CN103705452A - Antibacterial drug injection containing poloxamer 407 and oily medium - Google Patents
Antibacterial drug injection containing poloxamer 407 and oily medium Download PDFInfo
- Publication number
- CN103705452A CN103705452A CN201410005508.0A CN201410005508A CN103705452A CN 103705452 A CN103705452 A CN 103705452A CN 201410005508 A CN201410005508 A CN 201410005508A CN 103705452 A CN103705452 A CN 103705452A
- Authority
- CN
- China
- Prior art keywords
- injection
- medicine carrying
- antibacterials
- preparation
- carrying microgranule
- 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.)
- Granted
Links
- 238000002347 injection Methods 0.000 title claims abstract description 69
- 239000007924 injection Substances 0.000 title claims abstract description 69
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 title abstract description 4
- 229940124350 antibacterial drug Drugs 0.000 title abstract 3
- 229920001992 poloxamer 407 Polymers 0.000 title abstract 3
- 229940044476 poloxamer 407 Drugs 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 95
- 239000003814 drug Substances 0.000 claims abstract description 79
- 238000000227 grinding Methods 0.000 claims abstract description 5
- 239000004531 microgranule Substances 0.000 claims description 46
- 230000000844 anti-bacterial effect Effects 0.000 claims description 33
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- KEQFDTJEEQKVLM-JUODUXDSSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-(furan-2-carbonylsulfanylmethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydron;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC(=O)C1=CC=CO1 KEQFDTJEEQKVLM-JUODUXDSSA-N 0.000 claims description 14
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- 229960002531 marbofloxacin Drugs 0.000 claims description 3
- YKQOSKADJPQZHB-RGYSVOEGSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(6r,9s,12r,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-hydr Chemical compound CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)C([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 YKQOSKADJPQZHB-RGYSVOEGSA-N 0.000 claims description 3
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses an oily long-acting injection containing antibacterial drug/poloxamer 407 drug-loading particles, which is prepared by combining the antibacterial drug with poloxamer 407 into drug-loading particles and further dispersing the drug-loading particles into an oily medium and grinding. Hydroxypropyl methyl cellulose or high-substituted hydroxypropyl cellulose also can be added into the drug-loading particles, and the sustained-release effect of the preparation is obviously enhanced. The preparation process of the injection is simple, the drug release is uniform, the biocompatibility is good, irreversible damage to the tissue of the injection part is avoided, and the adopted sustained-release carrier can be degraded and excreted.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, being specifically related to poloxamer188 and oil medium is carrier, and preparation is containing the long-acting veterinary injection of antibacterials.
Background technology
Poloxamer is polyoxyethylene polyoxypropylene ether analog copolymer, this base polymer has plurality of specifications, wherein the aqueous solution of poloxamer188 (hereinafter to be referred as P407) has " characteristic that raises and transformed to gel by colloidal sol with temperature ", generally at 28 ℃, there is above gelling in certain density P407 aqueous solution, characteristic accordingly, P407 is used to the preparation of slow releasing injection, and said preparation is referred to as in-situ gelling preparation.After being injected in vivo containing the in-situ gelling injection of P407, under the effect of body temperature, generally, about 1 minute, by colloidal sol, change gel (semisolid) into, medicine is wrapped in gel, thereby has slowed down rate of releasing drug, and duration of efficacy is extended.The disclosed in-situ gelling injection containing P407 of document and patent, the solvent of its preparation is water, in preparation, the concentration of P407 will reach and more than 20% just have good slow releasing function; In preparation, add the blocker such as a certain amount of methylcellulose, sodium carboxymethyl cellulose, Hydroxypropylcelliloxe (H-HPC) or hydroxypropyl emthylcellulose (HPMC), can strengthen slow releasing function, but can cause preparation viscosity to raise, make injection more difficult.
