JP3109161B2 - Infusion preparation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an infusion preparation, and more particularly to an infusion preparation containing a reducing emulsion in a fat emulsion and having improved stability.

[0002]

2. Description of the Related Art Conventionally, in the maintenance of a patient's life, oral nutrition and tube feeding have been impossible or inadequate, or even if they are possible, the digestive and absorptive function of the patient is reduced. In cases where the condition is extremely poor or the passage of food through the digestive tract leads to an exacerbation of the underlying disease, an infusion is administered intravenously for nutritional supplementation. Examples of such infusion preparations include sugar infusions containing reducing sugars, etc., amino acid infusions containing essential amino acids, etc., electrolyte infusions containing minerals, fat emulsions containing vegetable oil emulsions, etc., and mixed vitamin preparations. These infusion preparations are appropriately mixed at the time of use according to the symptoms of the patient and the like. However, mixing during use of the infusion preparation is a complicated operation for the worker, and there is a problem of bacterial contamination during mixing. From such a problem, an infusion preparation in which two or three of the above infusions are mixed in advance has been proposed.

[0003]

However, when a preparation prepared by mixing a reducing emulsion with a fat emulsion is prepared, there is a disadvantage that the reducing sugar is decomposed with time during heat sterilization and storage, and the infusion preparation is colored. . In general, infusion preparations containing reducing sugar, a sulfite-based coloring inhibitor such as sodium bisulfite and sodium pyrosulfite is blended in order to prevent discoloration of the preparation due to decomposition of reducing sugar during heat sterilization and storage. ing. Such a sulfite-based coloring inhibitor,
When added to an infusion formulation containing a reducing emulsion in a fat emulsion,
Aggregation of the emulsion by sulfite occurs, and aggregates precipitate. This tendency is particularly noticeable after heat sterilization, and it is difficult to use as an infusion. Due to such a problem, a sulfite-based coloring inhibitor cannot be used in an infusion preparation prepared by mixing a reducing sugar with a fat emulsion. As described above, in an infusion preparation in which a reducing emulsion is blended with a fat emulsion, an effective means for preventing coloring due to decomposition of the reducing sugar is not known, so that an operation of mixing the fat emulsion and the sugar infusion at the time of use is required. There is a long-awaited need for a stable one-pack formulation without coloring. The present invention has been made to solve the above-mentioned problems of the prior art, and the present invention relates to an infusion formulation containing a reducing emulsion in a fat emulsion, which is less colored during sterilization and storage. The purpose is to provide.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have intensively studied the prevention of coloration of an infusion preparation containing a reducing emulsion in a fat emulsion, and found that thioglycerol and / or The inventors have found that the incorporation of dithiothreitol can suppress the coloring of the infusion solution during sterilization and storage without causing aggregation of the emulsion, thereby completing the present invention. That is, the infusion preparation of the present invention is an infusion preparation in which a reducing emulsion is blended with a fat emulsion, and one or two selected from thioglycerol and dithiothreitol are blended as a coloring inhibitor.

[0005] In the present invention having the above structure, as the fat emulsion, various fat emulsions used for infusion can be used. For example, fats and oils are emulsified with an emulsifier so that the average particle diameter of fat particles is 1 μm or less. Oil-in-water type fat emulsion emulsified to preferably 0.5 μm or less, more preferably 0.3 μm or less. More specifically, a fat emulsion is prepared by adding a fat and an emulsifier to water and then stirring to prepare a coarse emulsion, and then emulsifying the coarse emulsion by a conventional method such as a high-pressure emulsification method. Can be. When the above emulsification is performed by a high-pressure emulsification method, for example, using an emulsifier such as a Menton-Gaulin homogenizer, the coarse emulsion is 20 to 700 kg / g.
It is carried out by passing about 5 to 50 times under the condition of about cm ² .

