FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
STABLE GATIFLOXACIN OPHTHALMIC COMPOSITION
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Limited, D4-MIDC Area, Chikalthana,
Aurangabad-431 210 (M.S.) INDIA.
3.PREAMBLE TO THE DESCRIPTION
The present invention provides a stable aqueous liquid formulation suitable for
ophthalmic administration comprising gatifloxacin and polyethoxylated castor
oil.
The following specification particularly describes the invention and the manner
in which it is to be performed.

4. Description
The present invention provides a stable aqueous liquid formulation suitable for ophthalmic administration comprising gatifloxacin and polyethoxylated castor oil.
Gatifloxacin, a fluoroquinolone antibiotic is marketed under the trade name of ZYMAR® by Allergan as a 0.3% sterile ophthalmic solution. Molecular composition of Gatifloxacin sesquihydrate is C1gH22FN3O4 • 1.5 H2O and molecular weight is 402.42. Its structural formula is:

Gatifloxacin is indicated for the treatment of bacterial conjunctivitis caused by susceptible strains aerobic gram-positive bacteria such as Cornyebacterium propinquum, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus mitis, Streptococcus pneumoniae and aerobic gram-negative bacteria such as Haemophilus influenzae.
US Patent No. 4,980,470 discloses 8-Alkoxyquinolonecarboxylic acid derivatives, which generically covers gatifloxacin, the hydrates or the pharmaceutically acceptable acid addition or alkali salts thereof.
US Patent No. 6,333,045 discloses an aqueous liquid pharmaceutical composition, which comprises gatifloxacin or its salt and disodium edetate, which improves corneal permeability, prevents precipitation of crystals and coloration of gatifloxacin.
US Patent No. 6,740,664 discloses method of treating otic infections or ophthalmic infections attributable to a Microbacterium species.


US Application No. 20030176444 discloses a prophylactic or therapeutic medicament for inflammation caused by a cytokine.
US Application No. 2006074053 discloses an ophthalmic solution comprising as an active ingredient a quinolone antimicrobial compound or a salt thereof, and at least one member selected from the group consisting of water-soluble vinyl polymeric compounds and water-soluble cellulose derivatives.
US Application No. 2005085446 discloses an aqueous pharmaceutical composition comprising of fluoroquinolone and/or steroidal or non-steroidal antiinflammatory agent cyclodextrin and hydroxy acid.
US Application No. 2006177430 discloses a sterile ophthalmic formulation for the treatment of an ophthalmic condition comprising methylsulfonylmethane as permeation enhancer.
US Application No. 2005009836 discloses a self-preserved ophthalmic composition consisting essentially of gatifloxacin and an aqueous carrier vehicle containing a polyhydric alcohol.
The present inventors while working on the gatifloxacin ophthalmic formulation have surprisingly found that a stable aqueous liquid formulation can be prepared with the sole use of polyethoxylated castor oil. The said formulation reduces formation of impurities and avoids precipitation of active ingredient from solution during stability.
One of the aspects of the present invention provides a stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutically acceptable salt or hydrates thereof and polyethoxylated castor oil.


In one of the embodiments of the present invention, the polyethoxylated castor oil is selected from the group comprising of polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), PEG-30 castor oil (Incrocas 30), PEG-35 castor oil (Cremophor EL, Incrocas 35), or PEG-40 castor oil (Cremophor EL, Incrocas), Cremophor EL, Emulphor EL, polyethoxylated castor oil, purified grades of Cremophor EL (Cremophor ELP), and the like.
In one of the embodiments of the present invention, the stable aqueous liquid ophthalmic formulation has a pH from about 5 to 7.0 and an osmolality between about 270 to 330 mOsm/kg.
In another aspect of the present invention there is provided a stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutically acceptable salt or hydrates thereof and polyethoxylated castor oil, wherein the formulation is essentially free of disodium edetate.
In yet another aspect of the present invention there is provided a stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutically acceptable salt or hydrates thereof and polyethoxylated castor oil, wherein the formulation is essentially free of disodium edetate and the said formulation reduces formation of impurities and avoids precipitation of active ingredient from solution during stability.
The aqueous liquid ophthalmic composition may further include other pharmaceutically acceptable excipients such as buffering agents, tonicity adjusting agents, viscosity enhancing agents, antimicrobial preservatives and the like.


The suitable buffering agents include but are not limited to acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid and the pharmaceutically acceptable salts thereof.
The suitable tonicity adjusting agents may be one or more of sodium chloride, potassium chloride, mannitol, dextrose, glycerine, propylene glycol and the like.
The viscosity enhancing 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.
The suitable antimicrobial preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, sorbic acid, polyquaternium-1 and other agents known to those skilled in the art.
Gatifloxacin ophthalmic solution is tested for stability initially as well as under accelerated stability conditions viz. 40°C/25%Relative Humidity. The relative impurities (known and unknown) of the sample are tested by using HPLC analysis method. The different impurity values obtained indicated that the formulation is stable at accelerated storage conditions. The stability results are provided in Tables 2. The single highest known impurity is nothing but the known impurity having maximum value selected from all known impurity peak areas. The single highest unknown impurity is unknown impurity having maximum value selected from all unknown impurity peak areas. Sum of peak areas of single highest known impurity and single highest unknown impurity is represented as total.


Example 1
Table 1: Ophthalmic Composition of Gatifloxacin (0.3%)

S.No. Ingredients Weight %
1 Gatifloxacin Hemihydrate 0.3
! CM CO Cremophor ELP (Polyoxyl-35-castor oil) 0.5 to 2.5
Sodium Chloride 0.1 to 0.9
4 5 Sodium Hydroxide Hydrochloric Acid q.s. for pH q.s. for pH
6 Benzalkonium Chloride 0.005
7 Water for injection pH q.s 100
6.0
Osmolality 300 mOsm
Procedure: The above composition is prepared by simple mixing that involves the step of dissolving sodium chloride in water for injection followed by addition of cremophore ELP and preservative (dissolved in water of injection) with stirring. Fluoroquinolone antibiotic is finally added to the above solution with stirring till a clear solution is obtained. The pH of the final solution is adjusted with 1N NaOH or 1N HCI and than the solution is filtered through membrane grade sterilization filter.
Table 2 - Stability data for example 1.

Parameters Initial One Month (40°C/25%RH)
Assay of gatifloxacin 103.8 10477"
Related Substances- 0.074 0.026
1. Single Highest Known impurity
2. Single Highest Unknown impurity 0.051 0.233 ^ 0.074
3. Total RS 0.400
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.


WE CLAIM:
1. A stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutical^ acceptable salt or hydrates thereof and polyethoxylated castor oil.
2. A stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutically acceptable salt or hydrates thereof and polyethoxylated castor oil, wherein the formulation is essentially free of disodium edetate.
3. A stable aqueous liquid formulation for ophthalmic administration comprising gatifloxacin, its pharmaceutically acceptable salt or hydrates thereof and polyethoxylated castor oil, wherein the formulation is essentially free of disodium edetate and the said formulation reduces formation of impurities and avoids precipitation of active ingredient from solution during stability.
4. The stable aqueous liquid formulation of claim 1 to 3, wherein the polyethoxylated castor oil is selected from the group comprising of polyoxyl 40 hydrogenated castor oil (Cremophor RH 40), polyoxyl 60 hydrogenated castor oil (Cremophor RH 60), PEG-30 castor oil (Incrocas 30), PEG-35 castor oil (Cremophor EL, Incrocas 35), or PEG-40 castor oil (Cremophor EL, Incrocas), Cremophor EL, Emulphor EL, polyethoxylated castor oil, purified grades of Cremophor EL (Cremophor ELP) and the like.
5. The stable aqueous liquid formulation of claim 4, wherein the polyethoxylated castor oil is PEG-35 castor oil.
6. The stable aqueous liquid formulation of claim 1 to 3, further comprises one or more other pharmaceutically acceptable excipients selected from buffering agents, tonicity adjusting agents, viscosity enhancing agents antimicrobial preservatives and the like.


7. The stable aqueous liquid formulation for ophthalmic administration of claim 6, wherein the suitable buffering agents include but are not limited to acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutical^ acceptable salts of the foregoing.
8. The stable aqueous liquid formulation position for ophthalmic administration of claim 6, wherein the suitable tonicity agents include but are not limited to sodium chloride, potassium chloride, mannitol, dextrose, glycerine, propylene glycol and the like.
9. The stable aqueous liquid formulation for ophthalmic administration of claim 6, wherein the suitable viscosity enhancing agents include polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents know to those skilled in the art.
10. The stable aqueous liquid formulation for ophthalmic administration of claim 6, wherein the suitable antimicrobial preservatives include benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, sorbic acid, polyquaternium-1 and other agents known to those skilled in the art.

Abstract
The present invention provides a stable aqueous liquid formulation suitable for ophthalmic administration, comprising gatifloxacin and polyethoxylated castor oil.