CN1421199A - Veterinary emulsion injection containing parasiticide prepared via micropowder crystallization process - Google Patents
Veterinary emulsion injection containing parasiticide prepared via micropowder crystallization process Download PDFInfo
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- CN1421199A CN1421199A CN 01140194 CN01140194A CN1421199A CN 1421199 A CN1421199 A CN 1421199A CN 01140194 CN01140194 CN 01140194 CN 01140194 A CN01140194 A CN 01140194A CN 1421199 A CN1421199 A CN 1421199A
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Abstract
The present invention is the preparation process of veterinary suspending injection containing macrobides insectifuge or N-phenyl pyrazole insectifuge. The preparation process of the oil suspending injection includes: dissolving the active compound, mixing to vegetable oil or other ester solvent through stirring, adding hydrocarbon, and stirring for some more time. The outstanding feature of the present invention is that the insectifuge has the particle size range of 0.5-5 micron, high stability, high biological utilization and obvious delay release function.
Description
Macrolide and N-phenyl pyrazoles anthelmintic are efficient, broad-spectrum anti-parasite medicine for animals.N-phenyl pyrazoles anthelmintic effective, widespread usage is fluorine worm nitrile fipronil, and it is mainly used in the control of house pet flea class parasite and cattle Ticks.Commercial Macrolide anthelmintic comprises: ivermectin ivermectin, avilamycin abamectin, Ai Purui rhzomorph eprinomectin, road draw rhzomorph doramectin, moxidectin moxidectin, they are anti-tame carcass interior lines worm and the highest, safest medicines of epizoa activity of finding up to now, the formulation products annual sales amount of this class medicine reaches 1,500,000,000 dollars more than, is first of veterinary drug individual event sales volume.Existing Macrolide anthelmintic dosage form comprises injection, powder, tablet, capsule, oral liquid, dashing agent, paste, bullet implants.Except that bolus, the control phase of other preparation, mostly about 10-30 days, bolus was a kind of in-vivo embed agent with special construction that is implanted in cattle, the sheep cud, and medicine slowly discharges through drug release hole from bullet, persistent period can reach 100 days, is a kind of long-acting slow-release preparation.But bolus administration inconvenience need special administration apparatus, and the cabinet of powder charge is trapped in the cud for a long time.
Because animal feeding such as pig, cattle, sheep or grazing habit are unhygienic, therefore, the easy repeated infection parasite of most of animals, so every year, repeatedly medication was prevented and treated, otherwise, can cause the underproduction or death.Repeatedly medication, very inconvenient, therefore, in recent years, people disclose the patent of invention of many relevant long-acting novel formulation of veterinary antiparasitic in active research exploitation long-acting veterinary parasiticide novel formulation.
Patent CN1283990T discloses a kind of long-acting veterinary injection based on castor oil hydrogenated, and hydrogenated castor wet goods hydrophobic carrier is used to prepare the durative action preparation that contains avilamycin or ivermectin, and the lasting period can reach 42 days or longer.
Patent CN1215331A discloses based on the avermectins of Oleum Ricini and the ejection preparation of milbemycin, this oil solution type injection medicine lasting period can reach 35 days (A Lifschitz et al, " Veterianryparasitology, 86:203-215).
It is the injection that contains the Macrolide anthelmintic and the dashing agent of the oil solution type of solvent preparation with vegetable oil and monohydroxy aromatic alcohol that patent WO97/11709 discloses a kind of, also is a kind of slow releasing preparation.
The slow release long-acting preparation that contains avilamycin or ivermectin---aqueous suspension and oil suspending agent have been introduced among the patent CN1241404A, durative action preparation described in this patent is different with the durative action preparation described in other disclosed patent, it is characterized in that said preparation is to be suspended in based in the medium of water or oil and the suspending agent of preparation with the solid particle state by active component, the outstanding feature of clinical drug effect is this suspensoid control phase can reach 50-100 days.Weak point is that the avilamycin that adds in the preparation or ivermectin are the microgranules less than 10 μ m that the method with micronizing is prepared into, production practices show, adopting the micronizing legal system to be equipped with particle diameter is very difficult less than avilamycin or the ivermectin microgranule of 10 μ m, and it is higher to consume energy, still need will be very expensive equipment (as super micron mill etc.), pulverize and require under the aseptic condition of strictness, to carry out, therefore, the former powder of avilamycin or ivermectin should not adopt machinery to grind or comminution by gas stream prepares superfine powder, its reason is: its powder is difficult for oven dry, and easily degrade when temperature is too high, the water of remaining minute quantity or ethanol or Methanamide equal solvent promptly cause its viscosity to increase in the former powder, this is to cause to adopt machinery to grind method or comminution by gas stream is difficult for ground main cause, like this, in production reality, the preparation particle diameter has just become to produce the key problem in technology of aqueous suspension or oil suspending agent less than 10 μ m avilamycin or ivermectin ultramicro powder.
