CN1523037A - Method of eliminating endotoxin from interferon preparation - Google Patents
Method of eliminating endotoxin from interferon preparation Download PDFInfo
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- CN1523037A CN1523037A CNA031110363A CN03111036A CN1523037A CN 1523037 A CN1523037 A CN 1523037A CN A031110363 A CNA031110363 A CN A031110363A CN 03111036 A CN03111036 A CN 03111036A CN 1523037 A CN1523037 A CN 1523037A
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- 102000014150 Interferons Human genes 0.000 title claims abstract description 38
- 108010050904 Interferons Proteins 0.000 title claims abstract description 38
- 229940079322 interferon Drugs 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000002158 endotoxin Substances 0.000 title abstract description 11
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 229920001661 Chitosan Polymers 0.000 claims abstract description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 9
- SYECJBOWSGTPLU-UHFFFAOYSA-N hexane-1,1-diamine Chemical compound CCCCCC(N)N SYECJBOWSGTPLU-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- 230000003068 static effect Effects 0.000 claims abstract description 5
- 238000001179 sorption measurement Methods 0.000 claims abstract description 4
- 239000012528 membrane Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 18
- 238000009472 formulation Methods 0.000 claims description 16
- 231100000284 endotoxic Toxicity 0.000 claims description 14
- 230000002346 endotoxic effect Effects 0.000 claims description 14
- 230000003834 intracellular effect Effects 0.000 claims description 13
- 239000003053 toxin Substances 0.000 claims description 13
- 231100000765 toxin Toxicity 0.000 claims description 13
- 229960003964 deoxycholic acid Drugs 0.000 claims description 7
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 claims description 7
- 239000000835 fiber Substances 0.000 claims description 3
- 229920000936 Agarose Polymers 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
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- 239000011324 bead Substances 0.000 claims description 2
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- 239000002245 particle Substances 0.000 claims description 2
- 229920001282 polysaccharide Polymers 0.000 claims description 2
- 239000005017 polysaccharide Substances 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 13
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 abstract description 8
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 abstract description 8
- 238000011084 recovery Methods 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- FHHPUSMSKHSNKW-SMOYURAASA-M sodium deoxycholate Chemical compound [Na+].C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 FHHPUSMSKHSNKW-SMOYURAASA-M 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 15
- 241000283973 Oryctolagus cuniculus Species 0.000 description 9
- 238000004900 laundering Methods 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000004913 activation Effects 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 3
- 240000002853 Nelumbo nucifera Species 0.000 description 3
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- 230000005611 electricity Effects 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 238000011013 endotoxin removal Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002523 gelfiltration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 239000012506 Sephacryl® Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- -1 alkyl diamines Chemical class 0.000 description 1
- JSAIENUMNDAGTD-UHFFFAOYSA-N benzene ethene styrene Chemical compound C1=CC=CC=C1.C=C.C=C.C=CC1=CC=CC=C1 JSAIENUMNDAGTD-UHFFFAOYSA-N 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
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- 125000003700 epoxy group Chemical group 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The present invention relates to a production of recombinant protein medicine, in the concrete, it relates to a method for removing endotoxin from interferon preparation. It is characterized by that the chitosan or desoxycholate sodium or hexanediamine is used as affinity ligand, and can be covalently combined on the porous medium, then a dynamic filtration or static adsorption mode can be used to make operation so as to remove endotoxin from interferon preparation, in which the quantity of affinity ligand on the porous medium is 0.02%-3% nitrogen content. Said invention is high in endotoxin removing rate, high in interferon activity recovery and good in specificity.
Description
Technical field
The present invention relates to the production of recombinant protein drug, specifically a kind ofly from interferon formulation, remove endotoxic method.
Background technology
Increasingly mature along with genetic engineering technique, increasing recombinant protein drug is exploited, owing to relate to Gram-negative bacteria and separation and purification process complexity in the production process, therefore can cause endotoxic pollution.
Affine technology is the effective means of separation and purification biomacromolecule, mainly utilizes the affinity interaction principle between aglucon and the biomacromolecule; Aglucon is just obtained affinity media by covalent bonding to porous medium, can be used for optionally adsorbing intracellular toxin, realize from recombinant protein solution, removing endotoxic target; Existing affinity ligand and affinity media comprise: monoclonal antibody, polyclonal antibody, microbiotic, PXB, polymine, Histidine, gel-filtration column, affinity membrane, granule adsorbent etc.
