CN104587444B - A kind of preparation method of high protein content Cerebrolysin Vial - Google Patents
A kind of preparation method of high protein content Cerebrolysin Vial Download PDFInfo
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Abstract
The present invention discloses a kind of preparation method of high protein content Cerebrolysin Vial, including the homogenate of (1) tissue；(2) liquefy；(3) protein concentration；(4) pepsin digests；(5) trypsin digestion；(6) ultrafiltration.Described step (3) is reclaimed gel, recycled using N substitution polyacrylamides or N substitution polyacrylamide copolymer gels in 5 25 DEG C of protein concentrates, LCST temperatures above.The present invention solves the problems, such as that existing method Cerebrolysin Vial protein content is low, at the same it is unexpected solve organic solvent degreasing, the problem of causing dissolvent residual and environmental hazard.Hydrolyzate content of peptides meets national standard up to more than 88% obtained by this method.
Description
Technical field
The present invention relates to medicine and field of health care food, more particularly to a kind of preparation method of Cerebrolysin Vial.
Background technology
Cerebrolysin Vial is a kind of active peptides for obtaining animal brain after enzyme hydrolysis, can be made in many ways
For nervous centralis, regulation and the metabolism for improving neuron promote the formation of cynapse, the differentiation of Induction of neuronal, and further
Protect nerve cell from the infringement of various ischemics and neurotoxin.
The basic production technique of Cerebrolysin Vial is as follows：After animal brain removes the mucous membrane and bloodstain on surface, add water
Homogenate, degreasing, pepsin enzymolysis, trypsin digestion, ultrafiltration.
Low, the national drug standards WS1-XG- using brain protein hydrolyzate nitrogen content prepared by prior art production technology
025-2000 provides that material nitrogen content is 8%-10% after drying, and is converted into amino acid and content of peptides 60% or so, 40%
Unknown materials caused by potential clinical risk well imagine that therefore State Food and Drug Administration is to the mark of such product
Standard is improving constantly, and is phased out backward products.
In addition, the purpose of degreasing is more thorough for proteolysis in existing process, filtering is unobstructed, method typically using acetone or
Acetone double solvents degreasing, such as Chinese patent 200410043939.2,94104516.1, but because largely using organic solvent,
Environmental hazard and dissolvent residual can be caused.
The content of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide a kind of preparation method of Cerebrolysin Vial.Its
It is homogenized including (1) tissue；(2) liquefy；(3) protein concentration；(4) pepsin digests；(5) trypsin digestion；(6) ultrafiltration.
(1) tissue is homogenized：Freezing or fresh mammal brain, cleaning, add water to be homogenized；
(2) liquefy：3-5 times is added in above-mentioned homogenate and measures water for injection, 0.1MNaOH adjusts pH value to 7.5-8.5, stirred
Mix 10min-20min, 5 DEG C -20 DEG C of temperature.
(3) protein concentration：By alkaline solution filtering obtained by step (2), thermo-sensitive gel concentration and recovery water solubility therein is used
Albumen, the poly- N- substituted acrylamides of thermo-sensitive gel system or poly- N- substituted acrylamides copolymer, its basic structure are [- CH2-
CHRCONR ' R " -] m [- A-] n [- B-] x, wherein R be H or 1-5 carbon atom alkyl；R ' is the alkane of H or 2-5 carbon atom
Base；R " is the alkyl of 2-5 carbon atom；It is preferred that R is H or methyl, R ' and R ' ' for 2-4 carbon alkyl；- A- is optional group,
From hydrophilic monomer, it is preferred that-A- moles of accounting 1%-5%；- B- radical sources in monomer bi-functional cross-linking agent, mole
Accounting 0.5%-10%.N can be wider for 0, m and x mobility scale, is determined according to monomer and crosslinking agent mol ratio.It is preferred that
Gel is poly-N-isopropyl acrylamide, poly- (NIPA-co- methacrylic acids) sodium salt, with N, N '-methylene
Bisacrylamide (BIS) is crosslinking agent.
