CN1479614A - 控释氢可酮制剂 - Google Patents

控释氢可酮制剂 Download PDF

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CN1479614A
CN1479614A CNA018202659A CN01820265A CN1479614A CN 1479614 A CN1479614 A CN 1479614A CN A018202659 A CNA018202659 A CN A018202659A CN 01820265 A CN01820265 A CN 01820265A CN 1479614 A CN1479614 A CN 1479614A
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黄华斌
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A·P·托内里
J·马塞林克
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Abstract

揭示了一种氢可酮固体口服控释剂型,所述剂型包含止痛有效量的氢可酮或者其在制药上可接受的盐以及控释材料。

Description

控释氢可酮制剂
发明领域
本发明是针对患者给药后能够至少表现出约24小时或24小时以上的治疗效果的氢可酮的处方设计。
发明背景
每日一次的阿片类缓释制剂被发布在美国专利No.5,478,577、5,672,360、5,958,459、6,103,261、6,143,332、5,965,161、5,958,452和5,968,551中,这里引用的所有文献,包括前面所述,全部被包含在参考文献中,来用于各种用途。
发明概述
当前这项发明的目标之一是大大改善对中度疼痛患者镇痛的效果和质量。
当前这项发明的某些实施方式的一个目标是提供适于每日一次给药,显著改善镇痛效果和质量的生物可利用的氢可酮制剂。
当前这项发明的某些实施方式的一个目标是提供适于每日一次给药,镇痛效果持续时间显著长于速释氢可酮制剂的生物可利用的氢可酮控释制剂。
当前这项发明的某些实施方式的一个目标是提供适合每日一次给药的口服控释阿片样制剂,它不仅起效迅速,在给药间期内达到最高浓度后具有相对平缓的血浆曲线,阿片样物质的血浆水平的C24/Cmax之比为大约0.55到1.0,并可有效的缓解患者的疼痛。
上述及其他目标可藉本发明来实现,在某些实施方式中,它提供了一种固体口服控释剂型,其中包含镇痛有效量的氢可酮或其药学上认可的盐和足量的某种控释材料,以使这种剂型适合每天一次给药,该剂型一个患者或患者群给药后,体内氢可酮血浆浓度峰值出现时间更为适宜的为约4个到14个小时(Tmax)之间,C24/Cmax比值在0.55到1.0之间。
在本发明的某些实施方式中,这种剂型提供体内氢可酮达血浆浓度峰值的时间(Tmax)在给药后约6个到12个小时,约8个到10个小时,约4个到10个小时或约8个到14个小时。
在本发明的某些实施方式中,这种剂型提供的C24/Cmax比值可以是在0.55到1.0,约0.55到0.85左右,0.55到0.75或者0.60到0.70左右。
在某些优选的实施方式中,通过USP转篮法(the USP Basket Method)进行测试,于700毫升的37℃模拟胃液(Simulated Gastric Fluid,SGF)中,100转/分钟(rpm)振摇一个小时,然后转到900毫升的37℃ pH7.5的磷酸盐缓冲液中.对这种控释剂型进行体外释放率的测试:4个小时至少有20重量%氢可酮或其盐被释放,8个小时大约20重量%到大约65重量%的氢可酮或其盐被释放,在12个小时大约45重量%到大约85重量%的氢可酮或其盐被释放,在24个小时至少80重量%的氢可酮或其盐被释放。虽然,根据要求,这种体外释放率可以是pH依赖性的,也可以使非pH依赖性的.在本发明优选的实施方式中,氢可酮的释放是非pH依赖性的。
在某些优选的实施方式中,通过USP转篮法进行测试,在700毫升的37℃pH=1.2的缓冲水溶液中,100转/分钟(rpm),对氢可酮的这种控释剂型进行一个体外释放率的测试,1个小时有10重量%到大约45重量%的氢可酮或其盐被释放。
在本发明的某些实施方式中,通过USP转篮法进行测试,在900毫升的37℃ pH1.6到7.2之间的缓冲水溶液中,100转/分钟(rpm),对氢可酮或其药学上认可的盐的这种控释剂型进行体外释放率的测试,1个小时约0重量%到35重量%被释放,4个小时约10重量%到70重量%被释放,8个小时约20重量%到75重量%被释放,12个小时约30重量%到80重量%被释放,18个小时约40重量%到90重量%被释放,24个小时超过60重量%被释放;用美国药典(U.SParmacopeia XXII版,1990)收录的USP桨法,在900毫升的缓冲水溶液中,以100转/分钟(rpm)测定体外释放率,基本呈非pH依赖性的,在任何时间,在某一pH时阿片样物质的释放量和另外任一pH时的释放量的差值不超过10%。
在某些优选的实施方式中,本发明的缓释口服剂型的氢可酮每24小时给药一次血浆水平是有效的,可用W50值来描述,氢可酮的W50在4到22小时之间。  在某些实施方式中,W50值至少为4小时,较好的至少为12小时,更好的至少为18小时。
在某些实施方式中,本发明的缓释口服剂型由包含某种缓释材料的基质和氢可酮或其药学上认可的盐组成。在某些实施方式中,基质被压制成片剂,基质外面还可以任选的包一层包衣,除了基质的缓释材料之外它可以控制氢可酮或其药学上认可的盐从制剂中释放,因此,血中活性成分水平可以在长时间内维持在治疗范围内。在另一些实施方式中,基质可以填充胶囊。
在某些实施方式中,本发明的缓释口服剂型由包含氢可酮或其药学上认可的盐的多种药学上认可的缓释基质组成,这种剂型在给予患者后,氢可酮的血浆水平可以在长时间内维持治疗范围。
在某些实施方式中,本发明的缓释口服剂型是渗透剂型,由含有氢可酮或其药学上认可的盐的单层或双层核心,一种具有膨胀性的多聚物,包绕在芯核四周的半透膜和半透膜中使氢可酮或其药学上认可的盐缓释释放的通道,因此,这种剂型在给予患者后,血中活性成分的水平可以在长时间内维持在治疗范围内。
在本发明的某些优选实施方式中,提供了一种每日一次的氢可酮口服控释剂型,该剂型的氢可酮的Cmax低于等剂量速释氢可酮参比制剂(例如Lortab)Cmax的约60%,约50%或约40%,并可在24小时的给药期间内有效镇痛。
在本发明的某些优选实施方式中,提供了一种每日一次的氢可酮口服控释剂型,该剂型提供了口服给药后从Tmax到大约24小时时的吸收速率大约是在相同时间内的消除速率的45%到85%。
在某些优选实施方式中,本发明的这种剂型在给药后提供至少大约24小时的治疗效果。
在某些实施方式中,上述任何一种或全部的体内参数都可以通过对一名患者或患者群进行首次给予这种剂型后获得。
在某些另外的实施方式中,上述任何一种或全部的体内参数都可以通过对一名患者或患者群进行稳态给予这种剂型后获得。
就本发明目的而言,“氢可酮”包括氢可酮游离碱,及其药学上认可的盐和复合物。
术语“USP桨法或转篮法(USP Paddle or Basket Method)”为US药典XX11版(1990)中记载的方法,在这里引证包含在参考文献中。
就本发明目的而言,“pH依赖性”表示随周围pH而改变的特性(例如溶出)。
就本发明目的而言,“非pH依赖性”表示基本不受周围pH影响的特性(例如溶出)。
就本发明目的而言,“生物利用度”表示单位剂型中药物(例如氢可酮)被吸收的程度。
就本发明目的而言,“控释”表示药物(例如氢可酮)的释放速率令血液(如血浆)浓度在约12小时或更长时间内维持在治疗范围内,但低于毒性浓度。
“Cmax”表示给药间期内达到的最高血浆浓度。
