CN105193722B - Dimercaprol fat emulsion injection - Google Patents
Dimercaprol fat emulsion injection Download PDFInfo
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- CN105193722B CN105193722B CN201510713336.7A CN201510713336A CN105193722B CN 105193722 B CN105193722 B CN 105193722B CN 201510713336 A CN201510713336 A CN 201510713336A CN 105193722 B CN105193722 B CN 105193722B
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Abstract
The invention relates to a dimercaprol fat emulsion injection which comprises the following components of 1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 4-10 g of glycerol, 1-10 g of EDTA and 990 g of water for injection.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to dimercaprol fat emulsion injection and a preparation method thereof.
Background
Dimercaprol is a nearly colorless, free flowing liquid, acidic, has a specific gravity of 1.238-1.240, and has a scallion-like odor (which is common for all mercapto compounds). The air can be slowly oxidized to reduce the content. The solubility in water is 1:13, but the compound is easy to decompose and lose efficacy in aqueous solution, can be dissolved in benzyl benzoate, and can increase the co-stability, so that the benzyl benzoate and sesame oil are commonly used as a solvent in the preparation of injections (pharmaceutical report, 5 th period). Dimercaprol injection, which is mainly used for treating arsenic, mercury and gold poisoning and is used for treating children acute lead encephalopathy by combining with calcium disodium edetate. However, dimercaprol has unpleasant smell, and prepared utensils and work clothes can be boiled and washed by adding soap into the distilled water so as to remove the offensive smell. The existence of the defects limits the clinical application and popularization of dimercaprol to a certain extent.
The difficult soluble or slightly soluble medicine is prepared into intravenous injection preparation, and the common solution method comprises the following steps: 1. preparing soluble salt; 2. adding a cosolvent; 3. using a mixed solvent; 4. a solubilizer is used.
Since the blank fat milk Intralipid was officially approved in sweden for clinical use in 1961, nutritional fat milk for intravenous injection has been widely used as an important component of parenteral nutrition to provide nutrition to critically ill patients. In recent years, with the need of disease treatment and further research, the research of fat emulsion is not limited to the application of parenteral nutrition, the drug is dissolved in the fatty oil, emulsified by lecithin and dispersed in the water phase to prepare the drug-loaded fat emulsion with the particle size of 100nm, the selectivity of the administration route can be increased, and the fat emulsion can be widely applied to the aspects of intravenous injection, pulmonary administration, ophthalmic administration, nasal administration and the like. In the drug-containing fat emulsion injection, most of the drugs are distributed on an oil phase or an oil-water interface, so that the drugs are prevented from being directly contacted with water, and the drug-containing fat emulsion injection has the effect of improving the stability of the drugs which are easy to hydrolyze or sensitive to water. The fat emulsion avoids the irritation of intravenous injection caused by introducing organic solvent.
However, not all poorly soluble drugs can be made into fat emulsion injection, and problems such as drug precipitation during dilution, pain at injection site or phlebitis, toxicity of additive to human body, etc. may occur. Therefore, the development of fat emulsion injection of dimercaprol is valuable, while a number of technical problems need to be overcome.
Technical scheme
Dimercaprol fat emulsion injection, which is prepared from the following components:
1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 4-10 g of glycerol, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 1-10 g of sodium oleate, 4-10 g of glycerol, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 1-10 g of oleic acid, 4-10 g of glycerol, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 1-10 g of sodium oleate, 4-10 g of glycerol, 1-10 g of vitamin E, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 1-10 g of oleic acid, 4-10 g of glycerol, 1-10 g of vitamin E, 1-10 g of EDTA, and 850-990 g of water for injection.
1-10 g of dimercaprol, 5-80 g of soybean oil, 5-80 g of medium chain triglyceride, 10-40 g of lecithin, 4-10 g of glycerol, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 5-80 g of soybean oil, 5-80 g of medium chain triglyceride, 10-40 g of lecithin, 1-10 g of sodium oleate, 4-10 g of glycerol, 1-10 g of EDTA, and 850-990 g of water for injection.
