CN107213128A - 控释氢可酮制剂 - Google Patents
控释氢可酮制剂 Download PDFInfo
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Abstract
本发明揭示了一种固体口服控释剂型的氢可酮。该剂型包含镇痛有效量的氢可酮或其药学上认可的盐和足量的控释材料,使得该剂型适合人患者每日给药两次,该剂型的C12/Cmax之比为0.55‑0.85,该剂型的疗效可持续至少约12小时。
Description
发明背景
由于药物治疗难以治愈疼痛,尤其是慢性疼痛,所以,阿片类镇痛剂是理想的控释给药制药物。本发明是关于一种用于治疗疼痛的固体口服控释剂型。
所有控释(缓释)制剂的目的都是在给药后能比速释剂型更持久地提供药粒作用。这样的长效与速释制剂的短效相比具有许多治疗上的好处。这样可以在不打扰患者睡眠的前提下继续治疗,例如在治疗中等至剧烈疼痛患者(例如术后患者,癌症患者等)时,或对于醒时会发生偏头痛的患者来说,或对于亟需睡梦的衰弱患者来说,这非常重要。
速效药物治疗除非精心定时给药以维持药物稳定的有效血浆浓度,由于对化合物的迅速吸收、全身性排泄和代谢灭活,活性药物的血浆水平会出现峰谷,因此在对患者疗效的维持上造成问题。长效药物的另一优点是提高了患者的顺应性,因为它避免了患者因遗忘而遗漏给药。
制备可在人和动物口服后缓慢释放所含药学活性物质的组合物在制药业中是已知技术。此类缓释组合物被用来使得药物吸收延迟至到达消化道特定部位时才发生。与传统速释剂型给药相比,这种药物在消化道内的控释可在更长时间内将药物的血液浓度维持在要求的水平。
有关制备和使用从载体中缓慢释放活性化合物的组合物的现有技术都涉及活性物质向消化道生理液中的释放。然而,都知道,单独存在于胃肠液内的活性物质本身不能确保其生物利用度。
为了被吸收,活性药物必需呈溶液状态。单位剂型释出一定量活性物质所需的时间可在标准条件下测定,表示为特定时间内由该单位剂型释放出的活性药物量比例。生理肠胃液是测定溶出时间的介质。现有技术认可许多试验可测定药物组合物的溶出时间,这些试验在世界各地的各类正式药典中都有所论述。
虽然有许多因素影响着药物从其载体中的溶出,但试验测得活性药物从具体组合物中溶出的时间相对稳定并具有重复性。影响溶出时间的因素包括药物接触溶剂介质的表面积,溶液的pH,药物在具体溶剂中的溶解度,和溶剂中物质的饱和浓度的驱动力。因此,当活性药物在组织部位被吸收而从溶剂中消除时,其溶出浓度动态地保持着稳态。在生理条件下,溶质的饱和水平得到剂型中储量的补充,因而在溶剂中维持着相对均一和恒定的溶出浓度,以实现稳定吸收。
胃肠道组织吸收部位的跨组织运输受到膜两侧Donnan渗透平衡力的影响,因为,驱动力的方向就是膜两侧活性物质的浓度差,即,溶于胃肠液内和血液内活性物质量的差异。由于血液浓度因稀释、循环改变、组织储存、代谢转化和全身性排泄而不断改变,所以,活性物质的流向是从胃肠道进入血液。
已有多种技术被用于制备控释剂型。具体地说,包衣丸粒、片剂和胶囊通过其包衣的选择性崩解或通过与特定基质混合以影响药物释放来缓慢释放活性药物,这是本领域的已知技术。某些控释制剂可实现单剂活性化合物给药后在预定时段顺次释放。
专利文献中记载的控释阿片类制剂例如:美国专利4,990,341和4,844,909(Goldie等),此两专利均已转让给了本发明的受让人,其中,经37℃,900ml缓冲液(pH1.6-7.2),100rpm的USP桨法或转篮法测定,所述氢吗啡酮组合物剂型的体外溶出率为:1小时后为12.5-42.5wt%氢吗啡酮,2小时后为25-55wt%,4小时后为45-75wt%,6小时后为55-85wt%,体外释放率在pH1.6-7.2区间内与pH无关,而且,体内氢吗啡酮血浆浓度峰值出现在给药后2-4小时之间。上述氢吗啡酮制剂缓解疼痛至少可达12小时。
目前,非常需要可用于治疗中度疼痛的其他阿片类镇痛剂的缓释剂型。而且,非常需要其药物动力学特性可提供最佳镇痛疗效的控释剂型。
发明概述
本发明目的之一是显著提高对中度疼痛患者镇痛疗效。
本发明目的还在于提供可显著改善镇痛效率和效果的可生物利用的氢可酮制剂。
本发明目的还在于提供可生物利用的氢可酮控释制剂,其疗镇痛效果效持续时间显著长于速释氢可酮制剂,但起效迅速。
本发明的目的还在于提供适合每日两次给药的口服控释阿片类制剂,它起效早,在给药间期内达到最高浓度后具有相对平缓的血浆曲线,阿片样物质血浆水平的C12/Cmax之比为0.55-0.85,并可有效地缓解患者的疼痛。在另一些实施方式中,所述剂型的C12/Cmax之比为0.65-0.75。
上述及其他目的可藉本发明的特征得以实现,在某些实施方式中,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控释材料,以使该剂型适合每日两次给药,该剂型在一次给予人患者后,体内氢可酮血浆浓度峰值出现时间约为2-8小时后(Tmax),达到最高浓度后的C12/Cmax之比为0.55-0.85。
在部分优选实施方式中,通过USP转篮法测定:37℃,先在700ml模拟胃液(SGF)中,100rpm,55分钟,然后转入900ml模拟肠液(SIF)中,37℃,测得所述控释剂型1小时后的氢可酮或其盐体外释放率为18-42.5wt%。
在部分优选实施方式中,通过USP转篮法测定:37℃,900ml pH1.2-7.5缓冲液中,100rpm,所述氢可酮剂型的氢可酮或其药学上认可的盐的体外溶出率为:2小时后约为25-65wt%,4小时后为45-85wt%,8小时后超过60wt%。虽然,根据要求,体外释放率可以是非pH依赖性的,也可以是pH依赖性的,在本发明优选实施方式中,氢可酮的释放是非pH依赖性的。
