High-stability amoxicillin powder for veterinary use and method for preparing the same

Abstract

The present application relates to a kind of high stability veterinary amoxicillin powder, and 100kg amoxicillin powder mainly consists of the following weight ratio of raw materials: amoxicillin 10-30kg, potassium clavulanate 2.5-7.5kg, hydroxypropyl-β-cyclodextrin-bangkyin+chlorogenic acid complex inclusion compound 0.6-0.7kg, citric acid+calcium carbonate controlled-release microspheres 1.8-2.4kg, oat beta-glucan 23.7-45kg, pre-gelatinized cassava starch 18-25kg, mannitol 3-4kg, silanized microcrystalline cellulose 8-12.7kg, nano silicon dioxide 0.8-1.2kg, hydroxypropyl methyl cellulose 2.0-2.5kg, zinc castor oil acid 0.6-1.0kg.The powder is dried at low temperature, reduces the degradation rate of beta-lactam ring, increases the stability of amoxicillin, and improves the bioavailability of drug.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a highly stable veterinary amoxicillin powder and its preparation method. Background Technology

[0002] Statistics from the Ministry of Agriculture and Rural Affairs show that in 2023, amoxicillin-resistant strains accounted for 45% of pig farms, and the efficacy of traditional compound preparations declined due to improper formulation. The National Action Plan for Reducing the Use of Veterinary Antibiotics requires a reduction in antibiotic use in livestock and poultry farming, but existing preparations cannot balance efficacy and dosage reduction.

[0003] Conventional spray drying is energy-intensive and the drug loading rate of particles is less than 10%; wet granulation is a complex process and is not suitable for small and medium-sized veterinary drug companies.

[0004] In addition, existing microencapsulation drug delivery technologies have technical drawbacks such as the need for expensive equipment like coating machines and freeze-drying towers, and the need for treatment of residual organic solvents; while ordinary fluidized bed drying processes have problems such as the inability to precisely control the porosity of particles, resulting in unstable drug dissolution behavior; and β-lactamase inhibitors are prone to degradation under high temperature and high humidity environments.

[0005] Based on this, this application was developed. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a highly stable amoxicillin powder for veterinary use. This powder is dried at low temperature, which reduces the degradation rate of the β-lactam ring, increases the stability of amoxicillin, and improves the bioavailability of the drug.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned highly stable veterinary amoxicillin powder.

[0008] A third objective of this invention is to provide laboratory and clinical trial analyses of the aforementioned highly stable veterinary amoxicillin powder.

[0009] To achieve the above objectives, the present invention adopts the following technical solution: A highly stable veterinary amoxicillin powder, wherein 100 kg of amoxicillin powder is mainly composed of the following raw materials in the indicated weight ratios: Amoxicillin 10-30kg, potassium clavulanate 2.5-7.5kg, hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex 0.6-0.7kg, citric acid + calcium carbonate controlled-release microspheres 1.8-2.4kg, oat β-glucan 23.7-45kg, pregelatinized cassava starch 18-25kg, mannitol 3-4kg, silanized microcrystalline cellulose 8-12.7kg, nano silica 0.8-1.2kg, hydroxypropyl methylcellulose (HPMC, viscosity grade E5) 2.0-2.5kg, zinc ricinoleate 0.6-1.0kg.

[0010] Specifically, the hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex is prepared by the following steps: hydroxypropyl-β-cyclodextrin, baicalin, and chlorogenic acid are stirred in purified water at 50-70℃ for 2-4 hours, and then spray-dried to obtain microspheres with a diameter of 50-80 μm.

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

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

[0013] Furthermore, the weight ratio of citric acid to calcium carbonate is 1:1-2; the weight ratio of the sum of the masses of citric acid and calcium carbonate to the 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] This invention provides a method for preparing the above-mentioned highly stable veterinary amoxicillin powder, which includes the following steps: 1) Turn on nitrogen protection and keep the temperature ≤25℃. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer for dry mixing (5-20 min). 2) Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix (7-15 minutes, 20-30 rpm). Then add amoxicillin, potassium clavulanate, and mannitol to the three-dimensional motion mixer and mix (3-15 minutes, 7-15 rpm). Add citric acid and calcium carbonate controlled-release microspheres and mix (3-8 minutes, 10-20 rpm). Finally, add hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix (15-25 minutes, 10-30 rpm). 3) Spray in HPMC binder hydroxypropyl methylcellulose solution, and simultaneously turn on the chopping blade to control the particle growth rate; 4) The above wet materials are extruded and granulated through a 10-20 mesh sieve, and then subjected to pulse fluidized bed drying; 5) Spray zinc ricinoleate into the bottom of the fluidized bed and continue fluidizing for 10-30 minutes for lubrication treatment to obtain the product of this invention.

