Stable Solid Formulation of a GC-C Receptor Agonist Polypeptide Suitable for Oral Administration

Abstract

Solid, stable formulations of linaclotide suitable for oral administration are described herein as are methods for preparing such formulations. The formulations described herein contain a polypeptide consisting of the amino acid sequence Cys Cys Glu Tyr Cys Cys Asn Pro Ala Cys Thr Gly Cys Tyr (“linaclotide”; SEQ ID NO:1) or a pharmaceutically acceptable salt thereof. The linaclotide formulations described herein are stable and have a sufficient shelf life for manufacturing, storing and distributing the drug.

1 . A pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the chromatographic purity of the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, or 4% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         3 . A unit dosage form of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         4 . The unit dosage form according to  claim 3 , wherein the chromatographic purity of the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5% or 4% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         5 . A sealed container comprising a plurality of unit dosage forms of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         6 . The sealed container according to  claim 5 , wherein the chromatographic purity of the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5% or 4% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         7 . A pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the assay value for linaclotide determined on a weight/weight basis decreases by less than 10% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the assay value for the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         9 . A unit dosage form of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the assay value for linaclotide determined on a weight/weight basis decreases by less than 10% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         10 . The unit dosage form according to  claim 9 , wherein the assay value for the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         11 . A sealed container comprising a plurality of unit dosage forms of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient wherein the assay value for linaclotide in the unit dosage forms determined on a weight/weight basis decreases by less than 10% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         12 . The sealed container according to  claim 11 , wherein the assay value for the linaclotide decreases by less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2% or 1% after (a) 18 months of storage the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         13 . The unit dosage form according to any one of  claim 3 - 4  or  9 - 10 , wherein each unit dosage form contains from 50 μg to 2 mg linaclotide. 
     
     
         14 . The sealed container according to any one of  claim 5 - 6  or  11 - 12 , wherein each unit dosage form contains from 50 μg to 2 mg linaclotide. 
     
     
         15 . The pharmaceutical composition according to either of  claim 1  or  2 , wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         16 . The unit dosage form according to either of  claim 3  or  4 , wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 24 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         17 . The sealed container according to either of  claim 5  or  6 , wherein the chromatographic purity of the linaclotide decreases by less than 10% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         18 . The pharmaceutical composition according to either of  claim 7  or  8 , wherein the assay value of the linaclotide decreases by less than 10% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         19 . The unit dosage form according to either of  claim 9  or  10 , wherein the assay value of the linaclotide decreases by less than 10% after (a) 24 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         20 . The sealed container according to either of  claim 11  or  12 , wherein the assay value of the linaclotide decreases by less than 10% after (a) a first 24 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         21 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, linaclotide and one or more agents selected from (i) a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+ , or (ii) a sterically hindered primary amine, wherein the agent improves at least one attribute of the composition, relative to a pharmaceutical composition without said agent, after (a) a first 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) a first 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant, wherein said attribute is selected from a decrease in the rate of degradation of linaclotide as measured by linaclotide content, a decrease in the rate of degradation of linaclotide as measured by chromatographic purity of linaclotide, a decrease in the amount of a linaclotide oxidation product relative to the amount of linaclotide, a decrease in the amount of a linaclotide hydrolysis product relative to the amount of linaclotide, or a decrease in the amount of a linaclotide formaldehyde imine product of linaclotide relative to the amount of linaclotide. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+ . 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. 
     
     
         25 . The pharmaceutical composition according to  claim 22 , wherein said agent is Mg 2+ , Ca 2+  or Zn 2+ . 
     
     
         26 . The pharmaceutical composition according to  claim 25 , wherein said Mg 2+ , Ca 2+  or Zn 2+  is provided as magnesium chloride, calcium chloride or zinc acetate. 
     
     
         27 . The pharmaceutical composition according to  claim 22 , wherein said agent is Ca 2+ . 
     
     
         28 . The pharmaceutical composition according to  claim 27 , wherein said Ca 2+  is provided as calcium chloride. 
     
     
         29 . The pharmaceutical composition according to  claim 21 , wherein said agent is a sterically hindered primary amine. 
     
     
         30 . The pharmaceutical composition according to  claim 29 , wherein the sterically hindered primary amine is an amino acid. 
     
     
         31 . The pharmaceutical composition according to  claim 30 , wherein the amino acid is a naturally-occurring amino acid. 
     
     
         32 . The pharmaceutical composition according to  claim 31 , wherein the naturally-occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan or valine. 
     
     
         33 . The pharmaceutical composition according to  claim 32 , wherein the naturally-occurring amino acid is histidine, phenylalanine, leucine, methionine, isoleucine, tryptophan or valine. 
     
     
         34 . The pharmaceutical composition according to  claim 33 , wherein the naturally-occurring amino acid is leucine, isoleucine, alanine or methionine. 
     
     
         35 . The pharmaceutical composition according to  claim 34 , wherein the naturally-occurring amino acid is leucine or methionine. 
     
     
         36 . The pharmaceutical composition according to  claim 35 , wherein the naturally-occurring amino acid is leucine. 
     
     
         37 . The pharmaceutical composition according to  claim 30 , wherein the sterically hindered primary amine is a non-naturally occurring amino acid or an amino acid derivative. 
     
     
         38 . The pharmaceutical composition according to  claim 37 , wherein the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine. 
     
