High-stability veterinary amoxicillin powder and preparation method thereof

Abstract

The invention relates to high-stability amoxicillin powder for livestock. 100 kg of the amoxicillin powder mainly comprises the following raw materials by weight: 10 to 30 kg of amoxicillin, 2.5 to 7.5 kg of potassium clavulanate, 0.6 to 0.7 kg of a hydroxypropyl-beta-cyclodextrin-baicalin and chlorogenic acid compound inclusion body, 1.8 to 2.4 kg of citric acid and calcium carbonate controlled release microspheres, 23.7 to 45 kg of oat beta-glucan, 18 to 25 kg of pre-gelatinized cassava starch, 3 to 4 kg of mannitol, 8 to 12.7 kg of silanized microcrystalline cellulose, and the balance of water. The coating comprises the following components by weight: 0.8 to 1.2 kg of nano silicon dioxide, 2.0 to 2.5 kg of hydroxypropyl methylcellulose and 0.6 to 1.0 kg of zinc diricinoleate. The powder is dried at low temperature, so that the degradation rate of beta-lactam rings is reduced, the stability of amoxicillin is improved, and the bioavailability of the medicine is improved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of veterinary drug preparation, and particularly relates to a high-stability veterinary amoxicillin powder and a preparation method thereof. BACKGROUND

[0002] According to statistics of the Ministry of Agriculture and Rural Affairs, the proportion of amoxicillin-resistant strains in large-scale pig farms reached 45% in 2023. The traditional compound preparation has reduced efficacy due to improper compatibility. The National Action Plan for Reducing the Use of Veterinary Antibiotics requires reducing the use of antibiotics in livestock breeding. Existing preparations cannot balance efficacy and reduction.

[0003] The conventional spray drying method has high energy consumption, and the drug loading rate of the particles is less than 10%. The wet granulation process is complex and is not suitable for small and medium-sized veterinary drug enterprises.

[0004] In addition, the existing microencapsulation drug loading technology requires expensive equipment such as a coating machine and a freeze-drying tower, and needs to be treated for organic solvent residues. The ordinary fluidized bed drying process cannot precisely control the porosity of the particles, resulting in unstable drug dissolution behavior. The beta-lactamase inhibitor is easily degraded in a high-temperature and high-humidity environment.

[0005] Therefore, the present application is developed. SUMMARY

[0006] The present application aims to overcome the defects of the prior art and provide a high-stability veterinary amoxicillin powder. The powder is dried at low temperature, which reduces the degradation rate of the beta-lactam ring, increases the stability of amoxicillin, and improves the bioavailability of the drug.

[0007] Another object of the present application is to provide a preparation method of the high-stability veterinary amoxicillin powder.

[0008] A third object of the present application is to provide laboratory tests and clinical test analysis of the high-stability veterinary amoxicillin powder.

[0009] To achieve the above objects, the present application adopts the following technical solutions: A high-stability veterinary amoxicillin powder, wherein 100 kg of the amoxicillin powder is mainly composed of the following raw materials in the following weight ratio: Amoxicillin 10-30 kg, potassium clavulanate 2.5-7.5 kg, hydroxypropyl-β-cyclodextrin-baicalin+chlorogenic acid complex inclusion body 0.6-0.7 kg, citric acid+calcium carbonate controlled release microspheres 1.8-2.4 kg, oat beta-glucan 23.7-45 kg, pre-gelatinized cassava starch 18-25 kg, mannitol 3-4 kg, silanized microcrystalline cellulose 8-12.7 kg, nano-silicon dioxide 0.8-1.2 kg, hydroxypropyl methyl cellulose (HPMC, viscosity grade E5) 2.0-2.5 kg, zinc ricinoleate 0.6-1.0 kg.

[0010] Specifically, the hydroxypropyl-β-cyclodextrin-baicalin+chlorogenic acid complex inclusion body is prepared by the following steps: stirring hydroxypropyl-β-cyclodextrin with baicalin and chlorogenic acid in 50-70°C purified water for 2-4 hours, and spray drying, to obtain microspheres with a diameter of 50-80 μm.

