CN1307486A - 含左旋甲状腺素的药物制剂 - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/18—Iodine; Compounds thereof
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- Public Health (AREA)
- Veterinary Medicine (AREA)
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Abstract
本发明涉及的药物制剂包含左旋甲状腺素钠,碘化钾,微晶纤维素和粘合剂或其它辅助剂,其不含抗氧剂,以及该药物制剂的生产方法。
Description
本发明涉及一种新的稳定药物制剂，其包括左旋甲状腺素钠，碘化钾，微晶纤维素和粘合剂或其它赋形剂，但不含有抗氧剂。
赋形剂是防止碘形成的物质，例如，氢氧化钾。
用作为抗氧剂的硫代硫酸盐稳定的甲状腺素制剂记载于DE 195 41128。
另外已知的含甲状腺素的商品制剂ThyreocombN(Red List1998，74015)含有辅助剂氢氧化钾，其迫使碘化物和碘酸盐起成比例反应，倾向于起始原料一边。 利用这种方法使碘的产生被遏制。
包含有左旋甲状腺素钠以及碘化钾(后者对活性化合物左旋甲状腺素钠起稳定作用)的制剂被公开于US 5,635,209。对于低剂量，用于稳定左旋甲状腺素钠的所需碘化钾量的比率为4∶1，例如，25μg左旋甲状腺素钠与100μg碘化钾。对于高剂量，其比率为1.5∶1，例如，300μg左旋甲状腺素钠与300-450μg碘化钾。对100μg左旋甲状腺素钠的稳定需要300μg碘化钾。
活性化合物左旋甲状腺素钠(＝左旋甲状腺素-Na＝LT4)对光，热和氧气敏感。由于这些已知的稳定性问题，因而药物制剂的剂量要过量至多达20％。
如果除了在药物制剂中的活性化合物左旋甲状腺素-Na外，碘是另外含有的，该药物制剂在储存时会褪色，这是因为碘化钾中的阴离子碘能被氧化成碘，或能与碘酸钾起成比例反应而产生碘。而且，增加了左旋甲状腺素-Na片剂体外释放的要求。药典讨论会的专题草案(Pharm.Preview，1995，21，1459-1461)，除了有根据的试验1(磷酸盐缓冲液pH 7.4，在80分钟内＞55％)，倾向通过试验2(水溶液45分钟内＞70％)。
本发明基于制备新的药物制剂形式，该制剂比已知能使用于同样目的的药剂具有更好的性质。
通过新制剂的发现，该目标被达到。
按照本发明的新制剂实质上显示出不会褪色，且具有改善的稳定性。它能被用作甲状腺激素组合制剂，这归因于高含量的碘化物作为第二活性化合物，从而可用于甲状腺机能正常的缺碘的甲状腺肿和/或在切除缺碘的甲状腺肿之后的复发预防。
仅仅在稳定的阳离子(例如K+)存在下，活性化合物碘化物能作为阴离子被包含，于是在药物制剂中作为盐。130μg碘化钾相当于100μg碘化物。
本发明制剂由于防止了游离碘形成避免了脱色。而且，该新制剂在体外具有很好的活性化合物释放。
本发明优选涉及上述药物制剂，其特征在于它含有5-400μg，优选10-300μg，特别是50-200μg左旋甲状腺素钠，以及5-400μg，优选10-300μg，特别是25-200μg碘化钾。
进一步讲，本发明优选涉及上述药物制剂，其特征在于它含有微粒化状态且粒径为5-25μm(达95％)，特别优选粒径为5-15μm(达95％)的左旋甲状腺素钠。
进一步讲，本发明优选涉及上述药物制剂，其特征在于其含有羟丙基甲基纤维素和/或明胶作为粘合剂。
特别优选的药物制剂的特征在于它是片剂形式的固体制剂。
特别优选的实施方案含有50，75或100μg左旋甲状腺素钠和每个都是100μg的碘化物，100μg碘化物相当于130μg碘化钾的量。特别优选的实施方案含有100μg左旋甲状腺素钠和100μg碘化物。
基于左旋甲状腺素钠的已知不稳定性，该活性化合物在制剂中过量5％。
当羟丙基甲基纤维素和/或明胶作为粘合剂时，本发明的制剂具有出人意料的稳定性。同时，在无抗氧剂混合物或其它所需辅助剂下，碘的形成出人意料地被抑制。
稳定性研究数据列于表I和表II，这是通过批号005204(13/97)和004609(3/96)的举例证明。基于这些结果能够看出，本发明的含有左旋甲状腺素钠(100μg)和碘化物(100μg)的片剂至少在两年里是稳定的，如果在低于30℃保存时。同样地，在此期间被观察到药物制剂并未变成棕色，即没有碘的形成。
进一步讲，如果应用微粒化形式的活性化合物，则有利于活性化合物左旋甲状腺素钠的释放。左旋甲状腺素钠历难溶于水和乙醇。可是粒径在5和25μm(达95％)之间，特别优选在5和15μm之间，相应于两个测试系统的活性化合物的释放便发生(表I和II)。表I
批号005204(13/97)的稳定性和释放；左旋甲状腺素-Na(LT4)100μg/碘化物100μg片；制备方法类似于实施例1：PP管25℃/60％
注释：LT4过量5％表II
| 周期储存日期调查日期 | LT4含量[μg] | 碘含量[μg] | 用缓冲液释放[％] | 用水释放[％] | 水含量(按KF)[％] | 崩解时间[sec] | 易碎性[N] |
| 起始值 | 108.3 | 99.5 | 30分钟：94.360分钟：99.280分钟：100.6 | 15分钟：91.330分钟：93.545分钟：95.1 | 2.51 | 43-55 | 42-50 |
