FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"PHARMACEUTICAL OPHTHALMIC COMPOSITION"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Mumbai Central, Mumbai - 400 008, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to pharmaceutical compositions for ophthalmic use. There is also provided a process for preparing the said compositions and their use in the treatment of ophthalmic infections associated with inflammation.
BACKGROUND OF INVENTION:
The eye is susceptible to bacterial and parasitic infections arising from both traumatic and non-traumatic related events. Infections are a concern after ocular surgery and precautions are correspondingly taken to prevent the onset of infection. However, even without the invasive trauma of a surgical procedure, infections in the eyelids, conjunctiva, cornea, and other ocular tissues are most commonly observed.
Treating infections in ocular tissues can be challenging and/or problematic because of the difficulty in delivering medicaments, specially an antibiotic to the affected tissue. In general, ocular infections are treated by local injection, systemic administration, or topical application of an antibiotic. The route of administration depends on the antibiotic selected, the location of the infection and the type of infection.
A simple and direct approach of topically applying the antibiotic to the exterior of the eye has several benefits, including the avoidance of side effects and reduced chance of developing resistant strains of bacteria as compared to systemic administration.
The use of quinolone antibiotics to treat infections, especially class of fluoroquinolones represents the current state of the art in the field of ophthalmic pharmaceutical compositions and methods of treatment. For example, a topical ophthalmic composition containing the quinolone moxifloxacin is marketed by Alcon Laboratories, Inc. under the name VIGAMOX™ (Moxifloxacin 0.5%) Ophthalmic Solution.
The foregoing antibiotic compositions are generally effective in treating ophthalmic infections, and have distinct advantages over prior ophthalmic antibiotic compositions, particularly those having relatively limited spectrums of antimicrobial activity, such as: neomycin, polymyxin B, gentamicin and tobramycin, which are primarily useful against gram negative pathogens; and bacitracin, gramicidin, and erythromycin, which are

primarily active against gram positive pathogens. Amongst the various generations of fluoroquinolones class, Besifloxacin has demonstrated potent activity against Gram-positive bacteria that were resistant to other fluoroquinolones. Compared with other fluoroquinolones, besifloxacin has specific advantage of being available only for topical ophthalmic use, which should limit overall exposure and potentially reduce the development of resistance.
Ophthalmic infections are frequently accompanied by inflammation of the infected ophthalmic tissues and perhaps even surrounding tissues. Similarly, ophthalmic surgical procedures that lead to a susceptible risk of microbial infections frequently, also cause inflammation of the affected tissues. Thus, there was also a need for ophthalmic pharmaceutical compositions that combine the anti-infective activity of one or more antibiotics with the anti-inflammatory activity of one or more steroid agents in a single composition; however such combinations are generally known and commercially available in the ophthalmic pharmaceutical art.
US 6716830 discloses a topical composition comprising of moxifloxacin along with a steroidal or a non-steroidal agent or a prostaglandin H synthetase inhibitors, cyclooxygenase type II selective inhibitors, PAF antagonists, and PDEIV inhibitors.
US 6509327 discloses a topical composition comprising of moxifloxacin and dexamethasone for treatment against Mycobacterium alconae and Mycobacterium otitidis.
WO 1990/01933 discloses an antibiotic/anti-inflammatory ophthalmic pharmaceutical composition for topical delivery to the eye containing a quinolone antibiotic, such as ciprofloxacin and a steroid such as rimexolone, dexamethasone, fluorometholone and the like for topical ophthalmic delivery.
WO 2008/115951 discloses a composition comprising fluoroquinolones for treating, reducing, ameliorating, or preventing an infection in a subject. It further discloses compositions comprising fluoroquinolones in combination with an anti-inflammatory agent selected from the group consisting of glucocorticosteroids, non-steroidal anti-

