Ultramicro dinitolmide dispersion and preparation method thereof

Abstract

The invention relates to the technical field of veterinary preparations, in particular to an ultramicro dinitolmide dispersion and a preparation method thereof. The ultramicro dinitolmide dispersion is prepared from the following raw materials in parts by mass: 1 to 5 parts of dinitolmide, 0.5 to 2 parts of nano clay, 0.5 to 1 part of a coating agent, 6 to 18 parts of a filling agent, 1 to 2 parts of a dispersing agent, 11 to 25 parts of a solid dispersion carrier and 1 to 2 parts of a thickening agent. According to the dinitolmide dispersoid obtained by the invention, the use amount of an organic solvent is reduced, the pollution to the environment is reduced, the preparation method is simple and controllable, and industrial mass production is easy to realize.

Description

Technical Field

[0001] This invention relates to the field of veterinary drug formulation technology, and in particular to an ultrafine dinitropyridine dispersion and its preparation method. Background Technology

[0002] Coccidiosis in chickens is a serious parasitic disease caused by Eimeria coccidia parasitizing the intestinal epithelial cells of chickens, with a morbidity and mortality rate as high as 80%. This disease can severely damage the intestinal mucosa of poultry, causing symptoms such as bloody diarrhea, feed-related diarrhea, and watery diarrhea. In severe cases, it can cause large-scale mortality. Even after recovery, the growth of chicks will be stunted, and adult chickens, although not showing symptoms, will experience a decline in weight gain and egg production, posing a significant threat to the poultry industry.

[0003] Dinitropamide, as a highly effective drug for preventing and treating coccidiosis in poultry, has advantages such as no side effects, low toxicity, and stable performance. It exhibits good stability when added to feed, is not easily decomposed, and can promote poultry weight gain and improve feed utilization. Its aqueous solution has an appealing aroma to chickens with anorexia, and its unique mechanism of action allows it to be used in combination with other drugs. It is suitable for the treatment and prevention of coccidiosis, as well as the prevention and treatment of small intestinal coccidiosis in rabbits, turkeys, and other animals.

[0004] However, dinitrofurazone has extremely low solubility in water, resulting in significantly insufficient bioavailability and severely affecting its anticoccidial efficacy. Currently, most commercially available products are prepared through simple physical mixing and the addition of excipients, leading to poor material homogeneity and solubility, which can easily result in excessively high or low local drug concentrations. Excessively high concentrations may pose a risk of drug residues, while excessively low concentrations fail to achieve effective prevention and control, limiting its clinical application value. Therefore, developing a dinitrofurazone dispersion with high dispersibility, excellent bioavailability, and good animal absorption is of significant research importance. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by proposing an ultrafine dinitropyridine dispersion and its preparation method.

[0006] An ultrafine dinitrothione dispersion comprises the following raw materials by weight: 1-5 parts dinitrothione, 0.5-2 parts nano-clay, 0.5-1 part coating agent, 6-18 parts filler, 1-2 parts dispersant, 11-25 parts solid dispersion carrier, and 1-2 parts thickener.

[0007] Preferably, the coating agent is hydroxypropyl-β-cyclodextrin.

[0008] Preferably, the filler is light calcium carbonate and / or mannitol.

[0009] More preferably, the mass ratio of light calcium carbonate to mannitol is 5-15:1-3.

[0010] Preferably, the solid dispersion carrier is polyvinylpyrrolidone and / or polyethylene glycol.

[0011] More preferably, the mass ratio of polyvinylpyrrolidone to polyethylene glycol is 10-20:1-5.

[0012] Preferably, the thickener is carboxypropyl methylcellulose.

[0013] Preferably, the dispersant is polyvinyl alcohol.

[0014] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, coating agent and nano clay to 10-20 parts of acetone and sonicate for 1-2 hours at an ultrasonic frequency of 70-80kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Mix the pretreated dinitropyridine, some filler, and dispersant, and ball mill under nitrogen protection for 1-5 hours to obtain predispersed dinitropyridine. S3. Mix the pre-dispersed dinitropyridine, solid dispersion carrier, remaining filler and thickener evenly, and send them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure inside the reactor at 18-20 MPa and the temperature inside the reactor at 40-50℃. Maintain the pressure for 2-5 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0015] Preferably, in S2, the ball milling speed is 150-200 r / min and the ball-to-material ratio is 10-15:1.