P407 is also the good non-ionic surface active agent of a kind of water solublity, is to be more used to prepare Emulsion, ointment, aqueous suppository, drop pill etc.; P407 is also used as the dispersible carrier of insoluble medicine (medicine that water solublity is very poor), and for the preparation of solid solution, mostly the published solid solution of preparing with P407, be the preparation for oral preparations.
The present invention is different from published technology, the present invention forms medicine and P407 (or with P407 and cellulose ethers) medicine carrying microgranule (as agglomerate) of solid solution or other form, and (isopropyl myristate, hereinafter to be referred as IPM with oil medium; Vegetable oil) place of water is prepared the oily injection containing P407 medicine carrying microgranule.This preparation injects under animal skins or intramuscular, medicine carrying microgranule is after " breakthrough " oil phase contact body fluid (water), by means of P407 " water suction (body fluid) " or water absorption and swelling (when HPMC or H-HPC exist), " adhesive aggregation " together, in injection site, form high concentration and full-bodied and there is the semi-solid agglomerate of " bioadhesive " (when H-HPC or HPMC exist), medicine is wrapped in agglomerate, thereby has effectively extended the release time of medicine.And due to the peptizaiton of P407, make insoluble medicine release more complete, thereby improved the bioavailability of hydrophobic drug, reduced injection site drug residue.
The antibacterials that the present invention relates to comprise: fumaric acid tiamulin, enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, for meter Ke Xing, tylosin, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin.
Experiment shows, above these antibacterials can be combined into the medicine carrying microgranule (as agglomerate) of solid solution fine particle or other form with P407 or with P407/HPMC (or H-HPC), and are scattered in oil medium, prepare the slow releasing injection of expectation.
" character, pharmacology and the purposes " of above antibacterials etc. are < < veterinary drug handbook > > (Zhu Mozhong chief editor, Chemical Industry Press, July in 2002 the 1st edition) all on the books and describe in.Commercially available injection containing these antibacterials, majority be take water as primary solvent or with organic solvent (as 1,2-propylene glycol, dimethyl acetylamide, N-Methyl pyrrolidone, formal glycerine etc.) be solution type preparation prepared by primary solvent, also have and take the oily injection that the oily compounds of vegetable oil or synthetic prepared as medium; The disclosed injection containing above-mentioned antibacterials of document or patent has solution type preparation, suspension type preparation, Emulsion, has the long-acting injection containing different slow-released carriers, also has to take the in-situ gelling injection containing P407 that water is medium.But the oily long-acting injection containing antibacterials/P407 medicine carrying microgranule has no report.In oil medium, adding suitable slow releasing carrier material, traditional oily injection is improved, is the feasible way of the efficient long-acting veterinary injection of exploiting economy.
Summary of the invention
By medicine and P407, or by medicine and P407 and HPMC (or H-HPC) composition medicine carrying microgranule, with medicine carrying microgranule state, be suspended in preparation, be prepared into oily long-acting injection, this is the prominent features of this preparation.
This preparation forms and preparation method is described below:
Preparation forms: this preparation is mainly comprised of antibacterials, P407 and oil medium.In every liter of injection, containing antibacterials 25-200g, P407 25-150g, oil medium, add to 1 liter.
Described antibacterials comprise: fumaric acid tiamulin, enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, for meter Ke Xing, tylosin, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin.These antibacterials are all commercial medicines, in < < Chinese veterinary pharmacopoeia > > and veterinary drug handbook and pertinent literature, all can find.
Described oil medium is a kind of in IPM, injection soybean oil, Semen Maydis oil, Oleum Camelliae.
In every liter of described injection, also can add 20-60g HPMC or H-HPC, HPMC or H-HPC need be combined into solid solution or form medicine carrying microgranule with P407 together with antibacterials with P407, could be used for the preparation of this preparation.H-HPC has good dissolubility in the low boiling point organic solvents such as methanol, ethanol, most antibacterials have equally good dissolubility in these low boiling point organic solvents, this is that H-HPC, P407 and antibacterials can form one, is prepared into the important foundation of medicine carrying microgranule.
