CN109420159A - A kind of novel stabilising preparation of recombinant protein medicine - Google Patents
A kind of novel stabilising preparation of recombinant protein medicine Download PDFInfo
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- CN109420159A CN109420159A CN201710734358.0A CN201710734358A CN109420159A CN 109420159 A CN109420159 A CN 109420159A CN 201710734358 A CN201710734358 A CN 201710734358A CN 109420159 A CN109420159 A CN 109420159A
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- fusion protein
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- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
A kind of novel stabilising preparation of recombinant protein medicine, belongs to pharmaceutical formulations research field.Protein drug preparation provided by the invention includes effective component recombination fusion protein, phosphate buffer, trehalose, amino acid and Sodium Caprylate.Pharmaceutical preparation of the invention is suitable for the administration of the approach such as subcutaneous or vein, is suitble to this pharmaceutical preparation of dosage that can treat neutrophilic granulocytopenia by injecting.
Description
Technical field
A kind of novel stabilising preparation of recombinant protein medicine of the present invention, is related to recombination human serum albumin-human granular leukocyte collection
The preparation method of G-CSF (rHSA/G-CSF) fusion protein liquid preparation, belongs to pharmaceutical preparation research field.
Background technique
Granulocyte colony stimulating factor (granulocytecolony-stimulatingfactor, G-CSF) is by monokaryon
A kind of hemopoieticgrowth factor that cell, fibroblast and endothelial cell generate can promote in conjunction with the special receptor of cell surface
Neutrophil series hematopoietic progenitor cells is set to grow and break up, protection neutrophil leucocyte avoids apoptosis and reinforces their function.Closely
With the product of cell biology, molecular biology, evidence-based medicine EBM, the high speed development of implantation technique and Clinical Experience over year
Tired, rhG-CSF has been not only limited to the granulocyte reduction after treatment tumor chemoradiotherapy, in hematopoietic stem cell transplantation, acute white blood
Disease treatment, organ transplant immunological regulation etc. have also played important function.
Natural or recombination G-CSF is since molecular weight is smaller, easily by glomerular filtration, in the intracorporal circulating half-life of people
Very short, only 2-4 hours, each chemotherapy cycles needed injection 1-2 times, continuous injection 5-7 days daily.Extend G-CSF preparation body
Interior half-life period can reduce administration number of times.
Human serum albumins (HSA) is spontaneous most common blood protein in people's circulatory system, is kept in the circulating cycle
Exceed 20 days.Albumin is carrier protein, has minimum activity under physiological concentration.HSA and recombinant human albumin (rHSA) are in people
All there is same long circulating half-life period in body.The rHSA/ that gene engineering method obtains human albumin and G-CSF amalgamation and expression
G-CSF improves the half-life period of G-CSF in vivo.
Patent ZL200910199337.9 (G-CSF fusion protein mutant and its preparation and application) discloses the present invention and relates to
And rHSA/G-CSF preparation method, the gene of human serum albumins and Filgrastim's Gene Fusion are existed
Together, suitable recombinant expression method is selected to can be obtained corresponding fusion protein.The recombination human serum albumin-formed after fusion
Filgrastim's fusion protein overcome in traditional Filgrastim's therapeutic process repeatedly to
The shortcomings that medicine；And it has several advantages that and 1) extends the retention time of Filgrastim in vivo；2) it rises most
Curative effect also can be improved in the potential side effect or toxicity of big therapeutic effect, the traditional Filgrastim of reduction.
Recombination human serum albumin-Filgrastim's fusion protein is large biological molecule, and structure is very
It is complicated.During production and storage, the physical changes such as absorption, unfolding denaturation, aggregation and precipitating can occur for protein molecular.Also
Deamidation, isomerization, the chemical changes such as oxidation can occur.Above-mentioned variation may generate final products safety and validity
It influences.Therefore, select suitable preparation prescription that can ensure the stability and safety of product.
Summary of the invention
The object of the present invention is to provide a kind of novel stabilising preparations of recombinant protein medicine.