Gel used in this step is graininess, and it expands and shrinkage temperature should be in the range of 5 DEG C, and minimum may expand as its is original
5 times of volume.Temperature should be less than the minimum critical phase transition temperature (LCST) of thermo-sensitive gel used when step (3) concentrates, and preferably 5
℃-25℃。
Can heat up contraction after thermo-sensitive gel expansion used in this step, recycle, shrinkage temperature is higher than minimum critical phase alternating temperature
Spend (LCST).Volume is the 5%-20% of swelling volume after it shrinks.Usable thermo-sensitive gel concentrates repeatedly, until protein concentration
Up to 15%-25%.
The equipment that the concentration of this step uses is double-deck cylindric drum, and internal layer drum contains thermo-sensitive gel, and side wall opens 40 mesh sieves
Hole, and freely can be taken out from outer layer bucket, agitating paddle gos deep into internal layer bucket to stir thermo-sensitive gel.
(4) pepsin digests：Add water to be homogenized filter residue obtained by step (3), hydrochloric acid adjustment pH=1-3, be warming up to 35 DEG C-
45 DEG C, the pepsin of brain weight 1%~3% is added, stirring, hydrolyzes 10-20 hours, is cooled down, filtering, obtains gastric enzyme hydrolyzate；
Preferably, pH=2 is adjusted, 40 DEG C of temperature, the pepsin of brain weight 1.5% is added, hydrolyzes 15 hours.
(5) trypsin digestion：Step (4) gastric enzyme hydrolyzate is adjusted into pH=7-9 with NaOH, is warming up to 40 DEG C -60 DEG C,
Brain weight 1%-3% trypsin digestion is added, stirring, hydrolyzes 2-10 hours, heating micro-boiling 10min is finished and inactivates, cooling,
Filtering, obtains trypsin hydrolysis liquid；Preferably, pH=7.6-8.0, temperature 45 C, the tryptose of 2% brain weight of addition are adjusted
Enzyme, hydrolyze 5 hours.
(6) ultrafiltration：By enzymolysis liquid obtained by step (5), regulation pH value is with molecular cut off to neutral (6.5-7.5)
The ultrafilter of 10000 dalton carries out ultrafiltration, collects the liquid that molecular weight is less than 10000 dalton, gained ultrafiltrate is brain egg
White hydrolysate.
Mammal of the present invention means other mammals except people, including pig, ox, horse, sheep, rabbit, dog etc.,
It is preferred that pig, ox, sheep.
The Cerebrolysin Vial and one or more carriers and/or diluent system of the further requirement protection present invention of the present invention
Medicine and Halth-care composition, the acceptable any formulation of in the market can be made.
For it is oral when, can be made into conventional solid pharmaceutical preparation, such as tablet, capsule, pill, granule：It may be made as
Oral liquid, such as oral solution, oral suspensions, syrup.When oral formulations are made, suitable fill out can be added
Fill agent, adhesive, disintegrant, lubricant etc..During for parenteral, can be made into injection, including parenteral solution, injection without
Bacterium powder end and concentrated solution for injection.When injection is made, the conventional method production in existing pharmaceutical field can be used, prepares injection
During agent, additives can be added without, suitable additives can be also added according to the property of medicine.
The Cerebrolysin Vial of the further requirement protection present invention of the present invention is preparing treatment and/or prevention brain disorder
Medicine and/or health products in application.
Compared with prior art, the present invention has advantages below and beneficial effect：
(1) present invention is from N- substitution polyacrylamides or N- substitution polyacrylamide copolymer thermo-sensitive gel concentrate eggs
In vain, effectively remove small molecular weight impurity, reduce that product is clinical or risk used in everyday..
(2) while the present invention solves the problems, such as Cerebrolysin Vial protein content, it is found surprisingly that, is taken off without using solvent
Fat, the present invention equally solves the thorough sex chromosome mosaicism of proteolysis, and subsequent technique filtering is smooth, and final products fat content is low.
Embodiment
Embodiments of the invention are described in detail below, it is necessary to which explanation, the present embodiment is narrative, is not limited
, it is impossible to protection scope of the present invention is limited with this.
Comparing embodiment 1
Different process is respectively adopted to be tested, compares final products yield, active peptides content, filtering difficulty or ease, solvent
Residual, fat content.
