Production and technology of fat emulsion

Fat emulsion is an important part of parenteral nutrition and a supplement of energy Clinically, fat emulsion not only provides energy for metabolism, but also provides polyunsaturated fatty acids for metabolism of biofilm and bioactive substances, so as to prevent and correct the lack of essential fatty acids At present, the commonly used fat emulsion in clinic is long chain triglyceride (LCT) fat emulsion The basic formula is made of soybean oil (LCT) as the main component, refined lecithin as the emulsifier, glycerin as the isotonic agent, and homogenized under high pressure Many years of clinical application studies have found that continuous use of long-chain fat emulsion in large doses or for a long time will cause hyperlipidemia, damage the immune system and affect the function of reticuloendothelial system, liver and other important organs Based on the in-depth study of long-chain fat emulsion, B Braun company of Germany created a new generation of fat emulsion - Lipofundin MCT / LCT in the mid-1980s Medium chain triglyceride (MCT), which is more easily absorbed by the body, is used as the energy source in the formulation of medium / long chain fat emulsion injection, while part of LCT is retained as the source of essential fatty acids This formula makes full use of the characteristics of MCT, such as easy hydrolysis in vivo, rapid oxidation and simple metabolic process, and makes up for the shortage of LCT fat emulsion Compared with LCT fat emulsion, medium / long chain fat emulsion has the advantages of faster energy supply, better protein synthesis, better liver tolerance and nutritional effect of maintaining normal immune function In foreign countries, medium / long chain fat emulsion injection has been widely used in clinical nutrition support The product entered the market of China in 1991, its exact clinical nutritional effect has been confirmed by the domestic clinical application research, and it has been listed as class a medicine of national medical insurance In order to speed up the development of intravenous nutrition in China, we have successfully developed medium / long chain fat emulsion injection Now the research content of the preparation process is as follows 1 Prescription 11 10% medium / long chain fat emulsion injection consists of 50 g soybean oil for injection, 50 g medium chain triglyceride for injection, 12 g lecithin for injection, 25 g glycerin for injection and 1000 ml water for injection 1.1 the prescription is based on the prescription of medium / long chain fat emulsion injection approved by foreign countries 1.2 function of each component in the prescription soybean oil and medium chain triglyceride are the main components, lecithin is the emulsifier, glycerin is the isotonic regulator 2 Optimization experiment of emulsification process the optimization experiment plan of emulsification process is based on the preparation process of long-chain fat emulsion injection, combined with the characteristics of medium / long-chain fat emulsion injection, the orthogonal test method is used to select the process conditions with great influence, so as to determine the suitable preparation process 2.1 experimental materials and instruments: medium chain triglyceride for injection (condea company, Germany), soybean oil for injection (lipoid company, Germany), lecithin for injection (lipoid company, Germany), glycerin for injection (Shanning amino acid Co., Ltd.) Experimental high-pressure homogenizer, coulter particle analyzer, acidimeter, a set of experimental glass instrument 2.2 experimental method the core technology of the preparation process of fat emulsion is emulsification process According to the experience of developing and producing long-chain fat emulsion injection and the characteristics of each component in the medium / long-chain fat emulsion injection, the factors and levels that may have a greater impact on the particle size and distribution of milk particles in the preparation process are listed L9 (34) orthogonal table [2] is selected to design the experiment The distribution of milk particles in each group was determined by Kurt particle analyzer For data processing, the percentage of particles above 1 μ m accounting for particles above 0.5 μ m is used as the calculation result The small value means that the large particles are less and the milk particles are evenly distributed (see Table 1 for each factor level) Table 1 factor level table (omitted) 2.3 experiment results are shown in Table 2 Table 2 L9 (34) test plan and test results table (omitted) through calculation of comprehensive average value and range, it is concluded that the order of influence of each factor on emulsification process of medium / long chain fat emulsion is homogeneous pressure → pH value → homogeneous temperature The experimental results show that the main factors affecting the emulsification process are homogenization pressure, followed by pH value and homogenization temperature Under the experimental conditions, the optimal level combination of Zui is: homogenization pressure 21 MPa, pH 8.0, homogenization temperature 60 ℃ 3 Preparation process: according to the results of the above emulsification process optimization experiment, the preparation process of medium / long-chain fat emulsion injection is determined as follows: weigh the soybean oil and medium chain triglyceride in the preparation pot, mix them evenly with high-speed masher, heat them to 80 ℃, add lecithin, mash them to complete dissolution at high speed, and make them into uniform and clear solution In addition, take the prescription amount of water for injection and add glycerin, put it into another solution preparation pot, mix it evenly under the condition of nitrogen protection, and heat it to 60 ℃ Slowly add the phospholipid oil solution into the glycerine aqueous solution under high-speed agitation, and adjust the pH value to about 8.0 with sodium hydroxide After repeated homogenization by high-pressure homogenizer, the particles are about 0.33 μ m, filtered by 1 μ m microporous filter membrane, filled in the infusion bottle, filled with nitrogen, added with butyl rubber plug and sealed with aluminum cap It can be obtained by rotating sterilization at 115 ℃ for 25 min 4 Validation of the preparation process: three batches of samples were prepared with the preparation process of the above optimized level combination, and tested according to the quality standard of medium / long chain fat emulsion injection, and all indexes met the requirements Take the above three batches of samples for observation at 25 ℃ for 18 months Except for the slight decrease of pH value, there is no obvious change in other indicators, all of which meet the requirements of quality standards See Table 3 for the observation data of retention samples Table 3: sample observation at 25 ℃ for 18 months (omitted) 5 Other relevant measures to ensure the quality of the product The fat emulsion with good quality requires proper particle size, uniform distribution, stable shelf-life and good clinical tolerance In order to meet the above requirements, in addition to the strict control of the process conditions mentioned in the optimization experiment, full attention should be paid to the source and quality control of raw and auxiliary materials, the process measures to prevent oxidation, the selection of sterilization temperature and method, and the temperature control during preparation and storage, etc., and relevant measures should be taken to ensure According to the requirements of current process conditions, the temperature of homogenization process shall be controlled at (60 ± 1) ℃, pH value between 7.5 and 8.5, and the whole preparation process shall be carried out under the condition of nitrogen protection In order to ensure that the formed emulsion in the sterilization process will not be damaged, the whole process container should be evenly heated, so the rotary sterilization method must be used At the same time, the product shall be stored in a cool place below 25 ℃ and kept away from light 6 It is discussed that 61 fatty emulsion belongs to O / W type emulsion, which is an heterogeneous dispersion system composed of two immiscible liquid phases It is an unstable system in terms of kinetic classification Medium / long chain fat emulsion injection contains 5% MCT, MCT is composed of saturated fatty acids containing 6-12 carbon atoms, its molecular weight is less than LCT, but its water solubility is about 100 times higher than LCT Based on the analysis of the formation principle of O / W emulsion, the longer the hydrocarbon chain of oil, the stronger the lipophilicity of oil, and the better the stability of emulsion On the contrary, the stability is relatively poor Compared with long-chain fat emulsion, medium / long-chain fat emulsion injection, due to the addition of MCT, has a relatively low oil affinity in the whole system During the homogenization process, it is easy to have oil slick and uneven distribution of emulsion particles, which increases the preparation difficulty The equipment used in the preparation process of medium / long chain fat emulsion injection is roughly the same as that of long chain fat emulsion, but the specific process conditions of medium / long chain fat emulsion injection are more strict, mainly in the aspects of homogenization pressure, homogenization temperature, pH value control, sterilization temperature and time The results of pharmaceutical research show that the quality of the medium / long chain fat emulsion injection prepared by the above process is controllable and the product is stable in storage period The results of clinical research show that the clinical application of the product is safe and its effectiveness is similar to that of the medium / long chain fat emulsion injection approved by the import 62 In order to prepare fat emulsion injection with stable quality and good clinical tolerance, in addition to strict preparation process and controllable quality standard, the selection of raw and auxiliary materials is very important, which is the prerequisite for the development and production of fat emulsion, and it is related to the clinical medication safety Medium / long chain fat emulsion injection belongs to biochemical medicine Soybean oil, MCT and lecithin are all extracted from relevant parts of plants or animals and refined by physical or chemical methods Different producing areas and extraction processes may change the composition of raw materials, even cause the change of physical and chemical constants, and affect the emulsification effect What's more serious is that impurities that cannot be controlled by the quality standard may be brought into the raw and auxiliary materials The influence of these trace impurities on the safety of clinical medication has attracted the attention of foreign clinical nutritionists The adverse reactions of fat emulsion in clinical use, such as fever and liver function abnormality, are mostly caused by the trace impurities brought in from the raw and auxiliary materials The consequences of large dosage and long-term use are more serious, and the toxic and side effects are even irreversible It has been found that different fat emulsions can cause different organ damage in the subacute test of dogs reported abroad, and even die before the end of the test In order to investigate the safety of the product, the subacute toxicity test of beagle dogs was carried out according to the internationally recognized experimental design scheme We used soybean oil, MCT and lecithin from different manufacturers to prepare medium / long chain fat emulsion with the same preparation process, and administered the drug continuously for 28 days at the dose of 9 g / kg? D-1 (10 times the dose of human) To observe the subacute reaction of dogs and its effect on target organs The results showed that the effects of soybean oil and lecithin from different manufacturers on the liver of dogs were very different In serious cases, irreversible focal necrosis of the liver could be caused The results of animal experiments indicate that in addition to the control of raw and auxiliary materials required for fat emulsion production according to the corresponding quality standards, the dog subacute test should be carried out at the same time, and the raw material manufacturers should be determined according to the experimental results Through this effective measure, to ensure the safety of clinical medication But fat emulsion injection is difficult to prepare, the main problem is that the physical stability and heat source are not easy to meet the requirements The main fat emulsion is an important part of parenteral nutrition and a supplement of energy Clinically, fat emulsion not only provides energy for metabolism, but also provides polyunsaturated fatty acids for metabolism of biofilm and bioactive substances, so as to prevent and correct the lack of essential fatty acids At present, the commonly used fat emulsion in clinic is long chain triglyceride (LCT) fat emulsion The basic formula is made of soybean oil (LCT) as the main component, refined lecithin as the emulsifier, glycerin as the isotonic agent, and homogenized under high pressure Many years of clinical application studies have found that continuous use of long-chain fat emulsion in large doses or for a long time will cause hyperlipidemia, damage the immune system and affect the function of reticuloendothelial system, liver and other important organs Braun, Germany