Chimeric natriuretic peptide compositions and methods of preparation

Abstract

Therapeutic compositions containing chimeric natriuretic peptides for treating chronic kidney disease alone, heart failure alone, or chronic kidney disease with concomitant heart failure are described. The therapeutic compositions have enhanced stability characteristics to facilitate storage and delivery by provisioning apparatuses under conditions of elevated temperature and mechanical stress. Methods for increasing the stability of therapeutic compositions containing chimeric natriuretic peptides are further described.

We claim: 
     
         1 . A protein composition, comprising:
 a peptide selected from the group consisting of CD-NP, CU-NP, B-CDNP, CDNP-B, and variants thereof;   meta-cresol;   water; and   one or more buffers selected from the group consisting of tris(hydroxymethyl)aminomethane and a phosphate buffer.   
     
     
         2 . The protein composition of  claim 1 , wherein the peptide is selected from the group consisting of SEQ ID No.'s 1, 4 and 8-11. 
     
     
         3 . The protein composition of  claim 1 , wherein the concentration of tris(hydroxymethyl)aminomethane is from about 5 to about 100 mM. 
     
     
         4 . The protein composition of  claim 1 , wherein the protein composition has a pH from about 6.5 to about 7.6. 
     
     
         5 . The protein composition of  claim 4 , wherein the protein composition has a temperature of 25° C. 
     
     
         6 . The protein composition of  claim 1 , wherein the protein composition further comprises glycerol from about 0.1 to about 5% by weight of the protein composition. 
     
     
         7 . The protein composition of  claim 1 , wherein the protein composition comprises tris(hydroxymethyl)aminomethane at a concentration of about 50 mM, meta-cresol at a concentration of about 0.25% by weight, and further comprises about 1.6% glycerol by weight and has a pH of about 7.3. 
     
     
         8 . The protein composition of  claim 1 , wherein the protein composition comprises meta-cresol at a concentration from about 0.15 to about 0.315% by weight; the peptide at a concentration from about 0.05 to about 20 mg/mL; sodium chloride at a concentration from about 0.2 to about 10 grams per liter; and one or more buffers selected from tris(hydroxymethyl)aminomethane at a concentration from about 5 to about 100 mM and phosphate buffer at a concentration from about 0.2 to about 10 grams per liter. 
     
     
         9 . The protein composition of  claim 1 , wherein the peptide comprises from about 20 to about 42 amino acid residues and wherein about 35% or more of the amino acid residues comprising the peptide are selected from the group consisting of valine, isoleucine, leucine, methionine, proline, phenylalanine, proline and tryptophan. 
     
     
         10 . A method for stabilizing a peptide selected from the group consisting of CD-NP, CU-NP, B-CDNP, CDNP-B, and variants thereof in solution, comprising the steps of: dissolving an initial mass of the peptide in a buffer composition comprising water; meta-cresol; and one or more buffers selected from the group consisting of tris(hydroxymethyl)aminomethane and a phosphate buffer to form a protein composition; and
 storing the protein composition in a container at a temperature from about 25 to about 45° C. for a period of about 3 days or more.   
     
     
         11 . The method of  claim 10 , wherein the peptide is selected from the group consisting of SEQ ID No.'s 1, 4 and 8-11. 
     
     
         12 . The method of  claim 10 , wherein the protein composition comprises meta-cresol at a concentration from about 0.15 to about 0.315% by weight; the peptide at a concentration from about 0.05 to about 20 mg/mL; sodium chloride at a concentration from about 0.2 to about 10 grams per liter; and one or more buffers selected from tris(hydroxymethyl)aminomethane at a concentration from about 5 to about 100 mM and phosphate buffer at a concentration from about 0.2 to about 10 grams per liter. 
     
     
         13 . The method of  claim 10 , wherein the change in relative purity of the peptide in the protein composition after storage is about 15% or less. 
     
     
         14 . The method of  claim 10 , wherein the purity of peptide recoverable from the protein composition after storage is at least about 80% pure or higher. 
     
     
         15 . The method of  claim 10 , wherein the percent recovery of the protein composition after storage is at least about 80% of the initial mass of the peptide dissolved in the buffer composition. 
     
     
         16 . The method of  claim 10 , wherein about 30% or more of the amino acid residues comprising the peptide are selected from the group consisting of valine, isoleucine, leucine, methionine, phenylalanine, proline and tryptophan. 
     
     
         17 . The method of  claim 10 , wherein the protein composition has a pH from about 6.5 to about 7.6. 
     
     
         18 . The method of  claim 17 , wherein the protein composition has a temperature of 25° C. 
     
     
         19 . The method of  claim 10 , wherein the protein composition further comprises glycerol at a concentration from about 0.1 to about 5% glycerol by weight of the protein composition. 
     
     
         20 . A method for administering a protein composition to a patient, comprising the steps of:
 storing the protein composition in a container at a temperature from about 25 to about 45° C. for a period of at least about 3 days, the protein composition having an initial mass of the peptide; and   administering the protein composition to the patient using a pump or a provisioning apparatus,   wherein the percent recovery of the peptide from the protein composition administered is at least about 80% of the initial mass of the peptide dissolved in the buffer composition, and the protein composition comprises meta-cresol at a concentration from about 0.15 to about 0.315% by weight; the peptide at a concentration from about 0.05 to about 20 mg/mL; sodium chloride at a concentration from about 0.2 to about 10 grams per liter; and one or more buffers selected from tris(hydroxymethyl)aminomethane at a concentration from about 5 to about 100 mM and phosphate buffer at a concentration from about 0.2 to about 10 grams per liter.   
     
     
         21 . The method of  claim 20 , wherein at least about 80% or higher of the initial mass of the peptide dissolved in the buffer composition is present in the administered protein composition. 
     
     
         22 . The method of  claim 20 , wherein the change in relative purity of the peptide in the administered protein composition is about 15% or less after storage.