CN112245426A - Pharmaceutical composition and pharmaceutical preparation of phenol derivative and etomidate and application of pharmaceutical composition and pharmaceutical preparation - Google Patents

Pharmaceutical composition and pharmaceutical preparation of phenol derivative and etomidate and application of pharmaceutical composition and pharmaceutical preparation Download PDF

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CN112245426A
CN112245426A CN202011151583.XA CN202011151583A CN112245426A CN 112245426 A CN112245426 A CN 112245426A CN 202011151583 A CN202011151583 A CN 202011151583A CN 112245426 A CN112245426 A CN 112245426A
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etomidate
compound
pharmaceutical
formula
mixture
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严庞科
郑伟
倪佳
余彦
莫毅
陈娅姝
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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    • 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
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants

Abstract

The invention relates to a pharmaceutical composition containing phenol derivatives and etomidate, a preparation method thereof and application thereof in the field of central nervous, wherein the phenol derivatives are compounds shown as a formula (I) or stereoisomers, pharmaceutically acceptable salts or prodrugs thereof.

Description

Pharmaceutical composition and pharmaceutical preparation of phenol derivative and etomidate and application of pharmaceutical composition and pharmaceutical preparation
Technical Field
The invention relates to a pharmaceutical composition of a phenol derivative and etomidate and application thereof in the field of central nerves.
Background
Propofol activates multiple GABAAThe receptor subtype is a clinically mature intravenous anesthetic, is widely used for induction and maintenance of general anesthesia, and has the advantages of quick response, easy awakening and the like.
However, propofol also has obvious limitations and disadvantages. It has been reported that about 70% of patients experience some degree of pain or discomfort upon injection of propofol (Pascale Picard (2000), Anesthesia & Analgesia,90,963 and 969). Although pre-treatment with other drugs or combinations of drugs have been reported to reduce the incidence and severity of propofol injection pain (C.H.Tan et al (1998). Anaesthesia,53, 302-. The administration dosage is generally 2.0-2.5 mg/kg, the propofol injection is generally used together with an analgesic, and the propofol injection for anesthesia induction parts can be mixed with 0.5W/V% or 1W/V% lidocaine injection according to the ratio of more than 20: 1 to reduce injection pain.
Propofol has been shown to lower systolic, diastolic and mean arterial blood pressure, thus clinically causing hypotension. At the same time, respiratory depression is a not negligible risk when using propofol. These adverse effects largely hamper the use of propofol in some clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.
International patent application WO2014180305 discloses propofol analogs, which are highly lipid-soluble substances that, when administered directly into the bloodstream, can cause a rapid onset of anesthesia, and in particular, compound 1 and related structures have a good anesthetic effect, and compound 1 has the following structure:
Figure BDA0002741275950000011
etomidate is a non-barbiturate hypnotic intravenous anesthetic with strong and short effect, has high safety and is one of the commonly used drugs for anesthesia induction. When the conventional dosage is used, the influence on the respiratory system and the circulatory system is small, and the hemodynamics of a patient can be kept stable. The etomidaku is safer to apply to patients with malignant hyperpyrexia and leaf forest disease and pregnant women. Can slightly expand coronary artery, reduce intracranial pressure and maintain cerebral perfusion, and is especially suitable for the elderly, coronary heart disease, hypertension and shock patients. However, etomidate has side effects of myoclonus, epileptogenic effect, nausea and vomiting, inhibition of synthesis of steroids in adrenal cortex and the like after application.
Based on the defects in the prior art, the intravenous anesthetic with good stability, high drug effect, small dosage, good safety, less side effect, injection pain reduction, good compliance or low cost is required to be provided.
Disclosure of Invention
The invention provides a pharmaceutical composition containing etomidate and a compound shown as a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the molar ratio of etomidate to the compound shown as the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 1: 0.01-1: 15,
Figure BDA0002741275950000021
wherein R is1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group; n is selected from 1 or 2;
preferably, R1Selected from methyl, ethyl or isopropyl; r2Selected from methyl, ethyl, isopropyl or cyclopropyl.
In a preferred embodiment of the present invention, the compound of formula (I) in the pharmaceutical composition is selected from one of the following structures:
Figure BDA0002741275950000022
in a preferred embodiment of the invention, the compound of formula (I) in the pharmaceutical composition is selected from the following structures:
Figure BDA0002741275950000023
in a preferred embodiment of the present invention, the molar ratio of etomidate to the compound of formula (I) in the pharmaceutical composition is 1: 0.05-1: 10, preferably 1: 0.1-1: 10, more preferably 1: 0.6, 1: 1.5, 1: 3 or 1:6.
the invention also provides a pharmaceutical composition containing etomidate and the compound shown as the general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the definition of the compound shown as the general formula (I) is defined as above,
Figure BDA0002741275950000031
wherein the mass ratio of etomidate to the compound of the general formula (I) in the pharmaceutical composition is 1: 0.05-1: 10, preferably 1: 0.1-1: 10, preferably 1: 0.5, 1: 1.25, 1: 1.67, 1: 2.0, 1: 2.5, 1: 3.33, 1: 5. 1:6.67 or 1: 10, more preferably 1: 0.5, 1: 1.25, 1: 2.5 or 1: 5.
the invention relates to a pharmaceutical composition containing etomidate and a compound shown as a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the two drugs in the pharmaceutical composition are mixed into a mixed solution according to a proportion and then sold, or are packaged into different containers according to a proportion and sold in a binding manner.
