CN102133173B - Moxidectin pour sprinkling preparation and preparation method thereof - Google Patents
Moxidectin pour sprinkling preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a novel and environmental-friendly Moxidectin pour sprinkling preparation and an industrialized preparation method thereof. The pour sprinkling preparation developed in the invention is prepared by taking Moxidectin as an active ingredient for resisting parasites inside and out of animals and adding an appropriate amount of auxiliaries, such as an antioxidant, a trandermal absorbent, an adhesive, an oil solvent and the like; and the formulation of the preparation is the oily pour sprinkling preparation and belongs to the field of novel veterinary medicinal antiparasitic preparations. The pour sprinkling preparation does not contain an aromatic compound with a low flash point and the potential safety hazard in industrial production. In order to improve medicinal effect, the trandermal absorbent is selected through an in-vitro trandermal absorption test so as to improve the bioavailability of the Moxidectin pour sprinkling preparation in the animals. The environmental-friendly Moxidectin pour sprinkling preparation which has a long-term effect, and is safe and easy to industrially produce is prepared finally.
Description
Technical field
The present invention relates to the preparation of ectoparasite disease in a kind for the treatment of and the prevention animal body, particularly, the present invention relates to a kind of moxidectin dashing agent and industrialized preparation method thereof of novel environment friendly.
Background technology
The same ivermectin of moxidectin (Moxidectin) (Ivermetin) is the same with avilamycin (Avermectin), being a kind of wide spectrum of veterinary clinic, efficient, novel Macrolide anthelmintic antibiotic of being widely used at present, is a member in milbemycin (Milbemycin) family.Structural formula is as follows:
The difference of moxidectin (Moxidectin) and other Macrolide antiparasitic ivermectins (Ivermetin) and avilamycin (Avermectin) is that it is that single component has higher anthelmintic activity and the characteristic such as long-acting, safe, and the endoparasite and ectoparasites activity such as very strong nematicide and arthropod are just arranged under the very low dose.Moxidectin has the anti-anthelmintic activity of wide spectrum, has the expeling of height active to the nematicide of dog, cattle, sheep and horse and arthropodan parasite.US Patent No. 4916154A has protected this chemical compound.In order to be used for clinical treatment, this chemical compound is made different dosage forms by drug preparation technique, such as injection, and dashing agent.
And the moxidectin dashing agent be by the US6514951 patent protection of the U.S. rich road animal health company application prepare the preparation method of moxidectin dashing agent with aromatic hydrocarbon.This patent has utilized 15% aromatic hydrocarbon solvent, has prepared
Pour On.The strong solubility of aromatic hydrocarbon is
Pour On has increased preparation technology's ease for operation, but the toxicity of aromatic hydrocarbon is large, and abnormal smells from the patient is large, and flash-point low (about 40 ℃) is volatile, and the shortcoming such as set off an explosion easily.Give all toxic and potential safety hazards of producers, user and target animals.China's aromatic hydrocarbon solvent in pharmaceutically application seldom causes aromatic hydrocarbon solvent purity, the quality of China and abroad compares to be still waiting to improve in addition, and it is not only uneconomical therefore to utilize aromatic hydrocarbon to prepare the moxidectin dashing agent, nor environmental protection is dangerous.
In view of above shortcoming, difficult and aromatic hydrocarbon toxicity and the shortcoming such as set off an explosion easily for the dissolving that overcomes Process configuration.We seek new approach, find by a large amount of and test of many times screening, by adding short cutaneous permeable agent isopropyl myristate and binding agent polyisobutylene or polybutene, just can prepare the respond well moxidectin dashing agent of Transdermal absorption.This test is to produce with the U.S. rich road animal health company
Dashing agent be reference substance, utilize Transdermal absorption test to carry out prescription screening, select to produce according to the rich road of dashing agent Transdermal absorption effect and the U.S. animal health company that is patent formulation of the present invention
The suitable Recipe of Transdermal absorption effect of Pour On.
Summary of the invention
Purpose of the present invention: the moxidectin dashing agent that a kind of novel environment friendly is provided on the one hand.
The present invention realizes by following technical proposal:
The moxidectin dashing agent of this patent invention, it contains moxidectin, antioxidant, isopropyl myristate, polyisobutylene or polybutene, oil solvent.
