CN1682750A - 注射用三磷酸腺苷二钠固体组合物及其制备方法 - Google Patents
注射用三磷酸腺苷二钠固体组合物及其制备方法 Download PDFInfo
- Publication number
- CN1682750A CN1682750A CN 200510042552 CN200510042552A CN1682750A CN 1682750 A CN1682750 A CN 1682750A CN 200510042552 CN200510042552 CN 200510042552 CN 200510042552 A CN200510042552 A CN 200510042552A CN 1682750 A CN1682750 A CN 1682750A
- Authority
- CN
- China
- Prior art keywords
- adenosine triphosphate
- magnesium chloride
- injection
- disodium salt
- solid composite
- 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.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 38
- 239000007924 injection Substances 0.000 title claims abstract description 38
- TTWYZDPBDWHJOR-IDIVVRGQSA-L adenosine triphosphate disodium Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O TTWYZDPBDWHJOR-IDIVVRGQSA-L 0.000 title claims abstract description 21
- 239000008247 solid mixture Substances 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 title 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims abstract description 61
- 229910001629 magnesium chloride Inorganic materials 0.000 claims abstract description 35
- 239000007787 solid Substances 0.000 claims abstract description 11
- 239000003381 stabilizer Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 150000001413 amino acids Chemical class 0.000 claims abstract description 5
- 150000005846 sugar alcohols Chemical class 0.000 claims abstract description 4
- 229960003001 adenosine triphosphate disodium Drugs 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002131 composite material Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 8
- 229930064664 L-arginine Natural products 0.000 claims description 8
- 235000014852 L-arginine Nutrition 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 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 claims description 7
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- 239000008103 glucose Substances 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 4
- 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 4
- 239000004472 Lysine Substances 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 claims description 3
- 229960001456 adenosine triphosphate Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 239000012982 microporous membrane Substances 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 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 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000006172 buffering agent Substances 0.000 abstract 1
