Compound sulfachloropyrazine sodium soluble powder as well as preparation method and application thereof

Abstract

The invention discloses compound sulfachloropyrazine sodium soluble powder as well as a preparation method and application thereof, and belongs to the technical field of veterinary drugs. Every 100 g of the soluble powder comprises 15-30 g of sulfachloropyrazine sodium, 4-8 g of methamprine, 6-12 g of a carrier I, 3-6 g of a carrier II, a surfactant, a metal chelating agent, an antioxidant and a filler. The preparation method is characterized by comprising the following steps: dissolving the methampheline and the carrier I in absolute ethyl alcohol, adding the carrier II for dispersion, heating for volatilization, cooling for solidification and drying to prepare the methampheline composite carrier solid dispersion; and mixing the sulfachloropyrazine sodium with sulfachloropyrazine sodium and other auxiliary materials to obtain a finished product. The dissolving and dispersing performance of the methampheline is remarkably improved through a solid dispersion technology, synchronous dissolution of the methampheline and the sulfachloropyrazine sodium is ensured, the preparation is good in water solubility and high in stability, and the excellent synergistic interaction effect and the animal growth promoting effect are shown in chicken and sheep coccidiosis prevention and treatment.

Description

Technical Field

[0001] This application relates to the field of veterinary drug technology, specifically to a compound sulfachlorpyridazine sodium soluble powder, its preparation method and application, and more specifically to a compound anticoccidial veterinary drug preparation that improves the dispersibility and solubility of the synergist in the compound preparation by introducing a methotrexate amorphous solid dispersion. Background Technology

[0002] Coccidiosis is a common and serious parasitic disease caused by protozoa of the genus *Eimeria*, and it is widespread in livestock and poultry farming. Chicken coccidiosis is one of the most serious diseases in the poultry industry, especially affecting chicks, causing severe growth retardation, extremely high mortality rates in acute infections, and significant economic losses. Similarly, sheep coccidiosis is prevalent worldwide. Infected lambs show obvious clinical symptoms, causing diarrhea, growth retardation, and other problems. With the shift towards large-scale, indoor farming, its harm is becoming increasingly prominent.

[0003] Currently, chemical drug control remains the primary means of managing this disease. Sulfachloropyrazine sodium (SPZ), an animal-specific sulfonamide anticoccidial drug, works by interfering with coccidia's folic acid metabolism and is widely used clinically. However, with the long-term and widespread use of the drug, coccidia's resistance to sulfachloropyrazine sodium has become increasingly prominent, and the efficacy of its single-drug formulation has gradually been limited, making it difficult to meet the current demand for highly effective control in aquaculture production.

[0004] To improve efficacy and delay drug resistance, sulfonamides are often used in combination with antibacterial potentiators in clinical practice, producing a synergistic effect through dual blockade of the folic acid metabolism pathway. Aditoprim (ADP) is a novel benzylidene pyrimidine potentiator. Compared with traditional benzylidene pyrimidine drugs such as trimethoprim, omeprine, and bromoprine, it has pharmacokinetic advantages such as a longer half-life and higher bioavailability. Combined with sulfachlorpyridazine sodium, it has the potential to enhance anticoccidial activity. However, methomyl itself has extremely poor water solubility, which poses a significant challenge to its application in compound preparations. In existing compound anticoccidial soluble powder preparations, a simple physical mixing process of sulfachlorpyridazine sodium and methomyl is often used. Due to the significant differences in their physicochemical properties—sulfachlorpyridazine sodium is readily soluble, while methomyl is poorly soluble—this simple mixing method cannot ensure that the two active ingredients achieve synchronous and uniform dispersion during dissolution. After administration, the readily soluble components dissolve rapidly, while the poorly soluble components remain in the gastrointestinal tract, resulting in asynchronous drug concentrations in the body. This prevents the achievement of the optimal sequential blocking effect and severely restricts the full realization of the synergistic effect of the compound. In addition, uneven dispersion of the poorly soluble components may also affect the uniformity of the formulation content and the accuracy of the dosage.

[0005] Solid dispersion technology is one of the effective strategies for improving the dissolution rate of poorly soluble drugs. It increases the dissolution rate and extent by highly dispersing the drug in a hydrophilic carrier in an amorphous state. While this technology is known, there is a lack of systematic solutions in the current technology for how to specifically apply it to solve the synergistic dissolution problem of methotrexate and sulfachlorpyrifos sodium in the aforementioned compound formulations, and for designing specific composite carrier systems and processes with good stability suitable for industrial production.

[0006] Therefore, there is an urgent need to develop a new compound sulfachlorpyridazine sodium soluble powder and its preparation method, which can fundamentally improve the dispersion and solubility of methotrexate in the formulation, ensure that it dissolves synchronously with sulfachlorpyridazine sodium and works synergistically, thereby enhancing the overall anticoccidial effect and application value of the compound formulation. Summary of the Invention

[0007] In view of this, the purpose of this application is to provide a compound sulfachlorpyridazine sodium soluble powder, its preparation method and application. This application prepares methotrexate into an amorphous solid dispersion supported by a specific composite carrier, and then formulates it into a soluble powder with sulfachlorpyridazine sodium and excipients, thereby significantly improving the dispersion and dissolution performance of methotrexate, ensuring the simultaneous dissolution of the two active ingredients, and improving the stability and anticoccidial effect of the formulation.

[0008] Therefore, this application provides the following technical solution:

[0009] In a first aspect, this application provides a compound sulfachlorpyridazine sodium soluble powder, wherein each 100g of the soluble powder is composed of the following components: 15-30g of sulfachlorpyridazine sodium, 4-8g of methomyl, 6-12g of carrier I, 3-6g of carrier II, 1-5g of surfactant, 0.1-3g of metal chelating agent, 0.1-3g of antioxidant, and the balance being filler; wherein carrier I is a polyvinylpyrrolidone-vinyl acetate copolymer or polyvinylpyrrolidone K30, and carrier II is mesoporous silica.

[0010] In some preferred embodiments, each 100 g of the soluble powder consists of the following components: 18-25 g of sodium sulfachlorpyrifos, 4-5 g of methomyl, 6-8 g of carrier I, 3-4 g of carrier II, 2.5-3 g of surfactant, 0.3-2 g of metal chelating agent, 0.3-2 g of antioxidant, and the balance being filler.

[0011] In this application, the amount and mass ratio of carrier I and carrier II are important parameters affecting the microstructure and performance of the system. Carrier II, as a porous inorganic framework material, provides nanoscale confinement space, which helps maintain structural stability; carrier I promotes uniform drug dispersion and improves redispersibility through intermolecular interactions. When the amount of carrier I or carrier II deviates from the appropriate range, both the system structure and dispersion state may be affected, thus hindering the maintenance of solubility. Experimental results show that when carrier I is 6–8 g, carrier II is 3–4 g, and their mass ratio is controlled at approximately 2.0:1–2.7:1, the system achieves a relatively harmonious balance between structural stability and redispersibility, resulting in superior overall performance; when the ratio deviates from this range, the performance declines.

[0012] In some preferred embodiments, the surfactant is selected from at least one of sodium dodecyl sulfate, Tween 80, and poloxamer 188.