1-10 g of dimercaprol, 5-80 g of soybean oil, 5-80 g of medium chain triglyceride, 10-40 g of lecithin, 1-10 g of oleic acid, 4-10 g of glycerol, 1-10 g of EDTA, and 990 g of water for injection.
1-10 g of dimercaprol, 5-80 g of soybean oil, 5-80 g of medium chain triglyceride, 10-40 g of lecithin, 1-10 g of sodium oleate, 4-10 g of glycerol, 1-10 g of vitamin E, 1-10 g of EDTA and 990 g of water for injection.
1-10 g of dimercaprol, 5-80 g of soybean oil, 5-80 g of medium chain triglyceride, 10-40 g of lecithin, 1-10 g of oleic acid, 4-10 g of glycerol, 1-10 g of vitamin E, 1-10 g of EDTA, and 990 g of water for injection.
The lecithin is preferably egg yolk lecithin.
The invention relates to dimercaprol fat emulsion injection, which comprises the following preparation processes:
preparation of a batching system: sterilizing the whole batching system at the high temperature of 115-121 ℃ by using boiling water, removing air in the whole batching system, replacing the air by nitrogen, and repeating the steps for 3-5 times;
preparation of the standby water: adding a proper amount of water for injection into the primary emulsion tank, filling nitrogen to drive oxygen, and keeping the temperature at 25-30 ℃ for later use;
preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing the water for injection in a water phase tank, sterilizing the water for 15min at the high temperature of 115-121 ℃, cooling the water to 25-30 ℃, uniformly mixing the water with standby water through a filter, continuously filling nitrogen to drive oxygen, adding a sodium hydroxide solution, uniformly mixing, and keeping the temperature to 25-30 ℃ for standby;
preparation of oil phase: steam drying an oil phase tank, weighing dimercaprol and soybean oil in the oil phase tank, opening nitrogen to bubble from the bottom, uniformly stirring, heating to 40-60 ℃, slowly adding lecithin under the protection of nitrogen flow, and stirring at a high speed until the lecithin is uniformly dispersed;
preparing a primary emulsion: mixing the oil phase and the water phase according to a certain ratio (1:5-1:20) by an emulsification pump, adding water for injection to full volume, controlling the temperature to be 40-45 ℃, and adjusting the pH value of the primary emulsion to 8.0-8.5 by using sodium hydroxide;
filling nitrogen and filling: filtering the uniform emulsion through a filter, filling the uniform emulsion under the protection of nitrogen flow, and cleaning an infusion bottle, rolling a stopper and sealing the bottle by a conventional method to ensure that the residual oxygen content in the bottle is less than 3 percent; the filtration was through a5 μm microporous membrane.
Rotating and sterilizing: and (4) bottling the emulsion after capping, putting the emulsion into a high-pressure steam rotary sterilization cabinet, and performing hot-pressing rotary sterilization at the temperature of 115-121 ℃ for 30-45 minutes.
The invention relates to dimercaprol fat emulsion injection, which comprises the following preparation processes:
high-pressure homogenization: under the protection of nitrogen flow, the primary emulsion is homogenized between two tanks by a homogenizer under the conditions of certain pressure and temperature, the pressure adopts the primary valve pressure of 150bar and the secondary valve pressure of 500bar, the primary emulsion is repeatedly homogenized for 2-6 times until the pH value of the liquid medicine is 8.0-8.5, the temperature is 40-45 ℃, and the emulsion particles are qualified;
low-pressure homogenization: unloading the primary pressure, adjusting the secondary pressure to 80bar, and cooling to 28-32 ℃ through a heat exchanger.
