Ophthamological drugs

Abstract

The present invention relates generally to ophthamological drugs. More specifically, the inventon relates to a method of modifying (derivatizing) ophthamological drugs so as to increase their penetration through the cornea. The invention also relates to drugs modified (derivatized) in accordance with the instant method and to the use of same in treating conditions associated with elevated intraocular pressure, particularly, glaucoma.

1 . A composition comprising: 
 a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety comprising at least one of a phenoxyacetic acid, a cinnamic acid, and a mixture thereof.    
   
   
       2 . The composition  claim 1 , wherein the phenoxyacetic acid comprises at least one of ticrynafen, ethacrynic acid, and a mixture thereof.  
   
   
       3 . The composition  claim 1 , wherein the sugar alcohol comprises at least one of threitol, erythritol, arabinitol, xylitol, ribitol, lyxitol, glucitol, galactitol, mannitol, gulitol, altitol, allitol, iditol talitol, 2-deoxyribitol, 2-deoxyglucitol, 2-deoxyxylitol, and a mixture thereof.  
   
   
       4 . The composition of  claim 1 , wherein the sugar alcohol comprises at least one of threitol, erythritol, arabinitol, xylitol, ribitol, lyxitol, glucitol, galactitol, mannitol, gulitol, altitol, allitol, iditol talitol, and a mixture thereof.  
   
   
       5 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       6 . The pharmaceutical composition of  claim 5 , wherein the carrier comprises at least one of a liquid, gel, cream and ointment.  
   
   
       7 . The pharmaceutical composition of  claim 5 , wherein the carrier comprises a physiological saline solution.  
   
   
       8 . The pharmaceutical composition of  claim 7 , wherein the saline solution is maintained at a pH between 4.5 and 8.0.  
   
   
       9 . The pharmaceutical composition of  claim 5 , further comprising at least one of a pharmaceutically-acceptable preservative, stabilizer and surfactant.  
   
   
       10 . A pharmaceutical composition comprising the compound of  claim 1  and an ophthalmically acceptable pharmaceutical excipient.  
   
   
       11 . The composition of  claim 1 , wherein the compound has the structure:  
       (X—COO)—CH 2 (CHY) m CH 2 Y  wherein 
 (X—COO) is the carboxylated drug moiety;  
 Y is independently selected from the group consisting of H, OH, and OR;  
 R is (CH 2 ) n CH 3 ;  
 m is 1 to 6;  
 n is 0 to 6;  
 X is an aromatic group or (CH 2 ) p CH 3  where p is 1 to 5; and  
   any pharmaceutically-acceptable salt of the above structure.    
   
   
       12 . The composition of  claim 11 , wherein m is 1 to 4.  
   
   
       13 . The composition of  claim 11 , wherein n is 0 to 4.  
   
   
       14 . A pharmaceutical composition comprising the compound of  claim 11 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       15 . A pharmaceutical composition comprising the compound of  claim 11  and an ophthalmically acceptable pharmaceutical excipient.  
   
   
       16 . The composition of  claim 1 , wherein the compound has the structure:  
     
       
         
         
             
             
         
       
       wherein:  
       (X—COO) is the drug moiety;  
       each Y is independently H, OH, or OR;  
       R is an alkyl group;  
       m and n are each independently 0 to 6; and  
       the sum of m+n is less than 9.  
     
   
   
       17 . A pharmaceutical composition comprising the compound of  claim 16 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       18 . A pharmaceutical composition comprising the compound of  claim 16  and an ophthalmically acceptable pharmaceutical excipient.  
   
   
       19 . The composition of  claim 1 , wherein the compound has the structure  
       (X—COO)-SA  
     wherein: 
 (X—COO) is the drug moiety; and  
 SA is a sugar alcohol, attached to either a primary, secondary, or tertiary hydroxyl, the sugar alcohol containing more than 3 but fewer than 9 carbons, and having a ratio of hydroxyl groups to carbons of less than 1:1, but containing at least one free hydroxyl wherein any missing hydroxyl groups are independently replaced by the following a chlorine atom, an amine group, an amido group, an amide group, a fluorine atom, a hydrogen atom, a nitrile group, an aryloxy group and any missing hydrogen groups are replaced by alkyl groups.  
 
