CN107744504A - A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine - Google Patents
A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine Download PDFInfo
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- CN107744504A CN107744504A CN201711040924.4A CN201711040924A CN107744504A CN 107744504 A CN107744504 A CN 107744504A CN 201711040924 A CN201711040924 A CN 201711040924A CN 107744504 A CN107744504 A CN 107744504A
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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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- 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
- A61K39/12—Viral antigens
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/525—Virus
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2720/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsRNA viruses
- C12N2720/00011—Details
- C12N2720/12011—Reoviridae
- C12N2720/12311—Rotavirus, e.g. rotavirus A
- C12N2720/12334—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
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Abstract
The present invention provides a kind of MA104 cells and prepares lyophilized technique method of the people with rotavirus live vaccine, wherein semi-finished product are made in described not purified Rotavirus Vaccine stoste after being mixed with excipient, protective agent, starts pre-freeze；The pre- canned cillin bottle for there are semi-finished product is positioned on the shelf of freeze dryer, is put into temp probe and eutectic point detection probe, carry out pre-freeze；Practical vacuum degree is maintained between 0.15mbar~0.2mbar using 30min duration；After vacuum is constant, shelf divides four-stage heating to be respectively warming up to 35 DEG C for 40 DEG C, and 35 DEG C are warming up to 25 DEG C, and 25 DEG C are warming up to 15 DEG C, and 15 DEG C are warming up to 5 DEG C；Further vacuumize；Between temperature is risen into 15 DEG C~25 DEG C in subsequent 60min, 200min~400min is maintained, end article is obtained after vacuum state lower cover export；Advantage is：Improve the stability of people prepared by MA104 cell culture with rotavirus live vaccine, in favor of its long-term storage and transport.Raw material is easy to get, in the absence of collapse, atrophy, duricrust and wall built-up problem.
Description
Technical field
The present invention relates to vaccine for man research and development technology field, and people is prepared with colyliform disease more particularly, to a kind of MA104 cells
The lyophilized technique method of virus live vaccine.
Background technology
Rotavirus is the main pathogen for causing autumn-winter infantile diarrhea.Nearly all children before 5 years old all by
Rotavirus infection is crossed, the whole world there are about 1.11 hundred million -1.35 hundred million rotavirus diarrhea cases every year, cause about 650,000 babies dead
Die.But rotavirus infection, without specific treatment medicine, vaccine is the means of preferred prevention and control rotavirus infection.
Rotavirus is not suitable with general tissue cultures, need to select special cell line MA104 strains（Rhesus macaque embryonic kidney is thin
Born of the same parents）Culture, but problems be present：First, stoste made of MA104 cell culture rotavirus is without purification step, its
In containing the uncontrollable material such as part cell fragment, foreign protein, salt, collapsed so the product completed using conventional lyophilized technique is present
The problems such as sunken, duricrust, atrophy and wall built-up；Secondly, such vaccine only has one kind on domestic market, is Lanzhou Institute of Biological Products
The rood prestige of Co., Ltd's production, and the vaccine is liquid oral seedling, limitation be present in terms of long-term preservation and transport,
Therefore to improve the market utilization rate of product, a kind of effective lyophilized technique method of research and development, which carries out the lyophilized of such vaccine, is
Urgent problem to be solved.
The content of the invention
It is an object of the invention to be solution the deficiencies in the prior art, and a kind of MA104 cells are provided and prepare people's colyliform
The lyophilized technique method of viral lived vaccine.
The new technical scheme of the present invention is：A kind of MA104 cells prepare lyophilized technique side of the people with rotavirus live vaccine
Method, described processing step are：
1）Semi-finished product are made in not purified Rotavirus Vaccine stoste after being mixed with excipient, protective agent, start pre-freeze；
2）By the pre- canned cillin bottle for having semi-finished product, specification is 0.5ml/ branch, is positioned on the shelf of freeze dryer, and selection has generation
The cillin bottle of table, temp probe and eutectic point detection probe are put into, carry out pre-freeze：With 2 DEG C/min speed, use
12.5min duration is cooled to 0 DEG C from 25 DEG C, and maintains 60min；With 1 DEG C/min speed, using 10min duration from 0 DEG C
- 20 DEG C are cooled to, and maintains 60min；With 1 DEG C/min speed, -40 DEG C are cooled to from -20 DEG C using 10min duration, and
Maintain 120min；
3）The vacuum in freeze dryer is down to 0.1mbar using 30min duration, practical vacuum degree maintain 0.15mbar~
Between 0.2mbar；
4）After vacuum is constant, shelf divides four-stage heating to be respectively warming up to -35 DEG C for -40 DEG C, and -35 DEG C are warming up to -25
DEG C, -25 DEG C are warming up to -15 DEG C, and -15 DEG C are warming up to -5 DEG C；
5）Further vacuumize, the vacuum in freeze dryer is down to 0.01mbar by 0.1mbar using 30min duration, together
When shelf be warming up to 5 DEG C by -5 DEG C；
6）Between temperature is risen into 15 DEG C~25 DEG C in subsequent 60min, 200min~400min is maintained, vacuum state lower cover goes out
End article is obtained behind storehouse, outward appearance, dissolution time, moisture, titre reach requirement.
