CN1242987A - 齐拉昔酮制剂 - Google Patents
齐拉昔酮制剂 Download PDFInfo
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- CN1242987A CN1242987A CN99111119A CN99111119A CN1242987A CN 1242987 A CN1242987 A CN 1242987A CN 99111119 A CN99111119 A CN 99111119A CN 99111119 A CN99111119 A CN 99111119A CN 1242987 A CN1242987 A CN 1242987A
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Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
- A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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Abstract
含有具有平均粒度等于或小于约85μm的齐拉昔酮游离碱晶体或齐拉昔酮盐酸盐晶体颗粒和药学上可接受的载体的组合物基本上是生物等价的,这些组合物可用来治疗精神病如精神分裂症。
Description
本发明涉及含有具有最大尺寸截止值的齐拉昔酮(ziprasidone)结晶颗粒的齐拉昔酮药物制剂组合物,本发明还涉及用这样的制剂治疗精神病的方法。
齐拉昔酮是一个已知的化合物,具有如下结构:该化合物公开在US4,831,031和5,312,925中,这两篇文献的全文在此引入作为参考,该化合物具有作为精神安定剂的用途,因此可用作抗精神病药。该化合物通常以盐酸加成盐的形式给药。该盐酸盐的优点是:药物穿透性高,这有利于增加生物利用度。然而,该盐酸盐水溶性较低,这对于生物利用度是不利的。
从制剂观点看,低溶解度化合物在药物领域中是有问题的。典型的解决途径包括(1)应用增加溶解度的特殊制剂赋形剂例如表面活性剂,和/或(2)用小颗粒药物配制,由此增加药物表面积以促进更迅速的溶解。然而,后一种方法得到的制剂有难度并且费用高,同时质量控制困难。
现在已经确定:对于含有齐拉昔酮游离碱或其盐酸盐(为了方便,统称为“齐拉昔酮”)晶体的组合物,当其平均粒度小于或等于约85μm时,则在生理pH条件下显示良好的溶解性质。令人惊奇的是:含有粒度小于或等于85μm的齐拉昔酮游离碱或其盐酸盐的制剂基本上是生物等价的,这意味着不管影响齐拉昔酮生物等价的因素是什么,它们基本上与粒度小于约85μm的颗粒无关。因此,本发明提供一种含有用Malvern光散射测定平均粒度小于或等于约85μm的晶体齐拉昔酮游离碱或其晶体盐酸盐颗粒和药学上可接受的稀释剂或载体的药物组合物。在组合物中优选齐拉昔酮颗粒的D90不超过170μm。应该注意:Dx表示X%的颗粒直径小于特定直径D。因此,170μm的D90表示齐拉昔酮组合物中优选90%的颗粒直径小于170μm。
齐拉昔酮颗粒的优选平均粒度小于或等于50μm。本发明所用的优选平均粒度范围是2-50μm,更优选5-50μm,特别更优选5-40μm,最优选5-30μm。此处以及权利要求书中规定的粒度是指用Malvern光散射确定的粒度。
本发明还提供一种治疗精神病的方法,包括:向需要所述治疗的患者施用有效量的组合物,组合物含有用Malvern光散射测定平均粒度小于或等于85μm的齐拉昔酮游离碱晶体或其盐酸盐晶体颗粒和药学上可接受的载体。可以用任何活性晶体形式应用齐拉昔酮盐酸盐,但优选齐拉昔酮盐酸盐一水合物。