     
         39 . The pharmaceutical composition according to  claim 29 , wherein the sterically hindered primary amine has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are independently selected from: H; —C(O)OH; C 1 -C 6  alkyl, optionally substituted by —CO 2 H, —CONH 2 , or a 5-10 membered aryl or heteroaryl; C 1 -C 6  alkoxyalkyl; or C 1 -C 6  thioalkoxyalkyl, wherein any of the alkyl or aryl groups above can be singly or multiply substituted with halogen or —NH 2 , and provided that no more than two of R 1 , R 2  and R 3  are H. 
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine. 
     
     
         41 . The pharmaceutical composition according to  claim 29 , wherein the sterically hindered primary amine is a polymeric amine. 
     
     
         42 . The pharmaceutical composition according to  claim 41 , wherein the polymeric amine is chitosan. 
     
     
         43 . The pharmaceutical composition according to any one of  claims 29 - 42 , wherein said pharmaceutical composition further comprises Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+ . 
     
     
         44 . The pharmaceutical composition according to  claim 43 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate. 
     
     
         45 . The pharmaceutical composition according to  claim 44 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na or Al 3+  is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. 
     
     
         46 . The pharmaceutical composition according to any one of  claims 29 - 42 , wherein said pharmaceutical composition further comprises Mg 2+ , Ca 2+  or Zn 2+ . 
     
     
         47 . The pharmaceutical composition according to  claim 46 , wherein said Mg 2+ , Ca 2+  or Zn 2+  is provided as magnesium chloride, calcium chloride or zinc acetate. 
     
     
         48 . The pharmaceutical composition according to  claim 46 , wherein said pharmaceutical composition further comprises Ca 2+ . 
     
     
         49 . The pharmaceutical composition according to  claim 48 , wherein said Ca 2+  is provided as calcium chloride. 
     
     
         50 . The pharmaceutical composition according to any one of  claims 21 - 49 , further comprising an antioxidant. 
     
     
         51 . The pharmaceutical composition according to  claim 50 , wherein said antioxidant is BHA, vitamin E or propyl gallate. 
     
     
         52 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier, linaclotide, a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+ , and a sterically hindered primary amine. 
     
     
         53 . The pharmaceutical composition according to  claim 52 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate. 
     
     
         54 . The pharmaceutical composition according to  claim 53 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. 
     
     
         55 . The pharmaceutical composition according to  claim 52 , wherein said cation is selected from Mg 2+ , Ca 2+  or Zn 2+ . 
     
     
         56 . The pharmaceutical composition according to  claim 55 , wherein said Mg 2+ , Ca 2+  or Zn 2+  is provided as magnesium chloride, calcium chloride or zinc acetate. 
     
     
         57 . The pharmaceutical composition according to  claim 55 , wherein said cation is Ca 2+ . 
     
     
         58 . The pharmaceutical composition according to  claim 57 , wherein said Ca 2+  is provided as calcium chloride. 
     
     
         59 . The pharmaceutical composition according to any one of  claims 52 - 56 , wherein the sterically hindered primary amine is an amino acid. 
     
     
         60 . The pharmaceutical composition according to  claim 59 , wherein the amino acid is a naturally-occurring amino acid. 
     
     
         61 . The pharmaceutical composition according to  claim 60 , wherein the naturally-occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, methionine or valine. 
     
     
         62 . The pharmaceutical composition according to  claim 61 , wherein the naturally-occurring amino acid is histidine, phenylalanine, leucine, methionine, isoleucine, tryptophan or valine. 
     
     
         63 . The pharmaceutical composition according to  claim 62 , wherein the naturally-occurring amino acid is leucine, isoleucine, alanine or methionine. 
     
     
         64 . The pharmaceutical composition of  claim 63 , wherein the naturally-occurring amino acid is leucine. 
     
     
         65 . The pharmaceutical composition according to  claim 52 , wherein the sterically hindered primary amine is a non-naturally occurring amino acid or an amino acid derivative. 
     
     
         66 . The pharmaceutical composition according to  claim 65 , wherein the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine. 
     
     
         67 . The pharmaceutical composition according to  claim 52 , wherein the sterically hindered primary amine has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are independently selected from: H; —C(O)OH; C 1 -C 6  alkyl, optionally substituted by —CO 2 H, —CONH 2 , or a 5-10 membered aryl or heteroaryl; C 1 -C 6  alkoxyalkyl; or C 1 -C 6  thioalkoxyalkyl, wherein any of the alkyl or aryl groups above can be singly or multiply substituted with halogen or —NH 2 , and provided that no more than two of R 1 , R 2  and R 3  are H. 
     
     
         68 . The pharmaceutical composition according to  claim 67 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine. 
     
     
         69 . The pharmaceutical composition according to  claim 52 , wherein the sterically hindered primary amine is a polymeric amine. 
     
     
         70 . The pharmaceutical composition according to  claim 69 , wherein the sterically hindered primary amine is chitosan. 
     
     
         71 . The pharmaceutical composition according to any one of  claims 52 - 70 , further comprising a pharmaceutically acceptable glidant, lubricant or additive that acts as both a glidant and lubricant. 
     
     
         72 . The pharmaceutical composition according to any one of  claims 52 - 71  further comprising an antioxidant. 
     
     
         73 . The pharmaceutical composition according to  claim 72 , wherein said antioxidant is BHA, vitamin E or propyl gallate. 
     
     
         74 . The pharmaceutical composition according to any one of  claims 52 - 73 , further comprising a pharmaceutically acceptable binder. 
     
     
         75 . The pharmaceutical composition according to  claim 74  wherein the pharmaceutically acceptable binder is selected from polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether. 
     
     
         76 . The pharmaceutical composition of  claim 75  wherein the pharmaceutically acceptable binder is a cellulose ether. 
     
