CN107080846A - 用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统 - Google Patents
用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统 Download PDFInfo
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Abstract
本申请涉及用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统。提供了用于短半衰期化合物(例如抗糖尿病的依碳酸瑞格列净)的组合立即/延迟释放递送系统,其提供了具有两种不同释放相的剂型——一种制剂促进所述化合物在摄入后立即释放,而另一种制剂延迟所述化合物的释放,从而可实现每天一次的依碳酸瑞格列净给药方案,同时提供对血浆葡萄糖的有效控制并使所述化合物的夜间暴露尽可能小。所述递送系统包括但不限于立即释放制剂之肠溶包衣的组合,从而提供释放的延迟。还提供了用于形成所述立即/延迟释放递送系统并且使用所述递送系统用于治疗糖尿病的方法。
Description
本申请是申请日为2011年7月7日、申请号为“201180039967.5”、发明名称为“用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统”的中国专利申请的分案申请,原申请是国际申请PCT/US2011/043143的中国国家阶段申请。
技术领域
本发明涉及用于包括瑞格列净的短半衰期药物的组合立即/延迟释放递送系统。
背景技术
糖尿病的流行日益受到全世界人的关注。在2007年,约有2.46亿人受该疾病影响,并且每年有另外7百万人患上该疾病。估计到2025年将有3.8亿人患有糖尿病。
糖尿病是以高血糖为特征的代谢综合征,它由胰岛素分泌的绝对缺乏引起(1型糖尿病)或者由对胰岛素作用的抗性与胰岛素分泌的补偿性增加不充分组合引起(2型糖尿病)。慢性高血糖是微血管并发症(例如,视网膜病、肾病和神经病)的主要风险因素。如果采用较健康生活方式的尝试未能达到并维持目标血糖水平,则需要额外的治疗。
发明内容
本发明涉及用于短半衰期药物(例如抗糖尿病的依碳酸瑞格列净(remogliflozinetabonate))的新剂型,所述剂型提供立即释放的药物并且还提供延迟释放的第二批(bolus)药物,从而可实现每天一次至少250mg依碳酸瑞格列净的给药方案,同时提供对血浆葡萄糖的有效控制;并且本发明涉及采用这种剂型治疗糖尿病的方法。
附图说明
图1是本文所述药物组合物之片剂的横截面示意图。
图2是本文所述药物组合物之片剂的第二实施方案的横截面示意图。
图3是本文所述药物组合物之片剂的第三实施方案的横截面示意图。
图4是本文所述药物组合物之胶囊的横截面示意图。
缩写
SGLT(钠葡萄糖协同转运蛋白) A1C(血红蛋白A1C)
UKPDS(英国前瞻性糖尿病研究) HDL(高密度脂蛋白)
ADA(美国糖尿病协会) QD(每天一次)
BID(每天两次) T2DM(2型糖尿病)
GI(胃肠) GLP-1(胰高血糖素样肽-1)
DPP-IV(二肽基蛋白酶IV) HMG CoA(3-羟基-3-甲基-戊二酸单酰辅酶A)
ACAT(酰基辅酶A:胆固醇O-酰基转移酶)
LHRH(黄体生成素释放激素)
AUC(曲线下面积) IR(立即释放)
MR(修饰/持续释放) MTP(微粒体甘油三酯转移)
FPG(空腹血浆葡萄糖)
糖尿病
最近,人们已将注意力集中在作为治疗糖尿病之新药物靶标的钠葡萄糖协同转运蛋白2(sodium glucose cotransporter 2,SGLT2)的潜力上(1)。SGLT家族由主动转运葡萄糖和半乳糖穿过肠膜和肾膜(与钠离子转运偶联的过程)的多种同种型组成(2)。SGLT2是主要位于肾近端小管S1段中的低亲和力、高容量的钠-葡萄糖协同转运蛋白(3)。在健康人中,肾中滤出的大于99%的血浆葡萄糖被重新吸收。SGLT2有助于约90%的这种重新吸收。剩余的10%很可能由SGLT1(位于肠中和肾近端小管中的高亲和力协同转运蛋白)介导。SGLT2突变失活的人表现出持久的肾糖尿,但在其他方面是健康的(4,5)。因此,抑制SGLT2似乎是改善葡萄糖稳态的有吸引力的方法。期望SGLT2抑制通过提高尿葡萄糖排泄来从血流中清除葡萄糖,该机制不需要来自起不重要作用之胰β细胞的胰岛素分泌。
理想地,这种葡萄糖转运蛋白的抑制应该发生在餐后葡萄糖移动(glucoseexcursion)阶段(餐后葡萄糖进入血液)期间。在健康的非糖尿病对象中,餐后2小时的血液葡萄糖水平通常<120mg/dl并且很少>140mg/dl。在开始进餐后~1小时葡萄糖水平达到峰值,然后在2~3小时内恢复至餐前水平(6,7)。餐后葡萄糖水平的这种升高和降低由第一相胰岛素应答介导,其中大量内源性胰岛素通常在10分钟内响应于营养摄入而释放。在患有2型糖尿病的个体中,第一相胰岛素应答严重降低或不存在,导致在整个一天的大多数时间中持续升高的餐后葡萄糖(8)。
为了回答靶向餐后高血糖是否改善总体血糖控制的问题,在对经磺酰脲类治疗二次失败的2型糖尿病患者的研究中,Feinglos等(9)表明在进餐时使用与磺酰脲类组合的赖脯胰岛素(insulin lispro)(优泌乐(Humalog))改善餐后高血糖症,不仅降低了餐后2小时的葡萄糖移动,而且使空腹葡萄糖和A1C二者水平从9.0%降低至7.1%(P<0.0001)。赖脯胰岛素组中的对象还受益于显著降低的总胆固醇水平和提高的HDL胆固醇浓度。
在Bastyr等(10)的研究中还报道了A1C水平的改善,其表明相对于降低空腹葡萄糖,针对降低餐后葡萄糖的治疗可更有益于降低糖化血红蛋白水平。此外,在妊娠糖尿病患者的研究中,De Veciana等(11)证明对餐后1小时的葡萄糖水平(而不是空腹葡萄糖)的靶向治疗降低了糖化血红蛋白水平并改善了新生儿结局。
关于餐后葡萄糖是否促成以及以何种程度促成微血管和大血管并发症的发生仍有持续的争论。ADA共识会议关于餐后葡萄糖的报告重申了来自糖尿病控制和并发症试验、熊本研究(Kumamoto Study)和UKPDS的发现,该报告证明针对实现正常血糖的治疗降低了长期微血管并发症的发生并延缓其进展(12)。此外,如先前提到的,对UKPDS数据的流行病学分析表明降低血糖水平还改善大血管结局(13)。因此,如果餐后葡萄糖是总体血糖的促成因素,则餐后葡萄糖控制一定是发生糖尿病并发症的促成因素。
许多流行病学研究已表明升高的餐后/负荷后葡萄糖是大血管并发症的独立且重要的风险因素,并且提高了死亡风险。火奴鲁鲁心脏研究(Honolulu Heart Study)(14)发现负荷后葡萄糖水平与心血管性死亡的发生率之间的强相关性。新诊断患有2型糖尿病之患者的糖尿病干预研究(Diabetes Intervention Study)(15)发现,与空腹葡萄糖相比,适度的餐后高血糖更反映动脉粥样硬化,并且发现餐后葡萄糖(而不是空腹葡萄糖)是心血管性死亡的独立风险因素。追踪超过25,000个对象平均7.3年时间的DECODE研究(16)表明,与空腹血浆葡萄糖相比,提高的死亡风险与葡萄糖负荷2小时后的血浆水平远远更密切地相关。与这些发现类似,deVegt等(17)发现由餐后2小时的葡萄糖浓度引起的风险程度是由A1C水平引起的风险程度的近两倍。
餐后葡萄糖控制的安全性取决于所使用的治疗,并且具体取决于当低血糖发生时每个患者对其进行识别和治疗低血糖的能力。虽然在2型糖尿病患者中的重度低血糖非常少,但是对于(患者和提供者中)低血糖的担心仍然是实现餐后葡萄糖控制以及可能的更严格的总体血糖控制的主要障碍。所提议的瑞格列净制剂提供了可每天服用一次的安全、有效剂量的sglt2抑制剂,从而有助于确保患者的顺从性。
虽然在2型糖尿病患者中可能难以实现更严格的餐后葡萄糖控制,但是目前的新胰岛素制剂和经口治疗可为该挑战提供部分解决方案。与常规人胰岛素相比,速效胰岛素类似物(例如门冬胰岛素(Novolog)和赖脯胰岛素),更早产生更高的血清胰岛素水平并且具有更短的作用持续时间,从而在2型糖尿病患者中产生更低的餐后葡萄糖移动、更短的餐后高血糖症持续时间以及降低的重度低血糖发生率(18,19)。在这方面,配制的依碳酸瑞格列净与上述胰岛素制剂的组合可提供更好的对餐后葡萄糖的控制机制。
虽然可辩称如果患者已使用与家庭葡萄糖监测技术(在研究开始时并不广泛可用)组合的新型胰岛素类似物和经口药剂,则UKPDS报道的低血糖发生率和严重程度可能已降低,但是2型糖尿病中低血糖的风险仍不能忽视。所有的降糖治疗(促分泌素(secretagogue)和胰岛素)都具有引起重度低血糖的可能性。因此,重要的是,卫生保健提供者理解与所采用的每种疗法相关的风险水平,以及当每种治疗确实发生时其与每个患者识别和响应于低血糖的能力适当匹配。很可能是因为作用机制,所以瑞格列净显示出非常少的引起低血糖事件的证据。
大型随机干预研究提供了决定性证据,其表明达到并维持严格的血糖控制(<6.5%A1C)显著地降低糖尿病微血管和大血管并发症的风险。遗憾的是,大型流行病学研究不仅表明2型糖尿病通常管理不善,而且表明在美国糖尿病现正在流行。因为2型糖尿病流行的最大增长发生在30~39岁成年人中,所以将有更多患2型糖尿病的人活得更长。因此,卫生保健提供者发现改善其治疗糖尿病之有效性的方法是势在必行的,从而防止多年的虚弱并发症和卫生保健系统的巨大财政负担。
对于新血糖目标(因为其不安全或者太难实现)不合适的争辩与合理的临床判断相反。因为A1C的任何降低都显著地降低糖尿病并发症的风险,所以对于每个患者应将注意力集中于实现可能达到的最好血糖控制。帮助患者实现其可能达到的最好血糖控制水平需要采用适当的治疗、适当监测以及糖尿病自我管理中的综合指导。
引文
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依碳酸瑞格列净
依碳酸瑞格列净还称为5-甲基-4-[4-(1-甲基乙氧基)苄基]-1-(1-甲基乙基)-1H-吡唑-3-基-6-O-(乙氧羰基)-β-D-吡喃葡萄糖苷(如以下式(I)):
