CN1602187A - 通过喷雾干燥法制备的口内崩解的伐地考昔组合物 - Google Patents
通过喷雾干燥法制备的口内崩解的伐地考昔组合物 Download PDFInfo
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Abstract
提供了口内崩解的伐地考昔速溶片剂和制备这类剂型的方法。这些组合物可用于治疗或预防环加氧酶-2介导的病症和疾病。
Description
发明领域
本发明涉及口内崩解的药物组合物,含有伐地考昔作为活性成分,还涉及制备这类组合物的方法和治疗环加氧酶-2介导疾病的方法,包含对受治疗者口内给药这类组合物。
发明背景
化合物4-(5-甲基-3-苯基-4-异噁唑基)苯磺酰胺在本文中也被称为伐地考昔,Talley等的美国专利5,633,272号公开了这种化合物以及制备该化合物和有关化合物的方法,在此引用作为参考。伐地考昔具有下列结构:
包括伐地考昔在内的上述美国专利5,633,272号所报道的化合物在其中被公开作为有用的消炎、止痛与退热药,相对于环加氧酶-1(COX-1)而言对环加氧酶-2(COX-2)的抑制作用具有高度的选择性。上述美国专利5,633,272号还包含对这类化合物给药制剂的一般性参考,包括口服可释放的剂型,例如片剂和胶囊剂。
伐地考昔在水中的溶解性极低。例如参见Dionne(1999),″COX-2inhibitors-IBC Conference,12-13 April 1999,Coronado,CA,U.S.A.″,IDrugs,2(7),664-666。
美国专利5,576,014号,在此引用作为参考,公开了颊内溶解的模压制剂,它是借助湿法造粒过程制备的,其中将一种模压性低的糖与一种模压性高的糖一起造粒,形成颗粒,然后压制成模制物。所得模制物能够掺入药物,据说在口腔前庭显示快速的崩解和溶解,但是维持足够的硬度,以便在生产和分配期间不会破碎。美国专利5,576,014号的模压制剂是一类被称为“速溶片”的剂型,表现药物在口内的迅速崩解,通常与载体材料通常为糖结合,并且伴有在口内迅速溶解或分散,通常除了唾液所含有的水以外不需要额外的水。配制在这样一种片剂中的药物是容易吞咽的。
共同转让的国际专利公开WO 01/41761号公开了口服可释放的伐地考昔组合物,具有快速起效的性质。其中所公开的组合物没有一个是口内崩解的组合物。
很多口内崩解的组合物,甚至含有糖和/或甜味剂和/或矫味剂的那些所面临的众所周知的问题是由其中活性药物的存在所致令人不快的味道。一般而言,随着存在于特定口内崩解剂型中的活性药物量降低,和/或随着药物水溶性降低,剂型的苦味和/或酸味将更少。例如参见Lieberman等(1989),Pharmaceutical Dosage Forms:Tablets Vol.1,pp.381.Marcel Dekker,New York。伐地考昔是一种水溶性非常低,并且剂量需求相对低的药物,因此将被预期当配制成口内崩解的组合物时,具有可接受的,或者最少仅为适度令人不快的感官性质。不过惊人的是,我们现已发现伐地考昔极其令人不快的味道。因而,仍然需要口内崩解性伐地考昔组合物,具有可接受的感官性质。
通过抑制适度或高度水溶性药物的口内溶解而起作用的味道掩蔽技术已经应用于药物剂型。例如参见Lieberman等(1989),同上。在这种情况下,据信减少在进入胃肠道之前溶解在口中的药物量可以改善味道。不过既然伐地考昔的水溶性已经极低,不能预期任意进一步减少伐地考昔的口内溶解会引起感官性质改善。进而,预期另外减少伐地考昔的水溶性会导致不可接受的治疗起效延迟。不过惊人的是,我们现已发现了制备感官上可接受的口内崩解性伐地考昔组合物的方法,该组合物表现改善了的感官性质,而且仍然表现治疗效果的迅速起效。
发明概述
因此,现在提供制备口内崩解性伐地考昔组合物(例如速溶片剂)的方法,该方法包含提供微粒形式伐地考昔的步骤;在容器内水中溶解至少一种表现迅速口内溶解的药学上可接受的赋形剂的步骤;将伐地考昔分散在水中的步骤,和任选的将水加热的步骤。溶解、分散和任选的加热步骤是按任意顺序或者同时进行的,得到可喷雾的液体。该方法进一步包含将可喷雾液体喷雾干燥形成压片掺合物的步骤,和将该压片掺合物压制成片剂的步骤。在本发明的方法中,将至少一种表现迅速口内溶解的药学上可接受的赋形剂溶于水,总量是这样的,一旦该过程完成,至少一种表现迅速口内溶解的赋形剂为约50%至约99%,优选约50%至约95%,更优选约50%至约90%,按片剂重量计。
该方法任选地进一步包含在喷雾干燥步骤之前,向容器加入湿润剂或这类湿润剂的水溶液的步骤。
用这样一种方法制备的组合物代表本发明的一个实施方案。
现在还提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种表现迅速口内溶解的药学上可接受的赋形剂,它与伐地考昔微粒是紧密结合的。该组合物是感官上可接受的,至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,优选约50%至约95%,更优选约50%至约90%,按组合物重量计。
本文中的“紧密结合”例如包括与表现迅速口内溶解的赋形剂混合的伐地考昔、包埋或掺入在表现迅速口内溶解的赋形剂中的伐地考昔、在表现迅速口内溶解的赋形剂微粒上形成包衣的伐地考昔或反之亦然、和基本上均匀的伐地考昔遍及表现迅速口内溶解的赋形剂的分散体。这样一种紧密结合例如由上文公开的方法所形成;另外,在制备本发明的组合物时可以采用其他手段形成这样一种紧密结合。
与表现迅速口内溶解的赋形剂紧密结合(association)的伐地考昔在本文中也被称为“伐地考昔复合物”。本文关于包含多种组分的复合物或药物组合物的术语“基本上均匀”意味着这些组分是充分混合的,以便个别组分在组合物内不呈现离散的层,并且不形成浓度梯度。不受理论所限,据信本发明方法和组合物中相对高比例的表现迅速口内溶解的赋形剂与伐地考昔、和/或伐地考昔与表现迅速口内溶解的赋形剂的紧密结合导致具有改良感官性质的伐地考昔复合物的形成。
特别有用的本发明口内崩解的组合物是一种迅速崩解的口用剂型,它无需饮水或其他液体即可溶解在口中(例如速溶)。本文所用的术语“速溶”表示这样一种组合物,例如药片,其中活性成分或药物分配或分散在由载体构成的基质中,该载体在组合物对受治疗者口内给药后在口腔中崩解,由此释放药物,通常为微粒形式,通过吞咽进入胃肠道,随后吸收。术语“口腔”包括口的整个内部,不仅包括口腔前庭(牙齿和齿龈前面的口腔部分),而且包括舌下和舌上空间。
“感官上可接受的”剂型或具有“可接受的感官性质”的剂型是这样一种剂型,在提供单剂治疗剂的量的口内相互作用后,不会产生过分令人不快的味道、气味或口感,例如明显的苦味,这是由大多数人类受治疗者所感知的,或者是由盲味道评价研究分析所测定的,如下文所述。
