Preparation method of medium-chain and long-chain fat emulsion injection

Abstract

The invention discloses a preparation method of a medium-chain and long-chain fat emulsion injection, which comprises the following specific steps: S1, dissolving glycerol and part of sodium oleate in water for injection under the protection of nitrogen, heating, stirring and dispersing to obtain a water phase; s2, under the protection of nitrogen, dissolving egg yolk lecithin in the mixed oil, heating, shearing and stirring to dissolve the egg yolk lecithin, so as to obtain an oil phase; s3, under the protection of nitrogen, continuously feeding the oil phase and the water phase into a shearing machine according to a weight ratio, and shearing to obtain primary emulsion; s4, performing high-pressure homogenization on the primary emulsion for 2-3 times, supplementing the residual sodium oleate, and performing low-pressure homogenization once to obtain final emulsion; and S5, filling the final emulsion under a low-oxygen condition, filling nitrogen, plugging, capping, and sterilizing to obtain the medium-chain and long-chain fat emulsion injection product. The particle size distribution of the product can be effectively improved, the medium-chain and long-chain fat emulsion injection with uniform and stable particle size is prepared, and the stability of three-cavity liquid medicine in the mixing or compatibility process is guaranteed.

Description

Technical Field

[0001] The invention relates to a method for preparing a medium- and long-chain fat emulsion injection, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Parenteral nutrition (PN), also known as intravenous nutrition, is a nutritional support method that provides essential nutrients for the body's metabolic needs through a parenteral (intravenous) route. The safe use of fat emulsion injection is a milestone in the development of parenteral nutrition. Compared to glucose and amino acids, fat emulsion has high energy density, low osmotic pressure, low vascular irritation, and minimal interference with insulin secretion, making it a key component of parenteral nutrition.

[0003] Fat emulsion injections can provide the body with energy and essential fatty acids, maintain cell structure and function, influence the immune system, improve organ function, and aid in recovery. In 1961, Swedish Professor Wretlind successfully developed the first intravenous long-chain fat emulsion injection (Intralipid) using soybean oil and egg yolk lecithin, ushering in a new era of truly effective parenteral nutrition.

[0004] However, long-chain triglycerides must bind to apolipoproteins for transport in the blood and require the assistance of carnitine to enter the mitochondria and participate in the tricarboxylic acid cycle. Furthermore, long-chain triglycerides have a strong pro-inflammatory effect, and long-term, high-volume use of soybean oil emulsions can increase the risk of cholestasis. To address these issues, second-generation emulsions have been supplemented with coconut oil, olive oil, and fish oil, resulting in medium- and long-chain triglyceride emulsions.

[0005] Medium- and long-chain fatty acids do not require binding to apolipoproteins for transport, nor do they require the involvement of carnitine for entry into mitochondria. Their metabolism is faster than that of long-chain fatty acids, facilitating rapid energy supply. Furthermore, since saturated fatty acids do not contain carbon-carbon double bonds, they avoid the lipid peroxidation risk of soybean oil and the pro-inflammatory effects of omega-6 fatty acids.

[0006] Although medium- and long-chain triglyceride emulsion injection has many advantages, the following technical problems still exist in the preparation process:

[0007] 1. Shearing: Colostrum is prepared by shear mixing the oil and water phases. During this stage, the oil and water phases are mixed and sheared using a high-speed shearing machine, breaking down large particles in the oil-water mixture into small particles to produce high-performance colostrum. Colostrum quality is a key factor influencing the performance of fat emulsion injection products. The particle size and distribution of colostrum will affect the stability of the colostrum before homogenization and the effect of homogenization, which in turn affects the stability and shelf life of the fat emulsion injection product.

[0008] As the core equipment for shearing, the shearing performance of the blade head of the shearing machine plays a decisive role in the quality of colostrum. Shearing is performed using a shearing machine of the prior art, such as a shearing assembly for thinning liquid and a linear shearing machine disclosed in Application No. 202122334678.1, which is provided with a rotor and a stator that are engaged with each other, and the annular flanges of the rotor and the stator are interlaced and plugged into each other, and the adjacent annular flanges rotate in contact to form a shearing surface for shearing the liquid. Each annular flange is provided with a number of inclined shearing channels for shearing the liquid along the circumferential direction, thereby achieving a thinning effect on the liquid.