Technical solution of the present invention: a kind of novel stabilising preparation of recombinant protein medicine includes effective component recombination fusion
Trehalose, amino acid is added in phosphate-buffered liquid system in albumen, and Sodium Caprylate adjusts PH to 6.9-7.0:
It is recombination human serum albumin-human granulocyte colony thorn that recombination fusion protein in the present invention, which refers mainly to recombinant protein,
Swash the factor (rHSA/G-CSF) fusion protein, (G-CSF is merged the preparation method of the albumen referring to patent ZL200910199337.9
Protein mutant and its preparation and application).Fusion protein is because of its pharmaceutical activity of degradation reduction, fusion egg of the invention in order to prevent
Albumin concentration is selected in 5-80mg/ml, preferred concentration 50mg/ml.
For the preservation of recombination fusion protein, the present invention selects a kind of medicinal buffer as the molten of recombination fusion protein
Agent.The medicinal buffer is including but not limited to citric acid/disodium hydrogen phosphate sodium mixture, acetic acid salt mixture, phosphoric acid hydrogen two
Sodium/phosphorus acid dihydride sodium mixture.The preferred buffer system of the present invention is disodium hydrogen phosphate/sodium dihydrogen phosphate mixture, and buffer is dense
Degree is 10-50mM, preferred concentration 50mM.
In order to make pharmaceutical preparation solution meet the isotonic state of physiology, recombination fusion protein preparation solution of the present invention is added isotonic
Agent, the isotonic agent include NaCl, mannitol, sucrose, trehalose, xylitol etc..Preferred isotonic agent is mannitol, seaweed
Sugar, xylitol etc., preferred isotonic agent are trehalose, concentration range 5-30mM, preferred concentration 10mM.
In order to increase recombination fusion protein preparation solution stability, the present invention adds amino acid conduct in some embodiments
Stabilizer, addition amino acid include glycine, serine, cysteine, alanine, threonine, lysine, arginine, hydrochloric acid
Arginine, proline, isoleucine, histidine, methionine, leucine, tryptophan, glutamic acid, aspartic acid etc., wherein it is preferred that
Amino acid is R-gene and glycine.Amino acid concentration is 10-120mM, and preferred concentration is R-gene 100mM, sweet
Propylhomoserin 50mM.
Recombination fusion protein preparation solution of the invention was saved at 2-8 DEG C more than 180 days, and recombination fusion protein drug is living
Property may remain in the range of regulation.
Pharmaceutical preparation described herein can be stored in many ways, in some embodiments, the pharmaceutical preparation storage
In cillin bottle, in further embodiments, the pharmaceutical preparation is stored in syringe.
Pharmaceutical preparation of the present invention is mainly used for that the drug for the treatment of disease can be prepared, and is particularly suitable for prevention receiving
It treats, the infection of the cancer patient of radiotherapy and bone-marrow transplantation, the patient's for leukopenia and neutrophilic granulocytopenia
Treatment, the treatment for acute myeloid leukemia patient.In one embodiment of the invention, fusion protein of the invention is used for
Treat leukopenia and neutrophilic granulocytopenia.
Pharmaceutical preparation of the invention can be administered alone, or with various combination medicine-feedings, and together with other healing potions
Combining form administration.
Specific embodiment
1 difference rHSA/G-CSF fusion protein solution formula of embodiment
Gained rHSA/G-CSF fusion protein ultrafiltration will be purified into pure water, and respective concentration buffer mother liquor is added, so
After each auxiliary material solid is added to respective concentration, specific preparation prescription is see table 1.
1 each group preparation prescription formula of table
Note: PB is disodium hydrogen phosphate/phosphate sodium dihydrogen buffer solution in buffer system, and His is slow for histidine/histidine monohydrochloride
Fliud flushing, AC are acetic acid/sodium-acetate buffer.
The rHSA/G-CSF fusion protein solution of 2 different formulations of the embodiment 1 month stability in 2-8 DEG C and 25 DEG C respectively
Research
Preparation prescription each in table 1 is placed 1 month in 2-8 DEG C and 25 DEG C, detection pH variation, SEC purity, RP are pure respectively
Degree and SDS-PAGE purity.
