CN1946379A - 含有托拉塞米和基质成型聚合物的缓释组合物 - Google Patents
含有托拉塞米和基质成型聚合物的缓释组合物 Download PDFInfo
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Abstract
含有托拉塞米作为活性成分的缓释利尿组合物。本发明的组合物可用于避免由常规的即释组合物引起的令人苦恼的尿急。
Description
发明领域
本发明涉及含有托拉塞米作为活性成分的缓释利尿组合物。
附图的简要说明
图1显示了即释(IR)托拉塞米片剂和实施例8所述的缓释(PR)托拉塞米片剂的体外释放率(积累值)比较曲线。
图2显示了即释(IR)托拉塞米片剂和实施例8所述的缓释(PR)托拉塞米片剂的体外释放率的比较曲线。
图3显示了即释(IR)托拉塞米片剂和实施例8所述的缓释(PR)托拉塞米片剂给药后的人体内血浆浓度比较曲线。
图4显示了即释(IR)托拉塞米片剂和实施例8所述的缓释(PR)托拉塞米片剂给药后人体内产生尿急次数相对于时间的比较曲线。
背景技术
托拉塞米(US 4018929)是一种具有广泛临床应用的有效利尿剂。托拉塞米主要通过在Henle’s循环上升段抑制钠的再吸收来发挥作用(Puschett JB和Jordan LL，托拉塞米在人体内的作用方式，药物学和临床药物学进展，1990；8(1)：7-13)。托拉塞米干扰腔细胞膜上的Na+2Cl-K+泵，并阻碍基侧氯化物的传导(Greger R，托拉塞米时厚层Henle循环上升段活性NaCl再吸收的抑制作用，Arzneim Forsch./Drug Res.1988；38(1)：151-155)。
口服后托拉塞米的生物利用度达到80-90％，其动力学特征为线形，以及消亡半衰期为3-4小时。其药物代谢动力学图谱的特征是最大血浆浓度(Cmax)在相当短的时间内(tmax：约1小时)达到峰值并快速消亡(t1/2：约3-4小时)(Neugebauer G，Besenfelder E和Mllendorf E.托拉塞米在人体内的药物代谢动力学和代谢，Arzneim Forsch./Drug Res.1988；38(1)：164-166)。托拉塞米在剂量2.5-20毫克范围内显示了与尿量间的线性响应关系。钠的排泄物对钾的作用影响很小。(scheen AJ.托拉塞米在健康志愿者体内的响应曲线，Arzneim Forsch./Drug Res.1988；38(1)：156-159；Barr WH等人，药物代谢动力学与药效学的托拉塞米剂量比例，药物学与临床药物学进展，1990；8(1)：29-37)。口服后约2小时能观察到托拉塞米对尿及电解质排泄物的最大影响(Lesne M.托拉塞米和呋塞米在健康志愿者体内的药物代谢动力学和药效的比较，Arzneim Forsch./Drug Res.1988；38(1)：160-163)。所有这些影响在临床上明显表现为急性多尿，间歇性尿急和耻骨弓不适(Lambe R，KennedyO，Kenny M和Darragh A.托拉塞米的口服或静脉给药在健康志愿者体内的耐受和利尿特性的研究.Eur J Clin Pharmacol 1986；31(Suppl)：9-14)。
因此，托拉塞米组合物的应用，其可避免由常规的即释组合物引起的令人苦恼的尿急，因此引起很大的兴趣。
发明概述
本发明的目的是制备利尿组合物，其可以提供更稳定血浆水平的托拉塞米以避免初始的峰值。这提供了具有更少波动和更稳定水平的动力学图谱。因此，尿急的频率降低了，这使得需要使用托拉塞米进行治疗的患者更加舒适。
本发明的组合物包括作为活性成分的托拉塞米，以及选自基质成型聚合物的赋形剂，例如，丙烯酸、纤维素、甘油山嵛酸盐、瓜尔胶、黄原胶、壳聚糖、明胶、聚乙烯醇等的聚合物。在每一个组合物中可以仅使用一种聚合物或它们的混合物。构成本发明组合物的其它成分是药物学技术中常规的赋形剂，包括稀释剂，例如乳糖、纤维素、甘露醇、磷酸钙等，以及它们的混合物；粘合剂和崩解剂，例如Aerosil200、淀粉等，以及它们的混合物；润滑剂，例如硬脂酸镁、滑石粉等，以及它们的混合物。通常地，本发明的组合物中活性成分的含量为0.5-20％，以及基质成型聚合物的含量为1-40％。
本发明的组合物是进行口服给药的片剂。
本发明的组合物能维持利原作用达最长24小时，优选为前12小时的范围；因此，避免了可能的夜遗尿的打搅。由于给药后获得的血浆水平Cmax很小，防止了由即释组合物引起的令人苦恼的尿急。
发明详述
本发明的片剂含有活性成分托拉塞米，含量为0.5-20mg。实践中，优选每片的剂量是5、10和20mg。基质成型聚合物选自下述的组：1)丙烯酸聚合物，例如Carbopol(卡波姆一丙烯酸聚合体的聚合物)，Kollicoat(甲基丙烯酸共聚物)，及其它们的类似物和衍生物；2)纤维素聚合物，例如，Methocel(羟丙基甲基纤维素)，甲基纤维素，羧甲基纤维素钠，Natrosol(羟乙基纤维素)，及其它们的类似物或衍生物；3)Compritol(甘油山嵛酸盐)；4)Meyprogat(瓜尔胶)及其类似物和衍生物；5)黄原胶；6)壳聚糖；7)明胶；和8)聚乙烯醇及其衍生物。
