38 results about "Tildipirosin" patented technology

The present invention provides a tildipirosin preparation method, tylosin as a starting reactant is used for preparation of 23-hydroxyl-5-O-mycaminose-tylosin lactone, 14-aldehyde-5-O-mycaminose-tylosin lactone is further prepared, and finally tildipirosin(IV) is prepared; by determining of reasonable oxidizing conditions, the use of expensive iodine can be avoided, the reaction conditions can be reduced; by controlling of the reaction conditions, two times of hydrolysis reaction can be performed in one pot, the operation steps can be reduced, the technical purpose of overall cost reduction can be achieved, and the method is less in step, simple in process, low in cost, and suitable for large-scale industrial production need.

The invention discloses a tildipirosin hapten and an artificial antigen as well as preparation methods thereof, wherein the preparation method of the tildipirosin hapten comprises the following step of: introducing 3-carboxyl propionyl or 2-carboxyl benzoyl on the base of the base structure of the tildipirosin, so that the prepared tildipirosin hapten not only keeps the base structure of the tildipirosin but also is beneficial to the coupling of a carrier protein, is used for preparing the artificial antigen, and can be easily identified by an animal body; and the artificial antigen of the tildipirosin takes the tildipirosin hapten as a base, and is prepared by a mixed anhydride method or an active ester method, and the prepared tildipirosin hapten can be used for detecting the ELISA (enzyme-linked immuno sorbent assay) residual of the tildipirosin. Compared with the existing detection method for the joint use of solid phase extraction liquid-mass (SPE-HPLC-MS / MS) (solid phase extraction-high performance liquid chromatography-memory system / memory system), the preparation method has the advantages of being simple and convenient, quick, high in sensitivity, suitable for high throughput screening. The preparation method provided by the invention is used for preparing the tildipirosin hapten and the artificial antigen.

The invention provides a preparation method of tildipirosin. The preparation method comprises the following steps: tylosin A is hydrolyzed in an acidic solution, a hydrolysis product is extracted into an organic solvent A after hydrolysis, a sulfonate esterification reagent is added for sulfonate acidification reaction in the presence of alkali, extraction and layering are performed after the reaction, and a sulfonate esterified product is prepared; finally, the sulfonate esterified product is dissolved in an organic solvent B, piperidine and formic acid are added for a reductive amination reaction, a solvent is removed by distillation after the reaction, then an organic solvent C is added to dissolve the remaining reaction product, piperidine and alkali are added for an ammoniation reaction, acid is added after the reaction for extraction, layering and alkali regulation, and the final product of tildipirosin is prepared. The preparation method has the advantages that the reaction route is shortened, the total yield is increased, the reaction condition is mild, the operation is simple, and industrial production is facilitated.

The invention relates to a synthetic method of tildipirosin. The method comprises the following key synthetic steps: synthesizing 23-hydroxyl-20-carbonyl-5-O-carbon-enzyme glucosamine-tylactone in a one-pot method, synthesizing 20, 23-carbonyl-5-O-carbon-enzyme glucosamine-tylactone in a catalytic oxidation method and synthesizing the tildipirosin in a one-step ammoniation method. The tildipirosin is synthesized from tylosin only in three steps, so that the procedures are simple, the reaction yield is relatively high, the average total yield is 90 percent or more, and the purity of a final product is 98 percent or more; and moreover, all raw materials are safe and easy to get, byproducts are likely to recycle, and the industrialized application value is relatively high.

The invention relates to injection tildipirosin composition freeze-dried powder and a method for preparing the same. The injection tildipirosin composition freeze-dried powder is characterized in that raw material liquid is subjected to freeze-drying to obtain the injection tildipirosin composition freeze-dried powder and comprises tildipirosin, organic acid and excipients. The injection tildipirosin composition freeze-dried powder and the method have the advantages that the sterile injection tildipirosin composition freeze-dried powder can be prepared by the aid of the method and can be dissolved in sterile physiological saline to obtain solution during clinical use, the solution is low in viscosity and easy to suck and inject, the injection tildipirosin composition freeze-dried powder is easy and convenient to clinically use and little in irritation on animals, and accordingly the service stability, safety and convenience of the injection tildipirosin composition freeze-dried powder can be improved.

