CN1399560A - 新的无白蛋白的因子ⅷ制剂 - Google Patents
新的无白蛋白的因子ⅷ制剂 Download PDFInfo
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- CN1399560A CN1399560A CN00806304A CN00806304A CN1399560A CN 1399560 A CN1399560 A CN 1399560A CN 00806304 A CN00806304 A CN 00806304A CN 00806304 A CN00806304 A CN 00806304A CN 1399560 A CN1399560 A CN 1399560A
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- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940027029 hemofil Drugs 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000019136 lipoic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960005337 lysine hydrochloride Drugs 0.000 description 1
- 229910001425 magnesium ion Inorganic materials 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 229940047431 recombinate Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004153 renaturation Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- IREPZTZSVPKCAR-WCCKRBBISA-M sodium;(2s)-2-amino-4-methylsulfanylbutanoate Chemical compound [Na+].CSCC[C@H](N)C([O-])=O IREPZTZSVPKCAR-WCCKRBBISA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007655 standard test method Methods 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
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- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
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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
- A61K47/02—Inorganic compounds
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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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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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
- A61K47/16—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K47/16—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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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- 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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- Peptides Or Proteins (AREA)
Abstract
Description
Tris | 三-(羟甲基)-氨基甲烷 |
BIS-Tris丙烷 | 1,3-双-[三-(羟基-甲基)-甲氨基]-丙烷 |
PIPES | 哌嗪-N,N’-双-(2-乙磺酸) |
MOPS | 3-(N-吗啉代)丙磺酸 |
HEPES | N-2-羟乙基-哌嗪-N’-2-乙磺酸 |
MES | 2-(N-吗啉代)乙磺酸 |
ACES | N-2-乙酰氨基-2-氨基乙磺酸 |
N-乙酰基-L-半胱氨酸/高半胱氨酸 |
谷胱甘肽 |
6-羟基-2,5,7,8-四甲基色满-2-羧酸(Trolox) |
硫辛酸 |
甲硫氨酸 |
硫代硫酸钠 |
铂 |
甘氨酸-甘氨酸-组氨酸(三肽) |
丁化羟基甲苯(BHT) |
样品代码 | 起始因子VIII(IU/ml) | 蔗糖% |
IAIBIC | 6006060 | --2 |
冷冻/工艺方法 | 说明 |
I(冷冻) | 冷却至+5℃;以1℃/分钟速度冷却至-5℃,保持20分钟;以1℃/分钟速度冷却至-20±5℃,保持1小时(最多3小时);以0.5℃/分钟速度冷却至-45℃,保持1小时; |
II | 一次方法I的冷冻(Freeze per method I)于-35℃下保持48小时; |
III | 一次方法I的冷冻于-35℃下保持48小时;于-20℃下保持48小时; |
IV(冷冻-干燥) | 在首次冷冻约55小时(最多100小时)期间支架温度-32℃;在初次干燥期间产品温度<-40℃;以0.2℃/分钟速度由-32℃上升至+40℃;在二次干燥3小时期间支架温度为+40℃ |
制备方法 | 各步骤中失去的因子VIII活性% | ||
制剂IA(600IU/ml) | 制剂IB(60IU/ml) | 制剂IC(60IU/ml,2%蔗糖) | |
I | 6.7 | 37.5 | 41.7 |
