Fat emulsion injection as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biological medicines, and discloses a fat emulsion injection as well as a preparation method and application thereof. The fat emulsion injection provided by the invention is prepared from the following components: oil for injection, polysorbate 80, PEG-40 stearate, glyceryl monostearate, an isoosmotic adjusting agent, a pH (Potential of Hydrogen) adjusting agent, water for injection and sodium cholate. After the fat emulsion injection provided by the invention is sterilized, the average particle size of the fat emulsion is 198nm-242nm, the proportion of PFAT5 in an oil phase is 0.006%-0.015%, and the fat emulsion injection is not easily influenced by external conditions such as high temperature or illumination and is stable in property. The invention further provides application of the fat emulsion injection in a three-cavity bagged parenteral nutrition injection, the safety of clinical use is improved to a certain extent, and the fat emulsion injection has important social significance and economic value.

Description

Technical Field

[0001] The present invention relates to the field of biopharmaceutical technology, and specifically discloses a fat emulsion injection, a preparation method thereof, and an application thereof. Background Art

[0002] Parenteral nutrition support and treatment can effectively maintain the healthy nutritional status of patients, maintain the positive nitrogen balance of the body, and play a positive role in improving the disease tolerance of patients, promoting wound healing, and increasing the success rate of rescue. The parenteral nutrition "three-chamber bag" (TCB) is a ready-to-use premixed multi-chamber bag form of parenteral nutrition bag, which has three separate chamber structures, containing glucose injection, amino acid injection, and fat emulsion injection respectively. Before infusion, the nutrition bag is squeezed to separate the inter-chamber spacer strips, and the components are mixed with each other, and then it can be directly infused clinically. Doctors can also directly add electrolytes, vitamins, and trace elements to the TCB doctor's order according to the patient's nutritional status. TCB has the advantages of convenient use, relatively comprehensive components, reasonable nutrient ratio, and long storage time. According to statistics, currently in European countries such as France, Belgium, and Sweden, the usage amount of TCB accounts for more than 80% of parenteral nutrition, becoming the mainstream choice of parenteral nutrition.

[0003] Before clinical use of the parenteral nutrition three-chamber bag, after mixing the fat emulsion injection, amino acid injection, and glucose injection by extrusion, the drugs coexist in the form of a mixture of colloidal solution and emulsion, which is a thermodynamically unstable system, and its stability is affected by additives such as electrolytes. Since vitamins and trace elements are not added in the prescription and the electrolyte content is also small, if TCB is given for a long time without supplementing vitamins, patients may develop other diseases due to vitamin or electrolyte deficiency (such as Wernicke encephalopathy caused by vitamin B1 deficiency). Therefore, during clinical use, doctors often add fat-soluble vitamins, water-soluble vitamins, potassium chloride, sodium chloride, or various trace elements to TCB according to the needs of the patient's body.

[0004] However, in the prior art, the stability of the fat emulsion injection mixed with other components is generally poor, and the fat emulsion injection is prone to phenomena such as emulsion destruction, increase in emulsion particles, or oil floating. The quality of the fat emulsion injection (such as average particle size, its particle size distribution, and stability) is directly related to the safety of patient medication. For example, particles >5 - 20 μm will block the pulmonary capillaries and cause pulmonary embolism; if PFAT5 > 0.4%, it will cause fat emulsion separation or demulsification, forming yellow-brown oil droplets near the parenteral nutrition liquid surface, and infusion can endanger the patient's life. Summary of the Invention

[0005] In view of the problem that the fat emulsion injection in the parenteral nutrition three-chamber bag in the prior art is unstable after being mixed with amino acid injection, glucose injection, electrolyte or vitamin, the present invention provides a stable fat emulsion injection applicable to parenteral nutrition in a three-chamber bag and its preparation method by adjusting the fat emulsion prescription, improving the preparation process and other means.

[0006] To achieve the above invention purpose, the present invention adopts the following technical solutions: In the first aspect, the present invention provides a fat emulsion injection. Every 1000 mL of the fat emulsion injection comprises the following components: 100 g of injection oil, 5.5 g - 7.5 g of emulsifier, 2 g - 4 g of emulsification aid, 15 g - 20 g of isotonicity regulator, pH regulator and injection water; Wherein, the emulsifier comprises polysorbate 80, PEG-40 stearate and glycerol monostearate; The emulsification aid comprises sodium cholate.

