CN102164579B - 苯达莫司汀的液体配制品 - Google Patents
苯达莫司汀的液体配制品 Download PDFInfo
- Publication number
- CN102164579B CN102164579B CN200980137977.5A CN200980137977A CN102164579B CN 102164579 B CN102164579 B CN 102164579B CN 200980137977 A CN200980137977 A CN 200980137977A CN 102164579 B CN102164579 B CN 102164579B
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- Prior art keywords
- preparation
- bendamustine
- approximately
- pharmaceutically acceptable
- preparations
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- 229960002707 bendamustine Drugs 0.000 title claims abstract description 91
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 239000012669 liquid formulation Substances 0.000 title abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims description 95
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 64
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- -1 dimethyl sulfoxine Chemical compound 0.000 claims description 8
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 3
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- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 3
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 3
- 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 claims description 3
- 230000002421 anti-septic effect Effects 0.000 claims description 2
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- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 claims 1
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- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 description 9
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- 239000000047 product Substances 0.000 description 7
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
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- 239000000539 dimer Substances 0.000 description 4
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- 238000001802 infusion Methods 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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- 239000000010 aprotic solvent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 3
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- GPYWLSZJZNELNN-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]-4-hydroxybutanoic acid Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(C(O)CCC(O)=O)=NC2=C1 GPYWLSZJZNELNN-UHFFFAOYSA-N 0.000 description 2
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
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- 241000282693 Cercopithecidae Species 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
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- 208000034578 Multiple myelomas Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
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- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 101001000212 Rattus norvegicus Decorin Proteins 0.000 description 2
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- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FVJZSBGHRPJMMA-UHFFFAOYSA-N distearoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC FVJZSBGHRPJMMA-UHFFFAOYSA-N 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
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- 239000010413 mother solution Substances 0.000 description 2
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
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- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
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- 239000005711 Benzoic acid Substances 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- 239000004594 Masterbatch (MB) Substances 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
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- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract
本说明书公开了苯达莫司汀和它的药学上可接受的盐以及极性非质子溶剂的稳定的液体配制品。
Description
技术领域
本发明涉及苯达莫司汀以及它的药用盐的液体配制品。
发明背景
苯达莫司汀,4-{5-[双(2-氯乙基)氨基]-1-甲基-2-苯并咪唑基}丁酸,是一个具有苯并咪唑环的不规则结构,该结构包括一个活性氮芥。苯达莫司汀最初于1963年在德意志民主共和国合成,并且从1971到1992年在该处以商品名Cytostasan可得。自那时以后,它已经以商品名Ribomustin在德国市场化。它现在在美国以商品名Treanda(Cephalon,Inc.,Frazer,PA)可供使用。它已经被广泛用于治疗慢性淋巴细胞白血病、何杰金氏病、非何杰金氏淋巴瘤、多发性骨髓瘤以及乳癌
像其他氮芥一样,苯达莫司汀在水溶液中水解,其中主要降解物是伯醇HP1(参见美国申请No.11/330,868,它的全文结合在此):
鉴于苯达莫司汀在水溶液中的不稳定性,它现在主要作为用于注射的冻干粉末而提供。就在它的输注前,医学工作者将该粉末用无菌水复水用于注射。复水应该产生一种透明的、无色到浅黄色的溶液并且该粉末应该在约5分钟内完全溶解。如果观察到微粒状物质,则该复水产品不应被使用并应该被丢弃掉。然后在复水30分钟以内将该复水产品转移到0.9%的氯化钠注射输液袋中。这一混合物应该是透明的、并且无色到微黄的溶液。如果该混合物包括微粒状物质或是变色的,则它应该被丢弃并且制备新鲜的样品。
