Abstract:
Disclosed are pharmaceutical compositions comprising tobramycin and fluorometholone or fluorometholone acetate for topical ophthalmic delivery and methods of treatment comprising administering said composition when indicated for infection and control of inflammatory response for optimal wound healing and normalization of the eye.

Description:
This is a continuation of application Ser. No. 07/165,952, filed Mar. 9, 1988, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     This invention relates to the topical ophthalmic use of antibiotics in combination with anti-inflammatory steroids for treating ophthalmic infections and attendant inflammation. Such combinations or formulations are available in the ophthalmic art. However, there are concerns and expressed reservations in the ophthalmic community about the safety and efficacy of such prior art combinations. There is, moreover, a long felt need for an effective and safe topical ophthalmic pharmaceutical composition of a potent steroid and a broad spectrum antibiotic which, when administered to the eye when indicated for bacterial infection or as a prophylactic after ophthalmic trauma and injury, will not, as a possible expression of the steroid component, inhibit the activity of the antibiotic nor interfere with normal wound healing, but at the same time will control inflammation. Unexpectedly it has been discovered that the broad spectrum aminoglycoside antibiotic tobramycin in combination with the potent steroid fluorometholone or its acetate meets these criteria. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The compositions of the present invention are administered topically. The dosage range is 0.001 to 5.0 mg/per eye; wherein the cited mass figures represent the sum of the two components, fluorometholone or its acetate and tobramycin. Fluorometholone acetate is preferred. The compositions of the present invention can be administered as solutions, suspensions, or emulsions (dispersions) in a suitable ophthalmic vehicle. 
     In forming compositions for topical administration, the mixtures are preferably formulated as 0.01 to 2.0 percent by weight solutions in water at a pH of 4.5 to 8.0 (figures relate to combined presence of tobramycin and fluorometholone or fluorometholone acetate). While the precise regimen is left to the discretion of the clinician, it is recommended that the resulting solution be topically applied by placing one drop in each eye two times a day. 
     Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention include preservatives, co-solvents and viscosity builder agents. 
     Antimicrobial Preservative 
     Ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium sorbic acid, Onamer M, 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% by weight. 
     Co-Solvents 
     The solubility of the components of the present compositions may be enhanced by a surfactant or other appropriate co-solvent in the composition. Such co-solvents include polysorbate 20, 60, and 80, Pluronic F-68, F-84 and P-103, cyclodextrin, or other agents known to those skilled in the art. Typically such co-solvents are employed at a level of from 0.01% to 2% by weight. 
     Viscosity Agents 
     Viscosity increased above that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulation, to decrease physical separation of components of a suspension or emulsion of the formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity builder agents include as examples polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a level of from 0.01% to 2% by weight. 
     The following example are representative pharmaceutical compositions of the invention for topical use when indicated against inflammation and infection. 
     EXAMPLE I 
     
         __________________________________________________________________________Fluorometholone Acetate, USP            1.0 mg +                 5% excess                       0.10% +                            5% excessTobramycin, USP  3.0 mg +                 5% excess                       0.30 +                            5% excessBenzalkonium Chloride           0.001 ml +                 10% excess                       0.10% +                            10% excess.sup.1Solution (10%), NFEdetate Disodium, USP           0.1 mg      0.01%Sodium Chloride, USP           3.0 mg       0.3%Sodium Sulfate, USP           12.0 mg      1.2%Tyloxapol, USP  0.5 mg      0.05%Hydroxyethylcellulose           2.5 mg      0.25%Sulfuric Acid and/or           QS for pH adjustment to 5.5 ± 0.5Sodium Hydroxide, NFPurified Water, USP           QS to 1 ml  QS to 100%__________________________________________________________________________ .sup.1 The benzalkonium chloride, NF concentration is equivalent to 0.01% (+10% excess). 
    
     EXAMPLE II 
     
         __________________________________________________________________________Fluorometholone Acetate, USP           0.1% + 2% excess                       1 mg + 2% excessTobramycin, Micronized, USP           0.3% + 7% excess                       3 mg + 7% excessChlorobutanol, Anhydrous, NF            0.5% + 25% excess                        5 mg + 15% excessMineral Oil, USP             5%        50 mgWhite Petrolatum, USP           QS 100%     QS 1 g__________________________________________________________________________ 
    
     The invention has been described herein by reference to certain preferred embodiments. However, as obvious variations thereon will become apparent to those skilled in the art, the invention is not to be considered as limited thereto.