已经发现本发明的方法和组合物克服了伐地考昔的不可接受的感官性质,不会不可接受地牺牲迅速起效特征或治疗有效性。因而,作为显著的技术进步,现在提供伐地考昔的感官上可接受的速溶制剂。本发明组合物的确切优点是它们具有改善了的感官性质,而不表现治疗起效时间有实质性延长,并且借助本文所述方法能够有效地制备这类组合物。
发明的详细说明
具体的本发明实施方案是口内速溶组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种表现迅速口内溶解的药学上可接受的赋形剂;其中该组合物是感官上可接受的。该组合物中至少一种表现迅速口内溶解的药学上可接受的赋形剂与伐地考昔微粒是紧密结合的,总含量为约50%至约99%,优选约50%至约95%,更优选约50%至约90%,按重量计。
有关的本发明实施方案提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与所述伐地考昔微粒是紧密结合的;其中该组合物是感官上可接受的;其中至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,按组合物重量计;并且其中在置于人类受治疗者口腔中之后,该组合物在60秒内崩解,优选在约30秒内,更优选在约15秒内崩解。
另一有关的本发明实施方案提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与所述伐地考昔微粒是紧密结合的;其中该组合物是感官上可接受的;其中至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,按组合物重量计;并且其中在置于美国药典24体外崩解试验701号中时,该组合物表现小于约300秒的崩解时间,优选小于约200秒,更优选小于约100秒。
另一有关的本发明实施方案提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与所述伐地考昔微粒是紧密结合的;其中该组合物是感官上可接受的;其中至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,按组合物重量计;并且其中该组合物对人类受治疗者的给药导致伐地考昔的治疗效果阈浓度出现在给药后约0.5小时内,优选在约0.3小时内。
“治疗效果阈浓度”表示与给药伐地考昔的特定适应症的治疗益处一致的血清中最低伐地考昔浓度。通常,该阈浓度为至少约20ng/ml,例如约25ng/ml至约75ng/ml。
将被理解的是,剂量单元中有效提供治疗效果阈浓度的伐地考昔量尤其依赖于受治疗者的体重。举例来说,若受治疗者是儿童或小型动物(例如狗),在约1mg至约100mg的治疗有效范围内的相对低的伐地考昔量很可能提供与阈浓度和Cmax标准一致的血清浓度。若受治疗者是成人或大型动物(例如马),所示伐地考昔血清浓度很可能需要相对更大的伐地考昔剂量。就成人而言,适合于提供所示血清浓度的本发明组合物中每剂伐地考昔量通常为约5mg至约40mg。
有关的本发明实施方案提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与所述伐地考昔微粒是紧密结合的;其中该组合物是感官上可接受的;其中至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,按组合物重量计;并且其中该组合物对人类受治疗者的给药导致最大血清浓度(Cmax)不小于约100ng/ml。
另一有关的本发明实施方案提供口内崩解的组合物,包含(a)治疗有效量的微粒状伐地考昔,和(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与所述伐地考昔微粒是紧密结合的;其中该组合物是感官上可接受的;其中至少一种表现迅速口内溶解的药学上可接受的赋形剂的总含量为约50%至约99%,按组合物重量计;并且其中该组合物对人类受治疗者的给药导致达到最大血清浓度的时间(Tmax)不大于约5小时,优选不大于约4小时,更优选不大于约3小时。
本发明组合物的成分
本发明的组合物包含伐地考昔作为活性成分和至少一种表现迅速口内溶解的药学上可接受的赋形剂。任选地,本发明的组合物可以含有另外一种或多种药学上可接受的赋形剂,包括但不限于水溶性润滑剂、水不溶性润滑剂、崩解剂、助流剂、甜味剂、矫味剂、着色剂等。这类任选的额外组分应当在物理上和化学上与组合物其他成分是相容的,并且必须对受体是无害的。
伐地考昔
本发明的方法和组合物特别适合于以伐地考昔作为活性药物。制备微粒状伐地考昔的方法是本身已知的,例如上文引用的美国专利5,474,995号所述,在此引用作为参考。重要的是,任意固态形式的伐地考昔都可以用在本发明的方法和组合物中,例如国际专利公开98/06708号所述任意形式,在此引用作为参考。
本发明的伐地考昔剂量单元包含治疗有效量的伐地考昔,为约1mg至约100mg,优选约5mg至约50mg。本发明的组合物含有微粒形式的伐地考昔。例如通过碾磨或研磨或者从溶液中沉淀所生成的原生伐地考昔微粒能够聚集形成次生聚集微粒。本文所用的术语“粒径”表示原生微粒大小的最长尺寸,上下文另有要求除外。粒径据信是影响伐地考昔临床有效性的重要参数。因而在一种实施方案中,伐地考昔剂型具有这样的伐地考昔粒径分布,以便D90粒径不大于约75μm。“D90粒径”在本文中被定义为这样一种粒径,90重量%的微粒在它们的最长尺寸上小于该粒径。
另外或者作为替代选择,本发明剂型中的伐地考昔微粒优选地具有约1μm至约10μm,最优选约5μm至约7μm的重均粒径。
显示迅速口内溶解的赋形剂
显示迅速口内溶解的适合的赋形剂是那些药学上可接受的赋形剂,它们在水中是可溶性的、可自由溶解的或非常易溶性的,例如Ansel等(1995)Pharmaceutical Dosage Forms and Drug Delivery Systems 6th Ed,pp.228.Williams&Wilkins,Baltimore所述。优选地,这类赋形剂具有甜味。当前优选用在本发明组合物和方法中的一类显示迅速口内溶解的赋形剂是碳水化合物类。特别优选的表现迅速口内溶解的赋形剂是糖类,既包括低模压性糖,也包括高模压性糖。
当前优选的低模压性糖包括乳糖和甘露糖醇,特别是甘露糖醇的非直接压制或粉末形式,如Kibbe(2000)Handbook of PharmaceuticalExcipients,3rd Ed.,Pharmaceutical Press,pp.324-328所述。当前优选的高模压性糖包括麦芽糖、麦芽糖醇和山梨糖醇。作为替代选择,某些低聚糖可能是有用的。所使用的低聚糖是没有特别限制的,只要它在口腔中显示迅速的溶解并且由两个或多个单糖残基组成即可。若使用低聚糖,由2至6个单糖残基组成者是优选的,构成低聚糖的单糖残基类型与组合是没有限制的。特别优选的高模压性糖是麦芽糖和麦芽糖醇,特别是麦芽糖。
