A solution formulation of fluralaner and a method of preparing the same

Abstract

The application belongs to the technical field of new preparations of veterinary drugs, and particularly relates to a flucloronide solution preparation and a preparation method thereof. The preparation comprises flucloronide, gelatin or guar gum, glycerin monostearate or sucrose fatty acid ester, a stabilizer, a metal chelating agent and a preservative. The prescription components of the preparation are safe and low-toxic, no surfactant and organic solvent which must be added in traditional processes are used, and the preparation method is simple; the obtained preparation has the advantages of high stability, convenient clinical use and high safety.

Description

Technical Field

[0001] This invention belongs to the field of new veterinary drug formulation technology, specifically relating to a fluranar sodium solution formulation and its preparation method. Background Technology

[0002] Fluranal is an isoxazoline insecticide and acaricide that works by antagonizing gamma-aminobutyric acid (GABA) and glutamate receptor-gated chloride ion channels, preventing chloride ions from penetrating the postsynaptic membrane and interfering with transmembrane signal transmission in the nervous system, leading to nervous system disorders and death in insects. Clinically, it is used to treat flea (Ctenopharynx cateris), tick (Ixodes esculenta, Dermosus reticulata, Dermosus variegata, Heterodontia hexandra, and Ixodes axolotl), and mite (sarcodactyly and Demodex mites) in dogs, and can also be used to control flea allergic dermatitis.

[0003] The CAS number for freranil is 864731-61-3, and its chemical name is 4-(5(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)benzamide, with the structural formula shown below: .

[0004] Fluranal active pharmaceutical ingredient (API) is a white or off-white crystalline powder with extremely poor water solubility, with a solubility of only about 0.0016 mg / L at 25°C. However, it has higher solubility in organic solvents such as methanol, ethanol, acetone, ethyl acetate, and dimethyl sulfoxide. Currently, the main marketed dosage form of fluranal is chewable tablets, which have poor drug compliance and are prone to causing adverse reactions such as vomiting, decreased appetite, and flatulence in animals. Existing technology has been developed to produce a spray formulation, but this has drawbacks such as uneven spraying and low absorption rate due to obstruction by animal hair, which in turn affects efficacy. Although solutions are widely used in veterinary clinics due to their convenience and easy absorption, developing fluranar into a solution formulation still faces technical bottlenecks: First, to overcome its extremely poor water solubility and ensure that the finished solution does not precipitate or become cloudy when diluted with water in any proportion, a large amount of solubilizer or co-solvent must be added to the formulation; second, fluranarar is easily degraded by hypochlorite in aqueous systems, and metal ions in water can also cause it to precipitate, posing a problem of formulation stability; in addition, the introduction of a large amount of surfactant will cause the drug solution to easily generate foam during stirring and mixing, and the viscosity of the system will increase, which can easily cause drug residues during production and packaging, affecting the accuracy of the dosage.

[0005] CN201680036814.8 discloses a vitamin-containing isoxazoline solution for disinfecting drinking water, which uses tocopherol as an antioxidant, diethylene glycol monoethyl ether as a solvent, and adds a large amount of Tween 80 as a solubilizer to prepare a flurana solution; CN202111631718.7 discloses a flurana insecticide and its preparation method and use, which uses N,N-dimethylacetamide or N,N-dimethylformamide as a solvent to dissolve flurana, and uses a multi-solvent mixture system composed of Tween 80, anhydrous ethanol and soybean oil as a diluent; CN202411277556.5 discloses a flurana solution adapted to different water qualities and its preparation method, the formulation of which includes flurana, a composite solvent composed of solubilizer, cosolvent and defoamer, and stabilizer. To overcome the foaming problem caused by the large amount of surfactant used, this scheme adds a large amount of propylene glycol or polypropylene glycol as a defoamer.