[0009] However, when the above-mentioned shearing machine is shearing colostrum, although the inclined shear channel can enhance local shearing, the structure of the staggered insertion of the annular flanges makes it difficult to form a continuous high-pressure area, resulting in insufficient shear force and difficulty in efficiently breaking up the fat droplets. In addition, the single-stage staggered flange structure makes it easy for the material to undergo only one shearing, resulting in insufficient local shearing and insufficient number of fat particle refinement, and prone to uneven particle size distribution or large particles remaining, affecting the stability of the subsequent colostrum before homogenization and the effect during homogenization, and thus affecting the stability and shelf life of the fat emulsion injection product; in addition, the inclined shear channel will prolong the residence time of the material, resulting in increased frictional heat, which can easily lead to fat oxidation or protein compression denaturation, affecting the final quality.

[0010] For example, a new type of stator and rotor high-shear emulsifier disclosed in application number 202123330240.2 adopts a three-layer interrupted rotor design and a double-layer interrupted stator design. The three-layer interrupted rotor and the double-layer interrupted stator are meshed to achieve the purpose of crushing and uniform mixing.

[0011] However, when the above-mentioned shearing machine is used to shear colostrum, it relies on a high-speed rotating interrupted three-layer rotor and a double-layer stator for shearing. However, the gap is large, which makes the shearing strength dispersed, and the interrupted design has a flow dead angle, resulting in some materials not being fully sheared, which is prone to uneven particle size distribution or large particles remaining, affecting the stability of the subsequent colostrum before homogenization and the effect during homogenization, and thus affecting the stability and shelf life of the fat emulsion injection product; in addition, high-speed rotation may cause local overheating, which can easily lead to fat oxidation or protein compression denaturation, affecting the final quality.

[0012] 2. Homogenization: The purpose of homogenization is to further reduce the particle size within the emulsion, making its distribution finer and more uniform. This is crucial for improving the emulsion's stability and extending its shelf life. Existing technologies require frequent homogenization, which can lead to stability issues such as an increase in the number of small particles, a wide particle size distribution, and changes in particle size and distribution during the mixing or formulation of the three-chamber drug solutions. These issues affect the safety of fat emulsion injections. Summary of the Invention

[0013] In order to solve the above technical problems, the present invention provides a method for preparing a medium- and long-chain fat emulsion injection, which can effectively improve the particle size distribution of the product, prepare a medium- and long-chain fat emulsion injection with uniform and stable particle size, and ensure the stability during the mixing or compatibility process of the three-cavity liquid.

[0014] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0015] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0016] S1. Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection, heat, and stir to disperse to obtain the aqueous phase;

[0017] S2. Under nitrogen protection, dissolving the egg yolk lecithin in the mixed oil, heating, shearing and stirring to dissolve it, to obtain an oil phase;

[0018] S3. Under nitrogen protection, the oil phase and the water phase are continuously fed into a shearing machine according to the weight ratio, and sheared to produce colostrum;

[0019] S4. The colostrum is first homogenized at high pressure for 2 to 3 times, and then the remaining sodium oleate is added and then homogenized at low pressure once to obtain the final milk;

[0020] S5. Fill the final emulsion under low oxygen conditions, fill with nitrogen, add a stopper, press the cap, and sterilize to obtain the medium- and long-chain fat emulsion injection product.

[0021] The technical solution of the present invention is further improved in that the amount of sodium oleate added to S1 is 10% to 30% of the total amount, the water phase temperature is controlled at 50 to 85°C, and the weight ratio of glycerol to sodium oleate is 83:1.

[0022] A further improvement of the technical solution of the present invention is that the mixed oil phase in S2 includes soybean oil and medium-chain triglycerides, the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides is 3:25:25, and the oil phase temperature is controlled at 50-85°C.

[0023] A further improvement of the technical solution of the present invention is that the mixing weight ratio of the oil phase to the water phase in S3 is 1:2 to 1:4.

[0024] A further improvement of the technical solution of the present invention is that: the shearing machine head used for the mixed shearing of the oil phase and the water phase in S3 includes a base and a fixed sleeve mounted on the surface of the base and equipped with a servo motor; a bottom bushing for accommodating the flow of the liquid and shearing the liquid, two third-stage blades, a second-stage blade, and an upper bushing are sequentially arranged above the fixed sleeve; a feed port is provided at the top of the upper bushing and is connected to one end of a three-way connecting flange pipe, and the other two ends of the three-way connecting flange pipe are connected to the oil phase pipeline and the water phase pipeline respectively; a discharge port is provided in the bottom bushing and is provided with a discharge port addition valve;

[0025] The three-stage cutter head and the two-stage cutter head include a cutter head body consisting of a base with an opening in the center and an outer wall surrounding the periphery of the base and having a certain height. A stator with teeth on the top is fixed at the opening of the cutter head body; a rotor that fits with the stator gap and can rotate is provided inside the stator, and a narrow gap is formed between the rotor and the stator. The rotor is fixed to the output shaft of the servo motor and has a bite groove on the bottom that fits with the teeth of the stator for shearing.