[0007] By optimizing the prescription in the fat emulsion injection, especially improving the types and dosages of the emulsifier and emulsification aid, the present invention provides a fat emulsion injection with stable performance. After sterilization, the average particle size of the fat emulsion is between 198 nm and 242 nm, the proportion of PFAT5 in the oil phase is 0.006% - 0.015%, and indexes such as anisidine value all meet the standards. Affected by external conditions such as high temperature or light, various performance parameters change little and the property is stable.

[0008] In the fat emulsion injection provided by the present invention, polysorbate 80, PEG-40 stearate and glycerol monostearate in specific proportions are used as the emulsifier, and sodium cholate is used as the emulsification aid. When the preferred emulsifier and emulsification aid are used in the fat emulsion injection, they have a synergistic effect in aspects such as solubilization, promoting emulsification and improving stability. Specifically as follows: In terms of solubilization, in the fat emulsion injection, polysorbate 80, PEG-40 stearate, glycerol monostearate and sodium cholate act together to expand the scope and effect of solubilization. They can respectively start from different structural characteristics and action modes to solubilize different fat-soluble components in the fat emulsion, so that more oil substances can be stably dispersed in the aqueous phase, improving the stability of the fat emulsion and the dissolution degree of the drug, and ensuring the uniform distribution of the oil phase components in the whole system of the fat emulsion injection. For example, when polysorbate 80 or PEG-40 stearate is used together with sodium cholate, a mixed micelle can be formed and the solubilization effect is better; the long hydrophilic chain of PEG-40 stearate enhances the thickness of the hydration layer of the micelle, while the lipid structure of glycerol monostearate promotes the encapsulation of fat-soluble components, jointly expanding the solubilization range; In terms of emulsification, when hydrophilic emulsifiers (polysorbate 80 and PEG - 40 stearate) are used in combination with lipophilic emulsifier (glycerol monostearate), they can form a more compact and stable interfacial film at the oil - water interface. This can better reduce the surface tension at the oil - water interface, make the oil droplets more evenly dispersed in the aqueous phase, form finer and more uniform emulsion particles, and improve the emulsification effect. Sodium cholate increases the repulsive force between emulsion droplets through electrostatic repulsion, and at the same time forms mixed micelles with polysorbate 80 and PEG - 40 stearate, optimizing the interfacial charge distribution, further reducing the interfacial tension, and acting together with the emulsifiers to enhance the strength and stability of the interfacial film. Their mutual cooperation makes the formed fat emulsion have smaller particle size and more uniform distribution, improves the emulsification effect and stability of the fat emulsion, and prevents phenomena such as stratification and demulsification during storage and use of the fat emulsion.

[0009] In terms of stability, the composite interfacial film combines steric hindrance (polysorbate 80, PEG - 40) and electrostatic repulsion (sodium cholate), which can effectively resist the Ostwald ripening and aggregation of emulsion droplets; non - ionic surfactants are insensitive to changes in pH and ionic strength, while sodium cholate maintains charge stability in the physiological environment, and the two complement each other to reduce the hydrolysis risk of drugs or lipids; the multi - component surfactant system provided by the present invention delays phase separation by reducing the interfacial free energy and forming a high - energy potential barrier. Their combined action can resist the interference of external factors (such as temperature changes, electrolyte effects, etc.) on the fat emulsion system, enable the fat emulsion to maintain good stability under different environmental conditions, extend its shelf life, and ensure the safety and effectiveness of clinical use.

[0010] Preferably, the mass ratio of polysorbate 80, PEG - 40 stearate and glycerol monostearate in the emulsifier is 1 - 2:2 - 4:1.5 g - 3.5 g; The injection oil is composed of soybean oil for injection, olive oil and medium - chain triglycerides in a mass ratio of 1 - 2:9 - 12:9 - 15; The isotonicity regulator includes glycerol; The pH regulator includes sodium hydroxide.

[0011] The injection oil in the present invention is composed of soybean oil for injection, olive oil and medium - chain triglycerides in a specific ratio. The present invention finds that the stability of the fat emulsion prepared by mixing medium - chain triglycerides, soybean oil and olive oil is significantly higher than that of the fat emulsion prepared from soybean oil. The reasons may be as follows: (1) The chemical differences in the oil phase significantly affect the energy barrier required for the stability of the dispersion. When water is used as the dispersion medium, the short - chain hydrocarbons (C 8 -C 10 ) in medium - chain triglycerides and the long - chain hydrocarbons (average C 18Compared with [[ID=]], it has a lower free energy and more stable properties; (2) Medium-chain triglycerides or olive oil may also contain sodium oleate that can act as a co-emulsifier.

[0012] In addition, olive oil also contains abundant α-tocopherol (the active form of vitamin E, which can act as an antioxidant), which can inhibit the formation of lipid peroxides and improve the stability of the oil.

[0013] Preferably, the pH of the fat emulsion injection is 7.5 - 9.5. More preferably, the pH of the fat emulsion injection is 8.0 - 8.5.

[0014] In a second aspect, the present invention also provides a method for preparing the above fat emulsion injection, and the preparation method includes the following steps: S1. Under the protection of a protective gas, heat the injection oil, and sequentially add an emulsifier and an emulsification aid, and mix well to obtain an oil phase; S2. Heat 50% - 80% of the prescribed amount of injection water, add the isotonicity regulator, mix well, and filter to obtain an aqueous phase; S3. Under the protection of a protective gas, stir at a speed of 5000 revolutions per minute to 20000 revolutions per minute, and add the oil phase to the aqueous phase and stir for 15 minutes to 30 minutes to obtain a primary emulsion; S4. Make up the injection water to the full volume for the primary emulsion, mix well, then add it to a microfluidic high-pressure homogenizer for homogenization, and add a pH regulator to obtain an emulsion; S5. Cool and filter the emulsion to obtain a fat emulsion injection.

[0015] The preparation method of the fat emulsion injection provided by the present invention, by optimizing the feeding sequence, controlling the preparation process parameters, and simultaneously using a microfluidic high-pressure homogenizer to prepare the fat emulsion, significantly reduces the particle size and PFAT5 of the prepared fat emulsion, and improves the medication safety of patients.

[0016] Preferably, in step S1, the heating temperature is 60°C to 80°C; Under the stirring at a speed of 5000 revolutions per minute to 10000 revolutions per minute, add the emulsifier and the emulsification aid.

[0017] Preferably, in step S2, the heating temperature is 60°C to 80°C; In step S2, for the filtration, a filter membrane with a pore size of 0.4μm to 0.5μm is selected. In the examples of the present invention, a 0.45μm filter membrane is taken as an example for illustration.

[0018] Preferably, in step S4, the pressure of the homogenization is 10000 psi to 15000 psi; The number of times of the homogenization is 3 to 4 times.

[0019] Preferably, in step S5, the cooling temperature is 20°C to 40°C; The filtration in step S5 is coarse filtration, and a filter membrane with a pore size of 2 μm to 5 μm is selected.

[0020] In the present invention, the protective gas includes any one of nitrogen, carbon dioxide, or noble gases. In the embodiments of the present invention, nitrogen is taken as an example for illustration.

[0021] The preparation process of the fat emulsion injection provided by the present invention is simple, the operation is controllable, and it is easy to realize industrialization.

[0022] In a third aspect, the present invention also provides a three-chamber bag parenteral nutrition injection, which contains the fat emulsion injection according to any one of claims 1 to 3.

[0023] In a fourth aspect, the present invention also provides a preparation method of the above three-chamber bag parenteral nutrition injection. The preparation method includes the following steps: filling the fat emulsion injection, amino acid injection, and glucose injection into different chambers of a three-chamber bag respectively, and then sterilizing to obtain the product.

[0024] Among them, the amino acid injection and glucose injection can be compound amino acid injection and glucose injection in the prior art.

[0025] Exemplarily, every 1000 mL of amino acid injection may include the following components: alanine 10 g to 15 g, arginine 5 g to 10 g, glycine 3 g to 8 g, histidine 1 g to 5 g, isoleucine 2 g to 5 g, leucine 3 g to 8 g, lysine hydrochloride 2 g to 6 g, methionine 1.5 g to 4.5 g, phenylalanine 2 g to 6 g, proline 2 g to 6 g, serine 1.5 g to 5 g, threonine 1 g to 5 g, tryptophan 0.05 g to 3 g, tyrosine 0.1 g to 3 g, valine 1 g to 5 g, sodium acetate 2 g to 6 g, phosphate 3 g to 8 g, sodium chloride 1.5 g to 5 g, magnesium chloride 0.5 g to 3 g, pH regulator, and injection water; Every 1000 mL of glucose injection may include the following components: glucose 100 g to 300 g, pH regulator, and injection water; Among them, the pH regulator includes at least one of hydrochloric acid, citric acid, or acetic acid.

[0026] In the present invention, the sterilization can be selected as moist heat sterilization, the sterilization temperature is 110°C to 125°C, and the sterilization time is 10 minutes to 15 minutes.

[0027] The three-chamber bag parenteral nutrition injection provided by the present invention has good stability. When clinically infused and mixed or mixed with other electrolytes or vitamins, the emulsion of the fat emulsion will not be destroyed, the oil particles are stable, and phase separation does not occur. Within 24 hours of storage at 0°C to 4°C, the growth trend of PFAT5 in the system is relatively slow, ranging from 0.024% to 0.027%. The three-chamber bag parenteral nutrition injection provided by the present invention improves the safety of clinical use to a certain extent and has important social significance and economic value. Detailed implementation mode

[0028] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0029] The raw materials and reagents used in the present invention are all conventional commercially available products without special instructions; the methods used in the present invention are all conventional methods in the art without special instructions.

[0030] The model of the microfluidic high-pressure homogenizer selected in the embodiment of the present invention is NanoGenizer-II; The conventional high-pressure homogenizer selected in the comparative example of the present invention is produced by SPX Flow Technology Co., Ltd. and the model is RANNIE55-25.95; The medium-chain triglyceride for injection is caprylic / capric triglyceride, and the brand is KLK Malaysia.

[0031] In order to better illustrate what is provided in the embodiment of the present invention, further examples are given below through embodiments.

[0032] Example 1 This embodiment provides a fat emulsion injection. Each 1000 mL of the fat emulsion injection includes the following components: 5 g of soybean oil for injection, 50 g of olive oil for injection, 45 g of caprylic / capric triglyceride, 1 g of polysorbate 80, 3.5 g of PEG-40 stearate, 1.5 g of glycerol monostearate, 2 g of sodium cholate, 15 g of glycerol, an appropriate amount of sodium hydroxide, and the balance is water for injection; This embodiment also provides a preparation method for the above fat emulsion injection, which is specifically as follows: S1. Under nitrogen protection, stir the soybean oil for injection, olive oil for injection and caprylic / capric triglyceride evenly and heat to 60°C, and add polysorbate 80, PEG-40 stearate, glycerol monostearate and sodium cholate and mix evenly under stirring at 10,000 revolutions per minute to obtain an oil phase; S2. Heat 700 mL of water for injection to 62°C, add glycerol, mix evenly, and filter through a 0.45 μm filter membrane to obtain an aqueous phase; S3. Under nitrogen protection, add the above oil phase to the water phase while stirring at a speed of 20,000 revolutions per minute, and continuously stir for 15 minutes to obtain the primary emulsion; S4. Rapidly cool the primary emulsion to 50 °C, make up the volume to the full amount with injection water, mix well and then add it to a microfluidic high-pressure homogenizer, homogenize 4 times at 10,000 psi and 50 °C, and add 1 mol / L sodium hydroxide solution to adjust the pH to 9 to obtain the emulsion; S5. Cool the emulsion to 40 °C, filter it through a 5-μm filter membrane to obtain the fat emulsion injection, denoted as fat emulsion injection Ⅰ.

[0033] Example 2 This example provides a fat emulsion injection. Each 1000 mL of the fat emulsion injection contains the following components: 8 g of soybean oil for injection, 48 g of olive oil for injection, 44 g of medium-chain triglyceride, 0.5 g of polysorbate 80, 4 g of PEG-40 stearate, 2.5 g of glycerol monostearate, 4 g of sodium cholate, 20 g of glycerol, an appropriate amount of sodium hydroxide, and the balance is injection water; This example also provides a preparation method for the above fat emulsion injection, which is as follows: S1. Under nitrogen protection, stir the soybean oil for injection, olive oil for injection and medium-chain triglyceride evenly and heat to 80 °C, and add polysorbate 80, PEG-40 stearate, glycerol monostearate, cholic acid and sodium cholate while stirring at 5000 revolutions per minute to mix well to obtain the oil phase; S2. Heat 440 mL of injection water to 80 °C, add glycerol, mix well, and filter through a 0.45-μm filter membrane to obtain the water phase; S3. Under nitrogen protection, add the above oil phase to the water phase while stirring at a speed of 5000 revolutions per minute, and continuously stir for 30 minutes to obtain the primary emulsion; S4. Rapidly cool the primary emulsion to 45 °C, make up the volume to the full amount with injection water, mix well and then add it to a microfluidic high-pressure homogenizer, homogenize 3 times at 15,000 psi and 45 °C, and add 1 mol / L sodium hydroxide solution to adjust the pH to 7.5 to obtain the emulsion; S5. Cool the emulsion to 30 °C, filter it through a 2-μm filter membrane to obtain the fat emulsion injection, denoted as fat emulsion injection Ⅱ.

[0034] Example 3 This example provides a fat emulsion injection. Each 1000 mL of the fat emulsion injection contains the following components: 4 g of soybean oil for injection, 36 g of olive oil for injection, 60 g of medium-chain triglyceride, 1.5 g of polysorbate 80, 2.5 g of PEG-40 stearate, 1.5 g of glycerol monostearate, 2 g of sodium cholate, 18 g of glycerol, an appropriate amount of sodium hydroxide, and the balance is injection water; This example also provides a preparation method of the above fat emulsion injection, which is as follows: S1. Under nitrogen protection, stir the soybean oil for injection, olive oil for injection and caprylic / capric triglyceride evenly and heat to 70°C. Add polysorbate 80, PEG-40 stearate, glycerol monostearate and sodium cholate while stirring at 8000 rpm and mix evenly to obtain the oil phase; S2. Heat 650 mL of water for injection to 70°C, add glycerol, mix evenly, and filter through a 0.45 μm filter membrane to obtain the aqueous phase; S3. Under nitrogen protection, add the above oil phase to the aqueous phase while stirring at a speed of 10000 rpm, and continue stirring for 20 minutes to obtain the primary emulsion; S4. Rapidly cool the primary emulsion to 40°C, make up the volume to the full amount with water for injection, mix evenly, then add it to a microfluidic high-pressure homogenizer, and homogenize 3 times at 12000 psi and 40°C. Add 1 mol / L sodium hydroxide solution to adjust the pH to 9.5 to obtain the emulsion; S5. Cool the emulsion to 20°C, and filter through a 3 μm filter membrane to obtain the fat emulsion injection, denoted as fat emulsion injection III.

[0035] Example 4 This example provides a fat emulsion injection. Each 1000 mL of the fat emulsion injection contains the following components: 6 g of soybean oil for injection, 44 g of olive oil for injection, 50 g of caprylic / capric triglyceride, 2 g of polysorbate 80, 2 g of PEG-40 stearate, 3.5 g of glycerol monostearate, 3 g of sodium cholate, 16 g of glycerol, an appropriate amount of sodium hydroxide, and the balance is water for injection; This example also provides a preparation method of the above fat emulsion injection, which is as follows: S1. Under nitrogen protection, stir the soybean oil for injection, olive oil for injection and caprylic / capric triglyceride evenly and heat to 65°C. Add polysorbate 80, PEG-40 stearate and sodium cholate while stirring at 6000 rpm and mix evenly to obtain the oil phase; S2. Heat 650 mL of water for injection to 65°C, add glycerol, mix evenly, and filter through a 0.45 μm filter membrane to obtain the aqueous phase; S3. Under nitrogen protection, add the above oil phase to the aqueous phase while stirring at a speed of 12000 rpm, and continue stirring for 18 minutes to obtain the primary emulsion; S4. Rapidly cool the primary emulsion to 45°C, make up the volume to the full amount with water for injection, mix evenly, then add it to a microfluidic high-pressure homogenizer, and homogenize 3 times at 12000 psi and 45°C. Add 1 mol / L sodium hydroxide solution to adjust the pH to 8.5 to obtain the emulsion; S5. Cool the emulsion to 35°C, and filter through a 2.5 μm filter membrane to obtain the fat emulsion injection, denoted as fat emulsion injection IV.

[0036] Example 5 This example provides a three-chamber bag parenteral nutrition injection and its preparation method, and the specific content is as follows: I. The three-chamber bag parenteral nutrition injection provided in this example includes the fat emulsion injection Ⅰ prepared in Example 1, as well as a conventional amino acid injection and a glucose injection.

[0037] The present invention is illustrated by the following amino acid injection. Every 1000 mL of the amino acid injection includes: alanine 11.39 g, arginine 6.33 g, glycine 5.67 g, histidine 2.64 g, isoleucine 3.30 g, leucine 4.02 g, lysine hydrochloride 3.99 g, methionine 2.20 g, phenylalanine 3.08 g, proline 3.74 g, serine 2.75 g, threonine 2.31 g, tryptophan 0.99 g, tyrosine 0.22 g, valine 3.19 g, sodium acetate 4.31 g, dipotassium hydrogen phosphate 5.23 g, sodium chloride 2.24 g, magnesium chloride 1.03 g, glacial acetic acid and water for injection; The preparation method of the amino acid injection is as follows: Take 750 mL of water for injection, introduce nitrogen under stirring at 6000 revolutions per minute until the dissolved oxygen in the water for injection reaches below 2 ppm, add the above amino acids and electrolytes, stir and dissolve, add water for injection to 1000 mL, adjust the pH to 5.5 - 5.7, and filter through a 5 μm filter membrane to obtain the amino acid injection.

[0038] The composition of the glucose injection is: Every 1000 mL of the glucose injection includes: anhydrous glucose 209 g, hydrochloric acid and water for injection; The preparation method of the glucose injection is as follows: Take 800 mL of water for injection, introduce nitrogen under stirring at 6000 revolutions per minute until the dissolved oxygen in the water for injection reaches below 2 ppm, add glucose, stir and dissolve, add water for injection to 1000 mL, adjust the pH to 4.2 - 4.5 with hydrochloric acid, and filter through a 5 μm filter membrane to obtain the glucose injection.

[0039] II. This example also provides a preparation method of the above three-chamber bag parenteral nutrition injection, which specifically includes the following steps: After respectively and precisely filtering (selecting a 0.65 μm filter membrane in this example) the above fat emulsion injection, amino acid injection and glucose injection, adjust the filling volume of each liquid medicine, fill and seal with nitrogen in a three-chamber bag; then sterilize by moist heat at 121 °C for 12 minutes, and conduct lamp inspection to obtain the three-chamber bag parenteral nutrition injection, denoted as three-chamber bag Ⅰ.

[0040] Among them, the filling volumes of the fat emulsion injection, amino acid injection, and glucose injection can be adjusted accordingly according to the volumes indicated on the product. In this embodiment, the volumes of the three are 205 mL, 310 mL, and 530 mL in sequence. Examples 6 - 8 Examples 6 - 8 respectively provide a three - chamber bag parenteral nutrition injection and its preparation method. Its composition and preparation method are basically the same as those of Example 5, with the only difference being that: the fat emulsion injection selected for the three - chamber bag parenteral nutrition injection provided in Example 6 is Fat Emulsion Injection Ⅱ, the fat emulsion injection selected for the three - chamber bag parenteral nutrition injection provided in Example 7 is Fat Emulsion Injection Ⅲ, and the fat emulsion injection selected for the three - chamber bag parenteral nutrition injection provided in Example 8 is Fat Emulsion Injection Ⅳ. The compositions and preparation methods of the remaining injections are the same as those of Example 5. The three - chamber bag parenteral nutrition injections prepared in Examples 6 - 8 are sequentially denoted as Three - chamber Bag Ⅱ~Three - chamber Bag Ⅳ.

[0041] Comparative Example 1 This comparative example provides a fat emulsion injection and its preparation method. Among them, the components and dosages of the fat emulsion injection are the same as those of Example 3. The preparation method of the fat emulsion injection provided in this comparative example is basically the same as that of Example 3, with the only difference being that in step S4, a conventional high - pressure homogenizer is used for homogenization, and after adjusting the pH, homogenization is carried out once again. The remaining steps and their parameters are the same as those of Example 3. S4 is as follows: S4. Rapidly cool the primary emulsion to 40 °C, make up the injection water to the full volume, mix well and then add it into the high - pressure homogenizer. The homogenization pressure is 650 bar for the first - stage valve and 120 bar for the second - stage valve. Homogenize 4 times, add 1 mol / L sodium hydroxide solution to adjust the pH to 8, mix well and then homogenize 1 time again. The homogenization pressure is 160 bar for the first - stage valve and 120 bar for the second - stage valve to obtain the emulsion.

[0042] The fat emulsion injection prepared in this comparative example is denoted as Fat Emulsion Injection Pair Ⅰ.

