JPS6379826A - Fat emulsion for intravenous injection - Google Patents

Abstract

PURPOSE:To obtain the titled emulsion for nutrition supply having extremely low hemolytic action and excellent safety in organism free from side effects, comprising fats and oils and water as main components and containing a polyoxyethylene hardened castor oil with added ethylene oxide in a specific ratio. CONSTITUTION:A fat emulsion comprising fats and oils as main components and containing 0.05-5wt% polyoxyethylene hardened castor oil having 55-200 averaging mols of ethylene oxide addition. A soybean oil, corn oil, olive oil, safflower oil, etc., are used as the fats and oils and the amount of the fats and oils used is preferably about 5-20wt%. The aimed fat emulsion is produced by uniformly blending the fats and oils with water and the emulsifying agent, etc., by a conventional procedure by a homogenizer of pressure spray type or an ultrasonic homogenizer. A sugaralcohol such as glycerin, sorbitol, etc., may be added as an osmotic pressure adjuster.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel fat emulsion for intravenous injection (hereinafter referred to as a fat emulsion).

[Conventional technology]

Fat emulsions are used for parenteral nutrition of patients as a source of calories or essential fatty acids. When administering fats and oils into the body, it is necessary to emulsify the fats and oils with an emulsifier and administer them in the form of fine particles. Conventionally, egg yolk lecithin and soybean lecithin have been used as emulsifiers (Japanese Unexamined Patent Publication No. 1983-1983)
912, Japanese Patent Publication No. 55-12887, Japanese Patent Publication No. 60-30652).

[Problem that the invention seeks to solve]

The fat emulsion is required to have uniform emulsion particles, a particle diameter of 0.3 μm or less so as not to get stuck in capillaries, and good emulsion stability that can withstand long-term storage. When soybean lecithin is used as an emulsifier, it is easily oxidized because it contains a large amount of unsaturated fatty acids, and when administered for a long period of time, side effects such as anemia are exhibited. Therefore, egg yolk lecithin is mainly used, but egg yolk lecithin has a weaker emulsifying power than soybean lecithin, so a large amount of highly purified (approximately 98%) and expensive egg yolk lecithin must be used. For this reason, it has been pointed out that when this lecithin is administered in vivo, the lecithin is deposited in organs as a problem. Furthermore, lecithin has a weak emulsifying power, so in order to obtain emulsified particles of a predetermined size, a high-pressure emulsifying machine is used and the solution is recycled many times.
A homogenization process must be carried out.

It is necessary to consider safety such as interaction with the drug and hemolysis. Therefore, as an emulsifier for fat emulsions,
It must not exhibit hemolytic properties and must have strong emulsifying power. In other words, the present inventors have found an emulsifier that has lower hemolytic properties than high-purity egg yolk lecithin, has strong emulsifying power, can produce fine-particle emulsions, and has good emulsion stability. In order to address the above-mentioned problems, as a result of extensive research to develop a practical and excellent emulsifier, we have discovered an excellent emulsifier that does not have the above-mentioned drawbacks, and based on this knowledge, we have completed the present invention.

Polyoxyethylene hydrogenated castor oil which is 200005
The object of the present invention is to provide a fat emulsion characterized by containing ~5% by weight.

The emulsifier used in the present invention is one in which ethylene oxide is added to a hardened oil obtained by adding hydrogen to castor oil, and the average number of added moles is 55 to 200.

The amount of the emulsifier used is 0.05 to 5% by weight; if the amount of the emulsifier is less than 0.05% by weight, the emulsifying power is insufficient and a good fat emulsion cannot be obtained; Since its function is fully demonstrated, it is not necessary to add a large amount.

The emulsifier used in the present invention has superior emulsifying power compared to conventional emulsifiers that use egg yolk lecithin, etc. When using egg yolk lecithin, it takes eight or more passes in a high-pressure homogenizer to obtain an average particle size of 0.3 μm or less. Although homogenization treatment must be performed several times, when using the emulsifier of the present invention, the target particle size can be achieved with one or two passes. Furthermore, compared to conventional emulsifiers, the target particle size can be achieved with a lower concentration of emulsifier.

