Albendazole and ivermectin premix and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary drugs, and particularly relates to an albendazole and ivermectin premix and a preparation method thereof. The albendazole and ivermectin premixing agent is prepared from the following raw materials in parts by weight: 5 to 10 parts of albendazole, 0.1 to 0.2 part of ivermectin, 8 to 15 parts of modified carboxymethyl cellulose, 5 to 10 parts of sodium pyruvate, 2 to 10 parts of lauryl sodium sulfate, 1 to 5 parts of sodium citrate, 10 to 20 parts of glucose and 60 to 70 parts of beta-cyclodextrin. The modified carboxymethyl cellulose and the sodium pyruvate in the premix can achieve a synergistic effect, and the redispersibility and the bioavailability of the albendazole and the ivermectin in the premix are further improved, so that the drug effect is improved. 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 an important factor affecting animal health and growth. Parasites not only cause slow growth, indigestion, and decreased immunity of animals, but also increase breeding costs and reduce breeding benefits.

[0003] Albendazole and ivermectin are two commonly used antiparasitic drugs. Albendazole is a white or off-white powder, odorless, tasteless, insoluble in water, but soluble in glacial acetic acid. It has a broad-spectrum anthelmintic activity and can effectively expel a variety of nematodes, trematodes and tapeworms. However, due to its insoluble nature in water, the bioavailability of albendazole is low, which limits the effectiveness of its drug. Ivermectin is a broad-spectrum, highly effective antiparasitic drug that has a good expelling and killing effect on parasites inside and outside the body. The combination of albendazole and ivermectin can play their complementary roles, broaden the scope 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 the drug is administered in mixed feeding, uneven administration or insufficient administration is prone to occur, affecting the drug effect or poisoning accidents.

[0004] Traditional premix preparation methods often have problems such as unstable drug components, low solubility, and poor bioavailability, which affect the efficacy and safety of the drug. Therefore, how to prepare an albendazole and ivermectin premix with high stability and good dispersibility has always been a difficult problem in the field of 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] The 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 according to the above weight proportions 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;

[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 mixed solution.

[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 is added with 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 synergistic effect of the modified carboxymethyl cellulose and sodium pyruvate can improve the dispersibility and stability of the albendazole ivermectin premix in water, thereby improving its bioavailability and enhancing the efficacy.

[0022] 2. The present invention adopts high-speed shearing and high-pressure homogenization when preparing the albendazole ivermectin premix, further improving the uniform distribution of the drug components in the premix and improving 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 embodiments described below or the technical features can be arbitrarily combined to form new embodiments. The specific conditions not specified in the embodiments are carried out according to conventional conditions or conditions recommended by the manufacturer. The 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: first, ethanol and water are mixed at 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 at a mass ratio of 1:1.2:0.3, heated at 95°C and stirred for 2h, filtered, solids are collected, washed, and dried to obtain 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 in a mass ratio of albendazole to glacial acetic acid of 1:10, 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;

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

[0030] Example 2

[0031] An albendazole-ivermectin premix comprises 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: first, ethanol and water are mixed at 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 at a mass ratio of 1:1:0.2, heated at 80°C and stirred for 3h, filtered, solids are collected, washed, and dried to obtain 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 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;

[0035] (2) Add the mixed solution A dropwise to the mixed solution B and perform shearing at 8500 rpm for 20 min; and perform high pressure (60 MPa) homogenization for 30 min to obtain a mixed solution C, and spray dry the mixed solution C, and set the inlet air temperature of the spray granulator to 80°C and the inlet air frequency 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: first, ethanol and water are mixed at 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 at a mass ratio of 1:0.8:0.1, heated and stirred at 70°C for 5 hours, filtered, solids are collected, washed, and dried to obtain 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 albendazole to glacial acetic acid 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 perform high pressure (50 MPa) homogenization for 50 min to obtain a mixed solution C, and spray dry the mixed solution C, and set the inlet air temperature of the spray granulator to 75°C and the inlet air frequency 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 beta-cyclodextrin; the rest is consistent with 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 parts are consistent with 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 beta-cyclodextrin; other parts are consistent with 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 parts are consistent with 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] Weigh the above samples separately and add them into water to prepare a suspension with a concentration of 2.5%. Let it stand for 20 hours. Record how many times each group of samples can return to the initial suspension state after being inverted in the test tube. The experimental results are recorded in Table 1.