[0043] Comparative Example 2 This comparative example provides a fat emulsion injection. Among them, the fat emulsion injection provided in this comparative example is based on Example 3 and only does not add PEG - 40 stearate and cholalic acid. The remaining components and their dosages are the same as those of Example 3. The difference in the preparation method of the fat emulsion injection provided in this comparative example from that of Example 3 is only that PEG - 40 stearate and sodium cholate are not added during preparation, and the remaining steps and parameters are the same. Among them, each 1000 mL of the fat emulsion injection provided in this comparative example includes the following components: 4 g of soybean oil for injection, 36 g of olive oil for injection, 60 g of medium - chain triglyceride, 1.5 g of polysorbate 80, 1.5 g of glycerol monostearate, 18 g of glycerol, an appropriate amount of sodium hydroxide, and the balance is injection water.

[0044] The fat emulsion injection prepared in this comparative example is denoted as fat emulsion injection pair II.

[0045] Effect Example 1 One object of the present invention is to provide a fat emulsion injection suitable for a three-chamber bag parenteral nutrition injection. Before filling the fat emulsion injection, glucose injection, and amino acid injection into the three-chamber bag, fine filtration is required, and after filling, unified sterilization is required. Therefore, the fat emulsion injections prepared in the above examples and comparative examples are not subjected to fine filtration and sterilization. To investigate the performance of the fat emulsion injection before infusion, the fat emulsion injections prepared in Examples 1-4 and Comparative Examples 1-2 of the present invention were finely filtered through a 0.65 μm filter membrane, and according to the conventional operation of fat emulsion injections in the art, nitrogen was filled and filled into a 50 mL infusion bag, and sterilized by moist heat at 121 °C for 12 min to obtain the corresponding finished fat emulsion injections, which were denoted as fat emulsion I to fat emulsion IV, fat emulsion pair I to fat emulsion pair II in sequence, and their properties, average particle size, PFAT5, and p-anisidine value and other indicators were measured, and the measurement method was based on the method described in the Chinese Pharmacopoeia 2020 Edition. Since lysophosphatidyl choline (LPC) and lysophosphatidyl ethanolamine (LPE) are degradation products of egg yolk lecithin during the preparation and storage process, and egg yolk lecithin is not used in the present invention, these two indicators are not measured in the present invention for the time being. The specific measurement results are shown in Table 1 below.

[0046] Table 1

[0047] As can be seen from Table 1, after sterilization, the fat emulsion injections prepared in Examples 1-4 are milky white uniform milky liquids, with an average particle size in the range of 198 nm to 242 nm, the proportion of PFAT5 in the oil phase is 0.006% to 0.015%, and the p-anisidine value is 0.63 to 0.81.

[0048] After changing the homogenization condition from microfluidic homogenization to conventional homogenization treatment, or after not adding PEG-40 stearate and sodium cholate, the average particle size and PFAT5 of the prepared fat emulsion pair I and fat emulsion pair II are significantly higher than those of fat emulsion III.

[0049] In addition, the above-prepared fat emulsion I to fat emulsion IV, fat emulsion pair I to fat emulsion pair II were treated at high temperature (60 °C) and light (5500 ± 500 lx) for 10 days respectively to investigate their stability. After observation, the various performance parameters of fat emulsion I to fat emulsion IV and fat emulsion pair I changed little during the investigation period and were stable, while after the fat emulsion pair II was treated at high temperature for 10 days, its PFAT5 increased significantly from 0.022% to 0.041%, and its properties were unstable.

[0050] In summary, the fat emulsion injection provided in Embodiments 1-4 of the present invention has stable properties, and indicators such as average particle size, PFAT5, and anisidine value all meet the standards. Affected by external conditions such as high temperature or light, various performance parameters change little and the properties are stable.

[0051] Effect Example 2 In order to simulate the clinical requirements of parenteral nutrition three-chamber bags with water-soluble vitamins, fat-soluble vitamins, potassium chloride, concentrated sodium chloride, and various trace elements, the present invention prepares a three-chamber parenteral nutrition injection (denoted as three-chamber bag pair II) from the fat emulsion injection provided in Comparative Example 2 according to the preparation method provided in Example 5. Further, the three-chamber bags I-IV, the three-chamber bag pair II are mixed with vitamins, electrolytes, trace elements, etc., and the stability of the fat emulsion after mixing is investigated. The specific content is as follows: Mix the liquids in the three chambers of the above different three-chamber bags, and sequentially add 10 mL of Wellman water-soluble vitamins for injection and 10 mL of fat-soluble vitamin injection (II) (Sichuan Kelun Pharmaceutical Co., Ltd.), then add 10 mL of multiple trace element injection (II) (Addamel), and then add 10 mL of potassium chloride injection (Shijiazhuang No. 4 Pharmaceutical Co., Ltd.) and 10 mL of concentrated sodium chloride injection (Shijiazhuang No. 4 Pharmaceutical Co., Ltd.). When adding electrolytes, disperse them in time. After gently shaking and mixing thoroughly, samples are taken at 0 h, 4 h, 8 h, and 12 h respectively when placed at 0 °C to 4 °C to test PFAT5. The test results of PFAT5 at different placement times for different groups are shown in Table 2.

