Compound sulfachloropyrazine sodium sustained-release injection and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary drugs, and particularly relates to a compound sulfachloropyrazine sodium sustained-release injection and a preparation method thereof, the injection is a suspension injection, and comprises sulfachloropyrazine sodium, a sustained-release carrier, Tween-80, EDTA-Na2, a synergist, an antioxidant, an organic solvent and a solvent. The preparation method comprises the following steps: uniformly mixing the tween-80 and the solvent, and then adding the ideoprim; uniformly mixing an organic solvent and a solvent, adding the slow-release carrier, completely dissolving, adding EDTA-Na2 and an antioxidant, completely dissolving, adding sulfachloropyrazine sodium, and uniformly stirring; uniformly mixing the two systems, and shearing by using a high-shear homogenizer until the solution is well suspended; the compound sulfachloropyrazine sodium sustained-release injection prepared by the invention has a sustained-release function.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs, and particularly relates to a compound sulfachloropyrazine sodium sustained-release injection and a preparation method thereof. Background Art

[0002] Sulfadiazole sodium is a common sulfonamide anticoccidial drug with the same anticoccidial mechanism of action as sulfaquinoxaline. It is currently widely used in the treatment of coccidiosis in production. Due to long-term use, coccidia have developed a certain resistance to sulfadiazole sodium. In therapeutic applications, the effect of single use is poor, so it is generally used in combination with a synergist during the treatment process, which can not only improve the anticoccidial effect of sulfadiazole sodium, but also increase the anticoccidial spectrum. It is a very typical synergistic drug combination.

[0003] Ideprim is a new type of benzylaminopyrimidine drug, which was first studied by Roche in Switzerland. Yuan Zonghui's research group at Huazhong Agricultural University took the lead in China in conducting research on the synthesis of Ideprim intermediates. Ideprim, trimethoprim, baquinoprim, and ormeprim are all antibacterial synergists, and are often used in combination with sulfonamides to enhance the antibacterial efficacy of sulfonamides. Compared with other benzylaminopyrimidines, Ideprim has the advantages of wide distribution in the body, large apparent volume, long biological half-life, and high bioavailability. It can be used as a substitute for trimethoprim and baquinoprim, and has broad market prospects.

[0004] Sulfonamide chloropyrazine sodium is well soluble in water, but its synergist idepline is insoluble in water. The difference in water solubility of the two drugs will inevitably lead to difficulty in uniform dispersion during use, resulting in inconsistent absorption rates of the drugs by the animal body after administration, and the uniform ratio of the main drug and the synergist cannot be guaranteed. When used to treat coccidiosis, sulfonamides are generally taken orally, but oral administration is slow and has a first-pass effect.

[0005] Polylactic acid-glycolic acid copolymer (PLGA) is a biodegradable polymer material made of glycolic acid and lactic acid. It can be slowly degraded in the body. The final products are carbon dioxide and water. The degradation rate is about 1 month. Due to its easy synthesis, stable quality, biocompatibility, biodegradability, mechanical strength, adjustable degradation rate and good plasticity, it has been widely used as a carrier material for controlled release systems in the past 10 years. PLGA controlled release system can improve the release rate of drugs, maintain effective blood drug concentration, reduce the number of dosing times, and play a role in sustained release and long-term effect. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention aims to provide a compound sulfachloropyrazine sodium sustained-release injection and a preparation method thereof. The present invention prepares a suspension injection of compound sulfachloropyrazine sodium by adding a synergist ideprim, a surfactant Tween-80, a metal complexing agent EDTA-Na2, an antioxidant and a sustained-release carrier to a sulfachloropyrazine sodium aqueous solution, thereby ensuring the stability of the drug, improving the therapeutic effect of the drug, and greatly enhancing the efficacy of the drug.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] A compound sulfachloropyrazine sodium sustained-release injection, each 100 ml of injection is composed of the following components:

[0009]

[0010] Make up to 100 ml with water.

[0011] Furthermore, the particle size of the idepline is ≤15 μm.

[0012] Furthermore, the sustained-release carrier is one or more of a cellulose carrier, a gum carrier, and a polylactic acid-glycolic acid copolymer.

[0013] Furthermore, the sustained-release carrier is a combination of sodium carboxymethyl cellulose and polylactic acid-glycolic acid copolymer, and the mass ratio of sodium carboxymethyl cellulose to polylactic acid-glycolic acid copolymer is 3:1.

[0014] Furthermore, the antioxidant is one of anhydrous sodium sulfite, sodium pyrosulfite or sodium thiosulfate.

[0015] Furthermore, the antioxidant is anhydrous sodium sulfite.

[0016] Furthermore, the organic solvent is one or more of glycerol, propylene glycol, and anhydrous ethanol.

