WO2018014770A1 - Dérivé de phénol et composition pharmaceutique d'étomidate, préparation pharmaceutique et leur application - Google Patents

Dérivé de phénol et composition pharmaceutique d'étomidate, préparation pharmaceutique et leur application Download PDF

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WO2018014770A1
WO2018014770A1 PCT/CN2017/092722 CN2017092722W WO2018014770A1 WO 2018014770 A1 WO2018014770 A1 WO 2018014770A1 CN 2017092722 W CN2017092722 W CN 2017092722W WO 2018014770 A1 WO2018014770 A1 WO 2018014770A1
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compound
etomidate
formula
pharmaceutical preparation
preparation according
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PCT/CN2017/092722
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English (en)
Chinese (zh)
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严庞科
郑伟
倪佳
余彦
莫毅
陈娅姝
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四川海思科制药有限公司
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Priority to CN201780035396.5A priority Critical patent/CN109310676A/zh
Publication of WO2018014770A1 publication Critical patent/WO2018014770A1/fr

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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

Definitions

  • the present invention relates to a pharmaceutical composition of a phenol derivative and etomidate and its use in the field of central nervous system.
  • Propofol can activate a variety of GABA A receptor subtypes. It is a clinically mature intravenous anesthetic. It is widely used in the induction and maintenance of general anesthesia. It has the advantages of rapid onset and easy to wake up.
  • propofol also has obvious limitations and disadvantages. It has been reported that about 70% of patients have some degree of pain or discomfort when taking propofol (Pascale Picard (2000). Anesthesia & Analgesia, 90, 963-969). Although it has been reported that pretreatment or combination therapy with other drugs can reduce the incidence and severity of propofol injection pain (C.H. Tan et al. (1998). Anaesthesia, 53, 302–305), this pain is still difficult to avoid.
  • the dosage is generally 2.0-2.5 mg/kg, generally used in combination with an analgesic, and the propofol injection for the anesthesia-inducing part can be 0.5 W/V% or 1 W/V% in a ratio of more than 20:1.
  • the lidocaine injection is mixed to reduce the pain of injection.
  • Propofol has been shown to reduce systolic blood pressure, diastolic blood pressure and mean arterial blood pressure, thus causing hypotension in the clinic.
  • respiratory depression is also a risk that cannot be ignored when using propofol.
  • These adverse reactions have largely hampered the use of propofol in a number of clinical cases, such as cardiovascular disease, brain damage and chronic hypotension.
  • the international patent application WO2014180305 discloses a propofol analog, which is a high-fat soluble substance, which is directly administered into the bloodstream, and can cause rapid onset of anesthesia, especially the compound 1 and other related structures have good anesthetic effects, compounds
  • the structure of 1 is as follows:
  • Etomidate is a potent and short-acting non-barbital hypnotic intravenous anesthetic with high safety and is one of the commonly used drugs for anesthesia induction. When using regular doses, it’s breathing and The effects of the circulatory system are small and maintain the patient's hemodynamic stability. For patients with malignant hyperthermia, phylloxic disease and pregnant women, it is safer to use Dependent Cool. Can slightly dilate the coronary artery, reduce intracranial pressure and maintain cerebral perfusion, especially for elderly, coronary heart disease, hypertension, shock patients. However, after application of etomidate, side effects such as myoclonus, epileptic-like effects, nausea and vomiting, and inhibition of the synthesis of corpus callosum in the adrenal cortex may occur.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein etomidate and a compound of the formula (I) Or the molar ratio of its stereoisomer, pharmaceutically acceptable salt or prodrug is 1:0.01 to 1:15.
  • R 1 and R 2 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl; n is selected from 1 or 2;
  • R 1 is selected from methyl, ethyl or isopropyl
  • R 2 is selected from methyl, ethyl, isopropyl or cyclopropyl.
  • the compound of the formula (I) in the pharmaceutical composition is selected from one of the following structures:
  • the compound of formula (I) in the pharmaceutical composition is selected from the following structures:
  • the molar ratio of etomidate to the compound of the formula (I) in the pharmaceutical composition is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:10, further preferably 1: 0.6, 1:1.5, 1:3 or 1:6.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, the definition of the compound of the formula (I) As defined above,
  • the mass ratio of etomidate to the compound of the formula (I) in the pharmaceutical composition is from 1:0.05 to 1:10, preferably from 1:0.1 to 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 present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein the pharmaceutical composition is the two
  • the medicines are mixed in proportion to a mixed solution and then sold, or distributed in different containers and bundled for sale.
  • the invention further relates to a pharmaceutical preparation comprising an active ingredient in the pharmaceutical preparation comprising etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, wherein etomidate is
  • the molar ratio of the compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:10, further preferably 1:0.6,1 : 1.5, 1:3 or 1:6; or the mass ratio of etomidate to the compound of the formula (I) is 1:0.05 to 1:10, preferably 1:0.1 to 1:10, further 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, still more preferably 1:0.5, 1:1.25, 1:2.5 or 1:5.
  • R 1 and R 2 are each independently selected from C 1-4 alkyl or C 3-6 cycloalkyl; n is selected from 1 or 2.
  • R 1 is selected from methyl, ethyl or isopropyl
  • R 2 is selected from methyl, ethyl, isopropyl or cyclopropyl.
  • the compound of the formula (I) in the pharmaceutical preparation is selected from one of the following structures:
  • the pharmaceutical preparation is an aqueous preparation comprising:
  • etomidate the content of which is from 0.01 w/v% to 5 w/v%, preferably from 0.05 w/v% to 3 w/v%, More preferably 0.1w / v% ⁇ 2w / v%; a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, in an amount of from 0.01 w / v% to 5 w / v%; Preferably 0.05w/v% to 3w/v%; further preferably 0.1w/v% to 2w/v%;
  • solubilizer the content of which is from 0.1 w/v% to 20 w/v%; preferably from 0.1 w/v% to 15 w/v%; further preferably from 0.2 w/v% to 10 w/v%;
  • a latent solvent having a content of from 0 w/v% to w/v 30%; preferably from 0.1 w/v% to 20 w/v%; further preferably from 0.1 w/v% to 10 w/v%.
  • the solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate (ie solutol HS15) Or any one or a mixture of any of the poloxamers; preferably Tween-80, Tween-20 or polyethylene glycol 15 hydroxystearate (ie Solutol HS15);
  • the solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of a few in any ratio.
  • the pharmaceutical preparation is a lyophilized preparation comprising:
  • the solution to be lyophilized and to be lyophilized comprises:
  • Etomidate the content of which is 0.01 w/v% to 5 w/v%, preferably 0.05 w/v% to 3 w/v%, further preferably 0.1 w/v% to 2 w/v%; general formula (I) a compound or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, in an amount of from 0.01 w/v% to 5 w/v%; preferably from 0.05 w/v% to 3 w/v%; further preferably from 0.1 to 2 w/ v%;
  • solubilizer the content of which is from 0.1 w/v% to 20 w/v%; preferably from 0.1 w/v% to 15 w/v%; further preferably from 0.2 w/v% to 10 w/v%;
  • a latent solvent the content of which is 0 to 30 w/v%; preferably 0.1 w/v% to 20 w/v%; further preferably 0.1 w/v% to 10 w/v%;
  • the solubilizing agent is selected from the group consisting of Tween-80, Tween-20, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol 15 hydroxystearate or poloxamer. Any one or any mixture of any ratio;
  • the latent solvent is selected from any one of ethanol, glycerin, propylene glycol or polyethylene glycol or a mixture of any of any ratio;
  • the filler Any one selected from the group consisting of lactose, sucrose, glucose, mannitol, sodium dihydrogen phosphate, sodium phosphate, sodium chloride, disodium hydrogen phosphate, cysteine, glycine, sorbitol, calcium lactobionate, dextran or polyvinylpyrrolidone One or any mixture of any ratio.
  • the lyophilized preparation or aqueous solution preparation further comprises at least one pH adjusting agent in an amount of from 0 to 10 w/v%, preferably from 0 to 5 w/v%.
  • the pH adjusting agent is selected from any one or more of sodium hydroxide, potassium hydroxide, triethanolamine, hydrochloric acid, phosphoric acid, citric acid, acetic acid, malic acid; preferably sodium hydroxide, hydrogen Any one or a mixture of any one of potassium oxide, triethanolamine, phosphoric acid, citric acid, or hydrochloric acid; further preferably one or a mixture of any of sodium hydroxide or hydrochloric acid in any ratio.