另一种命名约定将该分子提供为3-(6-O-乙氧羰基-β-D-吡喃葡萄糖基氧基)-4-[(4-异丙氧基苯基)甲基]-1-异丙基-5-甲基吡唑。依碳酸瑞格列净还称为GSK 189075或KGT-1681。式(i)化合物的盐可用作本发明药物表述物(presentation)的活性成分。此类盐可如2006年8月1日公布的美国专利7,084,123所述,其通过引用并入本文。此类盐的实例包括与无机酸(例如,盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等)的酸加成盐,与有机酸(例如,甲酸、乙酸、甲磺酸、苯磺酸、对甲苯磺酸、丙酸、柠檬酸、琥珀酸、酒石酸、富马酸、丁酸、草酸、丙二酸、马来酸、乳酸、苹果酸、碳酸、谷氨酸、天冬氨酸、己二酸、油酸、硬脂酸等)的酸加成盐,以及与无机碱的盐(例如,钠盐、钾盐、钙盐、镁盐等)。
由上式(I)表示的化合物包括其与可药用溶剂(例如乙醇和水)的溶剂化物。
依碳酸瑞格列净可如美国专利7,084,123和7,375,087(尤其是美国专利7,084,123的实施例1)所述进行制备,所述专利均通过引用并入本文。
依碳酸瑞格列净是瑞格列净(还称为GSK189074或KGT-1650)的前药。
依碳酸瑞格列净具有用作治疗T2DM之单药治疗的可能性。迄今为止,研究已评估了长达12周的有效性、安全性和耐受性,有效性各异,所以需要表征若干所选配制剂量在12周时间中的特征。
将该研究设计为具有安慰剂治疗组,以能够进一步表征药物特征并且实现最大的血糖作用。但是,为了使对象可具有次佳血糖控制的时间最短,已将双盲研究的药物治疗限制为持续12周。此外,已包括的标准允许具有高FP的那些对象在6周后引入补救治疗(rescue therapy)。
每天一次(250、500和1000mg QD)和每天两次(50mg至1000mg BID)给药的12周研究都实现了血糖控制的改善。此外,有证据表明在这些剂量下,还可以有临床相关的体重减轻(新的T2DM治疗的关键要求)(20)。因为250mg以上的剂量BID可与对血糖和体重减轻的相对较小的增量益处有关,并且有剂量越低耐受性越好的趋势,所以以后研究的总日剂量可小于500mg/天。分析表明,在睡眠期显著抑制SGLT2转运蛋白的瑞格列净暴露与LDL-c的小幅升高相关。尤其是,250mg和500mg的bid剂量表现出LDL-c显著升高。认为LDL-c的这种单独升高的主要机制是因为以下的组合:1)由利尿作用(类似于使用利尿剂所见的作用)造成的血浓缩(21,22)和2)SGLT2过夜抑制。这还得到了以下的支持:较高QD剂量表现出血细胞比容(血浓缩的替代指标)的提高而没有相应的LDL-c升高。此外,早晨QD给予组合IR/SR剂量还可为血糖和体重减轻提供有意义的益处。从安全性观点出发,除了在脂质特征和血细胞比容上观察到的小幅作用之外,安全性特征基于施用频率的差别很小。
吸收限制于上胃肠道并且在远端小肠、大肠和结肠中吸收不良的药物通常被认为不适合候选用于配制成经口控制递送系统。这种对吸收(例如,上胃肠道中的吸收)的限制被称为“吸收窗(absorption window)”。
胃肠道的作用是推进所吞下的物质从胃(消化发生之处)进入小肠(吸收主要发生之处)并到大肠(水作为体液调节过程一部分被吸收/分泌之处)中。不易消化的物质在胃中的停留时间取决于处置的是饱腹对象或是空腹对象。颗粒材料(直径大于几毫米)的典型胃排空时间在空腹状态的几十分钟至饱腹状态的几小时之间变化。通过小肠的运送时间始终为3至4小时左右。
经口控制释放递送系统通过在施用后长时间释放其有效负载的药物来发挥作用。因此,控制释放剂型在可发生某些药物良好吸收的胃肠道区域中可仅花费相对短的时间。虽然所述剂型仍有显著百分比的有效负载待递送,但是所述剂型将传递至某些药物吸收不良或不存在吸收的肠区域,仍然释放其所包含的药物。当药物在所述情况下从剂型中释放时将不被吸收。因此,在常规控制释放递送系统中将药物对象施用于吸收窗可导致亚治疗血液水平和药物所旨在应用之疾病状态的无效治疗。
在控制释放剂型中,配制者尝试通过例如将药物包埋于聚合物基质中,或者用聚合物屏障膜(药物必须扩散通过所述膜以被释放用于吸收)将所述药物包围来降低分解速率。为了将药物从所述剂型中释放的速率降低至适当水平(与水溶性非常高的药物所期望的血液水平特征相一致),需要非常大量的聚合物用于基质或屏障膜。如果待递送药物的总日剂量仅为约几毫克,则这可以是可行的,但是具有所述溶解特性的许多药物需要的总日剂量为几百毫克左右。虽然通过使用大量聚合物可产生用于这种产物的经口控制释放剂型,但是可导致不可接受的大剂型。
采用依碳酸瑞格列净之治疗方案的改善可通过使给药频率降低(即每日一次相对于每日两次)的剂型来实现,这为患者提供了可改善顺从性的便利。已证明常规修饰释放制剂对于该分子固有的短半衰期没有补偿,因此表明递送依碳酸瑞格列净的唯一方法是每天给药两次。为了降低给药频率,从剂型释放的类型应使得有效血浆水平延长,但是以该速率有效递送的可能性被以下组合影响所破坏:经近端小肠向下到达结肠后药物的渗透性的显著降低并且在药物被很好地吸收的胃肠道区域中的停留时间受限。到达胃肠道“有用”区域的运送时间很可能仅为几小时左右。以组合方式释放依碳酸瑞格列净之剂型的维持或者甚至提高的生物利用度为期望的时间段(通常在患者清醒时)提供了期望的药物血浆水平。
制剂
用于产生控制释放经口剂型的典型现有技术可包括基质系统或多颗粒系统。基质系统可通过以下来配制:将药物与亲水聚合物(例如,羟丙甲纤维素、羟丙纤维素、聚氧化乙烯、卡波姆(carbomer)、某些甲基丙烯酸衍生的聚合物、藻酸钠或选自这些之组分的混合物)均匀混合;然后将所得混合物压制成片剂(当需要时,使用另一些赋形剂)。可将疏水聚合物(例如,乙基纤维素、某些聚合甲基丙烯酸酯、乙酸丁酸纤维素、(乙烯-醋酸乙烯)共聚物)均匀地掺入以上材料中以产生对释放的额外控制。另一种替代方法涉及通过造粒或将药物与蜡(例如,巴西棕榈蜡、微晶纤维素蜡或可商购的纯化脂肪酸酯)简单地混合以将药物包埋于蜡基片剂中。如上所述,这些方法不能用于水溶性非常高的药物。
多颗粒系统由基于多种载药球体(drug loaded sphere)的剂型组成,所述载药球体通过以下方法制备:使药物在核心(通常是直径约0.8mm的糖-淀粉混合物球体)上成层直至达到足够水平,然后在载药球体周围提供药物释放屏障。载药球体还可通过以下方法制备:将药物与赋形剂的混合物湿团化,使湿团通过多孔筛形成短束(short strand),在干燥和施加药物释放屏障之前将所述短束在滚圆装置(spheronisation apparatus)中变圆。所述药物释放屏障可以是蜡(例如,巴西棕榈蜡或甘油肪酸酯)或聚合物屏障(例如,乙基纤维素与羟丙甲纤维素的混合物)。这些适合用于剂量单位为几毫克/天至小于几百毫克/天的中度可溶性药物。
在多个实施例中,系统通过改善多颗粒系统方法似乎为水溶性非常好的药物提供了控制释放制剂。Fisher公开了用于高度可溶药物(特别是阿片激动剂)的多颗粒系统(23),所述多颗粒系统基于使包含药物的核心被在高度酸性pH下具有部分可溶特性的药物释放控制屏障包围。
Hansraj(24)用甲基丙烯酸或丙烯酸衍生的聚合物(其性质通过包含至少一种阴离子表面活性剂而修饰)包被载药核心。在这样的系统中,高度水溶性药物的药物释放受到控制,并且无需依赖于在释放速率控制层上使用厚的包衣。
Rollet(25)基于亲水和疏水二氧化硅或硅酸盐的细小颗粒实现了药物从多颗粒制剂中的延长释放。推测该系统可用于高水溶性药物。
因为在尝试将这种颗粒压制成片剂时引起对所述颗粒的破坏,所以多颗粒系统通常被填充到胶囊中以提供单位剂型。单个单位中包含的总剂量受限于易于吞咽大小的硬明胶胶囊中可能的负载并且通常不超过几百毫克。
可用于高度水溶性药物的单个单位控制释放系统包括在剂型周围使用多个层,如Howard(26)所述。当不采用包衣时,使用聚合物的特殊混合物或者与药物形成复合物。Macrae(27)使用聚氧化乙烯和羟丙甲纤维素与任选的肠溶性聚合物的混合物以产生高度水溶性药物的恒定释放速率。Belenduik(28)将高度水溶性药物与基于丙烯酸的亲水聚合物组合并且将其分散于疏水基质中。已描述了适用于高度水溶性药物(例如盐酸文拉法辛)的ALZA渗透系统的变化形式(29)。这些系统需要两层——药物层和渗透驱动替换层,其均被水渗透/药物不渗透的膜包围,并且在该膜中具有药物的排出通道。
制备高度水溶性的克拉维酸的微粒(30)必须采用疏水蜡材料的屏障层,从而在与控制释放阿莫西林三水合物颗粒共同配制成胶囊或压制片剂时提供该材料的控制释放。
具体实施方式
本发明包括配制具有相对短半衰期和受限吸收窗的药物(例如在上胃肠道中具有吸收窗的依碳酸瑞格列净或其盐),以提供在患者清醒期间可提供有效暴露的剂型。本发明的制剂提供了(a)通常在早餐之前或早餐时所述药物的立即释放,和(b)足以在当天晚些时候提供对葡萄糖移动之充足覆盖的延迟释放。本发明的制剂将提供药物的立即/延迟释放制剂。
在依碳酸瑞格列净的情况下,本发明制剂允许患者的给药方案为以一种固体剂型(例如片剂)或一种胶囊的形式每天一次至少250mg依碳酸瑞格列净至每天一次500mg依碳酸瑞格列净,同时提供血浆葡萄糖的有效控制。本发明的依碳酸瑞格列净制剂可以上述剂量每天一次施用以有效治疗糖尿病,并且避免如可在每天两次依碳酸瑞格列净给药时遇到的可与高夜间血浆依碳酸瑞格列净水平有关的问题,同时提供最佳治疗控制和最佳安全特征。
本发明适用于具有短半衰期和受限吸收窗的所有治疗糖尿病的药物,尤其是其中作用机制涉及使膳食葡萄糖移动减弱或迟钝的药物。
本发明的组合立即释放递送系统是异质的两相系统,其包含(1)单独微粒或颗粒的固体颗粒相,所述颗粒或微粒包含(a)具有短半衰期和受限吸收窗(例如在上胃肠道中)的药物(优选依碳酸瑞格列净)和(b)由一种或更多种亲水聚合物和/或一种或更多种疏水聚合物和/或一种或更多种其他类型疏水材料(例如一种或更多种蜡、脂肪醇和/或脂肪酸酯)形成的延迟释放材料;以及(2)固体相,其中分散并且包埋有所述延迟释放固体颗粒相的微粒或颗粒,所述固体相主要由立即释放材料形成,所述立即释放材料由一种或更多种亲水聚合物和/或一种或更多种疏水聚合物和/或一种或更多种其他类型疏水材料(例如一种或更多种蜡、脂肪醇和/或脂肪酸酯)形成。
