CN101804062A - Long-acting veterinary compound doxycycline injection and preparation method thereof - Google Patents
Long-acting veterinary compound doxycycline injection and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a long-acting veterinary compound doxycycline injection, which consists of doxycycline or doxycycline hydrochloride serving as a main medicament, a synergist, a solvent, a complexing agent, an antioxidant and a pH regulator, wherein the main medicament adopts the doxycycline or the doxycycline hydrochloride, and the doxycycline content is 10.0 to 20.0 grams; the synergist adopts any or a combination of trimethoprim and astragalus polysaccharides, and the content of the synergist is 0.2 to 5 grams respectively; a molar ratio of the complexing agent to the doxycycline is 1.00-1.10:1.00; and the using amount of the antioxidant is 0.10 to 1.00; and the solvent for injection is added to 100ml and adopts any or a combination of water for injection, propylene glycol, alpha-pyrrolidone, N-methyl alpha-pyrrolidone, dimethylformamide and dimethylacetamide. The curative effect of the injection is improved by the synergist trimethoprim; and the astragalus polysaccharides are antiviral and can strengthen the immune function.
Description
Technical field
The present invention is drug for injection for animals field, particularly a kind of long-acting veterinary compound doxycycline injection and preparation method thereof.
Background technology
Doxycycline (Doxycycline) has another name called doxycycline, and molecular formula is C
22H
24N
2O
8Molecular weight is 444.40, is semi-synthetic broad ectrum antibiotic, and antimicrobial spectrum is identical with tetracycline, but it is all strong in its body than other tetracyclines such as oxytetracyclines with external activity, its injection is widely used in the control of multiple livestock and poultry, with itself and complexing of metal ion, can prolong drug action time, reach long lasting purpose, simultaneously also can improve pH value and stability, thereby improve curative effect, the wide development application prospect is arranged.Long-acting doxycycline injection adopting in the market mostly is single preparations of ephedrine, adopt and complexing of metal ion, infiltration rate there is certain influence, thereby reduced the quick-acting of medicine, the compound preparation that some and other antibiotic are formed, principal agent does not often reach higher content (20%), thereby is difficult to reach quick-acting and long lasting purpose yet.Publication number is composition and the preparation technology thereof that C N 101301268A discloses a kind of doxycycline hydrochloride injection for animals.Form by principal agent, solvent, doxycycline hydrochloride chelating agent, antioxidant.The metal ion (MG2+) that adopts high level is showing doxycycline hydrochloride dissolubility and pH value and improves as the doxycycline hydrochloride chelating agent, and the stability of its injection is strengthened; The most important thing is medicine through after the complexation, toxicity and tissue irritation reduce.Select for use 2-Pyrrolidone and propylene glycol or dimethyl acetylamide mixed solvent as solvent, increased the stability of injection, under low temperature (4 ℃) condition, do not separate out and freeze, and having adopted concentrated hydrochloric acid, ethanolamine is the PH regulator, this invention comprises principal agent, additives and solvent with magnesium ion and doxycycline hydrochloride complexation.Principal agent is a doxycycline hydrochloride; Additives are antioxidant, metal chelating agent and solvent for injection, and this technical scheme has solved the problem of doxycycline long-acting, but are difficult to realize quick-acting purposes; Publication number is the compound florfenicol injection of C N 1861084A, and the content of florfenicol and doxycycline is all very low, can not reach result efficiently; Publication number adopts abadox and tetramycin hydrochloride compound for C N101181276A, and to be that the invention of C N 101301268A is compared similar with publication number, can only reduce some costs; It is compound with clindamycin or woods Mycosporin and doxycycline that publication number is C N 10102014A, do not adopt the mode of metal ion complex to realize long-lasting.
Summary of the invention
The present invention seeks to: at the deficiencies in the prior art, propose a kind of with metal complex doxycycline and Trimethoprim trimethoprim, to have combining of the astragalus polysaccharides of antiviral and immunological enhancement or the two compound, when keeping doxycycline metal complex long-lasting, realize efficient quick-acting purpose, improve the antibacterial effect of medicine, enlarge the scope of application of product, reduced use cost.
