Pharmaceutical composition for preventing and treating cow mastitis and preparation method thereof

Abstract

The present invention discloses a pharmaceutical composition for preventing and treating mastitis in dairy cows and a preparation method thereof, relating to the field of veterinary medicine. The pharmaceutical composition is composed of the following components in weight percentage: 1-10% penicillin antibiotics, 0.5-5% beta-lactamase inhibitors, 0.1-2% corticosteroids, 0.5-10% oily solvents, 1-30% emulsifiers, 0.5-10% stabilizers, 0.1-2% antioxidants, and water. The present invention utilizes the above components to construct a multiphase homogeneous nanoemulsion, effectively improving the stability and bioavailability of the pharmaceutical composition.

Description

Technical Field

[0001] The present invention relates to the technical field of veterinary medicine, in particular to a pharmaceutical composition for preventing and treating cow mastitis and a preparation method thereof. Background Art

[0002] Mastitis in dairy cows is a major challenge in the dairy industry. This common and frequent disease not only leads to a significant drop in milk production in affected cows, but also results in the complete waste of milk, resulting in significant economic losses and material waste. Mastitis occurs when the nipple sphincter relaxes after milking or pumping, allowing pathogenic bacteria to invade the mammary gland.

[0003] The prevention and treatment of mastitis needs to distinguish between the dry period and the lactation period. The development idea of ​​the dry period preparation is long-lasting and long-lasting, while the development idea of ​​the lactation preparation is high efficiency and fast effect, with a shorter drug withdrawal period and a shorter weaning period. Among them, antibiotic treatment is one of the most commonly used means of drug treatment during lactation. At present, relevant lactation breast injection preparations mostly use oily components as dispersants with oily components as the main ingredients. The preparations are made into oily suspensions, and the active ingredients are dispersed in the matrix. For example, Chinese patent CN202110652836.X discloses a compound amoxicillin breast injection added with Ligustrum lucidum extract, and its dispersing matrix is ​​soybean oil. However, this preparation with oily components as dispersants has the disadvantage of low bioavailability, especially after a long period of stillness, there is a concern that the preparation will settle or the active ingredients will be uneven. Summary of the Invention

[0004] The technical problem to be solved by the present invention is to provide a pharmaceutical composition for preventing and treating cow mastitis, wherein the pharmaceutical composition is an oil-in-water nanoemulsion with strong stability and high bioavailability.

[0005] Another technical problem to be solved by the present invention is to provide a method for preparing a pharmaceutical composition for preventing and treating cow mastitis.

[0006] In order to solve the above technical problems, the present invention discloses a pharmaceutical composition for preventing and treating cow mastitis, which is composed of the following components in percentage by weight:

[0007] Penicillin antibiotics 1-10%, β-lactamase inhibitors 0.5-5%, corticosteroids 0.1-2%, oily solvents 0.5-10%, emulsifiers 1-30%, stabilizers 0.5-10%, antioxidants 0.1-2%, and water to make up.

[0008] Among them, the penicillin antibiotics are selected from one or more of ticarcillin and / or its salts, ampicillin and / or its salts, cloxacillin and / or its salts, suracillin and / or its salts, piperacillin and / or its salts, and amoxicillin and / or its salts, but are not limited thereto. Preferably, the penicillin antibiotics are selected from amoxicillin and / or its salts, and more preferably amoxicillin. The dosage of the penicillin antibiotics is 1-10%, exemplified by 1%, 3%, 5%, 7% or 9%, but are not limited thereto. Preferably, the dosage of the penicillin antibiotics is 5-8%.

[0009] Among them, the β-lactamase inhibitor is selected from one or more of clavulanic acid or its salt, sulbactam or its salt, tazobactam or its salt, but is not limited thereto. Preferably, the β-lactamase inhibitor is selected from sulbactam and / or its salt, and more preferably sulbactam. The dosage of the β-lactamase inhibitor is 0.5-5%, exemplified by 0.8%, 1.2%, 1.8%, 2.2%, 3%, 3.5% or 4.4%, but is not limited thereto. Preferably, the dosage of the β-lactamase inhibitor is 1-3%,

[0010] Wherein, the corticosteroid is selected from one or more of hydrocortisone or its salt, betamethasone or its salt, prednisolone or its salt, but is not limited thereto. Preferably, the corticosteroid is selected from prednisolone and / or its salt, more preferably prednisolone. The dosage of the corticosteroid is 0.1%-2%, exemplified by 0.2%, 0.6%, 1.1%, 1.4%, 1.7% or 1.8%, but is not limited thereto. Preferably, the dosage of the corticosteroid is 0.1-0.5%.

[0011] The oily solvent is selected from one or more of isopropyl myristate, triglycerides, vegetable oils (such as soybean oil, peanut oil, jojoba oil, rapeseed oil, etc.), and ethyl oleate, but is not limited thereto. Preferably, isopropyl myristate is selected from the oily solvent. The amount of the oily solvent is 1-10%, exemplified by 2%, 4%, 6%, 8% or 9%, but is not limited thereto. Preferably, the amount of the oily solvent is 1-10%.

[0012] The emulsifier is selected from one or more of a Tween series surfactant (such as Tween 80), gum arabic, poloxamer, soybean lecithin, hydrogenated castor oil, and lecithin, but is not limited thereto. Preferably, the emulsifier is poloxamer. The amount of the emulsifier is 1-30%, exemplified by 2%, 3%, 8%, 12%, 15%, 18%, 22%, or 28%, but is not limited thereto. Preferably, the amount of the emulsifier is 2-15%.

[0013] The stabilizer is selected from lower alcohols or low molecular weight polyethylene glycols, such as, but not limited to, one or more of propylene glycol, glycerol, butylene glycol, ethanol, PEG200, and PEG400. Preferably, PEG400 is selected as the stabilizer. The amount of the stabilizer is 0.5-10%.

[0014] The antioxidant is selected from one or more of BHT, BHA, vitamin E, and propyl gallate, but is not limited thereto. The amount of the antioxidant is 0.1-2%.

[0015] Based on the above formulation, a multi-phase homogeneous and stable nanoemulsion can be constructed. The nanoemulsion also effectively increases the loading capacity of the active ingredients and improves the bioavailability.

[0016] Preferably, in one embodiment of the present invention, the weight ratio of the corticosteroid to the oily solvent is 1:(10-20).

[0017] Preferably, in one embodiment of the present invention, the weight ratio of the oily solvent to the emulsifier is 1:(1.05-3).

[0018] Preferably, in one embodiment of the present invention, the weight ratio of the emulsifier to the stabilizer is (1-3):1.

[0019] Preferably, in one embodiment of the present invention, the water content of the pharmaceutical composition is greater than 60 wt %; more preferably, it is 73-85 wt %.

[0020] Preferably, in one embodiment of the present invention, the pharmaceutical composition for preventing and treating cow mastitis is composed of the following components in percentage by weight:

[0021] Penicillin antibiotics 5-8%, β-lactamase inhibitors 1-3%, corticosteroids 0.1-0.5%, oily solvents 1-10%, emulsifiers 2-15%, stabilizers 0.5-5%, antioxidants 0.1-1%, and water to make up.

[0022] Correspondingly, the present invention also discloses a method for preparing a pharmaceutical composition for preventing and treating cow mastitis, which is used to prepare the above-mentioned pharmaceutical composition for preventing and treating cow mastitis, comprising:

[0023] (1) mixing a corticosteroid, an oily solvent, an emulsifier, an antioxidant, and a stabilizer to obtain a material A;

[0024] (2) taking an equal volume of water to that of material A, adding penicillin antibiotics and β-lactamase inhibitors, and mixing to obtain material B;

[0025] (3) Mix material A and material B, add the remaining water, and mix well to obtain the product.

[0026] In one embodiment of the present invention, a high-pressure homogenizing device is used to mix material A and material B at a mixing temperature of 30-65°C. The mixture is fully mixed until the system becomes clear, transparent or milky white. The remaining water is then added and the mixture is fully stirred at room temperature until the mixture becomes homogeneous.

