CN104225601A - Freeze-dry and dry heat treatment protecting agent for human blood coagulation factor VIII - Google Patents
Freeze-dry and dry heat treatment protecting agent for human blood coagulation factor VIII Download PDFInfo
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Abstract
The invention discloses a freeze-drying and dry heat treatment protecting agent for human coagulation factor VIII. The freeze-drying and dry heat treatment protecting agent for human coagulation factor VIII does not contain human serum albumin or other animal-source proteins, sugar or sugar alcohol, is composed of soluble salt, amino acid and a surface active agent, is free from the risk of spreading other viruses or causative agents, and is applicable to a wide crowd range, including diabetics; after being freeze-dried, a product of the human coagulation factor VIII using the protecting agent is quick in redissolving and has a good redissolving effect, still keeps high potency and high specific activity, and has the potency higher than 80 percent and the specific activity higher than 40 IU/mg; in addition, the freeze-drying and dry heat treatment protecting agent for human coagulation factor VIII is low in cost, simple to prepare, has an obvious protecting effect, is safe and effective, and has an excellent industrial application prospect.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent.
Background technology
Hemophilia is a kind of hereditary hemorrhagic disease, is cause human body intravascular coagulation factor level to reduce due to coagulation factor gene sudden change or lack, thus causes hemorrhage.Shortage or the deficiency of thrombin F VIII cause hemophilia A, and shortage or the deficiency of plasma thromboplastin component cause hemophilia B.Thrombin replacement therapy is haemophiliachemophiliac primary treatment measure.
Along with the development of modern chromatographic technique, external blood products enterprise has developed high-purity human blood coagulation goods, meets the demand of hemophiliac.China considers from Viral safety, and national Yao Jian department is not yet Approved by the thrombin import of blood sources.Domestic blood products enterprise is limited to technical capability, and be main mainly with production human albumin and immunoglobulin, the market shares such as blood clotting factors are considerably less, wherein platelet cofactor Ⅰ (control hemophilia) extremely shortage.Therefore researching and developing blood clotting factors blood products new product, carry out new technologies research, will be the trend of the times in blood products field.
Be all raw material with human plasma owing to preparing human blood coagulation factor VII I product, therefore the probability propagating hepatitis B virus, hepatitis C virus, HIV (human immunodeficiency virus) or other virus/pathogen can not be got rid of, therefore the method for inactivation of virus or removal must be comprised in preparation technology's flow process, such as pasteurization, the deactivation of S/D method, 20 nm nano-film filtration method deactivations etc.And blood coagulation factor VIII easy in inactivation; lyophilization or dry heat treatment process easily destroy the protein stability of blood coagulation factor VIII; cause distortion, cause blood coagulation factor VIII inactivation, so certain protective agent or stabilizing agent must be added when blood coagulation factor VIII carries out lyophilization or dry heat treatment.
The blood coagulation factor VIII protective agent of current routine or stabilizing agent mainly use albumin or sugar alcohol; collaborative aminoacid, inorganic salt etc. play a role; introduce human albumin in protective agent disclosed in Chinese invention patent 201110240278.2 and 201210468069.8, Chinese invention patent 201210060299.0 adopts sugar alcohol and combination of amino acids as protective agent.But, not only cost is high to introduce human albumin, and probably there is the risk of other viruses of potential propagation or pathogen in the use of human albumin, and the product using sugar or sugar alcohol to obtain is not suitable for diabetics use, limit the range of application of these goods, these patent goods are after heat treatment inactivation of viruses simultaneously, and tiring of blood coagulation factor VIII declines seriously, blood coagulation activity yield only about 33% after heat treatment, actual application value is little.
Summary of the invention
The object of the invention is to overcome above-mentioned the deficiencies in the prior art, a kind of human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent be provided, not end user's blood albumin or other animal derived protein, also not containing sugar or sugar alcohol.
Above-mentioned purpose of the present invention is achieved by following technical solution:
A kind of human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, comprise sodium citrate 1 ~ 25 mmol/L, sodium chloride 10 ~ 150 mmol/L, calcium chloride 2 ~ 9 mmol/L, glycine 10 ~ 150 mmol/L, arginine 10 ~ 150 mmol/L, histidine 10 ~ 150 mmol/L, lysine 10 ~ 150 mmol/L, surfactant 0.01 ~ 0.25 mmol/L; Described surfactant is nonionic surfactant.
