CN105377249B - 去氧肾上腺素树脂酸盐颗粒及其在药物配方中的使用 - Google Patents
去氧肾上腺素树脂酸盐颗粒及其在药物配方中的使用 Download PDFInfo
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- CN105377249B CN105377249B CN201480015954.8A CN201480015954A CN105377249B CN 105377249 B CN105377249 B CN 105377249B CN 201480015954 A CN201480015954 A CN 201480015954A CN 105377249 B CN105377249 B CN 105377249B
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Abstract
本发明公开了适用于固体、半固体或液体剂型的去氧肾上腺素颗粒。
Description
技术领域
本发明涉及适用于固体、半固体或液体剂型的去氧肾上腺素颗粒。去氧肾上腺素颗粒可进行包覆,并在延长的时间段以可提供药学上合适的血浆浓度的速率释放去氧肾上腺素。本发明还涉及制造包含去氧肾上腺素颗粒的剂型的过程,以及减轻人类受检者鼻充血和呼吸器不畅的口服剂型的方法。该剂型还可包含一个或多个另外的治疗活性剂,其选自抗组胺剂、减充血剂、止痛药、抗炎剂、退热药、镇咳剂和祛痰药。
背景技术
去氧肾上腺素是一种强效的血管收缩剂,同时具有直接和间接的拟交感神经作用[Hoffman 2001]。主要且直接的影响是对α1-肾上腺素受体的激动作用。刺激位于鼻腔粘膜容血血管(毛细血管后微静脉)的α1-肾上腺素受体会引起血管收缩、血容量下降和鼻腔黏膜体积减小(减轻鼻充血)[Johnson 1993]。收缩的血管允许较少的流体进入鼻子、喉咙和窦衬里,使得鼻膜炎症减轻以及粘液产物减少[Johnson 1993]。因此,通过收缩主要位于鼻腔通道中的血管,去氧肾上腺素使得鼻充血减轻[Hoffman 2001,Empey 1981]。
去氧肾上腺素是I类(大体认为是安全有效的(GRASE))非处方(OTC)口服鼻腔减充血剂。去氧肾上腺素于20世纪60年代面市,并且从1966年开始在美国被广泛使用。盐酸去氧肾上腺素被广泛用于成人和儿童的OTC咳嗽和感冒药中,供成人和儿童用于暂时缓解由于感冒、花粉病或其他上部呼吸道过敏(过敏性鼻炎)引起的鼻充血。它可以10mg片剂的形式商购获得,用于成人口服。给药方法是每四小时一次10mg的剂量,24小时内不超过60mg(六次的剂量)。完整的信息可在被批准药物的OTC专著标签上获得。
去氧肾上腺素的化学名称为(R)-1-(3-羟基苯)-2-甲基乙醇胺,可作为盐酸盐的形式商购获得。其经验式为C9H13NO2·HCl,分子量为203.67。该化合物是一种白色至灰白色的结晶粉末,具有以下化学结构:
去氧肾上腺素代谢的主要途径是与硫酸结合(主要在肠壁)和由单胺氧化酶的A和B两种形式的氧化脱氨[Suzuki 1979]。也会发生葡糖苷酸化,但程度较轻。在一项研究中,在口服给药30mg剂量八小时内[Ibrahim 1983],去氧肾上腺素代谢为硫酸去氧肾上腺素、间羟基马来酸、去氧肾上腺素-葡糖苷酸和间羟基硫酸苯乙二醇,分别为剂量的47%、30%、12%和6%。脱氨基作用是静脉注射去氧肾上腺素后的主要代谢途径[Hengstmann 1982],而硫酸结合则是口服后的主要途径。人的去氧肾上腺素的I相和II相代谢物如下所示。示意图中的百分比值是指Ibrahim报道的口服剂量百分比。
用于成人的速释去氧肾上腺素的临床试验药效数据表明,去氧肾上腺素是一种有效的鼻腔减充血剂。
对乙酰氨基酚是对氨基苯酚衍生物,具有止痛和退热的活性。它用于与感冒、背痛、头痛、牙痛、经期痉挛和肌肉疼痛相关的轻微疼痛的暂时缓解;以及用于轻微关节炎疼痛的暂时缓解和发热的减少。在美国,对乙酰氨基酚的成人剂量为每四至六小时1000mg,在24小时内的最大量为4000mg。延释对乙酰氨基酚的成人剂量为每八小时1300mg,在24小时内的最大量为3900mg。
对乙酰氨基酚主要由肝脏代谢,经由三个主要平行途径:葡糖苷酸化、硫酸盐化和氧化[Miners 1983;Slattery 1989;Lee 1992;Miners 1992]。葡糖苷酸化和氧化途径两者遵循一级速率过程,这意味着被代谢的对乙酰氨基酚的浓度随其在肝脏中的浓度增加而增加。硫酸盐化途径遵循Michaelis-Menten动力学,这意味着当其在肝脏中的浓度增加到饱和水平之上时,被代谢的对乙酰氨基酚的浓度保持恒定。
对乙酰氨基酚的代谢示意图如下所示。在尿液中排出小于9%的治疗剂量为不变的[Miners 1992]。主要代谢途径为葡糖苷酸化,其中对乙酰氨基酚剂量的47%至62%与葡糖苷酸结合。这些葡糖苷酸结合物是非活性且无毒的[Koch-Weser 1976],并且被分泌到胆汁中并通过尿液排出。葡糖苷酸结合物主要由葡糖醛酸基转移酶的一种同种型(UGT1A6)催化[Court 2001],该酶含有尿苷5′-二磷酸葡萄糖醛酸作为主要辅因子。
对乙酰氨基酚代谢的第二个主要途径是硫酸盐化,其中剂量的25%至36%与硫酸盐结合。这些硫酸盐结合物也是非活性且无毒的[Koch-Weser 1976],并易于随尿液排出体外。硫酸盐化由磺基转移酶介导,该酶是异质的胞质酶,并且3′-磷酸腺苷5′-磷酸盐为辅因子。对乙酰氨基酚硫酸盐化的速率控制在于磺基转移酶的活性,而不是硫酸盐的消耗[Blackledge 1991]。
第三个途径是氧化,其中对乙酰氨基酚剂量的5%至8%通过细胞色素P-450酶***代谢。主要负责对乙酰氨基酚代谢的细胞色素P-450同功酶是CYP2E1[Manyike 2000]。当对乙酰氨基酚被CYP2E1代谢时,它形成高活性的中间体N-乙酰基对苯醌亚胺(NAPQI)。因为NAPQI是高活性的,它既不能在肝脏外测量,也不能积聚。此中间体因肝细胞中谷胱甘肽的储存而快速失活,形成半胱氨酸和硫醇结合物,它们都是非活性且无毒的[Koch-Weser1976]。这些结合物随尿液排出[Mitchell 1974]。
需要较低频率的去氧肾上腺素的递送。较低频率的施用可使患者的顺应性改善。另外,与施用多倍剂量的常规速释制剂时所看到的波动相比,恒定的活性组分治疗血浆水平可能更有效且甚至高效。持续有效的水平可以降低在血浆水平高峰值下观察到的副作用的严重程度和频率。因此,去氧肾上腺素制剂可以较低频率施用,例如,根据需要每6、8、12、16、20或24小时施用一次。
