JPH0761925A - Amino acid infusion formulation - Google Patents

Abstract

(57) [Summary] [Constitution] The present invention fills an amino acid infusion solution containing no sulfite or bisulfite stabilizer and containing at least one selected from salts such as cysteine and cystine and derivatives thereof. There is provided an amino acid transfusion preparation characterized in that the above plastic container is enclosed in a gas barrier packaging material together with a hydrogen sulfide adsorbent and a deoxidizer. [Effects] The amino acid infusion preparation of the present invention has no risk of side effects such as bronchospasm and anaphylactic shock, and also excellently prevents generation of hydrogen sulfide during heat sterilization or storage and is free from the disadvantages such as coloring and off-flavor.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an amino acid infusion preparation, more specifically, at least one selected from cysteine, cysteine hydrochloride, cystine, cystine hydrochloride and derivatives thereof without addition of a sulfite or bisulfite stabilizer. The present invention relates to an amino acid transfusion preparation in which a plastic container is filled with an amino acid transfusion containing seeds.

[0002]

2. Description of the Related Art Conventionally, amino acid infusions used by intravenous administration and the like contain various essential amino acids and non-essential amino acids, and it is impossible to orally take a nutritional source. It is applied to patients who have difficulty. Such amino acid infusion solution is usually blended with sulfur-containing amino acids such as cysteine and cystine as its constituents. According to the blending, they are thermally decomposed in the heat sterilization step during the production of the amino acid infusion solution. Hydrogen sulfide is generated, which causes an offensive odor. The generation of the offensive odor is often recognized not only in the above manufacturing process but also during storage of the infusion product, which is a serious problem. In the case of high calorie infusion, generally, trace element preparations are further added to the amino acid infusion as described above, but in this case, the generated hydrogen sulfide reacts with zinc, iron, copper, manganese, etc. to color the sulfide. The disadvantage of producing a precipitate is also recognized.

Therefore, conventionally, in the preparation of amino acid preparations containing sulfur-containing amino acids such as cysteine and cystine, sulfites or bisulfites have been added as stabilizers into the preparations to produce the above-mentioned sulfurization. Means to prevent the generation of hydrogen have generally been adopted. The above-mentioned sulfites and the like are those which have been recognized as additive substances in foods, drinking water, pharmaceuticals and the like as antioxidant substances.

However, in recent years, side effects such as bronchospasm and anaphylactic shock due to sulfite and bisulfite in the amino acid infusion are reported in some highly sensitive patients such as asthma patients and atopic non-asthma patients. In the present situation, there is a call for avoiding the use of stabilizers which may cause such side effects.

Furthermore, amino acid infusions are often administered as a mixed injection with a vitamin preparation, and even in this case, it is known that if sulfite ions coexist in the infusion, thiamine in the vitamin preparation is decomposed, There is a disadvantage in that a vitamin preparation containing such thiamine cannot be co-injected.

As described above, in the field of amino acid preparations containing sulfur-containing amino acids, the development of a new technique, which can be replaced with the use of sulfite and bisulfite as stabilizers, should be called hydrogen sulfide generation preventive measure. There is an urgent need, but the means to be fully satisfied are not yet developed.

Particularly recently, a method has been proposed in which a container filled with an infusion solution is enclosed in an exterior airtight container together with a deoxidizer (see Japanese Patent Laid-Open No. 4-210629), but this is for the purpose of deoxidation. It may only be possible to remove hydrogen sulfide to some extent as a by-product, and it is not possible to achieve a sufficient effect of removing hydrogen sulfide, and it takes a considerably long time to remove hydrogen sulfide, which is not practical. It was

Therefore, an object of the present invention is to provide a new means capable of exhibiting a sufficient hydrogen sulfide removing effect that meets the above-mentioned demands of the art.

[0009]

Means for Solving the Problems As a result of intensive studies conducted by the present inventors on the above-mentioned object, the combination of a hydrogen sulfide adsorbent and an oxygen scavenger meets the above object, unlike the above-mentioned proposed technology. It was found that the effect of the above can be achieved, and the present invention has been completed here.