[0027] The implementation of the present invention has the following beneficial effects:

[0028] The pharmaceutical composition for preventing and treating cow mastitis of the present invention forms a homogeneous and stable multiphase oil-in-water nanoemulsion by combining an oily solvent, an emulsifier, a stabilizer, water, and other active ingredients. This nanoemulsion can increase the solubility of poorly soluble drugs and improve their stability and bioavailability. Furthermore, the nanoemulsion has excellent biocompatibility and is biodegradable, making it suitable as a carrier for both fat-soluble and hydrolysis-sensitive drugs, reducing their irritation and toxic side effects. Furthermore, the nanoemulsion is thermodynamically stable and does not stratify or demulsify even after prolonged storage, making it an ideal carrier for poorly soluble drugs. DETAILED DESCRIPTION

[0029] In order to make the objectives, technical solutions and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with specific implementation methods.

[0030] The drugs used in the Examples and Comparative Examples of the present invention are as follows:

[0031] A: Penicillin antibiotics: ampicillin sodium (A1), amoxicillin (A2), ticarcillin (A3);

[0032] B: β-lactamase inhibitors: clavulanic acid (B1), sulbactam (B2), tazobactam (B3);

[0033] C: Corticosteroids: prednisolone (C1), betamethasone (C2);

[0034] D: Oily solvent: jojoba oil (D1), isopropyl myristate (D2), ethyl oleate (D3);

[0035] E: emulsifier: hydrogenated castor oil (E1), poloxamer (E2), Tween 80 (E3);

[0036] F: Stabilizer: PEG200 (F1), butylene glycol (F2), glycerol (F3);

[0037] G: Antioxidants: BHT (G1), propyl gallate (G2);

[0038] H: Water

[0039] Specifically, the preparation method of the pharmaceutical composition for preventing and treating cow mastitis in the embodiment is as follows:

[0040] (1) mixing a corticosteroid, an oily solvent, an emulsifier, a stabilizer, and an antioxidant to obtain a material A;

[0041] (2) taking an equal volume of water to that of material A, adding penicillin antibiotics and β-lactamase inhibitors, and mixing to obtain material B;

[0042] (3) Material A and material B are mixed using a high-pressure homogenizer at a mixing temperature of 35°C. Mix thoroughly until the system becomes clear and transparent or milky white. Then add the remaining water and stir thoroughly at room temperature (25°C) until the mixture is homogeneous.

[0043] The preparation method of the pharmaceutical composition for preventing and treating cow mastitis in Comparative Examples 1 and 5-7 is as follows: mixing the components with a high-pressure homogenizer at a mixing temperature of 35° C. to obtain the pharmaceutical composition.

[0044] The preparation method of the pharmaceutical composition for preventing and treating cow mastitis in Comparative Examples 2-4 is as follows:

[0045] (1) mixing a corticosteroid, an oily solvent, an emulsifier (if not included in the formula, do not add it), a stabilizer (if not included in the formula, do not add it), and an antioxidant to obtain material A;

[0046] (2) taking an equal volume of water to that of material A, adding penicillin antibiotics and β-lactamase inhibitors, and mixing to obtain material B;

[0047] (3) Material A and material B are mixed using a high-pressure homogenizer at a mixing temperature of 35°C. Mix thoroughly until the system becomes clear and transparent or milky white. Then add the remaining water and stir thoroughly at room temperature (25°C) until the mixture is homogeneous.

[0048] In addition, the present invention also provides a comparative example 8, whose specific formula is the same as that of Example 10, and its specific preparation process is: mixing the components using a high-pressure homogenizer at a mixing temperature of 35° C. to obtain the product.

[0049] Specifically, the group allocation ratios in each embodiment are shown in the following table:

[0050] Table 1 Example formula table

[0051]

[0052] Specifically, the group distribution ratios in each comparative example are shown in the following table:

[0053] Table 2 Comparative Example Formula

[0054]

[0055]

[0056] The pharmaceutical compositions obtained in each example and comparative example were placed in a stoppered transparent test tube, and the physical properties of the preparations were observed. The preparations were then allowed to stand for 7 days, and then observed again to see if there was any stratification. The preparations were then centrifuged at 4000 rpm to see if there were any changes. The specific test results are shown in the following table:

[0057] Table 3 Layered experimental results

[0058]

[0059] As can be seen from the table, after adopting the formula and process of the present invention, there is no stratification after standing for 7 days and centrifugation after standing for 7 days. However, when the formula or process of the present invention is changed, stratification occurs and the stability is poor.

[0060] Furthermore, the pharmaceutical compositions prepared in Examples 3 to 9 were subjected to stability tests. The specific test protocol is as follows:

[0061] The samples simulated commercial packaging and were placed under specific conditions (30±2°C, 60±5% RH) for 6 months. Stability was investigated by sampling at 0 days, 1 month, 3 months and 6 months.

[0062] Table 4 Stability test results

[0063]

[0064] In addition, the pharmaceutical composition prepared in Example 10 was used for clinical trials. The specific test method is as follows:

[0065] 1. Experimental location: a cattle farm near Beijing.

[0066] 2. Experimental animals: A number of experimental cows with obvious symptoms of dairy cow mastitis as identified by a licensed veterinarian.

[0067] 3. Trial Methods: Each treated udder served as an independent case. After selecting a case, the patient's age, calving date, parity, and udder lesion status were recorded. During the trial, the infected area was cleaned and disinfected, and milk was expressed. A single bolus tube containing the drug was then inserted into the udder. The plunger was gently advanced, and the entire contents of the tube were slowly pushed into the udder. This was administered twice daily (12 hours apart) for three consecutive days. Milk samples were collected before dosing and on days 7 and 14 after dosing to determine somatic cell counts and determine mastitis treatment efficacy (SCCs less than 1 million / ml). A control group was also established using the same experimental methods as the experimental group, with the drug administered as a commercially available oily suspension formulation of the same composition. The clinical cure rate for both groups was calculated (number of effective cases / total number of cases x 100%).

[0068] 2-4 Test Results

[0069]

[0070] It can be seen from the table that the clinical cure rate of the experimental group is 77.8%, and that of the control group is 60%. The therapeutic effect of the experimental group is better than that of the control group.

[0071] The above is a preferred embodiment of the 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 invention. These improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for preventing and treating mastitis in dairy cows, characterized in that: It is composed of the following components in percentage by weight: Penicillin antibiotics 1-10%, β-lactamase inhibitors 0.5-5%, corticosteroids 0.1-2%, oily solvents 0.5-10%, emulsifiers 1-30%, stabilizers 0.5-10%, antioxidants 0.1-2%, water to make up; The weight ratio of the corticosteroid to the oily solvent is 1:(10-20), the weight ratio of the oily solvent to the emulsifier is 1:(1.05-3), and the weight ratio of the emulsifier to the stabilizer is (1-3):1; Wherein, the oily solvent is selected from isopropyl myristate or ethyl oleate; The emulsifier is selected from one of Tween 80, poloxamer, and hydrogenated castor oil; The stabilizer is selected from one of glycerol, butylene glycol, and PEG200; The water content of the pharmaceutical composition is greater than 60 wt%.

2. The pharmaceutical composition for preventing and treating cow mastitis according to claim 1, wherein The penicillin antibiotic is selected from one or more of ticarcillin or its salt, ampicillin or its salt, cloxacillin or its salt, suracillin or its salt, piperacillin or its salt, and amoxicillin or its salt; The β-lactamase inhibitor is selected from one or more of clavulanic acid or its salt, sulbactam or its salt, and tazobactam or its salt.

3. The pharmaceutical composition for preventing and treating cow mastitis according to claim 1, wherein The water content of the pharmaceutical composition is 73-85 wt %.

4. The pharmaceutical composition for preventing and treating cow mastitis according to claim 1, wherein It is composed of the following components in percentage by weight: Penicillin antibiotics 5-8%, β-lactamase inhibitors 1-3%, corticosteroids 0.1-0.5%, oily solvents 1-10%, emulsifiers 2-15%, stabilizers 0.5-5%, antioxidants 0.1-1%, and water to make up.

5. A method for preparing the pharmaceutical composition for preventing and treating cow mastitis according to any one of claims 1 to 4, characterized in that: include: (1) mixing a corticosteroid, an oily solvent, an emulsifier, an antioxidant, and a stabilizer to obtain a material A; (2) taking an equal volume of water to that of material A, adding penicillin antibiotics and β-lactamase inhibitors, and mixing to obtain material B; (3) Mix material A and material B, add the remaining water, and mix well to obtain the product.

Images