[0006] In existing technologies, fluranaran solution formulations generally rely on large amounts of surfactants, solubilizers, and highly polar organic solvents, which not only pose potential toxic side effects but also lead to problems such as high drug viscosity, easy foaming, and drug residue. Therefore, there is an urgent need to provide a fluranaran solution formulation with a safe and low-toxicity formulation that is convenient for clinical use. Summary of the Invention

[0007] To address the shortcomings of existing technologies, this invention provides a fluranar sodium solution formulation and its preparation method. The formulation's components are safe and low in toxicity, and it does not use surfactants and organic solvents that are necessary in traditional processes. Furthermore, the preparation method is simple. The resulting formulation has the advantages of high stability, convenient clinical use, and high safety.

[0008] The technical solution of the present invention is: a flurana solution formulation comprising flurana, gelatin or guar gum, glyceryl monostearate or sucrose fatty acid ester, stabilizer, metal chelating agent and preservative.

[0009] Preferably, in the formulation, the weight ratio of gelatin or guar gum to freranil is 1 to 2:1.

[0010] More preferably, in the formulation, the weight ratio of gelatin or guar gum to fluranal is 1 to 1.5:1.

[0011] Preferably, in the formulation, the weight ratio of glyceryl monostearate or sucrose fatty acid ester to fluorana is 4 to 10:1.

[0012] More preferably, in the formulation, the weight ratio of glyceryl monostearate or sucrose fatty acid ester to fluoranal is 6-8:1.

[0013] Preferably, in the formulation, the weight ratio of stabilizer to fluranal is 0.8 to 3:1.

[0014] More preferably, in the formulation, the weight ratio of stabilizer to fluranal is 1~1.2:1.

[0015] Preferably, in the formulation, the stabilizer is selected from one or more of sodium alginate, lysine, and glutamic acid.

[0016] Preferably, in the formulation, the weight ratio of the metal chelating agent to fluranal is 0.005 to 0.05:1.

[0017] Preferably, in the formulation, the metal chelating agent is selected from one or both of EDTA and tartaric acid.

[0018] Preferably, in the formulation, the weight ratio of preservative to fluoranal is 0.1 to 0.15:1.

[0019] Preferably, the preservative in the formulation is potassium sorbate or sodium benzoate.

[0020] Preferably, the content of fluranal before dilution in the formulation is 1~15 g / L.

[0021] The fluranarin used in the formulation of this invention can be prepared in-house or purchased from commercially available products without affecting the implementation of this invention.

[0022] As a second aspect of the present invention, a method for preparing the above-mentioned freranal solution formulation is provided, comprising the following steps: adding glyceryl monostearate or sucrose fatty acid ester, stabilizer, metal chelating agent and preservative to an ethanol aqueous solution, stirring evenly, then adding freranal, and continuing to stir to mix thoroughly; subsequently adding swollen gelatin or guar gum, stirring under ultrasonic conditions until evenly mixed, and then evaporating to remove ethanol to obtain a freranal micelle solution; diluting with drinking water before use to obtain the freranal solution formulation.

[0023] Preferably, in the preparation method, the volume percentage concentration of the ethanol aqueous solution is 45-70%.

[0024] Preferably, in the preparation method, the volume ratio of the added ethanol aqueous solution to the mass ratio of the stabilizer is 50~80:1, where the volume is expressed in mL and the mass in g.

[0025] Preferably, in the preparation method, the swelling temperature is 50-60℃.

[0026] Preferably, in the preparation method, the stirring speed is 600-1200 r / min.

[0027] Preferably, in the preparation method, the ultrasonic stirring power is 300~800W and the time is 10~20 min.

[0028] Preferably, in the preparation method, when diluting with drinking water before use, the volume ratio of the dilution is 1:20~50 for the Freranar micelle solution and the drinking water.

