A kind of preparation method of fat emulsion

Abstract

The present invention provides a method for preparing a fat emulsion. The emulsion prepared by the method has good uniformity of milk particles and high stability, and the product quality is improved. The preparation method provided by the present invention is simple to operate, the process is stable and controllable, and it is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a method for preparing a fat emulsion. Background Art

[0002] Long-chain fat emulsion injection (OO) is an oil-in-water (O / W) emulsion made by emulsifying soybean oil and olive oil as the oil phase, supplemented with phospholipid emulsifiers, isotonic agents and water for injection. Long-chain fat emulsion injection was first launched in Europe in 1996 and was approved for import in my country in 2006 under the trade name "Clino". This fat emulsion injection is one of the sources of energy for the body during parenteral nutrition and can also provide essential fatty acids. Long-chain fat emulsion injection is also safe and non-irritating to veins.

[0003] Long-chain fat emulsion injection (OO) belongs to submicron emulsion, which is a thermodynamically unstable system and will show various unstable phenomena, such as aggregation and flocculation. "Ostwald ripening phenomenon" is one of the reasons for the instability of fat emulsion. The different sizes of fat emulsion droplets will cause larger droplets to adsorb small droplets. Small droplets fill between large droplets, causing droplets to aggregate, and then cause droplets to merge, resulting in excessive large droplets and emulsion stratification during the shelf life of fat emulsion.

[0004] In order to ensure the stability of long-chain fat emulsion injection (OO) during its shelf life, the uniformity of particles in the emulsion should be improved as much as possible. The existing preparation technology of this product is mostly to mix olive oil and soybean oil with lecithin, glycerin, sodium oleate and other auxiliary materials, add water for injection to the prescribed amount, and obtain the emulsion after emulsification and homogenization. Patent application CN201210131479.3 discloses a method for preparing a fat emulsion, comprising the following steps: (1) Add an appropriate amount of water for injection to a preparation tank, add glycerin, stir to dissolve it, add an appropriate amount of 1 mol / L sodium hydroxide solution, filter through a 0.2μm filter membrane, heat to 50-90°C, add lecithin and stir to evenly disperse it; (2) Filter the soybean oil through a 0.45μm filter membrane and heat to 50-90°C, Soybean oil and lecithin are mixed and stirred to form a primary emulsion, and water for injection is added to the prepared amount, stirred evenly, filtered with a 40μm filter membrane, and emulsified 6-7 times by a high-pressure emulsifier, and then the emulsion is released into a dilution tank; (3) After adjusting the pH value, the semi-finished product is checked, filtered with a 10μm filter membrane, filled with nitrogen, filled, and capped; (4) The infusion bottle filled with the emulsion is sterilized in a rotary high-pressure sterilizer at 100-122°C for 10-30 minutes, light inspection, and packaging to obtain the finished product. This method uses water for injection to the prescribed amount before homogenization during liquid preparation. The fat emulsion obtained has a wide distribution of milk particles and poor stability of the emulsion.

[0005] In order to improve the uniformity of the emulsion particles in the long-chain fat emulsion injection (OO), the inventors of the present application used the SPAN value as a detection index of uniformity and studied how to reduce the SPAN value of the long-chain fat emulsion injection (OO). The inventors tried to adjust the homogenization pressure. The results show that with the change of the homogenization pressure, the particle size of the particles changes, but the change of the SPAN value is not obvious. The inventors also tried to adjust the number of homogenization times and found that with the increase of the number of times, the particle size of the emulsion particles becomes smaller, but the effect on the SPAN value is not obvious. During the research process, the inventors found that when preparing fat emulsion, if part of the water phase is first measured and mixed with the prescribed amount of oil phase, and low-pressure homogenization is used to prepare colostrum in which the weight of the oil-water mixed phase accounts for about 70% of the total preparation volume, and then the homogenization method of first emulsion homogenization and then final homogenization is used, and finally the remaining water for injection is supplemented, the emulsion thus prepared has a significantly lower SPAN value after testing. Summary of the invention

[0006] In order to solve the problem of poor uniformity of fat emulsion particle size distribution, the present invention provides a method for preparing fat emulsion. The fat emulsion preparation prepared by the method has good particle size uniformity and stable product quality.