[0053] Table 1

[0054]

[0055]

[0056] From the experimental results of Table 1, it can be seen that the premix of the present invention has good redispersibility in water, wherein the suspension prepared by the product of Example 1 can return to the initial suspension state after standing for 20 hours by inverting 3 times; Comparative Example 1 replaces modified carboxymethyl cellulose with carboxymethyl cellulose and basic calcium phosphate, Comparative Example 2 omits the addition of sodium pyruvate (containing modified carboxymethyl cellulose), Comparative Example 3 omits the modified carboxymethyl cellulose to adjust the amount of sodium pyruvate, and Comparative Example 4 omits the sodium pyruvate to adjust the amount of modified carboxymethyl cellulose, and the redispersibility of the premix is ​​reduced. This shows that the synergistic effect of modified carboxymethyl cellulose and sodium pyruvate can improve the dispersibility of the albendazole ivermectin premix in water.

[0057] Test Example 2

[0058] Ivermectin content uniformity test

[0059] According to the inspection method of content uniformity of "Chinese Veterinary Pharmacopoeia" (2020 edition), each group of samples of Examples 1-3 and Comparative Examples 1-4 is tested (10 samples are taken in each group). Specifically as follows: take each group of samples (about 20 mg of ivermectin content) and place them in a 100mL measuring bottle, add an appropriate amount of methanol, shake and shake to dissolve ivermectin, dilute to the scale with methanol, measure by liquid chromatograph, and take ivermectin as a reference substance and measure it by 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 in the market 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, respectively. 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, and the experimental results are recorded in Table 3.

[0067] Table 3

[0068]

[0069]

[0070] It can be seen from the experimental results in Table 3 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-mentioned 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 substitutions made by technicians in this field on the basis of the present invention shall 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 fiber, 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.

2. The albendazole-ivermectin premix according to claim 1, characterized in that: The preparation process of the modified carboxymethyl cellulose is as follows: carboxymethyl cellulose, dodecanoic acid and basic calcium phosphate are added into an aqueous solution of ethanol, heated and stirred, filtered, washed and dried to obtain the modified carboxymethyl cellulose.

3. The albendazole-ivermectin premix according to claim 2, characterized in that: The mass ratio of the carboxymethyl cellulose, dodecanoic acid and basic calcium phosphate is 1:(0.8-1.2):(0.1-0.3).

4. The albendazole-ivermectin premix according to claim 2, characterized in that: The heating temperature is 70-95° C. and the heating time is 2-5 hours.

5. The albendazole-ivermectin premix according to claim 2, characterized in that: The ethanol aqueous solution is obtained by mixing ethanol and water in a volume ratio of (3-5):

1.

6. The method for preparing the albendazole-ivermectin premix according to claim 1, characterized in that: The following steps are involved: (1) adding albendazole and ivermectin to glacial acetic acid according to the above weight proportions 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; (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, and spray-drying the mixed solution C to obtain a mixed solution.

7. The method for preparing the albendazole-ivermectin premix according to claim 6, characterized in that: In step (1), the mass ratio of albendazole to glacial acetic acid is 1:(10-12).

8. The method for preparing the albendazole-ivermectin premix according to claim 6, characterized in that: In step (2), the pressure of the high-pressure homogenization is 50-60 MPa, and the homogenization time is 30-50 min.

9. The method for preparing the albendazole-ivermectin premix according to claim 6, characterized in that: In step (2), the shearing condition is 7500-8500 rpm and the time is 15-20 min.

10. The method for preparing the albendazole-ivermectin premix according to claim 6, characterized in that: 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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