| 13周18.07.199713.02.1998 | 106.9 | 104.2 | 15分钟：85.930分钟：89.945分钟：91.2 | 3.28 | 50-60 | 48-55 | |
| 26周17.10.199721.02.1998 | 102.1 | 102.8 | 15分钟：89.530分钟：91.645分钟：95.1 | 3.14 | 50-68 | 41-48 | |
| 39周19.01.1998 | 100.6 | 103.2 | 15分钟：84.630分钟：88.145分钟：89.3 | 3.28 | 49-60 | 41-49 | |
| 52周 | 100.9 | 103.2 | 15分钟：84.630分钟：87.245分钟：89.5 | 3.50 | 40-55 | 41-49 |
批号004609(3/96)的稳定性和释放；左旋甲状腺素-Na(LT4)100μg/碘化物100μg片；制备方法类似于实施例1：PP泡腾片25℃/60％
注释：LT4过量5％
| 周期储存日期调查日期 | LT4含量[μg] | 碘含量[μg] | 用缓冲液释放[％] | 用水释放[％] | 水含量(按KF)[％] | 崩解时间[sec] | 易碎性[N] |
| 起始值 | 108.3 | 103.6 | 30分钟：105.360分钟：105.380分钟：103.1 | 15分钟：101.030分钟：102.945分钟：106.1 | 3.18 | ||
| 13周23.12.1996 | 104.9 | 100.2 | 15分钟：94.630分钟：96.345分钟：96.7 | 4.8 | |||
| 26周10.04.199724.02.1998 | 104.8 | 103.6 | 15分钟：96.130分钟：97.245分钟：97.4 | 5.34 | |||
| 52周29.09.1997 | 101.5 | 102.7 | 15分钟：94.130分钟：95.345分钟：95.8 | 6.26 | 37-50 | 39-44 | |
| 78周24.02.1998 | 99.72 | 104.6 | 15分钟：95.830分钟：97.545分钟：98.6 | 5.69 | 30-38 | 35-40 |
按照常规和已知方法测定分析数据。
本发明也涉及包括左旋甲状腺素钠和碘化钾的药物制剂的制备方法，其特征在于左旋甲状腺素钠和碘化钾，以在含水的羟丙基甲基纤维素和/或明胶溶液中悬浮的形式存在，被喷雾到微晶纤维素上，在流化床中成粒，然后，与崩解剂和润滑剂混和，混合物被压成片剂。
羟丙基甲基纤维素和碘化钾溶于水，左旋甲状腺素钠悬浮在温度为5-40℃，优选10-35℃，更优选15-30℃的水中。
成粒过程中进口处的温度为60-80℃，优选65-75℃；出口处为10-50℃，优选20-40℃。本发明方法中喷雾压力为3-5巴。
本发明进一步涉及所述方法，其特征在于所用崩解剂是羧甲纤维素钠以及所用润滑剂为硬脂酸镁。
可加其它赋形剂或添加剂，例如粘合剂，着色剂，润滑剂，甜味剂和/或芳香物质。
优选的滑移剂或润滑剂是例如滑石粉，淀粉，硬脂酸镁和硬脂酸钙，硼酸，石蜡，可可脂，碳蜡，亮氨酸或苯甲酸钠；硬脂酸镁是特别优选的。
本发明制剂不用有机溶剂就能制备。
下列实施例涉及本发明药物制剂的生产和成分。实施例1
为制备50,000片片剂，所需量如下。
左旋甲状腺素钠100μg/碘化物100μg
组分 量[g]
左旋甲状腺素钠* 5.25
碘化钾 6.54
羟丙基甲基纤维素 175.00
微晶纤维素 4125.70
羧甲纤维素钠 175.00
硬脂酸镁 12.50
水，纯化的** 3259.00
*另外包括5％过量的左旋甲状腺素钠。
**水分经干燥重新除去。生产：
1.在室温搅拌下，将羟丙基甲基纤维素和碘化钾溶于90％水中。在室温下，左旋甲状腺素钠悬浮于大约10％水中。然后，该悬浮液借助于混合器和羟丙基甲基纤维素/碘化钾溶液合并。
2.将微晶纤维素引入流化床成粒器。成粒液被喷雾到粉末上。在成粒过程中，进口温度维持在大约70℃(±5℃)，出口在20-40℃，喷雾压力为3-5巴。喷雾之后，颗粒被干燥，直到出口处温度达到约40℃。然后，将干燥颗粒按照已知方法过筛(1mm)(＝混合物a)。羧甲纤维素钠和硬脂酸镁相应地被过筛。然后将这些组份和混合物a一起置于鼓式混合器内混和10分钟。然后，待压片的混合物被压成片剂。实施例2
90mg(±3mg)片剂的成分含有105μg左旋甲状腺素钠和130μg碘化钾，也即100μg碘化物：
左旋甲状腺素钠 0.105 mg
碘化钾 0.1308 mg
水* 65.00 mg
羟丙基甲基纤维素 3.50 mg
微晶纤维素 82.514 mg
羧甲纤维素钠 3.50 mg
硬脂酸镁 0.25 mg
90.00 mg
左旋甲状腺素钠过量5％。
*水分通过干燥除去。比较实施例
为制备例如60,000片药物片剂，需要以下量：
左旋甲状腺素钠100μg/碘化钾300μg
组分 量[g]
左旋甲状腺素钠* 7.03
碘化钾 17.99
纤维素 5885.72
羧甲纤维素钠 50.00
硬脂酸镁 25.00
水，纯化** 4140.00
*包括过量5％的左旋甲状腺素钠。
**水分通过干燥除去。
制备：
