CN114533852A - Compound amoxicillin and colistin sulfate suspension injection and preparation method thereof - Google Patents
Compound amoxicillin and colistin sulfate suspension injection and preparation method thereof Download PDFInfo
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- CN114533852A CN114533852A CN202210180120.9A CN202210180120A CN114533852A CN 114533852 A CN114533852 A CN 114533852A CN 202210180120 A CN202210180120 A CN 202210180120A CN 114533852 A CN114533852 A CN 114533852A
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- Prior art keywords
- colistin sulfate
- amoxicillin
- suspension injection
- sulfate suspension
- compound
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- 229960003022 amoxicillin Drugs 0.000 title claims abstract description 88
- 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 88
- 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 88
- 108010078777 Colistin Proteins 0.000 title claims abstract description 87
- 229960001127 colistin sulfate Drugs 0.000 title claims abstract description 87
- 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 87
- 239000000725 suspension Substances 0.000 title claims abstract description 72
- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- 150000001875 compounds Chemical class 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 29
- 239000002270 dispersing agent Substances 0.000 claims abstract description 20
- 239000000375 suspending agent Substances 0.000 claims abstract description 20
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 13
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 13
- 239000002612 dispersion medium Substances 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 10
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 claims description 21
- 229940093471 ethyl oleate Drugs 0.000 claims description 21
- 239000003549 soybean oil Substances 0.000 claims description 21
- 235000012424 soybean oil Nutrition 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims description 16
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims description 16
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 16
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 14
- 235000006708 antioxidants Nutrition 0.000 claims description 12
- 239000006185 dispersion Substances 0.000 claims description 10
- 238000004945 emulsification Methods 0.000 claims description 9
- 238000000265 homogenisation Methods 0.000 claims description 9
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 9
- 229960002216 methylparaben Drugs 0.000 claims description 9
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 8
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 8
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 8
- 229960003415 propylparaben Drugs 0.000 claims description 8
- 125000005456 glyceride group Chemical group 0.000 claims description 7
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- -1 polyoxyethylene Polymers 0.000 claims description 6
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 5
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 5
- 230000001804 emulsifying effect Effects 0.000 claims description 5
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 5
- 229940049964 oleate Drugs 0.000 claims description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 5
- 229920000223 polyglycerol Polymers 0.000 claims description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 229930003427 Vitamin E Natural products 0.000 claims description 4
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 235000019165 vitamin E Nutrition 0.000 claims description 4
- 229940046009 vitamin E Drugs 0.000 claims description 4
- 239000011709 vitamin E Substances 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 238000010008 shearing Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims 1
- 238000004062 sedimentation Methods 0.000 abstract description 11
- 238000004090 dissolution Methods 0.000 abstract description 3
- 230000009044 synergistic interaction Effects 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 description 6
- 230000035515 penetration Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002609 medium Chemical group 0.000 description 5
- 229910021645 metal ion Inorganic materials 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 3
- 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 3
- 230000007547 defect Effects 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000000273 veterinary drug Substances 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 210000002421 cell wall Anatomy 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000013522 chelant Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 229920000768 polyamine Polymers 0.000 description 2
- 238000004881 precipitation hardening Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229910001431 copper ion Inorganic materials 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- 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
-
- 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
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses a compound amoxicillin and colistin sulfate suspension injection, which comprises the following raw materials in parts by weight: 9-11 parts of amoxicillin bulk drug, 1-2 parts of colistin sulfate bulk drug, 2-5 parts of suspending agent, 0.5-1 part of antioxidant, 2-5 parts of dispersant and 79-95 parts of dispersion medium. The invention also discloses a preparation method of the compound amoxicillin and colistin sulfate suspension injection. The compound amoxicillin and colistin sulfate suspension injection prepared by the invention improves the medicine dissolution rate through the synergistic interaction of the specific suspending agent and the dispersing agent, simultaneously solves the problems of easy sedimentation and hardening of the amoxicillin and colistin sulfate suspension injection, and improves the medicine stability.
Description
Technical Field
The invention relates to the technical field of veterinary medicines, and in particular relates to a compound amoxicillin and colistin sulfate suspension injection and a preparation method thereof.
