JPH10287569A - Transfusion solution type kit injection preparation of acyclovir or its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a transfusion solution type kit injection preparation that causes no crystallization for a long period of time, even when a considerable amount of the active ingredient is dissolved, in and is chemically stable by adding a specific basic substance to acyclovir or its salt at a certain ratio. SOLUTION: This transfusion solution type kit injection preparation of acyclovir or its salt is prepared by filling vials or plastic bottles with an aqueous solution containing 0.02-1.0 w/v%), preferably 0.05-0.5 w/v% of acyclovir or its salt and 0.01-2.0 w/v%, preferably 0. 045-0.3 w/v%) of one or two kinds of specific bases selected from sodium hydroxide, trometamol or meglumine. The aqueous solution that is used for this transfusion solution type kit injection preparation may contain 0.1-1.0 w/v% of sodium hydrogen phosphate and/or 0.01-1.0 w/v% of sodium dihydrogen phosphate.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to acyclovir (acy)
Clovir) or a salt thereof as an active ingredient.

[0002]

BACKGROUND ART Acyclovir or a salt thereof is a compound known as an antiviral agent (JP-B-56-33396). As a drip intravenous injection, a freeze-dried solid preparation which is dissolved before use is known, but an infusion kit injection is not yet known.

[0003]

The injectable preparation for use at the time of use is prepared by filling a vial with a powder prepared in advance or by filling a solution and solidifying the solution in a vial by freeze-drying or the like. Either method is more likely to cause bacterial contamination or foreign matter contamination than the solution. In addition, the injection solution of the dissolution type at the time of use, even if there is no foreign matter that can be detected with the naked eye in the attached solvent,
It has also been pointed out that it is detected after lysis. The foreign substances detected after dissolution include the foreign substances contained in the solid pharmaceutical preparation for injection before dissolution and the foreign substances mixed from the outside air at the time of dissolution. For this reason, at present, the degree of contaminants in the in-use dissolving type injection is larger than that of the solution injection. Furthermore, the solid solution for injection of the dissolving type at the time of use is apt to cause errors during the preparation of the drug,
It has the disadvantage of being inferior in operation speed.

[0004] In recent years, the use of injections, ie, infusions, which are administered in large amounts intravenously, has been widespread. However, under the condition of intravenous large-volume administration, an extremely high level of safety of an injection is required, so that a more advanced technique such as prevention of foreign substances from being mixed in the injection is required. It is considered that injections used as infusions have a large injection amount and a high risk of bacterial contamination and contaminating foreign matter.

[0005] Therefore, there has been a demand for an infusion-type kit injection which is capable of direct intravenous drip intravenous injection, which is excellent in the risk of bacterial contamination and contamination with foreign substances and in the speed of operation without error in the preparation of medication.

The preparation of an infusion kit of acyclovir or a salt thereof for injection is not only intended to prevent crystal precipitation and decomposition of an aqueous solution containing a clinical dose of acyclovir or a salt thereof, but also to alleviate pain, local irritation and hemolysis. Sex, tonicity and pH adjustment to prevent atrophy of red blood cells must also be made.

Acyclovir is extremely insoluble in water.
To make a 250 mg single dose as a clear aqueous solution, 500 m of water
L or more is required. In addition, 0.025% of acyclovir (W /
V) Crystals precipitate in the aqueous solution after storage for 3 days at room temperature and the next day when stored in a cool place. For the purpose of preventing this crystal precipitation, polysorbate 80 as a surfactant, polyethylene hydrogenated castor oil, sodium deoxycholate, polyoxyl stearate 40, polyethylene glycol as an alcohol, ethanol, or a hydrophilic polymer as a solubilizing agent. Hydroxypropylcellulose was added, but in any case, crystals precipitated within 3 days after standing at room temperature, and were ineffective.

Further, in order to increase the chemical stability in solution, acyclovir or a salt thereof is added to sodium sulfite, sodium bisulfite or sodium pyrosulfite, as an antioxidant, or sodium edetate, a chelating agent, as a stabilizer. Cysteine hydrochloride, or an antioxidant and a stabilizer were combined to prepare an injection, but the expected stabilizing effect was not obtained.

[0009]

Means for Solving the Problems The present inventors have conducted intensive studies on infusion-type kit injections containing acyclovir or a salt thereof, and found that by adding a specific basic substance at a certain ratio, acyclovir or acyclovir was added. 0.0
Even when dissolved in a concentration range of 25 to 1.0% (W / V), no crystals were precipitated for a long period of time, and it was found that they were chemically stable, and the present invention was completed.

According to the present invention, acyclovir or a salt thereof is used in an amount of 0.025 to 1.0% (W / V), preferably 0.05 to 1.0%.
1.0% (W / V), more preferably 0.05 to 0.5% (W / V) and the specific basic substance in an amount of 0.01 to 2.0% (W / V), preferably 0.04
5 to 1.1% (W / V), more preferably 0.045 to 0.3% (W / V)
The present invention relates to an infusion-type kit injection of acyclovir or a salt thereof filled with an aqueous solution contained in a vial or a plastic bottle.

