Pharmaceutical combination containing etomidate derivative and ciprofol and use thereof

Abstract

A pharmaceutical combination of an etomidate derivative and ciprofol, and a pharmaceutical composition comprising the etomidate derivative and ciprofol. Use of the pharmaceutical combination or the pharmaceutical composition in anesthesia, sedation, and / or hypnosis of animals or humans. Compared to the administration of the etomidate derivative or ciprofol alone and the combined administration of etomidate and ciprofol, the pharmaceutical combination or the pharmaceutical composition shows an excellent synergistic effect, significantly improving the recovery time after anesthesia withdrawal, etc.

Description

Drug combinations containing etomidate derivatives and cyclopropanol and their uses

[0001] This application claims priority to Chinese Patent Application No. 202410659616.3, filed May 27, 2024, and Chinese Patent Application No. 202510476413.5, filed April 16, 2025. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to specific pharmaceutical combinations of etomidate derivatives and cyclopropofol, and pharmaceutical compositions comprising the etomidate derivative and cyclopropofol. The invention also provides the use of said pharmaceutical combinations or compositions for anesthesia, sedation, and / or hypnosis in animals or humans. Background Technology

[0003] Globally, there are over 300 million surgical procedures performed annually. Currently, commonly used anesthetic and sedative drugs, such as sevoflurane, midazolam, propofol, and etomidate, generally suffer from slow recovery and poor quality of anesthesia recovery when used for maintenance anesthesia, failing to meet clinical requirements for "safety, speed, and comfort" of new anesthetics.

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

[0005] Etomidate has advantages such as minimal impact on respiration, weak inhibitory effects on the sympathetic nervous system and cardiovascular system, slight dilation of coronary arteries, reduction of intracranial pressure, and maintenance of cerebral perfusion. However, some literature reports that etomidate use during anesthesia can easily lead to unstable blood glucose levels, manifested as significant increases or decreases compared to preoperative blood glucose levels. Furthermore, perioperative blood glucose fluctuations and electrolyte disturbances pose a potential risk of increased readmission and prolonged hospital stays. Improving perioperative blood glucose control and maintaining stable electrolyte levels has a profound impact on improving the medium- and long-term outcomes of patients, especially elderly patients 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 describes a phenol derivative, specifically a pharmaceutical composition of cyclopropofol and etomidate.

[0007] Although the etomidate derivatives mentioned above show promise for monotherapy in patients' anesthesia induction, research on their combined use with propofol derivatives, especially cyclopropofol, is currently lacking. Clinically, there is still an urgent need for more effective and safer anesthetic drugs, particularly in terms of improving the recovery and walking time after discontinuation of existing anesthetic drugs, which has become one of the clinical pain points. Summary of the Invention

[0008] This invention aims to improve the aforementioned problems by combining (or administering) a combination containing a specific etomidate derivative and cyclopropofol. Specifically, through in-depth research on the combined administration of drug combinations containing etomidate derivatives and cyclopropofol, the inventors have surprisingly discovered that, compared to administering etomidate derivatives or cyclopropofol alone, the combined administration of etomidate derivatives and cyclopropofol exhibits a very excellent synergistic effect, and also shows superior synergistic effects compared to the combination of etomidate and cyclopropofol, such as significantly improved awakening time.

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

[0010] Where R 1 C 1-6 alkyl.

[0011] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (hereinafter referred to as compound 2).

[0012] On the other hand, the present invention also provides a pharmaceutical combination comprising etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, and cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative.

[0013] In some embodiments, the etomidate derivative or its pharmaceutically acceptable salt may also be methoxyetomidate or its hydrochloride salt; the cyclopropofol may also be replaced with disodium fospropofol.

[0014] In another aspect, the present invention also provides a combination comprising etomidate derivatives, their pharmaceutically acceptable salts, their prodrugs, or their isotope derivatives, and cyclopropanol, their pharmaceutically acceptable salts, their prodrugs, or their isotope derivatives, for use in animals or humans for anesthesia, sedation, and / or hypnosis, as well as for the treatment and / or prevention of diseases such as nausea, vomiting, convulsions, or epilepsy; preferably for use in animals or humans for anesthesia, sedation, or hypnosis; wherein the anesthesia is anesthesia induction or maintenance; and the sedation is mild sedation, moderate sedation, or deep sedation.

[0015] Furthermore, the present invention also provides the use of a combination comprising etomidate derivatives, pharmaceutically acceptable salts thereof, their prodrugs, or isotopic derivatives thereof, and cyclopropanol, their pharmaceutically acceptable salts, their prodrugs, or isotopic derivatives thereof, in the preparation of a medicament for the anesthesia, sedation, and / or hypnosis of animals or humans, and for the treatment and / or prevention of nausea, vomiting, convulsions, or epilepsy; preferably for the anesthesia, sedation, or hypnosis of animals or humans; preferably the anesthesia is anesthesia induction or maintenance; preferably the sedation is mild sedation, moderate sedation, or deep sedation.

[0016] Furthermore, the present invention also relates to the following aspects:

[0017] (1) Use of a combination of etomidate derivatives, their pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives, and cyclopropanol, its pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives, in the preparation of a medicament for use in animals or humans as anesthesia, sedation, and / or hypnosis.

[0018] (2) Use of etomidate derivatives, particularly compound 2 or its pharmaceutically acceptable salts or prodrugs, in the preparation of medicaments for the anesthesia, sedation and / or hypnosis of animals or humans, wherein the etomidate derivative, its pharmaceutically acceptable salts, its prodrugs or its isotopic derivatives are administered in combination with cyclopropanol, its pharmaceutically acceptable salts, its prodrugs or its isotopic derivatives.

[0019] (3) Use of cyclopropofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives in the preparation of medicaments for the anesthesia, sedation and / or hypnosis of animals or humans, wherein the cyclopropofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives are administered in combination with etomidate derivatives or their pharmaceutically acceptable derivatives; or its prodrugs or their isotopic derivatives or their prodrugs or their isotopic derivatives are used for anesthesia, sedation and / or hypnosis;

[0020] (4) Etomidate derivatives, particularly compound 2, its pharmaceutically acceptable salt or its prodrug or its isotope derivatives, used for anesthesia, sedation and / or hypnosis in animals or humans, wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug or its isotope derivatives are administered in combination with cyclopropanol, its pharmaceutically acceptable salt, its prodrug or its isotope derivatives.

[0021] (5) Cycloprophenol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative thereof, used for anesthesia, sedation and / or hypnosis in animals or humans, wherein the cycloprophenol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative thereof is administered in combination with etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative thereof.