H-HPC and HPMC be nontoxic, without pharmacological action, on physiologically active, show extreme inertia.HPMC, H-HPC or P407 are insoluble in the oil mediums such as IPM, therefore, by H-HPC or HPMC and P407 composition microgranule, even be scattered in oil medium with higher concentration, can not make preparation viscosity obviously raise yet, but contain the medicine carrying microgranule of high concentration H-HPC or HPMC at injection part energy water absorption and swelling, form full-bodied agglomerate, full-bodied agglomerate has the effect of stronger retardance (slowing down) drug release, therefore, in medicine carrying microgranule, add appropriate H-HPC and HPMC, can reach the slow release effect of expection, especially for the long-acting injection of preparing containing water-soluble antibacterials, it is very necessary in medicine carrying microgranule, adding a certain amount of H-HPC and HPMC.
In every liter of injection, also can add 0.2-2g antioxidant, antioxidant comprises the mixture of one or more any ratios in tertiary butyl-4-hydroxy methoxybenzene (BHA), dibenzylatiooluene (BHT), propyl gallate (PG) or ascorbyl palmitate.
Preparation method: due to the different solubility of different antibacterials in low boiling point solvent, stability different (being mainly heat stability), so preparation method is also different, is summed up and mainly contains following three kinds.
(1) under heating or room temperature, antibacterials and P407 or antibacterials and P407 and HPMC or antibacterials and P407 and H-HPC mono-are reinstated to low boiling point solvent to be dissolved, then distilling under reduced pressure or vacuum freeze-drying, remove low boiling point solvent, obtain antibacterials/P407 solid solution or antibacterials/P407/HPMC solid solution or antibacterials/P407/H-HPC solid solution; The solid solution of preparation was pulverized to 40 mesh sieves, obtain medicine carrying microgranule, medicine carrying microgranule is scattered in part oil medium, with colloid mill, be ground to particle diameter and be less than 100 μ m, with sand mill, be ground to particle diameter again and be less than 20 μ m, add remaining media to final volume, with high-shear homogenizing machine, under 5000-10000rpm, further homogenize and obtain this preparation.
(2) medicine is scattered in oil medium, with colloid mill, is ground to particle diameter and is less than 100 μ m, then with sand mill, be ground to particle diameter and be less than 1 μ m, standby after centrifugalize; P407 is made it to melt in 60-70 ℃, then the medicine that the particle diameter of preparation is above less than to 1 μ m joins in the P407 of thawing, stirring and evenly mixing, through cooling curing, pulverize and sieve, obtain medicine carrying microgranule, medicine carrying microgranule is scattered in oil medium, further with colloid mill and sand mill, be ground to particle diameter and be less than 20 μ m, add remaining media, with high-shear homogenizing machine, homogenize and obtain this preparation.
(3) medicine and P407 or medicine and solid solution (P407/HPMC or P407/H-HPC) are scattered in part oil medium, with colloid mill and sand mill, are ground to particle diameter and are less than 20 μ m, add remaining media, with homogenizer this preparation that homogenizes to obtain.
P407/H-HPC or P407/HPMC solid solution preparation: under heating condition, HPMC or H-HPC and P407 be dissolved in to methanol or be dissolved in 80% alcoholic solution, mixing, under agitation removal of solvent under reduced pressure and get final product.
This preparation preparation process need be carried out under aseptic condition, and during grinding, temperature of charge can not surpass 40 ℃, and in preparation, the particle diameter of solid particle should be less than 20 μ m, more suitable to be less than 10 μ m.While preparing the suspensoid injectio of containing water-soluble medicine, drug particles is less, and slow release effect is better, is difficult for being wrapped by micelle when this may be larger with water-soluble pesticide composition granule, easily occurs due to drug microparticles " diafiltration ".
