CN1396828A - 含有培美西德以及一硫代甘油l－半胱氨酸或巯乙酸的药物组合物 - Google Patents
含有培美西德以及一硫代甘油l－半胱氨酸或巯乙酸的药物组合物 Download PDFInfo
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- CN1396828A CN1396828A CN01804441A CN01804441A CN1396828A CN 1396828 A CN1396828 A CN 1396828A CN 01804441 A CN01804441 A CN 01804441A CN 01804441 A CN01804441 A CN 01804441A CN 1396828 A CN1396828 A CN 1396828A
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- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 229960005079 pemetrexed Drugs 0.000 title claims abstract description 26
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 title claims abstract 4
- QZPSEFKPLVZNHV-DKWTVANSSA-N (2r)-2-amino-3-sulfanylpropanoic acid;3-sulfanylpropane-1,2-diol Chemical compound OCC(O)CS.SC[C@H](N)C(O)=O QZPSEFKPLVZNHV-DKWTVANSSA-N 0.000 title description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 22
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 22
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- 238000002360 preparation method Methods 0.000 claims description 42
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- 150000008538 L-cysteines Chemical class 0.000 claims 3
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 abstract 1
- 238000007911 parenteral administration Methods 0.000 abstract 1
- WBXPDJSOTKVWSJ-ZDUSSCGKSA-L pemetrexed(2-) Chemical compound C=1NC=2NC(N)=NC(=O)C=2C=1CCC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 WBXPDJSOTKVWSJ-ZDUSSCGKSA-L 0.000 description 23
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
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- ZXVOCOLRQJZVBW-UHFFFAOYSA-N azane;ethanol Chemical compound N.CCO ZXVOCOLRQJZVBW-UHFFFAOYSA-N 0.000 description 1
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- 230000001681 protective effect Effects 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000002787 reinforcement Effects 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
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- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229940071127 thioglycolate Drugs 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-O triethanolammonium Chemical compound OCC[NH+](CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-O 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- 239000008215 water for injection Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
