CN102805857B - Preparation method of compound amino acid (15) dipeptide (2) injecta - Google Patents
Preparation method of compound amino acid (15) dipeptide (2) injecta Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- -1 compound amino acid Chemical class 0.000 title abstract 4
- 108010016626 Dipeptides Proteins 0.000 title abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 32
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 229940024606 amino acid Drugs 0.000 claims abstract description 20
- 235000001014 amino acid Nutrition 0.000 claims abstract description 20
- 239000008215 water for injection Substances 0.000 claims abstract description 20
- XBGGUPMXALFZOT-VIFPVBQESA-N Gly-Tyr Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-VIFPVBQESA-N 0.000 claims abstract description 19
- 108010087823 glycyltyrosine Proteins 0.000 claims abstract description 19
- 108010010147 glycylglutamine Proteins 0.000 claims abstract description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 17
- PNMUAGGSDZXTHX-BYPYZUCNSA-N Gly-Gln Chemical compound NCC(=O)N[C@H](C(O)=O)CCC(N)=O PNMUAGGSDZXTHX-BYPYZUCNSA-N 0.000 claims abstract description 15
- 230000001954 sterilising effect Effects 0.000 claims abstract description 13
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- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims abstract description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 10
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims abstract description 10
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims abstract description 10
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims abstract description 10
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000013922 glutamic acid Nutrition 0.000 claims abstract description 10
- 239000004220 glutamic acid Substances 0.000 claims abstract description 10
- 229960000310 isoleucine Drugs 0.000 claims abstract description 10
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- 229960003136 leucine Drugs 0.000 claims abstract description 10
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960005190 phenylalanine Drugs 0.000 claims abstract description 10
- 239000004475 Arginine Substances 0.000 claims abstract description 9
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 9
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 9
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 8
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- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 8
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims abstract description 8
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims abstract description 8
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims abstract description 8
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 8
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- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims abstract description 8
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- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 claims abstract description 8
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- RRNJROHIFSLGRA-JEDNCBNOSA-N acetic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.NCCCC[C@H](N)C(O)=O RRNJROHIFSLGRA-JEDNCBNOSA-N 0.000 claims abstract description 8
- 235000004279 alanine Nutrition 0.000 claims abstract description 8
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- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims abstract description 8
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- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 3
- 150000001413 amino acids Chemical class 0.000 claims description 29
- 238000002347 injection Methods 0.000 claims description 24
- 239000007924 injection Substances 0.000 claims description 24
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- 102000004196 processed proteins & peptides Human genes 0.000 claims description 11
- 235000003704 aspartic acid Nutrition 0.000 claims description 9
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 9
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- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 description 4
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- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
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- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a preparation method of compound amino acid (15) dipeptide (2) injecta, specifically comprising the following steps of: under the whole-course protection of nitrogen, taking water for injection with a certain quantity, sequentially adding glycyl-L-glutamine, glycyl-L-tyrosine and arginine with prescription quantity, stirring and dissolving, clearly dissolving, adding aspartate, glutamic acid, leucine, isoleucine and phenylalanine with prescription quantity which is not less than 60 screen meshes, dissolving and clearly dissolving, adding alanine, histidine, L-lysine monoacetate, methionine, proline, serine, threonine, tryptophan and valine with prescription quantity, stirring and clearly dissolving, adjusting the pH at 5.4-5.8 by citric acid, adding full dose of 0.10% (w/v) of activated carbon, stirring for 30min under the temperature of 60DEG C, fixing the volume to total volume by the water for injection after filtering in a decarbonizing way, sieving by a filter membrane with 0.22 micrometers, filling, charging nitrogen, adding a plug, pricking an aluminum cap, and sterilizing for 8-12min in a hot-press way under the temperature of 121DEG C (F0 value is larger than 8), wherein the quality of the injecta can achieve the quality standard of an imported drug of the finished product of the German Fresenius Corporation.
Description
Technical field
The present invention relates to relate to the preparation method of the two peptides of a kind of amino acid (15) (2) injection.Belong to medical technical field.
Background technology
The former product of consulting and deliberating of the two peptides of amino acid (15) (2) injection are by name
german Fresenius Kabi on third generation amino acid transfusion basis, in the amino acid aqueous solution that can supplement glutamine and tyrosine the earliest in the world of nineteen ninety-five exploitation listing,
containing 20g/L glutamine and 2.28g/L tyrosine.This product multiple country listings in Europe, clinical use exceedes 10 years, at present import China.
Its prescription is composed as follows, in this product 1000ml, contains:
aminoacid formula meets the pattern of FAO-WHO, TPN solution comparison with standard, there is the function of intestinal canal of enhancing, improve immune defence, reduce infection rate, shorten the hospital stays, reduce by 6 months mortality rates, improve nitrogen balance, improve the clinical characters such as emotion, not only good stability, the report also having no adverse reaction while correctly use.
