CN116077438A - Preparation method of fat emulsion - Google Patents
Preparation method of fat emulsion Download PDFInfo
- Publication number
- CN116077438A CN116077438A CN202111310531.7A CN202111310531A CN116077438A CN 116077438 A CN116077438 A CN 116077438A CN 202111310531 A CN202111310531 A CN 202111310531A CN 116077438 A CN116077438 A CN 116077438A
- Authority
- CN
- China
- Prior art keywords
- oil
- water
- phase
- homogenizing
- emulsion
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61K47/14—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
- A61K47/44—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
- A61K9/0012—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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Dermatology (AREA)
- Colloid Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a preparation method of fat emulsion, and the emulsion prepared by the method has good emulsion particle uniformity, high stability and improved product quality. The preparation method provided by the invention is simple to operate, stable and controllable in process and suitable for industrial mass production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of fat emulsion.
Background
The long-chain fat emulsion injection (OO) is an oil-in-water (O/W) emulsion prepared by taking soybean oil and olive oil as oil phases and adding a phospholipid emulsifier, an isotonic agent and water for injection. Long chain fat emulsion injection was first marketed in europe in 1996 and was approved by the import of our country in 2006 under the trade name "gram Ling Nuo". The fat emulsion injection is one of sources of energy in parenteral nutrition and can also provide essential fatty acids. The long-chain fat emulsion injection also has the characteristics of good safety and no irritation to veins.
Long-chain fat emulsion injection (OO) belongs to submicron emulsion, is a thermodynamically unstable system, and can show various unstable phenomena such as aggregation, flocculation and the like. The Ostwald ripening phenomenon is one of the causes of unstable fat emulsion, the fat emulsion has the advantages that the emulsion drops have a small emulsion drop absorption effect due to the fact that the fat emulsion drops are not large, the small emulsion drops are filled between the large emulsion drops, aggregation of the emulsion drops is caused, and then the emulsion drops are combined, so that quality problems of exceeding of the large emulsion drops and emulsion layering occur in the shelf life of the fat emulsion.
In order to ensure the stability of long-chain fat emulsion injection (OO) in shelf life, the uniformity of particles in the emulsion should be improved as much as possible. The existing preparation technology of the product is to mix olive oil and soybean oil with auxiliary materials such as lecithin, glycerol, sodium oleate and the like, then add water for injection to the prescription amount, and obtain emulsion after emulsification and homogenization. Patent application CN201210131479.3 discloses a preparation method of fat emulsion, comprising the following steps: (1) Adding appropriate amount of injectable water into a preparation tank, adding glycerol, stirring to dissolve, adding appropriate amount of 1mol/L sodium hydroxide solution, filtering with 0.2 μm filter membrane, heating to 50-90deg.C, adding lecithin, and stirring to disperse uniformly; (2) Filtering soybean oil with 0.45 μm filter membrane, heating to 50-90deg.C, mixing soybean oil and lecithin, stirring to form primary emulsion, adding injectable water to the amount, stirring, filtering with 40 μm filter membrane, emulsifying for 6-7 times with high pressure homogenizer, and discharging emulsion in a diluting tank; (3) After regulating the pH value, checking the semi-finished product, filtering by a 10 mu m filter membrane, filling nitrogen, filling and capping; (4) Sterilizing the emulsion-filled infusion bottle in a rotary autoclave at 100-122 deg.C for 10-30 min, inspecting with a lamp, and packaging to obtain the final product. The method comprises the steps of adding water for injection to a prescription amount and homogenizing to obtain fat emulsion with wide particle distribution and poor emulsion stability.