[0015] Specifically, in step 3), the hydroxypropyl methylcellulose solution has a mass concentration of 2-5%, which is obtained by dissolving hydroxypropyl methylcellulose in an ethanol aqueous solution with a concentration of 25-35%.

[0016] Furthermore, in step 3), when spraying the hydroxypropyl methylcellulose solution, the pressure is 0.2-0.4 MPa, the atomized particle size is 80-120 μm, and the chopping blade speed is 2500-3000 rpm to control the particle growth rate.

[0017] Specifically, in step 4), the extrusion pressure is 1-2 kN during extrusion granulation, and during pulse fluidized drying, the hot air is dried at 50-60℃ for 5-10 minutes, and the cold air is cooled at 35-45℃ for 2-5 minutes. After pulse fluidized drying, the moisture content is ≤3.5%.

[0018] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: 1) This invention uses a hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex to achieve enteric-coated sustained release, targeting and covering the infection foci in the terminal ileum. Chlorogenic acid and baicalin form a hydrogen-bonded complex, which synergistically enhances intestinal targeting. 2) The product of this invention uses citric acid + calcium carbonate controlled-release microspheres for staged release, maintaining the optimal pH environment for amoxicillin and increasing bioavailability by 25%; 3) This invention uses low-temperature drying to reduce the degradation rate of the β-lactam ring and increase the stability of amoxicillin; 4) The product of this invention can reduce the treatment dosage for bacterial infections and shorten the withdrawal period; 5) No organic solvents are emitted during the production process, reducing environmental pollution. Detailed Implementation

[0019] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0020] In the following examples, all raw materials used are commercially available products that can be purchased directly or can be prepared using conventional techniques in the field.

[0021] The oat β-glucan was purchased from Hebei Bailing Biotechnology Co., Ltd., model number BL-OBG-23.

[0022] The pregelatinized cassava starch was purchased from Guangxi State Farms Mingyang Biochemical Group, model MY-Pregel-18.

[0023] The silanized microcrystalline cellulose was purchased from JRS GmbH, Germany, model VIVAPUR® 87.

[0024] Example 1: A 10% High-Stability Veterinary Amoxicillin Powder Its composition and the weight of raw materials used per 100kg of finished product are as follows: 10kg amoxicillin, 2.5kg potassium clavulanate (anhydrous), 0.6kg hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex, 1.8kg citric acid + calcium carbonate controlled-release microspheres, 45kg oat β-glucan, 20kg pregelatinized tapioca starch, 4kg mannitol, 12.7kg silanized microcrystalline cellulose, 0.8kg nano silica, 2.0kg hydroxypropyl methylcellulose (HPMC E5), and 0.6kg zinc ricinoleate.

[0025] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex: Hydroxypropyl-β-cyclodextrin was mixed with baicalin and chlorogenic acid and stirred in purified water at 60℃ for 3 hours, followed by spray drying (inlet air temperature 115℃ / outlet air 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 and 10% chitosan / pectin (weight ratio 6:4) complex solution were wet granulated (particle size 100-150μm) and microwave dried (800W, 40 seconds) to form a porous structure. 3. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (with nitrogen protection on, keep the temperature ≤25℃). 4. Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix at medium speed (25 rpm) for 10 minutes. Then add amoxicillin, potassium clavulanate, and mannitol and mix for 15 minutes (10 rpm). Next, add citric acid and calcium carbonate controlled-release microspheres and mix for 5 minutes (18 rpm). Finally, add the hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix at low speed (10 rpm) for 20 minutes (temperature ≤25℃, humidity ≤40%). 5. Spray in HPMC binder hydroxypropyl methylcellulose solution (pressure 0.3MPa, atomization particle size 80-120μm), and simultaneously turn on the shredder (2800rpm) to control the particle growth rate; 6. After the above wet materials are extruded and granulated through a 10-mesh sieve (extrusion pressure 1.5kN), they are subjected to pulse fluidized drying, hot air drying at 55℃ for 8 minutes, cold air cooling at 40℃ for 2 minutes, and circulated twice (total time 20 minutes, moisture content ≤3.5%). 7. Add zinc ricinoleate to the bottom of the fluidized bed and continue fluidizing for 15 minutes for lubrication treatment to obtain the product of this invention.