[0011] Further, the molar ratio of hydroxypropyl-β-cyclodextrin, baicalin and chlorogenic acid is 1:0.5-0.7:0.2-0.4. When spray drying, the inlet air temperature is 110-120°C, and the outlet air temperature is 50-70°C.

[0012] Specifically, the citric acid+calcium carbonate controlled release microspheres are prepared by the following steps: wet granulation (particle size 100-150 μm) of citric acid, calcium carbonate and 8-12% chitosan / pectin complex solution, and microwave drying (700-900 W, 30-50 seconds) to form a porous structure.

[0013] Further, the weight ratio of citric acid to calcium carbonate is 1:1-2; the weight ratio of the sum of the mass of citric acid and calcium carbonate to 10% chitosan / pectin complex solution is 1:2-4; and in the 10% chitosan / pectin complex solution, the mass ratio of chitosan to pectin is 6-7:4-3.

[0014] The present application provides a preparation method of the above-mentioned high-stability veterinary amoxicillin powder, which comprises the following steps: 1) Open the nitrogen protection, keep the temperature ≤25°C, and add oat beta-glucan and pre-gelatinized cassava starch into a three-dimensional motion mixer for dry mixing (5-20 min); 2) Silanized microcrystalline cellulose and nanosilica are added to a three-dimensional motion mixer, after mixing (7-15 minutes, 20-30 rpm), amoxicillin, potassium clavulanate and mannitol are added to the three-dimensional motion mixer, after mixing (3-15 minutes, 7-15 rpm), citric acid + calcium carbonate controlled release microspheres are added, after mixing (3-8 minutes, 10-20 rpm), hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion compound is added, and after mixing (15-25 minutes, 10-30 rpm), the product is obtained. 3) HPMC adhesive hydroxypropyl methylcellulose solution is sprayed, and the cutting knife is opened at the same time to control the growth rate of the particles; 4) The above wet material is extruded and granulated through a 10-20 mesh screen, and then pulse fluidized drying is performed; 5) Zinc ricinoleate is sprayed at the bottom of the fluidized bed, and lubrication treatment is performed for 10-30 minutes to obtain the product.

[0015] Specifically, in step 3), the mass concentration of the hydroxypropyl methylcellulose solution is 2-5%, and the hydroxypropyl methylcellulose is dissolved in an ethanol aqueous solution to obtain the solution, and the concentration of the ethanol aqueous solution is 25-35%.

[0016] Further, in step 3), when the hydroxypropyl methylcellulose solution is sprayed, the pressure is 0.2-0.4 MPa, the atomized particle size is 80-120 μm, and the cutting knife speed is 2500-3000 rpm to control the growth rate of the particles.

[0017] Specifically, in step 4), the extrusion pressure is 1-2 kN during extrusion granulation, and the pulse fluidized drying is performed at 50-60°C for 5-10 minutes, and then cooled at 35-45°C for 2-5 minutes, and the moisture content is ≤3.5% after pulse fluidized drying.

[0018] Compared with the prior art, the present application has the following advantages and beneficial effects: 1) The present application uses hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion compound to achieve enteric-coated sustained release, and target coverage of the terminal ileum infection site, wherein chlorogenic acid and baicalin form a hydrogen bond complex to synergistically enhance intestinal targeting; 2) The product of the present application uses citric acid + calcium carbonate controlled release microspheres to release in stages, maintains the optimal pH environment for amoxicillin, and increases the bioavailability by 25%; 3) The present application uses low-temperature drying to reduce the degradation rate of β-lactam ring and increase the stability of amoxicillin; 4) The product of the present application can reduce the treatment dose of bacterial infection and shorten the drug holiday; 5) No organic solvent is discharged during production, reducing environmental pollution. DETAILED DESCRIPTION

[0019] The technical solutions of the present application are further described in detail below in combination with examples, but the protection scope of the present application is not limited thereto.

[0020] In the following examples, the raw materials used are all ordinary commercially available products or can be prepared by using conventional techniques in the art.

[0021] Oat beta-glucan was purchased from Hebei Bailing Biotechnology Co., Ltd., model BL-OBG-23.

[0022] Pre-gelatinized cassava starch was purchased from Guangxi Nongken Mingyang Biochemical Group, model MY-Pregel-18.

