Water-soluble auxiliary material for veterinary drug as well as preparation method and application of water-soluble auxiliary material

Abstract

The invention belongs to the technical field of auxiliary materials for veterinary drugs, and particularly relates to a water-soluble auxiliary material for veterinary drugs as well as a preparation method and application thereof. The water-soluble auxiliary material for the veterinary drug comprises the following components in parts by mass: 70-80 parts of magnesium sulfate, 30-40 parts of fermented cassava starch, 0.1-1 part of polyvinylpyrrolidone, 0.5-3 parts of a surfactant, 1-2 parts of a pH regulator and 0.1-1 part of a sweetening agent. The fermented cassava starch is prepared by fermenting cassava native starch prepared from fresh cassava through compound bacteria, and the compound bacteria comprise bacillus velezensis, bacillus subtilis and bacillus amyloliquefaciens. The water-soluble veterinary drug auxiliary material prepared by the invention can improve the dissolution rate and storage stability of enrofloxacin.

Description

Technical Field

[0001] The present invention belongs to the technical field of veterinary excipients, and in particular relates to a water-soluble veterinary excipient and a preparation method and application thereof. Background Art

[0002] Enrofloxacin is a broad-spectrum fluoroquinolone antibiotic developed by Bayer. It is primarily used to treat various bacterial infections in animals, with excellent antibacterial activity against a wide range of Gram-positive and Gram-negative bacteria. As a veterinary drug, enrofloxacin is widely used to treat diseases in poultry, pigs, cattle, and companion animals (such as cats and dogs). Enrofloxacin can be administered orally and is rapidly absorbed and widely distributed in the animal body, effectively reaching the site of infection.

[0003] As a veterinary drug, the solubility and storage stability of enrofloxacin formulations are crucial to ensuring the drug's effectiveness and safety. Dissolution directly affects the rate and extent of drug dissolution in the body, which is particularly important for oral formulations. Good dissolution performance ensures that the drug can be quickly and completely released from the formulation and then absorbed into the blood circulation system, thereby achieving the desired therapeutic effect. High storage stability means that the drug can maintain its physical and chemical properties, including key indicators such as the content of the active ingredient and solubility, under specified conditions within its labeled expiration date, ensuring the drug's effectiveness throughout its entire use period. If the drug cannot remain stable over extended storage time, it may degrade and form potentially harmful byproducts, which not only reduces the drug's effectiveness but also increases the risk of toxicity. Improving storage stability can reduce waste caused by drug expiration and also reduce the cost of frequent inventory replacement, which is particularly important for veterinary drugs used on a large scale.

[0004] Currently, enrofloxacin tablets on the market generally use universal excipient carriers, such as starch and its derivatives, lactose, glucose, etc. In practice, it is found that these universal excipient carriers will reduce the solubility of enrofloxacin and the storage stability is also not ideal.

[0005] Therefore, there is an urgent need for a water-soluble veterinary excipient specifically for enrofloxacin. Summary of the Invention

[0006] The purpose of the present invention is to provide a water-soluble veterinary auxiliary material and a preparation method and application thereof.

[0007] In order to achieve the above object, the present invention provides the following technical solutions: A water-soluble veterinary auxiliary material comprises the following components in parts by mass: 70-80 parts of magnesium sulfate, 30-40 parts of fermented cassava starch, 0.1-1 part of polyvinylpyrrolidone K15, 0.5-3 parts of a surfactant, 1-2 parts of a pH regulator, and 0.1-1 part of a sweetener.

[0008] Preferably, the pH adjuster includes at least one of sodium carbonate, sodium bicarbonate, potassium bicarbonate, and potassium carbonate.

[0009] Preferably, the sweetener includes at least one of cyclamate, sucrose, maltose, and xylitol.

[0010] Preferably, the composition comprises the following components in parts by mass: 70-75 parts of magnesium sulfate, 32-37 parts of fermented cassava starch, 0.3-0.6 parts of polyvinylpyrrolidone K15, 1-2 parts of surfactant, 1-1.5 parts of pH regulator, and 0.1-0.3 parts of sweetener.

[0011] Preferably, the fermented cassava starch is prepared by fermenting native cassava starch prepared from fresh cassava using a composite bacteria.

