CN113209032B - 注射用门冬氨酸钾镁冻干粉针剂及其制备方法 - Google Patents
注射用门冬氨酸钾镁冻干粉针剂及其制备方法 Download PDFInfo
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- CN113209032B CN113209032B CN202110574594.7A CN202110574594A CN113209032B CN 113209032 B CN113209032 B CN 113209032B CN 202110574594 A CN202110574594 A CN 202110574594A CN 113209032 B CN113209032 B CN 113209032B
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- injection
- potassium
- magnesium aspartate
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- dried powder
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- 238000002347 injection Methods 0.000 title claims abstract description 94
- 239000007924 injection Substances 0.000 title claims abstract description 94
- LVBRFZFUCKKGDJ-HJWRJIQTSA-J magnesium;dipotassium;(2s)-2-aminobutanedioate;hydron Chemical compound [Mg+2].[K+].[K+].OC(=O)[C@@H](N)CC([O-])=O.OC(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC(O)=O.[O-]C(=O)[C@@H](N)CC(O)=O LVBRFZFUCKKGDJ-HJWRJIQTSA-J 0.000 title claims abstract description 61
- 229940111263 potassium magnesium aspartate Drugs 0.000 title claims abstract description 61
- 239000000843 powder Substances 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 39
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims abstract description 35
- 229960005261 aspartic acid Drugs 0.000 claims abstract description 35
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims abstract description 32
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 29
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000000243 solution Substances 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 235000011056 potassium acetate Nutrition 0.000 claims abstract description 16
- YKZPPPNXRZHVGX-PXYKVGKMSA-L dipotassium;(2s)-2-aminobutanedioate;hydron;hydrate Chemical compound [H+].[H+].O.[K+].[K+].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O YKZPPPNXRZHVGX-PXYKVGKMSA-L 0.000 claims abstract description 11
- 238000001914 filtration Methods 0.000 claims abstract description 11
- 229940068988 potassium aspartate Drugs 0.000 claims abstract description 11
- 230000001954 sterilising effect Effects 0.000 claims abstract description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- 229960001983 magnesium aspartate Drugs 0.000 claims abstract description 9