本发明特别适合于以以下控制方式递送短半衰期药物(例如依碳酸瑞格列净及其可药用盐):显著的药物初始快速释放,然后在与上GI道中吸收窗相关的某段时间中使药物延迟释放(从形成固体颗粒相的个体分散颗粒中释放)。药物从延迟释放制剂的颗粒中释放后实际上进入可用于吸收的上胃肠道中。
特别地,所述固体相立即释放制剂是具有颗粒或微粒的相或基质,所述颗粒或微粒包含分散于整个固体相立即释放制剂中并包埋于其中的药物(形成延迟释放固体相)。
此外,根据本发明,提供了用于降低胰岛素抗性或治疗糖尿病的方法,其中向需要治疗的患者施用包含抗糖尿病药物的本发明的组合立即/延迟释放制剂。
本文中使用的术语“糖尿病”是指2型糖尿病和1型糖尿病,通常是指2型糖尿病。
特别地,所采用的抗糖尿病药物是SGLT2抑制剂,例如依碳酸瑞格列净或其可药用盐(如盐酸盐),所有这些统称为依碳酸瑞格列净。依碳酸瑞格列净盐酸盐是用于本发明的具体活性成分。
在本发明的另一方面中,提供了用于降低胰岛素抗性或治疗糖尿病的方法,其中向需要治疗的患者施用包含依碳酸瑞格列净的本发明的组合立即/延迟释放制剂,并且施用的给药方案为每天一次至少约250mg(特别是每天一次约250mg至500mg)依碳酸瑞格列净。
固体颗粒相延迟释放制剂和固体相立即释放制剂中所存在的术语“释放材料”是指一种或更多种亲水聚合物和/或一种或更多种疏水聚合物和/或一种或更多种其他类型疏水材料(例如一种或更多种蜡、脂肪醇和/或脂肪酸酯)。虽然可使用不同等级或分子量的相同化学聚合物,但是延迟释放颗粒相中存在的“释放材料”可与立即释放固体相中存在的“释放材料”相同或不同。但是,通常是延迟释放颗粒相中存在的“释放材料”可与立即释放制剂中存在的“释放材料”不同。
在表征用于本发明制剂的药品、药剂或药物时的术语“受限吸收窗”或相似术语是指经口生物利用度小于约75%,通常小于约60%,通常随剂量提高而减小,并且几乎不变地具有渗透性/运送时间受限的吸收。
本发明的组合立即/延迟释放系统可包含延迟释放固体颗粒相,其与立即释放固体相的重量比在约0.5∶1至约4∶1(例如约0.8∶1至约2∶1)的范围内。
所述延迟释放固体颗粒相包含量为按重量计约10%至约98%(例如按重量计约15%至约95%)范围内的药物;和量为按重量计约5%至约95%(特别是按重量计约7%至约85%)范围内的亲水聚合物和/或疏水聚合物和/或其他疏水材料形式的延长释放材料(extended release material),以上%基于所述延迟释放固体颗粒相的重量。当采用混合物时,将以与疏水聚合物和/或其他疏水材料约0.05∶1至约19∶1(特别是约0.1∶1至约10∶1)范围内的重量比使用亲水聚合物。
所述延迟释放固体颗粒相的颗粒或微粒的平均粒径在约30μm至约0.8mm(特别是约50μm至约0.5mm)的范围内。
所述立即释放固体相将包含一种或更多种亲水聚合物和/或疏水聚合物和/或其他疏水材料形式的立即释放材料(通常不同于所述延迟释放固体颗粒相中所采用的材料),其量在约40%至约100%(特别是约60%至约100%)(基于所述立即释放固体相的重量)的范围内。
本发明药物制剂的总聚合物延长释放材料含量(包括延迟释放固体颗粒相中存在的亲水聚合物和/或疏水聚合物和/或其他疏水材料和立即释放固体相中存在的亲水聚合物和/或疏水聚合物和/或其他疏水材料)在基于所述药物制剂总重量的按重量计约25%至约75%(特别是约30%至约65%,更特别是按重量计约35%至约60%)的范围内。
可用于延迟释放固体颗粒相和/或立即释放固体相的亲水聚合物包括但不限于羟丙甲纤维素、羟丙纤维素、羧甲基纤维素钠、羧甲基纤维素钙、藻酸铵、藻酸钠、藻酸钾、藻酸钙、藻酸丙二醇酯、藻酸、聚乙烯醇、聚维酮、卡波姆、果胶酸钾(potassium pectate)、果胶酸钾(potassium pectinate)等。
可用于延迟释放固体颗粒相和/或立即释放固体相的疏水聚合物包括但不限于乙基纤维素、羟乙基纤维素、甲基丙烯酸铵共聚物(Eudragit RL.TM.或Eudragit RS.TM.)、甲基丙烯酸共聚物(Eudragit L.TM.或Eudragit S.TM.)、甲基丙烯酸-丙烯酸乙酯共聚物(Eudragit L100-5.TM.)、甲基丙烯酸酯中性共聚物(Eudragit NE 30D.TM.)、甲基丙烯酸二甲氨基乙酯-甲基丙烯酸酯共聚物(Eudragit E 100.TM.)、乙烯基甲基醚/马来酸酐共聚物、其盐和酯(Gantrez.TM.)。
可用于延迟释放固体颗粒相和/或立即释放固体相的其他疏水材料包括但不限于蜡,例如蜂蜡、巴西棕榈蜡、微晶蜡和地蜡(ozokerite);脂肪醇,例如鲸蜡硬脂醇、硬脂醇、鲸蜡醇和肉豆蔻醇;以及脂肪酸酯,例如单硬脂酸甘油酯、单油酸甘油酯、乙酰化单甘油酯、三硬脂酸甘油酯(tristearin)、三棕榈酸甘油酯(tripalmitin)、鲸蜡醇酯蜡、棕榈酰硬脂酸甘油酯、山嵛酸甘油酯和氢化蓖麻油。
当将亲水聚合物和/或疏水聚合物用于延迟释放固体颗粒相和/或立即释放固体相时,这些聚合物可以是离子的或非离子的,对于延迟释放固体颗粒相特别是离子的并且对于立即释放固体相特别是非离子的。
用于延迟释放固体颗粒相的具体离子聚合物包括藻酸钠、卡波姆(Carbopol.TM.)、羧甲基纤维素钙或羧甲基纤维素钠、黄原胶、甲基丙烯酸-丙烯酸乙酯共聚物、甲基丙烯酸二甲氨基乙酯-甲基丙烯酸酯共聚物、邻苯二甲酸乙酸纤维素、羟丙甲纤维素邻苯二甲酸酯、羟丙甲纤维素偏苯三酸酯和羟丙甲纤维素马来酸酯,特别是羧甲基纤维素钠。根据本发明的特别的两相立即/延迟释放递送系统如实施例中所述。
特别的活性成分为依碳酸瑞格列净盐酸盐。
组合
当期望时,依碳酸瑞格列净或其盐可与其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂组合使用,其可以在同一根据本发明的剂型、分开的经口剂型中经口施用,或者通过注射施用。将以与其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂约0.01∶1至约300∶1(特别是约0.05∶1至约250∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
与所述其他抗高血糖剂组合使用依碳酸瑞格列净或其盐可尤其用于实现与每一种这些药剂的单独相比的抗高血糖结果,并且大于由这些药物产生的联合的相加的抗高血糖作用。
此外,根据本发明,提供了用于降低胰岛素抗性或治疗高血糖症(包括2型糖尿病(NIDDM)和/或1型糖尿病(IDDM))的方法,其中向需要治疗的患者施用治疗有效量的本发明的组合制剂,所述组合制剂包含任选与其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂组合的依碳酸瑞格列净或其盐。
所述其他抗高血糖剂可以是经口抗高血糖剂,特别是双胍类如二甲双胍(常以Glucophage出售)或主要通过抑制肝产生葡萄糖来改善高血糖的其他已知双胍类。
所述其他抗高血糖剂可以是经口抗高血糖剂,特别是磺酰脲类,例如格列本脲(也称为优降糖)、格列美脲(美国专利No.4,379,785中公开)、格列吡嗪、格列齐特或氯磺丙脲、其他已知磺酰脲类或者作用于β细胞ATP依赖性通道的其他抗高血糖剂。
所用的依碳酸瑞格列净或其盐与磺酰脲类的重量比在约300∶1至约50∶1(特别是约250∶1至约75∶1)的范围内。
所述经口抗高血糖剂还可以是葡萄糖苷酶抑制剂,例如阿卡波糖(美国专利No.4,904,769中公开)或米格列醇(美国专利No.4,639,436中公开),并且可以以单独经口剂型施用。
以与葡萄糖苷酶抑制剂约300∶1至约2∶1(例如约200∶1至约25∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
依碳酸瑞格列净或其盐可与噻唑烷二酮类经口抗糖尿病剂(其对NIDDM患者具有胰岛素敏感性作用)组合使用,所述抗糖尿病剂例如曲格列酮(Warner-Lambert的Rezulin.RTM.,美国专利No.4,572,912中公开)、罗格列酮(SKB)、吡格列酮(Takeda)、Mitsubishi的MCC-555(美国专利No.5,594,016中公开)、Glaxo-Welcome的GL-262570、恩格列酮(CP-68722,Pfizer)或达格列酮(CP-86325,Pfizer)。
以与噻唑烷二酮类约75∶1至约0.1∶1(例如约5∶1至约0.5∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
可将量小于约150mg经口抗糖尿病剂的磺酰脲类和噻唑烷二酮类与作为单独迅速溶解层的本发明制剂并入单一片剂中。
依碳酸瑞格列净或其盐还可与非经口抗高血糖剂(例如胰岛素或胰高血糖素样肽-1(GLP-1)(例如GLP-1(1-36)酰胺、GLP-1(7-36)酰胺、GLP-1(7-37))(如Habener的美国专利No.5,614,492中所公开的,其公开内容通过引用并入本文)组合使用,所述非经口抗高血糖剂可通过注射、或通过经皮或口腔装置施用。
所述经口抗高血糖剂还可以是二肽基蛋白酶IV(DPP-IV)抑制剂,例如西他列汀、维达列汀、沙格列汀、利拉利汀(由Boehringer Ingelheim开发)或阿格列汀。
当存在时,磺酰脲类(例如格列本脲、格列美脲、glipyride、格列吡嗪、格列吡嗪、氯磺丙脲和格列齐特)和葡萄糖苷酶抑制剂(阿卡波糖或米格列醇)可用于上述制剂,并且量和剂量如医生的案头参考(Physician’s Desk Reference)所指示。
当存在时,噻唑烷二酮类抗糖尿病剂可采用的量在约0.01至约2000mg/天的范围内,可每天以单剂量或分剂量施用一至四次。
当存在时,胰岛素可如医生案头参考所指示的制剂、量和剂量使用。
当存在时,GLP-1肽可以以口含制剂施用、经鼻施用或肠胃外施用,如美国专利No.5,346,701(TheraTech)、美国专利No.5,614,492和5,631,224所述,这些专利文献通过引用并入本文。
依碳酸瑞格列净或其盐与所述其他具体抗高血糖剂组合使用可产生的抗高血糖结果大于这些药物每一种单独可产生的结果,并且大于这些药物产生的联合的相加的抗高血糖作用。
