CN101267808A - 新型制剂 - Google Patents

新型制剂 Download PDF

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CN101267808A
CN101267808A CNA2006800344737A CN200680034473A CN101267808A CN 101267808 A CN101267808 A CN 101267808A CN A2006800344737 A CNA2006800344737 A CN A2006800344737A CN 200680034473 A CN200680034473 A CN 200680034473A CN 101267808 A CN101267808 A CN 101267808A
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H·A·阿迈德
S·佩奇
N·H·莎
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Abstract

本发明涉及制备药物片剂组合物的方法，其中如权利要求1所述定义的式I的活性药物成分或其可药用的酸加成盐和水溶性的泊洛沙姆通过热熔挤出一起加工，之后与其它成分混合，并且其中所述片剂组合物随后可以用包含速释的薄膜包衣系统和纯水的组合物进行包衣。本发明还涉及通过这类方法制备的药物组合物。

Description

新型制剂
本发明涉及制备盖仑组合物(galenic composition)的新方法，特别是涉及用于口服给药的盖仑组合物的新方法。
口服剂型被设计成活性化合物在其作用部位能被充分利用。药物的生物利用度取决于若干参数，例如取决于活性化合物的理化性质、剂型以及生理因素。
由于生物利用度不高，现代药物开发中获得的许多物质存在问题。这些分子通常显示非常低的水溶性和在油类中有限的溶解性。而且很多物质表现出显著的食物效应，即药物和某些食物在同一时间服用时，它们可以互相影响从而降低所摄入药物的功效或减少食物营养素的吸收。另外，与处方药物一同服用的维生素和草药补充剂可导致不良反应。
食物和药物如何相互作用的一些实例包括：
■食物可以加快或减缓药物的作用。
■削弱维生素和矿物质在体内的吸收。
■刺激或抑制食欲。
■药物可以改变营养素在体内的使用。
现已发现一组晶体形式的、在25℃几乎不溶于水(例如＜0.0001mg/ml)和不溶于模拟胃液(例如0.08mg/ml)的式I的NK-1受体拮抗剂和其可药用的酸加成盐
其中
R是低级烷基、低级烷氧基、卤素或三氟甲基；
R1是卤素或氢；且当p是1时，R1除了上述取代基外可以与R一起形成-CH＝CH-CH＝CH-；
R2和R2’各自独立的是氢、卤素、三氟甲基、低级烷氧基或氰基；
且当n是1时，R2和R2’除了上述取代基外可形成-CH＝CH-CH＝CH-，其未被取代或被一个或两个选自低级烷基或低级烷氧基的取代基所取代；
R3和R3’是氢、低级烷基或与所连接的碳原子一起形成环烷基基团；
R4是氢、-N(R5)(CH2)nOH、-N(R5)S(O)2-低级烷基、-N(R5)S(O)2-苯基、-N＝CH-N(R5)2、-N(R5)C(O)R5、
Figure A20068003447300071
R5是氢、C3-6-环烷基、苄基或低级烷基；
R6是氢、羟基、低级烷基、-(CH2)nCOO-(R5)、-N(R5)CO-低级烷基、羟基-低级烷基、-(CH2)nCN、-(CH2)nO(CH2)nOH、-CHO或含有1至4个选自氧、氮和硫的杂原子的5-或6-元杂环，并且在所述环中有一个碳原子未被取代或被氧代基团所取代，其杂环直接连接或通过亚烷基与该分子其它部分连接；
Figure A20068003447300072