In order to improve the uniformity of milk particles in long-chain fat emulsion injection (OO), the inventors of the present application studied how to reduce the SPAN value of long-chain fat emulsion injection (OO) by using the SPAN value as a detection index of uniformity. The inventors tried a method of adjusting the homogenization pressure. The results show that with varying homogenization pressure, the particle size of the particles changed, but the SPAN value did not change significantly. The inventors also tried to adjust the number of homogenization, and found that the particle size of milk particles became smaller with increasing number of homogenization, but the effect on the SPAN value was not significant. In the research process, the inventor finds that if part of water phase is firstly measured and mixed with the prescription amount of oil phase, and colostrum which is prepared by low-pressure homogenization and has the weight of the oil-water mixed phase accounting for about 70 percent of the total volume is prepared, then the rest water for injection is finally supplemented by a homogenization method of firstly homogenizing the emulsion and finally homogenizing, and the SPAN value is obviously reduced through detection of the emulsion prepared by the method.
Disclosure of Invention
In order to solve the problem of poor uniformity of particle size distribution of fat emulsion, the invention provides a preparation method of fat emulsion, and the fat emulsion preparation prepared by the method has good uniformity of particle size and stable product quality.
The invention provides a preparation method of fat emulsion, which comprises the following steps:
(1) Preparing an oil phase: taking grease and heating to obtain an oil phase;
(2) Preparing an aqueous phase: taking water for injection, and heating to obtain a water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65-75% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk;
(5) Homogenizing finally;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to the preparation amount, and uniformly stirring to obtain the fat emulsion.
In some embodiments, the grease is selected from one or more of vegetable oil, fish oil; in some embodiments, the grease is soybean oil and olive oil; in some embodiments, the grease is soybean oil, medium chain triglycerides, olive oil, and fish oil; in some embodiments, the lipid is fish oil.
In some embodiments, the fish oil is fish oil triglycerides.
In some embodiments, step (1) is heated to 55-75 ℃; in some embodiments, step (1) is heated to 60-70 ℃.
In some embodiments, further comprising adding glycerol in step (2).
In some embodiments, heating to 50-80 ℃ in step (2); in some embodiments, the heating in step (2) is to 55-75 ℃.
In some embodiments, step (3) provides colostrum by a homogenization procedure, wherein the homogenization conditions are: homogenizing under 40-70bar at 50-70deg.C for 1-3 times; in some embodiments, the homogenization conditions of step (3) are: the homogenizing pressure is 60-70bar, homogenizing temperature is 55-65deg.C, and homogenizing times are 1-3 times.
In some embodiments, the weight of the oil-water mixed phase in step (3) is 65% (w/v) of the total formulated volume.
In some embodiments, the homogenization temperature in step (4) is 50-70 ℃.
In some embodiments, the homogenizing pressure in step (4) is 350-650bar for the primary valve and 40-120bar for the secondary valve; in some embodiments, the homogenizing pressure in step (4) is 380-400bar for the primary valve and 50-70bar for the secondary valve; in some embodiments, the homogenizing pressure in step (4) is 400-600bar for the primary valve and 40-70bar for the secondary valve; in some embodiments, the homogenizing pressure in step (4) is between 450 and 600bar for the primary valve and 50 and 70bar for the secondary valve.
In some embodiments, the number of homogenizations in step (4) is 3-8; in some embodiments, the number of homogenizations in step (4) is 5-8.
In some embodiments, the homogenization temperature in step (5) is 50-70 ℃; in some embodiments, the homogenizing pressure in step (5) is 200-350bar for the primary valve and 20-40bar for the secondary valve; in some embodiments, the homogenizing pressure in step (5) is 250-350bar for the primary valve and 20-40bar for the secondary valve;
in some embodiments, step (5) is performed for a number of homogenizations of 1-5 times; in some embodiments, the number of homogenizations of step (5) is 2-5.
In some embodiments, further comprising adding lecithin in step (1) or step (2).
In some embodiments, further comprising adding sodium oleate in step (1) or step (2).
In some embodiments, further comprising adjusting the pH to 7.5-9.0 after step (6).
Further, the invention provides a preparation method of the fat emulsion, which comprises the following steps:
(1) Preparing an oil phase: taking grease and heating to obtain an oil phase;
(2) Preparing an aqueous phase: taking glycerol, adding water for injection, heating and dissolving to obtain a water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65-75% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk: the homogenizing pressure is 350-650bar for the primary valve and 40-120bar for the secondary valve;
(5) Final homogenization: the homogenizing pressure is 200-350bar of the primary valve and 20-40bar of the secondary valve;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to the preparation amount, and uniformly stirring to obtain the fat emulsion.