还需要使去氧肾上腺素的持续时间与活性相匹配,以提供比速释去氧肾上腺素更长的持续时间。
授予Schering-Plough Corporation的已公布的美国专利申请20070281020公开了对人类受检者施用一种缓释片剂,该片剂包含30mg去氧肾上腺素、羟丙基甲基纤维素、羧甲基纤维素钠、Kollidon CL-M、胶态二氧化硅和硬脂酸镁,并将该缓释片剂与三倍剂量的10mg速释去氧肾上腺素进行比较。
授予McNeil-PPC,Inc.的美国专利8,282,957公开了包衣去氧肾上腺素颗粒及其在药物剂型(包括含有对乙酰氨基酚的剂型)中的使用,此颗粒含有具有第一包衣层和第二包衣层的盐酸去氧肾上腺素、改性淀粉和Eudragit NE30DTM,其中第一包衣层包含EudragitRS PO、乙酰柠檬酸三丁酯和硬脂酸镁并且第二包衣层包含Eudragit NE30DTM、EudragitFS30DTM、硬脂酸镁、月桂基硫酸钠和二甲基硅油。
授予Warner Lambert Company的美国专利6,001,392公开了一种药物/树脂复合物,该复合物包含与二乙烯基苯交联的有包衣和无包衣的AmberliteTM IR69混合物。
授予Schering-Plough Corporation的已公布的美国专利申请20100068280公开了缓释形式的包含去氧肾上腺素的药物剂型。根据一个实施例,在生物等效性研究中,将含有30mg去氧肾上腺素、乳糖一水合物、Methocel K100M CR、Klucel EXF和硬脂酸镁的单剂量去氧肾上腺素片剂与相隔4小时给药的两个10mg去氧肾上腺素速释片剂进行比较。
授予Sovereign Pharmaceuticals的已公布的美国专利申请20050266032和20060057205公开了含有去氧肾上腺素的药物剂型。根据一个实施例,将去氧肾上腺素结合到采用例如聚苯乙烯磺酸钠的离子交换树脂复合物中,并包覆迟释聚合物,例如,L 100、MAE和cPD。该实施例中的配方包含45mg缓释去氧肾上腺素和15mg速释去氧肾上腺素。
授予Tris Pharma,Inc.的美国专利8,062,667公开了包衣的药物-离子交换树脂复合物。根据一个实施例,将去氧肾上腺素结合到采用聚苯乙烯磺酸钠的离子交换树脂复合物中,并包覆KOLLICOATTM SR-30D、甘油三醋酸酯和水。
授予McNeil-PPC,Inc.的美国专利8,394,415公开了一种液体制剂,该制剂包含速释布洛芬和延释去氧肾上腺素-指定的离子交换树脂复合物,并包覆有包含指定成分的第一包衣层和第二包衣层。
授予McNeil-PPC,Inc.的美国专利申请11/761,698公开了一种固体组合物,该组合物包含布洛芬(IR)和去氧肾上腺素,并包覆有含有乙基纤维素的第一包衣层和含有保护性包衣的第二包衣层。
授予Schering-Plough Healthcare Products,Inc.的美国专利申请20100068280公开了一项生物利用度研究,对经由EnterionTM胶囊剂递送的10mg盐酸去氧肾上腺素、10mgSudafed PETM和经由EnterionTM胶囊剂递送的30mg盐酸去氧肾上腺素进行了比较。
授予Coating Place,Inc.的已公布的美国专利申请2007014239公开了将一种或多种药物装载到一个或多个离子交换树脂颗粒上以形成载药树脂颗粒的方法和组合物。
仍然需要具有上述属性的去氧肾上腺素产品。
发明内容
本发明涉及去氧肾上腺素颗粒,其将去氧肾上腺素或其可药用的盐传递至需要其的受检者,以便在摄入后约0.1至约16小时,优选地约0.5至约5小时,更优选地约1至约4.5小时提供最高血浆浓度的去氧肾上腺素,并且其中去氧肾上腺素在摄入后至少约6、约8、约12、约16、约20和/或约24小时保持在大于约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL的水平。
根据优选的实施例,本发明涉及包衣的去氧肾上腺素树脂酸盐颗粒,其将去氧肾上腺素或其可药用的盐传递至需要其的受检者,以便在摄入后约0.1至约16小时,优选地约0.5至约5小时,更优选地约1至约4.5小时提供最高血浆浓度的去氧肾上腺素,并且其中去氧肾上腺素在摄入后至少约6、约8、约12、约16、约20和/或约24小时内保持在大于约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL的水平。
本发明还涉及包含去氧肾上腺素颗粒的药物剂型,其将去氧肾上腺素或其可药用的盐传递至需要其的受检者,以便在摄入后约0.1至约16小时,优选地约0.5至约5小时,更优选地约1至约4.5小时提供最高血浆浓度的去氧肾上腺素,并且其中去氧肾上腺素在摄入后至少约6、约8、约12、约16、约20和/或约24小时保持在大于约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL的水平。
在另一个实施例中,提供去氧肾上腺素延释作用的去氧肾上腺素颗粒与速释形式的去氧肾上腺素结合。
在另一个实施例中,去氧肾上腺素颗粒与一种或多种另外的治疗剂混合以便速释或缓释。此类一种或多种药剂可被配制为在摄入后速释、缓释、伴随着去氧肾上腺素的至少一些在结肠释放、或它们的任何组合。在一个实施例中,另外的治疗剂未包衣。在另一个实施例中,另外的治疗剂被包衣。
另外的治疗剂可以是抗组胺药、减充血剂、止痛药、抗炎剂、退烧药、镇咳剂、祛痰剂或任何其他治疗剂、或这些药剂的组合,可用于缓解感冒、季节性和其他过敏症、花粉病或鼻窦问题的症状,其中任一种都可能引起鼻腔分泌物增多。优选地,一种或多种另外的治疗剂是对乙酰氨基酚。
抗组胺药和减充血剂的例子包括但不限于溴苯那敏、氯环嗪、右溴苯那敏、溴己新、苯茚胺、非尼拉敏、美吡拉敏、松齐拉敏、pripolidine、麻黄碱、伪麻黄碱、苯丙醇胺、扑尔敏、右美沙芬、苯海拉明、多西拉敏、阿司咪唑、特非那丁、非索非那丁、萘甲唑林、羟甲唑啉、孟鲁斯特、丙已君、苯丙烯啶、克立马丁、阿伐斯汀、普鲁米近、奥索马嗪、美喹他嗪、布克力嗪、溴已新、酮替芬、特非那丁、依巴斯汀、苯咪唑嗪、赛洛唑啉、氯雷他定、脱羧氯雷他定和西替利嗪;它们的异构体;以及它们的可药用盐和酯。
