CN1626094A - 夸噻平颗粒 - Google Patents
夸噻平颗粒 Download PDFInfo
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- CN1626094A CN1626094A CNA2004101011599A CN200410101159A CN1626094A CN 1626094 A CN1626094 A CN 1626094A CN A2004101011599 A CNA2004101011599 A CN A2004101011599A CN 200410101159 A CN200410101159 A CN 200410101159A CN 1626094 A CN1626094 A CN 1626094A
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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Abstract
本发明描述了夸噻平和其药学上可接受的盐的颗粒剂、其制备方法及其在治疗中枢神经系统疾病例如精神病包括精神分裂症中的用途。
Description
本申请是申请日为2000年9月18日,申请号为00813166.X的发明专利申请的分案申请。
本发明涉及一种新的药物制剂,其含有11-[4-[ 2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂或其药学上可接受的盐(以下均称为“药剂”),本发明还涉及此制剂的制备方法及其用途。具体地,本发明涉及一种在含水介质中易于混悬或溶解的制剂。
此“药剂”能用于治疗诸如精神病之类的中枢神经系统疾病。此“药剂”的一个具体例子是夸噻平富马酸盐(quetiapine fumarate,以Seroquel为商品名销售)。夸噻平富马酸盐用于治疗精神分裂症及相关疾病,已上市多年。也有相当多的文章详细介绍如何使用夸噻平富马酸盐。关于制备和使用这种“药剂”的具体参考文献包括欧洲专利申请EP240,228及282,236、美国专利4,879,288和国际专利申请WO97/45124。
目前上市的夸噻平富马酸盐是一种片剂。尽管医生、护士和其他的医护人员希望患者的服药能得到保证,但是精神病人的不顺从性经常会是个问题。例如,患者可能会将片剂藏于脸颊内而导致服药剂量的损失。如果能将此“药剂”改为以口服溶液或者混悬液的形式给药,那么就会减少顺从性的问题。口服溶液或混悬液另外的优点就是容易吞咽,因此对于吞服片剂有困难的病人是一种更好的服药方式。
为了避免该“药剂”变质,本发明的制剂采用含水量低的颗粒的形式,这些颗粒很容易在服用前溶解或悬浮在含水介质中。该颗粒还要流动自如,以确保小袋(sachets)填料和出料均匀,从而在服用治疗药物时有一个精确的剂量。
该“药剂”的各种低含水量的制剂在制备出来后,却被发现并不合适,因为这些颗粒不是太硬以至难以分散,就是流动性差使得其在静置或振动的时候密集在一起。
而最终我们得到了一种该“药剂”的颗粒剂,其既能流动自如又能轻而易举的溶解或混悬在含水介质中。因此,本发明提供了一种该“药剂”的既能流动自如又能轻而易举地溶解或混悬在含水介质中的颗粒剂。例如,服用这种制剂的所需时间应该合适。通常它应适于在15分钟之内服用完,优选的是低于5分钟,更优选的是不到2分钟。
具体地,本发明提供了一种颗粒剂,其含有11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂或其药学上可接受的盐及能任意溶解于水或极易溶于水的粘合剂,其中,颗粒的松密度在0.15g/ml到0.60g/ml之间,振实密度在0.20g/ml到0.70g/ml之间,80%的颗粒的粒径在75到850微米之间。
该“药剂”的制备、物理性质和有利的药理学性质记载于欧洲专利EP240,228和282,236以及美国专利4,879,288中,在此将这些专利全文引入作为参考。