苯达莫司汀的冻干粉末的复水是费时且麻烦的。此外,处于商业规模的固体的冷冻干燥要求专门的设备并且招致显著的费用。这样,对于不要求冷冻干燥和/或复水的苯达莫司汀的配制品存在需要。
已经报告了(GDR专利159289)在惰性气体的气氛下制备苯达莫司汀盐酸盐在无水丙二醇中的溶液。报告了使用薄层色谱法(用丁醇/乙酸/水(4∶1∶5)洗脱)对这些溶液的分析以及用德拉根道夫试剂和紫外线(360nm)的检测并没有表明任何分解。然而奇怪的是丙二醇配制品的商业发展迄今还没有被报道。因此,对于苯达莫司汀的改进的液体配制品仍然存在需要。
发明概述
本发明针对液体药物配制品,包括苯达莫司汀或它的一种药学上可接受的盐或药物前体,以及一种极性非质子溶剂。某些优选的实施方案包括液体药物配制品,该液体药物配制品包括苯达莫司汀或它的一种药学上可接受的盐或药物前体、一种极性非质子溶剂以及一种非水极性质子溶剂。还描述了制造和使用本发明的配制品的多种方法,以及使用提出权利要求的配制品来治疗癌症的方法。
附图简要说明
图1是苯达莫司汀在25℃下在不同溶剂中的稳定性分析的曲线图。
图2是苯达莫司汀在5℃下在不同溶剂中的稳定性分析的曲线图。
图3是在5℃和在25℃下、在99%丙二醇中苯达莫司汀纯度随时间变化的曲线图。
图4显示了雄性食蟹猴(N=4)内苯达莫司汀的平均+标准差浓度-对比-时间变化的曲线,这些雄性食蟹猴被给予了在3种不同配制品中的3mg/kg的弹丸静脉内剂量的苯达莫司汀盐酸盐。
发明详细说明
已经发现了苯达莫司汀的稳定的液体配制品并且在此进行了报告。
已经完成了生产商业上可行的丙二醇制剂的实验。不幸的是,在GDR专利159289中描述的结果是不可再现的。苯达莫司汀在99%的丙二醇中的溶液在经过与商业储存相等的一段时间后降解为非苯达莫司汀的产物。该杂质中的两种被鉴定为苯达莫司汀的丙二醇酯。这样,苯达莫司汀的100%丙二醇商业配制品对于药用目的来说是不可行的。
已经确定苯达莫司汀以及它的药学上可接受的盐(特别是盐酸盐)的药学上可接受的液体配制品可以通过使苯达莫司汀或它的药学上可接受的盐与一种极性非质子溶剂或多种极性非质子溶剂的混合物相结合来制备。极性非质子溶剂在本领域中是已知的并且包括,例如1-甲基-2-吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基乙酰胺、二甲亚砜、丙酮、四氢呋喃、1,4-二氧六环、乙腈、二甲基甲酰胺、碳酸丙烯酯。也见于例如Florence Mottu,et al.Organic solvents for pharmaceuticalparenterals and embolic liquids:A review of toxicity data,PDA J.Pharma.Sci.& Tech.vol 54,no.6,456-469(Nov.-Dec.2000).特别优选的极性非质子溶剂包括二甲基乙酰胺、二甲亚砜和它们的混合物。
不希望受任何特定理论所束缚,人们认为对于苯达莫司汀,极性非质子溶剂是足够非亲核性的,这样使得经过典型的商业储存条件的过程不会形成极性非质子溶剂-苯达莫司汀加合物。典型的商业储存条件包括多个时间段,例如约30天、约90天、约180天,以及约365天(约1个月、约3个月、约6个月,以及约1年)。典型的商业储存条件还包括约23℃的温度(周围室温)以及低于周围室温的冷藏温度,例如约5℃。优选地,本发明的液体配制品在冷藏温度下储存。
还已经发现,苯达莫司汀的稳定配制品可以通过将一种极性非质子溶剂或多种极性非质子溶剂的混合物与一种非水极性质子溶剂或多种非水极性质子溶剂的混合物进行混合而获得。药学上可接受的非水极性质子溶剂是在本领域中已知的并且包括烷基醇,例如乙醇、乙二醇、丙二醇、丁二醇、丙三醇、聚山梨醇酯(例如TWEEN 20、TWEEN40和TWEEN 80),以及环糊精(例如羟丙基-β-环糊精)、聚亚烷基二醇(例如聚乙二醇、聚丙二醇以及聚丁二醇),以及伯酰胺(例如烟酰胺)。
此类配制品将典型地包括按配制品的体积计90%或更少的非水极性质子溶剂。在其他优选实施方案中,配制品将包括按配制品的体积计在约20%和约85%之间的非水极性质子溶剂。在仍其他优选实施方案中,配制品将包括按配制品的体积计在约30%和约70%之间的非水极性质子溶剂。在最优选的实施方案中,配制品将包括按配制品的体积计约80%、约67%或约34%的非水极性质子溶剂。
可替代地,本发明的配制品将包括10摩尔/升或更少的非水极性质子溶剂。优选地,本发明的配制品将包括在约4摩尔/升和约9.5摩尔/升之间的非水极性质子溶剂。在某些实施方案中,配制品将包括约9.1摩尔/升的非水极性质子溶剂。在其他实施方案中,配制品将包括约4.6摩尔/升的非水极性质子溶剂。
虽然不希望被限制在任何特定理论,但是人们认为非水极性质子溶剂具有足够的亲核性来形成潜在的不希望的极性质子溶剂-苯达莫司汀加合物,如果该极性质子溶剂保持在本发明的范围以内,则此类加合物在典型的商业储存的过程中将不会形成。