此外,根据本发明,提供了用于降低胰岛素抗性或治疗高血糖(包括2型糖尿病(NIDDM)和/或1型糖尿病(IDDM))的方法,其中向需要治疗的患者施用治疗有效量的本发明制剂,所述制剂包含任选与抗肥胖剂组合的依碳酸瑞格列净或其盐。
此外,本发明还提供了用于影响体重减轻的方法,其中向需要治疗的患者施用治疗有效量的本发明制剂,所述制剂包含任选与抗肥胖剂组合的依碳酸瑞格列净或其盐。
所述抗肥胖剂可以是经口抗肥胖剂,特别是胰脂肪酶抑制剂、食欲抑制剂、大麻素(cannabinoid)受体(CB-1)拮抗剂、5HTC激动剂或多巴胺受体拮抗剂,例如赛尼可(xenical)、西布曲明(sibutramine)、芬特明(phentermine)、芬氟拉明(fenfluramine)、利莫那班(rimonabant)、氯卡色林(lorcaserin)或安非他酮(bupropion)。
所述抗肥胖剂可以是经口抗肥胖剂,特别是胰脂肪酶抑制剂,例如赛尼可(Orlistat/Alli)。
将以与抗肥胖剂约300∶1至约50∶1(例如约250∶1至约75∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
所述经口抗肥胖剂还可以是食欲抑制剂,例如芬特明、芬氟拉明或氯卡色林。
将以与食欲抑制剂约300∶1至约2∶1(例如约200∶1至约25∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
依碳酸瑞格列净或其盐可与经口抗肥胖剂(例如大麻素-1受体拮抗剂)组合使用。
将以与大麻素-1受体拮抗剂约75∶1至约0.1∶1(例如约5∶1至约0.5∶1)范围内的重量比使用依碳酸瑞格列净或其盐。
依碳酸瑞格列净或其盐也可与非经口抗肥胖剂(例如瘦蛋白(leptin))组合使用,所述抗肥胖剂可通过注射,或通过经皮或口腔装置施用。
可任选与依碳酸瑞格列净或其盐组合使用的降血脂剂可包括MTP抑制剂、HMG CoA还原酶抑制剂、角鲨烯合成酶抑制剂、纤维酸(fibric acid)衍生物、ACAT抑制剂、胆固醇吸收抑制剂、回肠Na+/胆汁酸协同转运蛋白抑制剂、胆汁酸螯合剂和/或烟酸及其衍生物。
本文中使用的MTP抑制剂包括美国专利No.5,595,872、美国专利No.5,739,135、美国专利No.5,712,279、美国专利No.5,760,246、美国专利No.5,827,875、美国专利No.5,885,983和1998年10月20日提交的美国申请序列号09/175,180(现在为美国专利No.5,563,440)中公开的MTP抑制剂。
待根据本发明使用的具体MTP抑制剂包括美国专利No.5,739,135和5,712,279以及美国专利No.5,760,246中所述的MTP抑制剂。
所述降血脂剂可以是HMG CoA还原酶抑制剂,其包括但不限于美国专利No.3,983,140中公开的美伐他汀及相关化合物、美国专利No.4,231,938中公开的洛伐他汀(美维诺林(mevinolin))及相关化合物、美国专利No.4,346,227中公开的普伐他汀及相关化合物、美国专利No.4,448,784和4,450,171中公开的辛伐他汀及相关化合物。本文中可使用的其他HMG CoA还原酶抑制剂包括但不限于美国专利No.5,354,772中公开的氟伐他汀,美国专利No.5,006,530和5,177,080公开的西立伐他汀,美国专利No.4,681,893、5,273,995、5,385,929和5,686,104中公开的阿托伐他汀,美国专利No.4,613,610中公开的甲羟戊酸内酯衍生物的吡唑类似物,PCT申请WO 86/03488中公开的甲羟戊酸内酯衍生物的茚类似物,美国专利No.4,647,576中公开的6-[2-(取代吡咯-1-基)-烷基)吡喃-2-酮及其衍生物,Searle的SC-45355(3-取代的戊二酸衍生物)二氯乙酸盐/酯,PCT申请WO 86/07054中公开的甲羟戊酸内酯的咪唑类似物,法国专利No.2,596,393中公开的3-羧基-2-羟基-丙烷-膦酸衍生物,欧洲专利申请No.0221025中公开的2,3-双取代吡咯、呋喃和噻吩,美国专利No.4,686,237中公开的甲羟戊酸内酯的萘基类似物,例如美国专利No.4,499,289中公开的八氢萘,欧洲专利申请No.142,146 A2中公开的美维诺林(洛伐他汀)的酮类似物,以及另一些已知的HMGCoA还原酶抑制剂。
此外,GB 2205837中公开了一些适用于本文的可用于抑制HMG CoA还原酶的膦酸化合物。
适用于本文的角鲨烯合成酶抑制剂包括但不限于美国专利No.5,712,396中公开的α-膦酸-磺酸盐/酯;Biller等,J.Med.Chem.,1988,第31卷,第10期,第1869-1871页公开的那些,包括类异戊二烯(氧膦基甲基)膦酸酯;以及美国专利No.4,871,721和4,924,024以及Biller,S.A.,Neuenschwander,K.,Ponpipom,M.M.,and Poulter,C.D.,CurrentPharmaceutical Design,2,1-40(1996)中公开的另一些角鲨烯合成酶抑制剂。
此外,另一些适用于本文的角鲨烯合成酶抑制剂包括P.Ortiz de Montellano等,J.Med.Chem.,1977,20,243-249中公开的萜焦磷酸酯,Corey and Volante,J.Am.Chem.Soc.,1976,98,1291-1293中公开的法尼基二磷酸酯类似物A和原角鲨烯焦磷酸酯(presqualene pyrophosphate,PSQ-PP),McClard,R.W.等,J.A.C.S.,1987,109,5544报道的氧膦基膦酸酯和Capson,T.L,PhD论文,1987年6月,Dept.Med.Chem.U of Utah,摘要、目录、第16、17、40-43、48-51页、总结中报道的环丙烷。
适用于本文的其他降血脂剂包括但不限于纤维酸衍生物(例如非诺贝特、吉非罗齐、氯贝丁酯、苯扎贝特、环丙贝特、克利贝特等)、美国专利No.3,674,836中公开的普罗布考及相关化合物(例如普罗布考和吉非罗齐)、胆汁酸螯合剂(例如考来烯胺、考来替泊和DEAE-Sephadex(Secholex.RTM.,Policexide.RTM.))以及lipostabil(Rhone-Poulenc)、Eisai E-5050(N-取代的乙醇胺衍生物)、imanixii(HOE-402)、四氢利泼斯汀(tetrahydrolipstatin)(THL)、istigmastanylphosphorylcholine(SPC,Roche)、氨基环糊精(Tanabe Seiyoku)、Ajinomoto AJ-814(薁衍生物)、甲亚油酰胺(Sumitomo)、Sandoz 58-035、Amcrican Cyanamid CL-277,082和CL-283,546(双取代脲衍生物)、烟酸、阿昔莫司、阿西呋喃(acifran)、新霉素、对氨基水杨酸、阿司匹林、例如美国专利No.4,759,923中公开的聚(二烯丙基甲胺)衍生物、例如美国专利No.4,027,009中公开的季铵聚(二烯丙基二甲基氯化铵)和紫罗烯(ionene)以及另一些已知的血清胆固醇降低剂。
所述降血脂剂可以是ACAT抑制剂,例如以下中所公开的:
″The ACAT inhibitor,CI-1011 is effective in the prevention andregression of aortic fatty streak area in hamsters″,Nicolosi et al,Atherosclerosis(Shannon,Irel).(1998),137(1),77-85;″The pharmacologicalprofile of FCE 27677:a novel ACAT inhibitor with potent hypolipidemicactivity mediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein″,Ghiselli,Giancarlo,Cardiovasc.Drug Rev.(1998),16(1),16-30;″RP 73163:a bioavailable alkylsulfinyl-diphenylimidazoleACAT inhibitor″,Smith,C.,et al,Bioorg.Med.Chem.Lett.(1996),6(1),47-50;″ACATinhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals″,Krause et al,Editor(s):Ruffolo,Robert R.,Jr.;Hollinger,Mannfred A.,Inflammation:Mediators Pathways(1995),173-98,Publisher:CRC,Boca Raton,Fla.;″ACAT inhibitors:potential anti-atheroscleroticagents″,Sliskovic et al,Curr.Med.Chem.(1994),1(3),204-25;″Inhibitors of acyl-CoA:cholesterol O-acyl transferase(ACAT)as hypocholesterolemic agents.6.Thefirst water-soluble ACAT inhibitor with lipid-regulating activity.Inhibitorsof acyl-CoA:cholesterol acyltransferase(ACAT).7.Development of a series ofsubstituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas with enhancedhypocholesterolemic activity″,Stout et al,Chemtracts:Org.Chem.(1995),8(6),359-62.