在部分优选实施方式中,提供了一种包含治疗有效量的氢可酮的控释剂型,该剂型在给药后12小时的氢可酮血浆浓度至少为5-6ng/ml,给药后2-8小时,至少为8ng/ml。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,该剂型的氢可酮Cmax低于等剂量速释氢可酮参比制剂(例如)Cmax的50%,并可在12小时的给药间期内有效镇痛。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,该剂型达到80%Cmax所需的时间约为等剂量速释氢可酮参比制剂(例如)的90-150%,以约90-110%为佳。较好的是,控释剂型达到80%氢可酮Cmax所需的时间为0.5-1.5小时左右,最好是0.8-1.2小时。另一些实施方式中,控释剂型达到80%氢可酮Cmax所需的时间为0.75-2.0小时左右,最好是0.9-1.5小时。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,该剂型达到90%Cmax所需的时间约为等剂量速释氢可酮参比制剂(例如)的150-400%,以约150-250%为佳。较好的是,控释剂型达到90%氢可酮Cmax所需的时间为1.5-2.5小时左右,最好是1.8-2.2小时。另一些实施方式中,控释剂型达到90%氢可酮Cmax所需的时间为1.5-4.0小时左右,最好是1.8-2.5小时。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,该剂型将血浆浓度维持在80%Cmax的时间可达约0.5-10小时,以1-9小时或4-8小时为佳。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,该剂型将血浆浓度维持在90%Cmax的时间可达约1-6.5小时,以2-5小时或2-6.5小时为佳。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,以含15mg氢可酮二酒石酸盐的口服剂型为基准,该剂型从给药到Tmax期间的平均体内吸收速度为1.5-5mg/h,从Tmax到给药间期末的平均吸收速度低于0.5mg/h。较好的是,以含15mg氢可酮二酒石酸盐的口服剂型为基准,该剂型从给药到Tmax期间的平均体内吸收速度约为2-4mg/h,从Tmax到12小时给药间期末的平均吸收速度约为0.08-0.4mg/h。
在本发明另一些优选实施方式中,提供了一种日用两次的氢可酮口服控释剂型,从Tmax到给药后12小时期间内,该剂型的吸收速度是消除速度的约55-85%。
较好的是,本发明上述及其他实施方式的Tmax时刻比等剂量速释氢可酮参比制剂迟3-4倍。较好的是,所述缓释制剂的Tmax出现在口服给药后约2-8小时,约3-7小时,或4-6小时。
本发明还涉及如下氢可酮制剂:其氢可酮Cmax低于等剂量速释参比产品的约50%,较好的是低于约40%。
例如,本发明出人意料的发现,当氢可酮配在美国专利4,861,598和4,970,075所述传递系统中时,所述系统的氢可酮Cmax相对于速释参比产品的百分比低于配制于相同传递系统内的羟考酮。虽然羟考酮和氢可酮控释制剂的体外溶出情况相似,但上述现象却十分明显。
用美国专利4,861,598和4,970,075所述传递系统配制本发明时,所述系统Cmax相对于速释参比产品的百分比低于50%,优选实施方式低于40%,羟考酮则高于50%。
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。
“USP桨法或转篮法”即US药典XXII(1990)中记载的方法。
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)的释放速度令血液(如血浆)浓度在至少约12小时内维持在疗效范围内,但低于毒性浓度。
“Cmax”表示给药间期内达到的最高血浆浓度。
“Tmax”表示达到最高血浆浓度(Cmax)所需的时间。
“T1/2(吸收)”表示半数可吸收剂量阿片样物质转运进入血浆所需的时间。
“稳态”表示给定药物达到的血浆浓度通过连续给药而维持在该药物最低疗效浓度以上、最低毒性血浆浓度以下。就阿片类镇痛剂而言,最低疗效浓度在一定程度上可根据特定患者所获得的疼痛缓解程度来确定。医药领域技术人员都知道,疼痛程度具有很强的主观性,而且患者间个体差异较大。
就本发明目的而言,“维持治疗”和“长期治疗”指在患者经阿片类镇痛剂给药达到上述稳态后给予患者的药物治疗。
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。
“平均共振时间(mean reasonance time”(MRT)定义为药物分子在体内的平均停留时间。该算得值与吸收、分布和消除有关,一定程度上取决于含活性成分的剂型。
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)是单独一名患者的药物动力学情况。
“患者群”表示表示所作的论述(或权利要求)是至少两名患者的药物动力学情况。
“突破性疼痛(breakthrough pain)”指尽管该患者正在接受一般有效量的含氢吗啡酮的本发明缓释固体口服剂型给药而仍然经受的疼痛,。
“援救”指给予正在经受突破性疼痛的患者的镇痛剂剂量。
“有效镇痛”指医生对患者接受镇痛治疗的反应的客观评价和接受该治疗的患者对治疗的主观评价。本领域熟练技术人员可以看出,有效镇痛取决于许多因素,其中包括患者的个体差异。
就本发明目的而言,“氢可酮速释参比制剂”是等剂量的(购自UCBPharma,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。
本发明中,所述的控释制剂和速释制剂都是剂量比例性的。此类制剂中,药物动力学参数(例如AUC和Cmax)从一个剂量强度向另一剂量强度的提高呈线性。所以,某一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。
本发明中,除非另作说明,所述的药物动力学参数都以一名患者单独一次给予氢可酮制剂为基础。基于患者群的药物动力学参数将以“平均”数表示。
“第一次给药”指在治疗开始时向一名患者或患者群的一次给药。
出人意料的是,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,在相当的日剂量上,采用本发明的控释口服固体剂型可获得更好的效果。
附图简述
附图用于说明本发明的实施方式而不是象权利要求那样限定本发明的范围。
图1显示实施例1,2,3和一种等剂量速释氢可酮的平均氢可酮血浆浓度。
图2显示实施例1,2和3的平均氢可酮血浆浓度,与之相比的是按照实施例4方法制成的控释羟考酮样品,按照实施例5方法制成的控释吗啡样品。
图3显示实施例1,2,3和一种等剂量速释氢可酮在不同时间的氢可酮吸收百分比。
详细描述
本发明的上述实施方式可用多种本领域已知的控释制剂来实施。例如美国专利4,861,598和4,970,075所述的控释剂型。
在本发明部分实施方式中,制剂中包含速释剂型的有效量的阿片样物质。所含速释剂型阿片样物质的量可有效缩短达到阿片样物质在血液(例如血浆)中最高浓度所需的时间,使得Tmax缩短至例如2-5小时或2-4小时。已发现,在单位剂型中包含上述有效量的速释阿片样物质可明显缓解患者较强烈的疼痛。在此类实施方式中,可将所述有效量的速释阿片样物质包涂在本发明基质之上。例如,在由控释包衣实现阿片样物质从制剂中延时释放时,可将速释层包在控释包衣之外。另一方面,当阿片样物质掺和在控释基质中时,可将速释层包在基质表面上。如果是将含有效单位剂量阿片样物质的多份缓释基质(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,可将阿片剂量的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阿片样物质速释层包衣。本领域技术人员知道,还有其他方式可将阿片样物质的速释部分加入单位剂量。这些方式应视为包含在后文权利要求中。