   
   
       20 . A pharmaceutical composition comprising the compound of  claim 19 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.  
   
   
       21 . A pharmaceutical composition comprising the compound of  claim 19  and an ophthalmically acceptable pharmaceutical excipient.  
   
   
       22 . A composition comprising: 
 a compound derived from the esterification of a carboxylate functionality of a drug moiety thereof, with the proviso that the drug moiety is not a prostaglandin.    
   
   
       23 . A pharmaceutical composition comprising the compound of  claim 22  and an ophthalmically acceptable pharmaceutical excipient.  
   
   
       24 . A compound selected from the group consisting of: 
 5-O-Ribitol[2,3-dichloro-4-(thiophene-2-carbonyl)]phenoxyacetate;    5-O-Xylitol 4-(2-phenylacryloyl)cinnamate;    5-O-{(9α,11α,15R)-15-[2-Benzo[b]thiophen-2-yl]-16,17,18,19,20-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl}xylitol;    11-Hydroxy-3,6,9-trioxaundecyl 4-(2-phenylacryloyl)cinnamate;    5-O-{(9α,11α,15R)-15-[2-Benzo[b]thiophen-2-yl]-16,17,18,19,20-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl}xylitol;    5-O-{(9α,11α,15R)-15-[2-Benzo[b]thiophen-2-yl]-16,17,18,19,20-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl}-D-ribitol;    4-O-{(9α,11α,15R)-15-[2-benzo[b]thiophen-2-yl]-16,17,18,19,20-pentanor-5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoyl}-L-threitol;    5-O-Xylitol 4-(2-phenylacryloyl)cinnamate;    1-O-D-Sorbitol 4-(2-phenylacryloyl)cinnamate;    1-O-D-Arabitol 4-(2-phenylacryloyl)cinnamate;    1-O-Glycerol[2,3-dichloro-4-(2-methylenebutyryl)]phenoxyacetate;    1-O-Erythritol[2,3-dichloro-4-(2-methylenebutyryl)]phenoxyacetate;    1-O-Ribitol[2,3-dichloro-4-(2-methylenebutyryl)]phenoxyacetate;    5-O-Ribitol[2,3-dichloro-4-(thiophene-2-carbonyl)]phenoxyacetate;    2-O-D-Sorbitol 4-(2-phenylacryloyl)cinnamate; and    2-O-Ribitol[2,3-dichloro-4-(2-methylenebutyryl)]phenoxyacetate.    
   
   
       25 . A method of treating an ophthamological disorder, said method comprising administering to a human or other animal a safe and effective amount of a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety comprising at least one of a phenoxyacetic acid, a cinnamic acid, and a mixture thereof.  
   
   
       26 . The method of  claim 25 , wherein the phenoxyacetic acid comprises at least one of ticrynafen, ethacrynic acid, and mixtures thereof.  
   
   
       27 . The composition  claim 25 , wherein the sugar alcohol comprises at least one of threitol, erythritol, arabinitol, xylitol, ribitol, lyxitol, glucitol, galactitol, mannitol, gulitol, altitol, allitol, iditol talitol, 2-deoxyribitol, 2-deoxyglucitol, 2-deoxyxylitol, and a mixture thereof.  
   
   
       28 . The composition of  claim 25 , wherein the sugar alcohol comprises at least one of threitol, erythritol, arabinitol, xylitol, ribitol, lyxitol, glucitol, galactitol, mannitol, gulitol, altitol, allitol, iditol talitol, and a mixture thereof.  
   
