A preparation method of ivermectin aqueous solution

Abstract

The present invention provides a method for preparing an ivermectin aqueous solution, relating to the technical field of ivermectin oral liquid. The ivermectin aqueous solution comprises ivermectin, a surfactant, cholesterol, a phospholipid, soybean oil for injection, castor oil, and vitamin E. The ivermectin is dissolved in a solvent, mixed with cholesterol and phospholipid to form a microemulsion, which is then mixed with soybean oil for injection, castor oil, and vitamin E. The microemulsion is then mixed with purified water through temperature-variable dropwise mixing and pressure-variable stirring to obtain a highly stable ivermectin aqueous solution. The present invention overcomes the shortcomings of the prior art by preparing a highly stable oral liquid by mixing ivermectin with a small amount of an oily solution and a larger amount of an aqueous solution. This ensures the safety of the oral liquid while also improving its stability, thereby comprehensively enhancing its effectiveness.

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: injection, emulsion, transdermal agent, premix, liposome, pour-on, tablet, sustained-release bolus and oral solution, among which oral solution is a dosage form with higher convenience of use.

[0003] Existing ivermectin oral solutions are widely used in animals such as cattle, horses, pigs, dogs, rabbits, and poultry. Although these preparations offer simple production processes and easy administration, they often use oil as a solvent, resulting in high overall costs. Due to the poor water solubility of ivermectin, few ivermectin oral solutions use water as a solvent.

[0004] Patent No. 201410793149.X discloses "A water-soluble oral solution of ivermectin for veterinary use and a preparation method thereof", which mainly uses a higher content of ethyl acetate and Tween-80 to improve the solubility of ivermectin in water to achieve the purpose of preparing an ivermectin aqueous solution. However, ethyl acetate itself has low toxicity, and the use of higher content of ethyl acetate and Tween-80 is relatively expensive. In addition, there is no relevant verification for the high temperature stability and low temperature storage stability of ivermectin in the final aqueous solution, which may have a significant impact on the shelf life of the oral preparation. Therefore, the market needs to develop a new aqueous oral preparation based on the properties of ivermectin. Summary of the Invention

[0005] In view of the shortcomings of the existing technology, the present invention provides a method for preparing an ivermectin aqueous solution. By mixing ivermectin with a small amount of oil and a larger amount of water, a highly stable oral liquid is prepared. This ensures the safety of the oral liquid and improves 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 a phospholipid to obtain a mixed solution for later use;

[0009] S2. Add soybean oil for injection, castor oil and vitamin E to the above mixture, centrifuge and stir, and then rotary evaporate to remove the solvent to obtain a mixture for later use;

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

[0011] S4. The mixture is pre-frozen at -15°C to -18°C and then taken out. The pre-treatment solution is heated to 60-65°C and kept warm. The warm pre-treatment solution is added dropwise to the mixture while stirring. After the pre-treatment solution is completely added, the mixture is allowed to stand in a water bath at 35-45°C for 6-8 hours to obtain a preliminary aqueous solution for use.

[0012] S5. Treat the preliminary aqueous solution in an ice-water bath 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 the solution 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, 0.2%-3% ivermectin, 0.1%-0.15% first surfactant, 0.2%-0.6% cholesterol, 0.1%-0.2% phospholipid, 4%-7% soybean oil for injection, 1%-2% castor oil, 0.4%-0.6% vitamin E, 0.6%-0.8% second surfactant, and the remainder is purified water.

[0014] Preferably, 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.

[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 in step S4 is 120-180 drops / min, and the stirring speed is maintained at 80-120 r / min at the beginning of the addition, and the speed is adjusted to 600-800 r / min after half of the pretreatment solution has been added.

[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 following advantages over the prior art:

[0023] The invention dissolves ivermectin in a solvent, mixes an oil agent and an antioxidant component, and prepares a microemulsion through centrifugal stirring and rotary evaporation. The microemulsion is then mixed with purified water, and a surfactant and temperature and pressure variable stirring treatment are performed to prepare a highly stable aqueous solution. The amount of the oil agent used is reduced, while the storage stability of the aqueous solution is improved, and the long-term effect of the drug is guaranteed, thereby comprehensively improving the market value and ease of use of the oral liquid. DETAILED DESCRIPTION

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention are clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall 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 Harling 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] Example 1:

[0040] Preparation of ivermectin aqueous solution:

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

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

[0043] (3) Mix the second surfactant with purified water and stir 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 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 in a 40°C water bath for 7 hours to obtain a preliminary aqueous solution for use.

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

[0046] Set up different experimental groups according to Table 1 below, and select the added mass percentage of each component according to the above preparation method;

[0047] Table 1

[0048]

[0049]

[0050] Comparative Example 1:

[0051] Preparation of ivermectin aqueous solution:

[0052] (1) Ivermectin and the mixed solvent were mixed in a mass ratio of 1:4, and then the first surfactant, cholesterol, and phospholipid were added, and the mixture was stirred at a speed of 300 r / min in a water bath at 40°C for 25 minutes to obtain a mixed solution for use;

[0053] (2) Add injection soybean oil, castor oil, and vitamin E to the above mixture, stir at a speed of 300 r / min for 15 minutes, and then remove the solvent by rotary evaporation to obtain a mixture for use;

[0054] The remaining steps (3) to (5) are the same as those in Example 1, and the mass percentage of each raw material is the same as that in Experimental Group 3.

[0055] Comparative Example 2:

[0056] Preparation of ivermectin aqueous solution:

[0057] During the preparation process, steps (1) to (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 by mass percentage;

[0058] The steps of step (4) are as follows:

[0059] The mixture was directly mixed with the pretreatment solution, stirred at a speed of 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.

[0060] Comparative Example 3:

[0061] Preparation of ivermectin aqueous solution:

[0062] During 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 by mass percentage;

[0063] The steps of step (5) are as follows:

[0064] The preliminary aqueous solution was stirred at 350 r / min in a water bath at 50° C. for 3 h, then taken out, filled, and sterilized at 115° C. for 5 min to obtain the ivermectin aqueous solution.

[0065] Detection:

[0066] The performance of the ivermectin aqueous solutions prepared in the experimental groups 1-3 and comparative examples 1-3 was tested:

[0067] Stability testing:

[0068] (1) High temperature stability test:

[0069] The ivermectin aqueous solution of each group was filled into a transparent penicillin bottle and sterilized, and then placed in a stabilization box. The storage temperature was controlled at 60°C. After 0 days, 10 days, 20 days and 30 days, the changes in the properties, visible foreign matter and ivermectin (IVM) of each group of ivermectin aqueous solution after storage were detected (the content data of ivermectin detected on the 0th day was set as 100%, and the relative content before and after was calculated). The specific results are shown in Table 2 below:

[0070] Table 2

[0071]

[0072] (2) Light stability test:

[0073] Each group of ivermectin aqueous solutions were filled into transparent vials, sterilized, and placed in a stabilization chamber. The light intensity was adjusted to 4500±500 lx, the temperature was 25±2°C, and the humidity was 50%±5%. The solutions were placed for 0 days, 10 days, 20 days, and 30 days. Samples were taken for testing at 5 days and 10 days. The properties, visible foreign matter, and IVM content of the ivermectin aqueous solution were examined based on 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, and then placed in a freezer at -20°C for 2 hours. The bottles were then taken out and thawed in a 30°C water bath, and then returned to room temperature to complete one freeze-thaw cycle. The properties, visible foreign matter, and IVM content of the ivermectin aqueous solutions in each group were tested after 0, 5, and 10 freeze-thaw cycles. The specific results are shown in Table 4 below:

[0079] Table 4

[0080]

[0081] From the above tests, it can be seen 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 they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. 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 various 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, ivermectin is mixed with a mixed solvent, a first surfactant, cholesterol, and a phospholipid, and stirred to obtain a mixed solution for use; the mixed solvent is a mixture of diethylene glycol ethyl ether and ethanol in a mass ratio of 4:1; the first surfactant is isopropyl myristate; S2. Add soybean oil for injection, castor oil and vitamin E to the above mixture, centrifuge and stir, and then remove the solvent by rotary evaporation to obtain a mixture for use; the speed of the centrifugal stirring is 3200-3500 r / min, and the centrifugal stirring time is 4-8 min; S3, mixing the second surfactant with purified water and stirring evenly to obtain a pretreatment solution for standby use; the second surfactant is a mixture of sodium oleate and sodium citrate in a mass ratio of 1:1; S4, the mixture was taken out after pre-freezing at -15--18 ° C, the pretreatment solution was heated to 60-65 ° C and kept warm, the warm pretreatment solution was added dropwise to the mixture, and stirred while adding dropwise, after the pretreatment solution was completely added dropwise, it was allowed to stand for 6-8 hours in a 35-45 ° C water bath to obtain a preliminary aqueous solution for standby use; the flow rate of the pretreatment solution was 120-180 drops / min, and the stirring speed was kept at 80-120 r / min at the beginning of the addition, and the speed was adjusted to 600-800 r / min after the pretreatment solution was added dropwise halfway; S5. The preliminary aqueous solution is treated in an ice water bath at pressures of 0.8-1.2 MPa, 4-8 MPa, and 12-14 MPa for 30-60 min, and then the water bath temperature is adjusted to 30-40° C., and then treated at pressures of 12-14 MPa, 4-8 MPa, and 0.8-1.2 MPa for 10-20 min, respectively. The solution is then taken out, filled, and sterilized to obtain an ivermectin aqueous solution. The treatment method is to stir the solution at a speed of 300-400 r / min.

2. The preparation method according to claim 1, wherein: The percentage content of each substance in the ivermectin aqueous solution is: 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.

3. The preparation method according to claim 1, wherein: The amount of the mixed solvent added in step S1 is 3-5 times the total mass of ivermectin.

4. The preparation method according to claim 1, wherein: 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.

5. The preparation method according to claim 1, wherein: The sterilization method in step S5 is sterilization at 115° C. for 5 minutes.

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