[0012] Preferably, the composite bacteria include Bacillus Velezii, Bacillus subtilis and Bacillus amyloliquefaciens.

[0013] Preferably, the preparation method of the fermented cassava starch comprises the following steps: (1) Peeling and cutting the cassava into pieces, beating the pulp with water, and performing two-stage screening to obtain cassava pulp, which is then separated to obtain starch milk, and the starch milk is dehydrated and dried to obtain cassava starch; (2) Add water and composite bacteria to cassava starch, ferment, sterilize, let stand, pour out the upper liquid, dehydrate the lower solid, dry, and crush to obtain fermented cassava starch.

[0014] Preferably, the preparation method of the fermented cassava starch comprises the following steps: (1) Peel fresh cassava, cut into cassava pieces ≤ 2 cm in size, add water, and use a pulper to beat into slurry, which is then screened in two stages through a 60-mesh centrifugal sieve and a 120-mesh fine residue sieve to obtain cassava pulp, which is then passed through a separator for hydrocyclone separation to remove impurities such as mud and sand containing a small amount of starch to obtain starch milk, which is then dehydrated and dried to obtain cassava starch; (2) Add water to the cassava starch, add the composite bacteria, and ferment aerobically at 30-35°C for 30-50 hours. Sterilize, let it stand, pour out the upper liquid, dehydrate the lower solid layer, dry it to a moisture content of less than 10%, and crush it to less than 80 mesh to obtain fermented cassava starch.

[0015] The present invention uses fermented cassava starch to improve the dissolution rate of enrofloxacin prepared from a water-soluble veterinary excipient. The fermentation process changes the structure of the cassava starch and increases its water solubility, thereby improving the dissolution rate and degree of the drug when preparing enrofloxacin.

[0016] Preferably, the dosage of the composite bacteria is 10 7 -10 8 CFU / mL water, wherein the water is the water added in step (2).

[0017] Preferably, the ratio of live bacteria of Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:(1.3-1.5):(0.2-0.4).

[0018] Preferably, the ratio of live bacteria of Bacillus velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:1.4:0.3.

[0019] Preferably, the surfactant comprises Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 1: (1.2-1.4): (0.6-0.8).

[0020] Preferably, the surfactant comprises Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 1:1.3:0.7.

[0021] Preferably, the mass percentage of the surfactant in the fermented cassava starch is 4-5%.

[0022] The present invention uses fermented cassava starch as a basic auxiliary material and adds a surfactant in an appropriate proportion, which helps improve the solubility of enrofloxacin and ensures its stability during storage, thereby protecting the effectiveness and safety of the drug. Analysis shows that the appropriate surfactant can improve the interaction between fermented cassava starch and enrofloxacin, making them more compatible and ensuring the stability and effectiveness of the drug.

[0023] Preferably, the following components are included in parts by mass: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinyl pyrrolidone (such as K15), 1.5 parts of surfactant, 1.2 parts of sodium bicarbonate, and 0.2 parts of cyclamate.

[0024] The second aspect of the present invention provides a method for preparing a water-soluble veterinary excipient, comprising the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinylpyrrolidone K15 and cyclamate, and finally adding sodium bicarbonate, stirring uniformly to obtain a water-soluble veterinary excipient.

[0025] The third aspect of the present invention provides a use of a water-soluble veterinary excipient in the preparation of veterinary drugs.

[0026] Compared with the prior art, the advantages and beneficial effects of the present invention are: 1. Enrofloxacin, a broad-spectrum fluoroquinolone antibiotic, has poor water solubility, which greatly limits its dissolution rate and absorption efficiency in the body, thereby affecting its bioavailability. The pharmaceutical excipient prepared in the present invention can improve the solubility of enrofloxacin preparations, help accelerate the release rate of the drug in the body, and enhance its therapeutic effect.

[0027] 2. Enrofloxacin may undergo physical or chemical changes during storage due to environmental factors, affecting its quality and safety. Good storage stability can extend the shelf life of the drug, reduce safety risks caused by degradation or deterioration, and ensure that the drug maintains its expected quality and efficacy within its shelf life.