所述胆固醇吸收抑制剂可以是Schering-Plough的SCH 48461或者如Atherosclerosis 115,45-63(1995)或J.Med.Chem.41,973(1998)中公开的。
所述回肠Na+/胆汁酸协同转运蛋白抑制剂可以是如Drugs of the Future,24,425-430(1999)中所公开的。具体降血脂剂有普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀和西立伐他汀。
上述美国专利通过引用并入本文。采用的量和剂量如医生案头参考中和/或上述专利中所指示。
将以与所述降血脂剂(存在时)在约500∶1至约1∶500(特别是约100∶1至约1∶100)范围内重量比使用本发明的式(I)化合物。
施用的剂量必须根据患者年龄、体重和状况,以及施用途径、剂型和方案和期望结果进行小心调整。
所述降血脂剂的剂量和制剂如以上讨论的多个专利、论文和申请中所公开。
待采用的另一些降血脂剂(可用时)的剂量和制剂如医生案头参考的最新版本中所列出。
对于经口施用,采用下述量的MTP抑制剂可得到满意结果:在约0.01mg/kg至约100mg/kg,例如约0.1mg/kg至约75mg/kg的范围内,每天一至四次。
一种具体经口剂型(例如片剂或胶囊)包含下述量的MTP抑制剂:约1至约500mg,特别是约2至约400mg,例如约5至约250mg,每天一至四次。
对于肠胃外施用,采用下述量的MTP抑制剂:在约0.005mg/kg体重至约10mg/kg,特别是约0.005mg/kg至约8mg/kg的范围内,每天一至四次。
对于经口施用,采用如医生案头参考指示的剂量(例如约1至约2000mg(特别是约4至约200mg)范围内的量)使用HMG CoA还原酶抑制剂(例如,普伐他汀、洛伐他汀、辛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀)可得到满意结果。
可以以量为约10mg至约2000mg(特别是约25mg至约200mg)范围内的剂量使用所述角鲨烯合成酶抑制剂。
具体的经口剂型(例如片剂或胶囊)包含下述量的HMG CoA还原酶抑制剂:约0.1至约100mg,例如约5至约80mg,更特别是约10至约40mg。
具体经口剂型(例如片剂或胶囊)包含下述量的角鲨烯合成酶抑制剂:约10至约500mg,特别是约25至约200mg。
依碳酸瑞格列净或其盐与降血脂剂可一起用于同一经口剂型或在分开的经口剂型中同时服用。
上述组合物可以以上述剂型并且以每天一次至每天多至四次的单剂量或分剂量施用。可取的是,开始以低剂量组合向患者施用并逐渐提高为高剂量组合。
具体的降血脂剂有普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀。
本发明递送系统中可采用以下另外类型的高水溶性药物:普伐他汀;与胍乙啶有关的抗高血压剂和抗抑郁剂(如美国专利No.2,928,829种所公开)和与胍诺西芬有关的抗高血压剂和抗抑郁剂(如BE612362种所公开);例如与脒霉素相关的抗生素和杀病毒剂(如JP21,418中所公开);司他霉素(如DE 1,039,198中所公开);奥伐美宁B(arphamenine B)(如公开的欧洲专利申请85/133550A2中所公开);几丁黄杆菌素-A(chitinovorin-A)(如公开的欧洲专利申请85/150.378A2和美国专利No.4,723,004中所公开);链霉素(如美国专利No.2,868,779中所公开);SB-59(如Justus Liebigs,Ann.Chem.(1973)7,1112-1140中所公开);TAN-1057-A(如美国专利No.4,971,965中所公开);链异烟肼(如J.Am.Chem.Soc.(1953)75,2261中所公开);与ST-789相关的免疫刺激剂(如公开的欧洲专利申请88/260588中所公开);与萘莫司他(nafamastat)相关的肽水解酶抑制剂(如美国专利No.4,454,338中所公开);加贝酯(gabexate)(如美国专利No.3,751,447中所公开);司匹司他(如美国专利No.4,777,182和4,820,730中所公开);与DX-9065a相关的因子Xa抑制剂(如公开的欧洲专利申请92/0540051中所公开);如美国专利No.2,877,269中所公开的与瑞尼托林(paranyline)相关的抗炎剂;肽基醛(如WO094/13693中所公开);与GMCHA-TBP(巴布司特,batebulast)相关的抗过敏剂(如美国专利No.4,465,851中所公开);与贝奈克酯(benexate)相关的抗溃疡剂(如美国专利No.4,348,410中所公开);脱氧精胍菌素(如美国专利No.4,518,532、4,658,058和4,983,328中所公开)和精氨酸。
适用于本文的其他水溶性药物包括分子量是约100至10,000(更特别地约100至约6,000)并且具有2至35个氨基酸部分的肽。更高分子量的肽(甚至是分子量超过10,000、高达约50,000的那些肽)也可适应于本发明制剂。
合适小肽具有约2至约10个,更特别地约2至约6个氢基酸部分。小肽包括纤维蛋白原受体拮抗剂(含RGD的肽),它是平均分子量为约600的四肽。这些肽拮抗剂是血浆水平低至1pmol/mL的高效血小板聚集抑制剂。具体的纤维蛋白原拮抗剂包括肽环(S,S)-Na-乙酰基-(Na-甲基)Arg-Gly-Asp-Pen-NH2(Ali等,EP 0341915,其公开内容通过引用并入本文)和肽环(S,S)-(2-巯基)苯甲酰基-(Na-甲基)Arg-Gly-Asp-(2-巯基)-苯基酰胺(EP 0423212,其公开内容通过引用并入本文)。可用于本发明的另一些纤维蛋白原拮抗剂是Pierschbacher等,WO 89/05150(U.S.Pat.No.8,804,403);Marguerie,EP 0275748;Adams等,美国专利No.4,857,508;Zimmerman等,美国专利No.4,683,291;Nutt等,EP 0410537、EP0410539、EP 0410540、EP 0410541、EP 0410767、EP 0410833、EP 0422937和EP 0422938;Ali等,EP 0372486;Ohba等,WO 90/02751(PCT/JP89/00926);Klein等,美国专利No.4,952,562;Scarborough等,WO 90/15620(PCT/US90/03417);Ali等,PCT/US90/06514和PCT/US92/00999中所公开的那些肽;Ali等,EP 0381033和EP 0384362中所公开的肽样化合物;以及RGD肽-环Na-乙酰基-Cys-Asn-Dtc-Amf-Gly-Asp-Cys-OH(其中Dtc是4,4’-二甲基噻唑烷-5-羧酸,并且Ami是4-氨基甲基苯基-丙氨酸)。
RGD肽可以以下述量可用地包含在本发明的制剂中:多至约600mg/g亲水相或0.1至60mg/g制剂。
可用于本发明的其他肽包括但不限于另一些含RGD的肽,例如Momany,美国专利No.4,411,890和美国专利No.4,410,513;Bowers等,美国专利No.4,880,778、美国专利No.4,880,777、美国专利No.4,839,344;以及WO 89/10933(PCT/US89/01829)中公开的那些;肽Ala-His-D-Nal-Ala-Trp-D-Phe-Lys-NH2(其中Nal表示b-萘基-丙氨酸);以及Momany,美国专利No.4,228,158、美国专利No.4,228,157、美国专利No.4,228,156、美国专利No.4,228,155、美国专利No.4,226,857、美国专利No.4,224,316、美国专利No.4,223,021、美国专利No.4,223,020、美国专利No.4,223,019和美国专利No.4,410,512中公开的肽。
其他合适的肽包括六肽,例如生长激素释放肽(GHRP)His-D-Trp-Ala-Trp-D-Phe-Lys-NH2(Momany,美国专利No.4,411,890,其公开内容通过引用整体并入本文)。其可以以下述量包含在制剂中:多至约250mg/g亲水相或0.1至25mg/kg。
用于本发明控制释放制剂的合适的较大多肽和蛋白质包括胰岛素、降钙素、依降钙素、降钙素基因相关肽(calcitoningene related peptide)和猪生长激素抑制素及其类似物和同源物。其他合适的较大多肽包括Pierschbacher等,美国专利No.4,589,881(>30个残基);Bittle等,美国专利No.4,544,500(20~30个残基);和Dimarchi等,EP 0204480(>34个残基)中公开的那些。
可用于本发明的其他化合物类型包括展现出强LH释放活性或抑制LHRH活性的LHRH类似物或同源物、具有造血活性的HP5类似物或同源物、具有降血压活性的内皮素类似物或同源物、具有抗感受伤害的活性(antinociceptive activity)的脑啡肽类似物或同源物、胆囊收缩素(chlorecystokinin)类似物或同源物、具有免疫抑制活性的环孢霉素A的类似物或同源物、心房钠尿因子(atrial natriuretic factor)类似物或同源物、肽能抗肿瘤剂、胃泌素释放肽类似物或同源物、生长激素抑制素类似物或同源物、胃泌素拮抗剂、缓激肽拮抗剂、神经降压素拮抗剂、铃蟾肽(bombesin)拮抗剂、催产素激动剂和拮抗剂、血管升压素激动剂和拮抗剂、水蛭素类似物或同源物、细胞保护性肽环肽(cytoprotectivepeptidecyclolinopeptide)类似物和同源物、αMSH类似物、MSH释放因子(Pro-Leu-Gly-NH2)类似物和同源物、抑制胶原酶的肽、抑制弹性蛋白酶的肽、抑制肾素的肽、抑制HIV蛋白酶的肽、抑制血管紧张素转化酶的肽、抑制糜酶(chymase)和类胰蛋白酶(tryptase)的肽以及抑制凝血酶的肽。
其他合适药物包括非肽治疗剂,例如抗生素、抗微生物剂、抗肿瘤剂、心血管剂和肾剂(例如卡托普利)、抗炎剂、免疫抑制剂和免疫刺激剂和CNS药。
制剂
本发明的组合立即/延迟释放制剂可被施用于有此治疗需要的多种哺乳类物种,例如狗、猫、人等。
本发明的系统可并入常规的全身剂型(例如片剂或胶囊)中。以上剂型还可包含必要的生理学上可接受的载体材料、赋形剂、润滑剂、缓冲剂、抗菌剂、膨胀剂(bulkingagent)(如甘露醇)、抗氧化剂(抗坏血酸或亚硫酸氢钠)等。
施用剂量可根据患者年龄、体重和状况,以及施用途径、剂型和方案以及期望的结果而进行小心调节。一般而言,上述包含依碳酸瑞格列净或其盐(无论是单独还是和其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂)之制剂的剂型可以以先前关于依碳酸瑞格列净盐酸盐所描述的量施用。
依碳酸瑞格列净或其盐与其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂的组合可分开配制,或者(可能时)采用常规配制步骤配制成单一制剂。
本发明的多种制剂可包含下述量的一种或更多种填充剂或赋形剂:在按重量计多至约90%,特别地按重量计约1至约80%的范围内,所述填充剂或赋形剂例如乳糖、糖、玉米淀粉、改性玉米淀粉、甘露醇、山梨醇、无机盐(如碳酸钙)和/或纤维素衍生物(例如木纤维素和微晶纤维素,也称为压缩助剂(compression aid))。
