CN106317245A - Preparation method of meningococcus group A capsular polysaccharide derivative - Google Patents
Preparation method of meningococcus group A capsular polysaccharide derivative Download PDFInfo
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- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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Abstract
The invention discloses a preparation method of a meningococcus group A capsular polysaccharide derivative. The preparation method includes materials and preparation processes. Meningococcus group A crude polysaccharide, cyanogens bromide, carbodiimide, distilled water, acetonitrile, hydrochloric acid, sodium chloride and sodium hydroxide, and the preparation processes of solution preparation, sugar dissolving, activating, deriving and ultrafiltration are adopted, so that oxygen acetyl content is ensured to meet standards, deriving rate of the meningococcus group A capsular polysaccharide derivative is increased, and the defect that the deriving rate of the prior art is difficult to increase is overcome. By the preparation method, the objective of increasing the deriving rate during preparing of the meningococcus group A capsular polysaccharide derivative is achieved.
Description
Technical field
The present invention relates to the preparation method of a kind of vaccine intermediate, specifically refer to for making the combination of A group meningitis cocci
A kind of preparation method of the A group meningitis cocci capsular polysaccharide derivant of the intermediate of vaccine.
Background technology
Nominal definition
Meningococcus: the formal name used at school of meningococcus (meningococcus) is Neisseria meningitidis
(n.meninyitidis), for the pathogen of epidemic cerebrospinal meningitis (epidemic encephalitis).Now cause the strain typing master of human lesion
A group to be had, B group, C group, Y group and W135 group.
Meningococcal polysaccharide vaccine: extract the outer capsular polysaccharide of the meningococcal antibacterial of specific bacterial strain, become epidemic disease through preparation
Seedling, is used for preventing the meningococcal invasion and attack of this bacterial strain to infect.
Meningococcus combined vaccine: extract the outer capsular polysaccharide of the meningococcal antibacterial of specific bacterial strain, by capsular polysaccharide
Carry out coupling with specific albumen or polypeptide, be prepared as conjugate, then become vaccine through preparation, be used for preventing this bacterial strain meningitis ball
The invasion and attack of bacterium are infected.
Capsular polysaccharide: the main component in the outer pod membrane of bacteria cell wall, can be homopolysaccharide or different polysaccharide.
Derivant: modified through chemical means by capsular polysaccharide, is formed and is prone to albumen or polypeptide is carried out in the one of coupling
Mesosome.
Derivative rate: evaluate the key parameter index of derivant preparation technology, be the weight having influence on conjugate quality standard
Want link parameter.
Oxygen acetyl group: all there is oxygen acetyl group in many bacterial eapsular polysaccharide, Acetoxylation is modified and is occurred to synthesize at polysaccharide
After, it has important meaning to the immunogenicity of antibacterial.
A meningococcal polysaccharide vaccine, hereinafter referred to as A epidemic encephalitis polysaccharide vaccine；Owing to A epidemic encephalitis polysaccharide vaccine is in 2 one full year of life
The antibody persistent period induced in following infants is short, it is impossible to inducing immunological memory, therefore A epidemic encephalitis polysaccharide vaccine is the most right
Adult has lasting immunity effect, to infant then without lasting immunity effect, to this end, take immunity inoculation is repeated several times, makes
Infant peace crosses meningitis popular season.Research shows, the capsular polysaccharide CPS in A epidemic encephalitis polysaccharide vaccine is that thymus-independent resists
Former TI-Ag, uses polysaccharide and protein carrier coupling, thymus independent antigen TI-Ag can be made to be changed into thymus dependent and resist
Former TD-Ag, thus change the antigenic property of capsular polysaccharide CPS, immunogenicity can be strengthened, induce immunological memory, by polysaccharide/egg
The white A group meningitis cocci combined vaccine combining preparation, is called for short A epidemic encephalitis combined vaccine, it is possible to provide long for 2 years old Infants Below
The immunization of phase anti-A epidemic encephalitis.
The preparation method of combined vaccine be broadly divided into directly in conjunction with use joint two class,
Directly in conjunction with method, the condensation reaction (shape of amido link being generally limited between carboxyl and the aldehyde radical with one-level amido
Become or amidatioon), its product need to reduce further could be stablized, such as reductive amination method (reductive amination), reduction
Amination method has been successfully used to prepare Hib, meningococcus combined vaccine.
