CN103800355A - Compound long-acting microsphere anthelmintic containing ivermectin, albendazol sulfoxide and praziquantel - Google Patents
Compound long-acting microsphere anthelmintic containing ivermectin, albendazol sulfoxide and praziquantel Download PDFInfo
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- CN103800355A CN103800355A CN201410064109.1A CN201410064109A CN103800355A CN 103800355 A CN103800355 A CN 103800355A CN 201410064109 A CN201410064109 A CN 201410064109A CN 103800355 A CN103800355 A CN 103800355A
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Abstract
The invention provides a compound long-acting microsphere anthelmintic containing ivermectin, albendazol sulfoxide and praziquantel. The invention provides a process for coating a polylactic acid microsphere with ivermectin, albendazol sulfoxide and praziquantel, wherein an organic solvent containing ivermectin, albendazol sulfoxide and praziquantel is dispersed with a polylactic acid aqueous solution at high speed, and the mixture is centrifugally separated and dried in vacuum to obtain a stable drug-containing microsphere after the organic solvent is volatized. The process is simple in equipment and environmental friendly in production process, and has great economical and social benefits.
Description
Technical field
The present invention relates to a kind of preparation preparation of compound recipe anthelmintic, being specifically related to veterinary drug raw material is ivermectin, albendazole and praziquantel, and pharmaceutic adjuvant is polylactic acid, is prepared into slow release, long-acting injection parasiticide veterinary drug.
Background technology
Fowl poultry kind parasite medicine is one of focus that veterinary drug research circle pays close attention to always, and exploitation good effect, effect are lasting, side effect broad-spectrum anti-parasite medicine little, noresidue is Ministry of Agriculture's emphasis brainstorm subject.China's most animals feeding environment is poor, and parazoon easily grows, through investigating nearly more than 2000 kinds of parasites, because the loss that parasitic disease brings to China's animal husbandry is huge.U.S.'s cattle-raising because of the loss that nematicide and parasite cause be annual 4000000000 dollars, the sheep husbandry of Australia is because of the annual loss of anthelmintic 2.2 hundred million Australian Dollars, and the whole world is annual because the economic loss of BABEI filaricide reaches more than 70 hundred million dollars.From existing single current system effect parasiticide veterinary drug, screening and carry out compound recipe combination, is conventional at present best good mode.Ivermectin, albendazole and praziquantel are curative effects and apply best several in conventional veterinary drug.
Ivermectin to be Merk company carry out to the best broad-spectrum anti-parasite medicine avilamycin that structure of modification obtains a wide spectrum more, efficiently, the derivant of high security, do not produce in addition drug resistance simultaneously and can kill endoparasite and ectoparasite (Ma Guangpeng simultaneously, Zhang Longxian, Qi Meng, the re-examine of tremendous economic loss and public health prevention and control leak thereof-to animal parasitosis hazardness. Chinese animal health .2009, (7): 32-37. Brown CGD. Dynamics and impact of tick borne diseases of cattle, Tropical animal Health and Production, 1997, (29): 1-3.).
Albendazole is the oxide of albendazole, and its precursor is albendazole, and its hydrochlorate is very high at the dissolubility of water and some alcohol apoplexy due to endogenous wind.It is showing the application prospect that it is potential aspect domestic animal parasite control and disinfectant use in agriculture: (1), due to its good water solubility, for this reason, can be prepared into more dosage form and meet the different needs.(2) good absorbing, bioavailability is high, this be albendazole can't be obtained.Its mechanism of action is for passing through multiple biochemical metabolism approach in the parasitic polypide of impact, can effectively kill rapidly polypide (Horton J. Albendazole:a broad spectrum anthelminthic for treatment of individuals and populations. Curr Opin Infect Dis, 2002,15 (6): 599-608. Fenton LD, Morris DL. The management of hydatid disease of the liver. Trop Doct. 1997,27 (2): 87-88.).
Praziquantel is a kind of heterocycle pyrazine isoquinoline compound, and it has good effect aspect schistosomicide.Have advantages of efficient, low toxicity, aspect degree of safety, performance is excellent especially.But, its special structure has and shows the shortcoming (Qian Mingxin that first pass effect is large, bioavailability is low, Liu John, Wang little Gen. left-handed praziquantel pharmacokinetics in vivo. Chinese Pharmacological communication, 1985,5 (3): 62-63. woods filial piety Pu, Mao Guanyuan, Zhang Shenghu. the schistosomicide of intramuscular injection praziquantel treatment milch cow. Chinese veterinary's impurity, 1991,3 (17) 40-41.).
To sum up tell, the Antiparasitic Activity of ivermectin, albendazole and praziquantel is all very good and toxic and side effects is little, but with respect to more than 2,000 kinds of parasites, the single use of above medicine is difficult to kill multiple insects on a large scale.Drug combination has great inconvenience for field large area, use on a large scale.For this reason, develop a kind of compound recipe, can contain above three kinds of active component simultaneously, and can have wide spectrum, long-acting injection parasiticide veterinary drug to be very important.