[0028] The pharmaceutical excipient of the present invention can take into account the above-mentioned properties, and helps to ensure that the enrofloxacin preparation has stable efficacy and high safety in veterinary use, which is particularly important in long-term use and large-scale veterinary clinical applications. DETAILED DESCRIPTION

[0029] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0030] The raw materials used in the following examples of the present invention are all commercially available commodities: Bacillus velez, product number TS377650, Ningbo Testo Biotechnology Co., Ltd.

[0031] Bacillus subtilis, product number TS276952, Ningbo Testo Biotechnology Co., Ltd.

[0032] Bacillus amyloliquefaciens, product number TS277629, Ningbo Testo Biotechnology Co., Ltd. Example 1

[0033] This embodiment provides a water-soluble veterinary excipient, comprising the following components in parts by mass: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinylpyrrolidone K15, 1.5 parts of a surfactant, 1.2 parts of sodium bicarbonate, and 0.2 parts of cyclamate.

[0034] The preparation method of the fermented tapioca starch comprises the following steps: (1) Peel fresh cassava, cut into cassava pieces ≤ 2 cm in size, add water, and use a pulper to beat into slurry, which is then screened in two stages through a 60-mesh centrifugal sieve and a 120-mesh fine residue sieve to obtain cassava pulp, which is then passed through a separator for hydrocyclone separation to remove impurities such as mud and sand containing a small amount of starch to obtain starch milk, which is then dehydrated and dried to obtain cassava starch; (2) Add water to the cassava starch, add the composite bacteria, and ferment it aerobically at 32°C for 40 hours. Sterilize it, let it stand, pour out the upper liquid, dehydrate the lower solid layer, dry it to a moisture content of 8%, and crush it to less than 80 mesh to obtain fermented cassava starch.

[0035] The dosage of the composite bacteria is 5×10 7 CFU / mL water, wherein the water is the water added in step (2); the composite bacteria comprises Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens; and the ratio of live bacteria of Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:1.4:0.3.

[0036] The surfactant comprises Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 1:1.3:0.7.

[0037] The preparation method of the water-soluble veterinary auxiliary material comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinyl pyrrolidone K15 and cyclamate, and finally adding sodium bicarbonate, stirring uniformly to obtain the water-soluble veterinary auxiliary material. Example 2

[0038] This embodiment provides a water-soluble veterinary excipient, comprising the following components in parts by mass: 70 parts of magnesium sulfate, 37 parts of fermented cassava starch, 0.3 parts of polyvinylpyrrolidone K15, 1.48 parts of a surfactant, 1 part of sodium bicarbonate, and 0.3 parts of cyclamate.

[0039] The preparation method of the fermented tapioca starch comprises the following steps: (1) Peel fresh cassava, cut into cassava pieces ≤ 2 cm in size, add water, and use a pulper to beat into slurry, which is then screened in two stages through a 60-mesh centrifugal sieve and a 120-mesh fine residue sieve to obtain cassava pulp, which is then passed through a separator for hydrocyclone separation to remove impurities such as mud and sand containing a small amount of starch to obtain starch milk, which is then dehydrated and dried to obtain cassava starch; (2) Add water to the cassava starch, add the composite bacteria, and ferment it aerobically at 30°C for 50 hours. Sterilize it, let it stand, pour out the upper liquid, dehydrate the lower solid layer, dry it to a moisture content of 9%, and crush it to less than 80 mesh to obtain fermented cassava starch.

[0040] The dosage of the composite bacteria is 10 7CFU / mL water, wherein the water is the water added in step (2); the composite bacteria comprises Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens; and the ratio of live bacteria of Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:1.3:0.4.

[0041] The surfactant comprises Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 1:1.2:0.8.

[0042] The preparation method of the water-soluble veterinary auxiliary material comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinyl pyrrolidone K15 and cyclamate, and finally adding sodium bicarbonate, stirring uniformly to obtain the water-soluble veterinary auxiliary material. Example 3

[0043] This embodiment provides a water-soluble veterinary excipient, comprising the following components in parts by mass: 80 parts of magnesium sulfate, 30 parts of fermented cassava starch, 1 part of polyvinylpyrrolidone K15, 1.5 parts of a surfactant, 2 parts of sodium bicarbonate, and 0.1 part of cyclamate.