- AHXFKBBDTCBYQA-KWIZKVQNSA-J magnesium disodium [[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl]oxy-oxidophosphoryl] hydrogen phosphate chloride Chemical compound [Cl-].[Mg+2].P([O-])(=O)(OP(=O)([O-])OP(=O)([O-])O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N1C=NC=2C(N)=NC=NC12)O)O.[Na+].[Na+] AHXFKBBDTCBYQA-KWIZKVQNSA-J 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 34
- 239000000047 product Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 238000005286 illumination Methods 0.000 description 5
- 238000005352 clarification Methods 0.000 description 4
- 235000019766 L-Lysine Nutrition 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010021143 Hypoxia Diseases 0.000 description 2
- 239000004201 L-cysteine Substances 0.000 description 2
- 235000013878 L-cysteine Nutrition 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 230000006567 cellular energy metabolism Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 210000003494 hepatocyte Anatomy 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 description 1
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000000474 Poliomyelitis Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000005393 Sodium-Potassium-Exchanging ATPase Human genes 0.000 description 1
- 108010006431 Sodium-Potassium-Exchanging ATPase Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 239000002389 essential drug Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种注射用三磷酸腺苷二钠固体组合物，由三磷酸腺苷二钠、氯化镁、稳定剂糖醇和缓冲剂氨基酸组成，其组成含量为25.0－50.0ωt％三磷酸腺苷二钠，8.0－16.0ωt％氯化镁，0.5－50.0ωt％稳定剂糖醇，0.5－50ωt％缓冲剂氨基酸。其中三磷酸腺苷二钠与氯化镁的重量比为100∶32。该固体组合物稳定性好、溶解度好，临床应用方便，避免了将三磷酸腺苷二钠的注射液与氯化镁注射液直接混合配制容易发生沉淀等不稳定因素，提高了三磷酸腺苷二钠－氯化镁注射液的临床应用水平及安全性。该固体组合物制备工艺简单，适于工业化生产。
Description
技术领域
本发明涉及一种含有三磷酸腺苷二钠的药物组合物，是关于一种三磷酸腺苷二钠注射用制剂的改进技术。
背景技术
三磷酸腺苷二钠氯化镁为高能复合物，可透过各重要脏器的细胞膜，增加组织和细胞内三磷酸腺苷(又称三磷酸腺苷二钠，简称ATP)水平。在缺血缺氧状态下给细胞直接供能，从而改善细胞能量代谢及细胞膜钠泵机制，减轻细胞肿胀，改善微循环障碍，恢复脏器功能。能改善休克所致的大鼠肝细胞膜通透性，有效恢复缺血性肝细胞功能，能改善细胞能量代谢、改善微循环障碍、改善巨噬细胞系统功能。本品能够进入缺血缺氧的心肌细胞线粒体，支持细胞供能，改善细胞内外的钠、钾、镁平衡失调，抑制细胞内Ca2+聚集。本品有一定清除氧自由基的作用，保护细胞，促进功能恢复。主要用于急性黄疸型肝炎、慢性活动型肝炎、缺血性脑血管病后遗症、脑损伤、脑性小儿麻痹、心肌炎等病症的辅助治疗。
目前，三磷酸腺苷二钠和氯化镁它们的原料和注射液已作为中华人民共和国国家的基本药物。市场上供应的三磷酸腺苷二钠氯化镁注射液为三磷酸腺苷二钠(ATP)的注射液(简称A液)与氯化镁的注射液(简称M液)等比例组合包装，肌肉或静脉注射。由于临床上应用三磷酸腺苷二钠和氯化镁注射前需要取三磷酸腺苷二钠的注射液(简称A液)与氯化镁的注射液(简称M液)混合配制，不仅手续繁琐，而且配制应用时不够稳定，容易发生沉淀，存在着严重的隐患，给临床应用带来很大的麻烦和不稳定因素。
发明内容
本发明目的之一是研制一种稳定性好、方便临床使用的三磷酸腺苷二钠注射用制剂。本发明的另一个目的是研制这种注射制剂的制备方法。
本发明的解决方案是：把注射用三磷酸腺苷二钠制备成一种固体组合物。在所说的固体组合物中包含有三磷酸腺苷二钠、氯化镁与稳定剂、缓冲剂等组分，其组分含量以重量百分数计为：25.0-50.0wt％的三磷酸腺苷二钠，8.0-16.0wt％的氯化镁，0.5-50.0wt％稳定剂，0.5-50.0wt％的缓冲剂及4.0wt％以下的水。
在本发明的三磷酸腺苷二钠固体组合物中三磷酸腺苷二钠和氯化镁的优选重量比为100∶32。
本发明中所用的稳定剂为糖醇，它选自甘露醇、山梨醇、葡萄糖、甘露糖、乳糖中的一种或两种以上的混合物均可。优选的为甘露醇，其优选的组分含量为15.0-45.0wt％。
选用的缓冲剂为氨基酸，它选自L-精氨酸、L-半胱氨酸、L-赖氨酸中的一种或两种以上的混合物。其中优选的为L-精氨酸，其优选的组分含量为5.0-35.0wt％。