The invention also relates to a pharmaceutical preparation, wherein the active ingredients in the pharmaceutical preparation comprise etomidate and a compound of general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the molar ratio of etomidate to the compound of general formula (I) or the stereoisomer, pharmaceutically acceptable salt or the prodrug thereof is 1: 0.05-1: 10, preferably 1: 0.1-1: 10, more preferably 1: 0.6, 1: 1.5, 1: 3 or 1: 6; or the mass ratio of etomidate to the compound of the general formula (I) is 1: 0.05-1: 10, preferably 1: 0.1-1: 10, more preferably 1: 0.5, 1: 1.25, 1: 1.67, 1: 2.0, 1: 2.5, 1: 2.5, 1: 3.33, 1: 5. 1:6.67 or 1: 10, more preferably 1: 0.5, 1: 1.25, 1: 2.5 or 1: 5.
Figure BDA0002741275950000032
wherein R is1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group; n is selected from 1 or 2.
Preferably, R1Selected from methyl, ethyl or isopropyl; r2Selected from methyl, ethyl, isopropyl or cyclopropyl.
In a preferred embodiment of the invention, the compound of general formula (I) in the pharmaceutical formulation is selected from one of the following structures:
Figure BDA0002741275950000041
preference is given to
Figure BDA0002741275950000042
Compound 1.
In one aspect of the present invention, the pharmaceutical formulation is an aqueous solution formulation comprising:
1) etomidate, the content of which is 0.01 w/v% -5 w/v%, preferably 0.05 w/v% -3 w/v%, and further preferably 0.1 w/v% -2 w/v%; the content of the compound of the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 0.01 w/v% -5 w/v%; preferably 0.05 w/v% to 3 w/v%; further preferably 0.1 w/v% to 2 w/v%;
2) the content of the solubilizer is 0.1 w/v% -20 w/v%; preferably 0.1 w/v% -15 w/v%; further preferably 0.2 w/v% to 10 w/v%;
3) the content of the latent solvent is 0 w/v% -w/v 30%; preferably 0.1 w/v% to 20 w/v%; further preferably 0.1 to 10 w/v%.
Preferably, the solubilizer is selected from any one of or a mixture of any several of tween-80, tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate (i.e. solutol HS15) or poloxamer in any proportion; preferably tween-80, tween-20 or polyethylene glycol 15 hydroxystearate (i.e. Solutol HS 15); the latent solvent is selected from any one of ethanol, glycerol, propylene glycol or polyethylene glycol or a mixture of any several of the ethanol, the glycerol, the propylene glycol or the polyethylene glycol in any proportion.
In another embodiment of the present invention, the pharmaceutical formulation is a lyophilized formulation comprising:
1) etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof;
2) a solubilizer;
3) a latent solvent;
4) a filler.
In the preparation process of the freeze-dried preparation, the solution to be freeze-dried after the preparation of the freeze-dried preparation comprises:
1) etomidate, the content of which is 0.01 w/v% -5 w/v%, preferably 0.05 w/v% -3 w/v%, and further preferably 0.1 w/v% -2 w/v%; the content of the compound of the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 0.01 w/v% -5 w/v%; preferably 0.05 w/v% to 3 w/v%; further preferably 0.1-2 w/v%;
2) the content of the solubilizer is 0.1 w/v% -20 w/v%; preferably 0.1 w/v% -15 w/v%; further preferably 0.2 w/v% to 10 w/v%;
3) the content of the latent solvent is 0-30 w/v%; preferably 0.1 w/v% to 20 w/v%; further preferably 0.1 w/v% to 10 w/v%;
4) a filler, the content of which is 1 w/v% -30 w/v%; preferably 3 w/v% to 15 w/v%; further preferably 5 w/v% to 10 w/v%.
Preferably, the solubilizer is selected from any one of or a mixture of any several of tween-80, tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer in any proportion; the latent solvent is selected from any one or a mixture of any several of ethanol, glycerol, propylene glycol or polyethylene glycol in any proportion; the filler is selected from one or a mixture of any of lactose, sucrose, glucose, mannitol, sodium dihydrogen phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactobionate, dextran or polyvinylpyrrolidone in any proportion.
In a preferable embodiment of the invention, the lyophilized preparation or the aqueous solution preparation further comprises at least one pH regulator in an amount of 0-10 w/v%, preferably 0-5 w/v%.
Preferably, the pH regulator is selected from any one or more of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, phosphoric acid, citric acid, acetic acid and malic acid; preferably any one or a mixture of any several of sodium hydroxide, potassium hydroxide, triethanolamine, phosphoric acid, citric acid and hydrochloric acid in any proportion; further preferably any one of sodium hydroxide or hydrochloric acid or a mixture of any several of them in any proportion.
In a further preferred embodiment of the invention, the lyophilized preparation or the aqueous solution preparation further comprises at least one isotonic adjusting agent in an amount of 0-5 w/v%, preferably 0-2 w/v%.
Preferably, the isotonic regulator is selected from any one or a mixture of any several of glycerol, saccharides or sugar alcohols in any proportion; preferably any one or mixture of any several of glycerol, glucose, fructose, maltose, polyethylene glycol, sorbitol, propylene glycol, xylitol or mannitol; more preferably any one or a mixture of any several of glycerol, sorbitol, propylene glycol, polyethylene glycol or mannitol in any proportion; any one or a mixture of any several of glycerol, polyethylene glycol or mannitol in any proportion is further preferred; further preferred is glycerin.