inflammatory drugs, inhibitors of cytokine production; but does not specifically teach combination as taught by the present invention.
WO 2009/042395 discloses a composition comprising a fluoroquinolone for treating or controlling an infection in a subject, wherein the composition has a pH in a range from about 3.5 to about 5.5 or from about 10.5 to about 12 and the fluoroquinolone is present in an amount effective to treat or control the infection; and wherein the composition is capable of inhibiting a growth or survival of mixed types of microorganisms causing said infection. It further discloses compositions comprising fluoroquinolones in combination with an anti-inflammatory agent selected from the group consisting of glucocorticosteroids, non-steroidal anti-inflammatory drugs, inhibitors of cytokine production; but does not specifically teach combination as taught by the present invention.
US 7612115 discloses aqueous pharmaceutical composition comprising at least one pharmaceutical agent selected from the group consisting of ciprofloxacin hydrochloride, norfloxacin, lomefloxacin hydrochloride, gatifloxacin, carteolol hydrochloride, betaxolol hydrochloride, timolol maleate, pilocarpine hydrochloride, isopropylunoproston, nipradirol, bromfenac sodium, pranoprofen, diclofenac sodium, ketotifen fumarate, acitazanolast, disodium cromoglicate, tranilast, betamethasone sodium phosphate, prednisolone acetate, fluorometholone, fluorescein sodium, gentamicin sulfate, prienoxine, cyclosporine A, acyclovir, tropicamide and phenylephrine hydrochloride. However, it does not specifically teach combination as taught by the present invention.
Although there are prior arts disclosing combinations of antibiotic and steroid, however there are still some unmet concerns and expressed reservations in the ophthalmic community about the safety and efficacy of such prior art combinations which really call for suitable combination products which not only provide safety measures but in turn lead to a synergistic effect without having the active ingredients causing interaction with each other leading to degradation; thereby providing a stable product. A person skilled in the art cannot extrapolate the teachings of two different actives and arrive at a specific combination due to various chemical and physiological factors as discussed above. There is, moreover, a long felt need for effective and safe topical ophthalmic pharmaceutical

composition containing a potent steroid and a broad spectrum antibiotic which, when administrated to the eye when indicated for microbial infection or as a prophylactic after ophthalmic trauma and injury, shall not, as a possible expression of the steroid component, inhibit the activity of the antibiotic or interfere with normal wound healing, but at the same time will control inflammation.
Hence, there still remains a need to formulate a pharmaceutical composition comprising specific combination of fluoroquinolone and steroid which is stable, efficacious, exhibits potent topical activity for the treatment and / or prevention of ophthalmic infections associated with inflammation.
OBJECT OF THE INVENTION:
An object of the present invention is to provide a stable topical ophthalmic pharmaceutical composition comprising specific combination of fluoroquinolone and steroid wherein the said actives do not lead to any chemical interaction..
Another object of the present invention is to provide a process for preparing a topical ophthalmic pharmaceutical composition comprising specific combination of fluoroquinolone and steroid with an ease of manufacturing.
Yet another object of the present invention is to provide a effective and safe topical ophthalmic pharmaceutical composition comprising specific combination of fluoroquinolone and steroid which, when administrated to the eye, shall not, as a possible expression of the steroid component, inhibit the activity of the antibiotic or interfere with normal wound healing, but at the same time will control inflammation.
Yet another object of the present invention is to provide a method for treatment and / or prevention of ophthalmic infections associated with inflammation which comprises administering a pharmaceutical composition comprising Besifloxacin and Fluorometholone.

SUMMARY OF THE INVENTION:
According to a first aspect of the present invention, there is provided a pharmaceutical ophthalmic composition comprising Besifloxacin and Fluorometholone and one or more pharmaceutically acceptable excipients.
According to a second aspect of the present invention, there is provided a process for preparing the pharmaceutical ophthalmic composition comprising Besifloxacin and Fluorometholone and one or more pharmaceutically acceptable excipients.
According to a third aspect of the present invention, there is provided a pharmaceutical composition comprising Besifloxacin and Fluorometholone for use in treating ophthalmic disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration an antibiotic and an anti-inflammatory steroid.
DETAILED DESCRIPTION OF THE INVENTION:
As described above, there still remains a need to formulate a pharmaceutical ophthalmic composition comprising specific combination of fluoroquinolone and steroid which is stable, efficacious, and wherein the said actives do not lead to any chemical interaction and exhibit potent topical activity for the treatment and / or prevention of ophthalmic infections associated with inflammation. Surprisingly, the inventors of the present invention have found a stable and efficacious topically administrable pharmaceutical formulation comprising Besifloxacin and Fluorometholone and other pharmaceutically acceptable excipients wherein the said actives do not lead to any chemical interaction and exhibit potent topical activity.
The terms "Besifloxacin" and "Fluorometholone" are used in broad sense to include, not only "Besifloxacin" and "Fluorometholone" per se, but also their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable esters, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, pharmaceutically acceptable prodrugs, pharmaceutically acceptable complex etc.