[0023] Silanized microcrystalline cellulose was purchased from Germany JRS Company, model VIVAPUR® 87.

[0024] Example 1 A high-stability amoxicillin powder for veterinary use 10% The composition and the raw material weight for 100 kg of finished product are as follows: amoxicillin 10 kg, potassium clavulanate (anhydrous) 2.5 kg, hydroxypropyl-beta-cyclodextrin-baicalin + chlorogenic acid complex inclusion body 0.6 kg, citric acid + calcium carbonate controlled-release microspheres 1.8 kg, oat beta-glucan 45 kg, pre-gelatinized cassava starch 20 kg, mannitol 4 kg, silanized microcrystalline cellulose 12.7 kg, nano-silicon dioxide 0.8 kg, hydroxypropyl methyl cellulose (HPMC E5) 2.0 kg, zinc ricinoleate 0.6 kg.

[0025] Preparation method: 1. Preparation of hydroxypropyl-beta-cyclodextrin-baicalin + chlorogenic acid complex inclusion body: hydroxypropyl-beta-cyclodextrin was mixed with baicalin and chlorogenic acid, stirred in 60°C purified water for 3 hours, and then spray dried (inlet temperature 115°C / outlet temperature 60°C) to obtain microspheres with a diameter of 50-80 μm; 2. Preparation of citric acid + calcium carbonate controlled-release microspheres: citric acid, calcium carbonate, and 10% chitosan / pectin (weight ratio 6:4) complex solution were granulated by wet method (particle size 100-150 μm), and microwave dried (800W, 40 seconds) to form a porous structure; 3. Oat beta-glucan and pre-gelatinized cassava starch were added to a three-dimensional motion mixer and dry mixed at 18 rpm for 10 minutes (nitrogen protection was turned on, and the temperature was maintained at ≤25°C); 4. Silanized microcrystalline cellulose and nano-silica are added to a three-dimensional motion mixer, mixed at medium speed 25 rpm for 10 minutes, then amoxicillin, potassium clavulanate and mannitol are added, mixed for 15 minutes (speed 10 rpm), then citric acid + calcium carbonate controlled release microspheres are added, mixed for 5 minutes (speed 18 rpm), then hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body is added, mixed at low speed 10 rpm for 20 minutes (temperature ≤ 25℃, humidity ≤ 40%); 5. HPMC adhesive hydroxypropyl methylcellulose solution is sprayed (pressure 0.3 MPa, atomized particle size 80-120 μm), and the chopping knife (2800 rpm) is opened synchronously to regulate the growth rate of the particles; 6. The above wet material is extruded through a 10-mesh screen (extrusion pressure 1.5 kN) and then subjected to pulse fluidization drying, 55℃ hot air drying for 8 minutes, 40℃ cold air cooling for 2 minutes, and circulation for 2 times (total time 20 minutes, moisture content ≤ 3.5%); 7. Zinc ricinoleate is added to the bottom of the fluidized bed, and lubrication treatment is carried out for 15 minutes, to obtain the product of the present application.

[0026] 1. In step 2, the weight ratio of citric acid + calcium carbonate to 10% chitosan / pectin complex (chitosan and pectin in a mass ratio of 6:4) solution is 1:3, and the weight ratio of citric acid to calcium carbonate is 1:1.5; 2. In step 1, the molar ratio of hydroxypropyl-β-cyclodextrin to baicalin and chlorogenic acid is 1:0.6:0.3; 3. In step 5, the mass content of hydroxypropyl methylcellulose solution is 3% (w / w), which is dissolved in 30% ethanol aqueous solution (volume percentage) to obtain.

[0027] Example 2 A high-stability amoxicillin powder for veterinary use 20% The composition and the weight of raw materials used for 100 kg of finished product are as follows: amoxicillin 20 kg, potassium clavulanate (anhydrous) 5 kg, hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body 0.6 kg, citric acid + calcium carbonate controlled release microspheres 1.8 kg, oat β-glucan 31 kg, pre-gelatinized cassava starch 24.7 kg, mannitol 4 kg, silanized microcrystalline cellulose 9.5 kg, nano-silica 0.8 kg, hydroxypropyl methylcellulose (HPMC E5) 2.0 kg, zinc ricinoleate 0.6 kg.