除填充剂之外或代替填充剂的一种或更多种黏合剂可以下述量存在:按组合物重量计的约0%至约35%,特别是约0.5%至约30%的范围内。适用于本文的这些黏合剂的实例包括聚乙烯吡咯烷酮(分子量范围为约5000至约80,000,特别是约40,000)、乳糖、淀粉(如玉米淀粉)、改性玉米淀粉、糖、阿拉伯树胶等、以及细粉末形式(小于500微米)的蜡黏合剂(例如巴西棕榈蜡、石蜡、鲸蜡(spermaceti)、聚乙烯或微晶蜡)。
当组合物是片剂形式时,它可包含下述量的一种或更多种压片润滑剂:按组合物重量计的约0.2%至约8%(例如约0.5%至约2%)范围内,所述压片润滑剂例如硬脂酸镁、硬脂酸、棕榈酸、硬脂酸钙、滑石粉、巴西棕榈蜡等。可任选存在的另一些常规成分包括防腐剂、稳定剂、防粘剂或硅石流动调节剂(silica flow conditioner)或助流剂(例如Syloid牌二氧化硅)以及FD&C颜料。
本发明的片剂还可任选地包含任选包衣层,所述包衣层可占按片剂组合物重量计的多至约15%。可应用在包含其中包埋有延迟释放固体相颗粒的立即释放固体相上的包衣层(其实际上可包含立即释放活性物)可包含任何常规包衣制剂,并且包含一种或更多种成膜剂或黏合剂,例如亲水聚合物(例如羟丙甲纤维素)和/或疏水聚合物(如甲基丙烯酸酯中性聚合物、乙基纤维素、纤维素乙酸酯、聚乙烯醇-马来酸酐共聚物、β-蒎烯聚合物、木材树脂的甘油酯等)以及一种或更多种增塑剂,例如柠檬酸三乙酯、邻苯二甲酸二乙酯、丙二醇、甘油、邻苯二甲酸丁酯、蓖麻油等。核心片剂和包衣制剂二者都可包含铝色淀以提供颜色。
从包含一种或更多种溶剂的溶剂系统应用所述成膜剂,所述溶剂包括水、醇(例如甲醇、乙醇或异丙醇)、酮(例如丙酮或乙基甲基酮)、氯化烃(例如二氯甲烷、二氯乙烷和1,1,1-三氯乙烷)。
当采用颜料时,所述颜料可与成膜剂、增塑剂和溶剂组合物一起使用或者可以是完全分开的顶层。
本发明的胶囊(例如图4中所示)可包含赋形剂或可药用载体,其内部是悬浮的立即释放颗粒和延迟释放颗粒。本文中使用的短语“可药用载体”意指可药用材料、组合物或载剂,例如液体或固体过滤剂、稀释剂、赋形剂、溶剂或封装材料。每一种载体在与所述制剂的其他成分相容并且对患者无损害的意义上必须是“可接受的”。可充当可药用载体的材料的一些实例包括(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和纤维素乙酸酯;(4)粉状西黄芪胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,例如可可豆脂和栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;(10)二醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;(12)酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14)缓冲剂,例如氢氧化镁和氢氧化铝;(15)藻酸;(16)无热原水;(17)等渗盐水;(18)林格液;(19)乙醇;(20)磷酸盐缓冲溶液;以及(21)用于药物制剂的其他无毒性相容物质。
胶囊制剂可包含被添加至胶囊中的典型赋形剂,其包括但不限于:填充剂如微晶纤维素、大豆多糖、磷酸钙二水合物、硫酸钙、乳糖、蔗糖、山梨醇或任何其他的惰性填充剂。此外,可以有助流剂,例如烘熏的二氧化硅、硅胶、硬脂酸镁、硬脂酸钙或赋予良好流动特性的任何其他材料。如果期望的话,还可添加润滑剂,例如聚乙二醇、亮氨酸、山嵛酸甘油酯、硬脂酸镁或硬脂酸钙。
所述制剂可便利地存在于单位剂型中并且可通过药学领域公知的任何方法来制备。所有方法包括将药物与构成一种或更多种辅助成分的载体或稀释剂组合。一般而言,所述制剂通过以下方法制备:使药剂与载体均匀并紧密组合,然后如果需要则将产物分成其单位剂型。本领域技术人员应理解,常规采用的且相对于活性剂为惰性的且在采用生物黏附包衣的实施方案中优选不干扰生物黏附的任何载剂或载体可用于制备和施用本发明药物组合物。此类载剂和载体的实例是例如Remington′s Pharmaceutical Sciences,第18版,(1990)中所述的那些,其公开内容通过引用并入本文。
载体和稀释剂的具体实例包括可药用水凝胶,例如藻酸盐、壳聚糖、甲基丙烯酸甲酯、纤维素及其衍生物(微晶纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素、乙基纤维素)、琼脂糖和POVIDONE.TM、高岭土、硬脂酸镁、淀粉、乳糖、蔗糖、密度控制剂(density-controlling agent)(如硫酸钡和油)、溶出增强剂(例如天冬氨酸、柠檬酸、谷氨酸、酒石酸、碳酸氢钠、碳酸钠、磷酸钠、甘氨酸、三甲基甘氨酸(tricine)、氨丁三醇和TRIS)。
本领域技术人员会认识到,施用的治疗作用所需的药量当然随所选药剂、病症特性和严重性以及动物经受的治疗改变而改变,并且最终由医生判定。此外,药物单独剂量的最佳量和间隔由所治疗病症的特性和程度,施用形式、途径和部位,所治疗的具体患者来确定,并且这种最佳条件可通过常规技术确定。还应理解,最佳疗程(即,给予剂量的次数)可由本领域技术人员使用常规的疗程确定测试来确定。
依碳酸瑞格列净可以以下述量每天一次施用:以一种固体形式(如片剂)或一种胶囊中的至少约200mg,特别是约250mg至500mg。
此外,根据本发明,本发明的立即/延迟释放依碳酸瑞格列净制剂经至少一小时达到血浆依碳酸瑞格列净浓度(Cmax),并且使达到最大依碳酸瑞格列净血浆浓度的时间(Tmax)提高至少约3小时(但范围为2~4小时),同时对血浆-依碳酸瑞格列净浓度时间曲线下面积(AUC)具有适中的作用。因此,本发明的立即/延迟释放依碳酸瑞格列净制剂可用于每天一次依碳酸瑞格列净给药以治疗糖尿病。
附图
图1提供了可通过3个单独具体实施方案表征的本发明片剂18。片剂18可具备立即释放第一药物活性成分的均匀层22、延迟释放第一药物活性成分的离散颗粒23、延迟释放黏合剂20和第二药物活性成分的离散颗粒24,在这种情况下所述离散颗粒24(鉴于其包含在黏合剂20中)是延迟释放的。
作为替代地以及其次,片剂18可具备第二活性物的立即释放层22、延迟释放第一药物活性成分的离散延迟释放颗粒23、立即释放黏合剂20和所述第一活性物的离散颗粒24。
第三,片剂18可具备颜色层22、延迟释放第一活性物的离散延迟释放颗粒23、立即释放黏合剂20和所述第一活性物的立即释放颗粒24。
图2可通过两个实施方案来表征。第一,片剂26可具备所述第一活性物的立即释放均匀层28、所述延迟释放第一活性物的离散颗粒31、延迟释放黏合剂30和第二活性物的离散颗粒32。
作为替代地以及其次,片剂26可具备所述第一活性物的立即释放均匀层28和所述第一活性物的立即释放颗粒32。所述延迟释放第一活性物作为立即释放黏合剂30中的延迟释放离散颗粒31而提供。
图3可通过两个实施方案来表征。第一,片剂10可包含完全覆盖固体核心12的包衣层16,其中所述层16是所述第一活性物的均匀立即释放制剂。布置在核心12内的是延迟释放第一活性物的颗粒13和延迟释放第二活性物的颗粒14。
作为替代地以及其次,片剂10可包含摄入后迅速溶解的包衣层16。布置在层16内的是立即释放黏合剂12和立即释放第一活性物的离散颗粒13和所述第一活性物延迟释放制剂的离散颗粒14。
图4可通过两个实施方案来表征。第一,明胶胶囊或囊片9可包含内部部分8,所述内部部分8包含立即释放珠/微丸/颗粒6和控制/延迟/持续释放珠/微丸/颗粒7。这些珠6和7的每一种都是含有第一药物成分或第一和第二药物成分的离散实体。胶囊9的其余内部8包含可以是固体或流动固体的赋形剂或载体以携带珠6和7。
作为替代地以及其次,胶囊或囊片9可包含内部部分8,其包含用于摄入后立即释放的第一药物活性成分的均匀混合物。基质8内还包含活性成分彼此释放时间不同的两种分开的珠/微丸/颗粒6和7。例如,珠6在摄入后可以约2~3小时的Tmax释放,而微丸7可在摄入后释放约4~5小时。因此,胶囊9可具有依碳酸瑞格列净的3种分开且不同的制剂,从而使瑞格列净的血液浓度在至少约5小时的时间中达到至少约50纳克/ml。
在图1、2、3和4的所有以上描述中,所述第一药物活性成分为依碳酸瑞格列净或其盐。所述第二活性物(如果存在)如本文所述进行选择。此外,第二活性物的描述可通过整体除去所述第二活性物而很容易地修改。
参照实施例1
依碳酸瑞格列净是抑制钠依赖性葡萄糖转运蛋白2(SGLT2)的活性实体瑞格列净(也称为GSK189074)的前药。但是,瑞格列净的短半衰期(约1.5至2小时)很可能必须每日给药两次才有效。进行了临床研究以确定多种修饰/持续释放(MR)制剂之一是否在给药间隔期间延长药物效应动力学(PD)作用,并因此允许比IR制剂所需剂量更低的总日剂量(每日施用两次)。MR制剂中的任何一种可提供每日一次给药机会的希望很小(表1)。
表1.修饰释放制剂对GSK189075之PK参数的作用
1.几何平均数(%CVb)2.中值(范围)
3.平均值(范围)
4.GSK189074的AUC(0-<XI)与GSK189075的AUC(0-∞)的比值
处理AA:GSK189075,200mg IR经口片剂
处理BB:GSK189075,250mg IR经口片剂
处理CC:具有GSK189075,200mg IR包衣的DiffCORE经口片剂
处理DD:包含GSK189075,200mg的双层基质经口片剂
处理EE:经口胶囊中的GSK189075,200mg肠溶微丸
处理FF:经口片剂中的GSK189075,200mg肠溶微粒
参照实施例2
已进行的临床研究表明依碳酸瑞格列净只在上GI道中被吸收(表2)。在经口施用立即释放IR制剂中的依碳酸瑞格列净之后,母体药物被迅速吸收并转化为瑞格列净(活性实体)。类似地,当将依碳酸瑞格列净的生物增强溶液或混悬液制剂直接施用于中段小肠时,依碳酸瑞格列净被迅速吸收并转化为瑞格列净。但是,当将生物增强溶液或混悬液制剂直接施用于盲肠/结肠时,观察到受限的依碳酸瑞格列净的吸收和/或向瑞格列净的转化。
基于tmax值,在所有处理之间体循环中依碳酸瑞格列净和瑞格列净的出现率相当,但是当将混悬液施用于盲肠/结肠时,在两个对象中观察到瑞格列净的tmax略微延迟。使用依碳酸瑞格列净的IR经口片剂作为参照处理,当将生物增强溶液或混悬液制剂直接施用于中段小肠时,由AUC(0-无穷大)或AUC(0-最终)测定的活性化合物瑞格列净的生物利用度程度分别降低约4%或12%;并且当将生物增强溶液或混悬液制剂直接施用于盲肠/结肠时,分别降低约83%或96%。与将生物增强溶液施用于中段小肠时相比,将混悬液施用于中段小肠时瑞格列净的生物利用度程度略低(8%);但是与将生物增强溶液施用于盲肠/结肠时相比,将混悬液施用于盲肠/结肠时瑞格列净的生物利用度程度显著降低(80%)。在所有的处理中,经口施用的IR片剂具有最高程度的瑞格列净生物利用度,而施用于盲肠/结肠的混悬液具有最低程度的瑞格列净生物利用度。
这些数据表明经口施用的依碳酸瑞格列净广泛并主要在中段小肠中吸收和/或转化为瑞格列净,而很少在盲肠/结肠中吸收和/或代谢转化为瑞格列净。与经口IR片剂或药物递送至中段小肠相比,当将依碳酸瑞格列净制剂直接递送至盲肠/结肠时,代谢物与母体AUC之比值要小得多。将IR片剂用作参照,将生物增强溶液或混悬液制剂直接施用于中段小肠时,依碳酸瑞格列净cmax分别降低约22%或40%;而将生物增强溶液或混悬液制剂直接施用于盲肠/结肠时,分别降低约82%或96%。
