Preparation method of neomycin sulfate soluble powder

Abstract

The invention provides a preparation method of neomycin sulfate soluble powder. The preparation comprises the following components: 3.25%-32.5% (pure) of neomycin sulfate, 1%-5% of an antioxidant, 1%-5% of a stabilizer and the balance of auxiliary materials. The neomycin sulfate soluble powder prepared by the method has the characteristics of low cost, good stability, low degradation of effective components after long-term placement, difficulty in color change, low hygroscopicity, stable aqueous solution and difficulty in rapid degradation.

Description

Technical field:

[0001] The invention belongs to the field of veterinary medicine in the field of biomedicine, and relates to a method for preparing neomycin sulfate soluble powder. Background technology:

[0002] Neomycin sulfate belongs to the aminoglycoside antibiotics, mainly used to treat gastrointestinal infections caused by sensitive Gram-negative bacteria. It is a white powder that is very soluble in water and very hygroscopic.

[0003] Neomycin sulfate soluble powder is a commonly used antibiotic preparation for livestock and poultry, and its price is relatively low. The high saturated concentration of the aqueous solution is convenient for administration through the water line, and it is very convenient to use in the breeding end.

[0004] However, neomycin sulfate is very hygroscopic, and the production process has high requirements for process formula, production environment, packaging, storage environment, etc. Under normal conditions, neomycin sulfate soluble powder is easy to absorb moisture and agglomerate, and is easy to oxidize and make the preparation yellow, resulting in a decrease in its effective ingredients. In the use stage, the aqueous solution of neomycin sulfate soluble powder is very unstable and easily degraded. This has brought great restrictions to the production, storage and use stages.

[0005] Neomycin sulfate is an antibiotic commonly used in breeding processes and has a relatively low overall price. In terms of its use, cost is an important factor that cannot be ignored.

[0006] Therefore, we have developed a product of neomycin sulfate soluble powder which has simple production process, low cost, good preparation stability and good stability of aqueous solution after the preparation is dissolved in water. Summary of the invention

[0007] The present invention adopts the following technical scheme:

[0008] The present invention provides a method for preparing neomycin sulfate soluble powder.

[0009] The components by weight are as follows: neomycin sulfate 3.25%-32.5% (pure), antioxidant 1%-5%, stabilizer 1-5%, and auxiliary material 41-94%.

[0010] The antioxidants are sodium isoVC and cysteine ​​hydrochloride.

[0011] The stabilizer is sodium bisulfite or sodium pyrosulfite.

[0012] The ratio of neomycin sulfate to antioxidant and stabilizer is 3.25-32.5:1:

[0013] The auxiliary materials are soluble starch, beta-cyclodextrin, sucrose and anhydrous glucose, preferably beta-cyclodextrin and sucrose.

[0014] A method for preparing soluble neomycin sulfate comprises the following steps:

[0015] Step 1. Preliminarily mix neomycin sulfate and β-cyclodextrin and set aside.

[0016] Step 2. Place the mixture from step 1 into a shearing mill, set the speed to 4500 rpm, turn on the cooling water to control the material temperature below 40 degrees, shear for 10 minutes, and set aside.

[0017] Step 3: Place the sheared mixture in a sealed stainless steel tank and introduce clean water with a water content of less than 1g / m 3 Use compressed air to make the pressure reach 0.8 MPa and maintain the pressure for 60 minutes.

[0018] Step 4. Mix sodium isoVC, cysteine ​​hydrochloride, sodium bisulfite and the remaining auxiliary materials in a multiple division method, grind and sieve for later use, and then mix them evenly with the materials obtained in step 3 and package them in aluminum-plastic composite bags.

