CN1301148A - 含有左甲状腺素钠的药物制剂 - Google Patents
含有左甲状腺素钠的药物制剂 Download PDFInfo
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Abstract
本发明涉及一种药物制剂,它含有左甲状腺素钠、明胶和填充剂并且不含有机溶剂残余物。本发明还涉及生产该制剂的方法。
Description
本发明涉及一种新的稳定的药物制剂，它包含左甲状腺素钠、明胶和填充剂并且不含有机溶剂残余物。
该新颖制剂具有改善的稳定性并且可以被用作甲状腺激素制剂。
该新颖制剂还具有改善的活性化合物体外释放。
本发明基于获得药物制剂形式的新药物的目的，所述药物具有比用于相同用途的已知药物更好的特性。
在联邦注册第62卷，第15期，1997年8月14日，第43535页中，健康和人类服务部，食品和药品管理局，分布了这样的事实：美国市场上出售的包含左甲状腺素钠并且供口服的产品具有稳定性问题而且因此必须有高达20％的过量剂量；生产商必须开发适宜的新的给药形式。所以，提高了对左甲状腺素钠片剂的体外释放的要求。制药学论坛专题草拟文本(药物学展望(Pharm.Preview)，1995,21,1459-1461)建议，除了生效的试验1(磷酸盐缓冲液pH7.4，在80分钟内＞55％)之外还要通过试验2(水，在45分钟内＞70％)。
该目的通过发现新的制剂而实现。
WO9717951中公开了含有甲状腺素以及其它添加剂(例如甘氨酸、碳水化合物和无机盐)的制剂。
DE19541128中公开了用硫代硫酸盐稳定的另一种甲状腺素制剂。
从US5,635,209知道了一种包含左甲状腺素钠和碘化钾的组合制剂。包含甲状腺素/环糊精复合物的另一种含甲状腺素的制剂公开于WO9719703。
除了左甲状腺素钠之外，本发明的药物制剂还可以包含碘塞罗宁钠(liothyronine sodium)。
本发明优选涉及一种如上所述的药物制剂，其特征在于，它含有5～400μg、优选10～300μg、特别是25～300μg的左甲状腺素钠。
本发明还优选涉及一种如上所述的药物制剂，其特征在于，它含有颗粒大小为5μm～25μm的微粉化左甲状腺素钠。
本发明还优选涉及一种如上所述的药物制剂，其特征在于，它含有选自乳糖和/或玉米淀粉和/或微晶纤维素的填充剂。
一种特别优选的药物制剂是这样的，其特征在于，它是呈片剂形式的固体制剂。
特别优选的实施方案含有25、50、75、100、125、150、175或200μg的左甲状腺素钠。
活性化合物对光、热和氧敏感。由于这种已知的不稳定性，活性化合物在制剂中呈高达5％的过量剂量。
当明胶用作粘合剂时，本发明的制剂具有出乎意料的稳定性。
如果用另一种常规粘合剂例如甲基纤维素(Methocel)代替它，甚至在稳定性研究开始时也会检测到活性化合物含量的降低，而且副产物的总和提高。
例如，如果在100μg的批料(其中明胶已被甲基纤维素代替)中测定活性化合物的起始值，发现仅为100.48％而不是预期的105％。
稳定性研究表明，含有左甲状腺素钠的本发明片剂如果在30℃以下的温度下贮存的话，它们能稳定至少2年。
此外，如果使用微粉化形式的活性化合物，那么对于活性化合物左甲状腺素钠的释放出乎意料地有利。左甲状腺素钠在水和乙醇中通常都很少量溶解。但是，在颗粒大小为5μm～25μm(达95％)的情况下，活性化合物在试验1中的释放达＞90％(磷酸盐缓冲液)，在试验2中达＞80％(水)。
出乎意料的是，还可以不用有机溶剂而制备本发明的组合物。如果本发明方法中使用的水被一种有机溶剂(例如甲醇)代替，那么在25℃的贮存温度和60％的相对湿度下1年后，可以观察到试验批料中左甲状腺素钠的含量降低10％。
用于本发明药物制剂的合适填充剂优选是乳糖、玉米淀粉和/或微晶纤维素，既可以作为单一填充剂又可以是与另一种的组合。特别优选的所述药物制剂含有玉米淀粉和乳糖。
本发明还涉及一种用于生产包含左甲状腺素钠和作选的碘塞罗宁钠的药物制剂的方法，其特征在于，在流化床粒化过程中，呈明胶水溶液中的悬浮形式的左甲状腺素钠和优选的碘塞罗宁钠被喷雾到填充剂上，然后将崩解剂和润滑剂掺合并且将该混合物压缩得到片剂。
本发明还涉及上述方法，其特征在于，所用的崩解剂是交联羧甲纤维素钠，所用的润滑剂是硬脂酸镁。
可以添加其它赋形剂或助剂，例如粘合剂、抗氧化剂、着色剂、润滑剂、甜味剂和/或芳香物质。
优选的助流剂或润滑剂例如是：滑石、淀粉、硬脂酸镁和硬脂酸钙、硼酸、石蜡、可可脂、聚乙二醇、亮氨酸或苯甲酸钠；硬脂酸镁是很特别优选的。
下列实施例涉及本发明药物制剂的生产和组成。实施例1
为制备例如两百万个片剂，需要如下用量：
*额外包含5％过量剂量的左甲状腺素钠。**通过干燥再一次脱除水分。制备：
| 左甲状腺素100μg | |
| 成分 | 用量[kg] |
| 左甲状腺素钠* | 0.210 |
| 乳糖一水合物 | 131.80 |
| 玉米淀粉 | 50.00 |
| 明胶 | 10.00 |
| 交联羧甲纤维素钠 | 7.00 |
| 硬脂酸镁 | 1.00 |
| 水，纯化的** | 56.66 |
1．在80～100℃的温度下，将明胶溶于大约90％的水中。
在室温下，将左甲状腺素钠悬浮于大约10％的水中。
然后在50℃(±5℃)下将悬浮液添加到明胶溶液中。这样达到的悬浮液(=粒化液体)温度为45～50℃。
2．将乳糖和玉米淀粉置于流化床造粒机中。将粒化液体喷雾在粉末上。喷雾过程中将粒化液体的温度保持在40～50℃。粒化过程中，将入口处温度保持在大约70℃(±5℃)，出口处温度保持在20～40℃。喷雾压力为3～5巴。喷雾后，将颗粒干燥，直到出口处达到大约为40℃的温度。