“C24”在这里表示给药24小时时的药物血浆浓度。
“Tmax”表示达到最高血浆浓度(Cmax)所需的时间。
就本发明目的而言,“W50”表示血浆浓度水平大于或等于50%药物峰浓度的持续时间。
就本发明目的而言,“C24/Cmax比值”表示给药后24小时的药物血浆浓度与给药间隔内达到的最大血药浓度之比。
就本发明目的而言,”半透性壁”是指这种壁,对于在应用的环境包括胃肠道中的外部液体是可透过的,例如含水的或生物性液体,而对于药物是不可透过的。
阿片类例如氢可酮的“最低镇痛有效浓度”或“MEAC”非常难以确定。然而,通常有一个氢可酮最低镇痛有效血浆浓度,该浓度以下没有镇痛效果。虽然在例如氢可酮血浆水平与镇痛效果之间存在着间接关联,但较高较持久的血浆水平通常与较佳的镇痛效果相关。氢可酮血浆水平达到最高的时刻与药物效果达到最大的时刻之间有一段滞后期。所有阿片类镇痛剂治疗疼痛都存在这一现象。
本发明中,除非另外说明,“一名患者”表示所作的论述(或权利要求)是单独一名患者或对象的药物动力学参数情况。
“患者群”表示所作的论述(或权利要求)是至少两名患者或对象的平均药物动力学参数情况。
就本发明目的而言,“氢可酮速释参比制剂”是等剂量的Lortab(购自UCB Pharma,Inc)中的氢可酮,或其他氢可酮或其药学上认可的盐的速释药物产品中的氢可酮。
就本发明目的而言,所述的控释制剂和速释制剂都是与剂量成比例的。此类制剂,从一个剂量强度变为另一剂量强度时药物动力学参数(例如AUC和Cmax)呈线性地增加。所以某特定剂量的药物动力学参数可由该制剂其他剂量的参数推导得出。
“第一次给药”指在治疗开始时向一名患者或患者群给予本发明的一次剂量。
“稳态”表示药物达到系统的量近似等于药物离开系统的量。因此,在稳态时,机体消除药物的速率近似等于机体通过吸收进入血流可被患者系统所利用的药物的速率。
本发明的控释口服固体剂型可节省阿片样物质的量。本发明控释口服固体剂型的日给药量可大大低于常规速释产品,但在镇痛效果上却没有差异。与常规速释产品相比,用相当的日剂量,采用本发明的控释口服固体剂型可获得更好的效果。
发明详述
本发明的上述这些实施方式都可以通过对控释制剂领域的熟练人员所了解的多种控释制剂进行改进来提供,例如,可对美国专利4,861,598、4,970,075、5,958,452和5,965,161发布的材料和方法进行改进制定本发明,这些参考文献因此都被收录供参考。
活性物质
本发明控释口服剂型宜包含约0.5mg-1250mg的氢可酮或当量的其药学上认可的盐。更优选的,是约5-60mg(例如30mg)氢可酮或其盐。氢可酮合适的药学上认可的盐包括:重酒石酸氢可酮,重酒石酸氢可酮水合物,盐酸氢可酮,对甲苯磺酸氢可酮,磷酸氢可酮,氢可酮缩氨硫脲,硫酸氢可酮,三氟乙酸氢可酮,氢可酮2.5混合物,五氟丙酸氢可酮,氢可酮对硝基苯腙,氢可酮O-甲基肟,氢可酮缩氨基脲,氢溴酸氢可酮,粘酸氢可酮,油酸氢可酮,二碱价磷酸(氢可酮),一碱价磷酸(氢可酮),氢可酮无机酸盐,氢可酮有机酸盐,乙酸氢可酮三水合物,双(七氟丁酸)氢可酮,双(甲基氨基甲酸)氢可酮,双(五氟丙酸)氢可酮,双(吡啶羧酸)氢可酮,双(三氟乙酸)氢可酮,盐酸氢可酮,和硫酸氢可酮五水合物。本发明优选重酒石酸氢可酮。
本发明剂型还可以包含一种或多种其他药物,它们与本发明的氢可酮镇痛剂可有或没有协同作用。此类药物的例子包括:非甾体类消炎药,如布洛芬,双氯芬酸,萘普生,苯噁洛芬,氟比洛芬,非诺洛芬,伏布芬(flubufen),酮洛芬,吲哚洛芬,吡洛芬,卡洛芬,噁丙嗪,普拉洛芬,莫拉洛芬,三氧洛芬(trioxaproten),舒洛芬,氨基洛芬(aminoprofen),噻洛芬酸,氟洛芬,布氯酸,吲哚美辛,舒林酸,托美丁,佐美酸,硫平酸,齐多美辛,阿西美辛,芬替酸,环氯茚酸,奥西平酸(oxpinac),甲芬那酸,甲氯芬那酸,氟芬那酸,尼氟灭酸,托芬那酸,二氟尼柳,氟苯柳,吡罗昔康,舒多昔康或依索昔康。此类非甾体消炎药还包括环加氧酶抑制剂,如celecoxib(SC-58635),DUP-697,flosulide(GCP-28238),美洛昔康,6-甲氧基-2-萘基乙酸(6-MNA),Vioxx(MK-966),萘丁美酮(6-MNA的前药),尼美舒利,NS-398,SC-5766,SC-58215和T-614,金刚烷胺(1-氨基金刚烷)和美金刚(3,5-二甲基氨基金刚烷),它们的混合物,以及它们药学上认可的盐。
其他药物还包括无毒的NMDA受体拮抗剂,例如右啡烷,右美沙芬,3-(1-萘基)-5-(膦酰基甲基)-L-苯丙氨酸,3-(1-萘基)-5-(膦酰基甲基)-DL-苯丙氨酸,1-(3,5-二甲基苯基)萘和2-(3,5-二甲基苯基)萘,2SR,4RS-4-(((1H-四唑-5-基)甲基)氧)哌啶-2-羧酸;2SR,4RS-4-((((1H-四唑-5-基)甲基)氧)甲基)哌啶-2-羧酸;E和Z 2SR-4-(O-(1H-四唑-5-基)甲基)甲酮肟基)哌啶-2-羧酸,2SR,4RS-4-((1H-四唑-5-基)硫)哌啶-2-羧酸,2SR,4RS-4-((1H-四唑-5-基)硫)哌啶-2-羧酸;2SR,4RS-4-(5-巯基-1H-四唑-1-基)哌啶-2-羧酸;2SR,4RS-4-(5-巯基-2H-四唑-2-基)哌啶-2-羧酸,2SR,4RS-4-(5-巯基-1H-四唑-1-基)哌啶-2-羧酸,2SR,4RS-4-(5-巯基-2H-四唑-2-基)哌啶-2-羧酸;2SR,4RS-4-(((1H-四唑-5-基)硫)甲基)哌啶-2-羧酸;2SR,4RS-4-((5-巯基-1H-四唑-1-基)甲基)哌啶-2-羧酸;或2SR,4RS-4-((5-巯基-2H-四唑-2-基)甲基)哌啶-2-羧酸,它们的混合物,以及它们药学上认可的盐。
可包含在本发明剂型中的其他合适的附加药物包括:对乙酰氨基酚,阿司匹林,神经活性甾体(例如美国专利申请09/026,520(1998年2月20日申请)中所述)以及其他非阿片类镇痛剂。
例如,如果制剂中包含第二个药物(非阿片类),该药物在其中的形式可以是控释剂型也可以是速释剂型。该附加药物可与阿片样物质一同包含在控释基质中;包含在控释包衣中;作为另一控释层或速释层包括在制剂中;或以粉末、颗粒等形式与本发明基质一同掺和在明胶胶囊中。
在本发明某些实施方式中,给药用的控释单位剂量氢可酮制剂中含有有效量的速释剂型氢可酮。该速释氢可酮最好其含量可有效缩短达到血液(例如血浆)内氢可酮Cmax所需的时间。该速释阿片类物质最好其含量可有效缩短达到血液(例如血浆)内阿片样物质Cmax所需的时间,因此,该Tmax被缩短到约4个到10个小时,或约6个到8个小时。此类实施方式中,有效量的速释氢可酮可包衣在本发明基质之上。例如,如果由一层控释包衣来实现氢可酮的延迟释放,则可将速释层包在控释包衣之上。另一方面,如果氢可酮包含在控释基质中,则可将速释层包在基质表面上。如果是将含有效单位剂量氢可酮的多份缓释基质(例如丸粒、球粒。小珠等的多颗粒系统)包含在一个硬明胶胶囊内,可将足量阿片类速释部分以粉末或颗粒形式掺入明胶胶囊。或者,明胶胶囊本身可包以氢可酮速释层包衣。本领域技术人员知道,还有其他方式可将速释氢可酮部分加入单位剂量。这些方式应视为包含在后文权利要求中。已发现,通过在单位剂型中加入有效量的速释氢可酮,可显著缓解患者较为严重的疼痛。
剂型
所述控释剂型可以任选地包含一种控释材料,将其与氢可酮一起掺入基质,或将其作为缓释包衣包在含药物的基质(所谓”基质”包括珠粒、丸粒、球体、片剂和片芯等)之外。根据需要,所述控释材料可以是疏水性的也可以是亲水性的。本发明口服剂型可以是例如颗粒,球粒,丸粒或其他多颗粒制剂。可将含量足以在一段时间内有效提供所需剂量阿片样物质的多颗粒装入胶囊,或加入其他任何合适的口服固体剂型,例如压成片剂。另一方面,本发明所述口服剂型可以制成片芯,然后包以控释包衣,或制成基质中包含药物、控释材料和任选的其他药学合适成分(例如稀释剂,粘合剂,色素,润滑剂等)的片剂。本发明的控释剂型也可以制成珠粒制剂或是渗透给药制剂。