[0013] In some preferred embodiments, the metal chelating agent is disodium edetate.

[0014] In some preferred embodiments, the antioxidant is selected from at least one of anhydrous sodium sulfite and sodium thiosulfate.

[0015] In some preferred embodiments, the filler is selected from at least one of anhydrous glucose and lactose.

[0016] Secondly, this application provides a method for preparing the compound sulfachlorpyrifos sodium soluble powder described in the first aspect, comprising the following steps:

[0017] (1) Methanielin and polyvinylpyrrolidone-vinyl acetate copolymer or polyvinylpyrrolidone K30 are dissolved in anhydrous ethanol, and then mesoporous silica is added and dispersed evenly to form a uniform dispersion system of methanielin loaded on a composite carrier.

[0018] (2) Heat the system obtained in step (1) to 70~85 °C, stir to evaporate and remove the solvent until a viscous substance is formed;

[0019] (3) Spread the viscous substance into a thin layer and then cool and solidify it;

[0020] (4) Dry the solidified material to constant weight, pulverize it and sieve it through an 80-100 mesh screen to obtain a methomylene solid dispersion;

[0021] (5) Mix sodium sulfachlorpyrifos, the methomyl solid dispersion obtained in step (4), the surfactant, metal chelating agent, antioxidant and filler described in the first aspect evenly;

[0022] (6) Grind and sieve the mixture obtained in step (5) to obtain compound sulfachlorpyrifos sodium soluble powder.

[0023] In some preferred embodiments, in step (3), the cooling and curing conditions are: cooling at 0 °C for 4 to 8 hours in an environment with a relative humidity of not more than 40%.

[0024] Thirdly, this application provides the use of the compound sulfachlorpyridazine sodium soluble powder described in the first aspect in the preparation of a drug for the prevention and treatment of coccidiosis in livestock and poultry.

[0025] In some preferred embodiments, the livestock or poultry is chicken or sheep.

[0026] In some preferred embodiments, the chicken is a chick and the sheep is a lamb.

[0027] In some preferred embodiments, the coccidiosis is caused by Eimeria tenella or Eimeria oviductii.

[0028] Compared with the prior art, this application has at least the following advantages:

[0029] 1. This application fundamentally improves the dispersion and dissolution behavior of the poorly soluble synergist methotrexate in water by preparing an amorphous solid dispersion using a PVP / VA 535 (or PVP K30) and mesoporous silica composite carrier. Experiments show that the solubility of methotrexate in the obtained solid dispersion can reach up to 0.8 mg / mL, approximately four times higher than that of the active pharmaceutical ingredient. When combined with sulfachlorpyrifos sodium, the resulting soluble powder rapidly dissolves in water to form a clear solution, effectively solving the problem of insufficient synergistic effect caused by asynchronous dissolution of the two components in traditional physically mixed formulations, ensuring uniform dosing and accurate dosage.

[0030] 2. The "solvent dispersion-low temperature curing-vacuum drying" preparation process used in this application is mild and has clear steps. The key process parameters effectively ensure that the drug exists stably in an amorphous form in the carrier and inhibit recrystallization during storage. Accelerated stability tests show that the key indicators such as the appearance, solubility, active pharmaceutical ingredient content, and related substances of the formulation do not change significantly, demonstrating excellent chemical and physical stability and the feasibility of large-scale production.

[0031] 3. Animal experiments have confirmed that the compound formulation of this application exhibits excellent synergistic effects. In a chick model artificially infected with Eimeria tenella, the anticoccidial index (ACI) of this formulation reached 169.40, significantly superior to the control groups of sulfachlorpyridazine sodium alone and sulfachlorpyridazine sodium / trimethoprim combination, and effectively promoted weight gain and reduced lesions and oocyst expulsion. In a lamb model naturally infected with coccidiosis, this formulation showed rapid onset of action after administration, with an oocyst reduction rate exceeding 98% on days 3-7, and significantly improved the daily weight gain of infected lambs. This indicates that this application not only effectively prevents and treats coccidiosis but also effectively improves the production performance of infected animals, possessing significant clinical application value.

[0032] 4. This application combines sulfachlorpyrifos sodium with methotrexate as a synergistic ingredient. The combined use of the two can broaden the insecticidal spectrum and enhance the insecticidal effect, which can meet the needs of the current large-scale breeding conditions for the treatment of infection. Through reasonable compound design, it is beneficial to reduce the amount of single drug used while ensuring the treatment effect, thereby reducing the cost of medication and reducing the potential risk of drug resistance. Detailed Implementation

[0033] To make the objectives, technical solutions, and advantages of this application clearer, the following detailed description is provided in conjunction with embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the scope of this application.

[0034] The materials used in the following embodiments are not limited to those listed below, and other similar materials may be used instead. Unless otherwise specified, the instruments shall be used under conventional conditions or as recommended by the manufacturer. Those skilled in the art should have relevant knowledge of the use of conventional materials and instruments.

[0035] To better understand this teaching and without limiting its scope, all figures and other numerical values ​​used in the specification and claims to express quantities, percentages, or proportions should, in all cases, be understood to be modified by the term "about." Therefore, unless otherwise stated, the numerical parameters set forth in the following specification and appended claims are approximate values ​​that may vary depending on the desired properties sought. At a minimum, each numerical parameter should be interpreted based at least on the reported significant figures and by applying common rounding techniques.

[0036] 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 the subject matter of this application pertains. Before providing a detailed description of this application, the following terms and definitions are provided to better understand it.

[0037] 1. Methotrexate Amorphous Solid Dispersion: This refers to the highly dispersed, molecular, colloidal, or microcrystalline form of the poorly soluble drug methotrexate in a composite solid matrix composed of a water-soluble polymeric carrier and a porous inorganic carrier. Methotrexate primarily exists in a non-crystalline, amorphous form. This system differs from simple physical mixtures; during solvent removal and solidification, intermolecular interactions and spatially confined structures form between the drug and the carrier, thus endowing the system with specific dispersion stability and dissolution behavior characteristics.

[0038] 2. Composite carrier: In this application, it specifically refers to a composite system in which a drug is jointly loaded by carrier I (water-soluble polymeric carrier) and carrier II (mesoporous inorganic carrier) through physical blending or interaction.

[0039] 3. Mesoporous silica: refers to silica materials with ordered or disordered pore structures with pore sizes between 2 and 50 nanometers. It possesses unique pore structures, high specific surface area, tunable pore size, and surface functionalization characteristics. In drug loading systems, the high specific surface area provides abundant adsorption sites, enabling drug molecules to be highly dispersed within the pores; simultaneously, the spatial confinement effect generated by the nanoscale pore size can reduce molecular migration and inhibit crystal nucleation and growth, thereby improving the kinetic stability of amorphous drug systems and enhancing their dissolution behavior.

[0040] 4. Cooling and solidification treatment: This refers to the process in which the viscous substance obtained after solvent evaporation is placed under low temperature (e.g., 0°C) and controlled humidity (e.g., RH≤40%) for a certain period of time (e.g., 4-8 hours) in the preparation method of this application, so that it changes from a viscous state to a solid state.