在典型的商业储存时间段的过程中,本发明的液体配制品是稳定的。如在此处使用的,“稳定”被定义为在典型的商业储存条件下,不超过约10%的苯达莫司汀的损失。优选地,在典型的商业储存条件下,本发明的配制品将具有不超过约10%的苯达莫司汀的损失,更优选地,不超过约5%的苯达莫司汀的损失。
当暴露至某些亲核试剂使,例如水和亚烷基二醇(例如丙二醇)中时,苯达莫司汀转化为多种非苯达莫司汀产物(即,“降解物”)。苯达莫司汀暴露在水中时可以产生不希望的“HP1”。
苯达莫司汀随时间变化可以转化成的另一种不希望的化合物是“BM1二聚物”。
苯达莫司汀随时间变化可以转化成的仍另一种化合物是“DCE”。
当暴露至一种亚烷基二醇(例如丙二醇)时,可以形成苯达莫司汀的酯,例如PG-1和PG-2。
在本发明的优选实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,对本发明的配制品的分析将呈现1.50%或更少的DCE。更优选地,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现1.0%或更少的DCE。甚至更优选地,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现0.5%或更少的DCE。最优选地,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现约0.1%或更少的DCE。
在本发明的其他实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,对配制品的分析将呈现约0.4%或更少的HP1。优选地,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现约0.10%或更少的HP1。
在本发明的某些其他实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,对配制品的分析将呈现约0.70%或更少的BM1二聚物。优选地,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现约0.30%或更少的二聚物。在最优选的实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,这些配制品将呈现约0.10%或更少的BM1二聚物。
在包括亚烷基二醇作为非水极性质子溶剂的那些本发明的实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,对那些配制品的分析将呈现1.5%或更少的苯达莫司汀的亚烷基二醇酯。例如,在那些包括丙二醇的实施方案中,在约5℃下约1年(约365天)后,如通过HPLC分析测定的,对那些配制品的分析将呈现1.5%或更少的丙二醇酯PG-1和PG-2。
本发明的液体配制品的分析可以使用本领域中已知的技术(包括例如HPLC、气相色谱法以及NMR)来完成。在暴露于典型的商业储存条件后,对本发明的配制品的分析将显示该配制品含有不少于暴露于储存条件之前所存在的苯达莫司汀的量的约90%。优选地,分析将显示该配制品含有不少于暴露于储存条件之前所存在的苯达莫司汀的量的约95%。
在本发明的优选实施方案中,对本发明的配制品的分析将显示该配制品含有不少于暴露于储存条件之前所存在的苯达莫司汀的量的约90%,这些储存条件包括温度为约5℃并且时间段为约30天(约1个月)到约365天(约一年)。优选地,对本发明的配制品的分析将显示该配制品含有不少于暴露于储存条件之前所存在的苯达莫司汀的量的约90%,这些储存条件包括温度为约5℃并且时间段为约30天(约1个月)、约90天(约三个月)以及约180天(约6个月)。优选地,分析将显示该配制品含有不少于暴露于储存条件之前存在的苯达莫司汀的量的约95%,这些储存条件包括温度为约5℃并且时间段为约30天(约1个月)到约365天(约一年)。更优选地,分析将显示该配制品含有不少于暴露于储存条件之前多存在的苯达莫司汀的量的约95%,这些储存条件包括温度为约5℃并且时间段为约30天(约1个月),约90天(约三个月)以及约180天(约6个月)。
本发明的配制品可以包括药学上有用的浓度的苯达莫司汀,或它的一种药学上可接受的盐。有用的浓度包括的浓度范围是从约5mg/mL到约200mg/mL。优选地,苯达莫司汀或它的一种药学上可接受的盐的浓度范围是从约5mg/mL到约120mg/mL。优选的浓度包括约5mg/mL、约10mg/mL、约20mg/mL、约30mg/mL、约40mg/mL、约50mg/mL、约60mg/mL、约100mg/mL以及约200mg/mL的苯达莫司汀或它的一种药学上可接受的盐。大于200mg/mL的苯达莫司汀或它的药学上可接受的盐,例如大于300mg/mL,也在本发明的范围内,苯达莫司汀或它的药学上可接受的盐的饱和溶液也是如此。
如在此处使用的,术语“约”被定义为±10%,优选地±5%。
