CN101594852A - 经熔融处理的伊马替尼剂型 - Google Patents
经熔融处理的伊马替尼剂型 Download PDFInfo
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- CN101594852A CN101594852A CNA2007800417427A CN200780041742A CN101594852A CN 101594852 A CN101594852 A CN 101594852A CN A2007800417427 A CNA2007800417427 A CN A2007800417427A CN 200780041742 A CN200780041742 A CN 200780041742A CN 101594852 A CN101594852 A CN 101594852A
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- imatinib
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
本发明提供了一种剂型,该剂型包含经过熔融处理的混合物,该混合物包括:(a)药学上有效量的伊马替尼或其盐,(b)至少一种聚合物粘合剂,和(c)至少一种可药用非离子表面活性剂。本发明提供了具有较高药物负载量的伊马替尼剂型,它可以根据简便有效的方法制备,还提供了活性成分自其中的释放基本上不依赖于pH的伊马替尼剂型以及缓释伊马替尼剂型。
Description
本发明涉及包含伊马替尼或其可药用盐的药物剂型。
伊马替尼为蛋白酪氨酸激酶(PTK)抑制剂,用于治疗非恶性和恶性增生性疾病,如慢性髓性白血病(CML)和胃肠道间质瘤(GIST)。伊马替尼的化学名为4-(4-甲基哌嗪-1-基甲基)-N-[4-甲基-3-(4-吡啶-3-基)嘧啶-2-基氨基)苯基]-苯甲酰胺,其结构式为式(I)
伊马替尼游离碱及其可接受的盐公开于欧洲专利申请0564409。伊马替尼甲磺酸盐和伊马替尼甲磺酸盐的α和β晶型公开于国际专利申请WO99/03854。
WO 03/090720公开了伊马替尼片剂,其中伊马替尼的重量为片剂总重量的30-80%。该片剂通过多步方法制备,包括下列步骤:将伊马替尼或其可药用盐与可药用赋形剂混合;湿法制粒;将颗粒与赋形剂混合;将混合物压制成片剂。
由于在其分子结构中存在多个碱性氮原子,在酸存在下伊马替尼很容易被质子化。伊马替尼盐在水性介质中易溶,而伊马替尼游离碱几乎不溶。因此,在酸性环境下伊马替尼自常规剂型中的释放是很快的,而在碱性环境下的释放明显缓慢。对于直到剂型到达小肠时活性化合物方才开始释放的缓释剂型而言,该释放行为是不利的,因为pH的增加会阻碍伊马替尼的释放。
因此需要具有高药物负载量的伊马替尼剂型,它可以根据简便有效的方法制备。
另外,还需要活性成分自其中的释放基本上不依赖于pH的伊马替尼剂型。
此外,还需要含有伊马替尼的缓释剂型,例如,该剂型可以降低血浆峰浓度并在较长的时间内保持血浆治疗水平。
因此,本发明提供了一种剂型,该剂型包含下列成分熔融处理的混合物:
(a)药学上有效量的伊马替尼或其盐,
(b)至少一种聚合物粘合剂,和
(c)至少一种可药用非离子表面活性剂。
伊马替尼可以为游离碱形式或其可药用盐。
伊马替尼的可药用盐包括但不限于可药用酸的加成盐。可药用酸的实例包括:无机酸,例如盐酸、硫酸或磷酸;或有机羧酸或磺酸,例如脂肪族单-或二-羧酸,例如三氟乙酸、乙酸、丙酸、乙醇酸、琥珀酸、马来酸、富马酸、羟基马来酸、苹果酸、酒石酸、柠檬酸或草酸;或氨基酸,例如精氨酸或赖氨酸;芳族羧酸,例如苯甲酸、2-苯氧基-苯甲酸、2-乙酰氧基-苯甲酸、水杨酸、4-氨基水杨酸;芳族-脂肪族羧酸,例如扁桃酸或肉桂酸;杂芳族酸,例如烟酸或异烟酸;脂肪族磺酸,例如甲磺酸、乙磺酸或2-羟基乙磺酸;或芳族磺酸,例如苯磺酸、对-甲苯磺酸或萘-2-磺酸。
在优选的实施方案中,采用伊马替尼盐,优选伊马替尼单甲磺酸盐。
通常,伊马替尼的盐在剂型中主要以结晶型存在。例如伊马替尼甲磺酸盐为α或β晶型,最优选为β晶型。
