CN116440085A - Amoxicillin and colistin sulfate soluble powder for livestock and preparation method thereof - Google Patents
Amoxicillin and colistin sulfate soluble powder for livestock and preparation method thereof Download PDFInfo
- Publication number
- CN116440085A CN116440085A CN202310387900.5A CN202310387900A CN116440085A CN 116440085 A CN116440085 A CN 116440085A CN 202310387900 A CN202310387900 A CN 202310387900A CN 116440085 A CN116440085 A CN 116440085A
- Authority
- CN
- China
- Prior art keywords
- amoxicillin
- colistin sulfate
- powder
- soluble powder
- sieving
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 title claims abstract description 76
- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 76
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 108010078777 Colistin Proteins 0.000 title claims abstract description 71
- 229960001127 colistin sulfate Drugs 0.000 title claims abstract description 67
- ZESIAEVDVPWEKB-ORCFLVBFSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O ZESIAEVDVPWEKB-ORCFLVBFSA-N 0.000 title claims abstract description 67
- 239000000843 powder Substances 0.000 title claims abstract description 52
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- 244000144972 livestock Species 0.000 title description 4
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- 239000000203 mixture Substances 0.000 claims abstract description 21
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000011975 tartaric acid Substances 0.000 claims abstract description 19
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 19
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 18
- 229930195725 Mannitol Natural products 0.000 claims abstract description 18
- 239000000594 mannitol Substances 0.000 claims abstract description 18
- 235000010355 mannitol Nutrition 0.000 claims abstract description 18
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 8
- 229960001367 tartaric acid Drugs 0.000 claims abstract description 6
- 229960001855 mannitol Drugs 0.000 claims abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 10
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 5
- GCLGEJMYGQKIIW-UHFFFAOYSA-H sodium hexametaphosphate Chemical compound [Na]OP1(=O)OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])OP(=O)(O[Na])O1 GCLGEJMYGQKIIW-UHFFFAOYSA-H 0.000 claims description 5
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- 229920000858 Cyclodextrin Polymers 0.000 claims description 2
- 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 description 2
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 2
- 229960004853 betadex Drugs 0.000 claims description 2
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- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000002639 sodium chloride Nutrition 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 230000001580 bacterial effect Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 206010059866 Drug resistance Diseases 0.000 abstract description 3
- 238000001228 spectrum Methods 0.000 abstract description 3
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229960004106 citric acid Drugs 0.000 description 4
- 229960003346 colistin Drugs 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 4
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 4
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 4
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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Classifications
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- 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
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Abstract
The invention provides amoxicillin and colistin sulfate soluble powder and a preparation method thereof, wherein the amoxicillin and colistin sulfate soluble powder is preferably composed of 10% of amoxicillin, 2% of colistin sulfate, 2% of tartaric acid, 20% of mannitol and 66% of refined auxiliary powder. The preparation method comprises (1) proportionally taking amoxicillin, colistin sulfate, tartaric acid, mannitol and refined auxiliary powder, and sieving with a 40-120 mesh sieve; (2) Premixing 50% of the auxiliary powder, mannitol, tartaric acid and colistin sulfate, and mixing with amoxicillin and the rest auxiliary powder for 30 minutes; (3) The mixture is mixed for 15 minutes by about 20 percent of the total material pouring amount of a material returning valve; (4) And (3) sieving the mixture through a 40-120-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder. The method has scientific design, simple and safe operation, convenient use, high stability, convenient storage and transportation and suitability for industrialized mass production; meanwhile, the combination of the two can enlarge the antibacterial spectrum and reduce the occurrence of bacterial drug resistance.
Description
Technical Field
The invention belongs to the technical field of veterinary medicine preparations, and particularly relates to amoxicillin and colistin sulfate soluble powder for animals and a preparation method thereof.
