The present invention relates to compositions including antibiotics and to methods for using such compositions. More particularly, the invention relates to compositions including antibiotics which have added protection against fungal contamination, which reduce inflammation or pain, for example, non-inflammatory pain, and/or which are useful in the treatment of corneal ulcers.
Various antibiotic components have been used in ocular applications, for example, to control or manage or prevent ocular infections and the like. Moreover, antibiotic components, such as tobramycin have been suggested for use in combination with other materials, such as ophthalmically acceptable non-steroidal anti-inflammatory drugs or NSAIDs. See, for example, Fu et al. U.S. Pat. No. 5,414,011, the disclosure of which is incorporated in its entirety herein by reference. Quinolones, such as ofloxacin, have been used in compositions for treating ocular infections. These antibiotic compositions include one or more additional components which act as preservatives, for example, benzalkonium chloride (BAK) or organomercurials.
Antibiotic compositions, even with preservatives, have been susceptible to microbial, for example, fungal, contamination. In addition, preservatives tend to cause irritation, allergic reactions, and/or other detrimental side effects when the preserved composition is administered to a patient.
Thus, it would be advantageous to provide antibiotic compositions, and methods for using such compositions, which have added protection against microbial contamination and/or which include relatively reduced concentrations of preservatives.
Injuries and traumas to mammals, including human, for example, ocular injuries and traumas, such as corneal ulcers and other corneal injuries and conditions, are quite painful and sometimes require lengthy periods of time to heal. At least a portion of the pain resulting from such injuries and traumas is often not associated with inflammation, that is is non-inflammatory pain. It would be advantageous to provide compositions and methods effective to reduce the non-inflammatory pain of these injuries and traumas, for example, while such injuries and traumas are healing.
New antibiotic compositions, for example, for use in mammalian eyes, preferably human eyes, and methods for using such compositions have been discovered. By administering present compositions to humans or animals, for example, to the eyes of humans or animals, desired therapeutic effects are provided, such as the prevention, control or management or substantial elimination of ocular microbial infections, reductions in inflammation and/or pain, reductions in non-inflammatory pain caused by injuries and traumas including, but not limited to, corneal and other injuries and traumas and the like.
The present compositions preferably have added protection against microbial, for example, fungal contamination. This feature provides added assurance to the user that the present compositions are free of detrimental microbial contamination. This feature may allow reduced concentrations of preservatives to be included in the present compositions, thereby advantageously reducing detrimental side effects caused by such preservatives when the compositions are administered to patients. The present compositions can be easily produced, for example, using conventional techniques and can be conveniently used, for example, employing conventional methods of administration.
In accordance with one aspect of the invention, the compositions comprise a quinolone component, a NSAID component and a carrier component. The quinolone component is present in an amount effective as a antibiotic when the composition is placed in a mammalian eye. In one useful embodiment, the quinolone component in the composition has fungistatic activity. That is, the quinolone components in the present compositions have sufficient anti-fungal properties or activity to substantially prevent increases in populations of fungi in such compositions. In effect, the present quinolone components act as effective preservatives against fungal growth or contamination in the present compositions. The fungistatic activity of the presently useful quinolone components in the present compositions provide benefits, for example, as described elsewhere herein, which are surprising and substantial. The NSAID component is present in an amount effective to reduce at least one of inflammation and pain when the composition is placed in a mammalian eye. The carrier component is present in an amount effective to act as a carrier for the quinolone component and the NSAID component in the composition, and preferably is ophthalmically acceptable.
The present compositions preferably include a quinolone component which is halogenated, more preferably fluorinated. Very useful compositions and results are obtained when the quinolone component is an ofloxacin component.
Although any NSAID component may be used, the NSAID components included in the present compositions preferably are carboxylic (xe2x80x94COOH) group-containing NSAID components. More preferably, the NSAID component is a pyrrolo pyrrole component, still more preferably a ketorolac component.
The present carrier components may contain one or more pharmaceutically or ophthalmically acceptable ingredients, for example, tonicity adjuster components, buffer components, viscosity components, lubricating components, surfactant components, preservative components and the like, conventionally used, for example, in ophthalmic formulations. Preferably, the compositions have pH""s in the physiological range of human beings, for example, in the range of about 4 to about 8.5.