But because this product is in the sterilization process of preparation production, primary raw material medicine glycyl-L-glutamine can be degraded to ring (glycyl-L-glutamine acyl), and glycyl-L-tyrosine can be degraded to ring (glycyl-L-tyrosyl), quality is far below import standard, reduce drug safety, domesticly before and after 2007, have tens pharmaceutical factories and declare this medicine, all moved back careful because overcoming the product stability problems causing under this injection high temperature sterilize by national Bureau of Drugs Supervision.
Given this, we design to have invented and can overcome the two peptides of amino acid (15) (2) the injection production way that degraded occurs because of high temperature sterilize.
Summary of the invention
By analyzing the former prescription that grinds, and each aminoacids characteristic is found: the guanidine radicals in the basic amino acid component arginine in prescription, can with the carboxyl salify of glycyl-L-glutamine and glycyl-L-tyrosine, reduce glycyl-L-glutamine and the carboxyl of glycyl-L-tyrosine self and the probability of amino ring formation under high temperature, thereby reduced the generation of ring (glycyl-L-glutamine acyl) and ring (glycyl-L-tyrosyl).So we design the production of this injection and feed intake in process, first drop into glycyl-L-glutamine, glycyl-L-tyrosine and arginic combination, make glycyl-L-glutamine become arginine salt with glycyl-L-tyrosine, reduced the generation of ring (glycyl-L-glutamine) and ring (glycyl-L-tyrosine).
In test, we find, the water-soluble of Aspartic Acid, glutamic acid, leucine, isoleucine and phenylalanine is very poor, we pulverize and sieve processing, cross respectively 60 orders, 80 orders and 100 mesh sieves, more than finding 60 mesh sieves, above-mentioned five seed amino acid recipe quantities substantially can be molten clear in the water of recipe quantity 60% in 10 minutes, improved rate of dissolution, reduce the risk of decomposing due to aminoacid in high-temperature digestion process, for safety preferred mistake 80 mesh sieves.
According to the conventional production process of injection, we do following explanation to molten material by volume and the temperature of water for injection:
In test, select molten material water for injection volume, rare the joining and dense conventional ratio and operability of joining in Main Basis injection production process, generally select 50～80% of overall accumulated amount, here preferably 60%; Molten material is selected by water for injection temperature, the insoluble aminoacid Aspartic Acid of main consideration, glutamic acid, leucine, isoleucine and phenylalanine can dissolve in right amount in hot water, removing endotoxic condition in conjunction with the decolouring of activated carbon in test is in addition 60 ℃, and amino-acid analyzer detection display solution temperature more the stability of homoamino acid is poorer, comprehensive dissolubility, stability and decolouring are except endotoxin effect, the temperature of selecting molten material water for injection is 40～80 ℃, preferably 60 ℃.
in sum:
The invention provides the preparation method of the two peptides of a kind of amino acid (15) (2) injection, can make degradation impurity ring (glycyl-L-glutamine acyl) and ring (glycyl-L-tyrosyl) that injection produces in high temperature sterilize process obviously reduce.Specific as follows:
Under omnidistance nitrogen protection; get the water for injection of overall accumulated amount 60%; add successively glycyl-L-glutamine, glycyl-L-tyrosine and the arginine of recipe quantity; stirring and dissolving and molten clear after; added Aspartic Acid, glutamic acid, leucine, isoleucine and the phenylalanine of 80 mesh sieve recipe quantities; stir molten clear; finally add alanine, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and the valine of recipe quantity, regulate pH5.4～5.8 with citric acid.Add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, and decarburization is filtered and stirred molten clearly, is settled to cumulative volume with water for injection, crosses the filter membrane of 0.22 micron, and fill, fills nitrogen, jumps a queue, and pricks aluminium lid.Respectively at 8 minutes, 10 minutes and 12 minutes 121 ℃ of pressure sterilizings.Detect by import drug standard, impurity result is as follows:
We do not do the design and the adjustment that feed intake simultaneously, and injection production way is routinely prepared a batch sample:
Under omnidistance nitrogen protection; get the water for injection of overall accumulated amount 60%; add successively alanine, arginine, Aspartic Acid (80 order), glutamic acid (80 order), histidine, leucine (80 order), isoleucine (80 order), valine, lysine acetate, methionine, the phenylalanine (80 order) of recipe quantity; proline, serine, threonine, tryptophan and glycyl-L-glutamine and glycyl-L-tyrosine; stir molten clearly, regulate pH5.4～5.8 with citric acid.Add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, and decarburization is filtered, and is settled to cumulative volume with water for injection, crosses the filter membrane of 0.22 micron, and fill, fills nitrogen, jumps a queue, and pricks aluminium lid.Respectively at 8 minutes, 10 minutes and 12 minutes 121 ℃ of pressure sterilizings.Detect by import drug standard, impurity result is as follows:
Find that through contrast the injection preparation method of the present invention design can well be controlled after high temperature sterilize the ring (Gly-Glu) in injection and encircle impurity such as (Gly-Tyrs).