[0044] The preparation method of the fermented tapioca starch comprises the following steps: (1) Peel fresh cassava, cut into cassava pieces ≤ 2 cm in size, add water, and use a pulper to beat into slurry, which is then screened in two stages through a 60-mesh centrifugal sieve and a 120-mesh fine residue sieve to obtain cassava pulp, which is then passed through a separator for hydrocyclone separation to remove impurities such as mud and sand containing a small amount of starch to obtain starch milk, which is then dehydrated and dried to obtain cassava starch; (2) Add water to the cassava starch, add the composite bacteria, and ferment aerobically at 35°C for 30 hours. Sterilize, let it stand, pour out the upper liquid, dehydrate the lower solid layer, dry it to a moisture content of 7%, and crush it to less than 80 mesh to obtain fermented cassava starch.

[0045] The dosage of the composite bacteria is 10 8 CFU / mL water, wherein the water is the water added in step (2); the composite bacteria comprises Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens; and the ratio of live bacteria of Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:1.3:0.2.

[0046] The surfactant comprises Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 1:1.4:0.6.

[0047] The preparation method of the water-soluble veterinary auxiliary material comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinyl pyrrolidone K15 and cyclamate, and finally adding sodium bicarbonate, stirring uniformly to obtain the water-soluble veterinary auxiliary material. Example 4

[0048] The difference between this embodiment and Example 1 is: a water-soluble veterinary excipient, comprising the following components in parts by mass: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinylpyrrolidone K15, 2.5 parts of a surfactant, 1.2 parts of sodium bicarbonate, and 0.2 parts of cyclamate. Example 5

[0049] The difference between this embodiment and Example 1 is: a water-soluble veterinary excipient, comprising the following components in parts by mass: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinylpyrrolidone K15, 1 part of a surfactant, 1.2 parts of sodium bicarbonate, and 0.2 parts of cyclamate.

[0050] Comparative Example 1 The difference between this comparative example and Example 1 is that fermented cassava starch is replaced by commercially available cassava starch, Shaanxi Panlong Yihai Pharmaceutical Co., Ltd., pharmaceutical grade cassava starch CAS: 9063-38-1.

[0051] Comparative Example 2 The difference between this comparative example and Example 1 is that the composite bacteria is replaced by Bacillus subtilis.

[0052] Comparative Example 3 The difference between this comparative example and Example 1 is that the composite bacteria includes Bacillus subtilis and Bacillus amyloliquefaciens; and the ratio of live bacteria of Bacillus subtilis to Bacillus amyloliquefaciens in the composite bacteria is 1:1.

[0053] Comparative Example 4 The difference between this comparative example and Example 1 is that the composite bacteria includes Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens; and the ratio of live bacteria of Bacillus Velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1.4:0.3:1.

[0054] Comparative Example 5 The difference between this comparative example and Example 1 is that the surfactant is Tween 20.

[0055] Comparative Example 6 The difference between this comparative example and Example 1 is that the surfactant includes Tween 20 and sodium lauryl sulfate in a mass ratio of 1:1.

[0056] Comparative Example 7 The difference between this comparative example and Example 1 is that the surfactant includes Tween 20, sodium lauryl sulfate and poloxamer 188 in a mass ratio of 0.7:1:1.3.

[0057] Performance Testing The water-soluble veterinary excipients prepared in Examples 1-5 and Comparative Examples 1-7 were mixed with enrofloxacin in a mass ratio of 4:1, dissolved in ethanol, and spray-dried to prepare samples. The control group consisted of commercially available enrofloxacin tablets (brand: Bayli, produced in Germany).

[0058] 1. Referring to the dissolution determination method in the appendix of the Veterinary Pharmacopoeia of the People's Republic of China, 900 mL of PBS solution with pH 7.0 was used as the solvent. The speed was 100 rpm. A sample containing 50 mg of enrofloxacin was added and stirred. 1 mL of samples were taken at 10 min, 30 min, and 60 min, respectively, to determine the dissolution rate of enrofloxacin.

[0059] 2. Conduct an accelerated test on the samples in accordance with the Guidelines for Stability Testing of Veterinary Drugs. Place the samples at 45±2°C and 80% relative humidity for 6 months, and use the same method as above to determine the 60-min dissolution rate.

[0060] The results are shown in Table 1.