本发明的组合物含有比例为0.5-20％的活性成分托拉塞米和比例为1-40％的基质成型聚合物。发现最方便的基质成型聚合物是瓜尔胶，优选的含量是4％。然而，其它的基质成型聚合物也可以用在组合物中；其含量可以在一个相对宽的范围内改变。因此，所述的Carbopol的浓度是1-20％，优选10％，Methocel甲基纤维素的浓度是1-50％，优选40％，Natrosol和Compritol的浓度是1-40％，优选20％，Kollicoat的浓度是1-40％，优选15％，和Meyprogat的浓度是1-40％，优选4％。
本发明的片剂按照制药技术中的标准方法进行直接压缩或湿粒化，在这种方法中得到的干颗粒的水分含量小于10％。
使用2/叶片搅拌装置(根据美国药典)在50rpm对本发明的片剂进行体外溶出测试。
为了获得完全模拟生理环境的溶出图谱，在最初的2小内检测在pH值为1时进行，随后pH值变为6.8。得到的结果显示在图1和2中。图1显示了托拉塞米的释放(积累值)，以及图2显示了托拉塞米的释放。
本发明将通过以下实施例进行进一步说明，但不局限于此。
实施例1：5mg托拉塞米片剂和Carbopol，总重量为85mg
托拉塞米 5.0mg
Carbopol 940 10.0mg
乳糖 48.0mg
硬脂酸镁 0.3mg
Aerosil200 0.5mg
余量为甘露醇 85mg
实施例2：5mg托拉塞米片剂和methocel，总重量为100mg
托拉塞米 5.0mg
methocel K 15M 40.0mg
乳糖 18.0mg
玉米淀粉 36.2mg
预胶凝淀粉 0.3mg
Aerosil200 0.5mg
实施例3：5mg托拉塞米片剂和Natrosal，总重量为85mg
托拉塞米 5.0mg
Natrosal HX 20.0mg
硬脂酸镁 0.3mg
Aerosil200 0.5mg
余量为微晶纤维素 85mg
实施例4：5mg托拉塞米片剂和Compritol，总重量为100mg
托拉塞米 5.0mg
Compritol 888 20.0mg
乳糖 38.0mg
玉米淀粉 36.2mg
硬脂酸镁 0.3mg
滑石粉 0.5mg
实施例5：10mg托拉塞米片剂和Kollicoat，总重量为85mg
托拉塞米 10.0mg
KollicoatSR 30D 30.0mg
硬脂酸镁 0.6mg
滑石粉 1.0mg
余量为磷酸钙 85mg
实施例6：5mg托拉塞米片剂和Meyprogat，总重量为100mg
托拉塞米 5.0mg
Meyprogat90 4.0mg
乳糖 54.0mg
玉米淀粉 36.2mg
硬脂酸镁 0.3mg
Aerosil200 0.5mg
实施例7：5mg托拉塞米片剂和Meyprogat，总重量为85mg
托拉塞米 5.0mg
Meyprogat90 3.4mg
玉米淀粉 30.77mg
Aerosil200 0.42mg
硬脂酸镁 0.25mg
乳糖 45.16mg
实施例8：10mg托拉塞米片剂和Meyprogat，总重量为170mg
托拉塞米 10.0mg
Meyprogat90 6.8mg
玉米淀粉 61.54mg
Aerosil200 0.85mg
硬脂酸镁 0.51mg
乳糖 90.30mg
实施例9：20mg托拉塞米片剂和Meyprogat，总重量为340mg
托拉塞米 20.0mg
Meyprogat90 13.6mg
玉米淀粉 123.08mg
Aerosil200 1.70mg
硬脂酸镁 1.02mg
乳糖 180.6mg
实施例10：托拉塞米在人体内的药物代谢动力学
对十名健康志愿者的组进行随机临床试验，让其交叉服用10毫克缓释托拉塞米片剂和10毫克市售的即释托拉塞米片剂(Sutril，Novag，Spain)。每种片剂的服用间隔时间为1周。缓释托拉塞米组合物表现出更低的血浆水平峰值(Cmax)，短期(tmax)得到具有更平稳的水平和更少的波动(图3)。缓释组合物比即释组合物产生了更低频率的急性多尿情况(图4)。
这些数据显示，本发明的托拉塞米组合物比即释组合物产生了更低的血浆水平峰值和更少的波动。此外，在缓释托拉塞米组合物后具有次数更少的尿急情况。
Claims (15)
1.含有托拉塞米作为活性成分并含有基质成型聚合物的缓释组合物。
2.根据权利要求1所述的缓释组合物，其中这些组合物是进行口服给药的片剂。
3.根据权利要求1或2所述的缓释组合物，其中基质成型聚合物选自的聚合物的组包括丙烯酸、纤维素、甘油山嵛酸盐、瓜尔胶、黄原胶、壳聚糖、明胶、聚乙烯醇等，及其混合物。
4.根据权利要求3所述的缓释组合物，其中丙烯酸基质成型聚合物选自的组包括丙烯酸聚合物等，和其衍生物及其混合物。
5.根据权利要求3所述的缓释组合物，其中纤维素基质成型聚合物选自的组包括羟丙基甲基纤维素、甲基纤维素、羧甲基纤维素、羟乙基纤维素等，和其药物学上可接受的盐及其混合物。
6.根据权利要求3所述的缓释组合物，其中基质成型聚合物是瓜尔胶。
7.根据前述权利要求所述的缓释组合物，其中托拉塞米的含量为0.5-20％。
8.根据权利要求7所述的缓释组合物，其中托拉塞米的含量为4-10％。
9.根据前述权利要求所述的缓释组合物，其中基质成型聚合物的含量为1-50％。
10.根据权利要求9所述的缓释组合物，其中基质成型聚合物的含量为2-40％。
11.根据前述权利要求所述的缓释组合物，另外包括一种或多种赋形剂，其选自的组包括稀释剂、粘合剂、崩解剂、润滑剂等。
12.根据权利要求11所述的缓释组合物，其中稀释剂选自的组包括乳糖、纤维素、甘露醇、磷酸钙等，和其混合物。
13.根据权利要求11所述的缓释组合物，其中粘合剂选自的组包括Aerosil200、淀粉等，和其混合物。
14.根据权利要求11所述的缓释组合物，其中崩解剂选自的组包括Aerosil200、淀粉等，和其混合物。
15.根据权利要求11所述的缓释组合物，其中润滑剂选自的组包括硬脂酸镁、滑石粉等，和其混合物。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200400740A ES2244324B1 (es) | 2004-03-25 | 2004-03-25 | Composiciones diureticas de liberacion prolongada. |
| ESP200400740 | 2004-03-25 | ||
| PCT/EP2005/051340 WO2005092291A1 (en) | 2004-03-25 | 2005-03-23 | Prolonged-release compositions comprising torasemide and a matrix-forming polymer |
Publications (2)
| Publication Number | Publication Date |
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| CN1946379A true CN1946379A (zh) | 2007-04-11 |
| CN1946379B CN1946379B (zh) | 2012-05-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2005800093895A Expired - Fee Related CN1946379B (zh) | 2004-03-25 | 2005-03-23 | 含有托拉塞米和基质成型聚合物的延长释放组合物 |
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| US (1) | US20080187585A1 (zh) |
| EP (1) | EP1732517B1 (zh) |
| JP (1) | JP4871258B2 (zh) |
| KR (1) | KR101203763B1 (zh) |
| CN (1) | CN1946379B (zh) |
| AR (1) | AR048432A1 (zh) |
| AU (1) | AU2005227095B2 (zh) |
| BR (1) | BRPI0509165A (zh) |
| CA (1) | CA2562142C (zh) |
| ES (2) | ES2244324B1 (zh) |
| MX (1) | MXPA06010833A (zh) |
| NO (1) | NO336582B1 (zh) |
| PA (1) | PA8627401A1 (zh) |
| PE (1) | PE20060015A1 (zh) |
| PL (1) | PL1732517T3 (zh) |
| PT (1) | PT1732517T (zh) |
| RU (2) | RU2006137671A (zh) |
| TW (1) | TWI351957B (zh) |
| UY (1) | UY28809A1 (zh) |
| WO (1) | WO2005092291A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180221394A1 (en) * | 2014-12-12 | 2018-08-09 | Ceva Sante Animale | Veterinary composition comprising torasemide for the treatment of pulmonary edema associated with heart failure in domestic animals |
| US12048677B2 (en) | 2014-12-12 | 2024-07-30 | Ceva Sante Animale | Compositions and uses thereof for the treatment of heart failure in domestic animals |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10463622B2 (en) * | 2013-10-06 | 2019-11-05 | Sarfez Pharmaceuticals, Inc. | Treatments and formulations comprising Torsemide |
| US10596119B1 (en) * | 2018-11-08 | 2020-03-24 | Sarfez Pharmaceuticals, Inc. | Methods of treatment comprising torsemide |
| EP3065718A4 (en) * | 2013-10-06 | 2017-07-12 | Sarfez Pharmaceuticals, Inc. | Controlled-release formulations comprising torsemide |
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| DE3305935C2 (de) * | 1983-02-21 | 1985-05-30 | Medice Chem.-Pharm. Fabrik Pütter GmbH & Co KG, 5860 Iserlohn | Kaliumneutrales Saluretikum mit antihypertensiver Wirkung |
| DE3529529A1 (de) * | 1985-08-17 | 1987-02-19 | Boehringer Mannheim Gmbh | Verfahren zur herstellung einer stabilen modifikation von torasemid |
| GB8601204D0 (en) * | 1986-01-18 | 1986-02-19 | Boots Co Plc | Therapeutic agents |
| JP3586471B2 (ja) * | 1991-06-25 | 2004-11-10 | 三菱ウェルファーマ株式会社 | トラセミド含有医薬組成物 |
| DE19637082A1 (de) * | 1996-09-12 | 1998-03-19 | Boehringer Mannheim Gmbh | Schnellzerfallende Pellets |
| GB9816899D0 (en) * | 1998-08-05 | 1998-09-30 | Boots Co Plc | Therapeutic agents |
| SI20816A (sl) * | 1999-08-11 | 2002-08-31 | Teva Pharmaceutical Industries Ltd. | Polimorfi torsemid-a |
| CA2410802A1 (en) * | 2000-02-17 | 2002-09-06 | Minutza Leibovici | A stable pharmaceutical formulation comprising torsemide modification ii |
| DE10013289A1 (de) * | 2000-03-17 | 2001-09-20 | Knoll Ag | Torasemid enthaltende pharmazeutische Zubereitungen |
| US20030119882A1 (en) * | 2001-10-22 | 2003-06-26 | Markus Maegerlein | Solid pharmaceutical composition containing torasemide |
| US20030091630A1 (en) * | 2001-10-25 | 2003-05-15 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data |
| US20030152622A1 (en) * | 2001-10-25 | 2003-08-14 | Jenny Louie-Helm | Formulation of an erodible, gastric retentive oral diuretic |
| US20030104052A1 (en) * | 2001-10-25 | 2003-06-05 | Bret Berner | Gastric retentive oral dosage form with restricted drug release in the lower gastrointestinal tract |
| US6863901B2 (en) * | 2001-11-30 | 2005-03-08 | Collegium Pharmaceutical, Inc. | Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration |
| HRP20020124A2 (en) * | 2002-02-11 | 2003-10-31 | Pliva D D | Sustained/controlled release solid formulation as a novel drug delivery system with reduced risk of dose dumping |
| MXPA06006677A (es) * | 2003-12-12 | 2006-08-31 | Penwest Pharmaceuticals Co | Formas de dosis de torasemida de liberacion sostenida. |
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- 2005-03-23 CN CN2005800093895A patent/CN1946379B/zh not_active Expired - Fee Related
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- 2005-03-23 MX MXPA06010833A patent/MXPA06010833A/es active IP Right Grant
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- 2005-03-23 AU AU2005227095A patent/AU2005227095B2/en not_active Ceased
- 2005-03-23 KR KR1020067021596A patent/KR101203763B1/ko active IP Right Grant
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180221394A1 (en) * | 2014-12-12 | 2018-08-09 | Ceva Sante Animale | Veterinary composition comprising torasemide for the treatment of pulmonary edema associated with heart failure in domestic animals |
| US12048677B2 (en) | 2014-12-12 | 2024-07-30 | Ceva Sante Animale | Compositions and uses thereof for the treatment of heart failure in domestic animals |
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA06010833A (es) | 2006-12-15 |
| CA2562142C (en) | 2012-06-05 |
| RU2449778C1 (ru) | 2012-05-10 |
| BRPI0509165A (pt) | 2007-09-11 |
| EP1732517A1 (en) | 2006-12-20 |
| PL1732517T3 (pl) | 2017-09-29 |
| TW200531693A (en) | 2005-10-01 |
| JP4871258B2 (ja) | 2012-02-08 |
| AR048432A1 (es) | 2006-04-26 |
| KR101203763B1 (ko) | 2012-11-23 |
| AU2005227095B2 (en) | 2010-10-28 |
| CA2562142A1 (en) | 2005-10-06 |
| TWI351957B (en) | 2011-11-11 |
| KR20060130756A (ko) | 2006-12-19 |
| PE20060015A1 (es) | 2006-02-02 |
| NO336582B1 (no) | 2015-09-28 |
| AU2005227095A1 (en) | 2005-10-06 |
| JP2007530510A (ja) | 2007-11-01 |
| WO2005092291A1 (en) | 2005-10-06 |
| EP1732517B1 (en) | 2017-05-03 |
| ES2244324A1 (es) | 2005-12-01 |
| ES2632354T3 (es) | 2017-09-12 |
| CN1946379B (zh) | 2012-05-16 |
| RU2006137671A (ru) | 2008-04-27 |
| NO20064834L (no) | 2006-12-07 |
| PA8627401A1 (es) | 2005-11-25 |
| UY28809A1 (es) | 2005-07-29 |
| US20080187585A1 (en) | 2008-08-07 |
| PT1732517T (pt) | 2017-08-03 |
| ES2244324B1 (es) | 2006-11-16 |
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