JP5597490B2 - 注射用含糖酸化鉄製剤 - Google Patents
注射用含糖酸化鉄製剤 Download PDFInfo
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- JP5597490B2 JP5597490B2 JP2010196214A JP2010196214A JP5597490B2 JP 5597490 B2 JP5597490 B2 JP 5597490B2 JP 2010196214 A JP2010196214 A JP 2010196214A JP 2010196214 A JP2010196214 A JP 2010196214A JP 5597490 B2 JP5597490 B2 JP 5597490B2
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- Japan
- Prior art keywords
- sugar
- iron oxide
- containing iron
- injection
- preparation
- 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.)
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 title claims description 73
- 238000002360 preparation method Methods 0.000 title claims description 69
- 238000002347 injection Methods 0.000 title claims description 48
- 239000007924 injection Substances 0.000 title claims description 48
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 44
- 239000002245 particle Substances 0.000 claims description 25
- 229910052742 iron Inorganic materials 0.000 claims description 22
- 229930006000 Sucrose Natural products 0.000 claims description 16
- 239000005720 sucrose Substances 0.000 claims description 16
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 15
- 239000004475 Arginine Substances 0.000 claims description 12
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 12
- 229940071643 prefilled syringe Drugs 0.000 claims description 9
- 239000000084 colloidal system Substances 0.000 claims description 7
- 229960005191 ferric oxide Drugs 0.000 description 60
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 59
- 229940090044 injection Drugs 0.000 description 43
- 238000009472 formulation Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 235000009697 arginine Nutrition 0.000 description 11
- 238000003860 storage Methods 0.000 description 11
- 239000012895 dilution Substances 0.000 description 10
- 238000010790 dilution Methods 0.000 description 10
- 238000004519 manufacturing process Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 230000002776 aggregation Effects 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 4
- 238000001246 colloidal dispersion Methods 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000003139 buffering effect Effects 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- -1 iron ions Chemical class 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 description 2
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000002296 dynamic light scattering Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004887 ferric hydroxide Drugs 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- IEECXTSVVFWGSE-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide Chemical compound [OH-].[O-2].[Fe+3] IEECXTSVVFWGSE-UHFFFAOYSA-M 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 230000009469 supplementation Effects 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- FWZTTZUKDVJDCM-CEJAUHOTSA-M disodium;(2r,3r,4s,5s,6r)-2-[(2s,3s,4s,5r)-3,4-dihydroxy-2,5-bis(hydroxymethyl)oxolan-2-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol;iron(3+);oxygen(2-);hydroxide;trihydrate Chemical compound O.O.O.[OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[O-2].[Na+].[Na+].[Fe+3].[Fe+3].[Fe+3].[Fe+3].[Fe+3].O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 FWZTTZUKDVJDCM-CEJAUHOTSA-M 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229940082629 iron antianemic preparations Drugs 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 125000000185 sucrose group Chemical group 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 235000019605 sweet taste sensations Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Description
2%(w/v)の鉄に相当する含糖酸化鉄のコロイド分散液(フェジン(登録商標)静注40mg、日医工株式会社製)に適量の水を加えた。次いで、最終濃度0.25%(w/v)になるようにアルギニン(特級、和光純薬工業株式会社製)を添加し、さらに最終濃度10%(w/v)になるようにスクロース(日本薬局方、和光純薬工業株式会社製)を添加した。その後、液のpHを塩酸を用いて10に調整し、さらに水を加えて、0.2%(w/v)の鉄に相当する含糖酸化鉄を含む注射用含糖酸化鉄製剤(製剤1)を製造した。各成分の含有割合(最終濃度)は、表1に示すとおりである。
最終濃度0.5%(w/v)になるようにアルギニンを添加したこと以外は実施例1と同様にして、各成分の最終濃度が表1に示すとおりとなるように注射用含糖酸化鉄製剤(製剤2)を製造した。
最終濃度15%(w/v)になるようにスクロースを添加したこと以外は実施例1と同様にして、各成分の最終濃度が表1に示すとおりとなるように注射用含糖酸化鉄製剤(製剤3)を製造した。
最終濃度20%(w/v)になるようにスクロースを添加したこと以外は実施例1と同様にして、各成分の最終濃度が表1に示すとおりとなるように注射用含糖酸化鉄製剤(製剤4)を製造した。
アルギニンを添加しなかったことおよび液のpHを塩酸を用いて10に調整しなかったこと以外は実施例1と同様にして、各成分の含有割合(最終濃度)が表1に示すとおりとなるように注射用含糖酸化鉄製剤(製剤a)を製造した。製剤aのpHの初期値は9.86であった。
最終濃度4%(w/v)になるようにスクロースを添加したこと以外は実施例1と同様にして、各成分の最終濃度が表1に示すとおりとなるように注射用含糖酸化鉄製剤(製剤b)を製造した。
上記実施例1、2および比較例1で製造した注射用含糖酸化鉄製剤(それぞれ製剤1、2およびa)を、製剤製造後すぐにネジ蓋付きポリプロピレン製試験管に収容して密封し、60℃または40℃の恒温器に入れて保存した。保存中の製剤のpHの経時変化を、pHメーター(堀場製作所社製)を用いて測定した。60℃における結果を表2に、40℃における結果を表3にそれぞれ示す。表中の「経過期間」は、製造日を起算日とした経過日数または経過月数を示す。
実施例2〜4および比較例2で製造した注射用含糖酸化鉄製剤(それぞれ製剤2〜4およびb)を、製剤製造後すぐにポリプロピレン製プレフィルドシリンジに収容して密封し、40℃の恒温器に入れて保存した。保存中の製剤中のコロイド粒子の平均粒子径の経時変化を、動的光散乱式粒径分布測定装置LB−550(堀場製作所社製)を用いて測定した。結果を表4に示す。表中の「経過期間」は、製造日を起算日とした経過日数または経過月数を示す。
Claims (4)
- 0.2〜0.4%(w/v)の鉄に相当する含糖酸化鉄、0.25〜0.5%(w/v)のアルギニン、および10〜20%(w/v)のスクロースを含有する、注射用含糖酸化鉄製剤。
- 前記含糖酸化鉄がコロイドであって、該コロイドの平均粒子径が10〜1000nmである、請求項1に記載の注射用含糖酸化鉄製剤。
- pHが9〜10である、請求項1または2に記載の注射用含糖酸化鉄製剤。
- 請求項1から3のいずれかの項に記載の注射用含糖酸化鉄製剤を含むプレフィルドシリンジ製剤。
Priority Applications (1)
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JP2010196214A JP5597490B2 (ja) | 2010-09-01 | 2010-09-01 | 注射用含糖酸化鉄製剤 |
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JP2010196214A JP5597490B2 (ja) | 2010-09-01 | 2010-09-01 | 注射用含糖酸化鉄製剤 |
Publications (2)
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JP2012051841A JP2012051841A (ja) | 2012-03-15 |
JP5597490B2 true JP5597490B2 (ja) | 2014-10-01 |
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Families Citing this family (2)
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CN103059072B (zh) * | 2013-01-18 | 2015-08-26 | 常州工程职业技术学院 | 一种绿色环保的蔗糖铁原料药的制备方法 |
CN103340827B (zh) * | 2013-07-16 | 2014-12-10 | 成都天台山制药有限公司 | 蔗糖铁注射液及其制法 |
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