优选的“药剂”是11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂或一种极易溶于水的其在药学上可接受的盐。更优选的“药剂”是11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂或其二盐酸盐、马来酸盐、柠檬酸盐或富马酸盐。最优选的“药剂”是夸噻平富马酸盐(Seroquel)。
能任意或极易溶解于水的粘合剂是指每一重量份的粘合剂可在少于十份的水中溶解的粘合剂,它包括麦芽糖糊精、甘露醇、木糖醇、预胶化淀粉、蔗糖或聚[1-2-(氧代-1-吡咯烷基)乙烯](聚维酮)。优选的粘合剂是每份粘合剂可溶解在少于一份的水中。
优选的极易溶解于水的粘合剂是麦芽糖糊精。
优选地,本发明提供的颗粒剂含有Seroquel和麦芽糖糊精,其中,颗粒具有的松密度范围从0.15g/cc到0.60g/cc,振实密度范围从0.20g/cc到0.7g/cc,且80%的颗粒粒径在75到850微米之间。
松密度是自由流动的粉末的密度。振实密度则是粉末在平面上经过振动或者轻轻拍击数次后的密度。松密度的测量是将体积为100ml的粉末倒至有刻度的量筒中,然后称其重量。振实密度的测量是通过将装有100ml用于松密度测量的粉末的相同的量筒放置于一件设备上使该量筒上下升降200次(在此标准测定中,升降的幅度是0.5英寸)。测量粉末的新体积,结合已知的粉末重量,就能算出振实密度的数值。
优选的颗粒的松密度在0.261g/ml到0.400g/ml之间,特别是0.261g/ml到0.368g/ml。
优选的颗粒的振实密度在0.342g/ml到0.500g/ml的范围内,特别是0.342g/ml到0.464g/ml。
可以用流化床方法以制备满足松密度、振实密度及颗粒粒径要求的颗粒。流化床方法包括将制剂的组分在气流床上流化成粉,加入水后再使之干燥。制剂的组分也可作为溶液或混悬液和水一起加入。
因此,在另一方面,本发明也提供了一种制备上述制剂的方法,包括:
i)在流化床中将一种或多种组分在气流床上流化;
ii)向流化床中加入任选地含有一种或多种组分的水;
iii)干燥。
优选地,“药剂”、任意或极易溶于水的粘合剂及其他任何组分都在气流床上流化。
流化床制粒是本领域公知的,参见例如Schaefer T.和Worts O.所著的《流化床制粒的控制》I中的《喷射角度、喷嘴高度及起始原料对颗粒大小和分布的影响》,Arch.Pharm.Chemi Sci.1977年第5版51-60页;Schaefer T.和Worts O.所著《流化床制粒的控制》II中的《雾化的粘合剂溶液液滴大小的估测》Arch.Pharm.Chemi Sci.1977年第5版178-193页;Schaefer T.和Worts O.所著的《流化床制粒的控制》III中的《入口空气的温度及液体流速对颗粒大小及分布的影响》,《在干燥阶段对颗粒含水量的控制》Arch.Pharm.ChemiSci.1978年第6版1-13页;Schaefer T.和Worts O.所著的《流化床制粒的控制》IV中的《粘合剂溶液和喷雾对颗粒大小及分布的影响》Arch.Pharm.Chemi Sci.1978年第6版14-25页;Schaefer T.,Worts O.所著的《流化床制粒的控制》V中的《颗粒成长的影响因素》Arch.Pharm.Chemi Sci.1978年第6版69-82页;Kawai S.所著的《使用流化床技术制粒和干燥粉状或液体材料》,Drying technology11(4)1993,719-731页及Kokubo H.和Sunada H.所著《操作变量对流化床制粒的颗粒的性质及其粘合剂分布的影响》,Chem.Pharm.Bull.1997,45(6),1069-1072页。
