Formulations Comprising Linaclotide

Abstract

The present invention relates to stable compositions comprising linaclotide, 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 and a stabilizing amount of a polymer, a stabilizing amount of a sterically hindered primary amine, or a stabilizing amount of a cation, or a combination or mixture thereof. 
     
     
         2 . The composition of  claim 1 , wherein the composition is a tablet or capsule. 
     
     
         3 . The composition of  claim 1 , wherein the composition releases at least 80% of the linaclotide within 30 minutes or within 15 minutes of entering a use environment. 
     
     
         4 . The composition of  claim 1 , wherein the composition releases at least 80% of the linaclotide within 30 minutes or within 15 minutes of entering an agitated buffer solution have a pH of 4.5. 
     
     
         5 . The composition of  claim 1 , wherein the composition comprises between 0.01 and 10%; between 0.01 and 4%; or between 0.01 and 2% by weight of a polymer, relative to the total weight of the composition. 
     
     
         6 . The composition of  claim 1 , wherein the polymer is polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA), hydroxylpropyl methyl cellulose (HPMC), hydroxylpropyl cellulose (HPC), methyl cellulose, methacrylate polymers, cyclodextrin, dextran, polyacrylic acid, chitosan, guar gum, xanthan gum, polyethylene polypropylene oxide, poly(sodium vinylsulfonate), polyethylene glycol, poly(arginine), poly carbophil, polyvinyl pyrrolidone-co-vinyl acetate, a poloxamer (PLURONIC®), or a combination or mixture thereof. 
     
     
         7 . The composition of  claim 1 , wherein the composition comprises a molar ratio of sterically hindered primary amine to linaclotide between 100:1 and 1:1; between 100:1 and 30:1; or 60:1 and 30:1. 
     
     
         8 . The composition of  claim 1 , wherein the sterically hindered primary amine is an amino acid selected from:
 a naturally-occurring amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine;   synthetic amino acid selected from lanthionine, theanine or 1-amino cyclohexane; and   amino sugars selected from chitosan or glucosamine; or   combination or mixtures thereof.   
     
     
         9 . The composition of  claim 1 , wherein the composition comprises a molar ratio of cation to linaclotide between 100:1 and 1:1; between 100:1 and 40:1; or 100:1 and 60:1. 
     
     
         10 . The composition of  claim 1 , wherein the cation is calcium, potassium, magnesium, zinc, aluminum, iron, tin, manganese, chromium, cobalt, nickel, barium, sodium, or a combination or mixture thereof. 
     
     
         11 . The composition of  claim 10 , wherein the cation is a divalent metal cation selected from Ca 2+ , Mg 2+ , Mn 2+ , Zn 2+ , or a mixture thereof. 
     
     
         12 . The composition of  claim 1 , wherein the composition comprises a stabilizing amount of a polymer, a stabilizing amount of a sterically hindered primary amine, and stabilizing amount of a cation. 
     
     
         13 . The composition of  claim 12 , wherein the composition comprises a stabilizing amount of a polymer selected from PVP and PVA, a stabilizing amount of an amino acid selected from leucine, isoleucine, alanine, and methionine, and a stabilizing amount of a cation selected from Ca 2+ , Mg 2+ , Zn 2+ , or a mixture thereof. 
     
     
         14 . The composition of  claim 13 , wherein the composition comprises (i) between 0.01 and 10 wt. % or between 0.01 and 2 wt. % by weight of a polymer selected from PVP and PVA, (ii) an amino acid selected from leucine, isoleucine, alanine, and methionine in a molar ratio of amino acid to linaclotide between 100:1 and 10:1 or between 100:1 and 30:1, (iii) a cation selected from Ca 2+ , Mg 2+ , Zn 2+ , or a mixture thereof, in a molar ratio of cation to linaclotide between 100:1 and 10:1 or between 100:1 and 60:1. 
     
     
         15 . The composition of  claim 1 , wherein the composition further comprises a hydrolysis product having a structure of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The composition of claim  45 , wherein the composition comprises less than 5% by weight; or from 0.05% to 5% by weight; or from 0.05% to 2% by weight of the hydrolysis product. 
     
     
         17 . The composition of  claim 1 , wherein the composition further comprises an oxidation product having a structure of: 
       
         
           
           
               
               
           
         
       
     
     
         18 . The composition of claim  53 , wherein the composition comprises less than 5% by weight; from 0.05% to 5% by weight; from 0.05% to 2% by weight of the oxidation product. 
     
     
         19 . The composition of  claim 1 , wherein the composition further comprises reduced form linaclotide. 
     
     
         20 . The composition of  claim 19 , wherein the composition comprises less than 5% by weight; from 0.05% to 5% by weight; or from 0.05% to 2% by weight of the reduced form linaclotide. 
     
     
         21 . The composition of  claim 1 , wherein the composition further comprises scrambled form linaclotide. 
     
     
         22 . The composition of  claim 21 , wherein the composition comprises less than 5% by weight; from 0.05% to 5% by weight; or from 0.05% to 2% by weight of the scrambled form linaclotide. 
     
     
         23 . The composition of  claim 1 , wherein the linaclotide is present in the composition in a concentration of 50 μg to 2 mg. 
     
     
         24 . The composition of  claim 1 , wherein the linaclotide is present in the composition in a concentration of 75 μg, 150 μg, 300 μg, or 600 μg. 
     
     
         25 . 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 . 
     
     
         26 . The method of  claim 25 , wherein the gastrointestinal disorder is selected from the group consisting of irritable bowel syndrome, constipation-predominant irritable bowel syndrome, dyspepsia (including functional dyspepsia or non-ulcer dyspepsia), gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), Crohn's disease, ulcerative colitis, inflammatory bowel disease, functional heartburn, gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudo-obstruction), and disorders and conditions associated with constipation, for example, chronic constipation, opioid induced constipation, post-surgical constipation (post-operative ileus), and constipation associated with neuropathic disorders, combination of symptoms thereof, or combination of irritable bowel syndrome and chronic constipation. 
     
     
         27 . A method of treating chronic constipation comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of  claim 1 . 
     
     
         28 . A method of treating irritable bowel syndrome comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of  claim 1 . 
     
     
         29 . A method of treating constipation-predominant irritable bowel syndrome comprising administering to a patient in need thereof, a therapeutically effective amount of the composition of  claim 1 . 
     
     
         30 . A method of making the composition of  claim 1 , comprising:
 i) preparing an aqueous solution comprises linaclotide, or a pharmaceutically acceptable salt thereof; and   ii) applying the aqueous solution to a pharmaceutically acceptable carrier.   
     
     
         31 . A composition prepared by the method of  claim 30 .