如上所述,由于在生理pH条件下显示良好的溶解性能,本发明制剂是特别有利的。然而关于这一点本发明令人惊奇的是:体外溶解速率并不与粒度相关。也就是说,通常粒度减少和/或表面积增加会使较低溶解度药物的溶解速率增加;然而令人惊奇的发现:对于齐拉昔酮的粒度至少为或小于85μm时,其在含水介质中的溶解速率基本上不随粒度的变化而变化,因此显得基本上与粒度无关。因此,应用通常的制剂学方法和设备,可以容易地得到合理粒度的组合物,将齐拉昔酮游离碱或其盐酸盐配制在该组合物中,没有必要采取激烈措施或者专门技术达到和维持较微小的颗粒以促进溶解。
当在体外进行本发明制剂的溶解试验时,该制剂优选显示下列溶解标准。即,该制剂显示的溶解特性为,当在含有900ml 0.05MNaH2PO4缓冲液(pH7.5)的、2%(w/w)十二烷基硫酸钠的、装有桨式搅拌器的USP-2装置中,在以75rpm的速度搅拌下,加入相当于100mgA(“mgA”是表示分子量412.9的游离碱形式的活性齐拉昔酮的缩写)或更少量的活性齐拉昔酮(100mgA游离碱时相当于113.2mg齐拉昔酮盐酸盐一水合物),在45分钟内至少有70%的齐拉昔酮游离碱或其盐酸盐被溶解。通常,该测试结果为预定剂量数目(如胶囊、片剂、混悬剂或其它剂型)的平均值,其中的预定数目通常是6。测试时通常使溶解介质的温度维持在37℃。应该注意,如所测试的剂型为胶囊,可能需要把1%(w/w)的胰酶或其它来源的胰蛋白酶加入到所述磷酸盐缓冲溶解介质中,从而不会使胶囊壳干扰测试。如后面所述,通常用HPLC确定齐拉昔酮所溶解的量。
术语“颗粒”是指单个颗粒,无论这些颗粒是单独存在或者以聚集状态存在。这样,含有齐拉昔酮盐酸盐颗粒的组合物可能含有聚集物,这些聚集物的粒度远远超出此处指定的85μm的界限。然而,如果含有聚集物的主要药物物质颗粒(即齐拉昔酮游离碱或其盐酸盐)各个颗粒平均粒度小于约85μm,则该聚集物本身被认为满足此处所定义的粒度限制,因此这样的组合物属于本发明的范围。
齐拉昔酮游离碱或其盐酸盐颗粒的平均粒度(此处可互换地用“VMD”代替“体积平均直径”)等于或小于给定直径或者在给定粒度范围之内的意思是:假定样品中齐拉昔酮颗粒为球形,所有颗粒的平均估计体积小于或等于直径为给定值的球形颗粒所计算得到的体积。本领域技术人员用已知的Malvern光散射方法可测量粒度分布,这在下面将得到进一步的公开和论述。
此处所述的“生物等价”是指:对于含有具有给定平均粒度的齐拉昔酮晶体颗粒和药学上可接受的载体的剂量形式,用交叉研究对其进行试验时(通常包括至少10个或更多人的一组受试验者);同时用粒度为20微米(μm)、特别优选D90约40μm的齐拉昔酮颗粒以等价物制剂对同一组受试验者服药,对于每一个交叉组,前者平均曲线下面积(AUC)和/或Cmax至少是后者相应平均AUC和/或Cmax的80%。实际上,20μm的粒度是一个标准,其它不同的剂型可以与它进行比较。AUCs是以齐拉昔酮血清浓度为纵坐标(Y轴)和以时间为横坐标(X轴)的时量曲线图。通常地,AUC的值代表从所有受试者病人得到的许多值,因此是整个受试人群的平均值。Gmax,在齐拉昔酮的血清浓度(Y轴)对时间(X轴)的时量曲线图中观测到的最大值,同样地是一个平均值。
另外,应用AUCs、Cmax和交叉研究当然是本领域熟知的。本发明或者可以真正地看作是:一种含有用Malvern光散射测定平均粒度小于或等于85μm的齐拉昔酮晶体颗粒和药学上可接受的载体的组合物,所述组合物与另外一种含有平均粒度为20μm的齐拉昔酮的等价组合物(即所用辅料以及齐拉昔酮盐酸盐的量相同)相比,前者的平均AUC和/或平均Cmax至少是后者相应平均AUC和/或Cmax的80%。为了本发明的目的,应用术语“AUC”表示对于所有试验组合物在一个至少含10个健康人的受试组内交叉试验,其中的试验组合物含有“标准”的20μm粒度组合物。
