A highly stable diclazuril composite preparation and preparation method thereof

Abstract

The present invention relates to the technical field of diclazuril preparations, and more particularly to a high-stability diclazuril composite preparation and a preparation method thereof. The above-mentioned high-stability diclazuril composite preparation, its raw materials include by mass: 5-15 parts of diclazuril, 1-5 parts of sodium alginate, 30-50 parts of vegetable oil, 1-3 parts of gum arabic, 1-5 parts of probiotics, 0.01-0.06 parts of calcium chloride, 1-3 parts of sucralose, 4-8 parts of colloidal silicon dioxide, 1-2 parts of defoaming agents, and 0.5-1.5 parts of antioxidants. The present invention has good stability, effectively solves the problem of poor water solubility of diclazuril, improves bioavailability, improves therapeutic effect, and the preparation method is simple, operability is strong, and it is conducive to mass production and large-scale promotion.

Description

Technical Field

[0001] The present invention relates to the technical field of diclazuril preparations, and in particular to a highly stable diclazuril composite preparation and a preparation method thereof. Background Art

[0002] Diclazuril is a triazine benzyl cyanide compound, a new generation of highly effective chemically synthesized anticoccidial drugs, and the anticoccidial drug with the lowest dosage currently used, with the characteristics of safety, low toxicity, and no residue. Diclazuril is effective at all stages of coccidia development, mainly inhibiting the proliferation of sporozoites and schizonts of coccidia, with the peak activity period being sporozoites and first-generation schizonts (i.e., the first 2 days of the coccidia life cycle).

[0003] At present, diclazuril has a good effect on coccidiosis in chickens, ducks and rabbits, and its effect on tender, acuminate, toxic, brucellous and giant Eimeria coccidia in chickens is the best. After taking the medicine, it can not only effectively control the occurrence and death of cecal coccidia, but also make all the coccidia oocysts of sick chickens disappear. It is an ideal coccidiostat. Clinical trials have shown that the prevention and control effect of diclazuril on coccidia is better than other conventional anticoccidial drugs, and it has no cross-resistance with ionic polyether drugs such as monensin, salinomycin, and maduramicin ammonium and other synthetic anticoccidial drugs. It is a new type of anticoccidial drug with small dosage, wide anticoccidial spectrum, no need to stop the drug before slaughter, and safe use.

[0004] The existing drug dosage forms of diclazuril are mainly premixes, granules and solutions. Premixes and granules are both solid forms of drugs, which are administered by mixing with materials, resulting in problems such as uneven mixing and inconvenient administration; solutions have poor stability and strict requirements on transportation, storage and use environment.

[0005] How to prepare a diclazuril preparation that effectively overcomes the shortcomings of existing drug dosage forms, has the characteristics of high stability, high bioavailability, and easy use, and has excellent application prospects. Summary of the invention

[0006] The purpose of the present invention is to solve the shortcomings of the prior art and to propose a highly stable diclazuril compound preparation and a preparation method thereof.

[0007] A highly stable diclazuril composite preparation, the raw materials of which include, by weight: 5-15 parts of diclazuril, 1-5 parts of sodium alginate, 30-50 parts of vegetable oil, 1-3 parts of gum arabic, 1-5 parts of probiotics, 0.01-0.06 parts of calcium chloride, 1-3 parts of sucralose, 4-8 parts of colloidal silicon dioxide, 1-2 parts of defoaming agent, and 0.5-1.5 parts of antioxidant.

[0008] Preferably, the vegetable oil is at least one of soybean oil, rapeseed oil, peanut oil and olive oil.

[0009] Preferably, the probiotics include: Clostridium butyricum and lactic acid bacteria.

[0010] Preferably, the concentration of live Clostridium butyricum is 4-8×10 9 cfu / g, the concentration of live lactic acid bacteria is 1-3×10 9 cfu / g.

[0011] Preferably, the defoaming agent is at least one of polyoxyethylene polyoxypropanolamine ether, polyoxypropylene glycerol ether, polyoxypropylene polyoxyethylene glycerol ether, and polydimethylsiloxane.

