JPH0585930A - Lyophilized preparation of vitamin - Google Patents

Abstract

PURPOSE:To obtain a lyophilized preparation of vitamin useful for high-calorie fusion therapy, having excellent stability in long-term preservation and clarity in redissolution. CONSTITUTION:A lyophilized preparation comprising an essential vitamin surfactant, especially polyoxyethylene sorbitan fatty acid-based surfactant and inositol as a stabilizer is prepared. A water-soluble vitamin and inositol are dissolved in water for injection and adjusted to pH4.5-5.5 by adding a pH adjuster such as sodium hydroxide. Separately, water for injection is added to a liposoluble vitamin and a surfactant to prepare a liposoluble vitamin-solubilized solution. Both the solutions are blended, further mixed with water for injection, filtered, sterilized, itemized into vials, lyophilized and sealed to give a lyophilized preparation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a freeze-dried vitamin preparation used for high-calorie infusion therapy.

[0002]

2. Description of the Related Art High-calorie infusion therapy (total parenteral nutrition, hereinafter T)
(Referred to as PN) is, for example, a calorie source, protein source, vitamin, trace element, etc. necessary for maintaining the metabolism in the living body of a patient who can not take any nutrition (or almost) orally or enterally. The purpose of this study is to improve the nutritional status of patients under pathophysiology by instilling a high-calorie infusion containing the above nutrients with a catheter placed in a central vein.
In patients undergoing TPN, essential vitamins cannot be obtained orally. Therefore, multivitamin preparations containing various essential vitamins are added to a high-calorie infusion solution and intravenously injected to obtain in-vivo vitamins. We must try to maintain and improve the kind. On the other hand, the multivitamin preparations used for TPN contain all essential vitamins in one preparation due to the fact that some vitamins interact with each other and the stable pH range of each vitamin is different. Was hard to get. Therefore, in consideration of the interaction between vitamins and the compounding stability, some of them are formulated as a kit product divided into a plurality of containers of 3 to 5 agents (Japanese Patent Publication No. 63-28892, Japanese Patent Publication No. 1-33087).
issue). However, in order to simplify the procedure and operation of adding to high-calorie infusion solutions to reduce the chance of bacterial contamination and contamination with foreign substances, and to rationalize the storage of preparations and preparation work, it is necessary to reduce the number of resolving agents as much as possible. Desirably, for this reason, all essential vitamins are ideally combined in the same formulation. Therefore, there has been a problem to develop a single-dose comprehensive vitamin preparation in which all essential vitamins can be filled in one container and the stability of each vitamin is guaranteed.

On the other hand, since vitamins are water-soluble and fat-soluble, it is necessary to homogenize them by adding a surfactant as an emulsifying agent or a solubilizing agent in order to make them one agent. In addition, some vitamins have unstable properties in solution, so after adding a surfactant such as polyoxyethylene hydrogenated castor oil to the vitamins to homogenize it, it is added to maintain stability. It is necessary to stabilize vitamins by adding a excipient and preparing a freeze-dried solid formulation. It has already been attempted to make a multivitamin preparation into a single preparation by this method. For example, Japanese Patent Publication No. 3-3752
No. 1 is dextran, hydroxyethyl starch,
Disclosed is a stable intravenous multivitamin preparation characterized in that at least one selected from the group consisting of gelatin and reducing sugars is added to a vitamin containing nine water-soluble essential vitamins. Further, JP-A-61-207327 describes a mixed vitamin freeze-dried preparation containing a fat-soluble vitamin containing dextran or sucrose as an excipient.

However, a lyophilized preparation prepared by using dextran or sucrose as an excipient has a candy-like lyophilized cake when preserved at high temperature, and has an unfavorable appearance as a medicine. Furthermore, side effects such as spleen enlargement were also observed in animal experiments using rats, which is not preferable from the viewpoint of safety. In addition, a formulation obtained by adding an excipient for stabilization to a solution in which a fat-soluble vitamin is solubilized with polyoxyethylene hydrogenated castor oil and freeze-drying causes turbidity or coloration of the solution when re-dissolved, Alternatively, there is a problem that the time from the addition of the solution to a clear solution is extended. Therefore, a comprehensive vitamin freeze-dried preparation containing no polyoxyethylene hydrogenated castor oil as a solubilizing agent or further containing a polyoxypropylene condensation-type nonionic surfactant and / or phospholipid is used. The proposed method (Japanese Patent Laid-Open No. 62-38) has the drawback that it cannot withstand long-term storage because it does not contain the excipients necessary for maintaining stability. Further, in JP-A-63-310815, coloring of a redissolved solution containing at least one selected from cysteine, formaldehyde sulfoxylate or salts of these compounds, and sulfite as a coloring stabilizer is described. An example of an improved multivitamin lyophilized formulation is disclosed, which
No special attention is paid to the decrease in the content of each component during long-term storage.

