CN101773470A - ivermectin submicron emulsion for injection - Google Patents
ivermectin submicron emulsion for injection Download PDFInfo
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Abstract
The invention relates to an ivermectin submicron emulsion for injection, which effectively solves the problems that the ivermectin submicron emulsion has poor stability and high toxic and side effects. The emulsion comprises the following effective components: ivermectin, vegetable oil for injection, an emulsifying agent, an assistant emulsifying agent, a stabilizing agent, an antioxygen of vitamin E and an isoosmotic adjusting agent of glycerol; the ivermectin submicron emulsion is prepared by the following steps: adding the stabilizing agent, the emulsifying agent, the ivermectin, the antioxygen of vitamin E and the vegetable oil for injection into water for injection to be dissolved; removing an organic solvent by reducing the pressure; heating and evenly stirring to obtain an oil phase; adding the assistant emulsifying agent and the isoosmotic adjusting agent of glycerol into the water or injection to be dissolved to obtain a water phase and keeping constant temperature; slowly injecting the oil phase into the water phase while stirring; rapidly stirring and adjusting the pH value with NaOH solution; homogenizing by using a homogenizer to obtain preliminary emulsion; passing the preliminary emulsion through a micro jet-flow instrument to obtain an emulsifying agent; subpackaging the emulsifying agent into a container; and then filling nitrogen gas into the container, sealing and sterilizing and inspecting to obtain the finished product. The invention has the advantages of simple preparation process, high medicine-carrying amount, stability, controllable quality and suitability for industrial production.
Description
One, technical field
The present invention relates to field of medicaments, particularly a kind of ivermectin submicron emulsion for injection.
Two, background technology
(Ivermectin is the semi-synthetic Macrolide multicomponent antibiotic that is produced by the Avid kyowamycin fermentation IVM) to ivermectin, mainly contains ivermectin B1 (B1a+B1b) and is not less than 93%, and wherein B1a must not be less than 85%.Ivermectin is novel wide spectrum, efficient, low toxicity antibiotics antiparasitic, and particularly nematicide and arthropod all have and well kill effect to endoparasite and ectoparasite.At present, have much with the antiparasitic formulations of ivermectin as effective ingredient abroad, at the international animal health-product market, ivermectin occupies first of sales volume.The also existing Duo Jia pharmaceutical factory of China produces and puts goods on the market.
Yet, what China was applied to veterinary clinic at present mainly is some ivermectin conventional formulation, the release of its medicine is undertaken by first order kinetics mostly, blood drug level rises and falls big, normal " peak valley " phenomenon that occurs, might exceed minimum poisoning concentration, and the effective blood drug concentration weak point of holding time, need repeatedly repeat administration just can reach effective therapeutic purposes.The dosage form repeat administration that has is bigger to the stimulation of animal, and stress is obvious, and it is slow that drug metabolism easily takes place, and the easier animal food Chinese medicine that causes is residual, and the influence mankind's is healthy.Medicine in the middle of environment, also has the influence that can not be ignored with feces, urine excretion to ecological balance simultaneously.
Submicron emulsion is to develop dosage form faster in the present field of medicaments; it has many characteristics, can protect encapsulated medicine, drug loading big, can improve medicine stability, prolong drug action time, reduce toxic and side effects, make medicament slow release, controlled release and have certain targeting etc.In addition, the preparation technology of submicronized emulsion is easy, be fit to suitability for industrialized production, so the injection submicron emulsion has good application prospects.Ivermectin is insoluble in water, and the injection submicron emulsion, can be used as the important carrier of poorly water-soluble or oil-soluble medicine, helps reducing untoward reaction, increases the dissolubility of medicine, better brings into play drug effect.
Open source literature 99107712.1 among the 99107713.X, discloses a kind of ivermectin micro emulsion, has all used a large amount of emulsifying agents and cosolvent in this patent prescription.It is mainly used in the green agriculture development, is used for as insect pest preventing and controlling on the crops such as fruit, vegetable, Cotton Gossypii.
