Flurala soluble powder and preparation method thereof

Abstract

The invention discloses fluralana soluble powder and a preparation method thereof, and belongs to the field of veterinary drug preparations. The flurala soluble powder provided by the invention is prepared from the following components in parts by weight: 0.5-2 parts of flurala, 2-10 parts of a solvent, 3-20 parts of a nonionic surfactant, 60-90 parts of a water-soluble carrier, 5-10 parts of a dispersing agent and 0.1-2 parts of an antioxidant. The preparation method comprises the following steps: (1) dissolving fluralan in a solvent, adding a surfactant, and uniformly stirring to obtain a solution A; (2) dissolving a dispersing agent in pure water to obtain a solution B; (3) mixing the solution A and the solution B, and uniformly stirring to obtain a solution C; and (4) uniformly spraying the solution C onto a mixture of the water-soluble carrier and the antioxidant, and drying to obtain the fluralan soluble powder. The fluralan soluble powder prepared from the solid dispersion can be completely dissolved in water, and is convenient for drinking water administration.

Description

Technical Field

[0001] The invention belongs to the field of veterinary drug preparations, and particularly relates to flurellanil soluble powder and a preparation method thereof. Background Art

[0002] Flurellan is an isoxazoline-type drug and the latest generation of antiparasitic drugs. It primarily inhibits the activity of invertebrate γ-aminobutyric acid (GABA) receptors, interfering with their nervous system, leading to parasite hyperexcitation, paralysis, and death. It is highly specific for invertebrates and has broad-spectrum activity against external parasites such as fleas, ticks, and mites. Flurellan was launched in Europe and the United States in 2014 as an antiparasitic drug specifically for pets. It was registered and launched in China in 2019 as an imported veterinary drug. Compared with traditional antiparasitic drugs, Flurellan boasts a rapid onset of action, a long half-life, a low metabolic rate, and a high safety profile, offering broad market prospects. Flurellan kills up to 99% of common external parasites of pets, such as fleas and ticks, and provides protection for up to 12 weeks.

[0003] Flurana was originally used as an agricultural insecticide, and only in recent years has it been adopted as an external anthelmintic for pets and chickens. Currently, flurana formulations available internationally include drops, solutions, and chewable tablets. Drops and chewable tablets are primarily used for dogs and cats, while solutions are primarily used in large-scale chicken flocks, where they are mixed with feed or drinking water to eliminate mite infestations. However, flurana is highly lipophilic and virtually insoluble in water, which has limited its development.

[0004] Soluble powders are water-soluble dry powder formulations made by pulverizing and uniformly mixing the drug and excipients. These formulations are specifically designed for administration to livestock and poultry through drinking water and are a commonly used dosage form. Compared to solutions, soluble powders are easier to transport, require less organic solvent, and have lower production costs, making them suitable for use in large-scale farms. Solid dispersion technology involves highly dispersing the drug in a microcrystalline, colloidal, amorphous, or molecular state within another solid carrier. This technology can increase the solubility and dissolution rate of poorly soluble drugs, improve bioavailability, and enhance drug stability. Currently, there are relatively few reports on flurellanide soluble powders. Patent CN118477183A uses hydroxypropyl-β-cyclodextrin as a carrier to encapsulate flurellanide, improving its solubility in water. However, the flurellanide soluble powder prepared by this method is milky white when dissolved in water, indicating incomplete dissolution. Patent CN1181211716A utilizes an isoxazoline insecticide-cyclodextrin inclusion complex and a Tween-dextrin inclusion compound to prepare a highly water-soluble isoxazoline soluble powder. The isoxazoline insecticide and cyclodextrin are stirred at high temperature for 0.5-6.0 hours, and the Tween and dextrin are ground to obtain the Tween-dextrin inclusion compound, which is then mixed. However, the preparation method is complex and time-consuming. Therefore, there is an urgent need to develop a highly efficient, stable, and easily scalable soluble powder of flurazole to meet the prevention and control needs of livestock and poultry farming. Summary of the Invention

[0005] In order to solve the above technical problems, the present invention provides a flurella soluble powder, which is composed of the following parts by weight: 0.5-2 parts of flurella, 2-10 parts of a solvent, 3-20 parts of a nonionic surfactant, 60-90 parts of a water-soluble carrier, 5-10 parts of a dispersant, and 0.1-2 parts of an antioxidant.