Several methods have been proposed to solve these problems. For example, JP-A-63-3137
No. 36, polyoxyethylene hydrogenated castor oil derivative,
It is said that the inclusion of the excipient and the polyhydric alcohol makes it possible to obtain a comprehensive vitamin freeze-dried preparation which is excellent in stability, appearance, and resolubility. In addition, JP-A 1-1
No. 32514 describes a multivitamin lyophilized formulation containing at least 9 water-soluble essential vitamins and basic amino acids to solve these problems. However, intravenous injection of polyoxyethylene hydrogenated castor oil is known to cause shock symptoms, and it is not preferable to use a preparation containing this as a pharmaceutical. Further, a preparation containing a basic amino acid may be colored during long-term storage. Thus, none of the conventional freeze-dried multivitamin preparations has achieved both stability during long-term storage and clarity during reconstitution.

[0006]

Therefore, the present inventors have
As a result of intensive research aimed at obtaining a freeze-dried preparation of vitamins with long-term stability guaranteed, no change in the appearance of freeze-dried cakes, and excellent clarity when re-dissolved, the results showed that essential vitamins and surfactants, especially It has been found that these objectives can be achieved by incorporating a polyoxyethylene sorbitan fatty acid ester-based surfactant and inositol as a stabilizer into a freeze-dried preparation.

The vitamin used in the present invention is not particularly limited, and conventionally known vitamins can be widely used. For example, vitamin B ₁ (thiamine hydrochloride, thiamine nitrate, etc.),
Vitamin B ₂ (sodium riboflavin phosphate, flavin adenine dinucleotide, etc.), Vitamin B ₆ (pyridoxine hydrochloride, pyridoxine phosphate, pyridoxamine phosphate, pyridoxal phosphate, etc.), vitamin B ₁₂ (cobamide, hydroxocobalamin acetate, cyanocobalamin, etc.)
Mecobalamin etc.), nicotinic acid (nicotinic acid, nicotinic acid amide etc.), folic acid, biotin, vitamin C (ascorbic acid etc.), pantothenic acid (calcium pantothenate,
Panthenol), Vitamin A (Retinol palmitate, Retinol acetate, Dehydroretinol, etc.), Vitamin D (Ergocalciferol, Cholecalciferol, etc.), Vitamin E (Tocopherol acetate, etc.), Vitamin K (Phytonadione, Menatetrenone, Menadione, etc.) ) And the like. The amount of these vitamins to be added is not particularly limited and can be selected from a wide range, but it is desirable that the amount can satisfy the daily requirement of human beings. Vitamin B ₁ is 2.5 to 5 mg, vitamin B _{1 2} is 2.5
To 5 mg, Vitamin B ₆ is 1.5 to 5 mg, Vitamin B ₁₂ is 0.005-0.05, nicotinic acid 10 to 40 mg, folic acid 0.4～1.5Mg, biotin is 0.05 to 0. 5 mg, vitamin C 50-250 mg, pantothenic acid 5-20 m
g, Vitamin A is 1250 to 4000 IU, Vitamin D
Is particularly preferable in the range of 100 to 400 IU, vitamin E in the range of 3 to 15 mg, and vitamin K in the range of 0.1 to 2 mg. Table 1 shows examples of specific components and blending amounts thereof. Table 1 Vitamin compounding amount Vitamin B ₁ (thiamine hydrochloride) 5 mg Vitamin B ₂ (riboflavin sodium phosphate) 5 mg Vitamin B ₆ (pyridoxine hydrochloride) 3 mg Vitamin B ₁₂ (cyanocobalamin) 0.03 mg Nicotinamide 20 mg Folic acid 1 mg Biotin 0.0 2 mg Vitamin C (ascorbic acid) 100 mg Panthenol 12 mg Vitamin A (retinol palmitate) 2500 IU Vitamin D ₃ (cholecalciferol) 200 IU Vitamin E (tocopherol acetate) 15 mg Vitamin K ₂ (menatetrenone) 2 mg