In the open source literature 99111296.2, disclose a kind of animal that contains avilamycin, ivermectin or closantel sodium and used parasiticide Emulsion.This Emulsion is compound anti-parasitic Emulsion, though its parasiticide spectrum has enlarged, said preparation easily causes Drug resistance, drug residue increase, drug waste and preparation cost to increase.
In the open source literature 200810016606.9; a kind of ivermectin emulsion is disclosed; be with ivermectin and benzyl benzoate; injection vegetable oil and water for injection are mixed and made into lipomul; this Emulsion; can overcome some shortcomings of existing injection; it is big to improve the blood drug level fluctuations; reduce the partial red and swollen reaction in back; it still comes with some shortcomings: less stable for example; do not contain antioxidant in the prescription, and do not have protection of nitrogen gas in the production technology, so this Emulsion is unstable in high temperature sterilize and storage process.
In the open source literature 200810150354.9, a kind of ivermectin nanoemulsion drug combination and preparation method thereof is disclosed, a large amount of emulsifying agent (Tween-80) and cosolvent (1 have also been used in this patent prescription, the 2-propylene glycol), said preparation is after injection, local pain can occur, form lump, even local tissue necrosis takes place; Enter untoward reaction such as also can causing haemolysis in the blood, damage to animal.
For the developing ecology green agriculture, improve the safety of meat food and animal-use drug effectively, safety and compliance, therefore need a kind of safe, effective, stable, quality controllable, ivermectin preparation that toxic and side effects is low of research and development.
Three, summary of the invention
At above-mentioned situation, for overcoming the prior art defective, the present invention's purpose just provides a kind of ivermectin submicron emulsion for injection, can effectively solve the ivermectin micro emulsion poor stability, the problem that toxic and side effects is high.
Technical scheme of the present invention is, emulsion of the present invention is by containing following active component among every ml: ivermectin 1～20mg/mL, injection vegetable oil 50～200mg/mL, emulsifying agent 8～24mg/mL, co-emulsifier 1～20mg/mL, stabilizing agent 0.1～3mg/mL, antioxidant vitamin E 0.8mg/mL and isoosmotic adjusting agent glycerol 22.5mg/mL make, its preparation method is, under 55～85 ℃, earlier with stabilizing agent, emulsifying agent, ivermectin, antioxidant vitamin E and injection vegetable oil join in the organic solvent and dissolve, under 30～45 ℃, organic solvent is removed in decompression, be heated to 55～85 ℃, stir, make oil phase, insulation, standby; Under 55～85 ℃, with co-emulsifier, isoosmotic adjusting agent glycerol joins in the water for injection and dissolves, make water, the temperature of water remains under 55～85 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stir fast, regulating pH value with sodium hydroxide solution is 7.2～7.4, and through the even matter of homogenizer, even matter speed is 6000～12000rpm, time is 2～15min, make colostrum, again colostrum is crossed the microjet instrument, under the pressure of 3000～18000PSI, even matter 6～20 times, get Emulsion, be sub-packed in the container inflated with nitrogen, seal, under 115 ℃, sterilization 30min or under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention; Said bulking value is meant that solid counts with g, and liquid is with ml meter (as follows); Said injection vegetable oil is any one or the two or more mixture in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid edible oil, the olive oil; Said emulsifying agent is any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soya phosphatide, the synthetic phospholipid; Said co-emulsifier is any one in poloxamer 188, polyglycol distearate, cholesterol, the chitosan; Said stabilizing agent is any one in oleic acid, the enuatrol; Said organic solvent is any one or the two or more mixture in ethanol, methanol, chloroform, the dichloromethane.
The present invention has increased the dissolubility of medicine, prolong drug action time in vivo, and have slow-releasing and controlled-releasing action and improve the therapeutic effect of medicine, toxic and side effects reduced, preparation technology of the present invention is simple, drug loading is high, stable, quality controllable, be fit to suitability for industrialized production.
Four, the specific embodiment
Below in conjunction with practical situation the specific embodiment of the present invention is elaborated.
