A method for preparing an isoxazoline anthelmintic formulation

Abstract

The present application relates to a kind of isoxazoline anthelmintic preparation preparation method, comprising the following steps: S1. the raw material drug is weighed with solvent component;Wherein, solvent component includes antioxidant, cosolvent, flavouring agent and surfactant;S2. first, add surfactant, while stirring, add cosolvent, then cooling;S3. flavouring agent, antioxidant, raw material drug are sequentially added, and stirring is dissolved;S4. filter, fill and pack, and the preparation obtained in the application is orally administered, can be mutually soluble with water in any ratio, has good stability, high safety, good curative effect, greatly expands the clinical application range of isoxazoline anthelmintic preparation, and preparation method is simple, suitable for mass production.

Description

Technical Field

[0001] This invention relates to the field of veterinary drugs, specifically to a method for preparing an isoxazoline anthelmintic formulation, and more specifically, to a method for preparing a fluranal formulation. Technical Background

[0002] Fluralaner is a novel, highly effective insecticide belonging to the isoxazoline class. It works by interfering with the gamma-aminobutyric acid (GABA)-gated chloride ion channels of parasites, leading to over-excitation of their nervous system and ultimately death. Compared to traditional insecticides, isoxazoline insecticides differ significantly in their target site, molecular structure, and selectivity. Isoxazoline insecticides are primarily used to treat fleas and ticks in pet cats and dogs, and red mites in poultry.

[0003] Fluranar has relatively low solubility in water, so it is usually administered to patients via intravenous injection or oral capsules. However, its solubility is affected by various factors, such as temperature, pH, and water quality. While existing fluranar formulations can achieve a certain insecticidal effect, they inevitably degrade rapidly under varying water volumes and even water quality conditions, resulting in low bioavailability. Furthermore, the formulations are often too viscous, requiring prolonged and vigorous stirring during both production and use to ensure uniform mixing. This viscous solution also leaves significant residue in production equipment and dispensing containers, leading to low dispensing efficiency. Summary of the Invention

[0004] To address the aforementioned limitations, this invention proposes a method for preparing isoxazoline-based anthelmintic formulations.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] This invention provides a method for preparing an isoxazoline anthelmintic formulation, comprising the following steps:

[0007] S1. Weigh the active pharmaceutical ingredient and solvent components; wherein the solvent components include antioxidants, cosolvents, flavoring agents and surfactants; wherein the amounts of the surfactants and cosolvents are in a mass ratio of (3-8):1.

[0008] S2. First, add the surfactant, then add the co-solvent while stirring, and then cool down;

[0009] S3. Add flavoring agent, stir, then quickly add antioxidant, stir until completely dissolved, then add raw drug, stir until dissolved;

[0010] S4. Filter and fill to obtain the product.

[0011] In some embodiments of the present invention, in step S1, the active pharmaceutical ingredient includes fluranal; further, the amount of fluranal used is 0.1-5 parts by mass.

[0012] In some embodiments of the present invention, in step S1, the antioxidant includes at least one of anhydrous sodium sulfite, sodium metabisulfite, sodium thiosulfate, and vitamin E; further, the amount of the antioxidant is 0.1-5 parts by mass.

[0013] In some embodiments of the present invention, in step S1, the surfactant includes at least one of Tween 20, Tween 40, Tween 80, and Span 85; further, the amount of the surfactant is 40-80 parts by mass.

[0014] In some embodiments of the present invention, in step S1, the co-solvent includes at least one of propylene glycol, carbomer, mannitol, ethanol, and polyethylene glycol 400; further, the amount of the co-solvent is 10-30 parts by mass; preferably, the co-solvent is a mixture of ethanol and polyethylene glycol 400 in a mixing ratio of 2:3.

[0015] In some embodiments of the present invention, the viscosity of the surfactant and cosolvent mixture is 100cp-3000cp (20℃-30℃), 100cp-1000cp (20℃-30℃), and most preferably 200cp-650cp (20℃-30℃). Appropriate viscosity ensures that the degradation of the active pharmaceutical ingredient due to water influence is mitigated without excessively increasing the drug's dissolution time.

[0016] In some embodiments of the present invention, in step S1, the flavoring agent includes at least one of xylitol, sucrose, sucralose, and sodium saccharin; further, the amount of the flavoring agent is 1-10 parts by mass.

[0017] In some embodiments of the present invention, in step S2, the stirring time is 1 hour; the cooling temperature is reduced to 40°C.

