CN113797171A - Pegylated recombinant human granulocyte colony stimulating factor freeze-dried preparation - Google Patents
Pegylated recombinant human granulocyte colony stimulating factor freeze-dried preparation Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/193—Colony stimulating factors [CSF]
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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Abstract
The invention provides a polyethylene glycol recombinant human granulocyte colony stimulating factor (PEG-rhG-CSF) freeze-dried preparation, which is prepared by carrying out spray freeze-drying treatment on PEG-rhG-CSF and an excipient, wherein the prepared PEG-rhG-CSF freeze-dried preparation is prepared by preparing a special solvent containing sodium chloride and acetate when being clinically used, and can be used after being mixed and dissolved with the special solvent. The PEG-rhG-CSF freeze-dried preparation prepared by the invention does not contain Tween 20 serving as a surfactant, has high medication safety and good stability, can be stored for a long time, and has simple preparation process and short production period.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a freeze-dried preparation of a pegylated recombinant human granulocyte colony stimulating factor and a preparation method thereof.
Background
Non-myeloid neutropenia after tumor chemotherapy is a common clinical chemotherapy complication and also one of the important causes of death of tumor patients. The recombinant human granulocyte colony stimulating factor (rhG-CSF) is an effective medicine for preventing and treating neutropenia caused by tumor chemoradiotherapy, and can promote the formation of granulocyte colony and the proliferation and differentiation of hematopoietic stem cells to neutrophils. Can promote migration, phagocytosis, enzyme production, active oxygen release, bactericidal activity, and foreign body adhesion to mature neutrophils. Mature neutrophils may also be mobilized from the bone marrow into the periphery. The early pluripotent hematopoietic stem cells can enter a cell cycle, and the bone marrow hematopoietic stem cells can be promoted to enter peripheral blood by daily application, however, the recombinant human granulocyte colony-stimulating factor (rhG-CSF) is easily degraded by protease in a body, the half-life period is only 1.3-4.2 hours, the administration is required every day, and the continuous administration can cause side effects such as drug eruption, fever, myalgia, ostealgia and the like, so that the clinical treatment effect is directly influenced, and the application of the recombinant human granulocyte colony-stimulating factor in clinical treatment is greatly limited.
The polyethylene glycol recombination human granulocyte colony stimulating factor (PEG-rhG-CSF) is formed by combining the recombination human granulocyte colony stimulating factor with polyethylene glycol, because the N end of the PEG-rhG-CSF is chemically modified by 20KD monomethoxy polyethylene glycol (Mpeg), the chances that the human granulocyte colony stimulating factor protein is contacted and enzymolyzed by protease in a human body are greatly reduced, compared with the conventional rhG-CSF, the plasma clearance rate is slowed down, and the half-life period is obviously prolonged to 46-62h, so the clinical use can reduce the administration times, the pain of repeated injection of a patient is avoided, and the PEG-rhG-CSF has the advantages of long acting, less adverse reaction and the like.
Currently, Amgen company in the united states has an injection on the market, and the trade name of the injection is Neulasta, wherein the injection contains polyethylene glycol recombinant human granulocyte colony stimulating factor, sorbitol, Tween 20, acetic acid and sodium acetate, wherein the sorbitol is used for adjusting osmotic pressure, acetic acid buffer salt can maintain the pH value to be about 4.0, the Tween 20 can prevent main drugs from aggregating, so that the injection is stable, but the Tween 20 has stronger hemolytic effect and can increase the risk of medication.