1.筛分左旋甲状腺素钠(1.05％)和约10％纤维素，在振荡混合器中混和20分钟。
2.将碘化钾(18％)溶于60％水。54％纤维素用该溶液湿润，经处理过的纤维素被捏合并且筛过(1mm)。在室温下经真空干燥后生成的颗粒(0.1％KI)通过0.75mm筛被筛分。
3.剩余量的碘化钾(82％)应用于类似步骤2的第三步中的纤维素。得到含有0.7％KI的筛分颗粒。
4.羧甲纤维素钠(也即Croscarmellose)和硬脂酸镁相应地被筛分(0.5mm)。
5.按照已知方法，将得自步骤1-4的颗粒或固体混合物合并并混合20分钟。压片在旋转压片机内进行(压力为13kN)。片剂呈黄色至棕色。
Claims (7)
1.含有左旋甲状腺素钠，碘化钾，微晶纤维素和粘合剂或其它辅助剂的药物制剂，其不含抗氧剂。
2.按照权利要求1的药物制剂，其特征在于其含有5-400μg左旋甲状腺素钠以及5-400μg碘化钾。
3.按照权利要求1的药物制剂，其特征在于其含有粒径在5-25μm之间的呈微粒化形式的左旋甲状腺素钠。
4.按照权利要求1的药物制剂，其特征在于其含有羟丙基甲基纤维素和/或明胶作为粘合剂。
5.按照权利要求1，2，3或4的药物制剂，其特征在于其是呈片剂形式的固体制剂。
6.权利要求1-5的药物制剂的生产方法，其特征在于：左旋甲状腺素钠和碘化钾，以悬浮形式存在于水性羟丙基甲基纤维素和/或明胶溶液，被喷雾到在流化床成粒的微晶纤维素上，然后与崩解剂和润滑剂混和，该混合物被压成片剂。
7.权利要求6的方法，其特征在于所用的崩解剂是羧甲纤维素钠，以及所用润滑剂是硬脂酸镁。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19830246.0 | 1998-07-07 | ||
| DE19830246A DE19830246A1 (de) | 1998-07-07 | 1998-07-07 | Pharmazeutische Zubereitung |
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| CN1307486A true CN1307486A (zh) | 2001-08-08 |
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| CN99808077A Pending CN1307486A (zh) | 1998-07-07 | 1999-06-29 | 含左旋甲状腺素的药物制剂 |
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| Country | Link |
|---|---|
| US (1) | US6491946B1 (zh) |
| EP (1) | EP1094841B1 (zh) |
| JP (1) | JP2002520296A (zh) |
| KR (1) | KR20010071765A (zh) |
| CN (1) | CN1307486A (zh) |
| AR (1) | AR019899A1 (zh) |
| AT (1) | ATE273697T1 (zh) |
| AU (1) | AU751575B2 (zh) |
| BR (1) | BR9911884A (zh) |
| CA (1) | CA2336748A1 (zh) |
| CZ (1) | CZ296897B6 (zh) |
| DE (2) | DE19830246A1 (zh) |
| HU (1) | HUP0104985A3 (zh) |
| ID (1) | ID27150A (zh) |
| NO (1) | NO20010089D0 (zh) |
| PL (1) | PL344834A1 (zh) |
| SK (1) | SK20042000A3 (zh) |
| WO (1) | WO2000002586A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE19821625C1 (de) * | 1998-05-15 | 2000-01-05 | Merck Patent Gmbh | Pharmazeutische Zubereitung |
| US9522217B2 (en) | 2000-03-15 | 2016-12-20 | Orbusneich Medical, Inc. | Medical device with coating for capturing genetically-altered cells and methods for using same |
| US8088060B2 (en) | 2000-03-15 | 2012-01-03 | Orbusneich Medical, Inc. | Progenitor endothelial cell capturing with a drug eluting implantable medical device |
| US6555581B1 (en) | 2001-02-15 | 2003-04-29 | Jones Pharma, Inc. | Levothyroxine compositions and methods |
