Preparation method of ivermectin aqueous solution

Abstract

The invention provides a preparation method of an ivermectin aqueous solution, and relates to the technical field of ivermectin oral liquid. The ivermectin aqueous solution is composed of ivermectin, a surfactant, cholesterol, phospholipid, soybean oil for injection, castor oil and vitamin E. The ivermectin is dissolved in a solvent and then mixed with the cholesterol and the phospholipid to prepare microemulsion, and then the microemulsion is mixed with the soybean oil for injection, the castor oil and the vitamin E. And then carrying out variable-temperature dropwise adding mixing and variable-pressure stirring treatment on the mixed solution and purified water to obtain a high-stability ivermectin aqueous solution. The ivermectin oral liquid overcomes the defects in the prior art, ivermectin is mixed with a small amount of oil and a large amount of water to prepare the high-stability oral liquid, the safety of the oral liquid is guaranteed, the stability of the oral liquid is improved, and the use effect is comprehensively improved.

Description

Technical Field

[0001] The invention relates to the technical field of ivermectin oral liquid, and in particular to a method for preparing an ivermectin aqueous solution. Background Art

[0002] Ivermectin is a very common type of veterinary drug on the market. It plays a certain role in promoting the prevention and treatment of animal diseases in animal husbandry. The commercially available dosage forms of ivermectin include injections, emulsions, transdermal preparations, premixes, liposomes, pour-ons, tablets, sustained-release boluses and oral solutions, among which oral solutions are a dosage form that is more convenient to use.

[0003] Existing ivermectin oral liquids are widely used in animals such as cattle, horses, pigs, dogs, rabbits and poultry. Although this type of preparation has the characteristics of simple production process and simple use of the drug, most ivermectin oral liquids use oil as a solvent, and the overall cost is relatively high. Due to the poor water solubility of ivermectin, there are few ivermectin oral liquids that use water as a solvent.

[0004] Patent No. 201410793149.X discloses "a water-soluble oral solution of ivermectin for veterinary use and a method for preparing the same", which mainly improves the solubility of ivermectin in water by using a higher content of ethyl acetate and Tween-80 to achieve the purpose of preparing an ivermectin aqueous solution. However, ethyl acetate itself has low toxicity, and the use of a higher content of ethyl acetate and Tween-80 is relatively expensive. There is no relevant verification of the high temperature stability and low temperature storage stability of ivermectin in the final aqueous solution, which may have a great impact on the shelf life of the oral preparation. Therefore, setting up a new aqueous solution oral preparation based on the properties of ivermectin is required by the market. Summary of the invention

[0005] In view of the shortcomings of the prior art, the present invention provides a method for preparing an ivermectin aqueous solution, wherein ivermectin is mixed with a small amount of oil and a larger amount of water to prepare an oral liquid with high stability, thereby ensuring the safety of the oral liquid and improving the stability of the oral liquid, thereby comprehensively improving the use effect.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented through the following technical solutions:

[0007] A method for preparing an ivermectin aqueous solution, the preparation method comprising the following steps:

[0008] S1, mixing ivermectin with a mixed solvent, a first surfactant, cholesterol, and phospholipids to obtain a mixed solution for later use;

[0009] S2, adding injection soybean oil, castor oil and vitamin E to the above mixed solution, centrifugally stirring and then rotary evaporating to remove the solvent, to obtain a mixed material for use;

[0010] S3, mixing the second surfactant with purified water and stirring evenly to obtain a pretreatment solution for standby use;

[0011] S4, pre-freeze the mixture at -15--18°C and take it out, heat the pre-treatment solution to 60-65°C and keep it warm, drop the warm pre-treatment solution into the mixture, and stir while adding, after the pre-treatment solution is completely added, let it stand for 6-8h in a water bath at 35-45°C to obtain a preliminary aqueous solution for use;

[0012] S5. Treat the preliminary aqueous solution under ice-water bath conditions at pressures of 0.8-1.2 MPa, 4-8 MPa, and 12-14 MPa for 30-60 min each, then adjust the water bath temperature to 30-40°C, and then treat at pressures of 12-14 MPa, 4-8 MPa, and 0.8-1.2 MPa for 10-20 min each, then take out, fill, and sterilize to obtain the ivermectin aqueous solution.

