A midocal dibutyrate injection and a preparation method thereof

Abstract

The application provides an imidocarb dipropionate injection and a preparation method thereof, and relates to the technical field of veterinary injection preparation. The imidocarb dipropionate injection is composed of imidocarb dipropionate, propylene glycol, polysorbate 80, lecithin, castor oil for injection, a stabilizer, mannitol and water for injection. The imidocarb dipropionate injection is prepared by the steps of supercritical carbon dioxide mixing treatment, pressure increase high-speed stirring, low-temperature circulation ultrasonic treatment and drop mixing high-temperature water for injection. The application overcomes the defects of the prior art, can effectively reduce the propylene glycol dosage while ensuring the solubility stability of imidocarb dipropionate, and comprehensively improves the safety of the injection.

Description

Technical Field

[0001] This invention relates to the field of veterinary injectable preparation technology, specifically to a dipropionate imidocal injection and its preparation method. Background Technology

[0002] Imidocal dipropionate injection, also known as imidazole dipropionate injection, is a novel antiprotozoal drug for animals, belonging to the diphenylurea class of compounds. It works by directly acting on the parasite, inhibiting its growth and reproduction, inducing nuclear expansion and disintegration, ultimately achieving a killing effect. This drug is not metabolized in the body, is eliminated slowly, maintains a long plasma concentration, and can be administered intravenously or intramuscularly. Its excretion is slow, resulting in a prolonged effect.

[0003] Imidazolidinyl dipropionate is poorly soluble in water, and propylene glycol is generally used for dissolution when preparing injection solutions. However, excessive addition of propylene glycol can easily harm animal health through hemolysis, skin irritation, allergic reactions, metabolic abnormalities, and systemic toxicity. In practical applications, the solubility of imidazolidinyl dipropionate has a significant impact on the stability and efficacy of its formulations. Insufficient propylene glycol can easily lead to poor stability of the subsequent injection solution. Therefore, to ensure uniform distribution and long-term stability of the drug in injections, it is necessary to select appropriate solvents and excipients and optimize the dissolution process. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a dipropionate imidoxane injection and its preparation method, which can effectively reduce the amount of propylene glycol used while ensuring the solubility stability of dipropionate imidoxane, thereby comprehensively improving the safety of the injection.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] A dipropionate imidoxar injection, wherein the contents of each component in 100 mL are as follows: imidazole urea dipropionate 4-15 g, propylene glycol 15-30 mL, polysorbate 80 2-4 mL, lecithin 1-2 mL, castor oil for injection 4-8 mL, stabilizer 0.01-0.03 g, mannitol 2.5-5.0 g, and the balance being water for injection.

[0007] Preferably, the stabilizer is obtained by mixing sorbitol and sodium octanoate in equal mass.

[0008] The preparation method of dipropionate imidocal injection includes the following steps:

[0009] S1. Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin, and castor oil for injection. Place it in a high-pressure reactor and pressurize it to 8-9 MPa. Then, introduce supercritical carbon dioxide, stir thoroughly, release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use.

[0010] S2. Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize with nitrogen to 2-3 MPa, and stir at high speed at 1200-1600 r / min to obtain a premix for later use.

[0011] S3. Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 2-4℃ to obtain a secondary mixture for later use.

[0012] S4. Return the secondary mixture to room temperature, then add the remaining water for injection at 70-80℃ while stirring to make up the volume. Adjust the pH to 4.5-5.0, then sterilize and fill with nitrogen to obtain dipropionate imidocal injection.

[0013] Preferably, the amount of supercritical carbon dioxide introduced in step S1 is 2-3 times the total volume of propylene glycol.

[0014] Preferably, in step S1, the stirring speed is 200-400 r / min and the stirring time is 15-30 min.

[0015] Preferably, the high-speed stirring time in step S2 is 8-12 minutes.

[0016] Preferably, the cyclic ultrasonic treatment in step S3 is performed by ultrasonic treatment at 400-600W for 4-8 minutes, followed by resting for 3-5 minutes, and then ultrasonic treatment again, for a total of 5-7 cycles.

[0017] Preferably, in step S4, the stirring speed during the addition of the remaining water for injection is 120-180 r / min, and the dropping rate is 2-5 mL / min.

