DESC:FIELD OF INVENTION:
The present invention relates to a novel pharmaceutical composition suitable for ophthalmic use comprising antibiotic and process to prepare the same. More particularly, the present invention relates to a pharmaceutical gel composition comprising aminoglycoside antibiotics such as plazomicin or its pharmaceutically acceptable salts thereof for the treatment of ocular infections.

BACKGROUND OF THE INVENTION
Of all the ocular infections caused worldwide, almost upto 74% are believed to be caused by bacteria, followed by viruses, fungus, and parasites. Infection can be mono or poly-microbial and is associated with many factors including contact lenses, trauma, surgery, age, dry eyes, chronic nasolacrimal duct obstruction and previous ocular infections.

Bacteria are generally associated with many types of ocular infections such as conjunctivitis, keratitis, endophthalmitis, blepharitis, orbital cellulitis and dacryocystitis manifestations. The most common bacteria involved in ocular infections are Staphylococcus aureus (S. aureus), Coagulase-negative staphylococci (CoNS), Streptococcus pneumoniae, Corynebacterium spp., Bacillus spp., Nocardia, Pseudomonas aeruginosa, Haemophilus influenzae and Enterobacteriaceae. Among these bacteria, S. aureus and CoNS strains are very important for their high prevalence of infection, while S. aureus is among the most common cause of blepharitis, conjunctivitis, dacryocystitis, keratitis and endophthalmitis.

There are many antibacterial agents which are currently approved to treat ocular infections such as penicillins, fluoroquinolones, tetracyclines, erythromycins, azithromycins, chloramphenicols, aminoglycosides.

Aminoglycoside antibiotics have a broad antibacterial spectrum against gram-positive and gram-negative bacteria, and it is said that their action mechanism is based on inhibition of bacterial protein synthesis. Aminoglycoside antibiotics show long-lasting inhibitory effect on the inhibition of bacterial growth, as they exhibit post-antibiotic effect (PAE) on the inhibition of bacterial growth even after the blood concentration of the aminoglycoside antibiotics is decreased to a concentration of MIC (minimum inhibitory concentration) or less. This long-lasting inhibitory effect on the inhibition of bacterial growth is seen even after a short period of contact with gram-positive and gram-negative bacteria. For this reason, various aminoglycoside antibiotics such as gentamicin, tobramycin, streptomycin, amikacin, arbekacin, and the like have been widely used for the treatment of ocular infections.

However, aminoglycosides like other classes of drugs, are prone to bacterial resistance. Resistance to aminoglycosides may occur based on several mechanisms: (1) enzymatic modification and inactivation of the aminoglycosides, mediated by aminoglycoside acetyltransferases, nucleotidyltransferases, or phosphotransferases and commonly observed across gram-positive and -negative bacteria. Bacterial resistance to aminoglycosides continues to escalate and is widely recognized as a serious health threat. The emergence of ESBL, MBL and pan-drug resistance among P. aeruginosa from ocular infections is an alarming finding which necessitates the earlier detection of both ESBL and MBL production as individual or co-existence in ocular isolates, which may pave the way for appropriate therapy for sight threatening conditions like endophthalmitis.

Thus, there remains a need for the use of novel antibiotic which has excellent activity against Coagulase negative S.aureus, MRSA and retains good activity against gram negative pathogens including Pseudomonas. Also, there remains a need for a gel composition which is able to prolong the contact time at the site of action for effective delivery.

Plazomicin is an aminoglycoside that was engineered to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside resistance mechanism in the Enterobacteriaceae. Thus, it is an objective of the present invention to provide an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof.

OBJECT OF THE INVENTION:
An object of the present invention is to provide an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof.

Another objective of this invention is to develop an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof for the treatment of external infections of the eye and its adnexa. The external infections of the eye may be caused by susceptible bacteria like S.aureus ( MSSA/MRSA), Coagulase negative S.aureus, S.epidermidis, Klebsiella and Proteus.

It is further an objective of this invention is to develop an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof for the treatment of bacterial keratitis. The composition may optionally contain a second antibacterial such as cephalosporin.

SUMMARY OF THE INVENTION
The present invention relates to a novel pharmaceutical composition suitable for ophthalmic use comprising antibiotic and a process to prepare the same. More particularly, the present invention relates to an ophthalmic gel composition comprising aminoglycoside antibiotics such as plazomicin or its pharmaceutically acceptable salts thereof for the treatment of ocular infections.

