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 (i) linaclotide, (ii) an amino acid selected from the group consisting of leucine or histadine, (iii) a divalent metal cation, (iv) a formaldehyde scavenger compound and (v) one or both of a peptide of the structure of formula (VI) (SEQ ID NO: 2) and formula (VII) (SEQ ID NO: 18): 
       
         
           
           
               
               
           
         
       
       wherein the formaldehyde scavenger compound is selected from the group consisting of: glycine, alanine, serine, threonine, cysteine, valine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, d-meglumine, taurine pyrrolysine, or a conjugate or mixture thereof. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the linaclotide composition comprises the total combined amount of the peptides of formula (VI) or formula (VII) is up to 3% by weight as compared to the weight of linaclotide. 
     
     
         5 . The composition of  claim 1 , wherein the linaclotide composition comprises the total combined amount of the peptides of formula (VI) or formula (VII) is up to 2% by weight as compared to the weight of linaclotide. 
     
     
         6 . The composition of  claim 1 , wherein the linaclotide composition comprises the total combined amount of the peptides of formula (VI) or formula (VII) is up to 1% by weight as compared to the weight of linaclotide. 
     
     
         7 . A linaclotide composition comprising (i) a formaldehyde scavenger compound (ii) an oral pharmaceutical dosage form comprising about 145 μg or about 290 μg of linaclotide or a pharmaceutically acceptable salt thereof, (iii) Ca 2+  or a salt thereof, (iv) an amino acid selected from the group consisting of leucine and histadine, and (v) at least one of a peptide having the structure of formula (VI) (SEQ ID NO: 2) or formula (VII) (SEQ ID NO: 18) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein the formaldehyde scavenger compound is selected from the group consisting of: glycine, alanine, serine, threonine, cysteine, valine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, citrulline, d-meglumine, taurine pyrrolysine, or a conjugate or mixture thereof. 
     
     
         8 . The composition of  claim 7 , wherein the total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is about 0.001 to about 2 wt. % relative to the total weight of the dosage form. 
     
     
         9 . The composition of  claim 7 , wherein the total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is about 0.001 to about 1 wt. % relative to the total weight of the dosage form. 
     
     
         10 . The composition of  claim 7 , wherein the total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is 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 total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form. 
     
     
         12 . The composition of  claim 1 , wherein the divalent metal cation is Ca 2+  or a salt thereof, the amino acid is leucine, and wherein the linaclotide composition comprises a molar ratio of divalent metal cation:amino acid:linaclotide of about 57-63:28-32:1. 
     
     
         13 . The composition of  claim 7 , wherein the Ca 2+  or a salt thereof and amino acid are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :amino acid:linaclotide of about 57-63:28-32:1. 
     
     
         14 . The composition of  claim 9 , wherein the Ca 2+  or a salt thereof and amino acid are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :amino acid:linaclotide of about 57-63:28-32:1. 
     
     
         15 . The composition of  claim 10 , wherein the Ca 2+  or a salt thereof and amino acid are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :amino acid:linaclotide of about 57-63:28-32:1. 
     
     
         16 . The composition of  claim 11 , wherein the Ca2+ or a salt thereof and amino acid are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :amino acid:linaclotide of about 57-63:28-32:1. 
     
     
         17 - 19 . (canceled) 
     
     
         20 . The composition of  claim 7 , wherein the Ca 2+  or a salt thereof and amino acid are present in the oral pharmaceutical dosage form in a molar ratio of Ca 2+ :amino acid:linaclotide of about 57-63:28-32:1, wherein the formaldehyde scavenger compound is selected from the group consisting of leucine and histidine, and wherein the total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is about 0.001 to about 1 wt. % relative to the total weight of the dosage form. 
     
     
         21 . The composition of  claim 20 , wherein the total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is 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 total combined amount of the peptides of formula (VI) or formula (VII) present in the oral pharmaceutical dosage form is about 0.001 to about 0.5 wt. % relative to the total weight of the dosage form. 
     
     
         23 - 31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . The composition of  claim 1 , wherein the divalent metal cation is Ca2+ or a salt thereof, amino acid is histidine, and wherein the linaclotide composition comprises a molar ratio of divalent metal cation:amino acid:linaclotide of about 57-63:28-32:1.