Provide by technical scheme, specifically implement as follows:
Embodiment 1:
Made by ivermectin 100mg, soybean oil 5000mg, soybean lecithin 800mg, poloxamer 188200mg, oleic acid 10mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is as follows:
(1), preparation oil phase: under 60 ℃, will dissolve in ivermectin, soybean oil, soybean lecithin, oleic acid and the antioxidant vitamin E adding ethanol, under 32 ℃, ethanol is removed in decompression, is heated to 60 ℃, stirs, and makes oil phase;
(2) preparation water: under 60 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 60 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.2, and through the even matter 6000rpm of homogenizer, even matter 15min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 3000PSI, even matter 20 times makes Emulsion;
(5) Emulsion is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
Embodiment 2
Made by ivermectin 100mg, soybean oil 10000mg, soybean lecithin 1200mg, poloxamer 188500mg, enuatrol 50mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 65 ℃, will dissolve in ivermectin, soybean oil, soybean lecithin, enuatrol and the antioxidant vitamin E adding methanol, under 35 ℃, methanol is removed in decompression, is heated to 65 ℃, stirs, and makes oil phase;
(2) preparation water: under 65 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 65 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.3, and through the even matter 8000rpm of homogenizer, even matter 10min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 6000PSI, even matter 15 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
Embodiment 3
Made by ivermectin 500mg, soybean oil 5000mg, olive oil 5000mg, Ovum Gallus domesticus Flavus lecithin 1600mg, polyglycol distearate 800mg, enuatrol 100mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 70 ℃, will dissolve in ivermectin, soybean oil, olive oil, Ovum Gallus domesticus Flavus lecithin, enuatrol and the antioxidant vitamin E adding chloroform, under 37 ℃, chloroform is removed in decompression, is heated to 70 ℃, stirs, and makes oil phase;
(2) preparation water: under 70 ℃, polyglycol distearate and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 70 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.4, through the even matter 5min of the even matter 10000rpm of homogenizer, makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 10000PSI, even matter 10 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
Embodiment 4
Made by ivermectin 1000mg, Oleum Ricini 15000mg, hydrogenated soya phosphatide 2000mg, cholesterol 1400mg, enuatrol 200mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 75 ℃, will dissolve in ivermectin, Oleum Ricini, hydrogenated soya phosphatide, enuatrol and the antioxidant vitamin E adding dichloromethane, under 40 ℃, dichloromethane is removed in decompression, is heated to 75 ℃, stirs, and makes oil phase;
(2) preparation water: under 75 ℃, cholesterol and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 75 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.2, and through the even matter 11000rpm of homogenizer, even matter 4min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 16000PSI, even matter 8 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
Embodiment 5
Made by ivermectin 2000mg, Oleum Camelliae 20000mg, Ovum Gallus domesticus Flavus lecithin 2000mg, hydrogenated soya phosphatide 200mg, chitosan 1800mg, oleic acid 250mg, antioxidant vitamin E 80mg, isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 80 ℃, with dissolving in ivermectin, Oleum Camelliae, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide, oleic acid and the antioxidant vitamin E adding dichloromethane, under 42 ℃, dichloromethane is removed in decompression, be heated to 80 ℃, stir, make oil phase;
(2) preparation water: under 80 ℃, chitosan and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 80 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.3, and through the even matter 11000rpm of homogenizer, even matter 4min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 16000PSI, even matter 8 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
Embodiment 6
Made by ivermectin 800mg, soybean oil 20000mg, Ovum Gallus domesticus Flavus lecithin 1200mg, soybean lecithin 1200mg, poloxamer 1882000mg, oleic acid 300mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 84 ℃, will dissolve in ivermectin, soybean oil, Ovum Gallus domesticus Flavus lecithin, soybean lecithin, oleic acid and the antioxidant vitamin E adding ethanol, under 44 ℃, ethanol is removed in decompression, is heated to 84 ℃, stirs, and makes oil phase;
(2) preparation water: under 84 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, form water;
(3) preparation colostrum: the temperature of water remains on 84 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.4, through the even matter 2min of the even matter 12000rpm of homogenizer, makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 18000PSI, even matter 6 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, at 121 ℃ of sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
The ivermectin submicron emulsion for injection of the present invention's preparation, adopt Nano-ZS90 type laser nano particle size analyzer to measure emulsion droplet particle diameter and zeta current potential, the result shows that the emulsion droplet of ivermectin submicron emulsion for injection is evenly distributed, mean diameter is 174.9nm, and average zeta current potential is-30.9mV.