[0026] A further improvement of the technical solution of the present invention is that: the third-level cutter head has a higher density of teeth and more turns than the second-level cutter head; the top of the outer wall of the third-level cutter head and the second-level cutter head are both provided with an embedding groove, and a sealing gasket is embedded in the embedding groove.

[0027] A further improvement of the technical solution of the present invention is that the three-way connecting flange pipe and the upper bushing are connected through the connecting flange pipe, and the connecting flange pipe and the three-way connecting flange pipe are fixed by a flange connecting clamp.

[0028] A further improvement of the technical solution of the present invention is that: a hinge seat is fixed on the surface of the fixed sleeve, and a sleeve is rotatably connected inside the hinge seat, an L-shaped fastener is slidably connected to the surface of the sleeve, a locking bolt slides in the through hole opened on the surface of the L-shaped fastener, one end of the locking bolt is threadedly connected in the sleeve, and a card groove is opened on the surface of the upper bushing that is adapted to the L-shaped clamping portion of the L-shaped fastener.

[0029] A further improvement of the technical solution of the present invention is that: the pressure of the high-pressure homogenization in S4 is 850 to 1000 bar, and the pressure of the low-pressure homogenization is 50 to 200 bar; when the pH value of the emulsion after homogenization is not within the range of 9.5 to 10.5, a pH regulator is used to adjust the pH value of the emulsion to 9.5 to 10.5, and the pH regulator is one or more mixed liquids of hydrochloric acid, sodium hydroxide, sodium oleate, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, citric acid, carbonic acid and their salts.

[0030] A further improvement of the technical solution of the present invention is that: the sterilization temperature in S5 is 121°C and the time is 12 minutes; the particle size PDI of the prepared medium- and long-chain fat emulsion injection is less than 0.2, the average particle size of the emulsion particles is 240-380 nm, 99% of the emulsion particles are no larger than 1 μm, and the weighted total volume of emulsion particles larger than 5 μm is ≤0.05%.

[0031] Due to the adoption of the above technical solution, the technical advancements achieved by the present invention are:

[0032] 1) Improved particle size distribution: The above technical solution significantly reduces the droplet breakup energy barrier, achieves monodispersity of nano-sized fat emulsion particles, and reduces the particle size distribution span (PDI value). This avoids the "bimodal distribution" or large particle tailing phenomenon caused by uneven shearing in traditional processes, laying the foundation for subsequent compatibility stability.

[0033] 2) Enhanced compatibility stability: The above technical solution produces a uniform and stable medium- and long-chain triglyceride (TCT) emulsion injection. Due to the more uniform particle size distribution, the TTC emulsion injection is less susceptible to stratification, precipitation, or aggregation during storage and use, ensuring the long-term stability of the product. In particular, during the mixing or compatibility process of the three-chamber solution, particle size uniformity reduces interfacial interference with amino acids, glucose, and other compatibility agents, avoiding local pH shifts, lipid phase migration, or emulsion stratification caused by particle size differences, effectively preventing stability issues caused by uneven particle size.

[0034] 3) Improved product quality and safety: Through the above technical solutions, the particle size distribution is optimized, which can effectively reduce the probability of large emulsions (particles >5μm), avoid the risk of microvascular embolism, reduce the adverse reactions that may be caused by aggregation into large emulsions due to uneven particle size, and improve the safety and effectiveness of the product.

[0035] 4) Improved Colostrum Quality: Colostrum shearing is achieved through a shear head that combines progressive multi-stage shearing with a narrow gap, high pressure, and a tooth-grip design. This achieves multi-stage progressive shearing, resulting in higher shearing efficiency. The narrow gap combined with the tooth-grip creates localized high pressure and shear force. Simultaneously, the multi-stage stator and rotor force the material through the narrow gap step by step, ensuring that all particles are evenly stressed. This effectively breaks up fat droplets and improves emulsification efficiency, eliminating uneven particle size distribution or residual large particles. This ensures the stability of the colostrum before and during homogenization, thereby ensuring the stability and shelf life of the fat emulsion injection product. Furthermore, multi-stage progressive shearing achieves high shear force at lower speeds, reducing temperature rise and preventing fat oxidation or protein denaturation, thus guaranteeing product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is a schematic diagram of the overall structure of the present invention;

[0037] Figure 2 Schematic diagram of the structure of the rotor, teeth and narrow gap of the present invention;

