CN113438941A - 可口制剂 - Google Patents
可口制剂 Download PDFInfo
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- CN113438941A CN113438941A CN202080015345.8A CN202080015345A CN113438941A CN 113438941 A CN113438941 A CN 113438941A CN 202080015345 A CN202080015345 A CN 202080015345A CN 113438941 A CN113438941 A CN 113438941A
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Abstract
本发明涉及一种软咀嚼组合物,其包含或含有治疗有效量的兽用活性剂,优选JAK抑制剂;动物基增味剂、非动物基增味剂、风味改良剂和至少一种选自崩解剂、粘合剂、润滑剂、湿润剂和助流剂中至少各一种的兽用可接受的赋形剂;并且其中用旋转式压片机压制软咀嚼片;以及用于治疗或预防动物中癌症、哮喘、特应性皮炎、自身免疫性障碍、与过敏性皮炎相关的瘙痒、过敏和慢性呼吸道疾病的方法。
Description
技术领域
本发明描述了一种稳定、可口的软咀嚼组合物,其包含至少一种兽用可接受的活性成分、至少一种动物基增味剂(palatant)、至少一种非动物基增味剂和至少一种另外的兽用可接受的赋形剂;以及用于治疗和/或预防多种疾病的使用方法,所述疾病包括但不限于癌症、心血管疾病、过敏、哮喘和其他呼吸道疾病、自身免疫性疾病、炎性疾病、骨疾病和其他代谢障碍。软咀嚼片在无需挤出的情况下制备并且使用旋转式压片机压制。
背景技术
蛋白激酶是催化蛋白质中特定残基的磷酸化的酶家族,被广泛分为酪氨酸和丝氨酸/苏氨酸激酶。由突变、过度表达或不适当的调节、反调节(dis-regulation)或去调节,以及生长因子或细胞因子的过度产生或不足产生引起的不适当的激酶活性与多种疾病有关,包括但不限于癌症、过敏、哮喘和其他呼吸道疾病、自身免疫性疾病和炎性疾病。不适当的激酶活性引发与细胞生长、细胞分化、存活、凋亡、有丝分裂、细胞周期控制和细胞迁移有关的多种生物细胞反应。
因此,蛋白激酶已经成为一类重要的酶,作为用于治疗干预的靶点。特别是,细胞蛋白酪氨酸激酶的JAK家族(JAK-1、JAK-2、JAK-3和Tyk-2)在细胞因子信号传导中起核心作用(Kisseleva等人,《基因(Gene)》,2002,285,1;Yamaoka等人《基因组生物学(GenomeBiology)》2004,5,253))。在与受体结合时,细胞因子激活JAK,然后使细胞因子受体磷酸化,从而为信号传导分子(特别是最终导致基因表达的信号转导和转录激活因子(STAT)的家族成员)创造停靠位点。已知多种细胞因子激活JAK家族。
将药物(即,活性剂)配制成可食用的药物(诸如可口的可咀嚼剂型)可以增加受试者对药物的接受度,尤其是倾向于抵制吞咽片剂或胶囊和咀嚼苦味和/或颗粒状剂型的动物。调味剂和聚合物包衣通常用于为剂型提供一定程度的适口性。可咀嚼组合物可以通过将活性兽用成分与油、脂肪、蜡和水制粒以制备用于挤出工艺的面团状组合物来制备。然而,这些组合物倾向于是油性和粘性的。其他可咀嚼组合物可以以类似的方式制备,但是将面团擀成不同厚度的薄片,并且然后冲切成合适的大小。本发明获得了一种可口的软咀嚼组合物,其可以通过旋转压制被压制成片剂。
先前已经描述了软咀嚼物。然而,现有的可口片剂已经通过以下制备:使用非动物基增味剂(WO2004/016252)、使用部分预胶化的淀粉(WO2005/013714);含有5-30%重量的脂肪、蜡和油的制剂(WO2014/033230),其倾向于赋予片剂“油腻”感;在低剪切条件下将API(含有油或不含油)与干的赋形剂混合,并且其中每个工艺步骤针对热不稳定活性物在不引入热的情况下进行(WO2007/067582);形成用于用旋转模塑机压制的面团状组合物(WO2014/079825);使用糖(5-75%)作为甜味填充剂(WO2004/014143);以及制造包含5-20%的油和5-20%的甘油的软(<2kp)片剂(WO2017/106812)。本发明的组合物不掺入脂肪、油、预胶化的淀粉、糖等;而是制备普通的混合和研磨的颗粒,其可以使用旋转式压片机被容易地压制成片剂。
发明内容
根据本发明,已经发现本发明的口服组合物是稳定、可口、安全且有效的。提高的稳定性与增加的保存期相关,并且最佳地与疗效相关,而适口性提高了患者的依从性。此外,可以使用旋转式压片机对颗粒进行压制。
在一个方面中,本发明描述了软咀嚼兽用组合物,其包含或含有兽用活性成分;至少一种动物基增味剂,至少一种非动物基增味剂;和至少一种兽用可接受的赋形剂。在另一个方面中,至少一种兽用可接受的赋形剂包括崩解剂、粘合剂、湿润剂、助流剂和润滑剂中的至少各一种;并且其中该组合物用旋转式压片机压制。
在一个方面中,本发明描述了软咀嚼兽用组合物,其包含或含有兽用活性成分,其中该活性成分是JAK抑制剂,至少一种动物基增味剂、至少一种非动物基增味剂和至少一种兽用可接受的赋形剂,该赋形剂包含崩解剂、粘合剂、湿润剂、助流剂和润滑剂中的至少各一种;并且其中该组合物用旋转式压片机压制。
在一个方面中,本发明描述了软咀嚼兽用组合物,其包含或含有兽用活性成分,其中该活性成分是JAK抑制剂、奥拉替尼(oclacitinib)、N-甲基-1-{反式-4-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]环己基}-甲磺酰胺或其兽用可接受的盐;至少一种动物基增味剂、至少一种非动物基增味剂和至少一种兽用可接受的赋形剂。在另一个方面中,活性成分是马来酸奥拉替尼(N-甲基-1-{反式-4-[甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基]环己基}-甲磺酰胺(2Z)-2-丁烯二酸盐(马来酸盐)),并且该组合物包含至少一种动物基增味剂、至少一种非动物基增味剂和至少一种兽用可接受的赋形剂,该赋形剂选自崩解剂、粘合剂、湿润剂、助流剂和润滑剂中的至少各一种。在一个方面中,马来酸奥拉替尼的量为片剂总重量的约4重量/重量%至5重量/重量%。在一个方面中,马来酸奥拉替尼的量为片剂总重量的约4重量/重量%(4.03重量/重量%)。