合适的止痛剂、抗炎剂和解热剂的例子包括但不限于非甾体抗炎药(NSAID),如丙酸衍生物(例如,布洛芬、萘普生、酮洛芬、氟比洛芬、芬布芬、非诺洛芬、吲哚洛芬、酮洛芬、氟洛芬、比丙芬、卡洛芬、噁丙嗪、普拉洛芬和舒洛芬)和COX抑制剂,如塞来考昔;对乙酰氨基酚;乙酰水杨酸;乙酸衍生物,如吲哚美辛、双氯芬酸、舒林酸和托美丁;芬那酸衍生物,如甲芬那酸、甲氯芬那酸和氟芬那酸;联苯羧酸衍生物,如二氟尼柳和氟苯柳;和昔康类,如吡罗昔康、舒多昔康、伊索昔康和美洛昔康;它们的异构体,以及它们的可药用盐和前药。
止咳剂和祛痰剂的例子包括但不限于苯海拉明、右美沙芬、诺斯卡品、氯苯达诺、薄荷醇、苯佐那酯、乙基***、可待因、乙酰半胱氨酸、羧甲半胱胺酸、氨溴索、颠茄生物碱、索布瑞醇、愈疮木酚和愈创木酚甘油醚;它们的异构体,以及它们的可药用盐和前药。
本发明的另一个方面是对需要治疗的受检者的感冒、流行性感冒、过敏症或非过敏性鼻炎症状进行治疗的方法,包括施用本发明的去氧肾上腺素颗粒。在某些实施例中,去氧肾上腺素颗粒约每6、8、12、16、20或24小时施用。在一个优选的实施例中,去氧肾上腺素颗粒约每12小时施用。在另一个优选的实施例中,去氧肾上腺素树脂酸盐颗粒约每8小时施用。
本发明的某些实施例是维持受检者体内去氧肾上腺素的持续生物利用度的方法,包括对受检者口服施用去氧肾上腺素颗粒,其中去氧肾上腺素的至少一部分从结肠吸收,并且其中在施用该组合物后约6小时,受检者血浆中的去氧肾上腺素浓度为至少约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL。在具体实施例中,施用该组合物后约8小时,受检者血浆中的去氧肾上腺素浓度为至少约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL。在具体实施例中,施用该组合物后约12小时,受检者血浆中的去氧肾上腺素浓度为至少约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL。在具体实施例中,施用该组合物后约20小时,受检者血浆中的去氧肾上腺素浓度为至少约20、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL。在具体实施例中,施用该组合物后约20小时,受检者血浆中的去氧肾上腺素浓度为至少约24、约40、约60、约80、约100、约120、约140、约160、约180或约200pg/mL。本发明的某些其他实施例是对受检者施用去氧肾上腺素的方法,包括口服施用去氧肾上腺素颗粒,所述组合物将去氧肾上腺素的至少一些传递至结肠,在此去氧肾上腺素释放于结肠并从结肠吸收。
本发明可以通过结合下面的附图、具体实施方式和实例来更加充分地理解。
附图说明
图1示出在施用含20mg去氧肾上腺素的包衣延释(ER)去氧肾上腺素树脂酸盐颗粒后的平均去氧肾上腺素血浆浓度曲线。参见图1,y轴代表血浆中游离去氧肾上腺素的浓度(以微微克(pg)/毫升(mL)表示)。x轴代表时间(以小时表示)。图1示出在约2小时处去氧肾上腺素的平均浓度达到峰值(Cmax)。图1还示出约12小时处的次峰。
图2示出在施用含20mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒后的单个去氧肾上腺素血浆浓度曲线。参见图2,受检者之间的差异性有利于调释型去氧肾上腺素。出现Cmax的范围在约1小时至约4.5小时之间。在约12小时处,所有受检者均观察到次峰。
图3示出在施用含20mg去氧肾上腺素的包衣ER盐酸去氧肾上腺素颗粒后的平均去氧肾上腺素血浆浓度曲线。参见图3,虚线是以便于比较的方式示出的图1曲线。观察到去氧肾上腺素树脂酸盐颗粒的稍高的Cmax。在约12小时处,两个曲线均观察到次峰。这可能是由于颗粒快速向下移动至胃肠道,使得较少的去氧肾上腺素被肠壁代谢而导致的结果。在结肠释放去氧肾上腺素将使得在稍后的时间处具有更高的吸收。
图4示出在施用含20mg去氧肾上腺素的包衣ER盐酸去氧肾上腺素颗粒后的单个去氧肾上腺素血浆浓度曲线。
图5示出在施用含15mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素(“ER-IR混合物”)后的平均去氧肾上腺素血浆浓度曲线。参见图5,连续线代表ER-IR混合物。同样,这种治疗的曲线与使用树脂酸盐和盐酸制剂所得到的曲线一致。对于ER-IR混合物,在前2小时内有两个峰;一个主要来自IR剂量,并且另一个来自IR和ER剂量的累积。更快达到了Cmax并保持更长的时间。因此,ER-IR混合物在起效方面表现出有利效果。
图6示出在施用含15mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的单个去氧肾上腺素血浆浓度曲线。
图7示出在施用含20mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的平均去氧肾上腺素血浆浓度曲线。参见图7,连续线代表当前市售的IR液态产品的曲线,并且虚线是以用于比较而示出的图5曲线。ER-IR混合物的Cmax低于IR形式的Cmax。
图8示出在施用含20mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的单个去氧肾上腺素血浆浓度曲线。
图9示出在施用含22.5mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含7.5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素(“ER-IR混合物”)后的平均去氧肾上腺素血浆浓度曲线,并与施用含20mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的平均去氧肾上腺素血浆浓度曲线进行对比。
图10A和10B将(1)施用含15mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后(图10A)和(2)施用含22.5mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含7.5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后(图10B)后的平均去氧肾上腺素血浆浓度曲线与(3)施用含20mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的平均去氧肾上腺素血浆浓度曲线进行对比。