Assay adopts high performance liquid chromatograph (Agilent 1100 types) to measure.Chromatographic condition: mobile phase is methanol: water=90: 10, and flow velocity 1ml/min, 30 ℃ of column temperatures detect wavelength 245nm, sample size 20 μ l.Get ivermectin submicron emulsion for injection 2mL, place the 200mL volumetric flask, add 15mL methanol, the vortex mixing makes the ivermectin submicron emulsion dissolving, is diluted to scale with methanol, shakes up, and filters.Precision is measured subsequent filtrate 20 μ L, injects chromatograph of liquid record chromatogram, as external standard, presses external standard method, with calculated by peak area with reference substance solution.The result shows that the average percentage composition of ivermectin is 98.8% in the ivermectin submicron emulsion for injection.
Regulation according to " veterinary drug stability test technical specification " Chinese medicine accelerated test is carried out stability test: three batches of ivermectin submicron emulsion for injection are placed 30 ℃, in the climatic chamber of relative humidity 60%, in the 0th, 1, took out sample in 2,3,6 months, investigate the changes of contents of outward appearance, particle diameter, pH value and the submicron emulsion Chinese medicine of Emulsion, the results are shown in Table 1.
Table-1 ivermectin submicron emulsion for injection stability test result (x ± s, n=3)
By the stability experiment result as can be known: the ivermectin submicron emulsion for injection good stability, every index all meets the requirements.
Carry out the test of ivermectin submicron emulsion for injection local irritation according to " veterinary drug experiment clinical trial technical specification ".Laboratory animal selects Mus health identical, that body weight is close in age to clean 40 of level Mus, be divided into experimental group (ivermectin submicron emulsion for injection) and matched group (commercially available common ivermectin injection) at random, subcutaneous injection administration respectively, dosage is the 0.1mg/kg body weight.Day by day observe the variation of injection site after the injection, the results are shown in Table 2.
Localized variation behind table-2 subcutaneous injections
In sum, the present invention can reduce than commercially available common ivermectin injection toxic and side effects and reaches more than 50%, have that preparation technology is simple, drug loading and stability is high, quality controllable, be fit to suitability for industrialized production, the present invention is intended to overcome the shortcoming of existing injection and lipomul, a kind of new ivermectin submicron emulsion for injection is provided, this submicron emulsion not only can be directly used in muscle and subcutaneous injection, and can be used for intravenous injection, curative effect is better than existing aqueous injection, has good safety and stability simultaneously.Intravenous injection ivermectin sub-micro can increase the dissolubility of medicine preferably, prolong drug action time in vivo, and have slow-releasing and controlled-releasing action and improve the therapeutic effect of medicine, reduce toxic and side effects.The ivermectin submicron emulsion for injection scope of application is wide, and various animal endoparasite and ectoparasites are all had the good effect of killing.
Claims (7)
1. ivermectin submicron emulsion for injection, it is characterized in that, this emulsion is by containing following active component among every ml: ivermectin 1～20mg/mL, injection vegetable oil 50～200mg/mL, emulsifying agent 8～24mg/mL, co-emulsifier 1～20mg/mL, stabilizing agent 0.1～3mg/mL, antioxidant vitamin E 0.8mg/mL and isoosmotic adjusting agent glycerol 22.5mg/mL make, its preparation method is, under 55～85 ℃, earlier with stabilizing agent, emulsifying agent, ivermectin, antioxidant vitamin E and injection vegetable oil join in the organic solvent and dissolve, under 30～45 ℃, organic solvent is removed in decompression, be heated to 55～85 ℃, stir, make oil phase, insulation, standby; Under 55～85 ℃, with co-emulsifier, isoosmotic adjusting agent glycerol joins in the water for injection and dissolves, make water, the temperature of water remains under 55～85 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stir fast, regulating pH value with sodium hydroxide solution is 7.2～7.4, and through the even matter of homogenizer, even matter speed is 6000～12000rpm, time is 2～15min, make colostrum, again colostrum is crossed the microjet instrument, under the pressure of 3000～18000PSI, even matter 6～20 times, get Emulsion, be sub-packed in the container inflated with nitrogen, seal, under 115 ℃, sterilization 30min or under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention; Said injection vegetable oil is any one or the two or more mixture in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid edible oil, the olive oil; Said emulsifying agent is any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soya phosphatide, the synthetic phospholipid; Said co-emulsifier is any one in poloxamer 188, polyglycol distearate, cholesterol, the chitosan; Said stabilizing agent is any one in oleic acid, the enuatrol; Said organic solvent is any one or the two or more mixture in ethanol, methanol, chloroform, the dichloromethane.
2. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 100mg, soybean oil 5000mg, soybean lecithin 800mg, poloxamer 188 200mg, oleic acid 10mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is as follows:
(1), preparation oil phase: under 60 ℃, will dissolve in ivermectin, soybean oil, soybean lecithin, oleic acid and the antioxidant vitamin E adding ethanol, under 32 ℃, ethanol is removed in decompression, is heated to 60 ℃, stirs, and makes oil phase;
(2) preparation water: under 60 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 60 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.2, and through the even matter 6000rpm of homogenizer, even matter 15min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 3000PSI, even matter 20 times makes Emulsion;
(5) Emulsion is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
3. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 100mg, soybean oil 10000mg, soybean lecithin 1200mg, poloxamer 188 500mg, enuatrol 50mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 65 ℃, will dissolve in ivermectin, soybean oil, soybean lecithin, enuatrol and the antioxidant vitamin E adding methanol, under 35 ℃, methanol is removed in decompression, is heated to 65 ℃, stirs, and makes oil phase;
(2) preparation water: under 65 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 65 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.3, and through the even matter 8000rpm of homogenizer, even matter 10min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 6000PSI, even matter 15 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 121 ℃, sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
4. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 500mg, soybean oil 5000mg, olive oil 5000mg, Ovum Gallus domesticus Flavus lecithin 1600mg, polyglycol distearate 800mg, enuatrol 100mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 70 ℃, will dissolve in ivermectin, soybean oil, olive oil, Ovum Gallus domesticus Flavus lecithin, enuatrol and the antioxidant vitamin E adding chloroform, under 37 ℃, chloroform is removed in decompression, is heated to 70 ℃, stirs, and makes oil phase;
(2) preparation water: under 70 ℃, polyglycol distearate and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 70 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.4, through the even matter 5min of the even matter 10000rpm of homogenizer, makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 10000PSI, even matter 10 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
5. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 1000mg, Oleum Ricini 15000mg, hydrogenated soya phosphatide 2000mg, cholesterol 1400mg, enuatrol 200mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 75 ℃, will dissolve in ivermectin, Oleum Ricini, hydrogenated soya phosphatide, enuatrol and the antioxidant vitamin E adding dichloromethane, under 40 ℃, dichloromethane is removed in decompression, is heated to 75 ℃, stirs, and makes oil phase;
(2) preparation water: under 75 ℃, cholesterol and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 75 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.2, and through the even matter 11000rpm of homogenizer, even matter 4min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 16000PSI, even matter 8 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
6. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 2000mg, Oleum Camelliae 20000mg, Ovum Gallus domesticus Flavus lecithin 2000mg, hydrogenated soya phosphatide 200mg, chitosan 1800mg, oleic acid 250mg, antioxidant vitamin E 80mg, isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 80 ℃, with dissolving in ivermectin, Oleum Camelliae, Ovum Gallus domesticus Flavus lecithin, hydrogenated soya phosphatide, oleic acid and the antioxidant vitamin E adding dichloromethane, under 42 ℃, dichloromethane is removed in decompression, be heated to 80 ℃, stir, make oil phase;
(2) preparation water: under 80 ℃, chitosan and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, make water;