是环叔胺，其可以包含另外一个选自氧、氮或硫的杂原子，其中存在于环中的任何硫原子是硫代或可以被氧化成亚砜或二氧化硫，所述环叔胺直接与该分子其余部分相连，或通过连接体-(CH2)nN(R5)-相连；
X是-C(O)N(R5)-、一(CH2)mO-、-(CH2)mN(R5)-、-N(R5)C(O)-或-N(R5)(CH2)m-；
n、p和q各自独立的是1至4；并且
m是1或2；
可以配置成适合于和可用于人类患者的制剂。这类制剂可以克服以前的这些化合物在模拟胃液中几乎不溶的缺点。优选剂型的制剂是含有400mg活性成分的片剂。
式I化合物是已知化合物，作为治疗CNS疾病例如抑郁、焦虑和呕吐的活化NK1受体的拮抗剂描述于EP 1,035,115中。
优选的式I化合物是具有下式的化合物2-(3，5-二-三氟甲基-苯基)-N-甲基-N-(6-吗啉-4-基-4-邻-甲苯基-吡啶-3-基)-异丁酰胺
并且其显示上述的不溶性，即在水中和pH 3.0-7.0的缓冲水溶液中＜0.0001mg/ml。
将提高生物利用度和降低副作用例如在400mg片剂中的食物效应作为主要目标，研究了新的盖仑制剂的方法。现已发现热熔挤出(HME)技术解决了上述问题。
本发明的目的是提供制备药物片剂组合物的方法，其中将式I的活性药物成分或其可药用的酸加成盐与水溶性的泊洛沙姆通过热熔挤出一起加工，之后与其它成分混合，并且其中所述片剂组合物随后可以用包含速释的薄膜包衣系统和纯水的组合物进行包衣。
现已发现一种热熔挤出(HME)方法，其中活性成分和水溶性泊洛沙姆，例如泊洛沙姆188(Lutrol F68)，一种片剂粘合剂和湿润剂，是通过挤压机处理的唯一组分，该方法造成具有低颗粒尺寸、可接受的颗粒分散性和溶出特性的微晶固体分散体，当其与其它赋形剂组合时生成了具有预期的药物溶出特性的片剂。
本文所用的下列常规术语的定义如下，无论所述及的术语单独或以组合的形式出现。应当指出，如说明书和所附权利要求中所用，单数形式“一个”和“该”包括其复数形式，除非文中另有清楚的说明。
术语“低级烷基”指含有1至7个碳原子的直链或支链烷基。低级烷基的非限制性的例子包括甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基等等。
术语“亚烷基”指在两端连接基团的低级烷基连接体。亚烷基的非限制性的例子包括亚甲基、亚乙基、亚丙基等等。
术语“低级烷氧基”指如上所定义的烷基，其通过氧原子连接。低级烷氧基的非限制性的例子包括甲氧基、乙氧基、丙氧基等等。
术语“环烷基”指含有3至6个碳原子的饱和碳环基团(例如非芳香族的环)。环烷基的非限制性的例子包括环丙基、环丁基、环戊基、环己基等。
术语“卤素”指氯、碘、氟和溴。
加工助剂是通过改善例如流动性和避免粘结来提高制剂可制造性的赋形剂。一类加工助剂是“胶体二氧化硅”，一种颗粒大小约15nm的亚显微的烟雾硅胶。它是轻的、疏松的、淡蓝色-白色无臭无味的非砂样无定形粉末。用于本发明的胶体二氧化硅的非限制性例子包括Aerosil 380和Cab-O-Sil。
片剂的填充剂/稀释剂非限制性的例子包括淀粉、改性淀粉衍生物、纤维素、钙盐、糖和糖醇。淀粉是包含淀粉酶和支链淀粉(两种基于α-葡萄糖的多糖)的物质。可用于本发明的一类淀粉是玉米淀粉。可用于本发明的玉米淀粉的非限制性例子包括Pure-Cote、Pure-Bind、Pure-Dent、Pure-Gel、Pure-Set、Melojel、Meritena、Paygel55、Perfectamyl D6PH、Purity 21、Purity 826和Tablet White。
可作为片剂填充剂/稀释剂的一类纤维素是微晶纤维素。“微晶纤维素”(MCC)是天然存在的聚合物，由通过1-4β糖苷键连接的葡萄糖单位组成。MCC可以通过特定级别的α纤维素衍生得到。可用于本发明的MCC的非限制性例子包括Avicel、Vivapur、Vivacel、Emcocel。可作为片剂填充剂/稀释剂的一类糖醇是甘露醇。可用于本发明的甘露醇的非限制性例子包括Parteck M 200。