The Chinese invention patent CN102028661B discloses a polyethylene glycol recombinant human granulocyte colony stimulating factor freeze-dried powder injection, which is prepared by adding freeze-drying protective agent in the prescription and freeze-drying in vacuum, wherein the freeze-drying is carried outThe protective agent is selected from one or more of mannitol, arginine and glycine; the obtained product has no color and clarity after being dissolved, purity of 95.60% and potency of 1.89 × 10 after being stored for 12 months in long-term stability examination (25 deg.C, RH 60%)8IU/ml; in accelerated stability examination (40 ℃, RH 75%), after 3 months of storage, the appearance is colorless and clear after dissolution, the purity is 95.40%, and the titer is 2.00 multiplied by 108IU/ml, in accelerated stability examination (50 ℃, RH 85%), after 1 month of storage, the appearance is colorless and clear after dissolution, the purity is 95.20%, and the potency is 2.01 multiplied by 108IU/ml; in accelerated stability testing (60 ℃, RH 90%), after 2 weeks of storage, the appearance was colorless and clear after dissolution, the purity was 95.50%, and the potency was 1.84X 108IU/ml。
However, the traditional freeze-drying technology cannot control the size of particles due to lack of a liquid forming process, has high energy consumption and long drying time, brings great challenges and difficulties to the stability of product quality, and has high cost investment.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a stable polyethylene glycol colony stimulating factor freeze-dried preparation, wherein the polyethylene glycol colony stimulating factor (PEG-rhG-CSF) is subjected to freeze spray drying treatment so as to improve the stability at room temperature and shorten the freeze-drying period. But the single freezing and spray drying treatment of the medicine has too large viscosity and small specification, and can not be subpackaged, and even the subpackaged product is redissolved slowly due to strong electrostatic action.
Specifically, the invention is realized by the following technical scheme:
a spray freeze-dried preparation of a pegylated recombinant human granulocyte colony stimulating factor comprises the pegylated recombinant human granulocyte colony stimulating factor and an excipient, and the freeze-dried preparation is prepared by a freeze-spray drying method.
Preferably, the excipient is selected from one or more of sorbitol, fructose and xylitol;
preferably, the excipient is sorbitol.
Preferably, the weight ratio of the pegylated recombinant human granulocyte colony stimulating factor to the excipient is 1: 2-30; more preferably 1: 2-15; the most preferable ratio is 1: 2-3.
Preferably, the spray freeze-drying method comprises the following steps:
1) dissolving excipient and PEG-rhG-CSF together in water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, and spray freezing at low temperature to form small ice crystals;
2) and drying the spray-frozen small ice crystals at low temperature and low pressure to obtain finished powder.
Preferably, the temperature of the spray freezing in the step 1) is-35 ℃ to-15 ℃, and more preferably-35 ℃ to-25 ℃.
Preferably, the concentration of the PEGylated recombinant human granulocyte colony stimulating factor in the solution for spray freezing in the step 1) is 5-10mg/ml, and the concentration of sorbitol is 20-200 mg/ml; further preferably, the concentration of the PEGylated recombinant human granulocyte colony stimulating factor is 8-10mg/ml, and the concentration of sorbitol is 20-125 mg/ml.
Preferably, in the spray freezing process in the step 1), the feeding flow is 10-30 mL/min; more preferably 15 to 25 mL/min.
Preferably, in the drying process in the step 2), the drying temperature is below-25 ℃; more preferably from-40 ℃ to-30 ℃.
Preferably, in the drying process in the step 2), the air pressure is below 50Pa during drying; more preferably 30Pa or less; most preferably 10 to 20 Pa.
Preferably, in the drying process in the step 2), the drying time is 4-12 hours.
When the pegylation recombinant human granulocyte colony stimulating factor spray freeze-dried preparation is clinically used, a special solvent containing sodium chloride and acetate is prepared, the pH range of the solvent is 4.0-6.0, and the freeze-dried preparation and the special solvent are mixed and dissolved for use.
Compared with the prior art, the invention has the following technical effects:
1. the prepared PEGylated recombinant human granulocyte colony stimulating factor spray-freeze-dried preparation does not contain a surfactant Tween 20, and has high medication safety.
2. The prepared polyethylene glycol recombinant human granulocyte colony stimulating factor spray freeze-dried preparation has good stability and can be stored for a long time.
3. The prepared polyethylene glycol recombinant human granulocyte colony stimulating factor spray freeze-dried preparation has good dispersibility and short redissolution time, and can be quickly restored to the form before freeze-drying when being compounded by a special acetate solvent.
4. The prepared polyethylene glycol recombinant human granulocyte colony stimulating factor spray freeze-drying preparation has simple preparation process and short production period.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
Example 1
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 3
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 100mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 25mL/min, and spray-freezing at-30 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 20Pa, drying at-40 deg.C for 8 hr to obtain powder, and packaging.
