JPH07277953A - Production of fat emulsion - Google Patents

Abstract

PURPOSE:To produce a fat emulsion for replenishment of nutrient, capable of being blended with an infusion containing sugar, an electrolyte, an amino acid, etc., without causing change of visual appearance or increase of the size of the fat particle and excellent in shelf life. CONSTITUTION:This method for production of a fat emulsion is carried out by adding water to an emulsifier dispersion containing at least an emulsifier and fats and oils, preparing a coarse emulsion and further refining the coarse emulsion under a high pressure so as to obtain an oil in water type fat emulsion for replenishment of nutrient containing 1 to 30W/V% fats and oils. In this production method, the refining is carried out while controlling the liquid temperature of the emulsion to 5 to 35 deg.C. As the preferable production conditions, preparation of the coarse emulsion at temperatures of the coarse emulsion controlled to 5 to 35 deg.C is used as an additional condition to the above-mentioned production method. Further preferably, dispersion of the emulsifier at liquid temperatures of the emulsifier dispersion controlled to 65 to 95 deg.C is used as an additional condition to the above-mentioned production method.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a fat emulsion, and more specifically, it does not cause a change in appearance or coarsening of fat particles even when mixed with a nutrient transfusion agent such as sugar, electrolyte, amino acid, etc. The present invention relates to a method for producing a nutritional supplement fat emulsion having excellent stability.

[0002]

2. Description of the Related Art Parenteral nutrition is widely used for nutritional support during various diseases or before and after surgery. At this time, if the calorie intake is insufficient, it is known that the amino acid is utilized as a calorie source even if the amino acid infusion is administered, and a sufficient wound healing effect cannot be obtained. Therefore, in parenteral nutrition, supplementation of calories with glucose and fat is important. 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. Further, the administration of fat is extremely important nutritionally because it supplements essential fatty acids such as linoleic acid, linoleic acid, and arachidonic acid, which contribute significantly to the organization of tissue cells and the execution of their normal functions. However,
Oil-in-water fat emulsion emulsified so that fat can be administered intravenously is contraindicated with other drugs, such as amino acids, sugars,
When mixed with nutrient infusions such as electrolytes, appearance changes and fat particles become coarse with time (Shima Shima et al., Shinyaku to Kakuhin, 32, 71,
1983). It is known that coarse fat particles are highly toxic (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 mixed with other nutritional infusion solutions, but was separately administered using a Y-tube, or was mixed and administered immediately before use.

As a method for mixing and storing a fat emulsion and another nutritional infusion solution, for example, a stabilization method has been disclosed in which citric acid is added when mixing with a solution containing a divalent metal ion. 5-32541 publication). However, this method can cause alkalosis when citrate is administered intravenously, and in addition, blood levels of 100
Reaching mg / dl (about 15mEq / l) is known to lead to cardiac depression, hypotension and peripheral circulatory failure (Surgery, M
ook, 13,116,1980), which is not a preferable method in terms of safety.

On the other hand, many of the past formulation researches on fat emulsions have examined how to produce a uniform and stable emulsion (emulsion) having a small average particle size and not containing coarse particles. There has been no study of the production method in consideration of the storage stability when mixed with the nutritional infusion. As a conventional method for producing a fat emulsion, for example, JP-A-5-
As described in 9111 publication, after adding an oil and fat and an emulsifier to water, a coarse emulsion is prepared by stirring, and then a method of finely emulsifying by a high pressure emulsification method using a Manton-Gaulin homogenizer or a microfluidizer. Is widely used.

However, an emulsifier dispersion step of dispersing an emulsifier in fats and oils, a coarse emulsification step of preparing water by adding water to the emulsifier dispersion, and a fine emulsification step of finely emulsifying the crude emulsion by a high pressure emulsification method or the like. There have been no studies in which the manufacturing conditions in each manufacturing process and the storage stability of the fat emulsion were related to each other.
As a conventional study example, for example, in JP-A-5-9111, the liquid temperature in the coarse emulsification step is 70 ° C. and the liquid temperature in the fine emulsification step is described as 70 ° C. or less. There is no description about the relationship between the conditions and the storage stability. Also,
Although it has been reported that a crude emulsion maintained at 80 ° C is immediately emulsified, there is no description of storage stability when a fat emulsion is mixed with other infusion solution (Ishii et al., J. Pharm. Pha.
rmacol. (journal off pharmacology & pharmacology), 42,513,199
0).

