JP2006187636A - Method of stabilizing vitamin b1-containing aqueous formulation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an improved method of stabilizing a vitamin B1-containing aqueous formulation by which the vitamin B1-containing formulation may be stably kept for a long time. <P>SOLUTION: In this method, a vitamin B1-containing aqueous formulation is filled into a gas permeable primary vessel and is sealed together with an oxygen scavenger into a secondary vessel comprising a gas hardly-permeable film with an aluminum evaporation layer or aluminum foil layer. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for stabilizing an aqueous preparation containing vitamin B1. More specifically, in order to keep the aqueous preparation containing vitamin B1 stable over a long period of time while preventing the decomposition and alteration of vitamin B1 from being carried out, the present invention comprises filling the primary container with the aqueous preparation containing vitamin B1. The present invention relates to a method for containing and stabilizing a specific secondary container together with an oxygen scavenger.

  Aqueous preparations containing vitamin B1 are widely used as health drinks, eye drops, injections and the like. In particular, high-calorie infusion therapy uses a high-concentration glucose infusion, so that vitamin B1 is generally administered at the same time so that the administered glucose is efficiently converted into energy and used. At that time, vitamin B1 is usually mixed with a glucose infusion before administration as a normal operation. This is because, when vitamin B1 is deficient during high-calorie fluid therapy, conversion of administered glucose to energy is not performed sufficiently, producing and accumulating lactic acid, inducing acidosis, This is because it easily causes serious side effects.

  When vitamin B1 is in the form of an aqueous preparation, it is easily decomposed under the influence of light, oxygen, heat, pH, etc., so many of the conventionally used vitamin B1 preparations have been lyophilized. It was a formulation in a vial. In addition, when vitamin B1 is used in the form of an aqueous preparation, it has been used by being filled in a glass container substantially free of gas permeability.

In addition, in recent years, during the implementation of high-calorie infusion therapy, in order to eliminate the complexity of mixing vitamin B1 with glucose infusions and to prevent forgetting to mix vitamin B1, stabilization while blending vitamin B1 Research on high-calorie infusions that have been planned has been conducted. For example, Patent Document 1 discloses an infusion solution for in-use mixed infusion in which vitamin B1 is blended in one of an amino acid infusion and a sugar infusion without sulfite ions, and these two liquids are sealed in another chamber. Has been. Patent Document 2 discloses a transfusion agent in a two-chamber container in which a transfusion containing pH 3.5 to 5.0 containing glucose and vitamin B1 and a transfusion containing an amino acid, an electrolyte, and a stabilizer are enclosed in separate chambers. ing. Further, Patent Document 3 discloses an infusion solution in which a reducing sugar infusion solution and an amino acid infusion solution are stored in two chambers, in which vitamin B1 is added to a reducing sugar infusion solution not containing sulfite, and vitamin B2 and vitamin C are combined in an amino acid infusion solution. Agents are disclosed.
In addition to the above-described conventional technology, Patent Document 4 describes that vitamin B1 is stabilized by adding phosphoric acid or hydrochloric acid to an aqueous preparation containing vitamin B1. Further, Patent Document 5 describes that vitamin B1 is stabilized by adding alanine, lysine and proline to an aqueous preparation containing vitamin B1.

  Although the above-described conventional techniques improve the stability of vitamin B1s, they are still not sufficient in terms of long-term stability, and there is a need for improvement. Each of the above-described conventional techniques is an improvement in the component aspect of a liquid preparation containing vitamin B1, or an improvement in a separate storage form of a liquid preparation containing vitamin B1 and another liquid preparation, and contains vitamin B1. It is not intended to improve the overall packaging form of the aqueous formulation itself.

Furthermore, since vitamin B1s are not stable in an aqueous solution, in preparation of an aqueous preparation containing vitamin B1s, vitamin B1s are added in excess of the necessary amount in anticipation of vitamin B1s that are lost by decomposition. This is a general situation, which has led to increased costs and complexity in terms of quality control. If the stability of vitamin B1 in an aqueous solution can be improved, it will be necessary to add only a necessary amount of vitamin B1 at the time of preparing an aqueous preparation, thereby preventing an increase in cost and complexity of product management.
Japanese Patent Application Laid-Open No. 8-14359 JP-A-11-35471 Japanese Patent Laid-Open No. 10-203959 JP-A-10-67660 Japanese Patent Laid-Open No. 11-35467 Japanese Patent No. 2675075 JP 2001-261579 A Japanese Patent Publication No. 1-16502

An object of the present invention is to provide a method for stabilizing an aqueous preparation containing vitamin B1 in order to maintain an aqueous preparation containing vitamin B1 stably over a long period of time. In particular, the main object of the present invention is to prevent the influence of light, oxygen, etc. on an aqueous preparation containing vitamin B1 and to keep the aqueous preparation containing vitamin B1 stable for a long period of time. It provides an improved method for stabilizing aqueous formulations containing.
The object of the present invention is to eliminate the need for blending an excessive amount of vitamin B1 in anticipation of a decrease in vitamin B1 during storage, and only contain the necessary amount of vitamin B1. It is to provide a method for stabilizing aqueous formulations.
Furthermore, an object of the present invention is to fill an aqueous preparation containing vitamin B1 with an aqueous preparation containing an amino acid or an aqueous preparation containing a fat-soluble vitamin into a multi-chamber container so that they can be mixed. It is to provide an improved method for stabilizing a multi-chambered aqueous formulation for stable maintenance over a long period of time.

As a result of various studies conducted by the present inventors in order to achieve the above-mentioned object, an aqueous preparation containing vitamin B1 is filled in a gas-permeable primary container, and then, together with an oxygen scavenger, an aluminum vapor deposition layer Or, when enclosed in a specific secondary container made of a light-shielding and gas-impermeable film having an aluminum foil layer and double-wrapped, vitamin B1s in the aqueous preparation can be stably maintained over a long period of time. I found it.
Furthermore, the present inventors have found that vitamin B1 can be kept stable in the aqueous preparation for a long time even when glucose is added to the aqueous preparation containing vitamin B1 packaged in double packaging. I found it.

Furthermore, the present inventors made a multi-chamber type container in which the primary container is divided into two or more chambers by a separating means capable of communicating with the primary container filled with vitamin B1. A light-shielding and gas-impermeable film having an aqueous preparation containing glucose and an aqueous preparation containing an amino acid in the second chamber and having an oxygen-deposited agent and an aluminum vapor-deposited layer or an aluminum foil layer. When the container is enclosed in a secondary container consisting of the above, a double-packed container is obtained, and the resulting multi-packed aqueous formulation-containing container can be stored stably for a long period of time, and at the time of use, the first chamber and the second chamber By simply connecting the aqueous preparation in the first chamber and the aqueous preparation in the second chamber by connecting the isolation means between them, the patient can be hygienic without any contamination by bacteria. It found that high-calorie nutrient infusion capable administration.
In addition, in the double packaging container, the inventors further include vitamins such as vitamin B6 and nicotinamide and electrolytes in the aqueous preparation filled in the first chamber of the primary container, and the second chamber is filled. Vitamins such as vitamin B2, vitamin C and panthenol are contained in an aqueous preparation, and fat-soluble vitamins such as vitamin A, vitamin D, vitamin E and vitamin K, vitamin B12, biotin and folic acid are contained in the third chamber. It was found that a nutritional infusion containing high-calorie and containing necessary vitamins and amino acids can be obtained by filling an aqueous preparation containing the above.