In yet another aspect of the present invention, the pharmaceutical formulation is a fat emulsion comprising:
1) etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof;
2) an oily component.
Preferably, the oily component is selected from any one or a mixture of any several of natural or (and) synthetic oil and fat which are biocompatible and can be metabolized in human body; preferably any one or mixture of any several of soybean oil, linseed oil, medium chain triglyceride, structural triglyceride, olive oil, corn oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil, coconut oil, castor oil, fish oil, sesame oil or tea oil in any proportion; preferably any one or a mixture of any several of soybean oil, olive oil, fish oil, structural triglyceride, linseed oil or medium chain triglyceride in any proportion; further preferred is soybean oil, medium chain triglyceride, or a mixture of two or more thereof in an arbitrary ratio.
In a preferred embodiment of the invention, the fat emulsion further comprises at least one emulsifier.
Preferably, the emulsifier is selected from glycerol monooleate, tween-80, tween-20, poloxamer, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, macrogol glyceride, macrogol 15 hydroxystearate, egg yolk lecithin, egg yolk phosphatidylcholine, soybean lecithin, soybean phosphatidylcholine, one or a mixture of any of hydrogenated egg yolk lecithin, hydrogenated egg yolk phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated soybean phosphatidylcholine, diphosphonoyl palmitate, dimyristoyl phosphatidylcholine, distearoyl phosphatidylcholine, dioleoyl phosphatidylcholine and the like, dimyristoyl phosphatidylcholine, distearoyl phosphatidylglycerol and the like, diphosphonoyl palmitate, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine or dioleoyl phosphatidylethanolamine; further preferably one or a mixture of any more of poloxamer, tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin or soybean lecithin in any proportion; more preferably, the mixture of any one or two of egg yolk lecithin and soybean lecithin in any proportion is selected.
In a preferred embodiment of the present invention, the fat emulsion comprises:
1) etomidate, the content of which is 0.01 w/v% -5 w/v%, preferably 0.05 w/v% -3 w/v%, and further preferably 0.1 w/v% -2 w/v%; the content of the compound of the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 0.01 w/v% -5 w/v%; preferably 0.05 w/v% to 3 w/v%; further preferably 0.1 w/v% to 2 w/v%;
2) oily components, the content of which is 5 w/v% -30 w/v%; preferably 5 w/v% to 20 w/v%; further preferably 5 w/v% to 15 w/v%;
3) emulsifier, its content is 0.5 w/v% -5 w/v%; preferably 0.5 w/v% to 3 w/v%; further preferably 0.5 to 2 w/v%.
In a preferred embodiment of the present invention, the fat emulsion further comprises at least one co-emulsifier, and the content of the co-emulsifier is 0-0.2 w/v%.
Preferably, the coemulsifier is selected from any one of sodium oleate, sodium cholate, sodium deoxycholate, oleic acid, cholic acid, deoxycholic acid or cholesterol or a mixture of any several of the above in any proportion; any one of oleic acid and sodium oleate or a mixture of two of them in any ratio is preferred.
In a preferred embodiment of the present invention, the fat emulsion further comprises at least one isotonicity adjusting agent in an amount of 0 w/v% to 5 w/v%.
Preferably, the isotonic regulator is selected from any one or a mixture of any several of glycerol, saccharides or sugar alcohols in any proportion; preferably any one or mixture of any several of glycerol, glucose, fructose, maltose, polyethylene glycol, sorbitol, propylene glycol, xylitol or mannitol; more preferably any one or a mixture of any several of glycerol, sorbitol, propylene glycol, polyethylene glycol or mannitol in any proportion; any one or a mixture of any several of glycerol, polyethylene glycol or mannitol in any proportion is further preferred; further preferred is glycerin.
In a preferred embodiment of the present invention, the fat emulsion further comprises at least one pH regulator, the content of which is 0% to 10 w/v%, and the pH regulator is selected from any one or more of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, and malic acid; preferably any one or a mixture of any several of sodium hydroxide, potassium hydroxide, triethanolamine and hydrochloric acid in any proportion; further, either one of sodium hydroxide and hydrochloric acid or a mixture of both at an arbitrary ratio is preferable.
In a preferred embodiment of the present invention, the fat emulsion comprises:
1) the etomidate content is 0.1 w/v% -2 w/v%; the content of the compound of the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 0.1 w/v% -2 w/v%;
2) the content of the mixture of any one or two of soybean oil or medium chain triglyceride in any proportion is 5 w/v% -15 w/v%;
3) the content of the egg yolk lecithin is 0.5 w/v% -2 w/v%;
4) glycerol, the content of which is 0 w/v% -5 w/v%;
5) sodium oleate, the content of which is 0-0.2 w/v%;
in a preferred embodiment of the present invention, the pH of the fat emulsion is 3.0-10.0; preferably 4.0-9.0; more preferably 6.0 to 9.0.
In a preferred embodiment of the present invention, the pharmaceutical preparation may further comprise other additives, including but not limited to any one or a mixture of several of antioxidants, antibacterial agents, etc. in any proportion.
The antibacterial agent comprises any one or more of methyl benzoate, sodium metabisulfite, disodium edetate, calcium disodium edetate and the like;
the antioxidant includes, but is not limited to, any one or more of sodium metabisulfite, sodium sulfite, sodium bisulfite, potassium metabisulfite, sodium thiosulfate, dibutylphenol, butylhydroxyanisole (i.e., BHA), Tertbutylhydroquinone (TBHQ), dibutylhydroxytoluene (i.e., BHT), disodium edetate, or calcium sodium edetate, etc.
