组织学特征在于嗜酸性粒细胞的增生。该疾病是疼痛的,导致吞咽困难并且使患者倾向于食物嵌塞及其他并发症。
对于EE的实验性和“没被临床试验认可的药物”的治疗包括将被配制并被批准的用于吸入的类固醇药物导向咽喉后壁,这样使得它们不被感知地吸入,并且指示患者在给药以后立即嗽口并且在给药以后两小时不吞咽食物或水。推荐漱洗是因为在口以及咽喉中的残余药物可能导致感染,并且禁忌吞咽是因为吞咽可能将药物从食管洗掉。还使旨在经由喷雾口服吸入的水溶性皮质类固醇制品与糖混合从而产生一种稠化变甜的液体用于给药。
对于EE的没被临床试验认可的药物的治疗还包括给予皮质类固醇片剂(包含类固醇,如泼尼松龙)。然而,皮质类固醇的全身性给药与多种已知的并且不希望的副作用相关联。例如,口服泼尼松龙可以产生全身免疫功能抑制,并且在儿童中、特别是源自长期全身暴露的麻烦的副作用包括生长停滞,它可以导致成年身高降低。
因此在本领域需要一种用于口服给予的皮质类固醇配制品,它提供胃肠道炎症的局部(而不是系统)治疗,特别是上胃肠道的炎症,如EE。
发明内容
相关申请的交叉引用
本申请要求于2009年10月1日提交的美国临时专利申请号61/247,642的优先权,出于所有目的通过引用将这项申请的所有内容结合在此。
发明概述
在一个实施方案中,本发明针对一种固体药用组合物,该固体药用组合物包括小于或等于20mg的一种皮质类固醇,其中该组合物在口服给药以后没有显著的全身性糖皮质激素或盐皮质激素活性,其中该固体药用组合物使用美国药典〈701〉崩解试验测试时在模拟唾液中60秒内崩解、和/或安置在人口腔时在60秒内崩解。
在一个实施方案中,本发明针对一种固体药用组合物,包括小于或等于20mg的一种皮质类固醇,其中该组合物在口服给药后没有显著的全身性糖皮质激素或盐皮质激素活性,其中在使用美国药典<701>崩解试验测试时,该固体药用组合物在模拟唾液流体中60秒内崩解。
在一些实施方案中,所述固体药用组合物可在30秒内崩解。
在一些实施方案中,所述皮质类固醇可选自下组,该组由以下各项组成:布地奈德、氟替卡松、氟尼缩松,环索奈德、莫米松、倍氯米松、以及它们的盐类、溶剂化物类、和酯类。
在一些实施方案中,所述固体药用还可包括一种粘合剂。优选地,该粘合剂可选自下组,该组由以下各项组成:蔗糖硫酸铝复合物、壳聚糖及其衍生物、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、交联或未交联的聚丙烯酸酯、交联的聚丙烯酸酯、酸性交联的或未交联的聚丙烯酸酯、聚丙烯酸均聚物或共聚物、甲基丙烯酸氨烷基酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、丙烯酸烷基酯/甲基丙烯酸烷基酯共聚物、甲基丙烯酸铵酯共聚物、卡波姆均聚物或共聚物、亲水性的聚糖树胶、麦芽糖糊精、交联的海藻酸钠树胶凝胶、聚羧酸乙烯基聚合物、果胶、黄原胶、海藻酸、改性的海藻酸、以及它们的组合。
优选地,该粘合剂与该皮质类固醇可以是密切相关联的。更优选地,所述皮质类固醇可被该粘合剂包围或密封。或者更优选地,该皮质类固醇可被安置在所述粘合剂的表面上。
在一些实施方案中,所述固体药用还可包括一种选自下组的崩解剂,该组由以下各项组成:交联聚乙烯吡咯烷酮、淀粉羟基乙酸钠、交联的羧甲基纤维素、低取代的羟丙基纤维素、甘露醇、木糖醇、山梨醇、麦芽醇、麦芽糖醇、乳糖、蔗糖、麦芽糖、以及它们的组合。
在一些实施方案中,所述固体药用还可包括一种选自下组的赋形剂,该组由以下各项组成:甘露醇、木糖醇、山梨醇、麦芽醇、麦芽糖醇、乳糖、蔗糖、麦芽糖、环糊精、以及它们的组合。
在一些实施方案中,所述固体药用可基本上不含润滑剂。
在一些实施方案中,所述固体药用还可包括至少一种抗真菌剂。优选地,该抗真菌剂可选自下组,该组由以下各项组成:有丝分裂抑制剂抗真菌药、嘧啶类似物抗真菌药、多烯抗真菌药、苯并咪唑抗真菌药、咪唑抗真菌药、三唑抗真菌药、噻唑抗真菌药、烯丙胺抗真菌药、棘白菌素抗真菌药、以及未分类的抗真菌药。更优选地,该抗真菌剂可选自下组,该组由以下各项组成:阿尼芬净、卡泊芬净、克霉唑、氟康唑、伊曲康唑、米卡芬净、制霉菌素、泊沙康唑、以及伏立康唑。
在一些实施方案中,所述固体药用还可包括至少一种抗病毒剂。优选地,该抗病毒剂可选自下组,该组由以下各项组成:干扰素、核苷和核苷酸反转录酶抑制剂、非核苷反转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂、融合抑制剂、成熟抑制剂、嘌啉类似物、嘧啶类似物、以及未分类的抗病毒药物。或者优选地,该抗病毒剂可选自下组,该组由以下各项组成:阿昔洛维、溴夫定、二十二烷醇、泛昔洛韦、更昔洛韦、碘苷、喷昔洛韦、三氟尿苷、曲金刚胺、伐昔洛韦、以及万乃洛韦。
在一些实施方案中,该药用组合物可处于口腔崩解片(ODT)的形式。优选地,该ODT可包括药物颗粒和快速分散颗粒,其中这些药物颗粒可包括该皮质类固醇,并且该快速分散颗粒可包括一种崩解剂以及一种糖醇和/或糖。
更优选地,这些药物颗粒可具有小于约400μm的平均粒度,这些快速分散颗粒可具有小于约300μm的平均粒度,并且该崩解剂以及糖醇和/或糖可具有小于约30μm的平均粒度;或者,这些药物颗粒可具有小于约4μm的平均粒度,这些快速分散颗粒可具有小于约300μm的平均粒度,并且该崩解剂以及糖醇和/或糖可具有小于约30μm的平均粒度;或者,该皮质类固醇可被安置在一种赋形剂的表面上,这些快速快速分散颗粒可具有小于约300μm的平均粒度,并且该崩解剂以及糖醇和/或糖可具有小于约30μm的平均粒度。
更优选地,该ODT可处于薄片或薄膜的形式。
更优选地,该ODT可包括一种冻干基质,其中该冻干基质可包括与至少一种赋形剂组合的皮质类固醇。优选地,该赋形剂可选自下组,该组由以下各项组成:甘露醇、木糖醇、山梨醇、麦芽醇、麦芽糖醇、乳糖、蔗糖、麦芽糖、以及它们的组合。或者优选地,该ODT可以是处于薄片或薄膜的形式。在另一个实施方案中,本发明针对一种口腔分散片,包括选自下组的小于或等于20mg的一种皮质类固醇,该组由以下各项组成:氟替卡松、布地奈德、莫米松、以及它们的盐类、溶剂化物和酯类,其中该口腔分散片在使用该美国药典<701>崩解试验时在模拟唾液流体中60秒内崩解。
在一些实施方案中,该口腔分散片可包括约0.05mg至0.3mg的氟替卡松。
在另一个实施方案中,本发明针对一种用于治疗胃肠道炎性病症的方法,包括在一位需要它的个体中给予一种药用组合物,所述药物组合物包括小于或等于20mg的一种皮质类固醇,其中该组合物在口服给药后没有显著的全身性糖皮质激素或盐皮质激素活性,其中在使用美国药典<701>崩解试验测试时,该固体药用组合物在模拟唾液流体中60秒内崩解。
在一些实施方案中,所述胃肠道炎性病症可包括食管的炎症。
在一些实施方案中,所述胃肠道炎性病症可以是嗜酸性食管炎。
在一些实施方案中,所述胃肠道炎性病症可包括声门、会厌软骨、扁桃体、或口咽的炎症。
在一些实施方案中,所述胃肠道炎性病症可以是病毒性的或细菌性的咽炎。
在一些实施方案中,所述胃肠道炎性病症可以是胃食管返流性疾病(GERD)、非侵蚀性返流性疾病(NERD)、或浸蚀性食管炎。
在一个实施方案中,本发明针对一种基本上非水液体药用组合物,包括一种皮质类固醇以及一种药学上可接受的液体。
在一些实施方案中,该液体可选自下组,该组由以下各项组成:药学上可接受的醇、油、乙二醇、乙二醇醚、吡咯烷酮、聚乙二醇、N-甲基-2-吡咯烷酮、2-吡咯烷酮、甘油、四甘醇、甘油缩甲醛、丙酮缩甘油、乙酸乙酯、乳酸乙酯、丁酸乙酯、丙二酸二丁酯、柠檬酸三丁酯、三-正-己基乙酰基柠檬酸酯、琥珀酸二乙酯、戊二酸二乙酯、丙二酸二乙酯、柠檬酸三乙酯、三乙酸甘油酯、三丁酸甘油酯、碳酸二乙酯、碳酸丙烯酯、丙酮、甲基乙基酮、二甲亚砜、二甲砜、四氢呋喃、己内酰胺、N,N-二乙基-间甲苯酰胺、1-正十二烷基氮杂环庚-2-酮、l,3-二甲基-3,4,5,6-四氢-2(lH)-嘧啶酮、以及它们的组合。优选地,该液体可自下组,该组由以下各项组成:醇、油;乙二醇;乙二醇醚;吡咯烷酮;聚乙二醇、甘油以及它们的组合。更优选地,该液体可选自下组,该组由以下各项组成:乙醇、甘油、丙二醇、甘油酯、分子量在约200与600之间的聚乙二醇、以及它们的组合。
在一些实施方案中,所述液体药用组合物还可包括一种溶解或悬浮在所述液体中的相变试剂,其中在给予一位患者以后,所述组合物一旦与所述患者胃肠道接触该组合物就经历物理性质的改变,由此加强和/或延长该皮质类固醇与该患者胃肠道的接触。
优选地,在给予一位患者以后,所述组合物可沉淀到患者胃肠道的粘膜上,由此加强和/或延长该皮质类固醇到该胃肠道粘膜上的沉淀。
优选地,在给予一位患者以后,所述组合物在患者胃肠道的粘膜接触时可形成一种胶,由此加强和/或延长该皮质类固醇到该胃肠道粘膜上的沉淀。更优选地,所述液体可以是水可混溶的并且所述相变试剂是具有低水溶性的生物胶凝聚合物。优选地,所述水可混溶溶剂可选自下组,该组由以下各项组成:乙醇、异丙醇、正-甲基-2-吡咯烷酮、2-吡咯烷酮、甘油、丙二醇、聚乙二醇、四甘醇、甘油缩甲醛、丙酮缩甘油、乙酸乙酯、乳酸乙酯、碳酸二乙酯、碳酸丙烯酯、丙酮、甲基乙基酮、二甲亚砜、二甲砜、四氢呋喃、以及它们的组合。优选地,所述生物胶凝聚合物可选自下组,该组由以下各项组成:聚交酯、聚甘醇酸、聚己酸内酯、聚二氧六环酮、聚碳酸酯、聚羟基丁酯、聚炔烃草酸酯、聚酐类、聚酰胺、聚酰胺酯、聚氨酯、聚缩醛、聚酮、聚原碳酸酯、聚磷腈、聚羟基戊酸共聚物、聚亚烷基琥珀酸酯、聚(苹果酸)、聚(氨基酸)、甲壳质、甲壳糖、聚原酸酯、纤维素衍生物、纤维素酯、甲基丙烯酸和甲基丙烯酸酯聚合物、以及它们的共聚物、三元共聚物以及混合物。优选地,所述生物胶凝聚合物是乙基纤维素。
优选地,所述相变试剂可以是一种水溶性差的聚合物。
优选地,所述相变试剂可以是一种热敏的聚合物,其水粘度可在大约15至40摄氏度的范围内改变。
优选地,所述相变试剂一旦与口咽的液体接触其粘度就增加。更优选地,所述粘度增加可至少是50%;或者所述粘度增加可至少是100%;或者所述粘度增加可至少是200%。
优选地,该相变试剂可以是选自下组的一种聚合物,该组由以下各项组成:聚(N-异丙基丙烯酰胺)、聚(乙二醇-(DL-乳酸-共-乙醇酸)-乙二醇)以及它们的混合物。
在一些实施方案中,在给予一位患者以后,所述组合物一旦与胃肠道的粘膜接触就增加粘度,由此延长该皮质类固醇在肠道粘膜上的滞留时间。
在一些实施方案中,所述皮质类固醇可选自下组,该组由以下各项组成:布地奈德、氟替卡松、氟尼缩松、环索奈德、莫米松、替可的松、倍氯米松、以及它们的盐类、溶剂化物类、以及酯类。
在另一个实施方案中,本发明针对一种液体药用组合物,该液体药用组合物包括一种皮质类固醇、以及一种药学上可接受的基本上非水的液体。
在另一个实施方案中,本发明针对一种用于治疗胃肠道炎性病症的方法。该方法包括:对一个需要它的对象给予本发明的药用组合物。
在另一个实施方案中,本发明针对一种液体药用组合物,该液体药用组合物包括一种皮质类固醇、一种药学上可接受的水性或基本上非水的液体、以及溶解在或悬浮在该液体中的药学上可接受的相变试剂,其中在给予患者以后,该组合物一旦与患者胃肠道接触就经受物理性质的改变。
在又另一个实施方案中,本发明针对一种处于固体或液体形态的额外包括环糊精的组合物。
本发明的组合物对于不同病况是有用的,包括胃肠道炎性病症的治疗。因此,本发明还提供用于在个体中治疗胃肠道炎性病症的方法。该方法包括:对一个需要它的对象给予本发明的药用组合物。
本发明的详细说明
出于所有目的通过引用将在本文中所涉及的全部文件(例如专利、专利公开文件、期刊文章等等)以其整体进行合并。
作为在此使用的术语“药物”、“活性物”、或“有活性的药用成分”包括一种药学上可接受的并且治疗学上有效的化合物(如皮质类固醇)、它的(如皮质类固醇的)药学上可接受的盐类、立体异构体以及立体异构体的混合物、溶剂化物(包括水合物)、和/或酯类。
术语“口腔崩解片”、“口腔分散片”、或“ODT”是指本发明的一种固体剂型,给药以后它在患者口腔中无需咀嚼就快速崩解。口腔崩解速率可以变化,但是显著地快于传统的固体剂型或可咀嚼的固体剂型(如片剂或胶囊,它们旨在给予以后立即吞下)的口腔崩解速率。本发明的ODT组合物可以包含药学上可接受的成分,这些成分溶胀、溶出或另外有助于该ODT组合物的崩解或溶出。这类成分可以包括药用的一种崩解剂、一种糖醇、一种糖类、或它们的一种混合物、一种水溶性粘合剂、一种可熔的固体(如一种蜡)(一旦进入胃它就可以释放皮质类固醇),等等。