The moxidectin dashing agent of this patent invention does not contain toxic large, flash-point low (about 40 ℃), the volatile arene compound that sets off an explosion easily.
The moxidectin dashing agent of this patent invention, for aromatic hydrocarbon toxicity and the shortcoming such as set off an explosion easily, we seek new approach, find by a large amount of and test of many times screening, add short cutaneous permeable agent isopropyl myristate and binding agent polyisobutylene or polybutene, just can prepare the respond well moxidectin dashing agent of Transdermal absorption (see Table 1, accompanying drawing 1).The moxidectin dashing agent for preparing among the present invention is that the molecular weight of application food stage is polyisobutylene or the polybutene of 1000-2500.In moxidectin dashing agent prescription, polyisobutylene or polybutene play sustained-release matrix, the effect of protection sustained release, simultaneously, prevent that the medicine that rainy weather pours in animals from being washed out by rainwater.The medicine single administration, drug effect can continue 40 days.Slow release effect is seen (table 6, accompanying drawing 2)
The moxidectin dashing agent of this patent invention, isopropyl myristate account for the amount preferably 1%～50% in the prescription, and described percentage amounts is weight and percent by volume, and unit is g/ml.
The moxidectin dashing agent of this patent invention can be selected polyisobutylene or the polybutene of different molecular weight, and preferred molecular weight is 1000～2500 polyisobutylene or polybutene.The amount of polyisobutylene or polybutene is to adjust according to its molecular weight is different, it is preferably measured with ratio: the amount that the polyisobutylene of molecular weight 1000～1900 or polybutene account for total prescription is 5%～30%, wherein percent is quality and percent by volume, unit is g/ml, with the preferred proportion of isopropyl myristate be 1: 5～10: 1; The amount that the polyisobutylene of molecular weight 1900～2500 or polybutene account for total prescription is 5%～20%, and wherein percent is quality and percent by volume, and unit is g/ml, with the preferred proportion of isopropyl myristate be 1: 10～5: 1.
The moxidectin dashing agent of this patent invention, the molecular weight of polyisobutylene or polybutene is more preferably 2100～2300, is 8%～12% in total amount of filling a prescription, and wherein percent is quality and percent by volume, unit is g/ml, with the more preferably ratio of isopropyl myristate be 1: 2～2: 1.
The moxidectin dashing agent of this patent invention, one or more in the preferred propyl gallate of wherein said antioxidant, dibenzylatiooluene, butylhydroxy anisole, the tertiarybutylhydroquinone, more preferably butylhydroxy anisole.
The moxidectin dashing agent of this patent invention, wherein said antioxidant also can comprise the reinforcing agent of antioxidant, wherein the preferred anhydrous citric acid of the reinforcing agent of antioxidant.
The moxidectin dashing agent of this patent invention, wherein said oil solvent preferred liquid paraffin, soybean oil, Oleum Ricini, Oleum Gossypii semen, ethyl oleate, median chain triglyceride oil, more preferably median chain triglyceride oil.
The moxidectin dashing agent of this patent invention is convenient to observe whether administration of animal for clinical practice, avoids repeat administration or omits medication, also can contain a kind of pigment.Seeking a kind of pigment must dissolve in oil, will consider that simultaneously target animals is to the sensitivity of color.Preferred violet, Oil Violet, lemon yellow, sunset yellow, more excellent Oil Violet.
According to the invention technical scheme, the consisting of of this patent invention moxidectin dashing agent:
Surplus is oil solvent, and wherein percent is quality and percent by volume, and unit is g/ml.
Convenient for clinical application, distinguish administration group and non-administered group.This patent invention preparation forms also can add a kind of pigment, so the composition of patent of the present invention can also be:
Surplus is oil solvent, and wherein percent is quality and percent by volume, and unit is g/ml.
Particularly, the optimization preparation of the moxidectin dashing agent of this patent invention consists of:
Surplus is median chain triglyceride oil, and wherein percent is quality and percent by volume, and unit is g/ml.
Another aspect of the present invention purpose: a kind of preparation method of moxidectin dashing agent is provided, may further comprise the steps:
A. moxidectin is mixed with antioxidant, add and stir fully dissolving in the oil solvent, for subsequent use;
B. polyisobutylene or polybutene are added fully dissolving of stirring in the oil solvent;
C. choose the adding pigment wantonly, pigment is added in the oil solvent dissolve;
D. with the solution of steps A gained or with the solution of steps A, C gained add stir fully dissolving in the B solution after, in mixed liquor, add isopropyl myristate, stirring and dissolving is with the oil solvent standardize solution and get final product.
