Preparation method and application of samidazuril long-acting injection

Abstract

The invention discloses a preparation method and application of a samizuril long-acting injection, and relates to the technical field of breeding. The salmizuril long-acting injection is prepared by mixing the following components in percentage by weight: 1 to 10 percent of salmizuril, 0.1 to 5 percent of suspending aid, 0.01 to 2 percent of wetting agent, 0.001 to 5 percent of bacteriostatic agent, 0.001 to 1 percent of antioxidant and the balance of vegetable oil. The salmidazuril long-acting injection provided by the invention can effectively prevent coccidiosis infection, prevent animal diarrhea caused by coccidiosis, improve the survival rate of piglets and the like and the health level of animals, and improve the production benefits of farms; the clinical use is convenient, the dosage is more accurate and controllable, the effective blood concentration can be kept for more than 10 days through one-time administration, the whole life history stage of coccidiosis is covered, coccidiosis infection and piglet coccidiosis can be prevented, the problems of piglet diarrhea and the like caused by the piglet coccidiosis are avoided, and the production performance and economic benefits of a farm are improved.

Description

Technical Field

[0001] The invention relates to the field of animal breeding, and in particular to a preparation method of a novel long-acting injection of anticoccidial drug samizurin and application thereof. Background Art

[0002] Ethanamizuril, CAS number: CAS: 1560840-75-6, is a new triazine anticoccidial drug developed by the Shanghai Veterinary Research Institute of the Chinese Academy of Agricultural Sciences. It has the advantages of broad spectrum, high efficiency and low toxicity. It was approved as a national Class I new veterinary drug in 2020. It is mainly used for the prevention and treatment of chicken coccidiosis. Currently, only one oral solution preparation is on the market. Representative triazine anticoccidial drugs include diclazuril and toltrazuril. The existing dosage forms are granules, premixes, oral solutions and suspensions. They are all oral preparations and are relatively suitable for group administration in chicken farms. However, in clinical practice in pig farms, there are common problems such as inconvenient administration of piglets, inaccurate dosage and unstable efficacy, which are not conducive to the effective prevention and control of piglet coccidiosis.

[0003] Coccidia are intracellular obligate parasites, with a wide variety of species, most of which have obvious species specificity. Coccidiosis is caused by one or more coccidia parasitizing different parts of the animal's intestines, and is a parasitic disease characterized by slow growth and development and severe damage to the intestinal mucosa. Among them, chicken coccidiosis is a disease caused by one or several single-cell parasitic protozoa of Eimeria in the apicomplexan parasites parasitizing the intestinal epithelial cells of chickens. It is the most common disease in intensive chicken farms in my country and the main cause of death of 6-10% of broilers, which seriously endangers the healthy development of the poultry industry. Rabbit coccidiosis is caused by Eimeria coccidia parasitizing the intestinal and bile duct epithelial cells, mainly including small Eimeria, medium Eimeria, yellow Eimeria, large Eimeria, cecal Eimeria, Eimeria sternii, etc. Among them, Eimeria sternii is prevalent worldwide, and the infection rate and mortality rate in my country are high, causing huge economic losses to the rabbit industry. Cystoisospora suis is a common disease caused by coccidia of the genus Cystoisospora in the family Eimeriaceae, characterized by diarrhea and stunted growth in piglets. The infection rate is 50% to 75%, causing serious damage and huge economic losses to the pig industry. Currently, there is no vaccine available, and its prevention and control is mainly based on drug prevention. The relatively effective drug is triazine anticoccidial drugs. Studies have shown that in intensive pig farms, 3-5 days after the birth of piglets, preventive treatment and intervention with toltrazuril can effectively inhibit the excretion of coccidia oocysts, protect piglets from damage caused by coccidia infection, improve production performance, and help prevent secondary necrotic enteritis and other diseases. However, since piglets cannot eat independently, traditional oral preparations have problems such as inconvenient administration and inaccurate dosage, which brings inconvenience and adverse effects to the prevention and control of coccidiosis in common animals such as piglets.