如前所述,本发明可应用可形成结晶的任何形式的齐拉昔酮游离碱或其盐酸盐,包括无水形式,或者对于其盐酸盐可以是齐拉昔酮盐酸盐一水合物。本文中、包括实施例中所用的齐拉昔酮盐酸盐是齐拉昔酮盐酸盐一水合物,为了方便,在整个申请中,通常简单地称之为齐拉昔酮盐酸盐。在搅拌下,通过把碱(如碱金属氢氧化物例如氢氧化钠)加入或滴定到齐拉昔酮酸加成盐的水悬浮液中,可以从盐酸盐得到晶体齐拉昔酮游离碱。优选加入碱的速率使pH值上升到至少约5。进行中和作用的优选pH值范围约5-7。进行中和反应可长达数小时或更长,这主要取决于所需中和盐酸盐的量、应用的体积和碱浓度等。近中性pH条件下,该游离碱较其酸加成盐的溶解度小,当中和作用完成时,从溶液中析出该游离碱结晶。当加入碱后pH值不再摆动时,表明其中的酸已经耗尽,即到达中和反应的终点。如果测量的粒度不小于85μm,可以研磨得到中间体物质或更小粒度,这是本领域已知的。
或者按U.S.5,338,846所记载,直接合成得到齐拉昔酮游离碱。该文献在此引入作为参考。
粉末生产领域的技术人员应该明白可以用许多已知方法生产平均粒度小于或等于约85μm的齐拉昔酮盐酸盐晶体。例如一般如US4831031所公开的,用HCl水溶液处理齐拉昔酮游离碱可得到齐拉昔酮盐酸盐。具体地说,有两种优选的结晶方法可供选择来生产齐拉昔酮盐酸盐一水合物结晶用于此处例证的生物等价学研究。第一种方法得到最小的粒度,典型的VMD约5-30μm,该方法包括:将齐拉昔酮游离碱以浆液的形式悬浮在以水为溶剂混合物主要成分的四氢呋喃(THF)和水的混合物中,加入HCl水溶液形成盐酸盐,回流,时间通常为数小时,这取决于实施的规模(实验室或工业生产)。典型地,水与THF的比例(v/v)为13-17(水)比0-5(THF)。该方法记载在US5,312,925中,在此引入作为参考。由于齐拉昔酮的低溶解度,该方法在没有获得溶液的情况下使齐拉昔酮游离碱转变成其盐酸盐。为了形成盐酸盐,该浆液需要较长的回流时间。当选择该方法时,长时间的回流和低溶解度得到较小的粒度。
另一种供选择的制备大结晶颗粒的方法包括:从溶液中结晶齐拉昔酮盐酸盐一水合物。在(或接近)回流下,在THF和水的混合物中制备齐拉昔酮游离碱溶液,其中的溶剂混合物以THF为主,THF与水的体积比典型地为22-35(THF)比1.5-8(水),优选24-30(THF)比2-6(水)。加热混合物,优选温度刚好低于回流的温度以避免晶体的机械变小,然后加入HCl水溶液得到齐拉昔酮盐酸盐一水合物。一旦开始加入HCl溶液,晶体即形成并开始从溶液中析出。由于回流温度通常约65℃,一般采用/维持60-64℃的温度。尽管为了得到较大的晶体通常避免回流,可以应用轻微的振荡如缓慢的搅拌来均衡反应容器内的温度。加热时间也取决于实施的规模(小型试验或工厂生产),但无论为任何形式,一般为几分钟至数小时。加热一完成,就冷却反应物,优选慢慢地冷却,对于工业生产,典型地冷却时间为至少2小时,优选至少4小时,直至达到室温。用该方法生产数批大颗粒。一般来说,富含THF的溶剂可增加晶体的粒度。一般地,用此方法可以生产VMD50-150μm的大颗粒。应该注意:如果得到VMD大于85μm的大粒度颗粒,可以进行研磨得到中间体物质或更小粒度的颗粒,这构成另一种制备适用于本发明的齐拉昔酮盐酸盐一水合物晶体颗粒的方法。
当培养粒度范围端值为85μm或更大的晶体时,许多因素对于产生大粒度晶体是重要的。首先,加入的齐拉昔酮游离碱有高纯度对培养大晶体是有帮助的。同时,正如已经指出的,在刚刚低于回流的温度进行结晶是有帮助的;并且,有可能降低温度刚刚在回流温度之下以降低对晶体的应力。并且,应用低搅拌速率进一步减少晶体的破裂。用稀盐酸代替浓盐酸进一步增大晶体的粒度。还发现有助于形成大晶体的两个因素是:(1)降低加入酸的速率;(2)当开始加入10%的酸后进行搅拌,这样在加入剩余的盐酸之前只产生较少的晶种。在实施例中有详细的实验步骤。
如上所述,这种制备齐拉昔酮盐酸盐大晶体的方法被认为是一种新方法,因此,这是本发明的另一个特征。因此,本发明提供一种制备齐拉昔酮盐酸盐一水合物大晶体的方法,包括的步骤是:
1)把齐拉昔酮游离碱溶于含有THF和水的溶剂中,THF与水的体积比约22-35单位体积比1.5-8单位体积;
2)加热步骤1)所得到的溶液;
3)把HCl加入到步骤2)所得到的溶液中;和