The moxidectin dashing agent of this patent invention is to be applied to prevent and treat the inside and outside parasite of animal body.
Therefore, can find out from above technical characterstic, but this patent invention provides a kind of moxidectin dashing agent and industrialized preparation method thereof that is not subjected to weather effect slow release long-acting, the clinical environmental protection of being convenient to observe.
Advantage of the present invention:
The present invention utilizes and adds short cutaneous permeable agent isopropyl myristate and binding agent polyisobutylene or polybutene, select simultaneously the molecular weight of polyisobutylene or polybutene and adjust both ratio, substituted aromatic hydrocarbon, the shortcoming such as improved aromatic hydrocarbon toxicity and set off an explosion easily can prepare the respond well moxidectin dashing agent of Transdermal absorption equally.
Description of drawings
Fig. 1: moxidectin dashing agent penetration curve
Time meta-moxidectin concentration scatterplot in Fig. 2: embodiment 4 and the matched group plasma sample
The specific embodiment
The present invention is further illustrated below in conjunction with specific embodiment.Should be noted that prescription related among the embodiment and consumption are for this patent and unrestricted patent better are described.Related prescription and consumption all should be subject to the protection of this patent in an embodiment.
Embodiment 1: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 5g |
| Tertiarybutylhydroquinone | 0.5g |
| Anhydrous citric acid | 0.5g |
| Isopropyl myristate | 50.0g |
| Polyisobutylene (molecular weight 2400) | 15.0g |
| Oil Violet | 0.06g |
| Median chain triglyceride oil | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 5g Antiparasitic Activity material moxidectin, 0.5g tertiarybutylhydroquinone and 0.5g anhydrous citric acid mix homogeneously after, join while stirring and make its dissolving in the 10ml median chain triglyceride oil;
2) polyisobutylene that takes by weighing 15.0g joins the median chain triglyceride oil of 10ml, adds while stirring, and stirring and dissolving is to clear;
3) then take by weighing the Oil Violet of 0.06g, the median chain triglyceride oil dissolve complete that joins 3ml is stirred on the limit;
4) with step 1) and 3) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
5) take by weighing the 50.0g isopropyl myristate and join step 4) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with median chain triglyceride oil and stir and got final product in 10 minutes.
Embodiment 2: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 0.1g |
| Butylhydroxy anisole | 0.02g |
| Isopropyl myristate | 30.0g |
| Polybutene (molecular weight 1900) | 8.0g |
| Oil Violet | 0.01g |
| Liquid paraffin | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 0.1g Antiparasitic Activity material moxidectin, 0.02g butylhydroxy anisole mix homogeneously after, join while stirring and make its dissolving among the 10ml in the liquid paraffin;
2) polybutene that takes by weighing 8.0g joins the liquid paraffin of 10ml, adds while stirring, and stirring and dissolving is to clear;
3) then take by weighing the Oil Violet of 0.01g, the liquid paraffin dissolve complete that joins 3ml is stirred on the limit;
4) with step 1) and 3) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
5) take by weighing the 30.0g isopropyl myristate and join step 4) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with liquid paraffin and stir and got final product in 10 minutes.
Embodiment 3: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 2.0g |
| Tertiarybutylhydroquinone | 0.1g |
| Isopropyl myristate | 20.0g |
| Polyisobutylene (molecular weight 1300) | 20.0g |
| Oleum Gossypii semen | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 2.0g Antiparasitic Activity material moxidectin, 0.1g tertiarybutylhydroquinone mix homogeneously after, join while stirring and make its dissolving among the 8ml in the Oleum Gossypii semen;
2) polyisobutylene that takes by weighing 20.0g joins the Oleum Gossypii semen of 15ml, adds while stirring, and stirring and dissolving is to clear;
3) with step 1) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
4) take by weighing the 20.0g isopropyl myristate and join step 3) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with Oleum Gossypii semen and stir and got final product in 10 minutes.
Embodiment 4: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 0.5g |
| Butylhydroxy anisole | 0.10g |
| Anhydrous citric acid | 0.01g |
| Isopropyl myristate | 15.0g |
| Polyisobutylene (molecular weight 2100) | 10.0g |
| Oil Violet | 0.02g |
| Median chain triglyceride oil | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 0.5g Antiparasitic Activity material moxidectin, 0.10g butylhydroxy anisole and 0.01g anhydrous citric acid mix homogeneously after, join while stirring and make its dissolving in the 5ml median chain triglyceride oil;
2) polyisobutylene that takes by weighing 10.0g joins the median chain triglyceride oil of 10ml, adds while stirring, and stirring and dissolving is to clear;
3) then take by weighing the Oil Violet of 0.02g, the median chain triglyceride oil dissolve complete that joins 3ml is stirred on the limit;
4) with step 1) and 3) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
5) take by weighing the 15.0g isopropyl myristate and join step 4) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with median chain triglyceride oil and stir and got final product in 10 minutes.
Embodiment 5: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 0.4g |
| Tertiarybutylhydroquinone | 0.04g |
| Isopropyl myristate | 15.0g |
| Polybutene (molecular weight 1300) | 25.0g |
| Median chain triglyceride oil | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 0.4g Antiparasitic Activity material moxidectin, 0.04g tertiarybutylhydroquinone mix homogeneously after, join while stirring and make its dissolving in the 8ml median chain triglyceride oil;
2) polybutene that takes by weighing 25.0g joins the median chain triglyceride oil of 15ml, adds while stirring, and stirring and dissolving is to clear;
3) with step 1) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
4) take by weighing the 15.0g isopropyl myristate and join step 3) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with median chain triglyceride oil and stir and got final product in 10 minutes.
Embodiment 6: preparation moxidectin dashing agent
| Supplementary material | Consumption |
| Moxidectin | 0.5g |
| Butylhydroxy anisole | 0.05g |
| Anhydrous citric acid | 0.05g |
| Isopropyl myristate | 3.0g |
| Polybutene (molecular weight 1000) | 5.0g |
| Oil Violet | 0.01g |
| Median chain triglyceride oil | Add to 100ml |
Prepare the moxidectin dashing agent with method of the present invention, concrete grammar may further comprise the steps:
1) take by weighing 0.5g Antiparasitic Activity material moxidectin, 0.05g butylhydroxy anisole and 0.05g anhydrous citric acid mix homogeneously after, join while stirring and make its dissolving in the 5ml median chain triglyceride oil;
2) polybutene that takes by weighing 5.0g joins the median chain triglyceride oil of 5ml, adds while stirring, and stirring and dissolving is to clear;
3) then take by weighing the Oil Violet of 0.01g, the median chain triglyceride oil dissolve complete that joins 2ml is stirred on the limit;
4) with step 1) and 3) solution prepared joins step 2) solution in, stir 0.5 hour mix homogeneously;
5) take by weighing the 3.0g isopropyl myristate and join step 4) solution stirring that disposes 1 hour, leave standstill 10 minutes after, be settled to 100ml with median chain triglyceride oil and stir and got final product in 10 minutes.
The present invention utilizes the Transdermal absorption test that the designed rich road of moxidectin dashing agent embodiment 1-6 prescription and U.S. animal health company is produced when prescription screening
Pour On (commercially available) does contrast, carries out the Transdermal absorption test.
Experimental result sees table 1, Fig. 1 for details.
Table 1 moxidectin dashing agent Transdermal absorption result of the test
Experimental technique is to select SD rat abdomen skin, and the ethanol normal saline of configuration 30% utilizes YRJ-B type drug transdermal diffusion test instrument to test acquired results as acceptable solution.The result shows that the accumulative total infiltration capacity of the accumulative total infiltration capacity of utilizing the prepared embodiment 1-6 of the present invention prescription and reference substance is suitable, illustrate that embodiment 1-6 fills a prescription and external consistent transdermal effect arranged with reference substance.
In order further to verify the effect of this patent invention product, select the dashing agent of embodiment 4 to carry out clinical experiment, and with
Pour On (commercially available) compares preparation, contrasts the clinical effectiveness of the two.
One, vermin test-bomb fly test
1. test drug
Test drug: moxidectin dashing agent of the present invention (embodiment 4).
Street drug: external group, trade name CYDECTIN, content 0.5%, U.S. Fort Dodge Animal Health, Iowa, USA, lot number: 26865.
2. test method
Step for a long time the town from Forage Land In Guoluo Prefecture Dari County, Qinghai Province and overstate that heat herds the yak group that committee can herd, select Young Yaks totally 100 wherein 0.5～0.7 years old cattle is 62 for examination, cattle was 38 in 1.5 years old.To test Niu Suiji and be divided into 5 groups, 20 every group, grouping is as follows with the administration situation:
Embodiment 4 low dose group pour administration by 0.25mg/kg body weight dosage along ox back center line skin;
Dosage group among the embodiment 4 pours administration by 0.5mg/kg body weight dosage along ox back center line skin;
Embodiment 4 high dose group pour administration by 1.0mg/kg body weight dosage along ox back center line skin;
Commercially available dashing agent matched group pours administration by 0.5mg/kg body weight dosage along ox back center line skin;
Not administration matched group, not administration.
In late October, 2009, measure the body chi by head before the dispensing of drug test group cattle, with following formula calculating body weight and dosage, respectively 2 kinds of medicines are poured by head along dorsal line by design dosage, and pursue head and make a mark, still to do as everybody else does on former grassland after the dispensing and herd, not administration matched group cattle gives placebo.Body weight (kg)=[chest measurement (m) 2 * software italic (m)/10800] * 0.85
After in late October, 2009 administration, in mid-March, 2010 (after the administration 5 months) and late May (after the administration 7 months) check that respectively organizing the yak skin of back has or not tumor bleb and worm channel, according to increase and decrease, the disappearance situation of tumor bleb and worm channel, result of calculation is estimated prevention effect as follows.
Cure rate (%)=(the cattle number is not cured in the positive cattle number-administration of matched group)/matched group cattle number * 100%
Deworming rates (%)=(matched group tumor bleb average-test group tumor bleb average)/matched group tumor bleb average * 100%
3. result of the test
Moxidectin dashing agent of the present invention (embodiment 4) is driven away yak warble 3, May check result and is seen Table respectively 2 and table 3.
Each test group of table 2 March (after the administration 5 months) bomb fly check result
Each test group of table 3 May (after the administration 7 months) bomb fly check result
From above-mentioned table 2, can find out in table 3 tables of data that moxidectin dashing agent of the present invention has good killing effect to bomb fly.Moxidectin dashing agent of the present invention high (1.0mg/kg body weight), in (0.5mg/kg body weight), low (0.25mg/kg body weight) dosage group the killing rate of bomb fly in the body is 100%, effect and commercially available dashing agent (0.5mg/kg body weight) are quite.
Two, endoparasite---yak gastrointestinal nematode and thread lungworm clinical trial
1. test drug
Test drug: moxidectin dashing agent of the present invention (embodiment 4).
Contrast medicine: commercially available dashing agent, trade name CYDECTIN, content 0.5%, U.S. Fort Dodge AnimalHealth, Iowa, USA, lot number: 26865.
2. test method
From the yak group that Long Rigan village, Moeller town, Qilian County, Qinghai Province herds, before administration, gathered the excrement sample in 1-2 days, carry out faecal egg and larva and check that choose 15 years old calf of 60 nematode infections positives and test, the calf body weight is 97～123.5kg.To test cattle and be divided at random 5 groups by worm's ovum and larva check result, 12 every group, grouping is as follows with the administration situation:
Embodiment 4 low dose group pour administration by 0.25mg/kg body weight dosage along ox back center line skin;
Dosage group among the embodiment 4 pours administration by 0.5mg/kg body weight dosage along ox back center line skin;
Embodiment 4 high dose group pour administration by 1.0mg/kg body weight dosage along ox back center line skin;
Commercially available dashing agent matched group pours administration by 0.5mg/kg body weight dosage along ox back center line skin;
Not administration matched group, not administration.
The the 7th, 14,21,28,35,42,49,56,63 day each group test cattle rectum adopted excrement after the administration same day (0 day, before the administration) and the administration, and each excrement sample is counted the EPG of line eggs in the feces with the Cecil McMaster method of counting; Check thread lungworm first phase larva with Bel's Man method.The statistics gastrointestinal nematode worm's ovum and the thread lungworm first phase larva.After the administration 16～18 days, cut open among the inspection embodiment 4 respectively 4 of dosage group (0.5mg/kg dosage group), commercially available dashing agent matched group (dosage 0.5mg/kg) and not administration matched group yaks, add up routinely anthelminthic effect.
Effect is judged: according to respectively organizing worm's ovum (larva) situation of change of cattle manure in just before and after the anthelmintic, calculate as follows anthelminthic effect: the front positive cattle number of worm's ovum (larva) negative conversion rate=(positive cattle number after front the positive cattle number-anthelmintic of anthelmintic) ÷ anthelmintic * 100%
Group worm's ovum number * 100% before worm's ovum (larva) slip=(organizing the worm's ovum number after the number-anthelmintic of group worm's ovum before the anthelmintic) ÷ anthelmintic
Count situation of change according to respectively organizing the cattle nematicide before and after the anthelmintic, calculate as follows anthelminthic effect:
Relative deworming rates=(not administration group nematicide number-administration group nematicide number) not administration of ÷ group nematicide number * 100%
3. result of the test
3.1 feces center line egg count result
Moxidectin dashing agent of the present invention (embodiment 4) is driven away gastrointestinal nematode, checks that worm's ovum the results are shown in Table 4 in the feces.
Each experimental group feces center line egg count result of table 4
Data can be found out from table 4, pour moxidectin dashing agent of the present invention (embodiment 4) from after the administration the 7th day for the yak back, can obviously lower the output of line eggs in the feces.Wherein moxidectin dashing agent of the present invention (embodiment 4) high dose group is after administration 14-42 days, and Redution of eggs reaches more than 90% in the feces; The dosage group is after administration 14-35 days in the moxidectin dashing agent of the present invention (embodiment 4), and Redution of eggs reaches (the 28th day worm's ovum slip is 89.20% after the administration, near 90%) more than 90% in the feces; Moxidectin dashing agent of the present invention (embodiment 4) low dose group is compared with not administration matched group, and the worm's ovum number obviously reduces, and Redution of eggs maintains in the 45%-89% scope in 7-63 days after administration.Commercially available dashing agent matched group after administration 14-35 days, Redution of eggs reaches more than 90% in the feces; Therefore the dosage group is suitable with commercially available dashing agent treatment of control group effect in the moxidectin dashing agent of the present invention (embodiment 4).
3.2 thread lungworm larva check result
Moxidectin dashing agent of the present invention (embodiment 4) is driven away thread lungworm, checks that the thread lungworm larva the results are shown in Table 5.
Each experimental group thread lungworm larva count results of table 5
Data can be found out from table 5, pour moxidectin dashing agent of the present invention (embodiment 4) from after the administration the 7th day for the yak back, can obviously lower the quantity of thread lungworm larva in the feces.Wherein, moxidectin dashing agent of the present invention (embodiment 4) is high, middle dosage group and commercially available dashing agent matched group after administration 14-63 days, and thread lungworm larva slip maintains 100% in the feces; Compare with not administration matched group, moxidectin dashing agent of the present invention (embodiment 4) low dose group thread lungworm larva number obviously reduces, and after administration 21-42 days, thread lungworm larva slip was 100%.Moxidectin dashing agent of the present invention (embodiment 4) high dose group is significantly better than commercially available dashing agent matched group, and moxidectin dashing agent of the present invention (embodiment 4) low dose group is suitable with commercially available dashing agent matched group insecticidal effect.
Three, pharmacokinetic
1. experimental animal
10 the healthy black-and-white flower lactating cows in cattle farm, Hebei, body weight is 500-600kg, the age is 3-5 year.The test milch cow is milked in cowshed, searches for food, and milks every day 2 times, distinguishes in the morning and evening, and the rear free choice feeding of milking is put in sports ground after searching for food.Freely drink water.The blood sampling testing result shows and does not detect moxidectin in the blood plasma before on-test.
2. experimental technique
The the 3rd, 6,9,12 hour and 1,2,3,4,5,6,8,10,12,15,20,25,30 and 40 day gather 10ml blood after administration respectively, and whole blood places the centrifuge tube that contains the anticoagulant heparin sodium.The blood sample of anticoagulant in rear 1 day of blood sampling under 2800rpm centrifugal 20 minutes is isolated blood plasma.It is to be checked blood plasma to be placed-20 ℃ of refrigerators preserve.Utilize high performance liquid chromatography to detect moxidectin content in the plasma sample, detect wavelength: excitation wavelength 365nm, emission wavelength 463nm;
HPLC detected value basis moxidectin concentration---standard curve of moxidectin detected value is asked the moxidectin concentration of calculating in blood sample, the milk sample, the time of drawing out blood sample, milk sample---the drug level scatterplot separately of each blood sample that records.To the time---the drug level curve carries out sunykatuib analysis in the blood plasma He in the milch cow, adopt non-chamber modal analysis approaches, which that the medicine codes or data is analyzed with PkSolution 2.0 pharmacokinetic analysis softwares (Ashland, OH, USA).Obtain corresponding Pharmacokinetics Parameter.