In some embodiments, the homogenizing pressure in step (4) is between 450 and 600bar for the primary valve and between 50 and 70bar for the secondary valve; in some embodiments, the homogenizing pressure in step (5) is 250-350bar for the primary valve and 20-40bar for the secondary valve.
Further, the invention provides a preparation method of the fat emulsion, which comprises the following steps:
(1) Preparing an oil phase: taking grease and heating to obtain an oil phase;
(2) Preparing an aqueous phase: taking glycerol, adding water for injection, heating and dissolving to obtain a water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65-75% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk: homogenizing pressure is 400-600bar of the primary valve, 40-70bar of the secondary valve, homogenizing temperature is 50-70 ℃, and homogenizing times are 5-8 times;
(5) Final homogenization: the homogenizing pressure is 200-350bar for the first-stage valve, 20-40bar for the second-stage valve, the homogenizing temperature is 50-70 ℃, and the homogenizing times are 2-5 times;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to the preparation amount, and uniformly stirring to obtain the fat emulsion.
Further, the invention provides a preparation method of the fat emulsion, which comprises the following steps:
(1) Preparing an oil phase: heating oil of formula amount to 55-75deg.C to obtain oil phase, wherein the oil is one or two of soybean oil and olive oil;
(2) Preparing an aqueous phase: adding water for injection into glycerol, heating to 60-70deg.C for dissolution to obtain water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk: the homogenizing pressure is 500-600bar for the first-stage valve, 55-70bar for the second-stage valve, the homogenizing temperature is 50-70 ℃, and the homogenizing times are 5-8 times;
(5) Final homogenization: the homogenizing pressure is 300-350bar of the primary valve, 20-40bar of the secondary valve, the homogenizing temperature is 50-70 ℃, and the homogenizing times are 2-5 times;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to a preparation amount, and uniformly stirring to obtain fat emulsion;
(7) Filling fat emulsion into an infusion bottle, adding a plug and a rolling cover after nitrogen filling, and preserving heat for 12 min at 121 ℃ in a rotary sterilization cabinet.
Description of the terms
The "% (w/v)" in the present invention is one of the ways of characterizing the content, which is understood in the art, as a weight volume percentage.
The term "primary valve" pressure as used herein refers to the pressure of the primary valve and not the total pressure; the "secondary valve" pressure refers to the pressure value of the secondary valve.
The SPAN (diameter distance) value is equal to (D90-D10)/D50, and represents the dispersion degree of the emulsion particles, and the smaller the value is, the better the dispersion degree is.
The invention has the beneficial effects that:
(1) The preparation method of the fat emulsion provided by the invention can prepare the fat emulsion with good particle uniformity, and improves the quality and stability of the product.
(2) The preparation method of the fat emulsion is suitable for preparing various fat emulsions, and emulsion with good uniformity can be obtained without homogenizing again after water supplementing, and the preparation method is simple and stable in process, good in repeatability, controllable in quality and suitable for industrial production.
Detailed Description
For further explanation of the present invention and to facilitate understanding of the present invention, only some examples are provided and described in detail. It will be appreciated by those skilled in the art that the following examples are not intended to limit the scope of the invention.
The SPAN value detection method comprises the following steps: taking fat milk product, and checking according to particle size and particle size distribution measurement method (third method of Chinese pharmacopoeia 2020 edition rule 0982), according to law (using laser scattering particle size analyzer based on Mie scattering theory, such as Mastersize r MS2000; recommended parameters are absorptivity 0, 0.001 or 0.01, refractive index 1.47-1.52, light shielding degree 5% -10%, or other suitable instrument).
Experiment 1
The inventors prepared emulsions using prior art methods of preparation.