[0019] The invention provides a method for preparing a neomycin sulfate soluble powder. The prepared neomycin sulfate soluble powder has low cost, good stability, low degradation of effective ingredients after long-term storage, is not easy to change color, has low hygroscopicity, and is stable in aqueous solution and not easy to degrade rapidly. The main principle of the invention is to form a certain inclusion state of neomycin sulfate and auxiliary materials through mechanical shearing and external pressure, and then add antioxidants and stabilizers to greatly improve the stability during the storage period and drinking period. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The appearance colors of samples 1, 2, 3, and 4 (from left to right) in Example 3 of the present invention after being placed for 0 hours;

[0021] Figure 2 The appearance colors of samples 1, 2, 3, and 4 (from left to right) in Example 3 of the present invention after being placed for 24 hours. DETAILED DESCRIPTION

[0022] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0023] Example 1. Comparison of hygroscopicity and solubility:

[0024] The hygroscopicity of drugs is one of the important factors affecting drug stability, which is directly related to whether the drugs absorb moisture during the production and storage process, causing agglomeration and deterioration. At the same time, the selection of excipients should take into account the convenience of clinical use. The higher the solubility, the easier it is to use.

[0025] Sample preparation:

[0026] Sample 1: Take 32.5g (pure) neomycin sulfate and add anhydrous glucose to 100g and mix well.

[0027] Sample 2: Take 32.5 g (pure) neomycin sulfate, 10 g β-cyclodextrin, and add anhydrous glucose to 100 g, and mix well.

[0028] Sample 3: Take 32.5g (pure) neomycin sulfate, 10g soluble starch and anhydrous glucose to 100g and mix well.

[0029] Sample 4: Take 32.5 g (pure) neomycin sulfate and 10 g β-cyclodextrin, add sucrose powder to 100 g and mix well.

[0030] Sample 5: Take 32.5 g (pure) neomycin sulfate and 10 g β-cyclodextrin, add sucrose powder to 100 g and mix well.

[0031] Samples 2, 3 and 4 were prepared by the method provided by the present invention through shearing and pressure holding. Samples 1 and 5 were prepared by a simple mixing method.

[0032] Saturated aqueous solution test: Take 100 ml of purified water and slowly add neomycin sulfate and the above four samples under room temperature and stirring continuously. Determine their solubility as follows:

[0033]

[0034] It can be seen that the solubility of anhydrous glucose, β-cyclodextrin and sucrose as auxiliary materials in water is relatively ideal. The solubility of the preparation prepared by the method of the present invention is better than that of the preparation not prepared by the method of the present invention.

[0035] Hygroscopicity test: Refer to the "Veterinary Pharmacopoeia of the People's Republic of China 2020 Edition Part 1" - Guidelines for hygroscopicity test of veterinary drugs. The test was carried out in accordance with the guidelines at a temperature of 25°C and a relative humidity of 80%±5% to determine the hygroscopicity of neomycin sulfate and the four samples.

[0036] Product Name Neomycin Sulfate Sample 1 Sample 2 Sample 3 Sample 4 Hygroscopicity 16.2％ 7.3％ 7.6％ 7.8％ 6.7％

[0037] It can be seen that the raw material neomycin sulfate is very hygroscopic, and the medicine prepared with sucrose and β-cyclodextrin as excipients is hygroscopic, but the hygroscopicity is greatly improved compared with the raw material.

[0038] At the same time, the results of Example 1 prove that sucrose and β-cyclodextrin are the best choices as auxiliary materials for neomycin sulfate soluble powder.

[0039] Example 2: Stability test

[0040] The composition of a drug has a direct relationship with its stability. Different antioxidants directly affect the stability of the drug's active ingredients. The stability of drug preparations can be quantitatively examined from appearance to active ingredients.

[0041] Sample 1: Add 32.5g neomycin sulfate (pure) to 10g β-cyclodextrin and 100g sucrose powder, mix well and pack into aluminum-plastic composite bags.

[0042] Sample 2: 32.5g neomycin sulfate (pure), add 5g VC, 10g β-cyclodextrin, and 100g sucrose powder, mix well, and pack into aluminum-plastic composite bags.

[0043] Sample 3: Add 32.5g neomycin sulfate (pure) to 5g sodium isoVC, 10g β-cyclodextrin, and 100g sucrose powder, mix well, and pack into aluminum-plastic composite bags.