The excipient of the d is free of gelatin, and mass percent concentration is：6%~8% mannitol, 1%~3% dextrose
Acid anhydride.
Described protectant mass percent concentration is：2%~3% sodium glutamate, 2%~3.5% histidine and
0.01%~1% human serum albumin.
Described excipient, protective agent concentration as requested, calculate and weigh mannitol needed for mother liquor is made respectively,
Dextran, sodium glutamate, histidine, it is dissolved in the water for injection of certain volume, wherein mannitol and dextran need 37
DEG C tepidarium, after being completely dissolved and being cooled to room temperature constant volume, 0.22 μm filtering with microporous membrane is degerming that mother liquor is made.
Described protective agent human serum albumin concentration as needed is fed directly in virus stock solution used.
Described end article outward appearance is loosening body；Moisture is 1.50%（Mass percent）；Dissolution time is 12s,
Without collapse, atrophy and wall built-up phenomenon.
The beneficial effects of the invention are as follows：Improve the stability of people prepared by MA104 cell culture with rotavirus live vaccine,
In favor of its long-term storage and transport.Raw material is easy to get, in the absence of collapse, atrophy, duricrust and wall built-up problem.
Brief description of the drawings
Fig. 1 is the process step of the invention.
Fig. 2 is the product description of the present invention.
Embodiment
A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine, and described processing step is：
1）Semi-finished product are made in not purified Rotavirus Vaccine stoste after being mixed with excipient, protective agent, start pre-freeze；
2）By the pre- canned cillin bottle for having semi-finished product, specification is 0.5ml/ branch, is positioned on the shelf of freeze dryer, and selection has generation
The cillin bottle of table, temp probe and eutectic point detection probe are put into, carry out pre-freeze：With 2 DEG C/min speed, use
12.5min duration is cooled to 0 DEG C from 25 DEG C, and maintains 60min；With 1 DEG C/min speed, using 10min duration from 0 DEG C
- 20 DEG C are cooled to, and maintains 60min；With 1 DEG C/min speed, -40 DEG C are cooled to from -20 DEG C using 10min duration, and
Maintain 120min；
3）The vacuum in freeze dryer is down to 0.1mbar using 30min duration, practical vacuum degree maintain 0.15mbar~
Between 0.2mbar；
4）After vacuum is constant, shelf divides four-stage heating to be respectively warming up to -35 DEG C for -40 DEG C, and -35 DEG C are warming up to -25
DEG C, -25 DEG C are warming up to -15 DEG C, and -15 DEG C are warming up to -5 DEG C；
5）Further vacuumize, the vacuum in freeze dryer is down to 0.01mbar by 0.1mbar using 30min duration, together
When shelf be warming up to 5 DEG C by -5 DEG C；
6）Between temperature is risen into 15 DEG C~25 DEG C in subsequent 60min, 200min~400min is maintained, vacuum state lower cover goes out
End article is obtained behind storehouse, outward appearance, dissolution time, moisture, titre reach requirement.
The excipient of the d is free of gelatin, and mass percent concentration is：6%~8% mannitol, 1%~3% dextrose
Acid anhydride.
Described protectant mass percent concentration is：2%~3% sodium glutamate, 2%~3.5% histidine and
0.01%~1% human serum albumin.
Described excipient, protective agent concentration as requested, calculate and weigh mannitol needed for mother liquor is made respectively,
Dextran, sodium glutamate, histidine, it is dissolved in the water for injection of certain volume, wherein mannitol and dextran need 37
DEG C tepidarium, after being completely dissolved and being cooled to room temperature constant volume, 0.22 μm filtering with microporous membrane is degerming that mother liquor is made.
Described protective agent human serum albumin concentration as needed is fed directly in virus stock solution used.
Described end article outward appearance is loosening body；Moisture is 1.50%（Mass percent）；Dissolution time is 12s,
Without collapse, atrophy and wall built-up phenomenon.