除了包括一种极性非质子溶剂或多种极性非质子溶剂的混合物,以及任选地,一种非水极性质子溶剂或多种溶剂的混合物,本发明的配制品可以进一步包括其他药学上可接受的赋形剂。药学上可接受的赋形剂是本领域内已知的并且包括,例如抗氧化剂(例如生育酚(维生素E)、抗坏血酸、对羟基苯甲酸甲酯、丁羟基茴香醚(BHA)、丁羟基甲苯(BHT)以及没食子酸丙酯),表面活性剂(例如聚山梨醇酯(TWEEN 20、TWEEN 40、TWEEN 80)),类脂(例如二肉豆蔻磷脂酰胆碱(DMPC)、二肉豆蔻磷脂酰甘油(DMPG)、二硬脂酰磷脂酰甘油(DSPG)),填充剂(例如甘露醇),有机酸(例如柠檬酸、乳酸、苯甲酸),亲水性聚合物(例如聚乙二醇(PEG 300、PEG 400)),络合剂(例如烟酰胺、烟酸、肌酸、环糊精)以及防腐剂(例如苯甲醇)。
同样在本发明范围之内的是用一种本发明的药物配制品治疗疾病(例如像慢性淋巴细胞白血病、何杰金氏病、非何杰金氏淋巴瘤、多发性骨髓瘤、或乳癌)的多种方法。这些方法包括向患者给予一个治疗有效量的从一种本发明的药物配制品制备的一种制剂。在此所使用的术语“治疗有效量”是指所确定的、产生预期的生理效应所要求的并且与一种给定的药物相关联的量,如对于给定的给药途径根据已确定的药物代谢动力学方法和技术所测量的。适当的并且具体的治疗有效的量可以由作为本领域的普通技术人员的主治诊断医生通过使用常规的技术很容易进行确定。有效剂量将取决于多种因素而变化,这些因素包括疾病或病症的类型和进展程度、具体患者的总体健康状况、所选择的化合物的相对生物学疗效、活性试剂与适当的赋形剂的配制品、以及给药途径。
在此描述的这些苯达莫司汀的液体配制品旨在通过注射给药,例如它们可以皮下地、皮内地、静脉内地、肌内地、关节内地、滑膜内地、胸骨内地、鞘内地、损伤区内地、颅内地或经输注给药。在一个典型的制备过程中,可以将对于所要求的剂量所需要的体积的本发明的液体配制品无菌地抽出并且转移到用于注射的0.9%氯化钠(或其他药学上可接受的静脉内溶液)的一个输液袋中。在转移之后,将该输液袋的内含物充分混合。通过静脉内输注的给药典型地是经从约30分钟至约60分钟的时间段来提供的。之前描述的苯达莫司汀的冻干配制品在输注前要求在与多种可接受的静脉内溶液混合前将冻干的苯达莫司汀进行复水。
所设想到的是,本发明的这些药物配制品和制剂可以与一种或多种抗肿瘤药组合给予,其中该抗肿瘤药是在给予本发明的配制品或制剂之前、与其同时、或之后给予。药学上可接受的抗肿瘤药在本领域中是已知的。优选的抗肿瘤药是披露于2006年1月12日提交的共同未决的美国申请号11/330,868(将其通过引用以全文结合在此)中的那些。
实例
在极性非质子溶剂中苯达莫司汀盐酸盐的溶解度和稳定性
对于多种溶剂确定了平衡溶解度,这些溶剂包括1-甲基-2-吡咯烷酮(NMP)、1,3-二甲基-2-咪唑啉酮(DMI)、二甲基乙酰胺(DMA)、二甲亚砜(DMSO)、丙酮、四氢呋喃(THF)、二甲基甲酰胺(DMF)以及碳酸丙烯酯(PC)。还对于两种溶液(在DMA中的25mg/mL烟酰胺以及66%的DMA/34%的丙二醇(PG))测定了苯达莫司汀盐酸盐的溶解度。对于每种溶剂或溶液将苯达莫司汀盐酸盐的饱和溶液制成一式三份并且在一个实验室振荡器上通过在室温下持续3天的温和混合以及低剪切进行混合。将每种悬浮液的一个样品放入一个微量离心管中,并且在一台Eppendorf微量离心机上以10,000rpm的速度旋转5分钟。将上清液移出并且放入一个干净的小瓶中。将每种溶液用样品溶剂(50%的NMP/50%的0.1%三氟乙酸在水中)稀释。使用一种针对苯达莫司汀盐酸盐的反相方法来测定由一种标准物计算出的每种样品的浓度。在制备稀释样品18小时以内进行分析。溶解度在以下表I中列出。每个值都是三个样品的平均值。
表I
样品* | %纯度 | 测定值(mg/mL) |
NMP | 99.1 | 104.0 |
DMI | 98.5 | 75.8 |
DMSO | 99.5 | 311.7 |
DMF | 99.6 | 71.8 |
66%DMA/34%PG | 99.5 | 110.1 |
DMA | 99.4 | 56.2 |
PC | 98.7 | 7.7 |
烟酰胺/DMA | 99.2 | 61.3 |
*丙酮和THF没有可测量的苯达莫司汀的溶解度。
将三个复制品合并并且充分混合,并且之后用移液管移进琥珀色HPLC小瓶中并且置于25℃和5℃的稳定性室内。所有样品都是透明并且无色的,除了DMI样品是透明并且黄色的。从约180天(约6个月)到约365天(约12个月,约1年),该25℃稳定性变得平稳。在5℃下,所有溶液都具有大于90%的纯度。对稳定性样品的分析可以从图1和图2的曲线图中看到。
表II
在5℃下储存约12个月后,苯达莫司汀盐酸盐的某些液体配制品的杂质曲线
ND=未检测到
用50%的NMP/50%的在水中的0.1%三氟乙酸作为流动溶剂,使用反相HPLC进行分析。
如图3中可出的,当在25℃下储存少于100天时,在99%的丙二醇中的苯达莫司汀(BM1)显著地降解。在5℃下储存约365天后,苯达莫司汀的纯度为约80%或更少。
在猴子体内的多种配制品的药物代谢动力学研究