[0038] Figure 3 It is a structural schematic diagram of the embedded slot and stator of the present invention;

[0039] Figure 4 It is a structural schematic diagram of the sleeve, locking bolt and hinged seat of the present invention;

[0040] Among them, 1. Base; 2. Fixed sleeve; 3. Bottom bushing; 4. Discharge port adding valve; 5. Three-stage cutter head; 6. Two-stage cutter head; 7. Upper bushing; 8. Rotor; 9. Teeth; 10. Sealing gasket; 11. Narrow gap; 12. Mounting groove; 13. Connecting flange pipe; 14. Flange connecting clamp; 15. T-connecting flange pipe; 16. Articulated seat; 17. Sleeve; 18. L-shaped fastener; 19. Locking bolt; 20. Slot; 21. Stator. DETAILED DESCRIPTION

[0041] A method for preparing a medium- and long-chain triglyceride (MTD) fat emulsion injection, wherein the prepared medium- and long-chain triglyceride (MTD) fat emulsion injection has a particle size PDI of less than 0.2, an average particle size of 240 to 380 nm, 99% of the particles are no larger than 1 μm, and the weighted total volume of particles larger than 5 μm is ≤ 0.05%. The method specifically comprises the following steps:

[0042] S1. Under nitrogen protection, dissolve glycerol and part of sodium oleate (sodium oleate accounts for 10% to 30% of the total amount) in water for injection. The weight ratio of glycerol to sodium oleate is about 83:1. Heat and control the temperature of the aqueous phase to 50-85°C. Stir and disperse to obtain the aqueous phase.

[0043] S2. Under nitrogen protection, dissolving egg yolk lecithin in a mixed oil phase, wherein the mixed oil phase comprises soybean oil and medium-chain triglycerides, and the weight ratio of egg yolk lecithin:soybean oil:medium-chain triglycerides is 3:25:25. The oil phase is heated to control the temperature of 50-85° C. and sheared and stirred to dissolve the mixture to obtain an oil phase.

[0044] S3. Under nitrogen protection, the oil phase and the water phase are continuously fed into a specific shearing machine through the oil phase pipeline and the water phase pipeline at a weight ratio of 1:2 to 1:4, respectively, to produce colostrum by shearing;

[0045] Among them, the blade of a specific shearing machine is as follows Figures 1 to 4 As shown, it includes a base 1 and a fixing sleeve 2 installed on the surface of the base 1;

[0046] A bottom bushing 3 is provided above the fixed sleeve 2, and a discharge port is integrally formed on the surface of the bottom bushing 3, and a discharge port adding valve 4 is provided on the discharge port. Two tertiary cutter heads 5 and a secondary cutter head 6 are sequentially provided on the surface of the bottom bushing 3, and an upper bushing 7 is provided on the side of the secondary cutter head 6 away from the tertiary cutter head 5, and a connecting flange pipe 13 is integrally formed on the surface of the upper bushing 7. Rotors 8 are provided inside the tertiary cutter head 5 and the secondary cutter head 6, and a stator 21 is provided outside the rotor 8. The stator 21 is fixedly installed in the tertiary cutter head 5 and the secondary cutter head 6 respectively, and the rotor 8 is connected to the output shaft of the servo motor installed in the fixed sleeve 2.

[0047] Two tertiary blades 5 and one secondary blade 6 are arranged in sequence. This layout is based on the optimization of the emulsion shearing and emulsification process. First, after the emulsion enters the shearing machine, it is first subjected to preliminary shearing and dispersion treatment by the secondary blade 6. Due to its own structural characteristics, the secondary blade 6 can perform a relatively coarse treatment on the emulsion and preliminarily crush the larger emulsion particles. Then, the emulsion passes through two tertiary blades 5. The teeth 9 of the tertiary blade 5 are dense and have many turns, which can perform fine shearing and refining on the emulsion, making the emulsion particles further smaller. After multiple shearing and refining, the particle size distribution of the emulsion is more uniform, which meets the product requirements for the emulsion particle size.

[0048] Furthermore, a narrow gap 11 is formed between the stator 21 and the rotor 8 inside the tertiary cutter head 5 and the secondary cutter head 6 .

[0049] The narrow gap 11 provides a clear shear path for the flow of the emulsion in the cutter head. When the material enters the central area of the rotor from the inlet, the material is thrown into the narrow gap 11 between the stator 21 and the rotor 8 at high speed, forming a shear area with the rotor. The rotor and stator teeth interlace to cut the material and collide with the tooth surface to crush it. The dispersed material is discharged from the outlet or circulated back to the inlet, making the flow of the emulsion more orderly and controllable. This can avoid turbulence or disordered flow of the emulsion in the cutter head, ensure that the emulsion can pass through the shear area between the stator 21 and the rotor 8 evenly, thereby ensuring that each part of the emulsion can receive a relatively uniform shearing effect.