[0044] Sample 4: 32.5g neomycin sulfate (pure), 5g sodium isoVC, 5g cysteine ​​hydrochloride, 10g β-cyclodextrin, and 100g sucrose powder, mix well, and pack into aluminum-plastic composite bags.

[0045] Sample 5: 32.5g neomycin sulfate (pure) plus 3g sodium isoVC, 3g cysteine ​​hydrochloride, 10g β-cyclodextrin, and sucrose powder to 100g, mix well, and pack into aluminum-plastic composite bags.

[0046] Sample 6: 32.5g neomycin sulfate (pure), add 1g sodium isoVC, 1g cysteine ​​hydrochloride, 10g β-cyclodextrin, and sucrose powder to 100g, mix well, and pack into aluminum-plastic composite bags.

[0047] Samples 2, 3, 4, 5, and 6 were all prepared by the method provided by the present invention, through the shearing and pressure-maintaining method.

[0048] Refer to the accelerated test under the guidance of the stability test of raw materials and preparations in the 2020 edition of the Veterinary Pharmacopoeia of the People's Republic of China. The above samples were placed in a stability test chamber with a temperature of 40 degrees and a relative humidity of 75% for accelerated testing. The results are as follows:

[0049]

[0050] It can be seen that the drug preparation without added antioxidants has changed in the fourth month. When VC is added as an antioxidant, VC is first oxidized to form yellow spots. As the cycle increases, the more VC is oxidized, the more obvious the change is.

[0051] The drug preparations with added sodium isoVC and cysteamine hydrochloride as antioxidants had no change. At the same time, the test showed that the addition amount of sodium isoVC and cysteamine hydrochloride to the drug weight ratio of 1:32.5 can play a good antioxidant role.

[0052] Example 3: Drug Aqueous Solution Stability Test

[0053] Neomycin sulfate is usually prepared into a 1% aqueous solution in clinical use and added to the water supply system through a dosing device for animal use. Generally, it is consumed within 24 hours, and in rare cases, it may take more than 48 hours.

[0054] Neomycin sulfate is an antibiotic obtained by fermentation, and its stability in aqueous solution is very unsatisfactory. The neomycin sulfate soluble powder prepared by the method can effectively ensure the stability of the aqueous solution of the preparation in the use link.

[0055] Sample 1: Add 32.5g neomycin sulfate (pure) to 10g β-cyclodextrin and 100g sucrose powder, mix well and pack into aluminum-plastic composite bags.

[0056] Sample 2: 32.5g neomycin sulfate (pure) plus 10g β-cyclodextrin, 1g sodium isoVC, 1g cysteamine hydrochloride, 0.5g sodium bisulfite, and sucrose powder to 100g, mix well, and pack into aluminum-plastic composite bags.

[0057] Sample 3: Add 32.5g neomycin sulfate (pure) to 10g β-cyclodextrin, 3g sodium isoVC, 3g cysteamine hydrochloride, 1g sodium bisulfite, and sucrose powder to 100g, mix well, and package in aluminum-plastic composite bags.

[0058] Sample 4: 32.5g neomycin sulfate (pure) plus 10g β-cyclodextrin, 5g sodium isoVC, 5g cysteamine hydrochloride, 2g sodium bisulfite, and sucrose powder to 100g, mix well, and pack into aluminum-plastic composite bags.

[0059] Samples 1, 2, 3, and 4 were all prepared by the method provided by the present invention, through the shearing and pressure-maintaining method.

[0060] Samples 1, 2, 3, and 4 were each taken and water was added to prepare a 1% aqueous solution, which was then placed in a stability test chamber with the temperature set at 35 degrees and the relative humidity set at 75% for 96 hours to identify its properties, pH value, and content.

[0061] 1. Trait results

[0062] Time / character 1 2 3 4 0h colorless colorless colorless colorless 0.5h colorless colorless colorless colorless 1h colorless colorless colorless colorless 2h colorless colorless colorless colorless 4h colorless colorless colorless colorless 8h colorless colorless colorless colorless 16h Light yellow colorless colorless colorless 24h Light yellow Almost colorless colorless colorless 48h yellow Light yellow Light yellow Light yellow 96h Brown Light yellow Light yellow Light yellow

[0063] The experiment shows that, although the same preparation method is used, the properties of the aqueous solution of the preparation without adding stabilizer and antioxidant (sample 1) (sample 1) are significantly different from the properties of the aqueous solution of the preparation with adding stabilizer and antioxidant (samples 2, 3, 4).