[0007] The present invention provides a method for preparing a fat emulsion, comprising the following steps:

[0008] (1) Preparation of oil phase: Take oil and heat it to obtain oil phase;

[0009] (2) Preparation of aqueous phase: Take water for injection and heat it to obtain an aqueous phase;

[0010] (3) Preparation of colostrum: the oil phase and the water phase are mixed and stirred to obtain an oil-water mixed phase, and the mixture is mixed evenly 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;

[0011] (4) Milk homogenization;

[0012] (5) Final homogenization;

[0013] (6) Rehydration: Add water for injection to the emulsion obtained by homogenization in step (5) to the prepared amount, stir evenly, and obtain a fat emulsion.

[0014] In some embodiments, the oil is selected from one or more of vegetable oil and fish oil; in some embodiments, the oil is soybean oil and olive oil; in some embodiments, the oil is soybean oil, medium chain triglycerides, olive oil and fish oil; in some embodiments, the oil is fish oil.

[0015] In some embodiments, the fish oil is fish oil triglycerides.

[0016] In some embodiments, the temperature in step (1) is heated to 55-75°C; in some embodiments, the temperature in step (1) is heated to 60-70°C.

[0017] In some embodiments, glycerol is further added in step (2).

[0018] In some embodiments, the temperature in step (2) is heated to 50-80°C; in some embodiments, the temperature in step (2) is heated to 55-75°C.

[0019] In some embodiments, step (3) obtains colostrum by homogenization operation, wherein the homogenization conditions are: homogenization pressure of 40-70 bar, homogenization temperature of 50-70°C, and homogenization times of 1-3 times; in some embodiments, the homogenization conditions of step (3) are: homogenization pressure of 60-70 bar, homogenization temperature of 55-65°C, and homogenization times of 1-3 times.

[0020] In some embodiments, the weight of the oil-water mixed phase in step (3) accounts for 65% (w / v) of the total preparation volume.

[0021] In some embodiments, the homogenization temperature in step (4) is 50-70°C.

[0022] In some embodiments, the homogenization pressure in step (4) is 350-650 bar for the primary valve and 40-120 bar for the secondary valve; in some embodiments, the homogenization pressure in step (4) is 380-400 bar for the primary valve and 50-70 bar for the secondary valve; in some embodiments, the homogenization pressure in step (4) is 400-600 bar for the primary valve and 40-70 bar for the secondary valve; in some embodiments, the homogenization pressure in step (4) is 450-600 bar for the primary valve and 50-70 bar for the secondary valve.

[0023] In some embodiments, the homogenization is performed 3-8 times in step (4); in some embodiments, the homogenization is performed 5-8 times in step (4).

[0024] In some embodiments, the homogenization temperature in step (5) is 50-70°C; in some embodiments, the homogenization pressure in step (5) is 200-350 bar for the primary valve and 20-40 bar for the secondary valve; in some embodiments, the homogenization pressure in step (5) is 250-350 bar for the primary valve and 20-40 bar for the secondary valve;

[0025] In some embodiments, the homogenization number of step (5) is 1-5 times; in some embodiments, the homogenization number of step (5) is 2-5 times.

[0026] In some embodiments, the method further comprises adding lecithin in step (1) or step (2).

[0027] In some embodiments, sodium oleate is further added in step (1) or step (2).

[0028] In some embodiments, the method further comprises adjusting the pH value to 7.5-9.0 after step (6).

[0029] Furthermore, the present invention provides a method for preparing a fat emulsion, comprising the following steps:

[0030] (1) Preparation of oil phase: Take oil and heat it to obtain oil phase;

[0031] (2) Preparation of aqueous phase: Take glycerol, add water for injection, heat and dissolve to obtain aqueous phase;

[0032] (3) Preparation of colostrum: the oil phase and the water phase are mixed and stirred to obtain an oil-water mixed phase, and the mixture is mixed evenly 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;

[0033] (4) Milk homogenization: homogenization pressure is 350-650 bar for the first valve and 40-120 bar for the second valve;

[0034] (5) Final homogenization: homogenization pressure is 200-350 bar for the first valve and 20-40 bar for the second valve;

[0035] (6) Rehydration: Add water for injection to the emulsion obtained by homogenization in step (5) to the prepared amount, stir evenly, and obtain a fat emulsion.

[0036] In some embodiments, the homogenization pressure in step (4) is 450-600 bar for the primary valve and 50-70 bar for the secondary valve; in some embodiments, the homogenization pressure in step (5) is 250-350 bar for the primary valve and 20-40 bar for the secondary valve.