Background
Amoxicillin is a semi-synthetic penicillin antibiotic, belongs to a reproductive stage bactericide (I class), is penicillin with an amino side chain, has several times of stronger drug effect than penicillin, can block the synthesis of cell wall mucopeptide, causes the cell wall of bacteria to be defective, and causes the bacteria to swell and crack to die, and is mainly used for infectious diseases of gram-positive bacteria and partial negative bacteria. Colistin sulfate is an alkaline polypeptide antibiotic, mainly acts on bacterial cell membranes, prevents and treats infection of sensitive bacteria and promotes the growth of livestock and poultry, and belongs to a stationary-period bactericide (II); meanwhile, the colistin sulfate can also influence the functions of nucleoplasm and ribosome, so that bacteria are not easy to generate drug resistance to the colistin sulfate, and the colistin sulfate does not have the phenomenon of cross drug resistance with other antibiotics, and is a biological veterinary drug with the most obvious effect for preventing and treating intestinal diseases caused by gram-negative bacteria internationally at present.
The chemical property of amoxicillin is unstable, and when amoxicillin acts with acid, alkali, hydroxylamine or some metal ions (copper ions, lead ions, mercury ions or silver ions), molecular rearrangement or hydrolysis is easy to occur, and the drug effect is lost. The molecule of the colistin sulfate is of a polyamine structure and is a negative electron molecule, and the colistin sulfate can chelate the metal ions, so that the defect that the amoxicillin is singly chelated with the metal ions is overcome, and the effect of the amoxicillin is exerted to the maximum extent. The molecule of the colistin sulfate is of a polyamine structure and is a negative electron molecule, and the colistin sulfate can chelate the metal ions, so that the defect that the amoxicillin is singly chelated with the metal ions is overcome, and the effect of the amoxicillin is exerted to the maximum extent.
In the prior art, the amoxicillin and colistin sulfate suspension on the market at present has the main defects of poor long-time stability, precipitation hardening, poor needle penetration, difficult injection process, large pain and irritation of animals, swelling of injection parts and difficult absorption.
Disclosure of Invention
The invention aims to provide a compound amoxicillin and colistin sulfate suspension injection and a preparation method thereof, which are used for solving the technical problems of poor stability, precipitation hardening and poor needle penetration of the amoxicillin and colistin sulfate suspension in the prior art.
In order to achieve the above purpose, one embodiment of the present invention provides a compound amoxicillin and colistin sulfate suspension injection, which comprises the following raw materials in parts by weight:
9 to 11 portions of amoxicillin bulk drug, 1 to 2 portions of colistin sulfate bulk drug,
2 to 5 portions of suspending agent, 0.5 to 1 portion of antioxidant, 2 to 5 portions of dispersant,
79 to 95 portions of dispersion medium.
In one preferable scheme of the invention, the compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight:
9 to 11 portions of amoxicillin bulk drug, 1 to 2 portions of colistin sulfate bulk drug,
3 to 4 portions of suspending agent, 0.5 to 1 portion of antioxidant, 2 to 3 portions of dispersant,
79 to 84.5 portions of dispersion medium.
In a preferred embodiment of the present invention, the suspending agent is at least one of oleoyl polyoxyethylene glyceride and glyceryl monooleate.
In a preferred embodiment of the present invention, the antioxidant is at least one of methyl paraben, propyl paraben and vitamin E.
In a preferred embodiment of the present invention, the dispersant is at least one of polyglycerol oleate and caprylic/capric macrogol glyceride.
In a preferred embodiment of the present invention, the dispersion medium is at least one of ethyl oleate, soybean oil and medium chain glycerate.
In one preferable scheme of the invention, the mass ratio of the amoxicillin bulk drug to the suspending agent and the dispersing agent is 5:1-2: 1-2.
In a preferred embodiment of the present invention, the dispersion medium is a mixture of ethyl oleate, soybean oil and medium-chain glycerate, wherein the mass ratio of ethyl oleate, soybean oil and medium-chain glycerate is 2:1-2: 1-2.
Based on the compound amoxicillin and colistin sulfate suspension injection disclosed by the invention, the invention also discloses a preparation method of the compound amoxicillin and colistin sulfate suspension injection, which comprises the following steps:
step (1): uniformly mixing the dispersion medium, the suspending agent and the antioxidant, adding ATP and uniformly stirring after uniformly mixing;
step (2): adding a dispersing agent into the solution obtained in the step (1), emulsifying to obtain a dispersion liquid after the emulsification is finished;
and (3): and (3) carrying out high-pressure homogenization on the dispersion liquid obtained in the step (2), and obtaining the compound amoxicillin and colistin sulfate suspension injection after the high-pressure homogenization is finished.
