JPH0778020B2 - Stable multivitamin freeze-dried preparation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a freeze-dried preparation of a multivitamin suitable for addition to a high calorie infusion applied to a patient who cannot ingest nutritionally orally after surgery.

[Conventional technology]

In recent years, nutritional management for patients who cannot ingest nutrition after surgery etc. has improved dramatically with the development of high calorie infusion therapy by central parenteral nutrition, and various essential vitamins should be added to this high calorie infusion. Is becoming common sense.

For this reason, multivitamin preparations added to high-calorie infusions have also been developed in various forms. The performance required for the formulation of this multivitamin is that the vitamin in the formulation is effectively and safely administered to the human body. Convenience in use is important to minimize bacterial contamination in the preparation of calorie infusions. Since many vitamins are unstable themselves and there are many combinations that become more unstable when vitamins are mixed together, multivitamins take into consideration the stability of the combination of these vitamins. It is being divided into containers and formulated. (JP-A-56-77222, JP-A-5
However, in order to improve the convenience of use, it is desirable to reduce the number of containers for the formulation as much as possible. Attempts have been made to stabilize multivitamins for the purpose of ease of use (JP-A-59-15).
2327, JP-A-61-207327). That is, in order to combine vitamin groups of combinations that become unstable in formulation and to formulate them, an excipient is added and freeze-dried to stabilize the vitamins.

[Problems to be solved by the invention]

However, in these formulations, the effect is insufficient although the stability of vitamin content is improved. In particular, in terms of storage stability, the appearance of the freeze-dried solid state was not significantly changed, but the color of the redissolved solution was significantly different from that immediately after production, and was unusable.

[Means for solving problems]

Therefore, as a result of intensive studies aimed at stabilizing a multivitamin preparation, the present inventors have found that at least one selected from the group consisting of cysteine, formaldehyde sulfoxylate (longarit) or salts of these compounds, and sulfites. The present invention has been completed by finding that the color stability after re-dissolving is improved by adding the lactic acid to a multivitamin and freeze-drying.

The vitamin used for the multivitamin is not particularly limited and may be a conventionally known one. For example, the water-soluble vitamins Vitamin _{B 1, B 2, B 6} , B 12, folic acid, nicotinic acid or nicotinic acid amide, pantothenic acid or pantothenyl alcohol, such as biotin and vitamin C. Further, fat-soluble vitamins obtained by adding an appropriate solubilizing agent to these vitamins may be added. Vitamins A, D, and E for fat-soluble vitamins
And / or vitamin K. The amount of these vitamins to be added is not particularly limited, but it is preferable to add an amount close to an amount that can supplement the daily intake required by humans. As an example of the amount of each vitamin compounded, vitamins
B ₂ 1-10mg, vitamin B ₆ 1-10mg, 5-25m pantothenic acid
g, vitamin C50-250mg, vitamin B ₁ 1-10mg, vitamin
B ₁₂ 1-30μg, folic acid 100-1000μg, biotin 20-300μ
g, nicotinic acid 10-50mg, vitamin A2000-5000IU, vitamin D200-1000IU, vitamin E5-20IU, vitamin K0.2
It is desirable to be blended at a ratio of -10 mg.

Table 1 shows specific examples of the blending amount.

Examples of the cysteine salt used in the present invention include hydrochloride, sulfate, phosphate and the like. Examples of the salt of formaldehyde sulfoxylate include Na salt and K salt.

Examples of the sulfite include sodium hydrogen sulfite, sodium sulfite, potassium hydrogen sulfite, potassium sulfite and the like.

The amount of the color stabilizer to be added is 0.5 to 10%, preferably 1 to 7% of the total amount of vitamins for cysteine (as free), and 0.2 to 3% for formaldehyde sulfoxylate (as free), preferably 0.5. ~ 2
%, 0.1 to 2% for sulfite, preferably 0.5 to 1
%. It is desirable that the amount of these stabilizers is increased or decreased in accordance with the type and amount of vitamins to be added.

Further, an excipient may be added to prepare a freeze-dried preparation.
As the excipient, sugar alcohols such as mannitol, lactose, monosaccharides such as maltose, oligosaccharides, amino acids such as histidine and arginine, and polymers such as chondroitin sulfate and dextran are used. The amount used is 0.1 to 3 times, preferably 0.3 to 2.5 times, the total amount of vitamins mixed. When adding a fat-soluble vitamin, it is necessary to use a solubilizing agent, and for example, polysorbate 80 or polyoxyethylene hydrogenated castor oil can be used. By using the solubilizer in an amount of 3 to 10 times that of the fat-soluble vitamin, a clear solution can be obtained when the freeze-dried preparation is redissolved.

The preparation of the present invention can be produced by a conventional method for producing an injection. That is, the water-soluble vitamin is dissolved in distilled water for injection, and after further dissolving the coloring stabilizer according to the present invention, the pH is adjusted to 4.5 to 6.5 with a pH adjuster such as sodium hydroxide to obtain a drug solution. . This drug solution is subdivided into containers and then freeze-dried to obtain a preparation. When a fat-soluble vitamin is further added, a mixture of the above drug and an aqueous solution of a fat-soluble vitamin solubilized with a surfactant may be subdivided into containers and freeze-dried. The concentration of the solid component in the drug solution is not particularly limited, but it is selected in consideration of the solubility of vitamins and excipients, the solubility of freeze-dried preparations, the difficulty and efficiency of freeze-drying. That is, if the concentration is too high, the solubility during preparation of the drug solution and the re-solubility due to crystal precipitation during freeze-drying will decrease, and if it is too thin, the water content to be removed will be small and the drying efficiency will decrease. Inspire. In the range of the amount of vitamins to be mixed in the present invention, it is desirable that the solid content is contained in 1 to 10 ml.

〔The invention's effect〕

The sample group prepared according to the present invention and the sample prepared without adding the color stabilizer as a control were stored under the condition of 50 ° C., and the appearance change of the preparation and the solubility and color of the redissolved solution were observed. The composition of the sample is as shown in Examples and Controls. The results are shown in Table 2. There was no change in appearance during storage with both the sample group according to the present invention and the control example, but after storage for 10 days,
The appearance of the redissolved solution became a brown solution in the control example, and a remarkable change was observed. On the other hand, in the sample of the present invention, the solution was pale yellow to yellow even after 30 days and almost no change was observed.

Example 1 Water-soluble vitamins are dissolved in distilled water for injection according to the amounts of vitamins shown in Table 1. To this solution, 2 mg of cysteine hydrochloride as a color stabilizer and 30 mg of lactose as an excipient are added and dissolved. A fat-soluble vitamin is solubilized in distilled water for injection using 60,80 mg of polyoxyethylene hydrogenated castor oil to form an aqueous solution. The two liquids were mixed and the pH was adjusted to about 5.5 with sodium hydroxide to make the total amount 3 ml. The obtained drug solution was filled in a vial, freeze-dried, and then a rubber stopper was attached to obtain a product of the present invention.

Example 2 In Example 1, 1 mg of cysteine hydrochloride was used instead of 2 mg.
Maltose was replaced by 30 mg instead of 0 mg and lactose by 30 mg, and otherwise the same operation as in Example 1 was carried out to obtain the product of the present invention.

Example 3 In Example 1, 1 mg of cysteine hydrochloride was used instead of 2 mg.
Maltose was replaced by 0 mg, lactose by 30 mg instead of maltose by 100 mg, polyoxyethylene hydrogenated castor oil 60 by 80 mg instead of polysorbate 80 by the same procedure as in Example 1, except that
The product of the present invention was obtained.

Example 4 A product of the present invention was obtained in the same manner as in Example 1 except that cysteine hydrochloride was replaced with 2 mg and rongalit was replaced with 1 mg.

Example 5 In Example 1, 1 mg of longaritus instead of 2 mg of cysteine hydrochloride, 100 mg of maltose instead of 30 mg of lactose, 80 mg of polyoxyethylene hydrogenated castor oil 60 instead of 80 mg of polysorbate 80, and others The same operation as in Example 1 was carried out to obtain the product of the present invention.

Example 6 A product of the present invention was obtained by the same procedure as in Example 1 except that cysteine hydrochloride was replaced by 2 mg and sodium sulfite was 0.3 mg.

Example 7 In Example 1, instead of 2 mg of cysteine hydrochloride, 1 mg of sodium sulfite hydrate, 200 mg of mannitol instead of 30 mg of lactose, polyoxyethylene hydrogenated castor oil 6
Polysorbate 80 was replaced with 80 mg instead of 80 mg, and the same operation as in Example 1 was carried out otherwise to obtain the product of the present invention.

Control Example A control product was obtained in the same manner as in Example 1 except that cysteine hydrochloride was not added.

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Claims (1)

[Claims] 1. A comprehensive vitamin freeze-dried preparation containing at least one selected from cysteine, formaldehyde sulfoxylate or salts of these compounds, and sulfite as a color stabilizer.