[0017] Furthermore, the organic solvent is glycerol.

[0018] Furthermore, the compound sulfachloropyrazine sodium sustained-release injection, each 100 ml injection is composed of the following components:

[0019]

[0020] Make up to 100 ml with water.

[0021] The present invention also provides a method for preparing the compound sodium sulfachlorpyrazine sustained-release injection, comprising the following steps:

[0022] 1. Dissolve Tween-80 in appropriate amount of water, then add Ideprim and mix well;

[0023] 2. After mixing the organic solvent and an appropriate amount of water evenly, add the sustained-release carrier and stir to dissolve at 70°C;

[0024] 3. Add antioxidant and EDTA-Na2 to the solution obtained in step 2 and stir to completely dissolve;

[0025] 4. Add sulfachloropyrazine sodium to the solution obtained in step 3 and mix well;

[0026] 5. Mix the products of step 1 and step 4 evenly, and dilute to 100 ml with water;

[0027] 6. The mixture obtained in step 5 is sheared using a high shear homogenizer at a speed of 4500 rpm for 20-40 minutes until the solution is well suspended.

[0028] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0029] The synergist idepline of the present invention needs to be micronized before being added so that it can be stably dispersed in the suspension. The slow-release carrier, the surfactant Tween-80, and the metal complexing agent EDTA-Na2 are added to the suspension, so that the drug does not produce accumulation precipitation after long-term standing, and the two drugs are mixed in water in proportion. During the medication process, the animal body can absorb them synchronously, and the synergistic effect of the two drugs is exerted; at the same time, the release rate of the drug is improved, so that the effective blood drug concentration is maintained, the number of drug administrations is reduced, the therapeutic effect of the drug is greatly improved, and the medication cost is reduced.

[0030] The present invention uses microencapsulation technology to disperse and encapsulate sulfachloropyrazine sodium in a sustained-release carrier, thereby delaying the rate of drug release in the body, prolonging the action time, reducing animal stress, and increasing compliance. In addition, due to the sustained-release effect, the drug is released slowly, which can reduce the toxic effect caused by excessive dosage. The combination of the two drugs can improve the anticoccidial effect and increase the anticoccidial spectrum range, and has broad market prospects. DETAILED DESCRIPTION

[0031] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is further described in detail below in conjunction with specific examples. However, it should be understood that the following examples are only used to illustrate the present invention, and are not used to limit the scope of protection claimed in the claims of the present invention. The experimental methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents, etc. used, unless otherwise specified, can all be obtained from commercial channels.

[0032] The poly(lactic acid-glycolic acid) copolymer used in the following examples has a lactic acid / glycolic acid ratio of 65:35, MW 40-75 kDa, Sigma Aldrich, product number: P2066.

[0033] Example 1

[0034] This embodiment provides a compound sulfachloropyrazine sodium sustained-release injection, the dosage of which is as follows:

[0035]

[0036]

[0037] Use purified water to make up to 200 ml; wherein the particle size of ideprine is ≤15 μm.

[0038] This embodiment also provides a method for preparing compound sodium sulfachlorpyrazine sustained-release injection, the specific steps are as follows:

[0039] 1. Dissolve Tween-80 in appropriate amount of water, then add Ideprim and mix well;

[0040] 2. After mixing glycerin and appropriate amount of water evenly, add sodium carboxymethyl cellulose and polylactic acid-glycolic acid copolymer, and stir to dissolve at 70°C;

[0041] 3. Add anhydrous sodium sulfite and EDTA-Na2 to the solution obtained in step 2 and stir to completely dissolve them;

[0042] 4. Add sulfachloropyrazine sodium to the solution obtained in step 3 and mix well;

[0043] 5. Mix the products of step 1 and step 4 evenly, and dilute to 200 ml with water;

[0044] 6. The mixture obtained in step 5 is sheared using a high shear homogenizer at a speed of 4500 rpm for 20-40 minutes until the solution is well suspended.

[0045] Example 2

[0046] This embodiment provides a compound sulfachloropyrazine sodium sustained-release injection, the dosage of which is as follows:

[0047]

[0048] Use purified water to make up to 200 ml; wherein the particle size of ideprine is ≤15 μm.

[0049] This embodiment also provides a method for preparing compound sodium sulfachlorpyrazine sustained-release injection, the specific steps are as follows:

[0050] 1. Dissolve Tween-80 in appropriate amount of water, then add Ideprim and mix well;

[0051] 2. After mixing propylene glycol and an appropriate amount of water, add sodium carboxymethyl cellulose and polylactic acid-glycolic acid copolymer, and stir to dissolve at 70°C;

[0052] 3. Add sodium thiosulfate and EDTA-Na2 to the solution obtained in step 2 and stir to completely dissolve them;

[0053] 4. Add sulfachloropyrazine sodium to the solution obtained in step 3 and mix well;

[0054] 5. Mix the products of step 1 and step 4 evenly, and dilute to 200 ml with water;

[0055] 6. The mixture obtained in step 5 is sheared using a high shear homogenizer at a speed of 4500 rpm for 20-40 minutes until the solution is well suspended.

