Pharmaceutical composition containing etomidate derivative and cyclopofol and application thereof

Abstract

The invention relates to a pharmaceutical composition of an etomidate derivative and cyclopofol, and a pharmaceutical composition containing the etomidate derivative and the cyclopofol. Use of the pharmaceutical combination or pharmaceutical composition for anesthesia, sedation and / or hypnosis of animals or humans. Compared with independent administration of the etomidate derivative or the cyclopofol and combined administration of the etomidate and the cyclopofol, the pharmaceutical composition or the pharmaceutical composition shows an excellent synergistic effect, and the waking time after anesthesia withdrawal is remarkably improved.

Description

[0001] This application claims priority to Chinese patent application No. 202410659616.3, filed May 27, 2024, and to Chinese patent application No. 202510476413.5, filed April 16, 2025. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to a specific pharmaceutical combination of an etomidate derivative and propofol, and a pharmaceutical composition comprising the etomidate derivative and propofol. The present invention also provides use of the pharmaceutical combination or the pharmaceutical composition for anesthesia, sedation and / or hypnosis in animals or humans. Background Art

[0003] More than 300 million surgical operations are performed worldwide each year. Currently, commonly used anesthetic sedatives in clinical practice, such as sevoflurane, midazolam, propofol, and etomidate, generally have problems such as slow awakening and poor quality of anesthesia awakening when used for anesthesia maintenance. They do not meet the clinical requirements for new anesthetics such as "safe, fast, and comfortable".

[0004] The use of anesthetic drugs requires precise monitoring to ensure patient safety, improve surgical success rates, and optimize postoperative recovery. After administering anesthesia, monitoring the time from drug withdrawal to awakening (hereinafter referred to as awakening time) and the time from drug withdrawal to the ability to walk normally (hereinafter referred to as walking time) is crucial for evaluating the effectiveness and safety of anesthesia.

[0005] Etomidate has the advantages of mild respiratory effects, weak sympathetic and cardiovascular inhibitory effects, and can mildly dilate coronary arteries, reduce intracranial pressure, and maintain cerebral perfusion. Literature reports that etomidate anesthesia can easily lead to blood glucose instability, manifested as a significant increase or decrease compared to preoperative blood glucose levels. However, perioperative blood glucose fluctuations and electrolyte imbalances have the potential to increase the risk of readmission and prolong hospitalization. Improving perioperative blood glucose control and maintaining stable electrolyte levels have profound implications for improving mid- to long-term outcomes for patients, particularly those in the elderly with metabolic diseases.

[0006] International patent application WO2017059827A1 discloses an etomidate derivative; international patent application WO2014180305A1 discloses a class of propofol derivatives; Chinese patent CN112245426A records a phenol derivative, specifically a pharmaceutical composition of propofol and etomidate.

[0007] Although the aforementioned etomidate derivatives are expected to be administered alone for anesthesia induction in patients, there is currently a lack of research on their combined administration with propofol derivatives, especially propofol. There is still an urgent need for more effective and safe anesthetics in clinical practice, especially how to improve the awakening and walking time after discontinuation of existing anesthetics, which has become one of the clinical pain points. Summary of the Invention

[0008] The present invention is expected to improve the above-mentioned problems by co-administering (or administering) a combination comprising a specific etomidate derivative and propofol. Specifically, the present inventors conducted in-depth research on the co-administration of a drug combination comprising an etomidate derivative and propofol, and surprisingly found that the co-administration of an etomidate derivative and propofol exhibited a very excellent synergistic effect compared to the administration of either the etomidate derivative or propofol alone, and also exhibited an excellent synergistic effect compared to the drug combination of etomidate and propofol, such as significantly improved awakening time.

[0009] Therefore, in one aspect, the present invention provides a method for inducing or maintaining anesthesia and / or promoting sedation in animals or humans, comprising administering to the animal or human an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, wherein the etomidate derivative is a compound represented by formula (1):

[0010]

[0011] where R 1 C 1-6 alkyl.

[0012] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (hereinafter referred to as compound 2).

[0013] On the other hand, the present invention also provides a drug combination comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof.

[0014] In some embodiments, the etomidate derivative or a pharmaceutically acceptable salt thereof may also be methoxyetomidate or its hydrochloride; the propofol may also be replaced by fospropofol disodium.

[0015] In another aspect, the present invention further provides a combination comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, for use in anesthesia, sedation, and / or hypnosis in animals or humans, and in the treatment and / or prevention of diseases such as nausea, vomiting, convulsions, or epilepsy; preferably, for anesthesia, sedation, or hypnosis in animals or humans; the anesthesia is anesthesia induction or anesthesia maintenance; and the sedation is mild sedation, moderate sedation, or deep sedation.

[0016] Furthermore, the present invention also provides a use of a combination comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, for preparing a medicament for anesthesia, sedation and / or hypnosis, and for treating and / or preventing nausea, vomiting, convulsions or epilepsy in animals or humans; preferably, the medicament is used for anesthesia, sedation or hypnosis in animals or humans; preferably, the anesthesia is anesthesia induction or anesthesia maintenance; and preferably, the sedation is mild sedation, moderate sedation or deep sedation.

[0017] In addition, the present invention also relates to the following aspects:

[0018] (1) Use of a combination of an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof in the preparation of a medicament for anesthesia, sedation and / or hypnosis for animals or humans;

[0019] (2) Use of an etomidate derivative, particularly Compound 2 or a pharmaceutically acceptable salt or prodrug thereof, in the preparation of a drug for anesthesia, sedation and / or hypnosis for animals or humans, wherein the etomidate derivative, pharmaceutically acceptable salt, prodrug or isotopic derivative thereof is administered in combination with propofol, pharmaceutically acceptable salt, prodrug or isotopic derivative thereof;

[0020] (3) Use of propyltrimonium chloride, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives in the preparation of a drug for anesthesia, sedation and / or hypnosis in animals or humans, wherein the propyltrimonium chloride, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives are administered in combination with etomidate derivatives or their pharmaceutically acceptable salts; or their prodrugs or their isotopic derivatives; or their prodrugs or their isotopic derivatives;

[0021] (4) Etomidate derivatives, in particular Compound 2, its pharmaceutically acceptable salts, prodrugs or isotopic derivatives, for use in anesthesia, sedation and / or hypnosis in animals or humans, wherein the etomidate derivatives, its pharmaceutically acceptable salts, prodrugs or isotopic derivatives are administered in combination with propofol, its pharmaceutically acceptable salts, prodrugs or isotopic derivatives;

[0022] (5) Propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, which is used for anesthesia, sedation and / or hypnosis in animals or humans, wherein the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in combination with an etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative.

[0023] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the mass ratio of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is in the range of about 10:1 to about 1:10, calculated based on the concentration of propofol and the mass ratio of propofol:Compound 2.

[0024] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is in the range of about 5:1 to about 0.25:10, for example, in the range of about 4:1 to about 1:5, in the range of about 3:1 to about 1:2, in the range of about 2:1 to about 1:1, or in the range of about 1.25:1 to about 1:1.

[0025] In some embodiments, the mass ratio of the propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof is calculated as the mass ratio of propofol:Compound 2, for example, in the range of about 4:1 to about 1:4, in the range of about 3:1 to about 1:3, in the range of about 3:1 to about 1:2, in the range of about 2:1 to about 1:2, and for example, in the range of about 4:1 to about 1:2.

[0026] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof is calculated as the mass ratio of propofol:Compound 2, for example, in the range of about 1:2 to about 4:1, in the range of about 1:2 to about 8:3, in the range of about 1:2 to about 2.5:1, in the range of about 1:2 to about 1.25:1, in the range of about 1:2 to about 0.625:1; or in the range of about 0.6 The range of about 25:1 to about 4:1, the range of about 0.625:1 to about 8:3, the range of about 0.625:1 to about 2.5:1, the range of about 0.625:1 to about 1.25:1; the range of about 1.25:1 to about 4:1, the range of about 1.25:1 to about 8:3, the range of about 1.25:1 to about 2.5:1; the range of about 2.5:1 to about 4:1, the range of about 2.5:1 to about 8:3; the range of about 8:3 to about 4:1.