The invention provides a tildipirosin-containing medicinal composition. The dosage form of the medicinal composition is an injection, the composition comprises, by mass / volume, 1-20% of tildipirosin, 10-25% of polyvinylpyrrolidone, an acid, and the balance of water, and the use amount of the acid makes the pH value of the composition be 5.5-6.5; and the tildipirosin is tildipirosin or a pharmaceutically acceptable salt thereof. Tildipirosin in above raw materials is a special antibiotic for livestock and poultry, does not bring a cross drug resistance problem for people, is a first selected medicine for treating animal respiratory tract diseases, and has a very good treatment effect on Streptococcus suis, Pasteurella multocida, Haemophilus parasuis, Actinobacillus pleuropneumoniae and mycoplasma.

The invention discloses a tildipirosin composition and applications thereof in treating or preventing poultry respiratory tract diseases. The tildipirosin composition comprises tildipirosin / pharmaceutically-acceptable salts of tildipirosin, sodium houttuyfonate, and a pharmaceutically-acceptable carrier; and can be made into different oral dosage forms such as soluble powder, granule, oral liquid, premix, and the like. The provided tildipirosin composition has the characteristics of wide distribution in poultry body, large apparent volume of distribution, long half life, slow elimination, little using amount, and good curative effect, and has a good curative effect on poultry respiratory tract diseases caused by bacteria and mycoplasma.

The invention relates to a tildipirosin injection. The injection comprises the following components in percentages by mass: 4-20% of tildipirosin, 1-9% of a pH regulator, 30-50% of an organic solvent, and the balance of water for injection, the sum of the mass percentages of the components is 100%. The invention also relates to a preparation method of the tildipirosin injection. By the tildipirosin injection and the preparation method thereof, a preparation technology is simple, raw materials are low in cost and easy to obtain, and the properties of a preparation are stable. The tildipirosin injection is suitable for industrial mass production, and therefore, the application prospect is wide.

The invention discloses a tildipirosin content determining method. The method is an HPLC (high performance liquid chromatography) method, an Agilent Zorbax SB-C18 5mu m 4 .6*250mm chromatographic column is adopted; 0.3% trifluoroacetic acid and phosphate buffer-acetonitrile in the volume ratio being 70-75:25-30 is taken as a mobile phase, and pH of the buffer is regulated to 2.5 by triethylamine;determining wavelength is 270-290 nm; column temperature is 30-40 DEG C; flow rate is 0.8 -1.2 ml / min; a sample is quantified according to the sum of areas of a main peak and an isomer peak with an external standard method. The mobile phase system is stable, and determining data is reliable; the method is good in specificity, reproducibility, precision, linearity and accuracy; an isomer can be detected accurately under the chromatographic conditions, and the main peak and the isomer peak can be separated effectively.

The invention discloses a long-acting compound tildipirosin injection and a preparation method thereof. The long-acting compound tildipirosin injection comprises the following main components: tildipirosin, flunixin meglumine and sinomenine. The invention provides a long-acting compound injection special for animals for veterinary clinic, wherein the injection not only can be used for treating respiratory system infectious diseases caused by sensitive bacteria, but also can help to treat or reduce the stress of sick animals; and combination of drugs can significantly improve the clinical symptoms, and can enhance the activity of antibacterial drugs, reduce the use amount of drugs, reduce the administration frequency, reduce animal stress, enhance animal compliance and reduce labor intensity, and the injection is convenient to use.

The present invention relates to a detection method of Tildipirosin content. The detection method uses high performance liquid chromatography to determine the content, and then the Tildipirosin content is calculated by an external standard method. The present invention uses high performance liquid chromatography to determine the content of Tildipirosin, and then the external standard method is used to quantify the content of Tildipirosin in sample. The method is accurate and simple, and has good reproducibility and high sensitivity. When Tildipirosin is between 0.1mg / ml-3.0mg / ml, good linear relationship exists, and the correlation coefficient is 0.9995. Through verification, the method is applicable to quality control and detection of Tildipirosin in veterinary drugs business.

