CN105636581A - 药物组合物 - Google Patents
药物组合物 Download PDFInfo
- Publication number
- CN105636581A CN105636581A CN201480056938.3A CN201480056938A CN105636581A CN 105636581 A CN105636581 A CN 105636581A CN 201480056938 A CN201480056938 A CN 201480056938A CN 105636581 A CN105636581 A CN 105636581A
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- pharmaceutical composition
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Classifications
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- 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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Abstract
本发明涉及包含比拓喷丁或其盐的膜包衣片剂形式的药物组合物。
Description
本发明涉及药物组合物并且尤其涉及包含比拓喷丁(bitopertin)或其盐的药物组合物。
更特别是,本发明涉及在155mg膜包衣的片剂中包含5、10或20mg比拓喷丁的药物组合物,其可通过如下获得
i.将比拓喷丁与一水合乳糖、玉米淀粉、交联羧甲基纤维素钠和聚乙烯吡咯烷酮混合,
ii.使用净化水将来自步骤i的混合粉末粒化,
iii.干燥和筛选来自步骤ii的颗粒,
iv.将滑石、硬脂酸镁和微晶纤维素加入至来自步骤iii的颗粒中并混合,
v.将颗粒压制为片剂,
vi.使用含有聚乙烯醇、二氧化钛、聚乙二醇3350、滑石和任选地黄色氧化铁和净化水的预混合物制备膜包衣悬浮液,和
vii.用来自步骤vi的悬浮液将片剂进行膜包衣。
本发明还涉及在膜包衣的片剂中包含3、30和60mg比拓喷丁的药物组合物。
比拓喷丁([4-(3-氟-5-三氟甲基-吡啶-2-基)-哌嗪-1-基]-(5-甲磺酰基-2-(S)-2,2,2-三氟-1-甲基-乙氧基)苯基]-甲酮)描述于WO2005/014563中,并且其可以通过抑制甘氨酸转运蛋白(GlyT1)(前脑的主要甘氨酸转运蛋白)用于治疗精神分裂症和其他精神病症。因此,如果谷氨酸缺乏涉及精神分裂症的病理生理学中,将预期增强谷氨酸传递,尤其是通过NMDA受体激活,以产生抗-精神病和认知增强效果二者。
因此,通过GlyT-1抑制增加NMDA受体的激活可以导致治疗精神病,精神分裂症,痴呆和其他其中认知过程受损的疾病,如注意力缺乏症或阿尔茨海默病的药剂。
比拓喷丁尤其可用于治疗精神分裂症中的负性症状,其是情感淡漠、不合群、情感迟钝,在每天的生活中期待快乐的能力受损,和用于治疗认知障碍,如用于治疗工作记忆、注意力和计划的困难。
现已发现,以3、5、10、20、30或60mg的剂量包含比拓喷丁的药物组合物在治疗精神分裂症中的负性或认知症状方面特别有效。此外,根据本发明的片剂制剂可以适于治疗自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,治疗早期阿尔茨海默病(AD)中的情感淡漠,治疗近期严重抑郁发作后动机的残留症状,治疗创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病(PD)中的情感淡漠和认知缺陷。
比拓喷丁实际上不可溶于水性缓冲液和水中,但可随意溶于极性有机溶剂。作为BCS2分子(根据生物制药学分类系统,其中所述分子具有高渗透性和低可溶性),API粒径分布被认为是药品的主要关键质量属性。在人和猕猴两者中的体内研究表明片剂中的API粒径分布和产生的制剂的生物利用度之间的正相关。因此,选择微粒化的API用于开发适当的制剂。
为了优化生物利用度和溶解性能,测试不同的赋形剂作为填料,粘合剂,崩解剂和润滑剂。令人惊讶地发现,得到的片剂的溶解行为取决于选择的赋形剂的粒径分布。溶解越好,选择的赋形剂的颗粒越细(参见图1)并且玉米淀粉和乳糖的组合提供最细小的粒径分布,具有最好的片剂溶解,其也能够保证适当颗粒粒径分布,用于片剂压制的最后掺混物的适当流动。假定的是,仅在使用具有细微平均粒径的填料赋形剂时,微粒化的比拓喷丁能够在片剂制剂内最佳地细微地分散,从而降低压紧步骤期间API烧结的风险。