图11将(1)施用含15mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒和含5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素后的平均去氧肾上腺素血浆浓度曲线与(2)施用(a)含15mg去氧肾上腺素的包衣ER去氧肾上腺素树脂酸盐颗粒、(b)含5mg去氧肾上腺素的液态IR盐酸去氧肾上腺素和(c)1300mg ER对乙酰氨基酚的组合后的平均去氧肾上腺素血浆浓度曲线进行对比。
具体实施方式
据信,根据本文的说明书,本领域的技术人员可最大限度地利用本发明。下面的具体实施例应该理解为仅仅是示例性的,并且无论如何都不会以任何方式限制本公开的其余部分。
除非另有定义,否则本文使用的所有技术和科学术语具有本发明所属技术领域普通技术人员通常理解的相同含义。此外,本文提及的所有出版物、专利申请、专利和其他参考文献均以引用方式并入。除非另外指明,否则本文所用的所有百分比均按重量计。而且,本文示出的所有范围旨在包括两个端值(包括端值)之间的值的任意组合。
定义
如本文所用,去氧肾上腺素的可药用盐包括但不限于盐酸去氧肾上腺素、酒石酸氢去氧肾上腺素、单宁酸去氧肾上腺素等。在一个优选的实施例中,去氧肾上腺素的可药用的盐为盐酸去氧肾上腺素。
如本文所用,“AUC”意指,对于任何指定的药物,用梯形规则计算的从药物的给药或活化到某一时间点的“浓度-时间曲线下面积”。AUC是示出药物随时间推移的血浆浓度的参数,也是血浆中药物总量和利用度的指示。
如本文所用,“Cmax”意指,在施用药物后且施用第二剂量前,药物在测试区域中达到的最大(或峰值)浓度。
如本文所用,“晶体形式”意指非无定形形式的活性成分,使得其显示出晶体样性质,包括但不限于衍射可见光的能力。晶体还可用于描述处于其纯化形式的活性成分,即例如没有其他赋形剂加入至其中。
所谓“迟释”意指在施用后至少一段时间活性成分不从剂型释放,即活性成分的释放不是在口服给药后立即发生。
如本文所用,“溶出介质”意指任何合适的液体环境,在该环境中本发明的混悬剂型可以溶解,例如,用于测定产品的体外溶出介质或胃肠液。用于测定一种或多种活性成分从本发明混悬剂型溶出的合适体外溶出介质包括美国药典中所述的那些。
如本文所用,“剂型”或“剂量”意指在某一时间施用的包含治疗活性剂的药物组合物的量。“剂型”或“剂量”包括在相同时间施用的一个或多个单位的药物组合物的给药。在一个实施例中,所述剂型为片剂。在一个实施例中,所述剂型为多层片剂。在包括多层片剂的实施例中,一层可包含速释部分,另一层可包含延释部分。在包括多层片剂的实施例中,一层可包含去氧肾上腺素树脂酸盐颗粒,另一层可包含速释形式的去氧肾上腺素和/或第二活性成分。在一个实施例中,包含去氧肾上腺素树脂酸盐颗粒的剂型为液体填充的软凝胶。
如本文所用,“药物-树脂复合物”意指活性成分(包括但不限于药物活性成分)和离子交换树脂的结合形式。药物-树脂复合物在本领域中还被称为“树脂酸盐(resinate)”。可根据本发明使用的离子交换树脂为AmberliteTM IRP 69(The Dow Chemical Company),这是一种不溶的强酸性钠型阳离子交换树脂,衍生自苯乙烯和二乙烯基苯的磺化共聚物。可移动的或可交换的阳离子为钠离子,它可以被许多阳离子(碱性)物类交换或替代,包括例如铜离子、锌离子、铁离子、钙离子、锶离子、镁离子和锂离子。将药物吸附于离子交换树脂颗粒上以形成药物/树脂复合物是众所周知的技术,如美国专利2,990,332和4,221,778所述。通常,将药物与树脂的水性悬浮液混合,随后洗涤并干燥该复合物。可通过测量反应介质的pH改变,或通过测量钠或药物的浓度改变,对树脂上药物的吸附进行检测。形成的药物/树脂复合物可用乙醇和/或水收集并洗涤,以确保去除任何未结合的药物。通常在室温或高温下,将复合物置于托盘中风干。药物/树脂复合物中去氧肾上腺素与树脂的比例为约0.25∶1至约0.65∶1,优选地约0.30∶1至约0.55∶1,优选地约0.35∶1至约0.45∶1。
“肠溶”意指能在大于约5.0或大于约5.5或大于约6.0或存在于肠道中的pH下溶解。
所谓“延释”意指在施用后,活性成分以基本上连续的、受控的方式从剂型释放出来,并且活性成分从该剂型释放完成(即耗尽)的时间比与相同成分的速释剂型相关的该时间更长。延释的类型包括控释、缓释、长效、零级释放、一级释放、脉冲式释放等等。
如本文所用,“速释”意指至少一种活性成分的溶出特征符合含有该活性成分的速释片剂的USP规定。具有速释性质的活性成分可溶解于胃肠内容物中,无意延迟或延长活性成分的溶出。
“液体剂型”可非排他性地包括混悬剂或酏剂,其中一种或多种活性成分被溶解、部分溶解或处于未溶解或悬浮的状态。
如本文所用,“调释”应适用于改变活性成分在溶出介质(诸如胃肠液)中的释放或溶出。调释的类型包括:1)延释;或2)迟释。通常,调释剂型被配制为使得活性成分在摄入后延长的时间内可以利用,这因而使得相对于常规剂型中相同活性成分的给药,给药频率降低。调释剂型还使得能使用其中一种活性成分的持续时间可与另一活性成分的持续时间不同的活性成分的组合。
如本文所用,“药效动力学”或“PD”是对作用位点的药物浓度与所得到的效果之间的关系的研究。
如本文所用,“药代动力学”或“PK”是对药物吸附、分布、代谢和***的时间进程的研究。
如本文所用,术语“去氧肾上腺素”意指苯炔甲醇3-羟基-α-[(甲基氨基)甲基],并且包括但不限于其可药用盐、酯、异构体或衍生物。
如本文所用,药物“释放速率”是指每单位时间药物从剂型释放的药物量,如每小时所释放的药物的毫克数(mg/h)。药物释放速率是在本领域已知的体外剂型溶出试验条件下计算的。如本文所用,在“给药后”的指定时间获得的药物释放速率是指在合适的溶出试验(如USP 24(美国药典24,United States Pharmacopeia Convention,Inc.,Rockville,MD)中所述的那些)开始后指定时间处获得的体外药物释放速率。
如本文所用,“半渗透性”意指在膜与合适的溶出介质(如胃肠液或体外溶出介质)接触时,水可以穿透,而其他分子(包括本文所述的盐和活性成分)能够缓慢扩散透过该膜。