[0041] 5. Soluble powder: refers to a solid powder formulation prepared according to the formula and process of this application, which can rapidly dissolve or uniformly disperse in water within a specified time (such as under stirring at room temperature) to form a clear or substantially clear solution.

[0042] The technical solution and its effects described in this application are illustrated below with more specific embodiments. The sources of the main reagents and materials used in the following embodiments are as follows:

[0043] Sulfachlorpyrifos sodium: Meets the standards for veterinary drug raw materials and was purchased from Zhengzhou Fuyuan Animal Pharmaceutical Co., Ltd.

[0044] Methobenzyl: Meets the standards for veterinary drug raw materials and is synthesized independently by the National Veterinary Drug Residue Reference Laboratory of Huazhong Agricultural University.

[0045] Polyvinylpyrrolidone-vinyl acetate copolymer (PVP / VA 535): pharmaceutical excipient, Mw = 28,000 g / mol, purchased from Ashland.

[0046] Polyvinylpyrrolidone K30 (PVP K30): Pharmaceutical excipient, purchased from Beijing Puxitang Biotechnology Co., Ltd.

[0047] Mesoporous silica (SBA-15): Nanomaterial, purchased from Sigma Aldrich, product number: 914614.

[0048] Sodium dodecyl sulfate (SDS) and Tween 80: pharmaceutical excipients, purchased from Sinopharm Chemical Reagent Co., Ltd.

[0049] Poloxamer 188: Pharmaceutical excipient, purchased from BASF, batch number: GNH03721B.

[0050] Disodium edetate, anhydrous sodium sulfite, sodium thiosulfate, anhydrous glucose, and lactose: analytical grade or pharmaceutical excipient grade, purchased from Sinopharm Chemical Reagent Co., Ltd.

[0051] Example 1: Preparation of Compound Sulfachloropyrazine Sodium Soluble Powder

[0052] This embodiment provides a compound sulfachlorpyrifos sodium soluble powder, the formulation of which is shown in Table 1 below:

[0053] Table 1 Composition and Formulation

[0054]

[0055] The preparation method is as follows:

[0056] (1) Dissolve 4 g of methomylene and 8 g of PVP / VA 535 copolymer in an appropriate amount of anhydrous ethanol and stir until completely dissolved. Then, add 4 g of mesoporous silica (SBA-15) and stir thoroughly to disperse the methomylene in a composite carrier composed of carrier I and carrier II to form a uniform dispersion system;

[0057] (2) Heat the homogeneous dispersion system obtained in step (1) to about 80 °C and remove the organic solvent by stirring until the system gradually becomes a viscous substance.

[0058] (3) Spread the viscous substance obtained in step (2) into a thin layer quickly, and cool it at 0 ℃ for 4~8 h under an environment with a relative humidity of no more than 40% to solidify the system.

[0059] (4) Take out the solidified material obtained in step (3), dry it in a vacuum drying oven at 40 °C until constant weight, then crush it and pass it through a 100-mesh sieve to obtain a methomyl solid dispersion;

[0060] (5) Mix sodium sulfachlorpyrifos, the methomyl solid dispersion obtained in step (4), disodium edetate, anhydrous sodium sulfite and sodium dodecyl sulfate according to the prescription ratio, and add anhydrous glucose and mix evenly;

[0061] (6) Grind the mixture obtained in step (5) and pass it through a 100-mesh sieve to obtain compound sulfachlorpyridazine sodium soluble powder.

[0062] Example 2: Preparation of soluble powder with a different type of carrier I

[0063] The difference between this embodiment and Example 1 is that carrier I is replaced by an equal amount (8 g) of polyvinylpyrrolidone K30 (PVP K30), while the other components, amounts and preparation processes are the same as in Example 1.

[0064] Examples 3-6 investigate the preparation of soluble powders with varying carrier dosage ratios.

[0065] This set of examples is used to investigate the effect of the ratio of carrier I to carrier II on product performance. The formulation composition of each example is shown in Table 2 below, and the preparation process is the same as in Example 1.

[0066] Table 2 Composition Formula

[0067]

[0068] Example 7: Preparation of soluble powder with modified surfactant type

[0069] The difference between this embodiment and Example 1 is that the surfactant is replaced by an equal amount (3g) of Tween 80 instead of sodium dodecyl sulfate. All other components, dosages and preparation processes are the same as in Example 1.

[0070] Example 8: Preparation of soluble powder with modified surfactant dosage

[0071] The difference between this embodiment and Example 1 is that the amount of sodium dodecyl sulfate is adjusted to 2.5 g, while the other components, amounts, and preparation processes are the same as in Example 1.

[0072] Example 9: Preparation of soluble powder with changed filler type

[0073] The difference between this embodiment and Embodiment 1 is that the filler is replaced with anhydrous glucose in an equal amount of lactose, while the other components, amounts and preparation processes are the same as in Embodiment 1.

[0074] Example 10: Preparation of soluble powder with adjusted carrier II dosage

[0075] Compared with the example, the amount of carrier II (SBA-15) in the formulation was reduced to 3 g, while the other components, amounts and preparation processes were the same as in Example 1.

[0076] Comparative Example 1: Preparation of carrier-free solid dispersion and soluble powder (II)

[0077] This comparative study investigated a system without inorganic carrier II and provided a compound sulfachlorpyrifos sodium soluble powder, the composition of which is shown in Table 3 below:

[0078] Table 3 Composition Formula

[0079]

[0080] The preparation method is as follows:

[0081] (1) Dissolve 4 g of methomylene and 8 g of PVP / VA 535 copolymer in an appropriate amount of anhydrous ethanol, stir and disperse thoroughly to form a uniform dispersion system;

[0082] (2) Heat the homogeneous dispersion system obtained in step (1) to about 80 °C and remove the organic solvent by stirring until the system gradually becomes a viscous substance.

[0083] (3) Spread the viscous substance obtained in step (2) into a thin layer quickly, and cool it at 0 ℃ for 4~8 h under an environment with a relative humidity of no more than 40% to solidify the system.

[0084] (4) Take out the solidified material obtained in step (3), dry it in a vacuum drying oven at 40 °C until constant weight, then crush it and pass it through a 100-mesh sieve to obtain a methomyl solid dispersion;

[0085] (5) Mix sodium sulfachlorpyrifos, the methomyl solid dispersion obtained in step (4), disodium edetate, anhydrous sodium sulfite and sodium dodecyl sulfate according to the prescription ratio, and add anhydrous glucose and mix evenly;

[0086] (6) The mixture obtained in step (5) is ground and passed through a 100-mesh sieve to obtain compound sulfachlorpyridazine sodium soluble powder.

[0087] Comparative Example 2: Methamidophos raw material

[0088] This comparative example provides Aditoprim raw material powder that meets the standards for veterinary drug raw materials. It is directly tested for solubility and subsequent compound formulation without any carrier loading or solid dispersion treatment.