本发明注射用三磷酸腺苷二钠固体组合物的制备方法是：首先把定量的三磷酸腺苷二钠、氯化镁、稳定剂、缓冲剂等组分，分别用一定体积的注射用水溶解；先将三磷酸腺苷二钠溶液和氯化镁溶液混匀，加入稳定剂，再用氨基酸水溶液的调节pH值为4.5-6.5；加入溶液量0.05％的活性炭吸附，过滤除炭后，再经0.22μm微孔滤膜过滤除菌，分装，冷冻干燥至水分少于4％之后，密封包装，即得本产品。
为表明本发明的进步性，我们对本发明三磷酸腺苷二钠固体组合物进行了稳定性试验，结果见表1、表2和表3。
表1三磷酸腺苷二钠氯化镁稳定性试验结果
| 试验条件 | 时间(天) | 性状 | 酸度 | 溶液澄清度与颜色 | 标示含量％ | |
| ATP | 氯化镁 | |||||
| 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 | |
| 光照4500±500Lx | 5 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.8 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.5 | 99.8 | |
| 高温60℃ | 5 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.4 | 99.7 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.7 | |
| 低温4℃ | 5 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.6 | 99.5 |
| 10 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.1 | 99.6 | |
表2三磷酸腺苷二钠氯化镁40℃加速试验结果
| 批号 | 时间(月) | 性状 | 酸度 | 溶液的澄清度与颜色 | 标示含量(％) | |
| ATP | 氯化镁 | |||||
| 1 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 |
| 3 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.1 | 99.8 | |
| 6 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.6 | |
| 2 | 0 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.0 | 99.4 |
| 3 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.0 | 99.6 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.7 | 99.7 | |
| 3 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.2 | 100.0 |
| 3 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.1 | 99.9 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.3 | 99.9 | |
表3三磷酸腺苷二钠氯化镁室温25℃长期留样试验结果
| 批号 | 时间(月) | 性状 | 酸度 | 溶液的澄清度与颜色 | 标示含量(％) | |
| ATP | 氯化镁 | |||||
| 1 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.4 | 99.9 |
| 3 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.0 | 99.9 | |
| 6 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.7 | |
| 9 | 白色冻干块状物 | 5.8 | 澄清无色 | 100.0 | 99.8 | |
| 12 | 白色冻干块状物 | 5.5 | 澄清无色 | 99.9 | 99.6 | |
| 2 | 0 | 白色冻干块状物 | 5.4 | 澄清无色 | 100.0 | 99.4 |
| 3 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.1 | 99.7 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.8 | 99.8 | |
| 9 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.0 | 99.5 | |
| 12 | 白色冻干块状物 | 5.6 | 澄清无色 | 99.8 | 99.7 | |
| 3 | 0 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.2 | 100.0 |
| 3 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.9 | |
| 6 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.3 | 99.8 | |
| 9 | 白色冻干块状物 | 5.5 | 澄清无色 | 100.0 | 99.8 | |
| 12 | 白色冻干块状物 | 5.6 | 澄清无色 | 100.1 | 99.9 | |
试验结果表明，本品在光照、高温、低温、加速试验、长期放置等条件下表现出很好的稳定性。
对本品进行了安全性试验，包括溶血性、过敏反应及血管刺激性试验。本品供试液对豚鼠的过敏试验表明，本品无过敏反应；溶血性试验结果表明，本品供试液对红细胞不产生溶血和凝集作用；对家兔的刺激试验结果表明，本品供试液几乎无刺激性。