4)冷却步骤3)所得到的溶液。
一旦溶液冷却后,就可以通过例如过滤和干燥方便地得到晶体。
对于含有平均粒度小于85μm的齐拉昔酮游离碱或齐拉昔酮盐酸盐的组合物,可以制备成常规的、通常为干燥的药物剂量形式如片剂、用于口服混悬剂的粉剂、单位剂量包和口服胶囊,可以用常规方法制备这样的剂量形式。如在美国同一日期的临时申请(Pfizer Docket 10509 JTJ)所记载,还可把齐拉昔酮游离碱加入到预先形成的口服悬浮液中,该文献在此引入作为参考。
除了含有齐拉昔酮游离碱或齐拉昔酮盐酸盐外,该组合物还可含有常规的药学上可接受的赋形剂,例如:填充剂和稀释剂如淀粉和糖;粘合剂如羧甲基纤维素和其它纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;崩解剂如琼脂、碳酸钙和碳酸氢钠、预胶凝淀粉、交联羧甲基纤维素钠、淀粉羟乙酸钠和交联聚乙烯吡咯烷酮;润滑剂如滑石粉、十二烷基硫酸钠、硬脂酸、硬脂酸钙和硬脂酸镁以及固体聚乙二醇。一些赋形剂可以有多种功能,例如崩解剂也可作为填充剂。
在优选的制备方法实施例中,为了保证所有组份不结块,可以首先用普通不锈钢筛或者碾磨机过筛或研磨齐拉昔酮游离碱或齐拉昔酮盐酸盐一水合物、乳糖一水合物和预胶凝淀粉。然后把混合物混合30分钟以保证良好的均匀性,例如用滚筒混合器如V-混合器或bin混合器。混合之后,加入硬脂酸镁(0.75%w/w),继续混合5分钟。混合后的混合物加入到滚筒压缩机的漏斗中,压制和研磨得到颗粒。如上所述将该颗粒再混合10分钟。混合之后,加入另外的润滑剂(硬脂酸镁0.5%w/w),又混合5分钟。然后如果需要,在例如用H&K或Bosch装胶囊机做成胶囊之前,将该混合物取样。
可以应用传统设备和常规方法制备片剂。
在含有本发明组合物的片剂、胶凝或其它剂型中,齐拉昔酮游离碱成齐拉昔酮盐酸盐的含量通常为5-100mg,一般口服给药每天两次,但是,该范围之外的含量和与此不同的给药频率在治疗中也是可行的。正如前面所述,这样的剂量形式对于治疗精神病是特别有用的,如US4831031所记载的治疗精神分裂症类型的精神病。
如上所述,可以用激光散射技术Malvern光散射来确定平均粒度大小。在下面的实施例中,应用带有小体积循环单位的Malvern Mastersizer MS1型粒度分析仪(Malvern Instruments Inc.,10 Southville Rd.,SouthboroughMA01772)测量齐拉昔酮盐酸盐一水合物药物物质的粒度。所用的透镜为300RFmm,光束长度(beam length)为2.4mm。循环速度设置在11点种(11o’colck)用来保证样品维持在悬浮状态。把秤好的齐拉昔酮盐酸盐(500±10mg)加入到16mL的小玻璃瓶中,得到分析用样品。在该小瓶中加入10ml悬浮介质,特别是前面制备的含1%司盘85的己烷(ACS试剂级)混合物。充分震摇约5秒钟以悬浮该齐拉昔酮盐酸盐。如果需要,还可进行60秒超声以有效地破坏聚集体并有助于悬浮颗粒。分析样品之前,通过用100ml悬浮介质填充测量池达到本底计数。为了进行样品分析,首先用一次性Pasteur移液管抽取并倒空悬浮液数次以保证样品瓶内容物的代表性抽样。然后,装满移液管,把数滴小瓶内容物加入到测量池中的悬浮介质中,直至达到约20%的昏暗(obscuration)值。持续震摇该小瓶避免抽样期间悬浮液的沉降,进行抽样步骤。得到体积分布;为了表示特性,特别列出D10、D50、D90和体积平均直径(VMD=D[4,3])值(注:此处提到的平均粒度值指测量的VMD值)。测量完成时,倒空并清洗样品池,再充满悬浮介质,重复抽样步骤,共进行3次。
