CN1479620A - 用于口服的延时释放的吉吡隆药剂 - Google Patents
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Abstract
本发明获得一种具有延时释放性能的口服药剂，所述药剂包含一定数量的盐酸吉吡隆、一定数量的纤维素聚合物基质和一定数量的微晶纤维素，其特征在于药学上可接受的纤维素聚合物基质的数量为70－85wt％，碳水化合物粘合剂的数量为7－10wt％，而盐酸吉吡隆的数量为13－21wt％。所述制剂用于治疗抑郁或相关的中枢神经系统疾病，其中吉吡隆在一天一次的吉吡隆的延时释放口服制剂中给药。
Description
本发明涉及具有延时释放性能的口服药剂，所述药剂包含一定数量的盐酸吉吡隆、一定数量的纤维素聚合物基质和一定数量的微晶纤维素。
这种药剂在EP 700 680中描述用于治疗CNS疾病如焦虑、抑郁和恐慌症。吉吡隆是一种在达到高峰值水平时诱导不期望的作用的药物。期望血液中药物水平的平均分配具有适当耐受的治疗剂量水平。据报道使用日剂量为至多100mg的盐酸吉吡隆实现严重抑郁疾病的最佳治疗(Wilcox et al；Psychopharmacology Bulletin)。通过在一天内间断地提供20mg盐酸吉吡隆延时释放片剂而施用的吉吡隆的总日数量在一天内分散。这样做的原因不仅是因为在现有技术(EP700 680)中指出延时释放制剂可以容易地生产，并在盐酸吉吡隆的总含量为至多12％，优选最大为11wt％，而微晶纤维素的含量至少为10％，优选最小为11wt％时产生缓慢释放的性能，还因为它即使在作为延时释放制剂给药的时候，可以预计一天一次的高剂量将被不良耐受。
与预计相反的是，发现适当较高浓度的延时释放片剂可以制备，且在一天一次剂型中被已经习惯于低剂量的患者良好地耐受。
显然，这些患者更适于拥有可获得的一天一次制剂。
本发明获得一种开始段落描述的药剂，其中药学上可接受的纤维素聚合物基质的数量为70-85wt％，碳水化合物粘合剂的数量为7-10wt％，而盐酸吉吡隆的数量为13-21wt％。该制剂可以进一步任选含有药学上可接受的添加剂，如助流剂、润滑剂和着色剂。
本发明获得一种使用在具有上述组成的口服药剂中的盐酸吉吡隆的一天一次的医药治疗。该治疗是有用的且被接受抑郁或相关的中枢神经系统疾病的治疗的患者良好地耐受，该患者开始治疗的方案开始于大约20mg盐酸吉吡隆/天的剂量，并逐渐增大到60-100mg盐酸吉吡隆/天。
口服药剂通常为片剂或胶囊。与根据EP 700 680的80mg片剂的重量的情况相反，根据本发明的片剂的总重可以为至多450mg。尽管盐酸吉吡隆具有高于纤维素聚合物基质材料和碳水化合物粘合剂的相对数量，仍可以制备在生产与处理期间具有可接受的吉吡隆溶解性能和充足稳定性的口服制剂，特别是片剂。
药学上可接受的纤维素聚合物基质具有保持盐酸吉吡隆以实现延时释放效果的功能。适宜的基质包括粘度为15,000cps-100,000cps的羟基烷基取代的烷基纤维素。优选等级K15M和K100M的羟甲基丙基纤维素(HPMC)，特别优选等级K100M，Premium(Methocel)。本发明药剂中组分的数量表示为通常作为片剂的制剂总重的重量百分数(wt％)。本文所用的术语烷基意指支链或非支链饱和未取代的碳链。考虑到所需的粘度，此段落中所指的烷基不包含大于6个碳原子。
关于用于实施本发明的适宜添加剂的术语药学上可接受的指药物辅料通常规定的要求。本领域技术人员已知关于安全性和不妨碍药剂的有效成分方面的要求。药学上可接受的载体和赋形剂的标准汇编见Handbook of Pharmaceutical excipients(药物赋形剂手册)(第二版，A.Wade和P.J.Weller编；美国药学会，华盛顿和药物出版社，伦敦于1994年出版)。药剂的添加剂，如载体、粘合剂、助流剂、润滑剂和着色剂用于获得一定的片剂粘性、着色性和流动性。在本发明的优选的实施方案中，使用硬脂酸镁、胶体二氧化硅和氧化铁色素。
助流剂和润滑剂是降低生产期间粉末混合物或片剂的粘性的试剂。这些添加剂的使用方法在制备药物组合物的技术中是已知的，例如Remington’s Pharmaceutical Sciences(第18版，编者A.R.Gennaro；Mack出版公司；Easton，宾夕法尼亚)第19章所述。
粘合剂是用于赋予药物组合物粘性导致生产和处理期间药物组合物损失最小的试剂。例如，碳水化合物粘合剂为纤维素、甲基纤维素、乙基纤维素、羟基丙基纤维素、糖、淀粉、支链淀粉、糊精、麦芽糊精、树胶和海藻酸盐。微晶纤维素，特别是Avicel pH101是用于本发明的优选粘合剂。
术语具有延时释放性能的口服药剂在本说明书中用于指出根据EP700 680的公开的吉吡隆的延时释放特征。具体而言，根据本发明的制剂具有一定的从该制剂中释放吉吡隆的速率，以需要大约8-24小时达到大约90至大约95％的吉吡隆吸收率。