本发明阿片样物质剂型的优点之一是,在基本达到治疗浓度的同时,伴生副作用的强度和/或程度没有明显增强,所述副作用例如常伴随阿片样物质高血液浓度发生的恶心、呕吐或嗜睡。还有证据表明,采用本发明剂型可降低药物成瘾的危险性。
活性物质
本发明控释口服剂型宜包含约0.5-1250mg氢可酮或等量的其药学上认可的盐,在优选实施方式中,可以是约5-60mg,例如15mg。氢可酮合适的药学上认可的盐包括:二酒石酸氢可酮,二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,氢可酮缩氨基硫脲,硫酸氢可酮,三氟乙酸氢可酮,氢可酮二倍半水合物,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,磷酸二氢氢可酮,磷酸氢氢可酮,氢可酮无机酸盐,氢可酮有机酸盐,乙酸氢可酮三水合物,二(七氟丁酸)氢可酮,二(甲基氨基甲酸)氢可酮,二(五氟丙酸)氢可酮,二(吡啶羧酸)氢可酮,二(三氟乙酸)氢可酮,盐酸氢可酮,和硫酸氢可酮五水合物。本发明优选二酒石酸氢可酮。
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或有或没有协同作用。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,苯洛芬,氟比洛芬,非诺洛芬,flubfen,酮洛芬,吲哚洛芬,吡洛芬,卡洛芬,丙嗪,普拉洛芬,莫拉洛芬,三氧洛芬,舒洛芬,氨基洛芬,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,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(CGP-28238),美罗昔康,6-甲氧基-2-萘基乙酸(6-MNA),Vioxx(MK-966),奈丁美酮(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酮),它们的混合物,以及它们药学上认可的盐。
其他附加药物包括无毒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Z2SR-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-(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。
可包含在本发明制剂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。
在本发明部分实施方式中,给药用的控释单位剂型氢可酮制剂中含有有效量的速释剂型氢可酮。该速释氢可酮的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。此类实施方式中,有效量的速释氢可酮可包在本发明基质之外。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外。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之外。如果是将含有效单位剂量阿片样物质的多份缓释基质(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,可将阿片剂量的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阿片样物质速释层包衣。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性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“基质包括丸粒、颗粒、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,丸粒粒(后文统称“多颗粒”)。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,或加入其他各种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、控释材料和可选性其他成分(例如稀释剂,粘合剂,色素,润滑剂等)的片剂。
控释基质制剂
在本发明部分实施方式中,控释制剂是由一种基质(例如基质片剂)制得的,该基质中包含有前述控释材料。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度,并具有pH依赖性或非pH依赖性的溶出方式。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1-80wt%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,虫漆和氢化蓖麻油、氢化植物油等油脂。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(尤其是羟丙基甲基纤维素)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(甲基丙烯酸酐)和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。较好的是,可用于本发明的疏水性粘合剂其熔点约为30-200℃,以45-90℃为佳。当所述疏水性物质是烃时,其熔点最好在25-90℃之间。在长链烃(C8-50)中,优选脂肪醇。本发明口服剂型可含至多80wt%的至少一种可消化长链烃。
较好的是,所述口服剂型含至多80wt%至少一种聚烷二醇。具体地说,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。合适的蜡包括例如峰蜡,糖蜡(glycowax),蓖麻蜡和巴西棕榈蜡。就本发明目的而言,蜡样物质指室温下一般为固体,熔点约为30-100℃的物质。
可用于本发明的优选疏水性粘合剂包括可消化的长链(C8-50,尤其是C12-40)饱和或不饱和烃,例如脂肪酸,脂肪醇,甘油脂肪酸酯,矿物油和植物油,天然及合成蜡和聚烷二醇。优选熔点约为25-90℃的烃。在长链烃粘合剂中,部分实施方式优选脂肪醇。本发明口服剂型可含有至多80wt%至少一种可消化长链烃。