     
         77 . The pharmaceutical composition of  claim 76  wherein the cellulose ether is selected from: methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose. 
     
     
         78 . The pharmaceutical composition of any of  claims 52 - 77 , further comprising a pharmaceutically acceptable filler. 
     
     
         79 . The pharmaceutical composition according to  claim 78 , wherein the pharmaceutically acceptable filler is cellulose, isomalt, mannitol or dibasic calcium phosphate. 
     
     
         80 . The pharmaceutical composition of  claim 79  wherein the cellulose is selected from microfine cellulose and microcrystalline cellulose. 
     
     
         81 . The pharmaceutical composition of any of  claims 78 - 80 , wherein the pharmaceutically acceptable filler comprises particles having an average diameter between 150 μm and 1000 μm. 
     
     
         82 . The pharmaceutical composition of any of  claims 52 - 81 , wherein pharmaceutical composition comprises a filler and the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:25 and 1:2,500. 
     
     
         83 . The pharmaceutical composition according to  claim 82 , wherein the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:100 and 1:2000. 
     
     
         84 . The pharmaceutical composition according to  claim 83 , wherein the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:100 and 1:1000. 
     
     
         85 . The pharmaceutical composition of any of  claims 52 - 84  wherein the sterically hindered amine is leucine and the molar ratio of leucine to linaclotide is at least 10:1. 
     
     
         86 . The pharmaceutical composition of  claim 85  wherein the molar ratio of leucine to linaclotide is at least 20:1. 
     
     
         87 . The pharmaceutical composition of  claim 86  wherein the molar ratio of leucine to linaclotide is at least 30:1. 
     
     
         88 . The pharmaceutical composition of any of  claims 52 - 87  wherein the cation is Ca 2+  and the molar ratio of Ca 2+  to leucine is at least 1:1. 
     
     
         89 . The pharmaceutical composition of  claim 88 , wherein the molar ratio of Ca 2+  to leucine is at least 1.5:1. 
     
     
         90 . The pharmaceutical composition of  claim 89  wherein the molar ratio of Ca 2+  to leucine is at least 2:1. 
     
     
         91 . The pharmaceutical composition according to any one of  claims 52 - 84 , wherein the molar ratio of cation:sterically hindered primary amine:linaclotide is 40-100:20-50:1. 
     
     
         92 . The pharmaceutical composition according to  claim 91 , wherein the cation is Ca 2+  and the sterically hindered primary amine is leucine. 
     
     
         93 . The pharmaceutical composition according to  claim 92 , wherein the molar ratio of Ca 2+ :leucine:linaclotide is 100:30:1, 80:40:1, 80:30:1, 80:20:1, 60:30:1, 60:20:1, 50:30:1, 50:20:1, 40:20:1, 20:20:1, 10:10:1, 10:5:1, 5:10:1 or 5:5:1. 
     
     
         94 . The pharmaceutical composition according to  claim 93 , wherein the molar ratio of Ca 2+ :leucine:linaclotide is 60:30:1. 
     
     
         95 . The pharmaceutical composition according to any one of  claims 92 - 94 , wherein Ca 2+  is provided as CaCl 2 . 
     
     
         96 . A unit dosage form comprising the pharmaceutical composition according to any one of  claims 92 - 95 . 
     
     
         97 . The unit dosage form according to  claim 96 , wherein each unit dosage form comprises 50 μg to 1 mg linaclotide. 
     
     
         98 . The unit dosage form according to  claim 97 , wherein each unit dosage form is a capsule or tablet, and wherein said unit dosage form comprises 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. 
     
     
         99 . A method for preparing a pharmaceutical composition comprising linaclotide or a salt thereof, the method comprising:
 (a) providing an aqueous solution comprising:
 (i) linaclotide or a pharmaceutically acceptable salt thereof 
 (ii) one or more of a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  or a sterically hindered primary amine; and, 
 (iii) optionally, a pharmaceutically acceptable binder; and 
   (b) applying the aqueous solution to a pharmaceutically acceptable filler to generate linaclotide-coated filler.   
     
     
         100 . The method of  claim 99 , wherein the aqueous solution comprises a sterically hindered primary amine. 
     
     
         101 . The method of  claim 99 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate. 
     
     
         102 . The method of  claim 101 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. 
     
     
         103 . The method of  claim 99 , wherein said cation is selected from Mg 2+ , Ca 2+  or Zn 2+ . 
     
     
         104 . The method of  claim 103 , wherein said Mg 2+ , Ca 2+  or Zn 2+  is provided as magnesium chloride, calcium chloride or zinc acetate. 
     
     
         105 . The method of  claim 103 , wherein said cation is Ca 2+ . 
     
     
         106 . The method of  claim 105 , wherein said Ca 2+  is provided as calcium chloride. 
     
     
         107 . The method of  claim 99 , wherein the sterically hindered primary amine is an amino acid. 
     
     
         108 . The method of  claim 107 , wherein the amino acid is a naturally-occurring amino acid. 
     
     
         109 . The method of  claim 108 , wherein the naturally-occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, methionine or valine. 
     
     
         110 . The method of  claim 109 , wherein the naturally-occurring amino acid is histidine, phenylalanine, leucine, methionine, isoleucine, tryptophan or valine. 
     
     
         111 . The method of  claim 110 , wherein the naturally-occurring amino acid is leucine, isoleucine, alanine or methionine. 
     
     
         112 . The method of  claim 111 , wherein the naturally-occurring amino acid is leucine. 
     