Because the recombinant protein kind is more, its purification procedures has nothing in common with each other, and in the production process wherein endotoxin content is required also variantly, therefore removes endotoxic method and effect can't be general fully.Korean Patent (KR8902068) adopts gel-filtration column Sephacryl S-200, and the intracellular toxin and the Interferon, rabbit that utilize the molecular sieve principle to come isolated molecule to vary in size are to remove the intracellular toxin in the Interferon, rabbit; But flow velocity is low, is 4ml/hr, needs to add other material such as Triton X-100 in the process.European patent (EP0800862) adopts and contains sulfonic styrene diethylene benzene copoly mer, utilizes the principle of ion-exchange, removes the intracellular toxin in recombinant protein tumour necrosis factor or the interleukin, mainly adsorbs recombinant protein.European patent (EP0337243) uses placed in-line two reversed-phase liquid chromatography posts, comes the purification of Recombinant human IL-2, in the purification of Recombinant human interleukin-2, removes intracellular toxin impurity, and flow velocity is low, the medium costliness.United States Patent (USP) (US4885168) adopts low-molecular weight chitoglycan, utilizes amino positively charged on the chitosan to come and electronegative nucleic acid and intracellular toxin effect, reach and remove nucleic acid and endotoxic purpose, but the utilization ratio of chitosan is low.A kind of hydrophobic lotus positive electricity affinity membrane that is used for endotoxin removal of Chinese patent (00123290.6) Wei Guilin etc. is bonded to the hydrophobic lotus positive electricity of amine affinity ligand on the cellulose membrane, obtains corresponding affinity membrane; The hydrophobic lotus positive electricity of amine affinity ligand comprise 2～12 carbon the alkyl diamines, have vinyl unsaturated heterocyclic compound, have the quaternary ammonium salt of epoxide group and have the quaternary ammonium salt of a plurality of hydrophobic groupings; It is mainly used in endotoxic removal in the water.D.Petsch, (1997, B.693 Journal of Chromatography 79-91) adopts sodium deoxycholate to T.C.Beeskow etc., or hexanediamine is medium as affinity ligand with the micropore nylon membrane, makes affinity membrane; Adopt individual affinity membrane, can remove the intracellular toxin in damping fluid or the bovine serum albumin; But flow velocity is low, the resistance height, and treatment capacity is few, is difficult for amplifying.
At the intracellular toxin in the interferon formulation production process, need be according to the content and the kind of other material in the scope of its molecular weight size, iso-electric point, the solution, judge and select the kind and the affinity media of affinity ligand, reach and remove intracellular toxin, reduce the purpose of interferon activity loss as far as possible again.The method of prior art can not satisfy the demand that interferon formulation is produced.
Summary of the invention
The objective of the invention is to, provide a kind of flow velocity higher, treatment capacity is big, meets the endotoxic method of removal from interferon formulation of production requirement.
For achieving the above object, the technical solution used in the present invention is: with chitosan, or sodium deoxycholate, or hexanediamine is as affinity ligand, be covalently bound on the porous medium, mode with dynamic filtration or Static Adsorption (or static immersing) is operated, in order to remove the intracellular toxin in the recombinant interferon preparation; Wherein the amount of affinity ligand on porous medium is: nitrogen content 0.02%～3%.
Described porous medium is to contain polyhydric polysaccharide medium, as Mierocrystalline cellulose, dextran or agarose; Or contain polyhydric synthetic medium, as polyvinyl alcohol; The pH of recombinant interferon solution is pH3.5～6.0; With the chitosan is affinity ligand, and the molecular weight ranges of chitosan is 10,000～1,000,000; The pattern of described porous medium is flat sheet membrane, hollow-fibre membrane, bead or particle; The flow velocity of described dynamic filtration recombinant interferon solution is 1～20ml/min; The operational condition of Static Adsorption be 4 ℃ to room temperature, left standstill 2～24 hours.
The present invention has following advantage:
1. the inventive method endotoxin removal rate height, interferon activity rate of recovery height.The endotoxin concns that filters back solution is reduced to＜10EU/ml from＞80EU/ml, and the activity of Interferon, rabbit (tiring) rate of recovery is 90%.
2. specificity of the present invention good (the recombinant interferon concentration difference of processing, or active difference) is fit to the requirement of producing.Filter back solution endotoxin concns (＜10EU/ml) meet the pharmacopeia production requirement.
3. usage range of the present invention is wide, and prospect is good.Can remove the endotoxin contaminants that contains in the interferon formulation production, solve its product quality problem, reach the production requirement of pharmacopeia regulation; Also be expected to be applied to the production process of other recombinant protein drug, remove in the bio-pharmaceutical objectionable impuritiess such as intracellular toxin, improve the drug manufacture level of China; Create high economic benefit.