[0052] Table 2

[0053] The data results in Table 2 show that after the three-chamber parenteral nutrition injections of different groups are mixed with water-soluble vitamins, fat-soluble vitamins, potassium chloride, concentrated sodium chloride, and various trace elements, the number of milk particles larger than 5 μm shows an upward trend with the increase of the placement time. The PFAT5 of the three-chamber bag prepared from the fat emulsion injection prepared in Comparative Example 2 is 0.055% after being stored for 24 hours, exceeding the relevant requirements, and there will be potential safety hazards if infused with this. After the three-chamber parenteral nutrition injections prepared in Embodiments 5-8 of the present invention are mixed with vitamins and electrolytes, within the 24-hour time limit, the growth trend of PFAT5 in the system is relatively slow, at 0.024% to 0.027%, and the emulsion properties are stable.

[0054] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A fat emulsion injection, characterized in that: Each 1000 mL of the fat emulsion injection includes the following components: 100 g of injection oil, 5.5 g to 7.5 g of emulsifier, 2 g to 4 g of emulsifying aid, 15 g to 20 g of isotonicity regulator, pH regulator and water for injection; Wherein, the emulsifier includes polysorbate 80, PEG-40 stearate and glyceryl monostearate; The emulsifying aid includes sodium cholate.

2. The fat emulsion injection according to claim 1, characterized in that: The mass ratio of polysorbate 80, PEG-40 stearate and glyceryl monostearate is 1-2:2-4:1.5g-3.5g; and / or The injection oil is soybean oil, olive oil and medium chain triglycerides in a mass ratio of 1-2:9-12:9-15; and / or The isotonicity adjusting agent comprises glycerol; and / or The pH adjuster includes sodium hydroxide.

3. The fat emulsion injection according to claim 1, characterized in that: The pH of the fat emulsion injection is 7.5-9.

5.

4. The method for preparing the fat emulsion injection according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: S1. Under protective gas protection, heat the injection oil, add the emulsifier and emulsifying aid in sequence, mix well, and obtain the oil phase; S2. Heat 50% to 80% of the prescribed amount of water for injection, add the isotonicity regulator, mix, filter, and obtain an aqueous phase; S3. Add the oil phase to the aqueous phase under protective gas protection and stirring at 5000 rpm to 20000 rpm, and stir for 15 to 30 minutes to obtain colostrum; S4. Add water for injection to the colostrum to the full amount, mix well, add to a microfluidizer for homogenization, add a pH regulator, and obtain an emulsion; S5. Cool and filter the emulsion to obtain fat emulsion injection.

5. The method for preparing the fat emulsion injection according to claim 4, characterized in that: In step S1, the heating temperature is 60°C to 80°C; and / or In step S1, the emulsifier and the emulsifying aid are added under stirring at 5000 rpm to 10000 rpm.

6. The method for preparing the fat emulsion injection according to claim 4, characterized in that: In step S2, the heating temperature is 60°C to 80°C; and / or In step S2, the filtration is performed using a filter membrane of 0.4 μm to 0.5 μm.

7. The method for preparing the fat emulsion injection according to claim 4, characterized in that: In step S4, the homogenization pressure is 10000psi~15000psi; and / or The number of times of homogenization is 3 to 4 times.

8. The method for preparing the fat emulsion injection according to claim 4, characterized in that: In step S5, the cooling temperature is 20°C to 40°C.

9. A three-chamber bag of parenteral nutrition injection, characterized in that: The invention comprises the fat emulsion injection as described in any one of claims 1 to 3.

10. The method for preparing the three-chamber bag parenteral nutrition injection according to claim 9, characterized in that: The preparation method comprises the following steps: filling the fat emulsion injection, the amino acid injection and the glucose injection into different chambers of a three-chamber bag respectively, and sterilizing to obtain the product.

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