The surfactant is a nonionic surfactant usually used for high calorie infusion preparations, preferably a polyoxyethylene sorbitan fatty acid ester surfactant, such as polysorbate 20 and polysorbate 4.
0, polysorbate 60, polysorbate 65, polysorbate 80 and the like. The amount used is 1 to 20 parts, preferably 2 to 10 parts, relative to the amount of fat-soluble vitamin. Inositol has nine stereoisomers (cis, e
pi, allo, neo, myo (or meso), muco, scyllo, D (+)
And L (−)-inositol) are present, but either may be used or a mixture thereof. Normally,
Use myo-inositol. The amount used is 0.5-10 parts, preferably 1 part, with respect to the amount of fat-soluble vitamins.
~ 5 parts. It is known that inositol has an anti-lipid liver action as one of the vitamin B groups, but the amount used is usually 0.5 to 2 g per day, and the isomer having this action is myo-inositol. Is. Generally, water-soluble vitamins are vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₁₂ , nicotinamide, folic acid, biotin, vitamin C and pantothenic acid, and fat-soluble vitamins are vitamin A, vitamin D, It is considered to be Vitamin E and Vitamin K. Further, an inorganic salt such as magnesium chloride which is usually added to a freeze-dried preparation can be appropriately used.

The preparation of the present invention can be produced by a conventional method for producing a freeze-dried preparation. That is, water-soluble vitamins and inositol are dissolved in water for injection, and a pH adjusting agent such as sodium hydroxide is added to adjust the pH to 4.5 to 5.5. Separately, a fat-soluble vitamin and a surfactant, for example, a polyoxyethylene sorbitan fatty acid ester-based surfactant is taken and water for injection is added to prepare a fat-soluble vitamin solubilized solution. Both solutions thus obtained are mixed, water for injection is further added thereto, and the mixture is sterilized by filtration, divided into vials, freeze-dried and then sealed.

Next, the present invention will be described based on Examples and Comparative Examples. Example 1 Of the components shown in Table 1, water-soluble vitamins are dissolved in water for injection. To this solution, add 50 mg of inositol and 5 mg of magnesium chloride, and use sodium hydroxide to adjust the pH.
Adjust to 5. On the other hand, 60 mg of fat-soluble vitamins and polysorbate 80 are taken, and water for injection is added to prepare a solubilized solution. After mixing both solutions, add water for injection to 2.5m
Let l. The obtained drug solution was sterilized by filtration, and the one filled in a vial was freeze-dried by a conventional method and then sealed with a rubber stopper to obtain a product of the present invention.

Example 2 A product of the present invention was obtained in the same manner as in Example 1 except that the amount of inositol added was 30 mg. Example 3 A product of the present invention was obtained by the same procedure as in Example 1 except that magnesium chloride was not added. Control Example 1 A control product was obtained in the same manner as in Example 1 except that inositol was not added. Control Example 2 A control product was obtained in the same manner as in Example 1 except that 50 mg of mannitol was used instead of adding 50 mg of inositol. Control Example 3 A control product was obtained in the same manner as in Example 1 except that 400 mg of mannitol was used instead of adding 50 mg of inositol. Control Example 4 A control product was obtained in the same manner as in Example 1 except that 30 mg of histidine hydrochloride was used instead of adding 50 mg of inositol. Control Example 5 A control product was obtained in the same manner as in Example 1 except that 50 mg of glucose was used instead of adding 50 mg of inositol.