[0089] Evaluation of the solubility of methomyl solid dispersion

[0090] To evaluate the effect of solid dispersion technology on improving the solubility of methotrexate, solubility was determined. The specific method is as follows:

[0091] Take an appropriate amount of distilled water and place it in an Erlenmeyer flask. Add excess amounts of the methomyl solid dispersions prepared in Examples 1-10 and Comparative Example 1, respectively. Simultaneously, Comparative Example 2 (ADP raw material) is also tested using the same method. After ultrasonic treatment to ensure thorough dispersion of the solid drug, the solution is placed in a constant temperature shaker at (37±0.5)℃ and shaken at 100 r·min. -1 Shake to ensure the presence of solid drug in the system. After equilibration for 72 h, take an appropriate amount of solution, filter it through a 0.45 μm microporous membrane, and dilute the filtrate appropriately for later use. The absorbance was measured at the characteristic absorption wavelength of methotrexate using ultraviolet spectrophotometry, and its solubility was calculated. The results are shown in Table 4 below.

[0092] Table 4. Solubility of Methoxanone Solid Dispersion in Water

[0093]

[0094] Experimental results showed that the solubility of the methomyl solid dispersions prepared in Examples 1-10 in water was higher than that in the raw material form (0.2 mg / mL), indicating that solid dispersion technology can effectively improve the water solubility of methomyl. Specifically, the solubility of Examples 1 and Examples 7-10 was relatively high (0.6-0.8 mg / mL), with Example 1 showing the highest (0.8 mg / mL), approximately four times higher than the raw material. In contrast, the solubility of Examples 2-6 was 0.4-0.5 mg / mL, which, although higher than the raw material and Comparative Example 1 (0.3 mg / mL), was generally lower than the aforementioned examples.

[0095] The differences in solubility among different embodiments indicate that the types and ratios of carrier I and carrier II significantly affect the dispersion and solubility of methomyl. Analysis of the carrier composition shows that when the amount of carrier I is 6-8 g and the amount of carrier II is 3-4 g, with a mass ratio of approximately 2.0:1-2.7:1, the system exhibits superior solubility. When the amount of carrier deviates from this range, the solubility decreases to some extent. These results suggest that there is a synergistic effect between carrier I and carrier II, and an appropriate ratio is beneficial for the high dispersion of methomyl in the carrier, thereby further improving its solubility.

[0096] Quality evaluation of compound sulfachlorpyrifos sodium soluble powder

[0097] Based on the evaluation of the solubility and other properties of the ADP solid dispersion, compound sulfachlorpyridazine sodium soluble powder was further prepared using the solid dispersion as raw material, and the following quality evaluation items were performed on the compound sulfachlorpyridazine sodium soluble powders prepared in Examples 1-10 and Comparative Examples 1 and 2.

[0098] 1. Solubility test

[0099] Take 1.0 g of each sample from the examples and comparative examples, add it to 1000 mL of distilled water, stir at room temperature to dissolve it, and observe the state of each solution after standing. The results are shown in Table 5 below.

[0100] Table 5 Solubility Evaluation Results

[0101]

[0102] As shown in Table 5, the soluble powders of compound sulfachlorpyrifos sodium prepared in Examples 1 and 7-9 were clear after dissolution under the specified conditions, and no obvious precipitation occurred after standing, demonstrating good solubility. The solution of Example 10 was basically clear after dissolution, and only a very small amount of precipitation occurred after standing, indicating a high level of solubility. The solutions of Examples 2-6 and Comparative Example 1 were basically clear after dissolution, but different degrees of precipitation occurred after standing. The solution of Comparative Example 2 was turbid after dissolution, and obvious insoluble particles appeared after standing. These results indicate that preparing methomyl as the composite carrier solid dispersion described in this application and applying it to compound soluble powder formulations can significantly improve the solubility of the formulation.

[0103] 2. Content determination

[0104] Accurately weigh 0.1 g of the soluble powder of compound sulfachlorpyrifos sodium prepared by the methods of Examples 1 and 7-10, place it in a 100 mL volumetric flask, add 10 mL of water to dissolve it, then dilute it to the mark with methanol, shake well, and use it as the test solution; accurately measure 10 μL, inject it into the liquid chromatograph, and record the chromatogram.

[0105] Take appropriate amounts of methomyl reference standard (prepared by Wuhan Huisheng Biotechnology Co., Ltd., purity 99.3%) and sulfachlorpyridazine sodium reference standard (China Institute of Veterinary Drug Control, purity 99.8%), dissolve and dilute with methanol to prepare reference solutions containing 200 μg of sulfachlorpyridazine sodium and 40 μg of methomyl per 1 mL, respectively, and determine them using the same method; separately take the sample, determine its relative density, and convert the weighing result to a volume value. Calculate the labeled content of sulfachlorpyridazine sodium and methomyl in the sample using the external standard method based on peak area. The results are shown in Table 6 below:

[0106] Table 6. Content determination results

[0107]

[0108] As can be seen from the results in Table 6, the actual contents of sodium sulfachlorpyrifos and methotrexate in Examples 1 and 7-10 are close to their labeled amounts. The test results are stable and have good repeatability, indicating that the two active ingredients in the formulation of this application are uniformly dispersed and fully dissolved, and have good content uniformity. The above results further illustrate that the solid dispersion and formulation system used in this application are beneficial to improving the stability and controllability of the content of active ingredients in compound soluble powder formulations.

[0109] 3. Formulation stability studies

[0110] (1) High temperature test

[0111] Samples from Examples 1 and 7-10 were placed at 60℃±2℃ for 10 days. Samples were taken on days 0, 5, and 10 to determine the contents of sodium sulfachlorpyrifos and methomyl. Simultaneously, the appearance, solubility, clarity of solution, moisture content, and related substances of the formulations were observed. The results are shown in Tables 7-1, 7-2, 7-3, and 7-4 below. In the tables, ADP-R7 represents N-demethylmethacin.

[0112] Table 7-1 High-temperature test results of sample from Example 1

[0113]

[0114] Table 7-2 High-temperature test results of sample 7 in Example 7

[0115]

[0116] Table 7-3 High-temperature test results of sample 8 in Example 8

[0117]

[0118] Table 7-4 High-temperature test results of sample 9 in Example 7

[0119]

[0120] Table 7-5 High-temperature test results of sample 10 in Example 10

[0121]

[0122] The results above show that all samples in Examples 1 and 7-10 are pale yellow powders, remain clear in solubility, have a decrease in active ingredient content of less than 2.0%, exhibit slow growth of related substances, and show minimal change in moisture content, indicating good high-temperature stability.

[0123] (2) Accelerated stability test

[0124] Accelerated stability testing was conducted according to the requirements of the "Guidelines for Stability Testing of Raw Materials and Preparations" (Appendix 9001) of the Pharmacopoeia of the People's Republic of China for Veterinary Drugs (2020 Edition). Samples from Examples 1 and 7-10 were placed at 30±2 ℃ and 65%±5% relative humidity for 6 months. Samples were taken at months 1, 2, 3, and 6, and the properties of appearance, solubility, solution clarity, related substances, content, and moisture content were tested according to the key stability testing items. The test results are shown in Tables 8-1, 8-2, 8-3, and 8-4, respectively. In the tables, ADP-R7 represents N-demethylmethazine.