Use joint method, use suitable probe to carry out albumen homopolysaccharide bridging coupling, and then form stable combination
Thing.Such as carbodiimide method, carbodiimides ADH can be used as probe, use CNBr activated polysaccharide in the basic conditions, then
The polysaccharide of activation is reacted formation PS-ADH derivant with ADH, under the mediation of EDC, forms stable knot afterwards with protein carrier
Compound.CNBr-ADH method is successfully used to prepare dysentery bacterium, Bacillus typhi, meningococcus combined vaccine, Hib knot
Close vaccine.
Present document relates to use in joint method for preparing a kind of method of the derivatives intermediates of A epidemic encephalitis combined vaccine, should
The full name of derivatives intermediates is: A group meningitis cocci capsular polysaccharide derivant；
The technique of A group meningitis cocci capsular polysaccharide derivant is prepared by each biological preparation producer and parameter is different, is obtained
Derivant quality be not quite similar, cause prepared conjugate, i.e. the quality of A epidemic encephalitis combined vaccine is difficult to unanimously；Preparation is spread out
Biological derivative technique is to determine the immunogenicity of conjugate, safety and the key of yield rate, and its difficult point is, derivant
Derivative rate is relation non-linear, shifting, unmanageable with oxygen acetyl content；
Prior art is guaranteeing that oxygen acetyl content meets Chinese Pharmacopoeia 2015 editions, A group meningitis ball many glycosyloxies acetyl group
On the premise of content requirement is not less than 2mmol/g standard, the derivative rate of prepared A group meningitis cocci capsular polysaccharide derivant
It is 0.23%～0.35%, on the low side；If improving derivative rate to 0.40%, then oxygen acetyl content is decreased obviously to less than mark
Accurate；Therefore, there are the problems and shortcomings that derivative rate is difficult to improve in prior art.
Summary of the invention
The problems and shortcomings existed for above-mentioned prior art, the present invention uses the rough polysaccharide of A group meningitis cocci, bromination
Cyanogen, carbodiimides, distilled water, acetonitrile, hydrochloric acid, sodium chloride and sodium hydroxide material, by solution preparation, molten sugar, activate, spread out
Raw, the preparation technology of ultrafiltration, on the premise of guaranteeing oxygen acetyl content conformance with standard, makes A group meningitis cocci capsular polysaccharide
The technical scheme that the derivative rate of derivant is improved, it is provided that the preparation side of a kind of A group meningitis cocci capsular polysaccharide derivant
Method, it is intended to make the preparation of A group meningitis cocci capsular polysaccharide derivant, reaches to improve the purpose of derivative rate.
The object of the present invention is achieved like this: the preparation method of a kind of A group meningitis cocci capsular polysaccharide derivant, bag
Include material and preparation technology, wherein:
Described material is:
The rough polysaccharide of A group meningitis cocci；
Bromine cyanide., analytical pure；
Carbodiimides, analytical pure；
A solvent, distilled water, analytical pure；
B solvent, acetonitrile, analytical pure；
Hydrochloric acid, analytical pure；
Sodium chloride, analytical pure；
Sodium hydroxide, analytical pure；
Described preparation technology, including solution preparation, molten sugar, activate, derivative and ultrafiltration, wherein:
Step one, solution preparation
Sodium chloride solution, 0.2mol/l, formulated with A solvent by sodium chloride；
C sodium hydroxide solution, 0.1mol/l, formulated with A solvent by sodium hydroxide；
D sodium hydroxide solution, 0.5mol/l, formulated with A solvent by sodium hydroxide；
Hydrochloric acid solution, 0.1mol/l, hydrochloric acid is formulated with A solvent；
Cyanogen bromide solution, 1g/ml, formulated with B solvent by Bromine cyanide.；
Carbodiimides solution, 0.1mol/l, formulated with described sodium chloride solution by carbodiimides；
