JP3484689B2 - Trace element preparation - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preparation for preventing various deficiency symptoms resulting from a deficiency of essential trace elements when performing high calorie infusion therapy on humans,
More specifically, it is possible to replenish essential trace elements including iron ions, copper ions, zinc ions, manganese ions, selenium ions and iodine ions at the time of carrying out the infusion therapy, and further to maintain the stability of the preparation. Regarding trace element formulations.

[0002]

2. Description of the Related Art Conventionally, high calorie infusion therapy is usually performed on patients who are unable or unsuitable for oral or enteral nutritional supplementation, and it is widely used. In high calorie infusion therapy, generally, carbohydrates and the like as heat sources, amino acids and the like as protein sources, and electrolytes and vitamins and the like are intravenously administered. Here, as the electrolyte, sodium chloride,
Potassium chloride, sodium acetate, calcium gluconate, magnesium sulfate and potassium dihydrogen phosphate are used. However, when a high-calorie infusion therapy containing these components is performed for a long period of time, humans lack essential trace elements. Currently, selenium, iron, zinc, copper,
Cases of deficiency of trace elements such as manganese, iodine, molybdenum and chromium have been reported.

Among the above trace elements, selenium is the intracellular peroxide-degrading enzyme glutathione peroxidase (G
It is a constituent of SH-Px). Deficiency of selenium during high calorie infusion therapy has been reported to cause deficiencies such as myalgia and cardiomyopathy.
88, p483, 1987 etc.). Traditionally, the essential trace element supplements for high calorie infusion therapy have been iron, zinc, and
Selenium is available, although "Elementemic" (trade name, manufactured by Hoechst Marion Roussel) and "Mineralin" (trade name, manufactured by Nippon Pharmaceutical Co., Ltd./Takeda Pharmaceutical Co., Ltd.) containing five elements of copper, manganese and iodine are on the market. Formulations containing is not yet on the market. Regarding selenium, in addition to the high calorie infusion formulation, a formulation prepared in a hospital is administered.

On the other hand, in Europe, along with selenium,
Trace element formulations containing nine elements iron, zinc, copper, manganese, chromium, molybdenum, iodine and fluorine, "Addame
l "(trade name, manufactured by Pharmacia & Upjohn) or" Tracuti
1 ”(brand name, manufactured by B. Braun) is marketed, and these formulations are usually adjusted to a pH of about 2. However, in general, the essential trace element replenisher is mixed with the sugar / electrolyte solution and the amino acid solution in the high-calorie infusion preparation, and then mixed with these mixed solutions. On the other hand, the pH after mixing the sugar / electrolyte solution and the amino acid solution is usually in the range of 4 to 6. For example, the pH of a high-calorie infusion preparation, "PTN Twin" (trade name, manufactured by Hoechst Marion Roussel) after mixing a sugar / electrolyte solution and an amino acid solution is about 5, and a high-calorie infusion preparation, "Aminotripa" The pH after mixing the sugar / electrolyte solution and the amino acid solution (trade name, manufactured by Otsuka Pharmaceutical Co., Ltd.) is about 5.6. The pH of the sugar / electrolyte / amino acid solution of “Unicaric” (trade name, Terumo / Tanabe Seiyaku Co., Ltd.) is about 4.3. Therefore, the pH of essential trace element supplements
When the content is low, if the essential trace element replenisher is co-injected after mixing the sugar / electrolyte solution and the amino acid solution, precipitation of the trace elements may occur, and the content of these elements may decrease or insoluble foreign matter may occur. For example, there is a concern that the composition may change after mixed injection.

Therefore, it is desirable that the pH of the trace element preparation is adjusted to a pH after mixing the sugar / electrolyte solution and the amino acid solution in the high calorie infusion preparation, that is, in the range of pH 4 to 6. However, a trace element preparation containing selenium ions and having a pH adjusted to 4 to 6 has not been known until now.

Regarding the stability of essential trace elements, first, the pH when selenium selenite is dissolved in water as selenium ion is 3.5, but the stable pH in an aqueous solution is about 2. Yes, specifically US Pharmacopoeia (23rd revision)
The listed selenious acid injections have a pH of 1.8-2.
It is set to 4.

Next, although iron ions are generally used as ferric chloride, they are present as ferric hydroxide by hydrolysis in an aqueous solution. In addition to ferric oxide and water, it contains the oxychloride FeOCl, which is further dissociated into FeO ⁺ and Cl ⁻ . That is, since the ferric hydroxide colloid is a hydrophobic colloid in which particles are positively charged, it easily aggregates, and when the pH becomes about 3 or more, precipitation occurs due to aggregation. Therefore, the stable pH of iron ions is predicted to be about 3 or less (“colloid chemistry” BJ
irgensons et al., translated by Bunichi Tamamushi, Baifukan Tokyo 1967
Year).