Claims (6)
1. a kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine, it is characterised in that：
Described processing step is：
1）Semi-finished product are made in not purified Rotavirus Vaccine stoste after being mixed with excipient, protective agent, start pre-freeze；
2）By the pre- canned cillin bottle for having semi-finished product, specification is 0.5ml/ branch, is positioned on the shelf of freeze dryer, and selection has generation
The cillin bottle of table, temp probe and eutectic point detection probe are put into, carry out pre-freeze：With 2 DEG C/min speed, use
12.5min duration is cooled to 0 DEG C from 25 DEG C, and maintains 60min；With 1 DEG C/min speed, using 10min duration from 0 DEG C
- 20 DEG C are cooled to, and maintains 60min；With 1 DEG C/min speed, -40 DEG C are cooled to from -20 DEG C using 10min duration, and
Maintain 120min；
3）The vacuum in freeze dryer is down to 0.1mbar using 30min duration, practical vacuum degree maintain 0.15mbar~
Between 0.2mbar；
4）After vacuum is constant, shelf divides four-stage heating to be respectively warming up to -35 DEG C for -40 DEG C, and -35 DEG C are warming up to -25
DEG C, -25 DEG C are warming up to -15 DEG C, and -15 DEG C are warming up to -5 DEG C；
5）Further vacuumize, the vacuum in freeze dryer is down to 0.01mbar by 0.1mbar using 30min duration, together
When shelf be warming up to 5 DEG C by -5 DEG C；
6）Between temperature is risen into 15 DEG C~25 DEG C in subsequent 60min, 200min~400min is maintained, vacuum state lower cover goes out
End article is obtained behind storehouse, outward appearance, dissolution time, moisture, titre reach requirement.
2. a kind of MA104 cells according to claim 1 prepare lyophilized technique method of the people with rotavirus live vaccine, its
It is characterised by：Described excipient is free of gelatin, and mass percent concentration is：6%~8% mannitol, 1%~3% dextrose
Acid anhydride.
3. a kind of MA104 cells according to claim 1 prepare lyophilized technique method of the people with rotavirus live vaccine, its
It is characterised by：Described protectant mass percent concentration is：2%~3% sodium glutamate, 2%~3.5% histidine and
0.01%~1% human serum albumin.
4. a kind of MA104 cells according to claim 1 prepare lyophilized technique method of the people with rotavirus live vaccine, its
It is characterised by:Described excipient, protective agent concentration as requested, calculate and weigh sweet dew needed for mother liquor is made respectively
Alcohol, dextran, sodium glutamate, histidine, it is dissolved in the water for injection of certain volume, wherein mannitol and dextran need
37 DEG C of tepidariums, after being completely dissolved and being cooled to room temperature constant volume, 0.22 μm filtering with microporous membrane is degerming that mother liquor is made.
5. a kind of MA104 cells according to claim 1 prepare lyophilized technique method of the people with rotavirus live vaccine, its
It is characterised by:Described protective agent human serum albumin concentration as needed is fed directly in virus stock solution used.
6. a kind of MA104 cells according to claim 1 prepare lyophilized technique method of the people with rotavirus live vaccine, its
It is characterised by:Described end article outward appearance is loosening body；Moisture is 1.50%（Mass percent）；Dissolution time is
12s, without collapse, atrophy and wall built-up phenomenon.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711040924.4A CN107744504A (en) | 2017-10-31 | 2017-10-31 | A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711040924.4A CN107744504A (en) | 2017-10-31 | 2017-10-31 | A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine |
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| Publication Number | Publication Date |
|---|---|
| CN107744504A true CN107744504A (en) | 2018-03-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711040924.4A Pending CN107744504A (en) | 2017-10-31 | 2017-10-31 | A kind of MA104 cells prepare lyophilized technique method of the people with rotavirus live vaccine |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202688A (en) * | 2008-11-07 | 2011-09-28 | 印度血清研究所有限公司 | Stable, dried rotavirus vaccine, compositions and process for preparation thereof |
-
2017
- 2017-10-31 CN CN201711040924.4A patent/CN107744504A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102202688A (en) * | 2008-11-07 | 2011-09-28 | 印度血清研究所有限公司 | Stable, dried rotavirus vaccine, compositions and process for preparation thereof |
Non-Patent Citations (1)
| Title |
|---|
| 傅超美: "《药用辅料学》", 31 October 2008, 中国中医药出版社 * |
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Application publication date: 20180302 |