控释基质制剂
在本发明某些优选实施方式中,控释制剂是由一种基质(例如基质片剂)制得的,该基质中包含有下面提到的控释材料。含控释基质的剂型具有优选范围内的阿片样物质体外溶出速率,并具有pH依赖性或非pH依赖性的释放方式。适合包含在控释基质内的材料取决于形成基质的方法。口服剂型可包含1-80重量%至少一种亲水性或疏水性控释材料。
适合包含在本发明控释基质中的控释材料包括但不限于以下亲水性和/或疏水性材料,例如树胶,纤维素醚,丙烯酸树脂,蛋白质衍生材料,蜡,虫胶和氢化蓖麻油、氢化植物油等油类。然而,任何药学上认可的疏水性或亲水性控释材料只要能实现阿片样物质的控释都可用于本发明。优选的控释聚合物包括烷基纤维素,例如乙基纤维素,丙烯酸和甲基丙烯酸聚合物及共聚物,纤维素醚,尤其是羟烷基纤维素(如羟丙基甲基纤维素)和羧基烷基纤维素。优选的丙烯酸和甲基丙烯酸聚合物及共聚物包括甲基丙烯酸甲酯,甲基丙烯酸甲酯共聚物,甲基丙烯酸乙氧基乙酯,甲基丙烯酸氰基乙酯,甲基丙烯酸氨基烷酯共聚物,聚(丙烯酸),聚(甲基丙烯酸),甲基丙烯酸-烷基胺共聚物,聚(甲基丙烯酸甲酯),聚(甲基丙烯酸)(酐),聚甲基丙烯酸酯,聚丙烯酰胺,聚(甲基丙烯酰酐),甲基丙烯酸缩水甘油酯共聚物。某些优选实施例将上述控释材料混合物用于本发明基质中。
所述基质还可包含粘合剂。在此类实施方式中,所述粘合剂最好对于氢可酮从控释基质中的有控释放具有一定贡献。
优选的疏水性粘合剂是或多或少具有明显亲水和/或疏水倾向的水不溶性物质。适用于本发明的较好的疏水性粘合剂材料包括可消化的,长链的(C8-C50,特别是C12-C40),被取代或未被取代的烃类,例如脂肪酸,脂肪醇,脂肪酸甘油酯,矿物油,植物油,天然或合成蜡和聚(亚烷基)二醇。较好的可用于本发明的疏水性粘合剂其熔点约为30到200℃,以约45到90℃为佳。当所述疏水性物质是烃时,其熔点最好在25到90℃之间。在长链烃(C8-C50)中,优选脂肪醇。本发明的口服剂型可含至多80重量%的至少一种可消化长链烃。
较好的是,所述口服剂型含至多80重量%的至少一种聚(亚烷基)二醇。疏水性粘合剂可包含天然或合成蜡,脂肪醇(例如月桂醇,肉豆蔻醇,硬脂醇,鲸蜡醇,或优选的鲸蜡硬脂醇),脂肪酸,包括但不限于脂肪酸酯,脂肪酸甘油酯(单酯,二酯或三酯),氢化脂肪,烃,普通蜡,硬脂酸,硬脂醇和具有烃骨架的疏水性和亲水性材料。合适的蜡包括例如蜂蜡,糖蜡(glycowax),蓖麻蜡和巴西棕榈蜡。对本发明目的而言,蜡样物质指室温下一般为固体,熔点约在30到100℃的物质。
在部分优选实施方式中,基质制剂中包含两种或两种以上疏水性粘合剂的混合物。如果含有另一种疏水性粘合剂,它最好选自天然及合成蜡、脂肪酸、脂肪醇及它们的混合物。其实例包括蜂蜡、巴西棕榈蜡,硬脂酸和硬脂醇。以上并非全部列举。
一种具体的优选控释基质包含至少一种水溶性羟烷基纤维素,至少一种C12-C36(C14-C22更好)的脂肪醇,以及可选的至少一种聚亚烷基二醇。所述羟烷基纤维素优选羟(C1-C6)烷基纤维素,例如羟丙基纤维素,羟丙基甲基纤维素,尤其是羟乙基纤维素。这至少一种羟烷基纤维素在本发明口服剂型中的含量取决于所要求的阿片样物质准确释放速率等因素。脂肪醇可以是例如月桂醇、肉豆蔻醇或硬脂醇。然而,在一特别优选的本发明口服剂型实施方式中,所述至少一种脂肪醇是鲸蜡醇或鲸蜡硬脂醇。本发明口服剂型中脂肪醇的含量,如前所述,取决于所要求的阿片样物质的准确释放速率,还取决于口服剂型中是否含有至少一种聚亚烷基二醇。如果没有聚亚烷基二醇,口服剂型宜包含20-50重量%脂肪醇;如果含有聚亚烷基二醇,则脂肪醇与聚亚烷基二醇含量之和宜为总剂量的20-50重量%。
在一优选实施方式中,例如至少一种羟烷基纤维素或丙烯酸树脂与至少一种脂肪醇/聚亚烷基二醇之比在相当程度上决定着阿片样物质从制剂中释放的速度。羟烷基纤维素与脂肪醇/聚亚烷基二醇之比为1∶2至1∶4,优选1∶3至1∶4。
所述聚亚烷基二醇可以是例如聚丙二醇或优选的聚乙二醇。所述至少一种聚亚烷基二醇的数均分子量以1,000-15,000为宜,以1,500-12,000为佳。
另一种合适的控释基质含有烷基纤维素(尤其是乙基纤维素),C12-C36脂肪醇和可选的聚亚烷基二醇。
除上述组分之外,控释基质还可包含适量的其他材料,例如制药业常用的稀释剂,润滑剂,粘合剂,造粒助剂,色素,香精和助流剂。
为了方便制备本发明固体控释口服剂型,本发明的另一方面内容是其制备方法,包括将阿片样物质或其盐混合到控释基质中。加入至基质的过程可如下进行:
(a)制作包含至少一种上述疏水性和/或亲水性物质(例如水溶性羟烷基纤维素)和氢可酮的颗粒;
(b)将至少含一种疏水性和/或亲水性物质的颗粒与至少一种C12-C36脂肪醇混合;
(c)可选的是,对颗粒进行压制和成形。
可用药物制剂业熟知的各种方法制备上述颗粒。例如,在一优选方法中,通过用水将羟烷基纤维素/阿片样物质湿法造粒来形成所述颗粒。在该方法的一种特别优选实施方式中,湿法造粒过程中水的加入量是阿片样物质干重的1.5-5倍,1.75-3.5倍更好。
在某些实施方式中,该剂型由上述的众多基质构成。
本发明的基质还可以通过熔融制丸技术来制备。此时,精细粉碎的阿片样物质与粘合剂(同为颗粒形式)以及可选的其他惰性成分混合,然后通过例如高剪切混合机中的机械作用将混合物制成丸粒(颗粒,球粒)。然后,筛选具有规定大小的丸粒(颗粒,球粒)。粘合剂最好呈颗粒形式,且熔点高于40℃。合适的粘合剂包括例如氢化蓖麻油,氢化植物油,其他氢化脂肪,脂肪醇,脂肪酸酯,脂肪酸甘油酯等。
也可通过例如熔融造粒或熔融挤塑技术来制备控释基质。熔融造粒技术一般包括将通常呈固态的疏水性粘合剂(例如蜡)熔化,在其中掺入药物粉末。为了获得控释剂型,可能需要将疏水性控释材料(例如乙基纤维素或水不溶性丙烯酸聚合物)掺入熔融的蜡类疏水性粘合剂中。有关熔融造粒技术制备的控释制剂的实例可参见美国专利4,861,598,该专利已转让给本发明的受让人,因此被全部收录在参考文献中。
疏水性粘合剂可包含一种或多种水不溶性蜡样热塑性物质,这些物质可能混合着一种或多种疏水性较低的蜡样热塑性物质。为了实现控释,该制剂中的各种蜡样物质在释放初期都必须基本上不在胃肠液中降解或溶解。有用的水不溶性蜡样粘合剂可以是水中溶解度低于约1∶5,000(w/w)的那些。
除以上组分之外,控释基质还可根据需要包含适量其他物质,例如制药业常用的稀释剂,润滑剂,粘合剂,造粒助剂,色素,香精和助流剂,它们的总量可达到颗粒总重量的约50重量%。这些附加材料的量应足以对所需制剂产生所需效果。
制备合适的本发明熔融挤塑型基质,包括将阿片类镇痛剂与控释材料,最好还有粘合剂,混合成均匀的混合物。然后加热该均匀混合物,直至其至少软化至可以挤塑。然后用例如双螺杆挤塑机进行混合物挤塑,形成条形体。然后最好用业内已知方法将该挤出物冷却,并切割成多颗粒,然后将多颗粒分成单位剂量,挤出物的直径以约0.1-5mm为宜,且应实现治疗用活性药物在约8-24小时的控释。
制备本发明熔融挤塑制剂的一种可选方法包括直接计量疏水性控释材料,治疗用活性药物和可选的粘合剂,并加入挤塑机;加热该均匀混合物;将均匀混合物挤塑成条;冷却该含有均匀混合物的条形体;将其切割成大小约0.1-12mm的颗粒;将所述颗粒分成单位剂量。在本发明的这部分内容中,可实现相对连续的生产过程。
可在熔融挤塑型基质中加入前文所述的增塑剂。所述增塑剂以占基质约0.1-30重量%为宜。本发明控释基质中还可包含滑石、单糖或多糖、色素、香精、润滑剂等其他药物赋形剂。它们的含量取决于需要获得的特性。
可通过调节挤塑机挤出孔的直径来改变挤出条形体的厚度。而且,挤塑机的挤出口不一定要是圆形而可以是椭圆、矩形等。挤出的条形体可用热线切割机或闸机等切成颗粒。
