Methods of increasing oral bioavailability of tetracyclines

Abstract

Methods for increasing the oral bioavailability of tetracycline compounds are described.

1 . A method for increasing oral bioavailability of a tetracycline compound in a subject, comprising administering said tetracycline compound to a subject in combination with a bioavailability enhancing agent such that the tetracycline compound is released in the intestinal tract. 
     
     
         2 . The method of  claim 1 , wherein the bioavailability is increased by about 5% or greater. 
     
     
         3 - 6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the bioavailability enhancing agent is a charge masking compound, a solubilizing compound, a reducing compound, a stabilizing compound, a lubricating compound, a permeability enhancing compound, or a combination thereof. 
     
     
         8 . The method of  claim 7 , wherein the bioavailability enhancing agent is polysorbate 80 (TWEEN-80), ethylenediaminetetraacetic acid (EDTA), sodium bisulfite, octanol, oil ethanol, calcium chloride, or silicon dioxide. 
     
     
         9 . The method of  claim 7 , wherein the bioavailability enhancing agent comprises a combination of a lubricating compound with another agent. 
     
     
         10 . The method of  claim 9 , wherein the bioavailability enhancing agent is a combination of a lubricating compound with sodium bisulfite. 
     
     
         11 . The method of  claim 10 , wherein said lubricating compound is AEROSIL 200. 
     
     
         12 . The method of  claim 1 , wherein the tetracycline compound is administered to the small intestine or to the duodenum. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the tetracycline compound is administered by a gastric feeding tube or by a duodenal feeding tube. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the tetracycline compound is formulated with an enteric coating. 
     
     
         17 . The method of  claim 1 , wherein said tetracycline compound is of formula I: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, amido, alkylamino, amino, arylamino, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, alkoxy, alkoxycarbonyl, alkylcarbonyloxy, alkyloxycarbonyloxy, arylcarbonyloxy, aryloxy, thiol, alkylthio, arylthio, alkenyl, heterocyclic, hydroxy, or halogen, optionally linked to R 2  to form a ring; 
 R 2″  is cyano or C(═O)—NR 2 R 2′ ; 
 R 2  is hydrogen, alkyl, halogen, alkenyl, alkynyl, aryl, hydroxyl, thiol, cyano, nitro, acyl, formyl, alkoxy, amino, alkylamino, heterocyclic, or absent, optionally linked to R 1  to form a ring; 
 R 2′ , R 4a , and R 4b  are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl amino, arylalkyl, aryl, heterocyclic, heteroaromatic or a pro drug moiety; 
 R 10 , R 11  and R 12  are each independently hydrogen, alkyl, aryl, benzyl, arylalkyl, or a pro-drug moiety; 
 R 12″  is O—R 12 , hydrogen, or substituted amino; 
 R 4  and R 4′  are each independently NR 4a R 4b , alkyl, acyl, alkenyl, alkynyl, hydroxyl, halogen, hydrogen, or taken together ═N—OR 4a ; 
 R 5  and R 5′  are each independently hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy; 
 R 6  and R 6′  are each independently hydrogen, methylene, absent, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 R 7  is hydrogen, dialkylamino, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, arylalkyl, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, boronic ester, alkylcarbonyl, thionitroso, or —(CH 2 ) 0-3  (NR 7c ) 0-1 C(═W′)WR 7a ; 
 R 8  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, amino, arylalkenyl, arylalkynyl, acyl, aminoalkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 8c ) 0-1 C(=E′)ER 8a ; 
 R 9  is hydrogen, hydroxyl, halogen, thiol, nitro, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, aryl alkyl, amino, arylalkenyl, arylalkynyl, acyl, amino alkyl, heterocyclic, thionitroso, or —(CH 2 ) 0-3  (NR 9c ) 0-1 C(═Z′)ZR 9a ; 
 R 7a , R 7b , R 7c , R 7d , R 7e , R 7f , R 8a , R 8b , R 8c , R 8d , R 8e , R 8f , R 9a , R 9b , R 9c , R 9d , R 9e , and R 9f  are each independently hydrogen, acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, heteroaromatic or a prodrug moiety; 
 R 13  is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 E is CR 8 R 8e , S, NR 8b  or O; 
 E 1  is O, NR 8 , or S, 
 Q is a double bond when R 2  is absent, Q is a single bond when R 2  is hydrogen, alkyl, halogen, hydroxyl, thiol, alkenyl, alkynyl, aryl, acyl, formyl, alkoxy, amino, alkylamino, cyano, nitro, or heterocyclic; 
 W is CR 7d , R 7e , S, NR 7b  or O, 
 W′ is O, NR 7f  or S; 
 X is CHC(R 13 Y′Y), C═CR 13 Y, CR 6 R 6 , S, NR 6 , or O; 
 Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; 
 Z is CR 9d R 9e , S, NR 9b  or O; 
 Z′ is O, S, or NR 9f , and pharmaceutically acceptable salts, esters and enantiomers thereof. 
 
     
     
         18 - 29 . (canceled) 
     
     
         30 . A pharmaceutical composition comprising a therapeutically effective amount of a tetracycline compound in combination with a bioavailability enhancing agent and a pharmaceutically acceptable carrier for administration of said tetracycline compound to the intestinal tract. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein said tetracycline compound and said bioavailability enhancing agent are formulated for separate administration. 
     
     
         32 . The pharmaceutical composition of  claim 30 , wherein said tetracycline compound and said bioavailability enhancing agent are formulated for concurrent administration. 
     
     
         33 . A kit comprising a tetracycline compound and instructions for administering a therapeutically effective amount of the tetracycline compound in combination with a bioavailability enhancing agent to the intestinal tract of a subject.