CN114452253A - Enrofloxacin injection and preparation method thereof - Google Patents
Enrofloxacin injection and preparation method thereof Download PDFInfo
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- CN114452253A CN114452253A CN202210186062.0A CN202210186062A CN114452253A CN 114452253 A CN114452253 A CN 114452253A CN 202210186062 A CN202210186062 A CN 202210186062A CN 114452253 A CN114452253 A CN 114452253A
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- enrofloxacin
- injection
- hydroxyethyl cellulose
- enrofloxacin injection
- ethylene diamine
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- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229960000740 enrofloxacin Drugs 0.000 title claims abstract description 99
- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims abstract description 34
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims abstract description 34
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims abstract description 34
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims abstract description 34
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 claims abstract description 24
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 24
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 claims abstract description 24
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 24
- 239000000661 sodium alginate Substances 0.000 claims abstract description 24
- 235000010413 sodium alginate Nutrition 0.000 claims abstract description 24
- 229940005550 sodium alginate Drugs 0.000 claims abstract description 24
- 239000011259 mixed solution Substances 0.000 claims abstract description 20
- 239000008215 water for injection Substances 0.000 claims abstract description 20
- 239000000463 material Substances 0.000 claims abstract description 18
- 229960003966 nicotinamide Drugs 0.000 claims abstract description 17
- 235000005152 nicotinamide Nutrition 0.000 claims abstract description 17
- 239000011570 nicotinamide Substances 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 10
- 239000011550 stock solution Substances 0.000 claims abstract description 8
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 5
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims abstract 5
- 239000000243 solution Substances 0.000 claims description 34
- 238000010438 heat treatment Methods 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 18
- 238000005303 weighing Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 8
- 238000003760 magnetic stirring Methods 0.000 claims description 8
- 230000001954 sterilising effect Effects 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 125000002091 cationic group Chemical group 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 2
- 238000010583 slow cooling Methods 0.000 claims description 2
- 238000003860 storage Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 239000012046 mixed solvent Substances 0.000 abstract 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 8
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 244000144972 livestock Species 0.000 description 3
- 244000144977 poultry Species 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 108020000946 Bacterial DNA Proteins 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000606860 Pasteurella Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The invention discloses an enrofloxacin injection and a preparation method thereof, wherein the enrofloxacin injection comprises raw enrofloxacin, auxiliary materials and stock solution; the auxiliary materials comprise cationized hydroxyethyl cellulose, sodium alginate, nicotinamide and disodium ethylene diamine tetraacetate; the stock solution is prepared by mixing water for injection, propylene glycol and polyethylene glycol. According to the invention, a mixed solvent of propylene glycol and polyethylene glycol is adopted, components in auxiliary materials are coordinated, the enrofloxacin mixed solution is sequentially treated step by step under different conditions, and finally, the enrofloxacin injection with high stability is obtained by cooling and fixing the volume. The enrofloxacin injection prepared by the invention is faintly acid, wherein the mass fraction of enrofloxacin can reach 20%; the injection has good stability, effectively overcomes the defects of the dissolubility and the storage performance of the existing enrofloxacin injection, and has good market prospect.
Description
Technical Field
The invention relates to the technical field of medicine and veterinary medicine preparation, in particular to enrofloxacin injection and a preparation method thereof.
Background
Enrofloxacin is also known as ethyl ciprofloxacin and enrofloxacin, and belongs to quinolone antibiotics. Enrofloxacin has strong antibacterial action on mycoplasma, belongs to broad-spectrum bactericides and has certain bactericidal action on escherichia coli, klebsiella, salmonella, proteus, pseudomonas aeruginosa, haemophilus, staphylococcus aureus, hemolytic pasteurella and other germs. Enrofloxacin is currently specified by the country as a special animal medicine, and has better tissue distribution; as a specific antibacterial drug for aquatic products and livestock and poultry, enrofloxacin directly acts on cell nucleuses of bacteria to inhibit bacterial DNA gyrase by mainly blocking the replication of bacterial DNA, so that the bacteria die quickly, and drug resistance is not easy to generate, and the enrofloxacin has an excellent antibacterial effect.