In the present invention, polyoxyethylene hydrogenated castor oil having an added mole number of ethylene oxide of 55 to 200 is used. After emulsification, the fat emulsion is filled into a sterilized bottle.
Sterilization is performed at a temperature of 115 to 121°C for 10 to 30 minutes, but if the number of added moles of the emulsifier of the present invention is less than 55, phase separation of the emulsion will occur after sterilization, which is unfavorable in terms of emulsion stability by heat sterilization. . Also, the number of added moles is 20
Those exceeding 0 are difficult to synthesize and difficult to obtain.

It is desirable to use fats and oils that meet pharmaceutical standards as the fats and oils used in the present invention, but normal oils and fats can be used. The amount of the fat or oil used in the present invention is not particularly limited, but is preferably about 5 to 20% by weight.

Moreover, sugar alcohols such as glycerin and nrubitol can be further added to the fat emulsion of the present invention as an osmotic pressure adjusting agent, if necessary.

In the method for producing the fat emulsion of the present invention, fats and oils, water, emulsifiers, etc. may be uniformly mixed by a conventional method, and homogenization can be performed using, for example, a pressure injection type homogenizer or an ultrasonic homogenizer.

〔Effect of the invention〕

The emulsifier used in the fat emulsion of the present invention has a stronger emulsifying power than conventional egg yolk lecithin, so the oil and fat are sufficiently finely divided with a small number of passes using a homogenizer, and exhibits good emulsion stability over time. Furthermore, the fat emulsion of the present invention has significantly less hemolytic action and has excellent in vivo safety. Furthermore, since it is manufactured with a lower concentration of emulsifier than in the past, problems such as emulsifier deposition within organs do not occur. In addition, it is possible to provide nutritional support with fats and oils without side effects such as diarrhea or anemia.
It is a clinically useful fat emulsion.

〔Example〕

Next, the present invention will be explained in detail using Examples and Comparative Examples.

Example 1 Distilled water for injection was added to 400 g of soybean oil, 100 g of glycerin for injection, and 489 polyoxyethylene hydrogenated castor oil (average number of added moles of ethylene oxide 60), and the total amount was 400 g.
It was set as 09. Mix this at 90℃ using an automixer for 1
Coarse emulsification was performed at 120 rpm for 30 minutes, and then this liquid was heated at 500 K using a high-pressure emulsifier (manufactured by Manto/Gorlin).
Under a pressure of f/ad, refined emulsification was performed by changing the number of passes of emulsification treatment from 1 to 16 times, and this was further subjected to high-pressure steam sterilization using an autoclave at 121° C. and 2 atm for 10 minutes. The average particle size of the fat emulsion thus prepared was measured and the results are shown in Table 1.

Comparative Example 1 Purified egg yolk lecithin was subjected to the same emulsification and sterilization treatments as in Example 1, and the average particle diameter of the resulting fat emulsion was measured. The results are shown in Table 1.

From the results in Table 1, it can be seen that when purified egg yolk lecithin was used as an emulsifier, a fat emulsion with an average particle size of 0.3 fim or less was obtained by 8 times of yeast extraction, compared to the polyoxyethylene of Example 1. Nine products using hydrogenated castor oil were obtained with a par number of 11 @, which indicates that the emulsifying power is excellent.

Example 2 The same composition as in Example 1 was used, the number of passes of the high-pressure emulsifier was two, and the emulsifier concentration was 0.6 as shown in Table 2.
The emulsification treatment and sterilization treatment were carried out in the same manner as in Example 1, except that the concentration was changed to 1.6% by weight.

The average particle size of the fat emulsion thus prepared was measured, and the results are shown in Table 21.

Comparative Example 2 Emulsification and sterilization were carried out in the same manner as in Example 2, except that purified egg yolk lecithin was used and the number of passes through the high-pressure emulsifier was changed to 8. The average particle size of the fat emulsion thus prepared was measured, and the results are shown in Table 2.