然后根据已知方法将干颗粒筛分(1mm)(=混合物a)。
相应地将交联羧甲纤维素钠和硬脂酸镁筛分。然后在鼓式混合机中将各个组分彼此之间以及与混合物a一起混合10分钟。
然后将待压的混合物压制得到片剂。实施例2
含100μg左甲状腺素钠的100mg(±3mg)片剂的组成为：
左甲状腺素钠 0.100mg
乳糖一水合物 65.90mg
玉米淀粉 25.00mg
明胶 5.00mg
交联羧甲纤维素钠 3.50mg
硬脂酸镁 0.50mg
100.00mg
左甲状腺素钠将以大约5％过量剂量存在。实施例3
含100μg左甲状腺素钠的100mg(±3mg)片剂的组成为：
左甲状腺素钠 0.100mg
碘塞罗宁钠 0.020mg
乳糖一水合物 65.88mg
玉米淀粉 25.00mg
明胶 5.00mg
交联羧甲纤维素钠 3.50mg
硬脂酸镁 0.50mg
100.00mg
左甲状腺素钠将以大约5％过量剂量存在。
Claims (8)
1．一种药物制剂，它包含左甲状腺素钠、明胶和填充剂并且不含有机溶剂残余物。
2．根据权利要求1的药物制剂，其特征在于，还任选含有碘塞罗宁钠。
3．根据权利要求1的药物制剂，其特征在于，含有5～400μg的左甲状腺素钠。
4．根据权利要求1的药物制剂，其特征在于，含有颗粒大小为5μm～25μm的微粉化的左甲状腺素钠。
5．根据权利要求1的药物制剂，其特征在于，含有选自乳糖和/或玉米淀粉和/或微晶纤维素的填充剂。
6．根据权利要求1、2或3的药物制剂，其特征在于，它是片剂形式的固体制剂。
7．生产药物制剂的方法，其特征在于，在流化床粒化作用中，将呈明胶水溶液中的悬浮形式的左甲状腺素钠和任选的碘塞罗宁钠喷雾到填充剂上，然后将崩解剂和润滑剂掺和并且将该混合物压缩得到片剂。
8．根据权利要求5的方法，其特征在于，所用崩解剂为交联羧甲纤维素钠，所用润滑剂为硬脂酸镁。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19821625.4 | 1998-05-15 | ||
| DE19821625A DE19821625C1 (de) | 1998-05-15 | 1998-05-15 | Pharmazeutische Zubereitung |
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| Publication Number | Publication Date |
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| CN1301148A true CN1301148A (zh) | 2001-06-27 |
| CN1145479C CN1145479C (zh) | 2004-04-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB998061751A Expired - Lifetime CN1145479C (zh) | 1998-05-15 | 1999-05-05 | 药物制剂 |
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| Country | Link |
|---|---|
| US (2) | US6646007B1 (zh) |
| EP (1) | EP1077681B1 (zh) |
| JP (1) | JP4709379B2 (zh) |
| CN (1) | CN1145479C (zh) |
| AR (1) | AR018607A1 (zh) |
| AT (1) | ATE225651T1 (zh) |
| AU (1) | AU742382B2 (zh) |
| BR (1) | BRPI9910445B8 (zh) |
| CA (1) | CA2333193A1 (zh) |
| CZ (1) | CZ300908B6 (zh) |
| DE (2) | DE19821625C1 (zh) |
| DK (1) | DK1077681T3 (zh) |
| ES (1) | ES2184452T3 (zh) |
| HU (1) | HU228958B1 (zh) |
| ID (1) | ID27281A (zh) |
| MY (1) | MY120570A (zh) |
| NO (1) | NO331655B1 (zh) |
| PL (1) | PL194088B1 (zh) |
| PT (1) | PT1077681E (zh) |
| RU (1) | RU2225711C2 (zh) |
| SK (1) | SK284155B6 (zh) |
| TW (1) | TW561058B (zh) |
| UA (1) | UA73474C2 (zh) |
| WO (1) | WO1999059551A1 (zh) |
| ZA (1) | ZA200007509B (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100430051C (zh) * | 2003-07-10 | 2008-11-05 | 葛兰素集团有限公司 | 包含左甲状腺素钠的药物制剂 |
| CN104582731A (zh) * | 2012-08-20 | 2015-04-29 | 默克专利股份有限公司 | 含有左甲状腺素的固体药物制剂 |
| CN109010295A (zh) * | 2018-08-29 | 2018-12-18 | 北京兴源联合医药科技有限公司 | 一种左甲状腺素钠冻干口腔崩解片 |
