CN110302154B - 2, 4-dinitrophenol fat emulsion and preparation method and application thereof - Google Patents
2, 4-dinitrophenol fat emulsion and preparation method and application thereof Download PDFInfo
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- CN110302154B CN110302154B CN201910697033.9A CN201910697033A CN110302154B CN 110302154 B CN110302154 B CN 110302154B CN 201910697033 A CN201910697033 A CN 201910697033A CN 110302154 B CN110302154 B CN 110302154B
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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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/06—Phenols the aromatic ring being substituted by nitro groups
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- 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
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- 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
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- 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
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides 2, 4-dinitrophenol fat emulsion, wherein each 1L of the 2, 4-dinitrophenol fat emulsion is prepared from the following raw materials in parts by weight: 0.1-20 g of 2, 4-dinitrophenol or salt thereof, 50-500 g of oil for injection, 1-100 g of emulsifier, 5-100 g of isotonic regulator and the balance of water for injection. The fat emulsion has good stability, can be stored for a long time without layering phenomenon, does not precipitate medicine, and ensures the efficacy and safety of the fat emulsion in use. In addition, no organic reagent is added in the preparation process of the fat emulsion, so that the residue of the organic reagent of the final product and the stimulation effect of the surfactant are avoided, and the product safety and the patient compliance are improved; meanwhile, the application of organic reagents in the production process is avoided, the preparation procedures can be reduced, and the production efficiency and safety are improved. The fat emulsion can be administered by intravenous drip to stabilize blood concentration, thereby improving safety. In addition, the fat emulsion has certain liver targeting property, and can improve the distribution of the fat emulsion in the liver, thereby improving the curative effect of the fat emulsion on liver pathological changes.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to 2, 4-dinitrophenol fat emulsion and a preparation method and application thereof.
Background
2, 4-dinitrophenol (2,4-DNP) is a yellow compound that has historically been used in the manufacture of dyes, explosives and fungicides. It was also used as an anti-obesity agent in the early part of the last century because it decouples mitochondrial oxidative phosphorylation. This compound was banned by the U.S. food and drug administration in 1938 because it has potentially fatal side effects including the initiation of hyperthermia, cataracts, agranulocytosis, hepatotoxicity, nephrotoxicity and cardiotoxicity. There is now increasing evidence that 2, 4-dinitrophenol has important effects in protecting neurons from neurodegeneration and enhancing neuroplasticity, and appropriate doses of 2, 4-dinitrophenol can induce mild mitochondrial uncoupling and promote neuronal survival. In addition, the uncoupling oxidation and phosphorylation of 2, 4-dinitrophenol proved to be effective on non-alcoholic fatty liver disease (NAFLD). Therefore, the clinical application of 2, 4-dinitrophenol is gradually attracting attention.
At present, the existing 2, 4-dinitrophenol medicament formulations in the market of China mainly comprise tablets, capsules, granules and the like, and the formulations have slow effect, and the blood concentration of single administration is often low, so that the clinical effect is difficult to achieve. In order to maintain effective blood concentration, the dosage forms mostly need to be repeatedly administered, but the repeated administration easily causes the blood concentration to be higher. Due to the strong toxicity of 2, 4-dinitrophenol, the narrow therapeutic window and the significant individual difference in metabolism, the fatal side effects mentioned above tend to occur at higher blood concentrations. Therefore, the clinical use of 2, 4-dinitrophenol is very limited.
The patent 201480059363.0 prepares 2, 4-dinitrophenol into a slow-release oral preparation, slowly releases the medicine, can stably maintain effective blood concentration for a long time, is convenient to use, and avoids peak-valley phenomenon; reduces the adverse reaction of the 2, 4-dinitrophenol and improves the curative effect. However, the sustained release agent has some disadvantages clinically: (1) the flexibility of clinical dose adjustment is low, and the treatment cannot be stopped in time when large side effects occur; (2) the production process of the sustained-release preparation is complex and the cost is high.
Disclosure of Invention
In order to solve the problems, the invention provides 2, 4-dinitrophenol fat emulsion and a preparation method and application thereof.
