CN104826117B - Storage stabilizing agent for human serum immunoglobulin solution preparation - Google Patents
Storage stabilizing agent for human serum immunoglobulin solution preparation Download PDFInfo
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- CN104826117B CN104826117B CN201510221517.8A CN201510221517A CN104826117B CN 104826117 B CN104826117 B CN 104826117B CN 201510221517 A CN201510221517 A CN 201510221517A CN 104826117 B CN104826117 B CN 104826117B
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- human serum
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- 108060003951 Immunoglobulin Proteins 0.000 title claims abstract description 37
- 102000018358 immunoglobulin Human genes 0.000 title claims abstract description 37
- 238000003860 storage Methods 0.000 title claims abstract description 25
- 239000003381 stabilizer Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 210000002966 serum Anatomy 0.000 title claims abstract description 10
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 8
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims abstract description 7
- 150000001413 amino acids Chemical class 0.000 claims abstract description 6
- 239000003223 protective agent Substances 0.000 claims abstract description 6
- 108010024636 Glutathione Proteins 0.000 claims abstract description 5
- 229960003180 glutathione Drugs 0.000 claims abstract description 5
- 239000004471 Glycine Substances 0.000 claims abstract description 4
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims abstract description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims abstract description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims abstract description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims abstract description 3
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims abstract description 3
- 239000000243 solution Substances 0.000 claims description 17
- 239000003186 pharmaceutical solution Substances 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 238000006116 polymerization reaction Methods 0.000 abstract description 4
- 235000018417 cysteine Nutrition 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 150000001945 cysteines Chemical class 0.000 abstract 1
- 239000000523 sample Substances 0.000 description 12
- 239000000178 monomer Substances 0.000 description 9
- 239000000539 dimer Substances 0.000 description 8
- 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 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000013068 control sample Substances 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940072221 immunoglobulins Drugs 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000000108 ultra-filtration Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000008100 Human Serum Albumin Human genes 0.000 description 3
- 108091006905 Human Serum Albumin Proteins 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000006395 Globulins Human genes 0.000 description 2
- 108010044091 Globulins Proteins 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal cation Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000013011 aqueous formulation Substances 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical class [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention discloses a kind of stabilizer that human serum immunoglobulin solution preparation is reduced or avoided and polymerize in storage process; containing L cysteines or its hydrochloride, one or more of mercapto-protective agents of glutathione, its concentration it is 3-20mmol/L in immunoglobulin solution preparation；One or more of sugared stabilizers containing maltose or trehalose, its concentration are 150-600mmol/L；And one or more of amino acid stabilizers containing proline or its salt, glycine or its salt, serine or its salt, its concentration is 12-150mmol/L, by adding stabilizer, immunoglobulin can be reduced because of high temperature, high concentration or storage time is longer and the polymerization that occurs, improve the validity of medicine.
Description
Technical field
The present invention relates to medicated premix, the storage of human serum immunoglobulin solution preparation specifically used for intravenous injection
Deposit the stabilizer used.
Background technology
Human serum immunoglobulin（IgG）Preparation is mainly used in primary and Secondary cases immunoglobulin deficiency, with
And other autoimmune diseases, such as primary thrombocytopenic purpura, Kawasaki disease.
IgG is to purify to obtain from human plasma, and it after B cell and thick liquid cell contact antigen by producing, and its molecular weight is about
For 150KDa, it is made up of four peptide chains, two identical light chains（L）And heavy chain（H）It is covalently attached to by two disulfide bond,
In addition, a Y type dimer symmetrically is formed with non-covalent.Light chain is made up of two homeodomains, weight
Chain is made up of four homeodomains, and these domains are characterized in including 2 beta sheet structures, including 3 to 5 anti-phase parallel
Beta chain, Stability Analysis of Structures is maintained by a disulfide bond.These domains are to thermo-responsive, and its secondary structure can under room temperature storage
Change, result in polymer, immunoglobulin preparation storage process polymer is continuously increased, and drug effect gradually reduces, and leads to
After crossing intravenous injection, polymer can also produce side effect.
CN103282042A discloses a kind of with histidine and the stable storing under faintly acid to neutral pH immune ball
Albumen aqueous formulation, including immunoglobulin, the histidine from 50mM to 500mM, the alkali metal cation from 0mM to 10mM,
And from 5.5 to 7.0 pH, immunoglobulin can be made stable under faintly acid to neutrallty condition.But high temperature, high concentration or
When storage time is longer, immunoglobulin extent of polymerization is still higher.