可用于本发明的不同类型的崩解剂如NVP吸水膨胀聚合物、交联羧甲纤维素和纤维素衍生物。“NVP吸水膨胀聚合物”是含有N-乙烯基吡咯酮例如N-乙烯基-2-吡咯酮的可溶的、膨胀的同聚物或杂聚物。
“可药用的酸加成盐”包括无机或有机酸，例如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等的盐。
“水溶性的泊洛沙姆”是环氧乙烷即聚氧乙烯(POE)，和环氧丙烷即聚氧丙烯(POP)的嵌段共聚物，它们是水溶性的并在药物制剂中用作湿润剂。用于本发明的泊洛沙姆的非限制性例子包括Lutrol F68(泊洛沙姆188)。
“挤出”是在可控条件下通过加压穿过模具而将原料转化成均匀形状和密度的产物。
本发明提供了包含热熔挤出物的组合物，所述热熔挤出物包含式I化合物和水溶性的泊洛沙姆。特别是，本发明提供包含热熔挤出物的组合物，所述挤出物包含式I的化合物如2-(3，5-二-三氟甲基-苯基)-N-甲基-N-(6-吗啉-4-基-4-邻-甲苯基-吡啶-3-基)-异丁酰胺盐酸盐，和水溶性的泊洛沙姆例如Lutrol F68。
所述的新的药物片剂组合物包括
a)式I的活性成分        30-60％
b)水溶性泊洛沙姆       10-20％
c)填充剂               20-30％
d)崩解剂               1-10％
e)加工助剂             0-5％，和
f)助流剂               0-5％，如果需要的话，
g)速释的薄膜包衣系统   片剂重量的2-5％
h)纯水
  一个代表性的制剂组合物的例子包含以下成分   mg/片
  2-(3，5-二-三氟甲基-苯基)-N-甲基-N-(6-吗啉-4-基-4-邻-甲苯基-吡啶-3-基)-异丁酰胺盐酸盐   400.00
  Lutrol F68   133.35
  微晶纤维素(Avicel PH102)   162.65
  Parteck M 200(甘露醇)   30.00
  Polyplasdone XL   16.00
  胶体二氧化硅(Aerosil 380)   16.00
  玉米淀粉   30.00
  硬脂酸镁   12.00
  片芯总重量   800.00
一个代表性的包衣组合物的例子包含
欧巴代黄色(Opadry Yellow)03K 12429   25.00
纯水                                 131.25
薄膜包衣片剂的总重量                 825.00
制备方法：
制备本发明的药物片剂组合物的方法包括下列步骤：
1)将活性药物成分与水溶性的泊洛沙姆混合，
2)使用从步骤1得到的粉末混合物制备热熔挤出物，
3)将挤出物通过筛选机以得到碾磨材料，其中为得到在所需颗粒大小范围内的原料，可能需要不止一个过筛步骤，
4)将从步骤3得到的碾磨挤出物与填充剂和崩解剂按第一步骤进行混合，
5)将从步骤4得到的混合物与加工助剂和助流剂混合，制备最终混合物，并且
6)将从步骤5制备的最终混合物压制成片剂。
更具体而言，所述方法包括下列步骤：
-将约50％的活性药物成分/药物放置在混合机中，例如PK、Bin或Bohle混合机。
-加入水溶性泊洛沙姆，随后加入剩余部分的药物。
-将所述原料混合约30分钟。
-使用储料漏斗进料器(例如K-Tron Soder)将从步骤3得到的粉末混合物转移到热熔挤压机(例如Leistritz)，并将该混合粉末通过热熔挤压机。
-在室温下收集热熔挤出物。
-此后首先将挤出物通过筛选机例如FitzMill，采用低速刀使之通过#3筛网，然后使用中速刀通过#2筛网。
