Probenecid solution for poultry and application thereof

Abstract

The invention belongs to the technical field of veterinary drugs for poultry, and discloses a probenecid solution for poultry and application thereof, and the probenecid solution is prepared from probenecid, a cosolvent, an antioxidant, a complexing agent, a stabilizer and the balance of water according to a specific proportion. The prepared probenecid solution has the characteristics of rapid and complete absorption after oral administration, is used for drinking water for poultry, and has the advantages of accurate dosage, easiness in administration, good safety and convenience in use. The probenecid solution solves the problems that the existing probenecid solution is poor in stability and inconvenient to orally take by poultry by adjusting the proportion of the raw material components and specifically adding specific auxiliary substances. The product disclosed by the invention is suitable for preparing the poultry anti-gout medicine.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs for poultry, in particular to a probenecid solution for poultry and application thereof. Background Art

[0002] Avian gout is a metabolic disease caused by the accumulation of uric acid in poultry, especially in the joints, kidneys and other parts of the body. It usually occurs when the breeding environment is poor, the feed is improperly managed or the poultry has immune system problems. The disease can cause a series of discomfort symptoms in poultry, affecting their growth, egg production and overall health.

[0003] Anti-inflammatory drugs such as colchicine are commonly used to treat poultry gout, which can relieve joint inflammation caused by uric acid crystals and reduce pain and swelling. However, this drug has significant side effects and needs to be used with caution. In addition, poultry gout is also treated by mixing diuretic and detumescent Chinese herbal medicines into feed, stopping the use of sulfonamides, and reducing the calcium content in feed. These treatments are slow to take effect, and once a large-scale outbreak of poultry gout occurs, it will cause serious economic losses to farmers.

[0004] In addition to anti-inflammatory drugs, probenecid can also be used to inhibit the renal tubular reabsorption of urate, increase the urinary excretion of uric acid, and reduce serum urate levels, thereby achieving the effect of rapid treatment of gout. However, due to the low solubility of probenecid, it is almost insoluble in water. The currently disclosed probenecid-related veterinary drugs are mostly solid preparations, which are inconvenient for poultry animals to use. Liquid preparations such as probenecid injections often have complex preparations, and the types of cosolvents involved are numerous, which increases the problem of cost, and the use of injections is compared to oral administration, and the convenience needs to be improved, and the storage conditions are also higher. The currently disclosed probenecid solution, such as the Chinese invention patent application with publication number CN112957318A, has the problem that the stability of the complexing agent in the solution needs to be improved. Summary of the invention

[0005] In order to solve the above deficiencies in the prior art, the present invention aims to provide a probenecid solution for poultry, which achieves the purpose of improving the solubility of probenecid, saving costs, and facilitating poultry administration through the synergistic effect of raw materials such as cosolvents, complexing agents, stabilizers, etc. in a specific proportion;

[0006] Another object of the present invention is to provide an application of the above-mentioned poultry probenecid solution for preparing a drug for resisting poultry gout.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] The invention discloses a probenecid solution for poultry. The raw materials for making the effective component of the solution per 1000 parts by volume are 100-200 parts by weight of probenecid, 15-20 parts by weight of cosolvent, 1-3 parts by weight of antioxidant, 0.1-0.4 parts by weight of complexing agent, 100-300 parts by volume of stabilizer and the balance of water.

[0009] The ratio of parts by weight to parts by volume is kg:L.

[0010] As a limitation of the present invention, the co-solvent is sodium hydroxide.

[0011] As a further limitation of the present invention, the antioxidant is anhydrous sodium sulfite.

[0012] As another limitation of the present invention, the complexing agent is at least one of calcium sodium edetate, citric acid and tartaric acid.

[0013] As a further limitation of the present invention, the complexing agent is disodium edetate.

[0014] As a third limitation of the present invention, the stabilizer is propylene glycol, or a mixture of propylene glycol and at least one of polyethylene glycol-300, polyethylene glycol-400 and glycerol.

[0015] The present invention also provides an application of the poultry probenecid solution, wherein the poultry probenecid solution is used for preparing a drug for resisting poultry gout.

[0016] As a further limitation of the present invention, the anti-avian gout drug is used in combination with an antibiotic.

[0017] Due to the adoption of the above technical solution, the present invention has the following beneficial effects compared with the prior art:

[0018] The raw materials of the poultry probenecid solution of the present invention are a cosolvent, an antioxidant, a chelating agent and a stabilizer in a specific dosage ratio. The drug used for preparing the anti-poultry gout drug has the advantages of accurate dosage, good safety, convenient storage and use, and faster effect and lower cost compared with diuretic and detumescent Chinese herbal medicines, discontinuation of sulfonamide drugs and reduction of calcium content in feed.

[0019] The poultry probenecid solution of the present invention uses sodium hydroxide as a cosolvent. When the weight ratio of sodium hydroxide to probenecid and a complexing agent is 15-20:100-200:0.1-0.4, the three are synergistically enhanced, so that the probenecid dissolution effect is better. The antioxidant added to the raw materials of the poultry probenecid solution of the present invention can effectively prevent the oxidation reaction of probenecid. Compared with the commonly used medicinal water-soluble antioxidants such as sodium bisulfite, sodium pyrosulfite and sodium thiosulfate, the anhydrous sodium sulfite aqueous solution used in the present invention is alkaline and can be used in coordination with a solution system containing sodium hydroxide. When the weight ratio of anhydrous sodium sulfite to sodium hydroxide and probenecid is 1-3:15-20:100-200, the oxidation reaction of probenecid can be more effectively prevented during the dissolution process.

[0020] The poultry probenecid solution of the present invention selects disodium edetate as a chelating agent. Compared with chelating agents such as calcium sodium edetate, citric acid, tartaric acid, etc., when the weight ratio of disodium edetate to probenecid is 0.1-0.4:100-200, disodium edetate and metal ions fully undergo chelation, thereby effectively avoiding the catalytic oxidation of probenecid by metal ions in the solution. Compared with chelating agents such as sodium salt of ethylenediaminetetraacetic acid, disodium edetate is combined with probenecid, an antioxidant, and a stabilizer containing propylene glycol to make the poultry probenecid solution more stable and more suitable for long-term storage.

[0021] When the stabilizer of the poultry probenecid solution contains propylene glycol, the stability of the probenecid solution can be significantly improved, the crystallization point can be reduced, the probenecid solution does not crystallize under low temperature, and the stability of the solution is maintained; and the propylene glycol has low cost, is safe, non-toxic and low irritation; the properties and content of the prepared probenecid solution meet the product quality standards and are more suitable for long-term storage. DETAILED DESCRIPTION

[0022] The present invention is further described in detail below through specific embodiments. It should be understood that the described embodiments are only used to explain the present invention, and are not intended to limit the present invention.

[0023] Example 1 A probenecid solution RY1 for poultry

[0024] This example is a probenecid solution for poultry, denoted as RY1. The raw materials for making the active ingredient of 1000 ml RY1 are as follows:

[0025] Table 1RY1 Raw materials

[0026]

[0027]

[0028] A poultry probenecid solution RY1 was divided into three groups placed upright, inverted and sideways for stability testing: each group was placed at a temperature of 40°C and a relative humidity of 75% for 7 months for accelerated testing. During the test, samples were taken at the end of the 0th month, 1st month, 2nd month, 3rd month, 6th month and 7th month to test the properties, microbial limits and stability of probenecid content, as follows:

[0029] (I) Product properties testing

[0030] Record the solution color and state by observing the appearance.