In the emulsification, in order to obtain a stable and finely divided emulsion, it is preferable to carry out the emulsification in the presence of glucose and / or glycerin. According to this method, an emulsion having an average particle diameter of 0.17 μm or less can be easily prepared. Can be prepared.
More specifically, the method can be carried out by adding fats and oils and an emulsifier to water and adding one or two kinds selected from glucose and / or glycerin, and then preparing a fat emulsion according to the above method. In this preparation method, fats and oils,
As the amount of emulsifier and glucose and / or glycerin used, the resulting fat emulsion is 0.1 to 30 W / V% of fats and oils (hereinafter, referred to as
Unless otherwise specified,% indicates W / V%), preferably about 2 to 10%, about 0.01 to 10% of an emulsifier, preferably 0.05
About 5%, glucose and / or glycerin about 30 to 70%,
Preferably, it is used so as to be composed of about 40 to 60%, and water necessary to make the total amount 100. In addition,
In this preparation method, glucose and / or glycerin may be present at the time of emulsification. For example, glucose and / or glycerin may be added to a crude emulsion prepared from fats and oils and an emulsifier to perform emulsification. The average particle size of the obtained emulsion can be measured by using a conventional measuring method such as a light scattering method.

As the above fats and oils, any fats and oils can be used as long as they are edible oils, for example, vegetable oils (for example, soybean oil,
Cottonseed oil, safflower oil, corn oil, coconut oil, perilla oil, sesame oil, etc.), fish oil (eg, cod liver oil, etc.), medium chain fatty acid triglycerides [eg, Panassate (trade name),
ODO (trade name) etc. and chemically synthesized triglycerides [eg, chemically defined such as 2-linoleoyl-1,3-dioctanoylglycerol (8L8), 2-linoleoyl-1,3-didecanoyylglycerol (10L10) and the like] triglyceride
s] is preferably used. Further, as the emulsifier, any emulsifier can be used as long as it is an emulsifier used in pharmaceutical preparations, for example, egg yolk phospholipid, hydrogenated egg yolk phospholipid, soybean phospholipid, hydrogenated soybean phospholipid and nonionic interface Activator [eg, Pluronic F68, HCO-60 (both trade names)
Etc.] are preferably used. Particularly preferably, soybean oil is used as the oil and fat, and egg yolk phospholipid is used as the emulsifier, and the average particle diameter of the fat particles is set to 0.1.
Fat emulsions adjusted to 3 μm or less, more preferably 0.17 μm or less, may be mentioned.

[0008] Examples of the reducing sugar as another component of the infusion preparation of the present invention include glucose, fructose, maltose and the like. These reducing sugars may be used as a mixture of two or more kinds. Further, a mixture of these reducing sugars and sorbitol, xylitol and / or glycerin may be used. The addition of these reducing sugars may be performed after preparing the fat emulsion or may be performed when preparing the fat emulsion.

In the present invention, one or two selected from thioglycerol and dithiothreitol are used as a coloring inhibitor for an infusion preparation. As described above, when sulfite is used as the coloring inhibitor, the emulsion aggregates to form aggregates, but thioglycerol and dithiothreitol do not cause aggregation of the emulsion, and the coloring due to the decomposition of reducing sugars. Has the effect of effectively suppressing.

The infusion preparation of the present invention is mainly composed of the above-mentioned components. The composition of the infusion is about 0.1 to 30 W / V%, preferably about 1 to 20%, more preferably about 2 to 10%, About 10%, preferably about 0.05 to 5%,
More preferably about 0.1 to 1.0%, about 1 to 60% of reducing sugar, preferably about 5 to 40%, more preferably about 10 to 30%, about 0.001 to 1.5% of a coloring inhibitor, preferably about 0.01 to 1.0% , More preferably about 0.1 to 0.3%, and water necessary to make the total amount 100. The infusion preparation of the present invention may contain a pH buffer (for example, an organic base such as L-histidine and arginine) in order to prevent a decrease in the pH of the infusion during sterilization and storage. The amount of the pH buffer added is usually about 1% or less. Further, an emulsifier, vitamins (for example, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K, etc.) may be added to the infusion preparation of the present invention.

