Quinolone carboxylic acid compositions and related methods of treatment

Abstract

The present invention relates to the use of quinolone carboxylic acid formulations in the treatment of ocular and periocular infections. The present invention also relates to sustained release compositions comprising specific quinolone carboxylic acid compounds. The invention also relates to quinolone carboxylic acid compositions and methods of preparing the same.

What is claimed is:  
     
         1 . A topical ophthalmic composition comprising: 
 a quinolone carboxylic acid derivative of formula (I),                          wherein R 1  is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R 2  is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH 2 , O, S, SO, SO 2 , or N—R 3 , wherein R 3  is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms.    
     
     
         2 . The composition of  claim 1 , wherein said composition provides sustained release of said quinolone carboxylic acid derivative.  
     
     
         3 . The composition of  claim 1 , further comprising a carboxy containing polymer.  
     
     
         4 . The composition of  claim 3 , wherein said carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.  
     
     
         5 . The composition of  claim 4 , wherein said polymer contains up to about 40% by weight of non-carboxyl containing monoethylenically unsaturated monomers.  
     
     
         6 . The composition of  claim 5 , wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.  
     
     
         7 . The composition of  claim 6 , wherein said particles have an average diameter less than about 10 microns.  
     
     
         8 . The composition as in  claim 1 , wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.005% to about 10% by weight based upon the total weight of the composition.  
     
     
         9 . The composition of  claim 8 , wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.  
     
     
         10 . The composition as in  claim 1 , further comprising one or more excipients.  
     
     
         11 . The composition as in  claim 1 , in which said quinolone carboxylic acid derivative of formula (I) is a pro-drug form of said quinolone carboxylic acid derivative.  
     
     
         12 . The composition as in  claim 1 , wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.  
     
     
         13 . The composition as in  claim 1 , wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.  
     
     
         14 . The composition of  claim 1 , wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.  
     
     
         15 . The composition of  claim 14 , wherein said particles have an average diameter less than about 10 microns.  
     
     
         16 . The composition of  claim 1 , further comprising a solubilizer.  
     
     
         17 . The composition of  claim 16 , wherein said solubilizer is hydroxypropyl-β-cyclodextrin.  
     
     
         18 . The composition of  claim 17 , wherein said hydroxypropyl-β-cyclodextrin is about 5.0% to about 20.0% by weight of said composition, based on the total weight of said composition.  
     
     
         19 . The composition of  claim 1 , further comprising a cross-linked carboxy containing polymer.  
     
     
         20 . The composition of  claim 19 , wherein said cross-linked carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.  
     
     
         21 . The composition of  claim 20 , wherein said cross-linked carboxy containing polymer comprises from about 0.5% to about 1.0% by weight of said composition, based on the total weight of said composition.  
     
     
         22 . A method of treating or preventing an infection in the ocular or periocular region comprising: 
 delivering to the ocular or periocular region a composition comprising a quinolone carboxylic acid derivative of formula (I),                          wherein R 1  is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R 2  is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH 2 , O, S, SO, SO 2 , or N—R 3 , wherein R 3  is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms.    
     
     
         23 . The method of  claim 22 , wherein said composition provides sustained release of said quinolone carboxylic acid derivative.  
     
     
         24 . The method of  claim 22 , wherein said composition further comprises a carboxy containing polymer.  
     
     
         25 . The method of  claim 24 , wherein said carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.  
     
     
         26 . The method of  claim 25 , wherein said polymer contains up to about 40% by weight of non-carboxyl containing monoethylenically unsaturated monomers.  
     
     
         27 . The method of  claim 26 , wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.  
     
     
         28 . The method of  claim 27 , wherein said particles have an average diameter less than about 10 microns.  
     
     
         29 . The method as in  claim 22 , wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.005% to about 10% by weight based upon the total weight of the composition.  
     
     
         30 . The method of  claim 29 , wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.  
     
     
         31 . The method of  claim 22 , wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.  
     
     
         32 . The method of  claim 31 , wherein said particles have an average diameter less than about 10 microns.  
     
     
         33 . The method of  claim 22 , wherein said composition further comprises one or more excipients.  
     
     
         34 . The method as in  claim 22 , in which said quinolone carboxylic acid derivative of formula (I) is a pro-drug form of said quinolone carboxylic acid derivative.  
     
     
         35 . The method as in  claim 22 , wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.  
     
     
         36 . The method as in  claim 22 , wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.  
     
     
         37 . The method of  claim 22 , wherein said composition further comprises a solubilizer.  
     
     
         38 . The method of  claim 37 , wherein said solubilizer is hydroxypropyl-β-cyclodextrin.  
     
     
         39 . The method of  claim 38 , wherein said hydroxypropyl-β-cyclodextrin is about 5.0% to about 20.0% by weight of said composition, based on the total weight of said composition.  
     
     
         40 . The method of  claim 22 , wherein said composition further comprises a cross-linked carboxy containing polymer.  
     
     
         41 . The method of  claim 40 , wherein said cross-linked carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.  
     
     
         42 . The method of  claim 40 , wherein said cross-linked carboxy containing polymer comprises from about 0.5% to about 1.0% by weight of said composition, based on the total weight of said composition.  
     
     
         43 . The method as in  claim 22 , wherein said composition is a solution, composition, ointment, or instillant.  
     
     
         44 . The method as in  claim 22 , wherein said infection is an infection of Gram positive bacteria, Gram negative bacteria, or a mixed infection of Gram positive and Gram negative bacteria.  
     
     
         45 . The method as in  claim 44 , wherein said infection is an infection of a bacteria selected from the group consisting of  Escherichia coli, Salmonella typhi, Shigella flexneri, Klebsiellia pneumonia, Proteus vulgaris, Proteus rettgeri, Haemophilus influenzae, Pseudomonas aeruginosia, Serratia marcescens, Moraxella morganii, Moraxella lacunata, Moraxella catarrhalis, Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis, Micrococcus lysodeikticus , and combinations thereof.  
     
     
         46 . The method of  claim 42 , wherein the infection is a mixed infection of Gram negative bacteria and Gram positive bacteria.  
     
     
         47 . A method of preparing a sustained release topical ophthalmic delivery system, comprising: 
 preparing an composition comprising a quinolone carboxylic acid derivative of formula (I),                          wherein R 1  is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed iii vivo, R 2  is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH 2 , O, S, SO, SO 2 , or N—R 3 , wherein R 3  is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and,    packaging said composition for administration to the eye.    
     
     
         48 . The method of  claim 47 , wherein said composition further comprises a carboxy containing polymer present from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.  
     
     
         49 . The method of  claim 48 , wherein said quinolone carboxylic acid derivative of formula (I) is present as particles having an average diameter less than about 10 microns, and wherein said particles are prepared by micronization of said quinolone carboxylic acid.