The invention provides application of a pharmaceutical composition containing etomidate and a compound shown as a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof in preparing a pharmaceutical preparation for inducing and maintaining anesthesia of animals or human beings, promoting sedation and hypnosis of the animals or the human beings, and treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion and epilepsy.
The present invention also provides a method of reducing side effects in an animal or human during sedation, induction, or maintenance of anesthesia, the method comprising:
administering to an animal a pharmaceutical composition or a pharmaceutical formulation according to the present invention; or
Animals are administered etomidate in the proportions described herein in combination with a compound of formula (I).
The invention also provides the application of the pharmaceutical composition or the pharmaceutical preparation in inducing and maintaining anesthesia of animals or human beings, promoting sedation and hypnosis of animals or human beings, and treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsion and epilepsy.
The invention also provides the use of etomidate in combination with a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, for inducing and maintaining anesthesia, promoting sedative-hypnosis, and treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
"w/v%" means weight (g) of each component per volume of the formulation (100 mL).
Preparation method of the preparation of the invention
The method comprises the following steps: method for preparing fat emulsion
Preparation of oil phase: weighing oily components, adding an emulsifier, a compound of formula (I) or a stereoisomer thereof and etomidate into the oily components under high-speed stirring in an inert gas environment, uniformly stirring to obtain an oil phase, and controlling the temperature of the oil phase to be 50-80 ℃.
Preparation of the aqueous phase: under the inert gas environment, adding an isotonic regulator and a co-emulsifier into a proper amount of water for injection, and uniformly stirring to obtain a water phase, wherein the temperature of the water phase is controlled to be 50-80 ℃.
Preparing an emulsion: slowly adding the oil phase into the water phase under high-speed stirring in an inert gas environment, and mixing to obtain primary emulsion, wherein the primary emulsion can be prepared at 50-80 ℃. Repeatedly homogenizing by a high-pressure homogenizer until the emulsion particles are qualified, filtering, encapsulating, sterilizing and cooling to obtain the emulsion injection of the compound of the formula (I) and etomidate.
The pH value of the fat emulsion is realized by adjusting the pH value of the water phase, and the pH value of a finished product is lower than that of the water phase; the pH of the final product is usually adjusted to 3.0-10.0, preferably pH 4.0-9.0, more preferably pH 6.0-9.0, the method for preparing the product is characterized in that the stirring mode, the rotating speed and the time are controlled according to the needs, a high shear mixing emulsifier is preferably used for preparing the primary emulsion, the selection can be carried out according to the needs, and the homogenization conditions and the time are well known to those skilled in the art for a high pressure homogenizer, as long as the average particle size of the homogenized milk particles is not more than 350nm, 95% of the particles are not more than 1.5 μm, and the particles with the particle size of more than 5 μm are not required. The sterilization may be performed by autoclaving, hot water immersion sterilization, spray sterilization, etc., and as a more preferable example of the sterilization process, autoclaving (e.g., 121 ℃, 12 minutes) may be used.
In the method for preparing a fat emulsion according to the present invention, the inert gas is selected from, but not limited to, nitrogen.
The fat emulsion preparation method adopted by the invention comprises the steps of uniformly dispersing the compound shown in the general formula (I) or the stereoisomer thereof and etomidate in oil for injection and an emulsifier, wrapping the oil phase, and then adding a water phase.
The second method comprises the following steps: method for preparing aqueous solution preparation
The method of mixing the components is not limited as long as a clear liquid preparation can be obtained, and may be performed according to a general process. For example: weighing a compound of a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, etomidate and a solubilizer, controlling the temperature to be 20-80 ℃, and uniformly stirring to obtain a mixed solution (1); weighing an isotonic regulator, adding injection water with the total preparation amount of 50-80%, stirring and dissolving to obtain a mixed solution (2), optionally adding the cosolvent and other additives into the (1) or (2) according to conditions, mixing the (1) and the (2) under stirring, and uniformly stirring to obtain a clear solution; adding a proper amount of activated carbon for injection, stirring and adsorbing for 5-30 min, then decarbonizing and filtering, adjusting the pH to 3.0-10.0 by using a pH regulator, preferably, the pH is 4.0-9.0, more preferably, the pH is 6.0-9.0, adding water for injection to the prepared volume, and uniformly stirring; filtering with 0.22 μm filter core, and bottling; sterilizing under hot pressure to obtain aqueous solution preparation.
The third method comprises the following steps: preparation method of freeze-dried preparation
The solution preparation and the freeze-drying process before freeze-drying are not limited as long as a qualified freeze-dried preparation can be obtained, and can be carried out according to a common process. For example: weighing the compound of the general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof, etomidate and a solubilizer, controlling the temperature to be 20-80 ℃, and uniformly stirring to obtain a mixed solution (1). Weighing an isotonic regulator and a filling agent, adding injection water with the total preparation amount of 50-80%, stirring and dissolving to obtain a mixed solution (2), optionally adding a cosolvent and other additives into the (1) or the (2) according to the situation, mixing the (1) and the (2) under stirring, and uniformly stirring to obtain a clear solution. Adding a proper amount of activated carbon for injection, stirring and adsorbing for 5-30 min, then decarbonizing and filtering, adjusting the pH to 3.0-10.0 by using a pH regulator, preferably, the pH is 4.0-9.0, more preferably, the pH is 6.0-9.0, adding water for injection to the prepared volume, and uniformly stirring. Filtering with a 0.22 μm filter element. Filling the mixture into a penicillin bottle according to a specified amount, half plugging the penicillin bottle, and pre-freezing the penicillin bottle in a front box of a freeze dryer. And (5) freeze drying. Vacuum or filling a proper amount of inert gas to press the stopper, and taking the stopper out of the box and rolling the cover.
