JP2614956B2 - Vitamin freeze-dried preparation - Google Patents

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 for use in high-calorie infusion therapy.

[0002]

2. Description of the Related Art High parenteral nutrition (hereinafter referred to as T)
PN) is, for example, for patients who cannot take (or hardly) nourish orally or enterally, calorie sources, protein sources, vitamins, trace elements, etc. necessary to maintain metabolism in the body The purpose of this study is to improve the nutritional status of patients under pathophysiology by intravenously infusing a high-calorie infusion containing nutrients from a catheter placed in the central vein.
In patients undergoing TPN, essential vitamins cannot be obtained orally. Therefore, by adding a multivitamin containing various essential vitamins to a high-calorie infusion solution and intravenously injecting the same, vitamins in vivo can be obtained. We need to maintain and improve the kind. On the other hand, multi-vitamin preparations used for TPN include those that cause interaction between vitamins, and because the stable pH range of each vitamin is different, a preparation containing all essential vitamins in one preparation Was difficult to get. In view of the above, in consideration of the interaction between vitamins and the stability of blending, there is a product which is formulated as a kit product divided into a plurality of containers of three to five agents (JP-B-63-28892, JP-B-1-33087).
issue). However, in order to simplify the procedures and operations for adding high-calorie infusions to reduce the chance of bacterial contamination and contamination, and to streamline the storage and preparation of the drug product, the number of splitting agents should be as small as possible. Desirably, for that, ideally all essential vitamins are formulated in the same formulation. Therefore, the development of a single-drug multivitamin preparation in which all essential vitamins can be filled in one container and the stability of each vitamin is guaranteed has been an issue.

[0003] On the other hand, vitamins are water-soluble and fat-soluble. Therefore, it is necessary to homogenize vitamins by adding a surfactant as an emulsifier or a solubilizer in order to combine them into one. In addition, some vitamins have instability in solution, so after adding a surfactant such as polyoxyethylene hydrogenated castor oil to the vitamin and homogenizing it, activate it to further maintain stability. It is necessary to stabilize vitamins by adding a fixative and making a freeze-dried solid preparation. Attempts have been made to combine multivitamin preparations by this method. For example, Japanese Patent Publication 3-3752
No. 1 includes dextran, hydroxyethyl starch,
There has been disclosed a stable intravenous multivitamin preparation characterized by adding at least one selected from the group consisting of gelatin and reducing sugar to a vitamin containing nine water-soluble essential vitamins. JP-A-61-207327 describes a freeze-dried mixed vitamin-containing vitamin-containing preparation containing dextran or sucrose as an excipient.

[0004] However, a freeze-dried preparation using dextran or sucrose as an excipient, when stored at a high temperature, turns the freeze-dried cake into a candy-like appearance, which gives an undesirable appearance as a pharmaceutical. Furthermore, side effects such as spleen hypertrophy have been 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 obtained by solubilizing a fat-soluble vitamin with polyoxyethylene hydrogenated castor oil and freeze-drying causes turbidity and coloration of the solution when redissolved, Alternatively, there is a problem in that the time from the addition of the dissolving solution until the solution becomes clear becomes longer. Therefore, polyoxyethylene hydrogenated castor oil containing no excipient is used as a solubilizing agent, and further, a general vitamin freeze-dried preparation containing a polyoxypropylene condensed nonionic surfactant and / or a phospholipid is used. Proposed (JP-A-62-38) has the drawback that it does not contain excipients necessary for maintaining stability and cannot withstand long-term storage. JP-A-63-310815 discloses the coloring of a re-dissolved solution containing at least one selected from cysteine, formaldehyde sulfoxylate or salts of these compounds, and sulfites as a color stabilizer. Examples of improved multi-vitamin lyophilized formulations are disclosed,
No special attention is paid to the reduction in the content of each component during long-term storage.