Realize that technical scheme of the present invention is as follows: long-acting veterinary compound doxycycline injection, described long-acting veterinary compound doxycycline injection, it is characterized in that forming by principal agent doxycycline or doxycycline hydrochloride, synergist, solvent, chelating agent, antioxidant, PH regulator, wherein principal agent is doxycycline or doxycycline hydrochloride, and content is counted 10.0～20.0 grams by doxycycline; Synergist is trimethoprim 0.2～5 gram or astragalus polysaccharides 0.2～5 gram or the combination of the two, and the consumption of the two is identical or different all in above-mentioned scope; Chelating agent be can with the Ca of polyhydroxy complexation on the doxycycline
2+, Mg
2+, Zn
2+Or Al
3+Metal ion compound adopts calcium oxide, magnesium oxide, zinc oxide, aluminium oxide, calcium chloride, magnesium chloride, magnesium sulfate, aluminum chloride etc., and the mol ratio of its consumption and doxycycline consumption is 1.00～1.10: 1.00; Used antioxidant is a kind of in sodium formaldehyde sulphoxylate, sodium thiosulfate, the sodium metabisulfite, or its combination, and its consumption is 0.10～1.00; Used pH regulator agent is hydrochloric acid, ethanolamine, diethanolamine, triethanolamine or its combination, the scope that pH value is regulated is 4.0～7.5, used solvent for injection is added into 100ml, and solvent for injection is water for injection, propylene glycol, alpha-pyrrolidone, N methyl alpha-pyrrolidone, dimethyl formamide, dimethyl acetylamide, PEG200, T 80 and combination thereof.
Described long-acting veterinary compound doxycycline injection preparation method is:
(1) chelating agent that measures and antioxidant are added in the part solvent for injection mixes;
(2) in solution (1), add doxycycline or doxycycline hydrochloride, warming while stirring is reacted to the solution clear, and control reaction temperature is 40～80 ℃, and the insulation reaction time is 10-100 minute, in complex reaction, regulate pH value, promote reaction to carry out;
(3) synergist that measures is added in an amount of solvent, be stirred to dissolving fully;
(4) solution (3) is added in the solution (2), stir and transfer pH value 4.0～6.5, after-teeming is penetrated water to formula ratio;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
The invention has the beneficial effects as follows: propose a kind of with the metal complex doxycycline with the Trimethoprim trimethoprim, especially have the astragalus polysaccharides of antiviral and immunological enhancement and especially the two combine compound, when keeping doxycycline metal complex long-lasting, realize efficient quick-acting purpose, improve the antibacterial effect of medicine, enlarge the scope of application of product, and reduced use cost.Product of the present invention is to light, heat stability height, effective action time of prolong drug.The present invention's complexation in solvent with metal and doxycycline, when complex reaction, promote complexation to carry out fast with alkaline P H regulator, complex reaction is finished fast, reduced doxycycline and decompose the shallow good stability of finished color, when guaranteeing that product is long-lasting, by drug effect reinforcing agent trimethoprim the injection curative effect is improved, and astragalus polysaccharides antiviral not only, but also enhance immunity effect, thereby further improve curative effect, reduce drug cost.
The specific embodiment
Embodiment 1
(1) gets propylene glycol 35ml, water for injection 10ml, add magnesium oxide 0.9 gram, sodium thiosulfate 0.2 gram, stir;
(2) add doxycycline hydrochloride 11.7 grams in solution (1), warming while stirring to 60～70 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 20ml, add trimethoprim 0.6 or 2.0 grams, trimethoprim can also adopt 4 or 5 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6.0, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 2
(1) gets propylene glycol 35ml, water for injection 12ml, add magnesium chloride 8.8 grams or zinc oxide 1.80 grams, sodium formaldehyde sulphoxylate 0.4 gram, stir;
(2) add doxycycline hydrochloride 23.5 grams in solution (1), warming while stirring to 50～60 ℃ reaction is slowly regulated pH value 5.5～6.0 with triethanolamine in complex reaction, and insulation reaction 25 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 25ml, add trimethoprim 4.0 or 5.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 3
(1) gets propylene glycol 40ml, water for injection 6ml, add magnesium oxide 1.75 grams, calcium oxide 2.52 grams or zinc oxide 3.60 grams, sodium thiosulfate 0.2 gram, stir;
(2) add doxycycline hydrochloride 23.6 grams in solution (1), warming while stirring to 65～75 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 60 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 30ml, add trimethoprim 4.0 grams or 5.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6.0, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 4
(1) get propylene glycol 35ml, water for injection 6ml, sodium sulfite 0.5 gram adds magnesium oxide 0.9 gram, calcium oxide 1.26 grams or zinc oxide 1.80 grams, stirs;
(2) add doxycycline hydrochloride 11.8 grams in solution (1), warming while stirring to 70～80 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl formamide 20ml, T 80 1.5 grams add astragalus polysaccharidess 1,4 or 5 grams, be stirred to dissolve fully astragalus polyose solution;
(4) astragalus polyose solution is joined in the doxycycline solution, after stirring, transfer pH value 4.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Experimental example 5
(1) get alpha-pyrrolidone 35ml, water for injection 6ml, sodium sulfite 0.5 gram adds magnesium oxide 0.9 gram, calcium oxide 1.26 grams or zinc oxide 1.80 grams, stirs;
(2) add doxycycline hydrochloride 11.8 grams in solution (1), warming while stirring to 70～80 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) in the astragalus polyose solution preparation process, add trimethoprim 0.2 or 2 grams, be stirred to dissolve fully astragalus polysaccharides and trimethoprim solution;
(4) astragalus polysaccharides trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 4.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.Also can use N methyl alpha-pyrrolidone or alpha-pyrrolidone and mixed with propylene glycol to use.