若高模压性糖和低模压性糖都存在于本发明组合物中,高模压性糖与低模压性糖的重量比对维持可接受的片剂硬度与迅速的口内崩解组合而言是重要的。适合的比例为每100重量份低模压性糖约2至约20重量份、优选约5至约10重量份、更优选约5至约7.5重量份的高模压性糖。
如果高∶低模压性糖的比例小于约2∶100重量比,那么片剂通常达不到它们的所需硬度,导致在贮存、运输或处置期间的破碎增加。或者,如果高∶低模压性糖的比例超过约20∶100重量比,片剂变得太硬,达不到所需的口腔中迅速崩解。
本发明组合物中显示迅速口内溶解的一种或多种赋形剂的总含量为约45%至约95%,优选约50%至约87%,更优选约55%至约80%。
湿润剂
本发明的组合物可选地包含一种或多种药学上可接受的湿润剂。表面活性剂、亲水性聚合物和某些粘土可以用作湿润剂,有助于疏水性药物,例如伐地考昔在湿法造粒期间被造粒流体湿润。若本发明的组合物是借助流化床造粒法制备的,组合物含有湿润剂是特别有利的。
可以用作本发明组合物中湿润剂的表面活性剂的非限制性实例包括季铵化合物,例如苯扎氯铵、苄索氯铵和氯化鲸蜡基吡啶鎓;二辛基磺基琥珀酸钠;聚氧乙烯烷基苯基醚,例如壬苯醇醚9、壬苯醇醚10和辛苯昔醇9;泊咯沙姆(聚氧乙烯与聚氧丙烯嵌段共聚物);聚氧乙烯脂肪酸甘油酯和油,例如聚氧乙烯(8)辛酸/癸酸单与二甘油酯(例如Gattefosse的LabrosolTM)、聚氧乙烯(35)蓖麻油和聚氧乙烯(40)氢化蓖麻油;聚氧乙烯烷基醚,例如聚氧乙烯(20)鲸蜡硬脂基醚;聚氧乙烯脂肪酸酯,例如聚氧乙烯(40)硬脂酸酯;聚氧乙烯脱水山梨醇酯,例如聚山梨醇酯20和聚山梨醇酯80(例如ICI的Tween 80);丙二醇脂肪酸酯,例如丙二醇月桂酸酯(例如Gattefosse的LauroglycolTM);月桂基硫酸钠;脂肪酸及其盐,例如油酸、油酸钠和三乙醇胺油酸盐;甘油脂肪酸酯,例如甘油单硬脂酸酯;脱水山梨醇酯,例如脱水山梨醇单月桂酸酯、脱水山梨醇单油酸酯、脱水山梨醇单棕榈酸酯和脱水山梨醇单硬脂酸酯;泰洛沙泊;和它们的混合物。在本发明的组合物中,月桂基硫酸钠是优选的湿润剂。
如果需要的话,一种或多种湿润剂在本发明组合物中的总含量通常为约0.05%至约5%,优选约0.075%至约2.5%,更优选约0.25%至约1%,例如约0.5%,按组合物重量计。
水不溶性润滑剂
本发明的组合物可选地包含一种或多种药学上可接受的水不溶性润滑剂作为载体材料。适合的水不溶性润滑剂包括单用或联用的甘油behapate(例如CompritolTM 888)、硬脂酸盐(镁、钙和钠)、硬脂酸、氢化植物油(例如SterotexTM)、胶体硅石、滑石、蜡和它们的混合物。任选地,水不溶性润滑剂可以与湿润剂混合使用,例如硬脂酸钙/月桂基硫酸钠混合物(例如SterowetTM)。
硬脂酸镁、硬脂酸及其混合物是优选的水不溶性润滑剂。
一种或多种水不溶性润滑剂可选地在本发明组合物中的典型总含量为约0.05%至约5%,优选约0.75%至约2.5%,更优选约1%至约2%,例如约1.5%,按组合物重量计。
水溶性润滑剂
本发明的组合物可选地包含一种或多种药学上可接受的水溶性润滑剂。水溶性润滑剂能够帮助改善片剂溶解特征。可以单独或联合用在本发明组合物中的水溶性润滑剂例如包括硼酸、苯甲酸钠、乙酸钠、富马酸钠、氯化钠、DL-亮氨酸、聚乙二醇(例如CarbowaxTM 4000和CarbowaxTM6000)和油酸钠。
崩解剂
本发明的组合物可选地包含一种或多种药学上可接受的崩解剂。不过,本文所提供的口服速溶片通常在口腔中迅速崩解,不需要加入崩解剂。如果需要的话,适合的崩解剂包括单用或联用的淀粉、淀粉羟乙酸钠、粘土(例如VeegumTM HV)、纤维素(例如纯化纤维素、甲基纤维素、羧甲基纤维素钠和羧甲基纤维素)、交联羧甲基纤维素钠、藻酸盐、预胶凝化玉米淀粉(例如Nathional 1551和National 1550)、交联聚维酮和树胶(例如琼脂、瓜尔胶、槐树豆胶、刺梧桐胶和黄蓍胶)。可以在组合物制备期间任意适合的步骤加入崩解剂,确切为造粒之前或者压片之前的掺合步骤期间。交联羧甲基纤维素钠和淀粉羟乙酸钠是优选的崩解剂。
一种或多种崩解剂可选地总含量为约0.05%至约15%,优选约0.5%至约10%,更优选约1%至约3.5%,按组合物重量计。
助流剂
本发明的组合物可选地包含一种或多种药学上可接受的助流剂,例如为了压片材料向片剂冲模的流动,防止压片材料黏附冲头和冲模,或者制成有光泽的片剂。可以在组合物制备期间任意适合的步骤加入助流剂,确切为造粒之前或者压片之前的掺合步骤期间加入。
不受理论所限,据信在有些情形中,助流剂、例如滑石或二氧化硅能够减少药物微粒之间的界面张力,具有抑制和/或减少药物聚集的效果,能够降低药物粉末表面的静电荷,还能够减少药物微粒的微粒间摩擦和表面皱褶。例如参见York(1975)J.Pharm.Sci.,64(7),1216-1221。
二氧化硅是优选的助流剂。适合用于制备本发明组合物的二氧化硅产品包括发烟硅石或胶体硅石(例如Cabot Corp.的Cab-O-SilTM和Degussa的AerosilTM)。二氧化硅当存在于本发明组合物中时,其总含量为约0.05%至约5%,优选约0.1%至约2%,更优选约0.25%至约1%,例如约0.5%,按组合物重量计。
甜味剂
本发明的组合物可选地包含一种或多种药学上可接受的甜味剂。可以用在本发明组合物中的甜味剂的非限制性实例包括甘露糖醇、丙二醇、糖精钠、乙酰舒泛K、neotame、阿斯巴坦等。
矫味剂
本发明的组合物可选地包含一种或多种药学上可接受的矫味剂。可以用在本发明组合物中的矫味剂的非限制性实例包括薄荷、留兰香、葡萄、樱桃、草莓、柠檬等。
片剂特征
大小和形状
在优选的实施方案中,本发明组合物是离散的固体剂量单元的形式,最优选片剂。本发明片剂可以被制成任意所需的大小,例如8mm、10mm、12mm等;形状,例如圆形、卵形、长圆形等;重量;和厚度。可选地,本发明的固体剂量单元可以在一侧或两侧具有刻痕或文字。
崩解
在置于标准体外崩解测定法中后(例如按照美国药典24(2000),TestNo.701进行),本发明优选的片剂组合物在不到300秒内崩解,优选不到约200秒,更优选不到约100秒,例如约30秒。
作为替代选择或者另外,在置于受治疗者口腔中后,本发明优选的速溶组合物在约60秒内崩解,优选在约30秒内,更优选在约15秒内崩解。
硬度
本发明固体剂型的硬度可以依赖于大小和形状以及组成等其他特征。片剂硬度可以借助本领域已知的任意方法测量,例如片剂硬度计(例如Schleuniger)。优选地,本发明组合物的硬度为约1至约10kp,更优选约1至约6kp。
在当前优选的实施方案中,本发明固体剂型具有足够处置的硬度,因此能够象普通片剂那样投入实际应用。本文所用的术语“足够处置的硬度”表示能够耐受从至少标准泡眼包装类型中取出的硬度,或者将耐受其他处置的硬度,例如包装、分配、携带等。
