JP5624281B2 - Liquid formulation containing quinolone antibacterial agent with excellent photostability - Google Patents

Description

  The present invention relates to a liquid preparation containing a quinolone antibacterial agent excellent in light stability, and particularly to a liquid preparation containing levofloxacin.

  Quinolone antibacterial agents have excellent antibacterial activity against gram-positive and gram-negative bacteria, and various preparations based on this have been developed. However, since quinolone antibacterial drugs themselves have low light stability, various methods for improving the light stability of quinolone antibacterial drug-containing preparations have been reported.

  Among liquid preparations containing quinolone antibacterial agents, as eye drops, for example, eye drops mainly composed of levofloxacin (trade name: Crabit (registered trademark) eye drops, containing 0.5 wt% of levofloxacin) are commercially available. Yes. This ophthalmic solution contains levofloxacin as an active ingredient, contains sodium chloride (isotonic agent) and a pH regulator as additives, has a pH of 6.2 to 6.8, and an osmotic pressure ratio of 1.0 to 1. A liquid preparation adjusted to 0.1, and its property is a sterile aqueous eye drop that is slightly yellow to light yellow clear.

  This levofloxacin ophthalmic solution does not contain a preservative such as benzalkonium chloride because levofloxacin itself has a broad antibacterial spectrum. Furthermore, there are few pH fluctuations due to the storage of this agent under light-shielding, and levofloxacin itself has a buffering capacity, so there is no need to add a buffering agent.

  Regarding the stability of levofloxacin ophthalmic solution to light, storage conditions are 25 ° C., 1,000 lx, storage state: 300 ml lx as a result of a severe test (stability to light) in a 5 mL polyethylene container (no label, exposure).・ At hr, 600,000 lx · hr, and 1.2 million lx · hr, the pH of the ophthalmic solution before irradiation may be lowered to pH 6.5, pH 6.4, and pH 6.2, respectively. Are known.

  In addition, the content (%) of levofloxacin, which is an active ingredient, also decreases to 92%, 90%, and 84%, respectively, compared to 101% before irradiation, and the storage conditions are 25 ° C. and 1,000 lx, storage state: It is also known that it is stable in a 5 mL polyethylene container (no label, in a brown shading bag) (Non-patent Document 1).

  Furthermore, levofloxacin ophthalmic solution is stable against slight temperature changes if it is sealed in a light-shielding bag in a state where it is filled in a polyethylene container. It has been reported that it is necessary to instruct to store it in a light-shielding bag because it falls outside the standard (Non-Patent Document 2).

  However, for quinolone antibacterial ophthalmic solutions such as levofloxacin, the packaging container (packaging body) is required to be transparent so that quality inspections such as visual inspection from the outside can be easily performed at the time of manufacture. Is done. Therefore, the packaging container for the quinolone antibacterial solution cannot be made a container that completely blocks the incidence of light from the outside.

Therefore, techniques for improving light stability have been reported for quinolone antibacterial drug-containing liquid preparations such as levofloxacin.
For example, a quinolone antibacterial agent is dissolved in at least one or two or more phosphate aqueous solutions having a buffering action against the quinolone antibacterial agent, and the pH of the solution is adjusted to 5.5 to 7 with an acid or an alkali agent. .5, and by adjusting the osmotic pressure ratio to 0.85 to 1.20 with a neutral salt, and adjusting the blending amount of phosphate to 0.5 to 3.3 wt / v% as an anhydride. Quinolone antibacterial liquid preparations for improving safety, and packaging of quinolone antibacterial liquid preparations in which this liquid preparation is filled in a packaging container made of a green transparent or translucent material (Patent Literature) 1).
Japanese Patent No. 3648132 Chemotherapy, Vol.16, No.6, p.103-106 (2000) Pharmaceutical Journal, Vol.42, No.6, p.1725-1729 (2006)

  However, even if such means are adopted, liquid preparations containing quinolone antibacterial agents are susceptible to the effects of coloration by light, decrease in pH, decrease in content, appearance of degradation products, etc. Even under use or storage, there is a demand for the development of a preparation that can sufficiently secure the light stability of the quinolone antibacterial agent in this liquid preparation.

  Therefore, in view of the above situation, the present invention provides a liquid preparation containing a quinolone antibacterial agent that has excellent light stability and can ensure the effectiveness of the contained quinolone antibacterial agent over a long period of time. Let it be an issue.

The present invention for solving this problem is as follows.
(1) Levofloxacin and at least one or two or more citrates with respect to levofloxacin are dissolved in 0.2 to 0.85 wt / v% water, and the pH of this solution is adjusted to 5. with an acid or an alkali agent. A levofloxacin- containing liquid formulation with improved light stability, characterized in that it is adjusted to 5-7.5 and the osmotic pressure ratio is adjusted to 0.85-1.20 with a neutral salt,
(2) The levofloxacin-containing ophthalmic solution according to (1) above, wherein the pH is adjusted by adding citric acid ,
It is.

