JPH0133087B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an intravenous multivitamin used during high calorie infusion therapy (hereinafter referred to as TPN). TPN is a method of intravenously administering nutritional sources such as calorie sources, protein sources, trace metals, and 13 essential vitamins necessary for sustaining life to patients who have difficulty receiving nutritional supplements orally. This is a therapy that has become rapidly popular in recent years. The vitamin preparation for TPN contains 13 essential vitamins, namely vitamin A, B ₁ , B ₂ , B ₆ ,
Most preferred is a single vitamin preparation containing all of B ₁₂ , C, D, E, K, pantothenic acid, biotin, nicotinic acid, and folic acid. However, essential vitamins include water-soluble and fat-soluble vitamins, and the more vitamins are mixed in the same container, the less stable they become, the lower their content, and the more they become discolored. The change in appearance becomes significant. For example, even in freeze-dried products, depending on the combination of vitamins, the appearance may change significantly even though the content does not change, or the content may significantly decrease even though the appearance does not change. Therefore, it is difficult to find a combination of vitamins that is stable in terms of content and appearance, and it is difficult to make a single preparation, so when making TPN infusions, individual injectable vitamin preparations are used in combination. is the current situation. However, this method is time-consuming because there are many types of vitamin preparations to be mixed at the time of use, and it is easy to make mistakes in the amount of vitamins mixed. Also, it takes time to prepare the infusion solution, and the infusion solution may be contaminated with bacteria, pyrogens, foreign substances, etc. Furthermore, depending on the combination, other vitamins may become unstable due to the influence of stabilizers added to commercially available vitamin preparations. In order to improve the above-mentioned drawbacks, we divided the 13 essential vitamins into 3 or 5 containers and added them to 1 container.
A vitamin preparation for TPN to be used as a set has been made (Japanese Patent Application Laid-Open No. 77222-1983). However, using the vitamins divided into five containers is time-consuming and extremely complicated, and the use of the three containers does not necessarily improve the stability of the vitamins. too
Not sufficient as a vitamin supplement for TPN. Therefore, the present inventors investigated various stable vitamin preparations for TPN, and found that 13 essential vitamins were found: vitamin B ₂ , vitamin B ₆ , pantothenic acid,
Vitamin C Vitamin B ₁ , Vitamin B ₁₂ , Folic acid At least one of the above contains both biotin and nicotinic acid, or one contains biotin and the other contains nicotinic acid Vitamin A, vitamin D, It has been found that an intravenous multivitamin preparation containing three containers each containing vitamin E and vitamin K is the most preferable in terms of stability. The present invention was completed based on the above findings. The stability of the combination according to the invention is quite surprising considering that vitamin C is known to degrade in the presence of vitamin _B2 or nicotinic acid. In the composition of the vitamin preparation of the present invention, from the viewpoint of formulation stability, among water-soluble vitamins, vitamin B ₂ ,
It is essential to separate vitamin B ₆ , pantothenic acid, and vitamin C into one group, and vitamin B ₁ , vitamin B ₁₂ , and folic acid into one group. However, there is no need to separate biotin and nicotinic acid, and it is sufficient that they are present in either of them. In addition, fat-soluble vitamins, namely vitamin A, vitamin D, vitamin E, and vitamin K, have different physicochemical properties than water-soluble vitamins, so they often accumulate and cause side effects, so the amount used should be limited. Since it is necessary to be able to change the parameters appropriately, this was set as one group. The specific composition of the vitamin preparation of the present invention is as follows. (1) Vitamin B ₂ , vitamin B ₆ , pantothenic acid,
Vitamin C, biotin Vitamin B ₁ , Vitamin B ₁₂ , Folic acid, Nicotinic acid Vitamin A, Vitamin D, Vitamin E, Vitamin K (2) Vitamin B ₂ , Vitamin B ₆ , Pantothenic acid,
Vitamin C Vitamin _B1 , Vitamin _B12 , Nicotinic acid,
Folic acid, biotin, vitamin A, vitamin D, vitamin E, vitamin K (3) vitamin B ₂ , vitamin B ₆ , pantothenic acid,
Vitamin C, biotin, nicotinic acid Vitamin B ₁ , Vitamin B ₁₂ , Folic acid Vitamin A, Vitamin D, Vitamin E, Vitamin K (4) Vitamin B ₂ , Vitamin B ₆ , Pantothenic acid,
Vitamin C, nicotinic acid Vitamin B ₁ , Vitamin B ₁₂ , Folic acid, Biotin Vitamin A, Vitamin D, Vitamin E, Vitamin K Vitamin B ₂ used in the present invention includes riboflavin, flavin mononucleotide, flavin adenine dinucleotide, etc. vitamin
Examples of B ₆ include pyridoxine hydrochloride, pyridoxal phosphate, and pyridoxamine phosphate; examples of pantothenic acid include calcium pantothenate and pantothenol; examples of vitamin C include ascorbic acid; and examples of vitamin B ₁ include thiamine hydrochloride,
Brosulthiamine, octothiamine, etc., vitamin _B12 include cyanocobalamin, hydroxocobalamin acetate, methylcobalamin, etc., nicotinic acid includes nicotinic acid, nicotinamide, etc., vitamin A includes retinol palmitate, etc., vitamin D Examples of vitamin E include dl-α-tocopherol and tocopherol acetate, and _examples of vitamin K include phytonadione, _{menatetrenone} , and menadione. . In addition, each component of the vitamin preparation of the present invention contains 1-10 mg of vitamin B ₂ and 1-10 mg of vitamin B ₆ .
mg, pantothenic acid 5-25 mg, vitamin C50-250
mg, vitamin B ₁ 1-10 mg, vitamin B ₁₂ 1-30 μg,