The invention provides a preparation method of tildipirosin. The preparation method of the tildipirosin comprises the following steps: mixing tylosin, piperidine, a reducing agent and an organic solvent and performing first amination reaction to obtain a compound I; mixing a compound I, acid and water and performing neutralizing reaction to obtain a salt solution; adding acid into the salt solution step by step to perform hydrolysis, and performing alkaline treatment to obtain a compound III; mixing the compound III, piperidine, a reducing agent and an organic solvent and performing second amination reaction to obtain the tildipirosin. The tylosin serves as the raw material, the 20th aldehyde group of the tylosin is transformed into piperidyl through the amination reaction, so that byproducts caused by hydrolysis of the aldehyde group in the subsequent hydrolysis reaction is avoided; the 4th glycosyl and 15th glycosyl are removed through the hydrolysis, the 23rd hydroxyl is transformedinto piperidyl through oxidation reaction and amination reaction sequentially, and the tildipirosin is obtained, so that the byproducts are effectively reduced and the total yield is increased.

The present invention relates to a method for preparing amorphous tildipirosin. The amorphous tildipirosin has an endothermic peak at 135-171 DEG C and has an exothermic peak at 186-210 DEG C in a TG-DSC spectrum and has no recognizable diffraction peak in an XPRD spectrum. The preparation method comprises steps as follows: selecting isopropyl ether as a solvent for dissolution, then adding water to precipitate solids, and drying a wet sample thoroughly after filtration to obtaining an amorphous product. The amorphous product has good stability and can be preserved for a long period without degradation. The amorphous tildipirosin is used for preparing a pharmaceutical preparation, and the dosage form of the pharmaceutical preparation can be premix, tablets, pills, powder, granules, capsules or injections. Compared with other crystal forms of tildipirosin, the amorphous tildipirosin has better solubility and higher bioavailability.

The invention discloses a Tildipirosin suspension injection and a preparation method thereof. Every 100ml of the Tildipirosin suspension injection contains the following components in mass proportion: 2-10g of Tildipirosin, 0.2-1.0g of a wetting agent, 0.5-2g of a suspending aid, 0.01-0.1g of a preservative, 1.0-2.0g of a deflocculating agent and 0.002-0.008g of a pH regulator, wherein the deflocculating agent is sodium tartrate. The Tildipirosin suspension injection disclosed by the invention has the advantages that the wetting agent is utilized for wetting a Tildipirosin medicine, and Tildipirosin is uniformly dispersed in water in a micron-scale particle state by utilizing physical smashing, shearing and dispersing effects of the suspending aid and a multifunctional emulsifying and dispersing machine. The preparation method of the Tildipirosin suspension injection is simple and easy to operate; and compared with common injection, solubility is low, conversion of isomers does not exist, a preparation is more stable, and Tildipirosin is taken as a time-dependent medicine. The suspension injection disclosed by the invention has slow release effect and can maintain longer-time effective blood concentration of a target animal, so that medicine efficacy is obviously improved.

The invention relates to a Tildipirosin hexamethylene compound and a preparation method. Characteristic peaks exist in an X-ray powder diffraction spectrum at diffraction angles 2 theta which is 4.94-5.34, 6.58-6.98, 7.68-8.08, 8.46-8.86, 10.44-10.84, 10.86-11.26, 12.06-12.46, 13.04-13.44, 13.72-14.12, 14.30-14.70, 15.98-16.38, 16.62-17.02, 17.08-17.48, 17.74-18.14, 18.50-18.90, 18.94-19.34, 19.68-20.08, 20.10-20.50, 20.54-20.94, 21.38-21.78 and the like. The preparation method is simple, and the Tildipirosin hexamethylene compound can be prepared by a constant temperature suspension crystal transition method or a cooling crystallisation method, obtained products are stick-shaped, have complete crystal habit and are uniform in particle size.

