COMPOSITIONS AND METHODS FOR ENHANCED MUCOSAL DELIVERY OF PARATHYROID HORMONE
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 .