A water-soluble veterinary drug adjuvant, a preparation method and application thereof

Abstract

The application belongs to the technical field of veterinary drug excipients, and particularly relates to a water-soluble veterinary drug excipient and a preparation method and application thereof. The water-soluble veterinary drug excipient 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 raw starch prepared from fresh cassava by using composite bacteria, and the composite bacteria comprise Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens. The water-soluble veterinary drug excipient prepared by the application can improve the dissolution rate and storage stability of enrofloxacin.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of veterinary drug excipients, and particularly relates to a water-soluble veterinary drug excipient and a preparation method and application thereof. BACKGROUND

[0002] Enrofloxacin is a broad-spectrum fluoroquinolone antibiotic developed by Bayer. It is mainly used for the treatment of various bacterial infections in animals, and has good antibacterial properties against a variety of gram-positive and gram-negative bacteria. As a veterinary drug, enrofloxacin is widely used in the treatment of diseases in poultry, pigs, cattle, companion animals (such as cats and dogs), etc. Enrofloxacin can be administered orally, and is rapidly absorbed and widely distributed in the animal body, effectively reaching the infection site.

[0003] As a veterinary drug, the dissolution and storage stability of enrofloxacin preparations are crucial for ensuring the effectiveness and safety of the drug. The dissolution directly affects the dissolution rate and extent of the drug in the body, which is particularly important for oral preparations. Good dissolution performance ensures that the drug can be quickly and completely released from the preparation and then absorbed into the blood circulation system, thereby achieving the expected therapeutic effect. High storage stability means that the drug can maintain its physical and chemical properties unchanged, including the content of active ingredients, dissolution, and other key indicators, under the specified conditions within its indicated shelf life, ensuring the drug to be effective throughout its use period. As the storage time increases, if the drug cannot remain stable, degradation may occur, forming potentially harmful byproducts, which not only reduces the effectiveness of the drug, but also increases the risk of toxicity. Improving the storage stability can reduce waste caused by ineffective drugs, and also reduce the cost of frequent inventory replacement, which is particularly important for large-scale use of veterinary drugs.

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

[0005] Therefore, there is an urgent need for a water-soluble veterinary drug excipient specifically for enrofloxacin. SUMMARY

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

[0007] In order to achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0008] The application discloses a water-soluble veterinary drug auxiliary material which comprises the following components in mass fraction: 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.

[0009] Preferably, the pH regulator comprises at least one of sodium carbonate, sodium bicarbonate, potassium bicarbonate and potassium carbonate.

[0010] Preferably, the sweetener comprises at least one of cyclamate, sucrose, maltose and xylitol.

[0011] Preferably, the water-soluble veterinary drug auxiliary material comprises the following components in mass fraction: 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 a surfactant, 1-1.5 parts of a pH regulator and 0.1-0.3 parts of a sweetener.

[0012] Preferably, the fermented cassava starch is prepared by fermenting cassava native starch prepared from fresh cassava by using composite bacteria.

[0013] Preferably, the composite bacteria comprise Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens.

[0014] Preferably, the preparation method of the fermented cassava starch comprises the following steps:

[0015] (1) peeling the cassava, cutting the cassava into pieces, adding water to the cassava pieces to make a pulp, performing two-stage screening to obtain cassava pulp, then separating the cassava pulp to obtain starch milk, and dehydrating and drying the starch milk to obtain cassava starch;

[0016] (2) adding water and composite bacteria to the cassava starch, fermenting the mixture, sterilizing the mixture, standing the mixture, discarding the upper liquid of the mixture, dehydrating the lower solid of the mixture, drying the lower solid, and crushing the lower solid to obtain fermented cassava starch.

[0017] Preferably, the preparation method of the fermented cassava starch comprises the following steps:

[0018] (1) peeling fresh cassava, cutting the fresh cassava into pieces with a size of less than or equal to 2 cm, adding water to the cassava pieces to make a pulp, performing two-stage screening to obtain cassava pulp, then rotating the cassava pulp to remove impurities such as mud and sand containing a small amount of starch by using a centrifugal separator to obtain starch milk, and dehydrating and drying the starch milk to obtain cassava starch;

[0019] (2) adding water and composite bacteria to the cassava starch, performing aerobic fermentation at 30-35 DEG C for 30-50 h, sterilizing the mixture, standing the mixture, discarding the upper liquid of the mixture, dehydrating the lower solid of the mixture, drying the lower solid to a water content of less than 10%, and crushing the lower solid to less than 80 mesh to obtain fermented cassava starch.

[0020] The present application can improve the dissolution rate of enrofloxacin prepared by using the fermented cassava starch as the water-soluble veterinary drug auxiliary material. The structure of the cassava starch can be changed and the water-solubility thereof can be increased through the fermentation process. When enrofloxacin is prepared, the dissolution speed and degree of the drug can be improved.