[0006] Furthermore, the soluble powder is prepared from the following components in parts by weight: 0.5-1.5 parts of flurella, 4-8 parts of solvent, 5-15 parts of nonionic surfactant, 65-90 parts of water-soluble carrier, 6-9 parts of dispersant, and 0.5-1.5 parts of antioxidant.

[0007] Furthermore, the soluble powder is prepared from the following components in parts by weight: 0.5-1 part of flurella, 4-6 parts of solvent, 7.5-10 parts of nonionic surfactant, 80-90 parts of water-soluble carrier, 7-8 parts of dispersant, and 0.5-1 part of antioxidant.

[0008] Preferably, the solvent is one or more of ethanol, methanol, and ethyl acetate.

[0009] Preferably, the nonionic surfactant is one or more of Tween-40, Tween-60, Tween-80, hydrogenated castor oil 35, hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 35, polyoxyethylene hydrogenated castor oil 40, and polyoxyethylene hydrogenated castor oil 50.

[0010] Preferably, the water-soluble carrier is one or more of glucose, soluble starch, and maltodextrin.

[0011] Preferably, the dispersant is one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, and β-cyclodextrin.

[0012] Preferably, the antioxidant is one or more of propyl gallate, butylated hydroxyanisole, and butylated hydroxytoluene.

[0013] The present invention also provides a method for preparing the flurellanine soluble powder. The flurellanine soluble powder is prepared by the following steps:

[0014] (1) adding flurellanil to a solvent and dissolving it, and adding a surfactant and stirring uniformly to obtain a solution A;

[0015] (2) dissolving the dispersant in pure water to obtain solution B;

[0016] (3) Mixing solution A and solution B, and stirring evenly to obtain solution C;

[0017] (4) The solution C is uniformly sprayed onto the mixture of the water-soluble carrier and the antioxidant using a fluidized bed to obtain flurellan soluble powder.

[0018] The beneficial effects of the present invention over the prior art are

[0019] The flurellanide soluble powder prepared by the present invention is completely soluble in water, and the solution is clear. The preparation process is simple and time-efficient. The flurellanide soluble powder prepared by the present invention does not contain organic solvents, has minimal environmental pollution, is easy to transport, and is low in cost. The filler uses a large amount of water-soluble excipients, resulting in low cost. DETAILED DESCRIPTION

[0020] The following examples are used to illustrate the present invention but are not intended to limit the scope of the present invention.

[0021] Example 1

[0022] 1.Solvent type and usage screening

[0023] Flurella was weighed and dissolved in pure water, methanol, ethanol, ethyl acetate, and acetonitrile, and the dissolution rates were observed. The specific amount of flurella, solvent composition, and amount are shown in Table 1.

[0024] Table 1 Solubility of flurella in different solvents

[0025] Flurellane amount (g) solvent Solvent volume (mL) Dissolution phenomenon 0.5 pure water 5 Insoluble 0.5 Methanol 5 Dissolves quickly and dissolves completely 2 Methanol 10 Dissolves quickly and dissolves completely 0.5 ethanol 5 Slow dissolution, can be completely dissolved 0.5 ethanol 2 Cannot be completely dissolved 0.5 ethanol 10 Dissolves quickly and dissolves completely 0.5 Ethyl acetate 5 Dissolves quickly and dissolves completely 2 Ethyl acetate 10 Dissolves quickly and dissolves completely 0.5 Acetonitrile 5 Dissolves quickly and dissolves completely 2 Acetonitrile 10 Dissolves quickly and dissolves completely

[0026] As shown in Table 1, flurana is completely insoluble in pure water (0.5 g / 5 mL). However, it exhibits excellent solubility in methanol, ethyl acetate, and acetonitrile. 0.5 g dissolves quickly and completely in 5 mL, and 2 g dissolves rapidly in 10 mL, demonstrating that these solvents are ideal dissolution media. In contrast, ethanol's solubility is significantly affected by solvent volume. While 0.5 g does not dissolve completely in 2 mL of ethanol, it dissolves slowly and completely in 5 mL, and dissolves more rapidly in 10 mL, indicating that its dissolution efficiency is closely related to solvent volume. Overall, methanol, ethyl acetate, and acetonitrile exhibit the best solubility, while ethanol can also maintain effective dissolution even when the proportion is appropriately controlled. Considering the influence of solvent price, methanol, ethanol, and ethyl acetate are preferred solvents for dissolving flurana.