3. result of the test
The pharmacokinetic data of moxidectin dashing agent of the present invention (embodiment 4) sees table 6, table 7 for details, Fig. 2.
Time meta-moxidectin drug level (0.5mgkg-1) in table 6 embodiment 4 and the matched group plasma sample
From table 6, table 7, Fig. 2 data and collection of illustrative plates can be found out, the moxidectin dashing agent (embodiment 4) of this patent invention pours administration according to 0.5mg/kg body weight dosage to lactating cow, the medicines such as the peak concentration of moxidectin, peak time, area under curve, absorption halftime, distribution half-life, drug residue time approach there was no significant difference (p＞0.05) for the 0.5% moxidectin dashing agent that the rich road of parameter and the commercially available U.S. produces in the blood plasma pharmacokinetic data of gained.
By above clinical trial and pharmacokinetic, the result shows that the moxidectin dashing agent of this patent invention has identical clinical effectiveness with commercially available U.S. Fu Dao company dashing agent.In today economic and that society is fast-developing, the veterinary drug of environmental protection low toxicity noresidue has been more and more to receive an acclaim.The inventor is just in line with this principle, and invention provides a kind of moxidectin dashing agent and industrialized preparation method thereof that is not subjected to weather effect, long-acting, the clinical safety and environmental protection of being convenient to observe.
Claims (13)
1. moxidectin dashing agent, contain moxidectin, antioxidant, isopropyl myristate, polyisobutylene or polybutene, oil solvent, it is characterized in that not containing arene compound, wherein the amount of polyisobutylene or polybutene is adjusted according to its molecular weight is different: the polyisobutylene of molecular weight 1000～1900 or polybutene account for 5%～30% of total prescription, described percent is quality and percent by volume, unit is g/ml, with the ratio of isopropyl myristate be 1: 5～10: 1; Or the amount that the polyisobutylene of molecular weight 1900～2500 or polybutene account for total prescription is 5%～20%, and described percent is quality and percent by volume, and unit is g/ml, with the ratio of isopropyl myristate be 1: 10～5: 1.
2. dashing agent according to claim 1 is characterized in that described antioxidant is selected from one or more in propyl gallate, dibenzylatiooluene, butylhydroxy anisole, the tertiarybutylhydroquinone.
3. dashing agent according to claim 2 is characterized in that described antioxidant also comprises the reinforcing agent of antioxidant.
4. dashing agent according to claim 3, the reinforcing agent that it is characterized in that described antioxidant is anhydrous citric acid.
5. dashing agent according to claim 1 is characterized in that the percentage amounts that described isopropyl myristate accounts in the prescription is 1%～50%, and described percent is quality and percent by volume, and unit is g/ml.
6. dashing agent according to claim 1, the molecular weight that it is characterized in that described polyisobutylene or polybutene is 2100～2300, amount at total prescription is 8%～12%, described percent is quality and percent by volume, unit is g/ml, with the ratio of isopropyl myristate be 1: 2～2: 1.
7. dashing agent according to claim 1 is characterized in that described oil solvent is selected from liquid paraffin, soybean oil, Oleum Ricini, Oleum Gossypii semen, ethyl oleate, median chain triglyceride oil.
8. dashing agent according to claim 1 is characterized in that containing a kind of pigment, is selected from violet, Oil Violet, lemon yellow, sunset yellow.
9. the described dashing agent of any one according to claim 1～8 is characterized in that described dashing agent forms:
A. moxidectin 0.1～5.0%
B. antioxidant 0.01～1.0%
C. isopropyl myristate 1.0～50%
D. polyisobutylene or polybutene 5.0～30.0%
Surplus is oil solvent, and wherein percent is quality and percent by volume, and unit is g/ml.
