CN112370424A - Florfenicol solution and preparation method and application thereof - Google Patents

Florfenicol solution and preparation method and application thereof Download PDF

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Publication number
CN112370424A
CN112370424A CN202011341865.6A CN202011341865A CN112370424A CN 112370424 A CN112370424 A CN 112370424A CN 202011341865 A CN202011341865 A CN 202011341865A CN 112370424 A CN112370424 A CN 112370424A
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florfenicol
parts
mixture
emulsifier
mixing
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赵一阳
黎剑坤
刘肖娟
王振兴
谭志坚
符德文
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Foshan Standard Bio Tech Co Ltd
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract

The invention provides a florfenicol solution and a preparation method and application thereof, wherein the florfenicol solution comprises the following components in parts by weight: 10-55 parts of florfenicol, 2-12 parts of a drug-loaded carrier, 5-20 parts of an emulsifier, 1-7 parts of a co-emulsifier, 5-25 parts of grease, 0.5-5 parts of a flavoring agent and 0.5-4 parts of a taste blocker; the flavoring agent comprises sweetener and aromatic. The product provided by the invention has strong stability, high efficiency and safety, tastes sour and sweet, stimulates drinking water, and has wide application prospect.

Description

Florfenicol solution and preparation method and application thereof
Technical Field
The invention belongs to the field of veterinary medicines, relates to a florfenicol solution and a preparation method and application thereof, and particularly relates to a florfenicol solution for pigs and a preparation method and application thereof.
Background
Florfenicol (florfenicol), also known as florfenicol, is a novel broad-spectrum antibacterial drug, has wide application in aquaculture and animal husbandry, and particularly has irreplaceable economic value in the aspects of prevention, control and treatment of diseases caused by actinobacillus pleuropneumoniae.
The main florfenicol preparations in the current veterinary pharmacopoeia are: florfenicol soluble powder, florfenicol injection, florfenicol powder, florfenicol premix and florfenicol solution. Generally, florfenicol powder and a florfenicol premix are taken as a dressing, and have the problems of inconvenient operation, uneven mixing, incapability of well controlling the dosage and the like. With the popularization of the automatic feeding in the breeding industry, the medicine is mixed and drunk through a drinking water line to form an optimal administration mode, and the administration is convenient, the distribution is uniform, and the method is suitable for large-scale breeding.
Florfenicol mixed drink administration has some problems to be solved urgently, according to pharmacopoeia, florfenicol soluble powder and florfenicol solution are mixed drink administration, counted by florfenicol. Mixing and drinking: every 1L of water, 100-200 mg of chicken, continuously using for 3-5 days. There are no instructions or requirements on the pigs. The number of taste buds of the pigs is 3-4 times that of the pigs, the pigs are very sensitive, the florfenicol is bitter, the water intake of the pigs can be reduced due to the direct water mixing of the common florfenicol solution, the treatment effect cannot be achieved, and the normal growth and development are influenced. Most florfenicol powder is added with a cosolvent, so that the florfenicol powder can be dissolved in water, but the drug effect of the florfenicol powder is damaged. According to the reports, the taste-modifying and taste-masking technology is only applied to powder and sustained-release granules, and no taste-modifying solution is reported. And the maximum content specification of the florfenicol solution is 10 percent at present, the solubility of the aqueous solution is limited, needle crystals are easy to precipitate to block the pipeline of a drinking water line, the administration dosage is difficult to control, and the clinical application of the large-scale breeding pig herd is severely limited.
CN111374949A discloses a preparation process of florfenicol soluble powder or solution, wherein the preparation process of the soluble powder comprises the following steps: firstly, sequentially crushing and detecting selected florfenicol to obtain 1-100nm florfenicol submicron powder; secondly, adding the selected beta-cyclodextrin into a ball mill, then sequentially adding a certain amount of water and florfenicol superfine powder to obtain a pasty mixture, and carrying out reduced pressure drying and X-ray diffractometer detection on the pasty mixture; and finally, taking the florfenicol beta-cyclodextrin inclusion compound and uniformly mixing with the sucrose fine powder to obtain the florfenicol soluble powder. The florfenicol beta-cyclodextrin inclusion compound is prepared by adopting a nanometer ultramicro powder technology and a beta-cyclodextrin inclusion technology, and florfenicol soluble powder or solution prepared from the florfenicol beta-cyclodextrin inclusion compound has the advantages of water solubility improved by more than 50 times, bioavailability improved and medicament stability enhanced. But it does not solve the problem of the reduction of water intake of pigs due to the bitter taste of florfenicol.
CN110882220A discloses a method for preparing water-soluble florfenicol powder, which comprises the following steps: mixing florfenicol, beta-cyclodextrin and an absorption enhancer in a mixer for 5min to prepare a physical mixture, wherein the mass ratio of each component is as follows: 10-30 w/w% of florfenicol, 69.5-89.5 w/w% of beta-cyclodextrin and 0.5 w/w% of absorption enhancer; and (2) putting the physical mixture obtained in the step (1) into a vibration grinder to be ground to obtain the water-soluble florfenicol powder. The maximum solubility of the florfenicol is 10000mg/L, which is equivalent to 200 times of the clinical use concentration, and the water-soluble florfenicol powder prepared by the method can realize drinking water administration of a farm. But the content of florfenicol is low, and the dosage and the application amount of the medicament cannot be flexibly controlled.
CN105380909B discloses a florfenicol soluble powder and a preparation method thereof, wherein the soluble powder consists of a florfenicol polydopamine compound and a matrix diluent: the preparation method of the florfenicol polydopamine compound comprises the following steps: 1) adding a surfactant and florfenicol into a weak base solution, and uniformly mixing to obtain a mixture A, wherein the surfactant can be added or not added; 2) and adding dopamine hydrochloride into the mixture A, continuously stirring to obtain a mixture B, and spray-drying to obtain the florfenicol polydopamine compound. The preparation method comprises the following steps: 1) firstly, calculating and weighing a matrix diluent and a florfenicol polydopamine compound, and then uniformly mixing the florfenicol polydopamine compound and the matrix diluent to obtain the florfenicol soluble powder. The soluble powder contains the florfenicol polydopamine compound, so that the solubility of the florfenicol can be effectively improved, and the dissolution speed can be increased. The method is simple and easy to implement, the preparation time is short, and the production energy consumption is low. But the problem that the water intake of pigs is reduced due to the bitter taste of the florfenicol is still not solved, and the florfenicol is compounded with polydopamine, so that the drug property of the florfenicol can be influenced.
The prior florfenicol premix for pigs has the problems of inconvenient operation, uneven mixing and incapability of well controlling the administration dosage, and the florfenicol solution has the problem of reduction of the water intake of pigs due to bitter taste of the florfenicol. Therefore, how to provide a florfenicol solution with good stability, low toxic and side effects, convenient preparation and good animal taste becomes a problem to be solved urgently.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a florfenicol solution and a preparation method and application thereof, in particular to a florfenicol solution for pigs and a preparation method and application thereof. The florfenicol solution provided by the invention is compounded by selecting a natural emulsifier and a nonionic surfactant, so that the florfenicol solution has stronger stability and low toxicity; the drug-loaded dispersion is prepared by adopting a melting method, and the florfenicol content can reach 55 percent at most by combining a molecular microemulsion technology; through the proper matching of the flavoring agent and the taste blocker, the medicine is taken by drinking water in a mode of olfaction induction drinking, sweet stimulation, certain paralytic taste buds and further stimulation of drinking water; the prepared florfenicol solution can be added with water in any proportion to obtain clear and transparent liquid, can be used for automatic drinking water line administration without precipitation, can well regulate and control the dosage and drinking amount of the medicament, can ensure that the product does not block a pipeline, and is convenient to operate; the flavoring agent and the taste blocking agent are added, so that the materials are selected safely, the taste is sour and sweet, drinking water is stimulated, and the method has a wide application prospect in the future large-scale breeding background.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a florfenicol solution, which comprises the following components in parts by weight: 10-55 parts of florfenicol, 2-12 parts of a drug-carrying carrier, 5-20 parts of an emulsifier, 1-7 parts of a co-emulsifier, 5-25 parts of grease, 0.5-5 parts of a flavoring agent and 0.5-4 parts of a taste blocker.
The flavoring agent comprises sweetener and aromatic.
Wherein florfenicol can be 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 55 parts, etc., drug-carrying carrier can be 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts or 12 parts, etc., emulsifier can be 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts or 20 parts, etc., co-emulsifier can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts or 7 parts, etc., grease can be 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts, 11 parts, 12 parts, 13 parts, 14 parts, 15 parts, 16 parts, 17 parts, 18 parts, 19 parts, 20 parts, 21 parts, 22 parts, 23 parts, 24 parts or 25 parts, etc., flavoring agent can be 1.5 parts, 2.5 parts, 5 parts, 2.5 parts, 5.5 parts, 2.5 parts, 5, 3, or 25 parts, etc., of flavoring, 3 parts, 3.5 parts, 4 parts, 4.5 parts or 5 parts, etc., and the taste blocker may be used in an amount of 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts or 4 parts, etc., but is not limited to the above-mentioned values, and other values not shown in the above-mentioned numerical ranges are also applicable.
The florfenicol solution prepared by combining the florfenicol drinking mixing administration mode and the physiological characteristics of pigs can form an oil-in-water emulsion by mixing the prepared florfenicol solution with water, and the active ingredients of the florfenicol are placed in an internal oil phase, so that the bitterness of the prepared microemulsion solution is reduced, and the toxicity of the surfactant is reduced by using the combination of natural and synthetic surfactants; the flavoring agent and the taste blocker are added into the system, the pig is induced to drink by the flavoring agent, and then the sweetening agent and the taste blocker stimulate the drinking water by sweet taste, and meanwhile, certain taste blocker can stimulate and paralyze taste buds to a certain extent, so that the adverse effect of the bitter taste of florfenicol on the drinking water of the pig is further reduced.
Preferably, the florfenicol solution comprises the following components in parts by weight: 30-50 parts of florfenicol, 4-10 parts of drug-loaded carrier, 8-15 parts of emulsifier, 2-5 parts of co-emulsifier, 8-20 parts of grease, 1-3 parts of flavoring agent and 0.5-2.5 parts of taste blocker.
Preferably, the florfenicol solution also includes water.
Preferably, the florfenicol solution comprises the following components in parts by weight: 10-55 parts of florfenicol, 2-12 parts of a drug-carrying carrier, 5-20 parts of an emulsifier, 1-7 parts of a co-emulsifier, 5-25 parts of grease, 0.5-5 parts of a flavoring agent, 0.5-4 parts of a taste blocker and water.
The florfenicol solution prepared by the specific combination can automatically form an oil-in-water emulsion, and the florfenicol active ingredients are placed in an internal oil phase, so that the bitterness of the prepared microemulsion solution is reduced, and the toxicity of the surfactant is reduced by using the combination of natural and synthetic surfactants; the flavoring agent and the taste blocker are added into the system, the pig is induced to drink by the flavoring agent, and then the water is stimulated to drink by the sweet taste and the taste blocker which are arranged in the water phase, and meanwhile, certain taste blocker can stimulate and paralyze taste buds to a certain extent, so that the adverse effect of the bitter taste of the florfenicol on the drinking water of the pig is further reduced.
Preferably, the sweetener comprises a natural sweetener and/or a synthetic sweetener.
Preferably, the natural sweetener includes one or a combination of at least two of sucrose, fructose, lactose, glucose, simple syrup, aromatic syrup, glycerin, sorbitol, mannitol, stevioside, glycyrrhizin, disodium glycyrrhizinate, tripotassium glycyrrhizinate, or trisodium glycyrrhizinate, such as sucrose and simple syrup, glycerin and sorbitol, or aromatic syrup and mannitol, but is not limited to the listed combinations, and other combinations not listed within the above combinations are also applicable.
Preferably, the synthetic sweetener includes any one or a combination of at least two of sodium cyclamate, aspartame, sodium cyclamate, neohesperidin dihydrochalcone, thaumatin, acesulfame-K, saccharin, or sodium saccharin, such as a combination of thaumatin and acesulfame-K, a combination of sodium cyclamate and aspartame, or a combination of saccharin and sodium saccharin, and the like, but is not limited to the listed combinations, and other combinations not listed within the above-mentioned combination ranges are equally suitable.
Preferably, the mass ratio of the natural sweetener to the synthetic sweetener is 1:1.5 to 1:3.5, such as 1:1.5, 1:1.7, 1:1.9, 1:2.1, 1:2.3, 1:2.5, 1:2.7, 1:2.9, 1:3.1, 1:3.3 or 1:3.5, but not limited to the ratios listed, and other ratios not listed within the ranges of ratios above are equally applicable.
Preferably, the aromatic includes any one or a combination of at least two of natural spice extract, ethyl maltol, ethyl vanillin, isoamyl acetate, ethyl acetate, vanillin, ethyl vanillin, citronellal, lemon extract, mint extract, and cinnamon extract, for example, a combination of lemon extract and mint extract, a combination of lemon extract and cinnamon extract, or a combination of cinnamon extract and mint extract, but is not limited to the combinations listed above, and other combinations not listed within the above-mentioned combinations are also applicable.
Preferably, the mass ratio of the sweetener to the flavoring agent is 5:1 to 5:4, such as 5:1, 5:1.5, 5:2, 5:2.5, 5:3, 5:3.5, or 5:4, but not limited to the recited ratios, and other unrecited ratios within the above ranges of ratios are equally applicable.
The combination of the above specified parameters further improves the unpleasant odor and taste of the solution, making it more difficult for the animal to perceive the bitter taste of florfenicol.
Preferably, the taste blocker includes any one or a combination of at least two of zanthoxylum bungeanum extract, pepper extract or pepper extract, such as a combination of pepper extract and zanthoxylum bungeanum extract, a combination of zanthoxylum bungeanum extract and pepper extract or a combination of pepper extract and pepper extract, etc., but is not limited to the listed combinations, and other combinations not listed in the above-mentioned combination range are also applicable.
The Zanthoxylum bungeanum extract and the Piper nigrum extract can be used as taste blocker to block florfenicol and taste receptors in oral cavity of animals, and reduce irritation to animals.
Preferably, the florfenicol is present in the florfenicol solution in a mass ratio of 20-30%, such as 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, but not limited to the recited values, and other values not recited within the above-mentioned ranges of values are also applicable.
The florfenicol solution with the specific mass ratio of florfenicol has good sterilization effect, and can be used on an automatic drinking line to well regulate and control the drug dosage and the drinking dosage.
Preferably, the drug-loaded carrier comprises a component a.
Preferably, the a component includes any one or a combination of at least two of polyethylene glycol 4000(PEG4000), polyethylene glycol 6000(PEG6000), polyoxyethylene castor oil, polyoxyethylene monooleate, vinylpyrrolidone-vinyl acetate copolymer, soybean phospholipid or pentaerythritol tetraacetate, for example, a combination of polyethylene glycol 4000 and polyethylene glycol 6000, a combination of polyoxyethylene castor oil and polyoxyethylene monooleate, or a combination of soybean phospholipid and pentaerythritol tetraacetate, etc., but is not limited to the enumerated combinations, and other combinations not enumerated within the above-mentioned combination range are also applicable.
Preferably, the drug-loaded carrier further comprises a component B.
Preferably, the B component includes any one or a combination of at least two of mannitol, xylitol, d-xylose, maltitol, fructose, glucose, glucan or alpha-lactose, such as a combination of glucose and mannitol, a combination of xylitol and d-xylose, or a combination of maltitol and fructose sugar alcohol, but is not limited to the listed combinations, and other combinations not listed in the above combination range are also applicable.
The drug carrier composed of the components A and B can increase the solubility of the original drug, improve the content of florfenicol, shorten the preparation time, reduce the dosage of the auxiliary emulsifier, facilitate the preparation and reduce the toxicity.
Preferably, the weight ratio of the A component to the B component is (1-2): (0-1), preferably 1:1-2:1, such as 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1 or 2:1, but not limited to the ratios recited, and other ratios not recited within the ranges of ratios above apply as well.
The drug carrier composed of the component A and the component B in the specific weight ratio has better effect, can further increase the solubility of the original drug, improve the content of florfenicol, shorten the preparation time, reduce the dosage of the co-emulsifier, facilitate the preparation and reduce the toxicity.
Preferably, the florfenicol solution further includes a co-solvent in an amount of 0.5-4 parts, such as 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 3.5 parts, or 4 parts, but not limited to the recited values, and other non-recited values within the above ranges of values are also applicable.
Preferably, the co-solvent comprises Dimethylformamide (DMF) and/or ethanol.
The cosolvent can promote the florfenicol to be dispersed in the drug-carrying carrier, and the solubility of the florfenicol is enhanced.
Preferably, the emulsifier comprises a natural emulsifier and a nonionic surfactant.
The combination of the natural emulsifier and the nonionic surfactant is specially adopted as the emulsifier in the florfenicol solution, which is related by the invention, because the nonionic surfactant has good pH stability and neutralizes the defect that the natural emulsifier is greatly influenced by pH; the natural emulsifier is easy to form a polymer film, and the nonionic surfactant can effectively reduce the water-oil interfacial tension. The molecular microemulsion formed by compounding the natural emulsifier and the nonionic surfactant has strong stability, high efficiency and safety. The combination of the two can obviously reduce the addition of the emulsifier, greatly reduce the toxic and side effects and improve the safety.
Preferably, the weight ratio of the natural emulsifier to the nonionic surfactant is 1:1 to 1:2, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2, but not limited to the ratios listed, and other non-listed ratios within the ranges of the ratios listed above are equally applicable.
The natural emulsifier and the nonionic surfactant in a specific weight ratio are compounded, so that the addition amount of the emulsifier is controlled within the range of 5-20%, the formula is lower than that of a common formula, and the toxic and side effects are greatly reduced.
Preferably, the natural emulsifier includes any one or a combination of at least two of lecithin, soybean lecithin, hydrogenated soybean lecithin, lanolin acid, casein, beeswax, cholesterol or gum arabic, tragacanth gum, gelatin, casein, cholesterol, such as a combination of lecithin and soybean lecithin, a combination of soybean lecithin and hydrogenated soybean lecithin, or a combination of casein and beeswax, but is not limited to the listed combinations, and other combinations not listed within the above-mentioned combinations are also applicable.
The natural emulsifier can further reduce the toxicity of the florfenicol solution. Meanwhile, the natural emulsifier is easy to form a polymer film and a molecular microemulsion.
Preferably, the nonionic surfactant includes any one or a combination of at least two of long-chain fatty alcohol polyoxyethylene ether, long-chain fatty alcohol polyoxyethylene ester, polyoxyethylene polyol fatty acid ester, polyol long-chain fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester, polyoxyethylene alkylamine, polyoxyethylene alkylamide, fatty acid glyceride and polyglycerol fatty acid ester, such as a combination of long-chain fatty alcohol polyoxyethylene ether and long-chain fatty alcohol polyoxyethylene ester, a combination of polyoxyethylene alkylamine and polyoxyethylene alkylamide, or a combination of polyol long-chain fatty acid ester and alkylphenol polyoxyethylene ether, etc., preferably any one or a combination of at least two of long-chain fatty alcohol polyoxyethylene ester, fatty acid glyceride or alkylphenol polyoxyethylene ether, such as a combination of long-chain fatty alcohol polyoxyethylene ester and fatty acid glyceride, a combination of fatty acid ester, a fatty, A combination of long-chain fatty alcohol polyoxyethylene ester and alkylphenol polyoxyethylene ether or a combination of fatty acid glyceride and alkylphenol polyoxyethylene ether, etc., and further preferably a combination of any one or at least two of tween 80, span 60, fatty acid glyceride, octylphenol polyoxyethylene ether or nonylphenol polyoxyethylene ether, for example, a combination of tween 80 and fatty acid glyceride, a combination of span 60 and fatty acid glyceride, or a combination of tween 80 and octylphenol polyoxyethylene ether, etc., but not limited to the combinations enumerated above, and combinations not enumerated above are also applicable.
The nonionic surfactant has good pH stability, neutralizes the disadvantage that the natural emulsifier is greatly influenced by pH, and can effectively reduce the water-oil interfacial tension, and the formed molecular microemulsion has strong stability, high efficiency and safety.
Preferably, the co-emulsifier comprises any one or a combination of at least two of ethylene glycol, propylene glycol, ethanol, butylene glycol, glycerol, n-butanol, polyglycerol ester or isopropanol, such as a combination of propylene glycol and ethanol, a combination of ethanol and glycerol or a combination of n-butanol and polyglycerol ester, and the like, but is not limited to the listed combinations, and other combinations not listed within the above combinations are equally applicable.
The addition of the co-emulsifier can ensure that the system has better emulsification effect and higher water solubility, and does not block pipelines.
Preferably, the grease includes any one or a combination of at least two of isopropyl myristate (IPM), liquid paraffin, olive oil, castor oil, ethyl acetate, caprylate, caprate, ethyl oleate, polyoxyethylene castor oil (EL) or polyoxyethylene hydrogenated castor oil (RH40), such as a combination of isopropyl myristate and liquid paraffin, a combination of olive oil and castor oil, a combination of castor oil and ethyl oleate, or a combination of ethyl oleate and polyoxyethylene castor oil, etc., but is not limited to the listed combinations, and other combinations not listed within the above combinations are also applicable.
The grease is matched with the emulsifier and the co-emulsifier, so that a stable O/W type molecular microemulsion system can be formed, the grease has good water solubility, can be added with water in any proportion to form a clear and transparent product, can be automatically administered by drinking water lines, does not block pipelines, is convenient to operate, and is suitable for disease prevention, control and treatment in large-scale culture.
In a second aspect, the present invention also provides a method for preparing the florfenicol solution as described above, comprising the steps of:
(1) fusing the drug-loaded carrier to obtain a fused drug-loaded carrier;
(2) mixing florfenicol with the drug-loaded carrier melted in the step (1) to obtain a mixture A; mixing an emulsifier, an auxiliary emulsifier and grease to obtain a mixture B;
(3) mixing the mixture A, the mixture B and the mixture C in the step (2) to obtain the florfenicol solution; the preparation method of the mixture C comprises the following steps: mixing a flavoring agent and a taste blocker to obtain the mixture C.
The preparation method of the florfenicol solution adopts a melting method to fully disperse the florfenicol in the drug-loaded carrier, thereby increasing the solubility of the florfenicol, shortening the preparation time, reducing the dosage of the auxiliary emulsifier, facilitating the preparation and reducing the toxicity.
Preferably, the melting temperature in step (1) is 58 to 80 ℃, such as 58 ℃, 60 ℃, 62 ℃, 64 ℃, 66 ℃, 68 ℃, 70 ℃, 72 ℃, 74 ℃, 76 ℃, 78 ℃ or 80 ℃, but not limited to the recited values, and other values not recited in the above numerical ranges are also applicable.
Preferably, the emulsifier, the co-emulsifier and the oil and fat are mixed in step (2) by stirring, the stirring time is 30-50min, and the stirring speed is 500-1000r/min, wherein the time can be 30min, 32min, 34min, 36min, 38min, 40min, 42min, 44min, 46min, 48min or 50min, etc., and the speed can be 500r/min, 550min, 600min, 650min, 700min, 750min, 800min, 850min, 900min, 950min or 1000min, etc., but is not limited to the recited values, and other non-recited values in the above numerical ranges are also applicable.
Preferably, the mixing manner in step (3) is stirring mixing, the stirring time is 0.5-2h, and the stirring speed is 500-1000r/min, wherein the time can be 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h or 2h, etc., and the speed can be 500r/min, 550min, 600min, 650min, 700min, 750min, 800min, 850min, 900min, 950min or 1000min, etc., but not limited to the enumerated values, and other unrecited values in the above numerical ranges are also applicable.
Preferably, the specific flow of mixing the mixture a, the mixture B and the mixture C in the step (2) in the step (3) is as follows: mixing the mixture A and the mixture B in the step (2), and then adding the mixture C.
Preferably, the step of mixing the flavoring agent and taste blocker in step (3) further comprises mixing with water.
As a preferred technical scheme of the invention, the preparation method of the florfenicol solution comprises the following steps:
(1) melting the drug-loaded carrier at 58-80 ℃ to obtain the melted drug-loaded carrier;
(2) stirring and mixing florfenicol, cosolvent and the drug-loaded carrier melted in the step (1) at the speed of 500-1000r/min for 30-50min to obtain a mixture A;
(3) stirring the emulsifier, the co-emulsifier and the grease for 30-50min at the speed of 500-1000r/min, and uniformly mixing to obtain a mixture B;
(4) stirring and mixing the mixture A in the step (2) and the mixture B in the step (3), dripping the mixture C into the mixture, and stirring the mixture for 0.5 to 2 hours at the speed of 500 and 1000r/min to obtain the florfenicol solution; the preparation method of the mixture C comprises the following steps: dissolving a flavoring agent and a taste blocker in water to obtain said mixture C.
In a third aspect, the invention also provides the application of the florfenicol solution in preparing veterinary drugs for pigs.
Florfenicol has irreplaceable economic value in the aspects of prevention, control and treatment of diseases caused by the porcine actinobacillus pleuropneumoniae. Because the taste bud number of the pig is 3-4 times of that of the human, the pig is very sensitive, the florfenicol is bitter, the drinking water amount of the pig is reduced due to the direct water mixing of the common florfenicol solution, the treatment effect cannot be achieved, and the normal growth and development are influenced. The florfenicol solution provided by the invention has the highest content of 55%, can be used on an automatic drinking line, can well regulate and control the dosage and drinking amount of the medicament, simultaneously, the aromatic, the sweetening agent and the taste blocking agent in the flavoring agent are matched together, and the drinking water is smoothly administrated by drinking water through the modes of drinking water induction, certain paralysis of taste buds, sour and sweet taste and further stimulation of drinking water; the product has sour and sweet taste, stimulates drinking water, and has good treatment effect on diseases caused by the actinobacillus pleuropneumoniae.
Compared with the prior art, the invention has the following beneficial effects:
the florfenicol solution provided by the invention has the characteristics of low toxicity, sour and sweet taste, stimulation to drinking water and capability of well regulating and controlling the dosage of medicines and drinking amount.
The emulsifier in the florfenicol solution provided by the invention is compounded by adopting a natural emulsifier and a nonionic surfactant, so that the florfenicol solution has strong stability, high efficiency and safety, the addition amount of the emulsifier can be controlled to be about 5-20%, and the addition amount is lower than that of a common formula, and the toxic and side effects are greatly reduced.
The grease in the florfenicol solution provided by the invention is matched with the emulsifier and the co-emulsifier, so that a stable O/W type molecular microemulsion system can be formed, the florfenicol solution has good water solubility, can be added with water in any proportion to form clear and transparent liquid, can be automatically administered by drinking water lines, does not block pipelines, is convenient to operate, and is suitable for disease prevention, control and treatment in large-scale culture.
The florfenicol solution provided by the invention is added with the flavoring agent and the taste blocker, the flavoring agent, the sweetening agent and the taste blocker in the flavoring agent are matched together, and drinking is induced, taste buds are paralyzed to a certain degree, and the sour and sweet taste further stimulates a drinking mode, so that drinking administration is smoothly carried out, the materials are selected safely, the taste is sour and sweet, drinking is stimulated, good palatability is realized, and the florfenicol solution has a wide application prospect in the future large-scale breeding background.
The florfenicol solution is combined with a solid dispersion preparation technology and a molecular microemulsion technology, a melting method is adopted to prepare the drug-loaded dispersion, so that an O/W type microemulsion solution is obtained, the bitter florfenicol is in an inner oil phase, and the stimulation of the bitter taste of the florfenicol to animal drinking water is weakened; meanwhile, the content of the florfenicol solution can reach 55 percent at most, the prepared florfenicol solution can be added with water in any proportion to form clear and transparent liquid, can be used for automatic drinking water line administration, has no precipitation, can well regulate and control the drug dosage and drinking amount, does not block pipelines, is convenient to operate, and is suitable for disease prevention, control and treatment in large-scale culture.
Detailed Description
To further illustrate the technical means and effects of the present invention, the following further describes the technical solution of the present invention with reference to the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.
Example 1
The embodiment provides a florfenicol solution, which comprises the following components in parts by weight:
florfenicol 30%
Pentaerythritol tetraacetate 2.25%
1.125 percent of mannitol
DMF 1％
Lecithin 3%
Tween 804.5%
N-butanol 4%
Isopropyl myristate (IPM) 18%
0.2 percent of cane sugar
Aike-Bentan 0.51%
0.29% of lemon extract
1% of pepper extract
Balance of water
The preparation method comprises the following steps:
heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, stirring until the mixture is molten, adding DMF and florfenicol, and stirring at 750r/min for 40min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing lecithin, Tween 80, n-butanol, and isopropyl myristate (IPM), stirring at 750r/min for 40min to obtain oil phase B. Dissolving sucrose, Ixose, fructus Citri Limoniae extract, and fructus Piperis extract in water to obtain water phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 1h at 750r/min, dropwise adding the water phase C into the system, and stirring while dropwise adding until a clear and transparent florfenicol solution is obtained.
Example 2
The embodiment provides a florfenicol solution, which comprises the following components in parts by weight:
florfenicol 40%
PEG 4000 4.5％
3 percent of fructose sugar alcohol
DMF 2％
Lecithin 5%
Polyoxyethylene nonyl phenyl ether 5%
3.5 percent of isopropanol
Olive oil 14%
0.44 percent of glycerin
Saccharin sodium 0.67%
Mint extract 0.89%
1.5 percent of pepper extract
Balance of water
The preparation method comprises the following steps:
heating the mixture of PEG4000 and fructosyl alcohol to 58 ℃, stirring until the mixture is molten, adding DMF and florfenicol, and stirring at 500r/min for 50min until the mixture is completely molten to obtain the drug-loaded compound A. Heating polyoxyethylene nonyl phenyl ether to 70 ℃, mixing with lecithin, isopropanol and olive oil, and stirring at 500r/min for 50min to obtain oil phase B. Dissolving glycerol, saccharin sodium, herba Menthae extract, and fructus Piperis extract in water to obtain water phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 2h at 500r/min, dropwise adding the water phase C into the system, and stirring while dropwise adding until a clear and transparent florfenicol solution is obtained.
Example 3
The embodiment provides a florfenicol solution, which comprises the following components in parts by weight:
florfenicol 50%
PEG 6000 5.25％
Alpha-lactose 4.5%
6 percent of soybean lecithin
12 percent of fatty glyceride
2 percent of polyglycerol ester
Polyoxyethylene hydrogenated castor oil (RH40) 8%
0.46 percent of simple syrup
Aike, Bentan 1.62%
0.42% of cinnamon extract
2 percent of pepper extract
Balance of water
The preparation method comprises the following steps:
heating the mixture of PEG6000 and alpha-lactose to 60 ℃, stirring until the mixture is molten, adding florfenicol, and stirring for 30min at a speed of 1000r/min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing soybean phospholipid, fatty glyceride, polyglycerol ester, and polyoxyethylene hydrogenated castor oil (RH40) at 1000r/min, and stirring for 30min to obtain oil phase B. Dissolving simple syrup, tabasheer, cortex Cinnamomi Japonici extract, and fructus Zanthoxyli extract in water to obtain water phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 0.5h at the speed of 1000r/min, dropwise adding the water phase C into the system, and stirring while dropwise adding until a clear and transparent florfenicol solution is obtained.
Example 4
The embodiment provides a florfenicol solution, which comprises the following components in percentage by weight;
florfenicol 25%
Pentaerythritol tetraacetate 7.2%
Mannitol 4.5%
DMF 4％
Lecithin 8%
Tween 8012%
N-butanol 7%
Isopropyl myristate (IPM) 25%
1.02 percent of sorbitol
Aike-Bentan 2.55%
1.43 percent of lemon extract
Fructus Piperis extract 4%
Balance of water
The preparation process is referred to example 1.
Example 5
The embodiment provides a florfenicol solution, which comprises the following components in percentage by weight;
florfenicol 55%
Pentaerythritol tetraacetate 1.2%
Mannitol 0.8%
DMF 0.5％
Lecithin 2%
Tween 803%
1 percent of n-butyl alcohol
Isopropyl myristate (IPM) 5%
Mannitol 0.1%
Aike-Bentan 0.26%
0.14% of lemon extract
Fructus Piperis extract 0.5%
Balance of water
The preparation process is referred to example 1.
Example 6
This example provides a florfenicol solution, the components of which differ from those of example 1 only in the ratio of 5% lecithin and 2.5% tween 80.
The preparation process is referred to example 1.
Example 7
This example provides a florfenicol solution, the components of which differ from the composition of example 1 only in that the ratio of lecithin is 1.875% and the ratio of tween 80 is 5.625%.
The preparation process is referred to example 1.
Example 8
This example provides a florfenicol solution whose components differ from the composition of example 1 only in that the florfenicol is 10% and the reduced portion is supplemented with water.
The preparation process is referred to example 1.
Example 9
This example provides a florfenicol solution whose components differ from the composition of example 1 only in that the florfenicol is 15% and the reduced portion is supplemented with water.
The preparation process is referred to example 1.
Example 10
The embodiment provides a florfenicol solution, which comprises the following components in parts by weight:
florfenicol 30%
Pentaerythritol tetraacetate 9%
Mannitol 5%
DMF 3％
Lecithin 5%
Tween 8015%
N-butanol 7%
Isopropyl myristate (IPM) 23%
0.2 percent of cane sugar
Aike-Bentan 0.5%
0.3 percent of lemon volatile oil
2 percent of pepper extract
The preparation method comprises the following steps:
heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, stirring until the mixture is molten, adding DMF and florfenicol, and stirring at 750r/min for 40min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing lecithin, Tween 80, n-butanol, and isopropyl myristate (IPM), stirring at 750r/min for 40min to obtain oil phase B. Mixing the aike, the Bentan, the lemon volatile oil and the pepper extract to obtain C. Adding the drug-loaded compound A into the oil phase B, stirring for 1h at 750r/min, adding the C, and stirring to obtain the florfenicol self-microemulsion solution.
Comparative example 1
A commercially available florfenicol solution.
Comparative example 2
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that the cinnamon extract and the zanthoxylum extract are not included, the reduced fraction is supplemented with water.
The preparation method comprises the following steps:
heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, stirring until the mixture is molten, adding florfenicol, and stirring at 750r/min for 40min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing lecithin, Tween 80, n-butanol, and isopropyl myristate (IPM), stirring at 750r/min for 40min to obtain oil phase B. Dissolving simple syrup, Ixon and Bentan in water to obtain water phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 0.5h at 1000r/min, dropwise adding the water phase C, and stirring while dropwise adding until a clear and transparent florfenicol microemulsion solution is obtained.
Comparative example 3
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that no simple syrup, no acek, no cinnamon extract, reduced portion supplemented with water are included.
The preparation method comprises the following steps:
heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, stirring until the mixture is molten, adding florfenicol, and stirring at 750r/min for 40min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing lecithin, Tween 80, n-butanol, and isopropyl myristate (IPM), stirring at 750r/min for 40min to obtain oil phase B. Dissolving fructus Zanthoxyli extract in water to obtain water phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 0.5h at 1000r/min, dropwise adding the C while stirring until a clear and transparent florfenicol solution is obtained.
Comparative example 4
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that the simple syrup, Izod Benzenweet, Zanthoxylum extracts, reduced fractions supplemented with water, are excluded.
The preparation method comprises the following steps:
heating the mixture of pentaerythritol tetraacetate and mannitol to 80 ℃, stirring until the mixture is molten, adding florfenicol, and stirring at 750r/min for 40min until the mixture is completely molten to obtain the drug-loaded compound A. Mixing lecithin, Tween 80, n-butanol, and isopropyl myristate (IPM), stirring at 750r/min for 40min to obtain oil phase B. The cinnamon extract is dissolved in water to obtain an aqueous phase C. Adding the drug-loaded compound A into the oil phase B, stirring for 0.5h at 1000r/min, dropwise adding C and water while stirring until a clear and transparent florfenicol solution is obtained.
Comparative example 5
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that the simple syrup, exendin, reduced portion is supplemented with water is not included.
Comparative example 6
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that no zanthoxylum bungeanum extract is included, the reduced fraction being supplemented with water.
Comparative example 7
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that the cinnamon extract is not included, and the reduced portion is supplemented with water.
Comparative example 8
This example provides a florfenicol solution whose components differ from the composition of example 3 only in that the simple syrup, Izod, Bentan, cinnamon extract and Zanthoxylum extracts are not included, and the reduced fractions are supplemented with water.
Test one: comparative test for emulsifier content
The test method comprises the following steps: the preparation method comprises the steps of preparing a mixture of a main drug and an oil phase by using 30g of florfenicol, 2.25g of pentaerythritol tetraacetate, 1.5g of mannitol, 1g of DMF, 7.5g of an emulsifier, 4g of n-butyl alcohol, 18g of IPM, 0.2g of cane sugar, 0.51g of Ixon, 0.29g of a lemon extract and 1g of a pepper extract as a formula, dropwise adding distilled water while stirring until a clear and transparent molecular microemulsion with good fluidity is formed, recording the amount of the used distilled water, and calculating the mass percentage of the emulsifier in a system. The results are shown in Table 1:
TABLE 1 percentage of different emulsifiers added to form a molecular microemulsion
Figure BDA0002798818860000211
The result shows that the compounding of the natural emulsifier and the nonionic surfactant can effectively reduce the addition of the emulsifier by 1.07-2.32%, is beneficial to reducing the toxicity of the emulsifier and improving the biological safety.
And (2) test II: acute toxicity test
Test animals: the weight of the long white pig is 15-20 kg, the long white pig is raised in a common animal house, and the long white pig is managed conventionally and can drink water freely.
The test method comprises the following steps: the method comprises the steps of randomly dividing 60 pigs into 6 groups according to body weight, 10 pigs in each group, preparing 5 groups of diluents with different concentrations from the florfenicol solution in the embodiment 1, performing intragastric administration on each group, observing poisoning symptoms, recording death numbers, and searching a dosage range when the death rate is 0-100%. The results are shown in Table 2:
TABLE 2 acute toxicity test results for florfenicol solution
Group of Number of Dosage (mg/kg. w) Number of deaths Mortality (%)
1 10 2000 0 0
2 10 2480 1 10
3 10 2980 3 30
4 10 3500 6 60
5 10 4040 9 90
6 10 4600 10 100
The dose range when the mortality of the florfenicol flavoring solution is 0-100% is 2000-4600 mg/kg & w through a test, LD50 is calculated by a probability unit weighted regression method, the fitting degree test P is 0.950, which shows that the fitting degree is good, the florfenicol solution LD50 is 3243.339mg/kg & w, and the 95% confidence limit is 2966.108-3525.361 mg/kg & w. According to the acute toxicity classification standard of chemical substances, the florfenicol-flavored solution belongs to a low-toxicity (501-5000 mg/kg.w) class medicine, the LD50 of the florfenicol-flavored solution is 130 times of the clinically recommended dosage (20-30 mg/kg.w), the toxicity is obviously reduced, and the florfenicol-flavored solution is safe to use within the clinical treatment dosage range.
And (3) test III: stability investigation test
The test method comprises the following steps: using the florfenicol solutions provided in examples 1, 4-7 and comparative example 1 as subjects, the subjects were placed in an incubator at 40. + -.2 ℃ and 75. + -.5% relative humidity for 1, 2, 3 and 6 months to observe appearance and detect the residual florfenicol content, and the residual percentage of the residual florfenicol content to the original florfenicol content was calculated. The results are shown in Table 3:
TABLE 3 accelerated test results for florfenicol solution
Figure BDA0002798818860000231
Figure BDA0002798818860000241
The result shows that in a high-temperature and high-humidity environment, compared with the existing commercial florfenicol solution, the florfenicol solution provided by the invention has the advantages of stable shape, uniform clarification, low content reduction of florfenicol, unobvious difference and excellent stability.
And (4) testing: water solubility test
The test method comprises the following steps: the florfenicol solutions provided by the examples 1, 4 to 7 and the comparative example 1 are mixed with water at a ratio of 1:20000, 1:50000 and 1:70000, the mixture is uniformly mixed and stood at room temperature, the stability of the florfenicol solution in water solubility is observed, the content of the residual florfenicol is measured on the days 1, 3, 6 and 10, and the residual percentage of the residual florfenicol content in the original florfenicol content is calculated. The results are shown in Table 4:
TABLE 4 florfenicol solution Water solubility test results
Figure BDA0002798818860000251
The result shows that compared with the florfenicol solution sold in the market, the florfenicol solution provided by the invention can be quickly dissolved in water to be uniform, is kept stand and observed for 10 days, has stable appearance shape, does not have the phenomena of layering demulsification and drug precipitation, and does not block a water line by automatic linear water mixing administration; the florfenicol content is measured, and is slightly reduced but the reduction amplitude is small, which shows that the water solution has excellent stability and is suitable for large-scale culture.
And (5) testing: palatability testing
The test method comprises the following steps: 100 pigs in a growing white fattening middle stage of a certain pig farm are selected as test objects, test pigs with similar development states are selected and grouped, the weight of the test pigs ranges from 60 kg to 70kg, the number of the test pigs is 10 for each group, and the total number of the test pigs is 10. The florfenicol solution provided by the embodiment 3 and the comparative examples 1-8 of the invention is mixed with 50kg of water per 1mL, the change of the water drinking amount of the pigs is observed, meanwhile, a commercially available florfenicol solution group is set to mix water with the same proportion, and a blank control group is normally drunk without adding medicines. The results are shown in Table 5:
TABLE 5 florfenicol solution palatability test results
Group of Time (h) required for drinking 10 kg of water
Example 3 37
Comparative example 1 78
Comparative example 2 76
Comparative example 3 75
Comparative example 4 75
Comparative example 5 76
Comparative example 6 72
Comparative example 7 68
Comparative example 8 77
Blank group 39
The results show that the taste sensitive pigs in example 3 did not reduce water intake, indicating that the florfenicol solution with added flavors and taste blockers stimulated the drinking of water with good palatability. Compared with the comparative example 1, the water intake is obviously reduced; comparative example 8, which contains no sweetener, aroma and taste blocker at all, and has a water intake equivalent to that of comparative example 1; while for the formula with only one or two of the sweetener, the aromatic and the taste blocker added, the water intake is only slightly increased compared with the water intake of the comparative example 1, but the increase amount is very limited. In summary, in the formula, under the synergistic effect of the sweetening agent, the aromatic agent and the taste blocking agent in the flavoring agent, the effect of drinking water of pigs can be not influenced, and the effect of drinking water administration can be obtained. The absence of any substance can obviously affect drinking water, and the effect of not affecting drinking water cannot be obtained, so that the treatment effect of drinking water administration is difficult to obtain. In comparative example 7, the water consumption was slightly increased due to the fragrance of Zanthoxylum bungeanum extract, which somewhat compensates for the lack of fragrance such as cinnamon extract, but was still much less than in example 3.
And (6) test six: clinical treatment trial
Test animals: the selected test animal is a 35-month-old February-old Changbai piglet which has no respiratory disease characteristics in clinic and normal lung respiratory sound. The porcine actinobacillus pleuropneumoniae is recovered by 10 percent-33mL of the dose of the medicine for eliminating the toxin of the trachea, and the medicine is fed regularly after the toxin is eliminated. After 15 days, cough and dyspnea appear, one sick piglet is randomly selected for autopsy, the lung has typical lesion, hemolytic bacterial colonies are separated from nasal and bronchial secretions and lung lesion positions and grow in cAMP and satellites, urease tests show positive, and infection success is determined.
The test method comprises the following steps: according to the report, the ratio of daily feed intake to water intake of pigs is 1 (2-2.5), and the usage amount of the florfenicol premix on the pigs is 1-2kg of premix added into every 1000kg of feed with the specification of 2 percent. The treatment test is carried out by using 40% florfenicol solution in example 2, and 3 test dose groups are determined by conversion, wherein the test dose groups comprise a low dose group of florfenicol with water being 1:50000, a normal dose group of florfenicol with water being 1:20000 and a high dose group of florfenicol with water being 1:3000 in parts by weight, and the test dose groups are freely drunk for 7 days after being mixed with water in corresponding proportions.
Taking the disappearance of the characteristic features of the typical diseases of the respiratory tract as curing, the weakening of the characteristic as effective, the non-weakening of the characteristic or the death of the suckling pigs as ineffective, dividing 30 sick pigs into 3 groups, recording the treatment effect of the florfenicol solution with low, normal and high dose, and recording the weight gain condition of the pigs before and after administration. The results are shown in tables 6 and 7:
TABLE 6 statistics of the therapeutic effect of florfenicol solution on swine mycoplasmal disease piglets
Group of Number of suckling pigs Number of invalid Effective number Number of cure Effective rate%
Low dose group 10 3 4 3 70
Normal dose group 10 1 4 5 90
High dose group 10 0 2 8 100
TABLE 7 piglet weight gain statistics before and after administration of florfenicol solution
Group of Initial average body weight (kg) Terminal average body weight (kg) Average daily gain (kg)
Low dose group 18.36±1.03 20.81±1.54 0.35±0.11
Normal dose group 18.45±1.22 21.66±1.63 0.46±0.43
High dose group 18.61±1.10 21.93±1.39 0.47±0.51
The results show that florfenicol solution in three groups shows excellent treatment effect, wherein the effective rate of the normal dosage group reaches 90%. In order to reduce the generation of drug resistance, the clinical application recommends normal dosage for treatment, namely, the florfenicol solution is calculated according to florfenicol, 20L of water is added into 1ml of florfenicol solution for free drinking, and the florfenicol solution can play a good role in treating respiratory diseases caused by mycoplasma suis infection.
The applicant states that the florfenicol solution and the preparation method and application thereof of the present invention are illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it is not meant that the present invention must rely on the above examples to be carried out. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.

Claims (10)

1. The florfenicol solution is characterized by comprising the following components in parts by weight: 10-55 parts of florfenicol, 2-12 parts of a drug-loaded carrier, 5-20 parts of an emulsifier, 1-7 parts of a co-emulsifier, 5-25 parts of grease, 0.5-5 parts of a flavoring agent and 0.5-4 parts of a taste blocker;
the flavoring agent comprises sweetener and aromatic.
2. The florfenicol solution as set forth in claim 1 comprising, in parts by weight: 30-50 parts of florfenicol, 4-10 parts of a drug-loaded carrier, 8-15 parts of an emulsifier, 2-5 parts of a co-emulsifier, 8-20 parts of grease, 1-3 parts of a flavoring agent and 0.5-2.5 parts of a taste blocker;
preferably, the florfenicol solution also includes water.
3. A florfenicol solution according to claim 1 or 2, wherein the sweetener comprises a natural sweetener and/or a synthetic sweetener;
preferably, the natural sweetener comprises any one or a combination of at least two of sucrose, fructose, lactose, glucose, simple syrup, aromatic syrup, glycerol, sorbitol, mannitol, stevioside, glycyrrhizin, disodium glycyrrhizinate, tripotassium glycyrrhizinate, or trisodium glycyrrhizinate;
preferably, the synthetic sweetener comprises any one or a combination of at least two of sodium cyclamate, aspartame, sodium cyclamate, neohesperidin dihydrochalcone, thaumatin, acesulfame-k, saccharin, or sodium saccharin;
preferably, the mass ratio of the natural sweetener to the synthetic sweetener is 1:1.5-1: 3.5;
preferably, the aromatic comprises any one or combination of at least two of natural spice extract, ethyl maltol, ethyl vanillin, isoamyl acetate, ethyl acetate, vanillin, ethyl vanillin, citronellal, lemon extract, mint extract, or cinnamon extract;
preferably, the mass ratio of the sweetening agent to the flavoring agent is 5:1-5: 4;
preferably, the taste blocker comprises any one or a combination of at least two of zanthoxylum bungeanum extract, pepper extract or capsicum extract;
preferably, the mass ratio of the florfenicol in the florfenicol solution is 20-30%.
4. The florfenicol solution of any one of claims 1-3 wherein the drug-loaded carrier includes a component A;
preferably, the component A comprises any one or a combination of at least two of PEG4000, PEG6000, polyoxyethylene castor oil, polyoxyethylene monooleate, vinyl pyrrolidone-vinyl acetate copolymer, soybean phospholipid or pentaerythritol tetraacetate;
preferably, the drug-loaded carrier further comprises a component B;
preferably, the component B comprises any one or a combination of at least two of mannitol, xylitol, d-xylose, maltitol, fructose, glucose, glucan or alpha-lactose;
preferably, the weight ratio of the A component to the B component is (1-2) to (0-1), preferably 1:1-2: 1;
preferably, the florfenicol solution also comprises 0.5-4 parts of cosolvent;
preferably, the co-solvent comprises dimethylformamide and/or ethanol;
preferably, the emulsifier comprises a natural emulsifier and a nonionic surfactant;
preferably, the weight ratio of the natural emulsifier to the nonionic surfactant is 1:1-1: 2;
preferably, the natural emulsifying agent comprises any one or a combination of at least two of lecithin, soybean lecithin, hydrogenated soybean lecithin, lanolin acid, casein, beeswax, cholesterol or gum arabic, tragacanth gum, gelatin, casein, cholesterol;
preferably, the nonionic surfactant comprises any one or a combination of at least two of long-chain fatty alcohol polyoxyethylene ether, long-chain fatty alcohol polyoxyethylene ester, polyoxyethylene polyol fatty acid ester, polyol long-chain fatty acid ester, alkylphenol polyoxyethylene ether, fatty acid polyoxyethylene ester, polyoxyethylene alkylamine, polyoxyethylene alkylamide, fatty glyceride and polyglycerol fatty acid ester, preferably any one or a combination of at least two of long-chain fatty alcohol polyoxyethylene ester, fatty glyceride and alkylphenol polyoxyethylene ether, and further preferably any one or a combination of at least two of tween 80, span 60, fatty glyceride, octylphenol polyoxyethylene ether and nonylphenol polyoxyethylene ether.
5. A florfenicol solution as claimed in any one of claims 1-4 wherein the co-emulsifier comprises any one or a combination of at least two of ethylene glycol, propylene glycol, ethanol, butylene glycol, glycerol, n-butanol, polyglycerol esters, or isopropanol.
6. A florfenicol solution as claimed in any one of claims 1-5 wherein the oil or fat comprises any one of isopropyl myristate, liquid paraffin, olive oil, castor oil, ethyl acetate, caprylate, caprate, ethyl oleate, polyoxyethylene castor oil or polyoxyethylene hydrogenated castor oil or a combination of at least two thereof.
7. A method for the preparation of a florfenicol solution according to any one of claims 1-6, characterized in that the method for the preparation of a florfenicol solution comprises the steps of:
(1) fusing the drug-loaded carrier to obtain a fused drug-loaded carrier;
(2) mixing florfenicol with the drug-loaded carrier melted in the step (1) to obtain a mixture A; mixing an emulsifier, an auxiliary emulsifier and grease to obtain a mixture B;
(3) mixing the mixture A, the mixture B and the mixture C in the step (2) to obtain the florfenicol solution; the preparation method of the mixture C comprises the following steps: mixing a flavoring agent and a taste blocker to obtain the mixture C.
8. The method for preparing a florfenicol solution according to claim 7, wherein the temperature of the melting in step (1) is 58-80 ℃;
preferably, the mixing manner of mixing the emulsifier, the co-emulsifier and the grease in the step (2) is stirring and mixing, the stirring time is 30-50min, and the stirring speed is 500-1000 r/min;
preferably, the mixing manner in the step (3) is stirring mixing, the stirring time is 0.5-2h, and the stirring speed is 500-1000 r/min;
preferably, the specific flow of mixing the mixture a, the mixture B and the mixture C in the step (2) in the step (3) is as follows: mixing the mixture A and the mixture B in the step (2), and then adding a mixture C into the mixture;
preferably, the step of mixing the flavoring agent and taste blocker in step (3) further comprises mixing with water.
9. The method for preparing a florfenicol solution according to claim 7 or 8, characterized in that the method for preparing a florfenicol solution comprises the steps of:
(1) melting the drug-loaded carrier at 58-80 ℃ to obtain the melted drug-loaded carrier;
(2) stirring and mixing florfenicol, cosolvent and the drug-loaded carrier melted in the step (1) at the speed of 500-1000r/min for 30-50min to obtain a mixture A;
(3) stirring the emulsifier, the co-emulsifier and the grease for 30-50min at the speed of 500-1000r/min, and uniformly mixing to obtain a mixture B;
(4) stirring and mixing the mixture A in the step (2) and the mixture B in the step (3), dripping the mixture C into the mixture, and stirring the mixture for 0.5 to 2 hours at the speed of 500 and 1000r/min to obtain the florfenicol solution; the preparation method of the mixture C comprises the following steps: dissolving a flavoring agent and a taste blocker in water to obtain said mixture C.
10. Use of a florfenicol solution according to any one of claims 1-6 in the preparation of veterinary drugs for swine.
CN202011341865.6A 2020-11-25 2020-11-25 Florfenicol solution and preparation method and application thereof Pending CN112370424A (en)

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Application publication date: 20210219