Embodiment 6
(1) gets propylene glycol 45ml, water for injection 6ml, add magnesium oxide 0.3 gram, magnesium chloride 3.0 grams, sodium thiosulfate 0.2 gram, stir;
(2) add doxycycline hydrochloride 11.7 grams in solution (1), warming while stirring to 40～50 ℃ reaction is slowly regulated pH value 6.0～6.5 with diethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 25ml, add trimethoprim 2.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 5.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 7
(1) gets alpha-pyrrolidone 40ml, water for injection 6ml, add magnesium chloride 4.5 grams, sodium thiosulfate 1.0 grams, stir;
(2) in solution (1), add doxycycline 10.1 grams, warming while stirring to 60～70 ℃ reaction,, in complex reaction, slowly regulate pH value 7.0～7.5 with ethanolamine, insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 25ml, add trimethoprim 1.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 8
(1) gets alpha-pyrrolidone 30ml, water for injection 6ml, add magnesium chloride 6.75 grams, sodium thiosulfate 0.4 gram, stir;
(2) in solution (1), add doxycycline 15.0 grams, warming while stirring to 60～70 ℃ reaction,, in complex reaction, slowly regulate pH value 7.0～7.5 with ethanolamine, insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 30ml, add trimethoprim 3.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Embodiment 9
(1) gets alpha-pyrrolidone 30ml, water for injection 6ml, add magnesium chloride 8.8 grams, sodium thiosulfate 0.4 gram, stir;
(2) in solution (1), add doxycycline 20.0 grams, warming while stirring to 60～70 ℃ reaction,, in complex reaction, slowly regulate pH value 7.0～7.5 with ethanolamine, insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 30ml, add trimethoprim 4.0 grams, astragalus polysaccharides 1.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim, astragalus polyose solution are joined in the doxycycline solution, after stirring, transfer pH value 6, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
Treatment preventive effect of the present invention:
Carry out the actual efficacy test on the pig farm by embodiment 3 preparation long-acting veterinary compound doxycycline injections (20% doxycycline, 4% trimethoprim, chelating agent are selected magnesium oxide for use), embodiment 9 preparation long-acting veterinary compound doxycycline injections (20% doxycycline, 4% trimethoprim, 1% astragalus polysaccharides) and folk prescription long-acting doxycycline injection adopting (20% doxycycline), test is divided into piglet health care and sow postpartum health care, and experimental program and result are as follows: piglet health care test:
(1) folk prescription long-acting doxycycline injection adopting piglet three pins health cares (100ml makes a call to 100)
Piglet the 3rd day the 1st pin 0.3ml/ head of being born
Piglet the 7th day the 2nd pin 0.3ml/ head of being born
Be born the 21st day the 3rd pin 0.4ml/ head of piglet amounts to: the 1.0ml/ head
(2) embodiment 3 preparation long-acting veterinary compound doxycycline injection piglet three pins health cares (100ml makes a call to 125)
Piglet the 3rd day the 1st pin 0.25ml/ head of being born
Piglet the 7th day the 2nd pin 0.25ml/ head of being born
Be born the 21st day the 3rd pin 0.3ml/ head of piglet amounts to: the 0.8ml/ head
(3) embodiment 9 preparation long-acting veterinary compound doxycycline injection piglet three pins health cares (100ml makes a call to 143)
Piglet the 3rd day the 1st pin 0.2ml/ head of being born
Piglet the 7th day the 2nd pin 0.2ml/ head of being born
Be born the 21st day the 3rd pin 0.3ml/ head of piglet amounts to: the 0.7ml/ head
Piglet health care result of the test shows that three kinds of health care schemes have reached following effect: help piglet to resist various bacterial diseases before wean, promote weightening finish, improve from newborn regularity; The generation of the attached eperythrozoonosis of prevention pig, asthma, contagious pleuropneumonia, atrophic rhinitis and dysentery; Reduce the mixed infection that reproductive and respiratory syndrome causes.The general effect of three kinds of health care schemes is suitable, cost benefit situation such as following table:
Table 1: piglet health care cost comparison sheet warp
| The product contrast | The composition specification | Piglet three pin amounts (ml) | Piglet cost (unit/head) | Sow cost (unit/head) | Increase benefit (ten thousand a yuan) sow) |
| Long-acting veterinary compound doxycycline injection | With embodiment 3 | ??0.20+0.20+0.3＝0.7 | ??1.10 | ??4.80 | ??0.56 |
| Long-acting veterinary compound doxycycline injection | With embodiment 9 | ??0.25+0.25+0.3＝0.8 | ??1.20 | ??5.30 | ??0.44 |
| The folk prescription doxycycline injection | 20% doxycycline | ??0.3+0.3+0.4＝1.0 | ??1.60 | ??6.0 |
Two, sow postpartum health care
Sow is every sow intramuscular injection doxycycline injection prevention puerperal infection mastitis, metritis and agalactia disease in 8 hours puerperal, the protection sow reproductive performance, and three kinds of health care schemes are as follows:
(1) sow every sow intramuscular injection folk prescription long-acting doxycycline injection adopting 4.0ml (100ml makes a call to 25) in 8 hours puerperal, effective percentage 83%;
(2) sow every sow intramuscular injection embodiment 3 preparation long-acting veterinary compound doxycycline injection 3.0ml (100ml makes a call to 33) in 8 hours puerperal, effective percentage 89%;
(3) sow every sow intramuscular injection embodiment 9 preparation long-acting veterinary compound doxycycline injection 2.5ml (100ml makes a call to 40) in 8 hours puerperal, effective percentage 93%;
The result shows: the curative effect of scheme (three) is the highest, and the curative effect of scheme (two) is taken second place, and the curative effect of scheme () is minimum, and economic benefit sees Table 1.
Press embodiment 3 preparation long-acting veterinary compound doxycycline injection (20% doxycycline by above-mentioned piglet health care and sow postpartum health care test explanation, 4% trimethoprim, chelating agent is selected magnesium oxide for use) and by executing example 9 preparation long-acting veterinary compound doxycycline injection (20% doxycycline, 4% trimethoprim, 1% astragalus polysaccharides) close aspect curative effect and economy, all be better than the folk prescription doxycycline injection that contrasts, both improved curative effect, reduced use cost again, there is certain economic to be worth, but this also is a kind of trial of preliminary property, realize extensive industrialization, need do more work aspect preparation technology and expansion clinical trial scope and the experimental scale, the while also wishes the guidance that the expert of association area is positive and exchanges.Therefore adopting antiviral, exempting from synergist is trimethoprim or astragalus polysaccharides or the combination of the two, has significantly immunological enhancement.Especially the combination of the two.
Claims (5)
1. long-acting veterinary compound doxycycline injection, it is characterized in that forming by principal agent doxycycline or doxycycline hydrochloride, synergist, solvent, chelating agent, antioxidant, PH regulator, wherein principal agent is doxycycline or doxycycline hydrochloride, content is counted weight portion by doxycycline, 10.0～20.0 grams; Synergist is trimethoprim, astragalus polysaccharides, and weight portion is 0.2～5 gram, or the two the combination of trimethoprim or astragalus polysaccharides; Chelating agent be can with the Ca of polyhydroxy complexation on the doxycycline
2+, Mg
2+, Zn
2+Or Al
3+Metal ion compound, i.e. calcium oxide, magnesium oxide, zinc oxide, aluminium oxide, calcium chloride, magnesium chloride, magnesium sulfate, aluminum chloride, the mol ratio of its consumption and doxycycline consumption is 1.00～1.10: 1.00; Used antioxidant is a kind of or its combination in sodium formaldehyde sulphoxylate, sodium thiosulfate, the sodium metabisulfite, and its consumption is 0.10～1.00 gram; Used pH regulator agent is hydrochloric acid, ethanolamine, diethanolamine, triethanolamine or its combination, the scope that pH value is regulated is 4.0～7.5, used solvent for injection is added into 100ml, and solvent for injection is water for injection, propylene glycol, alpha-pyrrolidone, N methyl alpha-pyrrolidone, dimethyl formamide, dimethyl acetylamide, PEG200, T80 and combination thereof.
