WO2021239130A1 - 一种药物制剂及其制备方法 - Google Patents

一种药物制剂及其制备方法 Download PDF

Info

Publication number
WO2021239130A1
WO2021239130A1 PCT/CN2021/096890 CN2021096890W WO2021239130A1 WO 2021239130 A1 WO2021239130 A1 WO 2021239130A1 CN 2021096890 W CN2021096890 W CN 2021096890W WO 2021239130 A1 WO2021239130 A1 WO 2021239130A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
source
sodium
pharmaceutical
preparation according
Prior art date
Application number
PCT/CN2021/096890
Other languages
English (en)
French (fr)
Inventor
莫毅
李洪湖
张玉权
唐玉
Original Assignee
四川海思科制药有限公司
辽宁海思科制药有限公司
海思科医药集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川海思科制药有限公司, 辽宁海思科制药有限公司, 海思科医药集团股份有限公司 filed Critical 四川海思科制药有限公司
Priority to CN202180037860.0A priority Critical patent/CN115968279A/zh
Priority to EP21814359.2A priority patent/EP4159197A4/en
Publication of WO2021239130A1 publication Critical patent/WO2021239130A1/zh
Priority to US17/993,506 priority patent/US20230118143A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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 preparation of a GABA A receptor enhancer and a preparation method thereof.
  • the GABA A receptor enhancer is compound (I) or a pharmaceutically acceptable salt or prodrug thereof. It belongs to the field of biomedical technology.
  • the drug-loaded fat emulsion contains a large amount of lipid components, which is conducive to the reproduction of bacteria.
  • lipid components which is conducive to the reproduction of bacteria.
  • CN201580001777 discloses a preparation method of a pharmaceutical preparation composition containing a GABA A receptor enhancer.
  • the disclosed composition contains a pharmaceutical preparation of the following formula (I), and the fat emulsion mentioned in the preparation method does not contain antibacterial Agent,
  • the present invention provides a stable and safe pharmaceutical preparation containing a GABA A receptor enhancer.
  • the pharmaceutical preparation of the present invention is not sensitive to bacterial growth under unintentional pollution and provides additional stability.
  • the pharmaceutical preparation of the present invention contains 0.01w/v% ⁇ 5w/v% active ingredient and 0.005w/v% ⁇ 0.1w/v% bacteriostatic agent, and the active ingredient is described in general formula (I)
  • R 1 and R 2 are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, or R 1 and R 2 and the carbon atom attached to them form a C 3-6 cycloalkyl; n is selected from 1 or 2.
  • the prodrug of the compound of formula (I) is selected from the compound of the following formula (II) or its stereoisomers or pharmaceutically acceptable salts:
  • the pharmaceutically acceptable salt refers to a salt formed by combining a compound of formula (II) with a metal cation, such as sodium salt and potassium salt.
  • R 1 is selected from H, methyl, ethyl, or isopropyl
  • R 2 is selected from methyl, ethyl, isopropyl, or cyclopropyl.
  • the compound of general formula (I) is selected from one of the following structures:
  • the pharmaceutical preparation is a fat emulsion, which comprises:
  • Oily ingredients the content of which is 5w/v%-30w/v%; preferably 5w/v%-25w/v%; more preferably 10w/v%-25w/v%;
  • Emulsifier the content of which is 0.1w/v% ⁇ 5w/v%; preferably 0.2w/v% ⁇ 3w/v%; more preferably 0.2w/v% ⁇ 2w/v%;
  • An osmotic pressure regulator the content of which is 0-10w/v%; preferably 0-5w/v%; more preferably 0-4w/v%;
  • Bacteriostatic agent the content of which is 0.0005% to 0.1%; preferably 0.001% to 0.05%; more preferably 0.001w/v% to 0.03w/v%.
  • the oily ingredients may be selected from any one of soybean oil, olive oil, fish oil, linseed oil, medium-chain triglycerides, and structural triglycerides, or a mixture of any several in any ratio; It is preferably selected from soybean oil, olive oil, medium-chain triglycerides, and structural triglycerides, or a mixture of any of several in any ratio; more preferably, is selected from soybean oil, medium-chain triglycerides, and structural triglycerides. Any one or a mixture of any several in any ratio; further preferably a mixture of any one or two of soybean oil and medium-chain triglycerides in any ratio.
  • Structural triglyceride refers to the triglyceride that changes the composition or position of fatty acids on the glycerol skeleton by chemical or biological enzymatic methods, so that it has a specific molecular structure and function.
  • Medium-chain triglycerides also known as medium-chain fatty acid triglycerides, are composed of 1 molecule of glycerol and 3 molecules of medium-chain fatty acids. Among them, fatty acids with 6-10 carbon atoms on the carbon chain are representative. The main ingredients are caprylic acid (C8, 8 carbon atoms) and capric acid (C10, 10 carbon atoms).
  • the emulsifier component is selected from poloxamer, Tween-80, polyethylene glycol 15 hydroxystearate, polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, egg yolk lecithin Or any one or a mixture of any number of soy lecithin in any ratio; preferably a mixture of any one or any number of any ratio of poloxamer, egg yolk lecithin or soy lecithin; more preferably from soybeans Any one of phospholipids or egg yolk lecithin or a mixture of two in any ratio.