It is desirable that the composition be blended in the following proportions: 100-1000 μg of folic acid, 20-300 μg of biotin, 10-50 mg of nicotinic acid, 2000-5000 IU of vitamin A, 200-1000 IU of vitamin D, 5-20 IU of vitamin E, and 0.2-10 mg of vitamin K. The vitamin preparation of the present invention is made up of 13 essential vitamins divided into the above-mentioned groups (-), which are combined into one set. From this point of view, freeze-dried preparations are preferred. The pH of the aqueous solution in the first group is preferably 5 to 6, and the pH of the aqueous solution in the second group is preferably 4 to 8, preferably 5 to 7, and it is more preferable to use a buffer from the viewpoint of stability. As the buffer, for example, acetic acid, citric acid, or tartaric acid is preferable, and the amount thereof is per 1 ml of solution.
It is sufficient to add 1.25 to 30 mg. When making a lyophilized preparation from the above group, it is preferable to add excipients and then lyophilize from the viewpoint of appearance and stability. Various excipients for pharmaceutical use are known, but the excipients used here are most preferably histidine, arginine, dextran, and chondroitin sulfate from the viewpoint of vitamin stability. Examples of chondroitin sulfate include sodium chondroitin sulfate. These excipients are 2
More than one species can be mixed and used, and the amount added is appropriately determined within the range of 5-50 mg in the case of the above-mentioned vitamin content. Next, the method for producing the vitamin preparation of the present invention will be described. The vitamin preparation of the present invention can be manufactured by conventional methods. For example, in the third group, the vitamins to be mixed are dissolved in distilled water for injection, the pH is adjusted to PH5-6, sterilized with a Millipore filter, and the solution is aseptically filled into containers such as ampoules or vials.
If necessary, an inert gas such as nitrogen gas may be filled in. In the first group, the vitamins and excipients as required are dissolved in distilled water for injection, and the pH is preferably 5-7.
After adjusting the pH to 5.5-6, the solution may be sterilized using a Millipore filter, filled into a container such as a vial, and then freeze-dried. In the first group, a surfactant is added to the vitamins to be mixed and dissolved under heat, then propylene glycol is added as a solubilizing agent, and distilled water for injection is further added to form an aqueous solution. Next, this aqueous solution is sterilized using a Millipore filter, and then aseptically filled into a container such as an ampoule or a vial, which may be filled with nitrogen gas if necessary. Next, the present invention will be specifically explained using Examples and Experimental Examples. Example 1 1-1 51 g of riboflavin sodium phosphate, 40 g of pyridoxine hydrochloride, 140 g of pantothenol, 1 g of biotin and 1 kg of ascorbic acid were dissolved in distilled water for injection to make a total volume of 50 g. After adjusting the pH to approximately 6 with sodium hydroxide and hydrochloric acid, sterilization was performed using a 0.22μ Millipore filter, 5 ml of the liquid was filled into an ampoule aseptically, nitrogen gas was sealed, and the ampoule was closed to form the first group. of vitamins were obtained. Next, 30g of thiamine hydrochloride, cyanocobalamin
100 mg, folic acid 4 g, nicotinic acid amide 400 g, and an appropriate amount of histidine HCl as an excipient were dissolved in distilled water to make a total volume of 10. After adjusting the pH to about 5.5 with sodium hydroxide and hydrochloric acid, sterilize it with a 0.22μ Millipore filter, aseptically fill 1 ml of the liquid into a vial, freeze-dry it, seal it with a rubber stopper, and remove the vitamins from the second group. was gotten. Next, 33 million IU of retinol palmitate, 24 _million IU of vitamin D, and 150 million IU of tocopherol acetate.
g, Phytonadione 20g, as a surfactant
After adding an appropriate amount of HCO-60 and dissolving it under heat, add an appropriate amount of propylene glycol, and then add distilled water for injection to bring the total volume to 20. After sterilization with a 0.22 μm Millipore filter, 2 ml of the solution was aseptically filled into an ampoule, the air was replaced with nitrogen, and the ampoule was sealed to obtain the third group of vitamins. These groups of vitamins constitute one set,
A vitamin preparation of the present invention was obtained. 1-2 The vitamin preparation of the present invention was obtained in the same manner as in 1-1 except that histidine hydrochloride was removed from the above group 1-1. 1-3 A vitamin preparation of the present invention was obtained by adding an appropriate amount of citric acid to the above group 1-1, and using the same composition and manufacturing method as in 1-1. Example 2 A vitamin preparation of the present invention was obtained in the same manner as in Example 1-1, except that the vitamin compositions of the first and second groups and the excipients of the second group were changed to the following compositions. Note that the blended amounts of vitamins in the first group and the second group and the vitamins in the third group are the same as in Example 1-1, so they are omitted. 2-1 Group Riboflavin Sodium Phosphate Pyridoxine Hydrochloride Pantothenol Ascorbic Acid Group Thiamine Hydrochloride Cyanocobalamin Folic Acid Nicotinamide Biotin Dextran 40 (Excipient) 2-2 Group Riboflavin Sodium Phosphate Pyridoxine Hydrochloride Pantotenol Nicotinamide Biotin Ascorbic acid Group Thiamine hydrochloride Cyanocobalamin Folic acid Arginine hydrochloride (excipient) 2-3 Group Riboflavin sodium phosphate Pyridoxine hydrochloride Pantothenol Nicotinamide Ascorbic acid Group Thiamine hydrochloride Cyanocobalamin Folic acid Biotin Sodium chondroitin sulfate (Excipient) ) Experimental Example 1 Storage stability test (vitamin composition) Using the vitamin preparations produced in the above example as samples, two types of commercially available products and a vitamin preparation (divided into three bottles) described in JP-A-56-77222 were tested. As a control,
A storage stability test was conducted for 4 weeks under severe conditions at 50°C. The results are shown in Table 1.

