Preparation method and application of etomidate fat emulsion injection

Abstract

The invention provides a preparation method and application of an etomidate fat emulsion injection. By optimizing a plurality of parameters in a preparation process of the etomidate fat emulsion injection, a plurality of indexes in a final finished product can meet the requirements of import registration standards, and the problem that impurities such as etomidate acid in an original developed preparation of the etomidate fat emulsion injection exceed the standard is solved. The preparation method of the etomidate fat emulsion injection, developed by the invention, is simple in process and convenient for large-scale industrial production, and has important industrial value.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a preparation method and application of etomidate fat emulsion injection. Background Art

[0002] Etomidate (Formula I below) is a short-acting intravenous anesthetic used for general anesthesia induction and sedation. Etomidate preparations currently on the market in China include ordinary injection and fat emulsion injection. Ordinary injection uses propylene glycol as a cosolvent, which is prone to adverse reactions such as injection site pain during injection, while etomidate fat emulsion injection can significantly reduce the incidence of injection pain and hemolysis.

[0003]

[0004] The properties, pH value, content, related substances, milk particles, osmotic pressure, free fatty acids, peroxide value, anisidine value, egg yolk phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, glycerol, and isomers of etomidate emulsion injection are all key quality parameters. For example, the import drug registration standard for etomidate emulsion injection stipulates that the pH should be 6.0-8.5, etomidic acid (Formula II below) in the related substances is ≤2.0%, other single impurities are ≤0.2%, and the sum of other impurities is ≤0.3%.

[0005]

[0006] Etomidate emulsion injection belongs to an injectable submicron emulsion, which is a thermodynamically unstable and kinetically unstable system. It is easy to undergo stratification, flocculation, demulsification, oil-water separation and other phenomena during production, storage and use. The original research company did not report the preparation process of etomidate emulsion injection. In addition, the inventors also found in practice that the key impurity etomidate acid in the original reference preparation exceeded the standard. It is of great industrial value to develop a method for preparing etomidate emulsion injection that is simple in process, easy to scale up for industrial production and has a finished preparation stability that meets the requirements. Summary of the invention

[0007] The present invention aims to provide a method for preparing an etomidate fat emulsion injection, comprising the following steps: (1) preparing an oil phase: dissolving egg yolk lecithin in medium chain triglycerides, and then sequentially adding soybean oil and etomidate, and stirring to dissolve;

[0008] (2) Preparation of aqueous phase: Add glycerol and sodium oleate to water for injection and stir to dissolve;

[0009] (3) Preparation of colostrum: adding the oil phase to the water phase, and subjecting the resulting mixture to shear emulsification to obtain colostrum;

[0010] (4) pH adjustment: Add an appropriate amount of pH adjuster to the colostrum to adjust the pH to a weak alkaline state;

[0011] (5) Preparation of final milk: homogenize the solution obtained in step (4) to obtain the final milk.

[0012] In a preferred embodiment of the present invention, in step (4), the pH adjuster is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof, preferably the pH adjuster is dilute hydrochloric acid, more preferably the pH adjuster is 3 mol / L dilute hydrochloric acid; preferably, the pH is adjusted to 8.0-8.5.

[0013] In a preferred embodiment of the present invention, the injection comprises 0.2% by weight of etomidate, 10% by weight of soybean oil, 10% by weight of medium chain triglycerides, 1.2% by weight of egg yolk lecithin, 2.5% by weight of glycerol, 0.03% by weight of sodium oleate, an appropriate amount of pH regulator, and water for injection.

[0014] In a preferred embodiment of the present invention, nitrogen protection is used throughout the preparation method.

[0015] In a preferred embodiment of the present invention, the system temperature in the oil phase preparation in step (1) is 60°C-70°C.

[0016] In a preferred embodiment of the present invention, the system temperature in the aqueous phase preparation of step (2) is 60°C-70°C.

[0017] In a preferred embodiment of the present invention, the system temperature in the colostrum preparation in step (3) is 60°C-70°C;

[0018] In a preferred embodiment of the present invention, the temperature of the solution is controlled below 30° C. in the final milk preparation of step (5).

[0019] In a preferred embodiment of the present invention, in the step (5) of preparing the final milk, the colostrum is homogenized seven to ten times at a homogenization pressure of 600-1000 bar.

[0020] In a preferred embodiment of the present invention, the preparation method further comprises filtering, filling and sterilizing steps after step (5).

[0021] In a preferred embodiment of the present invention, the drug solution is filtered using a polyethersulfone filter membrane, a polytetrafluoroethylene filter membrane or a polypropylene filter membrane, preferably using a polypropylene filter membrane, and more preferably using a 1 μm polypropylene filter membrane.

