JPH03279324A - Fat-soluble vitamin injection - Google Patents

Abstract

PURPOSE:To obtain the title injection being stable to steam sterilization and stable to long-term preservation by blending a vitamin with polyoxyethylene sorbitan fatty acid esters used as a solubilizing agent and polyethyleneglycols and saccharides used as a solubilizing and stabilizing agent. CONSTITUTION:The aimed injection containing (A) 1000-5000 vitamin A unit vitamin A, 100-1000 IU vitamin D, 5-20 IU vitamin E and 0.2-10mg vitamin K used as fat-soluble vitamin, (B) 2-150 m M of at least one kind of compound selected from organic acids and inorganic acids and salts thereof used as buffers, (C) polyoxyethylenesorbitan fatty acid esters, preferably Polysorbate 20 (0.1-0.6 times based on the ingredient A) or Polysorbate 80 (1.6-3 times based on the ingredient A) used as a solubilizing agent and (D) 0.5-4W/V% polyethylene glycols, preferably of liquid and 2-8W/V% saccharide, preferably nonreducting sugar.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to fat-soluble vitamin injections, more particularly stable injections containing vitamin A, vitamin D, vitamin E and vitamin K, which are usually carried out especially for sterilization. This invention relates to an injectable solution that is stable against steam sterilization.

Conventional technology In recent years, nutritional management for patients who have difficulty taking nutrients orally after surgery, etc., has been carried out through high-calorie infusion therapy through central parenteral nutrition.With the development of this therapy, simultaneous administration of essential vitamins has become common practice. It is becoming more and more popular. For this reason, various forms of multivitamin preparations to be added to high-calorie infusions have been developed. However, due to their physicochemical properties, essential vitamins are broadly classified into fat-soluble vitamins and water-soluble vitamins, and fat-soluble vitamin hypervitaminosis is known as a side effect. It is considered desirable that the multivitamin supplement added to the above-mentioned high-calorie infusion be in a form in which fat-soluble vitamins and water-soluble vitamins are separated. The above-mentioned water-soluble vitamins do not require special consideration in terms of composition in order to be made into an aqueous composition as an injection.
Naturally, the use of some kind of solubilizer is essential for aqueous liquefaction of fat-soluble vitamins. Conventionally, polyoxyethylene hydrogenated castor oils and polyoxyethylene sorbitan fatty acid esters have been widely used as the solubilizer. However, in recent years polyoxyethylene hydrogenated castor oils have been suspected of causing anaphylactic shock symptoms when administered parenterally (The 1mformed Prescr.
iber Vol, l, No, 2. 91986
etc.), and there is a desire to change the composition of fat-soluble vitamin injections containing polyoxyethylene hydrogenated castor oils as solubilizers to other safer solubilizers.

Problems to be Solved by the Invention The present inventors have conducted various studies on solubilizing agents that can replace polyoxyethylene hydrogenated castor oils, and have found that polyoxyethylene sorbitan fatty acid esters have high solubilizing power. We have successfully solubilized fat-soluble vitamins by using various polyoxyethylene sorbitan fatty acid esters. However, the cloud point of an aqueous solution of such a solubilizing agent is as low as 90 to 95°C, and a fat-soluble vitamin aqueous solution prepared using such a solubilizing agent must be heated above the cloud point in order to be sterilized for manufacturing injections. When heated to a temperature of
It became clear that the mixture became cloudy or separated into two layers. In addition, this cloud point tends to decrease with the addition of electrolytes, and when a buffer agent, which is usually added to stabilize the pH of injection solutions, is added,
Since the buffering agent is an electrolyte, the clouding point is lowered, and the temperature at which cloudiness or two-layer separation occurs tends to be lower than when the buffering agent is not included. Therefore, a fat-soluble vitamin aqueous solution containing polyoxyethylene sorbitan fatty acid esters as a solubilizing agent and 2-10 mM electrolyte as a buffer is stable at low temperatures, but becomes cloudy over time at temperatures above 30-50°C. Not only that, but in order to ensure that the solution is sterile as an injection solution, when steam sterilization is performed at a high temperature of 95°C or higher, it becomes cloudy or separates into two layers.
It became unusable as an injection solution.

Means for Solving the Problems The present inventors have conducted further intensive research with the aim of eliminating the white turbidity or two-layer separation that occurs when a fat-soluble vitamin aqueous solution containing a buffer is steam sterilized. However, by adding polyethylene glycols and saccharides as solubilization stabilizers to a fat-soluble vitamin aqueous solution containing polyoxyethylene sorbitan fatty acid esters as a solubilizing agent, it can be used for steam sterilization without cloudy or two-layered content. It was discovered that a desired injection solution that does not undergo physical changes such as separation and is stable for long-term storage can be obtained, and the present invention has now been completed.