本发明的优点是很明显的：本发明的注射用三磷酸腺苷二钠固体组合物稳定性好、溶解度好，临床应用方便，避免了将三磷酸腺苷二钠的注射液与氯化镁的注射液直接混合配制容易发生沉淀的等不稳定因素带来的严重隐患，提高了三磷酸腺苷二钠-氯化镁注射液的临床应用水平及安全性；本发明的注射用三磷酸腺苷二钠固体组合物制备方法简单，适用于工业化生产。
具体实施方式：
下面再用实施例方式对本发明作进一步说明，给出本发明的实施细节，但并不旨在限定本发明的保护范围。
制备注射用三磷酸腺苷二钠100mg-氯化镁32mg固体组合物
三磷酸腺苷二钠 100g
氯化镁 32g
L-精氨酸 50g
甘露醇 150g
注射用水 2000ml
1000瓶
操作步骤：(1)按处方量称取三磷酸腺苷二钠，加入注射用水60％溶解后，加L-精氨酸80％，搅拌使溶解；(2)称取处方量氯化镁，加入注射用水25％，搅拌使溶解；(3)将两溶液混合均匀。加入甘露醇搅拌至溶解，加剩余L-精氨酸控制pH为4.5~6.5；(4)补加注射用水至处方量；加入溶液量0.05％(g/ml)的药用活性炭，搅拌30分钟，粗滤除炭；(5)用0.22μm微孔滤膜过滤；(6)灌装于西林瓶中；(7)冷冻干燥至水分小于4％；(8)压塞、轧铝盖；(9)全检，包装。
如此制成的注射用三磷酸腺二钠固体组合物，每瓶中含三磷酸腺苷二钠100mg，氯化镁32mg。使用时，用5％葡萄糖注射液稀释至10-50ml，肌肉或静脉注射。
下面再用几个实例进一步说明本发明，见表4
| 实施例组分％ | 1 | 2 | 3 | 4 | 5 | 6 |
| 三磷酸腺苷二钠 | 28.92 | 43.24 | 30.24 | 34.25 | 35.20 | 44.6 |
| 氯化镁 | 9.25 | 13.84 | 9.68 | 10.96 | 11.26 | 14.27 |
| L-精氨酸 | 15.66 | 21.62 | 16.52 | 19.37 | ||
| L-半胱氨酸 | 14.32 | |||||
| L-赖氨酸 | 17.84 | |||||
| 甘露醇 | 43.37 | 18.80 | ||||
| 山梨醇 | 43.76 | |||||
| 葡萄糖 | 33.45 | |||||
| 甘露糖 | 59.56 | |||||
| 乳糖 | 33.92 | |||||
| 水 | 2.8 | 2.5 | 2.0 | 3.5 | 3.1 | 2.2 |
| 性能 三磷酸腺二钠标示含量％ | ||||||
| 高温60℃10天 | 100.1 | 99.9 | 99.7 | 100.1 | 99.7 | 99.6 |
| 40℃6个月 | 99.9 | 99.8 | 99.8 | 99.8 | 99.7 | 99.7 |
| 25℃12个月 | 99.9 | 100.0 | 99.8 | 99.7 | 99.8 | 99.6 |
(续)
| 实施例 | 7 | 8 | 9 | 10 | ||
| 组分％ | ||||||
| 三磷酸腺苷二钠 | 36.54 | 28.89 | 40.25 | 53.22 | ||
| 氯化镁 | 11.69 | 9.24 | 12.88 | 17.03 | ||
| L-精氨酸 | 11.23 | 15.23 | ||||
| L-半胱氨酸 | 7.56 | 7.25 | ||||
| L-赖氨酸 | 5.63 | |||||
| 甘露醇 | 21.73 | 31.58 | ||||
| 山梨醇 | 18.98 | 9.46 | ||||
| 葡萄糖 | 21.71 | |||||
| 甘露糖 | 9.44 | |||||
| 乳糖 | 18.96 | |||||
| 水 | 2.6 | 3.2 | 2.1 | 3.6 | ||
| 性能 三磷酸腺二钠标示含量％ | ||||||
| 高温60℃10天 | 99.8 | 99.7 | 99.6 | 99.7 | ||
| 40℃6个月 | 99.6 | 99.6 | 99.6 | 99.8 | ||
| 25℃12个月 | 99.7 | 99.8 | 99.7 | 99.7 | ||
本配方制备的注射用三磷酸腺苷二钠100mg-氯化镁32mg固体组合物用5％配成的注射液与市售的三磷酸腺苷二钠(ATP)的注射液(A液)与氯化镁的注射液(M液)配制的注射液稳定性比较。结果表明市售的三磷酸腺苷二钠(ATP)的注射液(A液)与氯化镁的注射液(M液)配制的注射液在室温放置6-12小时后往往会发生沉淀等变质现象，而本品在光照、高温、低温、长期放置等条件下表现出很好的稳定性。结果见表5
表5：实施例1得到的本品用5％葡萄糖配制注射液和市售A-M配制注射液光照、高温、低温、长期放置等条件下，观察注射液澄清度试验结果。
样品1：实施例1得到的本品用5％葡萄糖配制的注射液
样品2：市售A-M配制的注射液
| 放置条件 | 1注射液澄清度 | 2注射液澄清度 |
| 40℃6小时 | 澄清 | 浑浊 |
| 25℃24小时 | 澄清 | 浑浊 |
| 光照12小时 | 澄清 | 浑浊 |
| 0℃24小时 | 澄清 | 稍浊 |
Claims (5)
1、一种注射用三磷酸腺苷二钠固体组合物，由三磷酸腺苷二钠及药用载体组成，其特征在于所说的固体组合物中含有三磷酸腺苷二钠氯化镁、稳定剂和缓冲剂，其组份含量，以重量百分数计为：25.0-50.0ωt％的三磷酸腺苷二纳；8.0-16.0ωt％氯化镁，0.5-50.0ωt％稳定剂，它选自糖醇，0.5-50ωt％缓冲剂它选自氨基酸，及4％以下的水。
2、依照权利要求1所述的固体组合物，其特征在于在组合物中三磷酸腺苷二钠和氯化镁的重量比为100∶32。
3、依照权利要求1所述的固体组合物，其特征在于所说稳定剂糖醇，它选自甘露醇、山梨醇、葡萄糖、甘露糖、乳糖中的一种或几种的混合物。
4、依照权利要求1所述的固体组合物，其特征在于所说的缓冲剂氨基酸，它选自L-精氨酸、L半胱氨酸、L赖氨酸中的一种或几种的混合物。
5、依照权利要求1所述的固体组合物的制备方法，其特征在于包括以下主要步骤：
(1)把定量的三磷酸腺苷二钠、氯化镁、稳定剂、缓冲剂分别用适量注射用水溶解；
(2)先将三磷酸腺苷溶液与氯化镁溶液混匀；
(3)加入稳定剂混匀后，用氨基酸溶液调节PH值4.5-6.5；
(4)加入药用活性炭吸附后，过滤除炭；