(3) preparation colostrum: the temperature of water remains on 80 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.3, and through the even matter 11000rpm of homogenizer, even matter 4min makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 16000PSI, even matter 8 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, under 115 ℃, sterilization 30min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
7. ivermectin submicron emulsion for injection according to claim 1, it is characterized in that, made by ivermectin 800mg, soybean oil 20000mg, Ovum Gallus domesticus Flavus lecithin 1200mg, soybean lecithin 1200mg, poloxamer 1882000mg, oleic acid 300mg, antioxidant vitamin E 80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is:
(1) preparation oil phase: under 84 ℃, will dissolve in ivermectin, soybean oil, Ovum Gallus domesticus Flavus lecithin, soybean lecithin, oleic acid and the antioxidant vitamin E adding ethanol, under 44 ℃, ethanol is removed in decompression, is heated to 84 ℃, stirs, and makes oil phase;
(2) preparation water: under 84 ℃, poloxamer 188 and isoosmotic adjusting agent glycerol joined in the water for injection dissolve, form water;
(3) preparation colostrum: the temperature of water remains on 84 ℃ of constant temperature, while stirring oil phase slowly is injected into aqueous phase, stirs fast, and regulating pH value with sodium hydroxide solution is 7.4, through the even matter 2min of the even matter 12000rpm of homogenizer, makes colostrum;
(4) preparation of breast eventually: the colostrum that makes is crossed the microjet instrument, and under the pressure of 18000PSI, even matter 6 times makes Emulsion;
(5) Emulsion that makes is sub-packed in the container, inflated with nitrogen, sealing by fusing, at 121 ℃ of sterilization 15min, quality inspection promptly gets ivermectin submicron emulsion for injection of the present invention.
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| CN102188393A (en) * | 2011-04-29 | 2011-09-21 | 武汉大安制药有限公司 | Flurbiprofen axetil microsphere preparation |
| CN103417478A (en) * | 2012-05-18 | 2013-12-04 | 中国农业科学院兰州畜牧与兽药研究所 | Water based ivermectin O/W injection and preparation method thereof |
| CN104706592A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Oral ivermectin microemulsion concentrate and preparation method and application thereof |
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| CN114788524A (en) * | 2022-01-25 | 2022-07-26 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Bacteriostatic microemulsion preparation and preparation method and application thereof |
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| CN102188393A (en) * | 2011-04-29 | 2011-09-21 | 武汉大安制药有限公司 | Flurbiprofen axetil microsphere preparation |
| CN102188393B (en) * | 2011-04-29 | 2013-07-17 | 武汉大安制药有限公司 | Flurbiprofen axetil microsphere preparation |
| CN103417478A (en) * | 2012-05-18 | 2013-12-04 | 中国农业科学院兰州畜牧与兽药研究所 | Water based ivermectin O/W injection and preparation method thereof |
| CN103417478B (en) * | 2012-05-18 | 2014-09-10 | 中国农业科学院兰州畜牧与兽药研究所 | Water based ivermectin O/W injection and preparation method thereof |
| CN104706592A (en) * | 2013-12-16 | 2015-06-17 | 天津迈迪瑞康生物医药科技有限公司 | Oral ivermectin microemulsion concentrate and preparation method and application thereof |
| CN105213311A (en) * | 2015-11-05 | 2016-01-06 | 南阳农业职业学院 | The preparation method of diclazuril submicron emulsion |
| US10744112B2 (en) | 2016-11-24 | 2020-08-18 | Nestlé Skin Health S.A. | Composition comprising avermectin compounds without solvents and propenetrating agents of avermectin compounds |
| US10744147B2 (en) | 2016-11-24 | 2020-08-18 | Nestlé Skin Health S.A. | Composition comprising avermectin compounds without solid fatty substances |
| CN108992403A (en) * | 2018-08-31 | 2018-12-14 | 田红卫 | A kind of long-acting slow-release ivermectin injection and preparation method thereof |
| CN114788524A (en) * | 2022-01-25 | 2022-07-26 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Bacteriostatic microemulsion preparation and preparation method and application thereof |
| CN114788524B (en) * | 2022-01-25 | 2024-05-31 | 中国农业科学院烟草研究所(中国烟草总公司青州烟草研究所) | Antibacterial microemulsion preparation and preparation method and application thereof |
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