CN104826117A - Storage stabilizer for human serum immunoglobulin solution preparation - Google Patents
Storage stabilizer for human serum immunoglobulin solution preparation Download PDFInfo
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- CN104826117A CN104826117A CN201510221517.8A CN201510221517A CN104826117A CN 104826117 A CN104826117 A CN 104826117A CN 201510221517 A CN201510221517 A CN 201510221517A CN 104826117 A CN104826117 A CN 104826117A
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Abstract
The invention discloses a stabilizer capable of reducing or avoiding polymerization of a human serum immunoglobulin solution preparation during the storage process. The immunoglobulin solution preparation contains a mercapto protective agent selected from one or more of L-cysteine or its hydrochloride and glutathione at the concentration of 3-20mmol/L, a sugar stabilizer selected from one or more of maltose or mycose at the concentration of 150-600mmol/L and an amino acid stabilizer selected from one or more of proline or its salt, glycine or its salt and serine or its salt at the concentration of 12-150mmol/L. By adding the stabilizers, polymerization of immunoglobulin due to high temperature, high concentration or long storage time can be minimized, and effectiveness of a medicine is enhanced.
Description
Technical field
The present invention relates to medicated premix, the stabilizing agent of the storage use of human serum immunoglobulin solution preparation specifically used for intravenous injection.
Background technology
Human serum immunoglobulin (IgG) preparation is mainly used in constitutional and Secondary cases immunoglobulin deficiency, and other autoimmune disease, as idiopathic thrombocytopenic purpura, mucocutaneous lymphnode syndrome etc.
IgG is that purification obtains from human plasma, it to be contacted after antigen with plasma cell by B cell and produces, its molecular weight is approximately 150KDa, be made up of four peptide chains, article two, identical light chain (L) is connected by two disulfide bond covalency with heavy chain (H), in addition, a Y type dimer is symmetrically formed with non-covalent.Light chain is made up of two homeodomains, and heavy chain is made up of four homeodomains, and the feature of these domains comprises 2 beta sheet structures, comprises 3 to 5 anti-phase antiparallel P-strands, maintains Stability Analysis of Structures by a disulfide bond.These domains are to thermo-responsive, and under room temperature storage, its secondary structure can change, and cause forming polymer, and immunoglobulin preparation storage process polymer constantly increases, and drug effect reduces gradually, and after intravenous injection, polymer also can have side effects.
CN103282042A disclose a kind of have histidine and under faintly acid to neutral pH the immunoglobulin aqueous formulation of stable storing, comprise immunoglobulin, histidine from 50mM to 500mM, 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 when high temperature, high concentration or storage time are longer, immunoglobulin extent of polymerization is still higher.
Summary of the invention
The object of this invention is to provide a kind of stabilizing agent reducing or avoid human serum immunoglobulin solution preparation and be polymerized in storage process generation, by adding stabilizing agent, immunoglobulin Yin Gaowen, high concentration or storage time can be reduced longer and the polymerization of generation, improve the effectiveness of medicine.
Storage stabilizing agent of the present invention is one or more the mercapto-protective agent containing Cys or its hydrochlorate, glutathion in immunoglobulin solution preparation, and its concentration is 3-20mmol/L; One or more sugared stabilizing agent containing maltose or trehalose, its concentration is 150-600mmol/L; And one or more the amino acid stabilizers containing proline or its salt, glycine or its salt, serine or its salt, its concentration is 12-150mmol/L.
Preferably, the molar concentration of mercapto-protective agent is 4-8mmol/L, and the molar concentration of sugared stabilizing agent is 250-400mmol/L, and 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 grades and quarternary structure; sugar stabilizing agent is stablized for the protection of the secondary structure of β-pleated sheet in immunoglobulin molecules; amino acid stabilizers can even separation between Promote immunity globulin molecule, stablizes its native conformation.Can avoid or reduce immunoglobulin solution preparation to be thus polymerized further at prolonged storage, improve storage stability, in room temperature and the following environment of room temperature, formulation storage is after 2 years, immunoglobulin poly aggressiveness is less than 1%, in 37 DEG C of environment, formulation storage is after 2 years, and immunoglobulin polymer is less than 2%.
