CN101940596A - New method for preparing cerebroprotein hydrolysate - Google Patents
New method for preparing cerebroprotein hydrolysate Download PDFInfo
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- CN101940596A CN101940596A CN2009100724816A CN200910072481A CN101940596A CN 101940596 A CN101940596 A CN 101940596A CN 2009100724816 A CN2009100724816 A CN 2009100724816A CN 200910072481 A CN200910072481 A CN 200910072481A CN 101940596 A CN101940596 A CN 101940596A
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Abstract
The invention belongs to the technical field of medicines, in particular relates to a new method for preparing a cerebroprotein hydrolysate. The cerebroprotein hydrolysate prepared by the method contains 10 to 12mg/mL active polypeptides and 0.1 to 0.2mg/mL sialic acid and has the advantages of high content of active ingredients, safety and controllability.
Description
1, technical field
The invention belongs to medical technical field, be specifically related to a kind of new method for preparing Cerebrolysin Vial.
2, background technology
Cerebrolysin Vial is that trade name is sold with Cerebrolysin by Austrian EBEWE pharmaceutical factory the earliest.Cerebrolysin Vial is the aqueous solution of protein-free standardization organ specific amino acid mixture, wherein contain multiple human body essential amino acid, non essential amino acid, active polypeptide, sialic acid etc., can be used for craniocerebral trauma, apoplexy sequela with hypomnesis and the concentrated obstacle of attention, for the organic brain psychosyndrome of treatment, the compensatory deficiency of cerebrovascular, the neurasthenia state, development of infant brain is incomplete, and epilepsy apoplexy, encephalitis, cerebral concussion etc. have favorable effects.
In the Cerebrolysin Vial, free amino acid, active polypeptide and sialic acid play a part very important to the recovery of disordered brain function, but free aminoacid content is very low in the Cerebrolysin Vial that prior preparation method obtains, especially the content of free amino acid is very low, do not reach state-set standard, numerous Cerebrolysin Vial products are by adding exogenous amino acid to reach the requirement of required standard, therefore, country's medicine prison is done [2008] No. 734 documentation requirements Cerebrolysin Vials and must not be added exogenous amino acid, so, be badly in need of a kind of new revision national standard, safety that active constituent content is high of meeting of research and development, effectively, quality controllable natural brain protein hydrolysate.
3, summary of the invention
The present invention adopts nanofiltration that a kind of Cerebrolysin Vial for preparing from the mammal cerebral tissue is provided, use in the Cerebrolysin Vial of this technology preparation sialic content higher, its very big advantage is by blood brain barrier and guarantees curative effect, has great importance for safety and effectiveness, the expansion clinical practice of the quality that improves Cerebrolysin Vial and quality controllability, assurance Cerebrolysin Vial.
Technical scheme of the present invention is as follows:
A kind of method for preparing Cerebrolysin Vial from the mammal cerebral tissue comprises the steps:
(1) gastric enzyme liquid hydrolysis: get FF mammal cerebral tissue, add purified water or water for injection homogenate, homogenate adds gastric enzyme liquid and stirs, and hydrolysis, hydrolysis finish and heat little boiling, and filter, and get the gastric enzyme hydrolyzed solution;
(2) pancreatin hydrolysis: the gastric enzyme hydrolyzed solution, add pancreatin and stir, hydrolysis is filtered, and gets the Cerebrolysin Vial crude extract;
(3) remove basic protein;
(4) ultra-filtration and separation;
(5) receive and consider to concentrate;
(6) check bacterial endotoxin, get the Cerebrolysin Vial highly finished product.