     
         113 . The method of  claim 99 , wherein the sterically hindered primary amine is a non-naturally occurring amino acid or an amino acid derivative. 
     
     
         114 . The method of  claim 113 , wherein the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine. 
     
     
         115 . The method of  claim 99 , wherein the sterically hindered primary amine has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R I , R 2  and R 3  are independently selected from: H; —C(O)OH; C 1 -C 6  alkyl, optionally substituted by —CO 2 H, —CONH 2 , or a 5-10 membered aryl or heteroaryl; C 1 -C 6  alkoxyalkyl; or C 1 -C 6  thioalkoxyalkyl, wherein any of the alkyl or aryl groups above can be singly or multiply substituted with halogen or —NH 2 , and provided that no more than two of R 1 , R 2  and R 3  are H. 
     
     
         116 . The method of  claim 115 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine. 
     
     
         117 . The method of  claim 99 , wherein the sterically hindered primary amine is a polymeric amine. 
     
     
         118 . The method of  claim 117 , wherein the sterically hindered primary amine is chitosan. 
     
     
         119 . The method according to  claims 99 - 118 , wherein the aqueous solution further comprises an antioxidant. 
     
     
         120 . The method of  claim 119 , wherein said antioxidant is BHA, BHT, vitamin E, propyl gallate, ascorbic acid and salts or esters thereof, tocopherol and esters thereof, alpha-lipoic acid or beta-carotene. 
     
     
         121 . The method of  claim 99 , wherein the aqueous solution comprises both the cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  and the sterically hindered primary amine. 
     
     
         122 . The method of  claim 121 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium acetate, magnesium chloride, magnesium phosphate, magnesium sulfate, calcium acetate, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, zinc chloride, zinc phosphate, zinc sulfate, manganese acetate, manganese chloride, manganese phosphate, manganese sulfate, potassium acetate, potassium chloride, potassium phosphate, potassium sulfate, sodium acetate, sodium chloride, sodium phosphate, sodium sulfate, aluminum acetate, aluminum chloride, aluminum phosphate or aluminum sulfate. 
     
     
         123 . The method of  claim 122 , wherein said Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  is provided as magnesium chloride, calcium chloride, calcium phosphate, calcium sulfate, zinc acetate, manganese chloride, potassium chloride, sodium chloride or aluminum chloride. 
     
     
         124 . The method of  claim 121 , wherein said cation is selected from Mg 2+ , Ca 2+  or Zn 2+ . 
     
     
         125 . The method of  claim 124 , wherein said Mg 2+ , Ca 2+  or Zn 2+  is provided as magnesium chloride, calcium chloride or zinc acetate. 
     
     
         126 . The method of  claim 124 , wherein said cation is Ca 2+ . 
     
     
         127 . The method of  claim 126 , wherein said Ca 2+  is provided as calcium chloride. 
     
     
         128 . The method of  claim 121 , wherein the sterically hindered primary amine is an amino acid. 
     
     
         129 . The method of  claim 128 , wherein the amino acid is a naturally-occurring amino acid. 
     
     
         130 . The method of  claim 129 , wherein the naturally-occurring amino acid is histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan, methionine or valine. 
     
     
         131 . The method of  claim 130 , wherein the naturally-occurring amino acid is histidine, phenylalanine, leucine, methionine, isoleucine, tryptophan or valine. 
     
     
         132 . The method of  claim 131 , wherein the naturally-occurring amino acid is leucine, isoleucine, alanine or methionine. 
     
     
         133 . The method of  claim 132 , wherein the naturally-occurring amino acid is leucine. 
     
     
         134 . The method of  claim 121 , wherein the sterically hindered primary amine is a non-naturally occurring amino acid or an amino acid derivative. 
     
     
         135 . The method of  claim 134 , wherein the non-naturally occurring amino acid is 1-aminocyclohexane carboxylic acid, lanthanine or theanine. 
     
     
         136 . The method of  claim 121 , wherein the sterically hindered primary amine has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 3  are independently selected from: H; —C(O)OH; C 1 -C 6  alkyl, optionally substituted by —CO 2 H, —CONH 2 , or a 5-10 membered aryl or heteroaryl; C 1 -C 6  alkoxyalkyl; or C 1 -C 6  thioalkoxyalkyl, wherein any of the alkyl or aryl groups above can be singly or multiply substituted with halogen or —NH 2 , and provided that no more than two of R 1 , R 2  and R 3  are H. 
     
     
         137 . The method of  claim 136 , wherein the sterically hindered primary amine is cyclohexylamine or 2-methylbutylamine. 
     
     
         138 . The method of  claim 121 , wherein the sterically hindered primary amine is a polymeric amine. 
     
     
         139 . The method of  claim 138 , wherein the sterically hindered primary amine is chitosan. 
     
     
         140 . The method according to  claims 121 - 140 , wherein the aqueous solution further comprises an antioxidant. 
     
     
         141 . The method of  claim 140 , wherein said antioxidant is BHA, BHT, vitamin E, propyl gallate, ascorbic acid and salts or esters thereof, tocopherol and esters thereof, alpha-lipoic acid or beta-carotene. 
     
     
         142 . The method of  claim 141  wherein the antioxidant is BHA. 
     
     
         143 . The method of any one of  claims 99 - 142 , wherein the binder is present and is selected from polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether. 
     
     
         144 . The method of  claim 143  wherein the pharmaceutically acceptable binder is a cellulose ether. 
     
     
         145 . The method of  claim 144  wherein the cellulose ether is selected from: methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose. 
     