如在此使用的术语“约”是指一个数量,包括“准确的”。例如,“约60秒”包括准确的60秒连同接近60秒的值(如50秒、55秒、59秒、61秒、65秒、70秒、等等)。在使用术语“约”提及值的范围时,术语“约”是指该范围的最小值和最大值(如“约1-50μm”是指“约1μm到约50μm”)。
如在此所使用的术语“粘合剂”是指促进皮质类固醇与生物表面粘合的试剂,并且包括但不限于生物粘合剂。粘合剂可以包括粘附口咽粘膜的化合物,连同增加本发明的组合物在患者口咽粘膜的滞留时间的化合物。
如在此所使用的术语“密切相关联的”(描述在一种组合物的两个或更多个组分之间的空间关系)是指密切混合的组分,例如像在混合物、涂层、以及基质中。
如在此所使用的术语“不具有显著全身性糖皮质激素或盐皮质激素活性”,是指在身体内(经由吸收进入循环)不提供一种全身性的效应的皮质类固醇组合物,但通过与疾病组织局部接触确实提供局部效应。口服给予的具有高全身性糖皮质激素效能的皮质类固醇包括如氢化可的松、泼尼松、泼尼松龙、甲泼尼龙、地塞米松、倍他米松、等等或盐皮质激素效能(如醛固酮(alsosterone))。若这些皮质类固醇以一种充分的小剂量使用,或否则配制成这样使得它们不具有显著全身性糖皮质激素或盐皮质激素活性,它们可以是适合用于本发明中的组合物。适合于在本发明的这些组合物中使用的示例性的皮质类固醇包括但不限于布地奈德、氟替卡松、氟尼缩松、环索奈德、莫米松、倍氯米松、以及替可的松。
如在此所使用的术语“生物胶凝聚合物”是指一种聚合物,该聚合物例如一旦与生理性液体接触或在生理学的温度下在胃肠道生理条件下就形成一种凝胶。
术语“基本上非水的液体”是指完全无水的液体,或仅仅包括少量的水(如小于约10%的水,例如小于约9%、小于约8%、小于约7%、小于约6%、小于约5%、小于约4%、小于约3%、小于约2%、或小于约1%的水)。
术语“相变试剂”是指一种试剂,它一旦溶解或悬浮在本发明的基本上非水液体中,引起本发明的液体药用组合物在给予患者以后经历物理性质的改变。例如物理性质的这类改变包括该组合物的溶解或悬浮组分(如皮质类固醇、可任选的赋形剂、以及相变试剂)的沉淀;该组合物的胶化作用(如形成相变试剂与可任选的赋形剂的水凝胶,其中该水凝胶包括至少该皮质类固醇的一部分);或该组合物的粘度增加。在物理性质方面的这些改变具有增加或提高该皮质类固醇与患者胃肠道的粘膜接触的作用。
除非表明,否则全部百分数以及比率是按重量计算的。除非另外表明,全部百分数以及比率是基于总的组合物计算的。
本发明的固体和液体药用组合物适合于一种皮质类固醇的局部给药到胃肠道,例如上胃肠道,如食管。用于与胃肠道炎症相关联的病况的一种皮质类固醇的局部给药是希望的,因为与全身性的皮质类固醇给药相比它导致很少的副作用。借助于皮质类固醇,这类副作用被进一步降低,这些皮质类固醇没有显著的全身性糖皮质激素或盐皮质激素活性,因为它们降低了全身性暴露。
本发明的药用组合物适合于治疗胃肠道的炎性病症,例如上胃肠道(如食管)的炎症病况。因此,本发明包括通过给予需要它们的患者本发明的一种固体或液体药用组合物治疗胃肠道的炎症病况。可以根据本发明治疗的胃肠道的炎性病症包括:食管炎症、声门炎症、会厌软骨炎症、扁桃体炎症、口咽炎症、嗜酸性食管炎、胃食管返流疾病(GERD)、非浸蚀性返流疾病(NERD)、浸蚀性食管炎、Barrett食管炎(Barrett's esophagus)、嗜酸性胃肠炎、嗜酸性白细胞增多综合征、侵蚀性的(腐蚀性的)化学性食管炎、放射线诱导的食管炎、化学疗法诱导的食管炎、短暂的药物诱导的食管炎(又名药物治疗食管炎)、持续的药物诱导食管炎、食管的克罗恩病、硬皮病、以及硬皮病无皮肤硬化的硬皮病(scleroderma sinescleroderma)、系统性红斑狼疮、全身性血管炎、白细胞脉管炎、结节性动脉周围炎、许尔-斯特劳斯综合症(Churg-Strauss syndrome)、类风湿性脉管炎、以及伪膜性食管炎。
在其他的实施方案中,本发明的药用组合物适合于治疗胃肠道炎性病症,如一种自身免疫病、贝赫切特综合症(Behcet's syndrome)、川崎氏病、X连锁恶性淋巴组织增生综合征;由以下一个或多个病毒引起的病毒感染性疾病:腺病毒、冠状病毒、柯萨奇病毒、单纯性疱疹病毒、HIV、流感病毒(A型)、拉沙病毒(Lassa virus)、EB病毒、副流感病毒、或呼吸道合胞病毒;由以下一个或多个细菌引起的细菌感染性疾病:溶血隐秘杆菌(Arcanobacterium hemolyticum)、衣原体(Chlamydophila)、棒状杆菌、土拉弗朗西斯菌(Franci sella tularensis)、A、C、G族链球菌、肺炎球菌(S.pneumoniae)、化脓链球菌、B型流感嗜血杆菌、肺炎支原体、淋病奈瑟菌属、多重(如扁桃体周围的蜂窝织炎/脓肿);由假丝酵母属(如白色念珠菌)或组织胞浆菌属(如荚膜组织胞浆菌)引起的真菌感染疾病;由损伤或选自下组的一种刺激物引起的炎症,该组的构成为:气道异物、苯氯乙酮、氯苯亚甲基丙二腈(chlorobenzyli denemalononitri)、慢性抽烟暴露、吗啉、氟化硫酰、以及咽喉烫伤;毛虫接触性皮炎(lepidopterism)、季节性的过敏咽炎、以及史蒂文斯-詹森综合症(重症多形性红斑,Stevens-Johnson syndrome);或周期热;等等。
在一个实施方案中,本发明包括对食管炎症进行治疗的一种方法,该方法包括对需要它们的患者给予本发明的药用组合物。在一个这种实施方案中,本发明包括对嗜酸性食管炎进行治疗的一种方法,该方法包括对需要它们的患者给予本发明的药用组合物。
在另一个实施方案中,本发明包括对胃食管返流疾病(GERD)、非侵蚀性返流疾病(NERD)或浸蚀性食管炎进行治疗的一种方法,该方法包括对需要它们的患者给予本发明的药用组合物。
在另一个实施方案中,本发明包括一种方法,该方法用于治疗具有确定过敏原(如“特应性IBS”以及“特应性肠”)的食物过敏。
在一个实施方案中,本发明提供一种固体药用组合物,该固体药用组合物包括小于或等于20mg的一种皮质类固醇,其中该组合物在口服给药以后没有显著的全身性糖皮质激素或盐皮质激素活性,其中该固体药用组合物在使用美国药典〈701〉崩解试验测试时在模拟唾液中60秒内崩解。在另一个实施方案中,本发明的固体药用组合物在患者(如人)口腔中60秒内崩解。在又另一个实施方案中,本发明的固体药用组合物在模拟唾液(使用美国药典<701>崩解试验)中或在患者口腔中30秒内崩解。在又其他的实施方案中,本发明的固体或液体药用组合物在口服给予需要它们的患者之后局部地提供治疗学上有效量的皮质类固醇到胃肠道的发炎组织。
本发明的固体药用组合物可以包括例如一个ODT(如在此说明)、一个薄片、一个薄膜、或其他的固体剂型,它在口中快速崩解或溶出以形成皮质类固醇的一种溶液或分散体,它们可以容易地被吞下。
在另一个实施方案中,本发明提供一种液体药用组合物,该液体药用组合物包括一种皮质类固醇、以及一种药学上可接受的溶剂化物,其中该液体药用组合物没有显著的全身性糖皮质激素或盐皮质激素活性。在一个这类实施方案中,该组合物还包括一种溶解在该溶剂中的药学上可接受的生物-胶凝聚合物,并且该组合物一旦与一位个体的胃肠道接触其粘度就增加。在其他的实施方案中,本发明的液体组合物包括一种具有环糊精的皮质类固醇复合物,它典型地悬浮或溶解在一种液体载体中。本发明的液体组合物可以是溶液或悬浮体的形式。根据本发明的液体药用组合物是在标准温度和压力条件下为液体的组合物。
可以用于本发明的液体药用组合物的适当药学上可接受的液体包括、例如:醇、油、乙二醇、乙二醇醚、吡咯烷酮、聚乙二醇、N-甲基-2-吡咯烷酮(NMP)、2-吡咯烷酮、甘油、四甘醇、甘油缩甲醛、丙酮缩甘油、乙酸乙酯、乳酸乙酯、丁酸乙酯、丙二酸二丁酯、柠檬酸三丁酯、三-正-己基乙酰基柠檬酸、琥珀酸二乙酯、戊二酸二乙酯、丙二酸二乙酯、柠檬酸三乙酯、三乙酸甘油酯、三丁酸甘油酯、碳酸二乙酯、碳酸丙烯酯、丙酮、甲基乙基酮、二甲亚砜、二甲砜、四氢呋喃、己内酰胺、N,N-二乙基-间甲苯酰胺、1-正十二烷基氮杂环庚-2-酮、1,3-二甲基-3,4,5,6-四氢-2(lH)-嘧啶酮、以及它们的组合。在一个实施方案中,该液体是选自下组,其构成为:醇、油、乙二醇、乙二醇醚、吡咯烷酮、聚乙二醇、甘油以及它们的组合。在一个这类实施方案中,该液体是选自下组,其构成为:乙醇、甘油、丙二醇、甘油酯、分子量在约200与600之间的聚乙二醇、以及它们的组合。在其他的实施方案中,本发明的液体药用组合物可以包括一种皮质类固醇的水悬浮物或溶液。
在一个实施方案中,该生物胶凝聚合物是一种热敏的聚合物。适当的热敏聚合物包括聚丙烯酰胺、如聚(正-异丙基丙烯酰胺)连同聚(醚-酯)共聚物,如聚(乙二醇-(DL-乳酸-共-乙醇酸)-乙二醇)。这类热敏的聚合物一旦给予一位患者并且随后在胃肠道中暖化就可以沉淀或引起本发明的液体组合物的粘度增加。因此,本发明的这些组合物沉淀在患者胃肠道的粘膜上或具有较长的滞留时间,由此增加该皮质类固醇在胃肠道粘膜上的局部接触。结果是该皮质类固醇与胃肠道粘膜的接触得以增强和/或延长。
在另一个实施方案中,本发明的这些组合物包括一种生物粘附剂,它是脂质或脂类的混合物。这类脂类或脂质混合物与湿的生物制品表面接触就可以经历一种相变以形成一个粘附膜。这类脂类的实例包括所谓膜与非膜脂的混合物,它典型地将形成薄片状的和非薄片状结构,如对应地六边形的或立方体的相。这类脂类的实例是甘油磷脂,如磷脂酰胆碱、和二酰基甘油,如甘油二油酸酯。这类自组织结构证明了优越的延展性并且粘附到生物制品表面,并且具有优点或成为药学上可接受的材料。有利地可以将该活化剂(如一种皮质类固醇)溶解在该脂质成分中。
可以将适当的非水溶剂包括在本发明的液体药用组合物中,包括药学上可接受的非水溶剂,其中特别是生物胶凝聚合物是可溶性的。例如,该溶剂可以是一种醇(如乙醇)、N-甲基-吡咯烷酮(NMP)、甘油、丙二醇、液体聚乙二醇、二甘醇-单乙醚以及它们的混合物。在某些实施方案中,该溶剂是水易混合的并且该生物胶凝聚合物是不溶于水的,这样使得一旦给药该溶剂快速与来自患者消化道的水混合,引起该生物胶凝聚合物与皮质类固醇沉淀在患者的胃肠道粘膜上。结果是该皮质类固醇与胃肠道粘膜的接触得以增强和/或延长。
可以包括在本发明的液体药用组合物之内的其他生物胶凝聚合物包括纤维素衍生物(如酯类和/或醚、交联的纤维素酯和/或醚)纤维素酯、甲基丙烯酸以及甲基丙烯酸酯聚合物、聚交酯、聚乙交酯(polyglycolides)、聚己酸内酯、聚二氧环己酮(polydioxannones)、聚碳酸酯、聚羟基丁酯、聚链烯(polyalkyene)草酸酯、聚酐类、聚酰胺、聚酰胺酯、聚氨酯、聚缩醛、聚缩酮(polyketals)、聚原碳酸酯(polyorthocarbonates)、聚磷腈、聚羟基戊酸酯(polyhydroxyvalerates)、聚亚烷基琥珀酸酯、聚(苹果酸)、聚(氨基酸)、甲壳质、甲壳糖、聚原酸酯、以及共聚物、三元共聚物以及它们的混合物。生物胶凝聚合物一旦与胃肠道水分接触就溶胀和/或形成水凝胶,由此使本发明的组合物粘附在胃肠道的粘膜上或增加其粘度。结果是该皮质类固醇与胃肠道粘膜的接触得以增强和/或延长。
在某些实施方案中,本发明的液体药用组合物一旦与个体的胃肠道接触就增加粘度。在一个实施方案中,粘度的增加是至少50%(相对于给药之前的粘度)。在另一个这种实施方案中,粘度的增加是至少100%。在又另一个这种实施方案中,粘度的增加是至少200%。在与个体胃肠道接触之前这些组合物的粘度可以使用粘度计测量。这些组合物一旦与个体的胃肠道接触其粘度的改变可以通过在模拟生理条件下测量该组合物的粘度而确定。例如,一个给定组合物的粘度可以在模拟唾液中测量。
可以包括在本发明的这些药用组合物中的适当的皮质类固醇包括:布地奈德、氟替卡松、氟尼缩松、环索奈德、莫米松、倍氯米松、替可的松以及它们的盐类、溶剂化物、以及酯类。在一个具体的实施方案中,本发明的组合物包括氟替卡松。在其他的实施方案中,本发明的组合物包括布地奈德。若该组合物被改进以减少或抑制皮质类固醇的全身性吸收,则在口服给予时典型地具有全身性糖皮质激素或盐皮质激素活性的皮质类固醇还可以用于本发明的这些组合物。