  That is, as a result of the inventor's investigation, the quinolone antibacterial drug dissolved in the solution is present stably with respect to light, particularly due to the buffer effect, isotonicity, etc. due to the addition of citrate. It is what has.

According to the present invention, a quinolone antibacterial drug-containing liquid preparation that maintains the effectiveness of quinolone antibacterial agents, particularly levofloxacin, particularly levofloxacin, and has excellent light stability and usability, particularly eye drops. Can be provided.
In addition, since the quinolone antibacterial drug-containing liquid preparation of the present invention is excellent in stability to light, the packaging container (packaging body) filled with the liquid preparation may be transparent. Therefore, the quality inspection and the like can be easily performed by visual inspection from the outside, and a quinolone antibacterial drug-containing liquid preparation with superior safety can be provided.
In particular, in the present invention, the buffering action by citrate added as a stabilizer for levofloxacin and the buffering action of levofloxacin itself act synergistically, so that the above-mentioned is mentioned in spite of a few ingredients. Under a specific range of pH value and osmotic pressure ratio, the effect of significantly improving the light stability is exhibited, and the effect is unique.

The quinolone antibacterial agent as an active ingredient in the present invention is a synthetic antibacterial agent having a condensed pyridone carboxylic acid skeleton. , Pipemidic acid, pyrometic acid and the like.
In addition, the quinolone antibacterial drug-containing liquid preparation of the present invention refers to a liquid preparation containing the above-described quinolone antibacterial drug as an active ingredient. Specifically, for example, eye drops, nasal drops, ear drops, etc. Can be mentioned. Among these, a liquid preparation as an eye drop is particularly preferable.

  Hereinafter, the quinolone antibacterial drug-containing liquid preparation of the present invention will be described in detail by explaining the actual levofloxacin-containing liquid preparation using levofloxacin, which is a typical quinolone antibacterial drug.

In the levofloxacin-containing liquid preparation targeted by the present invention, levofloxacin as an active ingredient, one or more citrates are dissolved in water, and the pH of this solution is adjusted to 5.5-7 with an acid or an alkaline agent. 5 and a levofloxacin-containing liquid preparation with improved light stability, wherein the osmotic pressure ratio is adjusted to 0.85 to 1.20 with a neutral salt.

The blending amount of levofloxacin in the liquid preparation of the present invention is preferably 0.3 to 0.6 wt / v%, more preferably 0.3 to 0.5 wt / v%, particularly preferably about 0.5 wt / v. %.
This content can be appropriately changed according to the intended use of the liquid preparation.

  Moreover, as a citrate, the alkali metal salt of a citric acid, for example, sodium salt, potassium salt etc., or these crystal water addition products, and these mixtures can be mentioned.

  The amount of citrate in the levofloxacin-containing liquid formulation provided by the present invention is preferably 0.1 to 1.0 wt / v%, for example, as a sodium citrate hydrate. The blending amount may be an amount that ensures the buffering effect and the isotonicity of the levofloxacin to exhibit the light stability of the levofloxacin corresponding to the content of levofloxacin contained in the liquid preparation, more preferably, 0.2 to 0.85 wt / v%. If this blending amount is less than 0.1 wt / v%, there is a drawback that it is impossible to maintain an appropriate pH, and if it exceeds 1.0 wt / v%, there is a disadvantage that the liquid preparation becomes isotonic. is there.

The pH of the levofloxacin-containing liquid preparation provided by the present invention may be 5.5 to 7.5, and the effect of significantly improving the applicability of levofloxacin contained in the liquid preparation to the living body is effectively exhibited. Moreover, it becomes a more stable state. More preferably, the pH is in the range of 6.0 to 7.0, and particularly preferably the pH is about 6.5.
The pH of the liquid formulation can be adjusted alkaline agent such as sodium hydroxide qs, or hydrochloric acid, citric acid, by addition of an acid such as citric acid hydrate. Citric acid is preferable, and the amount of citric acid hydrate is preferably 0 to 0.1 wt / v%. More preferably, it is 0-0.06 wt / v%.

  The osmotic pressure ratio of the levofloxacin-containing liquid preparation of the present invention can be adjusted, for example, by adding a neutral salt such as sodium chloride or potassium chloride, preferably sodium chloride. The osmotic pressure ratio is preferably from 0.85 to 1.20, more preferably from 0.95 to 1.1.

  The levofloxacin-containing liquid preparation of the present invention can be produced by mixing and dissolving the above-described blended components at room temperature or under heating conditions. In the mixed dissolution, at least one or two or more citrates may be dissolved after levofloxacin is first dissolved in purified water, and at least one or two or more citrates may be dissolved first. After dissolving in purified water, levofloxacin may be added and dissolved.