Taking about 160g of olive oil and about 40g of soybean oil, adding 12g of lecithin, heating to 65 ℃, and shearing to disperse the lecithin in an oil phase; adding 22.5g of glycerol and 0.3g of sodium oleate into a proper amount of water for injection, stirring and dissolving, and heating to 60 ℃; after mixing and stirring the oil phase and the water phase, adding water for injection to 1000mL (100% of the total volume of the preparation), homogenizing once to obtain colostrum, wherein the homogenizing pressure is 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 550bar for the primary valve, 60bar for the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. Adjusting the pH to 7.5-8.0 to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.47.
Experiment 2
The inventors tried to change the homogenization conditions on the basis of the prior art and add the homogenization step.
About 160g of olive oil and about 40g of soybean oil are taken, 12g of lecithin is added, and the mixture is heated to 65 ℃ and sheared to disperse the lecithin in an oil phase; adding 22.5g of glycerol and 0.3g of sodium oleate into a proper amount of water for injection, stirring and dissolving, and heating to 70 ℃; after mixing and stirring the oil phase and the water phase, adding water for injection to 1000mL (100% of the total volume of the preparation), homogenizing once to obtain colostrum, wherein the homogenizing pressure is 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 590bar of the primary valve, 60bar of the secondary valve, the homogenizing temperature is 55 ℃, and the homogenizing times are 5 times. The homogenization pressure was adjusted to 300bar for the primary valve and 30bar for the secondary valve, and the number of homogenization was 2. Adjusting the pH to 7.5-8.0 to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.32.
Experiment 3
The inventor mixes part of water phase with the oil phase with prescription amount to prepare colostrum, and then obtains emulsion through the steps of water supplementing and homogenizing.
About 160g of olive oil and about 40g of soybean oil are taken, 12g of lecithin is added, and the mixture is heated to 65 ℃ and sheared to disperse the lecithin in an oil phase; adding 465g of glycerin and 0.3g of sodium oleate into water for injection to dissolve to obtain a water phase, stirring and dissolving, and heating to 60 ℃; mixing and stirring the oil phase and the water phase to obtain 700g of oil-water mixed phase, heating to 70 ℃ after stirring and dissolving, and homogenizing for one time to obtain the colostrum, wherein the homogenizing pressure is 60bar. Water for injection was added to 1000mL (100% of the total volume formulated). The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 590bar of the primary valve, 60bar of the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. The homogenization pressure was adjusted to 300bar for the primary valve and 30bar for the secondary valve, and the number of homogenization was 2. Adjusting the pH to 7.5-8.0 to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.31.
Experiment 4
The inventors studied the manner of adding the aqueous phase and the order of water replenishment and homogenization based on experiment 3.
About 160g of olive oil and about 40g of soybean oil are taken, 12g of lecithin is added, and the mixture is heated to 65 ℃ and sheared to disperse the lecithin in an oil phase; adding a proper amount of water for injection into 22.5g of glycerol and 0.3g of sodium oleate to dissolve to obtain a water phase, stirring and dissolving, and heating to 60 ℃; mixing the oil phase and the water phase, stirring, adding water for injection until the oil-water mixture is 700g, stirring and dissolving, heating to 70deg.C, homogenizing under low pressure for 1 time to obtain colostrum, and homogenizing under 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 590bar of the primary valve, 60bar of the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. Adding water for injection to 1000mL (100% of total volume), homogenizing after uniform mixing, wherein the homogenization conditions are as follows: the pressure was 200bar for the primary valve, 30bar for the secondary valve and the number of homogenizations was 2. Adjusting the pH to 7.5-8.0 to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.28.
Experiment 5
To further reduce the SPAN value, the inventors have intensively studied the homogeneous mode of operation.
About 160g of olive oil and about 40g of soybean oil are taken, 12g of lecithin is added, and the mixture is heated to 65 ℃ and sheared to disperse the lecithin in an oil phase; adding a proper amount of water for injection into 22.5g of glycerol and 0.3g of sodium oleate to dissolve to obtain a water phase, stirring and dissolving, and heating to 60 ℃; mixing the oil phase and the water phase, stirring, adding water for injection until the oil-water mixture is 700g, stirring and dissolving, heating to 70deg.C, homogenizing under low pressure for 1 time to obtain colostrum, and homogenizing under 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 590bar of the primary valve, 60bar of the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. Adding water for injection to 1000mL (100% of the total volume of the preparation), stirring and mixing uniformly, and regulating pH to 7.5-8.0 to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.30.