  The inventors of the present invention have made the primary container filled with vitamin B1 into a multi-chamber container in which the primary container is divided into two or more chambers by separating means that can communicate with each other. Filled with an aqueous preparation containing an aqueous preparation containing a fat-soluble vitamin in the second chamber, and a secondary gas composed of a gas impermeable film having an aluminum vapor deposition layer or an aluminum foil layer together with an oxygen scavenger When enclosed in a container to form a double packaging container, it can be stored stably for a long time without causing decomposition or alteration of vitamin B1, and the isolation means between the first chamber and the second chamber is communicated during use. By mixing the aqueous preparation containing vitamin B1 in the first chamber and the aqueous preparation containing fat-soluble vitamin in the second chamber, the mixed vitamin solution containing essential vitamins can be easily prepared. And it found hygienically be obtained without being contaminated with such bacteria in.

  And when the present inventors form a secondary container from a gas poorly permeable film whose oxygen permeation amount is a specific value or less in the above, the primary container filled with an aqueous preparation containing vitamin B1 is heat sterilized. In addition, it was found that the stability of vitamin B1s was sufficiently maintained, and the present invention was completed based on these various findings.

That is, the present invention
(1) A gas-permeable primary container filled with an aqueous preparation containing vitamin B1 is a secondary comprising a light-shielding and gas-impermeable film having an aluminum vapor deposition layer or an aluminum foil layer together with an oxygen scavenger. It is the stabilization method of the aqueous formulation containing vitamin B1 characterized by enclosing in a container.
And this invention,
(2) The method according to (1), wherein the aqueous preparation containing vitamin B1 further contains glucose.

Furthermore, the present invention provides
(3) The stabilization method according to (1) or (2) above, wherein the primary container is a single-chamber container, and the chamber is filled with an aqueous preparation containing vitamin B1 or vitamin B1 and glucose;
(4) The primary container is a multi-chamber container made of a gas-permeable flexible material partitioned into at least two chambers by a separating means that can communicate with each other, and vitamin B1 and glucose are contained in the first chamber of the primary container. The stabilization method of (2) above, wherein an aqueous preparation containing amino acid is filled and an aqueous preparation containing an amino acid is filled in the second chamber;
(5) The primary container is a multi-chamber container made of a gas permeable flexible material partitioned into three chambers by a separating means that can communicate with each other, and vitamin B1 class, glucose, Vitamin B6, nicotinamide, and aqueous preparation containing sodium, potassium, magnesium, calcium, phosphorus, chlorine and zinc ions as electrolytes are filled, and the second chamber contains amino acids, vitamin B2, vitamin C and panthenol And the stabilization method of (4) above, wherein the third chamber is filled with an aqueous preparation containing vitamin A, vitamin D, vitamin E, vitamin K, vitamin B12, biotin and folic acid in the third chamber; and
(6) The primary container is a multi-chamber container made of a gas-permeable flexible material partitioned into at least two chambers by a separating means that can communicate with each other, and contains vitamin B1 in the first chamber of the primary container The stabilization method of (1) described above, wherein the aqueous preparation is filled with the aqueous preparation containing the fat-soluble vitamins in the second chamber;
It is.

And this invention,
(7) The stabilization method according to any one of the above (1) to (6), wherein the primary container is heat sterilized in a state filled with an aqueous preparation;
(8) Any of the above (1) to (7), wherein the oxygen transmission amount of the secondary container is 1.0 ml / m ² · day or less when measured at 23 ° C., 90% RH, 101 kPa (1 atm) Any stabilization method;
It is.

According to the present invention, a vitamin B1-containing aqueous preparation filled in a gas permeable primary container is enclosed with a deoxidizer in a secondary container made of a gas poorly permeable film having an aluminum vapor deposition layer or an aluminum foil layer. Can eliminate the adverse effects of light, oxygen, etc., and provide an aqueous preparation containing vitamin B1 that is stable over a long period of time.
Furthermore, in the present invention, since the stability of the aqueous preparation containing vitamin B1 is improved, when preparing the aqueous preparation containing vitamin B1, it is not necessary to add an excessive amount in anticipation of the decomposition of vitamin B1. Since it is only necessary to add only vitamin B1 of this kind, product management of an aqueous preparation containing vitamin B1 is facilitated, and the cost can be reduced, and an inexpensive aqueous preparation containing vitamin B1 is provided. it can.

  In the stabilization method of the present invention, the primary container is a multi-chamber primary container, the first chamber is filled with an aqueous preparation containing vitamin B1 species, and the other chambers contain other nutritional components. When it is stored in a secondary container together with an oxygen scavenger, vitamin B1 in the aqueous preparation containing vitamin B1 filled in the first chamber is stable, so that vitamin B1 In addition, the amount of each nutrient component in the aqueous preparation filled in the first chamber and the second chamber of the primary container can be adjusted easily and smoothly. Moreover, by separating the separating means between the first chamber and the second and subsequent chambers during use, the aqueous preparation in the first chamber and the aqueous preparations in the second and subsequent chambers are mixed, whereby a predetermined nutrient solution is obtained. It can be obtained easily and hygienically without being contaminated with bacteria.

  In particular, the first chamber of the multi-chamber type primary container is filled with an aqueous preparation containing vitamin B1 and glucose, and the second chamber is filled with an aqueous preparation containing an amino acid, and it is vapor-deposited with an oxygen scavenger and aluminum. In the case of the stabilization method of the present invention, which is sealed in a secondary container made of a gas-impermeable film having a layer or an aluminum foil layer to form a double packaging container, it can be stored stably for a long period of time, and the first High calorie nutrition that can be administered to a patient in a very simple and hygienic manner just by mixing the isolation means between the room and the second room and mixing the aqueous preparation in the first room and the aqueous preparation in the second room An infusion can be obtained.

  Also, the first chamber of the multi-chamber primary container is filled with an aqueous preparation containing vitamin B1 and the second chamber is filled with an aqueous preparation containing fat-soluble vitamins, and this is combined with an oxygen scavenger along with an aluminum vapor deposition layer or aluminum. In the case of the stabilization method of the present invention, which is sealed in a secondary container made of a gas-impermeable film having a foil layer to form a double packaging container, it is stable over a long period of time without causing decomposition or alteration of vitamin B1. By mixing the isolation means between the first chamber and the second chamber at the time of use, and mixing the vitamin B1-containing aqueous preparation in the first chamber and the fat-soluble vitamin-containing aqueous formulation in the second chamber A mixed vitamin solution containing essential vitamins (particularly, a comprehensive vitamin solution) can be obtained easily and hygienically.