[0018] In some embodiments of the present invention, in step S3, before adding the active pharmaceutical ingredient, namely freranil, the solution stirring temperature is 20-60°C, and most preferably, the stirring temperature is 20-30°C; furthermore, after adding the flavoring agent, the stirring time is 10-15 minutes each time, which helps to shorten the dissolution time of the mixture system. If the antioxidant and the active pharmaceutical ingredient are added directly, the dissolution time of the entire mixture system will be prolonged.

[0019] In some embodiments of the present invention, in step S3, after adding the active pharmaceutical ingredient, namely flurana, the solution stirring temperature is 20-60°C; most preferably, the stirring temperature is 20-30°C; further, the stirring time after adding flurana is 1 hour.

[0020] In some embodiments of the present invention, in step S4, the filtration is membrane filtration; further, the filter membrane is polytetrafluoroethylene, nylon, or polyethersulfone, and the pore size of the filter membrane is 0.22 μm.

[0021] In some embodiments of the present invention, the active pharmaceutical ingredient and solvent components, by mass parts, include 0.1-5 parts of freranal, 60-80 parts of surfactant, 1-10 parts of flavoring agent, 10-30 parts of cosolvent, and 0.1-5 parts of antioxidant.

[0022] Compared with the prior art, the present invention has achieved at least the following technical effects:

[0023] (1) The combined addition of surfactants and cosolvents, along with the stirring process, improves the compatibility of the materials and makes the solution more stable.

[0024] (2) The addition of antioxidants makes the fluranar solution stable under the influence of high temperature, high humidity and light.

[0025] (3) The antioxidant must be added before the fluorellana. The solution temperature should not be too high when adding the antioxidant, otherwise it will affect the antioxidant effect. The solution needs to be stirred separately before adding the antioxidant, otherwise it will prolong the dissolution time of the mixture in the later stage.

[0026] (4) The filter membrane has a pore size of 0.22μm, which can remove bacteria and ensure that the Freranar solution is a sterile solution before opening.

[0027] (5) Fluranar is a drug that is almost insoluble in water. The fluranar solution obtained by the technical solution of the present invention can be prepared to be miscible with water in any proportion, which can better promote the absorption of fluranar. Detailed Implementation

[0028] This invention provides a method for preparing an isoxazoline anthelmintic formulation. Specifically, it includes the following steps:

[0029] S1. Weigh the active pharmaceutical ingredient and solvent components; wherein the solvent components include antioxidants, cosolvents, flavoring agents and surfactants; wherein the amounts of the surfactants and cosolvents are in a mass ratio of (3-8):1.

[0030] S2. First, add the surfactant, then add the co-solvent while stirring, and then cool down;

[0031] S3. Add flavoring agent, stir, then quickly add antioxidant, stir until completely dissolved, then add raw drug, stir until dissolved;

[0032] S4. Filter and fill to obtain the product.

[0033] The present invention will be further described in detail below with reference to embodiments. The description herein is merely illustrative and is not intended to limit the scope of the invention.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the specification is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. All reagents and instruments used herein are commercially available, and the characterization methods involved are described in relevant prior art and will not be repeated herein.

[0035] Example 1

[0036] Weigh out the following ingredients: 5g of fluranal, 1g of anhydrous sodium sulfite, 6g and 9g of ethanol, 9g of polyethylene glycol 400, 2g of sucrose, and 73g of Tween 80. Add Tween 80 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 20°C. Add sucrose and stir for 10 minutes. Then quickly add anhydrous sodium sulfite and stir until completely dissolved. Add fluranal and stir at 150 rpm until dissolved. Stir for another hour while maintaining the solution temperature in the mixing tank at 20°C. Filter the solution through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0037] Example 2

[0038] Weigh out 1g of the main components: flurana, 3g of sodium thiosulfate, 20g of polyethylene glycol 400, 70g of Tween 20, and 3g of xylitol. Add Tween 20 to a mixing tank, then add polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 30°C. Add xylitol and stir for 10 minutes. Then quickly add sodium thiosulfate and stir until completely dissolved. Add flurana, maintaining the solution temperature in the mixing tank at 30°C, and stir at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of flurana oral solution.