本发明片剂优选地具有一个最低硬度,以便在通过推动药片穿过覆盖片而从标准泡眼包装中取出期间防止药片破碎。适合的硬度就直径约8mm的片剂而言为约1kp或以上,就直径约10mm的片剂而言为约1.5kp或以上,就直径约12mm的片剂而言为约2kp或以上。
在另一种当前优选的实施方案中,本发明片剂具有足够的硬度,以便大量这样的药片能够包装在一起,例如在玻璃或塑料瓶中,无需单独包装,也不会在正常的运输和处置期间表现实质性破碎或黏附和/或混合在一起。打算如此包装的片剂优选地具有约3kp或以上的硬度。
包装
本发明组合物可以按照本领域已知的任意适合方式进行包装。举例来说,多重速溶片可以包装在一起,例如在玻璃或塑料瓶或容器中。作为替代选择,本发明速溶片可以单独包裹,例如在塑料或箔中,或者包装在已知形式的泡眼包装中。尤其可以用于包装本发明速溶片的泡眼包装具有改善了的力量分布性质,例如Grabowski的美国专利5,954,204号所公开的,在此引用作为参考。
速溶片的给药
根据受治疗者的选择或条件,受治疗者可以借助任意口内给药工具服用本发明组合物。举例来说,本发明速溶片可以无水服用。一旦置于口腔中,尤其是颊中或舌头上面,这样一种药片暴露于唾液,迅速崩解,溶解在其中。当向药片施加口内压力时,例如在颚与舌头之间的压力或者舐舔或吸吮压力,崩解和/或溶解的速率得以进一步增加。
作为替代选择,本发明药片可以借助水服用,水量足以使口腔湿润,帮助药片崩解。而且,在口腔中完全或部分崩解后,可以将本发明药片与少量水一起吞咽下去。还可以将本发明组合物与水直接吞咽下去。
制备速溶片的方法
下述方法是制备本发明伐地考昔速溶片的非限制性、例证性方法。重要的是,本领域技术人员能够容易地优化生产方法的具体设置和参数,目的是生产具有特别所需特征的片剂。
在这种例证性方法中,在容器内将麦芽糖和甘露糖醇溶于水,水被加热至大约50℃至约80℃,例如约70℃。然后利用匀化器将伐地考昔分散在容器内。在第二容器内将湿润剂、例如月桂基硫酸钠溶于水。然后合并第一与第二容器的内容物,形成混合物。利用Niro LaboratoryMobile Minor Spray Dryer将混合物喷雾干燥,形成干颗粒。然后可选地将干颗粒与任意所需的赋形剂,例如矫味剂、甜味剂和润滑剂掺合,形成压片掺合物。然后在旋转压片机上将所得压片掺合物压制成目标片重和硬度。然后处理所得药片,例如在湿度控制室内进行空气流处理,具有增加片剂硬度的效果。
压片
压片是这样的过程,在上下冲头之间压制适当体积的如上所述制备的压片掺合物,使原料固化成单一固体剂型,例如片剂。在本发明速溶片的制造过程中,可以采用任意适合于压片的工具,例如包括单冲压片机或高速旋转压片机。压片压力是没有限制的,可以选择适当的压力,这依赖于所得药片的所需硬度和溶解性质。若药片要经历下面直接所描述的温度与湿度处理,优选地将药片压制成约0.75至约1.5kp的初始硬度(在温度与湿度处理之前)。
温度与湿度处理
可选地,本发明药片可以在压片步骤之后经历热量与湿度处理。这类处理可以在湿度环境内进行,例如以增加片剂的硬度。举例来说,在这种处理期间,首先使药片受到低温、高湿气流条件处理,例如约25℃至约32℃和约80%相对湿度,历时约45至约120分钟。然后使药片受到高温、低湿条件处理,例如约35℃至约50℃和30%相对湿度,历时约45至约120分钟。不受理论所限,据信速溶片受低温/高湿环境处理继之以高温/低湿环境处理会增加片剂硬度,减少片剂脆性,而不会牺牲所需的速溶特征,例如迅速崩解和迅速溶解。
本发明组合物的实用性
本发明的模制品、以下也称为组合物可用于治疗和预防非常广泛的受环加氧酶-2(COX-2)介导的疾病,包括但不限于以炎症、疼痛和/或发热为特征的疾病。这类组合物尤其可用作消炎药,例如在关节炎的治疗中,其额外益处是毒副作用显著少于常规非甾族消炎药(NSAID)组合物,后者缺乏相对COX-1而言的COX-2选择性。确切而言,这类组合物与常规NSAID组合物相比,减少了胃肠毒性与胃肠刺激性的可能性,包括上部胃肠溃疡和出血;减少了肾副作用的可能性,例如肾功能下降,引起尿潴留和高血压恶化;减少了对出血时间的影响,包括对血小板功能的抑制;和可能弱化诱发阿司匹林敏感性气喘受治疗者的气喘发作的能力。因而,包含选择性COX-2抑制药的本发明组合物特别可用作常规NSAID的代用品,其中这类NSAID是禁忌使用的,例如患有消化溃疡、胃炎、局限性肠炎、溃疡性结肠炎、憩室炎的患者或具有胃肠损伤复发史的患者;患有胃肠出血、凝血疾病的患者,包括贫血,例如血凝血酶原过少、血友病或其他出血问题;患有肾疾病的患者;或者手术之前的患者或服用抗凝剂的患者。
这类组合物可用于治疗关节炎症,包括但不限于类风湿性关节炎、脊椎关节病、痛风性关节炎、骨关节炎、系统性红斑狼疮和青春期关节炎。
这类组合物还可用于治疗气喘、支气管炎、月经痛性痉挛、早产、腱炎、粘液囊炎、变应性神经炎、巨细胞病毒感染、编程性细胞死亡(包括HIV诱导的编程性细胞死亡)、腰痛、肝疾病(包括肝炎)、与皮肤有关的病症(例如牛皮癣、湿疹、痤疮、灼伤、皮炎和紫外辐射损伤,包括晒伤)、和术后炎症(包括继发于眼科手术者,例如白内障手术或屈光手术)。
这类组合物可用于治疗胃肠病症,例如炎性肠疾病、克罗恩氏病、胃炎、肠易激综合征和溃疡性结肠炎。
这类组合物可用于治疗见于一些疾病中的炎症,例如偏头痛、结节性动脉周炎、甲状腺炎、再生疾病性贫血、何杰金氏病、硬化病、风湿热、I型糖尿病、神经肌肉接点疾病(包括重症肌无力)、白质疾病(包括多发性硬化)、肉样瘤病、肾病综合征、贝切特氏综合征、多肌炎、齿龈炎、肾炎、过敏、术后肿胀(包括脑水肿)、心肌缺血等。
这类组合物可用于治疗眼科疾病,例如视网膜炎、巩膜炎、巩膜外层炎、结膜炎、视网膜病、眼色素层炎、畏光和眼组织急性损伤。
这类组合物可用于治疗肺部炎症,例如与病毒感染和囊性纤维变性有关的和骨吸收中的那些,例如与骨关节炎有关的那些。
这类组合物可用于治疗某些中枢神经系统病症,例如皮质性痴呆(包括阿尔茨海默氏病)、神经变性和由中风、缺血和创伤所致中枢神经系统损伤。本文中的术语“治疗”包括部分或完全地抑制痴呆,包括阿尔茨海默氏病、血管性痴呆、多梗塞性痴呆、早老性痴呆、酒精中毒性痴呆和老年性痴呆。
这类组合物可用于治疗变应性鼻炎、呼吸窘迫综合征、内毒素性休克综合征和肝疾病。
这类组合物可用于治疗疼痛,包括但不限于术后疼痛、牙痛、肌肉痛和由癌症所致疼痛。例如,这类组合物可用于缓解多种病症中的疼痛、发热和炎症,包括风湿热、流感与其他病毒感染(包括感冒)、背颈痛、痛经、头痛、牙痛、扭伤与劳损、肌炎、神经痛、滑膜炎、关节炎(包括类风湿性关节炎、变性性关节疾病(骨关节炎)、痛风和强直性脊椎炎)、粘液囊炎、灼伤、和外科与牙科手术后创伤。
这类组合物可用于但不限于治疗和预防受治疗者与炎症有关的心血管病症。这类组合物可用于治疗和预防血管疾病、冠状动脉疾病、动脉瘤、血管排斥、动脉硬化、动脉粥样硬化(包括心脏移植性动脉粥样硬化)、心肌梗塞、栓塞、中风、血栓形成(包括静脉血栓形成)、心绞痛(包括不稳定性绞痛)、冠脉血小板炎症、细菌诱发的炎症(包括衣菌诱发的炎症)、病毒诱发的炎症、和与外科手术有关的炎症(例如血管移植术,包括冠状动脉旁路手术,血管再造手术,包括血管成形术,斯滕特氏印模置换,动脉内膜切除术,或其他牵涉动脉、静脉和毛细管的侵入性手术)。