[0027] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the mass ratio of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:1, calculated based on the concentration of propofol and the mass ratio of propofol:Compound 2.

[0028] In some embodiments, in the combinations, pharmaceutical combinations, methods or uses of the present invention, the dosage administered must of course be carefully adjusted to the age, weight and condition of the individual being treated, as well as the route of administration, dosage form and dosage regimen, and the desired outcome, and the exact dosage should of course be determined by the physician. The actual dosage depends on the nature and severity of the disease being treated, the exact route of administration and dosage form, and may be varied by increasing the dosage according to the specific circumstances of the invention to produce the desired therapeutic effect, within the physician's discretion. The mass of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the mass of propofol, is about 0.1 to about 1000 mg, for example, about 1 to about 750 mg, which is suitable for therapeutic treatment; the mass of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the mass of Compound 2, is about 0.1 to about 1000 mg, for example, about 1 to about 750 mg, which is suitable for therapeutic treatment.

[0029] In some embodiments, in the combinations, pharmaceutical combinations, methods, or uses of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid formulation, such as an injectable formulation. In the combinations, pharmaceutical combinations, methods, or uses of the present invention, the concentration of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid formulation is about 0.1 mg / mL to about 50 mg / mL, calculated as the concentration of Compound 2.

[0030] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the psorafenib, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid formulation, such as an injectable formulation. In the combination, pharmaceutical combination, method or use of the present invention, the concentration of the psorafenib, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid formulation is about 0.1 mg / mL to about 50 mg / mL, calculated as the concentration of psorafenib.

[0031] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are administered (or applied) in combination, including but not limited to simultaneous, sequential or separate administration. In the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are administered continuously by intravenous infusion.

[0032] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are administered simultaneously; preferably, the two are mixed with an optional pharmaceutically acceptable carrier and administered simultaneously.

[0033] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are administered sequentially; preferably, the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered first, and the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative or its prodrug or its isotopic derivative is administered subsequently; or the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered first, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered subsequently.

[0034] In some embodiments, in the combination, drug combination, method or use of the present invention, the combined administration method further comprises the simultaneous, sequential or separate administration of any one or more of the following drugs: general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, anesthetic adjuvants, neuromuscular blocking drugs and analgesics.

[0035] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the anesthesia is anesthesia induction or anesthesia maintenance; the sedation is light sedation, moderate sedation or deep sedation.

[0036] In some embodiments, in the combinations, pharmaceutical combinations, methods or uses of the invention, the infusion rate will be determined based on the patient's age, weight or anxiety level. In some embodiments, in the combinations, pharmaceutical combinations, methods or uses of the invention, the infusion rate will be determined based on the duration or extent of the surgery.

[0037] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the infusion rate of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative or the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is between about 1 mL / h and about 1000 mL / h.

[0038] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative can also be mixed together for administration, including but not limited to directly mixing two commercial preparations obtained commercially, or mixing the two into a single preparation in accordance with pharmaceutical industry practice standards.

[0039] In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the puromycin, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative can be administered by a route selected from the following: intravenous infusion, intravenous push injection, intramuscular injection, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, intranasal, inhalation, by topical delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal; preferably intravenous infusion, intravenous push injection or inhalation injection. In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, it is preferred that the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are simply mixed together and continuously administered by intravenous infusion.

[0040] In some embodiments, in the combinations, pharmaceutical combinations, methods or uses of the present invention, an opioid analgesic is administered prior to the administration of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative. In some embodiments, the opioid analgesic is selected from one or more of fentanyl, remifentanil, sufentanil, alfentanil, etc.

[0041] The present invention relates to a pharmaceutical combination product, which comprises an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, wherein the etomidate derivative is an etomidate derivative of formula (1):

[0042]

[0043] where R 1 C 1-6 alkyl.

[0044] In some embodiments, the pharmaceutical combination product of the present invention consists of the etomidate derivative of formula (1), its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative and propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative.

[0045] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (also referred to as Compound 2).

[0046] In some embodiments, the mass ratio of the cyclopentolate, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, e.g., Compound 2, is in the range of about 10: 1 to about 1 : 10, e.g., about 4: 1 to about 1 : 5, about 3: 1 to about 1 : 2, about 2: 1 to about 1 : 1, about 1.25: 1 to about 1 : 1, calculated as a mass ratio of cyclopentolate: Compound 2.

[0047] In some embodiments, the mass ratio of the cyclopentolate, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, e.g., Compound 2, is in the range of about 5: 1 to about 0.25: 10, e.g., about 4: 1 to about 1 : 5, about 3: 1 to about 1 : 2, about 2: 1 to about 1 : 1, about 1.25: 1 to about 1 : 1, calculated as a mass ratio of cyclopentolate: Compound 2.

[0048] In some embodiments, the mass ratio of the cyclopentolate, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, e.g., Compound 2, is in the range of about 5: 1 to about 0.25: 10, e.g., about 4: 1 to about 1 : 5, about 3: 1 to about 1 : 2, about 2: 1 to about 1 : 1, about 1.25: 1 to about 1 : 1, calculated as a mass ratio of cyclopentolate: Compound 2.

[0049] In some embodiments, the mass ratio of the cyclopentolate, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, e.g., Compound 2, is in the range of about 5: 1 to about 0.25: 10, e.g., about 4: 1 to about 1 : 5, about 3: 1 to about 1 : 2, about 2: 1 to about 1 : 1, about 1.25: 1 to about 1 : 1, calculated as a mass ratio of cyclopentolate: Compound 2.

[0050] In some embodiments, the mass ratio of the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:1, calculated based on the concentration of propofol and the mass ratio of propofol:Compound 2.

[0051] In some embodiments, the dose administered must of course be carefully adjusted to the age, weight, and condition of the individual being treated, as well as the route of administration, dosage form, and dosing regimen, and the desired outcome, and the exact dose should of course be determined by the physician. The actual dose depends on the nature and severity of the disease being treated, the exact route of administration, and the dosage form, and can be varied by increasing the dose according to the specific circumstances of the invention, within the physician's discretion, to produce the desired therapeutic effect. A mass of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative calculated based on the mass of propofol is suitable for therapeutic treatment; a mass of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative calculated based on the mass of Compound 2 is suitable for therapeutic treatment.

[0052] In some embodiments, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid formulation, such as an injectable formulation. In the combination, pharmaceutical combination, method, or use of the present invention, the concentration of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid formulation is in the range of about 0.1 mg / mL to about 50 mg / mL, calculated as the concentration of Compound 2.

[0053] In some embodiments, the pivoxil, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid formulation, such as an injectable formulation. In the combination, pharmaceutical combination, method or use of the present invention, the concentration of the pivoxil, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid formulation is about 0.1 mg / mL to about 50 mg / mL of pivoxil calculated as the concentration of pivoxil.

[0054] In some embodiments, the pharmaceutical combination product consists of a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and one or more pharmaceutically acceptable carriers; the second pharmaceutical composition comprises an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and one or more pharmaceutically acceptable carriers; the first pharmaceutical composition and the second pharmaceutical composition are formed by mixing, subpackaging or combining to form the pharmaceutical combination product.

[0055] The present invention relates to a pharmaceutical composition, which is a pharmaceutical composition in the form of a single preparation, wherein propylparaben, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, and one or more pharmaceutically acceptable carriers are mixed to form a preparation; wherein the etomidate derivative is a compound of formula (1):

[0056]

[0057] where R 1 C 1-6 alkyl.