The invention provides a tildipirosin 1,4-dioxane solvate and a preparation method thereof. Characteristic peaks occur in an X-ray powder diffraction pattern represented by 2theta when 2theta is equal to 6.06+ / -0.2, 8.42+ / -0.2, 9.34+ / -0.2, 9.94+ / -0.2, 10.28+ / -0.2, 12.34+ / -0.2, 13.44+ / -0.2, 13.74+ / -0.2, 14.66+ / -0.2, 15.58+ / -0.2, 15.78+ / -0.2, 16.40+ / -0.2, 17.00+ / -0.2, 17.90+ / -0.2, 18.60+ / -0.2, 19.32+ / -0.2, 20.10+ / -0.2, 21.40+ / -0.2, 22.34+ / -0.2, 22.68+ / -0.2, 23.34+ / -0.2 and 24.18+ / -0.2. The preparation method employs a constant-temperature suspended crystal transformation process and is simple in process and low in energy consumption. The tildipirosin 1,4-dioxane solvate is in a rod shape and crystal is of a regular shape.

The invention relates to a method for quickly hydrolyzing 6-deoxy-D-allose in tylosin. The method comprises the following steps: immobilizing sulfo-containing carbon-based nano solid acid in a primarymicroreactor with active functional groups, then injecting an aqueous solution of tylosin hydrochloride into the primary microreactor, and carrying out a cyclic reaction, when the residual amount ofthe tylosin is less than 4%, pumping the above-mentioned reaction solution into a secondary microreactor, fully mixing the reaction solution with a halogenated hydrocarbon organic solvent and an alkali solution, and separating out a light phase by using a centrifugal extractor to obtain high-purity 6-deoxy-D-allocatolactone. According to the method, 6-deoxy-D-allose on tylosin lactone molecules can be rapidly and efficiently hydrolyzed, and production efficiency of full-hydrolyzed byproducts is reduced, so that the purposes of optimizing a reaction route of tildipirosin, shortening a reactionperiod, reducing production cost and improving product quality are achieved.

The invention relates to a Tildipirosin acetone solvent compound and a preparation method. An X-ray powder diffraction spectrum of the Tildipirosin acetone solvent compound has characteristic peaks at a diffraction angle 2theta which is equal to 6.12 degrees plus or minus 0.2 degrees, 8.48 degrees plus or minus 0.2 degrees, 9.39 degrees plus or minus 0.2 degrees, 9.98 degrees plus or minus 0.2 degrees, 10.32 degrees plus or minus 0.2 degrees, 11.40 degrees plus or minus 0.2 degrees, 13.46 degrees plus or minus 0.2 degrees, 13.90 degrees plus or minus 0.2 degrees, 14.58 degrees plus or minus 0.2 degrees, 15.78 degrees plus or minus 0.2 degrees, 16.64 degrees plus or minus 0.2 degrees, 17.20 degrees plus or minus 0.2 degrees, 17.94 degrees plus or minus 0.2 degrees, 18.88 degrees plus or minus 0.2 degrees, 19.58 degrees plus or minus 0.2 degrees, 20.16 degrees plus or minus 0.2 degrees, 20.64 degrees plus or minus 0.2 degrees, 22.10 degrees plus or minus 0.2 degrees, 22.74 degrees plus or minus 0.2 degrees, 23.38 degrees plus or minus 0.2 degrees, 24.64 degrees plus or minus 0.2 degrees and 26.30 degrees plus or minus 0.2 degrees. The preparation method is simple, and a prepared product is block-shaped, has a complete crystal habit and has the characteristics of good fluidity, high bulk density and good stability.

The invention discloses a crude product crystallization device for preparing tildipirosin, and relates to the technical field of tildipirosin preparation, wherein the crude product crystallization device comprises a crystallization kettle, a heating sleeve arranged on the outer wall of the lower part of the crystallization kettle in a sleeving manner and a motor arranged at the top of the crystallization kettle; feeding pipes are arranged on the two sides of the top surface of the crystallization kettle, and a rotating shaft is rotationally arranged in the middle of the inner top surface of the crystallization kettle; a stirring rod is arranged at the bottom end of the rotating shaft; and a rotating shaft body is sleeved with a flow guide mechanism used for distributing liquid medicine. An added solution can conveniently drop on the surface layer of an original solution in a kettle body through a flow baffle and a liquid discharge pipe in the flow guide mechanism, and the added solution can be conveniently mixed in the deep layer of the original solution under the action of centrifugal force during rotation through the arrangement of a liquid guide assembly and a sleeve, and the added solution is quickly dispersed and mixed into the original solution, so that the mixing uniformity of the two solutions is improved; and the crystal purity of the prepared crude tildipirosin product is improved, and the operation efficiency of the crude tildipirosin product during preparation is improved.