根据本发明的口服药剂可以由本领域中已知的方法，如在标准参考资料，Gennaro等人，Remington’s Pharmaceutical Sciences，(第18版，Mack出版公司，1990，特别见第8部分：Pharmaceutical Preparations and Their Manufacture(药物制剂和它们的制备))所述的方法制备。在处理本发明的压制的高浓度制剂中采取某些谨慎措施是可取的，以避免片剂破裂和断裂。
吉吡隆可以通过任何本领域中已知的方法制备。一般由美国专利4,423,049所述的方法制备化合物。在EP 700 680中公开了含有吉吡隆的药物延时释放组合物。本文引用这些文献的内容作为参考。
以下实施例用于例示如何完成本发明。
实施例1
160,000个片剂批量的制备方法
片剂组成(片剂中的数量为以mg为单位的数量)
| 成分 | 40mg | 60mg | 80mg | 功能 |
| 盐酸吉吡隆 | 40.0 | 60.0 | 80.0 | 有效成分 |
| 羟基丙基甲基纤维素(MethocelK100M，Premium) | 290.0 | 290.0 | 290.0 | 药物释放控制聚合物 |
| 微晶纤维素(Avicel pH101) | 52.12 | 31.0 | 33.7 | 稀释剂 |
| Euroxide黄或红(E7055、E7056或E7016 | 0.08 | 1.2 | 3.5 | 着色剂 |
| 胶体二氧化硅(cab-o-silM5) | 1.6 | 1.6 | 1.6 | 助流剂 |
| 硬脂酸镁NF | 1.2 | 1.2 | 1.2 | 润滑剂 |
活性预混合物：
将胶体二氧化硅、NF、着色剂(40mg：Euroxide黄E 7056；60mg：Euroxide黄E 7055；80mg：Euroxide黄E 7055和Euroxide红E 7016)、盐酸吉吡隆粉末和20％羟基丙基甲基纤维素USP转入2cu.Ft.行星式混合器(Hobart混合器)。在行星式混合器(Hobart混合器)中将成分混合15分钟。标记为“活性预混合物”。
击压混合物
在Fitzmill中使用多孔板0020号高速研磨活性预混合物，可以进一步冲击以解聚集团块。
将活性预混合物转入无I-棒的10cu.Ft.″V″-混合器，同时通过#12目筛，并将平衡量的80％ HPMC，微晶纤维素，NF和50％硬脂酸镁，NF转入无I-棒的″V″-混合器。在无I-棒的V-混合器中将成分混合24小时，并标记为“击压混合物”。
击压
使用7/8″转平面斜切边(40)斜平面(60，80)工具，使用旋转Kikusui-Hercules压制机将混合物压成半成品。
工艺控制
| 重量： | 2250mg |
| 硬度 | 7kp |
| 目标厚度 | 0.255″ |
最终混合物
使用螺旋进料器，利用多孔板号No.0093，以中等速度研磨S.S.Fitzmill中的半成品，进一步切割并将螺旋进料器设为3.5±0.5。将研磨的物质转移到无I-棒的10cu.Ft.S.S.V-混合器。将平衡量的50％硬脂酸镁，NF通过#18目筛，也转移到V-混合器。混合6分钟。
使用旋转Kikusui-Libra压片机，应用0.338″×0.405″Ovoid矩形冲模压片。
工艺控制：
| 强度，mg | 40 & 60 | 80 |
| 运转重量，mg | 385±27 | 410±29 |
| 硬度，kp | 18±4 | 20±8 |
| 厚度，英寸 | 0.230-0.260 | 0.235-0.265 |
储存在防水的容器中直至进一步使用或试验。
如此实施例所述制作片剂的药物释放曲线。
根据EP 700 680所述的方法制备另20mg片剂，以比较本发明的60片和80片剂的药物释放曲线。
片剂的吉吡隆释放图形(片剂中的数字代表片剂理论含量的溶解百分率)
| 之后的释放→： | 1小时 | 5小时 | 12小时 | 20小时 | 回收 |
| 20mg片剂 | 19 | 49 | 77 | 93 | 102 |
| 40mg片剂 | 21 | 50 | 77 | 93 | 100 |
| 60mg片剂 | 21 | 51 | 81 | 97 | 102 |
| 80mg片剂 | 22 | 52 | 80 | 96 | 101 |
实施例2
为了扩大800,000片剂批量的生产规模，应用某些改型：
因此，方法依据实施例1所述的方法，但活性预混合物在340qt.AZMF Glen混合器中混合28分钟，所用的V-混合器的尺寸为30cu.Ft.，并最终在7分钟内完成混合。片剂具有如实施例1所测的类似性能。特别注意80mg浓度片剂的脆性问题。优选以20转/分的压片机速度，即一般在压片机上设定小于30rpm的速度压制80mg片剂以减少断裂片剂的数量。
Claims (4)
1.具有延时释放性能的口服药剂，所述药剂包含一定数量的盐酸吉吡隆、一定数量的纤维素聚合物基质和一定数量的微晶纤维素，其特征在于药学上可接受的纤维素聚合物基质的数量为70-85wt％，碳水化合物粘合剂的数量为7-10wt％，而盐酸吉吡隆的数量为13-21wt％。
2.根据权利要求1的药剂，其特征在于纤维素聚合物基质是粘度为15,000cps-100,000cps的羟甲基丙基纤维素。