[0022] In a preferred embodiment of the present invention, moist heat sterilization is adopted, preferably 121°C / 15 min moist heat sterilization or 121°C / 12 min moist heat sterilization or 121°C / 30 min moist heat sterilization, more preferably 121°C / 12 min moist heat sterilization.

[0023] Another object of the present invention is to provide the etomidate fat emulsion injection prepared by the preparation method of the present invention.

[0024] Unless otherwise specified, when the present invention relates to the percentage between liquids, the percentage is volume / volume percentage; when the present invention relates to the percentage between liquids and solids, the percentage is volume / weight percentage (ml / g); when the present invention relates to the percentage between solids and liquids, the percentage is weight / volume percentage (g / ml); the rest are weight / weight percentages.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The present invention ensures that all indicators in the finished product meet the requirements of the import registration standard through scientific screening and optimization of multiple parameters in the preparation process of etomidate fat emulsion injection, and overcomes the problem of excessive impurities such as etomidic acid in the original preparation of etomidate fat emulsion injection.

[0027] The preparation method of the etomidate fat emulsion injection developed by the invention has simple process, is convenient for scaled-up industrial production, and has important industrial application value. DETAILED DESCRIPTION

[0028] To make the purpose, technical solution and advantages of the present invention more clear, the embodiments of the present invention will be described in detail below. It should be noted that the embodiments of the present invention and the features in the embodiments can be combined with each other arbitrarily without conflict.

[0029] Example 1 Preparation of etomidate fat emulsion injection

[0030] The prescription composition is shown in Table 1 below:

[0031] Table 1

[0032] Element Unit dose (mg) Weight percentage (%) effect Quantity for 100 sticks (g) Etomidate 20 0.2％ Active ingredients 2 Soybean oil (for injection) 1000 10％ Oil phase solvent 100 Medium Chain Triglycerides 1000 10％ Oil phase solvent 100 Egg yolk lecithin (for injection) 120 1.2％ Emulsifier 12 Glycerol (for injection) 250 2.5％ Osmotic pressure regulator 25 Sodium Oleate 3 0.03％ Stabilizer 0.3 Dilute hydrochloric acid Moderate / pH Adjusters Moderate Water for injection Up to 10ml to 100% Aqueous solvent Up to 1000ml

[0033] The preparation method is as follows:

[0034] (1) Preparation of oil phase: Place medium-chain triglycerides in a beaker, heat in a water bath to 60°C-70°C, add egg yolk lecithin, stir to dissolve, add soybean oil, add etomidate, stir until dissolved. Nitrogen protection is used throughout the process;

[0035] (2) Preparation of aqueous phase: Add water for injection into another beaker, add glycerol and sodium oleate, and stir in a water bath at 60℃-70℃ until the sodium oleate is dissolved. Nitrogen is used for protection throughout the process;

[0036] (3) Phase combination: Turn on the high-speed shearing machine, slowly pour the oil phase into the water phase, and shear at high speed for 10 minutes. Nitrogen is filled throughout the process for protection;

[0037] (4) Homogenization: The colostrum is injected into a high-pressure homogenizer and homogenized 9 times at a pressure of 600 bar; the homogenizer uses condensed water for cooling;

[0038] (5) Final milk filtration, filling, sealing and sterilization.

[0039] Example 2 Investigation of different ways of adding pH regulator

[0040] The import registration standard for etomidate fat emulsion injection has clear requirements for pH value. The effects of different pH adjuster addition methods on the pH and related substances of the finished product are examined. See Table 2 below for details:

[0041] Table 2

[0042]

[0043] Results: When adjusting the aqueous phase, the solution became turbid after the pH adjuster was added, which was a non-uniform system, so no subsequent experiments were conducted; the final milk adjustment had a significant impact on the relevant substances in the finished product compared with the colostrum adjustment. The pH value was adjusted in the colostrum stage.

[0044] Example 3 Investigation of colostrum pH regulation

[0045] Etomidate is easily hydrolyzed to form etomidic acid. Controlling the pH value is an important way to control this hydrolysis. In addition, the pH value of etomidate fat emulsion injection is specified in the import registration standard to be 6.0-8.5. The effect of adjusting the colostrum pH value to different levels (using 3 mol / L hydrochloric acid) during sample preparation on the stability of the formulation was investigated, as shown in Table 3 below:

[0046] Table 3

[0047]

[0048] The results showed that the colostrum pH of samples with a pH of 9.0 exceeded the limit after being placed at 60°C for 10 days, and the pH of samples with a colostrum pH of 5.5-7.5 was lower than the standard lower limit after being placed at 60°C for 10 days. After comprehensive consideration, the colostrum pH was adjusted to the range of 8.0-8.5.

[0049] Example 4 Investigation of pH Regulator Types and Concentrations

[0050] Commonly used injection pH regulators include dilute hydrochloric acid and glacial acetic acid. The effects of different regulators on sample quality were investigated. See Table 4 below for details:

[0051] Table 4

[0052]

[0053] The results showed that when glacial acetic acid was used to adjust the pH, the average particle size of the samples prepared by the same process was larger, and the risk of unqualified large emulsion particles in the finished product increased.

[0054] Example 5 Investigation of the oil phase preparation process

[0055] This product is an O / W emulsion, using egg yolk lecithin as an emulsifier, investigating the solubility of egg yolk lecithin in oil phases with different ratios of soybean oil and medium-chain triglycerides, and determining the oil phase preparation process, as shown in Table 5 below:

[0056] Table 5

[0057]

[0058] The results showed that egg yolk lecithin had better solubility in medium-chain triglycerides, and the higher the temperature, the faster it dissolved. Therefore, egg yolk lecithin was first dissolved in medium-chain triglycerides and then soybean oil was added.

[0059] Example 6 Investigation of the solubility of the raw material drug

[0060] The solubility of etomidate raw material in soybean oil and medium-chain triglyceride oils of different ratios was investigated to provide a reference for the selection of the oil phase preparation process of this product, as shown in Table 6 below:

[0061] Table 6

[0062]

[0063] Etomidate has the best solubility in a mixed oil of soybean oil and medium-chain triglycerides, and dissolves faster at higher temperatures. Therefore, etomidate is added last in the preparation of the oil phase.

[0064] Example 7 Investigation of the mixing order of oil phase and water phase

[0065] There are usually two methods for preparing colostrum, one is to add the oil phase to the water phase under high-speed shearing, and the other is to add the water phase to the oil phase under high-speed shearing. For etomidate emulsion injection, the colostrum preparation method was investigated based on properties and average particle size, as shown in Table 7 below:

[0066] Table 7

[0067] Colostrum Preparation Method Characteristics Average particle size (nm) Add oil phase to water phase White emulsion, no oil droplets 410.6 Add water phase to oil phase White emulsion, no oil droplets 5940.2

[0068] The results showed that there was no significant difference in the physical appearance of colostrum prepared by the two methods, but the colostrum particle size prepared by the method of adding water phase to oil phase was much larger than that prepared by the method of adding oil phase to water phase, so it was chosen to add oil phase to water phase.

[0069] Example 8 Investigation of colostrum preparation temperature

[0070] The quality of colostrum samples prepared at 50°C, 60°C, 70°C and 80°C was investigated respectively, as shown in Table 8 below:

[0071] Table 8

[0072]

[0073] Results: With the increase of the preparation temperature, the content of etomidic acid in the finished product increased; when the colostrum preparation temperature was 50℃ and 80℃, the average particle size of the final milk was larger; when the colostrum preparation temperature was 80℃, the color of the colostrum changed, so the colostrum preparation temperature was set at 60-70℃.

[0074] Example 9 Final emulsion solution temperature investigation

[0075] When the emulsion is homogenized under high pressure, a large amount of heat will be generated. Usually, cooling water is used to cool the solution to prevent the solution temperature from being too high and affecting the sample quality. Therefore, the quality of the samples prepared under the conditions of condensed water temperature of 3-5℃, 25℃, and 60-70℃ were investigated. See Table 9 below for details:

[0076] Table 9

[0077]

[0078] The results showed that the solution temperature during homogenization had no significant effect on the content of related substances in the sample, but the homogenization solution temperature affected the content of milk particles larger than 5μm in the finished product. In order to ensure the safety of the finished product, the solution temperature during homogenization should be controlled below 30℃.

[0079] Example 10 Preparation of etomidate fat emulsion injection

[0080] The preparation of pilot batch fat emulsion injection was carried out according to Table 10 below:

[0081] Table 10

[0082]

[0083] Preparation method:

[0084] (1) Preparation of oil phase: Place medium-chain triglycerides in an oil phase tank, turn on the oil phase tank mixer, heat in a water bath to 60°C-70°C, add egg yolk lecithin, rinse the container containing egg yolk lecithin with medium-chain triglycerides and add it to the oil phase tank, stir, add soybean oil to the oil phase tank, heat the solution to 60°C-70°C, add etomidate, rinse the container containing etomidate with soybean oil and add it to the oil phase tank, stir until dissolved. Nitrogen protection is passed through during the preparation of the oil phase;

[0085] (2) Preparation of the aqueous phase: Add water for injection into the colostrum tank, start stirring, add glycerol and sodium oleate, rinse the container containing glycerol and sodium oleate with water for injection, and then add it to the colostrum tank. Keep the temperature in a water bath at 60°C-70°C, stir until the sodium oleate is dissolved, and fill with nitrogen to maintain the pressure.

[0086] (3) Phase combination: fully open the water phase valve of the colostrum tank to allow the water phase to circulate, open the discharge valve of the oil phase tank, combine the water phase and the oil phase, and cool or heat the liquid in the colostrum tank in time during the combination process to control the liquid temperature in the colostrum tank at 60°C-70°C. During the combination process, nitrogen is passed through the colostrum tank for protection;

[0087] (4) Shear emulsification: The colostrum tank is subjected to cyclic shear emulsification, and the emulsion temperature is controlled between 60-70°C during the shear emulsification process. During the shear process, nitrogen is passed through the colostrum tank to protect the emulsion;

[0088] (5) pH adjustment: measure the pH of colostrum, add dilute hydrochloric acid (3 mol / L) and adjust the pH to 8.0-8.5;

[0089] (6) Homogenization: The primary emulsion was homogenized 9 times by a high-pressure homogenizer at a homogenization pressure of 600 bar, and the temperature of the homogenized liquid was controlled below 30° C. using 3-5° C. condensed water;

[0090] (7) Filtration, filling and sterilization of drug solution.

[0091] Example 11 Performance Study of Etomidate Fat Emulsion Injection

[0092] The performance and stability of the fat emulsion injection prepared in Example 10 were compared with the original reference preparation, as shown in Table 11 below (the specifications of the homemade preparation and the reference preparation are both 10 ml: 20 mg):

[0093] Table 11

[0094] Quality Standards Reference preparation Homemade preparations Anisidine value (≤5.0) 4.8 3.3 Egg yolk phosphatidylcholine (≤12.0mg / ml) 11.0 5.4 Peroxide value (≤1.0) 0.9 0 Etomidic acid ≤ 2.0% 2.190 0.319 Other maximum single impurity ≤ 0.2% 0.148 0.078 Other total impurities ≤ 0.3% 0.158 0.124

[0095] Although the embodiments disclosed in the present invention are as above, the contents described are only embodiments adopted to facilitate understanding of the present invention and are not intended to limit the present invention. Any technician in the field to which the present invention belongs can make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in the present invention, but the patent protection scope of the present invention shall still be subject to the scope defined in the attached claims.

Claims

1. A method for preparing etomidate fat emulsion injection, comprising the following steps: (1) Preparation of oil phase: dissolve egg yolk lecithin in medium chain triglycerides, then add soybean oil and etomidate in sequence, and stir to dissolve; (2) Preparation of aqueous phase: Add glycerol and sodium oleate to water for injection and stir to dissolve; (3) Preparation of colostrum: adding the oil phase to the water phase, and subjecting the resulting mixture to shear emulsification to obtain colostrum; (4) pH adjustment: Add an appropriate amount of pH adjuster to the colostrum to adjust the pH to a weak alkaline state; (5) Preparation of final milk: homogenize the solution obtained in step (4) to obtain the final milk.

2. The preparation method according to claim 1, characterized in that: In the step (4), the pH adjuster is selected from any one of hydrochloric acid, sulfuric acid, phosphoric acid or a combination thereof, preferably the pH adjuster is dilute hydrochloric acid, more preferably the pH adjuster is 3 mol / L dilute hydrochloric acid; preferably, the pH is adjusted to 8.0-8.

5.

3. The preparation method according to any one of claims 1 to 2, characterized in that: The injection comprises 0.2% by weight of etomidate, 10% by weight of soybean oil, 10% by weight of medium chain triglyceride, 1.2% by weight of egg yolk lecithin, 2.5% by weight of glycerol, 0.03% by weight of sodium oleate, an appropriate amount of pH regulator, and water for injection.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The preparation method adopts nitrogen protection throughout the whole process.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The system temperature in the oil phase preparation of step (1) is 60°C-70°C.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The system temperature in the aqueous phase preparation of step (2) is 60°C-70°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that: In the step (3) of preparing colostrum, the system temperature is 60°C-70°C.

8. The preparation method according to any one of claims 1 to 7, characterized in that: In the step (5) of preparing the final milk, the solution temperature is controlled below 30°C.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The preparation method further comprises filtering, filling and sterilizing steps after step (5).

10. The etomidate fat emulsion injection prepared according to the preparation method according to any one of claims 1 to 9.

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