     
         146 . The method of any one of  claims 99 - 145 , wherein the filler is selected from cellulose, isomalt, mannitol or dibasic calcium phosphate. 
     
     
         147 . The method of  claim 146 , wherein the filler is microfine cellulose or microcrystalline cellulose. 
     
     
         148 . The method of any one of  claims 99 - 147 , wherein the aqueous solution is applied to the filler by spraying. 
     
     
         149 . The method of any one of  claims 99 - 147 , wherein the aqueous solution is applied to the filler by mixing. 
     
     
         150 . The method of any one of  claims 99 - 149 , wherein the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:100 and 1:2500. 
     
     
         151 . The method according to  claim 150 , wherein the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:100 and 1:1000. 
     
     
         152 . The method according to any one of  claims 121 - 151 , wherein the molar ratio of cation:sterically hindered primary amine:linaclotide is 40-100:20-30:1. 
     
     
         153 . The method according to  claim 152 , wherein the cation is Ca 2+ . 
     
     
         154 . The method according to  claim 152 , wherein the sterically hindered primary amine is leucine. 
     
     
         155 . The method according to  claim 152 , wherein the cation is Ca 2+  and the sterically hindered primary amine is leucine, and the molar ratio of Ca 2+ :leucine:linaclotide is 100:30:1, 80:40:1, 80:30:1, 80:20:1, 60:30:1, 60:20:1, 50:30:1, 50:20:1, 40:20:1, 20:20:1, 10:10:1, 10:5:1 or 5:5:1. 
     
     
         156 . The method according to  claim 155 , wherein the molar ratio of Ca 2+ :leucine:linaclotide is 60:30:1. 
     
     
         157 . The method according to any one of  claims 152 - 156 , wherein the pharmaceutically acceptable filler is selected from cellulose, isomalt, mannitol or dibasic calcium phosphate. 
     
     
         158 . The method according to  claim 157 , wherein the pharmaceutically acceptable filler is microfine cellulose or microcrystalline cellulose. 
     
     
         159 . The method according to any one of  claims 152 - 158 , wherein the pharmaceutically acceptable binder is polyvinyl alcohol, polyvinylpyrrolidone (povidone), a starch, maltodextrin or a cellulose ether. 
     
     
         160 . The method of  claim 159  wherein the pharmaceutically acceptable binder is a cellulose ether. 
     
     
         161 . The method according to  claim 160 , wherein the pharmaceutically acceptable binder is methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose. 
     
     
         162 . The method according to any one of  claims 99 - 161 , wherein the method further comprises (c) applying a coating to the linaclotide-coated filler. 
     
     
         163 . The method according to  claim 162 , wherein said coating is selected from AQUACOAT, EUDRAGIT or OPADRY. 
     
     
         164 . The method according to any one of  claims 99 - 163 , wherein the linaclotide-coated filler is mixed with one or more pharmaceutically acceptable additives. 
     
     
         165 . The method according to any one of  claims 99 - 164 , further comprising tableting or encapsulating the linaclotide-coated filler in a tablet or capsule, respectively. 
     
     
         166 . The method according to  claim 165 , wherein said linaclotide-coated filler is encapsulated in a capsule. 
     
     
         167 . The method according to  claim 166 , wherein the capsule is a gelatin capsule. 
     
     
         168 . The method according to any one of  claims 165 - 167 , wherein each capsule or tablet contains 50 μg to 1 mg linaclotide. 
     
     
         169 . The method according to  claim 168 , wherein each capsule or tablet contains 50 μg, 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. 
     
     
         170 . The method according to  claim 169 , wherein each capsule or tablet contains 67.5 μg, 133 μg, 150 μg, 266 μg or 300 μg linaclotide. 
     
     
         171 . A method for treating a patient suffering from impaired intestinal motility, irritable bowel syndrome, constipation, pain associated with constipation, dyspepsia, gastroparesis, chronic intestinal pseudo obstruction, Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to the patient an effective amount of the pharmaceutical composition according to any one of  claims 1 - 98 . 
     
     
         172 . The method according to  claim 171 , wherein said irritable bowel syndrome is constipation-predominant irritable bowel syndrome or alternating irritable bowel syndrome. 
     
     
         173 . The method according to  claim 172 , wherein said irritable bowel syndrome is constipation-predominant irritable bowel syndrome. 
     
     
         174 . The method according to  claim 171 , wherein said constipation is chronic constipation, idiopathic constipation, post-operative ileus, or constipation caused by opiate use. 
     
     
         175 . The method according to  claim 174 , wherein said constipation is chronic constipation. 
     
     
         176 . The method according to any one of  claims 171 - 175 , wherein the pharmaceutical composition contains 50 μg to 1 mg linaclotide. 
     
     
         177 . The method according to  claim 176 , wherein the pharmaceutical composition contains 50 μg, 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. 
     
     
         178 . The method according to  claim 177 , wherein the pharmaceutical composition contains 67.5 μg, 133 μg, 150 μg, 266 μg or 300 μg linaclotide. 
     
     
         179 . The method according to any one of  claims 171 - 178 , wherein the pharmaceutical composition is administered once daily, twice daily, three times daily or four times daily. 
     
     
         180 . The method according to  claim 179 , wherein the pharmaceutical composition is administered once daily or twice daily. 
     
     
         181 . The method according to  claim 180 , wherein the pharmaceutical composition is administered once daily. 
     
     
         182 . The method according to  claim 181 , wherein the pharmaceutical composition is administered once daily as one or two tablets or capsules. 
     
     
         183 . The method according to  claim 182 , wherein the pharmaceutical composition is administered as a single tablet or capsule. 
     
