JPH04210629A - Sulfite ion-free double-pack type amino acid infusion pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To obtain the title pharmaceutical preparation causing no generation of offensive odor due to hydrogen sulfide, thus applicable to even patients of hypersensitive constitution by packing a hydrogen sulfide-permeable container with an amino acid infusion containing cysteine and/or cystine, etc. followed by encapsulating said container, together with a deoxident, in an airtight vessel. CONSTITUTION:(A) A container consisting of a polymer film with a hydrogen sulfide permeability of 50-1000ml(STP)/cm<2>.h at 20 deg.C and 65% R.H. is packed with (B) an amino acid infusion free from any sulfite or bisulfite having been used conventionally as a stabilizer, containing at least one substance selected from cysteine, cystine and derivatives therefrom. Thence, the resultant container is encapsulated, together with an deoxident, in an airtight vessel consisting of a polymeric film with an oxygen permeability of 5 or less (pref. 1 or less) ml(STP)/cm<2>.h at 20 deg.C and 60% R.H.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to a sulfite ion-free double-packed amino acid infusion preparation containing cysteine, cystine, or a derivative thereof.

(Prior Art) Amino acid infusions administered to patients who are unable or difficult to take nutritional sources orally contain various amino acids in order to exert nutritional effects. In particular, infusions administered to newborns and premature infants often contain cysteine and cystine, which are essential for these people. During heat sterilization and storage, a strange odor mainly composed of hydrogen sulfide is generated, so sulfites and bisulfites such as sodium sulfite and sodium bisulfite have traditionally been added to infusions as stabilizers. Ta.

However, when infusions containing sulfites or bisulfites are administered to hypersensitive or atopic patients, the sulfite ions present in the infusions can cause allergic reactions (e.g., hives, itching, wheezing, anaphylaxis
[Federal Register]
50 (22) 47558-47563, Pharmaceutical Journal (1986, 3,) Tani (3) 158-159)
, the presence of sulfite ions is never desirable.

On the other hand, as a package for amino acid infusion, one is known in which the amino acid infusion is filled in a plastic bag and the bag is sealed together with an oxygen absorber in an airtight bag (Japanese Patent Application Laid-Open No.
No. 3-275346), but this package is intended to prevent Amino M infusion from changing or producing peroxides, and does not use sulfites or bisulfites, and does not produce off-odor. It is not intended to prevent occurrence.

(Problems to be Solved by the Invention) The present invention aims to provide an amino acid infusion containing cysteine, cystine, or a derivative thereof, which does not generate an unpleasant odor and does not use a stabilizer that may cause side effects as described above. That is.

(Means for Solving the Problems) As a result of various studies, the present inventors filled a hydrogen sulfide permeable container with an infusion containing cysteine, cystine, or a derivative thereof, and further deoxidized the container. When sealed in an airtight container with the drug, the hydrogen sulfide generated by heat sterilization disappears in a short period of time, and a stable infusion without any strange odor can be provided without adding sulfites or bisulfites to the infusion. They discovered this and completed the present invention.

That is, in the present invention, a sulfite ion-free amino acid IJtI solution containing at least one selected from cysteine, cystine, and derivatives thereof is filled in a hydrogen sulfide permeable container, and the infusion solution filling container is provided with an oxygen absorber together with an oxygen scavenger. This is a sulfite ion-free, double-packaged amino acid infusion preparation that is sealed in an airtight container.

The infusion solution applied to the present invention contains cysteine, cystine, or derivatives thereof (e.g., N-acetylcysteine, S
-acetylcysteine, etc.) and does not contain sulfite ions, but may contain various essential and non-essential amino acids in addition to these amino acids. Examples of such amino acids include L-isoleucine, L-leucine, L-'J';, L-methionine, L-phenylalanine, L-threonine, L-tryptophan, L-valine, and L-serine. , L-tyrosine, L-arginine, L-histidine, L-alanine, L-aspartic acid, L-glutamic acid, aminoacetic acid, L-proline, and the like. These amino acids may be in free form or in the form of alkali metal salts such as potassium salts and sodium salts, alkaline earth metal salts such as magnesium salts and calcium salts, mineral acid salts such as sulfates and hydrochlorides, It may be an organic acid salt such as acetate or malate, and may also be a salt of an acidic amino acid and a basic amino acid.
Moreover, these amino acids may be acylated derivatives such as N-acetyltryptophan and N-acetyllysine.