为了评估剂型的溶解性质,在USP-2装置中通过溶解对其进行试验。如前所述,该装置含有900ml调至pH7.5的0.05M NaH2PO4缓冲液,同时含有2%(w/w)十二烷基硫酸钠。正如前面所述,如果所测试的剂型是胶囊,可加入1%的胰酶。可以用例如5N氢氧化钠或浓磷酸把pH调节到合适值。该USP-2装置中有浆式搅拌器,以75rpm的速度搅拌。把该剂型(如:片剂或胶囊)直接加入到水溶性介质中。如果是胶囊,将其插入到塑料夹中(商品Vankel,Part No.T-1045-8),这样在开始溶解时胶囊保持在容器底部。测试期间,溶解介质通常维持在37℃。在磷酸盐溶液中,如果在45分钟内至少有70%、优选75%的齐拉昔酮盐酸盐溶解,则该剂型属于本发明的范围。
溶解的齐拉昔酮的量,可通过HPLC按常规方法测定。作为用HPLC分析测定齐拉昔酮溶解性的一个实施例,测定溶解的齐拉昔酮的量可用合适的色谱柱如ZorbaxRx G8 Reliance(Mac-Mod Analytical Inc.,127 Common Court,PO Box 2600,Chadds Ford,PA 19317),4.0×80mm色谱柱,无梯度流动相组成为45%乙腈和55%0.05磷酸二氢钾缓冲液,其pH为6.5,流动速度1.0ml/min,温度40℃。用波长为215nm的紫外吸收检测。利用已知浓度的浓度-标准物峰高(或峰面积)的标准曲线图,把样品得到的HPLC峰高(或峰面积)与标准曲线图中的峰高(或峰面积)进行比较,可以容易地进行定量测定。通常地,所用的齐拉昔酮标准浓度选择在浓度-所用紫外检测器的紫外吸收的线性范围内。
通过下面非限制性实施例使本发明得到进一步例证和公开。
实施例1
为了说明本发明,进行开放的、随机的、分3期的、两组的和无消除期稳态条件下的人药代动力学交叉研究,其中用两种齐拉昔酮胶囊(相同的组合物,如实施例3中的表1),每种胶囊含有20mg活性齐拉昔酮,但齐拉昔酮盐酸盐的粒度不同,该两种胶囊总共给14例健康受试者服用,有男性(11例)也有女性(3例)。受试者每天口服药物2次(1×20mg胶囊,间隔12小时),在早餐或晚餐后立即服用,受试者的早餐或晚餐完全相同。服药时同时服用50ml水。每期时间的第3天(第3、6和9天),每个受试者进行一顿早餐,组成是:黄油炸鸡蛋2个、熏猪肉2条、捣碎的棕色土豆6盎司、烤面包2片并加2小块黄油和8盎司全牛奶。早餐后立即服用1×20mg胶囊,按下列时间抽取血样品:0(正好在服药前),0.5,1,2,3,4,6,8,10和12小时。在第1、2、4、5、7和第8天,早上服药之前得到另外的血清样品。用高压液相色谱按照Janiszewski等.,色谱学杂志(J.Chromatography)B:生物医学应用(Biomedical application),1995年6月9日,668(1),第133-139页提出的直线分析确定齐拉昔酮的血清浓度,下面对其进行描述:
通过固相提取(SPE)柱的弱交换作用制备血清样品。用甲醇和乙酸水溶液调节SPE柱后,每个SPE柱加入0.5ml等分试样的血清,然后加入0.05ml的内标,一般为每20ng/50μl 50%甲醇-50%水的溶液。真空抽吸使样品通过柱,应用少量试剂如乙酸水溶液、甲醇和0.25%三乙胺(TEA)的乙腈溶液洗涤。然后用单个柱床体积的溶剂如1.0% TEA的乙腈溶液把样品洗脱到硅玻璃测试管中。溶剂蒸发后(40-60℃,在N2下),在40μl的流动相(2∶1的去离子水/含0.05%三氟乙酸和0.08%三乙胺的乙腈)中,再溶解干燥的残余物,用浓HCl调节pH值至0.5。离心之后,分析样品:Supelco SupelcosilTM LC-18-DB小孔径柱,维持温度35℃,流速0.27ml/min,紫外吸收波长215nm。
该两种胶囊所用的平均粒度分别是20和46nm。直接从实验数据可以估计齐拉昔酮的最大血清浓度(Cmax)。记录Tmax(首次到达Cmax的时间)。用梯形近似法估计服药后0-12小时齐拉昔酮时量曲线下的面积(AUC0-12)。把46μm粒度制剂与20μm粒度制剂相比,从校准的稳态平均AUC0-12值的比例估计相对生物利用度。