In cultivation prevention and treatment, enrofloxacin is generally administered by means of injection, but enrofloxacin has extremely low solubility in neutral water for injection and certain solubility in alkaline solvents, so that sodium hydroxide aqueous solution is generally used as the alkaline solvent of enrofloxacin. However, the solubility of enrofloxacin in alkaline sodium hydroxide aqueous solution still has limitation, the prepared injection with higher concentration is easy to separate out crystal, and the alkaline injection can not be used for livestock and poultry with weak acid in vivo environment in a large amount. In view of the above, there is a need to develop an enrofloxacin injection with higher solubility, which is suitable for livestock and poultry.
Disclosure of Invention
Aiming at the self physicochemical characteristics of the existing enrofloxacin and the defects of the enrofloxacin injection prepared by the existing process method, the invention aims to provide the enrofloxacin injection and the preparation method thereof. According to the invention, the propylene glycol, the polyethylene glycol and the water for injection are mixed as a solvent, and are cooperated with auxiliary materials consisting of cationized hydroxyethyl cellulose, sodium alginate, nicotinamide and disodium ethylene diamine tetraacetate in proportion, so that the solubility and stability of the obtained injection to enrofloxacin are obviously improved.
The invention is realized by the following technical scheme:
the invention provides an enrofloxacin injection, which comprises the components of raw enrofloxacin, auxiliary materials and stock solution; the auxiliary materials comprise cationized hydroxyethyl cellulose, sodium alginate, nicotinamide and disodium ethylene diamine tetraacetate; the stock solution is prepared by mixing water for injection, propylene glycol and polyethylene glycol.
Further, the mass ratio of the enrofloxacin to the auxiliary materials is 1 (1.45-1.85).
Furthermore, the mass ratio of the cationic hydroxyethyl cellulose, the sodium alginate, the nicotinamide and the disodium ethylene diamine tetraacetate in the auxiliary materials is (2.5-4.5):0.02, (1.2-1.5): 0.4.
Furthermore, the volume ratio of the propylene glycol to the polyethylene glycol in the stock solution is 1 (3-4).
Further, the mass fraction of the enrofloxacin in the enrofloxacin injection is 7.5% -20%.
The invention also provides a preparation method of the enrofloxacin injection, which comprises the following steps:
1) weighing the raw materials according to a formula ratio for later use, and uniformly mixing propylene glycol, polyethylene glycol and water for injection to obtain a mixed solution;
2) adding enrofloxacin, sodium alginate, nicotinamide and part of cationized hydroxyethyl cellulose into the mixed solution obtained in the step 1), heating to 45-55 ℃, uniformly stirring, and standing for 0.5-1 hour at constant temperature to obtain a treatment solution;
3) adding disodium ethylene diamine tetraacetate and the rest cationized hydroxyethyl cellulose into the treatment solution obtained in the step 2) in sequence, and controlling the temperature to react;
4) slowly cooling the reaction liquid reacted in the step 3) to room temperature, adding injection water to full volume, and filtering, topping and sterilizing to obtain the enrofloxacin injection.
Further, the partially cationized hydroxyethylcellulose in step 2) was 1/4 based on the total amount thereof.
Further, the step 3) of controlling the temperature to carry out the reaction specifically comprises the following steps: adding disodium ethylene diamine tetraacetate into the treatment solution, heating to 70-75 ℃, and magnetically stirring; then adding the rest cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing, and keeping magnetic stirring until the enrofloxacin is completely dissolved.
Further, the vacuum degree of the vacuum is 0.1 MPa.