API烧结会导致较大的API粒子,并且因此导致溶解和生物利用度的降低。
图1:赋形剂的粒径对片剂溶解的影响。
表1:对于30mg比拓喷丁片剂,不同填料/稀释剂组合的评价
就患者顺从性而言,容易吞咽的固体剂型是优选的应用。已经发现,片剂制剂具有所需剂量的良好性能、用于运输和包装的坚固性。选择此片剂性能以满足立即释放制剂的标准并且其目的在于具有在15分钟内溶解的大于80%的药物载量,其最大释放量在60分钟后。
为了盖住苦味,选择膜包衣。
惊讶地发现,3、5、10、20、30和60mg的剂量范围的片剂形式的包含比拓喷丁的药物组合物在治疗或预防上述疾病方面特别有效。优选的剂量范围是5、10和20mg的比拓喷丁。
在本说明书中,术语″稀释剂″和‘填料’是指使片剂或胶囊的尺寸变大,使其实际生产和方便消费者使用的赋形剂。适当的稀释剂和填料包括例如药用惰性填料,如微晶纤维素,一水合乳糖,磷酸氢钙糖,糖醇,玉米淀粉,蔗糖,硅酸酐,多糖,N-甲基吡咯烷酮(Pharmasolve(ISP))和其混合物。术语糖和糖醇包含甘露糖醇,乳糖,果糖,山梨糖醇,木糖醇,麦芽糖糊精,葡萄糖结合剂,糊精,乳糖醇和其混合物。
将粘合剂添加于片剂制剂以向粉末添加粘结性,从而提供必要的粘合以形成颗粒,其在压紧的条件下形成压紧的团块作为片剂。甲基纤维素、羧甲基纤维素、羟丙基纤维素、羟甲基丙基纤维素、聚乙烯吡咯烷酮、聚乙烯醇、聚乙烯吡咯烷酮30、淀粉和预胶化的淀粉是粘合剂的适当实例。单种粘合剂,或两种、三种或多种粘合剂的混合物可用于制剂。
术语“崩解剂”是指这样的赋形剂,其在湿润时扩张并溶解,导致片剂在消化道中解体,并且通过表面积的增加可用于溶解促进释放活性成分,用于吸收。适当崩解剂包括例如轻交联的聚乙烯吡咯烷酮、玉米淀粉(cornstarch)、马铃薯淀粉、玉米淀粉(maizestarch)、和改性淀粉、交联羧甲基纤维素钠、羧甲基纤维素钙、羧甲基纤维素钠、交联聚乙烯吡咯烷酮(crossprovidone),羟乙酸淀粉钠和其混合物。
适当润滑剂(包括通过降低要压缩的粒间摩擦和内聚性作用于粉末的流动性的药剂)是胶体二氧化硅,如二甲硅油气凝胶(aerosil),滑石,硬脂酸,硬脂酸镁,硬脂酸钙,甘油二十二烷酸酯,硬脂酰醇富马酸钠和硅胶。
作为用于片剂的压缩辅剂,使用微晶纤维素。
术语“包衣”是指涂敷于片剂表面并且保护片剂成分免于由于空气中的水分而变质并且使得大的或口感不佳的片剂更容易吞咽的赋形剂。包衣剂的实例包括PVA(聚乙烯醇),HPMC(羟丙基甲基纤维素)和PEG(聚乙二醇)。
在膜包衣混合物中还包括着色剂,如二氧化钛和氧化铁黄。膜包衣中的适当增塑剂是聚乙二醇3350。
根据本发明,比拓喷丁的制剂预期为椭圆形每日一次的膜包衣的片剂,尺寸尽可能小(10x4.63mm),片剂重量为150mg并且5mg包衣重量。所有剂量强度具有相同尺寸,由雕版和不同色泽区分。该片剂是椭圆形的,双凸面的膜包衣的片剂。
本发明的一个目的是膜包衣的片剂,对于150mg片剂重量和5mg包衣重量包含3、5、10、20、30和60mg比拓喷丁。
膜包衣的片剂含有:
实施例1:对于150mg片剂重量(和5mg包衣重量),5mg比拓喷丁
实施例2:对于150mg片剂重量,10mg比拓喷丁
实施例3:对于150mg片剂重量,20mg比拓喷丁
含有3、30和60mg比拓喷丁的片剂具有相同的一致性,其中片剂中比拓喷丁和一水合乳糖的重量总是83,75mg,这意味着具有3mg比拓喷丁的片剂含有80.75mg一水合乳糖,或具有30mg比拓喷丁的片剂含有53.75mg一水合乳糖,或具有60mg比拓喷丁的片剂含有23.75mg一水合乳糖。
本发明还涉及上文所述的药物组合物,其用作药物,并且优选用作用于治疗精神分裂症和其他精神病症的药物,特别是用于治疗精神分裂症中的负性或认知症状,用于治疗自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,治疗早期阿尔茨海默病(AD)中的情感淡漠,用于治疗近期严重抑郁发作后动机的残留症状,治疗创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病(PD)中的情感淡漠和认知缺陷。
此外,本发明还涉及上文描述药物组合物用于治疗上述疾病的用途。