[0012] Preferably, the antioxidant is at least one of tea polyphenols, gallic acid and vitamin E.

[0013] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0014] S1. Add diclazuril and sodium alginate to vegetable oil and stir for 10-30 minutes, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0015] S2, adding the premix to water and stirring evenly, stirring for 5-15 minutes after the addition is complete, homogenizing at 1.2-2 MPa for 5-10 minutes, adding calcium chloride solution thereto and ultrasonically treating for 1-2 hours, and vacuum drying to obtain the embedded diclazuril;

[0016] S3. Add sucralose, colloidal silicon dioxide, defoaming agent and antioxidant to the embedded diclazuril, mix for 10-20 minutes, and sieve.

[0017] Preferably, in S2, the mass fraction of the calcium chloride solution is 1-3%.

[0018] Preferably, in S2, the ultrasonic frequency is 5-12 kHz.

[0019] Preferably, in S3, the mesh size of the sieve is 100 meshes.

[0020] Beneficial effects:

[0021] After the diclazuril is coated in the present invention, not only the system stability is high, but also the disadvantage of poor water solubility of diclazuril can be significantly improved, and the sustained-release effect is achieved during the release process, and the drug can effectively stay at the lesion site for a long time, which is safe and effective.

[0022] Coccidiosis in sheep is a common polyprotozoan disease caused by Eimeria coccidia parasitizing in the epithelial cells of the sheep intestinal mucosa. The disease mainly harms 2-4 week-old lactating lambs, and the main clinical manifestations are loss of appetite or even complete loss, emaciation, anemia, diarrhea, etc., which seriously hinders the healthy development of the sheep industry. Ewes are often carriers of worms and are an important source of infection of lamb coccidiosis and coccidiosis. The present invention coats diclazuril and then compounds it with probiotics, which has a significant synergistic effect and a significant anti-coccidiosis effect on ewes.

[0023] The test found that the sustained-release effect of the present invention is good, and it still has good stability when placed under accelerated conditions for 12 months, especially the storage stability is good at a temperature of 40°C. When the drug is used for ewes and lambs at the same time, the oocyst conversion rate is significant, and the coccidia oocyst reduction rate is extremely excellent.

[0024] The invention has good stability, effectively solves the problem of poor water solubility of diclazuril, increases bioavailability, and improves therapeutic effect; meanwhile, the preparation method is simple, operability is strong, and it is conducive to batch production and large-scale promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The particle size distribution change curve of the diclazuril composite preparation obtained in Example 5 and Comparative Examples 1-2.

[0026] Figure 2 The sedimentation volume ratio change curve of the diclazuril composite preparation obtained in Example 5 and Comparative Examples 1-2 is shown.

[0027] Figure 3 The cumulative dissolution change curves of the diclazuril composite preparations obtained in Example 5 and Comparative Examples 1-2 are shown.

[0028] Figure 4 It is a comparison chart of the oocyst reduction rate and the oocyst negative conversion rate of the sheep in Example 5, Comparative Example 1-3 and the non-drug administration group. DETAILED DESCRIPTION

[0029] The present invention will be further explained below in conjunction with specific embodiments.

[0030] Example 1

[0031] A highly stable diclazuril composite preparation, whose raw materials include: 50g of diclazuril, 10g of sodium alginate, 300g of soybean oil, 10g of gum arabic, 10g of probiotics, 0.1g of calcium chloride, 10g of sucralose, 40g of colloidal silicon dioxide, 10g of polyoxyethylene polyoxypropanolamine ether, and 5g of gallic acid.

[0032] Probiotics include: live bacteria concentration of 4×10 9 cfu / g of Clostridium butyricum, and the concentration of live bacteria was 1×10 9 cfu / g of lactic acid bacteria.