  • the lyophilized formulation or the aqueous solution formulation further comprises at least one isotonicity adjusting agent in an amount of from 0 to 5 w/v%, preferably from 0 to 2 w/v%.
  • the isotonicity adjusting agent is selected from any one of glycerin, a saccharide or a sugar alcohol or a mixture of any one of any ratio; preferably glycerin, glucose, fructose, maltose, polyethylene glycol, Any one or a mixture of any of sorbitol, propylene glycol, xylitol or mannitol in any ratio; more preferably any one or more of glycerin, sorbitol, propylene glycol, polyethylene glycol or mannitol Any mixture of ratios; more preferably any one of glycerin, polyethylene glycol or mannitol or a mixture of any of several ratios; further preferably glycerol.
  • the pharmaceutical preparation is a fat emulsion comprising:
  • the oily component is selected to be biocompatible and can be aged in the human body Any one or a mixture of any of the natural or (and) synthetic oils of metabolism; preferably soybean oil, linseed oil, medium chain triglyceride, structural triglyceride, olive oil, corn oil, cottonseed oil Any one or a mixture of any of a mixture of rapeseed oil, peanut oil, safflower oil, coconut oil, castor oil, fish oil, sesame oil or tea oil; preferably soybean oil, olive oil, fish oil, structural triglyceride Any one or a mixture of any of a plurality of fats, linseed oils or medium chain triglycerides; further preferably any one or a mixture of two of soybean oils, medium chain triglycerides, or any ratio of two.
  • the natural or (and) synthetic oils of metabolism preferably soybean oil, linseed oil, medium chain triglyceride, structural triglyceride, olive oil, corn oil, cotton
  • the fat emulsion further comprises at least one emulsifier.
  • the emulsifier is selected from the group consisting of glycerol monooleate, Tween-80, Tween-20, poloxamer, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyethylene glycol Glyceride, polyethylene glycol 15 hydroxystearate, egg yolk lecithin, egg yolk phosphatidylcholine, soy lecithin, soybean phosphatidylcholine, hydrogenated egg yolk lecithin, hydrogenated egg yolk phosphatidylcholine, hydrogenated soy lecithin , hydrogenated soybean phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyl phosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, etc.
  • the fat emulsion comprises:
  • Etomidate the content of which is 0.01 w/v% to 5 w/v%, preferably 0.05 w/v% to 3 w/v%, further preferably 0.1 w/v% to 2 w/v%; general formula (I) a compound or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, in an amount of from 0.01 w/v% to 5 w/v%; preferably from 0.05 w/v% to 3 w/v%; further preferably 0.1 w/v % ⁇ 2w/v%;
  • an oily component the content of which is 5 w/v% to 30 w/v%; preferably 5 w/v% to 20 w/v%; further preferably 5 w/v% to 15 w/v%;
  • an emulsifier having a content of 0.5 w/v% to 5 w/v%; preferably 0.5 w/v% to 3 w/v%;
  • the step is preferably from 0.5 w/v% to 2 w/v%.
  • the fat emulsion further comprises at least one co-emulsifier in an amount of from 0 to 0.2 w/v%.
  • the co-emulsifier is selected from the group consisting of sodium oleate, sodium cholate, sodium deoxycholate, oleic acid, cholic acid, deoxycholic acid or cholesterol, or a mixture of any of them in any ratio; Any one or a mixture of two of oleic acid and sodium oleate in any ratio.
  • the fat emulsion further comprises at least one isotonicity adjusting agent in an amount of from 0 w/v% to 5 w/v%.
  • the isotonicity adjusting agent is selected from any one of glycerin, a saccharide or a sugar alcohol or a mixture of any one of any ratio; preferably glycerin, glucose, fructose, maltose, polyethylene glycol, Any one or a mixture of any of sorbitol, propylene glycol, xylitol or mannitol in any ratio; more preferably any one or more of glycerin, sorbitol, propylene glycol, polyethylene glycol or mannitol Any mixture of ratios; more preferably any one of glycerin, polyethylene glycol or mannitol or a mixture of any of several ratios; further preferably glycerol.
  • the fat emulsion further comprises at least one pH adjusting agent in an amount of 0% to 10 w/v%, and the pH adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, and the like.
  • the pH adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, and the like. Any one or any one of ethanolamine, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, malic acid; preferably sodium hydroxide, potassium hydroxide, triethanolamine, or hydrochloric acid Any one or any mixture of any ratio; further preferably one of sodium hydroxide, hydrochloric acid or a mixture of two in any ratio.