Furthermore, sugar components, electrolytes, various vitamins, fats, etc. may be mixed simultaneously in this infusion.

The sugar component is not particularly limited as long as it is metabolized and utilized as a calorie source in the living body, and examples include reducing sugars such as glucose, fructose, and maltose, and sugar alcohols such as xylitol, sorbitol, and glycerol. can be used.

Electrolytes include sodium, potassium, magnesium, calcium, chlor, phosphorus, etc. Sources of sodium include sodium hydroxide, sodium chloride, sodium salts of organic acids, sodium salts of amino acids, etc. Sources of potassium include hydrochloric acid, sodium chloride, potassium chloride, amino acid hydrochloride, etc. Sources of potassium include potassium hydroxide, potassium chloride,
Sources of magnesium include magnesium chloride, magnesium sulfate, magnesium salts of organic acids, magnesium salts of amino acids, etc. Sources of calcium include calcium chloride and calcium. gluconate etc., phosphorus,
As sources of sodium and potassium, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, etc. can be used.

Furthermore, organic acids such as lactic acid and acetic acid or salts thereof may be added to this infusion.

In addition, the liquid properties of the infusion solution applied to the present invention are p) (4,0
~7.0, and for this purpose mineral acids such as hydrochloric acid or the above-mentioned organic acids can be used.

The hydrogen sulfide permeable container filled with the above-mentioned infusion solution has a hydrogen sulfide permeability of 20°C, 165% R1■, and 5
0 to 1000 IIdl(STP)/cm"·h can be suitably used. As the polymer film constituting the container, for example,
Consisting of polyethylene, polypropylene, polyvinyl chloride, polyvinyl acetate, polyolefin, vinyl polymers such as polystyrene, copolymers of vinyl monomers such as vinyl acetate, vinyl alcohol, vinyl acetoacecoole, and ethylene, polycarbonate, polyester, nylon, etc. Examples include single-layer or composite films, and among these, films made of polyethylene and polypropylene copolymers, polyethylene, polypropylene, polyvinyl chloride, crosslinked ethylene vinyl acetate copolymers, etc. can be preferably used.

The shape of the hydrogen sulfide permeable container is not particularly limited, but the shape of a bag or bottle is usually preferred.

Examples of oxygen scavengers include: ■ iron carbide, iron carbonyl compound, iron oxide, iron powder, iron hydroxide, or silicon iron coated with a metal halide; ■ alkaline earth metal hydroxide or alkaline earth metal carbonate. metals, activated carbon and water, compounds with water of crystallization, mixtures of alkaline substances or alcohol compounds and dithionites, ferrous compounds, salts of transition metals, salts of aluminum, alkali metals or alkaline earth metals a mixture of an alkali compound containing nitrogen, an alkaline compound or ammonium salt containing nitrogen and an alkaline earth metal sulfite, ■ a mixture of iron or zinc and sodium sulfate l hydrate, or a mixture of this mixture and a metal halide; Iron, copper, tin, zinc or nickel; sodium sulfate heptahydrate or decahydrate; and mixtures of metal halides; transition metals from period 4 of the periodic table; tin or antimony; and mixtures with water Alternatively, a mixture of the above mixture and a metal halide, (1) alkali metal or ammonium sulfite, hydrogen sulfite or pyrosulfite; transition metal salts or aluminum salts; and a mixture with water can be used.

In addition, commercially available oxygen absorbers can be suitably used, and examples of such commercial oxygen absorbers include:
There are products with trade names such as Ageless and Modulan.

In addition, if the above-mentioned oxygen absorber is in powder form, it is preferable to use it in a suitable air-permeable pouch, and if it is in tablet form, it may be used as is without packaging. .

Furthermore, as an airtight container, when airtightness is expressed by oxygen permeability, for example, 20°C, 60% R, J1. So, 5Id(
STP)/cIIlz-h or less, preferably l! (ST
P)/cm2·h or less can be suitably used. Examples of such polymer films include copolymers of vinyl chloride and vinyl acetate, copolymers of fluorinated ethylene and vinylidene chloride, vinyl alcohol, acrylic acid, ethyl acrylate, methacrylic acid, maleic anhydride, etc. Examples include films made of copolymers of vinyl monomer and ethylene, nylon coated with vinylidene chloride, polyethylene, polypropylene, and the like. In addition, the polymer film may be made of the above-mentioned polymers alone, or may be made of polyethylene, polypropylene, a copolymer of polyethylene and polypropylene, polyvinyl acetate, polybutadiene, polystyrene, polyvinyl alcohol, etc. vinyl polymer; metal foil such as aluminum; nylon;
It is also possible to use a composite film in which cellophane or the like is laminated in two or multiple layers as appropriate.

Among these, ethylene vinyl alcohol copolymer, polypropylene/polyvinyl alcohol/polyethylene,
Films made of nylon/polyvinyl alcohol/polyethylene, vinylidene chloride coated nylon/polyethylene, etc. can be suitably used.

° The shape of the above-mentioned airtight container is not particularly limited, but the shape of a bag or bottle is usually preferred.

Experimental example (experimental method) <Amino acid infusion prescription> L-isoleucine 8.5 g L-leucine 13.5 g L-lysine malate
12.2g L-methionine 3. OgL-
Phenylalanine 7.7g'L-threonine
4.8 gL-tryptophan
1.6 gL-valine 9. Og L-serine 4.2 g L-tyrosine 0.6 g L-arginine
11.1g and one histidine 4.7gL
-Alanine 8.6 gL-aspartic acid 0.5 gL-glutamic acid
0.5 g Aminoacetic acid 5.5 g L-proline 6.4 g L-cysteine malate 1.6 g The above ingredients were dissolved under nitrogen gas atmosphere in 800 d of distilled water for injection. After cooling, the pH of the solution was adjusted to 648 with succinic acid, and then the total amount was brought to 1°C. The solution was passed through a membrane filter (pore size:
0.22 μm) to obtain an amino acid solution.

Then, 200 d of the solution was packed into a hydrogen sulfide permeable crosslinked ethylene vinyl acetate copolymer film bag. 10
After being heat sterilized for 130 minutes at 0'C, an airtight vinylidene chloride coated nylon/polyethylene film outer bag was placed along with the oxygen absorber Ageless/Z-200 (manufactured by Mitsubishi Gas Chemical Co., Ltd., ingredients: a mixture of iron and iron oxide). The infusion preparation of the present invention was obtained by encapsulating the liquid in a container.

In addition, the amino acid infusion was made into a double bag in the same manner as above, except that Ageless was not used, and a control infusion preparation A was prepared. Furthermore, a control infusion preparation B was made into a double bag in the same manner as above except that the inside of the outer bag was replaced with nitrogen instead of Ageless.

These infusion preparations were allowed to stand at room temperature for 10 days and at 40° C. for 6 months, and then the inner bag space and the amount of hydrogen sulfide in the infusion were measured on the 10th day and 6th month.

(result) The results are shown in Table 1 below.

*The unit of hydrogen sulfide amount is ppm (Consideration) From the above results, the infusion preparation of the present invention is superior to the control infusion preparation A.
It can be seen that the hydrogen sulfide contained in the interior bag interior space and the infusion solution immediately after manufacture was significantly reduced compared to Samples and B.