Example 1
The inventors further studied the preparation method to obtain an emulsion with significantly improved SPAN value.
About 160g of olive oil and about 40g of soybean oil are taken, 12g of lecithin is added, and the mixture is heated to 65 ℃ and sheared to disperse the lecithin in an oil phase; adding 465g of glycerin and 0.3g of sodium oleate into water for injection to dissolve to obtain a water phase, stirring and dissolving, and heating to 60 ℃; mixing and stirring the oil phase and the water phase to obtain 700g of oil-water mixed phase (70% of the total volume of the preparation), and heating to 70 ℃ after stirring and dissolving; homogenizing to obtain colostrum at homogenizing pressure of 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 590bar of the primary valve, 60bar of the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. The homogenization pressure was adjusted to 200bar for the primary valve and 30bar for the secondary valve, and the number of homogenization was 2. Adding water for injection to 1000mL (100% of the total volume of the preparation) into the homogenized emulsion, stirring and mixing uniformly, and adjusting the pH to 7.5-8.0 if necessary to obtain uniform emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the long-chain fat emulsion injection (OO). The SPAN value was 1.08.
The test results of example 1 and experiment 4 demonstrate that the SPAN value of the emulsion can be significantly reduced by preparing the emulsion according to the preparation method of example 1. The technical solution of the present invention unexpectedly reduces the SPAN value of the fat emulsion. The reason for this is probably that the repeated redistribution of emulsion particle size and hence the reduction of SPAN value are affected by the water addition mode adopted in experiment 4 and the emulsion preparation mode of homogenizing first and then fixing the volume and finally homogenizing. In contrast to experiment 4, example 1 used a different water addition and homogenization method, wherein a final homogenization step was added after homogenization, and the milk particles had a certain "modification" effect, resulting in a better particle size distribution. In addition, the technical scheme of the invention completes the homogenization operation before water supplementing, and compared with the operation of homogenizing, constant volume and re-homogenizing in experiment 4, the method can obviously reduce the emulsion amount in the homogenization procedure, shorten the homogenization time, improve the homogenization efficiency, reduce the production cost and is more beneficial to industrialized mass production.
Examples 2 to 5
The inventors further examined the effect of the ratio of the weight of the oil-water mixed phase to the total volume of the formulation on the SPAN value of the emulsion. According to the preparation method in the example 1, different proportions of formulas of oil-water mixed phase weight accounting for total volume of the preparation are prepared, and SPAN values of the formulas are detected. The following are results of SPAN value detection of the emulsion when the weight ratio of the oil-water mixed phase to the total volume of the preparation is 60% (example 2), 65% (example 3), 75% (example 4) and 80% (example 5), respectively:
TABLE 1 influence of oil-Water mixture phase ratio on SPAN value
The SPAN value test results of examples 1-5 show that the SPAN value of the emulsion is obviously reduced when the weight of the oil-water mixed phase is 65-75% of the total volume of the preparation by using the preparation method of the invention. This is probably because the operation of homogenizing the emulsion first and then homogenizing the emulsion finally is favorable for the redistribution of the particle size, and the improvement of the SPAN value can be effectively realized, so that a qualified product is obtained. In the research, it is found that the SPAN value can not be effectively improved by only adopting the emulsion homogenizing, the average particle size of the emulsion can not meet the requirement by adopting the final homogenizing, and meanwhile, under the preparation method of the invention, the homogenizing pressure and the homogenizing times of the emulsion homogenizing and the final homogenizing also directly influence the SPAN value of the emulsion. On the other hand, when the weight of the oil-water mixed phase is more than 75% of the total volume of the preparation, the phospholipid concentration in the oil-water mixed phase is relatively reduced, the emulsification effect is affected, and the volume of the oil-water phase is increased, so that the emulsion amount in the homogenizing process is increased, the homogenizing time is increased, and the production time is prolonged; when the weight of the oil-water mixed phase is less than 65% of the total volume of the preparation, the concentration of the preparation liquid is increased, the number of emulsion particles in unit volume is increased, the collision probability of the emulsion particles is increased, the uniformity of particles is poor, and the SPAN value is not obviously improved. Meanwhile, as the concentration of the preparation liquid is increased and the viscosity is increased, the fluidity of the emulsion is also poor, which is unfavorable for production operation. In addition, the SPAN value of the product prepared by the preparation method disclosed by the invention is consistent with the SPAN value of gram Ling Nuo of the original ground product, so that the consistency between the imitated medicine and the original ground medicine is ensured, and the quality of the product is improved.