  • the antibacterial ingredient is selected from sodium caprylate, benzoic acid, benzyl alcohol, sodium benzoate, methyl benzoate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, pyrogallate, ethylenediaminetetraacetic acid Or ethylenediaminetetraacetate (such as edetate disodium, calcium edetate, calcium sodium edetate, etc.) any one or a mixture of any several in any ratio; more preferably from benzyl alcohol, sodium benzoate , Sodium metabisulfite, ethylenediaminetetraacetic acid, or ethylenediaminetetraacetate (such as disodium edetate, calcium edetate, calcium sodium edetate, etc.) or any mixture of several in any ratio It is further preferably selected from any one of ethylenediaminetetraacetic acid, disodium edetate or calcium sodium edetate or a mixture of any of
  • the osmotic pressure regulator is selected from any one of glycerin, sugars or sugar alcohols or a mixture of any of several in any ratio, preferably glycerol, glucose, fructose, maltose, polyethylene glycol, Any one of sorbitol, propylene glycol, xylitol or mannitol or a mixture of any of several in any ratio, preferably any one of glycerol, polyethylene glycol or mannitol or a mixture of any of several in any ratio, further Glycerin is preferred.
  • the pharmaceutical preparations of the present invention may also contain pH regulators, which are selected from the group consisting of sodium hydroxide and potassium hydroxide. Any one or more of, triethanolamine, hydrochloric acid, phosphoric acid, citric acid, acetic acid or malic acid, preferably any of sodium hydroxide, potassium hydroxide, triethanolamine, phosphoric acid, citric acid or hydrochloric acid A mixture of one or several in any ratio, and more preferably any one or a mixture of any one of sodium hydroxide or hydrochloric acid in any ratio.
  • the pH of the pharmaceutical preparation is 3.0 to 10.0, preferably 4.0 to 9.0, and more preferably 6.0 to 9.0.
  • the pharmaceutical preparations of the present invention can also add stabilizers for improving the stability of emulsions as required
  • stabilizers commonly used surfactants and the like can also be used as stabilizers.
  • the content range of the stabilizer is 0-2% (w/v) based on the fat emulsion preparation of the present invention.
  • oleic acid and sodium oleate are commonly used stabilizers for fat emulsion injections, but are not limited thereto.
  • the fat emulsion comprises:
  • the pH of the fat emulsion is 3.0 to 10.0, preferably 4.0 to 9.0, and more preferably 6.0 to 9.0.
  • the preparation method of the pharmaceutical preparation of the present invention includes the following steps:
  • the pH value of the pharmaceutical preparation of the present invention can usually be adjusted to 6.0-9.0.
  • the stirring mode, rotation speed and time are controlled according to needs.
  • the high-shear mixing emulsifier is preferred for the preparation of colostrum. This choice It can be carried out according to needs.
  • the homogenization conditions and time are well known to those skilled in the art, as long as the average particle size of the emulsion particles after homogenization should not exceed 300nm, 95% of the particle size It must not exceed 1.5 ⁇ m.
  • the sterilization can be high-pressure steam sterilization, hot water immersion sterilization, spray sterilization, etc. As a more preferred example of the sterilization process, high-pressure steam sterilization (for example, 121° C., 12 minutes) can be used.
  • the inert gas is selected from but not limited to nitrogen.
  • the preparation method adopted by the present invention is characterized in that the compound of general formula (I) is uniformly dispersed in the oily ingredients and emulsifiers and is wrapped by the oil phase, and then the water phase containing the bacteriostatic agent is added to make the water
  • the oil-in-fat emulsion has good stability and good clinical safety. Accelerated and long-term stability tests have proved that the quality of this emulsion is stable, which is conducive to large-scale production and guarantees the safety of clinical medication.
  • the pharmaceutical preparation obtained by the present invention can significantly reduce the risk of drug contamination due to some accidental non-sterile operations during clinical use, and improve the safety of clinical use.
  • the present invention also provides that the pharmaceutical preparations of the present invention are used to induce and maintain anesthesia in animals or humans, promote sedation and hypnosis in animals or humans, treat and/or prevent anxiety, depression, insomnia, nausea, vomiting, migraine, and mental illness. Application of schizophrenia, convulsions and epilepsy drugs.
  • W/v refers to the mass volume percentage, that is, "the weight of each component (g)/the volume of the solution before dispensing (ml)".
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about
  • egg yolk lecithin Lipoid E80
  • oleic acid source: Lipoid GmbH in Germany
  • compound 1 under high-speed stirring at 50°C, stir evenly, and control the temperature at 55 ⁇ 75°C as the oil phase
  • Edetate disodium source: Hunan Erkang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Xipu Chemical (Sichuan) Co., Ltd.
  • Adjust the pH value of the water phase to 10.10, and control the temperature at 55-75°C as the
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • the emulsion is filtered Nitrogen filling and sealing, sterilization in steam sterilizer, After passing the inspection, an emulsion injection containing compound 1 is obtained.
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • egg yolk lecithin Lipoid E80