The aqueous solution used in the infusion kit of the present invention contains sodium monohydrogen phosphate as a buffer.
~ 1.0% (W / V) and / or 0.01% sodium dihydrogen phosphate
~ 1.0% (W / V) can be contained.

Examples of the specific basic substance in the present invention include sodium hydroxide, trometamol, meglumine and the like, and particularly preferred is sodium hydroxide and trometamol. Salts of acyclovir include sodium salts and potassium salts.

Further, in the practice of the present invention, pH adjusters (hydrochloric acid, citric acid, sodium citrate, etc.) and tonicity agents (sodium chloride, glycerin, propylene glycol, etc.) usually used in injections are used. Can be added to the aqueous solution. Especially sodium chloride is 0.1-1.0%
(W / V). And from the viewpoint of prevention of crystal precipitation due to long-term storage, chemical stability, and local irritation, the aqueous solution used in the present invention has an osmotic pressure ratio of 0.7 to 1.
5, pH 9-12, preferably 0.9-1.1, pH 10-1
It is desirable to adjust to 1.

Then, the prepared aqueous solution is added in an amount of 25 mL to 100 mL.
Fill into a 0 mL glass or plastic container and use it as an infusion kit injection.

[0015]

Next, the present invention will be described with reference to Comparative Examples and Examples, but the present invention is not limited to these.

[Control Example 1] Acyclovir (0.25 g) was mixed with distilled water for injection (900 mL) and heated at 40 ° C. to dissolve the solution. This solution was filtered using a 0.2 μm membrane filter, filled into a glass vial having a capacity of 1000 mL, sealed, and sterilized to obtain an injection of an infusion kit of 0.025% (W / V) of acyclovir.

Control Example 2 Distilled water for injection was added to acyclovir (2.5 g) and polysorbate 80 (1.0 g), and the mixture was dissolved by heating at 40 ° C., and the total amount was adjusted to 1000 mL. This solution was filtered using a 0.2 μm membrane filter, filled in a 100-mL plastic container, sealed, and sterilized to obtain an injection of acyclovir 0.25% (W / V) infusion kit.

Control Example 3 Distilled water for injection was added to acyclovir (0.5 g) and hydroxypropylcellulose (0.1 g), and the mixture was dissolved by heating at 40 ° C., and the total amount was adjusted to 1000 mL. This solution was filtered using a 0.2 μm membrane filter, and filled into a 500 mL plastic container.
It was sterilized to obtain an injection of acyclovir 0.05% (W / V) infusion type kit.

[Control Example 4] Acyclovir (2.5 g) and sodium hydroxide (0.65 g) were dissolved by adding distilled water for injection, and then sodium chloride (8.0 g) and sodium edetate were added.
(50 mg) and sodium bisulfite (200 mg) were added, and the total volume was made up to 1000 mL with distilled water for injection. 0.2 μl of this solution
The solution was filtered using a membrane filter of 100 m, filled into a glass vial having a capacity of 100 mL, sealed, and sterilized to obtain an infusion kit of 0.25% (W / V) acyclovir infusion type kit.

[0020]

[Example 1] Acyclovir sodium salt (25.0 g) and trometamol (20.0 g) were dissolved in distilled water for injection, and the total amount was 1%.
0 L was set. This solution was filtered using a 0.2 μm membrane filter, filled into a 100-mL hard plastic bottle, sealed, and sterilized to obtain a 0.25% (W / V) infusion kit injection of acyclovir sodium salt. .

Example 2 Acyclovir potassium salt (5.0
g), trometamol (5.0 g) dissolved in distilled water for injection,
The total volume was 10 L. This solution was filtered using a 0.2 μm membrane filter, filled into a 500 mL plastic infusion bottle, sealed and sterilized, and a 0.05% (w / v) acyclovir potassium salt infusion kit injection was prepared. Obtained.

Example 3 Acyclovir (5.0 g), trometamol (30.0 g) and sodium chloride (50.0 g) were dissolved in distilled water for injection to make a total volume of 10 L. Add this solution to 0.2
Filter through a 500 μm membrane filter, 500 mL
After filling in a hard plastic bottle having a capacity, it was sealed and sterilized to obtain an injection of an infusion kit of 0.05% (W / V) of acyclovir.

Example 4 Acyclovir (25.0 g), sodium hydroxide (5.0 g), and sodium chloride (90.0 g) were dissolved in distilled water for injection to make a total volume of 10 L. This solution
Filter through a 0.2 μm membrane filter,
After filling into a plastic infusion bottle having a volume of mL, it was sealed and sterilized to obtain an infusion kit of 0.25% (W / V) infusion of acyclovir.

Example 5 Acyclovir (10.0 g), sodium hydroxide (2.4 g) and glycerin (20.0 g) were dissolved in distilled water for injection to make a total volume of 1000 mL. Add this solution to 0.
Filter using a 2 μm membrane filter and filter
After filling into a glass vial having a capacity, it was sealed and sterilized to obtain an injection of an infusion kit of 1.0% (W / V) of acyclovir. Example 6 Acyclovir (5.0 g), sodium hydroxide
(0.6 g), sodium chloride (6.8 g) and trometamol
(10.0 g) was dissolved in distilled water for injection to make a total volume of 1000 mL. This solution was filtered through a 0.2 μm membrane filter, filled in a 50 mL hard plastic container, sealed, sterilized, and then 0.5% (W / V) of acyclovir
An infusion kit injection was obtained.