在本发明的另一个方面中,该组合物包含或含有约55重量/重量%至约70重量/重量%的量的至少两种增味剂,包括一种动物基增味剂和一种非动物基增味剂。在本发明的另一个方面中,动物基增味剂的量为片剂总重量的约45重量/重量%至约55重量/重量%。在另一个方面中,动物基增味剂的量为片剂总重量的约46重量/重量%至约52重量/重量%。动物基增味剂的优选的量为片剂总重量的约48重量/重量%至约50重量/重量%。优选的动物基增味剂来自猪(猪)。更优选的动物基增味剂来自猪肝。最优选的动物基增味剂是猪肝粉。在本发明的另一个方面中,非动物基增味剂的量为片剂总重量的约10重量/重量%至约15重量/重量%。在另一个方面中,非动物基增味剂的优选的量为片剂总重量的约11重量/重量%至约14重量/重量%。优选的非动物基增味剂是酵母。优选的酵母是啤酒酵母。在本发明的另一个方面中,该组合物包含约46重量/重量%至约52重量/重量%的动物基增味剂和约11重量/重量%至约14重量/重量%的非动物基增味剂,两者均占片剂总重量的重量/重量%。
在本发明的另一个方面中,该组合物包含或含有占片剂总重量约0.4重量/重量%至约0.6重量/重量%的风味改良剂。优选的风味改良剂是氯化钠或氯化钾。优选的风味改良剂是氯化钠。
在本发明的另一个方面中,该组合物进一步包含或含有至少一种选自崩解剂、粘合剂、湿润剂、润滑剂和助流剂中的至少各一种的兽用可接受的赋形剂。
在本发明的一个方面中,至少一种崩解剂的量为片剂总重量的约8重量/重量%至约18重量/重量%。在又一个方面中,至少一种崩解剂的量为片剂总重量的约10重量/重量%至约15重量/重量%。在一个方面中,崩解剂选自由交联聚维酮、羧基乙酸淀粉钠或其混合物组成的组。在另一个方面中,崩解剂是硬脂酸镁和单硬脂酸甘油酯的混合物。
在本发明的又一个方面中,至少一种粘合剂的量为片剂总重量的约5重量/重量%至约7重量/重量%。在另一个方面中,粘合剂的量为片剂总重量的约5重量/重量%至约6.5重量/重量%。在一个方面中,至少一种粘合剂选自由聚乙二醇、树胶或其混合物组成的组。优选的聚乙二醇是聚乙二醇3350;并且优选的树胶是黄原胶。在一个方面中,该组合物包含或含有聚乙二醇3350和黄原胶的混合物。在一个方面中,聚乙二醇3350的量为片剂总重量的约5重量/重量%至约6重量/重量%。
在本发明的另一个方面中,至少一种湿润剂的量为片剂总重量的约10重量/重量%至约15重量/重量%。在另一个方面中,湿润剂的量为片剂总重量的约11重量/重量%至约14重量/重量%。在一个方面中,湿润剂是甘油。
在本发明的另一个方面中,至少一种润滑剂为片剂总重量的约1重量/重量%至约2重量/重量%。在另一个方面中,润滑剂选自由硬脂酸镁、单硬脂酸甘油酯或其混合物组成的组。在另一个方面中,润滑剂是硬脂酸镁和单硬脂酸甘油酯的混合物。
在本发明的另一个方面中,至少一种助流剂的量为片剂总重量的约1重量/重量%至约3重量/重量%。助流剂的优选的量为片剂总重量的约1.5重量/重量%至约2.5重量/重量%。在一个方面中,助流剂是胶体二氧化硅。
在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的动物基增味剂;约11重量/重量%至约14重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;11重量/重量%至约14重量/重量%的量的至少一种湿润剂,约1重量/重量%至约3重量/重量%的量的至少一种助流剂,以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量。在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的动物基增味剂;约11重量/重量%至约14重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;11重量/重量%至约14重量/重量%的量的至少一种湿润剂,约1重量/重量%至约3重量/重量%的量的至少一种助流剂,以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。
在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的为猪肝粉的动物基增味剂;约11重量/重量%至约14重量/重量%的量的为啤酒酵母的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的为氯化钠的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂,其为交联聚维酮和羧基乙酸淀粉钠的混合物;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂,其为聚乙二醇3350和黄原胶的混合物;约11重量/重量%至约14重量/重量%的量的为甘油的湿润剂;约1重量/重量%至约3重量/重量%的量的为胶体二氧化硅的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂,其为单硬脂酸甘油酯和硬脂酸镁的混合物;并且其中每个重量/重量%都是基于片剂总重量。在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的为猪肝粉的动物基增味剂;约11重量/重量%至约14重量/重量%的量的为啤酒酵母的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的为氯化钠的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂,其为交联聚维酮和羧基乙酸淀粉钠的混合物;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂,其为聚乙二醇3350和黄原胶的混合物;约11重量/重量%至约14重量/重量%的量的为甘油的湿润剂;约1重量/重量%至约3重量/重量%的量的为胶体二氧化硅的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂,其为单硬脂酸甘油酯和硬脂酸镁的混合物;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。