The invention solves above technical barrier, adopt micropowder crystallization process (rapid crystallization method) preparation reactive compound ultramicro powder.The micropowder crystallization process is that reactive compound is made supersaturated solution with specific solvent under the condition of heating, abrupt temperature drop under stirring rapidly then, rapid crystallization and micropowder, also can with the solution of reactive compound under certain conditions (as temperature, stir speed (S.S.), adding speed etc.) make it to separate out crystallization rapidly and the method that makes grain by the transduction or the chemical reaction of solvent.The method need not special destructor, and the grain size of micropowder overwhelming majority is below 10 μ m, and amplitude of variation less (Lu Bin chief editor, novel pharmaceutical formulation and new technique, page 2, People's Health Publisher, 1998).
The present invention is preferential, and what adopt is under the condition of control mixing speed, reaches the purpose of rapid crystallization by secondary solvent conversion, and the outstanding feature of this method is preparation disposable the finishing in same container with the preparation of ultramicro powder and preparation.The technical process of this method is: reactive compound is dissolved with cosolvent, under the situation of strictness control mixing speed, join in an amount of vegetable oil or other Ester, again to wherein adding mineral oil (as saxol) and other auxiliary agent, can obtain oil suspending agent of the present invention afterwards.
The advantage of oil suspending agent of the present invention and preparation method thereof is: preparation method is simple, does not need the destructor of complex and expensive, and raw material does not need strict drying, and aseptic condition is easy to control, therefore, and low production cost; The particle size range of active ingredient is narrow in the preparation, mostly between 0.5-5 μ m, better stability of preparation (change of physicochemical properties such as layering and drug degradation did not take place room temperature storage in 2 years), and can obtain the different active ingredient microgranule of size by changing rotating speed or changing the mineral oil kind, can adjust the control phase length of medicine by active ingredient size or dosage in the adjustment preparation; Preparation of the present invention is used for controlling animal parasites to be infected, and the control phase can reach 50-100 days.
Implementing key of the present invention is: (1) screening to Macrocyclolactone lactone kind medicine or N-phenyl pyrazoles anthelmintic dissolubility less than 0.5% and the lipophile liquid medium that dissolves each other with vegetable oil or other grease class; (2) determine the optimal proportion of this lipophile medium and vegetable oil or other grease class; (3) strict control speed of agitator and temperature; (4) the suitable cosolvent of screening; (5), determine concentration, drug microparticles size and the dosage of active ingredient in the preparation according to different animals and desired control phase.
The preparation that contains the outstanding injection of oil of Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic of the present invention forms and preparation method is:
(1) preparation is formed:
(a) reactive compound 0.2-20% (W/V);
(b) vegetable oil or glycerol triacetate or liquid ester compounds (that extract from organism or the synthetic) 10-95% (V/V) that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol;
(c) mineral oil 0-90% (V/V);
(d) in case of necessity, can add other auxiliary agent (as water, ethanol, 1,2-propylene glycol, glycerol and other cosolvent, surfactant, suspending agent, antioxidant etc.).
(2) preparation method:
Method one: get 0.2-20 part reactive compound and antioxidant and under heating condition, make supersaturated solution with acetone or ethyl acetate or glycerol triacetate or other solvent, add 0-5 part Methanamide then, be cooled to rapidly below 30 ℃ under the stirring (greater than 500rpm) rapidly, add injection vegetable oil or mineral oil (containing or do not contain suspending agent and antioxidant) or other auxiliary agent of high temperature sterilize afterwards, continue to stir 20 minutes or the longer time, remove or do not remove and desolvate, add glycerol triacetate or saxol (containing or do not contain suspending agent) to final volume, promptly get the injection suspensoid that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
Method two: get reactive compound and antioxidant dissolves with cosolvent, join afterwards the vegetable oil that contains suspending agent that stirring or extract from organism or the synthetic liquid ester compounds solution that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol, when treating in the liquid firm appearance cotton-shaped " crystallize ", add low boiling (under the normal pressure less than 100 ℃) liquefied hydrocarbon material at once, continue to stir, after about 80% reactive compound is separated out with graininess, with suspension distilling under reduced pressure (40 ℃), remove the low boiling point hydrocarbon material that exists in the suspension, with containing or do not contain the vegetable oil of suspending agent or using the ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol that extract from organism or synthetic to transfer to final volume.
Method three: get 0.2-20 part reactive compound and under heating condition, make supersaturated solution with specific solvent, add 0-5 part Methanamide then, stirring (greater than 500rpm) rapidly down below abrupt temperature drop to 10 ℃, treat that medicine separates out 80% when above, centrifugal or filter, particle diameter less than the reactive compound micropowder of 20 μ m, this micropowder is scattered in the medium based on vegetable oil or mineral oil, promptly get oil suspending agent.