The preparation method of Cerebrolysin Vial of the present invention is preferably:
(1) gastric enzyme liquid hydrolysis: get FF mammal cerebral tissue, negative catalysis, the ratio according to 1: 1～2 adds purified water or water for injection, colloid mill homogenate, 80～90 ℃ of homogenate heating, insulation 10～20min, be cooled to 35～40 ℃, adjust pH is 2.5～3.5, adds gastric enzyme liquid and stirs 37～45 ℃ of hydrolysis 12～18h, hydrolysis finishes, heat little 10min that boils, 100 order filter clothes filter, and get the gastric enzyme hydrolyzed solution;
(2) pancreatin hydrolysis: the gastric enzyme hydrolyzed solution is regulated pH value 7.5～8.5, add the pancreatin trypsin solution, stir, 45～55 ℃ of hydrolysis 4h, hydrolysis finishes, and regulating pH value was 4.0～5.0 (adding 1% active carbon by raw material weight), 100 ℃ of heating 20min, filter with 100 order filter clothes, get the Cerebrolysin Vial crude extract;
(3) remove basic protein: get the Cerebrolysin Vial crude extract, regulating pH value is 9.0～10.0, heats 80～90 ℃, and cooling is used filter paper filtering below 30 ℃, gets filtrate;
(4) ultra-filtration and separation: with gained filtrate adjust pH in (3) is 6.5～7.5, with the ultrafiltration post ultrafiltration of 10000 molecular weight, the freezing 48h of ultrafiltrate;
(5) concentrated, the charcoal treatment of nanofiltration: with the refrigerated ultrafiltrate negative catalysis of gained in (4), with 0.8 μ m membrane filtration, remove lipoprotein and foreign protein in the solution, the filtrate nanofiltration, adjust pH is 4.0～5.0, and adds 0.1～0.4% active carbon (w/w), fully stirs insulation 10～40min down, 0.45 μ m filtering with microporous membrane, filtrate are added two kinds of injection aminoacid.
(6) check bacterial endotoxin: in will (5) gained filtrate to adjust pH value is 7.0～7.5, again through the ultrafiltration post ultrafiltration of 10000 molecular weight, the ultrafiltrate bacterial endotoxin of taking a sample to check, qualified after, must the Cerebrolysin Vial highly finished product.
Described mammal refers to other mammals except the people, comprises pig, cattle, horse, sheep, rabbit, Canis familiaris L. etc., preferred pig, cattle.
The present invention further requires the Cerebrolysin Vial by method for preparing, and Cerebrolysin Vial of the present invention contains active polypeptide 10～12mg/mL and sialic acid 0.1～0.2mg/mL.
The pharmaceutical composition of the further claimed Cerebrolysin Vial of the present invention of the present invention and one or more pharmaceutical carriers and/or diluent system can be made pharmaceutically acceptable arbitrary dosage form.
When being used for oral administration, can be made into conventional solid preparation, as tablet, capsule, pill, granule etc.; Also can be made into oral liquid, as oral solution, oral suspensions, syrup etc.When making oral formulations, can add suitable filler, binding agent, disintegrating agent, lubricant etc.When being used for parenteral, can be made into injection, comprise injection, injectable sterile powder and concentrated solution for injection.When making injection, can adopt the conventional method production in the existing pharmaceutical field, during the preparation injection, can not add additives, also can add suitable additives according to the character of medicine.
The present invention further claimed Cerebrolysin Vial of the present invention treats and/or prevents application in the medicine of disordered brain function in preparation.Cerebrolysin Vial of the present invention can act on nervus centralis in many ways, regulates and improves neuronic metabolism, promotes the formation of synapse, induces neuronic differentiation, and further the neuroprotective cell is avoided the infringement of various ischemias and neurotoxin.Cerebrolysin Vial of the present invention can pass through blood brain barrier, promotes the synthetic of brain internal protein, influences respiratory chain; protective capability with anti-hypoxia; improve the metabolism of brain self-energy, other hormone system of activated adenyl cyclase and catalysis provides neurotransmitter, peptide hormone and coenzyme precursors.
Cerebrolysin Vial of the present invention has following advantage:
(1) in the Cerebrolysin Vial of the present invention, the Cerebrolysin Vial that active polypeptide and sialic content extract from mammal than existing methods significantly improves, meet the new regulation standard, quality controllability significantly improves, and improves clinical application safety and effectiveness greatly.
(2) active polypeptide, sialic acid, free amino acid are natural extract in the Cerebrolysin Vial of the present invention, and sialic detection makes the Cerebrolysin Vial component clearer and more definite, makes clinical application more safe and effective.
(3) preparation method of Cerebrolysin Vial of the present invention is simple, is beneficial to large-scale production.
Below routine by experiment, foregoing of the present invention is described in further detail, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The respiratory activity of experimental example Cerebrolysin Vial of the present invention relatively
Method system breathes inspection with Wa Shi and presses instrument to measure the breathing vigor of Cavia porcellus liver homogenate, calculates breathing vigor QO from the oxygen consumption that records
2(uLO
2/ mgh) and stimulation index (SI).