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。其实例包括峰蜡、巴西棕榈蜡,硬脂酸和硬脂醇。以上并非穷举。
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C12-36(C14-22更好)脂肪醇,以及可选的至少一种聚烷二醇。所述羟烷基纤维素优选C1-6羟烷基纤维素,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度等因素。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准确释放速度,还取决于口服剂型中是否含有至少一种聚烷二醇。如果没有聚烷二醇,口服剂型宜包含20-50wt%脂肪醇;如果含有聚烷二醇,则脂肪醇与聚烷二醇含量之和宜为剂型总量的20-50wt%。
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/聚烷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/聚烷二醇之比为1:2至1:4,优选1:3至1:4。
所述聚烷二醇可以是例如聚丙二醇或优选的聚乙二醇。所述至少一种聚烷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),C12-36脂肪醇和可选的聚烷二醇。
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,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C12-36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,通过用水进行羟烷基纤维素/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量是阿片样物质干重的1.5-5倍,1.75-3倍更好。
本发明的基质还可以通过熔体制丸(pellitization)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颗粒(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。
也可通过例如熔体造粒(granulation)或熔体挤塑技术来制备控释基质。熔体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,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。有关熔体造粒技术制备的控释制剂可参见美国专利4,861,598,该专利已转让给本发明的受让人。
附加的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另外的疏水性略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需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是水中溶解度低于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(glidant),它们的总量约为颗粒总量的50wt%。这些附加材料的量应足以对所需制剂产生所需效果。
用来配制口服剂型的药学上认可的载体和赋形剂的具体例子可参见药用辅料手 册,American Pharmaceutical Association(1986)。
制备合适的本发明熔体挤塑型基质包括: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0.1-5mm为宜,且应实现活性药物在约8-24小时内的控释。
制备本发明熔体挤塑制剂的一种可选方法包括直接计量疏水性控释材料,活性药物和可选的粘合剂,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。在这部分内容中,可实现相对连续的生产过程。
可在熔体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0.1-30wt%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切成颗粒。熔体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,“熔体挤塑型多颗粒”和“熔体挤塑型多颗粒系统”和“熔体挤塑型颗粒”都指单位个体的集合,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,并最好包含疏水性控释材料。较好的是,所述熔体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,所述熔体挤塑型多颗粒可以是以上大小的各种几何形状,例如珠、籽、丸粒等。或者,可以不经球化过程而直接将挤出物切割成所需长度的活性药物单位剂型。
在一优选实施方式中,所制备的口服剂型将有效量的熔体挤塑型多颗粒装入胶囊。例如,可将大量熔体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常规压片技术压成口服片。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)。
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。
可选的是,控释基质多颗粒系统或片剂或明胶胶囊可外裹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2-25wt%,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体挤塑型多颗粒的混合物。而且,所述剂型还可包括一定量的速释药物以获得即时疗效。所述速释药物可以是包含在明胶胶囊内的其他丸粒,或者包裹在珠粒或熔体挤塑型多颗粒之外。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肠液时缓慢释放出治疗活性药物。本发明熔体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,制备的熔体挤塑型制剂不含治疗活性药物,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。