流化床制粒中,可以通过改变例如所采用的温度、雾化空气压力、操作气体体积和喷加水速度等条件来影响颗粒的粒径和密度。影响颗粒性质的主要参数是颗粒的含水量。该含水量决定于流化床中产生的含水量。使用本领域公知的标准方法改变流化床内产生的含水量直到得到粒径范围及密度合适的颗粒,可以制得具有所需特性的颗粒。例如,当生产规模为15千克时,颗粒的含水量通常在4-10%之间。典型的15千克生产规模的条件是入口的空气温度为55-70℃、雾化空气压力为0.5-3.5巴、操作气体的体积为150-225cfm(立方英尺/分钟)、喷加水速度为100-150ml/min。使用超出以上范围的条件也能制得具有所需物理性质的颗粒。例如,在较大的生产规模上(225千克),本发明的颗粒可以用如下条件制得:即入口的空气温度为55-80℃、雾化空气压力为1.0-3.0巴、操作气体的体积为1600-2200cfm、喷加水速度为600-900ml/min。
在一个优选的方面,本发明提供了一种控制含水量以制得含水量范围为1.5-15%的颗粒的流化床工艺。
另一方面,本发明还提供了含水量在1.5-15%范围内的颗粒,优选为3-10%,更优选为4-8%。
优选地,流化床内的含水量导致含水量在3-10%之间的颗粒。更优选地,流化床内的含水量导致含水量在4-8%之间的颗粒。
在一个优选的方面,本发明提供了一种雾化空气压力范围为0.5-3.5巴的流化床工艺,例如雾化空气压力为1.0-3.0巴。
进一步,本发明提供了一种由流化床工艺制得的含有所述“药剂”及任意或极易溶于水的粘合剂的颗粒剂,其中,颗粒在干燥前的含水量范围为1.5-15%。
在一个优选方面,本发明提供了一种由流化床工艺制得的含有所述“药剂”及任意或极易溶于水的粘合剂的颗粒剂,该工艺中的雾化空气压力在0.5-3.5巴之间,例如1.0-3.0巴。
进一步,本发明提供了一种由流化床工艺制得的含有所述“药剂”及任意或极易溶于水的粘合剂的颗粒剂,其中,颗粒的松密度在0.15g/ml到0.60g/ml之间,振实密度在0.20g/ml到0.70g/ml之间,且80%的颗粒粒径在75到850微米之间。
优选地,本发明提供了一种由流化床工艺制得的颗粒剂,其含有Seroquel和麦芽糖糊精,其中的颗粒松密度在0.15g/ml到0.60g/ml之间,振实密度在0.20g/ml到0.70g/ml之间,且80%的颗粒粒径在75到850微米之间。
优选的制剂含有一种或多种甜味剂,用以改进口味。适宜的甜微剂包括阿司巴坦、MagnaSweet、蔗糖、糖精、环己氨基磺酸钠及丁磺氨钾。优选的甜味剂为阿司巴坦和MagnaSweet。
其它赋形剂,如可与该“药剂”相容的助悬剂也可以加入到制剂中以延长制剂在含水介质中保持混悬状态的时间。助悬剂的例子包括淀粉甘醇酸钠、淀粉、瓜尔胶和聚维酮。然而,我们发现即使不加入助悬剂或增稠剂,制剂依然能溶解或保持很好的混悬状态,这是本发明的另一特点。例如,25mg在以下实施例中提到的颗粒剂,大约在15-20秒内便能在30ml水中出人意外地形成溶液。150mg在以下实施例中提到的颗粒剂经轻轻搅拌,便能在大约10秒内在30ml水中形成混悬液,且悬浮状态能保持10分钟。轻轻转动该混悬液几秒钟,便能使之重新混悬。
我们惊奇的发现,本发明不仅一般不需要助悬剂,连最典型的助悬剂黄原胶一般都不适合在本发明的制剂中作为助悬剂。
优选地,此制剂不含有助悬剂。
同样,可以向此制剂中加入可与所述“药剂”相容的表面活性剂例如聚山梨醇酯、一油酸甘油酯和脱水山梨醇酯,但是我们发现即使没有表面活性剂,此制剂依然具有良好的性能。
优选地,此制剂不含有表面活性剂。
优选地,本发明提供了一种颗粒剂,其含有11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂或其在药学上可接受的盐、任意或极易溶于水的粘合剂及甜味剂,其中,颗粒的松密度在0.15g/ml到0.60g/ml之间,其振实密度在0.20g/ml到0.70g/ml之间,且80%的颗粒粒径在75到850微米之间。优选地,11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂以富马酸盐的形式存在。
本发明的颗粒能很容易地溶解或混悬在含水介质中。该含水介质不必是水,但包括含有足够量水的物质,例如水果/蔬菜汁、酱汁和果泥,例如甜点。
优选地,所得溶液/混悬液的pH值在pH4到pH9之间。更优选地,所得溶液/混悬液的pH值在pH5到pH6之间。
