CN105213311A - The preparation method of diclazuril submicron emulsion - Google Patents
The preparation method of diclazuril submicron emulsion Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of diclazuril submicron emulsion, it is characterized in that, this emulsion contains following active component by every mL: diclazuril 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 vitamins E? 0.8mg/mL and isoosmotic adjusting agent glycerol 22.5mg/mL.The diclazuril submicron emulsion utilizing the present invention to prepare, provide one and be more applicable for animal and use veterinary drug preparation, its preparation method is simple, duration of efficacy compared with long, toxic and side effects is little, application prospect is extensive.It uses existing new equipment, new technology, improve existing traditional processing technology, make production process more efficient, quick, be convenient to promote.
Description
Technical field
The present invention relates to field of veterinary medicine preparation, particularly a kind of preparation method of diclazuril submicron emulsion.
Background technology
Diclazuril (Diclazuril) belongs to triazine benzene acetonitrile platform thing by diclazuril, is novel, efficient, low toxicity anticoccidial drug, is widely used in chicken coccidiosis.
Diclazuril Anti-human globulin test mechanism is also not clear.To the coccidiosis Main Function peak phase, different with the different genera of coccidiosis, as to the sexual cycle of Eimeria tenella Main Function point 2nd generation schizont coccidiosis.But to huge, E.brunetti schizont is invalid.To the zygote stage of Eimeria maxima application point coccidiosis; Have efficiently the E.brunetti microgametophyte stage.A ground gram ball profit also has inhibitory action to formation Sporulated Oocysts.
At present, commercially available diclazuril preparation comprises the preparations such as diclazuril pre-mixing agent, solution of diclazuril, because diclazuril is almost insoluble in water, when preparing solution of diclazuril, need to add a large amount of organic solvents and carry out hydrotropy, the organic solvent of use comprises propylene glycol, glycerin methylal, dimethyl acetylamide etc., its consumption is 40% ~ 90%, there is large usage quantity, toxic and side effects strengthens, and production cost is higher, thus add aquaculture cost; And diclazuril pre-mixing agent by feedstuff with certain drug level concentration administration, gastronintestinal system obstacle or the animal of being off one's feed are difficult to use.The dosage forms such as traditional solution, pre-mixing agent have been difficult to development and the needs of satisfied present animal husbandry, therefore need a kind of safe, effective, quality controllable, new formulation that toxic and side effects is low.
In some diclazuril conventional formulation of China's veterinary clinic application, the release of its medicine is undertaken by first order kinetics mostly, blood drug level rises and falls large, normal appearance " peak valley " phenomenon, likely exceed minimum poisoning concentration, and effective blood drug concentration is held time short, need repeatedly repeat administration just can reach effective therapeutic purposes.Some dosage form repeat administrations are comparatively large to the stimulation of animal, and stress is obvious, and it is slow that drug metabolism easily occurs, and more easily causes animal food drug residue, affect the healthy of the mankind.Medicine is with in the middle of feces, urine drains to environment simultaneously, ecological balance is also had to the impact that can not be ignored.
Submicron emulsion develops dosage form faster in current field of medicaments; it has many features, can protect encapsulated medicine, drug loading large, medicine stability, prolong drug action time can be improved, reduce toxic and side effects, make medicament slow release, controlled release and there is certain targeting etc.In addition, the preparation technology of submicronized emulsion is easy, and be applicable to suitability for industrialized production, therefore diclazuril submicron emulsion has good application prospect.Diclazuril is insoluble in water, and submicron emulsion for oral use, can be used as the important carrier of poorly water-soluble or oil-soluble medicine, be conducive to reducing untoward reaction, increase the dissolubility of medicine, better play drug effect.
In order to developing ecology green agriculture, improve effective, safety and the compliance of the safety of processed meat food stuff and animal-use drug, therefore need to research and develop a kind of safe, effective, stable, quality controllable, diclazuril preparation that toxic and side effects is low.
Summary of the invention
The object of the present invention is just to provide a kind of diclazuril submicron emulsion for oral use, can effectively solve the problems such as solution of diclazuril poor stability, duration of efficacy is short, toxic and side effects is strong, meanwhile, also provide a kind of preparation method of diclazuril submicron emulsion.