适合本发明的典型的熔体挤塑生产系统包括: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,然后由例如运输带运去冷却,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.,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。
本发明还涉及熔体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,我们惊奇地发现,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。部分实施例中,我们惊奇地发现,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,在制备熔体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显著不同的物理特性。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。虽然这与一般想像相反,但我们发现,这种基本无孔隙制剂释放治疗活性药物的速度比非真空制备制剂快。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。
制备基质珠的方法
本发明的控释剂型可制备成基质珠制剂的形式。所述基质珠包含球化剂和氢可酮。
氢可酮宜占基质珠重量的约0.01-99wt%,以0.1-50wt%为佳。
可用来制备本发明基质珠的球化剂包括各种已知球化剂,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 PH 101(商标,FMC Corporation)。球化剂宜占基质珠重量的约1-99wt%。
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,本发明基质珠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基质珠的约1-80wt%。较好的是,所述控释材料在基质珠制剂中的含量足以实现阿片类镇痛剂从珠体中的有控释放。
基质珠制剂中还可以加有粘合剂、稀释剂等药物加工助剂。它们在助剂中的含量取决于需要制剂表现出的特性。
可在所述基质珠之外包裹一层含有前述控释材料的控释包衣。该控释包衣使得原基质珠增重约5-30%。控释包衣的量取决于许多因素,例如基质珠的组成,以及阿片类镇痛剂(即氢可酮)的化学和/或物理特性。
基质珠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珠。然后,任选地用前述方法在基质珠外包裹以控释包衣。
制备基质珠的另一种方法是,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C12-36脂肪醇混合;和(c)对颗粒进行压片和成形,该步骤可选。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重量的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。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,FMC Corporation)。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)虫漆或玉米蛋白。
控释珠制剂
在一特别优选的实施方式中,所述口服剂型是包含在明胶胶囊内的有效量的控释球粒。
在本发明另一优选实施方式中,所述控释剂型是裹有含控释材料的控释包衣的含活性成分的球粒。“球粒”在制药业指直径约0.1-2.5mm,尤其是0.5-2mm之间的球形颗粒。
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度(例如1小时后释放率至少约12.5%)等特性为宜。本发明的控释包衣配方应能形成光滑、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
本发明制剂可以任选地裹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。另一种优选实施方式是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12小时,更好的的24小时为患者提供镇痛作用。还可以配制成在胃肠道一处,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,将无保护药物包裹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漆、纤维素乙酸邻苯二甲酸酯(CAP)、聚乙烯乙酸邻苯二甲酸酯(PVAP)、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸酯共聚物、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,其中含有裹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。
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裹基质(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,所述控释包衣含有增塑剂。
部分实施方式中,有必要在含有阿片类镇痛剂的基质外包裹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2-50wt%(例如约2-25%)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(FMC Corp.,Philadelphia,Pennsylvania,USA)。的制备为:先将乙基纤维素溶于非水混溶性有机溶剂中,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,必需先将与合适的增塑剂充分混合。