Background
Amoxicillin, also known as amoxicillin, is a semisynthetic broad-spectrum beta-lactam antibiotic. Is mainly sensitive to gram-positive bacteria and some negative bacteria such as streptococcus, pasteurella, staphylococcus without producing penicillinase, escherichia coli, salmonella, proteus mirabilis and the like. The antibacterial mechanism is that beta-lactam ring in 6-aminopenicillanic acid is combined with penicillin binding egg on bacterial and bacterial cytoplasmic membrane to inhibit crosslinking of bacterial cell wall mucin, so that cell wall is defective, bacteria cannot maintain stable osmotic pressure in the bacteria, and the bacteria lose osmotic barrier to expand and crack, so that the bacteria die, and therefore, amoxicillin is a germicide in the propagation period.
Polymyxin is a polypeptide antibiotic secreted by Paenibacillus polymyxa, has bactericidal effect on bacteria in growth and reproduction and stationary phases, is not easy to generate drug resistance, has remarkable activity on most members of enterobacteriaceae, including escherichia coli, klebsiella, lemon bacillus, salmonella, shigella and the like, mainly acts on cell membranes of the bacteria, and when the polymyxin is contacted with sensitive bacteria, polycation rings of the polymyxin can act with lipid A of lipopolysaccharide, be inserted into phospholipid of the cell membranes to damage shielding function of cytoplasmic membranes, be combined with phosphate radicals with negative charges in phospholipid in the cytoplasmic membranes of the bacteria to reduce the surface tension of the cytoplasmic membranes, damage the permeability of the membranes and inhibit the growth of the bacteria or cause the death of the bacteria. Colistin can also enter the cytoplasm and affect nuclear and ribosomal functions, leading to bacterial death. Since the major component of the cell wall of gram-positive bacteria is a mucin rather than a phospholipid, colistin has no antibacterial activity against gram-positive bacteria. Therefore, the combination of the amoxicillin and the colistin sulfate not only can expand the antibacterial spectrum and is beneficial to treating various pathogen infections in clinic and effectively preventing and treating mixed infections or secondary infections of livestock and poultry, but also can reduce the dosage of administration and reduce the generation of drug-resistant strains by playing the synergistic antibacterial effect of the amoxicillin and the colistin sulfate through different antibacterial mechanisms.
The Chinese patent application with the name of 'long-acting amoxicillin and colistin sulfate injection and the preparation method thereof' is found by searching that the application number is 201710536704.4, the application publication number is CN 107261108A, and the Chinese patent application is an injection for combined administration of amoxicillin and colistin sulfate, and has the advantages of complex preparation process, high requirements on production conditions and equipment, complex operation and inconvenient administration.
The Chinese patent application with the application number of 201310186936.3 and the application publication number of CN 103285374A, named as an amoxicillin and colistin sulfate granule and a preparation method thereof, is a granule for combined administration of amoxicillin and colistin sulfate, has high production cost, is easy to deliquesce, and easily causes the reduction of the content of main components in the preparation process.
Disclosure of Invention
The invention provides amoxicillin and colistin sulfate soluble powder for livestock and a preparation method thereof, which aim to increase the dosage form of medicines and overcome the defects of the existing products and technologies.
In order to achieve the above object, the present invention adopts the following solutions: an amoxicillin and colistin sulfate soluble powder for animals is characterized in that: consists of 5 to 15 percent of amoxicillin, 1 to 5 percent of colistin sulfate, 0.5 to 3 percent of cosolvent, 5 to 40 percent of stabilizer and 40 to 90 percent of diluent.
Further, the cosolvent is one or a combination of more of citric acid, tartaric acid, sodium dihydrogen phosphate, oxalic acid, glutamic acid and fumaric acid; the stabilizer is one or a combination of several of anhydrous sodium sulfate, mannitol, sodium hexametaphosphate, EDTA-2Na and the like; the diluent is one or a combination of several of eudragit powder, lactose, sucrose, anhydrous glucose, water-soluble starch, sodium chloride, beta-cyclodextrin, polyethylene glycol, povidone K30 and the like.
Preferably, the amoxicillin and colistin sulfate soluble powder consists of 10% of amoxicillin, 2% of colistin sulfate, 2% of tartaric acid, 20% of mannitol and 66% of refined auxiliary powder.
