Preparation process of ivermectin for vacuum freeze-drying injection

Abstract

The invention discloses a preparation process of ivermectin for vacuum freeze-drying injection, which comprises the following steps: S1, mixing ivermectin, polyethylene glycol and water for injection to obtain a mixed solution A; s2, the mixed solution A and modified activated carbon are stirred and subjected to decarburization treatment, filtrate is obtained, and the modified activated carbon is prepared by modifying activated carbon through alanine and succinic anhydride in sequence; and S3, freeze-drying the filtrate to obtain the ivermectin for vacuum freeze-drying injection. The modified activated carbon is added in the preparation process and reacts with the ivermectin to form the salt, so that the redissolution speed and solubility of the ivermectin in subsequent water can be improved, and the used modified activated carbon can effectively filter and reduce the impurity content in the finished ivermectin, so that the quality of the ivermectin is improved. Compared with the conventional ivermectin injection produced by taking propylene glycol, glycerol formal and the like as solvents, the ivermectin injection prepared by the invention has the advantages of good solubility in water, high absorption speed, higher absorption completeness, large apparent distribution volume and high bioavailability.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparation, in particular to a preparation process of vacuum freeze-dried ivermectin for injection. BACKGROUND

[0002] Parasite diseases are very serious, and often occur and spread in the form of mixed infection of multiple parasites, and the drug resistance of parasites is increasingly prominent, which not only causes great economic losses to the breeding industry, but also poses potential public health and food safety problems. Ivermectin is a new type of broad-spectrum, high-efficiency, low-toxicity antibiotic parasitic drug, which has good killing effect on endo- and ecto-parasites, especially nematodes and arthropods.

[0003] In recent years, the main dosage form of ivermectin is injection. Water is the most commonly used solvent for injection, which can be completely absorbed and metabolized in the animal body. However, ivermectin is almost insoluble in water and needs to be dissolved in an organic solvent to exist relatively stably. Ivermectin is prepared into freeze-dried ivermectin for injection, and in the freeze-drying process, the ivermectin is dissolved in water by adding a cosolvent, so that the physical, chemical properties and shape of the dried material are basically unchanged, the loss of active ingredients is small, the rehydration is good, and the sealed storage period is long. However, the existing preparation method has limited degree in controlling the degradation of ivermectin, so that the obtained product has problems such as high content of impurities and unstable product quality.

[0004] Therefore, the present application is proposed. SUMMARY

[0005] The technical problem to be solved by the present application is that the current preparation process has limited degree in controlling the degradation of ivermectin, so that the product has problems such as high content of impurities and unstable product quality. Therefore, the present application provides a preparation process of vacuum freeze-dried ivermectin for injection, which can improve the rehydration speed and solubility of ivermectin in water by adding modified activated carbon to react with ivermectin to form a salt during preparation. Moreover, the modified activated carbon after use can be effectively filtered to reduce the impurity content in the finished ivermectin product. Compared with the ivermectin injection produced by using propylene glycol, glycerol formaldehyde and the like as solvents, the ivermectin prepared by the present application has good solubility in water, fast and more complete absorption speed, large apparent distribution volume and high bioavailability.

[0006] The present application is realized by the following technical scheme: The present application provides a preparation process of vacuum freeze-dried ivermectin for injection, which comprises the following steps: S1: mixing ivermectin, polyethylene glycol and water for injection to obtain a mixed solution A; S2: stirring and decarburizing the mixed solution A with modified activated carbon to obtain a filtrate; S3: freeze-drying the filtrate to obtain the vacuum freeze-dried injectable ivermectin.

[0007] In a specific embodiment, the modified activated carbon is prepared by sequentially modifying activated carbon with alanine and succinic anhydride.

[0008] In a specific embodiment, the method for preparing the modified activated carbon comprises the following steps: Mixing and stirring the activated carbon, alanine and water, heating to 70-90℃, and keeping the temperature for 9-12 h, filtering, washing, and drying to obtain component one; Mixing and stirring component one, succinic anhydride and tetrahydrofuran, heating to 30-40℃, and keeping the temperature for 3-6 h, filtering, and drying to obtain the modified activated carbon.

[0009] In a specific embodiment, the mass ratio of ivermectin to the modified activated carbon is 1:0.1-0.3.

[0010] In a specific embodiment, the mass ratio of the activated carbon, alanine and water is 100:7-15:100-500.

[0011] In a specific embodiment, the mass-volume ratio of component one, succinic anhydride and tetrahydrofuran is 100:10-15:500-1000.

[0012] In a specific embodiment, the mass-volume ratio of ivermectin, polyethylene glycol and injectable water is 100:80-120:500-1000.

[0013] In a specific embodiment, the specific steps of freeze-drying are as follows: controlling the vacuum degree at 10-40 Pa, cooling to -40℃ to -30℃, freezing for 1-6 h; continuing to control the vacuum degree at 2-6 Pa, heating to 40-50℃, and drying for 3-6 h.

[0014] In a specific embodiment, the cooling rate is 5-10℃ / h, and the heating rate is 1-10℃ / h.

[0015] In a specific embodiment, the specific method for decarburization treatment is sterile filtration to remove the modified activated carbon.

[0016] Compared with the prior art, the present application has the following advantages and beneficial effects: 1. The preparation process of the vacuum freeze-dried injectable ivermectin provided by the embodiment of the present application can make the ivermectin react into a salt by adding the modified activated carbon modified by alanine and succinic anhydride in the preparation process, improve the subsequent water resolubility and solubility of the ivermectin, effectively solve the problem that the ivermectin is insoluble in water, and the modified activated carbon used after can be effectively filtered to reduce the impurity content in the finished ivermectin. 2. The preparation process of the vacuum freeze-dried injectable ivermectin provided by the embodiment of the present application can produce the ivermectin injection with better water solubility, faster and more complete absorption speed, larger apparent distribution volume and higher bioavailability than the ivermectin injection produced by using propylene glycol, glycerol formaldehyde and the like as a solvent. 3. The preparation process of the vacuum freeze-dried injectable ivermectin provided by the embodiment of the present application uses water as a solvent in the preparation process to avoid the use of organic solvents such as propylene glycol and glycerol formaldehyde, thereby reducing the pollution to the environment. 4. The preparation process of the vacuum freeze-dried injectable ivermectin provided by the embodiment of the present application has simple process steps and low cost, the content of the prepared injectable ivermectin is more stable during storage, the related substances are more easily controlled, the administration route of the ivermectin is increased, clinical medication is facilitated, and the preparation process has a good application prospect. DETAILED DESCRIPTION

[0017] In order to make the purpose, technical scheme and advantages of the present application clearer, further detailed description will be made to the present application in combination with embodiments, and the illustrative embodiments of the present application and the description thereof are only used to explain the present application, and not as a limitation to the present application.

[0018] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present application. However, it will be apparent to one of ordinary skill in the art that the present application can be practiced without these specific details. In other instances, well-known methods have not been described in detail in order to avoid obscuring the present application.

[0019] Throughout the specification, references have been made to "one embodiment", "an embodiment", "one example" or "an example" meant that a particular feature, structure, or characteristic described in connection with the embodiment or example is included in at least one embodiment of the present application. Therefore, the phrases "one embodiment", "an embodiment", "one example" or "an example" appearing in various places throughout the specification are not necessarily all referring to the same embodiment or example. In addition, specific features, structures, or characteristics can be combined in any appropriate combination and / or sub-combination in one or more embodiments or examples.

[0020] "RANGES" disclosed herein are defined, for each range by endpoints, the endpoints defining the range limit. Ranges can either be inclusive or exclusive of the endpoints, and are arbitrarily combinable, i.e., any endpoint of any range can be combined with any other endpoint to form a range. For example, if a range from 60 to 120 and a range from 80 to 110 are listed, a range from 60 to 110 and a range from 80 to 120 are also contemplated. Furthermore, if a minimum range value of 1 and 2 are listed, and a maximum range value of 3, 4, and 5 are listed, then the following ranges are all contemplated: 1-3, 1-4, 1-5, 2-3, 2-4, and 2-5. In this application, unless otherwise indicated, a numerical range "a-b" indicates a range of values that includes any and all combinations of sub-ranges between a and b, where a and b are both real numbers. For example, the numerical range "0-5" indicates that all real numbers between 0 and 5 have been listed herein, and "0-5" is merely a shorthand for listing all of the sub-ranges between 0 and 5. Also, when a parameter is stated to be an integer ≥ 2, it is equivalent to disclose that the parameter is, for example, an integer 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0021] Preparation Example 1 The present preparation example provides a method for preparing a modified activated carbon, comprising the following steps: (1) 100 g of activated carbon, 7 g of alanine, and 100 mL of deionized water were added into a reaction bottle, mechanically stirred uniformly, heated to 70°C, and kept for 9 h of reaction, filtered, washed to neutral, and dried to obtain component one; (2) 100 g of component one, 10 g of succinic anhydride, and 500 mL of tetrahydrofuran were added into a reaction kettle, mechanically stirred uniformly, heated to 30°C, and kept for 3 h of reaction, filtered, and dried to obtain the modified activated carbon.

[0022] Preparation Example 2 The present preparation example provides a method for preparing a modified activated carbon, comprising the following steps: (1) 100 g of activated carbon, 10 g of alanine, and 300 mL of deionized water were added into a reaction bottle, mechanically stirred uniformly, heated to 80°C, and kept for 9 h of reaction, filtered, washed to neutral, and dried to obtain component one; (2) 100 g of component one, 12 g of succinic anhydride, and 800 mL of tetrahydrofuran were added into a reaction kettle, mechanically stirred uniformly, heated to 35°C, and kept for 3 h of reaction, filtered, and dried to obtain the modified activated carbon.

[0023] Preparation Example 3 The present preparation example provides a method for preparing a modified activated carbon, comprising the following steps: (1) 100 g activated carbon, 15 g alanine, 500 mL deionized water were added into a reaction bottle, mechanically stirred uniformly, heated to 90℃, and kept for 12 h, filtered, washed to neutral, and dried to obtain component one; (2) 100 g component one, 15 g succinic anhydride, 1000 mL tetrahydrofuran were added into a reaction kettle, mechanically stirred uniformly, heated to 40℃, and kept for 6 h, filtered and dried to obtain modified activated carbon.

[0024] Preparation Example 1 The preparation example provides a preparation method of modified activated carbon, comprising the following steps: 100 g activated carbon, 7 g alanine, 100 mL deionized water were added into a reaction bottle, mechanically stirred uniformly, heated to 70℃, and kept for 9 h, filtered, washed to neutral, and dried to obtain modified activated carbon.

[0025] Example 1 The example provides a preparation process of vacuum freeze-dried injectable ivermectin, comprising the following steps: S1, 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL injectable water were mixed to obtain a mixed solution A; S2, the mixed solution A was stirred with 20 g of the modified activated carbon prepared in preparation example 1, and was treated by decarburization filtration to obtain a filtrate; S3, the filtrate was freeze-dried, the vacuum degree was controlled at 10 Pa, the temperature was lowered to-40℃ at a rate of 5℃ / h, and was frozen for 3 h; the vacuum degree was controlled at 5 Pa, the temperature was raised to 45℃ at a rate of 5℃ / h, and was dried for 3 h to obtain vacuum freeze-dried injectable ivermectin.

[0026] Example 2 The example provides a preparation process of vacuum freeze-dried injectable ivermectin, comprising the following steps: S1, 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL injectable water were mixed to obtain a mixed solution A; S2, the mixed solution A was stirred with 20 g of the modified activated carbon prepared in preparation example 2, and was treated by decarburization filtration to obtain a filtrate; S3, the filtrate was freeze-dried, the vacuum degree was controlled at 10 Pa, the temperature was lowered to-40℃ at a rate of 5℃ / h, and was frozen for 3 h; the vacuum degree was controlled at 5 Pa, the temperature was raised to 45℃ at a rate of 5℃ / h, and was dried for 3 h to obtain vacuum freeze-dried injectable ivermectin.

[0027] Example 3 The example provides a preparation process of vacuum freeze-dried injectable ivermectin, comprising the following steps: S1, mix 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2, Mix the mixed solution A with 20 g of the modified activated carbon prepared in Preparation Example 3, stir, filter and decarbonize to obtain filtrate; S3. Freeze-dry the filtrate, controlling the vacuum at 10 Pa and cooling it to -40°C at a rate of 5°C / h for 3 h; continue to control the vacuum at 5 Pa and heating it to 45°C at a rate of 5°C / h for 3 h to obtain vacuum-freeze-dried ivermectin for injection.

[0028] Example 4 This embodiment provides a preparation process for vacuum freeze-dried ivermectin for injection, including the following steps: S1, mix 100 g ivermectin, 100 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2, Mix the mixed solution A with 20 g of the modified activated carbon prepared in Preparation Example 1, stir and decarbonize to obtain filtrate; S3. Freeze-dry the filtrate, controlling the vacuum at 10 Pa and cooling it to -40°C at a rate of 5°C / h for 3 h; continue to control the vacuum at 5 Pa and heating it to 45°C at a rate of 5°C / h for 3 h to obtain vacuum-freeze-dried ivermectin for injection.

[0029] Example 5 This embodiment provides a preparation process for vacuum freeze-dried ivermectin for injection, including the following steps: S1, mix 100 g ivermectin, 120 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2, Mix the mixed solution A with 20 g of the modified activated carbon prepared in Preparation Example 1, stir, filter and decarbonize to obtain filtrate; S3. Freeze-dry the filtrate, controlling the vacuum at 10 Pa and cooling it to -40°C at a rate of 5°C / h for 3 h; continue to control the vacuum at 5 Pa and heating it to 45°C at a rate of 5°C / h for 3 h to obtain vacuum-freeze-dried ivermectin for injection.

[0030] Comparative Example 1 This comparative example provides a preparation process for vacuum-lyophilized ivermectin for injection, comprising the following steps: S1, mix 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2, Mix the mixed solution A with 20 g of the modified activated carbon prepared in Comparative Example 1, stir, filter and decarbonize to obtain filtrate; S3. Freeze-dry the filtrate, controlling the vacuum at 10 Pa and cooling it to -40°C at a rate of 5°C / h for 3 h; continue to control the vacuum at 5 Pa and heating it to 45°C at a rate of 5°C / h for 3 h to obtain vacuum-freeze-dried ivermectin for injection.

[0031] Comparative Example 2 This comparative example provides a preparation process for vacuum-lyophilized ivermectin for injection, comprising the following steps: S1: Mix 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2: Mix the mixed solution A with 20 g of activated carbon, filter and decarbonize to obtain the filtrate; S3: Freeze-dry the filtrate, controlling the vacuum at 10 Pa and cooling it to -40°C at a rate of 5°C / h for 3 h; continue to control the vacuum at 5 Pa and heating it to 45°C at a rate of 5°C / h for 3 h to obtain vacuum-freeze-dried ivermectin for injection.

[0032] Comparative Example 3 This comparative example provides a preparation process for vacuum-lyophilized ivermectin for injection, comprising the following steps: S1: Mix 100 g ivermectin, 80 g polyethylene glycol 6000 and 500 mL water for injection to obtain mixed solution A; S2: Freeze-dry the mixed solution A, controlling the vacuum degree at 10 Pa and cooling it to -40°C at a rate of 5°C / h, and freeze for 3 hours; continue to control the vacuum degree at 5 Pa and heating it to 45°C at a rate of 5°C / h, and dry for 3 hours to obtain vacuum-freeze-dried ivermectin for injection.

[0033] Performance testing The impurity content and reconstitution time of the vacuum freeze-dried ivermectin for injection prepared in Examples 1-5 and Comparative Examples 1-3 were tested, and the test results are shown in Tables 1, 2 and 3.

[0034] Table 1 Product Characteristics Table 2 Ivermectin content in the product Table 3 Solubility of the product in water for injection As can be seen from the data in Tables 1, 2, and 3, the ivermectin prepared by adding activated carbon modified with alanine and succinic anhydride in Examples 1-5 of the present invention has the advantages of high stability and fast resolution rate.

[0035] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A process for the preparation of vacuum lyophilized injectable ivermectin characterized in that, The method comprises the following steps: S1: mixing ivermectin, polyethylene glycol and water for injection to obtain a mixed solution A; S2: stirring and decarburizing the mixed solution A with modified activated carbon to obtain a filtrate; S3: freeze-drying the filtrate to obtain vacuum freeze-dried ivermectin for injection.

2. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 1 wherein, The modified activated carbon is prepared by modifying activated carbon with alanine and succinic anhydride in sequence.

3. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 2, wherein, The preparation method of the modified activated carbon comprises the following steps: mixing activated carbon, alanine and water, heating to 70-90 DEG C, and keeping the temperature for 9-12 hours, then filtering, washing and drying to obtain component one; mixing component one, succinic anhydride and tetrahydrofuran, heating to 30-40 DEG C, and keeping the temperature for 3-6 hours, then filtering and drying to obtain the modified activated carbon.

4. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 1 wherein, The mass ratio of ivermectin to modified activated carbon is 1:0.1-0.

3.

5. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 3, wherein, The mass ratio of activated carbon, alanine and water is 100:7-15:100-500.

6. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 3, wherein, The mass-volume ratio of component one, succinic anhydride and tetrahydrofuran is 100:10-15:500-1000.

7. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 1 wherein, The mass-volume ratio of ivermectin, polyethylene glycol and water for injection is 100:80-120:500-1000.

8. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 1 wherein, The specific steps of freeze-drying are as follows: controlling the vacuum degree to be 10-40 Pa, cooling to-40 DEG C to-30 DEG C, freezing for 1-6 hours, continuing to control the vacuum degree to be 2-6 Pa, heating to 40-50 DEG C, and drying for 3-6 hours.

9. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 8, wherein, The cooling rate is 5-10 DEG C / h, and the heating rate is 1-10 DEG C / h.

10. A process for the preparation of Ivermectin for injection by lyophilization as claimed in claim 1 wherein, The specific way of decarburization treatment is to remove the modified activated carbon by sterile filtration with a filter membrane.

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