| CN115737576A (zh) * | 2022-11-14 | 2023-03-07 | 山东创新药物研发有限公司 | 一种左甲状腺素钠片剂及其制备方法 |
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| US6555581B1 (en) | 2001-02-15 | 2003-04-29 | Jones Pharma, Inc. | Levothyroxine compositions and methods |
| US20030224047A1 (en) * | 2001-02-15 | 2003-12-04 | Franz G. Andrew | Levothyroxine compositions and methods |
| ITMI20011401A1 (it) * | 2001-07-02 | 2003-01-02 | Altergon Sa | Formulazioni farmaceutiche per ormoni tiroidei |
| US20030099699A1 (en) * | 2001-11-13 | 2003-05-29 | Hanshew Dwight D. | Storage stable thyroxine active drug formulations and methods for their production |
| US20040152783A1 (en) * | 2002-11-05 | 2004-08-05 | Olon Lawrence Peter | Controlled absorption of admixed thyroid hormone formulations |
| ITMI20022394A1 (it) | 2002-11-13 | 2004-05-14 | Bracco Spa | Uso di triiodotironina 3-solfato come farmaco ad attivita' tireomimetica e relative formulazioni farmaceutiche. |
| ITMI20110713A1 (it) | 2011-04-29 | 2012-10-30 | Bracco Imaging Spa | Processo per la preparazione di un derivato solfatato di3,5-diiodo-o-[3-iodofenil]-l-tirosina |
| ATE390919T1 (de) | 2004-11-18 | 2008-04-15 | Uni Pharma Kleon Tsetis Pharmaceutical Lab Sa | Trockenpulver mit levothyroxin-natrium mit verabreichung über einen inhalator |
| GB0525461D0 (en) * | 2005-12-15 | 2006-01-25 | Archimedes Dev Ltd | Pharmaceutical compositions |
| ITMI20062254A1 (it) * | 2006-11-24 | 2008-05-25 | Acraf | Uso di un acido metossi-alcanoico dell'indazolo per preparare una composizione farmaceutca |
| EP2932963A1 (en) | 2014-04-16 | 2015-10-21 | Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. | Stable pharmaceutical dosage forms comprising Levothyroxine sodium |
| US9682045B2 (en) | 2014-11-21 | 2017-06-20 | Cadila Healthcare Limited | Stable pharmaceutical compositions of thyroid hormone drug |
| US20200046664A1 (en) | 2016-10-10 | 2020-02-13 | Ftf Pharma Private Limited | Method for preparation of liquid oral composition of l-thyroxin |
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| US3621098A (en) | 1969-03-17 | 1971-11-16 | Geigy Chem Corp | HYPOTENSIVE METHODS AND COMPOSITIONS UTILIZING HEXAHYDROBENZO{8 b{9 {0 QUINOLIZINES |
| US3621096A (en) * | 1969-04-03 | 1971-11-16 | Univ North Carolina | Antidepressant method and composition for same comprising a tricyclic antidepressant and a thyroid hormone |