2. long-acting veterinary compound doxycycline injection according to claim 1 is characterized in that:
(1) gets propylene glycol 40ml, water for injection 6ml, add magnesium oxide 1.75 grams, calcium oxide 2.53 grams or zinc oxide 3.60 grams, sodium thiosulfate 0.2 gram, stir;
(2) add doxycycline hydrochloride 23.6 grams in solution (1), warming while stirring to 65～75 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 60 minutes to solution clear gets doxycycline solution.
(3) get dimethyl acetylamide 30ml, add trimethoprim 4.0 grams or 5.0 grams, be stirred to dissolve fully trimethoprim solution;
(4) trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 6.0, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
3. long-acting veterinary compound doxycycline injection according to claim 2, it is characterized in that (1) get propylene glycol 35ml, water for injection 6ml, chelating agent is sodium sulfite 0.5 gram, adds magnesium oxide 0.9 gram, calcium oxide 1.26 grams or zinc oxide 1.80 grams, stirs;
(2) add doxycycline hydrochloride 11.8 grams in solution (1), warming while stirring to 70～80 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution.
(3) get dimethyl formamide 20ml, T80 1.5 grams add astragalus polysaccharidess 1,4 or 5 grams, be stirred to dissolve fully astragalus polyose solution;
(4) astragalus polyose solution is joined in the doxycycline solution, after stirring, transfer pH value 4.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
4. long-acting veterinary compound doxycycline injection according to claim 3 is characterized in that (1) get propylene glycol 35ml, water for injection 6ml, but chelating agent sodium sulfite 0.5 gram adds magnesium oxide, calcium oxide or zinc oxide 0.9 gram, stirs;
(2) add doxycycline hydrochloride 11.8 grams in solution (1), warming while stirring to 70～80 ℃ reaction is slowly regulated pH value 6.0～6.5 with ethanolamine in complex reaction, and insulation reaction 30 minutes to solution clear gets doxycycline solution;
(3) in the astragalus polyose solution preparation process, add trimethoprim 0.2 or 1 gram, be stirred to dissolve fully astragalus polysaccharides and trimethoprim solution;
(4) astragalus polysaccharides trimethoprim solution is joined in the doxycycline solution, after stirring, transfer pH value 4.5, after-teeming is penetrated water to 100ml;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
5. long-acting veterinary compound doxycycline injection preparation method is characterized in that the proportioning of described injection is:
Doxycycline or doxycycline hydrochloride content are counted weight portion by doxycycline, 10.0～20.0 grams;
Synergist is trimethoprim, astragalus polysaccharides, and weight portion is 0.2～5 gram, or the two the combination of trimethoprim or astragalus polysaccharides;
Chelating agent be can with the Ca of polyhydroxy complexation on the doxycycline
2+, Mg
2+, Zn
2+Or Al
3+Metal ion compound, i.e. calcium oxide, magnesium oxide, zinc oxide, aluminium oxide, calcium chloride, magnesium chloride, magnesium sulfate, aluminum chloride, the mol ratio of its consumption and doxycycline consumption is 1.00～1.10: 1.00;
Used antioxidant is a kind of in sodium formaldehyde sulphoxylate, sodium thiosulfate, the sodium metabisulfite, or its combination, and its consumption is 0.10～1.00;
Used PH regulator is hydrochloric acid, ethanolamine, diethanolamine, triethanolamine or its combination, the scope that pH value is regulated is 4.0～7.5, used solvent for injection is added into 100ml, and solvent for injection is water for injection, propylene glycol, alpha-pyrrolidone, N methyl alpha-pyrrolidone, dimethyl formamide, dimethyl acetylamide, PEG200, T80 and combination thereof; And be prepared with following step:
(1) chelating agent that measures and antioxidant are added in the part solvent for injection mixes;
(2) in solution (1), add doxycycline or doxycycline hydrochloride, warming while stirring is reacted to the solution clear, and control reaction temperature is 40～80 ℃, and the insulation reaction time is 10-100 minute, in complex reaction, regulate pH value, promote reaction to carry out;
(3) synergist that measures is added in an amount of solvent, be stirred to dissolving fully;
(4) solution (3) is added in the solution (2), stir and transfer pH value 4.0～6.5, after-teeming is penetrated water to formula ratio;
(5) with titanium rod or membrane filtration, in packing and ampoule bottle or the cillin bottle, get product after the sterilization.