   
       29 . The method of  claim 25 , wherein the compound has the structure:  
       (X—COO)—CH 2 (CHY) m CH 2 Y  wherein 
 (X—COO) is the carboxylated drug moiety;  
 Y is independently selected from the group consisting of H, OH, and OR;  
 R is (CH 2 ) n CH 3 ;  
 m is 1 to 6;  
 n is 0 to 6;  
 X is an aromatic group or (CH 2 ) p CH 3  where p is 1 to 5; and  
   any pharmaceutically-acceptable salt of the above structure.    
   
   
       30 . The method of  claim 29 , wherein m is 1 to 4.  
   
   
       31 . The method of  claim 29 , wherein n is 0 to 4.  
   
   
       32 . The method of  claim 25 , wherein the compound has the structure:  
     
       
         
         
             
             
         
       
       wherein:  
       (X—COO) is the drug moiety;  
       each Y is independently H, OH, or OR;  
       R is an alkyl group;  
       m and n are each independently 0 to 6; and  
       the sum of m+n is less than 9.  
     
   
   
       33 . The method of  claim 25 , wherein the compound has the structure  
       (X—COO)-SA  
     wherein: 
 (X—COO) is the drug moiety; and  
 SA is a sugar alcohol, attached to either a primary, secondary, or tertiary hydroxyl, the sugar alcohol containing more than 3 but fewer than 9 carbons, and having a ratio of hydroxyl groups to carbons of less than 1:1, but containing at least one free hydroxyl wherein any missing hydroxyl groups are independently replaced by the following a chlorine atom, an amine group, an amido group, an amide group, a fluorine atom, a hydrogen atom, a nitrile group, an aryloxy group and any missing hydrogen groups are replaced by alkyl groups.  
 
   
   
       34 . The method of  claim 25 , wherein the ophthamological disorder results from elevated intraocular pressure.  
   
   
       35 . The method of  claim 25 , wherein the ophthamological disorder comprises glaucoma.  
   
   
       36 . The method of  claim 25 , wherein the ophthamological disorder comprises macular degeneration.  
   
   
       37 . The method of  claim 25 , wherein the compound is administered orally.  
   
   
       38 . The method of  claim 25 , wherein the compound is administered topically.  
   
   
       39 . The method of  claim 38 , wherein 
 the compound is topically applied to a mammalian eye comprising a cornea and an adjacent anterior chamber filled with aqueous humor;    the compound penetrates into the cornea where esterases convert the compound to an active drug comprising a free acid; and    the active drug is sufficiently water-soluble to be released from the cornea into the aqueous humor.    
   
   
       40 . A method of determining the suitability of a compound for treating an ophthamological disorder, said method comprising 
 providing a compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol;    determining whether the compound releases its carboxcylic acid, in an assay under conditions mimicking conditions in an eye, within a predetermined half life; and    selecting the compound for treatment of an ophthamological disorder if the compound releases its carboxcylic acid within the predetermined half life.    
   
   
       41 . The method of  claim 40 , wherein an esterase is used in the determining step.  
   
   
       42 . The method of  claim 40 , wherein the drug moiety comprises a phenoxyacetic acid  
   
   
       43 . The method of  claim 40 , wherein the drug moiety comprises a cinnamic acid.  
   
   
       44 . The method of  claim 40 , wherein the drug moiety comprises a prostaglandin.  
   
   
       45 . The method of  claim 40 , wherein the predetermined half-life is greater than about one minute but less than about seven days.  
   
   
       46 . The method of  claim 40 , wherein the predetermined half-life is greater than about five minutes and less than about 24 hours.  
   
   
       47 . A method of treating an ophthamological disorder comprising the steps of  claim 40  and further comprising administering to a human or other animal a safe and effective amount of the compound.  
   
   
       48 . A compound derived from the esterification of a carboxylate functionality of a drug moiety with a sugar alcohol, the drug moiety being at least one of travaprost, latanoprost, and bimatoprost and mixtures thereof.