本发明的剂型优选具有较高的载药量,能够提供方便给药形式的伊马替尼的日剂量。特别是,伊马替尼或其盐的量以重量计为经熔融处理的混合物的总重量的至少50%,更优选至少为55%,例如至少为60%。通常,伊马替尼或其盐的量可以改变为经熔融处理的混合物的总重量的80%。如果采用相对小量的赋形剂,则能够获得物理上较小的剂型。尽管具有较高的载药量,但是,本发明的剂型较小,因而方便给药。这导致患者的依从性较好。
根据本发明,聚合物粘合剂的量以重量计可以在经熔融处理的混合物总重量的约1-45%的范围内变化,优选1-38%,特别是1-33%。
非离子表面活性剂的量以重量计可以在经熔融处理的混合物总重量的约5-20%的范围内变化,例如7-10%。
所述任选成分的量以重量计可以在经熔融处理的混合物总重量的至多20%的范围内变化,例如1-10%。
本发明的剂型优选为缓释剂型。“缓释”是指口服后活性化合物的含量在相对延长的时间段内逐渐但连续或持续释放。
在优选的实施方案中,当采用USP I篮法仪器并且于37℃、100rpm在900mL的0.1盐酸的条件下实验时,药物自剂型的释放在1小时时不超过80%,在10小时时不低于80%。
在更优选的实施方案中,当采用USP I篮法仪器并且于37℃、50rpm在900mL的0.1盐酸的条件下实验时,药物自剂型的释放在2小时时不超过80%,在8小时时不低于80%。
在本发明剂型的更优选的实施方案中,药物自剂型的释放基本上不依赖于pH。
例如,当采用USP I篮法仪器并且于37℃、50rpm在900mL的0.1盐酸的条件下实验时,其中药物在pH6.8时在8小时时自剂型释放所产生的释放度与pH1.0时所产生的释放度的比值至少为0.6。采用的适当的缓冲液如下面实施例中所述。
在优选的实施方案中,药物在pH6.8时在8小时时自剂型释放所产生的释放度与pH1.0时所产生的释放度的比值至少为0.7,优选至少为0.75,尤其是至少为0.8。
通常,本发明中使用的聚合物粘合剂的玻璃化转变温度Tg至少为约+10℃,优选至少为约+25℃,最优选为约40℃-180℃。测定有机聚合物Tg值的方法描述于“Introduction to Physical Polymer Science(物理聚合物科学介绍)”,第二版,L.H.Sperling编辑,John Wiley & Sons,Inc.印刷,1992。Tg值可以根据衍生自组成聚合物的各个单一单体i的均聚物的Tg值的加权和计算,即Tg=∑WiXi,其中W为有机聚合物中单体i的重量百分比,X为衍生自单体i的均聚物的Tg值。均聚物的Tg值可以参见“PolymerHandbook(共聚物手册)”,第二版,J.Brandrup和E.H.Immergut编辑,John Wiley & Sons,Inc.印刷,1975。
适当的可药用聚合物如下:
N-乙烯基内酰胺的均聚物和共聚物,特别是N-乙烯基吡咯烷酮的均聚物和共聚物,例如聚乙烯吡咯烷酮(PVP),N-乙烯基吡咯烷酮和乙酸乙烯基酯或丙酸乙烯基酯的共聚物;
纤维素衍生物和纤维素醚类,特别是甲基纤维素和乙基纤维素,羟烷基纤维素类,特别是羟丙基纤维素,羟烷基烷基纤维素,特别是羟丙基甲基纤维素,纤维素邻苯二甲酸酯类或琥珀酸酯类,特别是纤维素乙酸酯邻苯二甲酸酯和羟丙基甲基纤维素邻苯二甲酸酯,羟丙基甲基纤维素琥珀酸酯,羟丙基甲基纤维素乙酸酯琥珀酸酯或羟基丙基甲基纤维素乙酸酯邻苯二甲酸酯;
高分子量聚环氧烷类(例如聚环氧乙烷和聚环氧丙烷)以及环氧乙烷和环氧丙烷的共聚物;
聚丙烯酸酯类和聚甲基丙烯酸酯类,例如甲基丙烯酸/丙烯酸乙酯共聚物,甲基丙烯酸/甲基丙烯酸甲酯共聚物,甲基丙烯酸丁基酯/2-二甲基氨基乙基丙烯酸酯共聚物,聚(羟烷基丙烯酸酯类),聚(羟烷基甲基丙烯酸酯类);
聚丙烯酰胺类;
乙酸乙烯基酯聚合物,例如乙酸乙烯基酯和丁烯酸的共聚物,尤其是部分水解的聚乙酸乙烯酯(也称为部分皂化的聚乙烯醇);
聚乙烯醇;
寡-和多糖类,例如角叉菜多糖、半乳甘露聚糖和黄原胶或其一或多种的混合物。
其中,特别优选乙烯基吡咯烷酮的均聚物或共聚物,例如FikentscherK值为12-100(优选17-30)的聚乙烯吡咯烷酮,或30-70%(重量)N-乙烯基吡咯烷酮(VP)与70-30%(重量)乙酸乙烯基酯(VA)的共聚物,例如60%(重量比)VP与40%(重量比)VA的共聚物。