Instrument Wa Shi breathes inspection and presses instrument, homogenizer, intervalometer.
Reagent
10% sodium hydroxide solution is got sodium hydroxide 10g, is dissolved in water and is diluted to 100mL.
Soerensen buffer (pH value 7.4) is got sodium hydrogen phosphate (Na
2HPO
42H
2O) 9.72g and potassium dihydrogen phosphate 1.65g are dissolved in water and are diluted to 1000mL.
The Brodie manometric liquid is got sodium chloride 23g, natrii tauroglycocholas 5g, and the blue 100mg of her Wen is dissolved in water and is diluted to 500mL.Relative density is 1.033g/mL.
One of the male guinea pig of body weight 250g is got in the preparation of liver homogenate liquid, cervical region hits puts to death (needing fasting at least 24 hours before putting to death), cut off the strength arterial blood letting immediately, open the abdominal cavity and take out liver, put the Soerensen buffer (noting: do not damage gallbladder or bile duct) in the ice-water bath.Take by weighing the liver of 5.5g, and be cut into identical 7 of size, every Soerensen buffer homogenate (note: above operation must be carried out in ice-water bath) with 7mL.
Algoscopy
(1) in advance manometer flask is cleaned and drying, standby.
(2) install manometric liquid in pressure-measuring pipe, regulate liquid level to 150mm.
(3) add Soerensen buffer 1.1mL in the reaction bulb earlier, add test sample 0.2mL, add liver homogenate liquid 1.0mL then.
(4) add 10% sodium hydroxide solution 0.2mL cuvette in the middle of the reaction bulb of tool one little filter paper bar.
(5) because liver homogenate itself has the oxygen consumption effect, replace test sample with Soerensen buffer 0.2mL when historical facts or anecdotes is tested, the same sample cell of all the other reagent is as the blank pipe.
(6) reaction bulb that installs number is linked to each other with manometer (note airtight, do not make gas leakage) by pipe, put in 37 ℃ of waters bath with thermostatic control.
(7) 10 minutes (75 times/minute) make reaction bulb internal and external temperature unanimity to start the agitator jolting.Manometer right side post liquid level is transferred to 150mm, and liquid level reading (A) on the left of writing down is closed the three-dimensional piston then, picks up counting, and reacts after 30 minutes manometer right side post liquid level to be transferred to 150mm again, writes down the left side liquid level and removes reading (B).Open the three-dimensional piston, repeat said process, carry out next 30 minutes reaction and write down left side liquid level initial reading (C) and the liquid level reading (D) after 30 minutes.
(8) must supply to proofread and correct the temperature pressure meter of usefulness by an additional cover in the experimentation, the Soerensen buffer that in reaction bulb, adds 2.5mL, make its with the identical condition of developmental tube under test, observe the variation (Δ C) of its pressure, to eliminate temperature and atmospheric influence in the experimentation.
(9) get the 2.0mL liver homogenate, put in the weighing botle that sea sand is housed of constant weight, 110 ℃ are dried to constant weight, calculate twice weight difference Δ W (mg).
Be calculated as follows:
QO
2(uL·O
2/mg·h)＝〔(A-B+C-D)×K
1-ΔC×K
2〕/G/I
K in the formula
1Reaction bulb constant for blank or sample;
K
2Reaction bulb constant for temperature pressure meter;
G is the dry weight of every 1mL liver homogenate, mg, and G=Δ W/2-9.3,9.3 is the dry weight of Soerensen buffer, mg;
I is the response time, hour.
Stimulation index (SI)=test sample QO
2/ blank QO
2
Experimental result should meet the following conditions, otherwise invalid;
1. the QO of reference substance
2〉=4.0uLO
2/ mgh, and SI 〉=2.5;
2. barren QO
2〉=1.0uLO
2/ mgh.
5.0≤QO of experimental result Cerebrolysin Vial of the present invention
2≤ 7uLO
2/ mgh, and 2.5≤SI≤3.0.
Commercial 4.0uLO
2/ mghQO
2≤ 5.0uLO
2/ mgh, and 2.5≤SI≤3.0,
By experimental result as can be seen, Cerebrolysin Vial of the present invention is compared with the Cerebrolysin product, and stimulation index and respiratory activity are basic identical, shows that Cerebrolysin Vial biologically active of the present invention is consistent with the Cerebrolysin product quality.