[0029] Compared with the prior art, the present invention has the following outstanding advantages: 1. The formulation of this invention has safe and low toxicity components. It does not use a large amount of surfactants (such as polysorbates) and highly polar organic solvents (such as amides, diethylene glycol monoethyl ether, etc.) commonly used in the prior art, thus fundamentally avoiding the toxic side effects caused by these excipients. At the same time, it overcomes the process defects such as high viscosity of the drug solution, easy foaming during the production process, and inaccurate dosage caused by packaging residues due to a large amount of surfactants. 2. The preparation method of the present invention is simple and easy to implement, requiring no complex production equipment or additional defoamers or other auxiliary materials, thus reducing production costs and the difficulty of quality control. 3. The formulation of the present invention effectively reduces the impact of hypochlorite degradation and metal ion precipitation in water, which leads to a decrease in stability, through the synergistic effect of each component. This ensures the high stability and clarity of the formulation during storage and at any dilution ratio. Moreover, it can be easily and quickly administered in clinical use by simply diluting it with drinking water, thus improving the safety and effectiveness of veterinary clinical medication. Detailed Implementation

[0030] The following specific embodiments further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0031] Example 1 40g of glyceryl monostearate, 10g of sodium alginate, 0.05g of EDTA, and 1g of potassium sorbate were added to 500mL of a 45% (v / v) ethanol aqueous solution. The mixture was stirred at 600 r / min until homogeneous. Then, 10g of freranal was added and the mixture was stirred until fully mixed. Subsequently, 10g of gelatin, which had been pre-swelled in an appropriate amount of purified water and dissolved by heating at 50–60°C, was added to the aforementioned system. The mixture was ultrasonically stirred at 300W for 20 min until homogeneous. The ethanol was then removed by vacuum evaporation under a water bath at 45–50°C to obtain a freranal micelle solution. Before use, the micelle solution was diluted with drinking water at a volume ratio of 1:20 to obtain the freranal solution preparation.

[0032] Example 2 100g of sucrose fatty acid ester, 6g of lysine, 6g of glutamic acid, 0.5g of tartaric acid, and 1.5g of sodium benzoate were added to 800mL of 70% (v / v) ethanol aqueous solution. The mixture was stirred at 1200 r / min until homogeneous. Then, 10g of freranal was added and the mixture was stirred until fully mixed. Subsequently, 20g of guar gum, which had been pre-swelled in an appropriate amount of purified water and dissolved by heating at 50-60℃, was added to the aforementioned system. The mixture was ultrasonically stirred at 800W for 10 min until homogeneous. The ethanol was then removed by vacuum evaporation under a water bath at 45-50℃ to obtain a freranal micelle solution. Before use, the micelle solution was diluted with drinking water at a volume ratio of 1:50 to obtain the freranal solution preparation.

[0033] Comparative Example 1 40g Tween 80, 10g sodium alginate, 0.05g EDTA, and 1g potassium sorbate were added to 500mL of a 45% (v / v) ethanol aqueous solution. The mixture was stirred at 600 r / min until homogeneous. Then, 10g of freranal was added and the mixture was stirred until fully mixed. Subsequently, 10g of gelatin, which had been pre-swelled in an appropriate amount of purified water and dissolved by heating at 50–60°C, was added to the aforementioned system. The mixture was ultrasonically stirred at 300W for 20 min until homogeneous. The ethanol was then removed by vacuum evaporation under a water bath at 45–50°C to obtain a freranal micelle solution. Before use, the micelle solution was diluted with drinking water at a volume ratio of 1:20 to obtain the freranal solution preparation.

[0034] Comparative Example 2 40g of glyceryl monostearate, 0.05g of EDTA, and 1g of potassium sorbate were added to 500mL of a 45% (v / v) ethanol aqueous solution. The mixture was stirred at 600 r / min until homogeneous. Then, 10g of freranal was added and the mixture was stirred until fully mixed. Subsequently, 10g of gelatin, which had been pre-swelled in an appropriate amount of purified water and dissolved by heating at 50–60°C, was added to the aforementioned system. The mixture was ultrasonically stirred at 300W for 20 min until homogeneous. The ethanol was then removed by vacuum evaporation under a water bath at 45–50°C to obtain a freranal micelle solution. Before use, the micelle solution was diluted with drinking water at a volume ratio of 1:20 to obtain the freranal solution preparation.