The preparation method of the amoxicillin and colistin sulfate soluble powder for animals in a preferable scheme comprises the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, tartaric acid, mannitol and refined powder according to the prescription proportion, and sieving with a 40-120 mesh sieve;
(2) Mixing: premixing 50% of the auxiliary powder, mannitol, tartaric acid and colistin sulfate, and then mixing with amoxicillin and the rest auxiliary powder for 30 minutes;
(3) Pouring: the mixture is poured by a feed back valve for about 20 percent of the total amount, and then mixed for 15 minutes;
(4) Sieving: and (5) sieving the mixture through a 40-120-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
The invention has the beneficial effects that: the amoxicillin and colistin sulfate soluble powder prepared by the invention takes tartaric acid as a cosolvent, so that the stability of the product is ensured and the solubility of the product is increased; mannitol is used as a stabilizer, so that the product is effectively prevented from moisture absorption and caking, and the treatment effect of the product is ensured; the fine auxiliary powder is used as a diluent, so that the fluidity of the product is improved, and the split charging of the product is facilitated. The preparation method of amoxicillin and colistin sulfate soluble powder provided by the invention has the advantages of scientific design, simple and safe operation, convenient use, high stability, convenient storage and transportation, and suitability for industrialized mass production; meanwhile, the combination of the two can enlarge the antibacterial spectrum and reduce the occurrence of bacterial drug resistance.
Detailed Description
The present application is described in further detail below with reference to examples. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
It should be noted that, in the case of no conflict, the embodiments and features in the embodiments may be combined with each other. The present application will be described in detail with reference to examples.
Example 1
An amoxicillin and colistin sulfate soluble powder for animals is prepared from the following raw materials: 5% of amoxicillin, 2% of colistin sulfate, 1% of citric acid, 10% of anhydrous sodium sulfate and 82% of lactose.
The preparation method comprises the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, citric acid, anhydrous sodium sulfate and lactose according to the prescription proportion, and sieving with a 40-mesh sieve.
(2) Mixing: 50% lactose, anhydrous sodium sulfate, citric acid, colistin sulfate were premixed and then mixed with amoxicillin and the remaining lactose for 15 minutes.
(3) Pouring: the mixture was poured through a return valve for about 20% of the total amount, followed by mixing for 15 minutes.
(4) Sieving: and (5) sieving the mixture through a 40-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
Example 2
An amoxicillin and colistin sulfate soluble powder for animals is prepared from the following raw materials: 10% of amoxicillin, 2% of colistin sulfate, 2% of tartaric acid, 20% of mannitol and 66% of auxiliary powder.
The preparation method comprises the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, tartaric acid, mannitol and refined powder according to the prescription proportion, and sieving with 80-mesh sieve.
(2) Mixing: 50% of the auxiliary powder, mannitol, tartaric acid and colistin sulfate are premixed, and then mixed with amoxicillin and the rest auxiliary powder for 30 minutes.
(3) Pouring: the mixture was poured through a return valve for about 20% of the total amount, followed by mixing for 15 minutes.
(4) Sieving: and (3) sieving the mixture through a 80-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
Example 3
An amoxicillin and colistin sulfate soluble powder for animals is prepared from the following raw materials: 15% of amoxicillin, 5% of colistin sulfate, 5% of sodium dihydrogen phosphate, 5% of mannitol and 70% of lactose.
The preparation method comprises the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, sodium dihydrogen phosphate, mannitol and lactose according to the prescription proportion, and sieving with 80 mesh sieve.
(2) Mixing: 50% lactose, mannitol, sodium dihydrogen phosphate, colistin sulfate were premixed and then mixed with amoxicillin and the remaining lactose for 45 minutes.
(3) Pouring: the mixture was poured through a return valve for about 20% of the total amount, followed by mixing for 15 minutes.
(4) Sieving: and (3) sieving the mixture through a 80-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
Example 4
An amoxicillin and colistin sulfate soluble powder for animals is prepared from the following raw materials: 10% of amoxicillin, 1% of colistin sulfate, 5% of tartaric acid, 15% of sodium hexametaphosphate and 69% of sucrose.