[0056] Example 3

[0057] This embodiment provides a compound sulfachloropyrazine sodium sustained-release injection, the dosage of which is as follows:

[0058]

[0059] Use purified water to make up to 200 ml; wherein the particle size of ideprine is ≤15 μm.

[0060] This embodiment also provides a method for preparing compound sodium sulfachlorpyrazine sustained-release injection, the specific steps are as follows:

[0061] 1. Dissolve Tween-80 in appropriate amount of water, then add Ideprim and mix well;

[0062] 2. After mixing glycerin and appropriate amount of water evenly, add sodium carboxymethyl cellulose and polylactic acid-glycolic acid copolymer, and stir to dissolve at 70°C;

[0063] 3. Add anhydrous sodium sulfite and EDTA-Na2 to the solution obtained in step 2 and stir to completely dissolve them;

[0064] 4. Add sulfachloropyrazine sodium to the solution obtained in step 3 and mix well;

[0065] 5. Mix the products of step 1 and step 4 evenly, and dilute to 200 ml with water;

[0066] 6. The mixture obtained in step 5 is sheared using a high shear homogenizer at a speed of 4500 rpm for 20-40 minutes until the solution is well suspended.

[0067] Example 4: Quality evaluation of compound sulfachloropyrazine sodium injection

[0068] The quality of the compound sodium sulfachloropyrazine injection prepared in Examples 1, 2 and 3 was evaluated on the following items.

[0069] 1. Settlement

[0070] Take the compound sulfachloropyrazine sodium sustained-release injection and shake it for 30 seconds, then take 10 ml and place it in a graduated test tube (inner diameter 1.0-1.5 cm). No precipitation should be allowed within 10 minutes.

[0071] Table 1: Sedimentation test results

[0072]

[0073] 2. Redispersibility test

[0074] Place the compound sulfachloropyrazine sodium sustained-release injection in a stoppered measuring cylinder and let it stand for 24 hours. Then flip the measuring cylinder at a speed of 20 times / min and observe the number of flipping times required for the sediment at the bottom of the measuring cylinder to disappear.

[0075] Table 2: Drug redispersibility test results

[0076]

[0077] 3. Particle size determination

[0078] Take the test sample, shake it vigorously, take an appropriate amount of the test sample with a pipette, place it on a glass slide, cover it with a cover slip, press lightly to make the test sample evenly distributed, and be careful to prevent bubbles from mixing in. Place it on the microscope stage, first observe the uniformity of particle distribution in the field of view, then select a representative area, observe and take pictures with an objective lens (×20), and analyze the total particle number and distribution ratio.

[0079] Table 3: Particle size determination results

[0080]

[0081] 4. Needle penetration test

[0082] The compound sulfachloropyrazine sodium sustained-release injection was placed into a molded injection bottle, sealed with a stopper and a cap, and after vigorous shaking, 5 ml of air was injected into the injection bottle with a No. 7 needle, and then the injection solution was drawn out, and the volume drawn out within 1 minute was measured.

[0083] Table 4: Needle penetration test results

[0084]

[0085] 5. Content determination

[0086] Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as filler, and an aqueous solution containing 5 mM sodium heptane sulfonate and 0.01% (v / v) triethylamine (pH adjusted to 2.80 with trifluoroacetic acid)-acetonitrile (80:20) was used as mobile phase; detection wavelength was 220 nm; column temperature was 40°C; flow rate was 1.0 ml / min; running time was 26 min.

[0087] Determination method: Take about 0.1g of this product, weigh it accurately, put it in a 100ml volumetric flask, add 10ml of water to dissolve it, then add methanol to dilute to the scale, shake well, as the test solution, accurately measure 10μl, inject it into the liquid chromatograph, and record the chromatogram;

[0088] Take appropriate amount of ideprine reference substance (prepared by Wuhan Huisheng Biotechnology Co., Ltd., with a content of 99.3%) and sodium sulfachloropyrazine reference substance (China Veterinary Drug Administration, with a content of 99.8%), dissolve and dilute with 90% methanol to prepare a reference substance solution containing 200 μg sodium sulfachloropyrazine and 40 μg ideprine per 1 ml, and determine in the same way; take another product, determine its relative density, and convert the weight into milliliters. Calculate the labeled content of sodium sulfachloropyrazine and ideprine in the sample by peak area according to the external standard method.

