CN1903357B - Liver hydrolytic peptide for injection and preparation method therefor - Google Patents
Liver hydrolytic peptide for injection and preparation method therefor Download PDFInfo
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- CN1903357B CN1903357B CN2005100319268A CN200510031926A CN1903357B CN 1903357 B CN1903357 B CN 1903357B CN 2005100319268 A CN2005100319268 A CN 2005100319268A CN 200510031926 A CN200510031926 A CN 200510031926A CN 1903357 B CN1903357 B CN 1903357B
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- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
A freeze-dried hepatic hydropeptide contains proportionally hepatic hydropeptide and excipient. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to hydrolyzed peptide of liver injection and preparation method thereof.
Technical background
Hydrolyzed peptide of liver is the micromolecule polypeptide of the liver of pig, cattle through hydrolysis, includes 18 kinds of free amino acids and trace element, has cell cultured supernatant regeneration, recovers hepatocyte function, promotes the effect that the mitochondrion rough endoplasmic reticulum recovers.Chronic hepatitis B is had excellent curative, reduce ALT, the TBIL that disappears increases body's immunity, the hepatocyte injury of pathological changes is had excellent repairing and promotes regenerated effect, and do not have tangible untoward reaction.
Existing medicine is that injection of hydrolyzed peptide of liver has another name called the Liver Hydrolysate injection, be pig, cattle liver after hydrolysis, the micromolecule polypeptide of the biologically active of extraction, the aseptic aqueous solution that amino acids and nucleic acid material are made.Include 27 kinds of free amino acids and trace element; belong to liver source property hepatocyte growth factor; have the synthetic of cell cultured supernatant DNA, promote hepatocellular regeneration, recover hepatocellular function; strengthen the phagocytic function of liver Kupffer; reduce fat source property endotoxin hepatocyte is damaged, prevent liver failure, suppress that tumor necrosis factor is active to be induced; blocking-up hepatitis generation hepatic necrosis shields to hepatocyte by the CPO of blocking-up free radical.Be used for various acute, chronic hepatitis, liver cirrhosis etc. clinically, received satisfied curative effect, the welcome of being cured the patient deeply demonstrates wide application prospect.
Injection of hydrolyzed peptide of liver (name Liver Hydrolysate injection once) records in National Drug Administration's " national drug standards (the chemical drugs provincial standard rises the 9th of national standard) ", the applicant is for making things convenient for clinical application, increase medicine stability, be easy to store, take care of and transportation, enrich the clinical application kind, developed the injection hydrolyzed peptide of liver.
Summary of the invention
The invention provides injection hydrolyzed peptide of liver lyophilized injectable powder, it contains outside the effective ingredient hydrolyzed peptide of liver, also contains excipient, and the concentration of excipient in lyophilizing solution is 8～12%.
Hydrolyzed peptide of liver is 20 or 40mg in every bottle of injection hydrolyzed peptide of liver of polypeptide content.
Said excipient is preferably mannitol.
Its preparation technology comprises the steps:
Obtain edema caused by disorder of the liver by method of the prior art and separate stock solution, measure its content of peptides with forint phenol method.
(1) preparation: be mixed with certain density solution according to the content of peptides that hydrolyzed peptide of liver stock solution is measured, make the content of every bottle of injection hydrolyzed peptide of liver of preparation reach the amount of regulation, add excipient, the content that makes excipient in the solution is 8～12%, adjust pH to 5.5～7.5, filter with ultrafilter, sampling is made semi-finished product and is detected;
(2) by the volume that needs fill solution in every cillin bottle of content measuring and calculating in the polypeptide hydrolyzed peptide of liver in the solution of measuring, aseptic subpackaged;
(3) lyophilization: freezer dryer drying baker temperature is chilled to-40 ℃～-45 ℃ in advance, and goods are sent into immediately and are carried out lyophilization in the freeze dryer drying baker after the packing, and freezing dry process and technology controlling index are as follows:
Pre-freeze: products temperature is reduced to-40 ℃～-45 ℃ rapidly;
Sublimation drying: initial shelf temperature is-45 ℃, and the coagulator temperature is-55 ℃, and drying baker vacuum remains on below the 20Pa, continuous subliming by heating, and extremely-10 ℃ of goods ice sheets disappear substantially.
Redrying: shelf temperature rises to about 40 ℃ gradually, heat preservation and dryness, and the coagulator temperature is-50 ℃, drying baker vacuum 5～6Pa;
(4), close plug rolls lid, check, packing gets final product.
The time of pre-freeze is 4 hours in above-mentioned (3) step, and the time of redrying is 14 hours.