Method four: get 0.2-20 part Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic, add an amount of cosolvent dissolving, afterwards this solution is joined stir (rotating speed is greater than 100rpm) contain suspending agent and high temperature sterilize 10-80 part injection vegetable oil extract from organism or the synthetic ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol, add the mineral oil of high temperature sterilize (boiling point is greater than 100 ℃ under the normal pressure) afterwards to final volume, continue to stir 20 minutes or the longer time, remove or do not remove cosolvent, promptly get the injection oil suspending agent that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
Method five: get 0.2-20 part Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic and contain or do not contain cosolvent with 10-80 part, contain suspending agent and antioxidant high temperature sterilize vegetable oil solution or extract from organism or the synthetic ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol dissolve, under (rotating speed is greater than the 100rpm) condition of stirring, the mineral oil to 100 part that adds high temperature sterilize, continue to stir 20 minutes or the longer time, remove or do not remove cosolvent, promptly get the injection oil suspending agent that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
Vegetable oil of the present invention comprises Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum sesami, Oleum Gossypii semen, Oleum Brassicae campestris, soybean oil, Oleum Helianthi, almond oil, Oleum Ricini, peach kernel oil, olive oil, Oleum Camelliae, Oleum Cocois.Described mineral oil is by the liquefied hydrocarbon chemical compound or the mixture that refine in the oil; Described mineral oil is by hydrocarbon compound that refines in the oil or mixture; Preferred mineral oils comprises that boiling point under saxol and the normal pressure is equal to or less than 100 ℃ hydrocarbons and the hydrocarbons of fusing point in 40-95 ℃ of scope.
The cosolvent that the present invention selects comprises: contain 3 carbon above organic alcohols, aromatic alcohol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, Ethyl formate, acetone, dichloromethane, chloroform, azone and homologue thereof, pyrrolidones, amides compound and to Macrolide anthelmintic and N-phenyl pyrazoles anthelmintic dissolubility (under the normal temperature and pressure) greater than 10% and boiling point less than 100 ℃ organic compound, they can be formed cosolvent and use.The suspending agent of selecting comprises aluminium stearate, has glycerine fatty acid ester type compound, brazil wax, Cera Flava, castor oil hydrogenated and the hydrogenated vegetable oil of thickening power.The surfactant of selecting is a nonionic surfactant, and preferred surfactants is polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, alkylphenol polyoxyethylene, Oleum Ricini glymes.The antioxidant of selecting is a fat-soluble antioxidant, preferred butylated hydroxytoluene (BHT), BHA (BHA), methyl parahydroxybenzoate and propyl p-hydroxybenzoate, and the antioxidant that adds in the prescription can two or more mix use.
The preferred Macrolide anthelmintic drug of the present invention comprises: avilamycin abamectin, ivermectin ivermectin, Ai Purui rhzomorph eprinomectin, road draw rhzomorph doramectin, moxidectin moxidectin.Preferred N-phenyl pyrazoles anthelmintic is fluorine worm nitrile fipronil.
Preferred manufacturing procedure of the present invention is as follows:
(a) quantitatively get ivermectin or avilamycin or fluorine worm nitrile, antioxidant, add an amount of ethyl acetate, be heated to 60-100 ℃, ivermectin or avilamycin or fluorine worm nitrile and antioxidant are dissolved fully, must contain the ethyl acetate solution of ivermectin or avilamycin or fluorine worm nitrile and antioxidant.
(b) quantitatively get suspending agent and join in an amount of soybean oil or ethyl oleate, be heated to 55-130 ℃, make the suspending agent dissolving, must contain the soybean oil or the ethyl oleate solution of suspending agent.
(c) be that 60-75 ℃ the ethyl acetate solution that contains ivermectin or avilamycin or fluorine worm nitrile and antioxidant joins in 60-100 ℃ the soybean oil that contains suspending agent or ethyl oleate solution with temperature, to stir greater than the 50rpm rotating speed, when treating that temperature is reduced to 40-55 ℃, add saxol to 100%, and mixing speed transferred to more than the 200rpm, temperature is controlled between 5-25 ℃, continue to stir 1 hour or longer, get and do not remove the suspension of cosolvent (ethyl acetate), in 40 ℃ of these suspensions of distilling under reduced pressure, until ethyl acetate is removed substantially, then, add liquid paraffin oil subsidy to 100%, promptly get the oil suspending agent that contains ivermectin or avilamycin or fluorine worm nitrile.
The particularly preferred preparation method of the present invention is as follows:
Method one:
(a) get 5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 10 parts of ethyl acetate, heating makes the dissolving of ivermectin (or avilamycin) and antioxidant, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) get soybean oil (or ethyl oleate or Miglyol812) solution that 20-50 part contains aluminium stearate or castor oil hydrogenated and place preparing tank, be heated to 85-95 ℃, the ethyl acetate solution that more than adding under the 200-500rpm stirring condition, contains ivermectin (or avilamycin) and antioxidant, when cooling the temperature to 40-50 ℃, the saxol to 110 part that adds high temperature sterilize, cool the temperature to 5-25 ℃, continue to stir 1-2 hour, get and do not remove the suspension of ethyl acetate.
(c) suspension of step gained in 40 ℃ of distilling under reduced pressure is removed ethyl acetate, promptly gets the oil suspending agent that contains ivermectin (or avilamycin) 5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for cattle, sheep parasite control, subcutaneous injection, and every 50kg body weight injection 1-3ml, the control phase can reach 50-100 days.