依碳酸瑞格列净在胃肠道下部的固有不良渗透性,导致吸收几乎仅发生在胃肠道上部。其半衰期也很短(t1/2=1.5小时)。这可导致难以在三次主餐期间提供所需量化合物的释放和后续的葡萄糖血浆移动。
表2:对GSK189074局部吸收的分析
处理 | 单剂量,100mg,GW189075施用 |
A | 经口服用立即释放片剂 |
B | 向中段小肠施用混悬液 |
C | 向中段小肠施用生物增强溶液 |
D | 向盲肠/结肠施用生物增强溶液 |
E | 向中段小肠施用混悬液 |
实施例1
依碳酸瑞格列净胶囊(立即释放/延迟释放)
根据下表3将多种浓度的依碳酸瑞格列净配制得到包含250mg至500mg活性成分/胶囊的胶囊:
表3
立即释放制剂 | 延迟释放制剂 | 赋形剂 |
50mg | 200mg | 100mg |
100mg | 200mg | 150mg |
50mg | 250mg | 100mg |
100mg | 250mg | 150mg |
50mg | 300mg | 150mg |
100mg | 300mg | 200mg |
50mg | 350mg | 200mg |
100mg | 350mg | 200mg |
50mg | 400mg | 200mg |
100mg | 400mg | 200mg |
因为瑞格列净在下胃肠道中的不良渗透性,所以可看到在吸收几乎仅在上胃肠道中。根据食物摄取、个体差异等,该吸收窗的范围为3至6小时。瑞格列净的半衰期也很短(t=1.5小时)。为了解决这些问题,根据实施例1a至1j产生的片剂释放IR低剂量和DR高剂量的药物,以实现下述暴露特征:在三次主要葡萄糖移动(早餐、午餐和晚餐)期间最大程度地抑制SGLT2,而在睡眠期内使化合物暴露尽可能小。因此,实施例1c是包含IR制剂的约350mg压制片剂,使得摄入1小时后最大瑞格列净血浆浓度为160ng/mL。这个Cmax在3小时后从血清清除至40ng/mL。此时,使Tmax从摄入后提高至4~5小时的DR制剂将释放250mg的活性物,使Cmax为450ng/mL,然后在约下午10点清除至血浆水平为约10ng/mL。
用水/聚维酮溶液将依碳酸瑞格列净、微晶纤维素和交联羧甲基纤维素钠制粒。将微粒干燥并粉碎,然后与甘露醇、微晶纤维素和交联羧甲基纤维素混合。用硬脂酸镁润滑混合物并进行压制。
通过用包含微粒化依碳酸瑞格列净、聚维酮和纯化水的水性混悬液,然后用水性Opadry混悬液,然后用甲基丙烯酸共聚物、单硬脂酸甘油酯、聚山梨醇酯80、柠檬酸三乙酯和纯化水的水性肠溶性混悬液包被微晶纤维素球体,制备包肠溶衣的药物分层微丸。通过标准流程并使用常规赋形剂来制备该制剂。
将50mg和100mg IR配制的微丸各自与200mg、250mg、300mg和400mg包肠溶衣的微丸(DR制剂)定量混合并填充到羟丙甲纤维素(羟丙基甲基纤维素或HPMC)胶囊壳体中。或者,可将IR和DR配制的微丸压制成片剂,如实施例2所述。
实施例2
依碳酸瑞格列净片剂(立即释放/延迟释放)
根据下表4将多种浓度的依碳酸瑞格列净配制并压成片剂,得到每片包含350mg至700mg成分的立即释放/延迟释放片剂,其包含活性成分:
表4
立即释放制剂 | 延迟释放制剂 | 赋形剂 |
50mg | 200mg | 100mg |
100mg | 200mg | 150mg |
50mg | 250mg | 100mg |
100mg | 250mg | 150mg |
50mg | 300mg | 150mg |
100mg | 300mg | 200mg |
50mg | 350mg | 200mg |
100mg | 350mg | 200mg |
50mg | 400mg | 200mg |
100mg | 400mg | 200mg |
因此,本发明的新制剂在向进行糖尿病治疗的人每天一次施用依碳酸瑞格列净时表现出了显著的进步。
上述实施例中所述的依碳酸瑞格列净制剂可以一个、两个或更多个片剂或胶囊并且如上所述每天一次施用,以提供最佳治疗控制。
本发明包括这些方面和实施方案的组合,以及整个本说明书的如本文所述的具体实施方案。
除非另有说明,否则具体术语或短语没有具体定义的事实不应与不确定或不清楚相关,相反地,本文中的术语在其一般含义范围内使用。当本文中使用商标名时,申请人旨在独立地包括所述商标名产品和所述商标名产品的活性药物成分。
观察到的具体药理学应答可根据并依赖于所选择的具体活性化合物或是否存在药物载体,以及制剂类型和采用的施用方式而改变,并且根据本发明实践考虑了结果中的这些期望变化形式或差别。
虽然本文中详细阐明并描述了本发明的具体实施方案,但是本发明并不限于此。以上的详细描述仅作为本发明的示例提供,并且不应解释为构成本发明的任何限制。修改对于本领域技术人员是显而易见的,并且不偏离本发明精神的所有修改旨在包含于所附权利要求的范围内。
以下实施方案内容对应于原申请的权利要求书:
1.药物制剂,其包含(1)延迟释放固体颗粒相和(2)立即释放固体相,所述延迟释放固体颗粒相的颗粒分散并且包埋于所述立即释放固体相中,所述延迟释放固体颗粒相的所述颗粒包含(a)短半衰期化合物的药物,例如选自依碳酸瑞格列净或其可药用盐;和(b)延迟释放材料,并且所述立即释放固体相包含立即释放材料,其中所述延迟释放固体颗粒相和所述立即释放固体相二者中总释放材料的含量在按所述药物制剂的重量计约25%至约75%的范围内。
2.根据实施方案1所述的药物制剂,所述药物制剂是双相异质立即和延迟释放制剂,所述药物制剂被设计成使来自形成所述延迟释放固体颗粒相之所述颗粒的药物通过所述立即释放固体相释放到上胃肠道中。
3.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相和所述立即释放固体相二者中所述总释放材料的含量在按所述药物制剂的重量计约30%至约65%的范围内。
4.根据实施方案1所述的药物制剂,其中所述药物是依碳酸瑞格列净。
5.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述延迟释放材料不同于所述立即释放固体相中存在的所述立即释放材料。
6.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相和所述立即释放固体相二者中所述总释放材料的含量在按所述药物制剂重量计约35%至约60%的范围内。
7.根据实施方案3所述的药物制剂,其中所述延迟释放固体颗粒相包含基于所述延迟释放固体颗粒相重量约5%至约95%的延迟释放材料,并且所述立即释放固体相包含基于所述立即释放固体相重量约40%至约100%的立即释放材料。
8.根据实施方案1所述的药物制剂,当所述药物制剂被人摄入时使所述延迟释放材料达到最大瑞格列净血浆浓度的时间(Tmax)提高至少约3小时,同时使所述立即释放材料的所述时间为约1小时。
9.根据实施方案1所述的药物制剂,其包含治疗有效量的依碳酸瑞格列净,所述药物制剂允许患者每天一次的给药方案,同时提供对血浆葡萄糖的有效控制。
10.根据实施方案9所述的药物制剂,其最佳地仅在清醒期间减弱从患者摄入的膳食进入到血流中的葡萄糖移动,并且使得所述化合物在睡眠期间在血液中具有最小有效浓度。
11.根据实施方案9所述的药物制剂,其为一种或更多种片剂和/或一种或更多种胶囊的形式。
12.根据实施方案9所述的药物制剂,其提供每天一次约250mg至500mg的给药方案。
13.根据实施方案9所述的药物制剂,其中所述延迟释放固体颗粒相是离散的个体颗粒或微粒的形式,并且所述立即释放固体相基本上是基质,所述基质具有形成所述延迟释放固体颗粒相的个体颗粒,所述颗粒包埋于所述基质中并且分散于整个所述基质中。
14.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述延迟释放材料包含一种或更多种亲水聚合物,和/或一种或更多种疏水聚合物和/或一种或更多种其他疏水材料;并且所述立即释放固体相中的所述延长释放材料包含一种或更多种亲水聚合物,和/或一种或更多种疏水聚合物和/或一种或更多种其他疏水材料。
15.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述延迟释放材料包含一种或更多种离子聚合物,并且所述立即释放固体相中存在的所述立即释放材料包含一种或更多种非离子聚合物。
16.根据实施方案14所述的药物制剂,其中所述离子聚合物包括藻酸钠、卡波姆、羧甲基纤维素钙或羧甲基纤维素钠,并且所述非离子聚合物包括黏度等级范围为约4000cps至约100,000cps的羟丙甲纤维素2208USP和/或黏度等级范围为约3cps至约150cps的羟丙甲纤维素2910USP。
17.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相的平均粒径在约30μm至约0.8mm的范围内。
18.根据实施方案1所述的药物制剂,其中所述延迟释放固体颗粒相包含依碳酸瑞格列净,以及乙基纤维素和/或羧甲基纤维素钠和/或单硬脂酸甘油酯,并且所述立即释放固体相包含羟丙甲纤维素2208USP(100,000cps),和/或羟丙甲纤维素2910USP(5cps)和/或微晶纤维素。
19.根据实施方案1所述的药物制剂,其还包含其他抗高血糖剂和/或抗肥胖剂和/或降血脂剂。
20.根据实施方案19所述的药物制剂,其中所述其他抗高血糖剂是磺酰脲类、二甲双胍类、葡萄糖苷酶抑制剂、噻唑烷二酮类、胰岛素、胰高血糖素样肽-1或DPP-IV抑制剂。
21.根据实施方案20所述的药物制剂,其中所述其他抗高血糖剂是二甲双胍、格列本脲、格列吡嗪、吡格列酮、罗格列酮、西他列汀或艾塞那肽。
22.根据实施方案19所述的药物制剂,其中所述降血脂剂是MTP抑制剂、角鲨烯合成酶抑制剂、HMG CoA还原酶抑制剂、纤维酸衍生物、ACAT抑制剂、胆固醇吸收抑制剂、回肠Na+/胆汁协同转运蛋白抑制剂、胆汁酸螯合剂和/或烟酸或其衍生物。
23.根据实施方案22所述的药物制剂,其中所述降血脂剂是普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀。
24.根据实施方案19所述的药物制剂,其中所述抗肥胖剂是胰脂肪酶抑制剂、食欲抑制剂、大麻素受体(CB-1)拮抗剂、5HTC激动剂、多巴胺受体拮抗剂。
25.根据实施方案24所述的药物制剂,其中所述抗肥胖剂是赛尼可、西布曲明、芬特明、芬氟拉明、利莫那班、氯卡色林或安非他酮。
26.根据实施方案19所述的药物制剂,其中所述依碳酸瑞格列净以与所述其他抗高血糖剂、抗肥胖剂或降血脂剂约0.01∶1至约300∶1范围内的重量比存在。
27.用于制备双相立即/延迟释放递送系统之形式的根据实施方案1所述药物制剂的方法,其包括形成包含个体颗粒的固体颗粒相,所述颗粒包含依碳酸瑞格列净或其可药用盐和延迟释放材料;以及使形成所述固体颗粒相的所述个体颗粒与包含立即释放材料的固体相混合,从而使形成所述延迟释放固体颗粒相的所述个体颗粒分散并且包埋于所述立即释放固体相中。
