Technical Field of the Invention
The present invention relates to a stable aqueous pharmaceutical composition of gatifloxacin.
Background of the invention
Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent and is a subject of US Patent No. 4,980,470. Chemically, gatifloxacin is (±) -1-cyclopropyl-6-fluoro-1, 4-dihydro-8-methoxy-7- (3-methyl-1 -piperazinyl)-4-oxo-3-quinolinecarboxylic acid and has been proposed for application to ophthalmological infectious diseases such as conjunctivitis, dacryocystitis, hordeolum etc. and otorhinological infectious diseases such as otitis externa, otitis media, sinusitis etc. Gatifloxacin has low aqueous solubility which is influenced by pH. Formulation of aqueous pharmaceutical compositions with a low solubility drug poses stability problems in terms of precipitation of the drug from the solution. The precipitated particulates of the dissolved drug are undesirable and may cause irritation when used.
US 6,333,045 discloses gatifloxacin ophthalmic solution containing disodium edetate for preventing the precipitation and discoloration of gatifloxacin.
We hereby disclose an aqueous liquid pharmaceutical composition of gatifloxacin comprising sodium citrate, which are stable to precipitation.
Summary of the Invention
In one general aspect, the present invention relates to a stable aqueous pharmaceutical composition comprising gatifloxacin or its pharmaceutically acceptable salts or hydrates thereof and sodium citrate.
In another aspect, it relates to a stable aqueous pharmaceutical composition comprising gatifloxacin or its pharmaceutically acceptable salts or hydrates thereof and sodium citrate wherein the composition is in the form of eye/ear/nasal drops.
In another aspect, it relates to a stable aqueous pharmaceutical composition comprising gatifloxacin or its pharmaceutically acceptable salts or hydrates thereof and sodium citrate, and one or more of other excipients selected from isotonic agents, buffers, preservatives, thickening agents and pH adjusting agents.
In another aspect, it relates to a method for preventing precipitation of gatifloxacin in an aqueous pharmaceutical composition comprising incorporating sodium citrate into the aqueous pharmaceutical composition comprising gatifloxacin or its pharmaceutically acceptable salts or hydrates thereof.
In another aspect, it relates to a method of treating ophthalmological/otorhinological infections responsive to gatifloxacin therapy, wherein the method comprises administering an aqueous pharmaceutical composition comprising gatifloxacin or its pharmaceutically acceptable salts or hydrates thereof and sodium citrate.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
One of the key aspects, germane to formulating an aqueous pharmaceutical composition of a drug with low aqueous solubility is the precipitation of the drug on storage over the time. One of the methods of testing the stability of the aqueous compositions against precipitation is by subjecting the aqueous composition to repeated freezing and thawing and observe for any precipitates. Gatifloxacin has low aqueous solubility and has the tendency to precipitate from its solution. We have surprisingly found that in presence of sodium citrate precipitation of gatifloxacin from its solution is prevented. Our experiments have shown that better stability of gatifloxacin aqueous solutions may be achieved by use of sodium citrate in place of disodium edetate.
Gatifloxacin may be used as a base or in a pharmaceutically acceptable salt form, for example, salt with hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, lactic acid, oxalic acid, acetic acid, sodium, potassium, magnesium, calcium, etc. The hydrates includes hemihydrates, sesquihydrate, pentahydrate or mixtures thereof etc. The actual concentration of gatifloxacin in the aqueous pharmaceutical composition may be varied to an amount determined by the degree of infection of a particular subject. The amount of gatifloxacin, calculated as base, may vary from 0.1 to 1.0 % w/v, particularly from 0.1 to 0.8% w/v and more particularly from 0.3 to 0.5 % w/v of the composition.
The amount of sodium citrate may vary from 0.001 to 0.5 w/v %, particularly from 0.05 to 0.2% w/v of the composition.
Besides sodium citrate, gatifloxacin aqueous pharmaceutical compositions may contain one or more of other excipients selected from isotonic agents, buffers, preservatives, thickening agents and pH adjusting agents.
The isotonic agent(s) may be selected from sodium chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol, sorbitol, glucose and the like.
The buffer(s) may be selected from phosphate buffer, acetate buffer, borate buffer, citrate buffer, carbonate buffer and the like.
The preservative(s) may be selected from chlorobutanol, sodium dehydroacetate, benzalkonium chloride, cetyl pyridinium chloride, phenethyl alcohol, parahydroxybenzoic acid esters, benzethonium chloride and the like.
The thickening agent(s) may be selected from methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, carboxymethylcellulose, polyvinyl pyrrolidone and the like.
The pH adjusting agent(s) may be selected from sodium hydroxide, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid, acetic acid, hydrochloric acid and the like.