目测数据显示:第3天达到稳态系统曝露量(exposure)。不同性别的药代动力学参数没有明显区别。应该注意:由于14例受试者中只有3例是女性,因此性别效应只是有限的估计。Tmax值从0-12小时,然而在所有受试组中平均值是5-8小时。两个试验组没有观测到显著的Tmax的统计学差异(p=0.63),校准的平均Tmax值为分别6.8和6.3小时。两种粒度的制剂的曝露量(AUC)相似,与20μm胶囊相比,46μm胶囊的平均相对生物利用度是100.2%。类似地,46μm粒度与20μm粒度相比,校准的平均Cmax值的比例是96.6%。90%置信区间的是AUC0-12(89.1%,112.7%)和Cmax(86.0%,108.5%)。因此,用大粒度(46μm)制备的20mg胶囊,可以得到与用小粒度(20μm)制备得到的胶囊相当的系统曝露量。
实施例2
该实施例是对比实施例,进一步显示当以胶囊服用时,齐拉昔酮盐酸盐粒度对其系统曝露量的作用。
制备三种含20mg活性物质的齐拉昔酮盐酸盐胶囊(实施例3中表1所示),每种胶囊所用的不同的齐拉昔酮盐酸盐有不同的粒度,具体地讲,平均粒度(VMD)是20μm、84μm或105μm。含有20μm齐拉昔酮盐酸盐的胶囊与实施例3中胶囊相同。
这些剂型的粒度对齐拉昔酮生物利用度的效应通过对11例健康受试者的单剂量交叉人药代动力学研究进行确定,其中的药代动力学研究是开放的、随机的、分3期的和有3组试验。在第1、8和15天早餐后,受试者立即口服(1×2mg胶囊),其中的早餐是:黄油炸鸡蛋2个、熏猪肉2条、捣碎的棕色土豆2盎司、烤面包2片并加2小块黄油和8盎司全牛奶。每次服药时同时服用50ml水。按下列时间抽取血样品:服药后0(正好在服药前),1,2,3,4,6,8,12、18、24和36小时。对于每个受试者在每次服药之后,确定该药物的时量曲线下面积(AUC0-inf)和齐拉昔酮的最大血清浓度(Cmax)。
含大颗粒齐拉昔酮盐酸盐(84μm和105μm)胶囊得到的平均AUC0-inf和Cmax值,将其与含小颗粒20μm的齐拉昔酮盐酸盐胶囊得到的AUC0-inf和Cmax值相比,其比值用来评价齐拉昔酮粒度对口服生物利用度的作用。平均AUC0-inf(84μm)/AUC0-inf(20μm)和Cmax(84μm)/Cmax(20μm)分别是81%和90%;平均AUC0- inf(105μm)/AUC0-inf(20μm)和Cmax(105μm)/Cmax(20μm)分别是75%和77%。
实施例3-9
下列制剂是代表本发明范围内的代表性制剂。所有制剂应用平均粒度为20-85μm的齐拉昔酮盐酸盐颗粒通过如前所述优选的制备方法制备。所有制剂用来填充胶囊。
表1
(a)用干燥制粒方法制备(b)用直接填充法制备(c)以88.3%的理论效价因子(potency factor)为基础(d)以91.9%的效价因子为基础(e)为了维持一致的胶囊重量,根据齐拉昔酮盐酸盐一水合物小的效价变化调整乳糖一水合物的重量(f)如果需要,可以变化胶囊壳的颜色,不影响胶囊性能实施例10
实施例 | 3(a)(mg/胶囊) | 4(a)(mg/胶囊) | 5(a)(mg/胶囊) | 6(a)(mg/胶囊) | 7(a)(mg/胶囊) | 8(a)(mg/胶囊) | 9(a)(mg/胶囊) |
齐拉昔酮盐酸盐一水合物,Pfizer乳糖一水合物,Ph.Eur.预胶凝玉米淀粉,BP硬脂酸镁,Ph.Eur.硬脂酸镁,Ph.Eur.硬明胶,Locking胶囊壳,Pharm(f) | 22.65(c)66.10(e)10.000.750.50尺寸#4蓝/白 | 45.30(c)87.83(e)15.001.120.75尺寸#4蓝/蓝 | 21.76(d)245.24(e)30.003.00--尺寸#2黑/蓝 | 22.65(c)66.10(e)10.000.750.50尺寸#4蓝/蓝 | 67.95(c)131.74(e)22.502.81尺寸#3白/白 | 90.60(c)175.65(e)30.003.75尺寸#2蓝/白 | 113.25(c)219.56(e)37.504.69尺寸#1蓝/蓝 |