Further, the slow cooling speed of the step 4) is 15-25 ℃/hour.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, the propylene glycol and the polyethylene glycol are selected and mixed with the water for injection in an optimized proportion to serve as a solvent for subsequent treatment, so that the problem of insolubility of enrofloxacin can be primarily improved. In the preparation process of the injection, an auxiliary material is added to further enhance the solubility of enrofloxacin in the solvent prepared by the invention, and the auxiliary material comprises cationized hydroxyethyl cellulose, sodium alginate, nicotinamide and disodium ethylene diamine tetraacetate; according to the invention, the enrofloxacin mixed solution is sequentially treated by the components in the auxiliary materials step by step under different conditions, the compatibility of enrofloxacin and a solvent is effectively improved through the coordination of the cationic hydroxyethyl cellulose, the sodium alginate and the nicotinamide in the auxiliary materials, and finally the enrofloxacin injection with high stability is obtained by cooling and fixing the volume, wherein the mass fraction of enrofloxacin in the injection can reach 20%, and no crystal is separated out after the enrofloxacin injection is stored for a long time. The enrofloxacin injection prepared by the invention has good stability, weak acidity and good biological applicability; the method is simple to operate, is suitable for industrial production, and has a good application prospect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly and completely described below with reference to the embodiments. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Example 1
1. Weighing 3 kg of enrofloxacin, 3.42 kg of cationized hydroxyethyl cellulose, 19.5 g of sodium alginate, 1.38 kg of nicotinamide, 0.39 kg of disodium ethylene diamine tetraacetate, 2.2L of propylene glycol, 7.8L of polyethylene glycol and a plurality of water for injection; 2.2L of propylene glycol, 7.8L of polyethylene glycol and 5L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 3 kg of enrofloxacin, 19.5 g of sodium alginate, 1.38 kg of nicotinamide and 0.855 kg of cationized hydroxyethyl cellulose into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.7 hour at constant temperature to obtain the treatment solution.
3. Adding 0.39 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding the rest 2.565 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain a reaction solution.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 6.1 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (15%).
Example 2
1. Weighing 1.8 kg of enrofloxacin, 2.052 kg of cationized hydroxyethyl cellulose, 11.7 g of sodium alginate, 0.828 kg of nicotinamide, 0.234 kg of disodium ethylene diamine tetraacetate, 1.8L of propylene glycol, 6.2L of polyethylene glycol and a plurality of water for injection; 1.8L of propylene glycol, 6.2L of polyethylene glycol and 8L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 1.8 kg of enrofloxacin, 11.7 g of sodium alginate, 0.828 kg of nicotinamide and 0.513 kg of cationized hydroxyethyl cellulose into the mixed solution, heating to 52 ℃, uniformly stirring, keeping constant temperature and standing for 0.6 h to obtain a treatment solution.
3. Adding 0.234 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding the rest 1.539 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain reaction liquid.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 9.5 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (9%).
Example 3
1. Weighing 4 kg of enrofloxacin, 4.56 kg of cationized hydroxyethyl cellulose, 26 g of sodium alginate, 1.84 kg of nicotinamide, 0.52 kg of disodium ethylene diamine tetraacetate, 2.5L of propylene glycol, 8.2L of polyethylene glycol and a plurality of water for injection; 2.5L of propylene glycol, 8.2L of polyethylene glycol and 3.2L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 4 kg of enrofloxacin, 26 g of sodium alginate, 1.84 kg of nicotinamide and 1.14 kg of cationized hydroxyethyl cellulose into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.8 hour at constant temperature to obtain a treatment solution.
3. Adding 0.52 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding the rest 3.42 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain a reaction solution.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 3.8 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (20%).
Comparative example 1
1. Weighing 3 kg of enrofloxacin, 3.42 kg of cationized hydroxyethyl cellulose, 1.38 kg of nicotinamide, 0.39 kg of disodium ethylene diamine tetraacetate, 2.2L of propylene glycol, 7.8L of polyethylene glycol and a plurality of injection water; 2.2L of propylene glycol, 7.8L of polyethylene glycol and 5L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 3 kg of enrofloxacin, 1.38 kg of nicotinamide and 0.855 kg of cationized hydroxyethyl cellulose into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.7 hour at constant temperature to obtain a treatment solution.
