Stable Formulations of Linaclotide

Abstract

The present invention relates to stable pharmaceutical compositions comprising linaclotide or pharmaceutically acceptable salts thereof, as well as to various methods and processes for the preparation and use of the compositions.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising linaclotide, a cation or pharmaceutically acceptable salt thereof and an amine selected from meglumine or a mixture of meglumine and histidine. 
     
     
         2 . The composition of  claim 1 , wherein the amine is meglumine. 
     
     
         3 . A pharmaceutical composition comprising linaclotide, a cation or pharmaceutically acceptable salt thereof and histidine, wherein the composition has a molar ratio of cation:histidine of less than 2:1. 
     
     
         4 . The composition of  claim 1  or  claim 3 , wherein the composition further comprises a polymer. 
     
     
         5 . The composition of  claim 4 , wherein the polymer is selected from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or a mixture thereof. 
     
     
         6 . A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of  claim 1  or  claim 3 . 
     
     
         7 . The method of  claim 6 , wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, chronic constipation, opioid induced constipation and dyspepsia. 
     
     
         8 . The method of  claim 7 , wherein the gastrointestinal disorder is chronic constipation. 
     
     
         9 . The method of  claim 7 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome. 
     
     
         10 . A method of making the composition of  claim 1 , comprising combining linaclotide with a cation or pharmaceutically acceptable salt thereof and an amine selected from meglumine or a mixture of meglumine and histidine. 
     
     
         11 . A composition prepared by the method of  claim 10 . 
     
     
         12 . A method of making the composition of  claim 3 , comprising combining linaclotide with a cation or pharmaceutically acceptable salt thereof and histidine, wherein the composition has a molar ratio of cation:histidine of less than 2:1. 
     
     
         13 . A composition prepared by the method of  claim 12 . 
     
     
         14 . A pharmaceutical composition comprising linaclotide, a cation or pharmaceutically acceptable salt thereof and a dipeptide selected from glycine-leucine, leucine-glycine, or a mixture thereof. 
     
     
         15 . The composition of  claim 14 , wherein the composition further comprises a polymer. 
     
     
         16 . The composition of  claim 15 , wherein the polymer is selected from polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) or a mixture thereof. 
     
     
         17 . A method of treating a gastrointestinal disorder comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of  claim 14 . 
     
     
         18 . The method of  claim 17 , wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, chronic constipation, opioid induced constipation and dyspepsia. 
     
     
         19 . The method of  claim 18 , wherein the gastrointestinal disorder is chronic constipation. 
     
     
         20 . The method of  claim 18 , wherein the gastrointestinal disorder is constipation-predominant irritable bowel syndrome. 
     
     
         21 . A method of making the composition of  claim 14 , comprising combining linaclotide with a cation or pharmaceutically acceptable salt thereof and a dipeptide selected from glycine-leucine, leucine-glycine, or a mixture thereof. 
     
     
         22 . A composition prepared by the method of  claim 21 . 
     
     
         23 . The composition of  claim 1 , wherein the composition comprises Ca 2+  and an amino acid selected from meglumine or mixture of meglumine and histidine in a molar ratio of Ca 2+ :amino acid between about 1.3:1 and 0.7:1. 
     
     
         24 . The composition of  claim 1 , wherein the composition comprises Ca 2+  and an amino acid selected from meglumine or mixture of meglumine and histidine in a molar ratio of Ca 2+ :amino acid between about 1.1:1 and 0.9:1. 
     
     
         25 . The composition of  claim 3 , wherein the composition comprises Ca 2+  and histidine in a molar ratio of Ca 2+ :histidine between about 1.3:1 and 0.7:1. 
     
     
         26 . The composition of  claim 3 , wherein the composition comprises Ca 2+  and histidine in a molar ratio of Ca 2+ :histidine between about 1.1:1 and 0.9:1.