[0013] Preferably, ivermectin 0.2%-3%, first surfactant 0.1%-0.15%, cholesterol 0.2%-0.6%, phospholipid 0.1%-0.2%, soybean oil for injection 4%-7%, castor oil 1%-2%, vitamin E 0.4%-0.6%, second surfactant 0.6%-0.8%, and the rest is purified water.

[0014] Preferably, in step S1, the mixed solvent is obtained by mixing diethylene glycol ethyl ether and ethanol in a mass ratio of 4:1, and the added amount of the mixed solvent is 3-5 times the total mass of ivermectin.

[0015] Preferably, the first surfactant in step S1 is isopropyl myristate.

[0016] Preferably, the mixing and stirring in step S1 is carried out by stirring at a speed of 200-400 r / min for 20-30 min at a water bath temperature of 35-50° C.

[0017] Preferably, the rotation speed of the centrifugal stirring in step S2 is 3200-3500 r / min, and the time of the centrifugal stirring is 4-8 min.

[0018] Preferably, the second surfactant in step S3 is a mixture of sodium oleate and sodium citrate in a mass ratio of 1:1.

[0019] Preferably, the flow rate of the pretreatment solution dripping in step S4 is 120-180 drops / min, and the stirring speed is maintained at 80-120 r / min at the beginning of the dripping, and the speed is adjusted to 600-800 r / min after half of the pretreatment solution has been dripped.

[0020] Preferably, the preliminary aqueous solution in step S5 is stirred at a speed of 300-400 r / min during the pressure change treatment.

[0021] Preferably, the sterilization method in step S5 is sterilization treatment at 115° C. for 5 minutes.

[0022] The present invention provides a method for preparing an ivermectin aqueous solution, which has the advantages of:

[0023] The invention dissolves ivermectin in a solvent, mixes an oil agent and an antioxidant component, prepares a microemulsion through centrifugal stirring and rotary evaporation, mixes purified water, and prepares a highly stable aqueous solution through a surfactant and temperature and pressure change stirring treatment, reduces the amount of the oil agent, improves the storage stability of the aqueous solution, ensures the long-term effect of the drug, and comprehensively improves the market value and use convenience of the oral liquid. DETAILED DESCRIPTION

[0024] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention is clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] The reagents used in the following examples and comparative examples are as follows:

[0026] Ivermectin: Hebei Weiyuan Pharmaceutical Co., Ltd.;

[0027] Diethylene glycol ethyl ether: Shanghai MacLean Biochemical Technology Co., Ltd.;

[0028] Ethanol (chromatographic grade): Tianjin Siyou Fine Chemicals Co., Ltd.;

[0029] Isopropyl myristate: Hubei Kewode Chemical Co., Ltd.;

[0030] Cholesterol: Shanghai Harling Biotechnology Co., Ltd.;

[0031] Phospholipids: Shanghai Haring Biotechnology Co., Ltd.;

[0032] Soybean oil for injection: Lipoid GmbH, Germany;

[0033] Castor oil: Lipoid GmbH, Germany;

[0034] Vitamin E: Lipoid GmbH, Germany;

[0035] Sodium oleate: Shandong Longhui Chemical Co., Ltd.;

[0036] Sodium citrate: Shandong Longhui Chemical Co., Ltd.

[0037] Purified water: homemade in the laboratory;

[0038] The mixed solvent is obtained by mixing diethylene glycol ethyl ether and ethanol in a mass ratio of 4:1; the first surfactant is isopropyl myristate; and the second surfactant is obtained by mixing sodium oleate and sodium citrate in a mass ratio of 1:1.