4, the specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following embodiment.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation and the assay of embodiment 1 Cerebrolysin Vial of the present invention
One, the preparation of Cerebrolysin Vial of the present invention
(1) gastric enzyme liquid preparation: get meat grinder rubbing homogenate on the Gaster Sus domestica mucosa, add water for injection according to 0.5 times of amount, add hydrochloric acid again, add HCL20mL according to every kilogram of gastric mucosa, 47 ℃ of temperature, digestion time 3h promptly gets rough gastric enzyme liquid, contain pepsin, the mixture of multiple protein hydrolytic enzyme such as histone in the rough gastric enzyme liquid;
(2) gastric enzyme liquid hydrolysis: get FF mammal cerebral tissue, negative catalysis was according to 1: 1.5 ratio water for injection, colloid mill homogenate, 85 ℃ of homogenate heating, insulation 15min, be cooled to 40 ℃, with the 6mol/LHcl adjust pH is 3.5, adds gastric enzyme liquid and stirs 40 ℃ of hydrolysis temperatures, hydrolysis 16h, heat little 10min that boils, 100 order filter clothes filter, and get the gastric enzyme hydrolyzed solution;
(3) pancreatin hydrolysis: the gastric enzyme hydrolyzed solution is regulated pH value 7.5～8.5, adds pancreatin (pressing raw material 1% adds) and adds activator, 0.04mol/LCaCl
2Room temperature is placed and was added in the gastric enzyme hydrolyzed solution in 1 hour, it is 7.5-8.0 that reuse 5mol/L NaOH regulates pH value, 48 ℃ of hydrolysis time 4h of hydrolysis temperature, regulating pH value with 6mol/LHcl is 4.0～5.0,100 ℃ of 15min of (adding 1% active carbon) heated and boiled by the raw material total amount, filter with 100 order filter clothes, get the Cerebrolysin Vial crude extract;
(4) remove basic protein: get the Cerebrolysin Vial crude product, regulating pH value is 9.0～10.0, heats 80 ℃, and cooling is used filter paper filtering below 30 ℃, gets filtrate;
(5) ultra-filtration and separation: alkaline filter liquid adjust pH is 6.5～7.5, with the ultrafiltration post ultrafiltration of 10000 molecular weight, and ultrafiltrate dress keg, freezing 48h;
(6) concentrated, the charcoal treatment of nanofiltration: with gained filtrate negative catalysis in (5), with 0.8 μ m membrane filtration, remove lipoprotein and foreign protein in the solution, the filtrate nanofiltration, adjust pH is 4.0～5.0, and adds 0.1～0.4% active carbon (w/w), fully stirs following 100 ℃ of insulation 30min, 0.45 μ m filtering with microporous membrane gets filtrate.
(7) check bacterial endotoxin: in will (6) gained filtrate to adjust pH value is 7.2, again through the ultrafiltration post ultrafiltration of 10000 molecular weight, the ultrafiltrate bacterial endotoxin of taking a sample to check, qualified after, must the Cerebrolysin Vial highly finished product.
Two, the assay of Cerebrolysin Vial of the present invention
[polypeptide]
Get this product and make the solution that every 1mL contains polypeptide 0.15mg approximately,, measure according to forint phenol algoscopy as need testing solution.
[free amino acid]
Get this product and standard substance aminoacid is an amount of, carry out separation determination with suitable amino-acid analyzer or high performance liquid chromatograph, its free aminoacid content should be among every 1mL and contains 0.8～1.2mg.
[sialic acid]
It is an amount of that sialic acid reference reagent is got in the preparation of reference solution, adds 0.9% sodium chloride solution and make the solution that contains 50ug among every 1mL.
The preparation precision of standard curve is measured reference solution 0.0mL, 0.5mL, 1.0mL, 1.5mL, 2.0mL, put respectively in the tool plug test tube, respectively add water to 2.0mL, accurate respectively again adding resorcinol solution (is got 2% resorcinol solution 10mL, 2.5% copper-bath 0.25mL, hydrochloric acid 80mL, add water to 100mL) 2mL, shake up, put in the water-bath and reacted 15 minutes, taking-up was put in the cold water 10 minutes, precision adds n-butyl acetate-positive fourth (85: 15) 5mL respectively, places 15 minutes after the violent jolting, gets upper strata liquid and measures trap in the wavelength place of 585nm: manage as blank with 0.The trap that records is calculated regression equation with corresponding concentration.