[0021] Preferably, the amount of the complex bacteria is 10 7 -10 8 CFU / mL water, which is the water added in step (2).

[0022] Preferably, the ratio of the viable bacteria of the B. velezensis, B. subtilis and B. amyloliquefaciens in the complex bacteria is 1: (1.3-1.5): (0.2-0.4).

[0023] Preferably, the ratio of the viable bacteria of the B. velezensis, B. subtilis and B. amyloliquefaciens in the complex bacteria is 1:1.4:0.3.

[0024] Preferably, the surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 1: (1.2-1.4): (0.6-0.8).

[0025] Preferably, the surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 1:1.3:0.7.

[0026] Preferably, the surfactant accounts for 4-5% of the mass percentage of the fermented cassava starch.

[0027] On the basis of using the fermented cassava starch as the basic auxiliary material, the present application adds the surfactant at a proper ratio, which is helpful to improve the dissolution performance of enrofloxacin and can ensure the stability of enrofloxacin during the storage process, thereby guaranteeing the effectiveness and safety of the drug. The proper surfactant can improve the interaction between the fermented cassava starch and enrofloxacin, so that the two are more compatible, thereby guaranteeing the stability and effectiveness of the drug.

[0028] Preferably, the components include the following mass fractions: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinylpyrrolidone (for example, K15), 1.5 parts of surfactant, 1.2 parts of sodium bicarbonate and 0.2 parts of cyclamate.

[0029] The present application provides a preparation method of a water-soluble veterinary drug auxiliary material in the second aspect, which comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinylpyrrolidone K15 and cyclamate, finally adding sodium bicarbonate and uniformly stirring to obtain the water-soluble veterinary drug auxiliary material.

[0030] The third aspect of the present application provides a use of the water-soluble veterinary drug auxiliary material in the preparation of a veterinary drug.

[0031] Compared with the prior art, the present application has the advantages and beneficial effects that:

[0032] 1. Enrofloxacin is a broad-spectrum fluoroquinolone antibiotic with poor water solubility, which greatly limits its dissolution rate and absorption efficiency in the body, thereby affecting the bioavailability. The pharmaceutical auxiliary material prepared by the present application can improve the dissolution of enrofloxacin preparation, help to accelerate the release speed of the drug in the body, and enhance its therapeutic effect.

[0033] 2. Enrofloxacin may undergo physical or chemical changes due to environmental factors during storage, affecting its quality and safety. Good storage stability can extend the shelf life of the drug, reduce the safety risks caused by degradation or deterioration, and ensure that the drug maintains the desired quality and efficacy within the shelf life.

[0034] The pharmaceutical auxiliary material of the present application can take into account the performance of the above aspects, which helps to ensure that enrofloxacin preparations have stable efficacy and high safety in the use of veterinary drugs, especially in long-term use and large-scale veterinary clinical applications. DETAILED DESCRIPTION

[0035] The technical solutions in the embodiments of the present application will be described below in a clear and complete manner. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative labor fall within the scope of the present application.

[0036] The raw materials used in the following embodiments of the present application are all commercially available:

[0037] Bacillus velezensis, item number TS377650, Ningbo Tesotec Biotechnology Co., Ltd.

[0038] Bacillus subtilis, item number TS276952, Ningbo Tesotec Biotechnology Co., Ltd.

[0039] Bacillus amyloliquefaciens, item number TS277629, Ningbo Tesotec Biotechnology Co., Ltd. Example 1

[0040] The present embodiment provides a water-soluble veterinary drug auxiliary material, which comprises the following components in mass fraction: 72 parts of magnesium sulfate, 35 parts of fermented cassava starch, 0.4 parts of polyvinylpyrrolidone K15, 1.5 parts of surfactant, 1.2 parts of sodium bicarbonate, and 0.2 parts of cyclamate.

[0041] The preparation method of the fermented cassava starch comprises the following steps:

[0042] (1) peel fresh cassava and cut into cassava blocks with a size of ≤2 cm, add water, use a beater to beat into a slurry, pass through a 60-mesh centrifugal screen and a 120-mesh fine residue screen for two-stage screening in sequence, obtain cassava slurry, pass through a separator for hydrocyclone separation, remove impurities such as mud sand containing a small amount of starch, obtain starch milk, and after dehydration and drying of the starch milk, obtain cassava starch;

[0043] (2) add water to the cassava starch, add composite bacteria, aerobic ferment at 32℃ for 40h, sterilize, stand, pour off the upper liquid, dehydrate the lower solid, and dry to a water content of 8%, crush to less than 80 mesh, to obtain fermented cassava starch.

[0044] The amount of the composite bacteria is 5×10 7 CFU / mL of water, the water is the water added in step (2); the composite bacteria comprises Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens; the viable bacteria ratio of Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens in the composite bacteria is 1:1.4:0.3.

[0045] The surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 1:1.3:0.7.

[0046] The preparation method of the water-soluble veterinary auxiliary material comprises the following steps: uniformly stir magnesium sulfate, fermented cassava starch and a surfactant, continue to add polyvinylpyrrolidone K15 and sodium cyclamate, finally add sodium bicarbonate, and uniformly stir to obtain the water-soluble veterinary auxiliary material. Example 2

[0047] The embodiment provides a water-soluble veterinary auxiliary material, which comprises 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 sodium cyclamate.

[0048] The preparation method of the fermented cassava starch comprises the following steps:

[0049] (1) peel fresh cassava and cut into cassava blocks with a size of ≤2 cm, add water, use a beater to beat into a slurry, pass through a 60-mesh centrifugal screen and a 120-mesh fine residue screen for two-stage screening in sequence, obtain cassava slurry, pass through a separator for hydrocyclone separation, remove impurities such as mud sand containing a small amount of starch, obtain starch milk, and after dehydration and drying of the starch milk, obtain cassava starch;

[0050] (2) adding water into the cassava starch, adding the compound bacteria, aerobic fermentation for 50h at 30℃, sterilizing, standing, pouring off the upper liquid, dehydrating the lower solid, drying to the water content of 9%, crushing to less than 80 meshes, to obtain the fermented cassava starch.

[0051] The amount of the compound bacteria is 10 7 CFU / mL water, the water is the water added in step (2); the compound bacteria comprises Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens; the viable bacteria ratio of Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens in the compound bacteria is 1:1.3:0.4.

[0052] The surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 1:1.2:0.8.

[0053] The preparation method of the water-soluble veterinary adjuvant comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinylpyrrolidone K15 and sodium cyclamate, finally adding sodium bicarbonate, uniformly stirring, to obtain the water-soluble veterinary adjuvant. Example 3

[0054] The example provides a water-soluble veterinary adjuvant, which comprises 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 sodium cyclamate.

[0055] The preparation method of the fermented cassava starch comprises the following steps:

[0056] (1) peeling fresh cassava, cutting the cassava into blocks with a size of ≤2cm, adding water, using a beater to beat into a slurry, sequentially passing through a 60-mesh centrifugal screen and a 120-mesh fine residue screen for two-stage screening, obtaining cassava slurry, removing impurities such as mud and sand containing a small amount of starch by using a centrifugal separator for liquid centrifugal separation, obtaining starch milk, dehydrating and drying the starch milk, to obtain cassava starch;

[0057] (2) adding water into the cassava starch, adding the compound bacteria, aerobic fermentation for 30h at 35℃, sterilizing, standing, pouring off the upper liquid, dehydrating the lower solid, drying to the water content of 7%, crushing to less than 80 meshes, to obtain the fermented cassava starch.

[0058] The amount of the compound bacteria is 10 8 CFU / mL water, the water is the water added in step (2); the compound bacteria comprises Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens; the viable bacteria ratio of Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens in the compound bacteria is 1:1.3:0.2.

[0059] The surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 in a mass ratio of 1:1.4:0.6.

[0060] The preparation method of the water-soluble veterinary adjuvant comprises the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinylpyrrolidone K15 and sodium cyclamate, and finally adding sodium bicarbonate and uniformly stirring to obtain the water-soluble veterinary adjuvant. Example 4

[0061] The difference between this example and Example 1 is that the water-soluble veterinary adjuvant comprises the following components in mass fractions: 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 sodium cyclamate. Example 5

[0062] The difference between this example and Example 1 is that the water-soluble veterinary adjuvant comprises the following components in mass fractions: 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 sodium cyclamate.

[0063] Comparative Example 1

[0064] The difference between this comparative example and Example 1 is that the fermented cassava starch is replaced by commercially available cassava starch, which is pharmaceutical grade cassava starch CAS: 9063-38-1 from Shaanxi Panlong Yiyi Pharmaceutical Co., Ltd.

[0065] Comparative Example 2

[0066] The difference between this comparative example and Example 1 is that the complex bacteria are replaced by Bacillus subtilis.

[0067] Comparative Example 3

[0068] The difference between this comparative example and Example 1 is that the complex bacteria comprise Bacillus subtilis and Bacillus amyloliquefaciens, and the viable bacteria ratio of Bacillus subtilis to Bacillus amyloliquefaciens in the complex bacteria is 1:1.

[0069] Comparative Example 4

[0070] The difference between this comparative example and Example 1 is that the complex bacteria comprise Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens, and the viable bacteria ratio of Bacillus velezensis to Bacillus subtilis to Bacillus amyloliquefaciens in the complex bacteria is 1.4:0.3:1.

[0071] Comparative Example 5

[0072] The difference between this comparative example and Example 1 is that the surfactant is Tween 20.

[0073] Comparative Example 6

[0074] The difference between this comparative example and Example 1 is that the surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 0.7:1:1.3.

[0075] Comparative Example 7

[0076] The difference between this comparative example and Example 1 is that the surfactant comprises Tween 20, sodium dodecyl sulfate and poloxamer 188 at a mass ratio of 0.7:1:1.3.

[0077] Performance test

[0078] The water-soluble veterinary drug adjuvant and enrofloxacin prepared in Examples 1-5 and Comparative Examples 1-7 were mixed at a mass ratio of 4:1, dissolved in ethanol, and spray-dried to prepare samples. The control group was a commercially available enrofloxacin tablet (brand: Bayhav, origin: Germany).

[0079] 1. Referring to the dissolution test method in the Appendix of the Veterinary Drug of the People's Republic of China, 900 mL of PBS solution with pH 7.0 was used as the solvent, the rotation speed was 100 rpm, 50 mg of enrofloxacin was added to the sample, and the dissolution of enrofloxacin was measured by stirring and taking 1 mL of sample at 10 min, 30 min and 60 min, respectively.

[0080] 2. According to the Guidelines for Stability Test Research of Veterinary Drugs, the samples were subjected to accelerated testing at 45±2°C and 80% relative humidity for 6 months, and the dissolution at 60 min was measured using the same method as described above.

[0081] The results are shown in Table 1.

[0082] Table 1 Dissolution test results

[0083] 10 min 30 min 60 min 60 min 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 43.59 59.01 64.19 50.32

[0084] As can be seen from Table 1, the enrofloxacin samples prepared using the water-soluble veterinary drug adjuvant of Examples 1-3 have high dissolution and good storage stability, which are significantly better than the commercially available product. As can be seen from the results, in Examples 4 and 5, the amount of surfactant accounts for too much or too little of the fermented cassava starch, which will reduce the dissolution and storage stability.

[0085] In Comparative Example 1, the fermented cassava starch was replaced with commercially available cassava starch, and the dissolution of the enrofloxacin tablet was high and the storage stability was reduced.

[0086] In Comparative Examples 2-4, the composition ratio of the complex bacteria was changed, and the dissolution of the enrofloxacin sample was reduced.

[0087] The storage stability of the enrofloxacin sample decreased when the composition and ratio of the surfactants in Comparative Examples 5-7 were changed.

[0088] The above is the preferred embodiment of the present application, it should be noted that for those skilled in the art, without departing from the principles described in the present application, can also make several improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A water-soluble veterinary drug adjuvant, characterized by, The components include the following mass fractions: 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 adjuster, and 0.1-1 part of a sweetener. The preparation method of the fermented cassava starch includes the following steps: (1) peeling and cutting the cassava, adding water to pulp, performing two-stage screening to obtain cassava pulp, then separating to obtain starch milk, and dehydrating and drying the starch milk to obtain cassava starch; (2) adding water and a composite bacteria to the cassava starch, fermenting, sterilizing, standing, discarding the upper liquid, dehydrating and drying the lower solid, and crushing to obtain fermented cassava starch; The live bacteria ratio of the composite bacteria including Bacillus velezensis, Bacillus subtilis and Bacillus amyloliquefaciens is 1: (1.3-1.5): (0.2-0.4); The surfactant includes Tween 20, sodium dodecyl sulfate and poloxamer 188 in a mass ratio of 1: (1.2-1.4): (0.6-0.8).

2. The water-soluble veterinary adjuvant according to claim 1, characterized in that, The components include the following mass fractions: 70-75 parts of magnesium sulfate, 32-37 parts of fermented cassava starch, 0.3-0.6 parts of polyvinylpyrrolidone, 1-2 parts of a surfactant, 1-1.5 parts of a pH adjuster, and 0.1-0.3 parts of a sweetener.

3. The water-soluble veterinary adjuvant according to claim 1, characterized by, The complex bacteria is used in an amount of 10 7 -10 8 CFU / mL water, which is the water added in step (2).

4. The water-soluble veterinary adjuvant according to claim 1, characterized by, The mass percentage of the surfactant in the fermented cassava starch is 4-5%.

5. A method for preparing the water-soluble veterinary adjuvant according to any one of claims 1 to 4, characterized in that, The method includes the following steps: uniformly stirring magnesium sulfate, fermented cassava starch and a surfactant, continuously adding polyvinylpyrrolidone and a sweetener, and finally adding a pH adjuster and uniformly stirring to obtain a water-soluble veterinary adjuvant.

6. Use of the water-soluble veterinary adjuvant of any one of claims 1-4 in the preparation of enrofloxacin veterinary drugs.