这类组合物可用于但不限于治疗受治疗者与血管生成有关的病症,例如抑制肿瘤血管生成。这类组合物可用于治疗瘤形成,包括转移;眼科病症,例如角膜移植排斥、眼新血管形成、视网膜新血管形成(包括损伤或感染后的新血管形成)、糖尿病性视网膜病、黄斑变性、晶状体后纤维组织形成和青光眼(包括新血管性青光眼);溃疡性疾病,例如胃溃疡;病理性而非恶性病症,例如血管瘤(包括婴儿血管瘤、鼻咽血管纤维瘤)和骨的无血管坏死;和女性生殖系统疾病,例如子宫内膜异位。
这类组合物可用于预防或治疗良性与恶性肿瘤/瘤形成,包括癌症,例如结肠直肠癌、脑癌、骨癌、源于上皮细胞的瘤形成(上皮癌)(例如基底细胞癌)、腺癌、胃肠癌(例如唇癌、口癌、食管癌、小肠癌、胃癌、结肠癌)、肝癌、膀胱癌、胰腺癌、卵巢癌、宫颈癌、肺癌、乳腺癌、皮肤癌(例如鳞状上皮癌和基底细胞癌)、前列腺癌、肾细胞癌、和其他已知影响遍及机体的上皮细胞的癌症。本发明组合物特别可用于治疗的瘤形成是胃肠癌、巴瑞特氏食管、肝癌、膀胱癌、胰腺癌、卵巢癌、前列腺癌、宫颈癌、肺癌、乳腺癌和皮肤癌(例如鳞状上皮癌和基底细胞癌)。本发明组合物还可以用于治疗见于放射疗法中的纤维变性。这类组合物可以用于治疗患有腺瘤性息肉的患者,包括患有家族性腺瘤性息肉病(FAP)的那些。另外,这类组合物可以用于预防面临FAP危险的患者形成息肉。
这类组合物通过防止收缩性类前列腺素的合成而抑制类前列腺素诱导的平滑肌收缩,因此可以用于治疗痛经、早产、气喘和与嗜曙红细胞有关的病症。它们还可以用于减少骨损失,特别是绝经后的妇女(也就是治疗骨质疏松),和治疗青光眼。
本发明组合物的优选用途是治疗类风湿性关节炎和骨关节炎,一般性控制疼痛(特别是口部手术后疼痛、全身手术后疼痛、矫形手术后疼痛和骨关节炎的急性突发),治疗阿尔茨海默氏病,和化学预防结肠癌。
除了用于人类治疗以外,本发明组合物还可用于宠物、异种动物、农用动物等的兽医治疗,特别是哺乳动物,包括啮齿类。更确切地,本发明组合物可用于马、狗和猫环加氧酶-2介导病症的兽医治疗。
本发明还涉及治疗需要用环加氧酶-2抑制药治疗的病症或疾病的治疗方法,该方法包含一种或多种本发明组合物对需要的患者的口内给药。预防、缓解或改善病症或疾病的剂量方案优选地相当于每天一次或每天两次治疗,但是可以因多种因素而异。这些因素包括患者的类型、年龄、体重、性别、饮食与体格条件和疾病的属性与严重性。因而,实际上所采用的剂量方案可以各不相同,因此可以偏离于上述优选的剂量制度。
患有需要用环加氧酶-2抑制药治疗的病症或疾病的患者的初始治疗可以开始于如上所示的剂量方案。治疗一般根据需要持续若干周至若干月或年,直至已经控制或消除该病症或疾病。按照惯例可以借助本领域熟知的方法监测接受本发明组合物治疗的患者,以确定疗法的有效性。继续分析来自这类监测的数据,可以在疗法期间调整治疗方案,以便在任意时间点都给药最佳有效量的药物,以便可以确定治疗的持续时间。按照这种方式,可以在治疗过程中合理地调整治疗制度和给药方案,以便给药表现令人满意的有效性的最低量药物,以便给药仅仅持续成功治疗该病症或疾病所必需的时间。
本发明组合物可以用在与阿片类和其他止痛药的联合疗法中,所述药物包括麻醉止痛药、μ受体拮抗剂、κ受体拮抗剂、非麻醉性(即非成瘾性)止痛药、单胺摄取抑制剂、腺苷调节剂、类大麻素衍生物、P物质拮抗剂、神经激肽-1受体拮抗剂和钠通道阻滞剂以及其他。优选的联合疗法包含本发明组合物与一种或多种化合物的使用,该化合物选自醋氯芬酸、阿西美辛、e-乙酰氨基己酸、对乙酰氨基酚、醋氨沙洛、N-乙酰苯胺、乙酰水杨酸(阿司匹林)、S-腺苷甲硫氨酸、阿氯芬酸、阿芬他尼、烯丙罗定、阿明洛芬、阿洛普令、阿法罗定、双(乙酰水杨酸)铝、氨芬酸、氨氯苯噁嗪、3-氨基-4-羟基丁酸、2-氨基-4-甲基吡啶、氨丙吡酮、氨基比林、阿米西群、水杨酸铵、安吡昔康、胍氨托美丁、阿尼利定、安替比林、水杨酸安替比林、安曲非宁、阿扎丙宗、苄达酸、贝诺酯、苯噁洛芬、苄哌立隆、苄达明、苄基吗啡、贝尔洛芬、苯腈米特、α-红没药醇、溴芬那酸、对-溴-N-乙酰苯胺、5-溴水杨酸乙酸盐、溴水杨醇、布西丁、布氯酸、布可隆、丁苯羟酸、布马地宗、丁丙诺啡、布他西丁、异丁苯丁酸、布托啡诺、乙酰水杨酸钙、卡马西平、卡比芬、卡洛芬、卡沙兰、氯丁醇、氯西诺嗪、水杨酸胆碱、辛可芬、桂美辛、西拉马朵、环氯茚酸、氯美辛、氯尼他秦、氯尼克辛、氯吡酸、丁香、可待因、溴化甲基可待因、磷酸可待因、硫酸可待因、克罗丙胺、克罗乙胺、地索吗啡、右苯噁啶、右吗拉胺、地佐辛、地恩丙胺、双氯芬酸钠、二苯米唑、联苯吡胺、二氟尼柳、双氢可待因、双氢可待因酮烯醇乙酸酯、双氢吗啡、乙酰水杨酸二羟铝、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、diprocetyl、安乃近、地他唑、曲噁昔康、依莫法宗、苯乙氨茴酸、依匹唑、依他佐辛、依特柳酯、乙水杨胺、依索庚嗪、依托沙秦、乙甲噻丁、乙基吗啡、依托度酸、依托芬那酯、依托尼秦、丁香酚、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬太尼、芬替酸、非拉二醇、非普拉宗、夫洛非宁、氟芬那酸、氟诺洛芬、氟苯乙砜、氟吡啶、氟丙喹宗、氟比洛芬、磷酸柳酯、龙胆酸、格拉非宁、葡美辛、水杨酸乙二醇酯、愈创木
氢可酮、氢吗啡酮、羟哌替啶、异丁芬酸、布洛芬、布洛新、水杨酸咪唑、消炎痛、吲哚洛芬、异非来克、双甲氧苄醇胺、异美沙酮、羟烟甲苯胺、伊索克酸、伊索昔康、凯托米酮、酮洛芬、酮洛酸、对-乳酰乙氧基苯胺、勒非他明、左啡诺、洛芬太尼、氯那唑酸、氯诺昔康、环氧洛芬、乙酰水杨酸赖氨酸、乙酰水杨酸镁、甲氯芬那酸、甲芬那酸、哌替啶、美普他酚、美沙拉秦、美他佐辛、盐酸美沙酮、左美丙嗪、甲嗪酸、甲氧夫啉、美托酮、莫非布宗、莫非佐酸、吗拉宗、吗啡、盐酸吗啡、硫酸吗啡、水杨酸吗啡、麦罗啡、萘丁美酮、纳布啡、水杨酸1-萘基酯、萘普生、那碎因、奈福泮、尼可吗啡、尼芬那宗、尼氟灭酸、尼美舒利、5’-硝基-2’-丙氧基-N-乙酰苯胺、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、奥沙拉嗪、阿片、奥沙西罗、吲肟酸、奥沙普嗪、羟考酮、羟吗啡酮、羟布宗、阿片金碱、瑞尼托林、丙炔柳胺、喷他佐辛、哌立索唑、非那西汀、非那多松、非那佐辛、盐酸非那吡啶、非诺可、苯哌利定、非诺吡酮、乙酰水杨酸苯基酯、保泰松、水杨酸苯基酯、非尼拉朵、吡酮洛芬、匹米诺定、哌布宗、哌立酮、piprofen、氯氟吡唑酸、哌腈米特、吡罗昔康、普拉洛芬、丙谷美辛、普罗庚嗪、二甲哌替啶、丙帕他莫、丙吡兰、丙氧芬、异丙安替比林、普罗喹宗、吩噻嗪丙酸、异丙氨基比林、瑞芬太尼、甲硫酸吡嘧乙酯、醋水杨胺、水杨苷、水杨酰胺、水杨酰胺邻-乙酸、水杨基硫酸、双水杨酯、沙维林、西美曲特、水杨酸钠、舒芬太尼、柳氮磺胺吡啶、舒林酸、超氧化物歧化酶、舒洛芬、琥布宗、他尼氟酯、替尼达普、替诺昔康、特罗芬那酯、汉防己碱、噻唑丁炎酮、噻洛芬酸、噻拉米特、替利定、替诺立定、托芬那酸、托美丁、曲马朵、托匹星、氯苄吡醇、联苯丁酸、西蒙洛芬、扎托洛芬和佐美酸(参见The Merck Index,12th Edition(1996),Therapeutic Category and Biological Activity Index,其中题为“止痛药”、“消炎药”和“退热药”的表)。