在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约48重量/重量%至约50重量/重量%的量的为猪肝粉的动物基增味剂;约11重量/重量%至约14重量/重量%的量的为啤酒酵母的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的为氯化钠的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂,其为交联聚维酮和羧基乙酸淀粉钠的混合物;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂,其为聚乙二醇3350和黄原胶的混合物;约11重量/重量%至约14重量/重量%的量的为甘油的湿润剂;约1.5重量/重量%至约2.5重量/重量%的量的为胶体二氧化硅的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂,其为单硬脂酸甘油酯和硬脂酸镁的混合物;并且其中每个重量/重量%都是基于片剂总重量。在本发明的又一个方面中,是一种可口的软咀嚼片兽用组合物,其含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约48重量/重量%至约50重量/重量%的量的为猪肝粉的动物基增味剂;约11重量/重量%至约14重量/重量%的量的为啤酒酵母的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的为氯化钠的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂,其为交联聚维酮和羧基乙酸淀粉钠的混合物;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂,其为聚乙二醇3350和黄原胶的混合物;约11重量/重量%至约14重量/重量%的量的为甘油的湿润剂;约1.5重量/重量%至约2.5重量/重量%的量的为胶体二氧化硅的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂,其为单硬脂酸甘油酯和硬脂酸镁的混合物;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。
在本发明的又一个方面中,是一种通过口服施用软咀嚼片组合物来治疗或预防伴侣动物中癌症、哮喘、特应性皮炎、自身免疫性障碍、与过敏性皮炎相关的瘙痒、过敏和慢性呼吸道疾病的方法,该软咀嚼片组合物包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的动物基增味剂;约11重量/重量%至约14重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;约11重量/重量%至约14重量/重量%的量的湿润剂;约1重量/重量%至约3重量/重量%的量的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。
优选地,该组合物用于治疗和预防伴侣动物中特应性皮炎、与过敏性皮炎相关的瘙痒和过敏。优选地,伴侣动物是犬或马。
在本发明的又一个方面中,是软咀嚼片组合物用于通过将软咀嚼片组合物口服施用给有需要的伴侣动物来治疗或预防伴侣动物中癌症、哮喘、特应性皮炎、自身免疫性障碍、与过敏性皮炎相关的瘙痒、过敏和慢性呼吸道疾病的用途,该软咀嚼片组合物包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的动物基增味剂;约11重量/重量%至约14重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;11重量/重量%至约14重量/重量%的量的湿润剂;约1重量/重量%至约3重量/重量%的量的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。优选地,该用途用于治疗和预防伴侣动物中特应性皮炎、与过敏性皮炎相关的瘙痒和过敏。优选的伴侣动物是犬或马。
在本发明的又一个方面中,是软咀嚼片组合物用于制备用于治疗或预防伴侣动物中癌症、哮喘、特应性皮炎、自身免疫性障碍、与过敏性皮炎相关的瘙痒、过敏和慢性呼吸道疾病的药物中的用途,该软咀嚼片组合物包含或含有治疗有效量的约4重量/重量%至约5重量/重量%的量的马来酸奥拉替尼;约46重量/重量%至约52重量/重量%的量的动物基增味剂;约11重量/重量%至约14重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约10重量/重量%至约15重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;约11重量/重量%至约14重量/重量%的量的湿润剂;约1重量/重量%至约3重量/重量%的量的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量;并且其中片剂用旋转式压片机压制。优选地,用于治疗和预防伴侣动物中特应性皮炎、与过敏性皮炎相关的瘙痒和过敏。优选的伴侣动物是犬或马。
在本发明的又一个方面中,是一种为伴侣动物准备软食物的软咀嚼组合物,该软咀嚼组合物包含或含有约45重量/重量%至约55重量/重量%的量的动物基增味剂;约10重量/重量%至约15重量/重量%的量的非动物基增味剂;约0.4重量/重量%至约0.6重量/重量%的量的风味改良剂;约8重量/重量%至约18重量/重量%的量的至少一种崩解剂;约5重量/重量%至约7重量/重量%的量的至少一种粘合剂;约10重量/重量%至约15重量/重量%的量的湿润剂;约1重量/重量%至约3重量/重量%的量的助流剂;以及约1重量/重量%至约2重量/重量%的量的至少一种润滑剂;并且其中每个重量/重量%都是基于片剂总重量;并且其中所述食物用旋转式压片机压制。
定义
出于本发明的目的,如本文所描述和要求保护的,以下术语和短语定义如下:
除非另有说明,否则如本文所使用的“动物”是指非人脊椎动物,它们是动物学分类的成员。动物的非排他性示例包括伴侣动物和家畜。伴侣动物的非排他性示例包括:犬(犬科动物)、猫(猫科动物)和马(马科动物)。优选的伴侣动物是犬和猫。更优选的是犬。家畜的非排他性示例包括:猪、山羊、绵羊和牛。该术语还指其他动物,例如鹿、雪貂、豚鼠、兔子、动物园动物(例如,熊、大型猫、骆驼、袋鼠等)。
除非另有说明,否则如本文所使用的“至少一种”是指一种或多种药剂,例如,至少一种兽用可接受的赋形剂是指一种赋形剂;它也指2种赋形剂、3种赋形剂、4种赋形剂等。