Method two:
(a) get 2.5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 5 parts of azones, ivermectin and antioxidant are all dissolved, must contain the azone solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 10 parts of soybean oil (or ethyl oleate or Miglyol812) solution that contain 0.4% castor oil hydrogenated, be heated to 80-95 ℃, add the azone solution that contains ivermectin (or avilamycin) and antioxidant of going up the step gained down in the 200-500rpm stirring condition, the liquid paraffin oil solution to 100 that contains 0.4% castor oil hydrogenated part that adds high temperature sterilize afterwards, continue to stir 1-2 minute in 200-700rpm, afterwards, mixing speed is transferred to 150-250rpm, continue to stir about 1 hour in 5-20 ℃, promptly get the oil suspending agent that contains ivermectin (or avilamycin) 2.5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for the pig parasite control, subcutaneous or intramuscular injection, and every 20-25kg body weight injection 0.5-1ml, the control phase can reach 50-90 days.
Method three:
(a) get 1 part of ivermectin (or avilamycin) and proper quantity of antioxidant, add 2 parts of ethyl acetate, heating makes it dissolving, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, adding 20-50 part contains soybean oil (or ethyl oleate or Miglyol812) solution of aluminium stearate or castor oil hydrogenated, under the 200-500rpm stirring condition, add the ethyl acetate solution that contains ivermectin (or avilamycin), add saxol to 100 part afterwards, continue to stir 10-30 minute, add 100 parts of saxols containing aluminium stearate again, stirring reaction 1-2 hour, afterwards in 40 ℃ of distilling under reduced pressure, remove ethyl acetate, must contain the oil suspending agent of ivermectin (or avilamycin) 0.5%.
Said preparation is applicable to the toy parasite control, is preferred for rabbit, Canis familiaris L., piglet, lamb parasite control, subcutaneous injection, and every kg body weight injection 0.3-0.5ml, the control phase can reach more than 50 days.
With example preparation of the present invention is described below, but example do not limit the scope of the invention, scope of the present invention and core content are determined according to claims.
Example one
This example is the oil suspending agent that preparation contains ivermectin 5%.
Get ivermectin 5g, composite antioxidant 0.3g puts in the 25ml tool plug test tube, add the 10ml ethyl acetate, in 65-80 ℃ of water-bath, ivermectin and antioxidant are dissolved fully, afterwards this solution being joined temperature is that 80-95 ℃ of 50ml that is stirring contains in the soybean oil solution of 0.5g castor oil hydrogenated, when under stirring condition, making temperature reduce to 40-50 ℃, add 50ml saxol (high temperature sterilize), stirred 1-3 minute in 350rpm, afterwards, mixing speed is transferred to 150rpm, continue to stir 1 hour, must contain the suspension of ethyl acetate, this suspension temperature is controlled at 40 ℃ continue to be stirred and ethyl acetate is removed in distilling under reduced pressure, then, the suspension of removing ethyl acetate is reduced to 5-20 ℃ continue to stir 1 hour, promptly get 5% ivermectin oil suspending agent.
This preparation is used for the parazoon control, preferred cattle, sheep parasite control, and the every 50kg body weight injection of subcutaneous injection 1-3ml, the control phase is 50-100 days.
Example two
This example is the oil suspending agent that preparation contains avilamycin 2.5%.
Getting avilamycin 2.5g, composite antioxidant 0.3g puts in the 25ml tool plug test tube, add the 5ml azone, in 80-100 ℃ of water-bath, avilamycin and antioxidant are dissolved fully, afterwards this solution being joined the 20ml that is stirring contains in the soybean oil solution of 2% aluminium stearate (high temperature sterilize), add 75ml subsequently and contain saxol (high temperature sterilize) solution of 1% aluminium stearate, continue to stir 1-2 minute in 350rpm, afterwards, mixing speed is transferred to 150rpm, continue to stir 1 hour in 5-20 ℃, promptly get the oil suspending agent that contains avilamycin 2.5%.
This preparation is used for the parazoon control, is preferred for the pig parasite control, the every 20-25kg body weight injection of subcutaneous injection 0.5-1.5ml, and the control phase is 50-75 days.
Example three
This example is the oil suspending agent that preparation contains ivermectin 0.5%.
Get ivermectin 1g, composite antioxidant 0.2g puts in the 25ml tool plug test tube, add the 2ml ethyl acetate, in 65-80 ℃ of water-bath, make dissolvings such as ivermectin, afterwards this solution being joined the 30ml that is stirring contains in the soybean oil solution of 2% aluminium stearate (high temperature sterilize), add 70ml subsequently and contain saxol (high temperature sterilize) solution of 1% aluminium stearate, stirred 1-2 minute in 350rpm, after mixing speed is transferred to 150rpm, continue to stir 1 hour, afterwards the suspension temperature is controlled at 40 ℃ of distilling under reduced pressure and removes ethyl acetate, then, the suspension temperature of removing ethyl acetate is reduced to 5-20 ℃, continue to stir 1 hour, promptly get 1% ivermectin oil suspending agent.