-将约50％的碾磨材料和填充剂(例如Avicel PH 102或Parteck M200，其已通过#40筛网筛过)、玉米淀粉、崩解剂(例如Polyplasdone XL)和其它赋形剂(例如Aerosil 380，通过#12筛网筛过)放置在PK混合机或同类装置中，此后加入剩余的碾磨材料并混合30分钟。
-移去约50％的粉末混合物，并将助流剂(例如硬脂酸镁，通过#40筛网筛过)加入到混合机里的剩余材料中，并且再次加入另一半的粉末混合物并混合5分钟，并且
-使用如0.738”×0.344”椭圆型打孔机，将最终混合物压成片剂。
可以按如下方法将片芯包衣：
1)在不锈钢容器中将完全的薄膜包衣系统，例如欧巴代黄色，分散在纯水中，混合45分钟直到完全分散形成包衣混悬液，
2)将片芯放置于穿孔包衣锅中并且用间歇推入的45°+/-5℃的进口空气加热直到排出的空气达到40°+/-5℃，
3)此后将进气口温度提高至60°+/-5℃，使用空气喷雾装置将片芯用持续搅拌的包衣混悬液进行包衣，所述喷雾装置采用以每片折合干重计算的一定量的薄膜包衣(约2-5片重量％)，
4)缓慢干燥该包衣片剂直到含水量低于2％，并且
5)将片剂冷却至室温并储藏在密封的双层聚乙烯内衬的容器中。

Claims (14)

1.一种制备药物片剂组合物的方法，其中式I的活性药物成分或其可药用的酸加成盐
Figure A20068003447300021
其中
R是低级烷基、低级烷氧基、卤素或三氟甲基；
R1是卤素或氢；并且当p是1时，R1除了上述的取代基外可以与R一起形成-CH＝CH-CH＝CH-；
R2和R2’各自独立的是氢、卤素、三氟甲基、低级烷氧基或氰基；
且当n是1时，R2和R2’除了上述取代基外可形成-CH＝CH-CH＝CH-，其未被取代或被一个或两个选自低级烷基或低级烷氧基的取代基所取代；
R3和R3’是氢、低级烷基或与所连接的碳原子一起形成环烷基基团；
R4是氢、-N(R5)(CH2)nOH、-N(R5)S(O)2-低级烷基、-N(R5)S(O)2-苯基、-N＝CH-N(R5)2、-N(R5)C(O)R5、
Figure A20068003447300022
R5是氢、C3-6-环烷基、苄基或低级烷基；
R6是氢、羟基、低级烷基、-(CH2)nCOO-(R5)、-N(R5)CO-低级烷基、羟基-低级烷基、-(CH2)nCN、-(CH2)nO(CH2)nOH、-CHO或含有1至4个选自氧、氮和硫的杂原子的5-或6-元杂环，并且在所述环中有一个碳原子未被取代或被氧代基团所取代，其杂环直接连接或通过亚烷基与该分子其它部分连接；
Figure A20068003447300031
是环叔胺，其可以包含另外一个选自氧、氮或硫的杂原子，其中存在于环中的任何硫原子是硫代或可以被氧化成亚砜或二氧化硫，所述环叔胺直接与该分子其余部分相连，或通过连接体-(CH2)nN(R5)-相连；
X是-C(O)N(R5)-、-(CH2)mO-、-(CH2)mN(R5)-、-N(R5)C(O)-或-N(R5)(CH2)m-；
n、p和q各自独立的是1至4；并且
m是1或2；
和水溶性的泊洛沙姆通过热熔挤出一起加工，之后与其它成分混合，并且其中所述片剂组合物随后可以用包含速释的薄膜包衣系统和纯水的组合物进行包衣。
2.如权利要求1所述的制备药物片剂组合物的方法，其包括下列步骤
1)将活性药物成分与水溶性的泊洛沙姆混合，
2)使用从步骤1得到的粉末混合物制备热熔挤出物，
3)将挤出物通过筛选机以得到碾磨材料。为得到在所需颗粒大小范围内的原料，可能需要不止一个过筛步骤，
4)将从步骤3得到的碾磨挤出物与填充剂和崩解剂按第一步骤进行混合，
5)将从步骤4得到的混合物与加工助剂和助流剂混合，制备最终混合物，并且
6)将从步骤5制备的最终混合物压制成片剂。
3.如权利要求1或2所述制备的药物片剂组合物，包含
a)式I的活性成分    30-60％