“半固体剂型”意指高粘性的且具有液体的某些性质的剂型,这些性质包括但不限于(1)具有基本上适形于施加压力至其上并导致其形状改变的物体的能力;和(2)缺少与液体一样易于流动的能力。半固体剂型还具有固体的某些性质,包括但不限于具有较高密度和限定的形状。半固体剂型可非排他性地包括凝胶剂、耐嚼剂型、果胶基耐嚼剂型、糖果型耐嚼剂型、可模压的明胶类型的剂型。
“固体剂型”意指在室温下基本上为固体且具有至少约0.5g/cc的密度的剂型。固体剂型可非排他性地包括附聚的片剂、胶囊状药剂、粉末或粒子充填的胶囊剂、粉末或粒子充填的囊剂、压制片剂、包衣片剂、可咀嚼剂型和速溶剂型。
如本文所用,关于颗粒的“基本上包衣”意指小于约20%,例如小于约15%,或小于约1.0%的颗粒表面积是暴露的,例如没有用所需的包衣覆盖。如本文所用,当用于描述包衣的术语“基本上覆盖”或“基本上连续的”意指包衣大致是连续的并且大致覆盖芯或底层的整个表面,使得极少至没有活性成分或底层暴露。施加到颗粒的包衣可层积,其中每个层在含水(水基)体系或有机溶剂体系中制备并相继加入,直到达到所需的包衣水平。
如本文所用,“疗效”意指旨在诊断、治疗、治愈、缓和或预防疾病或影响身体的结构或任何功能的活性成分的任何效果或作用。
通过以下实例来举例说明本发明的具体实施例。本发明并不受限于在这些实例中所示出的具体限定。
实例
去氧肾上腺素延释颗粒的开发是为了便于配制成液体和固体剂型。去氧肾上腺素延释颗粒可用于使持续时间与其他活性物质(特别是疼痛活性物质)相匹配,从而提供比去氧肾上腺素更长的持续时间。这些活性物包括但不限于对乙酰氨基酚、布洛芬和萘普生以及它们的盐和衍生物。
实例1:包含包衣去氧肾上腺素延释颗粒的制剂的制备
制备含有由聚合物包衣包覆的去氧肾上腺素颗粒的制剂。该制剂可在延长的时间内释放去氧肾上腺素,已被证明在25℃/60%RH下可保持稳定24个月并且在40℃/75%RH下可保持稳定3个月。许多去氧肾上腺素粒状制剂随时间推移变得不稳定并会经历显著降解。
根据表1的配方制备一批3.203kg包衣去氧肾上腺素颗粒。定量配方和批量配方分别示于表1中。
表1:包衣延释去氧肾上腺素颗粒1
1:含20mg盐酸去氧肾上腺素的颗粒的单位剂量为约377.4mg。实际重量取决于颗粒中盐酸去氧肾上腺素的检测量。
2:固体重量。
3:包含乙基纤维素、鲸蜡醇和月桂基硫酸钠。
4:纯化水、丙酮和异丙醇在处理过程中被除去。
颗粒的层积:
1.将纯化水USP加入尺寸合适的不锈钢容器中。
2.加入丙烯酸乙酯NF与甲基丙烯酸甲酯共聚物分散体NF(NE 30D),并温和搅拌。
3.在搅拌混合的同时加入盐酸去氧肾上腺素USP并混合。
4.使用步骤3的混合物包覆(层积)预胶化的改性淀粉NF。
干燥和筛分:
5.干燥来自步骤4的层积盐酸去氧肾上腺素/预胶化改性淀粉,并通过20号筛网进行筛分。
用乙基纤维素包衣溶液包覆层积颗粒:
6.以下物质按照它们出现在尺寸合适的容器中的顺序,在温和搅拌下依次加入:异丙醇USP,之后是丙酮NF,之后是乙酰柠檬酸三丁酯NF。
7.在搅拌下加入乙基纤维素NF(Standard Premium 10),并混合直至形成澄清溶液。
8.在搅拌下将硬脂酸镁加入溶液中。
9.使用配有Wurster插件的合适的流化床包衣单元,用来自步骤8的溶液包覆来自步骤5的经筛分的层积去氧肾上腺素/预胶化改性淀粉颗粒。
固化:
10.在烘箱中固化通过步骤9得到的颗粒。
用 NE30D和Aquacoat 包覆 包衣颗粒:
11.向尺寸合适的容器中加入NE30D,然后加入纯化水USP和乙基纤维素水分散体NF(Aquacoat),并通过温和搅拌进行混合。
12.使用配有Wurster插件的合适的流化床包衣单元,用包衣溶液包覆来自步骤10的包衣层积颗粒。
13.将来自步骤12的包衣颗粒与胶态二氧化硅NF混合。
固化:
14.在烘箱中固化来自步骤13的颗粒。
溶出度分析
使用美国药典通则<711>溶出度(设备II)中所述的装置,旋转桨叶,在274纳米处进行紫外检测,分析通过步骤14得到的包衣去氧肾上腺素颗粒从0至14小时的溶出度。第一小时的溶出介质为750mL的0.1N HCl,然后第二小时至第十四小时的溶出介质为1000mL0.05M磷酸钠缓冲液(pH 6.8)。温度为37℃,并且旋转速度为50rpm。溶出试验表明,相比于在制剂中以100%量制备的去氧肾上腺素标准品,释放的去氧肾上腺素百分比在1小时中小于或等于50%,在3小时中大于或等于30%,并且在8小时中大于或等于50%。采用的方法如下,其结果示于下面的表2中。
溶出方法USP设备(2片桨叶,50rpm)
1.确认溶出介质温度达到目标值(37℃)。
2.称取相当于45mg盐酸去氧肾上腺素的样品。添加样品(至介质溶液表面上)至每个装有750mL的0.1N盐酸的容器并开始溶出试验,桨叶速度为50rpm。在0.1N盐酸中运行1小时后,完成1小时时间点的测量。添加250mL的0.20M磷酸三钠,立即进行至缓冲阶段。缓冲介质的pH为6.8±0.05。
3.测量在介质中释放的盐酸去氧肾上腺素的紫外吸光度,利用带有内嵌探头的LEAP光纤***在274nm处进行紫外测量。
4.溶出的盐酸去氧肾上腺素的量可以通过在274nm波长下将待测样品溶液的紫外吸光度与标准溶液的紫外吸光度对比而确定。溶出的盐酸去氧肾上腺素的量也可以利用以下的分析方法确定。
表2
时间(小时) | 溶出度% |
1 | 10%-30% |
2 | 30%-50% |
3 | 50%-70% |
4 | 60%-80% |
6 | 75%-95% |
8 | 85%-100% |
10 | 90%-100% |
12 | 90%-100% |
14 | 90%-100% |
分析方法
样品制备
1.准确称量约1600mg盐酸去氧肾上腺素颗粒并转移到200mL容量瓶中。(建议加入1mL的1%乙酸/水溶液润湿颗粒,以避免形成固体团块)。
2.添加70mL的1%乙酸/乙腈溶液;在摇动器平台上以低速摇动烧瓶1小时。注意:定期转动烧瓶以收集积聚在溶剂液面上方的颗粒。
3.添加约50mL的1%乙酸/水溶液至烧瓶,并以低速持续摇动烧瓶1小时。
4.用1%乙酸/水溶液稀释至刻度并充分混合。
5.用0.45μm Millipore Millex PVDF过滤器过滤溶液。丢弃最初的1-2mL滤液,然后收集滤液以便进一步稀释。
6.移取6mL滤液至50mL容量瓶中,用1%
乙酸/水溶液稀释至刻度并充分混合。
去氧肾上腺素的分析