Step 2, molten sugar
Take A group meningitis cocci rough polysaccharide 0.103g, be placed in beaker, add described sodium chloride solution 20ml, use magnetic
Power agitator stirs, speed of agitator 400 revs/min, mixing time 30 minutes, it is thus achieved that polysaccharide solution；Afterwards, polysaccharide will be filled molten
Heating in water bath in water-bath put into by the beaker of liquid, and water-bath temperature control is 23 ± 3 DEG C, described many with the regulation of described C sodium hydroxide solution
The pH value of sugar juice is to pH10.50 ± 0.20, it is thus achieved that J polysaccharide solution；
Step 3, activation
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add to J polysaccharide solution described in beaker
Entering described cyanogen bromide solution 150ml, carry out priming reaction, soak time 30 minutes, around here, with described D sodium hydroxide solution control
In beaker processed, the pH value of reactant keeps pH10.50 ± 0.20, it is thus achieved that H polysaccharide solution；Afterwards, institute is regulated with described hydrochloric acid solution
State the pH value of H polysaccharide solution to pH 9.0 ± 0.20, it is thus achieved that JH polysaccharide solution；
Step 4, derivative
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add to JH polysaccharide solution described in beaker
Enter described carbodiimides solution 600ml, carry out derivatization reaction, the derivative 15 minutes time, around here, molten with described D sodium hydroxide
In hydraulic control beaker, the pH value of reactant keeps pH9.00 ± 0.20, it is thus achieved that Y polysaccharide solution；Afterwards, described Y polysaccharide solution is moved
To in aseptic freezer, speed of agitator 600 revs/min, under the state of aseptic cold storehouse temperature 2～8 DEG C, carry out low temperature stirring,
Low temperature 16 hours used times of stirring, it is thus achieved that YP polysaccharide solution；
Step 5, ultrafiltration
By YP polysaccharide solution, carry out 6 times with the ultrafilter membrane bag of ultrafilter and 50kD and change membrane ultrafiltration, the concentrated solution after ultrafiltration,
It is A group meningitis cocci capsular polysaccharide derivant.
Beneficial effect
Testing result, the derivative rate of the A group meningitis cocci capsular polysaccharide derivant prepared by the present invention be 0.47%～
0.54%, oxygen acetyl content is 2.06～2.02mmol/g；That is, the derivative rate 0.47%～0.54% of the present invention is higher than existing
The 0.23%～0.35% of technology, the oxygen acetyl content 2.06～2.02mmol/g of the present invention meets Chinese Pharmacopoeia 2015 editions,
Oxygen acetyl content is not less than the requirement of 2mmol/g.
Above-mentioned, the present invention uses the rough polysaccharide of A group meningitis cocci, Bromine cyanide., carbodiimides, distilled water, acetonitrile, salt
Acid, sodium chloride and sodium hydroxide material, by solution preparation, molten sugar, activate, derive, the preparation technology of ultrafiltration, guaranteeing oxygen second
On the premise of acyl group content conformance with standard, make the technology that the derivative rate of A group meningitis cocci capsular polysaccharide derivant is improved
Scheme, overcomes prior art and there is the problems and shortcomings that derivative rate is difficult to improve, a kind of A group meningitis cocci pod provided
The preparation method of film polysaccharide derivates, makes the preparation of A group meningitis cocci capsular polysaccharide derivant, has reached to improve derivative rate
Purpose.
Embodiment explanation
Below by way of the specific embodiment preparation method to a kind of A group meningitis cocci capsular polysaccharide derivant of the present invention
Being described in further detail, those skilled in the art is referred to embodiment and prepares derivative rate is 0.47%～0.54%,
Oxygen acetyl content is the A group meningitis cocci capsular polysaccharide derivant of 2.06～2.02mmol/g, but should not be construed as this
Any restriction of invention.