In order to overcome the shortcoming of single drug and common drug combination, the microsphere preparation technology of adoption of innovation uniqueness of the present invention, technique is simple, the route of processing ease and environmental protection, take polylactic acid as pharmaceutical carrier adjuvant, organic solvent dissolution crude drug.Through screening and optimization, set up suitable various supplementary material ratios and prepare optimised process, prepare and meet the medicine microspheres containing ivermectin, albendazole and praziquantel that slow releasing injection uses.Can be applied to various parasiticide veterinary drug slow releasing agents.
Feature part of the present invention is: (1) has filtered out crude drug compound recipe group, comprises ivermectin, albendazole and praziquantel.(2) according to the parasiticide characteristic of three kinds of crude drug and pharmacology, drug effect feature, its usage ratio is 10:5:3.(3), take polylactic acid as pharmaceutical carrier, the 5-10 that polylactic acid consumption is crude drug doubly.(4) adopt the core process such as solvent evaporates, high-speed stirred and lyophilization to prepare medicine-containing microsphere.All be suitable for above the route of suitability for industrialized production from aspects such as property simple to operate, flow process controllabilities.
Summary of the invention
The key problem that the present invention need to solve is to overcome the shortcomings such as domestic and international existing antiparasitic broad spectrum activity is poor, duration of efficacy is short, set up and comprise the compound medicine microsphere of three kinds of best antiparasitics simultaneously, thereby for the preparation of wide spectrum, long-acting, low toxicity and anti-parasite medicine easy to use.
Object of the present invention is achieved through the following technical solutions, and concrete route is shown in Figure of description.
First configure the aqueous solution containing a certain amount of polylactic acid, then drip with certain speed the organic solvent that is dissolved with three kinds of crude drug, control temperature and high-speed stirred simultaneously, form S/O/W type emulsion.Then, at a certain temperature, vapor away organic facies, form microsphere and obtain by centrifugal, last vacuum decompression is dry, obtains stable medicine-containing microsphere.Concrete steps are as follows:
1, in No. 1 stainless steel cauldron with high-speed stirred, add successively deionized water, polylactic acid, stirring at room temperature is dissolved, and continues to stir after 10 minutes stand-by;
2, in No. 2 dissolving tanks, add successively ethanol, dichloromethane and three kinds of crude drug ivermectins, albendazole and praziquantel, heating, stirring and dissolving is stand-by;
3, open No. 1 stainless steel cauldron high-speed stirred, the pastille organic facies in No. 2 dissolving tanks is dropped to reactor No. 1 with certain speed, drip the mouth of pipe and want Shen to enter liquid level certain depth, approximately 1 h adds.Continue high-speed stirred, and be heated to 30 ℃, volatilization organic solvent dichloromethane.After 2 h, be more slowly cooled to 0-5 ℃ of left and right, continue stirring reaction 2 h left and right;
4, after reaction finishes, above-mentioned emulsion centrifugalize, obtains medicine-containing microsphere, and with a small amount of Diluted Alcohol solution washing, then carry out vacuum drying, obtain stable medicine-containing microsphere.
The invention provides polylactic acid microsphere bag and carry ivermectin, albendazole and praziquantel technique, organic solvent with polylactic acid aqueous solution high speed dispersion containing ivermectin, albendazole and praziquantel, after volatilization organic solvent, centrifugalize, vacuum drying obtain stable medicine-containing microsphere.This method has that equipment is simple, production routine environmental protection, has very large economic and social benefit.
Accompanying drawing explanation
Preparation technology's flow process of ivermectin, albendazole and praziquantel polylactic acid microsphere.
The specific embodiment
The macromolecule carrier screening of preparing medicine-containing microsphere is polylactic acid, and its molecular weight has 25000,50000 and 87000, wherein with polylactic acid the bests of 50000 molecular weight.The concentration of polylactic acid in aqueous solution is 0.5-5%, wherein take 1% left and right as optimum.In screening parasiticide compound recipe, screen the ivermectin of macrolide structure, the praziquantel of the albendazole of rosickyite benzimidazole structure and quino pyrazine structure.According to its onset amount, design proportion is ivermectin: albendazole: praziquantel=10:3-6:2-4, best proportion is ivermectin: albendazole: praziquantel=10:5:3.The organic solvent that dissolves three kinds of crude drug can be with dichloromethane or chloroform, again with ethanol with a certain proportion of mixed solvent, according to actual solute effect and toxicity, select dichloromethane and ethanol that best boiling point is lower to make solvent, dichloromethane: ethanol=7:3,10 times of organic solvent dissolution crude drug.In the time of preparation S/O/W type emulsion, mixing speed is 400-10000 rpm, and optimal velocity is 8000 rpm.Volatilization organic solvent temperature is 30 ℃, and precipitation medicine-containing microsphere temperature is 0-20 ℃, and optimum temperature is 5 ℃ of left and right.