For achieving the above object, the technical solution used in the present invention is:
The main component of diclazuril submicron emulsion of the present invention comprises: the compositions such as diclazuril, vegetable oil, emulsifying agent, co-emulsifier, antioxidant, antiseptic, thickening agent, purified water.
Its configuration proportion has: diclazuril 0.1 ~ 1%, vegetable oil 4 ~ 10%, emulsifying agent 4 ~ 10%, co-emulsifier 2 ~ 5%, antioxidant 0.2 ~ 0.5%, antiseptic 0.1 ~ 0.5%, organic solvent 2.5 ~ 5%, thickening agent 0.2 ~ 1%, adjustment reagent 0.5 ~ 1%, purified water 50 ~ 80%.
The preparation method of diclazuril submicron emulsion of the present invention:
First diclazuril is dissolved in organic solvent, adds adjustment reagent, make it dissolve completely, for subsequent use; Thickening agent, co-emulsifier are added in purified water, makes aqueous phase, for subsequent use; Again antioxidant, emulsifying agent are added in vegetable oil, make oil phase, oil phase is slowly injected in aqueous phase under remaining on 55 ~ 85 DEG C of constant temperature by temperature while stirring, stir, the liquid being dissolved with diclazuril is added, stir, this solution is added in colloid mill, with the rotating speed of 5000 turns/min, grinding 30min, and constantly reflux, make colostric fluid.After taking-up, antiseptic is added in emulsion with after appropriate dissolution with solvents respectively, then adds the capacity of appropriate purified water to regulation, make whole emulsion, colostric fluid is put into high pressure dispersing emulsification machine, under 3.089X104KPa pressure, breast even twice, makes Emulsion, through after the assay was approved, be sub-packed in vial or plastic bottle, sealing, to obtain final product.
Described vegetable oil is any one or two or more mixture of Oleum Camelliae, soybean oil, Oleum Sesami, Oleum Gossypii semen; Described emulsifying agent be Tween-60, tween 80, Si Ban-60, span-80 any one; Described co-emulsifier be glycerol, propylene glycol, n-butyl alcohol any one; Described thickening agent is any one in sodium carboxymethyl cellulose, microcrystalline Cellulose; Described antiseptic is any one in P-hydroxybenzoic acid, ethylparaben, methyl parahydroxybenzoate; Described antioxidant is vitamin E, and described organic solvent is dimethyl sulfoxine; Described adjustment reagent is any one in ethanolamine, triethanolamine.
Diclazuril submicron emulsion prepared by the present invention has obvious advantage compared with conventional formulation: 1. improve the stability of medicine, add the dissolubility of medicine.2. reduce the consumption of organic solvent, reduce toxic and side effects, reduce environmental pollution.3. improve drug absorption rate, reduce dosage.4. medicine in vivo can slow releasing, improves the therapeutic effect of medicine.5. there is obvious targeting, directly act on intestinal, and target site drug level can be improved.6. invention formulation can be watered use, and dosage easily controls, and is watered, and there will not be precipitation or crystalline polamer, can not block drinking-water system.7. preparation technology of the present invention is simple, and drug loading is high, quality controllable, is applicable to industrialization and large-scale production.
Diclazuril submicron emulsion prepared by the present invention, adopt Nano-ZS90 type laser nano particle size analyzer to measure emulsion droplet size and zeta current potential, result shows, and the emulsion droplet of diclazuril submicron emulsion is evenly distributed, mean diameter is 485.3nm, and average zeta current potential is-74.5mv.
According to the regulation of " veterinary drug stability test technical specification " pharmaceutical formulations accelerated test, carry out stability test, three batches of diclazuril submicron emulsion are placed in temperature is 40 ± 2 DEG C, relative humidity is the climatic chamber of 75 ± 5%, in the 0th, 1,2,3,4,5,6 month sampling and measuring respectively, investigate the outward appearance of Emulsion, particle diameter, pH value and content, the results are shown in Table 1.
Content assaying method: according to high effective liquid chromatography for measuring.