The preparation method comprises the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, tartaric acid, sodium hexametaphosphate and sucrose according to the prescription proportion, and sieving with a 100-mesh sieve.
(2) Mixing: 50% sucrose, sodium hexametaphosphate, tartaric acid, colistin sulfate were premixed and then mixed with amoxicillin and the remaining sucrose for 15 minutes.
(3) Pouring: the mixture was poured through a return valve for about 20% of the total amount, followed by mixing for 15 minutes.
(4) Sieving: and (5) sieving the mixture through a 100-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
The test detection method refers to: 1. detecting amoxicillin soluble powder content in Chinese veterinary pharmacopoeia (2020 edition); octadecylsilane chemically bonded silica is used as a filler; 0.05mol/L potassium dihydrogen phosphate solution (pH value is adjusted to 5.0 by 2mol/L potassium hydroxide solution) -acetonitrile (97.5:2.5) is taken as a mobile phase; the detection wavelength is 254nm. Taking about 25mg of amoxicillin system applicability reference substance, placing the amoxicillin system applicability reference substance into a 50ml measuring flask, dissolving with mobile phase, diluting to scale, shaking uniformly, taking 20ul of amoxicillin system applicability reference substance, injecting into a liquid chromatograph, and recording a chromatogram.
The measuring method comprises the following steps: taking a proper amount of the product, precisely weighing, adding a mobile phase to dissolve and dilute the product to prepare a solution containing about 0.5mg per 1ml, shaking the solution uniformly, precisely weighing 20 mu l of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; and taking a proper amount of amoxicillin reference substance, and determining by the same method. And calculating according to an external standard method and peak area to obtain the product.
The colistin sulfate soluble powder accords with European pharmacopoeia standards, and is detected according to the pharmacopoeia method: the column used was an octadecylsilane chemically bonded silica column (150 mm. Times.4.6 mm,5 μm). Sodium sulfate solution (4.46 g of anhydrous sodium sulfate is dissolved in 900ml of water, the pH is regulated to 2.4 by phosphoric acid, then water is added for dilution to 1000 ml) -acetonitrile (78:22) is taken as a mobile phase, the detection wavelength is 215nm, the flow rate is 1.0ml/min, the column temperature is 30 ℃, and the sample injection amount is 20 mu L.
The measuring method comprises the following steps: precisely weighing a proper amount of the product (about 100 ten thousand units of colistin sulfate), precisely weighing, placing into a 100ml volumetric flask, adding water for dissolution, diluting to scale, shaking, precisely weighing 20 μl, injecting into a liquid chromatograph, and recording a chromatogram; and taking a proper amount of colistin sulfate reference substance, and measuring by the same method. Calculated by the sum of peak areas of components of colistin according to an external standard method.
Test method one: solubility test:
the sample was weighed to be 0.15g in terms of amoxicillin, placed in 100ml of water at a temperature of 25 ℃ + -2 ℃ and stirred for 10min with a glass rod, and allowed to stand to observe dissolution.
TABLE 1 solubility test results
Test method one: aqueous solution normal temperature (25 ℃ C.) standing test
1.0g of amoxicillin and colistin sulfate soluble powder products in examples 1-4 are weighed and placed in 100ml of tap water, and each group is placed in room temperature to carry out content measurement at 0h, 2h, 4h, 6h, 8h, 10h, 12h, 16h, 20h and 24h respectively. The test results are shown in the following table:
TABLE 2 stability test results in aqueous solutions
And a test method II: (temperature 40 ℃ C.+ -. 2 ℃ C., humidity 75% + -5 ℃ C.) accelerated test
Taking a proper amount of amoxicillin and colistin sulfate soluble powder in examples 1-4, and detecting the content of amoxicillin in 0 month, 1 month, 2 months, 3 months and 6 months according to the method; and simultaneously measuring the content of colistin in 0 month, 1 month, 2 months, 3 months and 6 months. The test results are shown in the following table:
table 3 results of 6 month accelerated experiments
Test method III, taking a proper amount of amoxicillin and colistin sulfate soluble powder products in examples 1-4, putting the products at a high temperature (60 ℃) and accelerating for 10 days under an illumination experiment (4500+/-500 lx), and detecting the content change condition of the products.
