JPH08127529A - Stabilization of fat emulsion - Google Patents

Abstract

PURPOSE: To stabilize a fat emulsion without developing its appearance change and fat particle growth, by mixing an oil-in-water type fat emulsion with another injection agent such as glucose or electrolyte in the presence of a nonionic surfactant. CONSTITUTION: The stability of a fat emulsion is markedly improved by mixing an oil-in-water type fat emulsion with an injection agent in the presence of a nonionic surfactant. The injection is e.g. glucose, an electrolyte, a nutrient replenisher such as an amino acid, microelement(s), vitamine(s), antibiotic or carcinostatic. The fat emulsion can be prepared, for example, by emulsifying a kind of oil-and-fat selected from vegetable oils such as soybean oil, coconut oil, sesame oil and perilla oil, animal oils such as whale oil and fish oil, and medium chain fatty acid triglycerides with at least one kind of emulsifier selected from purified soybean phospholipids and hydrogenated soybean phospholipids, etc. The nonionic surfactant is pref. polyoxyethylene hardened castor oil-50, polyoxyethylene hardened castor oil-60, or polysorbate-80.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for stabilizing an oil-in-water fat emulsion (hereinafter simply referred to as a fat emulsion), and more specifically, a fat emulsion and other injections such as glucose, electrolytes, amino acids and other nutrients. Infusions, trace elements, vitamins,
The present invention relates to a method for stabilizing a fat emulsion, which does not cause a change in appearance or coarsening of fat particles even when mixed with an injection such as an antibiotic or an anti-cancer agent.

[0002]

2. Description of the Related Art Conventionally, intravenous, oral or enteral nutritional methods have been widely used for nutritional support during various diseases or before and after surgery. At this time, if the intake calorie is insufficient, it is known that the amino acid is used as calorie even if the amino acid composition is administered, and a sufficient wound healing effect cannot be obtained. Therefore, in intravenous, oral or enteral nutrition, it is important to supplement calories with glucose and fat. Among them, fat has twice the amount of heat per unit and is the largest calorie source stored in the living body. Has excellent advantages. In addition, the administration of fat is extremely important nutritionally because it supplements essential fatty acids such as linoleic acid, linolenic acid, and arachidonic acid, which greatly contribute to the composition of tissue fat and the execution of its normal function. However, it is said that it is necessary to avoid using the fat emulsion emulsified so that fat can be intravenously administered, if it is mixed with other drugs, for example, a commercially available amino acid infusion solution, because it will be oily. (Shunichi Noro et al., Pharmacy,
42, p. 17-, 1982). From such a background, there is a problem that the fat emulsion must be administered separately without mixing with other nutritional infusions or injections, or after mixing immediately before use. Therefore, as a method for mixing and storing the fat emulsion and another injection, for example, a stabilizing method in which citric acid is added at the time of mixing with a solution containing a divalent metal ion (Japanese Patent Laid-Open No. 5-32541) Is disclosed. However, while citric acid has a strong chelating power for divalent metal ions, it does not show a marked effect when mixed with other injections, such as amino acid infusion solutions.

[0003]

Accordingly, the present invention provides a fat emulsion and other injections such as glucose, electrolytes, nutrient infusions such as amino acids, trace elements, vitamins, antibiotics,
An object of the present invention is to provide a method for stabilizing a fat emulsion, which does not cause a change in appearance or coarsening of fat particles even when mixed with an injection such as an anticancer drug.

[0004]

[Means for Solving the Problems] The inventors of the present invention have made various studies to solve the above-mentioned problems. As a result, when a fat emulsion and other injections are mixed in the presence of a nonionic surfactant, It was found that the stability of the emulsion was remarkably improved, and the present invention could be completed.

That is, the present invention relates to a method for stabilizing a fat emulsion, which comprises mixing the fat emulsion with another injection in the presence of a nonionic surfactant, preferably a nonionic surfactant. As the activator, one or a mixture of two or more selected from polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 is used.

The present invention has the above-mentioned constitution, and the nonionic surfactant (additive) may be present when the fat emulsion is mixed with another injection. The formulation amount of the additive is appropriately adjusted according to the type and concentration of the injection, the particle system of the fat emulsion, and after mixing, it is 1 to 1200 mg / L, preferably 10 to
It should be about 120 mg / L.

The pH for intravenous injection after mixing the fat emulsion stabilized by the present invention is not particularly limited, but it is preferably adjusted to be 5.0 to 7.5 from the viewpoint of safety to the living body. At this time, a commonly used pH adjusting agent may be used and adjusted according to a known method.

Examples of the injection used in the present invention include nutritional infusions such as glucose, electrolytes and amino acids. As the electrolyte, any of those conventionally used is possible, for example, sodium chloride, sodium hydrogen carbonate, sodium carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium acetate, sodium lactate, sodium chloride, Examples thereof include potassium chloride, potassium iodide, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium lactate, potassium acetate, calcium lactate, calcium glycerophosphate, calcium gluconate and the like. As the amino acids, not only free amino acids but also sodium salts, acetate salts, and hydrochloride salts may be used, and some of the amino acids may be peptides.

Further, other injections other than the above include
Examples include trace elements such as zinc, iron, copper, iodine and manganese, and injections such as vitamins, antibiotics and anticancer agents.

The fat emulsion in the present invention is, for example, vegetable oil such as soybean oil, coconut oil, sesame oil, perilla oil, linseed oil, cottonseed oil and safflower oil, animal oil such as whale oil and fish oil, and chemically synthesized triglyceride such as medium chain fatty acid triglyceride. One or more kinds of fats and oils selected from the following are used with one or more kinds of emulsifiers selected from purified soybean phospholipids, hydrogenated soybean phospholipids, purified egg yolk phospholipids and hydrogenated egg yolk phospholipids. An oil-in-water type emulsion can be used.