[0037] Furthermore, the present invention provides a method for preparing a fat emulsion, comprising the following steps:

[0038] (1) Preparation of oil phase: Take oil and heat it to obtain oil phase;

[0039] (2) Preparation of aqueous phase: Take glycerol, add water for injection, heat and dissolve to obtain aqueous phase;

[0040] (3) Preparation of colostrum: the oil phase and the water phase are mixed and stirred to obtain an oil-water mixed phase, and the mixture is mixed evenly 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;

[0041] (4) Milk homogenization: homogenization pressure is 400-600 bar for the first valve, 40-70 bar for the second valve, homogenization temperature is 50-70°C, and homogenization times are 5-8 times;

[0042] (5) Final homogenization: the homogenization pressure is 200-350 bar for the first valve, 20-40 bar for the second valve, the homogenization temperature is 50-70 °C, and the homogenization times are 2-5 times;

[0043] (6) Rehydration: Add water for injection to the emulsion obtained by homogenization in step (5) to the prepared amount, stir evenly, and obtain a fat emulsion.

[0044] Furthermore, the present invention provides a method for preparing a fat emulsion, comprising the following steps:

[0045] (1) Preparation of oil phase: Take a prescribed amount of oil and heat it to 55-75° C. to prepare an oil phase, wherein the oil is selected from one or both of soybean oil and olive oil;

[0046] (2) Preparation of aqueous phase: Take glycerol, add water for injection, heat to 60-70°C to dissolve, and obtain an aqueous phase;

[0047] (3) Preparation of colostrum: the oil phase and the water phase are mixed and stirred to obtain an oil-water mixed phase, and the mixture is mixed evenly to obtain colostrum, wherein the weight of the oil-water mixed phase accounts for 65% (w / v) of the total volume of the preparation;

[0048] (4) Milk homogenization: homogenization pressure is 500-600 bar for the first valve, 55-70 bar for the second valve, homogenization temperature is 50-70°C, and homogenization times are 5-8 times;

[0049] (5) Final homogenization: the homogenization pressure is 300-350 bar for the first valve, 20-40 bar for the second valve, the homogenization temperature is 50-70 °C, and the homogenization times are 2-5 times;

[0050] (6) replenishing water: adding water for injection to the emulsion obtained by homogenization in step (5) to the prepared amount, stirring evenly, to obtain a fat emulsion;

[0051] (7) Fill the fat emulsion into an infusion bottle, fill it with nitrogen, add a stopper and a cap, and keep it in a rotary sterilizer at 121°C for 12 minutes.

[0052] Terminology

[0053] The "% (w / v)" mentioned in the present invention refers to the weight volume percentage, which is one of the ways to characterize the content that can be understood in the art.

[0054] The "primary valve" pressure mentioned in the present invention refers to the pressure of the primary valve rather than the total pressure; the "secondary valve" pressure refers to the pressure value of the secondary valve.

[0055] The SPAN (span) value of the present invention is equal to (D90-D10) / D50, which indicates the dispersion degree of the emulsion particles. The smaller the value, the better the dispersion degree.

[0056] The beneficial effects of the present invention are:

[0057] (1) The fat emulsion preparation method provided by the present invention can prepare a fat emulsion with good particle uniformity, thereby improving the quality and stability of the product.

[0058] (2) The fat emulsion preparation method provided by the present invention is suitable for the preparation of a variety of oil fat emulsions, and after replenishing water, an emulsion with good uniformity can be obtained without re-homogenization. The process is simple and stable, with good repeatability and controllable quality, and is suitable for industrial production. DETAILED DESCRIPTION

[0059] In order to further illustrate the present invention and facilitate understanding of the present invention, only some embodiments are provided and described in detail. It can be understood by those skilled in the art that the following embodiments are not intended to limit the scope of protection of the present invention.

[0060] Detection method of SPAN value: Take the fat emulsion product and inspect it according to the particle size and particle size distribution determination method (Method 3 of General Chapter 0982 of the 2020 Edition of the Chinese Pharmacopoeia) (using a laser scattering particle size analyzer based on Mie scattering theory, such as Mastersizer MS2000; recommended parameters are absorbance 0, 0.001 or 0.01, refractive index 1.47-1.52, shading 5%-10%; or other suitable instruments).