[0058] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (Compound 2 below).

[0059] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is in the range of about 5:1 to about 0.25:10, for example, in the range of about 4:1 to about 1:5, in the range of about 3:1 to about 1:2, in the range of about 2:1 to about 1:1, or in the range of about 1.25:1 to about 1:1.

[0060] In some embodiments, the mass ratio of propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into the mass ratio of propofol to Compound 2 (propofol: Compound 2) is in the range of 10:1 to 1:10, for example, in the range of 4:1 to 1:4, in the range of 3:1 to 1:3, in the range of 3:1 to 1:2, in the range of 2:1 to 1:2, in the range of 3:1 to 1:2, and in the range of 4:1 to 1:2.

[0061] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof is calculated as the mass ratio of propofol:Compound 2, for example, in the range of about 1:2 to about 4:1, in the range of about 1:2 to about 8:3, in the range of about 1:2 to about 2.5:1, in the range of about 1:2 to about 1.25:1, in the range of about 1:2 to about 0.625:1; or in the range of about 0.6 The range of about 25:1 to about 4:1, the range of about 0.625:1 to about 8:3, the range of about 0.625:1 to about 2.5:1, the range of about 0.625:1 to about 1.25:1; the range of about 1.25:1 to about 4:1, the range of about 1.25:1 to about 8:3, the range of about 1.25:1 to about 2.5:1; the range of about 2.5:1 to about 4:1, the range of about 2.5:1 to about 8:3; the range of about 8:3 to about 4:1.

[0062] In some embodiments, the mass ratio of propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into the mass ratio of propofol to Compound 2 (propofol: Compound 2) is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3 or about 4:1.

[0063] In some embodiments, the hydrolysis impurity fluoroetominic acid in the pharmaceutical composition in a single dosage form is reduced by about 70-80% compared to the hydrolysis impurity etominic acid in a corresponding pharmaceutical combination containing etomidate and propofol under the same conditions. In some embodiments, the propofol impurity 19 in the pharmaceutical composition in a single dosage form is reduced by at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70% or at least about 75% compared to the propofol impurity 19 in a corresponding pharmaceutical combination containing etomidate and propofol under the same conditions. In some embodiments, the total impurities in the pharmaceutical composition in a single dosage form are reduced by at least 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55% or at least about 60% compared to the total impurities in a corresponding pharmaceutical combination containing etomidate and propofol under the same conditions.

[0064] In some embodiments, the pharmaceutical composition in single dosage form is in the form of an emulsion.

[0065] In some embodiments, the content of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into Compound 2 is 0.01-5 wt% of Compound 2 relative to the total mass of the pharmaceutical composition in the form of a single formulation.

[0066] In some embodiments, the content of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into propofol is 0.01-5 wt% of the total mass of the pharmaceutical composition in the form of a single preparation.

[0067] In some embodiments, the pharmaceutically acceptable carrier is selected from one or more of an oily component, an emulsifier, a stabilizer, an osmotic pressure regulator, water for injection, an emulsifier aid, a pH regulator, a solubilizer, a cosolvent, and a filler.

[0068] In some embodiments, the oily component is selected from any one of soybean oil and medium-chain triglycerides, or a mixture of any of them in any proportion;

[0069] In some embodiments, the content of the oily component in the pharmaceutical composition is 5-30 wt %.

[0070] In some embodiments, the emulsifier is selected from egg yolk lecithin.

[0071] In some embodiments, the content of the emulsifier in the pharmaceutical composition is 0.5-3 wt %.

[0072] In some embodiments, the stabilizer is selected from sodium oleate, oleic acid, or any mixture thereof in any proportion.

[0073] In some embodiments, the content of the stabilizer in the pharmaceutical composition is 0.01-1% wt %.

[0074] In some embodiments, the osmotic pressure regulating agent is selected from glycerol.

[0075] In some embodiments, the content of the osmotic pressure regulator in the pharmaceutical composition is 1-5 wt%;

[0076] The present invention provides a method for preparing a pharmaceutical composition in the form of a single preparation, wherein the pharmaceutical composition contains an etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and propyltrimonium chloride, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and one or more pharmaceutically acceptable carriers. The method comprises mixing propyltrimonium chloride, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, an etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and one or more pharmaceutically acceptable carriers, wherein the etomidate derivative is an etomidate derivative of formula (1):

[0077] wherein R1 is C1-6 alkyl; and

[0078] The pharmaceutically acceptable carrier is selected from one or more of an oily component, an emulsifier, a stabilizer, an osmotic pressure regulator, injection water, an emulsifier aid, a pH regulator, a solubilizer, a latent solvent and a filler.

[0079] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (Compound 2 below).

[0080] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is in the range of about 5:1 to about 0.25:10, for example, in the range of about 4:1 to about 1:5, in the range of about 3:1 to about 1:2, in the range of about 2:1 to about 1:1, or in the range of about 1.25:1 to about 1:1.

[0081] In some embodiments, the mass ratio of propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into the mass ratio of propofol to Compound 2 (propofol: Compound 2) is in the range of 10:1 to 1:10, for example, in the range of 4:1 to 1:4, in the range of 3:1 to 1:3, in the range of 3:1 to 1:2, in the range of 2:1 to 1:2, in the range of 3:1 to 1:2, and in the range of 4:1 to 1:2.

[0082] In some embodiments, the mass ratio of propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into the mass ratio of propofol to Compound 2 (propofol: Compound 2) is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3 or about 4:1.

[0083] In some embodiments, the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof is calculated as the mass ratio of propofol:Compound 2, for example, in the range of about 1:2 to about 4:1, in the range of about 1:2 to about 8:3, in the range of about 1:2 to about 2.5:1, in the range of about 1:2 to about 1.25:1, in the range of about 1:2 to about 0.625:1; or in the range of about 0.6 The range of about 25:1 to about 4:1, the range of about 0.625:1 to about 8:3, the range of about 0.625:1 to about 2.5:1, the range of about 0.625:1 to about 1.25:1; the range of about 1.25:1 to about 4:1, the range of about 1.25:1 to about 8:3, the range of about 1.25:1 to about 2.5:1; the range of about 2.5:1 to about 4:1, the range of about 2.5:1 to about 8:3; the range of about 8:3 to about 4:1.

[0084] In some embodiments, the content of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into Compound 2 is 0.01-5 wt% of Compound 2 relative to the total mass of the pharmaceutical composition in the form of a single formulation.

[0085] In some embodiments, the content of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative converted into propofol is 0.01-5 wt% of the total mass of the pharmaceutical composition in the form of a single preparation.

[0086] In some embodiments, the method comprises: simultaneously adding an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to an oil phase, and then mixing the oil phase and the aqueous phase to form the pharmaceutical composition in the form of a single formulation, wherein the pharmaceutically acceptable carrier comprises an oily component, an emulsifier, a stabilizer, an osmotic pressure regulator, and water for injection, and one or more optional pharmaceutically acceptable carriers selected from a co-emulsifier and a pH regulator.

[0087] In some embodiments, the method comprises:

[0088] 1) Preparation of the oil phase: Mix the required amounts of the oil component, the emulsifier, and the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and stir uniformly at 50-80° C. to obtain the oil phase;

[0089] 2) Preparation of aqueous phase: Mix the required amounts of stabilizer, osmotic pressure regulator, water for injection, and optional pH regulator, and stir uniformly at 50-80° C. to obtain an aqueous phase;

[0090] 3) Emulsion preparation: The oil phase and the water phase are sheared at 50-80° C. to form colostrum, which is then homogenized in a homogenizer, followed by filling, nitrogen filling, and sterilization to obtain the pharmaceutical composition in the form of a single preparation.

[0091] In some embodiments, the oily component is soybean oil, medium chain triglycerides, or a combination thereof.