Feature of the present invention is summarized as follows:
This medicament drug release process is different from take the in-situ gelling preparation that water is medium, is also different from traditional oil preparation, and main difference part is to exist medicine carrying microgranule " breakthrough " oil phase to contact with body fluid and absorb water to form high viscosity agglomerate process.
By appropriate H-HPC or HPMC and P407 composition solid solution pellet, be scattered in oil phase, solved the simple technical barrier that is difficult to grind to form fine particle (being less than 20 μ m) with H-HPC (or HPMC) packaging medicine, retain H-HPC and HPMC simultaneously and there is water suction (body fluid) swelling, formed the characteristic of high viscosity agglomerate.Pastille " agglomerate " adheres in injection site tissue, is conducive to medicine and better absorbs, and guaranteed slow release effect to a certain degree, and it is high that this is that this agent has bioavailability, has again the basis of long-acting.
To be insoluble in the antibacterials of water, form medicine carrying microgranule application with the water-solubility carrier such as P407, can improve its bioavailability, reduce injection site drug residue.
By oil medium place of water, prepare the slow releasing injection containing P407, can reduce the consumption of P407, P407 consumption is when 5-10%, and preparation just has good slow releasing function.Take water as the in-situ gelling injection of solvent preparation containing P407, and the consumption of P407 will reach 20～45%, and preparation just can demonstrate good slow releasing function.Current domestic P407 price more expensive (medical grade is at 160～200 yuan/kg), therefore, P407 consumption in preparation is more, and preparation cost is higher, is unfavorable for applying in veterinary applications.
The specific embodiment
Embodiment 1, preparation 10% Ceftiofur Hydrochloride injection
Preparation forms: 90% Ceftiofur Hydrochloride 110g, P407 60g, H-HPC 30g, injection soybean oil add to 1 liter.
Preparation method: (1) by P407 in 60-70 ℃ of thawing, after adding H-HPC to mix, add the methanol that is equivalent to 2 times of amounts of Ceftiofur Hydrochloride, after dissolving, H-HPC is down to room temperature, add Ceftiofur Hydrochloride, fully mix, decompression Ex-all methanol, cooling, after solidifying, pulverize, cross 40 mesh sieves, obtain the medicine carrying microgranule of hydrochloric ceftiofur.(2) medicine carrying microgranule is scattered in part soybean oil, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 10 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the Ceftiofur Hydrochloride injection that particle diameter is less than 10 μ m.
Embodiment 2, preparation 8% Ceftiofur Hydrochloride injection
Preparation forms: 90% Ceftiofur Hydrochloride 90g, P407 80g, IPM adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds Ceftiofur Hydrochloride superfine powder by P407, fully mixes, cooling, pulverizes after solidifying, and crosses 40 mesh sieves, obtains the medicine carrying microgranule of hydrochloric ceftiofur.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 100 μ m, further with sand mill, grind, grind to particle diameter and be less than 20 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the Ceftiofur Hydrochloride injection that particle diameter is less than 20 μ m.
Embodiment 3, blood drug level detect
Control formulation: Ceftiofur Hydrochloride superfine powder 9g, P407 8g, sterilized water adds to 100ml, matching while using.
Select 6 of the health pig of approximately 30 kilograms of body weight, be divided at random two groups of A, B, 3 every group, difference intramuscular injection control formulation and embodiment 2 preparations, dosage is 8mg/kg b.w., adopt cross matching, twice intertrial interval 20 days, blood sampling on time, centrifugal separation plasma, by the plasma sample mixed in equal amounts of same group of same time, through processes such as extracting, purify, be concentrated, obtain test specimens, adopt high pressure lipuid chromatography (HPLC) (C
18post) measure the ceftiofur concentration in blood plasma.Experimental result is in Table 1 and table 2.
Table 1. is tested testing result for the first time
In ※ table, numerical value is the meansigma methods of every group of 3 porcine blood plasma drug level.
Table 2. is tested testing result for the second time
In ※ table, numerical value is the meansigma methods of every group of 3 porcine blood plasma drug level.