[0016] Beneficial effects: This invention uses a combination of dinitrodrug, hydroxypropyl-β-cyclodextrin, and nano-clay. Hydroxypropyl-β-cyclodextrin forms an inclusion structure with dinitrodrug molecules through its hydrophobic cavity, which significantly reduces the van der Waals forces between drug molecules and inhibits crystallization and aggregation. Meanwhile, nano-clay effectively blocks secondary aggregation between particles through physical adsorption, effectively avoiding the local concentration gradient problem caused by traditional physical mixing.

[0017] The present invention introduces carbon dioxide as a dispersion medium into a high-pressure reactor, which promotes the uniform dispersion of pre-dispersed dinitropyridine in a three-dimensional network formed by a solid dispersion carrier (polyvinylpyrrolidone, polyethylene glycol). Combined with a specific granulation method, it significantly increases the specific surface area of ​​the drug, laying the foundation for improving bioavailability. It can achieve excellent therapeutic effects when used to treat coccidiosis in chickens.

[0018] The dinitrothione dispersion obtained by this invention reduces the amount of organic solvent used and the environmental pollution, and the preparation method is simple and controllable, making it easy to achieve large-scale industrial production. Attached Figure Description

[0019] Figure 1The particle size and sedimentation volume ratio in water for 4 hours of the ultrafine dinitrothionide dispersions obtained in Example 5 and Comparative Examples 1-2 are given. Figure 2 This is a comparison chart of the anticoccidial index of Example 5, Comparative Example 1, Comparative Example 2, Positive Drug Group, Negative Control Group, and Healthy Control Group. Detailed Implementation

[0020] The present invention will be further explained below with reference to specific embodiments.

[0021] Example 1: An ultrafine dinitrodrug dispersion, the raw materials of which include: 1g dinitrodrug, 0.5g nano clay, 0.5g hydroxypropyl-β-cyclodextrin, 5g light calcium carbonate, 1g mannitol, 1g polyvinyl alcohol, 10g polyvinylpyrrolidone, 1g polyethylene glycol 6000, and 1g carboxypropyl methylcellulose.

[0022] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, hydroxypropyl-β-cyclodextrin and nano-clay to 10g acetone and sonicate for 1h at a frequency of 70kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 5 hours under nitrogen protection. The ball milling speed is 150 r / min and the ball-to-material ratio is 10:1 to obtain pre-dispersed dinitropyridine. S3. Mix pre-dispersed dinitropyrrolidone, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 18 MPa and the temperature at 40°C. Maintain the pressure for 2 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0023] Example 2: An ultrafine dinitrothione dispersion, the raw materials of which include: 5g dinitrothione, 2g nano clay, 1g hydroxypropyl-β-cyclodextrin, 15g light calcium carbonate, 3g mannitol, 2g polyvinyl alcohol, 20g polyvinylpyrrolidone, 5g polyethylene glycol 6000, and 2g carboxypropyl methylcellulose.

[0024] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, hydroxypropyl-β-cyclodextrin and nano-clay to 20g acetone and sonicate for 2h at an ultrasonic frequency of 80kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 1 hour under nitrogen protection. The ball milling speed is 200 r / min and the ball-to-material ratio is 15:1 to obtain pre-dispersed dinitropyridine. S3. Mix pre-dispersed dinitropyrrolidone, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 20 MPa and the temperature at 50°C. Maintain the pressure for 5 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0025] Example 3: An ultrafine dinitrodrug dispersion, the raw materials of which include: 2g dinitrodrug, 1.6g nano clay, 0.7g hydroxypropyl-β-cyclodextrin, 12g light calcium carbonate, 1.5g mannitol, 1.8g polyvinyl alcohol, 12g polyvinylpyrrolidone, 4g polyethylene glycol 6000, and 1.2g carboxypropyl methylcellulose.

[0026] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, hydroxypropyl-β-cyclodextrin and nano-clay to 18g acetone and sonicate for 80min at an ultrasonic frequency of 78kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 2 hours under nitrogen protection. The ball milling speed is 190 r / min and the ball-to-material ratio is 11:1 to obtain pre-dispersed dinitropyridine. S3. Mix pre-dispersed dinitrothione, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 19.5 MPa and the temperature at 42°C. Maintain the pressure for 4 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0027] Example 4: An ultrafine dinitrothione dispersion, the raw materials of which include: 4g dinitrothione, 0.8g nano clay, 0.9g hydroxypropyl-β-cyclodextrin, 8g light calcium carbonate, 2.5g mannitol, 1.2g polyvinyl alcohol, 18g polyvinylpyrrolidone, 2g polyethylene glycol 6000, and 1.8g carboxypropyl methylcellulose.