(5)用0.22μm微孔滤膜过滤除菌；
(6)分装，冷冻干燥至水分小于4％后，密封包装，制造本产品。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510042552XA CN100355426C (zh) | 2005-03-09 | 2005-03-09 | 注射用三磷酸腺苷二钠固体组合物及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200510042552XA CN100355426C (zh) | 2005-03-09 | 2005-03-09 | 注射用三磷酸腺苷二钠固体组合物及其制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1682750A true CN1682750A (zh) | 2005-10-19 |
| CN100355426C CN100355426C (zh) | 2007-12-19 |
Family
ID=35262369
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200510042552XA Expired - Fee Related CN100355426C (zh) | 2005-03-09 | 2005-03-09 | 注射用三磷酸腺苷二钠固体组合物及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100355426C (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102895259A (zh) * | 2012-09-24 | 2013-01-30 | 罗诚 | 一种含三磷酸腺苷二钠氯化镁化合物药物组合物 |
| CN103800364A (zh) * | 2014-01-29 | 2014-05-21 | 卜凡开 | 三磷酸腺苷二钠氯化镁冻干剂 |
| CN107890460A (zh) * | 2017-12-21 | 2018-04-10 | 广州白云山天心制药股份有限公司 | 一种三磷酸腺苷二钠组合物粉针剂 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1234874C (zh) * | 2002-09-26 | 2006-01-04 | 谢斌 | 氨酰基转运核糖核酸合成酶识别型蛋白芯片的制备方法 |
-
2005
- 2005-03-09 CN CNB200510042552XA patent/CN100355426C/zh not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102895259A (zh) * | 2012-09-24 | 2013-01-30 | 罗诚 | 一种含三磷酸腺苷二钠氯化镁化合物药物组合物 |
| CN103800364A (zh) * | 2014-01-29 | 2014-05-21 | 卜凡开 | 三磷酸腺苷二钠氯化镁冻干剂 |
| CN107890460A (zh) * | 2017-12-21 | 2018-04-10 | 广州白云山天心制药股份有限公司 | 一种三磷酸腺苷二钠组合物粉针剂 |
| CN107890460B (zh) * | 2017-12-21 | 2020-07-07 | 广州白云山天心制药股份有限公司 | 一种三磷酸腺苷二钠组合物粉针剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100355426C (zh) | 2007-12-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11083796B2 (en) | Peroxide removal from drug delivery vehicle | |
| CN101439031B (zh) | 一种含18种氨基酸的药物组合物 | |
| JPH0776177B2 (ja) | ギンクゴ・ビロバ葉の抽出物および用途 | |
| CN101933922B (zh) | 一种含抗氧化剂的氨基酸组合物 | |
| CN100355426C (zh) | 注射用三磷酸腺苷二钠固体组合物及其制备方法 | |
| TR201809354T4 (tr) | 5 alfa androstan (alkil) 3 beta,5,6 beta triol enjeksiyonu ve Bunun hazırlanmasına yönelik yöntem. | |
| DE112016001715T5 (de) | Stabile flüssige pharmazeutische Zusammensetzungen von Bortezomib | |
| US8129363B2 (en) | Method for obtaining conjugated estrogen mixtures from pregnant mare urine and use of a macroporous resin in the method | |
| CN103494779B (zh) | 一种注射用炎琥宁粉针制剂及其制备方法 | |
| US5834448A (en) | Dosage form of hydroxocobalamin and its use in cyanide poisoning | |
| CN101791315A (zh) | 复方甘草酸单铵s药物组合物及其大容量注射剂制备方法 | |
| CN1493283A (zh) | 具有良好稳定性的注射用依达拉奉粉针剂及其制备方法 | |
| JP3917820B2 (ja) | オザグレルナトリウム含有注射液およびその安定化方法 | |
| CN102233130B (zh) | 稳定的含有胸腺肽1衍生物的药物制剂 | |
| WO2018102145A1 (en) | Levothyroxine liquid formulations | |