另一方面,本发明涉及一种如上定义的能溶解或混悬于含水介质中的颗粒剂。
根据本领域公知的原则,考虑到不同的给药途径、治疗的持续时间、精神病况的严重程度、患者的形体大小和年龄、活性成分的效力及病人对其的反应,本发明化合物的给药剂量有必要随之改变。临床医生通过对各种标准的考虑及其对患者行为的最佳判断,可以容易地决定活性成分的有效剂量。通常,将化合物以有效剂量向恒温动物(例如人)给药,通常日给药剂量在大约0.01到大约40mg/kg体重之间。例如,当口服给药时,给药范围通常在大约0.1到大约40mg/kg体重之间。
优选地,本发明化合物的给药量大约为25、50、100、125或150mg。
本领域技术人员可以理解,该制剂可以与其它非医学上不相兼容的治疗或预防药剂和/或药物共同给药。通常本发明的化合物在几倍于活性成分的最低起效剂量时对于实验动物没有引起明显的毒性。
另一个方面,本发明提供了一种用作药物的如上定义的颗粒剂。
另一个方面,本发明提供了一种治疗精神病,尤其是精神分裂症的方法,该方法包括向需要此治疗的哺乳动物施用有效量的如上定义的颗粒剂。
本发明将在下述非限定性实施例中进一步阐述,实施例中的温度都以摄氏度表示。所用“药剂”采用欧洲专利EP240,228或282,236及美国专利4,879,288所描述的方法制备。
实施例
实施例1
制备两种不同浓度的制剂。第一种含有25mg夸噻平游离碱(25mg制剂),第二种含有150mg夸噻平游离碱(150mg制剂)。
制剂的组成如下:
成分 | 25mg(mg/剂) | 150mg(mg/剂) |
夸噻平富马酸盐麦芽糖糊精,NF阿司巴坦,NFMagnaSweet 135纯净水(美国药典) | 28.8950.021.2适量(~186.0) | 172.7767.330.030.0适量(~186.0) |
夸噻平富马酸盐相当于86.8%的夸噻平游离碱。以适当方式喷雾足够量的纯净水制得含水量为5.6%的颗粒。
麦芽糖糊精可以Maltrin M-100的形式从例如Grain ProcessingCorporation购得。MagnaSweet 135可从MAFCO WorldwideCorporation购得。
使用流化床工艺制备所述制剂。Glatt GPCG-60流化床加工器用于15kg及50kg的生产规模。Glatt GPCG-300流化床加工器用于225kg的生产规模。将流化床加工器装配后用于顶部喷雾的流化床制粒,如下所示:
装置 | Glatt GPCG-60 Glatt GPCG-300 |
水泵入口空气的露点孔径喷嘴口孔的数量喷嘴高度底部筛板振动型号振动间隔持续振动时间 | 蠕动泵 蠕动泵10℃ 10℃1.2mm 1.5m3 6#4 #4100目 100目GPCG GPCG30秒 60秒3秒 5秒 |
采用以下加工条件:
Glatt GPCG-60
加工参数 | |||||
批号 | 浓度 | 入口温度(℃) | 操作空气体积(cfm) | 雾化空气压力(巴) | 泵速(g/分钟)喷加水速度 |
abcd | 25mg150mg150mg150mg | 65656565 | 850850850850-750 | 2.02.01.71.5 | 360360360360 |
Glatt GPCG-300
加工参数 | |||||
批号 | 浓度 | 入口温度(℃) | 操作空气体积(cfm) | 雾化空气压力(巴) | 泵速(g/分钟)喷加水速度 |
ABCd | 25mg25mg150mg150mg | ~70~70~70~70 | 1850185018001800 | 2.02.01.51.5 | 800800800800 |
所有的成分都先加到流化床的制粒锅中,然后再粉碎这些原料。大约2到3分钟后,将水(186毫升/克组分)喷入到膨胀气室中。每批总的加工时间小于1小时。
GPCG-60(50kg生产规模)的结果
筛网分析数据1-不能过筛的颗粒数量%(μm) | 密度(g/ml) | 含水量2-% | |||||||||
批号 | 850 | 425 | 250 | 180 | 150 | 75 | 底盘 | 松- | 振实- | EOS3 | 最终4 |