[0092] In some embodiments, the emulsifier is refined egg yolk lecithin.

[0093] Beneficial effects

[0094] Compared with the prior art, the combination, drug combination, method or use of the present invention has the following beneficial effects:

[0095] (1) The drug combination of the present invention has a synergistic effect on significantly shortening the awakening time and walking time, and has a higher safety index: the drug combination of the etomidate derivative (Compound 2) and the propofol drug contained in the present invention is jointly administered, and its awakening time and walking time are not only significantly shorter than the propofol combined with etomidate group, but also significantly shorter than the propofol and compound (2) single drug group, and overcomes the problem of prolonged awakening time in the propofol combined with etomidate group in the prior art; in addition, the drug combination of the present invention has a higher safety index (significantly higher than the propofol combined with etomidate group), and widens the anesthesia safety window. The above beneficial effects indicate that the drug combination of the present invention has high clinical value in ensuring perioperative anesthesia safety, shortening awakening time, helping rapid recovery, improving surgical turnover rate, and improving awakening quality and anesthesia satisfaction.

[0096] (2) The drug combination of the present invention has a synergistic improvement effect on the fluctuation of blood glucose level and the decrease of blood potassium level: when the drug combination of the etomidate derivative (Compound 2) and propylparaben is administered in combination, the blood glucose level after administration is not significantly different from that before administration, while the propylparaben combined with etomidate group has a significant fluctuation (P < 0.05); similarly, the blood potassium level of the drug combination of the present invention during the infusion process and after drug withdrawal is not significantly different from that before administration or is significantly decreased, while the blood potassium level of the propylparaben combined with etomidate group during the infusion process and after drug withdrawal is significantly decreased (P < 0.05) or the degree of decrease is significant (> 20%), indicating that the drug combination of the present invention has a high clinical value in reducing the burden of perioperative metabolic or electrolyte monitoring and improving the long-term prognosis of elderly patients or patients with metabolic diseases.

[0097] (3) Compared to the drug combination of etomidate and propofol, the drug combination containing etomidate derivatives and propofol of the present invention has a significantly reduced content of hydrolysis impurities, namely, fluoroetomimic acid. The inventors of the present invention have found that the hydrolysis impurity fluoroetomimic acid in the drug combination of the present invention is reduced by about 70-80% compared to the hydrolysis impurity etomimic acid in the corresponding drug combination containing etomidate and propofol under the same conditions. Therefore, the drug combination of the present invention reduces the adverse reactions caused by hydrolysis products in patients and improves the safety and effectiveness of the drug.

[0098] (4) Compared to the drug combination of etomidate and propofol, the content of propofol impurity 19 in the drug combination containing etomidate derivatives and propofol of the present invention is significantly reduced. The inventors found that the propofol impurity 19 in the combination of the present invention is reduced by at least about 10-75% compared to the propofol impurity 19 in the corresponding drug combination containing etomidate and propofol under the same conditions; the total impurity content is reduced by about 30-60%, reducing the adverse reactions caused by propofol impurity 19 and other impurities in the drug composition, and improving the safety and efficacy of the drug.

[0099] (5) In the pharmaceutical combination of the etomidate derivative and propofol of the present invention, the encapsulation efficiency of the etomidate derivative is above 97.7%, which is much higher than the encapsulation efficiency of etomidate in the corresponding pharmaceutical composition of etomidate and propofol. Therefore, the pharmaceutical combination of the etomidate derivative and propofol of the present invention can effectively reduce the adverse reactions caused by free drug and further improve the stability and bioavailability of the drug.

[0100] (6) The drug combination of etomidate derivatives and propofol in the form of a single preparation of the present invention improves the convenience of drug use, is simple and easy to process, and is conducive to industrial production and promotion of use.

[0101] Definition of terms

[0102] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears herein, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0103] The term "C 1-6 "Alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.

[0104] The term "derivative" refers to a series of structurally related compounds obtained by modifying or remodeling the chemical structure of a lead compound. These derivatives generally possess superior physicochemical properties, pharmacological activity, or safety. In some embodiments, etomidate derivatives include, but are not limited to, those having the general formula 1, further exemplified by Compound 2 herein. Where applicable, the mass, concentration, and other parameters of the etomidate derivatives described herein may generally be calculated based on the mass, concentration, and other parameters achieved with an equimolar amount of Compound 2.

[0105] The term "pharmaceutically acceptable salt" refers to a salt formed by the reaction of the active ingredient with a pharmaceutically acceptable acid or base. These salts are safe and effective when administered to mammals and retain the original biological activity of the active ingredient. The "pharmaceutically acceptable salt of an etomidate derivative" described herein refers to a salt formed by the nitrogen atom of the imidazole ring in the structure of the etomidate derivative of Formula 1 or Compound 2 of the present invention and a pharmaceutically acceptable acid. In some embodiments, the pharmaceutically acceptable acid includes but is not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, or camphorsulfonic acid. The "pharmaceutically acceptable salt of propofol" described herein refers to a salt formed by propofol with a pharmaceutically acceptable base, such as a sodium salt, calcium salt, magnesium salt, disodium phosphate salt, or sodium monohydrogen phosphate salt.

[0106] The term "prodrug" refers to a compound that, through chemical modification, converts an active drug into an inactive or less active form, which then releases the active parent drug after biotransformation in vivo (e.g., via the action of metabolic enzymes or spontaneous chemical reactions). The "prodrugs of etomidate derivatives" of the present invention include those chemically modified compounds that are capable of releasing etomidate or etomidate derivatives in vivo. The "prodrugs of propofol" of the present invention also include those chemically modified compounds that are capable of releasing propofol in vivo.

[0107] The term "isotopic derivative" refers to a compound that differs from a compound described herein only in the presence of one or more isotopically enriched atoms. For example, a compound having the structure shown in the general formula with deuterium or tritium replacing hydrogen, and / or with 18 F replaces fluorine, and / or, with 11 C. 13 C or 14 Deuterated compounds generally retain comparable activity to their undeuterated counterparts, and deuteration at specific sites can achieve improved metabolic stability, leading to certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements).

[0108] The terms "combination", "drug combination" or "drug combination product" as used herein refer to a drug product formed by mixing or combining two or more active ingredients. In a drug combination product, these active ingredients may be mixed into a single preparation, or these active ingredients may be kept separate in different preparations, for example, the active ingredients are mixed with necessary pharmaceutically acceptable carriers in proportion to form a mixed solution and then sold, or they are packaged in different containers in a certain proportion and sold in a bundle, or commercial preparations containing these active ingredients are obtained from different commercial institutions through commercial channels and used in combination. The active ingredients in the drug combination product may be administered simultaneously, separately or sequentially. In addition, it should be understood that the drug combination product may also be provided in a non-standard commercial form, for example, the two or more active ingredients contained therein may be simply mixed with necessary pharmaceutically acceptable carriers and then administered in a medical setting.

[0109] The term "administration" or "application" as used herein refers to a method for delivering an active ingredient or a composition thereof to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intracerebroventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, or intravascular injection or infusion), topical administration, and rectal administration. In particular, administration by injection or oral administration is contemplated.

[0110] The term "combination" as used in the present invention, whether it is "combination" alone, "combination administration" or "combination administration", refers to the application of two or more active ingredients contained in the above-mentioned "combination", "drug combination" or "drug combination product" to animals or humans and other subjects through a suitable administration method or route to achieve the desired disease treatment and / or prevention effect. The administration method or route includes but is not limited to: intravenous infusion, intravenous push injection, intramuscular injection, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, intranasal, inhalation, local delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal and intrathecal administration, etc.

