Albendazole and ivermectin premix and preparation method thereof

Abstract

The invention belongs to the field of veterinary drug technology, and in particular to a kind of albendazole ivermectin premix and preparation method thereof.The albendazole ivermectin premix includes the following raw materials in parts by weight: 5-10 parts of albendazole, 0.1-0.2 parts of ivermectin, 8-15 parts of modified carboxymethyl cellulose, 5-10 parts of sodium pyruvate, 2-10 parts of sodium lauryl sulfate, 1-5 parts of sodium citrate, 10-20 parts of glucose, and 60-70 parts of beta-cyclodextrin.The modified carboxymethyl cellulose and sodium pyruvate in the premix can act synergistically, further improving the redispersibility and bioavailability of albendazole and ivermectin in the premix, thereby improving drug efficacy.In addition, the premix also has good stability and can be stored for a long time.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs, and particularly relates to an albendazole and ivermectin premix and a preparation method thereof. Background Art

[0002] In veterinary medicine and animal husbandry, parasitic diseases are a major factor affecting animal health and growth. Parasites not only lead to slow growth, indigestion, and decreased immunity, but also increase breeding costs and reduce breeding efficiency.

[0003] Albendazole and ivermectin are two commonly used antiparasitic drugs. Albendazole is a white or off-white powder that is odorless and tasteless and insoluble in water, but soluble in glacial acetic acid. It has broad-spectrum anthelmintic activity and can effectively expel a variety of nematodes, flukes, and tapeworms. However, due to its water insolubility, albendazole has a low bioavailability, which limits its efficacy. Ivermectin is a broad-spectrum, highly effective antiparasitic drug that has a good expelling and killing effect on both internal and external parasites. The combined use of albendazole and ivermectin can bring out their complementary effects, broaden the range of anthelmintics, and improve the anthelmintic effect. However, the albendazole-ivermectin premix is a hydrophobic drug that is difficult to disperse in water and cannot be administered through drinking water. When administered through mixed feed, uneven administration or insufficient dosage is prone to occur, affecting the drug's efficacy or causing poisoning accidents.

[0004] Traditional premix preparation methods often suffer from issues such as unstable drug components, low solubility, and poor bioavailability, which compromise the efficacy and safety of the drugs. Therefore, developing a highly stable and well-dispersed albendazole / ivermectin premix has long been a challenge in veterinary drug research and development. Summary of the Invention

[0005] In order to overcome the deficiencies of the prior art, one of the objects of the present invention is to provide an albendazole-ivermectin premix.

[0006] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 5-10 parts of albendazole, 0.1-0.2 parts of ivermectin, 8-15 parts of modified carboxymethyl cellulose, 5-10 parts of sodium pyruvate, 2-10 parts of sodium lauryl sulfate, 1-5 parts of sodium citrate, 10-20 parts of glucose, and 60-70 parts of beta-cyclodextrin.

[0007] Furthermore, the preparation process of the modified carboxymethyl cellulose is as follows: carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate are added to an aqueous solution of ethanol, heated and stirred, filtered, washed, and dried to obtain the modified carboxymethyl cellulose.

[0008] Furthermore, the mass ratio of the carboxymethyl cellulose, dodecanoic acid and basic calcium phosphate is 1:(0.8-1.2):(0.1-0.3).

[0009] Furthermore, the heating temperature is 70-95° C., and the heating time is 2-5 hours.

[0010] Furthermore, the ethanol aqueous solution is obtained by mixing ethanol and water in a volume ratio of (3-5):1.

[0011] A second object of the present invention is to provide a method for preparing an albendazole-ivermectin premix.

[0012] The second object of the present invention is achieved by adopting the following technical solution:

[0013] The preparation method of albendazole-ivermectin premix comprises the following steps:

[0014] (1) mixing albendazole, ivermectin and glacial acetic acid in the aforementioned proportions by weight to obtain a mixed solution A; and mixing sodium lauryl sulfate, sodium citrate, glucose, modified carboxymethyl cellulose, sodium pyruvate, β-cyclodextrin and water to obtain a mixed solution B;

[0015] (2) Adding the mixed solution A dropwise to the mixed solution B and subjecting the mixed solution to high-speed shearing and high-pressure homogenization to obtain a mixed solution, and spray drying the mixed solution to obtain a product.

[0016] Furthermore, in step (1), the mass ratio of albendazole to glacial acetic acid is 1:(10-12).

[0017] Furthermore, in step (2), the high-pressure homogenization condition is 50-60 MPa, and the homogenization time is 30-50 min.

