CN101766564A - High-efficiency water-solubility toltrazuril solution and preparation method thereof - Google Patents
High-efficiency water-solubility toltrazuril solution and preparation method thereof Download PDFInfo
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- CN101766564A CN101766564A CN200810192960A CN200810192960A CN101766564A CN 101766564 A CN101766564 A CN 101766564A CN 200810192960 A CN200810192960 A CN 200810192960A CN 200810192960 A CN200810192960 A CN 200810192960A CN 101766564 A CN101766564 A CN 101766564A
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- toltrazuril
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Abstract
The invention relates to a high-efficiency water-solubility toltrazuril solution which comprises the following components in percentage by weight: 2-6 percent of toltrazuril, 2-10 percent of inclusion agent, 1 percent of antistatic agent, 7-17 percent of composite emulsifying agent, 1-3 percent of pH regulator, 1 percent of antioxidant, 35-70 percent of composite organic solvent and the balance of purified water. In the invention, an advanced microemulsion preparation process is adopted, and the water insoluble toltrazuril is prepared into a water-insoluble microemulsion solution which can be mixed with water in any proportion, therefore, the dilution and precipitation problems are effectively solved, the bioavailability of the product is improved, and the medicine consumption is reduced; and compared with the prior art, the invention reduces the consumption of the organic solvent and the harmful pharmacological action, saves the cost and improves the security.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, particularly a kind of water-solubility toltrazuril solution and method for making of utilizing medicine inclusion technique and the preparation of microemulsion technology of preparing.
Background technology
Chicken coccidiosis is a kind of acute popular parasitic disease that one or more unicellular parasite by Eimeria cause.China has classified it as the sick kind of two class Animal diseases.The coccidiosis incidence rate is the highest in various fowl disease, accounts for 1/6-1/5, and especially mortality rate can reach 70%, and the chickling of recovering often is difficult for getting well in the several months with the easy infection morbidity of interior chickling 3 monthly ages.Adult chicken also is the carrier mostly.But other poultry such as duck, turkey, Columba livia, crane quail etc. are infection morbidity all, is having a strong impact on the development of China's aquaculture.
Toltrazuril claims methyl triazon again, belongs to the Triazinone derivant, and molecular formula is C
18H
14F
3N
3O
4S, molecular weight are 425.39, and fusing point is 193-196 ℃.
Toltrazuril is white or off-white color crystalline powder, and odorless is molten in the methanol part omitted at ethyl acetate, dichloromethane, Polyethylene Glycol, α-adjoin in the organic solvents such as pyrrolidone, propylene glycol and dissolve, and is insoluble in water.
Toltrazuril belongs to a kind of medicine of efficient treatment coccidiosis, insecticidal mechanism is still indeterminate, and present popular saying is that it can disturb division of coccidiosis nucleus and mitochondrion, influences breathing and the metabolic function of polypide, endocytoplasmic reticulum is expanded, serious ghostization takes place cause polypide death.Toltrazuril is very extensive to the site of action of coccidiosis, and two no sexual cycles of coccidiosis are all had effect, as suppressing schizont, the wall organizator of the karyokinesis of microgametophyte and microgametophyte.
At present, Toltrazuril is mainly used in coccidiosis of domestic fowls.To chicken heap type, Bu Shi, huge, tender, the gentle Eimeria of murder by poisoning; Turkey gland Eimeria, turkey Eimeria; And the goose Eimeria of goose, cut the shape Eimeria and all have good pressing down to kill effect.7mg/kg once for oral administration or with 25mg/kg concentration drinking-water 48h can prevent coccidiosis effectively, and the worm's ovum capsule is all disappeared, and does not influence that chick growth is grown and to the generation of immunity to coccidiosis power.
In recent years, along with the further investigation to Toltrazuril finds that its coccidiosis to domestic animals such as sheep, rabbits also has good prevention and therapeutic effect, and the application of this series products is further enlarged.
Toltrazuril is to introduce China in 1985 by Bayer A.G at first.2.5% toltrazuril solution (the clear solution of trade name hundred balls) of its production because its good disinsection effect, toxicity are low, has obtained extensive use.Though at present domestic existing like product listing, its production technology adopts pure organic solvent dissolution mostly, and as DMF etc., production cost is higher, and the zest of medicine is very big, and bad pharmacological action is obvious.