The content of the invention
Human serum immunoglobulin solution preparation can be reduced or avoided it is an object of the invention to provide one kind to store
The stabilizer of Cheng Fasheng polymerizations, by adding stabilizer, can reduce immunoglobulin because high temperature, high concentration or storage time are longer
And the polymerization occurred, improve the validity of medicine.
The storage stabilizing agent of the present invention is to contain Cys or its hydrochloride, paddy Guang in immunoglobulin solution preparation
One or more of mercapto-protective agents of sweet peptide, its concentration are 3-20mmol/L；One kind containing maltose or trehalose or with
On sugared stabilizer, its concentration is 150-600mmol/L；And contain proline or its salt, glycine or its salt, serine
Or one or more of amino acid stabilizers of its salt, its concentration are 12-150mmol/L.
Preferably, the molar concentration of mercapto-protective agent is 4-8mmol/L, the molar concentration of sugared stabilizer for 250-
400mmol/L, the molar concentration of amino acid stabilizers is 20-80mmol/L.
The pH value of immunoglobulin solution preparation is preferably 4-6.
Mercapto-protective agent used herein can protect immune globulin intramolecular disulfide bond, maintain its three-level and level Four knot
Structure, sugared stabilizer are used for the secondary structure stabilization for protecting β-pleated sheet in immunoglobulin molecules, and amino acid stabilizers can promote to be immunized
Uniform separation between globulin molecule, stablizes its native conformation.Thus immunoglobulin solution preparation can be avoided or reduce in length
Phase storage process further polymerize, and improves storage stability, and formulation storage is immunized after 2 years in room temperature and the following environment of room temperature
Globulin poly aggressiveness is less than 1%, and for formulation storage after 2 years, immunoglobulin polymer is less than 2% in 37 DEG C of environment.
Embodiment
Embodiment 1
Learn from else's experience the human serum chromatography of immunoglobulins solution after inactivation of virus（Purity 99.2%, concentration 0.37mmol/L）,
The immunoglobulin solution for being configured to that concentration is 10wt% is concentrated by ultrafiltration, takes 1L samples, addition glucose to 230mmol/L, regulation
PH to 4.1 is used as blank control sample, separately takes 3L, addition glutathione to 6mmol/L, maltose to 300mmol/L, proline
To 50mmol/L, pH to 4.1 is adjusted, is divided into sample 1, sample 2,3 each 1L of sample.Product is big to molecule under the conditions of room temperature storage
Small distribution is investigated.
Molecular size distribution is checked using high performance liquid chromatography：With hydrophilic silica gels Efficient numerical method post
（SEC, exclusion limit 300kD, 10 μm of granularity）, column diameter 7.5mm, long 60cm；With containing 1% isopropanol, pH value 7.0,0.2mol/L
Phosphate buffer（Take 0.5mol/L sodium dihydrogen phosphate 200ml, 0.5mol/L disodium hydrogen phosphates 420ml, isopropanol 15.5ml and
Water 914.5ml is uniformly mixed）For mobile phase；Detection wavelength is 280nm；Flow velocity is 0.6ml per minute；Every 1ml is taken to contain egg respectively
White matter is 12mg each 20 μ l of immunoglobulin, human serum albumin solution, is injected separately into chromatographic column, records chromatogram, and ball is immunized
The separation at protein control monomer peak and cracking body peak should be greater than 1.5, point of human serum albumin reference substance monomer peak and dimer peak
1.5 are should be greater than from degree, tailing factor is calculated by human serum albumin monomer peak and should be 0.95-1.40.Calculated by area normalization method,
Monomer adds the content at dimer peak in chromatogram, and as immunoglobulin monomer adds dimer content.
Measure immunoglobulin monomer adds dimer content when storing 3,6,9,12 and 24 months, as a result such as following table.
Embodiment 2
Learn from else's experience the human serum chromatography of immunoglobulins solution after inactivation of virus（Purity 99.5%, concentration 0.25mmol/L）,
The immunoglobulin solution for being configured to that concentration is 10wt% is concentrated by ultrafiltration, takes 1L samples, addition glucose to 220mmol/L, regulation
PH to 3.85 is used as blank control sample, separately takes 3L, addition cysteine to 4mmol/L, maltose to 500mmol/L, sweet ammonia
Acid adjusts pH to 3.85, respectively sample 1, sample 2, sample 3 to 130mmol/L.Product is under 37 DEG C of conditions of storage to molecule
Size distribution is investigated.