Embodiment 4, preparation 6% sulphuric acid cephalosporium quinol injection
Preparation forms: 90% sulphuric acid cephalosporium quinol 67g, P407 80g, injection Semen Maydis oil adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds sulphuric acid cephalosporium quinol superfine powder by P407, fully mixes, pulverizes after cooling curing, crosses 40 mesh sieves, obtains the medicine carrying microgranule of sulfur acid Cefquinome.(2) medicine carrying microgranule is scattered in part Semen Maydis oil, crossing colloid mill is ground to particle diameter and is less than 100 μ m, further with sand mill, grind, grind to particle diameter and be less than 20 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the Ceftiofur Hydrochloride injection that particle diameter is less than 20 μ m.
Embodiment 5, preparation 15% tetramycin hydrochloride injection
Preparation forms: hydrochloric oxytetracycline 15g, P407/HPMC (2: 1) solid solution 9g, BHA0.01g, BHT0.01g, PG0.005g in every 100ml injection, and EDTA-2 sodium 0.15g, IPM adds to final volume.
Preparation method: tetramycin hydrochloride and solid solution are scattered in part IPM, are ground to particle diameter with colloid mill and sand mill and are less than 10 μ m, add antioxidant and remaining media, homogenize and obtain this preparation with high-shear homogenizing machine.
This preparation is to pig intramuscular injection, and dosage is 20mg/kg b.w., and after administration 60 hours, blood drug level still maintained valid density scope (1-2 microgram/ml).
Embodiment 6, preparation 20% Danofloxacin mesylate injection
Preparation forms: Danofloxacin mesylate 200g, P407 100g, Oleum Camelliae adds to 1 liter.
Preparation method: Danofloxacin mesylate is scattered in vegetable oil, with colloid mill, is ground to particle diameter and is less than 100 μ m, then with sand mill, be ground to particle diameter and be less than 1 μ m, standby through centrifugalize; P407 is made it to melt in 60-70 ℃; The medicine that above particle diameter is less than to 1 μ m joins in the P407 of thawing, mixes curingly, pulverizes, and in part Oleum Camelliae, further with colloid mill and sand mill, is ground to particle diameter and is less than 20 μ m, adds remaining media, with high-shear homogenizing machine, homogenizes and obtains this preparation.
This preparation is to pig intramuscular injection, and dosage is 6.5mg/kg b.w., and after administration 92 hours, blood drug level still maintained valid density scope (0.07-0.2 microgram/ml).
Embodiment 7, preparation 16% enrofloxacin injection
Preparation forms: enrofloxacin 160g, P407 60g, HPMC35g, IPM adds to 1 liter.
Preparation method: enrofloxacin is scattered in oil medium, with colloid mill, is ground to particle diameter and is less than 100 μ m, then with sand mill, be ground to particle diameter and be less than 1 μ m, standby through centrifugalize; By P407 and HPMC and appropriate methanol mixed, reflux is after HPMC dissolves completely, add and be ground to the enrofloxacin that particle diameter is less than 1 μ m, fully mix, methanol is removed in decompression, further with colloid mill and sand mill, be ground to particle diameter after crushed and be less than 8 μ m, add remaining media, with homogenizer, homogenize and obtain this preparation.
Embodiment 8, blood drug level detect
Select 10 of the healthy sheep of about 30kg body weight, divide at random two groups, 5 every group, the hard of hearing subcutaneous injection embodiment of portion 7 preparations and Comparative formulation (16% enrofloxacin superfine powder, 6%P407,3.5%HPMC, sterilized water adds to 100ml.Matching while using), dosage is 15mg/kg b.w., blood sampling on time, and centrifugal separation plasma, will extract after the blood plasma mixed in equal amounts with the time on the same group, adopts high pressure lipuid chromatography (HPLC) (C
18post) measure the enrofloxacin concentration in blood plasma.Experimental result is as shown in the table:
Enrofloxacin concentration in table (μ g/ml) is every group of laboratory animal plasma drug level average.Numerical value finding from table, embodiment 7 preparations have obvious slow release effect, and at P407 content etc. simultaneously, its slow release effect is better than take the preparation that water is medium.Further clinical trial, for preventing and treating sheep and goat streptococcicosis and contagious pleuropneumonia, is 15mg by per kilogram of body weight dosage, shot embodiment 7 preparations, and duration of efficacy can reach more than 3 days.