熔融挤塑型多颗粒系统的形式可以是丸粒、球粒或颗粒,这取决于挤塑机的挤出孔。就本发明目的而言,“熔融挤塑型多颗粒”和“熔融挤塑型多颗粒系统”和“熔融挤塑型颗粒”都指许多单位的集合,最好它们都具有相近的大小和/或形状,并含有一种或多种活性药物以及一种或多种赋形剂,并最好包含这里提及的疏水性控释材料。较好的是,所述熔融挤塑型多颗粒中颗粒的长度约为0.1-12mm,直径约为0.1-5mm。此外,需要明白的是,所述熔融挤塑型多颗粒可以是以上大小范围内的各种几何形状。或者,可以不经球化过程而直接将挤出物切割成所需长度并分成治疗用活性药物的单位剂量。
在一优选实施方式中,所制备的口服剂型将有效量的熔融挤塑型多颗粒装入胶囊而制成。例如,可将大量熔融挤塑型多颗粒装入明胶胶囊,装量应足以在被摄食和接触胃液时提供有效控释剂量。
另一优选实施方式中,适量的多颗粒挤出物经标准技术以常规制片设备压制成口服片。制造片剂(压制片或模制片),胶囊(硬、软明胶胶囊)和丸剂的技术和配方还可参见Remington制药学(编辑:Arthur Osol),1553-1593(1980),在这里收录在参考文献中。
另一优选实施方式中,可如美国专利4,957,681(Klimesch等)所述将挤出物成形为片剂,在这里收录在参考文献中。
可选的是,控释基质多颗粒系统或片剂或明胶胶囊可包以前文所述的控释包衣。所述包衣宜包含足量疏水性和/或亲水性控释材料,以使得重量增加约2-25重量%,但是,所述包衣在更大程度上取决于具体所用阿片类镇痛剂的物理特性和所需的释放速度等因素。
本发明剂型还可包括含一种或多种阿片类镇痛剂的熔融挤塑型多颗粒的混合物。而且,所述剂型还可包括一定量的治疗用速释药物以获得即时疗效。所述治疗用速释药物可以是包含在明胶胶囊内的分散丸粒,或者包裹在如熔融挤塑型多颗粒表面上。为获得所需效果,本发明的单位剂型还可包含例如控释珠粒和基质多颗粒的混合物。
较好的是,本发明控释剂型可在被摄食并先后接触胃液和继而接触肠液时缓慢释放出治疗用活性药物。本发明熔融挤塑型制剂的控释曲线可以通过例如改变控释材料的量,改变增塑剂含量相对其他基质组份、疏水性材料的比例,加入其他成分或赋形剂,改变制造方法等加以改变。
在本发明其他实施方式中,制备的熔融挤塑型制剂不含治疗用活性药物,药物在挤塑后加入挤出物。这样的制剂一般是将治疗活性药物与挤出的基质材料混合,然后压片成缓释剂型。这样的制剂适合治疗活性药物对软化疏水材料和/或缓释材料所需温度敏感的情形。
适合本发明使用的典型的熔融挤塑生产系统包括:合适的挤塑机驱动马达,其速度可调但扭距恒定,具有开-关控制和电流计。此外,该生产系统应具有温控平台,其中包括沿挤塑机全长安装的温度传感器,冷却机构和温度显示机构。此外,该生产系统应包括诸如双螺杆挤塑机之类挤塑机,所述双螺杆挤塑机具有两根反向旋转的相互啮合的螺杆,它们位于所在筒体内,该筒体的出口处有一孔或模头。物料由加料斗进入,由螺杆推动沿筒体移动,受压通过模头后形成条形体,然后由例如输送带运去冷却,并运至制丸机或其他合适的机械,将挤出的条形体制成多颗粒系统。制丸机可由辊、固定刀片、旋转切割机等构成。合适的设备和系统可购自C.W.Brabender Instruments,Inc,of.South Hackensack,New Jersey等。其他合适的设备是本领域一般技术人员所公知的。
本发明另一部分还涉及上述熔融挤塑型多颗粒的制备方法,该方法需控制挤出物中的空气含量。通过控制挤出物中的空气含量,治疗活性药物从例如多颗粒挤出物中释放的速度被明显改变。在某些实施方式中,挤出产物的pH依赖性也被改变。
因此,在本发明的另一部分内容中,在制备熔融挤塑产物的挤塑期间需将空气基本排除。这可以通过例如用附带真空机构的Leistritz挤塑机实现。出人意料的是,本发明用Leistritz挤塑机在真空下制备的挤塑型多颗粒具有不同的物理特性。具体地说,用例如提供扫描电子显微照片(SEM)的扫描电子显微镜观察,该挤出物基本上没有孔隙。这种基本无孔隙的制剂释放治疗活性药物的速度比非真空制备的制剂快。真空下挤塑多颗粒的SEM看上去十分光滑,多颗粒的牢度高于非真空制备的多颗粒。已发现,至少在部分制剂中,真空挤塑形成的挤塑型多颗粒pH依赖性比非真空下制备的同等制剂高。熔融挤塑产物也可以用Werner-Pfleiderer双螺杆挤塑机制备。
在某些实施方式中,球化剂被加入到本发明颗粒或多微粒中,然后球化产生控释球粒。这种球粒可以任选的用前述方法包以控释衣。
可用来制备本发明多颗粒制剂的球化剂包括各种本领域已知的球化剂,优选纤维素衍生物,尤其是微晶纤维素。合适的微晶纤维素是例如Avicel pH101(商标,FMC Corporation)。球化剂宜占多颗粒重量的约1-99重量%。
除活性成分和球化剂之外,球状物中还可含有粘合剂。合适的粘合剂,例如低粘度水溶性聚合物类,是制药业熟练技术人员所熟知的。然而,优选的是水溶性羟基低级烷基纤维素,例如羟丙基纤维素。
除阿片类镇痛剂和球化剂之外,本发明多颗粒制剂还包含前述控释材料,优选的有丙烯酸及甲基丙烯酸聚合物或共聚物,以及乙基纤维素。包含于本发明制剂中时,所述控释材料的含量为多颗粒的约1-80重量%。较好的是,所述控释材料在多颗粒制剂中的含量足以实现阿片类镇痛剂从多颗粒中的有控释放。
多颗粒制剂中还可以加有粘合剂、稀释剂等药物加工助剂。它们在制剂中的含量取决于需要制剂表现出的特性。
用于制成本发明的口服控释制剂的药学可接受的载体和赋形剂的一些详尽例子参见药用赋形剂手册(Handbook of Pharmaceutical Excipients),美国药学会(1986),作参考被收录于这里。
可在所述多颗粒之外包裹一层含有前述控释材料的控释包衣。该控释包衣使得原多颗粒增重约5-30%。控释包衣的量取决于许多因素,例如多颗粒的组成,阿片类镇痛剂(即氢可酮)的化学和/或物理特性。
基质多颗粒一般通过将球化剂与阿片类镇痛剂混合在一起进行例如湿法造粒来制备。然后,将所得颗粒球化成基质多颗粒。然后,任选地用前述方法在基质多颗粒外包以控释包衣。
制备基质多颗粒的另一种方法是,例如:(a)制备含至少一种水溶性羟烷基纤维素和阿片样物质或其盐的颗粒;(b)将含有羟烷基纤维素的颗粒与至少一种C12-C36脂肪醇混合;和(c)任选地对颗粒进行压片和成形。较好的是,颗粒通过用水对羟烷基纤维素/阿片样物质进行湿法造粒制得。在该方法特别优选的一种实施方式中,湿法造粒步骤中的加水量为阿片样物质干重的1.5-5倍,1.75-3.5倍更好。
另一实施方式中,可将球化剂与活性成分一起球化形成球粒。所述球化剂优选微晶纤维素。合适的微晶纤维素是例如Avicel pH 101(商标,FMCCorporation)。此类实施方式中,除活性成分和球化剂之外,球粒中还可包含粘合剂。合适的粘合剂,例如低粘度水溶性聚合物,是制药业技术人员所熟知的。然而,优选的是水溶性羟基低级烷基纤维素,例如羟丙基纤维素。此外(或者),球粒可包含一种水不溶性聚合物,尤其是丙烯酸类聚合物,丙烯酸类共聚物,例如甲基丙烯酸-丙烯酸乙酯共聚物,或乙基纤维素。此类实施方式中,缓释包衣一般包含以下水不溶性材料,例如(a)单独的蜡或它们与脂肪醇的混合物或(b)虫胶或玉米蛋白。
本发明中的球粒包括如上文提到的基质制剂或在下文中提到的珠粒制剂,直径约0.1-2.5mm,尤其是0.5-2mm之间,
较好的是,这些球粒外面裹有控释材料包衣膜,该包衣可在水性介质中有控地释放出阿片样物质或其盐。该包衣膜的选择以能获得前文所述体外释放速率(例如1小时后释放至少约12.5%)等特性为宜。本发明的控释包衣配方最好能形成光滑、美观、能承载色素等其他包衣添加剂、无毒、惰性且无粘性的牢固而连续的膜。
包衣珠的制备
在本发明的某些实施方式中,本发明的固体口服控释剂型由大量包衣的基质组成,例如惰性药物珠粒(例如nu pariel 18/20珠)。氢可酮的控释可以用疏水性材料的水分散系包裹珠粒来提供。在某些实施方式中,可将一定量的所得稳定化固体控释珠粒装入明胶胶囊,装量应足以达到被摄入并接触胃液或溶出介质等周围液体时给出有效的控释剂量。