[0028] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin+chlorogenic acid complex inclusion body: hydroxypropyl-β-cyclodextrin is mixed with baicalin and chlorogenic acid, stirred in purified water at 60°C for 3 hours, and then spray dried (inlet temperature 115°C / outlet temperature 60°C) to obtain microspheres with a diameter of 50-80 μm; 2. Preparation of citric acid+calcium carbonate controlled-release microspheres: citric acid+calcium carbonate is granulated with a 10% chitosan / pectin (weight ratio 6:4) complex solution by the wet granulation method (granule size 100-150 μm), and microwave dried (800 W, 40 seconds) to form a porous structure; 3. Oat β-glucan and pre-gelatinized cassava starch are added to a three-dimensional motion mixer, and dry mixed at 18 rpm for 10 minutes (nitrogen protection is turned on, and the temperature is maintained at ≤25°C); 4. Silanized microcrystalline cellulose and nano-silicon dioxide are added to the three-dimensional motion mixer, mixed at medium speed 25 rpm for 10 minutes, then amoxicillin, potassium clavulanate and mannitol are added, mixed at 10 rpm for 15 minutes, then citric acid+calcium carbonate controlled-release microspheres are added, mixed at 18 rpm for 5 minutes, then hydroxypropyl-β-cyclodextrin-baicalin+chlorogenic acid complex inclusion body is added, mixed at 10 rpm for 20 minutes (temperature ≤25°C, humidity ≤40%); 5. HPMC adhesive hydroxypropyl methyl cellulose solution is sprayed (pressure 0.3 MPa, atomized particle size 80-120 μm), and the chopping knife (2800 rpm) is turned on at the same time to regulate the growth rate of the granules; 6. The above wet materials are extruded through a 10-mesh screen (extrusion pressure 1.5 kN), and then pulse fluidized drying is performed, 55°C hot air drying for 8 minutes, 40°C cold air cooling for 2 minutes, and circulation for 2 times (total time 20 minutes, moisture content ≤3.5%); 7. Zinc ricinoleate is added to the bottom of the fluidized bed, and lubrication treatment is performed by continuous fluidization for 15 minutes, to obtain the product of the present application.

[0029] 1. In step 2, the weight ratio of citric acid+calcium carbonate to 10% chitosan / pectin complex solution (chitosan and pectin in a mass ratio of 6:4) is 1:3, and the weight ratio of citric acid to calcium carbonate is 1:1.5; 2. In step 1, the molar ratio of hydroxypropyl-β-cyclodextrin to baicalin and chlorogenic acid is 1:0.6:0.3; 3. In step 5, the mass content of hydroxypropyl methyl cellulose solution is 3% (w / w), which is dissolved in 30% ethanol aqueous solution (volume percentage) to obtain.

[0030] Example 3 A high-stability veterinary amoxicillin powder 30% The composition and the weight of raw materials used for 100 kg of finished product are: amoxicillin 30 kg, potassium clavulanate (anhydrous) 7.5 kg, hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body 0.7 kg, citric acid+calcium carbonate controlled release microspheres 2.4 kg, oat beta-glucan 25.7 kg, pre-gelatinized cassava starch 18 kg, mannitol 3 kg, silanized microcrystalline cellulose 8 kg, nano-silicon dioxide 1.2 kg, hydroxypropyl methyl cellulose (HPMC E5) 2.5 kg, zinc ricinoleate 1.0 kg.