The present compositions may be in any form suitable for effective administration to the human or animal to be treated. Preferably, the compositions are present in a form selected from solutions, suspensions, gels, ointments solids and the like which are very effective for ocular administration. The carrier component may conveniently be selected and/or compounded to provide the composition in the form desired.
Methods of using these compositions are included in the scope of the present invention. Such methods comprise administering to a human or animal, preferably to a mammalian eye, a therapeutically effective amounts of the compositions as described herein. Such methods provide one or more benefits to the human or animal treated in accordance with the present methods. For example, such benefits include prevention, control or management of microbial infections, and reduction in inflammation and/or pain, for example, non-inflammatory pain.
In one embodiment, the present invention is directed to methods for reducing pain, for example, including pain which is not associated with or caused by inflammation, hereinafter referred to as non-inflammatory pain. Non-inflammatory pain can occur as the result of an injury or trauma, for example, prior to the injury or trauma site being inflamed and/or during inflammation of such site and/or after the inflammation has subsided. Non-inflammatory pain can occur alone or together or in combination with inflammatory pain, that is, pain associated with or caused by inflammation. Non-inflammatory pain can be ocular, that is can be associated with the eye or in or on the eye, for example, on the cornea of the eye, as a result of an injury or trauma to the tissues of the eye or in proximity to the eye.
The present methods for reducing pain comprise administering to a mammal having non-inflammatory pain a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic and a NSAID component in an amount effective, in combination with the quinolone component, to provide a reduction in the non-inflammatory pain. In a very useful embodiment, the mammal also has inflammatory pain and the NSAID component is present in an amount effective, in combination with the quinolone component, to provide a reduction in both non-inflammatory pain and inflammatory pain. The quinolone component and NSAID component preferably are as described elsewhere herein.
In another aspect of the present invention, methods for treating corneal injuries are provided. As used herein, the term xe2x80x9ccorneal injuryxe2x80x9d refers to an injury of the cornea which is infected by harmful and/or unwanted microorganism or which, if left untreated is likely to become so infected, for example, before this injury heals. A corneal ulcer is an example of a corneal injury. Such methods comprise administering to a mammalian eye having a corneal injury a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic in the mammalian eye and a NSAID component in an amount effective, in combination with the quinolone component, to provide a reduction in pain, such as non-inflammatory pain or a combination of non-inflammatory pain and inflammatory pain, caused by the corneal injury. Such reduction in pain, together with the antibiotic effectiveness of the presently useful compositions, reduces the discomfort to the patient resulting from the corneal injury and facilitates or promotes the healing of the injury. The present useful compositions preferably include a carrier component in an amount effective to act as a carrier for the quinolone component and the NSAID component in the presently useful composition.
In another aspect of the present invention, methods for treating ocular infections, such as corneal infections and the like, are provided. Such methods comprise administering to a mammalian eye having an infection caused by one or more microbes or pathogens a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic in the mammalian eye and an effective amount of a NSAID component. In one embodiment, the NSAID component is present in an amount effective to reduce the time needed to eliminate the infection relative to identically administering a similar composition without the NSAID component. The administering step preferably is effective to at least inhibit the offending microbe(s) or pathogen(s) from adhering to a surface of the mammalian eye and/or to inhibit colonization of the offending microbe(s) or pathogen(s) in the mammalian eye.
Any and all features described herein and combinations of such features are included within the scope of the present invention provided that the features of any such combination are not mutually inconsistent.
These and other aspects and advantages of the present invention are set forth in the following detailed description and Examples and claims.
The present compositions comprise quinolone components, NSAID components and carrier components.
Preferably, the present quinolone components exhibit fungistatic properties in the present compositions. That is, the quinolone components in the present compositions preferably are effective to preserve the present compositions against population growth of fungi, such as C. Albicans and A. niger. 
The fungistatic activity or properties of the present quinolone components provide added protection against microbial, for example, fungal, contamination of the present compositions. Such fungistatic activity can result in reducing the concentration of added preservative components in the present compositions, thereby reducing the risk of irritation and/or other uncomfortable side effects caused by the presence of such added preservatives. Even if the present compositions are substantially free of added preservative components, it has been found that many of the present compositions have sufficient preservative efficacy to meet or exceed the standards of the United States Preservative Efficacy Test (USPET).