The present invention is described in detail below.
As the vitamin B1 used in the present invention, any conventionally used vitamin B1 can be used, for example, thiamine; thiamine derivatives such as prosultiamine, acthiamine, thiamine disulfide, and fursultiamine; hydrochloric acid Examples include thiamine salts such as thiamine and thiamine nitrate, and one or more of these can be used. Of these, the above-described thiamine derivatives and / or thiamine salts are preferably used.

The “aqueous preparation containing vitamin B1” used in the present invention (hereinafter sometimes referred to as “vitamin B1 containing aqueous preparation”) means a preparation comprising an aqueous solution containing vitamin B1. , Drinks for maintaining health and nutrition, eye drops, vitamin injections, infusions containing vitamins, and the like.
The content of vitamin B1 in the aqueous preparation containing vitamin B1 and the composition of the aqueous preparation containing vitamin B1 are the types of the aqueous preparation containing vitamin B1, that is, the aqueous preparation containing vitamin B1 is a beverage, eye drops, vitamin injection, It can be appropriately adjusted depending on whether it is a vitamin B1 compound infusion solution or the like.
In general, the content of vitamin B1 in 1 liter of an aqueous preparation containing vitamin B1 is preferably 0.7 to 700 mg.

  The aqueous preparation containing vitamin B1 may contain only vitamin B1 depending on the type and use of the double packaging container according to the method of the present invention, or may not impair the stability of vitamin B1. May contain the nutritional component. Examples of other nutritional components that can be contained in an aqueous preparation containing vitamin B1 include vitamins such as vitamin B2, vitamin B6, nicotinamide, panthenol, and ascorbic acid, glucose, maltose, fructose, and xylitol The vitamin B1-containing aqueous preparation can contain one or more of these nutritional components.

  In particular, in the stabilization method of the present invention, vitamin B1 in the aqueous preparation filled in the primary container is kept stable over a long period of time, so that glucose can be contained in the vitamin B1-containing aqueous preparation. Thus, it is possible to prepare a high calorie glucose infusion containing long-term stability containing vitamin B1 that promotes digestion of glucose and conversion to energy. In a vitamin B1-containing aqueous preparation (glucose infusion) containing glucose, the glucose content is 14 to 700 g, particularly 50 to 500 g, and the vitamin B1 content is 0.7 to 70 mg per liter of the aqueous preparation. In particular, it is preferably 2 to 30 mg.

  In addition, the vitamin B1-containing aqueous preparation in the stabilization method of the present invention includes potassium dihydrogen phosphate, sodium chloride, potassium acetate, and L-sodium lactate depending on the type of aqueous preparation in addition to the above-described nutritional components. Electrolytes such as magnesium chloride, calcium gluconate and potassium chloride, and zinc sulfate and the like as trace elements can be contained. In particular, the vitamin B1 containing aqueous preparation containing vitamin B1 and glucose preferably contains the electrolyte described above.

  The pH of the aqueous preparation containing vitamin B1 in the present invention is preferably 2 to 7 regardless of the presence or absence of glucose, from the viewpoint of long-term stability of the aqueous preparation containing vitamin B1 and the like. It is more preferable that The adjustment of the aqueous preparation containing vitamin B1 to the pH described above may be performed using one or more of inorganic acids such as hydrochloric acid, organic acids such as succinic acid, acetic acid, lactic acid, citric acid, and malic acid. it can.

The shape, structure, dimensions, thickness, etc. of the primary container filled with the vitamin B1-containing aqueous preparation are not particularly limited, and can be determined according to the type and use of the double packaging container according to the stabilization method of the present invention. . For example, the primary container can be formed in a bag shape (bag shape), a bottle shape, or a cylindrical shape having a lid and a bottom.
The primary container in the stabilization method of the present invention may be a one-chamber container having only one chamber filled with vitamin B1 or an aqueous preparation containing vitamin B1 and glucose, or vitamin B1. A first chamber filled with an aqueous preparation containing sucrose or vitamin B1 and glucose, and a second chamber filled with another aqueous preparation isolated by isolation means capable of communicating with the first chamber, or more It may be a multi-chamber container having many chambers.

In particular, the present invention
A. Using a one-chamber container as the primary container, the chamber is filled with an aqueous preparation containing vitamin B1 or vitamin B1 and glucose, and the primary container is sealed in a secondary container together with an oxygen scavenger. A method of stabilizing in a heavy packaging container (hereinafter sometimes referred to as "stabilization method A");
B. As the primary container, a multi-chamber container made of a gas-permeable flexible material partitioned into at least two chambers by means of separating means that can communicate with each other, containing vitamin B1 and glucose in the first chamber of the primary container A method of stabilizing a double packaged container by filling an aqueous preparation containing an amino acid into the second chamber and filling the primary container with a deoxidizer in a secondary container (hereinafter referred to as this). And C. As a primary container, a multi-chamber container made of a gas-permeable flexible material partitioned into at least two chambers by a separating means that can communicate with each other is used. The first chamber of the primary container is filled with an aqueous preparation containing vitamin B1 and the second chamber is filled with an aqueous preparation containing fat-soluble vitamins, and the primary container is enclosed in a secondary container together with an oxygen scavenger. Double packaging How to stabilized (hereinafter this may be referred to as "stabilization method C");
Are included as specific embodiments.

The primary container used in the present invention is a two-chamber container comprising a first chamber filled with an aqueous preparation containing vitamin B1 and glucose and a second chamber filled with an aqueous preparation containing amino acids. Alternatively, it may be a multi-chamber type container having three or more chambers having a third chamber filled with another liquid agent in addition to the two chambers described above.
As a specific aspect of the primary container in the stabilization method B, a multi-chamber container made of a gas-permeable flexible material partitioned into three chambers by an isolating means that can communicate with the primary container is used. The first chamber is filled with an aqueous preparation containing vitamins B1, glucose, vitamin B6, nicotinamide and sodium, potassium, magnesium, calcium, phosphorus, chlorine and zinc ions as electrolytes, and the second chamber is filled with amino acids, A method of filling an aqueous preparation containing vitamin B2, vitamin C and panthenol and filling an aqueous preparation containing vitamin A, vitamin D, vitamin E, vitamin K, vitamin B12, biotin and folic acid in the third chamber, etc. Can be mentioned.
Further, the primary container in the stabilization method C of the present invention consists of a first chamber filled with an aqueous preparation containing vitamin B1 and a second chamber filled with an aqueous preparation containing a fat-soluble vitamin. It may be a chamber-type container, or may be a multi-chamber container having three or more chambers having a third chamber filled with another liquid agent in addition to the two chambers described above.