3.根据权利要求1的药剂，其特征在于微晶纤维素为AvicelpH101。
4.一种用于抑郁或相关的中枢神经系统疾病的治疗，所述治疗使用在一天一次的吉吡隆的延时释放口服制剂中给药的吉吡隆，其特征在于该制剂是权利要求1所述的制剂。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00204388.3 | 2000-12-08 | ||
| EP00204388 | 2000-12-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1479620A true CN1479620A (zh) | 2004-03-03 |
Family
ID=8172397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA018201792A Pending CN1479620A (zh) | 2000-12-08 | 2001-11-30 | 用于口服的延时释放的吉吡隆药剂 |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP1343504A2 (zh) |
| JP (1) | JP2004517083A (zh) |
| KR (1) | KR20040018314A (zh) |
| CN (1) | CN1479620A (zh) |
| AR (1) | AR031461A1 (zh) |
| AU (1) | AU2002226371A1 (zh) |
| BR (1) | BR0115976A (zh) |
| CA (1) | CA2436692A1 (zh) |
| CZ (1) | CZ20031589A3 (zh) |
| EC (1) | ECSP034627A (zh) |
| HU (1) | HUP0401021A2 (zh) |
| IL (1) | IL155855A0 (zh) |
| MX (1) | MXPA03005099A (zh) |
| NO (1) | NO20032581D0 (zh) |
| PL (1) | PL362445A1 (zh) |
| RU (1) | RU2003120446A (zh) |
| SK (1) | SK6942003A3 (zh) |
| WO (1) | WO2002045753A2 (zh) |
| ZA (1) | ZA200303915B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019085494A1 (zh) * | 2017-11-01 | 2019-05-09 | 四川科瑞德制药股份有限公司 | 氮哌酮类化合物提高副交感神经活性的用途 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060134193A1 (en) * | 2002-09-24 | 2006-06-22 | Pieter De Haan | Method to improve pharmaceutical tablets having a matrix of cellulose ether |
| EA013213B1 (ru) * | 2004-11-05 | 2010-04-30 | Фэйбр-Крэймер Холдингз, Инк. | Дозированная форма биоактивного метаболита гепирона с высокой дозировкой и длительным высвобождением, способ ее получения и способ лечения депрессии с ее использованием |
| JP7125978B2 (ja) * | 2017-07-26 | 2022-08-25 | アボット ラボラトリーズ | 栄養タブレットおよびその製造方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5478572A (en) * | 1994-09-06 | 1995-12-26 | Bristol-Myers Squibb Co. | Gepirone dosage form |
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2001
- 2001-11-30 CN CNA018201792A patent/CN1479620A/zh active Pending
- 2001-11-30 BR BR0115976-3A patent/BR0115976A/pt not_active Application Discontinuation
- 2001-11-30 IL IL15585501A patent/IL155855A0/xx unknown