[0028] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitrodrug, hydroxypropyl-β-cyclodextrin and nano-clay to 12g acetone and sonicate for 100min at an ultrasonic frequency of 72kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitrodrug. S2. Pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 2 hours under nitrogen protection. The ball milling speed is 170 r / min and the ball-to-material ratio is 13:1 to obtain pre-dispersed dinitropyridine. S3. Mix pre-dispersed dinitrothione, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 18.5 MPa and the temperature at 48°C. Maintain the pressure for 3 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0029] Example 5: An ultrafine dinitrothione dispersion, the raw materials of which include: 3g dinitrothione, 1.2g nano montmorillonite, 0.8g hydroxypropyl-β-cyclodextrin, 10g light calcium carbonate, 2g mannitol, 1.5g polyvinyl alcohol, 15g polyvinylpyrrolidone, 3g polyethylene glycol 6000, and 1.5g carboxypropyl methylcellulose.

[0030] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, hydroxypropyl-β-cyclodextrin and nano-montmorillonite to 15g acetone and sonicate for 90min at an ultrasonic frequency of 75kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 2 hours under nitrogen protection. The ball milling speed is 180 r / min and the ball-to-material ratio is 12:1 to obtain pre-dispersed dinitropyridine. S3. Mix pre-dispersed dinitropyrrolidone, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 19 MPa and the temperature at 45°C. Maintain the pressure for 3.5 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0031] Comparative Example 1: An ultrafine dinitrothione dispersion, the raw materials of which include: 3g dinitrothione, 11g light calcium carbonate, 3g mannitol, 1.5g polyvinyl alcohol, 15g polyvinylpyrrolidone, 3g polyethylene glycol 6000, and 1.5g carboxypropyl methylcellulose.

[0032] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Dinitropamine, light calcium carbonate, and polyvinyl alcohol are mixed and ball-milled for 2 hours under nitrogen protection. The ball milling speed is 180 r / min and the ball-to-material ratio is 12:1 to obtain pre-dispersed dinitropamine. S2. Mix pre-dispersed dinitropyrrolidone, polyvinylpyrrolidone, polyethylene glycol 6000, mannitol, and carboxypropyl methylcellulose evenly, and feed them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure at 19 MPa and the temperature at 45°C. Maintain the pressure for 3.5 hours, then quickly depressurize and open the reactor. Grind the product into ultrafine powder and pass it through a 500-mesh sieve.

[0033] Comparative Example 2: An ultrafine dinitrodrug dispersion, the raw materials of which include: 3g dinitrodrug, 1.2g nano montmorillonite, 0.8g hydroxypropyl-β-cyclodextrin, 28g light calcium carbonate, and 5g polyvinyl alcohol.

[0034] The preparation method of the above-mentioned ultrafine dinitropyridine dispersion includes the following steps: S1. Add dinitropyridine, hydroxypropyl-β-cyclodextrin and nano-montmorillonite to 15g acetone and sonicate for 90min at an ultrasonic frequency of 75kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Mix pretreated dinitropyridine, light calcium carbonate, and polyvinyl alcohol, and ball mill for 2 hours under nitrogen protection. The ball mill speed is 180 r / min and the ball-to-material ratio is 12:1. The product is then ultra-finely pulverized and passed through a 500-mesh sieve.

[0035] The ultrafine dinitrothione dispersions obtained in Example 5 and Comparative Examples 1-2 were added to purified water at 25°C and stirred until homogeneous. The particle size of the dispersion was measured using a particle size analyzer. The sedimentation volume ratio of the ultrafine dinitrothione dispersions obtained in Example 5 and Comparative Examples 1-2 in water was determined after 4 hours.

[0036] like Figure 1 As shown, the ultrafine dinitrodrug dispersion obtained in Example 5 has the smallest particle size, significantly better than Comparative Examples 1-2; while the ultrafine dinitrodrug dispersions obtained in Examples 5 and Comparative Example 3 have the highest sedimentation volume ratio, significantly better than Comparative Examples 1-2. This confirms that the ultrafine dinitrodrug dispersion obtained in Example 5 has the best dispersion performance and water stability.

[0037] SPF (Special Treatment Free) Silkie chickens were used as experimental subjects to evaluate the efficacy of dinitrotropium. At a chicken farm in Zhejiang Province, half male and half female Silkie chickens of uniform weight, unvaccinated against coccidiosis or any other vaccines, were fed under clean and well-ventilated conditions, along with formulated feed free of antibiotics and anticoccidial drugs, and clean tap water, with free access to food. At 20 days of age, they were randomly divided into 6 groups, with 5 replicates per group and 5 birds per replicate.