That is, the present invention contains vitamin A, vitamin D, vitamin E, and vitamin K as fat-soluble vitamins, contains at least one selected from organic acids and salts thereof, and inorganic acids and salts thereof as a buffer, and a solubilizer. The invention relates to a fat-soluble vitamin injection characterized by containing polyoxyethylene sorbitan fatty acid esters as a solubilization stabilizer and polyethylene glycols and saccharides as a solubilization stabilizer.

The fat-soluble vitamins used in the fat-soluble vitamin injection of the present invention include vitamin A, vitamin D, vitamin E, and vitamin K. Although there are no particular limitations on the amounts and ratios of these vitamins, it is desirable that the amounts of each vitamin be sufficient to cover the daily requirements of a person. A specific example of the amount of each compound is 1000 to 500 for vitamin A.
0 vitamin A units, vitamin D 100-1000r
U.

5-20 IU for vitamin E, 0.
A desirable example is a range of 2 to 10 cm.

Examples of organic acids used as buffers in the present invention include citric acid, acetic acid, tartaric acid, maleic acid, fumaric acid, and glutamic acid, and examples of organic hydrochloric acids include their sodium salts and potassium salts.

Examples of inorganic acids include phosphoric acid, and examples of inorganic acid salts include sodium salts and potassium salts. The blending amount of the buffer in the aqueous solution is preferably in the range of 2 to 150 mM, preferably 5 to 10 mM.

Examples of the polyoxyethylene sorbitan fatty acid ester as a solubilizer include polysorbate 20, polysorbate 21,
polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80,
Examples include polysorbate 81, polysorbate 85, etc., and mixtures thereof, with polysorbate 20, polysorbate 80, etc. being preferred from the standpoint of safety as an injection.

The blending amount range of the solubilizer is 0 to 1 times the total amount of blended fat-soluble vitamins in polysorbate 20, preferably 0.1 to 0.
．． For polysorbate 80, it is appropriate that the amount be 0.8 to 5 times, preferably 1.6 to 3 times, the total amount of fat-soluble vitamins.

Polyethylene glycols of any molecular weight can be used as the solubilization stabilizer polyethylene glycols. Considering ease of preparation of the injection solution of the present invention, liquid polyethylene glycols such as polyethylene glycol 300 and polyethylene glycol 400 are preferred.

The amount added is preferably 0.1 to 20 w/v%, preferably 0.5 to 4 w/v%, in the aqueous solution.

Sugars include glucose, fructose, lactose, sucrose, maltose, dextran, masonitol, xylitol,
Examples include sorbitol. In particular, in consideration of the stability of sugar in an aqueous solution, non-reducing sugars are preferable as the above-mentioned sugars.

The amount added is preferably 0.1 to 20 w/v%, preferably 2 to 8 w/v%, in the aqueous solution. It is preferable that the amounts of the solubilizing agent and solubilization stabilizer are appropriately increased or decreased depending on the amount and type of vitamins.

The injection of the present invention can be prepared according to conventional methods.

A typical preparation method involves, for example, dissolving fat-soluble vitamins in a solubilizer, dissolving it in water for injection, adding a solubilization stabilizer and a buffer, and adjusting the pH using sodium hydroxide as necessary. A method of adjusting the pH to 6 to 7 using a regulator can be exemplified. The drug solution thus obtained is filtered if necessary, divided into containers, sealed, and steam sterilized at 105° C. for 60 minutes or 110° C. for 40 minutes to obtain the desired injection solution.

Effects of the Invention The fat-soluble vitamin injection of the present invention shows no change at all even after steam sterilization, and also shows no decrease in light transmittance after being left at 40°C for 4 months. There is no two-layer separation, and the stability is extremely excellent.

EXAMPLES Below, Examples and Comparative Examples are given to explain the present invention in more detail.

Example 1 Vitamin A (retinol palmitate) 3300 vitamin A units, vitamin D (cholecalciferol) 200
TU, vitamin E (tocopherol acetate) 10■, vitamin K (phytonadione) 2■ polysorbate 804
After dissolving in 0■ and polysorbate 208■, add water for injection heated to 70℃ or higher to dissolve, and then add polyethylene glycol 400 40■ and sorbitol 2
80■, anhydrous citric acid 0.4■ and sodium citrate 5.35■ are added and dissolved, and the total amount is 411! Closed. The obtained chemical solution was sealed in an ampoule and steam sterilized 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 polyethylene glycol 400 was changed to 20 ■ and the amount of sorbitol was changed to 240 ■.

Example 3 A product of the present invention was obtained in the same manner as in Example 1 except that the amount of polyethylene glycol 400 was changed to 80 ■ and the amount of sorbitol was changed to 160 ■.

Example 4 A product of the present invention was obtained in the same manner as in Example 1 except that the amount of polyethylene glycol 400 was changed to 120 ■ and the amount of sorbitol was changed to 120 ■.

Example 5 Mannitol 2 was used instead of sorbitol in Example 1.
A product of the present invention was obtained in the same manner except that 80 ■ was used.

Example 6 In Example 1, xylitol 2 was used instead of sorbitol.
A product of the present invention was obtained in the same manner except that 80 ■ was used.

Example 7 A product of the present invention was obtained in the same manner as in Example 1 except that polyethylene glycol 30040 was used instead of polyethylene glycol 400.

Example 8 A product of the present invention was obtained in the same manner as in Example 1, except that the amount of polysorbate 20 was changed to 12 ■ and the amount of polysorbate 80 was changed to 60 ■.

Example 9 The amount of polysorbate 20 in Example 1 was changed to 12 ■, the amount of polysorbate 80 was changed to 60 ■, and polyethylene glycol 30 was used instead of polyethylene glycol 400.
A product of the present invention was obtained in the same manner except that 0.40 cm was used.

Example 10 The amount of vitamin A in Example 1 was reduced to 2000 vitamin A.
The product of the present invention was obtained in the same manner except that the amount of vitamin was 5 μm.

Example 11 The amount of vitamin A in Example 1 was changed to 1000 vitamin A.
The product of the present invention was obtained in the same manner except that the unit and amount of vitamin D was 100 IU.

Example 12 A product of the present invention was obtained in the same manner as in Example 1, except that the amount of vitamin E was changed to 5 ■ and the amount of vitamin was changed to 0.2 ■.

Example 13 A product of the present invention was obtained in the same manner as in Example 1, except that the amount of vitamin D was 1000 IU and the amount of vitamin E was 15 ■.

Example 14 The amount of vitamin A in Example 1 was reduced to 5000 vitamin A.
The product of the present invention was obtained in the same manner except that the amount of vitamin was 10 μm.

Comparative Example 1 A comparative product was obtained in the same manner as in Example 1 except that polyethylene glycol 400 and sorbitol were not added.

Comparative Example 2 A comparative product was obtained in the same manner as in the example except that polysorbate 20, polyethylene glycol 400, and sorbitol were not added.

Comparative Example 3 A comparative product was obtained in the same manner as in Example 1 except that propylene glycol 600 was used instead of polyethylene glycol 400 and sorbitol.

Comparative Example 4 A comparative product was obtained in the same manner as in Example 1 except that glycerin 360 was used instead of polyethylene glycol 400 and sorbitol.

Comparative Example 5 A comparative product was obtained in the same manner as in Example 1 except that propylene glycol 40 was used instead of polyethylene glycol 400.

<Stability test> Sample groups of the present invention products prepared in each of the above examples, samples prepared without adding a solubilizing stabilizer as a comparison group, and samples prepared with a composition of the solubilizing agent outside the scope of the present invention. and a sample to which propylene glycol, known as a solubilizing agent, was added were steam sterilized at 110°C for 40 minutes, observed for changes in the appearance of the injection solution, and stored at 40°C for 4 months. The light transmittance at 640 nm was measured.

The results are shown in Table 1 below.

Table 1 As is clear from Table 1 above, the sample group according to the present invention showed no change at all even during steam sterilization and at 40°C.
There was no decrease in the light transmittance at 640 nm even after being left for 4 months at 40°C, but all of the comparison groups exhibited cloudiness or two-layer separation after steam sterilization, or the light transmittance at 640 nm after being left at 40°C for 4 months did not decrease. The rate decreased and it became cloudy.

(that's all)

Claims (1)

[Claims] (1) Vitamin A, vitamin D as fat-soluble vitamins,
Contains vitamin E and vitamin K, contains at least one selected from organic acids and their salts and inorganic acids and their salts as a buffer, and polyoxyethylene sorbitan fatty acid esters and solubilization stabilizers as a solubilizer. A fat-soluble vitamin injection characterized by containing polyethylene glycols and saccharides as agents.