| DE2126533A1 (de) * | 1971-05-28 | 1972-12-14 | Merck Patent Gmbh, 6100 Darmstadt | Verfahren zur Herstellung pharma zeutischer Zubereitungen |
| HUT67319A (en) * | 1991-08-30 | 1995-03-28 | Life Medical Sciences Inc | Compositions for treating wounds |
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| GB9325644D0 (en) * | 1993-12-15 | 1994-02-16 | Smithkline Beecham Plc | Novel formulation |
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| SE9500897D0 (sv) * | 1995-03-14 | 1995-03-14 | Astra Ab | The pharmacological use of certain cystine derivatives |
| CN1126589A (zh) * | 1995-06-09 | 1996-07-17 | 中国科学院成都有机化学研究所 | 一种激素缓释微囊注射剂及其制备方法 |
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| FR2772615B1 (fr) * | 1997-12-23 | 2002-06-14 | Lipha | Comprime multicouche pour la liberation instantanee puis prolongee de substances actives |
| DE19830246A1 (de) * | 1998-07-07 | 2000-01-13 | Merck Patent Gmbh | Pharmazeutische Zubereitung |
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- 1999-05-05 AT AT99922182T patent/ATE225651T1/de active
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- 1999-05-05 PT PT99922182T patent/PT1077681E/pt unknown
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- 1999-05-05 AU AU39321/99A patent/AU742382B2/en not_active Expired
- 1999-05-05 UA UA2000127207A patent/UA73474C2/uk unknown
- 1999-05-05 ID IDW20002460A patent/ID27281A/id unknown
- 1999-05-05 CN CNB998061751A patent/CN1145479C/zh not_active Expired - Lifetime
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- 1999-05-05 SK SK1689-2000A patent/SK284155B6/sk not_active IP Right Cessation
- 1999-05-05 CA CA002333193A patent/CA2333193A1/en not_active Withdrawn
- 1999-05-05 DE DE59903028T patent/DE59903028D1/de not_active Expired - Lifetime
- 1999-05-05 HU HU0102125A patent/HU228958B1/hu unknown
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100430051C (zh) * | 2003-07-10 | 2008-11-05 | 葛兰素集团有限公司 | 包含左甲状腺素钠的药物制剂 |
| CN104582731A (zh) * | 2012-08-20 | 2015-04-29 | 默克专利股份有限公司 | 含有左甲状腺素的固体药物制剂 |
| US11298331B2 (en) | 2012-08-20 | 2022-04-12 | Merck Patent Gmbh | Solid pharmaceutical preparation containing levothyroxine |
| CN109010295A (zh) * | 2018-08-29 | 2018-12-18 | 北京兴源联合医药科技有限公司 | 一种左甲状腺素钠冻干口腔崩解片 |
| CN115737576A (zh) * | 2022-11-14 | 2023-03-07 | 山东创新药物研发有限公司 | 一种左甲状腺素钠片剂及其制备方法 |
| CN115737576B (zh) * | 2022-11-14 | 2024-05-07 | 山东创新药物研发有限公司 | 一种左甲状腺素钠片剂及其制备方法 |
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