除非另有说明,否则如本文所使用的“本发明的组合物”或“组合物”是指一种稳定、可口、柔软的可咀嚼组合物,其旨在用于口服施用给动物,优选地犬科动物、猫科动物或马科动物。
除非另有说明,否则如本文所使用的“治疗有效量”是指治疗、预防、减轻、改善、延迟或消除被治疗的动物的一种或多种症状的活性剂或活性剂的组合的量。
除非另有说明,否则如本文所使用的“治疗(treatment、treating)”等是指逆转、减轻或抑制例如瘙痒、哮喘、过敏性皮炎等。如本文所使用的,根据动物的状况,这些术语还包括预防障碍或病症的发作,或与障碍或病症相关的症状的发作,包括在所述病症折磨之前降低障碍或病症或与其相关的症状的严重程度。因此,治疗可以指将组合物与至少一种兽药一起施用给在施用时未受所述病症折磨的动物。治疗还包括预防与其相关的症状的复发。
除非另有说明,否则如本文所使用的“兽用可接受的”表示该物质或组合物在化学上和/或在毒理学上与包含制剂、组合物和/或用其治疗的动物的其他成分相容。
如本文所使用的,组合物的组分的百分比是指咀嚼片的总重量的百分比,并且被称为“%重量/重量”或“重量/重量%”,其定义了以百分比表示的组合物组分的质量分数,根据mi/mtot x 100确定,其中mi是组合物中存在的目标物质的质量,并且mtot是组合物的总质量。重量/重量%还定义了制粒混合物中活性成分或其他组成组分的量,例如咀嚼制粒中增味剂的量。
具体实施方式
本发明提供了一种稳定、可口、柔软的可咀嚼组合物,用于口服施用治疗有效量的兽用可接受的活性剂,并且其中所述咀嚼片在旋转式压片机上压制。
压片机是一种将粉末(即颗粒和/或混合物)压制成均匀大小和重量的片剂的机械装置。为了形成片剂,粒状材料必须被计量到由两个冲头和模具形成的空腔中,并且然后冲头必须以很大的力压在一起以将材料熔合在一起。片剂通过两个冲头和模具的联合压制作用来形成。在典型操作的第一步中,底部冲头在模具中下降,形成空腔,粒状原料被送入该空腔中。可以精确地控制下冲头的准确深度,以计量填充该空腔的粉末的量。多余的部分从模具的顶部刮下,并且下冲头被拉下并暂时盖住以防止溢出。然后,随着盖子被移除,上冲头向下与粉末接触。压制的力由高压压辊传递,压辊将粒状材料一起熔合成硬化的片剂。在压制后,使下冲头升起以弹出片剂。
存在两种类型的压片机:单冲头压片机和旋转式压片机。大多数高速压片机采用旋转转塔的形式,其可以容纳任意数量的冲头。当它们围绕转塔旋转时,冲头与控制冲头的垂直位置的凸轮接触。冲头和模具通常是为每个应用定制的,并且可以被制成各种大小、形状,并且可以用制造商代码和划线定制。根据片剂的大小、形状、材料和压机配置,典型的现代压机每小时可以生产250,000至超过1,000,000个片剂。常见的压片机的制造商包括Natoli、Stokes、Fette Compacting、Korsch、Kikusui、Manesty、B&D、PTK、IMA和Courtoy。
软咀嚼片通常是通过混合和挤出、混合和击打以及使用注射模具,使用蜡状、油性面团来制造的。为了挤出,将预混合的成分引入到其中具有单螺杆或双螺杆的挤出机机筒中,然后混合、凝结、膨胀和剪切成混合的混合物,随后施加额外的热量或水以用于适当的挤出。然后将混合和挤出的混合物在模板上形成为所需的形状,并切成单独的单元。来自不同批次的挤出材料的咀嚼物的质地、形状和重量可能不一致,并且倾向于缺乏效率。
旋转式模制机(例如,Formax公司(Formax Corporation)的Formax F6TM)通过在旋转模具辊之间移动面团并在没有冲压机构的情况下从模具中取出来工作。注射模制包括高压和潜在的高温,将原材料注射到模具中,模具将材料成型为任何所需的形状。它最常用于大规模生产过程中,在这种过程中,同一零件被连续生产数千次或者甚至数百万次。模具可以是单腔的或多腔的。在多腔模具中,每个腔可以是相同的并形成相同的零件,或者可以是独特的并在单个循环期间形成多个不同的几何形状。通常,最终产品必须从模具中移出。挤出机、成型机和旋转式模制机的使用存在与最终剂型的重量和物理形式有关的问题。此外,这种技术的使用可能需要调节最终剂型(例如干燥或固化最终形成的结构),以用于巩固所形成结构的形状和结构。此类技术、设备和工艺的使用是复杂、繁琐的,并且在传统上不用于典型的药物口服固体剂型制造设备中。
如本文所述,稳定、可口、柔软的咀嚼片用标准旋转式压片机压制。
根据本发明,优选的兽用可接受的活性剂是奥拉替尼或其兽用可接受的盐。奥拉替尼是式1的化合物,
奥拉替尼的另外的兽用可接受的盐包括但不限于:乙酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、乙二磺酸盐、酮戊二酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、甘油磷酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、甲基磺酸盐、萘磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、蔗糖盐、硬脂酸盐、琥珀酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
Apoquel是一种Janus激酶抑制剂(JAK-i),其针对Janus激酶-1(JAK-1)、Janus激酶-2(JAK-2)和Janus激酶-3(JAK-3),并且特别是JAK-1有疗效。因此,它可用作癌症、哮喘、特应性皮炎、自身免疫性障碍、瘙痒控制、过敏、慢性呼吸道疾病和其他其中需要免疫抑制和/或免疫调节的适应症的治疗剂。优选的用途是用于控制与过敏性皮炎相关的瘙痒和控制伴侣动物,特别是犬的特应性皮炎。
因此,式1的化合物或其兽用可接受的盐和兽用组合物可以用于治疗多种病症或疾病,诸如:
-哮喘和其他阻塞性气道疾病,包括慢性或根深蒂固的哮喘、迟发型哮喘、气道高反应性、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、粉尘性哮喘、复发性气道阻塞和慢性阻塞肺病;
-自身免疫性疾病或障碍,包括被指定为单一器官或单一细胞型自身免疫性障碍的那些,例如自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、自身免疫性血小板减少症、交感性眼炎、溃疡性结肠炎和膜性肾小球疾病,被指定为涉及系统性自身免疫性障碍的那些,例如系统性红斑狼疮、系统性硬化症和大疱性类天疱疮、骨关节炎(即退行性关节疾病)、非侵蚀性免疫介导的多关节炎、创伤性关节炎和另外的自身免疫性疾病,其可以是基于O细胞(体液)或基于T细胞的,包括自身免疫性脱发和甲状腺炎;