当然也可以采用所述聚合物的混合物。
优选的聚合物粘合剂选自纤维素衍生物(特别是羟丙基纤维素和乙基纤维素)和乙烯基吡咯烷酮的均聚物或共聚物及其混合物。
据认为,除了为剂型提供物理完整性以及足够的机械强度外,聚合物粘合剂还作为释放阻滞剂。
本文中所使用的术语“可药用表面活性剂”是指药学上可接受的非离子表面活性剂。该表面活性剂可以使得自剂型中释放的活性成分即时乳化和/或防止活性成分在胃肠道水性液体中的沉淀。
优选的表面活性剂选自多元醇脂肪酸酯类,例如,烷二醇脂肪酸单-或二酯类或脱水山梨醇脂肪酸酯类;聚烷氧基化的多元醇脂肪酸酯类,例如,聚烷氧基化的甘油酯类,聚烷氧基化的脱水山梨醇脂肪酸酯类或聚烷二醇脂肪酸酯类,或脂肪醇的聚烷氧基化的醚类。
这些化合物中的脂肪酸链通常包括8-22个碳原子。所述多元醇可以是二醇,例如乙二醇或丙二醇;三醇,例如丙三醇;或高级多元醇,例如脱水山梨醇。每个分子中的聚环氧烷嵌段平均含有2-100(例如4-50)个环氧烷单位。
适当的烷二醇脂肪酸酯类为烷二醇脂肪酸单酯、烷二醇脂肪酸二酯,或者为烷二醇脂肪酸单酯和二酯的混合物。优选的烷二醇脂肪酸单酯为丙二醇脂肪酸单酯,例如丙二醇月桂酸酯(可获自商品名为称为90或FCC,Gattefossé,法国)。优选的烷二醇脂肪酸二酯为丙二醇二辛酸酯(可获自商品名为PG,Gattefossé,法国)。
适当的脱水山梨醇脂肪酸酯类为脱水山梨醇单月桂酸酯、脱水山梨醇单棕榈酸酯、脱水山梨醇单硬脂酸酯、脱水山梨醇单油酸酯、脱水山梨醇三硬脂酸酯、脱水山梨醇三油酸酯、脱水山梨醇单硬脂酸酯、脱水山梨醇单月桂酸酯或脱水山梨醇单油酸酯。
适当的聚烷氧基化的脱水山梨醇脂肪酸酯类为聚氧乙烯(20)脱水山梨醇单月桂酸酯、聚氧乙烯(20)脱水山梨醇单棕榈酸酯、聚氧乙烯(20)脱水山梨醇单硬脂酸酯、聚氧乙烯(20)脱水山梨醇单油酸酯、聚氧乙烯(20)脱水山梨醇三硬脂酸酯、聚氧乙烯(20)脱水山梨醇三油酸酯、聚氧乙烯(4)脱水山梨醇单硬脂酸酯、聚氧乙烯(4)脱水山梨醇单月桂酸酯或聚氧乙烯(4)脱水山梨醇单油酸酯。
适当的聚烷氧基化的甘油酯可以例如通过天然或氢化的甘油酯的烷氧基化而获得,或者通过天然或氢化的甘油酯与聚烷二醇的酯交换反应而获得。可得自商业的实例为聚乙二醇蓖麻醇酸甘油酯35、聚乙二醇三羟基硬脂酸甘油酯40(RH40,BASF AG)以及在下列专有名称下可获得的聚烷氧基化的甘油酯:Gattefosse的和例如44/14(月桂酰基聚乙二醇32甘油酯,通过氢化的棕榈核油与PEG1500的酯交换反应制备得到),50/13(硬脂酰基聚乙二醇32甘油酯,通过氢化的棕榈油与PEG1500的酯交换反应制备得到)或LabrafilM1944CS(油酰基聚乙二醇6甘油酯,通过杏仁油与PEG300的酯交换反应制备得到)。
适当的聚烷二醇的脂肪酸酯类为例如PEG 660羟基硬脂酸酯(含有30mol%乙二醇的12-羟基脂肪酸的聚烷二醇酯(70mol%))。
适当的脂肪醇的聚烷氧基化的醚类为例如聚乙二醇6十六基十八基醚或聚乙二醇25十六基十八基醚。
优选的非离子表面活性剂为脂肪酸丙二醇单酯或二酯或其混合物。
在优选的实施方案中,非离子表面活性剂的HLB为4或更小,优选3.5或更小,最优选2.5或更小。HLB系统(Fiedler,H.B.,Encylopedia ofExcipients(赋形剂全书),第5版,Aulendorf:ECV-Editio-Cantor-Verlag(2002))提供了表面活性剂的数值,亲脂性物质具有较低的HLB酯,而亲水性物质具有较高的HLB值。优选的HLB值约为2的表面活性剂为丙二醇二辛基辛酸酯(propylene glycol dicaprylocaprate)(可获自商品名为PG)。如下面实施例中所示,采用HLB为4或更小的非离子表面活性剂可以使得具有基本上不依赖于pH的药物释放的伊马替尼剂型能够生产。
可以将增塑剂结合进经熔融处理的混合物中以降低玻璃化转变温度以及聚合物粘合剂的熔化粘性。