[0026] Wherein: 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; 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. The hydroxypropyl methylcellulose solution in step 5 has a mass content of 3% (w / w), which is obtained by dissolving hydroxypropyl methylcellulose in a 30% ethanol aqueous solution (volume percentage).

[0027] Example 2: A 20% High-Stability Veterinary Amoxicillin Powder Its composition and the weight of raw materials used per 100kg of finished product are as follows: 20kg amoxicillin, 5kg potassium clavulanate (anhydrous), 0.6kg hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex, 1.8kg citric acid + calcium carbonate controlled-release microspheres, 31kg oat β-glucan, 24.7kg pregelatinized tapioca starch, 4kg mannitol, 9.5kg silanized microcrystalline cellulose, 0.8kg nano silica, 2.0kg hydroxypropyl methylcellulose (HPMC E5), and 0.6kg zinc ricinoleate.

[0028] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex: Hydroxypropyl-β-cyclodextrin was mixed with baicalin and chlorogenic acid and stirred in purified water at 60℃ for 3 hours, followed by spray drying (inlet air temperature 115℃ / outlet air temperature 60℃) to obtain microspheres with a diameter of 50-80μm. 2. Preparation of citric acid + calcium carbonate controlled-release microspheres: The citric acid + calcium carbonate and 10% chitosan / pectin (weight ratio 6:4) complex solution were wet-granulated (particle size 100-150μm) and microwave-dried (800W, 40 seconds) to form a porous structure. 3. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (with nitrogen protection on, keep the temperature ≤25℃). 4. Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix at medium speed (25 rpm) for 10 minutes. Then add amoxicillin, potassium clavulanate, and mannitol and mix for 15 minutes (10 rpm). Next, add citric acid and calcium carbonate controlled-release microspheres and mix for 5 minutes (18 rpm). Finally, add the hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix at low speed (10 rpm) for 20 minutes (temperature ≤25℃, humidity ≤40%). 5. Spray in HPMC binder hydroxypropyl methylcellulose solution (pressure 0.3MPa, atomization particle size 80-120μm), and simultaneously turn on the shredder (2800rpm) to control the particle growth rate; 6. After the above wet materials are extruded and granulated through a 10-mesh sieve (extrusion pressure 1.5kN), they are subjected to pulse fluidized drying, hot air drying at 55℃ for 8 minutes, cold air cooling at 40℃ for 2 minutes, and circulated twice (total time 20 minutes, moisture content ≤3.5%). 7. Add zinc ricinoleate to the bottom of the fluidized bed and continue fluidizing for 15 minutes for lubrication treatment to obtain the product of this invention.

[0029] Wherein: 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; 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. The hydroxypropyl methylcellulose solution in step 5 has a mass content of 3% (w / w), which is obtained by dissolving hydroxypropyl methylcellulose in a 30% ethanol aqueous solution (volume percentage).

[0030] Example 3: A highly stable veterinary amoxicillin powder (30%) The composition and the weight of raw materials used per 100kg of finished product are as follows: 30kg amoxicillin, 7.5kg potassium clavulanate (anhydrous), 0.7kg hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex, 2.4kg citric acid + calcium carbonate controlled-release microspheres, 25.7kg oat β-glucan, 18kg pregelatinized cassava starch, 3kg mannitol, 8kg silanized microcrystalline cellulose, 1.2kg nano silica, 2.5kg hydroxypropyl methylcellulose (HPMC E5), and 1.0kg zinc ricinoleate.

[0031] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex: Hydroxypropyl-β-cyclodextrin was mixed with baicalin and chlorogenic acid and stirred in purified water at 60℃ for 3 hours, followed by spray drying (inlet air temperature 115℃ / outlet air temperature 60℃) to obtain microspheres with a diameter of 50-80μm. 2. Preparation of citric acid + calcium carbonate controlled-release microspheres: The citric acid + calcium carbonate and 10% chitosan / pectin (weight ratio 6:4) complex solution were wet-granulated (particle size 100-150μm) and microwave-dried (800W, 40 seconds) to form a porous structure. 3. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (with nitrogen protection on, keep the temperature ≤25℃). 4. Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix at medium speed (25 rpm) for 10 minutes. Then add amoxicillin, potassium clavulanate, and mannitol and mix for 15 minutes (10 rpm). Next, add citric acid and calcium carbonate controlled-release microspheres and mix for 5 minutes (18 rpm). Finally, add the hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix at low speed (10 rpm) for 20 minutes (temperature ≤25℃, humidity ≤40%). 5. Spray in HPMC binder hydroxypropyl methylcellulose solution (pressure 0.3MPa, atomization particle size 80-120μm), and simultaneously turn on the shredder (2800rpm) to control the particle growth rate; 6. After the above wet materials are extruded and granulated through a 10-mesh sieve (extrusion pressure 1.5kN), they are subjected to pulse fluidized drying, hot air drying at 55℃ for 8 minutes, cold air cooling at 40℃ for 2 minutes, and circulated twice (total time 20 minutes, moisture content ≤3.5%). 7. Add zinc ricinoleate to the bottom of the fluidized bed and continue fluidizing for 15 minutes for lubrication treatment to obtain the product of this invention.

