CN101766591B - Method for preparing water-soluble ethopabate and application thereof - Google Patents
Method for preparing water-soluble ethopabate and application thereof Download PDFInfo
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- CN101766591B CN101766591B CN 201010030232 CN201010030232A CN101766591B CN 101766591 B CN101766591 B CN 101766591B CN 201010030232 CN201010030232 CN 201010030232 CN 201010030232 A CN201010030232 A CN 201010030232A CN 101766591 B CN101766591 B CN 101766591B
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Abstract
The invention, belonging to a method for preparing water-soluble ethopabate and an application thereof, relates to an anticoccidial veterinary drug, wherein, ethopabate and Beta-cyclodextrin derivative or water-soluble cyclodextrin polymer by weight ratio of 1:10-65 are prepared into an inclusion compound according to ultrasonic sound or a hot stirring method, and the resulting inclusion compound can be directly used for preparing liquid or solid anticoccidial medicines. Due to inclusion technology, the solubility of ethopabate in water is obviously increased.
Description
[technical field]
The present invention relates to a kind of anticoccidial veterinary drug, particularly a kind of preparation method and application thereof for preparing water-soluble ethopabate.
[background technology]
Chicken coccidiosis is common a kind of disease important in the aviculture, and the harm that it is produced poultry is very serious, and according to statistics, the annual expenses for medicine that is used for the control chicken coccidiosis of China reaches several hundred million yuans, accounts for nearly 1/3rd of the whole expensess for prevention and control of fowl disease.Long serious hysteresis of the chicken all living creatures that coccidiosis is popular, and bring out other diseases thereupon, such as colibacillosis, mycoplasma etc.As far back as the forties, people just find that sulfa drugs can be used for preventing and treating coccidiosis, find successively again that afterwards the medicines such as other drug such as furans, alkaloids, ionophore class can both be used for preventing and treating coccidiosis.The anticoccidial drug of having reported reaches kind more than 50, and too large or unsatisfactory curative effect is eliminated the some of them medicine owing to toxicity, and the anticoccidial drug of still using aborning at present has more than 20 to plant, yet the drug resistance problem has namely appearred in most coccidiostat after promoting the use of the several years.
Ethopabate is the synergist of the anticoccidial drug such as Amprolium, and many and Amprolium, sulfaquinoxaline etc. are made into pre-mixing agent and are widely used in clinical.At present, prescription on the market has amprolium hydrochloride-ethopabate (125: 8) pre-mixing agent, amprolium hydrochloride-ethopabate-sulfaquinoxaline (100: 6: 50), nicarbazine-ethopabate (125: 8) pre-mixing agent, because drug interaction, enlarge the coccidiosis scope, delayed the generation of drug resistance, aspect the preventing and treating of avian coccidiosis, brought into play huge effect.After the chicken morbidity, feed intake usually descends afterwards, uses pre-mixing agent, because feed intake decline medicine is difficult to reach valid density, and for most of medium and small plants, without medicine mixing ability, medicine can not evenly be mixed in feedstuff, thereby affect the performance of drug effect.
Ethopabate at present most widely used dosage form mainly is pre-mixing agent, because it is insoluble in water, dissolution is lower, causes bioavailability poor, and medicine is difficult to reach the required blood drug level for the treatment of.Cyclodextrin can increase dissolubility and the stability of the relatively low medicine of some water solublity in water effectively, the stability of raising medicine and bioavailability etc.
[summary of the invention]
Main purpose of the present invention provides a kind of preparation method and application thereof for preparing water-soluble ethopabate, utilizes inclusion technique effectively to increase the dissolubility of ethopabate in water.