Detailed description of the invention
Embodiment 1
To learn from else's experience the human serum chromatography of immunoglobulins solution (purity 99.2% after inactivation of virus, concentration 0.37mmol/L), ultrafiltration and concentration is mixed with the immunoglobulin solution that concentration is 10wt%, gets 1L sample, add glucose to 230mmol/L, regulate pH to 4.1 as blank control sample, separately get 3L, add glutathion to 6mmol/L, maltose is to 300mmol/L, proline, to 50mmol/L, regulates pH to 4.1, is divided into sample 1, sample 2, each 1L of sample 3.Goods are investigated molecular size distribution under room temperature storage condition.
Molecular size distribution adopts high performance liquid chromatography to check: with hydrophilic silica gels Efficient numerical method post (SEC, exclusion limit 300kD, granularity 10 μm), column diameter 7.5mm, long 60cm; To contain 1% isopropyl alcohol, pH value 7.0,0.2mol/L phosphate buffer (getting 0.5mol/L sodium dihydrogen phosphate 200ml, 0.5mol/L sodium hydrogen phosphate 420ml, isopropyl alcohol 15.5ml and water 914.5ml Homogeneous phase mixing) is mobile phase; Determined wavelength is 280nm; Flow velocity is 0.6ml per minute; Get immunoglobulin, each 20 μ l of human albumin's solution that every 1ml is 12mg containing protein respectively, inject chromatographic column respectively, record chromatogram, immunoglobulin contrast monomer peak should be greater than 1.5 with being separated of cracking body peak, the separating degree at human albumin's reference substance monomer peak and dimer peak should be greater than 1.5, and tailing factor calculates by human albumin's monomer peak and should be 0.95-1.40.Calculate by area normalization method, in chromatogram, monomer adds the content at dimer peak, is immunoglobulin monomer and adds dimer content.
Measure immunoglobulin monomer when storing 3,6,9,12 and 24 months and add dimer content, result is as following table.
Embodiment 2
To learn from else's experience the human serum chromatography of immunoglobulins solution (purity 99.5% after inactivation of virus, concentration 0.25mmol/L), ultrafiltration and concentration is mixed with the immunoglobulin solution that concentration is 10wt%, gets 1L sample, add glucose to 220mmol/L, regulate pH to 3.85 as blank control sample, separately get 3L, add cysteine to 4mmol/L, maltose is to 500mmol/L, glycine, to 130mmol/L, regulates pH to 3.85, is respectively sample 1, sample 2, sample 3.Goods are investigated molecular size distribution under 37 DEG C of conditions of storage.
Molecular size distribution, according to embodiment 1, adopts high performance liquid chromatography to check.Measure immunoglobulin monomer when storing 3,6,9,12 and 24 months and add dimer content, result is as following table.
Embodiment 3
To learn from else's experience the chromatography of immunoglobulins solution (purity 98.7% after inactivation of virus, concentration 0.27mmol/L), ultrafiltration and concentration is mixed with the immunoglobulin solution that concentration is 5wt%, gets 1L sample, add glucose to 225mmol/L, regulate pH to 6.9 as blank control sample, separately get 3L, add glutathion to 8mmol/L, maltose is to 250mmol/L, serine, to 75mmol/L, regulates pH to 6.9, is divided into sample 1, sample 2, each 1L of sample 3.Goods are investigated molecular size distribution under 37 DEG C of conditions of storage.
Molecular size distribution, according to embodiment 1, adopts high performance liquid chromatography to check.Measure immunoglobulin monomer when storing 3,6,9,12 and 24 months and add dimer content, result is as following table.
