JPH01268698A - Preparation for injection of stable isepamicin sulfate - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention provides microparticles obtained by containing an injectable composition containing isepamycin sulfate as an active ingredient in a glass container treated with an aqueous solution of water-soluble sulfur oxide under heating conditions. The present invention relates to a stable isepamycin sulfate injection formulation that suppresses the occurrence of.

(Prior Art) Conventionally, ampoules and tube bottles for injections have been made of borosilicate glass, and molded bottles have been made of soda lime glass, which have been heat sterilized, dried, filled with an injection solution, and fused or sealed. It was available for use.

In addition, isepamycin sulfate [chemical name i (+) -〇-6-amino-6-zooxy-α-D-glucopyranosyl-(1→4)-0-(3-deoxy-4-C-methyl-3-(methylamino )-β-L-arabinopyranosyl-(1→6))-2-deoxy-N l -[(S)-
Isoseryl)-D-streptamine sulfate:
(+) -0-6-amino -6-deoxy-
at-D-glucopyranosyl-(1-
=4) -0-(3deOXV-4-C-meth
yl-3(methylamino)-β-L-
arabinopyranosyl -(1→6))-
2-deoxy -N'-((S) -1sose
ryl)-D-streptamine 5ul
Fate) is an antibacterial substance with a molecular weight of 569.61 (free base), and is a white to slightly yellowish white powder that is extremely soluble in water and almost insoluble in methanol, ethanol, and acetone.This injection is clear and colorless. and the pH is 5.5
7.5 and exhibits effective antibacterial activity against Escherichia coli, Citrobacter spp., Talebsiella spp., Enterobacter spp., Serratia spp., Proteus spp., Pseudomonas aeruginosa, etc., and is usually administered by intramuscular injection or intravenous drip infusion. used.

[Problems to be solved by the invention] Concerning isepamycin sulfate injection preparations, - Numerically, an aqueous injection solution containing isepamycin sulfate as an active ingredient is filled into borosilicate glass ampoules or soda lime glass bottles and sealed by melting. This is then heat sterilized to produce the desired injection preparation. However, although the injectable aqueous solution of isepamycin sulfate contained extremely small amounts of fine particles with a diameter of 2 to 20 μm before filling, after heat sterilization, the fine particles increased significantly in this injectable preparation, making it difficult to use as a preparation. It was inadequate and inappropriate.

[Means for solving problems]

As a result of intensive research into solving the above-mentioned problems regarding isepamycin sulfate injection preparations, the present inventors discovered, quite unexpectedly, that a borosilicate glass product used for filling an injectable aqueous solution containing isepamycin sulfate as an active ingredient. Water-soluble sulfate compounds that release sulfate ions, such as sulfuric acid, ammonium sulfate, and sodium sulfate, and their extracted water-soluble sulfite compounds, in glass containers such as ampoules and soda-lime glass bottles.
It has been discovered that by heating and contacting an aqueous solution of water-soluble sulfur oxide such as a water-soluble thiosulfate compound in advance, the formation of fine particles in an injectable preparation after heat sterilization is significantly suppressed, and a product suitable for the preparation can be obtained. Ta.

The present invention was completed based on the above findings, and consists of a stable isepamycin sulfate injection composition containing an injection composition containing isepamycin sulfate as an active ingredient in a glass container treated with a water-soluble sulfur oxide aqueous solution under heating conditions. It is a formulation.

First, as the water-soluble sulfur oxide used in the present invention, water-soluble sulfuric compounds that liberate and form stable sulfate ions as an aqueous solution are preferably mentioned, such as sulfuric acid, ammonium sulfate, sodium sulfate, potassium sulfate, and sulfuric acid. Examples include ammonium hydrogen, sodium hydrogen sulfate, potassium hydrogen sulfate, etc. Also, examples of compounds that can be used other than these water-soluble sulfuric compounds include sulfurous acid, sodium sulfite, potassium sulfite, sodium hydrogen sulfite, potassium hydrogen sulfite, etc. Examples include water-soluble sulfite compounds, sodium thiosulfate, sodium dithionite, ammonium peroxide disulfate, and water-soluble sulfur oxides such as aminosulfonic acid.

Next, when treating a glass container using this water-soluble sulfur oxide, first 0.01% of the water-soluble sulfur oxide was added.
An aqueous solution having the above concentration, preferably 0.1 to 10% concentration, is prepared, and an appropriate amount of this aqueous solution is placed in a glass container, such as a borosilicate glass injection ampoule or tube bottle, or a soda lime glass molded bottle. For example, about 0.05 to 1 mJ may be injected into a 1 to 2 mA capacity container, and the mixture may be heated at 300 to 7°C for usually 1 to 30 minutes.

Next, in order to contain an injection composition containing isepamycin sulfate as an active ingredient in a glass container treated with the water-soluble sulfur oxide aqueous solution obtained in this manner, the treated glass container was further washed thoroughly. After drying, add an appropriate amount of an injectable composition containing isepamycin sulfate as an active ingredient, for example, in the case of an intramuscular injection preparation, add 0.5 to 2 m of an aqueous injection solution containing isepamycin sulfate as an active ingredient at a concentration of 1 to 50%. Fill it aseptically and seal it.
In addition, the preparation for intravenous infusion may be appropriately filled and sealed, and the injectable composition containing isepamycin sulfate as an active ingredient may be prepared by dissolving isepamycin sulfate in distilled water for injection. (Also, hydrogen sulfite ion,
Compounds that can release sulfite and thiosulfate ions such as sodium bisulfite, potassium bisulfite, ammonium bisulfite, sodium sulfite, potassium sulfite, sodium thiosulfate, potassium thiosulfate, ammonium thiosulfate, and other antioxidants are combined with isepamicin sulfate 10
0.5 to 3 per 0 mg titer (titer; 720 μg/mg)
If necessary, for example, a buffer, an isotonizing agent such as sodium chloride or glucose, etc. may be used.
It may contain a preservative such as methyl paraoxybenzoate or propyl paraoxybenzoate, and other analgesic and solubilizing agents, and may be used after sterile filtration.

Furthermore, after sealing an injectable aqueous solution of isepamycin sulfate in the above-mentioned treated glass container, it is heat sterilized, e.g., heated in an autoflave at 115 to 130°C for 15 to 30 minutes to produce a stable isepamycin sulfate injection that suppresses the generation of the target particulates. The isepamycin sulfate injection preparation thus obtained may be administered to adults in a daily dose of 400 mg of isepamycin sulfate in divided doses.

〔Example〕

Next, examples of the present invention will be described, but the present invention is not limited thereto.

Example 1 A 2ml glass container made of borosilicate glass for injection of isepamycin sulfate! A large sample was used.

Further, as an injectable composition containing isepamycin sulfate as an active ingredient, a 10% concentration aqueous solution of isepamycin sulfate for injection was prepared and used after being filtered through a 0.22 μm pore size membrane filter (hereinafter referred to as pre-filling solution).

First, ammonium sulfate aqueous solution with 0.5% concentration of 2mA Affanpur 0.2mj! After filling, the ampoule was heated at 600° C. After ultrasonic cleaning, the ampoule was finally washed with distilled water and dry heat sterilized at 250° C. for 30 minutes.

As a control, 2 ml of untreated ammonium sulfate aqueous solution
After ultrasonically cleaning the ampoule, the ampoule was finally washed with distilled water and sterilized by dry heat at 250° C. for 30 minutes.

Next, both were filled with 2 ml of a 10% concentration aqueous solution for injection of isepamycin sulfate prepared by filtration with a 0.22 μm pore size membrane filter, and after melting and sealing these, they were heat sterilized at 115° C. for 30 minutes in an autoflave. After leaving it for one round at room temperature, the mixed particles were measured using a Hiasoku particle measuring device.

The results are shown in Table 1.

Table 1 (in 2 ml) As a result, although the aqueous solution for injection of 4-sepamycin sulfate before filling contains a small amount of fine particles with a diameter of 2 to 20 μm, it is possible to liberate sulfate ions such as ammonium sulfate. The aqueous solution of isepamycin sulfate for injection in the ampoule that is not treated with an aqueous solution has a significant increase in the number of fine particles with a diameter of 2 to 20 μm, whereas the aqueous solution of isepamycin sulfate for injection in the ampoule of the present invention has a particle size of 2 to 20 μm.
The increase in the size of fine particles was small, and the generation of fine particles was suppressed in the aqueous solution of isepamycin sulfate for injection in the control, and it is recognized as a stable preparation for injection of isepamycin sulfate.

〔Effect of the invention〕

The present invention relates to an injectable composition containing isepamycin sulfate as an active ingredient by using a glass container treated with a water-soluble sulfur oxide aqueous solution under heating conditions, and a stable isepamycin sulfate injection preparation that suppresses the formation of fine particles. It provides:

Claims (5)

[Claims] (1) A stable isepamycin sulfate injection preparation containing an injection composition containing isepamycin sulfate as an active ingredient in a glass container treated with a water-soluble sulfur oxide aqueous solution under heating conditions. (2) The injectable preparation according to claim 1, wherein the water-soluble sulfur oxide is a water-soluble sulfur oxide that liberates sulfate ions. (3) The injectable preparation according to claim 1, wherein the water-soluble sulfur oxide aqueous solution is a water-soluble sulfur oxide aqueous solution having a concentration of 0.01% or more. (4) The injection preparation according to claim 1, wherein the heating condition is 300 to 700°C. (5) The injectable preparation according to claim 1, wherein the injectable composition containing isepamycin sulfate as an active ingredient is an aqueous injection solution containing isepamycin sulfate as an active ingredient at a concentration of 1 to 50%.