在类似于下文建议的条件下,将标准品(1%乙酸/水中的0.05mg/mL盐酸去氧肾上腺素)和样品注入合适的HPLC***中。可对参数进行修改以优化色谱方法。利用待测样品溶液的峰面积与标准溶液的峰面积的比较来确定盐酸去氧肾上腺素的分析结果。
HPLC色谱分离条件
降解产物法
样品制备
2.准确称量约1600mg盐酸去氧肾上腺素颗粒并转移到200mL容量瓶中。(建议加入1mL的1%乙酸/水溶液润湿颗粒,以避免形成固体团块)。
2.添加70mL的1%乙酸/乙腈溶液;在摇动器平台上以低速摇动容量瓶1小时。注意:定期转动容量瓶以收集积聚在溶剂液面上方的颗粒。
3.添加约50mL的1%乙酸/水溶液至烧瓶,并以低速持续摇动烧瓶1小时。
4.用1%乙酸/水溶液稀释至刻度并充分混合。
5.用0.45μm Millipore Millex PVDF过滤器过滤溶液。丢弃最初的1-2mL滤液,然后收集滤液以便进一步稀释。
6.移取6mL滤液至50mL容量瓶中,用1%乙酸/水溶液稀释至刻度并充分混合。
去氧肾上腺素的分析
在类似于下文建议的条件下,将标准品(1%乙酸/水中的0.00025mg/mL的盐酸去氧肾上腺素)和样品注入合适的HPLC***中。可对参数进行修改以优化色谱方法。利用待测样品溶液的峰面积与标准溶液的峰面积的比较来确定盐酸去氧肾上腺素的分析结果。
HPLC色谱分离条件
实例2:包衣去氧肾上腺素树脂酸盐延释颗粒的制备
制备包含去氧肾上腺素和阳离子交换树脂的颗粒,再为其包覆半透膜。包衣成分的含量比例可在一定程度上改变,可以为例如2∶1、3∶1、4∶1或5∶1的醋酸纤维素∶羟丙基纤维素。包覆水平可在一定程度上改变,并且可以为例如按重量计的包衣颗粒的50%、45%、40%、35%、30%、25%或20%。起始的阳离子交换树脂中的大部分颗粒的粒度在约74μm和约177μm(微米)之间。
去氧肾上腺素树脂酸盐颗粒可在延长的时间内释放去氧肾上腺素,已被证明在25℃/60%RH下可保持稳定24个月并且在40℃/75%RH下可保持稳定3个月。许多去氧肾上腺素粒状制剂随时间推移变得不稳定并会经历显著降解。
根据表3的配方制备一批3.846kg包衣去氧肾上腺素树脂酸盐颗粒。定量配方和批量配方分别示于表3和表4中。
表3:包衣去氧肾上腺素树脂酸盐定量配方
1:包含20mg(A)和15mg(B)盐酸去氧肾上腺素的颗粒的单位剂量分别为约84.2mg和63.2mg。实际重量取决于颗粒中盐酸去氧肾上腺素的测定量。
2:量代表游离碱(1mg盐酸去氧肾上腺素相当于0.821mg去氧肾上腺素游离碱)。
3:丙酮和纯化水在处理过程中被去除。
表4:包衣去氧肾上腺素树脂酸盐批量配方
1:1克盐酸去氧肾上腺素相当于0.821克去氧肾上腺素游离碱。
2:丙酮和纯化水在处理过程中被去除。
利用以下工序制备包衣去氧肾上腺素树脂酸盐颗粒:
筛分:
1.使具有所需粒度的聚苯乙烯磺酸钠USP通过170目筛网,收集筛网上剩余的部分。
洗涤:
2.将来自步骤1的聚苯乙烯磺酸钠USP分散到纯化水中并混合。
3.混合时,过滤来自步骤2的部分浆液,并用纯化水USP洗涤。继续过滤,直至大部分水被去除。
4.将树脂转移到容器中。
5.重复步骤3和4,直至用完所有浆液。
药物装载:
6.将纯化水USP加入尺寸合适的不锈钢容器中。
7.混合时,将盐酸去氧肾上腺素添加至容器中,并混合直至溶解。
8.在连续混合的同时添加通过步骤5得到的洗涤后的树脂,并混合成浆液。
9.混合时,抽滤来自步骤8的部分浆液,并用纯化水USP洗涤。继续过滤,直至大部分水被去除。
10.将来自步骤9的经洗涤的过滤后去氧肾上腺素树脂酸盐转移到容器中。
11.重复步骤9和10,直至过滤所有浆液。
干燥:
12.干燥去氧肾上腺素树脂酸盐。
包衣溶液的制备:
13.将纯化水USP和丙酮NF加入尺寸合适的不锈钢容器中。
14.将羟丙基纤维素NF缓慢添加至容器中,并混合直至溶解。缓慢添加醋酸纤维素NF并混合直至溶解。
15.添加丙酮NF,直至溶液达到所需重量。
包衣:
16.使用配有Wurster柱的合适流化床包衣设备,用通过步骤15得到的包衣溶液包覆来自步骤12的去氧肾上腺素树脂酸盐。
17.将包衣去氧肾上腺素树脂酸盐置于容器中。
干燥:
18.干燥包衣去氧肾上腺素树脂酸盐。
筛分:
19.使干燥的包衣去氧肾上腺素树脂酸盐通过美国标准40目筛网进行筛分,收集穿过筛网的部分。
溶出度分析
使用美国药典通则<711>溶出度(设备II)中所述的装置,旋转桨叶,在274纳米处进行紫外检测,分析通过步骤19得到的包衣去氧肾上腺素树脂酸盐颗粒从0至14小时的溶出度。第一小时的溶出介质为750mL的0.1N HCl,第二小时至第十四小时的溶出介质为1000mL的0.05M磷酸钠缓冲液(pH 6.8)。温度为37℃,并且旋转速度为50rpm。溶出试验表明,相比于在制剂中以100%量制备的去氧肾上腺素标准品,释放的去氧肾上腺素百分比在1小时中小于或等于50%,在3小时中大于或等于30%,并且在8小时中大于或等于50%。采用的方法如下,其结果示于下面的表5中。
溶出方法USP设备(2片桨叶,50rpm)
1.确认溶出介质温度达到目标值。
2.添加样品(至介质溶液表面上)至每个装有750mL的0.1N盐酸的容器并开始溶出试验,桨叶速度为50rpm。在0.1N盐酸中运行1小时后,取出一小时的样品,然后添加250mL的0.20M磷酸三钠,立即进行至缓冲阶段。缓冲介质的pH为6.8±0.05。
3.在1小时、3小时、6小时(任选)和8小时后,从每个容器中取出10mL溶出样品溶液。利用Varian全流式过滤器(Varian Full Flow Filters)(10μm)过滤样品溶液。
4.溶出的去氧肾上腺素的量可以通过在274nm波长下将其紫外吸光度与标准溶液的紫外吸光度对比而确定。溶出的去氧肾上腺素的量也可以利用去氧肾上腺素分析方法确定。
5.通过对在较早时间点取出的量进行补充,校正在3、6和8小时处溶出的量。使用DISSL程序(或等同物)或以手动方式校正中间取样。
表5
时间(小时) | 溶出度% |
1 | 20%-40% |
2 | 40%-60% |
3 | 50%-70% |
4 | 60%-80% |
6 | 75%-95% |
8 | 80%-100% |
10 | 90%-100% |
12 | 90%-100% |
14 | 90%-100% |
实例3:粒度分布分析