The double packaging container stabilized by the stabilization method A of the present invention is useful as a long-term storage container for vitamin B1 for supplying vitamin B1 separately to an aqueous preparation containing glucose.
Further, in the double packaging container according to the stabilization method B of the present invention, two or more chambers are partitioned by taking out the primary container from the secondary container and applying a force such as pressing from the outside during use. The separation means is released by peeling, destruction, etc., and two or more chambers communicate with each other, and the aqueous preparation containing vitamin B1 and glucose filled in the first chamber is filled in the second chamber. Aqueous preparations containing amino acids, and in some cases, aqueous preparations containing fat-soluble vitamins filled in the third chamber and other aqueous preparations are mixed to form vitamin B1, glucose, amino acids and optionally fat-soluble vitamins. In addition, it is possible to obtain hygienically and easily a tube feeding nutrient solution containing other components such as other water-soluble vitamins and electrolytes.
And in the double packaging container by the stabilization method C of this invention, the isolation | separation means which divided the 2 chambers by taking out the primary container from the secondary container at the time of the use, and applying the force by pressing etc. from the outside. The two chambers communicate with each other after being released due to peeling, destruction, etc., and the aqueous preparation containing vitamin B1 filled in the first chamber and the aqueous preparation containing fat-soluble vitamin filled in the second chamber are mixed. Thus, a vitamin liquid containing a plurality of vitamins (particularly a comprehensive vitamin liquid) can be obtained hygienically and easily.

Flexibility in which two or more types of liquid agents are individually filled into a plurality of chambers partitioned by communication-isolating means, and two or more types of liquid agents are mixed and used at the time of use. There are various known multi-chamber containers made of materials, and in the present invention, any conventionally known one can be used as a primary container.
In particular, in the present invention, a bag-like container is formed from a heat-fusible sheet material as described in Patent Document 6, for example, and the periphery of the container is firmly heat-sealed at a high temperature so as not to peel off. On the other hand, the isolation means (isolation part) that divides a plurality of chambers is heat-sealed at a lower temperature than that, and by pressing the bag from the outside at the time of use, the heat-seal of the isolation part is released to fill the plurality of chambers An infusion container in which the prepared liquid is mixed is preferably used as the primary container in the double packaging container of the present invention.

The primary container used in the present invention may be any container made of a gas-permeable and liquid-impermeable material, but is preferably formed of a polymer material that is gas-permeable and impermeable to liquids. The multi-chamber primary container used for the double packaging container B and the double packaging container C is preferably formed of a flexible polymer material that is gas permeable and impermeable to liquids.
Preferred examples of the gas permeable and liquid impermeable polymer material forming the primary container include polyethylene resin, polypropylene resin, a mixture of polyethylene resin and polypropylene resin, polypropylene resin and styrene elastomer, and / or Or the mixture of an olefin type elastomer, an ethylene-vinyl acetate copolymer, etc. can be mentioned. The primary container may be composed of a single layer of the above-described polymer material, or may have a multilayer structure composed of two or more layers.

  In particular, when the primary container is a multi-chamber container, a mixture of two or more kinds of resins such as a mixture of a polypropylene resin and a styrene elastomer and / or an olefin elastomer, a mixture of a polyethylene resin and a polypropylene resin, etc. It is preferable that it is formed using. When the sheet-like material composed of the mixture described above is stacked up and down, the portion that becomes the peripheral portion of the container is heat-sealed at a high temperature, and the isolation means section partitioned into a plurality of chambers is heat-sealed at a temperature lower than that, the peripheral portion is A multi-chamber primary container that is firmly heat-sealed and can be easily released and communicated by applying an external force to the separating means can be easily manufactured. Moreover, such a primary container is also excellent in the stability of the function of the separating means formed by heat sealing at a low temperature.

The production method of the primary container is not particularly limited, and an appropriate production method can be adopted according to the type of material forming the primary container, the shape of the primary container, etc. For example, using the above-described polymer material, extrusion blow Adopt molding method, injection blow molding method, inflation molding method, injection molding method, casting method, method of producing sheets and fusing the surroundings with heat, etc., method of producing cylindrical body and attaching lid and bottom Can be manufactured.
In particular, a multi-chamber primary container is manufactured by, for example, a blow molding method, an inflation molding method, etc., and heat sealing so that a portion that becomes an isolation means of the container can be communicated later, and a sheet is produced. Then, it can be manufactured by a method of stacking two sheets, heat-sealing the periphery thereof at a high temperature, and heat-sealing a portion serving as a separating means at a low temperature.

In the stabilization method B of the present invention, the first chamber of the multi-chamber primary container is filled with an aqueous preparation containing vitamin B1 and glucose, and the second chamber is filled with an aqueous preparation containing an amino acid. However, as the vitamin B1 contained in the aqueous preparation filled in the first chamber, the above-described vitamin B1 is used.
In the stabilization method B, the aqueous preparation filled in the first chamber of the primary container may contain only vitamin B1 and glucose as nutrient components, or does not impair the stability of vitamin B1 and glucose. It may contain other nutritional components. The aqueous preparation filled in the first chamber of the primary container preferably contains vitamins such as vitamin B6 and nicotinamide together with vitamins B1 and glucose.
In stabilization method B, the pH of the aqueous preparation containing vitamin B1 and glucose filled in the first chamber of the primary container is particularly in the range of 3 to 5, such as long-term stability of vitamin B1. It is preferable from the point.

  In the stabilization method B, as the aqueous preparation containing an amino acid filled in the second chamber of the primary container, an amino acid infusion containing an essential amino acid and a non-essential amino acid conventionally used for nutritional supplementation is suitable. Used for. The amino acid-containing aqueous preparation filled in the second chamber preferably contains water-soluble vitamins such as vitamin C, vitamin B2, and panthenol.

Further, in stabilization method B, a third chamber is formed in the primary container, and the third chamber contains fat-soluble vitamins such as vitamins A, E, D, and K, vitamin B12, biotin, folic acid, and the like. It is preferable to fill with an aqueous preparation.
By making the primary container in the stabilization method B into a three-chamber container filled with three types of aqueous preparations containing the above-described components in the first to third chambers, By simply releasing the isolation means and mixing the aqueous preparation filled in the first to third chambers, a complete nutritional infusion solution containing all the necessary nutritional components can be prepared very simply and hygienically. .
In the stabilization method B, the first chamber and / or the second chamber of the primary container include various electrolytes such as those described above used in high-calorie infusion therapy, zinc, copper, manganese, iron, chromium, and the like. Trace elements may be included.

  In stabilization method B, the contents of vitamin B1 and glucose in the aqueous preparation filled in the first chamber of the primary container, and the amino acid content in the amino acid-containing aqueous preparation filled in the second chamber are generally It is preferable that glucose is 50 to 500 g, vitamin B1 is 1 to 50 mg, and amino acid is 10 to 55 g per 1000 ml of the mixed liquid after mixing the aqueous preparation filled in the plurality of chambers of the container. Moreover, it is preferable to contain about 1-10 mg of vitamin B2. Furthermore, about another vitamin, the quantity generally used by a high calorie infusion therapy can be mix | blended.

In the stabilization method C of the present invention, the first chamber of the multi-chamber primary container is filled with an aqueous preparation containing vitamin B1 and the second chamber is filled with an aqueous preparation containing a fat-soluble vitamin. ing. As the vitamin B1 to be contained in the aqueous preparation filled in the first chamber, the above-described vitamin B1 is used.
In the stabilization method C, the aqueous preparation filled in the first chamber of the primary container may contain only vitamin B1 as a nutrient component, or together with vitamin B1, for example, vitamin B2, vitamin B6, Vitamins such as nicotinamide can be contained.
In the stabilization method C, the pH of the vitamin B1-containing aqueous preparation filled in the first chamber of the primary container is particularly preferably in the range of 3 to 5 from the viewpoint of long-term stability of vitamin B1.