在本发明的这些药用组合物中存在的皮质类固醇的量将取决于所使用的具体皮质类固醇。然而总体上将选择该量值,使得从局部得到的治疗益处最大化同时使全身性吸收最小化。在本发明的固体药用组合物的实例中,在该组合物中皮质类固醇的量典型地是低于或等于20mg。在一个实施方案中,在该药用组合物中的皮质类固醇的量值是在约0.01mg与约20mg之间。在另一个实施方案中,在该药用组合物中的皮质类固醇的量值是在约1mg与约15mg之间。在又另一个实施方案中,在该药用组合物中的皮质类固醇的量值是在约2mg与约10mg之间。在又另一个实施方案中,在该药用组合物中的皮质类固醇的量值是在约2mg与约5mg之间。在又其他的实施方案中,皮质类固醇的量是约0.01mg、约0.02mg、约0.03mg、约0.04mg、约0.05mg、约0.06mg、约0.07mg、约0.08mg、约0.09mg、约0.1mg、约0.2mg、约0.3mg、约0.4mg、约0.5mg、约1mg、约2mg、约3mg、约4mg、约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约90mg、或约20mg,包括其间全部范围和子范围在内。
在本发明的这些固体药用组合物中皮质类固醇的典型量包括约0.25mg、约0.5mg、约1mg、约1.5mg、约2mg、约2.5mg、约3mg、约3.5mg、约4mg、约4.5mg、以及约5mg。在本发明的液体药用组合物的情况下,在该组合物中皮质类固醇的浓度典型地是这样使得与如上说明的量(即0.01mg到20mg)一致的皮质类固醇的量可以方便地给予一位个体。例如,皮质类固醇的浓度可以是这样使得从一个喷洒泵装置一次泵出递送约0.05mg、或任何其他治疗学上有效的预先选择量的皮质类固醇到一位个体的口腔中。在一个具体的实施方案中,本发明的组合物包括约0.25mg的氟替卡松。
一旦将本发明的一个固体药用组合物给予一位个体,该组合物就在患者口腔中崩解。在一个实施方案中,本发明的组合物是处于一种ODT的形式。一种ODT包括与快速分散微颗粒相结合的包含药物的颗粒(如在此所说明的可任选地包被的或与如在此所说明的一种粘合剂相结合的皮质类固醇)。可以如在US 2005/0232988或US20010014340中所说明的通过一种具有不超过约30μm平均粒度的崩解剂与一种具有不超过约30μm平均粒度的糖醇和/或糖类的造粒来制备快速分散微颗粒。并且若需要湿磨并且干燥以产生具有不超过约300μm(如约175-300μm)的一种平均粒度的快速分散微颗粒,可以在一个高剪切制粒机中用大约20%至25%水作为造粒流体来实施造粒。
在该快速分散微颗粒中该崩解剂与该糖醇、糖类、或它们的混合物的比率范围从约90/10到约99/01、例如约90/10、约91/9、约92/8、约93/7、约94/6、约95/5、约96/4、约97/3、约98/2、约99/1,包含全部值、范围、以及在其之间的子范围在内。
该快速分散微颗粒与包含药物的颗粒的比率范围从约5/1到约1/1,包括约5/1、4/1、3/1、2/1、1/1,包含全部值、范围、以及在其之间的子范围在内。
该ODT剂型的包含皮质类固醇的颗粒还应当具有足够小的粒度,这样使得该ODT在患者口腔崩解以后产生一种平滑容易吞咽的悬浮体。在大多数实施方案中,其中将本发明的药用组合物作为一种ODT剂型而提供,包含遮味剂非阿片样物质止痛剂/阿片样物质止痛剂药物的微颗粒的平均粒度不超过约400μm,或在一些实施方案中不超过约300μm。
如在此所说明的ODT剂型还可以包括典型地被用于分散片剂配制品的药学上可接受的赋形剂,如微晶纤维素以及喷雾干燥的甘露醇(可压缩的稀释剂)、交联羧甲基纤维素钠或交联聚乙烯吡咯烷酮(超级崩解剂)、着色剂、以及可任选的硬脂酸镁或硬脂富马酸钠(颗粒内混合或外部使用润滑剂以润滑冲模以及冲头表面)。
片剂剂型,包括ODT的剂型包括本发明的药物组合物,具有低脆性,如低于约1%(例如,低于约0.9%、低于约0.8%、低于约0.7%、低于约0.6%、低于约0.5%、低于约0.4%、低于约0.3%,等等,包括其间所有的范围和子范围在内)以便有充分的耐久性能承受推吸塑包装处理、运输、和/或包装。
一个合适的用于快速分散微颗粒的崩解剂的非限制名单包括:交联聚乙烯吡咯烷酮(交联PVP),淀粉乙醇酸钠,交联羧甲基纤维素钠,硅酸钙,以及低取代的羟丙基纤维素。在该ODT中崩解剂的量典型地在按重量计约1%到约10%的范围内。
一个合适糖醇的非限制性名单包括:甘露醇、山梨醇、木糖醇、麦芽糖醇、阿糖醇、核糖醇、卫茅醇、艾杜糖醇、异麦芽糖醇、乳糖醇、赤藓糖醇及其组合。一个合适糖的非限制名单包括:乳糖、蔗糖、麦芽糖、及其组合。在ODT中糖醇和/或糖的量范围从按重量计约30%到约70%。
药学上可接受的赋形剂包括:填料、稀释剂、助流剂、崩解剂、粘合剂以及润滑剂。其他药学上可接受的赋形剂包括:酸味剂、碱性剂、防腐剂、抗氧化剂、缓冲剂、螯合剂、着色剂、络合剂、乳化剂和/或增溶剂、调味剂、香味剂、保湿剂、甜味剂以及润湿剂。
合适的填料、稀释剂和/或粘合剂的例子包括乳糖(如喷雾干燥乳糖、-乳糖、β-乳糖、不同等级的或Fast-)、微晶纤维素(不同等级的 Ming 或Solka-)、羟丙基纤维素、L-羟丙基纤维素(低取代的)、低分子量的羟丙基甲基纤维素(HPMC)(如来自Dow Chemical的Methocel E、F和K、来自Shin-Etsu有限公司的Metolose SH)、羟乙基纤维素、羧甲基纤维素钠、羧甲基羟乙基纤维素和其他纤维素衍生物、蔗糖、琼脂、山梨醇、甘露醇、糊精、麦芽糊精、淀粉或改性淀粉(包括马铃薯淀粉、玉米淀粉和大米淀粉)、磷酸三钙(如碱性磷酸钙、磷酸氢钙、磷酸氢钙水合物)、硫酸钙、碳酸钙、海藻酸钠和胶原蛋白。
合适的稀释剂的例子包括:如碳酸钙,磷酸氢钙,磷酸三钙,硫酸钙,微晶纤维素,粉状纤维素,葡聚糖,糊精,葡萄糖,果糖,高岭土,乳糖,甘露醇,山梨醇,淀粉,预糊化淀粉,蔗糖和糖。
合适的崩解剂的例子包括:如海藻酸或海藻酸酯,微晶纤维素,羟丙基纤维素和其他纤维素衍生物,交联羧甲基纤维素钠,交联聚乙烯吡咯烷酮,波拉克林钾(polacrillinpotassium),淀粉乙醇酸钠,淀粉,预糊化淀粉,羧甲基淀粉(如和)。
具体的助流剂和润滑剂实例包括:硬脂酸,硬脂酸镁,硬脂酸钙或其他金属硬脂酸盐,滑石,蜡和甘油脂,轻矿物油,PEG,甘油山嵛酸酯,硅胶,氢化植物油,玉米淀粉,硬脂富马酸钠,聚乙二醇,烷基硫酸盐,苯甲酸钠和醋酸钠。
其他赋形剂包括:如调味剂,着色剂,遮味剂,pH值调节剂,缓冲剂,防腐剂,稳定剂,抗氧化剂,润湿剂,湿度调节剂,表面活性剂,助悬剂,吸收促进剂和改进释放的试剂。
可以使用其他功能赋形剂,如环糊精,如遮味剂(如,通过使它们与皮质类固醇络合)。环糊精也可能被用来作为一种载体和/或分散剂,以方便皮质类固醇在治疗活性的预定部位的传递和分布。
本发明的组合物以ODT的形式崩解成包含糖皮质激素的颗粒,而含糖醇/糖颗粒包含在快速溶出的组合物内,从而形成一个可以很容易吞食的平滑悬浮体。
还可以使用其他含皮质类固醇的口腔崩解剂型或口腔溶出剂型,如薄片或薄膜。例如,薄片可以包括干燥或冷冻干燥的组合物,如用冷冻干燥技术(例如,在美国专利号6,316,027中说明)制备的含皮质类固醇作为药物活性成分的口腔崩解或溶出剂型。薄膜剂型可包括可食性薄膜,如在美国6,596,298或美国6,740,332中所说明包含皮质类固醇作为药物活性成分的那些。
本发明的组合物在个人口腔中的崩解速率可以按以下等级:约60秒或更短,约50秒或更短,约40秒或更短,约30秒或更短,约20秒或更短,或约10秒或更短。
本发明的固体药用组合物的崩解速率可以使用不同体外试验方法测量,例如美国药典<701>崩解试验。当使用USP〈701〉崩解试验时,本发明的组合物崩解速率通常是约60秒或更短,约45秒或更短,约30秒或更短,约20秒或更短,或约10秒或更短。
在其他实施方案中,本发明的固体药用组合物在患者口腔中可以提供任何崩解或溶出速率,它为消化道炎症组织提供了一个治疗有效量的皮质类固醇。例如在一些实施方案中,根据本发明的固体药用组合物包括的组合物在口服给药后,为消化道炎症组织提供了约0.5mg至20mg的皮质类固醇。
在一个实施方案中,本发明的固体药用组合物包括一种粘合剂。合适的粘合剂包括蔗糖硫酸铝复合物、壳聚糖及其衍生物(例如三甲基壳聚糖、壳聚糖盐),聚乙烯吡咯烷酮,甲基纤维素,羧甲基纤维素钠,羟丙基纤维素,交联或未交联的聚丙烯酸酯,交联的聚丙烯酸酯,酸性交联或未交联的聚丙烯酸,聚丙烯酸均聚物或共聚物,甲基丙烯酸氨烷基酯共聚物,甲基丙烯酸/甲基丙烯酸甲酯共聚物,丙烯酸烷基酯/甲基丙烯酸烷基酯共聚物,甲基丙烯酸铵酯共聚物(ammoniomethacrylate),聚合物(E,L,S,NE,RL和RS级),卡波姆均聚物或共聚物,亲水多糖树胶,麦芽糊精,交联海藻酸钠(alignate)树胶凝胶,聚羧酸乙烯基聚合物,果胶,黄原胶,海藻酸,改性海藻酸,及其组合。
在本发明的固体药用组合物的某些实施方案中,该皮质类固醇与粘合剂是密切相关的。在这样一个实施方案中,该固体药用组合物包括由粘合剂包围或封装的皮质类固醇。在另一个这样的实施方案中,该固体药用组合物包括安置在粘合剂的表面上的皮质类固醇。在又另一个实施方案中,该固体药用组合物包括与该粘合剂混合或成粒的皮质类固醇。
将皮质类固醇局部给予个体的口腔已经与念珠菌感染相关。因此,一个实施方案中,本发明的药用组合物包括一个抗真菌剂。合适的抗真菌药物包括,但不限于有丝分裂抑制剂抗真菌药物,嘧啶模拟抗真菌药物,多烯类抗真菌药物,苯并咪唑类抗真菌药物,咪唑类抗真菌药物,多烯类抗真菌药物,三唑类抗真菌药物,噻唑类抗真菌药物,丙烯胺抗真菌,棘白菌素(echinocandin)抗真菌药物,以及其他在本领域中公认的不属于任何上述类别的“未分类”抗真菌药物(如托萘酯(tolnaflate)和环吡酮)。例如,可能被包括在本发明的固体药用组合物中的合适的抗真菌药物包括:阿巴芬净(abafungin),阿莫罗芬(amorolfme),阿尼芬净,联苯苄唑,布替萘芬,布康唑(butoconazole),candicin,卡泊芬净,环吡酮,克霉唑,益康,芬替康唑(fenticonazole),菲律宾菌素(filipin),氟康唑,氟胞嘧啶,灰黄霉素,isavuconizole,异康唑,伊曲康唑,酮康唑,米卡芬净,咪康唑,硝酸咪康唑,萘替芬,纳他霉素,制霉菌素,奥昔糠唑(oxiconazole),泊沙康唑,普拉康唑(pramiconazole),雷夫康唑(ravuconazole),龟裂霉素(rimocidin),舍他康唑(setaconizole),硫康唑(sulconazole),特比萘芬(terbafine),特康唑(terconazole),噻康唑(tioconazole),托萘酯(tolnaftate),十一烯酸,伏立康唑。
在另一个实施方案中,本发明的药用组合物包括抗病毒药剂。可能包括在本发明的固体药用组合物中的抗病毒药物包括:干扰素,核苷和核苷酸逆转录酶抑制剂,非核苷类逆转录酶抑制剂,蛋白酶抑制剂,整合酶抑制剂,融合酶抑制剂,成熟抑制剂,鸟苷类似物,嘌呤(puridine)类似物,嘧啶类似物,以及其他在本领域中公认的不属于任何上述类别的“未分类”抗病毒药物(如膦甲酸钠和米替福新)。例如,可能包括在本发明的固体药用组合物中的适当的抗真菌剂包括阿巴卡韦,无环鸟苷(也称阿昔洛韦),阿德福韦,金刚烷胺,氨多索韦(amdoxovir),安普那韦,aplaviroc,阿立他宾(apricitabine),阿比朵尔,阿扎那韦,贝韦立马(bevirimat),拜耳488043,博赛泼维(boceprevir),溴夫定(brivudine),西多福韦,DCM205,二十二烷醇(docosanol),地拉韦啶,地达诺新,达芦那韦(durunavir),依非韦伦,elvitegravir,艾夫他滨(elvucitabine),恩曲他滨,恩夫韦,儿茶素(epigallocatechin gallate),泛昔洛韦,福沙那伟,更昔洛韦,木脂素A,griffithsin,伊布丽珠单抗(ibalizumab),疱疹净,茚地那韦,拉米夫定,洛匹那韦,洛韦胺(loviride),马拉维若(maraviroc),尼非那韦(nelfmavir),奈韦拉平,奥司他韦,聚乙二醇干扰素a-2a,聚乙二醇干扰素a-2b,喷昔洛韦,帕拉米韦,普乐沙福(plerixafor),PRO 140,racivir,雷格特维(raltegrvir),利托那韦,利巴韦林,金刚乙胺,利匹韦林(rlipivirine),沙奎那韦,stampidine,司他夫定,替诺福韦,替拉那韦(tipranavir),TNX-355,三氟尿苷(trifluridine),曲金刚胺(tromantadine),万乃洛韦,缬更昔洛韦,vicriviroc,阿糖腺苷(vidarabione),韦拉米啶(viramidine),vivecon,扎西他滨(zalcitabine),扎那米韦,齐多夫定。
