CN110420186A - A kind of wide spectrum freeze-drying dosage form protein composition and preparation method thereof - Google Patents
A kind of wide spectrum freeze-drying dosage form protein composition and preparation method thereof Download PDFInfo
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- CN110420186A CN110420186A CN201910806084.0A CN201910806084A CN110420186A CN 110420186 A CN110420186 A CN 110420186A CN 201910806084 A CN201910806084 A CN 201910806084A CN 110420186 A CN110420186 A CN 110420186A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39591—Stabilisation, fragmentation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/34—Extraction; Separation; Purification by filtration, ultrafiltration or reverse osmosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention discloses a kind of wide spectrum freeze-drying dosage form protein compositions and preparation method thereof, including following parts by weight: protein active ingredients 1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM；And it is aided with a certain amount of glycine (10-40g/L) or sucrose (5-20g/L) or trehalose (5-20g/L).All there is a possibility that unstability and degradation chemically or physically in effective component of the present invention such as recombinant protein, enzyme, antibody protein etc., by the way that solid form is made to extend shelf life in they with Freeze Drying Technique；The present invention is using suitable freeze-drying composition, such as the suitable excipients of appropriate amount, guarantee recombinant protein, enzyme, the stability of antibody protein to the maximum extent, bioactivity, safety and negotiability, preparation method provided by the invention can widely be suitable for various concentration, different types of drug, to substantially increase production efficiency, production cost is reduced.
Description
Technical field
The present invention relates to protein composition technology related fieldss more particularly to a kind of wide spectrum to be freeze-dried dosage form protein combination
Object and preparation method thereof.
Background technique
All there is a possibility that unstability and degradation chemically or physically in recombinant protein, enzyme, antibody protein etc.,
Therefore the shelf life of recombinant protein, enzyme, antibody protein etc. is shorter, is not easy to be saved.It will with Freeze Drying Technique
Solid form, which is made, in they can extend shelf life.But the optimization of freeze-drying composition and process is one time-consuming, it is raw
Produce low efficiency, the big operation of energy consumption, high production cost.
For this purpose, we have proposed a kind of wide spectrum freeze-drying dosage form protein compositions and preparation method thereof.
Summary of the invention
The purpose of the present invention is to provide a kind of wide spectrum freeze-drying dosage form protein compositions and preparation method thereof, to solve
The problems mentioned above in the background art.
To achieve the goals above, present invention employs following technical solutions:
A kind of wide spectrum freeze-drying dosage form protein composition, including following parts by weight: protein active ingredients 1-50g/L,
Mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM；And it is aided with a certain amount of glycine (10-
40g/L) or sucrose (5-20g/L) or trehalose (5-20g/L).
Preferably, the preparation method comprises the following steps:
S1, it is isolated and purified to obtain protein active ingredients with chromatography method；
S2, the method by active constituent protein obtained in S1 by dialysis are exchanged into following solution composition: 1-50g/
L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and glycine 10-40g/L；
S3, active constituent protein solution obtained in S2 is filtered, and is quantitatively divided under sterile conditions
Dress, and every bottle of content is 1mL；
S4, bottled active constituent protein buffer liquid is freeze-dried, packet is sealed under conditions of vacuum
Dress.
Preferably, the freeze-drying preparation method the following steps are included:
S1, the good active constituent protein of quantitative separating is kept for 15-30 minutes in the environment of 5 DEG C, then by temperature
- 5 DEG C are dropped to, and is kept for 15-30 minutes, the temperature of all samples is made to keep uniform；
S2, -40 DEG C are cooled the temperature to, is kept for 90 minutes；
S3, it is made annealing treatment, temperature rises to -20 DEG C, is kept for 2 hours；
S4, temperature is dropped to -40 DEG C, and is kept for 4 hours, freeze sample completely；
S5, pressure is declined at this time and is always maintained to the vacuum state of 0.1mBar, the sample that will be freezed completely in S4
It is kept in the environment of -40 DEG C 2 hours, temperature is then risen to -20 DEG C, and kept for 15 hours, the preliminary of complete paired samples does
It is dry；
S6,20 DEG C are raised the temperature to, is kept for 5 hours, temperature is then risen to 40 DEG C, and kept for 6 hours, sample is complete
It is dry.
Preferably, the glycine can also use sucrose or trehalose instead, and the parts by weight of the sucrose are 5-20g/L,
The parts by weight of the trehalose are 5-20g/L.
Compared with prior art, the beneficial effects of the present invention are:
All there is chemically or physically unstable in effective component of the present invention such as recombinant protein, enzyme, antibody protein etc.
Property and degradation a possibility that, by the way that solid form is made to extend shelf life in they with Freeze Drying Technique；The present invention adopts
With suitable freeze-drying composition, such as the suitable excipients of appropriate amount, guarantee recombinant protein to the maximum extent, enzyme,
The stability of antibody protein etc., bioactivity, safety and negotiability, preparation method provided by the invention can be extensive
It is suitable for various concentration, different types of drug, to substantially increase production efficiency, reduces production cost.