[0061] Experiment 1

[0062] The inventors prepared the emulsion using the preparation method of the prior art.

[0063] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65°C, shear to disperse the lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate and add them to an appropriate amount of water for injection, stir and dissolve, and then heat to 60°C; after the oil phase and the water phase are mixed and stirred, add water for injection to 1000mL (100% of the total volume), homogenize once to obtain colostrum, and the homogenization pressure is 60bar. The colostrum is passed through a homogenizer, and the homogenization conditions are: the homogenization pressure is 550bar for the first valve, 60bar for the second valve, the homogenization temperature is 60°C, and the homogenization times are 6 times. Adjust the pH to 7.5-8.0 to obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize it at 121°C in a rotary sterilizer for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value is 1.47.

[0064] Experiment 2

[0065] The inventors attempted to change the homogenization conditions and add a homogenization step based on the prior art.

[0066] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65℃, shear to disperse the lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate and add them to an appropriate amount of water for injection, stir and dissolve, and then heat to 70℃; after the oil phase and the water phase are mixed and stirred, add water for injection to 1000mL (100% of the total volume), homogenize once to obtain colostrum, and the homogenization pressure is 60bar. Pass the colostrum through a homogenizer, and the homogenization conditions are: homogenization pressure is 590bar for the first valve, 60bar for the second valve, homogenization temperature is 55℃, and the number of homogenization times is 5 times. Adjust the homogenization pressure to 300bar for the first valve, 30bar for the second valve, and the number of homogenization times is 2 times. Adjust the pH to 7.5-8.0 to obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize it in a rotary sterilizer at 121°C for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value was 1.32.

[0067] Experiment 3

[0068] The inventor mixed part of the water phase with the prescribed amount of oil phase to prepare colostrum, and then obtained the emulsion through the steps of hydration and homogenization.

[0069] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65℃, shear to disperse lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate and add 465g of water for injection to dissolve to obtain the water phase, stir and dissolve and heat to 60℃; mix the oil phase and the water phase to obtain 700g of oil-water mixed phase, stir and dissolve and heat to 70℃, homogenize once to obtain colostrum, and the homogenization pressure is 60bar. Add water for injection to 1000mL (100% of the total volume). Pass the colostrum through a homogenizer, and the homogenization conditions are: homogenization pressure is 590bar for the first valve, 60bar for the second valve, homogenization temperature is 60℃, and the number of homogenizations is 6 times. Adjust the homogenization pressure to 300bar for the first valve, 30bar for the second valve, and 2 times for homogenization. Adjust the pH to 7.5-8.0 to obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize it in a rotary sterilizer at 121°C for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value was 1.31.

[0070] Experiment 4

[0071] Based on Experiment 3, the inventors studied the method of adding the water phase and the order of water replenishment and homogenization.

[0072] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65℃, shear to disperse lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate, add appropriate amount of injection water to dissolve to obtain the water phase, stir and dissolve and heat to 60℃; mix the oil phase and the water phase, add injection water until the oil-water mixed phase is 700g, stir and dissolve and heat to 70℃, low pressure homogenize once to obtain colostrum, the homogenization pressure is 60bar. Pass the colostrum through a homogenizer, the homogenization conditions are: homogenization pressure is 590bar for the first valve, 60bar for the second valve, homogenization temperature is 60℃, and the number of homogenizations is 6 times. Add injection water to 1000mL (100% of the total preparation volume), mix and homogenize, the homogenization conditions are: pressure is 200bar for the first valve, 30bar for the second valve, and the number of homogenizations is 2 times. Adjust the pH to 7.5-8.0 to obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize it in a rotary sterilizer at 121°C for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value was 1.28.

[0073] Experiment 5

[0074] In order to further reduce the SPAN value, the inventors conducted in-depth research on the homogenization operation mode.

[0075] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65℃, shear to disperse the lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate, add appropriate amount of injection water to dissolve to obtain the water phase, stir and dissolve, and heat to 60℃; mix the oil phase and the water phase, add injection water until the oil-water mixed phase is 700g, stir and dissolve, heat to 70℃, and homogenize once at low pressure to obtain colostrum, and the homogenization pressure is 60bar. Pass the colostrum through a homogenizer, and the homogenization conditions are: homogenization pressure is 590bar for the first valve, 60bar for the second valve, homogenization temperature is 60℃, and the number of homogenizations is 6 times. Add water for injection to 1000mL (100% of the total volume), stir and mix evenly, adjust the pH to 7.5-8.0, and obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize at 121°C in a rotary sterilizer for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value is 1.30.