[0027] 2. Screening of surfactant usage and type

[0028] Weigh the drug raw materials and excipients according to the following weight ratios of samples 1 to 7, and prepare the samples according to the preparation steps. The ingredients and contents of samples 1 to 7 are shown in Table 2.

[0029] Table 2 Different surfactants and their dosage

[0030]

[0031]

[0032] The test results are shown in Table 3. Samples 1 to 7 change the type and dosage of surfactant. Observing the appearance of the samples, it was found that sample 3 had poorer dispersibility than sample 1 and sample 2 and was prone to agglomeration. The water solubility test of samples 1 to 7 found that after dissolving sample 6 and sample 7 in water, the solution became milky white, and flurellan was not completely dissolved. After dissolving sample 1 to sample 5 in water, it became a colorless clear solution. The above results show that the amount of nonionic surfactant added to the formula cannot be too much. Too much will make the product appearance not meet the requirements of powder and have poor fluidity. Not all nonionic surfactants can be used, and the selection of nonionic surfactants is also very important.

[0033] Table 3 Sample performance

[0034]

[0035] 3. Amount of antioxidants used

[0036] Weigh the drug raw materials and excipients according to the following weight ratios, as shown in Table 4, and prepare samples according to the preparation steps.

[0037] Table 4 Effects of different antioxidants and their dosage

[0038]

[0039]

[0040] As shown in Table 5, the type and dosage of antioxidants were varied in Samples 8-11. Samples 8-11 were stored at 60°C for 10 days. Flurellanine content and physical properties were measured on Day 0 and Day 10. No significant change in flurellanine content was observed, and the samples remained white powders. This indicates that the antioxidant dosage was appropriate, ensuring sample stability. The antioxidant dosage range was 0.1-2 parts per million.

[0041] Table 5 Accelerated stability (60°C x 10 days) results

[0042] Test items Sample 8 (parts) Sample 9 (parts) Sample 10 (parts) Sample 11 (parts) Flurellanine content No significant changes No significant changes No significant changes No significant changes Physical properties Still white powder Still white powder Still white powder Still white powder

[0043] 4. Screening of dispersants

[0044] Weigh the drug raw materials and excipients according to the following weight ratios, as shown in Table 6, and prepare samples according to the preparation steps.

[0045] Table 6 Dispersant composition and ratio of different samples

[0046] Element Sample 12 Sample 13 Sample 14 Sample 15 Sample 16 Sample 17 Flurella 0.5 0.5 0.5 0.5 0.5 0.5 Methanol 4 4 4 4 4 4 Twain-80 3 3 3 3 3 3 glucose 82 87 87 87 87 87 β-cyclodextrin 10 - - - - - Polyvinylpyrrolidone K30 - 5 - - - - Hydroxypropyl methylcellulose - - 5 - - - Sodium carboxymethyl cellulose - - - 5 - - Sodium tripolyphosphate - - - - 5 - Polyethylene glycol 6000 - - - - - 5 Propyl gallate 0.5 - - - - - Butylated hydroxyanisole - 0.5 0.5 0.5 0.5 0.5

[0047] The test results are shown in Table 7. Samples 12-17 vary in the type of dispersant used. 2.5g of sample was dissolved in 100mL of water. The dispersibility and dissolution rates of the samples were observed. Samples 12, 13, and 14 exhibited good dispersibility and rapid dissolution, dissolving readily upon stirring. Samples 15, 16, and 17 exhibited relatively slow dissolution rates, with Sample 15 exhibiting a tendency to clump. Therefore, β-cyclodextrin, polyvinylpyrrolidone K30, and hydroxypropyl methylcellulose were suitable dispersants.

[0048] Table 7 Dispersion test results

[0049]

[0050]

[0051] Example 2 Preparation of the pharmaceutical composition of the present invention

[0052] Weigh the following raw and auxiliary materials according to weight ratio: 0.5 parts of flurella, 4 parts of ethanol, 7.5 parts of Tween-80, 80 parts of anhydrous glucose, 7 parts of polyvinylpyrrolidone K30, and 0.5 parts of butylated hydroxyanisole.

[0053] Prepare as follows:

[0054] (1) Dissolve flurellan in ethanol, add Tween-80 and stir evenly to obtain solution A;

[0055] (2) dissolving polyvinylpyrrolidone K30 in pure water to obtain solution B;

[0056] (3) Mixing solution A and solution B, and stirring evenly to obtain solution C;

[0057] (4) Solution C is uniformly sprayed onto a mixture of anhydrous glucose and butylated hydroxyanisole using a fluidized bed to obtain flurellan soluble powder.

[0058] Example 3 Preparation of the pharmaceutical composition of the present invention

[0059] Weigh the following raw and auxiliary materials according to weight ratio: 1 part of flurella, 2 parts of methanol, 403 parts of hydrogenated castor oil, 90 parts of maltodextrin, 10 parts of β-cyclodextrin, and 0.1 part of propyl gallate.

[0060] Prepare as follows:

[0061] (1) Fluorellana was dissolved in methanol, and 40 g of hydrogenated castor oil was added and stirred to obtain solution A;

[0062] (2) dissolving β-cyclodextrin in pure water to obtain solution B;

[0063] (3) Mixing solution A and solution B, and stirring evenly to obtain solution C;

[0064] (4) Solution C is evenly sprayed onto the mixture of maltodextrin and propyl gallate using a fluidized bed to obtain flurellan soluble powder.

[0065] Example 4 Preparation of the pharmaceutical composition of the present invention

[0066] Weigh the following raw and auxiliary materials according to weight ratio: 2 parts of flurella, 10 parts of ethyl acetate, 40-20 parts of polyoxyethylene hydrogenated castor oil, 60 parts of soluble starch, 5 parts of hydroxypropyl methylcellulose, and 2 parts of butylated hydroxytoluene.

[0067] Prepare as follows:

[0068] (1) Flurellanine was dissolved in ethyl acetate, and 40% polyoxyethylene hydrogenated castor oil was added and stirred to obtain solution A;

[0069] (2) dissolving hydroxypropyl methylcellulose in pure water to obtain solution B;

[0070] (3) Mixing solution A and solution B, and stirring evenly to obtain solution C;

[0071] (4) Using a fluidized bed, solution C is uniformly sprayed onto a mixture of soluble starch and butylated hydroxytoluene to obtain flurellan soluble powder.

[0072] Comparative Example 1

[0073] Weigh the following raw and auxiliary materials according to the weight ratio: 0.1 part of flurella, 2 parts of methanol, 0.227 parts of hydroxypropyl-β-cyclodextrin, 15 parts of pure water, and 82 parts of anhydrous glucose.

[0074] Prepare as follows:

[0075] (1) Fluorellanine was dissolved in methanol to obtain solution A;

[0076] (2) adding hydroxypropyl-β-cyclodextrin to pure water to obtain solution B;

[0077] (3) Solution A was slowly added to solution B and mixed, and stirred evenly with a magnetic stirrer to obtain solution C;

[0078] (4) After freeze-drying solution C, add an appropriate amount of anhydrous glucose and mix evenly to obtain flurellanide soluble powder.

[0079] The beneficial effects of the present invention are further illustrated by experiments below:

[0080] Test Example 1 Stability Test

[0081] Materials and methods: The samples of Examples 2-4 were subjected to high temperature tests and accelerated tests according to the technical guidelines for stability studies of veterinary chemical drugs in the Compilation of Technical Guidelines for Veterinary Drug Research 2006-2011.

[0082] High-Temperature Test: Samples from Examples 1-3 were stored at 60°C for 10 days. Changes in flurellanine content and physical properties were measured on days 0, 5, and 10. Accelerated Test: Samples from Examples 1-3 were tested for 6 months at 40±2°C and RH (75±5)% according to commercial packaging. Samples were collected at the end of months 0, 1, 2, 3, and 6 to measure changes in flurellanine content and physical properties.

[0083] Test Results: The results of the high-temperature and accelerated tests are shown in Tables 8 and 9. The high-temperature test results indicate that the samples of Examples 2-4 exhibited no significant changes in properties and content after 10 days at 60°C, meeting the stability guidelines. The accelerated test results in Tables 2-4 indicate that the content and properties of the samples were stable after 6 months at 40±2°C and RH (75±5). This demonstrates that the stability of the flurellane disclosed in this invention meets the requirements.

[0084] Table 8 High temperature stability test results

[0085]

[0086]

[0087] Table 9 Accelerated test stability test results

[0088]

[0089]

[0090] Test Example 2: Water Solubility Test of Flurella Soluble Powder

[0091] 1 g of each sample of Examples 2-4 and Comparative Example 1 was weighed and added into 1 L of water, stirred to dissolve, and the phenomenon of the sample after dissolution in water was observed.

[0092] Table 10 Flurellan dissolving phenomenon

[0093] Sample name solvent Post-dissolution phenomenon Test Example 2 water clarify Test Example 3 water clarify Test Example 4 water clarify Comparative Example 1 water milky

[0094] From the test results in Table 10, it can be seen that the flurellan soluble powder of the present invention has good solubility and can be completely dissolved in water without turbidity.

[0095] Experimental Example 3 Pharmacokinetic Study of Flurella Soluble Powder in Laying Hens

[0096] The pharmacokinetics of flurellan soluble powder (0.5%) prepared in Example 2 and a reference preparation (flurellan solution for poultry, 0.5%, Exzolt) were studied in laying hens. The main pharmacokinetic parameters are shown in Table 11.

[0097] Table 11 Pharmacokinetic parameters of Example 2 of the present invention and the reference preparation in laying hens (n=13)

[0098]

[0099] The relative bioavailability of the flurellanine soluble powder prepared by the present invention (Example 2) relative to the reference preparation is 89.4%, indicating that the flurellanine soluble powder prepared by the present method is as effective as the flurellanine solution for poultry.

[0100] The above studies show that the flurellan soluble powder prepared by the present invention is completely soluble in water and is clear and transparent, has stable properties, and has high bioavailability, thus meeting the requirements of a soluble powder.

[0101] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the technical principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A soluble powder of flurella, characterized in that: The soluble powder is composed of the following parts by weight: 0.5-2 parts of flurella, 2-10 parts of solvent, 3-20 parts of nonionic surfactant, 60-90 parts of water-soluble carrier, 5-10 parts of dispersant and 0.1-2 parts of antioxidant.

2. The soluble powder of flurellane according to claim 1, characterized in that The soluble powder is prepared from the following components in parts by weight: 0.5-1.5 parts of flurella, 4-8 parts of solvent, 5-15 parts of nonionic surfactant, 65-90 parts of water-soluble carrier, 6-9 parts of dispersant, and 0.5-1.5 parts of antioxidant.

3. The soluble powder of flurellane according to claim 2, characterized in that The soluble powder is prepared from the following components in parts by weight: 0.5-1 part of flurella, 4-6 parts of solvent, 7.5-10 parts of nonionic surfactant, 80-90 parts of water-soluble carrier, 7-8 parts of dispersant and 0.5-1 part of antioxidant.

4. The soluble powder of flurellane according to any one of claims 1 to 3, characterized in that The solvent is one or more of ethanol, methanol and ethyl acetate.

5. The soluble powder of flurellane according to any one of claims 1 to 3, characterized in that The nonionic surfactant is one or more of Tween-40, Tween-60, Tween-80, hydrogenated castor oil 35, hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 35, polyoxyethylene hydrogenated castor oil 40, and polyoxyethylene hydrogenated castor oil 50.

6. The soluble powder of flurellane according to any one of claims 1 to 3, characterized in that The water-soluble carrier is one or more of glucose, soluble starch and maltodextrin.

7. The soluble powder of flurellane according to any one of claims 1 to 3, characterized in that The dispersant is one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose and beta-cyclodextrin.

8. The soluble powder of flurellane according to any one of claims 1 to 3, characterized in that The antioxidant is one or more of propyl gallate, butylated hydroxyanisole and butylated hydroxytoluene.

9. The method for preparing the flurellan soluble powder according to any one of claims 1 to 8, characterized in that: The flurellane soluble powder is prepared by the following steps: (1) adding flurellanil to a solvent and dissolving it, and adding a surfactant and stirring uniformly to obtain a solution A; (2) dissolving the dispersant in pure water to obtain solution B; (3) Mixing solution A and solution B, and stirring evenly to obtain solution C; (4) The solution C is uniformly sprayed onto the mixture of the water-soluble carrier and the antioxidant using a fluidized bed to obtain flurellan soluble powder.

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