Further, copper sulfate used as a copper ion forms a hydroxide insoluble in water when the pH of the aqueous solution becomes 5.4 or more, and zinc sulfate used as a zinc ion also has an aqueous solution. At a pH of 6.5 or above, a hydroxide insoluble in water is formed. Therefore, the essential trace element preparation containing iron ions and selenium ions has a pH in the aqueous solution of 4 to 6 which is almost the same as that of the high calorie infusion preparation.
It is difficult to set in the range of.

[0009]

DISCLOSURE OF THE INVENTION An object of the present invention is that essential trace elements including iron ions and selenium ions have excellent thermal stability against high-pressure steam sterilization and aging, and in the pH range of high-calorie infusion preparations, The object is to provide a stable trace element preparation.

[0010]

[Means for Solving the Problems] In order to achieve the above-mentioned object, the present inventors have made various studies and found that selenium (IV) contained in the preparation is present together with an iron colloid containing chondroitin sulfate as a protective colloid. Although the content of selenium is slightly reduced by heating, manganese ion is added to the above two elements,
When zinc ion, copper ion and iodide ion are added, the decrease of selenium content by heating is the least, and iron colloid, selenium ion, manganese ion, zinc ion,
An aqueous solution containing copper ions and iodine ions at the same time is p
It was found that H5 to H6 were the most stable, and in this case, the stability by heating was the highest, and the present invention was reached.

That is, the present invention contains iron colloid and selenium ion, and contains manganese ion, zinc ion,
A trace element preparation comprising an aqueous solution containing copper ions and iodine ions and having a pH in the range of 5 to 6.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION Iron colloid means a substance in which fine iron particles are suspended as a hydrophobic colloid in an aqueous solution,
The iron colloid of the present invention is a colloid solution containing a chondroitin sulfate salt, for example, sodium chondroitin sulfate as a protective colloid, and has a pH adjusted to 4 to 8 to prevent aggregation of the colloid itself. Iron has a trivalent metal value, and examples thereof include ferric chloride hexahydrate. Sodium chondroitin sulfate, which is a protective colloid, has a molecular weight of about 1 in terms of uniformity and viscosity.
It is preferable to use those of 5,000 to 20,000. Also, sodium chondroitin sulfate is iron (element)
It is preferred to use at least about 5 times the amount. The iron colloid is produced by dissolving sodium chondroitin sulfate in water for injection and then adding a solution of ferric chloride hexahydrate in water for injection to the sodium chondroitin sulfate solution together with an appropriate amount of sodium hydroxide solution. A chondroitin iron sulfate colloidal solution is prepared.

As the selenium ion of the present invention, selenious acid, sodium selenite, sodium selenate and the like can be preferably used.

As the manganese ion of the present invention, either a sulfate or a hydrochloride can be used. For example, manganese chloride tetrahydrate, manganese sulfate pentahydrate, etc. are illustrated.

As the zinc ion of the present invention, either a sulfate or a hydrochloride can be used. Examples include zinc sulfate heptahydrate, zinc chloride and the like.

As the copper ion of the present invention, either a sulfate or a hydrochloride can be used. For example, copper sulfate-5
A hydrate, cuprous chloride, cupric chloride, etc. are illustrated.

As the iodide ion of the present invention, it is preferable to use potassium iodide, which has been widely used. Examples of potassium iodide include sodium iodide and the like.

Each of the above trace elements is dissolved in water for injection to give the trace element preparation of the present invention. The amount of each element as the daily dose is iron: 0.9 to 224 μmol, copper: 0.9 to 55 μmo
l, zinc: 3.85 to 210 μmol, manganese: 0 to 51
μmol, selenium: 0.025 to 5.0 μmol, iodine: 0
˜11 μmol, preferably iron: 9-70 μmol,
Copper: 9.1 to 27.3 μmol, zinc: 38.5 to 61.
5 μmol, manganese: 1.0 to 14.5 μmol, selenium:
0.25 to 2.5 μmol, iodine: 0.6 to 1.1 μmol
It is desirable that these elements be contained in a 2 to 20 ml aqueous solution as a trace element preparation. The trace element preparation of the present invention may optionally contain chromium, molybdenum, cobalt and fluorine. The trace element preparation of the present invention needs to have a pH of 5-6. If the pH is less than 5, the iron content in the trace element preparation will decrease, and if the pH exceeds 6, an insoluble precipitate will be formed, resulting in turbidity. To adjust the pH, pH adjuster,
For example, it is preferable to add sodium hydroxide or the like.

As the container for enclosing the trace element preparation of the present invention, for example, a glass container or a plastic container such as polypropylene can be used. The trace element preparation of the present invention is mixed with a high-calorie infusion preparation and administered to a patient according to a conventional method. The dose is a trace element preparation in the range of the above-mentioned daily amount of each element per adult human.

[0020]

EXAMPLES Hereinafter, the trace element preparation of the present invention will be specifically described with reference to Examples. In the examples, each ion was measured as follows. Iron ion, manganese ion, zinc ion and copper ion are atomic absorption spectrophotometric method (frame method)
And the selenium ion was measured by a fluorometric method. In addition, iodine ion was measured by liquid chromatography.

Example 1 <Step 1> An appropriate amount of ferric chloride solution and sodium hydroxide solution was added to a sodium chondroitin sulfate solution to prepare an iron colloid solution so that the iron concentration was 4 mg / ml. <Step 2> 1256 ml of the iron colloid solution prepared in Step 1 was added to water for injection to make about 7 L. While stirring the solution, 6.24 g of copper sulfate pentahydrate, zinc sulfate heptahydrate 86.25
g, manganese chloride tetrahydrate 2.97 g, selenious acid 0.32 g and potassium iodide 0.83 g were added and dissolved, and then
After adding sodium hydroxide solution to adjust the pH to 6.0, water for injection was further added to adjust the total amount to 10 L. Also, aqueous solutions having various pHs were obtained in the same manner. In addition, pH 7.0
The preparation of No. 1 could not be prepared because precipitation of iron colloid occurred during the preparation. <Step 3> The aqueous solution obtained in Step 2 was filtered through a membrane filter (pore size: 0.45 μm), filled in a 2 ml Pyrex glass ampoule under aseptic conditions, and sealed. After the melting and closing, high-pressure steam sterilization was performed.

Test Example 1 The pH of the aqueous solution in Example 1 was changed to 4.0, 5.0 and 6.0, respectively, and each formulation was subjected to high-pressure steam sterilization at 110 ° C. for 30 minutes to determine the residual rate of each component in the formulation. It was measured. The results are shown in Table 1.

[0023]

[Table 1]

As is clear from Table 1, among these preparations, the preparations having pH 5.0 and 6.0 maintain the residual ratio of each element at 90% or more after sterilization, and undergo the manufacturing process such as heat sterilization. However, it was revealed that the formulation was stable. p
Formulations of H4.0 had less than 90% iron after sterilization.

Further, the stability test for 6 months was carried out on the formulations of pH 5.0 and 6.0 which were stable by heat sterilization, under the conditions of 40 ° C. and 75% relative humidity. The results are shown in Table 2.

[0026]

[Table 2]

As is clear from Table 2, all the formulations
The residual rate of 90% or more is maintained, and it is speculated that these formulations can achieve stability at room temperature for 3 years.

Test Example 2 Preparation of selenium ion added to the above iron colloid, preparation of copper ion, zinc ion, manganese ion and iodine ion added to the preparation, and iron ion, selenium ion, copper ion, zinc ion, manganese The residual ratio of selenium (IV) after heating at 110 ° C. for 2.5 hours was measured for the preparation containing 6 elements of ion and iodine ion (Example 1), and the results are shown in Table 3.

[0029]

[Table 3]

As is clear from Table 3, the preparation of Example 1 has the lowest selenium (IV) reduction rate and is excellent in thermal stability upon heating. The preparations other than Example 1 were prepared in Example 1
It was manufactured in the same manner as.

Test Example 3 2 ml of the preparation of the present invention (Example 1), which had been subjected to high-pressure steam sterilization at 110 ° C. for 30 minutes, was co-injected into the following commercially available high-calorie infusion preparation, and after 24 hours at room temperature, these infusion solutions were prepared. The pH and properties of the formulation were observed. The results are shown in Table 4. The commercial high-calorie infusion solutions used were "Unicaric" (trade name, manufactured by Terumo / Tanabe Seiyaku Co., Ltd.), "Aminotripa" (trade name, manufactured by Otsuka Pharmaceutical Co., Ltd.), and "P-Twin" (trade name, Hoechst Marion). -Made by Roussel).

[0032]

[Table 4]

As is clear from Table 4, the formulation of the present invention (Example 1) did not cause a change in the formulation such as precipitation in the mixed solution even after 24 hours after being co-injected with the commercial high calorie infusion formulation.

[0034]

EFFECTS OF THE INVENTION The trace element preparation of the present invention has excellent thermal stability against high-pressure steam sterilization and aging, and excellent stability in the pH range of high-calorie infusion preparations. is there.

Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 33/32 A61K 33/32 33/34 33/34 (56) Reference JP-A-9-124478 (JP, A) Yamaji Akira, Kurata Yoshiaki , Kojima Oshima, Yasuko Fujii, Shingen Kasahara, Pankei Kishi, Noboru Onishi, Eiichi Hiraoka, Preparation of In-Hospital Formulation of Iron Injection for High Calorie Infusion and Stability in Infusion, Hospital Pharmacy, 1979, vol ． 5 No. 1,30-35 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 9/08

Claims (3)

(57) [Claims] 1. A method comprising iron colloid and selenium ion,
Moreover, a trace element preparation comprising an aqueous solution containing manganese ions, zinc ions, copper ions and iodine ions and having a pH in the range of 5 to 6. 2. The trace element preparation according to claim 1, wherein the iron colloid is an iron colloid solution containing chondroitin sulfate as a protective colloid. 3. The trace element preparation according to claim 2, wherein the chondroitin sulfate is sodium chondroitin sulfate.