CN1145479C - 药物制剂 - Google Patents
药物制剂 Download PDFInfo
- Publication number
- CN1145479C CN1145479C CNB998061751A CN99806175A CN1145479C CN 1145479 C CN1145479 C CN 1145479C CN B998061751 A CNB998061751 A CN B998061751A CN 99806175 A CN99806175 A CN 99806175A CN 1145479 C CN1145479 C CN 1145479C
- Authority
- CN
- China
- Prior art keywords
- sodium
- levothyroxine sodium
- levothyroxine
- filler
- pharmaceutical tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract description 10
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 claims abstract description 30
- 229960003918 levothyroxine sodium Drugs 0.000 claims abstract description 28
- 108010010803 Gelatin Proteins 0.000 claims abstract description 12
- 239000008273 gelatin Substances 0.000 claims abstract description 12
- 229920000159 gelatin Polymers 0.000 claims abstract description 12
- 235000019322 gelatine Nutrition 0.000 claims abstract description 12
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 12
- 239000000945 filler Substances 0.000 claims abstract description 10
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 9
- 229920002261 Corn starch Polymers 0.000 claims description 8
- 239000008120 corn starch Substances 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 6
- 230000003179 granulation Effects 0.000 claims description 6
- 229960002018 liothyronine sodium Drugs 0.000 claims description 6
- SBXXSUDPJJJJLC-YDALLXLXSA-M liothyronine sodium Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 SBXXSUDPJJJJLC-YDALLXLXSA-M 0.000 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 239000007884 disintegrant Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 229940099112 cornstarch Drugs 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 6
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 4
- 229960001375 lactose Drugs 0.000 description 4
- 229940034208 thyroxine Drugs 0.000 description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229960001021 lactose monohydrate Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229950008325 levothyroxine Drugs 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2063—Proteins, e.g. gelatin
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
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
发明领域
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。
发明背景
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％)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。
发明内容
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。
具体实施方式
实施例1
为制备例如两百万个片剂，需要如下用量：
| 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 |
*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：
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)
1.一种药物片剂，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的药物片剂，其特征在于，除了左甲状腺素钠以外，还含有碘塞罗宁钠。
3.根据权利要求1的药物片剂，其特征在于，含有5～400μg的左甲状腺素钠。
4.根据权利要求1-3任一的药物片剂，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1-3任一的药物片剂，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.生产权利要求1的药物片剂的方法，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。
7.根据权利要求6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6或7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 |
|---|---|---|---|
| DE19821625A DE19821625C1 (de) | 1998-05-15 | 1998-05-15 | Pharmazeutische Zubereitung |
| DE19821625.4 | 1998-05-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1301148A CN1301148A (zh) | 2001-06-27 |
| CN1145479C true CN1145479C (zh) | 2004-04-14 |
Family
ID=7867752
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998061751A Expired - Lifetime CN1145479C (zh) | 1998-05-15 | 1999-05-05 | 药物制剂 |
Country Status (25)
| 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) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| EP1565171A4 (en) * | 2002-11-05 | 2010-06-30 | Shire Llc | PROGRESSIVE ABSORPTION OF MIXED FORMULATIONS OF THYROID HORMONES |
| 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 |
| GB0316206D0 (en) * | 2003-07-10 | 2003-08-13 | Glaxo Group Ltd | Pharmaceutical formulation |
| PT1811987E (pt) | 2004-11-18 | 2008-05-26 | Uni Pharma Kleon Tsetis Pharmaceutical Lab Sa | Pó anidro contendo levotiroxina sódica, administrado por via de um inalador |
| 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 |
| PT2885005T (pt) * | 2012-08-20 | 2018-01-03 | Merck Patent Gmbh | Preparação farmacêutica sólida contendo levotiroxina |
| 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 |
| 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 |
| 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 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6191M (zh) | 1966-02-18 | 1968-07-22 | ||