Getting above-mentioned 1% oil suspending agent 100ml contains the soybean oil/saxol of 1% aluminium stearate with 100ml (3:7 V/V) mixes, and continues to stir about 40 minutes, promptly gets the oil suspending agent that contains ivermectin 0.5% under stirring condition.
This preparation is used for the parazoon control, is preferred for rabbit, Canis familiaris L. parasite control, the every kg body weight injection of subcutaneous injection 0.3-0.5ml, and the control phase is 50 days or longer.
Example four
The described method of this example is applicable on a large scale to be produced by batch.
(1) prescription is formed:
Ivermectin (or avilamycin) 5% (W/V)
Soybean oil or ethyl oleate or Miglyol812 30-45% (V/V)
Aluminium stearate 1-1.3% (W/V) or castor oil hydrogenated 0.3-0.5%
Composite antioxidant 0.2-0.4% (W/V)
Saxol to 100% (V/V)
(2) preparation process is:
(a) get ivermectin (or avilamycin) by above-mentioned prescription and antioxidant is put in the dissolving tank (A) with reflux, in ivermectin (or avilamycin) and ethyl acetate is the ratio of 1: 2 (W/V), in dissolving tank, add ethyl acetate, be heated to 65-80 ℃, make the dissolving of ivermectin (or avilamycin) and antioxidant, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) in the dissolving tank (B) of tool interlayer heating, quantitatively add soybean oil or ethyl oleate or Miglyol812 by above-mentioned prescription, add 1-1.3 part aluminium stearate again, be heated to 117-125 ℃, make the aluminium stearate dissolving (or add 0.3-0.5 part castor oil hydrogenated, be heated to 85 ℃ and make it dissolving), filtered while hot is removed insoluble impurity, filtrate injection is had the preparing tank of vacuum distillation apparatus, make it to be cooled to 60-95 ℃, under (100-200rpm) condition of stirring, add the above-mentioned ethyl acetate solution that contains ivermectin (or avilamycin) and antioxidant, adjust solution temperature, when making it to drop to 42-47 ℃, the saxol to 110 part that adds high temperature sterilize, and speed of agitator is adjusted to 400-500rpm, continue to stir 5 minutes, rotating speed being transferred to 150-250rpm stirred 1 hour again, suspension is heated to 35-40 ℃ afterwards, the ethyl acetate in the suspension is removed in distilling under reduced pressure, then, this product of aseptic packaging gets final product.
Claims (8)
1, a kind of preparation contains the new method of the outstanding injection of oil of Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic, it is characterized in that preparation is formed and preparation method is:
(1) preparation is formed:
(a) reactive compound 0.2-20% (W/V);
(b) vegetable oil or glycerol triacetate or liquid ester compounds (that extract from organism or the synthetic) 10-95% (V/V) that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol;
(c) mineral oil 0-90% (V/V);
(d) in case of necessity, can add other auxiliary agent (as water, ethanol, 1,2-propylene glycol, glycerol and other cosolvent, surfactant, suspending agent, antioxidant etc.).
(2) preparation method:
Method one: get 0.2-20 part reactive compound and antioxidant and under heating condition, make supersaturated solution with acetone or ethyl acetate or glycerol triacetate or other solvent, add 0-5 part Methanamide then, be cooled to rapidly below 30 ℃ under the stirring (greater than 500rpm) rapidly, add injection vegetable oil or mineral oil (containing or do not contain suspending agent and antioxidant) or other auxiliary agent of high temperature sterilize afterwards, continue to stir 20 minutes or the longer time, remove or do not remove and desolvate, add glycerol triacetate or saxol (containing or do not contain suspending agent) to final volume, promptly get the injection suspensoid that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
Method two: get reactive compound and antioxidant dissolves with cosolvent, join afterwards the vegetable oil that contains suspending agent that stirring or extract from organism or the synthetic liquid ester compounds solution that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol, when treating in the liquid firm appearance cotton-shaped " crystallize ", add low boiling (under the normal pressure less than 100 ℃) liquefied hydrocarbon material at once, continue to stir, after about 80% reactive compound is separated out with graininess, with suspension distilling under reduced pressure (40 ℃), remove the low boiling point hydrocarbon material that exists in the suspension, transfer to final volume with the vegetable oil that contains or do not contain suspending agent or with the ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol that derive from organism or synthetic.
Method three: get 0.2-20 part reactive compound and under heating condition, make supersaturated solution with specific solvent, add 0-5 part Methanamide then, stirring (greater than 500rpm) rapidly down below abrupt temperature drop to 10 ℃, treat that medicine separates out 80% when above, centrifugal or filter, particle diameter less than the reactive compound micropowder of 20 μ m, this micropowder is scattered in the medium based on vegetable oil or mineral oil, promptly get oil suspending agent.