b)水溶性的泊洛沙姆 10-20％
c)填充剂           20-30％
d)崩解剂               1-10％
e)加工助剂             0-5％，和
f)助流剂               0-5％，如果需要的话，
g)速释的薄膜包衣系统   片剂重量的2-5％
h)纯水。
4.如权利要求3所述的药物片剂组合物，其中所述片剂包含400mg的式I的活性成分。
5.如权利要求3所述的药物片剂组合物，其中所述活性成分是2-(3，5-二-三氟甲基-苯基)-N-甲基-N-(6-吗啉-4-基-4-邻-甲苯基-吡啶-3-基)-异丁酰胺。
6.如权利要求3所述的药物片剂组合物，其中所述水溶性泊洛沙姆是环氧乙烷(POE)和环氧丙烷(POP)的嵌段共聚物。
7.如权利要求6所述的药物片剂组合物，其中所述水溶性泊洛沙姆是Lutrol F68。
8.如权利要求3所述的药物片剂组合物，其中所述填充剂是玉米淀粉、微晶纤维素和糖醇的混合物。
9.如权利要求8所述的药物片剂组合物，其中所述填充剂是pure-Cote、Pure-Bind、Pure-Dent、Pure Gel、Pure-Set、Melojel、Meritena、Paygel55、perfectamylD6PH、Pu rity 21、Purity 826或Tablet White和Avicel、或Vivapur、Vivacel、Emcocel和Parteck M 200。
10.如权利要求3所述的药物片剂组合物，其中所述加工助剂是胶体二氧化硅。
11.如权利要求10所述的药物片剂组合物，其中所述加工助剂是Aerosil 380或Cab-O-Sil。
12.如权利要求3所述的药物片剂组合物，其中所述崩解剂是polyplasdone XL。
13.如权利要求3所述的药物片剂组合物，其中所述助流剂是硬脂酸镁。
14.如权利要求3所述的药物片剂组合物，其包含
-2-(3，5-二-三氟甲基-苯基)-N-甲基   400.00mg-N-(6-吗啉-4-基-4-邻-甲苯基-吡啶-3-基)-异丁酰胺盐酸盐
-Lutrol F68                         133.35mg
-微晶纤维素(Avicel PH102)           162.65mg
-Parteck 200(甘露醇)                30.00mg
-polyplasdone XL                    16.00mg
-胶体二氧化硅(Aorosil 380)          16.00mg
-玉米淀粉                           30.00mg
-硬脂酸镁                           12.00mg
-欧巴代黄色03K 12429                25.00mg
-纯水                               131.25ml。
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WO2007039420A1 (en) 2007-04-12
HK1198914A1 (zh) 2015-06-19
RU2431473C2 (ru) 2011-10-20
ES2335922T3 (es) 2010-04-06
HRP20100111T1 (hr) 2010-04-30
AU2006298898B2 (en) 2011-06-30
CA2623237C (en) 2013-07-09
CA2623237A1 (en) 2007-04-12
IL189929A0 (en) 2008-08-07
JP2013049686A (ja) 2013-03-14

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