-癌症或肿瘤,包括消化道/胃肠道癌、结肠癌、肝癌、皮肤癌(包括肥大细胞瘤和鳞状细胞癌)、乳房和乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性髓性白血病和慢性髓性白血病)、肾癌、肺癌、肌癌、骨癌、膀胱癌、脑癌、黑色素瘤(包括口腔和转移性黑色素瘤)、卡波西肉瘤、骨髓瘤(包括多发性骨髓瘤)、骨髓增生性障碍、增生性糖尿病视网膜病变和血管生成相关的障碍(包括实体瘤);
-眼部疾病、障碍或病症,包括眼部自身免疫性疾病、角膜结膜炎和干燥性角膜结膜炎(干眼症);
-肠道炎症、过敏或病症,包括溃疡性结肠炎、炎性肠病、腹腔疾病、直肠炎、嗜酸性胃肠炎和肥大细胞增多症;
-皮肤病、病症或障碍,包括特应性皮炎、湿疹、银屑病、硬皮病、瘙痒和其他瘙痒性病症;
-包括动物中过敏性皮炎的过敏反应,包括马过敏性疾病,诸如咬伤超敏、夏季湿疹和甜痒。
式1的化合物可以以兽用可接受的形式(例如软咀嚼片)单独施用,或者与一种或多种调节动物的免疫系统的附加药剂或抗炎药剂联合施用。这些药剂可以包括但不限于环孢菌素A、雷帕霉素、FK-506(他克莫司)、来氟米特、脱氧精胍菌素、霉酚酸酯、硫唑嘌呤、达普利珠单抗、阿司匹林、对乙酰氨基酚、布洛芬、萘普生、吡罗昔康和抗炎类固醇(例如泼尼松龙或地塞米松)。根据本领域技术人员已知的标准兽用实践,这些药剂可以作为相同剂型或单独剂型的一部分,通过相同或不同的施用途径并且以相同或不同的施用方案来施用。
根据本发明,除了之外,可以被配制成可口的软咀嚼组合物的其他兽用活性JAK抑制剂药剂包括:3-(3-((2-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)氨基)哌啶-1-基)-3-氧代丙腈和1-((3R,4S)-4-氰基四氢-2H-吡喃-3-基)-3-((2-氟-6-甲氧基吡啶-4-基)氨基)-1H-吡唑-4-甲酰胺。除了JAK抑制剂药剂之外,下列非限制性兽用活性剂可以与本发明的可口软咀嚼组合物一起配制,并且包括:抗微生物剂/抗菌剂(例如喹诺酮类、氟喹诺酮类、头孢菌素类(第1、2、3和4代)、四环素类、青霉素类、β-内酰胺类、大环内酯类、非尼考醇类、双羟萘酸噻嘧啶(双羟萘酸盐)、碳青霉烯类等);抗寄生虫药,包括异噁唑类似物(例如(S)-1-(5'-(5-(3,5-二氯-4-氟苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-3'H-螺[氮杂环丁烷-3,1'-异苯并呋喃]-1-基)-2-(甲基磺酰基)乙基-1-酮(sarolaner);4-(5-(3-氯-5-(三氟甲基)苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-N-(2-氧代-2-((2,2,2-三氟乙基)氨基)乙基)-1-萘酰胺(阿福拉纳(afoxolaner));4-(5-(3,5-二氯苯基)-5-(三氟甲基)-4,5-二氢异噁唑-3-基)-2-甲基-N-(2-氧代-2-((2,2,2-三氟乙基)氨基)乙基)-苯甲酰胺(氟雷拉纳(fluralaner));和3-甲基-N-{2-氧代-2-[(2,2,2-三氟乙基)氨基]乙基}-5-[(5S)-5-(3,4,5-三氯苯基)-5-(三氟甲基)-4,5-二氢-1,2-噁唑-3-基]噻吩-2-甲酰胺(洛替拉纳(lotilaner)));大环内酯类和米尔贝霉素(例如,多拉菌素、依普罗菌素、伊维菌素、莫西菌素、米尔贝霉素肟等);抗原生动物药(例如,甲硝唑、多西环素、氨丙啉、阿托伐醌、苯并咪唑等);抗真菌药(例如,酮康唑、氟康唑等);强心药(inotropes)(例如,匹莫苯(pimobendane));神经药物(例如,加巴喷丁、普瑞巴林、地西泮、苯巴比妥等);心血管药物(例如,ACE抑制剂(例如贝那普利、赖诺普利、喹那普利、雷米普利等)、β-阻断剂(例如,nadalol、美托洛尔、阿替洛尔、普萘洛尔等)和5HT2B抑制剂);NSAID和其他镇痛药(卡普罗芬、酮洛芬、地拉考昔、氟尼辛、尼美舒利、氟罗考昔、马伐考昔、罗贝考昔、美洛昔康、曲马多、金刚烷胺、地塞米松等);甲状腺药物(例如,左旋甲状腺素、甲巯咪唑等);类固醇(例如,泼尼松、泼尼松龙、地塞米松等);和行为调节剂和镇静剂(例如,地西泮、赛拉嗪、阿普唑仑、乙酰丙嗪、地托咪啶、阿米替林、氯米帕明、咪达唑仑等)。
在本发明的一个优选的方面中,该组合物包含或含有活性兽用药剂:马来酸奥拉替尼其量为片剂总重量的约4重量/重量%至约5重量/重量%。活性剂马来酸奥拉替尼的优选的量为约4重量/重量%(例如,4.03重量/重量%)。
本发明的组合物包含或含有至少一种动物基增味剂和一种非动物基增味剂。增味剂的量为片剂总重量的约55重量/重量%至约70重量/重量%。增味剂用于改变或增强天然食品(诸如肉类和蔬菜)的风味,或为没有所需风味的食品(诸如零食和口服药物)创造额外的风味。大多数类型的增味剂都集中在气味和味道上。人造增味剂是化学合成的化合物,其用于给食物调味,并且通常与在天然增味剂中发现的相同化合物一起配制。大多数人工香料是特定的并且通常是单一的天然存在的香料化合物的复杂混合物,以模仿或增强天然香料。这些混合物由风味学家配制,以赋予食品独特的风味,并且保持不同产品批次之间或在食谱改变后的风味一致性。已知调味剂的列表包括成千上万种分子化合物,并且可以被组合以获得像鸡肉、火鸡、牛肉、猪肉、羊肉、鱼、蛋、奶酪、海鲜、烟和多种其他的味道。天然增味剂被定义为精油、含油树脂、香精或提取物、蛋白质水解物、馏出物或任何烘焙、加热或酶解的产物,其含有来自香料、水果或果汁、蔬菜或蔬菜汁、可食用酵母(活性和非活性)、草药、树皮、芽、根、叶或植物、肉、海鲜、家禽、蛋、乳制品或其发酵产物的任何其他可食用部分的调味成分;并且可以包括甜味剂如蔗糖;其在食物中的主要功能是调味而不是营养。天然增味剂包括鸡肉、火鸡、牛肉、猪肉、羊肉、鱼、鸡蛋、奶酪、海鲜、蔬菜和植物物质、酵母(例如啤酒酵母)及其混合物。酵母提取物也被包含在天然香料中。风味(味道)调节剂,例如氯化钠、氯化钾,在本文中也被解释为增味剂。天然肉增味剂可以从肉、肉制品、器官肉、酵母提取物、植物物质及其混合物中获得。