In order to realize the foregoing invention purpose, the present invention adopts following technical scheme;
A kind of preparation method for preparing water-soluble ethopabate, be 1: 10～65 by weight with ethopabate and beta-cyclodextrin derivative or water-soluble cyclodextrin, adopt method ultrasonic or heated and stirred to be prepared into clathrate, the clathrate that is prepared into can be directly used in the preparation of liquid or solid coccidiostat; The preparation method of concrete water-soluble ethopabate is as follows:
1), gets ethopabate 1.6g～16g and measure dissolve with ethanols with 1.5～3 times;
2), getting the beta-cyclodextrin derivative of 10～65 times of amounts of ethopabate or water-soluble cyclodextrin adds 3～6 times of water gagings and prepares beta-cyclodextrin derivative or water-soluble cyclodextrin aqueous solution;
Slowly join when 3), step 1 being stirred in beta-cyclodextrin derivative or the water-soluble cyclodextrin aqueous solution, supersound process 60min or 60 ℃ of heated and stirred are even, after being evaporated to smart thick shape, above rear filtration of 12h left standstill in cold preservation, 40～60 ℃ of dryings of filter cake can be obtained described water-soluble ethopabate.
The preparation method of described preparation water-soluble ethopabate, wherein said beta-cyclodextrin derivative comprises HP-β-CD, hydroxyethyl-β-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin-; Water-soluble cyclodextrin comprises alpha-cyclodextrin polymer, beta cyclo dextrin polymer or gamma-cyclodextrin polymer; Preferred HP-β-CD wherein.
The preparation method of described preparation water-soluble ethopabate adds polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG) water soluble polymer when the dissolving ethopabate, consumption is 1-3g/L.
The application of described preparation water-soluble ethopabate;
The application of described preparation water-soluble ethopabate, described water-soluble ethopabate can be directly and other coccidiostat be prepared into oral administration solid, liquid dosage form.
The application of described preparation water-soluble ethopabate, when wherein preparing liquid oral, solid preparation, weight ratio is ethopabate with other coccidiostat coupling the time: other coccidiostat=1: 15～35.
The application of described preparation water-soluble ethopabate, described other anticoccidial constituents comprises one or both in amprolium hydrochloride, sulfaquinoxaline or the nicarbazine.
The application of described preparation water-soluble ethopabate, oral liquid recommended dose fowl 1L water oral liquid 1ml, 1L water or the 1kg feedstuff soluble powder 1g of preparation.
Need to prove that beta-cyclodextrin derivative of the present invention or water-soluble cyclodextrin are the water solublity pharmaceutic adjuvants, utilize beta-cyclodextrin derivative or water-soluble cyclodextrin that ethopabate is carried out enclose, improved the water solublity of ethopabate, make ethopabate directly apply to liquid, solid dosage forms with the form of clathrate, solved the defective that the ethopabate water solublity is low, can not directly apply to liquid dosage form.
Owing to having adopted technique scheme, the present invention to have following beneficial effect:
It is simple that the present invention prepares the water-soluble ethopabate method, easy operating, and the ethopabate behind cyclodextrin inclusion compound is soluble in water, is uniformly dispersed during mixed drink, is beneficial to the absorption of animal.
[specific embodiment]
The preparation of embodiment 1 water-soluble ethopabate:
1) gets HP-β-CD 160g and add 6 times of amounts of water, stir, preparation HP-β-CD aqueous solution;
2) get ethopabate 16g and add polyvinylpyrrolidone 0.125g and 25ml dissolve with ethanol;
3) with 2) slowly join in the HP-β-CD aqueous solution when stirring, supersound process 60min, be evaporated to thick after, cold preservation filters after leaving standstill 12h, 60 ℃ of dryings of filter cake, and get final product.Record yield 91.1%, envelop rate is 94.2%.
The preparation of embodiment 2 water-soluble ethopabates:
1) gets HP-β-CD 160g and add 3 times of amounts of water, stir, preparation HP-β-CD aqueous solution;
2) get ethopabate 8g 20ml dissolve with ethanol;
3) with 2) slowly join in the HP-β-CD aqueous solution when stirring, 60 ℃ of heated and stirred were processed 2 hours, be evaporated to thick after, cold preservation filters after leaving standstill 16h, 60 ℃ of dryings of filter cake, and get final product.Record yield 93.5%, envelop rate is 95.0%.