Besifloxacin, 7-[(3R) -3-aminoazepam- 1-yl]- 8-chloro- 1-cyclopropyi- 6-fluoro- 4-oxo-1,4- dihydroquinoline- 3-carboxylic acid, is a topical ophthalmic fourth generation fluoroquinolone and acts by inhibiting the essential bacterial enzymes DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme known to play a key role in the partitioning of the chromosomal DNA during cell division. Besifloxacin has activity against a broad spectrum of Gram-positive and -negative bacteria that commonly cause ocular infections (e.g. Haemophilus influenzae, Staphylococcus aureus, S. epidermidis and Streptococcus pneumoniae), including drug-resistant strains.
The present invention also comprises of Fluorometholone, which suppresses the inflammatory response to a variety of agents by suppressing the migration of polymorphonuclear leukocytes and reversal of increased capillary permeability thus decreasing inflammation.
According to one of the embodiment of present invention, Besifloxacin may be incorporated in the form of its salts with inorganic acids comprising hydrochloric acid, sulfuric acid, phosphoric acid etc; and those with organic acids comprising methanesulfonic acid, lactic acid, oxalic acid, acetic acid, etc or in the form of pharmaceutically useful hydrate thereof.
Besifloxacin can be formulated within the range of 0.005 to 2.0 % w/v.
According to one of the embodiment of present invention, Fluorometholone may be present in the form of its alcohol, esters, salts, derivatives, prodrugs, polymorphs, isomers and hydrate forms thereof.
Fluorometholone can be formulated within the range of 0.005% to 2.0% w/v.
The pharmaceutical composition of the present invention may be formulated in a suitable ocular dosage form. The composition of the present invention may thus be administered as, but not limited to ophthalmic liquids such as solution, suspension etc.; ophthalmic semi-solid such as ointment, cream, gel, in-situ gel etc.; or ophthalmic solid preparations

such as implants, ocuserts etc. According to one of the preferred embodiment, the composition of the present invention may be administered as ophthalmic suspension.
The ophthalmic compositions of the present invention are typically administered to the affected ophthalmic 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 tissues during surgical procedures.
The ophthalmic compositions of the present invention will contain Besifloxacin or its pharmaceutically acceptable salts and Fluorometholone or its pharmaceutically acceptable salts, in pharmaceutically acceptable vehicles. The compositions will typically have a pH in the range of 4.5 to 8.0. 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 200 to 400 milliosmoles per kilogram of water ("mOsm/kg).
The pharmaceutical ophthalmic compositions, according to the present invention may comprise one or more pharmaceutically acceptable excipients suitable for formulating the same which include, but are not limited to, suspending agents, pH adjusters, osmotic agents, emulsifiers or dispersing agents, surfactants, solubilizers, buffering agents, preservatives, chelating agents, wetting agents, viscosity modifying agents, antioxidants, gelling agents, stabilizing agents and mixtures thereof.
Ophthalmic pharmaceutical products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include but are not limited to quaternary ammonium derivatives, (benzalkonium chloride, benzylammonium chloride, cetylmethyl ammonium bromide, cetylpyridinium chloride), benzethonium chloride, chlorbutanol, chlorhexidine gluconate, chlorhexidine acetate, organomercury compounds (Thimerosal, phenylmercury acetate, phenylmercury nitrate), methyl and propyl p-hydroxy-benzoates, betaphenylethyl alcohol, benzyl alcohol, phenylethyl alcohol, phenoxyethanol, stabilized oxychloro complex

(SOC), sofzia, and sodium perborate and such other agents known to those skilled in the art and mixtures thereof. Typically such preservatives are employed at a level of from 0.001 % to 1.0% by weight.
Suitable suspending agents that may be incorporated in the pharmaceutical ophthalmic composition of the present invention may comprise one or more, but not limited to water-soluble/water-swellable polymers such as cellulosic polymers i.e. methyl cellulose, hydroxyl propyl methyl cellulose, hydroxyl propyl cellulose, hydroxyl ethyl cellulose, carboxy methyl cellulose, polyvinyl pyrrolidine, polyvinyl alcohol, carbopol, carbophil; and one or more water-insoluble polymers such as cross-linked carboxyl-containing polymers, ethyl cellulose, and mixtures thereof. Other suspending agents which may be used include, but are not limited to, acacia, agar, alginic acid, sodium alginate, bentonite, carrageenan, gelatin, tragacanth, xanthan gum, and derivatives thereof. Such polymers can be used in the range of 0.005% to 1.5%w/v.
Suitable surfactants or wetting agents that may be incorporated in the pharmaceutical ophthalmic composition of the present invention may comprise one or more, but not limited to Polyoxyethylene fatty acid esters such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 65, polysorbate 85, sorbitan fatty acid esters such as Span 20, Span 40, Span 60 Span 80, Span 120; sodium lauryl sulfate; polyethoxylated castor oil; polyethoxylated hydrogenated castor oil, sodium dodecyl sulfate, Lauryl dimethyl amine oxide, Docusate sodium, Cetyl trimethyl ammonium bromide (CTAB), Polyethoxylated alcohols, Octoxynol, N,N-dimethyldodecylamine-N-oxide, Polyoxyl 10 lauryl ether, Hexadecyltrimethylammonium bromide, polyoxyethylene surfactant (Brij), Bile salts (such as but not limited to sodium deoxycholate, sodium cholate), Polyoxyl castor oil, Nonylphenol ethoxylate, Cyclodextrins, Lecithin, Methylbenzethonium chloride. Carboxylates, Sulphonates, Petroleum sulphonates, alkylbenzenesulphonates, Naphthalenesulphonates, Olefin sulphonates, Alkyl sulphates, Sulphates, Sulphated natural oils & fats, Sulphated esters, Sulphated alkanolamides, Alkylphenols, Ethoxylated aliphatic alcohol, carboxylic esters, Polyethylene glycol esters, Anhydrosorbitol ester & it's ethoxylated derivatives, Glycol esters of fatty acids, Carboxylic amides, Monoalkanolamine condensates, Polyoxyethylene fatty acid amides, Quaternary ammonium salts, Amines with amide

linkages, Pofyoxyethylene alkyl & alicyclic amines, N,N,N,N tetrakis substituted ethylenediamines 2- alkyl 1- hydroxyethyl 2-imidazolines, N -coco 3-aminopropionic acid/ sodium salt, N-tallow 3 -iminodipropionate disodium salt, N-carboxymethyl n dimethyl n-9 octadecenyl ammonium hydroxide, n-cocoamidethyl n-hydroxyethylglycine sodium salt, polyoxyethylene/polyoxypropylene surfactants such as Pluronic F-68, F-84, P-103, poloxamines such as Tetronic® 1508, Tetronic® 908, octoxynol 40, tyloxapol, Cremophor and such other surfactants well known in the art and mixtures thereof. Surfactants can be used in the range of 0.001 to 3.0%w/v.
The formulation may further comprise stabilizing agents such as but not limited to phosphonates, such as those sold under the name "DEQUEST" (a trademark of Monsanto); disodium edetate; sodium thiosulfate; and sodium stannate.
The formulation of present invention may further comprise one or more pH adjusting acids, bases or buffering, agents to maintain the pH between 4.5 - 8. Examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric and the like and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylamino-methane), and the like. Salts and buffers include citrate/dextrose, Sodium Dihydrogen Phosphate Dihydrate, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
Osmotic/isotonicity adjusting agents, that may be used, comprise of sodium chloride, potassium chloride, zinc chloride, calcium chloride and mixtures thereof. Other isotonicity-adjusting agents may also include, but are not limited to, mannitol, anhydrous glucose, glycerol, sorbitol and boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, propylene glycol or other inorganic or organic solutes, dextrose and mixtures thereof.
The formulation may also contain complexing/ chelating agents such as edetic acid (EDTA) or one of the known salts thereof, e.g. sodium EDTA or disodium EDTA dihydrate (sodium edetate), trisodium edetate, malic acid, sodium citrate, condensed sodium phosphate in the concentrations of 0.001% to l%w/v.

The formulation may also contain viscosity enhancing agents to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions to increase ocular absorption of the active compounds by the target tissues or increase the retention time in the eye. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents know to those skilled in the art. Such agents can be used in the concentrations from 0.01% to 2% w/v.
The formulation may further comprise sterile water for injection as vehicle. Other aqueous and non-aqueous vehicles may be used as a vehicle for the present ophthalmic composition.
According to another embodiment of the present invention, the pharmaceutical composition of the present invention may comprise the actives in micronized form.
The actives in micronized form may be obtained by any of the process such as but not limited to ball milling, jet milling, sonication, homogenization and solvent precipitation.
According to still another embodiment of the present invention, the pharmaceutical composition of the present invention may also comprise the actives in nanosized form.
The nanoparticles of the present invention can be obtained by any of the process such as but not limited to milling, precipitation, homogenization, spray-freeze drying, supercritical fluid technology, double emulsion/solvent evaporation, PRINT, thermal condensation, ultrasonication and spray drying.
Accordingly, the process of milling comprises dispersing drug particles in a liquid dispersion medium in which the drug is poorly soluble, followed by applying mechanical means in the presence of grinding media to reduce the particle size of drug to the desired effective average particle size.

Accordingly, the process of precipitation involves the formation of crystalline or semi-crystalline drug nanoparticles by nucleation and the growth of drug crystals. In a typical procedure, active ingredients are first dissolved in an appropriate organic solvent such as acetone, tetrahydrofuran or N-methyl-2-pyrrolidone or any other suitable solvent at a super saturation concentration to allow for the nucleation of drug seeds. Drug nanocrystals are then formed by adding the organic mixture to an antisolvent like water in the presence of stabilizers such as surfactants. The choice of solvents and stabilizers and the mixing process are key factors to control the size and stability of the drug nanocrystals.
Accordingly, the process of homogenization involves passing a suspension of crystalline drug and stabilizers through the narrow gap of a homogenizer at high pressure (500-2000 bar). The pressure creates powerful disruptive forces such as cavitation, collision and shearing, which disintegrate coarse particles to nanoparticles.
Accordingly, the process of high pressure homogenization comprises drug presuspension (containing drug in the micrometer range) by subjecting the drug to air jet milling in the presence of an aqueous surfactant solution. The presuspension is then subjected to high-pressure homogenization in which it passes through a very small homogenizer gap of -25 urn which leads to a high streaming velocity. High-pressure homogenization is based on the principle of cavitations (i.e., the formation, growth, and implosive collapse of vapor bubbles in a liquid).
Accordingly, the process of spray-freeze drying involves the atomization of an aqueous drug solution into a spray chamber filled with a cryogenic liquid (liquid nitrogen) or halocarbon refrigerant such as chlorofluorocarbon or fluorocarbon. The water is removed by sublimation after the liquid droplets solidify.
Accordingly, the process of supercritical fluid technology involves controlled crystallization of drug from dispersion in supercritical fluids, carbon dioxide.
Accordingly, the process of double emulsion/solvent evaporation technique involves preparation of oil/water (o/w) emulsions with subsequent removal of the oil phase

through evaporation. The emulsions are prepared by emulsifying the organic phase containing drug, polymer and organic solvent in an aqueous solution containing emulsifier. The organic solvent diffuses out of the polymer phase and into the aqueous phase, and is then evaporated, forming drug-loaded polymeric nanoparticles.
Accordingly, the process of PRINT (Particle replication in non-wetting templates) involves utilization of a low surface energy fluoropolymeric mold that enables high-resolution imprint lithography, to fabricate a variety of organic particles. PRINT can precisely manipulate particle size of drug ranging from 20 nm to more than 100 nm.
Accordingly, the process of thermal condensation involves use of capillary aerosol generator (CAG) to produce high concentration condensation submicron to micron sized aerosols from drug solutions.
Accordingly, the process of ultrasonication involves application of ultrasound during particle synthesis or precipitation, which leads to smaller particles of drug and increased size uniformity.
Accordingly, the process of spray drying involves supplying the feed solution at room temperature and pumping it through the nozzle where it is atomized by the nozzle gas. The atomized solution is then dried by preheated drying gas in a special chamber to remove water moisture from the system, thus forming dry particles of drug.
According to a preferred embodiment of the present invention, the pharmaceutical composition may be obtained by milling of active particles with at least one surfactant, and at least one suspending agent.
The present invention also provides a process/s to manufacture the ophthalmic compositions according to the present invention.
According to an embodiment of the present invention, there is provided a process of preparing ophthalmic pharmaceutical composition which comprises (i) autoclaving a slurry comprising the active ingredients and optionally other excipients; (ii) preparing a

solution comprising other pharmaceutically acceptable excipients and autoclaving the same; (iii) aseptically adding the drug slurry to the excipient solution and (iv) finally making up the volume with vehicle.
According to preferred embodiment of the present invention, there is provided a process of preparing ophthalmic pharmaceutical composition which comprises (i) milling and autoclaving a slurry comprising the active ingredients, surfactant and suspending agent; (ii) preparing a solution comprising other pharmaceutically acceptable excipients and autoclaving the same; (iii) aseptically adding the preservative to the excipient solution; (iv) aseptically adding the drug slurry to the excipient solution and (v) finally making up the volume with vehicle.
According to another embodiment of the present invention, there is provided a process of preparing ophthalmic pharmaceutical composition which comprises (i) milling and autoclaving a slurry comprising the active ingredients, surfactant and suspending agent; (ii) preparing a solution comprising other pharmaceutically acceptable excipients, and preservative and autoclaving the same; (iii) aseptically adding the drug slurry to the excipient and preservative solution and (iv) finally making up the volume with vehicle.
The present invention also provides a method for the treatment and/or prevention of ophthalmic infections, which method comprises administration of a therapeutically effective amount of a pharmaceutical composition according to the present invention.
The formulation of the present invention may be used topically in the treatment of ophthalmic infections associated with inflammation such as conjunctivitis, dacryocystitis, hordeolum, keratitis, blepharitis and corneal ulcers thereof. The formulation of the present invention may also be used prophylactically in connection with various ophthalmic surgical procedures that create a risk of infection.
The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1

SrNo Ingredients Quantity (%w/v)
1 Fluorometholone Acetate 0.1
2 Besifloxacin Hydrochloride 0.6
Micronizing Diluent
3 Hydroxyethyl Cellulose 0.005
4 Tyloxapol 0.005
5 Water for Injection 0.4ml
Main Bulk Solution
6 Tyloxapol 0.045
7 Hydroxyethylcellulose 0.245
8 Sodium Chloride 0.780
9 Sodium Dihydrogen Phosphate Dihydrate 0.250
10 Sodium Hydroxide/Hydrochloric Acid q.s. pH 7.3 ± 0.2
11 Benzalkonium Chloride 0.01
12 Water for Injection q.s. to 100ml
Process:
1. A slurry of Hydroxyethylcellulose and water for injection was prepared at 50-60°C;
2. Tyloxapol, Besifloxacin, Fluorometholone and milling beads were added to step 1;
3. The milling slurry of step b comprising Besifloxacin, Fluorometholone, milling beads, Tyloxapol and Hydroxyethylcellulose was sterilized by autoclaving at 121°C/ 30min;
4. The milling slurry of step 3 was ball milled; and cooled;
5. A slurry comprising sodium chloride, Sodium Dihydrogen Phosphate Dihydrate, and water for injection was prepared;
6. pH of the slurry of step 5 was adjusted with Sodium Hydroxide/ Hydrochloric Acid;
7. Hydroxyethylcellulose was added to slurry of step 6 at 50-60°C;
8. The slurry of step 7 was sterilized by autoclaving at 12TC/ 30min; and cooled;
9. Benzalkonium Chloride was aseptically added through a screen to the suspension of step 8; and

10. The milling slurry of step 4 was aseptically added through a screen to the mixture from step 9;
11. Volume was made up with water for injection and the final formulation was filtered through a screen.
Example 2

SrNo Ingredients Quantity (%w/v)
1 Fluorometholone Acetate 0.1
2 Besifloxacin 0.6
Micronizing Diluent
3 Hydroxyethyl Cellulose 0.005
4 Tyloxapol 0.005
5 Water for Injection 0.4ml
Main Bulk Solution
6 Tyloxapol 0.045
7 Hydroxyethylcellulose 0.245
8 Sodium Chloride 0.780
9 Sodium Dihydrogen Phosphate Dihydrate 0.250
10 Sodium Hydroxide/Hydrochloric Acid q.s. pH 7.3 ± 0.2
11 Stabilized Oxychloro Complex 0.005
12 Dequest 2010 0.08
13 Water for Injection q.s. to 100ml
Process:
1. A slurry of Hydroxyethylcellulose and water for injection was prepared at 50-60°C;
2. Tyloxapol, Besifloxacin, Fluorometholone and milling beads were added to step 1;
3. The milling slurry of step b comprising Besifloxacin, Fluorometholone, milling beads, Tyloxapol and Hydroxyethylcellulose was sterilized by autoclaving at 121°C/ 30min;
4. The milling slurry of step 3 was ball milled; and cooled;

5. A slurry comprising sodium chloride, Sodium Dihydrogen Phosphate Dihydrate, Dequest 2010 and water for injection was prepared;
6. pH of the slurry of step 5 was adjusted with Sodium Hydroxide/ Hydrochloric Acid;
7. Hydroxyethy (cellulose was added to slurry of step 6 at 50-60°C;
8. The slurry of step 7 -was sterilized by autoclaving at 121°C1 30mm; and
9. Stabilized Oxycloro Complex was aseptically added through a screen to the suspension
of step 8; and
10. The milling slurry of step 4 was aseptically added through a screen to the mixture from step 9;
11. Volume was made up with water for injection and the final formulation was filtered through a screen.
It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by the preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and such modifications and variations are considered to be falling within the scope of the invention.
It is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items.
It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a propellant" includes a single propellant as well as two or more different propellants; reference to a "cosolvent" refers to a single cosolvent or to combinations of two or more cosolvents, and the like.

We Claim,
1. A pharmaceutical composition comprising (a) an antibacterial agent such as Besifloxacin; (b) a steroidal anti-inflammatory agent such as Fluorometholone; and (c) pharmaceutically acceptable excipients.
2. A pharmaceutical composition according to claim 1, wherein Besifloxacin and/ or Fluorometholone is provided as a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, pharmaceutically acceptable hydrate, pharmaceutically acceptable ester, pharmaceutically acceptable enantiomer, pharmaceutically acceptable derivative, pharmaceutically acceptable polymorph, pharmaceutically acceptable prodrug, or pharmaceutically acceptable complex thereof.
3. A pharmaceutical composition according to claim 1, wherein said Besifloxacin is present as Besifloxacin hydrochloride and said Fluorometholone is present as Fluorometholone acetate.
4. A pharmaceutical composition according to any preceding claim, wherein each Besifloxacin and/ or Fluorometholone is present in an amount ranging from Q.005
% w/v to 2.0 % w/v.
5. A pharmaceutical composition according to any preceding claim, in a dosage form suitable for ophthalmic delivery comprising Besifloxacin and Fluorometholone with pharmaceutically acceptable excipients.
6. A pharmaceutical composition according to claim 5, wherein the composition is in the form of ophthalmic liquids such as solution, suspension etc.; ophthalmic semisolid such as ointment, cream, gel, in-situ gel etc.; or ophthalmic solid preparations such as implants ocuserts etc.
7. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable excipients comprises at least one of suspending agents, surfactants, preservatives, pH adjusting agents, tonicity adjusting agents,

chelating agents, stabilizing agents, emulsifiers, dispersing agents, solubilizers, buffering agents, wetting agents, geiling agents, viscosity modifying agents, or combinations thereof.
8. A pharmaceutical ophthalmic composition comprising Besifloxacin and Fluorometholone along with at least one of suspending agents, surfactants, preservatives, pH adjusting agents, tonicity adjusting agents, chelating agents, stabilizing agents, buffering agents, viscosity modifying agents, or combinations thereof.
9. A pharmaceutical composition according to any preceding claim, wherein the pH of the composition is in the range of 4.0 to 8.0.
10. A pharmaceutical composition according to any preceding claim, wherein Besifloxacin and/ or Fluorometholone are in micronized or nanosized form.
11. A process for the manufacture of a pharmaceutical composition comprising the steps of;
(i) autoclaving a slurry comprising the active ingredients and optionally other
excipients;
(ii) optionally milling the above drug slurry
(iii) preparing a solution comprising other pharmaceutically acceptable excipients
and autoclaving the same;
(iv) aseptically adding the drug slurry to the exejpient solution and
(v) finally making up the volume with vehicle.
12. A pharmaceutical composition comprising Besifloxacin and Fluorometholone for use in treating ophthalmic disorders or conditions that respond to, or are prevented, ameliorated or eliminated by, the administration of an antibiotic and an anti-inflammatory steroid.
13. A pharmaceutical composition substantially as herein described with reference to the examples.

14. A process for making a pharmaceutical composition substantially as herein described with reference to the examples,