The aqueous pharmaceutical compositions of gatifloxacin may be prepared by processes well known to the skilled in the art. For example, the aqueous pharmaceutical compositions of gatifloxacin may be prepared by dissolving gatifloxacin, sodium citrate and other excipients in water, adjusting the pH of the resulting solution to about 6.0 by adding one or more pH adjusting agents, filtering and filling in USP Type I clear glass vials or clear LDPE plastic bottles with LDPE tips and an outer lid.
For avoiding local irritation due to very low or high pH, it may be desirable that the pH of the solution is adjusted to around physiological pH i.e. about 5.5 to about 8, and particularly about 6.
The following examples are illustrative of the invention, and are not intended to be construed as limiting the invention.
Comparative example 1: Aqueous pharmaceutical composition without any stabilizing agent.
(Table Removed)
Procedure: Gatifloxacin, sodium chloride and benzalkonium chloride are dissolved in water. The pH is adjusted to 6.0 with 0.1 M HCI or 0.1 M NaOH solution followed by filtration through 0.2 micron Nylon filter. The filtered solution is filled in USP Type I clear glass vials.
Comparative example 2: Aqueous pharmaceutical composition with disodium
(Table Removed)
Procedure: Gatifloxacin, sodium chloride, benzalkonium chloride and disodium edetate are dissolved in water. The pH is adjusted to 6.0 with 0.1 M HCI and 0.1 M NaOH solution followed by filtration through 0.2 micron Nylon filter. The filtered solution is filled in USP Type I clear glass vials.
Example A: Aqueous pharmaceutical composition with sodium citrate as stabilizer.
(Table Removed)
Procedure: Gatifloxacin, sodium chloride, benzalkonium chloride and sodium citrate are dissolved in water. The pH is adjusted to 6.0 with 0.1 M HCI and 0.1 M NaOH solutions
followed by filtration through 0.2 micron Nylon filter. The filtered solution is filled in USP Type I clear glass vials.
Freeze-thawing observations:
The compositions of comparative examples 1 and 2 and example A were frozen in freezer at 2-8°C and allowed to thaw at room temperature. The thawed samples exhibited presence of white flake like precipitates. When these compositions were sonicated, the white particles of formulation corresponding to example A containing sodium citrate went into solution easily resulting in a clear solution whereas particles formed in formulations corresponding to comparative example 1 containing no stabilizer and example 2 containing disodium edetate did not. This evidently demonstrates that sodium citrate acts as a better stabilizer than disodium edetate.

WE CLAIM:
1. A stable aqueous pharmaceutical composition comprising gatifloxacin or its
pharmaceutically acceptable salts or hydrates thereof and sodium citrate.
2. The composition of claim 1, wherein the amount of gatifloxacin or its
pharmaceutically acceptable salt or hydrate is from about 0.1 to 1.0 % w/v of the
composition.
3. The composition of claim 1, wherein the amount of sodium citrate is from 0.001 to
0.5% w/v of the composition.
4. The composition of claim 1, wherein the composition further comprises one or more
of other excipients selected from isotonic agents, buffers, preservatives, thickening
agents, and pH adjusting agents.
5. The composition of claim 4, wherein isotonic agents are selected from sodium
chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol,
sorbitol, glucose and the like.
6. The composition of claim 4, wherein buffers are selected from phosphate buffer,
acetate buffer, borate buffer, citrate buffer, carbonate buffer and the like.
7. The composition of claim 4, wherein preservatives are selected from chlorobutanol,
sodium dehydroacetate, benzalkonium chloride, cetyl pyridinium chloride, phenethyl
alcohol, parahydroxybenzoic acid esters and benzethonium chloride.
8. The composition of claim 4, wherein thickening agents are selected from
methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropyl-
methylcellulose, polyvinyl alcohol, carboxymethylcellulose and polyvinyl pyrrolidone.
9. The composition of claim 4, wherein pH adjusting agents are selected from sodium
hydroxide, potassium hydroxide, sodium carbonate, citric acid, phosphoric acid,
acetic acid and hydrochloric acid.
10. The composition of claim 1, wherein the composition is in the form of eye/ear/nasal
drops.
11. A method for preventing precipitation of gatifloxacin crystals comprising
incorporating sodium citrate into the aqueous liquid pharmaceutical composition
comprising gatifloxacin.
12. A method of treating ophthalmological/otorhinological infections responsive to
gatifloxacin therapy, wherein the method comprises administering an aqueous
pharmaceutical composition comprising gatifloxacin or its pharmaceutically
acceptable salts or hydrates thereof and sodium citrate.