Intranasal delivery of dihydroergotamine by precision olfactory device

Abstract

Methods are provided for acutely treating migraine headache with or without aura. The methods comprise administering to a subject with migraine headache an effective dose of a liquid pharmaceutical composition comprising dihydroergotamine (DHE) or a salt thereof, wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma DHE concentration (Cmax) of at least 750 pg/ml, (b) with a mean time to Cmax(Tmax) of DHE of less than 45 minutes, and (c) a mean plasma AUC0-inf of DHE of at least 2500 pg*hr/ml. Also provided are kits for acutely treating migraine with or without aura in which a liquid pharmaceutical composition comprising DHE or DHE salt is contained within a sealed vial that is attachable to a precision intranasal olfactory delivery device packaged therewith.

What is claimed is: 
     
         1 . A method of acutely treating migraine headache with or without aura, comprising:
 administering to a subject with migraine headache an effective dose of a liquid pharmaceutical composition comprising dihydroergotamine (DHE) or salt thereof,   wherein the dose is administered by a manually actuated, metered-dose, propellant-driven intranasal delivery device that provides, following intranasal administration,   (a) a mean peak plasma DHE concentration (C max ) of at least 750 pg/ml,   (b) with a mean time to C max (T max ) of DHE of less than 45 minutes, and   (c) a mean plasma AUC 0-inf  of DHE of at least 2500 pg*hr/ml.   
     
     
         2 . The method of  claim 1 , wherein the dose is 1.4-1.6 mg DHE or salt thereof. 
     
     
         3 . The method of  claim 1 , wherein the dose is administered as a plurality of divided doses. 
     
     
         4 . The method of  claim 1 , wherein the liquid composition comprises DHE mesylate. 
     
     
         5 . The method of  claim 1 , wherein the liquid composition comprises 4.0 mg/ml DHE mesylate, 10.0 mg/ml caffeine, and 50 mg/ml dextrose. 
     
     
         6 . The method of  claim 1 , wherein, following administration of the dose, the mean DHE C max  is at least 1200 pg/ml. 
     
     
         7 . The method of  claim 1 , wherein, following administration of the dose, the mean plasma AUC 0-inf  of DHE is at least 6000 pg*hr/ml. 
     
     
         8 . The method of  claim 1 , wherein, prior to first manual actuation, the liquid pharmaceutical composition and propellant are not in contact within the device. 
     
     
         9 . The method of  claim 1 , wherein each manual actuation brings a metered volume of liquid pharmaceutical composition and a separately metered volume of propellant into contact within a dose chamber of the device. 
     
     
         10 . The method of  claim 9 , wherein contact of propellant with liquid pharmaceutical composition within the dose chamber of the device creates a spray of liquid pharmaceutical composition as the formulation is expelled through a nozzle of the device. 
     
     
         11 . A kit for acutely treating migraine with or without aura, comprising:
 a vial, within which is sealably contained at least one effective dose of a liquid pharmaceutical composition comprising dihydroergotamine (DHE) or salt thereof, and   a device,   wherein the vial is configured to be attachable to the device, and   wherein the device, upon attachment of the vial, is a manually actuated, metered-dose, propellant-driven intranasal administration device capable of providing, after intranasal administration of a dose of liquid pharmaceutical composition,
 (a) a mean peak plasma DHE concentration (C max ) of at least 750 pg/ml, 
 (b) with a mean time to C max (T max ) of DHE of less than 45 minutes, and 
 (c) a mean plasma AUC 0-inf  of DHE of at least 2500 pg*hr/ml. 
   
     
     
         12 . The kit of  claim 11 , wherein the device comprises a canister, wherein the canister is a pressurized canister containing propellant. 
     
     
         13 . The kit of  claim 12 , wherein, following attachment of the vial to the device and prior to first manual actuation, the liquid pharmaceutical composition and propellant are not in contact within the device. 
     
     
         14 . The kit of  claim 13 , wherein, between successive manual actuations, the liquid pharmaceutical composition in the vial and propellant in the canister are not in contact within the device. 
     
     
         15 . The kit of  claim 13 , wherein each manual actuation brings a metered volume of liquid pharmaceutical composition and a separately metered volume of propellant into contact within a dose chamber of the device. 
     
     
         16 . The kit of  claim 15 , wherein contact of propellant with liquid pharmaceutical composition within the dose chamber of the device creates a spray of liquid pharmaceutical composition as the formulation is expelled through a nozzle of the device. 
     
     
         17 . The kit of  claim 11 , wherein the liquid composition comprises DHE mesylate. 
     
     
         18 . The kit of  claim 11 , wherein the liquid composition comprises 4.0 mg/ml DHE mesylate, 10.0 mg/ml caffeine, and 50 mg/ml dextrose. 
     
     
         19 . The kit of  claim 12 , wherein the pressurized canister contains an amount of propellant sufficient to administer at least one dose of the liquid pharmaceutical composition. 
     
     
         20 . An intranasal delivery device:
 wherein the device, upon attachment of a vial comprising a liquid pharmaceutical composition comprising dihydroergotamine (DHE) or salt thereof, is capable of providing, after intranasal administration of a dose of the liquid pharmaceutical composition,
 (a) a mean peak plasma DHE concentration (C max ) of at least 750 pg/ml, 
 (b) with a mean time to C max (T max ) of DHE of less than 45 minutes, and 
 (c) a mean plasma AUC 0-inf  of DHE of at least 2500 pg*hr/ml; and 
   wherein the device comprises:   a housing comprising an upper portion;   an actuator grip configured to move relative to the upper portion of the housing when a force is applied to the actuator grip;   a canister containing a propellant, wherein the canister is configured to release at least a portion of the propellant upon actuation of the canister;   a dose chamber in fluid communication with the canister and configured to receive the dose of liquid pharmaceutical composition and the propellant; and   a nozzle disposed at a distal end of the dose chamber, the nozzle configured to be inserted into a nostril of the user.   
     
     
         21 . The device of  claim 20 , further comprising a junction that couples the canister and the dose chamber, the junction comprising a first branch configured to couple to the canister, a second branch configured to couple to the vial containing the intranasal dosage form, and a third branch configured to couple to the nozzle. 
     
     
         22 . The device of  claim 21 , further comprising a one-way valve positioned within the second branch and configured to prevent released propellant in the first branch from entering the second branch. 
     
     
         23 . The device of  claim 22 , further comprising an extension spring that is coupled to the housing at a first end and to the actuator grip at a second end, wherein the spring is configured to increase a force threshold to actuate the canister. 
     
     
         24 . The device of  claim 23 , wherein the force threshold to actuate the canister is greater than a force threshold to actuate a dose pump coupled to the vial containing the intranasal dosage form, such that the force applied to the actuator grip by the user causes the intranasal dosage form to enter the dose chamber before the released propellant enters the dose chamber. 
     
     
         25 . The device of  claim 24 , wherein the actuator grip comprises a guiding feature that is configured to envelop at least a portion of the canister. 
     
     
         26 . The device of  claim 25 , wherein the guiding feature extends along a length of the canister and captures a first end of the canister opposite of a second end of the canister that is configured to release the at least portion of the propellant. 
     
     
         27 . The device of  claim 26 , wherein when the force is applied by the user, the guiding feature is configured to transmit the force to the canister, thereby actuating the canister. 
     
     
         28 . The device of  claim 20 , further comprising a nose cone integrated with the housing, wherein the nose cone is configured to guide or align the device during insertion into a nose of a user. 
     
     
         29 . The device of  claim 20 , wherein the dose chamber is further configured to sequentially receive the intranasal dosage form followed by the propellant.