As described above, in the conventional production method, the liquid temperature of each preparation liquid is controlled to a relatively high temperature of 50 to 80 ° C. in the emulsification process of the fat emulsion comprising the rough emulsification process and the fine emulsification process. . However, under the above-mentioned production conditions, the average particle size of fat particles is small, and although it is possible to produce a uniform emulsion containing no coarse particles, there is a problem that when mixed with other nutrient transfusions, the appearance changes and coarsening of fat particles occurs. Occurs.

[0007]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
An object of the present invention is to provide a fat emulsion for nutritional supplementation which is excellent in storage stability and does not cause a change in appearance or coarsening of fat particles even when mixed with a nutritional infusion solution such as an electrolyte or an amino acid.

[0008]

Means for Solving the Problems The present inventors cannot solve the above-mentioned problems by appropriately controlling the manufacturing conditions of each manufacturing process of a fat emulsion without using an additive such as citric acid. I thought about it. The inventors of the present invention have found that the preparation temperature of each preparation liquid in each manufacturing process of a fat emulsion is an important factor that affects the storage stability after mixing with other infusion agents, and the appropriate temperature is obtained. The study on the preparation temperature range was repeated.

As a result, by controlling the temperature of the preparation liquid in the emulsifying step, that is, the rough emulsifying step and the fine emulsifying step within the optimum range, a fat emulsion excellent in storage stability even when mixed with other nutritional infusion solutions. The present invention was completed by finding out that the above can be manufactured. Further, it is most important to control the preparation temperature of the fine emulsification step among the respective production steps, and by controlling the preparation temperature of the other production steps to the optimum range, further excellent storage stability can be obtained. I found a thing.

That is, according to the present invention, water is added to an emulsifier dispersion liquid containing at least an emulsifier and oil to coarsely emulsify to obtain a coarse emulsified liquid. A method for producing a fat emulsion for obtaining an oil-in-water type fat emulsion for nutritional supplement containing 1 to 30 W / V%, wherein a fat emulsion to be finely emulsified while controlling the liquid temperature of the emulsified liquid in the fine emulsification It is a production method, and preferable production conditions include a production method in which the above-mentioned production method is added to the conditions for coarse emulsification while controlling the liquid temperature of the coarse emulsion to 5 to 35 ° C., more preferably the emulsifier dispersion liquid. 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 when the present invention is described in detail in the order of manufacturing steps, the preparation of the emulsifier dispersion liquid in the emulsifier dispersion step which is the first step is carried out by using, for example, a high-speed homogenizer, a high-speed mixer or the like. Is dispersed in oil and fat and stirred until the solid content of the emulsifier is completely swollen. At this time, various isotonic agents can be added as required. The amount of the emulsifier added is preferably 5 to 25% based on the weight of the fat and oil. The preparation temperature of the emulsifier dispersion liquid in the emulsifier dispersion step is 65 to 95.
It is good to control the temperature to 70 ° C, preferably 70 to 80 ° C. If the phospholipid used as an emulsifier in the emulsifier dispersion is less than 5 w / v% with respect to fats and oils, the emulsification will be insufficient,
If it exceeds 25 w / v%, the viscosity increases and a stable fat emulsion cannot be produced.

The preparation of the coarse emulsion in the coarse emulsification step following the emulsifier dispersion step is carried out by, for example, immediately cooling the emulsifier dispersion produced by the above-mentioned method to 5 to 35 ° C., preferably 15
Distilled water for injection, which was cooled to -25 ° C and also cooled to 5-35 ° C, was added little by little to disperse, and the mixture was coarsely controlled using a high-speed homogenizer, a high-speed mixer, etc. so that the liquid temperature becomes 5-35 ° C. Prepare an emulsion.