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, and acetonitrile-0.2% phosphoric acid (57: 43) is mobile phase, and determined wavelength is 280nm.Number of theoretical plate calculates should be not less than 1500 by diclazuril.
It is appropriate, accurately weighed that algoscopy gets this product, adds dimethyl formamide and make the solution about containing 0.1mg in every 1ml, be measured in the same method, by external standard method with calculated by peak area; Separately get this product, its relative density of Simultaneously test, is converted into ml number by test sample amount, calculates, to obtain final product.
Table-1 diclazuril submicron emulsion stability test result
| Time (moon) | Character | PH value | Particle diameter | Content % |
| 0 | Milky uniform liquid, without layering | 7.63 | 485.9 | 99.6 |
| 1 | Milky uniform liquid, without layering | 7.57 | 490.3 | 99.0 |
| 2 | Milky uniform liquid, without layering | 7.61 | 489.2 | 98.9 |
| 3 | Milky uniform liquid, without layering | 7.58 | 481.7 | 98.6 |
| 4 | Milky uniform liquid, without layering | 7.67 | 482.5 | 98.0 |
| 5 | Milky uniform liquid, without layering | 7.70 | 487.4 | 98.1 |
| 6 | Milky uniform liquid, without layering | 7.81 | 482.0 | 97.9 |
The clinical trial of the diclazuril submicron emulsion adopting the present invention to prepare.
Diclazuril submicron emulsion is tested the therapeutic effect of chicken coccidiosis:
Chicken coccidiosis is a kind of parasitic disease very harmful to poultry husbandry.The loss that the whole world causes because of chicken coccidiosis every year reaches more than 10 hundred million dollars, and wherein the consumption of anticoccidial drug year is 3.2 hundred million dollars.In the market, coccidiostat is of a great variety and complicated, diclazuril as a kind of wide spectrum, the anticoccidial drug that efficient, cost is low deeply by utilization rate in the in vitro tests of the favor diclazuril of raiser less than 10%, living animal test also demonstrates this point.Therefore, the anticoccidial effect how improving coccidiostat is an extremely important problem.
1 EXPERIMENTAL DESIGN
Buy 1 age in days healthy chick, the feedstuff of feeding not containing any anticoccidial drug.Raise to 14 ages in days, the healthy chicken of weight differences within 10g is selected by only weighing, be divided into 5 groups, often organize each 50,1st, 2 groups are respectively not administration and do not attack worm matched group and infect not administration group, 3rd, 4,5 groups are respectively test group, are respectively diclazuril Emulsion group, diclazuril pre-mixing agent group, solution of diclazuril group.Administration from after infection the 3rd day, continuous 5 days.
Except blank group, each test group every chickling gavages the random capsule 1.0 × 10 of Eimeria Necatrix Sporulated at grouping crop on the same day
5individual, every day observed and recorded chicken spirit, dipsa, appetite, feces situation and death toll etc.After infecting the 5th, 6,7,8 day morning carried out hemafecia to each group and score.Within 8th day, each component another name weighs, cuts open and kill whole chicken, observes small intestinal pathological changes, and carries out egg capsule counting in small intestinal.
2 result of the tests
After artificial challenge the 4th day, infect not administration group and occur that a small amount of feedstuff just or Fructus Lycopersici esculenti sample feces, obviously, performance spirit was depressed, loss of appetite in chicken morbidity, but does not have chicken dead.Within 5th day, the abnormal feces quantity of chicken is many and serious, and chicken starts to occur death.Diclazuril pre-mixing agent group and solution of diclazuril group mental status difference and diet reduce, and diclazuril Emulsion group is searched for food and drunk water all normal, and the mental status is good.
Diclazuril Emulsion treatment artificial infection chicken Eimeria Necatrix curative effect index
Result of the test shows, there is not the symptom of infection small intestinal coccidiosis in the diclazuril Emulsion group of recommended dose, survival rate is 100%, and body weight increase rate is up to 98.3%, and small intestinal has no egg capsule, its anticoccidial index, up to 184.9, is all better than diclazuril pre-mixing agent group and solution of diclazuril group.Show that the dosage form by changing diclazuril medicine can obtain desirable anticoccidial effect.