[0076] Example 1

[0077] The inventors further studied the preparation method and obtained an emulsion with a significantly improved SPAN value.

[0078] Take about 160g of olive oil and about 40g of soybean oil, add 12g of lecithin and heat to 65℃, shear to disperse lecithin in the oil phase; take 22.5g of glycerol and 0.3g of sodium oleate and add 465g of water for injection to dissolve to obtain the water phase, stir and dissolve and heat to 60℃; mix the oil phase and the water phase to obtain 700g of oil-water mixed phase (70% of the total volume), stir and dissolve and heat to 70℃; homogenize once to obtain colostrum, and the homogenization pressure is 60bar. Pass the colostrum through a homogenizer, and the homogenization conditions are: homogenization pressure is 590bar for the first valve, 60bar for the second valve, homogenization temperature is 60℃, and the number of homogenizations is 6 times. Adjust the homogenization pressure to 200bar for the first valve, 30bar for the second valve, and the number of homogenizations is 2 times. Add injection water to the homogenized emulsion to 1000mL (100% of the total preparation volume), stir and mix evenly, and if necessary, adjust the pH to 7.5-8.0 to obtain a uniform emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize at 121°C in a rotary sterilizer for 12 minutes to obtain a long-chain fat emulsion injection (OO). After testing, the SPAN value is 1.08.

[0079] The test results of Example 1 and Experiment 4 show that the SPAN value of the emulsion can be significantly reduced by preparing the emulsion according to the preparation method in Example 1. It shows that the technical solution of the present invention unexpectedly reduces the SPAN value of the fat emulsion. The reason may be that the water adding method used in Experiment 4, as well as the emulsion preparation method of first homogenizing, then fixing the volume, and finally homogenizing, will lead to repeated redistribution of the emulsion particle size, thereby affecting the reduction of the SPAN value. Compared with Experiment 4, Example 1 adopts different water adding methods and homogenization methods, in which a final homogenization operation is added after the emulsion homogenization, which has a certain "modification" effect on the milk particles and makes the particle size distribution better. In addition, the technical solution of the present invention completes the homogenization operation before replenishing water. Compared with the homogenization, fixing the volume, and then homogenizing operations in Experiment 4, it can significantly reduce the amount of emulsion in the homogenization process, shorten the homogenization time, improve the homogenization efficiency, reduce the production cost, and is more conducive to large-scale industrial production.

[0080] Embodiment 2-5

[0081] The inventor further investigated the influence of the proportion of the weight of the oil-water mixed phase to the total volume of the preparation on the SPAN value of the emulsion. According to the preparation method in Example 1, different proportions of the weight of the oil-water mixed phase to the total volume of the preparation were prepared, and their SPAN values ​​were detected. The following are the SPAN value test results of the emulsion when the weight of the oil-water mixed phase to the total volume of the preparation was 60% (Example 2), 65% (Example 3), 75% (Example 4), and 80% (Example 5):

[0082] Table 1 Effect of oil-water mixed phase ratio on SPAN value

[0083]

[0084] The SPAN value test results of Examples 1-5 show that when the weight of the oil-water mixed phase accounts for 65-75% of the total preparation volume using the preparation method of the present invention, the SPAN value of the emulsion is significantly reduced. This may be because the operation of first emulsification homogenization and then final homogenization is conducive to the redistribution of particle size, which can effectively improve the SPAN value and obtain qualified products. The study found that only using emulsion homogenization cannot effectively improve the SPAN value, and only using final homogenization will not meet the requirements for the average particle size of the emulsion. At the same time, under the preparation method of the present invention, the homogenization pressure and the number of homogenization times of emulsion homogenization and final homogenization also directly affect the SPAN value of the emulsion. On the other hand, when the weight of the oil-water mixed phase accounts for more than 75% of the total preparation volume, the phospholipid concentration in the oil-water mixed phase is relatively reduced, affecting the emulsification effect, and the volume of the oil-water phase increases, resulting in an increase in the amount of emulsion in the homogenization process, which will increase the homogenization time and prolong the production time; and when the weight of the oil-water mixed phase accounts for less than 65% of the total preparation volume, the concentration of the preparation liquid increases, the number of emulsion particles per unit volume increases, and the collision probability of the emulsion particles increases, resulting in a deterioration in the uniformity of the particles, and the SPAN value cannot be significantly improved. At the same time, as the concentration of the preparation liquid increases and the viscosity increases, the fluidity of the emulsion will also deteriorate, which is not conducive to production operations. In addition, the SPAN value of the product prepared by the preparation method of the present invention is consistent with the SPAN value of the original product "Kelingnuo", which ensures the consistency between the generic drug and the original drug and improves the product quality.