[0004] At present, the patents for the preparations of Samizuli have been applied for oral solution and soluble powder preparations (CN110292561A, CN111658605A, CN114886854B). This type of oral preparation is more suitable for clinical group administration, which is not conducive to individualized treatment. The injection administration method has the advantages of accurate dosage and fast onset. The long-acting injection can effectively increase the release time of the drug in the body, reduce the frequency of administration, avoid the stress response of animals, avoid the risk of repeated coccidia infection, and has the advantages of good drug stability, high drug content, long duration of drug effect, and stable drug effect. In order to expand the scope of use of Samizuli and improve its anti-coccidial drug effect, the present invention is specially proposed. Summary of the invention

[0005] The purpose of the present invention is to provide a method for preparing a long-acting samizulil injection and its rational use in the prevention and treatment of animal coccidiosis.

[0006] The purpose of the present invention is achieved by the following technical means:

[0007] <First aspect>

[0008] The invention provides a samizuril injection, which is composed of 1-10wt.% of samizuril, 0.1-5wt.% of a suspending agent, 0.01-2wt.% of a wetting agent, 0.001-5wt.% of an antibacterial agent, 0.001-1wt.% of an antioxidant and the remainder of vegetable oil.

[0009] As an embodiment of the present invention, the vegetable oil includes at least one of corn oil, soybean oil, tea oil, peanut oil, linseed oil, castor oil and rapeseed oil.

[0010] As an embodiment of the present invention, the particle size of the samizuril is in the range of 0.1 μm to 10 μm.

[0011] As an embodiment of the present invention, the suspending agent includes at least one of aluminum stearate, aluminum distearate, calcium stearate, magnesium stearate, and aluminum monostearate.

[0012] As an embodiment of the present invention, the wetting agent includes at least one of poloxamer 188, polyoxyethylene castor oil, hydrogenated castor oil, Span 80, Span 40, Span 20, Tween 20, and meglumine.

[0013] As an embodiment of the present invention, the content of the wetting agent meglumine in the samizuril long-acting injection is 0.05-0.5%. Further, the content of meglumine in the samizuril long-acting injection is 0.05-0.5%, and the content of Span 40 is 0.01-0.9%.

[0014] As an embodiment of the present invention, the antibacterial agent includes at least one of phenol, cresol, benzyl alcohol, methylparabens, and chlorobutanol.

[0015] As an embodiment of the present invention, the antioxidant includes at least one of butylated p-cresol, p-hydroxyanisole, vitamin E, and propyl gallate.

[0016] As an embodiment of the present invention, each 100 mL of samizuril injection comprises the following components: 1-10 g of samizuril, 0.1-5 g of aluminum stearate, 0.01-0.9 g of Span 40, 0.1-5 g of benzyl alcohol, 0.001-0.05 g of vitamin E and the remainder of vegetable oil.

[0017] As one embodiment of the present invention, each 100 mL of samizuril injection comprises the following components: 1-10 g of samizuril, 0.1-5 g of aluminum stearate, 0.01-0.9 g of Span 40, 0.1-5 g of methylparaben, 0.001-0.1 g of tert-butylparacresol, 0.05-0.5 g of meglumine and the remainder of vegetable oil.

[0018] In some implementation examples, the embodiments of the present invention provide a samizuli injection, including the following components and their weight percentages:

[0019] Samizurin 1%-10%, for example: 1%, 3%, 5% or 10% Samizurin, Samizurin particle size range 0.1μm~10μm;

[0020] Suspending agent 0.1% to 5%, for example: 0.1% aluminum stearate, 1% aluminum stearate, 0.5% aluminum distearate, 2% calcium stearate, 0.5% magnesium stearate or 5% magnesium stearate;

[0021] Wetting agent 0.01% to 2%, for example: 0.01% Tween 20, 0.05% Span 80, 0.5% Span 40, 0.9% Span 40, 0.1% meglumine or 2% polyoxyethylene castor oil;

[0022] Antibacterial agent 0.001% to 2%, for example: 0.1% methylparabens, 1% methylparabens, 1% benzyl alcohol or 2% benzyl alcohol;

[0023] Antioxidants 0.001% to 1%, for example: 0.001% vitamin E, 0.005% vitamin E, 0.01% butylated cresol, 0.1% butylated cresol, 0.5% p-hydroxyanisole or 1% propyl gallate;

[0024] The dispersing medium vegetable oil includes corn oil, soybean oil, tea oil, peanut oil, linseed oil, castor oil, rapeseed oil, etc., and mixtures in different proportions.