     
         184 . A composition that is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% by weight a hydrolysis product of linaclotide. 
     
     
         185 . The composition of  claim 184  wherein the composition is at least 60%, at least 70% or at least 80% by weight a hydrolysis product of linaclotide. 
     
     
         186 . The composition of  claim 185  wherein the composition is at least 90%, at least 95% or at least 98% by weight a hydrolysis product of linaclotide. 
     
     
         187 . A composition that is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% by weight an oxidation product of linaclotide. 
     
     
         188 . The composition of  claim 187  wherein the composition at least 60%, at least 70% or at least 80% by weight an oxidation product of linaclotide. 
     
     
         189 . The composition of  claim 188  wherein the composition is at least 90%, at least 95% or at least 98% by weight an oxidation product of linaclotide. 
     
     
         190 . A composition that is at least 10%, at least 20%, at least 30%, at least 40% or at least 50% by weight a formaldehyde imine product of linaclotide. 
     
     
         191 . The composition of  claim 190  wherein the composition is at least 60%, at least 70% or at least 80% by weight a formaldehyde imine product of linaclotide. 
     
     
         192 . The composition of  claim 191  wherein the composition is at least 90%, at least 95% or at least 98% by weight a formaldehyde imine product of linaclotide. 
     
     
         193 . A method for assessing the purity of a pharmaceutical formulation comprising linaclotide, the method comprising:
 (a) providing a sample of the pharmaceutical formulation comprising linaclotide;   (b) measuring the amount of at least one degradation product in the sample selected from the group consisting of an oxidation product of linaclotide, a hydrolysis product of linaclotide and a formaldehyde imine product of linaclotide; and   (c) comparing the measured amount of the oxidation product of linaclotide, the hydrolysis product of linaclotide and/or the formaldehyde imine product of linaclotide to a reference standard amount of the oxidation product of linaclotide, the hydrolysis product of linaclotide or the formaldehyde imine product to assess the purity of the pharmaceutical formulation.   
     
     
         194 . A method for identifying an impurity in a sample comprising linaclotide comprising:
 (a) providing a reference sample comprising a reference marker and linaclotide;   (b) carrying out HPLC on the reference sample to determine the relative retention time of the reference marker compared to linaclotide;   (c) carrying out HPLC on the sample comprising linaclotide to determine the relative retention time of the impurity compared to linaclotide;   (d) comparing the relative retention times determined in steps (b) and (c); where, if the relative retention times are substantially the same, the impurity is identified as being the same as the reference marker;   wherein the reference marker is selected from the group consisting of an oxidation product of linaclotide; a hydrolysis product of linaclotide or a formaldehyde imine product of linaclotide.   
     
     
         195 . A method for determining the amount of an impurity in a sample of linaclotide comprising:
 (a) adding a known amount of a reference sample to the linaclotide sample;   (b) subjecting the linaclotide sample to HPLC;   (c) identifying and measuring the area of an HPLC peak associated with the impurity;   (d) identifying and measuring the area of an HPLC peak associated with the reference standard;   (e) calculating the amount of the impurity in the linaclotide sample based on the results of step (c) and (d);   wherein the reference sample is selected from the group consisting of an oxidation product of linaclotide; a hydrolysis product of linaclotide or a formaldehyde imine product of linaclotide.   
     
     
         196 . A method for determining the amount of an impurity in a sample of linaclotide comprising:
 (a) providing a sample of linaclotide containing an unknown concentration of the impurity;   (b) providing a sample of a known concentration of the impurity;   (c) subjecting at least a portion of the linaclotide sample and at least a portion of the impurity sample to HPLC;   (d) measuring the area of the impurity peaks obtained from the linaclotide sample and the impurity sample; and   (e) calculating the amount of the impurity in the linaclotide sample based on the measurements of step (d);   wherein the impurity is selected from the group consisting of an oxidation product of linaclotide; a hydrolysis product of linaclotide or a formaldehyde imine product of linaclotide.   
     
     
         197 . The pharmaceutical composition according to any one of  claim 1 ,  2 ,  15  or  21 - 95 , the unit dosage form according to any one of  claim 3 ,  4 ,  16  or  96 - 98 , or the sealed container according to any one of  claim 5 ,  6 ,  17  or  238 , wherein a hydrolysis product having a structure of 
       
         
           
           
               
               
           
         
       
       comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         198 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 197 , wherein the hydrolysis product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         199 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 198 , wherein the hydrolysis product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         200 . The pharmaceutical composition according to any one of  claim 1 ,  2 ,  15  or  21 - 95 , the unit dosage form according to any one of  claim 3 ,  4 ,  16  or  96 - 98 , or the sealed container according to any one of  claim 5 ,  6 ,  17  or  238 , wherein a formaldehyde imine product having a structure of 
       
         
           
           
               
               
           