The invention discloses a long-acting compound tildipirosin injection and a preparation method thereof. The long-acting compound tildipirosin injection comprises the following main components: tildipirosin, flunixin meglumine and sinomenine. The invention provides a long-acting compound injection special for animals for veterinary clinic, wherein the injection not only can be used for treating respiratory system infectious diseases caused by sensitive bacteria, but also can help to treat or reduce the stress of sick animals; and combination of drugs can significantly improve the clinical symptoms, and can enhance the activity of antibacterial drugs, reduce the use amount of drugs, reduce the administration frequency, reduce animal stress, enhance animal compliance and reduce labor intensity, and the injection is convenient to use.

The invention discloses a synthesis and purification method of tildipirosin. The method comprises the following steps of dissolving tylosin phosphate in an organic solvent, adding formic acid and piperidine, and performing a heating reaction; performing cooling, adding water and hydrobromic acid, and performing standing for layering; hydrolyzing an aqueous solution A, performing cooling, adding the organic solvent, and performing standing for layering; adding alkali into a water phase to adjust the pH value to 6.5-7.0, adding the organic solvent and alkali to adjust the pH value to be greater than 13, performing standing for layering to obtain a filtrate, and controlling the water content to be less than 0.1% through atmospheric distillation; adding triphenylphosphine and pyridine, performing heating, dropwise adding an iodine solution, continuously reacting, performing cooling, adding alkali for quenching, and performing standing for layering; adding an alkali catalyst and piperidine into the filtrate C, performing a heating reaction, performing cooling, adding acid to adjust the pH value to 6.20-6.80, and performing standing for layering; adding the organic solvent into the water phase, and performing standing for layering; and continuously adding the organic solvent and the alkali into the water phase to adjust the pH value to be greater than 13, and performing standing for layering to obtain a filtrate D. The method is simple to operate, mild in reaction condition, low in cost and high in product yield, and the purity and content of the obtained tildipirosin are both greater than 99%; and the method is beneficial to industrial production.

The invention provides a tildipirosin-containing medicinal composition. The dosage form of the medicinal composition is an injection, the composition comprises, by mass / volume, 1-20% of tildipirosin, 10-25% of polyvinylpyrrolidone, an acid, and the balance of water, and the use amount of the acid makes the pH value of the composition be 5.5-6.5; and the tildipirosin is tildipirosin or a pharmaceutically acceptable salt thereof. Tildipirosin in above raw materials is a special antibiotic for livestock and poultry, does not bring a cross drug resistance problem for people, is a first selected medicine for treating animal respiratory tract diseases, and has a very good treatment effect on Streptococcus suis, Pasteurella multocida, Haemophilus parasuis, Actinobacillus pleuropneumoniae and mycoplasma.

The invention discloses a Tildipirosin suspension injection and a preparation method thereof. Every 100ml of the Tildipirosin suspension injection contains the following components in mass proportion: 2-10g of Tildipirosin, 0.2-1.0g of a wetting agent, 0.5-2g of a suspending aid, 0.01-0.1g of a preservative, 1.0-2.0g of a deflocculating agent and 0.002-0.008g of a pH regulator, wherein the deflocculating agent is sodium tartrate. The Tildipirosin suspension injection disclosed by the invention has the advantages that the wetting agent is utilized for wetting a Tildipirosin medicine, and Tildipirosin is uniformly dispersed in water in a micron-scale particle state by utilizing physical smashing, shearing and dispersing effects of the suspending aid and a multifunctional emulsifying and dispersing machine. The preparation method of the Tildipirosin suspension injection is simple and easy to operate; and compared with common injection, solubility is low, conversion of isomers does not exist, a preparation is more stable, and Tildipirosin is taken as a time-dependent medicine. The suspension injection disclosed by the invention has slow release effect and can maintain longer-time effective blood concentration of a target animal, so that medicine efficacy is obviously improved.

The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for synthesizing a Tildipirosin intermediate 20-piperidinyl-23-iodine-5-O-mycaminose-tylactone.The method comprises the following steps of: 20-piperidinyl-5-O-mycaminose-tylactone and hydroiodic acid are subjected to a reflux reaction to obtain 20-piperidinyl-23-iodine-5-O-mycaminose-tylactone. The method has the advantages of simple treating process, small amount of waste liquid, low cost of treatment for environmental protection and high product yield; and the product obtained has high purity.

The invention discloses a method for determining the content of tildipirosin. The method uses a high-performance liquid chromatography for analysis and an external standard method for quantification.Octadecyl silane is used as a chromatographic column, determining is carried out at a wavelength of 285 nm, and through verification, the method has the characteristics of high sensitivity, good repeatability and high accuracy. The limit of quantification is 0.34 [mu]g / ml, the limit of detection is 0.113 [mu]g / ml, the linear relationship is good in the concentration range of 0.34-150 [mu]g / mL, wherein R<2>=0.9997. The method can be used for effectively detecting tildipirosin and is an accurate and efficient determination method.

The invention relates to a Tildipirosin acetone solvent compound and a preparation method. An X-ray powder diffraction spectrum of the Tildipirosin acetone solvent compound has characteristic peaks at a diffraction angle 2theta which is equal to 6.12 degrees plus or minus 0.2 degrees, 8.48 degrees plus or minus 0.2 degrees, 9.39 degrees plus or minus 0.2 degrees, 9.98 degrees plus or minus 0.2 degrees, 10.32 degrees plus or minus 0.2 degrees, 11.40 degrees plus or minus 0.2 degrees, 13.46 degrees plus or minus 0.2 degrees, 13.90 degrees plus or minus 0.2 degrees, 14.58 degrees plus or minus 0.2 degrees, 15.78 degrees plus or minus 0.2 degrees, 16.64 degrees plus or minus 0.2 degrees, 17.20 degrees plus or minus 0.2 degrees, 17.94 degrees plus or minus 0.2 degrees, 18.88 degrees plus or minus 0.2 degrees, 19.58 degrees plus or minus 0.2 degrees, 20.16 degrees plus or minus 0.2 degrees, 20.64 degrees plus or minus 0.2 degrees, 22.10 degrees plus or minus 0.2 degrees, 22.74 degrees plus or minus 0.2 degrees, 23.38 degrees plus or minus 0.2 degrees, 24.64 degrees plus or minus 0.2 degrees and 26.30 degrees plus or minus 0.2 degrees. The preparation method is simple, and a prepared product is block-shaped, has a complete crystal habit and has the characteristics of good fluidity, high bulk density and good stability.

The invention relates to tildipirosin nanoemulsion. Every 100 g of the tildipirosin nano-emulsion comprises the following components by weight: 0.01 to 6.0 g of tildipirosin, 2.0 to 10.0 g of lauric aldehyde, 0.1 to 8.0 g of isopropyl myristate, 5.0 to 15.0 g of polyoxyethylene lauryl ether, 15.0 to 25.0 g of polyoxyethylene (60) hydrogenated castor oil, 1.0 to 8.0 g of glycerol and the balance of deionized water. The tildipirosin nanoemulsion disclosed by the invention is oil-in-water emulsion, is solid when the temperature is lower than or equal to 35 DEG C, and is liquid when the temperature is higher than 35 DEG C; and the drug emulsion droplet particle size is 10 to 60nm. The tildipirosin nanoemulsion solves the problem that tildipirosin is insoluble in water, can be clinically administered by drinking water, and is more convenient to use; pharmacological bioavailability is improved; and the tildipirosin nanoemulsion is good in safety, and can be used for preventing and treating the diarrheal disease caused by calf escherichia coli infection. The invention further discloses a preparation method of the tildipirosin nanoemulsion. The preparation method is high in process operability; the tildipirosin nanoemulsion can be produced by conventional veterinary medicine production equipment, the technology is easy to transform, and the market prospect is wide.