例如,口服兽用组合物药物可以包括基于动物产品的调味品,诸如干燥的或粉状的肉和肉部分,诸如牛肉、猪肉、鸡肉、火鸡、鱼和羊肉;器官肉,诸如肝脏和肾脏;肉粉、骨粉和碎骨;并且可以使用动物来源的食物,诸如酪蛋白、牛奶(其可以包括干形式和低脂肪形式,诸如干脱脂奶)、酸奶、明胶、奶酪和鸡蛋(统称为“动物源性调味品”)。天然产品可以或可以不通过加热或其他类型的辐射(例如γ辐射)来灭菌。用于稳定、可口、可咀嚼组合物的优选的增味剂是天然动物基增味剂。本发明的组合物包含或含有至少两种增味剂,其量为咀嚼片的总重量的约55重量/重量%至约70重量/重量%。该组合物包含或含有至少一种动物基增味剂,其量为片剂总重量的约45重量/重量%至约55重量/重量%。优选的动物基增味剂的量为片剂总重量的约46重量/重量%至约52重量/重量%。优选的动物基增味剂的量为片剂总重量的约48重量/重量%至50重量/重量%。优选的动物基增味剂来自器官肉。优选的器官肉来自猪肝。优选的动物基增味剂是猪肝粉。该组合物包含或含有占片剂总重量的约10重量/重量%至约15重量/重量%(优选地片剂总重量的约11重量/重量/%至约14重量/重量%)的非动物基增味剂。优选地,非动物基增味剂是酵母。优选的酵母是啤酒酵母。该组合物还包含或含有占片剂总重量的约0.4重量/重量%至约0.6重量/重量%的风味改良剂。优选的风味改良剂是氯化钠。该组合物包含或含有占片剂总重量的约48重量/重量%至约50重量/重量%的动物基增味剂;约11重量/重量%至约14重量/重量%的非动物基增味剂,并且其中重量/重量%基于片剂总重量。
该稳定、可口的咀嚼组合物包含或含有至少一种兽用可接受的赋形剂。兽用可接受的赋形剂包括被解释为粘合剂、崩解剂、润滑剂、助流剂、湿润剂、抗氧化剂和着色剂的赋形剂。该软咀嚼片包含或含有活性剂、马来酸奥拉替尼、动物基增味剂、非动物基增味剂、风味改良剂和粘合剂、崩解剂、湿润剂、润滑剂和助流剂中的至少各一种;并使用旋转式压片机压制。
粘合剂用于为组合物增加粘结性,从而提供必要的粘合以形成粘性物质并确保合适的压制片剂形式。这些粘合剂通常用于直接压制片剂,并且在Lieberman等人,《兽用剂型(Veterinary Dosage Forms)》第2版,第1卷,(1990)中描述。兽用可接受的粘合剂的非限制性示例包括但不限于:微晶纤维素、羧甲基纤维素、羧甲基纤维素钠、羟丙基纤维素、聚乙烯吡咯烷酮(例如,聚维酮(Kollidon 25、30和90)和共聚维酮(co-povidone)(Kollidon VA64)、聚乙二醇(PEG)、阿拉伯胶、玉米糖浆固体、黄蓍胶、黄原胶、明胶、巴西棕榈蜡、藻酸盐及其混合物。聚乙二醇(PEG)是一种具有多种应用的聚醚化合物,从工业生产到药物。根据其分子量,PEG也被称为聚环氧乙烷(PEO)或聚氧乙烯(POE)。PEG的结构通常被表示为H(OCH2CH2)nOH,其中n是≥3的整数。PEG通过环氧乙烷的聚合来制备,并且可在300g/mol至10,000,000g/mol的宽分子量范围内购得。PEG是市售的。n为9的PEG具有约400道尔顿(g/摩尔)的平均分子量并且被方便地标记为PEG 400。类似地,n为45的PEG具有约2000道尔顿的平均分子量并且被方便地标记为PEG 2000。PEG 3350是分子量为3350g/摩尔的PEG。它常用于制药和兽用行业。本发明的组合物包含或含有占片剂总重量的约5重量/重量%至约7重量/重量%的至少一种粘合剂。用于本发明的组合物的优选的粘合剂是PEG 3350。该组合物进一步包含或含有至少一种粘合剂,该粘合剂是选自由黄蓍胶、黄原胶、阿拉伯胶、纤维素胶、瓜尔胶、刺槐豆胶或其混合物组成的组的树胶,并且优选黄原胶,其量为片剂总重量的约0.3重量/重量%至约0.7重量/重量%,优选地为片剂总重量的约0.4重量/重量%至约0.6重量/重量%,并且更优选地为片剂总重量的约0.5重量/重量%。该组合物包含或含有占片剂总重量的约5重量/重量%至约6重量/重量%的PEG 3350。
该稳定、可口的组合物包含或含有至少一种兽用可接受的赋形剂,该赋形剂为崩解剂,从而为该剂型提供了在潮湿时更容易膨胀和溶解和/或在咀嚼时崩解的手段。崩解剂通常用于直接压制片剂并且在Lieberman等人,《兽用剂型》,第2版,第1卷,(1990)中描述。兽用可接受的崩解剂的非排他性示例包括:淀粉,包括预胶化的和改性的淀粉、微晶纤维素、甲基纤维素、羧甲基纤维素、羧甲基纤维素钠、交联聚维酮、硅酸铝镁、瓜尔胶、海藻酸、海藻酸钠、海藻酸钙、壳聚糖、交联羧甲基纤维素钠(例如,Ac-Di-)、羧基乙酸淀粉钠等,及其混合物。优选的崩解剂选自由淀粉、羧甲基纤维素钠、交联聚维酮、交联羧甲基纤维素钠和羧基乙酸淀粉钠及其混合物组成的组。更优选的崩解剂是羧基乙酸淀粉钠和交联聚维酮或其混合物。最优选的崩解剂是交联聚维酮和羧基乙酸淀粉钠的混合物。组合物中崩解剂的量为片剂总重量的约8重量/重量%至约18重量/重量%。组合物中崩解剂的优选的量为片剂总重量的约10重量/重量%至约15重量/重量%。该组合物包含或含有片剂总重量的约4重量/重量%至约9重量/重量%的交联聚维酮和片剂总重量的约4重量/重量%至约9重量/重量%的羧基乙酸淀粉钠。
该稳定、可口的组合物包含或含有至少一种为湿润剂的兽用可接受的赋形剂。湿润剂被认为是吸湿性的,因为它们赋予组合物水分。用于该组合物的湿润剂的非限制性示例包括但不限于:丙三醇(甘油)、透明质酸、山梨醇、尿素、α-羟基酸、糖、乳酸、丙二醇、三乙酸甘油酯、氯化锂、多元醇如山梨醇、木糖醇和麦芽糖醇、聚合物多元醇如聚葡萄糖、天然提取物如皂树皮、己二酸、乳酸、油酸、硬脂酸、异硬脂酸、肉豆蔻酸和亚油酸的十六烷基、肉豆蔻基、异癸基和异丙基酯,以及多种它们的相应的醇酯(例如异硬脂酰-2-乳酸钠,癸酰基乳酰乳酸钠)。优选的湿润剂是甘油,并且其量为片剂总重量的约10重量/重量%至约15重量/重量%。湿润剂的优选的量为片剂总重量的约11重量/重量%至约14重量/重量%。
该稳定、可口的组合物包含或含有至少一种为润滑剂的兽用可接受的赋形剂。润滑剂用于通过减少颗粒间的摩擦来增强产品流动,并防止组成成分聚集在一起并防止组成成分粘附在片剂冲头上。润滑剂还确保片剂的形成和排出可以在片剂与模具壁之间的低摩擦下进行。润滑剂的非限制性示例包括:滑石、硬脂酸镁、单硬脂酸甘油酯、硼酸、苯甲酸钠、油酸钠、乙酸钠、十二烷基硫酸钠、十二烷基硫酸镁及其混合物。优选的润滑剂包括滑石、硬脂酸镁和单硬脂酸甘油酯。更优选的润滑剂是硬脂酸镁、单硬脂酸甘油酯及其混合物。该组合物包含为润滑剂的单硬脂酸甘油酯和硬脂酸镁,其量为片剂总重量的约1重量/重量%至约2重量/重量%。