Detailed description of the invention
Preparation condition, equipment
Ambient pressure a: atmospheric pressure；Ambient temperature: 15 DEG C；
Prepare facility, equipment: sterilizing room (C+A level), aseptic freezer, pH meter (FE 20), magnetic stirring apparatus (RCT
Basic), ultrafilter (50cm2-50kD), beaker, water-bath；
Embodiment
The name of an article: A group meningitis cocci capsular polysaccharide derivant
Material:
The rough polysaccharide of A group meningitis cocci；
Bromine cyanide., analytical pure；
Carbodiimides, analytical pure；
A solvent, distilled water, analytical pure；
B solvent, acetonitrile, analytical pure；
Hydrochloric acid, analytical pure；
Sodium chloride, analytical pure；
Sodium hydroxide, analytical pure；
Preparation technology is followed successively by: solution preparation, molten sugar, activate, derivative and ultrafiltration:
Step one, solution preparation
Sodium chloride solution, 0.2mol/l, formulated with A solvent by sodium chloride；
C sodium hydroxide solution, 0.1mol/l, formulated with A solvent by sodium hydroxide；
D sodium hydroxide solution, 0.5mol/l, formulated with A solvent by sodium hydroxide；
Hydrochloric acid solution, 0.1mol/l, hydrochloric acid is formulated with A solvent；
Cyanogen bromide solution, 1g/ml, formulated with B solvent by Bromine cyanide.；
Carbodiimides solution, 0.1mol/l, formulated with described sodium chloride solution by carbodiimides；
Step 2, molten sugar
Take A group meningitis cocci rough polysaccharide 0.103g, be placed in beaker, add described sodium chloride solution 20ml, use magnetic
Power agitator stirs, speed of agitator 400 revs/min, mixing time 30 minutes, it is thus achieved that polysaccharide solution；Afterwards, polysaccharide will be filled molten
Heating in water bath in water-bath put into by the beaker of liquid, and water-bath temperature control is 23 ± 3 DEG C, described many with the regulation of described C sodium hydroxide solution
The pH value of sugar juice is to pH10.50 ± 0.20, it is thus achieved that J polysaccharide solution；
Step 3, activation
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add to J polysaccharide solution described in beaker
Entering described cyanogen bromide solution 150ml, carry out priming reaction, soak time 30 minutes, around here, with described D sodium hydroxide solution control
In beaker processed, the pH value of reactant keeps pH10.50 ± 0.20, it is thus achieved that H polysaccharide solution；Afterwards, institute is regulated with described hydrochloric acid solution
State the pH value of H polysaccharide solution to pH 9.0 ± 0.20, it is thus achieved that JH polysaccharide solution；
Step 4, derivative
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add to JH polysaccharide solution described in beaker
Enter described carbodiimides solution 600ml, carry out derivatization reaction, the derivative 15 minutes time, around here, molten with described D sodium hydroxide
In hydraulic control beaker, the pH value of reactant keeps pH9.00 ± 0.20, it is thus achieved that Y polysaccharide solution；Afterwards, described Y polysaccharide solution is moved
To in aseptic freezer, speed of agitator 600 revs/min, under the state of aseptic cold storehouse temperature 2～8 DEG C, carry out low temperature stirring,
Low temperature 16 hours used times of stirring, it is thus achieved that YP polysaccharide solution；
Step 5, ultrafiltration
By YP polysaccharide solution, carry out 6 times with the ultrafilter membrane bag of ultrafilter and 50kD and change membrane ultrafiltration, the concentration obtained after ultrafiltration
Liquid, is A group meningitis cocci capsular polysaccharide derivant.
Through the detection of three batches, the derivative rate of above-mentioned A group meningitis cocci capsular polysaccharide derivant be 0.47%～
0.54%, oxygen acetyl content is 2.06～2.02mmol/g.