In stabilization method C, the aqueous preparation containing the fat-soluble vitamin filled in the second chamber of the primary container is one or more of fat-soluble vitamins such as vitamin A, vitamin D, vitamin E, and vitamin K. In particular, it contains at least three kinds of vitamin A, vitamin D and vitamin E, or contains at least four kinds of vitamin A, vitamin D, vitamin E and vitamin K. desirable.
At that time, any vitamin A (retinol) activity may be used as vitamin A, and specific examples include retinol palmitate and retinol acetate.
Vitamin D may be any as long as it has vitamin D activity, and specific examples thereof include vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol), and active forms thereof.
Vitamin E may be any as long as it has vitamin E activity, and specific examples include tocopherol acetate, tocopherol succinate, dl-α-tocopherol and the like.
Vitamin K may be any as long as it has vitamin K activity, and specific examples include phytonadione, menatetrenone, menadione, and derivatives thereof.

  In the stabilization method C, it is preferable to use a fat-soluble vitamin-containing aqueous preparation filled in the second chamber of the primary container, in which the fat-soluble vitamin is sufficiently emulsified or solubilized. In particular, in stabilization method C, in the second chamber of the primary container, polyoxyethylene sorbitan fatty acid esters as surfactants described in the specification of Patent Document 7 previously invented by the present inventors are used. A fat-soluble vitamin solubilized solution or the like solubilized using at least one selected from sugar alcohol and glycerin as a stabilizer is preferably used.

  In the stabilization method C, the content of each vitamin in the vitamin B1-containing aqueous preparation filled in the first chamber of the primary container and the fat-soluble vitamin-containing aqueous preparation filled in the second chamber is not particularly limited. It can be determined according to the use of the double packaging container obtained by the stabilization method C. In general, the daily vitamin intake required for adults is 2000-5000 IU for vitamin A, 200-1000 IU for vitamin D, 2-20 mg for vitamin E, 0.2-10 mg for vitamin K, 3 for vitamin B1. Since it is 100 mg, it may be determined in consideration of the amount.

  In the stabilization method C, the pH of the fat-soluble vitamin-containing aqueous preparation filled in the second chamber of the primary container is 5.0 to 7.0, particularly 5.5 to 6.5. From the viewpoints of solubilization and stability of the fat-soluble vitamin in the liquid. In adjusting the pH of the fat-soluble vitamin-containing aqueous preparation to the above-mentioned range, any compound that can be used as a pharmaceutical additive can be used. For example, citric acid, acetic acid, tartaric acid, lactic acid, fumaric acid, propionic acid, Organic acids such as adipic acid, gluconic acid, succinic acid, maleic acid, malic acid, inorganic acids such as carbonic acid, boric acid, phosphoric acid, sulfuric acid, hydrochloric acid; potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, The pH can be adjusted using an alkaline compound such as sodium bicarbonate.

In Stabilization Method C, the fat-soluble vitamin-containing aqueous preparation filled in the second chamber of the primary container may contain water-soluble vitamins (vitamin C, vitamin B12, folic acid, etc.), sugars, amino acids, electrolytes as necessary. You may contain 1 type, or 2 or more types of other components, such as a component.
In stabilization method C, the first chamber of the primary container is filled with an aqueous preparation containing vitamin B1 and vitamin B2, vitamin B6, and nicotinamide that can coexist with vitamin B1, and the second chamber is filled with vitamin A, vitamin D, When an aqueous preparation containing vitamins such as vitamin E, vitamin K and vitamin C, vitamin B12, folic acid, biotin and panthenol that can coexist with fat-soluble vitamins is filled, the isolation means of the first chamber and the second chamber is reduced. When released and mixed with both aqueous preparations, a comprehensive vitamin solution containing vitamins necessary for the human body can be obtained.

The primary container filled with the vitamin B1-containing aqueous preparation, or the primary container filled with the vitamin B1-containing aqueous preparation and other aqueous preparation isolated, is used as a secondary container together with the oxygen scavenger without performing heat sterilization. It may be enclosed. However, it is preferable from the viewpoints of hygiene, safety, and the like to enclose in a secondary container after heat sterilization. The heat sterilization treatment is preferably performed after filling the primary container with an aqueous preparation containing vitamin B1 or the vitamin B1 and other aqueous preparation and sealing the primary container.
The heat sterilization treatment of the primary container filled with the aqueous preparation may be performed by any method such as high-pressure steam sterilization method, water bath sterilization method, spray sterilization method (shower sterilization method), among which high-pressure steam sterilization method is preferably adopted Is done. In the heat sterilization treatment, the conditions defined in the Japanese Pharmacopoeia may be adopted, or other suitable conditions may be adopted depending on the properties of the vitamin B1-containing aqueous preparation.
In the heat sterilization of the primary container, as disclosed in, for example, Patent Document 8, sterilization using saturated water vapor that does not substantially contain oxygen can prevent alteration and decomposition of vitamins and amino acids during sterilization. ,desirable.

A vitamin B1-containing aqueous preparation can be stabilized by enclosing a primary container filled with vitamin B1-containing aqueous preparation or vitamin B1 and other aqueous preparation in a secondary container together with an oxygen scavenger. .
As the oxygen scavenger, any oxygen scavenger can be used as long as it has no problem of toxicity in use and can efficiently absorb oxygen and reduce oxygen in the atmosphere. Examples of oxygen scavengers include metal powders such as iron powder, ferrous salts, dithionites, sulfites, metal halides and other inorganic substances, ascorbic acid, erythorbic acid, their salts, hydroquinone Various compounds such as those mainly composed of organic compounds such as polyphenols such as catechol and catechol are known and any of them can be used as long as they are non-toxic and have excellent oxygen absorption performance. In addition, there are oxygen scavengers that only absorb oxygen and oxygen absorbers that release carbon dioxide together with oxygen absorption. Any of them can be used in the present invention. As commercially available products, “AGELESS” (trade name) manufactured by Mitsubishi Gas Chemical Co., Ltd. is known, and AGELESS can be suitably used in the present invention. Moreover, you may use what laminated the sheet | seat which has a deoxidation function inside as a film which comprises a secondary container.

  The amount of the oxygen scavenger used is the vitamin B1 containing aqueous preparation filled in the primary container or the vitamin B1 containing aqueous preparation filled in the primary container and other aqueous preparations, such as vitamin B1 and others. It is necessary for the amount of the component to be in an amount capable of maintaining an atmosphere having a low oxygen concentration that does not deteriorate or decompose due to oxygen. The specific use amount of the oxygen scavenger can be determined by the amount of oxygen in the double packaging container, the oxygen absorbing capacity of the oxygen scavenger, and the like.

  Furthermore, in order to prevent moisture evaporated from the primary container from condensing into the secondary container and wetting the outer surface of the primary container, when the primary container is sealed in the secondary container together with the oxygen scavenger, a moisture absorbing material is used. Can be enclosed together. As the moisture absorbing material, silica gel, Japanese paper, non-woven fabric, polymer absorbing material and the like can be used. Moreover, you may use what laminated the sheet | seat which has a water absorption function inside as a film which forms a secondary container.

