JP3472337B2 - Production method of fat emulsion - Google Patents

Description

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a fat emulsion, and more particularly, to a method for producing a fat emulsion, which can be changed in appearance even when mixed with a nutritional infusion such as sugar, electrolyte and amino acid. The present invention relates to a method for producing a nutritional supplement fat emulsion which does not cause coarsening of fat particles and has excellent storage stability. [0002] Parenteral nutrition is widely used for nutritional supplementation at the time of various diseases or before and after surgery. At this time, it is known that if the intake calorie is insufficient, the amino acid is used as a calorie source even if an amino acid infusion is administered, and a sufficient wound healing effect cannot be obtained. Therefore, in parenteral nutrition, it is important to replenish calories with glucose and fat. Among them, fat has about twice the calorific value per unit weight of glucose and the largest calorie stored in the body. It has excellent advantages as a source. In addition, the administration of fat is extremely important from the nutritional point of view for supplementing essential fatty acids such as linoleic acid, linoleic acid, and arachidonic acid, which greatly contribute to the organization of tissue cells and the performance of their normal functions. However,
Oil-in-water fat emulsions emulsified to allow intravenous administration of fats are contraindicated with other drugs, such as amino acids, sugars,
If mixed with nutrient infusions such as electrolytes, the appearance changes and fat particles become coarse with time (Yoshihiko Shimada et al., Shinyaku and Clinical, 32, 71,
1983). Also, coarsened fat particles are known to exhibit strong toxicity (Kazumasa Yokoyama et al., The Japanese Jour)
nal of Parenteral and Eenteral Nutrition (2,615,198)
0). From such a background, the fat emulsion was not combined with other nutrient infusions, and was separately administered using a Y-tube or mixed after immediately before use. [0003] As a method of mixing and storing a fat emulsion and another nutrient infusion, for example, a stabilization method in which citric acid is added when mixing with a solution containing a divalent metal ion is disclosed (Japanese Patent Application Laid-Open No. HEI 9-258572). 5-32541 publication). However, this method has the potential to cause alkalosis when citric acid is administered intravenously.
It is known that reaching mg / dl (about 15 mEq / l) results in suppression of cardiac function, lowering of blood pressure and peripheral circulatory failure (Surgery, M
ook, 13, 116, 1980), which is not a preferable method in terms of safety. [0004] On the other hand, there have been many studies on the preparation of fat emulsions so far, which examined how to produce a uniform and stable emulsion liquid having a small average particle size and containing no coarse particles. No production method has been studied in consideration of storage stability when mixed with a nutritional infusion. As a conventional method for producing a fat emulsion, for example,
As described in 9111 gazette, after adding fats and oils and an emulsifier to water, agitate to prepare a coarse emulsion, and then finely emulsify by high-pressure emulsification using a Manton-Gaulin homogenizer or a microfluidizer. Is widely used. However, the emulsifier dispersion step of dispersing the emulsifier in fats and oils, the coarse emulsification step of adding water to the emulsifier dispersion to prepare a coarse emulsion, and the fine emulsification step of finely emulsifying the coarse emulsion by a high-pressure emulsification method or the like. There is no example in which the production conditions in each production process were correlated with the storage stability of the fat emulsion.
For example, in Japanese Patent Application Laid-Open No. 5-9111, the liquid temperature in the coarse emulsification step is 70 ° C., and the liquid temperature in the fine emulsification step is only described as 70 ° C. or less, There is no description of the relationship between conditions and storage stability. Also,
It is reported that the coarse emulsion kept at 80 ° C. is immediately finely emulsified, but there is no description about the storage stability when the fat emulsion is mixed with another infusion (Ishii et al., J. Pharm.