Further illustrate in the following embodiments the present invention, this does not limit the scope of the invention.
embodiment 1the preparation of ivermectin, albendazole and praziquantel polylactic acid microsphere
In 200 L stainless steel cauldrons (No. 1 reactor), add successively the polylactic acid 1 kg stirring at room temperature that deionized water 100 L, molecular weight are 50000 to dissolve, and it is stand-by to continue to stir 10 min.No. 2 10 L solubilizing reaction stills add dichloromethane: dissolving 4 L of dehydrated alcohol=7:3, add again 200 g ivermectins, 100 g albendazoles and 60 g praziquantel, and stirring at room temperature is dissolved.Open No. 1 stainless steel cauldron high-speed stirred, rotating speed is 8000 rpm, the pastille organic facies in No. 2 dissolving tanks is dropped to reactor No. 1 with 6 mL/min speed simultaneously, drips the mouth of pipe and wants Shen to enter level below 2/3, and approximately 1 h adds.Continue high-speed stirred, and be heated to 30 ℃, volatilization organic solvent dichloromethane.After 2 h, dichloromethane is evaporated completely entirely substantially, is more slowly cooled to 5 ℃ of left and right, continues stirring reaction 2 h left and right, and medicinal microsphere forms in a large number.Stir on limit, and above-mentioned reactant liquor is proceeded to centrifuge by limit, obtains wet medicine-containing microsphere with 3000 rpm centrifugalize.With a small amount of washing with alcohol twice, decompression, 50 ℃ of dry 2 h, obtain stable medicine-containing microsphere.
embodiment 2the preparation of ivermectin, albendazole and praziquantel polylactic acid microsphere
In 200 L stainless steel cauldrons (No. 1 reactor), add successively the polylactic acid 0.8 kg stirring at room temperature that deionized water 100 L, molecular weight are 87000 to dissolve, and it is stand-by to continue to stir 20 min.No. 2 10 L solubilizing reaction stills add chloroform: dissolving 4 L of dehydrated alcohol=7:3, add again 200 g ivermectins, 100 g albendazoles and 60 g praziquantel, and stirring at room temperature is dissolved.Open No. 1 stainless steel cauldron high-speed stirred, rotating speed is 9000 rpm, the pastille organic facies in No. 2 dissolving tanks is dropped to reactor No. 1 with 5 mL/min speed simultaneously, drips the mouth of pipe and wants Shen to enter level below 2/3, and approximately 1.5 h add.Continue high-speed stirred, and be heated to 30 ℃, volatilization organic solvents, chloroform.After 2 h, chloroform volatilizees completely substantially, is more slowly cooled to 5 ℃ of left and right, continues stirring reaction 2 h left and right, and medicinal microsphere forms in a large number.Stir on limit, and above-mentioned reactant liquor is proceeded to centrifuge by limit, obtains wet medicine-containing microsphere with 3000 rpm centrifugalize.With a small amount of washing with alcohol twice, decompression, 50 ℃ of dry 2 h, obtain stable medicine-containing microsphere.
Claims (5)
1. a polylactic acid microsphere bag carries ivermectin, albendazole and praziquantel technique, organic solvent with polylactic acid aqueous solution high speed dispersion containing ivermectin, albendazole and praziquantel, after volatilization organic solvent, centrifugalize, vacuum drying obtain stable medicine-containing microsphere.
2. require described method according to right 1, it is characterized in that polylactic acid is first dissolved in water, concentration is 0.5-5%.
3. require described method according to right 1, it is characterized in that organic solvent dichloromethane or chloroform, then with ethanol with 7:3, mix, 10 times of organic solvent dissolution crude drug.
4. require described method according to right 1, it is characterized in that mixing speed is 400-10000 rpm, optimal velocity is 8000 rpm, and volatilization organic solvent temperature is 30 ℃, and precipitation medicine-containing microsphere temperature is 0-20 ℃.
5. require described method according to right 1, it is characterized in that after water centrifugalize microsphere, need to be with absolute ethanol washing, 50 ℃, vacuum is dry.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022077087A1 (en) * | 2020-10-16 | 2022-04-21 | Ipanema Industria De Produtos Veterinarios Ltda | Microsuspension against parasites and method for obtaining same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 中国科学院近代物理研究所 | Preparation method of ivermectin sustained-release microspheres |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102302457A (en) * | 2011-09-14 | 2012-01-04 | 中国科学院近代物理研究所 | Preparation method of ivermectin sustained-release microspheres |
Non-Patent Citations (2)
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| "伊维菌素PLA/PLGA缓释微球的研究", 《甘肃农业大学》 * |
| 天津必佳药业集团: "伊可安", 《伊可安说明书》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022077087A1 (en) * | 2020-10-16 | 2022-04-21 | Ipanema Industria De Produtos Veterinarios Ltda | Microsuspension against parasites and method for obtaining same |
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