The preparation method of the freeze-dried preparation adopted by the invention is obviously characterized by simple and easy preparation method, is more beneficial to long-term storage and convenient transportation, and is beneficial to large-scale production.
Drawings
Figure 1 is the results of the rat adrenocortical function assay in test example 2 (. beta. compared to blank fat milk, P < 0.05).
Detailed Description
The following detailed description is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDCl)3) Deuterated methanol (CD)3OD), internal standard Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI)) and Agilent 6120B (APCI));
HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6mm, 3.5. mu.M);
the thin-layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by thin-layer chromatography (TLC) is 0.15-0.20 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4-0.5 mm;
the column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier;
the known starting materials of the invention can be synthesized by adopting or according to the known method in the field, or can be purchased from companies such as Tatan science and technology, Annaiji chemistry, Shanghainemer, Chengdong chemical industry, Shaosuan chemical technology, Bailingwei science and technology, wherein etomidate is purchased from Youdouding era medical technology and technology limited company, the compound 1 is provided by Sichuan Cisco pharmaceutical limited company, etomidate emulsion injection is purchased from Jiangsu Enhua pharmaceutical industry GmbH, and the phenol derivative synthesis and preparation references WO2014180305 and WO 2016034079;
the nitrogen atmosphere refers to that the reaction bottle is connected with a nitrogen balloon with the volume of about 1L;
the hydrogen atmosphere refers to a reaction bottle connected with a hydrogen balloon with the volume of about 1L;
the hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times;
in the examples, the reaction was carried out under a nitrogen atmosphere, unless otherwise specified;
in the examples, unless otherwise specified, the solution means an aqueous solution;
in examples, the reaction temperature is not particularly limited, and is preferably room temperature, and the optimum reaction temperature is 20 ℃ to 30 ℃.
EXAMPLE 1 preparation of fat emulsion
Prescription:
Figure BDA0002741275950000111
under the protection of nitrogen, soybean oil for injection [ source: zhonghang (iron ridge) pharmaceutical Co., Ltd.), medium chain triglycerides [ source: zhonghang (Tieling) pharmaceutical Co., Ltd.) and heating to about 50 deg.C, adding refined egg yolk lecithin (source: Lipoid GmbH in Germany), compound 1 and etomidate under high speed stirring, stirring well, and controlling the temperature to 55-75 deg.C as oil phase; adding glycerol for injection (from lake Nanerkang pharmaceutical Co., Ltd.) and sodium oleate into appropriate amount of water for injection, mixing, adjusting pH of water phase to a proper range (ensuring pH of the finished product to be 6.0-9.0) with sodium hydroxide, and controlling temperature to be 55-75 deg.C to obtain water phase. Adding the oil phase into the water phase under high-speed stirring (high-shear mixing emulsifier, IKA production) to prepare primary emulsion, wherein the primary emulsion is prepared at the temperature of 55-75 ℃. Repeatedly homogenizing with high pressure homogenizer (produced by GEA Niro), checking that the emulsion meets the requirement, filtering the emulsion, introducing nitrogen, bottling, sterilizing in steam sterilizer, cooling, and checking to obtain 1/etomidate emulsion injection.
Example 2 preparation of fat emulsion
Prescription:
Figure BDA0002741275950000121
under the protection of nitrogen, soybean oil for injection [ source: zhonghang (iron ridge) pharmaceutical Co., Ltd.), medium chain triglycerides [ source: zhonghang (Tieling) pharmaceutical Co., Ltd.) and heating to about 50 deg.C, adding refined egg yolk lecithin (source: Lipoid GmbH in Germany), compound 1 and etomidate under high speed stirring, stirring well, and controlling the temperature to 55-75 deg.C as oil phase; adding glycerol for injection (from lake Nanerkang pharmaceutical Co., Ltd.) and sodium oleate into appropriate amount of water for injection, mixing, adjusting pH of water phase to a proper range (ensuring pH of the finished product to be 6.0-9.0) with sodium hydroxide, and controlling temperature to be 55-75 deg.C to obtain water phase. And adding the oil phase into the water phase under high-speed stirring (a high-shear mixing emulsifier, IKA) to prepare primary emulsion, wherein the primary emulsion is prepared at the temperature of 55-75 ℃. Repeatedly homogenizing with a high pressure homogenizer, checking that the emulsion granules meet the requirements, filtering the emulsion, introducing nitrogen, bottling, sterilizing in a steam sterilizer, cooling, and checking to be qualified to obtain the compound 1/etomidate emulsion injection.
Fat emulsions of compound 1+ etomidate in other ratios may be prepared with reference to example 1 or 2.
