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:
COMPOSITIONS OF FLUOROQUINOLONE ANTIBIOTICS FOR OPHTHALMIC, OTIC AND NASAL ADMINISTRATION
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 relates to stable solutions suitable for ophthalmic, otic, or nasal administration that include fluoroquinolone antibiotic or salts thereof and amino acid, optionally in combination with one or more drugs for the treatment of bacterial infections.
The following specification particularly describes the invention and the manner in which it is to be performed.
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4. DESCRIPTION
The present invention relates to stable solutions suitable for ophthalmic, otic or nasal administration that include fluoroquinolone antibiotic or salts thereof and amino acid, optionally in combination with one or more drugs for the treatment of bacterial infections.
Fluoroquinolone antibiotics are widely used in the management of infectious diseases. Their potent and broad spectrum of activity, efficacy and relative safety make them useful. They act by inhibiting the bacterial DNA gyrase or the topoisomerase IV enzyme, thereby inhibiting DNA replication and transcription. Quinolones can enter cells easily and therefore are often used to treat intracellular pathogens such as Legionella pneumophila and Mycoplasma pneumoniae.
The use of quinolone antibiotics to treat infections is known art in the field of ophthalmic pharmaceutical compositions and methods of treatment. Several quinolone antibacterial agents available in the market include gatifloxacin (available as Zymar®), Levofloxacin (available as Quixin® or Iquix®), Ciprofloxacin (available as Ciloxan®), Ofloxacin (available as Ocuflox®), Lomefloxacin (available as Lomeflox®), Moxifloxacin (available as Vigamox®) and Norfloxacin (available as Chibroxin®).
U.S. Patent No. 4,844,902 discloses a topically applicable formulation comprising by weight about 0.01 to 30% of an anti-bacterially active compound, 0.01 to 10% of a corticosteroid and a carrier.
U.S. Patent No. 6,333,045 discloses liquid pharmaceutical compositions of gatifloxacin or salt thereof and disodium edetate.
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U.S. Patent No. 6,716,830 discloses ophthalmic dosage forms of moxifloxacin or salts thereof in a concentration of 0.1% to 1% (w/w) and pharmaceutically acceptable vehicle.
U.S. Patent No. 6,359,016 relates to topical suspension formulations containing ciprofloxacin and dexamethasone.
U.S. Patent Application 20060183698 describes topical ophthalmic formulation that includes serum electrolytes; an antimicrobial compound and an antiinflammatory or steroidal compound. Several antimicrobial agents have been disclosed including nadifloxacin.
U.S. Patent Application 20040176337 discloses topical compositions of benzoquinolizine-2-carboxylic acid antimicrobial drug.
U.S. Patent Application 20040176321 discloses injectable pharmaceutical composition for intravenous delivery of an active agent that includes RS-(±)-nadifloxacin; S-(-)-nadifloxacin and hydrates thereof; or S-(-)-nadifloxacin arginine and salts thereof.
PCT Publication WO 04/00360 describes pharmaceutical compositions of several active ingredients including nadifloxacin for topical use for treatment of dermatosis.
European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salts thereof.
PCT application WO 02/39993 discloses a stable pharmaceutical preparation of a combination drug, comprising an anti-infective agent, selected from the group consisting of quinolone derivatives, amino-glycoside derivatives and their pharmaceutically acceptable salts; an ant-inflammatory agent which is a
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corticosteroid; a complexation enhancing polymer; a solubilizer exhibiting an inclusion phenomena; pharmaceutical^ acceptable excipients within a suitable carrier system.
Journal of Ocular Pharmacology and Therapeutics, vol 23(3): 243-256, 2007 discloses (7-[(3R)-3-aminohexahydro-1H-azepine-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylivc acid as the topical agent for the treatment of ophthalmic infections.
The foregoing quinolone antibiotic compositions are generally effective in treating ophthalmic infections, and have distinct advantages over prior ophthalmic antibiotic compositions, particularly those having relatively limited spectrum 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.
However, despite the general efficacy of the ophthalmic quinolone therapies currently available, there is a need for improved compositions and methods of treatment based on the use of antibiotics that are more effective than existing antibiotics against key ophthalmic pathogens and less prone to the development of resistance by those pathogens.
There is an even greater need for effective stable topical compositions and methods for treating otic and nasal infections, particularly bacterial infections. The use of oral antibiotics to treat otic infections in children has limited efficacy, and creates a serious risk of pathogen resistance to the orally administered antibiotics. Hence it is the object of the present invention to provide a stable solution composition of fluoroquinolone antibiotic or salt thereof with amino acid optionally in combination with an anti-inflammatory/ anti-allergic agent, antifungal, steroid or macrolide.