Table 2rHSA/G-CSF fusion protein solution places 1 month purity item testing result in 2-8 DEG C and 25 DEG C respectively
In 2-8 DEG C or 25 DEG C placement, when SEC purity, RP purity or SDS-PAGE purity are determined as not when being lower than 95%
Qualification formula, no longer carries out the stability experiment of next stage.It is found according to experimental result, group 3, group 4, group 8, group 12 organizes 13 Hes
Group 17 has purity item to drop to 95% hereinafter, abandoning investigating after placing 1 month.
The rHSA/G-CSF fusion protein solution of 3 different formulations of the embodiment 3 months stability in 2-8 DEG C and 25 DEG C respectively
Research
By preparation prescription each in table 1, except 1 month in addition to unqualified group, places 3 months in 2-8 DEG C and 25 DEG C, detect respectively
PH variation, SEC purity, RP purity and SDS-PAGE purity.
Table 3rHSA/G-CSF fusion protein solution places 3 months purity item testing results in 2-8 DEG C and 25 DEG C respectively
It is found according to experimental result, group 5, group 6, group 7, organizes 14, group 15 and group 16 have purity item to decline after placing 3 months
To 95% hereinafter, abandoning investigating.
The rHSA/G-CSF fusion protein solution of 4 different formulations of the embodiment 6 months stability in 2-8 DEG C and 25 DEG C respectively
Research
By preparation prescription each in table 1,1 month is removed, outside unqualified group, places 6 months, divide in 2-8 DEG C and 25 DEG C within 3 months
It Jian Ce not pH variation, SEC purity, RP purity and SDS-PAGE purity.
Table 4rHSA/G-CSF fusion protein solution places 6 months purity item testing results in 2-8 DEG C and 25 DEG C respectively
According to experimental result, group 9, group 10 has purity item to drop to 95% or less after organizing 11 placement 6 months.It is final true
Surely 1 is organized, group 2 and group 18 can be used as rHSA/G-CSF fusion protein stability of solution formula.
Claims (8)
1. a kind of novel stabilising preparation of recombinant protein medicine, it is characterised in that include effective component recombination fusion protein, in phosphorus
In phthalate buffer system, addition trehalose, amino acid, Sodium Caprylate,
Recombination fusion protein 5-80mg/ml
Phosphate buffer 1 0-50mM
Trehalose 5-30mM
Amino acid 1 0-120mM
Sodium Caprylate 3-8mM
Adjust pH to 7.0.
2. stabilization formulations described in claim 1, wherein the recombinant protein is recombination human serum albumin-human granulocyte colony
Stimulating factor (rHSA/G-CSF) fusion protein, protein concentration are 50 mg/ml.
3. stabilization formulations described in claim 1, wherein the phosphate buffer is disodium hydrogen phosphate/sodium dihydrogen phosphate, it is dense
Degree is 50mM.
4. stabilization formulations described in claim 1, it is characterised in that trehalose concentration is 10 mM.
5. stabilization formulations described in claim 1, it is characterised in that the amino acid is R-gene and glycine.
6. stabilization formulations described in claim 5, it is characterised in that the R-gene concentration is 100 mM.
7. stabilization formulations described in claim 5, it is characterised in that the glycine concentration is 50 mM.
8. stabilization formulations described in claim 1, it is characterised in that the octanoic acid na concn is 5 mM.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395379A (en) * | 2009-01-16 | 2012-03-28 | 特瓦制药工业有限公司 | New stable formulations of recombinant human albumin-human granulocyte colony stimulating factor |
| CN102670522A (en) * | 2011-03-16 | 2012-09-19 | 江苏泰康生物医药有限公司 | Pharmaceutical preparation containing recombinant human serum albumin-human granulocyte colony stimulating factor fusion protein and preparation thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102395379A (en) * | 2009-01-16 | 2012-03-28 | 特瓦制药工业有限公司 | New stable formulations of recombinant human albumin-human granulocyte colony stimulating factor |
| CN102670522A (en) * | 2011-03-16 | 2012-09-19 | 江苏泰康生物医药有限公司 | Pharmaceutical preparation containing recombinant human serum albumin-human granulocyte colony stimulating factor fusion protein and preparation thereof |
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Application publication date: 20190305 |