Like product on the market at present, crystallization is easily separated out in the ubiquity dilution during clinical practice, and medicine disperses inhomogeneous, and the medicine sedimentation velocity is fast, causes sick body animal unable to drink to use the medicine of capacity, and bioavailability is lower.If this product of life-time service, can cause the sick body animal to produce drug resistance rapidly, and Toltrazuril also produce cross resistance with medicine such as diclazuril easily, in a disguised form quickened the superseded speed in market of Triazinone medicine.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of water-solubility toltrazuril solution and preparation method thereof is provided, make the water solublity of medicinal liquid and stability improve greatly.
Technical scheme of the present invention is: a kind of high-efficiency water-solubility toltrazuril solution, and the component of described solution and content (percetage by weight) are:
Toltrazuril 2-6%
Inclusion agents 2-10%
Antistatic additive 1%
Composite emulsifier 7-17%
PH regulator 1-3%
Antioxidant 1%
Composite organic solvent 35-70%
The purified water surplus
Preferably: described inclusion agents is a beta-schardinger dextrin-, and described antistatic additive is a sodium lauryl sulphate, and described PH regulator is a triethanolamine, and described antioxidant is a rongalite.
Preferably: described composite emulsifier is made up of Tween 80, sorbester p17 and isopropyl myristate, and its percentage by weight that accounts for solution is respectively: 5-12%, 1-2%, 1-3%.
Preferably: described composite organic solvent is made up of alpha-pyrrolidone and glycerin methylal, and its percentage by weight that accounts for solution is respectively: 30-50%, 5-20%.
A kind of preparation method of high-efficiency water-solubility toltrazuril solution, described preparation method is as follows:
(1) enclose: get Toltrazuril, inclusion agents, antistatic additive mix homogeneously and grinding, it is standby to obtain powders A;
(2) dissolving: will add powders A behind composite organic solvent, composite emulsifier PH regulator, antioxidant mix homogeneously and the heating in water bath, stirring and dissolving gets mixed liquid B; In mixed liquid B, add composite emulsifier, stir and obtain mixed liquor C;
(3) dilution: in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Preferably: the concrete steps of described preparation method are as follows:
(1) get Toltrazuril 2-6%, inclusion agents beta-schardinger dextrin-2-10%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put grinding in ball grinder 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 30-50%, glycerin methylal 5-20%, sorbester p17 1-2%, triethanolamine 1-3% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 5-12%, isopropyl myristate 1-3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Each component preferred weight proportioning that this method adopted is:
Toltrazuril 2.5%
Beta-schardinger dextrin-3%
Sodium lauryl sulphate 1%
Tween 80 10%
Sorbester p17 2%
Isopropyl myristate 3%
Alpha-pyrrolidone 40%
Glycerin methylal 10%
Triethanolamine 1%
Rongalite 1%
The purified water surplus
Beneficial effect of the present invention is as follows:
1, the present invention has adopted the new technique of pharmaceutical preparation, at first utilize inclusion agents enclose Toltrazuril to form and divide ascus, increase the dissolubility and the stability of Toltrazuril, inclusion technique has improved the dissolubility of medicine greatly, can make the valid density of Toltrazuril reach 6%; Add antistatic additive during enclose, can effectively stop when grinding enclose because the medicine that Electrostatic Absorption causes gathering.
2, stability of the present invention is obviously promoted, stability when composite emulsifier has increased drug dilution, PH regulator and antioxidant have increased the stability of drug storage, room temperature was deposited 6 months in the test, no variable color and precipitation, solution is joined respectively at the centrifugal 1h of 3000r/min in the centrifuge tube, the centrifugal 30min of 10000r/min by institute, all uniform distribution does not have precipitation and occurs.
3, solved domestic like product and now made and now join problem, medicinal liquid after dilution in the 48h medicine be evenly distributed, find no tangible sedimentation phenomenon, guaranteed poultry drink Shi Buhui occur taking less than or take uneven phenomenon.
4, adopted advanced microemulsion preparation technology, with water-fast Toltrazuril make can with the blended microemulsion solution of the arbitrary proportion of water, efficiently solve the bioavailability that dilution is separated out problem and improved product, reduced dosage, and compared with prior art, reduced consumption of organic solvent, saved cost, reduced bad pharmacological action, safety improves.