本发明中使用的增塑剂包括有机化合物,优选不挥发性化合物,例如,C7-C30-烷醇类,乙二醇、丙二醇、丙三醇、三甲醇丙烷、三乙二醇,丁二醇类,戊二醇类(例如季戊四醇)和己醇类,聚烷二醇类,优选分子量为200-1000的聚乙二醇,例如,聚乙二醇类(例如PEG300、PEG400),聚丙二醇类和聚乙二醇/聚丙二醇类,硅酮类,芳族羧酸酯类(例如邻苯二甲酸二烷基酯类,偏苯三酸三酯类(trimellitic esters),苯甲酸酯类,对苯二甲酸酯类(terephthalic esters))或脂肪族二羧酸酯类(例如己二酸二烷基酯类,癸二酸酯类,壬二酸酯类,柠檬酸酯和酒石酸酯类,特别是柠檬酸三乙基酯),脂肪酸酯类,例如甘油单-、二-或三乙酸酯或二乙基磺基丁二酸钠。特别优选的增塑剂选自三乙酸甘油酯、柠檬酸三乙基酯、聚乙二醇及其混合物。
优选增塑剂的量按重量计低于经熔融处理的混合物的总重量的20%,优选低于10%。
经熔融处理的混合物可以含有任选的成分。这些任选的成分包括可药用填充剂、崩解剂、乳化剂、助流剂、着色剂、矫味剂和防腐剂。本领域的这些术语通常上技术人员所已知的。对这些任选的成分加以选择以使得它们能够与活性成分以及其它使用的成分相容。
优选在经熔融处理的混合物中可以采用一或多种助流剂。一或多种下列成分可以用作助流剂:硅胶(例如200),三硅酸镁,粉末纤维素,淀粉,滑石粉,硬脂酸镁和硬脂酸钙,硬脂酰富马酸钠等。优选采用硅胶或/和硬脂酰富马酸钠。使用助流剂的适当的量按重量计为经熔融处理的混合物总重量的0.05-5%。
“经熔融处理的”是指向粘性状态或糊状的转化,其中一种成分可能均匀包埋在另一种成分中。熔融处理产生了具有粘性的可塑材料。通常,熔融处理包括将上述特定成分的混合物加热至所述聚合物粘合剂的软化温度以上。由于增塑剂的存在和/或非离子表面活性剂也可能具有增塑作用的事实,该软化温度可以略低于聚合物粘合剂的固有软化温度。软化温度可以定义为聚合物粘合剂粘性降低比率作为温度的函数发生改变时的温度。在熔融处理步骤中,加热温度不超过伊马替尼或伊马替尼盐熔融温度。
各成分的混合物可以在加热之前、加热期间或加热之后进行。例如,可以先将各成分混合,然后熔融,或者混合和熔融同时进行。通常,将材料匀化以使得活性成分有效地分散。也可以首先方便地将聚合物粘合剂熔融,然后与活性成分混合并匀化。
通常,进行熔融处理的温度范围为70-250℃,优选80-180℃,最优选100-140℃。
熔融处理在该目的所通常采用的设备中进行。特别适当的设备为挤压机(extruders)或捏合机(kneaders)。适当的挤压机包括单螺旋挤压机、齿合(intermeshing)螺旋挤压机和其它多螺旋挤压机,优选双螺旋挤压机,它可以正转或反转,任选配备捏合盘或其它螺旋部件,用于混合或分散融化物。可以理解,工作温度也由这种挤压机或者使用的挤压机中的这种配件的种类决定。挤压机中熔融和混合各成分所需要的能量部分可以通过加热配件提供。然而,挤压机中各材料的摩擦和剪切也可以为混合物提供一定量的能量,从而有助于各成分均匀融化物的形成。在挤压机的至少一个部件中可以提供真空,以便于除去残留的溶剂(例如水),从而防止赋形剂和活性成分之间的不相容性,或者防止对制剂稳定性的负面影响,例如单一剂量单位的硬度或活性成分的降解。
熔融处理优选通过熔融-挤出方法(即通过使用挤压机)进行。熔融-挤出方法包括下列步骤:
(a)将伊马替尼或其盐、至少一种聚合物粘合剂和至少一种可药用非离子表面活性剂以及任选的其它成分混合并加热,获得具有粘性的可塑材料;和
(b)将材料加压通过塑模。
根据本发明,所述具有粘性的可塑材料优选直接成形。术语“直接成形”是指将材料直接制成剂型的所需形状并使得材料固化的方法。该方法是相对于采用制粒(例如通过湿法制粒方法获得颗粒,或者通过熔融制粒方法获得颗粒)的常规方法而言的,然后将其与赋形剂混合并压缩或压制形成片剂。显然,直接成形方法的优点在于去掉了几个步骤。压缩/压制-模制片剂通常特征在于具有内相(相当于预成形的颗粒粒子)和围绕内相并使得内相结合在一起的外相。除了在具有粘性的可塑材料中已经存在的不均匀外,直接成形剂型基本上由单一相组成。
多种直接成形方法是技术人员已知的,其中优选压延(calendering)、注塑(injection-moulding)或热成形(thermoforming)方法。