[0033] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0034] S1. Add diclazuril and sodium alginate to soybean oil, stir at a speed of 1000 r / min for 10 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0035] S2, adding the premix to 1000g purified water and stirring evenly, stirring at a speed of 1000r / min for 5min after complete addition, homogenizing at 1.2MPa for 5min, adding 1% calcium chloride solution by mass and ultrasonically treating for 1h at an ultrasonic frequency of 5kHz, and vacuum drying to obtain the embedded diclazuril;

[0036] S3. Add sucralose, colloidal silicon dioxide, polyoxyethylene polyoxypropanolamine ether and gallic acid to the embedded diclazuril, mix at a speed of 50 r / min for 10 min, and pass through a 100-mesh sieve.

[0037] Example 2

[0038] A highly stable diclazuril composite preparation, whose raw materials include: 150g of diclazuril, 50g of sodium alginate, 500g of rapeseed oil, 30g of gum arabic, 50g of probiotics, 0.6g of calcium chloride, 30g of sucralose, 80g of colloidal silicon dioxide, 20g of polyoxypropylene glycerol ether, and 15g of vitamin E.

[0039] Probiotics include: live bacteria concentration of 8×10 9 cfu / g of Clostridium butyricum, and the concentration of live bacteria was 3×10 9 cfu / g of lactic acid bacteria.

[0040] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0041] S1. Add diclazuril and sodium alginate to rapeseed oil, stir at a speed of 2000 r / min for 30 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0042] S2, adding the premix to 1500g purified water and stirring evenly, stirring at a speed of 3000r / min for 15min after complete addition, homogenizing at 2MPa for 10min, adding 3% calcium chloride solution by mass and ultrasonically treating for 2h at an ultrasonic frequency of 12kHz, and vacuum drying to obtain the embedded diclazuril;

[0043] S3. Add sucralose, colloidal silicon dioxide, polyoxypropylene glycerol ether and vitamin E to the embedded diclazuril, mix at a speed of 100 r / min for 20 min, and pass through a 100-mesh sieve.

[0044] Example 3

[0045] A highly stable diclazuril composite preparation, whose raw materials include: 80g of diclazuril, 40g of sodium alginate, 350g of peanut oil, 25g of gum arabic, 20g of probiotics, 0.5g of calcium chloride, 15g of sucralose, 70g of colloidal silicon dioxide, 13g of polydimethylsiloxane and 12g of tea polyphenols.

[0046] Probiotics include: live bacteria concentration of 5×10 9 cfu / g of Clostridium butyricum and the concentration of live bacteria was 2.5×10 9 cfu / g of lactic acid bacteria.

[0047] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0048] S1. Add diclazuril and sodium alginate to peanut oil, stir at a speed of 1200 r / min for 25 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0049] S2, adding the premix to 1100g purified water and stirring evenly, stirring at a speed of 2500r / min for 8min after complete addition, homogenizing at 1.8MPa for 7min, adding a 2.5% calcium chloride solution thereto and ultrasonically treating for 80min at an ultrasonic frequency of 9kHz, and vacuum drying to obtain the embedded diclazuril;

[0050] S3. Add sucralose, colloidal silicon dioxide, polydimethylsiloxane and tea polyphenols to the embedded diclazuril, mix at a speed of 70 r / min for 18 min, and pass through a 100-mesh sieve.

[0051] Example 4

[0052] A highly stable diclazuril composite preparation, whose raw materials include: 120g of diclazuril, 20g of sodium alginate, 450g of soybean oil, 15g of gum arabic, 40g of probiotics, 0.3g of calcium chloride, 25g of sucralose, 50g of colloidal silicon dioxide, 17g of polyoxypropylene polyoxyethylene glycerol ether, and 8g of vitamin E.

[0053] Probiotics include: live bacteria concentration of 7×10 9 cfu / g of Clostridium butyricum and the concentration of live bacteria was 1.5×10 9 cfu / g of lactic acid bacteria.

[0054] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0055] S1. Add diclazuril and sodium alginate to soybean oil, stir at a speed of 1800 r / min for 15 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0056] S2, adding the premix to 1300g purified water and stirring evenly, stirring at a speed of 1500r / min for 12min after complete addition, homogenizing at 1.4MPa for 9min, adding 1.5% calcium chloride solution by mass fraction thereto and ultrasonically treating for 100min at an ultrasonic frequency of 6kHz, and vacuum drying to obtain the embedded diclazuril;

[0057] S3. Add sucralose, colloidal silicon dioxide, polyoxypropylene polyoxyethylene glycerol ether and vitamin E to the embedded diclazuril, mix at a speed of 90 r / min for 12 min, and pass through a 100-mesh sieve.