Existing process step is as follows：(1) pig brain is homogenized；(2) degreasing；(3) pepsin digests；(4) trypsin digestion；
(5) ultrafiltration, produce.
Present invention process step is as follows：(1) pig brain is homogenized；(2) liquefy；(3) gel protein concentrate；(4) pepsin enzyme
Solution；(5) trypsin digestion；(6) ultrafiltration, produce.
The corresponding product obtained of different process is as shown in Table：
1In terms of dry.
2Actual is polypeptide and free aminoacid content, and 6.25 calculating are multiplied by with Kjeldahl nitrogen determination nitrogen content.
3Gel 1 is poly-N-isopropyl acrylamide, and gel 2 is poly- (NIPA-co- methacrylic acids)
Sodium salt, crosslinking agent N, N '-methylene-bisacrylamide (BIS).
As a result show, using poly-N-isopropyl acrylamide and poly- (NIPA-co- methacrylic acids) sodium
Salt protein concentrate product content of peptides highest, yield is good, and filtering is simple, and acetone degreasing process product fat content is low, but effectively
Content of material is low, remains poisonous and harmful substance.
Embodiment 1
Fresh pig brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds pig brain
The water for injection of 3 times of weight, 0.1MNaOH adjust pH value to 8.0, stir 15min, filter, filtrate is standby.In concentrator
0.1 times of amount poly-N-isopropyl acrylamide thermo-sensitive gel of brain weight is added in layer bucket and (melts the limited public affairs of sunlight management of investment in Beijing
Research institute is taken charge of to provide) and a small amount of dimethyl silicone polymer (defoamer), the standby filtrate of upper step is added in concentrator, keeps filter
Liquid temperature degree stirs 40min between 15 DEG C -20 DEG C, proposes the gel of expansion, is carefully cleaned with a small amount of water for injection, and water lotion closes
It is incorporated to concentrate.The gel of expansion is inserted in 40 DEG C of waste liquid tanks, the gel after Phase change shrinkage can repeat aforesaid operations again, directly
Into concentrate, protein content reaches 20%.Concentrate is poured into enzymatic vessel, adds 1.5 times of brain weight waters for injection, is warming up to 42
DEG C, pH=1.5 is adjusted with 4.5% hydrochloric acid, adds the pepsin of brain weight 1.5%, maintains pH=1.5-1.7, is hydrolyzed 8 hours,
Pepsin hydrolysis slurries are adjusted into pH to 7.8 with 5M NaOH, add the trypsase of brain weight 1.5%, after stirring evenly, pH value dimension
Hold in 7.5-8.0,42 DEG C hydrolyze 4 hours, and enzymolysis is heated to micro-boiling after terminating, and keep 10min, cool, centrifuge
Centrifugation, by the supernatant after centrifugation through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, obtains faint yellow clear solution, i.e. pig brain albumen
Hydrolysate.
Cerebrolysin Vial dry nitrogen content 13.9%, fat content 0.8%, according to country as made from process above
Drug standards WS1- XG-025-2000 carries out high performance liquid chromatography inspection, Cerebrolysin Vial solution prepared by this technique
The reference colour spectrogram of Cerebrolysin Vial of the chromatogram with compareing is consistent.
Embodiment 2
Fresh pig brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds pig brain
The water for injection of 3 times of weight, 0.1MNaOH adjust pH value to 8.0, stir 15min, filter, filtrate is standby.In concentrator
Poly- (NIPA-co- methacrylic acids) the sodium salt thermo-sensitive gel of 0.1 times of amount of brain weight is added in layer bucket (in Beijing
The offer of research institute of sunlight management of investment Co., Ltd is provided) and a small amount of dimethyl silicone polymer (defoamer), by the standby filtrate of upper step
Add in concentrator, keep filtrate temperature to stir 40min between 15 DEG C -20 DEG C, propose the gel of expansion, with a small amount of injection
Carefully cleaned with water, water lotion is merged into concentrate.The gel of expansion is inserted in 40 DEG C of waste liquid tanks, the gel after Phase change shrinkage
Aforesaid operations can be repeated again, until protein content reaches 20% in concentrate.Concentrate is poured into enzymatic vessel, adds 1.5 times of brains
Weight water for injection, 42 DEG C are warming up to, adjust pH=1.5 with 4.5% hydrochloric acid, add the pepsin of brain weight 2%, maintain pH=
1.5-1.7, hydrolyze 8 hours, pepsin hydrolysis slurries are adjusted into pH to 7.8 with 5M NaOH, add the pancreas egg of brain weight 2.0%
White enzyme, after stirring evenly, pH value maintains 7.5-8.0, and 42 DEG C hydrolyze 4 hours, and enzymolysis is heated to micro-boiling after terminating, and keep
10min, cool, centrifuge, by the supernatant after centrifugation through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, obtain yellowish
Color clear solution, i.e. cerebroprotein hydrolysate.