Examples 6 to 10
To examine the durability of the resulting preparation, the inventors adjusted the prescribed amounts and preparation parameters of the preparation in example 1 and examined the SPAN value of the emulsion obtained. The results of the investigation are shown in the following table
Table 2 results of preparation method tolerability investigation
Experimental results show that the SPAN values of the emulsions prepared in examples 6-10 are obviously reduced.
Example 11
The preparation method disclosed by the invention can also solve the problem of uniformity of particle sizes of other types of fat emulsion injection, and the fat emulsion with a low SPAN value is obtained. The inventor prepares omega-3 fish oil fat emulsion injection, and the prescription is as follows:
the preparation method comprises the following parameters:
| preparation method | Parameters (parameters) |
| Oil phase temperature | 65℃ |
| Temperature of aqueous phase | 60℃ |
| Temperature of oil-water mixed phase | 60℃ |
| Homogenizing pressure of colostrum | 60bar |
| Homogenizing pressure of milk | First-stage valve 390bar and second-stage valve 60bar |
| Number of homogenization | 6 times |
| Final homogenizing pressure | The primary valve 270bar and the secondary valve 30bar |
| Number of homogenization | 2 times |
| Homogenizing temperature | 55℃ |
| pH value of | 8.0-8.7 |
| Sterilization conditions | Sterilizing at 121deg.C for 12 min |
The preparation method comprises the following steps:
taking 100g of fish oil triglyceride, adding 12g of lecithin, heating to 65 ℃, and shearing to disperse the lecithin in an oil phase; 25g of glycerin and 0.3g of sodium oleate are taken, 563g of water for injection is added to dissolve to obtain a water phase, the water phase is heated to 60 ℃ after stirring and dissolving, the oil phase and the water phase are mixed and stirred to obtain 700g of oil-water mixed phase (70% of the total volume of the preparation), the temperature is kept at 60 ℃ after stirring and dissolving, and the primary emulsion is obtained after homogenizing once, and the homogenizing pressure is 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure was 390bar for the primary valve, 60bar for the secondary valve, the homogenizing temperature was 55deg.C, and the number of homogenizing times was 6. The homogenization pressure was adjusted to 270bar for the primary valve, 30bar for the secondary valve, and the number of homogenization was 2. Adding water for injection to 1000mL (100% of the total volume of the preparation) into the homogenized emulsion, stirring and mixing uniformly, and adjusting the pH to 8.0-8.7 if necessary to obtain emulsion; filling the emulsion into a glass infusion bottle, adding a plug after filling nitrogen, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain the omega-3 fish oil fat emulsion injection. The SPAN value was 1.15.