In preparation process, the content of preferably controlling hydrolyzed peptide of liver in the hydrolyzed peptide of liver stock solution is counted with polypeptide and is not less than 20mg/ml.Need when concentration is too low to concentrate earlier.Otherwise, owing to be subjected to the restriction of cillin bottle volume, can cause the quantity not sufficient that contains of hydrolyzed peptide of liver in every bottle of freeze-dried powder.
In the process of preparation injection hydrolyzed peptide of liver freeze-dried powder, it is very important obtaining high-quality hydrolyzed peptide of liver stock solution.
Concrete operations are as follows:
(1) raw material is handled: cattle or pig liver, with cutting off non-liver organizations such as gallbladder, fascia, the cold sterile water for injection flushing of reuse, rub;
(2) system homogenate is extracted: will rub liver and water for injection and mix by 1: 0.5～1.5 mass ratio and place colloid mill homogenate, with between homogenate heating in water bath to 48～52 ℃, adjust pH to 8.0～8.5, the 0.5% pancreatin constant temperature continuous hydrolysis 6 hours that adds the liver quality, constantly adjust pH value, make it to keep between 8.0～8.5;
(3) remove foreign protein, centrifugal, filtration: adjust pH to 3.5, and be heated to 80～85 ℃ of maintenances 30 minutes, be cooled to room temperature rapidly, centrifugal, get supernatant with supernatant, between adjust pH to 6.5～6.8, separated out 16 hours for 40 ℃, use filtering with microporous membrane, get filtrate;
(4) molecular weight screening, bacterial endotoxin are removed: with filtrate ultrafilter ultrafiltration, collect solution with the cleaning sterile utensil.
Liver exsomatizes the back time can not be above 2 hours.Liver after the pack should advance-40 ℃ of freezers immediately and suddenly freeze processing.Employed liver cold preservation time can not be above 6 months.
The present invention has obtained stay-in-grade hydrolyzed peptide of liver lyophilized injectable powder by the preparation of research hydrolyzed peptide of liver stock solution and determining of freeze-dry process.
Description of drawings
Fig. 1 is hydrolyzed peptide of liver freeze-dried powder preparation technology's provided by the invention freeze-drying curve figure.
Specific embodiment
Embodiment 1
Preparation hydrolyzed peptide of liver stock solution
(1) raw material is handled: cattle or pig liver with cutting off non-liver organizations such as gallbladder, fascia, the cold sterile water for injection flushing of reuse, place the sterilization meat grinder to rub;
(2) system homogenate is extracted: will rub liver and water for injection and mix by 1: 1 mass ratio and place colloid mill homogenate, to spare between dress heating in water bath to 48～52 ℃, with 3M NaOH adjust pH to 8.0～8.5, the 0.5% pancreatin constant temperature continuous hydrolysis 6 hours that adds the liver quality, constantly adjust pH value, make it to keep between 8.0～8.5;
(3) remove foreign protein, centrifugal, filtration: with hydrolyzed solution 3M HCl adjust pH to 3.5, and be heated to 80～85 ℃ and kept 30 minutes, be cooled to room temperature rapidly, centrifugal, get supernatant, supernatant with between 3MNaOH adjust pH to 6.5～6.8, was separated out 16 hours for 40 ℃, with the filtering with microporous membrane of 0.45um, get filtrate;
(4) molecular weight screening, bacterial endotoxin are removed: with the ultrafilter ultrafiltration of filtrate with 10,000 Dalton molecular weights, collect the following solution of 10,000 molecular weight with the cleaning sterile utensil;
Embodiment 2
Determining of caffolding agent mannitol consumption: we select for use and add same principal agent hydrolyzed peptide of liver stock solution, add three not commensurability mannitol and have carried out freeze-dried test, and three batch samples have been carried out water content, formability, outward appearance, acidity, deliquescent investigation.The result is as follows:
The investigation result of table 1 caffolding agent different amounts
Can find out that from last table the acid-base value of three prescriptions, loss on drying, dissolubility are all good, but write out a prescription 1, prescription 2 is shaped relatively poorly, we select for use every to add 200mg mannitol as caffolding agent.
Embodiment 3
Freeze-dry process
(1) preparation: get the hydrolyzed peptide of liver solution that is up to the standards among the embodiment 1, feed intake by recipe quantity according to assay, be mixed with 2ml:20mg (polypeptide) solution, add mannitol and make excipient, making its concentration in solution is 10%, and adjust pH to 7.0 filters with ultrafilter, sampling is made semi-finished product and is detected.