[0005] Several methods have been proposed to solve these problems. For example, JP-A-63-3137
No. 36 includes a polyoxyethylene hydrogenated castor oil derivative,
It is stated that by containing an excipient and a polyhydric alcohol, a freeze-dried multivitamin preparation having good stability, appearance and resolubility can be obtained. In addition, Japanese Patent Laid-Open No. 1-1
No. 32514 states that a multivitamin lyophilized formulation containing at least 9 water-soluble essential vitamins and basic amino acids solves these problems. However, intravenous injection of polyoxyethylene hydrogenated castor oil is known to cause shock symptoms, and it is not preferable to use a formulation containing this as a pharmaceutical. In addition, a preparation containing a basic amino acid may be colored during long-term storage. As described above, no freeze-dried multivitamin preparation has been obtained that achieves both stability during long-term storage and clarity during reconstitution.

[0006]

Means for Solving the Problems Accordingly, the present inventors have:
Long-term stability is guaranteed, there is no change in the appearance of the freeze-dried cake, and as a result of earnest research to obtain a vitamin freeze-dried preparation with excellent clarity at the time of re-dissolution, surfactants are required for essential vitamins, especially surfactants It has been found that these objects can be achieved by incorporating a polyoxyethylene sorbitan fatty acid ester surfactant and inositol as a stabilizer into a lyophilized formulation.

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 (riboflavin sodium phosphate, flavin adenine dinucleotide, etc.), vitamin B ₆ (pyridoxine hydrochloride, pyridoxine phosphate, pyridoxamine phosphate, pyridoxal phosphate, etc.), vitamin B ₁₂ (cobamide, hydroxocobalamin acetate, cyanocobalamin,
Nicotinic acid (nicotinic acid, nicotinamide, etc.), folic acid, biotin, vitamin C (ascorbic acid, etc.), pantothenic acid (calcium pantothenate,
Vitamin A (such as retinol palmitate, retinol acetate, dehydroretinol), vitamin D (such as ergocalciferol, cholecalciferol), vitamin E (such as tocopherol acetate), vitamin K (phytonadione, menatetrenone, menadione, etc.) ). The amount of these vitamins are selected from particularly restricted broad range, it is desirable that the amount capable of satisfying the daily requirement of human, vitamin B ₁ is 2.5-5 mg, vitamin B 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 0.05 to 0. 5mg, 50-250mg for vitamin C, 5-20m for pantothenic acid
g, vitamin A is 1250-4000 IU, vitamin D
It is particularly desirable that the amount is within the range of 100 to 400 IU, the amount of vitamin E is 3 to 15 mg, and the amount of vitamin K is 0.1 to 2 mg. Table 1 shows examples of the specific components and amounts. Table 1 Vitamin amount vitamin B ₁ (thiamine hydrochloride) 5 mg vitamin B ₂ (sodium riboflavin phosphate) 5 mg vitamin B ₆ (pyridoxine hydrochloride) 3 mg Vitamin B ₁₂ (cyanocobalamin) 0.03 mg nicotinamide 20mg leaf acid 1mg biotin 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 in high-calorie infusion preparations, preferably a polyoxyethylene sorbitan fatty acid ester surfactant, such as polysorbate 20, polysorbate 4 or the like.
0, polysorbate 60, polysorbate 65, polysorbate 80 and the like. The amount used is 1 to 20 parts, preferably 2 to 10 parts, based on the amount of fat-soluble vitamin. Inositol has nine stereoisomers (cis, e)
pi, allo, neo, myo (or meso), muco, scyllo, D (+)
And L (-)-inositol), any of which may be used or a mixture thereof. Normally,
Use myo-inositol. Further, the amount used is 0.5 to 10 parts, preferably 1 to 10 parts, based on the amount of fat-soluble vitamin.
~ 5 parts. Inositol is known to have an anti-fatty liver activity as one of the vitamin B groups, but its usage is usually 0.5 to 2 g per day, and the isomer having this activity is myo-inositol It is. Generally, the 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 the fat-soluble vitamins are vitamin A, vitamin D, It is believed to be vitamin E and vitamin K. In addition, an inorganic salt such as magnesium chloride 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, the water-soluble vitamins and inositol are dissolved in water for injection, and the pH is adjusted to 4.5 to 5.5 by adding a pH adjuster such as sodium hydroxide. Separately, a fat-soluble vitamin and a surfactant, for example, a polyoxyethylene sorbitan fatty acid ester-based surfactant are taken, and water for injection is added to prepare a fat-soluble vitamin solubilized solution. The two solutions thus obtained are mixed, further added with water for injection, sterilized by filtration, divided into vials, freeze-dried, and sealed.