本发明的稳定化控释珠粒制剂在例如被摄入并先后接触胃液及肠液后,可缓慢地释放出阿片类镇痛剂。本发明制剂的控释曲线可通过改变疏水性控释材料的水分散系的包衣量,改变增塑剂加入疏水性控释材料水分散系的方式,改变增塑剂量相对于疏水性控释材料的比例,加入其他成分或赋形剂,改变制造方法等加以改变。终产物的溶出曲线还可以通过例如提高或降低控释包衣厚度加以改变。
包有治疗用活性药物的基质的制备可以是例如:将治疗用活性药物溶于水,然后,用Wuster插管(insert)喷涂溶液至基质(例如nu pariel 18/20珠)上,可选的是,还在包裹珠粒前加入其他成分以促进阿片样物质与珠粒的粘合,或使溶液具有颜色等。例如,可在溶液中加入包含羟丙基甲基纤维素等并含有或不含有色素(例如Opadry,Colorcon,Inc的产品)的产品,混合(例如约1小时)后涂敷到基质上。然后可以在所得有包衣的基质外再包以隔离剂,以将治疗活性药物与疏水性控释包衣隔开。
合适的隔离剂之一含有羟丙基甲基纤维素。然而,各种本领域的已知成膜剂都可使用。较好的隔离剂不会影响终产物的溶出速率。
然后可在基质外再包以这里提到的疏水性控释材料的水分散系。疏水性控释材料的水分散系最好还包含有效量的增塑剂,例如柠檬酸三乙酯。也可使用Aquacoat或Surelease等预制乙基纤维素水分散系。如果采用Surelease则不必另外添加增塑剂。或者,也可采用Eudragit之类预制丙烯酸类聚合物水分散系。
较好的是,本发明包衣溶液除成膜剂、增塑剂和溶剂系统(即水)之外还包含色素以令产品美观并易于区分。色素也可不加入疏水性材料水分散系而加入治疗活性药物溶液中,也可以两者都加。例如,可利用醇或丙二醇配制的色素分散系、研磨铝色淀和二氧化钛之类不透明剂,用剪切力将色素加入水溶性聚合物溶液,然后用低剪切力加入增塑后的Aquacoat,由此将色素加入Aquacoat。也可采用各种合适的方法将色素加入本发明制剂。在采用丙烯酸类聚合物水分散系时,使制剂具有颜色的合适成分包括二氧化钛和颜料,例如氧化铁颜料。然而,颜料的加入可能提高包衣的阻滞效应。
可用各种合适的已知喷涂设备将增塑后的疏水性控释材料水分散系喷涂到含有治疗活性物的基质上。优选方法之一采用了Wurster流化床系统,在其中,从下面注入的空气流将芯材流化,并在喷涂丙烯酸类聚合物包衣的同时进行干燥。较好的是,所涂疏水性材料水分散系的量应足以令其在接触胃液等水性溶液时能够实现所述治疗活性药物的预定控释,同时应考虑到治疗活性药物的物理特性,增塑剂的加入方式等。在裹以疏水性控释材料后,还可任选再加一层成膜剂,例如Opadry于珠粒之上。加该包衣层的目的是基本上消除珠粒的聚集。
生产约24小时控释珠粒制剂的另一种方法是粉末敷层。已转让于本发明受让人的美国专利5,411,745,在这里全部被收录在参考文献中,它提示了用主要由极细水合乳糖构成的加工助剂,通过粉末敷层技术制备24小时吗啡制剂的方法。粉末敷层珠粒的制备为:将粘合剂水溶液喷涂在惰性珠粒上,形成一层粘性表面,然后向该粘性珠粒上喷涂硫酸吗啡和极细水合乳糖的均匀混合物粉末。然后将珠粒干燥,并包以前文所述疏水性材料,以使最终产品在周围液体中按要求释放药物。然后,将适量控释珠粒装入胶囊,成为可在约24小时内维持吗啡有效血浆浓度的成品剂型。
控释渗透剂型
本发明控释剂型也可制成渗透剂型。该渗透剂型优先包括由药物层和递送或推动层组成的双层核。该双层核被半透性壁包围,其中并任选地有至少一个通道。在某些实施方式中,该双层核包括由氢可酮或其盐组成的药物层和置换层或推动层。在某些实施方式中,药物层还可包括至少一种聚合物水凝胶。该聚合物水凝胶的平均分子量可为约500-6,000,000。聚合物水凝胶的例子包括但不限于分子式为(C6H12O5)n·H2O的麦芽糖糊精聚合物,其中n为3-7,500;数均分子量为500-1,250,000的麦芽糖糊精聚合物;聚(亚烷基氧化物),代表性的有聚(环氧乙烷)和重均分子量为50,000-750,000的聚(环氧丙烷),更明确的代表有重均分子量至少为100,000;200,000;300,000或400,000之一的聚(环氧乙烷);羧基烷基纤维素碱金属盐,其中碱金属为钠或钾,烷基为甲基、乙基、丙基或丁基,重量均分子量为10,000-175,000;乙烯-丙烯酸共聚物,包括数均分子量为10,000-500,000的甲基丙烯酸和乙基丙烯酸。
在本发明的某些实施方式中,递送或推动层包括渗透聚合物。渗透聚合物的例子包括但不限于来自于聚亚烷基氧化物和羧基烷基纤维素的成员。该聚亚烷基氧化物的重均分子量为1,000,000-10,000,000。聚亚烷基氧化物可为以下成员之一:聚亚甲基氧化物,聚环氧乙烷,聚环氧丙烷,平均分子量为1,000,000的聚环氧乙烷,平均分子量为5,000,000的聚环氧乙烷,平均分子量为7,000,000的聚环氧乙烷,平均分子量为1,000,000的交联聚亚甲基氧化物和平均分子量为1,200,000的聚环氧丙烷。典型的羧基烷基纤维素渗透聚合物包括以下成员之一:羧基烷基纤维素碱金属盐,羧基甲基纤维素钠,羧基甲基纤维素钾,羧基乙基纤维素钠,羧基甲基纤维素锂,羧基乙基纤维素钠,羧基烷基羟烷基纤维素,羧基甲基羟乙基纤维素,羧基乙基羟乙基纤维素和羧基甲基羟丙基纤维素。用于置换层的渗透聚合物在半渗透壁两侧呈现渗透压梯度。渗透聚合物吸收液体进入剂型,从而溶胀,并膨张成渗透性水凝胶(也称作渗透胶(osmogel)),藉此它们推动氢可酮或其药学上认可的盐从渗透剂型中释放出来。
推动层也可包括一种或多种渗透有效化合物(也称作渗透剂(osmagent)和渗透有效溶质)。它们吸收环境例如胃肠道的液体进入剂型并形成置换层的递送动力。渗透活性化合物的例子包括渗透性盐和渗透性糖之一。特定的渗透剂的例子包括但不限于氯化钠,氯化钾,硫酸镁,磷酸锂,氯化锂,磷酸钠,硫酸钾,硫酸钠,磷酸钾,葡萄糖,果糖和麦芽糖。
该推动层可任选的包括羟丙基烷基纤维素。代表性的有羟丙基甲基纤维素,羟丙基乙基纤维素,羟丙基异丙基纤维素,羟丙基丁基纤维素和羟丙基戊基纤维素。
该推动层可任选地包括无毒的色素或染料。色素或染料的例子包括但不限于《食品与药品管理局色素》(FD&C)。例如FD&C一号蓝染料,FD&C四号红染料,红色氧化铁,黄色氧化铁,二氧化钛,碳黑,靛蓝。
该推动层也可任意的包括抗氧化剂来抑制成分的氧化。抗氧化剂的一些例子包括但不限于以下成员之一:抗坏血酸,抗坏血酸软脂酸酯,丁基化羟基苯甲醚,2-叔丁基-4-羟基苯甲醚和3-叔丁基-4-羟基苯甲醚的混合物,丁基化羟基甲苯,异抗坏血酸钠,二氢愈创木酸(dihydro-guaretic acid),山梨酸钾,硫酸氢钠,偏硫酸氢钠,山梨酸,抗坏血酸钾,维生素E,4-氯-2,6-二叔丁基酚,α-生育酚,丙基没食子酸盐。
在另一些实施方式中,该剂型包括一个均一的芯核,该均一芯核包含有氢可酮或其药学上认可的盐,药学上认可的聚合物(例如聚环氧乙烷),任意包含的崩解剂(例如聚乙烯吡咯烷酮),任意包含的吸收增强剂(例如脂肪酸,表面活性剂,螯合剂,胆酸计盐等等)。该均一芯核被有用来释放氢可酮或其药学上认可的盐的通路的半渗透性壁所包裹。
在某些实施方式中,该半渗透性壁包括以下之一:纤维素酯聚合物,纤维素醚聚合物,纤维素酯-醚聚合物。代表性的壁聚合物包括以下之一:酰基纤维素,二酰基纤维素,三酰基纤维素,醋酸纤维素,二醋酸纤维素,三醋酸纤维素,单,二和三纤维素烯酸酯,单,二和三纤维素炔酸酯。用于本发明的聚(纤维素)的数均分子量为20,000-7,500,000。