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- 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
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Abstract
本发明提供一种药物组合物，含有培美西德；至少一种选自一硫代甘油、L－半胱氨酸和巯乙酸的抗氧剂；和药学可接受赋形剂。该药物制剂适合液体非肠道给药。
Description
本发明涉及一种含有已知化合物培美西德(PEMETREXED)的液体组合物，具体来说，本发明涉及一种含有培美西德和抗氧剂的液体组合物；该液体组合物稳定且在药学上优异。
已知某些叶酸抗代谢物是抗肿瘤剂。这些化合物抑制涉及叶酸的代谢衍生物的酶转化。一种此类的由美国专利5,344,932所述的化合物目前被开发用作药物试剂。这种化合物被称作″培美西德″，人们非常希望将其配制成浓缩液体作为输注剂型给药。培美西德二钠是抗癌药物ALIMTA中的活性成分，其目前由Eli Lilly and Company作临床开发。
美国专利5,344,932教导的制剂提供了本文所述化合物可以以非肠道给药。
一种备用、稳定、易于重构的可以在室温下保存的溶液对于药物如培美西德来说特别理想，其中这种备用的制剂提供更加简易、更加安全的操作、储藏和分配。特别希望是否可以无需使用冻干技术来制备所述的稳定制剂。所希望的液体制剂可以为细胞毒性物质的治疗操作提供高安全性。此外，稳定的、易于使用的制剂更能为用户接受。
现在发现培美西德的简单、等渗盐水溶液从商业目的上来说是药学上不可接受的，因为该溶液降解形成不可接受的相关物质。目前发现当制剂含有某些抗氧剂时可以制备培美西德的药学可接受的、浓缩的、备用的液体溶液，所述的抗氧剂包括一硫代甘油、L-半胱氨酸和巯乙酸。人们也研究其他抗氧剂；然而，令人惊奇地，在被研究的抗氧剂中，只有这些具有在此所述的所需制剂特征。
所述的制剂具有可接受的稳定性，保留了药学上可取的外观，保持了所需的对映稳定性，并且符合保健供应者对稳定、备用液体制剂的要求。此外，在此提供的制剂适合非肠道给药，可以存放在透明瓶内提供给保健供应者且可以在4℃以上以高浓缩状态保存。
本发明达到了对药学上稳定的液体培美西德制剂的要求，其同时具有颜色稳定性和可接受的保存期，从而保持该溶液剂型且避免了成为不利相关物质的不可接受的降解作用。此外，保健供应者可以将所述的制剂稀释至所需的给药浓度。最后，本文所提供的制剂除了抗氧剂以外不需要加入任何防腐剂，从而保持预期浓度和稳定性。
本发明特别提供一种药物组合物，含有：a)培美西德；b)至少一种抗氧化剂，选自：i) 一硫代甘油，ii) 半胱氨酸，iii) 巯乙酸；和c)药学可接受赋形剂。
这三种抗氧剂对于所述的制剂具有独特的效果。令人惊奇地，常规抗氧剂，如偏亚硫酸氢钠、抗坏血酸、EDTA钠、一乙醇胺龙胆酸盐、甲醛次硫酸钠、硫酸氢钠，无法提供理想的制剂特征。
尤其优选的抗氧剂是一硫代甘油。
一硫代甘油的浓度首选是约1ppm(1part per million)-8.0mg/ml，对于一个指定的制剂该浓度可以基于接触该制剂的氧浓度而最佳化。一硫代甘油的浓度可以优选至少0.6mg/ml，更优选至少0.8mg/ml，尤其优选至少1.0mg/ml。一硫代甘油的浓度优选至多6mg/ml，更优选至多5mg/ml，和首选至多3mg/ml。
可以优选一硫代甘油的浓度是约0.6mg/ml-约6mg/ml。更优选，一硫代甘油的浓度是约0.8mg/ml-约5.0mg/ml。尤其优选一硫代甘油的浓度至少1.0mg/ml。尤其希望的浓度是1.40mg/ml-约3.0mg/ml。进一步希望的浓度是约2mg/ml-约3mg/ml。进一步优选的一硫代甘油的浓度是约1.2mg/ml-约2.4mg/ml。
通常，一硫代甘油、L-半胱氨酸或巯乙酸的浓度首选是约1ppm-8.0mg/ml，该浓度对于一种指定制剂来说可以基于接触该制剂的氧浓度进行最佳化。L-胱氨酸或巯乙酸在较高pH下常常最有效。可以优选一硫代甘油、L-半胱氨酸或巯乙酸的浓度是约1.0mg/ml-约6mg/ml。更优选，一硫代甘油、L-半胱氨酸或巯乙酸的浓度是约0.8mg/ml-约5.0mg/ml。尤其优选一硫代甘油、L-半胱氨酸或巯乙酸的浓度至少1.0mg/ml。对于一硫代甘油、L半胱氨酸或巯乙酸来说尤其希望的浓度是1.40mg/ml-约3.0mg/ml。进一步希望的浓度是约2mg/ml-约3mg/ml。进一步优选的一硫代甘油、L-半胱氨酸或巯乙酸的浓度是约1.2mg/ml-约2.4mg/ml。优选具有约0.1(十分之一)mg/ml-7mg/ml的浓度。当抗氧剂是一硫代甘油或L-胱氨酸时，优选的浓度范围是约0.1(十分之一)mg/ml-约10.0mg/ml。
L-半胱氨酸的浓度优选大于0.1(十分之一)mg/ml，更优选大于0.5(二分之一)mg/ml和首选大于1(一)mg/ml。
L-半胱氨酸的浓度优选小于10(十)mg/ml，更优选小于8(八)mg/ml，和首选小于6(六)mg/ml。
巯乙酸的浓度优选大于0.1(十分之一)mg/ml，更优选大于0.5(二分之一)mg/ml和首选大于1(一)mg/ml。