The specific embodiment
The invention will be further described below by specific embodiment, can not limit protection scope of the present invention with this.
Embodiment 1
A kind of composition weight proportioning and method for making of high-efficiency water-solubility toltrazuril solution are as follows
Toltrazuril 2.5%
Beta-schardinger dextrin-3%
Sodium lauryl sulphate 1%
Tween 80 10%
Sorbester p17 2%
Isopropyl myristate 3%
Alpha-pyrrolidone 40%
Glycerin methylal 10%
Triethanolamine 1%
Rongalite 1%
The purified water surplus
(1) get Toltrazuril 2.5%, inclusion agents beta-schardinger dextrin-3%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put in the planetary ball mill and ground 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 40%, glycerin methylal 10%, sorbester p17 2%, triethanolamine 1% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 10%, isopropyl myristate 3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Embodiment 2
A kind of composition weight proportioning and method for making of high-efficiency water-solubility toltrazuril solution are as follows
Toltrazuril 2%
Beta-schardinger dextrin-3%
Sodium lauryl sulphate 1%
Tween 80 5%
Sorbester p17 2%
Isopropyl myristate 2%
Alpha-pyrrolidone 30%
Glycerin methylal 10%
Triethanolamine 1%
Rongalite 1%
The purified water surplus
(1) get Toltrazuril 2%, inclusion agents beta-schardinger dextrin-3%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put in the planetary ball mill and ground 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 30%, glycerin methylal 10%, sorbester p17 2%, triethanolamine 1% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 5%, isopropyl myristate 2% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Embodiment 3
A kind of composition weight proportioning and method for making of high-efficiency water-solubility toltrazuril solution are as follows
Toltrazuril 3%
Beta-schardinger dextrin-4%
Sodium lauryl sulphate 1%
Tween 80 10%
Sorbester p17 2%
Isopropyl myristate 3%
Alpha-pyrrolidone 45%
Glycerin methylal 10%
Triethanolamine 2%
Rongalite 1%
The purified water surplus
(1) get Toltrazuril 3%, inclusion agents beta-schardinger dextrin-4%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put in the planetary ball mill and ground 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 45%, glycerin methylal 10%, sorbester p17 2%, triethanolamine 2% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 10%, isopropyl myristate 3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Embodiment 4
A kind of composition weight proportioning and method for making of high-efficiency water-solubility toltrazuril solution are as follows
Toltrazuril 5%
Beta-schardinger dextrin-8%
Sodium lauryl sulphate 1%
Tween 80 10%
Sorbester p17 2%
Isopropyl myristate 3%
Alpha-pyrrolidone 40%
Glycerin methylal 20%
Triethanolamine 3%
Rongalite 1%
The purified water surplus
(1) get Toltrazuril 5%, inclusion agents beta-schardinger dextrin-8%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put in the planetary ball mill and ground 0.5 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 40%, glycerin methylal 20%, sorbester p17 2%, triethanolamine 3% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 10%, isopropyl myristate 3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Embodiment 5
A kind of composition weight proportioning and method for making of high-efficiency water-solubility toltrazuril solution are as follows
Toltrazuril 6%
Beta-schardinger dextrin-10%
Sodium lauryl sulphate 1%
Tween 80 12%
Sorbester p17 2%
Isopropyl myristate 3%
Alpha-pyrrolidone 50%
Glycerin methylal 10%
Triethanolamine 3%
Rongalite 1%
The purified water surplus
(1) get Toltrazuril 6%, inclusion agents beta-schardinger dextrin-10%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put in the planetary ball mill and ground 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 50%, glycerin methylal 10%, sorbester p17 2%, triethanolamine 3% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 12%, isopropyl myristate 3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
Claims (6)
1. high-efficiency water-solubility toltrazuril solution, it is characterized in that: the component of described solution and content (percetage by weight) are:
Toltrazuril 2-6%;
Inclusion agents 2-10%;
Antistatic additive 1%;
Composite emulsifier 7-17%;
PH regulator 1-3%;
Antioxidant 1%;
Composite organic solvent 35-70%;
The purified water surplus.