压延表示下列方法:将具有粘性的可塑材料置于配备两种逆向旋转的滚筒的压延机中,所述滚筒能够在其表面相互匹配加压。通过采用不同的加压形式的滚筒,可以获得多种剂型。适当的方法描述于例如EP 0799013、EP 0802779或EP 1135092。
注塑表示下列方法:将可塑材料以高压注入塑模中,该塑模为需要的形状的反面。适当的方法描述于WO 01/43943。
热成形表示下列方法:将粉状混合物置于模塑腔中,将其加热至成形温度以诱导混合物的烧结。如此形成的具有粘性的可塑材料即为塑模腔的形状。随后将该可塑剂型固化。通过采用加热的冲压工具可以有助于混合物的变形。适当的方法描述于WO 05/016313。
剂型的形状可以改变,例如可以为圆形、椭圆形、长形、圆柱形或任何其它适当的形状。为了有助于哺乳动物服用此类剂型,最好使得剂型具有适当的形状。因此,可以被舒服地吞咽的较大的片剂优选长形而非圆形。
在剂型上进行薄膜包衣可以进一步使其易于吞服。薄膜包衣也可以改善味觉并提供精致的外观。如果需要,薄膜包衣可以为肠包衣。薄膜包衣通常包括聚合物膜形成材料,例如羟基丙甲基纤维素、羟丙基纤维素和丙烯酸酯或甲基丙烯酸酯共聚物。除了膜形成材料外,膜包衣还可以含有增塑剂,例如聚乙二醇、表面活性剂(例如类)和任选的色素(例如二氧化钛和氧化铁)。膜包衣也可以含有作为抗粘附的滑石粉。膜包衣通常占剂型重量的约5%以下。
本发明的剂型改善了抗摩擦性能和硬度。
发明的剂型用于伊马替尼的人用适应症,例如抗肿瘤治疗,例如非恶性和恶性增生性疾病,例如白血病、神经胶质瘤、肉瘤、前列腺瘤、乳房肿瘤、胃肠道肿瘤、肺肿瘤、卵巢肿瘤。
附图和下列非限定性实施例用于说明本发明。
图1-5表明在不同pH值情况下本发明剂型的药物释放。
实施例
下面表I中所示成分采用高速剪切混合机混合。液体赋形剂与固体原料一起制粒。然后将粉状混合物置于双螺旋挤压机(Rheomex PTW 16,Thermo Electron,Karlsruhe,德国),挤压机速率为0.8kg/h,处理温度为130℃。将挤出物传输于配有两个逆向旋转滚筒的压延机中,该滚筒的表面上具有相互匹配的空腔。从而获得约为1200mg(相当于800mg伊马替尼游离碱)的长方形片剂,长18.8mm,直径9.55mm。
根据USP方法,采用溶出设备(转篮),以100rpm和37℃的条件,测定获得的剂型的释放性能。溶出介质的体积为900mL。采用盐酸0.1mol/L(pH1.0)、乙酸钠50mmol/L(pH 4.5)和磷酸二氢钾50mmol/L(pH 6.8)作为溶出介质。于0.5、1、2、3、4、6和8小时各抽取10mL样品。采用适当体积的0.1mol/L盐酸稀释后,通过UV分光光度法于264nm测定样品。
溶出实验的结果列示于图1-5。
表I
成分 实施例1 实施例2 实施例3 实施例4 实施例5
伊马替尼甲磺酸盐 80 80 80 80 80
Klucel EF1 10 10 10
Klucel MF1 10
Ethocel V1002 2 1
Kollidon SR3 12
Lauroglycol FCC4 7 7
Lauroglycol 904 7
Labrafac PG5 7 5
硬脂酰富马酸钠 1 2 3 3 3
1)羟丙基纤维素
2)乙基纤维素
3)聚乙酸乙烯酯80/聚乙烯吡咯烷酮19
4)丙二醇单月桂酸酯
5)丙二醇二辛基辛酸酯。
Claims (12)
1.一种剂型,该剂型包含下列成分熔融处理的混合物:
(a)药学上有效量的伊马替尼或其盐,
(b)至少一种聚合物粘合剂,和
(c)至少一种可药用非离子表面活性剂。
2.权利要求1的剂型,其中伊马替尼或其盐的量以重量计至少为所述熔融处理的混合物总重量的50%。
3.权利要求1或2的剂型,该剂型为直接成形的。
4.权利要求3的剂型,其中直接成形通过压延、注塑或热成形方法实施。
5.前述权利要求任一项中的剂型,其中药物自剂型中的释放基本上不依赖于pH。
6.前述权利要求任一项中的剂型,其中药物在pH6.8时在8小时的释放所产生的释放度与pH1.0时所产生的释放度的比值至少为0.6。
7.前述权利要求任一项中的剂型,其中所述非离子表面活性剂为多元醇脂肪酸酯、聚烷氧基化的多元醇脂肪酸酯、聚烷氧基化的脂肪醇醚或其混合物。
8.权利要求7的剂型,其中增溶剂为丙二醇脂肪酸单-或二酯或其混合物。
9.前述权利要求任一项中的剂型,其中所述非离子表面活性剂的HLB为4或更小。
10.前述权利要求任一项中的剂型,其中所述聚合物粘合剂选自纤维素衍生物和乙烯基吡咯烷酮的均聚物或共聚物及其混合物。
11.制备权利要求1的剂型的方法,所述方法包括:
(a)将伊马替尼或其盐、至少一种聚合物粘合剂以及至少一种可药用非离子表面活性剂和任选的其它成分混合并加热,获得有粘性的可塑材料;并且
(b)将该材料加压通过塑模。
12.权利要求11的方法,该方法包括将所述有粘性的可塑材料直接制成该剂型的需要的形状。
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EP06023367.3 | 2006-11-09 | ||
EP06023367A EP1920767A1 (en) | 2006-11-09 | 2006-11-09 | Melt-processed imatinib dosage form |
PCT/EP2007/062100 WO2008055965A1 (en) | 2006-11-09 | 2007-11-08 | Melt-processed imatinib dosage form |
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CN101594852B CN101594852B (zh) | 2013-04-03 |
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CN2007800417427A Expired - Fee Related CN101594852B (zh) | 2006-11-09 | 2007-11-08 | 经熔融处理的伊马替尼剂型 |
CN2012100075672A Pending CN102512680A (zh) | 2006-11-09 | 2007-11-08 | 用于口服给药的酪氨酸激酶抑制剂的药物剂型 |
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US (1) | US8841303B2 (zh) |
EP (2) | EP1920767A1 (zh) |
JP (1) | JP5280369B2 (zh) |
CN (3) | CN101594851B (zh) |
AU (1) | AU2007316557B2 (zh) |
BR (2) | BRPI0718523B8 (zh) |
CA (1) | CA2668775C (zh) |
ES (1) | ES2565036T3 (zh) |
MX (1) | MX2009004858A (zh) |
PL (1) | PL2086516T3 (zh) |
RU (1) | RU2468788C2 (zh) |
WO (1) | WO2008055965A1 (zh) |
ZA (1) | ZA200903929B (zh) |
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CN102836159B (zh) * | 2011-06-24 | 2014-12-10 | 南京圣和药业股份有限公司 | 达沙替尼分散体及其制备方法和其在片剂中的应用 |
CN103764676A (zh) | 2011-08-04 | 2014-04-30 | 日本国立癌症研究中心 | Kif5b基因和ret基因的融合基因、以及以该融合基因为目标的判断癌症治疗有效性的方法 |
EP2782560A1 (en) | 2011-11-24 | 2014-10-01 | Imuneks Farma Ilaç Sanayi Ve Ticaret A.S. | Imatinib solid dosage forms reconstituted just before use |
AU2013208323B2 (en) * | 2012-01-13 | 2017-07-06 | Xspray Microparticles Ab | A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component. |
CN103301067B (zh) * | 2012-03-15 | 2018-09-11 | 苏州泽璟生物制药有限公司 | 一种改善吸收性能的固体分散体及其制备 |
JP5928159B2 (ja) * | 2012-05-28 | 2016-06-01 | ニプロ株式会社 | 医薬組成物 |
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CN106074554A (zh) * | 2015-04-27 | 2016-11-09 | 陈骏英 | 一种用于治疗食管癌的药物及使用方法 |
CN104888228A (zh) * | 2015-05-29 | 2015-09-09 | 连云港杰瑞药业有限公司 | 一种甲苯磺酸索拉非尼固体分散体及其制备方法 |
CN105126111A (zh) * | 2015-09-30 | 2015-12-09 | 清华大学 | 提高索拉非尼生物利用度的制剂 |
CN106974890A (zh) * | 2016-01-15 | 2017-07-25 | 常州方楠医药技术有限公司 | 一种无定型舒尼替尼l-苹果酸盐与药用辅料的固体分散体及其制备方法 |
ES2935158T3 (es) * | 2016-03-17 | 2023-03-02 | Sun Pharmaceutical Ind Ltd | Composición farmacéutica de nilotinib |
CN107157941B (zh) * | 2017-05-16 | 2020-12-25 | 北京化工大学 | 一种达沙替尼纳米制剂及其制备方法 |
CN110801434A (zh) * | 2019-10-31 | 2020-02-18 | 金华职业技术学院 | 一种冻干法制备甲苯磺酸拉帕替尼固体分散体的方法 |
EP4093379A1 (en) | 2020-01-24 | 2022-11-30 | Nanocopoeia LLC | Amorphous solid dispersions of dasatinib and uses thereof |
JP2023513045A (ja) | 2020-01-31 | 2023-03-30 | ナノコピーア リミテッド ライアビリティ カンパニー | 非晶質ニロチニブ微粒子及びその使用 |
CN112294971B (zh) * | 2020-02-20 | 2022-02-01 | 深圳市泰力生物医药有限公司 | 具有改进的溶解性的尼洛替尼组合物 |
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EP1920767A1 (en) | 2006-11-09 | 2008-05-14 | Abbott GmbH & Co. KG | Melt-processed imatinib dosage form |
-
2006
- 2006-11-09 EP EP06023367A patent/EP1920767A1/en not_active Withdrawn
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2007
- 2007-11-08 CN CN2007800417126A patent/CN101594851B/zh not_active Expired - Fee Related
- 2007-11-08 RU RU2009121653/15A patent/RU2468788C2/ru not_active IP Right Cessation
- 2007-11-08 WO PCT/EP2007/062100 patent/WO2008055965A1/en active Application Filing
