Antisense Compositions and Methods of Making and Using Same

Abstract

The present invention provides pharmaceutical formulations for oral administration of antisense oligonucleotides, such as antisense oligonucleotides against SMAD7. The pharmaceutical formulations can be used to treat Crohn's disease, ulcerative colitis and chronic inflammatory bowel disease.

1 .- 23 . (canceled) 
     
     
         24 . An oral dosage form, comprising:
 (a) an oligonucleotide comprising the nucleotide sequence of SEQ ID NO: 1 or a pharmaceutically acceptable salt thereof, and   (b) an enteric coating comprising an ethylacrylate-methacrylic acid copolymer;   wherein the oral dosage form, when administered to a patient, delivers substantially all of the oligonucleotide to the terminal ileum and/or right colon of the patient and results in minimal plasma concentration of the oligonucleotide.   
     
     
         25 . The oral dosage form of  claim 24 , wherein the internucleoside linkages of SEQ ID NO: 1 are O,O-linked phosphorothioates. 
     
     
         26 . The oral dosage form of  claim 24 , wherein the oligonucleotide is the sodium salt of SEQ ID NO: 1. 
     
     
         27 . The oral dosage form of  claim 24 , wherein the oral dosage form is a tablet. 
     
     
         28 . The oral dosage form of  claim 24 , comprising about 5% to about 20% by weight of the enteric coating. 
     
     
         29 . The oral dosage form of  claim 24 , comprising about 0.5% to about 10% by weight of the oligonucleotide. 
     
     
         30 . The oral dosage form of  claim 29 , further comprising:
 (c) about 30% to about 50% by weight mannitol; and   (d) about 10% to about 30% by weight microcrystalline cellulose.   
     
     
         31 . The oral dosage form of  claim 24 , comprising:
 a) an intra-granular phase comprising:
 (i) about 5% to about 10% by weight of the oligonucleotide, 
 (ii) about 40% by weight mannitol, 
 (iii) about 8% by weight microcrystalline cellulose, 
 (iv) about 5% by weight hydroxypropyl methyl cellulose, and 
 (v) about 2% by weight sodium starch glycolate; and 
   b) an extra-granular phase comprising:
 (i) about 17% by weight microcrystalline cellulose, 
 (ii) about 2% by weight sodium starch glycolate, and 
 (iv) about 0.4% by weight magnesium stearate. 
   
     
     
         32 . The oral dosage form of  claim 24 , comprising about 5% to about 10% by weight of the oligonucleotide and
 (c) about 40% by weight mannitol;   (d) about 25% by weight microcrystalline cellulose;   (e) about 5% by weight hydroxypropyl methyl cellulose;   (f) about 4% by weight sodium starch glycolate; and   (g) about 0.4% by weight magnesium stearate.   
     
     
         33 . A method of treating an inflammatory bowel disease, comprising orally administering to a patient in need thereof an oral dosage form of  claim 24 . 
     
     
         34 . The method of  claim 33 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.