The preparation of embodiment 3 water-soluble ethopabates:
1) gets beta cyclo dextrin polymer 520g and add 3 times of amounts of water, stir, preparation beta cyclo dextrin polymer aqueous solution;
2) get ethopabate 8g 20ml dissolve with ethanol;
3) with 2) slowly join in the beta cyclo dextrin polymer aqueous solution when stirring, 60 ℃ of heated and stirred were processed 4 hours, be evaporated to thick after, cold preservation filters after leaving standstill 12h, 60 ℃ of dryings of filter cake, and get final product.Record yield 90.4%, envelop rate is 92.7%.
The preparation of embodiment 4 water-soluble ethopabates:
1) gets HP-β-CD 80g and add 3 times of amounts of water, stir, preparation HP-β-CD aqueous solution;
2) get ethopabate 8g and add polyvinylpyrrolidone 0.025g and 25ml dissolve with ethanol;
3) with 2) slowly join in the HP-β-CD aqueous solution when stirring, 60 ℃ of heated and stirred were processed 6 hours, be evaporated to thick after, cold preservation filters after leaving standstill 12h, 50 ℃ of dryings of filter cake, and get final product.Record yield 88.3%, envelop rate is 90.2%.
The preparation of embodiment 5 water-soluble ethopabates:
1) gets alpha-cyclodextrin polymer 80g and add 5 times of amounts of water, stir, preparation alpha-cyclodextrin aqueous solutions of polymers;
2) get ethopabate 1.6g 5ml dissolve with ethanol;
3) with 2) slowly join in the alpha-cyclodextrin aqueous solutions of polymers when stirring, supersound process 60min, be evaporated to thick after, cold preservation filters after leaving standstill 12h, 60 ℃ of dryings of filter cake, and get final product.Record yield 86.8%, envelop rate is 87.4%.
The preparation of embodiment 6 water-soluble ethopabates:
1) gets HP-β-CD 160g and add 4 times of amounts of water, stir, preparation HP-β-CD aqueous solution;
2) get ethopabate 16g 30ml dissolve with ethanol;
3) with 2) slowly join in the HP-β-CD aqueous solution when stirring, supersound process 30min, be evaporated to thick after, cold preservation filters after leaving standstill 12h, 60 ℃ of dryings of filter cake, and get final product.Recording yield 86.1% envelop rate is 88.3%.
Embodiment 7 ethopabates, amprolium hydrochloride oral liquid:
Get the water-soluble ethopabate 40.6g (containing ethopabate 4g) of embodiment 1 preparation, amprolium hydrochloride 62.5g, EDTA-2Na 0.05g add purified water to 500ml, and mixing filters, and get final product.
Embodiment 8 ethopabates, amprolium hydrochloride, sulfaquinoxaline soluble powder:
Get water-soluble ethopabate 25.4g (containing ethopabate 2.5g), sulfaquinoxaline 30g, the amprolium hydrochloride 50g of embodiment 1 preparation, add lactose to 500g, mix homogeneously is crossed 80 mesh sieves, and be get final product.
Embodiment 8 dissolubility contrast tests
Carry out solubility test according to " People's Republic of China's veterinary drug allusion quotation " (2005 editions, one one).
Experimental condition
Test specimen: sample 1: according to the water-soluble ethopabate 500g of embodiment 1 preparation; Sample 2: ethopabate crude drug
Test apparatus and solvent: 200ml beaker, magnetic stirring apparatus
Experimental enviroment: 25 ℃
Test site: Henan Province's veterinary drug Engineering Technical Research Centre
Process of the test: get purified water 100ml and place the 200ml beaker, get the overdose of medicine matter sample and join in the purified water, place on the magnetic stirring apparatus and stir, 25 ℃ of temperature, observe the dissolving situation of medicine in solution, until reach capacity, measure drug solution concentration and get final product.
Table 1 dissolubility test result
| Sample | Dissolubility g/1000ml (in the amount of dissolving ethopabate) |
| Sample 1 | 5.1 |
| Sample 2 | 0.056 |
As can be seen from Table 1, its dissolubility of water-soluble ethopabate that utilizes the present invention to prepare has improved 91.1 times than the ethopabate crude drug.