  • the fat emulsion comprises:
  • the etomidate content is from 0.1 w/v% to 2 w/v%; the compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, the content of which is 0.1 w/v% 2w/v%;
  • glycerin the content of which is 0w/v% to 5w/v%;
  • the pH of the fat emulsion is from 3.0 to 10.0; preferably from 4.0 to 9.0; further preferably 6.0 to 9.0.
  • the pharmaceutical preparation may further comprise other additives, including but not limited to any one of antioxidants, antibacterial agents, and the like, or a mixture of any of several ratios.
  • the antibacterial agent includes, but is not limited to, any one or more of methyl benzoate, sodium metabisulfite, disodium edetate, sodium calcium edetate, and the like;
  • the antioxidants include, but are not limited to, sodium metabisulfite, sodium sulfite, sodium hydrogen sulfite, potassium pyrosulfite, sodium thiosulfate, dibutyl phenol, butylated hydroxyanisole (ie, BHA), tert-butyl-p-benzene. Any one or any of diphenol (TBHQ), dibutylhydroxytoluene (ie, BHT), disodium edetate, or sodium edetate.
  • TBHQ diphenol
  • BHT dibutylhydroxytoluene
  • disodium edetate or sodium edetate.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising etomidate and a compound of the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof for the preparation of an anesthetic for inducing and maintaining an animal or a human
  • a pharmaceutical preparation for promoting sedation, hypnosis, treatment and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions and epilepsy in animals or humans, the active ingredient being etomidate and (I) a compound or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug.
  • the invention also provides a method of reducing the side effects of an animal or a human during sedation, induction or maintenance of anesthesia, the method comprising:
  • the animals are administered a combination of etomidate and a compound of formula (I) in the ratios described herein.
  • the invention also provides a pharmaceutical composition or a pharmaceutical preparation according to the invention for inducing and maintaining anesthesia of an animal or a human, promoting sedative hypnosis of an animal or a human, treating and/or preventing anxiety, depression, insomnia, Uses of nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.
  • the present invention also provides a combination of etomidate and a compound of the formula (I) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof for inducing and maintaining anesthesia in an animal or human, promoting sedation in an animal or human Hypnosis, treatment, and/or prevention of anxiety, depression, insomnia, nausea, vomiting, migraine, schizophrenia, convulsions, and epilepsy.
  • w/v% means the weight of each component (g) / formulation volume (100 mL).
  • Preparation of oil phase Weigh the oily component and add the emulsifier, the compound of the formula (I) or its stereoisomer and etomidate to the oily component under high-temperature stirring under an inert gas atmosphere, and stir it evenly as an oil.
  • Phase, control oil phase temperature is 50 ⁇ 80 °C.
  • Preparation of the aqueous phase Under an inert gas atmosphere, the isotonic adjusting agent and the co-emulsifier are added to an appropriate amount of water for injection and stirred uniformly.
  • the temperature of the aqueous phase is controlled to be 50 to 80 °C.
  • Emulsion preparation Under an inert gas atmosphere, the oil phase is slowly added to the aqueous phase to obtain colostrum under high-speed agitation, and the colostrum preparation can be carried out at 50-80 °C. The mixture is repeatedly homogenized by a high-pressure homogenizer until the milk particles are qualified, filtered, potted, sterilized, and cooled to obtain a milky injection of the compound of the formula (I) and etomidate.
  • the pH of the fat emulsion of the present invention is achieved by adjusting the pH of the aqueous phase, and the pH of the finished product is lower than the pH value of the aqueous phase; the pH of the finished product is usually adjusted to 3.0-10.0, preferably, the pH is 4.0 to 9.0, more preferably The pH is from 6.0 to 9.0.
  • the stirring mode, the rotation speed and the time are controlled as needed, and the high-shear mixing emulsifier is preferred in the preparation of the colostrum. This selection can be carried out as needed.
  • the conditions and time of homogenization are well known to those skilled in the art, as long as the average particle size of the homogenized milk particles does not exceed 350 nm, and the particle size of 95% of the particles must not exceed 1.5 ⁇ m. There are particles having a particle size larger than 5 ⁇ m.