该稳定、可口的组合物包含或含有至少一种为助流剂的兽用可接受的赋形剂。助流剂用于通过减少颗粒间摩擦和内聚力来促进粉末流动。助流剂与润滑剂结合使用,因为它们不能减少模具壁的摩擦。示例包括气相二氧化硅、胶体二氧化硅、滑石和碳酸镁。优选的助流剂是胶体二氧化硅,并且其量为片剂总重量的约1重量/重量%至约3重量/重量%。组合物中助流剂的优选的量为片剂总重量的约1.5重量/重量%至约2.5重量/重量%。
该稳定、可口的组合物可以进一步包含或含有至少一种为抗氧化剂的兽用可接受的赋形剂。抗氧化剂的非排他性示例包括:抗坏血酸、维生素E(生育酚)、维生素E衍生物、偏亚硫酸氢钠、棕榈酸抗坏血酸酯、富马酸、柠檬酸、苹果酸、抗坏血酸钠、丁基化羟基茴香醚(BHA)和丁基化羟基甲苯(BHT)、没食子酸丙酯、硫代甘油等及其混合物。优选的抗氧化剂包括BHA、BHT、柠檬酸和没食子酸丙酯及其混合物。组合物中抗氧化剂的量可以在片剂总重量的约0重量/重量%至约0.05重量/重量%的范围内。
该稳定、可口的组合物还可以包含或含有至少一种为着色剂的兽用可接受的赋形剂。着色剂可以被添加到组合物中以增强其物理外观,并且其量可以是片剂总重量的约1重量/重量%(或更少)。
该稳定、可口的组合物是以普通混合物的形式制备的,该混合物可以用相同重量/重量%值的活性剂、增味剂和赋形剂压片成不同的片剂大小,这些可以通过常规的制粒、混合、研磨、过筛、压制和包装程序制造。
本发明的组合物可以通过用于制造普通混合物和通过旋转压制压片的已知方法来制备。
粘合剂溶液是通过将粘合剂PEG 3350与润滑剂(单硬脂酸甘油酯)和甘油在约90-100℃的温度下熔化和混合而制备以制备粘合剂溶液(A)。可替代地,可以制备含有溶解在甘油中的黄原胶的第二粘合剂溶液,以制备粘合剂溶液(B)。通过在高剪切造粒机中将活性剂(例如马来酸奥拉替尼)与增味剂、崩解剂、粘合剂(黄原胶)、风味改良剂和助流剂混合(共混)并造粒来制备活性调味干混颗粒。将干混合物研磨,并且然后与粘合剂溶液(A)混合,以制备湿颗粒。可替代地,在添加之前,首先将活性调味干混颗粒与一部分甘油混合,并进一步与粘合剂溶液(A)混合,以制备湿颗粒。此外,活性调味干混颗粒(不含粘合剂)可以与粘合剂溶液(A)和(B)混合以制备湿颗粒。将湿颗粒研磨,并且然后在流化床干燥器中在约45℃至65℃下固化约1至3小时。通过将组分混合在一起并且然后研磨来制备包含助流剂、增味剂和崩解剂的颗粒外组合物。将固化的活性调味颗粒和颗粒外组合物在低剪切箱式搅拌器中混合在一起,并将润滑剂筛入混合物中。然后使用旋转式压片机压制最终的混合物。将最终的片剂包装在HDPE瓶和/或泡罩中。
成品片剂包含片剂总重量的约4.03重量/重量%的马来酸奥拉替尼。根据片剂大小,优选的片剂强度为每片3.6mg、5.4mg和16.0mg奥拉替尼。此外,通过在压缩期间改变片剂模具的尺寸,片剂可以被制备成具有1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、7、18、19、20、21、22、23、24、25mg等的奥拉替尼,包括额外的分数量,例如2.5、7.7、12.3、16.6、22.3等,因为该组合物是普通的混合物。
奥拉替尼在犬体内的治疗有效剂量为0.4至0.6mg/kg体重,口服施用,每天两次,持续达14天,并且然后每天施用一次,用于维持疗法。根据犬的体重,可以施用单个咀嚼片,或者可以施用多个片剂,以确保对于较大的品种犬,施用有效的mg/kg剂量。此外,可以向猫、马和其他动物施用适当的剂量;这些剂量可能不同,并且可能在0.1至1mg/kg体重的范围内,这取决于动物和奥拉替尼在非犬科动物体内的半衰期药代动力学。
在表1中示出了来自普通混合物apoquel咀嚼组合物的平均片剂加工结果。
表1:来自Apoquel普通混合物的片剂加工结果
^(在100旋转时的%重量/重量)
组成实例
通过以下实例来进一步描述本发明,这些实例进一步说明了本发明,并且不旨在也不应该被解释为限制本发明的范围。
实例1.片剂组合物1
赋形剂/活性物质 | 总片剂的重量/重量% |
马来酸奥拉替尼 | 4.03 |
动物基增味剂 | 48.64 |
非动物基增味剂 | 13.13 |
崩解剂 | 11.40 |
助流剂 | 2.11 |
润滑剂 | 1.34 |
粘合剂 | 6.07 |
湿润剂 | 12.72 |
风味改良剂 | 0.56 |
总计 | 100 |
实例2.片剂组合物2
赋形剂/活性物质 | 总片剂的重量/重量% |
马来酸奥拉替尼 | 4.03 |
动物基增味剂 | 48.64 |
非动物基增味剂 | 11.63 |
崩解剂 | 12.90 |
助流剂 | 2.11 |
润滑剂 | 1.34 |
粘合剂 | 6.07 |
湿润剂 | 12.72 |
风味改良剂 | 0.56 |
总计 | 100 |
实例3.片剂组合物3
赋形剂/活性物质 | 总片剂的重量/重量% |
马来酸奥拉替尼 | 4.03 |
动物基增味剂 | 48.64 |
非动物基增味剂 | 13.63 |
崩解剂 | 11.4 |
助流剂 | 1.61 |
润滑剂 | 1.34 |
粘合剂 | 6.07 |
湿润剂 | 12.72 |
风味改良剂 | 0.56 |
总计 | 100 |
实例4.片剂组合物4
赋形剂/活性物质 | 总片剂的重量/重量% |
马来酸奥拉替尼 | 4.03 |
动物基增味剂 | 46.2 |
非动物基增味剂 | 12.5 |
崩解剂 | 13.4 |
助流剂 | 1.85 |
润滑剂 | 1.70 |
粘合剂 | 6.4 |
湿润剂 | 13.5 |
风味改良剂 | 0.42 |
总计 | 100 |
实例5.片剂组合物5
赋形剂/活性物质 | 总片剂的重量/重量% |
马来酸奥拉替尼 | 4.03 |
动物基增味剂 | 48.1 |
非动物基增味剂 | 13.8 |
崩解剂 | 13.9 |
助流剂 | 1.55 |
润滑剂 | 1.04 |
粘合剂 | 5.2 |
湿润剂 | 11.8 |
风味改良剂 | 0.58 |
总计 | 100 |
生物性
制备了含有马来酸奥拉替尼的可口软咀嚼组合物,并且评估了适口性和稳定性。
适口性
为了评估适口性,将3-9岁的成熟比格犬(N=48)随机分配到2序列、2阶段交叉设计研究中。向动物提供安慰剂(T01)软咀嚼片或含有5.4mg的的试验软咀嚼片(T02-组合物1)。每组犬(N=24/组)每天单独口服一个片剂,持续连续3天。安慰剂(T01)和(T02)软咀嚼片的可接受性分别为79.9%和78.5%。