在一个实施方案中,本发明的固体药用组合物包括包含皮质类固醇的颗粒。这些包含皮质类固醇的颗粒可能是包含皮质类固醇晶体和成膜粘结剂的颗粒(如通过造粒制备)。皮质类固醇晶体平均粒度范围约为1-300μm,例如约1-50μm,约1-100μm,约1-150μm,1-200μm左右,约1-250μm,约50-100μm,约50-150μm,约50-200μm,约50-250μm,约50-300μm,约100-150μm约100-200μm,约150-200μm,约150-250μm,约150-300μm,约200-250μm,约200-300μm,或约250-300μm。
在另一个实施方案中,皮质类固醇可能是晶体形式。这类晶体可能具有在亚微米范围内的平均大小(例如,平均粒度约<1μm),或可能是纳米颗粒(例如,平均粒度在1至100纳米范围内)。
在又另一个实施方案中,皮质类固醇可能是以无定形形式存在,例如与限制药品再结晶的稳定剂相结合,如聚乙烯吡咯烷酮(PVP)(包括聚乙烯吡咯烷酮的同源和共聚物以及N-乙烯基吡咯烷酮的均聚物或共聚物);交联聚乙烯吡咯烷酮;树胶;纤维素衍生物(包括羟丙基甲基纤维素(HPMC),羟丙基甲基纤维素邻苯二甲酸酯,羟丙基纤维素,乙基纤维素,羟乙基纤维素,羧甲基纤维素钠,羧甲基纤维素钙,羧甲基纤维素钠,和其他的);葡聚糖;阿拉伯树胶;vinyllactam的同源物和共聚物,以及它们的混合物,环糊精,明胶,羟丙基甲基纤维素邻苯二甲酸酯,糖,多元醇,聚乙二醇(PEG),聚乙烯氧化物环氧乙烷衍生物,聚乙烯醇,丙二醇衍生物以及类似物,十二烷基硫酸钠,表面活性剂,聚合物及其组合。
成膜粘结剂可能包括在造粒中使用的任何适当的粘结剂。适当的成膜粘结剂的非限制性实例包括溶于水的,溶于乙醇的或溶于丙酮/水的粘合剂,如聚乙烯吡咯烷酮(PVP),玉米淀粉,氧化聚乙烯,聚乙二醇,羟丙基甲基纤维素(HPMC),甲基纤维素或羟丙基纤维素(HPC)。在含皮质类固醇颗粒中成膜粘结剂含量的范围可以从约0.5%至约10%,包括约0.5%至1%,约0.5%至2%,约0.5%至5%,约0.5%至7%,约1%至2%,约1%至5%,约1%至7%,约1%至10%,约2%至5%,约2%至7%,约2%至10%,约5%至7%,约5%至10%,约7%至10%。
本发明的含皮质类固醇颗粒还可能包括其他药学上可接受的成分,例如,填料或稀释剂。对于含皮质类固醇颗粒中其他药学上可接受的成分的非限制的实例包括:例如甘露醇,乳糖,微晶纤维素,硫酸钾,磷酸钙,改性淀粉,以及它们的混合物。在含皮质类固醇颗粒中其他药学上可接受的成分(如填料或稀释剂)的量的范围可以从约5%至80%,包括约5%至70%,约5%至60%,约5%至50%,约5%至40%,约5%至30%,约5%至20%,约5%至15%,约5%至10%,约10%至70%,约10%至60%,约10%至50%,约10%至40%,约10%至30%,约10%至20%,约10%至15%,约20%至70%,约20%至60%,约20%至50%,约20%至40%,约20%至30%,约20%至25%,约30%至70%,约30%至60%,约30%至50%,约30%至40%,约30%至35%,约40%至70%,约40%至60%,约40%至50%,约40%至45%,约50%至70%,约50%至60%,约50%至55%,约60%至70%,或约60%至65%。
在另一个实施方案中,本发明的含皮质类固醇颗粒可以是皮质类固醇涂层珠的形式。皮质类固醇涂层的珠子包括一个芯,如药学上可接受的糖珠,涂有皮质类固醇层。可以制备这种皮质类固醇涂层的珠子,例如,通过溶解或悬浮皮质类固醇在聚合物粘结剂的溶液中,再将其喷或涂到惰性颗粒上(如糖球或纤维素球Celphere(R)的)。合适的聚合物粘结剂包括任何本文所披露的,如淀粉,改性纤维素(如羟丙基纤维素,羧甲基纤维素钠),海藻酸,聚乙烯吡咯烷酮(聚维酮),及其混合物。在该皮质类固醇层中皮质类固醇的量以及皮质类固醇层的厚度可以修改,以提供治疗有效量的皮质类固醇。该含皮质类固醇层包括约90%至99%的皮质类固醇,约1%至约10%的粘结剂。
本发明的含皮质类固醇颗粒可以通过任何合适的方法制备。例如,这些含皮质类固醇颗粒的制备可以通过在高剪切造粒机或流化床造粒机中使用一种或多种聚合物粘结剂的溶液使皮质类固醇晶体、一种或多种崩解剂、一种或多种填料(如糖醇,糖和/或微晶纤维素)造粒,并且在流化床设备或传统烤箱的托盘干燥,从而产生这些含皮质类固醇的颗粒。
本发明的固体药用组合物可能包括快速分散的颗粒,这些颗粒包括一个崩解剂和糖醇和/或糖。这些含崩解剂的颗粒可以包括崩解剂或所谓的超级崩解剂,如交联聚乙烯吡咯烷酮(交联PVP),乙醇酸钠淀粉,交联羧甲基纤维素钠,低取代羟丙基纤维素,以及它们的混合物。在快速分散颗粒中崩解剂的量可以从快速分散颗粒总重量的约1%至10%,或约5%至10%,包括其间所有的范围和子范围在内。
糖醇是碳水化合物的氢化形式,其中羰基(即醛或酮)已经降低为伯醇或仲醇羟基。对于本发明的药用组合物的快速分散颗粒适合的糖醇的非限制性实例包括:如阿糖醇,异麦芽糖,赤藓糖醇,甘油,乳糖,甘露醇,山梨醇,木糖醇,麦芽糖醇,及其混合物。术语“糖类”是术语“糖”(包括单糖,如葡萄糖,果糖,乳糖,核糖;以及双糖,如蔗糖,乳糖,麦芽糖,海藻糖,纤维二糖)的同义词。在一个实施方案中,对于在本发明的这些组合物中使用的适合的糖的非限制性例包括:乳糖,蔗糖,麦芽糖,及其混合物。在另一个实施方案中,这些快速分散颗粒包括至少一种与糖醇组合的崩解剂。在另一个实施方案中,这些快速分散的颗粒包括至少一种与糖类组合的崩解剂。在又另一个实施方案中,这些包含崩解剂的颗粒包括至少一种与糖醇以及一种糖类组合的崩解剂。在快速分散颗粒中糖醇和/或糖的量范围从包含崩解剂颗粒总重量的约99%至90%,或约95%至90%,包括其间所有的范围和子范围在内。在一个实施方案中,糖醇和/或糖的平均粒度为30μm或以下,例如约1至30μm,约5至30μm,约5至25μm,约5至20μm,约5至15μm,大约5至10μm,约10至30μm,约10至25μm,约10至20μm,约10至15μm,约15至30μm,约15至25μm,约15至20μm,约20至30μm,约20至25μm,或约25至30μm。
本发明的固体药用组合物的这些包含皮质类固醇颗粒(如晶体,颗粒剂,或药物涂层珠)还可以涂有一种遮味剂层以改善该组合物的适口性。这些包含皮质类固醇颗粒可以通过用不溶于水的聚合物涂这些包含皮质类固醇颗粒(如,晶体,颗粒剂,或药物涂层珠)而掩盖其味道。适合用于遮味层的不溶于水的聚合物的非限制性实例包括:乙基纤维素,聚醋酸乙烯聚乙烯醇(PVA),醋酸纤维素(CA),醋酸丁酸纤维素(CAB),甲基丙烯酸酯共聚物,如在商标“EUDRAGIT”下的那些(如RL,RS和NE30D的类型),及其组合物。
在一个实施方案中,不溶于水的聚合物是乙基纤维素,在25摄氏度下作为5%重量的80:20甲苯/乙醇溶液用Ubbelohde粘度计测试时其粘度约为90-110cps。
在一个实施方案中,本发明的固体药用组合物包括约25%至35%的皮质类固醇晶体,用遮味层使这些晶体微囊化,该遮味层包括不溶于水的聚合物(如乙基纤维素);约60%至70%的快速分散颗粒(如包括交联聚乙烯吡咯烷酮和甘露醇);约5%的额外崩解剂(如交联聚乙烯吡咯烷酮);约1%的一种或多种调味剂,以及约0.5%至1%的甜味剂(如三氯蔗糖)。
在本发明的一个实施方案中产生药物涂层珠的方法包括使皮质类固醇溶解或悬浮在聚合物粘结剂的溶液中并且使用配备有底部喷射Wurster镶件的流化床涂布机涂在惰性颗粒上(50-100目或直径在150μm至300μm),如糖球或纤维素球(如 CP-203)。然后可以通过流化床涂层或通过本文所述溶剂复合凝聚法将这些皮质类固醇涂层珠遮味。
在另一个实施方案中,本发明的组合物包括涂有遮味层的皮质类固醇的颗粒(如晶体)。可通过任何合适的方法将该遮味层(如本文所述)应用到皮质类固醇颗粒上,例如复合凝聚法或流化床包衣法。可替代的,本发明的这些组分可以包括与环糊精络合的一种皮质类固醇。
在一个实施方案中,制备本发明的组合物的方法包括遮味步骤。本发明的组合物的遮味含皮质类固醇颗粒(如皮质类固醇晶体,含皮质类固醇的微粒或药物涂层珠)可以通过不同方法制备,包括用不溶于水的聚合物(如乙基纤维素)的溶剂复合凝聚法。将不溶于水的聚合物(如乙基纤维素),相诱导剂(如聚乙烯),以及皮质类固醇装入一个含环己烷的复合凝聚罐。将罐中的混合物加热到约80摄氏度以使乙基纤维素溶解,然后在控制的条件下慢慢冷却,从而造成由乙基纤维素在相诱导下使皮质类固醇颗粒成微胶囊。微胶囊化或复合凝聚法是指灌输遮味(或缓释)特性的相分离过程。达到环境温度后,将微胶囊化的皮质类固醇颗粒悬浮物过滤,用新鲜环己烷洗涤并且干燥,以使溶剂残留水平减少到可接受的范围内(例如<4,000ppm),在一个实施方案中小于1000ppm。微胶囊化的皮质类固醇颗粒的涂层重量可以是范围从约5%到约30%,包括约10%,15%,20%和25%,包括其间所有的范围和子范围在内。这样的复合凝聚过程的实例披露于美国专利号5,252,337,5,639,475,6,139,865以及6,495,160中。
可替代的,复合凝聚溶液可以包括不溶于水的聚合物(如乙基纤维素)与不溶于水或胃可溶的造孔剂(如碳酸钙)的混合物。不溶于水的聚合物与造孔剂的比例范围可以从约50/50到95/05,包括约55/45,60/40,约65/35,约70/30,约75/25,约80/20,约85/15,约90/10,包括其间所有的范围和子范围在内。微胶囊化的皮质类固醇激素颗粒的涂层重量可以是范围从约5%到约30%,包括约10%,15%,20%和25%,包括其间所有的范围和子范围在内。在一个实施方案中,复合凝聚步骤包括在复合凝聚罐中在80摄氏度下使这些含药颗粒悬浮在一种不溶于水的乙基纤维素溶液中。冷却循环期间,在约58摄氏度下将微粒化的造孔剂引入该罐,同时不断搅拌悬浮物使之在成型/硬化阶段均匀分布在微胶囊膜上。这种复合凝聚过程的实例披露在美国专利公开号US 2006/0105038中。
在一个实施方案中,本发明的固体药用组合物是处于一种口腔崩解片(ODT)的形式。在这样一个实施方案中,该ODT包括药物颗粒和快速分散颗粒,其中这些药物颗粒包括该皮质类固醇,并且这些快速分散颗粒包括一种崩解剂以及一种糖醇和/或糖。例如,药物颗粒可能包括皮质类固醇晶体(具有或无涂层),皮质类固醇涂层珠或具有一个或多个附加组分的皮质类固醇颗粒。在某些实施方案中,ODT是处于一种薄片或薄膜的形式(例如说明于US 6,534,549、US 7,125,564等)。
在本发明的一个实施方案中,固体组合物包括一个冻干的基质,其中该冻干的基质包括皮质类固醇和一种赋形剂。合适的赋形剂包括甘露醇,木糖醇,山梨醇,麦芽糖醇,麦芽糖醇,乳糖,蔗糖,麦芽糖,及其组合。
在本发明的固体组合物中含皮质类固醇颗粒的量可以是范围从约5%到50%,包括约5%,约10%,约15%,约20%,约25%,约30%,约35%,约40%,约45%,约50%,包括其间所有的值,范围和子范围在内。在一个实施方案中,本发明的组合物是一种ODT,包括按重量计约30%的含皮质类固醇颗粒。
在一个实施方案中,用于生产本发明的味道令人愉快的皮质类固醇ODT制剂(包括平均粒度约为100-400μm的皮质类固醇微粒)的方法包括:(i)制备具有所需平均粒度的皮质类固醇晶体的含药芯,如微粒,皮质类固醇颗粒(如晶体),或药物涂层珠,(ii)制备包括崩解剂,糖醇及/或糖的颗粒,以及(iii)使用一个压片机(如配备有一个外部润滑系统(压缩前润滑冲头和冲模)的旋转压片机)压缩包括皮质类固醇微粒和崩解剂颗粒的混合物成为ODT形式,可任选地具有药学上可接受的一种或多种调味剂,一种或多种甜味剂,一种或多种其他崩解剂,一种或多种着色剂和/或压缩助剂,如足够数量的微晶纤维素。这些ODT片剂一旦暴露于口中唾液就迅速崩解成为平滑、易于吞咽、没有砂质回味的悬浮物。
在另一个实施方案中,用于制备本发明ODT制剂(包括平均粒度约为100-400μm的皮质类固醇微粒)的方法还可以包括:在混合和压缩成ODT片剂之前通过复合凝聚法或流化床包衣法将含皮质类固醇颗粒(如皮质类固醇晶体,含有皮质类固醇的颗粒或药物涂层珠)遮味的一个单元步骤。例如,具有平均粒度范围约为1μm至200μm,更具体的约为50μm至150μm的皮质类固醇晶体材料可以根据本发明的其他方面通过流化床包衣法或溶剂复合凝聚法涂有遮味层。
具有平均粒度范围约为5μm至50μm的皮质类固醇晶体材料还可以通过本文所述的溶剂复合凝聚法遮味。
在另一个实施方案中,本发明的组合物可以是口腔崩解片,其制备是通过混合皮质类固醇微粒或遮味皮质类固醇微粒,一个或多个调味剂,甜味剂,快速分散的微粒,微晶纤维素,和一个额外的崩解剂,并且将这种混合物压缩成口腔崩解片。从而形成口腔崩解片,在口腔中与唾液接触就快速崩解,并有一个令人愉快的味道(好的奶油口感),并且在胃中提供快速、完全的剂量释放。