In the present invention, it is necessary to use a container made of a light-shielding and gas-impermeable film having an aluminum vapor deposition layer or an aluminum foil layer for a secondary container.
When a container formed from a gas poorly permeable film (for example, a laminated film made only of a synthetic resin) that does not have an aluminum vapor deposition layer or an aluminum foil layer is used as a secondary container, it contains vitamin B1s filled in the primary container. The stability of vitamin B1s in the aqueous preparation is not sufficiently maintained, causing deterioration and degradation.

As the light-shielding and hardly gas permeable film forming the secondary container, any film having an aluminum vapor deposition layer or an aluminum foil layer and hardly gas permeable can be used. Alternatively, a laminated film in which an aluminum foil layer is sandwiched between gas permeable polymer material films is preferably used because it has excellent gas permeable properties, light shielding properties, and mechanical properties.
As a gas poorly permeable polymer material forming a light shielding and gas permeable laminated film constituting the secondary container, a biaxially stretched polyamide, an ethylene-vinyl alcohol copolymer, a polyester such as polyethylene terephthalate, Examples thereof include polyvinylidene chloride. An aluminum vapor deposition layer or an aluminum foil layer is present inside the laminated film, and one layer or two or more layers made of the above-mentioned gas-impermeable polymer material is used, for example, polyethylene, ethylene-vinyl acetate copolymer, etc. By using the low-melting point resin as an adhesive and heat-sealing and laminating, a light-shielding and gas-permeable laminated film that can be suitably used as a secondary container can be obtained. At that time, if a low melting point polymer layer such as polyethylene or ethylene-vinyl acetate copolymer is present on one surface of the gas permeable laminated film, the light shielding and gas permeable laminated film It is excellent in heat sealability when manufacturing the secondary container. By using a light-shielding and gas-impermeable film having an aluminum vapor-deposited layer or an aluminum foil layer as described above as a secondary container, stability of vitamins that cause photo-denaturation is also secured, and these alterations and Decomposition can be prevented.

Although not limited, as a light-shielding and gas-impermeable film for secondary containers preferably used in the present invention, for example,
(1) A laminated film having a layer structure composed of biaxially stretched polyamide (OPA) / polyethylene (PE) / aluminum-deposited polyethylene terephthalate (PET) / polyethylene (PE);
(2) Laminated film having a layer structure composed of OPA / PE / aluminum-deposited PET / PE;
(3) A laminated film having a layer structure composed of OPA / PE / aluminum foil / PE / PE;
(4) Laminated film having a layer structure composed of OPA / PE / aluminum foil / PE / PET / PE;
(5) Laminated film having a layer structure composed of PET / PE / aluminum-deposited PET / PE / ethylene-vinyl acetate copolymer (EVA) / PE;
(6) Laminated film having a layer structure composed of polyvinylidene chloride / PE / aluminum-deposited PET / PE;
(7) A laminated film having a layer structure made of PET / aluminum-deposited ethylene-vinyl alcohol copolymer (EVOH) / PE;
And so on.

In the case of the stabilization method of the present invention, vitamin B1 in an aqueous preparation containing vitamin B1 filled in a primary container, further, amino acids filled in the primary container, other vitamins, etc. can be stabilized over a longer period of time. From the point that it can be maintained, the oxygen permeation amount of the gas impermeable film constituting the secondary container is 1.0 ml / m 2 · day or less when measured at 23 ° C., 90% RH, 101 kPa (1 atm). Is preferably 0.60 ml / m 2 · day or less.
In addition, the thickness of the aluminum vapor-deposited layer or the aluminum foil layer in the gas permeable film constituting the secondary container is the same as that for preventing alteration and decomposition of vitamin B1 and other components, and the gas permeable film constituting the secondary container. From the viewpoint of ease of production, it is preferably 0.05 to 1.5 μm in the case of an aluminum vapor deposition layer and 5 to 15 μm in the case of an aluminum foil layer.

Using the light-shielding and gas-impermeable film having the aluminum vapor deposition layer or the aluminum foil layer described above, a bag-like container was prepared by heat fusion or the like, and the vitamin B1-containing aqueous preparation was filled from the opening. Put a primary container or a primary container filled with an aqueous preparation containing vitamin B1 separately from other aqueous preparations together with an oxygen scavenger, and seal the opening by heat sealing or the like to make a double packaging container. be able to.
According to the stabilization method of the present invention, as described above, depending on the type of aqueous preparation filled in the primary container of the double package container, the type of ingredients in the aqueous preparation, etc., for health maintenance and nutritional supplementation, Effectively used in drinks, eye drops, vitamin injections, medical infusions, etc.

Hereinafter, the present invention will be specifically described with reference to examples and the like, but the present invention is not limited to the following examples.
The contents of the secondary container films (i) to (v) used in the following examples or comparative examples are as follows.

(I) Biaxially stretched nylon (ON) (thickness 25 μm) / polyethylene (PE) (thickness 15 μm) / aluminum vapor-deposited polyethylene terephthalate (Al-PET) (aluminum vapor-deposited layer thickness 0.1 μm, PET thickness 12 μm) / PE (thickness 50 μm) light-shielding and gas-impermeable laminated film [Oxygen permeability measured at 23 ° C., 90% RH, 101 kPa (1 atm) = 0.55 ml / m 2 · day]

(Ii) A light-shielding and gas-permeable laminated film consisting of PET (thickness 15 μm) / aluminum deposition EVOH (aluminum deposition layer thickness 0.1 μm, EVOH thickness 12 μm) / PE (thickness 30 μm) [23 Oxygen permeability measured at 0 ° C., 90% RH, 101 kPa (1 atm) = 0.55 ml / m 2 · day]

(Iii) Light shielding and gas comprising uniaxially stretched polypropylene (CPP) (thickness 15 μm) / ON / ethylene-vinyl alcohol copolymer (EVOH) / ON (thickness 25 μm) / PE (thickness 50 μm) Colored laminated film with poor permeability [Oxygen permeability measured at 23 ° C., 90% RH, 101 kPa (1 atm) = 0.44 ml / m 2 · day; Anthraquinone yellow, quinacridone mazeda, carbon black as coloring agent Containing a benzotriazole UV absorber and coating the outer surface with an ink and coloring it orange to give light shielding properties]

(Iv) Gas poorly permeable laminated film consisting of ON (thickness 15 μm) / EVOH (thickness 15 μm) / very low density polyethylene (LLDPE) (thickness 60 μm) [23 ° C., 90% RH, 101 kPa (1 atm) Oxygen permeability measured at 0. 0.47 ml / m 2 · day]

(V) PET (thickness 12 μm) / colored PE (PE containing anthraquinone yellow, quinacridone mazeda, carbon black as a colorant and a benzotriazole ultraviolet absorber) (thickness 20 μm) / nylon ( Colored gas-impermeable laminated film consisting of 20 μm thick / EVOH (20 μm thick) / LLDPE (60 μm thick) [Oxygen permeability measured at 23 ° C., 90% RH, 101 kPa (1 atm) = 8. 01ml / m2 · day]

  The oxygen permeability of the films (i) to (v) for the secondary container was measured by JIS-K7126 B method at 23 ° C., 90 RH, and 101 kPa.