The related substance detection method wherein relating to is with reference to related substance detection method in JX20030306:
Pyroglutamic acid and ring (Gly-Glu) are measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Be mobile phase with 0.01mol/L ammonium dibasic phosphate solution (with phosphorus acid for adjusting pH to 1.6, scalable pH value separates each peak energy if desired), detection wavelength is 205nm.
The about 50mg of pyroglutamic acid reference substance is got in the preparation of standard curve, the about 80mg of ring (Gly-Glu) reference substance, accurately weighed respectively, put in same 100ml volumetric flask, be dissolved in water and be diluted to scale, shake up, product solution (1) in contrast, precision measures reference substance solution (1) 5ml respectively, 2ml, 0.5ml put in 10ml volumetric flask, be diluted with water to scale, shake up, in contrast solution (2), (3), (4); Precision measures above-mentioned four kinds of each 2ml of reference substance solution, adds to (internal diameter 1.5cm, high 7cm in ion exchange column, filler Dowex 50W × 8 are through 20ml water wash and suspend in water), add water wash, collect effluent in 100ml measuring bottle, until effluent, to scale, shakes up.Precision measures in each effluent 50 μ l difference injection liquid chromatographies, calculates regression equation with concentration and corresponding peak height.
Algoscopy precision measures this product 2ml, under sighting target directrix curve preparation, certainly " adds to ion exchange column ... until effluent, to scale, shakes up." operate with method.Precision measures effluent 50 μ l injection liquid chromatographies, records chromatogram, by the amount of pyroglutamic acid and ring (Gly-Glu) in regression equation calculation test sample.Pyroglutamic acid must not be crossed 350mg/L, and ring (Gly-Glu) must not be crossed 530mg/L.
Ring (Gly-Tyr) is measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000)
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler; Take methanol-0.01mol/L sodium dihydrogen phosphate (with phosphorus acid for adjusting pH to 3.0), (222-2000) as mobile phase, detection wavelength is 225nm.
The about 10mg of ring (Gly-Tyr) reference substance is got in the preparation of standard curve, accurately weighed, put in 100ml volumetric flask, be dissolved in water and be diluted to scale, shaking up, in contrast product solution (1), precision measures reference substance solution (1) 5ml respectively, 2ml, 0.5ml put in 10ml volumetric flask, be diluted with water to scale, shake up, in contrast solution (2), (3), (4); Precision measures above-mentioned four kinds of each 2ml of reference substance solution, adds to (internal diameter 1.5cm, high 7cm in ion exchange column, filler Dowex 50W × 8 are through 20ml water wash and suspend in water), add water wash, collect effluent in 100ml measuring bottle, until effluent, to scale, shakes up.Precision measures in each effluent 100 μ l difference injection liquid chromatographies, calculates regression equation with concentration and corresponding peak height.
Algoscopy precision measures this product 2ml, under sighting target directrix curve preparation, certainly " adds to ion exchange column ... until effluent, to scale, shakes up." operate with method.Precision measures effluent 100 μ l injection liquid chromatographies, records chromatogram, by the amount of regression equation calculation test sample medium ring (Gly-Tyr).Ring (Gly-Tyr) must not be crossed 60mg/L.
The specific embodiment
Below the preferred embodiments of the present invention are described, should be appreciated that preferred embodiment described herein, only for description and interpretation the present invention, is not intended to limit the present invention.
Glycyl-L-glutamine (C used below
7h
13n
3o
4h
2o) detect by national standard YHB15552006, all meet glycyl-L-tyrosine (C
11h
14n
2o
42H
2o) detect by national standard YHB15542006, all meet.