Method four: get 0.2-20 part Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic, add an amount of cosolvent dissolving, afterwards this solution is joined stir (rotating speed is greater than 100rpm) contain suspending agent and high temperature sterilize 10-80 part injection vegetable oil extract from organism or the synthetic ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol, add the mineral oil of high temperature sterilize (boiling point is greater than 100 ℃ under the normal pressure) afterwards to final volume, continue to stir 20 minutes or the longer time, remove or do not remove cosolvent, promptly get the injection oil suspending agent that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
Method five: get 0.2-20 part Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic and contain or do not contain cosolvent with 10-80 part, contain suspending agent and antioxidant high temperature sterilize vegetable oil solution or extract from organism or the synthetic ester type compound that forms by 7 above organic acid of carbon and monohydric alcohol or propylene glycol or glycerol dissolve, under (rotating speed is greater than the 100rpm) condition of stirring, the mineral oil to 100 part that adds high temperature sterilize, continue to stir 20 minutes or the longer time, remove or do not remove cosolvent, promptly get the injection oil suspending agent that contains Macrolide anthelmintic or N-phenyl pyrazoles anthelmintic.
2, by the described preparation of claim 1, it is characterized in that: (1) described vegetable oil comprises Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum sesami, Oleum Gossypii semen, Oleum Brassicae campestris, soybean oil, Oleum Helianthi, almond oil, Oleum Ricini, peach kernel oil, olive oil, Oleum Camelliae, Oleum Cocois.(2) described mineral oil is by hydrocarbon compound that refines in the oil or mixture; Preferred mineral oils comprises that boiling point under saxol and the normal pressure is equal to or less than 100 ℃ hydrocarbons and the hydrocarbons of fusing point in 40-95 ℃ of scope.
3, by the described preparation of claim 1, it is characterized in that preferred cosolvent comprises: contain 3 carbon above organic alcohols, aromatic alcohol, ethyl acetate, methyl acetate, propyl acetate, butyl acetate, Ethyl formate, acetone, dichloromethane, chloroform, azone and homologue thereof, pyrrolidones, amides compound and to Macrolide anthelmintic and N-phenyl pyrazoles anthelmintic dissolubility (under the normal temperature and pressure) greater than 10% and boiling point less than 100 ℃ organic compound, they can be formed cosolvent and use.The suspending agent of selecting comprises aluminium stearate, has glycerine fatty acid ester type compound, brazil wax, Cera Flava, castor oil hydrogenated and the hydrogenated vegetable oil of thickening power.The surfactant of selecting is a nonionic surfactant, and preferred surfactants is polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, alkylphenol polyoxyethylene, Oleum Ricini glymes.The antioxidant of selecting is a fat-soluble antioxidant, preferred butylated hydroxytoluene (BHT), BHA (BHA), methyl parahydroxybenzoate and propyl p-hydroxybenzoate, and the antioxidant that adds in the prescription can two or more mix use.
4, by the described preparation of claim 1, it is characterized in that preferred Macrolide anthelmintic drug comprises: avilamycin abamectin, ivermectin ivermectin, Ai Purui rhzomorph eprinomectin, road draw rhzomorph doramectin, moxidectin moxidectin.Preferred N-phenyl pyrazoles anthelmintic is fluorine worm nitrile fipronil.
5, by the described preparation of claim 1, it is characterized in that preferred manufacturing procedure is as follows:
(a) quantitatively get ivermectin or avilamycin or fluorine worm nitrile, antioxidant, add an amount of ethyl acetate, be heated to 60-100 ℃, ivermectin or avilamycin or fluorine worm nitrile and antioxidant are dissolved fully, must contain the ethyl acetate solution of ivermectin or avilamycin or fluorine worm nitrile and antioxidant.
(b) quantitatively get suspending agent and join in an amount of soybean oil or ethyl oleate, be heated to 55-130 ℃, make the suspending agent dissolving, must contain the soybean oil or the ethyl oleate solution of suspending agent.
(c) be that 60-75 ℃ the ethyl acetate solution that contains ivermectin or avilamycin or fluorine worm nitrile and antioxidant joins in 60-100 ℃ the soybean oil that contains suspending agent or ethyl oleate solution with temperature, to stir greater than the 50rpm rotating speed, when treating that temperature is reduced to 40-55 ℃, add saxol to 100%, and mixing speed transferred to more than the 200rpm, temperature is controlled between 5-25 ℃, continue to stir 1 hour or longer, get and do not remove the suspension of cosolvent (ethyl acetate), in 40 ℃ of these suspensions of distilling under reduced pressure, until ethyl acetate is removed substantially, then, add liquid paraffin oil subsidy to 100%, promptly get the oil suspending agent that contains ivermectin or avilamycin or fluorine worm nitrile.
6, by the described preparation of claim 1, it is characterized in that particularly preferred preparation method is as follows:
Method one:
(a) get 5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 10 parts of ethyl acetate, heating makes the dissolving of ivermectin (or avilamycin) and antioxidant, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) get 50 parts of soybean oil solution that contain 2% aluminium stearate (or 0.8-1% castor oil hydrogenated) and place preparing tank, be heated to 85-95 ℃, the ethyl acetate solution that more than adding under the 200-500rpm stirring condition, contains ivermectin (or avilamycin) and antioxidant, when cooling the temperature to 40-50 ℃, the saxol to 110 part that adds high temperature sterilize, cool the temperature to 5-25 ℃, continue to stir 1-2 hour, get and do not remove the suspension of ethyl acetate.