总量(mg/胶囊) | 100.00 | 150.00 | 300.00 | 100.00 | 225.00 | 300.00 | 375.00 |
本实施例说明制备齐拉昔酮盐酸盐一水合物大晶体的步骤。在该步骤中选择使用两次重结晶的齐拉昔酮游离碱。产品经分析纯度为99.7%。
在清洁干燥的搪玻璃反应罐中,加入180L THF、18L去离子水和6.0kg齐拉昔酮游离碱。加热该浆状液至回流得到澄清溶液。在另一个独立的装料罐中加入16L去离子水和1.8L浓盐酸制备得到HCl溶液。装料罐中的搅拌器以低速度搅拌。冷却前面的反应罐使刚刚低于回流温度(62-62℃,THF在约64℃时回流),加入起始的2kg HCl溶液。使结晶液至混浊点。维持该结晶液混合物62℃的温度30分钟,使形成晶种。搅拌后在45分钟时间内加入剩余的HCl溶液。加完后,该浆状液从62℃慢慢冷却至13℃使结晶完成。用搪玻璃封闭压力过滤器收集该齐拉昔酮盐酸盐一水合物产品,用6L新鲜的冷THF洗涤得到的过滤饼。
25-35℃下真空干燥该产品得到所需要的一水合物(Karl Fisher法测定水含量,KF=3.9-4.5%)。得到产品6.6kg,产率97%。HPLC分析显示该产品为单峰(LOQ<0.05%),与标准物的保留时间值相符。
得到的晶体大小为105μm,需注意的是:大粒度晶体可以研磨成粒度小于85μm的小粒度晶体。实施例11
按照如下方法制备悬浮制剂:733.1g水加热至70℃,用架设的搅拌器以约200rpm的速度搅拌,加入1.36g对羟基苯甲酸甲酯和0.17g对羟基苯甲酸丙酯。当这些对羟基苯甲酸酯完全溶解后,冷却温度至约30℃。然后按顺序加入下列成分:2.78g黄原胶、333.90g木糖醇、1.13g无水柠檬酸、1.21g柠檬酸三钠二水合物、0.55g吐温80、11.13g NaCl、11.33g标称粒度为38μm的齐拉昔酮盐酸盐一水合物、11.13g胶体二氧化硅和5.0g樱桃香精。如果需要,用氢氧化钠水溶液或盐酸调整pH值至4.0。实施例12
本实施例公开一种制备齐拉昔酮游离碱悬浮液的方法。
秤取812.9g水加入到2升的烧杯中,用架设的搅拌器以约200rpm的速度搅拌。把水加热至70℃。当温度达到70℃后,加入1.36g对羟基苯甲酸甲酯和0.17g对羟基苯甲酸丙酯。当这些对羟基苯甲酸酯完全溶解后,降低温度至40℃。往该溶液中缓缓加入3.27g粘度剂,CARBOPOL树脂974P(Union CarbideCorporation,Danbury,CT),注意避免较大团状物的形成,必要时增大搅拌速度。维持搅拌直至上述粘度剂完全分散和/或溶解。把218g蔗糖加入到该溶液中。待蔗糖溶解后,降低温度至30℃。往溶液中加入2.94g柠檬酸三钠。再往该溶液中加入0.544g吐温80。再往该溶液中缓缓加入11.325g齐拉昔酮游离碱。用10%NaOH溶液调整pH值至5.7。待pH保持平衡后,加入1.09g胶体二氧化硅(CAB-O-SIL,Cabot公司)。
Claims (34)
1、一种组合物,含有:具有平均粒度等于或小于约85μm的齐拉昔酮游离碱晶体颗粒或齐拉昔酮盐酸盐晶体颗粒和药学上可接受的稀释剂或载体。
2、如权利要求1所述的组合物,其中所述组合物含有齐拉昔酮盐酸盐一水合物。
3、如权利要求1所述组合物,其中所述的平均粒度等于或小于50μm。
4、如权利要求3所述组合物,其中所述的平均粒度为5-50μm。
5、如权利要求4所述组合物,其中所述的平均粒度为5-40μm。
6、如权利要求5所述组合物,其中所述的平均粒度为5-30μm。
7、如权利要求1所述组合物,其显示的平均AUC和/或Cmax至少是另一种等同制剂的平均AUC和/或Cmax的80%,此处的另一种制剂与所述组合物相同但所含有的齐拉昔酮盐酸盐平均粒度为20μm。
8、如权利要求1所述的组合物,其中,在含有900ml NaH2PO4缓冲水溶液、pH7.5、含2%(w/v)十二烷基硫酸钠、装有浆式搅拌器的USP-2装置中,当把相当于100mgA或更少齐拉昔酮的剂型量在75rpm搅拌下加入该装置中时,至少有70%的齐拉昔酮在45分钟内溶解。