[0039] Example 3

[0040] Weigh out 0.1g of the main ingredient, fluranal, 6g and 9g of ethanol, polyethylene glycol 400, 3g of vitamin E, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 30°C. Add sucralose and stir for 10 minutes. Quickly add vitamin E and stir until completely dissolved. Add fluranal, maintaining the solution temperature in the mixing tank at 30°C, and stir at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0041] Comparative Example 1

[0042] Weigh out 0.1g of the main ingredient, fluranal, 3g of vitamin E, 5g of sucralose, and 95g of Span 85. Add Span 85 to the mixing tank, maintaining the temperature of the mixing tank at 30 degrees Celsius. Add sucralose to the mixing tank and stir for 10 minutes. Then quickly add vitamin E and stir until completely dissolved. Add fluranal, maintaining the temperature of the mixing tank at 30 degrees Celsius, and stir at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0043] Comparative Example 2

[0044] Weigh out 0.1g of the main ingredient, fluranal, 6g and 9g of ethanol, polyethylene glycol 400, 3g of vitamin E, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 60°C. Add sucralose and stir for 10 minutes. Quickly add vitamin E and stir until completely dissolved. Add fluranal, maintaining the solution temperature in the mixing tank at 70°C and stirring at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0045] Comparative Example 3

[0046] Weigh out 0.1g of the main ingredient, fluranal, 6g and 9g of ethanol, polyethylene glycol 400, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 30°C. Add sucralose and stir for 10 minutes. Add fluranal, maintaining the solution temperature in the mixing tank at 30°C, and stir at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0047] Comparative Example 4

[0048] Weigh out 0.1g of the main ingredient, flurana, 6g and 9g of ethanol, polyethylene glycol 400, 3g of vitamin E, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the temperature of the solution mixing tank at 30°C. First, add sucralose and stir for 10 minutes. Add flurana and stir until completely dissolved. Then add vitamin E. Maintain the temperature of the solution mixing tank at 30°C and stir at 150 rpm until dissolved. Stir for another hour. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of flurana oral solution.

[0049] Comparative Example 5

[0050] Weigh out 0.1g of the main ingredient, fluranal, 6g and 9g of ethanol, polyethylene glycol 400, 3g of vitamin E, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 30°C. Add sucralose and stir for 10 minutes. Then quickly add vitamin E and stir until completely dissolved. Add fluranal, maintaining the solution temperature in the mixing tank at 30°C, and stir at 130 rpm until dissolved. Stir for another 0.5 hours. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0051] Comparative Example 6

[0052] Weigh out 0.1g of the main ingredient, fluranal, 6g and 9g of ethanol, polyethylene glycol 400, 3g of vitamin E, 5g of sucralose, and 80g of Span 85. Add Span 85 to a mixing tank, then add ethanol and polyethylene glycol 400 while stirring. Maintain the solution temperature in the mixing tank at 30°C. Add sucralose, then quickly add vitamin E, and then directly add fluranal. Maintain the solution temperature in the mixing tank at 30°C and stir at 150 rpm. If no dissolution is observed, continue stirring for 4 hours until completely dissolved. Filter through a 0.22μm polytetrafluoroethylene (PTFE) membrane and fill into vials to obtain 100ml of fluranal oral solution.

[0053] Example 4

[0054] The water solubility of samples from Examples 1-3 and Comparative Examples 1, 5, and 6 was investigated. 10 ml of each example sample was added to 10 ml, 50 ml, 100 ml, and 500 ml of water, respectively, and shaken well. The phenomena were observed. The results showed that the example samples were miscible with water in any ratio. The sample in Comparative Example 1 became turbid due to the lack of a co-solvent. This indicates that a co-solvent can improve the material compatibility of the solution, promoting its miscibility with water in any ratio. The sample in Comparative Example 5 became turbid due to the short stirring frequency and time, indicating that specific stirring time and frequency can improve the solubility of the sample. The sample in Comparative Example 6 was not miscible with water in any ratio because the next material was added without thorough stirring. Furthermore, the operations of Examples 1-3 and Comparative Example 6 show that if the flavoring agent is added without stirring, and the antioxidant and active pharmaceutical ingredient are added quickly, the stirring and dissolution time of the entire mixture will be greatly prolonged.

[0055] Table 1. Results of water solubility studies for samples from Examples 1-3 and Comparative Example 1.

[0056]

[0057] Example 5

[0058] The properties, content and related substances of the samples from Example 3 and Comparative Example 2 were investigated.

[0059] Table 2. Results of the investigation of sample properties, content, and related substances in Example 3 and Comparative Example 2.

[0060] Example 3 Comparative Example 2 Properties pale yellow clear solution Yellow clear solution Related substances - single impurities (%) 0.37 1.37 Related substances - Total impurities (%) 0.68 2.55 content 98.79 96.48

[0061] As shown in Table 2, excessively high solution preparation temperature will cause the sample color to darken and the content to decrease.

[0062] Example 6

[0063] The stability of the samples from Example 3 and Comparative Example 3 was investigated according to the guidelines of Part I, Section 9001 of the Chinese Veterinary Pharmacopoeia, examining their properties, content, and total related substances. The detection methods are as follows:

[0064] [Content Determination] Determined by high performance liquid chromatography (Appendix 0512).