[0061] Table 1 Dissolution test results 10min 30min 60min Accelerated test 60 minutes Example 1 55.15 80.12 88.64 88.21 Example 2 54.61 79.36 86.18 85.47 Example 3 54.24 79.74 87.50 86.79 Example 4 52.58 75.81 84.49 79.12 Example 5 51.73 75.27 82.62 78.56 Comparative Example 1 41.32 59.15 67.83 55.98 Comparative Example 2 45.96 63.40 71.21 62.33 Comparative Example 3 46.49 64.73 72.07 64.14 Comparative Example 4 49.35 70.56 76.76 71.68 Comparative Example 5 48.64 66.91 74.91 61.04 Comparative Example 6 49.07 67.64 75.35 65.87 Comparative Example 7 50.82 71.82 77.84 69.53 control group 43.59 59.01 64.19 50.32 As shown in Table 1, the enrofloxacin samples prepared using the water-soluble veterinary excipients of Examples 1-3 exhibited high solubility and good storage stability, significantly outperforming commercially available products. The results also indicate that if the amount of surfactant used in Examples 4 and 5 is too high or too low relative to the fermented cassava starch, dissolution and storage stability will decrease.

[0062] In Comparative Example 1, when the fermented cassava starch was replaced with commercially available cassava starch, the dissolution rate of the enrofloxacin tablets was high and the storage stability was reduced.

[0063] In Comparative Examples 2-4, the composition ratio of the composite bacteria was changed, and the dissolution rate of the enrofloxacin sample decreased.

[0064] In Comparative Examples 5-7, the composition and ratio of the surfactants were changed, and the storage stability of the enrofloxacin samples decreased.

[0065] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A water-soluble veterinary excipient, characterized in that: The invention comprises the following components in parts by mass: 70-80 parts of magnesium sulfate, 30-40 parts of fermented cassava starch, 0.1-1 part of polyvinyl pyrrolidone, 0.5-3 parts of surfactant, 1-2 parts of pH regulator and 0.1-1 part of sweetener.

2. The water-soluble veterinary excipient according to claim 1, characterized in that The invention comprises the following components in parts by mass: 70-75 parts of magnesium sulfate, 32-37 parts of fermented cassava starch, 0.3-0.6 parts of polyvinyl pyrrolidone, 1-2 parts of surfactant, 1-1.5 parts of pH regulator and 0.1-0.3 parts of sweetener.

3. The water-soluble veterinary excipient according to claim 2, characterized in that The fermented cassava starch is prepared by fermenting cassava starch prepared from fresh cassava using composite bacteria, wherein the composite bacteria comprises Bacillus velez, Bacillus subtilis and Bacillus amyloliquefaciens.

4. The water-soluble veterinary excipient according to claim 3, characterized in that The preparation method of the fermented tapioca starch comprises the following steps: (1) Peeling the cassava, cutting it into pieces, adding water to pulp, and performing two-stage screening to obtain cassava pulp, which is then separated to obtain starch milk, and the starch milk is dehydrated and dried to obtain cassava starch; (2) Add water and composite bacteria to cassava starch, ferment, sterilize, let stand, pour out the upper liquid, dehydrate the lower solid, dry, and crush to obtain fermented cassava starch.

5. The water-soluble veterinary excipient according to claim 4, characterized in that The dosage of the composite bacteria is 10 7 -10 8 CFU / mL water, wherein the water is the water added in step (2).

6. The water-soluble veterinary excipient according to claim 5, characterized in that The ratio of live bacteria of Bacillus velez, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1: (1.3-1.5): (0.2-0.4).

7. The water-soluble veterinary excipient according to claim 1, characterized in that The surfactants include Tween 20, sodium lauryl sulfate and poloxamer 188.

8. The water-soluble veterinary excipient according to claim 7, characterized in that: The surfactant accounts for 4-5% of the mass percentage of the fermented cassava starch.

9. A method for preparing the water-soluble veterinary excipient according to any one of claims 1 to 8, characterized in that: The method comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinyl pyrrolidone and a sweetener, and finally adding a pH regulator, stirring uniformly, and obtaining a water-soluble veterinary auxiliary material.

10. Use of the water-soluble veterinary excipient according to any one of claims 1 to 8 in the preparation of veterinary drugs.