[0018] Furthermore, in step (2), the shearing condition is 7500-8500 rpm and the time is 15-20 min.

[0019] Furthermore, in step (2), during the granulation process, the air inlet temperature of the spray granulator is set to 75-85° C. and the air inlet frequency is set to 40-50 Hz.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. The albendazole-ivermectin premix provided by the present invention contains modified carboxymethyl cellulose and sodium pyruvate, wherein the modified carboxymethyl cellulose is prepared by modifying carboxymethyl cellulose with dodecanoic acid and basic calcium phosphate, and the sodium pyruvate has good water solubility and biological activity. The modified carboxymethyl cellulose and sodium pyruvate act synergistically to enhance the dispersibility and stability of the albendazole-ivermectin premix in water, thereby improving its bioavailability and enhancing its efficacy.

[0022] 2. The present invention uses high-speed shearing and high-pressure homogenization when preparing the albendazole and ivermectin premix, further improving the uniform distribution of the drug components in the premix and increasing the bioavailability of the drug. At the same time, the method can also simplify the preparation steps and improve production efficiency. DETAILED DESCRIPTION

[0023] Below, in conjunction with specific embodiments, the present invention is further described. It should be noted that, under the premise of no conflict, the various embodiments described below or the various technical features can be arbitrarily combined to form new embodiments. Specific conditions not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are conventional products obtained through commercial channels.

[0024] Example 1

[0025] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 10 parts of albendazole, 0.2 parts of ivermectin, 15 parts of modified carboxymethyl cellulose, 10 parts of sodium pyruvate, 10 parts of sodium lauryl sulfate, 5 parts of sodium citrate, 20 parts of glucose, and 70 parts of beta-cyclodextrin.

[0026] The preparation process of the modified carboxymethyl cellulose is as follows: ethanol and water are first mixed in a volume ratio of 5:1 to obtain an ethanol aqueous solution, and then carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate are added to the ethanol aqueous solution in a mass ratio of 1:1.2:0.3, heated at 95°C with stirring for 2 hours, filtered, and the solid is collected, washed, and dried to obtain the modified carboxymethyl cellulose.

[0027] The preparation method of the above-mentioned albendazole-ivermectin premix comprises the following steps:

[0028] (1) Weighing the raw materials according to the above weight parts for use; adding albendazole to glacial acetic acid at a mass ratio of 1:10, stirring and dissolving, and then adding ivermectin to obtain a mixed solution A; mixing sodium lauryl sulfate, sodium citrate, glucose, modified carboxymethyl cellulose, sodium pyruvate, β-cyclodextrin and water to obtain a mixed solution B;

[0029] (2) Add the mixed solution A dropwise to the mixed solution B and perform shearing at 8500 rpm for 20 min; and homogenize under high pressure (55 MPa) for 40 min to obtain the mixed solution C, which is spray-dried. The air inlet temperature of the spray granulator is set to 85°C and the air inlet frequency is set to 50 Hz.

[0030] Example 2

[0031] The invention discloses an albendazole-ivermectin premix, comprising the following raw materials in parts by weight: 7 parts of albendazole, 0.1 parts of ivermectin, 10 parts of modified carboxymethyl cellulose, 7 parts of sodium pyruvate, 6 parts of sodium lauryl sulfate, 3 parts of sodium citrate, 15 parts of glucose and 65 parts of beta-cyclodextrin.

[0032] The preparation process of the modified carboxymethyl cellulose is as follows: ethanol and water are first mixed in a volume ratio of 4:1 to obtain an ethanol aqueous solution, and then carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate are added to the ethanol aqueous solution in a mass ratio of 1:1:0.2, heated at 80°C with stirring for 3 hours, filtered, and the solid is collected, washed, and dried to obtain the modified carboxymethyl cellulose.

[0033] The preparation method of the above-mentioned albendazole-ivermectin premix comprises the following steps:

[0034] (1) Weighing the raw materials according to the above weight parts for use; adding albendazole to glacial acetic acid in a mass ratio of 1:11, stirring and dissolving, and then adding ivermectin to obtain a mixed solution A; mixing sodium lauryl sulfate, sodium citrate, glucose, modified carboxymethyl cellulose, sodium pyruvate, β-cyclodextrin and water to obtain a mixed solution B;

[0035] (2) Add the mixed solution A dropwise to the mixed solution B and perform shearing at 8500 rpm for 20 min; and homogenize under high pressure (60 MPa) for 30 min to obtain the mixed solution C, which is spray-dried. The air inlet temperature of the spray granulator is set to 80°C and the air inlet frequency is set to 45 Hz.

