JP2011068589A - Pharmaceutical composition containing tosufloxacin or salt thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical composition that contains tosufloxacin or a salt thereof and has antiseptic effect and antipollution effect. <P>SOLUTION: The pharmaceutical composition comprises 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or its salt, a metal compound comprising aluminum as a constituent component, borax, an alkali metal chloride and a preservative. Therefore, the pharmaceutical composition comprises tosufloxacin or its salt, a metal compound comprising aluminum as a constituent component, borax, an alkali metal chloride and a preservative has excellent stability, antiseptic effect and antipollution effect and is useful especially as an ophthalmic solution, nasal solution and ear solution. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to tosfloxacin (7- (3-amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid) or a salt thereof, a metal compound containing aluminum as a constituent, borax, an alkali metal chloride, and a preservative, and this pharmaceutical composition is stable. And it is excellent in safety.

Tosfloxacin is widely known as an excellent antibacterial agent against gram-positive bacteria as well as gram-negative bacteria. As a method for stabilizing the solution, a method of adding a metal compound containing aluminum as a constituent, borax, and alkali metal chloride [Patent Document 1] is known.
By the way, the aqueous liquid applied to eye drops, nasal drops, ear drops and the like is often used in small amounts over a long period of time. For this reason, the aqueous liquid may be contaminated.
To date, there is no known pharmaceutical composition containing tosfloxacin or a salt thereof, a metal compound containing aluminum, borax, alkali metal chloride and a preservative.

Japanese Patent No. 3346586

  A pharmaceutical composition containing tosufloxacin or a salt thereof and having antiseptic and antifouling effects is desired.

  Under such circumstances, as a result of intensive studies, the present inventors have found that a pharmaceutical composition containing tosufloxacin or a salt thereof, a metal compound containing aluminum as a constituent, borax, an alkali metal chloride, and a preservative, The present invention has been completed by finding that it is excellent in stability, antiseptic effect and antifouling effect.

  The pharmaceutical composition containing tosufloxacin or a salt thereof of the present invention, a metal compound containing aluminum as a constituent, borax, alkali metal chloride and a preservative is excellent in stability, antiseptic and antifouling effects. It is useful as a liquid, nasal drop and ear drop.

  Hereinafter, the present invention will be described in detail.

  The pharmaceutical composition of the present invention is prepared by adding a metal compound containing aluminum as a component to a suspension of tosufloxacin or a salt thereof, and then adjusting the pH by adding borax. It can be made isotonic by adding substances, and further dissolved by adding a preservative.

Examples of the salt of tosufloxacin used in the pharmaceutical composition of the present invention include salts with inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; acetic acid, lactic acid, succinic acid, p-toluenesulfonic acid, methanesulfonic acid, maleic acid , Salts with organic acids such as malonic acid and gluconic acid; salts with amino acids such as aspartic acid and glutamic acid; sodium salts and potassium salts, and salts with p-toluenesulfonic acid are preferred.
In addition, when solvates, hydrates and crystals of various shapes are present in tosufloxacin or a salt thereof, the present invention can use all of them, and tosfloxacin p-toluenesulfonate hydrate can be used. It is preferable to use it.
The amount of tosufloxacin or a salt thereof used is 0.1 to 3%, preferably 0.3%, based on the pharmaceutical composition.

Examples of the alkali metal chloride used in the pharmaceutical composition of the present invention include sodium chloride and potassium chloride, and sodium chloride is preferred.
The amount of alkali metal chloride used is an amount necessary for making the solution isotonic.

Examples of the metal compound containing aluminum as a constituent component used in the pharmaceutical composition of the present invention include potassium aluminum sulfate, aluminum chloride, aluminum sulfate and hydrates thereof, and potassium aluminum sulfate dodecahydrate. Is preferred.
The amount of the metal compound containing aluminum as a constituent component is usually 0.1 to 30 times mol, preferably 0.1 to 10 times mol for tosufloxacin or a salt thereof.

  The pH of the pharmaceutical composition of the present invention is 3.5 to 7.0 at the time of dissolution, preferably 4.0 to 6.5, and the pH is adjusted by the amount of borax used. Other alkalis or acids may be added to the pharmaceutical composition of the present invention as needed. Examples of the alkali include sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Examples of the acid include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid, methanesulfonic acid, and the like.

Examples of the preservative used in the pharmaceutical composition of the present invention include benzethonium chloride, methyl paraoxybenzoate, ethyl paraoxybenzoate, chlorobutanol, sodium dehydroacetate and sodium benzoate, and ethyl paraoxybenzoate is preferred.
The amount of preservative used is preferably 0.001 to 0.1%, more preferably 0.03 to 0.05%, based on the pharmaceutical composition.

  A preferred example of the pharmaceutical composition of the present invention is to suspend tosufloxacin p-toluenesulfonate hydrate in water, add and dissolve potassium aluminum sulfate dodecahydrate, and then adjust the pH by adding borax. This solution is made isotonic by adding sodium chloride to this solution and further added with a preservative.

The pharmaceutical composition of the present invention can be applied mainly to preparations for injection (solution or dissolution type at the time of use), eye drops, nasal drops, ear drops, oral cavity or oral. In preparing the preparation, pharmaceutically acceptable adjuvants may be further added. Adjuvants include excipients, stabilizers, buffers, antioxidants, corrigents, thickeners, soothing agents and the like.
The administration method, the dosage, and the number of administrations can be appropriately selected according to the age, weight and symptoms of the patient. The pharmaceutical composition of the present invention is usually administered to an adult by oral or parenteral administration (for example, injection and administration to the rectal site, etc.) 0.1 to 50 mg / kg / day in terms of tosufloxacin once to several times. Can be divided and administered. In the case of administration such as eye drops, ear drops, and nose, the pharmaceutical composition of the present invention can be administered by dividing 1 to 100 μg / kg / day into 1 to several times in terms of tosufloxacin.