- RXMQCXCANMAVIO-CEOVSRFSSA-L magnesium;(2s)-2-amino-4-hydroxy-4-oxobutanoate Chemical compound [H+].[H+].[Mg+2].[O-]C(=O)[C@@H](N)CC([O-])=O.[O-]C(=O)[C@@H](N)CC([O-])=O RXMQCXCANMAVIO-CEOVSRFSSA-L 0.000 claims abstract description 9
- 239000000395 magnesium oxide Substances 0.000 claims abstract description 8
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims abstract description 8
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims abstract description 8
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004108 freeze drying Methods 0.000 claims abstract description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000008215 water for injection Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims description 38
- 238000010438 heat treatment Methods 0.000 claims description 24
- 238000000859 sublimation Methods 0.000 claims description 20
- 230000008022 sublimation Effects 0.000 claims description 20
- 238000004458 analytical method Methods 0.000 claims description 10
- 239000008176 lyophilized powder Substances 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 238000003795 desorption Methods 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 229940009098 aspartate Drugs 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims 3
- 239000004480 active ingredient Substances 0.000 claims 1
- 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 abstract description 22
- 239000008103 glucose Substances 0.000 abstract description 21
- 239000003814 drug Substances 0.000 abstract description 5
- 229940090044 injection Drugs 0.000 description 69
- 238000000034 method Methods 0.000 description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 5
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000000811 xylitol Substances 0.000 description 4
- 229960002675 xylitol Drugs 0.000 description 4
- 235000010447 xylitol Nutrition 0.000 description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 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 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 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 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- 229940091250 magnesium supplement Drugs 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910001414 