Injection containing methoxyetomidate hydrochloride and preparation method thereof

Abstract

The invention discloses an injection containing methoxyetomidate hydrochloride and a preparation method of the injection. The injection comprises the following components: methoxyetomidate hydrochloride, a pH regulator, a solubilizing stabilizer and a solvent. The preparation method of the injection is simple and convenient for commercial production. A stability result shows that the product has good stability and is convenient for clinical application.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and in particular relates to an injection containing methoxyetomidate hydrochloride and a preparation method thereof. Background Art

[0002] The chemical name of methoxyetomidate hydrochloride is: R-(+)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid methoxyethyl ester hydrochloride, and its structural formula is shown in Formula I:

[0003]

[0004] Methoxyetomidate hydrochloride is a hydrochloride in which the ethyl group in the side chain of etomidate is replaced by methoxyethyl. While ensuring the clinical anesthesia effect, it can significantly reduce the adrenal cortex suppression effect and has good safety. Based on the route of administration, the dosage form of this product is injection. Methoxyetomidate hydrochloride is easily soluble in water, acidic, and easily hydrolyzed (hydrolysis pathways such as Figure 1 As shown), it mainly produces etomidate acid and ethylene glycol methyl ether, among which ethylene glycol methyl ether is a restricted Class II solvent and has been proven to be carcinogenic to animals with a PDE value of 0.5 mg / day.

[0005] Therefore, it is of great significance to develop a methoxyetomidate hydrochloride injection that can reduce the hydrolysis reaction of methoxyetomidate hydrochloride and reduce the generation of impurities, especially ethylene glycol methyl ether, so as to obtain a methoxyetomidate hydrochloride injection with high stability and safety within a safety limit. Summary of the invention

[0006] The purpose of the present invention is to prepare methoxyetomidate hydrochloride into a pharmaceutical preparation which has good stability and is convenient for storage and clinical application.

[0007] In order to achieve the above object, the present invention adopts the following technical solution:

[0008] An injection containing methoxyetomidate hydrochloride comprises the following components: methoxyetomidate hydrochloride, a pH regulator, a solubilizing stabilizer and a solvent.

[0009] Furthermore, in the injection, the dosage range of methoxyetomidate hydrochloride can be 0.1% to 10.0% (w / w), preferably 0.5% to 2.0% (w / w).

[0010] Furthermore, the pH adjuster is selected from at least one of the following: sodium hydroxide, potassium hydroxide, sodium phosphate, disodium hydrogen phosphate, anhydrous disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, etc., preferably anhydrous disodium hydrogen phosphate.

[0011] Furthermore, the solubilizing stabilizer can be propylene glycol, polyethylene glycol, cyclodextrins, etc., preferably propylene glycol, and the acceptable dosage range is 0.01% to 70% (w / w), preferably 25.9% to 63.3% (w / w), and more preferably 36.2% to 63.3% (w / w).

[0012] Furthermore, the pH range of the injection is 3.5 to 9.5, preferably 5.5 to 7.5.

[0013] Furthermore, the solvent is preferably water for injection.

[0014] The present invention also provides a method for preparing the methoxyetomidate hydrochloride injection.

[0015] The preparation method of methoxyetomidate hydrochloride injection provided by the present invention comprises the following steps: adding a pH regulator to a solvent, adjusting the pH value of the solution to within the range of 3.5 to 9.5, then adding a solubilizing stabilizer, and finally adding methoxyetomidate hydrochloride, mixing, fixing the volume with the solvent, filtering, encapsulating, and sterilizing to obtain the product.

[0016] Furthermore, the pH value of the solution is adjusted to 5.5-7.5.

[0017] Furthermore, the sterilization F0≥8, preferably F0≥12.

[0018] Furthermore, the sterilization conditions are: sterilization at 121° C. for 8 to 15 min, preferably sterilization at 121° C. for 12 to 15 min.

[0019] The present invention has the following beneficial effects:

[0020] The invention can reduce the hydrolysis reaction of methoxyetomidate hydrochloride and the generation of ethylene glycol methyl ether to keep it within a safe limit, thereby improving the stability and safety of the product and having important significance for the clinical application and commercial production of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 It is the hydrolysis pathway of methoxyetomidate hydrochloride;

[0022] Figure 2 This is the trend chart of etomidate acid changes at 2-8℃;

[0023] Figure 3 This is the trend chart of total impurities at 2-8℃;

[0024] Figure 4 This is the trend chart of ethylene glycol methyl ether at 2-8℃;

[0025] Figure 5 This is the trend chart of etomidate acid at 25℃ / 60%RH;

[0026] Figure 6 This is the total impurity change trend chart at 25℃ / 60%RH;

[0027] Figure 7 This is the trend chart of ethylene glycol methyl ether at 25℃ / 60%RH;

[0028] Figure 8 To accelerate the trend of etomidate acid at 40℃ / 75%RH;

[0029] Fig. 9 This is the trend chart of total impurity changes at 40℃ / 75%RH;

[0030] Fig.10 To accelerate the trend of 40℃ / 75%RH ethylene glycol methyl ether;

[0031] Fig.11 This is the trend chart of etomidate acid changes at 2-8℃;

[0032] Fig.12 This is the trend chart of total impurities at 2-8℃;

[0033] Fig.13 This is the trend chart of ethylene glycol methyl ether at 2-8℃;

[0034] Fig.14 This is the trend chart of etomidate acid at 25℃ / 60%RH;

[0035] Fig.15 This is the total impurity change trend chart at 25℃ / 60%RH;

[0036] Fig.16 This is the trend chart of ethylene glycol methyl ether at 25℃ / 60%RH;

[0037] Fig.17 To accelerate the trend of etomidate acid at 40℃ / 75%RH;

[0038] Fig.18 This is the trend chart of total impurity changes at 40℃ / 75%RH;

[0039] Fig.19 To accelerate the trend of 40℃ / 75%RH ethylene glycol methyl ether;

[0040] Fig. 20 This is the trend chart of etomidate acid changes at 2-8℃;

[0041] Fig.21 This is the trend chart of total impurities at 2-8℃;

[0042] Fig. 22 This is the trend chart of ethylene glycol methyl ether at 2-8℃;

[0043] Fig.23 This is the trend chart of etomidate acid at 25℃ / 60%RH;

[0044] Fig.24 This is the total impurity change trend chart at 25℃ / 60%RH;

[0045] Fig.25 This is the trend chart of ethylene glycol methyl ether at 25℃ / 60%RH;

[0046] Fig.26 To accelerate the trend of etomidate acid at 40℃ / 75%RH;

[0047] Fig. 27 This is the trend chart of total impurity changes at 40℃ / 75%RH;

[0048] Fig.28 To accelerate the trend of 40℃ / 75%RH ethylene glycol methyl ether;

[0049] Fig.29 This is the trend chart of etomidate acid at 40℃;

[0050] Fig.30 This is the trend chart of total impurities at 40℃;

[0051] Fig.31 This is the change trend chart of ethylene glycol methyl ether at 40℃. DETAILED DESCRIPTION

[0052] The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvement by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

[0053] The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

[0054] In the following examples, methoxyetomidate hydrochloride is referred to as API.

[0055] Embodiment 1, 2

[0056] Prescription composition:

[0057] Table 1 Prescription Information

[0058] Example 1 2 API 1%(w / w) 1%(w / w) Propylene glycol 36.2%(w / w) 63.3%(w / w) Disodium hydrogen phosphate anhydrous Adjust pH to 5.5-7.5 Adjust pH to 5.5-7.5 Water for injection Add to 100% Add to 100%

[0059] The preparation process of methoxyetomidate hydrochloride injection in Examples 1 and 2 is the same, specifically:

[0060] Preparation process: Take an appropriate amount of water for injection, add anhydrous disodium hydrogen phosphate, adjust the pH of the solution to 5.5-7.5, add the prescribed amount of propylene glycol, mix well and add API, make up to volume with water for injection, filter, fill into an ampoule, and sterilize at 121°C for 12 minutes.

[0061] Embodiment 3, 4

[0062] Prescription composition:

[0063] Table 2 Prescription Information

[0064] Example 3 4 API 1%(w / w) 1%(w / w) Propylene glycol 36.2%(w / w) 36.2%(w / w) Disodium hydrogen phosphate anhydrous Adjust pH to 3.5-5.4 Adjust pH to 7.6-9.5 Water for injection Add to 100% Add to 100%

[0065] The preparation process of methoxyetomidate hydrochloride injection in Examples 3 and 4 is the same, specifically:

[0066] Preparation process: Take an appropriate amount of water for injection, add anhydrous disodium hydrogen phosphate, adjust the pH of the solution to the corresponding range, add the prescribed amount of propylene glycol, mix well, add API, make up to volume with water for injection, filter, fill into an ampoule, and sterilize at 121°C for 12 minutes.

[0067] Example 5

[0068] Prescription composition:

[0069] Table 3 Prescription Information

[0070] Example 5 API 1%(w / w) Propylene glycol 36.2%(w / w) Sodium hydroxide Adjust pH to 5.5-7.5 Water for injection Add to 100%

[0071] Preparation process: Take an appropriate amount of water for injection, add 0.1 mol / L sodium hydroxide solution, adjust the pH of the solution to the corresponding range, add the prescribed amount of propylene glycol, mix well, add API, make up to volume with water for injection, filter, fill into an ampoule, and sterilize at 121°C for 12 min.

[0072] Example 6

[0073] Prescription composition:

[0074] Table 4 Prescription Information

[0075] Example 6 API 1%(w / w) Polyethylene glycol 36.2%(w / w) Disodium hydrogen phosphate anhydrous Adjust pH to 5.5-7.5 Water for injection Add to 100%

[0076] Preparation process: Take an appropriate amount of water for injection, add anhydrous disodium hydrogen phosphate, adjust the pH of the solution to the corresponding range, add the prescribed amount of polyethylene glycol, mix well, add API, make up to volume with water for injection, filter, fill into an ampoule, and sterilize at 121°C for 12 minutes.

[0077] Example 7

[0078] Prescription composition:

[0079] Table 5 Prescription Information

[0080] Example 7 API 1%(w / w) Propylene glycol 36.2%(w / w) Disodium hydrogen phosphate anhydrous Adjust pH to 5.5-7.5 Water for injection Add to 100%

[0081] Preparation process: Take an appropriate amount of water for injection, add anhydrous disodium hydrogen phosphate, adjust the pH of the solution to the corresponding range, add the prescribed amount of propylene glycol, mix well, add API, make up to volume with water for injection, filter, fill into an ampoule, and sterilize at 121°C for 8 minutes.

[0082] Example 8

[0083] The prescription composition is the same as that of Example 7.

[0084] The preparation process is different from that of Example 7 in that the product is sterilized at 121° C. for 15 min.

[0085] Comparative Example 1

[0086] The prescription composition is:

[0087] Table 6 Prescription Information

[0088] Comparative Example 1 API 1%(w / w) Water for injection Add to 100%

[0089] Preparation process: Add methoxyetomidate hydrochloride to water for injection, fill it into an ampoule after it is completely dissolved, and sterilize it at 121°C for 12 minutes to obtain the product.

[0090] The stability test results of Examples 1, 2 and Comparative Example 1 under different test conditions are as follows:

[0091] Table 7 2~8℃ stability test results

[0092]

[0093] The corresponding result diagram is shown in Figure 2 to Figure 4 Comparative Example 1 is an aqueous solution of API. The sample was placed at 2-8°C for 3 months. The etomidate acid, total impurities and ethylene glycol methyl ether increased significantly. Example 1 and Example 2 are samples prepared with propylene glycol contents of 36.2% and 63.3%. They were placed at 2-8°C for 3 months. The etomidate acid, total impurities and ethylene glycol methyl ether of the samples did not change significantly compared with 0 days, and the detected amount was significantly lower than that of Comparative Example 1. There was no significant difference in the detection results of etomidate acid, total impurities and ethylene glycol methyl ether between Example 1 and Example 2.

[0094] Table 8 25℃ / 60%RH stability test results

[0095]

[0096] The corresponding result diagram is shown in Figure 5 to Figure 7When comparative example 1 was placed under 25°C / 60%RH for 3 months, etomidate acid, total impurities and ethylene glycol methyl ether increased significantly, and the growth rate was much greater than that of example 1 and example 2, indicating that the stability of example 1 and example 2 was better than that of comparative example 1. There was no significant difference in the test results of etomidate acid, total impurities and ethylene glycol methyl ether between example 1 and example 2.

[0097] Table 9 Accelerated (40°C / 75%RH) stability test results

[0098]

[0099] The corresponding result diagram is shown in Figure 8 to Figure 10 When comparative example 1 was placed under 40°C / 75%RH for 3 months, etomidate acid, total impurities and ethylene glycol methyl ether increased significantly, and the growth rate was much greater than that of example 1 and example 2, indicating that the stability of example 1 and example 2 was better than that of comparative example 1. There was no significant difference in the test results of etomidate acid, total impurities and ethylene glycol methyl ether between example 1 and example 2.

[0100] The above results show that the stability of Examples 1 and 2 is better than that of Comparative Example 1, that is, the product prepared with a propylene glycol dosage of 36.2% to 63.3% has good stability, and there is no significant difference between the two, so the preferred propylene glycol concentration is 36.2% to 63.3%.

[0101] Test results of Examples 1, 3, 4 and Comparative Example 1:

[0102] Table 10 2~8℃ stability test results

[0103]

[0104] The corresponding result diagram is shown in Figure 11 to Figure 13 . The sample of Comparative Example 1 was placed at 2-8°C for 3 months, and the etomidate acid, total impurities and ethylene glycol methyl ether increased significantly; Examples 1, 3, and 4 were placed at 2-8°C for 3 months, and the etomidate acid, total impurities and ethylene glycol methyl ether of the samples did not change significantly compared with 0 days, and the detected amount was significantly lower than that of Comparative Example 1. There was no significant difference in the detection results of etomidate acid, total impurities and ethylene glycol methyl ether in Examples 1, 3, and 4.

[0105] Table 11 25℃ / 60%RH stability test results

[0106]

[0107] The corresponding result diagram is shown in Figure 14 to Figure 16. Comparative Example 1 was placed under 25°C / 60%RH for 3 months, and the levels of etomidate acid, total impurities and ethylene glycol methyl ether increased significantly. In Examples 1, 3, and 4, etomidate acid, total impurities and ethylene glycol methyl ether showed an increasing trend, but the detected amounts were much smaller than those in Comparative Example 1. This indicates that the stability of Examples 1, 3, and 4 is better than that of Comparative Example 1.

[0108] Table 12 Accelerated (40°C / 75%RH) stability test results

[0109]

[0110] The corresponding result diagram is shown in Figure 17 to Figure 19 . Comparative Example 1 was placed at 40°C / 75%RH for 3 months, and the levels of etomidate acid, total impurities and ethylene glycol methyl ether increased significantly. In Examples 1, 3, and 4, etomidate acid, total impurities and ethylene glycol methyl ether showed an increasing trend, but the detected amount was less than that of Comparative Example 1. There was no significant difference in the detection results of etomidate acid, total impurities and ethylene glycol methyl ether in Examples 1, 3, and 4.

[0111] The above results show that the stability of Examples 1, 3, and 4 is better than that of Comparative Example 1, indicating that the product prepared in the pH range of 3.5 to 9.5 has good stability, and the pH range is preferably 5.5 to 7.5.

[0112] Table 13 2~8℃ stability test results

[0113]

[0114] The corresponding result diagram is shown in Figure 20 to Figure 22 . The sample of Comparative Example 1 was placed at 2-8°C for 3 months, and the etomidate acid, total impurities and ethylene glycol methyl ether increased significantly; Examples 1, 5 and 6 were placed at 2-8°C for 3 months, and the etomidate acid, total impurities and ethylene glycol methyl ether of the samples did not change significantly compared with 0 days, and the detected amount was significantly lower than that of Comparative Example 1. There was no significant difference in the detection results of etomidate acid, total impurities and ethylene glycol methyl ether in Examples 1, 5 and 6.

[0115] Table 14 25℃ / 60%RH stability test results

[0116]

[0117] The corresponding result diagram is shown in Figure 23 to Figure 25 . Comparative Example 1 was placed under 25°C / 60%RH for 3 months, and the contents of etomidate acid, total impurities and ethylene glycol methyl ether increased significantly. In Examples 1, 5, and 6, etomidate acid, total impurities and ethylene glycol methyl ether showed an increasing trend, but the detected amount was much less than that of Comparative Example 1. This shows that the stability of Examples 1, 5, and 6 is better than that of Comparative Example 1. The contents of etomidate acid, total impurities and ethylene glycol methyl ether in Example 1 are slightly lower than those in Examples 5 and 6.

[0118] Table 15 Accelerated (40°C / 75%RH) stability test results

[0119]

[0120] The corresponding result diagram is shown in Figure 26 to Figure 28 . Comparative Example 1 was placed at 40°C / 75%RH for 3 months, and the levels of etomidate acid, total impurities and ethylene glycol methyl ether increased significantly. In Examples 1, 5, and 6, etomidate acid, total impurities and ethylene glycol methyl ether showed an increasing trend, but the detected amount was less than that of Comparative Example 1. The detected amounts of etomidate acid, total impurities and ethylene glycol methyl ether in Example 1 were lower than those in Examples 5 and 6.

[0121] The pH adjuster in Example 1 is anhydrous disodium hydrogen phosphate, and the pH adjuster in Example 5 is sodium hydroxide. The above results show that the stability of the sample prepared by using anhydrous disodium hydrogen phosphate is better than that of the sample prepared by using sodium hydroxide. Therefore, the pH adjuster may preferably be anhydrous disodium hydrogen phosphate.

[0122] The solubilizing stabilizer in Example 1 is propylene glycol, and the solubilizing stabilizer in Example 6 is polyethylene glycol. The above results show that the stability of the sample prepared by using propylene glycol is better than that of the sample prepared by using polyethylene glycol. Therefore, the solubilizing stabilizer may preferably be propylene glycol.

[0123] Table 16 Test results of influencing factors

[0124]

[0125] The corresponding result diagram is shown in Figure 29 to Figure 31 . There is no significant difference in etomidate acid, total impurities and ethylene glycol methyl ether at a high temperature of 40°C in Examples 1, 7 and 8, and the detected amounts are all lower than those in Comparative Example 1, indicating that the stability of Examples 1, 7 and 8 at 40°C is better than that of Comparative Example 1; after 12 days of illumination, the etomidate acid, total impurities and ethylene glycol methyl ether in the samples of Examples 1, 7 and 8 are all lower than those in Comparative Example 1, and there is no significant difference between Examples 1, 7 and 8. It indicates that there is no significant difference in the samples prepared by sterilization for 8 minutes, 12 minutes and 15 minutes. The above results indicate that this product can withstand terminal sterilization. To ensure the sterility level of the product, the preferred sterilization conditions are 121°C and sterilization for 12 to 15 minutes.

[0126] In summary, the present invention significantly improves the stability of the injection solution, has a simple production process, and can achieve commercial large-scale production.

[0127] The present invention has been described in detail above. It will be apparent to those skilled in the art that the present invention may be implemented in a wide range under equivalent parameters, concentrations and conditions without departing from the spirit and scope of the present invention and without the need for unnecessary experimentation. Although the present invention provides specific embodiments, it should be understood that further improvements may be made to the present invention. In short, according to the principles of the present invention, this application intends to include any changes, uses or improvements to the present invention, including changes made by conventional techniques known in the art that depart from the scope disclosed in this application. Applications of some of the basic features may be made within the scope of the following appended claims.

Claims

1. An injection containing methoxyetomidate hydrochloride, comprising the following components: methoxyetomidate hydrochloride, a pH regulator, a solubilizing stabilizer, and a solvent.

2. The injection according to claim 1, characterized in that: In the injection, the dosage of methoxyetomidate hydrochloride ranges from 0.1% to 10.0% (w / w), preferably from 0.5% to 2.0% (w / w).

3. The injection according to claim 1 or 2, characterized in that: The pH adjuster is selected from at least one of the following: sodium hydroxide, potassium hydroxide, sodium phosphate, disodium hydrogen phosphate, anhydrous disodium hydrogen phosphate, sodium carbonate, sodium bicarbonate, preferably anhydrous disodium hydrogen phosphate.

4. The injection according to any one of claims 1 to 3, characterized in that: The solubilizing stabilizer is selected from at least one of the following: propylene glycol, polyethylene glycol, and cyclodextrins, preferably propylene glycol.

5. The injection according to any one of claims 1 to 4, characterized in that: In the injection, the dosage of the solubilizing stabilizer ranges from 0.01% to 70% (w / w), preferably from 25.9% to 63.3% (w / w), and more preferably from 36.2% to 63.3% (w / w).

6. The injection according to any one of claims 1 to 5, characterized in that: The pH range of the injection is 3.5 to 9.5, preferably 5.5 to 7.

5.

7. The injection according to any one of claims 1 to 6, characterized in that: The solvent is water for injection.

8. The method for preparing the injection according to any one of claims 1 to 7, comprising the following steps: adding a pH regulator to a solvent, adjusting the pH value of the solution to within an appropriate range, adding a solubilizing stabilizer, and finally adding methoxyetomidate hydrochloride, mixing, fixing the volume with the solvent, filtering, encapsulating, and sterilizing to obtain the injection.

9. The preparation method according to claim 8, characterized in that: The pH value of the solution is adjusted to 3.5-9.5, preferably 5.5-7.

5.

10. The preparation method according to claim 8 or 9, characterized in that: The sterilization F0≥8, preferably F0≥12; And / or, the sterilization conditions are: sterilization at 121° C. for 8 to 15 min, preferably sterilization at 121° C. for 12 to 15 min.

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