Example 2
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 2
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 100mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 25mL/min, and spray freezing at-25 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 20Pa, drying at-30 deg.C for 8 hr to obtain powder, and packaging.
Example 3
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 15
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 120mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 15mL/min, and spray-freezing at-35 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-30 deg.C for 8 hr to obtain powder, and packaging.
Example 4
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 30
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 150mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 15mL/min, and spray freezing at-30 deg.C to form small ice crystals.
2) And (3) drying: -adjusting the pressure in the drying chamber to about 30Pa, the temperature in the drying chamber to-30 ℃, drying the small ice crystals obtained by spray freezing for 8 hours to obtain finished product powder, and subpackaging to obtain the finished product.
Example 5
Prescription:
name amount/g
PEG-rhG-CSF 1
Xylitol 30
The preparation method comprises the following steps:
1) spray freezing: dissolving xylitol and PEG-rhG-CSF together in 150mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 30mL/min, and spray freezing at-15 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-25 deg.C for 8 hr to obtain powder, and packaging.
Example 6
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 40
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 150mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at flow rate of 10mL/min, and spray freezing at-30 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-30 deg.C for 12 hr to obtain powder, and packaging.
Example 7
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 1
1) Spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 60mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 15mL/min, and spray-freezing at-30 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-30 deg.C for 6 hr to obtain powder, and packaging.
Example 8
Prescription:
name amount/g
PEG-rhG-CSF 1
Sorbitol 15
The preparation method comprises the following steps:
1) spray freezing: dissolving sorbitol and PEG-rhG-CSF together in 120mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at flow rate of 30mL/min, and spray freezing at-10 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to 50Pa, drying at-20 deg.C for 8 hr to obtain powder, and packaging.
Comparative example 1
Prescription:
name amount/g
PEG-rhG-CSF 1
Dextran 15
The preparation method comprises the following steps:
1) spray freezing: dissolving dextran and PEG-rhG-CSF together in 120mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 15mL/min, and spray-freezing at-35 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-30 deg.C for 8 hr to obtain powder, and packaging.
Comparative example 2
Prescription:
name amount/g
PEG-rhG-CSF 1
Glycine 15
The preparation method comprises the following steps:
1) spray freezing: dissolving glycine and PEG-rhG-CSF together in 120mL of water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, feeding at 15mL/min, and spray-freezing at-35 deg.C to form small ice crystals.
2) And (3) drying: adjusting the pressure in the drying chamber to about 30Pa, drying at-30 deg.C for 8 hr to obtain powder, and packaging.
Verification examples
The test samples are placed under the same conditions (25 ℃, RH 60%) for long-term stability examination for 12 months, sampling detection is carried out respectively at 1, 3, 6 and 12 months, the detection items are appearance, redissolution time, purity and titer, and the table 1 shows the long-term stability examination result.
The test samples are placed under the same acceleration condition (40 ℃, RH 75%) for 6 months for accelerated stability examination, sampling and detecting are carried out in 1, 3 and 6 months respectively, the detection items are appearance, redissolution time, purity and titer, and the table 2 is the accelerated stability examination result.
The test samples were placed under the same acceleration conditions (60 ℃, RH 90%) for 1 month for accelerated stability examination, and were sampled at 1 day, 15 days, and 30 days, respectively, with the test items being appearance, reconstitution time, purity, and titer, and table 2 is the accelerated stability examination result.
TABLE 1 stability test results (25 ℃, RH 60%)
TABLE 2 accelerated stability test results (40 ℃, RH 75%)
TABLE 3 accelerated stability test results (60 ℃, RH 90%)
As can be seen from tables 1, 2 and 3, the results of the long-term stability of the PEGylated recombinant human granulocyte colony stimulating factor spray-freeze-dried preparations prepared in examples 1 to 4 of the present invention at 25 ℃ RH 60% and the accelerated stability of the preparations at 40 ℃ RH 75% and 60 ℃ RH 90% demonstrate that the products prepared in examples 1 to 4 have good stability in terms of reconstitution time, appearance, purity and potency.