As a kind of preferred version; described human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent are made up of sodium citrate 10 ~ 15 mmol/L, sodium chloride 50 ~ 100 mmol/L, calcium chloride 4 ~ 7 mmol/L, glycine 50 ~ 100 mmol/L, arginine 50 ~ 100 mmol/L, histidine 50 ~ 100 mmol/L, lysine 50 ~ 100 mmol/L, surfactant 0.1 ~ 0.2 mmol/L, and described surfactant is nonionic surfactant.
As the further preferred version of one; described human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent are made up of sodium citrate 13 mmol/L, sodium chloride 80 mmol/L, calcium chloride 6 mmol/L, glycine 80 mmol/L, arginine 80 mmol/L, histidine 80 mmol/L, lysine 80 mmol/L, surfactant 0.15 mmol/L, and described surfactant is nonionic surfactant.
The present invention uses nonionic surfactant; not only can work in coordination with sodium citrate, sodium chloride, calcium chloride, glycine, arginine, histidine, lysine performance protective effect; improve the stability of human blood coagulation factor VII I; the dielectric constant that human blood coagulation factor VII I freeze-dried products is multiple water-soluble can also be reduced; avoid protein component to cause flocculation sediment because of electrically charged, ensure that the quality of last human blood coagulation factor VII I goods.In addition prove by experiment; it is superior that conventional cationic surfactant (as hexadecylpyridinium chloride, hexadecyltrimethylammonium chloride etc.) and anion surfactant (as sodium stearate, sodium lauryl sulphate, sulfosuccinate etc.) are obviously not so good as nonionic surfactant to the protective effect of human blood coagulation factor VII I; cationic surface active agent toxicity is larger simultaneously; anionic surfactant hemolytic activity is comparatively strong, can reduce the quality of human blood coagulation factor VII I product.
Preferably, described nonionic surfactant is Tween class (Polysorbate, tween), Span class (sorbitan fatty acid ester, span), OPEO class, NPE class, MM class or Pluronic class (poloxamer class) surfactant.
Particularly, described nonionic surfactant is Tween 80, polysorbate60, polysorbate40, sorbester p17, sorbester p18, span 20, TritonX-100, Neutronyx 600, Arlacel A etc.
More preferably, described nonionic surfactant is Tween class surfactant, as Tween 80, polysorbate60, polysorbate40 etc.
Most preferably, described surfactant is Tween 80, obtained human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent effect optimum.
As a kind of embodiment, the condition of dry heat treatment of the present invention is 80 DEG C of dry heat treatment 72 h or 100 DEG C dry heat treatment 0.5 h.
Lyophilizing of the present invention is the lyophilization process of this area routine.
The amino acid classes that the present invention selects and consumption proportion unconventional selection, the effect that must simultaneously use the protective agent of the glycine of above-mentioned consumption proportion, arginine, histidine and lysine could realize human blood coagulation factor VII I goods to keep high-titer and high specific acitivity through dry heat treatment inactivation of viruses.
Compared with prior art, the present invention has following beneficial effect:
(1) do not contain human albumin or other animal derived protein, also not containing sugar or sugar alcohol, be made up of soluble-salt, aminoacid and surfactant, there are not the risks propagating other viruses or pathogen, applicable crowd's scope is wide, comprises diabetics.
(2) use the present invention protectant human blood coagulation factor VII I goods after dry heat treatment inactivation of viruses, blood coagulation factor VIII still keeps high-titer and high specific acitivity, tire be greater than labelled amount 80%, specific activity is greater than 40 IU/mg.
(3) redissolve fast after using the lyophilizing of the present invention protectant human blood coagulation factor VII I goods, far below the quality standard of redissolution time 30min, and redissolve effective, the liquid that redissolves clarifies micro-band opalescence.
(4) lyophilizing of the present inventor's blood coagulation factor VIII and dry heat treatment protective agent be not containing human albumin, with low cost, and preparation is simple, and protected effect is obvious, safe and effective, has good prospects for commercial application.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further explained, but embodiments of the present invention is not limited in any way.Unless stated otherwise, involved in embodiment reagent, method are the conventional reagent in this area and method.
embodiment 1
One, human blood coagulation factor VII I solution is prepared
(1) cryoprecipitate and cryoprecipitate dissolving is made
With Fresh Frozen human plasma for raw material, through blood plasma thawing, centrifugal preparation cryoprecipitate, by the physiological saline solution containing 8 IU/ml heparin of cryoprecipitate with 15 ~ 20 DEG C of pre-coolings, the consumption of normal saline is 7 ~ 9 times of Sediment weight, leaves standstill 60 min after stirring and dissolving.