10. the described dashing agent of any one is characterized in that described dashing agent consists of according to claim 1～8:
A. moxidectin 0.1～5.0%
B. antioxidant 0.01～1.0%
C. isopropyl myristate 1.0～50%
D. polyisobutylene or polybutene 5.0～30.0%
E. pigment 0.01～0.50%
Surplus is oil solvent, and wherein percent is quality and percent by volume, and unit is g/ml.
11. the described dashing agent of any one according to claim 1～8 is characterized in that described dashing agent forms:
A. moxidectin 0.1～5.0%
B. butylhydroxy anisole 0.01～1.0%
Anhydrous citric acid 0.00～2.5%
C. isopropyl myristate 1.0～50%
D. polyisobutylene or polybutene 5.0～30%
E. Oil Violet 0.01～0.50%
Surplus is median chain triglyceride oil, and wherein percent is quality and percent by volume, and unit is g/ml.
12. the preparation method of arbitrary described moxidectin dashing agent according to claim 1-11 is characterized in that may further comprise the steps:
A. moxidectin is mixed with antioxidant, add and stir fully dissolving in the oil solvent, for subsequent use;
B. polyisobutylene or polybutene are added fully dissolving of stirring in the oil solvent;
C. choose the adding pigment wantonly, pigment is added in the oil solvent dissolve;
D. with the solution of steps A gained or with the solution of steps A, C gained add stir fully dissolving in the B solution after, in mixed liquor, add isopropyl myristate, stirring and dissolving is with the oil solvent standardize solution and get final product.
13. the described moxidectin dashing agent of any one application in the ectozoic medicine in preparation control animal body according to claim 1～11.
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| CN 201110050233 CN102133173B (en) | 2011-03-03 | 2011-03-03 | Moxidectin pour sprinkling preparation and preparation method thereof |
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| CN 201110050233 CN102133173B (en) | 2011-03-03 | 2011-03-03 | Moxidectin pour sprinkling preparation and preparation method thereof |
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| CN102133173B true CN102133173B (en) | 2013-04-03 |
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| US20200281848A1 (en) * | 2017-11-23 | 2020-09-10 | Ceva Sante Animale | Composition containing moxidectin for treating parasites infestations |
| CN108096564A (en) * | 2017-12-29 | 2018-06-01 | 塔里木大学 | A kind of externally applied drug for preventing livestock and poultry vermin |
| CN108743950A (en) * | 2018-06-29 | 2018-11-06 | 佛山市南海东方澳龙制药有限公司 | Insecticide and preparation method thereof |
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| US4916154A (en) * | 1986-09-12 | 1990-04-10 | American Cyanamid Company | 23-Imino derivatives of LL-F28249 compounds |
| US5824653A (en) * | 1994-11-28 | 1998-10-20 | Virbac S.A. | Anthelmintic compositions for equidae |
| US6514951B1 (en) * | 1989-12-15 | 2003-02-04 | American Cyanamid Company | Pour-on formulations effective for the control of internal and external parasites of homothermic animals |
| CN1406584A (en) * | 2001-08-27 | 2003-04-02 | 惠氏公司 | Gel composition for killing parasites |
| CN101677541A (en) * | 2007-06-05 | 2010-03-24 | 惠氏公司 | Stable non-aqueous pour-on compositions |
| CN101854926A (en) * | 2007-07-31 | 2010-10-06 | 惠氏有限责任公司 | Endoparasiticidal topical compositions |
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2011
- 2011-03-03 CN CN 201110050233 patent/CN102133173B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4916154A (en) * | 1986-09-12 | 1990-04-10 | American Cyanamid Company | 23-Imino derivatives of LL-F28249 compounds |
| US6514951B1 (en) * | 1989-12-15 | 2003-02-04 | American Cyanamid Company | Pour-on formulations effective for the control of internal and external parasites of homothermic animals |
| US5824653A (en) * | 1994-11-28 | 1998-10-20 | Virbac S.A. | Anthelmintic compositions for equidae |
| CN1406584A (en) * | 2001-08-27 | 2003-04-02 | 惠氏公司 | Gel composition for killing parasites |
| CN101677541A (en) * | 2007-06-05 | 2010-03-24 | 惠氏公司 | Stable non-aqueous pour-on compositions |
| CN101854926A (en) * | 2007-07-31 | 2010-10-06 | 惠氏有限责任公司 | Endoparasiticidal topical compositions |
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