Example 12
The inventor prepares various oil-fat emulsion injection with the following prescription:
| prescription composition | Prescription dosage |
| Soybean oil | 60g |
| Medium chain triglycerides | 60g |
| Olive oil | 50g |
| Fish oil triglyceride | 30g |
| Lecithin | 12g |
| Glycerol | 25g |
| Oleic acid sodium salt | 0.3g |
| Water for injection | Constant volume to 1000mL |
The preparation method comprises the following parameters:
| preparation method | Parameters (parameters) |
| Oil phase temperature | 65℃ |
| Temperature of aqueous phase | 70℃ |
| Temperature of oil-water mixed phase | 70℃ |
| Homogenizing pressure of colostrum | 60bar |
| Homogenizing pressure of milk | Primary valve 600bar and secondary valve 60bar |
| Number of homogenization | 6 times |
| Final homogenizing pressure | The primary valve is 300bar and the secondary valve is 30bar |
| Number of homogenization | 2 times |
| Homogenizing temperature | 60℃ |
| pH value of | 8.0-8.7 |
| Sterilization conditions | Sterilizing at 121deg.C for 12 min |
The preparation method comprises the following steps:
60g of soybean oil, 60g of medium-chain triglyceride, 50g of olive oil and 30g of fish oil triglyceride, adding 12g of lecithin, heating to 65 ℃, and shearing to disperse the lecithin in an oil phase; 25g of glycerin and 0.3g of sodium oleate are added into 513g of water for injection to be dissolved to obtain a water phase, the water phase is heated to 70 ℃ after stirring and dissolution, the oil phase and the water phase are mixed and stirred to obtain 750g of oil-water mixed phase (75% of the total volume is prepared), the temperature is kept at 70 ℃ after stirring and dissolution, primary emulsion is obtained after homogenizing once, and the homogenizing pressure is 60bar. The primary emulsion is passed through a homogenizer under the following homogenization conditions: the homogenizing pressure is 600bar for the primary valve, 60bar for the secondary valve, the homogenizing temperature is 60 ℃, and the homogenizing times are 6 times. The homogenization pressure was adjusted to 300bar for the primary valve and 30bar for the secondary valve, and the number of homogenization was 2. Adding water for injection to 1000mL (100% of the total volume of the preparation) into the homogenized emulsion, stirring and mixing uniformly, and adjusting the pH to 8.0-8.7 if necessary to obtain emulsion; filling the emulsion into a glass infusion bottle, adding nitrogen, adding a plug, rolling a cover, and sterilizing in a rotary sterilizing cabinet at 121 ℃ for 12 minutes to obtain various oil-fat emulsion injection. The SPAN value was found to be 0.98.
Example 13
The emulsions prepared in examples 1-5 and 11-12 were subjected to stability studies according to the rules of drug stability tests in the guidelines for the study of chemical drug stability. Aiming at the technical effect of improving the uniformity of emulsion particles of the fat emulsion injection, the inventor examines the stability change of emulsion in the long-term (temperature 25+/-2 ℃ and humidity 60+/-5%) placing process, such as emulsion layering and other phenomena, and the test results are as follows:
TABLE 3 results of fat emulsion stability test
The stability test result shows that the emulsion prepared by the preparation method provided by the invention has no delamination after being placed for 6 months under long-term conditions, and the emulsion has good stability.
In conclusion, the fat emulsion prepared by the preparation method provided by the invention has the advantages that the SPAN value is obviously reduced, the uniformity of emulsion particles is better, the stability of the emulsion is improved, the product quality is improved, and the process is simple and is suitable for industrial mass production.
Claims (10)
1. A method for preparing fat emulsion, which is characterized by comprising the following steps:
(1) Preparing an oil phase: taking grease and heating to obtain an oil phase;
(2) Preparing an aqueous phase: taking water for injection, and heating to obtain a water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65-75% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk;
(5) Homogenizing finally;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to the preparation amount, and uniformly stirring to obtain the fat emulsion.
2. The method of claim 1, wherein the grease is selected from one of three compositions:
(1) Soybean oil and olive oil;
(2) Soybean oil, medium chain triglycerides, olive oil and fish oil;
(3) Fish oil.
3. The method according to claim 1, wherein the weight of the oil-water mixed phase in the step (3) is 65% (w/v) of the total volume of the formulation.