在又另一个实施方案中,本发明的组合物可以是口腔崩解片,其形成是通过在配备了压片机外部润滑系统、预润滑的冲模和冲头的压片机中压缩含皮质类固醇的颗粒,快速分散的颗粒,以及可任选的调味剂,甜味剂,和其他药学上可接受的赋形剂而成,从而提供了否则不含润滑剂的片剂制剂。由此产生的口腔崩解片通常表现出足够的硬度和足够低的脆性,适合于包装在HDPE瓶中,以及使用常规设备推动通过薄膜支持或剥离纸支持的吸塑包装用于储存,运输和商业流通。
在另一个实施方案中,本发明的口腔崩解片的制造方法包括以下步骤:(a)在高剪切造粒机或流化床包衣机中通过使平均粒度约5至50μm的结晶糖皮质激素材料和一个或多个稀释剂/填料,如甘露醇,乳糖,微晶纤维素及其混合物与聚合物粘结剂造粒而制备含皮质类固醇的微粒;(b)在常规造粒机中使用水或醇水混合物将一个或多个糖醇及/或糖与交联聚乙烯吡咯烷酮崩解剂造粒(每个平均粒度不超过约30μm),并且在流化床设备或常规烤箱中使颗粒干燥,产生平均粒度不超过约400μm的快速分散微粒,如在2004年4月19日提出的美国专利公开号20050232988所说明;(c)使步骤(a)的皮质类固醇微粒与步骤(b)的一个或更多调味剂,甜味剂,微晶纤维素,额外的崩解剂,以及快速分散微粒混合;并且(d)使用配备有一个外部润滑系统,预润滑冲模和冲头的常规的旋转式压片机将步骤(c)的混合物压缩成片剂。
在另一个实施方案中,本发明的口腔崩解片的制造方法包括以下步骤:a)制备含药物芯颗粒(如皮质类固醇的晶体,药物涂层珠,或含皮质类固醇的微粒)是通过在高剪切造粒机或流化床包衣机中使药物和可任选的一个或多个稀释剂/甘露醇,乳糖,微晶纤维素以及其混合物与一种聚合物粘结剂造粒,或在流化床包衣机并且可任选地应用一个密封包衣(如 Clear)从包括聚合物粘合剂和药物的溶液/悬浮物将药物涂布到一种惰性颗粒上(60至100目糖球或纤维素球,如 CP-203);b)通过微胶囊化的遮味芯颗粒,如通过溶剂复合凝聚法或涂有不溶于水的聚合物(如乙基纤维素)、或涂有不溶于水的功能聚合物与水溶性/胃可溶的造孔剂的混合物(如乙基纤维素和氯化钠或碳酸钙的比例从约50/50到95/5)流化床微胶囊化以便产生具有所需粒度分布的好口味的微粒(如平均粒度不超过约400μm,不超过约300μm);c)如本文所披露将一个或多个糖醇及/或糖类与崩解剂(如交联聚乙烯吡咯烷酮)造粒,每个具有不超过30μm的平均粒度;d)将步骤(b)的这些遮味颗粒与一个或多个调味剂,甜味剂,微晶纤维素,其他崩解剂,以及步骤(c)的快速分散微粒混匀;以及e)使用例如常规的旋转式压片机(配备有一个外部润滑系统,预润滑的冲模和冲头)将步骤(d)的混合物压缩成片剂。
具体实施方式
实例1
氟替卡松丙酸酯微粒A:按95/5比率的甘露醇25(91.2%w/w)与交联聚乙烯吡咯烷酮XL-10(4.8%w/w)经由一个配备了0.225"间隔的制粉设备按约1400-1500rpm的速度通过经过该混合物各自共同研磨。使甘露醇、交联聚乙烯吡咯烷酮、以及氟替卡松丙酸酯(4%w/w)晶体材料混合约3-5分钟,以混合这些成分。用预混合的甘露醇、交联聚乙烯吡咯烷酮、以及氟替卡松丙酸酯充填一个配备有顶喷制粒室和造粒碗的Glatt GPCG-3流化床设备(批处理大小:1500g),并且通过以1.25巴的压力、喷射率为30-50mL/min喷洒纯净水(喷嘴:尖端1.2mm)使之成颗粒状,并且>70摄氏度的出口温度以及>33摄氏度的产品温度。使湿物质干燥直到水分含量(%干燥失重)小于约1%。
片剂:根据标准操作程序安置配备有真空传输系统、片剂除尘器、一个金属探测器、以及松井前润滑油系统(Matsui Ex-lube system)的一个Hata生产压片机。将硬脂酸镁用作加工助剂,即外部润滑冲床与模具表面,并且因此在这些片剂上只有痕量。对于这些片剂的重量范围典型的是目标片剂重量加或减5%。启动前润滑油系统以确保压片机运行时润滑剂正确喷涂。对这些制片参数,如填充深度(mm),压缩前的位置(mm或kN)与主要的压缩位置(mm或kN)进行了调整,以便生产符合下列典范规格的4mg片剂:
片剂:片剂参数
参数 | 靶值 | 范围 |
重量(mg) | 100 | 95-105 |
厚度(mm) | 2.4 | 2.0-2.8 |
硬度(N) | 28 | 8-48 |
脆碎度 | NMT 0.6% | 1.0% |
10个片剂重量(g) | 1.0g | 0.96-1.04 |
成功设置之后在“自动模式”运行压片机,直到完成。在运行过程中,片剂定期进行抽样,以确保生产片剂将满足以上列出的规格。
在USP〈701〉崩解试验中对这些片剂进行测试,并且在约60秒或更短时间崩解。
实例2
通过混合89.8%的95%乙醇、按重量计5%乙基纤维素,按重量计0.2%油酸、以及5%氟替卡松丙酸酯来制备液体。一旦涂抹到粘膜表面后就形成一种薄膜,这种薄膜容易粘附到皮肤或粘膜组织上。
通过混合以下组分制备一个基于乙醇的凝胶:按重量计67%的95%乙醇;按重量计8%的乙基纤维素,按重量计2%的羟丙基纤维素;按重量计2%的聚丙烯酸;按重量计14%的薄荷;按重量计5%的水USP;以及按重量计2%的氟替卡松丙酸酯。形成一个光滑、稍不透明的粘性凝胶。
从施加这种凝胶到黏膜表面产生的薄膜粘附到表面并且其去除要求机械力。
应当理解的是虽然为了说明目的已经描述了本发明的具体实施方案,在不背离本发明的精神和范围下,可以做出不同修改。因此,除所附的权利要求书之外本发明不受限制。
Claims (10)
1.一种口腔分散固体药用组合物,包括小于或等于20mg的一种局部施用的皮质类固醇和至少一种崩解剂,其中该固体药用组合物在口服给药后没有显著的全身性糖皮质激素或盐皮质激素活性,
其中在使用美国药典<701>崩解试验测试时,该固体药用组合物在60秒内崩解;
其中在给药后,所述皮质类固醇局部沉积在上胃肠道中;并且
其中所述上胃肠道选自由食管、声门、会厌软骨、扁桃体和口咽组成的组。
2.如权利要求1所述的固体药用组合物,其中所述固体药用组合物在30秒内崩解。
3.如权利要求1所述的固体药用组合物,其中所述皮质类固醇是选自下组,该组由以下各项组成:布地奈德、氟替卡松、氟尼缩松,环索奈德、莫米松、倍氯米松、以及它们的盐类、溶剂化物类、和酯类。
4.如权利要求1所述的药用组合物,进一步包括一种粘合剂。
5.如权利要求4所述的固体药用组合物,其中该粘合剂是选自下组,该组由以下各项组成:蔗糖硫酸铝复合物、壳聚糖及其衍生物、聚乙烯吡咯烷酮、甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、交联或未交联的聚丙烯酸酯、聚丙烯酸均聚物或共聚物、甲基丙烯酸氨烷基酯共聚物、甲基丙烯酸/甲基丙烯酸甲酯共聚物、丙烯酸烷基酯/甲基丙烯酸烷基酯共聚物、甲基丙烯酸铵酯共聚物、卡波姆均聚物或共聚物、亲水性的聚糖树胶、麦芽糖糊精、交联的海藻酸钠树胶凝胶、聚羧酸乙烯基聚合物、果胶、黄原胶、海藻酸、以及它们的组合。
6.如权利要求5所述的固体药用组合物,其中所述交联的聚丙烯酸酯是酸性交联的聚丙烯酸酯。
7.如权利要求5所述的固体药用组合物,其中所述海藻酸是改性的海藻酸。
8.如权利要求1所述的固体药用组合物,其中所述至少一种崩解剂选自下组,该组由以下各项组成:交联聚乙烯吡咯烷酮、淀粉羟基乙酸钠、交联的羧甲基纤维素、低取代的羟丙基纤维素、甘露醇、木糖醇、山梨醇、麦芽醇、麦芽糖醇、乳糖、蔗糖、麦芽糖、以及它们的组合。
9.如权利要求1所述的药用组合物,进一步包括一种选自下组的赋形剂,该组由以下各项组成:甘露醇、木糖醇、山梨醇、麦芽醇、麦芽糖醇、乳糖、蔗糖、麦芽糖、环糊精、以及它们的组合。
10.如权利要求1所述的固体药用组合物,它不含润滑剂。
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Families Citing this family (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8497258B2 (en) | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US20100216754A1 (en) * | 2007-11-13 | 2010-08-26 | Meritage Pharma, Inc. | Compositions for the treatment of inflammation of the gastrointestinal tract |
MX349677B (es) | 2007-11-13 | 2017-08-08 | Meritage Pharma Inc | Composiciones corticosteroides. |
US20090131386A1 (en) | 2007-11-13 | 2009-05-21 | Meritage Pharma, Inc. | Compositions for the treatment of inflammation of the gastrointestinal tract |
US20110097401A1 (en) * | 2009-06-12 | 2011-04-28 | Meritage Pharma, Inc. | Methods for treating gastrointestinal disorders |
ES2742525T3 (es) | 2009-10-01 | 2020-02-14 | Adare Pharmaceuticals Us L P | Composiciones de corticosteroides administradas oralmente |
EP3970726A1 (en) * | 2010-06-24 | 2022-03-23 | ViroPharma Biologics LLC | Methods of treatment for esophageal inflammation |
WO2012020279A1 (en) * | 2010-08-13 | 2012-02-16 | Compagnie Gervais Danone | Product for the upper gastric sphere |
US8765725B2 (en) | 2012-05-08 | 2014-07-01 | Aciex Therapeutics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
EP2847207B1 (en) | 2012-05-08 | 2019-03-27 | Nicox Ophthalmics, Inc. | Fluticasone propionate nanocrystals |
US9815865B2 (en) | 2013-01-07 | 2017-11-14 | Nicox Ophthalmics, Inc. | Preparations of hydrophobic therapeutic agents, methods of manufacture and use thereof |
CA2906029C (en) * | 2013-03-15 | 2017-09-05 | Aprecia Pharmaceuticals Company | Rapid disperse dosage form containing levetiracetam |
US10716802B2 (en) | 2013-03-15 | 2020-07-21 | The Brigham And Women's Hospital, Inc. | Compounds to modulate intestinal absorption of nutrients |
US9339489B2 (en) | 2013-03-15 | 2016-05-17 | Aprecia Pharmaceuticals Company | Rapid disperse dosage form containing levetiracetam |
GB201308933D0 (en) * | 2013-05-17 | 2013-07-03 | Diurnal Ltd | Paediatric composition |
US9078853B2 (en) | 2013-06-18 | 2015-07-14 | Cmpd Licensing, Llc | Dry pharmaceutical compositions for topical delivery of oral medications, nasal delivery and to treat ear disorders |
WO2015034678A2 (en) * | 2013-09-06 | 2015-03-12 | Aptalis Pharmatech, Inc. | Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis |
WO2015152517A1 (ko) * | 2014-03-31 | 2015-10-08 | (주)세하바이오 | 항산화 물질 활성 보호를 위한 프롤라민 기반 경구용 필름 제조방법 |
EP3047846A1 (en) | 2015-01-22 | 2016-07-27 | Ems S.A. | Dosage forms containing fluticasone propionate for the treatment of inflammatory conditions of the esophagus |
US9980975B2 (en) | 2015-01-22 | 2018-05-29 | Ems S.A. | Dosage forms containing fluticasone propionate for the treatment of inflammatory conditions of the esophagus |
EP3288556A4 (en) | 2015-04-29 | 2018-09-19 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
US9867834B2 (en) | 2015-06-15 | 2018-01-16 | Banner Life Sciences Llc | Non-systemic topical compositions comprising corticosteroids |
US9877971B2 (en) | 2015-06-15 | 2018-01-30 | Banner Life Sciences Llc | Soft lozenges comprising corticosteroids |
US10973846B2 (en) | 2015-09-24 | 2021-04-13 | The Brigham And Women's Hospital, Inc. | Water-activated mucoadhesive compositions to reduce intestinal absorption of nutrients |
CN105412123B (zh) * | 2015-11-06 | 2018-03-13 | 山东省千佛山医院 | 布地奈德联合三唑类抗真菌药物的应用及其产品 |
US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
TWI728172B (zh) | 2016-08-18 | 2021-05-21 | 美商愛戴爾製藥股份有限公司 | 治療嗜伊紅性食道炎之方法 |
US9999604B2 (en) | 2016-11-17 | 2018-06-19 | Cmpd Licensing, Llc | Compounded solutions of diclofenac and lidocaine and methods |
US11737975B2 (en) | 2016-11-17 | 2023-08-29 | Cmpd Licensing, Llc | Compounded compositions and methods for treating pain |
US10525025B2 (en) | 2016-11-17 | 2020-01-07 | Cmpd Licensing, Llc | Compounded compositions and methods for treating pain |
US10966946B2 (en) | 2016-11-17 | 2021-04-06 | Cmpd Licensing, Llc | Compounded compositions and methods for treating pain |
US11986448B2 (en) | 2016-11-17 | 2024-05-21 | Cmpd Licensing, Llc | Compounded compositions and methods for treating pain |
CN107595765A (zh) * | 2017-09-22 | 2018-01-19 | 沈阳兴齐眼药股份有限公司 | 一种眼用缓释药物递送系统及其制备方法 |
WO2019157453A1 (en) * | 2018-02-12 | 2019-08-15 | Trilogy Therapeutics, Inc. | Caspofungin compositions for inhalation |
SI25373A (sl) | 2018-05-08 | 2018-08-31 | Danijela Marković | Naravna orodisperzibilna tableta |
WO2020227437A1 (en) | 2019-05-06 | 2020-11-12 | Axial Biotherapeutics, Inc. | Sustained release solid dosage forms for modulating the colonic microbiome |
US20220347189A1 (en) * | 2019-10-01 | 2022-11-03 | Ellodi Pharmaceuticals, L.P. | Methods of treating eosinophilic esophagitis and reducing candidiasis |
KR102275997B1 (ko) * | 2019-11-07 | 2021-07-13 | 연세대학교 산학협력단 | 숙주지향치료를 위한 조성물 |
CN114146089B (zh) * | 2021-12-15 | 2023-06-16 | 安徽贝克生物制药有限公司 | 含依非韦伦、替诺福韦和恩曲他滨的药物组合物 |
CN116869927B (zh) * | 2023-09-06 | 2023-11-10 | 中国医学科学院北京协和医院 | 一种用于治疗嗜酸性食管炎的食道温敏凝胶 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1027864A (en) * | 1972-12-09 | 1978-03-14 | Hoechst Aktiengesellschaft | Orally administrable corticosteroid preparations |
CN1186428A (zh) * | 1995-04-13 | 1998-07-01 | 阿斯特拉公司 | 适于吸入使用的颗粒的制备方法 |
US20040106663A1 (en) * | 2002-09-06 | 2004-06-03 | Talley John Jeffrey | Inhibitors of fungal invasion |
US20050009848A1 (en) * | 2003-07-10 | 2005-01-13 | Icn Pharmaceuticals Switzerland Ltd. | Use of antivirals against inflammatory bowel diseases |
US20070059361A1 (en) * | 2005-09-09 | 2007-03-15 | University Of Manitoba | Fast-disintegrating epinephrine tablets for buccal or sublingual administration |
US20090123550A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Corticosteroid compositions |
US20090169620A1 (en) * | 2007-12-21 | 2009-07-02 | Venkatesh Gopi M | Orally disintegrating tablet compositions of temazepam |
Family Cites Families (89)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1170188A (en) * | 1967-09-15 | 1969-11-12 | Bayer Ag | N-trityl-imidazoles and salts and uses thereof |
SE378109B (zh) | 1972-05-19 | 1975-08-18 | Bofors Ab | |
US4080448A (en) | 1974-11-13 | 1978-03-21 | Mirsky Louis H | Method of treating cellular stress |
JPS56138200A (en) * | 1980-02-15 | 1981-10-28 | Glaxo Group Ltd | Androstane carbothioate compound |
SE8004580L (sv) | 1980-06-19 | 1981-12-20 | Draco Ab | Farmaceutisk beredning |
EP0057401B1 (en) * | 1981-02-02 | 1984-08-01 | Schering Corporation | Aromatic heterocyclic esters of steroids, their preparation and pharmaceutical compositions containing them |
GB8630913D0 (en) | 1986-12-24 | 1987-02-04 | Glaxo Group Ltd | Pharmaceutical compositions |
US5446070A (en) | 1991-02-27 | 1995-08-29 | Nover Pharmaceuticals, Inc. | Compositions and methods for topical administration of pharmaceutically active agents |
ZA892859B (en) | 1988-04-22 | 1989-12-27 | Advanced Polymer Systems Inc | Porous particles in preparations involving immiscible phases |
US5278175A (en) * | 1990-02-02 | 1994-01-11 | Pfizer Inc. | Triazole antifungal agents |
GB9002375D0 (en) | 1990-02-02 | 1990-04-04 | Pfizer Ltd | Triazole antifungal agents |
GR1001529B (el) * | 1990-09-07 | 1994-03-31 | Elmuquimica Farm Sl | Μέ?οδος για την λήψη νέων 21-εστέρων της 16-17-ακετάλης της πρ να-1,4-διενο-3,20-διόνης. |
CA2101773A1 (en) | 1991-01-31 | 1992-08-01 | Toyoichi Tanaka | Interpenetrating-polymer network phase-transition gels |