The clinical trial of 3 pairs of clinical natural infection small intestinal coccidiosiss
The chicken group 12 being infected to coccidiosis tests, chicken draws Fructus Lycopersici esculenti sample, fish intestines sample or feedstuff sample feces, and chemical examination is dissected to sick chicken, determine coccidium infection, but it is subjects that intestinal can't detect again clostridium, 4 chicken groups are one group, carry out contrast test respectively with diclazuril Emulsion, diclazuril pre-mixing agent, solution of diclazuril.
Result display uses 4 chicken groups of diclazuril Emulsion, after being finished, the feces of the 2nd day chicken group takes a turn for the better, within 3rd day, recover normal, cure rate reaches 96.2%, use taking a turn for the better to some extent the 3rd day or the 4th day feces respectively of diclazuril pre-mixing agent and solution of diclazuril, until the 5th day chicken group just recovers normally, cure rate is respectively 86.7% and 82.5%.
In sum, the anticoccidial index of diclazuril Emulsion to chicken small intestinal coccidiosis artificial challenge of recommended dose is greater than 180, belong to efficient anticoccidial drug, clinical trial natural infection chicken group cure rate is up to 96.2%, therefore the clinical treatment for chicken coccidiosis, diclazuril Emulsion is a kind of anticoccidial dosage form efficiently.
4 discuss
Diclazuril belongs to the derivant of benzene acetonitrile, acts on coccidiosis schizogony and Sporogony stage, and anticoccidial effect is fine, and residual concentration is low in the tissue, without the need to drug withdrawal before butchering.
This result of study shows, and diclazuril Emulsion infects the coccidiosis caused control to chicken Eimeria has significant curative effect.Due to the restriction of diclazuril dosage form, cause diclazuril bioavailability low.Diclazuril Emulsion, by the change of dosage form, substantially increases the absorbability of medicine at intestinal epithelial cell, diclazuril is absorbed rapidly, arrives site of action fast and controls coccidiosis breeding, suppress coccidiosis to the damage of intestinal mucosa, thus promote physical recovery.Therefore, diclazuril Emulsion is as a kind of new dosage form, and clinical effectiveness is very definite, has broad application prospects at treatment coccidiosis.
Detailed description of the invention
Below in conjunction with practical situation, the specific embodiment of the present invention is elaborated.
Embodiment 1:
(1) formula:
Diclazuril 0.1g, Oleum Camelliae 4ml, Tween-60 5ml, propylene glycol 2ml, vitamin E 0.3ml, methyl parahydroxybenzoate 0.1g, sodium carboxymethyl cellulose 0.2g, dimethyl sulfoxine 3ml, ethanolamine 0.5ml, ethanol 2ml, purified water add to 100ml.
(2) preparation technology:
1. get dimethyl sulfoxine, be heated to 50 DEG C, add diclazuril, stir, add ethanolamine, stir and make it dissolve completely, for subsequent use;
2. get vitamin E and Tween-60, add in Oleum Camelliae respectively, stir, make oil phase, for subsequent use;
3. add in purified water by sodium carboxymethyl cellulose, water temperature controls at 80 ~ 90 DEG C, stirs and makes it be uniformly dissolved, then added by propylene glycol, stir, make aqueous phase, for subsequent use;
4. first will 2. described liquid add in colloid mill, with the rotating speed of 5000 turns/min, grinding 5min, then will 3. described liquid put into wherein, mixed grinding 5min, after will 1. described liquid add wherein, mixed grinding 30min, after taking-up, is colostric fluid.
5. methyl parahydroxybenzoate is added after dissolving in ethanol, add in 4. described colostric fluid, then add the capacity of appropriate purified water to regulation, make whole emulsion.
6. by 5. described whole emulsion, put into high pressure dispersing emulsification machine, under 0.2 ~ 0.3MPa pressure, breast even twice, makes emulsion, through after the assay was approved, is sub-packed in vial or plastic bottle, and sealing, to obtain final product.
Embodiment 2
(1) formula:
Diclazuril 0.5g, soybean oil 6ml, tween 80 8ml, glycerol 5ml, vitamin E 0.4ml, ethylparaben 0.1g, sodium carboxymethyl cellulose 0.4g, dimethyl sulfoxine 4ml, triethanolamine 0.6ml, ethanol 2ml, purified water add to 100ml.