9、一种治疗精神病的方法,该方法包括:向需要所述治疗的患者施用有效量的权利要求1的组合物。
10、如权利要求9所述的方法,其中所述组合物含有齐拉昔酮盐酸盐一水合物。
11、如权利要求9所述的方法,其中所述的平均粒度等于或小于50μm。
12、如权利要求11所述的方法,其中所述的平均粒度为5-50μm。
13、如权利要求12所述的方法,其中所述的平均粒度为5-40μm。
14、如权利要求13所述的方法,其中所述的平均粒度为5-30μm。
15、如权利要求9所述的方法,其中组合物显示的平均AUC和/或Cmax至少是另一种等同组合物的平均AUC和/或Cmax的80%,此处的另一种等同组合物与该组合物相同但所含有的齐拉昔酮盐酸盐平均粒度为20μm。
16、如权利要求9所述的方法,其中,在含有900ml NaH2PO4缓冲水溶液、pH7.5、含2%(w/v)十二烷基硫酸钠、装有浆式搅拌器的USP-2装置中,当把相当于100mgA或更少齐拉昔酮的量的所述组合物在75rpm搅拌下加入该装置中时,至少有70%的齐拉昔酮在45分钟内溶解。
17、一种组合物,含有:通过Malvern光散射测定平均粒度等于或小于约85μm的齐拉昔酮游离碱晶体或齐拉昔酮盐酸盐晶体颗粒和药学上可接受的载体;该组合物显示的平均AUC和/或Cmax至少是另一种等同组合物的平均AUC和/或Cmax的80%,此处的另一种等同组合物与所述组合物相同但所含有的齐拉昔酮盐酸盐平均粒度为20μm。
18.如权利要求17所述的组合物,其中所述组合物含有齐拉昔酮盐酸盐一水合物晶体。
19、如权利要求17所述组合物,其中所述的平均粒度等于或小于50μm。
20、如权利要求19所述组合物,其中所述的平均粒度为5-50μm。
21、如权利要求20所述组合物,其中所述的平均粒度为5-40μm。
22、如权利要求21所述组合物,其中所述的平均粒度为5-30μm。
23、如权利要求17所述的组合物,其中,在含有900ml NaH2PO4缓冲水溶液、pH7.5、含2%(w/v)十二烷基硫酸钠、装有浆式搅拌器的USP-2装置中,当把相当于100mgA或更少量齐拉昔酮的所述组合物在75rpm搅拌下加入该装置中时,至少有70%的齐拉昔酮在45分钟内溶解。
24、一种治疗精神病的方法,包括:向需要所述治疗的患者施用有效量的权利要求17的组合物。
25、如权利要求24所述的方法,其中所述组合物含有齐拉昔酮盐酸盐一水合物。
26、如权利要求24所述的方法,其中所述的平均粒度等于或小于50μm。
27、如权利要求26所述的方法,其中所述的平均粒度为5-50μm。
28、如权利要求27所述的方法,其中所述的平均粒度为5-40μm。
29、如权利要求28所述的方法,其中所述的平均粒度为5-30μm。
30、如权利要求24所述的方法,其中,在含有900ml NaH2PO4缓冲水溶液、pH7.5的、含2%(w/v)十二烷基硫酸钠、装有浆式搅拌器的USP-2装置中,当把相当于100mgA或更少量齐拉昔酮的所述组合物在75rpm搅拌下加入该装置中时,至少有70%的齐拉昔酮在45分钟内溶解。
31、一种制备齐拉昔酮盐酸盐一水合物大晶体的方法,包括的步骤是:
1)把齐拉昔酮游离碱溶于含有THF和水的溶剂中,THF与水的体积比约22-35单位体积THF比1.5-8单位体积水;
2)加热步骤1)所得到的溶液;
3)把HCl加入到步骤2)所得到的溶液中;和
4)冷却步骤3)所得到的溶液。
32、如权利要求31所述的方法,其中,所述溶剂中,THF与水的体积比是24-30比2-6。
33、如权利要求31所述方法,其中在步骤3)中,所述溶液的温度维持在低于回流温度以下。
34、如权利要求33所述的方法,其中所述温度为60-64℃。
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