Compositions For Delivering Acyclovir

Abstract

The present invention relates to an acyclovir formulation having improved bioavailability resulting in better efficacy and/or requiring less frequent administration.

1 . A pharmaceutical composition comprising (a) acyclovir and (b) a delivery agent of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 Ar is phenyl or naphthyl; 
 Ar is optionally substituted with one or more of —OH, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkenyl, C 1 -C 4  alkoxy or C 1 -C 4  haloalkoxy; 
 R 7 is C 4 -C 20  alkyl, C 4 -C 20  alkenyl, phenyl, naphthyl, (C 1 -C 10  alkyl) phenyl, (C 1 -C 10  alkenyl)phenyl, (C 1 -C 10  alkyl) naphthyl, (C 1 -C 10  alkenyl) naphthyl, phenyl(C 1 -C 10  alkyl), phenyl(C 1 -C 10  alkenyl), naphthyl(C 1 -C 10  alkyl), or naphthyl(C 1 -C 10  alkenyl); 
 R 8  is hydrogen, C 1  to C 4  alkyl, C 2  to C 4  alkenyl, C 1  to C 4  alkoxy, or C 1 -C 4  haloalkoxy; 
 R 7  is optionally substituted with C 1  to C 4  alkyl, C 2  to C 4  alkenyl, C 1  to C 4  alkoxy, C 1 -C 4  haloalkoxy, —OH, —SH, —CO 2 R 9 , or any combination thereof; 
 R 9  is hydrogen, C 1  to C 4  alkyl, or C 2  to C 4  alkenyl; and 
 R 7  is optionally interrupted by oxygen, nitrogen, sulfur or any combination. 
 
     
     
         2 . A pharmaceutical composition comprising (a) acyclovir and (b) a delivery agent of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 R 1 , R 2 , R 3 , and R 4  are independently H, —H, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkoxy, —C(O)R 8 , —NO 2 , —NR 9 R 10 , or —N + R 9 R 10 R 11  (R 12 )—; 
 R 5  is H, —OH, —NO 2 , halogen, —CF 3 , —NR 14 R 15 , —N + R 14 R 15 R 16  (R 13 )—, amide, C 1 -C 12  alkoxy, C 1 -C 12  alkyl, C 2 -C 12  alkenyl, carbamate, carbonate, urea, or —C(O)R 18 ; 
 R 5  is optionally substituted with halogen, —OH, —SH, or —COOH; 
 R 6  is optionally interrupted by O, N, S, or —C(O)—; 
 R 6  is a C 1 -C 12  alkylene, C 2 -C 12  alkenylene, or arylene; 
 R 6  is optionally substituted with a C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 1 -C 4  alkoxy, —OH, —SH, halogen, —NH 2 , or —CO 2 R 8 ; 
 R 6  is optionally interrupted by O or N; 
 R 7  is a bond or arylene; 
 R 7  is optionally substituted with —OH, halogen, —C(O)CH 3 , —NR 10 R 11 , or —N + R 10 R 11 R 12  (R 13 )—; 
 each occurrence of R 8  is independently H, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, or —NH 2 ; 
 R 9 , R 10 , R 11 , and R 12  are independently H or C 1 -C 10  alkyl; 
 R 13  is a halide, hydroxide, sulfate, tetrafluoroborate, or phosphate; and 
 R 14 , R 15  and R 16  are independently H, C 1 -C 10  alkyl, C 1 -C 10  alkyl substituted with —COOH, C 2 -C 12  alkenyl, C 2 -C 12  alkenyl substituted with —COOH, or —C(O)R 17 ; 
 R 17  is —OH, C 1 -C 10  alkyl, or C 2 -C 12  alkenyl; and 
 R 18  is H, C 1 -C 6  alkyl, —OH, —NR 14 R 15 , or N + R 14 R 15 R 16  (R 13 )—. 
 
     
     
         3 . A pharmaceutical composition comprising (a) acyclovir and (b) a delivery agent of the formula 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein
 R 1 , R 2 , R 3 , R 4  and R are independently H, —CN, —OH, —OCH 3 , or halogen, at least one of R 1 , R 2 , R 3 , R 4  and R 5  being —CN; and 
 R 6  is a C 1 -C 12  linear or branched alkylene, alkenylene, arylene, alkyl(arylene) or aryl(alkylene). 
 
     
     
         4 . A pharmaceutical composition of any one of  claims 1 ,  2  or  3 , wherein the delivery agent is selected from the group consisting of Delivery agents is SNAC or SNAD or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the delivery agent is N-(8-[2-hydroxybenzoyl]-amino)caprylic acid or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The pharmaceutical composition of  claim 1  wherein the delivery agent is wherein the delivery agent is N-(10-[2-hydroxybelizoyl]-amino)decanoic acid or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The pharmaceutical composition of any  claims 1 - 6 , wherein the pharmaceutical composition provides bioavailability (i.e., AUC) substantially equivalent to the acyclovir formulation marketed as Zovirax® under U.S. FDA NDA No. 18828, 19909, or 20089 when:
 (1) 200, 400, or 800 mg of the acyclovir formulation is administered every 4 hours 5 times daily,   (2) 400 mg of the acyclovir formulation is administered 2 times daily,   (3) 200 mg of the acyclovir formulation is administered 3 times daily,   (4) 200 mg of the acyclovir formulation is administered 4 times daily, or   (5) 200 mg of the acyclovir formulation is administered 5 times daily.   
     
     
         8 . A dosage unit form comprising:
 (A) the pharmaceutical compositions of any one of the preceding claims; and   (B) (a) an excipient,
 (b) a diluent, 
 (c) a disintegrant, 
 (d) a lubricant, 
 (e) a plasticizer, 
 (f) a colorant, 
 (g) a dosing vehicle, or 
 (h) any combination thereof. 
   
     
     
         9 . The dosage unit form of  claim 8 , wherein the dosage unit form is in the form of a tablet, a capsule, a particle, a powder, a sachet, or a liquid. 
     
     
         10 . The dosage unit form of  claim 8 , wherein the dosing vehicle is a liquid selected from the group consisting of water, aqueous propylene glycol, phosphate buffer, 1,2-propane diol, ethanol, and any combination thereof. 
     
     
         11 . A method for administering an effective amount of acyclovir a patient in need of thereof, comprising the step of orally administering the pharmaceutical composition of any one of  claims 1 - 8 . 
     
     
         12 . A method of treating a viral infection in a patient in need thereof, comprising the step of administering to the patient an effective amount of the pharmaceutical composition of any one of  claims 1 - 8 . 
     
     
         13 . A method of treating a condition or disorder caused by a virus in a patient in need thereof, comprising the step of administering an animal an effective amount of the pharmaceutical composition of any one of  claims 1 - 8 . 
     
     
         14 . The method of  claim 13 , wherein the condition or disorder is caused by a virus selected from the group consisting of herpes simplex 1, herpes simplex 2, varicella zoster virus, cytomegalovirus and Epstein-Barr virus. 
     
     
         15 . A method of improving the bioavailability of acyclovir in an animal in need thereof, the method comprising the step of administering a formulation of any one of  claims 1 ,  2  or  3 . 
     
     
         16 . A method of preparing a pharmaceutical composition comprising the step of mixing at least one delivery agent compound and acyclovir or a salt or prodrug thereof.