Compositions and methods for enhanced mucosal delivery of parathyroid hormone

Abstract

Pharmaceutical compositions and methods are described comprising at least a parathyroid hormone peptide (PTH) preferably PTH 1-34 and one or more mucosal delivery-enhancing agents for enhanced nasal mucosal delivery of PTH, for treating or preventing osteoporosis or osteopenia in a mammalian subject, preferably a human.

1 . A pharmaceutical composition for intranasal delivery comprising an aqueous mixture of a PTH, a cyclodextrin, a phospholipid, ethylene diamine tetraacetic acid, a polyol, and a preservative, wherein the composition has at least 6% bioavailability of the PTH upon intranasal administration of the composition to a human. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the composition has at least 8% bioavailability of the PTH upon intranasal administration of the composition to a human. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the PTH is selected from SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, or methyl-β-cyclodextrin. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the cyclodextrin is methyl-β-cyclodextrin at a concentration of 4.5% (w/w). 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the phospholipid is didecanoylphosphatidylcholine (DDPC). 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the polyol is selected from sucrose, mannitol, sorbitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, trehalose, D-galactose, lactulose, cellobiose, and gentibiose. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the preservative is chlorobutanol or sodium benzoate. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the composition has a pH of from about 3 to about 6. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the composition is in the form of liquid droplets. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the liquid droplets have an average volume-mean particle size (Dv,50) of from about 1 micron to about 1000 microns. 
     
     
         12 . The pharmaceutical composition of  claim 10 , where in the liquid droplets have an average volume-mean particle size (Dv,50) of from about 5 microns to about 500 microns. 
     
     
         13 . The pharmaceutical composition of  claim 10 , where in the liquid droplets have an average volume-mean particle size (Dv,50) of from about 10 microns to about 100 microns. 
     
     
         14 . A method for treating osteoporosis or osteopenia in a human subject comprising administering intranasally to the human a pharmaceutical composition of  claim 1 . 
     
     
         15 . The method of  claim 14 , wherein upon intranasal administration to the human subject the PTH has a maximum serum concentration, Cmax, of about 100 pg/mL or greater. 
     
     
         16 . The method of  claim 14 , wherein the dose of PTH administered to the human subject is from about 1 microgram to about 2000 microgram. 
     
     
         17 . A method for preventing the onset of osteoporosis or osteopenia in a human subject comprising administering intranasally to the human a pharmaceutical composition of  claim 1 .