(2) fill: qualified after testing semi-finished product, by every bottle of 2.0ml loading amount, carry out aseptic subpackagedly, the false add plug is sent into freeze drying box and is carried out lyophilization.
(3) lyophilization: freezer dryer drying baker temperature is chilled to-40 ℃ in advance, and goods are sent into immediately and are carried out lyophilization in the freeze dryer drying baker, 29 hours time after the packing.Freezing dry process and technology controlling index are as follows:
Pre-freeze: products temperature is reduced to-40 ℃ rapidly, insulation 4h.
Sublimation drying: initial shelf temperature is-45 ℃, and the coagulator temperature is-55 ℃, and drying baker vacuum remains on below the 20Pa, continuous subliming by heating, and extremely-10 ℃ of goods ice sheets disappear substantially, about the about 11h of this process.
Redrying: shelf temperature rises to about 40 ℃ gradually, heat preservation and dryness, and the coagulator temperature is-50 ℃, drying baker vacuum 5～6Pa, about 14 hours of this process.
The freeze-drying process variation of temperature is seen Fig. 1 in detail.
(4), close plug rolls lid: tamponade in freeze drying box, the taking-up freeze-dried product moves into Cover-rolling machine and rolls lid.
(5), check.
(6), packing: undertaken by drafting packing.
Embodiment 4
It is a collection of to press embodiment 3 production samples, sampling places high light (4500Lx ± 500Lx) respectively with it, high humidity (RH92.5%), placed 10 days under high temperature (60 ℃) condition, character, drug content, acid-base value, clarity, high molecular weight material, the loss on drying of sample were investigated in sampling respectively in 5,10 days, and with 0 day relatively, estimate its stability (seeing Fig. 1～10).
Table two influence factor test
The result shows: this product (is tested its character, drug content, acid-base value, protein, high molecular weight material, Thymosin alpha under 4500Lx ± 500Lx), high humidity (92.5%), high temperature (60 ℃) condition at high light
1, active every index has no significant change, stability is better under high temperature, high humidity, illumination condition to show this product.The formulation and technology condition that this product is described is stablized feasible.
Claims (9)
1. injection hydrolyzed peptide of liver, it contains outside the effective ingredient hydrolyzed peptide of liver, also contains excipient, and the concentration of said excipient in lyophilizing solution is 8～12%; It is characterized in that said effective ingredient hydrolyzed peptide of liver obtains through the following step:
(1) raw material is handled: cattle or pig liver, cut off gallbladder, the non-liver organization of fascia, the cold sterile water for injection flushing of reuse, and rub;
(2) system homogenate is extracted: will rub liver and water for injection and mix by 1: 0.5～1.5 mass ratio and place colloid mill homogenate, with between homogenate heating in water bath to 48～52 ℃, adjust pH to 8.0～8.5, the 0.5% pancreatin constant temperature continuous hydrolysis 6 hours that adds the liver quality, constantly adjust pH value, make it to keep between 8.0～8.5;
(3) remove foreign protein, centrifugal, filtration: with hydrolyzed solution adjust pH to 3.5, and be heated to 80～85 ℃ of maintenances 30 minutes, be cooled to room temperature rapidly, centrifugal, get supernatant, between supernatant adjust pH to 6.5～6.8, separated out 16 hours for 40 ℃, use filtering with microporous membrane, get filtrate;
(4) molecular weight screening, bacterial endotoxin are removed: with filtrate ultrafilter ultrafiltration, collect solution with the cleaning sterile utensil and obtain hydrolyzed peptide of liver stock solution.
2. injection hydrolyzed peptide of liver according to claim 1 is characterized in that hydrolyzed peptide of liver is 20 or 50mg in every bottle of injection hydrolyzed peptide of liver of polypeptide content.
3. injection hydrolyzed peptide of liver according to claim 1 and 2 is characterized in that excipient is a mannitol.