[0111] As used herein, a "composition" or "pharmaceutical composition" refers to a formulation comprising one or more active ingredients in admixture with one or more pharmaceutically acceptable carriers. Pharmaceutical formulations facilitate administration of a compound to a subject (animal or human). Pharmaceutical formulations are typically tailored to a specific intended route of administration.

[0112] The term "pharmaceutically acceptable carrier" as used herein refers to a diluent, adjuvant, excipient, or vehicle administered with a therapeutic agent and suitable for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications consistent with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. In some embodiments, a pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solubilizer, latent solvent, cosolvent, or encapsulating material. Pharmaceutically acceptable carriers that can be used in pharmaceutical compositions include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc. The pharmaceutical composition may also contain a small amount of a wetting agent, emulsifier, pH adjuster, or osmotic pressure regulator as needed.

[0113] The term "entrapment efficiency" as used herein refers to the proportion of the drug or active ingredient encapsulated within the emulsion. A high encapsulation efficiency not only enables efficient, low-toxicity drug delivery but also significantly improves drug stability, effectively preventing drug inefficiency caused by reactions such as oxidation and hydrolysis during storage and transportation. Furthermore, the encapsulation efficiency directly impacts drug bioavailability. A high encapsulation efficiency ensures that more active ingredients reach the site of action, thereby enhancing therapeutic efficacy.

[0114] The term "s" is the time unit second, and "min" is the time unit minute.

[0115] The term "about" or "approximately" when used in conjunction with a numerical value indicates a set or range that includes the numerical value. For example, "about X" includes a range of values ​​of ±5%, ±2%, ±1%, ±0.5%, ±0.2%, or ±0.1% of X, where X is a numerical value. In some embodiments, the term "about" refers to a range of values ​​that are 5% more or less than the specified value. In some embodiments, the term "about" refers to a range of values ​​that are 2% more or less than the specified value. In some embodiments, the term "about" or "approximately" refers to a range of values ​​that are 1% more or less than the specified value.

[0116] The term "anesthesia" refers to a controllable, reversible, temporary loss of sensation or consciousness state for human medical or veterinary purposes. It can include partial or complete analgesia (relief or prevention of pain), paralysis (muscle relaxation), amnesia (memory loss), and unconsciousness, providing conditions for surgical treatment or other medical examination. The use and pharmaceutical combination described in the present application can be used alone in various medical scenarios such as general anesthesia, regional anesthesia, and local anesthesia, or can be administered simultaneously, sequentially, or separately with any one or more of general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, auxiliary drugs, neuromuscular blocking drugs, and analgesics.

[0117] The term "anesthesia induction" refers to the process of converting a patient from a conscious state to an anesthetized state by intravenous anesthesia or inhalation anesthesia, which can quickly and smoothly make the patient unconscious and suppress the stress response, including but not limited to intravenous rapid induction, inhalation anesthesia induction, and slow induction with preserved spontaneous breathing. The use and pharmaceutical combination described in the present application can be used alone for anesthesia induction, or can be administered simultaneously, sequentially, or separately with any one or more of general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, auxiliary drugs, neuromuscular blocking drugs, and analgesics.

[0118] The term "anesthesia maintenance" refers to the appropriate and stable depth of anesthesia of the human or animal body, which is manifested as loss of consciousness and no response to surgical stimulation, and stable vital signs. The use and pharmaceutical combination described in the present application can be used alone for anesthesia maintenance, or can be administered simultaneously, sequentially, or separately with any one or more of general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, auxiliary drugs, neuromuscular blocking drugs, and analgesics.

[0119] The term "sedation" refers to the inhibition of the central nervous system of the human or animal body by drugs, which reduces the level of consciousness and weakens or eliminates the response to external stimuli, while maintaining relatively stable respiratory and circulatory functions, to achieve the purpose of reducing or alleviating anxiety, restlessness, pain, and the like of the human or animal body. Sedation includes but is not limited to mild sedation, moderate sedation, and deep sedation, and the application scenarios include but are not limited to sedation for diagnostic and therapeutic procedures (short surgery, endoscopic examination), sedation in intensive care units, and the like. The use and pharmaceutical combination described in the present application can be used alone for sedation, or can be administered simultaneously, sequentially, or separately with any one or more of general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, auxiliary drugs, neuromuscular blocking drugs, and analgesics.

[0120] The etomidate derivative described in the present application is an etomidate derivative of formula 1:

[0121]

[0122] wherein R1 C 1-6 alkyl.

[0123] In some embodiments, the etomidate derivative is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (also known as Compound 2), the structure of which is shown below:

[0124]

[0125] The structure of the cyclamate of the present invention is shown below:

[0126]

[0127] The structural formula of the fluoroetomimic acid described in the present invention is as follows:

[0128]

[0129] The structural formula of etomidic acid described in the present invention is as follows:

[0130]

[0131] The structural formula of the propylparaben impurity 19 in the present invention is as follows:

[0132] DETAILED DESCRIPTION

[0133] Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiments are only used to illustrate the present invention and are not used in limiting the scope of the present invention.In addition, should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall equally within the scope limited by the appended claims of the application.

[0134] Example

[0135] The embodiments of the present invention are described in detail below with reference to the examples. Where specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or those recommended by the manufacturer. Reagents or instruments used, where the manufacturer is not specified, are commercially available conventional products. Unless otherwise specified, ratios or percentages used herein are by weight.

[0136] Example 1: Preparation of etomidate derivative (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (ie, compound 2)

[0137] The preparation was carried out according to the method of Example 9 of international patent application WO2017059827A1, with a purity of 99.1%.

[0138] Example 2: Preparation of Etomidate Derivative (i.e. Compound 2) Emulsion Injection

[0139] (1) 50 g soybean oil, 50 g medium-chain triglycerides, 6 g egg yolk lecithin, and 1 g of compound 2 prepared in Example 1 were heated and stirred at 65° C. until dissolved to form the oil phase;

[0140] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0141] (3) The aqueous phase and the oil phase are sheared at 65°C by a shearing machine to form colostrum. The colostrum is first homogenized once at low pressure in a homogenizer, and then homogenized 6 times at high pressure. It is then filtered, sealed, nitrogen-filled, and sterilized to obtain the injection solution.

[0142] Preparation of blank fat emulsion:

[0143] (1) 50 g soybean oil, 50 g medium-chain triglycerides, and 6 g egg yolk lecithin were heated and stirred at 65°C until dissolved to form the oil phase;

[0144] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0145] (3) The aqueous phase and the oil phase were sheared at 65°C to form colostrum. The colostrum was first homogenized once at low pressure in a homogenizer, and then homogenized 6 times at high pressure. The colostrum was then filtered, sealed, nitrogen-filled, and sterilized to obtain blank fat emulsion.

[0146] Example 3-8: Pharmaceutical Combination Comprising Etomidate Derivatives (i.e., Compound 2) and Propofol

[0147] A commercially available propofol injection preparation (20 ml: 50 mg, Hiseco Pharmaceutical Co., Ltd.) and the compound 2 injection preparation prepared according to Example 2 were mixed in different proportions as shown in Table 1 below to obtain different drug combinations containing an etomidate derivative (i.e., compound 2) and propofol, which can be diluted with blank fat emulsion according to the needs of different animal experiments.

[0148] Comparative Example 3-8: Drug combination containing etomidate and propofol

[0149] Commercially available propofol injection preparation (20 ml: 50 mg, Hiseco Pharmaceutical Co., Ltd.) and commercially available etomidate injection preparation (10 ml: 20 mg, Jiangsu Enhua Pharmaceutical Co., Ltd.) were mixed in different proportions as shown in Table 1 below to obtain different drug combinations containing etomidate and propofol, which can be diluted with blank fat emulsion according to the needs of different animal experiments.

[0150] Table 1 Drug combinations containing Compound 2, etomidate and propofol in different ratios

[0151] Group Propofol / Compound 2 (mass ratio) Group Propofol / etomidate (mass ratio) Example 3 8:3 Comparative Example 3 8:3 Example 4 5:2 Comparative Example 4 5:2 Example 5 5:4 Comparative Example 5 5:4 Example 6 5:8 Comparative Example 6 5:8 Example 7 1:2 Comparative Example 7 1:2

[0152] Test Example 1: Study on recovery time and serum potassium in dogs after infusion of different combinations of etomidate or its derivatives and propofol

[0153] Experimental method: Healthy adult beagle dogs were randomly divided into groups according to gender and weight, with 6 dogs in each group. The dogs' anesthesia ED was measured by sequential method in the early stage. 50 , use 2 times ED 50 Anesthesia was induced with a dose of 2 times the induction dose / hour as the starting dose for anesthesia maintenance. The animal's condition was observed and scored according to the MOAA / S score sheet. The maintenance speed was adjusted at any time to keep the animal at a score of 0. After 1 hour of infusion, the animal's awakening time (i.e., the time from drug discontinuation to awakening) and walking time (the time from drug discontinuation to normal walking) were observed and recorded. Venous blood was collected before administration, 0.5 hours after infusion, 1 hour after infusion, and 0.5 hours after drug discontinuation, and the blood potassium level was detected using a fully automatic biochemical immunoassay assembly line (Abbott C16000).

[0154] The test results are shown in Table 2, Table 3 and Table 2 below.

[0155] Table 2 Recovery time and walking time of dogs after administration of different drug combinations

[0156]

[0157]

[0158] Table 3 Median effective dose (ED) of anesthesia for dogs measured by sequential method 50

[0159] Group <![CDATA[ED 50 mg / kg]]> Example 3 0.56 Comparative Example 3 0.57 Example 4 0.47 Comparative Example 4 0.67 Example 5 0.55 Comparative Example 5 0.46 Example 6 0.40 Comparative Example 6 0.46 Commercially available propofol injection 0.67 Example 2 0.39 Commercially available etomidate injection 0.41

[0160] Table 2 Serum potassium levels in different drug combinations

[0161]

[0162]

[0163] * indicates significant difference between the groups before and after administration (P < 0.05)

[0164] Test Conclusion: As shown in Table 2, the different drug combinations representing embodiments of the present invention have significantly better awakening time and walking time than the control group and the single propylparaben or etomidate group. In addition, as shown in Table 2, the different drug combinations representing embodiments of the present invention have significantly better blood potassium stability than the control group.

[0165] Test Example 2: Therapeutic Index Study of Different Drug Combinations Containing Etomidate Derivatives and Propofol

[0166] Experimental method: Sequential method was used to determine the hypnotic ED of rats with different drug combinations 50 , rats were intravenously administered, and the disappearance of the righting reflex after administration was observed to determine whether the drug combination had an anesthetic effect. ED was calculated using AOT425 software. 50 value.

[0167] The sequential method was used to determine the LD50 of different drug combinations in rats 50 , rats were intravenously administered, and the survival and death of the animals were observed. LD 50 value.

[0168] Table 3 Therapeutic index of different drug combinations

[0169] <![CDATA[ED 50 mg / kg]]> LD 50 mg / kg Therapeutic Index (TI) Example 3 1.87 16.12 8.62 Comparative Example 3 1.95 9.36 4.80 Example 4 1.55 11.66 7.52 Comparative Example 4 2.40 9.63 4.01 Example 6 1.35 16.68 12.35 Comparative Example 6 1.20 12.11 10.09 Example 7 1.34 13.18 9.84 Comparative Example 7 1.34 11.98 8.94 Commercially available propofol injection 2.21 13.34 6.04

[0170] Test conclusion: From the data in Table 3, it can be seen that the therapeutic index of the drug combination representing the embodiment of the present invention is significantly better than that of the control example and the propofol group, indicating that the drug combination of the embodiment has a larger safety window and is safer for clinical use.

[0171] Test Example 3: Study on the blood glucose stability of different drug combinations containing etomidate derivatives and propofol

[0172] Experimental method: 64 SD rats (male, provided by Beijing Biotechnology Co., Ltd.) that passed quarantine were selected and divided into 8 groups based on similar body weight, with 8 rats in each group. Rats were fasted for 12 hours before administration. Each group received a single tail vein administration. The dose was 2 times the ED 50 The administration volume was 5 ml / kg. Blood was collected from the tip of the tail before and 0.5 h after administration, and blood glucose levels were measured using a blood glucose meter (Yuyue 590, provided by Jiangsu Yuyue Medical Equipment Co., Ltd.). Each animal was tested at least twice at each time point, and the average blood glucose level was used to compare the changes before and after administration.

[0173] Table 4 Effects of different drug combinations on blood glucose in rats

[0174] Group 0min blood glucose value (mmol / L) 30-minute blood glucose level (mmol / L) Example 3 4.71±0.32 4.73±0.51 Comparative Example 3 4.99±0.30 5.31±0.40* Example 4 5.19±0.33 5.60±0.56 Comparative Example 4 4.88±0.21 5.54±0.19** Example 5 4.87±0.39 5.42±0.25* Comparative Example 5 4.69±0.56 5.54±0.66** Example 6 5.10±0.43 5.24±0.39 Comparative Example 6 4.91±0.35 5.64±0.36**

[0175] *Indicates significant difference compared with before administration (P<0.05)

[0176] **Indicates that the difference is extremely significant compared with before administration (P < 0.01)

[0177] Test conclusion: From the data in Table 4, it can be seen that the blood sugar level of the embodiment of the present invention is more stable after administration than that of the control group, which indicates that the burden of blood sugar management during the perioperative period may be reduced.

[0178] Example 8 Preparation of Etomidate Derivative (i.e., Compound 2) and Propofol Emulsion Injection (Propofol: Compound 2 = 1.25:1)

[0179] (1) 50 g soybean oil, 50 g medium-chain triglycerides, 6 g egg yolk lecithin, 1 g compound 2 prepared in Example 1, and 1.25 g propofol were heated at 65° C. and stirred until dissolved to prepare the oil phase;

[0180] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0181] (3) The aqueous phase and the oil phase are sheared at 65°C by a shearing machine to form colostrum. The colostrum is first homogenized once at low pressure in a homogenizer, then homogenized six times at high pressure, and then filtered, filled, nitrogen-filled, and sterilized to obtain the injection solution.

[0182] Example 9 Preparation of Compound 2 and Propofol Emulsion Injection (Propofol: Compound 2 = 2.5:1)

[0183] (1) 50 g soybean oil, 50 g medium-chain triglycerides, 6 g egg yolk lecithin, 0.5 g compound 2 prepared in Example 1, and 1.25 g propofol were heated at 65° C. and stirred until dissolved to prepare the oil phase;

[0184] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0185] (3) The aqueous phase and the oil phase are sheared at 65°C by a shearing machine to form colostrum. The colostrum is first homogenized once at low pressure in a homogenizer, then homogenized six times at high pressure, and then filtered, filled, nitrogen-filled, and sterilized to obtain the injection solution.

[0186] Example 10 Preparation of Compound 2 and Propofol Emulsion Injection (Propofol: Compound 2 = 0.625:1)

[0187] (1) 50 g soybean oil, 50 g medium-chain triglycerides, 6 g egg yolk lecithin, 2 g compound 2 prepared in Example 1, and 1.25 g propofol were heated at 65° C. and stirred until dissolved to prepare the oil phase;

[0188] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0189] (3) The aqueous phase and the oil phase are sheared at 65°C by a shearing machine to form colostrum. The colostrum is first homogenized once at low pressure in a homogenizer, then homogenized six times at high pressure, and then filtered, filled, nitrogen-filled, and sterilized to obtain the injection solution.