rmacol. (Journal Off Pharmacy & Pharma Colosseum), 42,513,199
0). As described above, in the conventional production method, in the emulsification step of the fat emulsion comprising the coarse emulsification step and the fine emulsification step, the temperature of each prepared solution is controlled to a relatively high temperature of 50 to 80 ° C. . However, under the above production conditions, the average particle diameter of fat particles is small, and although a uniform emulsion can be produced without containing coarse particles, there is a problem that when mixed with other nutrient infusions, the appearance changes and the fat particles become coarse. Occurs. [0007] The object of the present invention is to provide a sugar,
An object of the present invention is to provide a nutritional supplement fat emulsion having excellent storage stability which does not cause appearance change or fat particle coarsening even when mixed with a nutritional infusion such as an electrolyte and an amino acid. Means for Solving the Problems The present inventors have achieved the above object by appropriately controlling the production conditions in each production step of a fat emulsion without using an additive such as citric acid. We studied hard to see if we could solve it. The present inventors have found that the preparation temperature of each preparation solution in each production step of a fat emulsion is an important factor influencing the storage stability after being mixed with another infusion agent, The preparation temperature range was studied repeatedly. As a result, by controlling the temperature of the preparation liquid in the emulsifying step, ie, the coarse emulsifying step and the fine emulsifying step, within the optimum range, a fat emulsion having excellent storage stability even when mixed with other nutritional infusions. Have been found, and the present invention has been completed. In each of the production steps, it is most important to control the preparation temperature of the fine emulsification step, and by controlling the preparation temperature of the other production steps within the optimal range, more excellent storage stability can be obtained. I found something. [0010] That is, the present invention provides a coarse emulsion by adding water to an emulsifier dispersion containing at least an emulsifier and a fat to obtain a coarse emulsion. In a method for producing a fat emulsion for obtaining an oil-in-water type nutritional supplement fat emulsion containing 1 to 30 W / V%, the fat emulsion to be finely emulsified while controlling the temperature of the emulsion in the fine emulsification to 5 to 35 ° C. It is a production method, and preferable production conditions include a production method in which the above-mentioned production method is added with a condition of coarse emulsification while controlling the temperature of the coarse emulsion at 5 to 35 ° C., and more preferably an emulsifier dispersion. This is a method for producing a fat emulsion in which conditions for dispersing an emulsifier are added while controlling the liquid temperature at 65 to 95 ° C. The present invention has the above-mentioned constitution, and the present invention will be described in detail in the order of the production steps. The preparation of the emulsifier dispersion in the first step of the emulsifier dispersion step is carried out, for example, by using a high-speed homogenizer, a high-speed mixer or the like. Is dispersed in fats and oils and stirred until the solid content of the emulsifier completely swells. At this time, various tonicity agents can be added as needed. The amount of the emulsifier added is preferably 5 to 25% based on the weight of the fat or oil. The preparation temperature of the emulsifier dispersion in the emulsifier dispersion step is 65 to 95.
° C, preferably 70-80 ° C. In addition, the phospholipid used as an emulsifier in the emulsifier dispersion liquid, emulsification becomes insufficient if less than 5 w / v% with respect to fats and oils,
If it exceeds 25% w / v, the viscosity increases and a stable fat emulsion cannot be produced. In the preparation of the coarse emulsion in the coarse emulsification step following the emulsifier dispersion step, for example, the emulsifier dispersion liquid produced by the above-mentioned method is immediately cooled to 5 to 35 ° C., preferably 15 to 35 ° C.
Cool to ~ 25 ° C, add distilled water for injection, also cooled to 5-35 ° C, little by little and disperse. Using a high-speed homogenizer, high-speed mixer, etc., control the solution temperature to 5-35 ° C while controlling the crude temperature. Prepare an emulsion. The preparation of the finely emulsified liquid in the finely emulsified step is carried out by high-pressure emulsification of the above coarsely emulsified liquid with a Manton-Gaulin homogenizer or a microfluidizer while controlling the liquid temperature at 5 to 35 ° C. Preferred emulsification conditions other than the liquid temperature control include a condition of 5000 to 25000 PSI and a number of passes of 5 to 25 as preferable conditions. The average particle size of the fat emulsion obtained through each of the above-mentioned production steps is 0.18 to 0.36 μm. If the average particle size is out of this range, a stable fat emulsion cannot be produced upon mixing with another infusion. As the fats and oils used in the present invention, any fats and oils can be used as long as they are edible oils, for example, vegetable oils such as soybean oil, coconut oil, sesame oil, perilla oil, linseed oil, cottonseed oil, safflower oil, whale oil, 1 selected from animal oils such as fish oil, and chemically synthesized triglycerides such as medium-chain fatty acid triglycerides.
Seeds or two or more kinds of fats and oils can be suitably used. Further, the emulsifier used in the present invention is one or a combination of two or more of purified soybean phospholipid, hydrogenated soybean phospholipid, purified egg yolk phospholipid, hydrogenated egg yolk phospholipid, nonionic surfactant and the like. Used. As the emulsifier, it is preferable to use purified egg yolk phospholipid, and more preferably to use purified egg yolk phospholipid in combination with a nonionic surfactant. The fat emulsion obtained by the production method of the present invention can be intravenously administered by mixing it with other nutritional infusions, that is, sugars, electrolytes and amino acids, if necessary. further,
The fat emulsion obtained by the production method of the present invention contains zinc, iron,
It can be blended in consideration of trace elements such as copper, iodine, manganese, vitamins, and other necessary amounts. In the production method of the present invention, commonly used pharmaceutical additives, that is, stabilizers and pH adjusters can be used. The fat emulsion obtained by the production method of the present invention is filled in a glass vial or a plastic bag made of polypropylene, polyethylene, ethylene-vinyl acetate copolymer or the like, and the space is replaced with nitrogen gas. It can be sterilized by the method. Further, the fat emulsion obtained by the production method of the present invention may be subjected to high-pressure steam sterilization, for example, by filling the fat emulsion and glucose in the lower layer of a two-compartment bag, and filling the remaining upper layer with amino acids and electrolytes. Then, the mixture may be mixed with another infusion agent by communicating between the two chambers after cooling or before use. The two-chamber bag is, for example, a flexible bag-shaped container made of plastic, the central part of which is heat-sealed in a strip shape so as to be peelable, and an infusion inlet or an outlet is provided in each of the two strictly isolated chambers. Can be used. Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples. Example 1 Refined soybean oil 30.0 g, glycerin 7.5
g and 3.6 g of purified egg yolk phospholipid were stirred vigorously using a polytron high-speed homogenizer while completely controlling the temperature at 80 ° C. until they were completely swollen to prepare an emulsifier dispersion. This emulsifier dispersion was immediately cooled to 20 ° C., 30 ml of distilled water for injection was added little by little, and while controlling the temperature at 20 ° C., a coarse emulsion was prepared with a polytron high-speed homogenizer. The crude emulsion thus obtained was immediately emulsified at 10,000 PSI using a microfluidizer (M-110Y type) while controlling the liquid temperature at 20 ° C. Next, distilled water for injection is added to the emulsified emulsion to make the total volume 300 ml.
After filtration through a 0 μm membrane filter, 100 m
One glass vial was filled, replaced with nitrogen, sealed, and subjected to high-pressure steam sterilization according to a conventional method to prepare a target fat emulsion. Example 2 A fat emulsion was prepared in the same manner as in Example 1 except that the preparation temperature of the coarse emulsion and the preparation temperature of the fine emulsion were set at 35 ° C. EXAMPLE 3 While controlling 31.0 g of purified soybean oil and 3.72 g of purified egg yolk lecithin at 80 ° C., the mixture was vigorously stirred using a polytron high-speed homogenizer to prepare an emulsifier dispersion. This emulsifier dispersion was immediately cooled to 20 ° C.
31 ml of a 50% glucose solution was added little by little, and while controlling the temperature at 20 ° C., a coarse emulsion was prepared using a polytron high-speed homogenizer. The crude emulsion thus obtained was immediately used with a microfluidizer (M-110Y type) for 20 minutes.
Fine emulsification was carried out at 10,000 PSI while controlling the temperature to ℃. Next, 300 ml of an aqueous solution in which 59.5 g of glucose and 0.78 g of sodium dihydrogen phosphate (dihydrate) were previously dissolved was added to the fine emulsion, and the total amount was adjusted to 700 ml with distilled water. This solution was filtered through a membrane filter having a pore size of 3.0 μm, filled in the lower layer of a two-chamber bag, and the space was replaced with nitrogen gas and sealed. Next, the upper layer composition shown in Table 1 below was heated and dissolved in distilled water for injection to make 250 ml, the pH was adjusted to 7.0 with a 1N aqueous acetic acid solution, and the total amount was made 300 ml. This solution was filtered through a membrane filter having a pore size of 0.22 μm, filled in the upper layer of the two-chamber bag, and the space was replaced with nitrogen gas, sealed and subjected to high-pressure steam sterilization according to a conventional method. [Table 1] Test Example 1 Using the fat emulsions of the examples and the control examples described below as test liquids, the quality of each test liquid immediately after production and the storage stability after mixing with other nutritional infusions were examined. . As a test solution to be mixed with each test solution, a sugar, an electrolyte and an amino acid solution having the composition shown in Table 2 were dissolved in distilled water for injection to make 900 ml, and the pH was adjusted to 6.2 with an aqueous acetic acid solution. What used as 1000 ml was used. Each test solution was mixed with the test solution by filtering the test solution with a membrane filter having a pore size of 0.22 μm, and then mixing each test solution with 62 ml.
Then, 138 ml of each test solution was aseptically sterilized for 200 m.
This was carried out by mixing and injection into a plastic bag. The storage stability was evaluated by examining the change in appearance of the mixed solution stored at 25 ° C. for 2 days after the mixing operation and the ratio of coarse particles in fat particles. In addition, 2 measured by the centrifugal sedimentation method
The ratio of fat particles of μm or more was defined as the ratio of coarse particles. Table 3 shows the ratio of coarse particles, the average particle size of fat particles, and the evaluation results of storage stability immediately after the production of each test solution (after high-pressure emulsification treatment). From the test results, it is clear that both Example 1 and Example 2 in which the preparation temperature of each production step was controlled to the optimum range did not produce coarse particles immediately after production and had no problem in storage stability. It became. However, as shown in Table 3, the fat emulsions of Comparative Examples 1 to 5 produced at different preparation temperatures from those of Examples 1 and 2 had poor quality immediately after production or storage stability. Was evaluated as having a problem. Furthermore, as a result of measuring the free fatty acid immediately after production of Comparative Example 6 prepared in the same manner as in Example 1 except that the preparation temperature in the emulsifier dispersion step was set to 100 ° C., the free fatty acid in Example 1 was 0%. .31
mEq / l, whereas Control Example 6 had 1.24 mE
The oil / fat was decomposed with a clear high value of q / l. From the above results, it has been clarified that in the production of a fat emulsion, there is an optimum range between the preparation temperature in the coarse emulsification step and the fine emulsification step and the preparation temperature during the dispersion of the emulsifier. [Table 2] [Table 3] Test Example 2 The two-room bag infusion preparation of Example 3 was communicated between the two chambers, observed for changes in appearance after storage at 25 ° C. for 2 days, and further subjected to centrifugal sedimentation to obtain coarse particles of 2 μm or more. When the ratio of the particles was measured, no change in appearance was observed, and no generation of coarse particles of 2 μm or more was observed at all. According to the present invention, even when mixed with other nutritional infusions, ie, glucose, electrolyte and amino acid infusions,
It is possible to produce a fat emulsion having excellent storage stability without causing a change in appearance or coarsening of fat particles.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-5-279258 (JP, A) JP-A-60-51105 (JP, A) JP-A-57-16818 (JP, A) JP-A-58-58 222014 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 9/00 A61K 47/00

Claims (1)

(1) A method for producing an oil-in-water type fat emulsion containing 1 to 30 W / V% of fats and oils for high intravenous nutritional supplementation using fat as a calorie source. A step of preparing an emulsifier dispersion by dispersing an emulsifier in fats and oils while controlling the liquid temperature to 65 to 95 ° C., adding water to the emulsifier dispersion while controlling the liquid temperature to 5 to 35 ° C. A method for producing a fat emulsion comprising a step of preparing a coarse emulsion and a step of finely emulsifying the coarse emulsion while controlling the liquid temperature to 5 to 35 ° C.