Long-chain fat emulsion injection (OO) and preparation method thereof

Abstract

The invention discloses a long-chain fat emulsion injection (OO) and a preparation method thereof. The preparation method comprises the following steps: mixing soybean oil, olive oil and egg yolk lecithin, and carrying out high-speed shearing, stirring and dissolving at 60-80 DEG C to obtain an oil phase; adding glycerol and sodium oleate into the water for injection, heating and dissolving at 60-80 DEG C, and regulating the pH value of the solution with a sodium hydroxide solution to obtain a water phase; mixing and emulsifying the oil phase and the water phase to obtain primary emulsion, and adding water for injection to a preparation amount; homogenizing the primary emulsion by using a homogenizer, and adding the residual sodium oleate before the last time of homogenization to continuously homogenize; and finally, filling and sterilizing. According to the long-chain fat emulsion injection (OO) prepared by the invention, the proportion of particles greater than 0.75 mu m is reduced, the stability of the long-chain fat emulsion injection (OO) product in the storage process and the safety of clinical medication are improved on the premise of ensuring the effectiveness of the long-chain fat emulsion injection (OO), and the long-chain fat emulsion injection (OO) has the characteristics of good product stability and high safety.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a long-chain fat emulsion injection (OO) and a preparation method thereof. Background Art

[0002] At present, the most widely used fat emulsions in clinical practice are long-chain fat emulsions and medium-chain fat emulsions based on soybean oil. About 62% of the fatty acids contained in soybean oil are polyunsaturated fatty acids. Large-scale infusion of polyunsaturated fatty acids will lead to reduced immune cell function and increase the risk of infection in patients. Olive oil contains a large amount of monounsaturated fatty acids, which can not only provide heat energy to the human body, but also adjust the ratio of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in human plasma, increase the level of high-density lipoprotein HDL (good cholesterol) in the human body and reduce the level of low-density lipoprotein LDL (bad cholesterol), thereby preventing excessive cholesterol in the human body. Long-chain fat emulsion injection (OO) is a fat emulsion made by mixing olive oil and soybean oil in a certain ratio (about 4:1). This variety was first launched in Europe in 1996 and was approved in my country in 2006. The trade name is "Clino".

[0003] Most fat emulsion injection products are thermodynamically unstable systems, which will show various unstable phenomena, such as oil bleaching, rancidity, aggregation, flocculation, etc. The above phenomenon is mainly caused by the different sizes of the emulsion particles themselves. The larger emulsion particles will adsorb the small emulsion particles, and the small emulsion particles will be filled between the large emulsion particles, causing the emulsion particles to aggregate and merge, resulting in the emulsion particles of the fat emulsion not meeting the requirements. The existing stability is mostly added to the water phase at one time, the proportion of small emulsion particles will increase, and the possibility of subsequent aggregation of homogenized small emulsion particles will increase, resulting in emulsion particle merging. Summary of the invention

[0004] The present invention solves the technical problem of unqualified emulsion particles under the existing fat emulsion injection process, and provides a preparation method of a long-chain fat emulsion injection (OO) containing olive oil and soybean oil. By analyzing the process and process parameters that affect the quality of emulsion particles, changing the original production process, and controlling the addition of materials, homogenization conditions, nitrogen protection, emulsification time, etc. in the preparation process, a stable emulsion with uniform particle size can be obtained.

[0005] The preparation method of the long-chain fat emulsion injection (OO) is as follows: (1) 40 parts by weight of soybean oil, 160 parts by weight of olive oil and 12 parts by weight of egg yolk lecithin are mixed and dissolved by high-speed shear stirring at 60-80° C. to obtain an oil phase; (2) Add 22.5 parts by weight of glycerol and 0.06-0.24 parts by weight of sodium oleate to water for injection, heat to 60-80°C to dissolve, and adjust the pH value of the solution to 10.0-10.4 with sodium hydroxide solution to obtain an aqueous phase; (3) Mix and emulsify the oil phase and the water phase to obtain colostrum, and add water for injection to the prepared amount; (4) homogenizing the colostrum with a homogenizer, adding the remaining 0.24-0.06 parts by weight of sodium oleate before the last homogenization and continuing the homogenization; (5) Finally, the emulsion is filtered through a filter element and then bottled and sterilized.

[0006] The shearing speed of step (1) is 10000 rpm, and the time is 1-10 min, preferably 5 min.