另外可用于本发明的半渗透性聚合物包括乙醛二甲基纤维素乙酸酯,纤维素乙酸酯氨基甲酸酯,纤维素乙酸酯甲基氨基甲酸酯,二乙酸纤维素、丙基氨基甲酸酯、纤维素乙酸酯二乙基氨基乙酸酯半渗透性聚酰胺,半渗透性聚尿烷,半渗透性磺化聚苯乙烯;根据美国专利3,173,876;3,276,586;3,541,005;3,541,006和3,546,876所述的由聚阴离子和聚阳离子共沉淀形成的半渗透性交联聚合物;根据美国专利3,133,132中Loeb和Sourirajan所述的半渗透性聚合物;半渗透性交联聚苯乙烯;半渗透性交联聚(苯乙烯磺酸钠);半渗透性交联聚(氯化乙烯基苄基三甲基铵)和半渗透性壁两侧以每一大气压流体静力学或渗透压差表示的液体渗透性为2.5×10-8-2.5×10-2(cm2/h·atm)的半渗透性聚合物。业内熟知的对本发明有用的其他聚合物可见于美国专利3,845,770;3,916,899和4,160,020以及俄亥俄州克利夫兰CRC出版社由Scott,J.R和W.J.Roff编的《常用聚合物手册》(1971)。
在某些实施方式中,优选的半渗透壁是无毒的,惰性的,并且它在药物的配制有效期内保持它的物理和化学性质。在部分实施方式中,本剂型包括上述的黏合剂。
在某些实施方式中,本剂型包括可在剂型制造过程中用来防止粘到模壁或冲头表面的润滑剂。润滑剂的例子包括但不限于硬脂酸镁,硬脂酸钠,硬脂酸,硬脂酸钙,油酸镁,油酸,油酸钾,辛酸,硬脂酸延胡索酸钠和软脂酸镁。
包衣
本发明制剂可以任选地包以一种或多种适合调节释放或保护制剂的包衣。实施方式之一中,包衣的目的是为了实现在例如与胃肠液接触时的pH依赖性或非pH依赖性释放。如果需要非pH依赖性释放,设计的包衣应在周围液体,例如胃肠道液体中不论pH如何变化始终保持最佳释放状态。另一些优选实施方式是pH依赖性包衣,它可以在胃肠道的所需部位,例如胃或小肠,释放阿片样物质,这样得到的吸收曲线能够在至少约12小时,更好的是24小时内为患者提供镇痛作用。还可以配制成在胃肠道某处,例如胃部,释放一部分剂量,然后在另一处,例如小肠,释放其余部分。
采用pH依赖性包衣的本发明制剂还可以产生重复作用效应,因此,将无保护的药物包在肠溶包衣之外以在胃内释放,被肠溶包衣所保护的其余部分则在以后的消化道内释放。可用于本发明的pH依赖性包衣含有诸如虫胶、纤维素乙酸邻苯二甲酸酯(CAP)、聚乙酸乙烯酯邻苯二甲酸酯(PVAP),羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸酯共聚物和玉米蛋白等控释材料。
本发明另一优选实施方式是一种稳定化的固体控释剂型,其中含有包有疏水性控释材料的阿片样物质,所需控释材料选自:(i)烷基纤维素;(ii)丙烯酸类聚合物;(iii)它们的混合物。所述包衣可由有机或水性溶液或分散系形成。
在部分优选实施方式中,所述控释包衣由疏水性控释材料的水性分散系形成。然后将含有阿片样物质的被包衣基质(例如片芯或惰性的药物珠粒或球粒)固化至基质具有稳定的溶出特性。该固化终点的确定可通过将刚固化后剂型的溶出曲线与经受加速保存条件作用后(例如,40℃,75%相对湿度作用至少一个月)剂型的溶出曲线比较。此类制剂可参见美国专利5,273,760和5,286,493,它们均已转让于本发明的受让人。可用于本发明的其他控释制剂和包衣的实例还包括美国专利5,324,351,5,356,467和5,472,712所述。
在优选实施方式中,所述控释包衣含有所述的增塑剂。
在部分实施方式中,有必要在含有阿片类镇痛剂的基质外包以足量的含有烷基纤维素或丙烯酸类聚合物的水分散系,以增加约2-50重量%(例如约2-25重量%)的重量,由此获得控释制剂。这层外包衣或多或少地取决于治疗活性药物的物理特性,要求的释放率,水性分散系中是否包含增塑剂及其混合的方式等因素。
烷基纤维素聚合物
包括烷基纤维素在内的纤维素类材料和聚合物是适合在本发明中包裹珠粒、片剂等基质的控释材料。例如,优选的烷基纤维素聚合物之一是乙基纤维素,但本领域技术人员知道,其他纤维素和/或烷基纤维素聚合物也可以单独或混合用作本发明疏水性包衣的全部或一部分。
一种市售的乙基纤维素水分散系是Aquacoat(FMC Corp,Philadelphia,Pennsylvania,USA)。Aquacoat的制备为:先将乙基纤维素溶于与水不混溶的有机溶剂中,然后在表面活性剂和稳定剂存在下将其乳化于水中。均化成亚微米液滴后,真空蒸发有机溶剂,形成假胶乳。在制造过程中,假胶乳中不加增塑剂。因此,在用作包衣之前,必需先将Aquacoat与合适的增塑剂充分混合。
另一种市售的乙基纤维素水分散系是Surelease(Colorcon,Inc.,WestPoint,Pennsylvania,USA)。该产品在其制造过程中即将增塑剂加入了分散系。先将聚合物热熔体、增塑剂(癸二酸二丁酯)和稳定剂(油酸)制备成均匀的混合物,然后用碱性溶液稀释,得到可直接包到基质上的水分散系。
丙烯酸类聚合物
在本发明的另一些实施方式中,含控释材料的控释包衣是药学上认可的丙烯酸类聚合物,这包括但不限于:丙烯酸和甲基丙烯酸共聚物,甲基丙烯酸甲酯共聚物,甲基丙烯酸乙氧基乙酯,甲基丙烯酸氰基乙酯,聚(丙烯酸),聚(甲基丙烯酸),甲基丙烯酸烷基酰胺共聚物,聚(甲基丙烯酸甲酯),聚甲基丙烯酸酯,聚(甲基丙烯酸甲酯)共聚物,聚丙烯酰胺,甲基丙烯酸氨基烷酯共聚物,聚(甲基丙烯酸酐)和甲基丙烯酸缩水甘油酯共聚物。
在部分实施方式中,所述丙烯酸类聚合物包含一种或多种铵甲基丙烯酸酯共聚物。铵甲基丙烯酸酯共聚物是业内熟知的,可参见NF XVII所述的含少量季铵基团的丙烯酸酯和甲基丙烯酸酯的全聚合共聚物。
为了获得所需的溶出曲线,或许有必要加入两种或更多种物理特性不同的铵甲基丙烯酸酯共聚物,所述不同特性是例如不同的季铵基团与中性(甲基)丙烯酸酯的摩尔比。
有些甲基丙烯酸酯类聚合物可用于制备本发明的pH依赖性包衣。例如,有一族共聚物,由甲基丙烯酸二乙基氨基乙酯与其他中性甲基丙烯酸酯合成,又称甲基丙烯酸共聚物或聚甲基丙烯酸酯,市售的有Rohm Tech,Inc.的Eudragit。Eudragit有数种不同类型。例如,Eudragit E是一种会在酸性介质中溶胀并溶出的甲基丙烯酸共聚物。Eudragit L是一种在pH5.7以下不溶胀,在pH6以上溶解的甲基丙烯酸共聚物。Eudragit S是一种在pH6.5以下不溶胀,在pH7以上溶解的甲基丙烯酸共聚物。Eudragit RL和Eudragit RS在水中可溶胀,吸收的水量取决于pH,然而,用Eudragit RL和Eudragit RS包衣的剂型却是非pH依赖性的。
在某些优选实施方式中,丙烯酸类包衣包含Robm Pharma的EudragitRL30D与Eudragi tRS30D这两种丙烯酸树脂漆的混合物。EudragitRL30D和EudragitRS30D是低季铵基含量的丙烯酸酯和甲基丙烯酸酯的共聚物,其中季铵基与中性(甲基)丙烯酸酯的摩尔比在EudragitRL30D中是1∶20,在EudragitRS30D中是1∶40。平均分子量约为150,000。RL(高渗透性)和RS(低渗透性)表示渗透性。EudragitRL/RS混合物不溶于水和消化液。然而,由它们形成的包衣可在水溶液和消化液中溶胀并被渗透。
可将本发明的EudragitRL/RS分散系按任意要求比例均匀混合以制得具有所需溶出曲线的控释制剂。例如,可由以下组成制得所需的控释制剂:100%EudragitRL,50%EudragitRL和50%EudragitRS,以及10%EudragitRL:90%ElldrllgitRS。当然本领域熟练技术人员知道,也可采用其他丙烯酸类聚合物,例如EudragitL。
增塑剂
在包衣含有疏水性控释材料水性分散系的实施方式中,在所述水分散系中加入有效量的增塑剂将进一步改善控释包衣的物理特性。例如,由于乙基纤维素具有较高的玻璃转化温度而且在一般包衣条件下不能形成韧性膜,所以,宜在含乙基纤维素的包衣剂中加入增塑剂后用作包衣材料。通常,增塑剂在包衣溶液中的含量取决于成膜剂的浓度,例如,通常为成膜剂的约1-50重量%。然而,增塑剂的浓度只有在用具体的包衣溶液和包衣方法进行仔细试验后才能准确确定。