Example 1
(1) Preparation of aqueous preparation containing vitamin B1 and glucose:
Among the components described in Table 1 below, glucose and electrolyte were dissolved in 500 ml of distilled water for injection heated to about 60 ° C., cooled to room temperature, and thiamine hydrochloride was added thereto for dissolution. Next, it was adjusted to pH 4.5 using hydrochloric acid and succinic acid, made up to 700 ml with distilled water for injection, filtered through a 0.22 μm membrane filter, and vitamin B1 having the composition shown in Table 1 below. And an aqueous preparation containing glucose.

(2) Preparation of amino acid-containing aqueous preparation:
Among the amino acids shown in Table 2 below, amino acids other than L-lysine sulfite and L-cysteine malate were dissolved in 300 ml of distilled water for injection at about 80 ° C., cooled to room temperature, and then L-lysine sulfite. And L-cysteine malate was added and dissolved. Next, adjust the pH to 6.5 using citric acid and succinic acid, bring the total volume to 400 ml with distilled water for injection, filter through a 0.22 μm membrane filter, and contain amino acids having the composition shown in Table 2 below. An aqueous formulation was prepared.

(3) Two rectangular sheets (thickness 300 μm) composed of a mixture of 65 parts by mass of a polypropylene resin and 35 parts by mass of a styrene elastomer (“Dynalon” manufactured by JSR) are stacked, and water is added to the upper center and lower center of the sheet. With the short tube made of polypropylene resin for filling the formulation, the periphery of the rectangular sheet was heat sealed at 130 ° C. Next, the isolation means formation scheduled part was heat-sealed at 105 ° C. to form isolation means, and a primary container having a first chamber and a second chamber that were isolated so as to communicate with each other was prepared.
(4) After filling the first chamber of the primary container obtained in (3) above with the aqueous preparation containing vitamin B1 and glucose prepared in (1) above, the filling port was sealed. Next, after filling the second chamber of the primary container with the amino acid-containing aqueous preparation prepared in (2) above, the filling port was sealed.
(5) After subjecting the primary container filled with the aqueous preparation obtained in (4) above to high-pressure steam sterilization in a saturated steam atmosphere substantially free of oxygen at a temperature of 110 ° C. for 20 minutes, Cooled down.

(6) The bag-shaped secondary produced from the heat-sterilized primary container obtained in (5) above using the light-shielding and gas-permeable laminated film having the aluminum vapor deposition layer of (i) above. The container was enclosed with an oxygen scavenger (“AGELESS” manufactured by Mitsubishi Gas Chemical Co., Inc .; 200 ml for oxygen absorption) to form a double packaging container.

Example 2
(1) The same operation as in (1) to (5) of Example 1 is performed to fill the first chamber of the primary container with an aqueous preparation containing vitamin B1 and glucose, and the second chamber with an amino acid-containing aqueous preparation. A heat-sterilized primary container filled with was prepared.
(2) The bag-like secondary produced from the heat-sterilized primary container obtained in (1) above using the light-shielding and gas-impermeable laminated film having the aluminum vapor deposition layer of (ii) The container was enclosed with an oxygen scavenger (“AGELESS” manufactured by Mitsubishi Gas Chemical Co., Inc .; 200 ml for oxygen absorption) to form a double packaging container.

<< Comparative Examples 1-3 >>
(1) The same operation as in (1) to (5) of Example 1 is performed to fill the first chamber of the primary container with an aqueous preparation containing vitamin B1 and glucose, and the second chamber with an amino acid-containing aqueous preparation. To produce a heat sterilized primary container.
(2) The heat-sterilized primary container obtained in (1) above is a laminated film (iii) (Comparative Example 1), (iv) (Comparative Example 2) that does not have an aluminum vapor deposition layer or an aluminum foil layer. ) And (v) (Comparative Example 3) were sealed in a bag-like container produced in the same manner together with the same oxygen scavenger as used in Example 1 to form a double packaging container.

<< Test Example 1 >>
About each double packaging container obtained in Examples 1-2 and Comparative Examples 1-3 above, vitamin B1 in the aqueous preparation containing vitamin B1 and glucose filled in the first chamber of the primary container When the residual ratio was measured as follows, it was as shown in Table 3 below.

[Measurement method of residual ratio of vitamin B1]
(1) The respective double packaging containers obtained in Examples 1-2 and Comparative Examples 1-3 described above were placed under conditions of a temperature of 50 ° C. for 30 days, and the primary containers after 14 days and 30 days The content of vitamin B1 in the aqueous preparation in the first chamber was measured by a method using liquid chromatography, and the residual rate (%) relative to the vitamin B1 content immediately before the start of the test was taken as 100%. .
(2) Each double packaging container obtained in Examples 1-2 and Comparative Examples 1-3 described above was placed under conditions of a temperature of 40 ° C. and a humidity of 75% RH for 30 days, and the primary container after 30 days. Measure the content of vitamin B1 in the aqueous preparation in the first chamber in the same manner as in (1) above, and determine the residual rate (%) relative to 100% of the content of vitamin B1 immediately before the start of the test. It was.

  From the results of Table 3 above, a primary container filled with an aqueous preparation containing vitamin B1 was sealed in a secondary container made of a light-shielding and gas-impermeable film having an aluminum vapor deposition layer together with an oxygen scavenger. In Example 1 and Example 2 made into the double packaging container, it enclosed with the secondary container which consists of a film which does not have an aluminum vapor deposition layer, and Comparative Examples 1 and 2 made into the double packaging container, and it did not have an aluminum vapor deposition layer In addition, it can be seen that the residual ratio of vitamin B1 is high and the stability is excellent as compared with Comparative Example 3 which is sealed in a secondary container made of a laminated film having high gas permeability and made into a double packaging container.

Example 3
(1) Preparation of aqueous preparation containing vitamin B1:
Dissolve 6 mg of vitamin B1, 10 mg of vitamin B2, 8 mg of vitamin B6 and 80 mg of nicotinamide in distilled water for injection, adjust the pH to 3.5 by adding dilute hydrochloric acid, and add distilled water for injection. The total amount was 10 ml and filtered through a 0.22 μm membrane filter to prepare a vitamin B1-containing aqueous preparation having the composition shown in Table 4 below.