That is, the present invention is a plastic filled with an amino acid infusion solution containing no sulphite or bisulfite stabilizer and containing at least one salt selected from cysteine, cystine, and other derivatives and derivatives. An amino acid infusion preparation characterized by enclosing a container together with a hydrogen sulfide adsorbent and a deoxidizer in a gas barrier packaging material, in particular, the hydrogen sulfide adsorbent selectively adsorbs hydrogen sulfide, and oxygen is substantially The present invention relates to the above-mentioned amino acid infusion preparation that does not adsorb, and the above-mentioned amino acid infusion preparation that is an organic deoxidant that selectively absorbs oxygen and does not substantially adsorb hydrogen sulfide.

Since the amino acid preparation of the present invention contains no stabilizer such as sulfite or bisulfite, there is a complete risk of side effects such as bronchospasm and anaphylactic shock due to the addition of these stabilizers. Not to mention that it has been avoided, it has a feature that hydrogen sulfide can be splendidly prevented during heat sterilization and during storage, even though no stabilizer is added. Moreover, the amino acid preparation of the present invention,
When this is mixed with a vitamin preparation or a trace element preparation and used in combination, no adverse effects such as the decomposition of vitamin, coloring, precipitation, and generation of off-flavor, which are observed in the conventional infusion preparations of this kind, are observed.

The amino acid preparation of the present invention will be described in detail below. It is selected from cysteine, cysteine hydrochloride, cystine, cystine hydrochloride, and derivatives thereof without addition of a sulfite or bisulfite stabilizer. Its greatest feature is that a plastic container filled with at least one amino acid infusion solution, a hydrogen sulfide adsorbent, and an oxygen absorber are enclosed in a gas barrier packaging material.

The hydrogen sulfide adsorbent that can be used here is preferably selected from those that selectively adsorb hydrogen sulfide and do not substantially adsorb oxygen. Specific examples thereof include crystalline hydrated aluminosilicates of alkali metal or alkaline earth metal such as zeolite, silica alumina gel, silica alumina gel and aluminum hydroxide, a mixture of metal oxide, and the like. .
The above-mentioned zeolite is generally a porous material having a large number of fine pores of 3 to 10 angstrom in the inside thereof,
It has a molecular sieving function and is particularly suitable as a selective adsorbent for hydrogen sulfide. In addition, it has a very large specific surface area, for example, about 1000 m ² /
Some of them have a specific surface area of g and are suitable for the present invention because of their extremely high adsorption performance. Further, zeolite has a characteristic that it adsorbs a large amount of hydrogen sulfide even at a low partial pressure as compared with other adsorbents and absorbents, and its adsorption performance does not deteriorate even at a high temperature, and in this respect also suitable for the present invention. is there.
Examples of the zeolite suitable for the present invention include natural zeolite and synthetic zeolite having a pore size of 3 to 10 angstroms, more preferably 4 to 10 angstroms. The metal ion of the metal oxide which is its constituent is usually a metal having a valence of 1 to 3, and examples of the monovalent metal include sodium, potassium and lithium.
The divalent metal includes, for example, magnesium, calcium, zinc, iron, nickel, cobalt and the like, and the trivalent metal includes, for example, iron and a rare earth element, and in the present invention, they are composed of these single or composite materials. Zeolites can be used. Further, the above metal ions can be replaced by the above-mentioned other respective metals or silver, copper and other heavy metals by ion exchange, and zeolite substituted with such metal ions is also advantageously used in the present invention.

The fact that the above-mentioned zeolite does not substantially adsorb oxygen is due to the fact that, for example, the production of oxygen-enriched air by using the PSA method (pressure oscillation adsorption method) using zeolite as a nitrogen adsorbent or the use of air as a raw material. It is clear from the fact that the production of pure oxygen is carried out.

The use form of the hydrogen sulfide adsorbent used in the present invention is not particularly limited, and in the case of a fine particle form such as a powder product, it is advantageous to put a required amount in a breathable pouch. A molded product such as a spherical product or a columnar product can be used by putting it in a pouch as described above, or can be used as it is.

The oxygen scavenger used in the present invention together with the above-mentioned hydrogen sulfide adsorbent is an organic type, and is preferably selected from those which selectively adsorb oxygen and do not substantially adsorb hydrogen sulfide. Examples thereof include ascorbic acid and its salts, phenols, polyhydric phenols such as catechol, polyhydric alcohols such as glycerin, ethylene glycol and propylene glycol, sugar alcohols such as xylitol, sorbitol and mannitol, and oleic acid. And the like, such as unsaturated fatty acids. These may be used alone or as a mixture, and may be used as a commercial product containing them as the main component. Typical examples of the above-mentioned commercial products include "Tamotsu" (manufactured by Oji Kako Co., Ltd.) and a freshness-retaining agent C.
(Manufactured by Toppan Printing Co., Ltd.) can be exemplified.