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| CN101947233A (en) * | 2010-10-15 | 2011-01-19 | 郑州后羿制药有限公司 | Compound medicinal composition for treating livestock and poultry respiratory disease and soluble powder thereof |
| CN101972226A (en) * | 2010-10-13 | 2011-02-16 | 郑州后羿制药有限公司 | Veterinary doxycycline hydrochloride injection and preparation method thereof |
| CN103055002A (en) * | 2012-12-05 | 2013-04-24 | 青岛绿曼生物工程有限公司 | Composition for treating respiratory disease of poultry and preparation method thereof |
| CN104274474A (en) * | 2014-09-12 | 2015-01-14 | 安徽天安动物药业有限公司 | Doxycycline hydrochloride injection and preparation method thereof |
| CN104622799A (en) * | 2015-01-21 | 2015-05-20 | 天津市中升挑战生物科技有限公司 | Doxycycline injection and preparation method thereof |
| CN109432107A (en) * | 2018-12-25 | 2019-03-08 | 扬州大学 | The composition and its application in the drug for preparing bacterial infection disease of melbine and Doxycycline |
| CN111603448A (en) * | 2020-06-22 | 2020-09-01 | 南京大方生物工程有限公司 | Compound doxycycline hydrochloride soluble powder and preparation method thereof |
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| CN100548305C (en) * | 2007-05-22 | 2009-10-14 | 江西核工业天地和药业有限公司 | Compound vibramycin injection for animals and preparation method thereof |
| CN101380301A (en) * | 2008-10-28 | 2009-03-11 | 陈建波 | Compound doxycycline hydrochloride injection for animals and preparation method thereof |
| CN101385704A (en) * | 2008-10-28 | 2009-03-18 | 陈建波 | Compound sulfamonomethoxine sodium injection and preparation method thereof |
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| CN101972226A (en) * | 2010-10-13 | 2011-02-16 | 郑州后羿制药有限公司 | Veterinary doxycycline hydrochloride injection and preparation method thereof |
| CN101972226B (en) * | 2010-10-13 | 2012-11-07 | 郑州后羿制药有限公司 | Veterinary doxycycline hydrochloride injection and preparation method thereof |
| CN101947233A (en) * | 2010-10-15 | 2011-01-19 | 郑州后羿制药有限公司 | Compound medicinal composition for treating livestock and poultry respiratory disease and soluble powder thereof |
| CN103055002A (en) * | 2012-12-05 | 2013-04-24 | 青岛绿曼生物工程有限公司 | Composition for treating respiratory disease of poultry and preparation method thereof |
| CN104274474A (en) * | 2014-09-12 | 2015-01-14 | 安徽天安动物药业有限公司 | Doxycycline hydrochloride injection and preparation method thereof |
| CN104622799A (en) * | 2015-01-21 | 2015-05-20 | 天津市中升挑战生物科技有限公司 | Doxycycline injection and preparation method thereof |
| CN104622799B (en) * | 2015-01-21 | 2018-01-02 | 天津市中升挑战生物科技有限公司 | A kind of doxycycline injection and preparation method thereof |
| CN109432107A (en) * | 2018-12-25 | 2019-03-08 | 扬州大学 | The composition and its application in the drug for preparing bacterial infection disease of melbine and Doxycycline |
| CN109432107B (en) * | 2018-12-25 | 2021-04-06 | 扬州大学 | Composition of metformin and doxycycline and application of composition in preparation of medicines for treating bacterial infectious diseases |
| CN111603448A (en) * | 2020-06-22 | 2020-09-01 | 南京大方生物工程有限公司 | Compound doxycycline hydrochloride soluble powder and preparation method thereof |
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