CN100469362C - Composite amino acid freeze dried powder injection and its preparation process - Google Patents
Composite amino acid freeze dried powder injection and its preparation process Download PDFInfo
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Abstract
The invention relaets to a compound amino acid freeze-dried powder injection, which comprises L-arginine hydrochloride, L-histidine hydrochloride, L-leucine, L-isoleucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine, L-tryptophan, glycine, L-alanine, L-proline, L-tyrosine, L-serine, L-cysteine hydrochloride, L- aspartic acid, L-glutamic acid and sodium bisulphate. Its preparing process is also disclosed in the invention.
Description
Technical field
The present invention relates to composite amino acid freeze dried powder injection and preparation method thereof, belong to medical technical field.
Background technology
Mixed amino acid is the novel compound preparation of a class, its each contained seed amino acid comprises essential and nonessential and semi-dispensable amino acid, several at least, 10 several at most, have also at different illness with need to cooperate various salts, saccharide and trace element.As be mainly used in the mixed amino acid Moriamin Forte (Moriumin Sorte) of digestive system: these product include 18 kinds of crystalline amino acids, and multivitamin and extraordinary nutrient are formed.Orally can provide enough essential amino acids, impel the synthetic of body protein, particularly albumin is synthetic, improves body autoimmunity.The clinical dysbolism that liver, renal insufficiency cause, the hypoproteinosis that various diseases causes, and the caused function of various diseases depleted and nutritional disorder, non-iron deficiency anemia etc. of can be used for.But because the aminoacids complex oral administration biaavailability is lower, so the aminoacids complex infusion solutions has appearred on the market.
The problem that existing amino acid infusion solutions exists:
1, (100ml:3.224g is 250ml:8.06g) because under the condition a little less than room temperature (10 ℃) for existing infusion solutions
Therefore there is crystallization to separate out, is prone to and in transportation, clinical use, meets low temperature and separate out crystalline polamer.
2, the infusion solutions herb liquid is owing to can ceaselessly contact with the infusion bottle plug, and it is qualified to cause the solution clarity to be difficult for.
3, what the isotonic agent of infusion solutions was used is xylitol, and using in clinical has limitation.
Problem based on above-mentioned prior art and existence, although those skilled in the art may expect proposing in conjunction with existing other medicine freeze-dried powder technology the imagination of the freeze-dried powder of preparation aminoacids complex related to the present invention, but because the preparation freeze-dried powder requires the water of low amount, and aminoacids complex poorly soluble under this water yield causes the composite amino acid freeze dried powder of failing to prepare fulfilling medicinal requirements so far.
Summary of the invention
The present invention provides a kind of injection composite amino acid freeze dried powder injection and preparation method thereof at the problems referred to above exactly, prepared freezing-dried powder injection is difficult for oxidation in storing, transporting, good, the no crystallization of dissolubility and clarity was separated out when clinical use was mixed with aqueous solution.
Technical scheme provided by the invention is: composite amino acid freeze dried powder injection, contain L-arginine hydrochloride, L-histidine monohydrochloride, L-leucine, L-isoleucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine, L-tryptophan, glycine, L-alanine, L-proline, L-tyrosine, L-serine, L-cysteine hydrochloride, L-Aspartic Acid, L-glutamic acid and sodium sulfite.
Above-mentioned L-arginine hydrochloride, the L-histidine monohydrochloride, the L-leucine, the L-isoleucine, the L-lysine hydrochloride, the L-phenylalanine, the L-threonine, the L-valine, the L-methionine, the L-tryptophan, glycine, the L-alanine, the L-proline, L-tyrosine, the L-serine, the L-cysteine hydrochloride, the L-Aspartic Acid, the consumption weight ratio of L-glutamic acid and sodium sulfite is 289 ± 10:246 ± 10:379 ± 10:170 ± 10:333 ± 10:283 ± 10:197 ± 10:136 ± 10:106 ± 10:39 ± 10:324 ± 10:188 ± 10:100 ± 10:11 ± 10:67 ± 10:44 ± 10:115 ± 10:197 ± 10:50 ± 10.
The agent of above-mentioned injection composite amino acid freeze dried powder also can contain sodium hydroxide, and sodium hydroxide concentration is 0.1-0.16 a times of L-proline weight.
The present invention also provides the preparation method of above-mentioned injection composite amino acid freeze dried powder agent, under aseptic condition, L-arginine hydrochloride, L-leucine, L-isoleucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine, glycine, L-alanine, L-proline, L-tyrosine, L-serine, L-Aspartic Acid and L-glutamic acid are dissolved with water for injection, add L-histidine monohydrochloride, L-tryptophan, L-cysteine hydrochloride and sodium sulfite then, be stirred to dissolving; Accent pH is 5.5-7.0, and adds activated carbon filtration, filtrate is carried out fine straining with microporous filter membrane get fine straining liquid; With pack into container and put into the fridge lyophilizing of fine straining liquid, obtain the agent of injection amino acid freeze dried powder; The consumption of water is above-mentioned aminoacid and sodium sulfite gross weight 10-30 a times.
The method for optimizing of above-mentioned aminoacid and sodium sulfite and water for injection mixed dissolution is: the order by L-arginine hydrochloride, L-leucine, L-isoleucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine, glycine, L-alanine, L-proline, L-tyrosine, L-serine, L-Aspartic Acid, L-glutamic acid, L-histidine monohydrochloride, L-tryptophan, L-cysteine hydrochloride and sodium sulfite is dissolved in the water for injection one by one, add then with the sodium sulfite after the water for injection dissolving, add water to full dose.
Perhaps, press the A group: L-Aspartic Acid, L-glutamic acid, L-serine, glycine, L-arginine hydrochloride; B group: L-threonine, L-alanine, L-proline, L-tyrosine, L-valine; C group: L-methionine, L-isoleucine, L-leucine, L-phenylalanine, L-lysine hydrochloride; (the input sequencing of A, B and C group is any) is dissolved in the water for injection by group, adds L-histidine monohydrochloride, L-tryptophan, L-cysteine hydrochloride then and with the sodium sulfite after the water for injection dissolving, adds water to full dose.
Above-mentioned filtrate is used 0.45 μ m and 0.22 μ m microporous filter membrane fine straining successively, or directly uses 0.22 μ m microporous filter membrane fine straining.
The present invention has overcome because of aminoacids complex poorly soluble under the conventional water yield of preparation freeze-dried powder, can't prepare the defective of composite amino acid freeze dried powder by art methods, adopts said method successfully to prepare composite amino acid freeze dried powder injection.
Composite amino acid freeze dried powder injection of the present invention is the parenteral alimentation medicine, by preparing by a certain percentage with non essential amino acid, can utilize acid to provide human body protein to synthesize, keep nutrition.Essential amino acids meets the Vuj-N formula proportion, and non essential amino acid meets Albumin's pattern.Every seed amino acid easily is used for the synthetic of human body protein, its bioavailability height effectively.Be usually used in wound, burn, perioperatively patient's protein and malnutrition, improve because the protein adsorption obstacle that the function of intestinal canal imbalance causes, protein synthesis disorder due to correction liver cirrhosis, the hepatopathy, treatment hepatic coma provides chronic, wasting diseases, acute infectious disease, has a delicate constitution and can not normally take food or superelevation metabolism, state of an illness critical patient's intravenous nutrition.
Usage and dosage: when the present invention used, every 3.224g added in 100m1 formula mannitol injection liquid or 5% glucose injection.To malnutrition, hypoproteinemia, once slow intravenous drip 16.12g; Or follow the doctor's advice.
Before and after the surgical operation, slow intravenous drip 48.36g once, by 30-40 drip/minute; Or follow the doctor's advice.
Composite amino acid freeze dried powder injection of the present invention is compared with the transfusion dosage form and had the following advantages: (1) powder pin more helps the stable of medicine.(2) packaging volume is little, and packaging material require low, have reduced packing cost and cost of transportation.(3) Zhi Bei freezing-dried powder injection is difficult for oxidation in storing, transporting, and good, the no crystallization of dissolubility and clarity was separated out when clinical use was mixed with aqueous solution.On the drug market that infusion products is numerous at present, especially in today that the medical support system is progressively popularized, composite amino acid freeze dried powder injection of the present invention is because its lower clinical expense has irreplaceable competitiveness.
The specific embodiment
Further specify the present invention by the following examples, therefore do not limit the present invention in the described scope of embodiments.
Embodiment 1:
Composite amino acid freeze dried powder injection, per 1000 bottles contain L-arginine hydrochloride 289g, L-leucine 379g, L-isoleucine 170g, L-lysine hydrochloride 333g, L-phenylalanine 283g, L-threonine 197g, L-valine 136g, L-methionine 106g, glycine 324g, L-alanine 188g, L-proline 100g, L-tyrosine 11g, L-serine 67g, L-Aspartic Acid 115g, L-glutamic acid 197g, L-histidine monohydrochloride 246g, L-tryptophan 39g, L-cysteine hydrochloride 44g, sodium sulfite 50g and sodium hydroxide 12.6 grams.
The preparation of composite amino acid freeze dried powder injection:
1. measure 18 seed amino acids, sodium sulfite and sodium hydroxide by the composition of above-mentioned composite amino acid freeze dried powder injection, other gets 96,000 gram waters for injection.
2. get 4/5 of above-mentioned water for injection full dose, use the 0.45um filtering with microporous membrane, be heated to boil after, stop heating, add the sodium hydroxide after dissolving with refrigerative water for injection.
3. the composition order by above-mentioned composite amino acid freeze dried powder injection drops into each seed amino acid one by one, and abundant stirring and dissolving (adding back again after dissolving), after having dissolved whole aminoacid, adds sodium sulfite (NaHSO
3Must drop into refrigerative water for injection dissolving back), add remaining water for injection standardize solution.
4. add 0.05% active carbon, adsorb after 30 minutes, filter decarburization, successively through 0.45um and 0.22um microporous filter membrane fine straining, smart solution branch packed into put into the fridge lyophilizing in 1000 bottle containers, gland promptly gets composite amino acid freeze dried powder injection.
Embodiment 2:
Composite amino acid freeze dried powder injection, per 1000 bottles contain composite amino acid freeze dried powder injection, and per 1000 bottles contain L-arginine hydrochloride 299g, L-leucine 369g, L-isoleucine 180g, L-lysine hydrochloride 323g, L-phenylalanine 293g, L-threonine 187g, L-valine 146g, L-methionine 96g, glycine 334g, L-alanine 178g, L-proline 110g, L-tyrosine 1g, L-serine 77g, L-Aspartic Acid 105g, L-glutamic acid 207g, L-histidine monohydrochloride 236g, L-tryptophan 49g, L-cysteine hydrochloride 34g and sodium sulfite 60g.
The preparation of composite amino acid freeze dried powder injection:
1. measure 18 seed amino acids and sodium sulfite by the composition of above-mentioned composite amino acid freeze dried powder injection, other gets 33,000 gram waters for injection.
2. get 4/5 of above-mentioned water for injection full dose, use the 0.45um filtering with microporous membrane, be heated to boil after, stop the heating.
3. the composition order by above-mentioned composite amino acid freeze dried powder injection drops into each seed amino acid one by one, and abundant stirring and dissolving (adding back again after dissolving), after waiting to drop into the L-histidine hydrochloride, stop to cast a kind of raw material, and begin cooling, after temperature is reduced to 50 ℃, stir and drop into L-tryptophan and L-cysteine hydrochloride down; After having dissolved whole aminoacid, add sodium sulfite (NaHSO
3Must drop into refrigerative water for injection dissolving back), add remaining water for injection standardize solution.
4. transferring pH is 5.5-7.0.
5. add 0.05% active carbon, adsorb after 30 minutes, filter decarburization, successively through 0.45um and 0.22um microporous filter membrane fine straining, with smart solution pack into suitable containers put into fridge carry out freezing, freeze good after with its pulverizing, and the clarity of taking a sample to check, aseptic, bacterial endotoxin, content, treat qualified after, install with vacuum packaging bag, obtain composite amino acid freeze dried powder injection.
Embodiment 3:
Composite amino acid freeze dried powder injection, per 1000 bottles contain L-arginine hydrochloride 279g, L-leucine 389g, L-isoleucine 160g, L-lysine hydrochloride 343g, L-phenylalanine 273g, L-threonine 207g, L-valine 126g, L-methionine 116g, glycine 314g, L-alanine 198g, L-proline 90g, L-tyrosine 21g, L-serine 57g, L-Aspartic Acid 125g, L-glutamic acid 187g, L-histidine monohydrochloride 256g, L-tryptophan 29g, L-cysteine hydrochloride 54g, sodium sulfite 40g and sodium hydroxide 14 grams.
The preparation of composite amino acid freeze dried powder injection:
1. measure 18 seed amino acids, sodium sulfite and sodium hydroxide by the composition of above-mentioned composite amino acid freeze dried powder injection, other gets 65,000 gram waters for injection.
2. get 4/5 of above-mentioned water for injection full dose, use the 0.45um filtering with microporous membrane, be heated to boil after, stop heating, add the sodium hydroxide after dissolving with refrigerative water for injection.
3. be divided into four groups by the aminoacid in the above-mentioned composite amino acid freeze dried powder injection: A, Aspartic Acid, glutamic acid, serine, glycine, arginine hydrochloride, B, threonine, alanine, proline, tyrosine, valine, C, methionine, isoleucine, leucine, phenylalanine, lysine hydrochloride, D, histidine monohydrochloride, tryptophan, cysteine hydrochloride; Every group aminoacid drops in the lump when feeding intake, feeding sequence A, B, C, D (or A, C, B, D, or B, A, C, D, or B, C, A, D, or C, B, A, D, or C, A, B, D, i.e. A, the input sequencing of B and C group can be arbitrarily), and fully stirring and dissolving (is dissolved while stirring, add one group of back after dissolving one group again), treat A, B, after three groups of C have thrown and dissolved, begin cooling, after temperature is reduced to 50 ℃, drop into the D group, and stirring makes it dissolving, after having dissolved whole aminoacid, add sodium sulfite (NaHSO3 must drop into refrigerative water for injection dissolving back), add remaining water for injection standardize solution.
4. add 0.05% active carbon, adsorb after 30 minutes, filter decarburization, through 0.22um microporous filter membrane fine straining, with smart solution pack into suitable containers put into freezing machine carry out freezing, freeze good after with its pulverizing, and the clarity of taking a sample to check, aseptic, bacterial endotoxin, content, treat qualified after, install with vacuum packaging bag, obtain composite amino acid freeze dried powder injection.
Drug quality of the present invention
The quality of medicine of the present invention character, discriminating, inspection (pH value, clarity, related substance, loss on drying, clarity, aseptic, bacterial endotoxin, heavy metal) and assay have been carried out.Adopt high performance liquid chromatography that sample is carried out the related substance inspection, and carried out tests such as linear relationship, the response rate, precision, result of the test meets the general analysis test requirements document.The 9 batch sample assay results that manufacture experimently according to the present invention are respectively one and see the following form: so the sign content limit of regulation this product is 80～120%.
Lot number 040,901 040,902 040,903 041,001 041,002 041,003 051,201 051,202 051203
Aspartic Acid % 98.85 99.32 99.80 100.3 100.3 99.8 103.6 100.7 100.3
Glutamic acid % 99.38 99.81 100.31 100.3 100.3 99.9 103.3 99.8 99.8
Serine % 99.59 99.98 100.49 101.7 101.8 101.6 103.6 100.2 100.0
Glycine % 99.49 99.98 100.58 100.7 100.9 100.7 104.2 100.4 100.6
Histidine monohydrochloride % 99.83 100.25 100.80 101.0 100.9 100.6 103.5 100.1 100.2
Arginine hydrochloride % 99.16 100.17 100.33 101.0 101.0 100.6 103.7 99.7 99.9
Threonine % 100.02 100.87 101.01 101.7 101.7 101.3 103.6 99.7 99.8
Alanine % 98.91 99.45 99.88 100.3 100.3 100.0 99.8 99.7 99.1
Proline % 101.62 102.17 102.22 102.8 104.4 105.4 99.2 98.3 99.5
Tyrosine % 102.48 106.54 92.64 100.5 101.5 102.2 100.2 100.2 101.2
Valine % 99.78 100.28 100.78 101.0 100.9 100.5 102.4 99.6 98.7
Methionine % 98.75 99.10 99.59 99.8 99.8 99.5 103.3 99.6 99.4
Isoleucine % 98.96 99.29 99.70 101.8 101.8 101.4 103.1 99.1 99.2
Leucine % 99.18 99.56 100.04 98.7 99.0 98.7 103.3 99.2 99.5
Phenylalanine % 99.16 99.39 99.86 100.6 100.5 99.9 104.2 100.4 100.5
Tryptophan % 99.61 99.85 100.26 101.1 101.1 100.2 100.7 101.4 98.6
Lysine hydrochloride % 99.73 100.09 100.57 101.1 100.9 100.3 104.3 100.4 100.6
The result shows that the quality of medicine of the present invention meets medicinal requirements.
Stability test
Influence factor's test:
Influence factor's result of the test: by test data as can be known, this product is placed 5 days, 10 days the every inspection of character, light transmittance, pH, clarity and content under high temperature, illumination condition all up to specification.
Placing 5 days, 10 days character under super-humid conditions has deliquescent phenomenon, and all other indexs are all up to specification in limit.
Accelerated test is 40 ℃ of temperature, place 1,2,3 under the humidity RH75% condition, June character, pH value, clarity, the basic no change of light transmittance, moisture slightly increases, content slightly descends.Accelerated test after 6 months this product quality basicly stable.The commercially available back form of drafting that is adopted can satisfy the requirement of ensuring the quality of products.
Long term test was placed under the humidity RH60% condition 0,3,6,9,12 month 25 ℃ of temperature, and moisture slightly increases, and character, content, pH value, clarity, light transmittance have no significant change.6, checked bacterial endotoxin and aseptic in 12 months, all qualified.Long-term test results shows this product steady quality.
Pharmacological tests
The blood vessel irritation test: compound amino acid for injection slowly injects for the rabbit auricular vein with the dosage of 320mg/10ml/kg, once a day, and for three days on end.24 hours perusal injection site situations after the last administration are drawn materials after last is observed and are carried out histopathologic examination.The perusal result shows that each example of administration group and matched group shows no obvious abnormalities in different time points.The result of histopathologic examination shows, each routine rabbit ear edge venous structures of matched group and administration group is complete, and tube chamber does not have obvious expansion, does not see vascular endothelial cell swelling, degeneration, necrosis, wall of vein and surrounding tissue thereof do not have obvious cell infiltration, no obvious thrombosis in the tube chamber.Conclusion (of pressure testing) be compound amino acid for injection under this experimental condition, the rabbit auricular vein is not produced obvious irritation.2. whole body sensitivity test initiatively: Cavia porcellus is divided 4 groups, and compound amino acid for injection is given two groups of guinea pig intraperitoneal injection 0.5ml/ sensitization respectively with 16mg/ml high concentration and 3.2mg/ml low concentration, the next day once, continuous 5 times.The 10th day each group attacked with 2 multiple doses respectively after last sensitization, and as positive control, 5% glucose injection is as negative control with 4% egg protein.The result anaphylactic reaction all do not occur after showing that the compound amino acid for injection of two kinds of dosage and 5% glucose injection are given the Cavia porcellus immune attack; The reaction of typical systemic anaphylaxis then appears in the positive control treated animal, shows as dyspnea, tic spasm, the death that falls down to the ground, and level of reaction is ++ ++ level.Conclusion (of pressure testing) be compound amino acid for injection under this experimental condition, Cavia porcellus is not caused systemic anaphylaxis reaction.
3. hemolytic test: the method for external hemolytic test is observed the compound amino acid for injection of 32mg/ml concentration to the erythrocytic influence of rabbit routinely.The result shows that compound amino acid for injection did not have obvious haemolysis to tame rabbit erythrocyte in 3 hours, also show cell agglutination phenomenon not.
Medicine of the present invention carries out blood vessel irritation, anaphylaxis, hemolytic test, and the result does not see remarkable blood vessel irritation reaction, and animal subject is not had sensitization, does not see haemolysis yet.
Test shows that drug quality of the present invention is stable, and safe and effective, preparation technology is reasonable.
Claims (6)
1. composite amino acid freeze dried powder injection is characterized in that: contain L-arginine hydrochloride, L-histidine monohydrochloride, L-leucine, L-isoleucine, L-lysine hydrochloride, L-phenylalanine, L-threonine, L-valine, L-methionine, L-tryptophan, glycine, L-alanine, L-proline, L-tyrosine, L-serine, L-cysteine hydrochloride, L-Aspartic Acid, L-glutamic acid and sodium sulfite; The L-arginine hydrochloride, the L-histidine monohydrochloride, the L-leucine, the L-isoleucine, the L-lysine hydrochloride, the L-phenylalanine, the L-threonine, the L-valine, the L-methionine, the L-tryptophan, glycine, the L-alanine, the L-proline, L-tyrosine, the L-serine, the L-cysteine hydrochloride, the L-Aspartic Acid, the consumption weight ratio of L-glutamic acid and sodium sulfite is 289 ± 10:246 ± 10:379 ± 10:170 ± 10:333 ± 10:283 ± 10:197 ± 10:136 ± 10:106 ± 10:39 ± 10:324 ± 10:188 ± 10:100 ± 10:11 ± 10:67 ± 10:44 ± 10:115 ± 10:197 ± 10:50 ± 10.
2. freezing-dried powder injection according to claim 1 is characterized in that: contain sodium hydroxide, sodium hydroxide concentration is 0.1-0.16 times of L-proline weight.
3. the preparation method of the described composite amino acid freeze dried powder injection of claim 1, it is characterized in that: under aseptic condition, press the L-arginine hydrochloride, the L-leucine, the L-isoleucine, the L-lysine hydrochloride, the L-phenylalanine, the L-threonine, the L-valine, the L-methionine, glycine, the L-alanine, the L-proline, L-tyrosine, the L-serine, the L-Aspartic Acid, L-glutamic acid, the L-histidine monohydrochloride, the L-tryptophan, the order of L-cysteine hydrochloride is dissolved in the water for injection one by one, add then with the sodium sulfite after the water for injection dissolving, add water to full dose; Regulating pH is 5.5-7.0, and adds activated carbon filtration, filtrate is carried out fine straining with microporous filter membrane get fine straining liquid; With pack into container and put into the fridge lyophilizing of fine straining liquid, obtain injection aminoacid sterile powder injection; The consumption of water is above-mentioned aminoacid and sodium sulfite gross weight 10-30 times.
4. the preparation method of the described composite amino acid freeze dried powder injection of claim 1 is characterized in that: under aseptic condition, press the A group: L-Aspartic Acid, L-glutamic acid, L-serine, glycine, L-arginine hydrochloride; B group: L-threonine, L-alanine, L-proline, L-tyrosine, L-valine; C group: L-methionine, L-isoleucine, L-leucine, L-phenylalanine, L-lysine hydrochloride; Be dissolved into by group in the water for injection, add L-histidine monohydrochloride, L-tryptophan, L-cysteine hydrochloride then and, add water to full dose with the sodium sulfite after the water for injection dissolving; Regulating pH is 5.5-7.0, and adds activated carbon filtration, filtrate is carried out fine straining with microporous filter membrane get fine straining liquid; With pack into container and put into the fridge lyophilizing of fine straining liquid, obtain injection aminoacid sterile powder injection; The consumption of water is above-mentioned aminoacid and sodium sulfite gross weight 10-30 times.
5. according to claim 3 or 4 described preparation methoies, it is characterized in that: with water for injection be heated to boil after, stop heating, add aminoacid then and stir and make its dissolving, after waiting to drop into the L-histidine monohydrochloride, begin cooling, after temperature is reduced to 50 ℃, drop into L-tryptophan, L-cysteine hydrochloride and sodium sulfite.
6. according to claim 3 or 4 described preparation methoies, it is characterized in that: filtrate is with 0.45 μ m and 0.22 μ m microporous filter membrane fine straining.
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| CN102145009B (en) * | 2010-12-29 | 2013-12-18 | 辰欣药业股份有限公司 | Octadeca compound amino acid injection and preparation method thereof |
| CN110339398A (en) * | 2019-07-18 | 2019-10-18 | 王月玲 | One kind Amvisc containing amino acid and preparation method thereof |
| CN111358753A (en) * | 2020-04-08 | 2020-07-03 | 河北科星药业有限公司 | Compound amino acid injection for livestock and preparation method thereof |
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| 复方氨基酸注射液制备工艺的研究. 朱复华等.中国医药工业杂志，第31卷第4期. 2000 |
| 复方氨基酸注射液制备工艺的研究. 朱复华等.中国医药工业杂志，第31卷第4期. 2000 * |
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