The preparation of the refined emulsion in the refinement step is carried out by high-pressure emulsification of the crude emulsion using a Manton-Gaulin homogenizer or a microfluidizer while controlling the temperature of the solution at 5-35 ° C. In addition, as the conditions for fine emulsification other than the liquid temperature control, conditions of 5000 to 25000 PSI and 5 to 25 passes are preferable.

The average particle size of the fat emulsion obtained through the above-mentioned manufacturing steps is 0.18 to 0.36 μm. If the average particle diameter is out of this range, a stable fat emulsion cannot be produced when mixed with other infusion agents.

As the oil and fat used in the present invention, any oil and fat can be used as long as it is an edible oil. For example, vegetable oil such as soybean oil, coconut oil, sesame oil, perilla oil, linseed oil, cottonseed oil and safflower oil, whale oil, 1 selected from animal oil such as fish oil and chemically synthesized triglyceride such as medium chain fatty acid triglyceride
Two or more types of fats and oils can be preferably used. The emulsifier used in the present invention is one or a combination of two or more of purified soybean phospholipids, hydrogenated soybean phospholipids, purified egg yolk phospholipids, hydrogenated egg yolk phospholipids, nonionic surfactants and the like. Used. As the emulsifier, it is preferable to use a purified egg yolk phospholipid, and more preferably to use a purified egg yolk phospholipid in combination with a nonionic surfactant.

The fat emulsion obtained by the production method of the present invention may be mixed with other nutritional infusions, that is, sugar, electrolytes and amino acids, if necessary, and administered intravenously. further,
The fat emulsion obtained by the production method of the present invention includes zinc, iron,
It can be blended in consideration of necessary amounts of trace elements such as copper, iodine and manganese, vitamins and the like.

In the production method of the present invention, the conventionally 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, 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.

Furthermore, the fat emulsion obtained by the production method of the present invention may be sterilized by high pressure steam by filling the lower layer of the two-chamber bag with the fat emulsion and glucose, and filling the remaining upper layer with the amino acid and the electrolyte. However, it 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 portion of which is heat-weld in a strip-like manner so that it can be peeled off, and an infusion inlet or an outlet is provided in each of the two chambers that are strictly isolated. You can use the specified one.

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited to these examples.

[0021]

Example 1 30.0 g of refined soybean oil and 7.5 glycerin
g and purified egg yolk phospholipids (3.6 g) were vigorously stirred using a Polytron high-speed homogenizer while controlling the temperature to 80 ° C. to prepare an emulsifier dispersion liquid. This emulsifier dispersion liquid was immediately cooled to 20 ° C., 30 ml of distilled water for injection was added little by little, and a polyemulsion high-speed homogenizer was used to prepare a crude emulsion liquid while controlling at 20 ° C. The thus-obtained crude emulsion 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 was added to the refined emulsion to make the total amount 300 ml.
100m after filtering with 0μm membrane filter
l A glass vial was filled, purged with nitrogen and sealed, and high-pressure steam sterilization was performed according to a conventional method to prepare a target fat emulsion.

[0022]

Example 2 A fat emulsion was prepared in the same manner as in Example 1 except that the preparation temperature of the crude emulsion and the preparation temperature of the refined emulsion were set to 35 ° C.

[0023]

Example 3 31.0 g of purified soybean oil and 3.72 g of purified egg yolk lecithin were vigorously stirred using a Polytron high speed homogenizer while controlling at 80 ° C. to prepare an emulsifier dispersion liquid. Immediately cool this emulsifier dispersion to 20 ° C.,
31 ml of 50% glucose solution was added little by little, and a crude emulsion was prepared with a Polytron high speed homogenizer while controlling at 20 ° C. The crude emulsion thus obtained was immediately used for 20 minutes using a microfluidizer (M-110Y type).
While controlling the temperature to be 0 ° C., fine emulsification was performed at 10,000 PSI. Next, 300 ml of an aqueous solution in which 59.5 g of glucose and 0.78 g of sodium dihydrogen phosphate (dihydrate) were dissolved in advance was added to the refined emulsion, and the total amount of the solution 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 the two-chamber bag, and the space was replaced with nitrogen gas and then sealed. Next, the upper layer composition shown in Table 1 below was dissolved in distilled water for injection under heating to 250 ml, and the pH was adjusted to 7.0 with 1N aqueous acetic acid solution, and then the total amount was 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, the space was replaced with nitrogen gas, and the container was sealed, and subjected to high-pressure steam sterilization according to a conventional method.

[0024]

[Table 1]

[0025]

[Test Example 1] Using the fat emulsions of Examples and 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 infusion solutions 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 900 ml, and the pH was adjusted to 6.2 with an acetic acid aqueous solution, and then the total amount was changed. What was made 1000 ml was used. 62 ml of each test liquid was prepared by mixing the test liquid with the test liquid after filtering the test liquid with a membrane filter having a pore diameter of 0.22 μm.
And aseptically 200m each of 138ml of test solution.
It was performed by co-injecting into a plastic bag. The storage stability was evaluated by examining the appearance change of the mixed solution stored for 2 days (25 ° C.) after the above mixing operation and examining the ratio of coarse particles in the 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 proportion of coarse particles immediately after the production of each test liquid (after high-pressure emulsification treatment), the average particle diameter of fat particles, and the evaluation results of storage stability. From the test results, it is clear that in both Example 1 and Example 2 in which the preparation temperature of each production process was controlled within the optimum range, coarse particles were not generated immediately after production and there was no problem in storage stability. 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 are not preferable in quality immediately after production, or have storage stability. The evaluation result that there is a problem was obtained. Further, as a result of measuring the free fatty acid immediately after the production of Comparative Example 6 prepared in the same manner as in Example 1 except that the preparation temperature in Example 1 and the emulsifier dispersion step was 100 ° C., the free fatty acid in Example 1 was 0. .31
mEq / l, while Comparative Example 6 has 1.24 mE
It showed a clear high value of q / l and the oil and fat had decomposed. From the above results, it has been clarified that in the production of the fat emulsion, the preparation temperature in the rough emulsification step and the fine emulsification step and the preparation temperature at the time of dispersing the emulsifier have optimum ranges.

[0026]

[Table 2]

[0027]

[Table 3]

[0028]

[Test Example 2] The two-chamber infusion preparation of Example 3 was communicated between the two chambers and observed for change in appearance after storage at 25 ° C. for 2 days. Further, the proportion of coarse particles of 2 μm or more was measured by a centrifugal sedimentation method. No change in appearance was observed, and no formation of coarse particles of 2 μm or more was observed.

[0029]

According to the present invention, when mixed with other nutritional infusions, namely glucose, electrolytes and amino acid infusions,
It is possible to produce a fat emulsion having excellent storage stability that does not cause a change in appearance or coarsening of fat particles.

Claims (3)

[Claims] 1. An emulsifier dispersion containing at least an emulsifier and fats and oils is added with water to roughly emulsify to obtain a coarse emulsified liquid, and the coarse emulsified liquid is further finely emulsified under high pressure to obtain fats and oils of 1 to 30 W.
In the method for producing a fat emulsion for obtaining an oil-in-water type fat emulsion for nutritional supplementation, the fat is characterized in that it is emulsified while controlling the liquid temperature of the emulsified liquid in the above-mentioned emulsification to 5 to 35 ° C. Emulsion manufacturing method. 2. The method for producing a fat emulsion according to claim 1, wherein the coarse emulsion is carried out while controlling the liquid temperature of the coarse emulsion to 5 to 35 ° C. 3. The method for producing a fat emulsion according to claim 2, wherein the emulsifier is dispersed while controlling the liquid temperature of the emulsifier dispersion liquid at 65 to 95 ° C.