potassium ion Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011895 specific detection Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000009777 vacuum freeze-drying Methods 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010061481 Renal injury Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 208000021264 digitalis poisoning Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 208000037806 kidney injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 208000024896 potassium deficiency disease Diseases 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
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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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- 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]
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
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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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
本发明提供一种注射用门冬氨酸钾镁冻干粉针剂及其制备方法,属于药物制备技术领域,所述制备方法是在非活性气体保护下,取注射用水加入赋形剂和L‑门冬氨酸溶解,所得门冬氨酸溶液分成两部分,一部分加入氧化镁制备门冬氨酸镁溶液,另一部分加入乙酸钾和氢氧化钾制备门冬氨酸钾溶液;再将门冬氨酸镁溶液和门冬氨酸钾溶液混匀,调pH值,脱色,除菌过滤,冻干,即得所述注射用门冬氨酸钾镁冻干粉针剂。本发明以乙酸钾代替部分氢氧化钾,同时辅以乙酸/乙酸钾调节pH值,从而抑制其与葡萄糖配伍时发生美拉德反应,提高门冬氨酸利用率,以解决注射用门冬氨酸钾镁冻干粉针剂与葡萄糖配伍使用时发生美拉德反应的问题。
Description
技术领域
本发明涉及无菌粉针剂的制备,尤其涉及一种注射用门冬氨酸钾镁冻干粉针剂及其制备方法。
背景技术
门冬氨酸钾镁是一种电解质补充药,用于治疗低钾血症、洋地黄中毒引起的心律失常(主要是室性心律失常),以及辅助治疗心肌炎后遗症、充血性心力衰竭、心肌梗塞等。
目前,市售的注射用门冬氨酸钾镁在使用过程中主要是与葡萄糖或配伍使用,但使用5%葡萄糖溶解时,门冬氨酸钾镁中所含氨基会与葡萄糖发生羟基氨基化反应,即美拉德反应,从而降低门冬氨酸利用率,加速葡萄糖分解。
公告号为CN1197623C的中国发明专利公开了一种用木糖醇作等渗调节剂的门冬氨酸钾镁输液,是以门冬氨酸、氧化镁、氢氧化钾及木糖醇为原料制备注射液,其中使用木糖醇代替葡萄糖,从而降低美拉德反应的发生,但木糖醇过量使用或过快滴注,可能会引起代谢性酸中毒、肾损伤、大脑功能损伤等严重反应。
发明内容
针对上述问题,本发明提供一种注射用门冬氨酸钾镁冻干粉针剂及其制备方法。
为实现上述目的,本发明所采用的技术方案为:
一种注射用门冬氨酸钾镁冻干粉针剂,以重量份数计,制成所述注射用门冬氨酸钾镁冻干粉针剂的有效成分的原料包括:L-门冬氨酸170份、赋形剂80~100份、氧化镁12~16份、氢氧化钾30~33份及乙酸钾3.0~3.5份。
进一步的,所述赋形剂为甘露醇或丙氨酸。
一种注射用门冬氨酸钾镁冻干粉针剂的制备方法,包括以下步骤:
1)在非活性气体保护下,取注射用水加入赋形剂溶解后,加热至80~95℃,加入L-门冬氨酸溶解,得门冬氨酸溶液;
2)在非活性气体保护下,取步骤1)配置量47~58%的所述门冬氨酸溶液,维持80~95℃,加入氧化镁反应,得门冬氨酸镁溶液;
在非活性气体保护下,取剩余的所述门冬氨酸溶液,依次加入乙酸钾和氢氧化钾反应,得门冬氨酸钾溶液;
3)在非活性气体保护下,取门冬氨酸镁溶液与门冬氨酸钾溶液混匀,调节pH值,脱色,除菌过滤,冻干,即得所述注射用门冬氨酸钾镁冻干粉针剂。
进一步的,所述pH值调节至5.2~7.0。
进一步的,所述调节pH值的pH值调节剂为乙酸或乙酸钾。
进一步的,所述冻干包括预冻、升华干燥和解析干燥;
其中,所述预冻是于-45~-40℃预冻4~6h;
所述升华干燥包括依次进行的以下步骤:
以1~2℃/h升温至-31~-29℃经第一次升华干燥1~2h;