[0050] Furthermore, the surfaces of the stators 21 inside the tertiary cutter head 5 and the secondary cutter head 6 are provided with teeth 9 , and the surface of the rotor 8 is provided with biting grooves.

[0051] When the emulsion passes through the cutter head, the bite grooves of the rotor 8 and the teeth 9 of the stator 21 interlace and cut the material emulsion, and collide with the tooth surface to break it, cutting the larger droplets or particles in the emulsion into smaller units, thereby realizing shear emulsification of the emulsion. For some larger emulsion particles, the teeth 9 and the bite grooves can apply shear forces from different directions, so that they are subjected to shearing effects in multiple directions, effectively improving the efficiency and effect of shearing.

[0052] Furthermore, the tertiary cutter head 5 has a higher density of teeth 9 and more turns than the secondary cutter head 6 .

[0053] The secondary cutter head 6 has relatively fewer teeth 9 density and turns, which preliminarily crush and disperse the emulsion and preliminarily process the larger emulsion particles, so that the particle size distribution of the emulsion begins to move towards uniformity. Subsequently, the emulsion enters the tertiary cutter head 5. More teeth 9 turns and higher teeth 9 density can process the emulsion more accurately, refine the particle size to the required degree, and ensure the quality of the final product.

[0054] Furthermore, an embedding groove 12 is provided on the surface of the tertiary cutter head 5 and the secondary cutter head 6 , and a sealing gasket 10 is embedded in the embedding groove 12 .

[0055] The sealing gasket 10 in the embedded groove 12 can effectively fill the gaps between the cutter heads or between the cutter heads and other components, preventing the emulsion from leaking from these parts under pressure. The sealing gasket 10 will form a sealing layer on the contact surface to ensure that the emulsion is confined inside the cutter head and the designed flow channel, ensuring the smooth progress of the shear emulsification process.

[0056] Furthermore, a three-way connecting flange pipe 15 is provided on the surface of the connecting flange pipe 13. The connecting flange pipe 13 and the three-way connecting flange pipe 15 are connected by a flange connecting clamp 14. The other two ports of the three-way connecting flange pipe 15 are connected to the oil phase pipeline and the water phase pipeline through pipelines respectively.

[0057] The oil and water phase feed ratios can be easily adjusted by connecting the oil and water phase lines to the three-way flange pipe 15. The flow rates of the oil and water phases can be precisely controlled by adjusting the valves or flow control devices on the respective lines to meet different product requirements, thereby achieving flexible adjustments to the emulsion formulation.

[0058] Furthermore, a hinge seat 16 is fixed on the surface of the fixed sleeve 2, a sleeve 17 is rotatably connected inside the hinge seat 16, an L-shaped fastener 18 is slidably connected to the surface of the sleeve 17, a locking bolt 19 is slidably provided in the through hole opened on the surface of the L-shaped fastener 18, one end of the locking bolt 19 is threadedly connected to the sleeve 17, and a card groove 20 adapted to the L-shaped clamping portion of the L-shaped fastener 18 is provided on the surface of the upper bushing 7.

[0059] The L-shaped fastener 18 is slidably connected to the surface of the sleeve 17, and the locking bolt 19 is passed through the through hole opened on the surface of the L-shaped fastener 18, so that one end of the locking bolt 19 is threadedly connected to the sleeve 17. By adjusting the position of the L-shaped fastener 18, its L-shaped clamping part is clamped into the clamping groove 20 opened on the surface of the upper bushing 7, and then the locking bolt 19 is tightened to firmly fix the upper bushing 7 in the corresponding position, providing structural stability for the entire cutter head.

[0060] S4. First, perform high-pressure homogenization at a homogenization pressure of 850-1000 bar for 2-3 times, then add the remaining sodium oleate and perform low-pressure homogenization once at a homogenization pressure of 50-200 bar to obtain the final milk.

[0061] After the emulsion undergoes the above-mentioned shearing and homogenization treatment, free fatty acids are easily generated, which can lower the pH of the drug solution. Therefore, after low-pressure homogenization, if the pH value of the homogenized emulsion is not within the range of 9.5-10.5 (the pH control limit of the emulsion intermediate requires a pH of 9.5-10.5), the pH value of the emulsion is adjusted to 9.5-10.5 with a pH adjuster. The pH adjuster is one or a mixture of hydrochloric acid, sodium hydroxide, sodium oleate, phosphoric acid, phosphates, citric acid, citrates, acetic acid, acetates, citric acid, carbonic acid, and their salts.

[0062] S5. Fill the final emulsion under hypoxic conditions, fill with nitrogen, add a stopper, press the cap, and sterilize at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0063] The present invention is described in further detail below in conjunction with the embodiments:

[0064] Example 1

[0065] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0066] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 30% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0067] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0068] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:4, and sheared to obtain colostrum;

[0069] ④ The colostrum is first homogenized twice at a high pressure of 1000 bar, and then the remaining sodium oleate is added, and then homogenized once at a low pressure of 50 bar. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0070] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0071] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0072] Example 2

[0073] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0074] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 10% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0075] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0076] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:2, and sheared to obtain colostrum;

[0077] ④ The colostrum is first homogenized at a high pressure of 850 bar for 3 times, and then the remaining sodium oleate is added and then homogenized at a low pressure of 200 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0078] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0079] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0080] Example 3

[0081] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0082] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 25% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0083] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0084] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:3.5, and sheared to obtain colostrum;

[0085] ④ The colostrum is first homogenized at a high pressure of 900 bar for 3 times, and then the remaining sodium oleate is added and then homogenized at a low pressure of 70 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0086] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0087] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0088] Example 4

[0089] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0090] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 15% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0091] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0092] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:2.5, and sheared to obtain colostrum;

[0093] ④ The colostrum is first homogenized twice at a high pressure of 950 bar, and then the remaining sodium oleate is added, and then homogenized once at a low pressure of 170 bar. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0094] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0095] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0096] Example 5

[0097] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0098] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 20% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0099] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0100] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:3, and sheared to obtain colostrum;

[0101] ④ The colostrum is first homogenized twice at a high pressure of 950 bar, and then the remaining sodium oleate is added, and then homogenized once at a low pressure of 150 bar. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0102] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0103] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0104] Example 6

[0105] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0106] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 10% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0107] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0108] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:2, and sheared to obtain colostrum;

[0109] ④ The colostrum is first homogenized at a high pressure of 950 bar for 3 times, and then the remaining sodium oleate is added, and then homogenized at a low pressure of 100 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0110] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0111] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0112] Example 7

[0113] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0114] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 25% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0115] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0116] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:4, and sheared to obtain colostrum;

[0117] ④ The colostrum is first homogenized at a high pressure of 1000 bar for 3 times, and then the remaining sodium oleate is added and then homogenized at a low pressure of 90 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0118] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0119] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0120] Example 8

[0121] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0122] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 20% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0123] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0124] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:3, and sheared to obtain colostrum;

[0125] ④ The colostrum is first homogenized at a high pressure of 900 bar for 3 times, and then the remaining sodium oleate is added and then homogenized at a low pressure of 120 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0126] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0127] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0128] Comparative Example 1

[0129] The difference between this comparative example and Example 8 is that the high-pressure homogenization pressure in this comparative example is small and the number of times is large.

[0130] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0131] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 20% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0132] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0133] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:3, and sheared to obtain colostrum;

[0134] ④ The colostrum is first homogenized at a high pressure of 400 bar for 6 times, and then the remaining sodium oleate is added, and then homogenized at a low pressure of 50 bar for 2 times. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0135] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0136] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0137] Comparative Example 2

[0138] The difference between this comparative example and Example 8 is that the sodium oleate in this comparative example is added to the aqueous phase all at once.

[0139] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0140] ① Under nitrogen protection, dissolve glycerol and all sodium oleate in water for injection, stir and disperse to obtain the aqueous phase, and control the temperature of the aqueous phase at 50-85°C;

[0141] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0142] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:3, and sheared to obtain colostrum;

[0143] ④ The colostrum is first homogenized at a high pressure of 900 bar for 3 times, and then at a low pressure of 120 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0144] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0145] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0146] Comparative Example 3

[0147] The difference between this comparative example and Example 8 is that in this comparative example, the ratio of the oil phase to the water phase before high-pressure homogenization is 1:1.5.

[0148] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0149] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 20% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0150] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0151] ③ Under nitrogen protection, the oil phase and the water phase are continuously fed into the specific shearing machine of the present invention at a weight ratio of 1:1.5, and sheared to obtain colostrum;

[0152] ④ The colostrum is first homogenized at a high pressure of 900 bar for 3 times, and then the remaining sodium oleate and water for injection are added to the full amount, and then homogenized at a low pressure of 120 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0153] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0154] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0155] Comparative Example 4

[0156] The difference between this comparative example and Example 8 is that the shearing machine in this comparative example adopts a shearing component for refining liquid and its linear shearing machine disclosed in application number 202122334678.1.

[0157] A method for preparing a medium- and long-chain fat emulsion injection comprises the following steps:

[0158] ① Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection. The amount of sodium oleate added is 20% of the total amount. Stir and disperse to obtain the aqueous phase. Control the temperature of the aqueous phase at 50-85°C.

[0159] ② Under nitrogen protection, dissolve egg yolk lecithin in a mixed oil phase of soybean oil and medium-chain triglycerides, with the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides being 3:25:25. Heat the oil phase to 50-85°C and dissolve it by shear stirring to obtain an oil phase.

[0160] ③ Under nitrogen protection, the oil phase and the water phase are mixed in a weight ratio of 1:3, and a shearing machine disclosed in application number 202122334678.1 is used to add the oil phase to the water phase, mix, and shear to obtain colostrum;

[0161] ④ The colostrum is first homogenized at a high pressure of 900 bar for 3 times, and then the remaining sodium oleate is added and then homogenized at a low pressure of 120 bar for 1 time. If necessary, the pH value of the emulsion is adjusted to 9.5-10.5 with a pH regulator to obtain the final milk;

[0162] ⑤ Fill the emulsion under low oxygen conditions, add stoppers and cap after nitrogen filling;

[0163] ⑥ Sterilize the canned emulsion at a temperature of 121°C for 12 minutes to obtain the medium- and long-chain fat emulsion injection product.

[0164] Experimental Example 1

[0165] The medium- and long-chain fat emulsions prepared in the examples and comparative examples were compared, and the results are shown in Table 1.

[0166] Table 1 Comparison of colostrum and medium-chain fat emulsion prepared in Example and Comparative Example

[0167]

[0168]

[0169] Note: After the colostrum in the above table is left for 30 minutes, observe whether there is any oil floating or stratification.

[0170] Experimental Example 2

[0171] Table 2: Results of stability studies on medium- and long-chain fatty acid emulsion injections of Examples and Comparative Examples

[0172] The products of Examples 1-8 and Comparative Examples 1-4 were stored at 40°C ± 2°C and a relative humidity of 75% ± 5% for 6 months. The samples were tested under these conditions for properties, pH, lysophosphatidylcholine, lysophosphatidylethanolamine, 5μm large emulsion particles, average particle size, and zeta potential at 0, 3, and 6 months. The experimental results are shown in Table 2 below.

[0173] Table 2 Stability study results of the example products and comparative example products

[0174]

[0175]

[0176] Conclusion: As can be seen from Table 2, compared with Example 8, Comparative Example 1 has a high number of high-pressure homogenization times, which leads to excessive material fragmentation and an increase in the number of small particles. After the accelerated test, the product obtained has poor stability and oil floating phenomenon, resulting in the failure of the specified properties and other indicators to meet the requirements. In Comparative Example 2, the sodium oleate is added all at once. Sodium oleate is a stabilizer and emulsifier. Adding it all before the high-pressure homogenization process can lead to a significant increase in the number of small particles in the sample. After the accelerated test, the product obtained has poor stability and oil floating phenomenon, resulting in the failure of the specified properties and other indicators to meet the requirements. In Comparative Example 3, the ratio of oil phase to water phase is 1:1.5. A large amount of injection water is added after high-pressure homogenization. The addition of a large amount of water without high-pressure homogenization poses certain challenges to the stability of the emulsion, resulting in poor particle size distribution, poor uniformity, and poor product stability. The shearing machine used in Comparative Example 4 is prone to local uneven shearing, resulting in a wide particle size distribution and poor product stability. After six months of accelerated testing, the pH values of the products prepared in Examples 1 to 8 decreased slowly, the average particle size of the milk particles in the products changed more slowly than in the comparative example, the volume content of 5μm-large milk particles was significantly lower than that in the comparative example, and the absolute value of the zeta potential was significantly higher than that of the product prepared in the comparative example. Compared with the comparative example, the products of Examples 1-8 demonstrated superior clinical safety and product stability.

Claims

1. A method for preparing a medium- and long-chain fat emulsion injection, characterized in that The steps include: S1. Under nitrogen protection, dissolve glycerol and part of sodium oleate in water for injection, heat, and stir to disperse to obtain the aqueous phase; S2. Under nitrogen protection, dissolving the egg yolk lecithin in the mixed oil, heating, shearing and stirring to dissolve it, to obtain an oil phase; S3. Under nitrogen protection, the oil phase and the water phase are continuously fed into a shearing machine according to the weight ratio, and sheared to produce colostrum; S4. The colostrum is first homogenized at high pressure for 2 to 3 times, and then the remaining sodium oleate is added and then homogenized at low pressure once to obtain the final milk; S5. Fill the final emulsion under low oxygen conditions, fill with nitrogen, add a stopper, press the cap, and sterilize to obtain the medium- and long-chain fat emulsion injection product.

2. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The amount of sodium oleate added to the S1 is 10% to 30% of the total amount, the temperature of the water phase is controlled at 50 to 85° C., and the weight ratio of glycerol to sodium oleate is 83:

1.

3. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The mixed oil phase in S2 includes soybean oil and medium-chain triglycerides, the weight ratio of egg yolk lecithin: soybean oil: medium-chain triglycerides is 3:25:25, and the oil phase temperature is controlled at 50-85°C.

4. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The mixing weight ratio of the oil phase to the water phase in S3 is 1:2 to 1:

4.

5. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The shearing machine head used for the mixed shearing of the oil phase and the water phase in S3 comprises a base (1) and a fixed sleeve (2) mounted on the surface of the base (1) and provided with a servo motor; a bottom bushing (3) for accommodating the flow of the liquid and shearing the liquid, two third-stage blades (5), a second-stage blade (6) and an upper bushing (7) are sequentially arranged above the fixed sleeve (2); a feed port is provided at the top of the upper bushing (7) and is communicated with one end of a three-way connecting flange pipe (15), and the other two ends of the three-way connecting flange pipe (15) are connected to the oil phase pipeline and the water phase pipeline respectively; a discharge port is provided at the bottom bushing (3) and a discharge port addition valve (4) is provided; The three-stage cutter head (5) and the two-stage cutter head (6) include a cutter head body composed of a base with an opening in the center and an outer wall surrounding the periphery of the base and having a certain height. A stator (21) with teeth (9) on the top is fixed at the opening of the cutter head body; a rotor (8) is provided inside the stator (21) and is capable of rotating and has a clearance fit with the stator (21). A narrow gap (11) is formed between the rotor (8) and the stator (21); the rotor (8) is fixed to the output shaft of the servo motor and has a bite groove on the bottom that is sheared with the teeth (9) of the stator.

6. The method for preparing a medium- and long-chain fat emulsion injection according to claim 5, characterized in that: The teeth (9) of the tertiary cutter head (5) are denser and have more turns than those of the secondary cutter head (6); the tops of the outer walls of the tertiary cutter head (5) and the secondary cutter head (6) are both provided with an embedding groove (12), and a sealing gasket (10) is embedded in the embedding groove (12).

7. The method for preparing a medium- and long-chain fat emulsion injection according to claim 5, characterized in that: The three-way connecting flange pipe (15) is communicated with the upper bushing (7) via a connecting flange pipe (13), and the connecting flange pipe (13) and the three-way connecting flange pipe (15) are fixed via a flange connecting clamp (14).

8. The method for preparing a medium- and long-chain fat emulsion injection according to claim 5, characterized in that: A hinge seat (16) is fixed on the surface of the fixed sleeve (2), and a sleeve (17) is rotatably connected in the hinge seat (16), an L-shaped fastener (18) is slidably connected to the surface of the sleeve (17), a locking bolt (19) is slidably arranged in a through hole opened on the surface of the L-shaped fastener (18), one end of the locking bolt (19) is threadedly connected in the sleeve (17), and a card slot (20) adapted to the L-shaped clamping portion of the L-shaped fastener (18) is opened on the surface of the upper bushing (7).

9. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The pressure of the high-pressure homogenization in S4 is 850-1000 bar, and the pressure of the low-pressure homogenization is 50-200 bar; when the pH value of the emulsion after homogenization is not within the range of 9.5-10.5, a pH regulator is used to adjust the pH value of the emulsion to 9.5-10.5, and the pH regulator is one or more mixed liquids of hydrochloric acid, sodium hydroxide, sodium oleate, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate, citric acid, carbonic acid and their salts.

10. The method for preparing a medium- and long-chain fat emulsion injection according to claim 1, characterized in that: The sterilization temperature in S5 is 121° C. and the sterilization time is 12 minutes. The prepared medium- and long-chain fat emulsion injection has a particle size PDI of less than 0.2, an average particle size of 240 to 380 nm, 99% of the particles are no larger than 1 μm, and the weighted total volume of particles larger than 5 μm is ≤0.05%.

Images