3. Adding 0.39 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding the rest 2.565 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain a reaction solution.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 6.1 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (15%).
Comparative example 2
1. Weighing 3 kg of enrofloxacin, 19.5 g of sodium alginate, 1.38 kg of nicotinamide, 0.39 kg of disodium ethylene diamine tetraacetate, 2.2L of propylene glycol, 7.8L of polyethylene glycol and a plurality of water for injection; 2.2L of propylene glycol, 7.8L of polyethylene glycol and 6.5L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 3 kg of enrofloxacin, 19.5 g of sodium alginate and 1.38 kg of nicotinamide into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.7 hour at constant temperature to obtain a treatment solution.
3. Adding 0.39 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring to obtain a reaction solution, wherein enrofloxacin cannot be completely dissolved.
Comparative example 3
1. Weighing 3 kg of enrofloxacin, 3.42 kg of cationized hydroxyethyl cellulose, 19.5 g of sodium alginate, 1.38 kg of nicotinamide, 0.39 kg of disodium ethylene diamine tetraacetate, 2.2L of propylene glycol, 7.8L of polyethylene glycol and a plurality of water for injection; 2.2L of propylene glycol, 7.8L of polyethylene glycol and 5L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 3 kg of enrofloxacin, 19.5 g of sodium alginate and 1.38 kg of nicotinamide into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.7 hour at constant temperature to obtain a treatment solution.
3. Adding 0.39 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding 3.42 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain a reaction solution.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 6.1 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (15%).
Comparative example 4
1. Weighing 3 kg of enrofloxacin, 3.42 kg of cationized hydroxyethyl cellulose, 19.5 g of sodium alginate, 0.39 kg of ethylene diamine tetraacetic acid, 2.2L of propylene glycol, 7.8L of polyethylene glycol and a plurality of injection water; 2.2L of propylene glycol, 7.8L of polyethylene glycol and 5.5L of water for injection are mixed uniformly to obtain a mixed solution.
2. Adding 3 kg of enrofloxacin, 19.5 g of sodium alginate and 0.855 kg of cationized hydroxyethyl cellulose into the mixed solution, heating to 52 ℃, uniformly stirring, and standing for 0.7 hour at constant temperature to obtain a treatment solution.
3. Adding 0.39 kg of disodium ethylene diamine tetraacetate into the treatment solution, heating to 72 ℃, and magnetically stirring; then adding the rest 2.565 kg of cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing to 0.1MPa, and keeping magnetic stirring until the enrofloxacin is completely dissolved to obtain a reaction solution.
4. Cooling the reaction solution to room temperature at the speed of 20 ℃/h, adding the injection water to the full amount (the final total injection water dosage is about 6.6 liters), and filtering, topping and sterilizing to obtain 20 liters of enrofloxacin injection (15%).
Comparative example 5
Enrofloxacin injection (10% by mass) was purchased as a commercially available sodium hydroxide aqueous solution as an alkaline solvent.
The storage performance of the enrofloxacin injection prepared in the above examples and comparative examples was tested, and the results are shown in table 1:
TABLE 1 results of storage Property measurements
The detection results in table 1 show that the enrofloxacin injection prepared by the invention has excellent solubility, the mass fraction of the enrofloxacin injection can reach 20%, the enrofloxacin injection with higher mass fraction still has good stability, the effective storage period is close to 2 years, and the enrofloxacin injection has qualitative leap compared with the enrofloxacin injection which uses the conventional sodium hydroxide as the alkaline solvent in the market. The sodium alginate and the nicotinamide added in the auxiliary materials can influence the stability of the prepared enrofloxacin injection, and although the solubility of the enrofloxacin cannot be directly influenced without adding the sodium alginate or the nicotinamide, the injection can be separated out and crystallized after a period of time. The cationized hydroxyethyl cellulose added in the auxiliary materials not only can influence the subsequent stability of the enrofloxacin injection, but also can directly influence the initial solubility of the enrofloxacin.