  • high-speed stirring source: Lipoid GmbH, Germany
  • compound 2 mix well, control the temperature at 55 ⁇ 75°C as the oil phase; mix calcium sodium edetate (source: Hunan Erkang Pharmaceutical Co., Ltd.) and glycerin (for injection) [source: Croda Sipu Chemical (Sichuan) Co., Ltd.], sodium oleate (source: Lipoid GmbH, Germany) was added to an appropriate amount of water for injection, mixed, and sodium hydroxide (source: Hunan Erkang Pharmaceutical Co., Ltd.) was used to adjust the pH of the water phase to 9.82, and the temperature was controlled As the water phase at 55-75°C.
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Add egg yolk lecithin Lipoid E80
  • compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature at 55 ⁇ 75°C as the oil phase
  • edetate disodium source: Hunan Er Kang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Cipu Chemical (Sichuan) Co., Ltd.]
  • sodium oleate source: Lipoid GmbH, Germany
  • was added to the appropriate amount of water for injection, mixed, and sodium hydroxide Source: Hunan Erkang Pharmaceutical Co., Ltd.
  • Adjust the pH value of the water phase to 9.91, and control the temperature at 55-75°C as the
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Add egg yolk lecithin Lipoid E80
  • source: Lipoid GmbH and compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55 ⁇ 75°C as the oil phase
  • use glycerin (for injection) [source: Wo Daxipu Chemical (Sichuan) Co., Ltd.], sodium oleate (source: Lipoid GmbH, Germany) were added to an appropriate amount of water for injection, mixed, and sodium hydroxide (source: Hunan Erkang Pharmaceutical Co., Ltd.) was used to adjust the pH of the water phase to 9.95 , Control the temperature at 55 ⁇ 75°C as the water phase.
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • egg yolk lecithin Lipoid E80
  • compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature at 55 ⁇ 75°C as the oil phase
  • calcium sodium edetate source: Hunan Er Kang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Cipu Chemical (Sichuan) Co., Ltd.]
  • sodium oleate source: Lipoid GmbH, Germany
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about Add egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany) and compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55-75°C as the oil phase; add edetate disodium (source: Hunan Er Kang Pharmaceutical Co., Ltd.), glycerin (for injection) [source: Croda Cipu Chemical (Sichuan) Co., Ltd.], sodium oleate (source: Lipoid GmbH, Germany), add an appropriate amount of water for injection, mix, and use sodium hydroxide ( Source: Hunan Erkang Pharmaceutical Co., Ltd.) Adjust the pH of the water phase to 9.69, and control the temperature at 55-75°C as the water phase
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • mix it under nitrogen protection heat to about 50°C
  • add egg yolk lecithin Lipoid E80
  • source Lipoid GmbH, Germany
  • compound under high-speed stirring 5.
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • the emulsion is filtered Nitrogen potting, Sterilize in a container, cool, and obtain an emulsion injection containing compound 5 after passing the inspection.
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about Add egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany) and compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55 ⁇ 75°C as the oil phase; add sodium metabisulfite (source: Hunan Erkang Pharmaceutical Co., Ltd.) Co., Ltd.), glycerin (for injection) [source: Croda Xipu Chemical (Sichuan) Co., Ltd.], sodium oleate (source: Lipoid GmbH, Germany) was added to the appropriate amount of water for injection, mixed, and sodium hydroxide (source: Hunan Erkang Pharmaceutical Co., Ltd.) adjust the pH of the water phase to 9.99, and control the temperature at 55
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Add egg yolk lecithin Lipoid E80
  • compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55-75°C as the oil phase
  • edetate disodium source: Hunan Er Kang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Cipu Chemical (Sichuan) Co., Ltd.]
  • sodium oleate source: Lipoid GmbH, Germany
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Add egg yolk lecithin Lipoid E80
  • compound 3 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55 ⁇ 75°C as the oil phase; use benzyl alcohol (source: Hunan Erkang Pharmaceutical Co., Ltd.) Co., Ltd.), glycerin (for injection) [source: Croda Sipu Chemical (Sichuan) Co., Ltd.], sodium oleate (source: Lipoid GmbH, Germany) was added to an appropriate amount of water for injection, mixed, and sodium hydroxide (source: Hunan Erkang Pharmaceutical Co., Ltd.) adjust the pH of the water phase to 9.49, and control the temperature at 55-75°
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about
  • egg yolk lecithin Lipoid E80
  • oleic acid source: Lipoid GmbH, Germany
  • compound 3 under high-speed stirring at 50°C, mix well, and control the temperature at 55 ⁇ 75°C as the oil phase
  • Sodium metabisulfite source: Hunan Erkang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source: Croda Xipu Chemical (Sichuan) Co., Ltd. add an appropriate amount of water for injection, mix, and use sodium hydroxide (source: Hunan Er Kang Pharmaceutical Co., Ltd.) adjust the pH value of the water phase to 9.75, and control the temperature at 55-75°C as the
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • egg yolk lecithin Lipoid E80
