Stable Solid Formulation of 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 - 273 . (canceled) 
     
     
         274 . A pharmaceutical composition comprising linaclotide and a pharmaceutically acceptable excipient, wherein
 (i) 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;   (ii) 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;   (iii) 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 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; or   (iv) 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.   
     
     
         275 . 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, or a decrease in the amount of a linaclotide hydrolysis product relative to the amount of linaclotide. 
     
     
         276 . The pharmaceutical composition of  claim 275 , wherein said agent is Mg 2+ , Ca 2+ , Zn 2+ , Mn 2+ , K + , Na +  or Al 3+  in which 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. 
     
     
         277 . The pharmaceutical composition of  claim 275 , wherein said agent is a sterically hindered primary amine selected from an amino acid, polymeric amine, or a compound of 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. 
     
     
         278 . The pharmaceutical composition of  claim 277 , wherein the sterically hindered primary amine is a naturally-occurring amino acid selected from the group consisting of histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan and valine. 
     
     
         279 . 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. 
     
     
         280 . The pharmaceutical composition of  claim 279 , 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. 
     
     
         281 . The pharmaceutical composition of  claim 279 , wherein said sterically hindered primary amine is selected from an amino acid, polymeric amine, or a compound of 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. 
     
     
         282 . The pharmaceutical composition of  claim 281 , wherein the sterically hindered primary amine is a naturally-occurring amino acid selected from the group consisting of histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan and valine. 
     
     
         283 . The pharmaceutical composition of  claim 279  further comprising one or more of an antioxidant; a pharmaceutically acceptable binder; a pharmaceutically acceptable filler; a pharmaceutically acceptable glidant; lubricant or additive that acts as both a glidant and lubricant. 
     
     
         284 . The pharmaceutical composition of  claim 283 , wherein the pharmaceutically acceptable binder is a cellulose ether selected from methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose; and the pharmaceutically acceptable filler is a cellulose filler selected from microfine cellulose and microcrystalline cellulose. 
     
     
         285 . The pharmaceutical composition of  claim 283 , wherein pharmaceutical composition comprises a pharmaceutically acceptable filler and the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:25 and 1:2,500 or between 1:100 and 1:1000. 
     
     
         286 . The pharmaceutical composition of  claim 279 , wherein the sterically hindered amine is leucine and the molar ratio of leucine to linaclotide is at least 10:1 or at least 30:1. 
     
     
         287 . The pharmaceutical composition of  claim 286 , wherein the cation is Ca 2+  and the molar ratio of Ca 2+  to leucine is at least 1:1 or at least 1.5:1. 
     
     
         288 . The pharmaceutical composition of  claim 279 , wherein the molar ratio of cation:sterically hindered primary amine:linaclotide is between 40-100:20-50:1; or selected from 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 and 5:5:1. 
     
     
         289 . A unit dosage form comprising the pharmaceutical composition according to  claim 279 , wherein each unit dosage form comprises between 50 μg to 1 mg of linaclotide, or selected from 67.5 μg, 100 μg, 133 μg, 150 μg, 200 μg, 266 μg, 300 μg, 400 μg, 500 μg and 600 μg of linaclotide. 
     
     
         290 . A method for preparing a pharmaceutical composition comprising linaclotide or a salt thereof, the method comprising:
 (a) providing an aqueous solution comprising:
 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.   
     
     
         291 . The method of  claim 290 , 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. 
     
     
         292 . The method of  claim 290 , wherein said agent is a sterically hindered primary amine selected from an amino acid, polymeric amine, or a compound of 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. 
     
     
         293 . The method of  claim 292 , wherein the sterically hindered primary amine is a naturally-occurring amino acid selected from the group consisting of histidine, phenylalanine, alanine, glutamic acid, aspartic acid, glutamine, leucine, methionine, asparagine, tyrosine, threonine, isoleucine, tryptophan and valine. 
     
     
         294 . The method of  claim 290 , 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. 
     
     
         295 . The method of  claim 290 , wherein the binder is a cellulose ether selected from methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, and the filler is microfine cellulose or microcrystalline cellulose. 
     
     
         296 . The method of  claim 290 , wherein the weight ratio of linaclotide to pharmaceutically acceptable filler is between 1:100 and 1:1000 and the molar ratio of cation:sterically hindered primary amine:linaclotide is 40-100:20-30:1. 
     
     
         297 . The method of  claim 290 , wherein the method further comprises (c) applying a coating to the linaclotide-coated filler. 
     
     
         298 . The method of  claim 290 , further comprising tableting or encapsulating the linaclotide-coated filler in a tablet or capsule, wherein each capsule or tablet contains between 50 μg to 1 mg of linaclotide or selected from 67.5 μg, 133 μg, 150 μg, 266 μg and 300 μg of linaclotide. 
     
     
         299 . 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  claim 279 . 
     
     
         300 . The method of  claim 299 , wherein said irritable bowel syndrome is selected from constipation-predominant irritable bowel syndrome or alternating irritable bowel syndrome and said constipation is selected from chronic constipation, idiopathic constipation, post-operative ileus, or constipation caused by opiate use. 
     
     
         301 . The method of  claim 300 , 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, reduced IBS-c symptom severity or reduced severity of constipation. 
     
     
         302 . The method of  claim 299 , wherein the effective amount is between 50 μg to 1 mg linaclotide or selected from 67.5 μg, 133 μg, 150 μg, 266 μg and 300 μg of linaclotide. 
     
     
         303 . A composition that comprises
 at least 10%, at least 20%, at least 30%, at least 40% or at least 50% by weight a hydrolysis product of linaclotide; or   at least 10%, at least 20%, at least 30%, at least 40% or at least 50% by weight an oxidation product of linaclotide.   
     
     
         304 . A pharmaceutical composition according to  claim 275 , wherein a hydrolysis product having a structure of 
       
         
           
           
               
               
           
         
       
       comprises less than 2% by weight, less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         305 . A pharmaceutical composition according to  claim 275 , wherein a linaclotide oxidation product having a molecular weight of 1542.8 comprises less than 2% by weight, less than 0.1% by weight or less than 0.05% by weight compared to the weight of the linaclotide. 
     
     
         306 . A pharmaceutical composition comprising:
 linaclotide;   Ca 2+ ;   leucine; and   hydroxypropyl methylcellulose,   
       wherein the molar ratio of Ca 2+ :leucine:linaclotide is between 5-100:5-50:1. 
     
     
         307 . A unit dosage form comprising the pharmaceutical composition of  claim 306 , wherein the linaclotide is present in the pharmaceutical composition in an amount between 100 μg to 600 μg. 
     
     
         308 . A pharmaceutical composition comprising coated beads, wherein the beads are coated with a coating solution comprising linaclotide. 
     
     
         309 . The pharmaceutical composition of  claim 308 , wherein the coating solution comprises:
 linaclotide;   Ca 2+ ;   leucine; and   hydroxypropyl methylcellulose,   
       wherein the molar ratio the of Ca 2+ :leucine:linaclotide is between 5-100:5-50:1. 
     
     
         310 . A unit dosage form comprising the pharmaceutical composition of  claim 308 , wherein the linaclotide is present in the pharmaceutical composition in an amount between 100 μg to 600 μg.