Example 1 <Prescription> L-isoleucine 6. Og L-leucine 11.3 g L-lysine hydrochloride 9.8 g L-methionine 4.3 g L-phenylalanine 9
．． 7 g L-threonine 5. OgL-tryptophan 1・OgL-valine
7. Og L-serine 4.7 gL-tyrosine
0.6g L-arginine hydrochloride 15. Og L-Histidine Hydrochloride 7.0 g L-Alanine
8. 2gL-aspartic acid 2
．． Og L-glutamic acid 1.0 g aminoacetic acid
15.7g L-proline io, 6g L-cystine
0.2g xylitol 50. The above ingredients are heated and dissolved in 800ml of distilled water for injection under a nitrogen gas atmosphere. After adjusting the pH of the solution to 6.8, the total amount was adjusted to 1! shall be. The solution was passed through a Millipore filter (pore size:
0. ．． After filtering through 22 μm), 205 ml of the solution was poured into a hydrogen sulfide permeable polyethylene bottle (capacity: 350 d).
Fill it. After replacing the space with nitrogen gas, the temperature is 100°C.
The product is heat sterilized for 130 minutes, packaged together with one Ageless Z-200 in an airtight outer bag made of ethylene vinyl alcohol copolymer (Ehar), and sealed.

Example 2 <Formulation> L-isoleucine 16 gL-leucine 30 gL-lysine hydrochloride 26 gL-methiolan
11 gL-phenylalanine
26 gL-threonine 13
gL-)Liptophan 5gL-valine 18gL-serine
12 gL-Tyrosine
1.5gL-arginine hydrochloride 40
gL-Histidine hydrochloride 19 gL-
Alanine 21 gL-aspartic acid 5gL-glutamic acid
3g aminoacetic acid 41g
L-proline 28 g L-cysteine malate 0.6 g xylitol
500 g of the above ingredients in a nitrogen gas atmosphere,
Heat and dissolve in distilled water for injection 82. pH of solution is 6.5
After adjusting the total amount to 1Of. After filtering the solution with a Millipore filter (pore size: 0.22 μm), the 510 relative was filtered into a hydrogen sulfide permeable polyvinyl chloride bag (
11600d). After replacing the space with nitrogen gas, heat sterilize at 100° for 6,130 minutes and use Ageless Z.
-200 and packaged in an Eval outer bag and sealed.

Example 3 <Formulation> L-isoleucine 23 gL-leucine 37 gL-lysine hydrochloride
27 gL-methionine 1
3 g L-phenylalanine 21 g
L-threonine 13 gL-)Lyptophun 4.4gL-valine
25 gL-serine 12
gL-Tyrosine 1.4gL-
Arginine hydrochloride 19 gL-arginine 15 gL-histidine
13 gL-alanine 24
g L-Aspartic acid 1.4 g L-Glutamic acid 3 g Amineacetic acid 15 g L-Proline
19 g L-acetyl cysteine 7 g Xylitol 750 g Potassium chloride 16 g Magnesium chloride (6H20) 3 g Phosphoric acid-potassium hydrogen 3 g Sodium lactate
28 g lactic acid 13
g The above components are heated and dissolved in distilled water for injection 81 under a nitrogen gas atmosphere. After adjusting the pH of the solution to 4.8, the total volume is adjusted to 10j2. Filter the solution through a Millipore filter.
(pore size: 0.22 μm), the 510 d was filtered through a hydrogen sulfide permeable polyethylene bag (capacity: ii600 μm).
d). After replacing the space with nitrogen gas, 100
Sterilize by heating at 130°C for 130 minutes, package together with one Ageless Z-200 in an airtight outer bag made of nylon/polyvinyl alcohol/polyethylene film, and seal.

(Effects of the Invention) The infusion preparation of the present invention has an odor caused by hydrogen sulfide, even though no stabilizer such as sulfite is added to the infusion containing cysteine, cystine, or their derivatives. It has the excellent feature that it does not occur. Furthermore, since the infusion does not contain sulfites or the like, it has the advantage that it can be safely used even by hypersensitive patients and atopic patients.

Claims (1)

[Claims] A sulfite ion-free amino acid infusion containing at least one selected from cysteine, cystine, and derivatives thereof is filled in a hydrogen sulfide permeable container, and the infusion filled container is sealed together with an oxygen scavenger in an airtight container. A sulfite ion-free, double-packaged amino acid infusion preparation.