JPH115743A - Injection of vancomycin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject injection controlled in coloring and stable by including vancomycin and an organic acid in water. SOLUTION: This injection of vancomycin, adjusted at a pH 3.00 to 3.40 for use and sealed with an inert gas, e.g. nitrogen, helium, argon or the like in the final production stage, is obtained by including (A) 90 to 99.8 wt.% of vancomycin, preferably in the form of salt with a free body, hydrochloric acid, nitric acid or the like, (B) 0.2 to 5 wt.% of an organic acid as an aliphatic hydrocarbon having a hydroxide group and ether bond, which has a carboxyl group or ionized body in the molecule, and shows an acidic pH level (e.g. acetic acid, propionic acid, butanoic acid, tartaric acid, citric acid or the like), and (C) an optional ingredient, in addition to the above essential ingredients, e.g. a buffer agent or the like of sodium citrate, potassium citrate, sodium hydrogen phosphate or the like, wherein the above percentages are based on the water-free composition. It is preferably freeze-dried, and administered at a dosage of 100 to 2000 mg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an injection of vancomycin, which is an antibiotic.

[0002]

BACKGROUND OF THE INVENTION Vancomycin is a glycopeptide antibiotic and is known to have an excellent action against multidrug-resistant Staphylococcus aureus. Antibiotics. Since vancomycin is a glycopeptide, it is not highly bioavailable for oral administration, and is therefore often used in highly bioavailable injections. The biggest problems in making injections are that coloring occurs during the manufacturing process, such as freeze-drying, and that depending on the manufacturing conditions, the formulation may gel during dissolution, making injection impossible. is there. In particular, since coloring may occur within a short period of time, this is a serious problem. Under such circumstances, various means have been devised for suppressing the coloring of vancomycin injection.
For example, a method in which ethanol is added at the time of freeze-drying, or a method in which mannitol or the like is added. However, the method of adding ethanol greatly changes the crystal system,
There was a problem in solubility during use, and concerns about the safety of residual ethanol could not be denied. Additives such as mannitol are often accompanied by a problem of gelation, and there are many cases where a problem remains in the reliability of the formulation system. That is,
The appearance of vancomycin injections with suppressed coloring has been awaited.

[0003]

An object of the present invention is to provide a vancomycin injection having suppressed coloring.

[0004]

In view of such circumstances, the present inventors have made intensive research efforts in search of vancomycin injections with reduced coloration.
Containing 99.8% by weight and 0.2 to 5% by weight of an organic acid,
Vancomycin injection, more specifically, 90 to 99.8% by weight of vancomycin and an organic acid of 0.1 to 9% by weight, wherein the pH at the time of use is adjusted to 3.0 to 3.40.
Such properties were found in vancomycin injections containing 2 to 5% by weight, and the invention was completed. Hereinafter, the present invention will be described in detail focusing on the embodiments of the present invention.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Organic acid used in the present invention The vancomycin injection of the present invention is characterized by containing an organic acid. Here, the organic acid referred to in the present invention is an aliphatic hydrocarbon which may have a hydroxyl group or an ether bond, has a carboxyl group or an ionizer in the molecule, and has an acidic pH. And specifically, acetic acid,
Preferred examples include propionic acid, butyric acid, succinic acid, oxalic acid, tartaric acid, citric acid, lactic acid, glycolic acid, gluconic acid, malic acid and the like. Of these, oxalic acid, tartaric acid and citric acid are more preferred, and citric acid is particularly preferred. The preferable content of these organic acids in the vancomycin injection of the present invention is 0.1 to the total amount of components other than water.
2 to 5% by weight, more preferably 0.2 to 4% by weight
And more preferably 0.2 to 3% by weight. In the vancomycin injection of the present invention, these organic acids may be used alone or in combination of two or more. or,
As for the content of the organic acid, the pH is from 3.0 to 3.0 in the situation at the time of use.
40, more preferably 3.05 to 3.40, and still more preferably 3.10 to 3.40.

(2) Vancomycin injection of the present invention Vancomycin injection of the present invention is 90 to 99.8% by weight, more preferably 93 to 99.8% by weight, more preferably 93 to 99.8% by weight, based on the total amount of components other than water. Is 95-9
It is characterized by containing 9.8% by weight and 0.2 to 5% by weight of an organic acid. Here, vancomycin is a known antibiotic, which is already commercially available and easily available. Vancomycin can be used in a free form or as a salt with hydrochloric acid, nitric acid or the like. Preferred is the hydrochloride salt. The injection of the present invention can contain, in addition to these essential components, optional components usually used in injections as long as the effects of the invention are not impaired. Such optional components include, for example, buffers such as sodium citrate, potassium citrate, sodium hydrogen phosphate and sodium acetate, isotonic agents such as sodium chloride and potassium chloride,
And sugars such as glucose. As the dosage form of the injection, for example, a vial-filled freeze-dried product or a liquid preparation can be used without any particular limitation, but a freeze-dried product is preferable from the viewpoint of storage stability. The term “injection” as used in the present invention means a form of administration to a blood vessel, intramuscularly, subcutaneously, or the like via an injection needle. The pharmaceutical classification includes both injections and / or drops. Means The injection of the present invention,
It can be used as it is as an injection, or the injection or lyophilized product of the present invention dissolved in an aqueous medium can be added to other infusions and administered.
The injection of the present invention is preferably in a dosage form capable of administering 100 to 2000 mg of vancomycin at a time. This is because a single dose is of this order. The method for producing the injection of the present invention may be performed according to a conventional method.For example, after dissolving all the components of the preparation and sterilizing by filtration, filling in an ampoule or filling in a vial, and freeze-drying You can do it. In the production process, it is preferable to replace the air in the preparation container with an inert gas such as nitrogen, helium, or argon in the final step in order to prevent coloring or the like and improve stability. or,
It is possible to add a small amount of ethanol or the like during freeze-drying in the production process of the injection of the present invention within a range that does not impair the effects of the present invention and that does not cause adverse effects such as gelation. The injection of the present invention does not impair safety by performing such an operation.

[0007]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the present invention is not limited to only these Examples.

Example 1 A lyophilized injection was prepared according to the following formulation. That is, the formulation components are dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, freeze-dried, sealed, and injected (vial).
I got Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.16. Vancomycin hydrochloride 500mg (98% by weight) Citric acid 10mg (2% by weight) Water 5ml

Example 2 A freeze-dried injection was prepared according to the following formulation. That is, the formulation components are dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, freeze-dried, sealed, and injected (vial).
I got Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.28. Vancomycin hydrochloride 500mg (99% by weight) Citric acid 5mg (1% by weight) Water 5ml

Example 3 A lyophilized injection was prepared according to the following formulation. That is, the formulation components are dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, freeze-dried, sealed, and injected (vial).
I got Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (use conditions), and the pH was measured to be 3.39. Vancomycin hydrochloride 500mg (99.6% by weight) Citric acid 1mg (0.4% by weight) Water 5ml

Example 4 A freeze-dried injection was prepared according to the following formulation. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.16. Vancomycin hydrochloride 500mg (98% by weight) Citric acid 10mg (2% by weight) Water 5ml

Example 5 A lyophilized injection was prepared according to the following formulation. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.28. Vancomycin hydrochloride 500mg (99% by weight) Citric acid 5mg (1% by weight) Water 5ml

Example 6 A lyophilized injection was prepared according to the following formulation. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (use conditions), and the pH was measured to be 3.39. Vancomycin hydrochloride 500 mg (99.8% by weight) Citric acid 1 mg (0.2% by weight) Water 5 ml

Example 7 The preparations of Examples 1 to 6 were subjected to a severe test to confirm the stability. That is, the preparation was treated in an autoclave at 110 ° C. for 10 minutes, and 5 ml of water
Was added and dissolved, and spectroscopic measurement was performed at 465 nm to examine the degree of coloring. Control Example 1 was obtained by freeze-drying only vancomycin, and Control Example 2 was obtained by freeze-drying only vancomycin and substituting with nitrogen. In addition, none of these control examples could be said to be in a freeze-dried state. Table 1 shows the results. The results in this table show that the injection of the present invention is excellent in stability. In addition, it is also found that the preparation having a nitrogen replacement step in the final step is more excellent in stability. Comparative Example 1
Was dissolved in 5 ml of distilled water for injection, the pH was 3.5.
0, and that of Control Example 2 was also 3.50. The experimental results also show that if the pH at the time of use is lower than 3.4, the stability of the preparation is improved.

[0015]

[Table 1]

<Example 8> The preparations of Examples 1 to 6 were subjected to an acceleration test. That is, the formulation was stored at 40 ° C. and 75% humidity for 6 months. When the titer was measured after storage, all the samples were equivalent to those at the start of the titer test.

Example 9 A lyophilized injection was prepared according to the following formulation. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating condition), and the pH was measured to be 3.23. or,
No coloring was observed with the naked eye even after treatment in an autoclave at 110 ° C. for 10 minutes. Vancomycin hydrochloride 500mg (98% by weight) Lactic acid 10mg (2% by weight) Water 5ml

<Example 10> According to the following formulation,
A lyophilized injection was prepared. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating condition), and the pH was measured to be 3.31.
No coloration was observed with the naked eye even at 110 ° C. for 10 minutes in an autoclave. Vancomycin hydrochloride 500mg (99% by weight) Malonic acid 5mg (1% by weight) Water 5ml

<Example 11> According to the following formulation,
A lyophilized injection was prepared. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.35.
No coloration was observed with the naked eye even at 110 ° C. for 10 minutes in an autoclave. Vancomycin hydrochloride 500 mg (98.8% by weight) Citric acid 5 mg (1% by weight) Sodium acetate 1 mg (0.2% by weight) Water 5 ml

Example 12 According to the following formulation,
A lyophilized injection was prepared. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (operating conditions), and the pH was measured to be 3.25.
No coloration was observed with the naked eye even at 110 ° C. for 10 minutes in an autoclave. Vancomycin hydrochloride 500 mg (98.8% by weight) Citric acid 5 mg (1% by weight) Monosodium citrate 1 mg (0.2% by weight) Water 5 ml

Example 13 According to the following formulation,
A lyophilized injection was prepared. That is, the prescription components were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two ampoules, replaced with nitrogen, and sealed to obtain an injection (ampoule). When the pH of one of the two ampules was measured, it was 3.29. Vancomycin hydrochloride 500mg (99% by weight) Citric acid 5mg (1% by weight) Water 10ml

Example 14 According to the following formula,
A lyophilized injection was prepared. That is, the ingredients were dissolved under aseptic conditions, sterilized by filtration through a 0.2 μm filter, filled into two vials, lyophilized, replaced with nitrogen, and sealed to obtain an injection (vial). Freeze drying was a beautiful finish. One of the two vials was dissolved in 5 ml of water (use conditions), and the pH was measured to be 3.29.
No coloration was observed with the naked eye even at 110 ° C. for 10 minutes in an autoclave. Vancomycin hydrochloride 500 mg (98.8% by weight) Citric acid 5 mg (1% by weight) Mannitol 1 mg (0.2% by weight) Water 5 ml

[0023]

According to the present invention, it is possible to provide vancomycin injection with suppressed coloring.

Claims (4)

[Claims] (1) In addition to water, vancomycin 90 to 99.8.
An injectable vancomycin solution containing 0.2% by weight of an organic acid and 0.2 to 5% by weight of an organic acid. 2. The vancomycin injection according to claim 1, wherein the pH at the time of use is adjusted to 3.0 to 3.40. 3. The vancomycin injection according to claim 1, wherein the organic acid is citric acid. 4. It is nitrogen-substituted,
The vancomycin injection according to any one of claims 1 to 3.