4. the preparation method of the described injection hydrolyzed peptide of liver of claim 1 is characterized in that this method comprises the following step:
(1) preparation: be mixed with certain density solution according to the content of peptides that hydrolyzed peptide of liver stock solution is measured, make the content of every bottle of injection hydrolyzed peptide of liver of preparation reach the amount of regulation, add excipient, the content that makes excipient in the solution is 8～12%, adjust pH to 5.5～7.5, filter with ultrafilter, sampling is made semi-finished product and is detected;
(2) by the volume that needs fill solution in every cillin bottle of content measuring and calculating in the polypeptide hydrolyzed peptide of liver in the solution of measuring, aseptic subpackaged;
(3) lyophilization: freezer dryer drying baker temperature is chilled to-40 ℃～-45 ℃ in advance, and goods are sent into immediately and are carried out lyophilization in the freeze dryer drying baker after the packing; Freezing dry process and technology controlling index are as follows:
Pre-freeze: products temperature is reduced to-40 ℃～-45 ℃ rapidly;
Sublimation drying: initial shelf temperature is-45 ℃, and the coagulator temperature is-55 ℃, and drying baker vacuum remains on below the 20Pa, continuous subliming by heating, and extremely-10 ℃ of goods ice sheets disappear substantially;
Redrying: shelf temperature rises to 40 ℃ gradually, heat preservation and dryness, and the coagulator temperature is-50 ℃, drying baker vacuum 5～6Pa;
(4), close plug rolls lid, check, packing gets final product.
5. the preparation method of the described injection hydrolyzed peptide of liver of claim 4, the content that it is characterized in that controlling hydrolyzed peptide of liver in the hydrolyzed peptide of liver stock solution is counted with polypeptide and is not less than 20mg/ml.
6. the preparation method of the described injection hydrolyzed peptide of liver of claim 4 is characterized in that the time of pre-freeze in (3) step is 4 hours, and the time of redrying is 14 hours.
7. produce the method for hydrolyzed peptide of liver stock solution, it is characterized in that this method comprises the following steps:
(1) raw material is handled: cattle or pig liver, cut off gallbladder, the non-liver organization of fascia, cold sterile water for injection flushing again, and rub;
(2) system homogenate is extracted: will rub liver and water for injection and mix by 1: 0.5～1.5 mass ratio and place colloid mill homogenate, with between homogenate heating in water bath to 48～52 ℃, adjust pH to 8.0～8.5, the 0.5% pancreatin constant temperature continuous hydrolysis 6 hours that adds the liver quality, constantly adjust pH value, make it to keep between 8.0～8.5;
(3) remove foreign protein, centrifugal, filtration: with hydrolyzed solution adjust pH to 3.5, and be heated to 80～85 ℃ of maintenances 30 minutes, be cooled to room temperature rapidly, centrifugal, get supernatant, between supernatant adjust pH to 6.5～6.8, separated out 16 hours for 40 ℃, use filtering with microporous membrane, get filtrate;
(4) molecular weight screening, bacterial endotoxin are removed: with filtrate ultrafilter ultrafiltration, collect solution with the cleaning sterile utensil.
8. the method for producing hydrolyzed peptide of liver stock solution according to claim 7 is characterized in that used cattle or pig liver are back time of exsomatizing to be no more than 2 hours, and advances immediately that-40 ℃ of freezers are anxious to freeze processing.
9. the method for producing hydrolyzed peptide of liver stock solution according to claim 8 is characterized in that used cattle or pig liver cold preservation time can not be above 6 months.
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| CN2005100319268A CN1903357B (en) | 2005-07-27 | 2005-07-27 | Liver hydrolytic peptide for injection and preparation method therefor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102228676B (en) * | 2011-07-07 | 2013-01-30 | 白求恩医科大学制药厂 | Heparolysate injection pharmaceutical composition |
| CN102294013B (en) * | 2011-09-08 | 2014-01-29 | 中国人民解放军第四五八医院 | Hepatocyte growth-promoting factor and application thereof |
| CN102294014B (en) * | 2011-09-08 | 2014-01-29 | 中国人民解放军第四五八医院 | Hepatocyte growth-promoting factor and preparation and application thereof |
| CN102764423B (en) * | 2012-08-20 | 2014-03-19 | 湖北济生医药有限公司 | Polypeptide drug composition obtained through hydrolysis of animal livers and preparation method thereof |
| CN103190557A (en) * | 2013-04-16 | 2013-07-10 | 缪为民 | Novel compound nutritional product with liver damage repairing efficacy |
| CN103301217B (en) * | 2013-06-05 | 2015-05-06 | 高浚铭 | Composition and applications thereof, pharmaceutical preparation and health-care product |
| CN109549955A (en) * | 2019-01-04 | 2019-04-02 | 湖南海济药业有限公司 | A kind of preparation method of cattle liver extracting solution |
| CN109568261A (en) * | 2019-01-04 | 2019-04-05 | 湖南海济药业有限公司 | A kind of polypeptide oral liquor and preparation method thereof of prevention and alleviation chemical damage |
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|---|---|---|---|---|
| SU706088A1 (en) * | 1978-07-07 | 1979-12-30 | Всесоюзный научно-исследовательский институт технологии кровезаменителей и гормональных препаратов | Method of obtaining hog liver hydrolisate |
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