【table】

[Table] As is clear from Table 1, the contents of vitamin B ₁ and C were found in controls 1 and 2, while the contents of vitamin B ₁ and B ₆ were found in control 3.
The content of _B12 and folic acid decreased significantly. In contrast, the contents of the products of the present invention were all 90% or more, indicating that they had excellent storage stability. Furthermore, among the products of the present invention, Example 1-1 containing an excipient has better storage stability of vitamin B ₁₂ and folic acid than Example 1-2, which does not contain an excipient. I understand that there is something. Experimental Example 2 Storage Stability Test (Excipients) Various excipients were added to the vitamins of the group, and after freeze-drying, a storage stability test was conducted for one week under harsh conditions at 50°C. The composition of the vitamins used in this test was vitamin B ₁ , B ₁₂ , folic acid, nicotinamide, and biotin. First, stability was determined using changes in appearance as an indicator.
The results are shown in Table 2.

【table】

【table】

[Table] Items with significant changes in performance or appearance Items using excipients as shown in Table 218
Six of the species had good appearance. The vitamin content of these six types was measured.
The results are shown in Table 3.

[Table] As is clear from Table 3, among those with good appearance, those using alanine and glycine as excipients had a significant decrease in the content of vitamins B ₁ , B ₁₂ and folic acid.
However, the contents of all samples using histidine, arginine, dextran, and chondroitin sulfate were 95% or more. Therefore, the vitamin preparation of the present invention has extremely good storage stability when these four excipients are used.

Claims (1)

[Claims] 1. The 13 essential vitamins are: vitamin B ₂ 1-10 mg, vitamin B ₆ 1-10 mg,
Pantothenic acid 5-25mg, vitamin C 50-250mg, vitamin B ₁ 1-10mg, vitamin B ₁₂ 1-30μg,
100-1000 μg of folic acid, at least one of the above contains both 20-300 μg of biotin, and 10-50 mg of nicotinic acid, or one of the above contains biotin and the other contains nicotinic acid. Vitamin A2000−5000IU, vitamin D200−
1000IU, vitamin E5−20IU, vitamin K0.2−
A multivitamin for intravenous injection, with one set containing 10mg of each composition divided into three containers. 2 The 13 essential vitamins are: vitamin B ₂ 1-10mg, vitamin B ₆ 1-10mg,
Pantothenic acid 5-25mg, vitamin C 50-250mg, vitamin B ₁ 1-10mg, vitamin B ₁₂ 1-30μg,
100-1000 μg of folic acid, at least one of the above contains both 20-300 μg of biotin, and 10-50 mg of nicotinic acid, or one of the above contains biotin and the other contains nicotinic acid. Vitamin A2000−5000IU, vitamin D200−
1000IU, vitamin E5−20IU, vitamin K0.2−
A multivitamin for intravenous injection containing 10mg of each composition divided into three containers, and further containing histidine, arginine, dextran, or chondroitin sulfate.