Methods and compositions for delivering peptides

Abstract

Methods are provided for purifying peptides and proteins by incorporating the peptide or protein into a diketopiperazine or competitive complexing agent to facilitate removal one or more impurities, from the peptide or protein. Formulations and methods also are provided for the improved transport of active agents across biological membranes, resulting for example in a rapid increase in blood agent concentration. The formulations include microparticles formed of (i) the active agent, which may be charged or neutral, and (ii) a transport enhancer that masks the charge of the agent and/or that forms hydrogen bonds with the target biological membrane in order to facilitate transport. In one embodiment, insulin is administered via the pulmonary delivery of microparticles comprising fumaryl diketopiperazine and insulin in its biologically active form. This method of delivering insulin results in a rapid increase in blood insulin concentration that is comparable to the increase resulting from intravenous delivery.

What is claimed is: 
     
         1 . A microparticle composition comprising microparticles containing a diketopiperazine and at least one of a peptide and a protein, wherein the microparticle composition is prepared by a method comprising forming at least a portion of the microparticles containing the diketopiperazine in the absence of at least one of the peptide and the protein. 
     
     
         2 . The composition of  claim 1 , wherein the microparticles containing the diketopiperazine comprise fumaryl diketopiperazine. 
     
     
         3 . The composition of  claim 1 , wherein the peptide or the protein is an insulin. 
     
     
         4 . A method of delivering an insulin to a patient in need thereof, comprising administering the composition of  claim 3  to the patient. 
     
     
         5 . A composition comprising microparticles of a diketopiperazine and at least one of a peptide and a protein, wherein the composition comprising microparticles of the diketopiperazine is prepared by a method comprising forming microparticles of the diketopiperazine from an aqueous solution that does not include at least one of the peptide and the protein. 
     
     
         6 . The composition of  claim 5 , wherein the diketopiperazine is fumaryl diketopiperazine. 
     
     
         7 . The composition of  claim 5 , wherein the peptide or the protein comprises an insulin. 
     
     
         8 . A method of treating diabetes, comprising administering a composition of  claim 7  to a diabetic patient in need of treatment. 
     
     
         9 . Peptide or protein-loaded diketopiperazine microparticles prepared by a process comprising adding the peptide or protein to a suspension comprising microparticles of a diketopiperazine. 
     
     
         10 . The peptide or protein-loaded microparticles of  claim 9 , wherein the microparticles comprise fumaryl diketopiperazine. 
     
     
         11 . The peptide or protein-loaded microparticles of  claim 9 , wherein the microparticles comprise an insulin. 
     
     
         12 . The peptide or protein-loaded microparticles of  claim 9 , wherein solvent is removed by lyophilization from the suspension comprising the peptide or protein and microparticles of the diketopiperazine. 
     
     
         13 . A method of pulmonary delivery of a protein or a peptide to a mammal in need thereof, the method comprising administering the peptide or protein-loaded microparticles of  claim 9  to the mammal by inhalation.