Formulations of guanylate cyclase c agonists and methods of use

Abstract

The invention provides low-dose formulations of guanylate cyclase-C (“GCC”) agonist peptides and methods for their use. The formulations of the invention can be administered either alone or in combination with one or more additional therapeutic agents, preferably an inhibitor of cGMP-dependent phosphodiesterase or a laxative.

1 . An oral dosage formulation comprising:
 a. a Guanylate Cyclase-C(GCC) agonist peptide in a per unit dose of 3.0 mg or 6.0 mg, wherein the GCC agonist peptide consists of an amino acid sequence of SEQ ID NO: 1 as a (4,12; 7,15) bicycle;   b. an inert low moisture carrier consisting of microcrystalline cellulose, wherein the microcrystalline cellulose has a moisture content of not more than 1.5% by weight of the microcrystalline cellulose; and   c. a lubricant consisting of magnesium stearate.   
     
     
         2 . The oral dosage formulation of  claim 1 , wherein the concentration of microcrystalline cellulose is at least 90% by weight of the formulation. 
     
     
         3 . The oral dosage formulation of  claim 2 , wherein the concentration of microcrystalline cellulose is at least 95% by weight of the formulation. 
     
     
         4 . The oral dosage formulation of  claim 1 , wherein the concentration of magnesium stearate is about 0.25% by weight of the formulation. 
     
     
         5 . The oral dosage formulation of  claim 1 , wherein the microcrystalline cellulose has a bulk density of 0.28 to 0.34 g/cc. 
     
     
         6 . The oral dosage formulation of  claim 1 , wherein the microcrystalline cellulose has a particle size of 50 to 200 microns. 
     
     
         7 . The oral dosage formulation of  claim 6 , wherein the microcrystalline cellulose has a particle size of 75 to 150 microns. 
     
     
         8 . The oral dosage formulation of  claim 1 , wherein the formulation is in the form of a capsule or tablet. 
     
     
         9 . The oral dosage formulation of  claim 8 , wherein the formulation is in the form of a tablet. 
     
     
         10 . The oral dosage formulation of  claim 1 , wherein the GCC agonist peptide per unit dose is 3.0 mg. 
     
     
         11 . The oral dosage formulation of  claim 1 , wherein the GCC agonist peptide per unit dose is 6.0 mg. 
     
     
         12 . An oral dosage formulation comprising a composition consisting essentially of of 3.0 or 6.0 mg of a [4,12; 7,15] bicyclic GCC agonist peptide with an amino acid sequence of SEQ ID NO: 1, low-moisture microcrystalline cellulose, and magnesium stearate. 
     
     
         13 . The oral dosage formulation of  claim 12 , wherein the magnesium stearate is 0.25% (w/w). 
     
     
         14 . The oral dosage formulation of  claim 12 , wherein the oral dosage formulation is a powder, granule, sachet, troche, tablet, or capsule. 
     
     
         15 . The oral dosage formulation of  claim 12 , wherein the oral dosage formulation is a capsule or tablet. 
     
     
         16 . The oral dosage formulation of  claim 15 , wherein the capsule or tablet is in a blister pack or strip. 
     
     
         17 . The oral dosage formulation of  claim 12 , wherein the low-moisture microcrystalline cellulose is at least 96% (w/w). 
     
     
         18 . The oral dosage formulation of  claim 12 , wherein the low-moisture microcrystalline cellulose has a particle size of from 50 to 900 microns.