Next, the present invention will be described based on Examples and Comparative Examples. Example 1 Among the components shown in Table 1, water-soluble vitamins are dissolved in water for injection. To this solution was added 50 mg of inositol and 5 mg of magnesium chloride, and the pH was adjusted using sodium hydroxide.
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
l. The resulting drug solution was sterilized by filtration, filled in a vial, freeze-dried by a conventional method, and then sealed with a rubber stopper to obtain the 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 in the same manner as in Example 1 except that no magnesium chloride was added. Comparative Example 1 A control product was obtained in the same manner as in Example 1, except that inositol was not added, except for the above. 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 The multivitamin preparations obtained in Example 1, Example 3 and Control Example 1 were stored at 15 ° C. for 6 months, and then the content of each vitamin was measured by a conventional method. Table 2 shows the results. 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 (sodium riboflavin 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 Biotin 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 Percentage remaining 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 dissolution of the re-dissolved solution were observed. . The results are shown in Tables 3 to 5. Table 3 Solution of freeze-dried redissolved solution immediately after production Appearance of cake 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 cloudiness ++ 33% Control Example 3 Slightly poor Yellow -95% Control Example 4 Good Yellow -97% Control Example 5 Good Yellow White + 69% Table 4 4 ° C. Stored for 6 months, freeze-dried solution of 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 cloudiness ++ 40% Control Example 2 Poor cloudiness +++ 15% Control Example 3 Slightly poor yellow-91% Control Example 4 Good Yellow-90% Control Example 5 Good Cloudy + 47% Table 5 40 ° C, 3 months Storage Lyophilized 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 Poor Yellow -82% Control Example 2 Poor Cloudiness +++ 25% Control Example 3 Slightly poor yellow ± 79% Control Example 4 Good Yellow-red ± 71% Control Example 5 Poor Yellow -80% 1) Good: No change. Somewhat poor: Cake becomes uneven. Bad: The cake looks candy-like. 2) Color of the solution 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 preparations of the present invention did not show any decrease in the content of each component in any of the storage conditions, and had good appearance and dissolved state of the re-dissolved solution. In the control example containing no inositol, a decrease in the vitamin content was observed, and a deterioration in the appearance and a decrease in the clarity of the re-dissolved solution were observed. Further, in the control examples containing additives other than inositol, remarkable changes occurred in the appearance and the dissolution state of the re-dissolved liquid in each case.
It was further found that the addition of magnesium chloride slightly improved the residual ratio. As in the present invention, by adding a polyoxyethylene sorbitan fatty acid ester-based surfactant and inositol to vitamins to prepare a freeze-dried preparation, the vitamin content does not decrease even during long-term storage, and the appearance during storage And a freeze-dried preparation of a total vitamin for TPN having excellent clarity of the re-dissolved solution.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Kenji Tateiwa 2-3-3 Morinomiya, Joto-ku, Osaka-shi, Osaka Fuso Pharmaceutical Co., Ltd. R & D Center (72) Inventor Shogo Tokuoka Joto-ku, Osaka-shi, Osaka Morinomiya 2-3-30, Fuso Pharmaceutical Co., Ltd. R & D Center

Claims (2)

(57) [Claims] 1. A freeze-dried vitamin preparation for high caloric infusion, comprising 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.