The infusion preparation of the present invention can be prepared by various methods. For example, a predetermined amount of a reducing sugar and a coloring inhibitor and, if necessary, a pH buffer are added to the above-mentioned fat emulsion. Mixing method: In preparing a fat emulsion, a predetermined amount of a coloring inhibitor is added to a roughly emulsified liquid and emulsified to obtain a fat emulsion. Then, a predetermined amount of reducing sugar and, if necessary, a pH buffering agent and the like are added. A method of adding and mixing; preparing a predetermined amount of fat and oil and a reducing sugar into an emulsion using an emulsifier, and then adding a predetermined amount of a coloring inhibitor and, if necessary, a pH buffering agent, and the like, and mixing. be able to. As the liquid property, the pH is usually about 5.0 to 8.0, preferably 5.5 to 8.0.
Adjusted to about 7.0.

The thus obtained infusion solution of the present invention can be heat-sterilized. In the heat sterilization, for example, the infusion solution is prepared by converting the infusion solution into a glass container or a plastic (for example, polypropylene,
Polyethylene, ethylene-vinyl acetate copolymer, polyvinyl chloride, etc.) Fill a container (eg, bag, bottle, etc.), then replace with an inert gas (eg, nitrogen gas, helium gas, etc.), and seal. This is done by subjecting it to a sterilization process. The sterilization step can be performed according to a conventional method, for example, by a method such as high-pressure steam sterilization, hot water immersion sterilization, or hot water shower sterilization. When a plastic container is used, sterilization is preferably performed in an atmosphere substantially free of oxygen.

The infusion preparation of the present invention is intravenously administered to a patient as it is or diluted with water, or alone or, if necessary, mixed with another amino acid infusion, electrolyte infusion or the like. Furthermore, it can be used for administration in oral or enteral administration forms.

[0014]

EXAMPLES 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 An appropriate amount of water was added to 60 g of soybean oil and 7.2 g of egg yolk phospholipid, and the mixture was stirred with a homomixer.
A coarse emulsion was obtained. The coarse emulsion was emulsified with a Manton-Gaulin homogenizer (manufactured by Gorin, Model 15M-8TA) to obtain an emulsion. 250 g of glucose and 500 g of L are added to 500 ml of the obtained emulsion.
-0.2 g of histidine was added, various coloring inhibitors shown in Table 1 were further added, water was added to make the total volume 1000 ml, and the pH was adjusted to 6 to prepare an infusion preparation. 50 ml of these preparations
Was dispensed into a glass container, replaced with nitrogen gas, plugged, and then subjected to high-pressure steam sterilization at 115 ° C. for 30 minutes. The thus-sterilized infusion preparation was subjected to an accelerated storage test at 80 ° C. for 48 hours, and the properties of the infusion, the average particle size of the emulsion, and the degree of coloring were measured over time. Table 1 shows the results. In addition,
The degree of coloration was determined by ultrafiltration of the preparation at a predetermined time, and measuring the absorbance at 450 nm (cell length: 1 cm) of the obtained filtrate to obtain the degree of coloration.

[0015]

[Table 1]

As is clear from Table 1, in the system (control) to which no coloring inhibitor was added, the coloring degree was increased after 48 hours.
Increased to 0.112. Further, in Comparative Examples to which a sulfite-based coloring inhibitor was added, although coloring was significantly suppressed,
The emulsion was aggregated and could not be used as an infusion. On the other hand, the preparation of the present invention to which thioglycerol or dithiothreitol was added suppressed coloration and maintained a homogeneous emulsion form without any adverse effects. Therefore, it was found that the preparation of the present invention has extremely excellent stability.

Example 2 An appropriate amount of water was added to 60 g of soybean oil and 7.2 g of egg yolk phospholipid, and the mixture was stirred using a homomixer.
A coarse emulsion was obtained. The coarse emulsion was emulsified with a Manton-Gaulin homogenizer (manufactured by Gorin, Model 15M-8TA) to obtain an emulsion. 250 g of glucose and 500 g of L-
Histidine (0.2 g) and thioglycerol (1 g) were added, water was added to make the total volume 1000 ml, and the pH was adjusted to 6 to prepare an infusion preparation. Table 2 shows the composition of the obtained infusion preparation. This formulation was dispensed into a 50 ml glass container, replaced with nitrogen gas, stoppered, and then subjected to high-pressure steam sterilization at 115 ° C. for 30 minutes. The properties before and after sterilization, the pH, the average particle size of the emulsion, and the degree of coloring were compared. Table 3 shows the results.

[0018]

As shown in Table 3, although the pH was slightly lowered by sterilization, the preparation was stable and the coloring was suppressed.

Example 3 An appropriate amount of water was added to 60 g of soybean oil, 7.2 g of egg yolk phospholipid and 500 g of glucose, and the mixture was stirred with a homomixer. The crude emulsion,
Menton Gorin homogenizer (manufactured by Gorin, 15M-
(8TA type) to obtain an emulsion. 500 ml of the obtained emulsion
0.2 g of L-histidine and 1 g of thioglycerol were added to
After adding water to 1000 ml, the pH was adjusted to 6 to prepare an infusion preparation. Dispense this formulation into a 50 ml glass container,
After purging with nitrogen gas, the container was capped and then subjected to high-pressure steam sterilization at 115 ° C. for 30 minutes. The properties before and after sterilization, the pH, the average particle size of the emulsion, and the degree of coloring were compared. Table 4 shows the results.

[0021]

As shown in Table 4, the pH was slightly lowered by sterilization, but the preparation was stable.

[0023]

As described above, in the present invention, thioglycerol and / or dithiothreitol are used as a coloring inhibitor in an infusion preparation containing a reducing emulsion in a fat emulsion, and the infusion preparation is sterilized. In addition, thioglycerol and dithiothreitol do not adversely affect the emulsion and do not form aggregates. Thus, according to the present invention,
As it can provide an infusion preparation with excellent stability and safety, and does not require an operation of blending a reducing emulsion with a fat emulsion,
This has the effect of simplifying the operation and preventing bacterial contamination during mixing.

──────────────────────────────────────────────────続 き Continuing on the front page (72) Ryoichiro Murashima, Inventor 2- 25-1, Otani, Hirakata-shi Inside the Central Research Laboratory of Midori Cross Corporation (72) Inventor, Shunichi Abe 2- 25-1, Invitation Otani, Hirakata-shi (72) Inventor Kazumasa Yokoyama 2-5-1, Otani Otani, Hirakata City Midori Cross, Central Research Institute (56) References JP-A-3-161430 (JP, A) 58-79528 (JP, A) JP-A 62-29511 (JP, A) JP-A 49-1224057 (JP, A) Edited by Mitsuo Namiki, Ryo Nakamura, Shunro Kawagishi, and Kenji Watanabe, “Modern Food Chemistry” The first edition, 4th print, 10. October. 1988 (10.10.88) Sankyo Edition, p. 98 (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/107 A61K 31/70 A61K 47/20 A61P 3/00

Claims (5)

(57) [Claims] 1. An infusion preparation comprising a fat emulsion and a reducing sugar, wherein one or two selected from thioglycerol and dithiothreitol are added as a coloring inhibitor. 2. The fat emulsion comprises one or more fats and oils selected from vegetable oil, fish oil, medium-chain fatty acid triglyceride and chemically synthesized triglyceride, as yolk phospholipid, hydrogenated egg yolk phospholipid, soybean phospholipid, hydrogen The infusion preparation according to claim 1, which is an oil-in-water fat emulsion emulsified using one or more emulsifiers selected from added soybean phospholipids and nonionic surfactants. 3. The reducing sugar is one or more kinds of reducing sugars selected from glucose, fructose and maltose, or one or more kinds of reducing sugars selected from sorbitol, xylitol and glycerin. Claim 1 which is a mixture.
Or the infusion preparation according to 2. 4. Fat and oil 0.1-30 W / V%, emulsifier 0.01-10 W / V
The infusion preparation according to any one of claims 1 to 3, comprising 1% to 60W / V% of reducing sugar, 0.001 to 1.5W / V% of a coloring inhibitor, and water necessary to make the total amount 100. 5. The fat emulsion according to claim 1, wherein the average particle diameter of the fat particles is 0.5.
The infusion preparation according to any one of claims 1 to 4, which has a particle size of 17 µm or less.