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The present inventors while working on the pharmaceutical compositions of fluoroquinolone antibiotics or salts thereof have surprisingly found that fluoroquinolones can be formulated into a stable dosage form with the help of addition of a suitable amount of a pharmaceutically acceptable amino acid. The stable solution is suitable for the treatment of ocular, otic and nasal infections. Further the invention provides a stable dosage form of fluoroquinolone or salt thereof, optionally in combination with one or more drugs selected from the group comprising steroids, anti-inflammatory/anti-allergics, anti-fungal or macrolide for the treatment of ophthalmic, otic or nasal bacterial infections. A stable ophthalmic solution composition may be expected to have better patient compliance and acceptance.
In one aspect of the invention there is provided a stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or a salt thereof, one or more pharmaceutically acceptable amino acid and pharmaceutically acceptable vehicle therefor.
The term "fluoroquinolone antibiotic or a salt thereof referred to in this invention includes, but not limited to, nadifloxacin, ciprofloxacin, ofloxacin, pefloxacin, grepafloxacin, enoxacin, amifioxacin, fleroxacin, temafloxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, gatifloxacin and moxifloxacin or salts or single enantiomers thereof.
The term "pharmaceutically acceptable" in relation to an amino acid herein means that having no undesired or detrimental effect on the health of the subject being treated. The addition of amino acid, in suitable amount provides increased solubility of fluoroquinolone antibiotic, lowered potential to induce phlebitogenicity, fulfilling the abnormal toxicity regulatory requirements and stability when stored for an extended period at specified temperature and humidity ranges. The amino acid can be used in concentration of 0.1% to 4.0% (w/v).
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The amino acid may be selected from one or more of arginine, histidine, arginine acetate, arginine-glutamate, arginine monohydrochloride, histidine acetate, histidine acetate dihydrate, histidine monohydrochloride, histidine monohydrochloride monohydrate, lysine, lysine acetate, lysine monohydrochloride, ornithine, tryptophan, L-arginine, L-histidine, L-arginine acetate, L-arginine-L-glutamate, L-arginine monohydrochloride, L-histidine acetate, L-histidine acetate dihydrate, L-histidine monohydrochloride, L-histidine monohydrochloride monohydrate, L-Lysine, L-Lysine acetate, L-Lysine monohydrochloride and/or a salts thereof and/or D or DL form of these amino acids or salts thereof.
In another aspect of the invention there is provided a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone atitibiotic or salt thereof, at least one amino acid, a steroid and pharmaceutically acceptable vehicle therefor.
For broader spectrum antibacterial activity, a second drug can be administered in co-therapy. In case of present embodiment, the second agent can be a steroid. Formulations containing steroids are useful for topical application to the eye, ear, nose or skin. Steroids are insoluble in water and thus are generally available in suspended form or are dissolved in oil or solvents when used in the formulation. However, for ophthalmic use it would be desirable to avoid the use of oil or solvents and provide a clear solution of steroid in a predominantly aqueous phase and a formulation in suspension form causes discomfort to the eye and requires inclusion of many additional excipients to formulate a stable suspension composition, which may also cause irritation to the eye. Thus a clear, stable solution composition is the most preferred formulation for administration to the eye.
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The suitable steroidal drug comprises one or more of beclomethasone, betamethasone, budesonide, dexamethasone, clobetasol, clobetasone, flumethasone, fluorometholone, hydrocortisone, prednisolone, triamcinolone loteprednol, methylprednisolone, medrysone and the like.
In yet another aspect of the invention there is provided a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, an antiinflammatory or anti-allergic agent and pharmaceutically acceptable vehicle therefor.
The suitable anti-inflammatory or anti-allergic agent drug comprises one or more of diclofenac, ketorolac, flurbiprofen, indomethacin, suprofen, ibuprofen, ketorolac tromethamine, emedastine, levocabastine, azelastine, olopatadine, ketotifen, cromolyn, or lodoxamide and the like.
In another aspect of the invention there is provided a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, an anti-fungal agent and pharmaceutically acceptable vehicle therefor.
An antifungal agent is any agent that prevents the growth of or kills a fungal organism. In addition, antifungal agents can be agents that interpolate fungal cell wall components or act as cell wall inhibitors. Suitable anti-fungal agent comprises one or more from butenafine, naftifine, terbinafine imidazoles: bifonazole, butoconazole, chlordantoin, chlormidazole, cloconazole, clotrimazole, econazole, enilconazole, fenticonazole, flutrimazole, isoconazole, ketoconazole, lanoconazole, miconazole, neticonazole, omoconazole, oxiconazole nitrate, sertaconazole, sulconazole, tioconazole and the like.
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In another aspect of the invention there is provided a stable solution dosage form for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotic or salt thereof, at least one amino acid, a macrolide and pharmaceutically acceptable vehicle therefor.
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. Suitable macrolide comprises one or more from erythromycin, azithromycin, roxithromycin, clarithromycin and the like.
In yet another aspect of the present invention there is provided a process for the preparation of a stable solution, the process comprising:
a) mixing water, one or more fluoroquinolone antibiotic or salt thereof and amino acid;
b) optionally adding another active agent, wherein the active agent is selected from the therapeutic categories of steroids, anti-inflammatory /anti-allergic agents, anti-fungals, and macrolides;
c) filtering the solution; and
d) filling in suitable containers.
In addition to the above agents, the stable ophthalmic solution composition of the present invention comprises a complexing agent capable of solubilizing the active agent in pharmaceutically acceptable vehicle by forming an inclusion complex. The complexing agents selected in the present invention may be a cyclodextrin and its derivatives, which can be well tolerated when, administered by ophthalmic route for e.g. alpha-, beta- or gamma-cyclodextrins or derivatives thereof.
The pharmaceutically acceptable vehicle may include water.
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The composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The stable solution dosage form for the ophthalmic, otic or nasal use, as part of present invention can be present 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, 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.
The ophthalmic, otic and nasal compositions of the present invention 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 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: polyquatemium-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% (w/v).
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A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions. In case of nadifloxacin 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), and cyclodextrin especially HP- p -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% (w/v). HP-p-CD has a tendency to form inclusion complex with many drugs including nadifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of nadifloxacin can be further reduced based on complexation with HP-p-CD.
The use of viscosity enhancing agents to provide the compositions of the 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% (w/v).
The term "stable" in the present context encompasses the solution that does not show any precipitation during the entire period of shelf life.
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.
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Examples: The composition of batches is provided in table 1. Following formulations are representatives of the preferred compositions of the present invention. The preparation of example 1 is detailed below.
Table 1 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 1 (% Composition) Example 2 (% Composition)
1 S-Nadifloxacin 0.3 0.2
2 L-Arginine 0.66 0.44
3 Hydroxypropyl betacyclodextrin 2.50 2.0
4 Polyvinyl alcohol 0.3 0.30
5 Benzalkonium chloride 0.01 0.01
6 Disodium EDTA 0.05 0.05
7 Sodium Chloride 0.50 0.50
8 Water for injection q.s. 100 ml q.s 100 ml
9 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 7.0 q.s 1 N solution for pH adjustment to 7.0
Procedure -
Nadifloxacin, amino acid and HP-p- CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI between 5.5 to 7.5. The solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22 m membrane filters and filled in desired containers under laminar flow.
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Table 2 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 3 (% Composition)
1 Ciprofloxacin 0.3
2 L-Arginine 0.66
3 Hydroxypropyl betacyclodextrin 2.00
4 Polyvinyl alcohol 0.3
5 Benzalkonium chloride 0.01
6 Disodium EDTA 0.05
7 Sodium Chloride 0.1-0.9
8 Water for injection q.s. 100 ml
9 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 4.5-7.0
Procedure -
Ciprofloxacin, amino acid and HP-p- CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI between 4.5 to 7.0. The solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22m membrane filters and filled in desired containers under laminar flow.
Table 3 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 4 (% Composition)
1 Diclofenac sodium 0.1
2 L-Arginine 0.2-0.4
3 Hydroxypropyl betacyclodextrin 0.5-2.50
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4 Polyvinyl alcohol 0.3
5 Benzalkonium chloride 0.01
6 Glycerine 2.1
8 Water for injection q.s. 100 ml
9 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 4.5-7.5
Procedure -
Diclofenac sodium, amino acid and HP-p-CD was dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI between 4.5 to 7.5. The solution was then adjusted to required osmolality using a solution of glycerin in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22|a membrane filters and filled in desired containers under laminar flow.
Table 4 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 5 (% Composition)
1 Gatifloxacin 0.3
2 L-Arginine 0.66
3 Hydroxypropyl betacyclodextrin 1.50
4 Polyvinyl alcohol 0.3
5 Benzalkonium chloride 0.01
6 Cremophor EL 1.0-2.5
7 Sodium Chloride 0.50
8 Water for injection q.s. 100 ml
9 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 6.0
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Procedure -
Gatifloxacin, amino acid and HP-p- CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI to 6.0. The solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22m membrane filters and filled in desired containers under laminar flow.
Table 5 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 6 (% Composition)
1 S-Nadifloxacin 0.3
2 Diclofenac sodium 0.1
3 L-Arginine 0.66
4 Hydroxypropyl betacyclodextrin 2.50
5 Polyvinyl alcohol 0.3
6 Benzalkonium chloride 0.01
7 Disodium EDTA 0.05
8 Sodium Chloride 0.50
9 Water for injection q.s. 100 ml
Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 7.0
Procedure -
Nadifloxacin, diclofenac sodium, amino acid and HP-p-CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI to 7.0. The solution was then adjusted to required osmolality using a solution of
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sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22m. membrane filters and filled in desired containers under laminar flow.
Table 6 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 7 (% Composition)
1 S-Nadifloxacin 0.3
2 Naphazoline hydrochloride 0.1
3 L-Arginine 0.2
4 Hydroxypropyl betacyclodextrin 1.0
5 Polyvinyl alcohol 0.5
6 Benzalkonium chloride 0.01
7 Disodium EDTA 0.01
8 Sodium Chloride 0.50
9 Water for injection q.s. 100 ml
10 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 5.5-7.5
Procedure -
Nadifloxacin, naphazoline hydrochloride, amino acid and HP-P- CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI between 5.5 to 7.5. The solution was then adjusted to required osmolality using a solution of sodium chloride (0.1 to 0.9%) in water for injection. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22\i membrane filters and filled in desired containers under laminar flow.
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Table 7 provides composition of batches of the present invention.

Sr.No Name of ingredient Example 8 (% Composition)
1 S-Nadifloxacin 0.3
2 Dexamethasone 0.1
3 L-Arginine 0.2
4 Hydroxypropyl betacyclodextrin 1.0
5 Polyvinyl alcohol 0.5
6 Benzalkonium chloride 0.01
7 Disodium EDTA 0.01
9 Water for injection q.s. 100 ml
10 Sodium Hydroxide or Hydrochloric acid q.s 1 N solution for pH adjustment to 5.5-7.5
Procedure -
Nadifloxacin, dexamethasone, amino acid and HP-|3- CD were dissolved in water for injection. To this was added a solution of polyvinyl alcohol and benzalkonium chloride in water for injection. A solution of disodium edetate was added to this and the pH of the resultant solution was adjusted using 1N HCI between 5.5 to 7.5. Osmolality of solution was adjusted to 250-350 mOsm/kg. The resultant solution was filtered using 0.22^ membrane filters and filled in desired containers under laminar flow.
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.
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WE CLAIM:
1. A stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotics or a salt thereof, one or more pharmaceutically acceptable amino acids and pharmaceutically acceptable vehicle therefor.
2. A stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotics or a salt thereof, one or more pharmaceutically acceptable amino acids, a steroid and pharmaceutically acceptable vehicle therefor.
3. A stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotics or a salt thereof, one or more pharmaceutically acceptable amino acids, an anti-inflammatory or an anti-allergic agent and pharmaceutically acceptable vehicle therefor.
4. A stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotics or a salt thereof, one or more pharmaceutically acceptable amino acids, an anti-fungal agent and pharmaceutically acceptable vehicle therefor.
5. A stable solution suitable for ophthalmic, otic or nasal administration comprising one or more fluoroquinolone antibiotics or a salt thereof, one or more pharmaceutically acceptable amino acids, a macrolide and pharmaceutically acceptable vehicle therefor.
6. A process for the preparation of a stable solution, the process comprising:
a) mixing water, one or more fluoroquinolone antibiotics or a salt thereof and amino acid;
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b) optionally adding another active agent, wherein the active agent is selected from the therapeutic categories of steroids, antiinflammatory/anti-allergic agents, anti-fungals, and macrolides;
c) filtering the solution; and
d) filling in suitable containers.

7. The stable solution according to claims 1 to 5, wherein pH of the solution is within the range 4.5 to 8.0.
8. The stable solution according to claims 1 to 5 further comprises cyclodextrin or pharmaceutically acceptable derivative thereof.
9. The stable solution according to claims 1 to 5 further comprises one or more pharmaceutically acceptable excipients.
10. The stable solution according to claims 1 to 5, wherein the pharmaceutically acceptable excipients comprise one or more preservatives, surfactants, and viscosity modifiers.
Dated this TH day of August 2007.


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Abstract
The present invention relates to stable solutions suitable for ophthalmic, otic, or nasal administration that include a fluoroquinolone antibiotic or salts thereof and amino acid, optionally in combination with one or more drugs.
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