(2) preparation technology:
1. get dimethyl sulfoxine, be heated to 50 DEG C, add diclazuril, stir, add triethanolamine, stir and make it dissolve completely, for subsequent use;
2. get vitamin E and tween 80, add in soybean oil respectively, stir, make oil phase, for subsequent use;
3. add in purified water by sodium carboxymethyl cellulose, water temperature controls at 80 ~ 90 DEG C, stirs and makes it be uniformly dissolved, then added by glycerol, stir, make aqueous phase, for subsequent use;
4. first will 2. described liquid add in colloid mill, with the rotating speed of 5000 turns/min, grinding 5min, then will 3. described liquid put into wherein, mixed grinding 5min, after will 1. described liquid add wherein, mixed grinding 30min, after taking-up, is colostric fluid.
5. ethylparaben is added after dissolving in ethanol, add in 4. described colostric fluid, then add the capacity of appropriate purified water to regulation, make whole emulsion.
6. by 5. described whole emulsion, put into high pressure dispersing emulsification machine, under 0.2 ~ 0.3MPa pressure, breast even twice, makes emulsion, through after the assay was approved, is sub-packed in vial or plastic bottle, and sealing, to obtain final product.
Embodiment 3
(1) formula:
Diclazuril 0.6g, Oleum Gossypii semen 6ml, Tween-60 8ml, glycerol 5ml, vitamin E 0.4ml, methyl parahydroxybenzoate 0.2g, sodium carboxymethyl cellulose 0.4g, dimethyl sulfoxine 4ml, ethanolamine 0.6ml, ethanol 2ml, purified water add to 100ml.
(2) preparation technology:
1. get dimethyl sulfoxine, be heated to 50 DEG C, add diclazuril, stir, add ethanolamine, stir and make it dissolve completely, for subsequent use;
2. get vitamin E and Tween-60, add in Oleum Gossypii semen respectively, stir, make oil phase, for subsequent use;
3. add in purified water by sodium carboxymethyl cellulose, water temperature controls at 80 ~ 90 DEG C, stirs and makes it be uniformly dissolved, then added by glycerol, stir, make aqueous phase, for subsequent use;
4. first will 2. described liquid add in colloid mill, with the rotating speed of 5000 turns/min, grinding 5min, then will 3. described liquid put into wherein, mixed grinding 5min, after will 1. described liquid add wherein, mixed grinding 30min, after taking-up, is colostric fluid.
5. methyl parahydroxybenzoate is added after dissolving in ethanol, add in 4. described colostric fluid, then add the capacity of appropriate purified water to regulation, make whole emulsion.
6. by 5. described whole emulsion, put into high pressure dispersing emulsification machine, under 0.2 ~ 0.3MPa pressure, breast even twice, makes emulsion, through after the assay was approved, is sub-packed in vial or plastic bottle, and sealing, to obtain final product.
Embodiment 4
(1) formula:
Diclazuril 1g, Oleum Sesami 10ml, tween 80 10ml, glycerol 5ml, vitamin E 0.5ml, ethylparaben 0.4g, sodium carboxymethyl cellulose 0.8g, dimethyl sulfoxine 5ml, ethanolamine 1ml, ethanol 2ml, purified water add to 100ml.
(2) preparation technology:
1. get dimethyl sulfoxine, be heated to 50 DEG C, add diclazuril, stir, add ethanolamine, stir and make it dissolve completely, for subsequent use;
2. get vitamin E and tween 80, add in soybean oil respectively, stir, make oil phase, for subsequent use;
3. add in purified water by sodium carboxymethyl cellulose, water temperature controls at 80 ~ 90 DEG C, stirs and makes it be uniformly dissolved, then added by glycerol, stir, make aqueous phase, for subsequent use;
4. first will 2. described liquid add in colloid mill, with the rotating speed of 5000 turns/min, grinding 5min, then will 3. described liquid put into wherein, mixed grinding 5min, after will 1. described liquid add wherein, mixed grinding 30min, after taking-up, is colostric fluid.