  • high-speed stirring source: Lipoid GmbH, Germany
  • oleic acid source: Lipoid GmbH, Germany
  • compound 4 stir evenly, and control the temperature at 55 ⁇ 75°C as the oil phase; use ethylenediaminetetraacetic acid (source: Chengdu Kelong Chemical Co., Ltd.), glycerin (supplied For injection)
  • source Croda Xipu Chemical (Sichuan) Co., Ltd.
  • Add an appropriate amount of water for injection mix, adjust the pH of the water phase to 9.98 with sodium hydroxide (Source: Hunan Erkang Pharmaceutical Co., Ltd.), and control the temperature as 55 ⁇ 75°C as the water phase.
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about Add egg yolk lecithin (Lipoid E80) (source: Lipoid GmbH, Germany), oleic acid (source: Lipoid GmbH, Germany), compound 5 under high-speed stirring at 50°C, mix well, and control the temperature at 55 ⁇ 75°C as the oil phase;
  • Sodium metabisulfite source: Hunan Erkang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source: Croda Xipu Chemical (Sichuan) Co., Ltd.] add an appropriate amount of water for injection, mix, and use sodium hydroxide (source: Hunan Er Kang Pharmaceutical Co., Ltd.) adjust the pH value of the water phase to 10.34, and control the temperature at 55-75°C as the water
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • Mix them under nitrogen protection, and heat to about
  • egg yolk lecithin Lipoid E80
  • compound 6 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55 ⁇ 75°C as the oil phase
  • disodium edetate source: Hunan Er Kang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Cipu Chemical (Sichuan) Co., Ltd.]
  • sodium oleate source: Lipoid GmbH, Germany
  • Add an appropriate amount of water for injection, mix, and use sodium hydroxide Source: Hunan Erkang Pharmaceutical Co., Ltd.
  • Adjust the pH of the water phase to 9.79, and control the temperature at 55-75°C as the water phase
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • soybean oil for injection for injection
  • source Liaoning Xinxing Pharmaceutical Co., Ltd.
  • medium-chain triglycerides source: Liaoning Xinxing Pharmaceutical Co., Ltd.
  • egg yolk lecithin Lipoid E80
  • compound 8 under high-speed stirring at 50°C, stir evenly, and control the temperature to 55 ⁇ 75°C as the oil phase
  • calcium sodium edetate source: Hunan Er Kang Pharmaceutical Co., Ltd.
  • glycerin for injection
  • source Croda Cipu Chemical (Sichuan) Co., Ltd.]
  • sodium oleate source: Lipoid GmbH, Germany
  • Adjust the pH value of the water phase to 9.91, and control the temperature at 55-75°C as the water phase
  • the oil phase is added to the water phase to make colostrum, which is repeatedly homogenized by a high-pressure homogenizer (produced by GEA Niro) to check that the milk particles meet the requirements.
  • a high-pressure homogenizer produced by GEA Niro
  • Example 3 and Example 6 are better than those of Example 4, indicating that adding edetate disodium to the prescription can significantly improve the stability of the drug .
  • Example 3 and Example 4 Take the samples of Example 3 and Example 4 as examples. Take the samples prepared in Example 3 and Example 4 respectively, and inoculate Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans according to the inspection method for antibacterial efficacy of the four parts 1121 of the 2015 edition of the Chinese Pharmacopoeia.
  • Suspension and Aspergillus niger spore suspension (about 10 5 ⁇ 10 6 cfu/ml) each 0.1ml to 10ml prepared samples, respectively at 0h, 2h, 4h, 6h, 8h, 10h, 12h according to the verified bacterial count
  • the determination method was used to determine the number of surviving bacteria of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Aspergillus niger.
  • the growth curves of various bacteria are shown in Figure 1 and Figure 2.
  • Example 3 The concentration of the bacteriostatic agent added in Example 3 cannot produce sufficient bacteriostasis, and does not meet the requirements of bacteriostatic efficacy in the 2015 edition of the Chinese Pharmacopoeia; however, the results of the above bacteriostatic test show that 0.005% of Yidi is added to the prescription Disodium acid does have the effect of slowing down the growth of microorganisms and can ensure the safety of clinical medication.
  • test results show that by adding appropriate amount of antibacterial ingredients such as edetate disodium, calcium sodium edetate, sodium metabisulfite, benzyl alcohol and ethylenediaminetetraacetic acid, etc., the growth of contaminating bacteria can be significantly inhibited.
  • the pharmaceutical preparation of the present invention (Example 3) has a significant inhibitory effect on the growth of contaminating bacteria during the service cycle on the basis of maintaining good preparation stability, and the sample without bacteriostatic agent (Example 4) ) Has no inhibitory effect on the growth of Staphylococcus aureus, Escherichia coli and Candida albicans. Therefore, the pharmaceutical preparation of the present invention reduces the risk of potential infection caused by uncertain factors during clinical use, and improves the safety of clinical use.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Dispersion Chemistry (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种包含GABA A受体增强剂和抑菌剂的药物制剂、其制备方法及其在制备用于诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的应用，GABA A受体增强剂为式(I)或者其立体异构体、药学上可接受的盐或前药。其中R 1、R 2和n为说明书中定义的。