II | 2.0 | 9.3 | 3.9 |
III | 7.3 | 11.6 | 5.0 |
IV(冻干) | 20.0 | 24.2 | 18.3 |
冷冻方法 | 说明 |
I | 冷却至+5℃;以0.5-1℃/分钟的速率冷却至-5℃,保持20分钟;以0.5-1℃/分钟的速率冷却至-55℃和-45℃之间,保持约1小时;以0.5-1℃/分钟的速率升温至-22℃(±5℃),保持1至3小时;以0.5-1℃/分钟的速率冷却至-45℃,保持约1小时。 |
加工步骤 | 温度 | 步骤时程 |
初次冷冻 | -40℃或更低 | 1小时 |
首次退火 | -23℃至-27℃之间 | 3小时 |
再次冷冻 | -55℃ | 1小时 |
再次退火 | -36℃ | 4小时 |
第三次冷冻 | -50℃ | 1小时 |
加工步骤 | 温度 | 步骤时程 |
首次干燥 | -35℃ | 最多100小时 |
二次干燥:第一步 | 40℃ | 3小时 |
二次干燥:第二步 | 45℃ | 3小时 |
二次干燥:第三步 | 50℃ | 3小时 |
样品代码 | 填充剂 | 蛋白稳定剂 |
123456789101112 | 8%甘露醇8%甘露醇8%甘露醇8%甘露醇8%甘露醇8%甘露醇8%甘露醇4%羟乙基淀粉8%甘氨酸8%甘氨酸400mM NaCl8%丙氨酸 | 2%蔗糖2%海藻糖2%棉子糖2%精氨酸2%赖氨酸2%山梨糖醇2%甘油2%蔗糖2%蔗糖2%海藻糖2%蔗糖2%蔗糖 |
样品代码 | Tpe(℃) | Te(℃) | Tg(℃) | 重配时间(秒) | 含水量(%) | 外观 |
123456789101112 | -14-20-15--n/c------ | -10-15-10--n/c------ | 545354--<10℃*<10℃*86546366- | 646277--63-4922181157 | n/c1.41.7--0.6-0.70.8-0.40.5 | 精致顶部部分坍塌精致部分坍塌坍塌精致精致精致但从侧面收缩精致精致精致(铺于底层)精致 |
制剂说明 | 温度(℃) | 以月计的初始百分比% | ||||
0 | 0.5 | 1 | 2 | 3 | ||
甘氨酸:蔗糖 | -70 | 100.00 | 97.43 | 101.71 | 99.89 | 97.97 |
25 | 100.00 | 85.44 | ||||
40 | 100.00 | 79.87 | 71.52 | 63.06 | ||
50 | 100.00 | 76.34 | 67.99 | 52.14 | 67.64 | |
甘氨酸:海藻糖 | -70 | 100.00 | 89.22 | 96.00 | 95.90 | 94.64 |
25 | 100.00 | 83.71 | ||||
40 | 100.00 | 79.93 | 72.42 | 68.03 | ||
50 | 100.00 | 80.97 | 64.28 | 57.60 | 50.92 | |
甘露醇:海藻糖 | -70 | 100.00 | 91.32 | 97.72 | 96.10 | 98.26 |
25 | 100.00 | 85.79 | ||||
40 | 100.00 | 82.54 | 70.72 | 59.44 | ||
50 | 100.00 | 66.16 | 65.51 | 48.81 | 52.06 | |
甘露醇:蔗糖 | -70 | 100.00 | 100.45 | 100.56 | 105.47 | 99.22 |
25 | 100.00 | 87.04 | ||||
40 | 100.00 | 85.59 | 80.78 | 55.42 | ||
50 | 100.00 | 81.68 | 75.53 | 57.88 | 43.46 | |
甘露醇:精氨酸 | -70 | 100.00 | 102.26 | 105.53 | 103.72 | 105.08 |
25 | 100.00 | 95.15 | ||||
40 | 100.00 | 91.53 | 80.93 | 69.19 | ||
50 | 100.00 | 82.28 | 68.06 | 56.32 | 45.94 | |
甘露醇:棉子糖 | -70 | 100.00 | 93.88 | 98.41 | 100.68 | 103.62 |
25 | 100.00 | 83.13 | ||||
40 | 100.00 | 81.09 | 73.61 | 67.16 | ||
50 | 100.00 | 71.69 | 68.52 | 54.25 | 47.11 | |
甘露醇:甘油 | -70 | |||||
25 | ||||||
40 | ||||||
50 | ||||||
甘露醇:山梨糖醇 | -70 | 100.00 | 104.06 | |||
25 | 100.00 | |||||
40 | 100.00 | |||||
50 | 100.00 | 32.73 | ||||
HES:蔗糖 | -70 | 100.00 | 102.74 | 103.03 | 100.90 | |
25 | 100.00 | |||||
40 | 100.00 | 76.89 | 77.47 | |||
50 | 100.00 | 71.47 | 67.40 | 30.02 | ||
NaCl:蔗糖 | -70 | 100.00 | 88.54 | 88.44 | 95.58 | |
25 | 100.00 | |||||
40 | 100.00 | 71.56 | 58.30 | |||
50 | 100.00 | 52.71 | 37.90 | 30.34 | ||
丙氨酸:蔗糖 | -70 | 100.00 | 109.78 | 109.67 | 108.96 | |
25 | 100.00 | |||||
40 | 100.00 | 92.99 | 73.03 | |||
50 | 100.00 | 83.25 | 74.91 | 57.65 | ||
甘氨酸:棉子糖 | -70 | 100.00 | 111.57 | 114.51 | 105.25 | |
25 | 100.00 | |||||
40 | 100.00 | 89.20 | 82.10 | |||
50 | 100.00 | 93.21 | 72.22 | 53.24 |
赋形剂 | 浓度 |
甘露醇或甘氨酸 | 6-9% |
精氨酸或海藻糖 | 1-3% |
吐温-80 | 0.005-0.04% |
NaCl | 200-250mM |
CaCl2 | 3-5mM |
TRIS | 20-30mM |
组氨酸或HEPES | 10-50mM |