[0125] Table 8-1 Results of accelerated stability test of sample in Example 1

[0126]

[0127] Table 8-2 Results of accelerated stability test of sample in Example 7

[0128]

[0129] Table 8-3 Results of accelerated stability test of sample in Example 8

[0130]

[0131] Table 8-4 Results of accelerated stability test of sample 9 in Example 8

[0132]

[0133] Table 8-5 Results of accelerated stability test of sample 10 in Example 10

[0134]

[0135] The test results above show that during the accelerated stability test, the compound sulfachlorpyridazine sodium soluble powder prepared in Examples 1 and 7-10 did not show significant changes in appearance and solubility, nor did the content change significantly. The changes in moisture and related substances were all within acceptable ranges, and all test indicators met the requirements, indicating that the compound sulfachlorpyridazine sodium soluble powder described in this application has good stability.

[0136] In summary, the amount and mass ratio of carrier I and carrier II significantly affect the structural stability and redispersibility of the methomylene solid dispersion. When the amount of carrier I is less than 6 g, its encapsulation and stabilizing effect on methomylene is insufficient; when the amount of carrier I is greater than 8 g, the system tends to be dense, which is not conducive to redispersibility. When the amount of carrier II is less than 3 g, the composite carrier structure is not sufficiently supported; when the amount of carrier II is greater than 4 g, the proportion of inorganic carrier is too high, which easily affects the homogeneity of the system. When the mass ratio of carrier I to carrier II is less than approximately 2.0:1, the structural stability of the composite carrier is insufficient; when this ratio is greater than approximately 2.7:1, the degree of system densification increases, and the redispersibility decreases. When the amount of carrier I is 6-8 g and the amount of carrier II is 3-4 g, and the mass ratio of the two is controlled at approximately 2.0:1-2.7:1, the resulting methomylene solid dispersion exhibits superior comprehensive performance in terms of structural stability and redispersibility.

[0137] Example 11: Application of Compound Sulfachlorpyrimethamine Sodium Soluble Powder in Chicken Coccidiosis Infection

[0138] 1. Test Methods

[0139] (1) Test drug

[0140] Control drug 1: Sulfachlorpyrifos sodium soluble powder (30%): batch number D20250403, manufacturer: Wuhan Huisheng Biotechnology Co., Ltd.

[0141] Control drug 2: Sulfachlorpyrifos sodium and trimethoprim soluble powder (100g: 20g sulfachlorpyrifos sodium + 4g trimethoprim): batch number 24090102, manufacturer: Henan Muxiang Biotechnology Co., Ltd.

[0142] Test drug: Compound sulfachlorpyridazine sodium soluble powder prepared in Example 1.

[0143] (2) Test insect strains

[0144] The Eimeria tenella was provided by the Parasitology Laboratory of Huazhong Agricultural University. The sporulated oocysts were stored in a 2.5% potassium dichromate solution and preserved at 4 ℃ to maintain their activity. Before use, they were multiplied and expanded in SPF chicks that were free of coccidia infection.

[0145] (3) Experimental animals

[0146] SPF White Leghorn chickens, 12 days old and free of coccidia, were identified by leg tags. Before the experiment, they were weighed and grouped after being examined for coccidia oocysts.

[0147] (4) Selection criteria for experimental animals

[0148] Chicks that meet the following criteria can be included in this experiment. The specific inclusion criteria are shown in Table 9, and the fecal score is referenced in Table 13.

[0149] Table 9. Information on Experimental Animals

[0150]

[0151] (5) Exclusion criteria for experimental animals

[0152] Chickens exhibiting the following conditions were excluded from this experiment:

[0153] 1) Chickens with other complications that require additional medication;

[0154] 2) Chickens that had received other drug treatments before the trial;

[0155] 3) Chickens that have received anticoccidial treatment within 2 weeks prior to selection.

[0156] (6) Behavioral performance scoring criteria

[0157] During the experiment, the chickens were observed and recorded daily for their feed and water intake, mental state, diarrhea, ruffled or dull feathers, and normal standing posture. Based on the literature reported by Zheng Yanqiong, Morehouse, and Baron, symptoms were scored according to clinical manifestations, as shown in Table 10.

[0158] Table 10 Behavioral Performance Scoring Table for Chicks Infected with Eimeria tenella

[0159]

[0160] (7) Identification and feeding management of experimental animals

[0161] During the experiment, the animal housing environment should be thoroughly cleaned before the experiment and disinfected with a 5% NaOH solution or disinfectant. Cleaning should be carried out daily during the experiment, and disinfection with disinfectant should be performed weekly. At the end of the experiment, a thorough cleaning should be performed, followed by disinfection with a 5% NaOH solution. Treatment with other drugs should be avoided during the experiment. An electronic thermometer and hygrometer should be placed in the room, and the temperature and humidity of the animal housing should be recorded at 9:00 AM and 5:00 PM daily. Chicks have relatively high light requirements; generally, 24-hour lighting is used in the first week, 19 hours of lighting in the second week, and from the third week onwards, 8 hours of lighting per day can be used in enclosed chicken houses. Appropriate adjustments should be made to the temperature, humidity, and light control measures during the actual experiment, and the reasons for and measures for these adjustments should be explained and recorded.

[0162] Feed the chickens twice daily, morning and evening, and provide free access to water. As the broilers grow, the indoor temperature needs continuous adjustment. Generally, the temperature around the chickens' bodies is used as the measurement range: 34-35℃ for chickens under 3 days old, 31-33℃ for 4-7 days old, 28-31℃ for 8-14 days old, 25-28℃ for 15-21 days old, 22-25℃ for 21-28 days old, and 20-25℃ from 29 days old until slaughter. The temperature should gradually decrease as the broilers age. Avoid using other medications during the trial period. Regularly observe and record the integrity of each feed trough and watering facility daily. Repair any damaged facilities promptly and record the damage in detail.

[0163] During the experiment, all experimental chickens were fed a complete feed that contained no anticoccidial drugs or traditional Chinese veterinary medicine ingredients; the drinking water for the experimental chickens met the national standards for domestic water hygiene.

[0164] (8) Culling of experimental animals

[0165] Chickens exhibiting any of the following abnormalities during observation should be culled immediately: 1) conditions causing pain or suffering to the chicken (e.g., lameness), or 2) abnormalities that may lead to further deterioration of the health of the chicken and its companions (e.g., infectious disease), and / or 3) abnormalities that affect the chicken's normal feed intake and water intake during the trial (e.g., death or illness).

[0166] (9) Trial grouping and administration

[0167] Chickens were bred in a coccidiotropic environment until 14 days of age. Before the experiment, feces were collected and examined under a microscope to confirm the absence of coccidia. Each chicken was weighed individually, and excessively large or small chickens were removed. Healthy chickens were randomly divided into 5 groups, and the weight of each group was weighed as a whole to minimize errors. The 5 groups were: uninfected and untreated control group (NC), challenged and untreated control group (IC), sulfachlorpyridazine sodium soluble powder group (SPZ), sulfachlorpyridazine sodium and trimethoprim soluble powder group (SPZ-TMP), and compound sulfachlorpyridazine sodium soluble powder group (SPZ-ADP). Except for the NC group, all other groups were orally inoculated with 5 × 10⁴ coccidia eggs per chicken. Each drug test group was administered medication on the second day (48 hours) after coccidia infection, according to the recommended dosage in the instructions or the experimental dosage, and administered for 5 consecutive days. Details of the experimental groups, coccidia infection, and drug testing are shown in Table 11.