[0085] Embodiment 6-10

[0086] In order to investigate the durability of the obtained preparation method, the inventors adjusted the dosage and preparation method parameters of the preparation method in Example 1, and tested the SPAN value of the prepared emulsion. The investigation results are shown in the following table

[0087] Table 2 Preparation method tolerance test results

[0088]

[0089] The experimental results show that the SPAN values ​​of the emulsions prepared in Examples 6-10 are significantly reduced.

[0090] Embodiment 11

[0091] The preparation method of the present invention can also solve the problem of particle size uniformity existing in other types of fat emulsion injections, and obtain a fat emulsion with a lower SPAN value. The inventor prepared an ω-3 fish oil fat emulsion injection, and the formula is as follows:

[0092]

[0093]

[0094] The preparation method parameters are as follows:

[0095] Preparation method parameter Oil phase temperature 65℃ Water phase temperature 60℃ Oil-water mixed phase temperature 60℃ Colostrum homogenization pressure 60bar Milk homogenization pressure First stage valve 390bar, second stage valve 60bar Homogenization times 6 times Final homogenization pressure Primary valve 270bar, secondary valve 30bar Homogenization times 2 times Homogenization temperature 55℃ pH 8.0-8.7 Sterilization conditions Sterilize at 121℃ for 12 minutes

[0096] The specific preparation method is as follows:

[0097] Take 100g of fish oil triglyceride, add 12g of lecithin and heat to 65°C, shear to disperse the lecithin in the oil phase; take 25g of glycerol and 0.3g of sodium oleate and add 563g of water for injection to dissolve to obtain the water phase, stir and dissolve and heat to 60°C, mix and stir the oil phase and the water phase to obtain 700g of oil-water mixed phase (70% of the total volume), stir and dissolve and keep the temperature at 60°C, homogenize once to obtain colostrum, and the homogenization pressure is 60bar. Pass the colostrum through a homogenizer, and the homogenization conditions are: the homogenization pressure is 390bar for the first valve, 60bar for the second valve, the homogenization temperature is 55°C, and the homogenization times are 6 times. Adjust the homogenization pressure to 270bar for the first valve, 30bar for the second valve, and the homogenization times are 2 times. Add injection water to the homogenized emulsion to 1000 mL (100% of the total preparation volume), stir and mix evenly, and if necessary, adjust the pH to 8.0-8.7 to obtain an emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize at 121° C. for 12 minutes in a rotary sterilizer to obtain an ω-3 fish oil fat emulsion injection. After testing, the SPAN value is 1.15.

[0098] Example 12

[0099] The inventors prepared a variety of oil fat emulsion injections, the prescriptions are as follows:

[0100] Prescription composition Prescription dosage Soybean Oil 60g Medium Chain Triglycerides 60g olive oil 50g Fish Oil Triglycerides 30g Lecithin 12g glycerin 25g Sodium Oleate 0.3g Water for injection Make up to 1000mL

[0101] The preparation method parameters are as follows:

[0102] Preparation method parameter Oil phase temperature 65℃ Water phase temperature 70℃ Oil-water mixed phase temperature 70℃ Colostrum homogenization pressure 60bar Milk homogenization pressure Primary valve 600bar, secondary valve 60bar Homogenization times 6 times Final homogenization pressure Primary valve 300bar, secondary valve 30bar Homogenization times 2 times Homogenization temperature 60℃ pH 8.0-8.7 Sterilization conditions Sterilize at 121℃ for 12 minutes

[0103] The specific preparation method is as follows:

[0104] 60g soybean oil, 60g medium-chain triglyceride, 50g olive oil, 30g fish oil triglyceride, add 12g lecithin and heat to 65°C, shear to disperse lecithin in the oil phase; take 25g glycerol and 0.3g sodium oleate, add 513g water for injection to dissolve to obtain the water phase, stir and dissolve, heat to 70°C, mix and stir the oil phase with the water phase to obtain 750g oil-water mixed phase (75% of the total volume), stir and dissolve, maintain the temperature at 70°C, homogenize once to obtain colostrum, and the homogenization pressure is 60bar. The colostrum is passed through a homogenizer, and the homogenization conditions are: the homogenization pressure is 600bar for the first valve, 60bar for the second valve, the homogenization temperature is 60°C, and the homogenization times are 6 times. Adjust the homogenization pressure to 300bar for the first valve, 30bar for the second valve, and 2 times for homogenization. Add injection water to the homogenized emulsion to 1000 mL (100% of the total preparation volume), stir and mix evenly, and if necessary, adjust the pH to 8.0-8.7 to obtain an emulsion; fill the emulsion into a glass infusion bottle, add a stopper after nitrogen filling, roll the cap, and sterilize at 121°C in a rotary sterilizer for 12 minutes to obtain a variety of oil fat emulsion injections. After testing, the SPAN value is 0.98.

[0105] Example 13

[0106] According to the provisions of the drug stability test in the "Guidelines for the Study of Chemical Drug Stability Technology", the emulsions prepared in Examples 1-5 and 11-12 were subjected to stability tests. In view of the technical effect of improving the homogeneity of the emulsion particles of the fat emulsion injection of the present invention, the inventors conducted a study on the stability changes of the emulsion during long-term storage (temperature 25±2°C and humidity 60±5%), such as emulsion stratification, and the test results are as follows:

[0107] Table 3 Fat emulsion stability test results

[0108]

[0109] The stability test results show that the emulsion prepared according to the preparation method of the present invention does not delaminate after being placed under long-term conditions for 6 months, and the emulsion has good stability.

[0110] In summary, the fat emulsion prepared according to the preparation method of the present invention has a significantly lower SPAN value and better uniformity of emulsion particles, which is beneficial to improving emulsion stability and product quality, and the process is simple and suitable for large-scale industrial production.

Claims

1. A method for preparing fat emulsion, It is characterized in that The preparation method comprises the following steps: (1) Preparation of oil phase: Take oil and heat it to obtain an oil phase; the oil is selected from one of the following three compositions: soybean oil and olive oil; soybean oil, medium-chain triglycerides, olive oil, and fish oil; fish oil; (2) Preparation of aqueous phase: Take water for injection and heat it to obtain an aqueous phase; (3) Preparation of colostrum: the oil phase and the water phase are mixed and stirred to obtain an oil-water mixed phase, and the mixture is mixed evenly 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) Milk homogenization: homogenization times are 3-8 times; (5) Final homogenization; (6) replenishing water: adding water for injection to the emulsion obtained by homogenization in step (5) to the prepared amount, stirring evenly, to obtain a fat emulsion; wherein, adding lecithin in step (1) or step (2), and In step (2), glycerol is added.

2. The preparation method according to claim 1, It is characterized in that In step (3), the weight of the oil-water mixed phase accounts for 65% (w / v) of the total preparation volume.

3. The preparation method according to claim 1, It is characterized in that The homogenization temperature in step (4) is 50-70°C.

4. The preparation method according to claim 1, It is characterized in that The homogenization temperature in step (5) is 50-70°C.

5. The preparation method according to claim 1, It is characterized in that The homogenization times in step (5) is 1 to 5 times.

6. The preparation method according to claim 1, It is characterized in that The method further comprises adding sodium oleate in step (1) or step (2).

7. The preparation method according to claim 1, It is characterized in that The homogenization pressure in step (4) is 350-650 bar for the first-stage valve and 40-120 bar for the second-stage valve.

8. The preparation method according to claim 7, It is characterized in that The homogenization pressure in step (4) is 450-600 bar for the first valve and 50-70 bar for the second valve.

9. The preparation method according to claim 1, It is characterized in that The homogenization pressure in step (5) is 200-350 bar for the primary valve and 20-40 bar for the secondary valve.

10. The preparation method according to claim 9, It is characterized in that The homogenization pressure in step (5) is 250-350 bar for the first-stage valve and 20-40 bar for the second-stage valve.

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