  About the levofloxacin containing liquid formulation which this invention provides, arbitrary components can be added as needed other than the said component. Examples of such components include polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol; alcohols such as ethyl alcohol and benzyl alcohol; polyvinyl pyrrolidone; preservatives such as benzalkonium chloride; Agents; antioxidants such as ascorbic acid; sodium edetate and the like.

  The levofloxacin-containing liquid preparation of the present invention prepared as described above is provided by being filled in a container according to each purpose, for example, as an eye drop, a nose drop, an ear drop or the like. Examples of such containers include various materials such as synthetic resin materials such as polyethylene, polypropylene, polyterephthalate, and glass materials made of transparent to translucent materials that function as containers filled with a liquid agent. Preferably, it is a container made of polyethylene resin.

As these packaging containers, transparent to translucent ones that are colored in white, blue, green, etc. can be used in addition to colorless and translucent ones.
The levofloxacin-containing liquid preparation provided by the present invention is particularly excellent in light stability, and can be filled into a transparent container as a container. It is possible to provide a liquid preparation containing a quinolone antibacterial agent which can be easily carried out and is superior in safety.

Hereinafter, the present invention will be described with reference to specific examples, but the present invention is not limited to these examples.
In Examples 1 to 10 below, the osmotic pressure ratio of the ophthalmic solution was adjusted to 1.05 using sodium chloride.
Also, eye drop was adjusted to pH6.5 using a pH modifier hydrochloric acid and / or sodium hydroxide.

Example 1:
Under normal temperature, levofloxacin 500 mg was added to 80 mL of purified water and dissolved by stirring, and then 850 mg of sodium citrate hydrate was added and dissolved by stirring. Next, 656 mg of sodium chloride was added to this solution and dissolved by stirring, and then 57 mg of citric acid hydrate was added to adjust the pH of this dissolved solution to 6.5, and purified water was added to a total of 100 mL. Then, a slightly yellow and clear ophthalmic solution was obtained by filtration.

Example 2:
In the formulation of Example 1, 57 mg of citric acid hydrate was changed to 30 mg, and the same treatment as in Example 1 was performed except that hydrochloric acid was adjusted to pH 6.5 with this hydrochloric acid solution. An ophthalmic solution was obtained.

Example 3:
A slightly yellow clear ophthalmic solution was obtained by the same treatment as in Example 2 except that 30 mg of citric acid hydrate was changed to 0 mg (that is, no addition) in the formulation of Example 2.

Hereinafter, the ophthalmic solutions of Examples 4 to 10 were prepared in the same manner as the formulations of Examples 1 to 3.
These compositions are summarized in Table 1. In addition, the numerical value in a table | surface shows mg in 1 mL of samples.

Comparative Examples 1-3:
A commercial product (trade name: Cravit (registered trademark) ophthalmic solution, containing 0.5 wt / v% levofloxacin) was used as Comparative Example 1. However, the pH of Comparative Example 1 was 6.55.
As Comparative Example 2, a sample having a pH of 6.5 was prepared by adding and dissolving levofloxacin in physiological saline and adding an appropriate amount of hydrochloric acid.
As Comparative Example 3, a sample having a pH of 6.5 was prepared by adding an acid or alkali pH adjuster to a levofloxacin dissolved in a phosphate buffer.
The compositions of these Comparative Examples 1 to 3 are summarized in Table 2.

  The numerical value of each component in the table indicates mg in 1 mL of the sample. Moreover, * shows that it is unknown from a commercial item.

Test Example 1: Light stability test of levofloxacin Each ophthalmic solution of Examples 1 to 10 and Comparative Examples 1 to 3 was filled in a colorless and transparent polyethylene container (cylindrical shape, 5 mL capacity, manufactured by Taisei Kako Co., Ltd.). Sealed and subjected to a photostability test.
A daylight fluorescent lamp was irradiated from above the container filled with each ophthalmic solution with a light intensity of 3000 lx · hr.
When the amount of light irradiation reached 600,000 lx · hr, the content of levofloxacin in the ophthalmic solution filled in each container was quantified, and the residual ratio of levofloxacin was calculated from the quantified value.
The results are shown in Table 3.

As a result, it was found that the photostability of levofloxacin was stabilized as the amount of sodium citrate hydrate was increased.
The residual ratio of levofloxacin in the samples of Examples 1 to 10 was found to be extremely high when compared with the residual ratio of the specimen samples of Comparative Examples 1 to 3, and had excellent light stability. did.

Comparing the residual ratio of levofloxacin, it can be seen that the residual ratio characteristics of the specimen samples in the examples of the present invention are significantly improved when compared with Comparative Example 1 (commercially available product).
Further, when compared with Comparative Example 2 (a solution obtained by removing citrate from the solution of the present invention), it is found that the solution of the present invention exhibits excellent light stability.
Furthermore, when compared with Comparative Example 3 (a liquid agent containing a phosphate buffer), it is found that the liquid agent of the present invention exhibits excellent light stability.

The method for quantifying levofloxacin in the sample is as follows.
Prepare the sample solution, standard solution and internal standard solution according to the following, and then perform the test by the Japanese general test method liquid chromatograph method to determine the ratio of the peak area of levofloxacin to the peak area of the internal standard substance, It was calculated based on the calculation formula.

[Sample solution]
Chemical solution (5 mg / mL) 2.5 mL / 0.01 mol / L-hydrochloric acid 50 mL 0.25 mg / mL
10 mL of the above chemical solution + 4 mL of internal standard / 50 mL of purified water

[Standard solution]
Levofloxacin 50 mg / 0.01 mol / L-hydrochloric acid 100 mL 0.5 mg / mL
5 mL of the levofloxacin solution + internal standard 4 mL / purified water 50 mL

For 10 μL of the sample solution and the standard solution, the test is performed by the JP General Test Method liquid chromatograph method under the following conditions, and the ratios Q _T and Q _S of levofloxacin peak area to the peak area of the internal standard substance are obtained. It was calculated based on the following formula.

Levofloxacin content relative to the indicated amount (%) =
Amount of levofloxacin collected (mg) x Qt / Qs x 1/4 x K x 100
In the formula, 1/4 indicates the dilution factor, and K = 1 / [displayed amount (mg) × sampled amount (mL)].
The internal standard solution is a methyl paraoxybenzoate solution (3 → 20000).

[HPLC conditions]
Detector: UV absorptiometer (measurement wavelength: 254 nm)
Column: A stainless steel tube having an inner diameter of about 4.6 mm and a length of 150 mm packed with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C.
Injection volume: 10 μL.

Mobile phase: Water is added to 1.298 g of sodium 1-octanesulfonate and 1.361 g of potassium dihydrogen phosphate to dissolve to 1000 mL, and the pH is adjusted to 3.0 with phosphoric acid. This solution and acetonitrile are mixed at a ratio of 4: 1.

Flow rate: Adjust so that the retention time of levofloxacin is about 13 minutes.

Selection of column: When operating under the above conditions for 10 μL of standard aqueous solution, use one that elutes in order of internal standard substance and levofloxacin.

  The purity test method is as follows. First, 1 mL of a sample sample is accurately measured, and 3 mL of a water / methanol mixture (1: 1) is accurately added to obtain a sample solution. Hereinafter, levofloxacin hydrate, purity test (2) was performed according to related substances (Japanese Pharmacopoeia Forum Vol. 16, No. 4 (2007) 476-477).

Test Example 2: Purity Test The amount of decomposition product contained in each sample of Examples 1 to 10 and Comparative Examples 1 to 3 was determined.
The results are shown in Table 4.

  The numbers in the table are in%.

  From the results shown in Table 4 above, it was found that the purity characteristics of levofloxacin tend to be exactly the same as the stability results.

  The quinolone antibacterial agent-containing solution of the present invention is excellent in light stability. For example, in the case of levofloxacin, the residual rate is preferably 84.0% or more at an irradiation light amount of 600,000 lx · hr. More preferably, the residual ratio is 85.3%, and still more preferably 86.2% or more.

  It has been found that when the package filled with the specimen sample of the present invention is packaged with a UV cut label, the specimen sample is further stabilized. The comparison of the sample of the example and the comparative example showed the same tendency as the result of light stability.

The quinolone antibacterial drug-containing liquid preparation provided by the present invention is excellent in light stability. Moreover, the outstanding performance can be exhibited effectively over a long period of time.
This stability to light is due to the fact that quinolone antibacterial drugs dissolved in the solution exist stably with respect to light due to buffering effect, isotonicity, etc. due to the addition of citrate. The properties are superior to conventional liquid preparations containing quinolone antibacterial agents.
Therefore, the medical usefulness of the present invention is enormous in that it can provide a liquid formulation containing a quinolone antibacterial agent with better stability.

Claims (2)

Levofloxacin and at least one or two or more citrates with respect to levofloxacin are dissolved in 0.2 to 0.85 wt / v% water, and the pH of this solution is adjusted to 5.5 to 7. with acid or an alkali agent. 5 and a levofloxacin-containing ophthalmic preparation with improved light stability, wherein the osmotic pressure ratio is adjusted to 0.85 to 1.20 with a neutral salt.   The levofloxacin-containing ophthalmic solution according to claim 1, wherein the pH is adjusted by adding citric acid.