巯乙酸的浓度优选小于10(十)mg/ml，更优选小于8(八)mg/ml，和首选小于6(六)mg/ml。
此外，这三种抗氧剂选自一硫代甘油、L-半胱氨酸和硫代甘油的联合形式也可以应用在本发明中。
培美西德的浓度优选约20-约100mg/ml。优选优选培美西德的浓度是约30mg/ml-约70mg/ml。进一步优选的实施方式是当培美西德的浓度为约35mg/ml-约50mg/ml时。进一步优选的实施方式是培美西德浓度是38mg/ml-约44mg/ml。尤其希望的培美西德的浓度是约40mg/ml。
在此所用的术语″培美西德″是指其稳定的盐、酸和游离碱形式。该术语包括，例如，游离酸，药学可接受碱金属、碱土金属、无毒金属、铵和被取代铵盐，如钠、钾、锂、钙、镁、铝、锌、铵、三甲铵、三乙铵、一乙醇铵、三乙醇铵、吡啶鎓、被取代的吡啶鎓等。被取代的铵盐是一组特别优选的盐。
在此所用的术语″药学可接受赋形剂″是指药学可接受的制剂载体、溶液或加强制剂特性的添加剂。此类添加剂是所属领域技术人员熟知的。尽管任何药学可接受稀释剂是适宜的，但特别优选非肠道给药的赋形剂是盐水溶液。例如，氯化钠、甘露糖醇等。
培美西德的二钠盐特别优选用于本发明的制剂中。
所述制剂的pH首选是约5.5-约12。钙制剂更优选约pH7-约11。尤其理想制剂的pH是8.0-9.0。当抗氧剂是一硫代甘油时进一步优选pH是约8-约9。当可以是L-半胱氨酸或巯乙酸或其任何盐形式，随后优选的pH是约8-约10。所述技术人员应理解，这些抗氧剂的联合形式可以提供新的优选pH范围。该组合物的标准改进可以提供本发明所述的不同pH的组合物。
一般优选制备制剂的方法包括使用清洗的惰性气体。此类惰性气体是例如氮气、氩气等。使用隔离器维持低氧条件是可取的，但并不是储藏本发明制剂所必须的。
虽然任何药学可接受的塞子可以用来密封含有所述制剂的瓶子，优选用硅化的塞子密封瓶子。要求用灭菌聚四氟乙烯涂层的塞子来密封存储瓶。
药学上最可接受的液体制剂瓶子或容器可以用来分配所述的制剂。希望容器使接触所述制剂的氧的浓度最小。所以，瓶子或安瓿对于所述的制剂来说尤其理想。在许多国家中出于商业目的密封瓶尤其理想。
所属领域技术人员应理解，对于非肠道用的灭菌液体制剂的储藏来说希望使用除热原的预洗瓶。瓶子可以带有颜色；然而，透明瓶是制剂储藏可接受的。任何药学可接受物质可以用来制备制剂的容器；然而，玻璃是尤为优选的容器材料。玻璃瓶是优选的容器。其他非肠道使用的包装材料如塑料瓶也是适宜的选择。譬如，可以使用塑料瓶。
在制备制剂的过程中可能希望保护本体溶液避光；然而，这种保护作用并不是本发明制剂所必须的。
所得的制剂可以利用所属领域技术人员熟知的方法灭菌。
这种灭菌方法可以包括，例如，灭菌过滤或加热。尤其有益的是本发明所述制剂在加热灭菌过程中保持稳定。
优选瓶子的顶部空间含有小于约8％(百分之八)v/v的氧；然而，如果适当调整了该制剂的其他条件，瓶子的顶部空间可以含有大于8％氧。更优选瓶子的顶部空间含有约2％-约5％的氧。尤其优选所述的顶部空间含有约3％-约5％的氧。进一步优选该顶部空间含有小于约1(一)ppm的氧。另外，当该顶部空间的氧含量小于约0.1％(千分之一)v/v氧时也优选。瓶子的顶部空间含有小于1％(百分之一)的氧也是优选的条件。
可以调整瓶子的顶部空间使所述制剂接触最少的氧。一般希望该顶部空间不超过该容器总容量的约1/3(三分之一)，同时填充占该容器总容量的至少约2/3(三分之二)。例如，对于7.5ml的瓶子可以优选填充5ml。如果希望顶部空间与填充的比例较大，则可以根据需要调整抗氧剂的浓度。
本发明提供的药物制剂同时适合于人体临床应用和兽医用于动物。
培美西德可以利用美国专利5,473,071(在此全文引入作为参考)所述的方法制备。培美西德的组合物可以有效治疗癌症，如专利5,344,932以及Seminars在Oncology，26卷，2期，增补(1999.4)中所述。
一硫代甘油购自化学供应商，其是所属领域技术人员熟知的。为了进一步澄清，一硫代甘油的化学文摘号：96-27-5。
另外，L-半胱氨酸(CAS：52-90-4)、L-半胱氨酸盐酸盐一水合物(CAS：7048-04-6)、L-半胱氨酸盐酸盐一水合物无水(CAS：52-89-1)和巯乙酸(CAS：68-11-1)很容易从精细化学的供应商获得。
优选实施方式的描述
本发明提供下列实施例更加全面清楚。
实施例1
培美西德制备成40mg/ml的水溶液。一硫代甘油用注射用水制备成2.4mg/ml的溶液。一硫代甘油溶液的pH用氢氧化钠调整至8.5。
保护本体溶液免于光照。向该溶液通入20分钟氮气且随后灭菌过滤。所述的制剂分配在预洗的除热原瓶子且随后用预洗、预灭菌聚四氟乙烯涂层塞子塞住。盖子用卷边机安装。灭菌过滤和分配步骤利用氮隔离气(5％v/v氧)进行。
将填充在瓶内的溶液加热灭菌。
实施例2
除了抗氧剂是0.03％L-半胱氨酸且培美西德的浓度是百分之四(4％)之外，基本上按照实施例1所述方法制备一种药物组合物。
实施例3
除了所述抗氧剂是0.03％巯乙酸盐且培美西德的浓度是百分之四(4％)之外，基本上按照实施例1所述方法制备一种药物组合物。
Claims (20)
1.一种药物组合物，含有：
a)培美西德；
b)至少一种选自下面的抗氧剂：
i)一硫代甘油，
ii)L-半胱氨酸，和
iii)巯乙酸；和
c)药学可接受赋形剂。
2.权利要求1所述的药物组合物，其中该组合物是适合非肠道给药的液体制剂。