[0031] Preparation method: 1. Preparation of hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body: hydroxypropyl-beta-cyclodextrin is mixed with baicalin and chlorogenic acid, stirred in 60℃ pure water for 3 hours, and then spray dried (inlet temperature 115℃ / outlet temperature 60℃) to obtain microspheres with a diameter of 50-80μm; 2. Preparation of citric acid+calcium carbonate controlled release microspheres: citric acid+calcium carbonate is granulated with 10% chitosan / pectin (weight ratio 6:4) complex solution by wet granulation (particle size 100-150μm), and microwave drying (800W, 40 seconds) is used to form a porous structure; 3. Oat beta-glucan and pre-gelatinized cassava starch are added to a three-dimensional motion mixer and dry mixed at 18rpm for 10 minutes (nitrogen protection is turned on and the temperature is maintained at ≤25℃); 4. Silanized microcrystalline cellulose and nano-silicon dioxide are added to the three-dimensional motion mixer, mixed at medium speed 25rpm for 10 minutes, then amoxicillin, potassium clavulanate and mannitol are added, mixed at 10rpm for 15 minutes, then citric acid+calcium carbonate controlled release microspheres are added, mixed at 18rpm for 5 minutes, then hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body is added, mixed at 10rpm for 20 minutes (temperature ≤25℃, humidity ≤40%); 5. HPMC adhesive hydroxypropyl methyl cellulose solution is sprayed (pressure 0.3MPa, atomization particle size 80-120μm), and the chopping knife (2800rpm) is turned on at the same time to regulate the growth rate of the particles; 6. The above wet materials are extruded through a 10 mesh screen (extrusion pressure 1.5kN) and then pulse fluidized dried, 55℃ hot air drying for 8 minutes, 40℃ cold air cooling for 2 minutes, and circulating for 2 times (total time 20 minutes, moisture content ≤3.5%); 7. Zinc ricinoleate is added to the bottom of the fluidized bed and lubricated for 15 minutes, and the product of the application is obtained.

[0032] Wherein: 1, the weight ratio of citric acid + calcium carbonate to 10% chitosan / pectin complex (chitosan, pectin mass ratio of 6:4) solution in step 2 is 1:3; the weight ratio of citric acid to calcium carbonate is 1:1.5; 2, the molar ratio of hydroxypropyl-β-cyclodextrin to baicalin, chlorogenic acid in step 1 is 1:0.6:0.3; 3, the mass content of hydroxypropyl methyl cellulose solution in step 5 is 3% (w / w), and the hydroxypropyl methyl cellulose is dissolved in 30% ethanol aqueous solution (volume percentage) to obtain.

[0033] Comparative Example 1 Some brand of compound amoxicillin powder The amoxicillin content is 10%.

[0034] Comparative Example 2 Remove functional component synergistic system

Process adjustment

[0035] The composition and the weight of the raw materials used for 100 kg of finished product are: amoxicillin 20 kg, potassium clavulanate (anhydrous) 5 kg, hydroxypropyl-β-cyclodextrin 0.34 kg, baicalin + chlorogenic acid complex 0.26 kg, citric acid + calcium carbonate 1.38 kg, chitosan / pectin complex (6:4 ratio) 0.42 kg, oat β-glucan 31 kg, pre-gelatinized cassava starch 24.7 kg, mannitol 4 kg, silanized microcrystalline cellulose 9.5 kg, nano silicon dioxide 0.8 kg, hydroxypropyl methyl cellulose (HPMC E5) 2.0 kg, zinc ricinoleate 0.6 kg.

[0036] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex mixture: mix hydroxypropyl-β-cyclodextrin with baicalin + chlorogenic acid complex (baicalin + chlorogenic acid directly mixed to obtain) uniformly; 2. Preparation of citric acid + calcium carbonate and chitosan / pectin complex (6:4 ratio) mixture: mix citric acid + calcium carbonate and chitosan / pectin complex (chitosan and pectin are directly mixed in a ratio of 6:4 to obtain) uniformly; 3. Add oat β-glucan and pre-gelatinized cassava starch to the three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (turn on nitrogen protection and keep the temperature ≤25℃); 4. Silanized microcrystalline cellulose and nano-silica are added to a three-dimensional motion mixer, mixed at medium speed 25 rpm for 10 minutes, then amoxicillin, potassium clavulanate and mannitol are added, mixed for 15 minutes (speed 10 rpm), then citric acid + calcium carbonate controlled release microspheres are added, mixed for 5 minutes (speed 18 rpm), then hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body is added, mixed at low speed 10 rpm for 20 minutes (temperature ≤ 25℃, humidity ≤ 40%); 5. HPMC adhesive hydroxypropyl methyl cellulose solution is sprayed (pressure 0.3 MPa, atomized particle size 80-120 μm), and the chopping knife (2800 rpm) is opened synchronously to regulate the growth rate of the particles; 6. The above wet material is extruded through a 10 mesh screen (extrusion pressure 1.5 kN) and then subjected to pulse fluidization drying, 55℃ hot air drying for 8 minutes, 40℃ cold air cooling for 2 minutes, and circulation for 2 times (total time 20 minutes, moisture content ≤ 3.5%); 7. Zinc ricinoleate is added to the bottom of the fluidized bed, and lubrication treatment is carried out for 15 minutes, to obtain the product of the present application.