[0032] Wherein: 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; 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. The hydroxypropyl methylcellulose solution in step 5 has a mass content of 3% (w / w), which is obtained by dissolving hydroxypropyl methylcellulose in a 30% ethanol aqueous solution (volume percentage).

[0033] Comparative Example 1: A commercially available brand of compound amoxicillin powder The amoxicillin content is 10%.

[0034] Comparative Example 2: Synergistic System with Removed Functional Components [Process Adjustment] The inclusion complex of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid and the controlled-release microspheres of citric acid + calcium carbonate were removed and replaced with ordinary physical mixing.

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

[0036] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex mixture: Hydroxypropyl-β-cyclodextrin and baicalin + chlorogenic acid complex (baicalin and chlorogenic acid are obtained by direct mixing) are mixed evenly; 2. Preparation of a mixture of citric acid + calcium carbonate and chitosan / pectin complex (6:4 ratio): Mix citric acid + calcium carbonate and chitosan / pectin complex (chitosan and pectin are directly mixed in a 6:4 ratio) evenly. 3. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (with nitrogen protection on, keep the temperature ≤25℃). 4. Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix at medium speed (25 rpm) for 10 minutes. Then add amoxicillin, potassium clavulanate, and mannitol and mix for 15 minutes (10 rpm). Next, add citric acid and calcium carbonate controlled-release microspheres and mix for 5 minutes (18 rpm). Finally, add the hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix at low speed (10 rpm) for 20 minutes (temperature ≤25℃, humidity ≤40%). 5. Spray in HPMC binder hydroxypropyl methylcellulose solution (pressure 0.3MPa, atomization particle size 80-120μm), and simultaneously turn on the shredder (2800rpm) to control the particle growth rate; 6. After the above wet materials are extruded and granulated through a 10-mesh sieve (extrusion pressure 1.5kN), they are subjected to pulse fluidized drying, hot air drying at 55℃ for 8 minutes, cold air cooling at 40℃ for 2 minutes, and circulated twice (total time 20 minutes, moisture content ≤3.5%). 7. Add zinc ricinoleate to the bottom of the fluidized bed and continue fluidizing for 15 minutes for lubrication treatment to obtain the product of this invention.

[0037] Wherein: 1. In step 2, 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. The hydroxypropyl methylcellulose solution in step 5 has a mass content of 3% (w / w), which is obtained by dissolving hydroxypropyl methylcellulose in a 30% ethanol aqueous solution (volume percentage).

[0038] Comparative Example 3: Key Auxiliary Material Substitution [Process Adjustment] Replace silanized microcrystalline cellulose with ordinary microcrystalline cellulose and cancel the silanization process.

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

[0040] Preparation method: 1. Preparation of hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex: Hydroxypropyl-β-cyclodextrin was mixed with baicalin and chlorogenic acid and stirred in purified water at 60℃ for 3 hours, followed by spray drying (inlet air temperature 115℃ / outlet air 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 and 10% chitosan / pectin complex (6:4 ratio) solution were wet granulated (particle size 100-150μm) and microwave dried (800W, 40 seconds) to form a porous structure. 3. Add oat β-glucan and pregelatinized tapioca starch to a three-dimensional motion mixer and dry mix at 18 rpm for 10 minutes (with nitrogen protection on, keep the temperature ≤25℃). 4. Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer and mix at medium speed (25 rpm) for 10 minutes. Then add amoxicillin, potassium clavulanate, and mannitol and mix for 15 minutes (10 rpm). Next, add citric acid and calcium carbonate controlled-release microspheres and mix for 5 minutes (18 rpm). Finally, add the hydroxypropyl-β-cyclodextrin-baicalin and chlorogenic acid complex inclusion complex and mix at low speed (10 rpm) for 20 minutes (temperature ≤25℃, humidity ≤40%). 5. Spray in HPMC binder hydroxypropyl methylcellulose solution (pressure 0.3MPa, atomization particle size 80-120μm), and simultaneously turn on the shredder (2800rpm) to control the particle growth rate; 6. After the above wet materials are extruded and granulated through a 10-mesh sieve (extrusion pressure 1.5kN), they are subjected to pulse fluidized drying, hot air drying at 55℃ for 8 minutes, cold air cooling at 40℃ for 2 minutes, and circulated twice (total time 20 minutes, moisture content ≤3.5%). 7. Add zinc ricinoleate to the bottom of the fluidized bed and continue fluidizing for 15 minutes for lubrication treatment to obtain the product of this invention.