The hydrogen sulfide adsorbent and the oxygen scavenger in the amino acid preparation of the present invention may be enclosed in the gas barrier packaging material separately, or both may be mixed in one pouch. You may put it together.

The amino acid infusion solution used in the present invention is usually an amino acid infusion solution containing no sulfite or bisulfite stabilizer and containing at least one selected from salts such as cysteine, cystine, and others and derivatives thereof. Any of various publicly known ones may be used. Examples of the salts and derivatives of cysteine and cystine include cysteine hydrochloride, cystine hydrochloride and N-acetylcysteine, S-
Examples thereof include acetyl substitution products such as acetylcysteine. Of course, the above amino acid infusion solution is
It may contain various essential and non-essential amino acids suitable for amino acid infusion, and may further contain saccharides, electrolytes, vitamins, fats, trace elements and the like at the same time as in the case of ordinary infusions of this kind. Further, an inorganic acid, an inorganic base, an organic acid, a salt thereof or the like for pH adjustment may be further added and blended.

The plastic container filled with the amino acid infusion may be made of various materials that have been generally used in the past. Specific examples thereof include polyethylene and the like.
Examples thereof include polyolefins such as polypropylene and copolymers such as polyvinyl chloride, ethylene vinyl acetate copolymer, polyester, and various polymers such as nylon.
The above-mentioned container does not have to be composed of a single layer of the same polymer, but may have a composite multi-layer structure of two or more kinds of polymers which are the same or different, and the shape, size, etc. of the container are the usual amino acid preparations. It is arbitrary as long as it can accommodate the above, and it is particularly preferable that it has a bag shape or a bottle shape. The gas permeability of the polymer constituting the container is determined by the strength of the bond between the used polymer chains, the gap between the polymer chains, the degree of crystallinity, etc., and is not particularly limited, but generally the above polymer is used. Has hydrogen sulfide permeability.

In the present invention, examples of the gas barrier packaging material for enclosing a plastic container filled with the hydrogen sulfide adsorbent, the oxygen scavenger and the amino acid infusion solution include, for example, ethylene / vinyl alcohol copolymer resin, vinylidene chloride resin, and poly (vinylidene chloride) resin. A multilayer film containing at least one gas barrier material such as acrylonitrile, polyvinyl alcohol, nylon resin and polyester, a silica vapor deposition film, an aluminum vapor deposition film, and a polymer film obtained by combining these are preferably used. In particular, the oxygen permeability is about 10 ml / m ² · day or less, more preferably about 1 ml / m 2.
A film having a barrier property of ² · day or less is suitable. The plastic container filled with the hydrogen sulfide adsorbent, the oxygen scavenger, and the amino acid infusion can be enclosed by this packaging material according to a conventional method, but it is more preferable to perform the nitrogen gas displacement packaging for the space portion.

Thus, the amino acid preparation of the present invention can be obtained. This product completely avoids the risk of side effects such as bronchospasm and anaphylactic shock due to the addition of stabilizers such as sulfites and bisulfites, and excellently prevents the generation of hydrogen sulfide during heat sterilization and storage. It is possible, and there is no disadvantage such as coloring and generation of offensive odor.

[0022]

EXAMPLES Examples will be given below to explain the present invention in more detail.

[0023]

Example 1 An amino acid raw material having the following composition was dissolved while cooling in distilled water for injection that had been degassed at 80 ° C., and pH was adjusted with glacial acetic acid.
After adjusting to 7.0, the total volume of 10 liters was filtered through a 0.2 μm membrane filter, and 200 ml thereof was filled and sealed in a polypropylene bag (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) under a nitrogen atmosphere. did.

<Amino acid composition (g per 10 liters of formulation)> L-leucine 140 g L-isoleucine 80 g L-valine 80 g L-lysine acetate 148 g L-threonine 57 g L-tryptophan 20 g L-methionine 39 g L-phenylalanine 70 g L -Cysteine 10 g L-tyrosine 5 g L-arginine 105 g L-histidine 50 g L-alanine 80 g L-proline 50 g L-serine 30 g aminoacetic acid 59 g L-aspartic acid 10 g L-glutamic acid 10 g Heat-sterilized with a hot water shower sterilizer Synthetic zeolite as a hydrogen sulfide adsorbent (trade name "Zeorum A-4, manufactured by Tosoh Corporation, pore size = 4 angstroms")
Consists of vinylidene chloride-stretched nylon / biaxially-stretched polyvinyl alcohol / linear low-density polyethylene together with 2 g in a breathable small bag and "Tamotsu D500" (manufactured by Oji Kako) as an oxygen absorber. The amino acid transfusion preparation of the present invention was prepared by enclosing it in a gas barrier film (manufactured by MOA Packaging Co., Ltd.) and vaccuum nitrogen gas substitution packaging.

The amino acid infusion preparation of the present invention obtained above was allowed to stand at room temperature for 7 days, and the oxygen partial pressure (%) in the packaging material was measured immediately after adjustment, after 1 day, and after 7 days. The measurement was performed using a type oxygen meter (manufactured by Toray Engineering Co., Ltd.), and the outer bag was opened and the presence or absence of a strange odor during the opening was judged according to the following criteria.

++ ... Strong hydrogen sulfide odor + ... Slight hydrogen sulfide odor -... No odor The obtained results are shown in Table 1.

[0027]

Examples 2 to 4 and Comparative Examples 1 and 2 In Example 1, instead of synthetic zeolite A-4 as a hydrogen sulfide adsorbent, synthetic zeolite (trade name: Zeolum A-3, A-
5 and F-9, both manufactured by Tosoh Corporation, were used to prepare the amino acid infusion preparation of the present invention in the same manner.

For comparison, an amino acid infusion preparation containing only a deoxidizer was prepared without using the synthetic zeolite as the hydrogen sulfide adsorbent (Comparative Example 1).

Further, a comparative amino acid infusion preparation prepared only by double packaging with a gas barrier film was prepared without using a hydrogen sulfide adsorbent or an oxygen absorber (Comparative Example 2).

Example 1 for each amino acid infusion preparation
In the same manner as above, the presence or absence of occurrence of such offensive odor and the oxygen partial pressure in the packaging material were measured.

The results obtained are shown in Table 1 below.

[0032]

[Table 1]

As is clear from Table 1 above, in all the amino acid infusion preparations of the present invention, a strong hydrogen sulfide odor was observed immediately after the preparation, but it disappeared almost completely after 7 days. On the other hand, in the samples prepared in Comparative Example 1 and Comparative Example 2, the same hydrogen sulfide odor as immediately after the adjustment remained even after 7 days, and it was found that no hydrogen sulfide adsorption was observed.

[0034]

Example 5 An amino acid raw material having the following composition was dissolved with cooling in degassed distilled water for injection at 80 ° C., the pH was adjusted to 6.0 with sodium hydroxide, and the total amount was adjusted to 10 liters. , 0.2 μm membrane filter, and 200 ml thereof was filled and sealed in a polypropylene bag (Otsuka Pharmaceutical Factory Co., Ltd.) under a nitrogen atmosphere.

<Amino acid composition (g per 10-liter formulation)> L-threonine 45 g L-serine 50 g L-proline 80 g L-cysteine hydrochloride 4 g aminoacetic acid 90 g L-alanine 75 g L-valine 84 g L-methionine 10 g L -Isoleucine 90g L-Leucine 110g L-Phenylalanine 10g L-Tryptophan 7g Lysine Hydrochloride 76g L-Histidine Hydrochloride 32g Arginine Hydrochloride 73g The above bag sterilized by heat with a hot water shower sterilizer was used as a synthetic zeolite (product). 2g of the name "Zeorum A-4, manufactured by Tosoh Corporation" in a small bag with good air permeability and "freshness-keeping agent C500" as an oxygen scavenger
Together with (Toppan Printing Co., Ltd.), it is enclosed in a gas barrier film (made by MPackaging Co., Ltd.) composed of vinylidene chloride coated stretched nylon / biaxially stretched polyvinyl alcohol / linear low-density polyethylene, and vacuum nitrogen gas replacement After packaging, the amino acid infusion preparation of the present invention was prepared.

The presence / absence of offensive odor and the oxygen partial pressure in the packaging material were measured in the same manner as in Example 1. As a result, the offensive odor immediately after adjustment was +, and after 1 day and 7 days both were −. Oxygen partial pressure is 0.3% immediately after adjustment, 0% and 7 days after adjustment.
It was 0% after the day.

[0037]

Example 6 In the same manner as in Example 1, a polyethylene bag (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) was used in place of the polypropylene bag (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.) as the amino acid infusion container. The amino acid infusion preparation of the present invention was prepared.

The presence or absence of an offensive odor of this product and the measurement of the oxygen partial pressure in the packaging material were carried out in the same manner as in Example 1. As a result, the offensive odor immediately after the adjustment was ++, but after 7 days it became a negative odor. Disappeared. The oxygen partial pressure was 0.3% immediately after the adjustment, but was 0% after 1 day and 0% after 7 days.

[0039]

[Example 7] The same as in Example 1 except that silica-alumina gel (trade name SECARD OW, manufactured by Shinagawa White Brick Co., Ltd.) was used as the hydrogen sulfide adsorbent instead of the synthetic zeolite A-4 as the hydrogen sulfide adsorbent. Then, the amino acid infusion preparation of the present invention was prepared.

The presence or absence of an offensive odor of this product and the measurement of the oxygen partial pressure in the packaging material were carried out in the same manner as in Example 1. As a result, the offensive odor immediately after the adjustment was ++, but after 7 days it became a negative odor. Disappeared. The oxygen partial pressure was 0.2% immediately after the adjustment, but was 0% after 1 day and 0% after 7 days.

[0041]

[Example 8] In Example 1, instead of a vinylidene chloride-coated stretched nylon / biaxially-stretched polyvinyl alcohol / linear low-density polyethylene gas barrier film (manufactured by MM Packaging Co.), a vinylidene chloride coat was used. The amino acid transfusion preparation of the present invention was prepared in the same manner using a gas barrier film (manufactured by Fujimori Industry Co., Ltd.) composed of biaxially oriented polypropylene / ethylene / vinyl alcohol copolymer / linear low-density polyethylene.

The presence or absence of an offensive odor and the oxygen partial pressure in the packaging material of this product were measured in the same manner as in Example 1. As a result, the offensive odor immediately after the adjustment was ++, but after 7 days it became a negative odor. Disappeared. The oxygen partial pressure was 0.3% immediately after the adjustment, but was 0% after 1 day and 0% after 7 days.

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[Procedure amendment]

[Submission date] March 7, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Correction content]

[Claims]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0010

[Correction method] Change

[Correction content]

[0010] The present invention is sulphite or bisulphite stabilizer additive-free in and cysteine, cystine, this such salts and this like plastic even without least selected from derivatives filling the amino acid infusion fluid containing one kind of An amino acid infusion preparation characterized by enclosing a container together with a hydrogen sulfide adsorbent and a deoxidizer in a gas barrier packaging material, in particular, the hydrogen sulfide adsorbent selectively adsorbs hydrogen sulfide, and oxygen is substantially The present invention relates to the above-mentioned amino acid infusion preparation that does not adsorb, and the above-mentioned amino acid infusion preparation that is an organic deoxidant that selectively absorbs oxygen and does not substantially adsorb hydrogen sulfide.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0012

[Correction method] Change

[Correction content]

The amino acid preparation of the present invention will be described in detail below. It is selected from cysteine, cysteine hydrochloride, cystine, cystine hydrochloride, and derivatives thereof without addition of a sulfite or bisulfite stabilizer. Its greatest feature is that a plastic container filled with an amino acid infusion solution containing at least one kind , a hydrogen sulfide adsorbent, and an oxygen scavenger are enclosed in a gas barrier packaging material.

Claims (3)

[Claims] 1. A plastic container filled with an amino acid infusion solution containing no sulphite or bisulfite stabilizer and containing at least one selected from salts such as cysteine, cystine, and other derivatives, and derivatives thereof. An amino acid infusion preparation characterized by being enclosed in a gas barrier packaging material together with a hydrogen sulfide adsorbent and an oxygen scavenger. 2. The amino acid infusion preparation according to claim 1, wherein the hydrogen sulfide adsorbent selectively adsorbs hydrogen sulfide and does not substantially adsorb oxygen. 3. The amino acid infusion preparation according to claim 1, wherein the oxygen scavenger is organic and selectively absorbs oxygen and does not substantially adsorb hydrogen sulfide.