[0035] Comparative Example 3 40g of glyceryl monostearate, 10g of sodium alginate, and 1g of potassium sorbate were added to 500mL of a 45% (v / v) ethanol aqueous solution. The mixture was stirred at 600 r / min until homogeneous. Then, 10g of freranal was added and the mixture was stirred until fully mixed. Subsequently, 10g of gelatin, which had been pre-swelled in an appropriate amount of purified water and dissolved by heating at 50–60°C, was added to the aforementioned system. The mixture was ultrasonically stirred at 300W for 20 min until homogeneous. The ethanol was then removed by vacuum evaporation under a water bath at 45–50°C to obtain a freranal micelle solution. Before use, the micelle solution was diluted with drinking water at a volume ratio of 1:20 to obtain the freranal solution preparation.

[0036] Comparative Example 4 Gelatin was swollen in an appropriate amount of purified water and heated to dissolve at 50-60°C. The mixture was sonicated for 5 minutes to prepare a 2 g / L solution. Then, 2 g / L of glyceryl monostearate was added and stirred until homogeneous. A 4 mmol / L fluranar solution was prepared and mixed with the above system. The mixture was then freeze-dried at -28°C for 48 hours to obtain a lyophilized powder. Before use, the lyophilized powder was mixed with deionized water at a volume ratio of 1:20.

[0037] Comparative Example 5 A flurana solution comprises 1.0 g flurana, 0.3 g urethane, 0.1 g citric acid, 0.1 g β-cyclodextrin, 0.3 g 2,3,5,6-tetrahydroxy-2-hexen-4-lactone, 0.3 g 2-ethyl-3-hydroxy-4H-pyranone, and ethanol:n-butyl acetate = 2:1 (V / V) to bring the volume to 100 ml. The operating steps are as follows: (1) Transfer 10 ml of n-butyl acetate to a clean glass three-necked flask, weigh 0.3 g of urethane and 0.1 g of β-cyclodextrin into the glass three-necked flask, and dissolve them by heating in an oil bath at 50°C with magnetic stirring. (2) Weigh 1.0g of fluranal raw material and add it to (1), then heat it in an oil bath at 50°C and stir it magnetically to dissolve it; (3) Transfer 20 ml of ethanol to a clean glass single-necked bottle, weigh 0.3 g of 2,3,5,6-tetrahydroxy-2-hexene-4-lactone and 0.3 g of 2-ethyl-3-hydroxy-4H-pyranone in sequence, and dissolve them by sonication; (4) Add the solution obtained in (3) dropwise to the solution obtained in (2), and mix quickly and evenly under oil bath heating at 50°C; (5) Weigh 0.1g of citric acid and add it to the solution obtained in (4). Dissolve the solution by heating in an oil bath at 50°C with magnetic stirring and adjust the acidity of the system. (6) Cool to room temperature, then dilute to 100 ml with an ethanol:n-butyl acetate = 2:1 (V / V) system, and sonicate to dissolve, thus obtaining the fluranar solution.

[0038] Comparative Example 6 A flurana solution comprising 10g flurana, 5g octenyl succinate hyaluronic acid, 5g octyl glucoside, 10g arginine and 0.5g cysteine, with purified water added to a final volume of 1000mL.

[0039] Preparation of Freranar solution: 1) Add 50% of the prescribed amount of purified water to a stirrer, heat to 50°C, and then add the prescribed amount of transparent water. Hyaluronic acid octenyl succinate and octyl glucoside are stirred and dissolved to obtain a mixed solution; 2) Add the prescribed amount of freranil to the mixed solution obtained in step 1), stir to dissolve, cool to 28°C, then add the prescribed amounts of arginine and cysteine ​​in sequence, stir to dissolve, and add the remaining purified water to make up to the total volume to obtain a crude solution. 3) The crude solution obtained in step 2) is filtered and sterilized using a 0.22 μm microporous membrane to obtain a fluranar solution.

[0040] Verification of Examples 1. Stability test The appearance, properties and stability of the fluranaran micelle solutions obtained in Examples 1-2 and Comparative Examples 1-3 were examined respectively. The properties and stability of the solutions after reconstitution with deionized water at a ratio of 1:20 in Comparative Example 4 were also examined. The long-term stability of the fluranaran micelle solutions obtained in Examples 1-2 and Comparative Examples 1-3, the lyophilized powder obtained in Comparative Example 4, and the solutions obtained in Comparative Examples 6-7 were also examined.

[0041] Table 1 Results of the stability test Note: "—" in the table indicates the item that was not measured. The results showed that the fluranar sodium micelle solution prepared by this invention was clear and transparent in appearance, and its properties remained unchanged after dilution. It exhibited high initial stability and also high stability in long-term stability studies. In contrast, the stability of the products obtained from Comparative Examples 1-4 (which replaced glyceryl monostearate, lacked stabilizer, lacked chelating agent, and did not prepare a micelle system, respectively) and Comparative Examples 5 and 6 using other formulation processes was significantly worse.

[0042] 2. Pharmacokinetic Study The diluted fluranar solution obtained in Example 1 and the fluranar solutions obtained by diluting with deionized water in Comparative Examples 5 and 6, with the same fluranar concentration, were used to evaluate the pharmacokinetic properties of 30 naturally infected cases (10 in each group) selected from a certain egg-laying hen breeding base.

[0043] Table 2 Results of the pharmacokinetic study The results showed that, compared with the comparative examples, the formulation obtained in the present invention had a higher peak concentration (Cmax) and total exposure (AUC), thus improving the oral bioavailability of fluranal.

Claims

1. A fluranar sodium solution formulation, characterized in that, The formulation contains freranil, gelatin or guar gum, glyceryl monostearate or sucrose fatty acid ester, stabilizers, metal chelating agents and preservatives.

2. The formulation according to claim 1, characterized in that, In the formulation, the weight ratio of gelatin or guar gum to freranil is 1 to 2:

1.

3. The formulation according to claim 1, characterized in that, In the formulation, the weight ratio of glyceryl monostearate or sucrose fatty acid ester to fluoraranol is 4 to 10:

1.

4. The formulation according to claim 1, characterized in that, In the formulation, the weight ratio of stabilizer to fluranal is 0.8 to 3:

1.

5. The formulation as described in claim 1, characterized in that, In the formulation, the stabilizer is selected from one or more of sodium alginate, lysine, and glutamic acid.

6. The formulation according to claim 1, characterized in that, In the formulation, the weight ratio of the metal chelating agent to fluranal is 0.005 to 0.05:

1.

7. The formulation according to claim 1, characterized in that, In the formulation, the metal chelating agent is selected from one or both of EDTA and tartaric acid.

8. The formulation according to claim 1, characterized in that, In the formulation, the weight ratio of preservative to fluranal is 0.1 to 0.15:

1.

9. The formulation according to claim 1, characterized in that, In the formulation, the preservative is potassium sorbate or sodium benzoate.

10. A method for preparing a fluranar sodium solution formulation as described in any one of the preceding claims, characterized in that, The preparation method includes the following steps: adding glyceryl monostearate or sucrose fatty acid ester, stabilizer, metal chelating agent and preservative to an ethanol aqueous solution, stirring evenly, then adding freranal, and continuing to stir to mix thoroughly; subsequently adding swollen gelatin or guar gum, stirring under ultrasonic conditions until evenly mixed, and then evaporating to remove ethanol to obtain a freranal micelle solution; diluting with drinking water before use to obtain the freranal solution preparation.

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