[0190] Comparative Example 8 Preparation of Etomidate and Propofol Emulsion Injection (Propofol: Etomidate = 1.25:1)

[0191] Comparative Example 8 was prepared using the same operation, conditions and amounts as Example 8, except that etomidate was used instead of Compound 2.

[0192] Comparative Example 9 Preparation of Etomidate and Propofol Emulsion Injection (Propofol: Etomidate = 2.5:1)

[0193] Comparative Example 9 was prepared using the same operation, conditions and amounts as Example 9, except that etomidate was used instead of Compound 2.

[0194] Comparative Example 10 Preparation of Etomidate and Propofol Emulsion Injection (Propofol: Etomidate = 0.625:1)

[0195] Comparative Example 10 was prepared using the same operation, conditions and amounts as Example 10, except that etomidate was used instead of Compound 2.

[0196] Comparative Example 11 Preparation of Propofol Emulsion Injection

[0197] (1) 50 g soybean oil, 50 g medium-chain triglycerides, 6 g egg yolk lecithin, and 1.25 g propofol were heated at 65°C and stirred until dissolved to form the oil phase;

[0198] (2) Take 388 g of water for injection, heat it to 65°C, add 12.5 g of glycerol and 0.15 g of sodium oleate, and mix them as the aqueous phase;

[0199] (3) The aqueous phase and the oil phase are sheared at 65°C by a shearing machine to form colostrum. The colostrum is first homogenized once at low pressure in a homogenizer, then homogenized six times at high pressure, and then filtered, filled, nitrogen-filled, and sterilized to obtain the injection solution.

[0200] Test Example 1 Stability Study of Compound 2 and Propofol Emulsion Injection

[0201] (1) Appearance

[0202] Table 5 Appearance and properties of each injection

[0203]

[0204] In the table, A is a white milky liquid, and B is a light yellow milky liquid.

[0205] From the data in Table 5, it can be seen that the appearance of the samples of Examples 8-10 and Propofol before and after sterilization was a white emulsion without significant change, indicating good stability; the samples of Comparative Examples 8-10 were white emulsions before sterilization, and after sterilization, some samples were white emulsions and some samples were light yellow emulsions, with uneven color and significant changes, which did not meet the quality requirements, indicating that the samples of Comparative Examples 8-10 had poor stability.

[0206] (2) Impurity detection results

[0207] Sample preparation:

[0208]

[0209] Chromatographic conditions:

[0210]

[0211] Elution procedure:

[0212]

[0213] The samples were injected according to the chromatographic conditions and the impurity content was calculated according to the external standard method.

[0214] The impurity test results are as follows:

[0215] Table 6 Content of hydrolyzed impurities in each injection

[0216]

[0217]

[0218] As can be seen from the data in Table 6, the content of the hydrolyzed impurity fluoroetominic acid in the example is significantly lower than the content of the etomidic acid in the comparative example etomidate and propofol emulsion injection. The relative percentage of impurity reduction is calculated based on the comparative example. For example, taking 60 days at 60° C. as an example, the fluoroetominic acid content in Example 8 is 0.31%, and the etomidic acid content in Comparative Example 8 is 1.61%. The relative percentage of impurity reduction = (1.6 - 0.31) / 1.61 * 100% = 80.75%.

[0219] Table 7 Content of Propofol Impurity 19 in Each Injection

[0220]

[0221] “ / ” in the table means not measured.

[0222] From the data in Table 7, it can be seen that the content of the propofol impurity 19 in the etomidate and propofol emulsion injection in the comparative example is significantly higher than that in the propofol emulsion, and the content of the propofol impurity 19 in the examples is significantly lower than that in the comparative example.

[0223] Table 8 Total impurity content in each injection

[0224]

[0225]

[0226] “ / ” in the table means not measured.

[0227] It can be seen from the data in Table 8 that the total impurity content in the examples is significantly lower than that in the comparative examples.

[0228] (3) Encapsulation efficiency:

[0229] The dialysis method was used to determine the encapsulation efficiency. Pre-treated dialysis bags were used. One end of the dialysis bag was tied tightly. About 1 ml of the test sample was placed in different dialysis bags. The other end of the dialysis bag was tied tightly with a rope to seal it. The dialysis was performed in a stability test chamber at 25°C for 36 hours. The liquid outside the dialysis bag was used as the test solution. The test solution was sampled and analyzed. The free drug content was determined by high performance liquid chromatography (HPLC).

[0230] Encapsulation efficiency EN% = (1-Cf / Ct) × 100%

[0231] Where Cf is the amount of free drug; Ct is the total amount of drug.

[0232] Table 9 Encapsulation efficiency of etomidate derivatives / etomidate in each injection

[0233]

[0234]

[0235] “ / ” in the table means not measured.

[0236] Table 10 Encapsulation efficiency of propofol in each injection

[0237]

[0238] From the data in Table 9 and Table 10, it can be seen that the encapsulation efficiency of the etomidate derivatives in the examples is much higher than that in the comparative examples. There is no significant difference in the encapsulation efficiency of propofol between the examples and the comparative examples, but the contents of propofol impurity 19 and total impurities in the comparative example are significantly increased.

[0239] Although the specific embodiments of the present invention have been described in detail, based on all the teachings disclosed, those skilled in the art may make various modifications and substitutions to the details of the technical solution of the present invention, and such modifications are within the scope of protection of the present invention. The full scope of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A method for anesthesia, sedation and / or hypnosis in animals or humans, comprising administering to the animals or humans a combination of an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, wherein the etomidate derivative is a compound of formula (1): where R 1 C 1-6 alkyl.

2. The method according to claim 1, wherein the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester (Compound 2).

3. The method according to claim 1 or 2, wherein the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is in the range of about 10:1 to about 1:10, for example, in the range of about 4:1 to about 1:4, in the range of about 3:1 to about 1:3, in the range of about 3:1 to about 1:2, in the range of about 2:1 to about 1:2, and for example, in the range of about 4:1 to about 1:

2.

4. The method according to claim 3, wherein the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:

1.

5. The method according to any one of claims 1 to 4, which satisfies one or more of the following conditions: (1) wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid preparation, preferably an injectable preparation; (2) wherein the concentration of the etomidate derivative, pharmaceutically acceptable salt thereof, prodrug thereof, or isotopic derivative thereof in the liquid formulation is from about 0.1 mg / mL to about 50 mg / mL, calculated based on the concentration of Compound 2; (3) wherein the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid preparation, preferably an injectable preparation; (4) wherein the concentration of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid preparation is about 0.1 mg / mL to about 50 mg / mL calculated as the concentration of propofol.

6. The method according to any one of claims 1 to 5, wherein the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof are administered in combination, preferably simultaneously, sequentially or separately.

7. The method according to any one of claims 1 to 5, wherein the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof are administered simultaneously; preferably, the two are mixed with an optional pharmaceutically acceptable carrier and administered simultaneously.

8. The method according to any one of claims 1 to 5, wherein the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof are administered sequentially; preferably, the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered first, and the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered subsequently; or the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered first, and the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered subsequently.

9. The method according to any one of claims 1 to 8, further comprising administering simultaneously, sequentially or separately any one or more of the following drugs: general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, anesthetic adjuvants, neuromuscular blocking drugs and analgesics.

10. The method according to any one of claims 1 to 9, wherein the anesthesia is anesthesia induction or anesthesia maintenance; and the sedation is light sedation, moderate sedation or deep sedation.

11. A pharmaceutical combination comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, wherein the etomidate derivative is a compound of formula (1): where R 1 C 1-6 alkyl.

12. The pharmaceutical combination according to claim 11, wherein the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester.

13. The pharmaceutical combination according to claim 11 or 12, wherein the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is in the range of about 10:1 to about 1:10, for example, in the range of about 4:1 to about 1:4, in the range of about 3:1 to about 1:3, in the range of about 2:1 to about 1:2, in the range of about 3:1 to about 1:2, and for example, in the range of about 4:1 to about 1:

2.