特别优选的联合疗法包含本发明组合物,例如本发明伐地考昔组合物与阿片类化合物的使用,更确切地该阿片类化合物是可待因、哌替啶、吗啡或其衍生物。
所要与伐地考昔联合给药的化合物可以与伐地考昔单独配制或者与伐地考昔共同配制在本发明组合物中。若将伐地考昔与第二种药物,例如阿片类药物共同配制,该第二种药物可以被配制成即时释放、迅速起效、持续释放或双重释放的形式。
在本发明实施方案中,确切而言环加氧酶-2介导病症是头痛或偏头痛,将伐地考昔组合物与血管调节剂联合给药,优选具有血管调节效果的黄嘌呤衍生物,更优选烷基黄嘌呤化合物联合给药。
其中烷基黄嘌呤化合物与如本文所提供的伐地考昔组合物共同给药的联合疗法也涵盖在这种发明实施方案中,无论该烷基黄嘌呤是血管调节剂与否和无论治疗有效性在任意程度上归因于血管调节效果与否。本文中术语“烷基黄嘌呤”涵盖具有一个或多个C1-4烷基、优选甲基取代基的黄嘌呤衍生物和这类黄嘌呤衍生物在药学上可接受的盐。
选择伐地考昔和血管调节剂或烷基黄嘌呤的总剂量和相对剂量,以便在治疗上和/或预防上有效缓解与头痛或偏头痛有关的疼痛。适合的剂量将依赖于疼痛的严重性和所选择的特定血管调节剂或烷基黄嘌呤。例如,在伐地考昔与咖啡因的联合疗法中,通常伐地考昔给药的每日剂量为约1mg至约100mg,优选约5mg至约50mg,咖啡因的每日剂量为约1mg至约500mg,优选约10mg至约400mg,更优选约20mg至约300mg。
联合疗法的血管调节剂或烷基黄嘌呤组分可以借助任意适合的途径以任意适合的剂型给药,优选口服。血管调节剂或烷基黄嘌呤可以可选地与伐地考昔共同配制在本发明模制品中。因而,本发明模制品可选地包含伐地考昔和血管调节剂或烷基黄嘌呤,例如咖啡因,总量和相对量与上述剂量一致。
关于伐地考昔和血管调节剂或烷基黄嘌呤在这种实施方案组合物中的量,短语“有效缓解疼痛的总量和相对量”意味着这些量是这样的,(a)这些组分一起有效缓解疼痛,和(b)每种组分能够或者将能对疼痛缓解效果作出贡献,如果其他组分的含量不是如此之大以致使这类贡献成为不必要的话。
实施例
下列实施例说明本发明各方面,但是不应被解释为限制。
实施例1
按照下列方法制备伐地考昔速溶片(A批,以下也称为速溶片A)。在第一容器内,将麦芽糖(28.03g)和甘露糖醇(367.6g)溶于水,同时加热(70℃)并搅拌。将伐地考昔(46.25g)分散在麦芽糖/甘露糖醇溶液中,利用Silverson匀化器匀化10分钟。在第二容器内将月桂基硫酸钠(SLS)溶于水,轻轻搅拌,形成湿润剂溶液。向第一容器加入湿润剂溶液,形成可喷雾溶液。利用Niro Laboratory Mobile Minor Spray Dryer将可喷雾溶液喷雾干燥,形成干颗粒,条件如下:喷雾速率32g/min;入口气流2.8mbar;系统压力1.6mbar;入口气压20mbar;雾化压力1.6bar;雾化流百分比57;入口温度160℃;出口温度约55℃;雾化气加热器温度287℃。
向聚乙烯袋加入硬脂酸镁(1g)、硬脂酸(3g)、乙酰舒泛K(1g)和薄荷矫味剂(1g),剧烈摇动,形成混合物。然后将混合物用如上制备的干颗粒呈几何级稀释,直至已经加入200g干颗粒。然后分别制备400mg压片掺合物,形成中等硬度1.5kp的药片。将所得药片在维持25℃和80%相对湿度的室中放置1小时,再在40℃和30%相对湿度下放置1小时。速溶片A的组成(重量%)如表1所示。
表1:速溶片A的组成
组分 | 量 |
伐地考昔 | 10 |
麦芽糖 | 6.06 |
甘露糖醇 | 79.48 |
SLS | 1.45 |
硬脂酸镁 | 0.5 |
硬脂酸 | 1.5 |
乙酰舒泛K | 0.5 |
薄荷 | 0.5 |
实施例2
为了测定伐地考昔速溶片A在beagle犬中的药动学性质而进行研究。向4只犬分别给药伐地考昔速溶片A。在给药前和口内给药后0.5、1、1.5、2、2.5、3、4、6、8、12和24小时采集静脉血。借助在3000G下离心从血液中分离血浆,将样本贮存在-20℃下直至分析。利用HPLC测定法分析血浆中的伐地考昔浓度。结果如表2所示。
表2:伐地考昔速溶片A在犬中的药动学性质
参数 | 速溶片A |
Cmax(ng/ml) | 8800 |
AUC(h*ng/ml) | 2710 |
Tmax(h) | 1.4 |
实施例3
按照下列方法制备伐地考昔速溶片(B批,以下也称为速溶片B)。将麦芽糖(0.158kg)和甘露糖醇(2.047kg)溶于水(14.167kg),混合形成溶液。向该溶液加入月桂基硫酸钠(0.037kg),混合直至溶解。将伐地考昔(0.258kg)分散在该溶液中,利用Silverson匀化器在大约5000RPM下匀化15分钟,形成浆液。然后利用常规船型叶轮使浆液混合,在大约300RPM下混合大约2小时。利用Niro Laboratory Mobile Minor SprayDryer将浆液喷雾干燥,形成干颗粒,条件如下:喷雾速率30g/min;入口气流40mmH2O;室压-100mmH2O;流体喷雾雾化压力1.0bar;雾化流动百分比70;入口气温175℃;出口气温约90℃。总的理论产量为2.500kg。重复进行上述工艺,得到喷雾干燥的颗粒A批(1414.3g)和B批(1971.9g)。
将喷雾干燥的颗粒A批和B批过筛,在V-掺合机中将过筛的颗粒与薄荷矫味剂(17.5g)和乙酰舒泛K(17.5g)干法掺合15分钟,形成混合物。向该混合物加入硬脂酸镁(17.5g)、微粉化硬脂酸(52.5g)和胶体二氧化硅(8.8g),再混合,形成压片掺合物。将压片掺合物压制成片,目标硬度为1.5kp,目标片重为391.58mg。压制后,将药片转移至IBC湿度处理室(17升),在25℃、80%相对湿度和75CFM气流下维持1小时,在40℃、30%相对湿度和75CFM气流下维持另1小时。速溶片的组成(mg/片)如表3所示。
表3:速溶片B的组成
组分 | 量(mg) |
A批颗粒 | 158.22 |
B批颗粒 | 220.61 |
硬脂酸镁NF | 1.96 |
硬脂酸NF(微粉化) | 5.87 |
胶体二氧化硅 | 1.00 |
乙酰舒泛K | 1.96 |
薄荷 | 1.96 |
总计 | 391.58 |
实施例4
利用1000ml 1%月桂基硫酸钠溶液和USP II型仪器测定实施例3速溶片B和商购的40mg Bextra片的体外溶解分布。数据如表4所示。本测定法中速溶片B显示非常迅速的溶解,所有伐地考昔在15分钟后都溶解了。