[0065] Chromatographic conditions and system suitability tests: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1% formic acid solution-acetonitrile (70:30) was used as the mobile phase; the flow rate was 0.6 mL / min; the column temperature was 45 °C; and the detection wavelength was 265 nm. The theoretical plate number, calculated based on the Freranar peak, was not less than 4000.

[0066] Assay: Accurately weigh an appropriate amount of this product, dissolve and dilute it in acetonitrile to prepare a solution containing 0.10 mg of fluranarana per ml. Inject 3 μl of this solution into the liquid chromatograph and record the chromatogram. Separately, accurately weigh an appropriate amount of fluranarana reference standard, dissolve and dilute it in acetonitrile to prepare a solution containing 0.10 mg per ml, and determine it using the same method. Simultaneously, determine the relative density of this product. Convert the amount of the test sample to milliliters and calculate the result using the external standard method based on the peak area.

[0067] The method for determining the content of substances under light exposure is as follows: Accurately measure an appropriate amount of the test solution under the content determination method, and quantitatively dilute it with acetonitrile to prepare a solution containing approximately 1.0 μg per ml, as a control solution. Inject 3 μl of the control solution into the liquid chromatograph, and adjust the detection sensitivity so that the peak height of the main component is approximately 20% of full scale. The resolution between the main component peak and related impurity peaks and adjacent peaks should meet the requirements. Then, accurately measure 3 μl each of the test solution and the control solution, and inject them separately into the liquid chromatograph, recording the chromatograms up to twice the retention time of the main peak. If there are impurity peaks in the chromatogram of the test solution, the total amount of impurities should not exceed twice the area of ​​the main peak of the control solution (2%).

[0068] High temperature test: Take samples from Example 3 and Comparative Examples 3-4, open them and place them in a constant temperature chamber at 60°C for 10 days. Take samples for testing on the 5th and 10th days.

[0069] High humidity test: Take samples from Example 3 and Comparative Examples 3-4, place them open in a stabilization chamber with a humidity of 75% for 10 days, and take samples for testing on the 5th and 10th days.

[0070] Light exposure test: Samples from Example 3 and Comparative Examples 3-4 were placed under an illuminance of 4500 lx ± 500 lx for 10 days, and samples were taken for testing on days 5 and 10. Table 3 shows that the sample from the examples exhibited good stability under high temperature, high humidity, and light exposure conditions. The sample from Comparative Example 3 showed decreased stability and increased related substances under high temperature, high humidity, and light exposure conditions due to the lack of antioxidants. The sample from Comparative Example 4 showed decreased stability and increased related substances because the antioxidant effect was weakened after the addition of freranilate under high temperature, high humidity, and light exposure conditions.

[0071] Table 3. Results of stability studies for samples from Example 3 and Comparative Example 3.

[0072]

[0073] It is understood that the above-described embodiments are merely exemplary embodiments used to illustrate the principles of the present invention; however, the present invention is not limited thereto and is therefore not intended to limit this application. For those skilled in the art, various modifications, alterations, equivalent substitutions, or improvements can be made without departing from the spirit and essence of the present invention, and all such modifications, alterations, equivalent substitutions, or improvements are considered to fall within the protection scope of the present invention.

Claims

1. A method for preparing an isoxazoline anthelmintic formulation, characterized by, The method comprises the following steps: S1. weighing the raw material medicine and solvent ingredients; wherein the solvent ingredients are composed of antioxidants, cosolvents, flavoring agents and surfactants; wherein the amount of the surfactants and the cosolvents is (3-10):1 in mass fraction; S2. first adding the surfactants, adding the cosolvents while stirring, and then cooling; S3. adding the flavoring agents, stirring, quickly adding the antioxidants, stirring until all are dissolved, adding the raw material medicine, and stirring until dissolved; S4. filtering and filling to obtain the product; In step S1, the raw material medicine is fluralaner; the antioxidants include at least one of anhydrous sodium sulfite, sodium pyrosulfite, sodium thiosulfate and vitamin E; the surfactants are at least one of Tween 20, Tween 40, Tween 80 and Span 85; the cosolvents are at least one of ethanol and polyethylene glycol 400; and the flavoring agents are at least one of xylitol, sucrose, sucralose and sodium saccharin; In step S2, the stirring time is 1 h; and the cooling temperature is lowered to 40℃; In step S3, the stirring temperature is 20-60℃; and the stirring time is 10-15 min.

2. The production method according to claim 1, characterized by, The raw material medicine and the solvent ingredients, in mass fraction, are fluralaner 0.1-5 parts, surfactants 60-80 parts, flavoring agents 1-10 parts, cosolvents 10-30 parts, and antioxidants 0.1-5 parts.

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