[0007] In the step (3), the mass ratio of the oil phase to the water phase is 38:37, and the number of emulsifications is 1-9 times, preferably 7-9 times.

[0008] The homogenization pressure in step (4) is 80-120 bar for the secondary pressure, 1-3 times for the homogenization, preferably 3 times; and 500-800 bar for the primary pressure, 5-8 times for the homogenization, preferably 8 times.

[0009] In the step (5), the mixture is filled into a three-layer co-extruded infusion bag.

[0010] The sterilization condition in step (5) is 121° C. for 8-20 min, preferably 15 min.

[0011] Nitrogen gas was used for protection during the above preparation and canning process.

[0012] The long-chain fat emulsion injection (OO) prepared by the present invention reduces the proportion of particles larger than 0.75 μm, and improves the stability of the long-chain fat emulsion injection (OO) product during storage and the safety of clinical use while ensuring the effectiveness of the long-chain fat emulsion injection (OO), and has the characteristics of good product stability and high safety. DETAILED DESCRIPTION

[0013] Several preferred embodiments of the present invention are described below, but are not intended to limit the present invention. Example 1

[0014] Weigh 160g of olive oil and 40g of soybean oil, heat to 60-80℃, add 12g of egg yolk lecithin, and disperse at high speed until the egg yolk lecithin is completely dissolved to obtain the oil phase. Measure 700ml of water for injection and heat to 60-80℃, weigh 22.5g of glycerol and 0.3g of sodium oleate and add them to 700ml of water for injection, stir until dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 10.0~10.4 to obtain the water phase. Mix the oil phase and the water phase, high-shear disperse and emulsify at 10000rpm for 1min, add water for injection to 1000ml to obtain colostrum. The colostrum is homogenized by a homogenizer, set the low pressure to 80-100bar, homogenize once, set the high pressure to 700bar and homogenize 5 times to obtain refined milk. Fill the emulsion into an infusion bag and sterilize it at 121℃×15min. Example 2

[0015] Weigh 160g olive oil and 40g soybean oil, heat to 60-80℃, add 12g egg yolk lecithin, and disperse at high speed until the egg yolk lecithin is completely dissolved to obtain the oil phase. Measure 700ml water for injection and heat to 60-80℃, weigh 22.5g glycerol and 0.3g sodium oleate and add them to 700ml water for injection, stir until dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 10.0~10.4 to obtain the water phase. Mix the oil phase and the water phase, high-shear disperse and emulsify at 10000rpm for 5min, add water for injection to 1000ml to obtain colostrum. The colostrum is homogenized by a homogenizer, set the low pressure to 80-100bar, homogenize once, and set the high pressure to 700bar for 5 times. Fill the emulsion into an infusion bag and sterilize it at 121℃×15min. Example 3

[0016] Weigh 160g olive oil and 40g soybean oil, heat to 60-80℃, add 12g egg yolk lecithin, and disperse by high-speed shear until the egg yolk lecithin is completely dissolved to obtain the oil phase. Measure 700ml water for injection and heat to 60-80℃, weigh 22.5g glycerol and 0.3g sodium oleate and add them to 700ml water for injection, stir until dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 10.0~10.4 to obtain the water phase. Mix the oil phase and the water phase, high-shear disperse and emulsify at 10000rpm for 10min, add water for injection to 1000ml to obtain colostrum. The colostrum is homogenized by a homogenizer, set the low pressure to 80-100bar, homogenize once, set the high pressure to 700bar and homogenize 5 times to obtain refined milk. Fill the emulsion into an infusion bag and sterilize it at 121℃×15min. Example 4

[0017] Weigh 160g of olive oil and 40g of soybean oil, heat to 60-80℃, add 12g of egg yolk lecithin, and disperse at high speed until the egg yolk lecithin is completely dissolved to obtain the oil phase. Measure 700ml of water for injection and heat to 60-80℃, weigh 22.5g of glycerol, and 0.06g of sodium oleate, add them to 700ml of water for injection, stir until dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 10.0-10.4, and obtain the water phase. Mix the oil phase and the water phase, high-shear dispersion and emulsification at 10000rpm for 10min, add water for injection to 1000ml, and obtain colostrum. The colostrum is homogenized by a homogenizer, set the low pressure to 80-100bar, homogenize once, set the high pressure to 700bar and homogenize 4 times, add 0.24g of sodium oleate, and homogenize once at high pressure to obtain refined milk. Nitrogen protection is provided during the preparation process. The emulsion was filled into an infusion bag and nitrogen was filled for protection during the filling process. The sample was sterilized at 121°C for 15 min.