[0037] 1. The weight ratio of citric acid to calcium carbonate in step 2 is 1:1.5; 2. The molar ratio of hydroxypropyl-β-cyclodextrin to baicalin and chlorogenic acid in step 1 is 1:0.6:0.3; 3. The mass content of hydroxypropyl methyl cellulose solution in step 5 is 3% (w / w), and the hydroxypropyl methyl cellulose is dissolved in 30% ethanol aqueous solution (volume percentage) to obtain.

[0038] Comparative Example 3 Key Adjuvant Substitution

Process Adjustment

[0039] The composition and the weight of the raw materials used for 100 kg of finished product are as follows: amoxicillin 30 kg, potassium clavulanate (anhydrous) 7.5 kg, hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body 0.7 kg, citric acid + calcium carbonate controlled release microspheres 2.4 kg, oat β-glucan 25.7 kg, pre-gelatinized cassava starch 18 kg, mannitol 3 kg, microcrystalline cellulose 8 kg, nano-silica 1.2 kg, hydroxypropyl methyl cellulose (HPMC E5) 2.5 kg, zinc ricinoleate 1.0 kg.

[0040] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body: hydroxypropyl-β-cyclodextrin, baicalin and chlorogenic acid are mixed and stirred in purified water at 60°C for 3 hours, then spray dried (inlet temperature 115°C / outlet temperature 60°C) to obtain microspheres with a diameter of 50-80 μm; 2. Preparation of citric acid + calcium carbonate controlled release microspheres: citric acid and calcium carbonate are granulated with a 10% chitosan / pectin complex solution (6:4 ratio) by the wet granulation method (particle size 100-150 μm), and microwave dried (800 W, 40 seconds) to form a porous structure; 3. Oat β-glucan and pre-gelatinized tapioca starch are added to a three-dimensional motion mixer and dry mixed at 18 rpm for 10 minutes (nitrogen protection is turned on and the temperature is maintained at ≤25°C); 4. Silanized microcrystalline cellulose and nanosilica are added to the three-dimensional motion mixer, mixed at medium speed 25 rpm for 10 minutes, then amoxicillin, potassium clavulanate and mannitol are added, mixed at 10 rpm for 15 minutes, then citric acid + calcium carbonate controlled release microspheres are added, mixed at 18 rpm for 5 minutes, then hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion body is added, mixed at 10 rpm for 20 minutes (temperature ≤25°C, humidity ≤40%); 5. HPMC adhesive hydroxypropyl methylcellulose solution is sprayed (pressure 0.3 MPa, atomized particle size 80-120 μm), and the chopping knife (2800 rpm) is turned on at the same time to regulate the growth rate of the granules; 6. The above wet material is extruded through a 10-mesh screen (extrusion pressure 1.5 kN) and then pulse fluidized dried, 55°C hot air drying for 8 minutes, 40°C cold air cooling for 2 minutes, and circulating 2 times (total time 20 minutes, moisture content ≤3.5%); 7. Zinc ricinoleate is added to the bottom of the fluidized bed and continuously fluidized for 15 minutes for lubrication treatment, thereby obtaining the product of the present application.

[0041] 1. In step 2, the weight ratio of citric acid + calcium carbonate to 10% chitosan / pectin complex solution (6:4 ratio) is 1:3, and the weight ratio of citric acid to calcium carbonate is 1:1.5; 2. In step 1, the molar ratio of hydroxypropyl-β-cyclodextrin to baicalin and chlorogenic acid is 1:0.6:0.3; 3. In step 5, the mass content of hydroxypropyl methylcellulose solution is 3% (w / w), which is dissolved in 30% ethanol aqueous solution (volume percentage) to obtain.