[0022] In some embodiments, in the combinations, pharmaceutical combinations, methods, or uses of the present invention, the mass ratio of said propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the concentration of propofol, is in the range of about 10:1 to about 1:10 based on the mass ratio of propofol to compound 2.

[0023] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and is in the range of about 5:1 to about 0.25:10, for example, about 4:1 to about 1:5, about 3:1 to about 1:2, about 2:1 to about 1:1, or about 1.25:1 to about 1:1.

[0024] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 4:1 to about 1:4, about 3:1 to about 1:3, about 3:1 to about 1:2, about 2:1 to about 1:2, or, for example, about 4:1 to about 1:2.

[0025] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 1:2 to about 4:1, about 1:2 to about 8:3, about 1:2 to about 2.5:1, about 1:2 to about 1.25:1, about 1:2 to about 0.625:1; about 0.6 The range of 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.

[0026] In some embodiments, in the combinations, pharmaceutical combinations, methods, or uses 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, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the concentration of propofol and the mass ratio of propofol to 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.

[0027] In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, the dosage administered must, of course, be carefully adjusted according to the age, weight, and condition of the individual being treated, as well as the route of administration, dosage form, and administration regimen, and the desired outcome, and the exact dosage should, of course, be determined by a physician. The actual dosage depends on the nature and severity of the disease being treated, the exact route of administration, and the dosage form, and, within the physician's judgment, can be varied by incrementally increasing the dosage according to the specific circumstances of the invention to produce the desired therapeutic effect. The mass of the cyclopropofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the mass of cyclopropofol, 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.

[0028] In some embodiments, in the combinations, pharmaceutical compositions, 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 compositions, 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 calculated based on the concentration of compound 2 from about 0.1 mg / mL to about 50 mg / mL.

[0029] In some embodiments, in the combinations, pharmaceutical compositions, methods, or uses of the present invention, the propofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives are administered in the form of a liquid formulation, such as an injectable formulation. In the combinations, pharmaceutical compositions, methods, or uses of the present invention, the concentration of the propofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives in the liquid formulation is calculated based on the concentration of propofol and is from about 0.1 mg / mL to about 50 mg / mL.

[0030] In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof are administered in combination (or applied), including but not limited to administering both simultaneously, sequentially, or separately. In the combinations, drug combinations, methods, or uses of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof, and the propofol are administered continuously by intravenous infusion.

[0031] 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 isotope derivative thereof, and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof are administered simultaneously; preferably, both are mixed with an optional pharmaceutically acceptable carrier before simultaneous administration.

[0032] In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered sequentially; preferably, the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered first, followed by the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, or its prodrug or its isotope derivative; or the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered first, followed by the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative.

[0033] In some embodiments, in the combination, drug combination, method or use of the present invention, the combined administration method further includes administering one or more of the following drugs simultaneously, sequentially or separately: general anesthetics, local anesthetics, hypnotics, dissociative drugs, sedatives, adjunctive anesthetics, neuromuscular blocking agents and analgesics.

[0034] In some embodiments, in the combination, combination of drugs, method or use of the present invention, the anesthesia is an induction of anesthesia or maintenance of anesthesia; the sedation is mild sedation, moderate sedation or deep sedation.

[0035] In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, the infusion rate will be determined based on the patient's age, weight, or anxiety level. In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, the infusion rate will be determined based on the duration or extent of the procedure.

[0036] 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 isotope derivative, or the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, is between about 1 mL / h and about 1000 mL / h.

[0037] 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 isotope derivative and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative may be mixed together for administration, including but not limited to directly mixing two commercially available formulations, or mixing the two in accordance with pharmaceutical industry practice to prepare a single formulation.

[0038] 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 isotope derivative, and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative can be administered via routes selected from: intravenous infusion, intravenous bolus, intramuscular injection, transdermal absorption, sublingual absorption, extragastric peritoneal, rectal, buccal, intranasal, inhalation, local delivery, subcutaneous, intrafacial, intra-articular, intraperitoneal, and intrathecal; preferably intravenous infusion, intravenous bolus, or inhalation injection. In some embodiments, in the combination, pharmaceutical combination, method or use of the present invention, it is preferred to simply mix the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative together with the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative and administer them continuously by intravenous infusion.

[0039] In some embodiments, in the combinations, drug combinations, methods, or uses of the present invention, anesthesia, sedation, and / or hypnosis of animals or humans is performed before administration of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, and prior to administration of an opioid analgesic. In some embodiments, the opioid analgesic is one or more selected from fentanyl, remifentanil, sufentanil, alfentanil, etc.

[0040] This invention relates to a pharmaceutical combination product comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and cyclopropanol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, wherein the etomidate derivative is an etomidate derivative of formula (1):

[0041] Where R 1 C 1-6 alkyl.

[0042] In some embodiments, the pharmaceutical combination product of the present invention comprises etomidate derivative of formula (1), its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, and cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative.

[0043] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (also known as compound 2).

[0044] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and is in the range of about 10:1 to about 1:10.

[0045] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and 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, about 3:1 to about 1:2, about 2:1 to about 1:1, or about 1.25:1 to about 1:1.

[0046] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 4:1 to about 1:4, about 3:1 to about 1:3, about 3:1 to about 1:2, about 2:1 to about 1:2, about 3:1 to about 1:2, or, for example, about 4:1 to about 1:2.

[0047] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 1:2 to about 4:1, about 1:2 to about 8:3, about 1:2 to about 2.5:1, about 1:2 to about 1.25:1, about 1:2 to about 0.625:1; about 0.6 The range of 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.

[0048] In some embodiments, the mass ratio of the cyclopropofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, calculated based on the concentration of cyclopropofol, is approximately 1:2, approximately 0.625:1, approximately 1.25:1, approximately 2.5:1, approximately 8:3, or approximately 4:1.

[0049] In some implementations, the dosage must, of course, be carefully adjusted according to the individual's age, weight, and condition, as well as the route of administration, dosage form, and 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 the dosage form, and, within the physician's judgment, can be varied by incrementally increasing the dosage according to the specific circumstances of the invention to produce the desired therapeutic effect. The mass of the said propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is approximately 0.1 to approximately 1000 mg, for example, approximately 1 to approximately 750 mg, calculated by the mass of propofol, is suitable for therapeutic treatment; the mass of the said etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is approximately 0.1 to approximately 1000 mg, for example, approximately 1 to approximately 750 mg, calculated by the mass of compound 2, is suitable for therapeutic treatment.

