WO2025247238A1 - Combinaison pharmaceutique contenant un dérivé d'étomidate et du ciprofol et son utilisation - Google Patents

Combinaison pharmaceutique contenant un dérivé d'étomidate et du ciprofol et son utilisation

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Publication number
WO2025247238A1
WO2025247238A1 PCT/CN2025/097562 CN2025097562W WO2025247238A1 WO 2025247238 A1 WO2025247238 A1 WO 2025247238A1 CN 2025097562 W CN2025097562 W CN 2025097562W WO 2025247238 A1 WO2025247238 A1 WO 2025247238A1
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WIPO (PCT)
Prior art keywords
derivative
pharmaceutically acceptable
prodrug
acceptable salt
etomidate
Prior art date
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Pending
Application number
PCT/CN2025/097562
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English (en)
Chinese (zh)
Inventor
徐祥清
梅占彪
田利伟
王伟
于民权
李子林
李冬冬
曹悦
梁宏玉
杨茜
孙世齐
刘雷
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nhwa Pharmaceutical Corp
Original Assignee
Nhwa Pharmaceutical Corp
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Filing date
Publication date
Application filed by Nhwa Pharmaceutical Corp filed Critical Nhwa Pharmaceutical Corp
Priority to CN202580001530.4A priority Critical patent/CN120769745A/zh
Publication of WO2025247238A1 publication Critical patent/WO2025247238A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • 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.
  • 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.
  • awakening time the time from drug withdrawal to awakening
  • walking time the time from drug withdrawal to being able to walk normally
  • 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.
  • 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.
  • 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.
  • This invention aims to improve the aforementioned problems by combining (or administering) a combination containing a specific etomidate derivative and cyclopropofol.
  • a combination containing a specific etomidate derivative and cyclopropofol a combination containing a specific etomidate derivative 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.
  • 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):
  • R1 is a C1-6 alkyl group.
  • the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (hereinafter referred to as compound 2).
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention also relates to the following aspects:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the anesthesia is an induction of anesthesia or maintenance of anesthesia;
  • the sedation is mild sedation, moderate sedation or deep sedation.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the opioid analgesic is one or more selected from fentanyl, remifentanil, sufentanil, alfentanil, etc.
  • 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):
  • R1 is a C1-6 alkyl group.
  • 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.
  • the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (also known as compound 2).
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • the etomidate derivative, its pharmaceutically acceptable salt, its prodrug, or its isotopic derivative is administered in a liquid formulation, such as an injectable formulation.
  • a liquid formulation such as an injectable formulation.
  • 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.
  • 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.
  • a liquid formulation such as an injectable formulation.
  • 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.
  • 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.
  • 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):
  • R1 is a C1-6 alkyl group.
  • the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazol-5-carboxylate (hereinafter compound 2).
  • 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.
  • 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 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • the single-formulation pharmaceutical composition is in emulsion form.
  • 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.
  • 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.
  • the oily component is selected from any one or a mixture of any number of 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 emulsifier content in the pharmaceutical composition is 0.5-3 wt%.
  • the stabilizer is selected from sodium oleate, oleic acid, or any mixture of several of them 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%;
  • 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):
  • R1 is a C1-6 alkyl group
  • 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.
  • the etomidate derivative of formula (1) is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazol-5-carboxylate (hereinafter compound 2).
  • 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.
  • 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 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • the method includes:
  • 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°C to obtain the oil phase.
  • Aqueous phase preparation Mix the required amounts of stabilizer, osmotic pressure regulator, injection water and optional pH adjuster, and stir evenly at 50-80°C to obtain the aqueous phase;
  • Emulsion preparation The oil phase and aqueous phase are sheared at 50-80°C 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.
  • the oily component is soybean oil, one or a combination of medium-chain triglycerides.
  • the emulsifier is refined egg yolk lecithin.
  • 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.
  • 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.
  • the drug combination of the present invention has a synergistic effect on improving blood glucose level fluctuations and blood potassium level decline:
  • etomidate derivative compound 2
  • 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);
  • 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.
  • 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.
  • the content of propofol impurity 19 in the drug combination of the present invention containing etomidate derivative and propofol is significantly reduced.
  • 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.
  • C1-6 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.
  • etomidate derivatives 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • etomidate derivative prodrug described in this invention includes chemically modified compounds capable of releasing etomidate or etomidate derivatives in vivo.
  • cyclopropanol prodrug described in this invention includes chemically modified compounds capable of releasing cyclopropanol in vivo.
  • isotope derivative refers to a compound that differs from the compounds described herein only in the presence of one or more isotopically enriched atoms. For example, it may have the structure shown in the general formula, replacing hydrogen only with “deuterium” or “tritium,” and/or, fluorine with 18F , and/or, carbon with 11C , 13C , or 14C , while the rest remains unchanged.
  • Deuterated compounds generally retain activity comparable to their undeuterated counterparts, and when deuterated at certain sites, they may achieve better metabolic stability, resulting in certain therapeutic advantages (such as increased in vivo half-life or reduced dose requirement).
  • ком ⁇ онент refers to a pharmaceutical product composed of a mixture or combination of two or more active ingredients.
  • these active ingredients can be mixed into a single formulation, or they can be kept separate in different formulations.
  • 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.
  • 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.
  • administration refers 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.
  • combination 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.
  • composition 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.
  • 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.
  • 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.
  • 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.
  • the term “about” or “approximately” when used in conjunction with a numerical value indicates a set or range that includes that value.
  • “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.
  • the term “about” refers to a range of values that are 5% more or less than a specified value.
  • the term “about” refers to a range of values that are 2% more or less than a specified value.
  • the term “about” or “approximately” refers to a range of values that are 1% more or less than a specified value.
  • 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.
  • 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.
  • 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.
  • 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.
  • the etomidate derivative of this invention is an etomidate derivative of Formula 1:
  • R1 is a C1-6 alkyl group.
  • the etomidate derivative is (R)-1-(1-phenylethyl)-1H-4-fluoro-imidazolium-5-carboxylate (also known as compound 2), with the following structure:
  • Example 2 Preparation of etomidate derivative (i.e., compound 2) emulsion injection
  • 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.
  • 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.
  • Examples 3-8 Drug combinations comprising etomidate derivative (i.e., compound 2) and cyclopropanol
  • 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.
  • Comparative Examples 3-8 Drug combinations containing etomidate and propofol
  • Table 1 contains drug combinations of compound 2, etomidate, and cyclopropanol in different proportions.
  • Test Example 1 A study of canine infusion recovery time and serum potassium levels in different combinations of etomidate or its derivatives and propofol.
  • Test Example 2 Therapeutic Index Study of Different Drug Combinations Including Etomidate Derivatives and Cycloprophen
  • the ED50 of different drug combinations in rats was determined using a sequential method. Rats were administered the drugs intravenously, and the disappearance of the righting reflex after administration was observed to determine whether the drug combination had an anesthetic effect. The ED50 value was calculated using AOT425 software.
  • the LD50 of different drug combinations in rats was determined using a sequential method. Rats were administered the drugs intravenously, and the survival and mortality of the animals were observed. The LD50 value was calculated using AOT425 software.
  • Test Example 3 Study on glycemic stability of different drug combinations containing etomidate derivatives and propofol
  • 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.
  • 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.
  • 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.
  • Comparative Example 8 was prepared using the same procedures, conditions, and amounts as Example 8, except that etomidate was used instead of compound 2.
  • Comparative Example 9 was prepared using the same procedures, conditions, and amounts as Example 9, except that etomidate was used instead of compound 2.
  • Comparative Example 10 was prepared using the same procedures, conditions, and amounts as Example 10, except that etomidate was used instead of compound 2.
  • 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.
  • A is a white milky liquid and B is a pale yellow milky liquid.
  • 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.
  • the impurity detection results are as follows:
  • 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 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.
  • 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).
  • HPLC high-performance liquid chromatography
  • Encapsulation efficiency EN% (1 - Cf/Ct) ⁇ 100%
  • Cf represents the amount of free drug
  • Ct represents the total amount of drug
  • Table 9 Encapsulation efficiency of etomidate derivative/etomidate in various injection solutions In the table, "/" indicates that it was not measured.

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Abstract

L'invention concerne une combinaison pharmaceutique d'un dérivé d'étomidate et de ciprofol, et une composition pharmaceutique comprenant le dérivé d'étomidate et le ciprofol. L'invention concerne également l'utilisation de la combinaison pharmaceutique ou de la composition pharmaceutique pour l'anesthésie, la sédation et/ou l'hypnose d'animaux ou d'êtres humains. Par rapport à l'administration du dérivé d'étomidate ou du ciprofol seul et l'administration combinée d'étomidate et de ciprofol, la combinaison pharmaceutique ou la composition pharmaceutique présente un excellent effet synergique, améliorant significativement le temps de récupération après dissipation de l'anesthésie, etc.
PCT/CN2025/097562 2024-05-27 2025-05-27 Combinaison pharmaceutique contenant un dérivé d'étomidate et du ciprofol et son utilisation Pending WO2025247238A1 (fr)

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