14. The pharmaceutical combination according to claim 13, wherein the mass ratio of propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof to the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, calculated as the mass ratio of propofol:Compound 2, is about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:

1.

15. The pharmaceutical combination according to any one of claims 11 to 14, which satisfies one or more of the following conditions: (1) wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid preparation, preferably an injectable preparation; (2) wherein the concentration of the etomidate derivative, pharmaceutically acceptable salt thereof, prodrug thereof, or isotopic derivative thereof in the liquid formulation is from about 0.1 mg / mL to about 50 mg / mL, calculated based on the concentration of Compound 2; (3) wherein the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in the form of a liquid preparation, preferably an injectable preparation; (4) wherein the concentration of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative in the liquid preparation is about 0.1 mg / mL to about 50 mg / mL calculated as the concentration of propofol.

16. The pharmaceutical combination according to any one of claims 11 to 15, wherein the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof are administered in combination, preferably simultaneously, sequentially or separately.

17. The pharmaceutical combination according to any one of claims 11 to 15, wherein the etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof are administered simultaneously; preferably, the two are mixed with an optional pharmaceutically acceptable carrier and administered simultaneously.

18. The pharmaceutical combination according to any one of claims 11 to 15, wherein the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof and the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof are administered sequentially; preferably, the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered first, and the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered subsequently; or the etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered first, and the propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof is administered subsequently.

19. The pharmaceutical combination according to any one of claims 11 to 18, further comprising the simultaneous, sequential or separate administration of any one or more of the following drugs: general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, anesthetic adjuvants, neuromuscular blocking drugs and analgesics.

20. The pharmaceutical combination according to any one of claims 11 to 19, comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition comprises propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, and optionally one or more pharmaceutically acceptable carriers; and the second pharmaceutical composition comprises an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotopic derivative thereof, and optionally one or more pharmaceutically acceptable carriers; and the first and second pharmaceutical compositions are mixed, packaged, or used in combination to form the pharmaceutical combination.

21. The pharmaceutical combination according to any one of claims 11 to 20, for use in anesthesia, sedation and / or hypnosis, and in the treatment and / or prevention of nausea, vomiting, convulsions or epilepsy in animals or humans; preferably for anesthesia, sedation or hypnosis in animals or humans; preferably, the anesthesia is anesthesia induction or anesthesia maintenance; preferably, the sedation is mild sedation, moderate sedation or deep sedation.

22. Use of an etomidate derivative (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazole-5-carboxylic acid ethyl ester, a pharmaceutically acceptable salt, a prodrug or an isotopic derivative thereof in the preparation of a drug for anesthesia, sedation and / or hypnosis in animals or humans, wherein the etomidate derivative, a pharmaceutically acceptable salt, a prodrug or an isotopic derivative thereof is administered in combination with propofol, a pharmaceutically acceptable salt, a prodrug or an isotopic derivative thereof.

23. A pharmaceutical composition in the form of a single preparation, wherein the pharmaceutical composition is formed by mixing propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof and an etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof with one or more pharmaceutically acceptable carriers; wherein the etomidate derivative is a compound of formula (1): where R 1 C 1-6 alkyl.

24. The pharmaceutical composition of claim 23, wherein the hydrolysis impurity fluoroetominic acid in the pharmaceutical composition in the form of a single dosage form is reduced by about 70-80% compared to the hydrolysis impurity etomidic acid in a corresponding pharmaceutical combination containing etomidate and propofol under the same conditions.

25. The pharmaceutical composition of any one of claims 23-24, wherein the pharmacopoietic impurity 19 in the pharmaceutical composition in a single dosage form is reduced by at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or at least about 75% compared to the pharmacopoietic impurity 19 in a corresponding pharmaceutical combination containing etomidate and pharmacopoietic under the same conditions.

26. The pharmaceutical composition of any one of claims 23-25, wherein the total impurities in the pharmaceutical composition in a single dosage form are reduced by at least 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% compared to the total impurities in a corresponding pharmaceutical combination comprising etomidate and propofol under the same conditions.

27. The pharmaceutical composition according to any one of claims 23 to 26, wherein the pharmaceutical composition in single dosage form is in the form of an emulsion.

28. The pharmaceutical composition according to any one of claims 23 to 27, wherein the content of the etomidate derivative, pharmaceutically acceptable salt thereof, prodrug thereof, or isotopic derivative thereof, converted into an amount of Compound 2, is 0.01-5 wt% of Compound 2 relative to the total mass of the pharmaceutical composition in the form of a single preparation.

29. The pharmaceutical composition according to any one of claims 23 to 28, wherein the content of the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is 0.01-5 wt% of propofol, calculated as propofol, relative to the total mass of the pharmaceutical composition in the form of a single preparation.

30. The pharmaceutical composition according to any one of claims 23 to 29, wherein the pharmaceutically acceptable carrier is selected from one or more of an oily component, an emulsifier, a stabilizer, an osmotic pressure regulator, water for injection, an emulsifier aid, a pH regulator, a solubilizer, a cosolvent and a filler.

31. The pharmaceutical composition of any one of claims 23 to 30, which satisfies one or more of the following conditions: The oily component is selected from any one of soybean oil and medium-chain triglycerides, or a mixture of any of them in any proportion; The content of the oily component in the pharmaceutical composition is 5-30wt%; The emulsifier is selected from egg yolk lecithin; The content of the emulsifier in the pharmaceutical composition is 0.5-3wt%; The stabilizer is selected from any one of sodium oleate and oleic acid or a mixture of any of them in any proportion: The content of the stabilizer in the pharmaceutical composition is 0.01-1%wt%; The osmotic pressure regulator is selected from glycerol; The content of the osmotic pressure regulator in the pharmaceutical composition is 1-5 wt %.

32. A method for preparing a pharmaceutical composition according to any one of claims 23 to 31, wherein the pharmaceutical composition comprises an etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and one or more pharmaceutically acceptable carriers, the method comprising mixing propofol, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, an etomidate derivative, a pharmaceutically acceptable salt, a prodrug, or an isotopic derivative thereof, and one or more pharmaceutically acceptable carriers.

33. The preparation method of claim 32, wherein the method comprises: The etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and propylparaben, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative are simultaneously added to the oil phase, and then the oil phase and the aqueous phase are mixed to form the pharmaceutical composition in the form of a single preparation, wherein the pharmaceutically acceptable carrier comprises an oily component, an emulsifier, a stabilizer, an osmotic pressure regulator, and water for injection, as well as one or more optional pharmaceutically acceptable carriers selected from the group consisting of a co-emulsifier and a pH regulator.

34. The preparation method of claim 33, wherein the method comprises: 1) Preparation of the oil phase: Mix the required amounts of the oil component, the emulsifier, and the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and stir and dissolve at 50-80° C. to obtain the oil phase; 2) Preparation of aqueous phase: Mix the required amounts of stabilizer, osmotic pressure regulator, water for injection, and optional pH regulator, and stir to dissolve at 50-80° C. to obtain an aqueous phase; 3) Emulsion preparation: The oil phase and the water phase are sheared at 50-80° C. to form colostrum, which is then homogenized in a homogenizer, followed by filling, nitrogen filling, and sterilization to obtain the pharmaceutical composition in the form of a single preparation.

35. The pharmaceutical composition according to any one of claims 23 to 31 , for use in anesthesia, sedation and / or hypnosis, and in the treatment and / or prevention of nausea, vomiting, convulsions or epilepsy in animals or humans; preferably for use in anesthesia, sedation or hypnosis in animals or humans; preferably, the anesthesia is anesthesia induction or anesthesia maintenance; preferably, the sedation is mild sedation, moderate sedation or deep sedation.

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