Halogenated xanthene-containing topical anti-gram-positive bacterial ophthalmic composition and method

1 . A method of treating a mammalian subject having a Gram-positive bacterially-infected eye that exhibits keratitis consisting of the steps of treating said Gram-positive bacterially-infected eye by administering to that microbially-infected eye a keratitis-treating effective amount of an ophthalmic composition containing a halogenated fluorescein or pharmaceutically acceptable salt, amide or ester thereof dissolved or dispersed in an aqueous ophthalmic carrier and present in a bacterial keratitis-treating effective concentration of about 0.2 μg/mL to about 50 μg/mL in the composition, said ophthalmic composition having a pH value of about 6.5 to about 7.6, a viscosity of about 10 to about 300 cps and an osmolality of about 270 mOsm/kg to about 340 mOsm/kg, and maintaining said treated eye in the substantial absence of actinic light for a time period of about 3 to about 12 hours so that said treatment is carried out in the substantial absence of actinic light.

2 . The method according to claim 1 , wherein said ophthalmic composition is maintained in a vessel opaque to actinic light prior to said administration.

3 . The method according to claim 1 , wherein said halogenated fluorescein or pharmaceutically acceptable salt or ester thereof has the chemical formula of one or both of FORMULA 1 and/or FORMULA 2

wherein R 1 is independently F, Cl, Br, I, H or C 1 -C 4 alkyl;

R 2 , R 3 , R 4 , and R 5 are independently Cl, H or I with at least one substituent selected from R 2 , R 3 , R 4 , R 5 being I; and

R 6 is independently H or C 1 -C 4 alkyl; R 11 is H or C 1 -C 4 alkyl; R 12 is H or C 1 -C 7 acyl; and all (a) tautomeric forms; (b) atropisomers, (d) enantiomers of lactone forms depicted in FORMULA 2, and (e) pharmaceutically acceptable salts thereof.

4 . The method according to claim 1 , wherein said halogenated fluorescein has either Formulas I or Formula II, below, X is oxygen or nitrogen, “n” is zero or 1 such that when X is

oxygen, n is zero, R 7 is absent, and R 8 is present as an aromatic ring-containing ester substituent, whereas when X is nitrogen, n is 1 and R 7 is present, and —XR 7 R 8 is an aromatic ring-containing amide substituent;

wherein said aromatic ring-containing substituent is a single ring containing 5- or 6-members, or a 5,6- or 6,6-fused aromatic ring system, in which the single aromatic ring or fused aromatic ring system contains 0, 1 or 2 hetero ring atoms that are independently nitrogen, oxygen or sulfur;

when X is nitrogen, R 7 and R 8 are the same or different and are selected from the group consisting of hydrogen, C 1 -C 4 alkyl, an aromatic ring-containing substituent or together with amido nitrogen atom R 7 and R 8 together with amido nitrogen atom form a 5- or 6-membered ring.

5 . The method according to claim 4 , wherein said aromatic ring-containing substituent of said aromatic ester or aromatic amide unsubstituted, and is selected from the group consisting of the following

where

 is

 or

 providing an ester or the R 8 group is hydrogen forming a monosubstituted amide, respectively.

6 . The method according to claim 1 , wherein said halogenated fluorescein or pharmaceutically acceptable salt or ester has the chemical formula of one or both of Formulas Ia and/or IIb

wherein M − is a pharmaceutically acceptable cation.

7 . The method according to claim 1 , wherein said halogenated fluorescein or pharmaceutically acceptable salt or ester thereof is rose bengal disodium.