Detailed description of the invention
Fig. 1 is that a kind of wide spectrum proposed by the present invention is freeze-dried cooling drying in dosage form protein composition and preparation method thereof
The control figure of time and temperature.
Specific embodiment
Following will be combined with the drawings in the embodiments of the present invention, and technical solution in the embodiment of the present invention carries out clear, complete
Site preparation description, it is clear that described embodiments are only a part of the embodiments of the present invention, instead of all the embodiments.
Referring to Fig.1, combined with specific embodiments below the present invention is made further to explain, purpose, which is only that, better understands this
Summary of the invention.
Embodiment one
The invention proposes a kind of wide spectrums to be freeze-dried dosage form protein composition, including following parts by weight: protein active
Ingredient 1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and glycine 10-40g/
L。
Wherein, preparation method the following steps are included:
S1, it is isolated and purified to obtain protein active ingredients with chromatography method；
S2, the method by active constituent protein obtained in S1 by dialysis are exchanged into following solution composition: 1-50g/
L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and glycine 10-40g/L；
S3, active constituent protein solution obtained in S2 is filtered, and is quantitatively divided under sterile conditions
Dress, and every bottle of content is 1mL；
S4, bottled active constituent protein buffer liquid is freeze-dried, packet is sealed under conditions of vacuum
Dress.
Wherein, freeze-drying preparation method the following steps are included:
S1, the good active constituent protein of quantitative separating is kept for 15-30 minutes in the environment of 5 DEG C, then by temperature
- 5 DEG C are dropped to, and is kept for 15-30 minutes, the temperature of all samples is made to keep uniform；
S2, -40 DEG C are cooled the temperature to, is kept for 90 minutes；
S3, it is made annealing treatment, temperature rises to -20 DEG C, is kept for 2 hours；
S4, temperature is dropped to -40 DEG C, and is kept for 4 hours, freeze sample completely；
S5, pressure is declined at this time and is always maintained to the vacuum state of 0.1mBar, the sample that will be freezed completely in S4
It is kept in the environment of -40 DEG C 2 hours, temperature is then risen to -20 DEG C, and kept for 15 hours, the preliminary of complete paired samples does
It is dry；
S6,20 DEG C are raised the temperature to, is kept for 5 hours, temperature is then risen to 40 DEG C, and kept for 6 hours, sample is complete
It is dry.
Embodiment two
The invention proposes a kind of wide spectrums to be freeze-dried dosage form protein composition, including following parts by weight: protein active
Ingredient 1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and sucrose 5-20g/L.
Wherein, preparation method the following steps are included:
S1, it is isolated and purified to obtain protein active ingredients with chromatography method；
S2, the method by active constituent protein obtained in S1 by dialysis are exchanged into following solution composition: 1-50g/
L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and sucrose 5-20g/L；
S3, active constituent protein solution obtained in S2 is filtered, and is quantitatively divided under sterile conditions
Dress, and every bottle of content is 1mL；
S4, bottled active constituent protein buffer liquid is freeze-dried, packet is sealed under conditions of vacuum
Dress.
Wherein, freeze-drying preparation method the following steps are included:
S1, the good active constituent protein of quantitative separating is kept for 15-30 minutes in the environment of 5 DEG C, then by temperature
- 5 DEG C are dropped to, and is kept for 15-30 minutes, the temperature of all samples is made to keep uniform；
S2, -40 DEG C are cooled the temperature to, is kept for 90 minutes；
S3, it is made annealing treatment, temperature rises to -20 DEG C, is kept for 2 hours；
S4, temperature is dropped to -40 DEG C, and is kept for 4 hours, freeze sample completely；
S5, pressure is declined at this time and is always maintained to the vacuum state of 0.1mBar, the sample that will be freezed completely in S4
It is kept in the environment of -40 DEG C 2 hours, temperature is then risen to -20 DEG C, and kept for 15 hours, the preliminary of complete paired samples does
It is dry；
S6,20 DEG C are raised the temperature to, is kept for 5 hours, temperature is then risen to 40 DEG C, and kept for 6 hours, sample is complete
It is dry.
Embodiment three
The invention also provides a kind of wide spectrums to be freeze-dried dosage form protein composition, including following parts by weight: protein is living
Property ingredient 1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and trehalose 5-
20g/L。
Wherein, preparation method the following steps are included:
S1, it is isolated and purified to obtain protein active ingredients with chromatography method；
S2, the method by active constituent protein obtained in S1 by dialysis are exchanged into following solution composition: 1-50g/
L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM and trehalose 5-20g/L；
S3, active constituent protein solution obtained in S2 is filtered, and is quantitatively divided under sterile conditions
Dress, and every bottle of content is 1mL；
S4, bottled active constituent protein buffer liquid is freeze-dried, packet is sealed under conditions of vacuum
Dress.