4. The process according to claim 1, wherein the homogenization temperature in steps (4) and (5) is 50 to 70 ℃.
5. The method according to claim 1, wherein the number of homogenization in step (4) is 3 to 8.
6. The method according to claim 1, wherein the number of homogenization in step (5) is 1 to 5.
7. The method of claim 1, further comprising adding lecithin or sodium oleate in step (1) or step (2).
8. The method of manufacturing according to claim 1, comprising the steps of:
(1) Preparing an oil phase: taking grease and heating to obtain an oil phase;
(2) Preparing an aqueous phase: taking glycerol, adding water for injection, heating and dissolving to obtain a water phase;
(3) Preparation of colostrum: mixing and stirring the oil phase and the water phase to obtain an oil-water mixed phase, and uniformly mixing to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65-75% (w/v) of the total volume of the preparation;
(4) Homogenizing the milk: the homogenizing pressure is 350-650bar for the primary valve and 40-120bar for the secondary valve;
(5) Final homogenization: the homogenizing pressure is 200-350bar of the primary valve and 20-40bar of the secondary valve;
(6) Supplementing water: adding water for injection into the emulsion obtained in the step (5) to the preparation amount, and uniformly stirring to obtain the fat emulsion.
9. The method according to claim 8, wherein the homogenizing pressure in the step (4) is 450 to 600bar for the first-stage valve and 50 to 70bar for the second-stage valve.
10. The method according to claim 8, wherein the homogenizing pressure in the step (5) is 250 to 350bar for the primary valve and 20 to 40bar for the secondary valve.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111310531.7A CN116077438A (en) | 2021-11-05 | 2021-11-05 | Preparation method of fat emulsion |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111310531.7A CN116077438A (en) | 2021-11-05 | 2021-11-05 | Preparation method of fat emulsion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116077438A true CN116077438A (en) | 2023-05-09 |
Family
ID=86187406
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111310531.7A Pending CN116077438A (en) | 2021-11-05 | 2021-11-05 | Preparation method of fat emulsion |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116077438A (en) |
-
2021
- 2021-11-05 CN CN202111310531.7A patent/CN116077438A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10772345B2 (en) | Beverage nanoemulstions produced by high shear processing | |
| JPH07121206B2 (en) | Enteral absorption nutritional product | |
| CN111296730A (en) | Lutein nanoemulsion with good stability and preparation method thereof | |
| EP2586449A2 (en) | Lipid emulsion having krill oil as an active ingredient and preparation method therefor | |
| CN109692154A (en) | In a kind of Propofol/preparation method of long chain fat emulsion injection | |
| EP2531044B1 (en) | Drink | |
| CN116077438A (en) | Preparation method of fat emulsion | |
| CN113181114B (en) | Hesperetin emulsion and preparation method thereof | |
| WO2020143910A1 (en) | Two-phase system | |
| CN113876658A (en) | Oil-in-water emulsion composition and method for producing the same | |
| CN112641821A (en) | Formula of fat emulsion injection and preparation method thereof | |
| CN109261088B (en) | Equipment and method for preparing lipid microspheres | |
| JP2950348B2 (en) | Fat emulsion and method for producing the same | |
| CN113966839B (en) | Composite emulsion containing walnut oil and dihydromyricetin and preparation method thereof | |
| KR101642657B1 (en) | Method for the Preparation of Emulsifier Comprising Hydrogenated Lecithin and Emulsifier Prepared by the Same | |
| CN114983939A (en) | Propofol emulsion injection and preparation method thereof | |
| WO2020017571A1 (en) | Flurbiprofen-axetil-containing fat emulsion and method for manufacturing same | |
| JP2566643B2 (en) | Emulsified composition using clear royal jelly aqueous solution and beverage containing the same | |
| CN117752596A (en) | Aprepitant mixed micelle injection and preparation method and application thereof | |
| CN113197853A (en) | Clevidipine butyrate emulsion for injection, and preparation method and application thereof | |
| JP2004000924A (en) | W/o/w type composite emulsion | |
| CN112402377A (en) | Propofol intravenous injection fat emulsion and preparation method thereof | |
| GB2511028A (en) | Nano emulsions, methods of forming the same and uses thereof | |
| JP2004277375A (en) | Method for producing solubilized liquid composition | |
| CN117482043A (en) | Fructus cannabis oral emulsion and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |