JP2006143599A - Multivitamin solution - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a multivitamin solution that has slight reduction in vitamin content even in long-term preservation at a room temperature, has excellent storage stability, is readily prepared and handled in administration and comprises 13 kinds of essential vitamins. <P>SOLUTION: The multivitamin solution comprises an aqueous solution preparation which is composed of a solution I, a solution II and a solution III obtained by fractionating 13 kinds of essential vitamins and charging them into three sealed containers. The solution I is adjusted to pH ≤4, the solution II is adjusted to pH4-8 and the solution III is adjusted to pH5-8. Fat-soluble vitamin contained in the solution III is solubilized with a surfactant. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a comprehensive vitamin solution that can be stably maintained at room temperature for a long period of time by separating and filling 13 essential vitamins in three sealed containers.

  Since essential vitamins are not synthesized in vivo, they are administered together with other essential ingredients required for patients by high-calorie infusion therapy to patients who have difficulty in oral or enteral feeding. In general, since a plurality of vitamins are administered simultaneously, a vitamin preparation containing a plurality of vitamins has been put into practical use as a comprehensive vitamin preparation. However, since some vitamins are difficult to ensure stability during storage, they have been commercialized by setting the storage temperature condition of the preparation in a refrigerator or by making the preparation into a lyophilized preparation. In addition, preparations containing 13 essential vitamins are difficult to guarantee the stability of all vitamins, and some preparations have been developed as comprehensive vitamin preparations that exclude unstable vitamins. is there.

  The total vitamin preparation that is currently developed with 13 essential vitamins is divided into two or three containers, but vitamin B1, which is an unstable vitamin in aqueous solution, Vitamin B12, folic acid and the like are formulated as lyophilized preparations. In addition, there is a preparation in which 13 essential vitamins are combined in one container and lyophilized for the purpose of reducing the complexity of adjustment. However, such a freeze-dried preparation requires a dissolving operation at the time of use, and adjustment becomes complicated. On the other hand, there are preparations in which 13 essential vitamins are mixed in a plurality of containers with an aqueous solution (see, for example, Patent Document 1), but these preparations may be stored in a cold place or stored in a refrigerator. . Moreover, even if it is storage at room temperature, the effective period is set short, which is not preferable from the viewpoint of storage management.

For this reason, the development of a comprehensive vitamin aqueous solution preparation excellent in storage stability at room temperature is desired.
JP 2003-104910 A

  As a result of intensive studies on the development of a general vitamin aqueous solution preparation that can be stored at room temperature, the present inventor has found that the general vitamin liquid preparation of the present invention is excellent in storage stability at room temperature, thereby completing the present invention. Furthermore, the present inventors have found that sterilization treatment, which is an essential condition for injection preparations, can be achieved by heat sterilization treatment with steam or the like due to improved stability, and the present invention has been completed.

  Accordingly, an object of the present invention is to provide a multivitamin solution that is excellent in storage stability at room temperature and can be easily adjusted at the time of administration.

That is, the present invention
(1) An aqueous solution preparation comprising the following solution I, solution II, and solution III in which 13 kinds of essential vitamins are separated and filled in three sealed containers, wherein the solution I is adjusted to pH 4 or less, and the solution II has a pH of 4 to 4 8, the solution III is adjusted to pH 5-8, and the fat-soluble vitamin contained in the solution III is solubilized by a surfactant.
Solution I: Vitamin B1, Vitamin B2, Vitamin B6 and nicotinic acids,
Solution II: vitamin C, vitamin H and pantothenic acid,
Solution III: vitamin A, vitamin E, vitamin K, vitamin D, vitamin B12 and folic acid,
(2) The general vitamin solution according to (1), wherein the solution I, the solution II, and the solution III have the following composition range:
Solution I: Vitamin B1 1-10 mg
Vitamin B2 1-10mg
Vitamin B6 1-10mg
Nicotinic acids 10-50mg
Solution II:
Vitamin C 25-200mg
Vitamin H 0.01-0.5mg
Pantothenic acid 1-30mg
Solution III:
Vitamin A 1000-5000 IU
Vitamin E 5-30mg
Vitamin K 0.5-5mg
Vitamin D 50-1000 IU
Vitamin B12 0.001-0.05mg
Folic acid 0.1-1 mg,
(3) The total vitamin solution according to (1) to (2), wherein the filling amount of each of the solution I, the solution II, and the solution III into the three sealed containers is 0.5 mL to 5 mL,
(4) The multivitamin solution according to any one of (1) to (3), further containing an antioxidant in the solution II,
(5) The comprehensive vitamin liquid according to (4), wherein the antioxidant is sodium bisulfite,
(6) The multivitamin solution according to any one of (1) to (5), further containing a pH buffer in the solution III,
(7) The comprehensive vitamin solution according to (6), wherein the pH buffer is sodium hydrogenphosphate, and (8) In the state where the three sealed containers are filled with the solution I, the solution II, and the solution III, respectively. The comprehensive vitamin liquid preparation according to any one of (1) to (7), which has been subjected to heat sterilization treatment.

  The comprehensive vitamin solution of the present invention is a comprehensive vitamin solution containing 13 kinds of essential vitamins, which can reduce the decrease in vitamin content even when stored at room temperature for a long period of time, has excellent storage stability and improved stability. Therefore, the sterilization treatment, which is an essential condition for the injection preparation, can be achieved by heat sterilization treatment such as steam sterilization treatment, and since it is a liquid preparation, the preparation operation at the time of administration is easy.

  The 13 essential vitamins contained in the general vitamin solution of the present invention (hereinafter referred to as the solution of the present invention) include vitamin A, vitamin D, vitamin E and vitamin K fat-soluble vitamins, vitamin B1, Vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin H, nicotinic acids, pantothenic acid and folic acid are water-soluble vitamins.

  In the present invention, vitamin A includes retinol acetate, retinol butyrate, retinol palmitate, 3-dehydroretinol, vitamin A oil and the like containing vitamin A components. Preferably, retinol palmitate or vitamin A oil is used.

  In the present invention, as vitamin D, ergocalciferol (vitamin D2) containing vitamin D component, cholecalciferol and its hydroxy derivative (vitamin D3), ergosterin (provitamin D2), dehydrocholesterin (provitamin D3), etc. Is mentioned. Preferred is ergocalciferol or cholecalciferol.

  In the present invention, examples of vitamin E include α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol acetate containing a vitamin E component, tocopherol succinate and a calcium salt thereof. Tocopherol acetate is preferable.

  In the present invention, vitamin K includes fetonadione (vitamin K1), phylloquinone (vitamin K1), menatetrenone (vitamin K2), menaquinone (vitamin K2), menadione (vitamin K3) and the like. Menatetrenone is preferable.

  In the present invention, as vitamin B1, thiamine, thiamine hydrochloride having the action of vitamin B1, thiamine nitrate, prosultiamine, acthiamine, fursultiamine, fursultiamine hydrochloride, thiamine disulfide, thiamine monophosphate disulfide, octothiamine , Benfotiamine and the like. Preferred is thiamine hydrochloride.

  In the present invention, vitamin B2 includes riboflavin, riboflavin phosphate having the action of vitamin B2 and its sodium salt, riboflavin hydrochloride, riboflavin butyrate, flavin mononucleotide, flavin adenine dinucleotide and its sodium salt, and the like. Riboflavin phosphate is preferable.

  In the present invention, vitamin B6 includes pyridoxine, pyridoxine hydrochloride having the action of vitamin B6, pyridoxine phosphate, pyridoxal and its phosphate. Pyridoxine hydrochloride is preferable.

  In the present invention, examples of vitamin B12 include cobalamin, cyanocobalamin having the action of vitamin B12, hydroxycobalamin, hydroxycobalamin acetate, hydroxycobalamin hydrochloride, methylcobalamin and the like. Preferably, it is cyanocobalamin.

  In the present invention, vitamin C includes ascorbic acid, sodium ascorbate having the action of vitamin C, ascorbyl palmitate, ascorbyl dipalmitate, ascorbic acid phosphate magnesium salt, and the like. Ascorbic acid is preferable.

  In the present invention, examples of vitamin H include biotin, a sodium salt having the action of biotin, a potassium salt, a magnesium salt, and a calcium salt. Preferred is biotin.

  In the present invention, examples of nicotinic acids include nicotinic acid and its amide, sodium salt, and methyl ester. Preferably, it is nicotinic acid amide.

  In the present invention, examples of pantothenic acid include pantothenic acid and pantothenic acid sodium salt, potassium salt, calcium salt, magnesium salt, panthenol and the like having the action of pantothenic acid. Preferably, it is panthenol.

  The content of the vitamin in the liquid preparation of the present invention is not particularly limited, but the following blending amount is preferable.

  Vitamin B1 is 1 to 10 mg, more preferably 2 to 6 mg.

  Vitamin B2 is 1 to 10 mg, more preferably 2 to 6 mg.

  Vitamin B6 is 1 to 10 mg, more preferably 2 to 6 mg.

  Nicotinic acids are 10-50 mg, More preferably, it is 20-45 mg.

  Vitamin C is 25 to 200 mg, and more preferably 50 to 110 mg.

  Vitamin H is 0.01 to 0.5 mg, and more preferably 0.05 to 0.15 mg.

  Pantothenic acid is 1 to 30 mg, and more preferably 7 to 16 mg.

  Vitamin A is 1000 to 5000 IU, and more preferably 2000 to 4500 IU.

  Vitamin E is 5 to 30 mg, and more preferably 7 to 16 mg.

  Vitamin K is 0.5 to 5 mg, and more preferably 1.0 to 2.5 mg.

  Vitamin D is 50 to 1000 IU, more preferably 200 to 450 IU.

  Vitamin B12 is 0.001 to 0.05 mg, more preferably 0.005 to 0.015 mg.

  Folic acid is 0.1 to 1 mg, and more preferably 0.2 to 0.5 mg.

  0.5-5 mL is preferable and the filling amount to each airtight container of the liquid agent of this invention has more preferable 1-2 mL.

  The liquid agent of the present invention is packed in three sealed containers, but these three sealed containers are separated by a separating means that can communicate with each other, and after communication, the solution I, the solution II, and the solution III are separated from the outside air. It is used by mixing at the time of use without being exposed to.

  The liquid preparation of the present invention is preferably subjected to sterilization for the purpose of sterilization, and heating such as steam sterilization is performed in a state where the above three sealed containers are filled with solution I, solution II and solution III, respectively. It is preferable to sterilize.

  When the stability of 13 aqueous vitamin solutions at various pH values was compared, vitamin B1 was stable in the acidic region and vitamin C was stable in the neutral region. Further, folic acid was desired to have a pH of 5 or more from the viewpoint of solubility.

  Based on the knowledge obtained about the pH-aqueous solution stability and the knowledge on the combination of vitamins that are not desirable to be blended in the same solution, the liquid preparation of the present invention has the solutions I and II classified into three conditions. And fractionated into solution III.

  Solution I contains vitamin B1, vitamin B2, vitamin B6, and nicotinic acids, and has a pH set to 4 or lower. By making pH into 4 or less, the solution I is excellent in storage stability. More preferably, the pH is 2.5 to 3.5.

  Solution II contains vitamin C, vitamin H, and pantothenic acid, and has a pH set to 4-8. By setting the pH to 4-8, the solution II is excellent in storage stability. More preferably, it is 5.0 to 7.0.

  Solution III contains vitamin A, vitamin E, vitamin K, vitamin D, vitamin B12 and folic acid, and has a pH set to 5-8. By setting pH to 5-8, the fall of the solubility of folic acid can be prevented and the solution III is excellent in storage stability. More preferably, it is 5.5 to 6.5.

  The pH adjustment is not particularly limited as long as it is physiologically acceptable. For example, various organic acids, inorganic acids, organic bases, and inorganic bases can be used. Examples thereof include citric acid, acetic acid, succinic acid, gluconic acid, lactic acid, malic acid, maleic acid, malonic acid and the like.

  Examples of inorganic acids include hydrochloric acid and phosphoric acid.

  Examples of the organic base include sodium citrate, sodium gluconate, sodium lactate, sodium malate, sodium acetate, sodium maleate, sodium malonate and the like.

  Examples of the inorganic base include sodium hydroxide and sodium hydrogen carbonate.

  Solution II contains vitamin C. However, since vitamin C is affected by dissolved oxygen and causes a decrease in the content, solution II may contain an antioxidant.

  Examples of the antioxidant include sodium bisulfite and sodium EDTA. Among these, sodium bisulfite is preferable.

  The content of the antioxidant is preferably 0 to 1 mg.

  Solution III contains fat-soluble vitamins Vitamin A, Vitamin E, Vitamin K, and Vitamin D, and contains a surfactant to achieve an aqueous solution of these fat-soluble vitamins.

  As the surfactant, polyoxyethylene-based activator, for example, polyoxyethylene sorbitan fatty acid ester (specifically, for example, polysorbate 80 manufactured by Nikko Chemicals), polyoxyethylene hydrogenated castor oil (specifically, Examples thereof include polyoxyethylene hydrogenated castor oil 60 manufactured by Nikko Chemicals Co., Ltd.), polyoxyethylene polyoxypropylene glycol, and the like. Among these, polysorbate and polyoxyethylene hydrogenated castor oil are preferable.

  The surfactant content is usually 0.1 to 100 g / L.

  Solution III contains vitamin A, vitamin E, vitamin K, vitamin D, vitamin B12 and folic acid, and has a pH of 5 or more from the viewpoint of folic acid solubility, and the pH-stable of the vitamins contained in solution III In order to ensure the properties, it is preferable to minimize the fluctuation of pH as much as possible. Therefore, a pH buffer may be added to the solution III.

  Examples of pH buffering agents include sodium hydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, sodium phosphate, potassium phosphate, citric acid, acetic acid, tartaric acid, maleic acid, fumaric acid, glutamic acid, sodium glutamate, and potassium glutamate. Among these, sodium dihydrogen phosphate having a buffering capacity in the neutral region is preferable among these.

  The content of the pH buffer is preferably 0 to 10 mg.

  By containing a pH buffering agent, it is possible to suppress pH fluctuation during storage of the liquid preparation of the present invention, and it is also possible to suppress pH fluctuation due to sterilization treatment for the purpose of sterilization of the liquid preparation of the present invention. .

  The liquid preparation of the present invention is one in which 13 sealed vitamins classified into three compositions are filled in three sealed containers. The sealed container may be a glass container or a plastic container.

  The solution II and the solution III are desirably manufactured so as to be hermetically filled in a state where oxygen is excluded. For example, it is preferable that the dissolved gas of the filling liquid is replaced with an inert gas such as nitrogen, and the head space portion of the filled liquid is replaced with an inert gas such as nitrogen. In the case of filling a plastic container, a method of creating anaerobic conditions by allowing an oxygen scavenger or the like to exist between the outer packaging and the container directly is also possible.

  Examples of the liquid preparation of the present invention include injection preparations, infusion preparations, oral preparations, syrup preparations, external preparations, eye drops, health functional foods (nutritive functional foods), and the like, and injections and infusion preparations are preferable.

Next, the present invention will be described with reference to examples, but the present invention is not limited thereto.
Example 1
<Storage stability of multivitamin solution>
Preparation of Solution I: Components other than hydrochloric acid having the composition of Formulation Example 1 Solution I described below were dissolved in water for injection, the pH of the solution was adjusted to 3.5 with hydrochloric acid, and water for injection was added to make the total volume 2 mL. .

  Preparation of Solution II: Components other than sodium hydroxide having the composition of Formulation Example 1 Solution II to be described later are dissolved in water for injection, and the pH of the solution is adjusted to 6.0 with sodium hydroxide. Was 2 mL.

  Preparation of solution III: Preparation Example 1 to be described later The fat-soluble vitamin and surfactant having the composition of solution III are heated and stirred, and then solubilized by adding water for injection. Then, the water-soluble vitamin is dissolved, and pH is adjusted with hydrochloric acid and sodium hydroxide. Was adjusted to 6.0, and water for injection was added to make the total volume 2 mL.

  The prepared solution I, solution II, and solution III were filled in nitrogen-filled containers, sealed, and stored in a thermostatic bath at 50 ° C, 40 ° C, and 25 ° C for a predetermined time. The rate was measured. The results are shown in Table 1. In addition, the survival rate shown in Table 1 is a survival rate when the vitamin content before the start of storage is 100%.

表１に示すように、本発明の液剤は、室温で保存安定性に優れ、室温でも保存が可能であることを示した。

As shown in Table 1, it was shown that the liquid preparation of the present invention was excellent in storage stability at room temperature and could be stored at room temperature.

(Example 2)
<Effect of addition of antioxidant in solution II>
The effect of adding sodium bisulfite as an antioxidant that may be included in Solution II was measured by the stability of vitamin C.

  Prepare a solution obtained by removing sodium bisulfite from the components of Formulation Example 1 Solution II, which will be described later, and a solution prepared by mixing sodium bisulfite with the components of Formulation Example 1 Solution II. Then, after being stored in a constant temperature bath at 60 ° C. for 1 week, the residual ratio of vitamins was measured.

  The results are shown in Table 2.

  The “remaining rate after storage at 60 ° C. for 1 week” in the table is the remaining amount when the vitamin content before the start of storage is 100%.

(Table 2)
――――――――――――――――――――――――――
Compounding amount 60 ° C, remaining rate after storage for 1 week
No formulation 85%
0.3mg 95%
――――――――――――――――――――――――――
As shown in Table 2, it can be seen that the stability of vitamin C is improved by the addition of sodium bisulfite.

(Example 3)
<Effect of adding pH buffer in solution III>
The effect of adding a pH buffer was measured by the pH variation of Solution III (fat-soluble vitamin solution).

  A liquid preparation obtained by removing sodium dihydrogen phosphate from the ingredients of formulation example 1 solution III, which will be described later, and a liquid preparation in which sodium dihydrogen phosphate is mixed with the ingredients of formulation example 1 solution III as described in Example 1. The solution was adjusted in the same manner as the solution III, and then heat sterilized.

  The pH before the heat sterilization treatment and the pH after sterilization were measured. Further, the solution state after sterilization was observed with the naked eye. Each result is shown in Table 3.

  In addition, the liquid agent before heat sterilization was clear regardless of the presence or absence of sodium dihydrogen phosphate.

(Table 3)
Compounding amount pH before sterilization pH after sterilization Solution after sterilization
―――――――――――――――――――――――――――――
No formulation 6.6 5.2 Cloudiness (precipitation formation)
0.8mg 6.5 6.1 Transparent
―――――――――――――――――――――――――――――
Formulation examples of the general vitamin solution of the present invention are shown below.

(Formulation example 1)
Solution I
Thiamine hydrochloride 5.0 mg
Pyridoxine hydrochloride 5.0 mg
Nicotinamide 40 mg
Riboflavin phosphate 5.0 mg
Hydrochloric acid pH 3.5
――――――――――――――――――――
The total volume is 2.0 mL with water for injection.
Solution II
Ascorbic acid 100 mg
Panthenol 15 mg
Biotin 0.1 mg
Sodium bisulfite 0.3 mg
Sodium hydroxide pH 6.0
――――――――――――――――――――
The total volume is 2.0 mL with water for injection.
Solution III
Vitamin A oil 4000 IU
Tocopherol acetate 15 mg
Menatetrenone 2.0 mg
Cholecalciferol 400 IU
Cyanocobalamin 0.01 mg
Folic acid 0.4 mg
Polyoxyethylene hydrogenated castor oil 60 50 mg
Polyoxyethylene polyoxypropylene glycol 10 mg
Sodium dihydrogen phosphate / anhydrous 0.8 mg
Hydrochloric acid / sodium hydroxide pH 6.0
―――――――――――――――――――――――――――――――――――
The total volume is 2.0 mL with water for injection.

In the following, formulation examples of Solution I, Solution II, and Solution III are shown. As the comprehensive vitamin solution of the present invention, any of Solution I, Solution II, and Solution III of Formulation Example 1 and Formulation Example below is combined. However, it can also be set as the comprehensive vitamin solution of the present invention.

(Formulation example 2)
Solution II
Ascorbic acid 100 mg
Panthenol 15 mg
Biotin 0.1 mg
Sodium bisulfite 0.3 mg
Sodium bicarbonate pH 6.0
――――――――――――――――――――
The total volume is 2.0 mL with water for injection.

(Formulation example 3)
Solution III
Retinol palmitate 4000 IU
Tocopherol acetate 15 mg
Menatetrenone 2.0 mg
Ergocalciferol 400 IU
Cyanocobalamin 0.01 mg
Folic acid 0.4 mg
Polysorbate 80 50 mg
Polyoxyethylene polyoxypropylene glycol 10 mg
Sodium dihydrogen phosphate / anhydrous 0.8 mg
Hydrochloric acid / sodium hydroxide pH 6.0
――――――――――――――――――――――――――――――――
The total volume is 2.0 mL with water for injection.

(Formulation example 4)
Solution I
Thiamine hydrochloride 2.5 mg
Pyridoxine hydrochloride 2.5 mg
Nicotinamide 20 mg
Riboflavin phosphate 2.5 mg
Hydrochloric acid pH 3.5
―――――――――――――――――――――
Total volume of 1.0 mL with water for injection.

(Formulation example 5)
Solution II
Ascorbic acid 50 mg
Panthenol 7.5 mg
Biotin 0.05 mg
Sodium bisulfite 0.15 mg
Sodium hydroxide pH 6.0
――――――――――――――――――――――
Total volume of 1.0 mL with water for injection.

(Formulation Example 6)
Solution III
Vitamin A oil 2000 IU
Tocopherol acetate 7.5 mg
Menatetrenone 1.0 mg
Cholecalciferol 200 IU
Cyanocobalamin 0.005 mg
Folic acid 0.2 mg
Polyoxyethylene hydrogenated castor oil 60 25 mg
Polyoxyethylene polyoxypropylene glycol 5.0 mg
Sodium dihydrogen phosphate / anhydrous 0.4 mg
Hydrochloric acid / sodium hydroxide pH 6.0
―――――――――――――――――――――――――――――――――――
Total volume 1.0 mL with water for injection

Claims (8)

An aqueous solution formulation consisting of the following solution I, solution II and solution III in which 13 kinds of essential vitamins are separated and filled in three sealed containers, wherein solution I is adjusted to pH 4 or lower and solution II is adjusted to pH 4-8 The solution III is adjusted to pH 5-8, and the fat-soluble vitamin contained in the solution III is solubilized by a surfactant.
Solution I: Vitamin B1
Vitamin B2,
Vitamin B6 and
Nicotinic acids,
Solution II:
Vitamin C,
Vitamin H and
Pantothenic acid,
Solution III:
Vitamin A,
Vitamin E,
Vitamin K,
Vitamin D,
Vitamin B12 and
Folic acid. The multivitamin solution according to claim 1, wherein the solution I, the solution II, and the solution III have the following composition ranges:
Solution I: Vitamin B1 1-10 mg
Vitamin B2 1-10mg
Vitamin B6 1-10mg
Nicotinic acids 10-50mg
Solution II:
Vitamin C 25-200mg
Vitamin H 0.01-0.5mg
Pantothenic acid 1-30mg
Solution III:
Vitamin A 1000-5000 IU
Vitamin E 5-30mg
Vitamin K 0.5-5mg
Vitamin D 50-1000 IU
Vitamin B12 0.001-0.05mg
Folic acid 0.1-1 mg.   The total vitamin liquid preparation according to claim 1 or 2, wherein a filling amount of each of the solution I, the solution II, and the solution III into the three sealed containers is 0.5 mL to 5 mL.   The comprehensive vitamin solution according to any one of claims 1 to 3, further comprising an antioxidant in the solution II.   The multivitamin solution according to claim 4, wherein the antioxidant is sodium bisulfite.   The comprehensive vitamin solution according to any one of claims 1 to 5, further comprising a pH buffer in the solution III.   The comprehensive vitamin liquid composition according to claim 6, wherein the pH buffer is sodium hydrogen phosphates. The total vitamin solution according to any one of claims 1 to 7, wherein heat sterilization is performed in a state where the three sealed containers are filled with the solution I, the solution II, and the solution III, respectively.