[0050] In some embodiments, the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in a liquid formulation, such as an injectable formulation. In the combinations, pharmaceutical compositions, 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 in the range of about 0.1 mg / mL to about 50 mg / mL, calculated based on the concentration of compound 2.

[0051] In some embodiments, the propofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives are administered in the form of a liquid formulation, such as an injectable formulation. In the combinations, pharmaceutical compositions, methods, or uses of the present invention, the concentration of the propofol, its pharmaceutically acceptable salts, its prodrugs, or its isotopic derivatives in the liquid formulation is calculated based on the concentration of propofol as about 0.1 mg / mL to about 50 mg / mL of propofol.

[0052] In some embodiments, the pharmaceutical combination product comprises 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 isotope derivative thereof, and one or more pharmaceutically acceptable carriers; the second pharmaceutical composition comprises etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and one or more pharmaceutically acceptable carriers; the first pharmaceutical composition and the second pharmaceutical composition are used in combination, dispensed, or formulated to form the pharmaceutical combination product.

[0053] This invention relates to a pharmaceutical composition, said pharmaceutical composition being a single formulation, wherein a formulation is formed by mixing propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative with one or more pharmaceutically acceptable carriers; wherein said etomidate derivative is a compound of formula (1):

[0054] Where R 1 C 1-6 alkyl.

[0055] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazol-5-carboxylate (hereinafter compound 2).

[0056] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and 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, about 3:1 to about 1:2, about 2:1 to about 1:1, or about 1.25:1 to about 1:1.

[0057] In some embodiments, the mass ratio of the cyclopropoxide, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative to the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, converted to a mass ratio of cyclopropoxide to compound 2 (cyclopropoxide:compound 2), is in the range of 10:1 to 1:10, for example, in the range of 4:1 to 1:4, 3:1 to 1:3, 3:1 to 1:2, 2:1 to 1:2, 3:1 to 1:2, or, for example, 4:1 to 1:2.

[0058] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 1:2 to about 4:1, about 1:2 to about 8:3, about 1:2 to about 2.5:1, about 1:2 to about 1.25:1, about 1:2 to about 0.625:1; about 0.6 The range of 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.

[0059] In some embodiments, the mass ratio of the cyclopropoxide, 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 converted into a mass ratio of cyclopropoxide to compound 2 (cyclopropoxide:compound 2) of about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:1.

[0060] In some embodiments, the hydrolyzed impurity fluoroetomidic acid in the single-formulation pharmaceutical composition is reduced by about 70-80% compared to the hydrolyzed impurity fluoroetomidic acid in a corresponding pharmaceutical composition containing etomidate and propofol under the same conditions. In some embodiments, the propofol impurity 19 in the single-formulation pharmaceutical composition 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 composition containing etomidate and propofol under the same conditions. In some embodiments, the total impurities in the single-formulation pharmaceutical composition 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 composition containing etomidate and propofol under the same conditions.

[0061] In some embodiments, the single-formulation pharmaceutical composition is in emulsion form.

[0062] In some embodiments, the amount of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, converted to 0.01-5 wt% of compound 2, relative to the total mass of the pharmaceutical composition in the single formulation.

[0063] In some embodiments, the amount of said propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, converted to the amount of propofol, is 0.01-5 wt% of propofol, the total mass of the pharmaceutical composition in the single formulation.

[0064] In some embodiments, the pharmaceutically acceptable carrier is selected from one or more of the following: oily components, emulsifiers, stabilizers, osmotic pressure regulators, water for injection, co-emulsifiers, pH regulators, solubilizers, cosolvents, and fillers.

[0065] In some embodiments, the oily component is selected from any one or a mixture of any number of medium-chain triglycerides in any proportion;

[0066] In some embodiments, the content of the oily component in the pharmaceutical composition is 5-30 wt%.

[0067] In some embodiments, the emulsifier is selected from egg yolk lecithin.

[0068] In some embodiments, the emulsifier content in the pharmaceutical composition is 0.5-3 wt%.

[0069] In some embodiments, the stabilizer is selected from sodium oleate, oleic acid, or any mixture of several of them in any proportion.

[0070] In some embodiments, the stabilizer content in the pharmaceutical composition is 0.01-1% wt%.

[0071] In some embodiments, the osmotic pressure regulator is selected from glycerol.

[0072] In some embodiments, the content of the osmotic pressure regulator in the pharmaceutical composition is 1-5 wt%;

[0073] This invention provides a method for preparing a pharmaceutical composition in a single formulation, the pharmaceutical composition comprising an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and cyclopropanol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and one or more pharmaceutically acceptable carriers, the method comprising mixing cyclopropanol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof with one or more pharmaceutically acceptable carriers, wherein the etomidate derivative is an etomidate derivative of formula (1):

[0074] Wherein R1 is a C1-6 alkyl group; and

[0075] The pharmaceutically acceptable carrier is selected from one or more of the following: oily components, emulsifiers, stabilizers, osmotic pressure regulators, water for injection, co-emulsifiers, pH regulators, solubilizers, cosolvents, and fillers.

[0076] In some embodiments, the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazol-5-carboxylate (hereinafter compound 2).

[0077] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and 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, about 3:1 to about 1:2, about 2:1 to about 1:1, or about 1.25:1 to about 1:1.

[0078] In some embodiments, the mass ratio of the cyclopropoxide, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative to the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, converted to a mass ratio of cyclopropoxide to compound 2 (cyclopropoxide:compound 2), is in the range of 10:1 to 1:10, for example, in the range of 4:1 to 1:4, 3:1 to 1:3, 3:1 to 1:2, 2:1 to 1:2, 3:1 to 1:2, or, for example, 4:1 to 1:2.

[0079] In some embodiments, the mass ratio of the cyclopropoxide, 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 converted into a mass ratio of cyclopropoxide to compound 2 (cyclopropoxide:compound 2) of about 1:2, about 0.625:1, about 1.25:1, about 2.5:1, about 8:3, or about 4:1.

[0080] In some embodiments, the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, for example, in the range of about 1:2 to about 4:1, about 1:2 to about 8:3, about 1:2 to about 2.5:1, about 1:2 to about 1.25:1, about 1:2 to about 0.625:1; about 0.6 The range of 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.

[0081] In some embodiments, the amount of the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, converted to 0.01-5 wt% of compound 2, relative to the total mass of the pharmaceutical composition in the single formulation.

[0082] In some embodiments, the amount of said propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, converted to the amount of propofol, is 0.01-5 wt% of propofol, the total mass of the pharmaceutical composition in the single formulation.