(2) aluminium glue absorption
Lysate after leaving standstill is warming up to 25 ~ 28 DEG C, add the gel aluminum hydroxide of synthermal mass concentration 3%, addition is 40% of cryoprecipitate weight, adopt and stir the lower mode infiltrated and add, namely under 80 ~ 100 rpm mixing speeds, below the liquid level with latex tubing gel aluminum hydroxide being pumped into lysate, interpolation speed is 80 ~ 100 ml/min, be cooled to 15 ~ 20 DEG C after interpolation, the centrifugal remove impurity of 12000 rpm, removes supernatant.
(3) S/D inactivation of virus
Supernatant is warming up to 35 DEG C, and add S/D virus inactivating agent insulation 3h and complete first time inactivation of virus, obtain inactivation of virus liquid, wherein S/D virus inactivating agent contains 1% polysorbate (Tween-80), 0.3% tributyl phosphate (TNBP).
(4) gel filtration chromatography purification
Gel column washing liquid 1 is balanced, inactivation of virus liquid loading gel filtration chromatography, under 280 nm length ultraviolet light detections, wash post 4 times of column volumes by washing liquid 2, with washing liquid 3 eluting blood coagulation factor VIII, and collect.Wherein gel model is DEAE-SAPHROSE FF, and loading and elution flow rate are 220 ~ 250 ml/min, and the formula of washing liquid 1 is 110 mM sodium chloride, 10 mM sodium citrate, 1 mM calcium chloride, 16 mM lysines, 120 mM glycine, pH7.0; The formula of washing liquid 2 is 150 mM sodium chloride, 10 mM sodium citrate, 1 mM calcium chloride, 16 mM lysines, 120 mM glycine, pH7.0; The formula of washing liquid 3 is 250 mM sodium chloride, 10 mM sodium citrate, 1 mM calcium chloride, 16 mM lysines, 120 mM glycine, pH7.0.
(5) ultrafiltration and concentration
The blood coagulation factor VIII of collection is carried out ultrafiltration dealcoholysis and desalination, obtains high concentration and concentrate blood coagulation factor VIII solution, tiring of blood coagulation factor VIII controls at 40 IU/ml.
Two, human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent is prepared
Take all kinds of inorganic salt, aminoacid and surfactant in proportion; adopt common medical used injection water to configure human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, in obtained human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, all kinds of original concentration is as follows: sodium citrate 13 mmol/L, sodium chloride 80 mmol/L, calcium chloride 6 mmol/L, glycine 80 mmol/L, arginine 80 mmol/L, histidine 80 mmol/L, lysine 80 mmol/L, Tween 80 0.15 mmol/L.
Three, human blood coagulation factor VII I lyophilizing and the protectant use of dry heat treatment
Human blood coagulation factor VII I lyophilizing obtained with step 2 for blood coagulation factor VIII solution obtained for step one and dry heat treatment protective agent are mixed according to volume ratio 1:1; tiring of blood coagulation factor VIII is made to control at 20 IU/ml; again mixed solution is dispensed into (10 ml/ bottle) in albumen bottle; lyophilization rear seal-cover; again through 80 DEG C of dry heat treatment inactivation of viruses, obtained human blood coagulation factor VII I finished product.
embodiment 2
One, human blood coagulation factor VII I solution is prepared
With reference to the step one of embodiment 1.
Two, human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent is prepared
Take all kinds of inorganic salt, aminoacid and surfactant in proportion; adopt common medical used injection water to configure human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, in obtained human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, all kinds of original concentration is as follows: sodium citrate 10 mmol/L, sodium chloride 100 mmol/L, calcium chloride 4 mmol/L, glycine 50 mmol/L, arginine 50 mmol/L, histidine 100 mmol/L, lysine 100 mmol/L, Tween 80 0.1 mmol/L.
Three, human blood coagulation factor VII I lyophilizing and the protectant use of dry heat treatment
With reference to the step 3 of embodiment 1.
embodiment 3
One, human blood coagulation factor VII I solution is prepared
With reference to the step one of embodiment 1.