| JP2004525109A (ja) * | 2001-02-15 | 2004-08-19 | キング・ファーマシューティカルズ・インコーポレイティッド | 安定化された甲状腺ホルモン医薬組成物、及びその製法 |
| US20030194436A1 (en) * | 2001-08-10 | 2003-10-16 | Franz Andrew G. | Immediate release pharmaceutical compositions |
| US20030199585A1 (en) * | 2001-08-10 | 2003-10-23 | Franz G Andrew | Levothyroxine compositions and methods |
| US20030195254A1 (en) * | 2001-08-14 | 2003-10-16 | Franz G. Andrew | Levothyroxine compositions having unique triiodothyronine Tmax properties |
| US20030099699A1 (en) * | 2001-11-13 | 2003-05-29 | Hanshew Dwight D. | Storage stable thyroxine active drug formulations and methods for their production |
| US7192657B2 (en) * | 2003-04-15 | 2007-03-20 | 3M Innovative Properties Company | Ethynyl containing electron transport dyes and compositions |
| MX2007007860A (es) * | 2004-12-27 | 2007-07-18 | King Pharmaceuticals Res & Dev | Envase impermeable al oxigeno con composiciones de la hormona tiroidea estabilizadas, secuestrante de oxigeno opcional, y metodos para el almacenamiento de composiciones farmaceuticas de la hormona tiroidea. |
| US7858663B1 (en) | 2007-10-31 | 2010-12-28 | Pisgah Laboratories, Inc. | Physical and chemical properties of thyroid hormone organic acid addition salts |
| US20150017236A1 (en) * | 2013-07-09 | 2015-01-15 | Jefferson J. Gregory | Pharmaceutical compositions of thyroid hormone |
| US20200046664A1 (en) | 2016-10-10 | 2020-02-13 | Ftf Pharma Private Limited | Method for preparation of liquid oral composition of l-thyroxin |
| DE102017122807B4 (de) | 2017-09-29 | 2023-02-09 | Berlin-Chemie Ag | Orales Schilddrüsentherapeutikum |
| DK3576795T3 (da) | 2017-02-03 | 2021-06-07 | Berlin Chemie Ag | Oralt skjoldbruskkirtelterapeutikum |
| KR20240039868A (ko) * | 2022-09-20 | 2024-03-27 | 한국유나이티드제약 주식회사 | 갑상선 보호용 약학조성물 및 이의 제조방법 |
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| US5225204A (en) * | 1991-11-05 | 1993-07-06 | Chen Jivn Ren | Stable dosage of levothyroxine sodium and process of production |
| DE19541128C2 (de) * | 1995-10-27 | 1997-11-27 | Henning Berlin Gmbh & Co | Stabilisierte schilddrüsenhormonhaltige Arzneimittel |
| US5635209A (en) * | 1995-10-31 | 1997-06-03 | Vintage Pharmaceuticals, Inc. | Stabilized composition of levothyroxine sodium medication and method for its production |