时间(min) | 速溶片B | Bextra片 |
15 | 101 | 62 |
30 | 101 | 79 |
45 | 100 | 88 |
60 | 101 | 93 |
实施例5
将实施例3速溶片B分别给药25名人类受治疗者。测定口内生物利用度参数,与40mg商购的Bextra片比较。数据如表5所示。
表5:速溶片B和40mg Bextra片在人类受治疗者中的口内生物利用度
参数 | 速溶片B | Bextra片 |
Tmax(hr) | 3.22 | 3.3 |
Cmax(ng/ml) | 580 | 468 |
AUC(ng/ml)/hr | 6833 | 6126 |
这些数据表明,速溶片B在对人类受治疗者给药后表现非常好的生物利用度性质。
实施例6
按照下列方法在味道研究中评价实施例3速溶片B。选择四至五名专业感觉评判人员,将速溶片放置在每名人员的舌头上。评判人员轻轻地将药片顶在口腔上壁,没有咀嚼,同时记录感觉信息和完全崩解的时间。感觉信息包括与每片有关的感观属性,例如口味品质、苦味、发胀、纹理、口感和回味。每种属性都分1-5级,以表示与其他市售溶化产品的知觉差异,对比包含樱桃、草莓、橙、薄荷或留兰香之一的伐地考昔速溶片,并且对比包含不同活性成分的速溶片。
药片的口内崩解后,评判人员记录30分钟内的感觉回味。一式三份评价每种速溶片,为评判人员对所有样本的描述作标记。速溶片B显示23.6秒的平均崩解时间。总之,伐地考昔速溶片B显示可接受的口味品质(数据没有示出)和崩解时间。
Claims (30)
1、口内速溶组合物,包含:
(a)治疗有效量的微粒状伐地考昔,和
(b)至少一种药学上可接受的赋形剂,它表现迅速的口内溶解,并且与伐地考昔微粒是紧密结合的;
其中至少一种表现迅速口内溶解的赋形剂的总含量为约50%至约99%,按重量计。
2、权利要求1的组合物,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂是一种碳水化合物。
3、权利要求1的组合物,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂是一种糖。
4、权利要求1的组合物,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂选自由麦芽糖、麦芽糖醇、山梨糖醇、乳糖和甘露糖醇组成的组。
5、权利要求1的组合物,其中至少一种表现迅速口内溶解的赋形剂的总含量为约50%至约90%,按重量计。
6、权利要求1的组合物,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂包含高模压性糖和低模压性糖。
7、权利要求6的组合物,其中高模压性糖与低模压性糖的重量比为每100份低模压性糖约2至约20份高模压性糖。
8、权利要求6的组合物,其中高模压性糖与低模压性糖的重量比为每100份低模压性糖约5至约7.5份高模压性糖。
9、权利要求1的组合物,具有约1至约10kp的硬度。
10、权利要求1的组合物,其中伐地考昔的量为约5至约50mg。
11、权利要求1的组合物,当置于美国药典24体外崩解试验701号中时,它表现小于约300秒的崩解时间。
12、权利要求1的组合物,当置于美国药典24体外崩解试验701号中时,它表现小于约100秒的崩解时间。
13、权利要求1的组合物,它在置于人类受治疗者口腔中之后约60秒内崩解。
14、权利要求1的组合物,它在置于人类受治疗者口腔中之后约30秒内崩解。
15、权利要求1的组合物,它是感官上可接受的。
16、制备口内崩解的伐地考昔片剂组合物的方法,该方法包含:
提供微粒形式伐地考昔的步骤;
在容器内水中溶解至少一种表现迅速口内溶解的药学上可接受的赋形剂的步骤,所述至少一种赋形剂被溶解的总量是这样的,一旦该过程完成,赋形剂占总片剂重量的约50%至约99%;
将伐地考昔分散在水中的步骤;
其中所述溶解和分散步骤是按任意顺序或者同时进行的,得到可喷雾的液体;
将可喷雾液体喷雾干燥的步骤,形成压片掺合物;和
将压片掺合物压制成片剂的步骤。
17、权利要求16的方法,进一步在所述溶解和/或分散步骤之前、同时或之后、但是在所述喷雾干燥步骤之前包含加热容器里的水的步骤。
18、权利要求16的方法,进一步在所述溶解和/或分散步骤之前、同时或之后、但是在所述喷雾干燥步骤之前包含将湿润剂溶于水的步骤。
19、权利要求16的方法,进一步在所述溶解和/或分散步骤之前、同时或之后、但是在所述喷雾干燥步骤之前包含湿润剂的水溶液溶于水的步骤。
20、权利要求16的方法,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂是一种碳水化合物。
21、权利要求16的方法,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂是一种糖。
22、权利要求16的方法,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂选自由麦芽糖、麦芽糖醇、山梨糖醇、乳糖和甘露糖醇组成的组。
23、权利要求16的方法,其中至少一种表现迅速口内溶解的赋形剂被溶解的总含量是这样的,一旦该过程完成,该赋形剂占总片剂重的约50%至约95%。
24、权利要求16的方法,其中至少一种表现迅速口内溶解的赋形剂被溶解的总含量是这样的,一旦该过程完成,该赋形剂占总片剂重的约50%至约90%。
25、权利要求16的方法,其中至少一种表现迅速口内溶解的药学上可接受的赋形剂包含高模压性糖和低模压性糖。
26、权利要求25的方法,其中高模压性糖与低模压性糖的重量比为每100份低模压性糖约2至约20份高模压性糖。
27、权利要求25的方法,其中高模压性糖与低模压性糖的重量比为每100份低模压性糖约5至约7.5份高模压性糖。
28、由权利要求16方法制备的口内崩解的伐地考昔片剂组合物。
29、治疗或预防受治疗者需要用环加氧酶-2抑制药治疗的病症或疾病的方法,包含权利要求1组合物对该受治疗者的口内给药。
30、治疗或预防受治疗者需要用环加氧酶-2抑制药的病症或疾病的方法,包含权利要求28组合物对该受治疗者的口内给药。
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US32808801P | 2001-10-10 | 2001-10-10 | |
US60/328,088 | 2001-10-10 |
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CN1602187A true CN1602187A (zh) | 2005-03-30 |