4只禁食(18-23小时)、初次接受药物的雄性食蟹猴按顺序接受单次的由3种不同的配制品制备的苯达莫司汀盐酸盐的3-mg/kg弹丸静脉内剂量。本研究中评估的这些配制品包括:
1)TREANDA(苯达莫司汀盐酸盐和甘露醇的冻干混合物;25mg的(苯达莫司汀盐酸盐)小瓶;2)一种66%二甲基乙酰胺(DMA)/34%丙二醇(PG)(w/w)溶液(90mg(苯达莫司汀盐酸盐)/mL母液);以及3)一种100%DMA溶液(45mg(苯达莫司汀盐酸盐)/mL母液)。该苯达莫司汀盐酸盐的冻干粉末和母料溶液用0.9%盐水复水或稀释(适当时)以在剂量给予前给出3mg苯达莫司汀盐酸盐/mL的溶液。将这些制成的溶液经由一根隐静脉以1.0mL/kg的固定体积作为一次弹丸进行给药。存在分开这些连续剂量的至少一个7天的洗脱期。在给药的所有3个阶段中,直接在给药前以及在穿过给药后12小时的预选时间点经由一根大腿静脉收集用于苯达莫司汀和它的2种活性循环代谢物(γ-羟基苯达莫司汀(M3)和N-去甲基苯达莫司汀(M4))的药物代谢动力学曲线的血样。使用带有串联质谱检测(LC-MS/MS)的一种证实的高效液相色谱法按如下所述测定血浆样品中苯达莫司汀、M3和M4的浓度。通过使用乙腈进行蛋白质沉淀从血浆中提取苯达莫司汀以及M3和M4代谢物。在提取后,将该等分的样品用1%的甲酸酸化,并且作为一种内标物添加在羧酸链中具有添加的碳的苯达莫司汀。将这些样品蒸发至干燥并且将残余物用一种乙腈/水/甲酸/甲酸铵混合物进行复水。将样品注入一个带有LC/MS/MS检测的HPLC系统内,使用一种具有乙腈/水/甲酸/甲酸铵作为流动相的Phenomenex SynergiMax-RP柱。使用无房室法进行药物代谢动力学分析。
在向雄性食蟹猴单次弹丸静脉内给予苯达莫司汀盐酸盐后,苯达莫司汀的平均血浆浓度-对比-时间的曲线的形状在这3种配制品的每一个中都是类似的(参见图4)。在所有情况下,在给药后0.083小时(即在给药后第一取样时间)达到了观察到的最高的苯达莫司汀血浆水平,并且随后该化合物从血浆中的去除以一种两阶段的方式发生,其特征为一个初始的快速分布阶段以及一个在某种程度上更慢的药物消除的末期阶段。对于每种配制品,该末期阶段的调和平均值t1/2为近似0.6小时(参见表III)。
除了这些平均血浆浓度-对比-时间的曲线在形状上的相似性之外,这3种配制品还在苯达莫司汀的系统性暴露(即Cmax和AUC)方面相类似。具体地讲,对于TREANDA配制品,苯达莫司汀的Cmax和AUC0-∞的平均值分别为6037ng/mL和2314ng·hr/mL,对于66%DMA/34%PG的配制品分别为7380ng/mL和2854ng·hr/mL,并且对于100%DMA的配制品分别为6209ng/mL和2372ng·hr/mL。苯达莫司汀的血浆清除率(CL)和分布容积(Vz和Vss)在这3种配制品的每一种之间也是可比较的(参见表III)。在表III中,tmax、hr作为中值[范围]给出,t1/2、hr作为调和均值给出,λz、hr-1在消除阶段中是线的斜率,被用来计算半衰期,并且MRT0-∞是平均停留时间。
总而言之,在对猴子进行单次弹丸静脉内给药后,对于苯达莫司汀盐酸盐的2种液体配制品而言苯达莫司汀、M3和M4的药物代谢动力学曲线在质量上以及数量上与对于TREANDA配制品所获得的那些曲线相类似。
表III显示了给予在三种不同的配制品中的单次3mg/kg弹丸静脉内剂量的苯达莫司汀盐酸盐的雄性食蟹猴(N=4)体内苯达莫司汀的均值+/-标准差药物代谢动力学参数。
表III
配制品的使用中研究
以高剂量(360mg苯达莫司汀盐酸盐)制备在0.9%氯化钠溶液(500mL的袋)中的混合物,并且在室温下使用HPLC测定随时间变化的纯度,持续长达8小时,使用了一个Zorbax Bonus-RP柱,其中的梯度是从93%的在水中的0.1%三氟乙酸(流动相A)/7%的在乙腈中的0.1%三氟乙酸(流动相B)到10%的流动相A/90%的流动相B。
66%DMA/34%PG配制品具有的苯达莫司汀盐酸盐的浓度为90mg/g,所以将4mL注入500mL的盐水袋中,倒转10次并且在室温下取样,持续8小时。8小时后纯度为95.4%。这在用于Treanda给药的标签要求之内。本发明的这种配制品可以在室温下使用长达8小时。通过对比,复水的Treanda只能在室温下储存达3小时。
该100%DMA的配制品具有45mg/g的浓度,所以将8mL注入到500mL的盐水袋中,倒转10次,并在室温下取样,持续4小时。4小时后纯度为97.9%。本发明的这种配制品可以在室温下使用长达4小时。
在25℃下4小时后,对比性的Treanda混合物纯度为95.0%。
如本领域的普通技术人员将理解到的,鉴于以上传授内容,本发明的多种改变和变更是有可能的。因此应理解的是,在权利要求书的范围之内,本发明可以如在此所确切说明的之外,以其他方式来实施,并且本发明的范围旨在涵盖所有的此类变化。
Claims (19)
1.一种稳定的、非水性液体药物配制品,包括溶解于极性非质子溶剂中的苯达莫司汀或它的一种药学上可接受的盐,其中该极性非质子溶剂是1-甲基-2-吡咯烷酮、1,3-二甲基-2-咪唑啉酮、二甲基乙酰胺、二甲亚砜、二甲基甲酰胺、碳酸丙烯酯或它们的一种混合物。