| US3808332A (en) * | 1969-01-27 | 1974-04-30 | Armour Pharma | Pharmaceutical compositions containing the reaction product of a tertiary phosphine with thyroxine |
| 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 |
| US5225204A (en) | 1991-11-05 | 1993-07-06 | Chen Jivn Ren | Stable dosage of levothyroxine sodium and process of production |
| CN1071570C (zh) * | 1993-06-14 | 2001-09-26 | 詹森药业有限公司 | 阿司咪唑和假麻黄碱的缓释薄膜包衣片 |
| GB9325644D0 (en) * | 1993-12-15 | 1994-02-16 | Smithkline Beecham Plc | Novel formulation |
| GB9421837D0 (en) * | 1994-10-28 | 1994-12-14 | Scherer Corp R P | Process for preparing solid pharmaceutical dosage forms |
| 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 |
| DE19541128C2 (de) * | 1995-10-27 | 1997-11-27 | Henning Berlin Gmbh & Co | Stabilisierte schilddrüsenhormonhaltige Arzneimittel |
| CA2235707A1 (en) * | 1995-11-14 | 1997-05-22 | Knoll Pharmaceutical Company | Stabilized thyroid hormone preparations and methods of making same |
| HUT75956A (en) * | 1995-11-29 | 1997-05-28 | Cyclolab | Pharmaceutical composition containing thyroxine |
| US20010039335A1 (en) * | 1997-04-10 | 2001-11-08 | Kenneth Jacobs | Secreted proteins and polynucleotides encoding them |
| 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 |
-
1998
- 1998-05-15 DE DE19821625A patent/DE19821625C1/de not_active Expired - Lifetime
-
1999
- 1999-05-05 SK SK1689-2000A patent/SK284155B6/sk not_active IP Right Cessation
- 1999-05-05 AU AU39321/99A patent/AU742382B2/en not_active Expired
- 1999-05-05 CA CA002333193A patent/CA2333193A1/en not_active Withdrawn
- 1999-05-05 WO PCT/EP1999/003087 patent/WO1999059551A1/de active IP Right Grant
- 1999-05-05 AT AT99922182T patent/ATE225651T1/de active
- 1999-05-05 CZ CZ20004201A patent/CZ300908B6/cs not_active IP Right Cessation
- 1999-05-05 RU RU2000131588/15A patent/RU2225711C2/ru active
- 1999-05-05 CN CNB998061751A patent/CN1145479C/zh not_active Expired - Lifetime
- 1999-05-05 ID IDW20002460A patent/ID27281A/id unknown
- 1999-05-05 UA UA2000127207A patent/UA73474C2/uk unknown
- 1999-05-05 US US09/700,421 patent/US6646007B1/en not_active Expired - Lifetime
- 1999-05-05 JP JP2000549216A patent/JP4709379B2/ja not_active Expired - Lifetime
- 1999-05-05 ES ES99922182T patent/ES2184452T3/es not_active Expired - Lifetime
- 1999-05-05 PT PT99922182T patent/PT1077681E/pt unknown
- 1999-05-05 HU HU0102125A patent/HU228958B1/hu unknown
- 1999-05-05 DE DE59903028T patent/DE59903028D1/de not_active Expired - Lifetime
- 1999-05-05 PL PL99346395A patent/PL194088B1/pl unknown
- 1999-05-05 DK DK99922182T patent/DK1077681T3/da active
- 1999-05-05 BR BRPI9910445A patent/BRPI9910445B8/pt not_active IP Right Cessation
- 1999-05-05 EP EP99922182A patent/EP1077681B1/de not_active Expired - Lifetime
- 1999-05-12 MY MYPI99001885A patent/MY120570A/en unknown
- 1999-05-14 AR ARP990102301A patent/AR018607A1/es active IP Right Grant
- 1999-05-14 TW TW088107870A patent/TW561058B/zh not_active IP Right Cessation
-
2000
- 2000-11-14 NO NO20005758A patent/NO331655B1/no not_active IP Right Cessation
- 2000-12-14 ZA ZA200007509A patent/ZA200007509B/en unknown
-
2003
- 2003-09-15 US US10/661,588 patent/US8008349B2/en not_active Expired - Fee Related
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1145479C (zh) | 药物制剂 | |
| CA1338344C (en) | Stabilized medicinal substances, a process for the preparation thereof, and stable medicinal formulations | |
| CN1131025C (zh) | 用于制备含有大量药物的快速崩解和快速溶解的组合物的颗粒 | |
| KR100343062B1 (ko) | 정제 조성물 | |
| JP3944150B2 (ja) | ガバペンチン含有固形製剤の製造方法 | |
| EP0159852A2 (en) | Directly compressible pharmaceutical compositions | |
| EP1711168A2 (en) | Oral pharmaceutical compositions of candesartan cilexetil | |
| CN1307486A (zh) | 含左旋甲状腺素的药物制剂 | |
| KR20080094837A (ko) | 플루바스타틴 나트륨 약학 조성물 | |
| JP5286662B2 (ja) | 安中散含有錠剤 | |
| WO2000071117A1 (fr) | Compositions medicinales a liberation immediate pour administration orale | |
| CN1543341A (zh) | 稳定固体甲状腺药物制剂 | |
| CN1259909C (zh) | 含有2,2－二氯－12－(4－氯苯基)－十二烷酸的药物组合物 | |
| JP2001354566A (ja) | ニセルゴリンの錠剤 | |
| JP2019210276A (ja) | 錠剤及びその製造方法 | |
| WO2004047822A1 (ja) | テプレノンを充填したヒドロキシプロピルメチルセルロースカプセル製剤 | |
| WO2019230017A1 (ja) | 錠剤及びその製造方法 | |
| JP2003119121A (ja) | 錠剤の製造方法 | |
| JP2003261446A (ja) | プラバスタチンナトリウム含有錠剤およびその製造方法 | |
| MXPA00011182A (en) | Pharmaceutical preparation containing levothyroxine sodium | |
| HU215191B (hu) | Eljárás Levodopa és Carbidopa hatóanyag-kombinációt tartalmazó, szabályozott hatóanyag-leadású, központi dopaminhiányos állapotok kezeléséhez alkalmas orális gyógyszerkészítmény előállítására |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1038192 Country of ref document: HK |
|
| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20040414 |