3.权利要求1和2任一项所述的药物组合物，其中培美西德是二钠盐。
4.权利要求1-3任一项所述的药物组合物，其中所述的抗氧剂是一硫代甘油。
5.权利要求1-4任一项所述的药物组合物，其中该一硫代甘油的浓度是约1(一)ppm-约8(八)mg/ml。
6.权利要求5的药物组合物，其中该一硫代甘油的浓度是约1(一)mg/ml-约6(六)mg/ml。
7.权利要求6的药物组合物，其中该一硫代甘油的浓度是约1(一)mg/ml-约2.5(二又二分之一)mg/ml。
8.权利要求4的药物组合物，其中所述的一硫代甘油的浓度是约0.5(二分之一)mg/ml-约3(三)mg/ml。
9.权利要求1-3任一项的药物组合物，其中所述的抗氧剂是L-半胱氨酸。
10.权利要求9的药物组合物，其中L-半胱氨酸的浓度是约1(一)ppm-约8(八)mg/ml。
11.权利要求10的药物组合物，其中该L-半胱氨酸的浓度是约1(一)mg/ml-约6(六)mg/ml。
12.权利要求1-3的药物组合物，其中所述的抗氧剂是巯乙酸。
13.权利要求12的药物组合物，其中该巯乙酸浓度是约1(一)ppm-约8(八)mg/ml。
14.权利要求13的药物组合物，其中该巯乙酸的浓度是约0.1(十分之一)mg/ml-约6(六)mg/ml。
15.权利要求4的药物组合物，其中该一硫代甘油的浓度是约0.1(十分之一)mg/ml-约10(十)mg/ml。
16.权利要求1 5的药物组合物，其中该一硫代甘油浓度是约0.1(十分之一)mg/ml-约6(六)mg/ml。
17.权利要求9的药物组合物，其中该L-半胱氨酸是约0.1(十分之一)mg/ml-约10(十)mg/ml。
18.权利要求17的药物组合物，其中该L-半胱氨酸是约0.1(十分之一)mg/ml-约6(六)mg/ml。
19.权利要求12的药物组合物，其中该巯乙酸是约0.1(十分之一)mg/ml-约10(十)mg/ml。
20.权利要求19的药物组合物，其中该巯乙酸是约0.1(十分之一)mg/ml-约6(六)mg/ml。
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| WO2015193517A2 (en) | 2014-10-16 | 2015-12-23 | Synthon B.V. | Liquid pharmaceutical composition comprising pemetrexed |
| KR101770605B1 (ko) * | 2014-11-17 | 2017-08-23 | 동아에스티 주식회사 | 페메트렉시드 또는 그것의 약제학적으로 허용가능 한 염을 함유하는 안정한 약제학적 조성물 |
| KR101919436B1 (ko) * | 2015-05-28 | 2018-11-16 | 주식회사 삼양바이오팜 | 안정화된 약학 조성물 및 그의 제조방법 |
| US20170239250A1 (en) | 2016-02-19 | 2017-08-24 | Eagle Pharmaceuticals, Inc. | Pemetrexed formulations |
| JP2019094284A (ja) * | 2017-11-21 | 2019-06-20 | 日本化薬株式会社 | ペメトレキセドを含有する注射用溶液製剤 |
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| KR0162654B1 (ko) * | 1989-12-11 | 1998-11-16 | 알렌 제이. 시니스갤리 | N-(피롤로[2,3-d]피리미딘-3-일아크릴)-글루타민산 유도체 |
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| CN103340826A (zh) * | 2013-07-05 | 2013-10-09 | 浙江震元制药有限公司 | 美他多辛注射用组合物及其制备方法 |
| CN105611932B (zh) * | 2013-10-03 | 2019-02-12 | 富士胶片株式会社 | 注射液制剂及其制造方法 |
| CN105611932A (zh) * | 2013-10-03 | 2016-05-25 | 富士胶片株式会社 | 注射液制剂及其制造方法 |
| CN106132416A (zh) * | 2014-03-28 | 2016-11-16 | 富士胶片株式会社 | 注射液制剂及其制造方法 |
| CN106132416B (zh) * | 2014-03-28 | 2019-03-26 | 富士胶片株式会社 | 注射液制剂及其制造方法 |
| US10391052B2 (en) | 2014-03-28 | 2019-08-27 | Fujifilm Corporation | Injection preparation and method for producing the same |
| CN108463251A (zh) * | 2015-12-14 | 2018-08-28 | 株式会社钟根堂 | 含有培美曲塞或其药学上可接受的盐的稳定药物组合物 |
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