Two, human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent is prepared
Take all kinds of inorganic salt, aminoacid and surfactant in proportion; adopt common medical used injection water to configure human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, in obtained human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, all kinds of original concentration is as follows: sodium citrate 15 mmol/L, sodium chloride 50 mmol/L, calcium chloride 7 mmol/L, glycine 100 mmol/L, arginine 100 mmol/L, histidine 80 mmol/L, lysine 80 mmol/L, Tween 80 0.2 mmol/L.
Three, human blood coagulation factor VII I lyophilizing and the protectant use of dry heat treatment
With reference to the step 3 of embodiment 1.
embodiment 4
Key step is identical with embodiment 1, and distinctive points is, when preparing human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2, Tween 80 is replaced with polysorbate60.
embodiment 5
Key step is identical with embodiment 1, and distinctive points is, when preparing human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2, Tween 80 is replaced with polysorbate40.
embodiment 6
Key step is identical with embodiment 1, and distinctive points is, when preparing human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2, Tween 80 is replaced with sorbester p17.
embodiment 7
Key step is identical with embodiment 1, and distinctive points is, when preparing human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2, Tween 80 is replaced with TritonX-100.
embodiment 8
Key step is identical with embodiment 1, and distinctive points is, when preparing human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2, Tween 80 is replaced with Neutronyx 600.
embodiment 9
Key step is identical with embodiment 1, Tween 80 is replaced with Arlacel A(anhydromannitol monoleate when distinctive points is to prepare human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent in step 2).
comparative example 1
Key step is identical with embodiment 1, and distinctive points is human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent not containing Tween 80 composition.
comparative example 2
Key step is identical with embodiment 1, and distinctive points is that the content of Tween 80 in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent is 0.5 mmol/L.
comparative example 3
Key step is identical with embodiment 1, and distinctive points is in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent not containing glycine.
comparative example 4
Key step is identical with embodiment 1, and distinctive points is in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent not containing arginine.
comparative example 5
Key step is identical with embodiment 1, and distinctive points is in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent not containing histidine.
comparative example 6
Key step is identical with embodiment 1, and distinctive points is in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent not containing lysine.
comparative example 7
Key step is identical with embodiment 1, when distinctive points is that step 2 prepares human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, Tween 80 is replaced with hexadecylpyridinium chloride.
comparative example 8
Key step is identical with embodiment 1, and distinctive points is, in human blood coagulation factor VII I lyophilizing obtained in step 2 and dry heat treatment protective agent, Tween 80 is replaced with sodium lauryl sulphate.
coherent detection
(1) above-described embodiment and comparative example are obtained human blood coagulation factor VII I finished product to test with reference to the detection method of Chinese Pharmacopoeia quality standard, adopt following index to carry out product quality and analyze:
1, product xeothermic after tire.
2, the xeothermic specific activity of product (pharmacopoeial quality standard is >=1.0 IU/mg protein).
3, (it is qualified for meeting States Pharmacopoeia specifications, and it is defective for not meeting States Pharmacopoeia specifications product appearance, visible foreign matters and redissolution time.States Pharmacopoeia specifications: outward appearance should be milky loosening body, after redissolving, solution should be achromaticity and clarification liquid, can be with slight opalescence; Visible foreign matters, except having allowed micro-tiny protein body, all the other should conform with the regulations; The redissolution time answers≤30 min).