Description

一种药物制剂及其制备方法 技术领域
本发明涉及一种GABA A受体增强剂的药物制剂及其制备方法，所述GABA A受体增强剂为化合物(I)或者其药学上可接受的盐或前药。属于生物医药技术领域。
背景技术
载药脂肪乳含有大量的脂质成分，有利于细菌繁殖，临床使用过程中，当用注射器从无菌容器中抽取药液时，或其它可能会因某些偶然的非无菌操作导致药物染菌，而带来一定染菌风险。
CN201580001777公开了含一种GABA A受体增强剂的药物制剂组合物制备方法，公开的组合物中含下式化合物(I)的药物制剂，该制备方法中提及的脂肪乳剂中不含抑菌剂，
Figure PCTCN2021096890-appb-000001
因此，需要一种对非故意污染情况下细菌繁殖不敏感的含化合物(I)的药物制剂。
发明内容
本发明提供了一种稳定、安全性好的含GABA A受体增强剂的药物制剂，本发明的药物制剂在非故意污染情况下细菌繁殖不敏感而且提供额外的稳定性。
本发明的药物制剂，含有0.01w/v％～5w/v％的活性成分以及0.005w/v％～0.1w/v％的抑菌剂，所述的活性成分为通式(I)所述化合物或者其立体异构体、药学上可接受的盐或前药，
Figure PCTCN2021096890-appb-000002
其中R 1和R 2各自独立的选自H、C 1-4烷基或C 3-6环烷基，或R 1和R 2与其连接碳原子形成C 3-6环烷基；n选自1或2。
所述式(I)化合物的前药选自如下式(II)所述化合物或者其立体异构体、药学上可接受的盐：
Figure PCTCN2021096890-appb-000003
所述药学上可接受的盐指式(II)化合物与金属阳离子结合形成的盐，例如钠盐、钾盐。
在一些实施例中，R 1选自H、甲基、乙基或异丙基；R 2选自甲基、乙基、异丙基或环丙基。
在一些实施例中，通式(I)所述化合物选自以下结构之一：
Figure PCTCN2021096890-appb-000004
在一些实施例中，选自以下结构之一：
Figure PCTCN2021096890-appb-000005
Figure PCTCN2021096890-appb-000006
关于本发明的药物制剂的优选方案，所述的药物制剂为脂肪乳剂，其包含：
(1)通式(I)化合物或者其立体异构体、药学上可接受的盐或前药，其含量为0.01w/v％～5w/v％；优选0.05w/v％～2.5w/v％；进一步优选0.1w/v％～2w/v％；
(2)油性成分，其含量为5w/v％～30w/v％；优选5w/v％～25w/v％；进一步优选10w/v％～25w/v％；
(3)乳化剂，其含量为0.1w/v％～5w/v％；优选0.2w/v％～3w/v％；进一步优选0.2w/v％～2w/v％；
(4)渗透压调节剂，其含量为0～10w/v％；优选0～5w/v％；进一步优选0～4w/v％；
(5)抑菌剂，其含量为0.0005％～0.1％；优选0.001％～0.05％；进一步优选0.001w/v％～0.03w/v％。
在一些实施例中，所述的油性成分可以选自大豆油、橄榄油、鱼油、亚麻油、中链甘油三酸酯、结构甘油三酯中的任一种或任几种任意比例的混合物；优选自大豆油、橄榄油、中链甘油三酸酯、结构甘油三酯中的任一种或任几种任意比例的混合物；更优选自大豆油、中链甘油三酸酯、结构甘油三酯中的任一种或任几种任意比例的混合物；进一步优选自大豆油、中链甘油三酸酯的任一种或两种任意比例的混合物。
结构甘油三酯是指通过化学法或生物酶法一定手段改变甘油骨架上脂肪酸组成或位置的分布，使其具有特定分子结构和功能的甘油三酯。
中链甘油三酸酯，也称为中链脂肪酸甘油三酯，是指由1分子甘油和3分子中链脂肪酸构成，其中链脂肪酸碳链上碳原子数为6-10的脂肪酸，代表性的主要成分是 辛酸(C8，8个碳原子数)和癸酸(C10，10个碳原子数)。
在一些实施例中，乳化剂成分选自泊洛沙姆、吐温-80、聚乙二醇15羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯40氢化蓖麻油、蛋黄卵磷脂或大豆卵磷脂中的任一种或任几种任意比例的混合物；优选自泊洛沙姆、蛋黄卵磷脂或大豆卵磷脂中的任一种或任几种任意比例的混合物；更优选自大豆磷脂或蛋黄卵磷脂中的任一种或两种任意比例的混合物。
在一些实施例中，抑菌剂成分选自辛酸钠、苯甲酸、苯甲醇、苯甲酸钠、苯甲酸甲酯、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠、焦性没食子酸酯、乙二胺四乙酸或乙二胺四乙酸盐(如依地酸二钠、依地酸钙、依地酸钙钠等)中的任一种或任几种任意比例的混合物；更优选自苯甲醇、苯甲酸钠、焦亚硫酸钠、乙二胺四乙酸或乙二胺四乙酸盐(如依地酸二钠、依地酸钙、依地酸钙钠等)中的任一种或任几种任意比例的混合物，进一步优选自乙二胺四乙酸、依地酸二钠或依地酸钙钠中的任一种或任几种任意比例的混合物。
在一些实施例中，渗透压调节剂选自甘油、糖类或糖醇类中的任一种或任几种任意比例的混合物，优选甘油、葡萄糖、果糖，麦牙糖、聚乙二醇、山梨醇、丙二醇、木糖醇或甘露醇中的任一种或任几种任意比例的混合物，优选甘油、聚乙二醇或甘露醇中的任一种或任几种任意比例的混合物，进一步优选甘油。
本发明的药物制剂除了活性剂式(I)化合物、油性成分、乳化剂、抑菌剂、渗透压调节剂外，还可以含有pH调节剂，pH调节剂选自所氢氧化钠、氢氧化钾、三乙醇胺、盐酸、磷酸、枸橼酸、醋酸或苹果酸中的任一种或任几种，优选氢氧化钠、氢氧化钾、三乙醇胺、磷酸、枸橼酸或或盐酸中的任一种或任几种任意比例的混合物，进一步优选氢氧化钠或盐酸中的任一种或任几种任意比例的混合物。所述药物制剂的pH为3.0～10.0，优选4.0～9.0，进一步优选6.0～9.0。
本发明的药物制剂除了活性剂式(I)化合物、油性成分、乳化剂、抑菌剂、渗透压调节剂外及pH调节剂外，还可以根据需要将用于改进乳剂稳定性的稳定剂加入本发明的药物制剂中，也可将常用的表面活性剂等用作稳定剂。所述稳定剂的含量范围基于本发明的脂肪乳剂制剂为0～2％(w/v)，如现在脂肪乳注射剂常用稳定剂油酸、油酸钠，但不仅限于此。
本发明关于药物制剂的优选方案，所述的脂肪乳剂，包含：
(1)式(I)的活性成分，其含量为0.1w/v％～2w/v％；
(2)大豆油或中链甘油三酸酯中的任一种或两种任意比例的混合物，其含量为10w/v％～20w/v％；
(3)蛋黄卵磷脂，其含量为0.2w/v％～2w/v％；
(4)依地酸二钠或依地酸钙钠或焦亚硫酸钠或苯甲醇中的任一种或两种任意比例的混合物，其含量为0.001w/v％～0.03w/v％；
(5)甘油，其含量为1w/v％～4w/v％
(6)油酸或油酸钠中的任一种或两种任意比例的混合物，其含量为0.01w/v％～2w/v％；
本发明关于药物制剂的优选方案，所述脂肪乳剂的pH为3.0～10.0，优选4.0～9.0，进一步优选6.0～9.0。
本发明药物制剂的制备方法，包括如下步骤：
(1)油相制备：在惰性气体环境下，将乳化剂、式(I)化合物加入油性组分中，搅拌均匀作为油相；
(2)水相制备：在惰性气体环境下，将渗透压调节剂、稳定剂、抑菌剂加入适量的注射用水中搅拌均匀，作为水相；
(3)制剂制备：在惰性气体环境下，搅拌下将油相缓缓加入水相混合得初乳。经高压均质机反复均质至乳粒合格，过滤，灌封后，灭菌，冷却后即得本发明所述药物制剂。
本发明药物制剂的pH值通常可调整为6.0～9.0，所述的制备方法中，搅拌的方式及转速、时间根据需要而进行控制，初乳制备时优选高剪切混合乳化机，这种选择可以根据需要而进行，对于高压均质机匀化时，匀化的条件和时间是本领域技术人员所熟知的，只要匀化后的乳粒平均粒径不得过300nm，95％的颗粒粒径不得过1.5μm。所述的灭菌可通过高压蒸汽灭菌、热水浸灭菌、喷淋灭菌等，作为更优选的灭菌工艺例子，可利用高压蒸汽灭菌(例如，121℃，12分钟)。
在本发明的制备方法中，所述惰性气体选自但不限于氮气。
本发明采用的制备方法，其显著的特征是通式(I)所述化合物在油性成分和乳化剂中分散均匀并被油相包裹，然后加入含抑菌剂的水相，所制成的水包油脂肪乳剂稳定性良好，临床安全性好，经过加速及长期稳定性试验证明本品质量稳定，有利于规模化生产和保证临床用药安全。
本发明所得的药物制剂，可显著降低临床使用过程中的可能会因某些偶然的非无菌操作导致药物染菌风险，提高临床使用安全性。
本发明还提供了本发明的药物制剂在制备用于诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的应用。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“w/v”是指质量体积百分含量，即“各组分的重量(g)/分装前溶液体积(ml)”。
附图说明
图1.实施例3制备样品中5种试验菌生长曲线。
图2.实施例4制备样品中5种试验菌生长曲线。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助本领域技术人员更好地理解本发明的实质和特点，不作为对本申请可实施范围的限定。
本发明所需的化合物的制备，均按照专利申请CN201580001777中公开的方法进行制备。
实施例1
配方如下：
Figure PCTCN2021096890-appb-000007
Figure PCTCN2021096890-appb-000008
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、油酸(来源：德国Lipoid GmbH)、化合物1，搅拌均匀，控制温度为55～75℃作为油相；将依地酸二钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至10.10，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，
Figure PCTCN2021096890-appb-000009
查合格后即得含化合物1的乳状注射液。
配方如下：
Figure PCTCN2021096890-appb-000010
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)，在氮气保护下加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物2，搅拌均匀，控制温度为55～75℃作为油相；将依地酸钙钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有 限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.82，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物2的乳状注射液。
实施例3
配方如下：
Figure PCTCN2021096890-appb-000011
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将依地酸二钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.91，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷
Figure PCTCN2021096890-appb-000012
合格后即得含化合物3的乳状注射液。
按如下配方制备不含抑菌剂的药物制剂：
Figure PCTCN2021096890-appb-000013
Figure PCTCN2021096890-appb-000014
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.95，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物3的乳状注射液。。
实施例5
配方如下：
Figure PCTCN2021096890-appb-000015
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将依地酸钙钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.87，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷
Figure PCTCN2021096890-appb-000016
合格后即得含化合物3的乳状注射液。
配方如下：
Figure PCTCN2021096890-appb-000017
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将依地酸二钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.69，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro 生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物3的乳状注射液。
实施例7
配方如下：
Figure PCTCN2021096890-appb-000018
称取注射用大豆油(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物5，搅拌均匀，控制温度为55～75℃作为油相；将依地酸钙钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至10.05，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，
Figure PCTCN2021096890-appb-000019
器中灭菌，冷却，检查合格后即得含化合物5的乳状注射液。
配方如下：
Figure PCTCN2021096890-appb-000020
Figure PCTCN2021096890-appb-000021
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将焦亚硫酸钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.99，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷
Figure PCTCN2021096890-appb-000022
合格后即得含化合物3的乳状注射液。
配方如下：
Figure PCTCN2021096890-appb-000023
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将依地酸二钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源： 德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.89，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物3的乳状注射液。
实施例50
配方如下：
Figure PCTCN2021096890-appb-000024
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将苯甲醇(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.49，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物3的乳状注射液。
实施例11
配方如下：
Figure PCTCN2021096890-appb-000025
Figure PCTCN2021096890-appb-000026