Claims (10)
1. A freeze-dried preparation of pegylated recombinant human granulocyte colony-stimulating factor comprises the pegylated recombinant human granulocyte colony-stimulating factor and an excipient, and the freeze-dried preparation is prepared by a freeze-spray drying method.
2. The lyophilized formulation of claim 1, wherein the excipient is selected from one or more of sorbitol, fructose, xylitol.
3. The lyophilized formulation of claim 1, wherein the weight ratio of pegylated recombinant human granulocyte colony stimulating factor to excipient is 1: 2-30, preferably 1:2 to 15.
4. The lyophilized formulation of claim 1, wherein the spray freeze-drying process comprises the steps of:
1) dissolving excipient and PEG-rhG-CSF together in water for injection, filtering with 0.22 μm filter membrane, adding into spray bottle, and spray freezing at low temperature to form small ice crystals.
2) And drying the spray-frozen small ice crystals at low temperature and low pressure to obtain finished powder.
5. The lyophilized formulation of claim 4, wherein the solution for spray freezing in step 1) has a concentration of pegylated recombinant human granulocyte colony stimulating factor of 5 to 10mg/ml and sorbitol of 20 to 200 mg/ml.
6. The lyophilized formulation of claim 4, wherein the temperature of the spray freezing of step 1) is from-35 ℃ to-15 ℃.
7. The lyophilized formulation according to claim 4, wherein the feed flow rate during the spray freezing of step 1) is 10 to 30 mL/min.
8. The lyophilized formulation of claim 4, wherein the drying temperature during the drying process of step 2) is below-25 ℃.
9. The lyophilized formulation of claim 4, wherein the air pressure at the time of drying in step 2) is below 50 Pa.
10. The lyophilized preparation according to any one of claims 1 to 9, wherein the spray-frozen preparation is prepared with a special solvent containing sodium chloride and acetate, and the spray-frozen preparation is mixed with the special solvent for dissolution for clinical use.
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| CN202110466722 | 2021-04-28 | ||
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114224853A (en) * | 2022-01-04 | 2022-03-25 | 山东新时代药业有限公司 | Freeze-dried preparation for injection of polyethylene glycol recombinant human granulocyte stimulating factor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563388A (en) * | 2004-03-29 | 2005-01-12 | 中国人民解放军第三军医大学 | Constructing genetic engineering Vaccine of adhesin of confluent Helicobacter pylor and preparation method |
| CN102028661A (en) * | 2010-12-31 | 2011-04-27 | 山东新时代药业有限公司 | Pegylated recombinant human granulocyte colony stimulating factor freeze-dried powder/injection and preparation method thereof |
| CN105273076A (en) * | 2014-06-18 | 2016-01-27 | 江苏奥赛康药业股份有限公司 | Preparation method and pharmaceutical composition of PEGylated recombinant human granulocyte colony-stimulating factor |
| CN112121009A (en) * | 2020-09-24 | 2020-12-25 | 科兴生物制药股份有限公司 | New preparation of polyethylene glycol modified recombinant human granulocyte stimulating factor |
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2021
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1563388A (en) * | 2004-03-29 | 2005-01-12 | 中国人民解放军第三军医大学 | Constructing genetic engineering Vaccine of adhesin of confluent Helicobacter pylor and preparation method |
| CN102028661A (en) * | 2010-12-31 | 2011-04-27 | 山东新时代药业有限公司 | Pegylated recombinant human granulocyte colony stimulating factor freeze-dried powder/injection and preparation method thereof |
| CN105273076A (en) * | 2014-06-18 | 2016-01-27 | 江苏奥赛康药业股份有限公司 | Preparation method and pharmaceutical composition of PEGylated recombinant human granulocyte colony-stimulating factor |
| CN112121009A (en) * | 2020-09-24 | 2020-12-25 | 科兴生物制药股份有限公司 | New preparation of polyethylene glycol modified recombinant human granulocyte stimulating factor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114224853A (en) * | 2022-01-04 | 2022-03-25 | 山东新时代药业有限公司 | Freeze-dried preparation for injection of polyethylene glycol recombinant human granulocyte stimulating factor |
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