适用于乙基纤维素的合适增塑剂例子包括水不溶性增塑剂。例如癸二酸二丁酯,邻苯二甲酸二乙酯,柠檬酸三乙酯,柠檬酸三丁酯和甘油三乙酸酯,但也可以采用其他水不溶性增塑剂(例如乙酰化甘油单酯,邻苯二甲酸酯,蓖麻油等)。就本发明乙基纤维素水分散系而言,柠檬酸三乙酯是特别好的增塑剂。
适用于本发明丙烯酸类聚合物的增塑剂例子包括但不限于:柠檬酸三乙酯NF XVI,柠檬酸三丁酯等柠檬酸酯,邻苯二甲酸二丁酯和1,2-丙二醇。还有其他增塑剂被证明可提高EudragitRL/RS树脂漆溶液等所成丙烯酸类膜的弹性,这包括聚乙二醇,丙二醇,邻苯二甲酸二乙酯,蓖麻油和甘油三乙酸酯。就本发明乙基纤维素水分散系而言,柠檬酸三乙酯是特别好的增塑剂。
某些实施例中,在控释包衣中加入少量滑石可降低水分散系在加工过程中黏结的倾向,并可作为抛光剂。
本发明控释制剂中活性物质的释放能够通过加入一种或多种释放调节物质,或提供一个或多个通过包衣的通路来进一步调节,例如,可调节到一个期望的速率。在其他因素中,疏水性的控释材料与水溶性材料之比由所需的释放速率和所选择材料的溶解性质所决定。
所述释放改变剂具有致孔作用,可以是有机或无机物质,包括那些可在使用环境中从包衣内溶出、萃取或浸出的物质。该致孔剂可包含一种或多种亲水性材料,例如羟丙基甲基纤维素。
本发明控释包衣还可以包含淀粉和树胶等促腐蚀剂。
本发明控释包衣还可以包含可在使用环境中形成微孔层的材料,例如聚合物链上重复出现碳酸酯基团的线型碳酸聚酯等聚碳酸酯。
释放改变剂还可以包含半渗透性聚合物。某些优选实施方式中的释放改变剂选自羟丙基甲基纤维素,乳糖,硬脂酸金属盐,以及它们的混合物。
本发明控释包衣还可包含一种由至少一条通路,小孔等构成的出口机制。所述通路可用以下美国专利所述方法形成:美国专利3,845,770;3,916,889;4,063,064和4,088,864。所述通路可以是各种形状的,例如圆形,三角形,正方形,椭圆形,不规则形等。
优选实施方案的详细描述
以下实施例说明了本发明的各方面内容。它们仅用以说明本发明,并不限定本发明的范围。
例1
按照表IA配方制备氢可酮缓释片剂:
                             表1A
成分     单位含量(mg)     批含量(g)
重酒石酸氢可酮     30.0     150.0
喷雾干燥的乳糖     90.0     450.0
聚乙烯吡咯烷酮     8.0     40.0
Eudragit RS30D(固体)     30.0     150.0
甘油三乙酸酯     6.0     30.0
硬脂醇     50.0     250.0
滑石     4.0     20.0
硬脂酸镁     2.0     10.0
Opadry Red YS1-15597-A     10.0     50.0
纯化水     *     *
总计     230.0     1150.0
*用于加工过程,残留于产品中水仅作为残存水分。
按照下列步骤操作:
1.造粒:用流化床造粒机将Eudragit/甘油三乙酸酯分散系喷雾在重酒石酸氢可酮、喷雾干燥乳糖和聚乙烯吡咯烷酮上。
2.研磨:放出造粒产物,令其通过磨机。
3.涂蜡:熔化硬脂醇,用混合机加到研磨后的颗粒中。任其冷却。
4.研磨:让冷却后的颗粒通过磨机。
5.润滑:用混合机,在颗粒中加入滑石和硬脂酸镁润滑。
6.压片:用压片机将颗粒压制成片。
7.包衣:在片剂外包裹一层水性膜衣。
用如下方法对片剂进行溶出试验:
1.仪器:USP I型(转篮法),100rpm。
2.介质:前55分钟为700ml SGF,然后加入磷酸盐缓冲液至900ml,pH7.5。
3.取样时间:1,2,4,8和12小时
4.分析方法:高效液相色谱法
溶出参数列于表1b
             表1B
    时间(小时)     溶出百分率
    1     25.5
    2     31.7
    4     41.5
    8     54.7
    12     65.0
例2按照表2A配方制备氢可酮缓释片剂:
                          表2A
  成分     单位含量(mg)     批含量(g)
  重酒石酸氢可酮     15.0     187.5
  Eudragit RSPO     78.0     975.0
  硬脂醇     27.0     337.5
  总计     120.0     1500.0
按照下列步骤操作:
1.研磨:用研磨机研磨片状硬脂醇。
2.混合:混合重酒石酸氢可酮,Eudragit和研磨过的硬脂醇。
3.挤塑:持续将混合的原料加入到双螺杆挤塑机中,将所得条形体收集于传送带。
4.冷却:在传送带上使条形体冷却。
5.制丸:用制丸机将冷却的条形体切成丸粒。
6.过筛:将丸粒过筛收集所需的过筛部分。
溶出方法:
1.仪器:USP法I型(转篮法),100rpm。
2.介质:700ml SGF,1小时,然后,加入磷酸盐缓冲液到pH7.5,900ml。
3.取样时间:1,2,4,8和12小时
4.分析方法:高效液相色谱法。
溶出参数如表2B所示:
               表2B
    时间(小时)     SGF/SIF溶出百分率
    1     19.5
    2     26.3
    4     38.2
    8     54.0
    12     63.8
例3按照表3A配方制备氢可酮缓释渗透片剂:
                  表3A
    成分     百分率
    药物层     药物层百分率
    重酒石酸氢可酮     25.4
    聚环氧乙烷     70.1
    聚乙烯吡咯烷酮     4
    硬脂酸镁     0.5
    置换层     置换层百分率
    聚环氧乙烷     68.57
    氯化钠     26
    羟丙甲纤维素     4.5
    氧化铁     0.6
    硬脂酸镁     0.25
    BHT     0.08
    半渗透壁     半渗透壁百分率
    乙酸纤维素     95
    聚乙二醇     5
根据下列步骤按照上述配方制备本剂型:
将一定量的重酒石酸氢可酮,平均分子量为200,000的聚(环氧乙烷)和聚(乙烯吡咯烷酮)加入到一行星式混合筒中混合,然后将变性的无水乙醇缓慢加入到混合的原料中,并且持续搅拌15分钟以制成湿颗粒。接着,让新制的湿颗粒通过20目筛,置于室温干燥,然后通过16目筛。接着将颗粒转入行星式混合机,混合,并用一定量的硬脂酸镁润滑。
推动层混合物按照下述方法制备:首先,溶解一定量的羟丙基甲基纤维素于水中制成黏合剂溶液,然后将丁基化羟基甲苯溶于变性的无水乙醇,将羟丙基甲基纤维素/水溶液加入到丁基化羟基甲苯/乙醇溶液中,并不断搅拌。接着将剩余的羟丙基甲基纤维素/水溶液加入到丁基化羟基甲苯/醇溶液中,并不断搅拌,制得黏合剂溶液。
然后,用Quadro Comil磨机减小一定量氯化钠的颗粒尺寸,用21目筛过筛原料。接着,将氧化铁通过40目筛过筛。然后将所有过筛的原料,平均分子量为7,000,000的药学上认可的聚(环氧乙烷)和羟丙基甲基纤维素加入到Glatt流化床制粒机的筒中,将筒连于制粒机上,开始有效制粒。接着将黏合剂溶液喷雾到粉末上。
溶液喷雾结束后,将所得的包过衣的已制成的粒状颗粒干燥,以QuadroComil碾磨,通过8目筛过筛,将颗粒混合,并加入一定量的硬脂酸镁润滑。
然后在Killian制片机上将重酒石酸氢可酮药物混合物和推动混合物压制成双层片。首先将重酒石酸氢可酮混合物加入到模孔,进行预压缩,然后加入推动混合物,压成双层排列片。