对若干批次的树脂和树脂基颗粒分析粒度分布。样品包括(1)可从The DOWChemical Company商购获得的AmberliteTM IRP69树脂、(2)具有所选粒度的未装载树脂(分别由流程A或流程B制得)和(3)已装载树脂酸盐颗粒(即,含有去氧肾上腺素)。在设置为90伏、11分钟的FMC Syntron Sieve分析器(FMC Syntron Sieve analyzer)(FMCTechnologies,Houston,TX)中,将每个样品使用约75克进行粒度分布分析。用低扬尘的硬脂酸镁对筛网进行处理,以防止操作过程中的粘附。结果在表6和7中示出。
粒度分布可以在较小规模内分析,使用例如ATM L3P Sonic Sifter(AdvantechManufacturing,New Berlin,WI),它利用声波脉冲并结合机械搅拌进行操作,以便提供有效的颗粒分离。
表6:“原样”和经过选取流程A和B的未装载树脂的粒度分析
1.商购获得的“原样”AmberliteTM IRP69
2.经过选取粒度“流程A”后的AmberliteTM IRP69
3.经过选取粒度“流程B”后的AmberliteTM IRP69
4.按照GRADISTAT,Blott,S.J.and Pye,K.(2001)GRADISTAT:a grain sizedistribution and statistics package for the analysis of unconsolidatedsediments.Earth Surface Processes and Landforms 26,1237-1248所述确定的D10、D50和D90。
表7:经过选取流程A和B的装载树脂的粒度分析
1.经过选取粒度“流程A”后的AmberliteTM IRP69
2.经过选取粒度“流程B”后的AmberliteTM IRP69
3.按照GRADISTAT,Blott,S.J.and Pye,K.(2001)GRADISTAT:a grain sizedistribution and statistics package for the analysis of unconsolidatedsediments.Earth Surface Processes and Landforms 26,1237-1248所述确定的D10、D50和D90。
观察药物-树脂比例对载药效率的影响。结果示于下表8和9中。
表8:代表性药物装载批次中药物-树脂比例对药物装载过程的影响
表9:药物-树脂比例对载药流程的影响汇总
1.基于浆液中的盐酸去氧肾上腺素计。
2.基于去氧肾上腺素的游离碱计。
去氧肾上腺素分析方法-针对表8和9的测量
样品制备
1.准确称量适量的包衣去氧肾上腺素树脂酸盐样品(含有相当于25mg盐酸去氧肾上腺素),并将称量的样品转移至500mL容量瓶中。
2.添加400mL稀释液(1N HCl);在摇动器平台上以低速摇动烧瓶不小于2小时。
3.为确保颗粒不会积聚在溶剂液面上方,定期用稀释液将颗粒冲洗到溶液中。
4.用稀释液稀释至刻度并充分混合。
5.使用0.45μm Millipore Millex PVDF注射式过滤器或等同物过滤等分试样。在收集HPLC瓶中的剩余部分进行分析之前,丢弃最初的大约5mL滤液。
去氧肾上腺素的分析
在类似于下文建议的条件下,将标准品(1N HCl中的0.05mg/mL盐酸去氧肾上腺素)和样品注入合适的HPLC***中。可对参数进行修改以优化色谱方法。在符合***适用性规范的情况下,分析结果是有效的。
HPLC色谱分离条件
实例4-PK研究材料的溶出度分析
采用实例2所述的方法,对用于实例5中的第一PK研究、第二PK研究和PD研究的包衣去氧肾上腺素树脂酸盐颗粒分析从零至8小时的溶出度。结果示于下表10A中。
表10A:溶出度分析(50rpm)
采用下述方法,对用于实例5中的第一PK研究、第二PK研究和PD研究的包衣去氧肾上腺素树脂酸盐颗粒分析从零至8小时的溶出度。结果示于下表10B中。
溶出方法USP设备(2片桨叶,75rpm)
1.确认溶出介质温度达到目标值。
2.添加样品(使用合适的管子使其直接进入介质溶液中)至每个装有750mL 0.1N盐酸的容器并开始溶出试验,桨叶速度为75rpm。在0.1N盐酸中运行1小时后,取出一小时的样品,然后添加250mL 0.20M磷酸三钠,立即进行至缓冲阶段。缓冲介质的pH为6.8±0.05。
3.在1小时、3小时、6小时(任选)和8小时后,从每个容器中取出10mL溶出样品溶液。利用Varian全流式过滤器(Varian Full Flow Filters)(10μm)过滤样品溶液。
4.通过在274nm波长下将紫外吸光度与标准溶液的紫外吸光度对比来确定溶出的去氧肾上腺素的量。
溶出的去氧肾上腺素的量也可以利用去氧肾上腺素分析方法确定。
5.通过对在较早时间点取出的量进行补充,校正在3、6和8小时处溶出的量。使用DISSL程序(或等同物)或以手动方式校正中间取样。
表10B:溶出度分析(75rpm)
稳定性研究
在25℃和60%相对湿度的条件下储存1个月后以及在40℃和75%相对湿度的条件下储存1个月后,对实例5的第一PK研究和第二PK研究中采用的包衣去氧肾上腺素树脂酸盐颗粒分析稳定性。在所有样品中,3-羟基苯甲醛的含量小于或等于0.5%;去氧肾上腺素4,6异构体(N-甲基-4,6-二羟基-1,2,3,4-四羟基异喹啉酮盐酸盐)和去氧肾上腺素4,8异构体(N-甲基-4,8-二羟基-1,2,3,4-四羟基异喹啉酮盐酸盐)的含量小于或等于2.0%。在每种环境下储存1个月后,根据去氧肾上腺素定量的总降解产物量小于或等于2.0%。
降解产物法
降解产物法的样品制备
1.准确称量适量的包衣去氧肾上腺素树脂酸盐样品(含有相当于25mg盐酸去氧肾上腺素),并将称量的样品转移至500mL容量瓶中。
2.添加400mL稀释液(1N HCl);在摇动器平台上以低速摇动烧瓶不小于2小时。
3.为确保颗粒不会积聚在溶剂液面上方,定期用稀释液将颗粒冲洗到溶液中。
4.用稀释液稀释至刻度并充分混合。
5.使用0.45μm Millipore Millex PVDF注射式过滤器或等同物过滤等分试样。在收集HPLC瓶中的剩余部分进行分析之前,丢弃最初的大约5mL滤液。
降解产物法的去氧肾上腺素分析
在类似于下文建议的条件下,将标准品(1N HCl中的0.00025mg/mL盐酸去氧肾上腺素)和样品注入合适的HPLC***中。可对参数进行修改以优化色谱方法。在符合***适用性规范的情况下,分析结果是有效的。