         
       
       comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         201 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 200 , wherein the formaldehyde imine product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         202 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 201 , wherein the formaldehyde imine product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         203 . The pharmaceutical composition according to any one of  claim 1 ,  2 ,  15  or  21 - 95 , the unit dosage form according to any one of  claim 3 ,  4 ,  16  or  96 - 98 , or the sealed container according to any one of  claim 5 ,  6 ,  17  or  238 , wherein a linaclotide oxidation product having a molecular weight of 1542.8 comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         204 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 203 , wherein the linaclotide oxidation product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         205 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 204 , wherein the linaclotide oxidation product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         206 . A pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the chromatographic purity of the linaclotide is greater than or equal to 90% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         207 . The pharmaceutical composition according to  claim 206 , wherein the chromatographic purity of the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95% or 96% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         208 . A unit dosage form of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the chromatographic purity of the linaclotide is greater than or equal to 90% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         209 . The unit dosage form according to  claim 208 , wherein the chromatographic purity of the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95% or 96% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         210 . A sealed container comprising a plurality of unit dosage forms of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient wherein the chromatographic purity of the linaclotide is greater than or equal to 90% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         211 . The sealed container according to  claim 210 , wherein the chromatographic purity of the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95% or 96% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         212 . A pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the assay value for linaclotide determined on a weight/weight basis is greater than or equal to 90% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         213 . The pharmaceutical composition according to  claim 212 , wherein the assay value for the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% after (a) 18 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         214 . A unit dosage form of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein the assay value for linaclotide determined on a weight/weight basis is greater than or equal to 90% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         215 . The unit dosage form according to  claim 214 , wherein the assay value for the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% after (a) 18 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         216 . A sealed container comprising a plurality of unit dosage forms of a pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient wherein the assay value for linaclotide in the unit dosage forms determined on a weight/weight basis is greater than or equal to 90% after (a) 18 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         217 . The sealed container according to  claim 216 , wherein the assay value for the linaclotide is greater than or equal to 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% after (a) 18 months of storage the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) 6 months of storage the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         218 . The unit dosage form according to any one of  claim 208 - 209  or  214 - 215  or the sealed container according to any one of  claim 210 - 211  or  216 - 217 , wherein each unit dosage form contains from 50 μg to 2 mg linaclotide. 
     
     
         219 . The unit dosage form or the sealed container according to  claim 218 , wherein each unit dosage form contains 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. 
     
     
         220 . The pharmaceutical composition according to either of  claim 206  or  207 , wherein the chromatographic purity of the linaclotide is greater than 90% after (a) 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         221 . The unit dosage form according to either of  claim 208  or  209 , wherein the chromatographic purity of the linaclotide is greater than 90% after (a) 24 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         222 . The sealed container according to either of  claim 210  or  211 , wherein the chromatographic purity of the linaclotide is greater than 90% after (a) a first 24 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) a first 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         223 . The pharmaceutical composition according to either of  claim 212  or  213 , wherein the assay value of the linaclotide is greater than 90% after (a) a first 24 months of storage of the pharmaceutical composition at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) a first 6 months of storage of the pharmaceutical composition at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         224 . The unit dosage form according to either of  claim 214  or  215 , wherein the assay value of the linaclotide is greater than 90% after (a) a first 24 months of storage of the unit dosage form at 25° C. at 60% relative humidity in a sealed container containing a desiccant or (b) a first 6 months of storage of the unit dosage form at 40° C. at 75% relative humidity in a sealed container containing a desiccant. 
     
     
         225 . The sealed container according to either of  claim 216  or  217 , wherein the assay value of the linaclotide is greater than 90% after (a) a first 24 months of storage of the sealed container containing a desiccant at 25° C. at 60% relative humidity or (b) a first 6 months of storage of the sealed container containing a desiccant at 40° C. at 75% relative humidity. 
     
     
         226 . The pharmaceutical composition according to any one of  claim 206 ,  207  or  223 , the unit dosage form according to either of  claim 208 ,  209  or  224 , or the sealed container according to any one of  claim 210 ,  211  or  225 , wherein a hydrolysis product having a structure of 
       
         
           
           
               
               
           
         
       
       comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         227 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 226 , wherein the hydrolysis product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         228 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 227 , wherein the hydrolysis product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         229 . The pharmaceutical composition according to any one of  claim 206 ,  207  or  223 , the unit dosage form according to any one of  claim 208 ,  209  or  224 , or the sealed container according to any one of  claim 210 ,  211  or  225 , wherein a formaldehyde imine product having a structure of 
       
         
           
           
               
               
           
         
       
       comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         230 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 229 , wherein the formaldehyde imine product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         231 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 230 , wherein the formaldehyde imine product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         232 . The pharmaceutical composition according to any one of  claim 206 ,  207  or  223 , the unit dosage form according to any one of  claim 208 ,  209  or  224 , or the sealed container according to any one of  claim 210 ,  211  or  225 , wherein a linaclotide oxidation product having a molecular weight of 1542.8 comprises less than 2% by weight compared to the weight of the linaclotide. 
     
     
         233 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 225 , wherein the linaclotide oxidation product comprises less than 1% by weight or less than 0.5% by weight compared to the weight of the linaclotide. 
     
     
         234 . The pharmaceutical composition, unit dosage form or sealed container according to  claim 233 , wherein the linaclotide oxidation product comprises less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         235 . A unit dosage form comprising the pharmaceutical composition according to any one of  claims 21 - 95 . 
     
     
         236 . The unit dosage form according to  claim 235 , wherein said unit dosage form contains 50 μg to 1 mg linaclotide. 
     
     
         237 . The unit dosage form according to  claim 236 , wherein said unit dosage form is a capsule or tablet and wherein each unit dosage form contains 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg or 600 μg linaclotide. 
     
     
         238 . A sealed container comprising a plurality of unit dosage forms according to any one of  claim 96 - 98  or  235 - 237 . 
     
     
         239 . A method for treating irritable bowel syndrome with constipation (IBS-c) in an adult patient in need thereof, comprising administering to the patient once daily an effective amount of the pharmaceutical composition according to any one of  claims 1 - 95 . 
     
     
         240 . The method according to  claim 239 , wherein said effective amount is 266 μg linaclotide. 
     
     
         241 . The method according to  claim 239 , wherein said effective amount is 133 μg linaclotide. 
     
     
         242 . The method according to any one of  claims 239 - 241 , wherein said treating is for a period of at least one week. 
     
     
         243 . The method according to  claim 242 , wherein said treating is for a period of at least four weeks. 
     
     
         244 . The method according to  claim 239 , wherein said treating improves at least one symptom selected from reduced abdominal pain, an increase in the number of complete spontaneous bowel movements (CSBM) in a week, an increase in the number of spontaneous bowel movements (SBM) in a week, improved stool consistency, reduced straining, reduced abdominal discomfort, reduced bloating or reduced IBS-c symptom severity. 
     
     
         245 . The method according to  claim 244 , wherein said treating improves at least one symptom selected from reduced abdominal pain, reduced abdominal discomfort or reduced bloating. 
     
     
         246 . The method according to  claim 244 , wherein said treating improves at least one symptom selected from an increase in the number of CSBM in a week, an increase in the number of spontaneous bowel movements SBM in a week, improved stool consistency or reduced straining. 
     
     
         247 . The method according to any one of  claims 239 - 246 , wherein a capsule or tablet comprises said pharmaceutical composition. 
     
     
         248 . A method for treating chronic constipation in an adult human patient in need thereof, comprising administering to the patient once daily an effective amount of the pharmaceutical composition according to any one of  claims 1 - 95 . 
     
     
         249 . The method according to  claim 248 , wherein said effective amount is 266 μg linaclotide. 
     
     
         250 . The method according to  claim 248 , wherein said effective amount is 133 μg linaclotide. 
     
     
         251 . The method according to any one of  claims 248 - 250 , wherein said treating is for a period of at least one week. 
     
     
         252 . The method according to  claim 251 , wherein said treating is for a period of at least four weeks. 
     
     
         253 . The method according to  claim 248 , wherein said treating improves at least one symptom selected from an increase in the number of complete spontaneous bowel movements (CSBM) in a week, an increase in the number of spontaneous bowel movements (SBM) in a week, improved stool consistency, reduced straining, reduced abdominal discomfort, reduced bloating or reduced severity of constipation. 
     
     
         254 . The method according to  claim 253 , wherein said treating improves at least one symptom selected from reduced abdominal discomfort, reduced bloating or reduced severity of constipation. 
     
     
         255 . The method according to  claim 253 , wherein said treating improves at least one symptom selected from an increase in the number of CSBM in a week, an increase in the number of spontaneous bowel movements SBM in a week, improved stool consistency or reduced straining. 
     
     
         256 . The method according to any one of  claims 248 - 255 , wherein a capsule or tablet comprises said pharmaceutical composition. 
     
     
         257 . A method for preparing a pharmaceutical composition comprising linaclotide or a salt thereof, the method comprising:
 (a) providing a solution comprising:
 (i) linaclotide or a pharmaceutically acceptable salt thereof 
 (ii) one or more of a cation selected from Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  or a sterically hindered primary amine; and, 
   (b) spray drying the solution to produce linaclotide microparticles.   
     
     
         258 . The method according to  claim 257 , wherein said solution is aqueous. 
     
     
         259 . The method according to  claim 257 , wherein said solution further comprises a binder or filler. 
     
     
         260 . A pharmaceutical composition comprising:
 linaclotide;   Ca 2+ ;   leucine; and   hydroxypropyl methylcellulose,   
       wherein the linaclotide is present in the pharmaceutical composition in an amount between 100 μg to 600 μg and the molar ratio of Ca 2+ :leucine:linaclotide is between 5-100:5-50:1. 
     
     
         261 . The pharmaceutical composition of  claim 260 , wherein the linaclotide is presented in an amount of 266 μg. 
     
     
         262 . The pharmaceutical composition of  claims 260 - 261 , wherein the Ca 2+  is provided as CaCl 2 . 
     
     
         263 . The pharmaceutical composition of  claims 262 , wherein the CaCl 2  is present in an amount of 1541 μg. 
     
     
         264 . The pharmaceutical composition of  claims 260 - 263 , wherein the leucine is present in an amount of 687 μg. 
     
     
         265 . The pharmaceutical composition of  claims 260 - 264 , wherein the hydroxypropyl methylcellulose is present in an amount of 700 μg. 
     
     
         266 . A pharmaceutical composition comprising coated beads, wherein the beads are coated with a coating solution comprising linaclotide. 
     
     
         267 . The pharmaceutical composition of  claim 266 , wherein the coating solution comprises:
 linaclotide;   Ca 2+ ;   leucine; and   hydroxypropyl methylcellulose,   
       wherein the linaclotide is present in the pharmaceutical composition in an amount between 100 μg to 600 μg and the molar ratio the of Ca 2+ :leucine:linaclotide is between 5-100:5-50:1. 
     
     
         268 . The pharmaceutical composition of  claim 267 , wherein the linaclotide is present in an amount of 266 μg. 
     
     
         269 . The pharmaceutical composition of  claims 267 - 268 , wherein the Ca 2+  is provided as CaCl 2 . 
     
     
         270 . The pharmaceutical composition of  claim 269 , wherein the CaCl 2  is present in an amount of 1541 μg. 
     
     
         271 . The pharmaceutical composition of  claims 267 - 270 , wherein the leucine is present in an amount of 687 μg. 
     
     
         272 . The pharmaceutical composition of  claims 267 - 271 , wherein the hydroxypropyl methylcellulose is present in an amount of 700 μg. 
     
     
         273 . The pharmaceutical composition of  claims 267 - 272 , wherein the beads comprise microcrystalline cellulose.