2.如权利要求1所述的配制品,其中该极性非质子溶剂是二甲基乙酰胺、二甲亚砜或它们的一种混合物。
3.如权利要求1所述的配制品,进一步包括一种非水极性质子溶剂。
4.权利要求3所述的配制品,包括按该配制品的体积计30%到70%的非水极性质子溶剂。
5.如权利要求3所述的配制品,其中该非水极性质子溶剂是一种醇、一种酰胺或它们的一种混合物。
6.权利要求5所述的配制品,其中醇是一种聚亚烷基二醇。
7.权利要求1所述的配制品,其进一步包括环糊精。
8.权利要求3所述的配制品,其中该极性非质子溶剂是二甲基乙酰胺并且该非水极性质子溶剂是丙二醇。
9.权利要求8所述的配制品,包括66%±10%(v/v)的二甲基乙酰胺和34%±10%(v/v)的丙二醇。
10.如权利要求1所述的配制品,包括5mg/mL到200mg/mL的苯达莫司汀或它的药学上可接受的盐。
11.权利要求10所述的配制品,包括100±10%mg/mL的苯达莫司汀或它的药学上可接受的盐。
12.权利要求10所述的配制品,包括90mg/mL的苯达莫司汀盐酸盐。
13.权利要求1所述的配制品,其中苯达莫司汀为苯达莫司汀盐酸盐。
14.如权利要求1或3所述的配制品,进一步包括至少一种药学上可接受的赋形剂。
15.如权利要求14所述的配制品,其中赋形剂是稀释剂。
16.如权利要求1或3所述的配制品,进一步包括一种抗氧化剂、一种表面活性剂、一种类脂、一种填充剂、一种有机酸、一种亲水性聚合物、一种络合剂、一种防腐剂或它们的一种组合。
17.一种制备苯达莫司汀或它的一种药学上可接受的盐的注射配制品的方法,包括:
提供权利要求1-16任一项所述的液体药物配制品;
用一种药学上可接受的注射稀释剂稀释该液体药物配制品。
18.权利要求17所述的方法,其中药学上可接受的注射稀释剂为0.9%氯化钠。
19.权利要求1-16任一项所述的液体药物配制品在制备用于治疗慢性淋巴细胞白血病或非何杰金氏淋巴瘤的药物中的应用。
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AR072777A1 (es) * | 2008-03-26 | 2010-09-22 | Cephalon Inc | Formas solidas de clorhidrato de bendamustina |
EP2889029A1 (en) | 2008-09-25 | 2015-07-01 | Cephalon, Inc. | Liquid formulations of bendamustine |
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2009
- 2009-09-23 EP EP15152744.7A patent/EP2889029A1/en not_active Withdrawn
- 2009-09-23 JP JP2011529180A patent/JP5670335B2/ja active Active
- 2009-09-23 WO PCT/US2009/058023 patent/WO2010036702A1/en active Application Filing
- 2009-09-23 MX MX2011002936A patent/MX2011002936A/es active IP Right Grant
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- 2009-09-23 CN CN200980137977.5A patent/CN102164579B/zh active Active
- 2009-09-23 EP EP09740213A patent/EP2326306A1/en not_active Withdrawn
- 2009-09-23 CA CA2735899A patent/CA2735899A1/en not_active Abandoned
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2011
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- 2011-12-01 HK HK15111733.2A patent/HK1211462A1/zh unknown
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2012
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2013
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2014
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- 2014-03-21 US US14/221,422 patent/US20140206733A1/en not_active Abandoned