Example 7 Acyclovir (12.5 g), sodium hydroxide (4.5 g), sodium chloride (84.0 g)
g), sodium monohydrogen phosphate (25.0 g) and sodium dihydrogen phosphate (1.0 g) were dissolved in distilled water for injection to make a total volume of 10 L. This solution was filtered using a 0.2 μm membrane filter, filled into a 200 mL plastic infusion bottle, sealed, and sterilized to obtain acyclovir 0.125% (W / V) infusion kit injection. .

[0026]

The injection of the infusion kit of the present invention is an injection having extremely excellent storage stability without precipitation of crystals even when left in a cold place for a long period of time and without decomposing acyclovir.

According to the present invention, the volume of the injection can be arbitrarily set in the range of 25 to 1000 mL. Furthermore, isotonicity and p
H adjustment has been made,
It does not require any dissolution and dilution operations, and can be used for treatment as an infusion-type injection that can be directly infused intravenously. As a result, it is possible to provide an infusion-type kit injection of acyclovir or a salt thereof, which is free from the risk of bacterial contamination and contamination with foreign substances and the error in preparation of the medicament, and is excellent in the speed of operation.

The test methods and test results for stability and operability are shown below.

1. Stability (1) Crystal Precipitation [Test Method] With respect to Comparative Examples 1 to 4 and Examples 1 to 7, the crystal precipitation at a cold place or at room temperature was observed. Judgment of crystal precipitation was conducted according to the insoluble foreign matter test method of the Japanese Pharmacopoeia.
Observation was made with the naked eye at the position of the brightness of lux, and the case where crystals were precipitated was marked as +, and the case where crystals were not seen was marked as-.

[Test Results] The results are shown in Table 1.

[0031]

[Table 1]

In Comparative Examples 1 to 3, acyclovir crystals were precipitated within one day in a cold place and within three days at room temperature. In Comparative Example 4, crystals were precipitated within one day in a cool place, but no crystals were found after storage at room temperature for 90 days.

In Examples 1 to 7, no crystal precipitation was observed in a cool place and at room temperature for 90 days.

(2) Chemical stability [Test method] For Control Examples 1-4 and Examples 1-7,
After storage at 40 ° C. for 6 months, changes in appearance and decomposition products were searched. Changes in appearance were visually observed, and retrieval of degraded products was tested by high performance liquid chromatography.

[Test Results] The results are shown in Table 2.

[0036]

[Table 2]

In Comparative Examples 1 to 3, crystal precipitation was observed. Control Example 4 and Examples 1 to 7 were colorless and clear liquids, and no change in appearance was observed. In addition, as a result of searching for a degraded product for a formulation in which no change in appearance was observed, a degraded product was found in Control Example 4. On the other hand, Example 1
In ~ 7, no decomposed product was observed and the composition was chemically stable. Operability Known in-use dissolution type intravenous drip injection (hereinafter “known injection”)
That. ) And the infusion kit of the present invention (hereinafter referred to as "kit injection") were compared and examined for operability until the infusion set was attached.

[Test Method] The procedure for mounting the infusion set for the known injection and the kit injection of Example 4 is as follows: (1) Preparation of drug / apparatus; (2) Preparation of drug (opening);
The time required for each step of (3) equipment preparation (opening), (4) mixing and dissolving operation, and (5) installation of an infusion set was 3 times by six subjects.
The measurement was performed consecutively.

[Test Results] Table 3 shows the average operation time of the six subjects and the total time until the completion of preparation for infusion start.

[0040]

[Table 3]

The total time required to complete the preparation for the start of infusion of the known injection was 199.3 seconds, and especially the mixing and dissolving operation required a lot of time. On the other hand, in the case of the kit injection of the present invention, since the preparation for the mixing and dissolving operation is unnecessary, the total time until the completion of the preparation for infusion start was about 1/4 of the known injection.

Claims (5)

[Claims] 1. Acyclovir or a salt thereof in an amount of 0.025 to 1.0%
(W / V) and an infusion-type kit of acyclovir or a salt thereof containing 0.01 to 2.0% (W / V) of one or more specific basic substances selected from sodium hydroxide, trometamol and meglumine. Injection. 2. A sodium monohydrogen phosphate 0.1-1.0% (W /
V) and / or sodium dihydrogen phosphate 0.01 to 1.0% (W /
The infusion-type kit injection according to claim 1, which contains V). 3. Acyclovir or a salt thereof having a concentration of 0.05 to 0.5.
% (W / V). 4. The method according to claim 1, wherein the concentration of the specific basic substance is 0.045 to 0.3% (W /
4. The infusion kit injection according to claim 1, which is V). 5. The method according to claim 1, wherein the specific basic substance is sodium hydroxide, trometamol, or a mixture thereof.
4. The infusion type kit injection according to 4.