In a preferred scheme of the invention, in the step (1), ATP is a mixture of amoxicillin bulk drug and colistin sulfate bulk drug which are uniformly mixed and stirred according to parts; in the step (2), the emulsification is finished in a high-speed emulsification shearing machine, and the emulsification time is 10-20 min; and (3) completing high-pressure homogenization in a high-pressure homogenizer, wherein the pressure of the high-pressure homogenizer is 30-40 MPa, and the high-pressure homogenization needs to be performed twice.
In conclusion, the beneficial effects of the invention are as follows:
1. according to the invention, the medicine dissolution rate is improved through the synergistic effect of the specific suspending agent and the dispersing agent, the problems of easy sedimentation and hardening of the amoxicillin and colistin sulfate suspension injection are solved, and the medicine stability is improved.
2. The invention adopts the specific auxiliary agent as the carrier to solve the problem of poor needle penetration of the amoxicillin and colistin sulfate suspension, improve the needle penetration and reduce the stress and pain of animals.
3. The technical scheme and the preparation process are convenient and safe; the preparation prepared by the invention is a compound suspension injection with uniform medicine distribution, good needle penetration, definite curative effect in clinical test, small toxic and side effect and low cost.
Detailed Description
Example 1
A compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight: 11 parts of amoxicillin bulk drug, 1 part of colistin sulfate bulk drug, 3 parts of suspending agent glyceryl monooleate, 0.7 part of mixture of antioxidant-methyl paraben and propyl paraben, 3 parts of dispersant polyglycerol oleate, and 81.3 parts of mixture of dispersion medium-ethyl oleate, soybean oil and medium chain glycerate;
wherein the mass ratio of the methyl paraben to the propyl paraben in the mixture of the methyl paraben and the propyl paraben is 8: 1; the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate in the mixture of the ethyl oleate to the soybean oil to the medium-chain glycerate is 1:1: 1.
A preparation method of a compound amoxicillin and colistin sulfate suspension injection comprises the following steps:
step (1): uniformly mixing the dispersion medium, the suspending agent and the antioxidant, adding ATP after uniform mixing, and uniformly stirring, wherein the ATP is a mixture of amoxicillin bulk drug and colistin sulfate bulk drug which are uniformly mixed and stirred according to parts;
step (2): adding a dispersing agent into the solution obtained in the step (1), emulsifying by a high-speed emulsifying shearing machine, emulsifying at the rotating speed of 4000-6000 r/min for 10-20 min, and obtaining a dispersion liquid after the emulsification is finished;
and (3): and (3) homogenizing the dispersion liquid obtained in the step (2) at high pressure by a high-pressure homogenizer, homogenizing at high pressure twice under the pressure of 30-40 Mpa, and obtaining the compound amoxicillin and colistin sulfate suspension injection after the high-pressure homogenization is finished.
Example 2
A compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight: 9 parts of amoxicillin bulk drug, 2 parts of colistin sulfate bulk drug, 4 parts of suspending agent oleoyl polyoxyethylene glyceride, 0.5 part of mixture of antioxidant-methyl paraben and propylparaben, 2 parts of dispersant polyglycerol oleate, and 82.5 parts of mixture of dispersion medium-ethyl oleate, soybean oil and medium chain glycerate;
wherein the mass ratio of the methyl paraben to the propyl paraben in the mixture of the methyl paraben and the propyl paraben is 5: 1; the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate in the mixture of the ethyl oleate to the soybean oil to the medium-chain glycerate is 2:1: 1.
Example 2 the preparation method of the compound amoxicillin and colistin sulfate suspension injection is the same as that of example 1.
Example 3
A compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight: 10 parts of amoxicillin bulk drug, 1.5 parts of colistin sulfate bulk drug, 2 parts of suspending agent oleoyl polyoxyethylene glyceride, 0.7 part of antioxidant vitamin E, 3 parts of dispersant polyglycerol oleate, and 82.8 parts of a mixture of dispersion medium-ethyl oleate, soybean oil and medium chain glycerate;
wherein the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate in the mixture of the ethyl oleate to the soybean oil to the medium-chain glycerate is 2:1: 2.
Example 3A compound amoxicillin and colistin sulfate suspension injection is prepared in the same manner as in example 1.
Example 4
A compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight: 10 parts of amoxicillin bulk drug, 1.5 parts of colistin sulfate bulk drug, 5 parts of suspending agent glyceryl monooleate, 1 parts of antioxidant vitamin E, 5 parts of dispersing agent caprylic capric polyethylene glycol glyceride, and 79 parts of a mixture of dispersing medium-ethyl oleate, soybean oil and medium chain glycerate;
wherein the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate in the mixture of the ethyl oleate to the soybean oil to the medium-chain glycerate is 4:3: 3.