Generally speaking, flow velocity height, the surface-area that affine embrane method had both combined film is big, the aperture is even, the little advantage of diffusion radius between liquid and the aglucon, combine affine method highly selective, high efficiency advantage again, affinity membrane is prepared into corresponding remover, realizes easily amplifying to satisfy the needs of drug manufacture.Therefore, the employing affinity membrane removes the intracellular toxin in the interferon formulation, and flow height, good, the effective constituent rate of recovery height of removal effect are better than the post affinity chromatography.
Embodiment
Embodiment 1.
Preparation is the affinity membrane of aglucon with the chitosan:
Get 50 diameters and be 47 millimeters cellulose membrane, rinse well with big water gaging, place the beaker of a 200ml, add NaOH and the 0.19gNaBH4 of 40ml epoxy chloropropane, 120ml 1M, mix, standing over night under the room temperature activates; Get the film after the activation next day, to neutral, drain, add 150ml 1% chitosan (molecular weight 350,000) solution (preparation of 1% acetum) then, in spend the night under 60 ℃ (more than 16 hours) with massive laundering; Get the film after the activation next day, to neutral, drain with massive laundering, add 100ml0.25% sodium borohydride solution (preparation of 0.1M pH8.5 phosphoric acid buffer) then, reduction reaction is 4 hours under the room temperature, gets the film after the reduction,, drain and dry to neutral with massive laundering.The nitrogen content of this affinity membrane is 0.02%.
With the chitosan is the effect of the affinity membrane of aglucon:
10 affinity membranes are made corresponding separator, filter interferon formulation 200ml (the Interferon, rabbit 91406IU/ml that tires with the flow velocity of 9ml/min, pH value of solution 3.5), the endotoxin concns that filters back solution is reduced to＜10EU/ml from＞80EU/ml, and the activity of Interferon, rabbit (tiring) rate of recovery is 90%.
Embodiment 2.
Preparation is the affinity membrane of aglucon with the hexanediamine:
Get 320 diameters and be 47 millimeters cellulose membrane, rinse well with big water gaging, place the beaker of a 1000ml, add in 650 milliliters of oxidation liquid (containing 2%NaIO4), 30 ℃ of baking ovens spend the night and activate; Next day, get the film after the activation,, drain to neutral with massive laundering, add 800ml1% hexanediamine (preparation of 0.1M pH=7 phosphoric acid buffer) then, 30 ℃ of baking ovens spend the night, and carry out crosslinking reaction; Get the film after crosslinked next day,, drain to neutral with massive laundering, add 800ml 0.6%NaBH4 (preparation of 0.1MpH=9 phosphoric acid buffer) and reduce, 30 ℃ of baking ovens spend the night.Extremely neutral with massive laundering again, drain and dry.The nitrogen content of this affinity membrane is 2.2%.
With the hexanediamine is the effect of the affinity membrane of aglucon:
10 affinity membranes are made corresponding separator, filter interferon formulation 225ml (the Interferon, rabbit 93976IU/ml that tires with the flow velocity of 18ml/min, pH value of solution 4.2), the endotoxin concns that filters back solution is reduced to＜10EU/ml from＞80EU/ml, and the activity of Interferon, rabbit (tiring) rate of recovery is 88%.
Embodiment 3.
Preparation is the affinity membrane of aglucon with the sodium deoxycholate:
Get 50 diameters and be 47 millimeters cellulose membrane, rinse well with big water gaging, place the beaker of a 200ml, add NaOH and the 0.19 gram NaBH4 of 40ml epoxy chloropropane, 120ml 1M, mix, standing over night under the room temperature activates; Get the film after the activation next day, to neutral, drain, add 125ml 1% hexanediamine solution (preparation of 1%pH9 phosphoric acid buffer) then, in spend the night under 60 ℃ (more than 16 hours) with massive laundering; Get film next day,, drain to neutral with massive laundering, add the MES damping fluid of 125ml 0.1M pH6.0 then, add 2.5 gram sodium deoxycholate, 1.25 gram EDC again, mixing spends the night under the room temperature.Get the film after crosslinked, to neutral, drain and dry with massive laundering.Promptly be able to the affinity membrane that sodium deoxycholate is an aglucon.
With the sodium deoxycholate is the effect of the affinity membrane of aglucon:
10 affinity membranes are made corresponding separator, filter interferon formulation 200ml (the Interferon, rabbit 91406IU/ml that tires with the flow velocity of 9ml/min, pH value of solution 6), the endotoxin concns that filters back solution is reduced to＜40EU/ml from＞80EU/ml, and the activity of Interferon, rabbit (tiring) rate of recovery is 70%.