5. ethylparaben is added after dissolving in ethanol, add in 4. described colostric fluid, then add the capacity of appropriate purified water to regulation, make whole emulsion.
6. by 5. described whole emulsion, put into high pressure dispersing emulsification machine, under 0.2 ~ 0.3MPa pressure, breast even twice, makes emulsion, through after the assay was approved, is sub-packed in vial or plastic bottle, and sealing, to obtain final product.
Each case study on implementation is above to further explanation of the present invention, in actual production process, is not violating under prerequisite of the present invention, adjustment that can be suitable.
Claims (2)
1. the preparation method of a diclazuril submicron emulsion, it is characterized in that, this emulsion contains following active component by every mL: diclazuril 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 vitamins E0.8mg/mL and isoosmotic adjusting agent glycerol 22.5mg/mL makes, its preparation method is: at 55 ~ 85 DEG C, first by stabilizing agent, emulsifying agent, diclazuril, antioxidant vitamins E and injection vegetable oil join in organic solvent and dissolve, at 30 ~ 45 DEG C, decompression removing organic solvent, be heated to 55 ~ 85 DEG C, stir, make oil phase, insulation, for subsequent use, at 55 ~ 85 DEG C, by co-emulsifier, isoosmotic adjusting agent glycerol joins in water for injection and dissolves, make aqueous phase, under the temperature of aqueous phase remains on 55 ~ 85 DEG C of constant temperature, while stirring oil phase is slowly injected in aqueous phase, rapid stirring, be 7.0 ~ 8.0 by sodium hydroxide solution adjust ph, homogeneous through homogenizer, homogeneous speed is 6000 ~ 12000rpm, time is 2 ~ 15min, obtained colostrum, again colostrum is crossed microjet instrument, 3000 ~ 18000 [, under the pressure of sI, homogeneous 6 ~ 20 times, obtain Emulsion, be sub-packed in container, inflated with nitrogen, sealing, at 115 DEG C, sterilizing 30min or at 121 DEG C, sterilizing 15min, inspection, obtain diclazuril submicron emulsion of the present invention, described injection vegetable oil is any one or two or more mixtures in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid edible oil, olive oil, described emulsifying agent is any one in Ovum Gallus domesticus Flavus lecithin, soybean lecithin, hydrogenated soya phosphatide, synthetic phospholipid, described co-emulsifier is any one in PLURONICS F87, polyglycol distearate, cholesterol, chitosan, described stabilizing agent is any one in oleic acid, enuatrol, described organic solvent is any one or two or more mixtures in ethanol, methanol, chloroform, dichloromethane.
2. diclazuril submicron emulsion according to claim 1, it is characterized in that, be made up of diclazuril 100mg, soybean oil 5000mg, soybean lecithin 800mg, PLURONICS F87 200mg, oleic acid 10mg, antioxidant vitamins E80mg and isoosmotic adjusting agent glycerol 2250mg, its preparation method is as follows:
(1) prepare oil phase: at 60 DEG C, diclazuril, soybean oil, soybean lecithin, oleic acid and antioxidant vitamins E are added in ethanol and dissolve, at 32 DEG C, decompression removing ethanol, is heated to 60 DEG C, stirs, make oil phase;
(2) prepare aqueous phase: at 60 DEG C, PLURONICS F87 and isoosmotic adjusting agent glycerol are joined in water for injection and dissolves, make aqueous phase;
(3) colostrum is prepared: the temperature of aqueous phase remains on 60 DEG C of constant temperature, is slowly injected in aqueous phase by oil phase while stirring, rapid stirring, is 7.2 by sodium hydroxide solution adjust ph, through the homogeneous 6000rpm of homogenizer, homogeneous 15min, obtained colostrum;
(4) newborn eventually preparation: obtained colostrum is crossed microjet instrument, homogeneous 20 times, obtained Emulsion;
(5) be sub-packed in container by Emulsion, inflated with nitrogen, sealing by fusing, at 121 DEG C, sterilizing 15min, quality inspection, obtains diclazuril submicron emulsion of the present invention.
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Application publication date: 20160106 |