[0089] Table 5: Assay results

[0090]

[0091] 6. Preparation stability study

[0092] (1) Strong light irradiation test

[0093] After preparing the suspension according to the prescription of Example 1, Example 2 and Example 3, the suspension samples were placed under strong light irradiation (4500lx±500lx) after the content was determined on the same day, and samples were taken at intervals on the 5th day and the 10th day to determine the content of sulfachloropyrazine sodium and idepaline, and the color change, sedimentation, redispersibility, related substances, etc. of the preparation were observed at the same time.

[0094] Related substance detection methods:

[0095] Chromatographic conditions and system suitability test: Octadecylsilane bonded silica gel was used as filler, and an aqueous solution containing 5 mM sodium heptane sulfonate and 0.01% (v / v) triethylamine (pH adjusted to 2.80 with trifluoroacetic acid)-acetonitrile (87:13) was used as the mobile phase; the detection wavelength was 220 nm; the column temperature was 50°C; the flow rate was 1.0 ml / min; and the running time was 70 min.

[0096] Determination method: Take 0.5g of this product, weigh accurately, place in a 100ml volumetric flask, add 10ml of water to dissolve, then add methanol to dilute to the scale, shake well; accurately measure 10μl and inject into the liquid chromatograph. If there are impurity peaks in the test solution, calculate by area normalization method, the peak area of ​​the largest single impurity shall not exceed 2.0% of the total peak area, and the total impurity shall not exceed 3.0% of the total peak area. Chromatographic peaks less than 0.02% of the total peak area in the test solution can be ignored.

[0097] Table 6: Strong light irradiation test results

[0098]

[0099] (2) High temperature test

[0100] After preparing the suspension according to the prescription of Example 1, Example 2 and Example 3, the suspension samples were placed under high temperature (60°C ± 2°C) conditions after the content was determined on the same day, and samples were taken at intervals on the 5th day and the 10th day to determine the content of sulfachloropyrazine sodium and ideprim, and the color change, sedimentation, redispersibility, related substances, etc. of the preparation were observed at the same time.

[0101] Table 7: High temperature test results

[0102]

[0103]

[0104] It can be seen from the above experiments that after the prescription design of compound sulfachloropyrazine sodium injection was completed, good results were achieved in quality control such as sedimentation, redispersibility, particle size, needle permeability, content, and stability.

Claims

1. A compound sulfachloropyrazine sodium sustained-release injection, characterized in that: Each 100ml injection solution consists of the following components:

2. The compound sodium sulfachloropyrazine sustained-release injection according to claim 1, characterized in that: Each 100ml injection solution consists of the following components:

3. The compound sodium sulfachloropyrazine sustained-release injection according to claim 1 or 2, characterized in that: The particle size of the ideprine is ≤15 μm.

4. The compound sodium sulfachloropyrazine sustained-release injection according to claim 1 or 2, characterized in that: The sustained-release carrier is one or more of a cellulose carrier, a glue carrier, and a polylactic acid-glycolic acid copolymer.

5. The compound sodium sulfachloropyrazine sustained-release injection according to claim 4, characterized in that: The sustained-release carrier is a combination of sodium carboxymethyl cellulose and polylactic acid-glycolic acid copolymer, and the mass ratio of sodium carboxymethyl cellulose to polylactic acid-glycolic acid copolymer is 3:

1.

6. The compound sodium sulfachloropyrazine sustained-release injection according to claim 1 or 2, characterized in that: The antioxidant is one of anhydrous sodium sulfite, sodium pyrosulfite and sodium thiosulfate.

7. The compound sodium sulfachloropyrazine sustained-release injection according to claim 6, characterized in that: The antioxidant is anhydrous sodium sulfite.

8. The compound sodium sulfachloropyrazine sustained-release injection according to claim 1 or 2, characterized in that: The organic solvent is one or more of glycerol, propylene glycol and anhydrous ethanol.

9. The compound sodium sulfachloropyrazine sustained-release injection according to claim 8, characterized in that: The organic solvent is glycerol.

10. A method for preparing the compound sodium sulfachloropyrazine sustained-release injection according to any one of claims 1 to 9, characterized in that: The following steps are involved: 1) Dissolve Tween-80 in water, add Ideprim and mix well; 2) After the organic solvent and water are evenly mixed, the sustained-release carrier is added and stirred to dissolve at 70°C; 3) adding antioxidant and EDTA-Na2 to the solution obtained in step 2) and stirring to completely dissolve them; 4) adding sulfachloropyrazine sodium to the solution obtained in step 3) and mixing evenly; 5) After the products of step 1) and step 4) are uniformly mixed, the volume is made up to 100 ml with water; 6) The mixture obtained in step 5) is sheared with a high shear homogenizer at a rotation speed of 4500 rpm for 20-40 minutes to obtain a uniform suspension.

Images