Embodiment 4
Learn from else's experience the human serum chromatography of immunoglobulins solution (purity 99.0%, concentration 0.26mmol/L) after inactivation of virus, ultrafiltration and concentration is mixed with the immunoglobulin solution that concentration is 5wt%.Get 1L sample, add glucose 200mmol/L, regulate pH to 5.5 as blank control sample.Separately get 3L, add glutathion to 8mmol/L, maltose is to 350mmol/L, and glycine, to 80mmol/L, regulates pH to 5.5, is divided into sample 1, sample 2, each 1L of sample 3.Goods are investigated molecular size distribution under 15 DEG C of conditions of storage.
Molecular size distribution, according to embodiment 1, adopts high performance liquid chromatography to check.Measure immunoglobulin monomer when storing 3,6,9,12 and 24 months and add dimer content, result is as following table.
Claims (5)
1. the storage stabilizing agent for human serum immunoglobulin solution preparation, it is characterized in that: one or more the mercapto-protective agent containing Cys or its hydrochlorate, glutathion in described immunoglobulin solution preparation, its concentration is 3-20mmol/L; One or more sugared stabilizing agent containing maltose or trehalose, its concentration is 150-600mmol/L; And one or more the amino acid stabilizers containing proline or its salt, glycine or its salt, serine or its salt, its concentration is 12-150mmol/L.
2. storage stabilizing agent according to claim 1, it is characterized in that, the concentration of described mercapto-protective agent is 4-10mmol/L.
3. storage stabilizing agent according to claim 1, it is characterized in that, the concentration of described sugared stabilizing agent is 250-400mmol/L.
4. storage stabilizing agent according to claim 1, it is characterized in that, the concentration of described amino acid stabilizers is 20-80mmol/L.
5. storage stabilizing agent according to claim 1, is characterized in that, described immunoglobulin solution preparation pH=4-6.
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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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| CN201510221517.8A CN104826117B (en) | 2015-05-05 | 2015-05-05 | Storage stabilizing agent for human serum immunoglobulin solution preparation |
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| CN104826117B CN104826117B (en) | 2017-11-14 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112798373A (en) * | 2020-12-30 | 2021-05-14 | 广州金域医学检验中心有限公司 | Detection method of blood Bbstein |
Citations (4)
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| WO1999062500A1 (en) * | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Stabilizers for lyophilized vaccines |
| CN1671410A (en) * | 2002-06-21 | 2005-09-21 | 诺沃挪第克公司 | Stabilised solid compositions of factor VII polypeptides |
| CN103282042A (en) * | 2010-09-17 | 2013-09-04 | 巴克斯特国际公司 | Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral ph |
| CN103550780A (en) * | 2013-10-30 | 2014-02-05 | 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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2015
- 2015-05-05 CN CN201510221517.8A patent/CN104826117B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999062500A1 (en) * | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Stabilizers for lyophilized vaccines |
| CN1671410A (en) * | 2002-06-21 | 2005-09-21 | 诺沃挪第克公司 | Stabilised solid compositions of factor VII polypeptides |
| CN103282042A (en) * | 2010-09-17 | 2013-09-04 | 巴克斯特国际公司 | Stabilization of immunoglobulins through aqueous formulation with histidine at weak acidic to neutral ph |
| CN103550780A (en) * | 2013-10-30 | 2014-02-05 | 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 |
Non-Patent Citations (3)
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| 王立兰: ""加热灭活病毒的静脉注射免疫球蛋白的研究"", 《微生物学免疫学进展》 * |
| 王立兰: "加热灭活病毒的静脉注射免疫球蛋白的研究", 《微生物学免疫学进展》 * |
| 赵鹤皋: "《冷冻干燥技术与设备》", 30 June 2005 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112798373A (en) * | 2020-12-30 | 2021-05-14 | 广州金域医学检验中心有限公司 | Detection method of blood Bbstein |
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