ABCd | 0.40.30.21.6 | 4.822.03.312.2 | 19.813.718.228.9 | 21.820.021.920.0 | 11.111.710.87.7 | 31.638.933.119.1 | 10.513.212.510.5 | 0.290.360.340.31 | 0.390.350.410.42 | 9.37.97.48.7 | 5.43.84.35.9 |
GPCG-300(225kg生产规模)的结果
筛网分析数据1-不能过筛的颗粒数量%(目)(μm) | 密度(g/ml) | 含水量2-% | |||||||||
批号 | 850 | 425 | 250 | 180 | 150 | 75 | 底盘 | 松- | 振实- | EOS3 | 最终4 |
a | 2.8 | 13.1 | 33.4 | 23.8 | 10.1 | 13.0 | 3.8 | 0.26 | 0.35 | 6.2 | 6.0 |
b | 1.7 | 12.2 | 32.9 | 25.3 | 9.9 | 15.7 | 2.3 | 0.26 | 0.28 | 7.5 | 6.7 |
c | 2.5 | 17.6 | 33.6 | 19.5 | 9.5 | 11.3 | 6.0 | 0.36 | 0.42 | 6.7 | 5.3 |
d | 5.8 | 23.9 | 32.7 | 17.2 | 8.3 | 8.0 | 4.1 | 0.29 | 0.37 | 7.4 | 6.6 |
1这些数据是通过将100克样品在Tyler摇摆筛上加工5分钟得到的。
2含水量是使用设定在105℃的Computrac湿度天平测得的。
3喷雾结束时。
4颗粒干燥后的含水量。
实施例2
以常规方式将以上实施例1中制得的颗粒剂分装入小袋中。
Claims (12)
1、一种含有11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b,f][1,4]硫氮杂的富马酸盐或其在药学上可接受的盐和任意或极易溶于水的粘合剂的颗粒剂,其中颗粒的松密度在0.261g/cc到0.400g/cc之间,振实密度在0.342g/cc到0.500g/cc之间。
2、权利要求1的制剂,其中任意或极易溶于水的粘合剂包括麦芽糖糊精、甘露醇、木糖醇、预胶化淀粉、蔗糖或聚[1-2-(氧代-1-吡咯烷基)乙烯]。
3、权利要求2的制剂,其中的粘合剂是麦芽糖糊精。
4、权利要求1的制剂,其中还含有甜味剂。
5、权利要求2的制剂,其中还含有甜味剂。
6、权利要求3的制剂,其中还含有甜味剂。
7、权利要求1的制剂,其中,颗粒含水量在1.5到15%之间。
8、权利要求2的制剂,其中,颗粒含水量在1.5到15%之间。
9、权利要求3的制剂,其中,颗粒含水量在1.5到15%之间。
10、权利要求1的制剂,其中,颗粒含水量在4到5%之间。
11、权利要求2的制剂,其中,颗粒含水量在4到5%之间。
12、权利要求3的制剂,其中,颗粒含水量在4到5%之间。
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---|---|---|---|---|
GB9922271D0 (en) * | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Formulation |
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-
1999
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2000
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- 2000-09-18 AT AT00960855T patent/ATE288272T1/de active
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