(c) suspension of step gained in 40 ℃ of distilling under reduced pressure is removed ethyl acetate, promptly gets the oil suspending agent that contains ivermectin (or avilamycin) 5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for cattle, sheep parasite control, subcutaneous injection, and every 50kg body weight injection 1-3ml, the control phase can reach 50-120 days.
Method two:
(a) get 2.5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 5 parts of azones, ivermectin and antioxidant are all dissolved, must contain the azone solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 10 parts of soybean oil solution that contain 0.4% castor oil hydrogenated, be heated to 80-95 ℃, add the azone solution that contains ivermectin (or avilamycin) and antioxidant of going up the step gained down in the 200-500rpm stirring condition, the liquid paraffin oil solution to 100 that contains 0.4% castor oil hydrogenated part that adds high temperature sterilize afterwards, continue to stir 1-2 minute in 200-700rpm, afterwards, mixing speed is transferred to 150-250rpm, continue to stir about 1 hour in 5-20 ℃, promptly get the oil suspending agent that contains ivermectin (or avilamycin) 2.5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for the pig parasite control, subcutaneous or intramuscular injection, and every 20-25kg body weight injection 0.5-1ml, the control phase can reach 50-90 days.
Method three:
(a) get 1 part of ivermectin (or avilamycin) and proper quantity of antioxidant, add 2 parts of ethyl acetate, heating makes it dissolving, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 30 parts of soybean oil solution that contain 1% aluminium stearate (or 0.8-1% castor oil hydrogenated), under the 200-500rpm stirring condition, add the ethyl acetate solution that contains ivermectin (or avilamycin), add the liquid paraffin oil solution to 100 part contain 1% aluminium stearate afterwards, continue to stir 10-30 minute, add 100 parts of saxols containing 1% aluminium stearate again, stirring reaction 1-2 hour, afterwards in 40 ℃ of distilling under reduced pressure, remove ethyl acetate, must contain the oil suspending agent of ivermectin (or avilamycin) 0.5%.
Said preparation is applicable to the toy parasite control, is preferred for rabbit, Canis familiaris L., piglet, lamb parasite control, subcutaneous injection, and every kg body weight injection 0.3-0.5ml, the control phase can reach more than 50 days.
7, by the described preparation of claim 1, it is characterized in that particularly preferred preparation method is as follows:
Method one:
(a) get 5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 10 parts of ethyl acetate, heating makes the dissolving of ivermectin (or avilamycin) and antioxidant, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) get 40 parts of ethyl oleate solution that contain 2% aluminium stearate (or 0.8-1% castor oil hydrogenated) and place preparing tank, be heated to 85-95 ℃, the ethyl acetate solution that more than adding under the 200-500rpm stirring condition, contains ivermectin (or avilamycin) and antioxidant, when cooling the temperature to 40-50 ℃, the saxol to 110 part that adds high temperature sterilize, cool the temperature to 5-25 ℃, continue to stir 1-2 hour, get and do not remove the suspension of ethyl acetate.
(c) suspension of step gained in 40 ℃ of distilling under reduced pressure is removed ethyl acetate, promptly gets the oil suspending agent that contains ivermectin (or avilamycin) 5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for cattle, sheep parasite control, subcutaneous injection, and every 50kg body weight injection 1-3ml, the control phase can reach 50-120 days.
Method two:
(a) get 2.5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 5 parts of azones, ivermectin (or avilamycin) and antioxidant are all dissolved, must contain the azone solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 10 parts of ethyl oleate solution that contain 0.4% castor oil hydrogenated, be heated to 80-95 ℃, add the azone solution that contains ivermectin (or avilamycin) and antioxidant of going up the step gained down in the 200-500rpm stirring condition, the liquid paraffin oil solution to 100 that contains 0.4% castor oil hydrogenated part that adds high temperature sterilize afterwards, continue to stir 1-2 minute in 200-700rpm, afterwards, mixing speed is transferred to 150-250rpm, continue to stir about 1 hour in 5-20 ℃, promptly get the oil suspending agent that contains ivermectin (or avilamycin) 2.5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for the pig parasite control, subcutaneous or intramuscular injection, and every 20-25kg body weight injection 0.5-1ml, the control phase can reach 50-90 days.
Method three:
(a) get 1 part of ivermectin (or avilamycin) and proper quantity of antioxidant, add 2 parts of ethyl acetate, heating makes it dissolving, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 30 parts of ethyl oleate solution that contain 1% aluminium stearate (or 0.8-1% castor oil hydrogenated), under the 200-500rpm stirring condition, add the ethyl acetate solution that contains ivermectin (or avilamycin), add the liquid paraffin oil solution to 100 part contain 1% aluminium stearate afterwards, continue to stir 10-30 minute, add 100 parts of saxols containing 1% aluminium stearate again, stirring reaction 1-2 hour, afterwards in 40 ℃ of distilling under reduced pressure, remove ethyl acetate, must contain the oil suspending agent of ivermectin (or avilamycin) 0.5%.
