Intranasal dhe for the treatment of headache

Abstract

Presented herein are powder formulations comprising dihydroergotamine (DHE), or a pharmaceutically acceptable salt thereof. In addition to such formulations, also presented herein are methods comprising intranasally administering powder formulations comprising dihydroergotamine, or a pharmaceutically acceptable salt thereof. The presented methods can be used for treating headache, for example, for rapid onset treatment of headache, including migraine, e.g. acute treatment of migraine with or without aura.

What is claimed is: 
     
         1 . A method, comprising:
 intranasally administering to a human a powder formulation comprising: a) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof, wherein the total dose of DHE administered is 0.1-10.0 mg; b) a microcrystalline cellulose component comprising at least 15% of the total weight of the formulation.   
     
     
         2 . The method of  claim 1 , further comprising at least one of the following:
 a) wherein a mean T max  of DHE after administration of the powder formulation is about 1 to about 120 minutes;   b) wherein a (AUC 0-30 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 2.5%;   c) wherein a (AUC 0-30 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 2.5% to 25%;   d) wherein a (AUC 0-60 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 10%;   e) wherein a (AUC 0-60 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 10% to 45%;   f) wherein a (AUC 0-120 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 25%;   g) wherein a (AUC 0-120 min /AUC 0-inf )×100% of DHE after administration of the powder formulation is greater than 25% to 75%;   h) wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a (AUC 0-30 min /AUC 0-inf )×100% is greater than 10%;   i) wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a (AUC 0-60 min /AUC 0-inf )×100% is greater than 20%;   j) wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a (AUC 0-120 min /AUC 0-inf )×100% is greater than 40%.   
     
     
         3 . The method of any of  claims 1 - 2 , wherein the microcrystalline cellulose component has a mean particle size diameter of about 100 μm or less. 
     
     
         4 . The method of  claim 3 , wherein the microcrystalline cellulose component comprises a first microcrystalline cellulose portion with a mean particle diameter size of about 30 μm or less, and a second microcrystalline cellulose portion with a mean particle size diameter of about 30 to about 100 μm. 
     
     
         5 . The method of  claim 4 , wherein the first microcrystalline cellulose portion has a mean particle diameter size of about 15 to about 30 μm and the second microcrystalline cellulose portion has a mean particle diameter size of about 45 to about 65 μm. 
     
     
         6 . The method of  claim 5 , wherein the microcrystalline cellulose component is substantially free of particles with a mean particle diameter size of about 31 to about 44 μm. 
     
     
         7 . The method of  claim 6 , wherein the first microcrystalline cellulose portion has a mean particle size of about 20 μm and the second microcrystalline cellulose portion has a mean particle size diameter of about 50-55 μm 
     
     
         8 . The method of  claim 7 , wherein the powder formulation has an angle of repose 530 or less. 
     
     
         9 . The method of any of  claims 4 - 8 , wherein the first microcrystalline cellulose portion is about 5% to about 90% of the total weight of the powder formulation, and the second microcrystalline portion is about 10% of the total weight of the powder formulation. 
     
     
         10 . The method of  claim 9 , wherein the microcrystalline cellulose component comprises about 15% to about 99% of the total weight of the powder formulation. 
     
     
         11 . The method of  claim 10 , wherein the first microcrystalline cellulose component comprises about 70% to about 90% of the total weight of the powder formulation. 
     
     
         12 . The method of any one of  claims 1 - 11 , wherein the powder formulation further comprises a fluidizing agent. 
     
     
         13 . The method of  claim 12 , wherein the fluidizing agent is tribasic calcium phosphate. 
     
     
         14 . The method of  claim 13 , wherein the tribasic calcium phosphate is about 0.5% to about 1.5% of the total weight of the powder formulation. 
     
     
         15 . The method of  claim 14 , wherein the tribasic calcium phosphate is about 0.8% of the total weight of the powder formulation. 
     
     
         16 . The method of any of  claims 1 - 15 , wherein the powder formulation further comprises at least one of the following: an adenosine receptor antagonist, a phosphodiesterase inhibitor, an acetylcholinesterase inhibitor, a vasodilator, xanthine, caffeine, paraxanthine, theobromine, theophylline. 
     
     
         17 . The method of  claim 16 , wherein the powder formulation comprises caffeine. 
     
     
         18 . The method of  claim 17 , wherein the powder formulation comprises about 1% to 60% caffeine. 
     
     
         19 . The method of  claim 18 , wherein the powder formulation comprises about 5% to 10% caffeine. 
     
     
         20 . The method of any of  claims 17 - 19 , wherein the caffeine is anhydrous caffeine. 
     
     
         21 . The method of any of  claims 1 - 20 , wherein a total dose of the powder formulation administered is about 0.1 to about 25 mg. 
     
     
         22 . The method of  claim 21 , wherein the total dose of the powder formulation administered is about 25 mg. 
     
     
         23 . The method of any of  claims 1 - 22 , wherein the powder formulation comprises a total dose of DHE administered of about 0.1 to about 4.0 mg. 
     
     
         24 . The method of  claim 23 , wherein the powder formulation comprises a total dose of DHE administered of about 0.5 mg. 
     