The embodiments described above merely represent some preferred embodiments of the present invention, which are described in more detail and detail, but are not intended to limit the present invention. It should be understood that various changes and modifications can be made by those skilled in the art, and any modification, equivalent replacement, improvement and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. The enrofloxacin injection is characterized by comprising the components of raw enrofloxacin, auxiliary materials and stock solution; the auxiliary materials comprise cationized hydroxyethyl cellulose, sodium alginate, nicotinamide and disodium ethylene diamine tetraacetate; the stock solution is prepared by mixing water for injection, propylene glycol and polyethylene glycol.
2. The enrofloxacin injection as claimed in claim 1, wherein the mass ratio of the enrofloxacin to the auxiliary material is 1 (1.45-1.85).
3. The enrofloxacin injection as claimed in claim 1, wherein the mass ratio of the cationic hydroxyethyl cellulose, the sodium alginate, the nicotinamide and the disodium ethylene diamine tetraacetate in the auxiliary materials is (2.5-4.5):0.02, (1.2-1.5): 0.4.
4. The enrofloxacin injection as claimed in claim 1, wherein the volume ratio of the propylene glycol to the polyethylene glycol in the stock solution is 1 (3-4).
5. The enrofloxacin injection as claimed in claim 1, wherein the mass fraction of enrofloxacin in the enrofloxacin injection is 7.5% -20%.
6. The preparation method of enrofloxacin injection as described in any one of claims 1 to 5, wherein the preparation method comprises the following steps:
1) weighing the raw materials according to a formula ratio for later use, and uniformly mixing propylene glycol, polyethylene glycol and water for injection to obtain a mixed solution;
2) adding enrofloxacin, sodium alginate, nicotinamide and part of cationized hydroxyethyl cellulose into the mixed solution obtained in the step 1), heating to 45-55 ℃, uniformly stirring, and standing for 0.5-1 hour at constant temperature to obtain a treatment solution;
3) adding disodium ethylene diamine tetraacetate and the rest cationized hydroxyethyl cellulose into the treatment solution obtained in the step 2) in sequence, and controlling the temperature to react;
4) slowly cooling the reaction liquid reacted in the step 3) to room temperature, adding injection water to full volume, and filtering, topping and sterilizing to obtain the enrofloxacin injection.
7. The method for preparing enrofloxacin injection according to claim 6, wherein the amount of the partially cationized hydroxyethyl cellulose in step 2) is 1/4.
8. The method for preparing enrofloxacin injection according to claim 6, wherein the step 3) of controlling the temperature to perform the reaction is specifically operated as follows: adding disodium ethylene diamine tetraacetate into the treatment solution, heating to 70-75 ℃, and magnetically stirring; then adding the rest cationized hydroxyethyl cellulose, heating to 90 ℃, vacuumizing, and keeping magnetic stirring until the enrofloxacin is completely dissolved.
9. The method for preparing enrofloxacin injection according to claim 8, wherein the vacuum degree is 0.1 MPa.
10. The method for preparing enrofloxacin injection as claimed in claim 6, wherein the slow cooling rate in step 4) is 15-25 ℃/hr.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267142A (en) * | 2015-10-15 | 2016-01-27 | 四川鼎尖动物药业有限责任公司 | Enrofloxacin injection and preparation method thereof |
| CN106038482A (en) * | 2016-07-15 | 2016-10-26 | 华南农业大学 | Enrofloxacin uterus perfusion liquid as well as preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105267142A (en) * | 2015-10-15 | 2016-01-27 | 四川鼎尖动物药业有限责任公司 | Enrofloxacin injection and preparation method thereof |
| CN106038482A (en) * | 2016-07-15 | 2016-10-26 | 华南农业大学 | Enrofloxacin uterus perfusion liquid as well as preparation method and application thereof |
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