[0031] (II) Microbial limit detection

[0032] The microbial count method (Appendix 1105 of the Pharmacopoeia 2015 Edition) and the control bacteria inspection method (Appendix 1105 of the Pharmacopoeia 2015 Edition) are used to determine the microbial limits of the samples to be tested; referring to the microbial limit standards for non-sterile veterinary drugs in Appendix 1107 of the Pharmacopoeia 2015 Edition, the limit requirements for microbial content are: aerobic bacteria shall not exceed 100 cfu / mL, the total number of molds shall not exceed 100 cfu / mL, and Escherichia coli shall not be detected.

[0033] (III) Probenecid content detection

[0034] Take 2mL of 0.1mol / L hydrochloric acid solution in a volumetric flask, add anhydrous ethanol, and dilute to 100mL to obtain an ethanol solution containing hydrochloric acid;

[0035] Take 2 mL of the sample to be tested, dilute to 100 mL with ethanol solution containing hydrochloric acid to obtain a diluent; then take 1 mL of the diluent and place it in a 100 mL volumetric flask, add ethanol solution containing hydrochloric acid to dilute to the mark, and shake well to obtain a test solution; use a UV-visible spectrophotometer to measure the absorbance of the test solution at a wavelength of 249 nm, probenecid C 13 H 19 The absorption coefficient of NO4S is 338, and the probenecid content is further calculated based on the absorbance.

[0036] The results are as follows:

[0037] Table 2 Stability test results of poultry probenecid solution RY1 positive group

[0038]

[0039] Table 3 Stability test results of poultry probenecid solution RY1 inversion group

[0040]

[0041] Table 4 Stability test results of poultry probenecid solution RY1 side-placed group

[0042]

[0043] It can be seen from Tables 2 to 4 that the poultry probenecid solution RY1 of the present invention shows good stability under the accelerated test conditions, regardless of the placement method, and the appearance and probenecid content of the sample do not show obvious changes, and the microbial limit also meets the requirements.

[0044] Comparative Example 1

[0045] Compared with Example 1, this comparative example only changes the type of raw materials, specifically: an equal amount of sodium bisulfite is used instead of anhydrous sodium sulfite as an antioxidant, and other raw materials and amounts are the same as those in Example 1.

[0046] According to the formula of this comparative example, a solution CK1 containing probenecid was prepared and stability tested. The results are shown in the following table:

[0047] Table 5 Stability test results of solution CK1 containing probenecid

[0048]

[0049] Comparative Example 2

[0050] Compared with Example 1, this comparative example only changes the type of raw materials, specifically: an equal amount of disodium ethylenediaminetetraacetate is used instead of disodium edetate as the complexing agent, and other raw materials and amounts are the same as those in Example 1.

[0051] According to the formula of this comparative example, a solution CK2 containing probenecid was prepared and stability tested. The results are shown in the following table:

[0052] Table 6 Stability test results of solution CK2 containing probenecid

[0053]

[0054]

[0055] Comparative Example 3

[0056] Compared with Example 1, this comparative example only changes the amount of raw materials, and keeps the amount of probenecid unchanged, specifically: the weight ratio of sodium hydroxide to antioxidant, probenecid and complexing agent is changed to 10:5:100:0.6, and other raw materials and amounts are the same as in Example 1.

[0057] According to the formula of this comparative example, a solution CK3 containing probenecid was prepared and stability tested. The results are shown in the following table:

[0058] Table 7 Stability test results of solution CK3 containing probenecid

[0059]

[0060] Comparative Example 4

[0061] Compared with Example 1, this comparative example only changes the amount of raw materials, and keeps the amount of probenecid unchanged, specifically: the weight ratio of sodium hydroxide to antioxidant, probenecid and chelating agent is changed to 25:0.8:100:0.05, and other raw materials and amounts are the same as in Example 1.

[0062] According to the formula of this comparative example, a solution CK4 containing probenecid was prepared and stability tested. The results are shown in the following table:

[0063] Table 8 Stability test results of solution CK4 containing probenecid

[0064]

[0065]

[0066] According to the stability test results of Comparative Examples 1-4, it is shown that the probenecid solution prepared by the raw materials and dosage ratio of the present invention has more outstanding stability. Compared with the use of the antioxidant sodium bisulfite which is acidic after being dissolved in water, the antioxidant selected by the present invention can obtain a product with a relatively stable probenecid content after storage for 7 months; compared with the use of ethylenediaminetetraacetic acid sodium salt as a complexing agent, the combination of disodium edetate with probenecid, antioxidant, and stabilizer containing propylene glycol makes the poultry probenecid solution more stable and more suitable for long-term storage. According to Comparative Examples 3-4, only by using the raw material dosage ratio of the present invention, the poultry probenecid solution obtained has better stability.

[0067] Example 2 A probenecid solution RY2 for poultry

[0068] This example is a probenecid solution for poultry, denoted as RY2. The raw materials for making the active ingredient of 1000 ml of RY2 are as follows:

[0069] Table 9RY2 Raw Materials

[0070] Raw material types Raw material effect Dosage Probenecid(g) API 150 Sodium hydroxide (g) Solvent 15 Anhydrous sodium sulfite (g) Antioxidants 2 Citric acid(g) Complexing agent 0.2 Propylene glycol + glycerol (ml) Stabilizer 50+50 Purified water (ml) Solvents Add to 1000ml

[0071] Example 3 A probenecid solution RY3 for poultry

[0072] This example is a probenecid solution for poultry, denoted as RY3. The raw materials for making the active ingredient of 1000 ml RY3 are as follows:

[0073] Table 10RY3 raw materials

[0074] Raw material types Raw material effect Dosage Probenecid(g) API 200 Sodium hydroxide (g) Solvent 17 Anhydrous sodium sulfite (g) Antioxidants 3 Tartaric acid(g) Complexing agent 0.1 Propylene glycol (ml) Stabilizer 260 Purified water (ml) Solvents Add to 1000ml

[0075] Example 4 A probenecid solution RY4 for poultry

[0076] This example is a probenecid solution for poultry, denoted as RY4. The raw materials for making the active ingredient of 1000 ml of RY4 are as follows:

[0077] Table 11RY4 raw materials

[0078] Raw material types Raw material effect Dosage Probenecid(g) API 175 Sodium hydroxide (g) Solvent 20 Anhydrous sodium sulfite (g) Antioxidants 1 Calcium sodium edetate + tartaric acid (g) Complexing agent 0.1+0.3 Propylene glycol (ml) Stabilizer 300 Purified water (ml) Solvents Add to 1000ml

[0079] Example 5 A probenecid solution RY5 for poultry

[0080] This example is a probenecid solution for poultry, denoted as RY5. The raw materials for making the active ingredient of 1000 ml of RY5 are as follows:

[0081] Table 12RY5 raw materials

[0082] Raw material types Raw material effect Dosage Probenecid(g) API 100 Sodium hydroxide (g) Solvent 18 Anhydrous sodium sulfite (g) Antioxidants 2 Disodium edetate + citric acid + tartaric acid (g) Complexing agent 0.1+0.1+0.05 Propylene glycol (ml) Stabilizer 200 Purified water (ml) Solvents Add to 1000ml

[0083] Stability tests were performed on RY2 to RY5 prepared in Examples 2 to 5 of the present invention, and the results were similar to those in Example 1, indicating that RY2 to RY5 had good stability.

[0084] In other embodiments, in the raw materials for making a probenecid solution for poultry, the stabilizer is a mixture of propylene glycol and at least one of polyethylene glycol-300, polyethylene glycol-400 and glycerol, and testing has shown that all of them have good stability and anti-avian gout effects.

[0085] Example 6 Application of a poultry probenecid solution

[0086] In this example, RY1 prepared in Example 1 was used to prepare an aqueous solution at a mass volume ratio of 1g:10L, and was fed to 2,000 15-day-old Taizhou geese in a farm as an anti-avian gout drug. Among them, some geese in the flock showed symptoms such as loss of appetite, weight loss, lameness, and white loose feces. After dissection, "spotted kidneys" appeared in the kidneys. Goose with severe symptoms had white urate precipitation in the subcutaneous, pericardial, liver and other parts. The local veterinarian confirmed that the sick geese suffered from avian gout.

[0087] The experimental process of using anti-avian gout drugs is recorded as follows:

[0088] (1) Experimental plan:

[0089] Control group: A goose house containing 1,000 geese was provided with 500 mL of drinking water, one bottle in the morning and one bottle in the afternoon. The geese were allowed to drink freely for three hours every day for five consecutive days.

[0090] Experimental group: For a goose house containing 1,000 geese, 50 g of probenecid solution RY1 was taken and added to 500 mL of drinking water to prepare a bottle of anti-avian gout solution. A total of 10 bottles were prepared, one bottle in the morning and one bottle in the afternoon. The geese were allowed to drink freely for three hours every day for 5 consecutive days.

[0091] The mortality rate and joint swelling rate of the geese (number of geese with joint swelling problems / total number of geese) were recorded daily.

[0092] (2) Experimental results:

[0093] Table 13 Anti-avian gout drug use experimental results

[0094]

[0095] The above results show that the control group without any drug reached a peak of death on the second or third day, and then the death rate slowly decreased. Further statistics showed that the death time lasted for 7-10 days, and the mortality rate was high. The probenecid solution RY1 of the present invention is used to prepare anti-avian gout drugs, which has a significant effect on anti-avian gout. After use, the mortality rate and joint swelling rate are significantly reduced. It shows that the use of a poultry probenecid solution of the present invention can significantly reduce the mortality rate of the building house, which can reduce breeding losses.

[0096] The above application of RY2 to RY5 in the present invention has obtained relatively consistent experimental results.

[0097] In other embodiments, a poultry probenecid solution is prepared into an aqueous solution at a mass volume ratio of 1g:10L and used in combination with penicillin and ampicillin as an auxiliary drug for anti-avian gout. Both have obvious therapeutic effects on anti-avian gout, can inhibit the excretion of antibiotics, increase blood drug concentration and maintain it for a long time.

[0098] It should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the above embodiments, those skilled in the art can still modify the technical solutions described in the above embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the scope of protection of the claims of the present invention.

Claims

1. A probenecid solution for poultry, characterized in that: The raw materials for making the effective component per 1000 parts by volume are 100-200 parts by weight of probenecid, 15-20 parts by weight of cosolvent, 1-3 parts by weight of antioxidant, 0.1-0.4 parts by weight of complexing agent, 100-300 parts by volume of stabilizer and the balance of water; The ratio of parts by weight to parts by volume is kg:L.

2. A probenecid solution for poultry according to claim 1, characterized in that: The co-solvent is sodium hydroxide.

3. A poultry probenecid solution according to claim 2, characterized in that: The antioxidant is anhydrous sodium sulfite.

4. A probenecid solution for poultry according to any one of claims 1 to 3, characterized in that: The complexing agent is at least one of calcium sodium edetate, citric acid and tartaric acid.

5. A probenecid solution for poultry according to claim 3, characterized in that: The complexing agent is disodium edetate.

6. A probenecid solution for poultry according to claim 1-3 or 5, characterized in that: The stabilizer is propylene glycol, or a mixture of propylene glycol and at least one of polyethylene glycol-300, polyethylene glycol-400 and glycerol.

7. The use of a probenecid solution for poultry according to any one of claims 1 to 6, characterized in that: The poultry probenecid solution is used for preparing medicines for resisting poultry gout.

8. The use of a probenecid solution for poultry according to claim 7, characterized in that: The drug against avian gout is used in combination with antibiotics.

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