Algoscopy is got this product, adds 0.9% sodium chloride and makes the solution that contains sialic acid 50ug among every 1mL, as need testing solution.Precision is measured need testing solution 2mL, and the method under the preparation of sighting target directrix curve from " the accurate resorcinol solution that adds ", is measured in accordance with the law, tries to achieve the concentration of need testing solution from regression equation, and multiply by extension rate, is sialic acid content.
The preparation of embodiment 2 Cerebrolysin Vial lyophilized injectable powders of the present invention
Prescription:
Cerebrolysin Vial solution 3000mL polypeptide 50mg/ml; Sialic acid 1.37mg/ml
Mannitol 200g
Water for injection adds 2250mL
Prepare 1500 altogether
Technology:
(1) mannitol that takes by weighing recipe quantity adds water for injection, stirs and makes dissolving, adds needle-use activated carbon according to 0.1% of solution amount, and 80 ℃ are stirred 30min, and it is clear and bright to be filtered to solution, standby;
(2) get the Cerebrolysin Vial solution of recipe quantity, mix with above-mentioned solution, add the injection water to 90% of solution total amount, regulating pH value is 7.0, and after-teeming is penetrated water to full dose;
(3) cross 0.2 μ m microporous filter membrane, measure content;
(4) fill;
(5) lyophilizing.
The preparation of embodiment 3 brain protein hydrolysate injections of the present invention
Prescription:
Cerebrolysin Vial 6818mL (polypeptide 22.0mg/ml; Sialic acid 0.551mg/ml)
Add water for injection 8182mL adjust pH 7.2, the 0.22um filtering with microporous membrane fills the nitrogen filling and sealing,
110 ℃ of sterilize 30min lamp inspection, packings.Prepare 1500 (10ml) altogether.
Claims (5)
1. a method for preparing Cerebrolysin Vial from the mammal cerebral tissue is characterized in that, comprises the steps:
(1) gastric enzyme liquid hydrolysis: get FF mammal cerebral tissue, add purified water or water for injection homogenate, homogenate adds gastric enzyme liquid and stirs, and hydrolysis, hydrolysis finish and heat little boiling, and filter, and get the gastric enzyme hydrolyzed solution;
(2) pancreatin hydrolysis: the gastric enzyme hydrolyzed solution, add pancreatin, stir, hydrolysis is filtered, and gets the Cerebrolysin Vial crude extract;
(3) remove basic protein;
(4) ultra-filtration and separation;
(5) receive and consider to concentrate;
(6) check bacterial endotoxin, get the Cerebrolysin Vial highly finished product.
2. the preparation method of Cerebrolysin Vial as claimed in claim 1 is characterized in that, comprises the steps:
(1) gastric enzyme liquid hydrolysis: get FF mammal cerebral tissue, negative catalysis, the ratio according to 1: 1～2 adds purified water or water for injection, colloid mill homogenate, 80～90 ℃ of homogenate heating, insulation 10～20min, be cooled to 35～40 ℃, adjust pH is 2.5～3.5, adds gastric enzyme liquid and stirs 37～45 ℃ of hydrolysis 12～18h, hydrolysis finishes, heat little 10min that boils, 100 order filter clothes filter, and get the gastric enzyme hydrolyzed solution;
(2) pancreatin hydrolysis: the gastric enzyme hydrolyzed solution is regulated pH value 7.5～8.5, adds pancreatin (pressing raw material 1% adds) and adds activator, 0.04mol/LCaCl
2Room temperature is placed and was added in the gastric enzyme hydrolyzed solution in 1 hour, it is 7.5-8.0 that reuse 5mol/L NaOH regulates pH value, 45～55 ℃ of hydrolysis 4h, hydrolysis finishes, regulating pH value is 4.0～5.0, add 100 ℃ of heating of 1% active carbon 15min by the raw material total amount, filter, get the Cerebrolysin Vial crude extract with 100 order filter clothes;
(3) remove basic protein: get the Cerebrolysin Vial crude extract, regulating pH value is 9.0～10.0, heats 80～90 ℃, insulation 10min, and cooling is used filter paper filtering below 30 ℃, gets filtrate;
(4) ultra-filtration and separation: with gained filtrate adjust pH in (3) is 6.5～7.5, with the ultrafiltration post ultrafiltration of 10000 molecular weight, the freezing 48h of ultrafiltrate;
(5) concentrated, the charcoal treatment of nanofiltration: with the refrigerated ultrafiltrate negative catalysis of gained in (4), with 0.8 μ m membrane filtration, remove lipoprotein and foreign protein in the solution, the filtrate nanofiltration, nanofiltration liquid is 4.0～5.0 with the 6mol/LLHcl adjust pH, and adds 0.1～0.4% active carbon (w/w), fully stirs following 100 ℃ of insulation 10～40min, 0.45 μ m filtering with microporous membrane, filtrate are added two kinds of injection aminoacid.