The invention firstly provides 2, 4-dinitrophenol fat emulsion, and each 1L of the 2, 4-dinitrophenol fat emulsion is prepared from the following raw materials by weight:
0.1-20 g of 2, 4-dinitrophenol or salt thereof, 50-500 g of oil for injection, 1-100 g of emulsifier, 5-100 g of isotonic regulator and the balance of water for injection.
Further, each 1L of 2, 4-dinitrophenol fat emulsion is prepared from the following raw materials by weight:
0.5-10 g of 2, 4-dinitrophenol or salt thereof, 100-300 g of oil for injection, 10-50 g of emulsifier, 10-90 g of isotonic regulator and the balance of water for injection.
Further, each 1L of 2, 4-dinitrophenol fat emulsion is prepared from the following raw materials by weight:
2-10 g of 2, 4-dinitrophenol or salt thereof, 100-300 g of oil for injection, 10-30 g of emulsifier, 10-50 g of isotonic regulator and the balance of water for injection.
Further, the oil for injection is one or more of soybean oil, medium chain triglyceride, peanut oil, olive oil and fish oil;
preferably, the oil for injection is one or more of soybean oil, medium chain triglyceride, olive oil and fish oil;
more preferably, the oil for injection is soybean oil, or consists of soybean oil and medium chain triglycerides, or consists of soybean oil, medium chain triglycerides, olive oil and fish oil.
Further, the emulsifier is one or more of lecithin, hydrogenated phospholipid, sodium oleate, polyethylene glycol lithium dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester;
preferably, the emulsifier is one or more of lecithin, poloxamer 188, sodium oleate, and alpha-tocopherol succinic acid polyethylene glycol ester;
more preferably, the emulsifier is lecithin.
Further, the lecithin is one or more of soybean lecithin and egg yolk lecithin.
Further, the isotonic regulator is one or more of glucose, sodium chloride, glycerol and xylitol;
preferably, the isotonic regulator is one or more of glucose and glycerol;
more preferably, the isotonicity adjusting agent is glycerol.
Further, the pH value of the fat milk is 4-9; preferably, the pH is 5-7; more preferably, the pH is 6.5.
The invention also provides a preparation method of the 2, 4-dinitrophenol fat emulsion, which comprises the following steps:
(1) heating the oil for injection to 60-80 ℃, adding 2, 4-dinitrophenol and an emulsifier for removing sodium sulfate into the oil for injection, and stirring at a high speed to obtain an oil phase;
(2) adding isoosmotic adjusting agent and emulsifier sodium oleate into water for injection, heating to 60-80 deg.C for dissolving to obtain water phase;
(3) mixing the oil phase and the water phase, stirring at high speed to obtain primary emulsion, and emulsifying the primary emulsion under high pressure;
(4) adjusting pH, and sterilizing.
Further, in the step (1), the oil for injection is heated to 60 ℃; and/or in the step (1), the high-speed stirring speed is 5000 r/min; and/or, in the step (2), the heating is carried out to 60 ℃ for dissolution; and/or in the step (3), the high-speed stirring speed is 10000r/min, and the time is 5 min; and/or in the step (3), homogenizing the high-pressure milk for 8 times under the pressure of 800 bar; and/or in the step (4), adjusting the pH value to 4-9 by using a sodium hydroxide solution; preferably, the pH value is adjusted to be 5-7; more preferably, the pH is adjusted to 6.5; and/or in the step (4), the sterilization is carried out for 30min at 115 ℃ under the hot-pressing sterilization.
The invention also provides a 2, 4-dinitrophenol freeze-dried powder injection which is prepared by freeze drying the 2, 4-dinitrophenol fat emulsion.
The invention also provides the application of the 2, 4-dinitrophenol fat emulsion or the 2, 4-dinitrophenol freeze-dried powder injection in preparing medicines for preventing and/or treating hepatitis, fatty liver, hepatic fibrosis, liver cirrhosis, liver cancer, type 2 diabetes and metabolic syndrome.
Further, the fatty liver is non-alcoholic fatty liver; the metabolic syndrome is acquired lipodystrophy or hereditary lipodystrophy.
The water for injection in the invention is water which meets the requirements of the Chinese pharmacopoeia water for injection, namely distilled water or water obtained by distilling deionized water, so the water for injection is also called double distilled water.
The polyethylene glycol alpha-tocopherol succinate in the invention is water-soluble vitamin E, and is also abbreviated as alpha-tocopherol in the invention.
The 2, 4-dinitrophenol is prepared into the fat emulsion, and the fat emulsion can be injected into blood circulation in a mode of intravenous drip, has the advantages of quick absorption, quick response, 100 percent of bioavailability, more accurate dosage, easier control of blood concentration, maintenance of stable blood concentration, reduction of toxic and side effects of the 2, 4-dinitrophenol and improvement of curative effect. Meanwhile, the fat emulsion has certain liver targeting property, and can improve the distribution of the fat emulsion in the liver and improve the curative effect of the fat emulsion on liver pathological changes.
The 2, 4-dinitrophenol fat emulsion has good stability, can be stored for a long time without layering phenomenon, does not precipitate medicine, and ensures the efficacy and safety of the fat emulsion in use. In addition, no organic reagent and surfactant are added in the preparation process of the 2, 4-dinitrophenol fat emulsion, so that the residue of the organic reagent and the stimulation of the surfactant in the final product are avoided, and the product safety and the patient compliance are improved; meanwhile, the application of organic reagents in the production process is avoided, the preparation procedures can be reduced, and the production efficiency and the safety are improved. The 2, 4-dinitrophenol fat emulsion is administrated by intravenous drip, so that the blood concentration can be stable, and the safety is improved. In addition, the fat emulsion has certain liver targeting property, and can improve the distribution of the fat emulsion in the liver, thereby improving the curative effect of the fat emulsion on liver pathological changes.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products.
Example 1 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 100g of soybean oil, placing the soybean oil in a beaker, heating the soybean oil to 60 ℃, adding 12g of lecithin and 3g of 2, 4-dinitrophenol into the soybean oil, and stirring the mixture at a high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 2 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 12g of lecithin and 3g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 3 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 300g of soybean oil, placing the soybean oil in a beaker, heating the soybean oil to 60 ℃, adding 12g of lecithin and 3g of 2, 4-dinitrophenol into the soybean oil, and stirring the mixture at a high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 4 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 10g of lecithin and 3g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 5 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 30g of lecithin and 3g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 6 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 300g of soybean oil, placing the soybean oil in a beaker, heating the soybean oil to 60 ℃, adding 20g of lecithin and 3g of 2, 4-dinitrophenol into the soybean oil, and stirring the mixture at a high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 7 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 12g of lecithin, 2g of poloxamer 188 and 5g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 8 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 20g of lecithin, 4g of poloxamer 188 and 10g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 10g of glycerol is added into water for injection, and the mixture is heated to 60 ℃ to be dissolved to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 9 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 20g of lecithin, 4g of poloxamer 188 and 4g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. Adding 50g glucose into water for injection, and heating to 60 deg.C to dissolve to obtain water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 10 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 50g of soybean oil and 50g of medium chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 5g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 11 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 100g of soybean oil and 100g of medium chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 8g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 12 preparation of a 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 150g of soybean oil and 150g of medium chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 8g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 13 preparation of a 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 75g of soybean oil and 25g of medium-chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 5g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 14 preparation of a 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 60g of soybean oil, 60g of medium-chain triglyceride, 30g of fish oil and 50g of olive oil in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.135g of alpha-tocopherol, 12g of lecithin and 5g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min until complete dissolution to obtain an oil phase. Adding 0.3g of sodium oleate and 25g of glycerol into water for injection, and heating to 60 ℃ to dissolve to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 15 preparation of 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 30g of soybean oil, 30g of medium-chain triglyceride, 15g of fish oil and 25g of olive oil in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.135g of alpha-tocopherol, 12g of lecithin and 3g of 2, 4-dinitrophenol, and stirring at a high speed of 5000r/min until complete dissolution to obtain an oil phase. Adding 0.3g of sodium oleate and 25g of glycerol into water for injection, and heating to 60 ℃ to dissolve to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 16 preparation of a 2, 4-dinitrophenol fat emulsion of the invention
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 90g of soybean oil, 90g of medium-chain triglyceride, 45g of fish oil and 75g of olive oil in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.135g of alpha-tocopherol, 12g of lecithin and 3g of 2, 4-dinitrophenol, and stirring at a high speed of 5000r/min until complete dissolution to obtain an oil phase. Adding 0.3g of sodium oleate and 25g of glycerol into water for injection, and heating to 60 ℃ to dissolve to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Example 17 preparation of 2, 4-dinitrophenol lyophilized powder for injection
And (3) freezing and drying the 2, 4-dinitrophenol fat emulsion prepared in any one of the embodiments 1-16 to obtain the 2, 4-dinitrophenol freeze-dried powder injection.
Comparative example 1 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 700g of soybean oil, placing the soybean oil in a beaker, heating the soybean oil to 60 ℃, adding 12g of lecithin and 3g of 2, 4-dinitrophenol into the soybean oil, and stirring the mixture at a high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 2 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 300g of soybean oil and 300g of medium chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 3g of 2, 4-dinitrophenol, and stirring at a high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 3 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 180g of soybean oil, 180g of medium-chain triglyceride, 90g of fish oil and 150g of olive oil in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.135g of alpha-tocopherol, 6g of lecithin and 5g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min until complete dissolution to obtain an oil phase. Adding 0.3g of sodium oleate and 25g of glycerol into water for injection, and heating to 60 ℃ to dissolve to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 4 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: 200g of soybean oil is weighed and placed in a beaker, heated to 60 ℃, 12g of lecithin and 80g of 2, 4-dinitrophenol are added into the soybean oil, and stirred at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 5 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 75g of soybean oil and 75g of medium-chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 12g of lecithin and 80g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 6 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 75g of soybean oil and 75g of medium-chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 2g of lecithin and 80g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min to obtain an oil phase. 22.5g of glycerol was added to water for injection, and dissolved by heating to 60 ℃ to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
Comparative example 7 preparation of 2, 4-dinitrophenol fat emulsion
Preparation of 1L of 2, 4-dinitrophenol fat emulsion: weighing 180g of soybean oil, 180g of medium-chain triglyceride, 90g of fish oil and 150g of olive oil in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.135g of alpha-tocopherol, 3g of lecithin and 80g of 2, 4-dinitrophenol, and stirring at high speed of 5000r/min until complete dissolution to obtain an oil phase. Adding 0.3g of sodium oleate and 25g of glycerol into water for injection, and heating to 60 ℃ to dissolve to obtain a water phase. Adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar for 8 times), adjusting pH to 6.5 with sodium hydroxide solution, packaging, and sterilizing at 115 deg.C under hot pressure for 30 min.
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 study of stability of 2, 4-dinitrophenol fat emulsion
The 2, 4-dinitrophenol fat emulsions prepared in examples 1 to 16 and comparative examples 1 to 7 were stored at room temperature, and after 1 month, they were taken out and observed whether each fat emulsion was layered or precipitated. The test results are shown in table 1.
TABLE 12 test results for stability of 4-dinitrophenol fat emulsions
The test result shows that: the 2, 4-dinitrophenol fat emulsion prepared by the invention has good stability, and has no layering after being placed for 1 month, and no drug precipitation is generated. The 2, 4-dinitrophenol fat emulsion outside the protection range of the invention has layering phenomenon after being placed for 1 week and/or has drug precipitation and separation, and has poor stability.
In conclusion, the 2, 4-dinitrophenol fat emulsion has good stability, can be stored for a long time without layering phenomenon and drug precipitation, and ensures the drug effect and safety of the fat emulsion in use. In addition, no organic reagent and surfactant are added in the preparation process of the 2, 4-dinitrophenol fat emulsion, so that the residue of the organic reagent and the stimulation of the surfactant in the final product are avoided, and the product safety and the patient compliance are improved; meanwhile, the application of organic reagents in the production process is avoided, the preparation procedures can be reduced, and the production efficiency and the safety are improved. The 2, 4-dinitrophenol fat emulsion is administrated by intravenous drip, so that the blood concentration can be stable, and the safety is improved. In addition, the fat emulsion has certain liver targeting property, and can improve the distribution of the fat emulsion in the liver, thereby improving the curative effect of the fat emulsion on liver pathological changes.
Claims (18)
1. A2, 4-dinitrophenol fat emulsion is characterized in that: every 1L of 2, 4-dinitrophenol fat emulsion is prepared from the following raw materials by weight:
2-10 g of 2, 4-dinitrophenol or salt thereof, 100-300 g of oil for injection, 10-30 g of emulsifier, 10-50 g of isotonic regulator and the balance of water for injection;
the oil for injection is one or more of soybean oil, medium chain triglyceride, peanut oil, olive oil and fish oil;
the emulsifier is one or more of lecithin, hydrogenated phospholipid, sodium oleate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester;
the isotonic regulator is one or more of glucose, sodium chloride, glycerol and xylitol.
2. 2, 4-dinitrophenol fat emulsion according to claim 1, characterized in that: the oil for injection is one or more of soybean oil, medium chain triglyceride, olive oil and fish oil.
3. 2, 4-dinitrophenol fat emulsion according to claim 2, characterized in that: the oil for injection is soybean oil, or consists of soybean oil and medium chain triglyceride, or consists of soybean oil, medium chain triglyceride, olive oil and fish oil.
4. 2, 4-dinitrophenol fat emulsion according to claim 1, characterized in that: the emulsifier is one or more of lecithin, poloxamer 188, sodium oleate and alpha-tocopherol succinic acid polyethylene glycol ester.
5. A2, 4-dinitrophenol fat emulsion according to claim 4, wherein: the emulsifier is lecithin.
6. 2, 4-dinitrophenol fat emulsion according to claim 5, wherein: the lecithin is one or more of soybean lecithin and egg yolk lecithin.
7. 2, 4-dinitrophenol fat emulsion according to claim 1, characterized in that: the isotonic regulator is one or more of glucose and glycerol.
8. 2, 4-dinitrophenol fat emulsion according to claim 7, wherein: the isotonic regulator is glycerol.
9. A2, 4-dinitrophenol fat emulsion according to any one of claims 1 to 8, wherein: the pH of the fat milk is 4-9.
10. 2, 4-dinitrophenol fat emulsion according to claim 9, wherein: the pH is 5-7.
11. 2, 4-dinitrophenol fat emulsion according to claim 10, wherein: the pH was 6.5.
12. A method of producing a 2, 4-dinitrophenol fat emulsion according to claim 1, wherein: it comprises the following steps:
(1) heating the oil for injection to 60-80 ℃, adding 2, 4-dinitrophenol and an emulsifier for removing sodium sulfate into the oil for injection, and stirring at a high speed to obtain an oil phase;
(2) adding isoosmotic adjusting agent and emulsifier sodium oleate into water for injection, heating to 60-80 deg.C for dissolving to obtain water phase;
(3) mixing the oil phase and the water phase, stirring at high speed to obtain primary emulsion, and emulsifying the primary emulsion under high pressure;
(4) adjusting pH, and sterilizing.
13. The method of manufacturing according to claim 12, wherein: in the step (1), the oil for injection is heated to 60 ℃; and/or in the step (1), the high-speed stirring speed is 5000 r/min; and/or, in the step (2), the heating is carried out to 60 ℃ for dissolution; and/or in the step (3), the high-speed stirring speed is 10000r/min, and the time is 5 min; and/or in the step (3), homogenizing the high-pressure milk for 8 times under the pressure of 800 bar; and/or in the step (4), adjusting the pH value to 4-9 by using a sodium hydroxide solution; and/or in the step (4), the sterilization is carried out for 30min at 115 ℃ under the hot-pressing sterilization.
14. The method of manufacturing according to claim 13, wherein: in the step (4), the pH value is adjusted to be 5-7.
15. The method of claim 14, wherein: in the step (4), the pH value is adjusted to 6.5.
16. A2, 4-dinitrophenol freeze-dried powder injection is characterized in that: it is prepared by freeze drying the 2, 4-dinitrophenol fat emulsion according to any one of claims 1 to 11.
17. Use of the 2, 4-dinitrophenol fat emulsion according to any one of claims 1 to 11 or the 2, 4-dinitrophenol lyophilized powder for injection according to claim 16 in the preparation of a medicament for treating hepatitis, fatty liver, hepatic fibrosis, liver cirrhosis, liver cancer, type 2 diabetes, and metabolic syndrome.
18. Use according to claim 17, characterized in that: the fatty liver is non-alcoholic fatty liver; the metabolic syndrome is acquired lipodystrophy or hereditary lipodystrophy.
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