2. high-efficiency water-solubility toltrazuril solution as claimed in claim 1 is characterized in that: described inclusion agents is a beta-schardinger dextrin-, and described antistatic additive is a sodium lauryl sulphate, and described PH regulator is a triethanolamine, and described antioxidant is a rongalite.
3. high-efficiency water-solubility toltrazuril solution as claimed in claim 1 is characterized in that: described composite emulsifier is made up of Tween 80, sorbester p17 and isopropyl myristate, and its percentage by weight that accounts for solution is respectively: 5-12%, 1-2%, 1-3%.
4. high-efficiency water-solubility toltrazuril solution as claimed in claim 1 is characterized in that: described composite organic solvent is made up of alpha-pyrrolidone and glycerin methylal, and its percentage by weight that accounts for solution is respectively: 30-50%, 5-20%.
5. the preparation method of a high-efficiency water-solubility toltrazuril solution, it is characterized in that: described preparation method is as follows:
(1) enclose: get Toltrazuril, inclusion agents, antistatic additive mix homogeneously and grinding, it is standby to obtain powders A;
(2) dissolving: will add powders A behind composite organic solvent, composite emulsifier, PH regulator, antioxidant mix homogeneously and the heating in water bath, stirring and dissolving gets mixed liquid B; In mixed liquid B, add composite emulsifier, stir and obtain mixed liquor C;
(3) dilution: in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
6. the preparation method of high-efficiency water-solubility toltrazuril solution as claimed in claim 5, it is characterized in that: the concrete steps of described preparation method are as follows:
(1) get Toltrazuril 2-6%, inclusion agents beta-schardinger dextrin-2-10%, antistatic additive sodium lauryl sulphate 1% mix homogeneously, put grinding in ball grinder 1 hour, the gained powder is crossed 80 mesh sieves, makes material A, and is standby;
(2) get alpha-pyrrolidone 30-50%, glycerin methylal 5-20%, sorbester p17 1-2%, triethanolamine 1-3% mix homogeneously, add 1% antioxidant rongalite, heating in water bath to 60 ℃ adds material A, and stirring and dissolving gets mixed liquid B;
(3) add Tween 80 5-12%, isopropyl myristate 1-3% in mixed liquid B, stirring and dissolving gets mixed liquor C;
(4) in mixed liquor C, slowly drip purified water, continue to stir, be high-efficiency water-solubility toltrazuril solution up to obtaining clarifying pale yellow solution.
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| CN200810192960A CN101766564A (en) | 2008-12-31 | 2008-12-31 | High-efficiency water-solubility toltrazuril solution and preparation method thereof |
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| CN200810192960A CN101766564A (en) | 2008-12-31 | 2008-12-31 | High-efficiency water-solubility toltrazuril solution and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106819A (en) * | 2010-12-29 | 2011-06-29 | 中国药科大学 | Preparation method and application of medicament-cyclodextrin inclusion compound self-emulsifying composition |
| CN102512366A (en) * | 2011-12-28 | 2012-06-27 | 广州市和生堂动物药业有限公司 | Toltrazuril suspension emulsion and preparation method thereof |
| CN103251549A (en) * | 2013-04-19 | 2013-08-21 | 潍坊浩源工业助剂有限公司 | Toltrazuril solid dispersion |
| CN103694185A (en) * | 2013-12-18 | 2014-04-02 | 湖北龙翔药业有限公司 | Toltrazuril alkali metal salt as well as preparation method and application thereof |
-
2008
- 2008-12-31 CN CN200810192960A patent/CN101766564A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106819A (en) * | 2010-12-29 | 2011-06-29 | 中国药科大学 | Preparation method and application of medicament-cyclodextrin inclusion compound self-emulsifying composition |
| CN102512366A (en) * | 2011-12-28 | 2012-06-27 | 广州市和生堂动物药业有限公司 | Toltrazuril suspension emulsion and preparation method thereof |
| CN103251549A (en) * | 2013-04-19 | 2013-08-21 | 潍坊浩源工业助剂有限公司 | Toltrazuril solid dispersion |
| CN103694185A (en) * | 2013-12-18 | 2014-04-02 | 湖北龙翔药业有限公司 | Toltrazuril alkali metal salt as well as preparation method and application thereof |
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Application publication date: 20100707 |