| CN1289094C (zh) | 三磷酸腺苷盐组合物 | |
| RU2313346C2 (ru) | Фармацевтическая композиция | |
| CN104645334B (zh) | N‑乙酰半胱氨酸活性炭组合物及其制备方法和应用 | |
| CN1813674A (zh) | 一种用于静脉给药的维生素c钠制剂及其制备方法 | |
| CN109985011B (zh) | 一种左卡尼汀注射制剂的制备方法 | |
| CN109953949B (zh) | 一种左卡尼汀注射制剂及其制备方法 | |
| CN109381457A (zh) | 一种含14种氨基酸的药物组合物及其制备方法 | |
| CN100497352C (zh) | 甲萘氢醌二磷酸酯钠及其药物制剂 | |
| CN104958255A (zh) | 一种氟马西尼注射液及其制备方法 | |
| CN117045634A (zh) | 一种二肽衍生物组合物及其制备方法和用途 |
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 | ||
| PP01 | Preservation of patent right |
Effective date of registration: 20100325 Granted publication date: 20071219 |
|
| PD01 | Discharge of preservation of patent |
Date of cancellation: 20110325 Granted publication date: 20071219 |
|
| ASS | Succession or assignment of patent right |
Owner name: WANG FAPING Free format text: FORMER OWNER: SHANDONG A+T PHARM CO., LTD. Effective date: 20111018 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20111018 Address after: 250100, No. 1, unit 13, Baihua District, Licheng District, Shandong, Ji'nan 303 Patentee after: Wang Faping Address before: 250100 No. 67 Industrial South Road, Shandong, Ji'nan Patentee before: Aite Medicine Research Co.,Ltd. Shandong |
|
| ASS | Succession or assignment of patent right |
Owner name: BU JUN Free format text: FORMER OWNER: WANG FAPING Effective date: 20140207 |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 250100 JINAN, SHANDONG PROVINCE TO: 262607 WEIFANG, SHANDONG PROVINCE |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140207 Address after: Temple town of Shandong County in Linqu province 262607 Cui Cecun No. 313 Patentee after: Bu Jun Address before: 250100, No. 1, unit 13, Baihua District, Licheng District, Shandong, Ji'nan 303 Patentee before: Wang Faping |
|
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20051019 Assignee: GUANGDONG ZHONGSHENG PHARMACEUTICAL Co.,Ltd. Assignor: Bu Jun Contract record no.: 2015370000203 Denomination of invention: Disodium adenosine triphosphate solid composition for injection and its preparing method Granted publication date: 20071219 License type: Common License Record date: 20151225 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191217 Address after: 250100 North 5th floor, No. 592, Gangxing 1st Road, comprehensive bonded zone, Jinan City, Shandong Province Patentee after: JINAN PANSHI PHARMACEUTICALS TECH. Co.,Ltd. Address before: Temple town of Shandong County in Linqu province 262607 Cui Cecun No. 313 Patentee before: Bu Jun |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20071219 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |