Pharmaceutical preparation of N-substituted imidazole carboxylate chiral compound containing ether side chain and preparation method of pharmaceutical preparation

Abstract

The invention discloses a pharmaceutical preparation of an ether side chain-containing N-substituted imidazole carboxylate chiral compound and a preparation method thereof, and belongs to the technical field of medicines. The pharmaceutical preparation disclosed by the invention is sterile powder for injection; the sterile powder for injection is composed of an ether side chain-containing N-substituted imidazole carboxylic ester chiral compound and a filler. The pharmaceutical preparation is an anhydrous environment preparation, namely sterile powder for injection, the hydrolysis reaction of the N-substituted imidazole carboxylic ester chiral compound containing the ether side chain is reduced, the generation of impurities, especially ether impurities, is reduced, and the stability and safety of the pharmaceutical preparation are improved.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a pharmaceutical preparation of an N-substituted imidazole carboxylate chiral compound containing an ether side chain and a preparation method thereof. Background Art

[0002] The N-substituted imidazole carboxylate chiral compound containing an ether side chain is a new compound. The ethyl group in the etomidate side chain is replaced by an imidazole side chain, which ensures the clinical anesthesia effect while significantly reducing the adrenal cortex inhibition effect, and has good safety. Based on the route of administration, the dosage form of this product is an injection. Due to the structural characteristics of the compound itself, it is easy to undergo hydrolysis reaction, mainly producing etomidate acid and ether impurities (see Figure 1 ), some ether impurities such as ethylene glycol methyl ether are restricted Class II solvents, which have been proven to be carcinogenic to animals.

[0003] For example, one of the chiral N-substituted imidazole carboxylate compounds containing an ether side chain is a hydrochloride in which the ethyl group in the etomidate side chain is replaced by a methoxyethyl group, which is referred to as methoxyetomidate hydrochloride. It is easily soluble in water and is acidic. It is easily hydrolyzed in the presence of water, and the higher the temperature, the greater the degree of hydrolysis, and etomidate acid and ethylene glycol methyl ether will be produced (see Figure 2 ), among which ethylene glycol methyl ether belongs to the second class solvent with restricted use, and the PDE value is 0.5 mg / day. How to prepare anhydrous environment preparations of N-substituted imidazole carboxylic acid ester chiral compounds containing ether side chains, reduce their hydrolysis reaction, and reduce the generation of impurities, especially ether impurities, is an urgent problem to be solved. Summary of the invention

[0004] The present invention provides a pharmaceutical preparation of an N-substituted imidazole carboxylate chiral compound containing an ether side chain and a preparation method thereof. The pharmaceutical preparation of the present invention is an anhydrous environment preparation, i.e., a sterile powder for injection, which reduces the hydrolysis reaction of the N-substituted imidazole carboxylate chiral compound containing an ether side chain, reduces the generation of impurities, especially ether impurities, and improves the stability and safety of the pharmaceutical preparation.

[0005] The present invention firstly provides a pharmaceutical preparation of an N-substituted imidazole carboxylate chiral compound containing an ether side chain, which is a sterile powder for injection; the sterile powder for injection consists of the N-substituted imidazole carboxylate chiral compound containing an ether side chain and a filler.

[0006] In the above-mentioned pharmaceutical preparation, the mass ratio of the N-substituted imidazole carboxylate chiral compound containing an ether side chain to the filler is 1:0.5 to 1:3, preferably 1:0.75 to 1:1.5.

[0007] In the above-mentioned pharmaceutical preparation, the N-substituted imidazole carboxylate chiral compound containing an ether side chain is methoxyetomidate hydrochloride;

[0008] The filler is mannitol, sucrose or glucose; preferably, the filler is mannitol.

[0009] The moisture content of the pharmaceutical preparation is no more than 2.0% (mass percentage).

[0010] The present invention further provides a method for preparing the above-mentioned pharmaceutical preparation, comprising the following steps:

[0011] The N-substituted imidazole carboxylate chiral compound containing an ether side chain and a filler are dissolved in water to obtain a drug solution; the drug solution is dried to remove moisture to obtain the drug preparation.

[0012] In the above preparation method, the mass ratio of the N-substituted imidazole carboxylate chiral compound containing an ether side chain to the filler is 1:0.75 to 1:1.5;

[0013] In the drug solution, the mass percentage concentration of the N-substituted imidazole carboxylate chiral compound containing an ether side chain is 1% to 30%, preferably 4% to 10%.

[0014] In the above-mentioned preparation method, the drying is spray drying or freeze drying.

[0015] Specifically, the freeze-drying method is carried out under the following conditions: pre-freezing is first performed, followed by primary drying and analytical drying.

[0016] In the above preparation method, the pre-freezing conditions are as follows: temperature -8°C to -60°C, time 1h to 5h, freezing into a solid below the freezing point; pre-freezing is at normal pressure;

[0017] The conditions of the primary drying are as follows: temperature -20°C to 5°C, time 5h to 30h, and vacuum degree 0mbar to 0.25mbar during the primary drying process;

[0018] The conditions of the analytical drying are as follows: temperature 15° C. to 30° C., time 2 h to 12 h, and vacuum degree 0 mbar to 0.25 mbar during the analytical drying process.

[0019] In some embodiments of the present invention, the freeze-drying conditions are as follows 1) or 2):

[0020] 1) Pre-freeze the drug solution, i.e., reduce the temperature to -35°C, return to -22°C and keep it at a constant temperature for 1 hour, continue to reduce the temperature to -45°C and keep it at a constant temperature for 2.5 hours, and freeze it into a solid below the freezing point; pre-freeze to normal pressure; then perform a (sublimation) drying, i.e., heat to -20°C within 3 hours, then keep it at a constant temperature for 3 hours, heat to -10°C within 14.5 hours, keep it at a constant temperature for 7 hours, heat to 0°C within 7 hours, and maintain the vacuum degree at 0.16 mbar during the primary drying process; finally, perform analytical drying, i.e., heat to 24°C and keep it at a constant temperature for 8 hours, and maintain the vacuum degree at 0.16 mbar during the analytical drying process.

[0021] 2) Pre-freeze the drug solution, i.e., reduce the temperature to -8°C and keep the temperature constant for 1 hour, then cool it to -45°C within 1.5 hours and keep the temperature constant for 2 hours, and freeze it into a solid below the freezing point; pre-freeze to normal pressure; then perform a (sublimation) drying, i.e., heat it to -10°C within 1.5 hours, then keep the temperature constant for 13.3 hours, and maintain the vacuum degree at 0.20 mbar during the primary drying process; then perform analytical drying, i.e., heat it to 24°C within 1 hour and keep the temperature constant for 5 hours, and maintain the vacuum degree at 0.20 mbar during the process, and finally maintain 24°C and draw an extreme vacuum (the vacuum degree is set to 0 mbar) for 1.5 hours.

[0022] The pharmaceutical preparation of the invention creates an anhydrous environment for methoxyetomidate hydrochloride, reduces the occurrence of hydrolysis reaction and the generation of ethylene glycol methyl ether, and improves the stability and safety of the pharmaceutical preparation; it can be industrially produced on a large scale, and creates considerable economic and social benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 It is a hydrolysis route for chiral compounds of N-substituted imidazole carboxylates containing ether side chains.

[0024] Figure 2 This is the hydrolysis pathway of methoxyetomidate hydrochloride.

[0025] Figure 3 This is the change trend of etomidate acid (40℃ / 75%RH).

[0026] Figure 4 This is the change trend of ethylene glycol methyl ether (40℃ / 75%RH).

[0027] Figure 5 This is the changing trend of etomidate acid (2~8℃).

[0028] Figure 6 This is the change trend of etomidate acid (25℃ / 60%RH).

[0029] Figure 7 This is the change trend of etomidate acid (40℃ / 75%RH). DETAILED DESCRIPTION

[0030] The present invention is further described in detail below in conjunction with specific embodiments. The given examples are only for illustrating the present invention, but not for limiting the scope of the present invention.

[0031] The experimental methods in the following examples are all conventional methods unless otherwise specified.

[0032] Unless otherwise specified, the materials and reagents used in the following examples can be obtained from commercial sources.

[0033] The structural formula of the raw material methoxyetomidate hydrochloride used in the following examples is as follows:

[0034]

[0035] CAS No.: 2170233-07-3

[0036] Example 1

[0037] The preparation method is as follows: according to the prescription in Table 2, the raw material and sucrose are dissolved in purified water to prepare a drug solution; then the drug solution is pre-frozen, that is, the shelf temperature is reduced to -35°C, the temperature is returned to -22°C and kept constant for 1 hour, and the temperature is further reduced to -45°C and kept constant for 2.5 hours, and it is frozen into a solid below the freezing point; the pre-freezing is normal pressure; then a (sublimation) drying is performed, that is, the temperature is increased to -20°C within 3 hours, and then the temperature is kept constant for 3 hours, the temperature is increased to -10°C within 14.5 hours, the temperature is kept constant for 7 hours, and the temperature is increased to 0°C within 7 hours, and the vacuum degree is maintained at 0.16 mbar during the primary drying process; finally, analytical drying is performed, that is, the temperature is increased to 24°C and kept constant for 8 hours, and the vacuum degree is maintained at 0.16 mbar during the analytical drying process; the freeze-dried preparation of the dry product is obtained by directly sublimating the ice to remove moisture, and the process parameters are shown in Table 1.

[0038] Table 1 Freeze drying parameters

[0039]

[0040] Table 2 Summary of prescription information and lyophilized forms

[0041]

[0042] Example 2

[0043] The preparation method is as follows: according to the prescription in Table 4, the raw material and glucose are dissolved in purified water to prepare a drug solution; then the drug solution is pre-frozen, that is, the shelf temperature is reduced to -8°C and kept at a constant temperature for 1 hour, and then the temperature is reduced to -45°C within 1.5 hours and kept at a constant temperature for 2 hours, and it is frozen into a solid below the freezing point; pre-freeze to normal pressure; then a (sublimation) drying is performed, that is, the temperature is increased to -10°C within 1.5 hours, and then the temperature is maintained for 13.3 hours, and the vacuum degree is maintained at 0.20 mbar during the primary drying process; then analytical drying is performed, that is, the temperature is increased to 24°C within 1 hour and the temperature is maintained for 5 hours, and the vacuum degree is maintained at 0.20 mbar during the process, and finally 24°C is maintained to draw an ultimate vacuum (the vacuum degree is set to 0 mbar) for 1.5 hours; the freeze-dried preparation of the dry product is obtained by directly sublimating the ice to remove moisture, and the process parameters are shown in Table 3.

[0044] Table 3 Freeze drying parameters

[0045]

[0046] Table 4 Prescription information and freeze-dried form summary

[0047]

[0048] Example 3

[0049] The preparation method is as follows: according to the prescription in Table 5, the raw material drug and mannitol are dissolved in purified water to prepare a drug solution; then the drug solution is pre-frozen to freeze into a solid below the freezing point; and then the ice is directly sublimated by primary (sublimation) drying and analytical drying to remove water to obtain a lyophilized preparation of a dry product. The process parameters are shown in Table 1.

[0050] Table 5 Prescription information and freeze-dried form summary

[0051]

[0052] Example 4

[0053] The preparation method is as follows: according to the prescription in Table 6, the raw material drug and mannitol are dissolved in purified water to prepare a drug solution; then the drug solution is pre-frozen to freeze into a solid below the freezing point; and then the ice is directly sublimated by primary (sublimation) drying and analytical drying to remove water to obtain a lyophilized preparation of a dry product. The process parameters are shown in Table 1.

[0054] Table 6 Prescription information and freeze-dried form summary

[0055]

[0056] From the data of Examples 1 to 4 above, it can be seen that mannitol, sucrose, and glucose are selected as freeze-dried fillers. Judging from the freeze-dried morphology, mannitol is the best, sucrose is the second, and glucose cannot form a cake-like morphology; therefore, mannitol is preferred as the freeze-dried filler. Further optimization and verification showed that when the mass ratio of the API to mannitol was 1:0.75 to 1:1.5, the freeze-dried cake was full, the surface was smooth, and the freeze-dried morphology met the requirements.

[0057] Example 5

[0058] The preparation method is as follows: according to prescription 3 in Table 6, the raw material drug and mannitol are dissolved in purified water to prepare a drug solution; the drug solution is then pre-frozen to freeze into a solid below the freezing point; and then the ice is directly sublimated by primary (sublimation) drying and analytical drying to remove water to obtain a freeze-dried preparation of a dry product. The process parameters are shown in Table 1.

[0059] Comparative Example

[0060] 1. The prescription composition is shown in Table 7:

[0061] Table 7 Comparative Example Prescription Information

[0062] Comparative Example Injection containing 35% propylene glycol (sterile) Injection (API aqueous solution, non-sterile) Methoxyetomidate hydrochloride 1%(w / w) 1%(w / w) Propylene glycol 35%(V / V) / Anhydrous disodium hydrogen phosphate 4.5%(w / w) / Water for injection Add to 100% Add to 100%

[0063] 2. The preparation method is as follows:

[0064] Injection containing 35% propylene glycol (sterile): dissolve the raw materials and excipients in purified water according to the prescription in Table 7 to prepare the liquid medicine; fill the liquid medicine into 10mL ampoule with a filling volume of 10mL; sterilize it in a steam sterilizer at 121℃ for 12 minutes.

[0065] Injection (API aqueous solution, not sterile): prepare the drug solution by purifying water with the raw material and auxiliary material solution according to the prescription in Table 7; fill the drug solution into a 10mL vial with a filling volume of 1.25mL; and roll the rubber stopper and aluminum cap to obtain the drug solution.

[0066] 3. Stability study

[0067] The lyophilized preparation (Example 5) and the injection solution containing 35% propylene glycol (sterilized) were subjected to an accelerated comparative test at 40°C / 75%RH. The test results are shown in Table 8, and the impurity change trend diagram is shown in Figures 3-4 .

[0068] The stability comparison test of the lyophilized preparation (Example 5) and the injection (API aqueous solution, not sterilized) was carried out at 40°C / 75%RH, 25°C / 60%RH and 2-8°C respectively. The test results are shown in Table 9 and the impurity change trend diagram is shown in Figures 5 to 7 .

[0069] Table 8 Comparison of accelerated test results of freeze-dried preparation and injection containing 35% propylene glycol (sterilization)

[0070]

[0071] Table 9 Comparison of the results of etomidate acid impurities under various test conditions for lyophilized preparations and injections (API aqueous solution, non-sterile)

[0072]

[0073] The lyophilized preparation (Example 5) was subjected to a long-term stability test at 25°C / 60%RH and 2-8°C. The test results are shown in Tables 10 and 11.

[0074] Table 10 Summary of stability test results of freeze-dried preparations (25°C / 60%RH)

[0075]

[0076] Table 11 Summary of stability test results of freeze-dried preparations (2°C to 8°C)

[0077]

[0078] The results show that the stability of the freeze-dried preparation of the anhydrous system is significantly better than that of the aqueous injection. The present invention can improve the stability and safety of the drug preparation, and can carry out large-scale commercial production, with good social and economic benefits.

Claims

1. A pharmaceutical preparation of a chiral N-substituted imidazole carboxylate compound containing an ether side chain, characterized in that: The pharmaceutical preparation is sterile powder for injection; the sterile powder for injection is composed of an N-substituted imidazole carboxylate chiral compound containing an ether side chain and a filler.

2. The pharmaceutical preparation according to claim 1, characterized in that: The mass ratio of the N-substituted imidazole carboxylate chiral compound containing an ether side chain to the filler is 1:0.5 to 1:3, preferably 1:0.75 to 1:1.

5.

3. The pharmaceutical preparation according to claim 1 or 2, characterized in that: The N-substituted imidazole carboxylate chiral compound containing an ether side chain is methoxyetomidate hydrochloride; The filler is mannitol, sucrose or glucose.

4. The pharmaceutical preparation according to claim 3, characterized in that: The filler is mannitol.

5. The method for preparing the pharmaceutical preparation according to any one of claims 1 to 4, comprising the following steps: The N-substituted imidazole carboxylate chiral compound containing an ether side chain and a filler are dissolved in water to obtain a drug solution; the drug solution is dried to remove moisture to obtain the drug preparation.

6. The preparation method according to claim 5, characterized in that: The mass ratio of the N-substituted imidazole carboxylate chiral compound containing an ether side chain to the filler is 1:0.75 to 1:1.5; In the drug solution, the mass percentage concentration of the N-substituted imidazole carboxylate chiral compound containing an ether side chain is 1% to 30%.

7. The preparation method according to claim 6, characterized in that: In the drug solution, the mass percentage concentration of the N-substituted imidazole carboxylate chiral compound containing an ether side chain is 4% to 10%.

8. The preparation method according to any one of claims 5 to 7, characterized in that: The drying is performed by spray drying or freeze drying.

9. The preparation method according to claim 8, characterized in that: The freeze-drying method is carried out under the following conditions: pre-freezing is performed first, followed by primary drying and analytical drying.

10. The preparation method according to claim 9, characterized in that: The pre-freezing conditions are as follows: temperature -8°C to -60°C, time 1h to 5h, freezing into a solid below the freezing point; pre-freezing is at normal pressure; The conditions of the primary drying are as follows: temperature -20°C to 5°C, time 5h to 30h, and vacuum degree 0mbar to 0.25mbar during the primary drying process; The conditions of the analytical drying are as follows: temperature 15° C. to 30° C., time 2 h to 12 h, and vacuum degree 0 mbar to 0.25 mbar during the analytical drying process.

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