Embodiment 9, preparation 12% fumaric acid tiamulin injection
Preparation forms: fumaric acid tiamulin 120g, P407 70g, H-HPC 40g, IPM adds to 1 liter.
Preparation method: (1) by P407 in 60-70 ℃ of thawing, after adding H-HPC to mix, add the methanol that is equivalent to 3 times of amounts of fumaric acid tiamulin, after H-HPC dissolves, add fumaric acid tiamulin, after all dissolving, decompression Ex-all methanol, cooling, after solidifying, pulverize, cross 40 mesh sieves, obtain fumaric acid tiamulin/P407/H-HPC medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 10 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the fumaric acid tiamulin injection that particle diameter is less than 10 μ m.
Preliminary clinical experiment shows, this preparation is used for preventing and treating Mycoplasma ovipneumonia and mycoplasmal pneumonia of swine, Sanguis sus domestica dysentery, by per kilogram of body weight 15-20mg administration, be administered once at interval of 3 days, and administration 2-3 time, cure rate is more than 80%.
Embodiment 10, preparation 15% hydrochloric acid lincomycin injection
Preparation forms: lincomycin hydrochloride 150g, P407 100g, IPM adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds lincomycin hydrochloride and the methanol that is equivalent to 3 times of amounts of lincomycin hydrochloride by P407, after all dissolving, decompression Ex-all methanol, cooling, after solidifying, pulverize, cross 40 mesh sieves, obtain hydrochloric acid lincomycin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 10 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the lincomycin hydrochloride injection that particle diameter is less than 10 μ m.
Embodiment 11, preparation 8% Mequindox injection
Preparation forms: Mequindox 80g, P407 100g, injection soybean oil adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds particle diameter to be less than the Mequindox superfine powder of 1 μ m P407, mixes rear coolingly, pulverizes after cured, crosses 40 mesh sieves, obtains Mequindox/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part soybean oil, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 10 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the Mequindox injection that particle diameter is less than 10 μ m.
This preparation confirms through clinical experiment, for preventing and treating Sanguis sus domestica dysentery, once measures, and 7.5-10mg/kgb.w., intramuscular injection, cure rate can reach more than 90%.This preparation good biocompatibility, is particularly useful for the control of piglet dysentery.
Embodiment 12, preparation 15% florfenicol injection
Preparation forms: florfenicol 150g, P407 60g, IPM adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds P407 florfenicol and is equivalent to the acetone that florfenicol 2.5-3 doubly measures, and refluxes, after all dissolving, decompression Ex-all acetone, cooling, after solidifying, pulverize, cross 40 mesh sieves, obtain florfenicol/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 3 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the florfenicol injection that particle diameter is less than 3 μ m.
Embodiment 13, preparation 10% erythromycin injection
Preparation forms: erythromycin 100g, P40780g, IPM adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds erythromycin and the methanol that is equivalent to 2 times of amounts of erythromycin by P407, backflow, after all dissolving, decompression Ex-all methanol, cooling, curing rear pulverizing, crosses 40 mesh sieves, obtains erythromycin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 3 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the erythromycin injection that particle diameter is less than 3 μ m.
Embodiment 14, preparation 10% tilmicosin injection
Preparation forms: tilmicosin 100g, P407 80g, IPM adds to 1 liter.