Example 4A compound amoxicillin and colistin sulfate suspension injection is prepared in the same manner as in example 1.
Example 5
A compound amoxicillin and colistin sulfate suspension injection comprises the following raw materials in parts by weight: 9 parts of amoxicillin bulk drug, 1 part of colistin sulfate bulk drug, 5 parts of suspending agent glyceryl monooleate, 0.9 part of antioxidant methyl paraben, 4 parts of dispersant caprylic/capric polyethylene glycol glyceride, and 95 parts of a mixture of dispersion medium-ethyl oleate, soybean oil and medium-chain glycerate;
wherein the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate in the mixture of the ethyl oleate to the soybean oil to the medium-chain glycerate is 4:3: 4.
Example 5A compound amoxicillin and colistin sulfate suspension injection is prepared in the same manner as in example 1.
Experimental detection
Experiment 1: accelerated compound amoxicillin and colistin sulfate suspension injection experiment
Putting a sample to be detected into an accelerated test box, detecting the performance parameters of the property, identification, moisture content, amoxicillin content and colistin sulfate content of the sample when the sample is stored for 0 day, 1 month, 2 months, 3 months and 6 months under the conditions that the temperature is 30 +/-2 ℃ and the humidity is RH 65% +/-5%, and detecting the performance parameters according to the standard of Chinese veterinary drug dictionary, wherein the results are shown in Table 1:
table 1: EXAMPLES 1 to 5 tables of results of Properties, identification, moisture and content measurement
As can be seen from table 1: the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1 to 5 meets the standard of Chinese veterinary drug dictionary, the compound amoxicillin and colistin sulfate suspension injection prepared in the example 1 has a light yellow suspension, the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 2, 4 and 5 has a white-like suspension, and the compound amoxicillin and colistin sulfate suspension injection prepared in the example 3 has a white suspension.
Experiment 2: comparative experiment on redispersibility, suspension property and injection performance of compound amoxicillin and colistin sulfate suspension injection
(1) Suspension test
Will be as per example 1, example 2, example 3, example4 and the compound amoxicillin and colistin sulfate suspension injection prepared in the example 5, respectively taking 50ml with a stoppered measuring cylinder, closing the stopper, shaking forcefully for 1min, and recording the height H of the suspension0. Calculating the sedimentation ratio according to the formula: sedimentation volume ratio of H/H0. Then placing the mixture into a colorimetric tube, standing for 30min, 1h, 2h, 6h and 24h, and observing the sedimentation ratio, wherein the result of the sedimentation ratio is shown in table 2.
Table 2: result of sedimentation ratio
As can be seen from table 2: the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1 to 5 has the sedimentation ratio value near 1, which shows that the compound amoxicillin and colistin sulfate suspension injection prepared in the example is not easy to have sedimentation phenomenon; and 5 examples have no obvious difference, and relatively speaking, the sedimentation ratio value of example 3 is closer to 1, so that the compound amoxicillin and colistin sulfate suspension injection prepared in example 3 is more difficult to settle, and the anti-settling performance of the compound amoxicillin and colistin sulfate suspension injection is more excellent.
(2) Redispersibility test
10ml of compound amoxicillin and colistin sulfate suspension injection prepared according to the examples 1, 2, 3, 4 and 5 are respectively put into a centrifuge tube, centrifuged at high speed for 2min and then shaken for 30 s (the rotation speed during centrifugation is respectively 1000r/min, 2000r/min and 3000r/min), and the redispersibility is observed after centrifugation is finished, and the redispersibility results are shown in the table 3.
Table 3: redispersibility results
As can be seen from table 3: the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1-5 has excellent redispersibility, but the compound amoxicillin and colistin sulfate suspension injection prepared in the example 3 has better redispersibility than the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1, 2, 4 and 5.
(3) Needle penetration test
The amoxicillin and colistin sulfate suspension injection prepared in example 1, example 2, example 3, example 4 and example 5 was extracted by a 9-gauge needle (animals usually use 9-17 gauge needles) for 5ml and 10ml respectively, and the extraction time was recorded, and the extraction time results are shown in Table 4.