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、油酸(来源：德国Lipoid GmbH)、化合物3，搅拌均匀，控制温度为55～75℃作为油相；将焦亚硫酸钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.75，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物3的乳状注射液。
实施例12
配方如下：
Figure PCTCN2021096890-appb-000027
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)，在氮气保护下加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、油酸(来源：德国Lipoid GmbH)、化合物4，搅拌均匀，控制温度为55～75℃作为油相；将乙二胺四乙酸(来源：成都市科隆化学品有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.98，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物4的乳状注射液。
实施例13
配方如下：
Figure PCTCN2021096890-appb-000028
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、油酸(来源：德国Lipoid GmbH)、化合物5，搅拌均匀，控制温度为55～75℃作为油相；将焦亚硫酸钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至10.34，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质 机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物5的乳状注射液。
实施例14
配方如下：
Figure PCTCN2021096890-appb-000029
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物6，搅拌均匀，控制温度为55～75℃作为油相；将依地酸二钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.79，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物6的乳状注射液。
实施例15
配方如下：
Figure PCTCN2021096890-appb-000030
Figure PCTCN2021096890-appb-000031
称取橄榄油(来源：德国Lipoid GmbH)，在氮气保护加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物7，搅拌均匀，控制温度为55～75℃作为油相；将焦亚硫酸钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至10.55，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物7的乳状注射液。
实施例16
配方如下：
Figure PCTCN2021096890-appb-000032
称取注射用大豆油(供注射用)(来源：辽宁新兴药业股份有限公司)、中链甘油三酸酯(来源：辽宁新兴药业股份有限公司)，在氮气保护下混合，加热至约50℃，高速搅拌下加入蛋黄卵磷脂(Lipoid E80)(来源：德国Lipoid GmbH)、化合物8，搅拌均匀，控制温度为55～75℃作为油相；将依地酸钙钠(来源：湖南尔康制药股份有限公司)、甘油(供注射用)[来源：禾大西普化学(四川)有限公司]、油酸钠(来 源：德国Lipoid GmbH)加入适量注射用水中，混合，用氢氧化钠(来源：湖南尔康制药股份有限公司)调节水相pH值至9.91，控制温度为55～75℃作为水相。在高速搅拌(高剪切混合乳化机，IKA生产)下将油相加入水相中制成初乳，经高压均质机(GEA Niro生产)反复均质，检查乳粒符合要求，乳液过滤后通氮灌封，蒸汽灭菌器中灭菌，冷却，检查合格后即得含化合物8的乳状注射液。
稳定性测试：
将实施例3、4、6所制备样品于30±2℃/65％±5％RH、25±2℃/60％±5％RH条件下稳定性留样，数据如下表1-3所示：
表1、实施例3所制备样品稳定性测试结果
Figure PCTCN2021096890-appb-000033
表2、实施例6所制备样品稳定性测试结果
Figure PCTCN2021096890-appb-000034
Figure PCTCN2021096890-appb-000035
表3、实施例4所制备样品稳定性测试结果
Figure PCTCN2021096890-appb-000036
试验结果表明，在质量标准范围内，实施例3和实施例6的甲氧基苯胺值、杂质C情况优于实施例4，说明在处方中加入依地酸二钠，可明显改善药物稳定性。
生物测试例
测试方法：
参照《中国药典》2015年版四部1121抑菌效力检查法，取本发明药物制剂，分别接种0.1ml(10 5～10 6cfu/ml)的金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌、白色念珠菌菌悬液和黑曲霉孢子悬液，混合均匀，分别在第0h、2h、4h、6h、8h、10h、12h按上述验证的菌数测定方法测定金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌，白色念珠菌、黑曲霉的存活菌数，以菌数变化情况评价其抑菌效力。
以实施例3和实施例4样品为例。分别取实施例3和实施例4所制备样品，参照《中国药典》2015年版四部1121抑菌效力检查法，分别接种金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌、白色念珠菌菌悬液和黑曲霉孢子悬液(约10 5～10 6cfu/ml)各0.1ml至10ml所制备样品中，分别在第0h、2h、4h、6h、8h、10h、12h按验证的菌数测定方法测定金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌、白色念珠菌、黑曲霉的存活菌数，各种菌的生长曲线见附图1和附图2。
由附图1、2可知，实施例3制备样品中金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌、白色念珠菌和黑曲霉的12小时存活菌数与0小时存活菌数比较均小于0.5lg；实施例4制备样品中仅有铜绿假单胞菌和黑曲霉的12小时存活菌数与0小时存活菌数比较小于0.5lg。
实施例3中添加的抑菌剂浓度不能产生足够的抑菌作用，不符合中国药典2015年版四部中的抑菌效力要求；然而，上述抑菌试验结果表明，在处方中加入0.005％的依地酸二钠确有减缓微生物生长作用，可保证临床用药安全。
测试结果：
表1供试品接种菌悬液后不同放置时间计数及换算为对数值cfu/ml(lg)
Figure PCTCN2021096890-appb-000037
Figure PCTCN2021096890-appb-000038
试验结果表明，通过添加适量的抑菌剂成分如依地酸二钠、依地酸钙钠、焦亚硫酸钠、苯甲醇及乙二胺四乙酸等，可以明显的抑制污染菌的生长。例如，本发明药物制剂(实施例3)在保持较好的制剂稳定性的基础上，在使用周期内对污染菌的生长有明显的抑制生长作用，不含抑菌剂的样品(实施例4)对金黄色葡萄球菌、大肠埃希菌和白色念珠菌的生长无抑制作用。故本发明药物制剂降低了在临床使用过程中受不确定因素导致的潜在染菌风险，提高了临床使用安全性。
虽然已经对本发明的具体实施方案进行了描述，但是本领域技术人员应认识到，在不偏离本发明的范围或精神的前提下可以对本发明进行多种改变与修饰。因而，本发明意欲涵盖落在附属权利要求书及其同等物范围内的所有这些改变与修饰。

Claims (13)

  1. 一种药物制剂，其特征在于包括：
    (A)0.01w/v％～5w/v％的活性成分，所述的活性成分为通式(I)所述化合物或者其立体异构体、药学上可接受的盐或前药，
    Figure PCTCN2021096890-appb-100001
    其中R 1和R 2各自独立地选自H、C 1-4烷基或C 3-6环烷基；n选自1或2，或R 1和R 2与其连接碳原子形成C 3-6环烷基；以及
    (B)0.0005w/v％～0.1w/v％的抑菌剂。
  2. 根据权利要求1所述的药物制剂，其特征在于：
    R 1选自H、甲基、乙基或异丙基；
    R 2选自甲基、乙基、异丙基或环丙基。
  3. 根据权利要求2所述的药物制剂，其特征在于通式(I)所述化合物选自以下结构之一：
    Figure PCTCN2021096890-appb-100002
    Figure PCTCN2021096890-appb-100003
    或者
    Figure PCTCN2021096890-appb-100004
  4. 根据权利要求1所述的药物制剂，其特征在于通式(I)所述化合物选自以下结构之一：
    Figure PCTCN2021096890-appb-100005
  5. 根据权利要求1所述的药物制剂，其特征在于式(I)所述化合物的前药选自如下式(II)所述化合物或者其立体异构体、药学上可接受的盐：
    Figure PCTCN2021096890-appb-100006
  6. 根据权利要求1-5任意一项所述的药物制剂，其特征在于所述的药物制剂为脂肪乳剂的形式，所述脂肪乳剂进一步包含5w/v％～30w/v％的油性成分和0.1w/v％～5w/v％的乳化剂。
  7. 根据权利要求6所述的药物制剂，其特征在于所述脂肪乳剂包含0.05w/v％～2.5w/v％的所述活性成分、10w/v％～25w/v％的油性成分、0.2w/v％～2w/v％的乳化剂和0.001w/v％～0.03w/v％的抑菌剂。
  8. 根据权利要求7所述的药物制剂，其特征在于所述脂肪乳剂还包含0～4w/v％的渗透压调节剂。
  9. 根据权利要求8所述的药物制剂，其特征在于：
    所述的油性成分选自大豆油、橄榄油、鱼油、亚麻油、中链甘油三酸酯或结构甘油三酯中的任一种或任几种任意比例的混合物；
    所述的乳化剂选自泊洛沙姆、吐温-80、聚乙二醇15羟基硬脂酸酯、聚氧乙烯35蓖麻油、聚氧乙烯40氢化蓖麻油、蛋黄卵磷脂或大豆卵磷脂中的任一种或任几种任意比例的混合物；
    所述的抑菌剂选自辛酸钠、苯甲酸、苯甲醇、苯甲酸钠、苯甲酸甲酯、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠、焦性没食子酸酯、乙二胺四乙酸、依地酸二钠、依地酸钙或依地酸钙钠中的任一种或任几种任意比例的混合物；
    所述的渗透压调节剂选自甘油、糖类或糖醇类中的任一种或任几种任意比例的混合物。
  10. 根据权利要求8所述的药物制剂，其特征在于所述脂肪乳剂进一步包含pH调节剂，所述的pH调节剂选自氢氧化钠、氢氧化钾、三乙醇胺、盐酸、磷酸、枸橼酸、醋酸或苹果酸中的任一种或任几种；所述药物制剂的pH值范围为3.0～10.0、4.0～9.0或6.0～9.0。
  11. 根据权利要求10所述的药物制剂，其特征在于所述脂肪乳剂进一步包含0w/v％～2w/v％的稳定剂，所述的稳定剂选自油酸或油酸钠中的任一种或两种任意比例的混合物。
  12. 根据权利要求11所述的药物制剂，其特征在于所述药物制剂包含0.1w/v％～2w/v％的所述活性成分、10w/v％～20w/v％的大豆油或中链甘油三酸酯中的任一种或两种任意比例的混合物、0.2w/v％～2w/v％的蛋黄卵磷脂、0.001w/v％～0.03w/v％的依地酸二钠或依地酸钙钠或焦亚硫酸钠或苯甲醇中的任一种或两种任意比例的混合物、1w/v％～4w/v％的甘油和0.01w/v％～2w/v％的油酸或油酸钠中的任一种或两种任意比例的混合物。
  13. 一种根据权利要求1-12任意一项所述的药物制剂在制备用于诱导和维持动物或者人类的麻醉、促进动物或者人类的镇静催眠、治疗和/或预防焦虑、抑郁、失眠、恶心、呕吐、偏头痛、精神分裂、惊厥和癫痫药物中的应用。
PCT/CN2021/096890 2020-05-29 2021-05-28 一种药物制剂及其制备方法 WO2021239130A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CN202180037860.0A CN115968279A (zh) 2020-05-29 2021-05-28 一种药物制剂及其制备方法
EP21814359.2A EP4159197A4 (en) 2020-05-29 2021-05-28 PHARMACEUTICAL PREPARATION AND PREPARATION METHOD THEREFOR
US17/993,506 US20230118143A1 (en) 2020-05-29 2022-11-23 Pharmaceutical preparation and preparation method therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010472446.X 2020-05-29
CN202010472446 2020-05-29

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/993,506 Continuation US20230118143A1 (en) 2020-05-29 2022-11-23 Pharmaceutical preparation and preparation method therefor

Publications (1)

Publication Number Publication Date
WO2021239130A1 true WO2021239130A1 (zh) 2021-12-02

Family

ID=78722779

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/096890 WO2021239130A1 (zh) 2020-05-29 2021-05-28 一种药物制剂及其制备方法

Country Status (5)

Country Link
US (1) US20230118143A1 (zh)
EP (1) EP4159197A4 (zh)
CN (1) CN115968279A (zh)
TW (1) TW202143951A (zh)
WO (1) WO2021239130A1 (zh)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016034079A1 (zh) * 2014-09-04 2016-03-10 四川海思科制药有限公司 一种gabaa受体增强剂用于制备镇静麻醉的药物中的用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112245426A (zh) * 2016-07-22 2021-01-22 四川海思科制药有限公司 一种苯酚衍生物和依托咪酯的药物组合物、药物制剂及其用途
CN106137963B (zh) * 2016-07-27 2019-07-30 武汉科福新药有限责任公司 抗心律失常药物脂肪乳注射液及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016034079A1 (zh) * 2014-09-04 2016-03-10 四川海思科制药有限公司 一种gabaa受体增强剂用于制备镇静麻醉的药物中的用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4159197A4

Also Published As

Publication number Publication date
CN115968279A (zh) 2023-04-14
TW202143951A (zh) 2021-12-01
US20230118143A1 (en) 2023-04-20
EP4159197A4 (en) 2023-11-22
EP4159197A1 (en) 2023-04-05

Similar Documents

Publication Publication Date Title
US20230139672A1 (en) O/w-emulsions comprising semifluorinated alkanes
JP5668004B2 (ja) ２，６−ジイソプロピルフェノール（プロポフォール）の水性医薬組成物およびその使用
JP5887368B2 (ja) 共溶媒処方物
AU2014329412B2 (en) Epinephrine-based ophthalmic compositions for intraocular administration and methods for fabricating thereof
SK286375B6 (sk) Sterilná farmaceutická kompozícia na parenterálnepoužitie
CN111297803A (zh) S-盐酸氯胺酮的药物组合物
TWI772659B (zh) 醫藥配方
TWI359022B (en) Composition of loteprednol etabonate and tobramyci
WO2021239130A1 (zh) 一种药物制剂及其制备方法
CN109906076A (zh) 硫辛酸胆碱酯组合物和稳定为药学上相关的药物产品的方法
JP2004514692A (ja) トラマドールとジクロフェナクの塩の懸濁液を含有する非経口投与可能な剤形
US9132090B2 (en) Propofol based anesthetic with preservative
JP2024500187A (ja) 非経口カンナビノイド配合物およびその使用
US20190070123A1 (en) Transdermal preparation
CN109985005A (zh) 氟比洛芬酯脂肪乳及其制备方法
US7169812B2 (en) Process for producing injectable gabapentin compositions
CN109985002A (zh) 一种氟比洛芬酯脂肪乳及其制备方法
WO2022138842A1 (ja) エピナスチン又はその塩と硫黄系抗酸化剤を含有する経皮投与用医薬組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21814359

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2021814359

Country of ref document: EP

Effective date: 20230102