本发明还涉及治疗精神分裂症和其他精神病症的方法,尤其是用于治疗精神分裂症中的负性或认知症状,用于治疗自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,治疗早期阿尔茨海默病(AD)中的情感淡漠,治疗近期严重抑郁发作后动机的残留症状,治疗创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病(PD)中的情感淡漠和认知缺陷,所述方法包括向需要其的患者给药上文所述的药物组合物的步骤。
更特别是,本发明涉及一种药物组合物,其在150mg片剂大小中包含3,5,10,2030或60mg比拓喷丁,具有5mg包衣重量,其可通过如下获得
i.将比拓喷丁与稀释剂、填料、崩解剂和粘合剂混合,
ii.使用净化水将来自步骤i的混合粉末粒化,
iii.干燥和筛选来自步骤ii的颗粒,
iv将润滑剂和压缩辅剂加入至来自步骤iii的颗粒并混合,
v.将颗粒压制为片剂,
vi.使用含有包衣剂、着色剂、增塑剂、润滑剂和净化水的预混合物制备膜包衣悬浮液,和
vii.用步骤vi的悬浮液对片剂进行膜包衣。
更具体地,本发明涉及一种药物组合物,其在150mg片剂大小中包含3、5、10、20、30或60mg比拓喷丁,具有5mg包衣重量,其可通过如下获得
i.将比拓喷丁与一水合乳糖、玉米淀粉、交联羧甲基纤维素钠和聚乙烯吡咯烷酮混合,
ii.使用净化水将来自步骤i的混合粉末粒化,
iii.干燥和筛选来自步骤ii的颗粒,
iv.将滑石、硬脂酸镁和微晶纤维素加入至来自步骤iii的颗粒并混合,
v.将颗粒压制为片剂,
vi.使用含有聚乙烯醇、二氧化钛、聚乙二醇3350、滑石和黄色氧化铁的预混合物和净化水制备膜包衣悬浮液,和
vii.用来自步骤vi的悬浮液对片剂进行膜包衣。
为了制备片剂,可以按照以下程序:
使用湿高剪切粒化、流化床干燥、掺混、压制、和膜包衣的常规药物操作制造片剂。
制造方法的详细描述:
1.在高剪切混合器中加载比拓喷丁碾碎的药品、一水合乳糖、玉米淀粉、交联羧甲基纤维素钠和聚乙烯吡咯烷酮30。
2.以适当rpm掺混5至10分钟。
3.在10分钟的过程中加入水并且以适当rpm捏合另外5至10分钟。
4.经5mm筛将湿的颗粒转移到流化床干燥器,并且在以下条件下干燥:入口空气温度:50至70℃,空气流量:300至600m3/h。干燥终点4%(范围:2.5-5.5%),通过LOD确定,持续时间:45分钟。
5.经1.5mmFrewitt锥形筛,以适当转子转速筛选颗粒。
6.经0.5mm的手筛向颗粒中原样加入微晶纤维素并且加入滑石和硬脂酸镁并且利用仓式掺混器(binblender)以6rpm掺混20分钟。
7.以适当的压制力和转子转速将来自[步骤6]的最终掺混物压制为片剂核心,获得50-90N硬度的片剂。
8.使用净化水和欧巴代II黄85F32645膜包衣混合物(部分水解的聚乙烯醇、二氧化钛、聚乙二醇/PEG3350、滑石)和氧化铁黄)制备包衣悬浮液并搅拌至少一小时。
9.将来自[步骤8]的包衣悬浮液喷涂到来自[步骤7]的片剂核心上。
Claims (13)
1.一种膜包衣片剂形式的药物组合物,其包含比拓喷丁或其盐。
2.根据权利要求1所述的药物组合物,其中片剂重量为150mg并且膜包衣重量为5mg。
3.根据权利要求1和2中任一项所述的药物组合物,其用于治疗精神分裂症中的负性或认知症状,自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,早期阿尔茨海默病(AD)中的情感淡漠,近期严重抑郁发作后的动机的残留症状,创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病中的情感淡漠和认知缺陷。
4.根据权利要求1、2和3中任一项所述的药物组合物,其包含3、5、10、20、30或60mg的比拓喷丁或其盐,其可通过如下获得
i.将比拓喷丁与稀释剂、填料、崩解剂和粘合剂混合,
ii.使用净化水将来自步骤i的混合粉末粒化,
iii.干燥和筛选来自步骤ii的颗粒,
iv.将润滑剂和压制辅剂加入至来自步骤iii的颗粒并且混合,
v.将颗粒压制为片剂,
vi.使用含有包衣剂、着色剂、增塑剂、润滑剂和净化水的预混合物制备膜包衣悬浮液,和
vii.用来自步骤vi的悬浮液将片剂进行膜包衣。
5.根据权利要求4所述的包含3、5、10、20、30或60mg的比拓喷丁或其盐的药物组合物,其可通过如下获得
i.将比拓喷丁与一水合乳糖、玉米淀粉、交联羧甲基纤维素钠和聚乙烯吡咯烷酮混合,