Claims (1)
1. a preparation method for A group meningitis cocci capsular polysaccharide derivant, including material and preparation technology, wherein:
Described material is:
The rough polysaccharide of A group meningitis cocci；
Bromine cyanide., analytical pure；
Carbodiimides, analytical pure；
A solvent, distilled water, analytical pure；
B solvent, acetonitrile, analytical pure；
Hydrochloric acid, analytical pure；
Sodium chloride, analytical pure；
Sodium hydroxide, analytical pure；
Described preparation technology is:
Step one, solution preparation
Sodium chloride solution, 0.2mol/l, formulated with A solvent by sodium chloride；
C sodium hydroxide solution, 0.1mol/l, formulated with A solvent by sodium hydroxide；
D sodium hydroxide solution, 0.5mol/l, formulated with A solvent by sodium hydroxide；
Hydrochloric acid solution, 0.1mol/l, hydrochloric acid is formulated with A solvent；
Cyanogen bromide solution, 1g/ml, formulated with B solvent by Bromine cyanide.；
Carbodiimides solution, 0.1mol/l, formulated with described sodium chloride solution by carbodiimides；
Step 2, molten sugar
Take A group meningitis cocci rough polysaccharide 0.103g, be placed in beaker, add described sodium chloride solution 20ml, stir with magnetic force
Mix device stirring, speed of agitator 400 revs/min, mixing time 30 minutes, it is thus achieved that polysaccharide solution；Afterwards, polysaccharide solution will be filled
Heating in water bath in water-bath put into by beaker, and water-bath temperature control is 23 ± 3 DEG C, regulates described polysaccharide with described C sodium hydroxide solution molten
The pH value of liquid is to pH10.50 ± 0.20, it is thus achieved that J polysaccharide solution；
Step 3, activation
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add institute to J polysaccharide solution described in beaker
State cyanogen bromide solution 150ml, carry out priming reaction, soak time 30 minutes, around here, control to burn with described D sodium hydroxide solution
In Bei, the pH value of reactant keeps pH10.50 ± 0.20, it is thus achieved that H polysaccharide solution；Afterwards, described H is regulated with described hydrochloric acid solution
The pH value of polysaccharide solution to pH 9.0 ± 0.20, it is thus achieved that JH polysaccharide solution；
Step 4, derivative
Water-bath temperature control 23 ± 3 DEG C, under the state that speed of agitator is 400 revs/min, add institute to JH polysaccharide solution described in beaker
Stating carbodiimides solution 600ml, carry out derivatization reaction, the derivative 15 minutes time, around here, with described D sodium hydroxide solution control
In beaker processed, the pH value of reactant keeps pH9.00 ± 0.20, it is thus achieved that Y polysaccharide solution；Afterwards, described Y polysaccharide solution is moved to nothing
In bacterium freezer, speed of agitator 600 revs/min, under the state of aseptic cold storehouse temperature 2～8 DEG C, carry out low temperature stirring, low temperature
16 hours used times of stirring, it is thus achieved that YP polysaccharide solution；
Step 5, ultrafiltration
By YP polysaccharide solution, carry out 6 times with the ultrafilter membrane bag of ultrafilter and 50kD and change membrane ultrafiltration, the concentrated solution after ultrafiltration, it is A
Group meningitis cocci capsular polysaccharide derivant.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105031642A (en) * | 2015-08-31 | 2015-11-11 | 成都欧林生物科技股份有限公司 | Meningococcal A capsular polysaccharide conjugate vaccine and preparation method thereof |
| CN105056221A (en) * | 2015-08-31 | 2015-11-18 | 成都欧林生物科技股份有限公司 | Method for preparing polysaccharide-ADH derivative by means of A-group meningococcal refined sugar |
| CN105056228A (en) * | 2015-08-31 | 2015-11-18 | 成都欧林生物科技股份有限公司 | Method for preparing group A meningococcal capsular polysaccharide conjugate vaccine |
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2016
- 2016-09-13 CN CN201610836848.7A patent/CN106317245A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105031642A (en) * | 2015-08-31 | 2015-11-11 | 成都欧林生物科技股份有限公司 | Meningococcal A capsular polysaccharide conjugate vaccine and preparation method thereof |
| CN105056221A (en) * | 2015-08-31 | 2015-11-18 | 成都欧林生物科技股份有限公司 | Method for preparing polysaccharide-ADH derivative by means of A-group meningococcal refined sugar |
| CN105056228A (en) * | 2015-08-31 | 2015-11-18 | 成都欧林生物科技股份有限公司 | Method for preparing group A meningococcal capsular polysaccharide conjugate vaccine |
Non-Patent Citations (3)
| Title |
|---|
| CHRISTOPHER JONES等: "Use and validation of NMR assays for the identity and O-acetyl content of capsular polysaccharides from Neisseria meningitidis used in vaccine manufacture", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| R SCHNEERSON等: "Preparation,characterization,and immunogenicity of haemophilus influenzae type b polysaccharide-protein conjugates", 《JOURNAL OF EXPERIMENTAL MEDICINE》 * |
| 刘方蕾等: "A群奈瑟氏脑膜炎球菌荚膜多糖-破伤风类毒素", 《微生物学免疫学进展》 * |
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Application publication date: 20170111 |