Claims (5)
1. method for preparing water-soluble ethopabate, it is characterized in that: be 1: 10～65 by weight with ethopabate and beta-cyclodextrin derivative or water-soluble cyclodextrin, adopt method ultrasonic or heated and stirred to be prepared into clathrate, the clathrate that is prepared into can be directly used in the preparation of liquid or solid coccidiostat; The preparation method of concrete water-soluble ethopabate is as follows:
1), gets ethopabate 1.6g～16g and measure dissolve with ethanols with 1.5～3 times;
2), getting the beta-cyclodextrin derivative of 10～65 times of amounts of ethopabate or water-soluble cyclodextrin adds 3～6 times of water gagings and prepares beta-cyclodextrin derivative or water-soluble cyclodextrin aqueous solution;
3) the ethopabate alcoholic solution that, step 1 is prepared slowly joins in beta-cyclodextrin derivative or the water-soluble cyclodextrin aqueous solution when stirring, supersound process 60min or 60 ℃ of heated and stirred are even, be evaporated to thick after, above rear filtration of 12h left standstill in cold preservation, 40～60 ℃ of dryings of filter cake can be obtained described water-soluble ethopabate;
Wherein said beta-cyclodextrin derivative is selected from HP-β-CD, hydroxyethyl-β-cyclodextrin, dihydroxypropyl-beta-schardinger dextrin-; Water-soluble cyclodextrin is selected from alpha-cyclodextrin polymer, beta cyclo dextrin polymer or gamma-cyclodextrin polymer;
Add polyvinylpyrrolidone (PVP), Polyethylene Glycol (PEG) water soluble polymer when the dissolving ethopabate, consumption is 1-3g/L.
2. the application of the water-soluble ethopabate of method according to claim 1 preparation is characterized in that: described water-soluble ethopabate can be directly and other coccidiostat be prepared into oral administration solid, liquid dosage form.
3. the application of water-soluble ethopabate according to claim 2, it is characterized in that: when wherein preparing liquid oral, solid preparation, weight ratio is ethopabate with other coccidiostat coupling the time: other coccidiostat=1: 15～35.
4. the application of water-soluble ethopabate according to claim 3 is characterized in that: described other anticoccidial class medicine comprises one or both in amprolium hydrochloride, sulfaquinoxaline or the nicarbazine.
5. the application of water-soluble ethopabate according to claim 2 is characterized in that: oral formulations recommended dose fowl 1L water oral liquid 1ml, 1L water or the 1kg feedstuff soluble powder 1g of preparation.
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| CN 201010030232 CN101766591B (en) | 2010-01-22 | 2010-01-22 | Method for preparing water-soluble ethopabate and application thereof |
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| CN101954089A (en) * | 2010-09-08 | 2011-01-26 | 洛阳惠中兽药有限公司 | Animal medicine inclusion compound, preparation method and application thereof |
| CN102813938A (en) * | 2012-09-14 | 2012-12-12 | 扬州大学 | Llex A-cyclodextrin polymer medicine composition for preventing and curing atherosclerosis and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129390A (en) * | 2007-08-26 | 2008-02-27 | 青岛康地恩实业有限公司 | Compound coccidiostat pharmaceutical formulation |
| CN101450038A (en) * | 2008-12-29 | 2009-06-10 | 天津瑞普生物技术股份有限公司 | Nicarbazin and ethopabate nano suspension agent and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101129390A (en) * | 2007-08-26 | 2008-02-27 | 青岛康地恩实业有限公司 | Compound coccidiostat pharmaceutical formulation |
| CN101450038A (en) * | 2008-12-29 | 2009-06-10 | 天津瑞普生物技术股份有限公司 | Nicarbazin and ethopabate nano suspension agent and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 李丽杰等.制剂新技术在兽药研发中的应用.《兽药与饲料添加剂》.2008,第13卷(第01期),第14-16页. * |
| 谷福根等.环糊精包合物研究进展.《中国新药杂志》.2005,第14卷(第6期),第686-693页. * |
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