Cerebrolysin Vial dry nitrogen content 14.1%, fat content 0.8%, according to country as made from process above
Drug standards WS1- XG-025-2000 carries out high performance liquid chromatography inspection, Cerebrolysin Vial solution prepared by this technique
The reference colour spectrogram of Cerebrolysin Vial of the chromatogram with compareing is consistent.
Embodiment 3
Fresh pig brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds pig brain
The water for injection of 4 times of weight, 0.1MNaOH adjust pH value to 7.7, stir 15min, filtering, filtrate be refrigerated to 5 DEG C it is standby.Dense
Poly- (NIPA-co- methacrylic acids) the sodium salt thermo-sensitive gel of 0.1 times of amount of brain weight is added in contracting equipment internal layer bucket
(offer of research institute of sunlight management of investment Co., Ltd is provided in Beijing) and a small amount of dimethyl silicone polymer (defoamer), upper step is standby
Added with filtrate in concentrator, keep filtrate temperature to stir 40min between 5 DEG C -10 DEG C, the gel of expansion is proposed, with a small amount of
Water for injection carefully cleans, and water lotion is merged into concentrate.The gel of expansion is inserted in 40 DEG C of waste liquid tanks, after Phase change shrinkage
Gel can repeat aforesaid operations again, until protein content reaches 20% in concentrate.Concentrate is poured into enzymatic vessel, adds 1.5
Times brain weight water for injection, is warming up to 40 DEG C, and pH=2.0 is adjusted with 4.5% hydrochloric acid, adds the pepsin of brain weight 1.5%, dimension
PH=1.5-1.7 is held, is hydrolyzed 8 hours, pepsin hydrolysis slurries are adjusted into pH to 7.8 with 5M NaOH, add brain weight 2.0%
Trypsase, after stirring evenly, pH value maintains 7.5-8.0, and 40 DEG C hydrolyze 4 hours, and enzymolysis is heated to micro-boiling after terminating, and protect
10min is held, is cooled, centrifuge, by the supernatant after centrifugation through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, is obtained light
Yellow clear solution, i.e. cerebroprotein hydrolysate.
Cerebrolysin Vial dry nitrogen content 13.7%, fat content 1.0%, according to country as made from process above
Drug standards WS1- XG-025-2000 carries out high performance liquid chromatography inspection, Cerebrolysin Vial solution prepared by this technique
The reference colour spectrogram of Cerebrolysin Vial of the chromatogram with compareing is consistent.
Embodiment 4
Fresh pig brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds pig brain
The water for injection of 3 times of weight, 0.1MNaOH adjust pH value to 8.0, stir 15min, filter, filtrate is standby.In concentrator
0.1 times of amount poly-N-isopropyl acrylamide thermo-sensitive gel of brain weight is added in layer bucket and (melts the limited public affairs of sunlight management of investment in Beijing
Research institute is taken charge of to provide) and a small amount of dimethyl silicone polymer (defoamer), the standby filtrate of upper step is added in concentrator, keeps filter
Liquid temperature degree stirs 40min between 15-20 DEG C, proposes the gel of expansion, centrifuge dripping, and centrifugate is merged into concentrate.Will expansion
Gel insert in 40 DEG C of waste liquid tanks, the gel after Phase change shrinkage can again repeat aforesaid operations, until concentrate in albumen contain
Amount reaches 25%.Concentrate is poured into enzymatic vessel, adds 2 times of brain weight waters for injection, is warming up to 42 DEG C, pH is adjusted with 4.5% hydrochloric acid
=2.0, the pepsin of brain weight 1.5% is added, maintains pH=1.5-1.7, is hydrolyzed 8 hours, with 5M NaOH by pepsin
Hydrolyze slurries and adjust pH to 8.0, add the trypsase of brain weight 2.0%, after stirring evenly, pH value maintains 7.5-8.0,42 DEG C of hydrolysis
4 hours, enzymolysis was heated to micro-boiling after terminating, and keeps 10min, cools, centrifuge, by the supernatant after centrifugation
Through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, faint yellow clear solution, i.e. cerebroprotein hydrolysate are obtained.
