Formulations for treating or preventing mucositis

Abstract

Mucositis is treated and/or prevented by administrating to a patient a formulation comprising a tetracycline that is poorly absorbed from the gastro-intestinal tract. The tetracycline may be in the form of a pharmaceutically acceptable salt or a base. The formulations may optionally also contain an antifungal agent to prevent fungal overgrowth due to reduction in the normal oral flora by the tetracycline. Such compositions have the advantage of treating the entire gastrointestinal tract since the active ingredient is not removed from the tract via absorption. Further, such compositions minimize systemic exposure and accompanying side effects.

1 . A pharmaceutical composition for treating or preventing mucositis comprising an effective amount of a poorly absorbed tetracycline in a carrier for topical administration to the mucosa.  
   
   
       2 . The composition of  claim 1  wherein the tetracycline is selected based on poor oral absorption from the group consisting of tetracyclines defined by the following structure:  
     
       
         
         
             
             
         
       
     
     wherein R 1 -R 5  may be a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic composition comprising from 1-8 carbon atoms and optionally include a heteroatom such as nitrogen, oxygen, in linear, branched, or cyclic structural formats.  
   
   
       3 . The composition of  claim 2  wherein R 1  and R 2  are hydrogen or a hydroxyl group; R 3  is hydrogen or a methyl group; R 4  is a hydrogen atom, a halogen, or a nitrogen containing entity; and R 5  is a hydrogen atom, or nitrogen containing ring structure.  
   
   
       4 . The composition of  claim 2  wherein the tetracycline is modified by substitution of H at carbon 9 by a substituted amido group.  
   
   
       5 . The composition of  claim 2  wherein the tetracycline is modified at any of positions 1 through 4 and 10 through 12.  
   
   
       6 . The composition of  claim 2  having the following structure:  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  can be H, C1-C3 alkyl, phenyl, and aryl groups; and  
     wherein X is an H, alkyl, alkoxy, phenoxy, aryloxy, amino group, amide, acyl, and halo group; and pharmaceutically acceptable salts thereof.  
   
   
       7 . The composition of  claim 6  wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8  are H; wherein R 3  is CH 3 ; and wherein X is a chloro group.  
   
   
       8 . The composition of  claim 1  wherein the carrier for topical administration to the mucosa of the oral cavity and gastro-intestinal tract is selected from the group consisting of a mouthwash, lozenge, tablet, paste and gel.  
   
   
       9 . The composition of  claim 1  wherein the carrier for topical administration comprises the tetracycline coated onto or encapsulated into a carrier selected from the group consisting of powders, pellets, microcapsules, liposomes, and emulsions.  
   
   
       10 . The composition of  claim 9  wherein the tetracycline is formulated as a dry powder.  
   
   
       11 . The composition of  claim 1  wherein less than 10% of the tetracycline is absorbed into the systemic circulation when topically administered to the mouth and then swallowed.  
   
   
       12 . The composition of  claim 8  wherein the tetracycline is in the form of a polyvalent metal ion complex.  
   
   
       13 . The composition of  claim 12  wherein the polyvalent metal ion is calcium or magnesium.  
   
   
       14 . The composition of  claim 1  wherein the tetracycline is formulated to be topically administered to the mucosa as an aerosol.  
   
   
       15 . A method for treating a patient in need thereof comprising administering to the patient an effective amount of a poorly absorbed tetracycline in a carrier for topical administration to the mucosa.  
   
   
       16 . The method of  claim 15  wherein the tetracycline is selected based on poor absorption from the group consisting of tetracyclines defined by the following structure:  
     
       
         
         
             
             
         
       
     
     wherein R 1 -R 5  may be a hydrogen atom, a halogen atom, a hydroxyl group, or any other organic composition comprising from 1-8 carbon atoms and optionally include a heteroatom such as nitrogen, oxygen, in linear, branched, or cyclic structural formats.  
   
   
       17 . The method of  claim 15  wherein the tetracycline is selected from the group consisting of compounds with the formula wherein R 1  and R 2  are hydrogen or a hydroxyl group; R 3  is hydrogen or a methyl group; R 4  is a hydrogen atom, a halogen, or a nitrogen containing entity and R 5  is a hydrogen atom, or nitrogen containing ring structure, compounds wherein the tetracycline is modified at any of positions 1 through 4 and 10 through 12, and compounds wherein the tetracycline is modified by substitution of H at carbon 9 by a substituted amido group.  
   
   
       18 . The method of  claim 16  wherein the tetracycline has the following structure:  
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  can be H, C1-C3 alkyl, phenyl, and aryl groups; and  
     wherein X is an H, alkyl, alkoxy, phenoxy, aryloxy, amino group, amide, acyl, and halo group; and pharmaceutically acceptable salts thereof.  
   
   
       19 . The method of  claim 18  wherein the tetracycline is meclocycline,  
     wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8  are H;  
     wherein R 3  is CH 3 ; and wherein X is a chloro group.  
   
   
       20 . The method of  claim 15  wherein the carrier for topical administration to the mucosa of the oral cavity and gastro-intestinal tract is selected from the group consisting of a mouthwash, lozenge, tablet, paste and gel.  
   
   
       21 . The method of  claim 15  wherein the carrier for topical administration comprises the tetracycline coated onto or encapsulated into a carrier selected from the group consisting of powders, pellets, microcapsules, liposomes, and emulsions, comprising suspending or dissolving the tetracycline and carrier in a liquid for adminstration of the tetracycline to the patient.  
   
   
       22 . The method of  claim 15  wherein the tetracycline is administered daily starting at least one day before the patient is treated with radiation or chemotherapy.  
   
   
       23 . The method of  claim 15  wherein the patient is treated between one and six times daily.  
   
   
       24 . A method for making a composition for treating a patient to prevent or treat mucositis comprising making a formulation for topical administration to the mucosa of an effective amount of a tetracyline which has less than 10% bioavailability when orally adminstered.