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CNA028246772A Pending CN1602187A (zh) | 2001-10-10 | 2002-10-10 | 通过喷雾干燥法制备的口内崩解的伐地考昔组合物 |
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EP (1) | EP1450769A1 (zh) |
JP (1) | JP2005508348A (zh) |
KR (1) | KR20050035138A (zh) |
CN (1) | CN1602187A (zh) |
AP (1) | AP2004003022A0 (zh) |
BG (1) | BG108675A (zh) |
BR (1) | BR0213152A (zh) |
CA (1) | CA2462881A1 (zh) |
CO (1) | CO5570687A2 (zh) |
CZ (1) | CZ2004456A3 (zh) |
EA (1) | EA200400423A1 (zh) |
EC (1) | ECSP045056A (zh) |
GE (1) | GEP20063857B (zh) |
HR (1) | HRP20040331A2 (zh) |
HU (1) | HUP0401776A2 (zh) |
IL (1) | IL161253A0 (zh) |
IS (1) | IS7211A (zh) |
MA (1) | MA27543A1 (zh) |
MX (1) | MXPA04003404A (zh) |
NO (1) | NO20041894L (zh) |
NZ (1) | NZ532184A (zh) |
OA (1) | OA12666A (zh) |
PL (1) | PL370136A1 (zh) |
SK (1) | SK1662004A3 (zh) |
TN (1) | TNSN04056A1 (zh) |
WO (1) | WO2003030876A1 (zh) |
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US7815937B2 (en) | 1998-10-27 | 2010-10-19 | Biovail Laboratories International Srl | Quick dissolve compositions and tablets based thereon |
WO2012087113A1 (en) * | 2010-12-24 | 2012-06-28 | N.V. Nutricia | Improved nutritional tablet |
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US5576014A (en) * | 1994-01-31 | 1996-11-19 | Yamanouchi Pharmaceutical Co., Ltd | Intrabuccally dissolving compressed moldings and production process thereof |
TR199802345T2 (xx) * | 1996-05-17 | 1999-03-22 | Merck & Co., Inc. | Siklooksijenaz-2-arac�l� hastal�klarda g�nde bir kez tatbikat i�in bile�imler. |
AU1930301A (en) * | 1999-12-08 | 2001-06-18 | Pharmacia Corporation | Valdecoxib compositions |
US6316029B1 (en) * | 2000-05-18 | 2001-11-13 | Flak Pharma International, Ltd. | Rapidly disintegrating solid oral dosage form |
CN1638739A (zh) * | 2000-08-18 | 2005-07-13 | 法玛西雅厄普约翰美国公司 | 治疗成瘾性障碍的化合物 |
ATE329583T1 (de) * | 2000-08-18 | 2006-07-15 | Pharmacia Corp | Schnell zerfallende orale arzneizubereitung enthaltend valdecoxib |
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MXPA04003404A (es) | 2004-06-18 |
PL370136A1 (en) | 2005-05-16 |
GEP20063857B (en) | 2006-06-26 |
CA2462881A1 (en) | 2003-04-17 |
ZA200402728B (en) | 2005-03-17 |
IS7211A (is) | 2004-04-07 |
SK1662004A3 (sk) | 2005-07-01 |
YU37104A (sh) | 2006-08-17 |
BG108675A (en) | 2005-03-31 |
ECSP045056A (es) | 2004-08-27 |
NO20041894D0 (no) | 2004-05-07 |
HRP20040331A2 (en) | 2005-12-31 |
OA12666A (en) | 2006-06-19 |
JP2005508348A (ja) | 2005-03-31 |
WO2003030876A1 (en) | 2003-04-17 |
EA200400423A1 (ru) | 2004-10-28 |
CO5570687A2 (es) | 2005-10-31 |
IL161253A0 (en) | 2004-09-27 |
BR0213152A (pt) | 2004-10-19 |
TNSN04056A1 (fr) | 2006-06-01 |
KR20050035138A (ko) | 2005-04-15 |
NZ532184A (en) | 2005-12-23 |
MA27543A1 (fr) | 2005-10-03 |
CZ2004456A3 (cs) | 2005-03-16 |
HUP0401776A2 (hu) | 2004-12-28 |
NO20041894L (no) | 2004-07-07 |
AP2004003022A0 (en) | 2004-06-30 |
EP1450769A1 (en) | 2004-09-01 |
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