Claims (6)
1. from interferon formulation, remove endotoxic method for one kind, it is characterized in that: with chitosan, or sodium deoxycholate, or hexanediamine is as affinity ligand, be covalently bound on the porous medium, mode with dynamic filtration or Static Adsorption is operated, in order to remove the intracellular toxin in the recombinant interferon preparation; Wherein the amount of affinity ligand on porous medium is nitrogen content 0.02%～3%.
2. remove endotoxic method according to claim 1 is described from interferon formulation, it is characterized in that: described porous medium is to contain polyhydric polysaccharide media fibers element, dextran or agarose; Or contain polyhydric synthetic medium polyvinyl alcohol.
3. remove endotoxic method according to claim 1 is described from interferon formulation, it is characterized in that: the pH of recombinant interferon solution is pH3.5～6.0.
4. remove endotoxic method according to claim 1 is described from interferon formulation, it is characterized in that: be affinity ligand with the chitosan, the molecular weight ranges of chitosan is 10,000～1,000,000.
5. remove endotoxic method according to claim 1 is described from interferon formulation, it is characterized in that: the pattern of porous medium is flat sheet membrane, hollow-fibre membrane, bead or particle.
6. according to the described a kind of endotoxic method of removing from interferon formulation of claim 1, it is characterized in that: the flow velocity of described dynamic filtration recombinant interferon solution is 1～20ml/min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031110363A CN1324048C (en) | 2003-02-21 | 2003-02-21 | Method of eliminating endotoxin from interferon preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031110363A CN1324048C (en) | 2003-02-21 | 2003-02-21 | Method of eliminating endotoxin from interferon preparation |
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| Publication Number | Publication Date |
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| CN1523037A true CN1523037A (en) | 2004-08-25 |
| CN1324048C CN1324048C (en) | 2007-07-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB031110363A Expired - Lifetime CN1324048C (en) | 2003-02-21 | 2003-02-21 | Method of eliminating endotoxin from interferon preparation |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298468B (en) * | 2007-04-30 | 2011-06-01 | 齐鲁制药有限公司 | Method for removing endotoxin from protein medicine in one step |
| CN115739031A (en) * | 2021-09-02 | 2023-03-07 | 中国科学院理化技术研究所 | Application of chitosan or derivatives thereof in removing endotoxin in gelatin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1093428C (en) * | 1997-03-26 | 2002-10-30 | 中国科学院大连化学物理研究所 | Chemical modification of microporous nylon film and preparation of affinity film with histidine ligand |
-
2003
- 2003-02-21 CN CNB031110363A patent/CN1324048C/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101298468B (en) * | 2007-04-30 | 2011-06-01 | 齐鲁制药有限公司 | Method for removing endotoxin from protein medicine in one step |
| CN115739031A (en) * | 2021-09-02 | 2023-03-07 | 中国科学院理化技术研究所 | Application of chitosan or derivatives thereof in removing endotoxin in gelatin |
| CN115739031B (en) * | 2021-09-02 | 2024-05-28 | 中国科学院理化技术研究所 | Application of chitosan or derivatives thereof in removal of endotoxin in gelatin |
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| Publication number | Publication date |
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| CN1324048C (en) | 2007-07-04 |
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Effective date of registration: 20090320 Address after: Building 3, building 6, Jingdong street, Beijing economic and Technological Development Zone, postcode: 100176 Co-patentee after: BEIJING KAWIN BIOTECHNOLOGY Co.,Ltd. Patentee after: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. Address before: Building 3, building 6, Jingdong street, Beijing economic and Technological Development Zone, postcode: 100176 Patentee before: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. |
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Address after: 3 building, No. 6, Jingdong street, Yizhuang economic and Technological Development Zone, Beijing 100176, China Patentee after: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. Patentee after: Beijing Furui Tiancheng Biotechnology Co.,Ltd. Address before: 3 building, No. 6, Jingdong street, Beijing economic and Technological Development Zone, 100176 Patentee before: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. Patentee before: BEIJING KAWIN BIOTECHNOLOGY Co.,Ltd. |
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Effective date of registration: 20150211 Address after: 3 building, No. 6, Jingdong street, Yizhuang economic and Technological Development Zone, Beijing 100176, China Patentee after: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. Address before: 3 building, No. 6, Jingdong street, Yizhuang economic and Technological Development Zone, Beijing 100176, China Patentee before: BEIJING KAWIN TECHNOLOGY SHARE-HOLDING Co.,Ltd. Patentee before: Beijing Furui Tiancheng Biotechnology Co.,Ltd. |
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Granted publication date: 20070704 |
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