     
         25 . The method of any of  claims 1 - 24 , wherein the powder formulation comprises dihydroergotamine (DHE) mesylate. 
     
     
         26 . The method of any of  claims 1 - 25 , wherein the method is used for treating headache. 
     
     
         27 . The method of  claim 26 , wherein the method is used for treating migraine. 
     
     
         28 . The method of  claim 27 , wherein the method of treating migraine is a method for the acute treatment of migraine headaches with or without aura. 
     
     
         29 . The method of any of  claims 1 - 28 , wherein at least a portion of the powder formulation is administered to a single nostril of the human. 
     
     
         30 . The method of any of  claims 1 - 28 , wherein at least a portion of the powder formulation is administered to each nostril of the human. 
     
     
         31 . The method of any of  claims 1 - 30 , wherein the powder formulation is administered such that an intersubject variability in DHE C max  is less than 30%. 
     
     
         32 . The method of any of  claims 1 - 31 , wherein the mean T max  of DHE is about 10 to about 30 minutes, wherein a mean C max  of DHE after administration of the powder formulation is about 0.5 to about 6 ng/mL, a mean AUC 0-inf  of DHE after administration of the powder formulation is about 1 to about 15 ng·h/mL, and a mean T 1/2  of DHE after administration of the powder formulation is about 100 to about 300 minutes. 
     
     
         33 . The method of any of  claims 1 - 31 , wherein the mean T max  of DHE is about 10 to about 50 minutes, wherein a mean C max  of DHE after administration of the powder formulation is about 1 to about 15 ng/mL, a mean AUC 0-inf  of DHE after administration of the powder formulation is about 10 to about 50 ng·h/mL, and a mean T 1/2  of DHE after administration of the powder formulation is about 100 to about 300 minutes. 
     
     
         34 . The method of any of  claims 1 - 31 , wherein the mean T max  of DHE is about 10 to about 50 minutes, wherein a mean C max  of DHE after administration of the powder formulation is about 2 to about 20 ng/mL, a mean AUC 0-inf  of DHE after administration of the powder formulation is about 15 to about 110 ng·h/mL, and a mean T 1/2  of DHE after administration of the powder formulation is about 100 to about 300 minutes. 
     
     
         35 . The method of any of  claims 1 - 31 , wherein the mean T max  of DHE is about 10 to about 50 minutes, wherein a mean C max  of DHE after administration of the powder formulation is about 2 to about 50 ng/mL, a mean AUC 0-inf  of DHE after administration of the powder formulation is about 15 to about 200 ng·h/mL, and a mean T 1/2  of DHE after administration of the powder formulation is about 100 to about 300 minutes. 
     
     
         36 . The method of any of  claims 1 - 35 , wherein the mean T max  of DHE after administration of the powder formulation is about 2 to about 50 minutes. 
     
     
         37 . The method of any of  claims 1 - 36 , wherein a mean C max  of DHE after administration of the powder formulation is about 0.1 to about 150 ng/mL. 
     
     
         38 . The method of any of  claims 1 - 37 , wherein a mean AUC 0-inf  of DHE after administration of the formulation is about 1 to about 700 ng·h/mL. 
     
     
         39 . The method of any of  claims 1 - 38 , wherein a mean AUC 0-t  of DHE after administration of the formulation is about 1 to about 700 ng·h/mL. 
     
     
         40 . The method of any of  claims 1 - 39 , wherein a mean T 1/2  of DHE after administration of the formulation is about 10 to about 300 minutes. 
     
     
         41 . The method of any of  claims 1 - 40 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean T max  of DHE is about 0.5 to about 70 minutes. 
     
     
         42 . The method of  claim 41 , wherein when the powder formulation is administered to the primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean T max  of DHE is about 1 to about 60 minutes. 
     
     
         43 . The method of any of  claims 1 - 42 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean C max  of DHE is about 0.1 to about 150 ng/mL. 
     
     
         44 . The method of any of  claims 41 - 43 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean AUC 0-inf  of DHE is about 1 to about 700 ng·h/mL. 
     
     
         45 . The method of any of  claims 41 - 44 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean T 1/2  of DHE is about 10 to about 300 minutes. 
     
     
         46 . A method, comprising:
 intranasally administering to a human a powder formulation comprising: a) dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof, wherein the total dose of DHE administered is 0.1-10.0 mg; b) a microcrystalline cellulose component comprising at least 15% of the total weight of the formulation;   
     
     
         47 . The method of  claim 46 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean T max  of DHE is about 2 to about 50 minutes. 
     
     
         48 . The method of any of  claims 46 - 47 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean C max  of DHE is about 0.1 to about 150 ng/mL. 
     
     
         49 . The method of any of  claims 46 - 48 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean AUC 0-inf  of DHE is about 1 to about 700 ng·h/mL. 
     
     
         50 . The method of any of  claims 46 - 49 , wherein when the powder formulation is administered to a primate, preferably a monkey, and preferably a Cynomolgus monkey, a mean T 1/2  of DHE is about 10 to about 300 minutes. 
     
     
         51 . A powder formulation composition comprising dihydroergotamine (DHE) or a pharmaceutically acceptable salt thereof. 
     
     
         52 . The method of any claim, wherein the administering is intranasally administering.