- 2001-11-30 HU HU0401021A patent/HUP0401021A2/hu unknown
- 2001-11-30 SK SK694-2003A patent/SK6942003A3/sk unknown
- 2001-11-30 WO PCT/EP2001/014189 patent/WO2002045753A2/en not_active Application Discontinuation
- 2001-11-30 KR KR10-2003-7007555A patent/KR20040018314A/ko not_active Application Discontinuation
- 2001-11-30 EP EP01995688A patent/EP1343504A2/en not_active Withdrawn
- 2001-11-30 MX MXPA03005099A patent/MXPA03005099A/es unknown
- 2001-11-30 CZ CZ20031589A patent/CZ20031589A3/cs unknown
- 2001-11-30 RU RU2003120446/15A patent/RU2003120446A/ru not_active Application Discontinuation
- 2001-11-30 CA CA002436692A patent/CA2436692A1/en not_active Abandoned
- 2001-11-30 AU AU2002226371A patent/AU2002226371A1/en not_active Abandoned
- 2001-11-30 PL PL01362445A patent/PL362445A1/xx not_active Application Discontinuation
- 2001-11-30 JP JP2002547535A patent/JP2004517083A/ja not_active Withdrawn
- 2001-12-07 AR ARP010105683A patent/AR031461A1/es not_active Application Discontinuation
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2003
- 2003-05-20 ZA ZA200303915A patent/ZA200303915B/en unknown
- 2003-05-28 EC EC2003004627A patent/ECSP034627A/es unknown
- 2003-06-06 NO NO20032581A patent/NO20032581D0/no not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019085494A1 (zh) * | 2017-11-01 | 2019-05-09 | 四川科瑞德制药股份有限公司 | 氮哌酮类化合物提高副交感神经活性的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20040018314A (ko) | 2004-03-03 |
| MXPA03005099A (es) | 2004-02-12 |
| CA2436692A1 (en) | 2002-06-13 |
| JP2004517083A (ja) | 2004-06-10 |
| WO2002045753A2 (en) | 2002-06-13 |
| NO20032581L (no) | 2003-06-06 |
| AR031461A1 (es) | 2003-09-24 |
| IL155855A0 (en) | 2003-12-23 |
| ZA200303915B (en) | 2004-08-20 |
| CZ20031589A3 (cs) | 2003-11-12 |
| AU2002226371A1 (en) | 2002-06-18 |
| WO2002045753A3 (en) | 2002-08-29 |
| BR0115976A (pt) | 2003-12-30 |
| EP1343504A2 (en) | 2003-09-17 |
| ECSP034627A (es) | 2004-09-28 |
| SK6942003A3 (en) | 2003-10-07 |
| PL362445A1 (en) | 2004-11-02 |
| NO20032581D0 (no) | 2003-06-06 |
| RU2003120446A (ru) | 2005-02-20 |
| HUP0401021A2 (hu) | 2004-09-28 |
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