Linaclotide compositions

Abstract

The present invention is directed to stable linaclotide compositions and methods of treating gastrointestinal disorders in patients in need thereof by providing the stable linaclotide compositions.

1 . A linaclotide composition comprising linaclotide, a sterically hindered primary amine, a divalent metal cation and a formaldehyde scavenger compound. 
     
     
         2 . The composition of  claim 1 , wherein the composition further comprises a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The composition of  claim 2 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 5% by weight as compared to the weight of linaclotide. 
     
     
         4 . The composition of  claim 2 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 3% by weight as compared to the weight of linaclotide. 
     
     
         5 . The composition of  claim 2 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 2% by weight as compared to the weight of linaclotide. 
     
     
         6 . The composition of  claim 2 , wherein the linaclotide composition comprises the peptide of formula (I) in a concentration of up to 1% by weight as compared to the weight of linaclotide. 
     
     
         7 . A linaclotide composition comprising a formaldehyde scavenger compound and an oral pharmaceutical dosage form comprising about 145 μg or about 290 μg of linaclotide or a pharmaceutically acceptable salt thereof, Ca 2+  or a salt thereof, leucine, and a peptide having the structure of formula (I) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The composition of  claim 7 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 2 wt. % relative to the total weight of the dosage form. 
     
     
         9 . The composition of  claim 7 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 1 wt. % relative to the total weight of the dosage form. 
     
     
         10 . The composition of  claim 7 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.75 wt. % relative to the total weight of the dosage form. 
     
     
         11 . The composition of  claim 7 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form. 
     
     
         12 . The composition of  claim 2 , wherein the divalent metal cation is Ca 2+  or a salt thereof, the sterically hindered primary amine is leucine, and wherein the linaclotide composition comprises a molar ratio of divalent metal cation:sterically hindered primary amine:linaclotide of about 57-63:28-32:1 
     
     
         13 . The composition of  claim 7 , wherein the Ca 2+  or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1. 
     
     
         14 . The composition of  claim 9 , wherein the Ca 2+  or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1. 
     
     
         15 . The composition of  claim 10 , wherein the Ca 2+  or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1. 
     
     
         16 . The composition of  claim 11 , wherein the Ca 2+  or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1. 
     
     
         17 . The composition of  claim 9 , wherein the oral pharmaceutical dosage form further comprises an oxidation product having a structure of: 
       
         
           
           
               
               
           
         
         in an amount from about 0.05% to about 5% by weight relative to the total weight of the dosage form. 
       
     
     
         18 . The composition of  claim 17 , wherein the oxidation product in present in the dosage form in an amount of about 0.05% to about 2% relative to the total weight of the dosage form. 
     
     
         19 . The composition of  claim 17 , wherein the oxidation product in present in the dosage form in an amount of about 0.05% to about 1% relative to the total weight of the dosage form. 
     
     
         20 . The composition of  claim 7 , wherein the Ca 2+  or a salt thereof and leucine are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :leucine:linaclotide of about 57-63:28-32:1, wherein the formaldehyde scavenger compound is selected from the group consisting of d-meglumine and histidine, and wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 1 wt. % relative to the total weight of the dosage form. 
     
     
         21 . The composition of  claim 20 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.75 wt. % relative to the total weight of the dosage form. 
     
     
         22 . The composition of  claim 20 , wherein the peptide of formula (I) is present in the oral pharmaceutical dosage form in an amount of about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form. 
     
     
         23 . The composition of  claim 3 , wherein the formaldehyde scavenger compound is an amino acid or derivative thereof. 
     
     
         24 . The composition of  claim 23 , wherein the formaldehyde scavenger compound is selected from the group consisting of leucine, glycine, aspartame, d-meglumine, histidine, asparagine, proline, or a mixture thereof. 
     
     
         25 . The composition of  claim 23 , wherein the formaldehyde scavenger compound is d-meglumine, histidine or a mixture thereof. 
     
     
         26 . The composition of  claim 23 , wherein the formaldehyde scavenger compound is d-meglumine 
     
     
         27 . The composition of  claim 23 , wherein the formaldehyde scavenger compound is histidine. 
     
     
         28 . The composition of  claim 24 , wherein the formaldehyde scavenger compound is present in the linaclotide composition in molar ratio of formaldehyde scavenger compound to linaclotide between 5:1 and 1:1. 
     
     
         29 . The composition of  claim 28 , wherein the formaldehyde scavenger compound is present in the linaclotide composition in molar ratio of formaldehyde scavenger compound to linaclotide between 3:1 and 1:1. 
     
     
         30 . A method of treating a gastrointestinal disorder selected from constipation-predominant irritable bowel syndrome and chronic idiopathic constipation comprising providing a patient in need thereof the linaclotide composition of  claim 3 . 
     
     
         31 . A method of treating a gastrointestinal disorder selected from constipation-predominant irritable bowel syndrome and chronic idiopathic constipation comprising providing a patient in need thereof the linaclotide composition of  claim 28 .