FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule13)
1. TITLE OF THE INVENTION:
AN AQUEOUS LIQUID PHARMACEUTICAL COMPOSITIONS OF GATIFLOXACIN AND p-CYCLODEXTRINS
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai- 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides an aqueous liquid pharmaceutical composition comprising of gatifloxacin or pharmaceutically acceptable salt thereof.
The following specification particularly describes the invention and the manner
in which it is to be performed.
4. DESCRIPTION
The present invention provides an aqueous liquid pharmaceutical composition comprising gatifloxacin or pharmaceutically acceptable salt thereof.
Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent. Chemically, gatifloxacin is (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the treatment of infections due to susceptible strains of microorganisms.
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Gatifloxacin its solvate or hydrate or pharmaceutical^ acceptable salt thereof hereinafter will be refered simply as gatifloxacin.
US Patent No 4,980,470 (the '470 patent) claims Gatifloxacin, its hydrates and pharmaceutical^ acceptable salts thereof as. antibacterial agent, process for their preparation, and antibacterial agents containing this compounds.
US Patent No 6,333,045 (the '045 Patent) provide an aqueous liquid pharmaceutical composition, which comprises Gatifloxacin or its salt, where in there are provided a method for raising corneal permeability of Gatifloxacin, a method for preventing precipitation of Gatifloxacin crystals, and a method for preventing coloration of Gatifloxacin by incorporating disodium edetate into an aqueous liquid preparation containing Gatifloxacin or its salt.
European Patent EP 275,515 and US Patent No 4,923,862 provide aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salt thereof. US Patent No 6,716,830 provide ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of 0.1% to 1% w/w and pharmaceutically acceptable vehicle.
US Application 20050009836 claims ophthalmic compositions of gatifloxacin and polyhydric alcohol includes one or more alcohols selected from the group consisting of glycerin, propylene glycol, polyethylene glycol having an average molecular weight less than 1000 daltons, mannitol and sorbitol , which renders the drug substantially isoosmotic in the said formulation.
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The use of quinolone antibiotics to treat infections is known the art in the field of ophthalmic pharmaceutical compositions and methods of treatment. Several quinolone antibacterial such as gatifloxacin (available as Zymar®), Levofloxacin (available as Quixin® or Iquix®), Ciprofloxacin (available as Giloxan®), Ofloxacin (available as Ocuflox®), Lomefloxacin (available as Lomeflox®), Moxifloxacin (available as Vigamox®) and Norfloxacin (available as Chibroxin®).
It was noticed from '045 Patent that the Gatifloxacin aqueous liquid pharmaceutical composition are having poor membrane permeability; also there exist a problem of precipitation at physiological pH & moreover the drug brings about coloration of the tissue and the formulation.
While working on the development of an aqueous liquid pharmaceutical composition comprising gatifloxacin present inventors have embarked upon a formulation, which eliminates the said problems. This was achieved by formulating aqueous liquid pharmaceutical composition comprising gatifloxacin or salt thereof with hydroxy propyl b Cyclodextrin (hereinafter refered as HP-b-CD), citric acid, sodium metabisulfite and other pharmaceutically acceptable excipients.
In one aspects of the present invention there is provided an aqueous liquid pharmaceutical composition comprising gatifloxacin, HP-b-CD along with other pharmaceutically acceptable excipients.
In yet another aspect of the present invention there is provided an aqueous liquid pharmaceutical composition comprising gatifloxacin, HP-b-CD, citric acid along with other pharmaceutically acceptable excipients.
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In yet another aspects of the present invention there is provided an aqueous liquid pharmaceutical composition comprising gatifloxacin, HP-b-CD, citric acid, sodium metabisulphite along with other pharmaceutically acceptable excipients.
It was found by the present inventors that the solubility enhancer component such as HP-b-CD not only prevents the precipitation of gatifloxacin, but also decreases the irritation associated with the said drug. The permeability enhancer component, which includes citric acid, provides a high permeation to an otherwise poor permeable drug like gatifloxacin. The presence of sodium metabisulphite serves dual purpose, apart from acting as a coloration inhibitor its serves as an antioxidant.
The liquid dosage form for the ophthalmic, otic or nasal use as part of present invention can be present as solution, suspension or drops in a single use or multi-use container. The compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
The compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, one to four times per day. However, the compositions may also be formulated as irrigating solutions that are applied to the affected ophthalmic, otic or nasal tissues during surgical procedures.
Normally, the amount of gatifloxacin or its salt to be formulated in the liquid pharmaceutical composition of the present invention is varied according to the degree of infection of a particular subject, but normally, gatifloxacin is formulated
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within the range of 0.01 to 1.0% w/v, preferably 0.1 to 0.8% w/v, more preferably 0.3 w/v.
The ophthalmic, otic and nasal compositions of the present invention will typically have a pH in the range of 4.0 to 6.0 The ophthalmic compositions must also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water ("mOsm/kg"), but will preferably be about 300 mOsm/kg.
Ophthalmic, otic and nasal pharmaceutical products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. Typically such preservatives are employed at a level of from 0.001 % to 1.0% by weight.
A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions. In case of gatifloxacin due to its poor water solubility use of co-solvents or complex forming agents helps in achieving the desired results. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin especially HP-b-CD, or other agents known to those skilled in the art. Typically such co-solvents are employed at a level of from 0.01% to 5% by weight. HP-b-CD has a tendency to form inclusion complex with many drugs including gatifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of gatifloxacin can be further reduced based on complexation with HP-b-CD.
The use of viscosity enhancing agents to provide the compositions of the
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invention with viscosities greater than the viscosity of simple aqueous solutions is desirable to increase ocular absorption, and reduce irritability of the active compounds by the target tissues or increase the retention time in the eye, ear or nose. Such agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents know to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example
The composition of gatifloxacin
Citric acid (0.08%) and sodium citrate (0.18%) was dissolved in water for injection, to the clear solution so obtained a blend of gatifloxacin (0.3%) and HP-b-CD in concentration of 1-1.5% was dissolved. A previously stirred solution of sodium chloride (0.65%) and sodium metabisulfite (0.05%) was added to the above said solution. To this a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using NaOH/Hcl solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2m filter, filled and packed in suitable container and closure system.
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Table 1: Example of Gatifloxacin formulation batch 1.

Ingredient Example 1
(% Quantity)
Gatifloxacin 0.3%
HP-p-CD 1.0% to 1.5%
Citric acid 0.08%
Sodium citrate 0.18%
Sodium Chloride 0.65%
Sodium metabisulfite 0.05%
Benzalkonium chloride 0.01%
Water for Injection qs to make 100ml

WE CLAIM:
1. An aqueous liquid pharmaceutical composition, which comprises Gatifloxacin or its pharmaceutical^ acceptable salt with HP-p-CD and other excipients.
2. An aqueous liquid pharmaceutical composition according to claim 1, wherein the concentration of HP-p-CD is in the range of 1.0% to 1.5% w/v.
3. An aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprises citric acid.
4. An aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprise sodium metabisulphite.
5. The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition is for ophthalmic, otic and nasal instillation.
6. The aqueous liquid pharmaceutical composition according to claim 1, having osmolarity of about 200 to 400 mOsm/kg
Dated this 28th day of March 2006.
For Wockhardt Limited

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