Molecular size is distributed according to embodiment 1, is checked using high performance liquid chromatography.Storage 3,6,9,12 and 24
Measure immunoglobulin monomer adds dimer content during the moon, as a result such as following table.
Embodiment 3
Learn from else's experience the chromatography of immunoglobulins solution after inactivation of virus（Purity 98.7%, concentration 0.27mmol/L）, it is concentrated by ultrafiltration
The immunoglobulin solution that concentration is 5wt% is configured to, takes 1L samples, addition glucose to 225mmol/L, regulation pH to 6.9 makees
For blank control sample, 3L, addition glutathione to 8mmol/L, maltose to 250mmol/L, serine to 75mmol/ are separately taken
L, pH to 6.9 is adjusted, is divided into sample 1, sample 2,3 each 1L of sample.Product molecular size is distributed under 37 DEG C of conditions of storage into
Row is investigated.
Molecular size is distributed according to embodiment 1, is checked using high performance liquid chromatography.Storage 3,6,9,12 and 24
Measure immunoglobulin monomer adds dimer content during the moon, as a result such as following table.
Embodiment 4
Learn from else's experience the human serum chromatography of immunoglobulins solution after inactivation of virus（Purity 99.0%, concentration 0.26mmol/L）,
The immunoglobulin solution for being configured to that concentration is 5wt% is concentrated by ultrafiltration.1L samples are taken, add glucose 200mmol/L, adjust pH
Blank control sample is used as to 5.5.Another to take 3L, addition glutathione is to 8mmol/L, and maltose to 350mmol/L, glycine is extremely
80mmol/L, pH to 5.5 is adjusted, is divided into sample 1, sample 2,3 each 1L of sample.Product is under 15 DEG C of conditions of storage to molecular size
Distribution is investigated.
Molecular size is distributed according to embodiment 1, is checked using high performance liquid chromatography.Storage 3,6,9,12 and 24
Measure immunoglobulin monomer adds dimer content during the moon, as a result such as following table.
Claims (4)
- A kind of 1. storage stabilizing agent for human serum immunoglobulin solution preparation, it is characterised in that：The immune globulin Contain Cys or its hydrochloride, one or more of mercapto-protective agents of glutathione, its concentration in white pharmaceutical solutions For 3-20mmol/L；One or more of sugared stabilizers containing maltose or trehalose, its concentration are 150-600mmol/ L；And one or more of amino acid stabilizers containing proline or its salt, glycine or its salt, serine or its salt, its Concentration is 12-150mmol/L, immunoglobulin solution preparation pH=4-6.
- 2. storage stabilizing agent according to claim 1, it is characterised in that the concentration of the mercapto-protective agent is 4-10mmol/ L。
- 3. storage stabilizing agent according to claim 1, it is characterised in that the concentration of the sugared stabilizer be 250- 400mmol/L。
- 4. storage stabilizing agent according to claim 1, it is characterised in that the concentration of the amino acid stabilizers be 20- 80mmol/L。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510221517.8A CN104826117B (en) | 2015-05-05 | 2015-05-05 | Storage stabilizing agent for human serum immunoglobulin solution preparation |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510221517.8A CN104826117B (en) | 2015-05-05 | 2015-05-05 | Storage stabilizing agent for human serum immunoglobulin solution preparation |
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| Publication Number | Publication Date |
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| CN104826117A CN104826117A (en) | 2015-08-12 |
| CN104826117B true CN104826117B (en) | 2017-11-14 |
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| CN112798373B (en) * | 2020-12-30 | 2023-04-25 | 广州金域医学检验中心有限公司 | Method for detecting blood Benzhou's protein |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6290967B1 (en) * | 1996-12-20 | 2001-09-18 | Merck & Co., Inc. | Stabilizers for lyophilized vaccines |
| JP4648002B2 (en) * | 2002-06-21 | 2011-03-09 | ノボ ノルディスク ヘルス ケア アクチェンゲゼルシャフト | Stabilized solid composition of factor VII polypeptide |
| JP6055412B2 (en) * | 2010-09-17 | 2016-12-27 | バクスアルタ ゲーエムベーハー | Immunoglobulin stabilization via aqueous formulations with histidine at mildly acidic to neutral pH |
| CN103550780B (en) * | 2013-10-30 | 2015-03-18 | 郑州邦和生物药业有限公司 | Protein protective agent for Pasteur inactivating human intravenous immunoglobulin and inactivation method of protein protective agent |
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