另一种市售乙基纤维素水分散系是(Colorcon,Inc.,West Point,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,得到可直接加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(甲基丙烯酸酯),甲基丙烯酸烷酰胺共聚物,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。
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 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。
部分优选实施方式中,丙烯酸类包衣包含Rohm Pharma的 RL30D与 RS30D这两种丙烯酸树脂的混合物。 RL30D和 RS30D是低季铵含量的丙烯酸酯和甲基丙烯酸酯共聚物,其中季铵基团与其余中性(甲基)丙烯酸酯的摩尔比在 RL30D中是1:20,在 RS30D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。 RL/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 RL/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% RL,50% RL:50% RS,以及10% RL:90% RS。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 L。
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1-50wt%。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NFXVI,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 RL/RS树脂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。
还发现,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。
包衣珠粒制剂的制备
在用疏水性材料水分散系包裹例如惰性药物珠粒(例如nu pariel 18/20珠)等基质后,可将一定量的所得稳定化固体控释珠粒装入明胶胶囊,装量应足以在被摄食并接触胃肠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食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水分散系包衣量,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。
裹有治疗活性药物的基质的制备可以是例如:将治疗活性药物溶于水,然后,用Wuster插管(insert)喷涂到基质(例如nu pariel 18/20珠)上。可选的是,还可以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Colorcon,Inc的产品)的产品,混合(例如约1小时)后加到基质上。然后可以在所得有包衣基质外再裹以隔离剂,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。较好的是,隔离剂不会影响终产物的溶出速度。
然后可在基质外再裹以疏水性控释材料的水分散系。疏水性控释材料水分散系最好还包含有效量的增塑剂,例如柠檬酸三乙酯。也可使用或等预制乙基纤维素水分散系。如果采用则不必另外添加增塑剂。或者,也可采用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由此将色素加入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药物的基质上。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,还可以再加一层成膜剂,例如加该包衣层的目的是基本上消除珠粒的聚集。
还可以通过加入一种或多种释放改变剂或提供一条或多条穿过包衣的通路来影响治疗活性药物从本发明控释制剂中的释放,例如将其调节至所需的释放速度。疏水性控释材料与水溶性材料之比取决于所需的释放速度和所选材料的溶解度等因素。
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、萃出或渗出的物质。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有碳酸酯基团的线性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。部分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,一个微孔等构成的渗出机制。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,不规则形等。
生产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混合物粉末。然后将珠粒干燥,并裹以前文所述疏水性材料,以实现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12小时内维持吗啡有效血浆浓度的成品剂型。
优选实施方式的详细描述
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。
实施例1
按照表I配方制备氢可酮缓释片剂:
表I
成分 | 单位含量(mg) | 批含量(g) |
二酒石酸氢可酮 | 15.0 | 150.0 |
喷雾干燥的乳糖 | 56.0 | 560.0 |
聚乙烯吡咯烷酮 | 4.0 | 40.0 |
Eudragit RS30D(固体) | 10.0 | 100.0 |
甘油三乙酸酯 | 2.0 | 20.0 |
硬脂醇 | 20.0 | 200.0 |
滑石 | 2.0 | 20.0 |
硬脂酸镁 | 1.0 | 10.0 |
总量 | 110.0 | 1100.0 |
制备过程:
1.阻滞剂分散系:用lightnin混合机混合Eudragit RS30D与甘油三乙酸酯。
2.熔化硬脂醇。
3.用流化床造粒机将阻滞剂分散系喷涂到二酒石酸氢可酮、喷雾干燥乳糖和聚乙烯吡咯烷酮上。
4.将整批产品在不锈钢盘上干燥15分钟,或者干燥至恒重。
5.用Hobart混合机将熔融硬脂醇加入该批产物。