[0168] Table 11 Animal grouping, infection and drug use

[0169]

[0170] (10) Experimental observation and data collection

[0171] During the experiment, clinical symptoms and disease incidence were observed daily in the experimental chickens. Water intake, feed consumption, mental state, plumage color, fecal condition, and necropsy results of chickens that died from coccidiosis were recorded. Weight data, intestinal samples, and pathological indicators were collected from each group of chickens at 14 and 22 days of age. Fecal samples were collected from days 5 to 8 post-coccidiosis infection (i.e., 19 to 22 days of age), and data on coccidia oocyst excretion were collected from each group.

[0172] (11) Criteria for Evaluating Therapeutic Effect

[0173] 1) Relative weight gain rate

[0174] Each group of chickens was weighed individually at 14 days of age before coccidiosis infection or drug administration, and again at 22 days of age before euthanasia (i.e., 8 days after infection). Following the method of Suo et al. (1997), the average weight gain of each experimental group was first calculated, and then the relative weight gain rate was calculated using the following formula:

[0175] Average weight gain per group = (Total weight at the end of the trial - Total weight at the beginning of the trial) ÷ ​​Number of chickens

[0176] (Note: Chickens that die during the trial should be culled.)

[0177] Relative weight gain rate (%) = (Average weight gain in the infection treatment group ÷ Average weight gain in the blank control group) × 100%

[0178] 2) Survival rate calculation

[0179] Following the method of Suo et al. (1997), the number of dead chickens in each group was recorded daily after infection, and the cause of death was determined by necropsy. Chickens that died from non-coccidiosis were excluded. The survival rate of chickens in each experimental group was calculated using the following formula:

[0180] Survival rate (%) = Number of surviving chickens ÷ Initial number of chickens in the experiment × 100%

[0181] Referring to the method of Johnson & Reid (1970) and Tables 12 and 13, intestinal tissues of chickens in each group were collected on the 8th day after infection. The lesion scores of chickens in each experimental group were recorded, and the lesion values ​​of chickens in each group were calculated according to the lesion or bloody stool scores (Tables 12 and 13) and the following formulas, as follows:

[0182] Table 12 Lesion Scoring

[0183]

[0184] Table 13 Fecal Score

[0185]

[0186] Average lesion (or fecal) score = sum of lesion (fecal) scores for each group ÷ number of animals with scores.

[0187] 4) Fecal ovarian cyst count

[0188] Following the method of Suo et al. (1997), fecal samples were collected from each group of chickens on days 5-8 post-infection. The number of coccidia oocysts (OPG) and the total number of OPGs per gram of feces were calculated for each group of chickens using the McMaster counting method. The OPG saturated saline flotation counting method was as follows: 2 g of feces was placed in a 100 mL graduated beaker. A small amount of saturated saline was added and stirred thoroughly. Then, saturated saline was added until the total volume was 60 mL. After thorough mixing, an appropriate amount of suspension was quickly injected into the counting chamber of the McMaster counting chamber (note that there should be no air bubbles below the scale). After standing for 5 min, the coccidia oocysts in the two counting chambers were counted using a microscope.

[0189] The formula for calculating OPG is as follows:

[0190] OPG=(X1+X2) / 2÷0.15×30=(X1+X2)×100

[0191] (Note: X1 and X2 represent the number of coccidia oocysts in the two counting chambers of the McMaster counting chamber, respectively.)

[0192] The average total number of ovulation sacs in each group of chickens was calculated as follows:

[0193] Average total number of ovulation sacs = OPG × total fecal volume ÷ number of chickens

[0194] 5) Calculation of ovarian sac value

[0195] Referring to the method of Suo et al. (1997), the conversion was performed based on the coccidia oocyst ratio using the following formula and Table 14:

[0196] Oocyte ratio % = Number of ovarian cysts in the treatment group / Number of ovarian cysts in the non-treatment group × 100.

[0197] Note: The number of oocysts is the OPG in the feces of chickens in each experimental group or the average total number of oocysts released.

[0198] Table 14 Conversion of Oocyte Values

[0199]

[0200] 6) Calculation of the anticoccidial index

[0201] Based on the relative weight gain, survival rate, lesion value, and oocyst value of each experimental chicken, the anticoccidial index (ACI) was calculated according to the formula of Merck & Co., Ltd.

[0202] ACI = (Relative weight gain rate + Survival rate) - (Disease value + Oocyte value).

[0203] 7) Determination of overall drug efficacy

[0204] Referring to the method of Suo et al. (1997), under the condition that all indicators of the control group chickens are normal, the effect of drug treatment or prevention on the drug test group is judged according to the following criteria (Table 15) based on the ACI.

[0205] Table 15 Efficacy Assessment

[0206]

[0207] 2. Test Results

[0208] (1) Clinical symptoms

[0209] Before and within three days after coccidiosis infection, the chickens in all groups showed normal behavior, appetite, water intake, and feces. On days 4-5 after infection, the chickens in the NC group showed normal behavior, appetite, water intake, and feces, while the chickens in the IC group showed obvious symptoms such as lethargy, emaciation, crowding, decreased appetite, rough and dull feathers, and bloody feces. The chickens in all drug-treated groups showed a decrease in food and water intake. Two chickens in the IC group died on day 5 after coccidiosis infection. On days 6-7 after infection, except for the chickens in the IC group who still showed symptoms such as lethargy, reduced food and water intake, the chickens in the other groups did not show obvious clinical symptoms.

[0210] (2) Body weight indicators

[0211] The weight index results are shown in Table 16 below.

[0212] Table 16 Weight gain and survival of chickens in each experimental group

[0213]

[0214] Note: Data are presented as mean ± standard deviation. Superscript letters "a, b, c, d" are used to indicate differences between groups. Data with different superscript letters are significantly different (p≤0.05), while data with the same superscript letter are not significantly different (p>0.05).

[0215] (3) Pathological indicators

[0216] On day 8 post-coccidiosis, necropsy results of chickens in each group showed that the NC group had no intestinal lesions, while the IC group had the most severe intestinal lesions, characterized by cecal atrophy, significant thickening of the intestinal wall, and large areas of dark red congestion on the mucosa containing mucus, brownish contents, or dark red caseous intestinal cores. The average lesion score was 2.80. The SPZ group showed less intestinal lesions than the IC group, mainly manifested as mild gas distension in parts of the cecum, with a lower incidence of caseous cecal cores. The average lesion score was 2.20, but some degree of lesions could still be observed. The SPZ-TMP and SPZ-ADP groups showed further reductions in intestinal lesions, with very few caseous cecal cores. The average lesion scores were 1.49 and 1.31, respectively (see Table 17 for details).

[0217] Table 17 Intestinal Lesion Scores and Lesion Values

[0218]

[0219] Note: Data are presented as mean ± standard deviation. The superscript letters "a, b, c" are used to indicate differences between groups. Data with different letters indicate significant differences (p≤0.05), while data with the same letter indicate no significant differences (p>0.05).