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2015
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- 2015-07-31 US US14/814,570 patent/US20150335750A1/en not_active Abandoned
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2016
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- 2016-10-19 AU AU2016247123A patent/AU2016247123A1/en not_active Abandoned
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2017
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2018
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2020
- 2020-03-31 US US16/835,562 patent/US20210008035A1/en not_active Abandoned
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DD159289A1 (de) * | 1981-06-01 | 1983-03-02 | Uwe Olthoff | Verfahren zur herstellung stabiler injektionsloesungen von n-lostverbindungen |
CN101119708A (zh) * | 2005-01-14 | 2008-02-06 | 赛福伦公司 | 苯达莫司汀冻干药物组合物 |
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US8344006B2 (en) | 2013-01-01 |
JP2012503666A (ja) | 2012-02-09 |
CA2735899A1 (en) | 2010-04-01 |
AU2016203246A1 (en) | 2016-06-09 |
AU2018202107A1 (en) | 2018-04-19 |
US20180125824A1 (en) | 2018-05-10 |
HK1211462A1 (zh) | 2016-05-27 |
EP2889029A1 (en) | 2015-07-01 |
AU2015207940A1 (en) | 2015-08-20 |
US20110190363A1 (en) | 2011-08-04 |
US20140080881A1 (en) | 2014-03-20 |
AU2009296734A1 (en) | 2010-04-01 |
CN104224703A (zh) | 2014-12-24 |
US20150335750A1 (en) | 2015-11-26 |
US20210008035A1 (en) | 2021-01-14 |
JP5670335B2 (ja) | 2015-02-18 |
AU2009296734B2 (en) | 2016-02-18 |
US20140128443A1 (en) | 2014-05-08 |
US20120129904A1 (en) | 2012-05-24 |
US20140206733A1 (en) | 2014-07-24 |
CN102164579A (zh) | 2011-08-24 |
AU2016203246B2 (en) | 2017-09-21 |
WO2010036702A1 (en) | 2010-04-01 |
MX2011002936A (es) | 2011-04-11 |
AU2016247123A1 (en) | 2016-11-03 |
EP2326306A1 (en) | 2011-06-01 |
AU2015207940B2 (en) | 2016-11-10 |
US20210113530A1 (en) | 2021-04-22 |
US20130041004A1 (en) | 2013-02-14 |
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Address after: Pennsylvania, America Patentee after: Safran Co.,Ltd. Address before: Pennsylvania, America Patentee before: CEPHALON, Inc. |