| BR9611306A (pt) | 1995-11-14 | 1999-12-28 | Knoll Pharmaceuticals Co | Preparação farmacêutica e, composto farmacêutica estável. |
| HUT75956A (en) * | 1995-11-29 | 1997-05-28 | Cyclolab | Pharmaceutical composition containing thyroxine |
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- 1998-07-07 DE DE19830246A patent/DE19830246A1/de not_active Withdrawn
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1999
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- 1999-06-29 WO PCT/EP1999/004485 patent/WO2000002586A1/de active IP Right Grant
- 1999-06-29 US US09/743,114 patent/US6491946B1/en not_active Expired - Fee Related
- 1999-06-29 CN CN99808077A patent/CN1307486A/zh active Pending
- 1999-06-29 DE DE59910298T patent/DE59910298D1/de not_active Expired - Lifetime
- 1999-06-29 ID IDW20010180A patent/ID27150A/id unknown
- 1999-06-29 HU HU0104985A patent/HUP0104985A3/hu unknown
- 1999-06-29 CA CA002336748A patent/CA2336748A1/en not_active Abandoned
- 1999-06-29 AU AU47793/99A patent/AU751575B2/en not_active Ceased
- 1999-06-29 KR KR1020017000222A patent/KR20010071765A/ko not_active Application Discontinuation
- 1999-06-29 CZ CZ20010074A patent/CZ296897B6/cs not_active IP Right Cessation
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- 1999-06-29 AT AT99931209T patent/ATE273697T1/de active
- 1999-06-29 EP EP99931209A patent/EP1094841B1/de not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| AU751575B2 (en) | 2002-08-22 |
| EP1094841B1 (de) | 2004-08-18 |
| SK20042000A3 (sk) | 2001-09-11 |
| US6491946B1 (en) | 2002-12-10 |
| CZ296897B6 (cs) | 2006-07-12 |
| ATE273697T1 (de) | 2004-09-15 |
| JP2002520296A (ja) | 2002-07-09 |
| DE59910298D1 (de) | 2004-09-23 |
| CA2336748A1 (en) | 2000-01-20 |
| BR9911884A (pt) | 2001-03-27 |
| ID27150A (id) | 2001-03-08 |
| NO20010089L (no) | 2001-01-05 |
| HUP0104985A3 (en) | 2003-03-28 |
| AU4779399A (en) | 2000-02-01 |
| CZ200174A3 (en) | 2001-05-16 |
| KR20010071765A (ko) | 2001-07-31 |
| DE19830246A1 (de) | 2000-01-13 |
| EP1094841A1 (de) | 2001-05-02 |
| HUP0104985A2 (hu) | 2002-04-29 |
| NO20010089D0 (no) | 2001-01-05 |
| WO2000002586A1 (de) | 2000-01-20 |
| PL344834A1 (en) | 2001-11-19 |
| AR019899A1 (es) | 2002-03-20 |
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