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 formulation for delivery of PTH across a mucosal cellular layer comprising an aqueous mixture of PTH, a cyclodextrin, and a two-chain phospholipid having a first chain and a second chain, wherein the formulation consists of droplets, of which droplets less than 10% are less than 10 microns in diameter.  
     
     
         2 . The formulation of  claim 1 , wherein the PTH is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.  
     
     
         3 . The formulation of  claim 1 , wherein the first chain and the second chain are each 12 or more carbon atoms in length.  
     
     
         4 . The formulation of  claim 1 , wherein the first chain and the second chain are each 14 or more carbon atoms in length.  
     
     
         5 . The formulation of  claim 1 , wherein the first chain and the second chain are each 16 or more carbon atoms in length.  
     
     
         6 . The formulation of  claim 1 , wherein the first chain is 12 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         7 . The formulation of  claim 1 , wherein the first chain is 14 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         8 . The formulation of  claim 1 , wherein the first chain is 16 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         9 . The formulation of  claim 1 , wherein the two-chain phospholipid is didecanoylphosphatidylcholine.  
     
     
         10 . The formulation of  claim 1 , wherein the cyclodextrin is selected from the group consisting of hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and methyl-β-cyclodextrin.  
     
     
         11 . The formulation of  claim 10 , wherein the cyclodextrin is methyl-β-cyclodextrin.  
     
     
         12 . The formulation of  claim 1 , further comprising a chelating agent selected from the group consisting of ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid.  
     
     
         13 . The formulation of  claim 1 , further comprising one or more polyols.  
     
     
         14 . The formulation of  claim 13 , wherein the one or more polyols are selected from the group consisting of sucrose, mannitol, sorbitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, trehalose, D-galactose, lactulose, cellobiose, gentibiose, glycerin, and polyethylene glycol.  
     
     
         15 . The formulation of  claim 14 , wherein the one or more polyols are lactose and sorbitol.  
     
     
         16 . The formulation of  claim 1 , further comprising one or more surface-active agents.  
     
     
         17 . The formulation of  claim 16 , wherein the surface-active agent is selected from the group consisting of nonionic polyoxyethylene ether, bile salts, sodium glycocholate, deoxycholate, fusidic acid and its derivatives, sodium taurodihydrofusidate, polysorbate 80, polysorbate 20, polyethylene glycol, cetyl alcohol, polyvinylpyrolidone, polyvinyl alcohol, lanolin alcohol, and sorbitan monooleate.  
     
     
         18 . The formulation of  claim 1 , wherein the mixture further comprises a preservative selected from the group consisting of chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, sodium benzoate, sorbic acid, phenol, ortho-, meta-, and paracresol.  
     
     
         19 . The formulation of  claim 1 , wherein the formulation has a pH of about 3 to about 6.  
     
     
         20 . The formulation of  claim 1 , wherein the mixture further comprises a molecule capable of blocking the activity of PTH in chondrocytes.  
     
     
         21 . A formulation for the delivery of PTH across a mucosal cellular layer comprising an aqueus mixture of PTH, a cyclodextrin, a two-chain phospholipid having a first chain and a second chain, a chelating agent, a buffering agent, and water, the formulation consisting of droplets, of which droplets less than 10% are less than 10 microns in diameter.  
     
     
         22 . The formulation of  claim 21 , wherein the mucosal cellular layer is intranasal.  
     
     
         23 . The formulation of  claim 21 , wherein the PTH molecule is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3.  
     
     
         24 . The formulation of  claim 21 , wherein the cyclodextrin is methyl-β-cyclodextrin.  
     
     
         25 . The formulation of  claim 21 , wherein the first chain and the second chain are each 12 or more carbon atoms in length.  
     
     
         26 . The formulation of  claim 21 , wherein the first chain and the second chain are each 14 or more carbon atoms in length.  
     
     
         27 . The formulation of  claim 21 , wherein the first chain and the second chain are each 16 or more carbon atoms in length.  
     
     
         28 . The formulation of  claim 21 , wherein the first chain is 12 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         29 . The formulation of  claim 21 , wherein the first chain is 14 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         30 . The formulation of  claim 21 , wherein the first chain is 16 or more carbon atoms in length and the second chain is 18 or more carbon atoms in length.  
     
     
         31 . The formulation of  claim 21 , wherein the two-chain phospholipid is didecanoylphosphatidylcholine.  
     
     
         32 . The formulation of  claim 21 , wherein the chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid.  
     
     
         33 . The formulation of  claim 21 , wherein the buffering agent is selected from the group consisting of citrate, acetate, succinic, and phosphate.  
     
     
         34 . The formulation of  claim 21 , wherein the formulation has a pH of about 3 to about 6.  
     
     
         35 . The formulation of  claim 21 , further comprising a preservative selected from the group consisting of chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, sodium benzoate, sorbic acid, phenol, cresols, ortho-cresol, meta-cresol, and para-cresol.