以1~2℃/h升温至-21~-20℃经第二次升华干燥1~2h;
以1~2℃/h升温至-11~-9℃经第三次升华干燥1~2h;
以1~2℃/h升温至-5~0℃经第四次升华干燥10~20h;
所述解析干燥包括依次进行的以下步骤:
以1~2℃/h升温至10~15℃经第一次解析干燥1~2h;
以1~2℃/h升温至25~30℃经第二次解析干燥1~3h;
以1~2℃/h升温至40~50℃经第三次解析干燥2~7h。
进一步的,所述升华干燥的压力为10~20Pa;所述解析干燥的压力为10~20Pa。
进一步的,所述除菌过滤是先使用0.22μm一次除菌滤器过滤,再使用0.22μm二次终端除菌过滤。
进一步的,所述注射用门冬氨酸钾镁冻干粉针剂还需进行无菌分装。
本发明的注射用门冬氨酸钾镁冻干粉针剂及其制备方法的有益效果为:
通过实验研究发现,在pH值为5.2~7.0时,能够有效抑制门冬氨酸钾镁与配伍的葡萄糖发生美拉德反应;本发明以乙酸钾代替部分氢氧化钾,同时辅以乙酸/乙酸钾调节pH值,其中所含乙酸根对pH值能够起到一定的缓冲作用,维持注射用门冬氨酸钾镁冻干粉针剂的pH值稳定性,在与葡萄糖配伍使用时,能够抑制注射用门冬氨酸钾镁冻干粉针剂中所含氨基与葡萄糖发生美拉德反应,提高门冬氨酸利用率;
本发明中的乙酸根还能够抑制L-门冬氨酸转化为R-门冬氨酸,同时也能够抑制门冬氨酸钾镁中的杂质产生;
本发明以甘露醇/丙氨酸作为赋形剂,在保证制备的注射用门冬氨酸钾镁冻干粉针的饱满性和疏松状的情况下,降低了美拉德反应发生的可能性;
进一步的,制备过程中始终使用非活性气体保护,能够降低门冬氨酸在制备过程中与空气接触而发生氧化作用;
本发明选用合适的工艺条件,采用冻干法制备注射用门冬氨酸钾镁冻干粉针剂,所得产品稳定性好、杂质含量少,安全性高,复溶性优良,利于长期储存。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述。在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
实施例1一种注射用门冬氨酸钾镁冻干粉针剂的制备方法
本实施例为一种注射用门冬氨酸钾镁冻干粉针剂的制备方法,具体制备过程包括以下步骤:
1)取注射用水煮沸备用;
在氮气保护下,取1kg甘露醇加至3L注射用水中,搅拌至完全溶解,加热至85℃(加热后的温度标记为T1),加入1.7kg门冬氨酸,维持85℃,搅拌至完全溶解,得门冬氨酸溶液;
2)制备门冬氨酸镁溶液:在氮气保护下,取步骤1)配置量50%的门冬氨酸溶液,维持85℃,加入0.14kg氧化镁,85℃搅拌进行中和反应(中和反应的温度标记为T2;需要注意的是,T2不应低于80℃),得门冬氨酸镁溶液;
制备门冬氨酸钾溶液:在氮气保护下,取剩余的50%门冬氨酸溶液,依次加入30.6g乙酸钾和0.310kg的氢氧化钾,搅拌至完全溶解,得门冬氨酸钾溶液;需要注意的是,制备门冬氨酸钾的过程中,无需维持80℃以上。
3)在氮气保护下,取门冬氨酸镁溶液和门冬氨酸钾溶液混合,搅拌至充分混匀后,使用少量1mol/L的乙酸钾水溶液调节pH值至6.5,再加入20g药用活性炭,室温搅拌脱色30min,过滤,滤液经0.22μm一次除菌滤器过滤,再经0.22μm二次终端除菌过滤,有效去除细菌微生物,所得无菌药液移入预冷好的冻干机中进行真空冷冻干燥,真空冷冻干燥分为预冻、升华干燥和解析干燥;
预冻:先将冻干机箱内制品降温至-40℃,维持-40℃预冻5h;
升华干燥:抽真空使箱内压力为10Pa,以1.2℃/h升温至-30℃,进行第一次升华干燥2h;
保持箱内压力为10Pa,以1.2℃/h升温至-20℃,进行第二次升华干燥1.5h;
保持箱内压力为10Pa,以1.2℃/h升温至-10℃,进行第三次升华干燥1.5h;
保持箱内压力为10Pa,以1.2℃/h升温至0℃,进行第四次升华干燥15h;
解析干燥:保持箱内压力为10Pa,以1.2℃/h升温至10℃,进行第一次解析干燥2h;
保持箱内压力为10Pa,以1.2℃/h升温至25℃,进行第二次解析干燥2h;
保持箱内压力为10Pa,以1.2℃/h升温至40℃,进行第三次解析干燥5h。
干燥完成后,经检验合格进行无菌分装【规格:每瓶含门冬氨酸1.7g、钾0.228g、镁0.0084g)】,即得注射用门冬氨酸钾镁冻干粉针剂。
本实施例中的氮气也可使用其它惰性气体代替,比如氩气、二氧化碳等,但考虑到生产成本,一般都使用氮气。
实施例2~6注射用门冬氨酸钾镁冻干粉针剂的制备方法
实施例2~6分别为一种注射用门冬氨酸钾镁冻干粉针剂的制备方法,它们的步骤与实施例1基本相同,不同之处仅在于原料用量及工艺参数的不同,具体详见表1:
表1实施例2~6中各项工艺参数一览表
实施例2~6其它部分的内容,与实施例1相同。
实施例1~6制备的注射用门冬氨酸钾镁冻干粉针剂稳定性好、主药含量高、杂质少,复溶性优良。
实验例1注射用门冬氨酸钾镁冻干粉针剂的性能测试
对比例1~5为实施例1中注射用门冬氨酸钾镁冻干粉针剂【规格:每瓶含门冬氨酸1.7g】的制备过程的对比试验,区别仅在于:
对比例1中pH值调节为4.5;
对比例2中pH值调节为7.5,由于乙酸钾无法调节pH值至7.5,需要辅以氢氧化钾进行调节;
对比例3中赋形剂为乳糖;
对比例4中不添加乙酸钾,但添加0.328kg氢氧化钾,并以氢氧化钾或盐酸调节pH值;