6.在不锈钢盘上进行30分钟干燥蜡造粒,或至造粒温度达35℃或以下。
7.用CoMil研磨冷却后的造粒产物。
8.用Hobart混合机加入滑石和硬脂酸镁作为润滑剂。
9.用压片机将造粒产物压制成片剂。
然后如下测定片剂溶出率:
1.仪器:USP法I(转篮法),100rpm。
2.介质:700ml SGF,55分钟,然后,900ml无酶SIF
3.取样时间:1,2,4,8和12小时
4.分析方法:高效液相色谱。
溶出参数如表II所示:
表II
时间(小时) | 溶出百分比 |
1 | 39.7 |
2 | 51.5 |
4 | 67.4 |
8 | 86.4 |
12 | 96.1 |
然后在一生物利用度试验中得到实施例1(CR)和一速释参比标准(IR)的Cmax和Tmax,比较15mg氢可酮以速释制剂(Lortab 7.5mg×2)和以上述CR制剂形式给予健康人受试者的差异,结果见表III:
表III
实施例2
按表IV配方制备氢可酮缓释片剂:
表IV
成分 | 单位含量(mg) | 批含量(g) |
二酒石酸氢可酮 | 15.0 | 150.0 |
喷雾干燥的乳糖 | 51.0 | 510.0 |
聚乙烯吡咯烷酮 | 4.0 | 40.0 |
Eudragit RS30D(固体) | 10.0 | 100.0 |
甘油三乙酸酯 | 2.0 | 20.0 |
硬脂醇 | 25.0 | 250.0 |
滑石 | 2.0 | 20.0 |
硬脂酸镁 | 1.0 | 10.0 |
总量 | 110.0 | 1100.0 |
制备过程同实施例1。
按照实施例1的方法获得溶出参数,见表V:
表V
时间(小时) | 溶出百分比 |
1 | 36 |
2 | 45.8 |
4 | 60.5 |
8 | 78.9 |
12 | 90.4 |
实施例3
按表VI配方制备氢可酮缓释胶囊:
表VI
成分 | 单位含量(mg) | 批含量(g) |
二酒石酸氢可酮 | 15.0 | 320.0 |
Eudragit RSPO | 76.0 | 1520.0 |
Eudragit RLPO | 4.0 | 80.0 |
硬脂醇 | 25.0 | 500.0 |
总量 | 120.0 | 2400.0 |
制备方法如下:
1.用Hobart混合机研磨混合硬脂醇,Eudragit RLPO,二酒石酸氢可酮和EudragitRSPO。
2.挤塑造粒产物:用粉末加料机,熔体挤塑机(装有6×1mm模头),传送带,Lasermike和造丸机,条件如下:
粉末进料速度:40g/min;螺杆速度:185rpm;真空度:980mBar
传送带:使得挤出物的直径为1mm
造丸机:切成1mm长的丸粒
3.用16号和20号筛筛选丸粒。收集通过16号筛网而滞留在20号筛网上的物料。
4.将丸粒装入2号明胶胶囊。范围:NLT 114mg,NMT 126mg。
然后按照实施例1的方法获取溶出参数。结果见表VII:
表VII
时间(h) | 溶出百分比 |
1 | 23.9 |
2 | 34.7 |
4 | 51.7 |
8 | 74.6 |
12 | 85.2 |
实施例4
按照表VIII配方制备羟考酮缓释片:
表VIII
成分 | 单位含量(mg) | 批含量(g) |
盐酸羟考酮 | 20.0 | 22.0 |
喷雾干燥乳糖 | 59.25 | 65.175 |
聚乙烯吡咯烷酮 | 5.0 | 5.5 |
Eudragit RS30D(固体) | 10.0 | 11.0 |
甘油三乙酸酯 | 2.0 | 2.2 |
硬脂醇 | 25.0 | 27.5 |
滑石 | 2.5 | 2.75 |
硬脂酸镁 | 1.25 | 1.375 |
Opadry粉红Y-S-14518A | 4.0 | 4.26 |
总量 | 129.0 | 141.76 |
方法如下:
1.造粒:用流化床造粒机将Eudragit/甘油三乙酸酯分散系喷涂在盐酸羟考酮、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作为润滑剂。
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。
然后,如下对片剂进行溶出试验:
1.仪器:USP II型(桨法),150rpm
2.介质:第一小时为700ml SGF,然后加入磷酸盐缓冲液至900ml,pH7.5。
3.取样时间:1,2,4,8,12,18和24小时
4.分析方法:高效液相色谱
溶出参数见表IX:
表VII
时间(h) | 溶出百分比 |
1 | 45 |
2 | 55 |
4 | 70 |
8 | 87 |
12 | 96 |
18 | 101 |
24 | 102 |
然后,通过生物利用度研究获取实施例4和标准速释参比样品的Cmax和Tmax,见表X:
表X
实施例5
按表XI配方制备吗啡缓释片:
表XI
成分 | 单位含量(mg) | 批含量(g) |
硫酸吗啡 | 30.0 | 138.0 |
喷雾干燥的乳糖 | 70.0 | 322.0 |
羟乙基纤维素 | 10.0 | 46.0 |
鲸蜡硬脂醇 | 35.0 | 161.0 |
滑石 | 3.0 | 13.8 |
硬脂酸镁 | 2.0 | 9.2 |
Opadry YS-1-4729 | 5.0 | 23.0 |
总量 | 155.0 | 713.0 |
方法如下:
1.造粒:在一混合机中,将水加入硫酸吗啡、喷雾干燥乳糖和羟乙基纤维素,用流化床造粒机干燥。
2.筛选:放出颗粒,过筛。
3.涂蜡:熔化鲸蜡硬脂醇,用混合机将其加入经研磨的颗粒。任其冷却。
4.筛选:将冷却后的颗粒过筛。
5.润滑:用混合机将滑石和硬脂酸镁加入颗粒作为润滑剂。
6.压片:用压片机将颗粒压制成片。
7.包衣:在片剂外包以水性膜。
如下进行片剂的溶出试验:
1.仪器:USP方法I(转篮法),50rpm
2.介质:900ml纯水,37℃
3.取样时间:1,2,3,4和6小时。
4.分析方法:285nm和305nm UV检测,用5cm池,2点法。
溶出参数见表XII:
表XII
时间(h) | 溶出百分比 |
1 | 34.2 |
2 | 49.9 |
3 | 64.2 |
4 | 75.5 |
6 | 90.3 |
然后,通过生物利用度研究测定实施例5和一标准速释参比样品的Cmax和Tmax:
表XIII
实施例6
比较实施例1,4和5的药物动力学参数,出人意料的发现,尽管实施例1盐酸氢可酮控释片的溶出非常类似于实施例4的控释羟考酮片和实施例5的硫酸吗啡控释片,但氢可酮制剂CR与IR的Cmax之比为38%,而羟考酮和吗啡片剂则高于50%。比较结果见表XIV:
表XIV
实施例7
以实施例1,2,3的控释氢可酮制剂和两片速释(二酒石酸氢可酮7.5mg/对乙酰氨基酚500mg)片剂对空腹正常态志愿者进行单剂量、4次治疗、标签公开(open lable)的药物动力学比较。各制剂的血浆浓度见表15-18:
药物动力学参数见表19:
表19
a:AUC和Cmax的几何平均值(0,最后),Tmax,W50,T1/2(abs)(吸收半衰期)和T1/2(elim)(消除半衰期)的算术平均值。
b:比例和90%CI所基于的是最小二乘方平均值。
c:比例(%):(试验平均值/参比平均值)×100,所基于的是最小二乘方平均值。
实施例8
按表XX配方制备氢可酮缓释片:
表XX
成分 | mg/片 | kg/批 |
二酒石酸氢可酮 | 15 | 15.0 |
磷酸氢钙 | 31 | 31.0 |
甘油山萮酸酯 | 10 | 10.0 |
硬脂醇 | 22 | 22.0 |
微晶纤维素 | 31 | 31.0 |
硬脂酸镁 | 1.0 | 1.0 |
Opadry紫YS-1-10371-A | 5.0 | 5.0 |
纯水 | N/A1 | 28.331 |
115.0mg | 115.0kg |
1:在加工过程中被蒸发,不包含在最终产品中
方法如下:
1.研磨:令硬脂醇薄片通过磨机。
2.混合:用合适的混合机,将二酒石酸氢可酮、磷酸氢钙、甘油山萮酸酯,硬脂醇和微晶纤维素混合。
3.挤塑:连续地将混合物料加入双螺杆挤塑机,挤塑机温度被升高以软化并形成挤出物。
4.冷却:挤出物在传送带上冷却。
5.研磨:将冷却后的挤出物通过磨机,得到所需大小的颗粒。
6.混合:将研磨后的挤出物与硬脂酸镁混合。
7.压片:用压片机将所得颗粒压制成片。
8.包衣:将Opadry分散在纯水中制备成包衣膜溶液,将其涂在片剂上。
如下进行片剂的试验:
1.仪器:USP I型(转篮法),100rpm。
2.介质:最初55分钟为700ml SGF(不含酶),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。
溶出参数见表XXI:
表XXI
时间(h) | 溶出百分比 |
1 | 22 |
2 | 37 |
4 | 58 |
8 | 84 |
12 | 99 |
实施例9
进行如下三路交叉药物动力学比较:给予进食和空腹常态志愿者单剂量15mg氢可酮控释片(实施例8);给予空腹常态志愿者15mg氢可酮速释剂(2×7.5mg/片),Q6H,2次以上。
然后,通过生物利用度研究获得了实施例8和标准速释参比片的Cmax和Tmax,见表XXII和XXIII:
表XXII
表XXIII
Claims (15)
1.一种每日给药两次的固体口服控释片剂,其中包含:
基质,其中包含(i)控释材料和(ii)氢可酮或其药学上认可的盐,所述控释材料选自树胶、纤维素醚、丙烯酸树脂、蜡、油脂以及它们之间的任意混合物;
所述片剂的平均氢可酮C12/Cmax之比为0.55-0.85,人首次给药后的平均氢可酮Tmax为约2小时至约8小时;
按给予含15mg二酒石酸氢可酮的片剂计,约2小时至约8小时的氢可酮平均血浆浓度至少8ng/ml,且约12小时的氢可酮平均血浆浓度至少为6ng/ml;并且
根据USP转篮法测定:先在37℃,700ml模拟胃液(SGF)内,100rpm,55分钟,然后转入900ml模拟肠液(SIF),37℃,其1小时释放18wt%至约42.5wt%的氢可酮。
2.一种口服剂型,包含约5mg至约1250mg氢可酮或其药学上认可的盐和赋形剂,所述赋形剂占所述剂型的1-80wt%,其中,
氢可酮或其药学上认可的盐是所述剂型中的惟一药物,
所述剂型提供:
氢可酮或其药学上认可的盐约8-24小时的控释,
口服后约8小时的氢可酮血浆浓度至少8ng/ml,以及
口服后12小时的氢可酮血浆浓度约5ng/ml或更高。
3.一种口服剂型,包含治疗有效量的氢可酮或其药学上认可的盐,所述剂型以如下速率释放氢可酮或其药学上认可的盐:该速率将氢可酮血浆浓度于治疗范围维持约12小时或更长,
氢可酮或其药学上认可的盐是所述剂型中的惟一药物,
所述剂型口服后约8小时的氢可酮血浆浓度至少约8ng/ml,
所述剂型口服后12小时的氢可酮血浆浓度约5ng/ml或更高,并且
所述剂型是片剂或胶囊。
4.如权利要求2或3所述的剂型,人首次空腹给药后的平均氢可酮C12/Cmax之比为0.55-0.85。
5.如权利要求4所述的剂型,所述给药后的平均氢可酮C12/Cmax之比为0.65-0.85。
6.如权利要求1所述的剂型,所述剂型的平均氢可酮C12/Cmax之比为0.65-0.85,所述给药是空腹给药。
7.一种每日给药两次的固体口服控释剂型,该剂型包含:
颗粒,所述颗粒的基质包含镇痛有效量的二酒石酸氢可酮和选自纤维素醚和丙烯酸树脂的控释材料,
所述控释材料占所述剂型的1-80wt%,
所述剂型于人首次给药后,所述给药后约2-8小时的氢可酮血浆浓度至少8ng/ml,Tmax至给药后约12小时期间的氢可酮吸收速度为该期间氢可酮消除速度的约55-85%。
8.一种固体口服控释剂型,该剂型包含:
基质,所述基质包含镇痛有效量的二酒石酸氢可酮和使得所述剂型适合向人每日给药两次的控释材料,
所述控释材料选自纤维素醚和丙烯酸树脂,
所述剂型于群体首次给药后约2小时至约8小时的平均氢可酮血浆浓度至少8ng/ml,平均氢可酮Tmax为约2小时至约8小时,平均C12/Cmax之比为0.55-0.85,并且
二酒石酸氢可酮的体外溶出速率如下所述:根据USP转篮法测定,37℃,900ml pH1.2的缓冲水溶液,100rpm,其2小时后的二酒石酸氢可酮释放率为约25-65wt%,4小时后约45-85wt%,8小时后高于约60wt%。
9.如权利要求8所述的剂型,首次给药后的氢可酮Cmax低于等剂量氢可酮速释参比制剂Cmax的50%。
10.如权利要求8所述的剂型,首次给药后,其达到80%平均Cmax所需时间是等剂量氢可酮速释参比制剂所需时间的90-110%。
11.如权利要求8所述的剂型,按口服给药含15mg二酒石酸氢可酮的剂型计,首次给药后,人口服给药到Tmax期间的平均体内吸收速度约2-4mg/小时,Tmax到给药后12小时期间的平均体内吸收速度约0.08-0.4mg/小时。
12.如权利要求1所述的剂型,所述控释材料选自纤维素醚和丙烯酸树脂。
13.如权利要求1所述的剂型,所述基质还含有脂肪醇。
14.如权利要求1-3中任一项所述的剂型,所述基质含5mg至60mg氢可酮或等当量的其药学上认可的盐和选自纤维素醚和丙烯酸树脂的控释材料。
15.一种制备固体口服控释剂型的方法,包括将镇痛有效量的二酒石酸氢可酮和选自纤维素醚和丙烯酸树脂的控释材料加入基质,和提供如权利要求1-14中任一项所述的剂型。
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