EXAMPLE 3 preparation of fat emulsion
Prescription:
Figure BDA0002741275950000122
under the protection of nitrogen, soybean oil for injection [ source: zhonghang (iron ridge) pharmaceutical Co., Ltd.), medium chain triglycerides [ source: mixing, heating to about 50 ℃, adding refined egg yolk lecithin (source: Lipoid GmbH in Germany) and the compound 1 under high-speed stirring, and uniformly stirring, wherein the temperature is controlled to be 55-75 ℃ to serve as an oil phase; adding glycerol for injection (from lake Nanerkang pharmaceutical Co., Ltd.) and sodium oleate into appropriate amount of water for injection, mixing, adjusting pH value of water phase to a proper range (ensuring pH value of the finished product to be 6.0-9.0), and controlling temperature to be 55-75 ℃ to serve as water phase. Adding the oil phase into the water phase under high-speed stirring (high-shear mixing emulsifier, IKA production) to prepare primary emulsion, wherein the primary emulsion is prepared at the temperature of 55-75 ℃. Repeatedly homogenizing with high pressure homogenizer (produced by GEA Niro), checking that the emulsion granule meets the requirement, filtering the emulsion, introducing nitrogen, bottling, sterilizing in steam sterilizer, cooling, and checking to obtain compound 1 emulsion injection.
Fat emulsions of other contents of compound 1 can be prepared with reference to example 3.
Biological test example
Test example 1: canine efficacy test of different doses of compound 1 in combination with etomidate
Beagle dog (Dysdorhodo Biotech Co., Ltd.) 8-9kg, 6 dogs, female and male. Beagle dogs were fasted for 16 hours prior to dosing. On the day of administration, etomidate emulsion injection (Jiangsu Enhua pharmaceutical Co., Ltd.) and a mixture of compound 1 and etomidate in different dose ratios were injected intravenously once, and the induction time and duration of anesthesia of beagle dogs were recorded, while the occurrence of muscle spasm, nausea and vomiting of beagle dogs was observed. The results of the experiment are shown in table 1:
anesthesia induction time: time to disappearance of righting reflex after administration;
duration of anesthesia: the time from disappearance of the righting reflection to restoration of the righting reflection;
TABLE 1 Canine efficacy test of Compound 1 in combination with Etomidate
Figure BDA0002741275950000131
And (4) conclusion: when etomidate is used alone, the duration of anesthesia is increased along with the increase of etomidate dosage, and meanwhile, the incidence rate of adverse reactions such as muscle spasm, nausea, vomiting and the like is also increased; after the compound 1 is combined with different doses, the anesthesia induction time is shortened, the anesthesia duration is prolonged, and no adverse reactions such as muscle spasm, nausea and vomiting are observed.
After the compound 1 and etomidate are used together, the anesthetic effect can be achieved when the etomidate is used alone, the adverse reaction can be obviously improved when the etomidate is used alone, the medication safety is improved, and the experience of patients is improved.
Test example 2 rat adrenocortical function assay
SPF grade SD rats, 250- & ltSUB & gt, 300g, male, provided by Beijing Wittison, were fasted without water deprivation prior to the experiment, and all animals were randomly divided into 4 groups the following day according to body weight. Each group of animals was injected intravenously with dexamethasone at 0.2mg/kg, and blood was collected in the jugular sinus at 200. mu.l 2h after injection. After blood collection, the injection is intravenously administered again, and dexamethasone sodium phosphate injection 0.2mg/kg, the tested compound (blank fat milk or compound 1 or etomidate or compound 1 combined with etomidate) and N-terminal 24 peptide (ACTH (1-24)) of adrenocorticotropic hormone 25 μ g/kg are intravenously injected in sequence; blood was collected from the jugular sinus at a volume of 200. mu.l 15min and 30min after injection, respectively. The dosing regimen is shown in table 2 below. After the whole blood collected twice is coagulated for 30min at room temperature, the supernatants are respectively collected and stored at-80 ℃, the serum corticosterone concentration is detected by an enzyme-linked immunosorbent assay (ELISA), and the result of the rat adrenal cortex function detection is shown in figure 1.
TABLE 2 rat adrenocortical function testing dosing regimen
Name (R) Dosage to be administered Number of animals
Blank fat emulsion 10ml/kg 8
Compound 1 2.5mg/kg 8
Etomidate 2mg/kg 8
Compound 1+ Etomidate 1.25mg/kg+1mg/kg 8
And (4) conclusion: etomidate alone at a dose of 2mg/kg has an obvious inhibition effect on rat adrenal cortex function, and after etomidate is combined with compound 1, the inhibition effect of etomidate on renal cortex function can be obviously improved.
Test example 3 study of the safety of the combination of Compound 1 with Etomidate
The purpose of the test is as follows:
the safety of a single dose of intravenous compound 1 in combination with etomidate was evaluated for anesthesia induction.
Test protocol:
the test is open (open label) and a combination of compound 1 and etomidate is administered intravenously in a single dose to a subject and evaluated for its anesthetic/sedative effect as well as safety.
Adult healthy male subjects were selected and randomly divided into 4 groups (control group, test group 1, test group 2, test group 3) of 5 persons each. The following doses were administered to each group:
control group: 0.648mg/kg Compound 1;
test group 1: a combination of 0.324mg/kg compound 1 and 0.15mg/kg etomidate,
test group 2: a combination of 0.216mg/kg compound 1 and 0.20mg/kg etomidate,
test group 3: a combination of 0.432mg/kg compound 1 and 0.10mg/kg etomidate.
The above administration dose allowed the control group, test group 1, test group 2 and test group 3 to reach the same depth of anesthesia.
The administration mode and the route are as follows: each group of subjects will be administered intravenously at the above-mentioned dose, wherein the combination of compound 1 and etomidate in test groups 1, 2, 3 is a premixed injection solution containing compound 1 and etomidate. The medication is intravenously injected into the subject's antecubital fossa using an infusion pump for a period of time greater than 60 seconds. All subjects will be in the study room from night day 1 to morning day 2 from the start of the trial, and then leave the study room, with the subjects being asked to return on day 7. The test results are shown in tables 3, 4 and 5.