[0042] Test Example 1. Test materials Products prepared in Examples 1, 2 and 3.

[0043] Comparative Example 1: A commercially available brand of compound amoxicillin powder.

[0044] Comparative Example 2: The hydroxypropyl-beta-cyclodextrin-baicalin + chlorogenic acid complex inclusion compound and the citric acid + calcium carbonate controlled-release microspheres are replaced by ordinary physical mixing.

[0045] Comparative Example 3: The silanized microcrystalline cellulose is replaced by ordinary microcrystalline cellulose, and the silanization treatment is cancelled.

[0046] 2. Test method 2.1 Dissolution test: USP method II, rotation speed 50 rpm Simulated gastric fluid (pH 2.0, containing 0.1M HCl + 0.2% NaCl).

[0047] Simulated intestinal fluid (pH 6.8, containing 0.05M KH2PO4+ 0.2% SLS sodium dodecyl sulfate).

[0048] 2.2 Stability of main drug: 40℃ / 75%RH humidity, 6-month accelerated test.

[0049] 2.3 Animal efficacy experiment: 60 three-way hybrid pigs (Duroc x Landrace x Yorkshire) infected with Streptococcus suis serotype 2 (isolated from clinical cases) were randomly divided into 6 groups, and the following method was used for drug administration (calculated as amoxicillin): 8 mg / kg / day, mixed with feed, fed twice a day (08:00, 18:00), and continuously administered for 7 days.

[0050] 2.4 Preparation performance: flowability test, angle of repose.

[0051] 3. Test results 3.1 Dissolution test data Table 1: Two-stage dissolution data As can be seen from Table 1, the intestinal / gastric release ratio of Examples 1 and 2 is >5:1, which is significantly better than Comparative Examples 1 to 3; even if the drug loading of Example 3 is 30%, the gastric fluid release is still ≤18%, while the hygroscopicity of Comparative Example 3 increases due to the absence of silanization, and the intestinal fluid release efficiency decreases by 20%.

[0052] Therefore, the product of the present application has obvious targeting advantages and high drug loading stability.

[0053] 3.2 Accelerated stability test data Table 2: Stability test of main ingredient retention rate (six months) From table 1, the retention rate of amoxicillin and potassium clavulanate in examples 1, 2 and 3 is obviously higher than that in comparative examples 1, 2 and 3, and the isomerization rate of baicalin+chlorogenic acid complex is obviously lower than that in comparative examples 2 and 3 (<0.5%), and the structure of baicalin+chlorogenic acid complex is destroyed due to non-siliconization and moisture absorption in comparative example 3.

[0054] Therefore, the product of the application can well protect the activity of baicalin+chlorogenic acid complex by using the inclusion process, and the stability of the main drug can be effectively improved by siliconization treatment.

[0055] 3.3 Animal efficacy experiment data Table 3: Streptococcus suis infection experiment data From table 3, the cure rate of example 1 is increased by 50% and the recurrence rate is reduced by 50% compared with comparative example 1, the cure rate of example 2 is increased by 28.6% and the recurrence rate is reduced by 33.3% compared with comparative example 2, and the cure rate of example 3 is increased by 12.5% compared with comparative example 3.

[0056] The physical stability of comparative example 3 is insufficient (non-siliconization), the efficacy is better than that of the commercially available product, but is still lower than that of the process described in the application.

[0057] Therefore, the product of the application has obvious curative effect on streptococcus suis infection.

[0058] 3.4 Flowability test data Table 4: Angle of repose comparison From table 4, the angle of repose of examples 1-3 is all <40°, and the flowability of examples 1-3 is increased by 34.6%, 26.4% and 27.4% respectively compared with comparative examples 1-3.

[0059] Comparative example 1 needs manual auxiliary packaging due to coarse particles (D90>250μm) and the angle of repose is close to 50°.

[0060] Comparative example 3 is not treated by siliconization, the particles are hygroscopic and agglomerated (water activity 0.6→0.8), and the angle of repose is increased to >50° (cannot be produced on a large scale).

[0061] Therefore, the process of the application can significantly improve the flowability.