[0036] Example 3

[0037] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 5 parts of albendazole, 0.1 parts of ivermectin, 8 parts of modified carboxymethyl cellulose, 5 parts of sodium pyruvate, 2 parts of sodium lauryl sulfate, 1 part of sodium citrate, 10 parts of glucose, and 60 parts of beta-cyclodextrin.

[0038] The preparation process of the modified carboxymethyl cellulose is as follows: ethanol and water are first mixed in a volume ratio of 3:1 to obtain an ethanol aqueous solution, and then carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate are added to the ethanol aqueous solution in a mass ratio of 1:0.8:0.1, heated at 70°C with stirring for 5 hours, filtered, and the solid is collected, washed, and dried to obtain the modified carboxymethyl cellulose.

[0039] The preparation method of the above-mentioned albendazole-ivermectin premix comprises the following steps:

[0040] (1) Weighing the raw materials according to the above weight parts for use; adding albendazole to glacial acetic acid in a mass ratio of 1:12, stirring to dissolve, and then adding ivermectin to obtain a mixed solution A; mixing sodium lauryl sulfate, sodium citrate, glucose, modified carboxymethyl cellulose, sodium pyruvate, β-cyclodextrin and water to obtain a mixed solution B;

[0041] (2) Add the mixed solution A dropwise to the mixed solution B and perform shearing at 7500 rpm for 15 min; and homogenize under high pressure (50 MPa) for 50 min to obtain the mixed solution C, which is spray-dried. The air inlet temperature of the spray granulator is set to 75°C and the air inlet frequency is set to 40 Hz.

[0042] Comparative Example 1

[0043] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 10 parts of albendazole, 0.2 parts of ivermectin, 6 parts of carboxymethyl cellulose, 1.8 parts of basic calcium phosphate, 10 parts of sodium pyruvate, 10 parts of sodium lauryl sulfate, 5 parts of sodium citrate, 20 parts of glucose, and 70 parts of β-cyclodextrin; other ingredients are the same as those in Example 1.

[0044] Comparative Example 2

[0045] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 10 parts of albendazole, 0.2 parts of ivermectin, 15 parts of modified carboxymethyl cellulose, 10 parts of sodium lauryl sulfate, 5 parts of sodium citrate, 20 parts of glucose, and 70 parts of beta-cyclodextrin; other ingredients are the same as those in Example 1.

[0046] Comparative Example 3

[0047] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 10 parts of albendazole, 0.2 parts of ivermectin, 25 parts of sodium pyruvate, 10 parts of sodium lauryl sulfate, 5 parts of sodium citrate, 20 parts of glucose, and 70 parts of β-cyclodextrin; other ingredients are the same as those in Example 1.

[0048] Comparative Example 4

[0049] An albendazole-ivermectin premix comprises the following raw materials in parts by weight: 10 parts of albendazole, 0.2 parts of ivermectin, 25 parts of modified carboxymethyl cellulose, 10 parts of sodium lauryl sulfate, 5 parts of sodium citrate, 20 parts of glucose, and 70 parts of beta-cyclodextrin; other ingredients are the same as those in Example 1.

[0050] Test Example 1

[0051] Test the dispersibility of the samples of Examples 1-3 and Comparative Examples 1-4 in water

[0052] The above samples were weighed separately and added to water to prepare a suspension with a concentration of 2.5%. The suspension was allowed to stand for 20 hours. The number of times each group of samples could return to the initial suspension state after being inverted in the test tube was recorded. The experimental results are recorded in Table 1.

[0053] Table 1

[0054]

[0055]

[0056] As can be seen from the experimental results of Table 1, the redispersibility of the premix of the present invention in water is better, wherein the suspension prepared by the product of Example 1 is inverted 3 times after standing for 20h to return to the initial suspension state; Comparative Example 1 replaces modified carboxymethyl cellulose with carboxymethyl cellulose and basic calcium phosphate, Comparative Example 2 eliminates the addition of sodium pyruvate (containing modified carboxymethyl cellulose), Comparative Example 3 eliminates the amount of modified carboxymethyl cellulose to adjust sodium pyruvate, and Comparative Example 4 eliminates the amount of sodium pyruvate to adjust modified carboxymethyl cellulose, and the redispersibility of the premix all decreases. This shows that the synergistic effect of modified carboxymethyl cellulose and sodium pyruvate can improve the dispersibility of albendazole ivermectin premix in water.

[0057] Test Example 2

[0058] Ivermectin content uniformity test

[0059] According to the inspection means of content uniformity of "Chinese Veterinary Pharmacopoeia" (2020 edition), each group of samples of Example 1-3 and Comparative Example 1-4 is detected (10 samples are taken in each group). Specifically as follows: take each group of samples (ivermectin content is about 20mg) and place it in a 100mL measuring flask, add an appropriate amount of methanol, shake and shake to dissolve ivermectin, dilute to the scale mark with methanol, measure by liquid chromatograph, and take ivermectin as a reference substance and measure it using the same method. Determine the relative content X with the labeled amount as 100, calculate its mean X and standard deviation S and the absolute value A (A=|100-X|) of the difference between the labeled amount and the mean, if the mixing uniformity A+2.20S≤15.0, it meets the requirements, if A+S>15.0, it does not meet the requirements; the results are recorded in Table 2.

[0060] Table 2

[0061]

[0062]

[0063] It can be seen from the experimental results in Table 2 that the ivermectin uniformity of the samples of Examples 1-3 meets the requirements, while the ivermectin uniformity of the samples of Comparative Examples 1 to 4 does not meet the requirements.

[0064] Test Example 3

[0065] Stability test

[0066] According to Appendix 9001 of Part 1 of the 2020 edition of the Chinese Pharmacopoeia of Veterinary Medicine, the premixes of Examples 1-3 and Comparative Examples 1-4 were packaged as sold and placed in a constant temperature and humidity chamber at 40±2°C and 75±5% for accelerated testing. Samples were taken for testing at the end of the 1st, 2nd, 3rd, and 6th months, and the appearance and content of the premixes under high temperature and high humidity conditions (the results of liquid phase analysis according to the detection method for albendazole and ivermectin in the Chinese Pharmacopoeia of Veterinary Medicine) were tested. The experimental results are recorded in Table 3.

[0067] Table 3

[0068]

[0069]

[0070] From the experimental results in Table 3, it can be seen that under the accelerated conditions of 6 months, the appearance of the premix of each group of samples of Examples 1-3 and Comparative Examples 1-4 still showed white granules without obvious changes, and the contents of albendazole and ivermectin met the requirements.

[0071] The above embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and replacements made by technicians in this field on the basis of the present invention fall within the scope of protection required by the present invention.

Claims

1. An albendazole-ivermectin premix, characterized in that: The invention comprises the following raw materials in parts by weight: 5-10 parts of albendazole, 0.1-0.2 parts of ivermectin, 8-15 parts of modified carboxymethyl cellulose, 5-10 parts of sodium pyruvate, 2-10 parts of sodium lauryl sulfate, 1-5 parts of sodium citrate, 10-20 parts of glucose, and 60-70 parts of beta-cyclodextrin; The preparation process of the modified carboxymethyl cellulose is as follows: carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate are added to an aqueous solution of ethanol, heated and stirred, filtered, washed, and dried to obtain the modified carboxymethyl cellulose; The mass ratio of the carboxymethyl cellulose, dodecanoic acid, and basic calcium phosphate is 1:(0.8-1.2):(0.1-0.3); the heating temperature is 70-95°C, and the heating time is 2-5 hours; the ethanol aqueous solution is obtained by mixing ethanol and water in a volume ratio of (3-5):

1.

2. The method for preparing the albendazole-ivermectin premix according to claim 1, wherein The following steps are involved: (1) adding albendazole and ivermectin to glacial acetic acid in the aforementioned parts by weight to obtain a mixed solution A; wherein the mass ratio of albendazole to glacial acetic acid is 1:(10-12); and mixing sodium lauryl sulfate, sodium citrate, glucose, modified carboxymethyl cellulose, sodium pyruvate, β-cyclodextrin, and water to obtain a mixed solution B; (2) Adding the mixed solution A dropwise to the mixed solution B and subjecting the mixed solution to high-speed shearing and high-pressure homogenization to obtain a mixed solution C, which is then spray-dried.

3. The preparation method of the albendazole-ivermectin premix according to claim 2, wherein In step (2), the pressure of the high-pressure homogenization is 50-60 MPa, and the homogenization time is 30-50 min.

4. The preparation method of the albendazole-ivermectin premix according to claim 2, wherein In step (2), the shearing condition is 7500-8500 rpm and the time is 15-20 min.

5. The preparation method of the albendazole-ivermectin premix according to claim 2, wherein In step (2), the spray drying conditions are: air inlet temperature is 75-85°C; air inlet frequency is 40-50Hz.

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