The invention relates to dimercaprol fat emulsion injection, which comprises the following preparation processes:
preparation of oil phase: steam drying the oil phase tank, weighing dimercaprol, soybean oil, oleic acid or sodium oleate or vitamin E in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 40-60 ℃, slowly adding lecithin under the protection of nitrogen flow, and stirring at high speed until the lecithin is uniformly dispersed.
The process optimization process comprises the following steps:
putting the dimercaprol raw material medicines into a constant temperature box with the temperature of 40-80 ℃, sampling on the 0 th day, the 5 th day and the 10 th day respectively, precisely measuring a proper amount of dimercaprol raw material medicines, and adding methanol to dilute to a solution containing about 0.1mg of propofol per 1 mL. Change in dimercaprol content was determined by HPLC.
Dimercaprol decomposes at a temperature of 40 ℃ to 80 ℃ to generate obviously increased impurities after 65 ℃.
The dimercaprol fat emulsion injection is optimized by using oil types and the using amount (N is 3, X +/-s).
0.4g of dimercaprol and 10-100g of soybean oil for injection.
Dimercaprol 0.4g, and injection medium chain triglyceride 10-100 g.
0.4g of dimercaprol, 5-50g of soybean oil for injection, 5-50g of medium chain triglyceride for injection,
the preparation of the drug-loaded fat emulsion is carried out on the premise that the main drug has a certain solubility in the oil for injection. Otherwise, the stable drug-loaded fat emulsion cannot be prepared. The dimercaprol fat emulsion injection is intended to be a drug-loaded fat emulsion which is stored for a long time and is stable within at least 2 years. Therefore, the oil for injection must have enough solubility and stability to dimercaprol, and the drug loading of the oil for injection needs to be improved.
Optimization of lecithin dosage of dimercaprol fat emulsion injection (N ═ 3, X + -s).
2g of dimercaprol, 45g of soybean oil, 2g of oleic acid, 5g of glycerol, 2-32g of egg yolk lecithin and 500mL of water for injection.
When the content of the yolk lecithin is increased to a certain extent, the particle size of the fat emulsion is not reduced any more and is saturated, and the yolk lecithin is preferably 16g/1000 ml.
Optimization of oleic acid dosage of dimercaprol fat emulsion injection (N ═ 3, X +/-s).
2g of dimercaprol, 45g of soybean oil, 0.5-8g of oleic acid, 5g of glycerol, 8g of egg yolk lecithin and water for injection added to 500 mL.
When the content of oleic acid is increased to a certain extent, the particle size of the fat emulsion is not reduced any more and is saturated, and the oleic acid is preferably 4g/1000 ml.
The prescription of dimercaprol fat emulsion injection is optimized.
The influence of the stabilizer and the antioxidant on the dimercaprol fat emulsion injection is researched and discussed by evaluating indexes such as appearance, particle size and the like through a single-factor experiment.
2g of dimercaprol, 45g of soybean oil, 2g of oleic acid, 5g of glycerol, 8g of egg yolk lecithin, EDTA (0-4g), VE (0-4g) and water for injection to 500 mL. Quality evaluation was conducted after leaving at 40 ℃ for 10 days.
Preference of homogenization pressure
The raw materials of the liquid medicine comprise 2g of dimercaprol, 45g of soybean oil, 2g of oleic acid, 5g of glycerol, 8g of yolk lecithin, EDTA2g, VE2g and 500mL of water for injection.
High-pressure homogenization: under the protection of nitrogen flow, the primary emulsion is homogenized by adjusting certain pressure and temperature between two tanks through a homogenizer, the pressure adopts primary valve pressure (100, 150 and 200) bar and secondary valve pressure (500, 550 and 600) bar, the primary emulsion is repeatedly homogenized for 3 times until the pH value of the liquid medicine is 8.0-8.5, the temperature is 40-45 ℃, and the emulsion particles are qualified;
the pressure optimization is carried out on 500mL9 g of primary emulsion, and the evaluation indexes comprise: the percentage of particles with the particle size of more than 200 nm and 300nm in the particles with the particle size of more than 100nm is used.
