WO1988008694A1

WO1988008694A1 - Packed transfusion

Info

Publication number: WO1988008694A1
Application number: PCT/JP1988/000429
Authority: WO
Inventors: Naoki Hayakawa; Hiroshi Uehara; Kazuko Shibata; Kazuo Okamoto
Original assignee: Terumo Kabushiki Kaisha
Priority date: 1987-05-07
Filing date: 1988-04-28
Publication date: 1988-11-17

Abstract

This invention provides a packed transfusion which comprises a gas-permeable, primary medical vessel and a substantially oxygen-impermeable secondary package vessel containing therein the primary vessel together with a disoxidant, said primary vessel containing a transfusion composed of an aqueous solution containing amino acids, an aqueous solution containing both amino acids and reducing sugar, or an O/W emulsion containing highly unsaturated fatty acids. This package effectively prevents browning of the transfusion during storage.

Description

Specification

Infusion package

〔Technical field〕

The present invention relates to a package for an infusion solution, and more particularly to a package for stably storing an infusion solution containing amino acid, electrolyte, sugar, or fat over time.

(Background technology)

Infusion therapy, also called infusion, is the delivery of a large volume of drug solution into [β [intravenous]. The infusions used in this infusion therapy include a parenteral feeding fluid for parenteral nutrition, electrolyte infusions mainly for treating dehydration and improving body fluids, and maintaining blood pressure during surgery. There is a target plasma volume solution.

Of these, carbohydrate infusions, amino acid infusions, and fat emulsions are widely used as nutrient solutions. All of them are used to improve physical strength before and after surgery in surgery and are particularly effective in cases where enteral food intake is not possible.

For the carbohydrate solution, reducing sugars such as glucose, fructose and maltose, and sugar alcohols such as xylitol are used.

Amino acid infusion is an injection that contains essential, semi-essential, and non-essential amino acids in a formulation that is most accessible to the human body. Several types are used, such as those based on the amino acid composition of milk proteins. In addition, a nutritional wheel solution prepared by mixing a sugar alcohol such as a reducing sugar such as glucose with an amino acid infusion solution, and a nutritional solution infusion solution provided with a digester are also used. The fat emulsion is an OZW type emulsion mainly using a suitable emulsifier which can physiologically accept a natural oil such as soybean oil. Therefore, its nutritional components are saturated fatty acids of palmitic acid and stearic acid and unsaturated fatty acids of oleic acid, linoleic acid and linolenic acid. Also, fat emulsions in which nutrientally important unsaturated fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, which are not contained in vegetable oils, are added and added are known.

Conventionally, the above-mentioned infusion agent is distributed and used in the form of a package filled in an appropriate medical container such as a vial bottle, a synthetic resin bottle, or a synthetic resin film bag. Each of these packaging forms has advantages and disadvantages, however, in terms of low packaging cost and less damage during distribution, plastic bottles or plastic film bags It is considered that the amount used will increase in the future.

The following properties are required of the synthetic resin used for the above-mentioned infusion container due to the specificity of its use.

① Do not transmit moisture.

② Be able to completely prevent the invasion of bacteria

③ Sufficient mechanical strength as a container for infusions.

有する It must have heat resistance to withstand heating during sterilization.

こと No problems caused by dissolution.

As a synthetic resin material satisfying these conditions, polyvinyl chloride resin or cross-linked ethylene-vinyl acetate copolymer resin

(Cross-linked EVA resin) is conventionally used. However, the above-mentioned infusions and fat emulsions containing amino acids, electrolytes, sugar alcohols, etc., have a problem in that the contents are colored brown during storage and lose commercial value (hereinafter, browning phenomenon). There is). The reason is that the components in the infusion are affected by dissolved oxygen and react during storage. In particular, in transfusions containing amino acids and reducing sugars, these components cause a Maillard reaction, and browning is remarkable.

The above-mentioned browning phenomenon is not merely a matter of appearance, but also results in a decrease in the content of nutrients such as sugar, amino acid or fat, and a reaction product which is not preferable to the human body. . In addition, in the case of fat emulsions, unsaturated fatty acids are decomposed into aldehydes, ketones or carboxylic acids via peroxides, which leads to a decrease in ρΠ value and a characteristic rancidity.

Such a browning phenomenon is relatively remarkable when a bottle or bag made of synthetic resin is used as a container. The reason is that vinyl chloride resin, cross-linked EVA resin, and the like, which are conventionally used as synthetic resin bottle or bag materials, have air permeability. In other words, the molecular oxygen is dissolved in the infusion solution through the container, so that the dissolved oxygen concentration becomes higher than in the vial.