- 2007-11-08 US US12/447,508 patent/US8841303B2/en active Active
- 2007-11-08 CN CN2007800417427A patent/CN101594852B/zh not_active Expired - Fee Related
- 2007-11-08 ES ES07822402.9T patent/ES2565036T3/es active Active
- 2007-11-08 PL PL07822402T patent/PL2086516T3/pl unknown
- 2007-11-08 BR BRPI0718523A patent/BRPI0718523B8/pt not_active IP Right Cessation
- 2007-11-08 AU AU2007316557A patent/AU2007316557B2/en not_active Ceased
- 2007-11-08 BR BRPI0718521-9A patent/BRPI0718521A2/pt not_active IP Right Cessation
- 2007-11-08 MX MX2009004858A patent/MX2009004858A/es active IP Right Grant
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- 2007-11-08 CA CA2668775A patent/CA2668775C/en active Active
- 2007-11-08 CN CN2012100075672A patent/CN102512680A/zh active Pending
- 2007-11-08 EP EP07822402.9A patent/EP2086516B1/en active Active
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JP2010509288A (ja) | 2010-03-25 |
CA2668775C (en) | 2014-08-12 |
AU2007316557B2 (en) | 2013-10-31 |
BRPI0718523B8 (pt) | 2022-09-13 |
BRPI0718521A2 (pt) | 2013-11-19 |
WO2008055965A1 (en) | 2008-05-15 |
CN101594851A (zh) | 2009-12-02 |
RU2009121653A (ru) | 2010-12-20 |
BRPI0718523A2 (pt) | 2013-11-19 |
JP5280369B2 (ja) | 2013-09-04 |
ES2565036T3 (es) | 2016-03-30 |
US8841303B2 (en) | 2014-09-23 |
ZA200903929B (en) | 2010-03-31 |
CA2668775A1 (en) | 2008-05-15 |
MX2009004858A (es) | 2009-05-21 |
BRPI0718523B1 (pt) | 2022-03-03 |
CN101594851B (zh) | 2013-01-02 |
PL2086516T3 (pl) | 2016-08-31 |
CN102512680A (zh) | 2012-06-27 |
EP1920767A1 (en) | 2008-05-14 |
EP2086516B1 (en) | 2016-01-06 |
RU2468788C2 (ru) | 2012-12-10 |
AU2007316557A1 (en) | 2008-05-15 |
CN101594852B (zh) | 2013-04-03 |
EP2086516A1 (en) | 2009-08-12 |
US20100240672A1 (en) | 2010-09-23 |
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