Claims

1. A highly stable amoxycillin powder for veterinary use, characterized in that, 100kg amoxicillin powder mainly consists of the following raw materials in the following weight ratio: 10-30kg of amoxicillin, 2.5-7.5kg of potassium clavulanate, 0.6-0.7kg of hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body, 1.8-2.4kg of citric acid+calcium carbonate controlled release microspheres, 23.7-45kg of oat beta-glucan, 18-25kg of pre-gelatinized tapioca starch, 3-4kg of mannitol, 8-12.7kg of silanized microcrystalline cellulose, 0.8-1.2kg of nano-silicon dioxide, 2.0-2.5kg of hypromellose, and 0.6-1.0kg of zinc ricinoleate.

2. The high stability amoxicillin powder for veterinary use according to claim 1, characterized in that, The hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body is prepared by the following steps: stirring hydroxypropyl-beta-cyclodextrin, baicalin and chlorogenic acid in purified water at 50-70℃ for 2-4 hours, and then spray drying to obtain the product.

3. The high stability amoxicillin powder for veterinary use according to claim 2, characterized in that, The molar ratio of the hydroxypropyl-beta-cyclodextrin, baicalin and chlorogenic acid is 1:0.5-0.7:0.2-0.4; the inlet air temperature is 110-120℃ and the outlet air temperature is 50-70℃ during spray drying.

4. The high stability amoxicillin powder for veterinary use according to claim 1, wherein The citric acid+calcium carbonate controlled release microspheres are prepared by the following steps: wet granulation of citric acid, calcium carbonate and 8-12% chitosan / pectin complex solution, and then microwave drying to obtain the product.

5. The high stability amoxicillin powder for veterinary use according to claim 4, wherein The weight ratio of citric acid to calcium carbonate is 1:1-2; the weight ratio of the sum of the mass of citric acid and calcium carbonate to 10% chitosan / pectin complex solution is 1:2-4; and the mass ratio of chitosan to pectin in the 10% chitosan / pectin complex solution is 6-7:4-3.

6. A process for the preparation of the highly stable amoxycillin powder for veterinary use according to any one of claims 1 to 5, characterized in that, The method comprises the following steps: 1) Open nitrogen protection and keep the temperature ≤25℃, and then add oat beta-glucan and pre-gelatinized tapioca starch into a three-dimensional motion mixer for dry mixing; 2) Add silanized microcrystalline cellulose and nano-silicon dioxide into the three-dimensional motion mixer, and then add amoxicillin, potassium clavulanate and mannitol into the three-dimensional motion mixer after mixing, and then add citric acid+calcium carbonate controlled release microspheres into the three-dimensional motion mixer after mixing, and then add hydroxypropyl-beta-cyclodextrin-baicalin+chlorogenic acid complex inclusion body into the three-dimensional motion mixer after mixing; 3) Spray hypromellose solution, and simultaneously open the chopping knife to control the growth rate of the particles; 4) After the above wet materials are extruded and granulated through a screen, pulse fluidization drying is performed; 5) Spray zinc ricinoleate at the bottom of the fluidized bed, and then continuously fluidize for 10-30 minutes for lubrication treatment to obtain the product.

7. The process for the preparation of high stability amoxycillin powder for veterinary use as claimed in claim 6, wherein, In step 3), the mass concentration of the hypromellose solution is 2-5%, and the hypromellose is dissolved in an ethanol aqueous solution with a concentration of 25-35% to obtain the hypromellose solution.

8. The process for the preparation of high stability amoxycillin powder for veterinary use as claimed in claim 6, wherein, In step 3), when the hypromellose solution is sprayed, the pressure is 0.2-0.4 MPa, the atomized particle size is 80-120μm, and the chopping knife rotating speed is 2500-3000rpm.

9. The process for the preparation of high stability amoxycillin powder for veterinary use as claimed in claim 6, wherein, In step 4), the extrusion pressure is 1-2 kN during extrusion granulation, the hot air drying temperature is 50-60℃ for 5-10 minutes, the cold air cooling temperature is 35-45℃ for 2-5 minutes, and the moisture content is ≤3.5% after pulse fluidization drying.

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