[0220] (4) Coccidia oocyst markers

[0221] The fecal coccidia oocyst counts of chickens in each group from day 5 to 8 post-infection showed that the IC group excreted the most coccidia oocysts, with a count of 0.18 × 10⁻⁶. 6 Chickens; compared with the IC group, the excretion rates of coccidia oocysts in the SPZ, SPZ-TMP, and SPZ-ADP groups were reduced by 44.44%, 88.89%, and 94.44%, respectively. See Table 18 for details.

[0222] Table 18 Total ovum expulsion in each experimental group

[0223]

[0224] (5) Anticoccidial Comprehensive Index

[0225] The Anticoccidial Comprehensive Index (ACI) was calculated using the formula [ACI = (relative weight gain rate + survival rate) - (lesion value + oocyst value)]. The ACI values ​​for each group of chickens were calculated. The ACI values ​​for the SPZ, SPZ-TMP, and SPZ-ADP treatment groups were 124.53, 162.40, and 169.40, respectively. See Table 19 for details.

[0226] Table 19. Anticoccidial Index (ACI) of the Experimental Groups

[0227]

[0228] (6) Determination of drug efficacy

[0229] According to the comprehensive drug efficacy evaluation criteria (ACI value 0~120 is ineffective, 121~160 is ineffective, 161~180 is moderately effective, and >180 is highly effective), the compound sulfachlorpyridazine sodium soluble powder of this application has a better comprehensive anticoccidial effect than sulfachlorpyridazine sodium soluble powder and sulfachlorpyridazine sodium trimethoprim soluble powder in chickens infected with Eimeria tenella.

[0230] In summary, the compound sulfachlorpyrifos sodium soluble powder prepared according to Example 1 has achieved excellent results in terms of quality control and clinical efficacy.

[0231] Example 12: Application of Compound Sulfachlorpyrifos Sodium Soluble Powder in Coccidiosis Infection in Sheep

[0232] 1. Test Methods

[0233] (1) Test drug

[0234] Reference drug: Sulfachlorpyrifos sodium soluble powder (30%): batch number D20250403, manufacturer: Wuhan Huisheng Biotechnology Co., Ltd.

[0235] Test drug: Compound sulfachlorpyridazine sodium soluble powder prepared in Example 1.

[0236] (2) Experimental animals

[0237] Lambs aged 45-55 days, weighing approximately 15-20 kg, were naturally infected with coccidia, with an oocyst excretion (OPG) of 10,000-20,000. During the trial, they were fed a basic diet that did not contain anticoccidial drugs or antibiotics.

[0238] (3) Case screening

[0239] To ensure that the coccidia infection levels in lambs were approximately equal across groups before the experimental drug administration, fecal samples were collected from the rectum and the number of coccidia oocysts (OPG) in the fecal samples was counted using the McMaster method. This ensured that the coccidia infection levels and body weights were consistent across groups. Cases with excessively high or low coccidia infection levels, or those that did not meet the target body weight, were excluded.

[0240] Symptoms in affected sheep: Loose feces remain in the sheepfold and on the sheep beds, with obvious diarrhea in the tail area of ​​the affected sheep. The feces of affected sheep are initially watery or pasty, with a fishy odor, sometimes mixed with blood. This is followed by clinical symptoms such as rough and disheveled coat, lethargy, drowsiness, decreased appetite, sunken eyes, anemia and pallor of visible mucous membranes, emaciation, and weakness in the limbs. Except for a few cases of elevated body temperature, the body temperature of the rest is within the normal range.

[0241] (4) Trial grouping and administration

[0242] On day D0, clinical symptoms and fecal characteristics of the candidate experimental lambs were observed, and fecal samples were collected for coccidia oocyst excretion (OPG) measurement and coccidia species identification. Based on pre-set inclusion and exclusion criteria, 30 lambs meeting the experimental conditions were selected, and corresponding experimental animal selection records were established. On day D0, the 30 selected lambs were arranged according to their ear tag numbers and randomly grouped into 3 groups of 10 lambs each using a computer-generated random number table. Weighing and grouping records were completed. On day D1, the weight of each group of experimental lambs was measured again, and administration was performed via gavage according to the drug administration protocol shown in Table 20, for 5 consecutive days (D1-D5). During the experiment, the experimental lambs were fed according to standard sheep farm feeding and management methods, with free access to feed and water, and feed consumption in each group was recorded.

[0243] Table 20 Animal Grouping and Drug Use

[0244]

[0245] (5) Experimental observation and data collection

[0246] During the experiment, the clinical manifestations of lambs in each group were observed and recorded daily. These clinical manifestations included mental state, feed intake, water intake, defecation, morbidity, and mortality. If any lambs died during the experiment, the number of dead lambs in each group was recorded, and the dead individuals were subjected to necropsy and coccidiosis identification to determine the cause of death.

[0247] 1) General clinical examination

[0248] Record the number of sheep that died in each group during the experiment (D0~D21). Check the clinical symptoms of each lamb regularly before administration (D0), during administration (D1~D5), and after discontinuation of administration (D7, D14, D21), and record the clinical symptoms.

[0249] 2) Pathogen identification

[0250] At D0, D5, and D21, five sheep from each of the three experimental sheep groups were randomly selected to examine the feces excreted by the lambs using the saturated saline flotation method. Morphological examination of the coccidia oocysts was performed, and the species of coccidia were identified by PCR.

[0251] 3) Determination of the number of coccidia oocysts in feces

[0252] To prevent contamination of feces by coccidia oocysts in the environment and to ensure that each fecal sample corresponds to a specific experimental sheep, feces were collected from each sheep individually using the anal stimulation defecation method. Each fecal sample weighed 10-20 g, was placed in a clean plastic bag and labeled, and then used for coccidia oocyst counting and species identification.

[0253] Fresh feces (5g) were collected from each lamb on days D0, D1-D7, D14, and D21. After mixing, the number of oocysts per gram of feces (OPG) was determined. Coccidia oocysts were isolated from the feces using the saturated salt flotation method, and the OPG value was determined using the McMaster counting method.

[0254] Method for determining fecal coccidia oocyst count (OPG): The McMaster counting method was used to determine the OPG of coccidia in feces. For counting, 5g of feces was weighed after thorough mixing. The 5g feces were first added to 50mL of water and stirred thoroughly. Then, 1mL of the fecal-water mixture was quickly added to 5mL of saturated saline solution. After mixing, the fecal solution was immediately drawn into the counting chamber of the counting chamber and allowed to stand for 5 minutes. The chamber was examined under a microscope at 100x magnification (10× eyepiece, 10× objective lens). The number of oocysts in each counting chamber was counted (the number of oocysts in two counting chambers could be counted, and the average value was taken). The volume of the counting chamber was 1×1×0.15=0.15 mL. 0.15 mL contained (5 / 50)÷6×0.15=0.0025 g of feces. Therefore, the OPG value was obtained by multiplying the number of oocysts by 400.