  • the sterilization may be by autoclaving, hot water immersion sterilization, spray sterilization, etc., as an example of a more preferred sterilization process, which may be sterilized by autoclaving (for example, 121 ° C, 12 minutes).
  • the inert gas is selected from, but not limited to, nitrogen.
  • the invention relates to a method for preparing a fat emulsion, which comprises the compound of the formula (I) or a stereoisomer thereof and etomidate dispersed uniformly in an injectable oil and an emulsifier and encapsulated by an oil phase, and then added to an aqueous phase.
  • a fat emulsion which comprises the compound of the formula (I) or a stereoisomer thereof and etomidate dispersed uniformly in an injectable oil and an emulsifier and encapsulated by an oil phase, and then added to an aqueous phase.
  • the oil-in-water fat emulsion has good stability and small clinical side reactions.
  • the accelerated and long-term stability test proves that the quality of the product is stable and is favorable for large-scale production.
  • the method of mixing the ingredients is not limited and can be The general process is carried out.
  • the solution preparation and lyophilization process before lyophilization are not limited, and can be carried out according to a general process.
  • a general process For example: weigh the compound of the formula (I) or its stereoisomer, pharmaceutically acceptable salt or prodrug and etomidate, solubilizer, control temperature of 20 ⁇ 80 ° C, stir evenly, to obtain a mixed solution (1 ).
  • a mixed solution (1 )
  • the isotonic regulator and filler add 50 ⁇ 80% of the total preparation amount of water for injection and stir to obtain the mixed solution (2).
  • the latent solvent and other additives can be added to (1) or (2) according to the situation. (1) and (2) are mixed under stirring, and the mixture is uniformly stirred to obtain a clear liquid.
  • a pH adjuster preferably, the pH is 4.0 to 9.0, more preferably, the pH is 6.0 to 9.0, and water for injection is added.
  • To the preparation volume stir evenly.
  • the 0.22 ⁇ m filter was filtered. Filled in a vial according to the specified amount, half-plugged, and pre-freeze in the front box of the freeze dryer. Freeze-dried. Vacuum or fill with a suitable amount of inert gas plug, out of the box and roll.
  • the preparation method of the lyophilized preparation used in the invention has the remarkable feature that the preparation method is simple and convenient, is more convenient for long-term storage and convenient transportation, and is advantageous for large-scale production.
  • Figure 1 is a test result of rat adrenal function in Test Example 2 (* compared with blank fat emulsion, P ⁇ 0.05).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS);
  • HPLC was determined using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18100 x 4.6 mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm;
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Titan Technology, An Naiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, Belling Technology, etc.
  • the manufacturer was Jiangsu Enhua Pharmaceutical Co., Ltd., phenol derivative. Synthesis and preparation of preparations reference WO2014180305 and WO2016034079;
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume;
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and operated three times;
  • reaction is carried out under a nitrogen atmosphere
  • the solution means an aqueous solution
  • the reaction temperature is room temperature, the optimum reaction temperature at room temperature, It is 20 ° C ⁇ 30 ° C.
  • egg yolk lecithin source: Lipip GmbH, Germany
  • compound 1, etomidate stir evenly
  • control temperature is 55-75 ° C as oil phase
  • glycerin for injection Source: Hunan Erkang Pharmaceutical Co., Ltd.
  • sodium oleate is added to the appropriate amount of water for injection, mixed and adjusted to the appropriate range with the pH of the aqueous phase with sodium hydroxide (to ensure the pH of the finished product is 6.0 to 9.0), and the control temperature is 55 to 75 ° C as the aqueous phase.
  • the emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA production) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C.
  • high-pressure homogenizer GAA Niro production
  • the emulsion is filtered and sterilized by nitrogen, sterilized in a steam sterilizer, cooled, and the compound 1 or etomidate is obtained after passing the test. Milky injection.
  • egg yolk lecithin source: Lipip GmbH, Germany
  • compound 1, etomidate stir evenly
  • control temperature is 55-75 ° C as oil phase
  • glycerin for injection Source: Hunan Erkang Pharmaceutical Co., Ltd.
  • sodium oleate is added to the appropriate amount of water for injection, mixed and adjusted to the appropriate range with the pH of the aqueous phase with sodium hydroxide (to ensure the pH of the finished product is 6.0 to 9.0), and the control temperature is 55 to 75 ° C as the aqueous phase.
  • the emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C.
  • high-pressure homogenizer After repeated homogenization by high-pressure homogenizer, after checking the milk particles to meet the requirements, the emulsion is filtered and sterilized by nitrogen, sterilized in a steam sterilizer, cooled, and the compound 1 / etomidate emulsion injection is obtained after passing the test.
  • the emulsified milk phase was added to the aqueous phase under high-speed agitation (high shear mixing emulsifier, IKA production) to prepare colostrum, and the colostrum preparation was carried out at 55 to 75 °C. It is repeatedly homogenized by high-pressure homogenizer (produced by GEA Niro). The emulsion is inspected to meet the requirements. After the emulsion is filtered, it is sealed with nitrogen, sterilized in a steam sterilizer, cooled, and the emulsion of Compound 1 is obtained after passing the test.
  • high-pressure homogenizer produced by GEA Niro
  • Test Example 1 Canine efficacy test of different doses of Compound 1 in combination with etomidate
  • Beagle (Chengdu Dashuo Biotechnology Co., Ltd.), 8-9kg, 6 females, half male and half female. Beagle dogs were fasted for 16 hours before administration. On the day of administration, a single intravenous injection of etomidate emulsion (Jiangsu Enhua Pharmaceutical Co., Ltd.) and a mixture of compound 1 and etomidate at different doses were used to record the induction time of beagle anesthesia. Time, while observing Beagle tendon and nausea and vomiting. The experimental results are shown in Table 1:
  • Anesthesia induction time the time from the administration to the disappearance of righting reflex
  • Duration of anesthesia the time when the righting reflex disappears until the righting reflex is restored;
  • Compound 1 When Compound 1 is combined with etomidate, it not only achieves the anesthetic effect when used alone, but also significantly improves the adverse reactions when etomidate is used alone, improves the safety of the drug and improves the patient experience.
  • SPF grade SD rats 250-300 g, male, were provided by Beijing Vital Lihua. Before the experiment, the animals were fasted and water was not allowed. On the next day, all animals were randomly divided into 4 groups according to body weight. Each group of animals received intravenous dexamethasone 0.2 mg/kg, and 200 ⁇ l of blood was collected from the jugular sinus 2 h after injection.
  • the etomidate alone can significantly inhibit the adrenal cortex function in rats at the dose of 2 mg/kg, and the combination of compound 1 with etomidate can significantly improve the inhibitory effect of etomidate on renal cortical function.
  • the test was an open label, and a single dose of Compound 1 and etomidate was administered intravenously to the subject to evaluate the anesthesia/sedation effect and safety.
  • Control group 0.648 mg / kg of compound 1;
  • Test group 1 a combination of 0.324 mg/kg of compound 1 and 0.15 mg/kg of etomidate,
  • Test group 2 a combination of 0.216 mg/kg of Compound 1 and 0.20 mg/kg of etomidate,
  • Test group 3 a combination of 0.432 mg/kg of Compound 1 and 0.10 mg/kg of etomidate.
  • the above doses were administered such that the control group, the test group 1, the test group 2, and the test group 3 were able to achieve the same depth of anesthesia.
  • Each group of subjects will be administered intravenously according to the above-mentioned administration dose, wherein the combination of Compound 1 and etomidate in Test Groups 1, 2, and 3 is a pre-compound containing Compound 1 and etomidate.
  • Mixed injections Use the infusion pump to take the medicine in more than 60 seconds
  • the injection is intravenously administered to the subject's elbow fossa. From the first night of the trial to the morning of the second day, all subjects will be in the study room, then leave the study room and ask the subject to return on day 7.
  • the test results are shown in Tables 3, 4, and 5.
  • the baseline value is the last reliable value obtained before administration (-15 min, -10 min, -5 min, 0 min), typically 0 min.
  • the baseline values are calculated in two ways, namely
  • SBP systolic blood pressure
  • DBP diastolic blood pressure