[0058] Example 5

[0059] A highly stable diclazuril composite preparation, whose raw materials include: 100g of diclazuril, 30g of sodium alginate, 400g of olive oil, 20g of gum arabic, 30g of probiotics, 0.4g of calcium chloride, 20g of sucralose, 60g of colloidal silicon dioxide, 15g of polyoxypropylene polyoxyethylene glycerol ether, and 10g of tea polyphenols.

[0060] Probiotics include: live bacteria concentration of 6×10 9 cfu / g of Clostridium butyricum, and the concentration of live bacteria was 2×10 9 cfu / g of lactic acid bacteria.

[0061] The method for preparing the above-mentioned highly stable diclazuril composite preparation comprises the following steps:

[0062] S1. Add diclazuril and sodium alginate to olive oil, stir at a speed of 1500 r / min for 20 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0063] S2, adding the premix to 1200g purified water and stirring evenly, stirring at a speed of 2000r / min for 10min after complete addition, homogenizing at 1.6MPa for 8min, adding 2% calcium chloride solution by mass and ultrasonically treating for 90min at an ultrasonic frequency of 7.5kHz, and vacuum drying to obtain the embedded diclazuril;

[0064] S3. Add sucralose, colloidal silicon dioxide, polyoxypropylene polyoxyethylene glycerol ether and tea polyphenols to the embedded diclazuril, mix at a speed of 80 r / min for 15 min, and pass through a 100-mesh sieve.

[0065] Comparative Example 1

[0066] A diclazuril composite preparation, whose raw materials include: 100g of diclazuril, 30g of sodium alginate, 400g of olive oil, 20g of gum arabic, 0.4g of calcium chloride, 35g of sucralose, 75g of colloidal silicon dioxide, 15g of polyoxypropylene polyoxyethylene glycerol ether, and 10g of tea polyphenols.

[0067] Probiotics include: live bacteria concentration of 6×10 9 cfu / g of Clostridium butyricum, and the concentration of live bacteria was 2×10 9 cfu / g of lactic acid bacteria.

[0068] The above-mentioned method for preparing the diclazuril composite preparation comprises the following steps:

[0069] S1. Add diclazuril and sodium alginate to olive oil, stir at a speed of 1500 r / min for 20 min, then add gum arabic and stir evenly to obtain a premix;

[0070] S2, adding the premix to 1200g purified water and stirring evenly, stirring at a speed of 2000r / min for 10min after complete addition, homogenizing at 1.6MPa for 8min, adding 2% calcium chloride solution by mass and ultrasonically treating for 90min at an ultrasonic frequency of 7.5kHz, and vacuum drying to obtain the embedded diclazuril;

[0071] S3. Add sucralose, colloidal silicon dioxide, polyoxypropylene polyoxyethylene glycerol ether and tea polyphenols to the embedded diclazuril, mix at a speed of 80 r / min for 15 min, and pass through a 100-mesh sieve.

[0072] Comparative Example 2

[0073] A diclazuril composite preparation, whose raw materials include: 100g of diclazuril, 30g of sodium alginate, 400g of olive oil, 20g of gum arabic, 30g of probiotics, 0.4g of calcium chloride, 20g of sucralose, 60g of colloidal silicon dioxide, 15g of polyoxypropylene polyoxyethylene glycerol ether, and 10g of tea polyphenols.

[0074] Probiotics include: live bacteria concentration of 6×10 9 cfu / g of Clostridium butyricum, and the concentration of live bacteria was 2×10 9 cfu / g of lactic acid bacteria.