[0064] 2PH Results

[0065]

[0066]

[0067] It can be seen from the experiment that although the same preparation method is used, the pH of the aqueous solution of the preparation without adding stabilizers and antioxidants (sample 1) does not change significantly compared with the pH of the aqueous solution of the preparation with adding stabilizers and antioxidants (samples 2, 3, 4).

[0068] The more antioxidants and stabilizers are added, the more obvious the pH value drops. Even after 96 hours, it is still within the standard range. The standard stipulates that the pH value range is 4.0-7.5. During the most common time in use (24 hours), the pH value does not change much.

[0069] 3 The content is tested with reference to the antibiotic microbiological assay in the Veterinary Pharmacopoeia of the People’s Republic of China, and the data are the comparison between the measured value and the labeled content.

[0070] Time / content 1 2 3 4 0h 100.5％ 101.2％ 98.8％ 99.4％ 8h 99.5％ 101.0％ 98.8％ 99.4％ 16h 98.7％ 100.7％ 98.6％ 99.4％ 24h 98.2％ 100.2％ 98.5％ 99.3％ 36h 97.8％ 99.6％ 98.5％ 99.1％ 48h 96.5％ 99.1％ 98.4％ 99.0％ 72h 93.1％ 98.2％ 98.1％ 98.7％

[0071] It can be seen from the experiment that although the same preparation method is used, the content of the aqueous solution of the preparation without adding stabilizer and antioxidant (sample 1) decreases faster than the content of the aqueous solution of the preparation with adding stabilizer and antioxidant (samples 2, 3, 4).

[0072] From the above data, it can be seen that the higher the content of stabilizer and antioxidant added, the better the stability of the aqueous solution of the preparation, but the faster the pH of the aqueous solution decreases.

[0073] It can be seen from the examples that the preparation process and formula provided by the present invention can well improve the stability of neomycin sulfate soluble powder and its aqueous solution.

Claims

1. A method for preparing neomycin sulfate soluble powder, comprising: Neomycin sulfate 3.25%-32.5% (pure), antioxidant 1%-5%, stabilizer 1-5%, and the rest are auxiliary materials.

2. A method for preparing a neomycin sulfate soluble powder according to claim 1, It is characterized in that The drug is neomycin sulfate.

3. A method for preparing a neomycin sulfate soluble powder according to claim 1, It is characterized in that The antioxidants are sodium isoVC and cysteine ​​hydrochloride, and the ratio of the antioxidants to neomycin sulfate is 1:3.25-32.

5.

4. The method for preparing a neomycin sulfate soluble powder according to claim 1, characterized in that: The stabilizer is sodium bisulfite or sodium pyrosulfite. Its usage ratio with neomycin sulfate is 1:3.25-32.

5.

5. The method for preparing a neomycin sulfate soluble powder according to claim 1, characterized in that: The auxiliary materials are soluble starch, beta-cyclodextrin, sucrose and anhydrous glucose.

6. A method for preparing neomycin sulfate soluble powder, comprising the following steps: (1) Preliminarily mix neomycin sulfate and β-cyclodextrin in the auxiliary materials. (2) Place the mixture in step 1 into a shearing mill, set the speed to 4500 rpm, control the material temperature below 40 degrees, and shear for 10 minutes. (3) The sheared mixture is placed in a sealed stainless steel tank, and clean, dehydrated compressed air is introduced to a pressure of 0.8 MPa, and the pressure is maintained for 60 minutes. (4) Mix sodium isoVC, cysteine ​​hydrochloride and sodium bisulfite with the remaining auxiliary materials in multiple times, grind them through a 60-mesh sieve, mix them evenly with the materials in step 3, and pack them in an aluminum-plastic composite bag.

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