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Abstract

La présente invention concerne un dérivé contenant du phénol, une composition pharmaceutique d'étomidate, leur procédé de préparation et leur application dans le domaine du traitement du système nerveux central. Un dérivé de phénol est un composé représenté par la formule (I) ou un stéréo-isomère, un sel ou un promédicament pharmaceutiquement acceptables de celui-ci.
PCT/CN2017/092722 2016-07-22 2017-07-13 Dérivé de phénol et composition pharmaceutique d'étomidate, préparation pharmaceutique et leur application WO2018014770A1 (fr)

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CN114668720A (zh) * 2020-12-24 2022-06-28 远大生命科学(武汉)有限公司 一种依托咪酯乳状注射液及其制备方法

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CN110063947A (zh) * 2018-01-24 2019-07-30 四川海思科制药有限公司 苯酚衍生物用于制备麻醉药物中的用途
TW202143951A (zh) * 2020-05-29 2021-12-01 大陸商四川海思科製藥有限公司 一種藥物製劑及其製備方法
CN114073675A (zh) * 2020-08-10 2022-02-22 复旦大学 一种丙泊酚混合胶束及其制备方法
US20240132445A1 (en) * 2021-01-28 2024-04-25 Hinye Pharmaceutical Co., Ltd. Phenol derivative and application thereof in medicaments

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CN103356609A (zh) * 2012-03-28 2013-10-23 陈希璇 一种复方静脉麻醉剂
WO2016034079A1 (fr) * 2014-09-04 2016-03-10 四川海思科制药有限公司 Utilisation d'un agent stimulant le récepteur gabaa dans le cadre de la préparation d'un médicament sédatif et anesthésique

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Publication number Priority date Publication date Assignee Title
CN103356609A (zh) * 2012-03-28 2013-10-23 陈希璇 一种复方静脉麻醉剂
WO2016034079A1 (fr) * 2014-09-04 2016-03-10 四川海思科制药有限公司 Utilisation d'un agent stimulant le récepteur gabaa dans le cadre de la préparation d'un médicament sédatif et anesthésique

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114668720A (zh) * 2020-12-24 2022-06-28 远大生命科学(武汉)有限公司 一种依托咪酯乳状注射液及其制备方法

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