Next, the present invention will be described with reference to examples, comparative examples, and test examples, but the present invention is not limited thereto.
As compound A, tosufloxacin p-toluenesulfonate hydrate was used.
The comparative preparation in Test Example 2 is an ophthalmic solution produced without adding a preservative in the same manner as in Example 1.

Example 1
0.3 g of Compound A and 0.12 g of potassium aluminum sulfate dodecahydrate were added to 90 mL of purified water and dissolved at 55 ° C. 0.1 g of borax and 0.1 g of ethyl paraoxybenzoate were added and dissolved. The solution was cooled to room temperature and then made isotonic with sodium chloride. The pH was adjusted to 5.2 with sodium hydroxide solution, and the total volume was adjusted to 100 mL with purified water. This solution was aseptically filtered through a membrane filter (0.22 μm) and then filled into a polyethylene eye drop bottle to produce an eye drop.

Example 2
An ophthalmic solution was prepared in the same manner as in Example 1 using 0.05 g of ethyl paraoxybenzoate.

Example 3
An ophthalmic solution was prepared in the same manner as in Example 1 using 0.03 g of ethyl paraoxybenzoate.

Example 4
An ophthalmic solution was prepared in the same manner as in Example 1 using 0.02 g of ethyl paraoxybenzoate.

Comparative Example 1
0.3 g of Compound A and 0.12 g of potassium aluminum sulfate dodecahydrate were suspended in 90 mL of purified water and dissolved at 55 ° C. In this solution, 0.1 g of borax and 0.82 g of sodium chloride were dissolved. Furthermore, 7 mL of purified water and 3 mL of 1 mg / mL benzalkonium chloride aqueous solution were added to this solution.
Insoluble matter was observed after the addition of benzalkonium chloride.

Test Example 1 (Effect of preservative on stability of formulation)
The formulation of Example 2 was stored at room temperature and refrigerated, and after 6 weeks, the concentration of Compound A was measured.
The residual ratio of Compound A after 6 weeks was determined.
Residual rate (%) = (Concentration of Compound A after 6 weeks / Concentration of Compound A at the start) × 100
The results are shown in Table 1.

  The formulation of Example 2 was stable.

Test example 2 (antiseptic effect)
The antiseptic effect was measured using a micro liquid dilution method according to the standard method M27-A3 for sensitivity measurement of yeast and the standard method M38-A2 for sensitivity measurement for filamentous fungi recommended by the Clinical and Laboratory Standards Institute (CLSI). As the sensitivity measurement medium, 0.67% Difco Yeast Nitrogen Base without Amino Acids (YNB) containing 0.5% glucose sterilized by filtration was used.
The inoculum of Candida albicans TIMM1623 was prepared by diluting the cryopreserved inoculum with 10 times the concentration of YNB so that the final inoculum (1 × 10 ³ CFU / mL) was 10 times the concentration.
The inoculum solution of Aspergillus fumigatus TIMM0063 was prepared by diluting the refrigerated cell solution with 10 times the concentration of YNB so that the final inoculum amount (1 × 10 ⁴ CFU / mL) was 10 times.
Examples 1 to 4 and the comparative preparation were diluted with distilled water up to 10 stages at a common ratio of 2 using distilled water on a multiplate MS-8096R (Sumitomo Bakelite, 96 well, flat bottom) for free culture. Further, 20 μL of each inoculum was inoculated into each well and suspended using a microplate mixer. After culturing at 35 ° C. for 48 hours, the determination was made visually. In the case of yeast, the culture solution was suspended using a microplate mixer before the determination.
In order to serve as an index of the antiseptic effect, the maximum dilution factor at which macroscopically clear wells were observed was determined. The results are shown in Table 2.

^a 原液において50％以上の発育阻害が認められた
^b 発育阻止は認められなかった

^a Growth inhibition of 50% or more was observed in the stock solution
^b Growth inhibition was not observed

  The preservative preparation without addition of ethyl paraoxybenzoate showed no inhibition of fungal growth. However, formulations containing 0.03-0.1% ethyl paraoxybenzoate completely prevented fungal growth.

  As is apparent from the above results, the pharmaceutical composition of the present invention containing tosufloxacin or a salt thereof, a metal compound containing aluminum as a constituent, borax, alkali metal chloride and a preservative has stability and antiseptic effects. It has an anti-contamination effect, and is particularly excellent as eye drops, nasal drops and ear drops.

Claims (4)

7- (3-Amino-1-pyrrolidinyl) -1- (2,4-difluorophenyl) -6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid or a salt thereof A pharmaceutical composition comprising a metal compound containing aluminum as a constituent, borax, alkali metal chloride and a preservative. The pharmaceutical composition according to claim 1, wherein the preservative is ethyl paraoxybenzoate. The pharmaceutical composition according to claim 1, wherein the metal compound containing aluminum as a constituent component is potassium aluminum sulfate dodecahydrate, the alkali metal chloride is sodium chloride, and the preservative is ethyl paraoxybenzoate. The pharmaceutical composition according to claim 3, wherein the content of ethyl paraoxybenzoate is 0.001 to 0.1% with respect to the pharmaceutical composition.