The stabilization method of the present invention can be carried out in various modes, but the additives may be present when the fat emulsion and other injections are mixed. That is, it may be added to the fat emulsion in advance, may be added at the time of mixing, or may be added to another injection.

In the present invention, the fat emulsion can be filled in a glass vial, a plastic bag made of polypropylene, polyethylene, or ethylene vinyl acetate polymer, etc., and after the space is replaced with nitrogen gas, it can be sterilized by a conventional method. And glucose into the first chamber of the two-chamber bag, amino acid and electrolyte in the remaining second chamber, after sterilization and cooling,
It may be mixed with another infusion agent by communicating between the two chambers 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 strictly separated chambers. Can be used. The fat emulsion thus obtained can be used in a patient intravenously or in a dosage form such as oral or enteral administration.

[0013]

EXAMPLES Next, the present invention will be described in more detail with reference to Examples, Reference Examples and Test Examples, but the present invention is not limited to these.

Example 1 300 g of purified soybean oil, 75 g of glycerin and 36 g of hydrogenated soybean phospholipid were heated on an oil bath and stirred with a Polytron homogenizer. After cooling the solution, an appropriate amount of distilled water was added and coarse emulsification was performed with a Polytron homogenizer. The liquid after rough emulsification was subjected to high-pressure emulsification using a Manton-Gaulin homogenizer.
The pH of the obtained emulsion is adjusted with an aqueous sodium hydrogen carbonate solution.
The mixture was adjusted to 6.0, and the total volume was adjusted to 3000 ml with distilled water, filtered through a membrane filter, filled in a 100 ml glass vial, replaced with nitrogen gas, and sealed tightly. Further, high pressure steam sterilization was performed according to a conventional method to produce a fat emulsion. The sugar, electrolyte and amino acid having the composition shown in Table 1 and polyoxyethylene hydrogenated castor oil 50 were dissolved in distilled water for injection to 900 ml, and the pH was adjusted to 6.0 with an acetic acid aqueous solution, and then the total amount was 1000 ml. And This solution
An additive-containing liquid was obtained by filtration with a membrane filter having a pore size of 0.22 μm. 62 ml of the fat emulsion and 138 ml of the additive-containing solution were aseptically mixed and poured into a 200 ml plastic bag.

[0015]

[Table 1]

[Examples 2 to 3] Preparation was carried out in the same manner as in Example 1 except that polyoxyethylene hydrogenated castor oil 60 and polysorbate 80 were used in place of polyoxyethylene hydrogenated castor oil 50.

Examples 4 to 12 Polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 6
0, the amount of polysorbate 80 added was reduced to 1/8 and p
It was prepared in the same manner as in Example 1 except that H was adjusted to 5.5, 6.5 and 7.5.

Reference Examples 1 to 15 Preparations were made in the same manner as in Example 1 except that the additives shown in Table 3 were added.

Example 13 31.0 g of purified soybean oil and 3.72 g of purified egg yolk phospholipid were stirred with a Polytron homogenizer. 31m of 50% glucose solution in this solution
1 was added and coarse emulsification was performed with a Polytron homogenizer.
Then, high pressure emulsification was performed using a microfluidizer. 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 obtained emulsion, and the total amount was adjusted to 700 ml with distilled water. This solution was filtered with a membrane filter and filled in the first chamber of a two-chamber bag, and the space was replaced with nitrogen gas and sealed. Next, the second chamber composition shown in Table 2 below was dissolved in distilled water by heating to 250 ml, and the pH was adjusted to 7.0 with 1N aqueous acetic acid solution.
ml. This solution was filtered with a membrane filter and filled in the second chamber of the two-chamber bag, and the space was replaced with nitrogen gas and sealed. This was subjected to high pressure steam sterilization according to a conventional method.

[0020]

[Table 2]

[Test Example 1] Examples 1 to 12, Control Example 1,
The storage stability of the fat emulsions of Reference Examples 1 to 15 is the appearance change of the mixed solution after storage for 2 days (25 ° C.), the average particle size of fat particles and the ratio of coarse particles of 2 μm or more, using the mixed preparation as a sample. Was measured. The results are shown in Tables 3 and 4.

[0022]

[Table 3]

[0023]

[Table 4]

From the above results, using the stabilizing method of the present invention, the appearance and the fat particle size did not change even after storage at 25 ° C. for 2 days, and formation of coarse particles of 2 μm or more was not observed. Therefore, it was revealed that the stabilization method of the present invention has extremely high stability.

[Test Example 2] The two chambers of the two-chamber infusion preparation of Example 13 were communicated with each other, and the appearance change after storage for 2 days at 25 ° C. was observed. Furthermore, the average particle size of fat particles and 2 μm or more were observed. The proportion of coarse particles was measured. As a result, appearance, change in average particle size of fat particles and formation of coarse particles of 2 μm or more were not observed at all.

[0026]

As is clear from the above results, according to the present invention, the fat emulsion and other injections such as glucose,
When mixed with electrolytes, nutrient transfusions such as amino acids, trace elements, vitamins, antibiotics, injections such as anti-cancer agents, the presence of a nonionic surfactant causes a change in appearance and coarsening of fat particles. It was possible to provide a highly stable fat emulsion that does not undergo oxidization.

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Claims (2)

[Claims] 1. A method for stabilizing a fat emulsion, which comprises mixing the fat emulsion with an injection in the presence of a nonionic surfactant. 2. The fat according to claim 1, wherein the nonionic surfactant comprises one or a mixture of two or more selected from polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60 and polysorbate 80. Emulsion stabilization method.