[0041] Wherein: 1. In step 2, the weight ratio of citric acid + calcium carbonate to 10% chitosan / pectin complex solution (6:4 ratio) is 1:3; 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. The hydroxypropyl methylcellulose solution in step 5 has a mass content of 3% (w / w), which is obtained by dissolving hydroxypropyl methylcellulose in a 30% ethanol aqueous solution (volume percentage).

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

[0043] Comparative Example 1: Compound amoxicillin powder from a certain brand sold in the market.

[0044] Comparative Example 2: The hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex and the citric acid + calcium carbonate controlled-release microspheres were removed and replaced with ordinary physical mixing.

[0045] Comparative Example 3: Silanized microcrystalline cellulose was replaced with ordinary microcrystalline cellulose, and the silanization treatment was cancelled.

[0046] 2. Test Methods 2.1 Dissolution test: USP Method II, rotation speed 50 rpm Simulated gastric juice (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 the active pharmaceutical ingredient: Accelerated test at 40℃ / 75%RH for 6 months.

[0049] 2.3 Animal efficacy experiment: Sixty three-way crossbred pigs (Duroc × Landrace × Large White) infected with Streptococcus suis serotype 2 (isolated from clinical cases) were randomly divided into 6 groups. All pigs were administered amoxicillin (calculated as amoxicillin) in the following manner: 8 mg / kg / day, mixed with feed, twice a day (08:00 and 18:00), for 7 consecutive days.

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

[0051] 3. Test Results 3.1 Dissolution test data Table 1 Two-stage dissolution data As shown in Table 1, the intestinal / gastric release ratio of Examples 1 and 2 is >5:1, which is significantly better than that of Comparative Examples 1 to 3. Even with a drug loading of 30%, the gastric juice release of Example 3 is still ≤18%, while the intestinal juice release efficiency of Comparative Example 3 is reduced by 20% due to increased hygroscopicity caused by lack of silanization.

[0052] Therefore, it can be seen that the product of this invention has significant targeting advantages and high drug loading stability.

[0053] 3.2 Accelerated Stability Test Data Table 2. Stability test results for retention rates of major components (6 months) As shown in Table 1, the retention rates of amoxicillin and potassium clavulanate in Examples 1, 2, and 3 were significantly higher than those in Comparative Examples 1, 2, and 3. The isomerization rate of the baicalin + chlorogenic acid complex was significantly lower than that in Comparative Examples 2 and 3 (<0.5%). In Comparative Example 3, the structure of the baicalin + chlorogenic acid complex was destroyed due to lack of silanization and hygroscopicity.

[0054] Therefore, it can be seen that the inclusion process of the product of this invention can effectively protect the activity of the baicalin + chlorogenic acid complex, and the silanization treatment can effectively improve the stability of the active ingredient.

[0055] 3.3 Animal therapeutic data Table 3 Experimental data on Streptococcus suis infection As shown in Table 3, Example 1 showed a 50% increase in cure rate and a 50% decrease in recurrence rate compared to Comparative Example 1; Example 2 showed a 28.6% increase in cure rate and a 33.3% decrease in recurrence rate compared to Comparative Example 2; and Example 3 showed a 12.5% ​​increase in cure rate compared to Comparative Example 3.

[0056] Comparative Example 3, due to insufficient physical stability (not silanized), although its therapeutic effect was better than that of commercially available products, was still lower than that of the process described in the embodiments of this application.

[0057] Therefore, it can be seen that the product of this invention has a significant therapeutic effect on streptococcal infection in pigs.