28.药物制剂,其包含(1)由依碳酸瑞格列净和延迟释放剂构成的固体颗粒相和(2)固体相,其中分散并且包埋有所述延迟释放剂加依碳酸瑞格列净之固体颗粒相的颗粒,所述固体颗粒相的颗粒包含(a)依碳酸瑞格列净或其可药用盐和(b)延迟释放材料;并且所述固体相包含立即释放材料,其中所述立即释放固体颗粒相中存在的所述延迟释放材料不同于所述固体相中存在的所述立即释放材料,并且其中所述延迟释放固体颗粒相和所述立即释放固体相二者中总释放材料的含量在按所述药物制剂重量计约25%至约75%的范围内。
29.根据实施方案28所述的药物制剂,所述药物制剂是双相异质立即/延迟释放制剂,所述药物制剂被设计成使来自形成所述延迟释放固体颗粒相之所述颗粒的瑞格列净通过所述立即释放固体相释放到上胃肠道中。
30.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相和所述立即释放固体相二者中所述总释放材料的含量在按所述药物制剂重量计约30%至约65%的范围内。
31.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相包含基于所述延迟释放固体颗粒相重量约5%至约95%的释放材料。
32.根据实施方案29所述的药物制剂,其中所述立即释放固体相包含基于所述立即释放固体相重量约40%至约100%的延长释放材料。
33.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相是离散的个体颗粒或微粒的形式,并且所述立即释放固体相基本上是基质,所述基质具有形成所述延迟释放固体颗粒相的个体颗粒,所述颗粒包埋于所述基质中并且分散于整个所述基质中。
34.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相以与所述立即释放固体相约0.5∶1至约4∶1范围内的重量比存在。
35.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述依碳酸瑞格列净的量在按所述延迟释放固体颗粒相重量计约10%至约98%的范围内。
36.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述延迟释放材料包含一种或更多种亲水聚合物,和/或一种或更多种疏水聚合物和/或一种或更多种其他疏水材料;并且所述立即释放固体相中的所述立即释放材料包含一种或更多种亲水聚合物,和/或一种或更多种疏水聚合物和/或一种或更多种其他疏水材料。
37.根据实施方案36所述的药物制剂,其中所述延迟释放固体颗粒相中存在的所述延迟释放材料包含一种或更多种离子聚合物,并且所述立即释放固体相中存在的所述立即释放材料包含一种或更多种非离子聚合物。
38.根据实施方案37所述的药物制剂,其中所述离子聚合物包括藻酸钠、卡波姆、羧甲基纤维素钙或羧甲基纤维素钠,并且所述非离子聚合物包括黏度等级范围为约4000cps至约100,000cps的羟丙甲纤维素2208USP和/或黏度等级范围为约3cps至约150cps的羟丙甲纤维素2910USP。
39.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相的平均粒径在约30mm至约0.8mm的范围内。
40.根据实施方案29所述的药物制剂,其中所述延迟释放固体颗粒相包含依碳酸瑞格列净,以及乙基纤维素和/或羧甲基纤维素钠和/或单硬脂酸甘油酯,并且所述立即释放固体相包含羟丙甲纤维素2208USP(100,000cps),和/或羟丙甲纤维素2910USP(5cps)和/或微晶纤维素。
41.根据实施方案29所述的药物制剂,其还包含其他抗高血糖剂和/或降血脂剂和/或抗肥胖剂。
42.根据实施方案41所述的药物制剂,其中所述其他抗高血糖剂是二甲双胍类、磺酰脲类、葡萄糖苷酶抑制剂、噻唑烷二酮类、胰岛素、DPP-IV抑制剂或胰高血糖素样肽-1。
43.根据实施方案42所述的药物制剂,其中所述其他抗高血糖剂是二甲双胍、格列本脲、格列吡嗪、吡格列酮、罗格列酮、西他列汀或艾塞那肽。
44.根据实施方案41所述的药物制剂,其中所述降血脂剂是MTP抑制剂、角鲨烯合成酶抑制剂、HMG CoA还原酶抑制剂、纤维酸衍生物、ACAT抑制剂、胆固醇吸收抑制剂、回肠Na+/胆汁协同转运蛋白抑制剂、胆汁酸螯合剂和/或烟酸或其衍生物。
45.根据实施方案44所述的药物制剂,其中所述降血脂剂是普伐他汀、辛伐他汀、洛伐他汀、阿托伐他汀、氟伐他汀或西立伐他汀。
46.根据实施方案41所述的药物制剂,其中所述抗肥胖剂是胰脂肪酶抑制剂、食欲抑制剂、大麻素受体(CB-1)拮抗剂、5HTC激动剂、多巴胺受体拮抗剂。
47.根据实施方案46所述的药物制剂,其中所述抗肥胖剂是赛尼可、西布曲明、芬特明、芬氟拉明、利莫那班、氯卡色林或安非他酮。
48.根据实施方案29所述的药物制剂,当所述药物制剂被人摄入时引起依碳酸瑞格列净以约1小时的Tmax释放并且使达到最大瑞格列净血浆浓度的时间(Tmax)提高至少约3小时至4小时,而对血浆瑞格列净浓度时间曲线下面积(AUC)的作用不显著。
49.根据实施方案1所述的药物制剂,其中所述短半衰期药物是依碳酸瑞格列净盐酸盐。
50.用于向哺乳动物经口施用的固体药物组合物,其包含:
i)第一相,其包含药物活性成分,并且所述药物活性成分在摄入后立即释放,和
ii)第二相,其包含所述药物活性成分,其在所述活性成分从所述第一相i)中基本上完全释放之后释放,
其中所述药物活性成分是依碳酸瑞格列净或其可药用盐。
51.根据实施方案50所述的固体药物组合物,其中所述组合物是片剂。
52.根据实施方案51所述的固体药物组合物,其中所述组合物包含含有所述第一相i)的外层和含有所述第二相ii)的内核。
53.根据实施方案52所述的固体药物组合物,其中所述外层完全覆盖所述内核。
54.根据实施方案51所述的固体药物组合物,其中所述组合物包含外层和内核,所述内核包含所述第一相i)和所述第二相ii)二者的离散颗粒。
55.根据实施方案50所述的固体药物组合物,其中所述药物活性成分是依碳酸瑞格列净盐酸盐。
56.根据实施方案50所述的固体药物组合物,其中所述组合物还包含第二药物活性成分。
57.根据实施方案50所述的固体药物组合物,其中所述组合物包含约250mg至500mg依碳酸瑞格列净或其可药用盐。
58.根据实施方案57所述的固体药物组合物,其中所述组合物在所述第一相i)中包含约50mg至200mg依碳酸瑞格列净或其可药用盐,并且在所述第二相ii)中包含约200mg至400mg依碳酸瑞格列净或其可药用盐。
59.根据实施方案50所述的固体药物组合物,其中所述组合物是胶囊。
60.治疗糖尿病的方法,其包括向有此需要的哺乳动物施用根据实施方案50所述的药物组合物。
61.根据实施方案60所述的方法,其中所述组合物每天施用一次。
62.依碳酸瑞格列净或其可药用盐的经口剂型,所述经口剂型包含依碳酸瑞格列净或其可药用盐的两种不同制剂,其中所述第一制剂在经口摄入后产生约1小时或更小的摄入后Tmax,并且所述第二制剂产生约2至6小时的第二Tmax。
63.根据实施方案62所述的经口剂型,其中所述第一制剂包含约50mg至100mg依碳酸瑞格列净或其可药用盐,并且所述第二制剂包含约200mg至400mg依碳酸瑞格列净或其可药用盐。
64.根据实施方案63所述的经口剂型,其中所述第一制剂包含50mg或100mg依碳酸瑞格列净或其可药用盐,并且所述第二制剂包含200mg、250mg、300mg或400mg依碳酸瑞格列净或其可药用盐。
65.根据实施方案62所述的经口剂型,其中所述剂型包含每单位剂型约500mg或更少的依碳酸瑞格列净或其可药用盐。
Claims (9)
1.经口剂型,其包含
A)离散颗粒,其包含200mg至400mg依碳酸瑞格列净和延迟释放材料,所述延迟释放材料包含离子聚合物;和
B)离散颗粒,其包含50mg至100mg依碳酸瑞格列净和立即释放材料,所述立即释放材料包含非离子聚合物,
其中所述延迟释放材料和立即释放材料的合并重量是所述经口剂型的总重量的35%至60%,并且其中所述经口剂型还包含抗高血糖剂。
2.根据权利要求1所述的经口剂型,其中所述离散颗粒(A)和所述离散颗粒(B)以(A)∶(B)的重量:重量比为0.8∶1至2∶1存在。
3.根据权利要求1所述的经口剂型,其中所述离散颗粒(A)的平均尺寸为30μm至800μm。
4.根据权利要求1所述的经口剂型,其中所述剂型是明胶胶囊羟丙基甲基纤维素胶囊。
5.根据权利要求1所述的经口剂型,其中所述离子聚合物是甲基丙烯酸-丙烯酸乙酯共聚物。
6.根据权利要求1所述的经口剂型,其中所述延迟释放材料还包含聚乙烯吡咯烷酮。
7.根据权利要求6所述的经口剂型,其中通过用依碳酸瑞格列净和延迟释放材料包被微晶纤维素球体以形成包含200mg至400mg依碳酸瑞格列净和延迟释放材料的所述离散颗粒(A)。
8.根据权利要求1至7中任一项所述的经口剂型,其中所述抗高血糖剂是二甲双胍、格列本脲、格列吡嗪、吡格列酮、罗格列酮、西他列汀或艾塞那肽。
9.根据权利要求8中任一项所述的经口剂型,其中所述抗高血糖剂是二甲双胍。
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MX2013000339A (es) | 2015-05-11 |
AU2011276254B2 (en) | 2016-11-03 |
JP2013531036A (ja) | 2013-08-01 |
RU2596787C2 (ru) | 2016-09-10 |
EP2590634A2 (en) | 2013-05-15 |
RU2013105481A (ru) | 2014-08-20 |
IL224142B (en) | 2018-01-31 |
ZA201300877B (en) | 2014-04-30 |
CN103153288B (zh) | 2017-02-15 |
ES2575860T3 (es) | 2016-07-01 |
AU2011276254A1 (en) | 2013-02-28 |
PL2590634T3 (pl) | 2016-10-31 |
WO2012006398A3 (en) | 2012-04-05 |
EP2590634B1 (en) | 2016-03-09 |
MX342120B (es) | 2016-09-14 |
RU2016125229A (ru) | 2018-12-04 |
JP2016188240A (ja) | 2016-11-04 |
WO2012006398A2 (en) | 2012-01-12 |
BR112013000626B1 (pt) | 2019-11-26 |
CA2804926A1 (en) | 2012-01-12 |
JP6042330B2 (ja) | 2016-12-14 |
CA2804926C (en) | 2019-01-08 |
CN103153288A (zh) | 2013-06-12 |
US10940159B2 (en) | 2021-03-09 |
US20130209563A1 (en) | 2013-08-15 |
BR112013000626A2 (pt) | 2016-05-24 |
MY161846A (en) | 2017-05-15 |
EP2590634A4 (en) | 2013-11-13 |
KR101942590B1 (ko) | 2019-01-25 |
KR20140018832A (ko) | 2014-02-13 |
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