Testing result is as shown in the table:
| ? | Tire after xeothermic (%) | Xeothermic specific activity (IU/mg protein) | Outward appearance | Visible foreign matters | The redissolution time (min) |
| Embodiment 1 | 86.6 | 44.41 | Qualified | Qualified | ≤5 |
| Embodiment 2 | 85.9 | 42.12 | Qualified | Qualified | ≤5 |
| Embodiment 3 | 86.2 | 42.19 | Qualified | Qualified | ≤5 |
| Embodiment 4 | 84.5 | 40.03 | Qualified | Qualified | ≤5 |
| Embodiment 5 | 84.1 | 40.01 | Qualified | Qualified | ≤5 |
| Embodiment 6 | 82.7 | 38.35 | Qualified | Qualified | ≤5 |
| Embodiment 7 | 81.8 | 37.69 | Qualified | Qualified | ≤5 |
| Embodiment 8 | 82.2 | 38.81 | Qualified | Qualified | ≤5 |
| Embodiment 9 | 81.6 | 37.23 | Qualified | Qualified | ≤5 |
| Comparative example 1 | 65.2 | 26.05 | Poor | More protein body | ≥30 |
| Comparative example 2 | 72.8 | 29.40 | Qualified | Qualified | ≤5 |
| Comparative example 3 | 73.6 | 29.81 | Qualified | Qualified | ≤5 |
| Comparative example 4 | 74.4 | 30.97 | Qualified | Qualified | ≤5 |
| Comparative example 5 | 75.2 | 30.68 | Qualified | Qualified | ≤5 |
| Comparative example 6 | 75.1 | 31.04 | Qualified | Qualified | ≤5 |
| Comparative example 7 | 67.2 | 27.13 | Poor | More protein body | ≥30 |
| Comparative example 8 | 67.4 | 27.21 | Poor | More protein body | ≥30 |
As can be seen from upper table result, every testing result of embodiment 1 ~ 9 all meets pharmacopoeial quality standard, and comparative example 1 ~ 8, after xeothermic tire and specific activity significantly declines, do not use the outward appearance of the comparative example 1,7 and 8 of nonionic surfactant, visible foreign matters and redissolution time not to reach pharmacopoeial quality standard simultaneously yet, explanation must use nonionic surfactant, glycine, arginine, histidine and lysine simultaneously, and consumption also needs to control could realize beneficial effect of the present invention at particular range.
(2) the detailed examining report result of embodiment 1 human blood coagulation factor VII I finished product is as follows, and this batch of goods are up to the standards:
| inspection item | quality standard | assay |
| discrimination test | only produce precipitation line with AHS or blood plasma, do not produce precipitation line with anti-horse, anti-cattle, anti-pig, anti-sheep blood serum or blood plasma. | qualified |
| outward appearance | should be milky loosening body, after redissolution, should be colourless clear liquid, slight opalescence can be with. | white powder, redissolves and clarifies, micro-band opalescence |
| vacuum | bluish violet aura should be there is | light blue |
| the redissolution time (minute) | ≤ 30 | 5 |
| visible foreign matters | allow micro-tiny protein body | accidental protein body |
| content uniformity | should conform with the regulations | conform with the regulations |
| moisture (%) | ≤ 3.0 | 1.28 |
| pH value | 6.5 ~ 7.5 | 6.95 |
| sodium ion (mmol/L) | ≤ 160 | 142 |
| citric acid ion concentration (mmol/L) | ≤ 25 | 12 |
| tire (%) | ? | 86.6 |
| specific activity (IU/mg protein) | >=1.0 | 44.41 |
| anti-A hemagglutinin | ≤ 1:64 | qualified |
| anti-B hemagglutinin | ≤ 1:64 | qualified |
| hBsAg | negative | negative |
| anti-HIV | negative | negative |
| anti-HCV | negative | negative |
| sterility test | asepsis growth | qualified |
| abnormal toxicity test (Cavia porcellus test, mouse test) | cavia porcellus should be good for and be deposited, and body weight increases; Mice should be good for and be deposited, and body weight increases | qualified |
| pyrogen test | should conform with the regulations | do not examine |
| tributyl phosphate content (μ g/ml) | ≤ 10 | 6.85 |
| polyoxyethylene sorbitan monoleate content (μ g/ml) | ≤ 100 | 20.04 |
| glycine Levels (mg/ bottle) | ≤ 130 | 92.6 |
| calcium ion content (mg/ bottle) | ≤ 9 | 1.30 |
(3) dry heating method deactivation is to the inactivation of virus effect of embodiment 1 ~ 9 human blood coagulation factor VII I finished product
The human blood coagulation factor VII I finished product of Example 1 ~ 9 carries out inactivation of virus effect detection, and result is as follows:
| Indicator virus | PRV(Pseudorabies virus) | Sindbis(sindbis alphavirus) |
| Embodiment 1 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 2 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 3 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 4 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 5 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 6 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 7 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 8 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
| Embodiment 9 inactivating efficacy | >4.5 LogTCID 50/0.1ml | >4.5 LogPFU/ml |
As can be seen from upper table result, the inactivation of virus effect of the human blood coagulation factor VII I finished product of the embodiment of the present invention 1 ~ 9 all can reach state specified standards (States Pharmacopoeia specifications value is for being greater than 4.0 Log).The lyophilizing of the present inventor's blood coagulation factor VIII and dry heat treatment protective agent also can not affect the deactivation of its dry heat treatment to virus while protection quality of item.