[0058] 3.4 Liquidity Test Data Table 4 Comparison of Angles of Repose As shown in Table 4, the angle of repose of Examples 1-3 is all <40°, achieving a flow improvement of 34.6%, 26.4%, and 27.4% respectively compared with Comparative Examples 1-3.

[0059] Comparative Example 1 has coarse particles (D90 > 250 μm) and an angle of repose approaching 50°, requiring manual assistance for dispensing.

[0060] Comparative Example 3, due to the lack of silanization treatment, resulted in the particles absorbing moisture and clumping (water activity 0.6→0.8), with the angle of repose increasing to >50° (making it impossible to scale up production).

[0061] Therefore, it can be seen that the process of the present invention can significantly improve flowability.

Claims

1. A highly stable amoxycillin powder for veterinary use, characterized in that, 100kg of amoxicillin powder is mainly composed of the following raw materials in the indicated weight ratios: Amoxicillin 10-30kg, potassium clavulanate 2.5-7.5kg, hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex 0.6-0.7kg, citric acid + calcium carbonate controlled-release microspheres 1.8-2.4kg, oat β-glucan 23.7-45kg, pregelatinized tapioca starch 18-25kg, mannitol 3-4kg, silanized microcrystalline cellulose 8-12.7kg, nano silica 0.8-1.2kg, hydroxypropyl methylcellulose 2.0-2.5kg, zinc ricinoleate 0.6-1.0kg; The hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex was prepared by the following steps: hydroxypropyl-β-cyclodextrin, baicalin, and chlorogenic acid were stirred in purified water at 50-70℃ for 2-4 hours, and then spray-dried to obtain the final product. The molar ratio of hydroxypropyl-β-cyclodextrin, baicalin and chlorogenic acid is 1:0.5-0.7:0.2-0.4; during spray drying, the inlet air temperature is 110-120℃ and the outlet air temperature is 50-70℃. The citric acid + calcium carbonate controlled-release microspheres were prepared by the following steps: citric acid, calcium carbonate and 8-12% chitosan / pectin complex solution were wet-granulated and microwave-dried to obtain the microspheres. The weight ratio of citric acid to calcium carbonate is 1:1-2; the weight ratio of the sum of the masses of citric acid and calcium carbonate to the 10% chitosan / pectin complex solution is 1:2-4; in the 10% chitosan / pectin complex solution, the mass ratio of chitosan to pectin is 6-7:4-3.

2. The process for the preparation of high stability amoxycillin powder for veterinary use according to claim 1, characterized in that, Includes the following steps: 1) Turn on nitrogen protection, keep the temperature ≤25℃, and add oat β-glucan and pregelatinized tapioca starch to the three-dimensional motion mixer for dry mixing; 2) Add silanized microcrystalline cellulose and nano-silica to a three-dimensional motion mixer. After mixing, add amoxicillin, potassium clavulanate, and mannitol to the three-dimensional motion mixer. After mixing, add citric acid + calcium carbonate controlled-release microspheres. After mixing, add hydroxypropyl-β-cyclodextrin-baicalin + chlorogenic acid complex inclusion complex and mix. 3) Spray in hydroxypropyl methylcellulose solution and simultaneously turn on the chopping blade to regulate the particle growth rate; 4) After the above wet materials are granulated by screen extrusion, they are subjected to pulse fluidized bed drying; 5) Spray zinc ricinoleate into the bottom of the fluidized bed and continue fluidizing for 10-30 minutes for lubrication treatment.

3. The process for the preparation of high stability amoxycillin powder for veterinary use as claimed in claim 2, wherein, In step 3), the hydroxypropyl methylcellulose solution has a mass concentration of 2-5%, which is obtained by dissolving hydroxypropyl methylcellulose in an aqueous ethanol solution with a concentration of 25-35%.

4. The method for preparing highly stable veterinary amoxicillin powder as described in claim 2, characterized in that, When spraying the hydroxypropyl methylcellulose solution in step 3), the pressure is 0.2-0.4 MPa, the atomization particle size is 80-120 μm, and the shredder rotation speed is 2500-3000 rpm.

5. The method for preparing highly stable veterinary amoxicillin powder as described in claim 2, characterized in that, In step 4), the extrusion pressure is 1-2 kN during extrusion granulation, and during pulse fluidized drying, the hot air is dried at 50-60℃ for 5-10 minutes, and the cold air is cooled at 35-45℃ for 2-5 minutes. After pulse fluidized drying, the moisture content is ≤3.5%.

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