(6) check bacterial endotoxin: in will (5) gained filtrate to adjust pH value is 7.0～7.5, again through the ultrafiltration post ultrafiltration of 10000 molecular weight, the ultrafiltrate bacterial endotoxin of taking a sample to check, qualified after, must the Cerebrolysin Vial highly finished product.
3. as the Cerebrolysin Vial of claim 1 or 2 preparations, it is characterized in that, contain active polypeptide 10～12mg/mL and sialic acid 0.1～0.2mg/mL.
4. as the pharmaceutical composition of the described Cerebrolysin Vial of claim 2 (5) (6) and one or more pharmaceutical carriers and/or diluent system, can make pharmaceutically acceptable arbitrary dosage form.
5. treat and/or prevent application in the medicine of disordered brain function as the described Cerebrolysin Vial of claim 2 (5) (6) in preparation.
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|---|---|---|---|
| CN200910072481.6A CN101940596B (en) | 2009-07-09 | 2009-07-09 | New method for preparing cerebroprotein hydrolysate |
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|---|---|---|---|
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|---|---|
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| CN101940596B CN101940596B (en) | 2014-07-16 |
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|---|---|---|---|
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166200A (en) * | 2011-04-12 | 2011-08-31 | 罗诚 | Freeze-drying composition containing cerebroprotein hydrolysates and preparation method of freeze-drying composition |
| CN102302767A (en) * | 2011-08-09 | 2012-01-04 | 杭州华津药业股份有限公司 | Novel extraction method of cerebroprotein hydrolysate solution |
| CN103833825A (en) * | 2012-11-23 | 2014-06-04 | 中国食品发酵工业研究院 | Method for removing bacterial endotoxin in foodborne oligopeptide |
| CN107303385A (en) * | 2016-04-15 | 2017-10-31 | 北京四环科宝制药有限公司 | A kind of preparation method of Cerebrolysin Vial solution |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562339A (en) * | 2004-03-19 | 2005-01-12 | 严家定 | Method for preparing pharmaceutics of hydrolysate of brain protein |
| CN101019889A (en) * | 2007-03-16 | 2007-08-22 | 石海 | Prepn process of brain protein hydrolysate injection |
-
2009
- 2009-07-09 CN CN200910072481.6A patent/CN101940596B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1562339A (en) * | 2004-03-19 | 2005-01-12 | 严家定 | Method for preparing pharmaceutics of hydrolysate of brain protein |
| CN101019889A (en) * | 2007-03-16 | 2007-08-22 | 石海 | Prepn process of brain protein hydrolysate injection |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102166200A (en) * | 2011-04-12 | 2011-08-31 | 罗诚 | Freeze-drying composition containing cerebroprotein hydrolysates and preparation method of freeze-drying composition |
| CN102302767A (en) * | 2011-08-09 | 2012-01-04 | 杭州华津药业股份有限公司 | Novel extraction method of cerebroprotein hydrolysate solution |
| CN102302767B (en) * | 2011-08-09 | 2013-04-24 | 杭州华津药业股份有限公司 | Novel extraction method of cerebroprotein hydrolysate solution |
| CN103833825A (en) * | 2012-11-23 | 2014-06-04 | 中国食品发酵工业研究院 | Method for removing bacterial endotoxin in foodborne oligopeptide |
| CN107303385A (en) * | 2016-04-15 | 2017-10-31 | 北京四环科宝制药有限公司 | A kind of preparation method of Cerebrolysin Vial solution |
| CN107303385B (en) * | 2016-04-15 | 2021-08-31 | 北京四环科宝制药有限公司 | Preparation method of cerebroprotein hydrolysate solution |
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|---|---|
| CN101940596B (en) | 2014-07-16 |
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