TABLE 4 results of high temperature 10d experiments
TABLE 5 illumination 10d experiment results
As can be seen from table 1, example 1 and example 3 are not as soluble as example 2 and example 4, sodium dihydrogen phosphate and citric acid are not as good as tartaric acid as co-solvents; in the aspect of stability of aqueous solution, because the amoxicillin content is reduced to different degrees by adding an acidic cosolvent, the reduction amplitude of colistin sulfate is relatively small, and the experimental results in table 2 show that the amoxicillin content and colistin sulfate content after 24 hours in the prescriptions of examples 1-3 meet pharmacopoeia specifications, the amoxicillin content in the prescriptions of example 4 is reduced more rapidly, the detection content after 16 hours is 88.34 percent less than 90.0 percent, and the amoxicillin content is lower than the range specified by the quality standard; tables 3 to 5 vary to different degrees in the acceleration test and the high temperature and light irradiation test examples 1 to 4, but the amoxicillin and colistin sulfate contents are within the range specified by the standard. With solubility as a reference index, examples 2 and 4 are better; comparing the stability of the aqueous solutions of the two can show that the cosolvent can influence the stability of amoxicillin and colistin sulfate to a certain extent; the two factors of solubility and stability are considered, and comparison experiment results tables 1-5 show that the amoxicillin and colistin sulfate soluble powder prepared in the embodiment 2 is good in solubility, stable in property, convenient to store and transport, and suitable for industrial production because the solution prepared in clinical use is not easy to degrade.
The foregoing description is only of the preferred embodiments of the present application and is presented as a description of the principles of the technology being utilized. It will be appreciated by persons skilled in the art that the scope of the invention referred to in this application is not limited to the specific combinations of features described above, but it is intended to cover other embodiments in which any combination of features described above or equivalents thereof is possible without departing from the spirit of the invention. Such as the above-described features and technical features having similar functions (but not limited to) disclosed in the present application are replaced with each other.
Claims (4)
1. An amoxicillin and colistin sulfate soluble powder for animals is characterized in that: consists of 5 to 15 percent of amoxicillin, 1 to 5 percent of colistin sulfate, 0.5 to 3 percent of cosolvent, 5 to 40 percent of stabilizer and 40 to 90 percent of diluent.
2. The veterinary amoxicillin and colistin sulfate soluble powder of claim 1, wherein: the cosolvent is one or a combination of more of citric acid, tartaric acid, sodium dihydrogen phosphate, oxalic acid, glutamic acid and fumaric acid; the stabilizer is one or a combination of several of anhydrous sodium sulfate, mannitol, sodium hexametaphosphate, EDTA-2Na and the like; the diluent is one or a combination of several of eudragit powder, lactose, sucrose, anhydrous glucose, water-soluble starch, sodium chloride, beta-cyclodextrin, polyethylene glycol, povidone K30 and the like.
3. A veterinary amoxicillin and colistin sulfate soluble powder as claimed in claim 2, wherein: the amoxicillin and colistin sulfate soluble powder consists of 10% of amoxicillin, 2% of colistin sulfate, 2% of tartaric acid, 20% of mannitol and 66% of refined auxiliary powder.
4. A method for preparing amoxicillin and colistin sulfate soluble powder for animals according to claim 3, comprising the following steps:
(1) Sieving: taking amoxicillin, colistin sulfate, tartaric acid, mannitol and refined powder according to the prescription proportion, and sieving with a 40-120 mesh sieve;
(2) Mixing: premixing 50% of the auxiliary powder, mannitol, tartaric acid and colistin sulfate, and then mixing with amoxicillin and the rest auxiliary powder for 30 minutes;
(3) Pouring: the mixture is poured by a feed back valve for about 20 percent of the total amount, and then mixed for 15 minutes;
(4) Sieving: and (5) sieving the mixture through a 40-120-mesh sieve after the total mixture to obtain amoxicillin and colistin sulfate soluble powder.
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