[0018] The colostrum prepared in the examples was used to observe the oil droplet conditions on the surface of the emulsion. The results are summarized in Table 1. Example 5

[0019] Weigh 160g olive oil and 40g soybean oil, heat to 60-80℃, add 12g egg yolk lecithin, and disperse at high speed until the egg yolk lecithin is completely dissolved to obtain the oil phase. Measure 700ml water for injection and heat to 60-80℃, weigh 22.5g glycerol, 0.06g sodium oleate and add them to 700ml water for injection, stir until dissolved, add sodium hydroxide solution to adjust the pH value of the solution to 10.0~10.4 to obtain the water phase. Adjust the mixing ratio of the oil phase and the water phase to 38:37, emulsify 1-9 times, observe the oil droplets on the surface of the colostrum, add water for injection to 1000ml, and obtain colostrum. The colostrum is homogenized by a homogenizer, set the low pressure to 80-120bar, homogenize 3 times, set the high pressure to 600bar and homogenize 7 times, add 0.24g sodium oleate, and homogenize once at high pressure. Nitrogen protection is provided during the preparation process. The emulsion was filled into an infusion bag and nitrogen was filled for protection during the filling process. The sample was sterilized at 121°C for 15 min.

[0020] Table 1 Oil droplet conditions on colostrum surface under different emulsification operations

[0021] Note: “-” indicates no floating oil or stratification, and “+” indicates the degree of floating oil or stratification.

[0022] The finished product prepared in the embodiment was tested for properties, milk particles, anisidine value, lysophosphatidylethanolamine, and lysophosphatidylethanolamine. The results are summarized in Table 2.

[0023] Table 2 Quality comparison of long-chain fat emulsions obtained by different preparation methods

[0024] Note: NA means not tested.

[0025] Conclusion: The finished product prepared according to Example 5 has significantly improved emulsion particles, methoxyaniline value, lysophosphatidylethanolamine, and stability of lysophosphatidylethanolamine than those of other examples, indicating that when preparing long-chain fat emulsion injection (OO), the oxidation index can be effectively reduced by controlling nitrogen protection during the preparation process, and the size of the emulsion particles can be effectively guaranteed by adding the stabilizer sodium oleate in stages, controlling the emulsification times, homogenization pressure, and homogenization times, reducing the number of emulsion particles larger than 0.75 μm, and improving the stability of the storage process and the safety of clinical medication.

Claims

1. A method for preparing a long-chain fat emulsion injection (OO), characterized in that: The specific steps of the preparation method are: (1) 40 parts by weight of soybean oil, 160 parts by weight of olive oil and 12 parts by weight of egg yolk lecithin are mixed and dissolved by high-speed shear stirring at 60-80° C. to obtain an oil phase; (2) Add 22.5 parts by weight of glycerol and 0.06-0.24 parts by weight of sodium oleate to water for injection, heat to 60-80°C to dissolve, and adjust the pH value of the solution to 10.0-10.4 with sodium hydroxide solution to obtain an aqueous phase; (3) Mix and emulsify the oil phase and the water phase to obtain colostrum, and add water for injection to the prepared amount; (4) homogenizing the colostrum with a homogenizer, adding the remaining 0.24-0.06 parts by weight of sodium oleate before the last homogenization and continuing the homogenization; (5) Finally, the emulsion is filtered through a filter element and then bottled and sterilized.

2. The preparation method according to claim 1, characterized in that: The shearing speed of step (1) is 10000 rpm, and the shearing time is 1-10 min, preferably 5 min.

3. The preparation method according to claim 1, characterized in that: In the step (3), the mass ratio of the oil phase to the water phase is 38:37, and the number of emulsifications is 1-9 times, preferably 7-9 times.

4. The preparation method according to claim 1, characterized in that: The homogenization pressure in step (4) is 80-120 bar for the secondary pressure, 1-3 times for the homogenization, preferably 3 times; and 500-800 bar for the primary pressure, 5-8 times for the homogenization, preferably 8 times.

5. The preparation method according to claim 1, characterized in that: In the step (5), the mixture is filled into a three-layer co-extruded infusion bag.

6. The preparation method according to claim 1, characterized in that: The sterilization condition in step (5) is 121° C. for 8-20 min, preferably 15 min.

7. The preparation method according to any one of claims 1 to 6, characterized in that: Nitrogen protection is used during emulsion preparation and filling.

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