[0075] The above-mentioned method for preparing the diclazuril composite preparation comprises the following steps:

[0076] Mix diclazuril, sodium alginate, gum arabic and probiotics evenly; add sucralose, colloidal silicon dioxide, polyoxypropylene polyoxyethylene glycerol ether and tea polyphenols, mix at a speed of 80 r / min for 15 minutes, and pass through a 100-mesh sieve.

[0077] Take 1 g of the diclazuril composite preparation obtained in Example 5 and Comparative Examples 1-2, add 50 mL of water respectively, shake thoroughly, measure the particle size distribution using a laser scattering instrument, and then place it in a stoppered graduated cylinder, record the starting height of the suspension (H0), and record the final height of the suspension (H1) again after standing for 3 hours. Calculate the sedimentation volume ratio (F=H1 / H0). The larger the F, the more stable the suspension.

[0078] The diclazuril composite preparations obtained in Example 5 and Comparative Examples 1-2 were sealed and placed at 40° C. and 75% humidity for 3, 6, 9, and 12 months, respectively, and then the particle size distribution and sedimentation volume ratio were measured again.

[0079] like Figure 1 and Figure 2 As shown, the sedimentation volume ratio of the diclazuril composite preparation obtained in Example 5 is always the highest, but the sedimentation volume ratio of the diclazuril composite preparation in Comparative Example 1 is similar to that in Example 5, lacking significant differences; the distribution of the diclazuril composite preparation obtained in Example 5 in a particle size of 200-500 nm is also always higher than 85%, proving that the diclazuril composite preparations obtained in Example 5 and Comparative Example 1 have good stability and are not easy to precipitate.

[0080] 1 g of the diclazuril composite preparations obtained in Example 5 and Comparative Examples 1-2 were respectively evenly spread in the dissolution cup, the medium was water (900 mL), the rotation speed was 100 r / min, and the temperature was 37±0.5° C. 5 mL of samples were taken at 5, 15, 30, 45, 60, and 90 min (while replenishing the same amount of medium at the same temperature), filtered through a 0.45 μm microporous membrane, and the filtrate was analyzed by high performance liquid chromatography to calculate the cumulative dissolution of diclazuril.

[0081] like Figure 3 As shown, the three groups of diclazuril compound preparations all have good dissolution behavior, but the sustained release performance of the diclazuril compound preparation obtained in Example 5 is better.

[0082] Comparative Example 3

[0083] A composite preparation, whose raw materials include: 30g of sodium alginate, 400g of olive oil, 20g of gum arabic, 30g of probiotics, 0.4g of calcium chloride, 20g of sucralose, 60g of colloidal silicon dioxide, 15g of polyoxypropylene polyoxyethylene glycerol ether, and 10g of tea polyphenols.

[0084] Probiotics include: live bacteria concentration of 6×10 9cfu / g of Clostridium butyricum, and the concentration of live bacteria was 2×10 9 cfu / g of lactic acid bacteria.

[0085] The method for preparing the above-mentioned composite preparation comprises the following steps:

[0086] S1. Add sodium alginate to olive oil, stir at a speed of 1500 r / min for 20 min, then add gum arabic and probiotics and stir evenly to obtain a premix;

[0087] S2, adding the premix to 1200g purified water and stirring evenly, stirring at a speed of 2000r / min for 10min after complete addition, homogenizing at 1.6MPa for 8min, adding 2% calcium chloride solution by mass and ultrasonically treating for 90min at an ultrasonic frequency of 7.5kHz, and vacuum drying to obtain an embedding material;

[0088] S3. Add sucralose, colloidal silicon dioxide, polyoxypropylene polyoxyethylene glycerol ether and tea polyphenols to the embedding material, mix at a speed of 80 r / min for 15 min, and pass through a 100-mesh sieve.