In comparison, the emulsifier concentration using polyoxyethylene hydrogenated castor oil of Example 2 is required to be 1.2% by weight or more, whereas the emulsifier concentration using polyoxyethylene hydrogenated castor oil of Example 2 can be obtained with an emulsifier concentration of 0.6% by weight. did it.

Examples 3 to 5 The same composition as in Example 1 was used except that the number of moles of ethylene oxide added to polyoxyethylene hydrogenated castor oil was 1,601,100 and 60, and the emulsifier concentration was 0.6% by weight. Increase the number of passes of emulsification processing in the emulsifier to 2
After performing the same treatment as in Example 1 except that the process was repeated 121 times, using an autoclave. High-pressure steam sterilization was performed for 130 minutes. Table 3 shows the emulsified state of this fat emulsion after sterilization.

Comparative Examples 3 to 5 The same treatment as in Example 3 was carried out using an emulsifier having an average number of added moles of ethylene oxide of 50.40 and 10 to polyoxyearth tyrene hydrogenated castor oil. Table 3 shows the emulsified state of this fat emulsion after sterilization.

Table 3 Emulsification state after sterilization From the results in Table 3, it can be seen that the emulsification state of the fat emulsions after heat sterilization in all of the examples was good, while the average number of added moles of ethylene oxide was 10 to 10. It can be seen that in the comparative example using No. 50, the fat emulsion separated after heat sterilization and the emulsification state was poor.

Examples 6-9.

Distilled water for injection was added to the prescribed amounts of lard 20ON, safflower oil 200g, glycerin for injection 1 ooy and polyoxyethylene hydrogenated castor oil (average added moles of ethylene oxide 60) at the concentrations shown in Table 4, and the total amount was mixed. 4000p
And so. This was coarsely emulsified in accordance with Example 1, and then this liquid was finely emulsified using a high-pressure emulsifier (San-Phase Machine ■) under a pressure of 45 ob/d with two passes. Further, this was subjected to high-pressure steam sterilization using an autoclave at 121° C., 2 atm, and 1° for 1 minute. Regarding these fat emulsions,
Measurement of particle size, emulsion stability test, and hemolysis test using human red blood cell suspension solution were performed, and the results were reported in the fourth section.
Shown in the table. The fat emulsions obtained in Example 3 and Example 4 were also tested in the same manner, and the results are shown in Table 4.

Comparative Examples 6-9 Fat emulsions were prepared in the same manner as in Examples 6-9, except that purified egg yolk lecithin with the concentration shown in Table 4 was used as the emulsifier and the number of passes of the high-pressure emulsifier was 8 times. obtained,
A similar test was conducted and the results are shown in Table 4.

Table 4 evening.

A sphere suspension was prepared. Add fat emulsion 1:1 to this.
(volume ratio), cultured in a constant temperature bath at 37°C for 30 minutes, and centrifuged (30oorpm, lo minutes).
Unhemolyzed red blood cells and red blood cell membranes were removed, and the supernatant was collected.

This supernatant was filtered using a 0.1 μm filter to remove emulsion particles, and then the amount of hemoglobin in the filtrate was measured using a spectrophotometer at a wavelength of 545 nm.

Note that the absorbance value of the supernatant obtained when distilled water was added to the red blood cell suspension and treated in the same manner as above was set to 100%.

3) The emulsified state of the fat emulsion was observed after it was stored at room temperature for 3 months.

From the results in Table 2, it is clear that the fat emulsions of the present invention shown in Examples have smaller particle sizes with fewer passes than Comparative Examples, have low hemolysis, and have excellent emulsion stability. be.

When the expected fat emulsion was administered to rats by intravenous injection, no abnormality was observed in any case, and the emulsion was excellent as a fat emulsion.

Claims (1)

[Claims] 1. A fat for intravenous injection, which is mainly composed of fats and oils and water, and contains 0.05 to 5% by weight of polyoxyethylene hydrogenated castor oil having an average added mole number of ethylene oxide of 55 to 200 as an emulsifier. emulsion.