Claims (9)
1. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent, it is characterized in that, comprise sodium citrate 1 ~ 25 mmol/L, sodium chloride 10 ~ 150 mmol/L, calcium chloride 2 ~ 9 mmol/L, glycine 10 ~ 150 mmol/L, arginine 10 ~ 150 mmol/L, histidine 10 ~ 150 mmol/L, lysine 10 ~ 150 mmol/L, surfactant 0.01 ~ 0.25 mmol/L; Described surfactant is nonionic surfactant.
2. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to claim 1; it is characterized in that; described human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent are made up of sodium citrate 10 ~ 15 mmol/L, sodium chloride 50 ~ 100 mmol/L, calcium chloride 4 ~ 7 mmol/L, glycine 50 ~ 100 mmol/L, arginine 50 ~ 100 mmol/L, histidine 50 ~ 100 mmol/L, lysine 50 ~ 100 mmol/L, surfactant 0.1 ~ 0.2 mmol/L, and described surfactant is nonionic surfactant.
3. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to claim 2; it is characterized in that; described human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent are made up of sodium citrate 13 mmol/L, sodium chloride 80 mmol/L, calcium chloride 6 mmol/L, glycine 80 mmol/L, arginine 80 mmol/L, histidine 80 mmol/L, lysine 80 mmol/L, surfactant 0.15 mmol/L, and described surfactant is nonionic surfactant.
4. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to any one of claim 1 ~ 3; it is characterized in that, described nonionic surfactant is Tween class, Span class, OPEO class, NPE class, MM class or Pluronic class surfactant.
5. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to any one of claim 1 ~ 3; it is characterized in that, described nonionic surfactant is Tween 80, polysorbate60, polysorbate40, sorbester p17, sorbester p18, span 20, TritonX-100, Neutronyx 600 or Arlacel A.
6. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to claim 4, it is characterized in that, described nonionic surfactant is Tween class surfactant.
7. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to claim 6, it is characterized in that, described Tween class surfactant is Tween 80, polysorbate60 or polysorbate40.
8. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to claim 7, it is characterized in that, described Tween class surfactant is Tween 80.
9. human blood coagulation factor VII I lyophilizing and dry heat treatment protective agent according to any one of claim 1 ~ 3, is characterized in that, the condition of described dry heat treatment is 80 DEG C of dry heat treatment 72 h or 100 DEG C dry heat treatment 0.5 h.
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Cited By (5)
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| CN107337727A (en) * | 2017-08-03 | 2017-11-10 | 国药集团武汉血液制品有限公司 | A kind of haematogenous human blood coagulation factors VIII preparation method |
| CN112138149A (en) * | 2019-06-28 | 2020-12-29 | 北京基科晟斯医药科技有限公司 | Recombinant factor VIII formulations |
| WO2023020914A1 (en) | 2021-08-18 | 2023-02-23 | Biotest Ag | Dry heat treatment of plasma-derived factor viii |
| CN115814099A (en) * | 2022-12-19 | 2023-03-21 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human blood coagulation factor IX, preparation and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105879038A (en) * | 2016-05-27 | 2016-08-24 | 成都蓉生药业有限责任公司 | Dry-heat treatment stabilizer for preparing human prothrombin complex and application of dry-heat treatment stabilizer |
| CN105879038B (en) * | 2016-05-27 | 2020-03-27 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for preparing human prothrombin complex and application thereof |
| CN107337727A (en) * | 2017-08-03 | 2017-11-10 | 国药集团武汉血液制品有限公司 | A kind of haematogenous human blood coagulation factors VIII preparation method |
| CN112138149A (en) * | 2019-06-28 | 2020-12-29 | 北京基科晟斯医药科技有限公司 | Recombinant factor VIII formulations |
| WO2023020914A1 (en) | 2021-08-18 | 2023-02-23 | Biotest Ag | Dry heat treatment of plasma-derived factor viii |
| CN115814099A (en) * | 2022-12-19 | 2023-03-21 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human blood coagulation factor IX, preparation and preparation method thereof |
| CN115814099B (en) * | 2022-12-19 | 2024-04-26 | 成都蓉生药业有限责任公司 | Dry heat treatment stabilizer for human coagulation factor IX, preparation and preparation method thereof |
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