[0039] Embodiment 1:

[0040] Preparation of ivermectin aqueous solution:

[0041] (1) ivermectin and a mixed solvent are mixed in a mass ratio of 1:4, and then a first surfactant, cholesterol, and phospholipid are added, and the mixture is stirred at a speed of 300 r / min for 25 minutes at a water bath temperature of 40° C. to obtain a mixed solution for use;

[0042] (2) adding injection soybean oil, castor oil and vitamin E to the above mixture, stirring at a centrifugal speed of 3400 r / min for 6 min, and then removing the solvent by rotary evaporation to obtain a mixture for use;

[0043] (3) mixing the second surfactant with purified water and stirring evenly to obtain a pretreatment solution for later use;

[0044] (4) The mixture was pre-frozen at -17°C for 2 hours and then taken out. The pre-treatment solution was heated to 63±2°C and kept warm. The warm pre-treatment solution was added to the mixture at a flow rate of 120-180 drops / min, and stirred at a speed of 100 r / min. When the amount of the pre-treatment solution added exceeded half, the speed was adjusted to 700 r / min for stirring. After the pre-treatment solution was completely added, it was allowed to stand for 7 hours in a 40°C water bath to obtain a preliminary aqueous solution for use;

[0045] (5) The preliminary aqueous solution was stirred in an ice water bath at a pressure of 1 MPa, 6 MPa, and 13 MPa for 40 min, and then the water bath temperature was adjusted to 35° C., and then stirred at a pressure of 13 MPa, 6 MPa, and 1 MPa for 15 min, during which the stirring speed was controlled at 350 r / min. The solution was then taken out, filled, and sterilized at 115° C. for 5 min to obtain an ivermectin aqueous solution.

[0046] Different experimental groups were set up according to Table 1 below, and the added mass percentage of each component was selected according to the above preparation method;

[0047] Table 1

[0048]

[0049] Comparative Example 1:

[0050] Preparation of ivermectin aqueous solution:

[0051] (1) ivermectin and a mixed solvent are mixed in a mass ratio of 1:4, and then a first surfactant, cholesterol, and phospholipid are added, and the mixture is stirred at a speed of 300 r / min for 25 minutes at a water bath temperature of 40° C. to obtain a mixed solution for use;

[0052] (2) adding injection soybean oil, castor oil and vitamin E to the above mixture, stirring at a speed of 300 r / min for 15 min, and then removing the solvent by rotary evaporation to obtain a mixture for later use;

[0053] The remaining steps (3)-(5) are the same as the preparation method of Example 1, and the mass percentage of each raw material is the same as the ratio of Experimental Group 3.

[0054] Comparative Example 2:

[0055] Preparation of ivermectin aqueous solution:

[0056] In the preparation process, steps (1)-(3) and step (5) are the same as those in Example 1, and the proportions of the components are the same as those in Experimental Group 3 in terms of mass percentage;

[0057] The operation steps of step (4) are as follows:

[0058] The mixture was directly mixed with the pretreatment solution, stirred at 700 r / min for 20 min in a water bath at 63±2°C, then the water bath temperature was adjusted to 40°C, and allowed to stand for 7 h to obtain a preliminary aqueous solution.

[0059] Comparative Example 3:

[0060] Preparation of ivermectin aqueous solution:

[0061] In the preparation process, steps (1) to (4) are the same as those in Example 1, and the proportions of the components are the same as those in Experimental Group 3 in terms of mass percentage;

[0062] The operation steps of step (5) are as follows:

[0063] The preliminary aqueous solution was stirred at 350 r / min in a water bath at 50°C for 3 hours, then taken out, filled and sterilized at 115°C for 5 minutes to obtain the ivermectin aqueous solution.

[0064] Detection:

[0065] The performance of the ivermectin aqueous solution prepared in the above experimental groups 1-3 and comparative examples 1-3 was tested:

[0066] Stability test:

[0067] (1) High temperature stability test:

[0068] Each group of ivermectin aqueous solution was filled into a transparent vial for sterilization and then placed in a stabilization box, the storage temperature was controlled at 60°C, and the solution was placed for 0 days, 10 days, 20 days and 30 days, and the changes in properties, visible foreign matter and ivermectin (IVM) of each group of ivermectin aqueous solution after placement were detected (the content data of ivermectin placed for 0 days was set as 100%, and the relative content before and after was calculated). The specific results are shown in Table 2 below:

[0069] Table 2

[0070]

[0071]

[0072] (2) Light stability test:

[0073] Each group of ivermectin aqueous solution was filled into a transparent vial and sterilized and placed in a stabilization box. The light intensity was adjusted to 4500±500lx, the temperature was 25±2℃, and the humidity was 50%±5%. The solution was placed for 0d, 10d, 20d, and 30d. Samples were taken for testing at 5d and 10d. The properties of the ivermectin aqueous solution, visible foreign matter, and IVM content were investigated according to the stability of the oral solution. The specific results are shown in Table 3 below:

[0074] Table 3

[0075]

[0076]

[0077] (3) Continuous freeze-thaw test:

[0078] Each group of ivermectin aqueous solutions was filled into transparent bottles for sterilization, placed in a freezer at -20°C for 2 hours, taken out and thawed in a 30°C water bath, and then restored to room temperature to complete one freeze-thaw cycle. The properties, visible foreign matter and IVM content of each group of ivermectin aqueous solutions were tested after 0, 5 and 10 freeze-thaw cycles. The specific results are shown in Table 4 below:

[0079] Table 4

[0080]

[0081] It can be seen from the above tests that the ivermectin aqueous solutions prepared in Examples 1-3 have higher stability under various conditions, and the stability is higher in Example 1 when the ivermectin concentration is lower than in Example 2 when the ivermectin concentration is higher.

[0082] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing an ivermectin aqueous solution, characterized in that: The preparation method comprises the following steps: S1, mixing ivermectin with a mixed solvent, a first surfactant, cholesterol, and phospholipids to obtain a mixed solution for later use; S2, adding injection soybean oil, castor oil and vitamin E to the above mixed solution, centrifugally stirring and then rotary evaporating to remove the solvent, to obtain a mixed material for use; S3, mixing the second surfactant with purified water and stirring evenly to obtain a pretreatment solution for standby use; S4, pre-freeze the mixture at -15--18°C and take it out, heat the pre-treatment solution to 60-65°C and keep it warm, drop the warm pre-treatment solution into the mixture, and stir while adding, after the pre-treatment solution is completely added, let it stand for 6-8h in a water bath at 35-45°C to obtain a preliminary aqueous solution for use; S5. Treat the preliminary aqueous solution under ice-water bath conditions at pressures of 0.8-1.2 MPa, 4-8 MPa, and 12-14 MPa for 30-60 min each, then adjust the water bath temperature to 30-40°C, and then treat under pressures of 12-14 MPa, 4-8 MPa, and 0.8-1.2 MPa for 10-20 min each, then take out and fill to obtain the ivermectin aqueous solution.

2. The preparation method according to claim 1, characterized in that: The percentage content of each substance in the ivermectin aqueous solution is: ivermectin 0.2%-3%, a first surfactant 0.1%-0.15%, cholesterol 0.2%-0.6%, phospholipid 0.1%-0.2%, soybean oil for injection 4%-7%, castor oil 1%-2%, vitamin E 0.4%-0.6%, a second surfactant 0.6%-0.8%, and the rest is purified water.

3. The preparation method according to claim 1, characterized in that: The mixed solvent in step S1 is obtained by mixing diethylene glycol ethyl ether and ethanol in a mass ratio of 4:1, and the added amount of the mixed solvent is 3-5 times the total mass of ivermectin.

4. The preparation method according to claim 1, characterized in that: In the step S1, the first surfactant is isopropyl myristate.

5. The preparation method according to claim 1, characterized in that: The mixing and stirring in step S1 is carried out in a manner of stirring at a speed of 200-400 r / min for 20-30 min at a water bath temperature of 35-50° C.

6. The preparation method according to claim 1, characterized in that: The rotation speed of the centrifugal stirring in step S2 is 3200-3500 r / min, and the time of the centrifugal stirring is 4-8 min.

7. The preparation method according to claim 1, characterized in that: In step S3, the second surfactant is a mixture of sodium oleate and sodium citrate in a mass ratio of 1:

1.

8. The preparation method according to claim 1, characterized in that: The flow rate of the pretreatment solution dripping in step S4 is 120-180 drops / min, and the stirring speed is maintained at 80-120 r / min at the beginning of the dripping, and the speed is adjusted to 600-800 r / min after half of the pretreatment solution has been dripped.

9. The preparation method according to claim 1, characterized in that: In the step S5, the preliminary aqueous solution is stirred at a speed of 300-400 r / min during the pressure change treatment.

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