HPLC色谱分离条件
实例5:临床研究
进行两项药代动力学(PK)研究和一项药效动力学(PD)研究。
A.第一PK研究
对十六名受检者进行初步研究,以确定实例1的包衣延释去氧肾上腺素颗粒和实例2的包衣延释去氧肾上腺素树脂酸盐颗粒的药代动力学曲线、生物利用度和代谢。在禁食一夜后,分配受检者以接收四种处理。在这四个周期之间有七天的洗脱期。对于两种颗粒,用苹果酱对健康受检者施用相当于20mg盐酸去氧肾上腺素剂量的包衣颗粒。另外,评价实例2的延释去氧肾上腺素树脂酸盐颗粒和市售速释液体的组合。在组合处理中,用苹果酱施用等于15mg盐酸去氧肾上腺素的包衣去氧肾上腺素树脂酸盐颗粒,而等于5mg盐酸去氧肾上腺素的10mL液体通过口服注射施用。
将实例1的包衣延释去氧肾上腺素颗粒和实例2的包衣延释去氧肾上腺素树脂酸盐颗粒与McNeil-PPC,Inc.的Non-Drowsy Children’s Sudafed鼻腔减充血剂(Non-Drowsy Children’s SudafedNasal Decongestant)液体(2.5mg/5mL盐酸去氧肾上腺素)进行比较。表11汇总了第一PK研究的处理。
表11
1大约84.2mg包衣ER去氧肾上腺素树脂酸盐颗粒的单位剂量相当于20mg盐酸去氧肾上腺素的剂量。大约63.2mg包衣ER去氧肾上腺素树脂酸盐颗粒的单位剂量相当于15mg盐酸去氧肾上腺素的剂量;后面的单位剂量是以10mL去氧肾上腺素液体(2.5mg/5mL)来施用的,总共为相当于20mg盐酸去氧肾上腺素的剂量。
在给药之前,按照所测得的量将包衣ER去氧肾上腺素树脂酸盐颗粒和ER盐酸去氧肾上腺素颗粒调入一杯4oz苹果酱中,然后口服施用。在不咀嚼的情况下吞咽这些单剂量颗粒,之后服用240mL水。使用口服注射器口服施用盐酸去氧肾上腺素液体。为了标准化参照处理给药条件,在两次口服10mg液体剂量中的第一次之后,服用一杯4oz苹果酱和240mL水。
在给药后的8小时或16小时内,于指定的时间点将一系列血液样品收集到K3-EDTA管中。
B.第二PK研究
进行第二初步研究:(i)假设相比两次相隔4小时的10mg剂量的速释去氧肾上腺素,确定30mg去氧肾上腺素能否达到相似的最大药物浓度;(ii)评价ER PK曲线以及20mg去氧肾上腺素和1300mg对乙酰氨基酚的生物利用度。
对二十名受检者进行第二初步研究,以确定(1)(a)等于15mg盐酸去氧肾上腺素的实施例2的包衣延释去氧肾上腺素树脂酸盐颗粒、(b)等于5mg盐酸去氧肾上腺素的10mL去氧肾上腺素液体和(c)1300mg延释对乙酰氨基酚的组合;(2)(a)等于22.55mg盐酸去氧肾上腺素的实例2的包衣延释去氧肾上腺素树脂酸盐颗粒和(b)等于7.5mg盐酸去氧肾上腺素的去氧肾上腺素液体的组合;(3)(a)等于20mg盐酸去氧肾上腺素的去氧肾上腺素液体和(b)1300mg延释对乙酰氨基酚的组合;以及(4)等于20mg盐酸去氧肾上腺素的去氧肾上腺素液体的药代动力学曲线、生物利用度和代谢。表12汇总了第二PK研究的处理。
表12
2延释对乙酰氨基酚片剂是相同的颗粒制剂,可从Arthritis商购获得。
在给药后的12小时或20小时内,于指定的时间点将一系列血液样品收集到K3-EDTA管中。
结果
PK研究的结果示于图1至图11和下表13中。
表13-第一PK研究的平均参数对比
注意:处理A、B和C=16小时的AUC。处理D=8小时的AUC
附图说明结束
总而言之,结果表明:
包含20mg去氧肾上腺素的ER-IR混合物的Cmax为10mg IR剂量的50%,其AUCinf比两个10mg IR剂量(20mg)多15%。
包含30mg去氧肾上腺素的ER-IR混合物的Cmax为10mg IR剂量的85%,其AUCinf比两个10mg IR剂量(20mg)多61%。
包含20mg去氧肾上腺素和1300mg对乙酰氨基酚的ER-IR混合物的Cmax为10mg去氧肾上腺素IR剂量的80%,其AUCinf比两个10mg IR剂量(20mg)多22%。
结果表明,本发明的制剂在延长的时间内提供药效。
这些结果还表明,本发明的制剂能够匹配延释对乙酰氨基酚的持续时间。
结果还表明,当去氧肾上腺素与对乙酰氨基酚混合时,相比于10mg速释剂量的去氧肾上腺素,去氧肾上腺素的暴露增加且去氧肾上腺素的PK曲线有所改善。这可能是由于肠壁代谢的竞争导致去氧肾上腺素的更大吸收而对对乙酰氨基酚没有影响;以及由于在较低的胃肠道处避免了肠壁代谢而使延释制剂具有更高的去氧肾上腺素吸收率。
C.药效动力学研究
进行随机、双盲、安慰剂对照研究,以确定去氧肾上腺素和去氧肾上腺素-对乙酰氨基酚延释制剂对因上呼吸道感染而引起充血和疼痛症状的受检者的药效。评估30mg ER剂量、45mg ER剂量以及与1300mg对乙酰氨基酚共同施用的30mg ER剂量,并与安慰剂进行对比。在每个实例中,采用本发明的包衣ER去氧肾上腺素树脂酸盐颗粒。根据第1天0至12小时的(1)鼻子不通/鼻塞;(2)鼻窦压力/压痛;及(3)鼻头充血的严重程度评分,30mg ER剂量、45mg ER剂量和与1300mg对乙酰氨基酚共同施用的30mgER剂量与安慰剂相比均表现良好。
上述实例并非旨在限制本发明的范围,本发明的范围可在权利要求书中给出。具体地讲,根据上述公开内容,本领域技术人员将会认识到多种等同形式和替代形式,并且这些也都处于本发明的范围之内。
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Claims (6)
1.一种延释颗粒,包含去氧肾上腺素和阳离子聚苯乙烯磺酸盐复合物,其中在与所述去氧肾上腺素混合之前,所述阳离子聚苯乙烯磺酸盐的至少90%包括74µm至177µm的粒度,其中所述去氧肾上腺素和阳离子聚苯乙烯磺酸盐复合物包覆有包衣,其中与包覆的药物树脂复合物相比的包衣的量为30%至45%重量,其中包衣包含醋酸纤维素和羟丙基纤维素。
2.根据权利要求1所述的延释颗粒,其中所述阳离子选自钠、铜、锌、铁、钙、锶、镁和锂。
3.根据权利要求2所述的延释颗粒,其中所述阳离子为钠。
4.一种药物制剂,包含根据权利要求1所述的延释颗粒。
5.根据权利要求4所述的药物制剂,还包含速释型去氧肾上腺素。
6.一种形成权利要求1中所述的延释颗粒的方法,包括对权利要求1中所述的去氧肾上腺素和阳离子聚苯乙烯磺酸盐复合物进行包覆。
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