In one embodiment, the ophthalmic gel composition of the present invention comprises about 0.01% w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin sulfate.

In a further embodiment, the ophthalmic gel composition of the present invention further comprises atleast one excipient selected from buffering agent, tonicity adjusting agent, gelling agent, preservative, chelating agent and optionally a pH adjusting agent.

In one embodiment, the ophthalmic gel composition of the present invention further comprises about 0.01% w/w to about 5% w/w buffering agent.

In one more embodiment, the ophthalmic gel composition of the present invention further comprises about 0.01% w/w to about 10 % w/w tonicity adjusting agent.

In another embodiment, the ophthalmic gel composition of the present invention further comprises about 0.001% w/w to about 5% w/w preservative.

In an embodiment, the ophthalmic gel composition of the present invention comprises about 0.005% w/w to about 5% w/w gelling agent.

In one more embodiment, the ophthalmic gel composition of the present invention comprises about 0.0001% w/w to about 1% w/w chelating agent.

In one embodiment, the ophthalmic gel composition of the present invention further comprises a pH adjusting agent.

In an embodiment, the ophthalmic gel composition of the present invention is an aqueous composition.

In one another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin or its pharmaceutically acceptable salt in a solubilized form.

In an embodiment, the present invention relates to an ophthalmic gel composition for use in ocular infections.

DETAILED DESCRIPTION OF THE INVENTION
The inventors of this invention have developed an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

Plazomicin is chemically known as (2"R,3"R,4"R,5"R)-2"-[(1S,2S,3R,4S,6R)-4-amino-6-[(2'"S)-4'"-amino-2'"-hydroxybutanamido)amino]-3-[(2'S,3'R)-3'-amino-6'-((2-hydroxyethylamino) methyl)-3',4'-dihydro-2H-pyran-2'-yloxy]-2-hydroxycyclohexyloxy]-5''-methyl-4''-(methylamino)tetrahydro-2H-pyran-3'',5''-diol. The molecular formula is C25H48N6O10 and the molecular weight is 592.69 g/mol. The chemical structure of plazomicin is as given below:

Suitable salts of plazomicin include, but are not limited to sulfate, hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid. In a preferred embodiment, the ophthalmic composition contains plazomicin sulfate.

Plazomicin has similar activity to gentamicin (and greater activity than amikacin) against MRSA, MSSA. Plazomicin has potent activity against species of Staphylococcus. Against Gram-negative enteric bacteria, plazomicin demonstrates more potent in vitro activity than amikacin, gentamicin, and tobramycin. The inventors of the present invention have intensively studied on the above problems, resulting in finding that an ophthlamic composition containing plazomicin or its pharmaceutically acceptable salts thereof are able to treat the ocular infection, especially the ones where there is a development of bacterial resistance.

Thus, one aspect of the invention is to formulate an ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

The ophthalmic gel 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, tonicity adjusting agents, emulsifiers or dispersing agents, surfactants, solubilizers, buffering agents, preservatives, chelating agents, wetting agents, gelling agents, antioxidants, 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, stabilized oxychloride complex, quaternium chloride, sodium perborate, benzododecinium bromide, zinc chloride, 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% w/w to 5.0% w/w. In a preferred embodiment, the ophthalmic gel composition of the present invention comprises stabilized oxychloro complex (SOC) as a preservative.

The ophthalmic gel composition of the present invention may optionally comprise one or more suspending agents. Suitable suspending agents can be selected from but are not limited to water soluble/water-swellable polymers such as cellulosic polymers i.e., methyl cellulose, hydroxyl propyl methyl cellulose, hydroxy propyl cellulose, hydroxy 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 agents can be used in the range of 0.005% w/w to 1.5%w/w or as deemed fit for the composition.

Suitable surfactants or wetting agents that may be incorporated in the ophthalmic gel composition of the present invention may comprise one or more, but are 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, Polyethoxylated alcohols, Octoxynol, N,N-dimethyldodecylamine-Noxide, 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, Polyoxyethylene 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 are well known in the art and mixtures thereof. Surfactants can be used in the range of 0.001 %w/w to 3.0% w/w.

The ophthalmic gel composition 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 ophthalmic gel composition of the present invention may further comprise one or more buffers or pH adjusting acids, bases or buffering agents to maintain the pH between 4.5 – 8 and more preferably between 6.5 to 7.5. 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, THAM (trishydroxymethylaminomethane), tromethamine and the like. Salts and buffers include citrate/ dextrose, sodium chloride, glycerine, mannitol, propylene glycol, Sodium Dihydrogen Phosphate Dihydrate, sodium bicarbonate, ammonium chloride or mixtures of the aforementioned acids and bases. In one embodiment, the composition of the present invention comprises about 0.01% w/w to about 5% w/w of a buffering agent. In a preferred embodiment, the ophthalmic gel composition of the present invention comprises boric acid as a buffering agent.

In one embodiment, the ophthalmic gel composition of the present invention may have a pH between about 6 to about 7.5.

Osmotic/tonicity 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, trehalose, boric acid, citric acid, sodium tartrate, sodium phosphate, potassium phosphate, sodium chloride, glycerin, propylene glycol or other inorganic or organic solutes, dextrose, or mixtures thereof. In one embodiment, the ophthalmic gel composition of the present invention comprises a tonicity adjusting agent in an amount between about 0.01% w/w to about 10% w/w. In a preferred embodiment, the ophthalmic gel composition of the present invention comprises propylene glycol as a tonicity adjusting agent. In another preferred embodiment, the ophthalmic gel composition of the present invention comprises sodium chloride as a tonicity adjusting agent. In one preferred embodiment, the ophthalmic gel composition of the present invention comprises mannitol as a tonicity adjusting agent.

The ophthalmic gel composition 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 0.0001% to 1%w/w. In a preferred embodiment, the ophthalmic gel composition of the present invention comprises disodium edetate as a chelating agent.
The ophthalmic gel composition may also contain gelling 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 gelling agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, poloxamer, carbomer, polycarbophil, sodium alginate or other agents know to those skilled in the art. Such agents can be used in the concentration from 0.005% to 5% w/w. In a preferred embodiment, the ophthalmic gel composition of the present invention comprises sodium alginate as a gelling agent. In another preferred embodiment, the ophthalmic gel composition of the present invention comprises hydroxy propyl methyl cellulose as a gelling agent. In a further preferred embodiment, the ophthalmic gel composition of the present invention comprises poloxamer as a gelling agent. In one more preferred embodiment, the ophthalmic gel composition of the present invention comprises polycarbophil as a gelling agent.

The ophthalmic gel composition 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 gel composition.

It will be understood, however, that the specific dose level and frequency of dosage according to the invention for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, the severity of the particular condition, and the host undergoing therapy.

In one embodiment, the ophthalmic gel composition comprises plazomicin or its pharmaceutically acceptable salts thereof in an amount from about 0.01% w/w to about 5% w/w of the composition. In a more preferred embodiment, the ophthalmic gel composition comprises plazomicin or its pharmaceutically acceptable salts thereof in an amount from about 0.1% w/w to about 2% w/w of the composition. In another preferred embodiment the ophthalmic gel composition comprises plazomicin or its pharmaceutically acceptable salts thereof in an amount from about 0.1% w/w to about 0.5% w/w of the composition. In one embodiment, the ophthalmic gel composition comprises about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w or about 0.5% w/w plazomicin or its pharmaceutically acceptable salts thereof.

According to another embodiment of the present invention, the ophthalmic gel 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 ophthalmic gel 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.

According to another embodiment of the present invention 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.

In one embodiment, the ophthalmic gel composition of the present invention comprises about 0.01% w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin sulfate.

In a further embodiment, the ophthalmic gel composition of the present invention further comprises atleast one excipient selected from buffering agent, tonicity adjusting agent, gelling agent, preservative, chelating agent and pH adjusting agent.
In one embodiment, the ophthalmic gel composition of the present invention further comprises about 0.01% w/w to about 5% w/w buffering agent.

In one more embodiment, the ophthalmic gel composition of the present invention further comprises about 0.01% w/w to about 10 % w/w tonicity adjusting agent.

In another embodiment, the ophthalmic gel composition of the present invention further comprises about 0.001% w/w to about 5% w/w preservative.

In an embodiment, the ophthalmic gel composition of the present invention comprises about 0.005% w/w to about 5% w/w gelling agent.

In one more embodiment, the ophthalmic gel composition of the present invention comprises about 0.0001% w/w to about 1% w/w chelating agent.

In one embodiment, the ophthalmic gel composition of the present invention further comprises a pH adjusting agent.

In an embodiment, the ophthalmic gel composition of the present invention is an aqueous composition.

In one another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin or its pharmaceutically acceptable salt in a solubilized form.
In a further embodiment, the ophthalmic gel composition of the present invention comprises plazomicin or its pharmaceutically acceptable salt in a suspended form.
In one embodiment, the ophthalmic gel composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.001% w/w to about 5% w/w preservative, about 0.01% w/w to about 5% w/w buffering agent, about 0.0001% w/w to about 1 % w/w chelating agent, about 0.01% w/w to about 10% tonicity adjusting agent, optionally a pH adjusting agent and water.

In another embodiment, the ophthalmic gel composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.01% w/w to about 5% w/w buffering agent, about 0.0001% w/w to about 1 % w/w chelating agent, about 0.01% w/w to about 10% tonicity adjusting agent, optionally a pH adjusting agent and water.

In a further embodiment, the ophthalmic gel composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.001% w/w to about 5% w/w preservative, about 0.01% w/w to about 5% w/w buffering agent, optionally a pH adjusting agent and water.

In one more embodiment, the ophthalmic gel composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.01% w/w to about 5% w/w buffering agent, optionally a pH adjusting agent and water.

In an embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropylmethyl cellulose about 0.25% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 0.2%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.055%w/w, sodium chloride 0.05% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropylmethyl cellulose about 0.35% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 1.0%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.055%w/w, sodium chloride 0.05% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In one embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropylmethyl cellulose about 0.5% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 1.6%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.055%w/w, sodium chloride 0.06% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In a further embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, hydroxypropylmethyl cellulose about 0.25% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 0.2%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.01%w/w, sodium chloride 0.05% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In one more embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, hydroxypropylmethyl cellulose about 0.35% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 1.0%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.03%w/w, sodium chloride 0.05% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, hydroxypropylmethyl cellulose about 0.5% w/w, poloxamer about 0.2%w/w, polycarbophil about 0.38%, glycerine about 0.88%w/w, boric acid about 0.5%w/w, mannitol about 1.6%w/w, propylene glycol about 0.44%w/w. disodium edetate about 0.1%w/w, sodium chloride 0.06% and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In an embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, carbomer about 0.25% w/w, mannitol about 4.0%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, carbomer about 0.35% w/w, mannitol about 2.5 %w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In one embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, carbomer about 0.50% w/w, mannitol about 1.6%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.
In a further embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, carbomer about 0.35% w/w, mannitol about 2.5%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In an embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropyl methylcellulose about 0.25% w/w, sodium alginate about 0.8%w/w, mannitol about 4.0%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In another embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropyl methylcellulose about 0.35% w/w, sodium alginate about 0.8%w/w, mannitol about 2.5%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In one embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, stabilized oxychloro complex about 0.1%w/w, hydroxypropyl methylcellulose about 0.5% w/w, sodium alginate about 0.8%w/w, mannitol about 1.6%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.

In a further embodiment, the ophthalmic gel composition of the present invention comprises plazomicin about 0.5%w/w, hydroxypropyl methylcellulose about 0.5% w/w, sodium alginate about 0.8%w/w, mannitol about 4.0%w/w, and about quantity sufficient to adjust pH hydrochloric acid or sodium hydroxide, and purified water.
The present invention also provides a method for the treatment and/or prevention of ophthalmic infections, which method comprises the administration of a therapeutically effective amount of an ophthalmic gel composition according to the present invention.
The ophthalmic gel composition of the present invention may be used topically in the treatment of ocular infections associated with inflammation such as conjunctivitis, dacryocystitis, hordeolum, keratitis, blepharitis, and corneal ulcers thereof. The composition 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:
Materials Quantity in % w/w
A B C D E F
Plazomicin 0.5 0.5 0.5 0.5 0.5 0.5
Stabilized Oxychloro Complex 0.1 0.1 0.1 - - -
Hydroxypropylmethylcellulose 0.25 0.35 0.5 0.25 0.35 0.5
Poloxamer 0.2 0.2 0.2 0.2 0.2 0.2
Polycarbophil 0.38 0.38 0.38 0.38 0.38 0.38
Glycerine 0.88 0.88 0.88 0.88 0.88 0.88
Boric Acid 0.5 0.5 0.5 0.5 0.5 0.5
Mannitol 0.2 1.0 1.6 0.2 1.0 1.6
Propylene Glycol 0.44 0.44 0.44 0.44 0.44 0.44
Disodium Edetate 0.055 0.055 0.055 0.01 0.03 0.1
Sodium Chloride 0.05 0.05 0.06 0.05 0.05 0.06
Purified Water q.s.t. 100%
Sodium Hydroxide q.s.t. pH adjustment
Hydrochloric Acid q.s.t. pH adjustment

Example 2:
Materials Quantity in %w/w
G H I J
Plazomicin 0.5 0.5 0.5 0.5
Stabilized Oxychloro Complex 0.1 0.1 0.1 -
Carbomer 0.25 0.35 0.50 0.35
Mannitol 4.0 2.5 1.6 2.5
Purified Water q.s.t. 100%
Sodium Hydroxide q.s.t. pH adjustment
Hydrochloric Acid q.s.t. pH adjustment

Example 3:
Materials Quantity in %w/w
K L M N
Plazomicin 0.5 0.5 0.5 0.5
Stabilized Oxychloro Complex 0.1 0.1 0.1 -
Hydroxypropylmethylcellulose 0.25 0.35 0.5 0.5
Sodium Alginate 0.8 0.8 0.8 0.8
Mannitol 4.0 2.5 1.6 4.0
Purified Water q.s.t. 100%
Sodium Hydroxide q.s.t. pH adjustment
Hydrochloric Acid q.s.t. pH adjustment

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
,CLAIMS:
1. An ophthalmic gel composition comprising plazomicin or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.
2. The ophthalmic gel composition of claim 1, wherein the plazomicin or its pharmaceutically acceptable salt thereof is present in concentration of about 0.01% w/w to about 1.00% w/w.
3. The ophthalmic gel composition of claim 1 wherein the pharmaceutically acceptable excipients are selected from buffering agent, tonicity adjusting agent, gelling agent, preservative, chelating agent and optionally pH adjusting agent.
4. The ophthalmic gel composition of claim 3 wherein the composition comprises about 0.01% w/w to about 5% w/w of a buffering agent.
5. The ophthalmic gel composition of claim 3, wherein the composition comprises about 0.01% w/w to about 10 % w/w of a tonicity adjusting agent.
6. The ophthalmic gel composition of claim 3, wherein the composition comprises about 0.001% w/w to about 5% w/w of a preservative.
7. The ophthalmic gel composition of claim 3, wherein the composition comprises about 0.005% w/w to about 5% w/w of a gelling agent.
8. The ophthalmic gel composition of claim 3, wherein the composition comprises about 0.0001% w/w to about 1% w/w of a chelating agent.
9. The ophthalmic gel composition of claim 1, wherein the composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.001% w/w to about 5% w/w preservative, about 0.01% w/w to about 5% w/w buffering agent, about 0.0001% w/w to about 1 % w/w chelating agent, about 0.01% w/w to about 10% tonicity adjusting agent, optionally a pH adjusting agent and water.
10. The ophthalmic gel composition of claim 1, wherein the composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.01% w/w to about 5% w/w buffering agent, about 0.0001% w/w to about 1 % w/w chelating agent, about 0.01% w/w to about 10% tonicity adjusting agent, optionally a pH adjusting agent and water.
11. The ophthalmic gel composition of claim 1, wherein the composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.001% w/w to about 5% w/w preservative, about 0.01% w/w to about 5% w/w buffering agent, optionally a pH adjusting agent and water.
12. The ophthalmic gel composition of claim 1, wherein the composition comprises about 0.01%w/w to about 1.00% w/w plazomicin or its pharmaceutically acceptable salt thereof, about 0.005% w/w to about 5% w/w gelling agent, about 0.01% w/w to about 5% w/w buffering agent, optionally a pH adjusting agent and water.
13. The ophthalmic gel composition of claim 1, wherein the composition is an aqueous composition.
14. The ophthalmic gel composition of claim 1, wherein the plazomicin or its pharmaceutically acceptable salt is present in a solubilized form.
15. The ophthalmic gel composition of claim 1, wherein the plazomicin or its pharmaceutically acceptable salt is present in a suspended form.
16. The ophthalmic gel composition of claim 1for use in the treatment or prevention of ocular infections.