ii.使用净化水将来自步骤i的混合粉末粒化,
iii.干燥和筛选来自步骤ii的颗粒,
iv.将滑石、硬脂酸镁和微晶纤维素加入至来自步骤iii的颗粒中并且混合,
v.将颗粒压制为片剂,
vi.使用含有聚乙烯醇、二氧化钛、聚乙二醇3350、滑石和黄色氧化铁的预混合物和净化水制备膜包衣悬浮液,和
vii.用来自步骤vi的悬浮液对片剂进行膜包衣。
6.根据权利要求1至5中任一项所述的药物组合物,其包含:
7.根据权利要求1至5中任一项所述的药物组合物,其包含:
8.根据权利要求1至5中任一项所述的药物组合物,其包含:
9.根据权利要求1至8中任一项所述的药物组合物,其用作药物,所述药物用于治疗精神分裂症中的负性或认知症状,自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,早期阿尔茨海默病(AD)中的情感淡漠,近期严重抑郁发作后动机的残留症状,创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病中的情感淡漠和认知缺陷。
10.根据权利要求1至8中任一项所述的药物组合物用于治疗精神分裂症中的负性或认知症状,自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,早期阿尔茨海默病(AD)中的情感淡漠,近期严重抑郁发作后动机的残留症状,创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病中的情感淡漠和认知缺陷的用途。
11.一种用于治疗精神分裂症中的负性或认知症状,自闭症谱系障碍(ASD)中的社会交际和交互的缺陷,早期阿尔茨海默病(AD)中的情感淡漠,近期严重抑郁发作后动机的残留症状,创伤后应激障碍(PTSD),用于对处于精神分裂症的高风险中的患者进行预防和用于治疗帕金森病中的情感淡漠和认知缺陷的方法,所述方法包括向需要其的患者给药根据权利要求1至8中任一项所述的药物组合物的步骤。
12.根据权利要求1至8中任一项所述的药物组合物,其每天给药一次。
13.如上所述的本发明。
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PCT/EP2014/076035 WO2015082367A1 (en) | 2013-12-03 | 2014-12-01 | Pharmaceutical composition |
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EP (1) | EP3076953A1 (zh) |
JP (1) | JP6336078B2 (zh) |
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EP2051583A4 (en) * | 2006-08-16 | 2011-09-14 | Aspreva Pharmaceuticals Ltd | COMPOSITIONS AND METHODS FOR TREATING VASCULAR, AUTOIMMUNE AND INFLAMMATORY DISEASES |
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KR20180088929A (ko) | 2018-08-07 |
JP6336078B2 (ja) | 2018-06-06 |
CA2924016A1 (en) | 2015-06-11 |
WO2015082367A1 (en) | 2015-06-11 |
EP3076953A1 (en) | 2016-10-12 |
AU2014359499A1 (en) | 2016-03-17 |
IL244365A0 (en) | 2016-04-21 |
HK1220143A1 (zh) | 2017-04-28 |
JP2016539141A (ja) | 2016-12-15 |
AR098572A1 (es) | 2016-06-01 |
MX2016006742A (es) | 2016-08-12 |
US20160271126A1 (en) | 2016-09-22 |
KR20160068975A (ko) | 2016-06-15 |
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