在双层排列片上包上一层半渗透壁。该造壁混合物由95%含39.8%乙酰基成分的醋酸纤维素和5%的聚乙二醇组成,将该混合物溶于丙酮∶水(95∶5重量:重量)的共溶剂中以制得4%的固体溶液。并将该混合物在24″Vector Hi包衣机中喷雾到双层片上及其周围。
然后,通过半渗透壁钻两个30mil(0.762mm)出口通道,使药物层和给药系统的表面连接。在50℃,50%湿度下干燥48h以除去残存溶剂,接着,将渗透剂型在50℃下干燥4h以除去过多的水分。
许多业内人士会明白基于本发明有许多其他变通,它们都在所附的权利要求的范围之内。

Claims (39)

1.一种适合患者24小时给药的固体控释口服剂型,它包括该剂型药学上可接受的基质,该基质包含镇痛有效量的氢可酮或其药学上认可的盐和控释材料;所述剂型给予患者后的C24/Cmax之比约为0.55-0.85,所述剂型的疗效可持续至少约24小时。
2.权利要求1所述的剂型,其特征在于所述剂型的C24/Cmax之比为0.55-0.75。
3.权利要求1所述的剂型,其特征在于所述基质呈多颗粒形式。
4.权利要求3所述的剂型,其特征在于所述多颗粒被压制成片。
5.权利要求3所述的剂型,其特征在于所述多颗粒装在药学上认可的胶囊内。
6.权利要求1所述的剂型,其特征在于所述剂型的C24/Cmax之比为0.60-0.70。
7.权利要求1所述的剂型,其特征在于采用USP转篮法测定:在37℃,700ml pH1.2的缓冲水溶液中,100rpm,其1小时的氢可酮或其盐体外溶出释放率至少为约10-45重量%。
8.权利要求1所述的剂型,其特征在于采用USP转篮法测定:先在37℃,700ml模拟胃液(SGF)中,100rpm,1小时,然后转入37℃,900ml,pH7.5磷酸盐缓冲液中,其4小时后的氢可酮或其盐体外溶出释放率至少为20重量%,其8小时的氢可酮或其盐体外释放率大约为20-65重量%,12小时后大约为45-85重量%,24小时至少为80重量%。
9.权利要求1所述的剂型,其特征在于患者口服后约4-14小时后到达氢可酮最高血浆浓度(Tmax)。
10.权利要求1所述的剂型,其特征在于患者口服后约6-12小时后到达氢可酮最高血浆浓度(Tmax)。
11.权利要求1所述的剂型,其特征在于所述氢可酮的Cmax低于等剂量氢可酮速释制剂Cmax的60%。
12.权利要求1所述的剂型,其特征在于所述给药是第一次给药。
13.权利要求1所述的剂型,其特征在于所述给药是稳态给药。
14.权利要求1所述的剂型,其特征在于它对患者群提供所述比例。
15.一种适合患者24小时给药的固体控释口服剂型,所述剂型包含镇痛有效量的氢可酮或其药学上认可的盐和控释材料,该剂型给人患者口服后,从Tmax至口服后约24小时期间的吸收速率为该期间药物消除速率的约45-85%,该剂型的疗效可持续至少约24小时。
16.一种提供患者至少约24小时有效镇痛的方法,所述方法包括口服含有药学上可接受基质的剂型,该基质含镇痛有效量的氢可酮或其药学上认可的盐和控释材料,该剂型给药于患者后的C24/Cmax之比约为0.55-0.85,疗效可持续至少约24小时。
17.一种制备固体口服控释剂型的方法,所述方法包括将镇痛有效量的氢可酮或其药学上认可的盐加入控释材料制成控释基质剂型,该剂型给于患者后的C24/Cmax之比约为0.55-0.85,疗效可持续至少约24小时。
18.适合患者24小时服用的固体口服控释剂型,所述剂型包含止痛有效量的氢可酮或其药学上认可的盐和控释材料组成的药学上认可的珠粒,该剂型根据USP转篮法测定:在37℃,900ml pH1.6-7.2的缓冲水溶液中,100rpm,其1小时的氢可酮或其盐体外释放率约为0-35重量%,其4小时的氢可酮或其盐体外释放率约为10-70重量%,其8小时的氢可酮或其盐体外释放率大约为20-75重量%,12小时大约为30-80重量%,18小时大约为40-90重量%,24小时后约为60重量%以上,其体外释放速率基本上不依赖于pH值,当在体外在900ml缓冲水溶液中以100rpm用美国药典XX II版(1990)所述桨法测定时,在任何给定时间,于某一pH释放的阿片类的量与任何另一pH释放的量的差不大于10%;患者口服后该剂型C24/Cmax之比约为0.55-0.85,疗效至少持续24小时。
19.权利要求18所述的剂型,其特征在于所述剂型的C24/Cmax之比为0.55-0.75。
20.权利要求18所述的剂型,其特征在于患者口服后约4-14小时后到达氢可酮最高血浆浓度(Tmax)。
21.权利要求18所述的剂型,其特征在于患者口服后约6-12小时后到达氢可酮最高血浆浓度(Tmax)。
22.权利要求18所述的剂型,其特征在于所述氢可酮的Cmax低于等剂量氢可酮速释制剂Cmax的60%。
23.权利要求18所述的剂型,其特征在于所述给药是第一次给药。
24.权利要求18所述的剂型,其特征在于所述给药是稳态给药。
25.权利要求18所述的剂型,其特征在于它对患者群提供所述比例。
26.为患者提供至少约24小时有效止痛的方法,包括给予患者口服权利要求18所述的剂型。
27.一种缓释口服剂型,所述剂型包括:
(a)包含下列两层的双层核:
(i)包含镇痛有效量的氢可酮或其药学上认可的盐的药物层;
(ii)包含渗透聚合物的置换层;
(b)包裹双层核的半渗透性壁,其中有用来释放所述氢可酮或其药学上认可的盐的通路;
所述剂型C24/Cmax之比约为0.55-0.85,且给予患者口服后疗效持续至少约24小时。
28.权利要求27所述的剂型,其特征在于所述剂型的C24/Cmax之比为0.55-0.75。
29.权利要求27所述的剂型,其特征在于患者口服后约4-14小时到达氢可酮最高血浆浓度(Tmax)。
30.权利要求27所述的剂型,其特征在于所述剂型被患者口服后约6-12小时到达氢可酮最高血浆浓度(Tmax)。
31.权利要求27所述的剂型,其特征在于所述氢可酮的Cmax低于等剂量氢可酮速释制剂Cmax的60%。
32.权利要求27所述的剂型,其特征在于所述给药是第一次给药。
33.权利要求27所述的剂型,其特征在于所述给药是稳态给药。
34.根据权利要27所述的剂型,采用USP转篮法测定;先在37℃,700ml模拟胃液(SGF)中,100rpm,1小时,然后转入37℃,900ml pH7.5磷酸盐缓冲液中,其4小时的氢可酮或其盐体外溶出释放率至少为20重量%,其8小时的氢可酮或其盐体外释放率大约为20-65重量%,12小时大约为45-85重量%,24小时至少为80重量%。
35.权利要求27所述的剂型,其特征在于它对患者群提供所述比例。
36.为患者提供至少约24小时的有效止痛的方法,该方法包括口服给药权利要求27所述的剂型。
37.一种缓释口服剂型,所述剂型包括:
(a)包含下列两层的双层核:
(i)包含镇痛有效量的氢可酮或其药学上认可的盐的药物层;
(ii)包含渗透聚合物的置换层;
(b)包裹双层核的半渗透性壁、其中有用来释放氢可酮或其药学上认可的盐的通道;
所述剂型采用USP转篮法测定,在37℃,900ml pH为1.6-7.2的缓冲水溶液中,100rpm,1小时的氢可酮或其盐体外释放率至少约为0-35重量%,4小时的氢可酮或其盐体外释放率约为10-70重量%。8小时的氢可酮或其盐体外释放率大约为20-75重量%,12小时大约为30-80重量%,18小时大约为40-90重量%,24小时约为60重量%以上;体外释放速率基本上不依赖于pH值,在一定时间内当在体外用美国药典XXII版(1990)所述桨法在900ml缓冲水溶液中,以100rpm测定时,不同pH值下阿片样物质释放量的差异在任何时刻均不大于10%。
38.为患者提供至少约24小时有效止痛的方法,所述方法包括让患者口服权利要求37所述的剂型。
39.权利要求1-15,17-25,27-35或37所述的剂型的用途,其特征在于所述剂型为患者提供至少约24小时的止痛。
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