Cerebrolysin Vial dry nitrogen content 14.2%, fat content 0.9%, according to country as made from process above
Drug standards WS1- XG-025-2000 carries out high performance liquid chromatography inspection, Cerebrolysin Vial solution prepared by this technique
The reference colour spectrogram of Cerebrolysin Vial of the chromatogram with compareing is consistent.
Embodiment 5
Fresh bovine brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds bovine brain
The water for injection of 3 times of weight, 0.1MNaOH adjust pH value to 8.0, stir 15min, filter, filtrate is standby.In concentrator
0.1 times of amount poly-N-isopropyl acrylamide thermo-sensitive gel of brain weight is added in layer bucket and (melts the limited public affairs of sunlight management of investment in Beijing
Research institute is taken charge of to provide) and a small amount of dimethyl silicone polymer (defoamer), the standby filtrate of upper step is added in concentrator, keeps filter
Liquid temperature degree stirs 40min between 15 DEG C -20 DEG C, proposes the gel of expansion, is carefully cleaned with a small amount of water for injection, and water lotion closes
It is incorporated to concentrate.The gel of expansion is inserted in 40 DEG C of waste liquid tanks, the gel after Phase change shrinkage can repeat aforesaid operations again, directly
Into concentrate, protein content reaches 20%.Concentrate is poured into enzymatic vessel, adds 1.5 times of brain weight waters for injection, is warming up to 42
DEG C, pH=1.5 is adjusted with 4.5% hydrochloric acid, adds the pepsin of brain weight 1.5%, maintains pH=1.5-1.7, is hydrolyzed 8 hours,
Pepsin hydrolysis slurries are adjusted into pH to 7.8 with 5M NaOH, add the trypsase of brain weight 1.5%, after stirring evenly, pH value dimension
Hold in 7.5-8.0,42 DEG C hydrolyze 4 hours, and enzymolysis is heated to micro-boiling after terminating, and keep 10min, cool, centrifuge
Centrifugation, by the supernatant after centrifugation through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, obtains faint yellow clear solution, i.e. bovine brain albumen
Hydrolysate.
Cerebrolysin Vial dry nitrogen content 14.1%, fat content 0.9% as made from process above.
Embodiment 6
Fresh sheep brain is removed into meninx and blood vessel, is eluted with water, drains, colloid mill is levigate, collects homogenate, adds sheep brain
The water for injection of 3 times of weight, 0.1MNaOH adjust pH value to 8.0, stir 15min, filter, filtrate is standby.In concentrator
0.1 times of amount poly-N-isopropyl acrylamide thermo-sensitive gel of brain weight is added in layer bucket and (melts the limited public affairs of sunlight management of investment in Beijing
Research institute is taken charge of to provide) and a small amount of dimethyl silicone polymer (defoamer), the standby filtrate of upper step is added in concentrator, keeps filter
Liquid temperature degree stirs 40min between 15 DEG C -20 DEG C, proposes the gel of expansion, is carefully cleaned with a small amount of water for injection, and water lotion closes
It is incorporated to concentrate.The gel of expansion is inserted in 40 DEG C of waste liquid tanks, the gel after Phase change shrinkage can repeat aforesaid operations again, directly
Into concentrate, protein content reaches 20%.Concentrate is poured into enzymatic vessel, adds 1.5 times of brain weight waters for injection, is warming up to 42
DEG C, pH=1.5 is adjusted with 4.5% hydrochloric acid, adds the pepsin of brain weight 1.5%, maintains pH=1.5-1.7, is hydrolyzed 8 hours,
Pepsin hydrolysis slurries are adjusted into pH to 7.8 with 5M NaOH, add the trypsase of brain weight 1.5%, after stirring evenly, pH value dimension
Hold in 7.5-8.0,42 DEG C hydrolyze 4 hours, and enzymolysis is heated to micro-boiling after terminating, and keep 10min, cool, centrifuge
Centrifugation, by the supernatant after centrifugation through the molecular weight mwco membrane ultrafiltration of ultrafilter 10,000, obtains faint yellow clear solution, i.e. sheep brain albumen
Hydrolysate.
