Heat-stable dry powder pharmaceutical compositions and methods

Abstract

Disclosed herein are heat-stable dry powders which include peptides or protein such as oxytocin for use as a pharmaceutical composition. The composition is highly stable at increased temperatures and relatively high humid environments, and are intended for storage at room temperature with an improved shelf-life. In particular, the dry powders are intended for inhalation, however, other routes of administration can be used when reconstituted in solution.

What is claimed: 
     
         1 . A dry powder pharmaceutical formulation comprising a peptide, a protein, or a derivative or analog of said peptide or protein; a citrate or tartrate, a cationic salt, an amino acid, and/or a pharmaceutically acceptable carrier or excipient. 
     
     
         2 . The dry powder pharmaceutical formulation of  claim 1 , wherein the peptide, protein, derivative, or analog thereof is oxytocin, an oxytocin derivative or an oxytocin analog. 
     
     
         3 . The dry powder pharmaceutical formulation of  claim 1 , wherein the citrate is sodium citrate, or zinc citrate. 
     
     
         4 . The dry powder pharmaceutical formulation of  claim 1 , wherein the cationic salt is a divalent cation salt which is zinc chloride, zinc citrate, zinc acetate, magnesium chloride or calcium chloride. 
     
     
         5 . The dry powder pharmaceutical formulation of  claim 1 , wherein the pharmaceutically acceptable carrier or excipient is a sugar selected from mannose, mannitol, trehalose, or sorbitol. 
     
     
         6 . The dry powder pharmaceutical formulation of  claim 1 , wherein the pharmaceutically acceptable carrier or excipient is polyvinylpyrrolidone, polyethylene glycol, or a diketopiperazine. 
     
     
         7 . The dry powder pharmaceutical formulation of  claim 6 , wherein the diketopiperazine is fumaryl diketopiperazine or succinyl diketopiperazine. 
     
     
         8 . The dry powder pharmaceutical formulation of  claim 1 , wherein the citrate salt is in an amount ranging from 100 to 20 equivalents per mole of the oxytocin, the oxytocin analog or derivative thereof. 
     
     
         9 . The dry powder pharmaceutical formulation of  claim 1 , wherein the cationic salt is in an amount ranging from 50 to 5 equivalents per mole of oxytocin in the composition. 
     
     
         10 . The dry powder pharmaceutical formulation of  claim 1 , wherein said peptide is an endocrine hormone, a growth factor, or a nociceptive peptide. 
     
     
         11 . The dry powder pharmaceutical formulation of  claim 10 , wherein said endocrine hormone is insulin, parathyroid hormone, calcitonin, glucagon, glucagon-like peptide 1, oxyntomodulin, an analog or active fragment of said endocrine hormone. 
     
     
         12 . The dry powder pharmaceutical formulation of  claim 10 , wherein said amino acid is leucine, isoleucine, trileucine, cysteine, lysine, glycine, arginine, methionine, or histidine. 
     
     
         13 . A method of making a dry powder formulation comprising spray-drying a solution in a nitrogen gas chamber, comprising a peptide, protein, fragments thereof and/or analogs thereof, wherein the dry powder formulation comprises a mixture of the peptide, protein, fragments thereof and/or analogs thereof; a citrate or tartrate and a cationic salt at a pH ranging from pH 4.5 to pH 6.5, and wherein the cationic salt is a divalent cationic salt. 
     
     
         14 . The method of  claim 13 , wherein said dry powder formulation comprises oxytocin. 
     
     
         15 . The method of  claim 13 , wherein the citrate is sodium citrate. 
     
     
         16 . The method of  claim 13 , further comprising an amino acid or a sugar. 
     
     
         17 . The method of  claim 16 , wherein the amino acid is leucine, isoleucine, trileucine, cysteine, lysine, glycine, arginine, methionine, or histidine. 
     
     
         18 . The method of  claim 16 , wherein the sugar is trehalose or mannitol. 
     
     
         19 . The method of  claim 13 , wherein the tartrate is sodium tartrate. 
     
     
         20 . A pharmaceutical dry powder formulation for inhalation comprising oxytocin, an analog of oxytocin or a derivative of oxytocin; sodium citrate, zinc chloride and a pharmaceutically acceptable excipient. 
     
     
         21 . The pharmaceutical dry powder formulation of  claim 20 , wherein the sodium citrate is greater than 0.5% (w/w); greater than 5% (w/w); greater than 10% (w/w), or greater than 20% (w/w) in the dry powder formulation. 
     
     
         22 . The method of  claim 13 , wherein the spray-drying comprises atomizing the flow of solution into a drying nitrogen gas flow at an inlet temperature of about 120° C. to 150° C. 
     
     
         23 . The method of  claim 17  wherein the amino acid is isoleucine.