[Disclosure of the Invention]

An object of the present invention is to provide a package of an infusion solution that can prevent browning and proper use of peroxide even when the infusion solution filled in a breathable container is stored for a long period of time. That is what you do. In the present invention, the degradation phenomenon of the wheel fluid and the generation of peroxide are reduced. We paid attention to the above-mentioned causes. Then, the infusion agent filled in the gas-permeable container was subjected to secondary packaging to prevent β-ingress of oxygen from outside the container, thereby preventing the browning phenomenon and the generation of peroxide.

That is, in the package of the infusion solution according to the present invention, the infusion solution composed of an aqueous solution containing amino acid or the like or the infusion solution composed of 0 ZW type emulsion containing polyunsaturated fatty acid has gas permeability. It is characterized in that an infusion agent filled in a medical primary container and filled in the medical primary container is stored in a gas-impermeable secondary packaging container together with an oxygen scavenger.

[Brief description of drawings]

FIG. 1 is a front view showing a package of an amino acid infusion solution according to one embodiment of the present invention, and FIG. 2 is a result of a comparative test for examining the storage stability in another embodiment of the present invention. This is a line 粜 indicating 粜.

[Best mode for carrying out the invention]

One of the infusions to which the present invention is applied is an amino acid infusion. The amino acid components include L-isoleucine, L-mouth lysine, L-lysine, L-methionine, L-phenylalanine, L-threonine, L-pa, lin, L -H-Shin Shin, L-tryptophan, L-arginine, L-histidine, L-alanine, L-asnoII. Laginic acid, L-aminoacetic acid, L-proline, L-serine, and the like. These amino acids may be blended and used in an appropriate formulation, or a specific amino acid may be used alone. In addition, glucose, fructoses, maltose, etc., reducing sugars, xylitol, sorbitol, etc., sugar alcohols, electrolytes, etc. are appropriately distributed as required. You may.

Another subject of the invention is fat emulsions. Examples of the fat component include vegetable oils such as soybean and safflower oil, unsaturated fatty acids such as linoleic acid, linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, and triglycerides or triglycerides of these unsaturated fatty acids. Esters such as alkyl esters, purified fish oils such as sardine oil and cod oil, and other lipids suitable for intravenous administration. As an emulsifier for stably dispersing these fat components in water, purified egg yolk lecithin or purified soybean lecithin can be used. '

As a gas-permeable primary container for directly filling and storing an infusion solution, a conventionally used polyvinyl chloride resin or a cross-linked ethylene-vinyl acetate copolymer resin ( A bottle or bag made of cross-linked EVA) can be used.

The gas-impermeable, secondary packaging volume S that stores the ring fluid 剂 filled in the primary container together with an oxygen scavenger has a temperature 2 (TC, oxygen permeability at 60% RH). Q cc / m-no 24ΠΪ [¾] The following is desirable: For example, a three-layer laminated film with a double-stretched vinylon film as an intermediate layer can be used.

As the oxygen absorber, any substance having an oxygen absorbing ability can be used, including those already marketed as oxygen absorbers. The following are examples.

(1) At least one of iron carbide, iron carbonyl, ferrous oxide, iron hydroxide, and iron oxide is covered with gold halide. ② A mixture of nitrite and one of the following. That is, the mixture is a hydroxide or carbonate of an alkaline earth metal, a compound having activated carbon and water, water of crystallization, an alkaline substance or an alcohol compound.

③ Al power A mixture of alkaline earth metal sulfite and any of the following. That is, the compound to be mixed is an iron compound containing a ferrous compound, a transition metal salt, a lithium salt, an alkali metal or an alkaline earth metal. Compound or ammonium salt.

混合 Mixture _c of one of F e, Z n and Na ₂ S 0 ₄ · H ₂ 0

⑤ F e, one Z n. _{One, N a 2 S 0 4 ·} H 2 0 and halogen of a mixture of metal. ;-

混合 One of F e, Cu, Sn, Zn, and Ni, a mixture of Na ₂ S 0 ₄ ♦ 7 H ₂₀ and a metal halide. .

混 One of F e, Cu, Sn, Zn, Ni, Na ₂ S 0 ₄ * 10 H ₂ 0 and a mixed metal halide. .

遷移 Transition gold of the 4th period of the Periodic Table ^, 3 11 or 5 1 — mixed with water.

遷移 A mixture of one of the transition metals of the fourth period of the periodic table, Sn and Sb, water and a metal halide.

A mixture of water, one of alkali metal or ammonium sulfite, hydrogen sulfite, pyrosulfite, a transition gold salt or an aluminum salt, and water.

As for these oxygen absorbers, it is desirable to use them in a suitable air-permeable pouch if they are powder. In addition, it is tableted If used, it may be used as is without packaging.

Next, the function and effect obtained by the present invention will be described in detail.

In the present invention, the infusion agent filled in the synthetic resin bottle or bag (primary container) is stored in a gas-impermeable secondary packaging container together with the oxygen scavenger, and the secondary packaging The interior of the container is kept hypoxic. For this reason, even if the primary container containing the infusion agent contained therein is permeable to gas, the amount of acid scouring into the container is extremely small, and the concentration of molecular oxygen in the infusion solution is high. Never. Therefore, even when the amino acid infusion or the fat emulsion is stored for a long time, the browning phenomenon and the generation of peroxide can be effectively prevented. .

When a gas-impermeable resin is used as the material of the synthetic resin bottle or bag, the same operation and effect as the present invention can be achieved. Since the material of the bottle bag needs to satisfy the various conditions described above, it is not possible to select a new material only by the gas-impermeable condition. In other words, the present invention is evaluated as being able to use a conventionally used resin material for a bottle or bag as it is, and to be able to prevent browning and peroxide formation by an oxidation reaction. .

According to the present invention, the browning phenomenon due to the Maillard reaction can also be effectively prevented. The following is a more detailed explanation of this point.

The phenomenon of degradation of the wheel solution due to the Maillard reaction is as follows: If a bottle or bag made of synthetic resin is placed in the container, It is more remarkable than in the case of using a vial. The inventor conducted various studies with an emphasis on this fact: (1), and for the first time confirmed that the Maillard reaction was accelerated by the influence of molecular oxygen. This indicates that molecular oxygen is dissolved in the infusion solution through the above gas-permeable container, and that the dissolved oxygen promotes the Maillard reaction. Since the Maillard reaction involves a complicated chain, it is not yet clear at which stage molecular oxygen is involved. However, it is thought to be not a reaction at the initial stage but a reaction at a relatively later stage leading to browning.

As described above, in the present invention, the infusion solution filled in the primary container is stored in the secondary packaging container maintained in a low oxygen state, so that even if the primary container has air permeability, When the molecular oxygen concentration in the infusion becomes high (even if the infusion solution containing amino acid and reducing sugar is stored for a long period of time), In addition, it is known that the Maillard reaction is more likely to occur in the coexistence of degrading.

The application of the present invention is particularly effective for an infusion solution containing an electrolyte in addition to the S element.

Hereinafter, the present invention will be described in more detail based on ft examples and test results.

Example 1

First, each component blended in the following formulation was dissolved in distilled water for injection, and adjusted to pH 6.2 by adding sodium hydroxide 0.90.

Prescription> L-Iso σ-Isin 5.97 g

L-leucine 11.88 g

ぃ barin 6.90 g

L-methionine 4.33 g

9.74 g of L-phenylalanine

L-Tyrosin 0.57 g

L-Sleonine 5.04 g

L-alanine 8.21 g

L-proline 10.63 g

4.67 g L-cell

Glycine 15.68 g

L-aspartic acid 2.02 g

L-glutamic acid 1.02 g

L-arginine hydrochloride 14.88 g

L-histidine hydrochloride 7.OB g

Gin hydrochloride 9.80 g

L-triple fan 1.87 g

L-cystine 0.23 g

Sodium bisulfite 0.50 g

Xylitol 50.00 g

Then, distilled water was added to adjust the total S to 1, and the mixture was filtered through Millipore Filtration. This was dispensed into a 500-ring fluid ffl bag made of crosslinked VA, sealed, and then extinguished with a low pressure steam. After cooling, the sample was taken out of the autoclave, the water droplets on the surface of the container were wiped off, and the container was subjected to secondary packaging as follows. As the packaging material, a 15-m-thick nylon film, a 15-thick biaxially-stretched vinylon film, and a 60-thick polyethylene film are laminated in this order. One film (made by Nichika Co., Ltd.) was used. As shown in FIG. 1, this laminating film is used as a bag 1 shown in FIG. 1 and in which the above-mentioned infusion solution 2 and oxygen absorber 3 (“Ageless FX-200 J Mitsubishi Gas Chemical Co., Ltd. The bag 1 is formed by laminating a film so that its polyethylene film is exposed to the inside and fusing the peripheral portion with a heat seal 4. Next, the opening of the bag 1 was also sealed with the heat seal 4 to produce the package of the infusion solution shown in FIG.

The use of a laminate film as a material for the secondary packaging not only facilitates the desired gas impermeability, but also includes a synthetic resin film having heat fusibility as shown in the above ri. This has the advantage that heat seal processing becomes a mouthpiece.

¾Example 2

A package of an amino acid infusion solution was produced in the same manner as in Example 1 except that the secondary packaging was vacuum packaging.

Comparative example 1

A package of an amino acid infusion solution was produced in the same manner as in Example 1 except that an oxygen scavenger was not used in the secondary packaging.

Comparative Example 2

A three-package of an amino acid infusion was produced in the same manner as in Example 2 except that deoxygenation was not used in the secondary packaging using the empty packaging. Comparison test of change over time 1

The infusion preparations obtained in Examples 1 and 2 and Comparative Examples 1 and 2 in §d above were examined for storage stability and compared. The storage conditions were 40 ° C in air. The evaluation was made by observing the appearance with the naked eye. The results are shown in Table 1 below. In each case, the number of samples is 5.

1 ¾

¾Example 3

First, the components formulated according to the following formula were dissolved in distilled water for injection, and 10% sodium hydroxide was added to adjust to ρΠ6.2.

75 g glucose

L-Iso C7 2.40 g

L-n incin 3.66 g

L-ballin 2.56 g

L-methionine 1.20 g

2.15 g

L-H mouth Cin 0.14 g

L-threonine i .35 g

L-alanine 2.40 g L-pulp ring 1, .94 ε

L-Serine 1.12 g

Glycine 1.51 g

0.14 g of L-aspartic acid

2.90 g L-arginine

L-histidine 1.30 g

2.91 g L-lysine hydrochloride

0.44 g L-tributane

1.30 g of sodium chloride

1.40 g of potassium chloride

0.30 g of monohydrogen phosphate

Magnesium chloride hexahydrate 0.25 g

Sodium bisulfite 0.40 δ

Lactic acid 1.25 g

Thereafter, the same procedure as in Example 1 was carried out to produce a package of the ring fluid shown in FIG.

Example 4

A package of an amino acid infusion solution was produced in the same manner as in Example 3, except that the secondary packaging was vacuum packaging.

Comparative Example 3

A package of an amino acid infusion solution was manufactured in the same manner as in Example 3 except that no oxygen scavenger was used in the secondary packaging.

Comparative Example 4

Except that the deoxidizing agent was not used for the secondary packaging by vacuum packaging, the packaging of the amino acid solution was performed in the same manner as in Example 4 of 'Λ'. Manufactured.

Aging test 2

The packaging stability of the infusion solutions obtained in Examples 3 and 4 and Comparative Examples 3 and 4 was examined for storage stability and compared. The storage conditions were 40 ° C in air. The evaluation was made by observing the appearance with the naked eye. The results are shown in Table 2 below. In each case, the number of samples is 5.

Perfect fuck

Example 5

5,8,11.14.17- Eicosapentaenoic acid ethyl ester 20 g, refined soybean oil 380 g, refined egg yolk lecithin 48 g, concentrated glycerin 100 g, IN-soluble soda 40 After dispersion with a homomixer, distilled water for injection was added to make the total solution S to 4. This was emulsified with a high-pressure homogenizer to prepare a fat emulsion solution. The obtained emulsion solution was dispensed into a cross-linked EVA 200 infusion bag, sealed, and then subjected to autoclaving using an autocrepe. After cooling, the sample was taken out of the auto creep, the water droplets on the surface were wiped off, and the secondary packaging was performed in the same manner as in Example 1 to produce a fat milk refill. . However, as an oxygen scavenger, “Ageless 50” (Mitsubishi (Manufactured by Gas Chemical Company).

Example 6

A fat emulsion package was manufactured in the same manner as in Example 5, except that “Ageless 100” (manufactured by Mitsubishi Gas Chemical Company) was used as the oxygen scavenger. ·

Example 7

A fat emulsion package was produced in the same manner as in Example 5, except that “Ageless 200” (manufactured by Mitsubishi Gas Chemical Company) was used as the oxygen scavenger.

Example 8

The total fatty acid block contains 1,690 5,8,11,14,17-eicosanoic acid and has a lipid content of 120 highly refined sardine fish oil and 280 refined soybean oil as shown in Table 3. 'g Purified egg yolk lecithin (48 g), concentrated glycerin (100 g), and IN-soda are added. Disperse the mixture in a homomixer, and add distilled water for injection to make a total volume of 4. Thereafter, in the same manner as in Example 5, a package of the fat emulsion was produced.

Table 3

Lipid composition in refined sardine oil.

Fat content (%)

Hydroxy oxyphosphate 3.61 Sterol resin sesoleol 6.84 Triglyceride 36.5 U

M Fatty acids 46.5.2 s-o-no. Five

Example

A package of a fat emulsion was produced in the same manner as in Example 8, except that “Ageless 100” (manufactured by Mitsubishi Chemical Corporation) was used as the oxygen scavenger.

Example 10

A fat emulsion package was manufactured in the same manner as in Example 8, except that “AGELES 200” (manufactured by Mitsubishi Gas Chemical Company) was used as the oxygen scavenger.

Comparative Example 5

A package of fat emulsion was produced in the same manner as in Example 5, except that a deoxidizing agent was not used.

Comparative Example 6

Except that no oxygen scavenger was used and vacuum packaging was carried out, a package of a fat infusion solution was manufactured in a lonely manner 5 and lu'j-like manner.

Time-dependent change test 3

The packaging solutions of the ring fluids obtained in the above Examples 5 to 10 and Comparative Examples 5 and 6 were examined for storage stability and compared. The storage conditions were air temperature of 40% and relative humidity of 75%.

The evaluation was performed by observing the appearance with the naked eye and measuring the change in the pH value of the infusion solution. As described above, in fatty milk preparations, peroxides of unsaturated fatty acids are converted to aldehydes or carboxylic acids, so that the PH value of the infusion is lowered. In each case, the number of samples is 5.

As a result of the above test, in the infusions of Comparative Examples 5 and 6, Although slightly colored by eyes, the infusion of Examples 5-1 did not change its appearance throughout the test period [¾]. Also, the results of the ρ 測定 value measurement are as shown in Fig. 2. In the figure, Ε ₃ to Ε ₅ show the test results for the infusions of Examples 5 to 7, respectively, and C ₃ and C ₄ show the test results for the infusions of Comparative Examples 5 and 6, respectively. ing. From the results shown in FIG. 2, it can be seen that the examples are much more excellent in storage stability. Similar results were obtained with the infusion solutions of Examples 8 to 10.

Claims

The scope of the claims

1. An infusion solution composed of an aqueous solution containing amino acid is filled in a gas-permeable primary medical container, and the infusion solution filled in the medical primary container substantially removes oxygen together with an oxygen scavenger. A package of an infusion solution characterized by being housed in a secondary packaging container that is impermeable.

2. An infusion solution comprising an aqueous solution containing an amino acid and a reducing sugar is filled in a gas-permeable primary medical container, and the ring fluid filled in the medical primary container is substantially deoxidized together with oxygen. A package of an infusion agent characterized by being housed in a secondary packaging container that is impermeable to oxygen.

3. The package of a ring solution according to claim 1 or 2, wherein the infusion solution contains an electrolyte.

4. The package of an infusion according to any one of the first to third aspects of the inquiry, wherein the infusion agent contains a sugar alcohol.

5. An infusion solution composed of an oil-in-water (0 / W) emulsion containing a polyunsaturated fatty acid was filled into a gas-permeable primary medical container and filled into the primary medical container. A package of a wheel solution, characterized in that the infusion solution is housed together with the oxygen scavenger in a secondary packaging container substantially impermeable to oxygen.

6. The package for an infusion solution according to any one of claims 1 to 5, wherein the medical primary container is a bottle or bag made of synthetic resin.

7. Acidic acid at a temperature of 20 ° C and a humidity of 6% in the secondary packaging container Permeability, 1.0 ccZm ² 24 hours package of infusion剂according to any one of claims paragraph 1 - paragraph 6 range shall be the Toku徵to that it is less.

8, wherein the secondary packaging container is a bag made of a laminated film of a synthetic resin film, and a heat-fusible synthetic resin film is exposed on an inner surface thereof. [8] A package of the infusion solution according to any one of [1] to [7].