US5252337A (en) | 1991-06-25 | 1993-10-12 | Eurand America, Inc. | Controlled release calcium channel blocker microcapsules |
DE69424181T2 (de) | 1993-12-20 | 2000-10-19 | Minnesota Mining & Mfg | Flunisolide aerosolformulierungen |
US5639475A (en) | 1995-02-03 | 1997-06-17 | Eurand America, Incorporated | Effervescent microcapsules |
GB9517062D0 (en) | 1995-08-18 | 1995-10-25 | Scherer Ltd R P | Pharmaceutical compositions |
DE19606151C2 (de) | 1996-02-20 | 1999-05-12 | Losan Pharma Gmbh | Ibuprofen-Brausezubereitung sowie Verfahren zur Herstellung derselben |
US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
DK0914818T3 (da) | 1996-06-14 | 2005-07-04 | Kyowa Hakko Kogyo Kk | Intraoralt hurtigt desintegrerbar tablet |
AU722289B2 (en) | 1996-10-01 | 2000-07-27 | Aptalis Pharmatech, Inc. | Taste-masked microcapsule compositions and methods of manufacture |
SE9604486D0 (sv) | 1996-12-05 | 1996-12-05 | Astra Ab | Novel formulation |
GB9707934D0 (en) * | 1997-04-18 | 1997-06-04 | Danbiosyst Uk | Improved delivery of drugs to mucosal surfaces |
IT1291362B1 (it) | 1997-05-13 | 1999-01-07 | Vectorpharma Int | Composizioni farmaceutiche multicomponente bifasiche contenenti sostanze atte a modificare la partizione dei principi attivi |
RO118174B1 (ro) | 1997-08-21 | 2003-03-28 | Aventis Pharma Deutschland Gmbh | Lac de unghii şi utilizarea acestuia |
GB9722426D0 (en) | 1997-10-23 | 1997-12-24 | Univ London Pharmacy | Controlled release formulations |
AU741992B2 (en) | 1998-03-06 | 2001-12-13 | Adare Pharmaceuticals S.R.L. | Fast disintegrating tablets |
FR2781156B1 (fr) * | 1998-07-20 | 2001-06-29 | Lafon Labor | Composition pharmaceutique destinee notamment a la prevention et au traitement des radiomucites et des chimiomucites |
US6596298B2 (en) | 1998-09-25 | 2003-07-22 | Warner-Lambert Company | Fast dissolving orally comsumable films |
US6863378B2 (en) | 1998-10-16 | 2005-03-08 | Silverbrook Research Pty Ltd | Inkjet printer having enclosed actuators |
PT1178808E (pt) | 1999-04-23 | 2012-08-16 | Leo Pharma As | Composição farmacêutica não aquosa para utilização dérmica para o tratamento da psoríase compreendendo uma vitamina d, um corticosteróide e de um componente solvente |
GB9915319D0 (en) | 1999-06-30 | 1999-09-01 | Unilever Plc | Hair treatment compositions |
CA2317999C (en) | 1999-09-11 | 2004-11-09 | Glaxo Group Limited | Pharmaceutical formulation of fluticasone propionate |
KR100446101B1 (ko) * | 2000-12-07 | 2004-08-30 | 주식회사 삼양사 | 수난용성 약물의 서방성 제형 조성물 |
EP1367999A4 (en) | 2001-02-16 | 2007-04-18 | Lavipharm Lab Inc | WATER-SOLUBLE AND PALATABLE COMPLEXES |
US20030050312A1 (en) | 2001-03-12 | 2003-03-13 | Hjorth Thyge Borup | Novel tablets and capsules and a process for its preparation |
CA2440935A1 (en) * | 2001-03-13 | 2002-09-19 | Richard Liggins | Micellar drug delivery vehicles and precursors thereto and uses thereof |
US6872405B2 (en) | 2001-05-10 | 2005-03-29 | Yamanouchi Pharmaceutical Co., Ltd. | Quick-disintegrating tablet in buccal cavity and manufacturing method thereof |
CA2419290C (en) * | 2001-05-10 | 2007-03-27 | Yuuki Takaishi | Quick-disintegrating tablet in the buccal cavity and manufacturing method thereof |
US6656493B2 (en) | 2001-07-30 | 2003-12-02 | Wm. Wrigley Jr. Company | Edible film formulations containing maltodextrin |
FR2831820B1 (fr) | 2001-11-05 | 2004-08-20 | Ethypharm Sa | Comprime orodispersible presentant une grande homogeneite et son procede de preparation |
US20030206978A1 (en) | 2001-11-29 | 2003-11-06 | Bob Sherwood | Agglomerated particles including an active agent coprocessed with silicified microcrystalline cellulose |
US20040009212A1 (en) | 2002-01-30 | 2004-01-15 | Pharma Power Biotec Co. Ltd. | Mucoadhesive thermoresponsive medicament-carrier composition |
JP4173670B2 (ja) * | 2002-03-08 | 2008-10-29 | 旭化成ファーマ株式会社 | 口腔内崩壊製剤 |
US6958192B2 (en) | 2002-04-05 | 2005-10-25 | The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration | Polyimides from 2,3,3′,4′-biphenyltetracarboxylic dianhydride and aromatic diamines |
DE60318035T2 (de) * | 2002-05-03 | 2008-12-11 | Janssen Pharmaceutica N.V. | Polymermikroemulsionen |
WO2004006481A2 (en) | 2002-07-10 | 2004-01-15 | I/O Controls Corporation | Fiber optic control network and related method |
AU2003272450A1 (en) | 2002-09-13 | 2004-04-30 | C. Steven Smith | Novel composition and method for treatment of upper respiratory conditions |
US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
EP1595533B1 (en) | 2003-01-21 | 2010-01-06 | Nippon Shinyaku Co., Ltd. | Tablet quickly melting in oral cavity |
ATE329594T1 (de) * | 2003-01-31 | 2006-07-15 | Orexo Ab | Schnell wirkende pharmazeutische zusammensetzung |
US20040208833A1 (en) | 2003-02-04 | 2004-10-21 | Elan Pharma International Ltd. | Novel fluticasone formulations |
US8012505B2 (en) | 2003-02-28 | 2011-09-06 | Alk-Abello A/S | Dosage form having a saccharide matrix |
US20040265375A1 (en) | 2003-04-16 | 2004-12-30 | Platteeuw Johannes J. | Orally disintegrating tablets |
DE602005014227D1 (de) | 2004-03-10 | 2009-06-10 | Bayer Schering Pharma Ag | Zusammensetzungen aus drospirenon in molekularer dispersion |
US8545881B2 (en) | 2004-04-19 | 2013-10-01 | Eurand Pharmaceuticals, Ltd. | Orally disintegrating tablets and methods of manufacture |
EP1634586B1 (en) | 2004-09-09 | 2007-02-14 | Laboratorio Medinfar-Produtos Farmaceuticos, S.A. | Fast water-dispersible domperidone tablets |