[0038] Five groups were selected for artificial oral infection with Eimeria tenella, with an infection dose of 1×10 sporulated oocysts. 5Individuals / animals. 48 hours after infection, Group 5 received a 3-day course of treatment using 1g of the ultrafine dinitrodrug dispersion obtained in Example 5 diluted in 2kg of water; Group 1 received the same treatment for 3 days; Group 2 received the same treatment for 3 days; Group 2 received the same treatment for 3 days; the positive control group received 0.5g / kg of commercially available dinitrodrug mixed into the basal feed; and the negative control group received only the basal feed. The remaining group was not artificially infected and was fed only the basal feed, designated as the healthy control group.

[0039] Three days after administration, medication was discontinued in all groups, and the groups were fed only with basal feed for another two days. Then, the survival rate, average weight gain, relative weight gain rate, lesion value, and oocyst value of each group were examined, and the anticoccidial index (ACI) was calculated.

[0040] ACI = (Survival rate + Relative weight gain rate) × 100 - (Disease value + Oocyte value).

[0041] An ACI greater than 180 is considered highly effective, an ACI of 160-179 is considered moderately effective, and an ACI less than 160 is considered ineffective or invalid.

[0042] like Figure 2 (As shown in the figure, the negative control group was not included because its anticoccidial index was too low.) Figure 2 (As shown in the figure), the anticoccidial index of Example 5 was as high as 188.76, confirming that the ultrafine dinitrothionine dispersion obtained in this invention is a highly effective anticoccidial drug. Meanwhile, the anticoccidial indices of Comparative Example 1, Comparative Example 2, and the positive control group were all within the range of 160-179, indicating that these three are medium-efficacy anticoccidial drugs.

[0043] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. An ultrafine dinitropyridine dispersion, characterized in that, The raw materials, by weight, include: 1-5 parts dinitrothione, 0.5-2 parts nano clay, 0.5-1 part coating agent, 6-18 parts filler, 1-2 parts dispersant, 11-25 parts solid dispersion carrier, and 1-2 parts thickener.

2. The ultrafine dinitrothione dispersion according to claim 1, characterized in that, The coating agent is hydroxypropyl-β-cyclodextrin.

3. The ultrafine dinitrothione dispersion according to claim 1, characterized in that, The filler is light calcium carbonate and / or mannitol.

4. The ultrafine dinitrothione dispersion according to claim 3, characterized in that, The mass ratio of light calcium carbonate to mannitol is 5-15:1-3.

5. The ultrafine dinitrothione dispersion according to claim 1, characterized in that, The solid dispersion carrier is polyvinylpyrrolidone and / or polyethylene glycol.

6. The ultrafine dinitrothione dispersion according to claim 5, characterized in that, The mass ratio of polyvinylpyrrolidone to polyethylene glycol is 10-20:1-5.

7. The ultrafine dinitrothione dispersion according to claim 1, characterized in that, The thickener is carboxypropyl methylcellulose.

8. The ultrafine dinitrothione dispersion according to claim 1, characterized in that, The dispersant is polyvinyl alcohol.

9. A method for preparing the ultrafine dinitrothione dispersion as described in any one of claims 1-8, characterized in that, Includes the following steps: S1. Add dinitropyridine, coating agent and nano clay to 10-20 parts of acetone and sonicate for 1-2 hours at an ultrasonic frequency of 70-80kHz. Remove the solvent by rotary evaporation and vacuum dry to obtain pretreated dinitropyridine. S2. Mix the pretreated dinitropyridine, some filler, and dispersant, and ball mill under nitrogen protection for 1-5 hours to obtain predispersed dinitropyridine. S3. Mix the pre-dispersed dinitropyridine, solid dispersion carrier, remaining filler and thickener evenly, and send them into a high-pressure reactor. Introduce carbon dioxide into the reactor to maintain the pressure inside the reactor at 18-20 MPa and the temperature inside the reactor at 40-50℃. Maintain the pressure for 2-5 hours, then quickly depressurize and open the reactor to pulverize the product into ultrafine particles.

10. The method for preparing the ultrafine dinitropyridine dispersion according to claim 9, characterized in that, In S2, the ball mill speed is 150-200 r / min, and the ball-to-material ratio is 10-15:1.

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