TABLE 3 anesthetic Effect of the groups
Figure BDA0002741275950000151
TABLE 4 comparison of blood pressure before and after administration of control group
Figure BDA0002741275950000152
Figure BDA0002741275950000161
Note: the baseline value is the last reliable value available before dosing (-15min, -10min, -5min, 0min), typically 0 min. The baseline value is calculated here in two ways, namely
*: t is 0 min; and (delta): t-15 min, t-10 min, t-5 min
SBP: contracting pressure; DBP: diastolic blood pressure
TABLE 5 comparison of blood pressure before and after administration in test groups 1, 2 and 3
Figure BDA0002741275950000162
And (4) conclusion: under the condition of reaching the same depth of anesthesia (equivalent), the combination of the two medicines ensures that the blood pressure of a patient is more stable and the side effect is possibly less.

Claims (34)

1. A pharmaceutical composition containing etomidate and a compound shown as a general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the mol ratio of the etomidate to the compound shown as the general formula (I) or the stereoisomer, the pharmaceutically acceptable salt or the prodrug thereof is 1: 0.01-1: 15,
Figure FDA0002741275940000011
wherein R is1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group; n is selected from 1 or 2.
2. The pharmaceutical composition of claim 1, wherein:
R1selected from methyl, ethyl or isopropyl; r2Selected from methyl, ethyl, isopropyl or cyclopropyl.
3. Pharmaceutical composition according to claim 2, characterized in that the compound of general formula (I) is selected from one of the following structures:
Figure FDA0002741275940000012
Figure FDA0002741275940000013
or
Figure FDA0002741275940000014
4. A pharmaceutical composition according to any one of claims 1-3, characterized in that the molar ratio of etomidate to the compound of general formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof is 1: 0.05-1: 10, preferably 1: 0.1-1: 10, more preferably 1: 0.6, 1: 1.5, 1: 3 or 1:6.
5. a pharmaceutical composition comprising etomidate and a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the compound of formula (I) is as defined in claim 3,
Figure FDA0002741275940000015
the etomidate and the compound with the general formula (I) are characterized in that the mass ratio of etomidate to the compound with the general formula (I) is 1: 0.05-1: 15, preferably 1: 0.5-1: 10, more preferably 1: 0.5, 1: 1.25, 1: 1.67, 1: 2.0, 1: 2.5, 1: 2.5, 1: 3.33, 1: 5. 1:6.67 or 1: 10.
6. a pharmaceutical preparation characterized by comprising an active ingredient comprising etomidate and a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the molar ratio of etomidate to compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof is 1: 0.05-1: 10;
Figure FDA0002741275940000021
wherein R is1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group; n is selected from 1 or 2.
7. The pharmaceutical formulation of claim 6,
R1selected from methyl, ethyl or isopropyl; r2Selected from methyl, ethyl, isopropyl or cyclopropyl.
8. Pharmaceutical preparation according to claim 7, characterized in that the compounds of the general formula (I) are defined in accordance with claim 3.
9. A pharmaceutical preparation, characterized by comprising an active ingredient, wherein the active ingredient comprises etomidate and a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the etomidate comprises 0.01 w/v% -5 w/v% and the compound of formula (I) comprises 0.01 w/v% -5 w/v%
Figure FDA0002741275940000022
The compounds of the general formula (I) are as defined in claim 3.
10. Pharmaceutical formulation according to any one of claims 6 to 9, characterized in that it is an aqueous solution formulation, a lyophilized formulation or a fat emulsion.
11. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is an aqueous solution preparation comprising 0.01 w/v% to 5 w/v% etomidate, 0.01 w/v% to 5 w/v% of the compound of formula (I), 0.1 w/v% to 20 w/v% of a solubilizing agent, and 0 to 30 w/v% of a cosolvent.
12. Pharmaceutical formulation according to claim 11, characterized in that the aqueous solution formulation comprises 0.05 to 3 w/v% etomidate, 0.05 to 3 w/v% of the compound of formula (I), 0.1 to 15 w/v% of a solubilizer, 0.1 to 20 w/v% of a cosolvent, preferably the aqueous solution formulation comprises 0.1 to 2 w/v% etomidate, 0.1 to 2 w/v% of the compound of formula (I), 0.2 to 10 w/v% of a solubilizer, 0.1 to 10 w/v% of a cosolvent.
13. The pharmaceutical formulation according to claim 11 or 12, characterized in that:
the solubilizer is selected from any one or a mixture of any several of tween-80, tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer in any proportion;
the latent solvent is selected from any one of ethanol, glycerol, propylene glycol or polyethylene glycol or a mixture of any several of the ethanol, the glycerol, the propylene glycol or the polyethylene glycol in any proportion.
14. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a lyophilized preparation, and the solution to be lyophilized comprises 0.01 w/v% to 5 w/v% etomidate, 0.01 w/v% to 5 w/v% of the compound of formula (I), 0.1 w/v% to 20 w/v% of a solubilizer, 0 to 30 w/v% of a cosolvent, and 1 w/v% to 30 w/v% of a bulking agent.