[0018] Preferably, citric acid is used for pH adjustment in step S4.

[0019] Preferably, the sterilization method in step S4 is to filter the injection solution using a 0.22-micron sterile filter membrane.

[0020] This invention provides a dipropionate midocarb injection and its preparation method, which has the following advantages compared with the prior art:

[0021] The present invention adds polysorbate 80, lecithin, castor oil for injection, and stabilizers to the injection solution, which can ensure the solubility of imidazole urea dipropionate while reducing the amount of propylene glycol used. At the same time, the subsequent supercritical carbon dioxide treatment combined with pressurized high-speed stirring and low-temperature cyclic ultrasonic treatment, as well as the addition and mixing of water for injection at a certain temperature difference, can effectively improve the stability of the final injection solution, prevent the drug from settling in the injection solution, and comprehensively improve the safety of the injection solution. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0023] The raw materials used in the following examples are from the following sources:

[0024] Imidazolium dipropionate (for injection, purity ≥99%), purchased from Shandong Yinfengda Pharmaceutical Co., Ltd.

[0025] Propylene glycol was purchased from Xi'an Taihua Pharmaceutical Technology Co., Ltd.

[0026] Polysorbate 80 was purchased from Xi'an Taihua Pharmaceutical Technology Co., Ltd.

[0027] Lecithin was purchased from Shaanxi Zhengyi Pharmaceutical Excipients Co., Ltd.

[0028] Castor oil for injection was purchased from Lipoid GmbH, Germany.

[0029] Mannitol was purchased from Xi'an Taihua Pharmaceutical Technology Co., Ltd.

[0030] Furthermore, the stabilizer is a mixture of sorbitol and sodium octanoate in equal mass.

[0031] Example 1:

[0032] Preparation of dipropionate imidocal injection:

[0033] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation amounts of each component are as follows: 4 g of dipropionate imidoxane urea, 15 mL of propylene glycol, 2 mL of polysorbate 80, 1 mL of lecithin, 4 mL of castor oil for injection, 0.01 g of stabilizer, 2.5 g of mannitol, and the remainder is water for injection.

[0034] (2) Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin and castor oil for injection, place in a high-pressure reactor and pressurize to 8.5 MPa, then add supercritical carbon dioxide three times the total volume of propylene glycol, stir at 300 r / min for 20 min, then release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use.

[0035] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0036] (4) Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 4°C. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0037] (5) The secondary mixture was brought back to room temperature. Then, while stirring at 160 r / min, the remaining water for injection at 75°C was added dropwise at a rate of 3 mL / min to make up the volume. The pH was then adjusted to 5.0 with citric acid. The mixture was then filtered through a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0038] Example 2:

[0039] Preparation of dipropionate imidocal injection:

[0040] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation amounts of each component are as follows: 15 g of dipropionate imidoxane urea, 30 mL of propylene glycol, 80 4 mL of polysorbate, 2 mL of lecithin, 8 mL of castor oil for injection, 0.03 g of stabilizer, 5.0 g of mannitol, and the remainder is water for injection.

[0041] (2) Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin and castor oil for injection, place in a high-pressure reactor and pressurize to 8.5 MPa, then add supercritical carbon dioxide three times the total volume of propylene glycol, stir at 300 r / min for 20 min, then release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use.

[0042] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0043] (4) Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 4°C. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0044] (5) The secondary mixture was brought back to room temperature. Then, while stirring at 160 r / min, the remaining water for injection at 75°C was added dropwise at a rate of 3 mL / min to make up the volume. The pH was then adjusted to 5.0 with citric acid. The mixture was then filtered through a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0045] Comparative Example 1:

[0046] Preparation of dipropionate imidocal injection:

[0047] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation amounts of each component are as follows: 15 g of dipropionate imidoxane urea, 30 mL of propylene glycol, 80 4 mL of polysorbate, 2 mL of lecithin, 8 mL of castor oil for injection, 0.03 g of stabilizer, 5.0 g of mannitol, and the remainder is water for injection.

[0048] (2) Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin, and castor oil for injection. Purge with nitrogen to adjust the pressure to 8.5 MPa, and stir at 300 r / min for 20 min to obtain a preliminary mixture for later use.

[0049] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0050] (4) Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 4°C. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0051] (5) The secondary mixture was brought back to room temperature. Then, while stirring at 160 r / min, the remaining water for injection at 75°C was added dropwise at a rate of 3 mL / min to make up the volume. The pH was then adjusted to 5.0 with citric acid. The mixture was then filtered through a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0052] Comparative Example 2:

[0053] Preparation of dipropionate imidocal injection:

[0054] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation amounts of each component are as follows: 15 g of dipropionate imidoxane urea, 30 mL of propylene glycol, 80 4 mL of polysorbate, 2 mL of lecithin, 8 mL of castor oil for injection, 0.03 g of stabilizer, 5.0 g of mannitol, and the remainder is water for injection.

[0055] (2) Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin and castor oil for injection, place in a high-pressure reactor and pressurize to 8.5 MPa, then add supercritical carbon dioxide three times the total volume of propylene glycol, stir at 300 r / min for 20 min, then release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use.

[0056] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0057] (4) Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 4°C. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0058] (5) The secondary mixture was brought back to room temperature, and then the remaining water for injection at room temperature was added to make up the volume. The pH was then adjusted to 5.0 with citric acid, and then filtered with a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0059] Comparative Example 3:

[0060] Preparation of dipropionate imidocal injection:

[0061] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation quantities of each component are as follows: 15 g of dipropionate imidoxane urea, 30 mL of propylene glycol, 0.03 g of stabilizer, 5.0 g of mannitol, and the remainder is water for injection;

[0062] (2) Add dipropionate imidazole urea to propylene glycol, place it in a high-pressure reactor and pressurize it to 8.5 MPa. Then, introduce supercritical carbon dioxide with a total volume of 3 times that of propylene glycol. Stir at a speed of 300 r / min for 20 min, then release the pressure and discharge the carbon dioxide to obtain a preliminary mixture for later use.

[0063] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0064] (4) Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 4°C. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0065] (5) The secondary mixture was brought back to room temperature. Then, while stirring at 160 r / min, the remaining water for injection at 75°C was added dropwise at a rate of 3 mL / min to make up the volume. The pH was then adjusted to 5.0 with citric acid. The mixture was then filtered through a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0066] Comparative Example 4:

[0067] Preparation of dipropionate imidocal injection:

[0068] (1) Based on 100 mL of dipropionate imidoxane injection, the preparation amounts of each component are as follows: 15 g of dipropionate imidoxane urea, 30 mL of propylene glycol, 80 4 mL of polysorbate, 2 mL of lecithin, 8 mL of castor oil for injection, 0.03 g of stabilizer, 5.0 g of mannitol, and the remainder is water for injection.

[0069] (2) Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin and castor oil for injection, place in a high-pressure reactor and pressurize to 8.5 MPa, then add supercritical carbon dioxide three times the total volume of propylene glycol, stir at 300 r / min for 20 min, then release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use.

[0070] (3) Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2.5 MPa, and stir at a high speed of 1400 r / min for 10 min to obtain the premix for later use.

[0071] (4) Add stabilizer and mannitol to the premix, and perform cyclic ultrasonic treatment at room temperature. After ultrasonic treatment at 400W for 6 minutes, let it stand for 3-5 minutes. Repeat this operation 6 times to obtain a secondary mixture for later use.

[0072] (5) The secondary mixture was brought back to room temperature. Then, while stirring at 160 r / min, the remaining water for injection at 75°C was added dropwise at a rate of 3 mL / min to make up the volume. The pH was then adjusted to 5.0 with citric acid. The mixture was then filtered through a 0.22-micron sterile filter membrane. Finally, the container was filled with nitrogen and sealed to obtain dipropionate imidocal injection.

[0073] Detection:

[0074] The content of dipropionate imidoxane urea in the dipropionate imidoxane injection prepared in Examples 1-2 and Comparative Examples 1-4 was tested under different environments (based on the prepared specification content of 100%, wherein the specification content of Example 1 is 4g / 100mL, and the specification content of Example 2 and Comparative Examples 1-4 is 15g / 100mL).

[0075] 1. Stability test at room temperature:

[0076] Each group of imidoxazone dipropionate injection solutions was filled into sealed 5mL ampoules and placed in a light-protected environment at a temperature of 22±2℃ and a humidity of 60%±5%. The relative content of imidazole dipropionate in each group of imidoxazone dipropionate injection solutions was measured at 0d, 100d, 200d, and 300d, as shown in Table 1 below.

[0077] Table 1

[0078]

[0079] As shown in the table above, Examples 1-2 and Comparative Example 4 have good overall stability when stored in a stable environment at room temperature and away from light, while Comparative Example 3 has poor overall stability.

[0080] 2. High-temperature storage stability test:

[0081] Each group of imidoxazone dipropionate injection solutions was filled into sealed 5mL ampoules and placed in a light-protected environment at a temperature of 38±2℃ and a humidity of 60%±5%. The relative content of imidazole dipropionate in each group of imidoxazone dipropionate injection solutions was measured at 0d, 30d, 80d, and 150d, as shown in Table 2 below.

[0082] Table 2

[0083]

[0084] As can be seen from the table above, Examples 1-2 can maintain good stability at high temperatures.

[0085] 3. Low-temperature storage stability test:

[0086] Each group of imidoxazone dipropionate injection solutions was filled into sealed 5mL ampoules and placed in a light-protected environment at a temperature of -8℃±2℃ and a humidity of 60%±5%. The relative content of imidoxazone dipropionate in each group of imidoxazone dipropionate injection solutions was measured at 0d, 30d, 80d, and 150d, as shown in Table 3 below.

[0087] Table 3

[0088]

[0089] As shown in the table above, the content of dipropionate imidazole urea in Examples 1 and 2 is relatively stable at low temperatures.

[0090] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A dipropionate imidocal injection, characterized in that, The dipropionate imidoxane injection, per 100 mL, contains the following components: imidazole urea dipropionate 4-15 g, propylene glycol 15-30 mL, polysorbate 80 2-4 mL, lecithin 1-2 mL, castor oil for injection 4-8 mL, stabilizer 0.01-0.03 g, mannitol 2.5-5.0 g, with the remainder being water for injection; The stabilizer is obtained by mixing equal masses of sorbitol and sodium octanoate. The preparation method of the dipropionate imidocal injection includes the following steps: S1. Add dipropionate imidazole urea to propylene glycol, then add polysorbate 80, lecithin, and castor oil for injection. Place it in a high-pressure reactor and pressurize it to 8-9 MPa. Then, introduce supercritical carbon dioxide, stir thoroughly, release the pressure and remove the carbon dioxide to obtain a preliminary mixture for later use. S2. Add the above preliminary mixture to 1 / 2 of the total volume of water for injection, then pressurize it with nitrogen to 2-3 MPa, and stir at high speed at 1200-1600 r / min to obtain a premix for later use. S3. Add stabilizer and mannitol to the premix, and perform low-temperature cyclic ultrasonic treatment at 2-4℃ to obtain a secondary mixture for later use. S4. Return the secondary mixture to room temperature, then add the remaining water for injection at 70-80℃ while stirring to make up the volume. When adding the remaining water for injection, the stirring speed should be 120-180r / min and the dropping rate should be 2-5mL / min. Then adjust the pH to 4.5-5.0, sterilize and fill with nitrogen to obtain dipropionate imidocal injection.

2. The dipropionate imidocal injection according to claim 1, characterized in that: The amount of supercritical carbon dioxide introduced in step S1 is 2-3 times the total volume of propylene glycol.

3. The dipropionate imidocal injection according to claim 1, characterized in that: In step S1, the stirring speed is 200-400 r / min, and the stirring time is 15-30 min.

4. The dipropionate imidocal injection according to claim 1, characterized in that: The high-speed stirring time in step S2 is 8-12 minutes.

5. The dipropionate imidocal injection according to claim 1, characterized in that: In step S3, the cyclic ultrasonic treatment is performed by ultrasonic treatment at 400-600W for 4-8 minutes, followed by resting for 3-5 minutes, and then ultrasonic treatment again, for a total of 5-7 cycles.

6. The dipropionate imidocal injection according to claim 1, characterized in that: In step S4, citric acid is used for pH adjustment.

7. The dipropionate imidocal injection according to claim 1, characterized in that: The sterilization method in step S4 is to filter the injection solution using a 0.22-micron sterile filter membrane.

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