Preparation method: (1) in 60-70 ℃ of thawing, adds P407 tilmicosin and is equivalent to the methanol for 2 times of amounts of meter Ke Xing, after all dissolving, distilling under reduced pressure Ex-all methanol, cooling, after solidifying, pulverize, cross 40 mesh sieves, obtain tilmicosin/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in part IPM, crossing colloid mill is ground to particle diameter and is less than 50 μ m, further with sand mill, grind, grind to particle diameter and be less than 3 μ m, add remaining media, with high-shear homogenizing machine, under about 5000rpm condition, after repeatedly homogenizing, make the tilmicosin injection that particle diameter is less than 3 μ m.
Claims (6)
1. containing a veterinary injection for antibacterials, it is characterized in that every liter of injection comprises following component:
Antibacterials 25-200g
Poloxamer188 25-150g
Oil medium adds to 1 liter
Described oil medium is a kind of in isopropyl myristate, injection soybean oil, Semen Maydis oil, Oleum Camelliae;
Described antibacterials comprise: enrofloxacin, Danofloxacin mesylate, Marbofloxacin, Mequindox, tylosin, fumaric acid tiamulin, for meter Ke Xing, tetramycin hydrochloride, colistine sulfate, Ceftiofur Hydrochloride, sulphuric acid cephalosporium quinol, gentamycin sulfate, lincomycin hydrochloride, florfenicol, erythromycin.
2. by veterinary injection claimed in claim 1, it is characterized in that can also adding hydroxypropyl emthylcellulose or the Hydroxypropylcelliloxe of 20-60g in every liter of injection.
3. by veterinary injection claimed in claim 1, it is characterized in that also can adding 0.2-2g antioxidant in every liter of injection, antioxidant is the mixture of one or more any ratios in tertiary butyl-4-hydroxy methoxybenzene, dibenzylatiooluene, propyl gallate or ascorbyl palmitate.
4. by the veterinary injection described in claim 1 or claim 3 any one, it is characterized in that antibacterials and poloxamer188 to be prepared into medicine carrying grain, then medicine carrying microgranule is scattered in oil medium, through grinding, be prepared into the oily injection containing antibacterials/poloxamer188 medicine carrying microgranule, in preparation, the weight percent content of medicine carrying microgranule is 5-35%.
5. by the veterinary injection described in claim 1-3 any one, it is characterized in that antibacterials and poloxamer188 and Hydroxypropylcelliloxe to be prepared into medicine carrying microgranule, then medicine carrying microgranule is scattered in oil medium, through grinding, is prepared into the oily injection containing antibacterials/poloxamer188/Hydroxypropylcelliloxe medicine carrying microgranule.
6. by the veterinary injection described in claim 1-3 any one, it is characterized in that antibacterials and poloxamer188 and hydroxypropyl emthylcellulose to be prepared into medicine carrying microgranule, then medicine carrying microgranule is scattered in oil medium, through grinding, is prepared into the oily injection containing antibacterials/poloxamer188/hydroxypropyl emthylcellulose medicine carrying microgranule.
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| AU2016222532B2 (en) * | 2015-02-26 | 2018-07-12 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| AU2018205137B2 (en) * | 2015-02-26 | 2019-08-08 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| US10561641B2 (en) | 2015-02-26 | 2020-02-18 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| EA035993B1 (en) * | 2015-02-26 | 2020-09-10 | Мериал, Инк. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| US11484528B2 (en) | 2015-02-26 | 2022-11-01 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| CN113288867A (en) * | 2020-02-24 | 2021-08-24 | 东莞市东阳光动物保健药品有限公司 | Marbofloxacin composition and preparation method thereof |
| CN113288867B (en) * | 2020-02-24 | 2024-04-26 | 东莞市东阳光动物保健药品有限公司 | Marbofloxacin composition and preparation method thereof |
| CN117982413A (en) * | 2024-04-03 | 2024-05-07 | 山东恒邦中科生物工程有限公司 | Preparation method of cefquinome sulfate injection |
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