Optimization of homogenization temperature and times
The liquid medicine consists of dimercaprol 2g, soybean oil 45g, oleic acid 2g, glycerin 5g, yolk lecithin 8g, EDTA2g, VE2g and water for injection added to 500 mL.
High-pressure homogenization: under the protection of nitrogen flow, the primary emulsion is homogenized by adjusting certain pressure and temperature between two tanks through a homogenizer, the pressure adopts primary valve pressure of 150bar and secondary valve pressure of 500bar, the primary emulsion is repeatedly homogenized for 2, 3 and 4 times until the pH value of the liquid medicine is 8.0-8.5 and the temperature is (35, 40, 45, 50 and 55) DEG C, and the emulsion particles are qualified;
the pressure optimization is carried out on 500mL9 g of primary emulsion, and the evaluation indexes comprise: the percentage of particles with the particle size of more than 200 nm and 300nm in the particles with the particle size of more than 100nm is used.
Detailed description of the preferred embodiments
Example 1
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 45g of soybean oil, 20 g of egg yolk lecithin, 10 g of glycerin, 5g of EDTA and 100g of water for injection.
Preparation of a batching system: sterilizing the whole batching system at 115 ℃ by boiling water, removing air in the whole batching system, replacing the air by nitrogen, and repeating the steps for 3 times;
preparation of the standby water: adding appropriate amount of water for injection into the primary emulsion tank, charging nitrogen gas to drive out oxygen, and keeping the temperature at 2530 ℃ for later use;
preparation of the aqueous phase: placing 10% of water for injection and glycerol in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuously introducing nitrogen gas to remove oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C;
preparation of oil phase: steam drying the oil phase tank, weighing dimercaprol and soybean oil in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding egg yolk lecithin under the protection of nitrogen flow, and stirring at high speed until the egg yolk lecithin is uniformly dispersed;
preparing a primary emulsion: mixing the oil phase and the water phase at a certain ratio (1:15) by an emulsification pump, adding water for injection to full volume, controlling the temperature at 45 ℃, and adjusting the pH value of the primary emulsion to 8.2 by using sodium hydroxide;
high-pressure homogenization: under the protection of nitrogen flow, the primary emulsion is homogenized between two tanks by a homogenizer under the conditions of certain pressure and temperature, the pressure adopts a primary valve pressure of 150bar and a secondary valve pressure of 500bar, the primary emulsion is repeatedly homogenized for 3 times until the pH value of the liquid medicine is 8.0, the temperature is 45 ℃, and the emulsion particles are qualified;
low-pressure homogenization: the primary pressure is unloaded, the secondary pressure is adjusted to 80bar, and the temperature is reduced to 28 ℃ by a heat exchanger.
Filling nitrogen and filling: filtering the uniform emulsion through a filter, filling the uniform emulsion under the protection of nitrogen flow, and cleaning an infusion bottle, rolling a stopper and sealing the bottle by a conventional method to ensure that the residual oxygen content in the bottle is less than 3 percent; the filtration was through a5 μm microporous membrane.
Rotating and sterilizing: after capping, bottling the emulsion, placing the emulsion in a high-pressure steam rotary sterilization cabinet, and performing rotary sterilization at 115 ℃ for 30 minutes.
Example 2
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 45g of soybean oil, 20 g of yolk lecithin, 5g of sodium oleate, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying the oil phase tank, weighing dimercaprol, soybean oil and sodium oleate into the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding yolk lecithin under the protection of nitrogen flow, and stirring at high speed until the yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 3
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 45g of soybean oil, 20 g of egg yolk lecithin, 5g of oleic acid, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying the oil phase tank, weighing dimercaprol, soybean oil and oleic acid in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding egg yolk lecithin under the protection of nitrogen flow, and stirring at a high speed until the egg yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 4
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 45g of soybean oil, 20 g of yolk lecithin, 5g of sodium oleate, 5g of vitamin E, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying oil phase tank, weighing dimercaprol, soybean oil, sodium oleate and vitamin E in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding yolk lecithin under the protection of nitrogen flow, and stirring at high speed until the yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 5
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 45g of soybean oil, 20 g of egg yolk lecithin, 5g of oleic acid, 5g of vitamin E, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying the oil phase tank, weighing dimercaprol, soybean oil, oleic acid and vitamin E in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding yolk lecithin under the protection of nitrogen flow, and stirring at high speed until the yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 6
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 20 g of soybean oil, 25 g of medium chain triglyceride, 20 g of egg yolk lecithin, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying oil phase tank, weighing dimercaprol, soybean oil and medium chain triglyceride, placing in oil phase tank, opening nitrogen gas, bubbling from bottom, stirring, heating to 45 deg.C, slowly adding yolk lecithin under protection of nitrogen gas flow, and stirring at high speed until yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 7
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 20 g of soybean oil, 25 g of medium chain triglyceride, 20 g of yolk lecithin, 5g of sodium oleate, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying oil phase tank, weighing dimercaprol, soybean oil, medium chain triglyceride, sodium oleate, placing in oil phase tank, opening nitrogen gas, bubbling from bottom, stirring, heating to 45 deg.C, slowly adding yolk lecithin under protection of nitrogen gas flow, and stirring at high speed until yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 8
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 20 g of soybean oil, 25 g of medium chain triglyceride, 20 g of egg yolk lecithin, 5g of oleic acid, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying oil phase tank, weighing dimercaprol, soybean oil, medium chain triglyceride and oleic acid, placing in oil phase tank, opening nitrogen gas, bubbling from bottom, stirring, heating to 45 deg.C, slowly adding yolk lecithin under protection of nitrogen gas flow, and stirring at high speed until yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 9
The dimercaprol fat emulsion injection comprises 5g of dimercaprol, 20 g of soybean oil, 25 g of medium chain triglyceride, 20 g of egg yolk lecithin, 5g of oleic acid, 5g of vitamin E, 10 g of glycerol, 5g of EDTA and 100g of water for injection.
Preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing in a water phase tank, sterilizing at 115 deg.C for 15min, cooling to 25 deg.C, mixing with water for standby through a filter, continuing to fill nitrogen gas to drive oxygen, adding sodium hydroxide solution, mixing, and keeping the temperature to 25 deg.C for standby;
preparation of oil phase: steam drying oil phase tank, weighing dimercaprol, soybean oil, medium chain triglyceride, oleic acid and vitamin E in the oil phase tank, opening nitrogen to bubble from the bottom, stirring uniformly, heating to 45 ℃, slowly adding egg yolk lecithin under the protection of nitrogen flow, and stirring at high speed until the egg yolk lecithin is uniformly dispersed;
the rest of the preparation steps are the same as example 1.
Example 10
The fat emulsion injection disclosed by the invention has good stability and clinical safety, the long-chain fat emulsion injection (C8-24) disclosed by the invention is prepared according to the examples 1-10, and the sterilization condition is that hot-pressing rotary sterilization is carried out for 35min at 117 ℃, so that the product 1-10 disclosed by the invention is obtained. Placing the mixture in a room temperature environment, respectively placing the mixture for 3, 6, 12 and 24 months immediately after placing, sampling and testing, observing the properties of the mixture, and determining the pH value, the content of milk particles, the sterile medium chain triglyceride, the fat content, the lysophospholipid and the dimercaprol value, wherein the test results are as follows:
after the fat emulsion injection is stored for 24 months at room temperature, the product properties are not changed.
The milk particles are smaller and more uniform. No emulsion particles with the particle size of more than 500nm exist, and more than 98% of the emulsion particles with the particle size of 200-300nm exist. The microorganisms are all qualified. The content of soybean oil and medium chain triglyceride is basically unchanged compared with the initial storage. The lysophospholipid content and dimercaprol were not substantially changed from the initial storage period.
The results of the allergy test of the products 1 to 10 of the invention are negative. The results of the hemolytic tests of the products 1-10 of the invention are negative. The intravenous drip of the product 1-10 of the invention has no obvious vascular stimulation.
Claims (1)
1. The dimercaprol fat emulsion injection is characterized in that: the composition consists of the following components: 1-10 g of dimercaprol, 20-50 g of soybean oil, 10-40 g of lecithin, 1-10 g of oleic acid, 4-10 g of glycerol, 1-10 g of EDTA (ethylene diamine tetraacetic acid), 850-990 g of water for injection,
preparation of a batching system: sterilizing the whole batching system at the high temperature of 115-121 ℃ by using boiling water, removing air in the whole batching system, replacing the air by nitrogen, and repeating the steps for 3-5 times;
preparation of the standby water: adding a proper amount of water for injection into the primary emulsion tank, filling nitrogen to drive oxygen, and keeping the temperature at 25-30 ℃ for later use;
preparation of the aqueous phase: taking 10% of water for injection, glycerol and EDTA, placing the water for injection in a water phase tank, sterilizing the water for 15min at the high temperature of 115-121 ℃, cooling the water to 25-30 ℃, uniformly mixing the water with standby water through a filter, continuously filling nitrogen to drive oxygen, adding a sodium hydroxide solution, uniformly mixing, and keeping the temperature to 25-30 ℃ for standby;
preparation of oil phase: steam drying an oil phase tank, weighing dimercaprol, soybean oil and oleic acid in the oil phase tank, opening nitrogen to bubble from the bottom, uniformly stirring, heating to 40-60 ℃, slowly adding lecithin under the protection of nitrogen flow, and stirring at a high speed until the lecithin is uniformly dispersed;
preparing a primary emulsion: mixing the oil phase and the water phase according to a certain proportion through an emulsification pump, supplementing the injection water to the full amount, controlling the temperature to be 40-45 ℃, and adjusting the pH value of the primary emulsion to 8.0-8.5 by using sodium hydroxide;
high-pressure homogenization: under the protection of nitrogen flow, regulating pressure and temperature of the primary emulsion between the two tanks by a homogenizer, homogenizing for 3 times under the pressure of 150bar of a primary valve and 500bar of a secondary valve until the pH value of the liquid medicine is 8.0-8.5, the temperature is 40-45 ℃, and the milk particles are qualified;
low-pressure homogenization: unloading the primary pressure, adjusting the secondary pressure to 80bar, and cooling to 28-32 ℃ through a heat exchanger;
filling nitrogen and filling: filtering the uniform emulsion through a filter, filling the uniform emulsion under the protection of nitrogen flow, and cleaning an infusion bottle, rolling a stopper and sealing the bottle by a conventional method to ensure that the residual oxygen content in the bottle is less than 3 percent; the filtration is carried out by a5 mu m microporous membrane;
rotating and sterilizing: after capping, bottling the emulsion, putting the emulsion into a high-pressure steam rotary sterilization cabinet, and performing hot-pressing rotary sterilization at the temperature of 115-121 ℃ for 30-45 minutes;
the lecithin is egg yolk lecithin.
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| JPS61255353A (en) * | 1985-05-08 | 1986-11-13 | Kao Corp | Toner for developing electrostatic charge image |
| CN1502335A (en) * | 2002-11-21 | 2004-06-09 | 安徽省安泰医药生物技术有限责任公司 | Application of Netilmicin sulfate in preparation of eye drops |
| CN102083415A (en) * | 2008-04-18 | 2011-06-01 | 纳米生物公司 | Methods for treating herpes virus infections |
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| 二巯基丙醇注射液的试制;程楷;《药学通报》;19571231;第5卷(第5期);第222页左栏第9-21行 * |
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