Test Example 1 After storing the multivitamin preparations obtained in Example 1, Example 3 and Control Example 1 at 15 ° C. for 6 months, the content of each vitamin was measured by a conventional method. The results are shown in Table 2. Table 2 Residual Rate (%) * Vitamin Example 1 Example 3 Control Example 1 Vitamin B ₁ (thiamine hydrochloride) 98.1 97.6 92.0 Vitamin B ₂ (riboflavin sodium phosphate) 99.8 99.2 85 .4 Vitamin B ₆ (pyridoxine hydrochloride) 99.2 98.8 96.3 Vitamin B ₁₂ (cyanocobalamin) 99.5 96.8 95.8 Nicotinamide 99.7 99.0 93.5 Folic acid 98.6 97.2 84.5 Bithion 99.7 99.5 98.6 Vitamin C (ascorbic acid) 99.8 98.6 83.8 Panthenol 99.0 96.3 79.9 Vitamin A (retinol palmitate) 98 .6 98.1 85.0 Vitamin D ₃ (cholecalciferol) 98.2 99.5 98.0 Vitamin E (tocopherol acetate) 99.3 98.7 92.8 Vitamin K ₂ (menatetrenone) 97.1 95 .1 72.7 *: Made Remaining rate when the content at the time of manufacture is 100.

Test Example 2 Immediately after production, the vitamin preparations obtained in Examples and Controls were stored at 4 ° C. for 6 months and at 40 ° C. for 3 months, and the appearance of the freeze-dried cake and the solubility of the redissolved solution were observed. .. The results are shown in Tables 3-5. Table 3 Appearance of the dissolved cake of the re-dissolved solution that was lyophilized immediately after production 1) Color 2) Clarity 3) Transmittance 4) Example 1 good yellow-97% Example 2 good yellow-98% Example 3 good Yellow-95% Control Example 1 Poor Yellow-97% Control Example 2 Poor White turbidity ++ 33% Control Example 3 Slight Poor Yellow-95% Control Example 4 Good Yellow-97% Control Example 5 Good Yellow White + 69% Table 4 4 ° C , 6 months Storage of lyophilized redissolved solution Appearance of cake 1) Color 2) Clarity 3) Transmittance 4) Example 1 good yellow-97% Example 2 good yellow-97% Example 3 good yellow- 93% Control Example 1 Poor white turbidity ++ 40% Control Example 2 Poor white turbidity ++ 15% Control Example 3 Slightly poor yellow-91% Control Example 4 Good yellow-90% Control Example 5 Good white turbidity + 47% Table 5 40 ° C, 3 months Storage of freeze-dried redissolved solution Appearance of cake 1) 2) Clarity 3) Transmittance 4) Example 1 good yellow-87% Example 2 good yellow-88% Example 3 good yellow-83% Control Example 1 bad yellow-82% Control Example 2 bad white turbidity +++ 25% Control Example 3 Somewhat poor Yellow ± 79% Control Example 4 Good Yellow Red ± 71% Control Example 5 Poor Yellow -80% 1) Good: No change. Slightly bad: The cake is uneven. Bad: The cake has a candy-like shape. 2) The color of the liquid dissolved by adding 5 ml of water for injection. 3) −: Clear. ±: Almost clear. +: Slightly cloudy. ++: Cloudy. ++: Strongly cloudy. 4) 640nm, 10mm cell, water control

[0014]

As is clear from Tables 2 to 5, the formulations of the present invention showed no decrease in the content of each component under any storage condition, and the appearance and the solubility of the re-dissolved solution were good. In the control example containing no inositol, a decrease in vitamin content was observed, and a deterioration in appearance and a decrease in clearness of the redissolved solution were observed. In addition, in the control examples containing additives other than inositol, in all cases, the appearance and the solubility of the redissolved solution were significantly changed.
Furthermore, it was found that the addition of magnesium chloride slightly improved the residual rate. As in the present invention, by adding a polyoxyethylene sorbitan fatty acid ester-based surfactant and inositol to a vitamin and preparing a freeze-dried preparation, the vitamin content does not decrease even during long-term storage, and the appearance during storage As a result, a freeze-dried multivitamin preparation for TPN having excellent clarity of the re-dissolved solution was obtained.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kenji Tateiwa 2-30-3 Morinomiya Morinomiya, Joto-ku, Osaka-shi, Osaka Prefecture, Research & Development Center, Fuso Pharmaceutical Co., Ltd. (72) Shogo Tokuoka Morinomiya, Joto-ku, Osaka-shi, Osaka Prefecture 2 to 3-30 Fuso Yakuhin Kogyo Co., Ltd. R & D Center

Claims (2)

[Claims] 1. A freeze-dried vitamin preparation for high-calorie infusion, which contains inositol as a stabilizer and a surfactant. 2. The freeze-dried vitamin preparation according to claim 1, wherein the surfactant is a polyoxyethylene sorbitan fatty acid ester-based surfactant.