The preparation of the two peptides of embodiment 1 amino acid (15) (2) injection:
Weigh each amino acid starting material according to following table ratio, in 1000ml, contain:
Under nitrogen protection, the water for injection of getting overall accumulated amount 60% is 3000 milliliters, be heated to 60 ℃, add successively glycyl-L-glutamine and the glycyl-L-tyrosine of recipe quantity, the molten arginine that adds recipe quantity after clear, stir and molten clear after, added rapidly the Aspartic Acid of 80 mesh sieve recipe quantities, glutamic acid, leucine, isoleucine and phenylalanine, stir molten clear, finally add the alanine of recipe quantity, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and valine, stir molten clear, regulate pH5.4～5.8 with citric acid, add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, decarburization is filtered, be settled to 5000 milliliters of cumulative volumes with water for injection, cross the filter membrane of 0.22 micron, fill 500ml/ bottle, fill nitrogen, jump a queue, prick aluminium lid.By setup program by product 121 ± 1 ℃ of sterilizings 12 minutes.Product after sterilizing, after lamp inspection is qualified, detects related substances, and result is as follows:
The preparation of the two peptides of embodiment 2 amino acids (15) (2) injection:
Press embodiment 1 ingredient proportion, under nitrogen protection, the water for injection of getting overall accumulated amount 60% is 3000 milliliters, be heated to 60 ℃, add the arginine of recipe quantity, moltenly add glycyl-L-glutamine and glycyl-L-tyrosine after clear, stir and molten clear after, added rapidly the Aspartic Acid of 80 mesh sieve recipe quantities, glutamic acid, leucine, isoleucine and phenylalanine, stir molten clear, finally add the alanine of recipe quantity, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and valine, stir molten clear, regulate pH5.4～5.8 with citric acid, add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, decarburization is filtered, be settled to 5000 milliliters of cumulative volumes with water for injection, cross the filter membrane of 0.22 micron, fill 500ml/ bottle, fill nitrogen, jump a queue, prick aluminium lid.By setup program by product 121 ± 1 ℃ of sterilizings 12 minutes.Product after sterilizing, after lamp inspection is qualified, detects related substances, and result is as follows:
The preparation of the two peptides of embodiment 3 amino acids (15) (2) injection:
Press embodiment 1 ingredient proportion, under nitrogen protection, the water for injection of getting overall accumulated amount 60% is 3000 milliliters, be heated to 60 ℃, add glycyl-L-glutamine and the glycyl-L-tyrosine of recipe quantity, moltenly add arginine after clear, stirring and dissolving and molten clear after, add the alanine of recipe quantity, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and valine, stir molten clear, added rapidly again the Aspartic Acid of 80 mesh sieve recipe quantities, glutamic acid, leucine, isoleucine and phenylalanine, stir molten clear, regulate pH5.4～5.8 with citric acid, add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, decarburization is filtered, be settled to 5000 milliliters of cumulative volumes with water for injection, cross the filter membrane of 0.22 micron, fill 500ml/ bottle, fill nitrogen, jump a queue, prick aluminium lid.By setup program by product 121 ± 1 ℃ of sterilizings 12 minutes.Product after sterilizing, after lamp inspection is qualified, detects related substances, and result is as follows:
The preparation of the two peptides of embodiment 4 amino acids (15) (2) injection
Press embodiment 1 ingredient proportion, under nitrogen protection, the water for injection of getting overall accumulated amount 60% is 60000 milliliters, be heated to 60 ℃, add successively glycyl-L-glutamine and the glycyl-L-tyrosine of recipe quantity, moltenly add arginine after clear, stirring and dissolving and molten clear after, added rapidly the Aspartic Acid of 80 mesh sieve recipe quantities, glutamic acid, leucine, isoleucine and phenylalanine, stir molten clear, finally add the alanine of recipe quantity, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and valine, stir molten clear, regulate pH5.4～5.8 with citric acid, add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, decarburization is filtered, be settled to 100000 milliliters of cumulative volumes with water for injection, cross the filter membrane of 0.22 micron, fill 500ml/ bottle, fill nitrogen, jump a queue, prick aluminium lid.By setup program by product 121 ± 1 ℃ of sterilizings 8 minutes, 10 minutes, 12 minutes.Product after sterilizing, after lamp inspection is qualified, detects related substances, and result is as follows:
Claims (1)
1. the preparation method of the two peptides of amino acid (15) (2) injection: it is characterized in that this injection needs whole process to fill a nitrogen, feeds intake in the following order:
In water for injection, add successively 1. glycyl-L-glutamine, glycyl-L-tyrosine and arginine by recipe quantity, stir molten clear; 2. cross the Aspartic Acid, glutamic acid, leucine, isoleucine and the phenylalanine that are not less than 60 mesh sieves, stir molten clear; 3. alanine, histidine, lysine acetate, methionine, proline, serine, threonine, tryptophan and valine, stir molten clear after, regulate pH5.4～5.8 with citric acid, add the active carbon of full dose 0.10% (w/v), 60 ℃ are stirred 30 minutes, and decarburization is filtered, be settled to cumulative volume with water for injection, cross the filter membrane of 0.22 micron, fill, fills nitrogen, jump a queue, prick aluminium lid, 121 ℃ of pressure sterilizings 8～12 minutes
The two peptides of amino acid of living in (15) (2) injection formula is composed as follows, in 1000ml, contains:
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| CN110693827A (en) * | 2019-11-22 | 2020-01-17 | 天津金耀集团湖北天药药业股份有限公司 | Compound amino acid dipeptide injection and preparation method thereof |
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