Formulation

Abstract

The present invention relates a formulation and capsule suitable for oral administration. The invention further relates to the use of the formulation and capsule for treating inflammatory bowel diseases, for instance ulcerative colitis (UC) or Crohn's disease.

1 . A formulation suitable for oral administration comprising (i) an oligonucleotide containing a CpG dinucleotide and having 6 to 40 nucleotides, and (ii) esters which are monoesters and/or diesters of propylene glycol with caprylic acid or monoesters and/or diesters of glycerol with caprylic acid. 
     
     
         2 . The formulation according to  claim 1 , wherein the oligonucleotide is an oligonucleotide having the sequence 5′-Xm-CG-Yn-3′ wherein X is A, T, C or G, Y is A, T, C, or G, m is 0-38, n is 0-38, provided that the total length of the oligonucleotide is between 6 and 40 nucleotides 
     
     
         3 . The formulation according to  claim 1  or  2 , wherein the oligonucleotide comprises the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2). 
     
     
         4 . The formulation according to any preceding claim, wherein at least one CG dinucleotide is unmethylated. 
     
     
         5 . The formulation according to any preceding claim, wherein at least one nucleotide in said oligonucleotide has a backbone modification, preferably wherein said backbone modification is a phosphate backbone modification represented by a phosphorothioate or a phosphorodithioate modification, more preferably wherein said backbone modification is located in the 5′- and/or the 3′-end of said oligonucleotide. 
     
     
         6 . The formulation according to any preceding claim, wherein said oligonucleotide has the sequence 5′-GGAACAGTTCGTCCATGGC-3′ (SEQ ID NO:2), wherein the CG dinucleotide is unmethylated; preferably wherein oligonucleotide has the sequence 5′-G*G*A*ACAGTTCGTCCAT*G*G*C-3′ (SEQ ID NO:1), wherein the CG dinucleotide is unmethylated; more preferably wherein said oligonucleotide is cobitolimod. 
     
     
         7 . The formulation according to any preceding claim, wherein (ii) the esters are monoesters and/or diesters of propylene glycol with caprylic acid, and preferably wherein (ii) the esters comprise between 55 and 80% by weight propylene glycol monocaprylate and between 20 and 45% by weight propylene glycol dicaprylate, relative to the total weight of esters. 
     
     
         8 . The formulation according to any preceding claim, further comprising a gelling agent, preferably wherein the gelling agent is hydroxypropyl methylcellulose (HPMC). 
     
     
         9 . The formulation according to any preceding claim, further comprising an antioxidant, preferably wherein the antioxidant is butylated hydroxytoluene (BHT). 
     
     
         10 . The formulation according to any preceding claim, further comprising a pH buffer, preferably wherein the pH buffer is tromethamine. 
     
     
         11 . A capsule suitable for oral administration, said capsule comprising:
 a) a gelatin container, and within the container   b) a formulation as defined in any one of  claims 1  to  10 .   
     
     
         12 . The capsule according to  claim 11 , further comprising
 c) a coating on the exterior surface of the container.   
     
     
         13 . The capsule according to  claim 12 , wherein the coating comprises a first polymer and a second polymer. 
     
     
         14 . The capsule according to  claim 13 , wherein the first polymer is poly(methacrylic acid-co-ethyl acrylate) 1:1 and the second polymer is poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1. 
     
     
         15 . The capsule according to  claim 14 , wherein the poly(methacrylic acid-co-ethyl acrylate) 1:1 and poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 are present in a weight ratio of from 5:1 to 1:5, preferably in a weight ratio of from 2:1 to 1:4, more preferably in a weight ratio of from 1:1 to 1:3. 
     
     
         16 . The capsule according to any one of  claims 13  to  15 , wherein the first polymer is soluble above pH 5.5 and the second polymer is soluble above pH 7. 
     
     
         17 . The capsule according to any one of  claims 12  to  16 , wherein the coating is obtainable by coating the capsule in a coating solution, said coating solution comprising a first polymer and a second polymer as defined in  claims 14  to  16 . 
     
     
         18 . The capsule according to any one of  claims 11  to  17 , wherein said capsule is configured to release an oligonucleotide as defined in any one of  claims 1  to  6 , preferably cobitolimod, at the ileo-cecal junction. 
     
     
         19 . The capsule according to any one of  claims 11  to  18 , wherein said capsule is configured to release an oligonucleotide as defined in any one of  claims 1  to  6 , preferably cobitolimod, at pH 6.5 to 7.5, preferably at pH 6.5 to 6.8, preferably over a period of at least 2 hours, more preferably over a period of from 3 to 18 hours, and even more preferably over a period of from 5 to 12 hours. 
     
     
         20 . The capsule according to any one of  claims 11  to  17 , wherein said capsule is configured to release an oligonucleotide as defined in any one of  claims 1  to  6 , preferably cobitolimod, in the ileum. 
     
     
         21 . The capsule according to any one of  claim 11  to  17  or  20 , wherein said capsule is configured to release an oligonucleotide as defined in any one of  claims 1  to  6 , preferably cobitolimod, at pH 5.5 to 6. 
     
     
         22 . A formulation according to any one of  claims 1  to  10 , or a capsule according to any one of  claims 11  to  21  for use in the treatment of an inflammatory bowel disease, preferably wherein said inflammatory bowel disease is ulcerative colitis or Crohn's disease. 
     
     
         23 . The formulation or capsule for use according to  claim 22 , wherein said formulation or capsule is administered orally. 
     
     
         24 . A method of treating inflammatory bowel disease in a subject, the method comprising orally administering to said subject a formulation as defined in any one of  claims 1  to  10  or capsule as defined in any one of  claims 11  to  21 . 
     
     
         25 . Use of a formulation according to any one of  claims 1  to  10  or a capsule according to any one of  claims 11  to  21  for the manufacture of a medicament for treatment of inflammatory bowel disease.