[0083] In some embodiments, the method includes: simultaneously adding etomidate derivatives, their pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives, propofol, their pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives to an oil phase, and then mixing the oil phase and the aqueous phase to form the pharmaceutical composition in the single formulation form, wherein the pharmaceutically acceptable carrier includes 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 self-emulsifiers and pH regulators.

[0084] In some implementations, the method includes:

[0085] 1) Preparation of oil phase: Mix the required amount of oily components, emulsifier, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, and stir evenly at 50-80℃ to obtain the oil phase.

[0086] 2) Aqueous phase preparation: Mix the required amounts of stabilizer, osmotic pressure regulator, injection water and optional pH adjuster, and stir evenly at 50-80℃ to obtain the aqueous phase;

[0087] 3) Emulsion preparation: The oil phase and aqueous phase are sheared at 50-80℃ to form a primary emulsion, which is then homogenized in a homogenizer, followed by filling, nitrogen filling and sterilization to obtain the drug composition in the single formulation form.

[0088] In some embodiments, the oily component is soybean oil, one or a combination of medium-chain triglycerides.

[0089] In some implementations, the emulsifier is refined egg yolk lecithin. Beneficial effects

[0090] Compared with the prior art, the advantages of the combinations, drug combinations, methods or uses of the present invention are as follows:

[0091] (1) The drug combination of the present invention has a synergistic effect on significantly shortening the recovery time and walking time, and has a higher safety index: The combined administration of the etomidate derivative (compound 2) and propofol contained in the present invention results in a recovery time and walking time that are not only significantly shorter than those of the propofol combined with etomidate group, but also significantly shorter than those of the propofol and compound (2) single drug group. It also overcomes the problem of prolonged recovery 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 that of the propofol combined with etomidate group), which broadens the safety window of anesthesia. The above-mentioned beneficial effects suggest that the drug combination of the present invention has high clinical value in ensuring perioperative anesthesia safety, shortening recovery time, helping rapid recovery, improving surgical turnover rate, and improving recovery quality and anesthesia satisfaction.

[0092] (2) The drug combination of the present invention has a synergistic effect on improving blood glucose level fluctuations and blood potassium level decline: When the drug combination of etomidate derivative (compound 2) and propofol contained in the present invention is administered in combination, there is no significant difference in blood glucose level after administration compared with that before administration, while significant fluctuations occur in the propofol combined with etomidate group (P<0.05); Similarly, the blood potassium level of the drug combination of the present invention is not significantly different or significantly decreased compared with that before administration during infusion and after discontinuation, while the blood potassium level of the propofol combined with etomidate group is significantly decreased (P<0.05) or significantly decreased (>20%) at one or more time points during infusion and after discontinuation, suggesting that the drug combination of the present invention has high clinical value in reducing the perioperative metabolic or electrolyte monitoring burden and improving the medium- and long-term outcomes of elderly or metabolic disease patients.

[0093] (3) Compared to the drug combination of etomidate and propofol, the content of hydrolyzed impurities, namely fluoroetomidic acid, in the drug combination of the present invention containing etomidate derivatives and propofol is significantly reduced. The inventors of the present invention have found that the hydrolyzed impurity fluoroetomidic acid in the combination of the present invention is reduced by approximately 70-80% under the same conditions compared to the hydrolyzed impurity etomidate in the corresponding drug combination containing etomidate and propofol. Therefore, the drug combination of the present invention reduces adverse reactions in patients due to hydrolysis products and improves the safety and efficacy of the drug.

[0094] (4) Compared to the drug combination of etomidate and propofol, the content of propofol impurity 19 in the drug combination of the present invention containing etomidate derivative and propofol 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 adverse reactions caused by propofol impurity 19 and other impurities in the drug composition, and improving the safety and efficacy of the drug.

[0095] (5) In the etomidate derivative and propofol drug combination of the present invention, the encapsulation efficiency of the etomidate derivative is above 97.7%, which is much higher than that of etomidate in the corresponding drug combination of etomidate and propofol. Therefore, the etomidate derivative and propofol drug combination of the present invention can effectively reduce the adverse reactions caused by free drug and further improve the stability and bioavailability of the drug.

[0096] (6) The combination of etomidate derivative and cyclopropofol in a single formulation of the present invention improves the convenience of drug use, and the process is simple and easy to implement, which is conducive to industrial production and promotion.

[0097] Terminology Definition

[0098] 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 pertains. In case of any conflict, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0099] Term "C" 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1-6 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.

[0100] The term "derivative" refers to a series of structure-related compounds obtained by modifying or altering the chemical structure of a lead compound, which typically possess superior physicochemical properties, pharmacological activity, or safety. In some embodiments, etomidate derivatives include, but are not limited to, etomidate derivatives having the general formula 1, the latter further being, for example, compound 2 as referred to herein. Where applicable, in the context of this invention relating to the mass, concentration, etc., of etomidate derivatives, these values ​​are generally calculated based on the mass, concentration, etc., achieved by equimolar amounts of compound 2.

[0101] The term "medicinal salt" refers to a salt formed by the reaction of the mentioned active ingredient with a pharmaceutically acceptable acid or base. These salts are safe and effective when applied to mammals, preserving the original biological activity of the active ingredient. The "medicinal salt of etomidate derivative" as described in this invention 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 involved in this 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 "medicinal salt of propofol" as described in this invention refers to a salt formed by propofol and a pharmaceutically acceptable base, such as a sodium salt, calcium salt, magnesium salt, disodium phosphate salt, or sodium monohydrogen phosphate salt.

[0102] The term "prodrug" refers to a compound in which an active drug is chemically modified to a non-active or less active form, and then releases the active parent drug in vivo through biotransformation (such as by metabolic enzymes or spontaneous chemical reactions). The "etomidate derivative prodrug" described in this invention includes chemically modified compounds capable of releasing etomidate or etomidate derivatives in vivo. Similarly, the "cyclopropanol prodrug" described in this invention includes chemically modified compounds capable of releasing cyclopropanol in vivo.

[0103] The term "isotope derivative" refers to a compound that differs from the compounds described herein only in the presence of one or more isotope-enriched atoms. For example, compounds with the structure shown in the general formula, but using "deuterium" or "tritium" instead of hydrogen, and / or, using... 18 F replaces fluorine, and / or, with 11 C 13 C or 14 C replaces carbon, while the rest remains unchanged. Deuterated compounds can generally retain activity comparable to their undeuterated counterparts, and when deuterated at certain sites, they can achieve better metabolic stability, thus gaining certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirements).

[0104] The terms "combination," "drug combination," or "drug combination product" used in this invention refer to a pharmaceutical product composed of a mixture or combination of two or more active ingredients. In a drug combination product, these active ingredients can be mixed into a single formulation, or they can be kept separate in different formulations. For example, the active ingredients can be mixed with a necessary pharmaceutically acceptable carrier in a specific ratio to form a mixed solution for sale, or packaged in different containers for bundled sale, or commercial formulations containing these active ingredients can be obtained separately from different commercial entities and used in combination. The active ingredients in a drug combination product can be administered simultaneously, separately, or sequentially. Furthermore, it should be understood that the drug combination product may not be provided in a standardized commercial form; for example, it may be administered directly in a medical setting after simple mixing of the two or more active ingredients with a necessary pharmaceutically acceptable carrier.

[0105] The terms "administration" or "application" used in this invention refer to methods that deliver an active ingredient or a combination thereof to a desired biological site of action. These methods include, but are not limited to, oral or parenteral administration (including intraventricular, intravenous, subcutaneous, intraperitoneal, intramuscular, and intravascular injection or infusion), local administration, and rectal administration. In particular, injection or oral administration.

[0106] The term "combination" as used in this invention, whether alone, or in "combined administration" or "combined drug delivery," refers to applying two or more active ingredients contained in the aforementioned "combination," "drug combination," or "drug combination product" to subjects such as animals or humans through a suitable method or route of administration to achieve the desired therapeutic and / or preventive effects on diseases. The method or route of administration includes, but is not limited to: intravenous infusion, intravenous bolus injection, intramuscular injection, transdermal absorption, sublingual absorption, extragastric and intraperitoneal administration, rectal administration, buccal administration, intranasal administration, inhalation, local delivery, subcutaneous administration, intra-fat administration, intra-articular administration, intraperitoneal administration, and intrathecal administration.

[0107] The term "composition" or "pharmaceutical composition" as used in this invention refers to a formulation formed by mixing one or more active ingredients with one or more pharmaceutically acceptable carriers. Pharmaceutical formulations facilitate the administration of compounds to subjects (animals or humans). Pharmaceutical formulations are typically tailored to a specific intended route of administration.

[0108] The term "medicatable carrier" as used in this invention refers to a diluent, excipient, vehicle, or medium that is administered co-administered with a therapeutic agent and is suitable, to the extent of reasonable medical judgment, for contact with human and / or other animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio. 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, cosolvent, co-solvent, 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, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. Physiological saline and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerin, propylene glycol, water, ethanol, etc. The pharmaceutical composition may also contain small amounts of wetting agents, emulsifiers, pH adjusters, or osmotic pressure adjusters as needed.

[0109] The "encapsulation rate" described in this invention refers to the proportion of a drug or active ingredient encapsulated within an emulsion. A high encapsulation rate not only enables efficient and low-toxicity drug delivery but also significantly improves drug stability, effectively preventing drug degradation due to oxidation, hydrolysis, or other reactions during storage and transportation. Furthermore, the encapsulation rate directly affects drug bioavailability; a high encapsulation rate ensures that more active pharmaceutical ingredients reach the site of action, thereby enhancing therapeutic efficacy.

[0110] The term "s" refers to the unit of time, second, and "min" refers to the unit of time, minute.

[0111] The term "about" or "approximately" when used in conjunction with a numerical value indicates a set or range that includes that 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 a specified value. In some embodiments, the term "about" refers to a range of values ​​that are 2% more or less than a specified value. In some embodiments, the term "about" or "approximately" refers to a range of values ​​that are 1% more or less than a specified value.

[0112] The term "anesthesia" refers to a controlled, reversible, temporary loss of sensation or consciousness for medical or veterinary purposes. It may include partial or complete analgesia (relief or prevention of pain), paralysis (muscle relaxation), amnesia (memory loss), and unconsciousness, providing conditions for surgical procedures or other medical examinations. The uses and drug combinations described in this invention 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 agents, sedatives, adjuvant drugs, neuromuscular blocking agents, and analgesics.

[0113] The term "anesthesia induction" refers to the process of transitioning a patient from a conscious state to an anesthetic state through intravenous or inhalation anesthesia. It can rapidly and smoothly induce unconsciousness and suppress stress responses in humans or animals, including but not limited to rapid intravenous induction, inhalation anesthesia induction, and slow induction while preserving spontaneous breathing. The uses and drug combinations described in this invention 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, adjuvant drugs, neuromuscular blocking agents, and analgesics.

[0114] The term "anesthesia maintenance" refers to a sustained, appropriate, and stable depth of anesthesia in a human or animal, characterized by loss of consciousness and unresponsiveness to surgical stimuli, with stable vital signs. The uses and drug combinations described in this invention 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 agents, sedatives, adjuvant drugs, neuromuscular blocking agents, and analgesics.

[0115] The term "sedation" refers to the use of drugs to suppress the central nervous system of a human or animal, thereby lowering their level of consciousness, reducing or eliminating their response to external stimuli, while maintaining relatively stable respiratory and circulatory functions, thus reducing or alleviating anxiety, agitation, pain, etc. Sedation includes, but is not limited to, mild, moderate, and deep sedation, and its applications include, but are not limited to, sedation during diagnostic and therapeutic procedures (minor surgeries, endoscopy), and sedation in intensive care units. The uses and drug combinations described in this invention 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 agents, sedatives, adjuvant drugs, neuromuscular blocking agents, and analgesics.

[0116] The etomidate derivative of this invention is an etomidate derivative of Formula 1:

[0117] Where R 1 C 1-6alkyl.

[0118] In some embodiments, the etomidate derivative is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (also known as compound 2), with the following structure:

[0119] The structure of the cyclopropanol described in this invention is shown below:

[0120] The structural formula of the fluoroetotimidic acid described in this invention is shown below:

[0121] The structural formula of etomidate described in this invention is shown below:

[0122] The structural formula of the cyclopropanol impurity 19 described in this invention is as follows: Detailed Implementation

[0123] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the teachings of this invention, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0124] Example

[0125] The embodiments of the present invention will be described in detail below with reference to examples. Unless otherwise specified, specific conditions in the examples are performed under conventional conditions or conditions recommended by the manufacturer. Reagents or instruments used, unless otherwise specified, are all commercially available products. Unless otherwise specified, all proportions or percentages used herein are by weight.

[0126] Example 1: Preparation of etomidate derivative (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylic acid ethyl ester (i.e., compound 2)

[0127] It was prepared according to the method of Example 9 in International Patent Application WO2017059827A1, with a purity of 99.1%.

[0128] Example 2: Preparation of etomidate derivative (i.e., compound 2) emulsion injection

[0129] (1) Take 50g of soybean oil, 50g of medium-chain triglycerides, 6g of egg yolk lecithin, and 1g of compound 2 obtained in Example 1 and heat and mix them at 65°C until dissolved to form the oil phase;

[0130] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0131] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, and then homogenized 6 times under high pressure. Then it is filtered, filled, filled with nitrogen, and sterilized to obtain the injection solution.

[0132] Preparation of blank fat emulsion:

[0133] (1) Take 50g soybean oil, 50g medium-chain triglycerides and 6g egg yolk lecithin and heat them at 65℃ to mix and stir until dissolved, and use this as the oil phase;

[0134] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0135] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, then homogenized 6 times under high pressure, and then filtered, filled, filled with nitrogen, and sterilized to obtain a blank fat emulsion.

[0136] Examples 3-8: Drug combinations comprising etomidate derivative (i.e., compound 2) and cyclopropanol

[0137] Commercially available propofol injection formulation (20ml:50mg, Hisun Pharmaceutical Co., Ltd.) and compound 2 injection formulation prepared according to Example 2 were mixed in different proportions as shown in Table 1 below to obtain different drug combinations containing etomidate derivative (i.e., compound 2) and propofol. These combinations can be diluted with blank fat emulsion according to different animal experimental needs.

[0138] Comparative Examples 3-8: Drug combinations containing etomidate and propofol

[0139] Commercially available propofol injection formulation (20ml:50mg, Hisun Pharmaceutical Co., Ltd.) and commercially available etomidate injection formulation (10ml:20mg, 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. These combinations can be diluted with blank fat emulsion according to different animal experimental needs.

[0140] Table 1 contains drug combinations of compound 2, etomidate, and cyclopropanol in different proportions.

[0141] Test Example 1: A study of canine infusion recovery time and serum potassium levels in different combinations of etomidate or its derivatives and propofol.

[0142] Experimental Methods: Healthy, qualified adult beagles were randomly divided into groups of six based on sex and weight. The ED (excessive tumescence) under anesthesia was measured using a sequential method in the initial stage. 50 , use 2 times ED 50 Anesthesia was induced with a dose twice the induction dose per hour, which was then infused as the initial maintenance dose. The animal's condition was observed, and its score was assessed using the MOAA / S scoring system. The maintenance rate was adjusted as needed to maintain the animal at a score of 0. One hour after infusion, the animal's recovery time (from drug discontinuation to awakening) and walking time (from drug discontinuation to normal walking) were observed and recorded. Blood samples were collected intravenously before administration, 0.5 hours after infusion, 1 hour after infusion, and 0.5 hours after drug discontinuation. Serum potassium levels were measured using a fully automated biochemical and immunoassay analyzer (Abbott C16000).

[0143] The test results are shown in Tables 2 and 3 below.

[0144] Table 2. Recovery time and walking time of dogs after administration of different drug combinations.

[0145] Table 3. Median effective dose (EDD) of anesthesia in dogs, determined by the sequential method. 50

[0146] Table 2. Serum potassium levels of different drug combinations

[0147] Compared with before drug administration, * indicates a significant difference (P < 0.05).

[0148] Test conclusions: As shown in Table 2, the different drug combinations representing the embodiments of the present invention showed significantly better recovery and walking times than the control group and the groups using either propofol or etomidate alone. Furthermore, as shown in Table 2, the different drug combinations representing the embodiments of the present invention showed significantly better blood potassium stability than the control group.

[0149] Test Example 2: Therapeutic Index Study of Different Drug Combinations Including Etomidate Derivatives and Cycloprophen

[0150] Experimental methods: The hypnotic ED of rats with different drug combinations was determined using a sequential method. 50 The drug combination was administered intravenously to rats, and the disappearance of the righting reflex after administration was observed to determine whether the combination had an anesthetic effect. The ED was calculated using AOT425 software. 50 value.

[0151] The LD50 of different drug combinations in rats was determined using a sequential method. 50 Rats were administered the drug intravenously, and the survival and mortality of the animals were observed. The LD50 was calculated using AOT425 software.50 value.

[0152] Table 3. Therapeutic index of different drug combinations

[0153] Test conclusion: As shown in Table 3, the therapeutic index of the drug combination representing the embodiment of the present invention is significantly better than that of the control case and the cyclopropofol group, indicating that the drug combination of the embodiment has a larger safety window and is safer for clinical use.

[0154] Test Example 3: Study on glycemic stability of different drug combinations containing etomidate derivatives and propofol

[0155] Experimental Methods: Sixty-four quarantined, male SD rats (provided by Spifort (Beijing) Biotechnology Co., Ltd.) were selected and divided into eight groups of eight rats each, based on similar body weight. The rats were fasted for 12 hours before administration. All groups received a single tail vein injection. The dosage was twice the ED dose. 50 The administration volume was 5 ml / kg. Blood was collected from the tail tip before administration and 0.5 h after administration. Blood glucose levels were measured using a blood glucose meter (Yuwell 590 model, provided by Jiangsu Yuwell Medical Equipment Co., Ltd.). Each animal was tested at least twice at each time point, and the average blood glucose level was taken to compare the changes in blood glucose before and after administration.

[0156] Table 4. Effects of different drug combinations on blood glucose in rats * indicates a significant difference compared to before administration (P < 0.05) ** indicates an extremely significant difference compared to before administration (P < 0.01)

[0157] Test conclusion: As shown in Table 4, the blood glucose levels in the embodiments of the present invention are more stable after administration compared with the control group, which suggests that the burden of blood glucose management during the perioperative period may be reduced.

[0158] Example 8: Preparation of etomidate derivative (i.e., compound 2) and cyclopropofol emulsion injection (cyclopropofol: compound 2 = 1.25:1)

[0159] (1) Take 50g soybean oil, 50g medium-chain triglycerides, 6g egg yolk lecithin, 1g compound 2 obtained in Example 1 and 1.25g polyphenol, heat and mix them at 65°C until dissolved, and use them as the oil phase;

[0160] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0161] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, and then homogenized six times under high pressure. Then it is filtered, filled, filled with nitrogen, and sterilized to obtain the injection solution.

[0162] Example 9: Preparation of Compound 2 and Pyrosol Emulsion Injection (Pyrosol: Compound 2 = 2.5:1)

[0163] (1) Take 50g soybean oil, 50g medium-chain triglycerides, 6g egg yolk lecithin, 0.5g compound 2 obtained in Example 1 and 1.25g polyphenol, heat and mix them at 65°C until dissolved, and use them as the oil phase;

[0164] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0165] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, and then homogenized six times under high pressure. Then it is filtered, filled, filled with nitrogen, and sterilized to obtain the injection solution.

[0166] Example 10: Preparation of Compound 2 and Propofol Emulsion Injection (Propofol: Compound 2 = 0.625:1)

[0167] (1) Take 50g soybean oil, 50g medium-chain triglycerides, 6g egg yolk lecithin, 2g compound 2 obtained in Example 1 and 1.25g polyphenol, heat and mix them at 65°C until dissolved, and use them as the oil phase;

[0168] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0169] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, and then homogenized six times under high pressure. Then it is filtered, filled, filled with nitrogen, and sterilized to obtain the injection solution.

[0170] Comparative Example 8: Preparation of etomidate and propofol emulsion injection (propofol: etomidate = 1.25:1)

[0171] Comparative Example 8 was prepared using the same procedures, conditions, and amounts as Example 8, except that etomidate was used instead of compound 2.

[0172] Comparative Example 9: Preparation of etomidate and propofol emulsion injection (propofol: etomidate = 2.5:1)

[0173] Comparative Example 9 was prepared using the same procedures, conditions, and amounts as Example 9, except that etomidate was used instead of compound 2.

[0174] Comparative Example 10: Preparation of etomidate and propofol emulsion injection (propofol: etomidate = 0.625:1)

[0175] Comparative Example 10 was prepared using the same procedures, conditions, and amounts as Example 10, except that etomidate was used instead of compound 2.

[0176] Comparative Example 11: Preparation of Povidone-Iodine Emulsion Injection

[0177] (1) Take 50g soybean oil, 50g medium-chain triglycerides, 6g egg yolk lecithin, and 1.25g polyphenols, heat and mix them at 65℃ until dissolved, and use this as the oil phase;

[0178] (2) Take 388g of water for injection, heat it to 65℃, add 12.5g of glycerol and 0.15g of sodium oleate and stir to form the aqueous phase;

[0179] (3) The aqueous phase and oil phase are sheared by a shearing machine at 65°C to form a primary emulsion. The primary emulsion is first homogenized once under low pressure in a homogenizer, and then homogenized six times under high pressure. Then it is filtered, filled, filled with nitrogen, and sterilized to obtain the injection solution.

[0180] Stability study of compound 2 and piroxicam emulsion injection in Experimental Example 1

[0181] (1) Appearance

[0182] Table 5 Appearance characteristics of each injection solution

[0183] In the table, A is a white milky liquid and B is a pale yellow milky liquid.

[0184] As can be seen from the data in Table 5, the samples of Examples 8-10 and cyclopropofol were white milky liquids before and after sterilization without significant changes in appearance, indicating good stability. The samples of Comparative Examples 8-10 were white milky liquids before sterilization, but after sterilization, some samples were white milky liquids and some were pale yellow milky liquids, 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.

[0185] (2) Impurity detection results

[0186] Sample preparation:

[0187] Chromatographic conditions:

[0188] Washing procedure:

[0189] Inject the sample according to the chromatographic conditions and calculate the impurity content using the external standard method.

[0190] The impurity detection results are as follows:

[0191] Table 6. Content of hydrolyzed impurities in each injection solution

[0192] As can be seen from the data in Table 6, the content of hydrolyzed impurity fluoroetomidic acid in the examples is significantly lower than that in the etomidate and cyclopropionate emulsion injections of the comparative examples. The relative percentage reduction of impurities is calculated based on the comparative examples. For example, taking 60 days of storage at 60°C as an example, the % content of fluoroetomidic acid in Example 8 is 0.31%, and the % content of etomidate in Comparative Example 8 is 1.61%. Therefore, the relative percentage reduction of impurities = (1.6-0.31) / 1.61*100% = 80.75%.

[0193] Table 7. Content of impurity 19 of propofol in each injection solution In the table, " / " indicates that it was not measured.

[0194] As can be seen from the data in Table 7, the content of propofol impurity 19 in etomidate and propofol emulsion injection in the comparative example is significantly higher than that in propofol emulsion, while the content of propofol impurity 19 in the examples is significantly lower than that in the comparative example.

[0195] Table 8 Total Impurities in Each Injection Solution In the table, " / " indicates that it was not measured.

[0196] As can be seen from the data in Table 8, the total impurity content in the examples is significantly lower than that in the comparative examples.

[0197] (3) Encapsulation ratio:

[0198] Encapsulation efficiency was determined by dialysis. Pre-treated dialysis bags were used. One end of the dialysis bag was tied tightly, and approximately 1 ml of the test sample was placed into different dialysis bags. The other end of the dialysis bag was then tied tightly with a string. The bags were dialyzed in a stability test chamber at 25°C for 36 hours. The liquid outside the dialysis bag was collected as the test solution. This test solution was then injected for analysis. The free drug content was determined by high-performance liquid chromatography (HPLC).

[0199] Encapsulation efficiency EN% = (1 - Cf / Ct) × 100%

[0200] In the formula, Cf represents the amount of free drug; Ct represents the total amount of drug.

[0201] Table 9 Encapsulation efficiency of etomidate derivative / etomidate in various injection solutions In the table, " / " indicates that it was not measured.

[0202] Table 10 Encapsulation efficiency of piroxicam in various injection solutions

[0203] As can be seen from the data in Tables 9 and 10, the encapsulation efficiency of etomidate derivative in the examples is much higher than that of etomidate in the comparative examples; there is no significant difference in the encapsulation efficiency of propofol between the examples and the comparative examples, but the content of propofol impurity 19 and total impurities is significantly increased in the comparative examples.

[0204] Although specific embodiments of the present invention have been described in detail, those skilled in the art can make various modifications and substitutions to the details of the technical solutions of the present invention based on all the teachings disclosed, and all such modifications and substitutions 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, the method comprising administering, in combination to the animal or human, an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and cyclopropanol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope 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-imidazol-5-carboxylate (compound 2).

3. The method according to claim 1 or 2, wherein the mass ratio of said cyclopropofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is calculated as the mass ratio of cyclopropofol to compound 2, and 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, about 3:1 to about 1:3, about 3:1 to about 1:2, about 2:1 to about 1:2, and again for example, about 4:1 to about 1:

2.

4. The method of claim 3, wherein the mass ratio of the cyclopropofol, 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 calculated as the mass ratio of cyclopropofol to compound 2, and 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 1-4, wherein it satisfies one or more of the following conditions: (1) The etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof are administered in liquid form, preferably in injectable form. (2) The concentration of etomidate derivative, pharmaceutically acceptable salt thereof, prodrug thereof, or isotope derivative thereof in the liquid formulation is calculated based on the concentration of compound 2 as approximately 0.1 mg / mL to approximately 50 mg / mL; (3) The cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivatives thereof are administered in liquid form, preferably in injectable form; (4) The concentration of the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative in the liquid formulation is calculated based on the concentration of cyclopropanol and is approximately 0.1 mg / mL to approximately 50 mg / mL.

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

7. The method according to any one of claims 1-5, wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered simultaneously; preferably, both are mixed with an optional pharmaceutically acceptable carrier before simultaneous administration.

8. The method according to any one of claims 1-5, wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered sequentially; preferably, the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative is administered first, followed by the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative; or the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative is administered first, followed by the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative.

9. The method according to any one of claims 1-8, further comprising administering simultaneously, sequentially, or separately any one or more of the following drugs: general anesthetic, local anesthetic, hypnotic, dissociative drug, sedative, adjunctive anesthetic, neuromuscular blocking agent, and analgesic.

10. The method according to any one of claims 1-9, wherein the anesthesia is anesthesia induction or anesthesia maintenance; and the sedation is mild 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 cyclopropanol, 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-imidazol-5-carboxylic acid ethyl ester.

13. The pharmaceutical combination according to claim 11 or 12, wherein the mass ratio of said propofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative to etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is calculated as the mass ratio of propofol to compound 2, and 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, about 3:1 to about 1:3, about 2:1 to about 1:2, about 3:1 to about 1:2, and again for example, about 4:1 to about 1:

2.

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

1.

15. A pharmaceutical combination according to any one of claims 11-14, wherein it satisfies one or more of the following conditions: (1) The etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative thereof are administered in liquid form, preferably in injectable form. (2) The concentration of etomidate derivative, pharmaceutically acceptable salt thereof, prodrug thereof, or isotope derivative thereof in the liquid formulation is calculated based on the concentration of compound 2 as approximately 0.1 mg / mL to approximately 50 mg / mL; (3) The cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivatives thereof are administered in liquid form, preferably in injectable form; (4) The concentration of the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative in the liquid formulation is calculated based on the concentration of cyclopropanol and is approximately 0.1 mg / mL to approximately 50 mg / mL.

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

17. The pharmaceutical combination according to any one of claims 11-15, wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative and the cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered simultaneously; preferably, both are mixed with an optional pharmaceutically acceptable carrier and administered simultaneously.

18. The pharmaceutical combination according to any one of claims 11-15, wherein the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative and the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative are administered sequentially; preferably, the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative is administered first, followed by the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative; or the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative is administered first, followed by the propofol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative.

19. The drug combination according to any one of claims 11-18, further comprising the simultaneous, sequential, or separate administration of any one or more of the following drugs: general anesthetic, local anesthetic, hypnotic, dissociative drug, sedative, adjunctive anesthetic, neuromuscular blocking agent, and analgesic.

20. The pharmaceutical combination according to any one of claims 11-19, wherein the pharmaceutical combination comprises 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; the second pharmaceutical composition comprises 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 pharmaceutical composition and the second pharmaceutical composition are used in combination by blending, dispensing, or formulation to form the pharmaceutical combination.

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

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

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

24. The pharmaceutical composition of claim 23, wherein the hydrolyzed impurity fluoroetomidic acid in the single formulation of the pharmaceutical composition is reduced by about 70-80% under the same conditions compared to the hydrolyzed impurity fluoroetomidic acid in the corresponding pharmaceutical composition containing etomidate and cyclopropanol.

25. The pharmaceutical composition of any one of claims 23-24, wherein the cyclopropofol impurity 19 in the single formulation of the pharmaceutical composition 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% under the same conditions compared to the cyclopropofol impurity 19 in a corresponding pharmaceutical composition containing etomidate and cyclopropofol.

26. The pharmaceutical composition of any one of claims 23-25, wherein the total impurities in the single formulation of the pharmaceutical composition 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% under the same conditions compared to the total impurities in a corresponding pharmaceutical composition containing etomidate and cyclopropanol.

27. The pharmaceutical composition of any one of claims 23-26, wherein the single formulation of the pharmaceutical composition is in emulsion form.

28. The pharmaceutical composition of any one of claims 23-27, wherein the amount of said etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative, converted to the amount of compound 2, is 0.01-5 wt% of compound 2 relative to the total mass of the pharmaceutical composition in the single formulation.

29. The pharmaceutical composition of any one of claims 23-28, wherein the content of said cyclopropofol, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is 0.01-5 wt% cyclopropofol relative to the total mass of the pharmaceutical composition in the single formulation.

30. The pharmaceutical composition of any one of claims 23-29, wherein the pharmaceutically acceptable carrier is selected from one or more of oily components, emulsifiers, stabilizers, osmotic pressure regulators, water for injection, co-emulsifiers, pH regulators, solubilizers, cosolvents, and fillers.

31. The pharmaceutical composition of any one of claims 23-30, wherein it satisfies one or more of the following conditions: The oily component is selected from any one or a mixture of several of soybean oil and medium-chain triglycerides in any proportion; The content of the oily component in the pharmaceutical composition is 5-30 wt%. The emulsifier is selected from egg yolk lecithin; The content of emulsifier in the pharmaceutical composition is 0.5-3 wt%; The stabilizer is selected from any one or a mixture of several of sodium oleate and oleic acid in any proportion: The stabilizer content 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 23-31, wherein the pharmaceutical composition comprises an etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, and one or more pharmaceutically acceptable carriers, the method comprising mixing propofol, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof, etomidate derivative, a pharmaceutically acceptable salt thereof, a prodrug thereof, or an isotope derivative thereof with one or more pharmaceutically acceptable carriers.

33. The preparation method of claim 32, wherein the method comprises: Etomidate derivatives, their pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives, propofol, their pharmaceutically acceptable salts, their prodrugs, or their isotopic derivatives 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 single formulation form, wherein the pharmaceutically acceptable carrier includes 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 self-emulsifiers and pH regulators.

34. The preparation method of claim 33, wherein the method comprises: 1) Preparation of oil phase: Mix the required amount of oily components, emulsifier, etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, cyclopropanol, its pharmaceutically acceptable salt, its prodrug, or its isotope derivative, and stir to dissolve at 50-80℃ to obtain the oil phase; 2) Aqueous phase preparation: Mix the required amounts of stabilizer, osmotic pressure regulator, injection water and optional pH adjuster, and stir to dissolve at 50-80℃ to obtain the aqueous phase; 3) Emulsion preparation: The oil phase and aqueous phase are sheared at 50-80℃ to form a primary emulsion, which is then homogenized in a homogenizer, followed by filling, nitrogen filling and sterilization to obtain the drug composition in the single formulation form.

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

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