谷胱甘肽 | 0.15-0.25mg/ml |
制剂#1 | 制剂#2 | 制剂#3 |
10mM HEPES20mM Tris225mM NaCl0.03%(v/v)吐温-808%(w/v)甘露醇2%(w/v)海藻糖0.2mg/ml还原性谷胱甘肽4mM CaCl2 | 10mM HEPES20mM Tris225mM NaCl0.03%(v/v)吐温-808%(w/v)甘氨酸2%(w/v)海藻糖0.2mg/ml还原性谷胱甘肽4mM CaCl2 | 10mM HEPES20mM Tris225mM NaCl0.03%(v/v)吐温-808%(w/v)甘露醇2%(w/v)精氨酸0.2mg/ml还原性谷胱甘肽4mM CaCl2 |
制剂#4 | 制剂#5 |
25mM组氨酸20mM Tris225mM NaCl0.03%(v/v)吐温-808%(w/v)甘露醇2%(w/v)海藻糖0.2mg/ml还原性谷胱甘肽4mM CaCl2 | 25mM组氨酸20mM Tris225mM NaCl0.03%(v/v)吐温-808%(w/v)甘氨酸2%(w/v)海藻糖0.2mg/ml还原性谷胱甘肽4mM CaCl2 |
Claims (35)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US25527999A | 1999-02-22 | 1999-02-22 | |
US09/255279 | 1999-02-22 | ||
US45275299A | 1999-12-01 | 1999-12-01 | |
US09/452752 | 1999-12-01 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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CN2009101711245A Division CN101683522B (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
CN200910171121A Division CN101810854A (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子viii制剂 |
Publications (2)
Publication Number | Publication Date |
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CN1399560A true CN1399560A (zh) | 2003-02-26 |
CN100553678C CN100553678C (zh) | 2009-10-28 |
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Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
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CN200910171121A Pending CN101810854A (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子viii制剂 |
CNB008063044A Expired - Lifetime CN100553678C (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
CN2009101711245A Expired - Lifetime CN101683522B (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
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CN200910171121A Pending CN101810854A (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子viii制剂 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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CN2009101711245A Expired - Lifetime CN101683522B (zh) | 1999-02-22 | 2000-02-22 | 新的无白蛋白的因子ⅷ制剂 |
Country Status (19)
Country | Link |
---|---|
US (8) | US6586573B1 (zh) |
EP (5) | EP1154796B1 (zh) |
JP (9) | JP5149470B2 (zh) |
CN (3) | CN101810854A (zh) |
AT (1) | ATE365052T1 (zh) |
AU (1) | AU777972B2 (zh) |
BR (1) | BR0008405B1 (zh) |
CA (4) | CA2362927C (zh) |
CY (2) | CY1108030T1 (zh) |
CZ (3) | CZ307715B6 (zh) |
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CN110381962A (zh) * | 2016-12-21 | 2019-10-25 | 孙崇谨 | 用于血浆蛋白的活性保存的新颖方法 |
WO2018112780A1 (en) * | 2016-12-21 | 2018-06-28 | Chung Chin Sun | Novel method for blood plasma protein activity preservation |
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CN112121009A (zh) * | 2020-09-24 | 2020-12-25 | 科兴生物制药股份有限公司 | 一种聚乙二醇修饰重组人粒细胞刺激因子新制剂 |
CN112121009B (zh) * | 2020-09-24 | 2022-12-02 | 科兴生物制药股份有限公司 | 一种聚乙二醇修饰重组人粒细胞刺激因子新制剂 |
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