(2) Preparation of aqueous preparation containing fat-soluble vitamins:
(I) After dissolving 250 mg of vitamin C in distilled water for injection and adjusting the pH to 10 by adding sodium hydroxide, 1.0 mg of folic acid, 0.25 mg of biotin, 25 μg of vitamin B12 and 35 of panthenol .1 mg was dissolved in order, and distilled water for injection was added to make the total volume 5 ml.
(Ii) Separately from the liquid of (i) above, 8250 IU of vitamin A in distilled water for injection, 25 μg of vitamin D2, 37.5 mg of vitamin E and 5 mg of vitamin K1, polyoxyethylene sorbitan fatty acid ester (solubilizing agent) ) ("Polysorbate 80" manufactured by Nikko Chemicals Co., Ltd .: trade name TO-10M) was dissolved at a rate of 200 mg, and distilled water for injection was added to make the total volume 5 ml.
(Iii) 4 ml of the liquid prepared in (i) above and 4 ml of the liquid prepared in (ii) above are heated and mixed, and 2.0 g of propylene glycol (stabilizer) is added and dissolved therein, and citric acid is dissolved in this liquid. In addition, after adjusting the pH to 6.0, water for injection was added to make a total volume of 10 ml, filtered through a 0.22 μm membrane filter, and a fat-soluble vitamin-containing aqueous solution having the composition shown in Table 5 below. A formulation was prepared.

(3) Two rectangular sheets (thickness 300 μm) composed of a mixture of 65 parts by mass of a polypropylene resin and 35 parts by mass of a styrene elastomer (“Dynalon” manufactured by JSR) are stacked, and water is added to the upper center and lower center of the sheet. The peripheral part of the rectangular sheet was heat-sealed at 130 ° C. with a short tube made of polypropylene resin for filling the preparation. Next, a primary container having a first chamber and a second chamber separated from each other so as to communicate with each other is formed by performing heat sealing at 105 ° C. in a lateral direction at a substantially central height position of the rectangular sheet to form a separating means. Produced.
(4) The first chamber of the primary container obtained in (3) above was filled with 5 ml of the vitamin B-containing aqueous preparation prepared in (1) above, and then the filling port was sealed. Next, the second chamber of the primary container was filled with 5 ml of the fat-soluble vitamin-containing aqueous preparation prepared in (2) above, and the filling port was sealed.
(5) The primary container filled with the aqueous preparation obtained in the above (4) was autoclaved at 110 ° C. for 20 minutes in a saturated steam atmosphere substantially free of oxygen, and then cooled.

(6) The bag-shaped secondary produced from the heat-sterilized primary container obtained in (5) above using the light-shielding and gas-permeable laminated film having the aluminum vapor deposition layer of (i) above. The container was enclosed with an oxygen scavenger (“AGELESS” manufactured by Mitsubishi Gas Chemical Co., Inc .; 200 ml for oxygen absorption) to form a double packaging container as a combined vitamin preparation for mixed injection into a high calorie infusion.

Example 4
(1) The same operation as (1) to (5) in Example 3 is performed, and the first chamber of the primary container is filled with the aqueous solution containing vitamin B1 and the second chamber is filled with the aqueous solution containing fat-soluble vitamins. A heated primary sterilized primary container was prepared.
(2) The bag-like two produced by using the light-shielding and gas-permeable laminated film having the aluminum vapor deposition layer of (ii) above for the heat-sterilized primary container obtained in (1) above. The next container was enclosed with an oxygen scavenger (“AGELESS” manufactured by Mitsubishi Gas Chemical Co., Inc .; 200 ml for oxygen absorption) to form a double packaging container.

<< Comparative Examples 4-6 >>
(1) The same operation as (1) to (5) in Example 3 is performed, and the first chamber of the primary container is filled with the aqueous solution containing vitamin B1 and the second chamber is filled with the aqueous solution containing fat-soluble vitamins. A heat-sterilized primary container was produced.
(2) The heat-sterilized primary container obtained in (1) above is a laminated film (iii) (Comparative Example 4), (iv) (Comparative Example 5) that does not have an aluminum vapor deposition layer or an aluminum foil layer. ) And (v) (Comparative Example 6) in a bag-like container produced in the same manner together with the same oxygen scavenger as used in Example 3, and a combined vitamin preparation for high-calorie infusion As a double packaging container.

<< Test Example 2 >>
About each double packaging container obtained by said Examples 3-4 and Comparative Examples 4-6, the residual rate of vitamin B1 in the vitamin B1-containing aqueous preparation with which the 1st chamber of the primary container was filled was tested. When measured in the same manner as in Example 1, it was as shown in Table 6 below.

  Based on the results of Table 6 above, the primary container filled with the vitamin B1-containing aqueous preparation was sealed in a secondary container made of a gas-impermeable film having an aluminum vapor deposition layer together with an oxygen scavenger to form a double packaging container. In Examples 3 and 4, Comparative Examples 4 to 5 were sealed in a secondary container made of a film having no aluminum vapor deposition layer to form a double packaging container, and lamination having no gas vapor deposition layer and high gas permeability It can be seen that the residual ratio of vitamin B1 is high and the stability is excellent as compared with Comparative Example 6 in which the film is sealed in a secondary container made of a film to form a double packaging container.

In the case of the present invention, the vitamin B1-containing aqueous preparation can be kept stable over a long period of time while preventing the decomposition and alteration of vitamin B1. Therefore, it is useful as a method for stabilizing the vitamin B1-containing aqueous preparation.

Claims (8)

  A gas-permeable primary container filled with an aqueous preparation containing vitamin B1 is enclosed in a secondary container made of a light-shielding and gas-impermeable film having an aluminum vapor deposition layer or an aluminum foil layer together with an oxygen scavenger. A method for stabilizing an aqueous preparation containing vitamin B1.   The stabilization method according to claim 1, wherein the aqueous preparation containing vitamin B1 further contains glucose.   The stabilization method according to claim 1 or 2, wherein the primary container is a single-chamber container, and the room is filled with vitamin B1 or an aqueous preparation containing vitamin B1 and glucose.   The primary container is a multi-chamber container made of a gas permeable flexible material partitioned into at least two chambers by a separating means that can communicate with each other, and contains a vitamin B1 class and glucose in the first chamber of the primary container. The stabilization method according to claim 2, wherein an aqueous preparation is filled and an aqueous preparation containing an amino acid is filled in the second chamber.   The primary container is a multi-chamber type container made of a gas permeable flexible material partitioned into three chambers by a separating means that can communicate with each other, and the first chamber of the primary container has vitamins B1, glucose, vitamin B6, An aqueous preparation containing nicotinamide and an aqueous preparation containing ions of sodium, potassium, magnesium, calcium, phosphorus, chlorine and zinc as an electrolyte, and containing an amino acid, vitamin B2, vitamin C and panthenol in the second chamber And the third chamber is filled with an aqueous preparation containing vitamin A, vitamin D, vitamin E, vitamin K, vitamin B12, biotin, and folic acid.   An aqueous preparation comprising a multi-chamber container made of a gas permeable flexible material partitioned into at least two chambers by a separating means capable of communicating, wherein the primary container contains vitamin B1 in the first chamber of the primary container The stabilization method according to claim 1, wherein an aqueous preparation containing fat-soluble vitamins is filled in the second chamber.   The stabilization method in any one of Claims 1-6 which heat-sterilizes a primary container in the state with which the aqueous preparation was filled. The stabilization according to any one of claims 1 to 7, wherein the oxygen permeation amount of the secondary container is 1.0 ml / m ² · day or less when measured at 23 ° C, 90% RH, and 101 kPa (1 atm). Method.