Table 4: extract time results list
As can be seen from table 4: the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1 to 5 takes no longer time than 5ml and 10ml, which shows that the compound amoxicillin and colistin sulfate suspension injection prepared in the examples 1 to 5 has good injection property; meanwhile, as can be seen from the comparison among examples 1, 2, 3, 4 and 5, the extraction time of 5 examples is greatly different, and the extraction time of example 3 is significantly shorter than that of examples 1, 2, 4 and 5, so that the compound amoxicillin and colistin sulfate suspension injection prepared in example 3 has better injection performance than the compound amoxicillin and colistin sulfate suspension injection prepared in examples 1, 2, 4 and 5.
According to the experimental results, the compound amoxicillin and colistin sulfate suspension injection prepared in the example 1, the example 2, the example 3, the example 4 and the example 5 has excellent anti-settling performance, redispersion performance and injection performance. Meanwhile, as can be seen from comparative examples 1 to 5, example 3 is the best process because the compound amoxicillin and colistin sulfate suspension injection prepared in example 3 has better anti-settling property, redispersion property and injection-promoting property than those prepared in examples 1, 2, 4 and 5.
In conclusion, the compound amoxicillin and colistin sulfate suspension injection prepared by the invention has the advantages that the medicine dissolution is improved through the synergistic interaction of the specific suspending agent and the dispersing agent, the problems of easy sedimentation and hardening of the amoxicillin and colistin sulfate suspension are solved, and the redispersibility and the stability of the medicine are improved. The compound amoxicillin and colistin sulfate suspension injection prepared by the invention adopts a specific auxiliary agent as a carrier to solve the problem of poor injection property of the amoxicillin and colistin sulfate suspension, improve the injection property and reduce the stress and pain of animals.
Claims (10)
1. A compound amoxicillin and colistin sulfate suspension injection is characterized in that: the material comprises the following raw materials in parts by weight:
9 to 11 portions of amoxicillin bulk drug, 1 to 2 portions of colistin sulfate bulk drug,
2 to 5 portions of suspending agent, 0.5 to 1 portion of antioxidant, 2 to 5 portions of dispersant,
79 to 95 portions of dispersion medium.
2. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which comprises the following raw materials in parts by weight:
9 to 11 portions of amoxicillin bulk drug, 1 to 2 portions of colistin sulfate bulk drug,
3 to 4 portions of suspending agent, 0.5 to 1 portion of antioxidant, 2 to 3 portions of dispersant,
79 to 84.5 portions of dispersion medium.
3. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which is characterized in that: the suspending agent is at least one of oleoyl polyoxyethylene glyceride and glyceryl monooleate.
4. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which is characterized in that: the antioxidant is at least one of methyl paraben, propyl paraben and vitamin E.
5. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which is characterized in that: the dispersing agent is at least one of polyglycerol oleate and caprylic capric acid polyethylene glycol glyceride.
6. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which is characterized in that: the dispersion medium is at least one of ethyl oleate, soybean oil and medium-chain glycerate.
7. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 1, which is characterized in that: the mass ratio of the amoxicillin bulk drug to the suspending agent and the dispersing agent is 5:1-2: 1-2.
8. The compound amoxicillin and colistin sulfate suspension injection as claimed in claim 6, which is characterized in that: the dispersion medium is a mixed solution of ethyl oleate, soybean oil and medium-chain glycerate, wherein the mass ratio of the ethyl oleate to the soybean oil to the medium-chain glycerate is 2:1-2: 1-2.
9. A preparation method of compound amoxicillin and colistin sulfate suspension injection is characterized in that: the method comprises the following steps:
step (1): uniformly mixing the dispersion medium, the suspending agent and the antioxidant, adding ATP and uniformly stirring after uniformly mixing;
step (2): adding a dispersing agent into the solution obtained in the step (1), emulsifying to obtain a dispersion liquid after the emulsification is finished;
and (3): and (3) carrying out high-pressure homogenization on the dispersion liquid obtained in the step (2), and obtaining the compound amoxicillin and colistin sulfate suspension injection after the high-pressure homogenization is finished.
10. The method for preparing the compound amoxicillin and colistin sulfate suspension injection as claimed in claim 9, which is characterized in that: in the step (1), ATP is a mixture of amoxicillin bulk drug and colistin sulfate bulk drug which are mixed and stirred uniformly according to parts; in the step (2), emulsification is finished in a high-speed emulsification shearing machine, and the emulsification time is 10-20 min; in the step (3), the high-pressure homogenization is completed in a high-pressure homogenizer, wherein the pressure of the high-pressure homogenizer is 30MPa-40MPa, and the high-pressure homogenization needs to be performed twice.
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