US20060105038A1 (en) | 2004-11-12 | 2006-05-18 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions prepared by coacervation |
US20070020330A1 (en) | 2004-11-24 | 2007-01-25 | Medpointe Healthcare Inc. | Compositions comprising azelastine and methods of use thereof |
US20060292099A1 (en) | 2005-05-25 | 2006-12-28 | Michael Milburn | Treatment of eye disorders with sirtuin modulators |
US8497258B2 (en) * | 2005-11-12 | 2013-07-30 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
US8679545B2 (en) | 2005-11-12 | 2014-03-25 | The Regents Of The University Of California | Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract |
US8324192B2 (en) | 2005-11-12 | 2012-12-04 | The Regents Of The University Of California | Viscous budesonide for the treatment of inflammatory diseases of the gastrointestinal tract |
CN1985799B (zh) * | 2005-12-19 | 2011-11-09 | 量子高科(北京)研究院有限公司 | 口腔崩解制剂的制备方法 |
BRPI0620578A2 (pt) | 2005-12-27 | 2011-12-06 | Jubilant Organosys Ltd | composição farmacêutica que dissolve na boca e processo para o preparo da mesma |
US20080260655A1 (en) * | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
EP1958613A1 (en) | 2007-02-15 | 2008-08-20 | Polichem S.A. | Dermal film-forming liquid formulations for drug release to skin |
EP2148659A2 (en) | 2007-04-13 | 2010-02-03 | Somaxon Pharmaceuticals, Inc. | Low-dose doxepin formulations |
US20150231156A1 (en) | 2007-11-13 | 2015-08-20 | Meritage Pharma, Inc. | Corticosteroid compositions |
US20100216754A1 (en) | 2007-11-13 | 2010-08-26 | Meritage Pharma, Inc. | Compositions for the treatment of inflammation of the gastrointestinal tract |
MX349677B (es) | 2007-11-13 | 2017-08-08 | Meritage Pharma Inc | Composiciones corticosteroides. |
US20090123551A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Gastrointestinal delivery systems |
CA2708152A1 (en) * | 2007-12-10 | 2009-06-18 | Eurand, Inc | Orally disintegrating tablets comprising diphenhydramine |
JP2009173552A (ja) * | 2008-01-21 | 2009-08-06 | Lion Corp | 胃腸薬 |
SE533435C2 (sv) | 2008-04-03 | 2010-09-28 | Hm Power Ab | Vridmomentsöverförande arrangemang vid ett vindkraftverk |
PL2151235T3 (pl) | 2008-07-21 | 2011-05-31 | Dr Falk Pharma Gmbh | Preparat farmaceutyczny do leczenia górnego przewodu pokarmowego |
US20100034894A1 (en) | 2008-08-08 | 2010-02-11 | Szymczak Christopher E | Use of Sucralose as a Granulating Agent |
HUE051538T2 (hu) | 2008-08-20 | 2021-03-01 | Univ California | Kortikoszteroidok a gyomor-bél traktus gyulladásos betegségeinek kezelésére |
US20110097401A1 (en) | 2009-06-12 | 2011-04-28 | Meritage Pharma, Inc. | Methods for treating gastrointestinal disorders |
ES2742525T3 (es) | 2009-10-01 | 2020-02-14 | Adare Pharmaceuticals Us L P | Composiciones de corticosteroides administradas oralmente |
US20120282335A1 (en) | 2010-12-02 | 2012-11-08 | Aptalis Pharmatech Inc. | Rapidly dispersing granules, orally disintegrating tablets and methods |
WO2015034678A2 (en) | 2013-09-06 | 2015-03-12 | Aptalis Pharmatech, Inc. | Corticosteroid containing orally disintegrating tablet compositions for eosinophilic esophagitis |
SI2886108T2 (sl) | 2013-12-23 | 2023-02-28 | Dr. Falk Pharma Gmbh | Optimizirana farmacevtska formulacija za zdravljenje vnetnih sprememb požiralnika |
US10294517B2 (en) | 2014-03-17 | 2019-05-21 | Children's Hospital Medical Center | Genetic test for determining susceptibility for eosinophilic esophagitis |
US10176301B2 (en) | 2014-09-11 | 2019-01-08 | Meritage Pharma, Inc. | Systems, methods, and software for providing a patient-reported outcome measure of dysphagia patients with eosinophilic esophagitis |
US9980975B2 (en) | 2015-01-22 | 2018-05-29 | Ems S.A. | Dosage forms containing fluticasone propionate for the treatment of inflammatory conditions of the esophagus |
TWI728172B (zh) * | 2016-08-18 | 2021-05-21 | 美商愛戴爾製藥股份有限公司 | 治療嗜伊紅性食道炎之方法 |
CN112334189A (zh) | 2018-02-21 | 2021-02-05 | 美国阿代尔制药公司 | 管理嗜酸细胞性食管炎的方法 |
US20220347189A1 (en) | 2019-10-01 | 2022-11-03 | Ellodi Pharmaceuticals, L.P. | Methods of treating eosinophilic esophagitis and reducing candidiasis |
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Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1027864A (en) * | 1972-12-09 | 1978-03-14 | Hoechst Aktiengesellschaft | Orally administrable corticosteroid preparations |
CN1186428A (zh) * | 1995-04-13 | 1998-07-01 | 阿斯特拉公司 | 适于吸入使用的颗粒的制备方法 |
US20040106663A1 (en) * | 2002-09-06 | 2004-06-03 | Talley John Jeffrey | Inhibitors of fungal invasion |
US20050009848A1 (en) * | 2003-07-10 | 2005-01-13 | Icn Pharmaceuticals Switzerland Ltd. | Use of antivirals against inflammatory bowel diseases |
US20070059361A1 (en) * | 2005-09-09 | 2007-03-15 | University Of Manitoba | Fast-disintegrating epinephrine tablets for buccal or sublingual administration |
US20090123550A1 (en) * | 2007-11-13 | 2009-05-14 | Meritage Pharma, Inc. | Corticosteroid compositions |
US20090169620A1 (en) * | 2007-12-21 | 2009-07-02 | Venkatesh Gopi M | Orally disintegrating tablet compositions of temazepam |
Non-Patent Citations (2)
Title |
---|
BOWER,等: "Manifestations and Treatment of Laryngeal Sarcoidosis", 《THE AMERICAN REVIEW OF RESPIRATORY DISEASE》 * |
JULIE L. WEI MD,等: "Efficacy of Single-Dose Dexamethasone as Adjuvant Therapy for Acute Pharyngitis", 《THE LARYNGOSCOPE》 * |
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