CN115581665A - Sodium oleate-free medium/long-chain fat emulsion injection and preparation method thereof - Google Patents
Sodium oleate-free medium/long-chain fat emulsion injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a sodium oleate-free medium/long-chain fat emulsion injection and a preparation method thereof, and relates to the technical field of pharmacy. The sodium oleate-free medium/long-chain fat emulsion injection is prepared from the following components: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of yolk lecithin, 0.01-0.3 g of vitamin E, 10-50 g of osmotic pressure regulator and the balance of water for injection; the preparation method comprises the following steps: adopting a high-pressure homogenization method to prepare the sodium oleate-free medium/long-chain fat emulsion injection, wherein in the high-pressure homogenization process, the ratio of the high-pressure valve pressure to the low-pressure valve pressure is 3:1 to 6:1. the medium/long-chain fat emulsion injection prepared by the preparation method does not contain sodium oleate, can realize the same or better emulsification effect as the prior product on the premise of not additionally adding a co-emulsifier, solves the problem of oil floating on the surface of the product caused by not adding sodium oleate in the formula, and simultaneously reduces the potential toxic and side effect risk caused by adding sodium oleate.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to a sodium oleate-free medium/long-chain fat emulsion injection and a preparation method thereof.
Background
Fat milk is one of the main components of parenteral nutrition, achieves the effect of nutrition support and management by intravenous administration with the aim of supplying and managing nutrition and water necessary for maintaining human life under the condition that the nutrition cannot be taken orally or the nutrition is not sufficient, provides energy required by metabolism, provides a biological membrane and polyunsaturated fatty acid required by metabolism of bioactive substances for the organism, and can prevent or correct the lack of the essential fatty acid of the organism.
The early fat emulsion injection mainly comprises long-chain triglyceride, and the medium/long-chain fat emulsion injection is developed subsequently due to the ketogenesis effect and slow metabolic energy supply of the long-chain fat emulsion. However, the polarity of medium chain triglyceride is relatively large, so that the problem of poor emulsification effect is solved by additionally adding a co-emulsifier, namely sodium oleate in the formula, the sodium oleate is used as a fatty acid sodium salt, belongs to an anionic surfactant, and is beneficial to the homogenization of the particle size in the processes of the preparation of the primary emulsion and high-pressure homogenization of the fat emulsion, and in addition, the sodium oleate can also be used as a potential regulator to be beneficial to the maintenance of high-order charges of emulsion particles in the long-term storage process of the fat emulsion, so that emulsion droplets are not easy to polymerize, the generation of large emulsion particles can be obviously reduced, and the problem of poor emulsification effect of the medium/long chain fat emulsion injection is solved. However, the addition of sodium oleate in the medium/long-chain fat emulsion injection is easy to cause potential safety risks, such as hemolysis, phlebitis and the like, and if the sodium oleate is not added in the formula, the emulsification effect is reduced, and the problem of surface oil floating of the finished product can occur.
Disclosure of Invention
Aiming at the problems brought forward by the background technology, the invention aims to provide a preparation method of a sodium oleate-free medium/long-chain fat emulsion injection, the prepared medium/long-chain fat emulsion injection does not contain sodium oleate, the same or even better emulsification effect as the existing product can be still realized on the premise of not additionally adding a co-emulsifier, the problem of product surface oil floating caused by no addition of sodium oleate in a formula is solved, and the potential toxic and side effect risk caused by the addition of sodium oleate can be reduced.
The invention also aims to provide the sodium oleate-free medium/long-chain fat emulsion injection, which simplifies the prescription of the existing product and reduces the potential toxic and side effect risk caused by the additional addition of the auxiliary emulsifier (sodium oleate).
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of yolk lecithin, 0.01-0.3 g of vitamin E, 10-50 g of osmotic pressure regulator and the balance of water for injection;
the sodium oleate-free medium/long-chain fat emulsion injection is prepared by adopting a high-pressure homogenization method, and in the high-pressure homogenization process, the ratio of the high-pressure valve pressure to the low-pressure valve pressure is 3: 1-6: 1.
Further, the preparation method comprises the following steps:
(1) Heating and stirring soybean oil, medium-chain triglyceride and vitamin E uniformly, adding egg yolk lecithin, heating and stirring for dissolving to obtain an oil phase;
(2) Adding an osmotic pressure regulator into water for injection, and heating and stirring uniformly to obtain a water phase;
(3) Adding the oil phase into the water phase, mixing uniformly to prepare primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing pressure is 80-1200 bar, and the pressure ratio of the high-pressure valve to the low-pressure valve is 3: 1-6: 1;
(5) Filling the final milk obtained in the step (4) into an inner packaging soft bag, and performing sterilization treatment;
(6) And drying the surface of the sterilized sample, and packaging the sample into an outer barrier bag to obtain the sodium oleate-free medium/long-chain fat emulsion injection, wherein the pH value of the sodium oleate-free medium/long-chain fat emulsion injection is 6.0-9.0.
Further, the operation method of the step (1) is as follows: under the protection of nitrogen, soybean oil, medium-chain triglyceride and vitamin E are mixed, heated to 55-80 ℃ and stirred uniformly, egg yolk lecithin is added and stirred for dissolution, and an oil phase is obtained.
Further, the operation method of the step (2) is as follows: adding an osmotic pressure regulator into water for injection under the protection of nitrogen, and uniformly stirring at 55-80 ℃ to obtain a water phase.
Further, the operation method of the step (3) is as follows: adding the oil phase into the water phase, mixing by adopting a stirring and mixing method or a high-speed shearing method at the temperature of 55-80 ℃ for 2-60 min to obtain primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
when the mixing is carried out by a high-speed shearing method, the shearing speed is 1000-15000 rpm/min.
Further, the operation method of the step (4) is as follows: homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing temperature is 20-60 ℃, the homogenizing pressure is 100-1200 bar, the pressure ratio of the high-pressure valve to the low-pressure valve is 3: 1-6: 1, and the cycle times are 2-8.
Further, the pH regulator is sodium hydroxide.
The sodium oleate-free medium/long-chain fat emulsion injection is prepared by the preparation method of the sodium oleate-free medium/long-chain fat emulsion injection.
Further, the medium/long chain fat emulsion injection without sodium oleate comprises the following components: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of egg yolk lecithin, 0.15-0.25 g of vitamin E, 20-30 g of osmotic pressure regulator and the balance of water for injection.
Further, the osmotic pressure regulator is glycerol.
The technical scheme has the following beneficial effects:
1. the preparation method of the technical scheme is adopted to prepare the sodium oleate-free medium/long-chain fat emulsion injection, the same or even better emulsification effect as the existing product can be still realized on the premise of not additionally adding the auxiliary emulsifier, the problem of oil floating on the surface of the product caused by not adding sodium oleate in the formula is solved, the formula of the existing product is simplified, and the potential toxic and side effect risk caused by additionally adding the auxiliary emulsifier (sodium oleate) is reduced.
2. The medium/long chain fat emulsion injection without the sodium oleate is packaged by adopting the combination of the inner packaging soft bag and the outer barrier bag, and a completely sealed packaging system is adopted, so that the defect that the sealing performance of the glass bottles sold in the market at present is not good to cause microbial pollution can be avoided, the medium/long chain fat emulsion injection has the advantages of convenience in transportation, difficulty in crushing, mature preparation process and the like, industrial batch production can be realized, and the risk of microbial pollution caused by long-time infusion when clinical patients use fat emulsion injection products is effectively solved.
Drawings
FIG. 1 is a graph showing the distribution of the average particle size of sodium oleate-free medium/long-chain fat emulsion injection prepared by the preparation method of the present invention using different high pressure valve pressures and low pressure valve pressures;
FIG. 2 is a graph showing the tendency of the content of free fatty acid in each sample of effect example 1 in a high temperature 30-day examination;
FIG. 3 is a graph showing the trend of the change in the oxygen content of gas in the examination of each sample in effect example 2 at a high temperature for 30 days;
FIG. 4 is a graph showing the trend of the change in the dissolved oxygen content of the liquid medicine in the examination of each sample in effect example 2 at a high temperature for 30 days;
FIG. 5 is a graph showing the change tendency of anisidine value and peroxide value in stability test of effect example 3 for 24 months;
FIG. 6 is a graph showing the tendency of change in the content of lysophospholipid in each sample of effect example 4 in the examination at a high temperature for 30 days.
Detailed Description
The technical solution of the present invention is further described below with reference to the accompanying drawings and the detailed description.
The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of yolk lecithin, 0.01-0.3 g of vitamin E, 10-50 g of osmotic pressure regulator and the balance of water for injection;
the sodium oleate-free medium/long-chain fat emulsion injection is prepared by adopting a high-pressure homogenization method, and the ratio of the pressure of a high-pressure valve to the pressure of a low-pressure valve is 3: 1-6: 1 in the high-pressure homogenization process.
It is worth noting that the medium-chain triglyceride has relatively large polarity, which easily causes the problem of poor emulsification effect of the medium/long-chain fat emulsion injection and the problem of surface oil floating of the finished product, so that the conventional medium/long-chain fat emulsion injection usually needs to add sodium oleate (co-emulsifier) to the components to overcome the problem of poor emulsification effect, but the addition of sodium oleate in the medium/long-chain fat emulsion injection easily causes potential safety risks such as hemolysis and phlebitis. Therefore, sodium oleate is not added in the medium/long-chain fat emulsion injection in the technical scheme, so that potential safety risks such as hemolysis and phlebitis are reduced, meanwhile, when the medium/long-chain fat emulsion injection in the technical scheme is prepared, the medium/long-chain fat emulsion injection without sodium oleate is prepared by adopting a high-pressure homogenization method, in the high-pressure homogenization process, the ratio of the pressure of a high-pressure valve to the pressure of a low-pressure valve is set to be 3: 1-6: 1, and by adjusting the pressure ratio range of the high-pressure valve and the low-pressure valve, a better particle size distribution effect can be realized, and the problem of product surface oil floating caused by no sodium oleate added in a formula can be solved.
Generally speaking, when the product is subjected to particle size homogenization treatment by a high-pressure homogenization method, two pressure valves, namely a high-pressure valve and a low-pressure valve, are used for pressurization treatment, and at present, in the preparation of fat emulsion injection, the ratio of the high-pressure valve to the low-pressure valve is usually maintained in a range of 12: 1-8: 1, and such setting is favorable for protecting the service life of the low-pressure valve, namely, the particle size distribution of the prepared sample is better along with the synchronous rise of the pressures of the high-pressure valve and the low-pressure valve in a certain range. However, the technical scheme is that the pressure of the low-pressure valve is increased, the pressure of the high-pressure valve is reduced, the same or even better particle size distribution effect can be achieved after sodium oleate is added, as shown in fig. 1, different pressures of the high-pressure valve and the low-pressure valve are respectively set, the average particle size is considered as an investigation index, and as can be seen from fig. 1, the technical scheme can realize better particle size distribution by adjusting the ratio range of the pressure of the high-pressure valve and the pressure of the low-pressure valve, in addition, the pressure of the high-pressure valve is obviously reduced, the damage of the high-pressure valve can be effectively avoided, and meanwhile, the power energy consumption can be greatly reduced.
Preferably, the total content of the egg yolk Phosphatidylcholine (PC) and the egg yolk Phosphatidylethanolamine (PE) in the egg yolk lecithin in the technical scheme is more than or equal to 85 percent, so that the emulsifying effect can be further improved.
Further illustratively, the preparation method comprises the steps of:
(1) Heating and stirring soybean oil, medium-chain triglyceride and vitamin E uniformly, adding egg yolk lecithin, heating and stirring for dissolving to obtain an oil phase;
(2) Adding an osmotic pressure regulator into water for injection, and heating and stirring uniformly to obtain a water phase;
(3) Adding the oil phase into the water phase, mixing uniformly to prepare primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing pressure is 80-1200 bar, and the pressure ratio of the high-pressure valve to the low-pressure valve is 3: 1-6: 1;
(5) Filling the final milk obtained in the step (4) into an inner packaging soft bag, and performing sterilization treatment;
(6) And drying the surface of the sterilized sample, and packaging the sample into an outer barrier bag to obtain the sodium oleate-free medium/long-chain fat emulsion injection, wherein the pH value of the sodium oleate-free medium/long-chain fat emulsion injection is 6.0-9.0.
It is worth to be noted that the inner packaging material of the medium/long chain fat emulsion injection in the technical scheme is soft bag packaging, the used inner packaging soft bag is made of polyethylene or polypropylene, and the composition form can be one layer, two layers, three layers, four layers, five layers, six layers, seven layers and the like. The outer barrier bag is made of polyethylene, polypropylene, polyethylene-polypropylene and the like, and is required to have barrier effect on oxygen, water vapor and the like, the packaging accessories comprise one or more of an antioxidant, a deoxidizer, an indicator and the like besides the inner packaging soft bag and the outer barrier bag, and the packaging accessories of the antioxidant, the deoxidizer, the indicator and the like are placed in the outer barrier bag. At present, the medium/long-chain fat emulsion injection containing vitamin E on the market at home basically contains sodium oleate components, and most packaging materials are glass bottles. However, the packaging form of the glass bottle has the defects of poor sealing property, easy infection, fragility, incomplete airtight infusion and the like in clinical use; and the auxiliary material sodium oleate added in the prescription has the safety risk of stimulating blood vessel cells. Aiming at the defects of the medium/long-chain fat emulsion injection containing vitamin E, the technical scheme adopts a packaging system combining an inner packaging soft bag and an outer barrier bag, can ensure the whole sealing property in the clinical infusion process, does not introduce external air, can realize the whole sealing process of the infusion, and has the remarkable advantages of light transportation, difficult breakage and the like.
According to the preparation method, the completely sealed packaging system is used, so that the oxidation index of the liquid medicine in the long-term storage process is greatly guaranteed, and the risk of microbial pollution caused by poor sealing property of the medicine in the use process is avoided.
Specifically, in the step (5) of the preparation method of the technical scheme, the sterilization method is one of a moist heat sterilization method and an overkill method, and when the moist heat sterilization method is adopted, the F0 value is required to be more than or equal to 8.0, and more preferably, the F0 value is more than or equal to 12; when the sterilization treatment is carried out by adopting an overkill method, the sterilization temperature is 121 ℃, the sterilization time is 12-15min, and the F0 value is more than or equal to 12.
The operation method of the step (6) is as follows: and drying the surface of the sterilized sample, packaging the sample into an outer barrier bag, and adding one or more of an antioxidant, a deoxidizer and an indicator into the outer barrier bag to obtain the sodium oleate-free medium/long-chain fat emulsion injection.
It is worth pointing out that the specification of the medium/long chain fat emulsion injection without sodium oleate can be different specifications such as 50 ml/bag, 100 ml/bag, 250 ml/bag, 500 ml/bag and the like.
Further, the operation method of step (1) is as follows: under the protection of nitrogen, soybean oil, medium-chain triglyceride and vitamin E are mixed, heated to 55-80 ℃ and stirred uniformly, egg yolk lecithin is added and stirred for dissolution, and an oil phase is obtained.
Specifically, when the oil phase is prepared, the temperature is required to be heated to 55-80 ℃, and the temperature can reach the phase transition temperature of the egg yolk lecithin within the temperature range of 55-80 ℃, so that the phase transition temperature of the egg yolk lecithin is the premise of ensuring the emulsification effect.
Further, the operation method of step (2) is as follows: adding an osmotic pressure regulator into water for injection under the protection of nitrogen, and uniformly stirring at 55-80 ℃ to obtain a water phase.
It is worth to say that the temperature of the water phase is controlled within the range of 55-80 ℃, so that the egg yolk lecithin can not cause phase change due to temperature change in the oil-water mixing process, and the temperature of the oil phase and the water phase is kept consistent.
Further, the operation method of step (3) is as follows: adding the oil phase into the water phase, mixing by adopting a stirring and mixing method or a high-speed shearing method at the temperature of 55-80 ℃ for 2-60 min to obtain primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
when the mixing is carried out by a high-speed shearing method, the shearing speed is 1000-15000 rpm/min.
It is worth to be noted that, because the pH of the liquid medicine is reduced during the high-pressure homogenization process and the high-temperature sterilization process, in order to ensure that the pH of the sterilized finished product is within the standard range (6.0-9.0), and the pH of the liquid medicine can not be adjusted after the high-pressure homogenization process and the high-temperature sterilization process, the pH is adjusted to 9.0-11 when the colostrum is prepared in the step (3), so as to ensure that the pH of the sterilized finished product can meet the standard requirement, therefore, the technical scheme only needs to adjust the pH of the colostrum, and the subsequent processes do not need to adjust any more.
Specifically, in the step (3), the oil-water mixing effect during the preparation of the primary emulsion can be ensured by controlling the mixing temperature to be 50-80 ℃, the mixing time to be 2-60 min and the shearing speed to be 1000-15000 rpm/min, so that the oil-water mixing effect is better.
Preferably, when the mixing is carried out by a high-speed shearing method, the shearing speed is 2000 to 1000rpm/min.
Further, the operation method of the step (4) is as follows: homogenizing the primary emulsion by high pressure homogenization to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing temperature is 20-60 ℃, the homogenizing pressure is 100-1200 bar, the pressure ratio of the high-pressure valve to the low-pressure valve is 3: 1-6: 1, and the cycle times are 2-8.
It is worth to say that by limiting the homogenizing temperature to be 20-60 ℃, the homogenizing pressure to be 100-1200 bar, the pressure ratio of the high-pressure valve to the low-pressure valve to be 3: 1-6: 1 and the cycle number to be 2-8, better particle size distribution can be realized.
Further illustratively, the pH adjusting agent is sodium hydroxide.
The sodium oleate-free medium/long-chain fat emulsion injection is prepared by the preparation method of the sodium oleate-free medium/long-chain fat emulsion injection.
It is worth to be noted that the sodium oleate-free medium/long-chain fat emulsion injection prepared by the preparation method of the technical scheme has the following advantages:
(1) The medium/long-chain fat emulsion injection in the technical scheme can still realize the same emulsification effect as the existing product on the premise of not additionally adding the auxiliary emulsifier, and simultaneously solves the problem of oil floating on the surface of the product caused by not adding sodium oleate in the prescription, thereby not only simplifying the prescription of the existing product, but also reducing the potential toxic and side effect risk caused by additionally adding the auxiliary emulsifier (sodium oleate).
(2) According to the medium/long-chain fat emulsion injection prepared by the technical scheme, as the sodium oleate auxiliary material is not added in the formula, the impurity content in the product stability process can be ensured to be at a lower level, which is very important for ensuring the quality of a safer product in the validity period, and even can reach the validity period for a longer time, the index of the reaction oxidation level in 24 months of the medium/long-chain fat emulsion injection prepared by the technical scheme is good, and the validity period can at least reach 24 months.
(3) According to the technical scheme, the oil phase component of the medium/long-chain fat emulsion injection contains a proper amount of antioxidant vitamin E, the vitamin E is a safe and reliable antioxidant in clinical application, the oxidation index of the medicine in the long-term storage process can be guaranteed to meet the requirement, the antioxidant function can be exerted in vivo (protecting a biological membrane), the medium/long-chain fat emulsion injection has double effects of in vitro and in vivo, and the addition of the antioxidant vitamin E in the medium/long-chain fat emulsion injection is an effective means for guaranteeing the long-term storage of the medium/long-chain fat emulsion injection.
(4) The medium/long chain fat emulsion injection adopts the combination of the inner packaging soft bag and the outer separation bag to package, adopts a completely sealed packaging system, can avoid the defect that the sealing performance of the currently sold glass bottle is not good to cause microbial contamination, has the advantages of convenient transportation, difficult breakage, mature preparation process and the like, can realize industrialized batch production, and effectively solves the risk of microbial contamination caused by long-time infusion when clinical patients use fat emulsion injection products.
Further, the medium/long chain fat emulsion injection without sodium oleate comprises the following components: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of egg yolk lecithin, 0.15-0.25 g of vitamin E, 20-30 g of osmotic pressure regulator and the balance of water for injection.
Further illustratively, the osmolality adjusting agent is glycerol.
The technical solution is further illustrated by the following examples.
Example 1
The components of the medium/long-chain fat emulsion injection without sodium oleate in the embodiment are as follows: each 1000ml of injection contains 50g of soybean oil, 50g of medium-chain triglyceride, 6g of egg yolk lecithin, 0.1g of vitamin E, 22.5g of osmotic pressure regulator (glycerol) and the balance of water for injection.
The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps:
(1) Under the protection of nitrogen, mixing soybean oil, medium-chain triglyceride and vitamin E, heating to 55 ℃, stirring and mixing uniformly, adding egg yolk lecithin, and continuously stirring and dissolving at 55 ℃ to obtain an oil phase;
(2) Adding an osmotic pressure regulator (glycerol) into water for injection under the protection of nitrogen, heating to 55 ℃, and stirring to fully and uniformly mix to obtain a water phase;
(3) Slowly adding the oil phase into the water phase, mixing by stirring, stirring and mixing at 60 deg.C for 15min to obtain colostrum, and regulating pH of the colostrum to 9.0 with pH regulator (sodium hydroxide);
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing temperature is 20 ℃, the pressure of a high-pressure valve of the homogenizer is 800bar, the pressure of a low-pressure valve of the homogenizer is 150bar, the pressure ratio of the high-pressure valve and the low-pressure valve is 5.33: 1, and the homogenizing pressure circulation times are 6 times at 800 bar;
(5) Filling the final emulsion obtained in the step (4) into a 50ml inner packaging soft bag made of a three-layer co-extrusion transfusion film, sealing, and sterilizing the sample by adopting a damp-heat sterilization method under the condition that the F0 value is more than or equal to 12.0;
(6) And drying the surface of the sterilized sample, packaging the sample into an outer barrier bag, and adding a deoxidizer and an oxygen indicator to obtain the sodium oleate-free medium/long-chain fat emulsion injection.
The sodium oleate-free medium/long-chain fat emulsion injection prepared in the embodiment 1 is examined for key indexes, wherein the examined indexes comprise an average particle size, a D90 value, a particle size distribution index, a anisidine value and a peroxide value, and the examination results are shown in the following table 1 according to the national drug standard draft of the medium/long-chain fat emulsion injection published by the pharmacopoeia committee.
Example 2
The components of the medium/long-chain fat emulsion injection without sodium oleate in the embodiment are as follows: each 1000ml of injection contains 100g of soybean oil, 100g of medium-chain triglyceride, 8g of egg yolk lecithin, 0.15g of vitamin, 25g of osmotic pressure regulator (glycerol) and the balance of water for injection.
The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps:
(1) Under the protection of nitrogen, mixing soybean oil, medium-chain triglyceride and vitamin E, stirring at 60 ℃ to uniformly mix, adding egg yolk lecithin, and continuously stirring at 60 ℃ to dissolve to obtain an oil phase;
(2) Adding osmotic pressure regulator (glycerol) into water for injection under nitrogen protection, heating to 60 deg.C, stirring to mix well to obtain water phase;
(3) Slowly adding the oil phase into the water phase, mixing by stirring, stirring at 60 deg.C for 20min to obtain primary emulsion, and adjusting pH of the primary emulsion to 11;
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing temperature is 60 ℃, the pressure of a high-pressure valve of the homogenizer is 600bar, the pressure of a low-pressure valve of the homogenizer is 100bar, the pressure ratio of the high-pressure valve and the low-pressure valve is 6:1, and the number of homogenizing pressure cycles is 7 at 600 bar;
(5) Filling the final emulsion obtained in the step (4) into a 100ml inner packaging soft bag made of five-layer co-extrusion transfusion films, sealing, and sterilizing the sample by adopting a damp-heat sterilization method under the condition that the F0 value is more than or equal to 12.0;
(6) And (3) drying the surface of the sterilized sample, packaging the sample into an outer barrier bag, and adding a deoxidizer and an oxygen indicator to obtain the sodium oleate-free medium/long-chain fat emulsion injection.
The key indexes reflecting the product quality stability of the sodium oleate-free medium/long-chain fat emulsion injection prepared in the embodiment 2 are examined, the examination indexes comprise an average particle size, a D90 value, a particle size distribution index, a anisidine value and a peroxide value, the measurement methods of the items are according to the national drug standard draft of the medium/long-chain fat emulsion injection published by the pharmacopoeia committee, and the examination results are shown in the following table 1.
Example 3
The components of the medium/long-chain fat emulsion injection without sodium oleate in the embodiment are as follows: each 1000ml of injection contains 100g of soybean oil, 100g of medium-chain triglyceride, 12g of egg yolk lecithin, 0.2g of vitamin E, 25g of osmotic pressure regulator (glycerol) and the balance of water for injection.
The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps:
(1) Under the protection of nitrogen, mixing soybean oil, medium-chain triglyceride and vitamin E, stirring at 65 ℃ to uniformly mix, adding egg yolk lecithin, and continuously stirring at 65 ℃ to dissolve to obtain an oil phase;
(2) Adding osmotic pressure regulator (glycerol) into water for injection under nitrogen protection, heating to 65 deg.C, stirring to mix well to obtain water phase;
(3) Slowly adding the oil phase into the water phase, and performing high-speed shearing at 65 ℃ at the shearing speed of 5000rpm/min for 10min to obtain primary emulsion; adjusting pH of the colostrum to 10 with pH regulator;
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; wherein, in the high-pressure homogenizing process, the homogenizing temperature is 50 ℃, the pressure of a high-pressure valve of the homogenizer is 600bar, the pressure of a low-pressure valve of the homogenizer is 110bar, the pressure ratio of the high-pressure valve and the low-pressure valve is 5.45: 1, and the number of homogenizing pressure cycles is 6 at 600 bar;
(5) Filling the final emulsion obtained in the step (4) into a 250ml inner packaging soft bag made of a three-layer co-extrusion transfusion film, sealing, and sterilizing the sample by adopting a damp-heat sterilization method under the condition that the F0 value is more than or equal to 12.0;
(6) And drying the surface of the sterilized sample, packaging the sample into an outer barrier bag, and adding a deoxidizer and an oxygen indicator to obtain the sodium oleate-free medium/long-chain fat emulsion injection.
The sodium oleate-free medium/long-chain fat emulsion injection prepared in this example 3 is subjected to key index investigation reflecting product quality stability, the investigation indexes include average particle size, D90 value, particle size distribution index, anisidine value and peroxide value, the determination methods of the items are according to the national drug standard draft of medium/long-chain fat emulsion injection published by the pharmacopoeia committee, and the investigation results are shown in table 1 below.
Example 4
The components of the medium/long-chain fat emulsion injection without sodium oleate are as follows: every 1000ml of injection contains 100g of soybean oil, 100g of medium-chain triglyceride, 12g of egg yolk lecithin, 0.25g of vitamin E, 30g of osmotic pressure regulator (glycerol) and the balance of water for injection.
The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection comprises the following steps:
(1) Under the protection of nitrogen, mixing soybean oil, medium-chain triglyceride and vitamin E, stirring at 80 ℃ to uniformly mix, adding egg yolk lecithin, and continuously stirring at 80 ℃ to dissolve to obtain an oil phase;
(2) Adding osmotic pressure regulator (glycerol) into water for injection under nitrogen protection, heating to 80 deg.C, stirring to mix well to obtain water phase;
(3) Slowly adding the oil phase into the water phase, and performing high-speed shearing at 80 ℃ at a shearing speed of 8000rpm/min for 15min to obtain primary emulsion;
(4) Homogenizing the primary emulsion with high pressure to obtain final emulsion; wherein, in the high-pressure homogenizing process, the homogenizing temperature is 50 ℃, the pressure of a high-pressure valve of the homogenizer is 600bar, the pressure of a low-pressure valve of the homogenizer is 200bar, the pressure ratio of the high-pressure valve and the low-pressure valve is 3:1, and the homogenizing pressure circulation times at 600bar is 6 times;
(5) Filling the final emulsion obtained in the step (4) into a 500ml inner packaging soft bag made of five-layer co-extrusion transfusion films, sealing, and sterilizing the sample by adopting a damp-heat sterilization method under the condition that the F0 value is more than or equal to 15.0;
(6) And drying the surface of the sterilized sample, packaging the sample into an outer barrier bag, and adding a deoxidizer and an oxygen indicator to obtain the sodium oleate-free medium/long-chain fat emulsion injection.
The key indexes reflecting the product quality stability of the sodium oleate-free medium/long-chain fat emulsion injection prepared in the embodiment 4 are examined, the examination indexes comprise an average particle size, a D90 value, a particle size distribution index, a anisidine value and a peroxide value, the measurement methods of the items are according to the national drug standard draft of the medium/long-chain fat emulsion injection published by the pharmacopoeia committee, and the examination results are shown in the following table 1.
TABLE 1 examination indexes of examples 1 to 4
As can be seen from the examination index data in table 1, the average particle size of the medium/long-chain fat emulsion injection prepared in examples 1 to 4 is small, and the particle size distribution index (PDI) is also small, which indicates that the medium/long-chain fat emulsion injection prepared in examples 1 to 4 has a good particle size distribution effect, and the medium/long-chain fat emulsion injection prepared in examples 1 to 4 has a very low anisidine value, and the peroxide value detection result is small or even undetected, and thus, the medium/long-chain fat emulsion injection prepared in examples 1 to 4 has stable quality and is not easy to oxidize and deteriorate.
Comparative example 1
The comparative example is a medium/long chain fat emulsion injection product containing sodium oleate which is sold in the market at present, and it should be noted that the fat emulsion injection in the comparative example contains sodium oleate which can be purchased directly in the market, and the preparation process of the product sold in the comparative example 1 cannot be obtained because the sodium oleate is directly purchased in the market.
Specifically, 15L of sodium oleate-free medium/long-chain fat emulsion injection is prepared by the method in example 3, the prepared sodium oleate-free medium/long-chain fat emulsion injection is used as a test sample, the sodium oleate-containing medium/long-chain fat emulsion injection in comparative example 1 is used as a comparison sample, the test sample and the comparison sample are compared, and key quality indexes of the test sample and the comparison sample are respectively detected, wherein the key technical indexes of detection comprise average particle size, particle size distribution index, D90 value and lysophospholipid content (the content of lysophospholipid is determined by comprising Lysophosphatidylcholine (LPC) and Lysophosphatidylethanolamine (LPE)), and in order to further compare the effects of the test sample and the comparison sample, the test sample and the comparison sample are respectively subjected to a high temperature influence factor test, and the key indexes are considered and compared, and the detection results are shown in the following table 2:
TABLE 2 comparison of test results of comparative example 1 and example 3
As can be seen from Table 2, the medium/long-chain fat emulsion injection (test sample) prepared by the technical scheme of the embodiment 3 can achieve the same emulsification effect as the commercial product (comparative sample), and the measurement results of key indexes related to the emulsification effect show that the average particle size,The particle size distribution index, D90 value, lysophospholipid and results after 30 days at elevated temperature are comparable to the commercial product. Also, the average particle diameters, PDI and D of the test sample and the comparative sample 90 The ratio is slightly reduced, which indicates that the sodium oleate-free medium/long-chain fat emulsion injection prepared by the preparation method of example 3 can achieve better emulsification effect than the commercially available products. Therefore, by adopting the preparation method of the technical scheme, the same emulsification effect as that of a commercially available product can be realized under the condition that an auxiliary emulsifier (sodium oleate) is not additionally added, and even the emulsification effect is better than that of the commercially available product.
Example 5
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the present example are substantially the same as those in example 3, except that in the present example, the pressure of the high-pressure valve of the homogenizer is 650bar, the pressure of the low-pressure valve of the homogenizer is 110bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 5.9: 1, and the number of cycles of homogenization at 650bar is 6.
Example 6
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the embodiment are substantially the same as those in embodiment 3, except that in the embodiment, the pressure of a high-pressure valve of a homogenizer is 600bar, the pressure of a low-pressure valve of the homogenizer is 130bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 4.6: 1, and the number of cycles of homogenization at 600bar is 6.
Example 7
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the present example are substantially the same as those in example 3, except that in the present example, the pressure of the high-pressure valve of the homogenizer is 550bar, the pressure of the low-pressure valve of the homogenizer is 150bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 3.67: 1, and the number of cycles of homogenization at 550bar is 6.
Example 8
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the present example are substantially the same as those in example 3, except that in the present example, the pressure of the high-pressure valve of the homogenizer is 500bar, the pressure of the low-pressure valve of the homogenizer is 170bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is about 3:1, and the number of homogenization pressure cycles is 6 at 500 bar.
Comparative example 2
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the comparative example are substantially the same as those in example 3, except that in the comparative example, the pressure of the high-pressure valve of the homogenizer is 600bar, the pressure of the low-pressure valve of the homogenizer is 60bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 10: 1, and the number of cycles of homogenization at 600bar is 6.
Comparative example 3
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the comparative example are substantially the same as those in example 3, except that in the comparative example, the pressure of the high-pressure valve of the homogenizer is 800bar, the pressure of the low-pressure valve of the homogenizer is 80bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 10: 1, and the number of cycles of homogenization at 800bar is 6.
Comparative example 4
The formulation and preparation method of the sodium oleate-free medium/long-chain fat emulsion injection in the comparative example are substantially the same as those in example 3, except that in the comparative example, the pressure of the high-pressure valve of the homogenizer is 960bar, the pressure of the low-pressure valve of the homogenizer is 80bar, the ratio of the pressure of the high-pressure valve to the pressure of the low-pressure valve is 12: 1, and the number of cycles of homogenization at 96bar is 6.
Specifically, according to the methods of examples 5 to 8 and comparative examples 2 to 4, the sodium oleate-free medium/long chain fat emulsion injection is prepared, the average particle size and the large emulsion particle content of the sodium oleate-containing medium/long chain fat emulsion injection prepared in examples 5 to 8 and comparative examples 2 to 4 are detected, and the surface appearance (whether oil is floating) is visually observed, and the detection results are as follows in table 3:
table 3 test results of examples 5 to 8 and comparative examples 2 to 4
It can be seen from the detection data in table 3 that, in the case of not adding sodium oleate, the technical scheme properly increases the pressure of the low pressure valve, so that the ratio of the pressure of the high pressure valve to the pressure of the low pressure valve is in the range of 3:1 to 6:1, and the ratio of the pressure of the high pressure valve to the pressure of the low pressure valve is in the range of 10: 1 to 12: 1, so that a better particle size distribution effect can be achieved. Moreover, when the pressure of the low-pressure valve is increased, the pressure of the high-pressure valve can be obviously reduced, the damage of the high-pressure valve can be reduced, and meanwhile, the power energy consumption can be greatly reduced.
From the test results of comparative example 2, it is known that when the pressure of the high pressure valve is 600bar and the pressure of the low pressure valve is 60bar (high pressure valve: low pressure valve = 10: 1), the average particle size is 336nm and the large milk particle size is 0.03% after 6 times of homogenization, but a slight degree of oil star is observed on the surface of the sample after homogenization, and since sodium oleate, which is a co-emulsifier, is not added to the formulation of comparative example 2, when the pressure of the high pressure valve: low pressure valve = 10: 1, the emulsification effect of egg yolk lecithin may be exerted during the homogenization, so that the final product may slightly drift oil.
From the test results of comparative example 3, it is understood that when the high-pressure valve pressure is 800bar and the low-pressure valve pressure is 80bar (high-pressure valve pressure: low-pressure valve pressure = 10: 1), the average particle size is 301nm and the large milk particles are 0.02% after 6 times of homogenization, and a slight degree of oil star is also observed on the surface of the sample after homogenization, so that as the homogenization pressure is increased, the average particle size is reduced and the large milk particles are also slightly reduced, but the problem of oil floating on the surface of the product still cannot be solved.
From the test results of comparative example 4, it was found that when the high-pressure valve pressure was 960bar and the low-pressure valve pressure was 80bar (high-pressure valve pressure: low-pressure valve pressure =12 1), the average particle size was further reduced after 6 times of homogenization, the level of large milk particles was substantially unchanged, but the surface of the product still had slightly floating oil. Therefore, when sodium oleate is not added into the medium/long-chain fat emulsion injection, the problem of floating oil on the surface of the product cannot be solved by increasing the homogenization pressure.
Effect example 1
Nutritional fat milk products are clinically high-risk preparations and therefore quality standards are rather strict with respect to impurity control. Wherein, free fatty acid and lysophospholipid are taken as key impurity control items to be brought into quality standard supervision, and the standard is severer, according to the quality standard assessment draft of Chinese/long chain fat emulsion injection (C8-24) published by pharmacopoeia commission, the control limit of the free fatty acid is as follows: the content of free fatty acid in per 1g of oil (containing soybean oil 0.5g and medium chain triglyceride 0.5 g) is not more than 0.07mmol; the control limits for lysophosphatidylation are: every 1ml contains no more than 2.0mg of lysophosphatidylcholine and no more than 0.5mg of lysophosphatidylethanolamine.
Effect example a sample containing no sodium oleate was prepared using the formulation and preparation method of example 3, and a sample containing sodium oleate was prepared using the formulation (sodium oleate content: 0.03%,0.05%,0.10%, respectively) and preparation method of example 3, and the four prepared samples and the commercially available product of comparative example 1 were subjected to high temperature test examination simultaneously, and the free fatty acids were measured at high temperatures for 5 days, 10 days, 20 days, and 30 days, respectively, and the detailed results are shown in fig. 2 below.
As can be seen from fig. 2, the medium/long chain fat emulsion injection without sodium oleate in example 3 can have lower impurity level of free fatty acid during the stability process, and has significantly better impurity control effect compared with the commercial product. And as can be seen from fig. 2, the free fatty acid change of samples with different contents of sodium oleate during 30 days at high temperature is in positive correlation with the content of sodium oleate, and it can be seen that sodium oleate causes the content of free fatty acid in the samples to be high during the stability process (the high temperature test result is referable to predicting the quality change trend during the drug storage process, which is well known to those skilled in the art). The generation of free fatty acid indicates the degradation of grease (bulk drug) and lecithin (key auxiliary material) in the fat emulsion preparation, and the content of the free fatty acid in the stability process is increased, which indicates that the raw and auxiliary materials in the product are degraded. For fat emulsion preparations, the national standard strictly controls the content of free fatty acid, mainly aims to ensure the stability of raw and auxiliary materials in the storage process of the products, and further ensures the quality of the products. It can be seen from the effect examples that if sodium oleate is added into the formula, free fatty acid of the product is in a significantly increasing trend (although not exceeding the national standard) in the stability process, and the medium/long-chain fat emulsion injection containing no sodium oleate has a lower increasing trend of free fatty acid in the storage process, so that the quality of the product of the technical scheme is more stable.
Effect example 2
The sodium oleate-free medium/long-chain fat emulsion injection prepared in example 3 and the commercial product in comparative example 1 were subjected to simultaneous quality investigation, which involves the following aspects:
(1) use advantage investigation: the packaging material adopted in the example 3 is different from the commercial product, the example 3 adopts the soft bag package, and has the advantages of good sealing performance, difficult breakage, convenient transportation, difficult generation of foreign matters and the like, while the commercial product of the comparative example 1 adopts the glass bottle package, and has the defects of poor sealing performance, easy breakage, easy generation of glass scraps and the like.
(2) And (3) investigating the sealing property: the content of oxygen in the packaging material and the content of dissolved oxygen in the liquid medicine were measured at a high temperature for 30 days, and it was found from the measurements that the content of oxygen in the packaging material in example 3 and the content of dissolved oxygen in the packaging material in accordance with the time at a high temperature were changed slowly, while the content of oxygen in the glass bottle of the commercially available product and the content of dissolved oxygen in the liquid medicine were significantly increased, and the results of the measurements are shown in fig. 3 and 4, from which it can be seen from fig. 3 and 4 that the content of oxygen in the inner bag of the commercially available product and the content of dissolved oxygen in the liquid medicine were both slightly increased, while the content of oxygen in the inner bag of the sample in example 3 and the content of dissolved oxygen in the liquid medicine were kept substantially unchanged and the initial values were both lower than those of the commercially available product, and it can be seen that the sealing performance of the product in example 3 was significantly higher than that of the commercially available product.
(3) And (3) oxidation index investigation: the long-term 24-month stability examination of the sample of example 3 and the commercial product revealed that the key quality indicators for the sample of example 3 and the commercial product are: the results of pH, average particle size, lysophospholipid, oil content and the like all meet the quality standard requirements of the product, the general trend of change in 24 months is equivalent, the indexes to be emphasized are a anisidine value and a peroxide value, and the long-term stability test result in 24 months shows that the sample in example 3 has certain advantages in oxidation indexes, the detailed results are shown in figure 5, and the long-term stability examination result in figure 5 shows that the anisidine value and the peroxide value of the commercial product and the anisidine value and the peroxide value of example 3 both meet the quality standard requirements (anisidine value is less than or equal to 2.2 and peroxide value is less than or equal to 3.0) and are far lower than the standard limit requirements, but the comparison analysis shows that the peroxide value is more gradually changed in the long-term examination result in example 3, and although the peroxide value is slightly increased, the increase amplitude is smaller than the reference value.
Effect example 3
Because the emulsion particles of the fat emulsion preparation for injection are usually between 200 and 500nm, the particles in the emulsion are small, the dispersion degree is high, the integral surface area is large, and the surface free energy is high, the fat emulsion preparation belongs to a thermodynamically unstable system, and the emulsion particles in the system tend to grow from small to large, so that the emulsion particles are continuously merged, and finally emulsion breaking is realized. However, based on Stokes' formula, this merging process is relatively slow due to the relatively small size of the milk particles of the fat milk. The sodium oleate is used as an auxiliary material commonly used in fat emulsion preparations, has the main function of serving as an auxiliary emulsifier, and can further improve the emulsifying effect of the egg yolk lecithin. Besides, the sodium oleate has another main function of forming potential energy on the surface of the emulsion membrane to make the emulsion membrane of the emulsion droplets negatively charged. According to the principle that like charges repel each other, the addition of the sodium oleate can effectively avoid the combination of emulsion droplets, and theoretically, the long-term stability of the fat emulsion product can be ensured. However, the addition of sodium oleate brings a certain degree of safety problem to clinical application, and sodium oleate has a certain irritation to part of people with physical constitutions as an indication activity of fatty acid salts, and even can cause more serious adverse reactions such as hemolysis and inflammation.
In order to show that the medium/long-chain fat emulsion injection without the sodium oleate has better safety, the invention is provided with a contrast test. The medium/long-chain fat emulsion injection (C8-24 Ve) (without sodium oleate) is prepared by adopting the prescription composition and the preparation process in the example 3, and is subjected to safety test researches such as allergy, hemolysis, irritation and the like with the commercial product (containing sodium oleate) in the comparative example 1, the safety test is entrusted to the development of an institution with GLP qualification at home, and the research results are as follows:
the results of the study show that the formulation of example 3 of the present invention, which does not contain sodium oleate, is less irritating.
The test methods and results are as follows:
(1) new Zealand rabbits were administered by intravenous injection once a day for 7 consecutive days. The results of observations carried out 72 hours and 14 days after the last administration respectively show that the sodium oleate-free medium/long-chain fat emulsion injection in example 3 has no irritation to the ear vein of New Zealand rabbits; whereas the commercial formulation of comparative example 1 was slightly irritating to the ear vein of New Zealand rabbits, indicating recovery after withdrawal.
(2) The low and high doses of the sample of example 3 and the low and high doses of the commercial drug of comparative example 1 (0.25 ml/pig, 0.5 ml/pig, and 1.0 ml/pig, respectively) were negative for active allergic reaction in SPF-grade Hartley guinea pigs, with a 0% positive rate.
(3) Example 3 low and high doses of the sample and low and high doses of the commercial drug of comparative example 1 (sensitizers were 0.25 ml/pig and 0.5 ml/pig, respectively) were negative to passive skin allergic reaction in SPF-grade Hartley guinea pigs with a positive rate of 0%.
(4) Example 3 samples and commercially available drugs (clinical concentrations) did not show hemolysis in rabbit erythrocytes in vitro and did not cause erythrocyte aggregation.
Specifically, the test method and the results of the effect example are shown in table 4 below:
table 4 effects test method and results of example 3
Effect example 4
The egg yolk lecithin, a key adjuvant of the fat milk preparation, contains two trace lysophospholipids, namely Lysophosphatidylcholine (LPC) and Lysophosphatidylethanolamine (LPE), besides Phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM) and Phosphatidylinositol (PI). In addition, LPC and LPE are present in egg yolk lecithin, and new LPC and LPE are gradually generated during storage due to hydrolysis of egg yolk lecithin.
The related substances in the egg yolk lecithin, namely Lysophosphatidylcholine (LPC) and Lysophosphatidylethanolamine (LPE), have strong surface activity, and can rupture red blood cell membranes at higher concentration to cause hemolysis or cell necrosis. Therefore, LPC and LPE are also generally impurities strictly controlled in the fat emulsion preparation, and there is a clear limit control in the quality standards of each product. LPE is generally relatively stable in content and the level of content is essentially unchanged during the stabilization process, whereas LPC shows a pronounced tendency to increase gradually during the stabilization process, mainly due to the fact that the emulsifier egg yolk lecithin used in the fat emulsion formulation is gradually hydrolyzed during the sample placement process to form new LPC.
At present, the hydrolysis process of egg yolk lecithin is mainly carried out under heating and alkaline conditions, and the hydrolysis mechanism of egg yolk lecithin is known by those skilled in the art, so details are not described in the technical scheme of the invention. The effect embodiment sets a series of tests to verify the relationship between the content of LPC and sodium oleate in the product stability process, and the test method and the results are as follows:
the formulation composition and preparation method of example 3 are adopted to prepare the sodium oleate-free medium/long-chain fat emulsion injection (C8-24 Ve), and the formulation composition and preparation method of example 3 are adopted to prepare the sodium oleate-containing medium/long-chain fat emulsion injection (C8-24 Ve) (containing 0.01%, 0.02%, 0.03%,0.05% and 0.10% of sodium oleate, respectively), and the prepared medium/long-chain fat emulsion injection is simultaneously examined at high temperature for 30 days, and the examination items are mainly the LPC level of the preparation, and the study result is shown in fig. 6, as can be seen from fig. 6, the LPC level and the addition ratio of sodium oleate in the preparation formulation have a positive correlation trend in the process of high temperature for 30 days, and as the yolk lecithin is hydrolyzed to generate LPC under the high temperature environment, the LPC level is gradually increased along with the time, therefore, the addition of sodium oleate can promote the hydrolysis process of yolk lecithin, and compared with the formulation without the addition of sodium oleate, the formulation formula of LPC has a more obvious correlation, and the increase of the addition of sodium oleate is also positively increased. Therefore, the sodium oleate-free medium/long-chain fat emulsion injection prepared by the method can obviously reduce the LPC content in the product storage process, and further reduces the safety risk of the preparation.
In conclusion, the sodium oleate-free medium/long-chain fat emulsion injection prepared by the technical scheme can fully overcome various problems of products sold in the market at present, the quality can meet the standard requirements, and the sodium oleate-free medium/long-chain fat emulsion injection is even superior to the products sold in the market in terms of key impurity items and clinical medication safety.
The technical principle of the present invention is described above in connection with specific embodiments. The description is made for the purpose of illustrating the principles of the invention and should not be taken in any way as limiting the scope of the invention. Based on the explanations herein, those skilled in the art will be able to conceive of other embodiments of the present invention without inventive effort, which would fall within the scope of the present invention.
Claims (10)
1. The preparation method of the sodium oleate-free medium/long-chain fat emulsion injection is characterized in that the sodium oleate-free medium/long-chain fat emulsion injection is prepared from the following components in parts by weight: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of yolk lecithin, 0.01-0.3 g of vitamin E, 10-50 g of osmotic pressure regulator and the balance of water for injection;
preparing the sodium oleate-free medium/long-chain fat emulsion injection by adopting a high-pressure homogenization method, wherein in the high-pressure homogenization process, the ratio of the high-pressure valve pressure to the low-pressure valve pressure is 3:1 to 6:1.
2. the method of preparing sodium oleate-free medium/long chain fat emulsion injection as claimed in claim 1, wherein the method comprises the following steps:
(1) Heating and stirring soybean oil, medium-chain triglyceride and vitamin E uniformly, adding egg yolk lecithin, heating and stirring for dissolving to obtain an oil phase;
(2) Adding an osmotic pressure regulator into water for injection, and heating and stirring uniformly to obtain a water phase;
(3) Adding the oil phase into the water phase, mixing uniformly to prepare primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
(4) Homogenizing the primary emulsion by high pressure homogenization to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing pressure is 80-1200 bar, and the pressure ratio of the high-pressure valve to the low-pressure valve is 3:1 to 6:1;
(5) Filling the final milk obtained in the step (4) into an inner packaging soft bag, and performing sterilization treatment;
(6) And drying the surface of the sterilized sample, and packaging the sample into an outer barrier bag to obtain the sodium oleate-free medium/long-chain fat emulsion injection, wherein the pH value of the sodium oleate-free medium/long-chain fat emulsion injection is 6.0-9.0.
3. The method for preparing sodium oleate-free medium/long-chain fat emulsion injection according to claim 2, wherein the operation method of the step (1) is as follows: under the protection of nitrogen, soybean oil, medium-chain triglyceride and vitamin E are mixed, heated to 55-80 ℃ and stirred uniformly, egg yolk lecithin is added and stirred for dissolution, and an oil phase is obtained.
4. The method for preparing sodium oleate-free medium/long-chain fat emulsion injection according to claim 2, wherein the operation method of the step (2) is as follows: adding an osmotic pressure regulator into water for injection under the protection of nitrogen, and uniformly stirring at 55-80 ℃ to obtain a water phase.
5. The method for preparing sodium oleate-free medium/long-chain fat emulsion injection according to claim 2, wherein the operation method of the step (3) is as follows: adding the oil phase into the water phase, mixing by adopting a stirring and mixing method or a high-speed shearing method at the temperature of 55-80 ℃ for 2-60 min to obtain primary emulsion, and adjusting the pH value of the primary emulsion to 9.0-11 by using a pH regulator;
when the mixing is carried out by a high-speed shearing method, the shearing speed is 1000-15000 rpm/min.
6. The method for preparing sodium oleate-free medium/long-chain fat emulsion injection according to claim 2, wherein the operation method of the step (4) is as follows: homogenizing the primary emulsion with high pressure to obtain final emulsion; in the high-pressure homogenizing process, the homogenizing temperature is 20-60 ℃, the homogenizing pressure is 100-1200 bar, and the pressure ratio of the high-pressure valve to the low-pressure valve is 3:1 to 6:1, the cycle times are 2-8.
7. The method for preparing sodium oleate-free medium/long-chain fat emulsion injection according to claim 2, wherein the pH regulator is sodium hydroxide.
8. An injection of sodium oleate-free medium/long-chain fat emulsion, which is prepared by the method for preparing the sodium oleate-free medium/long-chain fat emulsion injection of any one of claims 1 to 7.
9. The sodium oleate-free medium/long-chain fat emulsion injection as claimed in claim 8, wherein the sodium oleate-free medium/long-chain fat emulsion injection comprises the following components: every 1000ml of injection contains 50-100 g of soybean oil, 50-100 g of medium-chain triglyceride, 6-12 g of yolk lecithin, 0.15-0.25 g of vitamin E, 20-30 g of osmotic pressure regulator and the balance of water for injection.
10. The sodium oleate-free medium/long chain fat emulsion injection of claim 9, wherein the osmotic pressure regulator is glycerol.
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