[0089] At a livestock farm in Henan Province, 30 peripartum ewes with similar delivery periods and 46 lactating lambs that were confirmed to be naturally infected with coccidia by fecal examination were selected. 32 peripartum ewes were randomly divided into 5 groups, and the lambs followed their ewes into the groups. Among them, the composite preparation obtained in Example 5 was added to its drinking water in Group 5 of Example 5, the composite preparation obtained in Comparative Example 1 was added to its drinking water in Group 1 of Comparative Example 1, the composite preparation obtained in Comparative Example 2 was added to its drinking water in Group 2 of Comparative Example 2, and the composite preparation obtained in Comparative Example 3 was added to its drinking water in Group 3 of Comparative Example 3. The composite preparations were all 50g diluted with 100kg of water. After 3 consecutive days of administration, the drug was stopped and continued to be fed for 4 days; the remaining group was not given the drug.

[0090] All the sheep were fed in the same sheep house and the feeding and management conditions were the same. Before and after the test, 10-20g of feces (including lambs) were taken from each sheep, and the OPG (number of oocysts per gram of feces) was checked and counted using the McMaster counting method, and the oocyst reduction rate and oocyst negative conversion rate were calculated. After the test, all sheep were given drugs to kill coccidia.

[0091] Oocyst reduction rate = (OPG before medication - OPG after medication) ÷ OPG before medication × 100%

[0092] Oocyst negative conversion rate = number of sheep with oocyst negative conversion / number of sheep tested × 100%

[0093] like Figure 4 As shown, the oocyst reduction rate and oocyst negative conversion rate of Example 5 group were the highest, better than the other groups. Compared with Comparative Example 1 group and Comparative Example 3 group, Example 5 group used diclazuril and probiotics to form a synergistic effect, effectively enhancing the anticoccidial effect.

[0094] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A highly stable diclazuril composite preparation, characterized in that: The raw materials include, by mass, 5-15 parts of diclazuril, 1-5 parts of sodium alginate, 30-50 parts of vegetable oil, 1-3 parts of gum arabic, 1-5 parts of probiotics, 0.01-0.06 parts of calcium chloride, 1-3 parts of sucralose, 4-8 parts of colloidal silicon dioxide, 1-2 parts of defoaming agent and 0.5-1.5 parts of antioxidant.

2. The highly stable diclazuril composite formulation according to claim 1, characterized in that: The vegetable oil is at least one of soybean oil, rapeseed oil, peanut oil and olive oil.

3. The highly stable diclazuril composite formulation according to claim 1, characterized in that: Probiotics include: Clostridium butyricum, lactic acid bacteria.

4. The highly stable diclazuril composite formulation according to claim 3, characterized in that: The concentration of live Clostridium butyricum is 4-8×10 9 cfu / g, the concentration of live lactic acid bacteria is 1-3×10 9 cfu / g.

5. The highly stable diclazuril composite formulation according to claim 1, characterized in that: The defoaming agent is at least one of polyoxyethylene polyoxypropanolamine ether, polyoxypropylene glycerol ether, polyoxypropylene polyoxyethylene glycerol ether and polydimethylsiloxane.

6. The highly stable diclazuril composite formulation according to claim 1, characterized in that: The antioxidant is at least one of tea polyphenols, gallic acid and vitamin E.

7. A method for preparing a highly stable diclazuril composite formulation according to any one of claims 1 to 6, characterized in that: The steps include: S1. Add diclazuril and sodium alginate to vegetable oil and stir for 10-30 minutes, then add gum arabic and probiotics and stir evenly to obtain a premix; S2, adding the premix to water and stirring evenly, stirring for 5-15 minutes after the addition is complete, homogenizing at 1.2-2 MPa for 5-10 minutes, adding calcium chloride solution thereto and ultrasonically treating for 1-2 hours, and vacuum drying to obtain the embedded diclazuril; S3. Add sucralose, colloidal silicon dioxide, defoaming agent and antioxidant to the embedded diclazuril, mix for 10-20 minutes, and sieve.

8. The method for preparing the highly stable diclazuril composite formulation according to claim 7, characterized in that: In S2, the mass fraction of the calcium chloride solution is 1-3%.

9. The method for preparing the highly stable diclazuril composite formulation according to claim 7, characterized in that: In S2, the ultrasound frequency is 5-12kHz.

10. The method for preparing the highly stable diclazuril composite formulation according to claim 7, characterized in that: In S3, the mesh size of the sieve is 100 meshes.

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