Wherein, freeze-drying preparation method the following steps are included:
S1, the good active constituent protein of quantitative separating is kept for 15-30 minutes in the environment of 5 DEG C, then by temperature
- 5 DEG C are dropped to, and is kept for 15-30 minutes, the temperature of all samples is made to keep uniform；
S2, -40 DEG C are cooled the temperature to, is kept for 90 minutes；
S3, it is made annealing treatment, temperature rises to -20 DEG C, is kept for 2 hours；
S4, temperature is dropped to -40 DEG C, and is kept for 4 hours, freeze sample completely；
S5, pressure is declined at this time and is always maintained to the vacuum state of 0.1mBar, the sample that will be freezed completely in S4
It is kept in the environment of -40 DEG C 2 hours, temperature is then risen to -20 DEG C, and kept for 15 hours, the preliminary of complete paired samples does
It is dry；
S6,20 DEG C are raised the temperature to, is kept for 5 hours, temperature is then risen to 40 DEG C, and kept for 6 hours, sample is complete
It is dry.
It is tested by bioactivity to three obtained recombinant proteins of embodiment and stability, the knot obtained
Fruit is: the bioactivity (seeing the above table) and stability of recombinant protein are greatly improved.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Anyone skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (4)
1. a kind of wide spectrum is freeze-dried dosage form protein composition, which is characterized in that including following parts by weight: protein active ingredients
1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM；And it is aided with a certain amount of sweet ammonia
Sour (10-40g/L).
2. a kind of preparation method of protein composition as described in claim 1, which is characterized in that the preparation method includes following
Step:
S1, it is isolated and purified to obtain protein active ingredients with chromatography method；
S2, the method by active constituent protein obtained in S1 by dialysis are exchanged into following solution composition: protein active
Ingredient 1-50g/L, mannitol 20-40g/L, trishydroxymethylaminomethane 1-50mM, sodium chloride 1-50mM；And it is aided with a certain amount of
Glycine (10-40g/L) or sucrose (5-20g/L) or trehalose (5-20g/L).
S3, active constituent protein solution obtained in S2 is filtered, and carries out quantitative separating under sterile conditions, and
Every bottle of content is 1mL；
S4, bottled active constituent protein solution is freeze-dried, packaging is sealed under conditions of vacuum.
3. a kind of preparation method of wide spectrum freeze-drying dosage form protein composition according to claim 2, which is characterized in that
The preparation method of the freeze-drying the following steps are included:
S1, the good active constituent protein of quantitative separating is kept for 15-30 minutes in the environment of 5 DEG C, then declines temperature
It to -5 DEG C, and is kept for 15-30 minutes, the temperature of all samples is made to keep uniform；
S2, -40 DEG C are cooled the temperature to, is kept for 90 minutes；
S3, it is made annealing treatment, temperature rises to -20 DEG C, is kept for 2 hours；
S4, temperature is dropped to -40 DEG C, and is kept for 4 hours, freeze sample completely；
S5, pressure is declined at this time and is always maintained to the vacuum state of 0.1mBar, by the sample freezed completely in S4 -40
It is kept in the environment of DEG C 2 hours, temperature is then risen to -20 DEG C, and kept for 15 hours, the preliminarily dried of complete paired samples；
S6,20 DEG C are raised the temperature to, is kept for 5 hours, temperature is then risen to 40 DEG C, and kept for 6 hours, sample is completely dry
It is dry.
4. a kind of wide spectrum according to claim 1 is freeze-dried dosage form protein composition, which is characterized in that the glycine
Sucrose or trehalose instead can also be used, the parts by weight of the sucrose are 5-20g/L, and the parts by weight of the trehalose are 5-20g/
L。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857711A (en) * | 2006-03-23 | 2006-11-08 | 夏中宁 | Brain protein hydrolysate and production process of its freeze dried preparation |
| CN102228687A (en) * | 2011-06-24 | 2011-11-02 | 浙江普康生物技术股份有限公司 | Freeze-dried live attenuated hepatitis A vaccine not containing gelatin or human albumin protective agent and preparation method for freeze-dried live attenuated hepatitis A vaccine |
| CN102631328A (en) * | 2012-05-04 | 2012-08-15 | 常州千红生化制药股份有限公司 | Recombinant human antithrombosis protein lyophilized powder injection and preparation method thereof |
-
2019
- 2019-08-29 CN CN201910806084.0A patent/CN110420186A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1857711A (en) * | 2006-03-23 | 2006-11-08 | 夏中宁 | Brain protein hydrolysate and production process of its freeze dried preparation |
| CN102228687A (en) * | 2011-06-24 | 2011-11-02 | 浙江普康生物技术股份有限公司 | Freeze-dried live attenuated hepatitis A vaccine not containing gelatin or human albumin protective agent and preparation method for freeze-dried live attenuated hepatitis A vaccine |
| CN102631328A (en) * | 2012-05-04 | 2012-08-15 | 常州千红生化制药股份有限公司 | Recombinant human antithrombosis protein lyophilized powder injection and preparation method thereof |
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