[0025] <Second Aspect>

[0026] The present invention provides a preparation method of samizuli injection, which comprises: firstly gelling a dispersion medium, then adding samizuli and the like in proportion, grinding and mixing. Specifically, firstly gelling a suspending agent, an antibacterial agent, an antioxidant and a vegetable oil, then adding a wetting agent and samizuli in proportion, grinding and mixing.

[0027] <Third Aspect>

[0028] The invention provides use of a long-acting samizulil injection as a drug for preventing and treating animal coccidiosis.

[0029] As an embodiment of the present invention, it includes the prevention and treatment of coccidiosis in piglets, and the prevention and treatment of coccidiosis in other animals, including the prevention and treatment of coccidiosis in pet dogs, cats, and large livestock cattle, sheep, etc.

[0030] As an embodiment of the present invention, it includes administration time, dosage and administration method, so that piglets can avoid coccidia infection and effectively prevent and control the harm of pig coccidiosis.

[0031] As an embodiment of the present invention, the samizuli long-acting injection is injected intramuscularly or subcutaneously, and the dosage of each injection is 0.5 to 50 mg / kg.

[0032] The present invention has the following beneficial effects:

[0033] 1) The present invention provides an injection preparation of samizuril, which changes the oral administration route of traditional anticoccidial drugs, facilitates individual administration to animals such as piglets, and has a precise and controllable dosage. It can also maintain an effective drug concentration in the animal for more than 10 days, greatly improving the prevention and treatment effect of coccidiosis in animals, and improving the production performance of economic animals and the health level of pets.

[0034] 2) The present invention provides an injection solution of samizuril, which only requires a single subcutaneous or intramuscular injection for 3- to 5-day-old piglets to effectively prevent coccidiosis infection in piglets, reduce the incidence of diarrhea in piglets, and improve the production efficiency of pig farms. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Other features, objects and advantages of the present invention will become more apparent from the detailed description of non-limiting embodiments made with reference to the following drawings:

[0036] Figure 1 Particle size distribution of Examples 1, 2 and 3;

[0037] Figure 2 Drug particles under a microscope;

[0038] Figure 3 In vitro cumulative release profile of samizuril solution for injection;

[0039] Figure 4 In vitro cumulative release profile of samizurin suspension injection;

[0040] Figure 5 High temperature affects the particle size change in the test;

[0041] Figure 6 Low temperature affects the particle size change in the test;

[0042] Figure 7 Particle size changes in light-effect tests;

[0043] Figure 8 In vitro hemolysis test results;

[0044] Fig. 9 Administration site muscle;

[0045] Fig.10 Muscle tissue sections at the administration site; Note: a is the normal saline control group for 2 days (100 times); b is the normal saline control group for 2 days (200 times); c is the EZL injection for 2 days (100 times); d is the EZL injection for 2 days (200 times); e is the EZL injection for 7 days (100 times); f is the EZL injection for 7 days (200 times); g is the EZL injection for 14 days (100 times); h is the EZL injection for 14 days (200 times). DETAILED DESCRIPTION

[0046] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] The present invention provides a samizuril suspension injection, which comprises samizuril, a suspending agent, a wetting agent, an antibacterial agent, an antioxidant and a dispersion medium in a specific proportion. The administration method is intramuscular or subcutaneous injection, which changes the traditional administration route of samizuril and is used for the prevention and treatment of coccidiosis in various animals, thereby improving the efficacy and clinical application range of samizuril.

[0048] Firstly, the present invention provides a samizuril suspension injection, which is composed of 1-10wt.% of samizuril, 0.1-5wt.% of suspending agent, 0.01-2wt.% of wetting agent, 0.001-5wt.% of antibacterial agent, 0.001-1wt.% of antioxidant and the remainder of vegetable oil.

[0049] In some embodiments, each 100 mL of samizuli injection may include 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g and 10g of samizuli. The suspending agent may be one, two or more of aluminum stearate, aluminum distearate, calcium stearate or magnesium stearate. The wetting agent may be one, two or more of Tween 20, Span 80, Span 40, meglumine or polyoxyethylene castor oil. The antibacterial agent may be one, two or more of methylparabens or benzyl alcohol; the antioxidant may be one, two or more of vitamin E, butylated p-cresol, p-hydroxyanisole or propyl gallate.

[0050] Preferably, the suspending agent may be aluminum stearate or magnesium stearate, the wetting agent may be Span 80 or Span 40 or meglumine, the antibacterial agent may be methylparaben or benzyl alcohol, the antioxidant may be vitamin E or tert-butylparacresol, and the dispersant vegetable oil may be corn oil, soybean oil or castor oil.

[0051] Preferably, the suspending agent is 0.5% magnesium stearate or 1% aluminum stearate.

[0052] Preferably, the wetting agent is 0.5% Span 40.

[0053] Preferably, the wetting agent is 0.9% Span 40 and 0.1% meglumine.

[0054] Preferably, the antibacterial agent is 1% benzyl alcohol or 1% methylparaben.

[0055] Preferably, the antioxidant is 0.001% vitamin E or 0.1% tert-butyl-p-cresol.

[0056] Preferably, the dispersant vegetable oil is castor oil or corn oil.

[0057] The features and performance of the present invention are further described below in conjunction with embodiments.

[0058] Example 1

[0059] Weigh 93 g of castor oil in a flask, add 0.5 g of magnesium stearate, stir and heat to 150° C., continue stirring and keep warm for 1.5 hours, let it cool, then add 5 mg of vitamin E and 1 g of benzyl alcohol, stir evenly to obtain gelled castor oil, which is set aside.

[0060] Weigh 0.5 g of Span-40 and 5 g of Samizurin, place in a ball mill, grind at 1000 rpm for 10 minutes, add the above gelled castor oil, grind at 1000 rpm for 20 minutes, and dispense into vials to obtain Samizurin oily suspension injection.

[0061] Example 2

[0062] Weigh 90.9 g of castor oil in a flask, add 1 g of magnesium stearate, stir and heat to 150° C., continue stirring and keep warm for 1 hour, let it cool, then add 0.1 g of tert-butyl-p-cresol and 2 g of benzyl alcohol, stir evenly to obtain gelled castor oil, which is set aside.

[0063] Weigh 1 g of Span-80 and 5 g of Samizurin, place in a ball mill, grind at 1000 rpm for 10 minutes, add the above gelled castor oil, grind at 1200 rpm for 20 minutes, and dispense into vials to obtain Samizurin oily suspension injection.

[0064] Example 3

[0065] Weigh 91.9 g corn oil in a flask, add 1 g aluminum stearate, stir and heat to 160°C, continue stirring and keep warm for 1 hour, let it cool, then add 0.1 g tert-butyl-p-cresol and 1 g methylparaben, stir evenly to obtain gelled corn oil, which is set aside.

[0066] Weigh 0.9 g of Span-40, 0.1 g of meglumine, and 5 g of samizurin, place in a ball mill, grind at 1000 rpm for 20 minutes, then add the above gelled corn oil, grind at 1200 rpm for 20 minutes, and dispense into vials to obtain samizurin oily suspension injection.

[0067] The redispersibility of the samples obtained in Examples 1, 2 and 3 is shown in Table 1. The results show that the three batches of samples can be dispersed evenly after shaking, and there is no obvious agglomeration at the bottom. The particle size inspection results of the samples obtained in Examples 1, 2 and 3 are shown in Table 2. Figure 1 , 2 The method is in accordance with the requirements of "0982 Particle Size and Particle Size Distribution Determination Method" in the appendix of the 2020 edition of the "Chinese Veterinary Pharmacopoeia". The entire field of view of the sample was observed under a 50-100x microscope, and no agglomeration phenomenon was observed, and there were no particles with a particle size of 50μm or more. Under a 400x microscope, the number of unqualified particles in all samples was less than 5%, which met the requirements.

[0068] Table 1 Redispersibility test results of the preparations

[0069] batch number Redispersibility Dispersion evaluation Example 1 93.0％ good Example 2 90.0％ good Example 3 96.0％ good

[0070] Table 2 Injection particle size ratio

[0071]

[0072]

[0073] The sample of Example 3 was selected, and the "9013 Guidelines for Sustained Release, Controlled Release and Delayed Release Preparations" in Appendix 1 of the 2020 edition of the Chinese Veterinary Pharmacopoeia was used as a control. The indirect release method-dynamic dialysis method was used for in vitro release studies, and PBS buffer containing 1% Tween 80, pH 7.4, was used as the release medium. The dialysis bag molecular weight cutoff was 10-14 kDa, the temperature was 37 ° C, and the speed was 100 r / min. The cumulative release was calculated according to Formula 1. In the formula, i is the number of samplings, Ci is the sample concentration measured at the i-th sampling, V0 is the total volume of the release medium 200 mL, V1 is the volume of the first 6 samplings 1 mL, V2 is the volume of 7-n samplings 6 mL, n is the total number of samplings, the control injection is 15 times, and the EZL long-acting injection is 17 times (the sampling time increases by 11d, 12d).

[0074]

[0075] Origin 2022 software was used to fit the drug release models of two different preparations. The fitting equations were zero-order equation, first-order equation and Higuchi equation. The model with the correlation coefficient closest to 1 was selected as the best model. The fitting results are shown in Tables 3 and Figure 3 , 4 :

[0076] Table 3 In vitro release model fitting

[0077]

[0078] The results showed that the in vitro release behavior of EZL samizuril solution injection conformed to the first-order kinetic equation, and the in vitro release behavior of samizuril suspension injection was more consistent with the Higuchi equation. The in vitro release of samizuril solution injection reached 50% in about 24 hours, and the cumulative release exceeded 90% in 72 hours. The cumulative release of samizuril suspension injection reached about 50% in 96 hours, and the cumulative release reached about 90% in 240 hours. During the entire in vitro release process, the drug release was slow and stable, and could be continuously released for more than 10 days.

[0079] The preliminary stability of the samples of Examples 1, 2 and 3 was tested with reference to the Technical Guidelines for Stability Research of Chemical Drugs. The influencing factor test of Example 3 and the accelerated stability test of Examples 1, 2 and 3 were conducted. The high temperature test results are shown in Table 4. Figure 5 The low temperature test results are shown in Table 5. Figure 6 The results of the illumination test are shown in Table 6. Figure 7 The results of the accelerated test are shown in Tables 7 and 8. The results show that the light conditions have a great influence on the appearance of the preparation, indicating that this product is sensitive to light and should be stored away from light. The main quality evaluation parameters of the preparation did not change significantly, and the prescription preparations of Examples 1, 2 and 3 were relatively stable.

[0080] Table 4 High temperature impact test results

[0081]

[0082] Table 5 Low temperature effect test results

[0083]

[0084] Table 6 Light effect test results

[0085]

[0086] Table 7 Determination results of related substances in accelerated test

[0087]

[0088] Table 8 Accelerated test results

[0089] Sample name Month 0 Month 1 Month 2 Month 3 RSD% Example 1 100.00％ 100.86％ 102.79％ 100.43％ 1.055 Example 2 99.57％ 99.78％ 100.87％ 103.91％ 1.715 Example 3 100.00％ 100.00％ 100.85％ 101.27％ 0.548

[0090] The irritation or pain of the injection at the administration site will seriously affect the absorption of the drug, thereby causing incomplete drug absorption and even tissue damage and necrosis. Therefore, the irritation of the injection is one of the important indicators of safety. In order to investigate the safety of the samizulidine suspension injection, we selected the prescription preparation of Example 3 and conducted an in vitro hemolysis test and a rabbit muscle stimulation test. The method used 6 New Zealand rabbits, and each rabbit’s left hind limb quadriceps muscle was injected with 0.5 mL of samizulidine suspension injection, and the right hind limb quadriceps muscle was injected with 0.5 mL of normal saline as a control. The reaction of the skin surface at the injection site was observed within 48 hours after injection. Two rabbits were killed at 2d, 7d, and 14d after administration, and the muscle stimulation reaction was observed by longitudinal autopsy. The degree of muscle stimulation reaction was calculated according to the muscle stimulation reaction grading standard, and the average value was calculated. At the same time, the muscle tissue at the injection site was taken for histopathological examination. The results of the in vitro hemolysis test are shown in Figure 8 , muscle irritation test results are shown in Fig. 9 , Fig.10 The results showed that the prescription preparation of Example 3 had no hemolysis and red blood cell aggregation, and the muscle irritation rating was mild, and it could be used for intramuscular injection.

[0091] Eimeria falciformis (E. falciformis) is a coccidia parasitic in the mouse intestine, which can cause indigestion, diarrhea, weight loss and even death in mice. Currently, all approved routes of administration of anticoccidial drugs are oral mixed feeding or mixed drinking. In order to explore the effectiveness of samizurin injection, this test uses the sample of Example 3 to conduct a clinical effectiveness test on artificially infected mice with Eimeria falciformis.

[0092] The test groups and methods are as follows:

[0093] Table 9 Grouping and treatment of experimental animals

[0094]

[0095] After grouping, except for the healthy control group, each mouse in the other groups was artificially infected with 300,000 sporulated oocysts of Eimeria falciparum by gavage, and the day of infection was recorded as day 0 of infection.

[0096] The mice in the drug treatment groups were treated with samizuril and diclazuril, respectively. The dosages of the low-dose and high-dose groups of samizuril injection were 5 mg / kg·bw and 10 mg / kg·bw, respectively, and they were injected subcutaneously at the back of the neck once one day after infection; the dosage of the diclazuril oral solution group was 0.5 mg / kg·bw, administered by gavage, starting one day after infection, once a day, for 7 consecutive days.

[0097] Results of weight changes

[0098] The average body weight data of mice in each group on days 0, 5, and 10 after infection are shown in Table 10 below. It can be seen that the average body weight of mice in the healthy control group increased steadily during the experiment, and the body weight of mice in the infected control group showed a significant downward trend on the 10th day after infection with coccidia. The body weight of mice in the samizuril injection group showed an upward trend, which was not significantly different from the healthy control group (p>0.05), but was significantly different from the infected control group (p<0.05). Among them, the weight gain of the high-dose group was greater than that of the low-dose group. The body weight of mice in the diclazuril oral solution group showed an overall upward trend, but it was significantly different from the healthy control group (p<0.05), and was not significantly different from the infected control group (p>0.05).

[0099] Table 10 Average body weight and weight gain of mice in each group

[0100]

[0101] There was no significant difference compared with the healthy control group (p>0.05)

[0102] bThe difference was statistically significant compared with the infected control group (p<0.01).

[0103] Results of coccidia oocyst counts

[0104] The feces of mice in each group were collected, and the number of coccidia oocysts per gram of feces was obtained by the modified McFarland method. The results are shown in Table 11. It can be seen from the table that the mice in the infection control group began to excrete oocysts on the 7th day after coccidia infection, and the egg excretion reached a peak on the 8th day, after which the egg excretion began to decrease. In the drug administration group, both injection of samizuri and oral administration of diclazuril can inhibit the proliferation of sickle-shaped Eimeria in mice. After the administration of diclazuril, the excretion of coccidia oocysts was reduced to a certain extent, and the excretion time of coccidia oocysts was delayed. The OPG values ​​on the 7th and 8th days were significantly different from those of the infection control group (p<0.05), and the OPG values ​​on the 9th and 10th days were not significantly different from those of the infection control group (p>0.05). Compared with oral diclazuril, injection of samizuril showed better anti-coccidial effect. Coccidian oocysts began to be discharged on the 9th day after infection, which was delayed by 2 days compared with the infection control group and 1 day compared with the oral diclazuril group. In addition, the OPG value of the low-dose injection group of samizuril was much lower than that of the infection control group. The OPG values ​​on the 7th, 8th and 9th days were significantly different from those of the infection control group (p<0.05). This shows that injection of samizuril has a better inhibitory effect on Eimeria sickle in mice than oral diclazuril, and also proves that injection of samizuril has better clinical effect.

[0105] Table 11 Coccidia oocysts per gram of feces

[0106]

[0107]

[0108] Examination of cecal lesions

[0109] On the 10th day after mice were infected with coccidia, all mice were killed by carbon dioxide asphyxiation, and the abdominal cavity was opened to examine the cecal lesions. The results showed that the cecum of the mice in the infected control group had severe bleeding spots. The inner wall of the cecum was found to be thickened by touching the cecum, and the feces inside were loose and yellow-brown. The cecum of mice in the low-dose injection group of samizuril and the oral solution group of diclazuril also showed the same symptoms as above, while the appearance of the cecum of the high-dose injection group of samizuril was normal, which was basically the same as the appearance of the healthy control group.

[0110] The test results show that when the preparation of the present invention is subcutaneously injected to treat mouse sickle Eimeria infection, it can significantly delay the time of mouse oocyst excretion, reduce the number of mouse oocyst excretion, and inhibit the proliferation of mouse sickle Eimeria in the body, indicating that the injection of samizuril can also exert a good anticoccidial effect, and this preparation has the potential to treat coccidiosis in other animals.

[0111] In summary, the long-acting injection of samizulil provided by the present invention can effectively prevent coccidiosis infection, prevent animal diarrhea caused by coccidiosis, improve the survival rate of piglets and the health level of animals, and improve the production efficiency of farms; and it is convenient for clinical use, the dosage is more precise and controllable, and a single administration can maintain an effective blood drug concentration for more than 10 days, covering the entire life history stage of coccidia, which is beneficial to prevent coccidiosis infection and the occurrence of piglet coccidiosis, avoid problems such as piglet diarrhea caused by piglet coccidiosis, and improve the production performance and economic benefits of farms.

[0112] The above describes the specific embodiments of the present invention. It should be understood that the present invention is not limited to the above specific embodiments, and those skilled in the art may make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A long-acting injection of samizuli, characterized in that: The samizuril long-acting injection is prepared by mixing 1-10wt.% of samizuril, 0.1-5wt.% of a suspending agent, 0.01-2wt.% of a wetting agent, 0.001-5wt.% of an antibacterial agent, 0.001-1wt.% of an antioxidant and the remainder of vegetable oil.

2. The samizuli long-acting injection according to claim 1, characterized in that: The vegetable oil includes at least one of corn oil, soybean oil, tea oil, peanut oil, linseed oil, castor oil and rapeseed oil.

3. The samizuli long-acting injection according to claim 1, characterized in that: The particle size of the samizuril is in the range of 0.1 μm to 10 μm.

4. The samizurel long-acting injection according to claim 1, characterized in that: The suspending agent includes at least one of aluminum stearate, aluminum distearate, calcium stearate, magnesium stearate, and aluminum monostearate.

5. The samizurel long-acting injection according to claim 1, characterized in that: The wetting agent includes at least one of poloxamer 188, polyoxyethylene castor oil, hydrogenated castor oil, Span 80, Span 40, Span 20, Tween 20, and meglumine.

6. The samizurel long-acting injection according to claim 1, characterized in that: The antibacterial agent includes at least one of phenol, cresol, benzyl alcohol, methylparabens, and chlorobutanol; the antioxidant includes at least one of butylated p-cresol, p-hydroxyanisole, vitamin E, and propyl gallate.

7. The samizurel long-acting injection according to claim 1, characterized in that: Each 100 mL of samizuril injection is composed of 1-10 g of samizuril, 0.1-5 g of aluminum stearate, 0.01-0.9 g of Span 40, 0.1-5 g of methylparaben, 0.001-0.1 g of tert-butylparacresol, 0.05-0.5 g of meglumine and the remainder of vegetable oil.

8. A method for preparing the samizurel long-acting injection according to any one of claims 1 to 7, characterized in that: The method comprises the steps of gelling the suspending agent, the antibacterial agent, the antioxidant and the vegetable oil, and then adding the wetting agent and samizurin in proportion to grind and mix the mixture.

9. A use of the long-acting injection of samizuret according to any one of claims 1-7 as a drug for the prevention and treatment of animal coccidiosis; including the prevention and treatment of coccidiosis in piglets; and the prevention and treatment of coccidiosis in other animals, including the prevention and treatment of coccidiosis in pet dogs, cats, and domestic cattle and sheep.

10. The use according to claim 9, characterized in that The samizuli long-acting injection is injected intramuscularly or subcutaneously, and the dosage of each injection is 0.5 to 50 mg / kg.

Images