Said preparation is applicable to the toy parasite control, is preferred for rabbit, Canis familiaris L., piglet, lamb parasite control, subcutaneous injection, and every kg body weight injection 0.3-0.5ml, the control phase can reach more than 50 days.
8, by the described preparation of claim 1, it is characterized in that particularly preferred preparation method is as follows:
Method one:
(a) get 5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 10 parts of ethyl acetate, heating makes the dissolving of ivermectin (or avilamycin) and antioxidant, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) get triglyceride or the propylene glycol caprylate/decanoin solution that 20-50 part contains the medium chain of aluminium stearate or castor oil hydrogenated and place preparing tank, be heated to 85-95 ℃, the ethyl acetate solution that more than adding under the 200-500rpm stirring condition, contains ivermectin (or avilamycin) and antioxidant, when cooling the temperature to 40-50 ℃, the saxol to 110 part that adds high temperature sterilize, cool the temperature to 5-25 ℃, continue to stir 1-2 hour, get and do not remove the suspension of ethyl acetate.
(c) suspension of step gained in 40 ℃ of distilling under reduced pressure is removed ethyl acetate, promptly gets the oil suspending agent that contains ivermectin (or avilamycin) 5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for cattle, sheep parasite control, subcutaneous injection, and every 50kg body weight injection 1-3ml, the control phase can reach 50-120 days.
Method two:
(a) get 2.5 parts of ivermectins (or avilamycin) and proper quantity of antioxidant, add 5 parts of azones, ivermectin (or avilamycin) and antioxidant are all dissolved, must contain the azone solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, add 10 parts of triglyceride or propylene glycol caprylate/decanoin solution that contain the medium chain of 0.4% castor oil hydrogenated, heating 80-95 ℃ 2, add the azone solution that contains ivermectin (or avilamycin) and antioxidant of going up the step gained down in the 200-500rpm stirring condition, the liquid paraffin oil solution to 100 that contains 0.4% castor oil hydrogenated part that adds high temperature sterilize afterwards, continue to stir 1-2 minute in 200-700rpm, afterwards, mixing speed is transferred to 150-250rpm, continue to stir about 1 hour in 5-20 ℃, promptly get the oil suspending agent that contains ivermectin (or avilamycin) 2.5%.
Said preparation is used for pig, cattle, sheep parasite control, is preferred for the pig parasite control, subcutaneous or intramuscular injection, and every 20-25kg body weight injection 0.5-1ml, the control phase can reach 50-90 days.
Method three:
(a) get 1 part of ivermectin (or avilamycin) and proper quantity of antioxidant, add 2 parts of ethyl acetate, heating makes it dissolving, must contain the ethyl acetate solution of ivermectin (or avilamycin) and antioxidant.
(b) in the preparation container, adding 20-50 part contains the triglyceride or the propylene glycol caprylate/decanoin solution of the medium chain of aluminium stearate or castor oil hydrogenated, under the 200-500rpm stirring condition, add the ethyl acetate solution that contains ivermectin (or avilamycin), add the saxol to 100 part contain 1% aluminium stearate afterwards, continue to stir 10-30 minute, add 100 parts of saxols containing 1% aluminium stearate again, stirring reaction 1-2 hour, afterwards in 40 ℃ of distilling under reduced pressure, remove ethyl acetate, must contain the oil suspending agent of ivermectin (or avilamycin) 0.5%.
Said preparation is applicable to the toy parasite control, is preferred for rabbit, Canis familiaris L., piglet, lamb parasite control, subcutaneous injection, and every kg body weight injection 0.3-0.5ml, the control phase can reach more than 50 days.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01140194 CN1421199A (en) | 2001-11-29 | 2001-11-29 | Veterinary emulsion injection containing parasiticide prepared via micropowder crystallization process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01140194 CN1421199A (en) | 2001-11-29 | 2001-11-29 | Veterinary emulsion injection containing parasiticide prepared via micropowder crystallization process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1421199A true CN1421199A (en) | 2003-06-04 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 01140194 Pending CN1421199A (en) | 2001-11-29 | 2001-11-29 | Veterinary emulsion injection containing parasiticide prepared via micropowder crystallization process |
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| Country | Link |
|---|---|
| CN (1) | CN1421199A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008072985A2 (en) * | 2006-12-13 | 2008-06-19 | Bomac Research Limited | Pour on formulation |
-
2001
- 2001-11-29 CN CN 01140194 patent/CN1421199A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008072985A2 (en) * | 2006-12-13 | 2008-06-19 | Bomac Research Limited | Pour on formulation |
| WO2008072985A3 (en) * | 2006-12-13 | 2008-08-28 | Bomac Research Ltd | Pour on formulation |
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