[0255] 4) Weight gain and feed conversion

[0256] The weight of each lamb was measured on days D0 and D21. The amount of feed prepared and leftover for the experimental sheep during the period from D0 to D21 was recorded, and the feed consumption of the three groups of experimental sheep was calculated for each time period.

[0257] 5) Pathological autopsy

[0258] During the experiment (D0~D21), necropsies were performed on all dead lambs in each group, with a focus on observing intestinal tissue lesions, analyzing the cause of death, and recording the findings. In cases of death due to coccidiosis, necropsies should reveal bloody feces in the intestinal lumen, grayish-white spots or protrusions on the intestinal wall, and a large number of coccidia oocysts in the feces.

[0259] (6) Criteria for evaluating therapeutic efficacy

[0260] 1) Number of coccidia oocysts and rate of reduction of coccidia oocysts

[0261] The number of coccidia oocysts (OPG) in the feces of each lamb in the three experimental groups was measured on days D0, D1-D7, D14, and D21. The average OPG of lambs in each group was calculated, and the relative reduction rate of coccidia oocysts in the drug group was calculated based on the average OPG on day D0, using the following formula:

[0262] OPG reduction rate (%) = [(average OPG before administration - average OPG after administration) / average OPG before administration] × 100

[0263] 2) Weight gain rate and relative weight gain rate

[0264] The weights of lambs in each group were measured on days D0 and D21. Using the weight on day D0 as the baseline, the weight gain rate of each lamb during the period from D0 to D21 was calculated. Furthermore, the average weight gain rate and relative weight gain rate of each group were calculated using the following formulas:

[0265] Weight gain rate (%) = [(D21 weight - D0 weight)] / D0 weight × 100

[0266] Relative weight gain rate (%) = (Average weight gain in the drug group / Average weight gain in the negative control group) × 100%

[0267] 2. Test Results

[0268] (1) Coccidia oocyst markers

[0269] After administration, coccidia oocysts in sheep feces were counted on days D0, D1-D7, D14, and D21. The results are shown in Table 21.

[0270] Table 21 Oocyte expulsion status in each experimental group

[0271]

[0272] Note: Data are presented as mean ± standard deviation. The superscript letters "a", "b", and "c" are used to indicate differences between groups. Data with different letter labels are significantly different (p ≤ 0.05), while data with the same letter label are not significantly different (p > 0.05).

[0273] (2) Coccidia oocyst reduction rate

[0274] The reduction rate of coccidia oocysts in each experimental group was calculated, and the results are shown in Table 22.

[0275] Table 22 Reduction rate of coccidia oocysts in each experimental group

[0276]

[0277] (3) Body weight indicators

[0278] The weight indicators are shown in Table 23 below:

[0279] Table 23 Weight gain of sheep in each experimental group

[0280]

[0281] Note: Data are presented as mean ± standard deviation. The superscript letters "a, b, c" are used to indicate differences between groups. Data with different letters indicate significant differences (p≤0.05), while data with the same letter indicate no significant differences (p>0.05).

[0282] The experimental results showed that the compound sulfachlorpyridazine sodium soluble powder described in this application significantly reduced the amount of coccidia oocysts excreted in feces in a naturally infected lamb coccidiosis model. Three to seven days after administration, the reduction rate of coccidia oocysts in the compound preparation group reached over 98%, and maintained a high level of inhibition at 14 and 21 days, with an overall anticoccidial effect superior to the sulfachlorpyridazine sodium monotherapy group. Simultaneously, the compound preparation significantly promoted the weight gain of infected lambs, with both the average weight gain and relative weight gain rate being significantly better than the control group and the monotherapy group. These results indicate that the compound preparation of this application has rapid onset and long-lasting anticoccidial activity, and can effectively improve the growth performance of infected animals.

[0283] The present application has been described in detail above. Specific examples have been used to illustrate the principles and implementation methods of the present application. The descriptions of the embodiments above are only for the purpose of helping to understand the present application and its core ideas. It should be noted that those skilled in the art can make several improvements and modifications to the present application without departing from the principles of the present application, and these improvements and modifications also fall within the protection scope of the claims of the present application.

Claims

1. A compound sulfachlorpyrifos sodium soluble powder, wherein each 100 g of the soluble powder is composed of the following components: The mixture consists of 15-30 g of sodium sulfachlorpyrifos, 4-8 g of methomyl, 6-12 g of carrier I, 3-6 g of carrier II, 1-5 g of surfactant, 0.1-3 g of metal chelating agent, 0.1-3 g of antioxidant, and the remainder being filler; carrier I is a polyvinylpyrrolidone-vinyl acetate copolymer or polyvinylpyrrolidone K30, and carrier II is mesoporous silica.

2. The compound sulfachlorpyrifos sodium soluble powder according to claim 1, wherein each 100 g of the soluble powder is composed of the following components: The ingredients are: sodium sulfachlorpyrifos 18-25 g, methomyl 4-5 g, carrier I 6-8 g, carrier II 3-4 g, surfactant 2.5-3 g, metal chelating agent 0.3-2 g, antioxidant 0.3-2 g, and the remainder is filler.

3. The compound sulfachlorpyrifos sodium soluble powder according to claim 1, wherein the surfactant is selected from at least one of sodium dodecyl sulfate, Tween 80, and poloxamer 188; and the metal chelating agent is disodium edetate.

4. The compound sulfachlorpyrifos sodium soluble powder according to claim 1, wherein the antioxidant is selected from at least one of anhydrous sodium sulfite and sodium thiosulfate; and the filler is selected from at least one of anhydrous glucose and lactose.

5. The method for preparing the compound sulfachlorpyrifos sodium soluble powder according to claim 1, comprising the following steps: (1) Methanielin and polyvinylpyrrolidone-vinyl acetate copolymer or polyvinylpyrrolidone K30 are dissolved in anhydrous ethanol, and then mesoporous silica is added and dispersed evenly to form a uniform dispersion system of methanielin loaded on a composite carrier. (2) Heat the system obtained in step (1) to 70~85 °C, stir to evaporate and remove the solvent until a viscous substance is formed; (3) Spread the viscous substance into a thin layer and then cool and solidify it; (4) Dry the solidified material to constant weight, pulverize it and sieve it through an 80-100 mesh screen to obtain a methomylene solid dispersion; (5) Mix sodium sulfachlorpyrifos, the methomyl solid dispersion obtained in step (4), the surfactant, metal chelating agent, antioxidant and filler as described in claim 1 evenly; (6) Grind and sieve the mixture obtained in step (5) to obtain compound sulfachlorpyrifos sodium soluble powder.

6. According to the preparation method of claim 5, in step (3), the cooling and solidification treatment conditions are: cooling at 0 ℃ for 4-8 hours in an environment with a relative humidity not higher than 40%.

7. The use of the compound sulfachlorpyridazine sodium soluble powder according to any one of claims 1-4 in the preparation of a drug for the prevention and treatment of coccidiosis in livestock and poultry.

8. The application according to claim 7, wherein the livestock or poultry is a chicken or a sheep.

9. The application according to claim 8, wherein the chicken is a chick and the sheep is a lamb.

10. The application according to any one of claims 7-9, wherein the coccidiosis is caused by Eimeria tenella or Eimeria oviductella.

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