在另一项适口性研究中,将>1岁的混合品种犬(N=96)随机分配到4阶段交叉设计研究中。向动物提供安慰剂(T01)软咀嚼片或含有5.4mg的的试验软咀嚼片[T02-组合物1;T03-组合物2;和T04-组合物3]。每组犬(N=24/组)每天单独口服一个片剂,持续连续3天。安慰剂和软咀嚼片的可接受性为85%(T01)、84%(T02)、83%(T03)和83%(T04)。总体而言,含有奥拉替尼的组合物是可口的。
稳定性
对于3.6mg、5.4mg和16mg软咀嚼片,软咀嚼片在HDPE瓶中在40℃/75%相对湿度下在1个月和2个月内显示出是稳定的,其中测定(标签声明的%)结果在98.3至101.5%的范围内。
Claims (15)
1.一种可口的软咀嚼片兽用组合物,其包含:
a.治疗有效量的兽用活性剂;
b.至少一种动物基增味剂,其量为所述片剂总重量的约45重量/重量%至约55重量/重量%;
c.至少一种非动物基增味剂,其量为所述片剂总重量的约10重量/重量%至约15重量/重量%;
d.至少一种兽用可接受的赋形剂;并且
其中所述软咀嚼片用旋转式压片机压制。
2.根据权利要求1所述的组合物,其中所述兽用可接受的活性剂是奥拉替尼(oclacitinib),并且所述动物基增味剂是猪肝粉。
3.根据权利要求2所述的组合物,其中所述至少一种兽用可接受的赋形剂选自崩解剂、粘合剂、湿润剂、润滑剂、助流剂和风味改良剂中的至少各一种;并且其中所述非动物基增味剂是酵母。
4.根据权利要求3所述的组合物,其中所述兽用可接受的崩解剂是交联聚维酮、羧基乙酸淀粉钠或其混合物。
5.根据权利要求4所述的组合物,其中所述崩解剂是交联聚维酮和羧基乙酸淀粉钠的混合物,并且以所述片剂总重量的约10重量/重量%至约15重量/重量%的量组合。
6.根据权利要求3所述的组合物,其中所述兽用可接受的粘合剂包含聚乙二醇、树胶或其混合物。
7.根据权利要求6所述的组合物,其中所述聚乙二醇是聚乙二醇3350,并且所述树胶是黄原胶,并且其中所述聚乙二醇和所述树胶的混合物占所述片剂总重量的约5重量/重量%至约7重量/重量%。
8.根据权利要求3所述的组合物,其中所述兽用可接受的湿润剂是占所述片剂总重量的约10重量/重量%至约15重量/重量%的甘油。
9.根据权利要求3所述的组合物,其中所述兽用可接受的润滑剂是硬脂酸镁和单硬脂酸甘油酯的混合物,并且其中所述组合物包含约1重量/重量%至约3重量/重量%的助流剂和约0.4重量/重量%至约0.6重量/重量%的风味改良剂。
10.一种可口的软咀嚼片兽用组合物,其包含:
a.治疗有效量的马来酸奥拉替尼,其量为所述片剂总重量的约4重量/重量%至约5重量/重量%;
b.至少一种来源于猪肝的动物基增味剂;
c.至少一种为啤酒酵母的非动物基增味剂;
d.至少一种兽用可接受的赋形剂,崩解剂、粘合剂、湿润剂、润滑剂、助流剂和风味改良剂各一种;并且其中所述软咀嚼片用旋转式压片机压制。
11.根据权利要求10所述的组合物,其中所述猪肝是粉末状的,并且其量为所述片剂总重量的约46重量/重量%至约52重量/重量%,并且所述啤酒酵母的量为所述片剂总重量的约11重量/重量%至约14重量/重量%。
12.根据权利要求11所述的组合物,其中所述至少一种崩解剂选自由交联聚维酮、羧基乙酸淀粉钠或其混合物组成的组,并且其量为所述片剂总重量的约10重量/重量%至约15重量/重量%;所述至少一种粘合剂选自由聚乙二醇3350、黄原胶或其混合物组成的组,并且其量为所述片剂总重量的约5重量/重量%至约7重量/重量%;所述至少一种湿润剂是甘油,并且其量为所述片剂总重量的约11重量/重量%至约14重量/重量%;所述润滑剂选自由硬脂酸镁、单硬脂酸甘油酯或其混合物组成的组,并且其量为所述片剂总重量的约1重量/重量%至约2重量/重量%;所述至少一种助流剂是胶体二氧化硅,其量为所述片剂总重量的约1重量/重量%至约3重量/重量%;并且所述风味改良剂是氯化钠,其量为所述片剂总重量的约0.4重量/重量%至0.6重量/重量%
13.一种可口的软咀嚼片兽用组合物,其包含:
a.治疗有效量的马来酸奥拉替尼,其量为所述片剂总重量的约4重量/重量%;
b.增味剂的混合物,其量为所述片剂总重量的约55重量/重量%至约70重量/重量%,包含动物基增味剂和非动物基增味剂;
c.粘合剂的混合物,其量为所述片剂总重量的约5重量/重量%至约7重量/重量%,选自聚乙二醇3350和黄原胶;
d.崩解剂的混合物,其量为所述片剂总重量的约8重量/重量%至约18重量/重量%,包含交联聚维酮和羧基乙酸淀粉钠;
e.湿润剂甘油,其量为所述片剂总重量的约11重量/重量%至约14重量/重量%;
f.风味改良剂,其量为所述片剂总重量的约0.4重量/重量%至约0.6重量/重量%;
g.助流剂胶体二氧化硅,其量为所述片剂总重量的约1重量/重量%至约3重量/重量%;并且其中所述软咀嚼片在旋转式压片机上压制。
14.一种可口的软咀嚼片兽用组合物用于治疗或预防伴侣动物中癌症、哮喘、特应性皮炎、自身免疫性障碍、与过敏性皮炎相关的瘙痒、过敏和慢性呼吸道疾病的用途,所述组合物包含:
a.治疗有效量的奥拉替尼;
b.动物基增味剂、非动物基增味剂和风味改良剂;
c.和崩解剂、粘合剂、湿润剂、润滑剂和助流剂中的至少各一种;并且其中所述软咀嚼片在旋转式压片机上压制。
15.根据权利要求14所述的用途,用于治疗或预防其为犬的伴侣动物中与过敏性皮炎和特应性皮炎相关的瘙痒。
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EP3927315A1 (en) | 2021-12-29 |
MX2021010066A (es) | 2021-09-21 |
AU2020224102A1 (en) | 2021-08-19 |
BR112021016480A2 (pt) | 2021-10-13 |
JP2022521245A (ja) | 2022-04-06 |
AU2020224102C1 (en) | 2023-03-16 |
CL2021002192A1 (es) | 2022-04-01 |
NZ779157A (en) | 2023-10-27 |
ECSP21059181A (es) | 2021-11-30 |
CA3127621C (en) | 2024-05-14 |
CA3127621A1 (en) | 2020-08-27 |
KR20210114978A (ko) | 2021-09-24 |
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