15. Pharmaceutical preparation according to claim 14, characterized in that the solution to be lyophilized after the compounding comprises 0.05 to 3 w/v% etomidate, 0.05 to 3 w/v% of the compound of formula (I), 0.1 to 15 w/v% of a solubilizer, 0.1 to 20 w/v% of a cosolvent and 3 to 15 w/v% of a bulking agent, preferably, after the solution preparation is finished, the solution to be lyophilized comprises 0.1 w/v% -2 w/v% of etomidate, 0.1 w/v% -2 w/v% of a compound shown in a general formula (I), 0.2 w/v% -10 w/v% of a solubilizer, 0.1 w/v% -10 w/v% of a cosolvent and 5 w/v% -10 w/v% of a filler.
16. The pharmaceutical formulation according to claim 14 or 15, characterized in that:
the solubilizer is selected from any one or a mixture of any several of tween-80, tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer in any proportion;
the latent solvent is selected from any one or a mixture of any several of ethanol, glycerol, propylene glycol or polyethylene glycol in any proportion;
the filler is selected from one or a mixture of any of lactose, sucrose, glucose, mannitol, sodium dihydrogen phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactobionate, dextran or polyvinylpyrrolidone in any proportion.
17. The pharmaceutical formulation according to any one of claims 11 to 16, characterized in that the aqueous solution formulation or the lyophilized formulation further comprises 0 w/v% to 10 w/v% of a pH adjusting agent, respectively.
18. The pharmaceutical preparation according to claim 17, wherein the pH adjusting agent is selected from any one or a mixture of any several of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, citric acid, and phosphoric acid.
19. The pharmaceutical formulation according to any one of claims 11 to 18, characterized in that the aqueous solution formulation or the lyophilized formulation, respectively, further comprises 0-5 w/v% of an isotonicity adjusting agent.
20. The pharmaceutical preparation according to claim 19, wherein the isotonic regulator is selected from any one or a mixture of glycerol, sorbitol, propylene glycol, polyethylene glycol or mannitol.
21. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a fat emulsion comprising 0.01 w/v% to 5 w/v% etomidate, 0.01 w/v% to 5 w/v% of the compound of formula (I), 5 w/v% to 30 w/v% of an oily component, and 0.5 w/v% to 5 w/v% of an emulsifying agent.
22. Pharmaceutical formulation according to claim 21, characterized in that the fat emulsion comprises 0.05 to 3 w/v% etomidate, 0.05 to 3 w/v% of the compound of formula (I), 5 to 20 w/v% of the oily component and 0.5 to 3 w/v% of the emulsifying agent, preferably the fat emulsion comprises 0.1 to 2 w/v% etomidate, 0.1 to 2 w/v% of the compound of formula (I), 5 to 15 w/v% of the oily component and 0.5 to 2 w/v% of the emulsifying agent.
23. The pharmaceutical formulation of claim 21 or 22, wherein:
the oily component is selected from any one or a mixture of any several of soybean oil, olive oil, fish oil, linseed oil, medium chain triglyceride and structural triglyceride in any proportion;
the emulsifier is selected from one or a mixture of any of poloxamer, tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin or soybean lecithin in any proportion.
24. Pharmaceutical formulation according to any of claims 21 to 23, characterized in that the fat emulsion further comprises 0-0.2 w/v% of a co-emulsifier.
25. The pharmaceutical formulation of claim 24, wherein the co-emulsifier is selected from the group consisting of oleic acid, sodium oleate, and mixtures thereof.
26. The pharmaceutical formulation according to any one of claims 21 to 25, characterized in that the fat emulsion further comprises 0-5 w/v% of an isotonicity adjusting agent.
27. The pharmaceutical preparation according to claim 26, wherein the isotonic regulator is selected from any one or a mixture of glycerol, sorbitol, propylene glycol, polyethylene glycol or mannitol.
28. The pharmaceutical formulation according to claim 27, wherein the fat emulsion comprises 0.1-2 w/v% etomidate, 0.1-2 w/v% of the compound of formula (I), 5-15 w/v% of either or a mixture of two of the soybean oil or the medium chain triglyceride in any ratio, 0.5-2 w/v% of egg yolk lecithin, 0-5 w/v% of glycerol and 0-0.2 w/v% of sodium oleate.
29. Pharmaceutical formulation according to claim 28, characterized in that the fat emulsion has a pH of 3.0-10.0, preferably a pH of 4.0-9.0, more preferably a pH of 6.0-9.0.
30. Use of a pharmaceutical composition according to any one of claims 1-5 for the manufacture of a medicament for inducing and maintaining anesthesia, promoting sedation and hypnosis, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in an animal or human.
31. A method of reducing side effects in an animal or human during sedation, induction, or maintenance of anesthesia, the method comprising:
administering to a human or animal a pharmaceutical composition according to any one of claims 1 to 5 or a pharmaceutical formulation according to any one of claims 6 to 29; or
Administering to a human or animal an etomidate in a ratio according to any of claims 1-5 in combination with a compound of formula (I).
32. A pharmaceutical composition according to any one of claims 1 to 5 or a pharmaceutical formulation according to any one of claims 6 to 29 for use in inducing and maintaining anesthesia, promoting sedative-hypnosis, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans.
33. Etomidate and a compound of formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, for use in combination with etomidate for inducing and maintaining anesthesia, promoting sedative-hypnosis, treating and/or preventing anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans,
Figure FDA0002741275940000051
wherein R is1And R2Each independently selected from C1-4Alkyl or C3-6A cycloalkyl group; n is selected from 1 or 2.
34. A pharmaceutical composition comprising etomidate and a compound of formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, characterized in that the two drugs are mixed in proportion to form a mixed solution according to any one of claims 1 to 5, or are divided into different containers in proportion.
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