对比例5中T1和T2温度均为70℃,步骤1)中门冬氨酸溶解速度降低,有极少量门冬氨酸不溶,步骤2)中氧化镁反应缓慢,且无法反应完全,因此不再进行冻干,制备粉针剂,后续也不再进行美拉德实验和稳定性试验。
A1)美拉德试验
注射用门冬氨酸钾镁冻干粉针剂在与葡萄糖配伍后放置过程中,葡萄糖含量和门冬氨酸含量的降低,能够说明葡萄糖与门冬氨酸发生了美拉德反应。本次试验将放置试验延长,以更好的验证美拉德反应进行程度。
取实施例1~6和对比例1~4中制得的注射用门冬氨酸钾镁冻干粉针剂及市售的注射用门冬氨酸钾镁冻干粉针剂,分别加至500mL的5%葡萄糖中溶解,观察其溶解速度,溶解后于室温下放置48h,期间分别于第1、3、6、12、24和48h取样,并与0h数据比较。
分别按照《中国药典》(2015版第二部)葡萄糖注射液中规定的葡萄糖含量测定方法和《HPLC法测定门冬氨酸钾镁注射液中门冬氨酸的含量》(安徽医药,2014年第8期)中规定的检测方法对葡萄糖和门冬氨酸进行检测,具体检测结果见下表:
表2美拉德试验检测结果一览表
由表2可以看出,本发明实施例1~6制得的注射用门冬氨酸钾镁冻干粉针剂在与葡萄糖配伍放置过程中,葡萄糖和门冬氨酸的含量均未出现明显降低;而对比例1~4制得的注射用门冬氨酸钾镁冻干粉针剂及市售的注射用门冬氨酸钾镁冻干粉针剂在与葡萄糖配伍放置过程中,葡萄糖和门冬氨酸的含量均有明显降低;同时还可以看出对比例3中,使用乳糖作为赋形剂,乳糖可与门冬氨酸发生美拉德反应,其在使用前即存在门冬氨酸含量降低的现象。上述实验说明,本发明制备的注射用门冬氨酸钾镁冻干粉针剂,能够有效抑制其中所含氨基与葡萄糖发生美拉德反应,提高门冬氨酸的利用率。
表2中还可以看出,本发明制备的注射用门冬氨酸钾镁冻干粉针剂具有良好的复溶性。
A2)稳定性试验
取实施例1~6和对比例1~4中制得的注射用门冬氨酸钾镁冻干粉针剂,分别于40±2℃、RH75±5%的条件下放置6个月,期间于第1、2、3和6个月取样,并与0天数据比较。
观察不同时间段的注射用门冬氨酸钾镁冻干粉针剂性状,并按照《HPLC法测定门冬氨酸钾镁注射液中门冬氨酸的含量》(安徽医药,2014年第8期)中规定的检测方法、《离子色谱法测定门冬氨酸钾镁注射液中钾、镁和钠离子含量》【中国医院药学杂志,2016(036)024】中规定的检测方法和《HPLC法测定门冬氨酸钾镁注射液中门冬氨酸有关物质及含量》(药物分析杂志2018年)检测注射用门冬氨酸钾镁冻干粉针剂中门冬氨酸、钾离子、镁离子及有关物质的含量,具体检测结果见下表:
表3稳定性检测结果一览表
由表3可以看出,本发明制备的注射用门冬氨酸钾镁冻干粉针剂具有良好的稳定性,且杂质含量较少,说明本发明的工艺参数更利于注射用门冬氨酸钾镁冻干粉针剂的制备和储存。
显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
Claims (5)
1.一种注射用门冬氨酸钾镁冻干粉针剂,其特征在于,以重量份数计,制成所述注射用门冬氨酸钾镁冻干粉针剂的有效成分的原料包括:L-门冬氨酸170份、赋形剂80~100份、氧化镁12~16份、氢氧化钾30~33份及乙酸钾3.0~3.5份;
所述赋形剂为甘露醇或丙氨酸;
所述注射用门冬氨酸钾镁冻干粉针剂的制备方法包括以下步骤:
1)在非活性气体保护下,取注射用水加入赋形剂溶解后,加热至80~95℃,加入L-门冬氨酸溶解,得门冬氨酸溶液;
2)在非活性气体保护下,取步骤1)配置量47~58%的所述门冬氨酸溶液,维持80~95℃,加入氧化镁反应,得门冬氨酸镁溶液;
在非活性气体保护下,取剩余的所述门冬氨酸溶液,依次加入乙酸钾和氢氧化钾反应,得门冬氨酸钾溶液;
3)在非活性气体保护下,取门冬氨酸镁溶液与门冬氨酸钾溶液混匀,调节pH值,脱色,除菌过滤,冻干,即得所述注射用门冬氨酸钾镁冻干粉针剂;
所述pH值调节至5.2~7.0;
所述调节pH值的pH值调节剂为乙酸或乙酸钾。
2.根据权利要求1所述的注射用门冬氨酸钾镁冻干粉针剂,其特征在于,所述制备方法中冻干包括预冻、升华干燥和解析干燥;
其中,所述预冻是于-45~-40℃预冻4~6h;
所述升华干燥包括依次进行的以下步骤:
以1~2℃/h升温至-31~-29℃经第一次升华干燥1~2h;
以1~2℃/h升温至-21~-20℃经第二次升华干燥1~2h;
以1~2℃/h升温至-11~-9℃经第三次升华干燥1~2h;
以1~2℃/h升温至-5~0℃经第四次升华干燥10~20h;
所述解析干燥包括依次进行的以下步骤:
以1~2℃/h升温至10~15℃经第一次解析干燥1~2h;
以1~2℃/h升温至25~30℃经第二次解析干燥1~3h;
以1~2℃/h升温至40~50℃经第三次解析干燥2~7h。
3.根据权利要求2所述的注射用门冬氨酸钾镁冻干粉针剂,其特征在于,所述制备方法中升华干燥的压力为10~20Pa;所述解析干燥的压力为10~20Pa。
4.根据权利要求1或3所述的注射用门冬氨酸钾镁冻干粉针剂,其特征在于,所述制备方法中除菌过滤是先使用0.22μm一次除菌滤器过滤,再使用0.22μm二次终端除菌过滤。
5.根据权利要求1或3所述的注射用门冬氨酸钾镁冻干粉针剂,其特征在于,所述制备方法中注射用门冬氨酸钾镁冻干粉针剂还需进行无菌分装。
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