Cerebrolysin Vial dry nitrogen content 14.2%, fat content 0.8% made from process above.
Claims (6)
1. a kind of preparation method of Cerebrolysin Vial, comprises the following steps：
(1) tissue is homogenized；
(2) liquefy；
(3) protein concentration；
(4) pepsin digests；
(5) trypsin digestion；
(6) ultrafiltration；
Characterized in that, step (2) condition is：NaOH adjusts pH value 7.5-8.5, stirs 10-20min；Step (4) bar
Part is：Pepsin dosage 1%~3%, pH value 1-3, hydrolysis temperature are 35 DEG C -45 DEG C, enzymolysis time 10-20h；The step
Suddenly (5) condition is：Trypsase dosage 1%~3%, pH value 7.8, hydrolysis temperature are 40 DEG C -60 DEG C, enzymolysis time 2-10h；
During described step (6), with the film ultrafiltration that relative molecular cut off is 10000 dalton；
Protein concentration described in step (3) is concentrated using polyacrylamide thermo-sensitive gel, and thickening temperature is 5 DEG C~25 DEG C,
Concentrate repeatedly, until protein concentration is up to 15%~25%.
2. the preparation method of the Cerebrolysin Vial described in claim 1, it is characterised in that the polyacrylamide thermo-sensitive gel
For poly N-isopropyl acrylamide gel.
3. the preparation method of Cerebrolysin Vial according to claim 1, it is characterised in that the polyacrylamide is temperature sensitive
Gel is poly- (NIPA-co- methacrylic acids) sodium salt.
4. the preparation method of the Cerebrolysin Vial according to Claims 2 or 3, it is characterised in that described poly- N- isopropyls
Base acrylamide gel and poly- (NIPA-co- methacrylic acids) sodium salt use N, N '-methylene bisacrylamide acyl
Amine (BIS) is made for crosslinking agent.
5. a kind of Cerebrolysin Vial, it is characterised in that the Cerebrolysin Vial is according to any one institute in claim 1-4
What the method stated was prepared.
6. the preparation method of Cerebrolysin Vial according to claim 5, it is characterised in that gained Cerebrolysin Vial agent
Type is oral solid formulation or injection.
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| CN1562339A (en) * | 2004-03-19 | 2005-01-12 | 严家定 | Method for preparing pharmaceutics of hydrolysate of brain protein |
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| CN104096215A (en) * | 2014-07-07 | 2014-10-15 | 湖南利诺生物药业有限公司 | Pure natural cerebroprotein hydrolysate raw material preparation method |
| CN104096214A (en) * | 2014-06-10 | 2014-10-15 | 广州一品红制药有限公司 | Cerebroprotein hydrolysate freeze-dried powder injection and preparation method thereof |
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2014
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| CN1562339A (en) * | 2004-03-19 | 2005-01-12 | 严家定 | Method for preparing pharmaceutics of hydrolysate of brain protein |
| CN101912598A (en) * | 2010-06-02 | 2010-12-15 | 刘燎原 | Method for preparing brain protein hydrolysate for injection and preparation thereof |
| CN102718857A (en) * | 2012-07-09 | 2012-10-10 | 河北智同医药控股集团有限公司 | Denatured protein powder and brain protein hydrolyzate prepared from same |
| CN104096214A (en) * | 2014-06-10 | 2014-10-15 | 广州一品红制药有限公司 | Cerebroprotein hydrolysate freeze-dried powder injection and preparation method thereof |
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