The present compositions include quinolone components. A number of such quinolone components are known and have been used for many years in antibiotic applications. For example, nalidixic acid has been available for the treatment of urinary tract infections. The useful quinolone components preferably are four-quinolones that contain a carboxylic moiety in the three position of the basic structure shown below: 
The present quinolone components preferably are halogenated. For example, a chlorinated quinolone component, such as 9-chloro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyridol[1,2,3-de][1,4]benzozaxine-6 carboxylic acid may be used.
More preferably, the present quinolone components are fluorinated. Examples of such fluorinated quinolones include norfloxacin, ciprofloxacin and ofloxacin. Such fluorinated quinolone components are highly effective against a range of bacteria and are useful in treating various microbial infections in the mammalian eye. Prior ofloxacin-containing compositions including such quinolone used for this purpose include additional preservatives, for example, BAK.
It has been found that the present quinolone components, such as ofloxacin, have sufficient fungistatic activity to be useful in the present compositions to act as a preservative against fungal contamination.
The present compositions include an antibiotically effective amount of the quinolone component. Such amounts may vary over a relatively broad range depending, for example, on the specific form of the composition being used, the specific quinolone component being used, the specific application for the composition, the frequency of use of the composition and the like factors. In many situations, the present compositions may include a quinolone component in an amount in a range of about 0.03% (w/v) or less to about 3% (w/v) or more. Preferably, the present compositions include the quinolone component in an amount in the range of about 0.15% (w/v) to about 0.5% (w/v) or about 1.1% (w/v).
The quinolone component may be any quinolone derivative which is acceptable or suitable for administration to the eye and has at least a portion, preferably a major portion or at least about 50% of the antibiotic effectiveness of the basic quinolone in the present composition in the mammalian eye. The present quinolone component may be selected from the quinolone itself or quinolone hydrates or ophthalmically acceptable salts of such quinolones, for example, including acid addition salts such as hydrochlorides, maleates, pamoates and the like, and alkali metal salts such as sodium and potassium salts, and mixtures thereof and the like.
The present compositions include a NSAID component in an amount effective to reduce inflammation and/or pain when the compositions are administered to a mammalian eye, for example, to prevent or treat diseases which are either caused by, associated with or accompanied by inflammatory processes and/or pain, including, among others, glaucoma, cystoid macular edema, uveitis, diabetic retinopathy and conjunctivitis, or any trauma caused by eye surgery or eye injury.
The NSAID component may or may not include a carboxylic (xe2x80x94COOH) group or moiety, or a carboxylic derived group or moiety. In one embodiment, the NSAID component inhibits the cyclo-oxygenase enzyme, which has two (2) isoforms, referred to as COX-1 and COX-2. Many of the well known NSAID components are basically non-selective COX inhibitors. NSAID components which are selective COX-2 inhibitors are also known. Both types of NSAID components, that is both non-selective COX inhibitors and selective COX-2 inhibitors are useful in accordance with the present invention. The NSAID component may be selected from phenylalkanoic acids, such as diclofenac, flurbiprofen, ketorolac, piroxicam and the like; indoles, such as indomethacin and the like; diarylpyrazoles, such as celecoxib and the like; pyrrolo pyrroles; and other agents that inhibit prostaglandin synthesis. A very useful NSAID component is the pyrrolo pyrrole which has a propionic acid moiety, known as ketorolac and derivatives thereof, such as non-toxic esters and salts thereof. Pyrrolo pyrroles have been suggested for use in the treatment of certain ophthalmic diseases in Waterbury U.S. Pat. No. 4,454,151, the disclosure of which is incorporated in its entirety herein by reference.
The NSAID component may be present in the present compositions in any suitable concentration effective to reduce inflammation or pain when the composition is placed in a mammalian eye. The NSAID component preferably is present in an amount in a range of about 0.001% (w/v) or less to about 10% (w/v) or more, and more preferably in a range of about 0.02% (w/v) to about 0.5% (w/v) or about 1% (w/v).
The present carrier components may be selected from pharmaceutically acceptable organic and/or inorganic components which, preferably, in the present compositions are ophthalmically acceptable. As used herein, the term xe2x80x9cophthalmically acceptablexe2x80x9d refers to a material which, at the concentration or amount in question, is compatible with ocular tissue, that is the material does not cause significant or undue detrimental effects when brought into contact with ocular tissue. The carrier component preferably is ophthalmically acceptable. Preferably, each component of the present compositions is also compatible with the other components of the compositions.
Examples of suitable materials useful in the present carrier components include water, mixtures of water and water-miscible solvents such as lower alkanols or aralkanols, vegetable oils, polyalkylene glycols, petroleum-based jelly, ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl mirstate, other conventionally employed pharmaceutically acceptable materials and the like.
The carrier component may also include auxiliary substances such as emulsifiers, wetting agents, bodying agents, buffer components, acids and/or bases, tonicity adjuster components, surfactant components, viscosity agents, lubricity components, preservative components, other materials useful in ophthalmic formulations and the like, including, but not limited to, such substances which are conventionally used in ophthalmic compositions.
Examples of optionally useful bodying agents include, but are not limited to, various polyethylene glycols, carbowaxes, petroleum jelly and the like.
Suitable buffers include, but are not limited to, inorganic buffers such as phosphate buffers, borate buffers and the like, and organic buffers, such as acetate buffers, citrate buffers, tromethamine and the like.
Tonicity adjusters optionally useful in the present compositions include, but are not limited to, dextrose, potassium chloride and/or sodium chloride and the like, preferably sodium chloride.
Acids optionally useful in the present compositions include boric acid, hydrochloric acid, acetic acid, other acids which are ophthalmically acceptable in the concentrations used, and the like.
Bases which may be included in the present compositions include, but are not limited to, sodium and/or potassium hydroxides, other alkali and/or alkaline earth metal hydroxides, organic bases, other bases which are ophthalmically acceptable in the concentrations used, and the like.
The acid/bases/buffers preferably are included, if at all, to provide and/or maintain the present compositions at a pH in the physiologically acceptable range, more preferably in a range of about 4 to about 8.5, still more preferably about 6 to about 8, and especially about 6.8 to about 8.
Surfactant components optionally useful in the compositions of the present invention include, but are not limited to, lipoprotein detergents that when present in the compositions reduce the surface tension between the compositions and the eye (lacrimal) fluid. Preferably, nonionic surfactants are used.
Viscosity agents optionally useful in the compositions of the present invention include, but are not limited to, cellulose derivatives such as hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, other viscosity inducing materials useful in ophthalmic formulations, and the like.
Lubricating components optionally useful in compositions of the present invention include, but are not limited to, polyvinyl alcohol, polyvinylpyrrolidone, carbopol and the like.
Preservative components optionally useful in the compositions of the present invention include, but are not limited to, BAK, organo-mercurials, such as thimerosal and phenylmercuric acetate and nitrate, quaternary ammonium compounds, methyl and propyl parabens, benzl alcohol, phenylethanol and the like. Because of the fungistatic activity of the quinolone components of the present compositions, the concentration of the preservative component, if present at all, in the present compositions may be, and preferably is, reduced, more preferably by at least about 10% or at least about 20%, relative to the concentration of the preservative needed in a similar composition including, in place of the presently useful quinolone component with fungistatic activity, an antibiotic component without such fungistatic activity and still be effectively preserved, for example, adequately preserved to pass the applicable United States and/or European preservative efficacy tests.
The present compositions may include effective amounts of chelating or sequestering components, such as ethylene diamine tetraacetic acid (EDTA), citric acid, tartaric acid and the like.
Other optional excipients useful in the present compositions include stabilizing agents such as antioxidants, for example, alkali metal metabisulfates, ascorbic acid and the like.
The carrier component may be in various forms. In one embodiment, the carrier component comprises a liquid, and the composition may be a solution or a suspension. In either situation, the carrier may simply contain water and one or more auxiliary components noted elsewhere herein.
The present compositions may be in any suitable form effective to be administered to the eye. Such forms include solutions, suspensions, ointments, gels, solids and the like. An ointment may be considered as a form intermediate between a suspension and a gel. Each of these forms of the present compositions can be prepared using techniques and processing which are conventional and well known in the art.
In another embodiment, the carrier component may be in the form of a clear material which forms a semi-solid xe2x80x9cgelxe2x80x9d at human body temperatures. Various polymers, many of which are conventional and well known in the art, can be included in the carrier components to provide the present compositions in the form of gels. For example, a polymer system including alkylene diamine tetra substituted with about 40% to about 80% poly(oxyethylene) units and about 20% to about 60% poly(oxypropylene) units may be employed. The molecular weight of the polymer used preferably is at least about 7,000 and can be as high as about 50,000, more preferably in the range of about 7,000 to about 30,000. The gel forming component, if any is present in an amount effective to provide the composition in the form of a gel. For example, such gel forming component may be present in an amount in a range of about 10% or less to about 50% or more by weight of the total carrier component.
The compositions may also be in the form of solid inserts, for example a solid dosage form that is suitable for insertion into the cul-de-sac of a mammalian eye. To this end, the composition components can be included with a non-bioerodible insert, for example, one which after dispensing the active component or components remains essentially intact, or a bio-erodible insert, for example, one that either is soluble in lacrimal fluids, or otherwise disintegrates.
A solid water soluble polymer may be employed in the carrier component. Such polymers include, for example, cellulose derivatives such as methylcellulose, sodium carboxymethyl cellulose, or a hydroxy lower alkyl cellulose such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and the like; acrylates such as polyacrylic acid salts, ethyl acrylates, polyacrylamides, natural products such as gelatin, alginates, pectins, tragacanth, daraya, chondrus, agar, acacia; the starch derivatives such as starch acetate, hydroxyethyl starch ethers, hydroxypropyl starch, as well as other synthetic derivatives such as polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether, polyethylene oxide, neutralized carbopol and xanthan gum, mixtures thereof and the like.
The present compositions may be prepared using conventional techniques, for example, by formation of solutions, gels, suspensions, etc., using well known and conventional techniques. For a more detailed discussion of the preparation and administration of ophthalmic formulations see Remingtons Pharmaceutical Sciences, 15 Ed., Pgs. 1489 to 1504 (1975) which is incorporated in its entirety herein by reference.
In one embodiment, the present invention is directed to methods for reducing pain, for example, including without limitation, non-inflammatory pain. Non-inflammatory pain can be ocular, that is can be associated with the eye or on the eye, for example, on the cornea of the eye, as a result of an injury or trauma to the tissues of the eye or in proximity to the eye. Corneal injuries, such as corneal ulcers, are believed to result in both non-inflammatory pain and inflammatory pain. Other types of non-inflammatory pain include, without limitation:
peripheral neuropathic painxe2x80x94caused by a lesion or dysfunction in the peripheral nervous system, for example, painful neuropathies where pain persists long after the tissue damage has healed;
central painxe2x80x94caused by a lesion or dysfunction of the central nervous system, for example, thalmic lesions accompanied by severe pain in an unaffected part of the body;
deafferentation painxe2x80x94due to loss of sensory impart into the central nervous system, for example, pain resulting from an injury where dorsal roots are torn away from the spinal cord;
chronic nociceptive pain, for example, certain types of cancer pain;
noxious stimulus of nociceptive receptorsxe2x80x94pain felt in response to tissue damage or impending tissue damage;
phantom painxe2x80x94pain felt in a part of the body that no longer exists;
pain felt by psychiatric patientsxe2x80x94where no physical cause exists;
wandering painxe2x80x94pain which repeatedly changes location in the body; and the like.
The present methods for reducing non-inflammatory pain comprise administering to a mammal, human or animal, having non-inflammatory pain a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic and a NSAID component in an amount effective, in combination with the quinolone component, to provide a reduction in the non-inflammatory pain. The mammal may also have inflammatory pain and the NSAID component is preferably present in an amount effective, in combination with the quinolone component, to provide a reduction in both non-inflammatory pain and inflammatory pain.
In a very useful embodiment, the mammal has non-inflammatory pain caused by an ocular injury or an ocular trauma, such as is caused by surgery, a corneal injury or trauma, such as a corneal ulcer, and the like. As noted above, non-inflammatory pain may be accompanied by, or occur at the same time as and/or in the same location, as inflammatory pain. The present methods are highly advantageous in such instances in that the combination of NSAID component and quinolone component is effective to provide a reduction in both non-inflammatory pain and inflammatory.
In general, the present methods for treating mammalian eyes comprise administering to the mammalian eye a therapeutically effective amount of the present composition thereby providing an effective antibiotic in the mammalian eye and reducing inflammation and/or pain in the mammalian eye.
Methods for treating corneal injuries, such as corneal ulcers, are also included within the scope of the present invention. Such methods comprise administering to a mammalian, preferably human, eye having a corneal injury a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic in the mammalian eye and a NSAID component in an amount effective, in combination with the quinolone component, to provide a reduction in pain caused by the corneal injury. Such reduction in pain, together with the antibiotic effectiveness of the presently useful compositions reduces the discomfort to the patient resulting from the corneal injury and facilitates or promotes the healing of the injury. Corneal injuries include, but are not limited to, abrasions, lacerations, scratches, surgical trauma, accidental or incidental trauma, bruises and the like to the cornea which are infected or are likely to become infected which cause pain to the mammal.
The present useful corneal injury-treating compositions preferably include a carrier component in an amount effective to act as a carrier for the quinolone component and the NSAID component in the presently useful compositions.
The quinolone components, NSAID components and carrier components useful in treating corneal injuries preferably are as described elsewhere herein. The presently useful compositions can be in any suitable form effective to treat the corneal injury, preferably in a form as described elsewhere herein.
Methods for treating ocular infections, such as corneal infections, are also included within the scope of the present invention. Such infections are caused by the presence of one or more microbes or pathogens in or on the eye in an amount or quantity to detrimentally affect the eye, for example, causing irritation, inflammation, redness, pain, tissue damage and the like. Examples of such infections include, but are not limited to, keratitis, such as bacterial keratitis, as well as bacterial conjunctivitis and the like infections. The present infection treating methods comprise administering to a mammalian, preferably human, eye having an infection caused by one or more microbes or pathogens a therapeutically effective amount of a composition comprising a quinolone component in an amount effective as an antibiotic in the mammalian eye and an effective amount of a NSAID component.
In one embodiment, the NSAID component is effective to reduce the time needed to eliminate the infection relative to identically administering a similar composition without the NSAID component. In addition, or alternately, the administering step, and preferably the NSAID component used in the administering step, is effective to at least inhibit the one or more microbes or pathogens causing the infection from adhering to a surface of the eye. In a very useful embodiment, the administering step, and preferably the NSAID component used in the administering step, is effective to at least inhibit, or even substantially prevent, colonization of the one or more microbes or pathogens in the eye.
The presently useful ocular infection-treating compositions preferably include a carrier component in an amount effective to act as a carrier for the quinolone component and the NSAID component in the presently useful compositions.
The quinolone components, NSAID components and carrier components useful in treating ocular infections preferably are as described elsewhere herein. The presently useful compositions can be in any suitable form effective to treat the ocular infection, preferably in a form as described elsewhere herein.
The present use methods may be considered to be curative and/or preventative when applied, presurgically or immediately post traumatically, that is before a microbial infection develops, or before inflammation and/or pain and/or infection is apparent. The present use methods are effective to reduce the risk of the formation of such infections and to reduce the severity of any inflammation or pain which may develop.
The present methods of use, including the general methods of use, the methods of treating corneal ulcers and the methods of treating ocular infections, may involve any suitable administration step or steps to provide an effective amount of the composition to the mammalian eye. Such administering may include, but is not limited to, topical application to the eye, instillation into the eye, placing an insert into the cul-de-sac (space) between the eyeball and the eyelid and the like. Other conventional methods of administering compositions to the eye may be employed provided that the compositions are administered so as to provide the benefits desired.
The dosage level of the composition depends, of course, on many factors, for example, the particular application involved, the particular active components employed, the concentration of the active components in the composition, the severity of the infection/inflammation/pain/corneal ulcer and the individual""s response to the treatment. Such dosage can be easily determined by routine and well known techniques to achieve the desired results in the individual patient being treated.
The following non-limiting examples illustrate certain aspects of the present invention.